CN103833827A

CN103833827A - Amide compounds, medicine compositions, preparation method and application thereof

Info

Publication number: CN103833827A
Application number: CN201210490498.5A
Authority: CN
Inventors: 黄雨; 单汉滨; 朱雪焱; 俞雄; 袁哲东; 李敏
Original assignee: Shanghai Institute of Pharmaceutical Industry
Current assignee: Livzon Pharmaceutical Group Inc
Priority date: 2012-11-27
Filing date: 2012-11-27
Publication date: 2014-06-04
Anticipated expiration: 2032-11-27
Also published as: CN103833827B

Abstract

The invention discloses amide compounds shown in a formula (I) or pharmaceutically acceptable salts and a preparation method thereof. According to the preparation method I, a compound II and a compound III generate a coupling reaction under an inert gas in an anhydrous solvent under the effect of a condensation reagent. In addition, the invention further discloses an application of the compounds shown in the formula (I) in preparation of a reagent for inhibiting thrombin or a medicine for treating and/or preventing thrombin-mediated and/or thrombin-associated diseases. The invention further provides an application of the compounds shown in the formula (I) in preparation of an active medicine for regulating or inhibiting serine protease of tryptase. The invention further discloses medicine compositions which comprise the compounds shown in the formula (I) and pharmaceutically acceptable carriers of the compounds. The amide compounds disclosed by the invention have excellent thrombin inhibiting activity and are suitable for preparing various medicine preparations.

Description

Amide compound, pharmaceutical composition, preparation method and application thereof

Technical Field

The invention relates to an amide compound, a pharmaceutical composition, a preparation method and application thereof.

Background

The mortality rate of cardiovascular and cerebrovascular diseases in the world is always the second place, wherein thromboembolism is the main cause of morbidity and mortality of the cardiovascular and cerebrovascular diseases. The incidence of the diseases is on a continuously rising trend along with the change of life style of people and the increasing aging degree of the population. This makes the search and research of effective drugs for preventing and treating these diseases urgent, and has great significance in both clinical application and basic research.

The traditional anticoagulant drugs used clinically at present, such as heparin, warfarin, hirudin and the like, have serious defects in the aspects of curative effect and safety, so that the application of the traditional anticoagulant drugs is greatly limited. Such as heparin, must be injected and has no effect on thrombin in the blood clot and can cause thrombocytopenia; warfarin has no definite drug target, so that individual anticoagulation reaction difference is large, influence factors are many, and blood coagulation function monitoring is needed. Therefore, it is very important to research and develop artificial synthetic new anticoagulant drugs with oral activity.

Blood coagulation is the result of a complex series of enzymatic actions, the key step of which is the activation of prothrombin to thrombin. Thrombin is a trypsin-like serine protease that primarily functions to hydrolyze fibrin to form insoluble, fibrous aggregates. Plays a key role in the blood coagulation cascade. It has been clinically proven that Direct Thrombin Inhibitors (DTIs) can block the formation of thrombi and overcome the application limitations of traditional anticoagulants. It is clear that thrombin inhibitors which are convenient for therapeutic control of the thrombotic stroke, potent and selective and have oral bioavailability represent an attractive target.

Over the last thirty years, a great deal of progress has been made in the research of synthetic thrombin inhibitors as anticoagulant activity, and a large number of highly active and highly selective small molecule thrombin inhibitors have been reported. Tripeptide aldehyde thrombin inhibitors of D-Phe-Pro-Arg-H and Me-D-Phe-Pro-Arg-H are reported as in US 47030368. Recently, D-Phe-Pro-agmatine and its derivatives have been described as thrombin inhibitors in US4346078 and WO 9311152. Later, a tripeptide type inhibitor was reported in WO9429336 and WO9523609, incorporating 4-amidinobenzylamine at position P1 in place of agmatine and the like.

Trigen, US2007185060, discloses a class of boronic acid inhibitors, of which flovagatrandodium has potent thrombin inhibiting activity and good selectivity, and was developed as an injection formulation. Phase I clinical trials show that the product is absorbed rapidly after intravenous drip administration, the blood concentration is increased rapidly, and the blood concentration is reduced rapidly after intravenous drip is stopped (Drugs Fut, 2007, 32, 310). Phase III clinical studies were performed in 2006.

In US4101653, Okamoto et al disclose that a series of arginine derivatives were designed and synthesized using N-p-toluenesulfonylarginine methyl ester (TAMA) as a thrombin substrate, and argatroban (argatroban) was found to have a good inhibitory activity against thrombin. Pharmacological clinical research has been approved by FDA in 2001 to be on the market as injection, argatroban is a reversible competitive thrombin inhibitor, acts by combining with the active site of thrombin, and has high selectivity to thrombin. The composition is clinically used for treating peripheral thrombosis and acute cerebral apoplexy, and can also be used for treating heparin-induced thrombocytopenia and thrombotic syndrome.

Similarly, St ü rzebecher et al designed and synthesized a series of benzamidines according to the structure of TAMA, and further structural modification found that NAPAP has a thrombin inhibitory activity twice as strong as that of argatroban (J MedChem, 1994, 37, 3889). The series of compounds obtained by changing benzamidine of NAPAP into piperidine formamidine also has high thrombin inhibiting activity, wherein napsagatran synthesized by Hoffmann-La Roche has the strongest activity (Bioorg Med Chem Lett, 1999, 9, 1957), and also has effect on fibrinogen protease, phase II clinical research has been carried out, but the half-life is short and the oral bioavailability is poor.

The company Astra, WO9429336, discloses a class of benzamidine analogs in which melagatran (melagatran) has potent thrombin inhibitory activity, is safe for Deep Vein Thrombosis (DVT) without significant bleeding problems, but has low oral bioavailability, and further synthesizes his dual precursor drug, ximelagatran (ximelagatran), which was marketed in 2004. The anticoagulant is the first anticoagulant taken orally in more than 60 years after warfarin, but severe liver injury is found in clinic after the market, and the clinical application is ended in 2006 and 2 months.

In addition, a class of thrombin inhibitors with a unique D-diphenylglycine at position P3 is reported in WO9311152, WO9715190, US 5510369. The compounds are reported to have higher antithrombin activity than the corresponding D-phenylglycine analogues (J Med Chem, 1997, 40, 830), some of which have better oral bioavailability (J Med Chem, 1997, 40, 3687; J Med Chem, 1997, 40, 3726; J Med Chem, 1998, 41, 1011; J Med Chem, 2003, 46, 3612).

WO9837075 discloses a series of benzamidine peptidomimetic derivatives, wherein dabigatran (dabigatran) inhibits thrombin strongly and has a low binding rate to proteins. The prodrug dabigatran etexilate (dabigatran etexilate) was synthesized and may be administered orally (J Med Chem, 2002, 45, 1757). It was marketed in 2008.

Only a few of the reported compounds have suitable in vivo pharmacokinetic and pharmacodynamic properties. To date, the study of thrombin inhibitors remains one of the subjects of intense research in the field of pharmaceutical chemistry at present.

Disclosure of Invention

The technical problem to be solved by the invention is to provide an amide compound, a pharmaceutical composition, a preparation method and an application thereof, in order to overcome the defects of low oral bioavailability, obvious side effect, large individual difference and the like of a thrombin inhibitor in the prior art. The amide compound has excellent thrombin inhibiting activity and is suitable for preparing various pharmaceutical preparations.

One of the objects of the present invention is to provide an amide compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-SO₃R¹、-COR¹、-CO₂R¹、-PO(OR¹)₂、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-SO₃R¹、-C_1～6alkyl-COR¹、-C_1～6alkyl-CO₂R¹or-C_1～6alkyl-PO (OR)¹)₂；

R¹Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, -C_l～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-to 6-membered aromatic heterocycle or-NR²R³；R²And R³Independently represent hydrogen, C_1～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen or C_l～6Alkyl (preferably hydrogen);

Z₁and Z₂Independently represent hydrogen, C_1～6Alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy, mercapto, alkylthio, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or C with the above groups_1～6Alkyl groups of (a);

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁴、R⁵Or

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O, NH or S; r⁶Represents hydrogen, C_1～6Alkyl or

q represents 0 to 3; y is_lRepresents O, NH or CH₂；R⁷Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle.

Preferably, in the amide compound shown in the formula (I),

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR^l、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-COR¹or-C_1～6alkyl-CO₂R¹；

B represents hydrogen;

Z₁and Z₂Independently represents hydrogen, halogen, hydroxy, amino or C with the above groups_1～6Alkyl groups of (a);

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁴、R⁵Or

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O; r⁶Represents hydrogen, C_l～6Alkyl orq represents 0 to 3; y is_lRepresents O or NH; r⁷Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_l～6An alkyl-5-to 6-membered aromatic heterocycle.

Among the above-mentioned preferred amide-based compounds represented by the formula (I),

a represents C_l～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR¹、-C_1～6Alkyl-cycloalkyl, -C_l～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_l～6alkyl-SO₂R¹、-C_1～6alkyl-COR¹or-C_l～6alkyl-CO₂R¹；

R¹Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_l～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_l～6Alkyl-aryl, -C_l～6Alkyl-5-to 6-membered aromatic heterocycle or-NR²R³；R²And R³Independently represent hydrogen, C_l～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen;

Z_land Z₂Independently represents hydrogen, halogen, hydroxy, amino or C with the above groups_l～6Alkyl groups of (a);

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁵；R⁵Represents halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle.

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR^l、-C_l～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_l～6alkyl-SO₂R¹、-C_l～6alkyl-COR¹or-C_l～6alkyl-CO₂R¹；

R¹Represents hydrogen, C_l～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_l～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1~6Alkyl-5-to 6-membered aromatic heterocycle or-NR²R³；R²And R³Independently represent hydrogen, C_1～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen;

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁵；R⁵Represents a 5-6 membered aromatic heterocycle.

In the invention, in the amide compound shown as the formula (I),

when A is-SO₂R¹When preferred, halogenated aryl-SO₂-、C_1～4Alkylsulfonyl radical, C_1～4Alkyl-substituted aminosulfonyl, arylsulfonyl, C_1～4alkylphenyl-SO₂-, halo C_1～3alkylphenyl-SO₂-、C_2～4Amidophenyl-SO₂-, cyanophenyl-SO₂-, naphthalenesulfonyl, quinolinesulfonyl, alkylamino-substituted naphthalenesulfonyl, -SO₂-C_3～6Cycloalkyl, more preferably methanesulfonyl, ethanesulfonyl, N-dimethylaminosulfonyl, phenylsulfonyl, p-F-Ph-SO₂-、p-CH₃-Ph-SO₂-、p-C(CH₃)₃-Ph-SO₂-、p-CF₃-Ph-SO₂-、p-CH₃CONH-Ph-SO₂-、p-CN-Ph-SO₂-, 4-bromo-2-fluoro-benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, 8-quinolinesulfonyl, 1, 2, 3, 4-tetrahydro-7-quinolinesulfonyl, 5-N, N-dimethyl-1-naphthalenesulfonyl, cyclopropanesulfonyl;

when A is-COR¹When, C is preferred_2～6Alkyl acyl, halo C_2～6Alkyl acyl group, Ph (CH)₂)_0～3CO-, substituent-substituted Ph (CH)₂)_0～3CO-、C_l～3Alkoxy-substituted phenylacetyl, halogen-substituted phenylacetyl, C_2～6Amido-substituted phenylacetyl, C_3～6Cycloalkylacetyl, N-C_1～6Alkyl-substituted piperidinecarboxyl, hydronaphthylformyl, substituent-substituted fused ring heteroarylformyl, and more preferably-COCH₃、-COCHF₂、-COPh、-COCH₂Ph、-CO(CH₂)₂Ph、-COCH₂CH(NH₂)Ph、p-OCH₃-Ph-CH₂CO-、p-Br-Ph-CH₂CO-、p-CH₃CONH-Ph-CH₂CO-、m-OCH₃-Ph-CH₂-CO-, 3, 4-dimethoxyphenylacetyl, cyclopentylacetylN-methyl-piperidine-4-formyl, 1, 2, 3, 4-tetrahydro-7-naphthoyl, 2-methyl-imidazo [1, 2-alpha ]]And pyridine-3-formyl;

when A is-C_1～6When alkyl-cycloalkyl is present, preference is given to-C_1～3alkyl-C_3～6Cycloalkyl, more preferably-C₁-a cyclohexyl group;

when A is-C_1～6In the case of alkyl-aryl, phenyl-C substituted with a substituent is preferred₁Alkyl-, more preferably phenyl-C₁Alkyl-;

when A is-C_1～6When the aromatic heterocyclic group is an alkyl-5 to 6-membered aromatic heterocyclic group, a 5 to 6-membered aromatic heterocyclic group-C substituted with a substituent is preferable_1～3Alkyl-, more preferably-C₁Alkyl-2-pyridyl, -C₁Alkyl-5-methyl-2-thienyl;

when A is-C_1～6alkyl-SO₂R¹When it is preferable to use-C_1～3alkyl-SO₂R¹；

When A is-C_1～6alkyl-COR¹When it is preferable to use-C_1～3alkyl-COR¹More preferably-C₁alkyl-CONH₂；

When A is-C_1～6alkyl-CO₂R¹When it is preferable to use-C₁alkyl-CO₂H、-C₁alkyl-CO₂C(CH₃)₃、-C₂alkyl-CO₂H. -C2 alkyl-CO₂C₂H₅。

When R is¹Is C_1～6When alkyl, C is preferred_1～4Alkyl, halo C_1～4An alkyl group;

when R is¹When it is cycloalkyl, it is preferably C_3～C₆A cycloalkyl group;

when R is¹When aryl, phenyl, halophenyl, C are preferred_1～4Alkyl-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, C_2～6Acylamino radical extractionSubstituted phenyl, naphthyl, hydrogenated naphthyl, quinolyl, hydrogenated quinolyl, substituted piperidyl, and substituted fused heterocyclic aryl, more preferably phenyl, p-F-Ph-, p-CH₃-Ph、p-C(CH₃)₃-Ph、p-CF₃-Ph-、p-CN-Ph-、p-CH₃CONH-Ph-, 4-bromo-2-fluoro-phenyl, 1-naphthyl, 2-naphthyl, 8-quinolyl, 1, 2, 3, 4-tetrahydro-7-quinolyl, 5-N, N-dimethyl-1-naphthyl, N-methyl-4-piperidyl, l, 2, 3, 4-tetrahydro-7-naphthyl, 2-methyl-imidazo [1, 2-alpha ]]Pyridine-3-yl), 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl (preferably-C)_1～3alkyl-C_3～6Cycloalkyl, most preferably-C₁Alkyl-cyclopentyl);

when R is¹is-C_1～6When the alkyl-aryl group is substituted, -C is preferred_1～4Alkylphenyl, -amino-substituted C_1～4Alkyl phenyl, C_1～4Alkoxy-substituted phenyl-C_1～4Alkyl-, halophenyl-C_1～3Alkyl-, C_2～6Amidophenyl-C_1～3Alkyl-, more preferably-C₁Alkyl-phenyl, -C₂Alkyl-phenyl, -CH₂CH(NH₂)Ph、p-OCH₃-Ph-CH₂-、p-Br-Ph-CH₂-、p-CH₃CONH-Ph-CH₂-、m-OCH₃-Ph-CH₂-, 3, 4-dimethoxyphenylmethyl.

When Z is₁And Z₂Is C_1～6Alkyl, preferably C_1～3An alkyl group;

when Z is₁And Z₂Is halogen, preferably fluorine.

When R is⁵When it is halogen, chlorine is preferred;

when R is⁵When the aromatic heterocyclic ring is a 5-to 6-membered aromatic heterocyclic ring, a 5-to 6-membered nitrogen heteroaromatic ring or a 5-to 6-membered nitrogen sulfur heteroaromatic ring is preferable, and 4-thiadiazo, 1-pyrazolyl, 2-imidazolyl, 1-triazolyl, 1-tetrazolyl, 1-methyl-5-tetrazolyl, and 2-pyrazinyl are more preferable.

When R is⁶Is C_1～6When alkyl, C is preferred_1～3Alkyl, halo C_1～3Alkyl, more preferably methyl, -CH₂CF₃。

When R is⁷Is C_1～6When alkyl, C is preferred_1～3An alkyl group;

when R is⁷When it is cycloalkyl, it is preferably C_3～6A cycloalkyl group;

when R is⁷When heterocycloalkyl, azacycloalkyl is preferred, and piperidin-3-yl is more preferred;

when R is⁷is-C_1～6When alkyl-cycloalkyl is present, preference is given to-C_1～3alkyl-C_3～6Cycloalkyl, more preferably-C_lAlkyl-cyclohexyl;

when R is⁷is-C_l～6When the alkyl-aryl group is substituted, -C is preferred₁Alkyl-phenyl.

More preferably, the amide compound shown in (I) or the pharmaceutically acceptable salt thereof is any one of the specific compounds shown in the following numbers 1-81,

in the above table, the numbers of the compounds correspond to the numbers of the respective examples, for example, compound number 1 corresponds to the preparation method and parameters in example 1.

Among the above-mentioned more preferable amide-based compounds represented by the formula (I),

in the above tables, the groups of each row combine to form specific compounds of formula (I) according to the invention, which are preferred compounds of formula (I) in the above preferred ranges.

In the invention, the pharmaceutically acceptable salt of the amide compound shown in the formula (I) can comprise pharmaceutically acceptable inorganic acid salt or organic acid salt. The inorganic acid salt is preferably sulfate, sulfite, hydrochloride, hydrobromide, nitrate, phosphate, metaphosphate, pyrophosphate or perchlorate. The organic acid salt is preferably acetate, maleate, fumarate, succinate, citrate, p-toluenesulfonate, tartrate, formate, acetate, propionate, heptanoate, oxalate, benzoate, malonate, succinate, maleate, hydroxybutyrate, citrate, methanesulfonate, benzenesulfonate, lactate or mandelate.

In the present invention, the amide-based compounds represented by the formula (I) have one or more chiral carbon atoms and thus may also exist as racemates, diastereomeric mixtures and pure enantiomers, and all of these isomers are included in the scope of the present invention.

In the present invention, the following definitions are used:

as is customary in the art, the structural formulae used herein

For delineating the bond at the point of attachment of the moiety or substituent to the core or backbone structure.

“C_1～6Alkyl "means a straight or branched chain monovalent residue of 1 to 6 saturated and/or unsaturated carbon and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), isobutyl, tert-butyl (t-Bu), ethenyl, pentenyl, propenyl, butenyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like, which may be unsubstituted or substituted by one or more identical or different substituents selected from the group defined below.

"cycloalkyl" means a non-aromatic monovalent monocyclic, bicyclic, or tricyclic residue containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more of the same or different substituents selected from the group defined below.

"heterocycloalkyl" means a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic residue containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms and including 1, 2, 3, 4, 5, or 6 heteroatoms, which may or may not be the same, selected from nitrogen, oxygen, and sulfur. Each of which may be saturated or unsaturated and may be unsubstituted or substituted by one or more identical or different substituents selected from the group defined below.

"aryl" refers to phenyl and naphthyl. May be unsubstituted or substituted by one or more identical or different substituents selected from those defined below, and may be fused with a cycloalkyl, heterocycloalkyl or 5-6 membered heteroaromatic ring which may itself be unsubstituted or substituted by one or more identical or different substituents selected from those defined below.

A5-to 6-membered heteroaromatic ring is a five-or six-membered heteroaromatic ring which contains 1, 2, 3 or 4 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, in addition to carbon atoms in the ring. May be unsubstituted or substituted by one or more identical or different substituents selected from the group defined below, and may be fused with a cycloalkyl, heterocycloalkyl, aryl or 5-6 membered heteroaromatic ring which may itself be unsubstituted or substituted by one or more identical or different substituents selected from the group defined below.

The "substituent" is halogen, carboxyl, ester group, C_1～6Alkyl, alkoxy, acyl, acylamino, sulfonyl, mercapto, alkylthio, cycloalkyl, heterocycloalkyl, amino, alkylamino, dialkylamino, cyano, difluoromethyl, trifluoromethyl or C with the above groups_l～4Alkyl group of (1).

The invention also aims to provide a preparation method of the amide compound shown in the formula (I), which is any one of the following methods:

in the first method, under the action of a condensation reagent, a compound II and a compound III are subjected to coupling reaction in an anhydrous solvent under the action of inert gas; wherein R is R⁴、R⁵Or

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O or S; r⁶Represents hydrogen, C_l～6Alkyl or

q represents 0 to 3; y is_lRepresents O, NH or CH₂；R⁷Represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_l～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle; a is-SO₂R¹、-COR¹or-CO₂R¹(ii) a B is hydrogen or C_1～6Alkyl (preferably hydrogen); z₁Is hydrogen, halogen, amino, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or methyl; z₂Is hydrogen or fluorine; k is 0 to 2; m is 0 to 2; n is 0 to 2;

in the second method, under the action of a condensation reagent, the compound IV and the compound V are subjected to coupling reaction in an anhydrous solvent under the action of inert gas; wherein R is R⁴、R⁵Or

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogenDifluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O or S; r⁶Represents hydrogen, C_1～6Alkyl or

q represents 0 to 3; y is_lRepresents O, NH or CH₂；R⁷Represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle; a is-SO₂R¹、-COR¹or-CO₂R¹(preferably-SO)₂R¹) (ii) a B is hydrogen or C_1～6Alkyl (preferably hydrogen); z₁Is hydrogen, halogen, amino, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or methyl; z₂Is hydrogen, halogen, alkoxy, alkylthio, ester, difluoromethyl, trifluoromethyl or methyl; k is 0 to 2; m is 0 to 2; n is 0 to 2;

carrying out coupling reaction according to the preparation method of the first method; carrying out deprotection reaction on the compound obtained in the step I; wherein R is-X-R⁶(ii) a X is NH; r⁶Represents hydrogen or C_1～6An alkyl group; a is-SO₂R¹or-COR¹(ii) a B is hydrogen; z₁Is hydrogen, halogen, amino, hydroxyl, mercapto or methyl; z₂Is hydrogen, halogen, hydroxyl, mercapto, ester, difluoromethyl, trifluoromethyl or methyl; k is 0 to 2; m is 0 to 2; n is 0 to 2;

carrying out coupling reaction according to the preparation method of the first method; secondly, under the action of an acid binding agent, performing alkyl substitution reaction on the compound obtained in the first step and an alkylating reagent; the compound obtained in the step I is N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorphenyl) methylamide;

in the solvent, performing nucleophilic substitution reaction on D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide;

the sixth method is that the coupling reaction is carried out according to the preparation method of the first method; ② the compound obtained in the step I is performed decarboxylation acid protecting group reaction; the compound obtained in the step I is N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-ethoxycarbonylmethyl) -5-chlorphenyl ] methylamide;

carrying out nucleophilic substitution reaction according to the fifth method; ② the compound obtained in the step I is performed decarboxylation acid protecting group reaction; the compound obtained in the step I is N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide or N- (tert-butoxycarbonyl) ethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide;

eighth, carrying out coupling reaction according to the preparation method of the first method; carrying out detritylation reaction on the compound obtained in the step I to obtain N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1H-imidazole-4-yl) -5-chlorphenyl ] methylamide trifluoroacetate;

ninth, first, carry on the coupling reaction according to the preparation method of the first method; carrying out azide reduction reaction on the compound obtained in the step one; the compound obtained in the step I is N-benzenesulfonyl-D-leucyl-L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide;

in a solvent, N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide is subjected to N alkylation reaction;

the first method is to carry out coupling reaction according to the preparation method of the first method; ② removing amino protecting group from the compound obtained in the step I; the compound obtained in the step I is 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide.

