CN105399698A

CN105399698A - Aromatic heterocyclic derivatives and applications of aromatic heterocyclic derivatives in medicines

Info

Publication number: CN105399698A
Application number: CN201510559907.6A
Authority: CN
Inventors: 张英俊; 刘兵; 余天柱; 张翔宇; 张仕国; 张健存; 郑常春
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2014-09-04
Filing date: 2015-09-02
Publication date: 2016-03-16
Anticipated expiration: 2035-09-02
Also published as: TWI689497B; CN105399698B; TW201609678A; WO2016034134A1

Abstract

The present invention discloses aromatic heterocyclic derivatives and applications of the aromatic heterocyclic derivatives in medicines, and specifically provides a class of aromatic heterocyclic compounds or stereoisomers, geometric isomers, tautomers, racemic bodies, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutical compositions containing the compounds. The present invention further discloses uses of the compounds or pharmaceutical compositions in drug preparation, wherein the drug is used for treatment of respiratory diseases, particularly chronic obstructive pulmonary disease (COPD).

Description

Virtue heterocyclic derivative and the application in medicine thereof

Invention field

The invention belongs to medical art, be specifically related to a class virtue heterocyclic compound, comprise the pharmaceutical composition of described compound, and as the purposes of PDE4 inhibitor to treat chronic obstructive pulmonary disease (COPD).

Background of invention

Cyclic nucleotide phosphodiesterase (Cyclicnucleotidephosphodiesterases, PDEs) be the important super enzyme family of a class, by the hydrolysis to cAMP and cGMP, intracellular cAMP and the cGMP concentration of effective control, thus the biochemical action that in control agent, second messenger is conducted.PDEs is widely distributed in mammalian tissues, and its diversity causes different PDE enzymes to have specific distribution at cell and subcellsular level, and alternative adjustment various kinds of cell function is good medicinal design and therapy target.

Known ring-type adenosine-3 ', 5 '-monophosphate (cAMP) shows the effect (Sutherland and Roll, Pharmacol.Rev, 1960,12:265) of important intracellular secondary courier.Be hydrolyzed to adenosine 5 '-monophosphate (AMP) in cAMP born of the same parents and cause many inflammatory conditions, include, but is not limited to psoriatic, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic grnuloma, allergic conjunctivitis, osteoarthritis and ulcerative colitis.Cyclic nucleotide phosphodiesterase (PDE) is the biochemistry of this enzyme and the superfamily of functional highly divergent isolate, is the factor of important control cAMP (and cGMP) level.There is the family different more than 11 of phosphodiesterase of 25 kinds of gene products.Although PDE1, PDE2, PDE3, PDE4 and PDE7 all use cAMP as substrate, PDE4 and PDE7 type is only had to have high selectivity to cAMP hydrolysis.Therefore, PDE inhibitor, particularly PDE4 inhibitor (such as Rolipram (rolipram) or Ro-1724) be considered to cAMP toughener.Immunocyte contains PDE3 and PDE4, and wherein PDE4 is prevalent in human monocyte.Therefore, IV type phosphodiesterase is suppressed to be to regulate thus for the therapeutic interventional target of various lysis.Research display gives PDE4 inhibitor and in animal model, (comprises those models of Alzheimer's disease) have effect (ExpertOpinTher.Targets, 2005,9 (6): 1283-1305 that refresh memory loses; DrugDiscoveryToday, 2005,10 (22): 1503-19).

4 type phosphodiesterases (PDE4) have been shown as the essential mediator of the ring-type AMP of airway smooth muscle and inflammatory cell.PDE4 is the main cAMP-metabolic enzyme found in inflammatory cell and immunocyte.Prove that PDE4 inhibitor has the potentiality as antiphlogiston, particularly in pulmonary inflammatory disease such as asthma, COPD and rhinitis.Their release of other inflammatory signal of T suppression cell Summing Factor and the generation of inhibit activities oxygen.The inhibitor of PDE4 can be used for treating various disease, comprises the virus etc. of supersensitivity and inflammatory diseases, diabetes, central nervous system disease, pain and generation TNF.The feature of PDE4 is second messenger's ring-type adenosine-3 ', the selectivity high affinity hydrolytic deterioration of 5 '-monophosphate (cAMP), makes it studiedly be used for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Draw one section of article in BritishJournalofPharmacology, " since the eighties in 20th century; PDE4 inhibitor is under development as novel anti-inflammatory therapy, using asthma and chronic obstructive pulmonary disease (COPD) as principal indication.In most of the cases, owing to lacking validity, the PDE4 inhibitor of various structure-type, the exploitation comprising cilomilast (cilomilast), Filaminast (filaminast), Li meter Si Te (lirimilast), Piclamilast (piclamilast), appropriate Fei Site (tofimilast) etc. stops.Matter of utmost importance is the low treatment ratio of these compounds, and it seriously limits the dosage that can be applied.Really, for these compounds most, probably maximum tolerated dose is sub-therapeutic dose or the bottommost at validity dose response curve.Therefore, problems faced overcomes this restriction.”(Giembycz,Brit.J.Pharmacol.155,2008,288-290)。

Summary of the invention

The compounds of this invention is PDE4 inhibitor, based target ultimate principle (targetrationale) and vitro efficacy, the described compound of expection is used for preventing, process, treat or alleviate the respiratory disease such as the disease relevant with PDE4, particularly chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary emphysema, asthma, chronic pneumonia.

Compound of the present invention has restraining effect to PDE4.Especially, the compound that the present invention relates to and pharmaceutically acceptable pharmaceutical composition, can be effective as PDE4 inhibitor.

On the one hand, the present invention relates to a kind of compound, it is the steric isomer such as formula compound shown in the compound shown in (I) or formula (I), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

R ¹for H, deuterium, alkyl, haloalkyl, aminoalkyl group, hydroxyl replace alkyl, cyano group replace alkyl, alkyl-C (=O)-, alkyl-S (=O) ₂-, R ^a-C (=O)-alkylidene group, R ^a-S (=O) ₂-alkylidene group, thiazolinyl, alkynyl, cycloalkylalkyl, cycloheteroalkylalkyl, arylalkyl or heteroarylalkyl;

Each R ²be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, alkyl, haloalkyl, aminoalkyl group, the hydroxyl alkyl, the cyano group that replace replace alkyl, alkoxyl group, halogenated alkoxy or alkylamino;

R ³for H, deuterium, alkyl, haloalkyl, aminoalkyl group, hydroxyl replace alkyl, cyano group replace alkyl, alkyl-C (=O)-, alkyl-S (=O) ₂-, alkyl-C (=O)-alkylidene group, alkyl-O-C (=O)-alkylidene group, alkyl-S (=O) ₂-alkylidene group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkylalkyl, cycloheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl-C (=O)-alkylidene group or heterocyclic radical-C (=O)-alkylidene group;

R ⁴for deuterium, NH ₂, C _2-10alkyl, R that the alkyl that alkyl, haloalkyl, aminoalkyl group, hydroxyl replace, cyano group replace ^a-C (=O)-alkylidene group, R ^a-S (=O) ₂-alkylidene group, thiazolinyl, alkynyl, alkoxyl group, alkylamino ,-C (=O)-NH ₂or-S (=O) ₂-NH ₂;

X is N (R ^b), O or S;

Y is O or S;

A is the heterocyclic radical containing at least one nitrogen-atoms;

Each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-alkylidene group, R ⁶-C (=O)-alkenylene, R ⁶-C (=O)-alkylidene group-O-C (=O)-, R ⁶-C (=O)-alkenylene-O-C (=O)-, R ⁶-C (=O) O-alkylidene group-O-C (=O)-, R ⁶-C (=O) O-alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-alkylidene group, R ^cr ^bn-C (=O)-alkenylene, R ^cr ^bn-C (=O)-alkylidene group-O-C (=O)-, R ^cr ^bn-C (=O)-alkenylene-O-C (=O)-, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-alkylidene group, R ⁶-C (=O)-N (R ^b)-alkenylene, R ⁶-C (=O)-alkylidene group-N (R ^b)-, R ⁶-C (=O)-alkenylene-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-alkenylene, R ^cr ^bn-C (=O)-alkylidene group-N (R ^b)-, R ^cr ^bn-C (=O)-alkenylene-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C (=O)-, R ⁶-C (=O)-N (R ^b)-C (=O)-alkylidene group, R ⁶-C (=O)-N (R ^b)-C (=O)-alkenylene, R ^6a-O-alkylidene group, R ^6aalkyl, alkoxyl group, halogenated alkoxy, alkyloxy-alkoxy, alkylamino, alkylamino alkylamino, alkylaminoalkoxy, alkoxyl group alkylamino, alkylthio, thiazolinyl, the thiazolinyl of carboxyl substituted, alkynyl, R that the alkoxyalkyl of the alkyl that the alkyl that-O-alkenylene, oxo, alkyl, haloalkyl, aminoalkyl group, hydroxyl replace, cyano group replace, the alkyl of carboxyl substituted, alkoxyalkyl, hydroxyl replacement, the alkoxyalkyl of carboxyl substituted, alkyl amino alkyl, aryloxy replace ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-alkylidene group, R ⁶-S (=O) ₂-alkenylene, R ⁶-S (=O) ₂-N (R ^b)-, R ⁶-S (=O) ₂-N (R ^b)-alkylidene group, R ⁶-S (=O) ₂-N (R ^b)-alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-alkylidene group, R ^cr ^bn-S (=O) ₂-alkenylene, cycloalkyl, cycloalkyl oxy, cycloalkyl amino, cycloalkylalkyl, cycloalkenyl group, cycloalkenyl oxy, cycloalkenyl group amino, cycloalkenyl alkyl, heterocyclic radical, heterocyclyloxy base, heterocyclylamino group, cycloheteroalkylalkyl, aryl, aryloxy, arylamino, arylalkyl, heteroaryl, heteroaryl oxygen base, heteroaryl amino or heteroarylalkyl;

Each R ^aand R ⁶be H, deuterium, OH, NH independently ₂, alkyl, haloalkyl, aminoalkyl group, the alkyl that hydroxyl replaces, the alkyl that cyano group replaces, alkoxyalkyl, alkoxyl group, halogenated alkoxy, the alkoxyl group that hydroxyl replaces, the alkoxyl group of carboxyl substituted, alkyloxy-alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl, heteroarylalkoxy, alkylamino, cycloalkyl, cycloalkylalkyl, cycloalkyl oxy, heterocyclic radical, cycloheteroalkylalkyl, heterocyclyloxy base, aryl, arylalkyl, aryloxy, heteroaryl, heteroaryl oxygen base or heteroarylalkyl,

Each R ^6abe H independently, alkyl, haloalkyl, the hydroxyl alkyl, the alkyl of carboxyl substituted, alkoxyalkyl, cycloalkylalkyl, cycloheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclic radical, aryl or the heteroaryl that replace;

Each R ^band R ^cbe H independently, deuterium, alkyl, haloalkyl, the hydroxyl alkyl, the alkyl of carboxyl substituted, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, aryl, arylalkyl, heteroaryl or the heteroarylalkyl that replace; Or R ^b, R ^c3-12 former molecular ring is formed together with the nitrogen-atoms be attached thereto;

M is 0,1,2 or 3;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

Wherein said R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ^6a, R ^a, R ^band R ^cin alkyl, haloalkyl, aminoalkyl group, the hydroxyl alkyl, the cyano group that replace replace alkyl, the alkyl of carboxyl substituted, alkyl-C (=O)-, alkyl-S (=O) ₂-, alkyl-C (=O)-alkylidene group, alkyl-O-C (=O)-alkylidene group, alkyl-S (=O) ₂-alkylidene group, R ^a-C (=O)-alkylidene group, R ^a-S (=O) ₂alkoxyl group, the alkoxyl group of carboxyl substituted, alkylamino, cycloalkyl-C (=O)-alkylidene group, heterocyclic radical-C (=O)-alkylidene group, C that the thiazolinyl of-alkylidene group, thiazolinyl, carboxyl substituted, alkynyl, alkoxyl group, halogenated alkoxy, hydroxyl replace _2-10alkyl, R ⁶-C (=O)-, R ⁶-C (=O)-alkylidene group, R ⁶-C (=O)-alkenylene, R ⁶-C (=O)-alkylidene group-O-C (=O)-, R ⁶-C (=O)-alkenylene-O-C (=O)-, R ⁶-C (=O) O-alkylidene group-O-C (=O)-, R ⁶-C (=O) O-alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-alkylidene group, R ^cr ^bn-C (=O)-alkenylene, R ^cr ^bn-C (=O)-alkylidene group-O-C (=O)-, R ^cr ^bn-C (=O)-alkenylene-O-C (=O)-, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-alkylidene group, R ⁶-C (=O)-N (R ^b)-alkenylene, R ⁶-C (=O)-alkylidene group-N (R ^b)-, R ⁶-C (=O)-alkenylene-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-alkenylene, R ^cr ^bn-C (=O)-alkylidene group-N (R ^b)-, R ^cr ^bn-C (=O)-alkenylene-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C (=O)-, R ⁶-C (=O)-N (R ^b)-C (=O)-alkylidene group, R ⁶-C (=O)-N (R ^b)-C (=O)-alkenylene, R ^6a-O-alkylidene group, R ^6aalkyl, alkyloxy-alkoxy, alkylamino alkylamino, alkylaminoalkoxy, alkoxyl group alkylamino, alkylthio, R that the alkoxyalkyl that-O-alkenylene, alkoxyalkyl, hydroxyl replace, the alkoxyalkyl of carboxyl substituted, alkyl amino alkyl, aryloxy replace ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-alkylidene group, R ⁶-S (=O) ₂-alkenylene, R ⁶-S (=O) ₂-N (R ^b)-, R ⁶-S (=O) ₂-N (R ^b)-alkylidene group, R ⁶-S (=O) ₂-N (R ^b)-alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-alkylidene group, R ^cr ^bn-S (=O) ₂-alkenylene, cycloalkyl, cycloalkyl oxy, cycloalkyl amino, cycloalkylalkyl, cycloalkyl alkoxy, cycloalkenyl group, cycloalkenyl oxy, cycloalkenyl group is amino, cycloalkenyl alkyl, heterocyclic radical, 3-12 former molecular ring, heterocyclyloxy base, heterocyclylamino group, cycloheteroalkylalkyl, heterocyclylalkoxy, aryl, aryloxy, arylamino, arylalkyl, alkoxy aryl, heteroaryl, heteroaryl oxygen base, heteroaryl amino, heteroarylalkyl or heteroarylalkoxy are independently optionally by one or more R ⁷replace,

Wherein each R ⁷be H, deuterium, F, Cl, Br, I, CN, NO independently ₂, OH, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, oxo, C _1-6alkyl, C _1-6alkoxyl group, halo C _1-6alkyl, halo C _1-6alkoxyl group, C _1-6alkyl-C (=O)-or C _1-6alkyl-O-C (=O)-.

Some of them embodiment is, R ¹for H, deuterium, C _1-4alkyl, halo C _1-4alkyl, amino C _1-3the C that alkyl, hydroxyl replace _1-3the C that alkyl, cyano group replace _1-3alkyl, C _1-3alkyl-C (=O)-, C _1-3alkyl-S (=O) ₂-, C _2-4thiazolinyl or C _2-4alkynyl;

Each R ²be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, C _1-3alkyl, halo C _1-3alkyl, amino C _1-3the C that alkyl, hydroxyl replace _1-3the C that alkyl, cyano group replace _1-3alkyl, C _1-3alkoxyl group, halo C _1-3alkoxyl group or C _1-3alkylamino;

R ⁴for deuterium, NH ₂, C _2-4alkyl, halo C _1-4alkyl, amino C _1-4the C that alkyl, hydroxyl replace _1-4the C that alkyl, cyano group replace _1-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _1-3alkoxyl group, C _1-3alkylamino ,-C (=O)-NH ₂or-S (=O) ₂-NH ₂;

M is 0,1,2 or 3.

Other embodiment is, R ¹for H, deuterium ,-CH ₃,-CH ₂cH ₃,-CH ₂cH ₂cH ₃,-CH (CH ₃) CH ₃,-CH ₂cl ,-CHCl ₂,-CCl ₃,-CH ₂f ,-CHF ₂,-CF ₃,-CH ₂cH ₂cl ,-CH ₂cHCl ₂,-CH ₂cH ₂f or-CH ₂cHF ₂;

Each R ²be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, methyl or methoxy;

R ⁴for NH ₂,-CH ₂cH ₃,-CH ₂cH ₂nH ₂,-CH (CH ₃) NH ₂,-CH ₂cH ₂cH ₂nH ₂,-CH (CH ₂cH ₃) NH ₂,-CH ₂cH (CH ₃) NH ₂,-CH (CH (CH ₃) ₂) NH ₂,-C (=O)-NH ₂or-S (=O) ₂-NH ₂.

Some of them embodiment is, R ³for H, deuterium, C _1-6alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6alkyl, C _1-6alkyl-C (=O)-, C _1-6alkyl-S (=O) ₂-, C _1-6alkyl-C (=O)-C _1-6alkylidene group, C _1-6alkyl-O-C (=O)-C _1-8alkylidene group, C _1-6alkyl-S (=O) ₂-C _1-6alkylidene group, C _2-6thiazolinyl, C _2-6alkynyl, C _3-8cycloalkyl, C _2-10heterocyclic radical, C _6-10aryl, C _1-9heteroaryl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl C _1-6alkyl, C _3-8cycloalkyl-C (=O)-C _1-6alkylidene group or C _2-10heterocyclic radical-C (=O)-C _1-8alkylidene group.

Other embodiment is, R ³for C _1-3alkyl, halo C _1-3alkyl, C _1-3alkyl-C (=O)-C _1-6alkylidene group, C _1-3alkyl-O-C (=O)-C _1-6alkylidene group, C _1-3alkyl-S (=O) ₂-C _1-6alkylidene group, C _3-6cycloalkyl, C _2-6heterocyclic radical, C _6-10aryl, C _1-5heteroaryl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl C _1-3alkyl, C _3-6cycloalkyl-C (=O)-C _1-6alkylidene group or C _2-6heterocyclic radical-C (=O)-C _1-6alkylidene group.

Other embodiment is, R ³for CH ₃-O-C (=O)-C _1-6alkylidene group, CH ₃cH ₂-O-C (=O)-C _1-6alkylidene group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1, 1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclohexyl methyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1, 1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, benzyl, styroyl, cyclohexyl-C (=O)-C _1-6alkylidene group, piperidyl-C (=O)-C _1-6alkylidene group, morpholinyl-C (=O)-C _1-6alkylidene group, piperazinyl-C (=O)-C _1-6alkylidene group, thio-morpholinyl-C (=O)-C _1-6alkylidene group, 1-oxo-thiomorpholin base-C (=O)-C _1-6alkylidene group or 1,1-dioxo-thiomorpholinyl-C (=O)-C _1-6alkylidene group.

Some of them embodiment is, A be containing at least one nitrogen-atoms by 3-12 former molecular heterocyclic radical.

Other embodiment is, A is following subformula:

Wherein:

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

Each Z ¹be NH, O, S, S (=O) or S (=O) independently ₂;

Each W is CH independently ₂, NH or O;

Each V is CH independently ₂or NH;

Each E is CH or N independently;

Each G is O or NH independently;

Each p is 0,1,2 or 3 independently;

Each q is 1 or 2 independently;

Each r is 0,1,2 or 3 independently;

Each s is 1,2 or 3 independently.

Other embodiment is, A is following subformula:

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (II) or formula (II), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵with n, there is implication as described in the present invention;

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

T is 0,1,2 or 3.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIa) or formula (IIa), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIb), formula (IIc) or formula (IIb), formula (IIc), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

Some of them embodiment is, each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-6alkylidene group, R ⁶-C (=O)-C _2-6alkenylene, R ⁶-C (=O)-C _1-6alkylidene group-O-C (=O)-, R ⁶-C (=O)-C _2-6alkenylene-O-C (=O)-, R ⁶-C (=O) O-C _1-6alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-6alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-6alkylidene group, R ^cr ^bn-C (=O)-C _2-6alkenylene, R ^cr ^bn-C (=O)-C _1-6alkylidene group-O-C (=O)-, R ^cr ^bn-C (=O)-C _2-6alkenylene-O-C (=O)-, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C _1-6alkylidene group, R ⁶-C (=O)-N (R ^b)-C _2-6alkenylene, R ⁶-C (=O)-C _1-6alkylidene group-N (R ^b)-, R ⁶-C (=O)-C _2-6alkenylene-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-C _1-6alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-C _2-6alkenylene, R ^cr ^bn-C (=O)-C _1-6alkylidene group-N (R ^b)-, R ^cr ^bn-C (=O)-C _2-6alkenylene-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C (=O)-, R ⁶-C (=O)-N (R ^b)-C (=O)-C _1-6alkylidene group, R ⁶-C (=O)-N (R ^b)-C (=O)-C _2-6alkenylene, R ^6a-O-C _1-8alkylidene group, R ^6a-O-C _2-8alkenylene, oxo, C _1-8alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-6alkoxy C _1-6the C that alkyl, hydroxyl replace _1-6alkoxy C _1-6the C of alkyl, carboxyl substituted _1-6alkoxy C _1-6alkyl, C _1-6alkylamino C _1-6alkyl, C _6-10the C that aryloxy replaces _1-6alkyl, C _1-6alkoxyl group, halo C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkoxyl group, C _1-6alkylamino, C _1-6alkylamino C _1-6alkylamino, C _1-6alkylamino C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkylamino, C _1-6alkylthio, C _2-6the C of thiazolinyl, carboxyl substituted _2-6thiazolinyl, C _2-6alkynyl, R ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-C _1-6alkylidene group, R ⁶-S (=O) ₂-C _2-6alkenylene, R ⁶-S (=O) ₂-N (R ^b)-, R ⁶-S (=O) ₂-N (R ^b)-C _1-6alkylidene group, R ⁶-S (=O) ₂-N (R ^b)-C _2-6alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-C _1-6alkylidene group, R ^cr ^bn-S (=O) ₂-C _2-6alkenylene, C _3-8cycloalkyl, C _3-8cycloalkyl oxy, C _3-8cycloalkyl amino, C _3-8cycloalkyl C _1-6alkyl, C _3-8cycloalkenyl group, C _3-8cycloalkenyl oxy, C _3-8cycloalkenyl group is amino, C _3-8cycloalkenyl group C _1-6alkyl, C _2-10heterocyclic radical, C _2-10heterocyclyloxy base, C _2-10heterocyclylamino group, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl, C _6-10aryloxy, C _6-10arylamino, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl, C _1-9heteroaryl oxygen base, C _1-9heteroaryl amino or C _1-9heteroaryl C _1-6alkyl;

Each R ⁶be H, deuterium, OH, NH independently ₂, C _1-8alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6alkyl, C _1-6alkoxy C _1-6alkyl, C _1-8alkoxyl group, halo C _1-6the C that alkoxyl group, hydroxyl replace _1-8the C of alkoxyl group, carboxyl substituted _1-6alkoxyl group, C _1-6alkoxy C _1-6alkoxyl group, C _3-8cycloalkyl C _1-6alkoxyl group, C _2-10heterocyclic radical C _1-6alkoxyl group, C _6-10aryl C _1-6alkoxyl group, C _1-9heteroaryl C _1-6alkoxyl group, C _1-6alkylamino, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-6alkyl, C _3-8cycloalkyl oxy, C _2-10heterocyclic radical, C _2-10heterocyclic radical C _1-6alkyl, C _2-10heterocyclyloxy base, C _6-10aryl, C _6-10aryl C _1-6alkyl, C _6-10aryloxy, C _1-9heteroaryl, C _1-9heteroaryl oxygen base or C _1-9heteroaryl C _1-6alkyl;

Each R ^6abe H, C independently _1-8alkyl, halo C _1-8the C that alkyl, hydroxyl replace _1-8the C of alkyl, carboxyl substituted _1-8alkyl, C _1-6alkoxy C _1-6alkyl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl C _1-6alkyl, C _3-8cycloalkyl, C _2-10heterocyclic radical, C _6-10aryl or C _1-9heteroaryl;

Each R ^band R ^cbe H, deuterium, C independently _1-8alkyl, halo C _1-6the C that alkyl, hydroxyl replace _1-8the C of alkyl, carboxyl substituted _1-8alkyl, C _1-6alkoxy C _1-6alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl or C _1-9heteroaryl C _1-6alkyl; Or R ^b, R ^c3-8 former molecular ring is formed together with the nitrogen-atoms be attached thereto.

Other embodiment is, each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-3alkylidene group, R ⁶-C (=O)-C _2-4alkenylene, R ⁶-C (=O) O-C _1-4alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-4alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-C _2-4alkenylene, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C _1-3alkylidene group, R ⁶-C (=O)-N (R ^b)-C _2-4alkenylene, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-C _2-4alkenylene, R ^6a-O-C _1-6alkylidene group, R ^6a-O-C _2-6alkenylene, oxo, C _1-6alkyl, halo C _1-4alkyl, amino C _1-4the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-4the C of alkyl, carboxyl substituted _1-4alkyl, C _1-6alkoxy C _1-3the C that alkyl, hydroxyl replace _1-6alkoxy C _1-3the C of alkyl, carboxyl substituted _1-6alkoxy C _1-4alkyl, C _1-3alkylamino C _1-3alkyl, C _6-10the C that aryloxy replaces _1-3alkyl, C _1-3alkoxyl group, C _2-4the C of thiazolinyl, carboxyl substituted _2-4thiazolinyl, C _2-4alkynyl, R ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-C _1-3alkylidene group, R ⁶-S (=O) ₂-C _2-4alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-C _1-3alkylidene group, R ^cr ^bn-S (=O) ₂-C _2-4alkenylene, C _3-6cycloalkyl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _1-6heteroaryl or C _1-6heteroaryl C _1-3alkyl;

Each R ⁶be H, deuterium, OH, NH independently ₂, C _1-6alkyl, C _1-6the C that alkoxyl group, hydroxyl replace _1-6the C of alkoxyl group, carboxyl substituted _1-6alkoxyl group, C _1-3alkoxy C _1-4alkoxyl group, C _3-6cycloalkyl C _1-3alkoxyl group, C _2-6heterocyclic radical C _1-3alkoxyl group, C _6-10aryl C _1-3alkoxyl group, C _1-5heteroaryl C _1-3alkoxyl group, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-3alkyl, C _3-8cycloalkyl oxy, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _2-6heterocyclyloxy base, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _6-10aryloxy, C _1-6heteroaryl, C _1-5heteroaryl oxygen base or C _1-6heteroaryl C _1-3alkyl;

Each R ^6abe H, C independently _1-6alkyl, halo C _1-6the C that alkyl, hydroxyl replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-3alkoxy C _1-4alkyl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl C _1-3alkyl, C _3-6cycloalkyl, C _2-6heterocyclic radical, C _6-10aryl or C _1-5heteroaryl;

Each R ^band R ^cbe H, deuterium, C independently _1-6alkyl, halo C _1-3the C that alkyl, hydroxyl replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-3alkoxy C _1-4alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl or C _1-5heteroaryl C _1-3alkyl; Or R ^b, R ^c3-6 former molecular ring is formed together with the nitrogen-atoms be attached thereto.

Other embodiment is, each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-3alkylidene group, R ⁶-C (=O)-C _2-4alkenylene, R ⁶-C (=O) O-C _1-4alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-4alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-C _2-4alkenylene, R ⁶-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^6a-O-C _1-6alkylidene group, R ^6a-O-C _2-6the C that the propyl group that the ethyl that the methyl that alkenylene, oxo, methyl, cyano group replace, carboxymethyl, ethyl, cyano group replace, propyloic, propyl group, cyano group replace, carboxylic propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, hydroxyl replace _1-4alkyl, phenoxymethyl, Phenoxyethyl, C _1-5alkoxy C _1-3the C that alkyl, hydroxyl replace _1-5alkoxy C _1-3the C of alkyl, carboxyl substituted _1-4alkoxy C _1-3alkyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, halo C _1-3the vinyl of alkyl, vinyl, carboxyl substituted, propenyl, the propenyl of carboxyl substituted, ethynyl, proyl, R ⁶-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1, 1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1, 1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, phenyl, indenyl, naphthyl, benzyl, styroyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyridyl-ethyl group, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl or pyridazinyl ethyl,

Each R ⁶be H, deuterium, OH, NH independently ₂, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, methoxyl group, the methoxyl group that hydroxyl replaces, the methoxyl group of carboxyl substituted, oxyethyl group, the oxyethyl group that hydroxyl replaces, the oxyethyl group of carboxyl substituted, propoxy-, the propoxy-that hydroxyl replaces, the propoxy-of carboxyl substituted, isopropoxy, the isopropoxy that hydroxyl replaces, the isopropoxy of carboxyl substituted, butoxy, the butoxy that hydroxyl replaces, the butoxy of carboxyl substituted, isobutoxy, the isobutoxy that hydroxyl replaces, the isobutoxy of carboxyl substituted, methoxymethoxy, methoxy ethoxy, methoxy propoxy, oxyethyl group methoxyl group, ethoxy ethoxy, benzyloxy, phenyl ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, cyclo propyl methoxy, cyclobutyl methoxyl group, cyclopentylmethoxy, cyclohexyl methoxy, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1,1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1,1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, phenyl, indenyl, naphthyl, benzyl, styroyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridylmethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl or pyridazinyl ethyl,

Each R ^6abe H independently, methyl, ethyl, propyl group, sec.-propyl, butyl, methylol, hydroxyethyl, hydroxypropyl, the sec.-propyl that hydroxyl replaces, hydroxyl butyl, 2-hydroxy-2-methyl propyl group, carboxymethyl, propyloic, carboxylic propyl group, 2-carboxyl-2-methylethyl, methoxymethyl, methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl-ethyl, phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl,

Each R ^band R ^cbe the C of H, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, hydroxyl replacement independently _1-5the C of alkyl, carboxyl substituted _1-4alkyl, methoxymethyl, methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl-ethyl, phenyl, benzyl, styroyl or phenyl propyl; Or R ^b, R ^cazetidine, tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholin or 1,1-Dioxo-thiomorpholin is formed together with the nitrogen-atoms be attached thereto.

One aspect of the present invention relates to pharmaceutical composition, comprises compound of the present invention, or their steric isomer, geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or their prodrug.

Some of them embodiment is, pharmaceutical composition of the present invention comprises pharmaceutically acceptable carrier further, vehicle, thinner, at least one in assistant agent or vehicle.

Some of them embodiment is, pharmaceutical composition of the present invention comprises additional treatment agent further, and these additional treatment agent are for being used for the treatment of the medicine of chronic obstructive pulmonary disease (COPD), pharmaceutically active agents or their combination.

Other embodiment is, additional treatment agent of the present invention is Sodium.alpha.-ketopropionate, doxofylline (Doxofylline), roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tai Lusite (Tipelukast), theophylline (Theophylline), formoterol (Formoterol), Salmeterol (Salmeterol), FLUTICASONE PROPIONATE (Fluticasonepropionate), Salmeterol/fluticasone propionate compound (SalmeterolXinafoate/FluticasonePropionate), rolipram (Rolipram), this spy of pyrrole rummy (Piclamist), cilomilast (Cilomilast), CDP-840, QAB-149 (Indacaterol), Ao Dateluo (olodaterol), QVA149, Midesteine (Midesteine), neat circulation (Zileuton), husky butanolamine, carmoxirole, budesonide and epimer thereof, Viarox, Triamcinolone Acetonide, flunisolide, furoic acid momisone, Rofleponide, ciclesonide, ipratropium bromide (IpratropiumBromide), ipratropium bromide and salbutamol compound, oxitropium bromide, tiotropium bromide (Tiotropiumbromide), Glycopyrronium Bromide, overgrown with weeds ground bromine ammonium (Umeclidiniumbromide), Wei Lanteluo (vilanterol), overgrown with weeds ground bromine ammonium/Wei Lanteluo compound (umeclidinium/vilanterol), aclidinium bromide (aclidiniumbromide), aclidinium bromide/Formoterol Fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/Wei Lanteluo compound (fluticasonefuroate/vilanterol, FF/VI), Benralizumab, tralokinumab, Revatropate or their combination.

The present invention relates on the other hand the pharmaceutical composition that uses a kind of compound of the present invention or comprise compound of the present invention for the preparation of the purposes of medicine preventing, process, treat or alleviate the disease relevant with 4 type phosphodiesterases (PDE4).

Some of them embodiment is, the disease relevant with 4 type phosphodiesterases (PDE4) of the present invention is respiratory disease, allergy and inflammation, central nervous system (CNS) disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus.

Other embodiment is, respiratory disease of the present invention is: chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis lesion, pulmonary cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, acute respiratory distress syndrome (ARDS) or respiratory inflammation.

Other embodiment is, inflammation of the present invention is: anaphylaxis conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, rhinallergosis, ulcerative colitis, ankylosing spondylitis, rheumatic arthritis or psoriatic arthritis.

On the one hand, the present invention relates to preparation formula (I), the intermediate of compound that (II), (IIa), (IIb) or (IIc) comprise.

The preparation of compound that the present invention relates on the other hand formula (I), (II), (IIa), (IIb) or (IIc) comprise, the method for abstraction and purification.

Content noted earlier only outlines some aspect of the present invention, but the content being not limited to these aspects and other aspect will do more specifically complete description below.

Detailed description of the invention book

Definition and general terms

Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with of the present invention and material can be used in putting into practice the present invention.The present invention is never limited to method of the present invention and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.

Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.

Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.

Unless otherwise indicated, following definition used in the present invention should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " OrganicChemistry ", ThomasSorrell, UniversityScienceBooks, Sausalito:1999, and " March'sAdvancedOrganicChemistry " byMichaelB.SmithandJerryMarch, JohnWiley & Sons, description in NewYork:2007, its full content is incorporated to the present invention by reference.

Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.

Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.

Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.

Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.

" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.

" chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.

" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.

" diastereomer " refers to two or more chiral centre and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.

Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-HillDictionaryofChemicalTerms (1984) McGraw-HillBookCompany, NewYork; AndEliel, E.andWilen, S., " StereochemistryofOrganicCompounds ", JohnWiley & Sons, Inc., NewYork, 1994.

Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.

Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.

The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.

By known method, the method that the racemic modification of any gained end product or intermediate is familiar with by those skilled in the art can be split into optical antipode, e.g., by being separated its diastereoisomeric salt obtained.Racemic product also can be separated by chiral chromatography, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, enantiomer can be prepared by asymmetric synthesis, such as, and can with reference to Jacques, etal., Enantiomers, RacematesandResolutions (WileyInterscience, NewYork, 1981); PrinciplesofAsymmetricSynthesis (2 ^nded.RobertE.Gawley, JeffreyAub é, Elsevier, Oxford, UK, 2012); Eliel, E.L.StereochemistryofCarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S.H.TablesofResolvingAgentsandOpticalResolutionsp.268 (E.L.Eliel, Ed., Univ.ofNotreDamePress, NotreDame, IN1972); ChiralSeparationTechniques:APracticalApproach (Subramanian, G.Ed., Wiley-VCHVerlagGmbH & Co.KGaA, Weinheim, Germany, 2007).

Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (lowenergybarrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropictautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valencetautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.

As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano group, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxyl group, alkoxyalkyl, alkyloxy-alkoxy, alkoxyl group alkylamino, aryloxy, heteroaryl oxygen base, heterocyclyloxy base, alkoxy aryl, heteroarylalkoxy, heterocyclylalkoxy, cycloalkyl alkoxy, alkylamino, alkyl amino alkyl, alkylamino alkylamino, cycloalkyl amino, amino-n-cycloalkyl, alkylthio, haloalkyl, halogenated alkoxy, the alkyl that hydroxyl replaces, the alkylamino that hydroxyl replaces, the alkyl that cyano group replaces, the alkoxyl group that cyano group replaces, the alkylamino that cyano group replaces, the amino alkyl replaced, alkyl acyl, assorted alkyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, heterocyclylacyl, aryl, arylalkyl, virtue is amino, heteroaryl, heteroarylalkyl, heteroaryl amino, amide group, alkylsulfonyl, amino-sulfonyl etc.

In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.With R ^bfor example, structural formula NR ^br ^c-C (=O)-and formula R ⁶-C (=O)-N (R ^bthe R of)-between the two ^bconcrete option between be independent of each other; At same structure formula NR ^br ^c-C (=O)-N (R ^b)-Nei, multiple R ^bconcrete option between be independent of each other.

At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C ₁-C ₆alkyl " or " C _1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C ₃alkyl, C ₄alkyl, C ₅alkyl and C ₆alkyl.

At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.

The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; Also in one embodiment, alkyl group contains 1-3 carbon atom.

The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH ₃), ethyl (Et ,-CH ₂cH ₃), n-propyl (n-Pr ,-CH ₂cH ₂cH ₃), sec.-propyl (i-Pr ,-CH (CH ₃) ₂), normal-butyl (n-Bu ,-CH ₂cH ₂cH ₂cH ₃), isobutyl-(i-Bu ,-CH ₂cH (CH ₃) ₂), sec-butyl (s-Bu ,-CH (CH ₃) CH ₂cH ₃), the tertiary butyl (t-Bu ,-C (CH ₃) ₃), n-pentyl (-CH ₂cH ₂cH ₂cH ₂cH ₃), 2-amyl group (-CH (CH ₃) CH ₂cH ₂cH ₃), 3-amyl group (-CH (CH ₂cH ₃) ₂), 2-methyl-2-butyl (-C (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butyl (-CH (CH ₃) CH (CH ₃) ₂), 3-methyl isophthalic acid-butyl (-CH ₂cH ₂cH (CH ₃) ₂), 2-methyl-1-butene base (-CH ₂cH (CH ₃) CH ₂cH ₃), n-hexyl (-CH ₂cH ₂cH ₂cH ₂cH ₂cH ₃), 2-hexyl (-CH (CH ₃) CH ₂cH ₂cH ₂cH ₃), 3-hexyl (-CH (CH ₂cH ₃) (CH ₂cH ₂cH ₃)), 2-methyl-2-amyl group (-C (CH ₃) ₂cH ₂cH ₂cH ₃), 3-methyl-2-amyl group (-CH (CH ₃) CH (CH ₃) CH ₂cH ₃), 4-methyl-2-amyl group (-CH (CH ₃) CH ₂cH (CH ₃) ₂), 3-methyl-3-amyl group (-C (CH ₃) (CH ₂cH ₃) ₂), 2-methyl-3-amyl group (-CH (CH ₂cH ₃) CH (CH ₃) ₂), 2,3-dimethyl-2-butyl (-C (CH ₃) ₂cH (CH ₃) ₂), 3,3-dimethyl-2-butyl (-CH (CH ₃) C (CH ₃) ₃), n-heptyl, n-octyl, etc.

Term " alkylidene group " represents the saturated bivalent hydrocarbon radical group removing two hydrogen atoms and obtain from saturated straight or branched hydrocarbon.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylidene group contains 1-6 carbon atom; In another embodiment, alkylidene group contains 1-4 carbon atom; In yet another embodiment, alkylidene group contains 1-3 carbon atom; Also in one embodiment, alkylidene group contains 1-2 carbon atom.Such example comprises methylene radical (-CH ₂-), ethylidene (-CH ₂cH ₂-), propylidene (-CH ₂cH ₂cH ₂-), isopropylidene (-CH (CH ₃) CH ₂-) etc.

Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp ²double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " tans ", or the location of " E " and " Z ".In one embodiment, alkenyl group comprises 2-8 carbon atom; In another embodiment, alkenyl group comprises 2-6 carbon atom; In yet another embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to, vinyl (-CH=CH ₂), allyl group (-CH ₂cH=CH ₂), propenyl (CH ₃-CH=CH-) etc.

Term " alkynyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely have a carbon-to-carbon sp triple bond, wherein, described alkynyl group can optionally replace by one or more substituting group described in the invention.In one embodiment, alkynyl group comprises 2-8 carbon atom; In another embodiment, alkynyl group comprises 2-6 carbon atom; In yet another embodiment, alkynyl group comprises 2-4 carbon atom.The example of alkynyl group comprises, but is not limited to, ethynyl (-C ≡ CH), propargyl (-CH ₂c ≡ CH), 1-proyl (-C ≡ C-CH ₃) etc.

Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The substituting group that described alkoxy base can optionally be described by one or more the present invention replace.

The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH ₃), oxyethyl group (EtO ,-OCH ₂cH ₃), 1-propoxy-(n-PrO, n-propoxy-,-OCH ₂cH ₂cH ₃), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH ₃) ₂), 1-butoxy (n-BuO, n-butoxy ,-OCH ₂cH ₂cH ₂cH ₃), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH ₂cH (CH ₃) ₂), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH ₃) CH ₂cH ₃), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH ₃) ₃), 1-pentyloxy (n-pentyloxy ,-OCH ₂cH ₂cH ₂cH ₂cH ₃), 2-pentyloxy (-OCH (CH ₃) CH ₂cH ₂cH ₃), 3-pentyloxy (-OCH (CH ₂cH ₃) ₂), 2-methyl-2-butoxy (-OC (CH ₃) ₂cH ₂cH ₃), 3-methyl-2-butoxy (-OCH (CH ₃) CH (CH ₃) ₂), 3-methyl-l-butoxy (-OCH ₂cH ₂cH (CH ₃) ₂), 2-methyl-l-butoxy (-OCH ₂cH (CH ₃) CH ₂cH ₃), etc.

Term " alkoxyalkyl " represent alkyl group replace by one or more alkoxy base, wherein alkyl group and alkoxy base have implication as described in the present invention, such example comprises, but be not limited to methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, methoxy-propyl, ethoxycarbonyl propyl etc.

Term " alkyloxy-alkoxy " represent alkoxy base replace by one or more alkoxy base, wherein alkoxy base has implication as described in the present invention, such example comprises, but be not limited to methoxymethoxy, methoxy ethoxy, methoxy propoxy, oxyethyl group methoxyl group, ethoxy ethoxy etc.

Term " haloalkyl ", " haloalkenyl group " or " halogenated alkoxy " represents alkyl, thiazolinyl or alkoxy base replace by one or more halogen atom, such example comprises, but is not limited to ,-CF ₃,-CHF ₂,-CH ₂cl ,-CH ₂cF ₃,-CH ₂cHF ₂,-CH ₂cH ₂cF ₃,-OCF ₃,-OCHF ₂,-OCHCl ₂,-OCH ₂cHF ₂,-OCH ₂cHCl ₂,-OCH (CH ₃) CHF ₂deng.

Term " cyano group replace alkyl " represent alkyl group replace by one or more CN, such example comprises, but is not limited to ,-CH ₂cN ,-CH ₂cH ₂cN ,-CH ₂cH ₂cH ₂cN etc.

Term " hydroxyl replace alkyl " or " alkoxyl group that hydroxyl replaces " represent alkyl group or alkoxy base replace by one or more OH, such example comprises, but is not limited to ,-CH ₂oH ,-CH ₂cH ₂oH ,-CH (CH ₃) OH ,-C (CH ₃) ₂oH ,-CH ₂c (CH ₃) ₂oH ,-CH ₂cH ₂cH ₂oH ,-OCH ₂oH ,-OCH ₂cH ₂oH ,-OCH ₂c (CH ₃) ₂oH etc.

Term " alkyl of carboxyl substituted " or " alkoxyl group of carboxyl substituted " represent alkyl group or alkoxy base replace by one or more COOH, such example comprises, but is not limited to ,-CH ₂cOOH ,-CH ₂cH ₂cOOH ,-CH (CH ₃) COOH ,-C (CH ₃) ₂cOOH ,-CH ₂cH ₂cH ₂cOOH ,-CH (CH (CH ₃) ₂) COOH ,-OC (CH ₃) ₂cOOH etc.

Term " aminoalkyl group " or " amino replace alkyl " comprise the C that replaces by one or more amino _1-10straight or branched alkyl group.Some of them embodiment is, aminoalkyl group the C that replaces by one or more amino group _1-6" more rudimentary aminoalkyl group ", such example comprises, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Some of them embodiment is, alkylamino is one or two C _1-6alkyl is connected to the more rudimentary alkylamino group on nitrogen-atoms.Other embodiment is, alkylamino is C _1-3more rudimentary alkylamino group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example comprises, but is not limited to, N-methylamino-, N-ethylamino, N, N-dimethylamino, N, N-diethylin etc.

Term " alkyl amino alkyl " represent alkyl group replace by one or more alkylamino radicals, wherein alkyl group and alkylamino radicals have implication as described in the present invention, such example comprises, but be not limited to N-Methyaminomethyl, N-Ethylaminomethyl, N, N-dimethylaminoethyl, N, N-diethyllaminoethyl etc.

Term " alkylamino alkylamino " represent alkylamino radicals replace by one or more alkylamino radicals, wherein alkylamino radicals has implication as described in the present invention.

Term " alkylaminoalkoxy " represent alkoxy base replace by one or more alkylamino radicals, wherein alkylamino and alkoxy base have implication as described in the present invention.

Term " alkoxyl group alkylamino " represent alkylamino radicals replace by one or more alkoxy base, wherein alkylamino and alkoxy base have implication as described in the present invention.

Term " alkylthio " refers to C _1-10the alkyl of straight or branched is connected on the sulphur atom of divalence, and wherein alkyl group has implication as described in the present invention.Such example comprises, but is not limited to methylthio group (CH ₃s-), ethylmercapto group etc.

Term " carbocylic radical " or " carbocyclic ring " expression contain 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.Carbon bicyclic group comprises spiral shell carbon bicyclic group and condenses carbon bicyclic group, and suitable carbocylic radical group comprises, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbocylic radical group comprises further, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.

Term " cycloalkyl " expression contains 3-12 carbon atom, saturated monocycle, dicyclo or the three-ring system of unit price or multivalence.In one embodiment, cycloalkyl comprises 3-12 carbon atom; In another embodiment, cycloalkyl comprises 3-8 carbon atom; In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can not be substituted independently or replace by one or more substituting group described in the invention.Such example comprises, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc.

Term " cycloalkyl oxy " comprises the optional cycloalkyl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein group of naphthene base has implication as described in the present invention, and such example comprises, but be not limited to cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base etc.

Term " cycloalkyl amino " represent amino group replace by one or two group of naphthene base, such example comprises, but is not limited to cyclopropylamino, Cyclobutylamino, clopentylamino, Cyclohexylamino.Some of them embodiment is, the cycloalkyl on cycloalkyl amino can be replaced by substituting group described in the invention further.

Term " cycloalkylalkyl " represent alkyl group replace by one or more group of naphthene base, wherein alkyl group and group of naphthene base have implication as described in the present invention, and such example comprises, but be not limited to Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclobutylpropyl, cyclopentyl-methyl, cyclopentyl ethyl, cyclopentylpropyi, cyclohexyl methyl, cyclohexyl-ethyl, Cyclohexylpropyl etc.

Term " cycloalkyl alkoxy " represent alkoxy base replace by one or more group of naphthene base, wherein alkoxy base and group of naphthene base have implication as described in the present invention, and such example comprises, but be not limited to cyclo propyl methoxy, cyclopropylethoxy, cyclopropyl propoxy-, cyclobutyl methoxyl group, cyclobutyl oxyethyl group, cyclobutyl propoxy-, cyclopentylmethoxy, cyclopentyl oxyethyl group, cyclopentyl propoxy-, cyclohexyl methoxy, cyclohexylethoxy radical, cyclohexyl propoxy-etc.

Term " cycloalkenyl group " represents containing 3-12 carbon atom, the unsaturated monocycle of part of unit price or multivalence, dicyclo or three-ring system.The example of cycloalkenyl groups comprises, but is not limited to 1-cyclopentyl-1-thiazolinyl, 1-cyclopentyl-2-thiazolinyl, 1-cyclopentyl-3-thiazolinyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1-cyclohexyl-3-thiazolinyl, cyclohexadienyl, etc.

Term " cycloalkenyl oxy " comprises the optional cycloalkenyl group replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein cycloalkenyl groups has implication as described in the present invention, and such example comprises, but is not limited to cyclopentenyl oxygen base, cyclohexenyl oxygen base, cyclohexadienyl oxygen base etc.

Term " cycloalkenyl group amino " represent amino group replace by one or two cycloalkenyl groups, such example comprises, but be not limited to cyclopentenyl amino, cyclohexenyl is amino, cyclohexadienyl is amino.Some of them embodiment is, the cycloalkenyl group on cycloalkenyl group amino can be replaced by substituting group described in the invention further.

Term " cycloalkenyl alkyl " represent alkyl group replace by one or more cycloalkenyl groups, wherein alkyl group and cycloalkenyl groups have implication as described in the present invention, such example comprises, but be not limited to cyclopentenylmethyl, cyclopentenylethyl, cyclohexenyl methyl, cyclohexenylethyl, cyclohexadiene ylmethyl, cyclohexadienyl ethyl etc.

Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or the undersaturated monocycle of part, dicyclo or three rings, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical comprises, but be not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1, 1-dioxo-thiomorpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, high morpholinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, indoline base, 1, 2, 3, 4-tetrahydric quinoline group, 1, 2, 3, 4-tetrahydro isoquinolyl, 1, 3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base, benzopyrrolodinyl, dihydro benzo furyl, benzo morpholinyl, 3, 4-dihydro-pyrido [3, 2-b] [1, 4] oxazinyl, 1, 3-benzo dioxolane base, tetrahydro pyridyl, 1, 4-benzdioxan base, pyridine-2 (1H)-one-3-base, pyridine-2 (1H)-one-4-base, pyridine-2 (1H)-one-5-base, pyridine-2 (1H)-one-6-base, pyrazine-2 (1H)-one-3-base, pyrazine-2 (1H)-one-5-base, pyrazine-2 (1H)-one-6-base.-CH in heterocyclic radical ₂-group is included, but are not limited to by the example of-C (=O)-replacement: 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but are not limited to: tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can optionally replace by one or more substituting group described in the invention.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " heterocyclic radical ", then should be appreciated that, should the sub-heterocyclyl groups that connects of " heterocyclic radical " representative.

In one embodiment, heterocyclic radical is 4-7 former molecular heterocyclic radical, and refer to and comprise the saturated of 4-7 annular atoms or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 4-7 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 4-7 former molecular heterocyclic radical comprises, but be not limited to: azelidinyl, oxetanylmethoxy, thietanyl, pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base.-CH in heterocyclic radical ₂-group is included, but are not limited to by the example of-C (=O)-replacement: 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but are not limited to: tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Described 4-7 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 4 former molecular heterocyclic radicals, refers to and comprises the saturated of 4 annular atomses or the undersaturated monocycle of part, and wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom and replaces.Unless otherwise indicated, 4 former molecular heterocyclic radicals can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 4 former molecular heterocyclic radicals includes, but are not limited to: azelidinyl, oxetanylmethoxy, thietanyl.Described 4 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 5 former molecular heterocyclic radicals, and refer to and comprise the saturated of 5 annular atomses or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 5 former molecular heterocyclic radicals can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 5 former molecular heterocyclic radicals includes, but are not limited to: pyrrolidyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopentyl, two sulphur cyclopentyl.-CH in heterocyclic radical ₂-group is included, but are not limited to by the example of-C (=O)-replacement: 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkyl.The example that in heterocyclic radical, sulphur atom is oxidized includes, but are not limited to: tetramethylene sulfone base.Described 5 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

In another embodiment, heterocyclic radical is 6 former molecular heterocyclic radicals, and refer to and comprise the saturated of 6 annular atomses or the undersaturated monocycle of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 6 former molecular heterocyclic radicals can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 6 former molecular heterocyclic radicals includes, but are not limited to: THP trtrahydropyranyl, dihydro pyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base.-CH in heterocyclic radical ₂-group is included, but are not limited to by the example of-C (=O)-replacement: 2-piperidone base, 3,5-dioxopiperidine base and pyrimidine dione base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but are not limited to: 1,1-dioxothiomorpholinyl.Described 6 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

Also in one embodiment, heterocyclic radical is 7-12 former molecular heterocyclic radical, and refer to and comprise the saturated of 7-12 annular atoms or the undersaturated spiral shell dicyclo of part or condensed-bicyclic, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, 7-12 former molecular heterocyclic radical can be carbon back or nitrogen base, and-CH ₂-group can optionally by-C (=O)-substitute, the sulphur atom of ring can optionally be oxidized to S-oxide compound, and the nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of 7-12 former molecular heterocyclic radical includes, but are not limited to: indoline base, 1,2,3,4-tetrahydric quinoline group, 1,2,3,4-tetrahydro isoquinolyl, and 1,3-benzene is two Evil cyclopentadienyls also, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.Described 7-12 former molecular heterocyclyl groups can optionally replace by one or more substituting group described in the invention.

Term " heterocyclyloxy base " comprises the optional heterocyclic radical replaced, and as defined herein, is connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heterocyclyl groups has implication as described in the present invention, and such example comprises, but be not limited to pyrrolidyl oxygen base, piperidyl oxygen base, piperazinyl oxygen base, morpholinyl oxygen base, thio-morpholinyl oxygen base, 1-oxo-thiomorpholin base oxygen base, 1,1-dioxo-thiomorpholinyl oxygen base, THP trtrahydropyranyl oxygen base etc.

Term " heterocyclylamino group " represent amino group replace by one or two heterocyclyl groups, such example comprises, but is not limited to pyrrolidyl amino, piperidyl amino, and piperazinyl is amino, and morpholinyl is amino etc.Some of them embodiment is, the heterocyclic radical on heterocyclylamino group can be replaced by substituting group described in the invention further.

Term " cycloheteroalkylalkyl " refers to the alkyl that heterocyclic radical replaces; Wherein heterocyclic radical and alkyl group have implication as described in the present invention.Such example comprises, but is not limited to thiomorpholine-4-ylmethyl, tetrahydrofuran (THF)-3-ylmethyl, trimethylene oxide-3-ylmethyl, pyrrolidin-2-yl methyl, morpholine-4-ylmethyl etc.

Term " heterocyclylalkoxy " represent alkoxy base replace by one or more heterocyclyl groups, wherein alkoxy base and heterocyclyl groups have implication as described in the present invention, such example comprises, but is not limited to pyrrolidyl methoxyl group, pyrrolidyl oxyethyl group, piperidyl methoxyl group, piperidinylethoxy, piperazinyl methoxyl group, piperazinyl oxyethyl group, morpholinyl methoxyl group, morpholinyl oxyethyl group etc.

Term " heterocycle containing at least one nitrogen-atoms " refers to except described nitrogen-atoms, this heterocycle is not containing other heteroatoms, or this heterocycle contains one, two, three, four, five or six other heteroatomss, described other heteroatoms is selected from nitrogen, oxygen or sulphur, and-the CH of makeup ring ₂-optionally by-C (=O)-substitute, the sulphur atom of makeup ring is optionally oxidized to S-oxide compound and obtains picture S (=O) or S (=O) ₂group, the nitrogen-atoms of makeup ring is optionally oxidized to N-oxygen compound.The described heterocyclyl groups containing at least one nitrogen-atoms can optionally replace by one or more substituting group described in the invention.Such example comprises, but is not limited to

deng.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 3-10 atom.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 4-10 atom.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 3-8 atom.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 4-8 atom.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 3-7 atom.

In one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 4-7 atom.

In another embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 5-7 atom.

Also in one embodiment, the heterocyclyl groups containing at least one nitrogen-atoms is made up of 5-6 atom.Such example comprises, but is not limited to deng.

Term " condensed-bicyclic " and " condensed-bicyclic base " commutative use herein, refer to the undersaturated bridged-ring system of saturated or part of unit price or multivalence, described bridged-ring system refers to the bicyclic system of non-aromatic, such system can comprise independently or the unsaturated system of conjugation, but its core texture does not comprise aromatic nucleus or fragrant heterocycle (but aromatic group can as the substituting group on it).Term " bridged ring " refers to that any two rings share two atoms being directly connected or not directly being connected.Such as, as below described by formula a and formula b, ring A ¹with ring A ², ring B ¹with ring B ²share two C atoms (being designated as 1 and 2 in formula); Picture is below described by formula c and formula d, ring A ³with ring A ⁴, ring B ³with ring B ⁴share 1 C atom and 1 atom N (being denoted as 3 and 4 in formula).Each ring in condensed-bicyclic is carbocyclic ring or is heterocycle, and such example comprises, but is not limited to, hexahydro furyl also [3,2-b] furans, 2,3,3a, 4,7,7a-six hydrogen-1H-indenes, 7-azabicyclo [2.2.1] heptane, condensed-bicyclic [3.3.0] octane, condensed-bicyclic [3.1.0] hexane, 1,2,3,4,4a, 5,8,8a-octahydro naphthalene, these are included within the system of condensed-bicyclic, and described condensed-bicyclic base can be substituted or non-substituted.

Term " condenses assorted dicyclo " and represents saturated or the undersaturated fused ring system of part, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprise 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, this S or P optionally replace by one or more Sauerstoffatom obtain picture SO, SO ₂, PO, PO ₂group, such example comprises, but is not limited to hexahydro furyl also [3,2-b] furans, 7-azabicyclo [2.2.1] heptane, 3-azabicyclo [3.3.0] octane, 3,5,8-trioxa-l-phosphabicyclo [5,1,0] octane, 1-azepine-4,6-dioxy-bicyclo [3.3.0] octane etc., and described in condense assorted bicyclic group can be substituted or non-substituted.

Term " spiral shell bicyclic group " or " spiral shell dicyclo " commutative use herein, refer to the unsaturated member ring systems of saturated or part of unit price or multivalence, and one of them ring originates from specific ring carbon atom on another ring.Such as, as below described by formula f, ring D ¹with ring D ²in two saturated member ring systems, share a carbon atom, be called as " volution " or " spiral shell dicyclo ".Each ring in spiral shell bicyclic group can be carbocylic radical or heterocyclic radical, and each ring optionally replace by one or more substituting group described in the invention.

Term " spiral shell mix bicyclic group " represents that a ring originates from ring-type carbon special on another ring, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 3-7 ring, namely comprise 1-6 carbon atom and be selected from N, 1-3 the heteroatoms of O, P, S, at this S or P optionally replace by one or more Sauerstoffatom and obtain such as SO, SO ₂, PO, PO ₂group, such example comprises, but is not limited to 4-azaspiro [2.4] heptane-5-base, 4-oxaspiro [2.4] heptane-5-base, 5-azaspiro [2.4] heptane-5-base, 7-hydroxyl-5-azaspiro [2.4] heptane-5-base etc.

Term " Heterocyclylalkyl " refers to the saturated monocycle of unit price containing 3-12 annular atoms or multivalence, dicyclo or three-ring system, and wherein at least one annular atoms is selected from nitrogen, sulphur or Sauerstoffatom.

Term " n former molecular ", wherein n is integer, typically describes the number of ring member nitrogen atoms in molecule, and in described molecule, the number of ring member nitrogen atoms is n.Such as, piperidyl is 6 former molecular Heterocyclylalkyls, and 1,2,3,4-naphthane is 10 former molecular carbocylic radical groups.

Term " undersaturated " used in the present invention represents in group containing one or more degree of unsaturation.

Term " heteroatoms " refers to O, S, N, P and Si, comprises the form of any oxidation state of N, S and P; The form of primary, secondary, tertiary amine and quaternary ammonium salt; Or the form that the hydrogen in heterocycle on nitrogen-atoms is substituted, such as, N (N as in 3,4-dihydro-2 h-pyrrole base), NH (NH as in pyrrolidyl) or NR (NR as in the pyrrolidyl that N-replaces).

Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Term " azido-" or " N ₃" represent a nitrine structure.This group can be connected with other groups, such as, can be connected to form triazonmethane (MeN with a methyl ₃), or be connected to form phenylazide (PhN with a phenyl ₃).

Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more attachment point to be connected with the rest part of molecule.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group can comprise phenyl, indenyl, naphthyl and anthracene.Described aromatic yl group can independently optionally replace by one or more substituting group described in the invention.

Term " aryloxy " or " aryloxy " comprise the optional aryl replaced, as defined herein, be connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein aromatic yl group has implication as described in the present invention, and such example comprises, but is not limited to phenoxy group, to tolyloxy, to second phenoxy group etc.

Term " virtue amino " or " arylamino " represent amino group replace by one or two aromatic yl group, such example comprises, but is not limited to N-phenylamino.Some of them embodiment is, the aromatic ring on fragrant amino can be substituted further.

Term " arylalkyl " or " aralkyl " represent alkyl replace by one or more aromatic yl group, wherein alkyl and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to benzyl, phenylethyl, p-methylphenyl ethyl etc.

Term " alkoxy aryl " represent alkoxyl group replace by one or more aromatic yl group, wherein alkoxyl group and aromatic yl group have implication as described in the present invention, and such example comprises, but is not limited to benzyloxy, phenyl ethoxy, to toluene oxyethyl group etc.

Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Described heteroaryl groups optionally replace by one or more substituting group described in the invention.In one embodiment, 5-10 former molecular heteroaryl comprises 1,2,3 or 4 and is independently selected from O, the heteroatoms of S and N.

The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..

Term " heteroaryl oxygen base " comprises the optional heteroaryl replaced, and as defined herein, is connected on Sauerstoffatom, and be connected with molecule rest part by Sauerstoffatom, wherein heteroaryl groups has implication as described in the present invention, and such example comprises, but be not limited to imidazolyl oxygen base, pyrazoloxy ， oxazolyl oxygen base isoxazolyl oxygen base, pyrryl oxygen base, pyridyl oxygen base, pyrimidyl oxygen base, pyridazinyl oxygen base, thiazolyl oxygen base etc.

Term " heteroaryl amino " represent amino group replace by one or two heteroaryl groups, such example comprises, but is not limited to imidazolyl amino, and pyrazolyl is amino, thienyl is amino, pyridinylamino, pyrimidinyl-amino, pyrazinyl is amino, and pyridazinyl is amino, etc.Some of them embodiment is, the hetero-aromatic ring on heteroaryl amino can be substituted further.

Term " heteroarylalkyl " represent alkyl group replace by one or more heteroaryl groups, wherein alkyl group and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-base ethyl, thiazol-2-yl methyl, imidazoles-2-base ethyl, pyrimidine-2-base propyl group etc.

Term " heteroarylalkoxy " represent alkoxy base replace by one or more heteroaryl groups, wherein alkoxy base and heteroaryl groups have implication as described in the present invention, such example comprises, but be not limited to pyridine-2-base oxethyl, thiazol-2-yl methoxyl group, imidazoles-2-base oxethyl, pyrimidine-2-base propoxy-etc.

No matter term " carboxyl ", be used alone or be used in conjunction with other terms, as " carboxyalkyl ", and expression-CO ₂h or-COOH; No matter term " carbonyl ", be used alone or be used in conjunction, as " aminocarboxyl " with other terms; " acyloxy ", " alkyl acyl ", " cycloalkanoyl "; " heterocyclylacyl ", " aryl-acyl " or " heteroaroyl ", represent-(C=O)-.

Term " oxo " refers to=O, represents that oxygen links with double bond with the atom of the position of substitution.

Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH ₂cH ₂sO ₂ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: TW.Greene, ProtectiveGroupsinOrganicSynthesis, JohnWiley & Sons, NewYork, 1991; AndP.J.Kocienski, ProtectingGroups, Thieme, Stuttgart, 2005.

Term used in the present invention " prodrug ", represents a compound and is converted into formula (I), formula (II), formula (IIa), formula (IIb) or the compound shown in formula (IIc) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug _1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.HiguchiandV.Stella, Pro-drugsasNovelDeliverySystems, Vol.14oftheA.C.S.SymposiumSeries, EdwardB.Roche, ed., BioreversibleCarriersinDrugDesign, AmericanPharmaceuticalAssociationandPergamonPress, 1987, J.Rautioetal., Prodrugs:DesignandClinicalApplications, NatureReviewDrugDiscovery, 2008, 7, 255-270, andS.J.Heckeretal., ProdrugsofPhosphatesandPhosphonates, JournalofMedicinalChemistry, 2008, 51, 2328-2345.

" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.

" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Bergeetal., describepharmaceuticallyacceptablesaltsindetailinJ.Pharm aceuticalSciences, described in 1977,66:1-19..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N ⁺(C _1-4alkyl) ₄salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C _1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.

" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

Term as used in the present invention " treatment " any disease or illness, wherein in some embodiments, " treatment " refers to improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom).In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.

" inflammation " used in the present invention refer to caused by tissue damaged or destruction topical protective response, it for destroy, dilute or separate (completely cut off) be harmful to material and impaired tissue.Inflammation and white corpuscle flow into and/or Neutrophil chemotaxis has and contacts significantly.Inflammation can result from the infection of pathogenic organism and virus and non-infectious mode, as the wound after myocardial infarction or apoplexy or Reperfu-sion, to immunne response and the autoimmune response of exotic antigen.Therefore, can comprise by the inflammatory diseases of the open compounds for treating of the present invention: to react to specificity system of defense and non-specific defense system reacts relevant disease.

" arthritis disease " refers to be attributable to any disease that various etiologic etiological arthritis damage is feature as used in the present invention." dermatitis " refers to be attributable to any one in the extended familys of the dermatosis that various etiologic etiological skin inflammation is feature as used in the present invention.

Pharmaceutically useful acid salt can be formed with mineral acid and organic acid, such as acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate, muriate/hydrochloride, chloro theophylline salt, Citrate trianion, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, poly-semi-lactosi hydrochlorate, propionic salt, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. can be comprised by its derivative mineral acid obtaining salt.

Such as acetic acid, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, citric acid, phenylformic acid, amygdalic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, sulphosalicylic acid etc. can be comprised by its derivative organic acid obtaining salt.

Pharmaceutically acceptable base addition salt can be formed with mineral alkali and organic bases.

Can be comprised by its derivative mineral alkali obtaining salt, the metal of I race to the XII race of such as ammonium salt and periodictable.In certain embodiments, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper; Particularly suitable salt comprises ammonium, potassium, sodium, calcium and magnesium salts.

Can comprise primary amine, secondary amine and tertiary amine by its derivative organic bases obtaining salt, the amine of replacement comprises the amine, cyclic amine, deacidite etc. of naturally occurring replacement.Some organic amine comprises, such as, and Isopropylamine, dibenzylethylenediamine dipenicillin G (benzathine), choline salt (cholinate), diethanolamine, diethylamine, Methionin, meglumine (meglumine), piperazine and Trometamol.

Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' sPharmaceuticalSciences ", the 20th edition, MackPublishingCompany, Easton, Pa., 1985; " pharmaceutical salts handbook: character, choice and application (HandbookofPharmaceuticalSalts:Properties; Selection; andUse) ", StahlandWermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.

In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.

Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as ²h, ³h, ¹¹c, ¹³c, ¹⁴c, ¹⁵n, ¹⁷o, ¹⁸o, ¹⁸f, ³¹p, ³²p, ³⁵s, ³⁶cl and ¹²⁵i.

On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as ³h, ¹⁴c and ¹⁸those compounds of F, or wherein there is non radioactive isotope, as ²h and ¹³c.The compound of such isotopic enrichment can be used for metabolism research and (uses ¹⁴c), reaction kinetics research (uses such as ²h or ³h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. ¹⁸the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, formula (II), formula (IIa), formula (IIb) or formula (IIc), compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.

In addition, particularly deuterium is (that is, for higher isotope ²h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I), formula (II), formula (IIa), formula (IIb) or formula (IIc) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent ₂o, acetone-d ₆, DMSO-d ₆those solvates.

The description of the compounds of this invention

Compound of the present invention and the treatment of pharmaceutical composition to chronic obstructive pulmonary disease (COPD) thereof have potential purposes.

Wherein:

X is N (R ^b), O or S;

Y is O or S;

A is the heterocyclic radical containing at least one nitrogen-atoms;

M is 0,1,2 or 3;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

Some of them embodiment is, R ¹for H, deuterium, C _1-4alkyl, halo C _1-4alkyl, amino C _1-3the C that alkyl, hydroxyl replace _1-3the C that alkyl, cyano group replace _1-3alkyl, C _1-3alkyl-C (=O)-, C _1-3alkyl-S (=O) ₂-, C _2-4thiazolinyl or C _2-4alkynyl.

Some of them embodiment is, each R ²be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, C _1-3alkyl, halo C _1-3alkyl, amino C _1-3the C that alkyl, hydroxyl replace _1-3the C that alkyl, cyano group replace _1-3alkyl, C _1-3alkoxyl group, halo C _1-3alkoxyl group or C _1-3alkylamino.

Some of them embodiment is, R ⁴for deuterium, NH ₂, C _2-4alkyl, halo C _1-4alkyl, amino C _1-4the C that alkyl, hydroxyl replace _1-4the C that alkyl, cyano group replace _1-4alkyl, C _2-4thiazolinyl, C _2-4alkynyl, C _1-3alkoxyl group, C _1-3alkylamino ,-C (=O)-NH ₂or-S (=O) ₂-NH ₂.

Some of them embodiment is, m is 0,1,2 or 3.

Other embodiment is, R ¹for H, deuterium ,-CH ₃,-CH ₂cH ₃,-CH ₂cH ₂cH ₃,-CH (CH ₃) CH ₃,-CH ₂cl ,-CHCl ₂,-CCl ₃,-CH ₂f ,-CHF ₂,-CF ₃,-CH ₂cH ₂cl ,-CH ₂cHCl ₂,-CH ₂cH ₂f or-CH ₂cHF ₂.

Other embodiment is, each R ²be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, COOH ,-C (=O)-NH ₂,-S (=O) ₂-NH ₂, methyl or methoxy.

Other embodiment is, R ⁴for NH ₂,-CH ₂cH ₃,-CH ₂cH ₂nH ₂,-CH (CH ₃) NH ₂,-CH ₂cH ₂cH ₂nH ₂,-CH (CH ₂cH ₃) NH ₂,-CH ₂cH (CH ₃) NH ₂,-CH (CH (CH ₃) ₂) NH ₂,-C (=O)-NH ₂or-S (=O) ₂-NH ₂.

Other embodiment is, A is following subformula:

Wherein:

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

Each Z ¹be NH, O, S, S (=O) or S (=O) independently ₂;

Each W is CH independently ₂, NH or O;

Each V is CH independently ₂or NH;

Each E is CH or N independently;

Each G is O or NH independently;

Each p is 0,1,2 or 3 independently;

Each q is 1 or 2 independently;

Each r is 0,1,2 or 3 independently;

Each s is 1,2 or 3 independently.

Other embodiment is, A is following subformula:

Wherein:

Each R ⁵with n, there is implication as described in the present invention;

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

T is 0,1,2 or 3.

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIb) or formula (IIb), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIc) or formula (IIc), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IId) or formula (IId), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIe) or formula (IIe), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Some of them embodiment is, the present invention relates to a kind of compound, it is for such as formula the steric isomer of compound shown in the compound shown in (IIf) or formula (IIf), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each R ⁵there is implication as described in the present invention.

Wherein each R ⁶, R ^6a, R ^band R ^cthere is implication as described in the present invention.

Some of them embodiment is, each R ⁶be H, deuterium, OH, NH independently ₂, C _1-8alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6alkyl, C _1-6alkoxy C _1-6alkyl, C _1-8alkoxyl group, halo C _1-6the C that alkoxyl group, hydroxyl replace _1-8the C of alkoxyl group, carboxyl substituted _1-6alkoxyl group, C _1-6alkoxy C _1-6alkoxyl group, C _3-8cycloalkyl C _1-6alkoxyl group, C _2-10heterocyclic radical C _1-6alkoxyl group, C _6-10aryl C _1-6alkoxyl group, C _1-9heteroaryl C _1-6alkoxyl group, C _1-6alkylamino, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-6alkyl, C _3-8cycloalkyl oxy, C _2-10heterocyclic radical, C _2-10heterocyclic radical C _1-6alkyl, C _2-10heterocyclyloxy base, C _6-10aryl, C _6-10aryl C _1-6alkyl, C _6-10aryloxy, C _1-9heteroaryl, C _1-9heteroaryl oxygen base or C _1-9heteroaryl C _1-6alkyl.

Some of them embodiment is, each R ^6abe H, C independently _1-8alkyl, halo C _1-8the C that alkyl, hydroxyl replace _1-8the C of alkyl, carboxyl substituted _1-8alkyl, C _1-6alkoxy C _1-6alkyl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl C _1-6alkyl, C _3-8cycloalkyl, C _2-10heterocyclic radical, C _6-10aryl or C _1-9heteroaryl.

Some of them embodiment is, each R ^band R ^cbe H, deuterium, C independently _1-8alkyl, halo C _1-6the C that alkyl, hydroxyl replace _1-8the C of alkyl, carboxyl substituted _1-8alkyl, C _1-6alkoxy C _1-6alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl or C _1-9heteroaryl C _1-6alkyl.

Some of them embodiment is, R ^b, R ^c3-8 former molecular ring is formed together with the nitrogen-atoms be attached thereto.

Other embodiment is, each R ⁶be H, deuterium, OH, NH independently ₂, C _1-6alkyl, C _1-6the C that alkoxyl group, hydroxyl replace _1-6the C of alkoxyl group, carboxyl substituted _1-6alkoxyl group, C _1-3alkoxy C _1-4alkoxyl group, C _3-6cycloalkyl C _1-3alkoxyl group, C _2-6heterocyclic radical C _1-3alkoxyl group, C _6-10aryl C _1-3alkoxyl group, C _1-5heteroaryl C _1-3alkoxyl group, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-3alkyl, C _3-8cycloalkyl oxy, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _2-6heterocyclyloxy base, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _6-10aryloxy, C _1-6heteroaryl, C _1-5heteroaryl oxygen base or C _1-6heteroaryl C _1-3alkyl.

