CN116535460A - Sulfur-containing peptidomimetic compounds, and preparation method and application thereof - Google Patents

Abstract

The invention discloses a class of sulfur-containing peptidomimetic compounds represented by formula I and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, and their Pharmaceutical compositions, and their use as SARS-CoV-2 main protease inhibitors and methods of use thereof. The sulfur-containing peptidomimetic compound has good antiviral activity, especially anti-new coronavirus activity.

Description

A class of sulfur-containing peptidomimetic compounds and preparation methods and uses thereof

Technical Field

The present invention belongs to the field of pharmacy, and specifically relates to a class of sulfur-containing peptidomimetic compounds and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers thereof, as well as pharmaceutical compositions containing them, and their use as SARS-CoV-2 main protease inhibitors and methods of use thereof. The sulfur-containing peptidomimetic compounds have good antiviral activity, especially anti-new coronavirus activity.

Background Art

Coronaviruses (CoVs) are single-stranded, large, enveloped, spherical RNA viruses with spherical protrusions on their surface. Coronaviruses can infect a variety of mammals, including humans, causing respiratory diseases and gastroenteritis. Based on genetic and antigenic criteria, coronaviruses are divided into four genera: α, β, γ, and δ, of which α and β coronaviruses are associated with human diseases.

SARS-CoV-2, SARS-CoV and MERS-CoV belong to the beta coronavirus family. The SARS-CoV-2 genome has 82% sequence similarity with SARS-CoV and has similar pathogenic mechanisms. Coronavirus uses the surface spike protein (S protein) to bind to the host cell surface receptor and enter the cell through endocytosis, then translates functional proteins: main protease (M ^pro ) or 3-chymotrypsin-like protease (3CL ^pro ), papain-like protease (PL ^pro ) and RNA polymerase (RdRp), and transcribes and replicates under their synergistic action, and finally releases them outside the host cell. These enzymes and proteins are potential targets for anti-coronavirus drugs, and inhibiting their activity can inhibit viral replication.

Coronavirus 3CL ^pro (or M ^pro ) is a cysteine protease composed of about 300 amino acids, which plays an important role in the life process of the virus, such as replication and transcription of the viral genome, protein translation, cleavage and modification, etc. In addition, 3CL ^pro shows high structural similarity and conservation among known coronavirus species. Therefore, 3CL ^pro is an important new drug research target for the development of anti-coronavirus drugs that inhibit the proliferation of coronaviruses.

Summary of the invention

The technical purpose of the present invention is to provide a sulfur-containing peptidomimetic compound shown in Formula I and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, which can be used as a SARS-CoV-2 main protease inhibitor and have a good inhibitory effect on the activity of the SARS-CoV-2 main protease.

According to one aspect of the present invention, an object of the present invention is to provide a sulfur-containing peptidomimetic compound represented by the following formula I and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers:

wherein C* ¹ , C* ² , and C* ³ are each independently of the S type or the R type;

X is S or S-S;

R ₁ is selected from substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C6-14 aryl C1-C3 alkyl, substituted or unsubstituted five- to ten-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 5 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, -COORa, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, wherein Ra is selected from H or C _1-6 alkyl;

_R2 is selected from substituted or unsubstituted C1-C10 straight or branched alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, _C1-6 alkyl, C3-C10 cycloalkyl;

R ₃ is selected from

wherein R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C2-C10 straight or branched alkenyl, substituted or unsubstituted C2-C10 straight or branched alkynyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C6-14 arylC1-C3 alkyl, substituted or unsubstituted five- to ten-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to each of the above groups having a group selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-6 alkyl, halogenated C _1-6 alkyl, C 1 to 5 substituents of _1-6 alkoxy, C6-10 aryl,

R ₇ , R ₈ and R ₉ are each independently selected from H, halogen, C1-C10 straight chain or branched chain alkyl, C1-C10 straight chain or branched chain alkoxy.

Preferably, R ₁ is selected from substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, substituted or unsubstituted five- to six-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, -COORa, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, wherein Ra is selected from H or C _1-3 alkyl;

More preferably, R ₁ is selected from substituted or unsubstituted C1-C3 straight or branched alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, substituted or unsubstituted five- to six-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 5 substituents selected from H, halogen, hydroxyl, carbonyl, -COORa, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, wherein Ra is selected from H or C _1-3 alkyl;

More preferably, R ₁ is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, naphthyl, benzyl, phenethyl, thienyl, thiazolyl, isothiazolyl, wherein the “substituted” means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, -COORa, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, pentafluoroethyl, wherein R _a is selected from H, methyl, ethyl, propyl, isopropyl;

Preferably, R ₂ is selected from substituted or unsubstituted C1-C6 straight or branched alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-3 alkyl, C3-C6 cycloalkyl;

More preferably, _R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropylisopropyl, cyclopropyl-n-butyl, cyclobutylmethyl, cyclobutylethyl, cyclobutyl-n-propyl, cyclobutylisopropyl, cyclobutyl-n-butyl, cyclopentylmethyl, cyclopentylethyl, cyclopentyl-n-propyl, cyclopentylisopropyl, cyclopentyl-n-butyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyl-n-propyl, cyclohexyl-n-butyl.

Preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C2-C6 straight or branched alkenyl, substituted or unsubstituted C2-C6 straight or branched alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 arylC1-C3 alkyl, substituted or unsubstituted five- to eight-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to eight-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" refers to each of the above groups having a group selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-3 alkyl, halogenated C _1-3 alkyl, C 1 to 3 substituents of _1-3 alkoxy, C6-10 aryl,

More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C4 straight or branched alkyl, substituted or unsubstituted C2-C4 straight or branched alkenyl, substituted or unsubstituted C2-C4 straight or branched alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, amide, C6-10 aryl,

More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl, naphthyl, benzyl, phenethyl, vinyl, phenylvinyl, naphthylvinyl, phenylpropenyl, naphthylpropenyl,

More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from

Preferably, R ₇ , R ₈ and R ₉ are each independently selected from H, halogen, C1-C6 straight chain or branched chain alkyl, C1-C6 straight chain or branched chain alkoxy.

More preferably, R ₇ , R ₈ and R ₉ are each independently selected from H, halogen, C1-C4 straight chain or branched chain alkyl, C1-C4 straight chain or branched chain alkoxy.

More preferably, R ₇ , R ₈ , and R ₉ are each independently selected from H, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

More preferably, _R3 is selected from

In a specific embodiment, the sulfur-containing peptidomimetic compound and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers according to the present invention are represented by the following formula II:

wherein the substituents R1, R2, R3 and X are as defined in formula I.

In a specific embodiment, the sulfur-containing peptidomimetic compound and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers according to the present invention are represented by the following formula II-1, formula II-2, formula II-3, formula II-4, formula II-5, formula II-6, formula II-7, formula II-8, formula II-9, formula II-10, formula II-11, formula II-12, formula II-13 or formula II-14:

wherein the substituents R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ have the same meanings as in formula I.

In a specific embodiment, the sulfur-containing peptidomimetic compound according to the present invention and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers are selected from the following compounds:

According to another aspect of the present invention, another object of the present invention is to provide a method for preparing a sulfur-containing peptidomimetic compound as shown in Formula I, Formula II, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10, Formula II-11, Formula II-12, Formula II-13 or Formula II-14 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer thereof, the method being carried out according to one of the following exemplary methods:

Method 1

As shown in the above reaction formula, the method comprises the following steps:

ⅰ) (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid methyl ester (Compound 1) is subjected to ester hydrolysis reaction at 0-50°C under base catalysis to generate Compound 1a;

ii) Compound 1a reacts with the corresponding thiol or thiophenol in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 1b;

iii) removing the Boc protecting group from compound 1b in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 1c;

iv) Compound 1d reacts with compound 1e in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate compound 1f;

v) Compound 1f is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 1g;

vi) Compound 1c reacts with compound 1g in an aprotic solvent in the presence of a condensing agent and an organic base at 0-50° C. to generate compound 1h;

ⅶ) removing the Boc protecting group from compound 1h in the presence of hydrochloric acid or trifluoroacetic acid at 0-35° C. to generate compound 1i;

viii) Compound 1j reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50°C in the presence of a condensing agent and an organic base to produce a compound of formula VI;

Where n is 1 or 2;

The base in steps i) and v) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate and the like.

In steps ii), iv), vi) and viii), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. The organic base is selected from triethylamine, diisopropylethylamine, pyridine, and 4-N-lutidine.

The aprotic solvent in steps ii), iv), vi) and viii) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile and the like.

Method 2

As shown in the above reaction formula, the method comprises the following steps:

ⅰ) (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid methyl ester (Compound 1) is deprotected by removing the Boc protecting group in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate Compound 2a;

ii) Compound 2a and Compound 2b undergo amide condensation reaction in an aprotic solvent in the presence of a condensing agent and an organic base at 0-50° C. to generate Compound 2c;

iii) Compound 2c is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 2d;

iv) 2d reacts with the corresponding thiol in an aprotic solvent at 0-50°C in the presence of a condensing agent and an organic base to generate compound 2e;

v) removing the Boc protecting group from compound 2e in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 2f;

vi) Compound 2f reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to form a compound of formula II-1;

Where n is 1 or 2;

The base in steps i) and iii) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine and the like.

In steps ii), iv) and vi), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. The organic base is selected from triethylamine, diisopropylethylamine, pyridine, and 4-N-lutidine.

The aprotic solvent in steps ii), iv) and vi) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile and the like.

Method 3

As shown in the above reaction formula, the method comprises the following steps:

i) Compound 1c reacts with compound 3 in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 3a;

ii) removing the Boc protecting group from compound 3a in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 3b;

iii) Compound 3e reacts with compound 3d in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate compound 3e;

iv) Compound 3e is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 3f;

v) Compound 3b reacts with compound 3f in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate a compound of formula V;

Where n is 1 or 2;

The aprotic solvent in steps i), iii) and v) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile and the like.

In step iv), the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine and the like.

In steps i), iii) and v), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. The organic base is selected from triethylamine, diisopropylethylamine, pyridine, and 4-N-lutidine.

Method 4

As shown in the above reaction formula, the method comprises the following steps:

i) removing the Boc protecting group from compound 2c in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 4a;

ii) Compound 4a reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 4b;

iii) Compound 4b undergoes ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 4c;

iv) Compound 4c is subjected to a sulfidation reaction to generate compound 4d, using carbodiimide hydrochloride (EDCI) as a coupling agent and Na ₂ S as a hydrogen sulfide ion source, and the reaction is carried out at room temperature;

v) Compound 4d is subjected to an oxidation reaction to generate a compound of formula II-2, using I ₂ as an oxidant and CH ₃ COONa as an acid-binding agent, and the reaction is carried out at room temperature;

The aprotic solvent in step ii) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile and the like.

In step ii), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc. The organic base is selected from triethylamine, diisopropylethylamine, pyridine, and 4-N-lutidine.

In step iii), the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine and the like.

In the above reaction formula, substituents R1, R2, and R4 are as defined above.

The above methods are merely exemplary, and those skilled in the art can reasonably change the steps, sequence, reactants, reaction conditions, etc. of the above methods according to the structure of the target compound.

According to another aspect of the present invention, another object of the present invention is to provide a pharmaceutical composition, which comprises a therapeutically effective amount of a sulfur-containing peptidomimetic compound as shown in Formula I, Formula II, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10, Formula II-11, Formula II-12, Formula II-13 or Formula II-14 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers thereof as active ingredients, and pharmaceutically acceptable excipients.

According to another aspect of the present invention, another object of the present invention is to provide a sulfur-containing peptidomimetic compound as shown in Formula I, Formula II, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10, Formula II-11, Formula II-12, Formula II-13 or Formula II-14 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, or the use of the pharmaceutical composition according to the present invention for preparing a coronavirus main protease inhibitor, which is used to treat and/or prevent and alleviate related diseases caused by infection with the 2019 novel coronavirus (2019-nCoV), wherein the coronavirus is a pathogenic coronavirus such as severe acute respiratory syndrome virus (SARS-COV), novel severe acute respiratory syndrome virus (SARS-COV-2), and Middle East respiratory syndrome virus (MERS-CoV).

According to another aspect of the present invention, the present invention provides a method for treating and/or preventing and alleviating coronavirus 3CL ^pro related diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of a sulfur-containing peptidomimetic compound as shown in Formula I, Formula II, Formula II-1, Formula II-2, Formula II-3, Formula II-4, Formula II-5, Formula II-6, Formula II-7, Formula II-8, Formula II-9, Formula II-10, Formula II-11, Formula II-12, Formula II-13 or Formula II-14 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers thereof, or the pharmaceutical composition according to the present invention.

Preferably, the disease or condition associated with 3CL ^pro is a viral infectious disease or condition, and the virus is a pathogenic coronavirus such as severe acute respiratory syndrome virus (SARS-COV), novel severe acute respiratory syndrome virus (SARS-COV-2), and Middle East respiratory syndrome virus (MERS-CoV).

Beneficial Effects

The novel sulfur-containing peptidomimetic compound according to the present invention has been verified by pharmacological experiments to have very good SARS-CoV-2 main protease inhibitory activity, and therefore can be used to treat SARS-CoV-2 infection; in view of the high conservation of the coronavirus main protease, the compound of the present invention also has a therapeutic effect on SARS-CoV-1, MERS-CoV and other coronavirus infections.

DETAILED DESCRIPTION

Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred embodiments for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

As used herein, the terms "include", "comprising", "having", "containing" or any other similar terms are open-ended transitional phrases, which are intended to cover non-exclusive inclusions. For example, a composition or article containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or article. In addition, unless otherwise expressly stated, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist). In addition, as used herein, the terms "include", "comprising", "having", and "containing" should be interpreted as having been specifically disclosed and simultaneously covering closed or semi-closed transitional phrases such as "consisting of" and "consisting essentially of".

In this article, all features or conditions defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values within the range, especially integer values. For example, the range description of "1 to 8" should be deemed to have specifically disclosed all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially secondary ranges defined by all integer values, and should be deemed to have specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise specified, the above interpretation method applies to all contents of the entire present invention, regardless of whether the range is broad or not.

If the quantity or other numerical value or parameter is expressed as a range, a preferred range or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, if a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

In this document, under the premise of achieving the purpose of the invention, numerical values should be understood to have the accuracy of the significant digits of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

In this article, for the use of Markush groups or optional terms to describe the features or embodiments of the present invention, those skilled in the art should understand that all subgroups of elements in the Markush group or optional list or any individual element can also be used to describe the present invention. For example, if X is described as "selected from the group consisting of X1, X2 and X3", it also means that the claim that X is X1 and the claim that X is X1 and/or X2 have been fully described. Furthermore, for the use of Markush groups or optional terms to describe the features or embodiments of the present invention, those skilled in the art should understand that any combination of all subgroups of elements in the Markush group or optional list or individual elements can also be used to describe the present invention. Accordingly, for example, if X is described as "selected from the group consisting of X1, X2 and X3", and Y is described as "selected from the group consisting of Y1, Y2 and Y3", it means that the claim that X is X1 or X2 or X3 and Y is Y1 or Y2 or Y3 has been fully described.

definition

The expression "compound of the present invention" used herein refers to the amide compound represented by Formula 1 and pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers thereof.

The term "alkyl" refers to a group of straight or branched saturated hydrocarbon groups having 1 to 10 carbon atoms ("C _1-05 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C _1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C _1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C _1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C _1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C _1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C ₁ alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C _2-6 alkyl"). Examples of C _1-6 alkyl groups include methyl (C ₁ ), ethyl (C ₂ ), propyl (C ₃ ) (e.g., n-propyl, isopropyl), butyl (C ₄ ) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C ₅ ) (e.g., n-pentyl, 3-pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl) and hexyl (C ₆ ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C ₇ ) and the like.

"Alkoxy" refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. In the present disclosure, alkoxy groups generally contain 1 to 10 carbon atoms ("C _1-10 alkoxy"), including, for example, methoxy, ethoxy, isopropoxy, tert-butyloxy, and the like.

"Alkenyl" refers to a group of straight or branched hydrocarbon groups having 2 to 10 carbon atoms, one or more carbon-carbon double bonds and no triple bonds ("C _2-10 alkenyl"). In some embodiments, alkenyl has 2 to 7 carbon atoms ("C _2-7 alkenyl"). In some embodiments, alkenyl has 2 to 6 carbon atoms ("C _2-6 alkenyl"). In some embodiments, alkenyl has 2 to 5 carbon atoms ("C _2-5 alkenyl"). In some embodiments, alkenyl has 2 to 4 carbon atoms ("C _2-4 alkenyl"). In some embodiments, alkenyl has 2 to 3 carbon atoms ("C _2-3 alkenyl"). In some embodiments, alkenyl has 2 carbon atoms ("C ₂ alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl ( _C2 ), 1-propenyl ( _C3 ), 2-propenyl ( _C3 ), 1-butenyl ( _C4 ), 2-butenyl ( _C4 ), butadienyl ( _C4 ), etc. Examples of _{C2-6 alkenyl} groups include the aforementioned _C2-4 alkenyl groups as well as pentenyl ( _C5 ), pentadienyl ( _C5 ), hexenyl ( _C6 ), etc. Additional examples of alkenyl groups include heptenyl ( _C7 ), etc. In certain embodiments, in alkenyl groups, a C=C double bond of unspecified stereochemistry may be an (E)- or (Z)-double bond.

"Alkynyl" refers to a straight or branched hydrocarbon radical having 2 to 10 carbon atoms, one or more carbon-carbon triple bonds, and optionally one or more double bonds ("C _2-10 alkynyl"). In some embodiments, the alkynyl has 2 to 7 carbon atoms ("C _2-7 alkynyl"). In some embodiments, the alkynyl has 2 to 6 carbon atoms ("C _2-6 alkynyl"). In some embodiments, the alkynyl has 2 to 5 carbon atoms ("C _2-5 alkynyl"). In some embodiments, the alkynyl has 2 to 4 carbon atoms ("C _2-4 alkynyl"). In some embodiments, the alkynyl has 2 to 3 carbon atoms ("C _2-3 alkynyl"). In some embodiments, the alkynyl has 2 carbon atoms ("C ₂ alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of _C2-4 alkynyl groups include, but are not limited to, ethynyl ( _C2 ), 1-propynyl ( _C3 ), 2-propynyl ( _C3 ), 1-butynyl ( _C4 ), 2-butynyl ( _C4 ), etc. Examples of _C2-6 alkenyl groups include the above-mentioned _C2-4 alkynyl groups as well as pentynyl ( _C5 ), hexynyl ( _C6 ), etc.

"Cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon radicals having 3 to 10 ring carbon atoms (" _C3-10 cycloalkyl") and zero heteroatoms in a non-aromatic ring system. Exemplary _C3-6 cycloalkyls include, but are not limited to, cyclopropyl ( _C3 ), cyclopropenyl ( _C3 ), cyclobutyl ( _C4 ), cyclobutenyl ( _C4 ), cyclopentyl ( _C5 ), cyclopentenyl ( _C5 ), cyclohexyl ( _C6 ), cyclohexenyl ( _C6 ), cyclohexadienyl ( _C6 ), and the like. As shown in the foregoing examples, in certain embodiments, the cycloalkyl is a monocyclic ring ("monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system ("bicyclic cycloalkyl") and may be saturated or may be partially unsaturated. "Cycloalkyl" also includes ring systems in which the point of attachment of a cycloalkyl group as defined above to one or more aryl or heteroaryl groups is fused to a carbocyclic ring, and in this case, the carbon number continues to refer to the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a cycloalkyl group is independently optionally substituted, i.e., unsubstituted or substituted with one or more substituents.

"Heterocycloalkyl" refers to a group of a four to eight-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("four to eight-membered heterocyclyl"). In a heterocyclyl containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as the valence permits. Heterocycloalkyl may be a monocyclic ("monocyclic heterocycloalkyl") or a condensed ring, a bridged ring or a spirocyclic system, such as a bicyclic system ("bicyclic heterocycloalkyl"), and may be saturated or may be partially unsaturated. The heterocycloalkyl bicyclic system may contain one or more heteroatoms in one or both rings. "Heterocycloalkyl" also includes a ring system in which the point of attachment of a heterocycle as defined above to one or more carbocyclyl groups is fused to a carbocyclyl or heterocycle, or a ring system in which the point of attachment of a heterocycle as defined above to one or more aryl or heteroaryl groups is fused to a heterocycle, and in this case, the number of ring members continues to refer to the number of ring members in the heterocycle system.

"Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C _6-14 aryl"). In some embodiments, the aryl has 6 ring carbon atoms ("C ₆ aryl"; for example, phenyl). In some embodiments, the aryl has 10 ring carbon atoms ("C ₁₀ aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl has 14 ring carbon atoms ("C ₁₄ aryl"; for example, anthracenyl). "Aryl" also includes a ring system in which an aryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aromatic ring, and in this case, the number of carbon atoms continues to refer to the number of carbon atoms in the aromatic ring system.

"Heteroaryl" refers to a group of a five to eight membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("five to eight membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in this case, the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups wherein the point of attachment is on the aryl or heteroaryl ring, and in this case the number of ring members refers to the number of ring members in the fused (aryl/heteroaryl) ring system.

"Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br) or iodine (iodo, -I).

The invention includes all possible geometric isomers of the compounds within its scope, such as Z and E isomers (cis and trans isomers), and all possible optical isomers of the compounds of the invention, such as diastereomers and enantiomers. In addition, the invention includes individual isomers within its scope and any mixtures thereof, such as racemic mixtures. Individual isomers can be obtained using the corresponding isomeric form of the starting material, or they can be separated after the final compound preparation according to conventional separation methods. For separating optical isomers, such as enantiomers, from their mixtures, conventional resolution methods can be applied, such as fractional crystallization or preparative chiral chromatography.

The compounds of the present invention or their pharmaceutically acceptable salts may exist in the form of hydrates, solvates or prodrugs thereof. Therefore, hydrates, solvates or prodrugs of the compounds of the present invention or their pharmaceutically acceptable salts are also included in the scope of the present invention.

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

The term "pharmaceutically acceptable excipient" refers to any preparation or carrier 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 side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For other information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared by a compound with a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt (i.e., a pharmaceutically acceptable salt) can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples include inorganic acid salts and organic acid salts, the inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; the organic acid includes, for example, benzoic acid, 2-hydroxyethanesulfonic acid, aminosulfonic acid, benzenesulfonic acid, phenylacetic acid, mandelic acid, malonic acid , propionic acid, oxalic acid, p-aminobenzenesulfonic acid, p-toluenesulfonic acid, polygalacturonic acid, fumaric acid, pantothenic acid, fumaric acid, glutamic acid, succinic acid, methanesulfonic acid, tartaric acid, ascorbic acid, phthalic acid, maleic acid, citric acid, malic acid, glucoheptose, gluconic acid, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, pamoic acid, salicylic acid, suberic acid, phosphorous acid, etc.; acetic acid, edetic acid, glycolic acid, acetic acid, ethanesulfonic acid, isobutyric acid, stearic acid and the like; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

A typical formulation is prepared by mixing the compound represented by formula (I) of the present invention and auxiliary materials, diluents or excipients. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, etc.

The specific adjuvant, diluent or excipient used will be determined according to the mode and purpose of use of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the drug in an acceptable form for manufacture or use.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

The term "treatment" refers to reversing, alleviating, delaying the onset of a disease described herein, or inhibiting the development of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to susceptible subjects prior to the onset of symptoms (e.g., based on a history of symptoms and/or based on exposure to pathogens) to delay or prevent the onset of the disease. Treatment may also be continued after symptoms subside, for example, to delay or prevent recurrence.

With respect to a drug or pharmacologically active agent, 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 oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups.

When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

The following examples are only listed as examples of embodiments of the present invention, and do not constitute any limitation to the present invention. It will be appreciated by those skilled in the art that modifications within the scope of the spirit and concept of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products. Suitable starting materials can be used by a variety of synthetic routes similar to or according to known methods in the literature.

Example 1: Synthesis of benzyl 4-(((S)-1-(((S)-1-(benzylthio)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)piperidine-1-carboxylate. Compound number: CMH0721

Synthesis route:

Synthesis of compound 1-3:

Dissolve L-valine methyl ester hydrochloride (0.167g, 1mmol) in 6mL acetonitrile, slowly add triethylamine (0.56mL, 4mmol) at 0℃, and stir at 0℃ for 30min after the addition. Add 1-benzyloxycarbonylpiperidine-4-carboxylic acid (0.263g, 1mmol) and HBTU (0.379g, 1mmol) to the reaction solution in sequence. After reacting at room temperature for 12h, extract with saturated ammonium chloride solution (10×3mL), saturated sodium bicarbonate solution (10×3mL) and saturated sodium chloride solution (10×3mL), respectively, combine the organic phases, and dry with anhydrous sodium sulfate. The solution was spin-dried to obtain colorless oil 1-3 (0.375g, 99.61%). ¹ H NMR (600MHz, chloroform-d) δ5.96 (d, J=8.7Hz, 1H), 5.24 (s, 1H), 4.49 (dd, J=8.8, 4.9Hz, 1H), 3.67 (s, 3H), 3.17 (qd, J=7.3, 5.0Hz, 2H), 2.26 (tt, J=11.6, 3.8Hz , 1H), 2.09 (m, J=6.9, 4.9Hz, 1H), 1.58 (m, 2H), 1.38 (s, 9H), 1.31 (t, J=7.3Hz, 3H), 0.84 (dd, J=18.3, 6.9Hz, 6H). ESI-MS m/z: [M+H] ⁺ : 377.20.

Synthesis of compound 1-4:

Compound 1-3 (0.375 g, 1 mmol) was dissolved in 10 mL of ethanol, and H ₂ O (4 mL) and LiOH·H ₂ O (0.084 g, 2 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (10×3 mL). The aqueous phases were combined, and the pH was adjusted to 4 with 2M HCl aqueous solution, extracted with ethyl acetate, and washed with saturated sodium chloride solution. The organic phases were combined and dried with anhydrous sodium sulfate, and then 1-4 (0.280 g, 77.30%) was obtained by spin drying as a colorless oil. ¹ H NMR (600MHz, chloroform-d) δ7.38–7.29 (m, 5H), 6.12 (d, J=8.3Hz, 1H), 5.13 (s, 2H), 4.60–4.54 (m, 1H), 4.22 (d, J=12.3Hz, 2H), 2.86 (s, 2H), 2.38 (d, J=13.0 Hz, 1H), 2.28–2.20 (m, 1H), 2.08 (d, J=31.7Hz, 1H), 1.75–1.62 (m, 2H), 1.26 (t, J=7.1Hz, 1H), 0.95 (dd, J=16.8, 6.6Hz, 6H). ESI-MS m/z: [M+H] ⁺ : 363.19.

Synthesis of compound 1-6:

Compound 1-5 (1.423 g, 5 mmol) was dissolved in 20 mL of ethanol, and H ₂ O (20 mL) and LiOH·H ₂ O (0.42 g, 10 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (50×3 mL). The aqueous phases were combined, and the pH was adjusted to 4 with 2M HCl aqueous solution, extracted with ethyl acetate, and washed with saturated sodium chloride solution. The organic phases were combined and dried with anhydrous sodium sulfate, and then 1-6 (1.192 g, 87.55%) was obtained by spin drying as a colorless solid. ESI-MS m/z: [M+Na] ⁺ : 295.12.

Synthesis of compound 1-7:

Compound 1-6 (0.545 g, 2 mmol) was dissolved in dichloromethane (6 mL), cooled to 0°C, and then benzyl mercaptan (0.235 mL, 2 mmol), DMAP (0.05 g, 0.4 mmol), and DCC (0.495 g, 2.4 mmol) were added in sequence. After stirring at 0°C for 0.5 h, the mixture was transferred to room temperature for reaction for 14 h. The white insoluble solid was removed by suction filtration, and the filtrate was extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate = 30:70) to obtain a colorless solid 1-7 (0.745 g, 98.4%). ¹ H NMR (600MHz, chloroform-d) δ7.33–7.31 (m, 1H), 7.30–7.27 (m, 5H), 4.14–4.04 (m, 3H), 3.34 (dt, J=9.2, 4.9Hz, 2H), 2.50–2.36 (m, 2H), 2.09–2.02 (m, 1H), 1 .94–1.79 (m, 2H), 1.44 (d, J=2.2Hz, 9H).ESI-MS m/z: [M+Na] ⁺ : 401.15.

Synthesis of compound 1-8:

Compound 1-7 (0.731 g, 1.93 mmol) was dissolved in dichloromethane (6 mL), HCl/ethyl acetate (1.64 mL, 6.56 mmol) was slowly added dropwise, and the mixture was reacted at room temperature for 12 h. The solvent was evaporated to dryness to obtain intermediate 1-8, which was directly used for the next step of reaction. ESI-MS m/z: [M+H] ⁺ : 279.11.

Synthesis of compound 1:

The intermediate 1-8 (0.718 g, 1.93 mmol) and acetonitrile (12 mL) were added to an eggplant-shaped bottle, triethylamine (1.07 mL, 7.72 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. Compound 1-4 (0.699 g, 1.93 mmol) and HBTU (0.732 g, 1.93 mmol) were then added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (40×3 mL), saturated sodium bicarbonate (40×3 mL) and saturated sodium chloride (40×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with a mobile phase of dichloromethane/methanol (50:1). After elution, the mixture was spin-dried to obtain a colorless solid 1-9 (0.435 g, 36.19%). ¹ H NMR (600MHz, chloroform-d) δ 8.62 (d, J = 5.7Hz, 1H), 7.83 (d, J = 6.6Hz, 1H), 7.37–7.33 (m, 4H), 7.28 (m, 6H), 5.12 (s, 2H), 4.60 (d, J = 7.4Hz, 1H), 4.46 (d, J = 7.4Hz, 1H) ), 4.09(s, 2H), 3.34(d t, J=10.4, 5.8Hz, 6H), 2.83 (s, 1H), 2.43 (d, J=4.6Hz, 1H), 2.34 (d, J=3.6Hz, 1H), 2.23–2.16 (m, 1H), 2.04 (s, 5H), 1.98–1.92 (m, 2H), 0.92 (ddd, J=27. 4, 18.8, 6.7Hz, 6H).ESI-MS m/z: [M+H] ⁺ : 623.29.

Example 2: Synthesis of tert-butyl 4-(((S)-1-(((S)-1-(ethylthio)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)piperidine-1-carboxylate. Compound number: CMH0727-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a colorless solid with a yield of 39.60%. ¹ H NMR (600 MHz, chloroform-d) δ8.42 (d, J=6.1 Hz, 2H), 4.60-4.41 (m, 2H), 4.13 (d, J=13.2 Hz, 2H), 3.44-3.37 (m, 2H), 3.19-3.14 (m, 1H), 2.86 (dq, J=10.7, 7.4 Hz, 2H), 2.76 (q, J=12.3 Hz, 2H), 2.49 (t, J =7.2Hz, 1H), 2.36 (m, 2H), 2.15–2.08 (m, 1H), 2.00–1.93 (m, 1H), 1.91–1.78 (m, 3H), 1.69–1.60 (m, 2H), 1.45 (s, 9H), 1.23 (dt, J=9.2, 7.4Hz, 3H), 0. 96 (td, J=24.1, 23.3, 6.8Hz, 6H).ESI-MS m/z: [m+Na] ⁺ : 549.32.

Example 3: Synthesis of tert-butyl 3-(((S)-1-(((S)-1-(ethylthio)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)pyrrolidine-1-carboxylate. Compound number: CMH0727-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a colorless solid with a yield of 44.16%. ¹ H NMR (600MHz, chloroform-d) δ 8.47 (s, 1H), 6.66–6.31 (m, 2H), 4.56 (dd, J=8.8, 5.0Hz, 2H), 2.43–2.35 (m, 1H, 2.32–2.21 (m, 3H), 2.15–2.07 (m, 2H), 1.97 (ddd, J=14.0, 5.5, 3.7Hz, 1H), 1.87 (dq, J=12.7, 9.3Hz, 1H), 1.45 (d, J=3.3Hz, 9H), 1.23 (t, J=7.4Hz, 3H), 1.05–0.92 (m, 6H). ESI-MS m/z: [m+H] ⁺ : 513.27.

Example 4: Synthesis of benzyl 4-(((S)-1-(((S)-1-(ethylthio)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)piperidine-1-carboxylate. Compound number: CMH0727-3.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a colorless solid with a yield of 41.19%. ¹ H NMR (600 MHz, chloroform-d) δ8.46 (s, 1H), 7.35 (s, 5H), 6.53-6.10 (m, 2H), 5.12 (s, 2H), 4.50 (dd, J = 8.8, 5.4 Hz, 2H), 4.21 (s, 2H), 3.39 (d, J = 8.8 Hz, 2H), 3.20-3.07 (m, 1H), 2.85 (dq, J = 14.3, 7.3Hz,4H),2.47(s,1H),2.37(d,J＝11.1Hz,2H),2.29–2.06(m,2H),2.00–1.92(m,1H),1.89–1.83(m,2H),1.75–1.62(m,2H),1.22(dt,J＝13.9,7.4 Hz,3H),1.02–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 561.31.

Example 5: Synthesis of tert-butyl 4-(((S)-1-(((S)-1-(benzylthio)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)piperidine-1-carboxylate. Compound number: CMH0728-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a colorless solid with a yield of 43.85%. ¹ H NMR (600 MHz, chloroform-d) δ8.56 (d, J=5.6 Hz, 1H), 7.30-7.27 (m, 2H), 7.24 (ddd, J=11.1, 7.7, 5.3 Hz, 3H), 6.44-6.07 (m, 2H), 4.58-4.43 (m, 1H), 4.14-4.03 (m, 4H), 3.36 (d, J=9.3H z, 2H), 2.12 (tdd, J＝10.8, 6.8, 4.4Hz, 1H), 1.94 (dtd, J＝16.9, 10.5, 9.7, 4.8Hz, 1H), 1.84–1.77 (m, 2H), 1.67–1.57 (m, 2H), 1.46 (d, J＝5.8Hz, 9H), 0.98 –0.88(m,6H).ESI-MS m/z:[m+H] ⁺ : 589.32.

Example 6: Synthesis of tert-butyl 3-(((S)-1-(((S)-1-(benzylthio)-1-oxo-3-(((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamoyl)pyrrolidine-1-carboxylate. Compound number: CMH0728-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 1 as a colorless solid with a yield of 39.24%. ¹ H NMR (600 MHz, chloroform-d) δ8.56 (s, 1H), 7.30-7.27 (m, 2H), 7.26-7.21 (m, 3H), 6.45-6.39 (m, 1H), 4.57 (dd, J = 8.0, 4.9 Hz, 1H), 4.49 (dt, J = 10.8, 5.0 Hz, 1H), 4.10 (s, 2H), 3.66-3.43 (m, 3H), 3.38-3.29 (m, 3H ),2.97–2.90(m,1H),2.44(s,1H),2.39–2.31(m,1H),2.24(dq,J＝13.1,6.5Hz,1H),2.16–2.04(m,3H),1.95(dd,J＝8.6,3.9Hz,1H),1.88–1.79(m,1H), 1.45(d,J＝3.5Hz,9H),1.02–0.86(m,6H).ESI-MS m/z:[m+H] ⁺ : 575.28.

Example 7: Synthesis of S-benzyl (S)-2-((S)-2-(1-cinnamoylpiperidine-4-carboxamido)-3-methylbutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0737-1.

Synthesis route:

Synthesis of intermediate 7-10:

Compound 5-9 (0.15 g, 0.255 mmol) was dissolved in dichloromethane (2 mL), HCl/ethyl acetate (0.25 mL, 0.867 mmol) was added dropwise, and stirred at room temperature until compound 5-9 was completely reacted. The solvent was removed by distillation under reduced pressure to obtain intermediate 7-10, which was directly used in the next step reaction.