In the first method, the coupling reaction is performed by a standard peptide coupling method, and the reaction conditions and steps can be performed by referring to the standard peptide coupling method. In the present invention, the standard peptide coupling method is preferably selected from the group consisting of an azide method, a mixed anhydride method, a carbodiimide (dicyclohexylcarbodiimide DCC, diisopropylcarbodiimide EDC) method, an active ester method, a carbonyldiimidazole method or a phosphorus reagent method (e.g., BOP-Cl). 1-hydroxybenzotriazole can also be added in the first method. The dosage of the 1-hydroxybenzotriazole is preferably 1 to 1.4 equivalent. An acid-binding agent can also be added in the coupling reaction. The acid-binding agent is preferably organic tertiary amine. The organic tertiary amine is preferably diisopropylethylamine, triethylamine, trimethylamine, pyridine or N-methylmorpholine, and particularly preferably N-methylmorpholine (NMM) or Diisopropylethylamine (DIEA). The dosage of the acid-binding agent is preferably 1-1.3 equivalents of the compound II, and more preferably 1 equivalent of the compound II.

In the first method, the anhydrous solvent in the coupling reaction can be a solvent conventional in the art for such reactions, and preferably one or more of dichloromethane, tetrahydrofuran, diethyl ether, acetonitrile, dichloroethane, ethyl acetate, N-dimethylformamide and dimethylsulfoxide. The amount of the anhydrous solvent is preferably 10 to 40ml/g of the compound II, and more preferably 20ml/g of the compound II.

In the first process, the condensation reagent in the coupling reaction is preferably a Katt reagent, a mixture of EDCI and HOBt, CDI, HATU, HBTU, TBTU or PyBOP. The molar amount of the condensation reagent is preferably 1 to 2 equivalents of the compound II, and more preferably 1.1 equivalents of the compound II. Wherein in the mixture of EDCI and HOBt, the molar ratio of EDCI to HOBt is preferably 1-2, and more preferably 1.5.

In the first method, in the coupling reaction, the molar ratio of the compound II to the compound III is preferably 1 to 2, and more preferably 1.1.

In the first method, the reaction temperature in the coupling reaction is preferably 0-30 ℃.

In the first method, the inert gas in the coupling reaction is preferably nitrogen.

In the first method, the progress of the reaction in the coupling reaction can be monitored by HPLC, and the end point of the reaction is generally determined as the disappearance of the compound II, preferably 2 to 24 hours.

In the first method, a post-treatment step can be further included after the coupling reaction is finished so as to further purify the product. The work-up step may be any work-up step conventional in the art, such as column chromatography and recrystallization.

In the second method, the coupling reaction is performed by a standard peptide coupling method, and the reaction conditions and steps can be performed by referring to the standard peptide coupling method. In the present invention, the standard peptide coupling method is preferably selected from the group consisting of an azide method, a mixed anhydride method, a carbodiimide (dicyclohexylcarbodiimide DCC, diisopropylcarbodiimide EDC) method, an active ester method, a carbonyldiimidazole method or a phosphorus reagent method (e.g., BOP-Cl). 1-hydroxybenzotriazole can also be added in the second method. The dosage of the 1-hydroxybenzotriazole is preferably 1 to 1.4 equivalent. An acid-binding agent can also be added in the coupling reaction. The acid-binding agent is preferably organic tertiary amine. The organic tertiary amine is preferably diisopropylethylamine, triethylamine, trimethylamine, pyridine or N-methylmorpholine, and particularly preferably N-methylmorpholine (NMM) or Diisopropylethylamine (DIEA). The dosage of the acid-binding agent is preferably 1-1.3 equivalents of the compound IV, and more preferably 1 equivalent of the compound IV.

In the second method, the anhydrous solvent in the coupling reaction can be a conventional solvent in the field of such reaction, and preferably one or more of dichloromethane, tetrahydrofuran, diethyl ether, acetonitrile, dichloroethane, ethyl acetate, N-dimethylformamide and dimethyl sulfoxide. The amount of the anhydrous solvent is preferably 10 to 80ml/g of the compound IV, and more preferably 20ml/g of the compound IV.

In the second process, the condensation reagent in the coupling reaction is preferably a Katt reagent, a mixture of EDCI and HOBt, CDI, HATU, HBTU, TBTU or PyBOP. The molar amount of the condensation reagent is preferably 1 to 2 equivalents of the compound IV, and more preferably 1.1 equivalents of the compound IV. Wherein in the mixture of EDCI and HOBt, the molar ratio of EDCI to HOBt is preferably 1-2, and more preferably 1.5.

In the second method, the molar ratio of the compound IV to the compound V in the coupling reaction is preferably 1-2, and more preferably 1.1.

In the second method, the reaction temperature in the coupling reaction is preferably 0-30 ℃.

In the second method, the inert gas in the coupling reaction is preferably nitrogen.

In the second method, the progress of the reaction in the coupling reaction can be monitored by HPLC, and the end point of the reaction is generally determined as the disappearance of the compound IV, and the reaction is preferably carried out for 2 to 24 hours.

In the second method, a post-treatment step can be further included after the coupling reaction is finished so as to further purify the product. The work-up step may be any work-up step conventional in the art, such as column chromatography and recrystallization.

In the third method, the deprotection reaction may be a deprotection reaction which is conventional in the art, and preferably comprises the following steps: and (4) mixing the compound obtained in the step (I) with a solvent, mixing with an acid, and reacting. The acid is preferably an inorganic acid. The inorganic acid is preferably hydrochloric acid. The solvent in the acid is generally alcohols, ethers or ethyl acetate. The ethers may be those conventional in the art, and are preferably methyl ether, ethyl ether or tetrahydrofuran. The mass percentage concentration of the hydrochloric acid is preferably 15%. The amount of the acid is preferably 3 to 10 equivalents of the compound obtained in the first step of the third process. In the deprotection reaction, the solvent used is preferably an organic solvent. The organic solvent is preferably ethyl acetate or alcohols. The alcohol can be alcohol solvent conventional in the art, such as methanol, ethanol or propanol. In the deprotection reaction, the amount of the solvent used is not particularly limited as long as it does not affect the normal progress of the reaction, and it is preferably 3 to 10 equivalents of the compound obtained in the step (i). The deprotection temperature is generally 10 ℃ to 40 ℃. The progress of the deprotection reaction can be monitored by HPLC, and is generally the end point of the reaction when the reactants disappear. After the deprotection reaction is finished, the method can further comprise post-treatment to further purify the product, and the post-treatment step preferably comprises the following steps: filtering, removing solvent, sequentially adding ethanol, 15% HCl and ethyl acetate mixed solution, and diethyl ether, precipitating solid, filtering, and drying. In the post-treatment process, the temperature can be reduced overnight after solid is separated out. The temperature reduction is preferably carried out to-10 ℃ to 0 ℃.

In the fourth method, the alkyl substitution reaction may be an alkyl substitution reaction which is conventional in the art. The alkylating agent may be an alkylating agent conventional in the art, preferably alkyl bromide, alkyl iodide, alkyl chloride, alkyl sulfonate, alkyl benzene sulfonate, alkyl p-toluenesulfonate, alkyl methanesulfonate or dimethyl sulfate, more preferably alkyl bromide, alkyl iodide or alkyl p-toluenesulfonate. The alkyl iodide is preferably methyl iodide. The alkyl bromide is preferably 1-bromo-2, 2, 2-trifluoroethane. The amount of the alkylating agent to be used is preferably 1 to 3 equivalents, more preferably 1 to 1.5 equivalents, of N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorophenyl) methylamide. In the fourth method, when the alkylating reagent used is alkyl iodide, the alkyl substitution reaction generally needs to be carried out under the condition of keeping out light.

In the fourth method, the acid-binding agent used in the alkyl substitution reaction can be an inorganic base or an organic base. The inorganic base is preferably an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal bicarbonate, or an alkali metal or alkaline earth metal hydrogen phosphate. The hydroxide of the alkali metal is preferably sodium hydroxide. The alkali metal hydride is preferably sodium hydride. The carbonate of the alkali metal is preferably cesium carbonate. The hydrogen phosphate salt of an alkali metal is preferably dipotassium hydrogen phosphate. The organic base is preferably piperidine or an organic tertiary amine. The organic tertiary amine is preferably diisopropylethylamine, triethylamine, trimethylamine, pyridine or N-methylmorpholine, and more preferably Diisopropylethylamine (DIEA). The dosage of the acid-binding agent is preferably 1-3 equivalents of N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorphenyl) methylamide, and more preferably 1-1.5 equivalents.

In the fourth method, the solvent used in the alkyl substitution reaction is preferably one or more of tetrahydrofuran, dioxane, acetonitrile, acetone and N, N- -' methyl formamide. The dosage of the solvent is preferably 3-20 ml/g reactant, and more preferably 3-10 ml/g reactant.

In the fourth method, the temperature of the alkyl substitution reaction is preferably 30 to 80 ℃.

In method IV, the progress of the alkyl substitution reaction can be monitored by HPLC, typically as the end point of the reaction when N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorophenyl) methylamide disappears.

In the fourth method, a post-treatment step may be further included after the alkyl substitution reaction is completed, so as to further purify the product, and the post-treatment step preferably includes: extracting, washing an organic layer by using a sodium thiosulfate aqueous solution with the mass fraction of 5% and saturated saline solution in sequence, drying the organic layer, filtering, concentrating the filtrate, and purifying by column chromatography. The conditions and procedures of column chromatography can refer to those of column chromatography which are conventional in the art.

In method five, the nucleophilic substitution reaction may be a nucleophilic substitution reaction conventional in the art. The nucleophilic substitution reaction preferably comprises the steps of: in a solvent, under the action of an acid-binding agent, D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl acylAmine, with C_1～6Alkyl bromides or C_2～6And (3) reacting the alkyl bromate.

In the fifth method, in the nucleophilic substitution reaction, the acid-binding agent may be an inorganic base or an organic base. The inorganic base is preferably an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal bicarbonate, or an alkali metal or alkaline earth metal hydrogen phosphate. The hydroxide of the alkali metal is preferably sodium hydroxide. The alkali metal hydride is preferably sodium hydride. The carbonate of the alkali metal is preferably cesium carbonate. The hydrogen phosphate salt of an alkali metal is preferably dipotassium hydrogen phosphate. The organic base is preferably piperidine or an organic tertiary amine. The organic tertiary amine is preferably diisopropylethylamine, triethylamine, trimethylamine, pyridine or N-methylmorpholine, and more preferably Diisopropylethylamine (DIEA). The dosage of the acid-binding agent is preferably 1-3 equivalents of D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide, and more preferably 1-1.5 equivalents.

In method five, the solvent is preferably one or more of N, N-Dimethylformamide (DMF), acetonitrile, tetrahydrofuran and dichloromethane. The dosage of the solvent does not influence the normal operation of the reaction, and preferably 3-10 ml/g reactant. Said C_1～6The alkyl bromide is preferably bromoethane or n-propyl bromide. Said C_2～6The brominated alkyl acid ester is preferably tert-butyl bromoacetate or ethyl bromoacetate. Said C_1～6Alkyl bromides or C_2～6The dosage of the bromoalkyl acid ester is preferably D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl]1 to 3 equivalents of methylamide. The temperature of the nucleophilic substitution reaction is preferably 20 ℃ to 80 ℃, more preferably 40 ℃. The progress of the nucleophilic substitution reaction can be monitored by HPLC, typically using D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl]The end point of the reaction is when the methyl amide disappears. After the nucleophilic substitution reaction is completed, a post-treatment step can be included to further purify the product, thusThe post-treatment step preferably comprises: concentrating the reaction system, adding ethyl acetate for extraction, and sequentially using saturated sodium bicarbonate aqueous solution with the mass concentration of 5% KHSO for the organic phase₄Washing the aqueous solution, water and saturated saline solution, drying, filtering, concentrating the filtrate, and purifying by column chromatography. The conditions and steps of the column chromatography can be selected with reference to the conditions and steps conventional in column chromatography in the art.

In methods six and seven, the decarboxylated acid protecting group reaction is described in reference to protecting groups in organic synthesis, third edition, t.w.green and Peter g.m.wuts (1999), publishers: john Wiley & Sons, Inc., and can generally be carried out in the presence of a base or acid, or by reduction with hydrogen in the presence of a catalyst.

In the sixth and seventh processes, when the compound obtained in the first step is N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-ethoxycarbonylmethyl) -5-chlorophenyl ] methylamide, the decarboxylating acid-protecting group reaction may be carried out in the presence of a base. The base includes an organic base or an inorganic base. The organic base is preferably diisopropylethylamine or triethylamine. The inorganic base is preferably an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal carbonate or an alkali metal or alkaline earth metal bicarbonate. The hydroxide of the alkali metal is preferably sodium hydroxide or potassium hydroxide. The alkali metal hydride is preferably sodium hydride. The carbonate of the alkali metal is preferably potassium carbonate. The bicarbonate of an alkali metal is preferably sodium bicarbonate. The amount of the base is preferably 3 to 10 equivalents, more preferably 3 to 5 equivalents, of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-ethoxycarbonylmethyl) -5-chlorophenyl ] methylamide.

In the sixth and seventh methods, when the compound obtained in the first step is N- (t-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide or N- (t-butoxycarbonyl) ethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide, the decarboxylation protecting group reaction is performed under an acidic condition. The acidic condition is preferably a solution of hydrochloric acid in ethyl acetate. The mass percentage concentration of the ethyl acetate solution of hydrochloric acid is preferably 15%. The dosage of the hydrochloric acid is preferably 3-10 equivalents of N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide or N- (tert-butoxycarbonyl) ethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide, and more preferably 3-10 equivalents.

In the sixth and seventh methods, when the decarboxylated acid protecting group reaction is reduced with hydrogen gas in the presence of a catalyst, the catalyst may be a metal catalyst such as palladium, platinum, nickel, or the like. The mass ratio of the catalyst to the reactant is preferably 0.05-0.3, and more preferably 0.1-0.2.

In the sixth and seventh processes, the decarboxylating acid protecting group reaction can be carried out in the presence of a solvent which does not adversely affect the reaction in general. The solvent is preferably one or more of water, alcohol (such as methanol, ethanol, etc.), tetrahydrofuran, dioxane and acetone. The dosage of the solvent is generally enough not to influence the normal operation of the reaction, and preferably 3-20 ml/g reactant.

In the sixth method and the seventh method, the temperature for the decarboxylation protecting group reaction is preferably 0-30 ℃. The progress of the decarboxylated acid protecting group reaction can be monitored by HPLC, and the end point of the reaction is generally determined when the reactants disappear. After the decarboxylation acid protecting group reaction is finished, a post-treatment process can be carried out to further purify a reaction product. When the decarboxylation protecting group reaction is carried out under acidic conditions, the post-treatment step preferably includes: filtering, and concentrating. When the decarboxylation protecting group reaction is carried out under basic conditions, the post-treatment process preferably comprises: concentrating the reaction system, washing the water layer with isopropyl ether, cooling, adjusting the pH value to 3, extracting with ethyl acetate, washing the organic layer with a 5% potassium bisulfate aqueous solution, water and a saturated salt aqueous solution in sequence, drying the organic layer with anhydrous sodium sulfate, filtering and concentrating.

In method eight, the detritylation reaction may be a detritylation reaction as is conventional in the art. The step of detritylation preferably comprises: and (3) in a solvent, under the action of alkyl silane, performing detritylation reaction on the compound obtained in the step (I). The solvent for detritylation is preferably trifluoroacetic acid. The dosage of the solvent for the detritylation reaction is preferably 3-20 ml/g reactant. The alkylsilane is preferably triethylsilane. The preferable dosage of the triethylsilane is 3-8 equivalents of the compound obtained in the first step in the eighth method. The temperature of the detritylation reaction is preferably 10 ℃ to 30 ℃. The progress of the detritylation reaction can be monitored by HPLC, typically with the disappearance of the reactants as the end point of the reaction. After the detritylation reaction is finished, a post-treatment process can be further included to further purify the product, and the post-treatment process is preferably performed by column chromatography. The conditions and steps of the column chromatography can be selected according to the conditions and steps of the conventional column chromatography.

In the ninth method, the azide reduction reaction may be an azide reduction reaction which is conventional in the art. The azide reduction reaction preferably comprises the following steps: and (2) mixing a solution of the compound obtained in the step (i) in an anhydrous organic solvent with triphenylphosphine and water, and reacting. The anhydrous organic solvent is preferably anhydrous tetrahydrofuran. The dosage of the anhydrous organic solvent is preferably 3-20 ml/g reactant. The dosage of the triphenylphosphine is preferably 1-1.5 equivalent of N-benzenesulfonyl-D-leucyl-L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide. The dosage of the water is preferably 0.1-0.5 equivalent of N-benzenesulfonyl-D-leucyl-L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide. The temperature of the azide reduction reaction is preferably 50 to 100 ℃, and more preferably 60 ℃. The progress of the azide reduction reaction can be monitored by HPLC, and is generally the end point of the reaction when the reactants disappear. After the azide reduction reaction is finished, a post-treatment process can be further included to further purify the product, and the post-treatment process preferably comprises the following steps: filtering, concentrating the filtrate, and purifying by column chromatography. The conditions and steps of the column chromatography can be selected according to the conditions and steps of the conventional column chromatography.

In the method ten, the N alkylation reaction can adopt a reductive amination method or a nucleophilic substitution method.

In the tenth embodiment, the nucleophilic substitution method preferably comprises the following steps: in a solvent, under the action of an acid-binding agent, reacting N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide with an alkylating reagent. The alkylating agent is preferably alkyl bromide, alkyl iodide, alkyl chloride, alkyl sulfonate, alkyl benzene sulfonate, alkyl p-toluene sulfonate, alkyl methane sulfonate or dimethyl sulfate, preferably alkyl bromide, alkyl iodide or alkyl p-toluene sulfonate. The dosage of the alkylating reagent is preferably 1 to 3 equivalents of N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide, and more preferably 1 to 2 equivalents. The acid-binding agent can be inorganic base or organic base. The inorganic base is preferably an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal bicarbonate, or an alkali metal or alkaline earth metal hydrogen phosphate. The hydroxide of the alkali metal is preferably sodium hydroxide. The alkali metal hydride is preferably sodium hydride. The carbonate of the alkali metal is preferably cesium carbonate. The hydrogen phosphate salt of an alkali metal is preferably dipotassium hydrogen phosphate. The organic base is preferably piperidine or an organic tertiary amine. The organic tertiary amine is preferably diisopropylethylamine, triethylamine, trimethylamine, pyridine or N-methylmorpholine, and more preferably diisopropylethylamine. The dosage of the acid-binding agent is preferably 1-3 equivalents of N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide, and more preferably 1-1.5 equivalents. The solvent adopted by the nucleophilic substitution method is one or more of tetrahydrofuran, dioxane, acetonitrile, acetone and N, N-dimethylformamide. The dosage of the solvent is preferably 3-20 ml/g reactant, and more preferably 3-10 ml/g reactant. The reaction temperature of the nucleophilic substitution method is preferably 30-80 ℃.

In process ten, when a reductive amination process is used, it preferably comprises the following steps: in a solvent, reacting the reactant with aldehyde under the action of a reducing agent. The reducing agent may be a reducing agent conventional in the art, and is preferably lithium tri-tert-butoxide, potassium borohydride, sodium triacetoxyborohydride, raney nickel, or lithium triethylborohydride, and more preferably potassium borohydride or sodium triacetoxyborohydride. The amount of the reducing agent is preferably 1 to 2 equivalents, more preferably 1 to 1.5 equivalents, of N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide. The solvent may be a solvent commonly used in the art, preferably one or more of methanol, ethanol, tetrahydrofuran, dichloroethane, and acetonitrile. The dosage of the solvent is preferably 3-20 ml/g reactant, and more preferably 3-10 ml/g reactant. The aldehyde is preferably cyclohexylformaldehyde, benzaldehyde, 2-pyridinecarboxaldehyde or 5-methyl-2-thiophenecarboxaldehyde. The amount of the aldehyde is preferably 1 to 2 equivalents, more preferably 1 to 1.3 equivalents, of N- (t-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide or D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide. The reaction temperature of the reductive amination method is preferably 0-50 ℃.

In method ten, the progress of the N-alkylation reaction can be monitored by HPLC, typically with the disappearance of the reactants as the end point of the reaction. The N alkylation reaction may further include a post-treatment process after the N alkylation reaction is completed, to further purify the product, and the post-treatment process preferably includes: concentrating the reaction system, and purifying by column chromatography. The conditions and steps of the column chromatography can be selected according to the conventional conditions and steps of the column chromatography in the field.