Other embodiment is, each R ^6abe H, C independently _1-6alkyl, halo C _1-6the C that alkyl, hydroxyl replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-3alkoxy C _1-4alkyl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl C _1-3alkyl, C _3-6cycloalkyl, C _2-6heterocyclic radical, C _6-10aryl or C _1-5heteroaryl.

Other embodiment is, each R ^band R ^cbe H, deuterium, C independently _1-6alkyl, halo C _1-3the C that alkyl, hydroxyl replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-3alkoxy C _1-4alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl or C _1-5heteroaryl C _1-3alkyl.

Other embodiment is, R ^b, R ^c3-6 former molecular ring is formed together with the nitrogen-atoms be attached thereto.

Other embodiment is, each R ⁶be H, deuterium, OH, NH independently ₂, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, methoxyl group, the methoxyl group that hydroxyl replaces, the methoxyl group of carboxyl substituted, oxyethyl group, the oxyethyl group that hydroxyl replaces, the oxyethyl group of carboxyl substituted, propoxy-, the propoxy-that hydroxyl replaces, the propoxy-of carboxyl substituted, isopropoxy, the isopropoxy that hydroxyl replaces, the isopropoxy of carboxyl substituted, butoxy, the butoxy that hydroxyl replaces, the butoxy of carboxyl substituted, isobutoxy, the isobutoxy that hydroxyl replaces, the isobutoxy of carboxyl substituted, methoxymethoxy, methoxy ethoxy, methoxy propoxy, oxyethyl group methoxyl group, ethoxy ethoxy, benzyloxy, phenyl ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, cyclo propyl methoxy, cyclobutyl methoxyl group, cyclopentylmethoxy, cyclohexyl methoxy, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1,1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1,1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, phenyl, indenyl, naphthyl, benzyl, styroyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridylmethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl or pyridazinyl ethyl.

Other embodiment is, each R ^6abe H independently, methyl, ethyl, propyl group, sec.-propyl, butyl, methylol, hydroxyethyl, hydroxypropyl, the sec.-propyl that hydroxyl replaces, hydroxyl butyl, 2-hydroxy-2-methyl propyl group, carboxymethyl, propyloic, carboxylic propyl group, 2-carboxyl-2-methylethyl, methoxymethyl, methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl-ethyl, phenyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl.

Other embodiment is, each R ^band R ^cbe the C of H, deuterium, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, hydroxyl replacement independently _1-5the C of alkyl, carboxyl substituted _1-4alkyl, methoxymethyl, methoxy ethyl, methoxy-propyl, ethoxyl methyl, ethoxyethyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclopropylethyl, Cyclopropylpropyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclopentyl ethyl, cyclohexyl methyl, cyclohexyl-ethyl, phenyl, benzyl, styroyl or phenyl propyl.

Other embodiment is, R ^b, R ^cazetidine, tetramethyleneimine, piperidines, piperazine, morpholine, thiomorpholine, 1-oxo-thiomorpholin or 1,1-Dioxo-thiomorpholin is formed together with the nitrogen-atoms be attached thereto.

On the one hand, the present invention relates to a kind of compound, comprise but be never limited to the compound with one of following structure or there is the steric isomer of one of following structural compounds, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment respiratory disease, allergy and inflammation, central nervous system (CNS) disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus, comprise that those are described in the invention.

Compound of the present invention is used for alleviating for the production of a kind of pharmaceuticals equally, stops, and controls or treat illness, particularly chronic obstructive pulmonary disease (COPD) that PDE4 mediates.

The present invention comprises pharmaceutical composition, this pharmaceutical composition comprises formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or the compound representated by (IIf) and the pharmaceutically acceptable carrier of at least one, the effective treatment consumption needed for the combination of assistant agent or thinner.

Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, metabolic precursor thereof, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.

Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.

The salt of compound of the present invention also comprise for the preparation of or purifying formula (I), (II), (IIa), (IIb), (IIc), (IId), the intermediate of compound shown in (IIe) or (IIf) or formula (I), (II), (IIa), (IIb), (IIc), (IId), compound separation shown in (IIe) or (IIf) the salt of enantiomer, but not necessarily pharmacy acceptable salt.

If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.

If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.

The compounds of this invention and pharmaceutical composition, preparation and administration

Its racemic mixture, enantiomer, diastereomer, rotational isomer, N-oxide compound, polymorphic form, solvate and pharmacy acceptable salt and active metabolite form can be produced and be formulated as to compound of the present invention; Also can produce containing the compound shown in formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or its metabolite, enantiomer, non-corresponding isomer, N-oxide compound, polymorphic form, solvate or pharmacy acceptable salt and pharmaceutically acceptable carrier and the pharmaceutical composition of vehicle that optionally comprises.

Pharmaceutical composition of the present invention can be produced and administration by dose unit, and constituent parts comprises acceptable addition salt on a certain amount of at least one compound of the present invention and/or its physiology of at least one.Dosage can change in the scope of non-constant width, even this is because this compound low dosage level is also effective, and nontoxicity comparatively speaking.This compound can treat effective low micromolar administration, as required dosage can be brought up to the maximal dose that patient can bear.

When can be used for treatment, the formula (I) for the treatment of significant quantity, (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) shown compound and pharmacy acceptable salt thereof can be used as unprocessed pharmaceutical chemicals and give, and the activeconstituents that also can be used as pharmaceutical composition provides.Therefore, content of the present invention also provides pharmaceutical composition, and this pharmaceutical composition comprises compound shown in the treatment formula (I) of significant quantity, (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle.

In fact, pharmacopedics compounding technology conveniently, compound of the present invention or its pharmacy acceptable salt can as activeconstituents with intimately mixed mode and pharmaceutical carrier combined.Carrier can have various form, and this depends on the form of wishing to carry out the preparation used, such as oral or parenteral (comprising intravenously).Therefore, described pharmaceutical composition can exist as being suitable for the Orally administered unit separated, such as glue Nang, flat Nang agent or tablet, wherein each activeconstituents containing predetermined amount.In addition, described composition can exist with following form: powder, granule, solution, suspension, non-aqueous liquid, oil-in-water emulsion or water-in-oil liquid emulsion in waterborne liquid.Except the common formulations of showing above, described compound or its pharmacy acceptable salt, also can be used by controlled release means and/or delivery apparatus.Described composition can be prepared by any method in pharmacy industry.Usually, these class methods comprise step combined to activeconstituents and carrier (its form one or more must composition).Usually, described composition by by the solid carrier of activeconstituents and liquid vehicle or segmentation or both evenly and mix nearly and prepare.Then, described product can be made into desired form easily.

The pharmaceutical carrier adopted can be solid, liquid or gas.The example of solid carrier comprises lactose, terra alba, sucrose, talcum, gelatin, agar, pectin, gum arabic, Magnesium Stearate and stearic acid.The example of liquid vehicle is syrup, peanut oil, sweet oil and water.The example of carrier gas comprises carbonic acid gas and nitrogen.

Term used in the present invention " treatment significant quantity " refers to the total amount of each active ingredient being enough to demonstrate significant patient benefit.When using independent activeconstituents individually dosed, this term only refers to this composition.When Combination application, and though this term then refer to combination, successively or simultaneously administration time, all cause the combined amount of the activeconstituents of result for the treatment of.Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) shown compound and pharmacy acceptable salt thereof are described above.From compatible with other compositions of preparation and harmless to its recipient meaning, carrier, thinner or vehicle must be acceptable.According to the another aspect of content of the present invention, also be provided for the method for useful in preparing drug formulations, the method comprises and formula (I), (II), (IIa), (IIb), (IIc), (IId), compound shown in (IIe) or (IIf) or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier, thinner or vehicle being mixed.Term used in the present invention " pharmaceutically acceptable " refers to such compound, raw material, composition and/or formulation, they are in the scope that rational medicine judges, to be applicable to patient tissue contacts and without excessive toxicity, pungency, transformation reactions or the other problems symmetrical with rational interests/Hazard ratio and complication, and to be effective to given application.

Usually, compound of the present invention is applied to treat significant quantity by any conventional method of application of the material for playing similar effectiveness.Suitable dosage range typically is 1-500mg every day, preferred every day 1-100mg, most preferably every day 1-30mg, this depends on many factors, such as the seriousness of institute's disease therapy, the age of subject and relative health, the effect of compound used therefor, the approach used and form, use for indication and the preference of relevant medical practitioner and experience.Treat the those of ordinary skill of described disease areas without the need to too much testing the treatment significant quantity relying on the disclosure of personal knowledge and the application can determine the compounds of this invention of given disease.

The administration of the compounds of this invention can be carried out according to needs of patients, such as, oral administration, nose administration, parenterai administration (in subcutaneous, intravenously, intramuscular, breastbone and infusion), inhalation, per rectum administration, intravaginal administration, Topical administration, topical, transdermal administration and administration through eye.

Various solid oral dosage form can be used for the administration of the compounds of this invention, the such as solid dosage of tablet, soft capsule, capsule, caplet, particle, lozenge and bulk powder.Can by the compounds of this invention individually dosed or with various pharmaceutically acceptable carrier known in the art, thinner (such as, sucrose, N.F,USP MANNITOL, lactose, starch) and excipient composition administration, include but not limited to suspending agent, solubilizing agent, buffer reagent, tackiness agent, disintegrating agent, sanitas, tinting material, seasonings, lubricant etc.Timed release capsule, tablet and gelifying agent are also favourable for the administration of the compounds of this invention.

Tablet can be prepared by suppressing or being molded, and uses one or more ancillary components or auxiliary agent alternatively.Compressed tablets is prepared, alternatively with tackiness agent, lubricant, inert diluent, tensio-active agent or dispersant with the activeconstituents of free-flowing form (such as powder or particle) by suppressing in suitable machine.Prepared by the mixture of the powdered compounds that molded tablet soaks by mold pressing inert liquid diluent in suitable machine.The activeconstituents of each tablet preferably containing about 0.lmg to about 500mg; The activeconstituents preferably containing about 0.1mg to about 500mg with each flat Nang agent or glue Nang.Therefore, when take one or two tablet, flat Nang agent or glue Nang (once a day, twice or three times), tablet, flat Nang agent or glue Nang are easily containing the activeconstituents of 0.lmg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg or 500mg.

By compound of the present invention with plurality of liquid oral dosage form, moisture and anhydrous solution, emulsion, suspension, syrup and elixir can also be comprised.This formulation can also comprise applicable inert diluent as known in the art, such as water, and applicable vehicle as known in the art, such as sanitas, lubricant, sweeting agent, seasonings.And for making the compounds of this invention emulsification and/or becoming the reagent of suspension.Compound of the present invention can with the form drug administration by injection of isotonic sterile solution, such as, and intravenous injection.Other prepared product is also possible.

Suppository for the rectal administration of the compounds of this invention can by preparing compound as theobroma oil, salicylate and polyoxyethylene glycol mix with the excipients be applicable to.

Preparation for vagina administration can be creme, gelifying agent, paste, foam or spray form, also comprises such as applicable carrier known in the art in addition to the active component.

For topical, pharmaceutical composition can for being suitable for the form of creme, ointment, liniment, washing lotion, emulsion, suspension, gelifying agent, solution, paste, pulvis, sprays and drops to skin, eyes, ear or nasal administration.Topical can also comprise the transdermal administration undertaken by the mode of such as percutaneous plaster.

For the treatment of respiratory tract disease, preferred compound of the present invention passes through inhalation.For this reason, with pulvis (being preferably micronised form) directly administration, or the spray solution agent or the suspension administration that contain them can be passed through.

Can suck prepared product comprise can suck pulvis, containing the metered aerosol of propelling agent or not containing the inhalative solution formulation of propelling agent.

Diluent or carrier can be added to powder compounds of the present invention, described diluent or carrier normally nontoxic and be chemically inert for compound of the present invention, such as lactose or be suitable for improve can breathe part any other additive.

The inhalation aerosol of air inclusion propelling agent such as hydro fluoroalkanes can comprise the compounds of this invention of solution or discrete form.The preparation of propellant actuated can also comprise other compositions, such as cosolvent, stablizer and other optional vehicle.

Containing the compounds of this invention can not be solution in water-bearing media, alcoholic medium or aqueous alcoholic medium or form of suspension containing the inhalative solution formulation of propelling agent, and they can be sent by the known blast atomizer of prior art or ultrasonic atomizer, or by mist spraying gun (soft-mistnebulizers) such as send.

Compound of the present invention can as independent active agent delivery or with the administration of other medicines active ingredient combinations, described other drug activeconstituents comprises those that be used for the treatment of respiratory condition at present, such as, β 2-agonist, such as husky butanolamine, formoterol, Salmeterol and carmoxirole (TA2005); Cortical steroid, such as budesonide and epimer thereof, Viarox, Triamcinolone Acetonide, fluticasone propionate, flunisolide, furoic acid momisone, Rofleponide and ciclesonide; With anticholinergic or antimuscarinic drug, such as ipratropium bromide, oxitropium bromide, tiotropium bromide, Glycopyrronium Bromide, Revatropate or the compound disclosed in WO03/053966.

Preferably, give with independent or with compound shown in the formula (I) of other active ingredient combinations, (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) for preventing and/or treating the respiratory tract disease being characterised in that obstruction of the air passage, such as asthma, chronic bronchitis or chronic respiratory obstruction tuberculosis (COPD).

Term " combinationally uses " or " combination " is appreciated that as following implication: each composition can side by side or more or less side by side or administration respectively in succession.Wherein in some embodiments, a kind of therapeutical agent/active constituents of medicine can morning dose, another kind of at time administration after a while on the same day.In further embodiments, a kind of agent/active constituents of medicine for the treatment of can be administered once for one day, and another kind is then administered once for one week.Be appreciated that time, if each composition is directly one after the other administration, then the delay of the second ingredient administration should not make the beneficial therapeutic effect losing this combination.

Administration simultaneously can be undertaken by any suitable approach, and be better such as by make these therapeutical agents by peroral route or intravenous route or through intramuscular route or subcutaneous injection to the object administration having these needs, make this form of medication have the fixed proportion of each therapeutical agent.

The more or less simultaneously administration of each therapeutical agent or in succession administration can by any suitable approach, include but not limited to peroral route, through intravenous route, carry out through intramuscular route and absorbing via mucosal tissue.These therapeutical agents can also can by different approaches administration by identical approach.Such as, two kinds of therapeutical agents of this combination can oral administration.

The compounds of this invention can be comprised in pharmaceutical composition.Described pharmaceutical composition comprises compound described in the invention or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable carrier; And optionally comprise other treatment composition or auxiliary agent (adjuvant).Optionally other therapeutic component comprises, such as i) LTRA, ii) inhibitors of leukotriene biosynthesis, iii) reflunomide, iv) H1 receptor antagonist, v) beta 2 adrenoreceptor agonists, vi) COX-2 selective depressant, vii) statin, viii) nonsteroid anti-inflammatory drugs (" NSAID "), and ix) M2/M3 antagonist.

The composition that described composition comprises and is suitable for oral, rectum, local and parenteral (comprising subcutaneous, intramuscular and intravenously) are used, although in a given situation, most suitable approach depends on concrete host, and uses the character of symptom and the severity of described activeconstituents in order to it.Described pharmaceutical composition can exist easily in a unit, and by using any method known in pharmacy field to prepare.

Comprise the ointment of described compound, ointment, jelly, solution or suspension and can be used for local use.For the purposes of the present invention, in the scope that local uses, mouth wass and mouth wash shua is comprised.

The pharmaceutical composition being suitable for parenteral administration can be made into the solution of activeconstituents in water or suspension.Suitable tensio-active agent can be comprised, such as hydroxypropylcellulose.Dispersion can also be prepared in glycerine, liquid polyethylene glycol and their mixture (in oil).In addition, sanitas can be comprised to prevent the obnoxious growth of microorganism.

Be suitable for injecting those pharmaceutical compositions used and comprise aseptic aqueous solution or dispersion.Described composition can be the form of sterilized powder, for immediate system for this type of sterile injectable solution or dispersion.In all cases, final injectable forms must be aseptic, and must be that effectively flowing is can easily inject.

Described pharmaceutical composition must be stable under the conditions of manufacture and storage; Therefore, preferably should protect for the contamination of microorganism (such as bacterium and fungi).Described carrier can be solvent or dispersion medium, comprises such as water, ethanol, polyvalent alcohol (such as, glycerine, propylene glycol and liquid polyethylene glycol), vegetables oil and suitable mixture thereof.

Described pharmaceutical composition can such as, for being suitable for the form that local uses, aerosol, ointment, ointment, washing lotion, face powder etc.In addition, described composition can, for being suitable for the form used in transdermal device, can, by conventional working method, use compound or its pharmacy acceptable salt to prepare these preparations.As an example, ointment and ointment are prepared by following manner: the compound of mixing hydrophilic material and water and about 5wt% to about 10wt%, thus produce ointment or the ointment with desirable consistency.

The invention provides and treat tuberculosis (such as, COPD in the patient needing this treatment, asthma or fibrocyst) method, the method comprises at least one formula (I) of combining and giving described bacterium, (II), (IIa), (IIb), (IIc), (IId), or compound shown in (IIf) (IIe), or its pharmacy acceptable salt or solvate, and at least one is selected from following compound: steroid (as glucocorticosteroid), 5-lipoxidase inhibitor, beta-2-adrenoceptor (adrenoceptor) agonist, alpha-2 adrenoceptor agonists, muscarine M1 antagonist, muscarine M3 antagonist, muscarine M2 agonist, NK3 antagonist, LTB4 antagonist, cysteinyl leukotriene antagonist, bronchodilator, PDE4 inhibitor, PDE inhibitor, elastase inhibitor, MMP inhibitor, PLA 2 inhibitors, phospholipase D inhibitors, Histamine H1 Antagonists, histamine H 3 antagonists, dopamine agonist, adenosine A 2 agonist, NK1 and NK2 antagonist, GABA-b agonist, nociception peptide agonists, expectorant, mucolytic agent, Decongestant, mast cell stabilizers, antioxidant, anti-IL-8 antibody, anti-IL-5 antibody, anti-IgE antibody, anti-TNF antibody, IL-10, adhesion molecule inhibitors, tethelin and other PDE4 inhibitor.

For formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or the limiting examples of resistance amine agent of compound conbined usage shown in (IIf) comprise: astemizole (astemizole), azatadine (azatadine), azelastine (azelastine), acrivastine (acrivastine), Parabromdylamine (brompheniramine), cetirizine (certirizine), chlorphenamine (chlorpheniramine), clemastine (clemastine), cyclizine (cyclizine), carebastine (carebastine), Cyproheptadine (cyproheptadine), carbinoxamine (carbinoxamine), decarbonylation oxyethyl group loratadine (descarboethoxyloratadine), doxylamine (doxylamine), Dimetindene (dimethindene), ebastine (ebastine), epinastine (epinastine), Efletirizine (efletirizine), fexofenadine (fexofenadine), hydroxyzine (hydroxyzine), ketotifen (ketotifen), Loratadine (loratadine), levocabastine (levocbastine), mizolastine (mizolastine), his piperazine (equitazine) of Chinese mugwort quinoline, mianserin (mianserin), R 64947 (noberastine), Meclozine (meclizine), norastemizole (norastemizole), picumast (picumast), Pyrilamine (pyrilamine), promethazine (promethazine), terfenadine (terfenadine), tripelennamine (tripelennamine), temelastine (temelastine), Trimeprazine (trimeprazine) and triprolidine (triprolidine).

The limiting examples of histamine H 3 receptor antagonists comprises: Thioperamide (thioperamide), SKF 92676 (impromidine), Burimamide (burimamide), clobenpropit, impentamine, mifentidine (mifetidine), S-sopromidine (S-sopromidine), R-sopromidine (R-sopromidine), SKF-91486, GR-175737, GT-2016, UCL-1199 and leoponex (clozapine).Currently known methods can be adopted to evaluate other compounds, to determine the activity to H3 acceptor, described method comprise cavy meninx measure and cavy nervosa ileum contraction mensuration, these two kinds of methods all at United States Patent (USP) 5,352, have description in 707.Another useful mensuration utilizes rat brain membrane and by West etc. at " IdentificationofTwo-H3-HistamineReceptorSubtypes (qualifications of two kinds of histamine receptor sub-types) " MolecularPharmacology, 1990, Vol.38,610-613 describe.

Term " leukotriene inhibitors " comprises suppression, prevention, postpone or with the effect of leukotriene or active interactional any medicament or compound.The limiting examples of leukotriene inhibitors comprises: Singulair (montelukast) and sodium salt thereof; 1-(((R)-(3-(2-(6, the fluoro-2-quinolyl of 7-bis-) vinyl) phenyl)-3-(2-(2-hydroxyl-2-propyl group) phenyl) sulfenyl) methyl cyclopropane acetic acid and sodium salt thereof, they are at United States Patent (USP) 5,270, there is description in 324; 1-(((1 (R)-3 (3-(2-(2,3-dichloro-thiophene also [3,2-b] pyridine-5-base)-(E)-vinyl) phenyl)-3-(2-(1-hydroxyl-1-methylethyl) phenyl) propyl group) sulfenyl) methyl) cyclopropaneacetic acid and sodium salt thereof, they are at United States Patent (USP) 5,472, there is description in 964; Pranlukast (pranlukast); Zafirlukast (zafirlukast); [2-[[2 (the 4-tertiary butyl-2-thiazolyl)-5-benzofuryl] oxygen ylmethyl] phenyl] acetic acid, it is at United States Patent (USP) 5, and 296, there is description in 495.

The limiting examples of receptor,β agonist comprises: salbutamol (albuterol), bitolterol (bitolterol), Isoetarine (isoetharine), mataproterenol, perbuterol, Salmeterol (salmeterol), terbutaline (terbutaline), Racemic isoproterenol (isoproterenol), ephedrine (ephedrine) and suprarenin (epinephrine).The limiting examples of alpha-2 adrenoceptor agonists comprises aromatic yl alkyl amine (such as Phenylpropanolamine and pseudoephedrine (pseudephedrine)), imidazoles (such as naphazoline (naphazoline), oxymetazoline (oxymetazoline), Yxin (tetrahydrozoline) and xylometazoline (xylometazoline)) and Cycloalkyl amine (such as propylhexedrine (propylhexedrine)).

The limiting examples of mast cell stabilizers is sodium nedocromil (nedocomilsodium).The limiting examples of expectorant is Guaifenesin (guaifenesin).The limiting examples of decongestant drug is pseudoephedrine (pseudoephedrine), Phenylpropanolamine (phenylpropanolamine) and synephrine (phenylephrine).

The limiting examples of NK1, NK2 and NK3 tachykinin receptor antagonists comprises CP-99, and 994 and SR48968.The limiting examples of muscarine antagonist comprises ipratropium bromide (ipratropiumbromide) and tiatropiumbromide.

GABA _bthe limiting examples of agonist comprises baclofen (baclofen) and 3-aminopropyl-phosphonic acids.Dopamine agonist comprises quinpirole (quinpirole), Ropinirole (ropinirole), pramipexole (pramipexole), pergolide (pergolide) and bromocriptine (bromociptine).

" 5-lipoxygenase inhibitor " comprise can suppress, prevent, postpone or with the interactional any medicament of the enzyme effect of 5-lipoxygenase or compound.The limiting examples of 5-lipoxygenase inhibitor comprises zileuton (zileuton), docebenone (docbenone), piriprost (piripost), ICI-D2318 and ABT761.

Comprise the methods for the treatment of of the compounds of this invention or pharmaceutical composition administration, comprise administration patient being carried out to other anti-chronic respiratory obstruction medicines (combination therapy) further, wherein the medicine of other anti-chronic respiratory obstruction is Sodium.alpha.-ketopropionate, rolipram (Rolipram), this spy of pyrrole rummy (Piclamist), cilomilast (Cilomilast), CDP-840, QAB-149 (Indacaterol), Ao Dateluo (olodaterol), QVA149, doxofylline (Doxofylline), roflumilast (Roflumilast), Apremilast (Apremilast), Tetomilast (Tetomilast), Tipelukast, theophylline (Theophylline), formoterol (Formoterol), Salmeterol (Salmeterol), FLUTICASONE PROPIONATE (Fluticasonepropionate), Salmeterol/fluticasone propionate compound (SalmeterolXinafoate/FluticasonePropionate), Midesteine (Midesteine), neat circulation (Zileuton), husky butanolamine, carmoxirole, budesonide and epimer thereof, Viarox, Triamcinolone Acetonide, flunisolide, furoic acid momisone, Rofleponide, ciclesonide, ipratropium bromide (IpratropiumBromide), ipratropium bromide and salbutamol compound, oxitropium bromide, tiotropium bromide (Tiotropiumbromide), Glycopyrronium Bromide, overgrown with weeds ground bromine ammonium (Umeclidiniumbromide), Wei Lanteluo (vilanterol), overgrown with weeds ground bromine ammonium/Wei Lanteluo compound (umeclidinium/vilanterol), aclidinium bromide (aclidiniumbromide), aclidinium bromide/Formoterol Fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/Wei Lanteluo compound (fluticasonefuroate/vilanterol, FF/VI), Benralizumab, Revatropate or their combination.

The dosage of compound of the present invention depends on many factors, comprises the feature of disease specific, the severity of symptom, route of administration, spacing of doses frequency, particular compound used, the effect of compound, Toxicological Characterization and the pharmacokinetics that will treat.

Combined thus the amount producing the activeconstituents of single dose form will can depend on the host and specific method of application that are treated and change with solid support material.Such as, be intended to Orally administered to the preparation of people can easily containing about 0.5mg to the promoting agent of about 5g, itself and the suitable and solid support material measured easily (about 5% of total composition to about 95% can be accounted for) phase compound.Unit dosage form generally by comprising the activeconstituents of about 1mg to about 1000mg, is generally 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

For any specific patient, concrete dosage level will depend on series of factors, comprise age, body weight, general health, sex, diet, use the severity of specified disease of opportunity, route of administration, discharge rate, medication combined and experience treatment.

Advantageously, they are with 0.01-1000mg/ days, preferably 0.1-500mg/ days dosed administrations.

When by inhalation route administration, compound of the present invention can with 0.01-10mg/ days, preferred 0.05-5mg/ days, more preferably the dosed administration of 0.1-2mg/ days.

The purposes of the compounds of this invention and pharmaceutical composition

The feature of pharmaceutical composition of the present invention comprises formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or the compound shown in (IIf) or the compound listed by the present invention, and pharmaceutically acceptable carrier, assistant agent or vehicle.

In composition of the present invention compound amount can effectively detectably antagonism PDE4 with treatment: pain (such as, acute pain, acute inflammatory pain, chronic inflam-matory pain and neuropathic pain), acute inflammation, chronic inflammatory diseases, rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adult respiratory distress, sacroiliitis, inflammatory bowel disease, Crohn disease, ulcerative colitis, septic shock, endotoxin shock, gram-negative bacteria septicemia, toxic shock syndrome, apoplexy, ischemic damage and reperfusion damage, renal reperfusion injury, glomerulonephritis, Parkinson's disease, Alzheimer, mild cognitive impairment (MCI), dysthymia disorders, anxiety disorder, graft versus host reaction (that is, graft versus host disease), homograft rejection (such as, acute allograft rejection and chronic allograft rejections), Acute Respiratory Distress syndrome, delayed-type hypersensitivity, arteriosclerosis, cerebral ischemia, osteoarthritis, multiple sclerosis, vasculogenesis, osteoporosis, gingivitis, Respirovirus, simplexvirus, hepatitis virus, HIV, Kaposi's sarcoma correlated virus (that is, Kaposi's sarcoma), meningitis, fibrocyst, premature labor, cough, pruritus, multiple organ dysfunction, arthritic psoriasis, bleb, encephalitis, traumatic brain injury, cns tumor, interstitial pneumonia, irritated, the sacroiliitis that crystallization is brought out, acute pancreatitis, chronic pancreatitis, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, ocular inflamation, cornea new vascular generation, polymyositis, acne, esophagitis, glossitis, airflow obstruction, airway allergic (i.e. airway hyperreactivity), bronchiectasis, bronchiolitis, bronchiolitis (i.e. bronchiolitis syndrome), chronic bronchitis, cystic fibrosis, expiratory dyspnea, pulmonary emphysema, adult respiratory disease, acute respiratory distress syndrome, respiration system virus, hypercapnia, lung hyperinflation (hyperinflation), blood oxygen is too low, the inflammation that hyperoxia brings out, hypoxia, pulmonary fibrosis, pulmonary hypertension, the peritonitis (CAPD) relevant to continuous first aid peritoneal dialysis, granulocyte ehrlichioses, sarcoidosis, small airway (smallairway) disease, airway obstruction, ventilation and blood perfusion imbalance, stridulate, flu, gout, alcoholic liver disease, lupus, periodontitis, cancer is levied, Transplantation Reperfusion Injury, early stage transplant rejection (such as, acute allograft rejection), airway hyperreactivity, allergic contact dermatitis, allergic rhinitis, non-allergic rhinitis, alopecia areata, Autoimmune deafness (comprising such as, Menetrier's disease), autoimmune hemolytic anemia syndrome, autoimmune hepatitis, autoimmune neurological disorders becomes, autoimmunity ovarian failure, autoimmunity ball is scorching, autoimmune thrombocytopenic reduces to be levied, chronic inflammatory Demyelinating Polyneuropathy is sick, liver cirrhosis, dermatomyositis, diabetes, drug-induced autoimmunization, endometriosis, fibrotic disease, gastritis, Goodpasture Cotard, Graves' disease, Gullain-Barre is sick, struma lymphomatosa, the autoimmunization that hepatitis is relevant, the auto-immune syndromes that HIV-is relevant and hematologic disease, pituitary secretion very few (hypophytis), interstitial cystitis, juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, langerhans' cells tissue cell proliferation, lichen planus, the autoimmunization of metal induced, myocarditis (comprising viral myocarditis), myositis, DPN (comprises such as, IgA DPN, cytolemma DPN and idiopathic neuropathies become), nephritic syndrome, optic neuritis, pancreatitis, autoimmunization after infecting, primary gall-bladder hardens, reactive arthritis, ankylosing spondylitis, conjunctivo-urethro-synovial syndrome, reperfusion injury, scleritis, scleroderma, the Secondary cases blood disorder (such as anaemia) of autoimmune disorder, the autoimmune disorder that polysiloxane-based (silicone) implant is relevant, siogren's syndrome, systemic lupus erythematous, transverse myelitis, tubulointerstitial nephritis, uveitis and hickie, the method comprises at least one formula (I) imposing on this sufferer significant quantity, (II), (IIa), (IIb), (IIc), (IId), or compound or its pharmacy acceptable salt or solvate shown in (IIf) (IIe).

" significant quantity " or " effective dose " of compound of the present invention or pharmaceutically acceptable composition refer to process or alleviate one or more the present invention mention the significant quantity of the severity of illness.According to method of the present invention, compound and composition can be any dosage and any route of administration come effectively for the treatment of or the severity that palliates a disease.Situation according to patient changes by required measuring accurately, and this depends on race, the age, the general condition of patient, the severity of infection, special factor, administering mode, etc.Compound or composition can with one or more other treatment agent Combined Preparation, as discussed in the present invention.

General building-up process

Usually, compound of the present invention can be prepared by method described in the invention, unless there are further instruction, wherein substituent definition is such as formula shown in (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf).Reaction scheme below and embodiment are used for illustrating content of the present invention further.

Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.

The embodiments described below, to be decided to be degree Celsius unless other aspects show all temperature.Reagent is bought in goods providers as AldrichChemicalCompany, ArcoChemicalCompanyandAlfaChemicalCompany, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.

Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.

Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.

Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.The test condition of proton nmr spectra is: under room temperature condition, and the nuclear magnetic resonance spectrometer of Brooker (Bruker) 400MHz or 600MHz, with CDC1 ₃, d ⁶-DMSO, CD ₃oD or d ⁶-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), q (quartet, quartet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, double doublet), dt (doubletoftriplets, two triplet).Coupling constant, represents with hertz (Hz).

The condition of Algorithm (MS) data determination is: Agilent6120QuadrupoleHPLC-MS (pillar model: ZorbaxSB-C18,2.1x30mm, 3.5 μm, 6min, flow velocity is 0.6mL/min, and moving phase: 5%-95% is (containing the CH of 0.1% formic acid ₃cN) (containing the H of 0.1% formic acid ₂o) ratio in)), detect at 210/254nm UV, with electron spray ionisation pattern (ESI).

The characteristic manner of compound purity is: Agilent1260 preparative high performance liquid chromatography (Pre-HPLC) or CalesepPump250 preparative high performance liquid chromatography (Pre-HPLC) (pillar model: NOVASEP, 50/80mm, DAC), detect at 210nm/254nm UV.

The use of brief word below runs through the present invention:

G gram

Mg milligram

Mol mole

Mmol mmole

H hour

Min minute

L liter

ML, ml milliliter

R.t, RT room temperature

Rt retention time

HPLC high performance liquid chromatography

H ₂o water

HCl hydrogenchloride

MeOH, CH ₃oH methyl alcohol

CD ₃oD deuterated methanol

EtOH, ethanol ethanol

HCOOH formic acid

HOAc, CH ₃cOOH acetic acid

CH ₃cN, MeCN acetonitrile

DCM, CH ₂cl ₂methylene dichloride

CHCl ₃chloroform, trichloromethane

CDCl ₃deuterochloroform

Cyclohexane hexanaphthene

DMSO dimethyl sulfoxide (DMSO)

EtOAc ethyl acetate

Petroleumether, PE sherwood oil

HOATN-hydroxyl-7-azepine benzotriazole

EDCI1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride

CDIN, N'-carbonyl dimidazoles, N'N-carbonyl dimidazoles

DIPEAN, N-diisopropylethylamine

DBU1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene

THF tetrahydrofuran (THF)

NaHCO ₃sodium bicarbonate

Na ₂sO ₄sodium sulfate

NaOH sodium hydroxide

LiOH lithium hydroxide

BOC, Boc tertbutyloxycarbonyl

CBZ, Cbz carbobenzoxy-(Cbz)

Synthetic method one:

Target compound (11)can be prepared by synthetic method one, wherein R ¹, R ², R ³, R ⁵, A, m and n have implication as described in the present invention.Compound (1)with glycine methyl ester hydrochloride (2)condensation obtains compound (3); Compound (3)compound is obtained by lawesson reagent sulfuration (4); Compound (4)under the condition of trimethylammonium oxygen Tetrafluoroboric acid, form methylthio group obtain compound (5); Compound (5)with fluoride compounds (6)be obtained by reacting compound (7); Compound (7)hydrolysis obtains compound (8); Compound (8)and compound (9)reacting generating compound (10); Compound (10)deprotection obtains target compound (11).

Synthetic method two:

Target compound (11)can be prepared by synthetic method two, wherein R ¹, R ², R ³, R ⁵, A, m and n have implication as described in the present invention; R ^5xr ⁵-PG, optionally, PG is amino blocking group, or PG does not exist.Compound (8)and compound (9-a)reacting generating compound (10-a); Compound (10-a)deprotection obtains target compound (11).

Synthetic method three

Target compound (11-a)can be prepared by synthetic method three, wherein R ¹, R ², R ³, R ⁵, R ^b, A and m have implication as described in the present invention; W>=0, v>=1, and w+v is 1,2,3,4,5,6,7,8,9 or 10; R ^5yfor R ^6y-C (=O)-, R ^6y-C (=O)-alkylidene group, R ^6y-C (=O)-alkylidene group-O-C (=O)-, R ^6y-C (=O)-N (R ^b)-, R ^6y-C (=O)-N (R ^b)-alkylidene group, R ^6y-C (=O)-alkylidene group-N (R ^b)-, R ^6y-C (=O)-N (R ^b)-C (=O)-or R ^6y-C (=O)-N (R ^b)-C (=O)-alkylidene group; R ^6yfor alkoxyl group, the alkoxyl group of carboxyl substituted, alkyloxy-alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl or heteroarylalkoxy that alkoxyl group, halogenated alkoxy, hydroxyl replace; R ^5zfor HO-C (=O)-, HO-C (=O)-alkylidene group, HO-C (=O)-alkylidene group-O-C (=O)-, HO-C (=O)-N (R ^b)-, HO-C (=O)-N (R ^b)-alkylidene group, HO-C (=O)-alkylidene group-N (R ^b)-, HO-C (=O)-N (R ^b)-C (=O)-or HO-C (=O)-N (R ^b)-C (=O)-alkylidene group.Compound (8)and compound (9-b)reacting generating compound (10-b); Compound (10-b)compound is obtained in the basic conditions through a step or polystep reaction (10-c); Compound (10-c)deprotection obtains target compound (11-a).

Synthetic method four

Target compound (11-b)can be prepared by synthetic method four, wherein R ¹, R ², R ³, R ⁵, R ^b, A and m have implication as described in the present invention; U>=1, v>=1, and u+v is 2,3,4,5,6,7,8,9 or 10; R ^5xr ⁵-PG, optionally, PG is amino blocking group, or PG does not exist; R ^5yfor R ^6y-C (=O)-, R ^6y-C (=O)-alkylidene group, R ^6y-C (=O)-alkylidene group-O-C (=O)-, R ^6y-C (=O)-N (R ^b)-, R ^6y-C (=O)-N (R ^b)-alkylidene group, R ^6y-C (=O)-alkylidene group-N (R ^b)-, R ^6y-C (=O)-N (R ^b)-C (=O)-or R ^6y-C (=O)-N (R ^b)-C (=O)-alkylidene group; R ^6yfor alkoxyl group, the alkoxyl group of carboxyl substituted, alkyloxy-alkoxy, cycloalkyl alkoxy, heterocyclylalkoxy, alkoxy aryl or heteroarylalkoxy that alkoxyl group, halogenated alkoxy, hydroxyl replace; R ^5zfor HO-C (=O)-, HO-C (=O)-alkylidene group, HO-C (=O)-alkylidene group-O-C (=O)-, HO-C (=O)-N (R ^b)-, HO-C (=O)-N (R ^b)-alkylidene group, HO-C (=O)-alkylidene group-N (R ^b)-, HO-C (=O)-N (R ^b)-C (=O)-or HO-C (=O)-N (R ^b)-C (=O)-alkylidene group.Compound (8)and compound (9-c)reacting generating compound (10-d); Compound (10-d)compound is obtained in the basic conditions through a step or polystep reaction (10-e); Compound (10-e)deprotection obtains target compound (11-b).

Synthetic method five

Target compound (12)can be prepared by synthetic method five, wherein R ¹, R ², R ³with m, there is implication as described in the present invention; R ¹²for alkyl, the alkyl of carboxyl substituted, alkoxyalkyl, cycloalkylalkyl, cycloheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl that H, alkyl, haloalkyl, hydroxyl replace, R ¹²substituting group optionally described by the present invention replaced.Compound N-Boc-allohydroxyproline methyl esters and 4-toluene sulfonyl chloride react, and obtain compound (2S, 4S)-2-methoxycarbonyl-4-tolysulfonyl oxygen base tetramethyleneimine-1-t-butyl formate; Compound (2S, 4S)-2-methoxycarbonyl-4-tolysulfonyl oxygen base tetramethyleneimine-1-t-butyl formate and reaction of sodium azide, obtain compound (2S, 4R)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate; Compound (2S, 4R)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate, by shortening, obtains compound (2S, 4R)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate; Compound (2S, 4R)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate is obtained by reacting compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate in the basic conditions; Compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate is hydrolyzed in the basic conditions and obtains compound (2S, 4R)-1-(tertbutyloxycarbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid.Compound (2S, 4R)-1-(tertbutyloxycarbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid and R ¹²oH reacts, and obtains compound (12-1); Compound (12-1)deprotection obtains compound (12-2); Compound (12-2)and compound (8)reacting generating compound (12-3); Compound (12-3)deprotection obtains target compound (12).

Synthetic method six

Target compound (13)can be prepared by synthetic method six, wherein R ¹, R ², R ³, R ^b, R ^cwith m, there is implication as described in the present invention.Compound (2S, 4R)-1-(tertbutyloxycarbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid and NHR ^br ^creaction, obtains compound (13-1); Compound (13-1)deprotection obtains compound (13-2); Compound (13-2)and compound (8)reacting generating compound (13-3); Compound (13-3)deprotection obtains target compound (13).

Embodiment

embodiment 1: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(cyclopropyl carbonyl base) piperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) benzamide) methyl acetate

By 3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenylformic acid (3g, 11.63mmol), HOAT (2.374g, 17.44mmol) with EDCI (3.331g, 17.44mmol) be dissolved in DCM (40mL), after at room temperature continuing to stir 30min, add glycine methyl ester hydrochloride (1.744g again, 13.95mmol), under ice bath, slowly drip DIPEA (8.1mL, 46.51mmol) after, at room temperature continue stirring one night, after adding water (30mL), use CH ₂cl ₂(25mL × 3) extract, and after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 3.295g white solid, yield: 86.1%.

¹HNMR(400MHz,CDCl ₃):δppm7.47(s,1H),7.29(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.18(d,J＝8.3Hz,1H),6.68(t,J _F-H＝75.0Hz,1H),4.22(d,J＝5.0Hz,2H),3.92(d,J＝7.0Hz,2H),3.80(s,3H),1.25-1.32(m,1H),0.62-0.67(m,2H),0.33-0.37(m,2H)；

MS-ESI:m/z330.2[M+H] ⁺.

Step 2: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) benzene thioformamide) methyl acetate

By compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) benzamide) methyl acetate (3.295g, 10.02mmol) with lawesson reagent (4.051g, 10.02mmol) be dissolved in THF (30mL), after continuing reaction 2h at 75 DEG C, removing THF, adds saturated NaHCO ₃solution (30mL), then use ethyl acetate (25mL × 3) to extract, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 3.3195g yellow solid, yield: 96%.

¹HNMR(400MHz,CDCl ₃):δppm8.07(s,1H),7.55(d,J＝2.0Hz,1H),7.24(d,J＝2.1Hz,1H),7.16(d,J＝8.3Hz,1H),6.68(t,J _F-H＝75.0Hz,1H),4.56(d,J＝4.6Hz,2H),3.94(d,J＝7.0Hz,2H),3.85(s,3H),1.27-1.32(m,1H),0.65-0.67(m,2H),0.36-0.38(m,2H)；

MS-ESI:m/z346.2[M+H] ⁺.

Step 3: the synthesis of compound 2-(((3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate

Under the condition of-78 DEG C, by the CH of compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) benzene thioformamide) methyl acetate (3.3195g, 9.62mmol) ₂cl ₂(10mL) solution is slowly added drop-wise to the CH of trimethylammonium oxygen Tetrafluoroboric acid (2.846mg, 19.24mmol) ₂cl ₂(10mL) in solution, under 0 DEG C of condition, after continuing reaction 3h, saturated NaHCO is added ₃solution (25mL) cancellation is reacted, then uses DCM (25mL × 3) to extract, and uses anhydrous Na ₂sO ₄drying, except desolventizing, obtains 3.3222g yellow oily liquid, yield: 96.1%.

MS-ESI:m/z360.1[M+H] ⁺.

Step 4: the synthesis of compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate

By N-tert-butoxycarbonyl-l-alanine (6.5g, 34.4mmol) with triethylamine (5.27mL, 37.83mmol) be dissolved in methylene dichloride (60mL), under-40 DEG C of conditions, in this solution, drip cyanuric fluoride (5.62mL, 68.8mmol), under-10 DEG C of conditions, react 2h, with frozen water (20mL × 5) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, obtains 5.84g white solid: (S)-(the fluoro-1-oxo third of 1--2-base) t-butyl carbamate, productive rate: 89%.

Under the condition of-78 DEG C, by potassium hexamethyldisilazide (1M, THF (32.4mL) solution 32.39mmol) is slowly added drop-wise to compound 2-(((3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate (3.3222g, 9.25mmol) with compound (S)-(the fluoro-1-oxo third of 1--2-base) t-butyl carbamate (2.651g, in THF (25mL) solution 13.88mmol), after continuing reaction 1h, add H ₂o (25mL) cancellation is reacted, then uses ethyl acetate (25mL × 3) to extract, and merges organic phase, uses anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 2.3944g white solid, yield: 53.7%.

¹HNMR(400MHz,CDCl ₃):δppm7.64(s,1H),7.62(d,J＝8.4Hz,1H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.43-5.47(m,1H),3.98(s,3H),3.96(d,J＝7.0Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.27-1.29(m,1H),0.65-0.68(m,2H),0.36-0.39(m,2H)；

MS-ESI:m/z483.1[M+H] ⁺.

Step 5: the synthesis of compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid

Compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate (1.75g, 3.63mmol) is dissolved in THF (20mL) and H ₂in the mixed solvent of O (10mL), add a hydronium(ion) Lithium Oxide 98min (762.4mg again, 18.15mmol), at 40 DEG C of reaction 4h, removing THF, then use HCl (1M) that the pH value of solution is adjusted to about 1, extract by ethyl acetate (25mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 1.4509g yellow solid, yield: 87.9%.

¹HNMR(600MHz,CD ₃OD):δppm7.80(d,J＝1.8Hz,1H),7.66(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.29(d,J＝8.3Hz,1H),6.90(t,J _F-H＝74.8Hz,1H),5.51(m,1H),4.03(d,J＝7.0Hz,2H),1.54(d,J＝7.1Hz,3H),1.44(s,9H),1.35-1.38(m,1H),0.67-0.70(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z467.3[M-H] ^-.

Step 6: the synthesis of compound (S)-(1-(4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.35g, 0.75mmol), compound cyclopropyl-piperazine-1-base-methyl ketone hydrochloride (185mg, 0.97mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (214mg, 1.12mmol) with N-hydroxyl-7-azepine benzotriazole (135mg, 1.12mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.52mL, 3.0mmol), stirring at room temperature 4h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 280mg white solid, yield: 62%.

¹HNMR(400MHz,CDCl ₃):δppm7.60(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.56(d,J＝1.8Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.24-5.28(m,1H),3.99(d,J＝6.9Hz,2H),3.77-3.82(m,6H),1.57(d,J＝7.0Hz,3H),1.44(s,9H),1.30-1.37(m,2H),1.03-1.07(m,2H),0.83-0.85(m,2H),0.69-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z605.2[M+H] ⁺.

Step 7: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(cyclopropyl carbonyl) piperazine-1-base) methanone hvdrochloric acid salt

To compound (S)-(1-(4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (0.28g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.46mmol), 8mL), stirring at room temperature 15min, except desolventizing, obtain 250mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.75(d,J＝1.6Hz,1H),7.73(d,J＝8.4Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.06-5.11(m,1H),4.30-4.20(m,2H),4.05(d,J＝6.9Hz,2H),3.76-3.95(m,6H),1.80(d,J＝7.0Hz,3H),1.30-1.37(m,2H),0.86-0.96(m,4H),0.67-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z505.3[M+H-HCl] ⁺.

embodiment 2: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(pyrimidine-2-base) piperazine-1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.33g, 0.70mmol), 1-(2-pyrimidyl) piperazine (0.12mL, 0.85mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (202mg, 1.06mmol) with N-hydroxyl-7-azepine benzotriazole (144mg, 1.06mmol) be dissolved in methylene dichloride (10mL), after 0 DEG C of stirring 30min, drip N, N-diisopropylethylamine (0.37mL, 2.11mmol), stirring at room temperature 17h, add water (10mL × 3) wash, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 260mg white solid, yield: 60%.

¹HNMR(400MHz,CDCl ₃):δppm8.36(d,J＝4.7Hz,2H),7.61(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.57(d,J＝1.8Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),6.58(t,J＝4.7Hz,1H),5.24-5.32(m,1H),3.88-4.15(m,8H),3.99(d,J＝6.9Hz,2H),1.58(d,J＝7.0Hz,3H),1.42(s,9H),1.32-1.36(m,1H),0.68-0.73(m,2H),0.41-0.45(m,2H).

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(pyrimidine-2-base) piperazine-1-base) ketone dihydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(pyrimidine-2-base) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.26g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.42mmol), 8mL), stirring at room temperature 30min, except desolventizing, obtain 200mg white solid, yield: 86%.

¹HNMR(400MHz,CD ₃OD):δppm8.68(d,J＝5.2Hz,2H),7.78(s,1H),7.75(d,J＝8.4Hz,1H),7.34(d,J＝8.2Hz,1H),7.08(t,J＝5.1Hz,1H),6.93(t,J _F-H＝74.8Hz,1H),5.11-5.13(m,1H),4.46(s,2H),4.06(d,J＝6.9Hz,2H),4.01-4.14(m,6H),1.82(d,J＝6.8Hz,3H),1.32-1.36(m,1H),0.67-0.70(m,2H),0.43-0.47(m,2H)；

MS-ESI:m/z515.3[M+H-2HCl] ⁺.

embodiment 3: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-pyridinecarboxylic base piperazine-1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound N-(2 '-picolinoyl) piperazine hydrochloride

By 2-pyridine carboxylic acid (2g, 16.25mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (4.65g, 24.37mmol) with N-hydroxyl-7-azepine benzotriazole (3.31g, 24.37mmol) be dissolved in methylene dichloride (30mL), stirring at room temperature 40min, add N-Boc piperazine (3.63g, 19.5mmol), 0 DEG C is stirred 30min, drip N, N-diisopropylethylamine (8.5mL, 48.74mmol), stirring at room temperature 14h, add water after stopped reaction (20mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, evaporating column chromatographic separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 3.92g yellow solid: compound N-(2 '-picolinoyl)-N-Boc piperazine, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.60(d,J＝4.5Hz,1H),7.83(td,J ₁＝7.7Hz,J ₂＝1.7Hz,1H),7.69(d,J＝7.8Hz,1H),7.36-7.39(m,1H),3.78-3.79(m,2H),3.56-3.62(m,4H),3.47-3.49(m,2H),1.49(s,9H)；

MS-ESI:m/z292.3[M+H] ⁺.

To compound N-(2 '-picolinoyl)-N-Boc piperazine (3.9g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (10mL) solution 13.4mmol); 15mL); stopped reaction after stirring at room temperature 2h; except desolventizing; obtain 3g white solid: compound N-(2 '-picolinoyl) piperazine hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δ(ppm)7.27(d,J＝5.2Hz,1H),6.83(t,J＝7.9Hz,1H),6.49(d,J＝7.2Hz,1H),6.33-6.36(m,1H),2.37-2.49(m,4H),1.80-1.85(m,4H)；

MS-ESI:m/z192.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-picolinoyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), compound N-(2 '-picolinoyl) piperazine hydrochloride (175mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (183mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (131mg, 0.96mmol) be dissolved in methylene dichloride (10mL), 0 DEG C is stirred 30min, drip N, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 14h, add water (10mL × 3) wash, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 180mg thick white thing, yield: 44%.

¹HNMR(400MHz,CDCl ₃):δ(ppm)8.66(br.s,1H),7.91(br.s,1H),7.76(d,J＝7.7Hz,1H),7.54-7.58(m,2H),7.45(m,1H),7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.94(br.s,1H),5.20-5.26(m,1H),3.68-3.99(m,8H),1.57(d,J＝7.0Hz,3H),1.44(s,9H),1.29-1.30(m,1H),0.70-0.71(m,2H),0.40-0.43(m,2H).

Step 3: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-picolinoyl piperazine-1-base) ketone dihydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-picolinoyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (120mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.20mmol); 4mL); stirring at room temperature 20min; except desolventizing; obtain 150mg faint yellow solid, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δ(ppm)8.82(s,1H),8.39(t,J＝7.5Hz,1H),8.00-8.02(br.s,1H),7.89(br.s,1H),7.73-7.76(m,2H),7.32(br.s,1H),6.91(t,J _F-H＝74.7Hz,1H),5.08-5.10(m,1H),4.30-4.36(m,2H),3.67-4.13(m,8H),1.80(d,J＝7.2Hz,3H),1.20-1.28(m,1H),0.67-0.69(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z542.2[M+H-2HCl] ⁺.

embodiment 4: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N-bis- the synthesis of methyl isophthalic acid-piperazine sulfonamide hydrochloride

Step 1: compound N, the synthesis of N-dimethyl-1-piperazine sulfonamide hydrochloride

By N-Boc piperazine (1g, 5.36mmol) be dissolved in methylene dichloride (19mL), under 0 DEG C of condition, drip dimethylin SULPHURYL CHLORIDE (1.15g respectively, 8.05mmol) with triethylamine (1.5mL, 10.73mmol), stirring at room temperature 4h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1); obtain 1.4g white solid: 4-(N, N-dimethyl methyl acyl group) piperazine-1-t-butyl formate, yield: 89%.

¹HNMR(400MHz,CDCl ₃):δ(ppm)3.50(t,J＝5.1Hz,4H),3.22(t,J＝5.1Hz,4H),2.86(s,6H),1.49(s,9H).

To compound 4-(N; N-dimethyl methyl acyl group) piperazine-1-t-butyl formate (1.3g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 4.4mmol); 5mL); stirring at room temperature 3h, except desolventizing, obtains 1g white solid: compound N; N-dimethyl-1-piperazine sulfonamide hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δ(ppm)3.50(t,J＝5.2Hz,4H),3.32-3.34(m,4H),2.88(s,6H)；

MS-ESI:m/z194.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(N, N-dimethyl methyl acyl group) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), compound N, N-dimethyl-1-piperazine sulfonamide hydrochloride (176mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (131mg, 0.96mmol) be dissolved in methylene dichloride (10mL), 0 DEG C is stirred 30min, drip N, N-diisopropylethylamine (0.45mL, 2.6mmol), stirring at room temperature 14h, add water (10mL × 3) wash, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 186mg white solid, yield: 44%.

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.59(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.55(d,J＝1.7Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.22-5.25(m,1H),4.06-4.15(m,2H),3.99(d,J＝6.9Hz,2H),3.80-3.90(m,2H),3.37-3.38(m,4H),2.88(s,6H),1.56(d,J＝7.0Hz,3H),1.44(s,9H),1.33-1.37(m,1H),0.69-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z644.4[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N-dimethyl-1-piperazine sulfonamide hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(N; N-dimethyl methyl acyl group) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (186mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.29mmol); 3mL); stirring at room temperature 20min; except desolventizing; obtain 150mg white solid, yield: 87%.

¹HNMR(400MHz,CD ₃OD):δ(ppm)7.75(s,1H),7.72(d,J＝8.4Hz,1H),7.33(d,J＝8.3Hz,1H),6.91(t,J _F-H＝74.7Hz,1H),5.04-5.09(m,1H),4.23-4.27(m,2H),4.05(d,J＝6.8Hz,2H),3.84-3.87(m,2H),3.37-3.41(m,4H),2.87(s,6H),1.80(d,J＝6.8Hz,3H),1.32-1.35(m,1H),0.66-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z544.2[M+H-HCl] ⁺.

embodiment 5: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(cyclopropyl sulphur acyl group) piperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound 1-(Cyclopropylsulfonyl) piperazine hydrochloride

By cyclopropane sulfonic acid (2g, 16.38mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (4.7g, 24.56mmol) with N-hydroxyl-7-azepine benzotriazole (3.4g, 24.56mmol) be dissolved in methylene dichloride (25mL), stirring at room temperature 20min, add N-Boc piperazine (3.7g, 19.65mmol), under 0 DEG C of condition, drip N, N-diisopropylethylamine (8.6mL, 49.12mmol), stirring at room temperature 15h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 4.7g white solid: N-Boc-N-Cyclopropylsulfonyl piperazine, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm4.51(t,J＝5.1Hz,4H),4.24(t,J＝5.0Hz,4H),3.21-3.25(m,1H),2.46(s,9H),2.14-2.18(m,2H),1.96-2.00(m,2H).

The ethyl acetate solution (4M, 10mL) of HCl is added in methylene dichloride (5mL) solution of compound N-Boc-N-Cyclopropylsulfonyl piperazine (4.75g, 16.4mmol); stirring at room temperature 12h; except desolventizing, obtain 3.6g white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm3.29(t,J＝4.8Hz,4H),2.96(t,J＝4.9Hz,4H),2.25-2.29(m,1H),1.17-1.19(m,2H),0.98-1.01(m,2H)；

MS-ESI:m/z191.1[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(Cyclopropylsulfonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclopropane ylmethoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), compound 1-(Cyclopropylsulfonyl) piperazine hydrochloride (110mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.80mmol) be dissolved in methylene dichloride (10mL), 0 DEG C is stirred 30min, drip N, N-diisopropylethylamine (0.28mL, 1.60mmol), stirring at room temperature 14h, add water (10mL × 3) wash, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 190mg white solid, yield: 56%.

¹HNMR(600MHz,CDCl ₃):δ(ppm)7.59(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.55(d,J＝1.7Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.84(br.s,1H),5.24-5.26(m,1H),4.11-4.15(m,2H),3.98(d,J＝6.9Hz,2H),3.41-3.47(m,4H),3.39(s,2H),2.29-2.32(m,1H),1.56(d,J＝7.1Hz,3H),1.43(s,9H),1.33-1.37(m,1H),1.20-1.22(m,2H),1.00-1.05(m,2H),0.69-0.72(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z641.2[M+H] ⁺.

Step 3: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(Cyclopropylsulfonyl) piperazine-1-base) methanone hvdrochloric acid salt

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(Cyclopropylsulfonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (155mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.24mmol); 2mL); stirring at room temperature 40min; except desolventizing; obtain 130mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.73(d,J＝8.3Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.6Hz,1H),5.05-5.08(m,1H),4.27(br.s,2H),4.04(d,J＝6.9Hz,2H),3.87-3.89(m,2H),3.45-3.47(m,4H),2.56-2.57(m,1H),1.79(d,J＝6.8Hz,3H),1.33-1.35(m,1H),1.08-1.10(m,4H),0.67-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z541.9[M+H-HCl] ⁺.

embodiment 6: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(4-pyridine first base) piperazine-1-base) synthesis of ketone tri hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(4-picolyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.25g, 0.53mmol), 1-(4-picolyl) piperazine (114mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (109mg, 0.80mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.28mL, 0.60mmol), stirring at room temperature 5h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: EtOAc/MeOH (v/v)=20/1), obtain 220mg white solid, yield: 65%.

¹HNMR(600MHz,CDCl ₃):δppm8.60(d,J＝4.2Hz,2H),7.58(d,J＝8.3Hz,1H),7.54(s,1H),7.39(d,J＝4.2Hz,2H),7.24(d,J＝8.3Hz,1H),6.71(t,J _F-H＝75.0Hz,1H),6.00(br.s,1H),5.22-5.26(m,1H),3.97(d,J＝6.9Hz,2H),4.06-4.01(m,2H),3.65(s,2H),3.93-3.94(m,1H),3.80-3.84(m,1H),2.61-2.65(m,4H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.32-1.37(m,1H),0.69-0.72(m,2H),0.40-0.43(m,2H)；

MS-ESI:m/z628.3[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(4-picolyl) piperazine-1-base) ketone tri hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(4-picolyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.22g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.35mmol), 3mL), stirring at room temperature 0.5h, except desolventizing, obtain 190mg white solid, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm8.95(d,J＝3.6Hz,2H),8.33(d,J＝5.1Hz,2H),7.75(s,1H),7.72(d,J＝6.4Hz,1H),7.33(d,J＝8.1Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.12-5.14(m,1H),4.62(s,2H),4.08-4.16(m,1H),4.04(d,J＝6.8Hz,2H),3.41-3.45(m,4H),1.80(d,J＝6.8Hz,3H),1.32-1.35(m,1H),0.68-0.70(m,2H),0.43-0.44(m,2H)；

MS-ESI:m/z528.3[M+H-3HCl] ⁺.

embodiment 7: compound (S)-1-(4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1- base) synthesis of-2-cyclopropyl acetophenone hydrochloride

Step 1: the synthesis of compound 2-cyclopropyl-1-(1-piperazinyl) acetophenone hydrochloride

By N-Boc-piperazine (1g, 5.37mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (1.54g, 8.05mmol) with N-hydroxyl-7-azepine benzotriazole (1.09g, 8.05mmol), Cyclopropylacetic acid (0.65g, 6.44mmol) be dissolved in methylene dichloride (25mL), stirring at room temperature 20min, under 0 DEG C of condition, drip N, N-diisopropylethylamine (2.8mL, 16.10mmol), stirring at room temperature 4h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1); obtain 1.01g white solid: 4-(2-Cyclopropyl-acetyl) piperazine-1-t-butyl formate, yield: 70%.

¹HNMR(600MHz,CDCl ₃):δppm3.61-3.63(m,2H),3.43-3.45(m,6H),2.30(d,J＝6.8Hz,2H),1.49(s,9H),1.04-1.07(m,1H),0.58-0.61(m,2H),0.18-0.21(m,2H).

To compound 4-(2-Cyclopropyl-acetyl) piperazine-1-t-butyl formate (1.01g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (10mL) solution 3.76mmol); 6mL); stirring at room temperature 2h; except desolventizing; obtain 0.77g colorless viscous thing: 2-cyclopropyl-1-(1-piperazinyl) acetophenone hydrochloride, yield: 100%.

¹HNMR(600MHz,CD ₃OD):δppm3.72-3.74(m,4H),3.12-3.16(m,4H),2.28(d,J＝6.8Hz,2H),0.90-0.91(m,1H),0.44-0.47(m,2H),0.08-0.10(m,2H)；

MS-ESI:m/z169.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(2-Cyclopropyl-acetyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 2-cyclopropyl-1-(1-piperazinyl) acetophenone hydrochloride (160mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), stirring at room temperature 30min, 0 DEG C drips N, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtain 300mg colorless viscous thing, yield: 75%.

¹HNMR(400MHz,CDCl ₃):δ(ppm)7.59(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.55(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.23-5.27(m,1H),3.98(d,J＝6.9Hz,2H),3.76-3.95(m,6H),3.55-3.59(m,2H),2.32-2.34(m,2H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.32-1.36(m,1H),1.05-1.09(m,1H),0.68-0.73(m,2H),0.60-0.62(m,2H),0.40-0.44(m,2H),0.21-0.22(m,2H)；

MS-ESI:m/z619.3[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-base)-2-cyclopropyl acetophenone hydrochloride

To compound (S)-(1-(4-(4-(2-Cyclopropyl-acetyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (290mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.47mmol); 4mL); stirring at room temperature 2h; except desolventizing; obtain 260mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.75(s,1H),7.72(d,J＝8.6Hz,1H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.06-5.08(m,1H),4.20-4.25(m,2H),4.04(d,J＝6.9Hz,2H),3.73-3.84(m,6H),2.42(d,J＝5.7Hz,2H),1.79(d,J＝6.6Hz,3H),0.67-0.71(m,2H),0.57-0.59(m,2H),0.42-0.46(m,2H),0.23-0.24(m,2H)；

MS-ESI:m/z519.2[M+H-HCl] ⁺.

embodiment 8 compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-methylpiperazine -1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), 1-methylpiperazine (0.09mL, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (217mg, 1.60mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 20h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=30/1), obtain 275mg colorless oil, yield: 78%.

¹HNMR(400MHz,CDCl ₃):δppm7.60(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.56(d,J＝1.9Hz,1H),7.25(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),5.21-5.25(m,1H),3.99(d,J＝6.9Hz,2H),3.93-4.02(m,2H),3.78-3.82(m,2H),2.51-2.53(m,2H),2.47-2.49(m,2H),2.36(s,3H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.33-1.36(m,1H),0.68-0.73(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z551.3[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-methylpiperazine-1-yl) ketone dihydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.26g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.47mmol), 3mL), stirring at room temperature 50min, except desolventizing, obtain 233mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.73(d,J＝8.3Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.39(br.s,1H),5.12-5.14(m,1H),4.80-4.84(m,1H),4.05(d,J＝6.9Hz,2H),3.74-3.78(m,1H),3.62-3.66(m,2H),3.36-3.38(m,1H),3.24-3.30(m,1H),3.00(s,3H),1.80(d,J＝6.9Hz,3H),1.33-1.37(m,1H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z451.2[M+H-2HCl] ⁺.

embodiment 9: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (piperazine-1-base) the synthesis of ketone dihydrochloride

Step 1: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-carbonyl) piperazine-1-t-butyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), N-Boc piperazine (143mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (217mg, 1.60mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 17h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 397mg white solid, yield: 97%.

¹HNMR(600MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.56(d,J＝1.6Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.98(br.s,1H),5.21-5.26(m,1H),3.98(d,J＝7.0Hz,2H),3.94-3.97(m,1H),3.87-3.90(m,1H),3.72-3.78(m,2H),3.54-3.58(m,4H),1.56(d,J＝7.0Hz,3H),1.50(s,9H),1.44(s,9H),1.33-1.35(m,1H),0.69-0.72(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z637.3[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (piperazine-1-base) ketone dihydrochloride

To compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-t-butyl formate (0.40g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.63mmol), 5mL), stirring at room temperature 40min, except desolventizing, obtain 319mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.73(dd,J ₁＝8.4Hz,J ₂＝1.4Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.12-5.14(m,1H),4.52-4.55(m,2H),4.05(d,J＝6.8Hz,2H),4.05-4.07(m,2H),3.41-3.44(m,4H),1.80(d,J＝6.8Hz,3H),1.34-1.36(m,1H),0.67-0.70(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z437.3[M+H-2HCl] ⁺.

embodiment 10: compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of methyl-formiate dihydrochloride

Step 1: the synthesis of compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-3-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.6g, 1.28mmol), 1-Boc-3-piperazinecarboxylic acid methyl esters (376mg, 1.54mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (368mg, 1.92mmol) with N-hydroxyl-7-azepine benzotriazole (435mg, 3.20mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.89mL, 5.12mmol), stirring at room temperature 6h, add saturated nacl aqueous solution (15mL × 3) washing, anhydrous Na is used after organic phase ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 714mg white solid, yield: 80%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(s,1H),7.52-7.54(m,1H),7.24-7.27(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.21-5.28(m,1H),4.60-4.68(m,2H),3.99(d,J＝6.9Hz,2H),3.81(s,3H),3.24-3.29(m,1H),3.00-3.10(m,1H),1.52-1.57(m,3H),1.49(s,9H),1.44(s,9H),1.32-1.37(m,1H),0.68-0.73(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z695.3[M+H] ⁺.

Step 2: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-methyl-formiate dihydrochloride

To compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-3-methyl-formiate (0.21g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.30mmol), 3mL), stirring at room temperature 40min, except desolventizing, obtain 170mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.78(m,1H),7.67-7.72(m,1H),7.34(t,J＝6.7Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.13-5.18(m,1H),4.01-4.12(m,3H),3.91(s,3H),3.61-3.70(m,1H),3.38-3.55(m,2H),3.28-3.33(m,1H),1.80(t,J＝6.7Hz,3H),1.32-1.36(m,1H),0.69-0.70(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z495.2[M+H-2HCl] ⁺.

embodiment 11: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of methyl-formiate dihydrochloride

Step 1: the synthesis of compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.25g, 0.53mmol), 1-Boc-2-piperazinecarboxylic acid methyl esters (157mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (181mg, 1.33mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.13mmol), stirring at room temperature 5h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 260mg colorless viscous thing, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.55-7.62(m,2H),7.26(d,J＝8.4Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),5.25-5.29(m,1H),3.97-4.01(m,3H),3.79(br.s,1H),3.58-3.63(m,2H),1.50-1.52(m,3H),1.48(s,9H),1.45(s,9H),1.32-1.35(m,1H),0.68-0.73(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z695.3[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-methyl-formiate dihydrochloride

To compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-methyl-formiate (0.26g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.37mmol), 5mL), stirring at room temperature 50min, except desolventizing, obtain 212mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.81(s,1H),7.72-7.75(m,1H),7.32-7.34(m,1H),6.93(t,J _F-H＝74.7Hz,1H),5.14-5.16(m,1H),4.63-4.69(m,1H),4.05(d,J＝6.8Hz,2H),3.89-3.94(m,3H),3.61-3.64(m,1H),3.40-3.54(m,1H),1.80(d,J＝6.8Hz,3H),1.37-1.42(m,1H),0.67-0.72(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z495.2[M+H-2HCl] ⁺.

embodiment 12: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1,3- the synthesis of dicarboxylic acid methyl ester hydrochloride

Step 1: the synthesis of compound piperazine-1,3-dicarboxylic acid methyl ester hydrochloride

Under 25 DEG C of conditions, to N ' N-carbonyl dimidazoles (205mg, 1.23mmol) with triethylamine (0.26mL, 1-Boc-2-piperazinecarboxylic acid methyl esters (250mg is dripped in dry DMF (6mL) solution 1.84mmol), dry DMF (10mL) solution 1.02mmol), 60 DEG C of reaction 30min, add anhydrous methanol (10mL), 60 DEG C of reaction 21h, except desolventizing, add saturated nacl aqueous solution (10mL × 3) washing, ethyl acetate (15mL × 2) extracts, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 194mg colorless oil: 1-tert-butoxycarbonyl-piperazine-2,4-dicarboxylic acid methyl ester, yield: 62%.

¹HNMR(400MHz,CDCl ₃):δppm4.59-4.78(m,2H),3.81-4.03(m,2H),3.76(s,3H),3.72(m,1H),2.90-3.17(m,3H),1.49(s,9H)；

MS-ESI:m/z203.2[M+H-100] ⁺.

To compound 1-tert-butoxycarbonyl-piperazine-2,4-dicarboxylic acid methyl ester (0.18g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.61mmol), 3mL), stirring at room temperature 1h, except desolventizing, obtains 146mg white solid: compound piperazine-1,3-dicarboxylic acid methyl ester hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.30-4.40(m,2H),4.05-4.10(m,1H),3.91(s,3H),3.77(m,1H),3.40-3.54(m,3H),3.18-3.24(m,1H).

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1,3-dicarboxylic acid methyl ester

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.25g, 0.53mmol), compound piperazine-1, 3-dicarboxylic acid methyl ester hydrochloride (150mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (181mg, 1.33mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.13mmol), stirring at room temperature 17h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtain 260mg clear yellow viscous thing, yield: 74%.

¹HNMR(400MHz,CDCl ₃):δppm7.56-7.62(m,1H),7.52-7.54(m,1H),7.24-7.27(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.25-5.29(m,1H),4.01-4.68(m,3H),3.99(dd,J ₁＝6.9Hz,J ₂＝3.0Hz,2H),3.81(s,3H),3.75(s,3H),3.30-3.35(m,3H),1.53-1.57(m,3H),1.44(s,9H),1.32-1.37(m,1H),0.69-0.73(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z653.2[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1,3-dicarboxylic acid methyl ester hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1,3-dicarboxylic acid methyl ester (0.25g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.39mmol), 3mL), stirring at room temperature 1.5h, except desolventizing, obtain 211mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.77(m,1H),7.63-7.71(m,1H),7.32-7.34(m1H),6.80-7.05(m,1H),5.05-5.14(m,1H),4.90-4.95(m,1H),4.61-4.65(m,1H),4.40-4.43,3.40-3.44(m,m,0.5H,1.5H),4.06-4.10(m,1H),4.04-4.08(m,2H),3.81-3.82(m,3H),3.74(s,3H),3.17-3.25(m,1H),1.77-1.80(m,3H),1.34-1.37(m,1H),0.69-0.70(m,2H),0.44-0.45(m,2H)；

MS-ESI:m/z553.2[M+H-HCl] ⁺.

embodiment 13: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-is amino the synthesis of formyl piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 3-formamyl piperazine-1-methyl-formiate

To compound piperazine-1; 3-dicarboxylic acid methyl ester hydrochloride (399mg; methyl alcohol (8mL) solution of ammonia is added in methyl alcohol (7mL) solution 1.67mmol); 70 DEG C of reaction 30h in tube sealing; except desolventizing; obtain 310mg thick white thing: compound 3-formamyl piperazine-1-methyl-formiate, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.16-4.19(m,1H),3.89-3.92(m,1H),3.73(s,3H),3.49-3.52(m,1H),3.06-3.12(m,3H),2.80-2.86(m,1H).

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.25g, 0.53mmol), compound 3-formamyl piperazine-1-methyl-formiate (120mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (181mg, 1.33mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.13mmol), stirring at room temperature 16h, add saturated nacl aqueous solution (10mL × 5) washing, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 20mg clear yellow viscous thing, yield: 5%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.59(m,2H),7.24-7.26(m,1H),6.70(t,J _F-H＝75.0Hz,1H),5.17-5.20(m,1H),4.88-4.92(m,1H),3.97(d,J＝6.8Hz,2H),3.75(s,3H),3.17-3.25(m,3H),1.37-1.41(m,3H),1.33(s,9H),1.27-1.29(m,1H),0.67-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z638.2[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate (22mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.03mmol); 2mL); stirring at room temperature 2.5h; except desolventizing; obtain 19mg faint yellow solid, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm7.73(s,1H),7.64-7.68(m,1H),7.30-7.34(m,1H),6.91(t,J _F-H＝73.9Hz,1H),5.04-5.10(m,2H),4.48-4.58(m,1H),4.22-4.23(m,1H),4.00-4.04(m,2H),3.85-3.98(m,2H),3.73(s,3H),3.56-3.65(m,2H),1.77(d,J＝5.0Hz,3H),1.42-1.46(m,1H),0.68-0.69(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z538.1[M+H-HCl] ⁺.

embodiment 14: compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxy carbonyl) synthesis of piperazine-2-carboxylic acid hydrochloride

Step 1: the synthesis of compound 1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonyl) piperazine-2-formic acid

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1,3-dicarboxylic acid methyl ester (351mg, sodium hydroxide (108mg is added in tetrahydrofuran (THF) (16mL) 0.53mmol) and the mixed solvent of water (8mL), 2.69mmol), 45 DEG C of reaction 3h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (10mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 330mg white solid, productive rate: 96%.