Synthesis of compound 7-11:

Add intermediate 7-10 (0.087 g, 0.127 mmol) and acetonitrile (2 mL) into an eggplant-shaped bottle, add triethylamine (0.07 mL, 0.508 mmol) dropwise at 0°C, stir at 0°C until intermediate 7-10 is completely dissolved, then add cinnamic acid (0.02 g, 0.127 mmol) and HBTU (0.048 g, 0.127 mmol) in sequence, and react at room temperature overnight. Extract with saturated ammonium chloride (10×3 mL), saturated sodium bicarbonate (10×3 mL) and saturated sodium chloride (10×3 mL), respectively, combine the organic phases, dry over anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is purified by silica gel column chromatography with a mobile phase of dichloromethane/methanol (30:1). After elution, spin-drying is performed to obtain a white solid 7-11 (0.019 g, 24.20%). ¹ H NMR (600MHz, chloroform-d) δ8.70–8.29(m,1H),7.57(d,J＝15.4Hz,1H),7.44(d,J＝6.7Hz,2H),7.32–7.25(m,3H),7.21(d,J＝7.3Hz,1H),7.17(dt,J＝16.6,6.8Hz,4 H),6.80(d,J＝15.5Hz,1H),6.37(s,2H),4.53(dd,J＝8.8,4.9Hz,2H),4.41(ddd,J＝11.5,5.8,4.0Hz,1H),4.02(s,2H) ,3.41(s,1H),3.26(p,J＝9.6,9.2Hz,2H),3.10(s,1H),2.74(s,1H),2.44–2.36(m,1H),2.33(dt,J＝16.4,6.5Hz,1H),2.29–2.22(m,1H),2.18(dq,J =13.4, 6.7Hz, 1H), 2.08–2.02 (m, 1H), 1.86 (dt, J = 13.8, 6.8Hz, 3H), 1.77–1.64 (m, 3H), 0.87 (dd, J = 33.0, 6.8Hz, 6H). ESI-MS m/z: [m+H] ⁺ : 619.30.

Example 8: Synthesis of S-benzyl (S)-2-((S)-2-(1-(4-methoxy-1H-indole-2-carbonyl)piperidine-4-carboxamide)-3-methylbutyrylamide)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0737-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 45.80%. ¹ H NMR (600 MHz, chloroform-d) δ9.27 (s, 1H), 8.66 (d, J = 4.9 Hz, 1H), 7.28 (dd, J = 7.1, 1.2 Hz, 1H), 7.26-7.17 (m, 5H), 7.03 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.00 (s, 1H), 4.68 (d, J = 12.8 Hz, 2H), 4.51 (ddd, J = 24.2, 9.8, 4.9 Hz, 2H), 4. 17–4.03(m,2H),3.95(s,3H),3.34(d,J＝8.5Hz,2H),2.54(s,1H),2.48–2.34(m,2H),2.27(dq,J＝13.3,6.8Hz,1H),2.07(td,J＝13.1,11.7,7.6Hz,1H ), 2.01–1.93(m,3H),1.84(dd,J＝19.6,11.0Hz,6H),0.96(dd,J＝32.6,6.8Hz,6H).ESI-MS m/z:[m+H] ⁺ : 662.3008.

Example 9: Synthesis of S-ethyl (S)-2-((S)-2-(1-cinnamoylpiperidine-4-carboxamido)-3-methylbutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0738-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 51.99%. ¹ H NMR (600 MHz, chloroform-d) δ8.67-8.51 (m, 1H), 7.65 (d, J = 15.4 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.37 (q, J = 8.9, 7.7 Hz, 3H), 6.88 (d, J = 15.4 Hz, 1H), 6.37 (d, J = 7.2 Hz, 1H), 6.21 (s, 1H), 4.57 (dd, J = 8.6, 4.7 Hz, 1H), 4.44 (dt, J = 10.9, 4.7 Hz, 1H), 3.42-3.33 (m, 2H), 3.03 (s, 1H), 2 .86(q,J＝7.4Hz,2H),2.49(t,J＝11.0Hz,1H),2.46–2.36(m,2H),2.29(dq,J＝13.0,6.5Hz,1H),2.08(td,J＝13.2,12.3,7.0Hz,1H),1.99–1.92(m,3H), 1.87 (q, J＝10.4, 10.0Hz, 1H), 1.79 (q, J＝13.1, 11.5Hz, 2H), 1.30–1.19 (m, 6H), 0.98 (dd, J＝26.9, 6.8Hz, 6H). ESI-MS m/z: [m+H] ⁺ : 557.29.

Example 10: Synthesis of S-ethyl (S)-2-((S)-2-(1-(4-methoxy-1H-indole-2-carbonyl)piperidine-4-carboxamide)-3-methylbutyrylamide)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0738-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 37.74%. ¹ H NMR (600 MHz, chloroform-d) δ9.49 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.50 (d, J = 7.8 Hz, 1H), 6.29 (s, 1H), 4.80-4.62 (m, 2H), 4.61-4.43 (m, 2H), 3.39-3.26 (m, 2H), 3.13 (s, 1H) ,2.87(q,J＝7.4Hz,2H),2.55(s,1H),2.44(s,1H),2.28(dq,J＝13.0,6.5Hz,3H),2.09(dt,J＝12.2,7.1Hz,1H),2.02–1.92(m,3H),1.85(dd,J＝21.1,10 .4Hz, 3H), 1.24 (q, J＝7.3Hz, 5H), 0.98 (dd, J＝29.2, 6.8Hz, 6H). ESI-MS m/z: [m+H] ⁺ ：600.2850.

Example 11: Synthesis of S-ethyl (2S)-2-((2S)-2-(1-cinnamoylpyrrolidine-3-carboxamide)-3-methylbutyramido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0741-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 54.81%. ¹ H NMR (600 MHz, chloroform-d) δ8.83-8.39 (m, 1H), 7.71 (dd, J = 15.4, 3.3 Hz, 1H), 7.53 (d, J = 6.5 Hz, 2H), 7.37 (d, J = 7.1 Hz, 3H), 6.72 (d, J = 15.4 Hz, 1H), 6.57 (d, J = 49.4 Hz, 1H), 6.04 (s, 1H), 4.60-4.42 (m, 2H), 4.05-3.75 (m, 3H), 3. 41–3.33(m,2H),3.08(s,1H),2.87(ddd,J＝14.8,6.8,2.7Hz,2H),2.50–2.36(m,3H),2.35–2.20(m,3H),2.12–1.95(m,2H),1.87(q,J＝8.9,8.0Hz,1H ), 1.23 (td, J＝7.4, 3.2Hz, 3H), 0.99 (dd, J＝24.9, 6.6Hz, 6H). ESI-MS m/z: [m+H] ⁺ : 543.26.

Example 12: Synthesis of S-ethyl (2S)-2-((2S)-2-(1-(4-methoxy-1H-indole-2-carbonyl)pyrrolidine-3-carboxamido)-3-methylbutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0741-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 60.91%. ¹ H NMR (600 MHz, chloroform-d) δ 10.12-9.76 (m, 1H), 7.19 (q, J = 7.5 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 14.7 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 65.7 Hz, 2H), 4.20-4.03 (m, 2H), 3.94 (s, 4H), 3.39-3.23 (m, 2H), 3.14 (d ,J＝50.7Hz,1H),2.87(dd,J＝15.1,7.7Hz,2H),2.46(s,1H),2.41–2.19(m,4H),2.15–2.08(m,1H),2.00–1.94(m,1H),1.83(dq,J＝22.5,10.3Hz,1H),1 .24(dq,J＝26.3,7.7Hz,6H),0.98(dd,J＝33.6,6.4Hz,6H).ESI-MS m/z:[m+H] ⁺ : 586.27.

Example 13: Synthesis of S-benzyl (2S)-2-((2S)-2-(1-cinnamoylpyrrolidine-3-carboxamido)-3-methylbutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0802-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 40.06%. ¹ H NMR (600 MHz, chloroform-d) δ 8.75-8.45 (m, 1H), 7.64-7.59 (m, 1H), 7.46-7.42 (m, 2H), 7.29 (d, J = 6.3 Hz, 4H), 7.19-7.12 (m, 4H), 6.67-6.55 (m, 2H), 4.54-4.39 (m, 2H), 4.04-4.00 (m, 2H) ,3.87–3.72(m,3H),3.66–3.45(m,2H),3.27(dd,J＝9.4,4.3Hz,2H),3.09–2.92(m,2H),2.37(d,J＝12.5Hz,1H),2.31–2.10(m,5H),2.08–1.97(m,2H) ,0.93–0.86(m,6H).ESI-MS m/z:[m+H] ⁺ : 605.28.

Example 14: Synthesis of S-benzyl (2S)-2-((2S)-2-(1-(4-methoxy-1H-indole-2-carbonyl)pyrrolidine-3-carboxamide)-3-methylbutyramido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0802-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 7 as a white solid with a yield of 48.28%. ¹ H NMR (600 MHz, chloroform-d) δ9.68 (d, J = 69.5 Hz, 1H), 8.68 (q, J = 54.3, 45.2 Hz, 1H), 7.29 (d, J = 14.2 Hz, 3H), 7.25-7.18 (m, 4H), 7.05 (t, J = 8.0 Hz, 1H), 6.50 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 4.62-4.45 (m, 2H), 4.10 ( d,J＝8.4Hz,2H),3.95(s,3H),3.39–3.27(m,2H),3.21–2.85(m,2H),2.31(d,J＝69.0Hz,5H),2.11–1.94(m,4H),1.83(dt,J＝28.0,10.5Hz,1H),1.42( d, J＝4.0Hz, 2H), 0.96 (dt, J＝35.3, 6.6Hz, 6H). ESI-MS m/z: [m+H] ⁺ : 648.29.

Example 15: Synthesis of S-ethyl (S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-(S)-3-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0804-1.

Synthesis route:

Synthesis of compound 15-1:

Compound 1-5 (1.145 g, 4 mmol) was dissolved in dichloromethane (12 mL), HCl/dioxane (3.4 mL, 13.6 mmol) was added dropwise, and the mixture was reacted at room temperature overnight. The mixture was distilled under reduced pressure to obtain colorless solid 15-2 (1.065 g, 100%). ESI-MS m/z: [m+H] ⁺ : 187.11.

Synthesis of compound 15-3:

Compound 15-1 (0.638 g, 2.5 mmol) and acetonitrile (15 mL) were added to an eggplant-shaped bottle, triethylamine (1.39 mL, 10 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C until compound 15-1 was completely dissolved. Then 15-2 (0.578 g, 2.5 mmol) and HBTU (0.948 g, 2.5 mmol) were added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (50×3 mL), saturated sodium bicarbonate (50×3 mL) and saturated sodium chloride (50×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with a mobile phase of dichloromethane/methanol (50:1). After elution, the colorless solid 15-3 (0.9 g, 90.17%) was obtained by spin drying. ESI-MS m/z: [m+H] ⁺ : 400.25.

Synthesis of compound 15-4:

Compound 15-3 (0.9 g, 2.25 mmol) was dissolved in 10 mL of ethanol, and H ₂ O (10 mL) and LiOH·H ₂ O (0.189 g, 4.5 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (20×3 mL). The aqueous phases were combined, and the pH was adjusted to 4 with 2M HCl aqueous solution, extracted with ethyl acetate, and washed with saturated sodium chloride solution. The organic phases were combined and dried with anhydrous sodium sulfate, and then spin-dried to obtain a colorless solid 15-4 (0.867 g, 100%). ESI-MS m/z: [m+H] ⁺ : 386.23.

Synthesis of compound 15-5:

Compound 15-4 (0.491 g, 1.25 mmol) was dissolved in dichloromethane (4 mL), cooled to 0°C, and ethanethiol (0.093 mL, 1.25 mmol), DMAP (0.031 g, 0.25 mmol), and DCC (0.309 g, 1.5 mmol) were added in sequence. After stirring at 0°C for 0.5 h, the mixture was reacted at room temperature for 14 h. The white insoluble solid was removed by suction filtration, and the filtrate was extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate = 30:70) to obtain a colorless solid 15-5 (0.312 g, 58.10%). ESI-MS m/z: [m+H] ⁺ : 430.24.

Synthesis of compound 15-6:

Compound 15-5 (0.312 g, 0.726 mmol) was dissolved in dichloromethane (3 mL), and HCl/dioxane (0.726 mL, 2.904 mmol) was added dropwise. The mixture was reacted at room temperature overnight. The mixture was distilled under reduced pressure to obtain a light green solid 15-6, which was used directly in the next step. ESI-MS m/z: [m+H] ⁺ : 330.19.

Synthesis of compound 15:

Compound 15-5 (0.299 g, 0.726 mmol) and acetonitrile (4 mL) were added to an eggplant-shaped bottle, triethylamine (0.404 mL, 2.904 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. Compound 15-7 (0.139 g, 0.726 mmol) and HBTU (0.272 g, 0.726 mmol) were then added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (20×3 mL), saturated sodium bicarbonate (20×3 mL) and saturated sodium chloride (20×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane/methanol (50:1) as the mobile phase. After elution, the white solid 15 (0.273 g, 74.81%) was obtained by spin drying. ¹ H NMR (600 MHz, DMSO-d ₆ )δ11.59(d,J＝2.3Hz,1H),8.72(d,J＝8.0Hz,1H),8.38(d,J＝8.3Hz,1H),7.63(s,1H),7.36(dd,J＝2.3,0.9Hz,1H),7.13–7.05(m,1H),7.00(d,J＝8.3Hz,1H ),6.50(d,J＝7.6Hz,1H),4.59(ddd,J＝10.4,8.2,4.8Hz,1H),4.39(ddd,J＝1 1.9,8.0,4.2Hz,1H),3.88(s,3H),3.17–3.03(m,2H),2.77(q,J＝7.3Hz,2H),2.22(tdd,J＝10.5,8.4,4.3Hz,1H),2.09–1.98(m,2H),1.78–1.67(m,2H) ,1.60–1.53(m,1H),1.13(t,J＝7.4Hz,3H),0.91(dd,J＝21.8,6.5Hz,6H).ESI-MS m/z:[m+H] ⁺ :503.2322.

Example 16: Synthesis of S-benzyl (S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0804-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 49.72%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ11.56 (d, J=17.6 Hz, 1H), 8.79 (dd, J=43.0, 7.8 Hz, 1H), 8.40 (dd, J=20.2, 8.2 Hz, 1H), 7.65 (d, J=27.1 Hz, 1H), 7.35 (s, 1H), 7.29-7.22 (m, 4H), 7.09 (t, J=7.9 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 4.6 9–4.42(m,2H),4.10–4.04(m,2H),3.88(s,3H),3.10(dq,J＝27.0,8.8Hz,2H),2.19(ddt,J＝20.9,15.7,9.2Hz,2H),2.08–2.00(m,2H),1.99(s,1H),1 .60–1.51(m,1H),1.17(t,J＝7.1Hz,1H),0.94–0.85(m,6H).ESI-MS m/z:[m+H] ⁺ : 565.25.

Example 17: Synthesis of S-(4-(trifluoromethyl)benzyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0918.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 32.29%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.62 (d, J = 2.5 Hz, 1H), 8.85 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 2.3 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 4.58 (ddd, J ＝10.3,8.2,5.0Hz,1H),4.44(ddd,J＝11.9,7.9,4.4Hz,1H),4.14(s,2H),3.88(s,3H),3.14–3.09(m,1H),3.05(td,J＝9.3,7.0Hz,1H),2.22(tdd,J＝10. 5,8.3,4.4Hz,1H),2.07–1.99(m,2H),1.73–1.56(m,5H),0.93–0.86(m,6H).ESI-MS m/z:[m+H] ⁺ : 633.2352.

Example 18: Synthesis of S-(4-chlorobenzyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0919.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 44.58%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.61 (s, 1H), 8.86-8.76 (m, 1H), 8.45 (dd, J=8.1, 2.8 Hz, 1H), 7.64 (s, 1H), 7.36 (d, J=2.2 Hz, 1H), 7.33-7.19 (m, 4H), 7.10 (t, J=7.9 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 6.51 (d, J=7.7 Hz, 1H), 4.58 (ddd, J=10.3, 8. 1,4.9Hz,1H),4.43(ddd,J＝12.0,7.9,4.3Hz,1H),4.04(d,J＝1.1Hz,2H),3.89(s,3H),3.14–3.03(m,2H),2.22(qd,J＝10.8,6.7Hz,1H),2.04–2.01(m,1 H),1.75–1.57(m,5H),0.90(dd,J＝27.8,6.4Hz,6H).ESI-MS m/z:[m+H] ⁺ :599.2089.

Example 19: Synthesis of S-(2-fluorobenzyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0923.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 61.40%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (d, J = 2.3 Hz, 1H), 8.76 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.37-7.33 (m, 2H), 7.29 (tdd, J = 7.5, 5.4, 1.8 Hz, 1H), 7.15 (ddd, J = 9.7, 8.2, 1.2 Hz, 1H), 7.12-7.08 (m, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1H), 4.56 (ddd, J = 1 0.4,8.1,4.9Hz,1H),4.45(ddd,J＝12.0,8.0,4.3Hz,1H),4.08(d,J＝2.5Hz,2H),3.89(s,3H),3.14–3.10(m,1H),3.05(td,J＝9.4,7.0Hz,1H),2.19(tdd, J＝10.6,8.4,4.3Hz,1H),2.06–1.99(m,2H),1.74–1.55(m,5H),0.89(dd,J＝29.2,6.4Hz,6H).ESI-MS m/z:[m+H] ⁺ :583.2385.

Example 20: Synthesis of S-(4-(tert-butyl)benzyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0924.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 69.46%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (d, J = 2.4 Hz, 1H), 8.76 (d, J = 8.0 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.36 (dd, J = 2.3, 0.9 Hz, 1H), 7.25-7.21 (m, 2H), 7.16-7.12 (m, 2H), 7.12-7.08 (m, 1H), 7.01 (dt, J = 8.1, 0.8 Hz, 1H), 6.51 (dd, J = 7.8, 0.7 Hz, 1H), 4.59 ( ddd,J＝10.4,8.3,5.0Hz,1H),4.44(ddd,J＝12.0,8.1,4.2Hz,1H),4.01(s,2H),3.33(s,3H),3.16–3.03(m,2H),2.21(tdd,J＝10.5,8.3,4.2Hz,1H),2.08 –1.99(m,2H),1.74–1.53(m,5H),1.22(s,9H),0.90(dd,J＝27.8,6.4Hz,6H).ESI-MS m/z:[m+H] ⁺ : 621.3106.

