TWI749881B - Dioxopiperoid derivatives, their preparation method and their application in medicine - Google Patents

Abstract

類衍生物、其製備方 法及其在醫藥上的應用。具體而言，本發明提供式(I)的化合物或其立體異構體、互變異構體、藥學上可接受的鹽，其中所有變數如本文所定義。這些化合物是選擇性因數XIa(Factor XIa，簡稱FXIa)的抑制劑。本發明還涉及包含這些化合物的藥物組合物以及使用該化合物治療血栓栓塞等疾病的藥物中的用途。 The present invention belongs to the technical field of chemical medicines, and relates to dioxoprazine

Derivatives, their preparation methods and their applications in medicine. Specifically, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. These compounds are inhibitors of selectivity factor XIa (Factor XIa, FXIa for short). The present invention also relates to a pharmaceutical composition containing these compounds and the use of the compounds in the treatment of diseases such as thromboembolism.

Description

Dioxopiper derivatives, their preparation method and their application in medicine

類衍生物、其製備方法及其在醫藥上的應用。具體而言，本發明提供式(I)的化合物或其立體異構體、互變異構體、藥學上可接受的鹽，其中所有變數如本文所定義。這些化合物是選擇性因數XIa(Factor XIa，簡稱FXIa)的抑制劑。本發明還涉及包含這些化合物的藥物組合物以及使用該化合物治療血栓栓塞等疾病的藥物中的用途。 The present invention belongs to the technical field of chemical medicines, and relates to dioxoprazine

Derivatives, their preparation methods and their applications in medicine. Specifically, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. These compounds are inhibitors of selectivity factor XIa (Factor XIa, FXIa for short). The present invention also relates to a pharmaceutical composition containing these compounds and the use of the compounds in the treatment of diseases such as thromboembolism.

Cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis, etc., claim the lives of nearly 12 million people worldwide each year, which is close to a quarter of the world’s total deaths, making them the number one enemy of human health. In China, more than 2.6 million people die from cardiovascular disease each year, and 75% of the surviving patients are disabled, of which more than 40% are severely disabled. Thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.

The human blood coagulation process consists of an intrinsic pathway, an extrinsic pathway, and a common pathway (Annu. Rev. Med. 2011.62: 41-57). It is a process that is initiated sequentially by a variety of zymogens. A chain reaction that continues to be strengthened and amplified. The coagulation cascade is initiated by the endogenous pathway (also called the contact initiation pathway) and the exogenous pathway (also called the tissue factor pathway) to generate FXa, and then through the common pathway to generate thrombin (FIIa), and finally form fibrin.

The endogenous pathway refers to the process by which the XII factor is activated to form the XIa-VIIIa-Ca2+-PL complex and activate the X factor. The exogenous coagulation pathway is the release from tissue factor (TF) to TF-VIIa-Ca ^{2 +} The process of forming the complex and starting the factor X. The common pathway refers to the process in which the two pathways are combined into one after the factor Xa is formed, which initiates prothrombin and finally generates fibrin. Among them, FXI is necessary to maintain the endogenous pathway and is in the process of amplification of the coagulation cascade. Play a key role. In the coagulation cascade, thrombin can feed back and start FXI, and activated FXI (FXIa) promotes the production of thrombin in large quantities, thereby amplifying the coagulation cascade. Therefore, FXI antagonists have been widely developed for the treatment of various thrombosis.

Traditional anticoagulant drugs, such as warfarin, heparin, low molecular weight heparin (LMWH), and new drugs marketed in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (darby Gatran etexilate, hirudin, etc.), have good effects on reducing thrombosis, occupying the vast cardiovascular and cerebrovascular market with its significant effectiveness, but its side effects are becoming more and more significant. Among them, the "bleeding risk" is Bear the brunt of one of the most serious problems (N Engl J Med 1991; 325: 153-8, Blood. 2003; 101: 4783-4788).

Studies have found that in the thrombosis model, inhibiting the FXIa factor can effectively inhibit the formation of thrombus, but in the case of more severe thrombosis, the effect of FXIa is minimal (Blood. 2010; 116(19): 3981-3989). Clinical statistics show that increasing the amount of FXIa will increase the prevalence of VTE (Blood 2009; 114: 2878-2883), and people with severe FXIa deficiency have a reduced risk of DVT (Thromb Haemost 2011; 105: 269-273) .

FXIa is currently an emerging target for inhibiting thrombosis. Patent applications that disclose compounds with FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017/023992, WO2018041122 and so on. Among them, currently only Bayer's antisense oligonucleotide BAY-2306001 has entered the clinical phase II study.

The compounds of the present invention have higher activity. In particular, the compound of the present invention exhibits excellent anticoagulant effects on human blood, and has good pharmacokinetic activity, and can be used to effectively treat and/or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms.

The present invention provides a series of oxopyridazine amide derivatives, their preparation methods and their medical applications.

Specifically, the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

These compounds are inhibitors of selectivity factor XIa (Factor XIa, FXIa for short). The present invention also relates to pharmaceutical compositions containing these compounds and the use of the compounds in drugs for treating diseases such as thromboembolism.

Specifically, the present invention is realized through the following technical solutions: the compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts:

其中，R₃選自氫、鹵素、C_1-4的烷基、鹵素取代的C_1-4的烷基；R₅、R₆、R₇獨立的選自氫、C_1-4的烷基、C_1-4的烷氧基-C_1-4烷基、 -SO₂-C_1-4烷、-SO₂-苯、-C_1-6的一元或者二元醇、

、-(CH₂)n-C_3-12的 脂肪環，或者其中NR₅與NR₆R₇之中的任意一個以上通過-(CH₂)n-成環；或者NR₆R₇一起構成C_3-12的脂肪環；前述C_3-12的脂肪環環上的一個以上碳原子被0-2個N、O、S原子所替代，所述脂肪環進一步被一個以上的R₉所取代；R₈選自氫、鹵素、C_1-4的烷基、羥基、-C_1-4的羧酸、-C_1-4的羧酸-C_1-4醇酯；R₉選自氫、-(CH₂)n-OH、-SO₂-C_1-4烷、-(CH₂)n-COOH、-醯胺、 氰基、NR₁₀R₁₁-C_1-4的烷氧基、C_1-4的烷基、C_1-4的烷氧基、C_1-4的烷氧-C_1-4烷 基、-CO-嗎啉、-CO-NR₁₂-(CH₂)n-OH、HOOC-C_1-4烷氧基、

； R₁₀、R₁₁、R₁₂獨立選自氫或C_1-4烷基；前述n=0-6的自然數。 R _{1 is} selected from R ₃ substituted or unsubstituted tetrazole, R ₃ substituted or unsubstituted triazole; R _{2 is} selected from R ₄ substituted or unsubstituted benzene ring, wherein R _{4 is} selected from -NR ₅ -( CH ₂ )n-CO-(CH ₂ )n-NR ₆ R ₇ , -NR ₅ -SO ₂ -NR ₆ R ₇ ; Ar is selected from at least one of the following groups substituted or unsubstituted by R8:

Wherein, R _{3 is} selected from hydrogen, halogen, C _1-4 alkyl, halogen-substituted C _1-4 alkyl; R ₅ , R ₆ , R _{7 are} independently selected from hydrogen, C _1-4 alkyl , C _1-4 alkoxy-C _1-4 alkyl, -SO ₂ -C _1-4 alkane, -SO ₂ -benzene, -C _1-6 mono-or dihydric alcohol,

, -(CH ₂ )nC _3-12 aliphatic ring, or wherein any one or more of _{NR 5} and NR ₆ R _{7 form a ring through -(CH 2} )n-; or NR ₆ R ₇ together form C _{3- 12} aliphatic ring; _{one or more carbon atoms on the aforementioned C 3-12} alicyclic ring are replaced by 0-2 N, O, S atoms, and the aliphatic ring is further substituted by more than one R ₉ ; R ₈ Selected from hydrogen, halogen, C _1-4 alkyl, hydroxyl, -C _1-4 carboxylic acid, -C _1-4 carboxylic acid -C _1-4 alcohol ester; R _{9 is} selected from hydrogen, -(CH ₂ ) n-OH, -SO ₂ -C _1-4 alkane, -(CH ₂ )n-COOH, -amide, cyano, NR ₁₀ R ₁₁ -C _1-4 alkoxy, C _1-4 The alkyl group, C _1-4 alkoxy group, C _1-4 alkoxy-C _1-4 alkyl group, -CO-morpholine, -CO-NR ₁₂ -(CH ₂ )n-OH, HOOC- C _1-4 alkoxy,

; R ₁₀ , R ₁₁ , and R _{12 are} independently selected from hydrogen or C _1-4 alkyl; the aforementioned natural number of n=0-6.

、

、

、

、

、

、

、

， 其中，R₇和R₉如上定義。 As a preferred technical solution of the present invention, the -NR ₅ -(CH ₂ )n-CO-(CH ₂ )n-NR ₆ R ₇ includes

,

,

,

,

,

,

,

, Where R ₇ and R ₉ are as defined above.

As a preferred technical solution of the present invention, the C _1-4 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; C _1-4 carboxylic acid is selected from formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, tert-butyric acid; -C _1-4 carboxylic acid-C _1-4 alcohol ester is selected from methyl formate, formic acid Ethyl, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl butyrate Ester, ethyl butyrate, propyl butyrate, butyl butyrate.

As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine, and iodine.

As a preferred aspect of the present invention, the C _1-4 alkyl is selected from methane, ethane, propane, iso-propane, n-butane, isobutane, sec-butane, tert butane; said C _{1- The alkoxy group of 4} is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy; the -(CH ₂ ) n-OH is selected from hydroxy, methanol, ethanol, n-propanol, n-butanol; the -C _1-6 monohydric or dihydric alcohol is selected from methanol, ethanol, n-propanol, n-butanol, tert-butanol , 1,3-butanediol, 3-methylbutan-1-ol, 3-methylpentan-1-ol, 4-methylpentan-1ol, 3-methylhexan-1ol, 4-methyl Alkyl hexan-1 alcohol; the _{alkoxy group of the NR 10} R ₁₁ -C _1-4 is selected from methylamine methoxy, ethylamine methoxy, propylamine methoxy, butylamine methoxy, methylamine ethoxy Ethyl, ethylamine ethoxy, propylamine ethoxy, butylamine ethoxy, methylamine propoxy, ethylamine propoxy, propylamine propoxy, butylamine propoxy, methylamine butoxy, ethylamine Butoxy, propylaminobutoxy, butylaminobutoxy, dimethylaminomethoxy, dimethylaminoethoxy, dimethylaminopropoxy, dimethylaminobutoxy; the C alkoxy _1-4 -C _1-4 alkyl is selected from methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxymethyl group, Butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, methoxybutyl, ethoxybutyl, propoxybutyl, butoxybutyl; the -CO- NR ₁₂ -(CH ₂ )n-OH is selected from -CO-NH-CH ₂ OH, -CO-N(CH ₃ )-CH ₂ OH, -CO-NH-CH ₂ CH ₂ OH, -CO-N( CH ₃ )-CH ₂ CH ₂ OH; the HOOC-C _1-4 alkoxy group is selected from HOOC-methoxy, HOOC-ethoxy, HOOC-propoxy, HOOC-isopropoxy, HOOC- N-butoxy, HOOC-isobutoxy, HOOC-sec-butoxy, HOOC-tert-butoxy.

、

、

、

、

、

、

、

、

、

、

、

、

、

。 As a preferred technical solution of the present invention, the C _3-12 aliphatic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane , Spiro[3,3]heptane ring, spiro[3,5]nonane ring, spiro[4,5]decane ring; _{more than one carbon atom of the C 3-12} fat is divided by 0-2 N, O, Replaced by S atom, selected from:

,

,

,

,

,

,

,

,

,

,

,

,

,

.

As a preferred technical solution of the present invention, n=0,1,2,3,4,5,6.

、

、

Ar選自以下基團：

、

、

As a preferred technical solution of the present invention, it is characterized in that R _{1 is} selected from tetrazole and triazole; R2 is selected from benzene ring,

,

,

Ar is selected from the following groups:

,

,

As a preferred embodiment of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

As a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to a compound prepared with a pharmaceutically acceptable acid or base.

As a preferred solution of the present invention, more than one hydrogen atom of the compound is substituted by the isotope deuterium.

Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers.

Another object of the present invention is to provide the compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, and containing the compound, or its stereoisomers, mutual The medicinal composition of the variant isomer and the pharmaceutically acceptable salt is used in the preparation of a medicine for the treatment of FXIa-related diseases, in particular, the medicinal use for thrombosis-related diseases.

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 uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used here refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a pharmaceutically acceptable acid or salt.

”為連接鍵。 Said "

"Is the connection key.

In addition to salt forms, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. Generally speaking, the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- And (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomers Enantiomerically enriched mixtures, all these mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.

The optically active (R)- and (S)-isomers, as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure all 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), it forms a diastereoisomeric salt with a suitable optically active acid or salt, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).

The atoms of the compound molecules of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, enhance the stability of metabolism, and increase the activity in the body. And, an embodiment is included in which at least one atom is substituted with atoms having the same atomic number (number of protons) and different mass numbers (sum of protons and neutrons). Examples of the isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which include ² H, ³ H, ¹³ C, ¹⁴ C, and ^{15 respectively.} N, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl. In particular, radioisotopes that emit radiation as they decay, such as ³ H or ¹⁴ C, can be used for topographical examinations of pharmaceutical preparations or compounds in the body. The stable isotope neither decays or changes with its amount, nor is it radioactive, so it can be used safely. When the atoms constituting the molecule of the compound of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as deuterium ( ² H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

Further, one or more hydrogen atoms of the compound of the present invention are replaced by the isotope deuterium ( ² H). After deuteration, the compound of the present invention has the effects of prolonging the half-life, reducing the clearance rate, enhancing the stability of metabolism, and improving the activity in vivo.

The preparation method of the isotope derivative usually includes a phase transfer catalysis method. For example, the preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu ₄ HSO ₄ ). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a ratio of deuterated silane (e.g. triethyl deuterated silyl) or Lewis acid such as triethyl deuterated silane in the presence of an acid (e.g., methanesulfonic acid) Aluminum chloride is reduced with deuterated sodium borate to introduce higher deuterium.

The term "pharmaceutically acceptable carrier" refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic or side effects to the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the content of which is incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.

With regard to drugs or pharmacologically active agents, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage form of the present invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. The determination of the effective amount varies from person to person and depends on the age of the recipient The age and general conditions also depend on the specific active substance, and the appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat the target disorder, disease or condition.

"Optional" or "optionally" means that the event or condition described later may but does not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur.

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

The present invention will be further described in detail below in conjunction with examples, but the implementation of the invention is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The measurement of NMR is carried out with Bruker AVANCE-III nuclear magnetic instrument, the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC) was used for the MS measurement.

High performance liquid chromatography (HPLC) analysis uses Thermo U3000 HPLC DAD high performance liquid chromatograph.

CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Yinlong HSGF254 or GF254 silica gel plate. The size of the silica gel plate used in thin layer chromatography (TLC) is 0.17mm~0.23mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ~0.5mm.

The silica gel column chromatography generally uses Rushan Shangbang silica gel 100~200 mesh silica gel as the carrier.

Example 1

-1-基)-N-(2-氧代-2,3-二氫-1H-苯並[d]咪唑-5-基)-3-苯基丙醯胺

Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) -N -(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-phenylpropionamide

The specific synthesis route is as follows:

Step A: Synthesis of 2-(5-chloro-2-nitrophenyl)amino)-2-oxoacetic acid

5-Chloro-2-nitroaniline (4.0 g, 23.2 mmol) was dissolved in dichloromethane (30.0 mL), and oxalic chloride (7.3 g, 58.2 mmol) was added to react at room temperature for one hour and then in an ice-water bath Slowly add water, bubbles are formed and light yellow solids are precipitated out, add water until no more bubbles are formed, stop the reaction.

The reaction solution was spun off dichloromethane under vacuum and filtered to obtain a light yellow filter cake. The filter cake was dried in a vacuum drying oven to obtain 5.2 g of light yellow solid 2-(5-chloro-2-nitrophenyl)amino) Crude -2-oxoacetic acid (yield: 91.7%). MS(ESI) M/Z: [M+H] ⁺ =244.98.

Step B: Synthesis of (2-((5-chloro-2-nitrophenyl)amino)-2-oxoacetyl)-L-phenylalanine tert-butyl ester

Combine 2-(5-chloro-2-nitrophenyl)amino)-2-oxoacetic acid (5.20 g, 21.31 mmol) and L-phenylalanine tert-butyl ester hydrochloride (6.57 g, 25.57 mmol) Mol) was dissolved in dichloromethane (30.0 ml), N , N -diisopropylethylamine (8.25 g, 63.93 mmol) was added, and 2-(7-benzotriazole oxide) -N,N was added ,N',N' -Tetramethylurea hexafluorophosphate (12.15g, 31.96mmol). Subsequently, it was stirred at room temperature for 2 hours.

Water (20 mL) was added to the reaction solution to quench the reaction. Ethyl acetate (150 mL) was added, and the mixture was washed with water and saturated brine (30 mL×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10) to obtain 5.80 g of pale yellow solid (2-((5-chloro-2-nitrophenyl)amino) -2-oxoacetyl)-L-phenylalanine tert-butyl ester (yield: 61.0%). MS(ESI) M/Z: [M+H] ⁺ =448.12.

-1-基)-3-苯基丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(5-chloro-2-nitrophenyl)-2,3-dioxopiperidine

-1-yl)-3-phenylpropionic acid tert-butyl ester

Dissolve (2-((5-chloro-2-nitrophenyl)amino)-2-oxoacetanyl)-L-phenylalanine tert-butyl ester (5.8 g, 12.97 mmol) in anhydrous acetonitrile (30.0 ml), potassium carbonate (8.9 g, 64.85 mmol), 1,2-dibromoethane (9.6 g, 51.90 mmol) were added, replaced with nitrogen three times, and the temperature was raised to 100 degrees Celsius to react for 16 hours.

-1-基)-3-苯基丙酸叔丁酯(收率：49.0%)。MS(ESI)M/Z：[M+H]⁺=474.13。 Ethyl acetate (300 mL) was added to the reaction solution, and the mixture was washed with water and saturated brine (50 mL×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/1) to obtain 3.0 g of yellow solid (S)-2-(4-(5-chloro-2-nitrobenzene) Yl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester (yield: 49.0%). MS(ESI) M/Z: [M+H] ⁺ =474.13.

-1-基)-3-苯基丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester

-1-基)-3-苯基丙酸叔丁酯(3.0克，6.34毫摩爾)溶於乙酸乙酯溶液(35毫升)中，加入乾鈀碳(300毫克，10%摩爾)。置換氫氣三次，於室溫下反應5小時。 (S)-2-(4-(5-chloro-2-nitrophenyl)-2,3-dioxopiper

1-yl)-3-phenylpropionic acid tert-butyl ester (3.0 g, 6.34 mmol) was dissolved in ethyl acetate solution (35 mL), and dry palladium on carbon (300 mg, 10% mol) was added. The hydrogen was replaced three times, and the reaction was carried out at room temperature for 5 hours.

-1-基)-3-苯基丙酸叔丁酯(收率：35.7%)。MS(ESI)M/Z：[M+H]⁺=444.16。 After the reaction was completed, the palladium carbon was filtered off, the filter cake layer was washed with methanol (10 ml×3 times), the filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/ 1) to obtain 1.0 g of light yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester (yield: 35.7%). MS(ESI) M/Z: [M+H] ⁺ =444.16.

-1-基)-3-苯基丙酸叔丁酯

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester

-1-基)-3-苯基丙酸叔丁酯(1.0克，2.26毫摩爾)溶於乙酸(15.0毫升)，於冰水浴下，加入原甲酸三乙酯(1.0克，6.77毫摩爾)，疊氮化鈉(440毫克，6.77毫摩爾)，緩慢升至80攝氏度繼續反應16小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester (1.0 g, 2.26 mmol) was dissolved in acetic acid (15.0 ml), and under an ice water bath, triethyl orthoformate (1.0 g, 6.77 mmol) was added , Sodium azide (440 mg, 6.77 mmol), slowly increase to 80 degrees Celsius and continue the reaction for 16 hours.

-1-基)-3-苯基丙酸叔丁酯(收率：46.0%)。MS(ESI)M/Z：[M+H]⁺=497.16。 Water was added to the reaction solution, there was an off-white precipitate, continue to add water until no solid was washed out, filtered, the filter cake was washed with water (10 ml×3 times), and dried to obtain 523 mg of off-white solid (S)-2-(4- (5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid tert-butyl ester (yield: 46.0%). MS(ESI) M/Z: [M+H] ⁺ =497.16.

-1-基)-3-苯基丙酸

Step F: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid

-1-基)-3-苯基丙酸叔丁酯(523毫克，2.26毫摩爾)溶於二氯甲烷(10.0毫升)，加入三氟乙酸(2.0毫升)，於室溫反應3小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

1-yl)-3-phenylpropionic acid tert-butyl ester (523 mg, 2.26 mmol) was dissolved in dichloromethane (10.0 mL), trifluoroacetic acid (2.0 mL) was added, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-苯基丙酸(收率：97.0%)。MS(ESI)M/Z：[M+H]⁺=441.10。 Rotate off dichloromethane and trifluoroacetic acid at low temperature to obtain 450 mg of light yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)- 2,3-dioxopiperidine

-1-yl)-3-phenylpropionic acid (yield: 97.0%). MS(ESI) M/Z: [M+H] ⁺ =441.10.

-1-基)-N-(2-氧代-2,3-二氫-1H-苯並[d]咪唑-5-基)-3-苯基丙醯胺

Step G: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-N-(2-oxo-2,3-dihydro-1 H -benzo[d]imidazol-5-yl)-3-phenylpropionamide

-1-基)-3-苯基丙酸(46毫克，0.10毫摩爾)，5-氨基-1,3-二氫-2H-苯並[d]咪唑-2-酮(17.8毫克，0.12毫摩爾)溶於N,N-二甲基甲醯胺(2.5毫升)中，加入N,N-二異丙基乙胺(65毫克，0.50毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(127毫克，0.40毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (46 mg, 0.10 mmol), 5-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one (17.8 mg, 0.12 mmol) Mol) was dissolved in N,N -dimethylformamide (2.5 mL), and N,N -diisopropylethylamine (65 mg, 0.50 mmol) was added. Subsequently, 1-propyl phosphoric anhydride (127 mg, 0.40 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-N-(2-氧代-2,3-二氫-1H-苯並[d]咪唑-5-基)-3-苯基丙醯胺(收率：54.0%)。 MS(ESI)M/Z：[M+H]⁺=572.15。¹H NMR(400MHz,DMSO)δ 10.57(d,J=28.5Hz,2H),10.13(s,1H),9.77(s,1H),7.94(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.43(d,J=1.9Hz,1H),7.37-7.22(m,5H),7.05(dd,J=8.4,1.9Hz,1H),6.85(t,J=8.4Hz,1H),5.32(s,1H),4.04(dd,J=14.2,7.1Hz,2H),3.73(s,2H),3.28(d,J=5.6Hz,1H),3.08(dd,J=14.2,10.0Hz,1H)。 The reaction was quenched by adding water, a solid was precipitated, filtered, and a filter cake was used to obtain 70 mg of the crude product. The crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 50 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper was obtained.

-1-yl)-N-(2-oxo-2,3-dihydro-1 H -benzo[d]imidazol-5-yl)-3-phenylpropanamide (yield: 54.0%) . MS(ESI) M/Z: [M+H] ⁺ =572.15. ¹ H NMR(400MHz,DMSO)δ 10.57(d, J = 28.5Hz, 2H), 10.13(s, 1H), 9.77(s, 1H), 7.94(d, J = 2.2Hz, 1H), 7.82(d , J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.43(d, J =1.9Hz,1H),7.37-7.22(m,5H),7.05(dd, J = 8.4,1.9Hz,1H),6.85(t, J =8.4Hz,1H),5.32(s,1H),4.04(dd, J =14.2,7.1Hz,2H),3.73(s,2H),3.28( d, J =5.6Hz,1H),3.08(dd, J =14.2,10.0Hz,1H).

Example 2

-1-基)-3-苯基丙醯胺基)苯甲酸

Synthesis of (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)benzoic acid

-1-基)-3-苯基丙醯胺基)苯甲酸叔丁酯

Step A: Synthesis of (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) tert-butyl benzoate

-1-基)-3-苯基丙酸(83毫克，0.18毫摩爾)，4-氨基苯甲酸叔丁酯(43.4毫克，0.22毫摩爾)溶於N,N-二甲基甲醯胺(2.5毫升)中，加入N,N-二異丙基乙胺(122毫克，0.94毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(239毫克，0.75毫摩爾)。將室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (83 mg, 0.18 mmol), tert-butyl 4-aminobenzoate (43.4 mg, 0.22 mmol) dissolved in N,N -dimethylformamide ( 2.5 mL), N,N -diisopropylethylamine (122 mg, 0.94 mmol) was added. Subsequently, 1-propyl phosphoric anhydride (239 mg, 0.75 mmol) was added to the above solution. React at room temperature for 18 hours.

-1-基)-3-苯基丙醯胺基)苯甲酸叔丁酯(收率：17.0%)。MS(ESI)M/Z：[M+H]⁺=616.20。 The reaction solution was diluted with ethyl acetate (30 mL), washed with water and saturated brine (10 mL×3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The obtained residue was purified by TLC plate (ethyl acetate/n-hexane=1:1) to obtain 20 mg of light yellow solid (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazole) -1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) benzoic acid tert-butyl ester (yield: 17.0%). MS(ESI) M/Z: [M+H] ⁺ =616.20.

-1-基)-3-苯基丙醯胺基)苯甲酸

Step B: Synthesis of (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)benzoic acid

-1-基)-3-苯基丙醯胺基)苯甲酸叔丁酯(20.0毫克，0.03毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) benzoic acid tert-butyl ester (20.0 mg, 0.03 mmol) was dissolved in dichloromethane (3.0 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-3-苯基丙醯胺基)苯甲酸(收率：75.0%)。MS(ESI)M/Z：[M+H]⁺=572.15。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 13.7 mg of yellow solid (S)-4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo were obtained. Piper

-1-yl)-3-phenylpropanamido)benzoic acid (yield: 75.0%). MS(ESI) M/Z: [M+H] ⁺ =572.15.

Example 3

-1-基)-N-(3-氧代異吲哚啉-5-基)-3-苯基丙醯胺

Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) -N -(3-oxoisoindolin-5-yl)-3-phenylpropionamide

-1-基)-N-(3-氧代異吲哚啉-5-基)-3-苯基丙醯胺

The specific synthetic route is as follows: Step A: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) -N -(3-oxoisoindolin-5-yl)-3-phenylpropionamide

-1-基)-3-苯基丙酸(47毫克，0.10毫摩爾)，6-氨基異吲哚啉-1-酮(17毫克，0.12毫摩爾)溶 於N,N-二甲基甲醯胺(2.0毫升)中，加入N,N-二異丙基乙胺(69毫克，0.53毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(136毫克，0.43毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (47 mg, 0.10 mmol), 6-aminoisoindolin-1-one (17 mg, 0.12 mmol) dissolved in N,N -dimethylform To amide (2.0 mL), N,N -diisopropylethylamine (69 mg, 0.53 mmol) was added. Subsequently, 1-propyl phosphoric anhydride (136 mg, 0.43 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-N-(3-氧代異吲哚啉-5-基)-3-苯基丙醯胺(收率：20.0%)。MS(ESI)M/Z：[M+H]⁺=571.15。¹H NMR(400MHz,DMSO)δ 10.40(s,1H),9.75(s,1H),8.56(s,1H),8.03(d,J=1.3Hz,1H),7.93(d,J=2.2Hz,1H),7.80(d,J=8.6Hz,1H),7.75(dd,J=8.6,2.2Hz,1H),7.69(dd,J=8.2,2.0Hz,1H),7.52(d,J=8.2Hz,1H),7.41-7.15(m,5H),5.33(s,1H),4.37-4.30(m,2H),4.10-3.91(m,2H),3.73(s,2H),3.37(dd,J=11.0,5.8Hz,1H),3.16-3.05(m,1H)。 The reaction was quenched by adding water, extracted with dichloromethane (10 ml×3 times), and distilled under reduced pressure. The residue obtained was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 11.98 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper was obtained.

-1-yl) -N- (3-oxoisoindolin-5-yl)-3-phenylpropionamide (yield: 20.0%). MS(ESI) M/Z: [M+H] ⁺ =571.15. ¹ H NMR(400MHz,DMSO)δ 10.40(s,1H),9.75(s,1H),8.56(s,1H), 8.03(d, J =1.3Hz,1H),7.93(d, J =2.2Hz ,1H),7.80(d, J =8.6Hz,1H),7.75(dd, J =8.6,2.2Hz,1H),7.69(dd, J =8.2,2.0Hz,1H),7.52(d, J = 8.2Hz, 1H), 7.41-7.15 (m, 5H), 5.33 (s, 1H), 4.37-4.30 (m, 2H), 4.10-3.91 (m, 2H), 3.73 (s, 2H), 3.37 (dd , J =11.0,5.8Hz,1H),3.16-3.05(m,1H).

Example 4

-1-基)-N-(3-氧代異吲哚啉-5-基)-3-苯基丙醯胺

Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) -N -(3-oxoisoindolin-5-yl)-3-phenylpropionamide

-1-基)-3-叔丁酯苯基丙氧基)苯基)-3-氧代-2,3-二氫-1H-吡唑-1-羧酸叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-tert-butyl phenylpropoxy)phenyl)-3-oxo-2,3-dihydro-1 H -pyrazole-1-carboxylic acid tert-butyl ester

-1-基)-3-苯基丙酸(88毫克，0.20毫摩爾)，5-(3-氨基苯基)-3-氧代-2,3-二氫-1H-吡唑-1-羧酸叔丁酯(66毫克，0.24毫摩爾)溶於N,N-二甲基甲醯胺(2.0毫升)中，加入N,N-二異丙基乙胺(129毫克，1.0毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(254毫克，0.8毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (88 mg, 0.20 mmol), 5-(3-aminophenyl)-3-oxo-2,3-dihydro-1 H -pyrazole-1 -Tert-butyl carboxylate (66 mg, 0.24 mmol) was dissolved in N,N -dimethylformamide (2.0 mL), and N,N -diisopropylethylamine (129 mg, 1.0 mmol) was added ). Subsequently, 1-propyl phosphoric anhydride (254 mg, 0.8 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-3-叔丁酯苯基丙氧基)苯基)-3-氧代-2,3-二氫-1H-吡唑-1-羧酸叔丁酯(收率：30.7%)。MS(ESI)M/Z：[M+H]⁺=698.21。 The reaction was quenched by adding water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL×3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue obtained was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 42.8 mg of yellow solid (S)-5-(3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-tert-butyl phenylpropoxy)phenyl)-3-oxo-2,3-dihydro-1 H -pyrazole-1-carboxylic acid tert-butyl ester (Yield: 30.7%). MS(ESI) M/Z: [M+H] ⁺ =698.21.

Example 5

-1-基)- N-(4-(5-氧代-2-5-二氫-1H-吡唑-3-基)苯基)-3-苯基丙醯胺

Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-N-(4-(5-oxo-2-5-dihydro-1 H -pyrazol-3-yl)phenyl)-3-phenylpropionamide

The specific synthesis route is as follows:

-1-基)-N-(4-(5-氧代-2-5-二氫-1H-吡唑-3-基)苯基)-3-苯基丙醯胺

Step A: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-N-(4-(5-oxo-2-5-dihydro-1 H -pyrazol-3-yl)phenyl)-3-phenylpropionamide

-1-基)-3-叔丁酯苯基丙氧基)苯基)-3-氧代-2,3-二氫-1H-吡唑-1-羧酸叔丁酯(40.0毫克，0.057毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-5-(3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-tert-butyl phenylpropoxy)phenyl)-3-oxo-2,3-dihydro-1 H -pyrazole-1-carboxylic acid tert-butyl ester (40.0 mg, 0.057 mmol) was dissolved in dichloromethane (3.0 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-N-(4-(5-氧代-2-5-二氫-1H-吡唑-3-基)苯基)-3-苯基丙醯胺(收率：10.0%)。MS(ESI)M/Z：[M+H]⁺=598.16。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 3.4 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper was obtained.

-1-yl) -N -(4-(5-oxo-2-5-dihydro-1 H -pyrazol-3-yl)phenyl)-3-phenylpropionamide (yield: 10.0 %). MS(ESI) M/Z: [M+H] ⁺ =598.16.

Example 6

-1-基)-3-苯基丙醯胺基)苯甲酸

Synthesis of (S)-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)benzoic acid

The specific synthesis route is as follows:

-1-基)-3-苯基丙醯胺基)苯甲酸叔丁酯

Step A: Synthesis of (S)-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) tert-butyl benzoate

-1-基)-3-苯基丙酸(43毫克，0.098毫摩爾)，3-氨基苯甲酸叔丁酯(23毫克，0.117毫摩爾)溶於N,N-二甲基甲醯胺(2.0毫升)中，加入N,N-二異丙基乙胺(63毫克，0.49毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(125毫克，0.392毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (43 mg, 0.098 mmol), tert-butyl 3-aminobenzoate (23 mg, 0.117 mmol) dissolved in N,N -dimethylformamide ( 2.0 mL), N,N -diisopropylethylamine (63 mg, 0.49 mmol) was added. Subsequently, 1-propyl phosphoric anhydride (125 mg, 0.392 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-3-苯 基丙醯胺基)苯甲酸叔丁酯(收率：38.0%)。MS(ESI)M/Z：[M+H]⁺=616.20。 The reaction was quenched by adding water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 23 mg of yellow solid (S )-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) benzoic acid tert-butyl ester (yield: 38.0%). MS(ESI) M/Z: [M+H] ⁺ =616.20.

-1-基)-3-苯基丙醯胺基)苯甲酸

Step B: Synthesis of (S)-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)benzoic acid

-1-基)-3-苯基丙醯胺基)苯甲酸叔丁酯(23.0毫克，0.037毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido) benzoic acid tert-butyl ester (23.0 mg, 0.037 mmol) was dissolved in dichloromethane (3.0 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-3-苯基丙醯胺基)苯甲酸(收率：64.0%)。MS(ESI)M/Z：[M+H]⁺=560.13。¹H NMR(400MHz,DMSO)δ 12.99(s,1H),10.40(s,1H),9.75(s,1H),8.26(s,1H),7.93(d,J=2.2Hz,1H),7.80(d,J=8.6Hz,2H),7.75(dd,J=8.6,2.2Hz,1H),7.66(d,J=7.7Hz,1H),7.45(t,J=7.9Hz,1H),7.28(dq,J=15.6,7.3Hz,5H),5.32(s,1H),4.19-3.94(m,2H),3.72(s,2H),3.36(s,1H),3.10(dd,J=14.4,10.2Hz,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 13.5 mg of yellow solid (S)-3-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo was obtained after purification Piper

-1-yl)-3-phenylpropanamido)benzoic acid (yield: 64.0%). MS(ESI) M/Z: [M+H] ⁺ =560.13. ¹ H NMR (400MHz, DMSO) δ 12.99 (s, 1H), 10.40 (s, 1H), 9.75 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.80 (d, J =8.6Hz,2H),7.75(dd, J =8.6,2.2Hz,1H),7.66(d, J =7.7Hz,1H),7.45(t, J =7.9Hz,1H),7.28 (dq, J =15.6,7.3Hz,5H),5.32(s,1H),4.19-3.94(m,2H),3.72(s,2H),3.36(s,1H),3.10(dd, J =14.4 , 10.2Hz, 1H).

Example 7

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -benzo[d]imidazole-2-carboxylic acid

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-phenylpropanamido)-1 H -benzo[d]imidazole-2-carboxylic acid tert-butyl ester

-1-基)-3-苯基丙酸(50毫克，0.11毫摩爾)，5-氨基-1H-苯並[d]咪唑-2-羧酸叔丁酯(32毫克，0.14毫摩爾)溶於N,N-二甲基甲醯胺(2.0毫升)中，加入N,N-二異丙基乙胺(72毫克，0.56毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(143毫克，0.45毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (50 mg, 0.11 mmol), 5-amino-1 H -benzo[d]imidazole-2-carboxylic acid tert-butyl ester (32 mg, 0.14 mmol) Dissolve in N,N -dimethylformamide (2.0 mL), and add N,N -diisopropylethylamine (72 mg, 0.56 mmol). Subsequently, 1-propyl phosphoric anhydride (143 mg, 0.45 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸叔丁酯(收率：48.0%)。MS(ESI)M/Z：[M+H]⁺=656.20。 The reaction was quenched by adding water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting residue was purified with a TLC plate (ethyl acetate: n-hexane). = 2: 1) to obtain 36 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxide Depiper

1-yl) -3-phenyl-propan-acyl amino) -1 H - benzo [d] imidazole-2-carboxylate (Yield: 48.0%). MS(ESI) M/Z: [M+H] ⁺ =656.20.