In method eleven, the reaction for removing the amino-protecting group can be carried out by a conventional method, as described in "protecting group in organic synthesis", third edition, t.w.green and Peter g.. m.wuts (1999), publisher: john Wiley & Sons, Inc. The method for removing the amino protecting group is preferably hydrolysis under acidic or basic conditions, or hydrogenolysis reduction with hydrogen in the presence of a catalyst. The acidic condition is preferably an organic acid or an inorganic acid. The organic acid is preferably trifluoroacetic acid, benzenesulfonic acid or formic acid. The inorganic acid is preferably hydrochloric acid, sulfuric acid or hydrobromic acid. The amount of the acid used is preferably 3 to 10 equivalents, more preferably 3 to 5 equivalents, of 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide. The alkaline condition is preferably an organic base or an inorganic base. The inorganic base is preferably an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal hydride, an alkali metal or alkaline earth metal carbonate or an alkali metal or alkaline earth metal bicarbonate. The hydroxide of the alkali metal is preferably sodium hydroxide or potassium hydroxide. The alkali metal hydride is preferably sodium hydride. The carbonate of the alkali metal is preferably potassium carbonate. The bicarbonate of an alkali metal is preferably sodium bicarbonate. The organic base is preferably diisopropylethylamine, triethylamine or piperidine. The amount of the base is preferably 1 to 3 equivalents, more preferably 1 to 2 equivalents, of 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide.

In the eleventh process, the catalyst is preferably a palladium, platinum or nickel catalyst. The dosage of the catalyst is preferably 0.05 to 0.3 equivalent, more preferably 0.1 to 0.2 equivalent of 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide. The hydrogenolysis reaction may be any conventional hydrogenolysis reaction in the art, and the reaction conditions and steps may be selected conventionally.

In the eleventh process, the reaction can be carried out in the presence of a solvent which does not adversely affect the reaction in general, and methylene chloride, an alcohol (e.g., methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, acetic acid, or ethyl acetate is preferable. The reaction temperature for removing the amino protecting group is preferably 0-40 ℃.

In method eleven, the progress of the reaction for removing the amino protecting group can be monitored by HPLC, and the end point of the reaction is generally determined when the reactant disappears. After the reaction for removing the amino protecting group is finished, a post-treatment process can be further included to further purify the product, and the post-treatment process preferably comprises the following steps: removing solvent, extracting with dichloromethane, sequentially washing organic layer with saturated sodium bicarbonate water solution, water and saturated saline solution, drying, filtering, concentrating, and purifying by column chromatography. The conditions and steps of the column chromatography can be selected according to the column chromatography conditions and steps conventional in the art.

In the present invention, the product of each step can be purified by methods known in the art such as column chromatography and recrystallization.

The invention also aims to provide application of the compound shown as the formula (I) in preparing a reagent for inhibiting thrombin or preparing a medicament for treating and/or preventing thrombin-mediated and/or thrombin-related diseases. Specifically, the compound shown as the formula (I) can be used for preparing an anticoagulant.

The fourth purpose of the invention is to provide the application of the compound shown as the formula (I) in preparing the active medicine for preparing or inhibiting the serine protease of tryptase. More particularly, the agents that modulate or inhibit the activity of tryptase serine proteases are useful in the treatment of thrombosis and other cardiovascular disorders.

Such thrombin-mediated and/or thrombin-associated diseases include, but are not limited to: venous thrombosis and pulmonary embolism, arterial thrombosis such as myocardial ischemia, myocardial infarction, unstable angina, stroke due to thrombosis, and peripheral arterial formation; atherosclerotic diseases such as coronary artery disease, cerebral artery disease and peripheral artery disease.

The compound shown in the formula (I) can also be used as an anticoagulant in an extracorporeal blood pipeline.

In addition, the compound shown in the formula (I) can be used together with a thrombolytic agent for preparing a medicament for preventing and/or treating myocardial infarction. In addition, the compounds of formula (I) of the present invention may also be used in the preparation of a medicament for preventing the re-thrombosis after microsurgery. In the invention, the compound shown as the formula (I) can also be used for preparing an anticoagulant medicament for treating hemodialysis and disseminated intravascular coagulation.

The thrombin inhibiting agents can be used for the ex vivo preservation of blood, plasma and other blood products.

The compounds of the invention may be administered by oral or parenteral routes such as intravenous infusion, intramuscular injection, or subcutaneous injection. The specific amount of the compound administered according to the invention to achieve a therapeutic and prophylactic effect will depend on the particular circumstances of the case, including the form of administration, the rate of administration and the condition being treated. Typical oral daily doses to produce efficacy are between about 0.01mg/kg and about 1000 mg/kg; typical daily dosages for parenteral administration are between about 0.001mg/kg and about 100 mg/kg. The mode of administration may vary, for example, a single dose per day, or multiple doses of 3 to 5 times per day may be suitable. It will be understood that the dosage and mode of administration may be routinely adjusted as necessary depending on the age and weight of the patient and the severity of the condition being treated. The exact dosage and route of administration should be at the discretion of the attendant physician.

The fifth object of the present invention is to provide a pharmaceutical composition comprising the compound represented by formula (I) and a pharmaceutically acceptable additive.

The pharmaceutical composition can also comprise various pharmaceutically common additives (such as diluents, excipients and the like) to prepare a pharmaceutical preparation. The pharmaceutical composition may be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, hard capsules, suppositories, injections (solutions and suspensions, generally injections), and the like, according to the therapeutic purpose.

For shaping the pharmaceutical composition in tablet form, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. If desired, the tablets can also be made as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer tablets and multilayer tablets with the usual coating materials.

For shaping the pharmaceutical composition in the form of a pill, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; adhesives such as gum arabic powder, xanthan gum powder, gelatin, ethanol, and the like; disintegrating agents, such as agar and kelp powder.

For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.

For the preparation of pharmaceutical compositions in the form of injection solutions, the solutions and suspensions may be sterilized and, preferably, suitable amounts of sodium chloride, glucose or glycerol, etc., may be added to prepare an injection solution which is isotonic with blood. In the preparation of injection, any carrier commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added. Coloring agents, preservatives, perfumes, flavoring agents, perfuming agents and other medicines may also be added as required during the treatment of schizophrenia.

The content of the compound represented by the formula (I) and the pharmaceutically acceptable salt thereof in the pharmaceutical composition of the present invention is not particularly limited, and may be selected from a wide range, generally from 0.1 to 99.9% by mass, preferably from 1 to 70% by mass, and more preferably from 1 to 30% by mass.

In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally; the injection can be administered alone, or mixed with injectable delivery solution (such as glucose solution and amino acid solution) for intravenous injection, or simply injected into muscle, skin or abdomen if necessary; the suppository is administered to the rectum.

In the present invention, the administration dose can be appropriately selected depending on the administration method, the age, sex and other conditions of the patient and the symptoms. Typical dosages administered may be: about 0. 1-300 mg of active ingredients of the medicine per kg of body weight per day. Generally, each unit dosage form for administration may contain 1 to 200mg of the pharmaceutically active ingredient.

The injection preferably contains 1% (W/V) of the compound shown in the formula (I) and 100% (W/V) of physiological saline. The injection may further comprise an antioxidant or a metal chelator. The antioxidant and metal chelator can be those commonly used in the formulation art, and their amounts can be selected according to the amounts conventionally used in the art.

The preparation method of the injection can be a preparation method which is conventional in the field, and preferably comprises the following steps: mixing the compound shown as the formula (I) with normal saline, adjusting the pH value to 4-8, and filtering and sterilizing. The reagent used for adjusting the pH value is dilute acid, dilute alkali or buffer salt. The preparation method of the injection can also comprise filling the injection into a sterile ampoule under the sterile condition. The sterilization can be the conventional sterilization in the preparation of injection, and the operation steps and conditions can be selected according to the conventional mode. The dilute acid, dilute base or buffer salt may be a dilute acid, dilute base or buffer salt commonly used in the art.

The tablet preferably contains 60 mg/tablet of the compound shown in the formula (I), 35 mg/tablet of microcrystalline cellulose, 4.5 mg/tablet of sodium carboxymethyl starch, 45 mg/tablet of corn starch, 0.5 mg/tablet of magnesium stearate and 1 mg/tablet of talcum powder. The hard capsule preferably contains 55% (W/W) of the compound shown in the formula (I), 43% (W/W) of dry starch and 2% (W/W) of magnesium stearate.

The preparation method of the tablet can be a conventional preparation method in the field, and preferably comprises the following steps: mixing the compound shown in formula (I) with excipient, sieving, and tabletting.

The preparation method of the hard capsule can be a conventional preparation method in the field, and preferably comprises the following steps: mixing the compound shown in formula (I) with excipient, and filling into hard gelatin capsule.

The suspension preferably contains 50mg/5ml of the compound shown in the formula (I), 75mg/5ml of sodium carboxymethyl cellulose, 1.2ml/5ml of syrup, 0.05ml/5ml of pigment, 0.05mg/5ml of benzoic acid and water; the water makes up the balance to 5 ml.

The preparation method of the suspension can be a preparation method conventional in the field, and preferably comprises the following steps: sieving the compound shown in formula (I), mixing with sodium carboxymethylcellulose and syrup to form uniform paste, and mixing with pigment and benzoic acid water solution under stirring.

The pharmaceutically acceptable carrier, diluent and excipient in the preparation in the composition are mutually compatible with the compound shown as the formula (I) and are harmless to accepted objects.

The compound shown in the formula (I) can be administrated in a mode of a pharmaceutical composition, and can also be prepared into a preparation for administration. For example, for oral administration, the compounds are formulated into capsules or tablets. For injection, the compound of formula (I) is dissolved in a pharmaceutically acceptable vehicle (e.g., sterile, pyrogen-free water, physiological saline).

Abbreviations appearing in the present invention are as follows:

boc: tert-butyloxycarbonyl radical

DIEA: diisopropylethylamine

EDCI: 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazoles

NMM: n-methylmorpholine

DMF: n, N' -dimethylformamide.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

Unless otherwise indicated, the terms and abbreviations disclosed herein have their standard meanings.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the amide compound has excellent thrombin inhibiting activity and is suitable for preparing various pharmaceutical preparations.

Detailed Description

The following examples will illustrate in detail the synthetic procedures of the present invention wherein preferred compounds of the invention are synthesized, but it is understood that the chemistry described may be modified somewhat to produce additional thrombin inhibitors of the invention, and that such modified procedures and resulting compounds are still within the scope of the invention. For example, non-exemplified compounds of the present invention may be successfully synthesized by modifications apparent to those skilled in the art. These examples are for illustration only and are not intended to limit the scope of the invention in any way.

The in vitro inhibition of thrombin activity of the compounds of the invention can be determined by chromogenic substrate method. In the experiment, S2238 (available from Chromogenix corporation) was used as a chromogenic substrate, and its activity for inhibiting human alpha-thrombin was determined. And calculates its IC₅₀The value is obtained.

The detection method comprises the following steps:

the NMR instrument was a Varian INOVA-400 NMR instrument with tetramethylsilicon as an internal standard and chemical shift in ppm. Thin layer chromatography (TLC, preformed silica gel plates using HSG-F254 HPLC, manufactured by Wako pure silica gel development laboratory Co., Ltd.) and HPLC were used to examine the reaction and product purity. The color development is carried out by using iodine vapor or irradiating under 254A and 310A ultraviolet lamps or 1% ninhydrin ethanol solution. The used reagents are analytically pure except for special instructions, and the anhydrous solvent and the reagents are treated by a conventional method. Melting points were determined using a micro melting point apparatus, using a thermometer without calibration.

HPLC: waters 1525; detector Waters 2487; a chromatographic column: PhenomenexC18 (4.6X 250mm, 5 μm); detection wavelength: 220nm and 254 nm; column temperature: 40 ℃; flow rate: 1.0 ml/min;

mobile phase 1: a: 0.1% aqueous trifluoroacetic acid B: acetonitrile

Mobile phase 2: a: phosphate buffer B at ph 6.8: acetonitrile

Mobile phase 3: a: phosphate buffer B at ph 8.0: acetonitrile

Example i: N-benzenesulfonyl-D-leucyl-L-prolyl- (3-chlorophenyl) methylamide

a) Preparation of N-benzenesulfonyl-D-leucine

Dissolving D-leucine (13.11g, 100mmol) in 1.5N sodium hydroxide solution (80ml), adding dioxane (80ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding benzene sulfonyl chloride (19.8g, 110mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid is dripped to adjust the pH value to 3, and dioxane is removed by decompression and concentration, and a large amount of solid is separated out; filtration was carried out, and the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain a white solid (22.2g, yield: 82%).

Rf 0.3 developing solvent petroleum ether to ethyl acetate: 1: 1 color development: ultraviolet, iodine and 1% ninhydrin solution

Melting point: 116-118 deg.C

MS：294(M+Na)。

b) Preparation of benzyl N-phenylsulfonyl-D-leucyl-L-proline

Dissolving N-benzenesulfonyl-D-leucine (21.7g, 80mmol) and L-proline benzyl ester hydrochloride (21.7g, 90mmol) in dichloromethane (500ml), adding DIEA (23g, 180mmol) dropwise under the protection of nitrogen gas and cooling, adding HOBt (11g, 80mmol) and EDCI (18g, 96mmol) after dropwise addition, and naturally raising the temperature to room temperature for reaction for 4 h. The reaction solution was removed by concentration under reduced pressure, and purified by direct column chromatography to give a white solid (31.8g, yield: 87%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 2: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：459(M+H)

1H NMR(CDCl₃)ppm：0.73(3H，d)，0.81(3H，d)，1.22(1H，m)，1.37～1.57(2H，m)，1.86-2.08(3H，m)，2.48(1H，m)，3.31(1H，m)，3.63(1H，m)，3.88(1H，m)，5.22(2H，s)，7.26-7.85(10H，m)。

c) Preparation of N-benzenesulfonyl-D-leucyl-L-proline

Benzyl N-benzenesulfonyl-D-leucyl-L-proline (23g, 50mmol) was dissolved in methanol (200ml), 10% palladium on carbon (2g) was added, and the mixture was reacted at room temperature for 3 hours with hydrogen. Filtration and concentration under reduced pressure removed the solvent to give a white foamy solid (17.8g, yield: 97%). Directly carrying out the next reaction.

MS：391(M+Na)。

d) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- (3-chlorophenyl) methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 3-chlorobenzylamine hydrochloride (180mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), and under nitrogen protection, after cooling to 0 ℃, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, followed by stirring at 0 ℃ for 20min, cooling to room temperature and reaction for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (260mg, yield: 53%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: ultraviolet and iodine

MS：492(M+H)

1H NMR(CDCl₃)ppm：0.74(3H，d)，0.85(3H，d)，1.23(1H，m)，1.46～1.52(2H，m)，1.93-2.05(3H，m)，2.39(1H，m)，3.36(1H，m)，3.62(1H，m)，3.93(1H，m)，4.43(2H，m)，4.57(1H，m)，7.56-7.87(8H，m)。

Example 2: N-benzenesulfonyl-D-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

a) Preparation of 2, 5-dichlorobenzylamine hydrochloride

Dissolving 2, 5-dichlorobenzonitrile (5.1g, 30mmol) in anhydrous tetrahydrofuran (150ml), cooling to 0 ℃ under nitrogen, and slowly adding 1M BH dropwise₃the-TI-IF solution (150ml) was stirred at 0 ℃ for 1 hour, heated to reflux for 3 hours, cooled naturally to room temperature, and then heated to reflux for 0.5 hour by slowly adding 2N hydrochloric acid solution (30 ml). Filtering, concentrating under reduced pressure to remove organic solvent, and washing water phase with diethyl ether (80ml × 2); after cooling, 10% potassium carbonate solution was added dropwise to adjust pH to 9, the aqueous phase was extracted with methylene chloride (80 ml. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an oil, which was dissolved in ether (150ml), and then 15% HCl/ethyl hexanoate solution (20ml) was added dropwise slowly to give a white solid (5.5 g), which was directly subjected to the next reaction.

Rf 0.2 developing agent petroleum ether and ethyl acetate 5: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：176(M+H)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 2, 5-dichlorobenzylamine hydrochloride (176mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, and then HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added thereto, stirred at 0 ℃ for 20min, allowed to naturally warm to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (300mg, yield: 57%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet and iodine

MS：526(M+H)

1H NMR(CDCl₃+D₂O) ppm: 0.73(3H, d), 0.89(3H, d), 1.26(1H, m), 1.54(1H, m), 1.76(1H, m), 1.94-2.08(3H, m), 2.38(1H, m), 3.38(1H, q), 3.65(1H, m), 3.99(1H, dd), 4.41(2H, qd), 7.14-7.57(6H, m), 7.82(2H, d). Example 3: N-benzenesulfonyl-D, L-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

a) Preparation of N-benzenesulfonyl-D, L-leucine

Dissolving D, L-leucine (2g, 15mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding benzene sulfonyl chloride (3g, 16.5mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid is dripped to adjust the PH value to 3, and dioxane is removed through decompression and concentration, and a large amount of solid is separated out; filtration was carried out, and the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain a white solid (3.7g, yield: 91%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

1H NMR(CDCl₃+D₂O)ppm：0.85(3H，d)，0.92(3H，d)，1.51-1.56(2H，m)，1.76(1H，m)，3.97(1H，m)，7.49-7.89(5H，m)。

b) Preparation of benzyl N-benzenesulfonyl-D, L-leucyl-L-proline

Dissolving N-benzenesulfonyl-D, L-leucine (2.7g, 10mmol) and benzyl L-proline (2.7g, 11mmol) in dichloromethane (50ml), under the protection of nitrogen, dropwise adding DIEA (3.1g, 24mmol) under cooling, adding HOBt (1.4g, 10mmol) and EDCI (2.6g, 14mmol) after dropwise adding, and naturally raising the temperature to room temperature for reaction for 4 h. The reaction solution was removed by concentration under reduced pressure, and purified by direct column chromatography to give a white solid (3.8g, yield: 82%).

MS：459(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.93(6H，m)，1.22-1.53(3H，m)，1.72-2.08(4H，m)，3.1-3.49(2H，m)，3.89(1H，m)，4.418-4.597(1H，m)，5.12(2H，s)，7.28-7.85(10H，m)。

c) Preparation of N-benzenesulfonyl-D, L-leucyl-L-proline

N-benzenesulfonyl-D, L-leucyl-L-proline benzyl ester (2g, 4.4mmol) was dissolved in methanol (40ml), 10% palladium on carbon (200mg) was added, and the mixture was reacted at room temperature for 3 hours with hydrogen. Filtration and concentration under reduced pressure removed the solvent to give a white foamy solid (1.6g, yield: 99%). Directly carrying out the next reaction.

MS：391(M+Na)。

d) Preparation of N-benzenesulfonyl-D, L-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

N-benzenesulfonyl-D, L-leucyl-L-proline (370mg, 1mmol), 2, 5-dichlorobenzylamine hydrochloride (176mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), and under nitrogen protection, after cooling to 0 ℃, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, followed by stirring at 0 ℃ for 20min, then naturally warmed to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (263mg, yield: 57%).

MS：526(M+H)

1H NMR(CDCl₃+D₂O)ppm:0.86-0.92(6H，t)，1.64(1H，m)，1.84(1H，m)，2.04-2.41(4H，m)，3.26(1H，m)，3.39(1H，m)，4.03(1H，m)，4.14(1H，m)，4.32-4.62(3H，m)，7.28-7.86(8H，m)。

Example 4: N-benzenesulfonyl-L-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

a) Preparation of N-benzenesulfonyl-L-leucine

Dissolving L-leucine (2g, 15mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding benzene sulfonyl chloride (3g, 16.5mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid is dripped to adjust the pH value to 3, and dioxane is removed by decompression and concentration, and a large amount of solid is separated out; filtration was carried out, and the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain a white solid (3.3g, yield: 81%).

MS：294(M+Na)。

b) Preparation of benzyl N-phenylsulfonyl-L-leucyl-L-proline

Dissolving N-benzenesulfonyl-L-leucine (2.7g, 10mmo1) and L-proline benzyl ester (2.7g, 11mmo1) in dichloromethane (50m1), dropwise adding DIEA (3.1g, 24mmo1) under the protection of nitrogen, adding HOBt (1.4g, 10mmo1) and EDCI (2.6g, 14mmo1) after dropwise adding, and naturally heating to room temperature for reacting for 4 hours. The reaction solution was removed by concentration under reduced pressure, and purified by direct column chromatography to give a white solid (3.8g, yield: 82%).

MS：459(M+H)。

c) Preparation of N-benzenesulfonyl-L-leucyl-L-proline

Benzyl N-benzenesulfonyl-L-leucyl-L-proline (1.4g, 3mmo1) was dissolved in methanol (40ml), lO% palladium on carbon (140mg) was added, and the mixture was reacted at room temperature for 3 hours with hydrogen. Filtration and concentration under reduced pressure removed the solvent to give a white foamy solid (1g, yield: 99%). Directly carrying out the next reaction.

MS：391(M+Na)。

d) Preparation of N-benzenesulfonyl-L-leucyl-L-prolyl- (2, 5-dichlorophenyl) methylamide

Dissolving N-benzenesulfonyl-L-leucyl-L-proline (370mg, 1mmo1), 2, 5-dichlorobenzylamine hydrochloride (176mg, lmmo1) and NMM (222mg, 2.2mmo1) in anhydrous dichloromethane (10ml), protecting with nitrogen, and cooling to 0. After C, HOBt (135mg, lmmo1), EDCI (230mg, 1.2mmo1) were added thereto, and the mixture was stirred at O ℃ for 20min, allowed to spontaneously warm to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (263mg, yield: 57%).