¹HNMR(400MHz,CD ₃OD):δppm7.60-7.73(m,2H),7.27-7.30(m,1H),6.89(t,J _F-H＝74.9Hz,1H),5.17-5.29(m,2H),4.65-4.68(m,1H),4.30-4.50(m,1H),4.09-4.13(m,1H),4.02-4.04(m,2H),3.74(s,3H),3.37-3.39(m,1H),1.49-1.54(m,3H),1.43(s,9H),1.32-1.35(m,1H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z639.2[M+H] ⁺.

Step 2: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonyl) piperazine-2-carboxylic acid hydrochloride

To compound 1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonyl) piperazine-2-formic acid (90mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.14mmol), 3mL), stirring at room temperature 2h, except desolventizing, obtain 80mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.74-7.76(m,1H),7.67-7.72(m,1H),7.32-7.35(m,1H),6.79-7.05(m,1H),5.04-5.12(m,1H),4.66-4.69(m,1H),4.30-4.33(m,1H),4.08-4.11(m,1H),4.03-4.06(m,2H),3.75(s,3H),3.40-3.50(m,2H),1.76-1.79(m,3H),1.35-1.37(m,1H),0.69-0.70(m,2H),0.44-0.45(m,2H)；

MS-ESI:m/z539.1[M+H-HCl] ⁺.

embodiment 15: compound 3-((pivaloyl oxygen base) methoxycarbonyl)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 3-((pivaloyl oxygen base) methoxycarbonyl)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

To compound 1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonyl) piperazine-2-formic acid (234mg, potassium hydroxide (21mg is added in dehydrated alcohol (6mL) solution 0.36mmol), 0.36mmol), 40 DEG C of reaction 20min, anhydrous N is added after removing ethanol, dinethylformamide (15mL), 25 DEG C drip Chloro methyl pivalate (0.16mL, 1.10mmol), 25 DEG C of reaction 6h, except adding frozen water (8mL) after desolventizing, ethyl acetate (10mL × 3) extracts, organic phase uses anhydrous Na after merging ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 228mg colorless viscous thing, yield: 82%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.59(m,1H),7.49-7.54(m,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.75-5.83(m,2H),5.22-5.25(m,1H),4.40-4.65(m,2H),3.97(d,J＝6.9Hz,2H),3.72(s,3H),3.10-3.34(m,3H),1.49-1.55(m,3H),1.42(s,9H),1.32-1.35(m,1H),1.11-1.21(m,9H),0.66-0.71(m,2H),0.41-0.42(m,2H)；

MS-ESI:m/z753.3[M+H] ⁺.

Step 2: the synthesis of compound 3-((pivaloyl oxygen base) methoxycarbonyl)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate hydrochloride

To compound 3-((pivaloyl oxygen base) methoxycarbonyl)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.29mmol), 3mL), stirring at room temperature 1.5h, except desolventizing, obtain 200mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.72-7.77(m,1H),7.64-7.72(m,1H),7.33(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.82-5.87(m,2H),5.06-5.15(m,1H),4.61-4.65(m,1H),4.35-4.41(m,1H),4.05-4.07(m,2H),4.06-4.09(m,1H),3.75(s,3H),3.42-3.45(m,1H),3.10-3.25(m,1H),1.75-1.81(m,3H),1.39-1.44(m,1H),1.11-1.23(m,9H),0.68-0.70(m,2H),0.45-0.47(m,2H)；

MS-ESI:m/z653.2[M+H-HCl] ⁺.

embodiment 16: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of formic acid dihydrochloride

Step 1: the synthesis of compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid

By compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-methyl-formiate (230mg, 0.33mmol) with sodium hydroxide (66mg, 1.65mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (18mL) and water (9mL), 50 DEG C of reaction 4h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (10mL × 3) extraction, organic phase uses anhydrous Na after merging ₂sO ₄drying, except desolventizing, obtains 220mg white solid, productive rate: 97%.

¹HNMR(400MHz,CD ₃OD):δppm7.58-7.61(m,1H),7.53(d,J＝8.1Hz,1H),7.17(d,J＝8.3Hz,1H),6.78(t,J _F-H＝76.0Hz,1H),5.03-5.08(m,1H),4.36-4.40(m,1H),3.91(d,J＝6.4Hz,2H),3.80-3.84(m,1H),3.63-3.65(m,1H),1.89-1.90(m,3H),1.37-1.39(m,9H),1.30-1.32(m,9H),1.19-1.24(m,1H),0.56-0.58(m,2H),0.31-0.32(m,2H)；

MS-ESI:m/z681.4[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid dihydrochloride

To compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid (0.21g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.31mmol), 3mL), stirring at room temperature 2h, except desolventizing, obtain 170mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.59-7.65(m,1H),7.57(d,J＝5.4Hz,1H),7.17(d,J＝8.2Hz,1H),6.77(t,J _F-H＝74.7Hz,1H),4.95-4.97(m,1H),4.33-4.45(m,1H),3.85-3.88(m,2H),3.75-3.78(m,1H),3.35-3.43(m,2H),3.24-3.30(m,1H),1.63-1.65(m,3H),1.17-1.19(m,1H),0.52-0.53(m,2H),0.27-0.28(m,2H)；

MS-ESI:m/z481.1[M+H-2HCl] ⁺.

embodiment 17: compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of formic acid dihydrochloride

Step 1: the synthesis of compound 4-tertbutyloxycarbonyl-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid

By compound 1-tertbutyloxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-3-methyl-formiate (250mg, 0.36mmol) with sodium hydroxide (72mg, 1.80mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (18mL) and water (9mL), 50 DEG C of reaction 3h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (10mL × 3) extraction, organic phase uses anhydrous Na after merging ₂sO ₄drying, except desolventizing, obtains 243mg white solid, productive rate: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.69-7.73(m,1H),7.60-7.67(m,1H),7.26-7.30(m,1H),6.90(t,J _F-H＝74.9Hz,1H),5.17-5.30(m,1H),4.56-4.68(m,1H),4.31-4.43(m,1H),4.01-4.03(m,2H),3.35-3.45(m,1H),3.01-3.20(m,1H),1.52-1.54(m,3H),1.49(s,9H),1.42-1.46(m,9H),1.35-1.38(m,1H),0.66-0.70(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z681.4[M+H] ⁺.

Step 2: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid dihydrochloride

To compound 4-tertbutyloxycarbonyl-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-formic acid (0.24g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.35mmol), 5mL), stirring at room temperature 2h, except desolventizing, obtain 195mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.78(m,1H),7.70-7.71(m,1H),7.32-7.35(m,1H),6.93(t,J _F-H＝74.9Hz,1H),5.13-5.17(m,1H),4.03-4.05(m,2H),4.01-4.03(m,1H),3.59-3.71(m,1H),3.41-3.52(m,2H),3.28-3.30(m,1H),1.78-1.81(m,3H),1.34-1.36(m,1H),0.65-0.71(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z481.3[M+H-2HCl] ⁺.

embodiment 18: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of keto hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-oxypiperazin-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 2-piperazinones (77mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 21h, add water (15mL) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=30/1), obtains 285mg colorless viscous thing, yield: 80%.

¹HNMR(600MHz,CDCl ₃):δppm7.57-7.59(m,1H),7.51-7.54(m,1H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.88-5.92(m,1H),5.25-5.26(m,1H),4.68-4.78(m,1H),4.35-4.39(m,1H),4.19-4.25(m,1H),3.96(d,J＝6.5Hz,2H),3.49-3.54(m,2H),1.53(d,J＝7.0Hz,3H),1.41(s,9H),1.30-1.35(m,1H),0.66-0.70(m,2H),0.39-0.41(m,2H)；

MS-ESI:m/z551.4[M+H] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-keto hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-oxypiperazin-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.27g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.50mmol), 5mL), stirring at room temperature 1h, except desolventizing, obtain 240mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.79(m,2H),7.32(d,J＝8.2Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.08-5.11(m,1H),4.38-4.42(m,1H),4.34(m,1H),4.04(d,J＝6.8Hz,2H),3.96-3.99(m,1H),3.56(m,1H),3.48(m,1H),1.80(d,J＝6.3Hz,3H),1.32-1.35(m,1H),0.68-0.69(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z451.3[M+H-HCl] ⁺.

embodiment 19: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-6-methyl the synthesis of piperazine-2-keto hydrochloride

Step 1: the synthesis of compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-methyl-5-oxypiperazin-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 6-methylpiperazine 2-ketone (88mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 16h, add water (15mL) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 325mg colorless viscous thing, yield: 89%.

¹HNMR(600MHz,CDCl ₃):δppm7.56-7.59(m,1H),7.52-7.54(m,1H),7.22-7.25(m,1H),6.70(t,J _F-H＝75.0Hz,1H),5.92(br.s,1H),5.24-5.27(m,1H),4.84-5.02(m,1H),4.62-4.65(m,1H),4.37-4.50(m,1H),3.95-3.97(m,2H),3.78-3.84(m,1H),3.17-3.21(m,1H),1.53-1.54(m,3H),1.41(s,9H),1.32-1.34(m,1H),1.28-1.30(m,3H),0.67-0.70(m,2H),0.40(m,2H)；

MS-ESI:m/z565.2[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-6-methylpiperazine-2-keto hydrochloride

To compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-methyl-5-oxypiperazin-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.31g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.55mmol), 6mL), stirring at room temperature 40min, except desolventizing, obtain 279mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(d,J＝11.6Hz,1H),7.71-7.73(m,1H),7.32-7.34(m,1H),6.92(t,J _F-H＝74.7Hz,1H),5.07-5.11(m,1H),4.62-4.75(m,1H),4.17-4.26(m,1H),4.04(d,J＝6.7Hz,2H),3.96-4.01,3.47(m,m,0.5H,0.5H),3.75-3.88(m,1H),1.79(d,J＝4.7Hz,3H),1.33-1.35(m,1H),1.29-1.31(m,3H),0.68-0.69(m,2H),0.44(m,2H)；

MS-ESI:m/z465.3[M+H-HCl] ⁺.

embodiment 20: compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrroles the synthesis of alkane-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound L-proline methyl ester hydrochloride

To Boc-L-proline(Pro) (1.50g under condition of ice bath, drip sulfur oxychloride (0.51mL, 6.97mmol) in methyl alcohol (20mL) solution 6.97mmol), under ice bath, react 30min, 70 DEG C of reaction 7h, except desolventizing, add the ethyl acetate solution (4M, 6mL) of methylene dichloride (8mL) and HCl, stirring at room temperature 5min, except desolventizing, obtain 800mg thick white thing, yield: 88%.

¹HNMR(400MHz,CD ₃OD):δppm4.47(t,J＝7.8Hz,1H),3.88(s,3H),3.37-3.45(m,2H),2.41-2.50(m,1H),2.07-2.21(m,3H).

Step 2: the synthesis of compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), L-PROLINE methyl ester hydrochloride (127mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 16h, add water (15mL) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 280mg white solid, yield: 75%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.61(m,1H),7.50-7.53(m,1H),7.20-7.24(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.24-5.35(m,1H),4.09-4.21(m,1H),3.96-4.00(m,2H),3.85-3.91(m,1H),3.73-3.79(m,1H),3.71(s,3H),2.22-2.34(m,2H),1.91-2.04(m,2H),1.50-1.52(m,3H),1.43(s,9H),1.30-1.34(m,1H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z580.1[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-methyl-formiate (102mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.17mmol), 4mL), stirring at room temperature 40min, except desolventizing, obtain 90mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.72(s,1H),7.65(d,J＝8.2Hz,1H),7.32(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.38-5.39(m,1H),5.17-5.20(m,1H),4.04-4.08(m,2H),3.80-3.85(m,1H),3.75-3.78(m,1H),3.73(s,3H),2.26-2.46(m,2H),2.01-2.12(m,2H),1.77-1.79(m,3H),1.32-1.37(m,1H),0.67-0.71(m,2H),0.45-0.46(m,2H)；

MS-ESI:m/z480.1[M+H-HCl] ⁺.

embodiment 21: compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrroles the synthesis of alkane-2-carboxylic acid hydrochloride

Step 1: the synthesis of compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3 (cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid

By compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-methyl-formiate (178mg, 0.30mmol) with sodium hydroxide (61mg, 1.53mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (10mL) and water (5mL), 90 DEG C of reaction 5h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (20mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 159mg white solid, productive rate: 91%.

¹HNMR(400MHz,CD ₃OD):δppm7.74(d,J＝1.9Hz,1H),7.61(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.26(d,J＝8.3Hz,1H),6.88(t,J _F-H＝75.0Hz,1H),5.44-5.50(m,1H),5.18-5.21(m,1H),4.02(d,J＝6.9Hz,2H),3.74-3.81(m,2H),2.23-2.41(m,2H),2.03-2.07(m,1H),1.96-2.00(m,1H),1.53(d,J＝7.1Hz,3H),1.43(s,9H),1.31-1.34(m,1H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z566.2[M+H] ⁺.

Step 2: the synthesis of compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carboxylic acid hydrochloride

To compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (154mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.27mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 135mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(d,J＝1.3Hz,1H),7.67(dd,J ₁＝8.3Hz,J ₂＝1.34Hz,1H),7.30(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.39-5.40(m,1H),5.09-5.18(m,1H),4.23-4.28(m,1H),4.02-4.05(m,2H),3.75-3.87(m,1H),2.23-2.33(m,1H),2.10-2.13(m,1H),1.95-2.05(m,2H),1.77(d,J＝6.9Hz,3H),1.34-1.38(m,1H),0.68-0.70(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z466.1[M+H-HCl] ⁺.

embodiment 22: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) imidazoles-4- the synthesis of keto hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-oxo-imidazole alkane-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (330mg, 0.70mmol), 4-imidazolidone hydrochloride (104mg, 0.85mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (203mg, 1.06mmol) with N-hydroxyl-7-azepine benzotriazole (240mg, 1.76mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.49mL, 2.82mmol), stirring at room temperature 5h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtain 360mg white solid, yield: 95%.

¹HNMR(400MHz,CDCl ₃):δppm7.56-7.61(m,1H),7.50-7.53(m,1H),7.24(d,J＝7.1Hz,1H),6.71(t,J _F-H＝74.2Hz,1H),5.52-5.62(m,1H),5.33-5.39(m,1H),5.10-5.13(m,1H),4.62-4.79(m,1H),4.22(m,1H),3.97(d,J＝6.9Hz,2H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.31-1.36(m,1H),0.65-0.71(m,2H),0.37-0.44(m,2H)；

MS-ESI:m/z537.3[M+H] ⁺.

Step 2: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) imidazol-4-one hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-oxo-imidazole alkane-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (350mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (12mL) solution 0.65mmol), 8mL), stirring at room temperature 2h, except desolventizing, obtain 308mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.68-7.69(m,2H),7.29(d,J＝8.2Hz,1H),6.80(t,J _F-H＝74.7Hz,1H),5.60(m,1H),5.11-5.12(m,1H),5.08(m,1H),4.72(m,2H),4.17(m,1H),4.01(d,J＝6.6Hz,2H),1.78(d,J＝6.4Hz,3H),1.31-1.32(m,1H),0.67-0.68(m,2H),0.42-0.43(m,2H)；

MS-ESI:m/z437.3[M+H-HCl] ⁺.

embodiment 23: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2- the synthesis of methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 2-morpholine carboxylate methyl ester hydrochloride (140mg, 0.76mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 6h, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 350mg colorless viscous thing, yield: 91%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.23(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.21-5.27(m,1H),4.25-4.33(m,1H),3.97(d,J＝6.7Hz,2H),3.70-3.82(m,4H),3.50-3.58(m,1H),3.15-3.22(m,1H),1.55(d,J＝7.0Hz,3H),1.42(s,9H),1.29-1.34(m,1H),0.66-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z596.1[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-methyl-formiate (135mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.22mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 120mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.74-7.79(m,1H),7.71(d,J＝8.2Hz,1H),7.32-7.35(m,1H),6.93(t,J _F-H＝74.7Hz,1H),5.08-5.10(m,1H),4.99-5.04(m,1H),4.65-4.67,4.35-4.51(m,m,0.5H,1.5H),4.10-4.18,3.92-3.93(m,m,1.5H,0.5H),4.03-4.06(m,2H),3.74-3.78(m,3H),3.81(m,1H),3.43-3.46(m,1H),1.79-1.80(m,3H),1.32-1.36(m,1H),0.68-0.70(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z496.3[M+H-HCl] ⁺.

embodiment 24: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2- the synthesis of carboxylic acid hydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-formic acid

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-methyl-formiate (200mg, 0.33mmol) with sodium hydroxide (67mg, 1.68mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (16mL) and water (8mL), 50 DEG C of reaction 2.5h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (20mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 195mg white solid, productive rate: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.71(br.s,1H),7.65(dd,J ₁＝8.4Hz,J ₂＝1.8Hz,1H),7.29(d,J＝8.3Hz,1H),6.89(t,J _F-H＝74.9Hz,1H),5.17(m,1H),4.50-4.59,4.09-4.10(m,m,0.5H,0.5H),4.20-4.31(m,2H),4.02(d,J＝6.9Hz,2H),3.72-3.80(m,1H),3.60-3.65,3.40-3.45(m,m,0.5H,0.5H),1.55(d,J＝7.1Hz,3H),1.43(s,9H),1.33-1.36(m,1H),0.66-0.70(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z582.3[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-carboxylic acid hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) morpholine-2-formic acid (194mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.33mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 170mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.62-7.66(m,1H),7.59(d,J＝8.4Hz,1H),7.20(d,J＝8.2Hz,1H),6.80(t,J _F-H＝74.8Hz,1H),4.96-4.98(m,1H),4.46-4.62(m,1H),4.09-4.26(m,2H),3.98-4.00(m,1H),3.91(d,J＝6.6Hz,2H),3.60-3.65(m,2H),3.20-3.30(m,1H),1.66-1.68(m,3H),1.20-1.23(m,1H),0.54-0.59(m,2H),0.30-0.34(m,2H)；

MS-ESI:m/z482.3[M+H-HCl] ⁺.

embodiment 25: compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-methyl-formiate hydrochloride

The synthesis of step 1: compound 2-(S)-methylpiperazine-1-methyl-formiate hydrochloride

To N ' N-carbonyl dimidazoles (1.00g, triethylamine (1.25mL is dripped in dry DMF (8mL) solution 5.99mmol), 8.99mmol) with (S)-4-N-tertbutyloxycarbonyl-2-methylpiperazine (1.00g, dry DMF (10mL) solution 4.99mmol), 60 DEG C are reacted 30min in tube sealing, add anhydrous methanol (15mL), 65 DEG C of reaction 24h, except desolventizing, add saturated nacl aqueous solution (10mL × 3) washing, ethyl acetate (15mL × 2) extracts, and merges organic phase, uses anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 409mg colourless liquid: 2-(S)-methyl-4-tert-butoxycarbonyl-piperazine-1-methyl-formiate, yield: 31%.

¹HNMR(600MHz,CDCl ₃):δppm4.27(m,1H),4.07-4.11,3.72-3.85(m,0.5H,2.5H),3.70(s,3H),3.06-3.10(m,1H),3.01(m,1H),2.76-2.86(m,1H),1.45(s,9H),1.14(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.2[M+H-100] ⁺.

To compound 2-(S)-methyl-4-tert-butoxycarbonyl-piperazine-1-methyl-formiate (0.40g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (5mL) solution 1.55mmol), 6mL), stirring at room temperature 2h, except desolventizing, obtain 300mg thick white thing: compound 2-(S)-methylpiperazine-1-methyl-formiate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.56-4.59(m,1H),4.14-4.17(m,1H),3.75(s,3H),3.34-3.38(m,2H),3.22-3.31(m,2H),3.04-3.11(m,1H),1.35(d,J＝7.2Hz,3H)；

MS-ESI:m/z159.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (600mg, 1.28mmol), 2-(S)-methylpiperazine-1-methyl-formiate hydrochloride (300mg, 1.54mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (368mg, 1.92mmol) with N-hydroxyl-7-azepine benzotriazole (434mg, 3.20mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.89mL, 5.12mmol), stirring at room temperature 16h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 552mg white solid, yield: 71%.

¹HNMR(400MHz,CDCl ₃):δppm7.55-7.58(m,1H),7.53(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.19-5.29(m,1H),4.36-4.66(m,3H),3.91-4.03(m,1H),3.96(d,J＝6.9Hz,2H),3.73(s,3H),3.40-3.43,3.18-3.24(m,m,0.5H,1.5H),3.02-3.04,2.85-2.95(m,m,0.5H,0.5H),1.54(d,J＝7.0Hz,3H),1.40(s,9H),1.29-1.34(m,1H),1.23-1.27(m,3H),0.66-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z609.2[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate hydrochloride

To compound (S)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (547mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.90mmol), 6mL), stirring at room temperature 2h, except desolventizing, obtain 489mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.68(s,1H),7.63-7.66(m,1H),7.25(d,J＝8.3Hz,1H),6.85(t,J _F-H＝74.7Hz,1H),4.96-5.05(m,1H),4.85-4.90(m,1H),4.36-4.44(m,2H),3.97(d,J＝6.7Hz,2H),3.93-3.95(m,1H),3.67(s,3H),3.52-3.55,3.19-3.22(m,m,0.5H,0.5H),3.28-3.30(m,1H),3.08-3.10,2.94-2.99(m,0.5H,0.5H),1.71(d,J＝6.1Hz,3H),1.25-1.31(m,1H),1.15-1.20(m,3H),0.59-0.63(m,2H),0.36-0.37(m,2H)；

MS-ESI:m/z509.2[M+H-HCl] ⁺.

embodiment 26: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (pyrroles-1-base) the synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(pyrroles-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), Pyrrolidine (0.06mL, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 12h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 225mg white solid, yield: 67%.

¹HNMR(600MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.53(d,J＝1.9Hz,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.24-5.27(m,1H),4.01-4.05(m,1H),3.97(d,J＝7.0Hz,2H),3.93-3.95(m,1H),3.66(t,J＝6.9Hz,2H),1.92-2.01(m,4H),1.53(d,J＝7.0Hz,3H),1.43(s,9H),1.32-1.35(m,1H),0.67-0.70(m,2H),0.39-0.42(m,2H)；

MS-ESI:m/z522.4[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (pyrroles-1-base) methanone hvdrochloric acid salt

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(pyrroles-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.38mmol), 3mL), stirring at room temperature 4h, except desolventizing, obtain 175mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.70(s,1H),7.67(d,J＝8.6Hz,1H),7.27(d,J＝8.2Hz,1H),6.89(t,J _F-H＝74.8Hz,1H),5.09-5.10(m,1H),4.08(t,J＝5.9Hz,1H),4.00(d,J＝6.8Hz,2H),3.62(t,J＝6.6Hz,1H),2.01-2.04(m,2H),1.92-1.97(m,2H),1.78(d,J＝6.4Hz,3H),1.26-1.33(m,1H),0.64-0.67(m,2H),0.40-0.42(m,2H)；

MS-ESI:m/z422.1[M+H-HCl] ⁺.

embodiment 27: compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N- the synthesis of dimethyl pyrrolidine-2-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride

By Boc-L-proline(Pro) (500mg, 2.32mmol), Dimethylammonium chloride (227mg, 2.79mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (668mg, 3.48mmol) with N-hydroxyl-7-azepine benzotriazole (790mg, 5.81mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.6mL, 9.29mmol), stirring at room temperature 4h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=50/1), obtains 540mg colorless oil: (S)-N, N-dimethyl-N-tertbutyloxycarbonyl tetramethyleneimine-2-methane amide, yield: 95%.

¹HNMR(400MHz,CDCl ₃):δppm4.64-4.67,4.51-4.54(m,0.5H,0.5H),3.53-3.63(m,1H),3.39-3.50(m,1H),3.06(d,J＝11.6Hz,3H),2.94(d,J＝6.8Hz,3H),1.98-2.18(m,2H),1.78-1.86(m,2H),1.38-1.44(m,9H)；

MS-ESI:m/z143.3[M+H-100] ⁺.

To compound (S)-N, N-dimethyl-N-tertbutyloxycarbonyl tetramethyleneimine-2-methane amide (520mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 2.14mmol), 6mL), stirring at room temperature 2h, except desolventizing, obtains 383mg thick white thing: compound (S)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.60(t,J＝7.9Hz,1H),3.33-3.40(m,1H),3.25-3.31(m,1H),3.02(s,3H),2.94(s,3H),2.43-2.52(m,1H),1.98-2.07(m,2H),1.85-1.91(m,1H)；

MS-ESI:m/z143.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-2-(dimethylamino formyl radical) pyrroles-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (S)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride (140mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=50/1), obtains 250mg white solid, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.44(s,1H),7.21(dd,J ₁＝8.2Hz,J ₂＝2.6Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.20-5.31(m,1H),5.55-5.57,5.01-5.04(m,0.5H,0.5H),4.11-4.21(m,1H),3.94-3.97(m,2H),3.15(d,J＝17.4Hz,3H),2.98(d,J＝5.0Hz,3H),2.04-2.34(m,2H),1.91-2.01(m,2H),1.50-1.53(m,3H),1.42(s,9H),1.31-1.34(m,1H),0.65-0.71(m,2H),0.37-0.42(m,2H)；

MS-ESI:m/z593.4[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-2-(dimethylamino formyl radical) pyrroles-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (239mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.40mmol); 4mL); stirring at room temperature 3h; except desolventizing; obtain 213mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.64-7.68(m,1H),7.55-7.61(m,1H),7.25-7.29(m,1H),6.73-6.98(m,1H),4.99-5.07(m,2H),4.27-4.32,4.08-4.12(m,0.5H,0.5H),3.97(d,J＝6.8Hz,2H),3.70-3.80(m,1H),3.17(d,J＝8.6Hz,3H),2.94,2.84(s,1.3H,1.7H),2.42-2.49,2.28-2.33(m,0.5H,0.5H),1.98-2.10(m,2H),1.83-1.90(m,1H),1.71(d,J＝6.9Hz,3H),1.25-1.28(m,1H),0.60-0.63(m,2H),0.34-0.38(m,2H)；

MS-ESI:m/z493.1[M+H-HCl] ⁺.

embodiment 28: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-ethyl the synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 2-ethyl piperazidine-1-methyl-formiate hydrochloride

To N ' N-carbonyl dimidazoles (468mg, triethylamine (0.59mL is dripped in anhydrous DMF solution (2mL) 2.80mmol), 4.20mmol) with N-tertbutyloxycarbonyl-3-ethyl piperazidine (500mg, dry DMF (2mL) solution 2.33mmol), room temperature reaction 30min in tube sealing, add anhydrous methanol (12mL), 60 DEG C of reaction 24h, except desolventizing, add saturated nacl aqueous solution (30mL), ethyl acetate (15mL × 2) extracts, and merges organic phase, uses anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 260mg colourless liquid: 4-tertbutyloxycarbonyl-2-ethyl piperazidine-1-methyl-formiate, yield: 40%.

¹HNMR(400MHz,CDCl ₃):δppm3.88-3.97(m,4H),3.70(s,3H),2.76-3.02(m,3H),1.52-1.61(m,2H),1.45(s,9H),0.89(t,J＝7.4Hz,3H)；

MS-ESI:m/z173.1[M+H-100] ⁺.

To compound 4-tertbutyloxycarbonyl-2-ethyl piperazidine-1-methyl-formiate (417mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 1.53mmol), 6mL), stirring at room temperature 1h, except desolventizing, obtain 319mg thick white thing: compound 2-ethyl piperazidine-1-methyl-formiate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.33-4.38(m,1H),4.18-4.23(m,1H),3.75(s,3H),3.38,3.27(m,m,0.5H,0.5H),3.31-3.34(m,3H),3.20-3.24(m,1H),3.07(td,J ₁＝12.3Hz,J ₂＝4.0Hz,1H),1.85-1.93(m,1H),1.67-1.75(m,1H),0.95(t,J＝7.4Hz,3H)；

MS-ESI:m/z173.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-ethyl piperazidine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 2-ethyl piperazidine-1-methyl-formiate hydrochloride (132mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 16h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 313mg colorless viscous thing, yield: 78%.

¹HNMR(400MHz,CDCl ₃):δppm7.56-7.58(m,1H),7.54(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.18-5.28(m,1H),4.77-4.80,4.55-4.63(m,0.5H,1.5H),4.21,3.35-3.38(m,m,0.5H,0.5H),4.09-4.10(m,1H),3.94-3.97(m,2H),3.73(s,3H),3.13-3.26(m,2H),2.87-2.98(m,1H),1.54(d,J＝7.0Hz,3H),1.41(s,9H),1.29-1.34(m,1H),0.81-0.95(m,3H),0.66-0.71(m,2H),0.39-0.40(m,2H)；

MS-ESI:m/z623.4[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-ethyl piperazidine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-ethyl piperazidine-1-methyl-formiate (298mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.48mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 266mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.68(s,1H),7.64-7.66(m,1H),7.27(dd,J ₁＝8.3Hz,J ₂＝3.3Hz,1H),6.85(t,J _F-H＝74.7Hz,1H),5.00-5.04(m,1H),4.89-4.97(m,1H),4.52-4.54,4.44-4.46(m,m,0.5H,0.5H),4.13-4.18(m,1H),4.01-4.03(m,1H),3.96-3.98(m,2H),3.68(s,3H),3.49-3.52,3.13(m,0.5H,0.5H),3.16-3.24(m,1H),3.01-3.04,2.91-2.96(m,0.5H,0.5H),1.71(d,J＝7.0Hz,3H),1.56-1.67(m,2H),1.26-1.30(m,1H),0.85-0.90(m,3H),0.61-0.64(m,2H),0.37-0.39(m,2H)；

MS-ESI:m/z523.1[M+H-HCl] ⁺.

embodiment 29: compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrroles the synthesis of alkane-2-isopropyl formate hydrochloride

Step 1: the synthesis of compound (S)-tetramethyleneimine-2-isopropyl formate hydrochloride

By Boc-L-proline(Pro) (500mg, 2.32mmol) and N ' N-carbonyl dimidazoles (1.16g, 6.97mmol) be dissolved in anhydrous tetrahydro furan (16mL), 50min is reacted under 60 DEG C of conditions, be cooled to room temperature, Virahol (0.21mL is dripped in this solution, 2.79mmol) with DBU (1.06mL, 6.97mmol), 10h is reacted under 60 DEG C of conditions, add saturated ammonium chloride solution (15mL) to wash, ethyl acetate (10mL × 2) extracts, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtains 419mg colourless liquid: (S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-isopropyl formate, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm4.99-5.06(m,1H),4.16-4.28(m,1H),3.35-3.58(m,2H),2.14-2.25(m,1H),1.82-1.97(m,3H),1.41(s,9H),1.22-1.25(m,6H)；

MS-ESI:m/z158.3[M+H-100] ⁺.

To compound (S)-1-tertbutyloxycarbonyl tetramethyleneimine-2-isopropyl formate (410mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 1.59mmol), 5mL), stirring at room temperature 1.5h, except desolventizing, obtain 308mg colorless oil: compound (S)-tetramethyleneimine-2-isopropyl formate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm5.05-5.11(m,1H),4.33-4.37(m,1H),3.31-3.39(m,2H),2.36-2.43(m,1H),2.00-2.11(m,3H),1.27(t,J＝5.6Hz,6H)；

MS-ESI:m/z158.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-isopropyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (S)-tetramethyleneimine-2-isopropyl formate hydrochloride (149mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 16h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out post separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 267mg white solid, yield: 68%.

¹HNMR(400MHz,CDCl ₃):δppm7.55(s,1H),7.53-7.54(m,1H),7.20(d,J＝8.4Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.24-5.37(m,1H),4.93-5.08(m,1H),4.09-4.22(m,1H),3.96-4.00(m,2H),3.71-3.88(m,2H),2.20-2.37(m,2H),1.89-2.04(m,2H),1.50-1.58(m,3H),1.43(s,9H),1.33-1.36(m,1H),1.18-1.27(m,3H),1.03-1.14(m,3H),0.65-0.70(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z608.0[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-isopropyl formate hydrochloride

To compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-isopropyl formate (258mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.42mmol), 3mL), stirring at room temperature 3h, except desolventizing, obtain 220mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.74-7.76(m,1H),7.66-7.68(m,1H),7.31(d,J＝8.8Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.39-5.42(m,1H),5.16-5.21(m,1H),4.95-5.01(m,1H),4.04-4.06(m,2H),3.75-3.86(m,2H),2.43-2.48(m,1H),2.24-2.28(m,1H),2.01-2.05(m,1H),1.90-1.97(m,1H),1.78-1.80(m,3H),1.34-1.38(m,1H),1.18(t,J＝6.1Hz,3H),1.13(t,J＝6.6Hz,3H),0.67-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z508.0[M+H-HCl] ⁺.

embodiment 30: compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of sec.-propyl piperazine-1-methyl-formiate hydrochloride

The synthesis of step 1: compound 2-(S)-sec.-propyl piperazine-1-methyl-formiate hydrochloride

To N ' N-carbonyl dimidazoles (1.10g, triethylamine (1.10mL is dripped in dry DMF (2mL) solution 6.57mmol), 7.88mmol) with (S)-1-BOC-3-sec.-propyl piperazine (1.00g, dry DMF (2mL) solution 4.38mmol), room temperature reaction 50min in tube sealing, add anhydrous methanol (12mL), 80 DEG C of reaction 48h, except desolventizing, add saturated nacl aqueous solution (10mL × 3) washing, ethyl acetate (15mL × 2) extracts, and merges organic phase, uses anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 339mg colourless liquid: 4-tertbutyloxycarbonyl-2-(S)-sec.-propyl piperazine-1-methyl-formiate, yield: 27%.

¹HNMR(400MHz,CDCl ₃):δppm3.75-4.16(m,4H),3.70(s,3H),2.77-2.95(m,3H),1.91-2.00(m,1H),1.46(s,9H),1.02(d,J＝6.5Hz,3H),0.82(d,J＝6.6Hz,3H)；

MS-ESI:m/z187.1[M+H-100] ⁺.

To compound 4-tertbutyloxycarbonyl-2-(S)-sec.-propyl piperazine-1-methyl-formiate (388mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 1.35mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 301mg white solid: compound 2-(S)-sec.-propyl piperazine-1-methyl-formiate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.22-4.26(m,1H),3.98-4.02(m,1H),3.75(s,3H),3.53-3.56(m,1H),3.28-3.30(m,1H),3.22-3.26(m,1H),3.04-3.19(m,2H),2.22-2.29(m,1H),1.07(d,J＝6.6Hz,3H),0.92(d,J＝6.6Hz,3H)；

MS-ESI:m/z187.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-sec.-propyl piperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 2-(S)-sec.-propyl piperazine-1-methyl-formiate hydrochloride (143mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 8h, add water (10mL × 2), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 342mg white solid, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.58(m,2H),7.23(d,J＝8.5Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.17-5.29(m,1H),4.81-4.97(m,1H),4.55-4.58(m,1H),3.93-3.97(m,2H),3.83-3.91(m,1H),3.73(s,3H),3.17-3.33(m,1H),3.07(m,1H),2.86-2.89(m,1H),2.04-2.07(m,1H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.29-1.34(m,1H),1.11,0.94(m,m,1.5H,1.5H),0.85(d,J＝6.6Hz,3H),0.66-0.71(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z637.0[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-sec.-propyl piperazine-1-methyl-formiate hydrochloride

To compound (S)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-sec.-propyl piperazine-1-methyl-formiate (330mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.52mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 290mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.71-7.73(m,1H),7.33-7.35(m,1H),6.92(t,J _F-H＝74.7Hz,1H),5.23-5.26,5.10-5.14(m,m,0.5H,0.5H),5.02-5.05(m,1H),4.80-4.83(m,1H),4.14(t,J＝14.3Hz,1H),4.02-4.05(m,2H),3.87-3.93(m,1H),3.75(s,3H),3.55-3.57,3.29-3.32(m,m,0.5H,0.5H),3.00-3.03(m,1H),2.03-2.10(m,1H),1.78(d,J＝7.0Hz,3H),1.30-1.37(m,1H),1.11,1.05(d,d,J＝6.5Hz,J＝6.4Hz,1.5H,1.5H),0.88(d,J＝6.9Hz,3H),0.69-0.70(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z537.0[M+H-HCl] ⁺.

embodiment 31: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-methyl the synthesis of-N-propylpiperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound 1-N-Methyl-N-propyl formamido-piperazine hydrochloride

By N, N-carbonyl dimidazoles (538mg, 3.22mmol) with N-Boc piperazine (500mg, 2.68mmol) be dissolved in dry DMF (6mL), in this solution, triethylamine (1.90mL is dripped under room temperature condition, 13.42mmol), 60 DEG C of reaction 30min, add N-methyl Tri N-Propyl Amine (0.96mL, 9.40mmol), under 80 DEG C of conditions, in tube sealing, react 29h, except desolventizing, add saturated nacl aqueous solution (15mL), ethyl acetate (10mL × 2) extracts, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 180mg faint yellow solid: 1-N-Methyl-N-propyl formamido--4-tert-butoxycarbonyl-piperazine, yield: 23%.

¹HNMR(400MHz,CDCl ₃):δppm3.42(t,J＝5.1Hz,4H),3.16(t,J＝5.2Hz,6H),2.82(s,3H),1.53-1.59(m,2H),1.46(s,9H),0.87(t,J＝7.4Hz,3H)；

MS-ESI:186.3[M-100+H] ⁺.

To compound 1-N-Methyl-N-propyl formamido--4-tert-butoxycarbonyl-piperazine (242mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.85mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain the faint yellow dope of 188mg: compound 1-N-Methyl-N-propyl formamido-piperazine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm3.29(t,J＝5.1Hz,4H),3.11(t,J＝5.0Hz,4H),3.06(t,J＝7.3Hz,2H),2.76(s,3H),1.43-1.49(m,2H),0.75(t,J＝7.4Hz,3H)；

MS-ESI:m/z186.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(methyl (propyl group) formamyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 1-N-Methyl-N-propyl formamido-piperazine hydrochloride (184mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 15h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 245mg colorless viscous thing, yield: 60%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54(d,J＝1.7Hz,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.19-5.23(m,1H),3.96(d,J＝6.9Hz,2H),3.90-3.98(m,2H),3.77(m,2H),3.30(m,4H),3.16(t,J＝7.4Hz,2H),2.85(s,3H),1.57-1.61(m,2H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.29-1.33(m,1H),0.89(t,J＝7.4Hz,3H),0.66-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z636.1[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-Methyl-N-propyl piperazine-1-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(methyl (propyl group) formamyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (240mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.38mmol); 4mL); stirring at room temperature 40min; except desolventizing; obtain 215mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.69(s,1H),7.66(d,J＝8.3Hz,1H),7.26(d,J＝8.3Hz,1H),6.86(t,J _F-H＝74.7Hz,1H),4.99-5.02(m,1H),4.13(m,2H),3.98(d,J＝6.8Hz,2H),3.75(m,2H),3.30(m,4H),3.17(t,J＝7.2Hz,2H),2.87(s,3H),1.74(d,J＝6.8Hz,3H),1.54-1.60(m,2H),1.26-1.28(m,1H),0.86(t,J＝7.3Hz,3H),0.61-0.64(m,2H),0.37-0.38(m,2H)；

MS-ESI:m/z536.0[M+H-HCl] ⁺.

embodiment 32: compound-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- methylpiperazine-1-yl) synthesis of-2-cyclopropyl acetophenone hydrochloride

Step 1: the synthesis of compound 1-cyclopropyl base ethanoyl-2-(R)-methylpiperazine hydrochloride

By compound (R)-4-Boc-2-methylpiperazine (200mg, 1.00mmol), Cyclopropylacetic acid (120mg, 1.20mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (287mg, 1.50mmol) with N-hydroxyl-7-azepine benzotriazole (340mg, 2.50mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.70mL, 4.00mmol), stirring at room temperature 16h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 260mg colourless liquid: 1-Cyclopropyl-acetyl-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine, yield: 92%.

¹HNMR(400MHz,CDCl ₃):δppm3.85-4.14(m,3H),3.31-3.55(m,1H),2.80-2.97(m,3H),2.30-2.33,2.20-2.23(m,m,0.5H,1.5H),1.46(s,9H),1.15-1.24(m,3H),1.03-1.07(m,1H),0.55-0.57(m,2H),0.15-0.18(m,2H).

To compound 1-cyclopropyl base ethanoyl-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine (260mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.90mmol); 4mL); stirring at room temperature 1.5h; except desolventizing; obtain 201mg white solid: compound 1-cyclopropyl base ethanoyl-2-(R)-methylpiperazine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.86-4.90,4.30-4.50(m,m,0.5H,0.5H),3.92-4.01,3.38-3.52(m,m,0.5H,0.5H),3.28-3.31(m,1H),3.22-3.24(m,1H),3.10-3.15(m,1H),2.91-2.97(m,1H),2.31-2.35(m,1H),2.20-2.26(m,1H),1.21-1.30(m,3H),0.88-0.94(m,1H),0.44-0.48(m,2H),0.08-0.11(m,2H)；

MS-ESI:m/z183.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-(2-Cyclopropyl-acetyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 1-Cyclopropyl-acetyl-2-(R)-methylpiperazine hydrochloride (168mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 17h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 226mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.3Hz,1H),7.53(s,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),6.09(br.s,1H),5.20-5.28(m,1H),4.50-4.85(m,3H),3.96(d,J＝6.9Hz,2H),3.44-3.68(m,2H),2.92-3.21(m,2H),2.21-2.40(m,2H),1.54-1.59(m,3H),1.41(s,9H),1.29-1.32(m,1H),1.24-1.27(m,3H),1.08-1.17(m,1H),0.66-0.71(m,2H),0.58-0.60(m,2H),0.40-0.41(m,2H),0.18-0.19(m,2H)；

MS-ESI:m/z633.1[M+H] ⁺.

Step 3: the synthesis of compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-yl)-2-cyclopropyl acetophenone hydrochloride

To compound ((S)-1-(4-((R)-4-(2-Cyclopropyl-acetyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (219mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.35mmol); 4mL); stirring at room temperature 1h; except desolventizing; obtain 190mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.77(m,2H),7.33(d,J＝7.6Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.06-5.09(m,1H),4.93-5.04(m,1H),4.41-4.58(m,2H),4.05(d,J＝6.0Hz,2H),3.93-3.95,3.46-3.61(m,m,0.5H,1.5H),2.95-3.16,2.52-2.54(m,m,1.5H,0.5H),2.38-2.40(m,1H),2.30-2.35(m,1H),1.79-1.82(m,3H),1.30-1.35(m,3H),1.23-1.26(m,1H),1.05-1.09(m,1H),0.69-0.70(m,2H),0.55-0.58(m,2H),0.44-0.45(m,2H),0.22-0.23(m,2H)；

MS-ESI:m/z533.0[M+H-HCl] ⁺.

embodiment 33: chemical combination (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-formic acid (2-methoxyl group) carbethoxy hydrochloride

The synthesis of step 1: compound 2-(R)-methylpiperazine-1-formic acid (2-methoxyl group) carbethoxy hydrochloride

By N, N-carbonyl dimidazoles (501mg, 3.00mmol) with (R)-4-Boc-2-methylpiperazine (500mg, 2.50mmol) be dissolved in dry DMF (4mL), in this solution, triethylamine (0.63mL is dripped under room temperature condition, 4.49mmol), stirring at room temperature 50min, add ethylene glycol monomethyl ether (10mL), in tube sealing, react 47h under 80 DEG C of conditions, except desolventizing, add ethyl acetate, saturated nacl aqueous solution (15mL × 2) is washed, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 372mg yellow liquid: 4-tertbutyloxycarbonyl-2-(R)-methylpiperazine-1-formic acid (2-methoxyl group) ethyl ester, yield: 49%.

¹HNMR(600MHz,CDCl ₃):δppm4.26-4.29(m,1H),4.23-4.25(m,2H),4.07-4.08,3.79-3.80(m,m,0.5H,0.5H),3.85-3.89(m,2H),3.59(t,J＝4.7Hz,2H),3.38(s,3H),3.07-3.12(m,1H),2.95-3.02(m,1H),2.72-2.85(m,1H),1.46(s,9H),1.15(d,J＝6.8Hz,3H).

To compound 4-tertbutyloxycarbonyl-2-(R)-methylpiperazine-1-formic acid (2-methoxyl group) ethyl ester (367mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 1.21mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 289mg yellow oil: compound 2-(R)-methylpiperazine-1-formic acid (2-methoxyl group) carbethoxy hydrochloride, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm4.58-4.60(m,1H),4.25-4.30(m,2H),4.16-4.19(m,1H),3.64(t,J＝4.6Hz,2H),3.39(s,3H),3.35-3.38(m,2H),3.29-3.31(m,1H),3.24-3.27(m,1H),3.06-3.11(m,1H),1.36(d,J＝7.2Hz,3H)；

MS-ESI:m/z203.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-formic acid (2-methoxyl group) ethyl ester

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 2-(R)-methylpiperazine-1-formic acid (2-methoxyl group) carbethoxy hydrochloride (184mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 17h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 241mg colorless viscous thing, yield: 57%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.3Hz,1H),7.53(s,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.20-5.30(m,1H),4.55-4.70(m,2H),4.27(t,J＝4.2Hz,2H),3.96(d,J＝5.6Hz,2H),3.61(t,J＝4.6Hz,2H),3.39(s,3H),3.21-3.25(m,2H),2.90-3.06(m,1H),2.20-2.31(m,2H),1.53-1.56(m,3H),1.42(s,9H),1.31-1.35(m,1H),1.24-1.27(m,3H),0.66-0.71(m,2H),0.40-0.41(m,2H)；

MS-ESI:m/z653.4[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-formic acid (2-methoxyl group) carbethoxy hydrochloride

To compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-formic acid (2-methoxyl group) ethyl ester (235mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.36mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 210mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(d,J＝8.0Hz,1H),7.71-7.74(m,1H),7.33(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.07-5.09(m,1H),4.96-4.98(m,1H),4.44-4.51(m,2H),4.24-4.30(m,2H),4.03-4.05(m,1H),4.05(d,J＝5.8Hz,2H),3.65(t,J＝4.5Hz,2H),3.60-3.62,3.28-3.30(m,m,0.5H,0.5H),3.40(s,3H),3.36-3.39(m,1H),3.17-3.19,3.03-3.08(m,m,0.5H,0.5H),1.80(d,J＝6.5Hz,3H),1.32-1.35(m,1H),1.31-1.32,1.24-1.25(m,m,1.5H,1.5H),0.67-0.70(m,2H),0.44-0.45(m,2H)；

MS-ESI:m/z553.1[M+H-HCl] ⁺.

embodiment 34: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-N-(Cvclopropvlmethvl)-2-methylpiperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (R)-N-(Cvclopropvlmethvl)-2-methylpiperazine-1-carboxamide hydrochloride

By N, N-carbonyl dimidazoles (626mg, 3.74mmol) be dissolved in dry DMF (4mL), in this solution, triethylamine (0.52mL is dripped under room temperature condition, 3.74mmol), slow dropping cyclopropylmethylamine (0.32mL, 3.74mmol), room temperature reaction 50min, adds (R)-4-Boc-2-methylpiperazine (300mg, dry DMF (3mL) solution 1.50mmol), 60 DEG C are reacted 23h in tube sealing, except desolventizing, add saturated nacl aqueous solution (15mL) and wash, ethyl acetate (10mL × 2) extracts, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtain 400mg white solid: (R)-4-((Cvclopropvlmethvl) carbonyl)-3-methylpiperazine-1-t-butyl formate, yield: 89%.

¹HNMR(400MHz,CDCl ₃):δppm4.50(m,1H),4.09-4.14(m,1H),3.60-3.83(m,1H),3.07-3.14(m,2H),3.02-3.05(m,3H),2.80-2.90(m,1H),1.46(s,9H),1.15(d,J＝6.5Hz,3H),0.96-0.99(m,1H),0.46-0.50(m,2H),0.14-0.18(m,2H).

To compound (R)-4-((Cvclopropvlmethvl) carbonyl)-3-methylpiperazine-1-t-butyl formate (684mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 2.30mmol), 6mL), stirring at room temperature 3.5h, except desolventizing, obtain 537mg colorless viscous thing: compound (R)-N-(Cvclopropvlmethvl)-2-methylpiperazine-1-carboxamide hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.33-4.36(m,1H),3.88-3.92(m,1H),3.20-3.23(m,1H),3.12-3.13(m,1H),3.04-3.08(m,1H),2.91(d,J＝7.0Hz,2H),2.88-2.89(m,2H),1.18(d,J＝7.1Hz,3H),0.87-0.88(m,1H),0.29-0.31(m,2H),0.04-0.06(m,2H)；

MS-ESI:m/z198.3[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-((cyclo propyl methoxy) carbonyl)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (R)-N-(Cvclopropvlmethvl)-2-methylpiperazine-1-carboxamide hydrochloride (224mg, 0.96mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (184mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (218mg, 1.60mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 15h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 241mg white solid, yield: 58%.

¹HNMR(600MHz,CDCl ₃):δppm7.56-7.58(m,1H),7.53(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.22-5.28(m,1H),4.65-4.70(m,1H),4.52-4.58(m,2H),4.20-4.25(m,1H),3.95-3.97(m,2H),3.72-3.85(m,1H),3.52-3.55,2.97-3.01(m,m,0.5H,0.5H),3.24-3.32(m,1H),3.10-3.12(m,2H),1.53-1.55(m,3H),1.41(s,9H),1.31-1.33(m,1H),1.24-1.26(m,3H),0.96-0.99(m,1H),0.67-0.70(m,2H),0.49-0.52(m,2H),0.39-0.41(m,2H),0.18-0.21(m,2H)；

MS-ESI:m/z648.5[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-(Cvclopropvlmethvl)-2-methylpiperazine-1-carboxamide hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-((cyclo propyl methoxy) carbonyl)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (232mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.36mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 208mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(d,J＝7.9Hz,2H),7.71-7.72(m,1H),7.33(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.06-5.08(m,1H),4.98-5.00(m,1H),4.44-4.53(m,1H),4.39-4.41(m,1H),4.04(d,J＝5.8Hz,2H),3.91-3.95(m,1H),3.58-3.61,3.37-3.39(m,m,0.5H,0.5H),3.17-3.25(m,1H),3.06-3.10(m,2H),3.02-3.04,3.27-3.30(m,m,0.5H,0.5H),1.80(d,J＝6.4Hz,3H),1.33-1.35(m,1H),1.29,1.21(d,J＝6.4Hz,d,J＝6.4Hz,1.5H,1.5H),1.04-1.06(m,1H),0.68-0.71(m,2H),0.47-0.50(m,2H),0.44-0.45(m,2H),0.22-0.24(m,2H)；

MS-ESI:m/z548.4[M+H-HCl] ⁺.

embodiment 35: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4- the synthesis of methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-methyl piperidine hydrochloride

To N-Boc-4-piperidine methyl formate (2.16g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 8.88mmol), 6mL), stirring at room temperature 1.5h, except desolventizing, obtain 1.59g white solid: compound 4-methyl piperidine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm3.73(s,3H),3.44-3.39(m,2H),3.15-3.09(m,2H),2.82-2.77(m,1H),2.21-2.16(m,2H),1.99-1.89(m,2H)；

MS-ESI:m/z144.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (1.5g, 3.20mmol), 4-methyl piperidine hydrochloride (690mg, 3.84mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (921mg, 4.80mmol) with N-hydroxyl-7-azepine benzotriazole (1.09g, 8.01mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (2.2mL, 12.8mmol), stirring at room temperature 12h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 1.49g pale yellow oil, yield: 78%.

¹HNMR(600MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.54(d,J＝1.9Hz,1H),7.22(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.22-5.18(m,1H),4.46(br.s,2H),3.96(d,J＝7.0Hz,2H),3.71(s,3H),2.65-2.60(m,1H),2.03-1.93(m,2H),1.82-1.78(m,2H),1.53(d,J＝7.1Hz,3H),1.42(s,9H),1.33-1.31(m,1H),0.69-0.66(m,2H),0.41-0.39(m,2H)；

MS-ESI:m/z594.0[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-methyl-formiate hydrochloride

To compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-methyl-formiate (210mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.35mmol), 3mL), stirring at room temperature 1.5h, except desolventizing, obtain 175mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(d,J＝1.8Hz,1H),7.71(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.32(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.04-5.01(m,1H),4.77-4.75(m,1H),4.49-4.47(m,1H),4.04(d,J＝6.9Hz,2H),3.72(s,3H),3.48-3.45(m,1H),3.13-3.10(m,1H),2.80-2.76(m,1H),2.07-2.05(m,2H),1.84-1.80(m,1H),1.79(d,J＝7.0Hz,3H),1.76-1.72(m,1H),1.35-1.32(m,1H),0.70-0.67(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z494.0[M+H-HCl] ⁺.

embodiment 36: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-ring third the synthesis of phenylpiperidines-4-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-formic acid

Compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-methyl-formiate (623mg, 1.05mmol) is dissolved in THF (10mL) and H ₂in the mixed solvent of O (5mL), add a hydronium(ion) Lithium Oxide 98min (220mg again, 5.25mmol), at 45 DEG C of reaction 1.5h, add HCl (1M) and the pH value of solution is adjusted to about 1, with ethyl acetate (10mL × 3) extraction, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 592mg white solid, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54(d,J＝1.7Hz,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.24-5.16(m,1H),4.45(br.s,2H),3.96(d,J＝6.9Hz,2H),3.40-3.30(m,1H),3.10-3.05(m,1H),2.70-2.65(m,1H),2.04-2.00(m,2H),1.85-1.80(m,2H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.34-1.32(m,1H),0.70-0.65(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z580.4[M+H] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperidines-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-formic acid (220mg, 0.38mmol), cyclopropylamine (0.03mL, 0.45mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (109mg, 0.57mmol) with N-hydroxyl-7-azepine benzotriazole (129mg, 0.95mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.27mL, 1.52mmol), stirring at room temperature 20h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=30/1), obtains 213mg white solid, yield: 90%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.20-5.17(m,1H),4.56-4.64(m,2H),3.96(d,J＝6.9Hz,2H),3.20-3.15(m,1H),2.90-2.85(m,1H),2.72-2.70(m,1H),2.37-2.30(m,1H),1.89-1.84(m,2H),1.80-1.74(m,2H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.35-1.32(m,1H),0.81-0.76(m,2H),0.70-0.66(m,2H),0.50-0.47(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z619.3[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-cyclopropyl piperidine-4-carboxamide hydrochloride

To compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperidines-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.32mmol); 3mL); stirring at room temperature 3h; except desolventizing; obtain 167mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(s,1H),7.71(dd,J ₁＝8.4Hz,J ₂＝1.3Hz,1H),7.32(d,J＝8.3Hz,1H),6.91(t,J _F-H＝74.7Hz,1H),5.04-5.01(m,1H),4.93-4.91(m,1H),4.66-4.64(m,1H),4.03(d,J＝6.8Hz,2H),2.96-2.92(m,1H),2.69-2.66(m,1H),2.56-2.53(m,1H),1.90-1.82(m,3H),1.78(d,J＝6.8Hz,3H),1.75-1.73(m,1H),1.35-1.32(m,1H),0.76-0.72(m,2H),0.70-0.66(m,2H),0.52-0.50(m,2H),0.45-0.42(m,2H)；

MS-ESI:m/z519.2[M+H-HCl] ⁺.

embodiment 37: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4- the synthesis of carboxylic acid hydrochloride

To compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-formic acid (150mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (3mL) solution 0.26mmol), 3mL), stirring at room temperature 2h, except desolventizing, obtain 128mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(s,1H),7.71(d,J＝8.3Hz,1H),7.32(d,J＝8.3Hz,1H),6.91(t,J _F-H＝74.8Hz,1H),5.04-5.01(m,1H),4.77-4.74(m,1H),4.49-4.47(m,1H),4.04(d,J＝6.8Hz,2H),3.49-3.45(m,1H),3.14-3.11(m,1H),2.74-2.71(m,1H),2.08-2.05(m,2H),1.79(d,J＝6.9Hz,3H),1.35-1.32(m,1H),0.70-0.67(m,2H),0.45-0.41(m,2H)；

MS-ESI:m/z480.0[M+H-HCl] ⁺.

embodiment 38: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-carboxylic acid benzyl ester hydrochloride

Step 1: the synthesis of compound 1-carbobenzoxy-(Cbz)-2-(R)-methylpiperazine hydrochloride

Under room temperature condition, to N ' N-carbonyl dimidazoles (1.0g, triethylamine (0.42mL is dripped in anhydrous THF (5mL) solution 5.99mmol), 3.00mmol), stirring at room temperature, slow dropping phenylcarbinol (0.62mL, 5.99mmol), room temperature reaction 20min, drip (R)-4-Boc-2-methylpiperazine (300mg, anhydrous THF (9mL) solution 1.50mmol), 75 DEG C of reaction 26h, add dilute hydrochloric acid solution (10mL × 3) washing to aqueous phase in acid, ethyl acetate (15mL × 2) extracts, organic phase saturated sodium bicarbonate solution (10mL × 2) washs, anhydrous Na is used after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 267mg colourless liquid: 1-carbobenzoxy-(Cbz)-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine, yield: 53%.

¹HNMR(400MHz,CDCl ₃):δppm7.36-7.31(m,5H),5.14(s,2H),4.32(br.s,1H),4.15-3.97(m,1H),3.91-3.83(m,2H),3.15-3.07(m,1H),3.01-2.82(m,2H),1.46(s,9H),1.16(d,J＝6.8Hz,3H)；

MS-ESI:m/z235.3[M+H-100] ⁺.

To compound 1-carbobenzoxy-(Cbz)-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine (260mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.78mmol), 5mL), stirring at room temperature 1.5h, except desolventizing, obtain 210mg colorless viscous thing: compound 1-carbobenzoxy-(Cbz)-2-(R)-methylpiperazine hydrochloride, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.39-7.34(m,5H),5.21-5.16(m,2H),4.61-4.59(m,1H),4.20-4.17(m,1H),3.38-3.36(m,2H),3.30-3.23(m,2H),3.09-3.07(m,1H),1.35(d,J＝7.2Hz,3H)；

MS-ESI:m/z235.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-benzyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), 1-carbobenzoxy-(Cbz)-2-(R)-methylpiperazine hydrochloride (173mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 12h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 246mg white solid, yield: 67%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.4Hz,1H),7.53(s,1H),7.37-7.33(m,5H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝74.7Hz,1H),5.29-5.20(m,1H),5.17(s,2H),4.70-4.40(m,3H),4.06-4.02(m,1H),3.96(d,J＝6.8Hz,2H),3.23-3.29(m,2H),3.06-2.93(m,1H),1.55-1.54(m,3H),1.42(s,9H),1.32-1.28(m,1H),1.26-1.21(m,3H),0.71-0.66(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z685.7[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-carboxylic acid benzyl ester hydrochloride

To compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-benzyl formate (246mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.36mmol), 4mL), stirring at room temperature 3h, except desolventizing, obtain 220mg white solid, yield: 98%.

¹HNMR(600MHz,CDCl ₃):δppm7.59-7.57(m,1H),7.55(s,1H),7.38-7.32(m,5H),7.20-7.18(m,1H),6.68(t,J _F-H＝74.9Hz,1H),5.18-5.13(m,2H),5.09-5.00(m,2H),4.48-4.46,4.39-4.37(m,m,1.5H,0.5H),4.03-4.00(m,1H),3.94(d,J＝4.3Hz,2H),3.48-3.46,3.24-3.20(m,m,0.5H,0.5H),3.31-3.29(m,1H),3.06-3.04,2.92-2.90(m,m,0.5H,0.5H),1.86-1.84(m,3H),1.31-1.28(m,1H),1.26-1.19(m,3H),0.65-0.63(m,2H),0.39-0.37(m,2H)；

MS-ESI:m/z585.8[M+H-HCl] ⁺.

embodiment 39: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (1,1-titanium dioxide thiomorpholine) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(1,1-titanium dioxide thiomorpholine-4-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), thiomorpholine-1, 1-dioxide. HCl (110mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 13h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 186mg white solid, yield: 58%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.52(d,J＝1.6Hz,1H),7.25(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.46(br.s,1H),5.28-5.21(m,1H),4.48-4.34(m,4H),3.96(d,J＝6.9Hz,2H),3.23-3.12(m,4H),1.56(d,J＝7.1Hz,3H),1.41(s,9H),1.34-1.30(m,1H),0.71-0.67(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z586.3[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (1,1-titanium dioxide thiomorpholine) methanone hvdrochloric acid salt

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(1,1-titanium dioxide thiomorpholine-4-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (183mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.31mmol), 4mL), stirring at room temperature 2h, except desolventizing, obtain 163mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.72(d,J＝8.2Hz,1H),7.32(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.13-5.11(m,1H),4.62-4.60(m,2H),4.23-4.20(m,2H),4.04(d,J＝6.7Hz,2H),3.40-3.37(m,2H),3.30-3.29(m,2H),1.80(d,J＝6.5Hz,3H),1.35-1.32(m,1H),0.69-0.67(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z486.9[M+H-HCl] ⁺.

embodiment 40: compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (3-methylpiperazine -1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-t-butyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), 1-Boc-2-methylpiperazine (130mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (155mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 5h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 215mg colorless viscous thing, yield: 60%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(d,J＝8.0Hz,1H),7.54(s,1H),7.24(d,J＝8.4Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.27-5.20(m,1H),4.64-4.43(m,3H),3.96(d,J＝6.7Hz,2H),3.92-3.89(m,1H),3.25-3.02(m,3H),1.54(d,J＝7.0Hz,3H),1.48(s,9H),1.41(s,9H),1.35-1.32(m,1H),1.22-1.14(m,3H),0.71-0.66(m,2H),0.41-0.40(m,2H)；

MS-ESI:m/z651.3[M+H] ⁺.

Step 2: the synthesis of compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (3-methylpiperazine-1-yl) ketone dihydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-t-butyl formate (196mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.30mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 156mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.72(d,J＝7.9Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.14-5.10(m,1H),4.69-4.65(m,1H),4.05(d,J＝6.9Hz,2H),3.85-3.79(m,1H),3.70-3.62(m,1H),3.55-3.45(m,2H),3.41-3.37(m,1H),3.28-3.15(m,1H),1.79(d,J＝7.0Hz,3H),1.46-1.43(m,3H),1.36-1.34(m,1H),0.71-0.68(m,2H),0.43-0.41(m,2H)；

MS-ESI:m/z451.4[M+H-2HCl] ⁺.

embodiment 41: compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- methylpiperazine-1-yl) synthesis of acetophenone hydrochloride

Step 1: the synthesis of compound N-acetyl-2-(R)-methylpiperazine hydrochloride

By compound (R)-4-Boc-2-methylpiperazine (528mg, 2.64mmol), glacial acetic acid (190mg, 3.16mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (758mg, 3.95mmol) with N-hydroxyl-7-azepine benzotriazole (897mg, 6.59mmol) be dissolved in methylene dichloride (20mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.8mL, 10.54mmol), stirring at room temperature 12h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 580mg colorless oil: compound N-acetyl-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine, yield: 90%.

¹HNMR(400MHz,CDCl ₃):δppm4.75,4.37-4.34(m,m,0.5H,0.5H),4.13-4.08(m,0.5H),3.95-3.75(m,2H),3.52-3.31(m,1H),2.99(m,1H),2.86-2.83(m,1.5H),2.08(d,J＝12.2Hz,3H),1.46(s,9H),1.30-1.12(m,3H).

To compound N-acetyl-4-tertbutyloxycarbonyl-2-(R)-methylpiperazine (580mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 2.39mmol); 5mL); stirring at room temperature 2h; except desolventizing; obtain 427mg thick white thing: compound N-acetyl-2-(R)-methylpiperazine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.59-4.48(m,1H),3.99,3.67-3.54(m,m,0.5H,0.5H),3.41-3.37(m,2H),3.19-3.02(m,2H),2.17(s,3H),1.43-1.31(m,3H)；

MS-ESI:m/z143.3[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-ethanoyl-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), N-ethanoyl-2-(R)-methylpiperazine hydrochloride (114mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 16h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 230mg white solid, yield: 72%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.2Hz,1H),7.53(s,1H),7.24(d,J＝8.4Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.25-5.23(m,1H),4.82-4.51(m,3H),3.96(d,J＝6.9Hz,2H),3.48-3.45(m,1H),3.21-3.01(m,3H),2.16-2.08(m,3H),1.55(d,J＝6.7Hz,3H),1.41(s,9H),1.29-1.27(m,1H),1.25-1.23(m,3H),0.71-0.66(m,2H),0.41-0.39(m,2H)；

MS-ESI:m/z593.3[M+H] ⁺.

Step 3: the synthesis of compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-yl) acetophenone hydrochloride

To compound ((S)-1-(4-((R)-4-ethanoyl-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (230mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.39mmol); 5mL); stirring at room temperature 3.5h; except desolventizing; obtain 205mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.75(s,1H),7.73-7.72(m,1H),7.33(d,J＝8.1Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.10-5.08(m,1H),5.01-4.94(m,1H),4.53-4.37(m,2H),4.05(d,J＝6.6Hz,2H),3.98-3.83(m,1H),3.60-3.53,3.24-3.08(m,m,1.5H,1.5H),2.21-2.17(m,3H),1.80(d,J＝6.0Hz,3H),1.40-1.39(m,1H),1.34-1.28(m,3H),0.70-0.68(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z493.9[M+H-HCl] ⁺.

embodiment 42: compound (S)-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(Cyclopentanecarbonyl) piperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound cyclopentyl (piperazine-1-base) methanone hvdrochloric acid salt

By compound 1-tert-butoxycarbonyl-piperazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (2.1g, 11mmol) with N-hydroxyl-7-azepine benzotriazole (1.1g, 8.1mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, chaulmoogric acid (0.74g is dripped respectively in this solution, 6.5mmol) and N, N-diisopropylethylamine (2.8mL, 16mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/4), obtains 1.1g white solid: 4-(Cyclopentanecarbonyl) piperazine-1-t-butyl formate, yield: 73%.

¹HNMR(400MHz,CDCl ₃):δppm3.58-3.63(m,2H),3.48-3.54(m,2H),3.39-3.54(m,4H),2.85-2.94(m,1H),1.79-1.87(m,4H),1.71-1.78(m,2H),1.54-1.63(m,2H),1.49(s,9H)；

MS-ESI:m/z228.10[M+H-55] ⁺.

By compound 4-(Cyclopentanecarbonyl) piperazine-1-t-butyl formate (1.1g, 3.9mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 7mL), stirring at room temperature 1h, except desolventizing, solid petrol ether/ethyl acetate (v/v=4/1) (5mL × 2) are washed, suction filtration, obtains 0.8g white solid: cyclopentyl (piperazine-1-base) methanone hvdrochloric acid salt, yield: 90%.

¹HNMR(400MHz,CD ₃OD):δppm3.85-3.90(m,4H),3.20-3.30(m,4H),3.06-3.14(m,1H),1.86-1.94(m,2H),1.62-1.81(m,6H)；

MS-ESI:m/z183.15[M+H] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(Cyclopentanecarbonyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), cyclopentyl (piperazine-1-base) methanone hvdrochloric acid salt (140mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 200mg white solid, yield: 49%.

¹HNMR(400MHz,CDCl ₃):δppm7.59-7.61(m,1H),7.56(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),5.92(br.s,1H),5.23-5.28(m,1H),3.99(d,J＝6.9Hz,2H),3.90-4.01(m,2H),3.66-3.81(m,6H),2.88-2.99(m,1H),1.82-1.91(m,4H),1.74-1.80(m,2H),1.57(d,J＝7.0Hz,3H),1.43(s,9H),1.28-1.38(m,3H),0.69-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z633.25[M+H] ⁺.

Step 3: the synthesis of compound (S)-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(Cyclopentanecarbonyl) piperazine-1-base) methanone hvdrochloric acid salt

By compound (S)-(1-(4-(4-(Cyclopentanecarbonyl) piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg, 0.32mmol) be dissolved in methylene dichloride (1mL), add the ethyl acetate solution (4M of HCl, 3mL), stirring at room temperature 30min, except desolventizing, solid sherwood oil (5mL × 3) is washed, obtain 135mg white solid, yield: 80%.

¹HNMR(400MHz,CD ₃OD):δppm7.76(s,1H),7.73(d,J＝8.4Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.08(q,J＝6.9Hz,1H),4.18-4.24(m,2H),4.05(d,J＝6.9Hz,2H),3.72-3.85(m,6H),3.13(s,1H),1.86-1.96(m,2H),1.80(d,J＝7.0Hz,3H),1.60-1.81(m,6H),1.31-1.37(m,1H),0.67-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z533.20[M+H-HCl] ⁺.

embodiment 43: compound (S)-1-(4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1- base) synthesis of acetophenone hydrochloride

Step 1: the synthesis of compound 1-(piperazine-1-base) acetophenone hydrochloride

By compound 1-tert-butoxycarbonyl-piperazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (2.1g, 11mmol) with N-hydroxyl-7-azepine benzotriazole (1.1g, 8.1mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, acetic acid (0.64g is dripped respectively in this solution, 11mmol) and N, N-diisopropylethylamine (2.8mL, 16mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 0.9g white solid: 4-Acetylpiperazine-1-t-butyl formate, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm3.59-3.61(m,2H),3.41-3.46(m,6H),2.13(s,3H),1.49(s,9H)；

MS-ESI:m/z173.30[M-55] ⁺.

To 4-Acetylpiperazine-1-t-butyl formate (300mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 1mmol); 2mL); stirring at room temperature 1h; except desolventizing; obtain 200mg white solid: 1-(piperazine-1-base) acetophenone hydrochloride, yield: 90%.

¹HNMR(400MHz,CD ₃OD):δppm3.83-3.86(m,4H),3.28-3.33(m,2H),3.21-3.25(m,2H),2.17(s,3H)；

MS-ESI:m/z129.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-Acetylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 1-(piperazine-1-base) acetophenone hydrochloride (158mg, 0.96mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 140mg white solid, yield: 38%.

¹HNMR(400MHz,CDCl ₃):δppm7.58-7.61(m,1H),7.56(d,J＝1.8Hz,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.21-5.29(m,1H),3.99(d,J＝6.9Hz,2H),3.70-3.87(m,4H),3.55-3.63(m,2H),2.13-2.19(s,3H),1.57(d,J＝7.1Hz,3H),1.45(s,9H),1.31-1.38(m,1H),0.69-0.74(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z579.20[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-base) acetophenone hydrochloride

To compound (S)-(1-(4-(4-Acetylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (130mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.23mmol); 3mL); stirring at room temperature 30min; except desolventizing; solid sherwood oil (5mL × 3) is washed; obtain 110mg white solid, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm7.71-7.75(m,2H),7.34(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.04-5.10(m,1H),4.20-4.27(m,2H),4.04(d,J＝6.9Hz,2H),3.75-3.84(m,2H),3.69-3.87(m,4H),2.19(s,3H),1.79(d,J＝7.0Hz,3H),1.33-1.38(m,1H),0.67-0.72(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z479.20[M+H-HCl] ⁺.

embodiment 44: compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-first the synthesis of acid methyl ester hydrochloride salt

Step 1: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 1-methyl-formiate piperazine (138mg, 0.96mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 160mg white solid, yield: 44%.

¹HNMR(600MHz,CDCl ₃):δppm7.58-7.60(m,1H),7.56(s,1H),7.26(d,J＝8.3Hz,1H),6.73(t,J _F-H＝75.0Hz,1H),5.22-5.27(m,1H),3.99(d,J＝6.9Hz,2H),3.90-3.99(m,2H),3.76(s,3H),3.73-3.81(m,2H),3.55-3.67(m,4H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.34-1.37(m,1H),0.69-0.72(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z595.30[M+H] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate hydrochloride

By compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (75mg, 0.13mmol) be dissolved in methylene dichloride (1mL), add the ethyl acetate solution (4M of HCl, 3mL), stirring at room temperature 30min, except desolventizing, obtain 65mg white solid, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm7.74(s,1H),7.71(d,J＝8.5Hz,1H),7.33(d,J＝8.2Hz,1H),6.91(t,J _F-H＝75.0Hz,1H),5.02-5.08(m,1H),4.19(s,2H),4.04(d,J＝6.8Hz,2H),4.79(s,2H),3.75(s,3H),3.64(s,4H),1.79(d,J＝6.2Hz,3H),1.30-1.37(m,1H),0.67-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z495.20[M+H-HCl] ⁺.

embodiment 45: compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-first the synthesis of amide hydrochloride

Step 1: the synthesis of compound piperazine-1-carboxamide hydrochloride

By compound 1-tert-butoxycarbonyl-piperazine (0.6g, 3.2mmol) with triethylamine (4.6mL, 32mmol) be dissolved in anhydrous tetrahydro furan (10mL), under room temperature condition, in this solution, drip trimethyl silicane based isocyanate (4.2mL, 32mmol), stirring at room temperature 1.5h, with frozen water (10mL), screws out tetrahydrofuran (THF), aqueous phase ethyl acetate (30mL × 3) extraction, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated, solid with ethyl acetate (2mL) ultrasonic cleaning 1min, suction filtration, obtains 0.3g white solid: 4-formamyl piperazine-1-t-butyl formate, yield: 40%.

¹HNMR(400MHz,CDCl ₃):δppm3.42-3.49(m,4H),3.37-3.42(m,4H),1.49(s,9H)；

MS-ESI:m/z252.05[M+Na] ⁺.

By compound 4-formamyl piperazine-1-t-butyl formate (0.16g; 0.7mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 2mL); stirring at room temperature 30min; except desolventizing, obtain 0.16g white solid: piperazine-1-carboxamide hydrochloride, yield: 100%.