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -benzo[d]imidazole-2-carboxylic acid

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸叔丁酯(36毫克，0.055毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -benzo[d]imidazole-2-carboxylic acid tert-butyl ester (36 mg, 0.055 mmol) dissolved in dichloromethane (3.0 mL) . Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-3-苯基丙醯胺基)-1H-苯並[d]咪唑-2-羧酸(收率：62.0%)。MS(ESI)M/Z：[M+H]⁺=600.14。¹H NMR(400MHz,MeOD)δ 9.45(s,1H),8.09(d,J=64.0Hz,3H),7.77(s,1H),7.70(d,J=8.1Hz,2H),7.56(s,1H),7.32(ddd,J=24.0,15.8,7.9Hz,6H),5.42(d,J=24.7Hz,1H),5.35(t,J=4.6Hz,1H),4.18(d,J=56.4Hz,2H),3.83(s,2H),3.44(dd,J=14.2,6.7Hz,1H),3.22-3.12(m,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 20 mg of light yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-diox were obtained Depiper

-1-yl)-3-phenylpropanamido)-1H-benzo[d]imidazole-2-carboxylic acid (yield: 62.0%). MS(ESI) M/Z: [M+H] ⁺ =600.14. ¹ H NMR (400MHz, MeOD) δ 9.45 (s, 1H), 8.09 (d, J = 64.0 Hz, 3H), 7.77 (s, 1H), 7.70 (d, J = 8.1 Hz, 2H), 7.56 (s ,1H),7.32(ddd, J =24.0,15.8,7.9Hz,6H),5.42(d, J =24.7Hz,1H),5.35(t, J =4.6Hz,1H),4.18(d, J = 56.4Hz, 2H), 3.83 (s, 2H), 3.44 (dd, J =14.2, 6.7 Hz, 1H), 3.22-3.12 (m, 1H).

Example 8

-1- 基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-苯基丙酸(41毫克，0.093毫摩爾)，5-氨基-1H-吲哚-2-羧酸叔丁酯(26毫克，0.11毫摩爾)溶於N,N-二甲基甲醯胺(2.0毫升)中，加入N,N-二異丙基乙胺(60毫克，0.46毫摩爾)。隨後，向上述溶液中加入1-丙基磷酸酐(118毫克，0.37毫摩爾)，室溫反應18小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (41 mg, 0.093 mmol), 5-amino-1 H -indole-2-carboxylic acid tert-butyl ester (26 mg, 0.11 mmol) dissolved in N, To N -dimethylformamide (2.0 mL), N,N -diisopropylethylamine (60 mg, 0.46 mmol) was added. Subsequently, 1-propyl phosphoric anhydride (118 mg, 0.37 mmol) was added to the above solution, and reacted at room temperature for 18 hours.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯(收率：73.0%)。MS(ESI)M/Z：[M+H]⁺=655.21。 The reaction was quenched by adding water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The resulting residue was purified with a TLC plate (ethyl acetate: n-hexane). =3:1) to obtain 45 mg of light yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester (yield: 73.0%). MS(ESI) M/Z: [M+H] ⁺ =655.21.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯(45毫克，0.068毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester (45 mg, 0.068 mmol) was dissolved in dichloromethane (3.0 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸(收率：73.0%)。MS(ESI)M/Z：[M+H]⁺=599.14。¹H NMR(500MHz,DMSO)δ 12.91(s,1H),11.71(s,1H),10.14(d,J=9.5Hz,1H),9.75(s,1H),7.99(s,1H),7.93(d,J=2.2Hz,1H),7.80(d,J=8.6Hz,1H),7.78-7.71(m,1H),7.38-7.22(m,7H),7.05(s,1H),5.32(dd,J=12.8,7.3Hz,1H),3.97(s,2H),3.71(s,2H),3.52-3.34(m,1H),3.09(dd,J=14.0,10.6Hz,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 30 mg of light yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-diox were obtained Depiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid (yield: 73.0%). MS(ESI) M/Z: [M+H] ⁺ =599.14. ¹ H NMR (500MHz, DMSO) δ 12.91 (s, 1H), 11.71 (s, 1H), 10.14 (d, J = 9.5 Hz, 1H), 9.75 (s, 1H), 7.99 (s, 1H), 7.93 (d, J =2.2Hz,1H),7.80(d, J =8.6Hz,1H),7.78-7.71(m,1H),7.38-7.22(m,7H),7.05(s,1H),5.32( dd, J =12.8, 7.3 Hz, 1H), 3.97 (s, 2H), 3.71 (s, 2H), 3.52-3.34 (m, 1H), 3.09 (dd, J =14.0, 10.6 Hz, 1H).

Example 9

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(119毫克，0.18毫摩爾)，哌啶-1-碳醯氯(28毫克，0.19毫摩爾)溶於二氯甲烷(5.0毫升)中，加入三乙胺(53毫克，0.53毫摩爾)。室溫反應18小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (119 mg, 0.18 mmol), piperidine-1-carbochloride (28 mg, 0.19 (Mmol) was dissolved in dichloromethane (5.0 mL), and triethylamine (53 mg, 0.53 mmol) was added. React at room temperature for 18 hours.

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸叔丁酯(收率：53.0%)。MS(ESI)M/Z：[M+H]⁺=881.34。 The reaction was quenched by adding water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 71 mg of light yellow solid ( S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid tert-butyl ester (yield : 53.0%). MS(ESI) M/Z: [M+H] ⁺ =881.34.

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(71毫克，0.08毫摩爾)溶於二氯甲烷(3.0毫升)。隨後，向上述溶液中加入三氟乙酸(0.6毫升)。室溫反應3小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (71 Mg, 0.08 mmol) was dissolved in dichloromethane (3.0 mL). Subsequently, trifluoroacetic acid (0.6 mL) was added to the above solution. React at room temperature for 3 hours.

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：38.0%)。MS(ESI)M/Z：[M+H]⁺=725.22。¹H NMR(500MHz,DMSO)δ 12.90(s,1H),11.70(s,1H),10.11(s,1H),9.78(s,1H),8.37(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.36(ddd,J=11.7,10.7,5.2Hz,4H),7.15(t,J=11.2Hz,2H),7.06(d,J=1.7Hz,1H),5.30(dd,J=9.8,5.8Hz,1H),4.05-3.83(m,2H),3.70(d,J=31.6Hz,2H),3.55(s,4H),3.23(dd,J=14.2,5.3Hz,1H),3.01(dd,J=14.0,10.1Hz,1H),1.61-1.53(m,2H),1.53-1.45(m,4H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, 30.5 mg of off-white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-diox were obtained Depiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (yield: 38.0%). MS(ESI) M/Z: [M+H] ⁺ = 725.22. ¹ H NMR (500MHz, DMSO) δ 12.90 (s, 1H), 11.70 (s, 1H), 10.11 (s, 1H), 9.78 (s, 1H), 8.37 (s, 1H), 8.00 (s, 1H) ,7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.36(ddd, J =11.7,10.7,5.2 Hz, 4H), 7.15 (t, J =11.2 Hz, 2H), 7.06 (d, J =1.7 Hz, 1H), 5.30 (dd, J = 9.8, 5.8 Hz, 1H), 4.05-3.83 (m, 2H) ), 3.70(d, J = 31.6Hz, 2H), 3.55(s, 4H), 3.23(dd, J =14.2, 5.3Hz, 1H), 3.01(dd, J=14.0, 10.1Hz, 1H), 1.61 -1.53 (m, 2H), 1.53-1.45 (m, 4H).

Example 10

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows: Step A: Synthesis of 3-chloro-5-nitro-1 H -indole-2-carboxylic acid

Dissolve 5-nitro-1 H -indole-2-carboxylic acid (500 mg, 2.43 mmol) and N -chlorosuccinamide (357 mg, 2.67 mmol) in N,N -dimethyl Formamide (4 mL) was stirred at room temperature for 4 hours.

The reaction solution was diluted with ethyl acetate (100 ml), respectively, with water (20 ml × 2 times) and saturated brine (20 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude 3-chloro-5- Nitro-1 H -indole-2-carboxylic acid was directly used in the next reaction. LCMS: RT=3.39min, [MH] ^- =239.03.

Step B: Synthesis of 3-chloro-5-nitro-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

The crude 3-chloro-5-nitro-1 H -indole-2-carboxylic acid (3.24 mmol) and di-tert-butyl dicarbonate (3.18 g, 14.58 mmol) were dissolved in N,N -dimethyl Formamide (3 ml), 4-dimethylaminopyridine (357 mg, 2.92 mmol) was added at 0 degrees Celsius, and the mixture was stirred at room temperature overnight.

The reaction solution was quenched with ice, diluted with ethyl acetate (100 mL), and then with water (20 mL×2 times) and saturated brine (20 mL) respectively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude product 3. -Chloro-5-nitro-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester was directly used in the next reaction. LCMS: RT=5.27min, [M-56-H] ^- =396.11.

Step C: Synthesis of 3-chloro-5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

Dissolve the crude 3-chloro-5-nitro-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (3.24 mmol) and palladium on carbon (60 mg) in ethanol (50 mL), and use hydrogen The balloon provides a hydrogen source and reacts for 3 hours at room temperature.

The reaction solution was diluted with ethanol (100 ml), filtered through Celite, the filter cake was washed with ethanol (100 ml), the organic phase was concentrated, and the crude product obtained was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8/1) . Obtained 220 mg of white solid 3-chloro-5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (three-step total yield: 18.6%). LCMS: RT=4.43min, [M+H] ⁺ =367.19.

-1-基)-3-苯基丙醯胺)-1H-吲哚-2-羧酸叔丁酯

Step D: Synthesis of (S)-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionamide)-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-苯基丙酸(47毫克，0.107毫摩爾)，3-氯-5-胺基-1H-吲哚-1,2- 二羧酸二叔丁酯(79毫克，0.214毫摩爾)，1-丙基磷酸酐(171毫克，0.535毫摩爾)和N,N-二異丙基乙胺(56微升，0.321毫摩爾)溶解於N,N-二甲基甲醯胺(1毫升)，室溫攪拌過夜。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper under nitrogen protection

-1-yl)-3-phenylpropionic acid (47 mg, 0.107 mmol), 3-chloro-5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (79 mg , 0.214 mmol), 1-propyl phosphoric anhydride (171 mg, 0.535 mmol) and N,N -diisopropylethylamine (56 μl, 0.321 mmol) were dissolved in N,N -dimethylformaldehyde Amide (1 mL), stir overnight at room temperature.

-1-基)-3-苯基丙醯胺)-1H-吲哚-2-羧酸叔丁酯(收率：68.0%)。LCMS：RT=4.55min,[M+H]⁺=689.39。 The reaction solution was diluted with ethyl acetate (100 ml), water (20 ml × 2 times) and saturated brine (20 ml) respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was purified by silica gel column chromatography (Petroleum ether: ethyl acetate = 1/1). Obtain 50 mg of yellow solid (S)-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-phenylpropionamide)-1 H -indole-2-carboxylic acid tert-butyl ester (yield: 68.0%). LCMS: RT=4.55min, [M+H] ⁺ =689.39.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Step E: Synthesis of (S)-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-苯基丙醯胺)-1H-吲哚-2-羧酸叔丁酯(50毫克，0.073毫摩爾)溶解於二氯甲烷(5毫升)，室溫條件下緩慢滴加三氟乙酸(1毫升)，室溫條件下繼續攪拌反應1.5小時。 (S)-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionamide)-1 H -indole-2-carboxylic acid tert-butyl ester (50 mg, 0.073 mmol) was dissolved in dichloromethane (5 mL) at room temperature Trifluoroacetic acid (1 ml) was slowly added dropwise, and the reaction was continued with stirring for 1.5 hours at room temperature.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸(收率：15.5%)。LCMS：RT=3.67min，[M-H]^-=631.27。¹H NMR(500MHz,DMSO)δ 13.36(s,1H),11.99(s, 1H),10.26(s,1H),9.75(s,1H),8.06(s,1H),7.94(d,J=2.2Hz,1H),7.81(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.42(s,2H),7.36-7.27(m,4H),7.24(t,J=7.2Hz,1H),5.35-5.30(m,1H),3.11(dd,J=14.3,10.2Hz,1H),2.05-1.94(m,1H)。 The reaction solution was concentrated with a rotary evaporator, and then it was further drained by an oil pump and dissolved in methanol. Then, n-hexane was added dropwise to the solution system. A large amount of solids precipitated. Continue stirring at room temperature for 1 hour, and filter to obtain 7.1 mg of brown solids (S )-3-chloro-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid (yield: 15.5%). LCMS: RT = 3.67 min, [MH] ^- =631.27. ¹ H NMR (500MHz, DMSO) δ 13.36 (s, 1H), 11.99 (s, 1H), 10.26 (s, 1H), 9.75 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 2.2Hz,1H),7.81(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.2Hz,1H),7.42(s,2H),7.36-7.27(m,4H),7.24( t, J = 7.2 Hz, 1H), 5.35-5.30 (m, 1H), 3.11 (dd, J=14.3, 10.2 Hz, 1H), 2.05-1.94 (m, 1H).

Example 11

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1-甲基-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1-methyl-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows: Step A: Synthesis of 1-methyl-5-nitro-1 H -indole-2-carboxylic acid ethyl ester

Ethyl 5-nitro-1 H -indole-2-carboxylate (2.5 g, 10.7 mmol) and potassium carbonate (2.9 g, 21.4 mmol) were dissolved in N,N -dimethylformamide ( 20.0 ml). Then, methyl iodide (2.3 g, 16.0 mmol) was added to the reaction solution, heated to 60° C. and stirred at constant temperature for 4 hours, LCMS monitored until the reaction was complete, and the reaction solution was cooled to room temperature.

The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, and the organic phase was saturated brine (30 ml×3 times) and dried over anhydrous sodium sulfate , Concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/petroleum ether = 2/1) to obtain 2.6 g of yellow solid 1-methyl-5-nitro-1 H -indole-2-carboxylic acid Ethyl ester (yield: 98.1%). LCMS: RT=4.25min, [M+H] ⁺ =249.02.

Step B: Synthesis of 1-methyl-5-nitro-1 H -indole-2-carboxylic acid

Ethyl 1-methyl-5-nitro-1 H -indole-2-carboxylate (2.0 g, 8.1 mmol) was dissolved in tetrahydrofuran (60.0 mL), and then sodium hydroxide solution (2M, 10.0 (Ml) was added to the reaction solution, and after stirring for 4 hours at room temperature, LCMS monitored until the reaction was complete.

The reaction solution was concentrated under reduced pressure, adjusted to pH 3 with dilute hydrochloric acid, and a large amount of solid was precipitated. The filter cake was washed with water (30 ml×3 times). The filter cake was collected and dried to obtain 1.6 g of white solid 1-methyl-5-nitrogen. -1- H -indole-2-carboxylic acid (yield: 89.9%). LCMS: RT=3.85min, [M+H] ⁺ =219.04.

Step C: Synthesis of 1-methyl-5-nitro-1 H -indole-2-carboxylic acid tert-butyl ester

Dissolve 1-methyl-5-nitro-1 H -indole-2-carboxylic acid (440 mg, 2.0 mmol) in N,N -dimethylformamide (4.0 mL), and then add CDI (486 mg, 3.0 mmol) was added to the reaction solution, and after stirring for 1 hour at room temperature, the tert-butanol (371 mg, 5.0 mmol) and 1,8-diazabicyclo[5.4.0]undecane -7-ene (396 mg, 2.6 mmol) was added to the reaction solution, and after stirring for 2 hours at room temperature, LCMS monitored until the reaction was complete.

The reaction solution was quenched by adding saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (40 ml×3 times), the organic phases were combined, and the organic phase was saturated brine (30 ml×3 times) and dried over anhydrous sodium sulfate It was concentrated under reduced pressure to obtain 402 mg of yellow solid 1-methyl-5-nitro-1 H -indole-2-carboxylic acid tert-butyl ester (yield: 72.8%). LCMS: RT=4.59min, [M+K] ⁺ =316.91.

Step D: Synthesis of 1-methyl-5-amino-1 H -indole-2-carboxylic acid tert-butyl ester

Under nitrogen protection, 1-methyl-5-nitro-1 H -indole-2-carboxylic acid tert-butyl ester (402 mg, 1.5 mmol) was dissolved in ethanol (8.0 mL) and ethyl acetate (4.0 mL). ), add palladium on carbon (80 mg, 20%) to the reaction solution, replace hydrogen, and stir at room temperature for 9 hours.

The reaction solution was filtered through Celite, and the filter cake was washed with ethyl acetate (20 ml×3 times). The filtrate and washing liquid were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/2). Obtained 317 mg of yellow solid 1-methyl-5-amino-1 H -indole-2-carboxylic acid tert-butyl ester (yield: 73.0%). LCMS: RT=2.83min, [M+H] ⁺ =247.17.

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯

Step E: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propylamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-(4-硝基苯基)丙酸(263毫克，0.5毫摩爾)和N,N-二異丙基乙胺(0.2毫升，1.5毫摩爾)溶於N,N-二甲基甲醯胺(3.0毫升)中。隨後，向上述溶液中加入2-(7-偶氮苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(380毫克，1.0毫摩爾)和1-甲基-5-氨基-1H-吲哚-2-羧酸叔丁酯(123.0毫克，0.5毫摩爾)。在室溫下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)propionic acid (263 mg, 0.5 mmol) and N,N -diisopropylethylamine (0.2 mL, 1.5 mmol) were dissolved in N,N -Dimethylformamide (3.0 mL). Subsequently, 2-(7-azobenzotriazole) -N,N,N',N' -tetramethylurea hexafluorophosphate (380 mg, 1.0 mmol) and 1- Tert-butyl methyl-5-amino- 1H -indole-2-carboxylate (123.0 mg, 0.5 mmol). Stir overnight at room temperature.

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(收率：60.0%)。LCMS：RT=4.24min,[M-H]^-=712.28。 The reaction was quenched by adding water to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). The organic phases were combined, and the organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/1). Obtain 230 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propylamino)-1-methyl- 1H -indole-2-carboxylic acid tert-butyl ester (yield: 60.0%). LCMS: RT=4.24min, [MH] ^- =712.28.

-1-基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯

Step F: Synthesis of (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2, 3-dioxopiperidine

-1-yl)propylamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(230毫克，0.3毫摩爾)溶於甲醇(8.0毫升)和冰醋酸(4.0毫升)中。隨後，向上述溶液中加入還原性鐵粉(168毫克，3.0毫摩爾)，在70℃下攪拌4小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propylamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester (230 mg, 0.3 mmol) dissolved in Methanol (8.0 mL) and glacial acetic acid (4.0 mL). Subsequently, reducing iron powder (168 mg, 3.0 mmol) was added to the above solution and stirred at 70°C for 4 hours.

-1-基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(收率93.0%)。LCMS：RT=4.23min,[M-H]^-=684.12。 The reaction solution was cooled to room temperature. Add sodium bicarbonate to neutralize, and extract the mixture with ethyl acetate (20 mL×3 times). The organic phases were combined, and the organic phase was first dried with saturated brine (10 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 205 mg of yellow solid (S)-5-(3-(4-aminophenyl)-2 -(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester (yield 93.0%). LCMS: RT=4.23min, [MH] ^- =684.12.

-1-基)-3-(-4-(哌啶-1-甲醯氨基)苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁 酯

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(piperidine-1-carboxamido)phenyl)propanamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(205毫克，0.3毫摩爾)和三乙胺(0.1毫升，0.75毫摩爾)溶於二氯甲烷(5.0毫升)中。於冰浴中向反應液中加入哌啶-1-羰基氯(53毫克，0.36毫摩爾)，在室溫下攪拌2小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propylamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester (205 mg, 0.3 mmol) and triethylamine (0.1 ml, 0.75 mmol) are dissolved in Methylene chloride (5.0 mL). Piperidine-1-carbonyl chloride (53 mg, 0.36 mmol) was added to the reaction solution in an ice bath, and the mixture was stirred at room temperature for 2 hours.

-1-基)-3-(-4-(哌啶-1-甲醯氨基)苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(收率：38%)。LCMS：RT=4.19min,[M+H]⁺=795.23。 Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1). To obtain 130 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(piperidine-1-carboxamide)phenyl)propanamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester Rate: 38%). LCMS: RT=4.19min, [M+H] ⁺ =795.23.

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1-甲基-1H-吲哚-2-羧酸

Step H: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1-methyl-1 H -indole-2-carboxylic acid

-1-基)- 3-(-4-(哌啶-1-甲醯氨基)苯基)丙醯氨基)-1-甲基-1H-吲哚-2-羧酸叔丁酯(90毫克，0.11毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(piperidine-1-carboxamide)phenyl)propionamino)-1-methyl-1 H -indole-2-carboxylic acid tert-butyl ester (90 Mg, 0.11 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)-3-(4-(哌啶-1-甲醯胺基)苯基)丙醯胺基)-1-甲基-1H-吲哚-2-羧酸(收率：35.0%)。LCMS：RT=3.66min,[M-H]^-=737.14。¹H NMR(500MHz,DMSO)δ 12.89(s,1H),10.16(s,1H),9.78(s,1H),8.38(s,1H),8.03(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.53(d,J=9.0Hz,1H),7.45-7.38(m,2H),7.18(d,J=6.4Hz,1H),7.14(d,J=8.2Hz,1H),5.75(s,1H),5.35-5.27(m,1H),4.00(s,2H),3.43-3.38(m,3H),3.23(d,J=14.1Hz,1H),3.06-2.97(m,1H),2.55-2.53(m,2H),1.56(d,J=5.3Hz,2H),1.48(d,J=4.1Hz,4H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 29 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl) )-2,3-dioxopiperidine

-1-yl)-3-(4-(piperidine-1-carboxamido)phenyl)propionamido)-1-methyl-1 H -indole-2-carboxylic acid (yield: 35.0%). LCMS: RT=3.66min, [MH] ^- =737.14. ¹ H NMR (500MHz, DMSO) δ 12.89 (s, 1H), 10.16 (s, 1H), 9.78 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 7.95 (d, J= 2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.53(d, J =9.0Hz,1H),7.45-7.38(m, 2H), 7.18(d, J =6.4Hz,1H), 7.14(d, J =8.2Hz,1H), 5.75(s,1H),5.35-5.27(m,1H),4.00(s,2H), 3.43-3.38(m,3H), 3.23(d, J =14.1Hz,1H), 3.06-2.97(m,1H), 2.55-2.53(m,2H), 1.56(d, J =5.3Hz,2H) ,1.48(d, J =4.1Hz,4H).

Example 12

-1-基)-3-(4-(4-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

Step A: Synthesis of the trifluoroacetate salt of piperidin-4-ol

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, trifluoroacetic acid (2.0 mL) was added to the above solution and stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure in an air bath to obtain 1.0 g of crude trifluoroacetate of piperidin-4-ol as a yellow solid (yield: 93.5%).

-1-基)-3-(4-(4-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.2毫摩爾)和哌啶-4-醇的三氟乙酸鹽(860毫克，4.0毫摩爾)溶於四氫呋喃(6.0毫升)中。隨後，向上述溶液中N,N-二異丙基乙胺(1.0毫升，6毫摩爾)。在60℃反應12小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.2 MM) and piperidin-4-ol trifluoroacetate (860 mg, 4.0 mmol) were dissolved in tetrahydrofuran (6.0 mL). Subsequently, add N,N -diisopropylethylamine (1.0 mL, 6 mmol) to the above solution. React at 60°C for 12 hours.

-1- 基)-3-(4-(4-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯粗品(收率：100%)。LCMS：RT=4.14min,[M-H]^-=867.42。 The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and the organic phase was dried with saturated brine (20 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 180 mg yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamido)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl crude (Yield: 100%). LCMS: RT=4.14min, [MH] ^- =867.42.

-1-基)-3-(4-(4-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step C: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(180毫克，0.2毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( 180 mg, 0.2 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)-3-(4-(4-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：18.2%)。LCMS：RT=3.16min,[M-H]^-=739.23。¹H NMR(400MHz,DMSO)δ 11.71(s,1H),10.13(s,1H),9.78(s,1H),8.43(s,1H),8.00(s,1H),7.95(d,J=1.9Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.43-7.30(m,3H),7.14(d,J=7.9Hz,1H),7.06(d,J=1.6Hz,1H),5.30(dd,J=9.5,5.6Hz,1H),3.82(d,J=13.7Hz,2H),3.70-3.60(m,2H),3.47(m,6H),3.22(dd,J=14.9,6.4Hz,2H),3.08-2.96(m,2H),2.54(s,1H),1.73(d,J=8.9Hz,2H),1.36-1.21(m,2H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 27 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl) )-2,3-dioxopiperidine

-1-yl)-3-(4-(4-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (yield: 18.2% ). LCMS: RT=3.16min, [MH] ^- =739.23. ¹ H NMR (400MHz, DMSO) δ 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.43 (s, 1H), 8.00 (s, 1H), 7.95 (d, J = 1.9Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.2Hz,1H),7.43-7.30(m,3H),7.14(d, J =7.9Hz, 1H), 7.06(d, J =1.6Hz,1H), 5.30(dd, J =9.5,5.6Hz,1H), 3.82(d, J =13.7Hz,2H), 3.70-3.60(m,2H), 3.47(m,6H),3.22(dd, J =14.9,6.4Hz,2H),3.08-2.96(m,2H),2.54(s,1H),1.73(d, J =8.9Hz,2H),1.36 -1.21(m,2H).

Example 13

-1-基)-3-(4-(3-(1,1-二氧代四氫-1H-噻喃-4-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(1,1-dioxotetrahydro-1 H -thiopyran-4-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid

-1-基)-3-(4-(3-(1,1-二氧代四氫-2H-噻喃-4-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

L-yl) -3- (4- (3- (1,1-dioxo-tetrahydro -2 H - thiopyran-4-yl) ureido) phenyl) propan-acyl amino) -1 H - indazole Dole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.2毫摩爾)和4-氨基四氫-2H-噻喃1,1-二氧化物(371毫克，2.0毫摩爾)溶於四氫呋喃(6.0毫升)中。隨後，向上述溶液中N,N-二異丙基乙胺(0.7毫升，4毫摩爾)。在60℃反應12小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.2 MM) and 4-aminotetrahydro- 2H -thiopyran 1,1-dioxide (371 mg, 2.0 mmol) were dissolved in tetrahydrofuran (6.0 mL). Then, add N,N -diisopropylethylamine (0.7 mL, 4 mmol) to the above solution. React at 60°C for 12 hours.

-1- 基)-3-(4-(3-(1,1-二氧代四氫-2H-噻喃-4-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：95.2%)。LCMS：RT=4.17min,[M+H]⁺=945.28。 The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and the organic phase was dried with saturated brine (20 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 180 mg yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

L-yl) -3- (4- (3- (1,1-dioxo-tetrahydro -2 H - thiopyran-4-yl) ureido) phenyl) propan-acyl amino) -1 H - indazole Dole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 95.2%). LCMS: RT=4.17min, [M+H] ⁺ =945.28.

-1-基)-3-(4-(3-(1,1-二氧代四氫-1H-噻喃-4-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(1,1-dioxotetrahydro-1 H -thiopyran-4-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid

-1-基)-3-(4-(3-(1,1-二氧代四氫-2H-噻喃-4-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(180毫克，0.19毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

L-yl) -3- (4- (3- (1,1-dioxo-tetrahydro -2 H - thiopyran-4-yl) ureido) phenyl) propan-acyl amino) -1 H - indazole Di-tert-butyl indole-1,2-dicarboxylate (180 mg, 0.19 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)-3-(4-(3-(1,1-二氧代四氫-1H-噻喃-4-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：17.2%)。LCMS：RT=3.24min,[M-H]^-=787.13。¹H NMR(400MHz,DMSO)δ 13.05-12.68(m,1H),11.71(s,1H),10.11(s,1H),9.78(s,1H),8.25(s,1H),7.99(s,1H),7.94(d,J=2.3Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.42-7.30(m,3H),7.13(d,J=8.1Hz,2H),7.06(d,J=1.6Hz,1H),6.39(d,J=7.5Hz,1H),5.75(s,1H),5.28(dd,J=10.2,5.8Hz,1H),3.84(s,2H),3.73(s,2H),3.26-3.17(m,2H),3.05(d,J=11.8Hz,2H),2.54(s,1H),2.12(s,2H),1.90(dd,J=21.0,10.2Hz,2H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 26 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl) )-2,3-dioxopiperidine

-1-yl)-3-(4-(3-(1,1-dioxotetrahydro-1 H -thiopyran-4-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid (yield: 17.2%). LCMS: RT=3.24min, [MH] ^- =787.13. ¹ H NMR (400MHz, DMSO) δ 13.05-12.68 (m, 1H), 11.71 (s, 1H), 10.11 (s, 1H), 9.78 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H),7.94(d, J =2.3Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.42-7.30(m,3H), 7.13(d, J =8.1Hz,2H),7.06(d, J =1.6Hz,1H), 6.39(d, J =7.5Hz,1H), 5.75(s,1H), 5.28(dd, J =10.2 ,5.8Hz,1H),3.84(s,2H),3.73(s,2H),3.26-3.17(m,2H),3.05(d, J =11.8Hz,2H),2.54(s,1H),2.12 (s, 2H), 1.90 (dd, J = 21.0, 10.2 Hz, 2H).

Example 14

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propanamido)-1 H -Indole-2-carboxylic acid

The specific synthesis route is as follows:

Step A: Synthesis of 1-oxa-8-azaspiro[4.5]dec-3-ol trifluoroacetate

Tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4-]decane-8-carboxylate (1.0 g, 5.0 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, trifluoroacetic acid (2.0 mL) was added to the above solution and stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure in an air bath to obtain 1.0 g of crude trifluoroacetate of yellow solid 1-oxa-8-azaspiro[4.5]dec-3-ol (yield: 94.8%).

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step B: Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-methanoamino)phenyl)propanoamino)-1 H -indole Dole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.2毫摩爾)和1-氧雜-8-氮雜螺[4.5]癸-3-醇的三氟乙酸鹽(542毫克，2.0毫摩爾)溶於四氫呋喃(6.0毫升)中。隨後，向上述溶液中N,N-二異丙基乙胺(0.7毫升，4毫摩爾)。在60℃反應12小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.2 MM) and 1-oxa-8-azaspiro[4.5]dec-3-ol trifluoroacetate (542 mg, 2.0 mmol) were dissolved in tetrahydrofuran (6.0 mL). Then, add N,N -diisopropylethylamine (0.7 mL, 4 mmol) to the above solution. React at 60°C for 12 hours.

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：100%)。LCMS：RT=4.14min,[M-H]^-=951.26。 The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and the organic phase was dried with saturated brine (20 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 190 mg yellow solid 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-methanoamino)phenyl)propanoamino)-1 H -indole Dole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 100%). LCMS: RT=4.14min, [MH] ^- =951.26.

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step C: Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propanamido)-1H- Indole-2-carboxylic acid

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯氨基)苯基)丙醯氨基)-1H-吲哚 -1,2-二羧酸二叔丁酯(190毫克，0.20毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 Put 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-methanoamino)phenyl)propanoamino)-1 H -indole Di-tert-butyl indole-1,2-dicarboxylate (190 mg, 0.20 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)-3-(4-(3-羥基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：17.2%)。LCMS：RT=3.24min,[M-H]^-=787.13。¹H NMR(500MHz,DMSO)δ 12.89(s,1H),11.70(s,1H),10.12(s,1H),9.78(s,1H),8.43(s,1H),8.08-7.87(m,2H),7.78(dt,J=8.6,5.3Hz,2H),7.49-7.25(m,3H),7.14(d,J=7.9Hz,2H),7.06(s,1H),5.30(dd,J=9.7,5.7Hz,1H),4.86(s,1H),4.32(s,1H),3.81(dd,J=9.2,4.9Hz,1H),3.73(s,1H),3.61-3.51(m,3H),3.38(s,1H),3.23(d,J=14.8Hz,1H),3.05-2.96(m,1H),1.87(dd,J=13.0,6.6Hz,1H),1.68(ddd,J=29.9,21.5,10.9Hz,3H),1.49(s,2H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 26 mg of yellow solid 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl) )-2,3-dioxopiperidine

-1-yl)-3-(4-(3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propanamido)-1 H -Indole-2-carboxylic acid (yield: 17.2%). LCMS: RT=3.24min, [MH] ^- =787.13. ¹ H NMR (500MHz, DMSO) δ 12.89 (s, 1H), 11.70 (s, 1H), 10.12 (s, 1H), 9.78 (s, 1H), 8.43 (s, 1H), 8.08-7.87 (m, 2H), 7.78(dt, J =8.6,5.3Hz,2H),7.49-7.25(m,3H),7.14(d, J =7.9Hz,2H),7.06(s,1H),5.30(dd, J =9.7,5.7Hz,1H),4.86(s,1H),4.32(s,1H),3.81(dd, J =9.2,4.9Hz,1H),3.73(s,1H),3.61-3.51(m, 3H), 3.38(s,1H), 3.23(d, J =14.8Hz,1H),3.05-2.96(m,1H),1.87(dd, J =13.0,6.6Hz,1H),1.68(ddd, J = 29.9, 21.5, 10.9 Hz, 3H), 1.49 (s, 2H).

Example 15

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.2毫摩爾)和4-(甲基磺醯基)哌啶(163毫克，1.0毫摩爾)溶於四氫呋喃(6.0毫升)中。隨後，向上述溶液中N,N-二異丙基乙胺(0.3毫升，2毫摩爾)。在60℃反應12小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.2 MM) and 4-(methylsulfonyl)piperidine (163 mg, 1.0 mmol) were dissolved in tetrahydrofuran (6.0 mL). Subsequently, add N,N -diisopropylethylamine (0.3 mL, 2 mmol) to the above solution. React at 60°C for 12 hours.

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯粗品(收率：100%)。LCMS：RT=4.16min,[M-H]^-=957.29。 The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and the organic phase was dried with saturated brine (20 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 192 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxy Crude di-tert-butyl acid (yield: 100%). LCMS: RT=4.16min, [MH] ^- =957.29.

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(192毫克，0.20毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester (192 mg, 0.20 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)-3-(4-(4-(甲基磺醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：15.0%)。LCMS：RT=3.24min,[M-H]^-=801.18。¹H NMR(400MHz,DMSO)δ 13.08-12.69(m,1H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.55(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.39(dd,J=11.2,8.7Hz,3H),7.33(dd,J=8.9,1.9Hz,1H),7.16(d,J=8.5Hz,2H),7.06(d,J=1.5Hz,1H),5.30(dd,J=9.6,5.9Hz,1H),4.26(d,J=13.4Hz,2H),3.74(s,4H),3.29-3.23(m,1H),3.22(s,1H),3.03(d,J=9.8Hz,1H),2.94(s,3H),2.83(t,J=12.0Hz,2H),2.03(d,J=8.5Hz,2H),1.53(d,J=11.9Hz,2H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 25 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl) )-2,3-dioxopiperidine

-1-yl)-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (Yield: 15.0%). LCMS: RT=3.24min, [MH] ^- =801.18. ¹ H NMR (400MHz, DMSO) δ 13.08-12.69 (m, 1H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.55 (s, 1H), 8.00 (s, 1H),7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.39(dd, J =11.2,8.7 Hz,3H),7.33(dd, J =8.9,1.9Hz,1H),7.16(d, J =8.5Hz,2H),7.06(d, J =1.5Hz,1H),5.30(dd, J =9.6 ,5.9Hz,1H),4.26(d, J =13.4Hz,2H),3.74(s,4H),3.29-3.23(m,1H),3.22(s,1H),3.03(d, J =9.8Hz ,1H), 2.94(s,3H), 2.83(t, J =12.0Hz,2H), 2.03(d, J =8.5Hz,2H), 1.53(d, J =11.9Hz,2H).