MS：526(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.93(6H，t)，1.57(1H，m)，1.78(1H，m)，1.98-2.34(4H，m)，3.19(1H，m)，3.34(1H，m)，3.89(1H，m)，4.01(1H，dd)，4.32(1H，m)，4.34-4.61(2H，m)，7.35-7.84(8H，m)。

Example 5: N-benzenesulfonyl-D-leucyl-L-prolyl- (2, 5-dichlorophenyl) amide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 2, 5-dichloroaniline (162mg, 1mmol) and NMM (111mg, 1.2mmol) were dissolved in anhydrous dichloromethane (10ml), and after cooling to 0 ℃ under nitrogen protection, a Kate condensing agent (531mg, 1.2mmol) was added, and the mixture was stirred at 0 ℃ for 20min, allowed to naturally warm to room temperature, and reacted for 24 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (163mg, yield: 32%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet and iodine

MS：512(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.97(6H，t)，1.59(1H，m)，1.75-1.92(2H，m)，1.99-2.15(3H，m)，2.59(1H，m)，3.37(1H，m)，3.79(1H，m)，4.02(1H，dd)，4.45(1H，m)，7.55-7.95(8H，m)。

Example 6: N-benzenesulfonyl-D-leucyl-L-prolyl- (2, 5-dichlorophenyl) ethylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 2, 5-dichlorophenethylamine (190mg, 1mmol) and NMM (111mg, 1.2mmol) were dissolved in anhydrous dichloromethane (10ml), and under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added thereto, followed by stirring at 0 ℃ for 20min, and then the mixture was allowed to warm to room temperature naturally for reaction for 24 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (416mg, yield: 77%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet and iodine

MS：540(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.87(3H，d)，0.91(3H，d)，1.53(1H，m)，1.82-1.91(2H，m)，2.01-2.13(3H，m)，2.41(1H，m)，3.17-3.4(3H，m)，3.63-3.96(3 H，m)，4(1 H，dd)，4.47(1 H，m)，7.19-7.84(8 H，m)。

Example 7: N-benzenesulfonyl-D-leucyl-L-prolyl- (2-amino-5-chlorophenyl) methylamide hydrochloride

a) Preparation of 2-aminomethyl-5-chloroaniline hydrochloride

2-amino-4-chlorobenzonitrile (520mg, 3.4mmol) was dissolved in methanol (20ml), and ammonia (1ml) and Raney nickel (1g) were added to react at room temperature for 3 hours. Filtering, concentrating under reduced pressure to remove solvent, adding diethyl ether (10ml) and 1N hydrochloric acid solution, and washing water phase with diethyl ether (8ml × 2); after cooling, 10% potassium carbonate solution was added dropwise to adjust pH to 9, the aqueous phase was extracted with ethyl acetate (8 ml. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an oil, and then ether (10ml) was added to dissolve it, 15% HCl/ethyl acetate solution (2ml) was added dropwise slowly, and filtered and dried to give 170mg of a white solid, which was directly subjected to the next reaction.

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution.

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- (2-amino-5-chlorophenyl) methylamide hydrochloride

N-benzenesulfonyl-D-leucyl-L-proline (466mg, 1.3mmol), 2-aminomethyl-5-chloroaniline hydrochloride (170mg, 1.1mmol) and NMM (134mg, 1.3mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, HOBt (159mg, 1.1mmol) and EDCI (253mg, 1.3mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, purified by column chromatography to give a yellow oil, dissolved with diethyl ether (2ml), added with a 15% HCl/ethyl acetate solution (1ml), added with diethyl ether (20ml), to precipitate a solid, left to stand in a refrigerator overnight, and filtered to dry to give the title product (100mg, yield: 18%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：507(M+H)。

Example 8: N-benzenesulfonyl-D-leucyl-L-prolyl- (2-aminomethyl-5-chlorophenyl) methylamide

a) Preparation of tert-butyl-4-chloro-2- (hydroxymethyl) benzylcarbamate

2-aminomethyl-5-chlorobenzyl alcohol (2.3g, 14mmol) was dissolved in dichloromethane (50ml), di-tert-butyl dicarbonate (3g, 14mmol) was slowly added dropwise with cooling, and the reaction was allowed to proceed at room temperature for 8 hours. A large amount of the solvent was removed by concentration under reduced pressure, n-hexane (30ml) was added, and filtration and drying were conducted to obtain a white solid (3.2g, yield: 84%).

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: 1 developing: ultraviolet, iodine and 1% ninhydrin solution

1H NMR(CDCl₃) ppm: 1.46 (9H, s), 4.35 (2H, s), 4.81 (2H, d), 5.51(1H, broad peak), 7.31-7.52 (3H, m).

b) Preparation of tert-butyl-4-chloro-2- (aminomethyl) benzylcarbamate

The product (3.2g, 12mmol) obtained in the above step and triethylamine (2.4g, 24mmol) were dissolved in hexyl acetate (100ml), cooled to-15 ℃, methanesulfonyl chloride (1.6g, 14mmol) was slowly added dropwise, allowed to naturally rise to room temperature for 2h, DMF (100ml) was added, sodium azide (1.7g, 27mmol) was added in portions, and allowed to react at room temperature for 48 h. Water (100ml) was added to the reaction solution, and the organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. Triethylamine (1.1g, 11mmol) and Lindla catalyst (0.6g) were added to the filtrate, and the mixture was reacted at 35 ℃ with hydrogen for 24 hours, filtered, concentrated under reduced pressure to remove most of the solvent, allowed to stand for crystallization, filtered and dried to obtain a white solid (2.3g, yield: 72%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

1H NMR(CDCl₃) ppm: 1.44 (9H, s), 4.05 (2H, s), 4.5 (2H, d), 5.97 (2H, broad peak), 7.22-7.37 (3H, m).

c) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- (2-aminomethyl-5-chlorophenyl) methylamide hydrochloride

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl-4-chloro-2- (aminomethyl) benzylcarbamate (276mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at O ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (475mg, yield: 76%).

MS：643(M+Na)

The solid obtained in the above step (450mg, 7mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/ethyl acetate solution (6ml) was added, reaction was carried out at room temperature for 2 hours, filtration was carried out, the solvent was removed by concentration under reduced pressure, dissolved in ethanol (2ml), 15% HCl/ethyl acetate solution (2ml) was added, ether (20ml) was added, the solid was precipitated, left to stand in a refrigerator overnight, and filtered and dried to obtain the title product (290mg, yield: 74%).

MS：521(M+H)

1H NMR(CDCl₃+D₂O) ppm: 0.82-0.93 (6H, t), 1.52 (1H, m), 1.74-1.86(2H, m), 1.99-2.13 (3H, m), 3.27 (1H, m), 3.48 (1H, m), 3.9 (1H, m), 4.07 (2H, broad peak), 4.35 (2H, m), 4.43 (1H, m), 7.34-7.85 (8H, m).

Example 9: N-benzenesulfonyl-D-leucyl-L-prolyl- (2-aminoethyl-5-chlorophenyl) methylamide

a) Preparation of tert-butyl-4-chloro-2- (aminomethyl) phenethylcarbamate

Tert-butyl-4-chloro-2- (hydroxymethyl) phenethylcarbamate (2.8g, 10mmol) was dissolved in tetrahydrofuran (40ml), cooled to-5 ℃, bicyclic amidine (2g, 13mmol) and diphenylphosphorylazide (3.6g, 13mmol) were slowly added, allowed to naturally warm to room temperature for 4h, and saturated sodium bicarbonate solution (50ml) and ethyl acetate (100ml) were added. The organic layer was washed with water and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by concentration under reduced pressure to give a crude product, which was purified by column chromatography to give a colorless oil (2.5g, yield: 81%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 4: 1: ultraviolet and iodine

MS：333(M+Na)

1H NMR(DMSO+D₂O)ppm：1.4(9 H，s)，2.78(2 H，t)，3.13(2 H，dr)，4.46(2 H，s)，7.27(1 H，d)，7.41(2 H，m)

The azide (2.5g, 8mmol) obtained in the above step was dissolved in tetrahydrofuran (40ml), triethylamine (900mg, 9mmol) and Lindla catalyst (0.6g) were added, and the mixture was reacted with hydrogen at 35 ℃ for 24 hours, filtered and concentrated under reduced pressure to obtain a colorless oil (1.73g, yield: 75%).

Rf 0.3 developing agent dichloromethane, methanol and triethylamine 15: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：307(M+Na)

1HNMR(DMSO+D₂O)ppm：1.44(9H，s)，2.68(2H，t)，3.11(2H，m)，3.56(2H，m)，7.12(1H，d)，7.3 1(2H，m)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- (2-aminoethyl-5-chlorophenyl) methylamide hydrochloride

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl-4-chloro-2- (aminomethyl) phenethylcarbamate (285mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to O ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (52lmg, yield: 82%).

MS：657(M+Na)

The solid obtained in the above step (500mg, 7.8mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/L ethyl acetate solution (6ml) was added, reacted at room temperature for 2 hours, filtered, concentrated under reduced pressure to remove the solvent, dissolved in ethanol (2ml), added with 15% HCl/ethyl acetate solution (2ml), added with diethyl ether (20ml), the solid was precipitated, left to stand in a refrigerator overnight, filtered and dried to obtain the title product (310mg, yield: 69%).

MS：535(M+H)。

Example 10: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-aminoethyl) -5-chlorophenyl ] methylamide

a) Preparation of tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] ethylcarbamate

Tert-butyl-1- [ 4-chloro-2- (hydroxymethyl) phenyl ] ethylcarbamate (855mg, 3mmol) was dissolved in tetrahydrofuran (20ml), cooled to-5 ℃, bicyclic amidine (608mg, 4mmol) and diphenyl azidophosphate (1.1g, 4mmol) were slowly added, allowed to naturally warm to room temperature for 12h, and saturated sodium bicarbonate solution (10ml) and ethyl acetate (20ml) were added. The organic layer was washed with water and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by concentration under reduced pressure to give a crude product, which was purified by column chromatography to give a yellow oil (660mg, yield: 71%).

MS：333(M+Na)

The azide (600mg, 2mmol) obtained in the above step was dissolved in tetrahydrofuran (10ml), triethylamine (200mg, 2mmol) and Lindla catalyst (0.2g) were added, and the reaction mixture was reacted with hydrogen at 35 ℃ for 24 hours, filtered and concentrated under reduced pressure to give a pale yellow oil (429mg, yield: 75%).

MS：307(M+Na)

1H NMR(DMSO+D₂O)ppm：1.42(9H，s)，1.68(3H，d)，3.86(1H，d)，4.02(1H，d)，5.18(1H，m)，7.23-7.35(3H，m)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-aminoethyl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] ethylcarbamate (285mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10m1), cooled to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (502mg, yield: 79%).

MS：657(M+Na)

The solid obtained in the above step (500mg, 7.9mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/ethyl acetate solution (6ml) was added, reacted at room temperature for 2 hours, filtered, concentrated under reduced pressure to remove the solvent, dissolved in ethanol (2ml), added with 15% HCl/ethyl acetate solution (2ml), added with diethyl ether (20ml) to precipitate a solid, left to stand in a refrigerator overnight, filtered and dried to obtain the title product (245mg, yield: 54%).

MS：535(M+H)。

Example 11: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-amino-2, 2, 2-trifluoroethyl) -5-chlorophenyl ] methylamide

a) Preparation of tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] -2, 2, 2-trifluoroethyl carbamate

Tert-butyl-1- [ 4-chloro-2- (hydroxymethyl) phenyl ] -2, 2, 2-trifluoroethylcarbamate (1g, 3mmol) was dissolved in tetrahydrofuran (20ml), cooled to-5 ℃, bicyclic amidine (608mg, 4mmol) and diphenyl azidophosphate (1.1g, 4mmol) were slowly added, allowed to spontaneously warm to room temperature for 4h, and saturated sodium bicarbonate solution (10ml) and ethyl acetate (20ml) were added. The organic layer was washed with water and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by concentration under reduced pressure to give a crude product, which was purified by column chromatography to give a colorless oil (712mg, yield: 64%).

Rf 0.5 developing agent petroleum ether and ethyl acetate 4: 1: ultraviolet and iodine

MS：387(M+Na)

1H NMR(CDCl₃)ppm：1.44(9H，s)，3.91(1H，d)，4.32(1H，d)，5.21(1H，s)，7.33-7.46(3H，m)

The azide (700mg, 1.9mm01) obtained in the above step was dissolved in tetrahydrofuran (10ml), and triethylamine (200mg, 2mmol) and Lindla catalyst (0.2g) were added to react with hydrogen at 35 ℃ for 12 hours, followed by filtration and concentration under reduced pressure to obtain a foamy solid (500mg, yield: 78%).

Rf 0.5 developing solvent dichloromethane methanol triethylamine 15: 1: 1, color development: ultraviolet, iodine and 1% ninhydrin solution

MS：361(M+Na)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-amino-2, 2, 2-trifluoroethyl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] -2, 2, 2-trifluoroethyl carbamate (338mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), nitrogen protected, cooled to 0 deg.C, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 deg.C for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (434mg, yield: 63%).

MS：711(M+Na)

The solid obtained in the above step (410mg, 0.6mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/ethyl acetate solution (6ml) was added, reaction was carried out at room temperature for 2 hours, filtration was carried out, the solvent was removed by concentration under reduced pressure, dissolved in ethanol (2ml), 15% HCl/ethyl acetate solution (2ml) was added, ether (20ml) was added, the solid was precipitated, left to stand overnight in a refrigerator, and filtered and dried to obtain the title product (248mg, yield: 66%).

MS：589(M+H)。

Example 12: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-amino-2, 2-difluoroethyl) -5-chlorophenyl ] methylamide

a) Preparation of tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] -2, 2-difluoroethylcarbamate

Tert-butyl-1- [ 4-chloro-2- (hydroxymethyl) phenyl ] -2, 2-difluoroethylcarbamate (1g, 3mmol) was dissolved in tetrahydrofuran (20ml), cooled to-5 ℃, bicyclic amidine (608mg, 4mmol) and diphenyl azidophosphate (1.1g, 4mmol) were slowly added, allowed to warm to room temperature for 4h, and saturated sodium bicarbonate solution (10ml) and ethyl acetate (20ml) were added. The organic layer was washed with water and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by concentration under reduced pressure to give a crude product, which was purified by column chromatography to give a colorless oil (728mg, yield: 70%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 4: 1: ultraviolet and iodine

MS：369(M+Na)

1H NMR(CDCl₃)ppm：1.46(9H，s)，3.82(1H，d)，4.36(1H，d)，5.12(1H，d)，6.25(1H，d)，7.24-7.54(3H，m)。

The azide (700mg, 2mmol) obtained in the above step was dissolved in tetrahydrofuran (10ml), triethylamine (200mg, 2mmol) and Lindla catalyst (0.2g) were added, and the mixture was reacted with hydrogen at 35 ℃ for 12 hours, filtered and concentrated under reduced pressure to obtain a foamy solid (487mg, yield: 76%).

Rf 0.4 developing agent dichloromethane, methanol and triethylamine 15: 1: l: ultraviolet, iodine and 1% ninhydrin solution

MS：343(M+Na)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-amino-2, 2-difluoroethyl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl-1- [ 4-chloro-2- (aminomethyl) phenyl ] -2, 2-difluoroethylcarbamate (320mg, 1mmol), NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), nitrogen protected, cooled to 0 deg.C, HOBt (135mg, 1mmol), EDCI (230mg, 1.2mmol) were added, stirred at 0 deg.C for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white viscous solid (389mg, yield: 58%).

MS：693(M+Na)

The solid obtained in the above step (350mg, 0.5mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/ethyl acetate solution (6ml) was added, reacted at room temperature for 2 hours, filtered, concentrated under reduced pressure to remove the solvent, dissolved in ethanol (2ml), added with 15% HCl/ethyl acetate solution (2ml), added with diethyl ether (20ml) to precipitate a solid, left to stand in a refrigerator overnight, filtered and dried to obtain the title product (182mg, yield: 60%).

MS：571(M+H)。

Example 13: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-fluoroaminomethyl) -5-chlorophenyl ] methylamide

a) Preparation of tert-butyl- [ 4-chloro-2- (aminomethyl) phenyl ] fluoromethylcarbamate

Tert-butyl- [ 4-chloro-2- (hydroxymethyl) phenyl ] fluoromethylcarbamate (870mg, 3mmol) was dissolved in tetrahydrofuran (20ml), cooled to-5 ℃, bicyclic amidine (608mg, 4mmol) and diphenyl azidophosphate (1.1g, 4mmol) were slowly added, allowed to naturally warm to room temperature for 4h, and saturated sodium bicarbonate solution (10ml) and ethyl acetate (20ml) were added. The organic layer was washed with water and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by concentration under reduced pressure to give a crude product, which was purified by column chromatography to give a colorless oil (614mg, yield: 65%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 3: 1: ultraviolet and iodine

MS：337(M+Na)

1H NMR(CDCl₃) PPm：1.44 (9H，s)，3.822(1H，d)，4.261(1H，d)，5.582(1H，d)，7.01-7.238(3H，m)

The azide (600mg, 1.9mmol) obtained in the above step was dissolved in tetrahydrofuran (10ml), and triethylamine (200mg, 2mmol) and Lindla catalyst (0.2g) were added to react with hydrogen at 35 ℃ for 12 hours, followed by filtration and concentration under reduced pressure to obtain a foamy solid (378mg, yield: 69%).

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution

MS：311(M+Na)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1-fluoroaminomethyl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), tert-butyl- [ 4-chloro-2- (aminomethyl) phenyl ] fluoromethyl carbamate (290mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white viscous solid (390mg, yield: 61%).

Rf 0.6 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet and iodine

MS：661(M+Na)

The solid obtained in the above step (320mg, 0.5mmol) was dissolved in ethyl acetate (10ml), 15% hydrochloric acid/ethyl acetate solution (6ml) was added, reacted at room temperature for 2 hours, filtered, concentrated under reduced pressure to remove the solvent, dissolved in ethanol (2ml), added with 15% HCl/ethyl acetate solution (2ml), added with ether (20ml), to precipitate a solid, left to stand in a refrigerator overnight, filtered and dried to obtain the title product (247mg, yield: 86%).

MS：539(M+H)。

Example 14: N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorophenyl) methylamide

a) Preparation of 2-hydroxy-5-chlorobenzylamine hydrochloride

2-hydroxy-5-chlorobenzaldehyde (31.4g, 200mmol), hydroxylamine hydrochloride 147g, 200mmol) and sodium acetate (16g, 200mmol) were dissolved in water/ethanol (180ml/360ml) and reacted at room temperature for 3 hours under nitrogen protection. Water (600m1) was added thereto, the mixture was stirred for 0.5 hour, and the mixture was filtered and dried to obtain a white solid (29g, yield: 84.5%). Directly carrying out the next reaction.

Rf 0.3 developing agent petroleum ether and ethyl acetate 8: 1: ultraviolet and iodine

The product (17g, 100mmo1) obtained in the above step was dissolved in methanol (30ml), and 6N hydrochloric acid solution (10ml) and 10% palladium on carbon (1.7g) were added to react at room temperature for 12 hours. Filtration and concentration under reduced pressure removed the solvent to give a white solid.

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

1H NMR(DMSO)ppm：3.81(2H，s)，6.66(1H，d)，7.02(1H，d)，7.18(1H，s)。

b) N-benzenesulfonyl-D-leucyl-L-prolyl- (2-hydroxy-5-chlorophenyl) methylamide

Dissolving N-benzenesulfonyl-D-leucyl-L-proline (2.2g, 6mmo1), 2-hydroxy-5-chlorobenzylamine hydrochloride (1.1g, 6mmo1) and NMM (1.3g, 13.2mmo1) in anhydrous dichloromethane (40ml), adding HOBt (810mg, 6mmo1) and EDCI (1.4g, 7.2mmo1) after cooling to 0 ℃, stirring at O ℃ for 20min, naturally raising the temperature to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (1.74g, yield: 57.3%)

Rf 0.15 developing agent petroleum ether and ethyl acetate 1: ultraviolet and iodine

MS：530(M+Na)。

Example 15: N-benzenesulfonyl-D-leucyl-L-prolyl- (2-methoxy-5-chlorophenyl) methylamide the product obtained in example 14 (500mg, 1mmo1) was dissolved in DMF (10ml), and cesium carbonate (325mg, 1mmo1) and iodomethane (160mg, 1.2mmo1) were added and reacted for 5 hours with exclusion of light. Adding ethyl acetate (10ml), washing the organic layer with water, 5% sodium thiosulfate solution and saturated brine solution in this order, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to give crude product, and purifying by column chromatography to give the title product (240mg, yield: 46%)

MS：522(M+I-I)。

Example 16: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (2, 2, 2-trifluoroethoxy) -5-chlorophenyl ] methylamide

The product obtained in example 14 (500mg, 1mmol) was dissolved in DMF (10ml), and cesium carbonate (325mg, 1mmol) and bromotrifluoroethane (200mg, 1.2mmol) were added to react at 40 ℃ for 24 hours. Ethyl acetate (10ml) was added, and the organic layer was washed with water, 5% sodium thiosulfate solution and saturated brine solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (194mg, yield: 33%)

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: ultraviolet and iodine

MS：590(M+H)。

Example 17: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-ethoxycarbonylmethyl) -5-chlorophenyl ] methylamide

a) Preparation of N-tert-butoxycarbonyl-2-hydroxy-5-chlorobenzylamine

2-hydroxy-5-chlorobenzylamine hydrochloride (19g, 100mmol) was dissolved in methylene chloride (500ml), DIEA (13g, 100mmol) and di-tert-butyl dicarbonate (26.1g, 120mmol) were added dropwise, and the reaction was carried out at room temperature for 8 hours. The organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an oily substance, which was purified by column chromatography to give a white solid (22.6g, yield: 88.3%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 10: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：280(M+Na)。

b) Preparation of N-tert-butoxycarbonyl-2- (O-ethoxycarbonylmethyl) -5-chlorobenzylamine

N-tert-Butoxycarbonyl-2-hydroxy-5-chlorobenzylamine (10g, 40mmol) was dissolved in dioxane (200ml), and cesium carbonate (14g, 44mmol) and ethyl bromoacetate (7.4g, 44mmol) were added and reacted at room temperature for 36 hours. The solvent was removed by concentration under reduced pressure, ethyl acetate (300ml) was added, the organic layer was washed with water and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a colorless oil (11.4g, yield: 83%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 10: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：366(M+Na)

1H NMR(CDCl₃)ppm：1.28(3 H，t)，1.46(9 H，s)，3.82(1 H，d)，4.24(2H，q)，4.44(2 H，s)，4.82(2 H，s)，6.87(1 H，d)，7.17(1 H，d)，7.33(1 H，d)。

c) Preparation of 2- (O-ethoxycarbonylmethyl) -5-chlorobenzylamine hydrochloride

The product (10g, 30mmol) obtained in the above step was dissolved in diethyl ether (100ml), and 15% HCl/ethyl acetate solution (60ml) was added to react at room temperature for 8 hours. Filtration and drying gave a white solid (8.4g, yield: 100%). Directly carrying out the next reaction.

d) N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-ethoxycarbonylmethyl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (11g, 30mmol), 2- (O-ethoxycarbonylmethyl) -5-chlorobenzylamine hydrochloride (8.4g, 30mmol) and NMM (6.67g, 66mmol) were dissolved in anhydrous dichloromethane (150ml), cooled to O ℃ under nitrogen protection, HOBt (4g, 30mmol) and EDCI (6.9g, 36mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (13.1g, yield: 74%)

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: ultraviolet and iodine

MS：594(M+H)。

Example 18: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-carboxymethyl) -5-chlorophenyl ] methylamide

The product (12g, 20mmol) obtained in example 17 was dissolved in methanol (80ml), cooled, and a 1N aqueous solution (80ml) of sodium hydroxide was added to react at room temperature for 5 hours. Concentration under reduced pressure to remove methanol, washing the aqueous layer with isopropyl ether, adjusting pH to 3 by adding dilute hydrochloric acid dropwise under cooling, extracting the aqueous layer with ethyl acetate (40 ml. times.3), washing the organic layer with 5% potassium hydrogensulfate solution, water and saturated aqueous salt solution in this order, drying over anhydrous sodium sulfate, filtering, and concentration under reduced pressure to give the titled product (9.6g, yield: 85%).

