WO2012016362A1 - Β-secretase inhibitors for treating alzheimer's disease and uses thereof - Google Patents

Abstract

Peptide compounds of formula I, and stereoisomers, salts having no physiology toxicity and prodrugs thereof for inhibiting β-secretase, and pharmaceutical composition comprising the above compounds as active ingredient are disclosed in the present invention. The peptide compounds of formula I, and stereoisomers, salts having no physiology toxicity and prodrugs thereof can prevent or treat diseases associated with β-secretase such as Alzheimer's disease.

Description

 Peptide β-secretase inhibitor for the treatment of Alzheimer's disease

 And its use

 The present invention relates to the field of medicinal chemistry, and in particular to a class of peptide sputum secretase inhibitors and their use for sputum secretase related diseases such as Alzheimer's disease. Background technique

Alzheimer's disease (AD) is an acquired mental retardation syndrome in the elderly due to brain dysfunction. The main feature of Alzheimer's disease is the abnormal deposition of amyloid in the brain in the form of extracellular plaques and intracellular neurofibrillary tangles. The pathogenic process is very complicated. At present, there is still no comprehensive substantive understanding of the pathogenic mechanism and biochemical changes of the disease. There are only a few hypotheses explaining the cause of AD. Among them, the amyloid protein theory is increasingly accepted. The amyloid accumulation rate is a comprehensive reflection of the rate of formation, accumulation, and outflow from the brain. The main component of amyloid plaque (SP) is amyloid (β-amylod, Αβ). Αβ is a CTF99 (99-amino-acid C-terminal fragment) obtained by cleavage of amyloid precursor protein (APP) by β secretases (or β amyloid cleaving enzyme, BACE). It was cut -secretase A β _4. And A β ". Among them Αβ ₄ . The ratio of Αβ ₄ to human 0 ₄₂ is 9: 1, Αβ _{42 is} more likely to polymerize each other, form amyloid plaque, abnormal deposition in the brain, thus forming the main pathology of Alzheimer's disease Symptoms (Dennis JS. Amyloid beta-protein and the genetics of Alzheimer's disease [J]. J. Biol. Chem, 1996, 271: 18295-18298; Christian H, Bart DS. The presenilins in Alzheimer's disease—proteolysis The key [J] . Science, 1999, 286: 916-919 ). Therefore, drugs that inhibit β-secretase activity can be used to treat Alzheimer's disease (Bart DS, Gerhard K. A firm base for drug development [J Nature, 1999, 402: 471-472; Dennis JS. Alzheimer's Disease: Genes, Proteins, and Therapy [J] .

Physiological Reviews. 2001, 81 (2): 741-766). The compound of the present invention can be used for the treatment of Alzheimer's disease by inhibiting the activity of P secretase and preventing the formation of Αβ and preventing the production of SP. Summary of the invention

 The present invention relates to a class of peptide compounds having P-secretase inhibitor activity, pharmaceutical compositions comprising these compounds, and the use of these compounds and pharmaceutical compositions for the treatment of P-secretase-related diseases.

 The present invention relates to a compound of formula (I), a stereoisomer thereof, a physiologically toxic salt or prodrug thereof.

 among them,

A is an amino group, an amino group having a substituent, and the substituent is -( ₆ acyl group, benzyl group;

8 ₁ and 8 ₂ are a dC ₃ decyl or alkenyl group which is deleted or substituted at 1, 2, 3 or partially substituted with R ₃ ;

R ₃ is halogen, C "C ₆ alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, aryl, heteroaryl, heteroaryl substituted or unsubstituted at any position. a ring group, the substituents are each independently - ( ₆ alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, aryl, heteroaryl or heterocyclic;

D is a deletion, -NHC0- or -NHC0-R ₄ -;

^ is C "C ₆ alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, aryl, heterocyclyl, heteroaryl, substituted or unsubstituted at any position, Substituents are each independently halogen, C-C ₆ alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, aryl, heterocyclyl or heteroaryl;

E is a bioelectronic isosteric structure of a deletion, halogen, -H, -OH, -NH ₂ , -C00H, - C00CH ₃ , a tetrazole ring, or -C00H;

! ^ and R ₂ are independent - C00H, -C00H bio-electronic isosteric structure, any bit Substituted or unsubstituted d- ₆ alkyl, C ₂ -C ₆ alkenyl, C plant 0: ₇ cycloalkyl, heterocyclic; substituent phenyl, benzyl, ^ gram > benzocane a thio group, a benzenesulfonyl substituted d- ₆ alkyl group, an arylalkyl group and a cycloalkyl structure, -OH, -N0 ₂ , 3⁄4 , -C00H, and a physiologically toxic salt or prodrug thereof;

 n is 1, 2, 3;