Example 16

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(3-(4-(4-carboxypiperidine-1-carboxamide)phenyl)-2-(4-(5-chloro-2-(1 H -tetrazole-1) -Yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(3-(4-(4-(tert-butoxycarbonyl)piperidine-1-carboxamido)phenyl)-2-(4- (5-Chloro-2-(1 H -tetrazol)-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.2毫摩爾)和哌啶-4-羧酸叔丁酯(251毫克，1.0毫摩爾)溶於四氫呋喃(6.0毫升)中。隨後，向上述溶液中N,N-二異丙基乙胺(0.3毫升，2毫摩爾)。在60℃反應12小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.2 MM) and tert-butyl piperidine-4-carboxylate (251 mg, 1.0 mmol) were dissolved in tetrahydrofuran (6.0 mL). Subsequently, add N,N -diisopropylethylamine (0.3 mL, 2 mmol) to the above solution. React at 60°C for 12 hours.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸 二叔丁酯粗品(收率：100%)。LCMS：RT=4.57min,[M-H]^-=979.36。 The reaction solution was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), the organic phases were combined, and the organic phase was dried with saturated brine (20 ml×3 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 76 mg of yellow solid (S)-5-(3-(4-(4-(tert-butoxycarbonyl)piperidine-1-carboxamido)phenyl)-2-(4-(5-chloro- 2-(1 H -tetrazol)-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl crude product (yield: 100%). LCMS: RT=4.57min, [MH] ^- =979.36.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(3-(4-(4-carboxypiperidine-1-carboxamide)phenyl)-2-(4-(5-chloro-2-(1 H -tetra (Azol-1-yl)phenyl)-2,3-dioxopiperidine

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(76毫克，0.20毫摩爾)溶於二氯甲烷(5.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)，在室溫下攪拌1小時。 (S)-5-(3-(4-(4-(tert-butoxycarbonyl)piperidine-1-carboxamido)phenyl)-2-(4-(5-chloro-2-( 1 H -tetrazol)-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (76 mg, 0.20 mmol) was dissolved in dichloromethane (5.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution, and the mixture was stirred at room temperature for 1 hour.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸(收率：6.4%)。LCMS：RT=3.24min,[M-H]^-=769.18。¹H NMR(500MHz,DMSO)δ 12.81(s,2H),11.71(s,1H),10.12(s,1H),9.78(s,1H),8.45(d,J=4.6Hz,1H),8.06-7.90(m,2H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.5,2.2Hz,1H),7.39(dd,J=13.7,8.7Hz,3H),7.33(d,J=8.8Hz,1H),7.14(d,J=7.9Hz,2H),7.06(s,1H),5.30(dd,J=9.8,5.8Hz,1H),4.01(d,J=13.3Hz,2H),3.74(s,2H),3.62(s,1H),3.24(s,2H),3.17(s,1H),3.08-2.96(m,1H),2.90(t,J=12.2Hz,2H),1.82(d,J=9.7Hz,2H),1.57-1.40(m,2H)。 The reaction solution was concentrated under reduced pressure in an air bath. The obtained residue was purified by preparative high performance liquid chromatography to obtain 4 mg of yellow solid (S)-5-(3-(4-(4-carboxypiperidine-1-methanoamino)phenyl)-2-( 4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

1-yl) propan-acyl amino) -1 H - indole-2-carboxylic acid (yield: 6.4%). LCMS: RT=3.24min, [MH] ^- =769.18. ¹ H NMR (500MHz, DMSO) δ 12.81 (s, 2H), 11.71 (s, 1H), 10.12 (s, 1H), 9.78 (s, 1H), 8.45 (d, J =4.6Hz, 1H), 8.06 -7.90(m,2H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.5,2.2Hz,1H),7.39(dd, J =13.7,8.7Hz,3H),7.33( d, J =8.8Hz,1H),7.14(d, J =7.9Hz,2H),7.06(s,1H),5.30(dd, J =9.8,5.8Hz,1H),4.01(d, J =13.3 Hz, 2H), 3.74 (s, 2H), 3.62 (s, 1H), 3.24 (s, 2H), 3.17 (s, 1H), 3.08-2.96 (m, 1H), 2.90 (t, J =12.2 Hz) , 2H), 1.82 (d, J =9.7 Hz, 2H), 1.57-1.40 (m, 2H).

Example 17

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.20毫摩爾)和甲基磺醯胺(190毫克，2.0毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(516毫克，4.0毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.20 mmol) and methylsulfonamide (190 mg, 2.0 mmol) in tetrahydrofuran (6.0 mL) were added dropwise with N,N -diisopropylethylamine (516 mg, 4.0 mmol), after the drop, 60 React overnight at °C.

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：56.0%)。LCMS：RT=4.20min,[M+H]⁺=891.23。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). Obtain 100 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( Yield: 56.0%). LCMS: RT=4.20min, [M+H] ⁺ =891.23.

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(100毫克，0.11毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。反應結束，蒸乾二氯甲烷並用油泵抽乾三氟乙酸，所得殘餘物用溶於二氯甲烷(1.0毫升)中，將其滴加入正己烷(10.0毫升)中，析出白色固體，抽濾，濾餅用正己烷洗滌，乾燥得到56毫克白色固體(S)-5-(2-(4-(5-氯-2-(1H-四唑-1-基)苯基)-2,3-二氧代哌

-1-基)-3-(4-(3-(甲基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：60.8%)。LCMS：RT=3.27min,[M-H]^-=733.08。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( 100 mg, 0.11 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 56 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-(methylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 60.8%) . LCMS: RT=3.27min, [MH] ^- =733.08.

Example 18

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.20毫摩爾)和乙基磺醯胺(436毫克，4.0毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(775毫克，6.0毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.20 mmol) and ethyl sulfonamide (436 mg, 4.0 mmol) in tetrahydrofuran (6.0 mL) were added dropwise N,N -diisopropylethylamine (775 mg, 6.0 mmol), the drop was completed, 60 React overnight at °C.

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧 酸二叔丁酯(收率：60.7%)。LCMS：RT=4.24min,[M+Na]⁺=927.14。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). Obtain 110 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( Yield: 60.7%). LCMS: RT=4.24min, [M+Na] ⁺ =927.14.

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(110毫克，0.12毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。反應結束，蒸乾二氯甲烷並用油泵抽乾三氟乙酸，所得殘餘物用溶於二氯甲烷(1.0毫升)中，將其滴加入正己烷(10.0毫升)中，析出白色固體，抽濾，濾餅用正己烷洗滌，乾燥得到48毫克白色固體(S)-5-(2-(4-(5-氯-2-(1H-四唑-1-基)苯基)-2,3-二氧代哌

-1-基)-3-(4-(3-(乙基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：53.3%)。LCMS：RT=3.33min,[M+H]⁺=749.03。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.72(s,1H),10.19(s,1H),10.13(s,1H),9.78(s,1H),8.79(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.38(d,J=8.6Hz,3H),7.36-7.30(m,1H),7.22(d,J=7.8Hz,2H),7.06(d,J=1.5Hz,1H),5.36-5.26(m,1H),4.25-3.55(m,4H),3.44(dd,J=14.6,7.2Hz,2H),3.25(dd,J=14.2,5.2Hz,1H),3.12-3.00(m,1H),1.26(t,J=7.4Hz,3H)。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( 110 mg, 0.12 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 48 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 53.3%) . LCMS: RT=3.33min, [M+H] ⁺ =749.03. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.72 (s, 1H), 10.19 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.79 (s, 1H) ,8.00(s,1H),7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.38(d, J =8.6Hz,3H),7.36-7.30(m,1H),7.22(d, J =7.8Hz,2H),7.06(d, J =1.5Hz,1H),5.36-5.26(m,1H), 4.25-3.55(m,4H),3.44(dd, J =14.6,7.2Hz,2H), 3.25(dd, J =14.2,5.2Hz,1H),3.12-3.00(m,1H),1.26(t, J = 7.4 Hz, 3H).

Example 19

-1- 基)-3-((4-((S)-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-((4-((S)-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-((S)-3-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-3-hydroxypiperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(178毫克，0.20毫摩爾)和(S)-哌啶-3-醇鹽酸鹽(550毫克，4.0毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(1.03克，8.0毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (178 mg, 0.20 mmol) and (S)-piperidin-3-ol hydrochloride (550 mg, 4.0 mmol) in tetrahydrofuran (6.0 mL) was added dropwise N,N -diisopropylethylamine (1.03 g, 8.0 Millimoles), after dripping, react overnight at 60°C.

-1-基)-3-(4-((S)-3-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：52.0%)。LCMS：RT=4.16min,[M+H]⁺=867.22。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). Obtain 93 mg of white solid (5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-3-hydroxypiperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (yield: 52.0%). LCMS: RT=4.16min, [M+H] ⁺ =867.22.

-1-基)-3-((4-((S)-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-((4-((S)-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((S)-3-羥基哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(93毫克，0.10毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。反應結束，蒸乾二氯甲烷並用油泵抽乾三氟乙酸，所得殘餘物用溶於二氯甲烷(1.0毫升)中，將其滴加入正己烷(10.0毫升)中，析出白色固體，抽濾，濾餅用正己烷洗滌，乾燥得到48毫克白色固體5-((S)-2-(4-(5-氯-2-(1H-四唑-1-基)苯基)-2,3-二氧代哌

-1-基)-3-((4-((S)-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：64.8%)。LCMS：RT=3.20min,[M-H]^-=739.16。δ 11.73(s,1H),10.14(s,1H),9.79(s,1H),8.42(s,1H),8.01(s,1H),7.95(d,J=2.3Hz,1H),7.82(d,J=8.5Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.41(s,1H),7.36(s,1H),7.32(dd,J=8.8,1.9Hz,1H),7.14(d,J=8.3Hz,2H),7.06(d,J=2.1Hz,1H),5.33-5.26(m,1H),3.88-3.72(m,7H),3.48-3.40(m,1H),3.26-3.18(m,1H),3.05-2.96(m,1H),2.92-2.83(m,1H),2.72-2.65(m,1H), 2.03-1.95(m,1H),1.89-1.80(m,1H),1.72-1.62(m,1H),1.38-1.30(m,1H)。 At room temperature, (5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-3-hydroxypiperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (93 mg, 0.10 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 48 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-((4-((S)-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid ( Yield: 64.8%). LCMS: RT=3.20min, [MH] ^- =739.16. δ 11.73(s, 1H), 10.14(s, 1H), 9.79(s, 1H), 8.42(s, 1H), 8.01(s, 1H), 7.95(d, J = 2.3Hz, 1H), 7.82( d, J =8.5Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.41(s,1H),7.36(s,1H),7.32(dd, J =8.8,1.9Hz,1H ), 7.14(d, J =8.3Hz,2H),7.06(d, J =2.1Hz,1H),5.33-5.26(m,1H),3.88-3.72(m,7H),3.48-3.40(m, 1H), 3.26-3.18 (m, 1H), 3.05-2.96 (m, 1H), 2.92-2.83 (m, 1H), 2.72-2.65 (m, 1H), 2.03-1.95 (m, 1H), 1.89- 1.80 (m, 1H), 1.72-1.62 (m, 1H), 1.38-1.30 (m, 1H).

Example 20

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)環丁烷-1-羧酸甲酯

The specific synthesis route is as follows: Step A: Synthesis of 3-(3-oxopiperidine

-1-yl) cyclobutane-1-methyl carboxylate

-2-酮(1.00克，10.0毫摩爾)和3-氧代環丁烷-1-羧酸甲酯(1.92克，15.0毫摩爾)的甲醇(20.0毫升)溶液中加入氰基硼氫化鈉(8.7毫克，13.0毫摩爾)和乙酸(0.4毫升)，加畢，室溫反應2小時。 At room temperature, to contain piper

-2-one (1.00 g, 10.0 mmol) and methyl 3-oxocyclobutane-1-carboxylate (1.92 g, 15.0 mmol) in methanol (20.0 mL) was added sodium cyanoborohydride ( 8.7 mg, 13.0 mmol) and acetic acid (0.4 ml), after the addition, react at room temperature for 2 hours.

-1-基)環丁烷-1-羧酸甲酯(收率45.0%)。LCMS：RT=0.69min,[M+H]⁺=213.11。 After the reaction was completed, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). Obtained 954 mg of light yellow oil 3-(3-oxopiper

-1-yl)cyclobutane-1-carboxylic acid methyl ester (yield 45.0%). LCMS: RT=0.69 min, [M+H] ⁺ =213.11.

-2-酮

Step B: Synthesis of 4-(3-(hydroxymethyl)cyclobutyl)piper

-2-one

-1-基)環丁烷-1-羧酸甲酯(848毫克，4.0毫摩爾)的四氫呋喃/甲醇(20.0/20.0毫升)溶液中加入硼氫化鋰(88毫克，4.0毫摩爾)，加畢，加熱至40℃反應3小時。 At room temperature, add 3-(3-oxo-piperidine

-1-yl) cyclobutane-1-methyl carboxylate (848 mg, 4.0 mmol) in tetrahydrofuran/methanol (20.0/20.0 ml) was added lithium borohydride (88 mg, 4.0 mmol), and the addition was complete , Heat to 40°C and react for 3 hours.

-2-酮(56.0%)。LCMS：RT=0.76min,[M+H]⁺=185.09。 After the reaction was completed, it was quenched with water (5 mL), extracted with dichloromethane (30 mL×2 times), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: dichloromethane). Methane/methanol=5/1). Obtained 412 mg of pale yellow oily 4-(3-(hydroxymethyl)cyclobutyl)piperidine

-2-one (56.0%). LCMS: RT=0.76min, [M+H] ⁺ =185.09.

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(602毫克，1.0毫摩爾)、4-(3-(羥甲基)環丁基)哌

-2-酮(184毫克，1.0毫摩爾)的甲苯(5.0毫升)溶液中加入碘化亞銅(190毫克，1.0毫摩爾)，碳酸銫(656毫克，2.0毫摩爾)，N ¹ ,N ² -二甲基乙二胺(176毫克，2.0毫摩爾)，加畢，加熱至110℃反應過夜。 Under the protection of nitrogen, to contain (S)-3-(4-bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxo Piper

-1-yl) tert-butyl propionate (602 mg, 1.0 mmol), 4-(3-(hydroxymethyl)cyclobutyl)piperidine

To a solution of -2-one (184 mg, 1.0 mmol) in toluene (5.0 mL) was added copper iodide (190 mg, 1.0 mmol), cesium carbonate (656 mg, 2.0 mmol), N ¹ , N ² -Dimethylethylenediamine (176 mg, 2.0 mmol), after the addition, heat to 110°C and react overnight.

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(50.0%)。LCMS：RT=3.30min,[M+H]⁺=706.18。 After the reaction was completed, it was quenched by adding water (5 mL), extracted with ethyl acetate (40 mL×2 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The material was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1). Obtain 352 mg of light yellow oil (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (50.0%). LCMS: RT=3.30min, [M+H] ⁺ =706.18.

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(2-amino-5-chloro-phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(352毫克，0.50毫摩爾)的二氯甲烷(4.0毫升)溶液中加入二甲基巴比妥酸(624毫克，4.0毫摩爾)，四三苯基膦鈀(29毫克，0.025毫摩爾)，加畢，加熱至40℃反應過夜。 Under the protection of nitrogen, add (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (352 mg, 0.50 mmol) in dichloromethane (4.0 mL) was added dimethyl barbituric acid (624 mg, 4.0 mmol), four three Phenylphosphine palladium (29 mg, 0.025 mmol), after the addition, heat to 40°C and react overnight.

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(70.4%)。LCMS：RT=3.16 min,[M+Na]⁺=648.23。 After the reaction is complete, dilute with dichloromethane (100ml), wash with saturated sodium bicarbonate (50ml) and saturated brine (50ml) successively, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and apply a silica gel column to the residue. Chromatographic purification (eluent: dichloromethane/methanol=30/1). Obtain 220 mg of light yellow oil (S)-2-(4-(2-amino-5-chloro-phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (70.4%). LCMS: RT=3.16 min, [M+Na] ⁺ =648.23.

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁基酯

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl) phenyl) tert-butyl propionate

-1-基)-3-(4-(4-(3-(羥甲基))環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(220毫克，0.35毫摩爾)乙酸(1.0毫升)溶液中加入原甲酸三乙酯(311毫克，2.1毫摩爾)，疊氮化鈉(114毫克，1.75毫摩爾)，加畢，加熱至80℃反應2小時。 Under the protection of nitrogen, add ((S)-2-(4-(2-amino-5-chloro-phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl))cyclobutyl)-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (220 mg, 0.35 mmol) in acetic acid (1.0 mL) was added triethyl orthoformate (311 mg, 2.1 mmol), sodium azide (114 mg , 1.75 mmol), after the addition, heat to 80°C and react for 2 hours.

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁基酯(收率75.3%)。LCMS：RT=2.91min,[M+H]⁺=679.16。 After the reaction is over, add sodium nitrite (200 mg) for quenching, extract with ethyl acetate (40 ml×2 times), combine the organic phases, wash with saturated brine (50 ml), dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1). Obtain 180 mg of light yellow oil (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield 75.3%). LCMS: RT=2.91min, [M+H] ⁺ =679.16.

-1-基)-3-(-4-(-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step F: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙酸叔丁基酯(100毫克，0.15毫摩爾)的二氯甲烷(4.0毫升)溶液中加入三氟乙酸(1.0毫升)，加畢，室溫反應1.5小時。減壓濃縮，所得粗產物直接用於下一步反應。 At room temperature, add (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl -1-yl)phenyl)propionate (100 mg, 0.15 mmol) in dichloromethane (4.0 mL). After the addition, the reaction was carried out at room temperature for 1.5 hours. It was concentrated under reduced pressure, and the obtained crude product was directly used in the next reaction.

The above crude product and di-tert-butyl 5-amino-1 H -indole-1,2-dicarboxylate (133 mg, 0.40 mmol) were dissolved in anhydrous N,N -dimethylformamide (2.0 ml ), HATU (152 mg, 0.40 mmol) and diisopropylethylamine (77 mg, 0.60 mmol) were added to the solution, and reacted at room temperature for 2 hours.

-1-基)-3-(-4-(-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率78.2%)。LCMS：RT=3.45min,[M+H]⁺=937.28。 After the reaction is over, add water (10 ml) to quench, extract with ethyl acetate (40 ml × 2 times), combine the organic phases, wash with water (40 ml × 2 times) and saturated brine (50 ml), and dry with anhydrous sodium sulfate The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1). Obtain 110 mg of light yellow oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield 78.2%). LCMS: RT=3.45min, [M+H] ⁺ =937.28.

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(-4-(-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(110毫克，0.12毫摩爾)的二氯甲烷(4.0毫升)溶液中加入三氟乙酸(1.0毫升)，加畢，室溫反應1小時。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-(-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

-1-yl) phenyl) propylamino) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (110 mg, 0.12 mmol) in dichloromethane (4.0 ml) was added three Fluoroacetic acid (1.0 ml), after the addition, react at room temperature for 1 hour.

-1-基)-3-(4-(4-(3-(羥甲基)環丁基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸三氟乙酸鹽。(收率74.5%)。LCMS：RT=2.69min,[M+H]⁺=781.08。¹H NMR(400MHz,DMSO)δ 11.75(s,1H),10.15(s,1H),9.77(s,1H),8.00(s,1H),7.94(d,J=2.2Hz,1H),7.81(d,J=8.5Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.41-7.29(m,5H),7.07(d,J=1.5Hz,1H),5.43-5.30(m,1H),3.70-3.58(m,13H),3.38(d,J=5.1Hz,2H),2.39-2.25(m,2H),2.19-2.08(m,1H),2.04-1.91(m,2H)。 Concentrated under reduced pressure, the obtained crude product was dissolved in dichloromethane (1.0 ml), and added dropwise to n-hexane (10.0 ml). A white solid precipitated out. The filter cake was washed with n-hexane and dried to obtain 78 mg of white solid. (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid trifluoroacetate. (Yield 74.5%). LCMS: RT=2.69min, [M+H] ⁺ =781.08. ¹ H NMR (400MHz, DMSO) δ 11.75 (s, 1H), 10.15 (s, 1H), 9.77 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=2.2Hz, 1H), 7.81 (d, J =8.5Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.41-7.29(m,5H),7.07(d, J =1.5Hz,1H),5.43-5.30( m, 1H), 3.70-3.58 (m, 13H), 3.38 (d, J = 5.1 Hz, 2H), 2.39-2.25 (m, 2H), 2.19-2.08 (m, 1H), 2.04-1.91 (m, 2H).

Example 21

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

Step A: Synthesis of (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate

At room temperature, to a solution of dichloromethane (20.0 mL) containing (tetrahydrofuran-3-yl)methanol (1.00 g, 10.0 mmol) and triethylamine (3.04 g, 30.0 mmol) was added p-toluenesulfonate Chlorine (2.86 g, 15.0 mmol), after the addition, react at room temperature for 5 hours.

After the reaction, it was diluted with dichloromethane (150 mL), washed with water (80 mL), saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution). Agent: n-hexane/ethyl acetate=4/1). 2.1 g of light yellow oily (tetrahydrofuran-3-yl)methyl 4-methylbenzenesulfonate was obtained (yield 81.9%). LCMS: RT=3.72min, [M+H] ⁺ =257.07.

-2-酮

Step B: Synthesis of 4-((tetrahydrofuran-3-yl)methyl)piper

-2-one

-2-酮(2.1克，21.0毫摩爾)和(四氫呋喃-3-基)甲基4-甲基苯磺酸酯(3.7克，14.0毫摩爾)的乙腈(50.0毫升)溶液中加入 碳酸鉀(3.9克，28.0毫摩爾)和碘化鈉(105毫克，0.7毫摩爾)，加畢，加熱至80℃反應6小時。 At room temperature, to contain piper

-2-one (2.1 g, 21.0 mmol) and (tetrahydrofuran-3-yl) methyl 4-methylbenzenesulfonate (3.7 g, 14.0 mmol) in acetonitrile (50.0 mL) was added potassium carbonate ( 3.9 g, 28.0 mmol) and sodium iodide (105 mg, 0.7 mmol), after the addition, heat to 80°C to react for 6 hours.

-1-基)環丁烷-1-羧酸甲酯(收率66.7%)。LCMS：RT=0.67min,[M+H]⁺=185.13。 After the reaction is complete, filter, and concentrate the filtrate under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent: dichloromethane/methanol=10/1). Obtain 1.7 g of light yellow oily 3-(3-oxopiperidin

-1-yl)cyclobutane-1-carboxylic acid methyl ester (yield 66.7%). LCMS: RT=0.67min, [M+H] ⁺ =185.13.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(542毫克，0.90毫摩爾)、3-(3-氧代哌

-1-基)環丁烷-1-羧酸甲酯(331毫克，1.8毫摩爾)的甲苯(4.5毫升)溶液中加入碘化亞銅(171毫克，0.90毫摩爾)，碳酸銫(590毫克，1.8毫摩爾)，N ¹ ,N ² -二甲基乙二胺(158毫克，1.8毫摩爾)，加畢，加熱至110℃反應過夜。 Under the protection of nitrogen, to contain (S)-3-(4-bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxo Piper

-1-yl) tert-butyl propionate (542 mg, 0.90 mmol), 3-(3-oxopiper

-1-yl) cyclobutane-1-methyl carboxylate (331 mg, 1.8 mmol) in toluene (4.5 mL) was added cuprous iodide (171 mg, 0.90 mmol), cesium carbonate (590 mg , 1.8 mmol), N ¹ , N ² -dimethylethylenediamine (158 mg, 1.8 mmol), after the addition, heat to 110°C and react overnight.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(62.9%)。 LCMS：RT=3.67min,[M+H]⁺=706.06。 After the reaction was completed, it was quenched by adding water (5 mL), extracted with ethyl acetate (40 mL×2 times), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The material was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1). Obtain 400 mg of light yellow oil (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (62.9%). LCMS: RT=3.67 min, [M+H] ⁺ =706.06.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(400毫克，0.56毫摩爾)的二氯甲烷(4.0毫升)溶液中加入二甲基巴比妥酸(700毫克，4.48毫摩爾)，四三苯基膦鈀(32毫克，0.027毫摩爾)，加畢，加熱至40℃反應過夜。 Under the protection of nitrogen, add (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (400 mg, 0.56 mmol) in dichloromethane (4.0 ml) was added dimethyl barbituric acid (700 mg, 4.48 mmol), four three Phenylphosphine palladium (32 mg, 0.027 mmol), after the addition, heat to 40°C and react overnight.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(85.6%)。LCMS：RT=3.08min,[M+H]⁺=626.58。 After the reaction is complete, dilute with dichloromethane (100ml), wash with saturated sodium bicarbonate (50ml) and saturated brine (50ml) successively, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and apply a silica gel column to the residue. Chromatographic purification (eluent: dichloromethane/methanol=30/1). Obtain 300 mg of light yellow oil (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (85.6%). LCMS: RT=3.08min, [M+H] ⁺ =626.58.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁基酯

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl) phenyl) tert-butyl propionate

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(300毫克，0.48毫摩爾)乙酸(1.0毫升)溶液中加入原甲酸三乙酯(427毫克，2.88毫摩爾)，疊氮化鈉(156毫克，2.4毫摩爾)，加畢，加熱至80℃反應2小時。 Under the protection of nitrogen, add (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (300 mg, 0.48 mmol) in acetic acid (1.0 mL) was added triethyl orthoformate (427 mg, 2.88 mmol), sodium azide (156 mg , 2.4 mmol), after the addition, heat to 80°C and react for 2 hours.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁基酯(收率61.4%)。LCMS：RT=3.03min,[M+H]⁺=679.32。 After the reaction is over, add sodium nitrite (200 mg) for quenching, extract with ethyl acetate (40 ml×2 times), combine the organic phases, wash with saturated brine (50 ml), dry with anhydrous sodium sulfate, and evaporate the solvent under reduced pressure The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1). Obtain 200 mg of light yellow oil (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)propionic acid tert-butyl ester (yield 61.4%). LCMS: RT=3.03min, [M+H] ⁺ =679.32.

-1-基)-3-(4-((四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step F: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙酸叔丁基酯(200毫克，0.29毫摩爾)的二氯甲烷(8.0毫升)溶液中加入三氟乙酸(2.0毫升)，加畢，室溫反應2小時。減壓濃縮，所得粗產物直接用於下一步反應。LCMS：RT=1.57min,[M-H]^-=621.11。 At room temperature, add (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

Trifluoroacetic acid (2.0 ml) was added to a solution of tert-butyl -1-yl)phenyl)propionate (200 mg, 0.29 mmol) in dichloromethane (8.0 ml), after the addition, the reaction was carried out at room temperature for 2 hours. It was concentrated under reduced pressure, and the obtained crude product was directly used in the next reaction. LCMS: RT=1.57min, [MH] ^- =621.11.

The above crude product and di-tert-butyl 5-amino-1 H -indole-1,2-dicarboxylate (199 mg, 0.60 mmol) were dissolved in anhydrous N,N -dimethylformamide (3.0 ml ), HATU (228 mg, 0.60 mmol) and diisopropylethylamine (116 mg, 0.90 mmol) were added to the solution, and reacted at room temperature for 2 hours.

-1-基)-3-(4-((四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率55.4%)。LCMS：RT=3.76min,[M+H]⁺=937.50。 After the reaction is over, add water (10 mg) to quench, extract with ethyl acetate (40 ml × 2 times), combine the organic phases, wash with water (40 ml × 2 times) and saturated brine (50 ml), and dry with anhydrous sodium sulfate The solvent was evaporated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1). Obtain 153 mg of light yellow oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield 55.4%). LCMS: RT=3.76min, [M+H] ⁺ =937.50.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(153毫克，0.16毫摩爾)的二氯甲烷(4.0毫升)溶液中加入三氟乙酸(1.0毫升)，加畢，室溫反應1小時。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((tetrahydrofuran-3-yl)methyl-2-oxopiper

-1-yl) phenyl) propylamino) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (153 mg, 0.16 mmol) in dichloromethane (4.0 ml) was added three Fluoroacetic acid (1.0 ml), after the addition, react at room temperature for 1 hour.

-1-基)-3-(4-(4-(四氫呋喃-3-基)甲基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸三氟乙酸鹽。(收率67.2%)。LCMS：RT=2.81min,[M-H]^-=779.13。¹H NMR(400MHz,DMSO)δ 11.74(s,1H),10.15(s,1H),9.77(s,1H),8.00(s,1H),7.94(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.43-7.26(m,6H),7.07(d,J=1.5Hz,1H),5.46-5.30(m,1H),4.23-3.52(m,15H),3.45(t,J=8.4Hz,1H),3.36(dd,J=14.4,5.2Hz,1H),3.14(dd,J=14.8,10.0Hz,1H),2.74-2.67(m,1H),2.15-2.06(m,1H),1.69-1.59(m,1H)。 Concentrated under reduced pressure, the obtained crude product was dissolved in dichloromethane (1.0 mL), and added dropwise to n-hexane (10.0 mL). A white solid precipitated out. The filter cake was filtered with suction and washed with n-hexane and dried to obtain 98 mg of white solid. (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid trifluoroacetate. (Yield 67.2%). LCMS: RT=2.81min, [MH] ^- =779.13. ¹ H NMR (400MHz, DMSO) δ 11.74 (s, 1H), 10.15 (s, 1H), 9.77 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.82 (d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.43-7.26(m,6H),7.07(d, J =1.5Hz,1H),5.46-5.30( m,1H),4.23-3.52(m,15H),3.45(t, J =8.4Hz,1H), 3.36(dd, J =14.4,5.2Hz,1H),3.14(dd, J =14.8,10.0Hz ,1H),2.74-2.67(m,1H),2.15-2.06(m,1H),1.69-1.59(m,1H).

Example 22

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(3-(4-(4-(carboxymethoxy)piperidine-1-carboxamide)phenyl)-2-(4-(5-chloro-2-(1 H -Tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(3-(4-(4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-methanamide Yl)phenyl)-2-(4-(5-)chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(100毫克，0.11毫摩爾)和叔丁基哌啶-4-基碳酸酯(277毫克，1.4毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(284毫克，2.2毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (100 mg, 0.11 mmol) and tert-butylpiperidin-4-yl carbonate (277 mg, 1.4 mmol) in tetrahydrofuran (6.0 mL) was added dropwise N,N -diisopropylethylamine (284 mg, 2.2 mmol) ), after dripping, react overnight at 60°C.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：45.0%)。LCMS：RT=4.48min,[M+H]⁺=1011.4。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/3). Obtain 50 mg of white solid (S)-5-(3-(4-(4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxamido)phenyl )-2-(4-(5-)chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 45.0%). LCMS: RT=4.48 min, [M+H] ⁺ =1011.4.

-1-基)丙醯胺基)-1H-吲哚-2-羧 酸

Step B: Synthesis of (S)-5-(3-(4-(4-(carboxymethoxy)piperidine-1-carboxamide)phenyl)-2-(4-(5-chloro-2- (1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(50毫克，0.05毫摩爾)加入二氯甲烷(5.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。 At room temperature, (S)-5-(3-(4-(4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxamido)phenyl )-2-(4-(5-)chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (50 mg, 0.05 mmol) was added to dichloromethane (5.0 mL), and trifluoroacetic acid was added dropwise (1.0 mL), react at room temperature for 3 hours.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸(收率：91.0%)。LCMS：RT=3.25min,[M-H]^-=797.26。¹H NMR(400MHz,DMSO)δ 12.74(s,2H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.47(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.50-7.35(m,3H),7.32(dd,J=8.9,1.8Hz,1H),7.14(d,J=8.1Hz,2H),7.06(d,J=1.6Hz,1H),5.30(dd,J=9.8,5.8Hz,1H),4.06(s,2H),3.97-3.67(m,5H),3.61-3.52(m,2H),3.30-3.18(m,1H),3.17-2.91(m,3H),1.85(dd,J=11.2,6.7Hz,2H),1.42(dd,J=14.0,6.9Hz,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 35 mg of white solid (S)-5-(3-(4-(4-(carboxymethoxy)piperidine-1-methanoamino)phenyl)-2-( 4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid (yield: 91.0%). LCMS: RT=3.25min, [MH] ^- =797.26. ¹ H NMR (400MHz, DMSO) δ 12.74 (s, 2H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H) ,7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.2Hz,1H),7.50-7.35(m,3H),7.32( dd, J =8.9,1.8Hz,1H),7.14(d, J =8.1Hz,2H),7.06(d, J =1.6Hz,1H),5.30(dd, J =9.8,5.8Hz,1H), 4.06(s,2H),3.97-3.67(m,5H),3.61-3.52(m,2H),3.30-3.18(m,1H),3.17-2.91(m,3H),1.85(dd, J =11.2 ,6.7Hz,2H),1.42(dd, J =14.0,6.9Hz,2H).

Example 23

-1- 基)-3-(4-(4-((2-羥乙基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)aminomethanyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-2-carboxylic acid

-1-基)-3-(4-(4-((2-羥乙基)氨甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-((2-hydroxyethyl)carbamyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole- Di-tert-butyl 1,2-dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(133毫克，0.15毫摩爾)和N-(2-羥乙基)哌啶-4-甲醯胺鹽酸鹽(312毫克，1.5毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(387毫克，3.0毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (133 mg, 0.15 mmol) and N- (2-hydroxyethyl)piperidine-4-carboxamide hydrochloride (312 mg, 1.5 mmol) in tetrahydrofuran (6.0 mL) was added dropwise N,N -diisopropyl Ethylamine (387 mg, 3.0 mmol) was dripped and reacted overnight at 60°C.

-1-基)-3-(4-(4-((2-羥乙基)氨甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：38.1%)。LCMS：RT=4.02min,[M+H]⁺=968.23。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH=10/1). Obtain 55.3 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)carbamyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole- Di-tert-butyl 1,2-dicarboxylic acid (yield: 38.1%). LCMS: RT=4.02min, [M+H] ⁺ =968.23.

-1-基)-3-(4-(4-((2-羥乙基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)aminomethanyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-2-carboxylic acid

-1-基)-3-(4-(4-((2-羥乙基)氨甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(53.3毫克，0.06毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)carbamyl)piperidine-1-carboxamide)phenyl)propionylamino)-1 H -indole- Di-tert-butyl 1,2-dicarboxylate (53.3 mg, 0.06 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-((2-羥乙基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：95.7%。LCMS：RT=3.07min,[M+H]⁺=812.30。¹H NMR(500MHz,DMSO)δ 10.59(s,1H),9.40(s, 1H),7.81(s,1H),7.47(s,1H),6.13(s,1H),5.69(s,1H),5.64(d,J=2.2Hz,1H),5.51(d,J=8.6Hz,1H),5.49-5.43(m,1H),5.09(t,J=7.5Hz,3H),5.06(s,2H),5.02(dd,J=9.0,1.8Hz,2H),4.84(d,J=7.8Hz,1H),4.75(d,J=1.7Hz,1H),3.44(s,1H),2.99(dd,J=9.7,5.9Hz,1H),2.31(t,J=5.3Hz,3H),1.80(d,J=13.8Hz,3H),1.43(s,2H),1.07(dd,J=11.8,6.0Hz,1H),0.97-0.88(m,1H),0.82-0.77(m,2H),0.70(dd,J=14.2,9.3Hz,2H),0.47(t,J=12.2Hz,3H),0.23(s,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 42.7 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)aminomethanyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-2-carboxylic acid (yield: 95.7%. LCMS: RT=3.07min, [M+H] ⁺ =812.30. ¹ H NMR (500MHz, DMSO) δ 10.59 (s, 1H), 9.40 (s, 1H) ),7.81(s,1H),7.47(s,1H),6.13(s,1H),5.69(s,1H),5.64(d, J =2.2Hz,1H),5.51(d, J =8.6Hz ,1H),5.49-5.43(m,1H),5.09(t, J =7.5Hz,3H),5.06(s,2H),5.02(dd, J =9.0,1.8Hz,2H),4.84(d, J =7.8Hz,1H),4.75(d, J =1.7Hz,1H),3.44(s,1H),2.99(dd, J =9.7,5.9Hz,1H),2.31(t, J =5.3Hz, 3H),1.80(d, J =13.8Hz,3H),1.43(s,2H),1.07(dd, J =11.8,6.0Hz,1H),0.97-0.88(m,1H),0.82-0.77(m , 2H), 0.70 (dd, J =14.2, 9.3 Hz, 2H), 0.47 (t, J =12.2 Hz, 3H), 0.23 (s, 1H).

Example 24

-1-基)-3-(4-(4-((2-羥乙基)(甲基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-((2-hydroxyethyl)(methyl)aminocarboxyl)piperidine-1-carboxamido)phenyl)propanamido)- 1 H -Indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(4-((2-羥基乙基)(甲基)氨基甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-((2-hydroxyethyl)(methyl)aminomethanyl)piperidine-1-carboxamido)phenyl)propionylamino)-1H- Indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(89毫克，0.1毫摩爾)和N-(2-羥乙基)-N-甲基哌啶-4-甲醯胺(300毫克，1.0毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(258毫克，2.0毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (89 mg, 0.1 mmol) and N- (2-hydroxyethyl)-N-methylpiperidine-4-carboxamide (300 mg, 1.0 mmol) in tetrahydrofuran (6.0 mL) was added dropwise N,N -diiso Propylethylamine (258 mg, 2.0 mmol) was dripped and reacted overnight at 60°C.

-1-基)-3-(4-(4-((2-羥基乙基)(甲基)氨基甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：43.2%)。LCMS：RT=3.39min,[M+H]⁺=982.38。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH=10/1). Obtain 42.2 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)(methyl)aminocarboxyl)piperidine-1-carboxamido)phenyl)propionylamino)-1 H -Indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 43.2%). LCMS: RT=3.39 min, [M+H] ⁺ =982.38.