MS：588(M+Na)。

Example 19: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (O-carboxamidomethyl) -5-chlorophenyl ] methylamide

The product obtained in example 18 (566mg, 1mmol), ammonium chloride (55mg, 1mmol) and NMM (111mg, 1mmol) were dissolved in anhydrous dichloromethane (20ml), cooled to O ℃ under nitrogen, HOBt (135mg, 1mmol 1) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to naturally warm to room temperature and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (118mg, yield: 21%)

MS：565(M+H)

1HNMR(CDCl₃+D₂O)ppm：0.93(6 H，t)，1.51(1 H，m)，1.84-1.96(2 H，m)，1.98-2.12(3 H，m)，2.28(1 H，m)，3.57(1 H，m)，3.78(1 H，m)，3.99(1 H，dd)，4.42(1 H，m)，4.43(2 H，d)，4.71(2 H，s)，6.99-7.74(8 H，m)。

Example 20: N-benzenesulfonyl-D-leucyl-L-prolyl- {2- [2- (ethylamino) -2-oxoethoxy ] -5-chlorophenyl } methylamide

The product obtained in example 18 (566mg, 1mmol), ethylamine (55mg, 1mmol) and NMM (111mg, 1mmol) were dissolved in dry dichloromethane (20ml), protected with nitrogen, cooled to O ℃, and then HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at O ℃ for 20min, allowed to naturally warm to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (397mg, yield: 67%)

MS：593(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.92(3 H，d)，0.95(3 H，d)，1.22(3 H，t)，1.49(1 H，m)，1.74-1.87(2 H，m)，1.98-2.11(3 H，m)，2.27(1 H，m)，3.247(2 H，q)，3.67(1 H，m)，3.778(1 H，m)，4.04(1 H，dd)，4.43(1 H，m)，4.47(2 H，d)，4.56(2 H，m)，6.99-7.74(8 H，m)。

Example 21: N-benzenesulfonyl-D-leucyl-L-prolyl- {2- [2- (cyclopropylamino) -2-oxoethoxy ] -5-chlorophenyl } methylamide

The product obtained in example 18 (566mg, 1mmol), cyclopropylamine (59mg, 1mmol) and NMM (111mg, 1mmol) were dissolved in dry dichloromethane (20ml), cooled to 0 ℃ under nitrogen, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, and the mixture was stirred at 0 ℃ for 20min, allowed to warm to room temperature and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (326mg, yield: 54%)

Rf 0.5 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet and iodine

MS：605(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.58(2 H，m)，0.77(2 H，m)，0.93(3 H，d)，0.96(3 H，d)，1.53(1 H，m)，1.75-1.8(2 H，m)，1.99-2.05(3 H，m)，2.25(1 H，m)，2.79(1 H，m)，3.64(1 H，m)，3.76(1 H，m)，4.01(1 H，dd)，4.42(1 H，m)，4.44(2H，m)，4.58(2 H，s)，7-7.74(8 H，m)。

Example 22: N-benzenesulfonyl-D-leucyl-L-prolyl- {2- [2- (trans-4-methylcyclohexylamino) -2-oxoethoxy ] -5-chlorophenyl } methylamide

The product obtained in example 18 (566mg, 1mmol), trans-4-methylcyclohexylamine (120mg, 1mmol) and NMM (111mg, 1mmol) were dissolved in anhydrous dichloromethane (20ml), and after cooling to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, followed by stirring at 0 ℃ for 20min, followed by warming to room temperature and reaction for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (382mg, yield: 58%)

MS：661(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.77-0.84(2 H，m)，0.94(3 H，d)，0.97(3 H，d)，1.07-1.28(4 H，m)，1.53-1.65(5 H，m)，1.77-1.85(2 H，m)，2-2.08(3 H，m)，2.25-2.41(2 H，m)，3.54(1 H，m)，3.69(1 H，m)，4.01(1 H，dd)，4.42(1 H，m)，4.44(2H，m)，4.77(2H，s)，6.98-7.78(8H，m)。

Example 23: N-benzenesulfonyl-D-leucyl-L-prolyl- {2- [2- (piperidin-3-ylamino) -2-oxoethoxy ] -5-chlorophenyl } methylamide

The product obtained in example 18 (566mg, lmmol), 1-t-butoxycarbonyl-3-aminopiperidine (200mg, 1mmol) and NMM (100mg, 1mmol) were dissolved in anhydrous dichloromethane (20ml), and then HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added thereto under nitrogen protection, followed by stirring at 0 ℃ for 20min, cooling to room temperature and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and purified by column chromatography to give a white foamy solid (569mg, yield: 76%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 1: ultraviolet and iodine

MS：770(M+Na)。

The product obtained in the above step (550g, 0.73mmo1) was dissolved in ethyl acetate (10mi), and 15% HCl/ethyl acetate solution (6m1) was added to the solution to react at room temperature for 4 hours. Filtration and drying gave the title product (340mg, yield: 68%).

MS：648(M+H)。

Example 24: N-benzenesulfonyl-D-leucyl-L-prolyl- {2- [2- (benzylamino) -2-oxoethoxy ] -5-chlorophenyl) methylamide

The product obtained in example 18 (566mg, 1mmol), benzylamine (107mg, 1mm0l), NMM (111mg, lmmo1) were dissolved in anhydrous dichloromethane (20ml), and after cooling to 0 ℃ under nitrogen protection, HOBt (135mg, lmmo1) and EDCI (230mg, 1.2mmol) were added, followed by stirring at 0 ℃ for 20min, followed by warming to room temperature and reaction for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (32lmg, yield: 49%)

MS：655(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.89(3H，d)，0.95(3H，d)，1.56(1H，m)，1.79(1H，m)，1.83(1H，m)，2.04-2.16(3H，m)，2.34(1H，m)，3.44(1H，m)，3.59(1H，m)，3.89(1H，dd)，4.4(1H，m)，4.44(2H，m)，4.57(2H，m)，4.87(2H，s)，6.76-7.89(13H，m)。

Example 25: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1, 2, 3-thiadiazol-4-yl) -5-chlorophenyl ] methylamide

Dissolving N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 2- (1, 2, 3-thiadiazol-4-yl) -5-chlorobenzylamine (226mg, 1mmol) and NMM (122mg, 1.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mo0L) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (260mg, yield: 45%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：576(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.99(6H，t)，1.53(1H，m)，1.69(1H，m)，1.8(1H，m)，2.01-2.19(3H，m)，2.27(1H，m)，3.4l(1H，m)，3.56(1H，m)，3.99(1H，dd)，4.49(1H，m)，4.61(2H，m)，7.26-7.89(8H，m)，8.65(1H，s)。

Example 26: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1H-pyrazol-1-yl) -5-chlorophenyl ] methylamide

a) Preparation of 5-chloro-2- (1H-pyrazol-1-yl) benzoic acid

5-chloro-2-hydrazinobenzoic acid (1.9g, 10mmol) and 1, 1, 3, 3-tetramethoxypropane (1.6g, 10mmol) were dissolved in water (30ml), concentrated hydrochloric acid (1.1ml) was added, the mixture was heated to reflux for 4 hours, concentrated under reduced pressure to remove methanol, and the aqueous solution was added to activated carbon and stirred at room temperature for 2 hours. Filtration and concentration under reduced pressure to remove the solvent gave a crude product, which was purified by column chromatography to give a white solid (1.1g, yield: 55%).

MS：245(M+Na)

1HNMR (DMSO) ppm: 6.48(1H, t), 7.51(1H, d), 7.56-7.72(3H, m), 8.1(1H, s), 12.87(1H, broad).

b) Preparation of 5-chloro-2- (1H-pyrazol-1-yl) benzylamine hydrochloride

5-chloro-2- (1H-pyrazol-1-yl) benzoic acid (1.1g, 5mmol), ammonium chloride (550mg, 10mmol) and NMM (1.1g, 10mmol) were dissolved in DMF (40ml), and under nitrogen protection, the mixture was cooled to 0 ℃ and then HOBt (1.35g, 10mmol) and EDCI (2.3g, 12mmol) were added thereto, followed by stirring at 0 ℃ for 20min, and then the mixture was allowed to spontaneously warm to room temperature for 5 hours to react. Washing the organic layer with saturated sodium bicarbonate solution, water and saturated brine solution in order, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, purifying by column chromatography to obtain white solid (886mg, yield: 80%)

MS：222(M+H)

Dissolving the solid (886mg, 4mmol) in anhydrous tetrahydrofuran (15ml), cooling to 0 deg.C under nitrogen protection, and slowly adding 1M BH dropwise₃-THF solution (15ml), heated to reflux for 3h, cooled naturally to room temperature, 2N hydrochloric acid solution (30ml) was added slowly and heated to reflux for 0.5 h. Filtering, concentrating under reduced pressure to remove organic solvent, and washing water phase with diethyl ether (80ml × 2); after cooling, 10% potassium carbonate solution was added dropwise to adjust pH to 9, the aqueous phase was extracted with dichloromethane (80 ml. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give an oil, which was dissolved by adding ether (150ml), and 15% HCl/ethyl acetate solution (20ml) was slowly added dropwise, filtered, and dried to give a white solid (264mg, yield: 27%).

1H NMR(CDCl₃) ppm: 3.99(2H, m), 6.58(1H, t), 7.36-7.56(3H, m), 7.95(2H, m), 8.77(2H, broad).

c) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1H-pyrazol-1-yl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 5-chloro-2- (1H-pyrazol-1-yl) benzylamine hydrochloride (244mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (323mg, yield: 58%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 4: ultraviolet and iodine

MS：558(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.78(3H，d)，0.86(3H，d)，1.63(1H，m)，1.72(1H，m)，1.85(1H，m)，1.94-2.06(3H，m)，2.35(1H，m)，3.46(1H，m)，3.63(1H，m)，4.09(1H，dd)，4.29(1H，m)，4.45(2H，m)，6.56(1H，dd)，7.18-7.89(10H，m)。

Example 27: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1H-imidazol-4-yl) -5-chlorophenyl ] methylamide

a) Preparation of alpha-bromo-2-bromo-4-chloroacetophenone

Dissolving 2-bromo-4-chloroacetophenone (2.3g, 10mmol) in methanol (30ml), adding trimethyl borate (1.35g, 13mmol), reacting at room temperature for 1h, slowly adding bromine dropwise (1.5g, 10mmol), and reacting at room temperature for 2h after dropwise addition. Water (30ml) was added and the reaction was heated to reflux for 1 h. After cooling to room temperature, ethyl acetate (30ml) was added, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product which was directly subjected to the next reaction (2.65g, yield: 85%).

MS：335(M+Na)。

b) Preparation of 4- (2 '-bromo-4' -chlorophenyl) -1H-imidazole

Alpha-bromo-2-bromo-4-chloroacetophenone (1.56g, 5mmol) and formamide (4.5g, 100mmol) were mixed, heated to 145 ℃ under nitrogen protection and reacted for 12 hours. The reaction solution was cooled, ethyl acetate (50ml) was added to dissolve it, 15% potassium carbonate solution was added in portions, the organic layer was washed successively with water and saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (953mg, yield: 74%)

MS：259(M+H)。

c) Preparation of 5-chloro-2- (1-trityl-1H-imidazol-4-yl) benzylamine oxalate

4- (2 '-bromo-4' -chlorophenyl) -1H-imidazole (953mg, 3.7mmol) and triethylamine (374mg, 3.7mmol) were dissolved in DMF (15ml), cooled to 0 ℃ under nitrogen, and then triphenylchloromethane (1.1g, 3.7mmol) was slowly added dropwise, and the mixture was allowed to warm to room temperature naturally for 2 hours. Ice water (30m1) was slowly added, and the mixture was filtered and dried to obtain the crude product, which was directly subjected to the next reaction (1.68g, yield: 91%).

The product from the previous step was dissolved in DMF (15ml), copper cyanide (370mg, 4mmol) was added and the reaction was heated to 85 ℃ for 12 h. Cooling, adding toluene (30ml), slowly adding ammonium hydroxide solution (15ml) dropwise, reacting for 1h, filtering, washing organic layer with water and saturated aqueous salt solution sequentially, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude product (1.3g, yield: 86%)

The product obtained in the above step was dissolved in tetrahydrofuran (20ml), and 1M lithium aluminum hydride-THF solution (3mmol) was slowly added dropwise and reacted at room temperature for 3 hours. 1N sodium hydroxide solution (10ml) was slowly added thereto, and the reaction was carried out at room temperature for 5 hours. Filtering, and concentrating under reduced pressure to obtain crude product.

The product obtained in the above step was dissolved in tetrahydrofuran (20ml), and oxalic acid (200mg, 2.2mmol) was added to react at room temperature for 0.5 h. The reaction solution was slowly dropped into n-hexane (50ml), and filtered and dried to obtain the oxalate salt of the titled product (1.55g, two-step yield: 71%).

1HNMR (DMSO) ppm: 4.11(2H, m), 7.06-7.15(6H, m), 7.32-7.51(12H, m), 7.64(2H, s), 8.57(2H, broad).

d) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (1H-imidazol-4-yl) -5-chlorophenyl ] methylamide trifluoroacetate

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 5-chloro-2- (1-trityl-1H-imidazol-4-yl) benzylamine (450mg, 1mmol), NMM (222mg, 2.2mm01) were dissolved in anhydrous dichloromethane (10ml), nitrogen protected, cooled to 0 deg.C, HOBt (135mg, 1mmol), EDCI (230mg, 1.2mmol) were added, stirred at 0 deg.C for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a condensation product (544mg, yield: 68%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 2: 1: ultraviolet and iodine

The product (480mg, 0.6mmol) obtained in the above step was dissolved in trifluoroacetic acid (1.5ml), and triethylsilane (348mg, 3mmol) was added thereto to react at room temperature for 3 hours. Direct column chromatography purification to obtain the title product (134mg, yield: 40%)

MS：558(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.89(3H，d)，0.94(3H，d)，1.64(1H，m)，1.71(1H，m)，1.79(1H，m)，1.98-2.09(3H，m)，2.34(1H，m)，3.56(1H，m)，3.65(1H，m)，4(1H，dd)，4.39(2H，m)，4.42(1H，m)，7.16-7.83(10H，m)。

Example 28: N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzonitrile

Dissolving 2, 4-dichlorobenzonitrile (17g, 100mmol) in anhydrous DMF (250ml), adding cesium carbonate (39g, 120mmol) and 1, 2, 4-triazole (8.3g, 120mmol) under the protection of nitrogen, heating to 85 ℃ for reaction for 24h, and naturally cooling to room temperature overnight. After filtration and concentration under reduced pressure to remove DMF, methylene chloride (400ml) was added, and the organic layer was washed successively with saturated sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was recrystallized from isopropyl ether to give a white solid (11g, yield: 53%).

1H NMR(CDCl₃)ppm：7.36(1H，d)，7.49(1H，s)，7.62(1H，d)，8.28(1H，s)，8.7(1H，s)。

b) Preparation of 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine

Dissolving 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzonitrile (1g, 5mmol) in ethanol (30ml), adding ammonia water (20ml) and Raney nickel (1g), introducing hydrogen, and reacting at room temperature for 8H. Filtering, concentrating under reduced pressure to remove solvent, adding diethyl ether (30ml) and 1N hydrochloric acid solution, and washing water phase with diethyl ether (15ml × 2); after cooling, 10% potassium carbonate solution was added dropwise to adjust the pH to 9, and the aqueous phase was extracted with ethyl acetate (10 ml. times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.14g of oil, which was directly subjected to the next reaction.

Rf 0.1 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution.

c) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) benzylamine (210mg, 1mmol) and NMM (112mg, 1.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under the protection of nitrogen, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (460mg, yield: 82%).

MS：559(M+H)

¹H NMR(CDCl₃)ppm：0.71(3H，d)，0.86(3H，d)，1.24(1H，m)，1.54(1H，m)，1.71(1H，m)，1.96-2.03(3H，m)，2.32(1H，m)，3.38(1H，m)，3.65(1H，m)，3.97(1H，dd)，4.15-4.41(2H，m)，4.52(1H，m)，7.24-7.59(6H，m)，7.83(2H，d)，8.16(1H，s)，8.45(1H，s)。

Example 29: N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1H-tetrazol-1-yl) phenyl ] methylamide

a) Preparation of 5-chloro-2- (1H-tetrazole-1-yl) benzonitrile

Tetrazole (1g, 14mmO1) is dissolved in anhydrous DMF (150m1), 40% tetrabutylammonium hydroxide solution (7.8g, 12mmo1) is added, water is removed by concentration under reduced pressure, 5-chloro-2-fluorobenzonitrile (1.9g, 12mmo1) is added to the mixed solution, and the mixture reacts for 48 hours at room temperature. Filtration and concentration under reduced pressure were carried out to remove DMF, and methylene chloride (40m1) was added, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (320mg, yield: 13%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: l: ultraviolet, iodine and 1% ninhydrin solution

1H NMR(CDCl₃)ppm：7.47(1H，d)，7.56(1H，s)，7.69(1H，d)，9.28(1H，s)。

b) Preparation of 5-chloro-2- (1H-tetrazole-1-yl) benzylamine

5-chloro-2- (1H-tetrazol-1-yl) benzonitrile (226mg, 1.1mmo1) was dissolved in ethanol (10m1), and ammonia (5m1) and Raney nickel (O.5g) were added to react with hydrogen at room temperature for 8 hours. Filtering, concentrating under reduced pressure to remove solvent, adding diethyl ether (30m1) and 1N hydrochloric acid solution, and washing the water phase with diethyl ether (15ml × 2); cooling, dripping 10% potassium carbonate solution to regulate pH to 9, extracting water phase with ethyl acetate (10ml × 3), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain 5-chloro-2- (1H-tetrazole-1-yl) benzylamine, and directly carrying out the next reaction.

c) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1H-tetrazol-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 5-chloro-2- (1H-tetrazol-1-yl) benzylamine and NMM (112mg, 1.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under the protection of nitrogen, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (350mg, yield: 62%).

Rf 0.15 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：560(M+H)

¹H NMR(CDCl₃+D₂O)ppm：0.88(3H，d)，0.92(3H，d)，1.59(1H，m)，1.71-1.82(2H，m)，2.01-2.17(3H，m)，2.25(1H，m)，3.52(1H，m)，3.61(1H，m)，4.03(1H，dd)，4.44(2H，m)，4.46(1H，m)，7.19-7.85(8H，m)，9.16(1H，s)。

Example 30: N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1-methyl-1H-tetrazol-5-yl) phenyl ] methyl amide

a) Preparation of 5-chloro-2- (1-methyl-1H-tetrazole-5-yl) benzylamine hydrochloride

N-tert-Butoxycarbonyl-5-chloro-2-cyanobenzylamine (4g, 15mmol), sodium azide (5g, 75mmol) and ammonium chloride (4g, 75mmol) were dissolved in anhydrous DMF (60ml) and the reaction was carried out at 115 ℃ for 12 hours. After cooling, ethyl acetate (100ml) was added, and the organic layer was washed successively with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (3.5g, yield: 76%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution

¹H NMR(CD₃OD)ppm：1.47(9H，s)，4.46(2H，s)，7.39(1H，s)，7.52-7.69(2H，m)。

The product (2.5g, 8mmol) from the above step was dissolved in DMF (50ml), and potassium carbonate (1.4g, 10mmol) and iodomethane (1.4g, 10mmol) were added and reacted at room temperature for 2 h. Water (30ml) and dichloromethane (40ml) were added; the organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixed product, which was purified by column chromatography to give a 1-methyl-substituted product (880mg, yield: 34%).

¹H NMR(CD₃OD)ppm：1.42(9 H，s)，4.06(3 H，s)，4.21(2 H，d)，7.32-7.69(3 H，m)。

The product (800mg, 2.5mmol) obtained in the above step was dissolved in ethyl acetate (10ml), and 15% HCl/ethyl acetate solution (8ml) was added to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white viscous substance.

c) Preparation of N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1-methyl-1H-tetrazol-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 5-chloro-2- (1-methyl-1H-tetrazol-5-yl) benzylamine hydrochloride (260mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at O ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (321mg, yield: 56%).

Rf 0.25 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：574(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.89(6 H，t)，1.53(1 H，m)，1.68(1 H，m)，1.79(1 H，m)，2.01-2.2(3 H，m)，2.35(1 H，m)，3.51(1 H，m)，3.63(1 H，m)，4.01(1 H，dd)，4.11(3 H，s)，4.34(2 H，m)，4.46(1 H，m)，7.14-7.85(8 H，m)。

Example 31: N-benzenesulfonyl-D-leucyl-L-prolyl- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

a) Preparation of N-benzenesulfonyl-D-leucyl-L-homoproline benzyl ester

Dissolving N-benzenesulfonyl-D-leucine (1.4g, 5mmol) and L-homoproline benzyl ester (1.3g, 5mmol) in dichloromethane (30ml), dropwise adding DIEA (1.4g, 11mmol) under the protection of nitrogen gas, after dropwise adding, adding HOBt (675mg, 5mmol) and EDCI (1.1g, 6mmol), and naturally raising the temperature to room temperature for reaction for 4 h. The reaction mixture was concentrated under reduced pressure and purified directly by column chromatography to give a white solid (1.7g, 74%).