Example 21: Synthesis of S-(thiophen-2-ylmethyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0926.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 62.58%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (d, J = 2.3 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 7.38-7.32 (m, 2H), 7.09 (t, J = 7.9 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.97 (dd, J = 3.4, 1.1 Hz, 1H), 6.89 (dd, J = 5.1, 3.4 Hz, 1H), 6.50 (dd, J = 7.7, 0.7 Hz, 1 H),4.58(ddd,J＝10.5,8.2,4.9Hz,1H),4.45(ddd,J＝12.0,8.0,4.3Hz,1H),4.29(s,2H),3.88(s,3H),3.14–3.04(m,2H),2.22(tdd,J＝10.5,8.3,4.4Hz,1 H),2.07–2.01(m,2H),1.74–1.56(m,5H),0.90(dd,J＝25.8,6.4Hz,6H).ESI-MS m/z:[m+H] ⁺ :571.2043.

Example 22: Synthesis of S-(3-fluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0946.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 20.08%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 17.5, 1.9 Hz, 1H), 8.96 (dd, J = 33.1, 7.7 Hz, 1H), 8.46 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 29.4 Hz, 1H), 7.50 (dtd, J = 14.5, 8.1, 6.1 Hz, 1H), 7.38 (dd, J = 8.2, 2.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.25 (tt, J = 8.8, 2.1 Hz, 1H), 7.20 (ddt, J = 8.8, 7.7 ,1.1Hz,1H),7.09(td,J＝8.0,2.6Hz,1H),7.00(dd,J＝8.2,4.6Hz,1H),6.51(dd,J＝7.7,2.2Hz,1H),4.79–4.53(m,2H),3.89(d,J＝2.0Hz,3H),3.17–3.06( m,2H),2.34–2.20(m,2H),2.15–2.05(m,1H),1.82–1.62(m,5H),0.97–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 569.2227.

Example 23: Synthesis of S-(4-bromophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1102-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 16.27%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 18.5, 2.3 Hz, 1H), 8.95 (dd, J = 28.9, 7.6 Hz, 1H), 8.46 (t, J = 8.5 Hz, 1H), 7.65 (dd, J = 13.7, 8.4 Hz, 2H), 7.38 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.09 (td, J = 7.9, 1.9 Hz, 1H), 7.00 (dd, J = 8.3, 4.1 Hz,1H),6.51(dd,J＝7.6,1.5Hz,1H),4.81–4.46(m,2H),3.89(d,J＝1.5Hz,3H),3.18–3.05(m,2H),2.29–2.19(m,2H),1.77(qd,J＝12.4,11.8,6.6Hz,2H) ,1.73–1.67(m,2H),1.65-1.58(m,2H),0.97–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 629.4129.

Example 24: Synthesis of S-(4-chlorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1102-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 17.24%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 18.4, 2.3 Hz, 1H), 8.95 (dd, J = 29.4, 7.6 Hz, 1H), 8.46 (t, J = 8.5 Hz, 1H), 7.68 (d, J = 29.1 Hz, 1H), 7.57-7.47 (m, 2H), 7.39-7.34 (m, 3H), 7.09 (td, J = 8.0, 2.0 Hz, 1H), 7. 00(dd,J＝8.2,4.1Hz,1H),6.51(dd,J＝7.8,1.6Hz,1H),4.78–4.51(m,2H),3.89(d,J＝1.6Hz,3H),3.17–3.06(m,2H),2.33–2.05(m,3H),1.83–1.65(m,5 H),0.97–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 585.1932.

Example 25: Synthesis of S-(4-fluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1102-3.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 32.47%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 18.2, 2.3 Hz, 1H), 8.94 (dd, J = 32.3, 7.7 Hz, 1H), 8.46 (dd, J = 9.9, 8.2 Hz, 1H), 7.68 (d, J = 29.8 Hz, 1H), 7.48-7.36 (m, 3H), 7.33-7.26 (m, 2H), 7.09 (td, J = 8.0, 2.2 Hz, 1H), 7.00(dd,J＝8.3,4.3Hz,1H),6.51(dd,J＝7.8,1.8Hz,1H),4.84–4.46(m,2H),3.89(d,J＝1.7Hz,3H),3.20–3.05(m,2H),2.34–2.04(m,3H),1.84–1.66(m ,5H),0.98–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ :569.2225.

Example 26: Synthesis of S-(2-chlorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1107-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 18.19%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.66 (dd, J=12.9, 2.3 Hz, 1H), 9.11 (dd, J=20.2, 7.5 Hz, 1H), 8.55 (dd, J=13.2, 8.1 Hz, 1H), 7.81-7.67 (m, 2H), 7.61-7.44 (m, 4H), 7.17 (td, J=7.9, 1.7 Hz, 1H), 7.08 (dd, J= 8.2,3.2Hz,1H),6.58(d,J＝7.6Hz,1H),4.86–4.57(m,2H),3.96(s,3H),3.19(dtd,J＝25.0,9.3,6.4Hz,2H),2.43–2.21(m,3H),1.90–1.69(m,5H),1. 05–0.98(m,6H).ESI-MS m/z:[m+H] ⁺ : 585.19.

Example 27: Synthesis of S-(3-bromophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1107-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 11.75%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (dd, J = 11.3, 2.3 Hz, 1H), 8.91 (dd, J = 21.2, 7.6 Hz, 1H), 8.41 (dd, J = 8.2, 5.4 Hz, 1H), 7.67-7.57 (m, 2H), 7.49 (dt, J = 3.5, 1.8 Hz, 1H), 7.37-7.28 (m, 3H), 7.03 (td, J = 8.0, 1.8 Hz, 1H ),6.94(dd,J＝8.2,3.0Hz,1H),6.44(dd,J＝7.7,1.5Hz,1H),4.74–4.44(m,2H),3.83(d,J＝1.2Hz,3H),3.12–2.99(m,2H),2.26–2.08(m,3H),1.76–1.58( m,5H),0.91–0.84(m,6H).ESI-MS m/z:[m+H] ⁺ : 629.14.

Example 28: Synthesis of S-(2-bromophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1107-3.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 11.75%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.53 (dd, J = 12.6, 2.3 Hz, 1H), 8.97 (dd, J = 19.5, 7.7 Hz, 1H), 8.41 (dd, J = 13.0, 8.1 Hz, 1H), 7.73 (td, J = 7.6, 1.5 Hz, 1H), 7.64 (d, J = 21.6 Hz, 1H), 7.46-7.30 (m, 4H), 7.03 (td, J = 8.0, 1.7 Hz, 1H),6.94(dd,J＝8.3,3.0Hz,1H),6.45(d,J＝7.6Hz,1H),4.74–4.43(m,2H),3.83(s,3H),3.12–3.00(m,2H),2.31–2.05(m,3H),1.67(dtt,J＝26.3,11 .3,5.0Hz,5H),0.92–0.84(m,6H).ESI-MS m/z:[m+H] ⁺ : 629.14.

Example 29: Synthesis of methyl 2-(((S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoyl)thio)benzoate. Compound number: CMH1107-4.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 28.26%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.62 (dd, J = 12.9, 2.4 Hz, 1H), 9.02 (dd, J = 28.1, 7.5 Hz, 1H), 8.49 (dd, J = 13.6, 8.1 Hz, 1H), 7.87 (dd, J = 7.2, 2.2 Hz, 1H), 7.72 (d, J = 22.6 Hz, 1H), 7.61 (td, J = 7.0, 1.8 Hz, 2H), 7.52-7.45 (m, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.12 (t, J = 2. ＝7.9Hz,1H),7.04(d,J＝8.3Hz,1H),6.53(d,J＝7.7Hz,1H),4.60(ddd,J＝11.7,8.2,4.6Hz,2H),3.91(s,3H),3.81(d,J＝14.4Hz,3H),3.22–3.04(m,2H),2. 37–2.05(m,3H),1.86–1.61(m,5H),0.97(dd,J＝14.4,6.2Hz,6H).ESI-MS m/z:[m+H] ⁺ : 609.23.

Example 30: Synthesis of S-(2-(trifluoromethyl)phenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1107-5.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 15.07%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.52 (dd, J = 12.7, 2.3 Hz, 1H), 8.98 (dd, J = 21.3, 7.4 Hz, 1H), 8.42 (dd, J = 23.3, 8.1 Hz, 1H), 7.82 (dd, J = 7.5, 5.5 Hz, 1H), 7.66 (ddt, J = 22.2, 14.6, 8.0 Hz, 3H), 7.50 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 2.7 Hz, 1H), 7.03 (td, J＝8.0,1.9Hz,1H),6.95(dd,J＝8.2,3.3Hz,1H),6.44(d,J＝7.6Hz,1H),4.73–4.39(m,2H),3.83(s,3H),3.03(ddt,J＝26.1,9.3,5.3Hz,2H),2.26–2.06(m, 3H),1.78–1.56(m,5H),0.87(dd,J＝15.5,6.7Hz,6H).ESI-MS m/z:[m+H] ⁺ : 619.22.

Example 31: Synthesis of S-(pyridin-4-yl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1107-6.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 12.64%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 6.1, 2.4 Hz, 1H), 8.53-8.50 (m, 2H), 8.41 (d, J = 8.7 Hz, 1H), 7.62 (d, J = 5.1 Hz, 1H), 7.56-7.52 (m, 2H), 7.35 (s, 1H), 7.10 (td, J = 7.9, 2.1 Hz, 1H), 7.01 (dd, J = 8.3, 1.8Hz,1H),6.51(dd,J＝7.8,2.6Hz,1H),4.78–4.50(m,2H),3.89(d,J＝2.0Hz,3H),3.17–3.00(m,2H),2.28–2.15(m,2H),1.76–1.65(m,6H),0.88(q,J＝ 8.3,7.5Hz,6H).ESI-MS m/z:[m+H] ⁺ : 552.23.

Example 32: Synthesis of S-(naphthalen-2-yl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0236.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 21.67%. ¹ H NMR (600 MHz, chloroform-d) δ9.13 (dd, J=113.3, 6.5 Hz, 1H), 7.83 (dd, J=5.9, 1.7 Hz, 1H), 7.79-7.70 (m, 3H), 7.48-7.38 (m, 3H), 7.33 (ddd, J=8.5, 3.3, 1.8 Hz, 1H), 7.13-7.03 (m, 3H), 6.96-6.90 (m, 1H), 4.9 5–4.80(m,2H),3.86(d,J＝1.9Hz,3H),3.24–3.01(m,2H),2.62–2.43(m,1H),2.32–2.21(m,1H),2.19–2.02(m,3H),2.01–1.93(m,2H),1.88(ddd,J＝ 13.6,8.6,5.0Hz,1H),0.86–0.81(m,6H).ESI-MS m/z:[m+H] ⁺ : 601.2478.

Example 33: Synthesis of S-(4-isopropylphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0302.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 44.18%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 17.9, 2.3 Hz, 1H), 8.91 (dd, J = 36.1, 7.7 Hz, 1H), 8.45 (dd, J = 12.6, 8.2 Hz, 1H), 7.38 (dd, J = 7.1, 2.2 Hz, 1H), 7.32 (dd, J = 12.9, 8.3 Hz, 2H), 7.25 (dd, J = 8.2, 3.8 Hz, 2H), 7.09 (td, J = 8.0, 2.1 Hz, 1H). H),7.00(dd,J＝8.2,4.4Hz,1H),6.50(dd,J＝7.6,1.7Hz,1H),4.77–4.44(m,2H),3.89(d,J＝1.7Hz,3H),3.17–3.05(m,2H),2.30–2.18(m,2H),2.14–2.04 (m,1H),1.82–1.60(m,6H),0.96–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 593.2791.

Example 34: Synthesis of S-(4-(tert-butyl)phenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0303.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 28.50%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ11.56 (d, J=2.3 Hz, 1H), 8.94 (d, J=7.4 Hz, 1H), 8.46 (d, J=8.2 Hz, 1H), 7.68 (d, J=31.3 Hz, 1H), 7.46 (dd, J=14.0, 8.5 Hz, 2H), 7.37 (d, J=2.2 Hz, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 1H),6.51(d,J＝7.6Hz,1H),4.84–4.53(m,2H),3.89(s,3H),3.16–3.05(m,2H),2.34–2.16(m,3H),1.78(td,J＝12.6,10.7,4.8Hz,2H),1.74–1.65(m ,3H),1.28(d,J＝7.2Hz,9H),0.94(dd,J＝14.8,6.3Hz,6H).ESI-MS m/z:[m+H] ⁺ : 607.2948.

Example 35: Synthesis of S-(4-methoxyphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentylamino)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0304.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 57.60%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 19.5, 2.3 Hz, 1H), 8.89 (dd, J = 34.4, 7.8 Hz, 1H), 8.44 (dd, J = 11.6, 8.2 Hz, 1H), 7.67 (d, J = 30.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.27-7.22 (m, 2H), 7.09 (td, J = 8.0, 2.0 Hz, 1H), 7.00 (dd, J = 13.0, 8.8 Hz,3H),6.50(dd,J＝7.8,1.8Hz,1H),4.76–4.49(m,2H),3.89(s,3H),3.78(d,J＝7.4Hz,3H),3.17–3.07(m,2H),2.32–2.16(m,3H),1.81–1.73(m,2H),1 .73–1.62(m,3H),0.94(dt,J＝15.9,5.5Hz,6H).ESI-MS m/z:[m+H] ⁺ : 581.2427.

Example 36: Synthesis of S-(2-methoxyphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0314.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 40.37%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (dd, J = 19.8, 2.3 Hz, 1H), 8.99 (d, J = 7.5 Hz, 1H), 8.44 (dd, J = 14.8, 8.2 Hz, 1H), 7.68 (s, 1H), 7.46 (ddd, J = 8.9, 7.3, 1.7 Hz, 1H), 7.37 (td, J = 3.2, 2.5, 1.2 Hz, 1H), 7.28 (ddd, J = 7.3, 5.6, 1.7 Hz, 1H), 7.13-7.07 (m, 2H), 7.02 –6.97(m,2H),6.50(dd,J＝7.6,1.8Hz,1H),4.73–4.47(m,2H),3.89(d,J＝1.6Hz,3H),3.75(d,J＝7.2Hz,3H),3.19–3.06(m,2H),2.34(dtd,J＝10.3,8.1, 6.2Hz,1H),2.28–2.16(m,2H),1.82–1.62(m,5H),0.97–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 581.2429.

Example 37: Synthesis of S-(2-fluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0319.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 40.37%. ¹ H NMR (600 MHz, chloroform-d) δ10.15 (s, 1H), 8.56 (d, J = 7.4 Hz, 1H), 7.37-7.24 (m, 2H), 7.17-7.13 (m, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.91 (s, 1H), 6.46 (d, J = 7.7 Hz, 1H), 4.89 (td, J = 8.6,5.1Hz,1H),4.67(q,J＝6.5Hz,1H),3.91(s,3H),3.26–3.11(m,2H),2.49(h,J＝8.0,6.6Hz,1H),2.24–2.14(m,2H),1.83–1.65(m,5H),0.95(t,J＝ 6.7Hz,6H).ESI-MS m/z:[m+H] ⁺ : 569.22.

Example 38: Synthesis of S-(3-methoxyphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0337.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 56.83%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 17.5, 2.3 Hz, 1H), 8.92 (dd, J = 29.8, 7.7 Hz, 1H), 8.46 (t, J = 8.8 Hz, 1H), 7.70 (s, 1H), 7.40-7.33 (m, 2H), 7.09 (dd, J = 9.3, 6.6 Hz, 1H), 7.05-6.99 (m, 2H), 6.94-6.87 (m, 3H). m,2H),6.51(d,J＝7.7Hz,1H),4.78–4.53(m,2H),3.88(d,J＝2.2Hz,3H),3.75(d,J＝14.1Hz,3H),3.18–3.06(m,2H),2.34–2.13(m,3H),1.85–1.64(m,5 H),0.97–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 581.2429.

Example 39: Synthesis of S-(2,4-dimethylphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0341.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 28.40%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (dd, J = 17.3, 2.3 Hz, 1H), 8.93 (dd, J = 27.9, 7.5 Hz, 1H), 8.45 (dd, J = 21.3, 8.2 Hz, 1H), 7.67 (d, J = 28.9 Hz, 1H), 7.39-7.36 (m, 1H), 7.20-7.14 (m, 2H), 7.11-6.98 (m, 3H), 6.50 (dd, J = 7.7, 1.6 Hz ,1H),4.72–4.43(m,2H),3.88(d,J＝1.4Hz,3H),3.17–3.05(m,2H),2.29(d,J＝8.7Hz,3H),2.27–2.19(m,2H),2.16(d,J＝12.3Hz,3H),2.14–2.04(m,1 H),1.81–1.59(m,5H),0.96–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 579.2637.

Example 40: Synthesis of S-(2,6-dimethylphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0343.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 43.96%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.56 (dd, J = 13.1, 2.3 Hz, 1H), 9.00 (dd, J = 18.2, 7.2 Hz, 1H), 8.46 (dd, J = 31.9, 8.3 Hz, 1H), 7.68 (d, J = 26.0 Hz, 1H), 7.39-7.36 (m, 1H), 7.28-7.14 (m, 3H), 7.09 (td, J = 8.0, 3.4 Hz, 1H) ,7.00(dd,J＝8.3,4.8Hz,1H),6.50(dd,J＝7.8,1.8Hz,1H),4.70–4.41(m,2H),3.88(d,J＝1.3Hz,3H),3.18–3.04(m,2H),2.34–2.13(m,9H),1.83–1.61( m,5H),0.97–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 579.2636.