-1-基)-3-(4-(4-((2-羥乙基)(甲基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-((2-hydroxyethyl)(methyl)aminocarboxyl)piperidine-1-carboxamido)phenyl)propanamido)- 1H-Indole-2-carboxylic acid

-1-基)-3-(4-(4-((2-羥基乙基)(甲基)氨基甲醯基)哌啶-1-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(42.2毫克，0.04毫摩爾)加入二氯甲烷(4.0 毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-((2-hydroxyethyl)(methyl)aminocarboxyl)piperidine-1-carboxamido)phenyl)propionylamino)-1 H -Di-tert-butyl indole-1,2-dicarboxylate (42.2 mg, 0.04 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-((2-羥乙基)(甲基)氨基甲醯基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：96.1%)。LCMS：RT=2.75min,[M-H]^-=826.23。¹H NMR(500MHz,DMSO)δ 12.90(s,1H),11.72(s,1H),10.14(s,1H),9.80(s,1H),8.56-8.21(m,3H),8.02(s,1H),7.96(t,J=2.3Hz,1H),7.84(dd,J=8.6,4.5Hz,1H),7.78(dt,J=8.6,2.6Hz,1H),7.47-7.37(m,3H),7.35(dd,J=8.6,2.7Hz,1H),7.18(t,J=14.1Hz,2H),7.09(t,J=8.4Hz,1H),5.41-5.19(m,2H),4.32-4.18(m,1H),4.05(dd,J=24.7,16.2Hz,3H),3.75(s,2H),3.66-3.52(m,2H),2.67-2.56(m,3H),2.05-1.93(m,2H),1.87(dd,J=30.9,12.8Hz,2H),1.74-1.61(m,1H),1.62-1.41(m,3H),0.87(t,J=6.9Hz,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 31.8 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(4-(4-((2-hydroxyethyl)(methyl)aminocarboxyl)piperidine-1-carboxamido)phenyl)propanamido)- 1 H -Indole-2-carboxylic acid (yield: 96.1%). LCMS: RT=2.75min, [MH] ^- =826.23. ¹ H NMR (500MHz, DMSO) δ 12.90 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.80 (s, 1H), 8.56-8.21 (m, 3H), 8.02 (s, 1H),7.96(t, J =2.3Hz,1H),7.84(dd, J =8.6,4.5Hz,1H),7.78(dt, J =8.6,2.6Hz,1H),7.47-7.37(m,3H ),7.35(dd, J =8.6,2.7Hz,1H),7.18(t, J =14.1Hz,2H),7.09(t, J =8.4Hz,1H),5.41-5.19(m,2H),4.32 -4.18 (m, 1H), 4.05 (dd, J = 24.7, 16.2 Hz, 3H), 3.75 (s, 2H), 3.66-3.52 (m, 2H), 2.67-2.56 (m, 3H), 2.05-1.93 (m, 2H), 1.87 (dd, J = 30.9, 12.8 Hz, 2H), 1.74-1.61 (m, 1H), 1.62-1.41 (m, 3H), 0.87 (t, J = 6.9 Hz, 1H).

Example 25

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole-2-carboxy acid

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(133毫克，0.15毫摩爾)和3-氨基-3-甲基丁-1-醇(154毫克，0.75毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(387毫克，1.5毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (133 mg, 0.15 mmol) and 3-amino-3-methylbutan-1-ol (154 mg, 0.75 mmol) in tetrahydrofuran (6.0 mL) were added dropwise N,N -diisopropylethylamine (387 mg, 1.5 Millimoles), after dripping, react overnight at 60°C.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：38.4%)。LCMS：RT=3.39min,[M+H]⁺=982.38。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH=10/1). Obtain 56.6 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (yield: 38.4%). LCMS: RT=3.39 min, [M+H] ⁺ =982.38.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole-2-carboxy acid

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(55.6毫克，0.06毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (55.6 mg, 0.06 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：92.4%)。LCMS：RT=3.28min,[M-H]^-=741.15。¹H NMR(500MHz,DMSO)δ 12.92(s,1H),11.72(s,1H),10.13(s,1H),9.80(s,1H),8.27(s,1H),8.04-7.94(m,2H),7.83(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.39(d,J=8.8Hz,1H),7.37-7.29(m,2H),7.10(dd,J=27.1,4.3Hz,3H),5.98(s,1H),5.29(dd,J=9.9,5.7Hz,2H),4.38(t,J=4.9Hz,1H),3.74(s,2H),3.51(dd,J=12.0,7.0Hz,2H),3.27-3.15(m,1H),3.01(dd,J=15.8,10.4Hz,3H),1.82(t,J=7.1Hz,2H),1.27(d,J=13.5Hz,6H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 43.1 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole-2-carboxy Acid (yield: 92.4%). LCMS: RT=3.28min, [MH] ^- =741.15. ¹ H NMR(500MHz,DMSO)δ 12.92(s,1H), 11.72(s,1H), 10.13(s,1H), 9.80(s,1H), 8.27(s,1H), 8.04-7.94(m, 2H), 7.83(d, J =8.6Hz,1H), 7.78(dd, J =8.6,2.3Hz,1H), 7.39(d, J =8.8Hz,1H), 7.37-7.29(m,2H), 7.10 (dd, J = 27.1, 4.3 Hz, 3H), 5.98 (s, 1H), 5.29 (dd, J = 9.9, 5.7 Hz, 2H), 4.38 (t, J = 4.9 Hz, 1H), 3.74 (s ,2H),3.51(dd, J =12.0,7.0Hz,2H),3.27-3.15(m,1H),3.01(dd, J =15.8,10.4Hz,3H),1.82(t, J =7.1Hz, 2H), 1.27(d, J =13.5Hz, 6H).

Example 26

-1-基)-3-(4-(3-((2R，3R)-1,3-二羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2R,3R)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((2S，3S)-1,3-二羥基丁-2-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((2S,3S)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole- Di-tert-butyl 1,2-dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(78毫克，0.2毫摩爾)和(2R,3S)-2-氨基丁烷-1,3-二醇(210毫克，2.0毫摩爾)的四氫呋喃(6.0毫升)中滴加N,N-二異丙基乙胺(5.6毫克，0.04毫摩爾)，滴畢，60℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (78 mg, 0.2 mmol) and (2R,3S)-2-aminobutane-1,3-diol (210 mg, 2.0 mmol) in tetrahydrofuran (6.0 mL) was added dropwise N,N -diisopropylethylamine (5.6 mg, 0.04 mmol), after dripping, react overnight at 60°C.

-1-基)-3-(4-(3-((2S，3S)-1,3-二羥基丁-2-基)脲基)苯基)丙醯 氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：36.4%)。LCMS：RT=4.05min,[M+H]⁺=901.33。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH=10/1). Obtain 65.7 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole- Di-tert-butyl 1,2-dicarboxylic acid (yield: 36.4%). LCMS: RT=4.05min, [M+H] ⁺ =901.33.

-1-基)-3-(4-(3-((2R，3R)-1,3-二羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2R,3R)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((2S，3S)-1,3-二羥基丁-2-基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(65.7毫克，0.07毫摩爾)加入二氯甲烷(4.0毫升)中，滴加三氟乙酸(1.0毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole- Di-tert-butyl 1,2-dicarboxylate (65.7 mg, 0.07 mmol) was added to dichloromethane (4.0 mL), trifluoroacetic acid (1.0 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((2R，3R)-1,3-二羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：96.5%)。LCMS：RT=3.09min,[M+H]⁺=745.27。¹H NMR(400MHz,DMSO)δ 12.93(s,2H),11.73(s,1H),10.15(s,1H),9.80(s,1H),8.69(s,1H),8.01(s,1H),7.96(d,J=2.3Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.41-7.30(m,3H),7.26-7.02(m,3H),5.97(d,J=8.3Hz,1H),5.36-5.19(m,1H),3.97(dt,J=14.1,7.1Hz,2H),3.39 (d,J=11.8Hz,3H),3.25-3.12(m,1H),3.09-2.92(m,1H),1.99(dt,J=7.9,2.2Hz,1H),1.24(s,4H),1.06(d,J=6.4Hz,2H),0.86(t,J=5.4Hz,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 52.4 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((2R,3R)-1,3-dihydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid (yield: 96.5%). LCMS: RT=3.09min, [M+H] ⁺ =745.27. ¹ H NMR (400MHz, DMSO) δ 12.93 (s, 2H), 11.73 (s, 1H), 10.15 (s, 1H), 9.80 (s, 1H), 8.69 (s, 1H), 8.01 (s, 1H) ,7.96(d, J =2.3Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.41-7.30(m,3H),7.26- 7.02(m,3H),5.97(d, J =8.3Hz,1H),5.36-5.19(m,1H),3.97(dt, J =14.1,7.1Hz,2H), 3.39 (d, J =11.8Hz) ,3H),3.25-3.12(m,1H),3.09-2.92(m,1H),1.99(dt, J =7.9,2.2Hz,1H),1.24(s,4H),1.06(d, J =6.4 Hz, 2H), 0.86 (t, J = 5.4 Hz, 1H).

Example 27

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows: Step A: Synthesis of tert-butyl (S)-2-amino-3-(4-bromophenyl)propionate

(S)-2-amino-3-(4-bromophenyl)propionic acid (10.0 g, 41.1 mmol) was dissolved in a solution of tert-butyl propionate (70.0 mL). Subsequently, 70% mass fraction of perchloric acid (6.1 g, 61.7 mmol) was added to the above solution, and nitrogen was replaced 3 times. Stir overnight at room temperature.

The reaction solution was slowly added dropwise to saturated sodium bicarbonate solution (250 mL) to quench the reaction. The mixture was extracted with ethyl acetate (200 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (100 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. 11.5 g of tert-butyl (S)-2-amino-3-(4-bromophenyl)propionate was obtained as a yellow oil (yield: 93.50%). LCMS: RT=2.80 min, [M+H] ⁺ =300.05.

Step B: Synthesis of tert-butyl (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionate

(S)-2-amino-3-(4-bromophenyl)-tert-butyl propionate (11.50 g, 38.3 mmol) and sodium hydroxide (3.16 g, 76.6 mmol) were dissolved in tetrahydrofuran (20 mL) And water (10 ml) mixed solution. Subsequently, di-tert-butyl dicarbonate (10.30 g, 4.1 mmol) was added to the above solution. Stir at room temperature for 1 hour.

Saturated ammonium chloride solution (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (50 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). 9.80 g of solid tert-butyl (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionate was obtained (yield: 64.0%).

-2-酮

Step C: Synthesis of 4-isopropylpiperidine

-2-one

-2-酮(11.0克，55.5毫摩爾)溶於甲醇(20.0毫升)和乙酸(0.5毫升)的混合溶液中。隨後，向上述溶液中加入丙酮(6.78克，111.0毫摩爾)和氰基硼氫化鈉(4.19克，66.6毫摩爾)。在60℃下攪拌過夜。 Piperazine

-2-one (11.0 g, 55.5 mmol) was dissolved in a mixed solution of methanol (20.0 mL) and acetic acid (0.5 mL). Subsequently, acetone (6.78 g, 111.0 mmol) and sodium cyanoborohydride (4.19 g, 66.6 mmol) were added to the above solution. Stir at 60°C overnight.

-2-酮(收率：38.0%)。LCMS：RT=0.83min，[M+H]⁺=143.11。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 3.00 g of white solid 4-isopropylpiperidine

-2-one (yield: 38.0%). LCMS: RT=0.83 min, [M+H] ⁺ =143.11.

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)tert-butyl propionate

-2-酮(5.68克，40.0摩爾)溶於甲苯(100毫升)的溶液中。隨後，向上述溶液中加入N,N-二甲基乙-1,2-二胺(3.50克，40.0毫摩爾)，碘化亞銅(3.80克，20.0毫摩爾)和碳酸銫(13.00克，40.0毫摩爾)。在110℃下攪拌18個小時。 Combine (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino) propionic acid tert-butyl ester (8.00 g, 20.0 mmol) and 4-isopropylpiper

The -2-one (5.68 g, 40.0 mol) was dissolved in a solution of toluene (100 ml). Subsequently, N,N -dimethylethyl-1,2-diamine (3.50 g, 40.0 mmol), cuprous iodide (3.80 g, 20.0 mmol) and cesium carbonate (13.00 g, 40.0 mmol). Stir at 110°C for 18 hours.

-1-基)苯基)丙酸叔丁酯(收率：35.0%)。LCMS：RT=3.55min，[M+H]⁺=462.30。 Saturated ammonium chloride solution (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (150 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (100 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). Obtain 3.25 g of yellow solid (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-isopropyl-2-oxopiperidin)

-1-yl)phenyl)tert-butyl propionate (yield: 35.0%). LCMS: RT=3.55min, [M+H] ⁺ =462.30.

-1-基)苯基)丙酸叔丁酯鹽酸鹽

Step E: Synthesis of (S)-2-amino-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)tert-butyl propionate hydrochloride

-1-基)苯基)丙酸叔丁酯(4.00克，8.67毫摩爾)溶於乙酸乙酯(35.0毫升)中。隨後，向上述溶液中加入鹽酸乙酸乙酯溶液(2摩爾/升，8.6毫升，17.36毫摩爾)。在室溫下攪拌8小時。 Add (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-isopropyl-2-oxopiper)

1-yl)phenyl)tert-butyl propionate (4.00 g, 8.67 mmol) was dissolved in ethyl acetate (35.0 mL). Subsequently, a hydrochloric acid ethyl acetate solution (2 mol/L, 8.6 mL, 17.36 mmol) was added to the above solution. Stir at room temperature for 8 hours.

-1-基)苯基)丙酸叔丁酯鹽酸鹽(收率：80.0%)。 The reaction solution was concentrated under reduced pressure. Obtained 2.50 g of solid (S)-2-amino-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propionic acid tert-butyl hydrochloride (yield: 80.0%).

-1-基)苯基)丙酸叔丁酯

Step F: Synthesis of (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-(4 -Isopropyl-2-oxopiperidin

-1-yl)phenyl)tert-butyl propionate

-1-基)苯基)丙酸叔丁酯鹽酸鹽(2.00克，5.5毫摩爾)和2-((5-氯-2-(二烯丙基氨基)苯基)氨基)-2-氧代乙酸(1.96克，6.6摩爾)溶於N,N-二甲基甲醯胺(20.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(3.20克，8.3毫摩爾)，N,N-二異丙基乙胺(1.40克，11.0毫摩爾)，在室溫下攪拌18個小時。 Add (S)-2-amino-3-(4-(4-isopropyl-2-oxopiper)

-1-yl) phenyl) tert-butyl propionate hydrochloride (2.00 g, 5.5 mmol) and 2-((5-chloro-2-(diallylamino)phenyl)amino)-2- Oxoacetic acid (1.96 g, 6.6 moles) was dissolved in a solution of N,N -dimethylformamide (20.0 ml). Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (3.20 g, 8.3 mmol) was added to the above solution, N,N -Diisopropylethylamine (1.40 g, 11.0 mmol), stirred at room temperature for 18 hours.

-1-基)苯基)丙酸叔丁酯(收率：50.0%)。LCMS：RT=3.65min，[M+H]⁺=638.30。 Saturated ammonium chloride solution (100 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (50 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (100 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). 1.80 g of white solid (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-( 4-isopropyl-2-oxopiperidine

-1-yl)phenyl)tert-butyl propionate (yield: 50.0%). LCMS: RT = 3.65 min, [M+H] ⁺ =638.30.

-1-基)-3-(4-(4-異丙基-2-氧代哌

)-叔丁基嗪-1-基)苯基)丙酸叔丁酯

Step G: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

)-Tert-Butylazin-1-yl)phenyl)tert-butyl propionate

-1-基)叔丁基基)苯基)丙酸叔丁酯(1.80克，2.8毫摩爾)和1,2-二溴乙烷(3.70克，19.7毫摩爾)溶於乙腈(20.0毫升)中。隨後，向上述溶液中加入碳酸鉀(2.70克，19.7毫摩爾)。在90℃下攪拌過夜。 (S)-2-(2-((5-Chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-(4-isopropyl 2-oxopiperidin

-1-yl)tert-butyl)phenyl)propionate (1.80g, 2.8mmol) and 1,2-dibromoethane (3.70g, 19.7mmol) dissolved in acetonitrile (20.0ml) middle. Subsequently, potassium carbonate (2.70 g, 19.7 mmol) was added to the above solution. Stir at 90°C overnight.

-1-基)-3-(4-(4-異丙基-2-氧代哌

)-叔丁基嗪-1-基)苯基)丙酸叔丁酯(收率：37.0%)。LCMS：RT=3.30min，[M+H]⁺=664.32。 The reaction solution was filtered, and the filter cake was washed with acetonitrile (50 ml×3 times). The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 500 mg of white oil (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

)-Tert-Butylazin-1-yl)phenyl)tert-butyl propionate (yield: 37.0%). LCMS: RT=3.30 min, [M+H] ⁺ =664.32.

-1-基)-3- (4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step H: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-異丙基-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(500毫克，0.86毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(587毫克，4.30毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(321毫克，0.05毫摩爾)。在40℃下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

)-1-yl)phenyl)tert-butyl propionate (500 mg, 0.86 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione Alkane (587 mg, 4.30 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (321 mg, 0.05 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：64.0%)。LCMS：RT=2.91min，[M+H]⁺=566.22。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 290 mg of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)tert-butyl propionate (yield: 64.0%). LCMS: RT=2.91min, [M+H] ⁺ =566.22.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step I: Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(150毫克，0.25毫摩爾)和原甲酸三乙酯(190毫克，1.28毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(83毫克，1.28毫摩爾)。在70℃下攪拌1小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

1-yl)phenyl)tert-butyl propionate (150 mg, 0.25 mmol) and triethyl orthoformate (190 mg, 1.28 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (83 mg, 1.28 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：73.0%)。LCMS：RT=2.90min，[M+H]⁺=637.24。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 120 mg of yellow solid (S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)tert-butyl propionate (yield: 73.0%). LCMS: RT=2.90min, [M+H] ⁺ =637.24.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸

Step J: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸叔丁酯(120毫克，0.20毫摩爾)溶於二氯 甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

1-yl)phenyl)tert-butyl propionate (120 mg, 0.20 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸(收率：91.0%)。 The reaction solution was concentrated under reduced pressure. Obtain 100 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propionic acid (yield: 91.0%).

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step K: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙酸(100毫克，0.2毫摩爾)和5-氨基-1H-吲哚-1,2-二羧酸二叔丁酯(69毫克，0.2摩爾)溶於N,N-二甲基甲醯胺(5.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(98毫克，0.3毫摩爾)，N,N-二異丙基乙胺(44毫克，0.4毫摩爾)，在室溫下攪拌18個小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propionic acid (100 mg, 0.2 mmol) and 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (69 mg, 0.2 mol) were dissolved in N ,N -dimethylformamide (5.0 mL) in a solution. Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (98 mg, 0.3 mmol) was added to the above solution, N,N -Diisopropylethylamine (44 mg, 0.4 mmol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(4-異丙基-2-氧代 哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：75.0%)。LCMS：RT=3.44min，[M+H]⁺=895.97。 Saturated ammonium chloride solution (10 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 115 mg of white oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 75.0%). LCMS: RT=3.44 min, [M+H] ⁺ =895.97.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step L: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propanamido)-1H-indole-2-carboxylic acid

-1-基)-3-二叔丁酯(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(115毫克，0.10毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-di-tert-butyl ester (4-(4-isopropyl-2-oxopiper)

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (115 mg, 0.10 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：60.0%)。LCMS：RT=2.71min，[M+H]⁺=739.40。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 57.6 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 60.0%). LCMS: RT=2.71min, [M+H] ⁺ =739.40.

Example 28

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1H-indole-2-carboxylic acid

The specific synthesis route is as follows:

Step A: Synthesis of (S)-3-(4-bromophenyl)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetin Amino) tert-butyl propionate

Combine (S)-2-amino-3-(4-bromophenyl) tert-butyl propionate (10.0 g, 33 mmol) and 2-((5-chloro-2-(diallylamino)benzene (Yl)amino)-2-oxoacetic acid (10.8 g, 36 mmol) was dissolved in a solution of N,N -dimethylformamide (100.0 ml). Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (19.0 g, 49 mmol) was added to the above solution, N, N -Diisopropylethylamine (8.6 mg, 66 mmol), stirred at room temperature for 18 hours.

Saturated ammonium chloride solution (200 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (100 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (100 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 12 grams of white solid (S)-3-(4-bromophenyl)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoethyl (Amino) tert-butyl propionate (yield: 62.0%). LCMS: RT=3.90min, [M+H] ⁺ =576.12.

-1-基)丙酸叔丁酯

Step B: Synthesis of (S)-3-(4-bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate

Add (S)-3-(4-bromophenyl)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)propyl Tert-butyl ester (12.0 g, 20.8 mmol) was dissolved in a solution of acetonitrile (100.0 ml). Subsequently, 1,2-dibromoethane (27.0 g, 148.0 mmol) and potassium carbonate (20.0 g, 145.0 mmol) were added to the above solution, and stirred at 90°C for 18 hours.

-1-基)丙酸叔丁酯(收率：29.5%)。LCMS：RT=3.85min，[M+H]⁺=602.13。 The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 3.7 g of colorless oil (S)-3-(4-bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxo Piper

-1-yl) tert-butyl propionate (yield: 29.5%). LCMS: RT = 3.85 min, [M+H] ⁺ =602.13.

-2-酮

Step C: Synthesis of 4-(4-methylcyclohexyl)piper

-2-one

-2-酮(1.0克，9.9毫摩爾)溶於甲醇(10.0毫升)和乙酸(0.2毫升)的混合溶液中。隨後，向上述溶液中加入4-甲基環己-1-酮(2.6克，19.9毫摩爾)和氰基硼氫化鈉(1.3克，19.9毫摩爾)。在60℃下攪拌過夜。 Piperazine

-2-one (1.0 g, 9.9 mmol) was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, 4-methylcyclohexan-1-one (2.6 g, 19.9 mmol) and sodium cyanoborohydride (1.3 g, 19.9 mmol) were added to the above solution. Stir at 60°C overnight.

-2-酮(收率：36.0%)。LCMS：RT=0.95min，[M+H]⁺=213.15。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 780 mg of white solid 4-(4-methylcyclohexyl)piperidine

-2-one (yield: 36.0%). LCMS: RT=0.95 min, [M+H] ⁺ =213.15.

-1-基)-3-(4-(4-(4-甲氧基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl))-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(1.0克，1.66毫摩爾)和4-(4-甲基環己基)哌

-2-酮(704毫克，3.22摩爾)溶於甲苯(15.0毫升)的溶液中。隨後，向上述溶液中加入N,N-二甲基乙-1,2-二胺(292毫克，3.22毫摩爾)，碘化亞銅(315毫克，1.66毫摩爾)和碳酸銫(1克，3.22毫摩爾)。在110℃下攪拌18個小時。 (S)-3-(4-Bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate (1.0 g, 1.66 mmol) and 4-(4-methylcyclohexyl)piper

-2-one (704 mg, 3.22 mol) was dissolved in a solution of toluene (15.0 ml). Subsequently, to the above solution was added N,N -dimethylethyl-1,2-diamine (292 mg, 3.22 mmol), cuprous iodide (315 mg, 1.66 mmol) and cesium carbonate (1 g, 3.22 mmol). Stir at 110°C for 18 hours.

-1-基)-3-(4-(4-(4-甲氧基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：90.0%)。LCMS：RT=3.44min，[M+H]⁺=734.33。 Saturated ammonium chloride solution (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (15 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). 1.1 g of yellow solid (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper was obtained

-1-yl)-3-(4-(4-(4-methoxycyclohexyl))-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 90.0%). LCMS: RT=3.44 min, [M+H] ⁺ =734.33.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯

Step E: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(4-甲氧基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯(1.1克，1.5毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(1.6克，10.0毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(103毫克，0.06毫摩爾)。在40℃下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl))-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (1.1 g, 1.5 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-triketone (1.6 g, 10.0 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (103 mg, 0.06 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(4-異丙基-2-氧代哌

-1-基)叔丁基酯基)苯基)丙酸叔丁酯(收率：45.0%)。LCMS：RT=3.05min，[M+H]⁺=654.30。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 450 mg of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(4-isopropyl-2-oxopiper)

-1-yl) tert-butyl ester group) phenyl) tert-butyl propionate (yield: 45.0%). LCMS: RT=3.05min, [M+H] ⁺ =654.30.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step F: Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(450毫克，0.68毫摩爾)和原甲酸三乙酯(713毫克，4.82毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(313毫克，4.82毫摩爾)。在70℃下攪拌1小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate (450 mg, 0.68 mmol) and triethyl orthoformate (713 mg, 4.82 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (313 mg, 4.82 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：71.0%)。LCMS：RT=3.05min，[M+H]⁺=707.31。 Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 330 mg of yellow solid (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 71.0%). LCMS: RT=3.05min, [M+H] ⁺ =707.31.

-1-基)-3-(4-(4-(4-(甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸

Step G: Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-(methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(330毫克，0.49毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

1-yl)phenyl)tert-butyl propionate (330 mg, 0.49 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(4-(甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸(收率：86.0%)。 The reaction solution was concentrated under reduced pressure. Obtain 280 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-(methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionic acid (yield: 86.0%).

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step H: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(4-(4-(甲氧基環己基)-2-氧代哌

-1-基)苯基)丙酸(280毫克，0.43毫摩爾)和5-氨基-1H-吲哚-1,2-二羧酸二叔丁酯(157毫克0.47摩爾)溶於N,N-二甲基甲醯胺(10.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(245毫克，0.64毫摩爾)，N,N-二異丙基乙胺(111毫克，0.86毫摩爾)，在室溫下攪拌18個小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-(methoxycyclohexyl)-2-oxopiper

-1-yl) phenyl) propionic acid (280 mg, 0.43 mmol) and 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (157 mg 0.47 mol) dissolved in N, N -dimethylformamide (10.0 ml) in solution. Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (245 mg, 0.64 mmol) was added to the above solution, N,N -Diisopropylethylamine (111 mg, 0.86 mmol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：103.0%)。LCMS：RT=3.57min，[M+H]⁺=865.40。 Saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 430 mg of colorless oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 103.0%). LCMS: RT=3.57 min, [M+H] ⁺ =865.40.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step I: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(430毫克，0.44毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (430 mg, 0.44 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(4-甲氧基環己基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：10.0%)。LCMS：RT=2.83min，[M+H]⁺=809.28。¹H NMR(500MHz,DMSO)δ 12.91(s,1H),11.73(s,1H),10.09(d,J=38.0Hz,2H),9.76(s,1H),7.99(s,1H),7.94(d,J=1.7Hz,1H),7.81(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.36(dt,J=19.8,8.6Hz,6H),7.06(t,J=4.0Hz,1H),5.38(s,1H),3.44-3.29(m,4H),3.23(t,J=8.0Hz,4H),3.13(dt,J=21.6,10.9Hz,2H),2.13(d,J=13.2Hz,2H),2.04-1.80(m,3H),1.65(t,J=51.2Hz,3H),1.44(t,J=13.0Hz,2H),1.33-1.09(m,2H)。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 34.2 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 10.0%). LCMS: RT=2.83min, [M+H] ⁺ =809.28. ¹ H NMR (500MHz, DMSO) δ 12.91 (s, 1H), 11.73 (s, 1H), 10.09 (d, J = 38.0Hz, 2H), 9.76 (s, 1H), 7.99 (s, 1H), 7.94 (d, J =1.7Hz,1H),7.81(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.36(dt, J =19.8,8.6Hz,6H) ,7.06(t, J =4.0Hz,1H),5.38(s,1H),3.44-3.29(m,4H),3.23(t, J =8.0Hz,4H),3.13(dt, J =21.6,10.9 Hz, 2H), 2.13 (d, J =13.2 Hz, 2H), 2.04-1.80 (m, 3H), 1.65 (t, J = 51.2 Hz, 3H), 1.44 (t, J =13.0 Hz, 2H), 1.33-1.09 (m, 2H).

Example 29

-1- 基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-2-酮

The specific synthesis route is as follows: Step A: Synthesis of 4-(2-methoxyethyl)piper

-2-one

-2-酮(2.0克，20.0毫摩爾)溶於乙腈(20.0毫升)中。隨後，向上述溶液中加入1-溴-2-甲氧基乙烷(5.6克，40.0毫摩爾)和碳酸鉀(5.5克，40.0毫摩爾)。在100℃下攪拌過夜。 Piperazine

-2-one (2.0 g, 20.0 mmol) was dissolved in acetonitrile (20.0 mL). Subsequently, 1-bromo-2-methoxyethane (5.6 g, 40.0 mmol) and potassium carbonate (5.5 g, 40.0 mmol) were added to the above solution. Stir overnight at 100°C.

-2-酮(收率：25.0%)。LCMS：RT=0.90min，[M+H]⁺=159.15。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 800 mg of white solid 4-(2-methoxyethyl)piperidine

-2-one (yield: 25.0%). LCMS: RT=0.90 min, [M+H] ⁺ =159.15.

-1-基)-3-(4-(4-(2-甲氧基乙基)-)2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step B: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-)2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(1.5克，2.5毫摩爾)和4-(2-甲氧基乙基)哌

-2-酮(767毫克，4.98毫摩爾)溶於甲苯(15.0毫升)的溶液中。隨後，向上述溶液中加入N，N-二甲基乙-1,2-二胺(438毫克，4.98毫摩爾)，碘化亞銅(473毫克，2.50毫摩爾)和碳酸銫(1.62克，4.98毫摩爾)。在110℃下攪拌18個小時。 (S)-3-(4-Bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate (1.5 g, 2.5 mmol) and 4-(2-methoxyethyl)piper

-2-one (767 mg, 4.98 mmol) was dissolved in a solution of toluene (15.0 mL). Subsequently, N,N-dimethylethyl-1,2-diamine (438 mg, 4.98 mmol), cuprous iodide (473 mg, 2.50 mmol) and cesium carbonate (1.62 g, 4.98 mmol). Stir at 110°C for 18 hours.

-1-基)-3-(4-(4-(2-甲氧基乙基)-)2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：48.0%)。LCMS：RT=3.36min，[M+H]⁺=680.31。 Saturated ammonium chloride solution (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (15 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). Obtain 700 mg of yellow solid (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-)2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 48.0%). LCMS: RT=3.36min, [M+H] ⁺ =680.31.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(2-甲氧基乙基)-)2-氧代哌

-1-基)苯基)丙酸叔丁酯(700毫克，1.0毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(964毫克，6.0毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(47毫克，0.04毫摩爾)。在40℃下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-)2-oxopiper

-1-yl) phenyl) tert-butyl propionate (700 mg, 1.0 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (964 mg, 6.0 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (47 mg, 0.04 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(收率：80.0%)。LCMS：RT=2.95min，[M+H]⁺=600.15。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 500 mg of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate (yield: 80.0%). LCMS: RT=2.95min, [M+H] ⁺ =600.15.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(500毫克，0.83毫摩爾)和原甲酸三乙酯(617毫克，4.17毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(270毫克，4.17毫摩爾)。在70℃下攪拌1小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate (500 mg, 0.83 mmol) and triethyl orthoformate (617 mg, 4.17 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (270 mg, 4.17 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：77.0%)。LCMS：RT=2.95min，[M+H]⁺=653.25。 Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 420 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 77.0%). LCMS: RT=2.95min, [M+H] ⁺ =653.25.

-1-基)-3-(4-(4-(2-(甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(methoxyethyl)-2-oxopiper

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(200毫克，0.4毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

1-yl)phenyl)tert-butyl propionate (200 mg, 0.4 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(2-(甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸(收率：95.0%)。 The reaction solution was concentrated under reduced pressure. Obtain 180 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(methoxyethyl)-2-oxopiper

-1-yl)phenyl)propionic acid (yield: 95.0%).

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step F: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(4-(2-(甲氧基乙基)-2-氧代哌

-1-基)苯基)丙酸(180毫克，0.30毫摩爾)和5-氨基-1H-吲哚-1,2-二羧酸二叔丁酯(361毫克0.36摩爾)溶於N,N-二甲基甲醯胺 (10.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)- N,N,N',N'-四甲基脲六氟磷酸鹽(171毫克，0.45毫摩爾)，N,N-二異丙基乙胺(77毫克，0.60毫摩爾)，在室溫下攪拌18個小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(methoxyethyl)-2-oxopiper

-1-yl) phenyl) propionic acid (180 mg, 0.30 mmol) and 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (361 mg 0.36 mol) dissolved in N, N -dimethylformamide (10.0 ml) in solution. Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (171 mg, 0.45 mmol) was added to the above solution, N,N -Diisopropylethylamine (77 mg, 0.60 mmol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：6.1%)。LCMS：RT=3.49min，[M+H]⁺=810.35。 Saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 17 mg of colorless oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 6.1%). LCMS: RT=3.49 min, [M+H] ⁺ =810.35.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(170毫克，0.018毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (170 mg, 0.018 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(2-甲氧基乙基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：81.0%)。LCMS：RT=2.73min，[M+H]⁺=755.24。 The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 12 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(4-(2-methoxyethyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 81.0%). LCMS: RT = 2.73 min, [M+H] ⁺ =755.24.

Example 30

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸化合物

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid compound

The specific synthesis route is as follows:

-2-酮

Step A: Synthesis of 4-(tetrahydro- 2H -pyran-4-yl)piper

-2-one

-2-酮(500毫克，2.5毫摩爾)溶於甲醇(10.0毫升)和乙酸(0.2毫升)的混合溶液中。隨後，向上述溶液中加入四氫-4H-吡喃-4-酮(788毫克，5.0毫摩爾)和氰基硼氫化鈉(317毫克，5.0毫摩爾)。在60℃下攪拌過夜。 Piperazine

-2-one (500 mg, 2.5 mmol) was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, tetrahydro-4H -pyran-4-one (788 mg, 5.0 mmol) and sodium cyanoborohydride (317 mg, 5.0 mmol) were added to the above solution. Stir at 60°C overnight.

-2-酮(收率： 69.0%)。LCMS：RT=0.96min，[M+H]⁺=185.12。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 420 mg of white solid 4-(4-methylcyclohexyl)piperidine

-2-one (yield: 69.0%). LCMS: RT=0.96min, [M+H] ⁺ =185.12.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯

Step B: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(1.0克，1.6毫摩爾)和4-(四氫-2H-吡喃-4-基)哌

-2-酮(611毫克，3.3毫摩爾)溶於甲苯(15.0毫升)的溶液中。隨後，向上述溶液中加入N,N-二甲基乙-1,2-二胺(292毫克，3.3毫摩爾)，碘化亞銅(315毫克，1.6毫摩爾)和碳酸銫(1.08克，3.3毫摩爾)。在110℃下攪拌18個小時。 (S)-3-(4-Bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate (1.0 g, 1.6 mmol) and 4-(tetrahydro- 2H -pyran-4-yl)piper

-2-one (611 mg, 3.3 mmol) was dissolved in a solution of toluene (15.0 mL). Subsequently, N,N -dimethylethyl-1,2-diamine (292 mg, 3.3 mmol), cuprous iodide (315 mg, 1.6 mmol) and cesium carbonate (1.08 g, 3.3 mmol). Stir at 110°C for 18 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(收率：50%)。LCMS：RT=3.31min，[M+H]⁺=706.33。 Saturated ammonium chloride solution (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (15 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). Obtain 590 mg of yellow solid (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 50%). LCMS: RT=3.31 min, [M+H] ⁺ =706.33.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(590毫克，0.83毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(913毫克，5.00毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(57毫克，0.05毫摩爾)。在40℃下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl) phenyl) tert-butyl propionate (590 mg, 0.83 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (913 mg, 5.00 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (57 mg, 0.05 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(收率：86.0%)。LCMS：RT=2.93min，[M+H]⁺=626.30。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 450 mg of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 86.0%). LCMS: RT=2.93min, [M+H] ⁺ =626.30.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(450毫克，0.71毫摩爾)和原甲酸三乙酯(840毫克，5.00毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(327毫克，5.00毫摩爾)。在70℃下攪拌1小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

1-yl)phenyl)tert-butyl propionate (450 mg, 0.71 mmol) and triethyl orthoformate (840 mg, 5.00 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (327 mg, 5.00 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(收率：86.0%)。LCMS：RT=2.92min，[M+H]⁺=679.27。 Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 400 mg of yellow solid (S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 86.0%). LCMS: RT=2.92min, [M+H] ⁺ =679.27.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸叔丁酯(400毫克，0.6毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

1-yl)phenyl)tert-butyl propionate (400 mg, 0.6 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸收率：93.0%)。 The reaction solution was concentrated under reduced pressure. Obtain 360 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

(-1-yl)phenyl)propionic acid yield: 93.0%).