¹HNMR(600MHz,CD ₃OD):δppm3.71-3.73(m,4H),3.25-3.27(m,4H)；

MS-ESI:m/z130.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound piperazine-1-carboxamide hydrochloride (127mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 250mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),7.26(d,J＝8.3Hz,1H),6.73(t,J _F-H＝75.0Hz,1H),5.93(br.s,1H),5.21-5.30(m,1H),3.92-4.07(m,2H),3.99(d,J＝6.9Hz,2H),3.82(br.s,2H),3.50-3.57(m,4H),1.57(d,J＝7.0Hz,3H),1.45(s,9H),1.27-1.37(m,1H),0.69-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z580.20[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-carboxamide hydrochloride

By compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (245mg; 0.42mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 3mL); stirring at room temperature 30min; except desolventizing; obtain 217mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.75(s,1H),7.72(d,J＝8.2Hz,1H),7.33(d,J＝8.1Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.02-5.10(m,1H),4.25(s,2H),4.04(d,J＝6.9Hz,2H),3.83(s,2H),3.65(s,4H),1.80(d,J＝5.7Hz,3H),1.31-1.35(m,1H),0.67-0.70(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z480.20[M+H-HCl] ⁺.

embodiment 46: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(4-fluorobenzene first acyl group) piperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (4-fluorophenyl) (piperazine-1-base) methanone hvdrochloric acid salt

By compound 1-tert-butoxycarbonyl-piperazine (1.0g, 5.4mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (1.5g, 8.1mmol) with N-hydroxyl-7-azepine benzotriazole (1.1g, 8.1mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, 4-fluorobenzoic acid (0.91g is dripped respectively in this solution, 6.4mmol) and N, N-diisopropylethylamine (2.8mL, 16mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/5), obtains 0.9g white solid: 4-(4-fluoro benzoyl) piperazine-1-t-butyl formate, yield: 50%.

¹HNMR(400MHz,CDCl ₃):δppm7.41-7.45(m,2H),7.10-7.14(m,2H),3.47-3.82(m,2H),3.47(s,6H),1.48(s,9H)；

MS-ESI:m/z331.20[M+Na] ⁺.

By compound 4-(4-fluoro benzoyl) piperazine-1-t-butyl formate (0.9g; 2.9mmol) be dissolved in methylene dichloride (3mL); add the ethyl acetate solution (4M of HCl; 6mL); stirring at room temperature 50min; except desolventizing, obtain 0.8g white solid: (4-fluorophenyl) (piperazine-1-base) methanone hvdrochloric acid salt, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.56-7.59(m,2H),7.23-7.27(m,2H),3.88(br.s,4H)；

MS-ESI:m/z209.00[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(4-fluorophenyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (4-fluorophenyl) (piperazine-1-base) methanone hvdrochloric acid salt (188mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (175mg, 0.77mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/2), obtains 310mg white solid, yield: 73%.

¹HNMR(600MHz,CDCl ₃):δppm7.54-7.59(m,2H),7.46-7.48(m,2H),7.26(d,J＝7.9Hz,1H),7.15(t,J＝8.2Hz,2H),6.73(t,J _F-H＝75.0Hz,1H),5.24-5.29(m,1H),3.94-4.10(m,2H),3.98(d,J＝6.7Hz,2H),3.69-4.95(m,4H),3.50-3.74(m,2H),1.57(d,J＝7.0Hz,3H),1.45(s,9H),1.33-1.36(m,1H),0.69-0.72(m,2H),0.41-0.43(m,2H)；

MS-ESI:m/z659.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(4-fluoro benzoyl) piperazine-1-base) methanone hvdrochloric acid salt

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(4-fluorophenyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (310mg, in methylene dichloride (2mL) solution 0.47mmol), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, solid sherwood oil (5mL × 3) is washed, obtain 275mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.72-7.74(m,2H),7.56-7.58(m,2H),7.29-7.35(m,1H),7.25(t,J＝8.4Hz,2H),6.92(t,J _F-H＝74.8Hz,1H),5.05-5.10(m,1H),4.18-4.34(m,2H),3.99-4.07(m,2H),3.78-3.94(m,4H),3.57-3.76(m,2H),1.80(d,J＝7.0Hz,3H),1.30-1.37(m,1H),0.67-0.70(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z559.20[M+H-HCl] ⁺.

embodiment 47: compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-(2,4-bis- luorobenzyl) synthesis of piperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound N-(2,4-difluorobenzyl) piperazine-1-carboxamide hydrochloride

By triethylamine (0.56mL, 4.1mmol) and N, N '-carbonyl dimidazoles (CDI) (653mg, 4.1mmol) be dissolved in dry DMF (2mL), add 2, 4-difluorobenzylamine (461mg, 3.2mmol), after stirring at room temperature 30min, add compound 1-tert-butoxycarbonyl-piperazine (500mg, dry DMF (3mL) solution 2.7mmol), stopped reaction after 60 DEG C of reaction 1h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtain 730mg white solid: 4-((2, 4-difluorobenzyl) formamyl) piperazine-1-t-butyl formate, yield: 77%.

¹HNMR(400MHz,CDCl ₃):δppm7.34-7.40(m,1H),6.77-6.88(m,2H),4.88-4.98(m,1H),4.43(d,J＝5.6Hz,2H),3.36-3.44(m,8H),1.47(s,9H)；

MS-ESI:m/z300.10[M-55] ⁺.

To compound 4-((2; 4-difluorobenzyl) formamyl) piperazine-1-t-butyl formate (730mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 2.1mmol); 4mL); stirring at room temperature 50min, except desolventizing, obtains 570mg white solid: N-(2; 4-difluorobenzyl) piperazine-1-carboxamide hydrochloride, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm7.41(dd,J ₁＝15.0Hz,J ₂＝8.2Hz,1H),6.93(t,J＝8.6Hz,2H),4.40(s,2H),3.68-3.71(m,4H),3.22-3.25(m,4H)；

MS-ESI:m/z256.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-((2,4-difluorobenzyl) formamyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound N-(2, 4-difluorobenzyl) piperazine-1-carboxamide hydrochloride (224mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (175mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 400mg white solid, yield: 88%.

¹HNMR(600MHz,CDCl ₃):δppm7.58-7.60(m,1H),7.55(s,1H),7.39-7.42(m,1H),7.26(d,J＝8.3Hz,1H),6.81-6.88(m,2H),6.72(t,J _F-H＝75.0Hz,1H),5.96(br.s,1H),5.22-5.27(m,1H),4.47(d,J＝5.7Hz,2H),4.03(br.s,2H),3.98(d,J＝6.9Hz,2H),3.80(br.s,2H),3.52(br.s,4H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.30-1.37(m,1H),0.69-0.72(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z706.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-(2,4-difluorobenzyl) piperazine-1-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-((2; 4-difluorobenzyl) formamyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (400mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.57mmol); 3mL); stirring at room temperature 30min; except desolventizing; solid sherwood oil (5mL × 3) is washed; obtain 360mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(s,1H),7.71(d,J＝8.4Hz,1H),7.41(dd,J ₁＝15.0Hz,J ₂＝8.3Hz,1H),7.33(d,J＝8.3Hz,1H),6.91-6.94(m,2H),6.92(t,J _F-H＝75.0Hz,1H),5.04-5.08(m,1H),4.41(s,2H),4.20(br.s,2H),4.03(d,J＝6.8Hz,2H),3.80(br.s,2H),3.60(br.s,4H),1.79(d,J＝6.6Hz,3H),1.31-1.35(m,1H),0.67-0.70(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z606.25[M+H-HCl] ⁺.

embodiment 48: compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-first the synthesis of acid ethyl ester hydrochloride salt

Step 1: the synthesis of compound piperazine-1-carboxvlate hvdrochloride

By triethylamine (130mg, 1.3mmol) and N, N '-carbonyl dimidazoles (CDI) (209mg, 1.3mmol) be dissolved in dry DMF (2mL), add 1-tert-butoxycarbonyl-piperazine (200mg, 1.1mmol), after stirring at room temperature 30min, add dehydrated alcohol (3mL), stopped reaction after 60 DEG C of reaction 1h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtain 230mg white solid: compound 4-ethoxycarbonylpiperazine-1-t-butyl formate, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δppm4.17(q,J＝7.1Hz,2H),3.43-3.45(m,8H),1.48(s,9H),1.28(t,J＝7.1Hz,3H).

By compound 4-ethoxycarbonylpiperazine-1-t-butyl formate (220mg, 0.85mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 160mg white solid: piperazine-1-carboxvlate hvdrochloride, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm4.18(q,J＝7.1Hz,2H),3.74-3.76(m,4H),3.23-3.26(m,4H),1.30(t,J＝7.1Hz,3H)；

MS-ESI:m/z159.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-ethyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound piperazine-1-carboxvlate hvdrochloride (149mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (175mg, 1.3mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 330mg white solid, yield: 84%.

¹HNMR(400MHz,CDCl ₃):δppm7.58-7.61(m,1H),7.56(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.21-5.28(m,1H),4.20(q,J＝7.1Hz,2H),3.99(d,J＝6.9Hz,2H),3.94(br.s,2H),3.77(br.s,2H),3.59(br.s,4H),1.57(d,J＝7.0Hz,3H),1.44(s,9H),1.34-1.37(m,1H),1.31(t,J＝7.1Hz,3H),0.69-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z609.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-carboxvlate hvdrochloride

By compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-ethyl formate (75mg, 0.54mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 275mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.71(d,J＝8.3Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.05-5.09(m,1H),4.17-4.21(m,4H),4.04(d,J＝6.9Hz,2H),3.79(br.s,2H),3.63(br.s,4H),1.80(d,J＝6.2Hz,3H),1.34-1.37(m,1H),1.31(t,J＝7.1Hz,3H),0.67-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z509.25[M+H-HCl] ⁺.

embodiment 49: compound 2-methoxycarbonyl-4-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) the synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 2-methoxycarbonyl piperazine-1-methyl-formiate hydrochloride

By triethylamine (201mg, 1.2mmol) and N, N '-carbonyl dimidazoles (CDI) (160mg, 0.98mmol) be dissolved in dry DMF (2mL), add 1-tertbutyloxycarbonyl-3-methyl-formiate piperazine (200mg, 0.82mmol), anhydrous methanol (5mL) is added after stirring at room temperature 30min, stopped reaction after 60 DEG C of reaction 24h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtain 60mg white solid: 3, 4-dimethoxycarbonyl piperazine-1-t-butyl formate, yield: 24%.

¹HNMR(400MHz,CDCl ₃):δppm4.71-4.77(m,0.5H),4.51-4.60(m,1.5H),3.90-4.09(m,1H),3.80-3.95(m,1H),3.72(s,3H),3.15-3.34(m,1H),3.05-3.07(m,1H),2.72-2.93(m,1H),1.42(s,9H)；

MS-ESI:m/z203.10[M+H-100] ⁺.

By compound 3,4-dimethoxycarbonyl piperazine-1-t-butyl formate (320mg, 1.1mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 250mg white solid: 2-methoxycarbonyl piperazine-1-methyl-formiate hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm4.19-4.26(m,2H),3.87-3.91(m,2H),3.37-3.41(m,3H)；

MS-ESI:m/z203.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound 2-methoxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 2-methoxycarbonyl piperazine-1-methyl-formiate hydrochloride (153mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 240mg white solid, yield: 58%.

¹HNMR(600MHz,CDCl ₃):δppm7.54-7.62(m,2H),7.26(d,J＝8.3Hz,1H),6.73(t,J _F-H＝75.0Hz,1H),5.38-5.54,5.06-5.17(m,0.5H,0.5H),5.25-5.29(m,1H),4.61-4.95(m,2H),3.73-4.07(m,1H),3.96-4.05(m,2H),3.74-3.82(m,4H),3.59-3.66(m,2H),3.26-3.55(m,2H),3.00-3.19(m,1H),1.50-1.55(m,3H),1.45(s,9H),1.31-1.38(m,1H),0.69-0.73(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z653.20[M+H] ⁺.

Step 3: the synthesis of compound 2-methoxycarbonyl-4-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate hydrochloride

By compound 2-methoxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (100mg, 0.15mmol) be dissolved in methylene dichloride (1mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 90mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.58-7.72(m,2H),7.22-7.27(m,1H),6.83(t,J _F-H＝75.0Hz,1H),5.46-5.60,4.42-4.51(m,0.5H,0.5H),4.83-4.93(m,2H),3.91-4.00(m,3H),3.60-3.71(m,5H),3.49-3.56(m,2H),2.95-3.03,3.19-3.23(m,0.5H,0.5H),3.29-3.36(m,1H),3.11-3.16(m,1H),1.62-1.70(m,3H),1.21-1.29(m,1H),0.56-0.62(m,2H),0.32-0.37(m,2H)；

MS-ESI:m/z553.25[M+H-HCl] ⁺.

embodiment 50: compound 4-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-((2,4-bis- luorobenzyl) formamyl) synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methoxycarbonyl piperazine-2-formic acid

By compound 2-methoxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (150mg, 0.23mmol) with NaOH (0.4g, 10mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (5mL) and water (5mL), 40 DEG C of reaction 2h, add hydrochloric acid (1M) and regulate pH to 1, add ethyl acetate (10mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 145mg white solid, productive rate: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.58-7.62,7.75-7.79(m,0.5H,0.5H),7.64-7.68(m,1H),7.29(d,J＝8.3Hz,1H),6.89(t,J _F-H＝75.0Hz,1H),5.13-5.28(m,1H),4.02(d,J＝6.9Hz,2H),3.76(d,J＝10.2Hz,2H),1.49-1.55(m,3H),1.45(s,9H),1.32-1.37(m,1H),0.66-0.71(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z639.30[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-((2,4-difluorobenzyl) formamyl) piperazine-1-methyl-formiate

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methoxycarbonyl piperazine-2-formic acid (150mg, 0.23mmol), 2, 4-difluorobenzylamine (41mg, 0.28mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (90mg, 0.47mmol) with N-hydroxyl-7-azepine benzotriazole (64mg, 0.47mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.13mL, 0.94mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 70mg white solid, yield: 39%.

¹HNMR(600MHz,CDCl ₃):δppm7.71-7.75(m,1H),7.49-7.58(m,2H),7.23(d,J＝8.3Hz,1H),7.67-7.76(m,2H),6.73(t,J _F-H＝75.0Hz,1H),5.25-5.31(m,1H),4.71-4.91(m,1H),4.42-4.48(m,2H),4.35-4.40(m,1H),4.10-4.11,4.32-4.34(m,0.5H,0.5H),4.20-4.27(m,1H),3.97-3.99(m,2H),3.78-3.82(m,3H),3.62-3.64,3.72-3.74(m,0.5H,0.5H),3.15-3.21,3.36-3.42(m,0.5H,0.5H),3.04-3.09,3.25-3.31(m,0.5H,0.5H),1.52-1.56(m,3H),1.45(s,9H),1.36-1.39(m,1H),0.69-0.73(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z764.30[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-((2,4-difluorobenzyl) formamyl) piperazine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-((2; 4-difluorobenzyl) formamyl) piperazine-1-methyl-formiate (60mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.08mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 55mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.68-7.74(m,2H),7.30-7.35(m,1H),7.15-7.26(m,1H),6.92(t,J _F-H＝75.0Hz,1H),6.74-6.86(m,2H),4.96-5.04(m,1H),4.41-4.49(m,1H),4.27-4.38(m,2H),3.98-4.08(m,3H),3.72-3.83(m,3H),3.40-3.57(m,2H),3.16-3.24(m,1H),1.76(d,J＝4.8Hz,3H),1.31-1.38(m,1H),0.65-0.70(m,2H),0.37-0.44(m,2H)；

MS-ESI:m/z664.20[M+H-HCl] ⁺.

embodiment 51: compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (2-methylpiperazine -1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methylpiperazine-1-t-butyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound N-tertbutyloxycarbonyl-3-methylpiperazine (154mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 130mg white solid, yield: 31%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(d,J＝8.3Hz,1H),7.54(s,1H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.98(br.s,1H),5.14-5.24(m,1H),3.97(d,J＝6.9Hz,2H),4.77-4.87(m,1H),4.32-4.48(m,1H),3.85-3.98(m,1H),3.47(s,3H),2.97-3.13(m,2H),1.53-1.55(m,3H),1.48(s,9H),1.42(s,9H),1.33-1.36(m,1H),1.28(d,J＝7.2Hz,3H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z651.30[M+H] ⁺.

Step 2: the synthesis of compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (2-methylpiperazine-1-yl) ketone dihydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methylpiperazine-1-t-butyl formate (120mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.18mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 90mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.73(d,J＝8.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.40-5.50,5.14-5.26(m,0.5H,0.5H),5.07-5.14(m,1H),4.04(d,J＝6.9Hz,2H),3.62-3.81(m,1H),3.41-3.51(m,5H),1.80(t,J＝6.7Hz,3H),1.52-1.67(m,3H),1.33-1.37(m,1H),0.67-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z451.25[M+H-2HCl] ⁺.

embodiment 52: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methyl the synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 2-methylpiperazine-1-methyl-formiate hydrochloride

By triethylamine (380mg, 3.75mmol) and N, N '-carbonyl dimidazoles (CDI) (486mg, 3.0mmol) be dissolved in dry DMF (2mL), add 3-methylpiperazine-1-t-butyl formate (500mg, 2.5mmol), anhydrous methanol (10mL) is added after stirring at room temperature 30min, stopped reaction after 60 DEG C of reaction 8h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtain 620mg white solid: 2-methyl-4-tert-butoxycarbonyl-piperazine-1-methyl-formiate, yield: 96%.

¹HNMR(400MHz,CDCl ₃):δppm4.24-4.34(m,1H),3.93-4.16(m,1H),3.79-3.92(m,2H),3.73(s,3H),3.07-3.14(m,1H),2.95-3.09(m,1H),2.73-2.93(m,1H),1.48(s,9H),1.17(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.20[M+H-100] ⁺.

To compound 2-methyl-4-tert-butoxycarbonyl-piperazine-1-methyl-formiate (600mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 2.3mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 420mg white solid: 2-methylpiperazine-1-methyl-formiate hydrochloride, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm4.53-4.61(m,1H),4.14-4.18(m,1H),3.75(s,3H),3.33-3.38(m,2H),3.22-3.30(m,2H),3.04-3.11(m,1H),1.35(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 2-methylpiperazine-1-methyl-formiate hydrochloride (150mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (246mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (175mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 186mg white solid, yield: 47%.

¹HNMR(400MHz,CDCl ₃):δppm7.60(d,J＝8.3Hz,1H),7.56(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.21-5.31(m,1H),4.39-4.67(m,3H),3.93-4.05(m,1H),3.99(d,J＝6.9Hz,2H),3.76(s,3H),3.20-3.52(m,2H),2.90-3.07(m,1H),1.57(d,J＝7.0Hz,3H),1.43(s,9H),1.31-1.38(m,1H),1.26(m,3H),0.69-0.73(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z609.25[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate hydrochloride

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (180mg, 0.3mmol) be dissolved in methylene dichloride (1mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 125mg white solid, yield: 77%.

¹HNMR(600MHz,CD ₃OD):δppm7.70-7.75(m,2H),7.34(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.03-5.09(m,1H),4.98(m,1H),4.45-4.52(m,2H),4.04(d,J＝6.9Hz,2H),3.99-4.06(m,1H),3.75(s,3H),3.57-3.63(m,1H),3.34-3.40(m,1H),3.21-3.28(m,1H),3.02-3.18(m,1H),1.79(d,J＝7.0Hz,3H),1.33-1.37(m,1H),1.22-1.31(m,3H),0.68-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z509.30[M+H-HCl] ⁺.

embodiment 53: compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of carboxamide dihydrochloride

Step 1: the synthesis of compound 3-formamyl piperazine-1-t-butyl formate

N-1-tertbutyloxycarbonyl-3-piperazinecarboxylic acid methyl esters (500mg, 2.04mmol) and methanolic ammonia solution (7M, 10mL) are placed in 100mL tube sealing, 60 DEG C of reactions, stopped reaction after 12h, screws out solvent, obtain 450mg white solid, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm4.01-4.08(m,1H),3.65-3.88(m,1H),3.31-3.38(m,1H),2.90-3.12(m,3H),2.73-2.82(m,1H),1.47(s,9H)；

MS-ESI:m/z130.20[M+H-100] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 3-formamyl piperazine-1-t-butyl formate (153mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.33mL, 1.93mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 220mg white solid, yield: 50%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.61(m,2H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.42-5.49(m,1H),5.15-5.23(m,1H),4.01(d,J＝6.9Hz,2H),3.71-3.79(m,1H),3.17-3.24(m,2H),1.59-1.64(m,3H),1.51(s,9H),1.42(m,9H),1.30-1.35(m,1H),0.69-0.73(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z680.30[M+H] ⁺.

Step 3: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-carboxamide dihydrochloride

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate (225mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.33mmol); 4mL); stirring at room temperature 30min; except desolventizing; obtain 180mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.70-7.75(m,2H),7.34(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.17-5.23(m,1H),4.06(d,J＝6.6Hz,2H),3.87-3.99(m,1H),3.35-3.57(m,3H),1.80-1.84(m,3H),1.32-1.37(m,1H),0.67-0.71(m,2H),0.42-0.47(m,2H)；

MS-ESI:m/z480.30[M+H-2HCl] ⁺.

embodiment 54: compound 4-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-(methoxy carbonyl base) synthesis of piperazine-2-carboxylic acid hydrochloride

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methoxycarbonyl piperazine-2-formic acid (180mg, 0.28mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 160mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.71-7.78(m,2H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.07-5.16,5.57-5.64(m,0.5H,0.5H),4.99-5.07(m,1H),4.57-4.83(m,1H),4.05(d,J＝6.8Hz,2H),3.99-4.09(m,1H),3.77(d,J＝10.1Hz,3H),3.36-3.47(m,1H),3.09-3.29(m,1H),1.77(t,J＝7.5Hz,3H),1.30-1.40(m,1H),0.61-0.71(m,1H),0.42-0.46(m,1H)；

MS-ESI:m/z539.20[M+H-HCl] ⁺.

embodiment 55: compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-is amino the synthesis of formyl piperazine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-formamyl piperazine-2-methyl-formiate hydrochloride

By compound N-1-tertbutyloxycarbonyl-2-piperazinecarboxylic acid methyl esters (0.2g, 0.82mmol) with triethylamine (1.2mL, 8.2mmol) be dissolved in anhydrous tetrahydro furan (5mL), under room temperature condition, in this solution, drip trimethyl silicane based isocyanate (1.1mL, 8.2mmol), stirring at room temperature 8h, with frozen water (10mL), screws out tetrahydrofuran (THF), aqueous phase ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated, obtain 0.2g white solid: 2-methoxycarbonyl-4-formamyl piperazine-1-t-butyl formate, yield: 90%.

¹HNMR(400MHz,CDCl ₃):δppm4.24(br.s,2H),4.30(d,J＝13.3Hz,1H),3.98-4.14(m,1H),3.83-3.94(m,1H),3.78(s,3H),3.18-3.28(m,1H),3.03-3.12(m,1H),2.79-2.96(m,1H),1.50(d,J＝16.7Hz,9H)；

MS-ESI:m/z232.25[M-55] ⁺.

By compound 2-methoxycarbonyl-4-formamyl piperazine-1-t-butyl formate (0.2g; 0.7mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 2mL); stirring at room temperature 30min; except desolventizing, obtain 0.15g white solid: 4-formamyl piperazine-2-methyl-formiate hydrochloride, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm4.24-4.32(m,2H),3.90-3.96(m,1H),3.86(s,3H),3.39-3.49(m,2H),3.32-3.38(m,1H),3.13-3.21(m,1H).

Step 2: the synthesis of compound 1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-formamyl piperazine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 4-formamyl piperazine-2-methyl-formiate hydrochloride (172mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.33mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=30/1), obtains 140mg white solid, yield: 34%.

¹HNMR(400MHz,CDCl ₃):δppm7.50-7.60(m,2H),7.22-7.25(m,1H),6.70(t,J _F-H＝75.0Hz,1H),5.23-5.32(m,1H),4.95(br.s,2H),4.37-4.43(m,1H),4.07-4.14(m,1H),3.96-3.98(m,2H),3.75-3.81(m,3H),3.36-3.57(m,1.5H),3.02-3.22(m,1.5H),1.54(t,J＝8.0Hz,3H),1.42(s,9H),1.31-1.35(m,1H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z638.20[M+H] ⁺.

Step 3: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-formamyl piperazine-2-methyl-formiate hydrochloride

By compound 1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-formamyl piperazine-2-methyl-formiate (120mg; 0.19mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 2mL); stirring at room temperature 30min; except desolventizing; obtain 100mg white solid, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm7.64-7.77(m,2H),7.32-7.35(m,1H),6.92(t,J _F-H＝75.0Hz,1H),578-5.82,5.20-5.24(m,0.5H,0.5H),5.05-5.14(m,1H),4.52-4.60(m,1H),4.33-4.40(m,1H),4.02-4.06(m,2H),3.94-4.04(m,1H),4.34-4.37,3.84-3.90(m,0.5H,0.5H),3.82(s,3H),3.46-3.55(m,1H),3.22-3.28(m,1H),1.78(t,J＝7.1Hz,3H),1.31-1.36(m,1H),0.67-0.73(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z538.25[M+H-HCl] ⁺.

embodiment 56: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-is amino the synthesis of formyl piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-formamyl piperazine-1-methyl-formiate

2-methoxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (150mg is added in 50mL tube sealing, 0.23mmol) with methanolic ammonia solution (7M, 15mL), stopped reaction after 60 DEG C of reaction 72h, except desolventizing, residuum carries out silicagel column separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtain 25mg white solid, yield: 17%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.59(m,2H),7.26(d,J＝8.3Hz,1H),6.73(t,J _F-H＝75.0Hz,1H),5.24-5.29(m,1H),3.98(d,J＝6.9Hz,3H),3.81(s,3H),1.56(t,J＝6.4Hz,3H),1.45(d,J＝4.9Hz,9H),1.31-1.36(m,1H),0.68-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z638.25[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-formamyl piperazine-1-methyl-formiate hydrochloride

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-formamyl piperazine-1-methyl-formiate (100mg; 0.16mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 2mL); stirring at room temperature 30min; except desolventizing; obtain 85mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.76(m,2H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.26-5.36(m,1H),4.99-5.02(m,1H),4.69-4.81(m,1H),4.41-4.49(m,1H),4.04(d,J＝6.9Hz,3H),3.75-3.81(m,4H),3.43-3.57(m,1H),3.13-3.19(m,1H),1.76-1.79(m,3H),1.31-1.37(m,1H),0.68-0.72(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z538.20[M+H-HCl] ⁺.

embodiment 57: imidazolidine also for compound 7-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) the synthesis of [1,5-a] pyrazine-1,3-(2H, 5H)-dione hydrochloride

Step 1: compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(1,3-dioxotetrahydro imidazo [1,5-a] pyrazine-7-carbonyl) oxazole-5-base) ethyl) synthesis of t-butyl carbamate

By compound 2-methoxycarbonyl-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (150mg, 0.23mmol) with methanolic ammonia solution (7M, 10mL) be placed in 100mL tube sealing, 60 DEG C of reactions, stopped reaction after 12h, screw out solvent, residuum is through column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtain 50mg white solid, yield: 35%.

¹HNMR(400MHz,CDCl ₃):δppm8.16(br.s,1H),7.60(d,J＝8.3Hz,1H),7.27(d,J＝8.8Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.25-5.30(m,1H),5.07-5.17,5.51-5.63(m,0.5H,0.5H),4.79(d,J＝11.0Hz,1H),4.17-4.34(m,2H),3.99(d,J＝6.9Hz,2H),3.09-3.25(m,2H),2.75-2.87(m,1H),1.54-1.59(m,3H),1.42(s,9H),1.30-1.36(m,1H),0.66-0.73(m,2H),0.41-0.43(m,2H)；

MS-ESI:m/z606.20[M+H] ⁺.

Step 2: compound 7-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) imidazolidine also [1,5-a] pyrazine-1, the synthesis of 3-(2H, 5H)-dione hydrochloride

To compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(1,3-dioxotetrahydro imidazo [1,5-a] pyrazine-7-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (150mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.25mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 120mg white solid, yield: 89%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.81(m,2H),7.33-7.35(m,1H),6.93(t,J _F-H＝75.0Hz,1H),5.12-5.20,5.45-5.53(m,0.5H,0.5H),5.07-5.13(m,1H),4.68-4.70,4.96-5.00(m,0.5H,0.5H),4.22-4.27,4.44-4.50(m,0.5H,0.5H),4.11-4.17(m,1H),4.04(d,J＝6.9Hz,2H),3.13-3.19,3.29-3.37(m,0.5H,0.5H),2.95-3.03(m,1H),1.77-1.82(m,3H),1.31-1.35(m,1H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z506.20[M+H-HCl] ⁺.

embodiment 58: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4 base) (morpholinyl) ketone the synthesis of hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(morpholine-4-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), morpholine (83mg, 0.96mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.34mL, 1.92mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 175mg white solid, yield: 51%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.55(d,J＝1.9Hz,1H),7.25(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),5.21-5.28(m,1H),4.00-4.08(m,2H),3.99(d,J＝6.9Hz,2H),3.74-3.81(m,6H),1.57(d,J＝7.0Hz,3H),1.45(s,9H),1.33-1.36(m,1H),0.68-0.73(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z538.20[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4 base) (morpholinyl) methanone hvdrochloric acid salt

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(morpholine-4-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (170mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.13mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 145mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(s,1H),7.71(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.1Hz,1H),5.05-5.88(m,1H),4.20(br.s,2H),4.04(d,J＝6.9Hz,2H),3.80(s,6H),1.79(d,J＝7.0Hz,3H),1.33-1.37(m,1H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z438.30[M+H-HCl] ⁺.

embodiment 59: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2- the synthesis of carboxamide dihydrochloride

Step 1: the synthesis of compound 2-formamyl piperazine-1-t-butyl formate

1-tertbutyloxycarbonyl-2-piperazinecarboxylic acid methyl esters (500mg, 2.04mmol) and ammonia methyl alcohol (7M, 10mL) solution are placed in 100mL tube sealing, 60 DEG C of reactions, stopped reaction after 72h, screws out solvent, obtain 200mg white solid, yield: 42%.

¹HNMR(400MHz,CD ₃OD):δppm5.47-5.76,6.11-6.36(m,0.5H,0.5H),4.51-4.68(m,1H),3.44-3.57(m,1H),2.89-3.02(m,2H),2.66-2.80(m,2H),1.47(m,9H)；

MS-ESI:m/z230.30[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-formamyl piperazine-1-t-butyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 2-formamyl piperazine-1-t-butyl formate (153mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.33mL, 1.93mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 90mg white solid, yield: 21%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.60(m,2H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.43-5.62(m,1H),5.21-5.32(m,1H),4.94-5.12(m,1H),4.58-4.84(m,1H),4.33-4.49(m,1H),3.99(d,J＝6.9Hz,2H),3.57-3.80(m,1H),3.05-3.29(m,2H),1.52-1.57(m,3H),1.52(s,9H),1.45(d,J＝3.9Hz,9H),1.32-1.38(m,1H),0.68-0.73(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z680.40[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2-carboxamide dihydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-formamyl piperazine-1-t-butyl formate (80mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.33mmol); 4mL); stirring at room temperature 30min; except desolventizing; obtain 60mg white solid, yield: 92%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.77(m,2H),7.34(d,J＝8.3Hz,1H),6.94(t,J _F-H＝75.0Hz,1H),5.23-5.28(m,1H),5.14-5.18(m,1H),4.34-4.50(m,1H),4.11-4.28(m,1H),4.05(d,J＝6.6Hz,2H),3.79-3.86(m,1H),3.51-3.60(m,2H),3.37-3.46(m,1H),1.78-1.82(m,3H),1.34-1.37(m,1H),0.67-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z480.15[M+H-2HCl] ⁺.

embodiment 60: compound (2S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) Pyrrolidine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound (2S)-2-methoxycarbonyl-4-methoxycarbonylamin pyrrolidine hydrochloride

By N-tertbutyloxycarbonyl-4-oxo-L-PROLINE methyl esters (520mg, 2.14mmol) be dissolved in dehydrated alcohol (10mL), sodium borohydride (86mg is added under ice bath, 2.14mmol), stopped reaction after 0 DEG C of reaction 20min, adds frozen water (10mL), screws out ethanol, aqueous phase ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated, obtain 510mg colourless liquid: (2S)-2-methoxycarbonyl-4-hydroxyl pyrrolidine-1-t-butyl formate, productive rate: 97%.

¹HNMR(400MHz,CDCl ₃):δppm4.32-4.40(m,1H),3.80(d,J＝6.0Hz,3H),3.50-3.75(m,3H),2.28-3.40(m,1H),2.07-2.13(m,1H),1.46(d,J＝16.9Hz,9H)；

MS-ESI:m/z146.25[M+H-100] ⁺.

By compound (2S)-2-methoxycarbonyl-4-hydroxyl pyrrolidine-1-t-butyl formate (210mg, 0.86mmol), p-methyl benzene sulfonic chloride (195mg, 1.03mmol), triethylamine (200mg, 2.14mmol) with DMAP (12mg, 0.086mmol) be dissolved in methylene dichloride (10mL), stopped reaction after room temperature reaction 6h, add water (20mL), methylene dichloride (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtain 110g colourless liquid: (2S)-2-methoxycarbonyl-4-to Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.78(d,J＝8.1Hz,2H),7.37(d,J＝7.8Hz,2H),5.07(d,J＝15.1Hz,1H),4.33-4.43(m,1H),3.71(d,J＝3.5Hz,3H),3.57-3.74(m,2H),2.36-2.49(m,2H),2.47(s,3H),1.46(s,9H).

By compound (2S)-2-methoxycarbonyl-4-to Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate (400mg, 1.00mmol) with sodiumazide (325mg, 5.00mmol) be dissolved in DMF (10mL), stopped reaction after 80 DEG C of reaction 2h, screw out DMF, add water (20mL), and ethyl acetate (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 240mg colourless liquid: (2S)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate, yield: 88%.

¹HNMR(600MHz,CDCl ₃):δppm4.34-4.46(m,1H),4.35(t,J＝7.6Hz,1H),4.22(dd,J ₁＝9.0Hz,J ₂＝4.8Hz,1H),3.77(m,3H),3.72-3.74(m,1H),3.48-3.61(m,1H),2.30-2.39(m,1H),2.17-2.22(m,1H),1.45(d,J＝30.9Hz,9H)；

MS-ESI:m/z171.20[M+H-100] ⁺.

By compound (2S)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate (500mg, 1.85mmol) with Pd/C (10%, 120mg) be dissolved in methyl alcohol (10mL), under room temperature, atmospheric hydrogen reduces, stopped reaction after reaction 12h, suction filtration, filtrate concentrates, and obtains 440mg colourless liquid: (2S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm4.36-4.46(m,1H),3.67-3.78(m,2H),3.75(d,J＝3.5Hz,3H),3.09-3.23(m,1H),2.11-2.19(m,1H),1.97-2.08(m,1H),1.45(d,J＝20.1Hz,9H)；

MS-ESI:m/z145.25[M+H-100] ⁺.

By triethylamine (136mg, 1.35mmol) and N, N '-carbonyl dimidazoles (CDI) (175mg, 1.08mmol) be dissolved in dry DMF (2mL), add compound (2S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (220mg, 0.90mmol), anhydrous methanol (5mL) is added after stirring at room temperature 30min, stopped reaction after 60 DEG C of reaction 24h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtain 260mg white solid: (2S)-2-methoxycarbonyl-4-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate, yield: 95%.

¹HNMR(400MHz,CDCl ₃):δppm4.86(br.s,1H),4.29-4.41(m,2H),3.78-3.84(m,1H),3.75(s,3H),3.69(br.s,3H),3.25-3.41(m,1H),2.14-2.31(m,2H),1.45(d,J＝18.2Hz,9H)；

MS-ESI:m/z203.20[M+H-100] ⁺.

To compound (2S)-2-methoxycarbonyl-4-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate (250mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.82mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 190mg sticky solid: (2S)-2-methoxycarbonyl-4-methoxycarbonylamin pyrrolidine hydrochloride, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm4.65(t,J＝8.6Hz,1H),4.29-4.33(m,1H),3.89(s,3H),3.68(s,3H),3.63-3.66(m,1H),3.38-3.43(m,1H),2.43-2.46(m,2H)；

MS-ESI:m/z203.20[M+H] ⁺.

Step 2: the synthesis of compound (2S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) Pyrrolidine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (400mg, 0.84mmol), compound (2S)-2-methoxycarbonyl-4-methoxycarbonylamin pyrrolidine hydrochloride (200mg, 0.84mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (320mg, 1.68mmol) with N-hydroxyl-7-azepine benzotriazole (230mg, 1.68mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.59mL, 3.35mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 224mg white solid, yield: 41%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.62(m,2H),7.23-7.27(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.30-5.38(m,1H),5.17-5.29(m,1H),5.04(m,1H),4.33-4.52(m,1H),3.97-4.07(m,3H),3.67-3.80(m,6H),2.23-2.50(m,2H),1.52-1.55(m,3H),1.45(s,9H),1.33-1.39(m,1H),0.69-0.73(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z653.20[M+H] ⁺.

Step 3: the synthesis of compound (2S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) Pyrrolidine-2-methyl-formiate hydrochloride

To compound (2S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) Pyrrolidine-2-methyl-formiate (210mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.32mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 170mg white solid, yield: 90%.

¹HNMR(600MHz,CD ₃OD):δppm7.64-7.77(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.49-5.52(m,1H),5.12-5.18(m,1H),4.38-4.42,4.75-4.79(m,0.5H,0.5H),4.25-4.35(m,1H),4.03-4.08(m,2H),3.66-3.73,3.95-3.99(m,0.5H,0.5H),3.66-3.79(m,6H),2.44-2.48(m,1H),2.25-2.35(m,1H),1.78(s,3H),1.32-1.39(m,1H),0.67-0.73(m,2H),0.42-0.47(m,2H)；

MS-ESI:m/z553.30[M+H-HCl] ⁺.

embodiment 61: compound (2S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base) Pyrrolidine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound (2S)-4-cyclopropylcarboxamido tetramethyleneimine-2-methyl-formiate hydrochloride

By compound cyclopropanecarboxylic acid (116mg, 1.35mmol), compound (2S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (220mg, 0.90mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (345mg, 1.80mmol) with N-hydroxyl-7-azepine benzotriazole (245mg, 1.80mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.47mL, 2.70mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/2), obtain 225mg colourless liquid: (2S)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate, yield: 80%.

¹HNMR(400MHz,CDCl ₃):δppm5.80-5.89(m,1H),4.52-4.60(m,1H),4.30-4.44(m,1H),3.77-3.83(m,1H),3.75(s,3H),3.29-3.45(m,1H),2.19-2.31(m,1H),1.44-1.48(m,9H),1.30-1.37(m,1H),0.96-1.00(m,2H),0.74-0.79(m,2H)；

MS-ESI:m/z213.10[M+H-100] ⁺.

To compound (2S)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.71mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 170mg sticky solid: (2S)-4-cyclopropylcarboxamido tetramethyleneimine-2-methyl-formiate hydrochloride, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm4.71(t,J＝8.6Hz,1H),4.45(br.s,1H),3.89(s,3H),3.65-3.69(m,1H),3.34-3.39(m,1H),2.46-2.49(m,2H),1.62-1.65(m,1H),0.85-0.89(m,2H),0.80-0.83(m,2H)；

MS-ESI:m/z213.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (2S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) Pyrrolidine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (2S)-4-cyclopropylcarboxamido tetramethyleneimine-2-methyl-formiate hydrochloride (160mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.28mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 134mg white solid, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.51-7.61(m,2H),7.23-7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),6.18(br.s,1H),5.37-5.44(m,1H),5.20-5.23(m,1H),4.63-4.79(m,1H),4.21-4.33(m,1H),3.97-4.01(m,3H),3.75(d,J＝32.8Hz,3H),2.31-2.52(m,2H),1.52-1.56(m,3H),1.44(s,9H),1.31-1.41(m,2H),0.96-1.03(m,2H),0.73-0.81(m,2H),0.68-0.73(m,2H),0.41-0.46(m,2H)；

MS-ESI:m/z663.40[M+H] ⁺.

Step 3: the synthesis of compound (2S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) Pyrrolidine-2-methyl-formiate hydrochloride

To compound (2S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) Pyrrolidine-2-methyl-formiate (130mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.20mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 115mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.76(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.55(m,1H),5.12-5.18(m,1H),4.27-4.32,4.53-4.57(m,0.5H,0.5H),4.40-4.47(m,1H),4.03-4.07(m,2H),3.97-4.03(m,1H),3.76(d,J＝32.8Hz,3H),3.73-3.76(m,1H),2.49(t,J＝6.7Hz,1H),2.20-2.37(m,1H),1.76-1.79(m,3H),1.31-1.41(m,2H),0.84-0.90(m,2H),0.74-0.82(m,2H),0.66-0.73(m,2H),0.43-0.47(m,2H)；

MS-ESI:m/z563.35[M+H-HCl] ⁺.

embodiment 62: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methyl the synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 3-methylpiperazine-1-methyl-formiate hydrochloride

By triethylamine (760mg, 7.5mmol) and N, N '-carbonyl dimidazoles (CDI) (970mg, 6.0mmol) be dissolved in dry DMF (2mL), add N-tertbutyloxycarbonyl-2-methylpiperazine (1.0g, 5.0mmol), after stirring at room temperature 30min, add anhydrous methanol (10mL), stopped reaction after 60 DEG C of reaction 8h, except desolventizing, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 710mg colourless liquid: 2-methyl-4-methoxycarbonyl piperazine-1-t-butyl formate, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm4.22-4.30(m,1H),3.91-4.12(m,1H),3.78-3.91(m,2H),3.73(s,3H),3.02-3.09(m,2H),2.81-2.96(m,1H),1.48(s,9H),1.15(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.25[M+H-100] ⁺.

To compound 2-methyl-4-methoxycarbonyl piperazine-1-t-butyl formate (700mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 2.7mmol), 6mL), stirring at room temperature 30min, except desolventizing, obtain 520mg thick white solid: 3-methylpiperazine-1-methyl-formiate hydrochloride, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm4.18-4.22(m,2H),3.75(s,3H),3.34-3.42(m,2H),3.21-3.34(m,1H),3.11-3.16(m,1H),2.99-3.10(m,1H),1.36(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methylpiperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (500mg, 1.07mmol), compound 3-methylpiperazine-1-methyl-formiate hydrochloride (250mg, 1.28mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (410mg, 2.14mmol) with N-hydroxyl-7-azepine benzotriazole (290mg, 2.14mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.75mL, 4.27mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 290mg white solid, yield: 45%.

¹HNMR(400MHz,CDCl ₃):δppm7.56-7.60(m,2H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.20-5.26(m,1H),4.80-4.93(m,1H),4.39-4.51(m,1H),3.99(d,J＝6.9Hz,2H),3.89-4.03(m,1H),3.76(s,3H),3.07-3.42m,3H),1.55-1.57(m,3H),1.43(s,9H),1.33-1.38(m,1H),1.30-1.34(m,3H),0.68-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z609.25[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methylpiperazine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-3-methylpiperazine-1-methyl-formiate (290mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.48mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 250mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.75(m,2H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.03-5.07(m,1H),4.75-4.85(m,1H),4.48,5.17(br.s,0.5H,0.5H),4.09-4.19(m,1H),4.05(d,J＝6.9Hz,3H),3.94-4.01(m,1H),3.76(s,3H),3.12-3.13(m,1H),2.99-3.11,3.54-3.62(m,0.5H,0.5H),1.78-1.80(m,3H),1.39-1.46(m,1H),1.29-1.36(m,3H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z509.30[M+H-HCl] ⁺.

embodiment 63: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methyl the synthesis of piperazine-2-methyl-formiate dihydrochloride

Step 1: the synthesis of compound 1-methylpiperazine-2-methyl-formiate hydrochloride

By 3-methoxycarbonyl piperazine-1-t-butyl formate (500mg, 2.05mmol), methyl iodide (580mg, 4.10mmol) with salt of wormwood (424mg, 3.07mmol) be added in 50mL tube sealing, add acetone (10mL), stopped reaction after 50 DEG C of reaction 6h, except desolventizing, add water (20mL), and methylene dichloride (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrate and obtain 290mg light yellow solid: 3-methoxycarbonyl-4-methylpiperazine-1-t-butyl formate, yield: 54%.

¹HNMR(400MHz,CDCl ₃):δppm4.65-4.83(m,1H),4.29-4.33(m,1H),4.18-4.23(m,1H),4.05-4.11(m,1H),3.80-3.94(m,3H),3.88(s,3H),3.66(s,3H),1.48(s,9H)；

MS-ESI:m/z259.30[M+H] ⁺.

To compound 3-methoxycarbonyl-4-methylpiperazine-1-t-butyl formate (290mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.1mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 220mg yellow solid: 1-methylpiperazine-2-methyl-formiate hydrochloride, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm4.88(dd,J ₁＝11.1Hz,J ₂＝3.8Hz,1H),3.93-3.99(m,2H),3.87-3.91(m,2H),3.84(s,3H),3.70-3.75(m,1H),3.63-3.68(m,1H),3.5(s,3H)；

MS-ESI:m/z159.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methylpiperazine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 1-methylpiperazine-2-methyl-formiate hydrochloride (160mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.28mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 40mg white solid, yield: 24%.

¹HNMR(600MHz,CDCl ₃):δppm7.54-7.63(m,1H),7.26(d,J＝8.3Hz,1H),6.73(t,J _F-H＝75.0Hz,1H),5.24-5.28(m,1H),4.15-4.21,4.48-4.64(m,0.5H,0.5H),4.33-4.48(m,1H),3.98-4.02(m,2H),3.77(d,J＝45.3Hz,3H),3.42-3.54(m,1H),3.01-3.21(m,2H),2.41(s,3H),1.56(d,J＝7.0Hz,3H),1.45(s,9H),1.31-1.37(m,1H),0.69-0.73(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z609.40[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methylpiperazine-2-methyl-formiate dihydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1-methylpiperazine-2-methyl-formiate (30mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.05mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 27mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.66-7.71(m,2H),7.26-7.28(m,1H),6.84(t,J _F-H＝75.0Hz,1H),5.04-5.09(m,1H),4.55-4.61(m,1H),4.38-4.44(m,1H),3.93-3.98(m,2H),3.80-3.86(m,3H),3.65-3.71(m,1H),3.48-3.58(m,1H),3.35-3.44(m,1H),3.01(s,3H),1.70(d,J＝7.0Hz,3H),1.23-1.30(m,1H),0.59-0.62(m,2H),0.34-0.36(m,2H)；

MS-ESI:m/z509.10[M+H-2HCl] ⁺.

embodiment 64: compound ((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrole cough up alkane-3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (S)-3-methoxycarbonylamin pyrrolidine hydrochloride

By compound (R)-3-hydroxyl pyrrolidine-1-t-butyl formate (1.0g, 5.3mmol), p-methyl benzene sulfonic chloride (1.5g, 8.0mmol), triethylamine (1.1g, 11mmol) with DMAP (65mg, 0.53mmol) be dissolved in methylene dichloride (10mL), stopped reaction after room temperature reaction 10h, add water (20mL), methylene dichloride (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 460mg colourless liquid: (R)-3-to Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate, yield: 25%.

¹HNMR(400MHz,CDCl ₃):δppm7.79(d,J＝8.0Hz,2H),7.35(d,J＝7.7Hz,2H),5.04(s,1H),3.38-3.50(m,4H),2.45(s,3H),1.97-2.15(m,2H),1.43(m,9H)；

MS-ESI:m/z286.20[M-55] ⁺.

By compound (R)-3-to Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate (460mg, 1.34mmol) with sodiumazide (380mg, 6.74mmol) be dissolved in DMF (5mL), stopped reaction after 80 DEG C of reaction 2h, screw out DMF, add water (20mL), and ethyl acetate (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 250mg colourless liquid: (S)-3-azido-tetramethyleneimine-1-t-butyl formate, yield: 87%.

¹HNMR(400MHz,CDCl ₃):δppm4.10-4.15(m,1H),3.34-3.49(m,4H),1.95-2.11(m,2H),1.46(s,9H)；

MS-ESI:m/z157.10[M-55] ⁺.

By compound (S)-3-azido-tetramethyleneimine-1-t-butyl formate (250mg, 1.18mmol) with Pd/C (10%, 50mg) be dissolved in methyl alcohol (10mL), under room temperature, atmospheric hydrogen reduces, stopped reaction after reaction 12h, suction filtration, filtrate concentrates, and obtains 210mg colourless liquid: (S)-3-amino-pyrrolidine-1-t-butyl formate, yield: 96%.

¹HNMR(600MHz,CDCl ₃):δppm3.42-3.56(m,3H),3.30-3.40(m,1H),2.96-3.07(m,1H),1.99-2.05(m,1H),1.58-1.67(m,1H),1.44(s,9H)；

MS-ESI:m/z131.20[M-55] ⁺.

By triethylamine (162mg, 1.61mmol) and N, N '-carbonyl dimidazoles (CDI) (208mg, 1.28mmol) be dissolved in dry DMF (5mL), add compound (S)-3-amino-pyrrolidine-1-t-butyl formate (200mg, 1.07mmol), anhydrous methanol (5mL) is added after stirring at room temperature 30min, stopped reaction after 60 DEG C of reaction 24h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 230mg colourless liquid: (S)-3-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate, yield: 87%.

¹HNMR(600MHz,CDCl ₃):δppm4.77(br.s,1H),4.23(br.s,1H),3.67(s,3H),3.58-3.61(m,1H),3.38-3.41(m,2H),3.15-3.21(m,1H),2.10-2.15(m,1H),1.76-1.88(m,1H),1.45(m,9H)；

MS-ESI:m/z145.20[M+H-Boc] ⁺.

To compound (S)-3-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.90mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 160mg sticky solid: (S)-3-methoxycarbonylamin pyrrolidine hydrochloride, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm4.16-4.20(m,1H),3.58(s,3H),3.34-3.41(m,2H),3.26-3.31(m,1H),3.16-3.21(m,1H),2.18-2.24(m,1H),1.95(m,1H)；

MS-ESI:m/z145.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (400mg, 0.854mmol), compound (S)-3-methoxycarbonylamin pyrrolidine hydrochloride (200mg, 0.854mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (327mg, 1.71mmol) with N-hydroxyl-7-azepine benzotriazole (232mg, 1.71mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.60mL, 3.42mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 250mg white solid, yield: 49%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.20-5.30(m,1H),4.27-4.37(m,1H),4.13-4.22(m,1H),3.98(d,J＝6.9Hz,2H),3.89-4.07(m,1H),3.69-3.82(m,2H),3.68(m,3H),2.14-2.28(m,1H),1.87-2.13(m,1H),1.51-1.54(m,3H),1.42(s,9H),1.27-1.34(m,1H),0.65-0.71(m,2H),0.37-0.43(m,2H)；

MS-ESI:m/z595.30[M+H] ⁺.

Step 3: the synthesis of compound ((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (240mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.40mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 210mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.61-7.64(m,2H),7.24(d,J＝8.2Hz,1H),6.82(t,J _F-H＝75.0Hz,1H),5.00-5.03(m,1H),4.21-4.23,3.98-4.04(m,0.5H,0.5H),4.09-4.20(m,2H),3.92-3.95(m,2H),3.76-3.79,3.66-3.71(m,0.5H,0.5H),3.60-3.65(m,1H),3.57(d,J＝10.0Hz,3H),2.09-2.22(m,1H),1.85-2.00(m,1H),1.69(d,J＝6.9Hz,3H),1.21-1.27(m,1H),0.58-0.62(m,2H),0.32-0.37(m,2H)；

MS-ESI:m/z495.30[M+H-HCl] ⁺.

embodiment 65: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-methyl the synthesis of piperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound N-methy piperazine-1-carboxamide hydrochloride

By compound 1-tert-butoxycarbonyl-piperazine (0.5g, 2.68mmol), triethylamine (1.2mL, 8.05mmol) and N, N '-carbonyl dimidazoles (CDI) (520mg, 3.22mmol) be dissolved in dry DMF (2mL), methylamine hydrochloride (720mg is added after stirring at room temperature 30min, 0.73mmol), stopped reaction after 60 DEG C of reaction 6h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=60/1), obtain 550mg white solid: 4-methylcarbamoyl piperazine-1-t-butyl formate, yield: 84%.

¹HNMR(400MHz,CDCl ₃):δppm3.50-3.60(m,2H),3.30-3.40(m,4H),2.81(d,J＝4.6Hz,3H),1.45(s,9H)；

MS-ESI:m/z144.10[M+H-100] ⁺.

To compound 4-methylcarbamoyl piperazine-1-t-butyl formate (0.16g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.7mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 160mg white solid: N methyl piperazine-1-carboxamide hydrochloride, yield: 100%.

¹HNMR(400MHz,CD ₃OD):δppm3.65-3.66(m,4H),3.20-3.24(m,4H),2.75(s,3H)；

MS-ESI:m/z144.25[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(methylcarbamoyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound N-methy piperazine-1-carboxamide hydrochloride (127mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (254mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 250mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.55-7.61(m,2H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.21-5.28(m,1H),4.49(s,1H),3.99(d,J＝6.9Hz,2H),3.98(br.s,2H),3.80(br.s,2H),3.51(br.s,4H),2.87(d,J＝3.8Hz,3H),1.56(d,J＝7.0Hz,3H),1.43(s,9H),1.32-1.36(m,1H),0.68-0.73(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z594.20[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N methyl piperazine-1-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(methylcarbamoyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (110mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.42mmol); 3mL); stirring at room temperature 30min; except desolventizing; obtain 90mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.60-7.64(m,2H),7.23(d,J＝8.3Hz,1H),6.81(t,J _F-H＝75.0Hz,1H),4.93-4.97(m,1H),4.08(br.s,1H),3.93(d,J＝6.9Hz,2H),3.68(br.s,2H),3.44(br.s,4H),2.66(s,3H),1.68(d,J＝6.8Hz,3H),1.22-1.26(m,1H),0.57-0.60(m,2H),0.32-0.35(m,2H)；

MS-ESI:m/z494.10[M+H-HCl] ⁺.

embodiment 66: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N-bis- the synthesis of methylpiperazine-1-carboxamide hydrochloride

Step 1: compound N, the synthesis of N-lupetazin-1-carboxamide hydrochloride

By compound 1-Boc-piperazine (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N, N '-carbonyl dimidazoles (CDI) (485mg, 3.00mmol) be dissolved in dry DMF (2mL), dimethylamine hydrochloride (810mg is added after stirring at room temperature 30min, 9.99mmol), stopped reaction after 80 DEG C of reaction 6h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=100/1), obtain 650mg white solid: 4-(dimethylcarbamoyl) piperazine-1-t-butyl formate, yield: 94%.

¹HNMR(400MHz,CDCl ₃):δppm3.40-3.44(m,4H),3.16-3.18(m,4H),2.83(s,6H),1.45(s,9H)；

MS-ESI:m/z158.30[M+H-100] ⁺.

To compound 4-(dimethylcarbamoyl) piperazine-1-t-butyl formate (0.3g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.17mmol); 4mL); stirring at room temperature 30min; except desolventizing; obtain 220mg white solid: N, N-lupetazin-1-carboxamide hydrochloride, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm3.25-3.29(m,4H),3.05-3.08(m,4H),2.71(s,6H)；

MS-ESI:m/z158.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(dimethyl formamide base) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (400mg, 0.85mmol), compound N, N-lupetazin-1-carboxamide hydrochloride (200mg, 1.03mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (327mg, 1.71mmol) with N-hydroxyl-7-azepine benzotriazole (232mg, 1.71mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.6mL, 3.42mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 230mg white solid, yield: 44%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.59(m,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.18-5.25(m,1H),3.89-4.01(m,2H),3.97(d,J＝6.9Hz,2H),3.77(br.s,2H),3.32(br.s,4H),2.86(s,6H),1.54(d,J＝6.9Hz,3H),1.42(s,9H),1.28-1.35(m,1H),0.66-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z608.40[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N-lupetazin-1-carboxamide hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(dimethyl formamide base) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (230mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.38mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 200mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.64(s,1H),7.61(d,J＝8.3Hz,1H),7.21(d,J＝8.2Hz,1H),6.81(t,J _F-H＝75.0Hz,1H),4.94-4.99(m,1H),4.09(br.s,2H),3.94(d,J＝6.8Hz,2H),3.70(br.s,2H),3.27(br.s,4H),2.81(s,3H),1.69(d,J＝6.7Hz,3H),1.21-1.26(m,1H),0.56-0.60(m,2H),0.3-0.34(m,2H)；

MS-ESI:m/z508.35[M+H-HCl] ⁺.

embodiment 67: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride

By N-tertbutyloxycarbonyl-allohydroxyproline methyl esters (210mg, 0.86mmol), p-methyl benzene sulfonic chloride (195mg, 1.03mmol), triethylamine (200mg, 2.14mmol) with DMAP (12mg, 0.086mmol) be dissolved in methylene dichloride (10mL), stopped reaction after room temperature reaction 10h, add water (20mL), methylene dichloride (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtain 110g colourless liquid: (2S, 4S)-2-methoxycarbonyl-4-tolysulfonyl oxygen base tetramethyleneimine-1-t-butyl formate, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.77(d,J＝8.1Hz,2H),7.35(d,J＝7.8Hz,2H),5.06(d,J＝15.1Hz,1H),4.31-4.34(m,1H),3.69(d,J＝3.5Hz,3H),3.55-3.66(m,2H),2.34-2.46(m,2H),2.47(s,3H),1.39-1.44(m,9H).

By compound (2S, 4S)-2-methoxycarbonyl-4-tolysulfonyl oxygen base tetramethyleneimine-1-t-butyl formate (400mg, 1.00mmol) with sodiumazide (325mg, 5.00mmol) be dissolved in DMF (10mL), stopped reaction after 80 DEG C of reaction 2h, screw out DMF, add water (20mL), ethyl acetate (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 240g colourless liquid: (2S, 4R)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate, yield: 88%.

¹HNMR(400MHz,CDCl ₃):δppm4.30-4.43(m,1H),4.16-4.21(m,1H),4.35(t,J＝7.6Hz,1H),3.74(d,J＝3.7Hz,3H),3.68-3.72(m,1H),3.44-3.60(m,1H),2.26-2.38(m,1H),2.13-2.21(m,1H),1.41-1.46(m,9H)；

MS-ESI:m/z171.20[M+H-100] ⁺.

By compound (2S, 4R)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate (500mg, 1.85mmol) and Pd/C (10%, 120mg) is dissolved in methyl alcohol (10mL), under room temperature, atmospheric hydrogen reduces, stopped reaction after reaction 12h, suction filtration, filtrate concentrates, obtain 440mg colourless liquid: (2S, 4R)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm4.33-4.43(m,1H),3.67-3.78(m,2H),3.74(s,3H),3.06-3.20(m,1H),2.08-2.15(m,1H),1.91-2.05(m,1H),1.40-1.45(m,9H)；

MS-ESI:m/z145.25[M+H-100] ⁺.

By triethylamine (136mg, 1.35mmol) and N, N '-carbonyl dimidazoles (CDI) (175mg, 1.08mmol) be dissolved in dry DMF (2mL), add compound (2S, 4R)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (220mg, 0.90mmol), anhydrous methanol (5mL) is added after stirring at room temperature 30min, stopped reaction after 60 DEG C of reaction 24h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtain 260mg white solid: (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate, yield: 95%.

¹HNMR(600MHz,CDCl ₃):δppm4.81-4.86(m,1H),4.26-4.38(m,2H),3.74-3.81(m,1H),3.73(s,3H),3.66(s,3H),3.25-3.38(m,1H),2.22(m,2H),1.45(d,J＝18.2Hz,9H)；

MS-ESI:m/z203.20[M+H-100] ⁺.

To compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate (250mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.82mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 190mg sticky solid: (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm4.58(t,J＝8.6Hz,1H),4.20-4.24(m,1H),3.81(s,3H),3.60(s,3H),3.54-3.60(m,1H),3.30-3.34(m,1H),2.35-2.38(m,2H)；

MS-ESI:m/z203.20[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (400mg, 0.84mmol), compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride (200mg, 0.84mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (320mg, 1.68mmol) with N-hydroxyl-7-azepine benzotriazole (230mg, 1.68mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.59mL, 3.35mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 224mg white solid, yield: 41%.

¹HNMR(400MHz,CDCl ₃):δppm7.49-7.60(m,2H),7.20-7.24(m,1H),6.69(t,J _F-H＝75.0Hz,1H),5.28-5.36(m,1H),5.16-5.27(m,1H),4.88-5.09(m,1H),4.29-4.35,4.70-4.75(m,0.5H,0.5H),4.35-4.50(m,1H),3.96-4.01(m,2H),3.67-3.78(m,6H),2.23-2.50(m,2H),1.49-1.53(m,3H),1.42(s,9H),1.29-1.36(m,1H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z653.20[M+H] ⁺.

Step 3: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate (210mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.32mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 170mg white solid, yield: 90%.

¹HNMR(600MHz,CD ₃OD):δppm7.64-7.77(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.10-5.19(m,1H),4.76-4.78,5.49-5.52(m,0.5H,0.5H),4.22-4.42(m,2H),4.04-4.07(m,2H),3.71-4.74,3.96-3.99(m,0.5H,0.5H),3.73,3.79(s,2H,1H),3.66(d,J＝9.0Hz,3H),2.45-2.48(m,1H),2.24-2.37(m,1H),1.76-1.78(m,3H),1.34-1.39(m,1H),0.68-0.73(m,2H),0.43-0.47(m,2H)；

MS-ESI:m/z553.30[M+H-HCl] ⁺.

embodiment 68: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound (2S, 4R)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride

By cyclopropanecarboxylic acid (116mg, 1.35mmol), compound (2S, 4R)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (220mg, 0.90mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (345mg, 1.80mmol) with N-hydroxyl-7-azepine benzotriazole (245mg, 1.80mmol) be dissolved in methylene dichloride (25mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.47mL, 2.70mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/2), obtain 225mg colourless liquid: (2S, 4R)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate, yield: 80%.

¹HNMR(400MHz,CDCl ₃):δppm5.86(d,J＝42.0Hz,1H),4.54(br.s,1H),4.27-4.44(m,1H),3.73-3.81(m,1H),3.73(s,3H),3.25-3.45(m,1H),2.13-2.32(m,1H),1.45(d,J＝18.2Hz,9H),1.28-1.35(m,1H),0.93-0.98(m,2H),0.71-0.78(m,2H)；

MS-ESI:m/z213.30[M+H-100] ⁺.

To compound (2S, 4R)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.71mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtains 170mg sticky solid: (2S, 4R)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm4.60(t,J＝8.6Hz,1H),4.31-4.37(m,1H),3.79(s,3H),3.55-3.60(m,1H),3.22-3.28(m,1H),2.35-2.39(m,2H),1.49-1.56(m,1H),0.68-0.80(m,4H)；

MS-ESI:m/z213.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (2S, 4R)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride (160mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.28mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 134mg white solid, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.50-7.59(m,2H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.34-5.40(m,1H),5.17-5.22(m,1H),4.61-4.77(m,1H),4.60-4.67,4.24-4.32(m,0.5H,0.5H),4.00(m,2H),3.95-4.00(m,1H),3.73(s,1H),3.70(s,2H),2.27-2.49(m,2H),1.51-1.55(m,3H),1.42(s,9H),1.31-1.39(m,2H),0.95-1.01(m,2H),0.72-0.79(m,2H),0.68-0.71(m,2H),0.40-0.43(m,2H)；

MS-ESI:m/z663.40[M+H] ⁺.

Step 3: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate (130mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.20mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 115mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.57-7.68(m,2H),7.26(d,J＝8.2Hz,1H),6.85(t,J _F-H＝75.0Hz,1H),5.05-5.11(m,1H),4.43-4.51,4.18-4.24(m,0.5H,0.5H),4.32-4.41(m,1H),3.95-4.00(m,2H),3.89-3.95(m,1H),3.64-3.71(m,1H),3.67(d,J＝27.5Hz,3H),2.40-2.43(m,1H),2.18-2.30(m,1H),1.71(d,J＝6.5Hz,3H),1.23-1.31(m,2H),0.77-0.83(m,2H),0.68-0.74(m,2H),0.59-0.64(m,2H),0.34-0.39(m,2H)；

MS-ESI:m/z563.35[M+H-HCl] ⁺.

embodiment 69: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound (R)-2-methylpiperazine-1-t-butyl formate hydrochloride

By triethylamine (380mg, 3.75mmol) and N, N '-carbonyl dimidazoles (CDI) (486mg, 3.0mmol) be dissolved in dry DMF (2mL), add N-tertbutyloxycarbonyl-(R)-3-methylpiperazine (500mg, 2.5mmol), anhydrous methanol (10mL) is added after stirring at room temperature 30min, stopped reaction after 80 DEG C of reaction 8h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtain 620mg white solid: (R)-1-methoxycarbonyl-2-methylpiperazine-1-t-butyl formate, yield: 96%.

¹HNMR(600MHz,CDCl ₃):δppm4.20-4.30(m,1H),3.75-3.96(m,3H),3.70(s,3H),3.05-3.11(m,1H),2.91-3.07(m,1H),2.71-2.88(m,1H),1.45(s,9H),1.15(d,J＝6.8Hz,3H)；

MS-ESI:m/z159.25[M+H-100] ⁺.

To compound (R)-1-methoxycarbonyl-2-methylpiperazine-1-t-butyl formate (600mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 2.3mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 420mg white solid: (R)-2-methylpiperazine-1-t-butyl formate hydrochloride, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm4.51-4.54(m,1H),4.06-4.13(m,1H),3.70(s,3H),3.27-3.32(m,1H),3.16-3.28(m,3H),2.98-3.06(m,1H),1.31(d,J＝7.2Hz,3H)；

MS-ESI:m/z159.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-2-methylpiperazine-1-t-butyl formate hydrochloride (150mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (246mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (175mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 186mg white solid, yield: 47%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(d,J＝8.3Hz,1H),7.53(s,1H),7.25(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),6.14(br.s,1H),5.20-5.27(m,1H),4.35-4.68(m,3H),3.91-4.02(m,1H),3.97(d,J＝6.9Hz,2H),3.73(s,3H),3.46-3.50,3.14-3.20(m,0.5H,0.5H),3.20-3.31(m,1H),2.89-3.06(m,1H),1.52-1.55(m,3H),1.42(d,J＝5.1Hz,9H),1.28-1.35(m,1H),1.17-1.25(m,3H),0.66-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z609.20[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate hydrochloride

To compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (180mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (1mL) solution 0.3mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 125mg white solid, yield: 77%.

¹HNMR(600MHz,CD ₃OD):δppm7.63-7.68(m,2H),7.27(d,J＝8.3Hz,1H),6.85(t,J _F-H＝75.0Hz,1H),4.97-5.00(m,1H),4.87-4.92(m,1H),4.37-4.45(m,2H),3.97(d,J＝6.9Hz,2H),3.92-3.98(m,1H),3.68(s,3H),3.49-3.52,3.17-3.22(m,0.5H,0.5H),3.23-3.32(m,1H),3.07-3.12,2.92-2.98(m,0.5H,0.5H),1.72(d,J＝6.6Hz,3H),1.22-1.30(m,1H),1.15-1.24(m,3H),0.60-0.64(m,2H),0.35-0.38(m,2H)；

MS-ESI:m/z509.15[M+H-HCl] ⁺.

embodiment 70: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, N, 2- the synthesis of tri methyl piperazine-1-carboxamide hydrochloride

Step 1: compound N, the synthesis of N, 2-tri methyl piperazine-1-carboxamide hydrochloride

By compound N-tertbutyloxycarbonyl-2-methylpiperazine (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N, N '-carbonyl dimidazoles (CDI) (485mg, 3.00mmol) be dissolved in dry DMF (2mL), dimethylamine hydrochloride (800mg is added after 60 DEG C of reaction 30min, 9.99mmol), stopped reaction after 80 DEG C of reaction 12h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=150/1), obtain 444mg light yellow liquid: 4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm3.64-4.01(m,3H),3.24-3.32(m,1H),3.01-3.17(m,2H),2.86-2.95(m,1H),2.81(s,6H),1.45(s,9H),1.17(d,J＝6.7Hz,3H)；

MS-ESI:m/z216.10[M-55] ⁺.

To compound 4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate (0.44g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.62mmol); 4mL); stirring at room temperature 30min; except desolventizing, obtain 330mg white solid: N, N; 2-tri methyl piperazine-1-carboxamide hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm3.69-3.76(m,1H),3.14-3.26(m,2H),3.04-3.11(m,2H),2.94-3.03(m,2H),2.71(s,6H),1.14(d,J＝6.7Hz,3H)；

MS-ESI:m/z172.25[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 220mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.51-7.60(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.19-5.29(m,1H),4.34-4.53(m,2H),3.97(m,1H),3.97(d,J＝6.9Hz,2H),3.35-3.60(m,2H),3.01-3.28(m,2H),2.85(s,6H),1.55(d,J＝7.0Hz,3H),1.41(s,9H),1.28-1.36(m,1H),1.22-1.30(m,3H),0.65-0.71(m,2H),0.37-0.43(m,2H)；

MS-ESI:m/z622.40[M+H] ⁺.

Step 3: compound 4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, the synthesis of N, 2-tri methyl piperazine-1-carboxamide hydrochloride

To compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (220mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.35mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 190mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.61-7.66(m,2H),7.24(d,J＝8.3Hz,1H),6.83(t,J _F-H＝75.0Hz,1H),4.94-5.01(m,1H),4.20-4.23,4.34-4.36(m,0.5H,0.5H),3.96(d,J＝6.9Hz,2H),3.89-3.98(m,1H),3.39-3.45,3.55-3.60(m,0.5H,0.5H),3.34-3.99(m,1H),3.17-3.25(m,1H),3.01-3.07,3.28-3.34(m,0.5H,0.5H),2.82(s,6H),1.70(d,J＝5.8Hz,3H),1.23-1.29(m,1H),1.15-1.23(m,3H),0.58-0.61(m,2H),0.32-0.38(m,2H)；

MS-ESI:m/z522.35[M+H-HCl] ⁺.

embodiment 71: compound 3-((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrole cough up alkane-3-base) synthesis of-1,1-dimethyl urea hydrochloride

Step 1: the synthesis of compound (S)-3-(3,3-dimethyl urea) pyrrolidine hydrochloride

By triethylamine (680mg, 6.7mmol) and N, N '-carbonyl dimidazoles (CDI) (261mg, 1.6mmol) be dissolved in dry DMF (5mL), add compound (S)-3-amino-pyrrolidine-1-t-butyl formate (250mg, 1.34mmol), dimethylamine hydrochloride (430mg is added after stirring at room temperature 30min, 5.4mmol), stopped reaction after 80 DEG C of reaction 24h, removing solvent DMF, add water (10mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=60/1), obtain 120mg light tan liquid: (S)-3-(3, 3-dimethyl urea) tetramethyleneimine-1-t-butyl formate, yield: 35%.

¹HNMR(400MHz,CDCl ₃):δppm4.32-4.39(m,2H),3.59-3.68(m,1H),3.34-3.47(m,2H),3.07-3.20(m,1H),2.89(s,6H),2.10-2.19(m,1H),1.73-1.88(m,1H),1.45(m,9H)；

MS-ESI:m/z202.20[M+H-55] ⁺.

To compound (S)-3-(3,3-dimethyl urea) tetramethyleneimine-1-t-butyl formate (120mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.47mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtains 90mg white solid: (S)-3-(3,3-dimethyl urea) pyrrolidine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.19-4.25(m,1H),3.31-3.42(m,2H),3.17-3.23(m,1H),3.11-3.16(m,1H),2.79(s,6H),2.14-2.23(m,1H),1.94-2.01(m,1H)；

MS-ESI:m/z158.20[M+H-HCl] ⁺.

Step 2: compound (S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-3-(3,3-dimethyl urea) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) synthesis of t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), compound (S)-3-(3, 3-dimethyl urea) pyrrolidine hydrochloride (100mg, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (165mg, 0.85mmol) with N-hydroxyl-7-azepine benzotriazole (120mg, 0.85mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.3mL, 1.71mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: EtOAc), obtains 180mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.22-5.29(m,1H),4.44-4.56(m,2H),4.20-4.29,4.00-4.06(m,0.5H,0.5H),3.97(d,J＝6.9Hz,2H),3.80-3.93(m,1H),3.73-3.79(m,1H),2.89-2.92(m,6H),2.17-2.31(m,1H),1.85-2.04(m,1H),1.54(d,J＝7.0Hz,3H),1.41(s,9H),1.28-1.36(m,1H),0.65-0.70(m,2H),0.39-0.42(m,2H)；

MS-ESI:m/z608.05[M+H] ⁺.