Example 41: Synthesis of S-(3,4-dimethoxyphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0349.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 17.88%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (dd, J = 18.1, 2.3 Hz, 1H), 8.88 (dd, J = 24.6, 7.8 Hz, 1H), 8.45 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 28.1 Hz, 1H), 7.38 (dd, J = 6.6, 2.2 Hz, 1H), 7.09 (td, J = 7.9, 2.6 Hz, 1H), 7.01 (dd, J = 12.9, 8.5 Hz, 2H), 6.89 (dt, J = 8.4, 2.1 Hz, 1H), 6.85 (d, J＝2.0Hz,1H),6.50(dd,J＝7.7,2.5Hz,1H),4.79–4.48(m,2H),3.88(d,J＝2.2Hz,3H),3.78(d,J＝7.7Hz,3H),3.72(d,J＝17.4Hz,3H),3.17–3.07(m,2H),2. 33–2.19(m,2H),2.12–2.05(m,1H),1.80–1.59(m,5H),0.96–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 611.2532.

Example 42: Synthesis of S-(2,5-dimethoxyphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0404.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 16.12%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (dd, J = 18.5, 2.3 Hz, 1H), 8.94 (d, J = 60.0 Hz, 1H), 8.44 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 43.1 Hz, 1H), 7.37 (dd, J = 5.0, 2.2 Hz, 1H), 7.14-6.95 (m, 4H), 6.85 (t, J = 2.7 Hz, 1H), 6.50 (dd ,J＝7.7,2.1Hz,1H),4.73–4.47(m,2H),3.88(d,J＝2.0Hz,3H),3.78–3.65(m,6H),3.18–3.04(m,2H),2.38–2.17(m,2H),2.14–2.04(m,1H),1.80–1.5 9(m,5H),0.97–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 611.2534.

Example 43: Synthesis of S-(2,5-dimethylphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0405.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 35.62%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (dd, J = 16.0, 2.3 Hz, 1H), 8.95 (dd, J = 20.8, 7.5 Hz, 1H), 8.45 (dd, J = 20.3, 8.2 Hz, 1H), 7.68 (d, J = 27.6 Hz, 1H), 7.38 (dd, J = 6.8, 2.2 Hz, 1H), 7.23 (dd, J = 14.3, 7.8 Hz, 1H), 7.17 (ddd, J = 13.3, 7.7, 1.8 Hz, 1H), 7.14-7.07 (m, 2H ),7.00(dd,J＝8.3,4.7Hz,1H),6.50(dd,J＝7.8,2.1Hz,1H),4.72–4.44(m,2H),3.89(d,J＝2.0Hz,3H),3.18–3.00(m,2H),2.32–2.20(m,5H),2.16(d,J＝13 .1Hz,3H),2.13–2.04(m,1H),1.81–1.59(m,5H),0.96–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 579.2636.

Example 44: Synthesis of S-(2,4-difluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0410.

The target compound was prepared according to the method of Example 15 except that the corresponding reaction raw materials were replaced. The yield was 21.72% as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ )δ11.58(dd,J＝18.6,2.4Hz,1H),9.02(dd,J＝28.6,7.6Hz,1H),8.47(dd,J＝14.3,8.1Hz,1H),7.47–7.43(m,1H),7.39(t,J＝9.6Hz,3H),7.09(t,J＝8.0Hz,1H ),7.03–6.98(m,1H),6.52–6.48(m,1H),4.87–4.43(m,2H),3.89(s,3H),3.18–3.06(m,2H),2.34–2.00(m,4H),1.84–1.72(m,5H),0.96–0.90(m,6H) ).ESI-MS m/z: [m+H] ⁺ ：587.2132.

Example 45: Synthesis of S-(2-chloro-4-fluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0417.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 18.32%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (dd, J = 18.6, 2.3 Hz, 1H), 9.03 (dd, J = 26.2, 7.5 Hz, 1H), 8.46 (dd, J = 17.5, 8.1 Hz, 1H), 7.73-7.64 (m, 2H), 7.56 (ddd, J = 13.2, 8.7, 6.1 Hz, 1H), 7.38 (ddd, J = 7.6, 2.3, 0.9 Hz, 1H), 7.35-7.27 (m, 1H), 7.11-7.0 6(m,1H),7.00(dd,J＝8.2,4.2Hz,1H),6.50(dd,J＝7.8,1.6Hz,1H),4.80–4.48(m,2H),3.89(d,J＝1.3Hz,3H),3.16–3.06(m,2H),2.33–2.21(m,2H),2.20 –2.11(m,1H),1.83–1.66(m,5H),0.96–0.90(m,6H).ESI-MS m/z:[m+H] ⁺ : 603.1838.

Example 46: Synthesis of S-(3,4-difluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: QXH0426.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 17.38%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ11.58 (dd, J=17.5, 2.3 Hz, 1H), 8.97 (dd, J=33.5, 7.6 Hz, 1H), 8.46 (t, J=7.8 Hz, 1H), 7.55-7.46 (m, 3H), 7.38 (dd, J=7.4, 2.3 Hz, 1H), 7.23-7.18 (m, 1H), 7.12-7.06 (m, 1H), 7.01-6.9 8(m,1H),6.50(dd,J＝7.7,2.0Hz,1H),4.84–4.47(m,2H),3.88(d,J＝1.8Hz,3H),3.19–3.04(m,2H),2.33–2.15(m,2H),2.15–2.06(m,1H),1.67–1.59( m,5H),0.96–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 587.2134.

Example 47: Synthesis of S-benzyl (S)-2-((S)-2-(3-chloro-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1034.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 74.92%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.98 (s, 1H), 8.99 (dd, J = 29.7, 7.8 Hz, 1H), 7.87 (dd, J = 26.3, 8.1 Hz, 1H), 7.68 (d, J = 20.1 Hz, 1H), 7.61-7.56 (m, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.32 (dddd, J = 8.3, 7.0, 2.7, 1.2 Hz, 1H), 7.29-7.24 (m . 80–1.58(m,6H),0.94(d,J＝6.5Hz,6H).ESI-MS m/z:[m+H] ⁺ : 569.1983.

Example 48: Synthesis of S-benzyl (S)-2-((S)-2-(3-bromo-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1046.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 70.03%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.07 (d, J = 2.8 Hz, 1H), 8.99 (dd, J = 34.7, 7.7 Hz, 1H), 7.94 (dd, J = 24.2, 8.1 Hz, 1H), 7.68 (d, J = 19.9 Hz, 1H), 7.50 (dd, J = 18.1, 8.2 Hz, 2H), 7.34-7.16 (m, 7H), 4.77-4.38 (m, 2H) ,4.14–4.04(m,2H),3.12(ddt,J＝19.4,16.3,9.6Hz,2H),2.18(t,J＝8.1Hz,3H),2.08–2.01(m,1H),1.91(q,J＝7.6Hz,3H),1.67–1.66(m,1H),0.93(td ,J＝6.5,3.5Hz,6H).ESI-MS m/z:[m+H] ⁺ : 615.1466.

Example 49: Synthesis of S-benzyl (S)-2-((S)-4-methyl-2-(3-methyl-1H-indole-2-carboxamido)pentanamido)-3-((S)2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1047.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 61.11%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.26 (s, 1H), 8.94 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.31-7.23 (m, 5H), 7.04 (t, J = 7.5 Hz, 1H), 4.66 (dtd, J = 23.2, 8.3, 5.4 Hz, 2H),4.09(s,2H),3.10(dtd,J＝18.7,9.7,7.3Hz,2H),2.18(td,J＝8.0,7.6,2.2Hz,3H),2.13(d,J＝2.9Hz,1H),1.91(s,2H),1.64(dtq,J＝18.6,8.3,2 .7Hz, 5H), 0.92 (dd, J＝8.7, 6.5Hz, 6H).ESI-MS m/z: [m+H] ⁺ : 549.2530.

Example 50: Synthesis of S-benzyl (S)-2-((S)-2-(4,5-dimethoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1048.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 55.43%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.45 (dd, J = 17.7, 2.3 Hz, 1H), 8.82 (dd, J = 42.8, 7.9 Hz, 1H), 8.45 (dd, J = 24.1, 8.3 Hz, 1H), 7.65 (d, J = 26.4 Hz, 1H), 7.36 (td, J = 2.5, 0.9 Hz, 1H), 7.31-7.20 (m, 5H), 7.08-7.05 (m, 1H), 7.00 (dd, J = 24.1, 8.3 Hz, 1H). ＝8.9,2.6Hz,1H),4.70–4.42(m,2H),4.10–4.04(m,2H),3.94(s,3H),3.78(d,J＝2.0Hz,3H),3.14–3.02(m,2H),2.26–2.14(m,2H),2.08–2.00(m,1H) ,1.76–1.63(m,4H),0.93–0.87(m,6H).ESI-MS m/z:[m+H] ⁺ : 595.2585.

Example 51: Synthesis of S-benzyl (S)-2-((S)-2-(4,5-difluoro-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1049.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 67.47%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 12.05-11.96 (m, 1H), 8.85 (dd, J=41.6, 7.8 Hz, 1H), 8.58 (dd, J=21.5, 8.2 Hz, 1H), 7.71-7.62 (m, 1H), 7.42-7.39 (m, 1H), 7.32-7.19 (m, 5H), 7.04-7.00 (m, 1H), 6.89 (tt, J=10.0, 2.0 Hz, 1H) ,4.70–4.43(m,2H),4.09–4.04(m,2H),3.16–3.04(m,2H),2.20(dtdd,J＝16.5,11.4,9.3,5.6Hz,2H),2.04(dddd,J＝13.8,10.2,5.4,2.2Hz,1H),1.72– 1.61(m,4H),0.93–0.87(m,6H).ESI-MS m/z:[m+H] ⁺ : 571.2184.

Example 52: Synthesis of S-benzyl (S)-2-((S)-2-(5-chloro-4-fluoro-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1050.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 45.56%. ¹ H NMR (600 MHz, DMSO-d ₆ )δ12.16(d,J＝13.5Hz,1H),8.91(dd,J＝39.8,7.8Hz,1H),8.69(dd,J＝21.6,8.2Hz,1H),7.70(d,J＝27.1Hz,1H),7.47(dd,J＝4.7,2.2Hz,1H),7.35–7.23(m,7 H),4.75–4.46(m,2H),4.11(dd,J＝17.4,1.9Hz,2H),3.22–3.07(m,2H),2.31–2.18(m,2H),2.12–2.03(m,1H),1.78–1.62(m,5H),0.98–0.91(m,6H) .ESI-MSm/z:[m+H] ⁺ :587.1890.

Example 53: Synthesis of S-benzyl (S)-2-((S)-2-(1H-benzo[d]imidazole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0950.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 25.64%. ¹ H NMR (600 MHz, DMSO-d ₆ )δ13.31(s,1H),8.89(dd,J＝11.3,7.8Hz,1H),8.65(t,J＝8.7Hz,1H),7.74(d,J＝5.5Hz,2H),7.69–7.61(m,2H),7.25–7.20(m,5H),4.73–4.58(m,2H),4 .07(d,J＝4.1Hz,2H),3.14–3.08(m,2H),2.26–2.16(m,3H),1.79(ddt,J＝12.6,10.4,4.7Hz,1H),1.70–1.61(m,5H),0.91(dd,J＝6.0,3.0Hz,6H).ESI-MS m/ z:[m+H] ⁺ :490.2846.

Example 54: Synthesis of S-(2-fluorobenzyl)(S)-2-((S)-2-(1H-benzo[d]imidazole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0940d.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 30.37%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ13.32 (s, 1H), 8.90 (d, J=7.9 Hz, 1H), 8.66 (d, J=8.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.63 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.36-7.27 (m, 4H), 7.15-7.09 (m, 2H), 4.63-4.59 (m, 1H), 4.44 (td, J=7.9, 4.0 Hz, 1H), 4.08 (d, J=3 .8Hz,2H),3.12(td,J＝8.3,1.7Hz,1H),3.07–3.02(m,1H),2.20(ddd,J＝10.7,4.4,2.3Hz,1H),2.02(dd,J＝4.2,2.4Hz,1H),1.79(ddd,J＝12.9,10.0,4.5Hz ,1H),1.68–1.57(m,5H),0.91(dd,J＝13.5,6.3Hz,6H).ESI-MS m/z:[m+H] ⁺ :508.2752.

Example 55: Synthesis of S-(thiophen-2-ylmethyl)(S)-2-((S)-2-(1H-benzo[d]imidazole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0940e.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 26.10%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ13.33 (s, 1H), 8.92 (d, J=7.9 Hz, 1H), 8.65 (d, J=8.8 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.35-7.27 (m, 3H), 6.96 (dd, J=3.4, 1.2 Hz, 1H), 6.88 (dd, J=5.1, 3.4 Hz, 1H), 4.65-4.60 (m, 1H), 4.44 (ddd, J=11.9, 7. 9,4.2Hz,1H),4.29(d,J＝2.6Hz,2H),3.15–3.11(m,1H),3.05(td,J＝9.3,7.0Hz,1H),2.23–2.19(m,1H),2.05–2.02(m,1H),1.80(ddd,J＝12.9,9.9,4. 7Hz, 1H), 1.63 (dddd, J＝27.4, 10.2, 8.1, 4.3Hz, 5H), 0.92 (dd, J＝9.5, 6.4Hz, 6H). ESI-MS m/z: [m+H] ⁺ ：542.1890.

Example 56: Synthesis of S-(4-(trifluoromethyl)benzyl)(S)-2-((S)-2-(1H-benzo[d]imidazole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1003b.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 46.10%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 13.32 (d, J = 10.0 Hz, 1H), 8.91 (dd, J = 19.8, 7.7 Hz, 1H), 8.66 (dd, J = 13.6, 8.9 Hz, 1H), 7.75 (t, J = 8.8 Hz, 1H), 7.69-7.65 (m, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.46 (dd, J = 10.5, 8.0 Hz, 2H) ,7.31(dt,J＝28.6,7.3Hz,2H),4.72–4.42(m,2H),4.15(d,J＝3.0Hz,2H),3.14–3.02(m,2H),2.28–2.14(m,2H),1.79(ddt,J＝12.6,9.8,4.4Hz,1H),1. 71–1.53(m,5H),0.92–0.89(m,6H).ESI-MSm/z:[m+H] ⁺ : 604.2201.

Example 57: Synthesis of S-(4-(tert-butyl)benzyl)(S)-2-((S)-2-(1H-benzo[d]imidazole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH1003c.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 15 as a white solid with a yield of 49.80%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 13.33 (s, 1H), 8.89 (dd, J = 21.6, 7.9 Hz, 1H), 8.65 (dd, J = 19.3, 8.9 Hz, 1H), 7.75 (s, 1H), 7.67 (dt, J = 5.5, 3.0 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.27-7.18 (m, 3H), 7.14 (dd, J = 10.3, 8.3 Hz, 2H), 4.72-4. 38(m,2H),4.07–4.02(m,2H),3.15–3.05(m,2H),2.20(dqd,J＝12.7,7.5,3.1Hz,2H),2.02(dddd,J＝14.2,12.3,10.0,4.2Hz,2H),1.68–1.61(m,4H),1 .23(d,J＝3.5Hz,9H),0.91(td,J＝4.8,4.4,1.8Hz,6H).ESI-MS m/z:[m+H] ⁺ : 592.2951.

Example 58: Synthesis of S-ethyl (S)-2-((S)-2-cinnamylamino-3-cyclohexylpropionamido)-3-(S)-3-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0807-1.

Synthesis route:

Synthesis of compound 58-2:

Compound 15-1 (1.065 g, 4 mmol) and acetonitrile (24 mL) were added to an eggplant-shaped bottle, triethylamine (2.22 mL, 16 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C until compound 15-1 was completely dissolved. Then, 58-1 (1.085 g, 4 mmol) and HBTU (1.517 g, 4 mmol) were added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (50×3 mL), saturated sodium bicarbonate (50×3 mL) and saturated sodium chloride (50×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with a mobile phase of dichloromethane/methanol (50:1). After elution, the mixture was spin-dried to obtain a colorless solid 58-2 (1.758 g, 100%). ESI-MS m/z: [m+H] ⁺ : 440.28.

Synthesis of compound 58-3:

Compound 58-2 (1.758 g, 4 mmol) was dissolved in dichloromethane (12 mL), and HCl/dioxane (4 mL, 16 mmol) was added dropwise. The mixture was reacted at room temperature overnight. The mixture was distilled under reduced pressure to obtain a colorless solid 58-3, which was used directly in the next step. ESI-MS m/z: [m+H] ⁺ : 340.23.

Synthesis of compound 58-5:

Compound 58-3 (4 mmol) and acetonitrile (24 mL) were added to an eggplant-shaped bottle, triethylamine (2.22 mL, 16 mmol) was added dropwise at 0°C, and stirred at 0°C for 30 minutes. Cinnamic acid (0.592 g, 4 mmol) and HBTU (1.517 g, 4 mmol) were then added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (50×3 mL), saturated sodium bicarbonate (50×3 mL) and saturated sodium chloride (50×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with ^a mobile phase of dichloromethane/methanol (50:1). After elution, the white solid 58-5 (1.792 g, 95.40%) was obtained by spin drying. NMR (600MHz, chloroform-d) δ8.01(d,J＝6.5Hz,1H),7.61(d,J＝15.6Hz,1H),7.49(dd,J＝7.4,1.9Hz,4H),7.36–7.34(m,4H),6.48(d,J＝15.6Hz,1H),4.73(td,J＝8.6, 5.7Hz,2H),4.50(ddd,J＝11.0,6.7,4.3Hz,2H),3.70(s,3H),3.36–3.32(m,2H ),2.50–2.35(m,3H),2.19(ddd,J＝14.3,11.1,5.5Hz,1H),1.89(ddd,J＝14.0,7.9,4.2Hz,2H),1.85–1.75(m,4H),1.62(ddd,J＝14.1,9.0,5.7Hz,4H),1.4 0–1.31(m,2H),1.30–1.24(m,1H),1.22–1.10(m,5H),1.01–0.87(m,3H).ESI-MS m/z:[m+H] ⁺ : 470.27.