MS：473(M+H)。

b. Preparation of N-benzenesulfonyl-D-leucyl-L-homoproline

N-benzenesulfonyl-D-leucyl-L-homoproline benzyl ester (480mg, 1mmol) was dissolved in methanol (10ml), 10% palladium on carbon (50mg) was added, hydrogen was introduced, and the reaction was carried out at room temperature for 3 hours. Filtration and concentration under reduced pressure removed the solvent to give a white foamy solid (380mg, yield: 99%). Directly carrying out the next reaction.

c) Preparation of N-benzenesulfonyl-D-leucyl-L-high prolyl- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucyl-L-homoproline (380mg, 1mmol), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (210mg, 1mmol) and NMM (112mg, 1.2mmol) in anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at O ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (470mg, yield: 82%).

MS：573(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.95(6 H，t)，1.49-1.61(5 H，m)，1.72-1.93(4H，m)，3.54(2 H，m)，3.91(1 H，dd)，4.31(1 H，t)，4.48(2 H，m)，7.14-7.85(8 H，m)，8.28(1 H，s)，8.73(1 H，s)。

Example 32: N-benzenesulfonyl-D-leucyl- (S) -azetidine-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of benzyl N-benzenesulfonyl-D-leucyl- (S) -azetidine-2-carboxylate

N-benzenesulfonyl-D-leucine (1.4g, 5mmol), (S) -azetidine-2-carboxylic acid benzyl ester hydrochloride (1g, 5mmol) was dissolved in dichloromethane (30ml), under nitrogen, DIEA (1.4g, 11mmol) was added dropwise with cooling, after addition, HOBt (675mg, 5mmol) and EDCI (1.1g, 6mmol) were added, and the mixture was allowed to warm to room temperature and allowed to react for 4 h. The reaction mixture was concentrated under reduced pressure and purified directly by column chromatography to give a white solid (1.5g, 69%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 2: 1: ultraviolet, iodine and 1% ninhydrin solution

MS：445(M+H)。

b) Preparation of N-benzenesulfonyl-D-leucyl- (S) -azetidine-2-carboxylic acid

Benzyl N-benzenesulfonyl-leucyl- (S) -azetidine-2-carboxylate (444mg, 1mmol) was dissolved in methanol (10ml), 10% palladium on carbon (50mg) was added, hydrogen was introduced, and the reaction was allowed to proceed at room temperature for 3 hours. Filtration and concentration under reduced pressure removed the solvent to give a white foamy solid (350mg, yield: 99%). Directly carrying out the next reaction.

c) Preparation of N-benzenesulfonyl-D-leucyl- (S) -azetidine-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucyl- (S) -azetidine-2-carboxylic acid (350mg, 1mmol), 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) benzylamine (210mg, 1mmol) and NMM (112mg, 1.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with saturated sodium bicarbonate solution, water and saturated brine solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (331mg, 61%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet, iodine and 1% ninhydrin solution

MS：545(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.83(3 H，d)，0.95(3 H，d)，1.54(1 H，m)，1.62(1 H，m)，1.75(1 H，m)，2.26(1 H，m)，2.59(1 H，m)，3.99(1 H，dd)，4.2-4.36(4H，m)，4.43(1 H，m)，7.44-7.85(8 H，m)，8.36(1 H，s)，8.71(1 H，s)。

Example 33: N-benzenesulfonyl-D-leucyl-L- (R-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of L- (R-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (R-4-fluoro) proline (466mg, 2mmo1), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (420mg, 2mmo1) and NMM (242mg, 2.4mmol) in anhydrous dichloromethane (10ml), protecting with nitrogen, cooling to 0 ℃, adding HOBt (270mg, 2mmo1) and EDCI (460g, 2.4mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (685mg, yield: 81%).

MS：446(M+Na)。

The product (420mg, 1mmol) from the above step was dissolved in ethyl acetate (5m1), and 15% HCl/ethyl acetate solution (4ml) was added to the solution to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white viscous substance. Directly carrying out the next reaction.

1HNMR(CD₃OD)ppm：2.17(1H，m)，2.69(1H，m)，3.59-3.72(2H，m)，4.33-4.45(2H，m)，4.56(1H，m)，7.54-7.59(2H，m)，7.67(1H，d)，8.57(1H，s)，9.27(1H，s)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (R-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, 1mmol), L- (R-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (346mg, yield: 60%).

Rf 0.35 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：577(M+H)

1HNMR(CD₃OD)ppm：0.92(6H，t)，1.61(1H，m)，1.66-1.81(2H，m)，2.11(1H，m)，2.56(1H，m)，3.83-4.01(2H，m)，4.16-4.31(2H，m)，4.42-4.48(2H，m)，4.64(1H，m)，7.34-7.85(8H，m)，8.23(1H，s)，8.79(1H，s)。

Example 34: N-benzenesulfonyl-D-leucyl-L- (S-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of L- (S-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (S-4-fluoro) proline (466mg, 2mmol), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (420mg, 2mmol) and NMM (242mg, 2.4mmol) with anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (270mg, 2mmol) and EDCI (460g, 2.4mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, and purified by column chromatography to give a white foamy solid (651mg, yield: 77%).

MS：446(M+Na)。

The product (420mg, 1mmol) obtained in the above step was dissolved in ethyl acetate (5ml), and 15% HCl/ethyl acetate solution (4ml) was added to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white viscous substance. Directly carrying out the next reaction.

1H NMR(CD₃OD)ppm：2.45(1H，m)，2.69(1H，m)，3.51(1H，m)，3.7(1H，m)，4.33(2H，s)，4.47(1H，m)，5.4(1H，m)，7.5 1-7.63(3H，m)，8.54(1H，s)，9.29(1H，s)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (S-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, 1mmol), L- (S-4-fluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (274mg, yield: 47%).

MS：577(M+H)

1H NMR(CD₃OD)ppm：0.86(3H，d)，0.92(3H，d)，1.64(1H，m)，1.68-1.83(2H，m)，2.04(1H，m)，2.33-2.62(2H，m)，3.86(1H，m)，4.06-4.21(2H，m)，4.3-4.38(2H，m)，4.55(1H，m)，7.48-7.86(8H，m)，8.35(1H，s)，8.93(1H，s)。

Example 35: N-benzenesulfonyl-D-leucyl-L- (4, 4-difluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

a) Preparation of L- (4, 4-difluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (4, 4-difluoro) proline (500mg, 2mmol), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (420mg, 2mmol) and NMM (242mg, 2.4mmol) with anhydrous dichloromethane (10ml), adding HOBt (270mg, 2mmol) and EDCI (460g, 2.4mmol) after cooling to 0 ℃, stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (777mg, yield: 88%).

MS：464(M+Na)。

The product (450mg, 1mmol) obtained in the above step was dissolved in ethyl acetate (5ml), and 15% HCl/ethyl acetate solution (4ml) was added to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white viscous substance. Directly carrying out the next reaction.

1H NMR(CD₃OD)ppm：2.55(1H，m)，3.01(1H，m)，3.79(2H，m)，4.43(2H，m)，4.63(1H，m)，7.54-7.58(2H，m)，7.7(1H，m)，8.57(1H，s)，9.27(1H，s)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (4, 4-difluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, 1mmol), L- (4, 4-difluoro) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (298mg, yield: 50%).

MS：595(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.91(6H，t)，1.55(1H，m)，1.64(1H，m)，1.77(1H，m)，2.43(1H，m)，2.75(1H，m)，4.01(1H，dd)，4.16-4.3(3H，m)，4.42(1H，m)，4.66(1H，m)，7.44-7.83(8H，m)，8.21(1H，s)，8.78(1H，s)。

Example 36: N-benzenesulfonyl-D-leucyl-L- (S-4-amino) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

a) Preparation of L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (S-4-azido) proline (512mg, 2mmol), 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) benzylamine (420mg, 2mmol) and NMM (242mg, 2.4mmol) with anhydrous dichloromethane (10ml), adding HOBt (270mg, 2mmol) and EDCI (460g, 2.4mmol) after cooling to 0 ℃, stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (669mg, yield: 75%).

MS：447(M+H)、469(M+Na)。

The product (450mg, 1mmol) from the above step was dissolved in ethyl acetate (5ml), and 15% HCl/ethyl acetate solution (4ml) was added to react at 0 ℃ for 2 h. Filtration and drying gave a white solid. Directly carrying out the next reaction.

MS：347(M+H)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, 1mmol), L- (S-4-azido) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), protecting with nitrogen, cooling to 0 ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (421mg, yield: 70%).

MS：600(M+H)。

c) Preparation of N-benzenesulfonyl-D-leucyl-L- (S-4-amino) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

The product (360mg, 0.6mmol) obtained in the above step was dissolved in anhydrous tetrahydrofuran (10ml), and triphenylphosphine (210mg, 0.77mm01) and water (1ml) were added to the solution, and the mixture was heated to 60 ℃ to react for 5 hours. Filtration and concentration under reduced pressure gave a crude product, which was purified by column chromatography to give the title product (204mg, yield: 59%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: 4: ultraviolet and iodine

MS：574(M+H)。

Example 37: N-benzenesulfonyl-D-leucyl-L- (R-3-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

a) Preparation of L- (R-3-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (R-3-methyl) proline (460mg, 2mmol), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (420mg, 2mmol) and NMM (242mg, 2.4mmol) with anhydrous dichloromethane (10ml), adding HOBt (270mg, 2mmol) and EDCI (460g, 2.4mmol) after cooling to 0 ℃, stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (706mg, yield: 84%).

MS：420(M+H)

1H NMR(CDCl₃)ppm：1.04(3H，d)，1.55(9H，s)，1.62(1H，m)，1.97(1H，m)，2.43(1H，m)，3.36(1H，m)，3.65(1H，m)，4.11(1H，d)，4.12-4.3(2H，m)，7.44-7.78(3H，m)，8.3(1H，s)，8.79(1H，s)。

The product (422mg, 1mmol) obtained in the above step was dissolved in ethyl acetate (5ml), and 15% HCl/ethyl acetate solution (4ml) was added to the solution to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white viscous substance. Directly carrying out the next reaction.

MS：320(M+H)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (R-3-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, 1mmol), L- (R-3-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (315mg, yield: 55%).

Rf 0.4 developing agent petroleum ether and ethyl acetate 1: 3: ultraviolet and iodine

MS：573(M+H)

1H NMR(CDCl₃)ppm：0.87(3H，d)，0.91(3H，d)，1.06(3H，d)，1.62-1.85(4H，m)，2.06(1H，m)，2.43(1H，m)，3.48(1H，m)，3.96(1H，m)，4.09(1H，dd)，4.2(1H，d)，4.34(2H，m)，7.48-7.89(8H，m)，8.55(1H，s)，9.13(1H，s)。

Example 38: N-benzenesulfonyl-D-leucyl-L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L- (5-methyl) proline (460mg, 2mmo1), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (420mg, 2mmo1) and NMM (242mg, 2.4mmo1) in anhydrous dichloromethane (10ml), protecting with nitrogen, cooling to O ℃, adding HOBt (270mg, 2mmo1) and EDCI (460g, 2.4mmo1), stirring at O ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (665mg, yield: 79%).

MS：420(M+H)。

The product from the above step (422mg, lmmo1) was dissolved in ethyl acetate (5m1), and 15% HCl/ethyl acetate solution (4m1) was added and reacted at room temperature for 2 h. Filtering, and concentrating under reduced pressure to obtain a pale yellow viscous substance. Directly carrying out the next reaction.

MS：320(M+H)

1H NMR(CD₃OD)ppm：1.41(3H，d)，1.65(1H，m)，1.96(1H，m)，2.23(1H，m)，2.39(1H，m)，3.72(1H，m)，4.3(1H，m)，4.45(2H，m)，7.54-7.59(2H，m)，7.66(1H，d)，8.6(1H，s)，9.39(1H，s)。

b) Preparation of N-benzenesulfonyl-D-leucyl-L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzenesulfonyl-D-leucine (270mg, lmmo1), L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), protecting with nitrogen, cooling to 0 ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (349mg, yield: 61%).

MS：573(M+H)。

Example 39: N-benzylsulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-L-proline (11.5g, 50mmol), 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) benzylamine (10.5g, 50mmol) and NMM (6g, 1.2mmol) in anhydrous dichloromethane (200ml), cooling to 0 ℃, adding HOBt (6.75g, 50mmol) and EDCI (9.6g, 60mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (16.6g, yield: 82%).

MS：428(M+Na)

1H NMR(CDCl₃)ppm：1.46(9 H，s)，1.62(1H，m)，1.66-1.77(2H，m)，2.03(1H，m)，3.35(1H，m)，3.59(1H，m)，4.14(1H，d)，4.28-4.39(2H，m)，7.41-7.78(3H，m)，8.36(1H，s)，8.85(1H，s)。

The product (12g, 30mmol) from the above step was dissolved in ethyl acetate (60ml), and 15% HCl/ethyl acetate solution (40ml) was added to react at room temperature for 2 h. Filtering, and concentrating under reduced pressure to obtain white foam. Directly carrying out the next reaction.

MS：306(M+H)。

b) Preparation of N-benzylsulfonyl-D-leucine

Dissolving D-leucine (2g, 15mmol) in 1.5N sodium hydroxide solution (20ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding benzylsulfonyl chloride (3.2g, 15mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid is dripped to adjust the pH value to 3, and dioxane is removed by decompression and concentration, and a large amount of solid is separated out; filtration was carried out, and the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain a white solid (3.2g, yield: 74.8%). .

Rf 0.8 developing agent n-butanol, water, acetic acid and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

MS：308(M+Na)。

c) Preparation of N-benzylsulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzylsulfonyl-D-leucine (285mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (338mg, yield: 59%).

MS：573(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.85-0.89(6 H，t)，1.26-1.36(2 H，m)，1.45(1H，m)，1.96-2.07(3 H，m)，2.35(1 H，m)，3.27(1 H，m)，3.56(1 H，m)，3.83(1 H，dd)，4.1(2 H，m)，4.45(2 H，m)，4.53(2 H，m)，7.27-7.79(8 H，m)，8.48(1 H，s)，8.81(1 H，s)。

Example 40: N-methanesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-methanesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding methane sulfonyl chloride (1.37g, 12mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. After cooling, diluted hydrochloric acid was added dropwise to adjust pH to 3, and then dioxane was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate (20 ml. times.3), the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2g of a crude product, which was purified by column chromatography to give a colorless oily substance (1.4g, yield: 66.9%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution

MS：232(M+Na)。

b) Preparation of N-methanesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-methanesulfonyl-D-leucine (210mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at O ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (348mg, yield: 70%).

MS：497(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.96-0.99(6 H，d)，1.35(1 H，m)，1.56(1 H，m)，1.86(1 H，m)，2.01-2.1(3 H，m)，2.33(1 H，m)，2.87(3 H，s)，3.45(1 H，m)，3.83(1 H，m)，4.14(1 H，dd)，4.43(2 H，d)，4.56(1 H，m)，7.36-7.73(8 H，m)，8.58(1 H，s)，8.9(1 H，s)。

Example 41: N-ethanesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-ethanesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mm01) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding ethanesulfonyl chloride (1.3g, 11mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.5g of a crude product, which was purified by column chromatography to give a colorless oily substance (1.17g, yield: 47%).

Rf 0.2 developing agent petroleum ether and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

MS：246(M+Na)。

b) Preparation of N-ethanesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-ethanesulfonyl-D-leucine (230mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mm01), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (347mg, yield: 68%).

MS：511(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.97(6 H，d)，1.24(3 H，t)，1.34(1 H，m)，1.57(1 H，m)，1.85(1 H，m)，1.96-2.11(3 H，m)，2.23(1 H，m)，2.93(2 H，q)，3.44(1 H，m)，3.81(1 H，m)，4.11(1 H，dd)，4.39(2 H，m)，4.55(1 H，m)，7.27-7.8(8H，m)，8.57(1 H，s)，8.77(1 H，s)。

Example 42: n, N-dimethylaminosulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N, N-dimethylaminosulfonyl-D-leucine

Dissolving D-leucine (1.44g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding N, N-dimethylamino sulfonyl chloride (1.4g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid was added dropwise to adjust the pH to 3, and the mixture was concentrated under reduced pressure to remove dioxane, and the aqueous phase was extracted with ethyl acetate (20 ml. times.3). The organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 1.5g of crude product, and purified by column chromatography to give a colorless oily substance (1g, yield: 43.6%)

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 4: ultraviolet, iodine and 1% ninhydrin solution

MS：261(M+Na)。

b) Preparation of N, N-dimethylaminosulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving N, N-dimethylaminosulfonyl-D-leucine (240mg, 1mmo1), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10m1), cooling to 0 ℃ under the protection of nitrogen, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (290mg, yield: 55%).

MS：526(M+H)

1HNMR(CDCl₃+D₂O)ppm：0.94-0.97(6H，d)，1.28(1H，m)，1.56(1H，m)，1.85(1H，m)，2-2.07(3H，m)，2.36(1H，m)，2.73(6H，s)，3.43(1H，m)，3.7(1H，m)，4(1H，dd)，4.43(2H，d)，4.58(1H，d)，7.26-7.8(8H，m)，8.57(1H，s)，8.77(1H，s)。

Example 43: n- (tert-butyloxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

Dissolving N-Boc-leucine (4.6g, 20mmo1), L-prolyl-2- [ 5-chloro-2- (1H-L, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (6.8g, 20mmo1) and NMM (4.45g, 44mmol) in anhydrous dichloromethane (10m1), cooling to O ℃, adding HOBt (2.7g, 20mmol) and EDCI (4.6g, 24mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a 5% potassium hydrogensulfate solution, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white foamy solid (8.7g, yield: 84%).

MS：541(M+Na)。

The product obtained in the above step (8.3g, 16mmol) was dissolved in ethyl acetate (60m1), and 15% HCl/ethyl acetate solution (40ml) was added to the solution to react at room temperature for 2 hours. Filtering, and concentrating under reduced pressure to obtain white foam. Directly carrying out the next reaction.

MS：419(M+H)。

b) Preparation of N- (tert-butoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl]Methylamide hydrochloride (1.3g, 3mmol) was dissolved in DMF (10m1), DIEA (388mg, 3mmol) was added and tert-butyl bromoacetate (702mg, 3.6mmol) was slowly added dropwise and reacted at 40 ℃ for 24 h. Concentrating under reduced pressure to remove a large amount of solvent, adding ethyl acetate (30m1), and mixing the organic phase with saturated sodium bicarbonate solution and 5% KHSO₄The solution, water and saturated brine were washed in this order, dried over anhydrous sodium sulfate, the filtrate was concentrated to give a crude product, which was purified by column chromatography to give the title product (1.17g, yield: 73%).

MS：533(M+H)

1HNMR(CDCl₃+D₂O)ppm：0.89-0.92(6H，t)，1.46(9H，s)，1.51-1.56(2H，m)，1.74(1H，m)，1.84-2.07(3H，m)，2.39(1H，m)，3.26(2H，m)，3.37(1H，m)，3.6(1H，m)，3.91(1H，m)，4.33(1H，m)，4.58(2H，m)，7.26-7.85(8H，m)，8.56(1H，s)，8.87(1H，s)。

Example 44: N-carboxymethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

The product (533mg, 1mmol) from example 43 was dissolved in ethyl acetate (8m1), and 15% HCl/ethyl acetate solution (6ml) was added to the solution to react at room temperature for 2 hours. Filtration and concentration under reduced pressure gave the titled product (390mg, yield: 76%).

MS：499(M+Na)。

Example 45: N-carboxyethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N- (tert-butoxycarbonyl) ethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl]Methylamide hydrochloride (1.3g, 3mmol) was dissolved in DMF (10ml), DIEA (388mg, 3mmol) was added, tert-butyl 3-bromopropionate (433mg, 3.6mmol) was slowly added dropwise and the reaction was carried out at 40 ℃ for 24 h. Concentrating under reduced pressure to remove a large amount of solvent, adding ethyl acetate (30ml), and mixing the organic phase with saturated sodium bicarbonate solution and 5% KHSO₄The solution, water and saturated brine were washed in this order, dried over anhydrous sodium sulfate, the filtrate was concentrated to give a crude product, which was purified by column chromatography to give a white foamy solid (689mg, yield: 42%).

MS：569(M+Na)

1H NMR(CDCl₃+D₂O)ppm：0.9-0.94(6H，t)，1.44(9H，s)，1.56(1H，m)，1.64(1H，m)，1.78(1H，m)，1.8-2.1(3H，m)，2.39-2.44(3H，m)，3.13(2H，m)，3.47(1H，m)，3.67(1H，m)，3.96(1H，m)，4.36(1H，m)，4.63(2H，m)，7.25-7.89(8H，m)，8.64(1H，s)，8.97(1H，s)。

b) Preparation of N-carboxyethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride

The product (547mg, 1mmol) obtained in the above step was dissolved in ethyl acetate (8ml), and 15% HCl/ethyl acetate solution (6ml) was added to the solution to react at room temperature for 2 hours. Filtration and concentration under reduced pressure gave the titled product (246mg, yield: 50%).

MS：513(M+Na)。

Example 46: n- (ethoxycarbonyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl]Methylamide hydrochloride (1.3g, 3mmol) was dissolved in DMF (10ml), DIEA (388mg, 3mmol) was added and bromoethyl acetate was slowly added dropwiseEthyl acid (600mg, 3.6mmol) was reacted at 40 ℃ for 24 h. Concentrating under reduced pressure to remove a large amount of solvent, adding ethyl acetate (30ml), and mixing the organic phase with saturated sodium bicarbonate solution and 5% KHSO₄The solution, water and saturated brine were washed in this order, dried over anhydrous sodium sulfate, the filtrate was concentrated to give a crude product, which was purified by column chromatography to give the title product (1g, yield: 66%).