Step 3: the synthesis of compound 3-((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl)-1,1-dimethyl urea hydrochloride

To compound (S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-3-(3,3-dimethyl urea) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (180mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.30mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 160mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.58(s,1H),7.56(d,J＝8.3Hz,1H),7.14-7.16(m,1H),6.75(t,J _F-H＝75.0Hz,1H),4.93-4.99(m,1H),4.14-4.29(m,2H),3.97-4.04,3.64-3.70(m,0.5H,0.5H),3.88(d,J＝6.9Hz,2H),3.75-3.84(m,1H),3.49-3.55,3.68-3.40(m,0.5H,0.5H),2.78(s,3H),2.77(s,3H),2.04-2.14(m,1H),1.86-1.96(m,1H),1.64(d,J＝6.9Hz,3H),1.13-1.20(m,1H),0.49-0.53(m,2H),0.25-0.30(m,2H)；

MS-ESI:m/z508.00[M+H-HCl] ⁺.

embodiment 72: compound 3-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of-1,1-dimethyl urea hydrochloride

Step 1: the synthesis of compound (R)-3-(3,3-dimethyl urea) pyrrolidine hydrochloride

By N-tertbutyloxycarbonyl-(S)-3-pyrrolidinol (1.5g, 8.0mmol), p-methyl benzene sulfonic chloride (2.7g, 14.0mmol), triethylamine (1.6g, 16mmol) with DMAP (980mg, 8.0mmol) be dissolved in methylene dichloride (10mL), stopped reaction after room temperature reaction 10h, add water (20mL), methylene dichloride (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtain 2.5g white solid: (S)-3-(tolysulfonyl oxygen base) tetramethyleneimine-1-t-butyl formate, yield: 91%.

¹HNMR(400MHz,CDCl ₃):δppm7.78(d,J＝8.1Hz,2H),7.35(d,J＝7.8Hz,2H),4.98-5.07(m,1H),3.36-3.48(m,4H),2.45(s,3H),1.90-2.18(m,2H),1.42(m,9H)；

MS-ESI:m/z286.00[M-55] ⁺.

By compound (S)-3-(tolysulfonyl oxygen base) tetramethyleneimine-1-t-butyl formate (460mg, 1.34mmol) with sodiumazide (380mg, 6.74mmol) be dissolved in DMF (5mL), stopped reaction after 80 DEG C of reaction 2h, screw out DMF, add water (20mL), and ethyl acetate (10mL × 3) extracts, and uses anhydrous Na after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 250mg colourless liquid: (R)-3-azido-tetramethyleneimine-1-t-butyl formate, yield: 87%.

¹HNMR(400MHz,CDCl ₃):δppm4.10-4.13(m,1H),3.34-3.49(m,4H),1.99-2.06(m,2H),1.45(s,9H)；

MS-ESI:m/z157.20[M-55] ⁺.

By compound (R)-3-azido-tetramethyleneimine-1-t-butyl formate (250mg, 1.18mmol) with Pd/C (10%, 50mg) be dissolved in methyl alcohol (10mL), under room temperature, atmospheric hydrogen reduces, stopped reaction after reaction 12h, suction filtration, filtrate concentrates, and obtains 210mg colourless liquid: (R)-3-amino-pyrrolidine-1-t-butyl formate, yield: 96%.

¹HNMR(600MHz,CDCl ₃):δppm3.39-3.49(m,3H),3.27-3.32(m,1H),2.95-3.03(m,1H),1.98-2.08(m,1H),1.63-1.70(m,1H),1.41(s,9H)；

MS-ESI:m/z131.20[M-55] ⁺.

By triethylamine (680mg, 6.7mmol) and N, N '-carbonyl dimidazoles (CDI) (261mg, 1.6mmol) be dissolved in dry DMF (5mL), add compound (R)-3-amino-pyrrolidine-1-t-butyl formate (250mg, 1.34mmol), dimethylamine hydrochloride (430mg is added after stirring at room temperature 30min, 5.4mmol), stopped reaction after 80 DEG C of reaction 24h, removing solvent DMF, add water (10mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=60/1), obtain 120mg light tan liquid: (R)-3-(3, 3-dimethyl urea) tetramethyleneimine-1-t-butyl formate, yield: 35%.

¹HNMR(400MHz,CDCl ₃):δppm4.30-4.40(m,2H),3.57-3.67(m,1H),3.34-3.46(m,2H),3.04-3.20(m,1H),2.88(s,6H),2.08-2.18(m,1H),1.44(m,9H)；

MS-ESI:m/z202.15[M-55] ⁺.

To compound (R)-3-(3,3-dimethyl urea) tetramethyleneimine-1-t-butyl formate (120mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.47mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtains 90mg white solid: (R)-3-(3,3-dimethyl urea) pyrrolidine hydrochloride, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm4.20-4.24(m,1H),3.30-3.41(m,2H),3.18-3.23(m,1H),3.12-3.15(m,1H),2.80(s,3H),2.16-2.22(m,1H),1.95-2.03(m,1H)；

MS-ESI:m/z158.30[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-(3,3-dimethyl urea) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), compound (R)-3-(3, 3-dimethyl urea) pyrrolidine hydrochloride (100mg, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (165mg, 0.85mmol) with N-hydroxyl-7-azepine benzotriazole (120mg, 0.85mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.3mL, 1.71mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: EtOAc), obtains 180mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(d,J＝8.4Hz,1H),7.52(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.23-5.30(m,1H),4.45-4.53(m,2H),4.21-4.26,4.01-4.11(m,0.5H,0.5H),3.97(d,J＝6.9Hz,2H),3.85-3.94(m,1H),3.73-3.78(m,1H),2.91(s,6H),2.22-2.32(m,1H),1.84-2.03(m,1H),1.51-1.55(m,3H),1.42(s,9H),1.28-1.35(m,1H),0.66-0.71(m,2H),0.37-0.42(m,2H)；

MS-ESI:m/z608.04[M+H] ⁺.

Step 3: the synthesis of compound 3-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl)-1,1-dimethyl urea hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-(3,3-dimethyl urea) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (180mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.30mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 160mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.66(s,1H),7.64(d,J＝8.3Hz,1H),7.22-7.24(m,1H),6.82(t,J _F-H＝75.0Hz,1H),4.99-5.05(m,1H),4.25-4.35(m,2H),4.03-4.09,3.71-3.77(m,0.5H,0.5H),3.96(d,J＝6.9Hz,2H),3.82-3.90(m,1H),3.57-3.64,3.42-3.47(m,0.5H,0.5H),2.84(d,J＝6.4Hz,6H),2.10-2.23(m,1H),1.98-2.06(m,1H),1.70(d,J＝6.4Hz,3H),1.19-1.28(m,1H),0.56-0.61(m,2H),0.32-0.36(m,2H)；

MS-ESI:m/z508.00[M+H-HCl] ⁺.

embodiment 73: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (R)-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride

By compound (R)-3-methylpiperazine-1-t-butyl formate (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N, N '-carbonyl dimidazoles (CDI) (485mg, 3.00mmol) be dissolved in dry DMF (2mL), after stirring at room temperature 30min, add dimethylamine hydrochloride (800mg, 9.99mmol), stopped reaction after 80 DEG C of reaction 12h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=150/1), obtain 444mg light yellow liquid: (R)-4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm3.63-4.02(m,3H),3.25-3.32(m,1H),3.02-3.19(m,2H),2.87-2.98(m,1H),2.81(s,6H),1.45(s,9H),1.17(d,J＝6.7Hz,3H)；

MS-ESI:m/z216.20[M-55] ⁺.

To compound (R)-4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate (0.44g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.62mmol); 4mL); stirring at room temperature 30min; except desolventizing, obtain 330mg white solid: (R)-N, N; 2-tri methyl piperazine-1-carboxamide hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm3.74-3.81(m,1H),3.22-3.32(m,2H),3.09-3.17(m,2H),2.99-3.02(m,2H),2.77(s,6H),1.20(d,J＝6.9Hz,3H)；

MS-ESI:m/z172.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 220mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),6.16(br.s,1H),5.19-5.26(m,1H),4.34-4.56(m,2H),3.97(m,1H),3.97(d,J＝6.9Hz,2H),3.34-3.60(m,2H),3.00-3.32(m,2H),2.85(s,6H),1.55(d,J＝7.0Hz,3H),1.41(s,9H),1.28-1.36(m,1H),1.19-1.28(m,3H),0.65-0.71(m,2H),0.37-0.43(m,2H)；

MS-ESI:m/z622.00[M+H] ⁺.

Step 3: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, the synthesis of N, 2-tri methyl piperazine-1-carboxamide hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (220mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.35mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 190mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.63-7.69(m,2H),7.27(d,J＝8.3Hz,1H),6.85(t,J _F-H＝75.0Hz,1H),4.96-5.02(m,1H),4.23-4.25,4.37-3.39(m,0.5H,0.5H),3.98(d,J＝6.9Hz,2H),3.93-3.98(m,1H),3.43-3.49,3.58-3.60(m,0.5H,0.5H),3.36-3.44(m,1H),3.21-3.28(m,2H),3.04-3.10,3.30-3.35(m,0.5H,0.5H),2.85(s,6H),1.73(d,J＝6.7Hz,3H),1.25-1.32(m,1H),1.18-1.26(m,3H),0.60-0.65(m,2H),0.35-0.39(m,2H)；

MS-ESI:m/z522.00[M+H-HCl] ⁺.

embodiment 74: compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride

By compound (S)-3-methylpiperazine-1-t-butyl formate (0.5g, 2.50mmol), triethylamine (1.74mL, 12.48mmol) and N, N '-carbonyl dimidazoles (CDI) (485mg, 3.00mmol) be dissolved in dry DMF (2mL), after stirring at room temperature 30min, add dimethylamine hydrochloride (800mg, 9.99mmol), stopped reaction after 80 DEG C of reaction 12h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=150/1), obtain 443mg light yellow liquid: (S)-4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm3.64-4.00(m,3H),3.24-3.33(m,1H),3.01-3.18(m,2H),2.86-2.98(m,1H),2.80(s,6H),1.45(s,9H),1.17(d,J＝6.7Hz,3H)；

MS-ESI:m/z216.20[M-55] ⁺.

To compound (S)-4-(formyl-dimethylamino)-3-methylpiperazine-1-t-butyl formate (0.44g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.62mmol); 4mL); stirring at room temperature 30min; except desolventizing, obtain 330mg white solid: (S)-N, N; 2-tri methyl piperazine-1-carboxamide hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm3.70-3.75(m,1H),3.14-3.26(m,2H),3.04-3.11(m,2H),2.94-3.03(m,2H),2.71(s,6H),1.15(d,J＝6.9Hz,3H)；

MS-ESI:m/z172.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (S)-N, N, 2-tri methyl piperazine-1-carboxamide hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 220mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.17-5.29(m,1H),4.34-4.55(m,2H),3.92-4.00(m,1H),3.97(d,J＝6.9Hz,2H),3.36-3.54(m,2H),3.20-3.31(m,1H),3.00-3.19(m,1H),2.85(s,6H),1.55(d,J＝7.0Hz,3H),1.41(s,9H),1.27-1.35(m,1H),1.21-1.30(m,3H),0.65-0.71(m,2H),0.37-0.43(m,2H)；

MS-ESI:m/z622.05[M+H] ⁺.

Step 3: compound (S)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N, the synthesis of N, 2-tri methyl piperazine-1-carboxamide hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-4-(formyl-dimethylamino)-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (220mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.35mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 190mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.62-7.67(m,2H),7.26(d,J＝8.3Hz,1H),6.84(t,J _F-H＝75.0Hz,1H),4.96-5.01(m,1H),4.70-4.76(m,1H),4.22-4.24,4.35-3.37(m,0.5H,0.5H),3.97(d,J＝6.9Hz,2H),3.90-3.98(m,1H),3.40-3.44,3.60-3.62(m,0.5H,0.5H),3.35-3.41(m,1H),3.18-3.26(m,1H),3.04-3.09,3.29-3.36(m,0.5H,0.5H),2.83(s,6H),1.70(d,J＝5.6Hz,3H),1.23-1.29(m,1H),1.16-1.22(m,3H),0.58-0.62(m,2H),0.34-0.39(m,2H)；

MS-ESI:m/z522.35[M+H-HCl] ⁺.

embodiment 75: compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((R)-4-(ring third base carbonyl)-3-methylpiperazine-1-yl) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (R)-cyclopropyl (2-methylpiperazine-1-yl) methanone hvdrochloric acid salt

By compound (R)-3-methylpiperazine-1-t-butyl formate (250mg, 1.25mmol), ethylene-acetic acid (130mg, 1.50mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (480mg, 2.50mmol) with N-hydroxyl-7-azepine benzotriazole (254mg, 1.87mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, in this solution, drip DIPEA (0.65mL, 3.74mmol), stirring at room temperature 10h, add water (10mL × 3) are washed, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtain 310mg colourless liquid: (R)-4-(cyclopropyl carbonyl)-3-methylpiperazine-1-t-butyl formate, yield: 93%.

¹HNMR(400MHz,CDCl ₃):δppm4.24-4.50(m,1H),3.78-4.07(m,2H),2.90-3.41(m,3H),2.81(s,6H),1.50(s,9H),1.12-1.36(m,4H),0.96-1.05(m,2H),0.74-0.82(m,2H)；

MS-ESI:m/z213.10[M-55] ⁺.

To compound (R)-4-(cyclopropyl carbonyl)-3-methylpiperazine-1-t-butyl formate (310mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 1.16mmol), 4mL), stirring at room temperature 50min, except desolventizing, obtain 220mg thick white solid: (R)-cyclopropyl (2-methylpiperazine-1-yl) methanone hvdrochloric acid salt, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm4.74-4.78(m,1H),4.30-4.38(m,1H),3.28(d,J＝12.4Hz,1H),3.20-3.22(m,1H),3.07-3.17(m,1H),2.88-2.99(m,1H),1.82-1.86(m,1H),1.18-1.32(m,3H),0.71-0.80(m,4H)；

MS-ESI:m/z169.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-(cyclopropyl carbonyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-cyclopropyl (2-methylpiperazine-1-yl) methanone hvdrochloric acid salt (130mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 6h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 300mg white solid, yield: 76%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(d,J＝8.3Hz,1H),7.54(s,1H),7.24(d,J＝8.7Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.19-5.30(m,1H),4.65-4.77(m,1H),4.56-4.64,4.36-4.47(m,0.5H,0.5H),4.48-4.55(m,1H),3.97(d,J＝6.9Hz,2H),3.42-3.66(m,1H),2.94-3.04,3.20-3.36(m,0.5H,0.5H),3.04-3.20(m,1H),2.51-2.68(m,1H),1.69-1.79(m,1H),1.53-1.57(m,3H),1.42(s,9H),1.28-1.36(m,4H),0.97-1.07(m,2H),0.76-0.84(m,2H),0.65-0.72(m,2H),0.38-0.43(m,2H)；

MS-ESI:m/z619.00[M+H] ⁺.

Step 3: the synthesis of compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((R)-4-(cyclopropyl carbonyl)-3-methylpiperazine-1-yl) methanone hvdrochloric acid salt

To compound ((S)-1-(4-((R)-4-(cyclopropyl carbonyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (300mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.35mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 260mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.76(m,2H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.04-5.11(m,1H),4.44-4.56(m,1H),4.26-4.42(m,1H),4.05(d,J＝6.6Hz,2H),3.57-3.75(m,1H),3.32-3.50(m,1H),3.05-3.29(m,2H),1.80(d,J＝6.4Hz,3H),1.97-2.06(m,1H),1.39-1.48(m,1H),1.24-1.43(m,3H),0.83-0.97(m,4H),0.64-0.75(m,2H),0.39-0.48(m,2H)；

MS-ESI:m/z519.35[M+H-HCl] ⁺.

embodiment 76: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N- the synthesis of cyclopropyl-2-methylpiperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (R)-N-cyclopropyl-2-methylpiperazine-1-carboxamide hydrochloride

By triethylamine (0.52mL, 3.74mmol) and N, N '-carbonyl dimidazoles (CDI) (607mg, 3.74mmol) be dissolved in dry DMF (5mL), room temperature adds ring third ammonia (213mg, 3.74mmol), reaction 20min, add compound (R)-3-methylpiperazine-1-t-butyl formate (300mg, 1.49mmol), stopped reaction after 80 DEG C of reaction 10h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=100/1), obtain 370mg light yellow liquid: (R)-4-(cyclopropylcarbamoyl)-3-methylpiperazine-1-t-butyl formate, yield: 87%.

¹HNMR(600MHz,CDCl ₃):δppm4.68(s,1H),4.00-4.15(m,1H),3.72-3.96(m,2H),2.98-3.10(m,2H),2.76-2.94(m,1H),2.64(s,1H),1.45(s,9H),1.08-1.17(m,3H),0.68-0.74(m,2H),0.43-0.49(m,2H)；

MS-ESI:m/z228.30[M-55] ⁺.

To compound (R)-4-(cyclopropylcarbamoyl)-3-methylpiperazine-1-t-butyl formate (180mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.64mmol); 2mL); stirring at room temperature 30min; except desolventizing; obtain 140mg thick white solid: (R)-N-cyclopropyl-2-methylpiperazine-1-carboxamide hydrochloride, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm4.24-4.31(m,1H),3.76-3.84(m,1H),3.06-3.17(m,2H),2.96-3.02(m,1H),2.77-2.84(m,1H),2.31-2.39(m,1H),1.10(d,J＝7.1Hz,3H),0.46-0.51(m,2H),0.27-0.30(m,2H)；

MS-ESI:m/z184.20[M+H] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-(cyclopropylcarbamoyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-N-cyclopropyl-2-methylpiperazine-1-carboxamide hydrochloride (140mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 6h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 240mg white solid, yield: 59%.

¹HNMR(600MHz,CDCl ₃):δppm7.56-7.58(m,1H),7.53(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),6.12(br.s,1H),5.21-5.23(m,1H),4.71(d,J＝12.3Hz,1H),4.43-4.46,4.53-4.55(m,0.5H,0.5H),4.13-4.21(m,1H),3.97-4.00(m,2H),3.81-3.84,3.67-3.69(m,0.5H,0.5H),3.49-3.53,2.93-2.99(m,0.5H,0.5H),3.20-3.31(m,1H),3.05-3.18(m,1H),2.64-2.70(m,1H),1.53-1.55(m,3H),1.41(s,9H),1.29-1.35(m,1H),1.15-1.25(m,3H),0.72-0.77(m,2H),0.66-0.71(m,2H),0.45-0.50(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z634.40[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-cyclopropyl-2-methylpiperazine-1-carboxamide hydrochloride

To compound ((S)-1-(4-((R)-4-(cyclopropylcarbamoyl)-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (230mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.36mmol); 4mL); stirring at room temperature 30min; except desolventizing; obtain 190mg white solid, yield: 92%.

¹HNMR(600MHz,CD ₃OD):δppm7.68-7.73(m,2H),7.32(d,J＝8.3Hz,1H),6.90(t,J _F-H＝75.0Hz,1H),4.99-5.07(m,1H),4.87-4.95(m,1H),4.40-4.48(m,1H),4.30-4.38(m,1H),4.03(d,J＝5.4Hz,2H),3.82-3.89(m,1H),2.95-3.04(m,0.5H,0.5H),3.21-3.36(m,1H),3.11-3.21(m,1H),2.53-2.59(m,1H),1.78(d,J＝5.9Hz,3H),1.28-1.36(m,1H),1.14-1.25(m,3H),0.64-0.71(m,4H),0.45-0.50(m,2H),0.39-0.45(m,2H)；

MS-ESI:m/z534.05[M+H-HCl] ⁺.

embodiment 77: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-isopropyl formate hydrochloride

Step 1: the synthesis of compound (2S, 4R)-2-butyloxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride

By compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate (360mg, 1.85mmol) and LiOHH ₂o (250mg, 5.95mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (10mL) and water (5mL), 40 DEG C of reaction 30min, add hydrochloric acid (1M) and regulate pH to 1, add ethyl acetate (10mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 280mg white solid: (2S, 4R)-1-tertbutyloxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid, productive rate: 82%.

¹HNMR(400MHz,CD ₃OD):δppm4.29-4.36(m,1H),4.20-4.27(m,1H),3.68-3.74(m,1H),3.65(s,3H),3.27-3.33(m,1H),2.22-2.2(m,2H),1.46(d,J＝14.2Hz,9H)；

MS-ESI:m/z189.20[M+H-100] ⁺.

By compound (2S, 4R)-1-tertbutyloxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (300mg, 1.04mmol) and N, N '-carbonyl dimidazoles (CDI) (506mg, 3.12mmol) be dissolved in anhydrous THF (10mL), cool after 60 DEG C of reaction 1h, add DBU (0.5mL, 3.12mmol) with Virahol (0.12mL, 1.56mmol), stopped reaction after 60 DEG C of reaction 4h, add saturated aqueous ammonium chloride (10mL) to wash, screw out THF, aqueous phase ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=6/1), obtain 230mg colourless liquid: (2S, 4R)-2-butyloxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate, yield: 67%.

¹HNMR(600MHz,CDCl ₃):δppm5.71-5.77(m,1H),5.06-5.10(m,1H),4.35-4.39(m,1H),4.23-4.32(m,1H),3.66(s,3H),3.46-3.57(m,1H),2.43-2.52(m,1H),1.94-1.99(m,1H),1.46(d,J＝14.2Hz,9H),1.25-1.32(m,6H)；

MS-ESI:m/z231.10[M+H-100] ⁺.

By compound (2S, 4R)-2-butyloxycarbonyl-4-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate (200mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.61mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 153mg sticky white solid: (2S, 4R)-2-butyloxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm5.13-5.19(m,1H),4.60(t,J＝8.6Hz,1H),4.28-4.33(m,1H),3.68(s,3H),3.63-3.67(m,1H),3.78-3.42(m,1H),2.40-2.45(m,2H),1.33-1.36(m,6H)；

MS-ESI:m/z231.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-isopropyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), compound (2S, 4R)-2-butyloxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride (110mg, 0.43mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (165mg, 0.85mmol) with N-hydroxyl-7-azepine benzotriazole (116mg, 0.85mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.3mL, 1.71mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 110mg white solid, yield: 38%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.62(m,2H),7.22-7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.31-5.41(m,1H),5.21-5.30(m,1H),4.96-5.13(m,2H),4.66-4.71,4.29-4.34(m,0.5H,0.5H),4.36-4.51(m,1H),3.98-4.01(m,2H),3.70(s,3H),2.35-2.47(m,2H),1.52-1.56(m,3H),1.45(s,9H),1.35-1.39(m,1H),1.25-1.29(m,2H),1.20(d,J＝6.3Hz,2H),1.10(d,J＝6.2Hz,2H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z681.00[M+H] ⁺.

Step 3: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-isopropyl formate hydrochloride

To compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-isopropyl formate (110mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.16mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 95mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.68-7.79(m,2H),7.33-7.36(m,1H),6.94(t,J _F-H＝75.0Hz,1H),5.06-5.15(m,1H),4.72-4.75,3.97-4.01(m,0.5H,0.5H),4.37-4.43(m,1H),4.24-4.33(m,1H),4.05-4.10(m,2H),3.73-3.76(m,1H),3.68(d,J＝9.1Hz,3H),2.43-2.53(m,1H),2.22-2.28,2.34-2.39(m,0.5H,0.5H),1.78-1.80(m,3H),1.36-1.41(m,1H),1.32(dd,J ₁＝22.3Hz,J ₂＝6.2Hz,3H),1.16(dd,J ₁＝22.0Hz,J ₂＝6.2Hz,3H),0.69-0.73(m,2H),0.44-0.48(m,2H)；

MS-ESI:m/z581.00[M+H-HCl] ⁺.

embodiment 78: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (R)-2-methylpiperazine-1-carboxamide hydrochloride

By compound (R)-4-tertbutyloxycarbonyl-2-methylpiperazine (0.5g, 2.5mmol) with triethylamine (1.1mL, 7.5mmol) be dissolved in anhydrous tetrahydro furan (10mL), under room temperature condition, trimethyl silicane based isocyanate (1.0mL is dripped in this solution, 7.5mmol), stirring at room temperature 1.5h, with frozen water (10mL), screw out tetrahydrofuran (THF), aqueous phase ethyl acetate (30mL × 3) extraction, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 500mg white solid: (R)-4-formamyl-3-methylpiperazine-1-t-butyl formate, yield: 82%.

¹HNMR(400MHz,CD ₃OD):δppm4.58(s,1H),4.16-4.22(m,1H),4.00(d,J＝12.2Hz,1H),3.85(d,J＝13.4Hz,1H),3.74(d,J＝13.1Hz,1H),3.09(td,J＝12.7,3.5Hz,2H),1.49(s,9H),1.16(d,J＝6.7Hz,3H)；

MS-ESI:m/z188.20[M+H-100] ⁺.

To compound (R)-4-formamyl-3-methylpiperazine-1-t-butyl formate (0.5g; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 2.1mmol); 4mL); stirring at room temperature 30min; except desolventizing; obtain 370mg white solid: (R)-2-methylpiperazine-1-carboxamide hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.51-4.54(m,1H),4.07-4.11(m,1H),3.35-3.43(m,3H),3.25-3.30(m,1H),3.05-3.14(m,1H),1.39(d,J＝6.7Hz,3H)；

MS-ESI:m/z144.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-formamyl-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-2-methylpiperazine-1-carboxamide hydrochloride (122mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (250mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 290mg white solid, yield: 76%.

¹HNMR(400MHz,CD ₃OD):δppm7.59(d,J＝8.2Hz,1H),7.55(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.11(br.s,1H),5.23-5.32(m,1H),4.64-4.73(m,1H),4.47-4.63(m,1H),4.20-4.26(m,1H),3.99(d,J＝6.9Hz,2H),3.76-3.87(m,1H),3.20-3.33(m,2H),2.99-3.15(m,1H),1.57(d,J＝6.9Hz,3H),1.43(s,9H),1.33-1.37(m,1H),1.22-1.27(m,3H),0.68-0.73(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z594.30[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-carboxamide hydrochloride

By compound ((S)-1-(4-((R)-4-formamyl-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (280mg; 0.47mmol) be dissolved in methylene dichloride (4mL) solution; add the ethyl acetate solution (4M of HCl; 6mL); stirring at room temperature 30min; except desolventizing; obtain 235mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.67-7.72(m,2H),7.30(d,J＝8.3Hz,1H),6.88(t,J _F-H＝74.8Hz,1H),5.02-5.06(m,1H),4.95-5.01(m,1H),4.42-4.49(m,1H),4.33-4.38(m,1H),4.01(d,J＝6.8Hz,2H),3.90-3.94(m,1H),3.58-3.61,3.26-3.30(m,0.5H,0.5H),3.33-3.40(m,1H),3.16-3.20,3.03-3.10(m,0.5H,0.5H),1.76(d,J＝6.9Hz,3H),1.28-1.33(m,1H),1.26(dd,J ₁＝45.0Hz,J ₂＝6.6Hz,3H),0.64-0.67(m,2H),0.39-0.42(m,2H)；

MS-ESI:m/z494.20[M+H-HCl] ⁺.

embodiment 79: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4- the synthesis of carboxamide hydrochloride

Step 1: the synthesis of compound piperidine-4-carboxamide hydrochloride

By compound N-tertbutyloxycarbonyl-4-piperidine methyl formate (1.0g, 4.1mmol) with a hydronium(ion) Lithium Oxide 98min (860mg, 21mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (10mL) and water (5mL), 45 DEG C of reaction 1h, add hydrochloric acid (1M) and regulate pH to 1, add ethyl acetate (20mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 860mg white solid: 1-(tertbutyloxycarbonyl) piperidines-4-formic acid, productive rate: 91%.

¹HNMR(400MHz,CD ₃OD):δppm3.97-4.02(m,2H),2.88-2.95(m,2H),2.48-2.55(m,1H),1.88-1.92(m,2H),1.54-1.61(m,2H),1.47(s,9H)；

MS-ESI:m/z174.20[M-55] ⁺.

By compound 1-(tertbutyloxycarbonyl) piperidines-4-formic acid (220mg, 0.96mmol), ammonium chloride (154mg, 2.88mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (367mg, 1.92mmol) with N-hydroxyl-7-azepine benzotriazole (195mg, 1.44mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, in this solution, drip DIPEA (1.0mL, 5.77mmol), stirring at room temperature 10h, add water (10mL × 3) are washed, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: EtOAc), obtains 160mg white solid: 4-carbamylpiperidine-1-t-butyl formate, yield: 73%.

¹HNMR(400MHz,CD ₃OD):δppm4.11(d,J＝13.4Hz,2H),2.76-2.86(m,2H),2.38-2.45(m,1H),1.79(d,J＝11.2Hz,2H),1.52-1.62(m,2H),1.47(s,9H)；

MS-ESI:m/z173.20[M-55] ⁺.

By compound 4-carbamylpiperidine-1-t-butyl formate (160mg; 0.7mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 2mL); stirring at room temperature 30min; except desolventizing, obtain 112mg white solid: piperidines-4-carboxamide hydrochloride, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm3.33-3.39(m,2H),2.95-3.24(m,2H),2.50-2.58(m,1H),1.95-1.99(m,2H),1.76-1.87(m,2H)；

MS-ESI:m/z129.20[M+H-HCl] ⁺.

Step 2: compound (S)-(1-(4-(4-carbamylpiperidine-1-carbonyl)-2-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) synthesis of t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound piperidine-4-carboxamide hydrochloride (125mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: EtOAc), obtains 240mg white solid, yield: 64%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.59(m,2H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.16-5.21(m,1H),4.52-4.65(m,2H),3.95(d,J＝6.9Hz,2H),3.13-3.30(m,1H),2.84-2.98(m,1H),2.45-2.52(m,1H),1.75-1.98(m,4H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.28-1.35(m,1H),0.65-0.70(m,2H),0.37-0.42(m,2H).

Step 3: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-carboxamide hydrochloride

By compound (S)-(1-(4-(4-carbamylpiperidine-1-carbonyl)-2-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg; 0.35mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 6mL); stirring at room temperature 50min; except desolventizing; obtain 130mg white solid, yield: 73%.

¹HNMR(600MHz,CD ₃OD):δppm7.74(s,1H),7.71(d,J＝8.3Hz,1H),7.32(d,J＝8.2Hz,1H),6.91(t,J _F-H＝74.8Hz,1H),4.99-5.04(m,1H),4.87-4.94(m,1H),4.62-4.67(m,1H),4.04(d,J＝6.9Hz,2H),3.32-3.37(m,1H),2.95-3.00(m,1H),2.62-2.67(m,1H),1.90-1.99(m,2H),1.73-1.84(m,2H),1.79(d,J＝6.5Hz,3H),1.30-1.35(m,1H),0.66-0.70(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z479.10[M+H-HCl] ⁺.

embodiment 80: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-(ring third alkane methyl) synthesis of piperidines-4-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-((cyclopropane methyl) carbonyl) piperidines-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-formic acid (170mg, 0.29mmol), compound cyclopropyl-methylamine (25mg, 0.35mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (115mg, 0.58mmol) with N-hydroxyl-7-azepine benzotriazole (60mg, 0.44mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.15mL, 0.88mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 150mg white solid, yield: 75%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝11.8Hz,1H),7.54(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.15-5.23(m,1H),4.60-4.66(m,2H),3.97(d,J＝6.9Hz,2H),3.14-3.26(m,1H),3.14(t,J＝5.9Hz,2H),2.85-2.95(m,1H),2.38-2.44(m,1H),1.78-1.95(m,4H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.29-1.35(m,1H),0.91-0.97(m,1H),0.65-0.70(m,2H),0.49-0.53(m,2H),0.38-0.42(m,2H),0.18-0.22(m,2H)；

MS-ESI:m/z633.35[M+H] ⁺.

Step 2: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-(cyclopropane methyl) piperidines-4-carboxamide hydrochloride

By compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-((cyclopropane methyl) carbonyl) piperidines-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (140mg, 0.23mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 125mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.58(dd,J ₁＝8.3Hz,J ₂＝11.8Hz,1H),7.35(d,J＝8.3Hz,1H),6.94(t,J _F-H＝74.8Hz,1H),5.04-5.06(m,1H),4.90-4.97(m,1H),4.68-4.70(m,1H),4.06(d,J＝6.9Hz,2H),3.30-3.39(m,1H),3.10(d,J＝6.9Hz,2H),2.96-3.02(m,1H),2.62-2.67(m,1H),1.78-1.97(m,4H),1.78-1.82(m,3H),1.32-1.37(m,1H),0.90-0.99(m,1H),0.68-0.73(m,2H),0.52-0.55(m,2H),0.43-0.47(m,2H),0.24-0.27(m,2H)；

MS-ESI:m/z533.30[M+H-HCl] ⁺.

embodiment 81: compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- the synthesis of methylpiperazine-1-carboxvlate hvdrochloride

Step 1: the synthesis of compound (R)-2-methylpiperazine-1-carboxvlate hvdrochloride

Anhydrous THF (5mL) is added to N, N '-carbonyl dimidazoles (CDI) (1.21g, 7.49mmol) in, add triethylamine (760mg, 7.49mmol) with dehydrated alcohol (344mg, 7.49mmol), after stirring at room temperature 15min, add 3-(R)-methylpiperazine-1-t-butyl formate (500mg, 2.5mmol), stop after 70 DEG C of reaction 24h, except desolventizing, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtain 140mg colourless liquid: (R)-1-ethoxycarbonyl-2-methyl piperazine-4-t-butyl formate, yield: 21%.

¹HNMR(600MHz,CDCl ₃):δppm4.25-4.32(m,1H),4.14(q,J＝7.1Hz,2H),3.75-3.89(m,2H),3.70(s,3H),2.98-3.11(m,2H),2.74-2.89(m,1H),1.92-1.99(m,1H),1.47(s,9H),1.44(t,J＝7.2Hz,3H),1.15(d,J＝6.8Hz,3H)；

MS-ESI:m/z173.20[M+H-100] ⁺.

To compound (R)-1-ethoxycarbonyl-2-methyl piperazine-4-t-butyl formate (140mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.51mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 101mg white liquid: (R)-2-methylpiperazine-1-carboxvlate hvdrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.54-4.61(m,1H),3.63(q,J＝7.0Hz,2H),3.35-3.39(m,1H),3.22-3.28(m,3H),3.02-3.10(m,2H),1.30-1.36(m,3H),1.20(d,J＝7.1Hz,3H)；

MS-ESI:m/z173.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-ethyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), compound (R)-2-methylpiperazine-1-carboxvlate hvdrochloride (130mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (204mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.8mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.36mL, 2.14mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 105mg white solid, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.3Hz,1H),7.53(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),6.15(br.s,1H),5.20-5.29(m,1H),4.36-4.67(m,3H),4.17(q,J＝7.1Hz,2H),3.96-4.03(m,1H),3.96(d,J＝6.9Hz,2H),3.46-3.50,3.14-3.20(m,0.5H,0.5H),3.20-3.30(m,1H),2.89-3.06(m,1H),1.52-1.55(m,3H),1.42(d,J＝5.1Hz,9H),1.28-1.35(m,1H),1.20(d,J＝7.1Hz,3H),1.17-1.25(m,3H),0.66-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z623.80[M+H] ⁺.

Step 3: the synthesis of compound (R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-carboxvlate hvdrochloride

To compound (R)-4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-ethyl formate (95mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.15mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 79mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.78(m,2H),7.35(d,J＝8.3Hz,1H),6.94(t,J _F-H＝75.0Hz,1H),5.07-5.13(m,1H),4.97-5.03(m,1H),4.47-4.54(m,2H),4.20(q,J＝7.1Hz,2H),4.08(d,J＝6.9Hz,2H),4.03-4.07(m,1H),3.37-3.42(m,1H),3.26-3.32(m,1H),3.18-3.21,3.04-3.09(m,0.5H,0.5H),1.82(d,J＝6.6Hz,3H),1.33-1.39(m,1H),1.32(d,J＝7.1Hz,3H),1.25-1.30(m,3H),0.70-0.73(m,2H),0.45-0.48(m,2H)；

MS-ESI:m/z523.30[M+H-HCl] ⁺.

embodiment 82: compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((R)-3-methyl -4-(methylsulfonyl) piperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (R)-2-methyl isophthalic acid-(methylsulfonyl) piperazine hydrochloride

By compound (R)-3-methylpiperazine-1-t-butyl formate (500mg, 2.5mmol) with triethylamine (700mg, 6.3mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, methylsulfonyl chloride (0.39mL, 4.99mmol) is dripped, stirring at room temperature 8h in this solution, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1); obtain 444mg white solid: (R)-3-methyl-4-(methylsulfonyl) piperazine-1-t-butyl formate, yield: 63%.

¹HNMR(400MHz,CDCl ₃):δppm4.04-4.24(m,2H),3.82-3.98(m,1H),3.54(d,J＝12.7Hz,1H),3.14-3.21(m,1H),3.04-3.18(m,1H),2.87-3.00(m,1H),2.88(s,3H),1.48(s,9H),1.26(d,J＝6.8Hz,3H)；

MS-ESI:m/z223.15[M-55] ⁺.

By compound (R)-3-methyl-4-(methylsulfonyl) piperazine-1-t-butyl formate (200mg; 0.72mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 6mL); stirring at room temperature 50min; except desolventizing, obtain 147mg white solid: (R)-2-methyl isophthalic acid-(methylsulfonyl) piperazine hydrochloride, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm4.32-4.40(m,1H),3.80-3.86(m,1H),3.47-3.55(m,1H),3.37-3.40(m,1H),3.30-3.34(m,2H),3.13-3.20(m,1H),3.05(s,3H),1.47(d,J＝6.8Hz,3H)；

MS-ESI:m/z179.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-methyl-4-(methylsulfonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-2-methyl isophthalic acid-(methylsulfonyl) piperazine hydrochloride (164mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 296mg white solid, yield: 73%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝7.9Hz,1H),7.51(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.20-5.31(m,1H),4.57-4.78(m,2H),4.17-4.26(m,1H),3.97(d,J＝6.9Hz,2H),3.54-3.71(m,1.5H),3.27-3.39(m,1.5H),2.98-3.15(m,1H),2.89(s,3H),1.55(d,J＝6.7Hz,3H),1.34(s,9H),1.31-1.36(m,1H),1.24-1.34(m,3H),0.67-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z629.70[M+H] ⁺.

Step 3: the synthesis of compound (5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((R)-3-methyl-4-(methylsulfonyl) piperazine-1-base) methanone hvdrochloric acid salt

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-methyl-4-(methylsulfonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (290mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.46mmol); 4mL); stirring at room temperature 50min; except desolventizing; obtain 254mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.76(m,2H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.00-5.10(m,2H),4.48-4.58(m,1H),4.21-4.30(m,1H),4.05(d,J＝5.0Hz,2H),3.69-3.76(m,1H),3.35-3.46(m,1H),3.09-3.25(m,2H),3.00(s,3H),1.79(d,J＝6.3Hz,3H),1.32-1.36(m,1H),1.31-1.41(m,3H),0.67-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z529.80[M+H-HCl] ⁺.

embodiment 83: compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- methylpiperazine-1-yl) synthesis of-2-methylpropane-1-keto hydrochloride

Step 1: the synthesis of compound (R)-2-methyl isophthalic acid-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride

By compound (R)-3-methylpiperazine-1-t-butyl formate (500mg, 2.5mmol), isopropylformic acid (263mg, 3.0mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (957mg, 5.0mmol) with N-hydroxyl-7-azepine benzotriazole (507mg, 3.7mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, in this solution, drip DIPEA (1.3mL, 7.49mmol), stirring at room temperature 10h, add water (10mL × 3) are washed, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 670mg white solid: (R)-4-isobutyryl-3-methylpiperazine-1-t-butyl formate, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm4.70-4.80,4.30-4.42(m,0.5H,0.5H),3.76-4.02(m,2H),3.54-3.68,3.32-3.34(m,0.5H,0.5H),2.70-2.97(m,4H),1.48(s,9H),1.12(d,J＝6.8Hz,9H)；

MS-ESI:m/z261.10[M-55] ⁺.

By compound (R)-4-isobutyryl-3-methylpiperazine-1-t-butyl formate (670mg; 2.48mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 6mL); stirring at room temperature 50min; except desolventizing, obtain 520mg light yellow liquid: (R)-2-methyl isophthalic acid-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride, yield: 100%.

¹HNMR(400MHz,CD ₃OD):δppm3.43-3.46(m,1H),3.45-3.39(m,2H),3.20-3.28(m,3H),3.02-3.10(m,2H),1.30-1.36(m,3H),1.20(d,J＝7.1Hz,6H)；

MS-ESI:m/z171.10[M+H-HC] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-isobutyryl-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-2-methyl isophthalic acid-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/2), obtains 290mg white solid, yield: 73%.

¹HNMR(400MHz,CDCl ₃):δppm7.60(d,J＝8.2Hz,1H),7.55(s,1H),7.26(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.1Hz,1H),6.11(br.s,1H),5.23-5.31(m,1H),4.60-4.66,4.87-4.99(m,0.5H,0.5H),4.68-4.80(m,1H),4.50-4.56(m,1H),3.99(d,J＝6.9Hz,2H),3.66-3.87(m,1H),3.36-3.55(m,1H),3.16-3.33(m,1H),2.99-3.10(m,1H),2.76-2.83(m,1H),1.57(d,J＝5.1Hz,3H),1.44(s,9H),1.31-1.36(m,1H),1.18(d,J＝6.6Hz,9H),0.68-0.73(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z621.80[M+H] ⁺.

Step 3: the synthesis of compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-yl)-2-methylpropane-1-keto hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-4-isobutyryl-3-methylpiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (270mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.44mmol); 4mL); stirring at room temperature 50min; except desolventizing; obtain 230mg white solid, yield: 92%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.80(m,2H),7.37(d,J＝8.3Hz,1H),6.96(t,J _F-H＝75.0Hz,1H),5.07-5.13(m,2H),4.95-5.01(m,1H),4.47-4.61(m,2H),4.08(d,J＝6.9Hz,2H),3.57-3.66(m,1H),3.11-3.26(m,1H),2.97-3.08(m,1H),1.84(d,J＝6.6Hz,3H),1.31-1.39(m,3H),1.15-1.27(m,7H),0.70-0.75(m,2H),0.45-0.50(m,2H)；

MS-ESI:m/z521.30[M+H-HCl] ⁺.

embodiment 84: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-Isosorbide-5-Nitrae-Gao the synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound Isosorbide-5-Nitrae-homopiperazine-1-methyl-formiate hydrochloride

Anhydrous THF (5mL) is added to N, N '-carbonyl dimidazoles (CDI) (1.21g, 7.49mmol) in, add triethylamine (760mg, 7.49mmol) with dehydrated alcohol (344mg, 7.49mmol), after stirring at room temperature 15min, add 1, 4-homopiperazine-1-t-butyl formate (500mg, 2.5mmol), stop after 70 DEG C of reaction 24h, except desolventizing, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtain 140mg colourless liquid: 4-methoxycarbonyl-1, 4-homopiperazine-1-t-butyl formate, yield: 21%.

¹HNMR(400MHz,CDCl ₃):δppm3.70(s,3H),3.36-3.46(m,8H),1.83-1.86(m,2H),1.46(s,9H)；

MS-ESI:m/z173.20[M+H-100] ⁺.

By compound 4-methoxycarbonyl-1,4-homopiperazine-1-t-butyl formate (140mg, 0.51mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M, 2mL) of HCl, stirring at room temperature 30min, except desolventizing, obtain 101mg colourless liquid: Isosorbide-5-Nitrae-homopiperazine-1-methyl-formiate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm3.78-3.79(m,4H),3.78(s,3H),3.63(d,J＝6.2Hz,3H),2.07-2.13(m,3H)；

MS-ESI:m/z173.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-Isosorbide-5-Nitrae-homopiperazine-1-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), compound 1, 4-homopiperazine-1-methyl-formiate hydrochloride (130mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (204mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.8mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.36mL, 2.14mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=4/1), obtains 105mg white solid, yield: 32%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.58(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),6.05(br.s,1H),5.18-5.25(m,1H),3.97(d,J＝6.9Hz,2H),3.87-3.97(m,2H),3.72(s,3H),3.42-3.77(m,6H),1.93-2.10(m,2H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.28-1.35(m,1H),0.60-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z609.70[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-Isosorbide-5-Nitrae-homopiperazine-1-methyl-formiate hydrochloride

By compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-1,4-homopiperazine-1-methyl-formiate (95mg, 0.15mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 79mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.80(m,2H),7.36(d,J＝8.3Hz,1H),6.94(t,J _F-H＝75.0Hz,1H),5.01-5.09(m,1H),4.22-4.26(m,1H),4.13-4.17(m,1H),4.08(t,J＝7.1Hz,2H),3.88-3.95(m,1H),3.76-3.87(m,2H),3.74(s,3H),3.69(s,1H),3.60-3.66(m,2H),2.05-2.11(m,1H),1.93-2.01(m,1H),1.81(d,J＝6.6Hz,3H),1.35-1.40(m,1H),0.70-0.73(m,2H),0.45-0.48(m,2H)；

MS-ESI:m/z509.80[M+H-HCl] ⁺.

embodiment 85: compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4- the synthesis of isopropyl formate hydrochloride

Step 1: the synthesis of compound 4-butyloxycarbonyl piperidine hydrochlorate

By compound 1-(tertbutyloxycarbonyl) piperidines-4-formic acid (260mg, 1.14mmol) and N, N '-carbonyl dimidazoles (CDI) (275mg, 1.70mmol) be dissolved in anhydrous THF (10mL), cool after 60 DEG C of reaction 1h, add DBU (0.33mL, 2.67mmol) with Virahol (0.14mL, 1.70mmol), stopped reaction after 60 DEG C of reaction 4h, adds saturated aqueous ammonium chloride (10mL), screws out THF, aqueous phase ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=10/1), obtains 90mg colourless liquid: 4-butyloxycarbonyl piperidines-1-t-butyl formate, yield: 29%.

¹HNMR(400MHz,CD ₃OD):δppm4.97-5.04(m,1H),3.94-4.05(m,2H),2.83(t,J＝11.8Hz,2H),2.35-2.42(m,1H),1.80-1.88(m,2H),1.56-1.66(m,2H),1.45(s,9H),1.22(d,J＝6.3Hz,6H)；

MS-ESI:m/z216.10[M-55] ⁺.

By compound 4-butyloxycarbonyl piperidines-1-t-butyl formate (150mg, 0.55mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 110mg light yellow liquid: 4-butyloxycarbonyl piperidine hydrochlorate, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm5.00-5.06(m,1H),3.33-3.42(m,2H),2.99-3.09(m,2H),2.51-2.60(m,1H),2.06-2.22(m,4H),1.23(d,J＝6.3Hz,6H)；

MS-ESI:m/z172.30[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-isopropyl formate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), compound 4-butyloxycarbonyl piperidine hydrochlorate (110mg, 0.53mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (204mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.8mmol) be dissolved in methylene dichloride (10mL), under 0 DEG C of condition, N is dripped in this solution, N-diisopropylethylamine (0.4mL, 2.14mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 170mg colourless liquid, yield: 51%.

¹HNMR(400MHz,CDCl ₃):δppm7.54-7.59(m,2H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),6.05(br.s,1H),5.15-5.22(m,1H),5.00-5.07(m,1H),4.37-4.49(m,2H),3.97(d,J＝6.9Hz,2H),3.23-3.40(m,1H),2.98-3.13(m,1H),2.54-2.61(m,1H),1.88-2.06(m,2H),1.72-1.85(m,2H),1.53(d,J＝7.0Hz,3H),1.42(s,9H),1.28-1.35(m,1H),1.24(d,J＝6.3Hz,6H),0.65-0.70(m,2H),0.37-0.42(m,2H)；

MS-ESI:m/z622.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-isopropyl formate hydrochloride

By compound (S)-1-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4-isopropyl formate (160mg, 0.26mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, obtain 140mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(s,1H),7.74(d,J＝8.3Hz,1H),7.36(d,J＝8.2Hz,1H),6.95(t,J _F-H＝74.8Hz,1H),5.05-5.08(m,2H),4.76-4.86(m,1H),4.47-4.54(m,1H),4.08(d,J＝6.9Hz,2H),3.47-3.54(m,1H),3.11-3.18(m,1H),2.72-2.77(m,1H),2.45-2.11(m,2H),1.74-1.88(m,2H),1.82(d,J＝6.6Hz,3H),1.34-1.41(m,1H),1.30(d,J＝6.2Hz,6H),0.71-0.73(m,2H),0.46-0.49(m,2H)；

MS-ESI:m/z522.25[M+H-HCl] ⁺.

embodiment 86: compound (S)-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(2,4 difluorobenzene base) piperazine-1-base) synthesis of ketone dihydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(2,4 difluorobenzene base) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (0.3g, 0.64mmol), 1-(2, 4-difluorophenyl) piperazine (152mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (183mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (131mg, 0.96mmol) be dissolved in methylene dichloride (10mL), N is dripped after 0 DEG C of stirring 30min, N-diisopropylethylamine (0.33mL, 1.92mmol), stirring at room temperature 17h, add water (10mL × 3) wash, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 300mg white solid, yield: 72%.

¹HNMR(400MHz,CDCl ₃):δppm7.61(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.57(d,J＝1.8Hz,1H),7.26(d,J＝8.3Hz,1H),7.00-6.95(m,1H),6.87-6.82(m,2H),6.72(t,J _F-H＝74.7Hz,1H),5.28-5.24(m,1H),4.20-4.10(m,2H),4.01-3.92(m,2H),3.99(d,J＝7.0Hz,2H),3.16-3.10(m,4H),1.58(d,J＝7.0Hz,3H),1.44(s,9H),1.33-1.30(m,1H),0.71-0.69(m,2H),0.43-0.42(m,2H).

Step 2: the synthesis of compound (S)-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(2,4 difluorobenzene base) piperazine-1-base) ketone dihydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-(2,4-difluorophenyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (0.3g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.46mmol), 10mL), stirring at room temperature 30min, except desolventizing, obtain 250mg faint yellow solid, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm7.76(s,1H),7.73(d,J＝8.4Hz,1H),7.33(d,J＝8.2Hz,1H),7.20-7.17(m,1H),7.02-6.97(m,2H),6.92(t,J _F-H＝74.7Hz,1H),5.09-5.07(m,1H),4.38-4.36(m,2H),4.04(d,J＝6.9Hz,2H),3.99-3.96(m,2H),3.23-3.19(m,4H),1.80(d,J＝6.8Hz,3H),1.35-1.32(m,1H),0.71-0.66(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z549.20[M+H-2HCl] ⁺.

embodiment 87: compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2- methylpiperazine-1-yl) synthesis of propane-1-keto hydrochloride

Step 1: the synthesis of compound (R)-1-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride

By compound (R)-4-Boc-2-methylpiperazine (500mg, 2.50mmol), propionic acid (0.22mL, 3.00mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (718mg, 3.74mmol) with N-hydroxyl-7-azepine benzotriazole (850mg, 6.24mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.7mL, 9.99mmol), stirring at room temperature 16h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 630mg colorless oil: (R)-3-methyl-4-propionyl piperazine-1-t-butyl formate, yield: 95%.

¹HNMR(400MHz,CDCl ₃):δppm4.76,4.36(m,m,0.5H,0.5H),4.00-3.94(m,1H),3.85-3.76(m,1H),3.53,3.29(m,m,0.5H,0.5H),2.98-2.96(m,1H),2.83-2.74(m,2H),2.34-2.26(m,2H),1.45(s,9H),1.13(t,J＝7.0Hz,6H).

To compound (R)-3-methyl-4-propionyl piperazine-1-t-butyl formate (630mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 2.46mmol); 4mL); stirring at room temperature 2h; except desolventizing; obtain 473mg thick white thing: (R)-1-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm3.14(m,1H),3.11(m,1H),3.07(m,1H),2.97-2.94(m,2H),2.82-2.76(m,2H),2.20-2.16(m,2H),0.85(t,J＝7.4Hz,6H)；

MS-ESI:m/z157.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-methyl-4-propionyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), (R)-1-(2-methylpiperazine-1-yl) propane-1-keto hydrochloride (123mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 5h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 230mg white solid, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.2Hz,1H),7.53(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.29-5.21(m,1H),4.83-4.71(m,1H),4.62-4.50(m,2H),3.96(d,J＝6.9Hz,2H),3.69,3.23(m,m,0.5H,0.5H),3.47-3.44(m,1H),3.01-2.92(m,2H),2.35-2.30(m,2H),1.55(d,J＝6.8Hz,3H),1.41(s,9H),1.32-1.30(m,1H),1.29-1.23(m,3H),1.17(t,J＝6.6Hz,3H),0.71-0.64(m,2H),0.42-0.36(m,2H)；

MS-ESI:m/z607.8[M+H] ⁺.

Step 3: the synthesis of compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-yl) propane-1-keto hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((R)-3-methyl-4-propionyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (220mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.36mmol); 4mL); stirring at room temperature 2h; except desolventizing; obtain 190mg white solid, yield: 96%.

¹HNMR(600MHz,CDCl ₃):δppm7.61-7.57(m,2H),7.21-7.19(m,1H),6.71(t,J _F-H＝74.9Hz,1H),5.05(br.s,1H),5.04-4.89(m,1H),4.50-4.48(m,1H),4.42-4.35,4.19-4.16(m,m,0.5H,0.5H),3.95(d,J＝4.4Hz,2H),3.74-3.71,3.30-3.28(m,m,0.5H,0.5H),3.50-3.42(m,1H),3.04-2.87(m,2H),2.43-2.33(m,2H),1.86-1.84(m,3H),1.35-1.32(m,1H),1.16-1.13(m,3H),0.87-0.83(m,3H),0.65-0.64(m,2H),0.39-0.38(m,2H)；

MS-ESI:m/z507.3[M+H-HCl] ⁺.

embodiment 88: compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2,6- the synthesis of dione hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3,5-dioxopiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), piperazine-2, 6-diketone (73mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 10h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=60/1), obtains 156mg faint yellow solid, yield: 51%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.56(d,J＝1.6Hz,1H),7.25(d,J＝8.2Hz,1H),6.71(t,J _F-H＝75.0Hz,1H),5.32-5.25(m,1H),5.01(br.s,2H),4.63(br.s,2H),3.98(d,J＝6.9Hz,2H),1.54(d,J＝7.0Hz,3H),1.40(s,9H),1.33-1.29(m,1H),0.71-0.66(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z465.2[M+H-100] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperazine-2,6-dione hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3,5-dioxopiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (149mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.26mmol), 4mL), stirring at room temperature 3h, except desolventizing, obtain 125mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(d,J＝1.8Hz,1H),7.74(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.19-5.18(m,2H),5.15-5.12(m,1H),4.62(br.s,2H),4.05(d,J＝6.9Hz,2H),1.79(d,J＝7.0Hz,3H),1.35-1.33(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z465.8[M+H-HCl] ⁺.

embodiment 89: compound (S)-1-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) cyclopropyl ammonia the synthesis of base formic acid (piperidin-4-yl) ester hydrochloride

Step 1: the synthesis of compound cyclopropylamino formic acid (piperidin-4-yl) ester hydrochloride

Under condition of ice bath, to N-Boc-4-piperidone (500mg, sodium borohydride (190mg is added in dehydrated alcohol (15mL) solution 2.51mmol), 5.02mmol), room temperature reaction 1.5h, removing ethanol, adds ethyl acetate (15mL), saturated ammonium chloride solution (10mL × 2) is washed, organic phase anhydrous Na ₂sO ₄drying, concentrated, obtain 500mg colorless oil: N-Boc-4-hydroxy piperidine, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm3.85-3.79(m,3H),3.05-2.98(m,2H),1.86-1.82(m,2H),1.49-1.47(m,1H),1.45(s,9H),1.42-1.40(m,1H)；

MS-ESI:m/z102.3[M-100+H] ⁺.

Under room temperature condition, to N ' N-carbonyl dimidazoles (623mg, triethylamine (0.35mL is dripped in dry DMF (5mL) solution 3.73mmol), 2.48mmol), stirring at room temperature, slow dropping N-Boc-4-hydroxy piperidine (250mg, dry DMF (8mL) solution 1.24mmol), room temperature reaction 30min, drips cyclopropylamine (0.26mL, dry DMF (2mL) solution 3.73mmol), 50 DEG C of reaction 24h, removing solvent DMF, adds ethyl acetate (15mL), water (10mL × 2) is washed, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 320mg colorless oil: 4-(cyclopropylamino methanoyl) piperidines-1-t-butyl formate, yield: 90%.

¹HNMR(400MHz,CDCl ₃):δppm4.90-4.80(m,2H),3.70-3.62(m,2H),3.20-3.15(m,2H),2.58-2.55(m,1H),1.86-1.82(m,2H),1.57-1.53(m,1H),1.45(s,9H),0.73-0.69(m,2H),0.52-0.49(m,2H)；

MS-ESI:m/z185.3[M-100+H] ⁺.

To compound 4-(cyclopropylamino methanoyl) piperidines-1-t-butyl formate (400mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 1.41mmol), 5mL), stirring at room temperature 1h, except desolventizing, obtain 310mg yellow oil: cyclopropylamino formic acid (piperidin-4-yl) ester hydrochloride, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm4.92-4.90(m,1H),3.36-3.34(m,1H),3.32-3.30(m,1H),3.24-3.20(m,2H),2.55-2.52(m,1H),2.15-2.12(m,2H),1.98-1.93(m,2H),0.71-0.69(m,2H),0.51-0.49(m,2H)；

MS-ESI:m/z185.1[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(cyclopropylamino methanoyl) piperidines-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), cyclopropylamino formic acid (piperidin-4-yl) ester hydrochloride (141mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 17h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 246mg colorless viscous thing, yield: 72%.

¹HNMR(600MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.54(d,J＝1.8Hz,1H),7.22(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.21-5.18(m,1H),4.98-4.86(m,2H),4.05-4.00(m,1H),3.95(d,J＝6.9Hz,2H),3.80-3.52(m,2H),2.60-2.57(m,1H),2.00-1.95(m,2H),1.75-1.71(m,2H),1.53(d,J＝7.1Hz,3H),1.42(s,9H),1.33-1.30(m,1H),0.74-0.72(m,2H),0.69-0.66(m,2H),0.54-0.51(m,2H),0.41-0.38(m,2H)；

MS-ESI:m/z635.3[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) cyclopropylamino formic acid (piperidin-4-yl) ester hydrochloride

To compound (S)-(1-(4-(4-(cyclopropylamino methanoyl) piperidines-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (236mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.37mmol), 4mL), stirring at room temperature 2h, except desolventizing, obtain 200mg white solid, yield: 94%.

¹HNMR(600MHz,CDCl ₃):δppm7.59-7.57(m,2H),7.19(d,J＝7.9Hz,1H),6.69(t,J _F-H＝74.9Hz,1H),5.10-5.07(m,1H),4.99-4.95(m,2H),4.32-4.24(m,1H),3.94(d,J＝6.4Hz,2H),3.88-3.82(m,1H),3.60-3.53(m,1H),2.59-2.57(m,1H),2.00-1.92(m,2H),1.79-1.69(m,2H),1.30-1.28(m,1H),0.72-0.71(m,2H),0.65-0.64(m,2H),0.54-0.52(m,2H),0.38-0.37(m,2H)；

MS-ESI:m/z535.8[M+H-HCl] ⁺.

embodiment 90: compound (1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3- base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound piperidine-3-ylcarbamic acid methyl ester hydrochloride

Under room temperature condition, to N ' N-carbonyl dimidazoles (1.25g, triethylamine (0.70mL is dripped in anhydrous THF (5mL) solution 7.49mmol), 4.99mmol), stirring at room temperature, slow dropping methyl alcohol (0.30mL, 7.49mmol), room temperature reaction 30min, drip 1-Boc-3-amino piperidine (500mg, anhydrous THF (10mL) solution 2.50mmol), 75 DEG C of reaction 13h, add dilute hydrochloric acid solution (1M) and the pH value of solution is adjusted to about 1, ethyl acetate (15mL × 2) extracts, organic phase saturated sodium bicarbonate solution (10mL × 2) washs, anhydrous Na is used after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=4/1), obtains 477mg colorless oil: 3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate, yield: 74%.

¹HNMR(400MHz,CDCl ₃):δppm3.66(s,3H),3.58-3.55(m,1H),3.36-3.32(m,1H),3.27-3.23(m,1H),1.83-1.81(m,1H),1.66-1.60(m,1H),1.56-1.51(m,2H),1.45(s,9H)；

MS-ESI:m/z159.2[M-100+H] ⁺.

To compound 3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate (464mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 1.80mmol), 6mL), stirring at room temperature 2h, except desolventizing, obtain 349mg white solid: piperidines-3-ylcarbamic acid methyl ester hydrochloride, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm4.11-4.04(m,1H),3.65(s,3H),3.36-3.32(m,1H),3.21-3.12(m,3H),1.91-1.75(m,3H)；

MS-ESI:m/z159.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), piperidines-3-ylcarbamic acid methyl ester hydrochloride (156mg, 0.80mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 17h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 235mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.64-7.55(m,2H),7.22(d,J＝8.5Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.22-5.17(m,1H),4.01-3.94(m,1H),3.98(d,J＝6.6Hz,2H),3.83-3.81(m,1H),3.67-3.64(m,3H),3.58-3.55(m,1H),3.27-3.15(m,1H),1.81-1.75(m,2H),1.55(d,J＝7.0Hz,3H),1.42(s,9H),1.33-1.29(m,1H),0.68-0.66(m,2H),0.41-0.40(m,2H)；

MS-ESI:m/z609.2[M+H] ⁺.

Step 3: the synthesis of compound (1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane hydrochloride

To compound (1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane (226mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.37mmol), 4mL), stirring at room temperature 2h, except desolventizing, obtain 202mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.85(s,1H),7.75-7.74(m,1H),7.33-7.31(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.03-5.00(m,1H),4.55-4.45(m,1H),4.14-4.11(m,1H),4.04(d,J＝6.6Hz,2H),3.77-3.75(m,1H),3.67-3.58(m,4H),3.49-3.45(m,1H),2.05-2.03(m,1H),1.93-1.90(m,1H),1.78(d,J＝6.4Hz,3H),1.70-1.64(m,2H),1.35-1.33(m,1H),0.69-0.68(m,2H),0.45-0.44(m,2H)；

MS-ESI:m/z509.9[M+H-HCl] ⁺.

embodiment 91: compound ((R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrroles alkane-3-base) synthesis of carbamic acid isopropyl ester hydrochloride

Step 1: the synthesis of compound (R)-pyrrolidin-3-yl carbamic acid isopropyl ester hydrochloride

Under room temperature condition, to compound (R)-1-Boc-3-amino-pyrrolidine (500mg, DIPEA (1.9mL, 10.73mmol) is dripped in methylene dichloride (15mL) solution 2.68mmol), stirring at room temperature, drip isopropyl chlorocarbonate (1.84mL, 13.42mmol), room temperature reaction 18h, add saturated sodium bicarbonate solution (10mL × 2) washing, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 735mg colourless liquid: (R)-3-(isopropoxycarbonylamino) tetramethyleneimine-1-t-butyl formate, yield: 98%.

¹HNMR(400MHz,CDCl ₃):δppm4.92-4.88(m,1H),4.71-4.70(m,1H),4.21-4.20(m,1H),3.61-3.57(m,1H),3.40-3.36(m,2H),3.18-3.12(m,1H),2.14-2.07(m,1H),1.45(s,9H),1.22(d,J＝6.2Hz,6H)；

MS-ESI:m/z173.2[M-100+H] ⁺.

To compound (R)-3-(isopropoxycarbonylamino) tetramethyleneimine-1-t-butyl formate (800mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 2.94mmol), 6mL), stirring at room temperature 1h, except desolventizing, obtain 613mg pale yellow oil: (R)-pyrrolidin-3-yl carbamic acid isopropyl ester hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.30-4.24(m,1H),3.50-3.44(m,2H),3.40-3.36(m,1H),3.29-3.25(m,1H),2.34-2.25(m,1H),2.07-2.03(m,1H),1.25(d,J＝6.7Hz,6H)；

MS-ESI:m/z173.1[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((R)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) carbamic acid isopropyl ester

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), (R)-pyrrolidin-3-yl carbamic acid isopropyl ester hydrochloride (134mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (153mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirred at ambient temperature 14h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 174mg white solid, yield: 52%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54-7.53(m,1H),7.23(d,J＝8.4Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.29-5.25(m,1H),4.93-4.79(m,2H),4.35-4.33(m,1H),4.23-4.19(m,1H),4.00-3.95(m,1H),3.97(d,J＝6.9Hz,2H),3.77-3.73(m,1H),2.24-2.19(m,1H),1.99-1.88(m,1H),1.55-1.52(m,3H),1.43(s,9H),1.33-1.29(m,1H),1.24(d,J＝6.0Hz,6H),0.71-0.66(m,2H),0.42-0.39(m,2H)；

MS-ESI:m/z623.4[M+H] ⁺.

Step 3: the synthesis of compound ((R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) carbamic acid isopropyl ester hydrochloride

To compound ((R)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) carbamic acid isopropyl ester (169mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.27mmol), 3mL), stirring at room temperature 3h, except desolventizing, obtain 151mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.74(m,1H),7.73-7.71(m,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.13-5.10(m,1H),4.36-4.33(m,1H),4.28-4.21(m,2H),4.09-4.06(m,1H),4.04(d,J＝6.6Hz,2H),3.90-3.86,3.79-3.76(m,m,0.5H,0.5H),3.76-3.73,3.61-3.58(m,m,0.5H,0.5H),2.29-2.20(m,1H),2.07-1.95(m,2H),1.78(d,J＝7.0Hz,3H),1.36-1.32(m,1H),1.24(d,J＝6.2Hz,6H),0.71-0.68(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z523.3[M+H-HCl] ⁺.

embodiment 92: compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-carbamoylpyrrolidin-3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate (550mg, 0.84mmol) is dissolved in THF (8mL) and H ₂in the mixed solvent of O (4mL), add a hydronium(ion) Lithium Oxide 98min (177mg again, 4.21mmol), 45 DEG C of reaction 1.5h, add HCl (1M) and the pH value of solution is adjusted to about 1, with ethyl acetate (10mL × 3) extraction, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 538mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.74-7.72(m,1H),7.68-7.60(m,1H),7.26(d,J＝8.3Hz,1H),6.89(t,J _F-H＝75.0Hz,1H),5.51-5.45(m,1H),5.34-5.29(m,1H),4.37-4.25(m,1H),4.02(d,J＝6.8Hz,2H),3.98-3.93(m,1H),3.76-3.73(m,1H),3.67(s,3H),2.45-2.28(m,2H),1.52(d,J＝7.0Hz,3H),1.43(s,9H),1.36-1.34(m,1H),0.71-0.66(m,2H),0.45-0.42(m,2H)；

MS-ESI:m/z639.7[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-5-formamyl-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (220mg, 0.34mmol), ammonium chloride (55mg, 1.03mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (99mg, 0.52mmol) with N-hydroxyl-7-azepine benzotriazole (117mg, 0.86mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.36mL, 2.07mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=20/1), obtains 123mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.5Hz,1H),7.55(s,1H),7.24(d,J＝8.5Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.35-5.23(m,2H),5.06-4.99(m,1H),4.82-4.80(m,1H),4.45-4.34(m,1H),3.98(d,J＝6.9Hz,2H),3.66(s,3H),2.66-2.61(m,1H),2.23-2.15(m,1H),1.55(d,J＝6.6Hz,3H),1.40(s,9H),1.33-1.31(m,1H),0.69-0.66(m,2H),0.42-0.40(m,2H).

Step 3: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-carbamoylpyrrolidin-3-base) Urethylane hydrochloride

To compound ((3R; 5S)-5-formamyl-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (117mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.18mmol); 4mL); stirring at room temperature 1h; except desolventizing; obtain 105mg white solid, yield: 99%.

¹HNMR(600MHz,d ₆-DMSO):δppm7.76(s,1H),7.66(d,J＝8.1Hz,1H),7.37(d,J＝8.5Hz,1H),7.10(t,J _F-H＝63.4Hz,1H),5.24-5.23,5.00-4.99(m,m,0.5H,0.5H),5.10-5.08,4.53-4.50(m,m,0.5H,0.5H),4.21-4.20(m,1H),4.10-4.07(m,1H),4.03(d,J＝6.5Hz,2H),4.00-3.96(m,1H),3.56-3.53(m,3H),2.28-2.14(m,2H),1.62-1.61(m,3H),1.29-1.26(m,1H),0.62-0.61(m,2H),0.42-0.40(m,2H)；

MS-ESI:m/z538.8[M+H-HCl] ⁺.

embodiment 93: compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(cyclopropylcarbamoyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound ((3R, 5S)-5-(cyclopropylcarbamoyl)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (220mg, 0.34mmol), cyclopropylamine (0.04mL, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (99mg, 0.52mmol) with N-hydroxyl-7-azepine benzotriazole (117mg, 0.86mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.24mL, 1.38mmol), stirring at room temperature 8h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=40/1), obtains 130mg white solid, yield: 55%.

¹HNMR(400MHz,CDCl ₃):δppm7.61-7.52(m,2H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.35-5.23(m,2H),4.76-4.73(m,1H),4.40-4.35(m,1H),4.05-4.02(m,1H),3.98(d,J＝7.0Hz,2H),3.66(s,3H),2.72-2.66(m,2H),2.23-2.15(m,1H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.33-1.31(m,1H),0.77-0.73(m,2H),0.69-0.66(m,2H),0.54-0.46(m,2H),0.42-0.40(m,2H)；

MS-ESI:m/z678.8[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(cyclopropylcarbamoyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((3R; 5S)-5-(cyclopropylcarbamoyl)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (128mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.19mmol); 4mL); stirring at room temperature 1.5h; except desolventizing; obtain 116mg white solid, yield: 100%.

¹HNMR(400MHz,CD ₃OD):δppm7.75-7.69(m,2H),7.33(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.41-5.37,4.62-4.58(m,m,0.5H,0.5H),5.16-5.10(m,1H),4.39-4.37(m,1H),4.27-4.22(m,1H),4.16-4.11,4.02-3.97(m,m,0.5H,0.5H),4.09-4.04(m,2H),3.67-3.65(m,3H),2.74-2.71,2.56-2.52(m,m,0.5H,0.5H),2.47-2.42,2.20-2.15(m,m,0.5H,0.5H),2.34-2.25(m,1H),1.78(d,J＝6.9Hz,3H),1.36-1.32(m,1H),0.77-0.75(m,1H),0.72-0.69(m,2H),0.64-0.57(m,2H),0.48-0.44(m,2H),0.41-0.37,0.29-0.25(m,m,0.5H,0.5H)；

MS-ESI:m/z578.8[M+H-HCl] ⁺.

embodiment 94: compound ((S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines -3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (S)-piperidines-3-ylcarbamic acid methyl ester hydrochloride

Under room temperature condition, to N ' N-carbonyl dimidazoles (2.5g, triethylamine (1.4mL is dripped in anhydrous THF (5mL) solution 15.0mmol), 9.99mmol), stirring at room temperature, slow dropping methyl alcohol (0.61mL, 15.0mmol), room temperature reaction 30min, drip (S)-1-Boc-3-amino piperidine (1.0g, anhydrous THF (10mL) solution 4.99mmol), 75 DEG C of reaction 5h, add dilute hydrochloric acid solution (1M) and the pH value of solution is adjusted to about 1, ethyl acetate (15mL × 2) extracts, organic phase saturated sodium bicarbonate solution (10mL × 2) washs, anhydrous Na is used after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=4/1), obtain 1.07g colorless oil: (S)-3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δppm4.77(br.s,1H),3.66(s,3H),3.58-3.55(m,1H),3.36-3.32(m,1H),3.28-3.24(m,1H),1.84-1.81(m,1H),1.65-1.61(m,1H),1.56-1.48(m,2H),1.45(s,9H)；

MS-ESI:m/z159.2[M-100+H] ⁺.

To compound (S)-3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate (1.04g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 4.04mmol), 6mL), stirring at room temperature 3h, except desolventizing, obtain 711mg white solid: (S)-piperidines-3-ylcarbamic acid methyl ester hydrochloride, yield: 90%.

¹HNMR(400MHz,CD ₃OD):δppm3.81-3.75(m,1H),3.67(s,3H),3.43-3.39(m,1H),3.30-3.28(m,1H),2.99-2.93(m,1H),2.89-2.84(m,1H),2.04-1.99(m,2H),1.85-1.75(m,1H),1.64-1.56(m,1H)；

MS-ESI:m/z159.3[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), (S)-piperidines-3-ylcarbamic acid methyl ester hydrochloride (156mg, 0.80mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (154mg, 0.80mmol) with N-hydroxyl-7-azepine benzotriazole (182mg, 1.33mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 9h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 302mg white solid, yield: 92%.

¹HNMR(400MHz,CDCl ₃):δppm7.64-7.55(m,2H),7.22(d,J＝8.2Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.21-5.17(m,1H),4.09-3.97(m,2H),3.98(d,J＝7.1Hz,2H),3.85-3.76(m,2H),3.70-3.68(m,1H),3.64(s,3H),1.83-1.77(m,2H),1.66-1.64(m,1H),1.55(d,J＝7.0Hz,3H),1.42(s,9H),1.34-1.31(m,1H),0.70-0.65(m,2H),0.42-0.39(m,2H)；

MS-ESI:m/z609.8[M+H] ⁺.