Synthesis of compound 58-6:

Compound 58-5 (0.935 g, 1.99 mmol) was dissolved in 6 mL of ethanol, and H ₂ O (6 mL) and LiOH·H ₂ O (0.167 g, 3.98 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (20×3 mL). The aqueous phases were combined, and the pH was adjusted to less than 4 with 1 M HCl aqueous solution, extracted with ethyl acetate, and washed with saturated sodium chloride solution. The organic phases were combined and dried with anhydrous sodium sulfate, and then spin-dried to obtain a white solid 58-6 (0.713 g, 78.65%). ESI-MS m/z: [m+H] ⁺ : 456.26.

Synthesis of compound 58:

Compound 58-6 (0.356 g, 0.78 mmol) was dissolved in dichloromethane (2 mL), cooled to 0°C, and ethanethiol (0.058 mL, 0.78 mmol), DMAP (0.019 g, 0.157 mmol), and DCC (0.193 g, 0.936 mmol) were added in sequence. After stirring at 0°C for 0.5 h, the mixture was transferred to room temperature for reaction for 14 h. The white insoluble solid was removed by suction filtration, and the filtrate was extracted with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and distilled under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane/methanol (80:1) as the mobile phase. After elution ^, the white solid 58 (0.171 g, 43.88%) was obtained by spin drying. NMR (600MHz, chloroform-d) δ8.35(s,1H),7.62(d,J＝15.6Hz,1H),7.50(d,J＝5.6Hz,2H),7.36(t,J＝5.7Hz,3H),6.48(d,J＝15.6Hz,1H),6.31(d,J＝71.1Hz,1H),4.74 (d,J＝5.8Hz,1H),4.59–4.44(m ,1H),3.33(dq,J＝18.4,9.5Hz,2H),2.84(dq,J＝34.0,7.3Hz,2H),2.74–2.23(m,2H),2.19–2.10(m,1H),1.88–1.58(m,8H),1.40(m,1H),1.21(m,6H ),1.07–0.80(m,3H).ESI-MSm/z:[m+H] ⁺ :500.26.

Example 59: Synthesis of S-benzyl (S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-(S)-3-oxopyrrolidin-3-yl)propanesulfate. Compound number: CMH0807-2.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 56 as a white solid with a yield of 47.24%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.86 (dd, J = 25.6, 7.8 Hz, 1H), 8.25 (dd, J = 20.0, 8.2 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 7.4 Hz, 2H), 7.45-7.35 (m, 4H), 7.30-7.23 (m, 4H), 6.75 (dd, J = 15.8, 7.7 Hz, 1H), 4.54 (p, J = 8.5, 7.6 Hz, 1H), 4.42 (ddd, J = 11.9, 8.0, 4.2 Hz, 1H). z,1H),4.11–4.02(m,2H),3.18–3.03(m,2H),2.22(ddt,J＝15.2,11.2,4.7Hz,1H),2.09–1.98(m,2H),1.73–1.54(m,8H),1.47(dtt,J＝19.2,9.5,5.9 Hz,1H),1.27–1.21(m,1H),1.12(dd,J＝19.6,9.4Hz,3H),0.93–0.82(m,2H).ESI-MS m/z:[m+H] ⁺ : 562.28.

Example 60: Synthesis of S-benzyl (5S, 8S, 11S)-8-isobutyl-5-isopropyl-3,6,9-trioxa-11-(S)-2-oxopyrrolidin-3-ylmethyl)-1-phenyl-2-oxa-4,7,10-triazadodecane-12-thioate. Compound number: CMH0845.

Synthesis route:

Synthesis of compound 60-2:

Dissolve L-valine methyl ester hydrochloride (1-2, 0.335 g, 2 mmol) in tetrahydrofuran (6 mL), add H ₂ O (6 mL), Na ₂ CO ₃ (0.424 g, 4 mmol) in turn, add benzyl chloroformate (60-1, 0.314 mL, 2.2 mmol) dropwise to the above suspension at 0°C, and then react at room temperature overnight. Extract with ethyl acetate/H ₂ O, add a small amount of 1M HCl to the aqueous phase to adjust the pH, extract, wash with saturated sodium chloride, combine the organic phases, dry with anhydrous sodium sulfate, filter, and spin dry to obtain a colorless oil 60-2 (0.531 g, 100%). ESI-MS m/z: [m+H] ⁺ : 266.13.

Synthesis of compound 60-3:

Compound 60-2 (0.531 g, 2 mmol) was dissolved in 8 mL of ethanol, and H ₂ O (8 mL) and LiOH·H ₂ O (0.168 g, 4 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (30×2 mL). The aqueous phases were combined, and the pH was adjusted to less than 4 with 1 M HCl aqueous solution, extracted with ethyl acetate, and washed with saturated sodium chloride solution. The organic phases were combined and dried with anhydrous sodium sulfate, and then spin-dried to obtain a white solid 60-3 (0.507 g, 100%). ESI-MS m/z: [m+H] ⁺ : 252.12.

Synthesis of compound 60-4:

Compound 1-8 (0.535 g, 1.88 mmol) and acetonitrile (7 mL) were added to an eggplant-shaped bottle, triethylamine (1.045 mL, 7.52 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then 15-3 (0.435 g, 1.88 mmol) and HBTU (0.713 g, 1.88 mmol) were added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (50×3 mL), saturated sodium bicarbonate (50×3 mL) and saturated sodium chloride (50×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate = 40:60) to obtain a white solid 60-4 (0.843 g, 91.20%). ESI-MS m/z: [m+H] ⁺ : 492.25.

Synthesis of compound 60-5:

Compound 60-4 (0.843 g, 1.715 mmol) was dissolved in dichloromethane (6 mL), and HCl/dioxane (1.29 mL, 5.144 mmol) was added dropwise. The mixture was reacted at room temperature overnight. The mixture was distilled under reduced pressure to obtain a light green oil 60-5, which was used directly in the next step. ESI-MS m/z: [m+H] ⁺ : 392.20.

Synthesis of compound 60:

Compound 58-5 (0.391 g, 1 mmol) and acetonitrile (6 mL) were added to an eggplant-shaped bottle, triethylamine (0.56 mL, 4 mmol) was added dropwise at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then 60-3 (0.253 g, 1 mmol) and HBTU (0.379 g, 1 mmol) were added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (20×3 mL), saturated sodium bicarbonate (20×3 mL) and saturated sodium chloride (20×3 mL), respectively. The organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by silica gel column chromatography with dichloromethane/methanol (80:1) as the mobile phase. After elution, the white solid 60 (0.092 g, 14.74%) was obtained by spin drying. ¹ HNMR (600 MHz, DMSO-d ₆ )δ8.38(d,J＝8.3Hz,1H),8.25(d,J＝8.1Hz,1H),7.64(s,1H),7.40–7.26(m,11H),5.08–5.01(m,2H),4.52–4.45(m,1H),4.34–4.27(m,1H),4.07(s,2 H),3.81(t,J＝7.4Hz,1H),3.14–3.05(m,2H) ,2.20(qd,J＝10.8,4.3Hz,1H),2.12–2.06(m,1H),2.00(dt,J＝13.2,7.1Hz,1H),1.91–1.86(m,1H),1.70–1.64(m,1H),1.62–1.56(m,2H),1.52(dt,J ＝8.9,4.6Hz,2H),0.87–0.80(m,12H).ESI-MS m/z:[m+H] ⁺ : 625.31.

Example 61: Synthesis of S-ethyl (5S, 8S, 11S)-8-isobutyl-5-isopropyl-3,6,9-trioxa-11-((S)-2-oxopyrrolidin-3-ylmethyl)-1-phenyl-2-oxa-4,7,10-triazadodecane-12-thioate. Compound number: CMH0846.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 58 as a white solid with a yield of 46.6%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ8.36 (d, J=8.3 Hz, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 7.39-7.31 (m, 6H), 5.08-5.02 (m, 2H), 4.43 (ddd, J=12.1, 8.3, 4.4 Hz, 1H), 4.33 (dq, J=9.9, 5.3 Hz, 1H), 3.84 (t, J=7.4 Hz, 1H), 3.11 (dd, J=30.7, 7.9 Hz, 2H), 2.7 8(q,J＝7.3Hz,2H),2.21(ddt,J＝14.9,10.8,4.3Hz,1H),2.10–1.99(m,2H),1.91(dq,J＝13.7,6.7Hz,1H),1.64(ddq,J＝20.1,10.7,5.3,4.8Hz,3H),1.52( d, J＝14.0Hz, 2H), 1.14 (t, J＝7.4Hz, 3H), 0.90–0.83 (m, 12H). ESI-MS m/z: [m+H] ⁺ ：563.29.

Example 62: Synthesis of SS-benzyl (S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: CMH0810.

Synthesis route:

Synthesis of compound 62-1:

Under argon protection, 58-6 (0.1 g, 0.22 mmol) was dissolved in DMF (3 mL), EDC (0.046 g, 0.241 mmol) was added at 0°C, and the mixture was stirred for 5-10 min. The reaction solution was then added dropwise to a suspension of finely ground Na ₂ S·9H ₂ O (0.158 g, 0.659 mmol) in DMF (2 mL). The mixture was stirred at room temperature for 3-4 h under argon protection until the starting material disappeared. The residue was dissolved in EA (5 mL), and then the pH was adjusted to 3 with 1 M KHSO ₄ at 0°C, and then extracted with ethyl acetate/H ₂ O, washed with saturated sodium chloride, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and dried to obtain a white solid product 62-1 (0.113 g, 100%). ESI-MS m/z: [m+H] ⁺ : 472.25.

Synthesis of compound 62:

62-1 (0.052 g, 0.11 mmol) was dissolved in THF (2 mL) and H ₂ O (1 mL), and CH ₃ COONa (0.072 g, 0.88 mmol), benzyl mercaptan (0.092 mL, 0.785 mmol) and I ₂ (0.112 g, 0.44 mmol) were added in sequence. The mixture was stirred at room temperature for 5 minutes. H ₂ O (10 mL) was added and the mixture was extracted with ethyl acetate (2×5 mL). The mixed organic phase was washed with saturated sodium thiosulfate aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried by rotation. The crude product was purified by silica gel column chromatography with dichloromethane/methanol (80:1) as the mobile phase. After ^elution , the white solid 62 (0.017 g, 26.03%) was obtained by rotation. NMR(600MHz, chloroform-d)δ7.60(t,J＝16.1Hz,1H),7.49(d,J＝7.1Hz,2H),7.39–7.33(m,4H),7.32–7.27(m,5H),7.25–7.21(m,1H),6.44(d,J＝15.6Hz,2H),4.86– 4.78(m,1H),4.72–4.61(m, 1H),3.86(d,J＝6.4Hz,2H),3.32(dd,J＝11.0,6.7Hz,2H),2.49–2.24(m,3H),2.05(dd,J＝12.7,6.9Hz,2H),1.90–1.77(m,4H),1.67–1.54(m,4H),1.22– 1.10(m,5H).ESI-MSm/z:[m+H] ⁺ ：594.25.

Example 63: Synthesis of SS-(thiophen-2-ylmethyl)(S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: CMH0916.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 52.96%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ9.02 (t, J=6.4 Hz, 1H), 8.29 (dd, J=13.8, 8.2 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.56 (d, J=7.4 Hz, 2H), 7.41 (tq, J=14.1, 6.9, 6.0 Hz, 5H), 6.98 (s, 1H), 6.93 (dt, J=12.8, 4.0 Hz, 1H), 6.76 (dd, J=15.8, 8.5 Hz, 1 H),4.76–4.48(m,2H),4.26–4.01(m,2H),3.19–3.07(m,2H),2.27–2.14(m,2H),2.07(t,J＝10.1Hz,1H),1.75–1.47(m,9H),1.34(d,J＝36.4Hz,1H),1. 15–1.10(m,2H),0.89(dt,J＝20.4,10.5Hz,2H).ESI-MS m/z:[m+H] ⁺ : 600.21.

Example 64: Synthesis of SS-(3-fluorophenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: CMH1007.

The target compound was prepared according to the method of Example 60, except replacing the corresponding reaction starting materials, as a white solid, with a yield of 6.43%. ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.19–9.05(m,1H),8.37–8.29(m,1H),7.63(dd,J＝7.8,1.7Hz,2H),7.47–7.41(m,6H),7.26(dd,J＝7.6,1.3Hz,2H),6.82–6.71(m, 1H),4.87–4.48(m,2H),3.21–3.04(m,2H),2.28–2.03(m,3H),1.77–1.49(m,9H),1.24(s,3H),1.12(q,J＝11.5,11.1Hz,3H).ESI-MS m/z:[m+H] ⁺ ：598 .2202.

Example 65: Synthesis of SS-(2-fluorophenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: CMH1008.

The target compound was prepared according to the method of Example 60, except replacing the corresponding reaction starting materials, as a white solid, with a yield of 17.81%. ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.19–9.05(m,1H),8.37–8.29(m,1H),7.63(dd,J＝7.8,1.7Hz,2H),7.47–7.41(m,6H),7.26(dd,J＝7.6,1.3Hz,2H),6.82–6.71(m, 1H),4.87–4.48(m,2H),3.21–3.04(m,2H),2.28–2.03(m,3H),1.77–1.49(m,9H),1.24(s,3H),1.12(q,J＝11.5,11.1Hz,3H).ESI-MS m/z:[m+H] ⁺ ：598 .2204.

Example 66: Synthesis of SS-(4-(trifluoromethyl)benzyl)(S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0139.

The target compound was prepared according to the method of Example 60, except replacing the corresponding reaction starting materials, as a white solid with a yield of 33.76%. ¹ H NMR (600MHz, chloroform-d) δ7.48(dd,J＝31.6,7.7Hz,4H),7.43–7.31(m,4H),7.31–7.22(m,4H),6.40(t,J＝16.2Hz,1H),4.82–4.48(m,2H),3.97(s,1H),3.84 –3.76(m,1H),3.24(s,2H),2.43–2.21(m,2H),1.96(d,J＝18.8Hz,2H),1.79–1.64(m,4H),1.61–1.55(m,5H),1.14–1.01(m,5H).ESI-MS m/z:[m+H] ⁺ ：66 2.23.

Example 67: Synthesis of SS-(2-fluorobenzyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0140.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 42.61%. ¹ H NMR (600 MHz, chloroform-d) δ8.83 (d, J=7.3 Hz, 1H), 7.55-7.40 (m, 3H), 7.29 (dtt, J=6.7, 5.1, 1.5 Hz, 3H), 7.22-7.11 (m, 2H), 7.04-6.91 (m, 2H), 6.70 (d, J=103.1 Hz, 1H), 6.45 (dd, J=18.7, 1 5.5Hz,1H),4.81–4.47(m,2H),3.91–3.73(m,2H),3.24(q,J＝4.0,3.5Hz,2H),2.41–2.17(m,2H),2.02–1.87(m,1H),1.81–1.47(m,9H),1.15–1.04(m ,3H),0.95–0.78(m,3H).ESI-MS m/z:[m+H] ⁺ : 612.23.

Example 68: Synthesis of SS-(4-(tert-butyl)benzyl)(S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0141.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 28.65%. ¹ H NMR (600 MHz, chloroform-d) δ8.79 (d, J=7.3 Hz, 1H), 7.51 (dd, J=15.7, 11.6 Hz, 1H), 7.28 (dd, J=8.0, 1.7 Hz, 4H), 7.20-7.13 (m, 5H), 6.44 (d, J=15.7 Hz, 1H), 4.80-4.54 (m, 2H), 3.94 (s, 2H), 2.44 ( d,J＝16.3Hz,1H),2.35–2.21(m,2H),2.16–2.08(m,1H),1.99–1.92(m,1H),1.75(dt,J＝22.5,10.5Hz,3H),1.70–1.61(m,5H),1.59–1.52(m,3H),1. 18(s,9H),0.78–0.75(m,2H).ESI-MS m/z:[m+H] ⁺ : 650.30.

Example 69: Synthesis of SS-ethyl (S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0145.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 60.70%. ¹ H NMR (600 MHz, chloroform-d) δ8.76 (d, J=7.3 Hz, 1H), 7.71-7.22 (m, 7H), 6.42 (s, 1H), 4.97-4.37 (m, 2H), 3.48 (m, 2H), 2.63 (d, J=7.0 Hz, 2H), 2.49-2.24 (m, 2H), 1.84-1.6 (m, 19H). ESI-MS m/z: [m+H] ⁺ ：532.23.

Example 70: Synthesis of SS-2-naphthyl (S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0601.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 28.97%. ¹ H NMR (600 MHz, DMSO-d ₆ )δ9.20–9.01(m,1H),8.40–8.28(m,1H),7.90(dddd,J＝16.9,14.2,8.7,4.6Hz,3H),7.73–7.63(m,2H),7.53(dddd,J＝22.7,12.6,6.5,2.5Hz,5H),7.44–7 .37(m,4H),6.79–6.73(m,1H),4.79–4.36(m,2H),3.17–3.06(m,2H),2.43–1.97(m,4H),1.83–1.50(m,11H),1.35(d,J＝9.5Hz,1H),1.25(d,J＝8.6Hz ,2H).ESI-MS m/z: [m+H] ⁺ ：630.25.

Example 71: Synthesis of SS-(4-isopropylphenyl)(S)-2-((S)cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0740.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 15.12%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.24-9.04 (m, 1H), 8.36-8.27 (m, 1H), 7.73-7.67 (m, 1H), 7.55 (d, J=8.3 Hz, 2H), 7.45-7.40 (m, 4H), 7.38 (d, J=7.4 Hz, 1H), 7.36-7.32 (m, 1H), 7.26 (d, J=8.3 Hz, 1H), 7.22 (dd, J=16.5, 8.1 Hz, 1H) ,6.78–6.73(m,1H),4.87–4.51(m,2H),3.17–3.08(m,2H),2.86(dddd,J＝17.8,11.0,7.8,4.5Hz,1H),2.26–2.04(m,3H),1.78–1.43(m,11H),1.20–1. 15(m,7H),1.12(dd,J＝6.9,2.0Hz,3H).ESI-MS m/z:[m+H] ⁺ : 622.28.

Example 72: Synthesis of SS-(4-tert-butyl)phenyl (S)-2-((S)-2-cinnamyl-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0741.