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step F: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙酸(360毫克，0.55毫摩爾)和5-氨基-1H-吲哚-1,2-二羧酸二叔丁酯(202毫克0.60摩爾)溶於N,N-二甲基甲醯胺(10.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(315毫克，0.82毫摩爾)，N,N-二異丙基乙胺(142毫克，1.10毫摩爾)，在室溫下攪拌18個小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl) phenyl) propionic acid (360 mg, 0.55 mmol) and 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (202 mg 0.60 mol) dissolved in N, N -dimethylformamide (10.0 ml) in solution. Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (315 mg, 0.82 mmol) was added to the above solution, N,N -Diisopropylethylamine (142 mg, 1.10 mmol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：71%)。LCMS：RT=3.47min，[M+H]⁺=837.37。 Saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 380 mg of colorless oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 71%). LCMS: RT=3.47 min, [M+H] ⁺ =837.37.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(380毫克，0.4毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-1,2-dicarboxylic acid di-tert-butyl ester (380 mg, 0.4 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：19.0%)。LCMS：RT=2.74min，[M+H]⁺=781.25。¹H NMR(500MHz,DMSO)δ 12.91(s,1H),11.72(s,1H),10.13(s,1H),9.75(s,1H),7.99(s,1H),7.94(d,J=2.0Hz,1H),7.81(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.42-7.30(m,5H),7.07(d,J=1.7Hz,1H),5.38(s,1H),3.98(d,J=9.5Hz,3H),3.35-3.29(m,3H),3.13(dd,J=14.4,10.2Hz,2H),2.94(s,3H),2.00(d,J=7.5Hz,3H),1.65(s,2H),1.24(s,2H)。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 52 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 19.0%). LCMS: RT=2.74min, [M+H] ⁺ =781.25. ¹ H NMR (500MHz, DMSO) δ 12.91 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.75 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 2.0Hz,1H),7.81(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.42-7.30(m,5H),7.07(d, J =1.7Hz, 1H),5.38(s,1H),3.98(d, J =9.5Hz,3H),3.35-3.29(m,3H),3.13(dd, J =14.4,10.2Hz,2H),2.94(s,3H ), 2.00 (d, J = 7.5 Hz, 3H), 1.65 (s, 2H), 1.24 (s, 2H).

Example 31

-1- 基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-4-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-4-yl)piper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-2-酮

The specific synthesis route is as follows: Step A: Synthesis of 4-(4-hydroxycyclohexyl)piper

-2-one

-2-酮(1.5克，7.5毫摩爾)溶於甲醇(20.0毫升)和乙酸(0.4毫升)的混合溶液中。隨後，向上述溶液中加入4-羥基環己烷-1-酮(1.7克，15.0毫摩爾)和氰基硼氫化鈉(951毫克，15.0毫摩爾)。在60℃下攪拌過夜。 Piperazine

-2-one (1.5 g, 7.5 mmol) was dissolved in a mixed solution of methanol (20.0 mL) and acetic acid (0.4 mL). Subsequently, 4-hydroxycyclohexane-1-one (1.7 g, 15.0 mmol) and sodium cyanoborohydride (951 mg, 15.0 mmol) were added to the above solution. Stir at 60°C overnight.

-2-酮(收率：50.0%)。LCMS：RT=0.82，[M+H]⁺=199.14。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 750 mg of white solid 4-(4-methylcyclohexyl)piper

-2-one (yield: 50.0%). LCMS: RT=0.82, [M+H] ⁺ =199.14.

-1-基)-3-(4-(4-(4-羥基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step B: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl))-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(600毫克，0.99毫摩爾)和4-(4-羥基環己基)哌

-2-酮(394毫克，1.99毫摩爾)溶於甲苯(15毫升)的溶液中。隨後，向上述溶液中加入N,N-二甲基乙-1,2-二胺(175毫克，1.99毫摩爾)，碘化亞銅(189毫克，0.99毫摩爾)和碳酸銫(645毫克，1.99毫摩爾)。在110℃下攪拌18個小時。 (S)-3-(4-Bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate (600 mg, 0.99 mmol) and 4-(4-hydroxycyclohexyl)piper

-2-one (394 mg, 1.99 mmol) was dissolved in a solution of toluene (15 mL). Subsequently, to the above solution was added N,N -dimethylethyl-1,2-diamine (175 mg, 1.99 mmol), cuprous iodide (189 mg, 0.99 mmol) and cesium carbonate (645 mg, 1.99 mmol). Stir at 110°C for 18 hours.

-1-基)-3-(4-(4-(4-羥基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：64.0%)。LCMS：RT=3.10min，[M+H]⁺=720.34。 Saturated ammonium chloride solution (30 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (15 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). Obtain 460 mg of yellow solid (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl))-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 64.0%). LCMS: RT = 3.10 min, [M+H] ⁺ =720.34.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(4-羥基環己基))-2-氧代哌

-1-基)苯基)丙酸叔丁酯(550毫克，0.76毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(834毫克，5.30毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(52毫克，0.045毫摩爾)。在40℃下攪拌過夜。 (S)-2-(4-(5-Chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl))-2-oxopiper

-1-yl) phenyl) tert-butyl propionate (550 mg, 0.76 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (834 mg, 5.30 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(收率：94.0%)。LCMS：RT=2.84min，[M+H]⁺=640.28。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 460 mg of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate (yield: 94.0%). LCMS: RT=2.84min, [M+H] ⁺ =640.28.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

)-1-基)苯基)丙酸叔丁酯(450毫克，0.7毫摩爾)和原甲酸三乙酯(1000毫克，7.0毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(456毫克，7.0毫摩爾)。在70℃下攪拌1小時。 (S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

)-1-yl)phenyl)tert-butyl propionate (450 mg, 0.7 mmol) and triethyl orthoformate (1000 mg, 7.0 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (456 mg, 7.0 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(收率：22.0%)。LCMS：RT=2.83min，[M+H]⁺=693.28。 Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 110 mg of yellow solid (S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)tert-butyl propionate (yield: 22.0%). LCMS: RT=2.83min, [M+H] ⁺ =693.28.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸

Step E: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸叔丁酯(110毫克，0.15毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

1-yl)phenyl)tert-butyl propionate (110 mg, 0.15 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸(收率：92.0%)。 The reaction solution was concentrated under reduced pressure. Obtain 93 mg of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionic acid (yield: 92.0%).

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯

Step F: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propylamino)-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙酸(83毫克，0.13毫摩爾)和5-氨基-1H-吲哚-2-羧酸叔丁酯(36毫克0.15摩爾)溶於N,N-二甲基甲醯胺(10.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(74毫克，0.19毫摩爾)，N,N-二異丙基乙胺(33毫克，0.26毫摩爾)，在室溫下攪拌18個小時。 (S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

-1-yl)phenyl)propionic acid (83 mg, 0.13 mmol) and tert-butyl 5-amino-1 H -indole-2-carboxylate (36 mg 0.15 mol) dissolved in N,N -dimethyl Methamide (10.0 ml) in solution. Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (74 mg, 0.19 mmol) was added to the above solution, N,N -Diisopropylethylamine (33 mg, 0.26 mmol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯(收率：59.0%)。LCMS：RT=3.13min，[M+H]⁺=851.33。 Saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml × 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 65 mg of colorless oil (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylate (Yield: 59.0%). LCMS: RT=3.13 min, [M+H] ⁺ =851.33.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸化合物

Step G: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid compound

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯(65毫克，0.07毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylate (65 mg, 0.07 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(4-(4-羥基環己基)-2-氧代哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸化合物(收率：83.0%)。LCMS：RT=2.33min，[M+H]⁺=795.27。¹H NMR(400MHz,DMSO)δ 11.74(s,1H),10.14(s,1H),9.77(s,1H),8.00(s,1H),7.94(d,J=1.8Hz,1H),7.82(d,J=8.6Hz,1H),7.78(dd,J=8.7,2.2Hz,1H),7.42-7.30(m,6H),7.08(d,J =1.9Hz,1H),5.44-5.36(m,1H),4.12-3.13(m,13H),3.13(dd,J=14.8,10.4Hz,1H),2.07-2.00(m,1H),1.96-1.91(m,1H),1.86-1.75(m,3H),1.61-1.41(m,3H)。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to obtain 50 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid compound (yield: 83.0%). LCMS: RT=2.33 min, [M+H] ⁺ =795.27. ¹ H NMR (400MHz, DMSO) δ 11.74 (s, 1H), 10.14 (s, 1H), 9.77 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.82 (d, J =8.6Hz,1H),7.78(dd, J =8.7,2.2Hz,1H),7.42-7.30(m,6H),7.08(d, J =1.9Hz,1H),5.44-5.36( m,1H),4.12-3.13(m,13H),3.13(dd, J =14.8,10.4Hz,1H),2.07-2.00(m,1H),1.96-1.91(m,1H),1.86-1.75( m, 3H), 1.61-1.41 (m, 3H).

Example 32

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-2-酮

Step A: Synthesis of 4-(tetrahydro- 2H -pyran-3-yl)piper

-2-one

-2-酮(500毫克，4.9毫摩爾)溶於甲醇(10.0毫升)和乙酸(0.2毫升)的混合溶液中。隨後，向上述溶液中加入二氫-2H-吡喃-3(4H)-酮(1.0克，10.0毫摩爾)和氰基硼氫化鈉(627毫克，10.0毫摩爾)。在60℃下攪拌過夜。 Piperazine

-2-one (500 mg, 4.9 mmol) was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, dihydro-2H -pyran-3( 4H )-one (1.0 g, 10.0 mmol) and sodium cyanoborohydride (627 mg, 10.0 mmol) were added to the above solution. Stir at 60°C overnight.

-2-酮(收率：43.0%)。LCMS：RT=1.04min，[M+H]⁺=185.12。 The reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 400 mg of white solid 4-(tetrahydro- 2H -pyran-3-yl)piper

-2-one (yield: 43.0%). LCMS: RT=1.04min, [M+H] ⁺ =185.12.

-1-基)-3-(4-(2-氧代-4-(四氫)-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯

Step B: Synthesis of (2S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro)-2 H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(600毫克，0.99毫摩爾)和4-(四氫-2H-吡喃-3-基)哌

-2-酮(370毫克，1.99毫摩爾)溶於甲苯(15.0毫升)的溶液中。隨後，向上述溶液中加入N,N-二甲基乙-1,2-二胺(175毫克，1.99毫摩爾)，碘化亞銅(189毫克，0.99毫摩爾)和碳酸銫(645毫克，1.99毫摩爾)。在110℃下攪拌18個小時。 (S)-3-(4-Bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl) tert-butyl propionate (600 mg, 0.99 mmol) and 4-(tetrahydro- 2H -pyran-3-yl)piper

-2-one (370 mg, 1.99 mmol) was dissolved in a solution of toluene (15.0 ml). Subsequently, to the above solution was added N,N -dimethylethyl-1,2-diamine (175 mg, 1.99 mmol), cuprous iodide (189 mg, 0.99 mmol) and cesium carbonate (645 mg, 1.99 mmol). Stir at 110°C for 18 hours.

-1-基)-3-(4-(2-氧代-4-(四氫)-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(收率：52.0%)。LCMS：RT=3.48min，[M+H]⁺=706.33。 Saturated ammonium chloride solution (30 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (15 mL×3 times), and the organic phases were combined. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10). Obtain 370 mg of yellow solid (2S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro)-2 H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 52.0%). LCMS: RT=3.48 min, [M+H] ⁺ =706.33.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯

Step C: Synthesis of (2S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(2-氧代-4-(四氫)-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(370毫克，0.52毫摩爾)和1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮烷(572毫克，3.6毫摩爾)溶於二氯甲烷(10.0毫升)中。隨後，向上述溶液中加入四(三苯基膦)鈀(36毫克，0.031毫摩爾)。在40℃下攪拌過夜。 Add (2S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro)-2 H -pyran-3-yl)piper

-1-yl) phenyl) tert-butyl propionate (370 mg, 0.52 mmol) and 1,3-dimethylpyrimidine-2,4,6(1 H ,3 H ,5 H )-trione (572 mg, 3.6 mmol) was dissolved in dichloromethane (10.0 mL). Subsequently, tetrakis(triphenylphosphine)palladium (36 mg, 0.031 mmol) was added to the above solution. Stir at 40°C overnight.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(收率：79.0%)。LCMS：RT=3.06min，[M+H]⁺=626.27。 Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (20 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (20 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 260 mg of yellow solid (2S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperidine

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 79.0%). LCMS: RT=3.06min, [M+H] ⁺ =626.27.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯

Step D: Synthesis of (2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(260毫克，0.4毫摩爾)和原甲酸三乙酯(430毫克，2.9毫摩爾)溶於醋酸(5.0毫升)中。隨後，向上述溶液中加入疊氮化鈉(188毫克，2.9毫摩爾)。在70℃下攪拌1小時。 (2S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

1-yl)phenyl)tert-butyl propionate (260 mg, 0.4 mmol) and triethyl orthoformate (430 mg, 2.9 mmol) were dissolved in acetic acid (5.0 mL). Subsequently, sodium azide (188 mg, 2.9 mmol) was added to the above solution. Stir at 70°C for 1 hour.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(收率：28.0%)。LCMS：RT=3.05min，[M+H]⁺=679.27。 Saturated sodium bicarbonate solution (40 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. Obtain 80 mg of yellow solid (2S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)tert-butyl propionate (yield: 28.0%). LCMS: RT=3.05min, [M+H] ⁺ =679.27.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸

Step E: Synthesis of (2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propionic acid

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸叔丁酯(80毫克，0.11毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 (2S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

1-yl)phenyl)tert-butyl propionate (80 mg, 0.11 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸(收率：89.0%)。 The reaction solution was concentrated under reduced pressure. Get 65 mg of yellow solid (2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propionic acid (yield: 89.0%).

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯

Step F: Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propylamino)-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙酸(65毫克，0.10毫摩爾)和5-氨基-1H-吲哚-2-羧酸叔丁酯(41毫克0.12摩爾)溶於N,N-二甲基甲醯胺(10.0毫升)的溶液中。隨後，向上述溶液中加入2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(59毫克，0.15毫摩爾)，N,N-二異丙基乙胺(27毫克，0.20摩爾)，在室溫下攪拌18個小時。 (2S)-2-(4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propionic acid (65 mg, 0.10 mmol) and tert-butyl 5-amino-1H-indole-2-carboxylate (41 mg 0.12 mol) dissolved in N,N -dimethyl In a solution of formamide (10.0 ml). Subsequently, 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (59 mg, 0.15 mmol) was added to the above solution, N,N -Diisopropylethylamine (27 mg, 0.20 mol), stirred at room temperature for 18 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯(收率：25.7%)。LCMS：RT=3.22min，[M+H]⁺=837.32。 Saturated ammonium chloride solution (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (10 ml×3 times). Combine the organic phases. The organic phase was first saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtained 25 mg of colorless oil 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylate (Yield: 25.7%). LCMS: RT=3.22 min, [M+H] ⁺ =837.32.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step G: Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

-1-yl)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯氨基)-1H-吲哚-2-羧酸叔丁酯(25毫克，0.026毫摩爾)溶於二氯甲烷(4.0毫升)中。隨後，向上述溶液中加入三氟乙酸(1.0毫升)。在室溫下攪拌2小時。 Put 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylate (25 mg, 0.026 mmol) was dissolved in dichloromethane (4.0 mL). Subsequently, trifluoroacetic acid (1.0 mL) was added to the above solution. Stir at room temperature for 2 hours.

-1-基)-3-(4-(2-氧代-4-(四氫-2H-吡喃-3-基)哌

-1-基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：65.0%)。LCMS：RT=2.83min，[M+H]⁺=781.25。¹H NMR(500MHz,DMSO)δ 12.94(s,1H),11.74(s,1H),10.15(s,1H),9.76(s,1H),8.00(s,1H),7.94(d,J=2.1Hz,1H),7.81(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.41-7.27(m,6H),7.07(d,J=1.7Hz,1H),5.38(brs,1H),3.97-3.13(m,9H),3.13(dd,J=14.3,10.1Hz,1H),2.54(s,2H),2.08(m,2H),1.99(m,2H),1.76(m,2H),1.60-1.38(m,3H)。 The reaction solution was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain 15 mg of white solid 5-((2S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(2-oxo-4-(tetrahydro- 2H -pyran-3-yl)piper

1-yl) phenyl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 65.0%). LCMS: RT=2.83min, [M+H] ⁺ =781.25. ¹ H NMR (500MHz, DMSO) δ 12.94 (s, 1H), 11.74 (s, 1H), 10.15 (s, 1H), 9.76 (s, 1H), 8.00 (s, 1H), 7.94 (d, J = 2.1Hz,1H),7.81(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.41-7.27(m,6H),7.07(d, J =1.7Hz, 1H),5.38(brs,1H),3.97-3.13(m,9H),3.13(dd, J =14.3,10.1Hz,1H),2.54(s,2H),2.08(m,2H),1.99(m , 2H), 1.76 (m, 2H), 1.60-1.38 (m, 3H).

Example 33

-1- 基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows: Step A: Synthesis of 6-nitro-1 H -indole-2-carboxylic acid tert-butyl ester

Under N2 protection and ice bath, add 70% perchloric acid dropwise to tert-butyl acetate (25.0 ml) containing 6-nitro-1 H-indole-2-carboxylic acid (200 mg, 0.97 mmol) (147 mg, 1.46 mmol), after dripping, react at room temperature for 2 hours.

After the reaction is over, add ethyl acetate to dilute, adjust the pH to 9 with saturated sodium carbonate, separate the layers, extract the mixture with ethyl acetate (20 ml×3 times), combine the organic phases, and use saturated brine (10 ml ×2 times) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1). Obtained 200 mg of tert-butyl 6-nitro-1 H -indole-2-carboxylate as a yellow oil (yield: 74.0%). LCMS: RT=4.20min, [MH] ^- =261.13.

Step B: Synthesis of 6-amino-1 H -indole-2-carboxylic acid tert-butyl ester

At room temperature, dissolve 6-nitro-1 H -indole-2-carboxylic acid tert-butyl ester (200 mg, 0.76 mmol) in ethyl acetate, add palladium on carbon (20 mg), install a hydrogen balloon, React at room temperature for 9 hours.

After the reaction is over, the palladium carbon is filtered, the filter cake is washed with ethyl acetate, the filtrate is concentrated under reduced pressure, and dried to obtain 46 mg of 6-amino-1 H -indole-2-carboxylic acid tert-butyl ester, which is directly used in the next step without purification. reaction. LCMS: RT=3.16 min, [M+H] ⁺ =233.19.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯

Step C: Synthesis of (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester

-1-基)-3-苯基丙酸(38毫克，0.09毫摩爾)、6-氨基-1H-吲哚-2-羧酸叔丁酯(20毫克，0.09毫摩爾)和2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(51毫克，0.13毫摩爾)加入N,N-二甲基甲醯胺(3.0毫升)中，滴加N,N-二異丙基乙胺(35毫克，0.27毫摩爾)，滴畢，N2保護下，室溫反應過夜。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropionic acid (38 mg, 0.09 mmol), 6-amino-1 H -indole-2-carboxylic acid tert-butyl ester (20 mg, 0.09 mmol) and 2-( 7-oxybenzotriazole) -N,N,N',N' -tetramethylurea hexafluorophosphate (51mg, 0.13mmol) was added to N,N -dimethylformamide (3.0ml) ), N,N -diisopropylethylamine (35 mg, 0.27 mmol) was added dropwise, and after the dropping, the reaction was carried out at room temperature overnight under the protection of N2.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯(收率：37.3%)。LCMS：RT=4.04min,[M+H]⁺=655.39。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 22 mg of yellow solid (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester (yield: 37.3%). LCMS: RT=4.04min, [M+H] ⁺ =655.39.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸

Step D: Synthesis of (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸叔丁酯(22毫克，0.03毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid tert-butyl ester (22 mg, 0.03 mmol) was added to dichloromethane (2.0 ml), and three Fluoroacetic acid (0.5 ml) was reacted at room temperature for 3 hours.

-1-基)-3-苯基丙醯胺基)-1H-吲哚-2-羧酸(收率：53.0%)。LCMS：RT=3.42min,[M-H]^-=597.09。¹H NMR(500MHz,DMSO)δ 12.87(s,1H),11.69(s,1H),10.28(s,1H),9.77(s,1H),7.98(s,1H),7.95(d,J=2.3Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.57(d,J=8.7Hz,1H),7.37-7.28(m,3H),7.25(t,J=7.2Hz,1H),7.18(dd,J=8.8,1.6Hz,1H),7.06-7.01(m,1H),5.42-5.35(m,1H),5.35-5.29(m,1H),3.32-3.27(m,2H),3.18-3.05(m,2H),2.08-1.92(m,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 9 mg of light yellow solid (S)-6-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2, 3-dioxopiperidine

-1-yl)-3-phenylpropanamido)-1 H -indole-2-carboxylic acid (yield: 53.0%). LCMS: RT=3.42min, [MH] ^- =597.09. ¹ H NMR (500MHz, DMSO) δ 12.87 (s, 1H), 11.69 (s, 1H), 10.28 (s, 1H), 9.77 (s, 1H), 7.98 (s, 1H), 7.95 (d, J = 2.3Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.57(d, J =8.7Hz,1H),7.37-7.28(m, 3H), 7.25(t, J =7.2Hz,1H), 7.18(dd, J =8.8,1.6Hz,1H), 7.06-7.01(m,1H),5.42-5.35(m,1H),5.35-5.29 (m, 1H), 3.32-3.27 (m, 2H), 3.18-3.05 (m, 2H), 2.08-1.92 (m, 2H).

Example 34

-1-基)-3-((4-羥基-2-氧代-1,2-二氫喹啉-6-基)氨基)-3-氧代丙基)苯基)-4-氰基哌啶-1-甲醯胺

Synthesis of ( S ) -N -(4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-((4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)amino)-3-oxopropyl)phenyl)-4-cyano Piperidine-1-carboxamide

-1-基)丙酸叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)- 2,3-dioxopiperidine

-1-yl) tert-butyl propionate

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(600毫克，1.1毫摩爾)和還原鐵粉(618毫克，11.0毫摩爾)加入冰醋酸(12.0毫升)中，100℃反應1小時。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)-tert-butyl propionate (600 mg, 1.1 mmol) and reduced iron powder (618 mg, 11.0 mmol) were added to glacial acetic acid (12.0 mL), React at 100°C for 1 hour.

-1-基)丙酸叔丁酯(收率：71.0%)。LCMS：RT=3.10min,[M+H]⁺=512.14。 At the end of the reaction, the reaction solution was adjusted to pH 8 with saturated sodium carbonate, filtered through a pad of diatomaceous earth, the filter cake was washed with 20 ml of dichloromethane, the filtrate was extracted with dichloromethane (10 ml×3 times), and the organic phases were combined. The phase was washed with saturated brine (10 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). Obtain 400 mg of yellow solid (S)-3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl) tert-butyl propionate (yield: 71.0%). LCMS: RT=3.10min, [M+H] ⁺ =512.14.

-1-基)-3-(4-((苯氧基羰基)基)氨基)苯基)丙酸叔丁酯

Step B: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)yl)amino)phenyl)tert-butyl propionate

-1-基)丙酸叔丁酯(400毫克，0.8毫摩爾)和三乙胺(326微升)的四氫呋喃(6.0毫升)中滴加氯甲酸苯酯(146微升)，滴畢，室溫反應1小時。 Under N2 protection, under ice bath, to contain (S)-3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)- 2,3-dioxopiperidine

-1-yl) tert-butyl propionate (400 mg, 0.8 mmol) and triethylamine (326 μl) in tetrahydrofuran (6.0 ml) were added dropwise with phenyl chloroformate (146 μl). Warm reaction for 1 hour.

-1-基)-3-(4-((苯氧基羰基)基)氨基)苯基)丙酸叔丁酯(收率：50.0%)。LCMS：RT=4.04min,[M+H]⁺=632.19。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane=1/1). Obtain 253 mg of white solid (S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)yl)amino)phenyl)tert-butyl propionate (yield: 50.0%). LCMS: RT=4.04min, [M+H] ⁺ =632.19.

-1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸叔丁酯

Step C: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl) tert-butyl propionate

-1-基)-3-(4-((苯氧基羰基)基)氨基)苯基)丙酸叔丁酯(253毫克，0.4毫摩爾)和4-氰基哌啶(442毫克，4.0毫摩爾)的四氫呋喃(10.0毫升)中滴加N,N-二異丙基乙胺(518毫克，4.0毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)yl)amino)phenyl) tert-butyl propionate (253 mg, 0.4 mmol) and 4-cyanopiperidine (442 mg, 4.0 N,N -diisopropylethylamine (518 mg, 4.0 mmol) was added dropwise to tetrahydrofuran (10.0 ml) in millimoles). After the dripping was completed, the reaction was carried out at 65°C overnight.

-1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸叔丁酯(收率：69.4%)。LCMS：RT=3.67min。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 180 mg of light yellow solid (S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl) tert-butyl propionate (yield: 69.4%). LCMS: RT=3.67min.

-1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸

Step D: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionic acid

- 1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸叔丁酯(180毫克，0.28毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl) tert-butyl propionate (180 mg, 0.28 mmol) was added to dichloromethane (2.0 mL) , Trifluoroacetic acid (0.5 ml) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸，無需純化，直接用於下一步反應。LCMS：RT=3.24min,[M-H]^-=590.11。 After the reaction was over, concentrated under reduced pressure to obtain 160 mg of yellow oil (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxide Depiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionic acid, without purification, was directly used in the next reaction. LCMS: RT=3.24min, [MH] ^- =590.11.

-1-基)-3-((4-羥基-2-氧代-1,2-二氫喹啉-6-基)氨基)-3-氧代丙基)苯基)-4-氰基哌啶-1-甲醯胺

Step E: Synthesis of (S) -N -(4-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-((4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)amino)-3-oxopropyl)phenyl)-4-cyano Piperidine-1-carboxamide

-1-基)-3-(4-(4-氰基哌啶-1-甲醯氨基)苯基)丙酸(160毫克，0.27毫摩爾)、6-氨基-4-羥基-2(1H)-喹啉酮(53毫克，0.30毫摩爾)和2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(206毫克，0.54毫摩爾)加入N,N-二甲基甲醯胺(4.0毫升)中，滴加N,N-二異丙基乙胺(105毫克，0.81毫摩爾)，滴畢，N₂保護下，室溫反應過夜。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamide)phenyl)propionic acid (160 mg, 0.27 mmol), 6-amino-4-hydroxy-2(1 H )-quinolinone (53 mg, 0.30 mmol) and 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (206 mg, 0.54 mmol) was added to N,N -dimethylformamide (4.0 mL), and N,N -diisopropylethylamine (105 mg, 0.81 mmol) was added dropwise, after dripping, under N ₂ protection, React overnight at room temperature.

-1-基)-3-((4-羥基-2-氧代-1,2-二氫喹啉-6-基)氨基)-3-氧代丙基)苯基)-4-氰基哌啶-1-甲醯胺(收率：26.7%)。LCMS：RT=3.16min,[M+H]⁺=750.20。¹H NMR(400MHz,DMSO)δ 11.36(s,1H),11.21(s,1H),10.30(s,1H),9.79(s,1H),8.53(s,1H),8.16(d,J=1.9Hz,1H),7.95(d,J=2.3Hz,1H),7.82(d,J=8.7Hz,1H),7.78-7.74(m,1H),7.62(dd,J=8.9,2.3Hz,1H),7.40(d,J=8.5Hz,1H),7.21(d,J =8.9Hz,1H),7.14(d,J=9.2Hz,1H),6.66(s,1H),5.74(d,J=1.0Hz,1H),5.32(t,J=4.8Hz,1H),5.26(dd,J=10.2,5.6Hz,1H),3.32-3.15(m,4H),3.14-2.92(m,4H),2.08-1.95(m,3H),1.95-1.79(m,2H),1.76-1.60(m,2H)。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: pure ethyl acetate. 54 mg of white solid (S)-N-(4-(2-(4-(5-chloro-2-(1 H- Tetrazol-1-yl)phenyl)-2,3-dioxopiperidine

-1-yl)-3-((4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)amino)-3-oxopropyl)phenyl)-4-cyano Piperidine-1-carboxamide (yield: 26.7%). LCMS: RT=3.16 min, [M+H] ⁺ =750.20. ¹ H NMR (400MHz, DMSO) δ 11.36 (s, 1H), 11.21 (s, 1H), 10.30 (s, 1H), 9.79 (s, 1H), 8.53 (s, 1H), 8.16 (d, J = 1.9Hz,1H),7.95(d, J =2.3Hz,1H),7.82(d, J =8.7Hz,1H),7.78-7.74(m,1H),7.62(dd, J =8.9,2.3Hz, 1H), 7.40(d, J =8.5Hz,1H), 7.21(d, J =8.9Hz,1H), 7.14(d, J =9.2Hz,1H), 6.66(s,1H), 5.74(d, J =1.0Hz,1H),5.32(t, J =4.8Hz,1H), 5.26(dd, J =10.2,5.6Hz,1H),3.32-3.15(m,4H),3.14-2.92(m,4H ), 2.08-1.95 (m, 3H), 1.95-1.79 (m, 2H), 1.76-1.60 (m, 2H).

Example 35

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-(5-chloro- 2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

Step A: Synthesis of tert-butyl (S)-2-amino-3-(4-nitrophenyl)propionate

Under N ₂ protection and ice bath, add dropwise to tert-butyl acetate (200 ml) containing (S)-2-amino-3-(4-nitrophenyl)propionic acid (20.0 g, 95.2 mmol) 70% perchloric acid (8.2 ml), after dripping, react at room temperature overnight.

When the reaction is over, add ethyl acetate to dilute, adjust the pH to 9 with saturated sodium carbonate, extract the mixture with ethyl acetate (150 ml×3 times), combine the organic phases, and use saturated brine (100 ml×2 times). ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1). Yield 15.2 g of yellow oil (S)-2-amino-3- (4-Nitrophenyl) butyl propionate (yield: 60.0%). LCMS: RT=2.05min.

Step B: Synthesis of tert-butyl (S)-2-(2-methoxy-2-oxoacetamino)-3-(4-nitrophenyl)propionate

Under the protection of N ₂ and under ice bath, add (S)-2-amino-3-(4-nitrophenyl) butyl propionate (15.2 g, 57.1 mmol) and triethylamine (6.9 g, 68.5 mmol). Mol) of dichloromethane (150 ml) was added dropwise chloromonomethyl oxalate (7.7 g, 62.8 mmol), after the dropping, the reaction was carried out at room temperature for 30 minutes.

After the reaction was over, it was quenched by adding water, and the mixture was extracted with dichloromethane (100 ml×3 times). The organic phases were combined, and the organic phase was washed with saturated brine (50 ml×3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 13.3 g of light yellow oil (S)-2-(2-methoxy Tert-butyl 2-oxoacetamido)-3-(4-nitrophenyl)propionate, without purification, was used directly in the next reaction. LCMS: RT=3.91min, [MH] ^- =351.12.

Step C: Synthesis of (S)-2-((1-(tert-butoxy)-3-(4-nitrophenyl)-1-oxopropan-2-yl)amino)-2-oxoacetic acid

Under ice bath, add tert-butyl (S)-2-(2-methoxy-2-oxoacetamino)-3-(4-nitrophenyl)propionate (13.3 g, 37.7 mmol) ) In tetrahydrofuran (160 ml), add lithium hydroxide dropwise (3.2 g, 75.4 mmol) aqueous solution (80 ml), the reaction is complete when the dropping is completed.

After the reaction is complete, add water to quench, adjust the pH to 4 with dilute aqueous hydrochloric acid (0.5 mol/L), extract the mixture with ethyl acetate (80 ml×3 times), combine the organic phases, and use saturated brine (50 (Ml×2 times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. Finally, it was concentrated under reduced pressure to obtain 10.2 g of light yellow oil (S)-2-((1-(tert-butoxy)-3-(4-nitrophenyl)-1-oxopropan-2-yl) Amino)-2-oxoacetic acid, without purification, was directly used in the next reaction. LCMS: RT=4.32min, [MH] ^- =337.16.

Step D: Synthesis of N,N -diallyl-4-chloro-2-nitroaniline

At room temperature, add 5-chloro-2-fluoronitrobenzene (20.0 g, 113.9 mmol), diallylamine (16.6 g, 170.9 mmol) and potassium carbonate (32.0 g, 231.9 mmol) to N , N - in dimethylformamide (200 mL), under N _2, the reaction 80 ℃ 3 hours.

After the reaction was over, a pad of anhydrous sodium sulfate was suction filtered, the filter cake was washed with 200 ml of ethyl acetate, the filtrate was extracted with ethyl acetate (100 ml × 3 times), the organic phases were combined, and the organic phase was first used with saturated brine (100 ml × 2 Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure to obtain 27.5 g of brown oil N,N -diallyl-4-chloro-2-nitroaniline, without purification, directly used in the next reaction . LCMS: RT=4.58min, [M+H] ⁺ =253.07.

Step E: Synthesis of N ¹ ,N ¹ -diallyl-4-chlorobenzene-1,2-diamine

At room temperature, add N,N -diallyl-4-chloro-2-nitroaniline (27.5 g, 108.8 mmol) to ethyl acetate, and add stannous chloride dihydrate in batches under ice bath The compound (122.8 g, 544.0 mmol) was reacted at room temperature overnight under the protection of _{N 2.}

After the reaction is over, it is quenched with saturated sodium bicarbonate aqueous solution, and then excess sodium bicarbonate solid is added to adjust the pH to weakly alkaline. The filter cake is suction filtered with a pad of celite. The filter cake is washed with 300 ml of ethyl acetate, and the filtrate is washed with ethyl acetate ( 100 ml × 3 times), the organic phases were combined, and the organic phase was washed with saturated brine (200 ml × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: pure n-hexane). 11.4 g of brown oily N ¹ ,N ¹ -diallyl-4-chlorobenzene-1,2-diamine was obtained (yield: 47.1%). LCMS: RT=4.44 min, [M+H] ⁺ =223.22.

Step F: Synthesis of (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-nitro Phenyl) tert-butyl propionate

At room temperature, the oil (S)-2-((1-(tert-butoxy)-3-(4-nitrophenyl)-1-oxopropan-2-yl)amino)-2 -Oxoacetic acid (15.7 g, 46.4 mmol), N ¹ , N ¹ -diallyl-4-chlorobenzene-1,2-diamine (11.4 g, 51.2 mmol) and 2-(7-oxidation Benzotriazole) -N,N,N',N' -tetramethylurea hexafluorophosphate (35.3g, 92.8mmol) was added to N,N -dimethylformamide (300ml), N,N -diisopropylethylamine (18.0 g, 138.3 mmol) was added dropwise under an ice bath, and after the dropping was completed, the reaction was carried out at room temperature overnight under the protection of _{N 2.}

After the reaction was completed, the mixture was quenched by adding water, the mixture was extracted with ethyl acetate (200 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (100 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/1). Obtain 20.0 grams of yellow oil (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4 -Nitrophenyl) tert-butyl propionate (yield: 79.4%). LCMS: RT=5.21min, [MH] ^- =541.14.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯

Step G: Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate

At room temperature, (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamide)-3-(4-nitro (20.0 g, 36.8 mmol) and potassium carbonate (31.0 g, 224.3 mmol) were added to a three-necked flask. _{Under N 2} protection, acetonitrile (250 mL) was added with a double-row needle. Then inject 1,2-dibromoethane (42.1 g, 224.3 mmol) with a syringe, and react at 100°C overnight.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(收率：49.8%)。LCMS：RT=4.44min,[M+H]⁺=569.23。 After the reaction was over, a pad of anhydrous sodium sulfate was suction filtered, the filter cake was washed with 200 ml of ethyl acetate, the filtrate was extracted with ethyl acetate (100 ml × 3 times), the organic phases were combined, and the organic phase was first used with saturated brine (100 ml × 2 Times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). Obtain 10.5 g of yellow solid (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate (yield: 49.8%). LCMS: RT=4.44 min, [M+H] ⁺ =569.23.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯

Step H: Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(10.50克，18.5毫摩爾)的二氯甲烷(150毫升)中加入1,3-二甲基巴比妥酸(17.30克，111.0毫摩爾)和四三苯基膦鈀(0.85克，0.7毫摩爾)，40℃反應過夜。 At room temperature, add (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)-tert-butyl propionate (10.50 g, 18.5 mmol) in dichloromethane (150 ml) was added 1,3-dimethylbarbituric acid (17.30 g, 111.0 mmol) and tetrakistriphenylphosphine palladium (0.85 g, 0.7 mmol), react overnight at 40°C.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(收率：92.9%)。LCMS：RT=3.98min，[M+H]⁺=489.15。 After the reaction is over, dilute with dichloromethane, adjust the pH to 8 with saturated sodium carbonate, extract the mixture with dichloromethane (100ml×3 times), combine the organic phases, and use saturated brine (50ml×2 times). ) Wash, then dry with anhydrous sodium sulfate, and finally concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 8.4 g of yellow solid (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate (yield: 92.9%). LCMS: RT=3.98min, [M+H] ⁺ =489.15.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯

Step I: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(8.4克，17.2毫摩爾)的冰醋酸(80毫升)中加入原甲酸三乙酯(12.7克，85.9毫摩爾)和疊氮化鈉(3.9克，60.0毫摩爾)，80℃反應5小時。 At room temperature, add (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)-tert-butyl propionate (8.4 g, 17.2 mmol) in glacial acetic acid (80 mL) was added triethyl orthoformate (12.7 g, 85.9 mmol) ) And sodium azide (3.9 g, 60.0 mmol) at 80°C for 5 hours.