Step 3: the synthesis of compound ((S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane hydrochloride

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane (298mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.49mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 266mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.70(m,2H),7.33-7.31(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.04-5.01(m,1H),4.60-4.49(m,1H),4.15-4.11(m,1H),4.07-4.04(m,2H),3.77-3.75(m,1H),3.67-3.59(m,4H),3.49-3.45(m,1H),2.05-2.03(m,1H),1.93-1.90(m,1H),1.78(d,J＝7.0Hz,3H),1.71-1.63(m,2H),1.36-1.33(m,1H),0.70-0.67(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z509.3[M+H-HCl] ⁺.

embodiment 95: compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carboxvlate hvdrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-ethyl formate

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (200mg, 0.31mmol), ethanol (0.03mL, 0.47mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (90mg, 0.47mmol) with N-hydroxyl-7-azepine benzotriazole (107mg, 0.78mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.22mL, 1.25mmol), stirring at room temperature 16h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 111mg colorless viscous thing, yield: 53%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.53(s,1H),7.24-7.20(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.27-5.21(m,1H),4.38-4.28(m,1H),4.26-4.18(m,2H),4.15-4.09(m,2H),3.99-3.97(m,2H),3.68(s,3H),2.47-2.26(m,2H),1.52(d,J＝7.1Hz,3H),1.42(s,9H),1.35-1.32(m,1H),1.26(t,J＝7.2Hz,3H),0.71-0.67(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z667.7[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carboxvlate hvdrochloride

To compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-ethyl formate (107mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.16mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 96mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.76-7.73(m,1H),7.66(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.54-5.51,4.77-4.73(m,m,0.5H,0.5H),5.18-5.11(m,1H),4.41-4.35(m,1H),4.29-4.22(m,2H),4.18-4.11(m,1H),4.05(d,J＝6.9Hz,2H),4.00-3.95(m,1H),3.75-3.70(m,1H),3.67(s,3H),2.47-2.45(m,1H),1.78-1.76(m,3H),1.39-1.35(m,1H),1.33-1.27(m,3H),0.72-0.69(m,2H),0.46-0.42(m,2H).

embodiment 96: compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (230mg, 0.36mmol), ethylene glycol monomethyl ether (36mg, 0.47mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (104mg, 0.54mmol) with N-hydroxyl-7-azepine benzotriazole (123mg, 0.90mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.25mL, 1.44mmol), stirring at room temperature 7h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 63mg colorless viscous thing, yield: 25%.

¹HNMR(400MHz,CDCl ₃):δppm7.60-7.53(m,1H),7.52(s,1H),7.24-7.20(m,1H),6.70(t,J _F-H＝75.1Hz,1H),5.35-5.31(m,1H),5.28-5.22(m,1H),4.76-4.73(m,1H),4.36-4.26(m,2H),4.23-4.19(m,1H),4.02-3.97(m,2H),3.69(s,3H),3.65-3.60(m,1H),3.51-3.49(m,1H),3.39,3.25(s,s,1.5H,1.5H),2.50-2.45(m,1H),2.30-2.25(m,1H),1.52(d,J＝7.1Hz,3H),1.42(s,9H),1.31-1.28(m,1H),0.70-0.67(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z697.7[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

To compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester (61mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.09mmol), 3mL), stirring at room temperature 1.5h, except desolventizing, obtain 50mg white solid, yield: 90%.

¹HNMR(600MHz,CD ₃OD):δppm7.76-7.74(m,1H),7.72(s,1H),7.35-7.31(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.58-5.56(m,1H),5.19-5.16(m,1H),4.37-4.34(m,1H),4.32-4.27(m,2H),4.21-4.17(m,1H),4.09-4.04(m,2H),4.00-3.97(m,1H),3.73-3.70(m,1H),3.67-3.66(m,3H),3.52-3.51(m,1H),3.40,3.21(s,s,1H,2H),2.50-2.48(m,1H),2.36-2.29(m,1H),1.78-1.76(m,3H),1.37-1.34(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z597.8[M+H-HCl] ⁺.

embodiment 97: compound (S)-(1-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-4- base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound piperidine-4-ylcarbamic acid methyl ester hydrochloride

Under room temperature condition, to N ' N-carbonyl dimidazoles (2.50g, triethylamine (1.40mL is dripped in anhydrous THF (5mL) solution 15.0mmol), 10.0mmol), stirring at room temperature, slow dropping methyl alcohol (0.61mL, 15.0mmol), room temperature reaction 30min, add 1-Boc-4-amino piperidine (1.00g, anhydrous THF (10mL) solution 4.99mmol), 75 DEG C of reaction 16h, add dilute hydrochloric acid solution (1M) and the pH value of solution is adjusted to about 1, ethyl acetate (15mL × 2) extracts, organic phase saturated sodium bicarbonate solution (10mL × 2) washs, anhydrous Na is used after merging organic phase ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 819mg colorless oil: 4-(methoxycarbonylamin) piperidines-1-t-butyl formate, yield: 63%.

¹HNMR(400MHz,CDCl ₃):δppm4.59(br.s,1H),4.02-3.95(m,2H),3.66(s,3H),3.65-3.61(m,1H),2.88-2.82(m,2H),1.92-1.89(m,2H),1.44(s,9H),1.31-1.27(m,2H)；

MS-ESI:m/z159.3[M+H-100] ⁺.

To compound 4-(methoxycarbonylamin) piperidines-1-t-butyl formate (809mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 3.13mmol), 5mL), stirring at room temperature 2.5h, except desolventizing, obtain 545mg white solid: piperidin-4-yl Urethylane hydrochloride, yield: 89%.

¹HNMR(600MHz,CD ₃OD):δppm3.73-3.69(m,1H),3.66(s,3H),3.43-3.39(m,2H),3.11(td,J ₁＝12.9Hz,J ₂＝3.1Hz,2H),2.13-2.10(m,2H),1.76-1.69(m,2H)；

MS-ESI:m/z159.2[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-(1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidin-4-yl) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (220mg, 0.47mmol), piperidin-4-yl Urethylane hydrochloride (119mg, 0.61mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (135mg, 0.70mmol) with N-hydroxyl-7-azepine benzotriazole (160mg, 1.17mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.33mL, 1.88mmol), stirring at room temperature 17h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 246mg white solid, yield: 86%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.23-5.16(m,1H),4.65-4.59(m,1H),4.54-4.50(m,2H),3.96(d,J＝6.9Hz,2H),3.83-3.76(m,1H),3.68(s,3H),3.34-3.25(m,1H),2.10-1.99(m,2H),1.53(d,J＝7.0Hz,3H),1.51-1.45(m,2H),1.42(s,9H),1.33-1.29(m,1H),0.70-0.66(m,2H),0.42-0.38(m,2H)；

MS-ESI:m/z609.8[M+H] ⁺.

Step 3: the synthesis of compound (S)-(1-(5-(1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidin-4-yl) Urethylane hydrochloride

To compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-(1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl) piperidin-4-yl) Urethylane (240mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 0.39mmol), 4mL), stirring at room temperature 2.5h, except desolventizing, obtain 214mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.73(s,1H),7.71(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.04-4.99(m,1H),4.82-4.79(m,1H),4.53-4.51(m,1H),4.03(d,J＝6.9Hz,2H),3.78-3.73(m,1H),3.66(s,3H),3.47-3.41(m,1H),3.11-3.07(m,1H),2.05-2.03(m,2H),1.77(d,J＝7.0Hz,3H),1.65-1.61(m,1H),1.55-1.51(m,1H),1.36-1.33(m,1H),0.71-0.68(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z509.3[M+H-HCl] ⁺.

embodiment 98: compound (S)-2-((2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide) synthesis of-3 Methylbutanoic acid hydrochloride

Step 1: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide)-3 Methylbutanoic acid methyl esters

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), (S)-2-amino-3 Methylbutanoic acid methyl esters (85mg, 0.51mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (113mg, 0.59mmol) with N-hydroxyl-7-azepine benzotriazole (133mg, 0.98mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.27mL, 1.57mmol), stirring at room temperature 16h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=40/1), obtains 225mg white solid, yield: 76%.

¹HNMR(400MHz,CDCl ₃):δppm7.58-7.51(m,2H),7.24-7.20(m,1H),6.70(t,J _F-H＝75.0Hz,1H),5.34-5.26(m,1H),5.01-4.96(m,1H),4.88-4.85,4.24-4.20(m,m,0.5H,0.5H),4.53-4.46(m,2H),4.03-3.97(m,2H),3.75,3.44(s,s,2H,1H),3.67(s,3H),2.72-2.61(m,1H),2.20-2.16(m,1H),1.55-1.51(m,3H),1.43-1.41(m,9H),1.35-1.31(m,1H),0.94-0.91(m,3H),0.90-0.85(m,3H),0.71-0.66(m,2H),0.44-0.39(m,2H)；

MS-ESI:m/z752.4[M+H] ⁺.

Step 2: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide)-3 Methylbutanoic acid

By compound (S)-2-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide)-3 Methylbutanoic acid methyl esters (217mg, 0.29mmol) is dissolved in THF (8mL) and H ₂in the mixed solvent of O (4mL), add a hydronium(ion) Lithium Oxide 98min (61mg, 1.44mmol), 45 DEG C of reaction 1h, add HCl (1M) and the pH value of solution are adjusted to about 1, extract by ethyl acetate (10mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 212mg white solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.5Hz,1H),7.54-7.51(m,1H),7.25-7.18(m,1H),6.70(t,J _F-H＝75.1Hz,1H),5.29-5.25(m,1H),4.87-4.81(m,1H),4.55-4.40(m,3H),4.33-4.16(m,2H),3.98(d,J＝6.9Hz,2H),3.67(s,3H),2.63-2.55(m,1H),2.26-2.20(m,1H),1.55-1.50(m,3H),1.43-1.41(m,9H),1.33-1.31(m,1H),0.87(d,J＝1.5Hz,1H),0.85(s,3H),0.71-0.66(m,2H),0.43-0.39(m,2H)；

MS-ESI:m/z738.4[M+H] ⁺.

Step 3: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide)-3 Methylbutanoic acid hydrochloride

To compound (S)-2-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-methane amide)-3 Methylbutanoic acid (212mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.29mmol), 3mL), stirring at room temperature 1.5h, except desolventizing, obtain 170mg white solid, yield: 87%.

¹HNMR(600MHz,CD ₃OD):δppm7.76-7.69(m,2H),7.34-7.30(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.69-5.67,4.20-4.18(m,m,0.5H,0.5H),5.13-5.09(m,1H),4.40-4.36(m,2H),4.27-4.23(m,1H),4.07-4.04(m,3H),3.67-3.66(m,3H),2.60-2.53(m,1H),2.43-2.41,2.36-2.33(m,m,0.5H,0.5H),2.28-2.24(m,1H),1.76(d,J＝6.8Hz,3H),1.37-1.34(m,1H),1.06-1.04(m,3H),0.77-0.75(m,2H),0.71-0.69(m,3H),0.46-0.43(m,2H)；

MS-ESI:m/z638.8[M+H-HCl] ⁺.

embodiment 99: compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (220mg, 0.34mmol), morpholine (36mg, 0.41mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (99mg, 0.52mmol) with N-hydroxyl-7-azepine benzotriazole (117mg, 0.86mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.24mL, 1.38mmol), stirring at room temperature 17h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=50/1), obtains 228mg faint yellow solid, yield: 93%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.53(d,J＝1.7Hz,1H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝74.9Hz,1H),5.25-5.21(m,1H),5.09-5.06(m,1H),4.52-4.48(m,1H),4.37-4.27(m,2H),3.97(d,J＝7.1Hz,2H),3.90-3.86(m,1H),3.80-3.74(m,2H),3.67(s,3H),3.70-3.62(m,3H),3.56-3.49(m,2H),2.35-2.24(m,2H),1.54-1.49(m,3H),1.43-1.39(m,9H),1.33-1.31(m,1H),0.71-0.66(m,2H),0.43-0.40(m,2H)；

MS-ESI:m/z708.7[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(morpholine-4-carbonyl) pyrrolidin-3-yl) Urethylane (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.31mmol), 3mL), stirring at room temperature 3h, except desolventizing, obtain 188mg white solid, yield: 93%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(d,J＝1.6Hz,1H),7.73(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.21-5.19,4.43-4.24(m,m,0.5H,2.5H),5.16-5.08(m,1H),4.06-4.03(m,2H),3.99-3.95,3.86-3.83(m,m,0.5H,0.5H),3.79-3.75(m,1H),3.74-3.70(m,2H),3.68-3.63(m,3H),3.66(s,3H),3.57-3.50,3.21-3.17(m,m,1.5H,0.5H),2.57-2.53,2.20-2.11(m,m,0.5H,0.5H),2.38-2.29(m,1H),1.77(d,J＝7.0Hz,3H),1.38-1.34(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z608.8[M+H-HCl] ⁺.

embodiment 101: compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid-(2-hydroxyethyl) ester hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid-(2-hydroxyethyl) ester

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), ethylene glycol (1.0mL, 19.6mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (113mg, 0.59mmol) with N-hydroxyl-7-azepine benzotriazole (133mg, 0.98mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.24mL, 1.37mmol), stirring at room temperature 17h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=40/1), obtains 187mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.59-7.51(m,2H),7.23(t,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.30-5.24(m,1H),5.05-4.90(m,1H),4.50-4.42(m,2H),4.35-4.23(m,2H),3.99(t,J＝6.3Hz,2H),3.90-3.76(m,3H),3.68(s,3H),2.48-2.30(m,2H),1.55-1.50(m,3H),1.42(s,9H),1.35-1.32(m,1H),0.71-0.67(m,2H),0.43-0.40(m,2H)；

MS-ESI:m/z683.4[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid-(2-hydroxyethyl) ester hydrochloride

To compound (2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-formic acid-(2-hydroxyethyl) ester (182mg, aqueous isopropanol (the 7M of HCl is added in methylene dichloride (4mL) solution 0.27mmol), 4mL), stirring at room temperature 2.5h, except desolventizing, obtain 160mg white solid, after preparing purifying, process obtains 10mg faint yellow solid, yield: 6%.

¹HNMR(600MHz,CD ₃OD):δppm7.75-7.71(m,1H),7.65(d,J＝8.2Hz,1H),7.31(t,J＝9.1Hz,1H),6.91(t,J _F-H＝74.8Hz,1H),5.52-5.50(m,1H),4.78-4.75(m,1H),4.65-4.56(m,1H),4.27-4.20(m,3H),4.12-4.08(m,1H),4.06-4.02(m,2H),4.00-3.97(m,1H),3.80-3.77(m,1H),3.67(s,3H),2.49-2.46(m,1H),2.36-2.29(m,1H),1.65-1.63(m,3H),1.36-1.33(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z583.7[M+H-HCl] ⁺.

embodiment 102: compound 1-((S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrole cough up alkane-2-carbonyl) synthesis of piperidines-4-carboxylic acid hydrochloride

Step 1: the synthesis of compound (S)-1-(tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate hydrochloride

By compd B oc-L-proline(Pro) (500mg, 2.32mmol), 4-piperidine methyl formate (499mg, 3.48mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (1.11g, 5.81mmol) with N-hydroxyl-7-azepine benzotriazole (474mg, 3.48mmol) be dissolved in methylene dichloride (16mL), under 0 DEG C of condition, in this solution, drip DIPEA (1.6mL, 9.29mmol), stirring at room temperature 12h, adds water (10mL × 2) and washes, dilute hydrochloric acid (1M, 10mL × 2) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtain 605mg colorless oil: (S)-1-(1-tertbutyloxycarbonyl tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate, yield: 76%.

¹HNMR(400MHz,CDCl ₃):δppm4.70-4.65,4.55-4.52(m,m,0.5H,0.5H),4.48-4.31(m,1H),3.92-3.80(m,1H),3.68(s,3H),3.59-3.38(m,2H),3.23-3.04(m,1H),2.91-2.75(m,1H),2.59-2.52(m,1H),2.17-2.08(m,1H),1.98-1.92(m,3H),1.87-1.80(m,2H),1.68-1.60(m,1H),1.45-1.38(m,9H)；

MS-ESI:m/z241.1[M+H-100] ⁺.

To compound (S)-1-(1-tertbutyloxycarbonyl tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate (595mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 1.75mmol), 6mL), stirring at room temperature 2h, except desolventizing, obtain 483mg colorless oil: (S)-1-(tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.74-4.66(m,1H),4.37-4.29(m,1H),3.89-3.83(m,1H),3.71(s,3H),3.47-3.35(m,2H),3.31-3.24(m,1H),3.06-2.95(m,1H),2.77-2.69(m,1H),2.58-2.49(m,1H),2.17-2.01(m,3H),1.98-1.89(m,2H),1.76-1.58(m,2H)；

MS-ESI:m/z241.1[M+H-HCl] ⁺.

Step 2: the synthesis of compound 1-((S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), (S)-1-(tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate hydrochloride (192mg, 0.69mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (205mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (109mg, 0.80mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.37mL, 2.14mmol), stirring at room temperature 12h, add water (10mL × 2) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1, methylene chloride/methanol (v/v)=20/1), obtains 243mg faint yellow solid, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.54(d,J＝1.7Hz,1H),7.22(d,J＝8.2Hz,1H),6.69(t,J _F-H＝75.2Hz,1H),5.67-5.58(m,1H),5.23-5.19(m,1H),5.07-5.03(m,1H),4.51-4.41(m,1H),4.25-4.19(m,1H),3.96(d,J＝6.9Hz,2H),3.94-3.88(m,2H),3.82-3.77(m,1H),3.71(s,3H),3.00-2.85(m,1H),2.60-2.48(m,1H),2.36-2.31(m,1H),2.21-2.07(m,2H),2.00-1.90(m,4H),1.51(d,J＝7.0Hz,3H),1.43(s,9H),1.33-1.31(m,1H),0.69-0.66(m,2H),0.43-0.40(m,2H)；

MS-ESI:m/z691.8[M+H] ⁺.

Step 3: the synthesis of compound 1-((S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carbonyl) piperidines-4-formic acid

Compound 1-((S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate (241mg, 0.35mmol) is dissolved in THF (8mL) and H ₂in the mixed solvent of O (4mL), add a hydronium(ion) Lithium Oxide 98min (73mg again, 1.74mmol), at 45 DEG C of reaction 1h, add HCl (1M) and the pH value of solution is adjusted to about 1, with ethyl acetate (10mL × 3) extraction, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 236mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.71(s,1H),7.67(d,J＝8.4Hz,1H),7.30-7.27(m,1H),6.90(t,J _F-H＝74.8Hz,1H),5.67-5.60(m,1H),5.41-5.31(m,1H),4.43-4.33(m,1H),4.15-4.07(m,2H),4.03(d,J＝6.7Hz,2H),3.87-3.79(m,2H),3.03-2.96(m,1H),2.83-2.77(m,1H),2.67-2.54(m,1H),2.47-2.41(m,1H),2.00-1.89(m,3H),1.53-1.51(m,3H),1.44(s,9H),1.37-1.35(m,1H),0.71-0.66(m,2H),0.44-0.41(m,2H)；

MS-ESI:m/z677.7[M+H] ⁺.

Step 4: the synthesis of compound 1-((S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carbonyl) piperidines-4-carboxylic acid hydrochloride

To compound 1-((S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-carbonyl) piperidines-4-formic acid (218mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.32mmol), 5mL), stirring at room temperature 1.5h, except desolventizing, obtain 197mg faint yellow solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(s,1H),7.72(d,J＝8.3Hz,1H),7.34-7.30(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.97-5.93(m,1H),5.13-5.04(m,2H),4.41-4.27(m,2H),4.19-4.13(m,1H),4.06-4.01(m,1H),4.04(d,J＝6.6Hz,2H),3.83-3.77(m,1H),2.71-2.65(m,1H),2.57-2.53(m,1H),2.41-2.35(m,1H),2.13-2.07(m,2H),1.94-1.90(m,2H),1.77(d,J＝6.7Hz,3H),1.70-1.57(m,2H),1.36-1.34(m,1H),0.71-0.67(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z577.8[M+H-HCl] ⁺.

embodiment 103: compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(4-methylpiperazine-1-carbonyl) pyrrolidin-3-yl) synthesis of Urethylane dihydrochloride

Step 1: the synthesis of compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(4-methylpiperazine-1-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (200mg, 0.31mmol) and N, N '-carbonyl dimidazoles (79mg, 0.47mmol) be dissolved in anhydrous tetrahydro furan (12mL), 60 DEG C of reaction 50min, drip 1-methylpiperazine (0.09mL, 0.78mmol), 60 DEG C of reaction 12h, add water (10mL × 3) wash, ethyl acetate (15mL) extracts, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=10/1), obtains 166mg white solid, yield: 73%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.53(s,1H),7.23(d,J＝8.5Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.25-5.18(m,1H),5.11-5.08(m,1H),4.50-4.45(m,1H),4.35-4.24(m,2H),3.96(t,J＝6.6Hz,2H),3.69-3.60(m,2H),3.68(s,3H),2.66-2.61(m,1H),2.52-2.48(m,1H),2.40-2.36(m,1H),2.33(s,3H),2.24-2.20(m,2H),1.54-1.49(m,3H),1.43(s,9H),1.33-1.30(m,1H),0.71-0.67(m,2H),0.43-0.41(m,2H)；

MS-ESI:m/z721.7[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(4-methylpiperazine-1-carbonyl) pyrrolidin-3-yl) Urethylane dihydrochloride

To compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(4-methylpiperazine-1-carbonyl) pyrrolidin-3-yl) Urethylane (162mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.22mmol), 4mL), stirring at room temperature 2.5h, except desolventizing, obtain 155mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.77(s,1H),7.73(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.33(d,J＝8.3Hz,1H),6.93(t,J _F-H＝74.8Hz,1H),5.28-5.24(m,1H),5.17-5.11(m,1H),4.40-4.34(m,3H),4.28-4.26(m,1H),4.05(d,J＝6.9Hz,2H),3.99-3.95(m,1H),3.79-3.76(m,1H),3.67(s,3H),3.53-3.44(m,2H),3.24-3.15(m,1H),3.00(s,3H),2.86-2.80(m,1H),2.60-2.55(m,1H),2.39-2.35(m,1H),2.24-2.21(m,1H),1.78(d,J＝6.8Hz,3H),1.37-1.33(m,1H),0.71-0.68(m,2H),0.46-0.44(m,2H)；

MS-ESI:m/z621.8[M+H-2HCl] ⁺.

embodiment 104: compound 4-((2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) synthesis of morpholine-2-carboxylic acid hydrochloride

Step 1: the synthesis of compound 4-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-methyl-formiate

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (350mg, 0.55mmol), morpholine-2-methyl-formiate hydrochloride (129mg, 0.71mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (263mg, 1.37mmol) with N-hydroxyl-7-azepine benzotriazole (112mg, 0.82mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.38mL, 2.19mmol), stirring at room temperature 12.5h, add saturated nacl aqueous solution (10mL × 3) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=50/1), obtains 320mg white solid, yield: 76%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.53(s,1H),7.24-7.21(m,1H),6.70(t,J _F-H＝75.1Hz,1H),5.25-5.21(m,1H),5.16-5.08(m,1H),4.55-4.49(m,1H),4.35-4.29(m,2H),3.97(d,J＝6.9Hz,2H),4.05-3.94(m,2H),3.87-3.84(m,2H),3.79-3.73(m,2H),3.68(s,3H),3.61-3.55(m,1H),3.45-3.42,3.15-3.09(m,m,0.5H,0.5H),2.26-2.21(m,1H),1.54-1.48(m,3H),1.43(s,9H),1.34-1.31(m,1H),0.71-0.66(m,2H),0.43-0.40(m,2H)；

MS-ESI:m/z766.4[M+H] ⁺.

Step 2: the synthesis of compound 4-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-formic acid

By compound 4-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-methyl-formiate (210mg, 0.28mmol) is dissolved in THF (10mL) and H ₂in the mixed solvent of O (5mL), add a hydronium(ion) Lithium Oxide 98min (60mg, 1.42mmol), 55 DEG C of reaction 2h, add HCl (1M) and the pH value of solution are adjusted to about 1, extract by ethyl acetate (10mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 185mg white solid, yield: 89%.

¹HNMR(400MHz,CD ₃OD):δppm7.72(s,1H),7.68-7.64(m,1H),7.29(d,J＝8.3Hz,1H),6.89(t,J _F-H＝74.9Hz,1H),5.40-5.35(m,1H),4.38-4.34(m,1H),4.27-4.21(m,2H),4.05-4.01(m,3H),3.97-3.89(m,2H),3.79-3.73(m,2H),3.67-3.65(m,3H),1.52-1.50(m,3H),1.43(s,9H),1.35-1.33(m,1H),0.69-0.67(m,2H),0.45-0.43(m,2H)；

MS-ESI:m/z752.4[M+H] ⁺.

Step 3: the synthesis of compound 4-((2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-carboxylic acid hydrochloride

To compound 4-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-formic acid (180mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.24mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 164mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.72(d,J＝8.3Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.12-5.07(m,1H),4.47-4.12(m,6H),4.05(d,J＝6.9Hz,2H),4.01-3.86(m,2H),3.80-3.76(m,1H),3.68-3.66(m,3H),3.58-3.50(m,1H),3.25-3.21(m,1H),2.38-2.30(m,1H),2.21-2.15(m,1H),1.78-1.77(m,3H),1.36-1.34(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z652.4[M+H-HCl] ⁺.

embodiment 105: compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(4-hydroxy piperidine-1-carbonyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(4-hydroxy piperidine-1-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (280mg, 0.44mmol), 4-hydroxyl piperidine hydrochloric acid salt (78mg, 0.57mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (210mg, 1.10mmol) with N-hydroxyl-7-azepine benzotriazole (90mg, 0.66mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under room temperature condition, N-diisopropylethylamine (0.31mL, 1.75mmol), stirring at room temperature 15h, add saturated nacl aqueous solution (10mL × 3) to wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=20/1), obtains 247mg white solid, yield: 78%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.53(s,1H),7.23(d,J＝8.4Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.16-5.11(m,1H),4.50-4.46(m,1H),4.37-4.32(m,1H),4.27-4.21(m,1H),3.97(d,J＝6.9Hz,2H),3.95-3.94(m,2H),3.67(s,3H),3.34-3.26(m,1H),2.27-2.20(m,2H),1.95-1.85(m,2H),1.54-1.49(m,3H),1.43(s,9H),1.33-1.29(m,1H),0.71-0.66(m,2H),0.43-0.38(m,2H)；

MS-ESI:m/z722.2[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(4-hydroxy piperidine-1-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((3R, 5S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-(t-butoxycarbonyl amino) ethyl) oxazole-4-carbonyl)-5-(4-hydroxy piperidine-1-carbonyl) pyrrolidin-3-yl) Urethylane (120mg, aqueous isopropanol (the 7M of HCl is added in methylene dichloride (4mL) solution 0.16mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 105mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.72(d,J＝8.3Hz,1H),7.33(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.26-5.23(m,1H),5.15-5.08(m,1H),4.45-4.24(m,3H),4.05(d,J＝6.8Hz,2H),4.03-4.01(m,1H),3.95-3.92(m,2H),3.82-3.77(m,1H),3.67-3.65(m,3H),3.57-3.50(m,1H),2.35-2.27,1.95-1.90(m,m,1.5H,1.5H),2.15-2.09(m,1H),1.77(d,J＝5.6Hz,3H),1.73-1.67(m,1H),1.36-1.33(m,1H),0.71-0.68(m,2H),0.46-0.44(m,2H)；

MS-ESI:m/z622.2[M+H-HCl] ⁺.

embodiment 106: compound (S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrroles the synthesis of alkane-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

Step 1: the synthesis of compound (S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester

By compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (146mg, 0.26mmol), ethylene glycol monomethyl ether (0.20mL, 2.58mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (99mg, 0.52mmol) with N-hydroxyl-7-azepine benzotriazole (53mg, 0.39mmol) be dissolved in methylene dichloride (16mL), in this solution, N is dripped under room temperature condition, N-diisopropylethylamine (0.18mL, 1.03mmol), stirring at room temperature 4h, add water (15mL) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 50mg colorless viscous thing, yield: 31%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.8Hz,1H),7.53(s,1H),7.23-7.20(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.34-5.24(m,2H),4.35-4.20(m,2H),4.00-3.96(m,2H),3.91-3.86(m,1H),3.78-3.73(m,1H),3.65-3.60(m,1H),3.53-3.50(m,1H),3.39,3.27(s,s,1H,2H),2.34-2.25(m,2H),2.02-1.93(m,2H),1.53-1.50(m,3H),1.43(s,9H),1.33-1.29(m,1H),0.70-0.66(m,2H),0.43-0.40(m,2H)；

MS-ESI:m/z624.2[M+H] ⁺.

Step 2: the synthesis of compound (S)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

To compound (S)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester (50mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.08mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 44mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.76-7.73(m,1H),7.67(dd,J ₁＝8.4Hz,J ₂＝1.8Hz,1H),7.34-7.31(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.47-5.45(m,1H),4.35-4.25(m,2H),4.21-4.17(m,1H),4.08-4.03(m,2H),3.86-3.83(m,1H),3.80-3.77(m,1H),3.67-3.65(m,1H),3.53-3.52(m,1H),3.39,3.22(s,s,1H,2H),2.49-2.44(m,1H),2.32-2.29(m,1H),2.15-2.01(m,2H),1.78-1.76(m,3H),1.37-1.35(m,1H),0.71-0.69(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z524.2[M+H-HCl] ⁺.

embodiment 107: compound (5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((S)-2-(morpholine-4- carbonyl) pyrrolidin-1-yl) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-2-(morpholine-4-carbonyl) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetramethyleneimine-2-formic acid (145mg, 0.25mmol), morpholine (0.03mL, 0.38mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (74mg, 0.38mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (12mL), in this solution, N is dripped under 20 DEG C of conditions, N-diisopropylethylamine (0.18mL, 1.03mmol), stirring at room temperature 15h, add saturated nacl aqueous solution (15mL × 2) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/3,0/1), obtains 119mg colorless viscous thing, yield: 73%.

¹HNMR(400MHz,CDCl ₃):δppm7.59(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.54(d,J＝1.7Hz,1H),7.25-7.21(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.24-5.20(m,1H),5.03-5.00(m,1H),4.26-4.20(m,1H),3.97-3.95(m,2H),3.91-3.74(m,3H),3.71-3.66(m,3H),3.61-3.53(m,3H),2.40-2.30(m,1H),2.21-2.16(m,1H),2.00-1.94(m,2H),1.54-1.50(m,3H),1.43(s,9H),1.34-1.31(m,1H),0.69-0.66(m,2H),0.42-0.39(m,2H)；

MS-ESI:m/z635.2[M+H] ⁺.

Step 2: the synthesis of compound (5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) ((S)-2-(morpholine-4-carbonyl) pyrrolidin-1-yl) methanone hvdrochloric acid salt

To compound ((S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-((S)-2-(morpholine-4-carbonyl) tetramethyleneimine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (117mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.18mmol), 4mL), stirring at room temperature 2.5h, except desolventizing, obtain 100mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.75(d,J＝1.8Hz,1H),7.73(dd,J ₁＝8.3Hz,J ₂＝1.9Hz,1H),7.38-7.33(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.15-5.09(m,1H),4.40-4.37,4.20-4.16(m,m,0.5H,0.5H),4.07-4.02(m,2H),3.86-3.79(m,2H),3.76-3.59(m,6H),3.56-3.54(m,1H),3.23-3.18(m,1H),2.57-2.54,2.39-2.35(m,m,0.5H,0.5H),2.15-2.08,1.99-1.93(m,m,1.5H,1.5H),1.77(d,J＝7.0Hz,3H),1.36-1.34(m,1H),0.71-0.68(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z535.3[M+H-HCl] ⁺.

embodiment 108: compound 4-((2S, 4R)-1-(5-((S)-1-aminoethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) synthesis of morpholine-2-methyl-formiate hydrochloride

To compound 4-((2S, 4R)-1-(5-((S)-1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(methoxycarbonylamin) tetramethyleneimine-2-carbonyl) morpholine-2-methyl-formiate (100mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.13mmol), 4mL), stirring at room temperature 1.5h, except desolventizing, obtain 91mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.76(s,1H),7.73(d,J＝8.4Hz,1H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.27-5.09(m,2H),4.40-4.27(m,3H),4.22-4.13(m,1H),4.05(d,J＝6.9Hz,2H),3.99-3.94(m,1H),3.87-3.78(m,3H),3.68-3.66(m,3H),3.61-3.55(m,1H),2.37-2.32(m,1H),2.26-2.12(m,1H),1.77(d,J＝6.9Hz,3H),1.35-1.33(m,1H),0.72-0.67(m,2H),0.46-0.43(m,2H)；

MS-ESI:m/z666.4[M+H-HCl] ⁺.

embodiment 109: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(ring third first acyl group)-homopiperazine-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound cyclopropyl (homopiperazine-1-base) methanone hvdrochloric acid salt

By compound ethylene-acetic acid (257mg, 3.0mmol), compound 1,4-homopiperazine-1-t-butyl formate (500mg, 2.5mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (957mg, 5.0mmol) with N-hydroxyl-7-azepine benzotriazole (680mg, 5.0mmol) be dissolved in methylene dichloride (15mL), under 0 DEG C of condition, in this solution, drip DIPEA (1.3mL, 7.49mmol), stirring at room temperature 10h, add water (10mL × 3) are washed, organic phase anhydrous Na ₂sO ₄dry; except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 660mg colourless liquid: 4-(cyclopropane carbonyl)-1; 4-phenodiazine suberane-1-t-butyl formate, yield: 98%.

¹HNMR(400MHz,CDCl ₃):δppm3.71-3.78(m,1H),3.61-3.67(m,2H),3.52-3.60(m,2H),3.43-3.47(m,2H),3.34-3.42(m,1H),1.92-2.00(m,1H),1.72-1.83(m,2H),1.47(s,9H),0.95-1.02(m,2H),0.75-0.79(m,2H)；

MS-ESI:m/z213.10[M-55] ⁺.

By compound 4-(cyclopropane carbonyl)-1; 4-phenodiazine suberane-1-t-butyl formate (210mg; 0.78mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M, 4mL) of HCl, stirring at room temperature 30min; except desolventizing; obtain 158mg colourless liquid: cyclopropyl (homopiperazine-1-base) methanone hvdrochloric acid salt, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm4.08-4.11(m,1H),3.91-3.95(m,1H),3.84-3.87(m,1H),3.70-3.73(m,1H),3.45-3.48(m,1H),3.29-3.39(m,3H),2.20-2.26(m,1H),2.07-2.13(m,1H),1.95-2.01(m,1H),0.87-0.95(m,4H)；

MS-ESI:m/z169.30[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(cyclopropane carbonyl)-homopiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound cyclopropyl (1, 4-phenodiazine suberane-1-base) methanone hvdrochloric acid salt (157mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 238mg white solid, yield: 60%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.57(m,2H),7.23(d,J＝8.2Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.18-5.26(m,1H),3.96(d,J＝6.9Hz,2H),3.69-3.97(m,8H),2.01-2.17(m,2H),1.71-1.79(m,1H),1.51-1.54(m,3H),1.42(s,9H),1.28-1.36(m,1H),0.97-1.04(m,2H),0.76-0.83(m,2H),0.65-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z619.80[M+H] ⁺.

Step 3: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (4-(cyclopropane carbonyl)-homopiperazine-1-base) methanone hvdrochloric acid salt

By compound (S)-(1-(4-(4-(cyclopropane carbonyl)-1; 4-phenodiazine suberane-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (221mg; 0.36mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 192mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.70-7.76(m,2H),7.32(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),4.98-5.06(m,1H),4.10-4.21(m,2H),4.05(t,J＝6.2Hz,2H),4.00-4.05(m,1H),3.78-3.89(m,4H),3.64-3.72(m,1H),2.06-2.10(m,1H),1.97-2.04(m,2H),1.79(d,J＝4.2Hz,3H),1.31-1.37(m,1H),0.81-0.90(m,4H),0.66-0.70(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z519.30[M+H-HCl] ⁺.

embodiment 110: compound (S)-1-(4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-Isosorbide-5-Nitrae- phenodiazine suberane-1-base) synthesis of-2-methylpropane-1-keto hydrochloride

Step 1: the synthesis of compound 1-(homopiperazine-1-base)-2-methylpropane-1-keto hydrochloride

By compound isopropylformic acid (158mg, 1.8mmol), compound 1, 4-homopiperazine-1-t-butyl formate (300mg, 1.5mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (574mg, 3.0mmol) with N-hydroxyl-7-azepine benzotriazole (305mg, 2.25mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.76mL, 4.49mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtain 313mg colourless liquid: 4-isobutyryl-1, 4-phenodiazine suberane-1-t-butyl formate, yield: 71%.

¹HNMR(400MHz,CDCl ₃):δppm3.32-3.65(m,8H),2.73-2.81(m,1H),1.77-1.90(m,2H),1.45-1.47(m,9H),1.12-1.15(m,6H)；

MS-ESI:m/z215.10[M-55] ⁺.

By compound 4-isobutyryl-1; 4-phenodiazine suberane-1-t-butyl formate (300mg; 1.1mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M, 4mL) of HCl, stirring at room temperature 30min; except desolventizing; obtain 219mg colourless liquid: 1-(homopiperazine-1-base)-2-methylpropane-1-keto hydrochloride, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm3.70-3.83(m,2H),3.58-3.66(m,2H),3.17-3.25(m,4H),2.81-2.88(m,1H),1.95-2.10(m,2H),1.03(d,J＝6.7Hz,6H)；

MS-ESI:m/z171.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-isobutyryl-homopiperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound 1-(1, 4-phenodiazine suberane-1-base)-2-methylpropane-1-keto hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 258mg white solid, yield: 65%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.58(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.18-5.25(m,1H),3.97(d,J＝6.9Hz,2H),3.87-4.03(m,2H),3.54-3.85(m,6H),2.77-2.84(m,1H),1.96-2.08(m,2H),1.51-1.55(m,3H),1.41(s,9H),1.27-1.35(m,1H),1.12-1.16(m,6H),0.65-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z621.35[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(4-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-homopiperazine-1-base)-2-methylpropane-1-keto hydrochloride

By compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(4-isobutyryl-1; 4-phenodiazine suberane-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (248mg; 0.39mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 221mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.69-7.77(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.00-5.08(m,1H),4.21-4.29(m,1H),4.09-4.17(m,1H),4.03-4.06(m,2H),3.91-4.00(m,1H),3.74-3.90(m,4H),3.66-3.72(m,1H),2.95-3.05(m,1H),1.92-2.05(m,2H),1.77(d,J＝6.6Hz,3H),1.31-1.38(m,1H),1.08-1.13(m,6H),0.67-0.71(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z521.30[M+H-HCl] ⁺.

embodiment 111: compound N-((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of cyclopropyl carboxamide hydrochloride

Step 1: the synthesis of compound (S)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-t-butyl formate

By ethylene-acetic acid (210mg, 2.42mmol), (S)-3-amino-pyrrolidine-1-t-butyl formate (300mg, 1.61mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (621mg, 3.22mmol) with N-hydroxyl-7-azepine benzotriazole (328mg, 2.42mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.8mL, 4.83mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 215mg colourless liquid, yield: 52%.

¹HNMR(400MHz,CDCl ₃):δppm5.81(br.s,1H),4.43-4.50(m,1H),3.59-3.62(m,1H),3.37-3.47(m,2H),3.13-3.25(m,1H),2.09-2.18(m,1H),1.77-1.89(m,1H),1.46(s,9H),1.29-1.35(m,1H),0.94-0.98(m,2H),0.71-0.76(m,2H)；

MS-ESI:m/z199.20[M-55] ⁺.

Step 2: the synthesis of compound (S)-N-(pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride

By compound (S)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-t-butyl formate (205mg, 0.86mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 151mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm4.34-4.40(m,1H),3.43-3.49(m,2H),3.29-3.36(m,1H),3.16-3.20(m,1H),2.23-2.32(m,1H),1.98-2.06(m,1H),1.55-1.62(m,1H),0.78-0.84(m,2H),0.72-0.77(m,2H)；

MS-ESI:m/z155.15[M+H-HCl] ⁺.

Step 3: the synthesis of compound ((S)-1-(4-((S)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (S)-N-(pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride (145mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 186mg white solid, yield: 48%.

¹HNMR(400MHz,CDCl ₃):δppm7.51-7.58(m,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.96-6.03(m,1H),5.25-5.30(m,1H),4.57-4.66(m,1H),4.12-4.19(m,1H),3.99-4.07(m,1H),3.96(d,J＝6.9Hz,2H),3.71-3.82(m,2H),2.17-2.27(m,1H),1.89-2.02(m,1H),1.55(t,J＝7.3Hz,3H),1.41(s,9H),1.29-1.35(m,1H),0.94-1.00(m,2H),0.71-0.78(m,2H),0.66-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z605.80[M+H] ⁺.

Step 4: the synthesis of compound N-((S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride

By compound ((S)-1-(4-((S)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (180mg, 0.30mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 146mg white solid, yield: 82%.

¹HNMR(600MHz,CD ₃OD):δppm7.74-7.78(m,2H),7.35-7.37(m,1H),6.95(t,J _F-H＝75.0Hz,1H),5.12-5.18(m,1H),4.45-4.51(m,1H),4.35-4.41(m,1H),4.23-4.29,4.10-4.15(m,0.5H,0.5H),4.08(d,J＝6.9Hz,2H),3.85-3.95(m,1H),3.77-3.82,3.62-3.67(m,0.5H,0.5H),2.25-2.36(m,1H),2.02-2.14(m,1H),1.83(d,J＝6.8Hz,3H),1.65-1.70(m,1H),1.36-1.41(m,1H),0.89-0.94(m,2H),0.80-0.84(m,2H),0.71-0.74(m,2H),0.46-0.49(m,2H)；

MS-ESI:m/z505.30[M+H-HCl] ⁺.

embodiment 112: compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of cyclopropyl carboxamide hydrochloride

Step 1: the synthesis of compound (R)-N-(pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride

By ethylene-acetic acid (210mg, 2.42mmol), (R)-3-amino-pyrrolidine-1-t-butyl formate (300mg, 1.61mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (621mg, 3.22mmol) with N-hydroxyl-7-azepine benzotriazole (328mg, 2.42mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.8mL, 4.83mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtain 215mg colourless liquid: (R)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-t-butyl formate, yield: 52%.

MS-ESI:m/z199.20[M-55] ⁺.

By compound (R)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-t-butyl formate (205mg, 0.86mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 151mg white solid: (R)-N-(pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride, yield: 98%.

MS-ESI:m/z155.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (R)-N-(pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride (145mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 186mg white solid, yield: 48%.

MS-ESI:m/z605.80[M+H] ⁺.

Step 3: the synthesis of compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) cyclopropyl carboxamide hydrochloride

By compound ((S)-1-(4-((R)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (180mg, 0.30mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 146mg white solid, yield: 82%.

MS-ESI:m/z505.30[M+H-HCl] ⁺.

embodiment 113: compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N- the synthesis of cyclopropa pyrrolidine-2-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride

By N-Boc-L-proline(Pro) (500mg, 2.32mmol), cyclopropylamine (160mg, 2.79mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (890mg, 4.65mmol) with N-hydroxyl-7-azepine benzotriazole (475mg, 3.48mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.2mL, 6.97mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1); obtain 494mg white solid: (S)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-t-butyl formate, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δppm4.13-4.26(m,1H),3.32-3.48(m,2H),2.68-2.75(m,1H),2.11-2.37(m,2H),1.81-1.96(m,2H),1.47(s,9H),0.73-0.81(m,2H),0.44-0.51(m,2H)；

MS-ESI:m/z155.25[M+H-100] ⁺.

By compound (S)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-t-butyl formate (485mg; 1.91mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing, obtain 360mg white solid: (S)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm4.25(t,J＝7.8Hz,1H),3.38-3.48(m,2H),2.76-2.80(m,1H),2.43-2.49(m,1H),2.08-2.13(m,2H),1.99-2.05(m,1H),0.79-0.85(m,2H),0.57-0.63(m,2H)；

MS-ESI:m/z155.15[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((S)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), (S)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride (146mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 186mg white solid, yield: 48%.

¹HNMR(400MHz,CDCl ₃):δppm7.60-7.68(m,1H),7.54-7.56(m,1H),7.23-7.26(m,1H),6.72(t,J _F-H＝75.1Hz,1H),5.21-5.39(m,1H),4.95-4.97,4.69-4.71(m,0.5H,0.5H),4.08-4.11,3.86-3.93(m,0.5H,0.5H),3.98-4.06(m,2H),3.72-3.84(m,1H),2.69-2.76(m,1H),2.34-2.44(m,1H),2.17-2.25,2.06-2.13(m,0.5H,0.5H),1.88-2.03(m,2H),1.54-1.58(m,3H),1.44(s,9H),1.33-1.38(m,1H),0.65-0.79(m,4H),0.51-0.61(m,1H),0.34-0.67(m,3H)；

MS-ESI:m/z605.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride

By compound ((S)-1-(4-((S)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (180mg; 0.30mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 146mg white solid, yield: 82%.

¹HNMR(600MHz,CD ₃OD):δppm7.69-7.75(m,2H),7.32-7.34(m,1H),6.92(t,J _F-H＝75.0Hz,1H),5.27-5.29,4.49-4.52(m,0.5H,0.5H),5.09-5.15(m,1H),4.27-4.32,3.82-3.86(m,0.5H,0.5H),4.27-4.31,3.74-3.78(m,0.5H,0.5H),4.04-4.09(m,2H),2.70-2.74,2.53-2.57(m,0.5H,0.5H),2.39-2.45,2.25-2.31(m,0.5H,0.5H),1.91-2.05(m,2H),1.76-1.78(m,3H),1.33-1.38(m,1H),0.68-0.71(m,2H),0.53-0.66(m,2H),0.43-0.47(m,2H),0.27-0.40(m,2H)；

MS-ESI:m/z505.90[M+H-HCl] ⁺.

embodiment 114: compound (R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrole cough up the synthesis of alkane-3-cyclopropyl carbamate hydrochloride

Step 1: the synthesis of compound (R)-pyrrolidin-3-yl cyclopropyl carbamate hydrochloride

By triethylamine (0.34mL, 2.41mmol) and N, N '-carbonyl dimidazoles (CDI) (315mg, 1.93mmol) be dissolved in anhydrous THF (5mL), room temperature adds compound (R)-3-hydroxyl pyrrolidine-1-t-butyl formate (300mg, 1.60mmol), reaction 20min, add compound cyclopropylamine (0.6mL, 8.01mmol), stop after 50 DEG C of reaction 10h, except desolventizing THF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 325mg white solid: (R)-3-((cyclopropylcarbamoyl) oxygen base) tetramethyleneimine-1-t-butyl formate, yield: 75%.

¹HNMR(400MHz,CDCl ₃):δppm5.21(s,1H),4.80-4.95(m,1H),3.32-3.53(m,4H),2.52-2.60(m,1H),1.97-2.06(m,2H),1.45(s,9H),0.65-0.74(m,2H),0.46-0.55(m,2H)；

MS-ESI:m/z215.20[M-55] ⁺.

By compound (R)-3-((cyclopropylcarbamoyl) oxygen base) tetramethyleneimine-1-t-butyl formate (300mg; 1.11mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing, obtain 216mg white solid: (R)-pyrrolidin-3-yl cyclopropyl carbamate hydrochloride, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm5.31(s,1H),3.39-3.50(m,4H),2.51-2.55(m,1H),2.18-2.28(m,2H),0.68-0.71(m,2H),0.49-0.51(m,2H)；

MS-ESI:m/z171.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound (R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl cyclopropyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-pyrrolidin-3-yl cyclopropyl carbamate hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.3mmol) with N-hydroxyl-7-azepine benzotriazole (174mg, 1.3mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.56mmol), stirring at room temperature 6h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 235mg white solid, yield: 59%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(d,J＝8.3Hz,1H),7.53(s,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.30-5.38(m,1H),5.22-5.30(m,1H),4.88-4.99(m,1H),4.23-4.34(m,1H),4.06-4.17(m,1H),3.95-3.98(m,2H),3.71-3.88(m,2H),2.53-2.61(m,1H),2.10-2.18(m,2H),1.54(d,J＝7.0Hz,3H),1.42(s,9H),1.29-1.37(m,1H),0.66-0.73(m,4H),0.49-0.55(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z621.80[M+H] ⁺.

Step 3: the synthesis of compound (R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl cyclopropyl carbamate hydrochloride

By compound (R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl cyclopropyl carbamate (220mg, 0.35mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 191mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.23-7.76(m,2H),7.34(d,J＝8.3Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.30-5.35(m,1H),5.12-5.16(m,1H),4.41-4.43(m,1H),4.17-4.30(m,1H),4.05-4.07(m,2H),3.72-3.91(m,2H),2.52-2.58(m,1H),2.19-2.28(m,1H),1.80(d,J＝6.9Hz,3H),1.34-1.39(m,1H),0.68-0.72(m,4H),0.46-0.51(m,4H)；

MS-ESI:m/z521.80[M+H-HCl] ⁺.

embodiment 115: compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-2-methylpiperazine-1-yl) synthesis of butane-1-keto hydrochloride

Step 1: the synthesis of compound (R)-1-(2-methylpiperazine-1-yl) butane-1-keto hydrochloride

By compound (R)-3-methylpiperazine-1-t-butyl formate (300mg, 1.5mmol), butanic acid (200mg, 2.3mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (595mg, 3.0mmol) with N-hydroxyl-7-azepine benzotriazole (306mg, 2.3mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.76mL, 4.5mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry; except desolventizing; concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 370mg colourless liquid: (R)-4-butyryl radicals-3-methylpiperazine-1-t-butyl formate, yield: 91%.

¹HNMR(600MHz,CDCl ₃):δppm4.74-4.81,4.34-4.41(m,0.5H,0.5H),3.80-4.12,3.53-3.60(m,2.5H,0.5H),3.26-3.35,2.75-2.98(m,0.5H,2.5H),2.26-2.35(m,2H),1.61-1.69(m,2H),1.47(s,9H),1.13-1.24(m,3H),1.12(t,J＝7.3Hz,3H)；

MS-ESI:m/z215.10[M-55] ⁺.

By compound (R)-4-butyryl radicals-3-methylpiperazine-1-t-butyl formate (360mg; 1.33mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 50min; except desolventizing, obtain 269mg light yellow liquid: (R)-1-(2-methylpiperazine-1-yl) butane-1-keto hydrochloride, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm4.88-5.02,4.49-4.67(m,0.5H,0.5H),4.01-4.14,3.49-3.64(m,0.5H,0.5H),3.34-3.41(m,2H),3.09-3.24(m,2H),2.38-2.49(m,2H),1.62-1.68(m,2H),1.30-1.45(m,3H),1.00(d,J＝7.4Hz,3H)；

MS-ESI:m/z171.30[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-4-butyryl radicals-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), compound (R)-1-(2-methylpiperazine-1-yl) butane-1-keto hydrochloride (158mg, 0.77mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.44mL, 2.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 275mg white solid, yield: 69%.

¹HNMR(600MHz,CDCl ₃):δppm7.56-7.58(m,1H),7.53(s,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.21-5.28(m,1H),4.93-5.00,4.68-4.76(m,0.5H,0.5H),4.81-4.87,4.46-4.55(m,0.5H,0.5H),4.59-4.62(m,1H),3.96(d,J＝6.6Hz,2H),3.64-3.71(m,1H),3.36-3.49(m,1H),3.16-3.28(m,1H),2.93-3.07(m,1H),2.30-2.40(m,2H),1.64-1.71(m,2H),1.53-1.55(m,3H),1.40-1.42(m,9H),1.29-1.35(m,1H),1.16-1.26(m,3H),0.98(t,J＝7.3Hz,3H),0.67-0.70(m,2H),0.38-0.41(m,2H)；

MS-ESI:m/z621.20[M+H] ⁺.

Step 3: the synthesis of compound 1-((R)-4-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-yl) butane-1-keto hydrochloride

To compound ((S)-1-(4-((R)-4-butyryl radicals-3-methylpiperazine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (265mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.43mmol); 4mL); stirring at room temperature 50min; except desolventizing; obtain 226mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.76(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.01-5.10(m,2H),4.88-4.97,3.89-3.98(m,0.5H,0.5H),4.40-4.57(m,2H),4.05(d,J＝6.2Hz,2H),3.45-3.60(m,1H),3.07-3.19(m,1H),2.42-2.53(m,2H),1.80(s,3H),1.64-1.71(m,2H),1.21-1.39(m,4H),1.01(t,J＝7.1Hz,3H),0.67-0.70(m,2H),0.42-0.47(m,2H)；

MS-ESI:m/z521.30[M+H-HCl] ⁺.

embodiment 116: compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrole cough up alkane-3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride

By triethylamine (162mg, 1.61mmol) and N, N '-carbonyl dimidazoles (CDI) (208mg, 1.28mmol) be dissolved in dry DMF (5mL), add compound (R)-3-amino-pyrrolidine-1-t-butyl formate (200mg, 1.07mmol), stirring at room temperature 30min, add anhydrous methanol (5mL), stop after 60 DEG C of reaction 24h, removing solvent DMF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 230mg colourless liquid: (R)-3-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate, yield: 87%.

¹HNMR(400MHz,CDCl ₃):δppm4.79(br.s,1H),4.18-4.24(m,1H),3.67(s,3H),3.57-3.62(m,1H),3.34-3.44(m,2H),3.12-3.24(m,1H),2.08-2.15(m,1H),1.76-1.86(m,1H),1.45(m,9H)；

MS-ESI:m/z189.10[M-55] ⁺.

To compound (R)-3-((methoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate (220mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.90mmol), 2mL), stirring at room temperature 30min, except desolventizing, obtain 160mg sticky solid: (R)-3-methoxycarbonylamin pyrrolidine hydrochloride, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm4.26-4.31(m,1H),3.69(s,3H),3.44-3.52(m,2H),3.36-3.42(m,1H),3.24-3.32(m,1H),2.27-2.36(m,1H),2.01-2.10(m,1H)；

MS-ESI:m/z145.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (400mg, 0.854mmol), compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride (200mg, 1.11mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (327mg, 1.71mmol) with N-hydroxyl-7-azepine benzotriazole (232mg, 1.71mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.60mL, 3.42mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 250mg white solid, yield: 49%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.22-5.30(m,1H),4.86-4.94,4.16-4.22(m,0.5H,0.5H),4.29-4.39(m,1H),3.93-4.07(m,1H),3.95-3.97(m,2H),3.69-3.82(m,2H),3.68(s,3H),2.17-2.28(m,1H),1.87-2.04(m,1H),1.51-1.55(m,3H),1.42(s,9H),1.28-1.35(m,1H),0.65-0.71(m,2H),0.38-0.43(m,2H)；

MS-ESI:m/z595.30[M+H] ⁺.

Step 3: the synthesis of compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (240mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.40mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 210mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.75(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.11-5.15(m,1H),4.33-4.37,4.08-4.14(m,0.5H,0.5H),4.19-4.30(m,2H),4.03-4.05(m,2H),3.71-3.90(m,1H),3.68(s,3H),2.21-2.31(m,1H),1.98-2.09(m,1H),1.80(d,J＝6.8Hz,3H),1.32-1.37(m,1H),0.68-0.71(m,2H),0.38-0.46(m,2H)；

MS-ESI:m/z495.30[M+H-HCl] ⁺.

embodiment 117: compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of isobutyramide hydrochloride

Step 1: the synthesis of compound (R)-N-(pyrrolidin-3-yl) isobutyramide hydrochloride

By isopropylformic acid (212mg, 2.42mmol), (R)-3-amino-pyrrolidine-1-t-butyl formate (300mg, 1.61mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (617mg, 3.22mmol) with N-hydroxyl-7-azepine benzotriazole (328mg, 2.42mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.8mL, 4.83mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 358mg white solid: (R)-3-isobutyl amide tetramethyleneimine-1-t-butyl formate, yield: 86%.

¹HNMR(400MHz,CDCl ₃):δppm5.62(br.s,1H),4.40-4.46(m,1H),3.58-3.62(m,1H),3.35-3.45(m,2H),3.10-3.16(m,1H),2.26-2.36(m,1H),2.07-2.17(m,1H),1.74-1.83(m,1H),1.45(s,9H),1.13(d,J＝6.9Hz,6H)；

MS-ESI:m/z201.12[M-55] ⁺.

To compound (R)-3-isobutyl amide tetramethyleneimine-1-t-butyl formate (160mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.63mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 110mg colourless liquid: (R)-N-(pyrrolidin-3-yl) isobutyramide hydrochloride, yield: 92%.

¹HNMR(400MHz,CD ₃OD):δppm4.30-4.36(m,1H),3.39-3.47(m,2H),3.24-3.32(m,1H),3.11-3.17(m,1H),2.38-2.45(m,1H),2.20-2.29(m,1H),1.93-2.01(m,1H),1.04(d,J＝6.9Hz,6H)；

MS-ESI:m/z157.20[M+H-HCl] ⁺.

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), (R)-N-(pyrrolidin-3-yl) isobutyramide hydrochloride (100mg, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (161mg, 0.85mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.30mL, 1.71mmol), stirring at room temperature 4h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 112mg white solid, yield: 43%.

¹HNMR(400MHz,CDCl ₃):δppm7.55-7.59(m,1H),7.51-7.54(m,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝74.8Hz,1H),5.22-5.30(m,1H),4.55-4.62(m,1H),4.17-4.22,4.04-4.09(m,0.5H,0.5H),3.92-4.02(m,1H),3.96(d,J＝6.9Hz,2H),3.73-3.83(m,2H),2.31-2.39(m,1H),2.18-2.28(m,1H),1.86-2.01(m,1H),1.53-1.56(m,3H),1.42(s,9H),1.29-1.35(m,1H),1.12-1.18(m,6H),0.66-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z607.80[M+H] ⁺.

Step 3: the synthesis of compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) isobutyramide hydrochloride

To compound ((S)-1-(4-((R)-3-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (100mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.16mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 88mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.70-7.74(m,2H),7.33-7.35(m,1H),6.92(t,J _F-H＝75.0Hz,1H),5.09-5.15(m,1H),4.40-4.45(m,1H),4.31-4.39(m,1H),4.19-4.25,4.06-4.10(m,0.5H,0.5H),4.04(d,J＝6.9Hz,2H),3.91-3.94,3.80-3.85(m,0.5H,0.5H),3.73-3.48,3.55-3.58(m,0.5H,0.5H),2.47-2.53(m,1H),2.21-2.34(m,1H),1.96-2.10(m,1H),1.79(d,J＝6.9Hz,3H),1.33-1.37(m,1H),1.11-1.35(m,6H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z507.90[M+H-HCl] ⁺.

embodiment 118: compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (3-fluorine nitrogen heterocyclic butane-1-base) synthesis of methanone hvdrochloric acid salt

Step 1: the synthesis of compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-fluorine azetidine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), 3-fluorine azetidine (57mg, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (163mg, 0.85mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.30mL, 1.71mmol), stirring at room temperature 5h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 156mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.51-7.58(m,2H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.43-5.50,5.29-5.34(m,0.5H,0.5H),5.25-5.34(m,1H),4.93-5.08(m,1H),4.73-4.87(m,1H),4.42-4.52(m,1H),4.25-4.35(m,1H),3.97(d,J＝6.9Hz,2H),3.74-3.81(m,6H),1.50-1.53(m,3H),1.43(s,9H),1.30-1.36(m,1H),0.67-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z526.30[M+H] ⁺.

Step 2: the synthesis of compound (S)-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-base) (3-fluorine azetidine-1-base) methanone hvdrochloric acid salt

By compound (S)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-fluorine azetidine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (150mg, 0.29mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 126mg white solid, yield: 96%.

¹HNMR(600MHz,CD ₃OD):δppm7.72-7.74(m,1H),7.71(dd,J ₁＝8.3Hz,J ₂＝1.7Hz,1H),7.34(d,J＝8.2Hz,1H),6.93(t,J _F-H＝74.8Hz,1H),5.52-5.55,5.42-5.46(m,0.5H,0.5H),5.10-5.20(m,2H),4.80-4.83(m,1H),4.51-4.58(m,1H),4.24-4.30(m,1H),4.05(d,J＝7.0Hz,2H),3.80(s,6H),1.79(d,J＝7.0Hz,3H),1.33-1.37(m,1H),0.69-0.72(m,2H),0.44-0.47(m,2H)；

MS-ESI:m/z426.20[M+H-HCl] ⁺.

embodiment 119: compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of propionamide hydrochloride

Step 1: the synthesis of compound (R)-N-(pyrrolidin-3-yl) propionamide hydrochloride

By propionic acid (240mg, 3.22mmol), (R)-3-amino-pyrrolidine-1-t-butyl formate (300mg, 1.61mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (617mg, 3.22mmol) with N-hydroxyl-7-azepine benzotriazole (328mg, 2.42mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.8mL, 4.83mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 360mg white solid: (R)-3-propionamido-tetramethyleneimine-1-t-butyl formate, yield: 92%.

¹HNMR(400MHz,CDCl ₃):δppm5.65(s,1H),4.41-4.48(m,1H),3.58-3.62(m,1H),3.34-3.45(m,2H),3.10-3.20(m,1H),2.19(q,J＝7.6Hz,2H),2.08-2.16(m,1H),1.73-1.85(m,1H),1.45(s,9H),1.14(t,J＝7.6Hz,3H)；

MS-ESI:m/z187.25[M-55] ⁺.

By compound (R)-3-propionamido-tetramethyleneimine-1-t-butyl formate (150mg, 0.62mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 30min, except desolventizing, obtain 103mg sticky solid: (R)-N-(pyrrolidin-3-yl) propionamide hydrochloride, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm4.25-4.31(m,1H),3.33-3.40(m,2H),3.20-3.27(m,1H),3.08-3.12(m,1H),2.14-2.23(m,1H),2.12(q,J＝7.6Hz,2H),1.90-1.96(m,1H),1.14(t,J＝7.6Hz,3H)；

MS-ESI:m/z143.25[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((R)-3-propionamido-tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), (R)-N-(pyrrolidin-3-yl) propionamide hydrochloride (91mg, 0.52mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (165mg, 0.86mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.30mL, 1.71mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: ethyl acetate), obtains 175mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.57(d,J＝8.3Hz,1H),7.51(d,J＝4.1Hz,1H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.22-5.30(m,1H),4.56-4.64(m,1H),4.02-4.20(m,1H),3.91-4.00(m,1H),3.96(d,J＝6.9Hz,2H),3.65-3.80(m,2H),2.22(q,J＝7.6Hz,2H),2.19-2.29(m,1H),1.87-2.02(m,1H),1.54(t,J＝7.3Hz,3H),1.42(s,9H),1.16(t,J＝7.6Hz,3H),0.66-0.71(m,2H),0.38-0.43(m,2H)；

MS-ESI:m/z593.80[M+H] ⁺.

Step 3: the synthesis of compound N-((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) propionamide hydrochloride

By compound ((S)-1-(4-((R)-3-propionamido-tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (170mg, 0.29mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 150mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.70-7.74(m,2H),7.32-7.34(m,1H),6.92(t,J _F-H＝75.1Hz,1H),5.09-5.15(m,1H),4.39-4.46(m,1H),4.30-4.38(m,1H),4.19-4.24,4.05-4.10(m,0.5H,0.5H),4.04(d,J＝6.9Hz,2H),3.73-3.83(m,1H),3.89-3.93,3.56-3.59(m,0.5H,0.5H),2.25(q,J＝7.6Hz,2H),2.21-2.33(m,1H),1.96-2.10(m,1H),1.80(d,J＝6.8Hz,3H),1.14(t,J＝7.6Hz,3H),1.33-1.37(m,1H),0.68-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z493.10[M+H-HCl] ⁺.

embodiment 120: compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of urethane ester hydrochloride

Step 1: the synthesis of compound (R)-3-ethoxycarbonylamino pyrrolidine hydrochloride

By triethylamine (0.75mL, 5.37mmol) and N, N '-carbonyl dimidazoles (CDI) (2.2g, 13.42mmol) be dissolved in anhydrous THF (5mL), add compound (R)-3-amino-pyrrolidine-1-t-butyl formate (500mg, 2.69mmol), stirring at room temperature 30min, add dehydrated alcohol (5mL), stopped reaction after 70 DEG C of reaction 24h, except desolventizing THF, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 420mg colourless liquid: (R)-3-((ethoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate, yield: 60%.

¹HNMR(400MHz,CDCl ₃):δppm4.86(br.s,1H),4.18-4.27(m,1H),4.13(q,J＝6.7Hz,2H),3.59-3.63(m,1H),3.37-3.47(m,2H),3.14-3.24(m,1H),2.09-2.18(m,1H),1.78-1.88(m,1H),1.46(m,9H),1.25(t,J＝7.0Hz,3H)；

MS-ESI:m/z203.20[M-55] ⁺.

By compound (R)-3-((ethoxycarbonyl) is amino) tetramethyleneimine-1-t-butyl formate (200mg, 0.77mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain the light brown liquid of 153mg: (R)-3-ethoxycarbonylamino pyrrolidine hydrochloride, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm4.19-4.25(m,1H),4.05(q,J＝6.7Hz,2H),3.38-3.45(m,2H),3.30-3.36(m,1H),3.19-3.24(m,1H),2.20-2.29(m,1H),1.96-2.15(m,1H),1.20(t,J＝7.0Hz,3H)；

MS-ESI:m/z159.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) urethanum

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), compound (R)-3-ethoxycarbonylamino pyrrolidine hydrochloride (125mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (204mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.8mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.36mL, 2.14mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 142mg white solid, yield: 44%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.27-5.30(m,1H),4.29-4.30(m,1H),4.07-4.23(m,3H),3.94-4.00(m,1H),3.99(d,J＝6.8Hz,2H),3.64-3.82(m,2H),2.17-2.28(m,1H),1.87-2.00(m,1H),1.43-1.55(m,3H),1.42(s,9H),1.28-1.35(m,1H),1.25(t,J＝6.7Hz,3H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z609.30[M+H] ⁺.

Step 3: the synthesis of compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) urethane ester hydrochloride

By compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) urethanum (135mg, 0.22mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 2h, except desolventizing, obtain 118mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.75(m,2H),7.34(d,J＝8.2Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.09-5.14(m,1H),4.33-4.36,4.08-4.14(m,0.5H,0.5H),4.19-4.31(m,2H),4.08-4.15(m,2H),4.03-4.05(m,2H),3.87-3.91,3.77-3.83(m,0.5H,0.5H),3.71-3.76,3.59-3.61(m,0.5H,0.5H),2.19-2.32(m,1H),1.95-2.10(m,1H),1.80(d,J＝6.8Hz,3H),1.33-1.37(m,1H),1.25(t,J＝7.1Hz,3H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z509.10[M+H-HCl] ⁺.

embodiment 121: compound (S)-N-(1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) nitrogen azetidine-3-base) synthesis of cyclopropyl carboxamide hydrochloride

Step 1: the synthesis of compound N-(azetidine-3-base) cyclopropyl carboxamide hydrochloride

By ethylene-acetic acid (224mg, 2.61mmol), 3-aminoazetidine-1-t-butyl formate (300mg, 1.74mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (667mg, 3.48mmol) with N-hydroxyl-7-azepine benzotriazole (355mg, 2.61mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.9mL, 5.23mmol), stirring at room temperature 6h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 386mg white solid: 3-(cyclopropyl carboxamide base) azetidine-1-t-butyl formate, yield: 92%.

¹HNMR(400MHz,CDCl ₃):δppm6.20(s,1H),4.61-4.69(m,1H),4.21-4.26(m,2H),3.72-3.77(m,2H),1.43(s,9H),1.34-1.40(m,1H),0.95-0.98(m,2H),0.73-0.79(m,2H)；

MS-ESI:m/z241.10[M+H] ⁺.

By compound 3-(cyclopropyl carboxamide base) azetidine-1-t-butyl formate (180mg, 0.75mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, obtain 129mg colourless liquid: N-(azetidine-3-base) cyclopropyl carboxamide hydrochloride, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm5.08-5.13,4.66-4.71(m,0.5H,0.5H),3.33-3.47(m,1H),4.23-4.30(m,1H),4.14-4.18(m,1H),3.34-3.40(m,1H),1.47-1.53(m,1H),0.98-1.01(m,1H),0.80-0.88(m,3H)；

MS-ESI:m/z141.10[M+H] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(3-(cyclopropyl carboxamide base) azetidine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (250mg, 0.53mmol), N-(azetidine-3-base) cyclopropyl carboxamide hydrochloride (112mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (205mg, 1.07mmol) with N-hydroxyl-7-azepine benzotriazole (110mg, 0.80mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.36mL, 2.14mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: dichloromethane/ethyl acetate (v/v)=2/1), obtains 175mg white solid, yield: 56%.

¹HNMR(400MHz,CDCl ₃):δppm7.57-7.60(m,1H),7.24(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.24-5.29(m,1H),4.28-4.32(m,2H),3.96-4.01(m,1H),3.98(d,J＝6.8Hz,2H),3.55-3.66(m,2H),1.52(d,J＝7.0Hz,2H),1.43(s,9H),1.29-1.35(m,2H),0.95-1.00(m,2H),0.85-0.90(m,2H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z591.30[M+H] ⁺.

Step 3: the synthesis of compound (S)-N-(1-(5-(1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) azetidine-3-base) cyclopropyl carboxamide hydrochloride

By compound (S)-(1-(4-(3-(cyclopropyl carboxamide base) azetidine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (170mg, 0.29mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 2h, except desolventizing, obtain 149mg white solid, yield: 22%.

¹HNMR(600MHz,CD ₃OD):δppm7.69-7.71(m,2H),7.35(d,J＝8.3Hz,1H),6.92(t,J _F-H＝75.0Hz,1H),5.07-5.17(m,2H),4.64-4.70(m,2H),4.49-4.52(m,1H),4.09-4.12(m,1H),4.03(d,J＝6.9Hz,2H),1.77(d,J＝6.8Hz,3H),1.62-1.66(m,1H),1.33-1.37(m,1H),0.89-0.92(m,2H),0.81-0.84(m,2H),0.67-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z491.90[M+H-HCl] ⁺.

embodiment 122: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-carboxamide hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-formic acid

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate (600mg, 0.91mmol) be dissolved in the mixed solvent of THF (10mL) and water (5mL), add a hydronium(ion) Lithium Oxide 98min (190mg again, 4.53mmol), stop after 45 DEG C of reaction 30min, enriching hydrochloric acid conditioning solution pH=1, extract by ethyl acetate (10mL × 3), after merging organic phase, with anhydrous sodium sulfate drying, concentrated, obtain 580mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.72-7.75(m,1H),7.61-7.69(m,1H),7.27(d,J＝8.5Hz,1H),6.89(t,J _F-H＝75.0Hz,1H),5.45-5.51(m,1H),5.29-5.38(m,1H),4.50-4.60(m,1H),4.02(d,J＝6.9Hz,2H),3.95-4.04(m,1H),3.67-3.76(m,1H),2.31-2.49(m,2H),1.58-1.64(m,1H),1.51-1.55(m,3H),1.43(s,9H),1.33-1.39(m,1H),0.87-0.92(m,2H),0.76-0.82(m,2H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z649.30[M+H] ⁺.

Step 2: the synthesis of compound ((S)-1-(4-((2S, 4R)-2-formamyl-4-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), ammonium chloride (61mg, 1.16mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (150mg, 0.77mmol) with N-hydroxyl-7-azepine benzotriazole (78mg, 0.58mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.4mL, 2.31mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=25/1), obtains 173mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.55-7.59(m,2H),7.18-7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.22-5.31(m,1H),4.84-4.99(m,1H),4.62-4.72(m,1H),4.17-4.21,3.78-3.84,(m,0.5H,0.5H),3.92-4.02(m,1H),4.00(d,J＝6.8Hz,2H),2.53-2.64(m,1H),2.18-2.31(m,1H),1.57(d,J＝6.9Hz,3H),1.42(s,9H),1.31-1.38(m,2H),0.92-1.01(m,2H),0.66-0.78(m,4H),0.41-0.44(m,2H)；

MS-ESI:m/z648.80[M+H] ⁺.