MS：505(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.86(3H，d)，0.9(3H，d)，1.33(3H，t)，1.55-1.69(2H，m)，1.81(1H，m)，2.01-2.11(3H，m)，2.34(1H，m)，3.51-3.62(3H，m)，3.73(1H，m)，3.98(1H，m)，4.28(2H，q)，4.4(1H，m)，4.64(2H，m)，7.19-7.8(8H，m)，8.39(1H，s)，8.75(1H，s)。

Example 47: n- (tert-butyloxycarbonyl) methyl-N-methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

The product (533mg, 1mmol) obtained in example 43 was dissolved in dichloromethane (10ml), DIEA (130mg, 1mmol) was added, methyl iodide (170mg, 1.2mmol) was slowly added dropwise, and the reaction was carried out at 40 ℃ for 24 hours. The organic phase was treated with saturated sodium bicarbonate solution, 5% KHSO₄The solution, water and saturated brine were washed successively, dried over anhydrous sodium sulfate, the filtrate was concentrated to give a crude product, which was purified by column chromatography to give the title product (229mg, yield: 42%).

MS：547(M+H)。

Example 48: n- (carbamoyl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

The product obtained in example 44 (190mg, 0.4mmol), ammonium chloride (22mg, 0.4mmol) and NMM (44mg, 0.4mmol) were dissolved in dry dichloromethane (10ml), and after cooling to 0 ℃ under nitrogen, HOBt (55mg, 0.4mmol) and EDCI (90mg, 0.48mmol) were added, followed by stirring at 0 ℃ for 20min, cooling to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (50mg, yield: 26%)

MS：476(M+H)。

Example 49: N-cyclohexylmethyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-L-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) was dissolved in tetrahydrofuran (10ml), DIEA (129mg, 1mmol), cyclohexylformaldehyde (135mg, 1.2mmol) and sodium triacetoxyborohydride (297mg, 1.4mmol) were added, and the mixture was reacted at room temperature for 16 hours. Water (10ml) was added thereto, the mixture was stirred for 1 hour, the solvent was concentrated under reduced pressure, and column chromatography was performed to purify the title product (267mg, yield: 52%).

MS：515(M+H)

Example 50: N-benzyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) was dissolved in tetrahydrofuran (10ml), DIEA (129mg, 1mmol), benzaldehyde (179mg, 1.2mmol) and sodium triacetoxyborohydride (297mg, 1.4mmol) were added, and the mixture was reacted at room temperature for 12 hours. Water (10ml) was added, stirred for 1h, the solvent was concentrated under reduced pressure, and purified by column chromatography to give the title product (330mg, yield: 65%).

MS：509(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.88-0.91(6H，t)，1.54(1H，m)，1.69(1H，m)，1.74(1H，m)，1.97-2.09(3H，m)，2.35(1H，m)，3.56(1H，m)，3.7-3.85(3H，m)，4.01(1H，m)，4.4(1H，m)，4.6(2H，m)，7.15-7.67(8H，m)，8.49(1H，s)，8.77(1H，s)。

Example 51: n- (pyridin-2-yl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) was dissolved in tetrahydrofuran (10ml), DIEA (129mg, 1mmol), 2-pyridinecarboxaldehyde (128mg, 1.2mmol) and sodium triacetoxyborohydride (297mg, 1.4mmol) were added, and the mixture was reacted at room temperature for 16 hours. Water (10ml) was added, stirred for 1h, the solvent was concentrated under reduced pressure, and purified by column chromatography to give the title product (311mg, yield: 61%).

MS：510(M+H)。

Example 52: n- (5-methylthiophen-2-yl) methyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) was dissolved in tetrahydrofuran (10ml), DIEA (129mg, 1mmol), 5-methyl-2-thiophenecarboxaldehyde (150mg, 1.2mmol) and sodium triacetoxyborohydride (297mg, 1.4mmol) were added, and the mixture was reacted at room temperature for 16 hours. Water (10ml) was added, stirred for 1h, the solvent was concentrated under reduced pressure, and purified by column chromatography to give the title product (327mg, yield: 62%).

MS：529(M+H)。

Example 53: N-acetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-acetyl-D-leucine (173mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (382mg, yield: 83%).

MS：461(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.93-0.97(6H，t)，1.49(1H，m)，1.59(1H，m)，1.66(3H，s)，1.68(1H，m)，1.94-2.09(3H，m)，2.29(1H，m)，3.49(1H，m)，4.05(1H，m)，4.29(1H，m)，4.46(1H，dd)，4.59(2H，q)，7.36-7.71(3H，m)，8.26(1H，s)，8.64(1H，s)。

Example 54: N-difluoroacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

a) Preparation of N-difluoroacetyl-D-leucine

Dissolving D-leucine (1.4g, 11mmo1) in 1.5N sodium hydroxide solution (10m1), adding dioxane (10m1), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding difluoroacetyl chloride (1.4g, 12mmo1) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting for 2 hours at the temperature of O, and naturally heating to room temperature for reacting for 2 hours. After cooling, diluted hydrochloric acid was added dropwise to adjust pH to 3, and then dioxane was removed by concentration under reduced pressure, the aqueous phase was extracted with ethyl acetate (20 ml. times.3), the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2g of crude product, which was purified by column chromatography to give a colorless oily substance (1.2g, yield: 54%).

Rf 0.3 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution

MS：232(M+Na)。

b) Preparation of N-difluoroacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-difluoroacetyl-D-leucine (210mg, 1mmo1), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, lmmo1) and NMM (222mg, 2.2mmo1) in anhydrous dichloromethane (10m1), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, lmmo1) and EDCI (230mg, 1.2mmo1), stirring at O ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (233mg, yield: 47%).

MS：497(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.94-0.99(6H，d)，1.45(1H，m)，1.56(1H，m)，1.72(1H，m)，2-2.13(3H，m)，2.31(1H，m)，3.51(1H，m)，3.91(1H，m)，4.24(1H，dd)，4.38(1H，d)，4.59(2H，m)，6.02(1H，s)，7.22-7.69(3H，m)，8.3(1H，s)，8.73(1H，s)。

Example 55: N-benzoyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of N-benzoyl-D-leucine

Dissolving D-leucine (2g, 15mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding benzoyl chloride (2.3g, 16.5mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil (2.5g, yield: 71%).

Rf 0.9 developing agent n-butanol, water, acetic acid and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

MS：258(M+Na)。

b) Preparation of N-benzoyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-benzoyl-D-leucine (235mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (387mg, yield: 74%).

MS：523(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.99(3H，d)，1.01(3H，d)，1.59(1H，m)，1.77(2H，m)，2.04-2.11(3H，m)，2.33(1H，m)，3.56(1H，m)，4.12(1H，m)，4.31(1H，dd)，4.6(2H，m)，4.71(1H，m)，7.13-7.83(8H，m)，8.25(1H，s)，8.76(1H，s)。

Example 56: N-phenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of N-phenylacetyl-D-leucine

Dissolving D-leucine (2g, 15mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding phenylacetyl chloride (2.4g, 16mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a colorless oil (2.7g, yield: 72%).

MS：272(M+Na)。

b) Preparation of N-phenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-phenylacetyl-D-leucine (250mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (403mg, yield: 75%).

MS：537(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.88-0.9(6 H，t)，1.46(3 H，m)，1.98-2.01(3H，m)，2.34(1 H，m)，3.2-3.33(2 H，m)，3.44(1 H，m)，3.98(1 H，m)，4.31(1 H，m)，4.43(2 H，m)，4.61(1H，m)，7.1-7.82(8 H，m)，8.29(1 H，s)，8.77(1 H，s)。

Example 57: N-phenylalanyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Phenylpropionic acid (150mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) are dissolved in anhydrous dichloromethane (10ml), protected by nitrogen, cooled to 0 ℃, added with HOBt (135mg, 1mmol) and EDCI (230mg, 1L2mmol), stirred at O ℃ for 20min, naturally warmed to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (440mg, yield: 80%).

MS：551(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.86-0.91(6 H，t)，1.49-1.63(3 H，m)，2-2.11(3 H，m)，2.36(1 H，m)，2.83(2 H，m)，3.25(2 H，t)，3.45(1 H，m)，3.99(1H，m)，4.36(1 H，dd)，4.46(2 H，m)，4.59(1H，m)，7.2-7.82(8 H，m)，8.26(1H，s)，8.84(1H，s)。

Example 58: n- (3-amino-3-phenyl) propionyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

Dissolving 3-Boc-amino-3-phenylpropionic acid (265mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at O ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (573mg, yield: 86%).

MS：666(M+H)

The product (400mg, 0.6mmol) obtained in the above step was dissolved in ethyl acetate (8ml), and 15% HCl/ethyl acetate solution (6ml) was added to react at room temperature for 2 hours. Filtration and concentration under reduced pressure gave the title product (285mg, yield: 79%).

MS：566(M+H)。

Example 59: N-p-methoxyphenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

P-methoxyphenylacetic acid (166mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (455mg, 1mmol), and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), and under nitrogen protection, after cooling to 0 deg.C, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 deg.C for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (374mg, yield: 66%).

MS：567(M+H)

1H NMR(CDCl₃)ppm：0.9-0.93(6 H，q)，1.5(2 H，m)，1.56(1 H，m)，1.97-2.07(3 H，m)，2.33(1 H，m)，3.18-3.32(2 H，q)，3.77(3 H，s)，4.02(1 H，m)，4.28(1 H，m)，4.44(2 H，m)，4.63(1 H，m)，5.87(1 H，d)，6.8-7.62(8 H，m)，8.11(1H，s)，8.67(1 H，s)。

Example 60: N-p-bromophenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

P-bromophenylacetic acid (218mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), protected with nitrogen, cooled to 0 ℃, added with HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirred at 0 ℃ for 20min, naturally warmed to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (376mg, yield: 61%).

MS：617(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.89(3 H，d)，0.91(3 H，d)，1.5(1 H，m)，1.57-1.63(2 H，m)，1.96-2.1(3 H，m)，2.26(1 H，m)，2.92-3.14(2 H，q)，3.36(1 H，t)，3.46(1 H，t)，4.14(1 H，dd)，4.48(2 H，m)，4.55-4.61(1 H，dd)，6.82-7.64(8H，m)，8.19(1 H，s)，8.71(1 H，s)。

Example 61: N-p-acetamido-phenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

P-acetaminophenylacetic acid (200mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10m1), nitrogen was used for protection, after cooling to O ℃, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at O ℃ for 20min, naturally warmed to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (255mg, yield: 43%).

MS：594(M+H)

1HNMR(CDCl₃+D₂O)ppm：0.88(3H，d)，0.92(3H，d)，1.55(1H，m)，1.52-1.64(2H，m)，1.94-2.04(3H，m)，2.23(1H，m)，2.42(3H，s)，3.33(1H，t)，3.4(1H，t)，4.05(1H，dd)，4.46(2H，m)，4.58(1H，dd)，6.9-7.59(8H，m)，8.18(1H，s)，8.7(1H，s)。

Example 62: N-m-methoxyphenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

M-methoxyphenylacetic acid (166mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (455mg, 1mmol), and NMM (222mg, 2.2mmol 1) were dissolved in anhydrous dichloromethane (10ml), and under nitrogen protection, after cooling to 0 ℃, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (306mg, yield: 54%).

MS：567(M+H)

1HNMR(CDCl₃+D₂O)ppm：0.9(3H，d)，0.92(3H，d)，1.46-1.56(3H，m)，1.98-2.06(3H，m)，2.35(1H，m)，2.84(3H，s)，3.25(1H，m)，3.42(1H，m)，3.74(2H，s)，4.01(1H，m)，4.4(2H，m)，4.61(1H，dd)，6.67-7.83(8H，m)，8.2(1H，s)，8.75(1H，s)。

Example 63: n-3, 4-dimethoxyphenylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

Dissolving 3, 4-dimethoxyphenylacetic acid (200mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (388mg, yield: 65%).

MS：597(M+H)。

Example 64: N-cyclopentylacetyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Cyclopentylacetic acid (130mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (455mg, 1mmol), NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), nitrogen protected, cooled to 0 deg.C, HOBt (135mg, 1mmol), EDCI (230mg, 1.2mmol) were added, stirred at 0 deg.C for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (386mg, yield: 73%).

MS：529(M+H)。

Example 65: n- (1-methylpiperidin-4-yl) formyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving 1-methylpiperidine-4-carboxylic acid (143mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mm01) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally cooling to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (386mg, yield: 71%).

MS：544(M+H)。

Example 66: N-p-fluorobenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

a) Preparation of N-p-fluorobenzenesulfonyl-D-leucine

Dissolving D-leucine (1.44g, 11mmol) in 1.5N sodium hydroxide solution (8ml), adding dioxane (15ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-fluorobenzenesulfonyl chloride (2g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with dichloromethane (30 ml); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3.2g of a crude product, which was purified by column chromatography to give a pale yellow oily substance (2.7g, yield: 94%).

MS：3 12(M+Na)。

b) Preparation of N-p-fluorobenzenesulfonyl-D-leucyl-L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

Dissolving N-p-fluorophenylsulfonyl-D-leucine (289mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (386mg, yield: 67%).

MS：577(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.7(3H，d)，0.86(3H，d)，1.36(1H，m)，1.52(1H，m)，1.65(1H，m)，1.98-2.08(3H，m)，2.3(1H，m)，3.38(1H，m)，3.67(1H，m)，3.96(1H，dd)，4.4(2H，m)，4.55(2H，m)，7.1-7.82(8H，m)，8.39(1H，s)，8.88(1H，s)。

Example 67: n-p-methyl benzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of N-p-toluenesulfonyl-D-leucine

Dissolving D-leucine (721mg, 5.5mmol) in 1.5N sodium hydroxide solution (4ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-toluenesulfonyl chloride (1g, 5mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. After cooling, dilute hydrochloric acid is dripped to adjust the pH value to 3, and dioxane is removed by decompression and concentration, and a large amount of solid is separated out; filtration was carried out, and the obtained solid was recrystallized from ethyl acetate/petroleum ether to obtain a white solid (1.26g, yield: 80.6%).

MS：308(M+Na)。

b) Preparation of N-p-methyl benzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-p-methyl benzenesulfonyl-D-leucine (286mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (424mg, yield: 74%).

MS：573(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.64(3H，d)，0.82(3H，d)，1.24(1H，m)，1.46～1.52(2H，m)，1.93-2.06(3H，m)，2.39(1H，m)，3.35(1H，m)，3.63(1H，m)，3.93(1H，dd)，4.43(2H，m)，4.56(1H，m)，7.25-7.84(8H，m)，8.36(1H，s)，8.85(1H，s)。

Example 68: N-p-tert-butylbenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-p-tert-butylbenzenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-tert-butylsulfonyl chloride (2.33g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (3g, yield: 83.3%).

Rf 0.6 developing agent petroleum ether and ethyl acetate 1: 2: ultraviolet, iodine and 1% ninhydrin solution

MS：350(M+Na)。

b) Preparation of N-p-tert-butylbenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide

Dissolving N-p-tert-butylbenzene sulfonyl-D-leucine (330mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (436mg, yield: 71%).

MS：615(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.74-0.83(6H，t)，1.29(9H，s)，1.32(1.，m)，1.45(1H，m)，1.5(1H，m)，1.97-2.05(3H，m)，2.36(1H，m)，3.4(1H，m)，3.6(1H，m)，3.98(1H，dd)，4.41(2H，m)，4.51(1H，m)，7.55-7.84(8H，m)，8.39(1H，s)，8.93(1H，s)。

Example 69: N-p-trifluoromethylbenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-L, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-p-trifluoromethylbenzenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-trifluoromethyl sulfonyl chloride (2.4g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (2.8g, yield: 83%).

MS：362(M+Na)。

b) Preparation of N-p-trifluoromethylbenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-p-trifluoromethylbenzenesulfonyl-D-leucine (340mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (389mg, yield: 62%).

MS：627(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.72(3H，d)，0.88(3H，d)，1.29(1H，m)，1.51(1H，m)，1.61(1H，m)，1.96-2.13(3H，m)，2.37(1H，m)，3.39(1H，m)，3.67(1H，m)，4.03(1H，dd)，4.44(2H，d)，4.55(1H，m)，7.2-7.94(8H，m)，8.4(1H，s)，9.01(1H，s)。

Example 70: N-p-acetamido-benzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of N-p-acetamido-benzenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 1lmmo1) in 1.5N sodium hydroxide solution (10m1), adding dioxane (10m1), and cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-acetamidobenzenesulfonyl chloride (2.33g, 10mmo1) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a white solid (3g, yield: 83%).

Rf 0.4 developing agent n-butanol, water, acetic acid and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

MS：351(M+Na)。

b) Preparation of N-p-acetamido-benzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N-p-acetamido-benzenesulfonyl-D-leucine (330mg, lmmo1), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmo1) and NMM (222mg, 2.2mmo1) in anhydrous dichloromethane (10m1), protecting with nitrogen, cooling to O ℃, adding HOBt (135mg, lmmo1) and EDCI (230mg, 1.2mmo1), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title product (462mg, yield: 75%).

MS：616(M+H)。

Example 71: N-p-cyanobenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-p-cyanobenzenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 1lmmo1) in 1.5N sodium hydroxide solution (10m1), adding dioxane (10m1), and cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding p-cyanobenzene sulfonyl chloride (2g, 10mmo1) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting at O ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (2g, yield: 68%).

MS：319(M+Na)。

b) Preparation of N-p-cyanobenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving N-p-cyanobenzenesulfonyl-D-leucine (300mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), protecting with nitrogen, cooling to 0 ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (321mg, yield: 55%).

MS：584(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.79(3H，d)，0.84(3H，d)，1.32(1H，m)，1.49-1.57(2H，m)，1.95-2.09(3H，m)，2.33(1H，m)，3.41(1H，m)，3.65(1H，m)，3.95(1H，dd)，4.43(2H，m)，4.58(1H，m)，7.25-7.88(8H，m)，8.29(1H，s)，8.76(1H，s)。

Example 72: N-4-bromo-2-fluorobenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-4-bromo-2-fluorobenzenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding 4-bromo-2-fluorobenzenesulfonyl chloride (2.7g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally heating to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (2.1g, yield: 53%).

Rf 0.3 developing agent n-butanol, water, acetic acid and ethyl acetate 1: ultraviolet, iodine and 1% ninhydrin solution

MS：390(M+Na)。

b) Preparation of N-4-bromo-2-fluorobenzenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

Dissolving N-4-bromo-2-fluorobenzenesulfonyl-D-leucine (370mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (393mg, yield: 60%).

MS：657(M+H)。

Example 73: N-1-naphthalenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-1-naphthalenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding 1-naphthalene sulfonyl chloride (2.27g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (3.46g, yield: 98%).

MS：344(M+Na)。

b) Preparation of N-1-naphthalenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving N-1-naphthalenesulfonyl-D-leucine (320mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to O ℃, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally heating to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (444mg, yield: 73%).

MS：609(M+H)。

Example 74: N-2-naphthalenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-2-naphthalenesulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding 2-naphthalene sulfonyl chloride (2.27g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (3g, yield: 85%).

MS：344(M+Na)。

b) Preparation of N-2-naphthalenesulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methylamide

Dissolving N-2-naphthalenesulfonyl-D-leucine (322mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMlVl (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (370mg, yield: 61%).

MS：609(M+H)。

Example 75: quinoline-8-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of quinoline-8-sulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding quinoline-8-sulfonyl chloride (2.27g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a white solid (2.2g, yield: 68%).

MS：345(M+Na)。

b) Preparation of quinoline-8-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

quinoline-8-sulfonyl-D-leucine (322mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) were dissolved in anhydrous dichloromethane (10ml), protected with nitrogen, cooled to 0 ℃, added with HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirred at 0 ℃ for 20min, naturally warmed to room temperature, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (505mg, yield: 83%).

MS：610(M+H)

1HNMR(CDCl₃)ppm：0.64(3H，d)，0.74(3H，d)，1.33-1.42(2H，m)，1.45-1.52(2H，m)，1.84-2.08(3H，m)，2.35(1H，m)，3.44(1H，m)，3.89(1H，m)，4.27-4.3(2H，m)，4.44-4.96(2H，m)，5.18(2H，d)，6.77(1H，d)，7.34-7.9(6H，m)，8.16(1H，dd)，8.28(1H，d)，8.36(1H，s)，8.77(1H，s)，8.91(1H，dd)。

Example 76: 1, 2, 3, 4-tetrahydroisoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

a) Preparation of 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmo1) in 1.5N sodium hydroxide solution (10m1), adding dioxane (10m1), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl chloride (3.27g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (3g, yield: 65%).

MS：445(M+Na)。

b) Preparation of 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-L-yl) phenyl ] methylamide

Dissolving 1, 2, 3, 4-tetrahydro-2- (trifluoroacetyl) isoquinoline-7-sulfonyl-D-leucine (422mg, lmmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide hydrochloride (342mg, 1mm0L) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), stirring at O ℃ for 20min under nitrogen protection, cooling to 0 ℃, adding HOBt (135mg, 1mmol), EDCI (230mg, 1.2mmol), stirring at O ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give a foamy solid (419mg, yield: 59%).

MS：710(M+H)。

c) Preparation of 1, 2, 3, 4-tetrahydroisoquinoline-7-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

The product (280mg, 0.4mmol) obtained in the above step was dissolved in methanol (5ml), and 2N potassium carbonate solution (5ml) was added to conduct a reaction at room temperature for 4 hours. After methanol was removed by concentration under reduced pressure, methylene chloride (10ml) was added, and the organic layer was washed with a saturated sodium hydrogencarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (157mg, yield: 64%).

MS：614(M+H)。

Example 77: n- (5-dimethylamino) naphthalene-1-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N- (5-dimethylamino) naphthalene-1-sulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding dansyl chloride (2.7g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value at 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (2.2g, yield: 57%).

MS：387(M+Na)。

b) Preparation of N- (5-dimethylamino) naphthalene-L-sulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide

Dissolving N- (5-dimethylamino) naphthalene-1-sulfonyl-D-leucine (365mg, 1mmol), L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under the protection of nitrogen, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (313 mg, yield: 48%).