-1-基)-3-(4-硝基苯基)丙酸叔丁酯。(收率：26.8%)。LCMS：RT=4.08min。 After the reaction is over, add 20 ml of water, add sodium nitrite (250 mg/ml) dropwise until no bubbles are generated, add 80 ml of ethyl acetate to disperse, filter with suction, wash the filter cake with 30 ml of ethyl acetate, and dry to obtain 2.5 g Off-white solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl) tert-butyl propionate. (Yield: 26.8%). LCMS: RT=4.08min.

-1-基)-3-(4-硝基苯基)丙酸

Step J: Synthesis of (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)propionic acid

-1-基)-3-(4-硝基苯基)丙酸叔丁酯(2.5克，4.6毫摩爾)的二氯甲烷(24.0毫升)中滴加三氟乙酸(6.0毫升)，室溫反應5小時。 At room temperature, add (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)-tert-butyl propionate (2.5 g, 4.6 mmol) in dichloromethane (24.0 ml) was added dropwise with trifluoroacetic acid (6.0 ml) at room temperature React for 5 hours.

-1-基)-3-(4-硝基苯基)丙酸，無需純化，直接用於下一步反應。LCMS：RT=3.48min,[M-H]^-=484.07。 After the reaction was over, it was concentrated under reduced pressure to obtain 1.8 g of yellow solid (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)propionic acid, without purification, was directly used in the next reaction. LCMS: RT=3.48min, [MH] ^- =484.07.

Step K: Synthesis of 5-nitro-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

At room temperature, add 5-nitroindole-2-carboxylic acid (8.0 g, 38.8 mmol) and di-tert-butyl dicarbonate (38.1 g, 174.6 mmol) to N,N -dimethylformamide ( 40 ml), under ice bath, add 4-dimethylaminopyridine (3.8 g, 31.1 mmol) in batches _{, and react under N 2} protection at room temperature overnight.

After the reaction is over, add water to quench, add 100 ml of ethyl acetate, pad celite for suction filtration, wash the filter cake with 50 ml of ethyl acetate, extract the filtrate with ethyl acetate (100 ml × 3 times), combine the organic phases, and organic The phase was washed with saturated brine (100 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 11.0 g of light yellow oily substance, 5-nitro-1 H -indole-1,2-di Di-tert-butyl carboxylate is directly used in the next reaction without purification. LCMS: RT=5.01min.

Step L: Synthesis of 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

At room temperature, dissolve 5-nitro-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (11.0 g, 30.4 mmol 1) in ethanol, add palladium on carbon (1.1 g), and install Hydrogen balloon, react at room temperature for 9 hours.

After the reaction was completed, the palladium carbon was filtered, the filter cake was washed with ethanol, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). 8.2 g of yellow solid 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 81.0%) was obtained. LCMS: RT=4.09min,, [M+H] ⁺ =333.20.

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step M: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propanamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-硝基苯基)丙酸(1.8克，3.7毫摩爾)、5-氨基-1H-吲哚-1,2-二羧酸二叔丁酯(1.4克，4.2毫摩爾)和2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(2.8克，7.4毫摩爾)加入N,N-二甲基甲醯胺(20.0毫升)中，滴加N,N-二異丙基乙胺(1.4克，11.2毫摩爾)，滴畢，N₂保護下，室溫反應過夜。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)propionic acid (1.8 g, 3.7 mmol), 5-amino-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (1.4 G, 4.2 mmol) and 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (2.8 g, 7.4 mmol) add N,N -To dimethylformamide (20.0 ml), add N,N -diisopropylethylamine (1.4 g, 11.2 mmol) dropwise, after dropping, under N ₂ protection, react at room temperature overnight.

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：43.2%)。LCMS：RT=4.45min,[M-H]^-=798.13。 After the reaction was over, it was quenched by adding water, the mixture was extracted with ethyl acetate (50 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 1.3 g of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 43.2%). LCMS: RT=4.45min, [MH] ^- =798.13.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step N: Synthesis of (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2, 3-dioxopiperidine

-1-yl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-硝基苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(1.3克，1.6毫摩爾)和還原鐵粉(0.9克，16.1毫摩爾)加入甲醇(15.0毫升)中，滴加冰醋酸(1.0毫升)，65℃反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (1.3 g, 1.6 mmol) and reduced iron The powder (0.9 g, 16.1 mmol) was added to methanol (15.0 mL), glacial acetic acid (1.0 mL) was added dropwise, and the reaction was carried out at 65°C for 3 hours.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：50.0%)。LCMS：RT=4.05min,[M-H]^-=768.20。 After the reaction is over, add 10 ml of ethyl acetate to the reaction solution for dilution, pad Celite for suction filtration, wash the filter cake with ethyl acetate, adjust the pH of the filtrate to 10 with saturated sodium bicarbonate, and use ethyl acetate (50 ml × 3 times) extraction, and the organic phases were combined. The organic phase was washed with saturated brine (20 ml × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 622 mg of yellow solid (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2 ,3-dioxopiperidine

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 50.0%). LCMS: RT=4.05min, [MH] ^- =768.20.

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step O: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(622毫克，0.8毫摩爾)和三乙胺(336微升)的四氫呋喃(6.0毫升)中滴加氯甲酸苯酯(202微升)，滴畢，室溫反應1小時。 N ₂ protection, under ice bath, to contain (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl) (Phenyl)-2,3-dioxopiperidine

-1-yl) propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (622 mg, 0.8 mmol) and triethylamine (336 μl) in tetrahydrofuran (6.0 ml) Phenyl chloroformate (202 microliters) was added dropwise to the mixture, and the reaction was completed at room temperature for 1 hour.

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：67.4%)。LCMS：RT=4.52min。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane=1/1). Obtain 480 mg of white solid (S)-5-(2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (Yield: 67.4%). LCMS: RT=4.52min.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step P: Synthesis of 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-(5 -Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和1,4-二惡烷-2-甲胺鹽酸鹽(207毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and 1,4-dioxane-2-methylamine hydrochloride (207 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg , 1.4 mmol), after dripping, react at 65°C overnight.

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：39.1%)。LCMS：RT=4.19min,[M+H]⁺=913.33。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). Obtain 50 mg of white solid 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-( 5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 39.1%). LCMS: RT=4.19min, [M+H] ⁺ =913.33.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Step Q: Synthesis of 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-(5 -Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(50毫克，0.05毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-( 5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (50 mg, 0.05 mmol) was added to dichloromethane (2.0 mL), and trifluoroacetic acid was added dropwise (0.5 ml), react at room temperature for 3 hours.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸(收率：63.4%)。LCMS：RT=3.20min,[M-H]^-=755.05。¹H NMR(500MHz,DMSO)δ 12.95(s,1H),11.75(s,1H),10.16(s,1H),9.81(s,1H),8.53(s,1H),8.02(s,1H),7.97(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.39(d,J=8.9Hz,1H),7.34(dd,J=9.7,2.8Hz,3H),7.15(d,J=5.3Hz,2H),7.08(d,J=1.6Hz,1H),6.23(t,J=5.4Hz, 1H),5.29(dd,J=10.0,5.3Hz,1H),3.81-3.69(m,3H),3.67-3.58(m,2H),3.58-3.49(m,2H),3.49-3.42(m,2H),3.28-3.19(m,2H),3.09-2.97(m,2H),2.12-1.91(m,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 24 mg of white solid 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl )-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

1-yl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 63.4%). LCMS: RT=3.20min, [MH] ^- =755.05. ¹ H NMR (500MHz, DMSO) δ 12.95 (s, 1H), 11.75 (s, 1H), 10.16 (s, 1H), 9.81 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H) ,7.97(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.78(dd, J =8.6,2.3Hz,1H),7.39(d, J =8.9Hz,1H) ,7.34(dd, J =9.7,2.8Hz,3H),7.15(d, J =5.3Hz,2H),7.08(d, J =1.6Hz,1H),6.23(t, J =5.4Hz, 1H) ,5.29(dd, J =10.0,5.3Hz,1H),3.81-3.69(m,3H),3.67-3.58(m,2H),3.58-3.49(m,2H),3.49-3.42(m,2H) , 3.28-3.19 (m, 2H), 3.09-2.97 (m, 2H), 2.12-1.91 (m, 2H).

Example 36

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和(R)-3-氨基丁醇(121毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢， 65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and (R)-3-aminobutanol (121 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol), After dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：48.5%)。LCMS：RT=4.15min,[M-H]^-=883.52。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 60 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (yield: 48.5%). LCMS: RT=4.15min, [MH] ^- =883.52.

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(60毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (60 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((R)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：64.7%)。LCMS：RT=3.19min,[M-H]^-= 727.19。¹H NMR(500MHz,DMSO)δ 12.92(s,1H),11.72(s,1H),10.13(s,1H),9.80(s,1H),8.31(s,1H),8.02(s,1H),7.97(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.37(dd,J=24.4,8.6Hz,4H),7.14(d,J=8.4Hz,2H),7.08(d,J=1.7Hz,1H),6.01(d,J=7.7Hz,1H),5.29(dd,J=10.0,5.7Hz,1H),3.78(dd,J=16.1,8.9Hz,3H),3.45(d,J=10.3Hz,4H),3.22(dd,J=13.8,6.2Hz,2H),3.01(dd,J=14.9,10.7Hz,2H),1.10(d,J=6.6Hz,3H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 33 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (Yield: 64.7%). LCMS: RT=3.19min, [MH] ^- = 727.19. ¹ H NMR (500MHz, DMSO) δ 12.92 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.80 (s, 1H), 8.31 (s, 1H), 8.02 (s, 1H) ,7.97(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.78(dd, J =8.6,2.3Hz,1H),7.37(dd, J =24.4,8.6Hz, 4H), 7.14(d, J =8.4Hz,2H), 7.08(d, J =1.7Hz,1H), 6.01(d, J =7.7Hz,1H), 5.29(dd, J =10.0,5.7Hz, 1H), 3.78(dd, J =16.1,8.9Hz,3H), 3.45(d, J =10.3Hz,4H), 3.22(dd, J =13.8,6.2Hz,2H),3.01(dd, J =14.9 ,10.7Hz,2H),1.10(d, J =6.6Hz,3H).

Example 37

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔 丁酯(120毫克，0.14毫摩爾)和(S)-3-氨基丁醇(121毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and (S)-3-aminobutanol (121 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) were added dropwise with N,N -diisopropylethylamine (174 mg, 1.4 mmol), After dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：44.5%)。LCMS：RT=4.15min,[M-H]^-=883.29。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 55 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (yield: 44.5%). LCMS: RT=4.15min, [MH] ^- =883.29.

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(55毫克，0.06毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propanamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (55 mg, 0.06 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((S)-4-羥基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：49.1%)。LCMS：RT=3.20min,[M-H]^-=727.15。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.73(s,1H),10.13(s,1H),9.79(s,1H),8.30(s,1H),8.01(d,J=1.4Hz,1H),7.96(d,J=2.3Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=9.0,1.8Hz,1H),7.42-7.31(m,3H),7.13(d,J=7.7Hz,2H),7.07(d,J=2.2Hz,1H),6.00(d,J=8.0Hz,1H),5.29(dd,J=9.8,5.6Hz,1H),3.77(dd,J=20.3,8.9Hz,3H),3.53-3.40(m,4H),3.20(d,J=10.0Hz,2H),2.98(s,2H),1.09(d,J=6.6Hz,3H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 25 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3- Dioxopiperidin

-1-yl)-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (Yield: 49.1%). LCMS: RT=3.20min, [MH] ^- =727.15. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.73 (s, 1H), 10.13 (s, 1H), 9.79 (s, 1H), 8.30 (s, 1H), 8.01 (d, J = 1.4Hz,1H),7.96(d, J =2.3Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =9.0,1.8Hz,1H),7.42-7.31(m, 3H), 7.13(d, J =7.7Hz,2H), 7.07(d, J =2.2Hz,1H),6.00(d, J =8.0Hz,1H), 5.29(dd, J =9.8,5.6Hz, 1H), 3.77(dd, J = 20.3, 8.9Hz, 3H), 3.53-3.40(m, 4H), 3.20(d, J =10.0Hz, 2H), 2.98(s, 2H), 1.09(d, J =6.6Hz,3H).

Example 38

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole -1,2-Di-tert-butyl dicarboxylic acid

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和L-纈氨醇(140毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and L-valinol (140 mg, 1.4 mmol) in tetrahydrofuran (3.0 ml) were added dropwise with N,N -diisopropylethylamine (174 mg, 1.4 mmol), and the drop was completed, 65 React overnight at °C.

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：77.5%)。LCMS：RT=4.21min,[M-H]^-=897.28。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 65 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole -Di-tert-butyl 1,2-dicarboxylic acid (yield: 77.5%). LCMS: RT=4.21min, [MH] ^- =897.28.

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(65毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸 (0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate (65 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((S)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：56.1%)。LCMS：RT=3.29min,[M-H]^-=741.20。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.72(s,1H),10.14(s,1H),9.80(s,1H),8.45(s,1H),8.01(s,1H),7.96(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.36(dd,J=17.8,8.6Hz,3H),7.13(d,J=8.4Hz,2H),7.07(d,J=2.3Hz,1H),5.98(d,J=9.2Hz,1H),5.28(dd,J=10.5,5.9Hz,1H),3.59-3.41(m,3H),3.33(s,3H),3.22(dd,J=15.2,1.4Hz,2H),3.01(dd,J=9.9,7.2Hz,2H),0.88(dd,J=11.8,6.8Hz,6H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 28 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid (yield: 56.1%). LCMS: RT=3.29min, [MH] ^- =741.20. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.80 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H) ,7.96(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.36(dd, J =17.8,8.6Hz, 3H), 7.13(d, J =8.4Hz,2H), 7.07(d, J =2.3Hz,1H), 5.98(d, J =9.2Hz,1H), 5.28(dd, J =10.5,5.9Hz, 1H),3.59-3.41(m,3H),3.33(s,3H),3.22(dd, J =15.2,1.4Hz,2H),3.01(dd, J =9.9,7.2Hz,2H),0.88(dd ,J=11.8,6.8Hz,6H).

Example 39

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2- 二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1 H -indole -1,2-Di-tert-butyl dicarboxylic acid

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和D-纈氨醇(140毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and D-valinol (140 mg, 1.4 mmol) in tetrahydrofuran (3.0 ml) were added dropwise with N,N -diisopropylethylamine (174 mg, 1.4 mmol), the drop was completed, 65 React overnight at °C.

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：73.9%)。LCMS：RT=4.21min,[M-H]^-=897.25。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 62 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1 H -indole -Di-tert-butyl 1,2-dicarboxylic acid (yield: 73.9%). LCMS: RT=4.21min, [MH] ^- =897.25.

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(62毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate (62 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：38.1%)。LCMS：RT=3.30min,[M-H]^-=741.16。¹H NMR(400MHz,DMSO)δ 12.93(s,1H),11.72(s,1H),10.13(s,1H),9.80(s,1H),8.44(s,1H),8.01(s,1H),7.96(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.36(dd,J=18.0,8.5Hz,3H),7.13(d,J=8.2Hz,2H),7.07(d,J=1.6Hz,1H),5.98(d,J=7.9Hz,1H),5.28(dd,J=10.0,5.1Hz,1H),3.44(dd,J=8.6,4.1Hz,3H),3.35(dd,J=12.0,6.7Hz,3H),3.26-3.16(m,2H),3.08-2.95(m,2H),0.88(dd,J=11.9,6.8Hz,6H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 19 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid (yield: 38.1%). LCMS: RT=3.30min, [MH] ^- =741.16. ¹ H NMR (400MHz, DMSO) δ 12.93 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.80 (s, 1H), 8.44 (s, 1H), 8.01 (s, 1H) ,7.96(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.36(dd, J =18.0,8.5Hz, 3H), 7.13(d, J =8.2Hz,2H), 7.07(d, J =1.6Hz,1H), 5.98(d, J =7.9Hz,1H), 5.28(dd, J =10.0,5.1Hz, 1H), 3.44(dd, J =8.6,4.1Hz,3H), 3.35(dd, J =12.0,6.7Hz,3H),3.26-3.16(m,2H),3.08-2.95(m,2H),0.88 (dd, J =11.9, 6.8Hz, 6H).

Example 40

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -1,2-Di-tert-butyl dicarboxylic acid

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和3-甲基-3-胺甲基-1-氧雜環丁烷(136毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and 3-methyl-3-aminomethyl-1-oxetane (136 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) were added dropwise with N,N -diisopropylethylamine (174 mg, 1.4 mmol), after dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲基)脲基)苯基)丙醯胺基)- 1H-吲哚-1,2-二羧酸二叔丁酯(收率：59.8%)。LCMS：RT=4.20min,[M+H]⁺=897.39。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 75 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -Di-tert-butyl 1,2-dicarboxylic acid (yield: 59.8%). LCMS: RT=4.20min, [M+H] ⁺ =897.39.

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((R)-1-羥基-3-甲基丁-2-基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(75毫克，0.08毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate (75 mg, 0.08 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：54.0%)。LCMS：RT=2.75min,[M+H]⁺=740.95。¹H NMR(400MHz,DMSO)δ 12.96(s,1H),11.75(s,1H),10.85(s,1H),10.15(s,1H),9.79(s,1H),9.34(s,1H),8.01(d,J=1.2Hz,1H),7.95(d,J=2.2Hz,1H),7.84(d,J=8.7Hz,1H),7.79(dd,J=8.6,2.2Hz,1H),7.37(dt,J=10.8,5.4Hz,3H),7.28(d,J=8.4Hz,2H),7.08(d,J=1.5Hz,1H),5.35(s,1H), 5.13(s,1H),4.47(d,J=9.1Hz,1H),4.33(d,J=11.9Hz,1H),3.42-3.26(m,5H),3.12(t,J=11.2Hz,2H),1.00(s,3H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 32 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid (yield: 54.0%). LCMS: RT=2.75min, [M+H] ⁺ =740.95. ¹ H NMR (400MHz, DMSO) δ 12.96 (s, 1H), 11.75 (s, 1H), 10.85 (s, 1H), 10.15 (s, 1H), 9.79 (s, 1H), 9.34 (s, 1H) ,8.01(d, J =1.2Hz,1H),7.95(d, J =2.2Hz,1H),7.84(d, J =8.7Hz,1H),7.79(dd, J =8.6,2.2Hz,1H) ,7.37(dt, J =10.8,5.4Hz,3H),7.28(d, J =8.4Hz,2H),7.08(d, J =1.5Hz,1H),5.35(s,1H), 5.13(s, 1H), 4.47(d, J =9.1Hz,1H),4.33(d, J =11.9Hz,1H),3.42-3.26(m,5H),3.12(t, J =11.2Hz,2H),1.00( s,3H).

Example 41

-1-基)-3-(4-((R)-2-(羥甲基)嗎啉-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)morpholine-4-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((R)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和(R)-2-嗎啉甲醇鹽酸鹽(208毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and (R)-2-morpholine methanol hydrochloride (208 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol) Mol), after dripping, react at 65°C overnight.

-1-基)-3-(4-((R)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：52.0%)。LCMS：RT=4.11min,[M-H]^-=911.35。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 65 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1H-indole-1,2-di Di-tert-butyl carboxylate (yield: 52.0%). LCMS: RT=4.11min, [MH] ^- =911.35.

-1-基)-3-(4-((R)-2-(羥甲基)嗎啉-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)morpholine-4-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((R)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(65毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (65 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((3-甲基氧雜環丁烷-3-基)甲 基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：47.2%)。LCMS：RT=3.14min,[M+H]⁺=757.17。¹H NMR(400MHz,DMSO)δ 12.87(s,1H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.52(s,1H),8.03-7.98(m,1H),7.95(d,J=2.3Hz,1H),7.82(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.3Hz,1H),7.40(dd,J=14.8,8.7Hz,3H),7.32(dd,J=8.9,1.9Hz,1H),7.15(d,J=8.3Hz,1H),7.06(d,J=1.5Hz,1H),5.30(dd,J=9.9,5.7Hz,1H),4.05(d,J=12.7Hz,2H),3.92(d,J=13.0Hz,2H),3.85(ddd,J=10.3,1.8,0.9Hz,2H),3.38(dd,J=8.9,5.8Hz,4H),3.23(dd,J=14.7,3.0Hz,2H),3.01(dd,J=16.3,9.3Hz,1H),2.88(td,J=12.6,3.1Hz,1H),2.68-2.56(m,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 25 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((3-methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1 H -indole -2-carboxylic acid (yield: 47.2%). LCMS: RT=3.14min, [M+H] ⁺ =757.17. ¹ H NMR (400MHz, DMSO) δ 12.87 (s, 1H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.52 (s, 1H), 8.03-7.98 (m, 1H),7.95(d, J =2.3Hz,1H),7.82(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.3Hz,1H),7.40(dd, J =14.8,8.7 Hz,3H),7.32(dd, J =8.9,1.9Hz,1H),7.15(d, J =8.3Hz,1H),7.06(d, J =1.5Hz,1H),5.30(dd, J =9.9 ,5.7Hz,1H),4.05(d, J =12.7Hz,2H),3.92(d, J =13.0Hz,2H), 3.85(ddd, J =10.3,1.8,0.9Hz,2H), 3.38(dd , J =8.9,5.8Hz,4H), 3.23(dd, J =14.7,3.0Hz,2H), 3.01(dd, J =16.3,9.3Hz,1H), 2.88(td, J =12.6,3.1Hz, 1H), 2.68-2.56 (m, 1H).

Example 42

-1-基)-3-(4-((S)-2-(羥甲基)嗎啉-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((S)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和(S)-2-嗎啉甲醇鹽酸鹽鹽酸鹽(208毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and (S)-2-morpholine methanol hydrochloride hydrochloride (208 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg , 1.4 mmol), after dripping, react at 65°C overnight.

-1-基)-3-(4-((S)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：47.0%)。LCMS：RT=4.10min,[M-H]^-=911.41。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 60 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (yield: 47.0%). LCMS: RT=4.10min, [MH] ^- =911.41.

-1-基)-3-(4-((S)-2-(羥甲基)嗎啉-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((S)-2-(羥基甲基)嗎啉-4-甲醯氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(60毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-methanoylamino)phenyl)propionylamino)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (60 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((S)-2-(羥甲基)嗎啉-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：56.6%)。LCMS：RT=3.15min,[M-H]^-=755.12。¹H NMR(400MHz,DMSO)δ 12.95(s,1H),11.73(s,1H),10.14(s,1H),9.80(s,1H),8.53(s,1H),8.01(s,1H),7.96(d,J=2.2Hz,1H),7.83(d,J=8.7Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.40(dd,J=14.9,8.7Hz,3H),7.33(dd,J=8.9,1.7Hz,1H),7.16(d,J=7.8Hz,2H),7.07(d,J=1.5Hz,1H),5.31(dd,J=10.2,5.2Hz,1H),4.06(d,J=13.8Hz,2H),3.98-3.81(m,3H),3.80-3.68(m,2H),3.43-3.34(m,4H),3.24(dd,J=15.6,7.0Hz,1H),3.09-2.96(m,1H),2.88(dd,J=17.0,6.9Hz,1H),2.74-2.57(m,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 30 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)morpholine-4-carboxamido)phenyl)propionamido)-1 H -indole-2- Carboxylic acid (yield: 56.6%). LCMS: RT=3.15min, [MH] ^- =755.12. ¹ H NMR (400MHz, DMSO) δ 12.95 (s, 1H), 11.73 (s, 1H), 10.14 (s, 1H), 9.80 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H) ,7.96(d, J =2.2Hz,1H),7.83(d, J =8.7Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.40(dd, J =14.9,8.7Hz, 3H),7.33(dd, J =8.9,1.7Hz,1H),7.16(d, J =7.8Hz,2H),7.07(d, J =1.5Hz,1H),5.31(dd, J =10.2,5.2 Hz,1H),4.06(d, J =13.8Hz,2H),3.98-3.81(m,3H), 3.80-3.68(m,2H),3.43-3.34(m,4H), 3.24(dd, J = 15.6, 7.0 Hz, 1H), 3.09-2.96 (m, 1H), 2.88 (dd, J =17.0, 6.9 Hz, 1H), 2.74-2.57 (m, 1H).

Example 43

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propionylamino)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和反式-4-氨基環己醇(155毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and trans-4-aminocyclohexanol (155 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol), After dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚- 1,2-二羧酸二叔丁酯(收率：27.4%)。LCMS：RT=4.12min,[M-H]^-=909.22。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 35 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (yield: 27.4%). LCMS: RT=4.12min, [MH] ^- =909.22.

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(35毫克，0.04毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propionylamino)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (35 mg, 0.04 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((1R,4S)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：49.6%)。LCMS：RT=3.18min,[M+H]⁺=755.14。¹H NMR(400MHz,DMSO)δ 12.93(s,1H),11.72(s,1H),10.13(s,1H),9.79(s,1H),8.25(s,1H),8.01(d,J=1.6Hz,1H),7.95(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.44-7.31(m,4H),7.13(d,J=7.7Hz,2H),7.07(d,J=1.8Hz,1H),5.99(d,J=7.7Hz,1H),5.28(dd,J=10.2,5.0Hz,1H),3.87-3.55(m,3H),3.21(d,J=12.8Hz,2H),3.08-2.93(m,1H),1.82(t,J=14.3Hz,4H),1.20(dt,J=21.9,11.2Hz,4H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 15 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((1R,4S)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid ( Yield: 49.6%). LCMS: RT=3.18min, [M+H] ⁺ =755.14. ¹ H NMR (400MHz, DMSO) δ 12.93 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.79 (s, 1H), 8.25 (s, 1H), 8.01 (d, J = 1.6Hz,1H),7.95(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.44-7.31(m, 4H), 7.13(d, J =7.7Hz,2H), 7.07(d, J =1.8Hz,1H), 5.99(d, J =7.7Hz,1H), 5.28(dd, J =10.2,5.0Hz, 1H), 3.87-3.55(m, 3H), 3.21(d, J =12.8Hz, 2H), 3.08-2.93(m, 1H), 1.82(t, J =14.3Hz, 4H), 1.20(dt, J =21.9, 11.2Hz, 4H).

Example 44

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- 2-carboxylic acid

The specific synthesis route is as follows: Step A: Synthesis of tert-butyl 5-nitrobenzofuran-2-carboxylate

At room temperature, add 5-nitrobenzofuran-2-carboxylic acid (1.8 g, 8.7 mmol) and di-tert-butyl dicarbonate (4.8 g, 22.0 mmol) to N,N -dimethylformamide (20 ml), under ice bath, add 4-dimethylaminopyridine (0.54 g, 4.4 mmol) in batches _{, and react under N 2} protection at room temperature overnight.

After the reaction is over, add water to quench, add 100 ml of ethyl acetate, pad celite for suction filtration, wash the filter cake with 50 ml of ethyl acetate, extract the filtrate with ethyl acetate (100 ml × 3 times), combine the organic phases, and organic The phase was washed with saturated brine (100 ml×2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain 1.9 g of light yellow solid 5-nitrobenzofuran-2-carboxylic acid tert-butyl ester without purification. , Directly used in the next reaction. LCMS: RT=4.34min.

Step B: Synthesis of tert-butyl 5-aminobenzofuran-2-carboxylate

At room temperature, dissolve 5-nitrobenzofuran-2-carboxylic acid tert-butyl ester (1.9 g, 7.2 mmol l) in ethyl acetate, add palladium on carbon (0.5 g), install a hydrogen balloon, at room temperature React for 9 hours.

After the reaction was completed, the palladium carbon was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). 1.4 g of tert-butyl 5-aminobenzofuran-2-carboxylate was obtained as a brown solid (yield: 83.4%). LCMS: RT=3.05min, [M+H] ⁺ =234.11.

-1-基)-3-(-4-硝基苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯

Step C: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester

-1-基)-3-(4-硝基苯基)丙酸(350毫克，0.7毫摩爾)、5-氨基苯並呋喃-2-羧酸叔丁酯(185毫克，0.8毫摩爾)和2-(7-氧化苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸鹽(411毫克，1.1毫摩爾)加入N,N-二甲基甲醯胺(5.0毫升)中，滴加N,N-二異丙基乙胺(280毫克，2.2毫摩爾)，滴畢，N₂保護下，室溫反應過夜。 At room temperature, (S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-nitrophenyl)propionic acid (350 mg, 0.7 mmol), tert-butyl 5-aminobenzofuran-2-carboxylate (185 mg, 0.8 mmol) and 2-(7-benzotriazole oxide) -N,N,N',N' -tetramethylurea hexafluorophosphate (411 mg, 1.1 mmol) was added to N,N -dimethylformamide (5.0 ml), N,N -diisopropylethylamine (280 mg, 2.2 mmol) was added dropwise, after the dropping, the reaction was carried out at room temperature overnight under the protection of _{N 2.}

-1-基)-3-(-4-硝基苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(收率：41.1%)。LCMS：RT=4.15min,[M+H]⁺=699.11。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 400 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester (yield: 41.1%). LCMS: RT=4.15min, [M+H] ⁺ =699.11.

-1-基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯

Step D: Synthesis of (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2, 3-dioxopiperidine

-1-yl) propanamido) benzofuran-2-carboxylic acid tert-butyl ester

-1-基)-3-(-4-硝基苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(400毫克，0.57毫摩爾)和還原鐵粉(320毫克，5.7毫摩爾)加入甲醇(15.0毫升)中，滴加冰醋酸(1.0毫升)，65℃反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-nitrophenyl) propanamido)benzofuran-2-carboxylic acid tert-butyl ester (400 mg, 0.57 mmol) and reduced iron powder (320 mg, 5.7 (Mmol) was added to methanol (15.0 ml), glacial acetic acid (1.0 ml) was added dropwise, and the reaction was carried out at 65°C for 3 hours.

-1-基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(收率：82.1%)。LCMS：RT=3.58min,[M+H]⁺=671.24。 After the reaction was completed, the reaction solution was diluted by adding 10 ml of ethyl acetate, filtered through a pad of celite, the filter cake was washed with ethyl acetate, the filtrate was adjusted to pH 10 with saturated sodium bicarbonate, and the mixture was diluted with ethyl acetate (30 ml × 3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml × 2 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 314 mg of yellow solid (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2 ,3-dioxopiperidine

-1-yl)propylamino)benzofuran-2-carboxylic acid tert-butyl ester (yield: 82.1%). LCMS: RT=3.58min, [M+H] ⁺ =671.24.

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯

Step E: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester

-1-基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(314毫克，0.47毫摩爾)四氫呋喃(6.0毫升)中滴加氯甲酸苯酯(117微升)，滴畢，室溫反應1小時。 N ₂ protection, under ice bath, to contain (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl) (Phenyl)-2,3-dioxopiperidine

-1-yl) propylamino) benzofuran-2-carboxylic acid tert-butyl ester (314 mg, 0.47 mmol) tetrahydrofuran (6.0 ml) was added dropwise to phenyl chloroformate (117 μl), and the dripping was completed. React at room temperature for 1 hour.

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(收率：39.5%)。LCMS：RT=4.20min,[M-H]^-=789.21。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/dichloromethane=1/1). Obtain 147 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester (yield: 39.5%). LCMS: RT=4.20min, [MH] ^- =789.21.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯

Step F: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- Tert-Butyl 2-carboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(80毫克，0.10毫摩爾)和L-異亮氨醇(120毫克，1.0毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(131毫克，1.0毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester (80 mg, 0.10 mmol) and L -Isoleucinol (120 mg, 1.0 mmol) in tetrahydrofuran (3.0 mL) was added dropwise with N,N -diisopropylethylamine (131 mg, 1.0 mmol), the dripping was completed, and the reaction was carried out at 65°C overnight.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(收率：55.3%)。LCMS：RT=3.98min,[M+H]⁺=814.16。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). Obtain 45 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- Tert-Butyl 2-carboxylate (yield: 55.3%). LCMS: RT=3.98min, [M+H] ⁺ =814.16.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸

Step G: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- 2-carboxylic acid

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(45毫克，0.05毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- Tert-butyl 2-carboxylate (45 mg, 0.05 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸(收率：24.1%)。LCMS：RT=3.58min, [M-H]^-=756.32。¹H NMR(500MHz,DMSO)δ 13.57(s,1H),10.38(s,1H),9.81(s,1H),8.47(s,1H),8.19(d,J=1.9Hz,1H),7.97(d,J=2.2Hz,1H),7.84(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.70(s,1H),7.68(d,J=9.0Hz,1H),7.59-7.54(m,2H),7.35(d,J=8.4Hz,2H),7.14(d,J=7.2Hz,2H),6.02(d,J=8.5Hz,1H),5.30(dd,J=10.0,5.6Hz,1H),3.59-3.45(m,3H),3.41(dd,J=10.5,4.5Hz,3H),3.28-3.14(m,2H),3.02(dd,J=12.6,9.5Hz,1H),1.68-1.56(m,1H),1.56-1.42(m,1H),1.08(dt,J=23.4,9.1Hz,1H),0.87(t,J=6.7Hz,6H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 10 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)benzofuran- 2-carboxylic acid (yield: 24.1%). LCMS: RT=3.58min, [MH] ^- =756.32. ¹ H NMR (500MHz, DMSO) δ 13.57 (s, 1H), 10.38 (s, 1H), 9.81 (s, 1H), 8.47 (s, 1H), 8.19 (d, J = 1.9Hz, 1H), 7.97 (d, J =2.2Hz,1H),7.84(d, J =8.6Hz,1H),7.78(dd, J =8.6,2.3Hz,1H),7.70(s,1H),7.68(d, J = 9.0Hz,1H), 7.59-7.54(m,2H), 7.35(d, J =8.4Hz,2H), 7.14(d, J =7.2Hz,2H), 6.02(d, J =8.5Hz,1H) ,5.30(dd, J =10.0,5.6Hz,1H),3.59-3.45(m,3H),3.41(dd, J =10.5,4.5Hz,3H),3.28-3.14(m,2H),3.02(dd , J =12.6,9.5Hz,1H),1.68-1.56(m,1H),1.56-1.42(m,1H),1.08(dt, J =23.4,9.1Hz,1H),0.87(t, J =6.7 Hz, 6H).

Example 45

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(200毫克，0.22毫摩爾)和3-羥甲基哌啶(260毫克，2.2毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(290毫克，2.2毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (200 mg , 0.22 mmol) and 3-hydroxymethylpiperidine (260 mg, 2.2 mmol) in tetrahydrofuran (5.0 mL) were added dropwise N,N -diisopropylethylamine (290 mg, 2.2 mmol), dropwise After that, react at 65°C overnight.

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：39.9%)。LCMS：RT=3.74min,[M-H]^-=909.22。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 80 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (yield: 39.9%). LCMS: RT=3.74min, [MH] ^- =909.22.

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(80毫克，0.09毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester (80 mg, 0.09 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：39.7%)。LCMS：RT=3.28min,[M+H]⁺=755.10。¹H NMR(500MHz,DMSO)δ 12.94(s,1H),11.74(s,1H),10.17(s,1H),9.82(s,1H),8.43(s,1H),8.02(s,1H),7.97(d,J=2.3Hz,1H),7.84(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.40(t,J=9.1Hz,3H),7.34(dd,J=8.9,1.9Hz,1H),7.15(d,J=8.0Hz,2H),7.08(d,J=1.5Hz,1H),5.31(dd,J=9.8,5.6Hz,1H),4.08(d,J=13.9Hz,2H),3.97(d,J=10.5Hz,2H),3.39-3.19(m,4H),3.08-2.91(m,2H),2.81(t,J=13.1Hz,1H),2.12-1.94(m,1H),1.74(d,J=12.0Hz,1H),1.63(d,J=12.5Hz,1H),1.55(s,1H),1.40(d,J=16.4Hz,1H),1.23-1.11(m,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 27 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (closed Rate: 39.7%). LCMS: RT=3.28 min, [M+H] ⁺ =755.10. ¹ H NMR (500MHz, DMSO) δ 12.94 (s, 1H), 11.74 (s, 1H), 10.17 (s, 1H), 9.82 (s, 1H), 8.43 (s, 1H), 8.02 (s, 1H) ,7.97(d, J =2.3Hz,1H),7.84(d, J =8.6Hz,1H),7.78(dd, J =8.6,2.3Hz,1H),7.40(t, J =9.1Hz,3H) ,7.34(dd, J =8.9,1.9Hz,1H),7.15(d, J =8.0Hz,2H),7.08(d, J =1.5Hz,1H),5.31(dd, J =9.8,5.6Hz, 1H),4.08(d, J =13.9Hz,2H),3.97(d, J =10.5Hz,2H),3.39-3.19(m,4H),3.08-2.91(m,2H),2.81(t, J =13.1Hz,1H),2.12-1.94(m,1H),1.74(d, J =12.0Hz,1H),1.63(d, J =12.5Hz,1H),1.55(s,1H),1.40(d , J =16.4Hz,1H),1.23-1.11(m,1H).