The target compound was prepared according to the method of Example 60 except that the corresponding reaction raw materials were replaced. The yield was 21.98% as a white solid. ¹ H NMR (600 MHz, DMSO-d ₆ )δ9.09(d,J＝8.0Hz,1H),8.33(d,J＝8.1Hz,1H),7.69(s,1H),7.56(d,J＝7.2Hz,2H),7.45(d,J＝2.9Hz,1H),7.42(s,2H),7.40(s,1H),7.38(d,J＝8.3Hz,2 H),7.36(s,1H),7.34(s,1H),6.77(d,J＝15.8Hz,1H),4.60-4.54(m,2H),3.17–3.10(m,2H),2.33–2.02(m,4H),1.72–1.57(m,9H),1.29–1.24(m,1 4H).ESI-MS m/z:[m+H] ⁺ :636.29.

Example 73: Synthesis of SS-(4-methoxyphenyl)(S)-2-((S)-2-cinnamamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0742.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 29.7%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.01 (t, J = 7.9 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.41 (td, J = 16.3, 8.5 Hz, 5H), 6.97-6.88 (m, 2H) ,6.79–6.70(m,1H),5.01–4.40(m,2H),3.79–3.74(m,3H),3.19–3.01(m,2H),2.32–2.00(m,3H),1.77-1.48(m,9H),1.12(d,J＝9.6Hz,4H),0.95–0. 82(m,2H).ESI-MS m/z:[m+H] ⁺ : 610.24.

Example 74: Synthesis of SS-(4-chlorophenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0803.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 21.33%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.32 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.58-7.49 (m, 4H), 7.48-7.35 (m, 7H), 6.81-6.72 (m, 1H), 4.86-4.37 (m, 2H), 3.18-3.07 (m, 2H), 2.30-2.03 (m, 3H), 1.76-1.52 (m, 9H), 1.27-1.21 (m, 3H), 1.13 (t, J = 9.0 Hz, 3H). ESI-MS m/z: [m+H] ⁺ : 614.19.

Example 75: Synthesis of SS-(2-methoxyphenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0804.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 23.68%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.27-8.97 (m, 1H), 8.41-8.21 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.55 (t, J=7.0 Hz, 2H), 7.46-7.31 (m, 5H), 7.27-7.22 (m, 1H), 7.05 (dq, J=9.7, 6.1, 4.9 Hz, 1H), 6.98-6.91 (m . 99–0.77(m,3H).ESI-MS m/z:[m+H] ⁺ : 610.23.

Example 76: Synthesis of SS-(2,4-dimethylphenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0820.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 22.97%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 9.03 (d, J = 7.5 Hz, 1H), 8.31 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 18.7, 9.6 Hz, 1H), 7.55 (s, 1H), 7.45-7.30 (m, 5H), 7.10 (d, J = 23.4 Hz, 1H), 7.05-6.94 (m, 2H), 6.76 (d, J = 15.8 Hz, 1H) ,4.55(dtd,J＝14.8,10.2,8.9,5.4Hz,2H),3.18–3.06(m,2H),2.40–2.35(m,3H),2.30–2.18(m,6H),1.76–1.47(m,10H),1.13(dd,J＝19.2,8.8Hz,3H ),0.94–0.86(m,2H).ESI-MS m/z:[m+H] ⁺ : 608.26.

Example 77: Synthesis of SS-(2,6-dimethylphenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0821.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 28.25%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.30 (ddd, J = 19.5, 9.8, 5.6 Hz, 1H), 7.68 (ddd, J = 23.7, 16.3, 5.6 Hz, 1H), 7.58-7.51 (m, 2H), 7.46-7.35 (m, 4H), 7.21-7.13 (m, 2H), 7.09 (d, J = 7.5 Hz, 2H), 6.79-6.69 (m, 1H) ,4.87–4.36(m,2H),3.11(ddd,J＝27.7,13.5,5.9Hz,2H),2.57–2.51(m,3H),2.47–2.36(m,2H),2.17(s,3H),1.77–1.52(m,9H),1.20–1.07(m,4H), 0.94–0.78(m,3H).ESI-MS m/z:[m+H] ⁺ : 608.26.

Example 78: Synthesis of SS-(2,5-dimethylphenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0822.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 27%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.30 (dt, J = 16.6, 7.5 Hz, 1H), 7.70-7.63 (m, 1H), 7.55 (d, J = 7.4 Hz, 2H), 7.44-7.36 (m, 5H), 7.30 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.05 (dd, J = 13.3, 7.6 Hz, 1H), 6.81-6.72 (m, 1H), 4.66-4.19 (m, 2H), 3.11 (dd q,J＝23.5,16.4,8.9,7.1Hz,2H),2.34(s,1H),2.32(d,J＝12.5Hz,3H),2.25(t,J＝4.6Hz,1H),2.23(d,J＝11.0Hz,3H),2.16(s,2H),1.74–1.57(m,9H), 1.14–1.07(m,3H),0.87(dt,J＝21.0,7.9Hz,2H).ESI-MS m/z:[m+H] ⁺ : 608.26.

Example 79: Synthesis of SS-(3-methoxyphenyl)(S)-2-((S)-2-cinnamylamido-3-cyclohexylpropionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0823.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 25.28%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ9.14 (d, J=7.5 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.68 (s, 1H), 7.54 (t, J=6.7 Hz, 2H), 7.45-7.35 (m, 4H), 7.28 (d, J=8.0 Hz, 1H), 7.10-7.05 (m, 1H), 6.98-6.90 (m, 1H), 6.85 (ddd, J=21.1, 8.0 ,2.1Hz,1H),6.75(dd,J＝15.8,5.0Hz,1H),4.88–4.42(m,2H),3.73(d,J＝6.1Hz,3H),3.18–3.06(m,2H),2.29–2.02(m,3H),1.75–1.50(m,9H),1.18–1 .07(m,4H),0.96–0.86(m,2H).ESI-MS m/z:[m+H] ⁺ : 610.22.

Example 80: Synthesis of SS-benzyl (S)-2-((S)-3-cyclohexyl-2-(1H-indole-2-carboxamido)propionamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0224-1.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 60 as a white solid with a yield of 33.03%. ¹ H NMR (600 MHz, chloroform-d) δ11.28 (s, 1H), 9.36 (d, J = 4.7 Hz, 1H), 7.62-7.58 (m, 1H), 7.46-7.41 (m, 1H), 7.27-7.20 (m, 8H), 7.06 (dd, J = 8.0, 6.9, 1H), 6.90-6.86 (m, 1H), 4.97 (ddt, J = 11.6, 8.3, 3.8 Hz,1H),4.46(dt,J＝11.7,4.8Hz,1H),3.96(s,1H),3.81(dd,J＝14.0,5.5Hz,2H),3.42(s,1H),2.59(t,J＝9.2Hz,1H),2.15–2.10(m,1H),1.86(d,J＝11. 1Hz,3H),1.70–1.50(m,13H).ESI-MS m/z:[m+H] ⁺ : 607.24.

Example 81: Synthesis of SS-benzyl (S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-3-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0115.

Synthesis route:

Synthesis of compound 81-1:

Compound 15-3 (2.00 g, 5 mmol) was dissolved in dichloromethane (20 mL), and HCl/dioxane (5 mL, 20 mmol) was added dropwise. The mixture was reacted at room temperature overnight. The mixture was distilled under reduced pressure to obtain a transparent colorless solid compound 81-1, which was directly used in the next step. ESI-MS m/z: [m+H] ⁺ : 300.19.

Synthesis of compound 81-2:

Compound 81-1 (1.7 g, 5 mmol) and acetonitrile (30 mL) were added to an eggplant-shaped bottle, triethylamine (2.78 mL, 20 mmol) was added dropwise at 0°C, stirred at 0°C for 30 minutes, and then compound 15-7 (0.956 g, 0.75 mmol) and HBTU (1.9 g, 5 mmol) were added in sequence, and the mixture was reacted at room temperature overnight. The mixture was extracted with saturated ammonium chloride (20×3 mL), saturated sodium bicarbonate (20×3 mL) and saturated sodium chloride (20×3 mL), respectively, and the organic phases were combined, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The crude product was purified by medium pressure liquid chromatography (petroleum ether/ethyl acetate = 30:70) to obtain a colorless solid compound 81-2 (2.41 g, 100%). ESI-MS m/z: [m+H] ⁺ : 473.24.

Synthesis of compound 81-3:

Compound 81-2 (0.945, 2 mmol) was dissolved in 28 mL of ethanol, and H ₂ O (208 g) and LiOH·H ₂ O (0.168 g, 4 mmol) were added in sequence. The mixture was reacted at room temperature overnight. EtOH was removed by rotary evaporation, and the remaining reaction solution was washed with ethyl acetate (20×3 mL). The aqueous phases were combined and the pH was adjusted to less than 4 with 1 M HCl aqueous solution. The mixture was stirred for 30 min, filtered, and dried under vacuum to obtain white solid compound 81-3 (0.51 g, 55.60%). ESI-MS m/z: [M+Na] ⁺ : 459.22.

Synthesis of compound 81-4:

Under argon protection, 81-3 (0.51 g, 0.112 mmol) was dissolved in DMF (6 mL), EDC (0.32 g, 1.668 mmol) was added at 0°C, and stirred for 5-10 min. The reaction solution was added dropwise to a suspension of finely ground Na ₂ S·9H ₂ O (1.068 g, 4.449 mmol) in DMF (3 mL), and stirred at room temperature for 3-4 h under argon protection until the starting material disappeared. The residue was dissolved in EA (10 mL), and then the pH was adjusted to 3 with 1M KHSO ₄ at 0°C, and then extracted with ethyl acetate/H ₂ O, washed with saturated sodium chloride, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel column chromatography with a mobile phase of dichloromethane/methanol (30:1). After elution, the compound 80-4 (0.156 g, 29.56%) was obtained as a light yellow solid. ESI-MS m/z: [m+H] ⁺ ：475.20.

Synthesis of compound 81:

Compound 81-4 (0.156 g, 0.329 mmol) was dissolved in THF (6 mL) and H ₂ O (3 mL), and CH ₃ COONa (0.216 g, 2.632 mmol), benzyl mercaptan (0.27 mL, 2.303 mmol) and I ₂ (0.334 g, 1.316 mmol) were added in sequence, and the mixture was stirred at room temperature for 5 minutes. H ₂ O (10 mL) was added and the mixture was extracted with ethyl acetate (2×5 mL). The mixed organic phase was washed with saturated sodium thiosulfate aqueous solution, dried over anhydrous sodium sulfate, filtered, and dried by rotation. The crude product was purified by silica gel column chromatography with dichloromethane/methanol (80:1) as the mobile phase, and the white solid compound 81 (0.048 g, 24.5%) was obtained by rotation drying. ¹ H NMR (600 MHz, DMSO-d ₆ )δ11.57(dd,J＝15.7,2.4Hz,1H),8.95(dd,J＝17.7,7.3Hz,1H),8.43(dd,J＝16.8,8.1Hz,1H),7.68(d,J＝21.5Hz,1H),7.34–7.26(m,6H),7.09(t,J＝8.0Hz,1 H),7.00(d ,J＝8.3Hz,1H),6.50(d,J＝7.7Hz,1H),4.77–4.36(m,2H),4.09(s,2H),3.88(s,3H),3.18–3.05(m,2H),2.29–2.01(m,3H),1.78–1.50(m,5H),0.95– 0.85(m,6H).ESI-MS m/z:[m+H] ⁺ : 597.22.

Example 82: Synthesis of SS-(2-chloro-4-fluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0512.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 28.86%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.67-11.49 (m, 1H), 9.22-8.97 (m, 1H), 8.47 (d, J=8.3 Hz, 1H), 7.67 (dd, J=5.8, 2.8 Hz, 1H), 7.64-7.53 (m, 1H), 7.41-7.35 (m, 1H), 7.35-7.27 (m, 1H), 7.09 (td, J=7.9, 1.9 Hz, 1H). z,1H),7.00(dd,J＝8.4,3.6Hz,1H),6.50(dd,J＝7.7,1.4Hz,1H),4.90–4.51(m,2H),3.88(s,3H),3.18–3.02(m,2H),2.34–2.05(m,3H),1.83–1.61(m,5 H),0.93(m,6H).ESI-MS m/z:[m+H] ⁺ : 635.16.

Example 83: Synthesis of SS-(naphthalene-2-yl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0601.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 24.31%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.59 (dtd, J = 14.9, 11.9, 3.2 Hz, 1H), 9.17-8.91 (m, 1H), 8.52-8.43 (m, 1H), 7.99-7.94 (m, 1H), 7.93-7.81 (m, 2H), 7.76-7.46 (m, 4H), 7.44-7.38 (m, 1H), 7.10 (td, J = 8.1, 3.4 Hz, 1H), 7.01 (dd, J = 8 0 .93(dddd,J=23.9,12.4,6.5,1.9Hz,6H).ESI-MS m/z:[m+H] ⁺ : 633.22.

Example 84: Synthesis of SS-(3,4-difluorophenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0716.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 21.3%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.59 (d, J = 2.3 Hz, 1H), 8.94 (d, J = 7.9 Hz, 1H), 8.45 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 29.1 Hz, 1H), 7.58-7.43 (m, 2H), 7.38 (d, J = 7.3 Hz, 1H), 7.21 (tdd, J = 8.4, 4.0, 1.6 Hz, 1H), 7.09 ( t,J＝7.9Hz,1H),7.00(d,J＝8.2Hz,1H),6.50(d,J＝7.7Hz,1H),4.83–4.46(m,2H),3.88(s,3H),3.18–3.04(m,2H),2.32–2.07(m,3H),1.79–1.58(m,5 H),0.97–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 619.18.

Example 85: Synthesis of SS-(4-isopropylphenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0718.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 22.04%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.65-11.46 (m, 1H), 8.49 (dd, J=13.3, 7.8 Hz, 1H), 8.37 (dd, J=8.3, 4.3 Hz, 1H), 7.73-7.60 (m, 1H), 7.48-7.18 (m, 3H), 7.09 (t, J=7.9 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.50 (d ,J＝7.7Hz,1H),4.81–4.18(m,2H),3.88(s,3H),3.62(d,J＝3.7Hz,1H),3.17-3.06(m,2H),2.32–2.03(m,3H),1.82–1.56(m,5H),1.34–1.07(m,6H),0 .96–0.87(m,6H).ESI-MS m/z:[m+H] ⁺ : 625.25.

Example 86: Synthesis of SS-(4-(tert-butyl)phenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0723.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 27.1%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.69-11.38 (m, 1H), 9.28-8.75 (m, 1H), 8.69-8.22 (m, 1H), 7.75-7.61 (m, 1H), 7.46-7.24 (m, 5H), 7.09 (t, J=8.0 Hz, 1H), 7.00 (dd, J=8.9, 2.7 Hz, 1H), 6.50 (d, J=7. 8Hz,1H),5.06–4.09(m,2H),3.88(s,3H),3.28–2.96(m,2H),2.34–1.97(m,3H),1.83–1.52(m,5H),1.29–1.24(m,9H),0.92(dtd,J＝22.3,8.1,6.5 ,3.6Hz,6H).ESI-MS m/z:[m+H] ⁺ : 639.27.

Example 87: Synthesis of SS-(4-(methoxy)phenyl)(S)-2-((S)-2-(4-methoxy-1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0724.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 34.36%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.76-11.41 (m, 1H), 9.16-8.78 (m, 1H), 8.59-8.19 (m, 1H), 7.74-7.61 (m, 1H), 7.51 (dd, J＝13.4, 8.8 Hz, 1H), 7.45-7.26 (m, 2H), 7.09 (t, J＝7.9 Hz, 1H), 7.03-6.82 ( m,3H),6.50(d,J＝7.7Hz,1H),4.94–4.21(m,2H),3.88(s,3H),3.80–3.72(m,3H),3.21–2.99(m,2H),2.34–2.00(m,3H),1.82–1.50(m,5H),0.97–0. 86(m,6H).ESI-MS m/z:[m+H] ⁺ : 613.21.

Example 88: Synthesis of SS-(4-isopropylphenyl)(S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0806.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 20.12%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 9.07 (d, J = 7.5 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.48-7.38 (m, 2H), 7.33-7.28 (m, 2H), 7.25 (dd, J = 17.1, 8.1 Hz, 1H), 7.20-7.16 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 7.4 z,1H),4.62(td,J＝9.8,7.9,4.9Hz,2H),3.11(dq,J＝24.8,8.8Hz,2H),2.91–2.74(m,1H),2.28–2.04(m,3H),1.81–1.56(m,5H),1.18(dd,J＝10.8,6.9 Hz, 3H), 1.10 (dd, J＝6.8, 3.6Hz, 3H), 0.92 (dd, J＝27.5, 6.4Hz, 6H). ESI-MS m/z: [m+H] ⁺ : 595.24.

Example 89: Synthesis of SS-(4-tert-butylphenyl)(S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0807.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 30.5%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.59 (d, J = 16.5 Hz, 1H), 9.09 (d, J = 7.4 Hz, 1H), 8.53 (q, J = 11.9, 9.9 Hz, 1H), 7.75-7.64 (m, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.45-7.36 (m, 3H), 7.35-7.26 (m, 3H), 7.18 (t, J = 7.4 Hz, 1H),7.03(t,J＝7.4Hz,1H),4.63(ddd,J＝15.8,12.8,8.2Hz,2H),3.10(dt,J＝23.4,7.9Hz,2H),2.28–2.04(m,3H),1.80–1.58(m,5H),1.28–1.21(m,9H ),0.96–0.89(m,6H).ESI-MS m/z:[m+H] ⁺ : 609.26.

Example 90: Synthesis of SS-(4-methoxyphenyl)(S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0808.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 25.13%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.58 (d, J = 20.9 Hz, 1H), 9.00 (dd, J = 13.3, 7.6 Hz, 1H), 8.50 (dd, J = 12.6, 8.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.42 (ddd, J = 13.7, 8.8, 4.8 Hz, 3H), 7.28 (t, J = 7.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 6 .94(d,J＝8.8Hz,2H),6.86(d,J＝8.9Hz,1H),4.82–4.57(m,2H),3.78(d,J＝7.3Hz,3H),3.15–3.05(m,2H),2.24–2.02(m,3H),1.68(dtdd,J＝49.8,19.3, 10.3,4.5Hz,5H),0.95–0.88(m,6H).ESI-MSm/z:[m+H] ⁺ : 583.20.