MS：652(M+H)。

Example 78: N-cyclopropylsulfonyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

a) Preparation of N-cyclopropylsulfonyl-D-leucine

Dissolving D-leucine (1.4g, 11mmol) in 1.5N sodium hydroxide solution (10ml), adding dioxane (10ml), cooling and controlling the temperature to be 0-5 ℃; slowly dropwise adding cyclopropanesulfonyl chloride (1.4g, 10mmol) and 1.5N sodium hydroxide solution, and maintaining the pH value to be 9-10; reacting at 0 ℃ for 2h, and naturally raising the temperature to room temperature for reacting for 2 h. Cooling, adding diluted hydrochloric acid dropwise to adjust pH to 3, concentrating under reduced pressure to remove dioxane, and extracting water phase with ethyl acetate (20ml × 3); the organic layer was washed with a 5% potassium hydrogensulfate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (1.3g, yield: 52%).

MS：258(M+Na)。

b) Preparation of N-cyclopropylsulfonyl-D-leucyl-L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving N-cyclopropylsulfonyl-D-leucine (236mg, 1mmol), L- (5-methyl) prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methyl amide hydrochloride (342mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally cooling to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (334mg, yield: 64%).

MS：523(M+H)。

Example 79: n- (5, 6, 7, 8-tetrahydronaphthalen-2-yl) formyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving 5, 6, 7, 8-tetrahydro-2-naphthoic acid (178mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (265mg, yield: 46%).

MS：577(M+H)。

Example 80: n- (2-methylimidazo [1, 2-a ] pyridin-3-yl) formyl-D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazol-1-yl) phenyl ] methylamide

Dissolving 2-methylimidazopyridine-3-carboxylic acid (176mg, 1mmol), D-leucyl-L-prolyl-2- [ 5-chloro-2- (1H-1, 2, 4-triazole-1-yl) phenyl ] methyl amide hydrochloride (455mg, 1mmol) and NMM (222mg, 2.2mmol) in anhydrous dichloromethane (10ml), cooling to 0 ℃ under nitrogen protection, adding HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol), stirring at 0 ℃ for 20min, naturally raising to room temperature, and reacting for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (213mg, yield: 37%).

MS：577(M+H)。

Example 81: N-benzenesulfonyl-D-leucyl-L-prolyl- [2- (pyrazin-2-yl) -5-chlorophenyl ] methylamide

N-benzenesulfonyl-D-leucyl-L-proline (370mg, 1mmol), 2- (pyrazin-2-yl) -5-chlorobenzylamine (220mg, 1mmol) and NMM (122mg, 1.2mmol) were dissolved in anhydrous dichloromethane (10ml), cooled to 0 ℃ under nitrogen protection, HOBt (135mg, 1mmol) and EDCI (230mg, 1.2mmol) were added, stirred at 0 ℃ for 20min, allowed to warm to room temperature naturally, and reacted for 5 hours. The organic layer was washed with a saturated sodium bicarbonate solution, water and a saturated aqueous salt solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title product (319mg, yield: 56%).

MS：570(M+H)

1H NMR(CDCl₃+D₂O)ppm：0.96(6H，t)，1.66(1H，m)，1.87(1H，m)，1.94(1H，m)，2.05-2.18(3H，m)，2.49(1H，m)，3.38(1H，m)，3.61(1H，m)，4.07(1H，dd)，4.36(1H，m)，4.56(2H，m)，7.43-7.85(8H，m)，8.61(1H，d)，8.78(1H，d)，8.83(1H，d)。

Example 82: antithrombin Activity test

In the experiment, a sample to be tested is added into an enzyme reaction system containing 0.15U/ml freeze-dried bovine thrombin standard purified from bovine blood, incubated for 15 minutes, added with a specific substrate S2238(0.075 μ M), and dynamically detected the change of absorbance at 405nM for 4 minutes at room temperature by using an ultraviolet detector.

The Inhibition rate (% Inhibition) of the enzyme activity by the sample was calculated according to formula 1,

% Inhibition ═ 1- Δ As/Δac × 100% formula 1

Where Δ As represents the rate of change in suppressed absorbance and Δ Ac represents the rate of change in uninhibited absorbance. IC (integrated circuit)₅₀The value (concentration of the drug at which the enzyme activity was inhibited by 50%) was calculated by fitting the Inhibition ratio (% Inhibition) to the logarithm X of the sample concentration by a nonlinear fit of formula 2.

% Inhibition = \frac{100}{1 + 10^{(LogIC 50 - X) * h}}

Equation 2

Wherein h represents the Hill coefficient

Thrombin inhibition IC of the compounds of the invention₅₀All values are less than 30. mu.M, and in the following table, the IC's of some of the compounds of the invention are listed₅₀Value (. mu.M).

Examples	IC₅₀
		1	4.47
2	0.31
		3	0.57
4	0.66
		5	7.89
6	11.62
		7	0.38
8	0.14
		9	0.95
10	0.3
		11	1.6
13	0.83

14	1.48
		15	0.55
16	0.76
		17	0.46
18	2.9
		19	0.91
21	0.05
		23	0.11
25	0.94
		26	7.87
27	5.2
		28	0.03
29	0.005
		30	0.04
3 1	0.14
		32	0.04
35	0.01
		39	0.009
40	0.03
		41	0.008
42	0.02
		44	0.015
45	0.085
		49	0.09
53	0.15
		55	0.016
56	0.04
		57	0.027
59	0.017
		60	0.028
61	0.056
		62	0.045
63	0.034
		64	0.28
66	0.041
		67	0.019
68	0.022

69	O.11
		70	0.004
73	0.015
		74	0.02
75	0.07
		76	0.19
81	3.65

The following formulation examples are illustrative only and are not intended to limit the scope of the present invention in any way. The active component refers to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

Example 83: in vivo pharmacokinetic testing in rats

The compound of example 44 was administered orally to SD rats at a dose of 20mg/kg, and the compound of example 44 was administered intravenously at a dose of 2mg/kg, and plasma was collected at different time points, the concentrations thereof were measured, and relevant pharmacokinetic parameters were calculated. The results of the experiment showed that the compound of example 44 had a maximum blood concentration of 1.75 μ M in rats with a half-life of 2.6 hours and an oral bioavailability of 23%.

Example 84: preparation of injection

Prescription:

	％W/V
		active component	1
Physiological saline	100

The pH can be adjusted to the most stable state by the addition of suitable dilute acids or bases or buffer salts, and antioxidants or metal chelating agents can also be included. The solution was sterilized by filtration and filled in sterile ampoules under sterile conditions.

Example 85: preparation of tablets

Prescription:

	mg/tablet
		Active component	60
Microcrystalline cellulose	35
		Sodium carboxymethyl starch	4.5

Corn starch	45
		Magnesium stearate	0.5
Talcum powder	1

Mixing the active components with excipient, sieving, and tabletting.

Example 86: preparation of hard capsules

Prescription:

	％W/W
		active component	55
Dried starch	43
		Magnesium stearate	2

The active ingredient is sieved, mixed with excipients and, using suitable equipment, the mixture is filled into hard gelatin capsules.

Example 87: preparation of suspensions

Prescription:

	mg/5ml
		active component	50
Sodium carboxymethylcellulose	75
		Syrup	1.2ml
Pigment	0.05ml
		Benzoic acid	0.05mg
Purified water is added to the total amount	5ml

The active ingredient is sieved, mixed with sodium carboxymethylcellulose and syrup to form a homogeneous paste, the pigment, benzoic acid are diluted with a portion of purified water, added to the paste with stirring, and then sufficient water is added to produce the desired volume.

While the invention has been described with respect to specific examples, it will be understood that it can be further modified by routine experimentation and that various obvious modifications and changes can be made by those skilled in the art without departing from the spirit of the invention and that such modifications and improvements are within the scope of the invention. Accordingly, the scope of the present invention is defined not by the description of the above embodiments but by the appended claims and their equivalents.

Claims

1. An amide compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

wherein,

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-SO₃R¹、-COR¹、-CO₂R¹、-PO(OR¹)₂、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-SO₃R¹、-C_1～6alkyl-COR¹、-C_1～-6alkyl-CO₂R¹or-C_1～6alkyl-PO (OR)¹)₂；

R¹Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-to 6-membered aromatic heterocycle or-NR²R³；R²And R³Independently represent hydrogen, C_1～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen or C_1～6An alkyl group;

Z₁and Z₂Independently represent hydrogen, C_1～4Alkyl, halogen, hydroxy, amino, alkylamino, dialkylamino, alkoxy, mercapto, alkylthio, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or C with the above groups_1～6Alkyl groups of (a);

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁴、R⁵Or

q represents 0 to 3; y is₁Represents O, NH or CH₂；R⁷Represents hydrogen, C_1～6Alkyl radicalCycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle.

2. The amide-based compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR¹、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-COR¹or-C_1～6alkyl-CO₂R¹；

B represents hydrogen;

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁴、R⁵Or

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O; r⁶Represents hydrogen, C_1～6Alkyl orq represents 0 to 3; y is₁Represents O or NH; r⁷Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle.

3. The amide-based compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein:

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR¹、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～4Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-COR¹or-C_1～6alkyl-CO₂R¹；

R¹Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-to 6-membered aromatic heterocycle or-NR²R³；R²And R³Independently represent hydrogen, C_1～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen;

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

4. The amide-based compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein:

a represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -SO₂R¹、-COR¹、-C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkanesradical-C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocycle, -C_1～6alkyl-SO₂R¹、-C_1～6alkyl-COR¹or-C_1～6alkyl-CO₂R¹；

R¹Represents hydrogen, C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl, -C_1～6Alkyl-5-6 membered aromatic heterocyclic ring or-NR²R³；R²And R³Independently represent hydrogen, C_1～6Alkyl, cycloalkyl or heterocycloalkyl;

b represents hydrogen;

n represents 0 to 2;

m represents 0 to 2;

k represents 0 to 3;

r represents R⁵；R⁵Represents a 5-6 membered aromatic heterocycle.

5. The amide-based compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: the amide compound shown in the formula (I) or the pharmaceutically acceptable salt thereof is any one specific compound shown in the following numbers 1-81,

6. the amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when A is-SO₂R¹When said-SO₂R¹Is halogenated aryl-SO₂-、C_1～4Alkylsulfonyl radical, C_1～4Alkyl-substituted aminosulfonyl, arylsulfonyl, C_1～4alkylphenyl-SO₂-, halo C_1～3alkylphenyl-SO₂-、C_2-4Amidophenyl-SO₂-, cyanophenyl-SO₂-, naphthalenesulfonyl, quinolinesulfonyl, alkylamino-substituted naphthalenesulfonyl or-SO₂-C_3～6A cycloalkyl group;

when A is-COR¹When, the-COR¹Is C_2～6Alkyl acyl, halo C_2～6Alkyl acyl group, Ph (CH)₂)_0～3CO-, substituent-substituted Ph (CH)₂)_0～3CO-、C_1～3Alkoxy-substituted phenylacetyl, halogen-substituted phenylacetyl, C_2～6Amido-substituted phenylacetyl, C_3～6Cycloalkylacetyl, N-C_1～6Alkyl substituted piperidinecarboxyl, hydronaphthylformyl, substituent substituted fused ring heteroarylformyl;

when A is-C_1～6When alkyl-cycloalkyl is said to be-C_1～6Alkyl-cycloalkyl being-C_1～3alkyl-C_3～6A cycloalkyl group;

when A is-C_1～6When alkyl-aryl is said to-C_1～6phenyl-C substituted by alkyl-aryl radicals₁Alkyl-;

when A is-C_1～6When the alkyl group is a 5-to 6-membered aromatic heterocycle, -C_1～65-6 membered aromatic heterocycle-C substituted by alkyl-5-6 membered aromatic heterocycle as substituent_1～3Alkyl-;

when A is-C_1～6alkyl-SO₂R¹When said is-C_1～6alkyl-SO₂R¹is-C_1～3alkyl-SO₂R¹；

When A is-C_1～6alkyl-COR¹When said is-C_1～6alkyl-COR¹is-C_1～3alkyl-COR¹；

When A is-C_1～6alkyl-CO₂R¹When said is-C_1～6alkyl-CO₂R¹is-C₁alkyl-CO₂H、-C₁alkyl-CO₂C(CH₃)₃、-C₂alkyl-CO₂H or-C₂alkyl-CO₂C₂H₅。

7. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when R is¹Is C_1～6When alkyl, said C_1～6Alkyl is C_1～4Alkyl or halo C_1～4An alkyl group;

when R is¹When it is cycloalkyl, said cycloalkyl is C₃～C₆A cycloalkyl group;

when R is¹When aryl is used, the aryl is phenyl, halogenated phenyl, C_1～4Alkyl-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, C_2～6Amido substituted phenyl, naphthyl, hydrogenated naphthyl, quinolyl, hydrogenated quinolyl, substituent substituted piperidyl and substituent substituted fused heterocyclic aryl;

when R is¹is-C_1～6When alkyl-aryl is said to-C_1～6Alkyl-aryl being-C_1～4Alkylphenyl, -amino-substituted C_1～4Alkyl phenyl, C_1～4Alkoxy-substituted phenyl-C_1～4Alkyl-, halophenyl-C_1～3Alkyl-or C_2～6Amidophenyl-C_1～3An alkyl group-.

8. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when Z is₁And Z₂Is C_1～6Alkyl radical, said C_1～6Alkyl is C_1～3An alkyl group;

when Z is₁And Z₂Is halogen, and the halogen is fluorine.

9. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when R is⁵When the halogen is chlorine, the halogen is chlorine;

when R is⁵In the case of a 5-to 6-membered aromatic heterocycle, the 5-to 6-membered aromatic heterocycle is a 5-to 6-membered nitrogen heteroaromatic ring or a 5-to 6-membered nitrogen sulfur heteroaromatic ring.

10. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: when R is⁶Is C_1～6When alkyl, said C_1～6Alkyl is C_1～3Alkyl or halo C_1～3An alkyl group.

11. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when R is⁷Is C_1～6When alkyl, said C_1～6Alkyl is C_1～3An alkyl group;

when R is⁷When it is cycloalkyl, said cycloalkyl is C_3～6A cycloalkyl group;

when R is⁷When the heterocyclic alkyl is the heterocyclic alkyl, the heterocyclic alkyl is azacycloalkyl;

when R is⁷is-C_1～6When alkyl-cycloalkyl is said to be-C_1～6Alkyl-cycloalkyl being-C_1～3alkyl-C_3～6A cycloalkyl group;

when R is⁷is-C_1～6When alkyl-aryl is said to-C_1～6Alkyl-aryl being-C₁Alkyl-phenyl.

12. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when A is-SO₂R¹When said-SO₂R¹Is methanesulfonyl, ethanesulfonyl, N-dimethylaminosulfonyl, phenylsulfonyl, p-F-Ph-SO₂-、p-CH₃-Ph-SO₂-、p-C(CH₃)₃-Ph-SO₂-、p-CF₃-Ph-SO₂-、p-CH₃CONI-I-Ph-SO₂-、p-CN-Ph-SO₂-, 4-bromo-2-fluoro-benzenesulfonyl, 1-naphthalenesulfonyl, 2-naphthalenesulfonyl, 8-quinolinesulfonyl, 1, 2, 3, 4-tetrahydro-7-quinolinesulfonyl, 5-N, N-dimethyl-1-naphthalenesulfonyl or cyclopropanesulfonyl;

when A is-COR¹When, the-COR¹is-COCH₃、-COCHF₂、-COPh、-COCH₂Ph、-CO(CH₂)₂Ph、-COCH₂CH(NH₂)Ph、p-OCH₃-Ph-CH₂CO-、p-Br-Ph-CH₂CO-、p-CH₃CONH-Ph-CH₂CO-、m-OCH₃-Ph-CH₂-CO-, 3, 4-dimethoxyphenylacetyl, cyclopentylacetyl, N-methyl-piperidine-4-formyl, 1, 2, 3, 4-tetrahydro-7-naphthoyl or 2-methyl-imidazo [1, 2-alpha ]]And pyridine-3-formyl;

when A is-C_1～6When alkyl-cycloalkyl is said to be-C_1～6Alkyl-cycloalkyl being-C₁-a cyclohexyl group;

when A is-C_1～6When alkyl-aryl is said to-C_1～6Alkyl-aryl being phenyl-C₁Alkyl-;

when A is-C_1～6When the alkyl group is a 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-5-6 membered aromatic heterocycle is-C₁Alkyl-2-pyridyl or-C₁Alkyl-5-methyl-2-thienyl;

when A is-C_1～6alkyl-COR¹When said is-C_1～6alkyl-COR¹is-C₁alkyl-CONH₂。

13. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when R is¹When aryl, the aryl is phenyl, p-F-Ph-, p-CH₃-Ph、p-C(CH₃)₃-Ph、p-CF₃-Ph-、p-CN-Ph-、p-CH₃CONH-Ph-, 4-bromo-2-fluoro-phenyl, 1-naphthyl, 2-naphthyl, 8-quinolyl, 1, 2, 3, 4-tetrahydro-7-quinolyl, 5-N, N-dimethyl-1-naphthyl, N-methyl-4-piperidyl, 1, 2, 3, 4-tetrahydro-7-naphthyl, 2-methyl-imidazo [1, 2-alpha ] -N]Pyridine-3-yl), 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl;

when R is¹is-C_1～6When alkyl-aryl is said to-C_1～6Alkyl-aryl being-C₁Alkyl-phenyl, -C₂Alkyl-phenyl, -CH₂CH(NH₂)Ph、p-OCH₃-Ph-CH₂-、p-Br-Ph-CH₂-、p-CH₃CONH-Ph-CH₂-、m-OCH₃-Ph-CH₂-or 3, 4-dimethoxyphenylmethyl.

14. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: when R is⁵When the aromatic heterocyclic ring is a 5-6-membered aromatic heterocyclic ring, the 5-6-membered aromatic heterocyclic ring is 4-thiadiazo, 1-pyrazolyl, 2-imidazolyl, 1-triazolyl, 1-tetrazolyl, 1-methyl-5-tetrazolyl or 2-pyrazinyl.

15. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: when R is⁶Is C_1-6When alkyl, said C_l～6Alkyl is methyl or-CH₂CF₃。

16. The amide-based compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

when R is⁷When the heterocyclic alkyl is the piperidine-3-yl group;

when R is⁷is-C^1～6When alkyl-cycloalkyl is said to be-C^l～6Alkyl-cycloalkyl being-C₁Alkyl-cyclohexyl.

17. The amide-based compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein: when R is¹When it is aryl, said-C_1--6Alkyl-cycloalkyl being-C_l～3alkyl-C_3～6A cycloalkyl group.

18. The amide-based compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein: when R is¹When it is aryl, said-C_l～6Alkyl-cycloalkyl being-C_lAlkyl-cyclopentyl.

19. The amide-based compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt comprises pharmaceutically acceptable inorganic acid salt or organic acid salt; the inorganic acid salt is sulfate, sulfite, hydrochloride, hydrobromide, nitrate, phosphate, metaphosphate, pyrophosphate or perchlorate; the organic acid salt is acetate, maleate, fumarate, succinate, citrate, p-toluenesulfonate, tartrate, formate, acetate, propionate, heptanoate, oxalate, benzoate, malonate, succinate, maleate, hydroxybutyrate, citrate, methanesulfonate, benzenesulfonate, lactate or mandelate.

20. The process for producing an amide-based compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises any one of the following steps:

R⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-6 membered aromatic heterocycle;x represents O or S; r⁶Represents hydrogen, C_l～6Alkyl or

q represents 0 to 3; y is_lRepresents O, NH or CH₂；R⁷Represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_l～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-monoaryl or-C_1～6An alkyl-5-to 6-membered aromatic heterocycle; a is SO₂R¹、-COR¹or-CO₂R¹(ii) a B is hydrogen or C_1～6An alkyl group; z₁Is hydrogen, halogen, amino, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or methyl; z₂Is hydrogen or fluorine; k is 0 to 2; m is 0 to 2; n is 0 to 2;

in the second method, under the action of a condensation reagent, the compound IV and the compound V are subjected to coupling reaction in an anhydrous solvent under the action of inert gas; wherein R is R⁴、R⁵OrR⁴Represents hydrogen or-X-R⁶；R⁵Represents hydrogen, halogen, difluoromethyl, trifluoromethyl or a 5-to 6-membered aromatic heterocycle; x represents O or S; r⁶Represents hydrogen, C_1～6Alkyl or

q represents 0 to 3; y is_lRepresents O, NH or CH₂；R⁷Represents C_1～6Alkyl, cycloalkyl, heterocycloalkyl, aryl, 5-to 6-membered aromatic heterocycle, -C_1～6Alkyl-cycloalkyl, -C_1～6Alkyl-heterocycloalkyl, -C_1～6Alkyl-aryl or-C_l～6An alkyl-5-to 6-membered aromatic heterocycle;a is-SO₂R¹、-COR¹or-CO₂R¹(ii) a B is hydrogen or C_l～6An alkyl group; z₁Is hydrogen, halogen, amino, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, cyano, ester, difluoromethyl, trifluoromethyl or methyl; z₂Is hydrogen, halogen, alkoxy, alkylthio, ester, difluoromethyl, trifluoromethyl or methyl; k is 0 to 2; m is 0 to 2; n is 0 to 2;

21. Use of an amide compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the preparation of a reagent for inhibiting thrombin, or for the preparation of a medicament for the treatment and/or prevention of thrombin-mediated and/or thrombin-associated diseases.

22. Use of the amide-based compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 19 for preparing a medicament for modulating or inhibiting the activity of serine protease of tryptase.

23. The use of claim 21, wherein: the thrombin-mediated and/or thrombin-associated diseases include: venous thrombosis and pulmonary embolism, arterial thrombosis such as myocardial ischemia, myocardial infarction, unstable angina, stroke due to thrombosis, and peripheral arterial formation; atherosclerotic diseases such as coronary artery disease, cerebral artery disease, and peripheral artery disease; the reagent for inhibiting thrombin is anticoagulant.

24. The use of claim 21, wherein: the thrombin inhibiting agents are useful for the ex vivo preservation of blood, plasma and other blood products.

25. A pharmaceutical composition characterized by: comprising the amide-based compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.