Example 46

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionamido)benzofuran-2-carboxylic acid

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(75毫克，0.09毫摩爾)和3-氨基-3-甲基-1-丁醇(98毫克，0.9毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(123毫克，0.9毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl ester (75 mg, 0.09 mmol) and 3 -Amino-3-methyl-1-butanol (98mg, 0.9mmol) in tetrahydrofuran (3.0ml) was added dropwise N,N -diisopropylethylamine (123mg, 0.9mmol), dripping , React at 65°C overnight.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔丁酯(收率：48.6%)。LCMS：RT=3.90min,[M+H]⁺=798.28。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). Obtain 35 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl Ester (yield: 48.6%). LCMS: RT=3.90min, [M+H] ⁺ =798.28.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionamido)benzofuran-2-carboxylic acid

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸叔 丁酯(35毫克，0.04毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)benzofuran-2-carboxylic acid tert-butyl The ester (35 mg, 0.04 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-(4-羥基-2-甲基丁-2-基)脲基)苯基)丙醯胺基)苯並呋喃-2-羧酸(收率：23.5%)。LCMS：RT=3.45min,[M-H]^-=742.12。¹H NMR(500MHz,DMSO)δ 13.57(s,1H),10.38(s,1H),9.81(s,1H),8.31(s,1H),8.19(d,J=1.8Hz,1H),7.97(d,J=2.2Hz,1H),7.84(d,J=8.6Hz,1H),7.78(dd,J=8.6,2.3Hz,1H),7.68(d,J=9.2Hz,2H),7.57(d,J=10.9Hz,1H),7.32(d,J=8.5Hz,2H),7.13(d,J=6.5Hz,2H),6.01(s,1H),5.30(dd,J=10.0,5.7Hz,1H),4.39(t,J=5.0Hz,1H),3.51(dd,J=11.8,7.2Hz,2H),3.23(dd,J=13.7,4.9Hz,1H),3.11-2.98(m,1H),2.02(dd,J=17.3,9.6Hz,1H),1.82(t,J=7.3Hz,2H),1.55-1.42(m,1H),1.28(s,6H),0.87(t,J=6.4Hz,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 7 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propanamido)benzofuran-2-carboxylic acid Rate: 23.5%). LCMS: RT=3.45min, [MH] ^- =742.12. ¹ H NMR (500MHz, DMSO) δ 13.57 (s, 1H), 10.38 (s, 1H), 9.81 (s, 1H), 8.31 (s, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.97 (d, J =2.2Hz,1H),7.84(d, J =8.6Hz,1H),7.78(dd, J =8.6,2.3Hz,1H),7.68(d, J =9.2Hz,2H),7.57 (d, J =10.9Hz,1H),7.32(d, J =8.5Hz,2H),7.13(d, J =6.5Hz,2H),6.01(s,1H),5.30(dd, J =10.0, 5.7Hz,1H), 4.39(t, J =5.0Hz,1H), 3.51(dd, J =11.8,7.2Hz,2H), 3.23(dd, J =13.7,4.9Hz,1H),3.11-2.98( m,1H),2.02(dd, J =17.3,9.6Hz,1H),1.82(t, J =7.3Hz,2H),1.55-1.42(m,1H),1.28(s,6H),0.87(t , J =6.4Hz,1H).

Example 47

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和順式-4-氨基環己醇(155毫克，1.4毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg, 0.14 mmol) and cis-4-aminocyclohexanol (155 mg, 1.4 mmol) in tetrahydrofuran (3.0 mL) was added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol), After dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：47.0%)。LCMS：RT=4.12min,[M-H]^-=909.22。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 60 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester (yield: 47.0%). LCMS: RT=4.12min, [MH] ^- =909.22.

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(60毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (60 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((1R,4R)-4-羥基環己基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：37.9%)。LCMS：RT=3.21min,[M+H]⁺=755.20。¹H NMR(400MHz,DMSO)δ 12.92(s,1H),11.73(s,1H),10.13(s,1H),9.80(s,1H),8.28(s,1H),8.01(d,J=1.8Hz,1H),7.96(d,J=2.3Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.39(d,J=9.0Hz,1H),7.33(d,J=8.6Hz,2H),7.13(d,J=9.1Hz,2H),7.07(d,J=2.0Hz,1H),5.28(dd,J=9.5,5.6Hz,1H),4.47(s,1H),3.74(s,1H),3.67-3.52(m,2H),3.21(dd,J=19.3,5.3Hz,2H),3.09-2.88(m,2H),1.77-1.27(m,8H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 20 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(3-((1R,4R)-4-hydroxycyclohexyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid ( Yield: 37.9%). LCMS: RT=3.21min, [M+H] ⁺ =755.20. ¹ H NMR (400MHz, DMSO) δ 12.92 (s, 1H), 11.73 (s, 1H), 10.13 (s, 1H), 9.80 (s, 1H), 8.28 (s, 1H), 8.01 (d, J = 1.8Hz,1H),7.96(d, J =2.3Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.39(d, J = 9.0Hz,1H),7.33(d, J =8.6Hz,2H),7.13(d, J =9.1Hz,2H), 7.07(d, J =2.0Hz,1H), 5.28(dd, J =9.5, 5.6Hz, 1H), 4.47 (s, 1H), 3.74 (s, 1H), 3.67-3.52 (m, 2H), 3.21 (dd, J =19.3, 5.3 Hz, 2H), 3.09-2.88 (m, 2H) ), 1.77-1.27 (m, 8H).

Example 48

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(120毫克，0.14毫摩爾)和L-脯氨醇(136毫克，0.14毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg , 0.14 mmol) and L-prolinol (136 mg, 0.14 mmol) in tetrahydrofuran (3.0 mL) were added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol), the dripping was completed, React at 65°C overnight.

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：31.8%)。LCMS：RT=3.78min,[M-H]^-=895.31。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 40 mg of white solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylic acid (yield: 31.8%). LCMS: RT=3.78min, [MH] ^- =895.31.

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(40毫克，0.045毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate (40 mg, 0.045 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：18.0%)。LCMS：RT=3.28min,[M+H]⁺=741.10。¹H NMR(400MHz,DMSO)δ 12.94(s,1H),11.73(s,1H),10.16(s,1H),9.80(s,1H),8.51(s,1H),8.01(s,1H),7.96(d,J=2.2Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.39(dd,J=8.5,6.3Hz,3H),7.33(dd,J=9.2,1.6Hz,1H),7.16(d,J=8.5Hz,2H),7.07(d,J=1.8Hz,1H),5.30 (dd,J=10.4,6.1Hz,1H),3.94(s,1H),3.82-3.75(m,2H),3.56(dd,J=11.6,6.2Hz,2H),3.23(dd,J=12.3,5.5Hz,1H),3.11-3.06(m,1H),3.06-2.93(m,1H),2.00(dd,J=15.9,9.1Hz,1H),1.89(dd,J=18.7,11.5Hz,2H),1.77(dd,J=14.5,7.3Hz,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 6 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- Carboxylic acid (yield: 18.0%). LCMS: RT=3.28 min, [M+H] ⁺ =741.10. ¹ H NMR (400MHz, DMSO) δ 12.94 (s, 1H), 11.73 (s, 1H), 10.16 (s, 1H), 9.80 (s, 1H), 8.51 (s, 1H), 8.01 (s, 1H) ,7.96(d, J =2.2Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.39(dd, J =8.5,6.3Hz, 3H),7.33(dd, J =9.2,1.6Hz,1H),7.16(d, J =8.5Hz,2H),7.07(d, J =1.8Hz,1H),5.30 (dd, J =10.4,6.1 Hz, 1H), 3.94 (s, 1H), 3.82-3.75 (m, 2H), 3.56 (dd, J =11.6, 6.2 Hz, 2H), 3.23 (dd, J =12.3, 5.5 Hz, 1H), 3.11 -3.06(m,1H),3.06-2.93(m,1H),2.00(dd,J=15.9,9.1Hz,1H),1.89(dd, J =18.7,11.5Hz,2H),1.77(dd, J =14.5,7.3Hz,2H).

Example 49

-1-基)-3-(4-((R)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((R)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate

-1-基)-3-(-4-((苯氧基羰基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔 丁酯(120毫克，0.14毫摩爾)和L-脯氨醇(136毫克，0.14毫摩爾)的四氫呋喃(3.0毫升)中滴加N,N-二異丙基乙胺(174毫克，1.4毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(-4-((phenoxycarbonyl)amino)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (120 mg , 0.14 mmol) and L-prolinol (136 mg, 0.14 mmol) in tetrahydrofuran (3.0 mL) were added dropwise N,N -diisopropylethylamine (174 mg, 1.4 mmol), the dripping was completed, React at 65°C overnight.

-1-基)-3-(4-((R)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：35.8%)。LCMS：RT=3.78min,[M-H]^-=895.25。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (20 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 45 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylic acid (yield: 35.8%). LCMS: RT=3.78min, [MH] ^- =895.25.

-1-基)-3-(4-((R)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- carboxylic acid

-1-基)-3-(4-((S)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(45毫克，0.05毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1, Di-tert-butyl 2-dicarboxylate (45 mg, 0.05 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((R)-2-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：54.0%)。LCMS：RT=3.28min,[M+H]⁺=741.13。¹H NMR(400MHz,DMSO)δ 13.04(s,1H),11.74(s,1H),10.16(s,1H),9.80(s,1H),8.52(s,1H),8.52(s,1H),8.01(s,1H),7.96(d,J=2.3Hz,1H),7.83(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.58-7.37(m,3H),7.35(d,J=3.8Hz,1H),7.16(d,J=8.3Hz,2H),7.07(d,J=1.5Hz,1H),5.30(dd,J=11.3,7.1Hz,1H),3.94(s,2H),3.87-3.63(m,3H),3.23(dd,J=16.8,2.5Hz,2H),3.03(dd,J=19.9,8.5Hz,1H),2.00(dd,J=14.1,7.9Hz,1H),1.88(dd,J=17.7,11.3Hz,2H),1.80-1.66(m,2H),1.59-1.40(m,1H),0.86(t,J=5.4Hz,1H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 18 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-((R)-2-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2- Carboxylic acid (yield: 54.0%). LCMS: RT=3.28 min, [M+H] ⁺ =741.13. ¹ H NMR (400MHz, DMSO) δ 13.04 (s, 1H), 11.74 (s, 1H), 10.16 (s, 1H), 9.80 (s, 1H), 8.52 (s, 1H), 8.52 (s, 1H) ,8.01(s,1H),7.96(d, J =2.3Hz,1H),7.83(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.58-7.37( m,3H),7.35(d, J =3.8Hz,1H),7.16(d, J =8.3Hz,2H),7.07(d, J =1.5Hz,1H),5.30(dd, J =11.3,7.1 Hz, 1H), 3.94 (s, 2H), 3.87-3.63 (m, 3H), 3.23 (dd, J =16.8, 2.5 Hz, 2H), 3.03 (dd, J =19.9, 8.5 Hz, 1H), 2.00 (dd, J =14.1,7.9Hz,1H),1.88(dd, J =17.7,11.3Hz,2H),1.80-1.66(m,2H),1.59-1.40(m,1H),0.86(t, J =5.4Hz,1H).

Example 50

-1-基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert Butyl

-1-基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert Butyl

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(200毫克，0.22毫摩爾)和哌啶-4-甲腈(29毫克，0.27毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(67毫克，0.67毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (200 mg, 0.22 Millimole) and piperidine-4-carbonitrile (29 mg, 0.27 mmol) in tetrahydrofuran (5.0 ml) were added dropwise N,N -diisopropylethylamine (67 mg, 0.67 mmol), and the dripping was completed. React at 65°C overnight.

-1-基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：64%)。LCMS：RT=4.26min,[M+H]⁺=906.33。¹H NMR(500MHz,DMSO)δ 10.35(s,1H),9.79(s,1H),8.53(s,1H),8.05(s,1H),7.95(d,J=2.1Hz,1H),7.86(d,J=9.0Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.1Hz,1H),7.56(dd,J=9.1,1.8Hz,1H),7.40(d,J=8.4Hz,2H),7.25(s,1H),7.16(t,J=10.8Hz,2H),5.31(dd,J=9.9,5.7Hz,1H),3.69(dd,J=9.5,5.6Hz,3H),3.30-3.21(m,4H),3.14-2.96(m,3H),1.91-1.85(m,2H),1.79-1.62(m,3H),1.60(s,9H),1.55(s,9H)。 After the reaction was completed, the mixture was quenched with water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10). Obtain 130 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert Butyl ester (yield: 64%). LCMS: RT=4.26min, [M+H] ⁺ =906.33. ¹ H NMR (500MHz, DMSO) δ 10.35 (s, 1H), 9.79 (s, 1H), 8.53 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 2.1Hz, 1H), 7.86 (d, J =9.0Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.1Hz,1H),7.56(dd, J =9.1,1.8Hz,1H) ,7.40(d, J =8.4Hz,2H),7.25(s,1H),7.16(t, J =10.8Hz,2H),5.31(dd, J =9.9,5.7Hz,1H),3.69(dd, J =9.5,5.6Hz,3H), 3.30-3.21(m,4H),3.14-2.96(m,3H),1.91-1.85(m,2H),1.79-1.62(m,3H),1.60(s, 9H), 1.55(s, 9H).

Example 51

-1- 基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-氰基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(93毫克，0.1毫摩爾)加入二氯甲烷(2.5毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert Butyl ester (93 mg, 0.1 mmol) was added to dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-氰基哌啶 -1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：39.5%)。 LCMS：RT=3.37min,[M+H]⁺=750.08。¹H NMR(500MHz,DMSO)δ 12.93(s,1H),11.72(s,1H),10.14(s,1H),9.79(s,1H),8.53(s,1H),8.00(s,1H),7.95(d,J=2.3Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.39(dd,J=12.4,8.8Hz,3H),7.32(dd,J=8.9,1.6Hz,1H),7.15(d,J=6.9Hz,2H),7.06(s,1H),5.30(dd,J=9.8,5.8Hz,1H),3.69(dd,J=9.3,5.6Hz,4H),3.30-3.15(m,4H),3.15-2.88(m,3H),1.88(dd,J=8.2,4.5Hz,2H),1.73-1.61(m,2H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 30.15 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-cyanopiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert Butyl ester (yield: 39.5%). LCMS: RT=3.37 min, [M+H] ⁺ =750.08. ¹ H NMR (500MHz, DMSO) δ 12.93 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.79 (s, 1H), 8.53 (s, 1H), 8.00 (s, 1H) ,7.95(d, J =2.3Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.39(dd, J =12.4,8.8Hz, 3H),7.32(dd, J =8.9,1.6Hz,1H),7.15(d, J =6.9Hz,2H),7.06(s,1H),5.30(dd, J =9.8,5.8Hz,1H), 3.69(dd, J =9.3,5.6Hz,4H),3.30-3.15(m,4H),3.15-2.88(m,3H),1.88(dd,J=8.2,4.5Hz,2H),1.73-1.61( m,2H).

Example 52

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-2-carboxylic acid

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(165毫克，0.18毫摩爾)和N,N-二甲基-2-(哌啶-4-基氧基)乙-1-胺(222毫克，0.56毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(191毫克，1.5毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (165 mg, 0.18 Millimoles) and N,N -dimethyl-2-(piperidin-4-yloxy)ethan-1-amine (222 mg, 0.56 mmol) in tetrahydrofuran (5.0 ml) was added dropwise N,N- Diisopropylethylamine (191 mg, 1.5 mmol) was dripped and reacted at 65°C overnight.

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：61.5%)。LCMS：RT=3.41min,[M+H]⁺=968.33。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/9). Obtain 110 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 61.5%). LCMS: RT=3.41min, [M+H] ⁺ =968.33.

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1-indole -2-carboxylic acid

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(110毫克，0.11毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Di-tert-butyl indole-1,2-dicarboxylate (110 mg, 0.11 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-(2-(二甲基氨基)乙氧基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：43.5%)。 LCMS：RT=2.77min,[M+H]⁺=812.41。¹H NMR(500MHz,DMSO)δ 12.93(s,1H),11.73(s,1H),10.14(s,1H),9.79(s,1H),9.23(s,1H),8.50(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.3Hz,1H),7.39(dd,J=12.9,8.8Hz,3H),7.33(dd,J=8.9,1.7Hz,1H),7.13(t,J=12.4Hz,2H),7.06(d,J=1.7Hz,1H),5.30(dd,J=9.7,5.8Hz,1H),3.80(d,J=13.5Hz,4H),3.75-3.71(m,3H),3.61-3.56(m,1H),3.31-3.09(m,6H),3.05-2.96(m,1H),2.80(d,J=4.9Hz,6H),1.87(d,J=9.7Hz,2H),1.44(d,J=8.9Hz,2H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 42 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(2-(dimethylamino)ethoxy)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole Dole-2-carboxylic acid (yield: 43.5%). LCMS: RT=2.77 min, [M+H] ⁺ =812.41. ¹ H NMR (500MHz, DMSO) δ 12.93 (s, 1H), 11.73 (s, 1H), 10.14 (s, 1H), 9.79 (s, 1H), 9.23 (s, 1H), 8.50 (s, 1H) ,8.00(s,1H),7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.3Hz,1H),7.39(dd, J =12.9,8.8Hz,3H),7.33(dd, J =8.9,1.7Hz,1H),7.13(t, J =12.4Hz,2H),7.06(d, J =1.7Hz,1H),5.30( dd, J =9.7,5.8Hz,1H),3.80(d, J =13.5Hz,4H),3.75-3.71(m,3H),3.61-3.56(m,1H),3.31-3.09(m,6H) , 3.05-2.96 (m, 1H), 2.80 (d, J = 4.9 Hz, 6H), 1.87 (d, J = 9.7 Hz, 2H), 1.44 (d, J = 8.9 Hz, 2H).

Example 53

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和4-甲氧基哌啶(39毫克，0.34毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 N,N -diisopropylethylamine (65 mg, 0.50 mmol) was added dropwise to 4-methoxypiperidine (39 mg, 0.34 mmol) in tetrahydrofuran (5.0 ml), and the dripping was completed. React at 65°C overnight.

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2- 二羧酸二叔丁酯(收率：37.2%)。LCMS：RT=4.29min,[M+H]⁺=911.25。 After the reaction was completed, the mixture was quenched with water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6). Obtain 57 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (yield: 37.2%). LCMS: RT=4.29 min, [M+H] ⁺ =911.25.

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(57.0毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (57.0 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-甲氧基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：40.4%)。LCMS：RT=3.33min,[M+H]⁺=755.15。¹H NMR(400MHz,DMSO)δ 12.92(s,1H),11.72(s,1H),10.14(s,1H),9.78(s,1H),8.46(s,1H),8.00(s,1H),7.94(d,J=2.2Hz,1H),7.78(dt,J=8.6,5.4Hz,2H),7.49-7.26(m,4H),7.09(dd,J=32.1,4.9Hz,3H),5.34-5.25(m,1H),3.76(d,J=13.8Hz,4H),3.25(s,2H),3.09(dd,J=16.3,6.6Hz,2H),3.05-2.95(m,1H),1.99(dd,J=14.4,6.8Hz,1H),1.81(s,2H),1.37(dd,J=11.3, 6.7Hz,2H),1.22(s,4H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 19.1 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-methoxypiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid (yield: 40.4 %). LCMS: RT=3.33min, [M+H] ⁺ =755.15. ¹ H NMR (400MHz, DMSO) δ 12.92 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.78 (s, 1H), 8.46 (s, 1H), 8.00 (s, 1H) ,7.94(d, J =2.2Hz,1H),7.78(dt, J =8.6,5.4Hz,2H),7.49-7.26(m,4H),7.09(dd, J =32.1,4.9Hz,3H), 5.34-5.25(m,1H), 3.76(d, J =13.8Hz,4H), 3.25(s,2H), 3.09(dd, J =16.3,6.6Hz,2H), 3.05-2.95(m,1H) ,1.99(dd, J =14.4,6.8Hz,1H),1.81(s,2H),1.37(dd, J =11.3, 6.7Hz,2H),1.22(s,4H).

Example 54

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methylpiper

-1-carboxamido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-methylpiper

-1-carboxamido) phenyl) propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.19毫摩爾)，4-甲基哌

-1-碳醯氯(47毫克，0.29毫摩爾)溶於二氯甲烷(5.0毫升)中，加入吡啶(61毫克，0.78毫摩爾)。室溫反應18小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propanamido) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.19 mmol), 4-methylpiperidine

-1-Carbon chloride (47 mg, 0.29 mmol) was dissolved in dichloromethane (5.0 mL), and pyridine (61 mg, 0.78 mmol) was added. React at room temperature for 18 hours.

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：48.3%)。LCMS：RT=3.47min,[M+H]⁺=896.29。 The reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 84 mg of light yellow solid ( S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methylpiper

-1-carboxamido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 48.3%). LCMS: RT=3.47 min, [M+H] ⁺ =896.29.

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methylpiper

-1-carboxamido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(84毫克，0.09毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-methylpiper

-1-carboxamido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (84 mg, 0.09 mmol) was added to dichloromethane (2.0 mL) In, trifluoroacetic acid (0.5 ml) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-甲基哌

-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：28.9%)。LCMS：RT=2.66min,[M+H]⁺=740.20。¹H NMR(400MHz,DMSO)δ 12.92(s,1H),11.72(s,1H),10.13(s,1H),9.79(s,1H),9.71(s,1H),8.73(s,1H),7.99(s,1H),7.94(d,J=2.2Hz,1H),7.78(dt,J=8.6,5.4Hz,2H),7.43-7.30(m,3H),7.26-7.01(m,3H),5.30 (dt,J=10.4,5.4Hz,1H),4.24(d,J=14.3Hz,2H),3.44(d,J=11.6Hz,2H),3.22(d,J=10.7Hz,1H),3.17-3.07(m,2H),2.99(d,J=10.1Hz,3H),2.81(d,J=3.7Hz,2H),1.99(dd,J=14.5,6.9Hz,1H),1.22(s,4H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 21 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-methylpiper

-1-Carboxamido)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 28.9%). LCMS: RT=2.66min, [M+H] ⁺ =740.20. ¹ H NMR (400MHz, DMSO) δ 12.92 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.79 (s, 1H), 9.71 (s, 1H), 8.73 (s, 1H) ,7.99(s,1H),7.94(d, J =2.2Hz,1H),7.78(dt, J =8.6,5.4Hz,2H),7.43-7.30(m,3H),7.26-7.01(m,3H) ),5.30 (dt, J =10.4,5.4Hz,1H), 4.24(d, J =14.3Hz,2H), 3.44(d, J =11.6Hz,2H),3.22(d, J =10.7Hz,1H ),3.17-3.07(m,2H),2.99(d, J =10.1Hz,3H), 2.81(d, J =3.7Hz,2H),1.99(dd, J =14.5,6.9Hz,1H),1.22 (s,4H).

Example 55

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-di Di-tert-butyl carboxylate

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(300毫克，0.34毫摩爾)和(R)-哌啶-3-醇(92毫克，0.67毫摩爾)的四氫 呋喃(10.0毫升)中滴加三乙胺(101毫克，1.01毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (300 mg, 0.34 Triethylamine (101 mg, 1.01 mmol) was added dropwise to (R)-piperidin-3-ol (92 mg, 0.67 mmol) in tetrahydrofuran (10.0 ml), after dripping, the reaction was carried out at 65°C overnight .

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1-吲哚-1,2-二羧酸二叔丁酯(收率：77.1%)。LCMS：RT=3.69min,[M+H]⁺=897.28。 After the reaction was completed, the mixture was quenched with water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/10). Obtain 233 mg of red-brown solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1-indole-1,2-dicarboxy Di-tert-butyl acid (yield: 77.1%). LCMS: RT=3.69min, [M+H] ⁺ =897.28.

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(233毫克，0.29毫摩爾)加入二氯甲烷(10.0毫升)中，滴加三氟乙酸(2.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-di Di-tert-butyl carboxylate (233 mg, 0.29 mmol) was added to dichloromethane (10.0 mL), trifluoroacetic acid (2.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((R))-3-羥基哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：39.9%)。LCMS：RT=3.19min,[M+H]⁺=741.21。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.72(s,1H),10.13(s,1H),9.78(s,1H),8.41(s,1H),8.00(s,1H),7.94(d,J=2.2Hz,1H),7.81(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.39(d,J=8.6Hz,2H),7.37-7.29(m,2H),7.13(d,J=8.1Hz,2H),7.05(d,J=1.6Hz,1H),5.29(dd,J=9.7,5.7Hz,1H),3.94(d,J=9.4Hz,2H),3.77(d,J=13.2Hz,2H),3.26-3.12(m,2H),3.08-2.80(m,3H),2.71-2.63(m,1H),1.75(dd,J=77.7,8.9Hz,3H),1.40-1.25(m,2H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 76.82 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid (closed Rate: 39.9%). LCMS: RT=3.19min, [M+H] ⁺ =741.21. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.72 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.41 (s, 1H), 8.00 (s, 1H) ,7.94(d, J =2.2Hz,1H),7.81(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.2Hz,1H),7.39(d, J =8.6Hz,2H) ,7.37-7.29(m,2H),7.13(d, J =8.1Hz,2H),7.05(d, J =1.6Hz,1H), 5.29(dd, J =9.7,5.7Hz,1H),3.94( d, J =9.4Hz,2H),3.77(d, J =13.2Hz,2H),3.26-3.12(m,2H),3.08-2.80(m,3H),2.71-2.63(m,1H),1.75 (dd, J = 77.7, 8.9 Hz, 3H), 1.40-1.25 (m, 2H).

Example 56

-1-基)-3-(4-(3-((2S，3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和(2S,3S)-2-氨基-3-甲基戊-1-醇(24毫克，0.20毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.5毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 (2S,3S)-2-amino-3-methylpentan-1-ol (24 mg, 0.20 mmol) in tetrahydrofuran (5.0 mL) was added dropwise N,N -diisopropylethylamine (65 mg, 0.5 mmol), after dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：46.4%)。LCMS：RT=4.29min,[M+H]⁺=913.33。 After the reaction was completed, the mixture was quenched with water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), and then dried with anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 71 mg of light yellow solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 46.4%). LCMS: RT=4.29 min, [M+H] ⁺ =913.33.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid

-1-基)-3-(4-(3-((2S，3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(71毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Di-tert-butyl indole-1,2-dicarboxylate (71 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((2S,3S)-1-羥基-3-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：48.2%)。LCMS：RT=3.40min,[M+H]⁺=757.35。¹H NMR(500MHz,DMSO)δ 12.94(s,1H),11.72(s,1H),10.14(s,1H),9.80(s,1H),8.44(s,1H),8.11-7.90(m,2H),7.90-7.70(m,2H),7.35(dd,J=22.4,8.5Hz,4H),7.27-6.98(m,3H),6.01(d,J=8.0Hz,1H),5.27(dd,J=9.9,5.5Hz,1H),4.64(s,1H),3.74(s,2H),3.46(dd,J=27.6,16.8Hz,3H),3.20(d,J=11.1Hz,1H),3.05-2.93(m,1H),1.63-1.42(m,2H),1.23(s,1H),1.14-0.98(m,1H),0.85(t,J=6.6Hz,5H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 76.82 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((2S,3S)-1-hydroxy-3-methylpent-2-yl)ureido)phenyl)propanamido)-1 H- Indole-2-carboxylic acid (yield: 48.2%). LCMS: RT=3.40min, [M+H] ⁺ =757.35. ¹ H NMR (500MHz, DMSO) δ 12.94 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.80 (s, 1H), 8.44 (s, 1H), 8.11-7.90 (m, 2H),7.90-7.70(m,2H),7.35(dd, J =22.4,8.5Hz,4H),7.27-6.98(m,3H),6.01(d, J =8.0Hz,1H),5.27(dd , J =9.9,5.5Hz,1H),4.64(s,1H),3.74(s,2H),3.46(dd, J =27.6,16.8Hz,3H), 3.20(d, J =11.1Hz,1H) , 3.05-2.93 (m, 1H), 1.63-1.42 (m, 2H), 1.23 (s, 1H), 1.14-0.98 (m, 1H), 0.85 (t, J = 6.6 Hz, 5H).

Example 57

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-carboxamido)phenyl)-2-(4-(5-chloro- 2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthetic route is as follows: Step A: Synthesis of (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-methanoamino)phenyl)-2- (4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(90毫克，0.10毫摩爾)和2-氧雜-7-氮雜螺[3.5]壬烷(38毫克，0.30毫摩爾)的四氫呋喃(2.0毫升)中滴加三乙胺(30毫克，0.30毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (90 mg, 0.10 Millimoles) and 2-oxa-7-azaspiro[3.5]nonane (38 mg, 0.30 mmol) in tetrahydrofuran (2.0 ml), and triethylamine (30 mg, 0.30 mmol) was added dropwise. , React at 65°C overnight.

-1-基)丙醯胺 基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：96.7%)。LCMS：RT=4.24min,[M+H]⁺=923.28。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5). Obtain 90 mg of light yellow solid (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-methylamino)phenyl)-2-(4- (5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)acrylamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 96.7%). LCMS: RT=4.24min, [M+H] ⁺ =923.28.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-carboxamido)phenyl)-2-(4-(5 -Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(90毫克，0.09毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-carboxamido)phenyl)-2-(4-( 5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (90 mg, 0.09 mmol) was added to dichloromethane (2.0 ml), and trifluoride was added dropwise Acetic acid (0.5 ml), react at room temperature for 3 hours.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸(收率：48.2%)。LCMS：RT=3.29min,[M+H]⁺=767.29。¹H NMR(500MHz,DMSO)δ 12.94(s,1H),11.73(s,1H),10.14(s,1H),9.80(d,J=5.9Hz,1H),8.40(d,J=35.0Hz,1H),8.00(s,1H),7.95(s,1H),7.87-7.66(m,2H),7.37(ddd,J=26.1,8.8,3.9Hz,4H),7.23- 7.11(m,2H),7.07(d,J=12.5Hz,1H),5.32-5.25(m,1H),3.49(s,2H),3.47-3.33(m,4H),3.30(d,J=9.1Hz,2H),3.22(d,J=9.3Hz,2H),3.00(s,1H),1.96(d,J=49.5Hz,1H),1.60-1.18(m,6H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, dry to obtain 24 mg of white solid (S)-5-(3-(4-(2-oxa-7-azaspiro[3.5]nonane-7-methanoamino)phenyl)-2- (4-(5-Chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

1-yl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 48.2%). LCMS: RT=3.29 min, [M+H] ⁺ =767.29. ¹ H NMR(500MHz,DMSO)δ 12.94(s,1H), 11.73(s,1H), 10.14(s,1H), 9.80(d, J =5.9Hz,1H), 8.40(d, J =35.0Hz) ,1H),8.00(s,1H),7.95(s,1H),7.87-7.66(m,2H),7.37(ddd, J =26.1,8.8,3.9Hz,4H),7.23-7.11(m,2H) ), 7.07(d, J =12.5Hz,1H),5.32-5.25(m,1H),3.49(s,2H),3.47-3.33(m,4H),3.30(d, J =9.1Hz,2H) , 3.22 (d, J =9.3Hz, 2H), 3.00 (s, 1H), 1.96 (d, J = 49.5Hz, 1H), 1.60-1.18 (m, 6H).

Example 58

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxy acid

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2 -Di-tert-butyl dicarboxylate

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.12毫摩爾)和嗎啉代(哌啶-4-基)甲酮(154毫克，0.49毫 摩爾)的四氫呋喃(2.0毫升)中滴加N,N-二異丙基乙胺(92毫克，0.72毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.12 Millimoles) and morpholino (piperidin-4-yl) ketone (154 mg, 0.49 mmol) in tetrahydrofuran (2.0 ml) was added dropwise N,N -diisopropylethylamine (92 mg, 0.72 mmol) Mol), after dripping, react at 65°C overnight.

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：96.7%)。LCMS：RT=4.19min,[M+H]⁺=994.37。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 100 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2 -Di-tert-butyl dicarboxylic acid (yield: 96.7%). LCMS: RT=4.19min, [M+H] ⁺ =994.37.

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxy acid

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(100毫克，0.1毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2 -Di-tert-butyl dicarboxylate (100 mg, 0.1 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-(嗎啉-4-羰基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：23.8%)。LCMS：RT=3.23min,[M+H]⁺=838.21。¹H NMR(500MHz,DMSO)δ 13.11(s,1H),11.51(s,1H),10.15(d,J=29.0Hz,1H),9.78(s,1H),8.45(s,1H),8.09-7.90(m,2H),7.87-7.72(m,2H),7.50(t,J=8.6Hz,1H),7.45-7.31(m,3H),7.29-7.01(m,3H),5.68(t,J=7.8Hz,1H),5.39-5.17(m,2H),4.21-4.08(m,3H),3.89-3.69(m,4H),3.25-3.19(m,1H),3.07-2.99(m,1H),2.84(t,J=11.7Hz,3H),2.25(d,J=6.8Hz,1H),2.10(d,J=20.3Hz,1H),1.99(ddd,J=14.3,13.2,6.1Hz,2H),1.87-1.81(m,1H),1.63(d,J=11.1Hz,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 20 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(4-(morpholine-4-carbonyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxy Acid (yield: 23.8%). LCMS: RT=3.23min, [M+H] ⁺ =838.21. ¹ H NMR (500MHz, DMSO) δ 13.11 (s, 1H), 11.51 (s, 1H), 10.15 (d, J = 29.0Hz, 1H), 9.78 (s, 1H), 8.45 (s, 1H), 8.09 -7.90(m,2H),7.87-7.72(m,2H),7.50(t, J =8.6Hz,1H),7.45-7.31(m,3H),7.29-7.01(m,3H),5.68(t , J = 7.8Hz, 1H), 5.39-5.17 (m, 2H), 4.21-4.08 (m, 3H), 3.89-3.69 (m, 4H), 3.25-3.19 (m, 1H), 3.07-2.99 (m ,1H),2.84(t, J =11.7Hz,3H),2.25(d, J =6.8Hz,1H),2.10(d, J =20.3Hz,1H),1.99(ddd, J =14.3,13.2, 6.1Hz, 2H), 1.87-1.81 (m, 1H), 1.63 (d, J =11.1Hz, 2H).

Example 59

-1-基)-3-(4-(3-(苯基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(3-(苯磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.19毫摩爾)，苯磺醯異氰酸酯(39毫克，0.21毫摩爾)溶於二氯甲烷(5.0毫升)中，加入吡啶(61毫克，0.78毫摩爾)。室溫反應18小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.19 mmol), benzenesulfonate isocyanate (39 mg, 0.21 mmol) dissolved To dichloromethane (5.0 mL), pyridine (61 mg, 0.78 mmol) was added. React at room temperature for 18 hours.

-1-基)-3-(4-(3-(苯磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：54.0%)。LCMS：RT=4.36min,[M-H]^-=951.18。 The reaction was quenched with water, diluted with ethyl acetate (20 mL), washed with water and brine (10 mL × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 100 mg of light yellow solid ( S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( Yield: 54.0%). LCMS: RT=4.36min, [MH] ^- =951.18.

-1-基)-3-(4-(3-(苯基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(3-(苯磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(100毫克，0.10毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( 100 mg, 0.10 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-(苯基磺醯基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：2.4%)。LCMS：RT=3.51min,[M-H]^-=795.23。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, dry to obtain 2 mg of white solid 5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-(phenylsulfonyl)ureido)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 2.4%) . LCMS: RT=3.51min, [MH] ^- =795.23.

Example 60

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(morpholine)-4-methamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(morpholine)-4-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和嗎啉(22毫克，0.25毫摩爾)的四氫呋喃(5.0毫升)中滴加三乙胺(51毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 Triethylamine (51 mg, 0.50 mmol) was added dropwise to tetrahydrofuran (5.0 mL) with morpholine (22 mg, 0.25 mmol), and the reaction was completed at 65°C overnight.

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：59.5%)。LCMS：RT=3.77min,[M+H]⁺=883.24。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 88 mg of white solid (S)-5-(2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(morpholine)-4-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( Yield: 59.5%). LCMS: RT=3.77min, [M+H] ⁺ =883.24.