Example 91: Synthesis of SS-(2-methoxyphenyl)(S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0809.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 15.32%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H), 9.24-8.80 (m, 1H), 8.54 (ddd, J=22.8, 13.9, 8.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.42 (dd, J=7.7, 1.4 Hz, 2H), 7.30-7.23 (m, 2H), 7.18 (t, J=7.6 Hz, 3H). z,1H),7.07–7.00(m,2H),6.98–6.91(m,1H),4.99–4.54(m,2H),3.87–3.81(m,3H),3.17–3.06(m,2H),2.31–2.05(m,3H),1.82–1.60(m,5H),0.92( dq,J＝21.1,6.2Hz,6H).ESI-MS m/z:[m+H] ⁺ : 583.21.

Example 92: Synthesis of SS-(2,4-dimethylphenyl)(S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propane (dithioperoxyester). Compound number: QXH0811.

Except for replacing the corresponding reaction raw materials, the target compound was prepared according to the method of Example 80 as a white solid with a yield of 30.07%. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 11.57 (d, J = 13.5 Hz, 1H), 9.03 (dd, J = 14.8, 7.5 Hz, 1H), 8.51 (dd, J = 16.1, 8.2 Hz, 1H), 7.76-7.59 (m, 2H), 7.44 (dd, J = 16.4, 8.0 Hz, 1H), 7.36-7.24 (m, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.12-6.96 (m, 2H). (m,3H),4.90–4.55(m,2H),3.16–3.05(m,2H),2.38(d,J＝6.0Hz,1H),2.34(s,1H),2.26(dd,J＝28.5,9.9Hz,4H),2.18(s,2H),2.10–1.98(m,1H),1.79 –1.57(m,5H),0.96–0.86(m,6H).ESI-MS m/z:[m+H] ⁺ : 581.22.

Test Example 1: Screening of SARS-CoV-2 main protease inhibitory activity

Test principle: The fluorescence resonance energy transfer (FRET) method is used, and its detection principle is as follows. Edans is a fluorescent donor (Donor), Dabcyl is a fluorescent acceptor (Acceptor) or called a quencher (Quencher), and the absorption spectra of these two fluorescent groups overlap to a certain extent. When the distance between the two fluorescent groups is appropriate (generally 7-10nm), the fluorescent energy is transferred from the donor to the acceptor, resulting in the fluorescence intensity of the donor fluorescent molecule itself attenuating. Edans and Dabcyl are connected to the two ends of the natural substrate of 2019-nCoV M ^pro /3CL ^pro protease, namely Dabcyl-KTSAVLQSGFRKME-Edans. When the 2019-nCoV M ^pro /3CL ^pro protease does not cut the substrate, the two groups are close enough to cause fluorescence resonance energy transfer, that is, Dabcyl can quench the fluorescence of Edans and cause no fluorescence to be detected; when the substrate is cut by the 2019-nCoV M ^pro /3CL ^pro protease, the head and tail ends of the polypeptide are separated, the two groups are separated, and the fluorescence of Edans is no longer quenched by Dabcyl, so the fluorescence of Edans can be detected. In this way, the enzyme activity of the 2019-nCoV M ^pro /3CL ^pro protease can be detected very sensitively by fluorescence detection. If an inhibitor of the 2019-nCoV M ^pro /3CL ^pro is added to the reaction system, the generation of fluorescence will be inhibited, and the fluorescence intensity is inversely proportional to the inhibitory effect of the inhibitor, so the inhibitory effect of the 2019-nCoV M ^pro /3CL ^pro protease inhibitor can be detected. The maximum excitation wavelength of Edans is 340nm, and the maximum emission wavelength is 490nm.

Test Materials and Methods:

Novel coronavirus M ^pro /3CL ^pro inhibitor screening kit, stored at -21℃, Shanghai Biotech Biotechnology Co., Ltd.

Positive control drug: Ebselen, Shanghai Bio-Tech Biotechnology Co., Ltd.

Test method: Take an appropriate amount of the sample to be tested and the positive drug Ebselen, and prepare a solution of the required concentration with DMSO. According to the number of test drugs, prepare an appropriate amount of Assay Reagent containing 1 μL 2019-nCoV M ^pro /3CL ^pro per 92 μL Assay Buffer. Use a black 96-well cell culture plate to set up a blank control group, a 100% enzyme activity control group, a positive inhibitor control group and a sample group. Add 93 μL Assay Buffer and 5 μL DMSO to the blank control group, 93 μL Assay Reagent and 5 μL DMSO to the 100% enzyme activity control group, and 93 μL Assay Reagent and 5 μL of the corresponding concentration of positive drug or sample solution to be tested to each of the remaining sample wells. Use a culture plate oscillator to shake for 1 minute to mix thoroughly. Under low temperature conditions, quickly add 2 μL Substrate to each well, shake and mix with an oscillator, incubate at 37°C in the dark for 5-20 minutes, and use a multifunctional enzyme label for fluorescence measurement, with an excitation wavelength of 340 nm and an emission wavelength of 490 nm. The samples to be tested were prepared into sample solutions with concentrations of 10 μM, 1 μM, and 0.1 μM, respectively, and the inhibitory activity of SARS-CoV-23CL ^pro in the reaction system was detected according to the above experimental method. The derivatives with an inhibition rate greater than 50% at a sample concentration of 10 μM were rescreened and the IC ₅₀ value was calculated. The test results are shown in Table 1 below.

Table 1

Note:

IC ₅₀ : The concentration at which a drug inhibits an enzyme by half.

Test Example 2: Cytotoxicity Test

Test cells: Vero-E6 cells (purchased from ATCC); Vero E6 was cultured in MEM medium (McGean Chemical Company) supplemented with 10% fetal bovine serum and 1% double antibody, the cells were digested, centrifuged, resuspended/counted, and prepared into a cell suspension with a concentration of 2×10 ⁵ cells/ml, and the prepared cell suspension was added to a 96-well plate (100 μL per well), that is, 2×10 ⁴ cells per well. The paved 96-well plate was placed in a constant temperature incubator at 37°C and 5% CO ₂ for 24 hours. After the cells attached, the old culture medium was discarded, and 200 μL of the corresponding drug-containing culture medium of different concentrations was added to each well. Three replicate wells were set for each group of samples, and blank control and negative control groups were set up. The 96-well plate with the drug added was placed in a cell culture incubator for 72 hours. Prepare the required amount of culture medium containing 10% CCK-8, discard the old culture medium, add 110 μL of the above culture medium to each well for staining, continue to culture in the incubator for 1 hour, then use a microplate reader to measure the OD value of each well at a wavelength of 450 nm, and calculate the cell viability.

Table 2

Note:

(1) “-” in the table means that the sample has no antiviral activity at the maximum non-toxic dose.

(2) CC ₅₀ : half cell concentration.

(3) SI: selection index, SI = CC ₅₀ /IC ₅₀ .

The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims (10)

1. The sulfur-containing peptidomimetic compound represented by formula I and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers: wherein C* ¹ , C* ² , and C* ³ are each independently of the S type or the R type; X is S or S-S; R ₁ is selected from substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C6-14 aryl C1-C3 alkyl, substituted or unsubstituted five- to ten-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 5 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, -COORa, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, wherein Ra is selected from H or C _1-6 alkyl; _R2 is selected from substituted or unsubstituted C1-C10 straight or branched alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, _C1-6 alkyl, C3-C10 cycloalkyl; R ₃ is selected from wherein R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C10 straight or branched alkyl, substituted or unsubstituted C2-C10 straight or branched alkenyl, substituted or unsubstituted C2-C10 straight or branched alkynyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C6-14 arylC1-C3 alkyl, substituted or unsubstituted five- to ten-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, substituted or unsubstituted five- to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from N, O and S, wherein the "substituted" refers to each of the above groups having a group selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-6 alkyl, halogenated C _1-6 alkyl, C 1 to 5 substituents of _1-6 alkoxy, C6-10 aryl, R ₇ , R ₈ and R ₉ are each independently selected from H, halogen, C1-C10 straight chain or branched chain alkyl, C1-C10 straight chain or branched chain alkoxy. 2. The sulfur-containing peptidomimetic compound of formula I according to claim 1 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, characterized in that: Preferably, R ₁ is selected from substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, substituted or unsubstituted five- to six-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, -COORa, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, wherein Ra is selected from H or C _1-3 alkyl; More preferably, R ₁ is selected from substituted or unsubstituted C1-C3 straight or branched alkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, substituted or unsubstituted five- to six-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" means that each of the above groups has 1 to 5 substituents selected from H, halogen, hydroxyl, carbonyl, -COORa, C _1-4 alkyl, halogenated C _1-4 alkyl, C _1-4 alkoxy, wherein Ra is selected from H or C _1-3 alkyl; More preferably, R ₁ is selected from substituted or unsubstituted methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl, naphthyl, benzyl, phenethyl, thienyl, thiazolyl, isothiazolyl, wherein the “substituted” means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, -COORa, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, pentafluoroethyl, wherein R _a is selected from H, methyl, ethyl, propyl, isopropyl; Preferably, R ₂ is selected from substituted or unsubstituted C1-C6 straight or branched alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-3 alkyl, C3-C6 cycloalkyl; More preferably, _R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl-n-propyl, cyclopropyl-isopropyl, cyclopropyl-n-butyl, cyclobutylmethyl, cyclobutylethyl, cyclobutyl-n-propyl, cyclobutyl-isopropyl, cyclobutyl-n-butyl, cyclopentylmethyl, cyclopentylethyl, cyclopentyl-n-propyl, cyclopentyl-isopropyl, cyclopentyl-n-butyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyl-n-propyl, cyclohexyl-n-butyl; Preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C2-C6 straight or branched alkenyl, substituted or unsubstituted C2-C6 straight or branched alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 arylC1-C3 alkyl, substituted or unsubstituted five- to eight-membered heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, substituted or unsubstituted five- to eight-membered heterocyclic group containing 1 or 2 heteroatoms selected from N, O and S, wherein the "substituted" refers to each of the above groups having a group selected from H, halogen, hydroxyl, carbonyl, amino, cyano, nitro, amide, C _1-3 alkyl, halogenated C _1-3 alkyl, C 1 to 3 substituents of _1-3 alkoxy, C6-10 aryl, More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from substituted or unsubstituted C1-C4 straight or branched alkyl, substituted or unsubstituted C2-C4 straight or branched alkenyl, substituted or unsubstituted C2-C4 straight or branched alkynyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C6-10 aryl C1-C3 alkyl, wherein the "substituted" means that each of the above groups has 1 to 3 substituents selected from H, halogen, hydroxyl, carbonyl, amino, cyano, amide, C6-10 aryl, More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from -CORb or -COORc, wherein Rb and Rc are each independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl, naphthyl, benzyl, phenethyl, vinyl, phenylvinyl, naphthylvinyl, phenylpropenyl, naphthylpropenyl, More preferably, R ₄ , R ₅ , and R ₆ are each independently selected from Preferably, R ₇ , R ₈ , and R ₉ are each independently selected from H, halogen, C1-C6 straight chain or branched chain alkyl, C1-C6 straight chain or branched chain alkoxy; More preferably, R ₇ , R ₈ , and R ₉ are each independently selected from H, halogen, C1-C4 straight chain or branched chain alkyl, C1-C4 straight chain or branched chain alkoxy; More preferably, R ₇ , R ₈ , and R ₉ are each independently selected from H, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy; More preferably, _R3 is selected from 3. The sulfur-containing peptidomimetic compound of formula I and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers according to claim 1, characterized in that the sulfur-containing peptidomimetic compound and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers are represented by the following formula II: Wherein, the definitions of substituents R1, R2, R3 and X are the same as those in claim 1. 4. The sulfur-containing peptidomimetic compound of formula I according to claim 1 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, characterized in that the sulfur-containing peptidomimetic compound and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers are represented by the following formula II-1, formula II-2, formula II-3, formula II-4, formula II-5, formula II-6, formula II-7, formula II-8, formula II-9, formula II-10, formula II-11, formula II-12, formula II-13 or formula II-14: wherein the substituents R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ have the same meanings as in claim 1. 5. The sulfur-containing peptidomimetic compound of formula I according to claim 1 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, characterized in that the sulfur-containing peptidomimetic compound and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers are selected from the following compounds: 6. A method for preparing the sulfur-containing peptidomimetic compound of formula I and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers according to any one of claims 1 to 5, characterized in that the method is carried out according to one of the following methods: Method 1 As shown in the above reaction formula, the method comprises the following steps: ⅰ) (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid methyl ester (Compound 1) is subjected to ester hydrolysis reaction at 0-50°C under base catalysis to generate Compound 1a; ii) Compound 1a reacts with the corresponding thiol or thiophenol in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 1b; iii) removing the Boc protecting group from compound 1b in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 1c; iv) Compound 1d reacts with compound 1e in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate compound 1f; v) Compound 1f is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 1g; vi) Compound 1c reacts with compound 1g in an aprotic solvent in the presence of a condensing agent and an organic base at 0-50° C. to generate compound 1h; ⅶ) removing the Boc protecting group from compound 1h in the presence of hydrochloric acid or trifluoroacetic acid at 0-35° C. to generate compound 1i; viii) Compound 1j reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50°C in the presence of a condensing agent and an organic base to produce a compound of formula VI; Where n is 1 or 2; The base in steps i) and v) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, etc.; In steps ii), iv), vi) and viii), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc.; the organic base is selected from triethylamine, diisopropylethylamine, pyridine, 4-N-lutidine; The aprotic solvent in steps ii), iv), vi) and viii) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile and the like; Method 2 As shown in the above reaction formula, the method comprises the following steps: ⅰ) (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid methyl ester (Compound 1) is deprotected by removing the Boc protecting group in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate Compound 2a; ii) Compound 2a and Compound 2b undergo amide condensation reaction in an aprotic solvent in the presence of a condensing agent and an organic base at 0-50° C. to generate Compound 2c; iii) Compound 2c is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 2d; iv) 2d reacts with the corresponding thiol in an aprotic solvent at 0-50°C in the presence of a condensing agent and an organic base to generate compound 2e; v) removing the Boc protecting group from compound 2e in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 2f; vi) Compound 2f reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to form a compound of formula II-1; Where n is 1 or 2; The base in steps i) and iii) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine, etc.; In steps ii), iv) and vi), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc.; the organic base is selected from triethylamine, diisopropylethylamine, pyridine, 4-N-lutidine; The aprotic solvent in steps ii), iv) and vi) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile, etc.; Method 3 As shown in the above reaction formula, the method comprises the following steps: i) Compound 1c reacts with compound 3 in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 3a; ii) removing the Boc protecting group from compound 3a in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 3b; iii) Compound 3e reacts with compound 3d in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate compound 3e; iv) Compound 3e is subjected to ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 3f; v) Compound 3b reacts with compound 3f in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to generate a compound of formula V; Where n is 1 or 2; The aprotic solvent in steps i), iii) and v) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile, etc.; The base in step iv) is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine, etc.; In steps i), iii) and v), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc.; the organic base is selected from triethylamine, diisopropylethylamine, pyridine, 4-N-lutidine; Method 4 As shown in the above reaction formula, the method comprises the following steps: i) removing the Boc protecting group from compound 2c in the presence of hydrochloric acid or trifluoroacetic acid at 0-35°C to generate compound 4a; ii) Compound 4a reacts with the corresponding carboxylic acid in an aprotic solvent at 0-50° C. in the presence of a condensing agent and an organic base to produce compound 4b; iii) Compound 4b undergoes ester hydrolysis reaction at 0-50°C under alkaline conditions to generate compound 4c; iv) Compound 4c is subjected to a sulfidation reaction to generate compound 4d, using carbodiimide hydrochloride (EDCI) as a coupling agent and Na ₂ S as a hydrogen sulfide ion source, and the reaction is carried out at room temperature; v) Compound 4d is subjected to an oxidation reaction to generate a compound of formula II-2, using I ₂ as an oxidant and CH ₃ COONa as an acid-binding agent, and the reaction is carried out at room temperature; The aprotic solvent in step ii) is selected from dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, dioxane, toluene, acetone, acetonitrile, etc.; In step ii), the condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) or benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), etc.; the organic base is selected from triethylamine, diisopropylethylamine, pyridine, 4-N-lutidine; In step iii), the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, lithium carbonate, triethylamine, etc.; In the above reaction formula, the substituents R1, R2, and R4 are defined the same as in claim 1. 7. A pharmaceutical composition comprising a therapeutically effective amount of a sulfur-containing peptidomimetic compound of formula I according to any one of claims 1 to 5 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer thereof as an active ingredient, and a pharmaceutically acceptable excipient. 8. The use of a sulfur-containing peptidomimetic compound of formula I according to any one of claims 1 to 5 and its pharmaceutically acceptable salts, racemic mixtures, enantiomers, optical isomers and tautomers, or a pharmaceutical composition according to claim 7 in the preparation of a coronavirus main protease inhibitor, wherein the coronavirus main protease inhibitor is used to treat and/or prevent and alleviate related diseases caused by coronavirus infection, wherein the coronavirus is a pathogenic coronavirus such as severe acute respiratory syndrome virus (SARS-COV), novel severe acute respiratory syndrome virus (SARS-COV-2), Middle East respiratory syndrome virus (MERS-CoV), etc. 9. A method for treating and/or preventing and alleviating coronavirus 3CL ^pro- related diseases, the method comprising administering to a patient in need thereof a therapeutically effective amount of a sulfur-containing peptidomimetic compound represented by formula I according to any one of claims 1 to 5 and a pharmaceutically acceptable salt, racemic mixture, enantiomer, optical isomer and tautomer thereof, or a pharmaceutical composition according to claim 7. 10. The method of claim 9, wherein the disease or condition associated with 3CL ^pro is a viral infectious disease or condition, and the virus is a pathogenic coronavirus such as severe acute respiratory syndrome virus (SARS-COV), novel severe acute respiratory syndrome virus (SARS-COV-2), and Middle East respiratory syndrome virus (MERS-CoV).