Step 3: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-carboxamide hydrochloride

By compound ((S)-1-(4-((2S; 4R)-2-formamyl-4-(cyclopropyl carboxamide base) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (165mg; 0.26mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 62mg white solid, yield: 49%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.74(m,1H),7.65-7.68(m,1H),7.26-7.29(m,1H),6.91(td,J _F-H＝75.0,7.8Hz,1H),5.36-5.38,4.62-4.65(m,0.5H,0.5H),4.70-4.74(m,1H),4.49-4.55(m,1H),4.31-4.34,4.14-4.17(m,0.5H,0.5H),4.02-4.04(m,2H),3.98-4.03,3.66-3.69(m,0.5H,0.5H),2.40-2.46(m,1H),2.25-2.36(m,1H),1.58-1.64(m,1H),1.54(d,J＝6.8Hz,3H),1.31-1.37(m,1H),0.85-0.91(m,2H),0.75-0.80(m,2H),0.67-0.70(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z548.80[M+H-HCl] ⁺.

embodiment 123: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride

Step 1: the synthesis of compound ((S)-1-(4-((2S, 4R)-4-(cyclopropyl carboxamide base)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), cyclopropylamine (66mg, 1.16mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (150mg, 0.77mmol) with N-hydroxyl-7-azepine benzotriazole (78mg, 0.58mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.4mL, 2.31mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 182mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.51-7.59(m,2H),7.21-7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.71-5.80(m,1H),5.22-5.37(m,1H),4.76-4.85(m,1H),4.59-4.65(m,1H),3.96-4.06,3.70-3.77(m,0.5H,0.5H),4.00(d,J＝6.8Hz,1H),2.55-2.74(m,2H),2.12-2.24(m,1H),1.57(d,J＝6.9Hz,3H),1.44(s,9H),1.31-1.41(m,2H),0.92-1.01(m,2H),0.68-0.78(m,6H),0.40-0.56(m,4H)；

MS-ESI:m/z688.40[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base)-N-cyclopropa pyrrolidine-2-carboxamide hydrochloride

By compound ((S)-1-(4-((2S; 4R)-4-(cyclopropyl carboxamide base)-2-(cyclopropylcarbamoyl) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (130mg; 0.20mmol) be dissolved in methylene dichloride (2mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 115mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.69-7.74(m,2H),7.33(d,J＝8.2Hz,1H),6.91(t,J _F-H＝75.0Hz,1H),5.40-5.44,4.61-4.66(m,0.5H,0.5H),5.10-5.15(m,1H),4.53-4.59,4.41-4.46(m,0.5H,0.5H),4.36-4.41,4.26-4.30(m,0.5H,0.5H),4.03-4.08(m,2H),3.99-4.02,3.68-3.72(m,0.5H,0.5H),2.70-2.74,2.50-2.55(m,0.5H,0.5H),2.44-2.50,2.16-2.20(m,0.5H,0.5H),2.27-2.35(m,1H),1.78(d,J＝6.6Hz,3H),1.59-1.64(m,1H),1.32-1.38(m,1H),0.82-0.91(m,2H),0.73-0.80(m,3H),0.66-0.71(m,2H),0.55-0.65(m,2H),0.42-0.48(m,2H),0.35-0.41,0.23-0.27(m,0.5H,0.5H)；

MS-ESI:m/z588.80[M+H] ⁺.

embodiment 124: compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (R)-3-methoxycarbonylamin piperidine hydrochlorate

By triethylamine (1.4mL, 10.0mmol) and N, N '-carbonyl dimidazoles (CDI) (3.2g, 20.0mmol) be dissolved in anhydrous THF (15mL), add anhydrous methanol (640mg, 20.0mmol), stirring at room temperature 10min, add compound (R)-3-amino piperidine-1-t-butyl formate (1.0g, 5.0mmol), stopped reaction after 75 DEG C of reaction 12h, except desolventizing, add water (15mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 1.2g colourless liquid: (R)-3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm4.76(br.s,1H),3.62-3.72(m,1H),3.66(s,3H),3.55-3.58(m,1H),3.29-3.40(m,2H),3.22-3.29(m,1H),1.78-1.86(m,1H),1.61-1.68(m,1H),1.47-1.59(m,2H),1.45(m,9H)；

MS-ESI:m/z203.10[M-55] ⁺.

To compound (R)-3-((methoxycarbonyl) is amino) piperidines-1-t-butyl formate (1.2g, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (6mL) solution 4.6mmol), 6mL), stirring at room temperature 30min, except desolventizing, obtain 820mg white solid: (R)-3-methoxycarbonylamin piperidine hydrochlorate, yield: 91%.

¹HNMR(400MHz,CD ₃OD):δppm3.78-3.83(m,1H),3.68(s,3H)3.40-3.44(m,1H),3.29-3.33(m,1H),2.86-3.01(m,2H),2.01-2.05(m,2H),1.77-1.87(m,1H),1.57-1.65(m,1H)；

MS-ESI:m/z159.10[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), (R)-3-methoxycarbonylamin piperidine hydrochlorate (100mg, 0.51mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (165mg, 0.86mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.3mL, 1.71mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 205mg white solid, yield: 79%.

¹HNMR(400MHz,CDCl ₃):δppm7.59-7.68(m,2H),7.24(d,J＝8.3Hz,1H),6.72(t,J _F-H＝75.0Hz,1H),5.17-5.30(m,1H),4.11-4.24(m,1H),3.97-4.03(m,1H),3.98-4.01(m,2H),3.78-3.87,3.55-3.60(m,0.5H,0.5H),3.68(s,3H),3.13-3.22,2.12-2.22(m,0.5H,0.5H),1.65-1.87(m,3H),1.53-1.58(m,3H),1.42(s,9H),1.28-1.35(m,1H),0.66-0.72(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z609.80[M+H] ⁺.

Step 3: the synthesis of compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane hydrochloride

By compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) piperidines-3-base) Urethylane (200mg, 0.33mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 2h, except desolventizing, obtain 175mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.86(s,1H),7.71-7.75(m,1H),7.33(d,J＝7.8Hz,1H),6.93(t,J _F-H＝74.8Hz,1H),5.01-5.04(m,1H),4.47-4.59(m,1H),4.40-4.43,4.12-4.16(m,0.5H,0.5H),4.04-4.07(m,2H),3.72-3.80(m,1H),3.61-3.68,3.44-3.54(m,0.5H,0.5H),3.68(s,1H),3.59(s,2H),3.33-3.40,3.03-3.10(m,0.5H,0.5H),2.03-2.08(m,1H),1.89-1.94(m,1H),1.79(d,J＝6.9Hz,3H),1.63-1.72(m,2H),1.33-1.37(m,1H),0.68-0.71(m,2H),0.43-0.46(m,2H)；

MS-ESI:m/z509.85[M+H-HCl] ⁺.

embodiment 125: compound 7-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetrahydrochysene the synthesis of-1H-oxazole also [3,4-a] pyrazine-3 (5H)-one hydrochloride

Step 1: the synthesis of compound tetrahydrochysene-1H-oxazole also [3,4-a] pyrazine-3 (5H)-one hydrochloride

By compound 3-methoxycarbonyl piperazine-1-t-butyl formate (1.0g, 4.1mmol), nickelous chloride (640mg, 4.9mmol) with dehydrated alcohol (10mL) mixing, in this solution, sodium borohydride (380mg is added under 0 DEG C of condition, 10.0mmol), stopped reaction after stirring 4h, with frozen water (5mL), add concentrated hydrochloric acid and regulate pH=1, after reaction system clarification, hydro-oxidation sodium water solution (1.0M) regulates pH=10, with ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated, obtain 890mg light green solid: 3-(methylol) piperazine-1-t-butyl formate, yield: 83%.

¹HNMR(400MHz,CD ₃OD):δppm3.99-4.02(m,1H),3.90-3.93(m,1H),3.48-3.54(m,2H),2.96-3.00(m,1H),2.83-2.93(m,1H),2.66-2.72(m,2H),2.56-2.66(m,1H),1.48(m,9H)；

MS-ESI:m/z217.10[M+H] ⁺.

By triethylamine (670mg, 6.5mmol) and N, N '-carbonyl dimidazoles (CDI) (2.6g, 16.2mmol) be dissolved in anhydrous THF (5mL), add anhydrous methanol (520mg, 16.2mmol), stirring at room temperature 15min, add 3-(methylol) piperazine-1-t-butyl formate (700mg, 3.2mmol), stopped reaction after 65 DEG C of reaction 6h, except desolventizing, add water (5mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtain 202mg white solid: 3-oxo tetrahydrochysene-1H-oxazole also [3, 4-a] pyrazine-7 (3H)-t-butyl formate, yield: 26%.

¹HNMR(600MHz,CDCl ₃):δppm4.41-4.44(m,1H),4.04-4.30(m,2H),3.92-3.95(m,1H),3.76-3.80(m,2H),2.97-3.02(m,1H),2.63-2.80(m,2H),1.46(m,9H)；

MS-ESI:m/z187.05[M-55] ⁺.

By compound 3-oxo tetrahydrochysene-1H-oxazole also [3,4-a] pyrazine-7 (3H)-t-butyl formate (100mg, 0.41mmol) dissolve in methylene dichloride (4mL), add the ethyl acetate solution (4M, 2mL) of HCl, stirring at room temperature 50min, except desolventizing, obtain 68mg sticky solid: tetrahydrochysene-1H-oxazole is [3,4-a] pyrazine-3 (5H)-one hydrochloride also, yield: 93%.

¹HNMR(400MHz,CD ₃OD):δppm4.53-4.58(m,1H),4.20-4.28(m,1H),4.13-4.16(m,1H),3.97-4.02(m,1H),3.53-3.57(m,1H),3.37-3.45(m,2H),3.08-3.14(m,2H)；

MS-ESI:m/z143.20[M+H-HCl] ⁺.

Step 2: the synthesis of compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-oxo six hydrogen-1H-oxazole also [3,4-a] pyrazine-7-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (150mg, 0.32mmol), tetrahydrochysene-1H-oxazole also [3, 4-a] pyrazine-3 (5H)-one hydrochloride (68mg, 0.38mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (125mg, 0.64mmol) with N-hydroxyl-7-azepine benzotriazole (64mg, 0.41mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.22mL, 1.28mmol), stirring at room temperature 12h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 116mg white solid, yield: 61%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.58(m,2H),7.25(d,J＝9.2Hz,1H),6.70(t,J _F-H＝75.0Hz,1H),5.17-5.27(m,1H),4.68-4.85(m,2H),4.36-4.52(m,1H),3.83-4.05(m,3H),3.96(d,J＝6.9Hz,2H),3.08-3.23(m,2H),2.70-2.88(m,1H),1.55(d,J＝7.0Hz,3H),1.41(s,9H),1.28-1.36(m,1H),0.67-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z493.30[M+H-100] ⁺.

Step 3: the synthesis of compound 7-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) tetrahydrochysene-1H-oxazole also [3,4-a] pyrazine-3 (5H)-one hydrochloride

By compound ((1S)-1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-4-(3-oxo six hydrogen-1H-oxazole also [3,4-a] pyrazine-7-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (110mg, 0.18mmol) dissolve in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, obtain 97mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.73-7.76(m,2H),7.34(d,J＝8.2Hz,1H),6.93(t,J _F-H＝74.7Hz,1H),5.12-5.22(m,1H),5.07-5.12(m,1H),4.82-4.86,4.69-4.72(m,1.5H,0.5H),4.52-4.57(m,1H),4.12-4.18,4.01-4.06(m,1.5H,0.5H),4.05(d,J＝6.9Hz,2H),3.86-3.91(m,1H),3.18-3.32(m,1H),2.87-2.98(m,1H),1.80(d,J＝6.9Hz,3H),1.34-1.38(m,1H),0.69-0.72(m,2H),0.44-0.46(m,2H)；

MS-ESI:m/z493.80[M+H-HCl] ⁺.

embodiment 126: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-carboxvlate hvdrochloride

Step 1: compound (2S, the 4R)-1-(synthesis of 5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) oxazolyl phenyl-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-ethyl formate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), dehydrated alcohol (71mg, 1.54mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (150mg, 0.77mmol) with N-hydroxyl-7-azepine benzotriazole (78mg, 0.58mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.4mL, 2.31mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: dichloromethane/ethyl acetate (v/v)=2/1), obtains 204mg white solid, yield: 78%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.61(m,2H),7.22-7.26(m,1H),6.72(t,J _F-H＝75.0Hz,1H),5.36-5.43(m,1H),5.21-5.26,4.62-4.67(m,0.5H,0.5H),4.69-4.77(m,1H),4.26-4.33(m,1H),4.10-4.25(m,2H),4.00(d,J＝5.7Hz,1H),3.97-4.03,3.80-3.86(m,0.5H,0.5H),2.31-2.52(m,2H),1.52-1.57(m,3H),1.44(s,9H),1.33-1.41(m,2H),1.17-1.29(m,3H),0.96-1.01(m,2H),0.74-0.79(m,2H),0.68-0.72(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z677.20[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-carboxvlate hvdrochloride

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-ethyl formate (200mg, 0.29mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 174mg white solid, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm7.66-7.76(m,2H),7.33(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.7Hz,1H),5.55-5.58,4.77-4.84(m,0.5H,0.5H),5.10-5.21(m,1H),4.52-4.59,4.26-4.31(m,0.5H,0.5H),4.00-4.48(m,1H),4.10-4.30(m,2H),4.02-4.06(m,2H),3.97-4.02,3.70-3.75(m,0.5H,0.5H),2.45-2.51(m,1H),2.25-2.41(m,1H),1.76-1.79(m,3H),1.59-1.66(m,1H),1.32-1.38(m,1H),1.16-1.33(m,3H),0.85-0.91(m,2H),0.75-0.81(m,2H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z577.20[M+H-HCl] ⁺.

embodiment 127: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride

Step 1: the synthesis of compound ((S)-1-(4-((2S, 4R)-4-(cyclopropyl carboxamide base)-2-(formyl-dimethylamino) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-formic acid (200mg, 0.31mmol), dimethylamine hydrochloride (100mg, 1.24mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (120mg, 0.62mmol) with N-hydroxyl-7-azepine benzotriazole (61mg, 0.46mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.35mL, 1.85mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=40/1), obtains 176mg white solid, yield: 84%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.57(m,1H),7.41-7.46(m,1H),7.19-7.23(m,1H),6.69(td,J _F-H＝75.0,2.5Hz,1H),5.55-5.58,5.34-5.40(m,0.5H,0.5H),5.10-5.23(m,1H),4.56-4.65(m,1H),4.19-4.32(m,1H),3.92-3.97(m,3H),3.16(s,1.5H),3.05(s,1.5H),2.99(s,1.5H),2.92(s,1.5H),2.19-2.47(m,2H),1.52-1.55(m,3H),1.41(s,9H),1.29-1.37(m,2H),0.93-0.97(m,2H),0.66-0.76(m,4H),0.37-0.43(m,2H)；

MS-ESI:m/z676.70[M+H] ⁺.

Step 2: compound (2S, 4R) the synthesis of-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base)-N, N-dimethyl pyrrolidine-2-carboxamide hydrochloride

By compound ((S)-1-(4-((2S; 4R)-4-(cyclopropyl carboxamide base)-2-(formyl-dimethylamino) tetramethyleneimine-1-carbonyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (170mg; 0.25mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 30min; except desolventizing; obtain 151mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.71-7.74(m,1H),7.62-7.67(m,1H),7.31-7.36(m,1H),6.91(td,J _F-H＝74.7,6.2Hz,1H),6.01-6.03,5.22-5.24(m,0.5H,0.5H),5.08-5.15(m,1H),4.55-4.58,4.29-4.32(m,0.5H,0.5H),4.40-4.47(m,1H),4.01-4.04(m,2H),3.95-4.00,3.75-3.78(m,0.5H,0.5H),3.24(s,3H),3.00(s,1.5H),2.86(s,1.5H),2.52-2.57,2.35-2.39(m,0.5H,0.5H),2.28-2.32,2.13-2.19(m,0.5H,0.5H),1.76(d,J＝6.9Hz,3H),1.60-1.65(m,1H),1.32-1.36(m,1H),0.84-0.88(m,2H),0.75-0.79(m,2H),0.67-0.70(m,2H),0.41-0.44(m,2H)；

MS-ESI:m/z576.35[M+H-HCl] ⁺.

embodiment 128: compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-carbonyl) tetramethyleneimine -3-base) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound 3-(cyclo propyl methoxy)-4-methoxyl methyl benzoate

3-hydroxyl-4-methoxyl methyl benzoate (5g, 27.47mmol) is dissolved in DMF (30mL), adds Anhydrous potassium carbonate (7.58g successively, 54.95mmol) with bromomethyl cyclopropane (3.8mL, 41.20mmol), tube sealing, 60 DEG C of reaction 4.5h.Add saturated NaCl solution (20mL), with ethyl acetate (25mL × 3) extraction, merge organic phase, then wash with water (30mL × 3), organic phase anhydrous Na ₂sO ₄dry 1h, except desolventizing, obtains 6.26g white solid, yield: 96.5%.

¹HNMR(400MHz,CDCl ₃):δppm7.66(d,J＝8.4Hz,1H),7.52(s,1H),6.87(d,J＝8.4Hz,1H),3.92(s,3H),3.89(d,J＝7.0Hz,2H),3.87(s,3H),1.32-1.36(m,1H),0.62-0.67(m,2H),0.34-0.38(m,2H)；

MS-ESI:m/z237.1[M+H] ⁺.

Step 2: the synthesis of compound 3-(cyclo propyl methoxy)-4-methoxybenzoic acid

By compound 3-(cyclo propyl methoxy)-4-methoxyl methyl benzoate (2g, 8.47mmol) be dissolved in ethanol (20mL), add sodium hydroxide (1.70g, 42.37mmol) again, at 60 DEG C of reaction 1.5h, removing ethanol, with water (20mL) dissolution residual substance, then use HCl (1M) that the pH value of solution is adjusted to about 1, extract by ethyl acetate (25mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 1.81g white solid, yield: 96.2%.

¹HNMR(400MHz,CDCl ₃):δppm7.65(d,J＝8.4Hz,1H),7.52(s,1H),7.00(d,J＝8.5Hz,1H),3.89(s,3H),3.86(d,J＝6.9Hz,2H),1.24-1.27(m,1H),0.58-0.63(m,2H),0.33-0.37(m,2H)；

MS-ESI:m/z223.0[M+H] ⁺。

Step 3: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl amide group) methyl acetate

By compound 3-(cyclo propyl methoxy)-4-methoxybenzoic acid (4.5g, 20.27mmol), HOAT (2.76g, 20.27mmol) with EDCI (5.81g, 30.41mmol) be dissolved in DCM (30mL), after at room temperature continuing to stir 30min, add glycine methyl ester hydrochloride (3.04g again, 24.32mmol), under ice bath, slowly drip DIPEA (14mL, 81.08mmol) after, at room temperature continue stirring one night, after adding water (30mL), use CH ₂cl ₂(25mL × 3) extract, and after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 3.68g white solid, yield: 61.9%.

¹HNMR(400MHz,CDCl ₃):δppm7.41(s,1H),7.34(d,J＝8.3Hz,1H),6.88(d,J＝8.4Hz,1H),6.57(s,1H),4.23(d,J＝5.0Hz,2H),3.92(s,3H),3.90(d,J＝7.0Hz,2H),3.80(s,3H),1.25-1.34(m,1H),0.62-0.66(m,2H),0.35-0.38(m,2H)；

MS-ESI:m/z294.2[M+H] ⁺。

Step 4: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-methoxyphenylthio amide group) methyl acetate

By compound 2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl amide group) methyl acetate (4g, 13.64mmol) with lawesson reagent (5.52g, 13.64mmol) be dissolved in tetrahydrofuran (THF) (30mL), 2h is reacted under 75 DEG C of conditions, after adding saturated solution of sodium bicarbonate (30mL), extract by ethyl acetate (20mL × 3), after merging organic phase, with anhydrous sodium sulfate drying, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtain 2.89g yellow solid, productive rate: 68%.

Step 5: the synthesis of compound 2-(((3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) (methylthio group) methylene radical) is amino) methyl acetate

Under-78 DEG C of conditions, to trimethylammonium oxygen Tetrafluoroboric acid (2.68g, compound 2-(3-(cyclo propyl methoxy)-4-methoxyphenylthio amide group) methyl acetate (2.8g is dripped in methylene dichloride (15mL) solution 18.1mmol), methylene dichloride (20mL) solution 9.05mmol), after stirring 3h at 0 DEG C, add saturated sodium bicarbonate solution (25mL × 3) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, obtains 2.8g yellow oil, productive rate: 96%.

Step 6: the synthesis of compound (S)-5-(1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-methyl-formiate

By compound 2-(((3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) (methylthio group) methylene radical) is amino) methyl acetate (2.8g, 8.66mmol) with compound (S)-(the fluoro-1-oxopropan of 1--2-base) t-butyl carbamate (3.3g, 17.32mmol) be dissolved in anhydrous tetrahydro furan (15mL), under-78 DEG C of conditions, tetrahydrofuran solution (the 21.65mL of potassium hexamethyldisilazide is dripped in this solution, 21.65mmol),-78 DEG C of reaction 1h, (30mL) cancellation that adds water is reacted, ethyl acetate (25mL × 3) extracts, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 2.58g white solid, productive rate: 67%.

Step 7: the synthesis of compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-formic acid

By compound (S)-5-(1-(t-butoxycarbonyl amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-methyl-formiate (2.58g, 5.78mmol) with a hydronium(ion) Lithium Oxide 98min (1.21g, 28.9mmol) be dissolved in the mixed solvent of tetrahydrofuran (THF) (20mL) and water (10mL), 40 DEG C of reaction 2h, add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (20mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 1.66g yellow solid, productive rate: 66%.

Step 8: the synthesis of compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-formic acid (250mg, 0.58mmol), compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride (120mg, 0.69mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (327mg, 1.71mmol) with N-hydroxyl-7-azepine benzotriazole (120mg, 0.87mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.40mL, 2.31mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 115mg white solid, yield: 35%.

¹HNMR(400MHz,CDCl ₃):δppm7.58(dd,J ₁＝8.4Hz,J ₂＝1.9Hz,1H),7.44-7.46(m,1H),6.92(d,J＝8.5Hz,1H),5.19-5.30,4.88-4.97(m,1.5H,0.5H),4.31-4.39(m,1H),4.05-4.13,4.04-4.12(m,0.5H,0.5H),3.90-4.01(m,1H),3.94(d,J＝2.5Hz,2H),3.93(s,3H),3.69-3.80(m,2H),3.68(s,3H),2.17-2.26(m,1H),1.89-1.99(m,1H),1.51-1.55(m,3H),1.41(s,9H),1.31-1.38(m,1H),0.65-0.70(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z559.90[M+H] ⁺.

Step 9: the synthesis of compound ((R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-p-methoxy-phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

By compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-methoxyl group) oxazolyl phenyl-4-carbonyl) pyrrolidin-3-yl) Urethylane (110mg, 0.20mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 96mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.70(dd,J ₁＝8.4Hz,J ₂＝1.6Hz,1H),7.57-7.58(m,1H),7.12(d,J＝8.5Hz,1H),5.05-5.10(m,1H),4.22-4.34(m,2H),4.16-4.22,4.04-4.09(m,0.5H,0.5H),3.94(d,J＝3.9Hz,2H),3.93(s,3H),3.84-3.88,3.69-3.80(m,0.5H,1.5H),3.65-3.67(m,3H),2.17-2.30(m,1H),1.94-2.07(m,1H),1.75(d,J＝6.9Hz,3H),1.29-1.35(m,1H),0.64-0.67(m,2H),0.38-0.40(m,2H)；

MS-ESI:m/z459.30[M+H-HCl] ⁺.

embodiment 129: compound 4-((((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carbonyl) oxygen base) methyl) synthesis of benzoate hydrochlorate

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate (2.8g, 4.3mmol) is dissolved in THF (20mL) and H ₂in the mixed solvent of O (10mL), then add a hydronium(ion) Lithium Oxide 98min (900mg, 21.0mmol), stop after 45 DEG C of reaction 1h, enriching hydrochloric acid conditioning solution pH=1, extracts by ethyl acetate (15mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 2.7g white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.60-7.74(m,2H),7.26(d,J＝8.3Hz,1H),6.88(t,J _F-H＝75.0Hz,1H),5.43-5.50(m,1H),5.25-5.34(m,1H),4.27-4.38(m,1H),4.02(d,J＝6.8Hz,2H),3.93-4.00(m,1H),3.63-3.70(m,1H),3.67(s,1H),2.28-2.47(m,2H),1.52(d,J＝7.0Hz,3H),1.42(s,9H),1.33-1.39(m,1H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z639.35[M+H] ⁺.

Step 2: compound 4-((((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base) methyl) benzoic synthesis

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (300mg, 0.47mmol) be dissolved in THF (5mL), N is added under room temperature, N '-carbonyl dimidazoles (CDI) (115mg, 0.71mmol), 60 DEG C of reaction 30min, add 4-hydroxymethyl-benzoic acid (143mg, 0.94mmol), stop after 70 DEG C of reaction 24h, drain solvent, add water (10mL), extract by ethyl acetate (10mL × 3), organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: DCM/MeOH (v/v)=30/1), obtains 141mg white solid, yield: 38%.

Step 3: the synthesis of compound 4-((((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base) methyl) benzoate hydrochlorate

By compound 4-((((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base) methyl) phenylformic acid (140mg, 0.18mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, obtain 62mg white solid, yield: 48%.

¹HNMR(600MHz,CD ₃OD):δppm7.51-7.75(m,3H),7.32-7.42(m,2H),7.15-7.26(m,2H),6.69-7.10(m,1H),5.57-5.64(m,1H),5.11-5.30(m,3H),4.25-4.32(m,1H),3.86-4.06(m,3H),3.64-3.77(m,4H),2.48-2.56(m,1H),2.28-2.46(m,1H),1.73-1.78(m,3H),1.27-1.36(m,1H),0.64-0.72(m,2H),0.38-0.46(m,2H)；

MS-ESI:m/z673.20[M+H-HCl] ⁺.

embodiment 130: compound ((R)-1-(5-((S)-1-amino-2-methyl propyl group)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (S)-5-(1-((tert-butoxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate

At room temperature, by N, N '-carbonyl dimidazoles (CDI) (1.20g, 7.5mmol) be dissolved in anhydrous THF (10mL), slowly add compound (S)-2-((tertbutyloxycarbonyl) is amino)-3 Methylbutanoic acid (1.4g, 6.3mmol), stirring at room temperature 20min, add 2-(((3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate (1.5g, 4.2mmol), under-78 DEG C of conditions, THF solution (the 1.0M of slow dropping potassium hexamethyldisilazide, 13mL), stop after reaction 1.5h, add water (25mL) cancellation reaction, ethyl acetate (25mL × 3) is used to extract again, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=5/1), obtains 1.0g white solid, yield: 47%.

¹HNMR(400MHz,CDCl ₃):δppm7.60-7.64(m,2H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.86-5.89(m,1H),5.07-5.12(m,1H),3.98(s,3H),3.97(d,J＝7.1Hz,2H),2.12-2.19(m,1H),1.44(s,9H),1.29-1.35(m,1H),1.05(d,J＝6.5Hz,3H),0.89(d,J＝6.6Hz,3H),0.65-0.70(m,2H),0.37-0.41(m,2H)；

MS-ESI:m/z511.30[M+H] ⁺.

Step 2: the synthesis of compound (S)-5-(1-((tert-butoxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate (1.00g, 2.0mmol) be dissolved in the mixed solvent of THF (10mL) and water (5mL), add a hydronium(ion) Lithium Oxide 98min (410mg again, 9.8mmol), stopped reaction after 45 DEG C of reaction 1h, add the pH=1 of concentrated hydrochloric acid regulator solution, removing THF, extract by ethyl acetate (15mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 960mg pale red solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.81(s,1H),7.67-7.69(m,1H),7.29(d,J＝8.3Hz,1H),6.90(t,J _F-H＝74.9Hz,1H),5.25-5.28(m,1H),4.03(d,J＝6.9Hz,2H),2.13-2.23(m,1H),1.44(s,9H),1.33-1.38(m,1H),1.08(d,J＝5.6Hz,3H),0.96(d,J＝6.7Hz,3H),0.66-0.71(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z441.80[M-55] ⁺.

Step 3: the synthesis of compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.61mmol), compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride (130mg, 0.73mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (230mg, 1.21mmol) with N-hydroxyl-7-azepine benzotriazole (120mg, 0.91mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.41mL, 2.42mmol), stirring at room temperature 10h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 391mg white solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.59(m,2H),7.23(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),4.80-4.87,4.18-4.23(m,1.5H,0.5H),4.30-4.40(m,1H),3.95-4.04(m,1H),3.96-3.99(m,2H),3.63-3.84(m,2H),3.68(s,3H),2.14-2.28(m,2H),1.86-2.03(m,1H),1.42(s,9H),1.28-1.35(m,1H),1.01-1.05(m,3H),0.82-0.87(m,3H),0.66-0.71(m,2H),0.38-0.43(m,2H)；

MS-ESI:m/z623.40[M+H] ⁺.

Step 4: the synthesis of compound ((R)-1-(5-((S)-1-amino-2-methyl propyl group)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

To compound ((R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (360mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 0.58mmol), 4mL), stirring at room temperature 30min, except desolventizing, obtain 315mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.70-7.74(m,2H),7.32(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),4.27-4.31,4.08-4.12(m,0.5H,0.5H),4.21-4.25(m,2H),4.02-4.04(m,2H),3.83-3.87,3.75-3.80(m,0.5H,0.5H),3.68-3.72,3.56-3.59(m,0.5H,0.5H),3.64-3.66(m,3H),2.44-2.50(m,1H),2.18-2.30(m,1H),1.94-2.07(m,1H),1.31-1.36(m,1H),1.18(d,J＝6.7Hz,3H),1.00(d,J＝6.7Hz,3H),0.66-0.69(m,2H),0.42-0.44(m,2H)；

MS-ESI:m/z523.85[M+H-HCl] ⁺.

embodiment 131: compound (R)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-carbonyl) pyrrolidin-3-yl) the synthesis of Urethylane

Step 1: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-methyl-formiate

At room temperature, by N, N '-carbonyl dimidazoles (CDI) (1.50g, 9.2mmol) be dissolved in anhydrous THF (10mL), slowly add propionic acid (620mg, 8.3mmol), stirring at room temperature 20min, add 2-(((3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate (1.5g, 4.2mmol), under the condition of-78 DEG C, THF solution (the 1.0M of slow dropping potassium hexamethyldisilazide, 13mL), stop after reaction 1.5h, add water (25mL) cancellation reaction, ethyl acetate (25mL × 3) is used to extract again, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=6/1), obtains 650mg white solid, yield: 42%.

¹HNMR(400MHz,CDCl ₃):δppm7.65(m,1H),7.59-7.62(m,1H),7.22(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),3.96(d,J＝7.0Hz,2H),3.95(s,3H),3.13(q,J＝7.6Hz,2H),1.34(t,J＝7.6Hz,3H),1.28-1.35(m,1H),0.63-0.69(m,2H),0.35-0.39(m,2H)；

MS-ESI:m/z368.90[M+H] ⁺.

Step 2: the synthesis of compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-formic acid

By compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-methyl-formiate (650mg, 1.8mmol) be dissolved in the mixed solvent of THF (10mL) and water (5mL), add a hydronium(ion) Lithium Oxide 98min (370mg again, 8.8mmol), stopped reaction after 45 DEG C of reaction 1h, add the pH=1 of concentrated hydrochloric acid regulator solution, removing THF, extract by ethyl acetate (15mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 590mg light yellow solid, yield: 94%.

¹HNMR(400MHz,CD ₃OD):δppm7.78(d,J＝1.8Hz,1H),7.63(dd,J ₁＝8.4Hz,J ₂＝1.9Hz,1H),7.29(d,J＝8.4Hz,1H),6.90(t,J _F-H＝75.0Hz,1H),4.03(d,J＝6.9Hz,2H),3.17(q,J＝7.6Hz,2H),1.37(t,J＝7.6Hz,3H),1.32-1.39(m,1H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z354.90[M+H] ⁺.

Step 3: the synthesis of compound (R)-(1-(2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound 2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl)-5-ethyl oxazole-4-formic acid (200mg, 0.56mmol), compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride (122mg, 0.68mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (215mg, 1.13mmol) with N-hydroxyl-7-azepine benzotriazole (115mg, 0.85mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.40mL, 2.26mmol), stirring at room temperature 10h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 180mg white solid, yield: 66%.

¹HNMR(600MHz,CDCl ₃):δppm7.51-7.56(m,2H),7.23(d,J＝7.4Hz,1H),6.68(t,J _F-H＝75.2Hz,1H),4.96-5.05(m,1H),4.28-4.38(m,1H),4.18-4.21,3.90-3.95(m,0.5H,0.5H),4.03-4.02(m,1H),3.95-3.97(m,2H),3.82-3.86,3.54-3.56(m,0.5H,0.5H),3.66-3.74(m,1H),3.66-3.69(m,3H),3.07-3.12(m,2H),2.16-2.23(m,2H),1.89-2.03(m,2H),1.32(t,J＝7.4Hz,3H),1.28-1.34(m,1H),0.64-0.69(m,2H),0.38-0.41(m,2H)；

MS-ESI:m/z480.30[M+H] ⁺.

embodiment 134: compound 1-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carbonyl) synthesis of piperidines-4-carboxylic acid hydrochloride

Step 1: the synthesis of compound 1-((2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (300mg, 0.47mmol), 4-piperidine methyl formate (101mg, 0.71mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (224mg, 1.17mmol) with N-hydroxyl-7-azepine benzotriazole (95mg, 0.71mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.25mL, 1.41mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/3), obtains 255mg white solid, yield: 71%.

¹HNMR(400MHz,CDCl ₃):δppm7.43-7.58(m,2H),7.22(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.1Hz,1H),5.05-5.30(m,2H),4.24-4.45(m,3H),3.88-3.99(m,3H),3.58-3.71(m,6H),3.10-3.38(m,1.5H),2.77-2.97(m,1H),2.56-2.70(m,1H),2.37-2.50(m,1H),2.16-2.30(m,1.5H),1.88-2.03(m,2H),1.72-1.85(m,1H),1.57-1.65(m,1H),1.49-1.56(m,3H),1.43(s,9H),1.28-1.36(m,1H),0.66-0.70(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z764.70[M+H] ⁺.

Step 2: the synthesis of compound 1-((2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) piperidines-4-formic acid

By compound 1-((2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) piperidines-4-methyl-formiate (250mg, 0.33mmol) is dissolved in THF (10mL) and H ₂in the mixed solvent of O (5mL), then add a hydronium(ion) Lithium Oxide 98min (52mg, 3.3mmol), stop after 45 DEG C of reaction 1.5h, enriching hydrochloric acid conditioning solution pH=1, extracts by ethyl acetate (10mL × 3), after merging organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, obtains 243mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.56-7.72(m,2H),7.27-7.35(m,1H),6.68-7.09(m,1H),5.31-5.41(m,1H),5.69-5.78,5.18-5.25(m,0.5H,0.5H),4.20-4.38(m,3H),3.98-4.05(m,2H),3.98-4.10,3.89-3.96(m,0.5H,0.5H),3.65-3.67(m,3H),3.16-3.30(m,1H),2.92-3.04(m,1H),2.63-2.81(m,1H),2.38-2.55(m,1H),2.10-2.31(m,2H),1.82-2.02(m,2H),1.59-1.69(m,1H),1.48-1.53(m,3H),1.44(s,9H),1.31-1.38(m,1H),0.61-0.71(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z750.40[M+H] ⁺.

Step 3: the synthesis of compound 1-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) piperidines-4-carboxylic acid hydrochloride

By compound 1-((2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) piperidines-4-formic acid (100mg, 0.13mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 2h, except desolventizing, obtain 90mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.64-7.76(m,2H),7.30-7.39(m,1H),6.71-7.12(m,1H),5.04-5.17(m,1H),6.05-6.10,5.20-5.25(m,0.5H,0.5H),4.20-4.42(m,3H),4.05(d,J＝6.8Hz,2H),3.90-4.03(m,1H),3.72-3.84(m,1H),3.65-3.68(m,3H),3.25-3.43(m,1H),2.87-3.04(m,1H),2.62-2.73(m,1H),2.48-2.60(m,1H),2.21-2.38(m,1H),2.10-2.19(m,1H),1.83-2.00(m,1.5H),1.77(d,J＝6.9Hz,3H),1.52-1.70(m,1.5H),1.31-1.38(m,1H),0.67-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z650.80[M+H-HCl] ⁺.

embodiment 135: compound (2S, 4R)-1-(5-((S)-1-amino-2-methyl propyl group)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole -4-carbonyl) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.61mmol), compound (2S, 4R)-2-methoxycarbonyl-4-((methoxycarbonyl) is amino) pyrrolidine hydrochloride (175mg, 0.73mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (290mg, 1.51mmol) with N-hydroxyl-7-azepine benzotriazole (123mg, 0.91mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.42mL, 2.42mmol), stirring at room temperature 10h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=3/1), obtains 285mg white solid, yield: 69%.

¹HNMR(400MHz,CDCl ₃):δppm7.50-7.60(m,2H),7.21-7.25(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.20-5.26,4.42-4.51(m,0.5H,0.5H),4.71-4.91(m,2H),4.30-4.40(m,1H),4.17-4.26,4.01-4.07(m,0.5H,0.5H),3.97-4.00(m,2H),3.68-3.77(m,6H),2.32-2.51(m,1H),2.12-2.32(m,2H),1.43(s,9H),1.29-1.37(m,1H),0.99-1.04(m,3H),0.81-0.86(m,3H),0.67-0.71(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z681.40[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate (280mg, 0.41mmol) is dissolved in THF (5mL) and H ₂in the mixed solvent of O (3mL), then add a hydronium(ion) Lithium Oxide 98min (172mg, 4.1mmol), stop after 45 DEG C of reaction 1h, enriching hydrochloric acid conditioning solution pH=1, extracts by ethyl acetate (15mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 260mg white solid, yield: 95%.

¹HNMR(400MHz,CD ₃OD):δppm7.73-7.75(m,1H),7.61-7.69(m,1H),7.25-7.30(m,1H),6.88(t,J _F-H＝75.0Hz,1H),5.27-5.32(m,1H),5.19-5.21(m,1H),4.30-4.33(m,1H),4.02(d,J＝6.8Hz,2H),3.93-4.05(m,1H),3.63-3.71(m,1H),3.67(s,1H),2.28-2.46(m,2H),2.14-2.24(m,1H),1.44(s,9H),1.33-1.38(m,1H),1.01-1.07(m,3H),0.87-0.92(m,3H),0.66-0.71(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z667.75[M+H] ⁺.

Step 3: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.37mmol), ethylene glycol monomethyl ether (142mg, 1.88mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (215mg, 1.13mmol) with N-hydroxyl-7-azepine benzotriazole (75mg, 0.56mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.2mL, 1.13mmol), stirring at room temperature 10h, add water (15mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 230mg white solid, yield: 84%.

¹HNMR(400MHz,CDCl ₃):δppm7.53-7.60(m,2H),7.20-7.25(m,1H),6.69(t,J _F-H＝75.2Hz,1H),5.28-5.35,4.72-4.78(m,0.5H,0.5H),4.78-4.90(m,2H),4.37-4.49(m,1H),4.25-4.36(m,2H),4.15-4.23(m,1H),3.95-4.03(m,2H),3.68(s,3H),3.58-3.64,3.48-3.50(m,0.5H,1.5H),3.38(s,1H),3.25(s,2H),2.39-2.51(m,1H),2.24-2.38(m,1H),2.11-2.23(m,1H),1.43(s,9H),1.29-1.36(m,1H),0.99-1.05(m,3H),0.81-0.87(m,3H),0.66-0.71(m,2H),0.40-0.44(m,2H)；

MS-ESI:m/z725.70[M+H] ⁺.

Step 4: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-2-methyl propyl group)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (2-methoxyl group) carbethoxy hydrochloride

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino)-2-methyl-propyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (2-methoxyl group) ethyl ester (230mg, 0.32mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 1h, except desolventizing, obtain 204mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.66-7.77(m,2H),7.32-7.35(m,1H),6.92(t,J _F-H＝74.8Hz,1H),5.55-5.58,4.77-4.79(m,0.5H,0.5H),4.97(d,J＝8.5Hz,1H),4.25-4.39(m,3H),4.18-4.22,3.97-4.00(m,0.5H,0.5H),4.02-4.09(m,2H),3.63-3.71(m,1H),3.66-3.67(m,3H),3.51-3.53(m,1H),3.40(s,1H),3.21(s,2H),2.43-2.49(m,2H),2.28-2.37(m,1H),1.33-1.39(m,1H),1.17-1.20(m,3H),0.99-1.02(m,3H),0.68-0.71(m,2H),0.44-0.46(m,2H)；

MS-ESI:m/z625.80[M+H-HCl] ⁺.

embodiment 136: compound (S)-2-(((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole -4-carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carbonyl) oxygen base) synthesis of-2-phenylacetate hydrochlorate

Step 1: the synthesis of compound (S)-2-(((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2-toluylic acid

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.39mmol) be dissolved in THF (5mL), N is added under room temperature, N '-carbonyl dimidazoles (CDI) (95mg, 0.59mmol), room temperature reaction 30min, add compound (S)-2-hydroxyl-2-toluylic acid (89mg, 0.59mmol), stop after 60 DEG C of reaction 12h, drain solvent, add water (10mL), extract by ethyl acetate (10mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 280mg light yellow solid, yield: 93%.

MS-ESI:m/z773.70[M+H] ⁺.

Step 2: the synthesis of compound (S)-2-(((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2-phenylacetate hydrochlorate

By compound (S)-2-(((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2-toluylic acid (310mg, 0.4mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, residuum is separated through preparative chromatography, obtain 60mg white solid, yield: 21%.

¹HNMR(600MHz,CD ₃OD):δppm7.61-7.75(m,2H),7.51(s,1H),7.32-7.44(m,5H),6.71-7.04(m,1H),5.96,5.79(s,0.3H,0.7H),5.73-5.75,5.06-5.11(m,0.7H,0.3H),5.12-5.18,4.90-4.92(m,0.7H,0.3H),4.36-4.45(m,1H),4.25-4.30(m,1H),4.00-4.04,3.78-3.81(m,1.4H,0.6H),3.69-3.76(m,1H),3.64-3.67(m,3H),2.73-2.77,2.48-2.53(m,0.7H,0.3H),2.56-2.62,2.40-2.46(m,0.7H,0.3H),1.70-1.76(m,3H),1.31-1.36(m,1H),0.66-0.70,0.62-0.65(m,0.6H,1.4H),0.42-0.44,0.33-0.36(m,0.6H,1.4H)；

MS-ESI:m/z673.30[M+H] ⁺.

embodiment 139: compound 2-(((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carbonyl) oxygen base) synthesis of-2 Methylpropionic acid hydrochloride

Step 1: the synthesis of compound 2-(((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2 Methylpropionic acid

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (350mg, 0.55mmol) be dissolved in THF (10mL), N is added under room temperature, N '-carbonyl dimidazoles (CDI) (135mg, 0.82mmol), 2-hydroxy-2-methyl propionic acid (89mg is added after 60 DEG C of reaction 30min, 0.59mmol), stop after 60 DEG C of reaction 12h, drain solvent, add water (10mL), extract by ethyl acetate (10mL × 3), after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, residuum is prepared chromatographic separation, obtains 253mg light yellow solid, yield: 63%.

MS-ESI:m/z725.70[M+H] ⁺.

Step 2: the synthesis of compound 2-(((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2 Methylpropionic acid hydrochloride

By compound 2-(((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) oxygen base)-2 Methylpropionic acid (240mg, 0.33mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, residuum is separated through preparative chromatography, obtain 206mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.68-7.75(m,2H),7.32-7.34(m,1H),6.79-7.05(m,1H),5.56-5.61,4.74-4.78(m,0.5H,0.5H),5.08-5.17(m,1H),4.25-4.42(m,2H),4.02-4.06(m,2H),3.97-4.01,3.68-3.72(m,0.5H,0.5H),3.63-3.72(m,3H),2.45-2.56(m,1H),2.31-2.39(m,1H),1.70-1.76(m,3H),1.64(s,1H),1.59(s,1H),1.47(s,2H),1.41(s,2H),1.33-1.36(m,1H),0.66-0.70(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z625.40[M+H-HCl] ⁺.

embodiment 141: compound ((3R, 5S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(dimethylcarbamoyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(dimethylcarbamoyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (200mg, 0.31mmol), dimethylamine hydrochloride (73mg, 1.65mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (180mg, 0.94mmol) with N-hydroxyl-7-azepine benzotriazole (63mg, 0.46mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.35mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 146mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm7.44-7.59(m,2H),7.20-7.24(m,1H),6.69(t,J _F-H＝75.1Hz,1H),5.55-5.64,5.28-5.36(m,0.5H,0.5H),5.16-5.27(m,1H),5.03-5.13(m,1H),4.38-4.48(m,1H),4.23-4.34(m,1H),3.93-3.98(m,2H),3.67(s,3H),3.17(s,1.7H),3.06(s,1.3H),3.00(s,1.7H),2.94(s,1.3H),2.19-2.42(m,2H),1.49-1.54(m,3H),1.42-1.43(m,9H),1.29-1.36(m,1H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z666.80[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(dimethylcarbamoyl) pyrrolidin-3-yl) Urethylane hydrochloride

By compound ((3R; 5S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(dimethylcarbamoyl) pyrrolidin-3-yl) Urethylane (146mg; 0.22mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 50min; except desolventizing; obtain 108mg white solid, yield: 81%.

¹HNMR(400MHz,CD ₃OD):δppm7.70-7.75(m,1H),7.62-7.66(m,1H),7.32-7.36(m,1H),6.91(t,J _F-H＝74.7,4.9Hz,1H),5.16-5.19,5.96-5.98(m,0.5H,0.5H),5.07-5.13(m,1H),4.36-4.41(m,1H),4.23-4.31(m,1H),4.01-4.05(m,2H),3.72-3.77,3.95-3.98(m,0.5H,0.5H),3.64-3.66(m,3H),3.23(s,1.5H),3.22(s,1.5H),3.00(s,1.5H),2.86(s,1.5H),2.50-2.55,2.31-2.36(m,0.5H,0.5H),2.26-2.30,2.12-2.17(m,0.5H,0.5H),1.76(d,J＝6.9Hz,3H),1.33-1.36(m,1H),0.67-0.70(m,2H),0.41-0.45(m,2H)；

MS-ESI:m/z566.40[M+H-HCl] ⁺.

embodiment 142: compound ((3R, 5S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base)-5-(methylcarbamoyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(methylcarbamoyl) pyrrolidin-3-yl) Urethylane

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (200mg, 0.31mmol), methylamine hydrochloride (105mg, 1.56mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (180mg, 0.94mmol) with N-hydroxyl-7-azepine benzotriazole (63mg, 0.46mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.35mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/2), obtains 160mg white solid, yield: 78%.

¹HNMR(400MHz,CDCl ₃):δppm7.48-7.58(m,2H),7.21-7.25(m,1H),6.70(t,J _F-H＝75.1Hz,1H),4.78-4.80,5.53-5.55(m,0.5H,0.5H),5.23-5.32(m,1H),4.30-4.44(m,1H),3.95-4.02,4.06-4.14(m,0.5H,0.5H),3.98(d,J＝6.9Hz,2H),3.81-3.91(m,1H),3.65(s,3H),2.83(d,J＝4.7Hz,2H),2.58-2.60(m,1H),2.08-2.23(m,1H),1.53-1.57(m,3H),1.42(s,9H),1.29-1.36(m,1H),0.66-0.71(m,2H),0.39-0.43(m,2H)；

MS-ESI:m/z652.40[M+H] ⁺.

Step 2: the synthesis of compound ((3R, 5S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(methylcarbamoyl) pyrrolidin-3-yl) Urethylane hydrochloride

By compound ((3R; 5S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-5-(methylcarbamoyl) pyrrolidin-3-yl) Urethylane (155mg; 0.24mmol) be dissolved in methylene dichloride (4mL); add the ethyl acetate solution (4M of HCl; 4mL); stirring at room temperature 50min; except desolventizing; obtain 137mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.67-7.76(m,2H),7.31-7.34(m,1H),6.92(td,J _F-H＝74.8,2.2Hz,1H),4.65-4.67,5.36-5.38(m,0.5H,0.5H),5.11-5.17(m,1H),4.35-4.39(m,1H),4.23-4.30(m,1H),4.04-4.07(m,2H),3.64-3.70,3.99-4.03(m,0.5H,0.5H),3.64-3.67(m,3H),2.79(m,1.5H),2.71(m,1.5H),2.35-2.45(m,1H),2.18-2.32(m,1H),1.78(d,J＝6.9Hz,3H),1.33-1.38(m,1H),0.67-0.71(m,2H),0.43-0.47(m,2H)；

MS-ESI:m/z552.80[M+H-HCl] ⁺.

embodiment 143: compound (S)-2-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole -4-carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-formamido-) synthesis of-2-phenylacetate hydrochlorate

Step 1: the synthesis of compound (S)-2-(amino)-2-methyl phenylacetate hydrochloride

By N, N '-carbonyl dimidazoles (CDI) (770mg, 4.8mmol) be dissolved in dry DMF (10mL), compound (S)-2-((tert-butoxycarbonyl) is amino)-2-toluylic acid (1.0g is added under room temperature, 4.0mmol), 60 DEG C of reaction 50min, add methyl alcohol (10mL), stop after continuing reaction 12h, drain solvent, add water (10mL), with ethyl acetate (10mL × 3) extraction, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=8/1), obtain 426mg light yellow solid: (S)-2-((tert-butoxycarbonyl) is amino)-2-methyl phenylacetate, yield: 40%.

¹HNMR(400MHz,CDCl ₃):δppm7.31-7.36(m,5H),5.22(s,1H),5.32(d,J＝7.1Hz,1H),3.72(s,3H),1.43(s,9H)；

MS-ESI:m/z288.00[M+Na] ⁺.

By compound (S)-2-((tert-butoxycarbonyl) is amino)-2-methyl phenylacetate (160mg, 0.61mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 50min, except desolventizing, obtain 119mg light yellow solid: (S)-2-(amino)-2-methyl phenylacetate hydrochloride, yield: 97%.

¹HNMR(400MHz,CD ₃OD):δppm7.49-7.53(m,5H),5.22(s,1H),3.83(s,3H)；

MS-ESI:m/z166.25[M+H-HCl] ⁺.

Step 2: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formamido-)-2-methyl phenylacetate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), (S)-2-(amino)-2-methyl phenylacetate hydrochloride (101mg, 0.5mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (180mg, 0.94mmol) with N-hydroxyl-7-azepine benzotriazole (90mg, 0.59mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.3mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/1), obtains 230mg colorless solid, yield: 75%.

¹HNMR(400MHz,CDCl ₃):δppm7.31-7.61(m,5H),7.23-7.28(m,1H),7.10-7.19(m,1H),6.99-7.06(m,1H),6.52-6.90(m,1H),5.53-5.61(m,1H),5.28-5.41(m,1H),5.16-5.27(m,1H),4.91-4.99(m,1H),4.37-4.50(m,1H),4.08-4.21(m,1H),3.94-4.06(m,2H),3.64-3.76(m,6H),2.58-2.74(m,1H),2.05-2.26(m,1H),1.53-1.59(m,3H),1.44(m,9H),1.31-1.39(m,1H),0.66-0.73(m,2H),0.37-0.44(m,2H)；

MS-ESI:m/z786.70[M+H] ⁺.

Step 3: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formamido-)-2-toluylic acid

By compound (S)-2-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formamido-)-2-methyl phenylacetate (220mg, 0.28mmol) is dissolved in THF (5mL) and H ₂in the mixed solvent of O (3mL), then add a hydronium(ion) Lithium Oxide 98min (60mg, 1.43mmol), stop after 45 DEG C of reaction 1h, enriching hydrochloric acid conditioning solution pH=4, extracts by ethyl acetate (10mL × 3), merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 212mg white solid, yield: 98%.

¹HNMR(400MHz,CD ₃OD):δppm7.64-7.71(m,1H),7.43-7.53(m,2H),7.33-7.41(m,1H),7.19-7.30(m,3H),7.07-7.12(m,1H),6.68-7.04(m,1H),5.41-5.49(m,1H),5.31-5.40(m,1H),4.28-4.36(m,1H),3.90-4.05(m,2H),3.80-3.86(m,1H),3.63-3.69(m,3H),2.35-2.50(m,2H),1.47-1.54(m,2H),1.43(s,9H),1.28-1.36(m,1H),0.65-0.71(m,2H),0.40-0.45(m,2H)；

MS-ESI:m/z772.40[M+H] ⁺.

Step 4: the synthesis of compound (S)-2-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formamido-)-2-phenylacetate hydrochlorate

By compound (S)-2-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formamido-)-2-toluylic acid (220mg, 0.28mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 50min, except desolventizing, obtain 202mg white solid, yield: 100%.

¹HNMR(400MHz,CD ₃OD):δppm7.65-7.74(m,1.5H),7.44-7.54(m,1.5H),7.29-7.41(m,2H),7.12-7.21(m,3H),6.73-7.10(m,1H),5.59-5.70(m,1H),5.25(s,1H),5.00-5.15(m,1H),4.23-4.40(m,2H),3.98-4.05(m,2H),3.89-3.94,3.73-3.80(m,0.5H,0.5H),3.63-3.76(m,3H),2.44-2.64(m,1H),2.23-2.35(m,1H),1.71-1.79(m,3H),1.29-1.37(m,1H),0.64-0.71(m,2H),0.39-0.46(m,2H)；

MS-ESI:m/z672.20[M+H-HCl] ⁺.

embodiment 145: compound 4-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4- carbonyl)-4-((methoxycarbonyl) amino) tetramethyleneimine-2-carbonyl) synthesis of morpholine-3-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) morpholine-3-methyl-formiate

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (300mg, 0.47mmol), 3-methyl-formiate morpholine (81mg, 0.56mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (271mg, 1.41mmol) with N-hydroxyl-7-azepine benzotriazole (95mg, 0.70mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.3mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=1/3), obtains 34mg white solid, yield: 9%.

¹HNMR(400MHz,CDCl ₃):δppm7.43-7.57(m,2H),7.18-7.22(m,1H),6.68(t,J _F-H＝75.1Hz,1H),5.75-5.82,5.28-5.34(m,0.5H,0.5H),5.13-5.27(m,2H),5.00-5.03,4.83-4.86(m,0.5H,0.5H),4.32-4.43(m,2H),4.17-4.28(m,1H),3.91-3.96(m,2H),3.85-3.91(m,1H),3.72-3.81(m,5H),3.62-3.69(m,3H),3.48-3.60(m,1H),3.22-3.44(m,1H),2.23-2.50(m,2H),1.47-1.53(m,3H),1.38-1.41(m,9H),1.28-1.33(m,1H),0.64-0.70(m,2H),0.37-0.41(m,2H)；

MS-ESI:m/z766.35[M+H] ⁺.

Step 2: the synthesis of compound 4-((2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) morpholine-3-methyl-formiate hydrochloride

By compound 4-((2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-carbonyl) morpholine-3-methyl-formiate (30mg, 0.04mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 1h, except desolventizing, obtain 26mg white solid, yield: 94%.

¹HNMR(400MHz,CD ₃OD):δppm7.73-7.77(m,2H),7.34-7.40(m,1H),6.94(td,J＝74.9,9.9Hz,1H),6.19-6.23,5.31-5.34(m,0.5H,0.5H),5.07-5.16(m,1H),4.89-4.97(m,2H),4.74-4.83(m,1H),4.23-4.46(m,3H),4.03-4.07(m,2H),3.91-4.00(m,2H),3.66-3.84(m,7H),3.49-3.59(m,1H),2.29-2.59(m,2H),1.78(d,J＝6.9Hz,3H),1.31-1.40(m,1H),0.68-0.73(m,2H),0.45-0.47(m,2H)；

MS-ESI:m/z666.30[M+H-HCl] ⁺.

embodiment 147: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-formic acid (4-hydroxyl) cyclohexyl hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-hydroxyl) cyclohexyl

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (280mg, 0.43mmol), 1, 4-cyclohexanediol (254mg, 2.19mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (340mg, 1.77mmol) with N-hydroxyl-7-azepine benzotriazole (90mg, 0.66mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.3mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 41mg white solid, yield: 12%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.62(m,2H),7.24-7.28(m,1H),6.72(t,J _F-H＝75.1Hz,1H),5.25-5.38(m,2H),4.68-4.86(m,2H),4.37-4.49(m,1H),3.98-4.02(m,2H),3.70-3.81(m,5H),2.22-2.49(m,2H),1.87-2.04(m,4H),1.66-1.85(m,4H),1.50-1.56(m,3H),1.44(s,9H),1.33-1.39(m,1H),0.69-0.73(m,2H),0.42-0.46(m,2H)；

MS-ESI:m/z737.30[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-hydroxyl) cyclohexyl hydrochloride

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-hydroxyl) cyclohexyl (35mg, 0.05mmol) be dissolved in methylene dichloride (2mL), add the aqueous isopropanol (4M of HCl, 2mL), stirring at room temperature 2h, except desolventizing, obtain 32mg white solid, yield: 99%.

¹HNMR(400MHz,CD ₃OD):δppm7.65-7.76(m,2H),7.33-7.36(m,1H),6.93(t,J _F-H＝75.1Hz,1H),4.95-5.20(m,2H),4.71-4.84(m,2H),4.24-4.41(m,1H),4.06(d,J＝6.9Hz,2H),3.57-3.73(m,5H),2.22-2.50(m,2H),1.83-2.04(m,4H),1.77(d,J＝6.9Hz,3H),1.40-1.63(m,4H),1.31-1.38(m,1H),0.68-0.74(m,2H),0.43-0.47(m,2H)；

MS-ESI:m/z637.50[M+H-HCl] ⁺.

embodiment 148: compound ((R)-1-(5-((R)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) synthesis of Urethylane hydrochloride

Step 1: the synthesis of compound (R)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate

At room temperature, by N, N '-carbonyl dimidazoles (CDI) (540mg, 3.33mmol) be dissolved in anhydrous THF (10mL), slowly add N-Boc-D-L-Ala (530mg, 2.80mmol), stirring at room temperature 20min, add 2-(((3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate (500mg, 1.39mmol), under the condition of-78 DEG C, THF solution (the 1.0M of slow dropping potassium hexamethyldisilazide, 5mL), stop after reaction 1.5h, add water (25mL) cancellation reaction, ethyl acetate (25mL × 3) is used to extract again, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=6/1), obtains 286mg white solid, yield: 42%.

¹HNMR(400MHz,CDCl ₃):δppm7.60-7.64(m,2H),7.23(d,J＝8.3Hz,1H),6.70(t,J _F-H＝75.1Hz,1H),5.67(br.s,1H),5.41-5.49(m,1H),3.98(s,3H),3.96(d,J＝7.0Hz,2H),1.54(d,J＝7.0Hz,3H),1.43(s,9H),1.29-1.35(m,1H),0.65-0.70(m,2H),0.36-0.40(m,2H)；

MS-ESI:m/z483.20[M+H] ⁺.

Step 2: the synthesis of compound (R)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid

Compound (R)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-methyl-formiate (280g, 0.58mmol) is dissolved in THF (10mL) and H ₂in the mixed solvent of O (5mL), then add a hydronium(ion) Lithium Oxide 98min (92mg, 2.19mmol), at 45 DEG C of reaction 2h, add dilute hydrochloric acid regulator solution about pH=1, removing THF, with ethyl acetate (15mL × 3) extraction, merge organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 243mg white solid, yield: 89%.

¹HNMR(600MHz,CD ₃OD):δppm7.81(d,J＝1.7Hz,1H),7.67(dd,J ₁＝8.4Hz,J ₂＝1.8Hz,1H),7.30(d,J＝8.3Hz,1H),6.90(t,J _F-H＝74.9Hz,1H),5.47-5.53(m,1H),4.04(d,J＝7.0Hz,2H),1.54(d,J＝7.1Hz,3H),1.44(s,9H),1.33-1.40(m,1H),0.66-0.71(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z467.10[M-H] ^-.

Step 3: the synthesis of compound ((R)-1-(5-((R)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane

By compound (R)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (200mg, 0.43mmol), compound (R)-3-methoxycarbonylamin pyrrolidine hydrochloride (92mg, 0.51mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (245mg, 1.28mmol) with N-hydroxyl-7-azepine benzotriazole (87mg, 0.64mmol) be dissolved in methylene dichloride (15mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.30mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/3), obtains 208mg white solid, yield: 8%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.59(m,2H),7.24(d,J＝8.3Hz,1H),6.69(t,J _F-H＝75.0Hz,1H),5.22-5.30(m,1H),4.27-4.37(m,1H),4.11-4.22(m,1H),4.00-4.07,3.84-3.91(m,0.5H,0.5H),3.96(d,J＝7.0Hz,2H),3.70-3.80(m,2H),3.65-3.70(m,3H),2.12-2.28(m,1H),1.97-2.08(m,1H),1.52-1.55(m,3H),1.42(s,9H),1.28-1.35(m,1H),0.66-0.71(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z595.25[M+H] ⁺.

Step 4: the synthesis of compound ((R)-1-(5-((R)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane hydrochloride

By compound ((R)-1-(5-((R)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl) pyrrolidin-3-yl) Urethylane (200mg, 0.34mmol) be dissolved in methylene dichloride (4mL), add the ethyl acetate solution (4M of HCl, 4mL), stirring at room temperature 30min, except desolventizing, obtain 176mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm7.71-7.74(m,2H),7.34(d,J＝8.3Hz,1H),6.92(t,J _F-H＝74.8Hz,1H),5.09-5.13(m,1H),4.30-4.34,4.09-4.14(m,0.5H,0.5H),4.23-4.28(m,2H),4.03-4.05(m,2H),3.77-3.90(m,1H),3.70-3.75,3.57-3.61(m,0.5H,0.5H),3.66-3.68(m,3H),2.19-2.31(m,1H),1.95-2.09(m,1H),1.79(d,J＝6.8Hz,3H),1.32-1.37(m,1H),0.68-0.71(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z495.10[M+H-HCl] ⁺.

embodiment 149: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-formic acid (4-methoxycarbonyl) benzyl ester hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-methoxycarbonyl) benzyl ester

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (200mg, 0.31mmol), 4-methyl hydroxy-benzoate (66mg, 0.4mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (187mg, 0.98mmol) with N-hydroxyl-7-azepine benzotriazole (68mg, 0.5mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.3mL, 2.0mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/1), obtains 133mg colorless solid, yield: 33%.

MS-ESI:m/z787.30[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-methoxycarbonyl) benzyl ester hydrochloride

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (4-methoxycarbonyl) benzyl ester (70mg, 0.09mmol) be dissolved in methylene dichloride (2mL), add the ethyl acetate solution (4M of HCl, 2mL), stirring at room temperature 40min, except desolventizing, obtain 59mg white solid, yield: 91%.

¹HNMR(400MHz,CD ₃OD):δppm8.00-8.02,7.68-7.73(m,0.5H,0.5H),7.50-7.60(m,2H),7.30-7.34(m,2H),7.11-7.21(m,2H),6.67-7.08(m,1H),5.76-5.61(m,1H),5.06-5.31(m,3H),4.22-4.28(m,1H),3.96-4.02(m,1H),3.81-4.02(m,2H),3.85(s,3H),3.70-3.74(m,1H),3.63-3.65(m,3H),2.47-2.52(m,1H),2.26-2.35(m,1H),1.71-1.76(m,3H),1.29-1.37(m,1H),0.64-0.68(m,2H),0.38-0.42(m,2H)；

MS-ESI:m/z687.40[M+H-HCl] ⁺.

embodiment 150: compound (S)-5-(5-(5-(1-amino-ethyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) synthesis of methyl valerate hydrochloride

Step 1: the synthesis of compound 3-(benzyloxy)-4-(difluoro-methoxy) methyl benzoate

By 3-hydroxyl-4-(difluoro-methoxy) methyl benzoate (5.0g, 22.94mmol), salt of wormwood (6.33g, 45.88mmol) be dissolved in DMF (60mL) with cylite (3.3mL, 27.53mmol), 4.5h is reacted at 60 DEG C, after adding water (40mL), with ethyl acetate (50mL × 3) extraction, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=5/1), obtains 6.99g white solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.75(s,1H),7.68(d,J＝8.2Hz,1H),7.48-7.38(m,5H),7.24(d,J＝8.3Hz,1H),6.67(t,J _F-H＝74.6Hz,1H),5.20(s,2H),3.93(s,3H)；

MS-ESI:309.0[M+H] ⁺。

Step 2: compound 3-(benzyloxy)-4-(difluoro-methoxy) benzoic synthesis

By compound 3-(benzyloxy)-4-(difluoro-methoxy) methyl benzoate (6.99g, 22.69mmol) with sodium hydroxide (2.27g, 56.74mmol) be dissolved in ethanol (60mL) with the mixed solvent of water (30mL), 1.5h is reacted at 60 DEG C, removing ethanol, regulate pH to 1 with hydrochloric acid (1M), with ethyl acetate (50mL × 3) extraction, after merging organic phase, use anhydrous Na ₂sO ₄drying, except desolventizing, obtains 6.70g white solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.49(d,J＝7.0Hz,2H),7.43-7.35(m,3H),7.26(d,J＝8.4Hz,1H),6.88(t,J _F-H＝74.5Hz,1H),5.23(s,2H)；

MS-ESI:293.1[M-H] ^-。

Step 3: the synthesis of compound 2-(3-(benzyloxy)-4-(difluoro-methoxy) benzamido) methyl acetate

By compound 3-(benzyloxy)-4-(difluoro-methoxy) phenylformic acid (6.70g, 22.79mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (6.60g, 34.19mmol) with I-hydroxybenzotriazole (4.62g, 34.19mmol) be dissolved in methylene dichloride (60mL), stirring at normal temperature 0.5h, glycine methyl ester hydrochloride (3.44g is added at 0 DEG C, 27.35mmol) and N, N-diisopropylethylamine (12.25mL, 68.37mmol), stirring at room temperature 12h, add water (40mL × 3) washing, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 7.95g white solid, yield: 96%.

¹HNMR(400MHz,CDCl ₃):δppm7.62(s,1H),7.47-7.33(m,6H),7.24(d,J＝8.3Hz,1H),6.67(br.s,1H),6.65(t,J _F-H＝74.5Hz,1H),5.20(s,2H),4.25(d,J＝5.0Hz,2H),3.83(s,3H)；

MS-ESI:m/z366.2[M+H] ⁺。

Step 4: the synthesis of compound 2-(3-(benzyloxy)-4-(difluoro-methoxy) phenylsulphamide) methyl acetate

By compound 2-(3-(benzyloxy)-4-(difluoro-methoxy) benzamido) methyl acetate (7.95g, 21.80mmol) with lawesson reagent (8.80g, 21.80mmol) be dissolved in tetrahydrofuran (THF) (60mL), 75 DEG C of return stirring 2h, after adding saturated sodium bicarbonate solution (40mL), with ethyl acetate (50mL × 3) extraction, after merging organic phase, use Na ₂sO ₄drying, except desolventizing, concentrated solution carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 8.33g yellow solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm8.08(br.s,1H),7.69(s,1H),7.50-7.28(m,6H),7.21(d,J＝8.3Hz,1H),6.64(t,J _F-H＝74.7Hz,1H),5.21(s,2H),4.57(d,J＝4.5Hz,2H),3.88(s,3H)；

MS-ESI:m/z380.0[M-H] ^-。

Step 5: the synthesis of compound 2-(((3-(benzyloxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate

Under-78 DEG C of conditions, by compound 2-(3-(benzyloxy)-4-(difluoro-methoxy) phenylsulphamide) methyl acetate (8.33g, methylene dichloride (30mL) solution 21.87mmol) is slowly added drop-wise to trimethylammonium oxygen Tetrafluoroboric acid (6.47g, in methylene dichloride (20mL) solution 43.74mmol), after continuing to stir 3h at 0 DEG C, add saturated sodium bicarbonate solution (25mL × 3) washing, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, obtains 8.55g yellow oil, productive rate: 99%.

MS-ESI:m/z396.2[M+H] ⁺。

Step 6: the synthesis of compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-methyl-formiate

By compound 2-(((3-(benzyloxy)-4-(difluoro-methoxy) phenyl) (methylthio group) methylene radical) is amino) methyl acetate (3.45g, 8.74mmol), compound (S)-(the fluoro-1-oxopropan of 1--2-base) t-butyl carbamate (4.45g, 23.30mmol) be dissolved in anhydrous tetrahydro furan (30mL), under-78 DEG C of conditions, drip the tetrahydrofuran solution (30.00mL of potassium hexamethyldisilazide, 30.00mmol), 1h is reacted under-78 DEG C of conditions, react with frozen water (20mL) cancellation, ethyl acetate (15mL × 3) extracts, anhydrous Na is used after merging organic phase ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=4/1), obtains 3.78g yellow solid, yield: 83%.

¹HNMR(400MHz,CDCl ₃):δppm7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.50-7.36(m,5H),7.29(d,J＝8.3Hz,1H),6.66(t,J _F-H＝74.7Hz,1H),5.68(br.s,1H),5.53-5.45(m,1H),5.23(s,2H),4.01(s,3H),1.57(d,J＝7.0Hz,3H),1.45(s,9H)。

Step 7: the synthesis of compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-methyl-formiate (0.55g, 1.06mmol) with lithium hydroxide monohydrate (0.22g, 5.30mmol) be dissolved in tetrahydrofuran (THF) (20mL) with the mixed solvent of water (10mL), 3h is reacted at 40 DEG C, removing tetrahydrofuran (THF), add hydrochloric acid (1M) adjust ph to 1, add ethyl acetate (30mL × 3) extraction, organic phase uses Na after merging ₂sO ₄drying, except desolventizing, obtains 0.53mg white solid, productive rate: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.80(s,1H),7.68(d,J＝8.4Hz,1H),7.51-7.35(m,5H),7.29(d,J＝8.4Hz,1H),6.66(t,J _F-H＝74.7Hz,1H),5.68(br.s,1H),5.53-5.46(m,1H),5.23(s,2H),1.57(d,J＝7.0Hz,3H),1.45(s,9H)；

MS-ESI:m/z449.2[M-55]。

Step 8: the synthesis of compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (1.0g, 1.98mmol), N-cyclopropyl carbonyl piperazine hydrochloride (454mg, 2.38mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (570mg, 2.97mmol) with N-hydroxyl-7-azepine benzotriazole (404mg, 2.97mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.4mL, 7.93mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 875mg white solid, yield: 69%.

¹HNMR(600MHz,CDCl ₃):δppm7.66(s,1H),7.62(d,J＝7.8Hz,1H),7.49(d,J＝7.4Hz,2H),7.43(t,J＝7.5Hz,2H),7.36-7.39(m,1H),7.29(d,J＝8.1Hz,1H),6.66(t,J _F-H＝74.6Hz,1H),5.23-5.32(m,1H),5.24(s,2H),3.75-3.97(m,8H),1.68-1.71(m,1H),1.57(d,J＝7.2Hz,3H),1.44(s,9H),1.30-1.33(m,1H),1.05-1.07(m,2H),0.84-0.91(m,2H)；

MS-ESI:m/z641.20[M+2H] ⁺.

Step 9: the synthesis of compound (S)-(1-(4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (875mg, 1.37mmol) with nickelous chloride (377mg, 2.91mmol) be dissolved in tetrahydrofuran (THF) (5mL), in this solution, sodium borohydride (459mg is dripped under 0 DEG C of condition, tetrahydrofuran (THF) (15mL) solution 12.1mmol), stirring at room temperature 8.5h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 200mg white solid, yield: 28%.

¹HNMR(600MHz,CDCl ₃):δppm7.61(s,1H),7.49(d,J＝8.4Hz,1H),7.20(d,J＝8.4Hz,1H),6.65(t,J _F-H＝73.2Hz,1H),5.25-5.27(m,1H),3.77-4.05(m,8H),1.74-1.82(m,1H),1.57(d,J＝6.6Hz,3H),1.44(s,9H),1.29-1.35(m,1H),1.05-1.07(m,2H),0.85-0.90(m,2H)；

MS-ESI:m/z551.25[M+H] ⁺.

Step 10: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate

By compound (S)-(1-(4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg, 0.36mmol), 5-bromo pentane acid A ester (106mg, 0.55mmol) with salt of wormwood (100mg, 0.73mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 5 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 200mg white solid, productive rate: 83%.

¹HNMR(600MHz,CDCl ₃):δppm7.60(d,J＝8.4Hz,1H),7.57(d,J＝1.8Hz,1H),7.26(d,J＝8.4Hz,1H),6.64(t,J _F-H＝74.4Hz,1H),5.24-5.27(m,1H),4.15(t,J＝6.0Hz,2H),3.76-3.83(m,8H),3.71(s,3H),2.46(t,J＝7.1Hz,2H),1.88-1.95(m,5H),1.57(d,J＝7.2Hz,3H),1.44(s,9H),1.33-1.35(m,1H),1.04-1.06(m,2H),0.84-0.91(m,2H)；

MS-ESI:m/z665.30[M+H] ⁺.

Step 11: the synthesis of compound (S)-5-(5-(5-(1-amino-ethyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate hydrochloride

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropyl carbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate (200mg, 0.30mmol) be dissolved in methylene dichloride (2mL), add the aqueous isopropanol (25% of HCl, 3mL), stirring at room temperature 40min, except desolventizing, obtain 170mg white solid, yield: 94%, preparative chromatography is separated, and obtains 20mg white solid.

¹HNMR(600MHz,CD ₃OD):δppm7.77(s,1H),7.73(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),6.88(t,J _F-H＝74.4Hz,1H),5.05-5.09(m,1H),4.20(t,J＝5.8Hz,2H),3.74-3.96(m,8H),3.68(s,3H),2.48(t,J＝7.1Hz,2H),2.00-2.06(m,1H),1.85-1.95(m,4H),1.79(d,J＝6.9Hz,3H),1.33-1.36(m,1H),0.93-0.96(m,2H),0.89-0.92(m,2H)；

MS-ESI:m/z565.20[M+H-HCl] ⁺.

embodiment 151: compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4- carbonyl) synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound (S)-4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (500mg, 0.99mmol), 1-piperazinecarboxylic acid methyl esters (171mg, 1.19mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (285mg, 1.49mmol) with N-hydroxyl-7-azepine benzotriazole (202mg, 1.49mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.52mL, 2.97mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 567mg white solid, yield: 91%.

¹HNMR(400MHz,CDCl ₃):δppm7.66(d,J＝2.0Hz,1H),7.62(dd,J ₁＝8.0Hz,J ₂＝2.0Hz,1H),7.49(d,J＝7.4Hz,2H),7.43(t,J＝7.5Hz,2H),7.36-7.39(m,1H),7.28(d,J＝8.0Hz,1H),6.66(t,J _F-H＝74.8Hz,1H),5.23-5.32(m,1H),3.25(s,2H),3.94(br.s,3H),3.77(s,3H),3.60(br.s,5H),1.56(d,J＝7.2Hz,3H),1.44(s,9H)；

MS-ESI:m/z631.20[M+H] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (567mg, 0.90mmol) with nickelous chloride (175mg, 1.35mmol) be dissolved in tetrahydrofuran (THF) (5mL), in this solution, sodium borohydride (459mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 12.1mmol), stirring at room temperature 8.5h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium water solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: MeOH/EtOAc (v/v)=1/20), obtains 442mg white solid, yield: 91%.