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(morpholine)-4-methamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(88毫克，0.1毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(morpholine)-4-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester ( 88 mg, 0.1 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(嗎啉)-4-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：37.4%)。LCMS：RT=3.25min,[M+H]⁺=727.17。¹H NMR(500MHz,DMSO)δ 12.92(s,1H),11.72(s,1H),10.14(s,1H),9.77(d,J=23.4Hz,1H),8.51(s,1H),8.00(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.41(d,J=8.5Hz,2H),7.37(d,J=8.9Hz,1H),7.32(d,J=7.3Hz,1H),7.17(t,J=14.2Hz,2H),7.05(s,1H),5.30(dd,J=9.8,5.8Hz,1H),3.74(s,2H),3.65-3.54(m,5H),3.44-3.39(m,4H),3.29-3.17(m,2H),3.06-2.98(m,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 26.9 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(morpholine)-4-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (yield: 37.4%). LCMS: RT=3.25min, [M+H] ⁺ =727.17. ¹ H NMR (500MHz, DMSO) δ 12.92 (s, 1H), 11.72 (s, 1H), 10.14 (s, 1H), 9.77 (d, J = 23.4 Hz, 1H), 8.51 (s, 1H), 8.00 (s,1H),7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.41(d, J = 8.5Hz,2H),7.37(d, J =8.9Hz,1H),7.32(d, J =7.3Hz,1H),7.17(t, J =14.2Hz,2H),7.05(s,1H),5.30 (dd, J =9.8,5.8Hz,1H),3.74(s,2H),3.65-3.54(m,5H),3.44-3.39(m,4H),3.29-3.17(m,2H),3.06-2.98 (m,1H).

Example 61

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(3-(4-(4-aminomethylamino-1-methylamino)phenyl)-2-(4-(5-chloro-2-(1 H -tetrazole- 1-yl)phenyl)-2,3-dioxopiperidine

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(3-(4-(4-aminomethanoyl-1-methanoamino)phenyl)-2-(4-(5-chloro-2-(1 H- Tetrazol-1-yl)phenyl)-2,3-dioxopiperidine

-1-yl) propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和哌啶-4-甲醯胺(32毫克，0.25毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 Millimoles) and piperidine-4-methanamide (32 mg, 0.25 mmol) in tetrahydrofuran (5.0 ml) was added dropwise N,N -diisopropylethylamine (65 mg, 0.50 mmol), and the dripping was completed. , React at 65°C overnight.

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：43.8%)。LCMS：RT=4.10min,[M+H]⁺=924.27。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 68 mg of yellow solid (S)-5-(3-(4-(4-aminomethanoyl-1-methanoamino)phenyl)-2-(4-(5-chloro-2-(1 H -Tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)acrylamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (yield: 43.8%). LCMS: RT=4.10min, [M+H] ⁺ =924.27.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(3-(4-(4-aminomethanoyl-1-methanoamino)phenyl)-2-(4-(5-chloro-2-(1 H- Tetrazol-1-yl)phenyl)-2,3-dioxopiperidine

-1-yl) propanamido)-1 H -indole-2-carboxylic acid

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(68毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, the (S)-5-(3-(4-(4-aminomethyl-1-methylamino)phenyl)-2-(4-(5-chloro-2-(1 H -Tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl) propanamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (68 mg, 0.07 mmol) was added to dichloromethane (2.0 ml), and trifluoride was added dropwise Acetic acid (0.5 ml), react at room temperature for 3 hours.

-1-基)丙醯胺基)-1H-吲哚-2-羧酸(收率：37.4%)。LCMS：RT=3.09min,[M+H]⁺=768.27。¹H NMR(500MHz,DMSO)δ 12.93(s,1H),11.73(s,1H),10.14(s,1H),9.79(s,1H),8.45(s,1H),8.01(s,1H),7.95(d,J=2.2Hz,1H),7.82(d,J=8.6Hz,1H),7.77(dd,J=8.6,2.2Hz,1H),7.36(ddd,J=12.5,10.6,5.1Hz,4H),7.27(s,1H),7.20-7.11(m,2H),7.07(d,J=9.5Hz,1H),6.79(s,1H),5.30(dd,J=9.7,5.9Hz,1H),4.10(d,J=13.0Hz,3H),3.74(s,1H),3.22(d,J=9.4Hz,2H),3.05-2.98(m,1H),2.78(t,J=11.8Hz,2H),2.29(t,J=11.5Hz,1H),1.70(d,J=12.0Hz,3H),1.46(d,J=12.2Hz,3H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 56 mg of white solid (S)-5-(3-(4-(4-aminomethanyl-1-methanoamino)phenyl)-2-(4-(5-chloro-2 -(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

1-yl) propan-acyl amino) -1 H - indole-2-carboxylic acid (Yield: 37.4%). LCMS: RT=3.09min, [M+H] ⁺ =768.27. ¹ H NMR (500MHz, DMSO) δ 12.93 (s, 1H), 11.73 (s, 1H), 10.14 (s, 1H), 9.79 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H) ,7.95(d, J =2.2Hz,1H),7.82(d, J =8.6Hz,1H),7.77(dd, J =8.6,2.2Hz,1H),7.36(ddd, J =12.5,10.6,5.1 Hz,4H),7.27(s,1H),7.20-7.11(m,2H),7.07(d, J =9.5Hz,1H),6.79(s,1H),5.30(dd,J=9.7,5.9Hz ,1H),4.10(d, J =13.0Hz,3H),3.74(s,1H),3.22(d, J =9.4Hz,2H),3.05-2.98(m,1H),2.78(t, J = 11.8Hz, 2H), 2.29(t, J =11.5Hz, 1H), 1.70(d, J =12.0Hz, 3H), 1.46(d, J =12.2Hz, 3H).

Example 62

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和4-(甲氧基甲基)哌啶(66毫克，0.51毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 MM) and 4-(methoxymethyl)piperidine (66 mg, 0.51 mmol) in tetrahydrofuran (5.0 mL) were added dropwise with N,N -diisopropylethylamine (65 mg, 0.50 mmol) , After dripping, react at 65°C overnight.

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲 哚-1,2-二羧酸二叔丁酯(收率：57.7%)。LCMS：RT=3.92min,[M+H]⁺=925.25。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4). Obtain 90 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-1,2-di Di-tert-butyl carboxylate (yield: 57.7%). LCMS: RT=3.92min, [M+H] ⁺ =925.25.

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(90毫克，0.09毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (90 mg, 0.09 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-(甲氧基甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：15.9%)。LCMS：RT=3.44min,[M+H]⁺=769.17。¹H NMR(400MHz,DMSO)δ 12.90(s,1H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.40(s,1H),8.03-7.89(m,2H),7.77(dt,J=8.6,5.4Hz,2H),7.40(d,J=8.5Hz,2H),7.37-7.28(m,2H),7.13(d,J=8.2Hz,2H), 7.05(d,J=1.5Hz,1H),5.29(dd,J=9.7,5.8Hz,1H),4.10(d,J=13.6Hz,2H),3.74(s,2H),3.26-3.16(m,6H),3.04-2.96(m,1H),2.72(dd,J=27.3,15.6Hz,3H),2.06-1.93(m,1H),1.81-1.58(m,4H),1.45(s,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 12 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(methoxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (Yield: 15.9%). LCMS: RT=3.44min, [M+H] ⁺ =769.17. ¹ H NMR (400MHz, DMSO) δ 12.90 (s, 1H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.40 (s, 1H), 8.03-7.89 (m, 2H),7.77(dt, J =8.6,5.4Hz,2H),7.40(d, J =8.5Hz,2H),7.37-7.28(m,2H),7.13(d, J =8.2Hz,2H), 7.05(d, J =1.5Hz,1H), 5.29(dd, J =9.7,5.8Hz,1H), 4.10(d, J =13.6Hz,2H), 3.74(s,2H),3.26-3.16(m ,6H),3.04-2.96(m,1H),2.72(dd, J =27.3,15.6Hz,3H),2.06-1.93(m,1H),1.81-1.58(m,4H),1.45(s,1H) ).

Example 63

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

The specific synthesis route is as follows:

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和4-羥甲基哌啶(65毫克，0.51毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65 ℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 N,N -diisopropylethylamine (65 mg, 0.50 mmol) was added dropwise to 4-hydroxymethylpiperidine (65 mg, 0.51 mmol) in tetrahydrofuran (5.0 mL), and the dripping was completed. React at 65°C overnight.

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：49.0%)。LCMS：RT=4.29min,[M+H]⁺=911.35。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1). Obtain 75 mg of yellow solid (S)-5-(2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (yield: 49.0%). LCMS: RT=4.29 min, [M+H] ⁺ =911.35.

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(75.0毫克，0.08毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2-dicarboxy Di-tert-butyl acid (75.0 mg, 0.08 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-(羥甲基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：13.1%)。LCMS：RT=3.20min,[M+H]⁺= 755.31。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.40(s,1H),8.00(s,1H),7.94(d,J=2.2Hz,1H),7.77(dt,J=8.6,5.4Hz,2H),7.47-7.24(m,4H),7.20-7.02(m,3H),6.97(s,1H),5.29(dd,J=9.7,5.8Hz,1H),4.11(d,J=13.0Hz,2H),3.92(s,2H),3.73(s,2H),3.25(d,J=6.2Hz,2H),3.13-2.85(m,2H),2.71(dd,J=24.1,13.0Hz,3H),1.65(d,J=12.9Hz,2H),1.55(s,1H),1.05(dd,J=21.3,11.9Hz,2H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 8.5 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3 -Dioxopiper

-1-yl)-3-(4-(4-(hydroxymethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (closed Rate: 13.1%). LCMS: RT=3.20min, [M+H] ⁺ = 755.31. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H) ,7.94(d, J =2.2Hz,1H),7.77(dt, J =8.6,5.4Hz,2H),7.47-7.24(m,4H),7.20-7.02(m,3H),6.97(s,1H) ), 5.29(dd, J =9.7,5.8Hz,1H),4.11(d, J =13.0Hz,2H),3.92(s,2H),3.73(s,2H),3.25(d, J =6.2Hz ,2H),3.13-2.85(m,2H),2.71(dd, J =24.1,13.0Hz,3H),1.65(d, J =12.9Hz,2H),1.55(s,1H),1.05(dd, J = 21.3, 11.9 Hz, 2H).

Example 64

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -carboxylic acid

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 ,2-Dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.17毫摩爾)和(S)-吡咯烷-3-基甲醇(34毫克，0.34毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.17 Millimole) and (S)-pyrrolidin-3-ylmethanol (34 mg, 0.34 mmol) in tetrahydrofuran (5.0 mL) was added dropwise N,N -diisopropylethylamine (65 mg, 0.50 mmol) , After dripping, react at 65°C overnight.

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：56.3%)。LCMS：RT=4.29min,[M+H]⁺=897.42。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 85 mg of yellow solid 5-((S)-2-(4-(5-chloro-2-( 1H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 ,2-Dicarboxylic acid di-tert-butyl ester (yield: 56.3%). LCMS: RT=4.29 min, [M+H] ⁺ =897.42.

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -carboxylic acid

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2- 二羧酸二叔丁酯(85.0毫克，0.08毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 Di-tert-butyl 2-dicarboxylate (85.0 mg, 0.08 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((S))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：13.1%)。LCMS：RT=3.14min,[M-H]^-=741.25。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, dry to obtain 5.7 mg of white solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((S))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -Carboxylic acid (yield: 13.1%). LCMS: RT=3.14min, [MH] ^- =741.25.

Example 65

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -carboxylic acid

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 ,2-Dicarboxylic acid di-tert-butyl ester

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(180毫克，0.20毫摩爾)和(R)-吡咯烷-3-基甲醇(24毫克，0.24毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(65毫克，0.50毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (180 mg, 0.20 Millimole) and (R)-pyrrolidin-3-ylmethanol (24 mg, 0.24 mmol) in tetrahydrofuran (5.0 mL) was added dropwise N,N -diisopropylethylamine (65 mg, 0.50 mmol) , After dripping, react at 65°C overnight.

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：49.7%)。LCMS：RT=4.19min,[M+H]⁺=897.33。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 90 mg of yellow solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 ,2-Di-tert-butyl dicarboxylic acid (yield: 49.7%). LCMS: RT=4.19min, [M+H] ⁺ =897.33.

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -carboxylic acid

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(90毫克，0.08毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1 Di-tert-butyl 2-dicarboxylate (90 mg, 0.08 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((R))-3-(羥甲基)吡咯烷-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：75.1%)。LCMS：RT=3.16min,[M+H]⁺=741.17。¹H NMR(400MHz,DMSO)δ 12.93(s,1H),11.71(s,1H),10.13(s,1H),9.78(s,1H),8.05(s,1H),7.99(s,1H),7.94(d,J=2.2Hz,1H),7.81(d,J=8.6Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.45(d,J=8.5Hz,2H),7.33(dt,J=8.9,5.4Hz,2H),7.13(d,J=7.9Hz,2H),7.05(d,J=1.6Hz,1H),5.29(dd,J=9.7,5.8Hz,1H),3.95(s,2H),3.73(s,2H),3.42(dd,J=7.0,3.5Hz,5H),3.26-3.09(m,3H),3.05-2.94(m,1H),2.31(dt,J=14.1,7.1Hz,1H),1.90(td,J=12.1,7.2Hz,1H),1.62(td,J=15.4,7.7Hz,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 56 mg of light yellow solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxide Depiper

-1-yl)-3-(4-((R))-3-(hydroxymethyl)pyrrolidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2 -Carboxylic acid (yield: 75.1%). LCMS: RT=3.16 min, [M+H] ⁺ =741.17. ¹ H NMR (400MHz, DMSO) δ 12.93 (s, 1H), 11.71 (s, 1H), 10.13 (s, 1H), 9.78 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H) ,7.94(d, J =2.2Hz,1H),7.81(d, J =8.6Hz,1H),7.76(dd, J =8.6,2.2Hz,1H),7.45(d, J =8.5Hz,2H) ,7.33(dt, J =8.9,5.4Hz,2H),7.13(d, J =7.9Hz,2H),7.05(d, J =1.6Hz,1H), 5.29(dd, J =9.7,5.8Hz, 1H), 3.95 (s, 2H), 3.73 (s, 2H), 3.42 (dd, J = 7.0, 3.5Hz, 5H), 3.26-3.09 (m, 3H), 3.05-2.94 (m, 1H), 2.31 (dt, J =14.1,7.1Hz,1H), 1.90(td, J =12.1,7.2Hz,1H), 1.62(td, J =15.4,7.7Hz,1H).

Example 66

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole -1,2-Di-tert-butyl dicarboxylic acid

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(235毫克，0.26毫摩爾)和(S)-2-氨基-4-甲基戊-1-醇(62毫克，0.53毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(101毫克，0.78毫摩爾)，滴畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (235 mg, 0.26 Millimoles) and (S)-2-amino-4-methylpentan-1-ol (62 mg, 0.53 mmol) in tetrahydrofuran (5.0 ml) was added dropwise N,N -diisopropylethylamine (101 Mg, 0.78 mmol), after dripping, react at 65°C overnight.

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：28.2%)。LCMS：RT=4.29min,[M+H]⁺=913.43。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3). Obtain 68 mg of yellow solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole -Di-tert-butyl 1,2-dicarboxylic acid (yield: 28.2%). LCMS: RT=4.29 min, [M+H] ⁺ =913.43.

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(68毫克，0.07毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, add 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole Di-tert-butyl 1,2-dicarboxylate (68 mg, 0.07 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(3-((S)-1-羥基-4-甲基戊-2-基)脲基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：75.1%)。LCMS：RT=3.40min,[M-H]^-=757.17。¹H NMR(400MHz,DMSO)δ 12.89(s,1H),11.71(s,1H),10.12(s,1H),9.78(s,1H),8.38(s,1H),8.03-7.90(m,2H),7.77(dt,J=8.6,5.4Hz,2H),7.35(dd,J=19.7,8.6Hz,4H),7.22-7.01(m,3H),5.93(d,J=8.4Hz,1H),5.27(dd, J=9.9,5.5Hz,1H),3.88(s,1H),3.73-3.51(m,5H),3.47-3.25(m,3H),3.14(ddd,J=17.1,14.8,8.5Hz,2H),3.06-2.93(m,1H),1.63(dt,J=13.3,6.5Hz,1H),1.36-1.04(m,6H),0.87(t,J=6.9Hz,6H)。 After the reaction was completed, the dichloromethane was evaporated and the trifluoroacetic acid was drained by an oil pump. The residue obtained was dissolved in dichloromethane (1.0 mL) and added dropwise to n-hexane (10.0 mL). A white solid precipitated out and filtered with suction. The filter cake was washed with n-hexane and dried to obtain 19.44 mg of light red solid 5-((S)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2, 3-dioxopiperidine

-1-yl)-3-(4-(3-((S)-1-hydroxy-4-methylpent-2-yl)ureido)phenyl)propanamido)-1 H -indole -2-carboxylic acid (yield: 75.1%). LCMS: RT=3.40min, [MH] ^- =757.17. ¹ H NMR (400MHz, DMSO) δ 12.89 (s, 1H), 11.71 (s, 1H), 10.12 (s, 1H), 9.78 (s, 1H), 8.38 (s, 1H), 8.03-7.90 (m, 2H),7.77(dt, J =8.6,5.4Hz,2H),7.35(dd, J =19.7,8.6Hz,4H),7.22-7.01(m,3H),5.93(d, J =8.4Hz,1H ), 5.27(dd, J =9.9,5.5Hz,1H),3.88(s,1H),3.73-3.51(m,5H),3.47-3.25(m,3H),3.14(ddd, J =17.1,14.8 ,8.5Hz,2H),3.06-2.93(m,1H),1.63(dt, J =13.3,6.5Hz,1H),1.36-1.04(m,6H),0.87(t, J =6.9Hz,6H) .

Example 67

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate

-1-基)-3-(4-((苯氧基羰基)氨基)苯基)丙醯氨基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.16毫摩爾)和2-(哌啶-4-基)乙-1-醇(65毫克，0.50毫摩爾)的四氫呋喃(5.0毫升)中滴加N,N-二異丙基乙胺(50毫克，0.50毫摩爾)，滴 畢，65℃反應過夜。 At room temperature, add (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.16 Millimole) and 2-(piperidin-4-yl)ethan-1-ol (65 mg, 0.50 mmol) in tetrahydrofuran (5.0 ml) was added dropwise N,N -diisopropylethylamine (50 mg, 0.50 mmol), after dripping, react at 65°C overnight.

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：48.1%)。LCMS：RT=4.29min,[M+H]⁺=925.45。 After the reaction was completed, it was quenched by adding water, the mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×2 times), then dried with anhydrous sodium sulfate, and finally Concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2). Obtain 75 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (yield: 48.1%). LCMS: RT=4.29 min, [M+H] ⁺ =925.45.

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(75.0毫克，0.08毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-1,2- Di-tert-butyl dicarboxylate (75.0 mg, 0.08 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-(4-(2-羥乙基)哌啶-1-甲醯胺基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：75.1%)。LCMS：RT=3.23min,[M+H]⁺=769.13。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, dry to obtain 8.5 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(4-(2-hydroxyethyl)piperidine-1-carboxamido)phenyl)propionamido)-1 H -indole-2-carboxylic acid (Yield: 75.1%). LCMS: RT=3.23min, [M+H] ⁺ =769.13.

Example 68

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(150毫克，0.23毫摩爾)，甲基氨磺醯氯(32毫克，0.23毫摩爾)溶於二氯甲烷(5.0毫升)中，加入N,N-二異丙基乙胺(58毫克，0.45毫摩爾)。室溫反應18小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propanamido) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (150 mg, 0.23 mmol), methyl sulfamoyl chloride (32 mg, 0.23 mmol) ) Was dissolved in dichloromethane (5.0 mL), and N,N-diisopropylethylamine (58 mg, 0.45 mmol) was added. React at room temperature for 18 hours.

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(收率：10.1%)。LCMS：RT=4.29min,[M-H]^-=875.21。 The reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 20 mg of light yellow solid ( S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (Yield: 10.1%). LCMS: RT=4.29min, [MH] ^- =875.21.

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(20.0毫克，0.02毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (20.0 mg, 0.02 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((N-乙基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：94.3%)。LCMS：RT=3.39min,[M+H]⁺=721.12。¹H NMR(400MHz,DMSO)δ 12.91(s,1H),11.71(s,1H), 10.12(s,1H),9.78(s,1H),9.57(s,1H),8.01-7.89(m,2H),7.78(dt,J=8.6,5.4Hz,2H),7.41-7.26(m,3H),7.15(dd,J=30.7,8.5Hz,4H),7.06(t,J=3.7Hz,1H),5.30(dd,J=9.6,6.0Hz,1H),3.72(s,4H),3.26-3.17(m,1H),3.07-2.97(m,1H),2.89-2.78(m,2H),0.96-0.80(m,3H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 15.5 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-((N-ethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 94.3%) . LCMS: RT=3.39min, [M+H] ⁺ =721.12. ¹ H NMR (400MHz, DMSO) δ 12.91 (s, 1H), 11.71 (s, 1H), 10.12 (s, 1H), 9.78 (s, 1H), 9.57 (s, 1H), 8.01-7.89 (m, 2H), 7.78(dt, J =8.6,5.4Hz,2H),7.41-7.26(m,3H),7.15(dd, J =30.7,8.5Hz,4H),7.06(t, J =3.7Hz,1H ),5.30(dd, J =9.6,6.0Hz,1H),3.72(s,4H),3.26-3.17(m,1H),3.07-2.97(m,1H),2.89-2.78(m,2H), 0.96-0.80 (m, 3H).

Example 69

-1-基)-3-(4-((N,N-二甲基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(( N,N -dimethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((N,N-二甲基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁基酯

The specific synthesis route is as follows: Step A: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(( N,N -dimethylsulfamoyl)amino)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester

-1-基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁酯(180毫克，0.23毫摩爾)，甲基氨磺醯氯(40毫克，0.28毫摩爾)溶於二氯甲烷(5.0毫升)中，加入吡 啶(37毫克，0.46毫摩爾)。室溫反應2小時。 (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-di Oxopiper

-1-yl) propanamido) -1 H -indole-1,2-dicarboxylic acid di-tert-butyl ester (180 mg, 0.23 mmol), methyl sulfamoyl chloride (40 mg, 0.28 mmol) ) Was dissolved in dichloromethane (5.0 mL), and pyridine (37 mg, 0.46 mmol) was added. React at room temperature for 2 hours.

-1-基)-3-(4-((N,N-二甲基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁基酯(收率41.5%)。LCMS：RT=4.32min,[M-H]^-=875.13。 The reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml × 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure. The residue was purified by TLC plate to obtain 85 mg of light yellow solid ( S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(( N,N -dimethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (41.5% yield). LCMS: RT=4.32min, [MH] ^- =875.13.

-1-基)-3-(4-((N,N-二甲基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸

Step B: Synthesis of (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-((N,N-dimethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid

-1-基)-3-(4-((N,N-二甲基氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-1,2-二羧酸二叔丁基酯(85毫克，0.09毫摩爾)加入二氯甲烷(2.0毫升)中，滴加三氟乙酸(0.5毫升)，室溫反應3小時。 At room temperature, (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxopiper

-1-yl)-3-(4-(( N,N -dimethylsulfamoyl)amino)phenyl)propionamido)-1 H -indole-1,2-dicarboxylic acid Tert-butyl ester (85 mg, 0.09 mmol) was added to dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 3 hours.

-1-基)-3-(4-((N,N-二甲基 氨磺醯基)氨基)苯基)丙醯胺基)-1H-吲哚-2-羧酸(收率：34.3%)。LCMS：RT=3.41min,[M-H]^-=721.31。¹H NMR(500MHz,DMSO)δ 12.93(s,1H),11.73(s,1H),10.12(s,1H),9.80(d,J=4.7Hz,2H),7.99(s,1H),7.94(d,J=2.2Hz,1H),7.79(dt,J=8.6,5.4Hz,2H),7.37(d,J=8.9Hz,1H),7.31(dd,J=8.9,1.8Hz,1H),7.18(dd,J=20.2,8.0Hz,4H),7.06(t,J=5.2Hz,1H),5.34-5.26(m,1H),4.19(s,1H),3.73(s,2H),3.23(dd,J=14.4,5.0Hz,1H),3.03(dd,J=14.0,10.2Hz,1H),2.64(s,6H),1.99(dt,J=12.5,6.9Hz,1H)。 The reaction liquid was distilled under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm * 150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm. After purification, it was dried to obtain 24.3 mg of white solid (S)-5-(2-(4-(5-chloro-2-(1 H -tetrazol-1-yl)phenyl)-2,3-dioxo Piper

-1-yl)-3-(4-(( N,N -dimethylsulfamoyl)amino)phenyl)propanamido)-1 H -indole-2-carboxylic acid (yield: 34.3%). LCMS: RT=3.41min, [MH] ^- =721.31. ¹ H NMR (500MHz, DMSO) δ 12.93 (s, 1H), 11.73 (s, 1H), 10.12 (s, 1H), 9.80 (d, J = 4.7 Hz, 2H), 7.99 (s, 1H), 7.94 (d, J =2.2Hz,1H),7.79(dt, J =8.6,5.4Hz,2H),7.37(d, J =8.9Hz,1H),7.31(dd, J =8.9,1.8Hz,1H) ,7.18(dd, J =20.2,8.0Hz,4H),7.06(t, J =5.2Hz,1H),5.34-5.26(m,1H),4.19(s,1H),3.73(s,2H), 3.23 (dd, J =14.4, 5.0 Hz, 1H), 3.03 (dd, J =14.0, 10.2 Hz, 1H), 2.64 (s, 6H), 1.99 (dt, J =12.5, 6.9 Hz, 1H).

Example 70: Detection of the biological activity of the compound of the present invention on the inhibition of human blood coagulation factor XIa by absorption spectroscopy

1. Experimental materials

Enzyme: Human Factor XIa (ENZYME RESEARCH, catalog number HFXIa 1111a)

Substrate: S-2366TM: (CHROMOGENIX, article number 82109039)

Buffer: 145mM NaCl, 5mM KCl, 1mg/mL PEG 8000, 30mM HEPES, PH7.4

2. Experimental steps

Dilute 10mM test compound dissolved in 100% DMSO with 100% DMSO to 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, 0.00128μM; add 98μL (77.7ng /mL) FXIa enzyme solution, add 98μL of buffer to the blank wells instead, and then add 2μL of compounds of different concentrations. Replace the blank and control wells with DMSO, mix with a shaker, and incubate at 37°C for 20min.

Finally, add 100μL of 800μM substrate to each well, and measure the absorbance at 405nm.

3. Data processing

Use GraphPad Prism software to perform curve fitting and calculate IC ₅₀ value, see Table 1.

Conclusion: The compound of the present invention has obvious inhibitory activity on human FXIa.

Example 71: Determination of the anticoagulant effect of the compound of the present invention on human plasma in vitro

1. Experimental materials

Plasma: Human blood is collected in a vacuum blood collection tube containing 3.2% sodium citrate (volume ratio 1:9), centrifuged at 3000 rpm for 10 minutes at room temperature, and the plasma is collected, aliquoted in EP tubes, and stored at -80°C.

Reagents: APTT determination kit (activated partial thromboplastin time detection kit, mindray), calcium chloride solution.

Instrument: coagulometer (mindray, C2000-A)

2. Experimental method

Take aliquots of cryopreserved human plasma after thawing at room temperature, and mix well. Dilute 10mM test compound dissolved in 100% DMSO with 100% DMSO to 1500, 750, 375, 187.5, 93.75, 46.88, 23.44, 11.72μM; add 98μL of human plasma to 1.5mL EP tube, and then add 2μL of different concentrations Add 2 μL 100% DMSO to the blank group, and incubate in a 37°C water bath for 10 min. Put the sample into the corresponding position in the coagulometer to perform APTT determination of the compound.

3. Data processing

Curve fitting was performed with GraphPad Prism software, and EC1.5× and EC2× values were calculated respectively, that is, 1.5 times and 2 times the concentration of the compound corresponding to the APTT of the blank control group. The results are shown in Table 2.

Conclusion: It can be seen from Table 2 that the compound of the present invention has a significant anticoagulant effect on human plasma.

Example 72: Investigation of rat pharmacokinetic characteristics of the compound of the present invention

1. Experimental materials

SD rats: male, 180-250g, purchased from Guangdong Medical Experimental Animal Center. Cynomolgus monkey: male, 4-6kg, purchased from Guangzhou Chunsheng Biological Research Institute Co., Ltd.

Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

Instrument: Thermo Fisher LC-MS (U300 UPLC, TSQ QUANTUMN ULTRA triple quadrupole mass spectrometer).

2. Experimental method

Weigh the compound and dissolve it in the DMSO-PEG-400-physiological saline (5:60:35, v/v/v) system. After intravenous or intragastric administration in rats/monkeys, at 5min, 15min, 30min, 1h, At 2h, 4h, 6h, 8h, 24h, 200 μL of venous blood was collected in a heparinized EP tube, centrifuged at 12000 rpm for 2 min, and the plasma was frozen at -80°C for testing. Accurately weigh a certain amount of the test substance and dissolve it to 1 mg/mL in DMSO as a stock solution. Accurately draw an appropriate amount of compound stock solution, add acetonitrile and dilute to prepare a standard series solution. Accurately draw 20μL of each of the above standard series solutions, add 180μL of blank plasma, vortex to mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 10, 30, 100, 300, 1000, 3000, and 5000 ng/mL. A double sample analysis was performed for each concentration to establish a standard curve. Take 20μL of plasma, add 200μL of acetonitrile solution of internal standard propranolol (5ng/mL), vortex to mix well, centrifuge at 4000rpm for 5min, take the supernatant LC- MS analysis. The LC-MS detection conditions are as follows:

Chromatographic column: Thermo Fisher Hypersil GOLD C-18 UPLC column, 100*2.1mm, 1.9μm.

Mobile phase: water (0.1% formic acid)-acetonitrile for gradient elution as shown in the table below

3. Data processing

After LC-MS detects the blood drug concentration, WinNonlin 6.1 software, non-compartmental model method is used to calculate the pharmacokinetic parameters. The results are shown in Tables 3 and 4.

Conclusion: The compound of the present invention has a shorter half-life after intravenous administration in rats and monkeys, a lower apparent volume of distribution, and a faster clearance rate. Stable quickly after intravenous administration, the drug is mainly distributed in the blood Among them, the targeting ability is good, and the drug can be quickly removed from the body after the drug is stopped, and it is suitable for the development of clinical intravenous infusion drugs with the main target in the blood.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, etc. made without departing from the spirit and principle of the present invention Simplified, all should be equivalent replacement methods, and they are all included in the protection scope of the present invention.

Claims (14)

A compound of formula (I) or its stereoisomer, tautomer, or pharmaceutically acceptable salt:

R _{1 is} selected from R ₃ substituted or unsubstituted tetrazole, R ₃ substituted or unsubstituted triazole; R _{2 is} selected from R ₄ substituted or unsubstituted benzene ring, wherein R _{4 is} selected from -NR ₅ -( CH ₂ )n-CO-(CH ₂ )n-NR ₆ R ₇ , -NR ₅ -SO ₂ -NR ₆ R ₇ ; Ar is selected from at least one of the following groups substituted or unsubstituted by _{R 8:}

,

Wherein, R _{3 is} selected from hydrogen, halogen, C _1-4 alkyl, halogen-substituted C _1-4 alkyl; R ₅ , R ₆ , R _{7 are} independently selected from hydrogen, C _1-4 alkyl , C _1-4 alkoxy-C _1-4 alkyl, -SO ₂ -C _1-4 alkyl, -SO ₂ -phenyl, -C _1-6 mono or dihydric alcohol,

, -(CH ₂ )nC _3-12 aliphatic ring, or wherein any one or more of _{NR 5} and NR ₆ R _{7 form a ring through -(CH 2} )n-; or NR ₆ R ₇ together form C _{3- 12} aliphatic ring; _{one or more carbon atoms on the aforementioned C 3-12} alicyclic ring are replaced by 0-2 N, O, S atoms, and the aliphatic ring is further substituted by more than one R ₉ ; R ₈ Selected from hydrogen, halogen, C _1-4 alkyl, hydroxyl, -C _1-4 carboxylic acid, -C _1-4 carboxylic acid -C _1-4 alcohol ester; R _{9 is} selected from hydrogen, -(CH ₂ ) n-OH, -SO ₂ -C _1-4 alkyl, -(CH ₂ )n-COOH, -amide, cyano, NR ₁₀ R ₁₁ -C _1-4 alkoxy, C _{1- 4} alkyl group, C _1-4 alkoxy group, C _1-4 alkoxy-C _1-4 alkyl group, -CO-morpholine, -CO-NR ₁₂ -(CH ₂ )n-OH, HOOC -C _1-4 alkoxy; R ₁₀ , R ₁₁ , and R _{12 are} independently selected from hydrogen or C _1-4 alkyl; the aforementioned n=0-6 is any natural number. The compound of formula (I) or its stereoisomer, tautomer, or pharmaceutically acceptable salt according to claim 1, wherein -NR ₅ -(CH ₂ )n-CO-(CH ₂ ) n-NR ₆ R ₇ includes

Among them, R ₇ and R _{9 are} as defined in claim 1. The compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts according to claim ₁ , wherein the C 1-4 alkyl group is selected from methyl and ethyl , Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; -C _1-4 carboxylic acid is selected from formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, tert Butyric acid; -C _1-4 carboxylic acid-C _1-4 alcohol ester selected from methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate Ester, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl butyrate, ethyl butyrate, propyl butyrate, butyl butyrate. The compound of formula (I) according to claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the halogen is selected from fluorine, chlorine, bromine, and iodine. The compound of formula (I) according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the C _1-4 alkane is selected from methane, ethane, propane , Isopropane, n-butane, isobutane, sec-butane, tert-butane; the C _1-4 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n Butoxy, isobutoxy, sec-butoxy, tert-butoxy; the -(CH ₂ )n-OH is selected from hydroxyl, methanol, ethanol, n-propanol, n-butanol; the -C _{1 -6} monohydric or dihydric alcohol is selected from methanol, ethanol, n-propanol, n-butanol, tert-butanol, 1,3-butanediol, 3-methylbutan-1-ol, 3-methylpentanol 1-alcohol, 4-methylpentan-1 alcohol, 3-methylhexan-1 alcohol, 4-methylhexan-1 alcohol; the _{alkoxy group of NR 10} R ₁₁ -C _1-4 is selected from methylamine Methoxy, ethylamine methoxy, propylamine methoxy, butylamine methoxy, methylamine ethoxy, ethylamine ethoxy, propylamine ethoxy, butylamine ethoxy, methylamine propoxy, Ethylamine propoxy, propylamine propoxy, butylamine propoxy, methylamine butoxy, ethylamine butoxy, propylamine butoxy, butylamine butoxy, dimethylaminomethoxy, dimethyl Aminoethoxy, dimethylaminopropoxy, dimethylaminobutoxy; the C _1-4 alkoxy-C _1-4 alkyl group is selected from methoxymethyl, ethoxymethyl, Propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, Methoxybutyl, ethoxybutyl, propoxybutyl, butoxybutyl; the -CO-NR ₁₂ -(CH ₂ )n-OH is selected from -CO-NH-CH ₂ OH, -CO-N (CH ₃ )-CH ₂ OH, -CO-NH-CH ₂ CH ₂ OH, -CO-N(CH ₃ )-CH ₂ CH ₂ OH; the HOOC-C _1-4 alkoxy group is selected from HOOC- Methoxy, HOOC-ethoxy, HOOC-propoxy, HOOC-isopropoxy, HOOC-n-butoxy, HOOC-isobutoxy, HOOC-sec-butoxy, HOOC-tert-butoxy . The compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts according to claim 1, wherein the C _3-12 aliphatic ring is selected from cyclopropane, cyclobutane Alkane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, spiro[3,3]heptane, spiro[3,5]nonane, spiro[4,5] Deca ring; _{more than one carbon atom on the C 3-12} alicyclic ring is replaced by 0-2 N, O, S atoms, selected from:

,

,

,

,

,

,

,

,

,

,

,

,

,

. The compound of formula (I) according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein n=0, 1, 2, 3, 4, 5 or 6. The compound of formula (I) according to claim 1 or its stereoisomers, tautomers, or pharmaceutically acceptable salts, wherein R1 is selected from tetrazole and triazole; R2 is selected from benzene ring ,

,

,

Ar is selected from the following groups:

,

,

The compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts as described in claim 1, characterized in that it is selected from the following compounds:

The compound of formula (I) according to any one of claims 1 to 9 or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt refers to Said The compound is prepared with a pharmaceutically acceptable acid or base. The compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: more than one hydrogen atom of the compound is Replaced by the isotope deuterium. A pharmaceutical composition comprising the compound of formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts and one or more pharmaceutically acceptable salts according to any one of claims 1 to 11 above Acceptable carriers, and their dosage forms include oral or injection administration. A use of the compound of formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts according to any one of claims 1 to 11 in the preparation of a medicament for the treatment of FXIa-related diseases, wherein , FXIa related diseases include thrombosis related diseases. A use of the pharmaceutical composition according to claim 12 in the preparation of a medicament for the treatment of FXIa-related diseases, wherein the FXIa-related diseases include thrombosis-related diseases.