¹HNMR(400MHz,CDCl ₃):δppm7.61(d,J＝1.6Hz,1H),7.48(dd,J ₁＝8.4Hz,J ₂＝1.6Hz,1H),7.18(d,J＝8.4Hz,1H),6.64(t,J _F-H＝73.2Hz,1H),5.22-5.26(m,1H),3.95(br.s,2H),3.77(s,3H),3.60(br.s,4H),1.56(d,J＝6.8Hz,3H),1.43(s,9H)；

MS-ESI:m/z541.25[M+H] ⁺.

Step 3: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (442mg, 0.82mmol), 5-bromo pentane acid A ester (239mg, 1.23mmol) with salt of wormwood (226mg, 1.64mmol) be dissolved in DMF (15mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtain 454mg colorless oil, productive rate: 85%.

¹HNMR(600MHz,CDCl ₃):δppm7.60(dd,J ₁＝8.4Hz,J ₂＝1.8Hz,1H),7.56(d,J＝1.8Hz,1H),7.26(d,J＝8.4Hz,1H),6.64(t,J _F-H＝75.0Hz,1H),5.23-5.27(m,1H),4.14-4.15(m,2H),3.94-3.99(m,2H),3.76(s,3H),3.71(s,3H),3.60(br.s,4H),2.45-2.47(m,2H),1.86-1.95(m,4H),1.56(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z655.25[M+H] ⁺.

Step 4: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(methoxycarbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (150mg, 0.23mmol) with sodium hydroxide (45mg, 1.15mmol) water-soluble (10mL) is with the mixed solvent of ethanol (20mL), 40 DEG C of reaction 1.5h, revolve and steam removing ethanol, add hydrochloric acid (1M) and regulate pH=1, ethyl acetate (25mL × 3) extracts, merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 128mg pale yellow oil, yield: 87%.

¹HNMR(400MHz,CD ₃OD):δppm7.72(d,J＝1.6Hz,1H),7.65(dd,J ₁＝8.4Hz,J ₂＝1.8Hz,1H),7.30(d,J＝8.4Hz,1H),6.86(t,J _F-H＝74.8Hz,1H),5.13-5.17(m,1H),4.18-4.21(m,2H),3.84(br.s,2H),3.74(s,3H),3.61(br.s,4H),2.42-2.45(m,2H),1.82-2.01(m,4H),1.55(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z641.30[M+H] ⁺.

Step 5: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(methoxycarbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (128mg, 0.20mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (57mg, 0.30mmol) with N-hydroxyl-7-azepine benzotriazole (40mg, 0.30mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (26mg, 0.30mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.10mL, 0.60mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 129mg white solid, yield: 91%.

¹HNMR(600MHz,CDCl ₃):δppm7.57-7.61(m,2H),7.25(d,J＝8.3Hz,1H),6.63(t,J _F-H＝74.6Hz,1H),5.22-5.27(m,2H),4.16-4.18(m,2H),3.94-3.99(m,3H),3.77(s,3H),3.69-3.83(m,6H),3.61-3.65(m,5H),3.51-3.52(m,2H),2.46-2.48(m,2H),1.89-1.98(m,4H),1.57(d,J＝7.1Hz,3H),1.44(s,9H)；

MS-ESI:m/z710.30[M+H] ⁺.

Step 6: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate hydrochloride

To compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (129mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.18mmol), 3mL), stirring at room temperature 40min, except desolventizing, obtain 110mg white solid, yield: 94%.

¹HNMR(600MHz,CD ₃OD):δppm7.77(s,1H),7.72(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),6.90(t,J _F-H＝74.4Hz,1H),5.05-5.08(m,1H),4.21-4.23(m,2H),3.80(br.s,2H),3.75(s,3H),3.59-3.69(m,14H),2.53-2.55(m,2H),1.93-1.96(m,2H),1.84-1.89(m,2H),1.78(d,J＝6.6Hz,3H)；

MS-ESI:m/z610.20[M+H-HCl] ⁺.

embodiment 152: compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4- carbonyl) synthesis of-N-cyclopropylpiperazin-1-carboxamide hydrochloride

Step 1: the synthesis of compound 4-(cyclopropylcarbamoyl) piperazine-1-t-butyl formate

By N, N-carbonyl dimidazoles (682mg, 4.20mmol) with triethylamine (1.22mL, 8.76mmol) be dissolved in anhydrous N, in dinethylformamide (5mL), ring third methylamine (200mg is dripped in this solution, N 3.50mmol), dinethylformamide (5mL) solution, stirring at room temperature 30 minutes, add 1-Boc-piperazine (0.651g again, N 3.50mmol), dinethylformamide (5mL) solution, 60 DEG C are stirred 1 hour, except desolventizing, add water (25mL), ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 674mg white solid, yield: 71%.

¹HNMR(400MHz,CD ₃OD):δppm3.40-3.41(m,4H),3.35-3.37(m,4H),2.53-2.58(m,1H),1.48(s,9H),0.65-0.70(m,2H),0.45-0.49(m,2H)；

MS-ESI:m/z214.15[M-55] ⁺.

Step 2: the synthesis of compound N-cyclopropylpiperazin-1-carboxamide hydrochloride

To compound 4-(cyclopropylcarbamoyl) piperazine-1-t-butyl formate (947mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (4mL) solution 2.50mmol); 6mL); stirring at room temperature 40min; except desolventizing; obtain 516mg white solid, yield: 100%.

¹HNMR(600MHz,CD ₃OD):δppm3.64(t,J＝7.8Hz,4H),3.21(t,J＝7.8Hz,4H),2.55-2.59(m,1H),0.68-0.72(m,2H),0.47-0.51(m,2H)；

MS-ESI:m/z170.20[M+H-HCl] ⁺.

Step 3: the synthesis of compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (250mg, 0.496mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (142mg, 0.743mmol) with N-hydroxyl-7-azepine benzotriazole (101mg, 0.743mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add N-cyclopropylpiperazin-1-carboxamide hydrochloride (122mg, 0.595mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.35mL, 1.98mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/3), obtains 282mg colorless oil, yield: 89%.

¹HNMR(400MHz,CDCl ₃):δppm7.66(d,J＝1.6Hz,1H),7.61(dd,J ₁＝8.4Hz,J ₂＝1.6Hz,1H),7.36-7.51(m,5H),7.28(d,J＝8.4Hz,1H),6.66(t,J _F-H＝74.8Hz,1H),5.21-5.32(m,1H),5.25(s,2H),3.77-4.01(m,4H),3.49-3.51(m,4H),2.70-2.72(m,1H),1.56(d,J＝7.2Hz,3H),1.44(s,9H),0.76-0.80(m,2H),0.50-0.53(m,2H)；

MS-ESI:m/z656.30[M+H] ⁺.

Step 4: the synthesis of compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (200mg, 0.305mmol) with nickelous chloride (79mg, 0.610mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (116mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 3.05mmol), stirring at room temperature 6h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methanol/ethyl acetate (v/v)=1/20), obtains 157mg white solid, yield: 91%.

¹HNMR(400MHz,CD ₃OD):δppm7.59(d,J＝2.0Hz,1H),7.52(dd,J ₁＝8.4Hz,J ₂＝2.0Hz,1H),7.25(d,J＝8.4Hz,1H),6.89(t,J _F-H＝74.6Hz,1H),5.11-5.14(m,1H),3.51-3.81(m,8H),2.56-2.59(m,1H),1.55(d,J＝7.2Hz,3H),1.42(s,9H),0.67-0.70(m,2H),0.47-0.51(m,2H)；

MS-ESI:m/z566.20[M+H] ⁺.

Step 5: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate

By compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate (157mg, 0.278mmol), 5-bromo pentane acid A ester (81mg, 0.416mmol) with salt of wormwood (76mg, 0.555mmol) be dissolved in DMF (15mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 130mg colorless oil, productive rate: 69%.

¹HNMR(600MHz,CDCl ₃):δppm7.56-7.60(m,2H),7.25(d,J＝8.4Hz,1H),6.64(t,J _F-H＝74.8Hz,1H),5.23-5.27(m,1H),4.13-4.16(m,2H),3.73-3.98(m,4H),3.69(s,3H),3.49(br.s,4H),2.68-2.70(m,1H),2.44-2.48(m,2H),1.87-1.95(m,4H),1.56(d,J＝6.8Hz,3H),1.44(s,9H),0.75-0.79(m,2H),0.49-0.52(m,2H)；

MS-ESI:m/z680.35[M+H] ⁺.

Step 6: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate (130mg, 0.191mmol) with sodium hydroxide (38mg, 0.956mmol) water-soluble (10mL) is with the mixed solvent of ethanol (20mL), 60 DEG C of reaction 1.5h, revolve and steam removing ethanol, add hydrochloric acid (1M) and regulate pH=1, ethyl acetate (25mL × 3) extracts, merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 123mg pale yellow oil, yield: 97%.

¹HNMR(400MHz,CDCl ₃):δppm7.66-7.84(m,2H),7.25(d,1H),6.63(t,J _F-H＝74.8Hz,1H),5.32-5.37(m,1H),4.22-4.28(m,2H),3.49-1.99(m,8H),2.69-2.71(m,1H),2.49-2.51(m,2H),1.76-1.85(m,4H),1.57(d,J＝6.8Hz,3H),1.45(s,9H),0.75-0.80(m,2H),0.50-0.53(m,2H).

Step 7: the synthesis of compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (123mg, 0.185mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (55mg, 0.277mmol) with N-hydroxyl-7-azepine benzotriazole (39mg, 0.277mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (25mg, 0.277mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.10mL, 0.554mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methanol/ethyl acetate (v/v)=1/20), obtains 101mg white solid, yield: 74%.

¹HNMR(600MHz,CDCl ₃):δppm7.58-7.60(m,2H),7.25(d,J＝8.3Hz,1H),6.63(t,J _F-H＝75.0Hz,1H),5.24-5.27(m,1H),4.15-4.18(m,2H),3.96-4.05(m,3H),3.74-3.86(m,2H),3.64-3.70(m,5H),3.50-3.51(m,5H),2.60-2.70(m,1H),2.46-2.48(m,2H),1.89-1.98(m,4H),1.57(d,J＝7.2Hz,3H),1.44(s,9H),0.76-0.79(m,2H),0.50-0.52(m,2H)；

MS-ESI:m/z735.30[M+H] ⁺.

Step 8: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-N-cyclopropylpiperazin-1-carboxamide hydrochloride

To compound (S)-(1-(4-(4-(cyclopropylcarbamoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (91mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.124mmol); 3mL); stirring at room temperature 40min; except desolventizing; obtain 82mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.76(s,1H),7.72(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),6.90(t,J _F-H＝74.4Hz,1H),5.06-5.07(m,1H),4.19-4.23(m,2H),3.65-3.77(m,8H),3.53-3.59(m,8H),2.57-2.60(m,1H),2.53-2.56(m,2H),1.94-1.95(m,2H),1.85-1.89(m,2H),1.78(d,J＝6.6Hz,3H),0.69-0.72(m,2H),0.49-0.51(m,2H)；

MS-ESI:m/z635.35[M+H-HCl] ⁺.

embodiment 153: compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-methylpiperazine-1-yl)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) synthesis of piperazine-1-methyl-formiate dihydrochloride

Step 1: the synthesis of compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-methylpiperazine-1-yl)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(methoxycarbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (130mg, 0.203mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (58mg, 0.304mmol) with N-hydroxyl-7-azepine benzotriazole (41mg, 0.31mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-methylpiperazine (26mg, 0.30mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.11mL, 0.609mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methanol/ethyl acetate (v/v)=1/20), obtains 117mg white solid, yield: 80%.

¹HNMR(400MHz,CD ₃OD):δppm7.72(d,J＝2.0Hz,1H),7.65(dd,J ₁＝8.0Hz,J ₂＝2.0Hz,1H),7.29(d,J＝8.0Hz,1H),6.87(t,J _F-H＝74.8Hz,1H),5.13-5.18(m,1H),4.19-4.22(m,2H),3.84(br.s,3H),3.74(m,3H),3.59-3.62(m,8H),2.52-2.56(m,2H),2.47-2.50(m,2H),2.42-2.44(m,2H),2.33(s,3H),1.91-1.96(m,2H),1.83-1.89(m,2H),1.55(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z723.30[M+H] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-methylpiperazine-1-yl)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate dihydrochloride

To compound (S)-4-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-methylpiperazine-1-yl)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-methyl-formiate (117mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.162mmol), 3mL), stirring at room temperature 40min, except desolventizing, obtain 101mg white solid, yield: 95%.

¹HNMR(600MHz,CD ₃OD):δppm7.79(s,1H),7.72(d,J＝7.8Hz,1H),7.34(d,J＝8.4Hz,1H),6.91(t,J _F-H＝74.4Hz,1H),5.05-5.08(m,1H),4.23-4.25(m,2H),4.20(br.s,2H),3.79(br.s,2H),3.76(s,3H),3.46-3.64(m,7H),3.02-3.26(m,3H),2.95(s,3H),2.60-2.62(m,2H),1.95-1.97(m,2H),1.87-1.90(m,2H),1.79(d,J＝7.2Hz,3H)；

MS-ESI:m/z623.20[M+H-2HCl] ⁺.

embodiment 154: compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-amino-ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) synthesis of-1-morpholinyl pentane-1-keto hydrochloride

Step 1: the synthesis of compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (300mg, 0.595mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (0.170g, 0.892mmol) with N-hydroxyl-7-azepine benzotriazole (125mg, 0.89mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add naphthalene-1-base (piperazine-1-base) methanone hvdrochloric acid salt (198mg, 0.714mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.31mL, 1.78mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 378mg white solid, yield: 88%.

MS-ESI:m/z727.25[M+H] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (378mg, 0.52mmol) with nickelous chloride (80mg, 0.52mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (100mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 2.60mmol), stirring at room temperature 19h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 209mg white solid, yield: 63%.

MS-ESI:m/z637.25[M+H] ⁺.

Step 3: the synthesis of compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate

By compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate (209mg, 0.329mmol), 5-bromo pentane acid A ester (80mg, 0.395mmol) with salt of wormwood (90mg, 0.658mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtain 224mg white solid, productive rate: 91%.

MS-ESI:m/z751.35[M+H] ⁺.

Step 4: the synthesis of compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate (220mg; 0.293mmol) with sodium hydroxide (58mg; 1.47mmol) water-soluble (10mL) is with the mixed solvent of ethanol (20mL); 60 DEG C of reaction 90min; revolve and steam removing ethanol; add hydrochloric acid (1M) and regulate pH=1; ethyl acetate (25mL × 3) extracts; merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 209mg white solid, yield: 97%.

MS-ESI:m/z737.25[M+H] ⁺.

Step 5: the synthesis of compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (209mg, 0.284mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (93mg, 0.425mmol) with N-hydroxyl-7-azepine benzotriazole (61mg, 0.425mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (40mg, 0.425mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.15mL, 0.851mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 147mg white solid, yield: 64%.

MS-ESI:m/z806.30[M+H] ⁺.

Step 6: the synthesis of compound (S)-5-(5-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-5-(1-amino-ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group)-1-morpholinyl pentane-1-keto hydrochloride

To compound (S)-(1-(4-(4-(1-naphthoyl) piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (147mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.182mmol); 3mL); stirring at room temperature 40min; except desolventizing; obtain 123mg white solid, yield: 91%.

¹HNMR(400MHz,CDCl ₃):δppm7.98-8.01(m,2H),7.88(d,J＝8.0Hz,1H),7.70-7.76(m,1H),7.56-7.65(m,4H),7.53-7.55(m,1H),7.24-7.37(m,1H),6.72-7.05(m,1H),4.99-5.03(m,1H),4.03-4.13(m,4H),3.72-3.75(m,2H),3.55-3.68(m,10H),3.33-3.44(m,2H),2.48-2.55(m,2H),1.88-1.89(m,4H),1.76(m,3H)；

MS-ESI:m/z706.30[M+H-HCl] ⁺.

embodiment 155: compound 1-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4- carbonyl) synthesis of piperazine-2-carboxamide dihydrochloride

Step 1: the synthesis of compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (300mg, 0.595mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (170mg, 0.892mmol) with N-hydroxyl-7-azepine benzotriazole (125mg, 0.892mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-tertbutyloxycarbonyl-3-piperazine carboxamides (164mg, 0.714mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.31mL, 1.78mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 330mg white solid, yield: 77%.

MS-ESI:m/z716.30[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate

By compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate (330mg, 0.461mmol) with nickelous chloride (60mg, 0.461mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (91mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 2.31mmol), stirring at room temperature 3h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 241mg white solid, yield: 84%.

MS-ESI:m/z626.20[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate (241mg, 0.385mmol), 5-bromo pentane acid A ester (90mg, 0.087mmol) with salt of wormwood (106mg, 0.14mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 229mg white solid, productive rate: 80%.

MS-ESI:m/z740.20[M+H] ⁺.

Step 4: the synthesis of compound 5-(5-(4-(4-(tertbutyloxycarbonyl)-2-formamyl piperazine-1-carbonyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate (229mg, 0.310mmol) with sodium hydroxide (60mg, 1.55mmol) water-soluble (10mL) is with the mixed solvent of ethanol (20mL), 60 DEG C of reaction 90min, revolve and steam removing ethanol, add hydrochloric acid (1M) and regulate pH=1, ethyl acetate (25mL × 3) extracts, merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 214mg white solid, yield: 95%.

MS-ESI:m/z726.30[M+H] ⁺.

Step 5: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate

By compound 5-(5-(4-(4-(tertbutyloxycarbonyl)-2-formamyl piperazine-1-carbonyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (214mg, 0.295mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (93mg, 0.442mmol) with N-hydroxyl-7-azepine benzotriazole (61mg, 0.442mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (40mg, 0.442mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (18mg, 0.14mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=10/1), (developping agent: methylene chloride/methanol (v/v)=15/1) is separated again through preparing silica-gel plate, obtain 110mg white solid, yield: 47%.

MS-ESI:m/z795.20[M+H] ⁺.

Step 6: the synthesis of compound 1-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-2-carboxamide dihydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-t-butyl formate (110mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.035mmol); 3mL); stirring at room temperature 40min; except desolventizing; obtain 87mg white solid, yield: 100%.

¹HNMR(400MHz,CD ₃OD):δppm7.70-7.77(m,2H),7.35(d,J＝8.0Hz,1H),6.91(t,J _F-H＝74.4Hz,1H),5.36-5.40(m,1H),5.17-5.20(m,1H),4.21-4.23(m,2H),3.78-3.92(m,2H),3.63-3.70(m,4H),3.57-3.60(m,4H),3.42-3.47(m,4H),2.53-2.56(m,2H),1.83-1.97(m,4H),1.80-1.83(m,3H)；

MS-ESI:m/z595.20[M+H-HCl] ⁺.

embodiment 156: compound 4-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4- carbonyl) synthesis of-3-formamyl piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (300mg, 0.595mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (171mg, 0.892mmol) with N-hydroxyl-7-azepine benzotriazole (121g, 0.892mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-methyl-formiate-3-piperazine carboxamides (191mg, 0.892mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (308mg, 2.38mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 161mg white solid, yield: 40%.

MS-ESI:m/z674.30[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate

By compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate (161mg, 0.239mmol) with nickelous chloride (31mg, 0.239mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (0.045g is dripped under 0 DEG C of condition, ethanol (20mL) solution 1.19mmol), stirring at room temperature 3h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 128mg white solid, yield: 92%.

MS-ESI:m/z584.20[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate (128mg, 0.219mmol), 5-bromo pentane acid A ester (51mg, 0.263mmol) with salt of wormwood (60mg, 0.439mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out post separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 61mg white solid, productive rate: 40%.

MS-ESI:m/z698.25[M+H] ⁺.

Step 4: the synthesis of compound 5-(5-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(2-formamyl-4-(methoxycarbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate (61mg, 0.087mmol) with lithium hydroxide monohydrate (18mg, 0.44mmol) water-soluble (10mL) is with the mixed solvent of tetrahydrofuran (THF) (20mL), 40 DEG C of reaction 90min, add hydrochloric acid (1M) and regulate pH=1, ethyl acetate (25mL × 3) extracts, merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 56mg white solid, yield: 94%.

MS-ESI:m/z684.25[M+H] ⁺.

Step 5: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate

By compound 5-(5-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(2-formamyl-4-(methoxycarbonyl) piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (56mg, 0.082mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (24mg, 0.12mmol) with N-hydroxyl-7-azepine benzotriazole (17mg, 0.12mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (20mg, 0.12mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (32mg, 0.25mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=10/1), (developping agent: methylene chloride/methanol (v/v)=20/1) is separated again through preparing silica-gel plate, obtain 35mg white solid, yield: 57%.

MS-ESI:m/z753.30[M+H] ⁺.

Step 6: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-3-formamyl piperazine-1-methyl-formiate (35mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.046mmol); 3mL); stirring at room temperature 40min; except desolventizing; dry; obtain 21mg white solid, yield: 66%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(s,1H),7.68-7.74(m,1H),7.32-7.36(m,1H),6.89(t,J _F-H＝74.4Hz,1H),5.05-5.12(m,2H),4.56-4.59(m,1H),4.48-4.51(m,0.5H),4.28-4.38(m,0.5H),4.19-4.23(m,2H),3.95-4.05(m,2H),3.74(s,2H),3.65-3.69(m,4H),3.54-3.59(m,6H),2.53-2.56(m,2H),1.93-1.96(m,2H),1.84-1.87(m,2H),1.74-1.80(m,3H)；

MS-ESI:m/z653.30[M+H-HCl] ⁺.

embodiment 157: compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4- carbonyl) synthesis of piperazine-1-carboxamide hydrochloride

Step 1: the synthesis of compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (300mg, 0.595mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (171mg, 0.892mmol) with N-hydroxyl-7-azepine benzotriazole (121mg, 0.892mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-piperazine carboxamides hydrochloride (200mg, 0.892mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.5mL, 9.52mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 176mg white solid, yield: 48%.

¹HNMR(400MHz,CDCl ₃):δppm7.66(d,J＝2.0Hz,1H),7.61(d,J ₁＝8.4Hz,J ₂＝2.0Hz,1H),7.36-7.50(m,5H),7.29(d,J＝8.4Hz,1H),6.66(t,J _F-H＝74.4Hz,1H),5.25-5.28(m,1H),5.25(s,2H),4.56(s,2H),3.83-4.00(m,4H),3.53-3.55(m,4H),1.57(d,J＝6.8Hz,3H),1.44(s,9H)；

MS-ESI:m/z616.30[M+H] ⁺.

Step 2: the synthesis of compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-(1-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-5-base) ethyl) t-butyl carbamate (176mg, 0.286mmol) with nickelous chloride (40mg, 0.286mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (60mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 1.43mmol), stirring at room temperature 3h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 128mg white solid, yield: 85%.

¹HNMR(400MHz,CDCl ₃):δppm7.62(d,J＝1.6Hz,1H),7.48(dd,J ₁＝8.7Hz,J ₂＝1.2Hz,1H),7.19(d,J＝8.4Hz,1H),6.66(t,J _F-H＝73.5Hz,1H),5.21-5.28(m,1H),4.90(s,2H),3.82-4.02(m,4H),3.53-3.59(m,4H),1.56(d,J＝6.8Hz,3H),1.44(s,9H)；

MS-ESI:m/z526.20[M+H] ⁺.

Step 3: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate

By compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-5-base) ethyl) t-butyl carbamate (128mg, 0.219mmol), 5-bromo pentane acid A ester (51mg, 0.263mmol) with salt of wormwood (60mg, 0.439mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 61mg white solid, productive rate: 40%.

¹HNMR(400MHz,CD ₃OD):δppm8.00(s,1H),7.71(d,J＝2.0Hz,1H),7.65(dd,J ₁＝8.4Hz,J ₂＝2.0Hz,1H),7.30(d,J＝8.4Hz,1H),6.86(t,J _F-H＝74.4Hz,1H),5.11-5.19(m,1H),4.18(t,J＝5.8Hz,2H),3.81-3.88(m,2H),3.68(s,3H),3.56-3.59(m,4H),2.47(t,J＝7.0Hz,2H),1.86-1.93(m,4H),1.56(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z640.30[M+H] ⁺.

Step 4: the synthesis of compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) methyl valerate (61mg; 0.087mmol) with lithium hydroxide monohydrate (18mg; 0.44mmol) water-soluble (10mL) is with the mixed solvent of tetrahydrofuran (THF) (20mL); 40 DEG C of reaction 90min; add hydrochloric acid (1M) adjust ph to 1; ethyl acetate (25mL × 3) extracts; merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 56mg white solid, yield: 94%.

¹HNMR(400MHz,CD ₃OD):δppm7.72(d,J＝1.7Hz,1H),7.65(dd,J ₁＝8.4Hz,J ₂＝1.7Hz,1H),7.30(d,J＝8.3Hz,1H),6.86(t,J _F-H＝74.4Hz,1H),5.15-5.17(m,1H),4.19(t,J＝5.8Hz,2H),3.85(br.s,4H),3.56-3.59(m,4H),2.43(t,J＝6.9Hz,2H),1.83-1.95(m,4H),1.56(d,J＝7.2Hz,3H),1.43(s,9H)；

MS-ESI:m/z626.30[M+H] ⁺.

Step 5: the synthesis of compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (56mg, 0.082mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (24mg, 0.12mmol) with N-hydroxyl-7-azepine benzotriazole (17mg, 0.12mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add morpholine (20g, 0.12mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (32mg, 0.25mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄dry, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=10/1), (developping agent: methylene chloride/methanol (v/v)=20/1) is separated again through preparing silica-gel plate, obtain 35mg white solid, yield: 57%.

¹HNMR(600MHz,CDCl ₃):δppm7.58-7.60(m,2H),7.25(d,J＝8.4Hz,1H),6.63(t,J _F-H＝74.4Hz,1H),5.23-5.28(m,1H),4.6(s,2H),4.18(t,J＝6.0Hz,2H),4.01-4.06(m,2H),3.79-3.85(m,2H),3.69-3.72(m,4H),3.63-3.65(m,2H),3.52-3.58(m,4H),3.50-3.52(m,2H),2.47(t,J＝7.3Hz,2H),1.90-1.97(m,4H),1.57(d,J＝7.2Hz,3H),1.44(s,9H)；

MS-ESI:m/z695.35[M+H] ⁺.

Step 6: the synthesis of compound (S)-4-(5-(1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) piperazine-1-carboxamide hydrochloride

To compound (S)-(1-(4-(4-formamyl piperazine-1-carbonyl)-2-(4-(difluoro-methoxy)-3-((5-morpholinyl-5-oxopentyl) oxygen base) phenyl) oxazole-5-base) ethyl) t-butyl carbamate (78mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.11mmol); 3mL); stirring at room temperature 40min; except desolventizing; pull an oar by ethyl acetate/petroleum ether (v/v=1/20); dry; obtain 69mg white solid, yield: 97%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(d,J＝1.2Hz,1H),7.73(dd,J ₁＝8.4Hz,J ₂＝1.2Hz,1H),7.74(d,J＝8.4Hz,1H),6.90(t,J _F-H＝74.4Hz,1H),5.06-5.10(m,1H),4.26(br.s,2H),4.23(t,J＝5.8Hz,2H),3.83(br.s,2H),3.64-3.70(m,8H),3.58-3.60(m,4H),2.55(t,J＝7.4Hz,2H),1.93-1.97(m,2H),1.84-1.89(m,2H),1.80(d,J＝7.2Hz,3H)；

MS-ESI:m/z595.30[M+H-HCl] ⁺.

embodiment 158: compound 4-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-(methoxycarbonyl) piperazine-1-base)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl) synthesis of-2-methylpiperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound (S)-2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-(1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-formic acid (300mg, 0.595mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (171mg, 0.892mmol) with N-hydroxyl-7-azepine benzotriazole (121mg, 0.892mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-methoxycarbonyl-2-methylpiperazine hydrochloride (217mg, 0.595mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.85mL, 4.76mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 383mg white solid, yield: 99%.

¹HNMR(400MHz,CDCl ₃):δppm7.60-7.66(m,2H),7.36-7.50(m,5H),7.28(d,J＝8.4Hz,1H),6.66(t,J _F-H＝74.8Hz,1H),5.28-5.32(m,1H),5.25(s,2H),4.39-4.67(m,3H),3.95-4.12(m,1H),3.77(s,3H),3.31-3.30(m,2H),2.88-2.98(m,1H),1.57(d,J＝7.2Hz,3H),1.44(s,9H),1.26(d,J＝6.8Hz,3H)；

MS-ESI:m/z645.10[M+H] ⁺.

Step 2: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound 4-(2-(3-(benzyloxy)-4-(difluoro-methoxy) phenyl)-5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (383mg, 0.594mmol) with nickelous chloride (77mg, 0.594mmol) be dissolved in ethanol (5mL), in this solution, sodium borohydride (113mg is dripped under 0 DEG C of condition, ethanol (20mL) solution 2.97mmol), stirring at room temperature 2h, add hydrochloric acid (1M) and regulate pH=1, stir to clarify, hydro-oxidation sodium solution (1M) regulates pH=14, ethyl acetate (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 308mg white solid, yield: 94%.

¹HNMR(600MHz,CDCl ₃):δppm7.63-7.65(m,1H),7.51-7.54(m,1H),7.20-7.22(m,1H),6.64(t,J _F-H＝73.2Hz,1H),5.24-5.32(m,1H),4.69-4.73(m,1H),4.48-4.60(m,2H),3.98-4.03(m,1H),3.76(s,3H),3.24-3.26(m,2H),2.92-3.07(m,1H),1.56(m,3H),1.44(s,9H),1.26-1.28(m,3H)；

MS-ESI:m/z555.30[M+H] ⁺.

Step 3: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-hydroxyphenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (308mg, 0.555mmol), 5-bromo pentane acid A ester (130mg, 0.667mmol) with salt of wormwood (154mg, 1.11mmol) be dissolved in DMF (10mL), 60 DEG C of tube sealing reactions 4 hours, suction filtration, removing salt of wormwood, concentrated filtrate, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtain 326mg white solid, productive rate: 88%.

MS-ESI:m/z669.30[M+H] ⁺.

Step 4: the synthesis of compound 5-(5-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(methoxycarbonyl)-3-methylpiperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid

By compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-methoxyl group-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (326mg, 0.488mmol) with lithium hydroxide monohydrate (102mg, 2.44mmol) water-soluble (10mL) is with the mixed solvent of tetrahydrofuran (THF) (20mL), 40 DEG C of reaction 1h, add hydrochloric acid (1M) adjust ph to 1, ethyl acetate (25mL × 3) extracts, merge organic phase, anhydrous Na ₂sO ₄drying, except desolventizing, obtains 313mg white solid, yield: 98%.

MS-ESI:m/z655.30[M+H] ⁺.

Step 5: the synthesis of compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-(methoxycarbonyl) piperazine-1-base)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate

By compound 5-(5-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-(methoxycarbonyl)-3-methylpiperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (157mg, 0.240mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (71mg, 0.360mmol) with N-hydroxyl-7-azepine benzotriazole (49mg, 0.360mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-methoxycarbonyl piperazine hydrochloride (65mg, 0.360mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.17mL, 0.595mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 171mg white solid, yield: 91%.

MS-ESI:m/z781.20[M+H] ⁺.

Step 6: the synthesis of compound 4-(5-((S)-1-amino-ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-(methoxycarbonyl) piperazine-1-base)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate hydrochloride

To compound 4-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(4-(difluoro-methoxy)-3-((5-(4-(methoxycarbonyl) piperazine-1-base)-5-oxopentyl) oxygen base) phenyl) oxazole-4-carbonyl)-2-methylpiperazine-1-methyl-formiate (165mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.211mmol), 3mL), stirring at room temperature 40min, except desolventizing, dry, obtain 133mg white solid, yield: 88%.

¹HNMR(600MHz,CD ₃OD):δppm7.78-7.79(m,1H),7.71-7.74(m,1H),7.34(d,J＝8.4Hz,1H),6.91(t,J _F-H＝74.4Hz,1H),5.05-5.12(m,1H),4.96-5.03(m,1H),4.42-4.53(m,2H),4.23(m,2H),4.03-4.05(m,1H),3.75(s,3H),3.73(s,3H),3.57-3.61(m,4H),3.53-3.46(m,4H),3.26-3.38(m,2H),3.00-3.17(m,1H),2.56(t,J＝7.3Hz,2H),1.93-1.96(m,2H),1.84-1.89(m,2H),1.80(d,J＝6.6Hz,3H),1.23-1.32(m,3H)；

MS-ESI:m/z681.20[M+H-HCl] ⁺.

embodiment 159: compound (2R, 4S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-methyl-formiate hydrochloride

Step 1: compound (2R, 4R)-2-methoxycarbonyl-4-is to the synthesis of Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate

By compound (2R, 4R)-1-tertbutyloxycarbonyl-4-L-Hydroxyproline methyl ester (1.0g, 4.08mmol), DMAP (50mg, 0.408mmol) with triethylamine (1.42mL, 10.2mmol) be dissolved in methylene dichloride (20mL), slow dropping Tosyl chloride (1.17g, methylene dichloride (10mL) solution 6.12mmol), stirring at room temperature 15h, add saturated nacl aqueous solution (20mL × 3), methylene dichloride (20mL × 3) extracts, organic phase Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=3/1), obtains 1.39g yellow oil, yield: 85%.

¹HNMR(600MHz,CDCl ₃):δppm7.76-7.79(m,2H),7.35-7.37(m,2H),5.03-5.08(m,1H),4.33-4.45(m,1H),3.69-3.70(m,3H),3.57-3.67(m,2H),2.46(s,3H),2.36-2.43(m,2H),1.41-1.45(m,9H)；

MS-ESI:m/z300.00[M+H-100] ⁺.

Step 2: the synthesis of compound (2R, 4S)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate

By compound (2R, 4R)-2-methoxycarbonyl-4-is to Methyl benzenesulfonyl oxygen base tetramethyleneimine-1-t-butyl formate (1.37g, 3.43mmol) with sodiumazide (1.15g, 17.1mmol) be dissolved in N, in dinethylformamide (10mL), 80 DEG C are stirred 5h, and add water (30mL), ethyl acetate (20mL × 3) extracts, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=2/1), obtains 803mg white solid, yield: 87%.

¹HNMR(400MHz,CDCl ₃):δppm4.32-4.44(m,1H),4.18-4.22(m,1H),3.75(m,3H),3.69-3.73(m,1H),3.46-3.61(m,1H),2.28-2.38(m,1H),2.18-2.21(m,1H),1.42-1.47(m,9H)；

MS-ESI:m/z171.25[M+H-100] ⁺.

Step 3: the synthesis of compound (2R, 4S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate

By compound (2R, 4S)-2-methoxycarbonyl-4-azido-tetramethyleneimine-1-t-butyl formate (150mg, 0.390mmol) join in methyl alcohol (150mg, 0.390mmol) with Pd/C (150mg, 0.390mmol), be filled with hydrogen, ventilation twice, stirring at room temperature 15h, except desolventizing, obtain 643mg grey oily matter, yield: 89%.

¹HNMR(600MHz,CD ₃OD):δppm4.38-4.41(m,1H),3.74-3.75(m,3H),3.64-3.69(m,1H),3.58-3.61(m,1H),3.16-3.21(m,1H),2.08-2.13(m,2H),1.42-1.48(m,9H)；

MS-ESI:m/z145.20[M+H-100] ⁺.

Step 4: the synthesis of compound (2R, 4S)-2-methoxycarbonyl-4-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate

By compound (2R, 4S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (112mg, 0.212mmol), N, N '-carbonyl dimidazoles (52mg, 0.318mmol) with triethylamine (0.15mL, 0.848mmol) be dissolved in dry DMF (10mL), 40 DEG C of stirring reactions 0.5 hour, add anhydrous methanol (10mL), 60 DEG C of stirring reactions 6 hours, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 245mg colorless oil, productive rate: 66%.

¹HNMR(400MHz,CDCl ₃):δppm4.84-4.88(m,1H),4.29-4.33(m,1H),3.78-3.83(m,1H),3.75(s,3H),3.69(s,3H),3.29-3.40(m,1H),2.23-2.26(m,2H),1.43-1.47(m,9H)；

MS-ESI:m/z203.20[M+H-100] ⁺.

Step 5: the synthesis of compound (2R, 4S)-2-methoxycarbonyl-4-methoxycarbonylamin pyrrolidine hydrochloride

To compound (2R, 4S)-2-methoxycarbonyl-4-methoxycarbonylamin tetramethyleneimine-1-t-butyl formate (245mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.810mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 189mg white solid, yield: 98%.

¹HNMR(600MHz,CD ₃OD):δppm4.65-4.68(m,1H),4.31-4.33(m,1H),3.89(s,3H),3.68(s,3H),3.64-3.67(m,1H),3.39-3.42(m,1H),2.44-2.46(m,2H)；

MS-ESI:m/z203.10[M+H-HCl] ⁺.

Step 6: the synthesis of compound (2R, 4S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (300mg, 0.64mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (180mg, 0.96mmol) with N-hydroxyl-7-azepine benzotriazole (130mg, 0.96mmol) add in methylene dichloride (20mL), stirring at room temperature 30min, add compound (2R, 4S)-2-methoxycarbonyl-4-methoxycarbonylamin pyrrolidine hydrochloride (140mg, 0.64mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.45mL, 2.60mmol), stirring at room temperature 10h, add water (25mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 198mg white solid, yield: 47%.

¹HNMR(400MHz,CDCl ₃):δppm7.52-7.61(m,2H),7.23-7.28(m,1H),6.72(t,J _F-H＝75.2Hz,1H),5.23-5.32(m,1H),4.32-4.44(m,2H),3.99-4.01(m,2H),3.68-3.80(m,8H),2.21-2.46(m,2H),1.54-1.57(m,3H),1.42-1.45(m,9H),1.34-1.35(m,1H),0.68-0.73(m,2H),0.42-0.45(m,2H)；

MS-ESI:m/z653.15[M+H] ⁺.

Step 7: the synthesis of compound (2R, 4S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (2R, 4S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-methyl-formiate (198mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.303mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 157mg white solid, yield: 94%.

¹HNMR(400MHz,CD ₃OD):δppm7.64-7.77(m,2H),7.33(d,J＝8.4Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.18-5.21(m,1H),4.35-4.43(m,1H),4.24-4.31(m,1H),4.05-4.07(m,2H),3.96-4.00(m,1H),3.79(s,1H),3.73(s,2H),3.69-3.73(m,1H),3.66-3.67(m,3H),2.45-2.47(m,1H),2.24-2.36(m,1H),1.33-1.36(m,3H),1.30-1.31(m,1H),0.69-0.72(m,2H),0.44-0.46(m,2H)；

MS-ESI:m/z553.30[M+H-HCl] ⁺.

embodiment 160: compound (2R, 4S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride

Step 1: the synthesis of compound (2R, 4S)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate

By ethylene-acetic acid (150mg, 1.74mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (501mg, 2.61mmol) with N-hydroxyl-7-azepine benzotriazole (356mg, 2.61mmol) add in methylene dichloride (20mL), stirring at room temperature 30min, add compound (2R, 4S)-2-methoxycarbonyl-4-amino-pyrrolidine-1-t-butyl formate (346mg, 1.42mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (1.2mL, 6.9mmol), stirring at room temperature 10h, add water (25mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/2), obtains 311mg white solid, yield: 70%.

¹HNMR(400MHz,CDCl ₃):δppm4.54-4.58(m,1H),4.31-4.43(m,1H),3.79-3.81(m,1H),3.75(s,3H),3.30-3.44(m,1H),2.22-2.28(m,2H),1.42-1.48(m,9H),1.30-1.36(m,1H),0.98-0.99(m,2H),0.76-0.79(m,2H)；

MS-ESI:m/z213.20[M+H-100] ⁺.

Step 2: the synthesis of compound (2R, 4S)-4-cyclopropylcarboxamido tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (2R, 4S)-2-methoxycarbonyl-4-cyclopropyl carboxamide base tetramethyleneimine-1-t-butyl formate (311mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.996mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 246mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm4.70-4.73(m,1H),4.44-4.45(m,1H),3.89(s,3H),3.61-3.69(m,1H),3.35-3.38(m,1H),2.45-2.50(m,2H),1.61-1.65(m,1H),0.88-0.92(m,2H),0.81-0.83(m,2H)；

MS-ESI:m/z213.20[M+H-HCl] ⁺.

Step 3: the synthesis of compound (2R, 4S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate

By compound (S)-5-(1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-formic acid (150mg, 0.32mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (92mg, 0.48mmol) with N-hydroxyl-7-azepine benzotriazole (65mg, 0.48mmol) add in methylene dichloride (20mL), stirring at room temperature 30min, add compound (2R, 4S)-4-cyclopropylcarboxamido tetramethyleneimine-2-methyl-formiate hydrochloride (79mg, 0.32mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.22mL, 1.28mmol), stirring at room temperature 10h, add water (25mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: petrol ether/ethyl acetate (v/v)=1/1), obtains 189mg white solid, yield: 89%.

¹HNMR(400MHz,CDCl ₃):δppm7.49-7.60(m,2H),7.22-7.28(m,1H),6.72(t,J _F-H＝75.2Hz,1H),5.27-5.34(m,1H),4.74-4.78,4.26-4.34(m,0.5H,0.5H),4.60-4.70(m,1H),4.01-4.10(m,1H),3.96-4.00(m,2H),3.80(s,1.5H),3.64(s,1.5H),2.44-2.48(m,1H),2.36-2.42,2.21-2.28(m,0.5H,0.5H),1.55-1.57(m,3H),1.42-1.46(m,9H),1.34-1.37(m,1H),1.29-1.32(m,1H),0.96-1.02(m,2H),0.85-0.90(m,2H),0.68-0.74(m,2H),0.43-0.45(m,2H)；

MS-ESI:m/z663.40[M+H] ⁺.

Step 4: the synthesis of compound (2R, 4S)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate hydrochloride

To compound (2R, 4S)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-(cyclopropyl carboxamide base) tetramethyleneimine-2-methyl-formiate (189mg, ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.285mmol), 4mL), stirring at room temperature 1h, except desolventizing, obtain 169mg white solid, yield: 99%.

¹HNMR(600MHz,CD ₃OD):δppm7.65-7.76(m,2H),7.33(d,J＝7.8Hz,1H),6.93(t,J _F-H＝75.0Hz,1H),5.52-5.54(m,1H),5.16-5.20(m,1H),4.53-4.57,4.29-4.31(m,0.5H,0.5H),4.41-4.49(m,1H),4.04-4.07(m,2H),3.99-4.02(m,1H),3.79(s,1H),3.73(s,2H),2.47-2.50(m,1H),2.28-2.39(m,1H),1.76-1.79(m,3H),1.59-1.66(m,1H),1.36-1.39(m,1H),0.86-0.89(m,2H),0.79-0.80(m,2H),0.69-0.72(m,2H),0.45-0.46(m,2H)；

MS-ESI:m/z563.35[M+H-HCl] ⁺.

embodiment 161: compound (S)-4-(5-(5-(5-(1-amino-ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) pentanoyl) synthesis of piperazine-1-methyl-formiate hydrochloride

Step 1: the synthesis of compound (S)-4-(5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) pentanoyl) piperazine-1-methyl-formiate

By compound (S)-5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) valeric acid (51mg, 0.082mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (23mg, 0.12mmol) with N-hydroxyl-7-azepine benzotriazole (17mg, 0.12mmol) be dissolved in methylene dichloride (20mL), stirring at room temperature 30min, add 1-methoxycarbonyl piperazine hydrochloride (25mg, 0.12mmol), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.05mL, 0.25mmol), stirring at room temperature 10h, add water (25mL × 3) wash, methylene dichloride (25mL × 3) extracts, merge organic phase, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: methylene chloride/methanol (v/v)=20/1), obtains 51mg white solid, yield: 83%.

¹HNMR(600MHz,CDCl ₃):δppm7.57-7.60(m,2H),7.24(d,J＝8.4Hz,1H),6.63(t,J _F-H＝75.0Hz,1H),5.24-5.32(m,1H),4.17(t,J＝6.0Hz,2H),4.00-4.08(m,2H),3.82(br.s,2H),3.75(s,3H),3.61-3.65(m,2H),3.49-3.55(m,10H),2.49(t,J＝7.3Hz,2H),1.94-1.97(m,2H),1.88-1.92(m,2H),1.56(d,J＝6.6Hz,3H),1.43(s,9H)；

MS-ESI:m/z752.40[M+H] ⁺.

Step 2: the synthesis of compound (S)-4-(5-(5-(5-(1-amino-ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) pentanoyl) piperazine-1-methyl-formiate hydrochloride

To compound (S)-4-(5-(5-(5-(1-((tertbutyloxycarbonyl) is amino) ethyl)-4-(4-formamyl piperazine-1-carbonyl) oxazole-2-base)-2-(difluoro-methoxy) phenoxy group) pentanoyl) piperazine-1-methyl-formiate (47mg; ethyl acetate solution (the 4M of HCl is added in methylene dichloride (2mL) solution 0.063mmol); 3mL); stirring at room temperature 40min; except desolventizing; obtain 39mg white solid, yield: 91%.

¹HNMR(600MHz,CD ₃OD):δppm7.78(s,1H),7.73(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),6.91(t,J _F-H＝74.4Hz,1H),5.06-5.09(m,1H),4.23(t,J＝6.0Hz,2H),4.20(br.s,2H),3.80(br.s,2H),3.73(s,3H),3.59-3.60(m,8H),3.53(br.s,2H),3.47(br.s,2H),4.57(t,J＝7.3Hz,2H),1.94-1.96(m,2H),1.85-1.88(m,2H),1.80(d,J＝7.2Hz,3H)；

MS-ESI:m/z652.20[M+H-HCl] ⁺.

embodiment 162: compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl base) synthesis of-4-((methoxycarbonyl) amino) tetramethyleneimine-2-formic acid ((4-hydroxy-cyclohexyl) methyl) methyl ester hydrochloride

Step 1: the synthesis of compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid ((4-hydroxy-cyclohexyl) methyl) methyl esters

By compound (2S, 4R)-1-(5-((S)-1-((tert-butoxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid (250mg, 0.39mmol), 6-methylol hexalin (61mg, 0.47mmol), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (300mg, 1.56mmol) with N-hydroxyl-7-azepine benzotriazole (79mg, 0.59mmol) be dissolved in methylene dichloride (10mL), in this solution, N is dripped under 0 DEG C of condition, N-diisopropylethylamine (0.67mL, 1.56mmol), stirring at room temperature 10h, add water (10mL × 3) wash, organic phase anhydrous Na ₂sO ₄drying, except desolventizing, concentrated solution carries out column chromatography for separation (eluent: Petroleumether/EtOAc (v/v)=2/5), obtains 97mg colorless solid, yield: 24%.

MS-ESI:m/z751.70[M+H] ⁺.

Step 2: the synthesis of compound (2S, 4R)-1-(5-((S)-1-amino-ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid ((4-hydroxy-cyclohexyl) methyl) methyl ester hydrochloride

By compound (2S, 4R)-1-(5-((S)-1-((tertbutyloxycarbonyl) is amino) ethyl)-2-(3-(cyclo propyl methoxy)-4-(difluoro-methoxy) phenyl) oxazole-4-carbonyl)-4-((methoxycarbonyl) is amino) tetramethyleneimine-2-formic acid ((4-hydroxy-cyclohexyl) methyl) methyl esters (70mg, 0.09mmol) be dissolved in methylene dichloride (2mL), add the aqueous isopropanol (25% of hydrogenchloride, 4mL), stirring at room temperature 40min, except desolventizing, obtain 79mg white solid, yield: 96%.

¹HNMR(400MHz,CD ₃OD):δppm7.67-7.78(m,2H),7.34-7.37(m,1H),6.94(t,J _F-H＝75.1Hz,1H),5.12-5.24(m,1H),4.40-4.46(m,1H),4.25-4.33(m,1H),4.06(d,J＝7.0Hz,2H),3.97-4.05(m,2H),3.85-3.89,3.71-3.76(m,0.5H,0.5H),3.68-3.70(m,3H),3.36-3.55(m,1H),2.24-2.52(m,2H),1.97-2.07(m,1H),1.81-1.88(m,2H),1.79(d,J＝6.9Hz,3H),1.50-1.68(m,3H),1.36-1.42(m,2H),0.90-1.07(m,3H),0.69-0.75(m,2H),0.44-0.48(m,2H)；

MS-ESI:m/z651.70[M+H-HCl] ⁺.

By the similar synthetic method of the embodiment of the present invention, and the synthetic method described in the present invention, with suitable optional starting raw material, prepare

Compound shown in table 1:

The structure of table 1 compound and MS data

Biological test

Biological Examples 1

The present invention adopts following methods to carry out biological test to the compound shown in formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf):

1. adopt BPS to produce test kit (BPS, 603343), the specification sheets provided according to manufacturers, adopt fluorescence polarization method detection compound to PDE4B2 enzyme inhibition.

2. PDE4B2 enzyme concn is formulated as 83.33pg/ μ L, final concentration is 27.78pg/ μ L; Substrate FAM-Cyclic-3 ', 5 '-AMP concentration is formulated as 300nM, and reaction final concentration is 100nM, and enzyme and substrate dilution all use test kit to carry damping fluid PDEAssaybuffer; BindingAgent utilizes test kit to carry BindingAgentDiluent to carry out 100 times of dilutions, for subsequent use.Reaction system is as shown in table 2 below.

Table 2 compound is to PDE4B2 enzyme IC ₅₀detection system

3. adopt 384 orifice plates to detect, Setup Experiments test sample sample wells, Positive control wells, negative control hole and blank control wells, the duplicate hole that utilizes each sample detects the restraining effect to PDE4B2 enzyme concn under 10 concentration, utilize PDE4B2 enzyme and FAM-Cyclic-3 ', 5 '-AMP substrate reactions hole is as positive control, FAM-Cyclic-3 ', 5 '-AMP substrate hole is as negative control, and buffering fluid apertures is as blank.After each hole adds respective sample, enzyme, substrate and damping fluid by table 2 order, 25 DEG C of thermostat containers hatch 1h, then every hole adds the BindingAgent15 μ L configured, and after 25 DEG C of constant temperature oscillator jolting 1h, utilize the multi-functional microplate reader of PHERAstarFS (BMG) to detect at FP485/525 wavelength place.Utilize GraphPadPrism5 software to map to PDE4B2 enzyme inhibition under compound different concns, calculate IC ₅₀.

According to the method described above to the mensuration of compound provided by the invention to PDE4B2 enzyme inhibition, the results are shown in Table 3.

Table 3 the compounds of this invention is to the measurement result of PDE4B2 enzyme inhibition

Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)
						Roflumilast	0.60	Embodiment 1	0.26	Embodiment 2	3.23
Embodiment 3	2.39	Embodiment 4	0.79	Embodiment 5	2.58
						Embodiment 6	1.52	Embodiment 7	2.62	Embodiment 8	39.52
Embodiment 9	99.95	Embodiment 10	7.95	Embodiment 11	2.50
						Embodiment 12	1.97	Embodiment 13	52.56	Embodiment 14	13.85
Embodiment 15	33.20	Embodiment 16	65.29	Embodiment 17	51.22
						Embodiment 18	5.93	Embodiment 19	25.47	Embodiment 20	1.38
Embodiment 21	13.08	Embodiment 22	12.77	Embodiment 23	7.67
						Embodiment 25	15.98	Embodiment 26	12.19	Embodiment 27	22.72
Embodiment 28	11.83	Embodiment 29	4.94	Embodiment 30	7.44
						Embodiment 31	0.48	Embodiment 32	2.48	Embodiment 33	10.26

Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)
						Embodiment 34	26.83	Embodiment 42	2.06	Embodiment 43	1.35
Embodiment 44	1.83	Embodiment 45	22.00	Embodiment 46	27.29
						Embodiment 47	39.74	Embodiment 48	9.55	Embodiment 49	5.14
Embodiment 50	2.50	Embodiment 51	44.20	Embodiment 52	10.74
						Embodiment 53	23.34	Embodiment 54	45.39	Embodiment 55	4.06
Embodiment 56	9.21	Embodiment 57	21.07	Embodiment 58	13.66
						Embodiment 59	33.1	Embodiment 60	0.24	Embodiment 61	0.21
Embodiment 62	38.05	Embodiment 63	5.49	Embodiment 64	1.94
						Embodiment 65	11.80	Embodiment 66	0.24	Embodiment 67	0.30
Embodiment 68	0.64	Embodiment 69	15.85	Embodiment 70	0.43
						Embodiment 71	2.95	Embodiment 72	2.16	Embodiment 73	0.31
Embodiment 74	0.36	Embodiment 75	1.46	Embodiment 76	18.41
						Embodiment 77	0.88	Embodiment 89	16.28	Embodiment 90	7.13
Embodiment 91	2.47	Embodiment 92	4.83	Embodiment 93	1.75
						Embodiment 94	0.56	Embodiment 95	0.15	Embodiment 96	0.25
Embodiment 97	4.10	Embodiment 99	0.57	Embodiment 101	0.19
						Embodiment 102	0.63	Embodiment 103	4.20	Embodiment 104	17.16
Embodiment 105	0.81	Embodiment 106	1.24	Embodiment 107	8.64
						Embodiment 108	2.19	Embodiment 111	3.49	Embodiment 112	2.32
Embodiment 113	13.21	Embodiment 114	2.65	Embodiment 115	9.80
						Embodiment 116	0.62	Embodiment 117	6.34	Embodiment 118	1.48
Embodiment 119	2.04	Embodiment 120	2.75	Embodiment 121	2.89
						Embodiment 122	9.75	Embodiment 123	5.94	Embodiment 124	3.36
Embodiment 125	5.39	Embodiment 126	0.37	Embodiment 127	1.40
						Embodiment 128	8.16	Embodiment 129	0.12	Embodiment 130	6.61
Embodiment 134	0.76	Embodiment 135	0.49	Embodiment 136	0.66
						Embodiment 139	1.67	Embodiment 141	1.01	Embodiment 142	0.85
Embodiment 143	59.08	Embodiment 145	11.86	Embodiment 147	0.14
						Embodiment 150	2.90	Embodiment 151	62.24	Embodiment 154	75.21
Embodiment 155	27.13	Embodiment 158	41.92	Embodiment 159	18.22
						Embodiment 160	16.77	Embodiment 164	0.50	Embodiment 165	2.17
Embodiment 169	3.73	Embodiment 184	1.16	Embodiment 185	17.19
						Embodiment 186	21.21	Embodiment 187	13.26	Embodiment 188	7.00

Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)	Embodiment is numbered	IC ₅₀(nM)
						Embodiment 205	2.92

Table 3 data presentation, compound of the present invention common manifestation in testing the in-vitro screening of PDE4B2 enzyme level goes out higher inhibit activities.

Biological Examples 2PK tests

Give male rat the compounds of this invention respectively by vein (i.v.) and gavage (i.g.), gather 0.083,0.25,0.5,1,2,4,6,8,10,24 and the blood of 36h time point, centrifugally prepare blood plasma.Measured the concentration of the compounds of this invention in its each time point blood plasma by LC/MS/MS, calculate the pharmacokinetic parameter that it is main, investigate the PK parameter etc. of the compounds of this invention in rat body.Concrete outcome is in table 4.

LC/MS/MS measuring method is: 4000QTRAP series LC/MS/MS mass spectrograph is equipped with Agilent 1200 binary syringe pump, 1290 automatic samplers and column oven; ESI source, positive ion MRM mode detection.WatersXbridgeC18 chromatographic column is used during analyzing;

Moving phase (A) is 2mM ammonium formiate+0.1% aqueous formic acid; Moving phase (B) is 2mM ammonium formiate+0.1% formic acid methanol solution; Flow velocity is 0.4mL/min; Column temperature 40 DEG C; Sample size 3 μ L.

The PK parameter of table 4 the compounds of this invention in rat body

(the countless certificate of note: N/A-; N/C-does not calculate)

Result shows, and the medicine of the compounds of this invention is all relatively good for experimental result, has certain druggability.

It will be apparent to one skilled in the art that present disclosure is not limited to foregoing illustrative embodiment, and can be embodied in other specific form and don't depart from its essential characteristics.Therefore, expect that each embodiment is all considered in all respects illustrative and nonrestrictive, should with reference to appended claims, instead of previous embodiment, therefore, all changes in the implication and scope of appended claims equivalents are all included in herein.

In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, identical embodiment or example are not necessarily referred to the schematic representation of above-mentioned term.And the specific features of description, structure, material or feature can combine in an appropriate manner in any one or more embodiment or example.

Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, those of ordinary skill in the art can change above-described embodiment within the scope of the invention when not departing from principle of the present invention and aim, revising, replacing and modification.

Claims

1. a compound, it is for such as formula the steric isomer of compound shown in the compound shown in (I) or formula (I), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

X is N (R ^b), O or S;

Y is O or S;

A is the heterocyclic radical containing at least one nitrogen-atoms;

M is 0,1,2 or 3;

N is 0,1,2,3,4,5,6,7,8,9 or 10;

2. compound according to claim 1, wherein R ¹for H, deuterium, C _1-4alkyl, halo C _1-4alkyl, amino C _1-3the C that alkyl, hydroxyl replace _1-3the C that alkyl, cyano group replace _1-3alkyl, C _1-3alkyl-C (=O)-, C _1-3alkyl-S (=O) ₂-, C _2-4thiazolinyl or C _2-4alkynyl;

M is 0,1,2 or 3.

3. compound according to claim 2, wherein R ¹for H, deuterium ,-CH ₃,-CH ₂cH ₃,-CH ₂cH ₂cH ₃,-CH (CH ₃) CH ₃,-CH ₂cl ,-CHCl ₂,-CCl ₃,-CH ₂f ,-CHF ₂,-CF ₃,-CH ₂cH ₂cl ,-CH ₂cHCl ₂,-CH ₂cH ₂f or-CH ₂cHF ₂;

4. compound according to claim 1, wherein R ³for H, deuterium, C _1-6alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6alkyl, C _1-6alkyl-C (=O)-, C _1-6alkyl-S (=O) ₂-, C _1-6alkyl-C (=O)-C _1-6alkylidene group, C _1-6alkyl-O-C (=O)-C _1-8alkylidene group, C _1-6alkyl-S (=O) ₂-C _1-6alkylidene group, C _2-6thiazolinyl, C _2-6alkynyl, C _3-8cycloalkyl, C _2-10heterocyclic radical, C _6-10aryl, C _1-9heteroaryl, C _3-8cycloalkyl C _1-6alkyl, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl C _1-6alkyl, C _3-8cycloalkyl-C (=O)-C _1-6alkylidene group or C _2-10heterocyclic radical-C (=O)-C _1-8alkylidene group.

5. compound according to claim 4, wherein R ³for C _1-3alkyl, halo C _1-3alkyl, C _1-3alkyl-C (=O)-C _1-6alkylidene group, C _1-3alkyl-O-C (=O)-C _1-6alkylidene group, C _1-3alkyl-S (=O) ₂-C _1-6alkylidene group, C _3-6cycloalkyl, C _2-6heterocyclic radical, C _6-10aryl, C _1-5heteroaryl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl C _1-3alkyl, C _1-5heteroaryl C _1-3alkyl, C _3-6cycloalkyl-C (=O)-C _1-6alkylidene group or C _2-6heterocyclic radical-C (=O)-C _1-6alkylidene group.

6. compound according to claim 5, wherein R ³for CH ₃-O-C (=O)-C _1-6alkylidene group, CH ₃cH ₂-O-C (=O)-C _1-6alkylidene group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1, 1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, Cvclopropvlmethvl, cyclopropylethyl, cyclobutylmethyl, CYCLOBUTYLETHYL, cyclopentyl-methyl, cyclohexyl methyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1, 1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, benzyl, styroyl, cyclohexyl-C (=O)-C _1-6alkylidene group, piperidyl-C (=O)-C _1-6alkylidene group, morpholinyl-C (=O)-C _1-6alkylidene group, piperazinyl-C (=O)-C _1-6alkylidene group, thio-morpholinyl-C (=O)-C _1-6alkylidene group, 1-oxo-thiomorpholin base-C (=O)-C _1-6alkylidene group or 1,1-dioxo-thiomorpholinyl-C (=O)-C _1-6alkylidene group.

7. compound according to claim 1, wherein A be containing at least one nitrogen-atoms by 3-12 former molecular heterocyclic radical.

8. compound according to claim 7, wherein A is following subformula:

Wherein:

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

Each Z ¹be NH, O, S, S (=O) or S (=O) independently ₂;

Each W is CH independently ₂, NH or O;

Each V is CH independently ₂or NH;

Each E is CH or N independently;

Each G is O or NH independently;

Each p is 0,1,2 or 3 independently;

Each q is 1 or 2 independently;

Each r is 0,1,2 or 3 independently;

Each s is 1,2 or 3 independently.

9. compound according to claim 8, wherein A is following subformula:

10. compound according to claim 1, it is for such as formula the steric isomer of compound shown in the compound shown in (II) or formula (II), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

Wherein:

Each Z is CH independently ₂, NH, O, S, S (=O) or S (=O) ₂;

T is 0,1,2 or 3.

11. compounds according to claim 1, it is for such as formula the steric isomer of compound shown in the compound shown in (IIa) or formula (IIa), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

12. compounds according to claim 1, it is for such as formula the steric isomer of compound shown in the compound shown in (IIb), formula (IIc) or formula (IIb), formula (IIc), geometrical isomer, tautomer, raceme, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

13. according to claim 1, 10, compound described in 11 or 12, wherein pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, pyruvate salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

14. compounds according to claim 1,10,11 or 12, wherein each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-6alkylidene group, R ⁶-C (=O)-C _2-6alkenylene, R ⁶-C (=O)-C _1-6alkylidene group-O-C (=O)-, R ⁶-C (=O)-C _2-6alkenylene-O-C (=O)-, R ⁶-C (=O) O-C _1-6alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-6alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-6alkylidene group, R ^cr ^bn-C (=O)-C _2-6alkenylene, R ^cr ^bn-C (=O)-C _1-6alkylidene group-O-C (=O)-, R ^cr ^bn-C (=O)-C _2-6alkenylene-O-C (=O)-, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C _1-6alkylidene group, R ⁶-C (=O)-N (R ^b)-C _2-6alkenylene, R ⁶-C (=O)-C _1-6alkylidene group-N (R ^b)-, R ⁶-C (=O)-C _2-6alkenylene-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-C _1-6alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-C _2-6alkenylene, R ^cr ^bn-C (=O)-C _1-6alkylidene group-N (R ^b)-, R ^cr ^bn-C (=O)-C _2-6alkenylene-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C (=O)-, R ⁶-C (=O)-N (R ^b)-C (=O)-C _1-6alkylidene group, R ⁶-C (=O)-N (R ^b)-C (=O)-C _2-6alkenylene, R ^6a-O-C _1-8alkylidene group, R ^6a-O-C _2-8alkenylene, oxo, C _1-8alkyl, halo C _1-6alkyl, amino C _1-6the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-6the C of alkyl, carboxyl substituted _1-6alkyl, C _1-6alkoxy C _1-6the C that alkyl, hydroxyl replace _1-6alkoxy C _1-6the C of alkyl, carboxyl substituted _1-6alkoxy C _1-6alkyl, C _1-6alkylamino C _1-6alkyl, C _6-10the C that aryloxy replaces _1-6alkyl, C _1-6alkoxyl group, halo C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkoxyl group, C _1-6alkylamino, C _1-6alkylamino C _1-6alkylamino, C _1-6alkylamino C _1-6alkoxyl group, C _1-6alkoxy C _1-6alkylamino, C _1-6alkylthio, C _2-6the C of thiazolinyl, carboxyl substituted _2-6thiazolinyl, C _2-6alkynyl, R ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-C _1-6alkylidene group, R ⁶-S (=O) ₂-C _2-6alkenylene, R ⁶-S (=O) ₂-N (R ^b)-, R ⁶-S (=O) ₂-N (R ^b)-C _1-6alkylidene group, R ⁶-S (=O) ₂-N (R ^b)-C _2-6alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-C _1-6alkylidene group, R ^cr ^bn-S (=O) ₂-C _2-6alkenylene, C _3-8cycloalkyl, C _3-8cycloalkyl oxy, C _3-8cycloalkyl amino, C _3-8cycloalkyl C _1-6alkyl, C _3-8cycloalkenyl group, C _3-8cycloalkenyl oxy, C _3-8cycloalkenyl group is amino, C _3-8cycloalkenyl group C _1-6alkyl, C _2-10heterocyclic radical, C _2-10heterocyclyloxy base, C _2-10heterocyclylamino group, C _2-10heterocyclic radical C _1-6alkyl, C _6-10aryl, C _6-10aryloxy, C _6-10arylamino, C _6-10aryl C _1-6alkyl, C _1-9heteroaryl, C _1-9heteroaryl oxygen base, C _1-9heteroaryl amino or C _1-9heteroaryl C _1-6alkyl;

15. compounds according to claim 14, wherein each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-3alkylidene group, R ⁶-C (=O)-C _2-4alkenylene, R ⁶-C (=O) O-C _1-4alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-4alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-C _2-4alkenylene, R ⁶-C (=O)-N (R ^b)-, R ⁶-C (=O)-N (R ^b)-C _1-3alkylidene group, R ⁶-C (=O)-N (R ^b)-C _2-4alkenylene, R ^cr ^bn-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-N (R ^b)-C _2-4alkenylene, R ^6a-O-C _1-6alkylidene group, R ^6a-O-C _2-6alkenylene, oxo, C _1-6alkyl, halo C _1-4alkyl, amino C _1-4the C that alkyl, hydroxyl replace _1-6the C that alkyl, cyano group replace _1-4the C of alkyl, carboxyl substituted _1-4alkyl, C _1-6alkoxy C _1-3the C that alkyl, hydroxyl replace _1-6alkoxy C _1-3the C of alkyl, carboxyl substituted _1-6alkoxy C _1-4alkyl, C _1-3alkylamino C _1-3alkyl, C _6-10the C that aryloxy replaces _1-3alkyl, C _1-3alkoxyl group, C _2-4the C of thiazolinyl, carboxyl substituted _2-4thiazolinyl, C _2-4alkynyl, R ⁶-S (=O) ₂-, R ⁶-S (=O) ₂-C _1-3alkylidene group, R ⁶-S (=O) ₂-C _2-4alkenylene, R ^cr ^bn-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-C _1-3alkylidene group, R ^cr ^bn-S (=O) ₂-C _2-4alkenylene, C _3-6cycloalkyl, C _3-6cycloalkyl C _1-3alkyl, C _2-6heterocyclic radical, C _2-6heterocyclic radical C _1-3alkyl, C _6-10aryl, C _6-10aryl C _1-3alkyl, C _1-6heteroaryl or C _1-6heteroaryl C _1-3alkyl;

16. compounds according to claim 15, wherein each R ⁵be H, deuterium, F, Cl, Br, I, CN, OH, NO independently ₂, NH ₂, R ⁶-C (=O)-, R ⁶-C (=O)-C _1-3alkylidene group, R ⁶-C (=O)-C _2-4alkenylene, R ⁶-C (=O) O-C _1-4alkylidene group-O-C (=O)-, R ⁶-C (=O) O-C _2-4alkenylene-O-C (=O)-, R ^cr ^bn-C (=O)-, R ^cr ^bn-C (=O)-O-, R ^cr ^bn-C (=O)-C _1-3alkylidene group, R ^cr ^bn-C (=O)-C _2-4alkenylene, R ⁶-C (=O)-N (R ^b)-, R ^cr ^bn-C (=O)-N (R ^b)-, R ^6a-O-C _1-6alkylidene group, R ^6a-O-C _2-6the C that the propyl group that the ethyl that the methyl that alkenylene, oxo, methyl, cyano group replace, carboxymethyl, ethyl, cyano group replace, propyloic, propyl group, cyano group replace, carboxylic propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, hydroxyl replace _1-4alkyl, phenoxymethyl, Phenoxyethyl, C _1-5alkoxy C _1-3the C that alkyl, hydroxyl replace _1-5alkoxy C _1-3the C of alkyl, carboxyl substituted _1-4alkoxy C _1-3alkyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, halo C _1-3the vinyl of alkyl, vinyl, carboxyl substituted, propenyl, the propenyl of carboxyl substituted, ethynyl, proyl, R ⁶-S (=O) ₂-, R ^cr ^bn-S (=O) ₂-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1, 1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1, 1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, phenyl, indenyl, naphthyl, benzyl, styroyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridylmethyl, pyridyl-ethyl group, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl or pyridazinyl ethyl,

Each R ⁶be H, deuterium, OH, NH independently ₂, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, methoxyl group, the methoxyl group that hydroxyl replaces, the methoxyl group of carboxyl substituted, oxyethyl group, the oxyethyl group that hydroxyl replaces, the oxyethyl group of carboxyl substituted, propoxy-, the propoxy-that hydroxyl replaces, the propoxy-of carboxyl substituted, isopropoxy, the isopropoxy that hydroxyl replaces, the isopropoxy of carboxyl substituted, butoxy, the butoxy that hydroxyl replaces, the butoxy of carboxyl substituted, isobutoxy, the isobutoxy that hydroxyl replaces, the isobutoxy of carboxyl substituted, methoxymethoxy, methoxy ethoxy, methoxy propoxy, oxyethyl group methoxyl group, ethoxy ethoxy, benzyloxy, phenyl ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, cyclo propyl methoxy, cyclobutyl methoxyl group, cyclopentylmethoxy, cyclohexyl methoxy, cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base, pyrrolidyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, 1-oxo-thiomorpholin base, 1,1-dioxo-thiomorpholinyl, THP trtrahydropyranyl, pyrrolidinylmethyl, tetrahydrofuran (THF) ylmethyl, piperidino methyl, piperizinylmethyl, morpholinyl methyl, thiomorpholinylmethyl, 1-oxo-thiomorpholin ylmethyl, 1,1-dioxo-thiomorpholinyl methyl, tetrahydropyrans ylmethyl, phenyl, indenyl, naphthyl, benzyl, styroyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazoles base, thiazolyl, isothiazolyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridylmethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl-methyl, pyrazinyl ethyl, pyridazinylmethyl or pyridazinyl ethyl,

17. compounds according to claim 1, its be have one of following structure compound or there is the steric isomer of one of following structural compounds, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:

18. 1 kinds of pharmaceutical compositions, it comprises the compound described in claim 1-17 any one.

19. pharmaceutical compositions according to claim 18, comprise at least one in pharmaceutically acceptable carrier, vehicle, thinner, assistant agent or vehicle further.

20. pharmaceutical compositions according to claim 18 or 19, comprise additional treatment agent further, and these additional treatment agent are for being used for the treatment of the medicine of chronic obstructive pulmonary disease (COPD), pharmaceutically active agents or their combination.

21. pharmaceutical compositions according to claim 20, wherein said additional treatment agent is: Sodium.alpha.-ketopropionate, doxofylline, roflumilast, Apremilast, Tetomilast, Tai Lusite, theophylline, formoterol, Salmeterol, FLUTICASONE PROPIONATE, Salmeterol/fluticasone propionate compound, rolipram, this spy of pyrrole rummy, cilomilast, CDP-840, QAB-149, Ao Dateluo, QVA149, Midesteine, neat circulation, husky butanolamine, carmoxirole, budesonide and epimer thereof, Viarox, Triamcinolone Acetonide, flunisolide, furoic acid momisone, Rofleponide, ciclesonide, ipratropium bromide, ipratropium bromide and salbutamol compound, oxitropium bromide, tiotropium bromide, Glycopyrronium Bromide, overgrown with weeds ground bromine ammonium, Wei Lanteluo, overgrown with weeds ground bromine ammonium/Wei Lanteluo compound, aclidinium bromide, aclidinium bromide/Formoterol Fumarate compound, LAS40464, LAS100977 (abediterol), AZD-8999, RPL-554, OCID-2987, CHF-6001, CR-3465, HPP-737, fluticasone furoate/Wei Lanteluo compound, Benralizumab, tralokinumab, Revatropate or their combination.

Compound described in 22. claim 1-17 any one or the pharmaceutical composition described in claim 18-21 any one are preparing the purposes in medicine, and wherein said medicine is used for preventing, process, treat or alleviate the disease relevant with 4 type phosphodiesterases (PDE4).

23. purposes according to claim 22, the wherein said disease relevant with 4 type phosphodiesterases (PDE4) is respiratory disease, allergy and inflammation, central nervous system (CNS) disease, pulmonary fibrosis or non-insulin-dependent diabetes mellitus.

24. purposes according to claim 23, wherein said respiratory disease is: chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary emphysema, asthma, chronic pneumonia, pneumoconiosis, bronchitis, allergic bronchitis, bronchiectasis, pulmonary tuberculosis fibrosis lesion, pulmonary cystic fibrosis, diffuse panbronchiolitis, bronchiolitis obliterans, acute respiratory distress syndrome (ARDS) or respiratory inflammation.

25. purposes according to claim 23, wherein said inflammation is anaphylaxis conjunctivitis, atopic dermatitis, allergic dermatitis, rheumatoid arthritis, interstitial cystitis, rhinallergosis, ulcerative colitis, ankylosing spondylitis, rheumatic arthritis or psoriatic arthritis.