 Q is a natural amino acid residue, or a formula ( Π ), or a formula (ΙΠ):

Wherein, 1\ is -0-, -S-, -NH-, -NR ₆ -, -CH ₂ -, -CHR ₆ - or -CR ₆ R ₆ '-;

R ₆ and R ₆ are each independently H, C "C ₆ linear or branched alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -d. cycloalkyl, any position is wholly or Partially substituted or unsubstituted aryl, heteroaryl, heterocyclic, substituents are each independently halogen, linear or branched alkyl of dC ₆ , c ₂ -c ₆ alkenyl or alkynyl, c ₃ a -c ₇ cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group;

 i is 0, 1, 2;

R ₅ is a _6- alkyl group substituted or unsubstituted at a partial or total position, C ₂ -( ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkenyl, aryl, a heterocyclic group or a heteroaryl group; the substituents thereof are each independently a C "C ₆ straight or branched alkyl group, a c ₂ -c ₆ alkenyl group or a blocked group, a c ₃ -c ₇ cycloalkyl group, a heterocyclic group , aryl, arylhetero, -OH, -NH ₂ , -N0 ₂ , halogen, -CN, -C00H, and its non-physiologically toxic salts or prodrugs;

W is a C plant substituted or unsubstituted at any position ( ₇ -cycloalkyl, aryl, C ₃ - (: ₇ cycloalkenyl, heteroaryl, heterocyclic, substituent halogen, -OH, -NH) ₂ , - C00H, - C00H bioisosteric structure, linear or branched alkyl group of dC ₆ , c ₂ -c ₆ alkenyl or alkynyl, c ₃ -c ₇ cycloalkyl, heterocyclic, hetero Aryl group, or formula (IV);

 IV

 among them,

T ₂ is - 0-, -S -, - NH-, - NR ₇ -, -CH ₂ -, -CHR or - CR ₇ R ₇ ,-;

R ₇ and R ₇ are each independently -H, a linear or branched alkyl group of a d-Ce optionally substituted or unsubstituted at any position, a C ₂ -C ₆ alkenyl group or an alkynyl group. Cycloalkyl, aryl, heteroaryl, heterocyclic; substituents are each independently halogen, d- straight or branched alkyl, C ₂ , C ₆ alkenyl or alkynyl, C ₃ -C ₇ a cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group;

1 is a linear or branched alkyl group of dC ₆ , a C ₂ -C ₆ alkenyl group or an alkynyl group, Cr. a cycloalkyl group, a C ₃ -C ₇ cycloalkenyl group, an aryl group, a heteroaryl group or a heterocyclic group which is wholly or partially substituted or unsubstituted at any position; the substituent is a linear or branched group of each independently dC ₆ Alkenyl, C "C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, heterocyclyl, aryl, aryl, -OH, -NH ₂ , -N0 ₂ , halogen, -CN, -C00H, and its non-physiological salt or prodrug;

 G is -0H, an amino acid residue, a peptide fragment consisting of 2-4 amino acid residues, or a structure of formula (V):

其中，

among them,

Z is -NH-, -Asp-Ala-ΝΗ-, -Asp-Ala-, -Problem - CZ^ZJ-, -Asp-ΝΗ-, -Asp- 02 ₁ (2 ₂ )- or - - 2 ₁ ( 2 ₂ )-02 ₁ (2 ₂ )-, wherein ∑! and Z ₂ are each independently -H, -0H, gas-CN, with alkyl or halogen of dC ₆ (here brackets mean Z!, Z ₂ is connected to the same carbon atom, instead of z ₂ );

1^ ₂ is C ₅ — i. A cycloalkyl group containing a double bond at any position. a cycloalkenyl group, an aryl group, a heteroaryl group or a heterocyclic group; X is a bioelectron isosteric structure of -H, -C00H, -C00H, -C0NHR ₈ , -OCH ₂ COOR ₈ , -OCH ₂ CONHR ₈ , -OH, - P0 ₄ H, -S0 ₃ H or - CZ ₃ ( Z ₄ ) X, (here the brackets mean that Z ₃ and Z ₄ are all attached to the same carbon atom, not Z ₃ and Z _{4 are} connected), wherein Z ₃ and Z ₄ are independent -H, -OH , -NH ₂ , -CN, -N0 ₂ , C "C ₆ alkyl, halogen, or formula (VI);

X, is H, -C00H, -C0NHR ₈ , -OCH ₂ COOR ₈ , -OCH ₂ CONHR ₈ , -OH, - P0 ₄ H or -S0 ₃ H,

Y and Y are independently -H, -C00H, -CONHRg, - 0R ₈ , -P0 ₄ H, - S0 ₃ H, halogen or methyl;

R ₈ AH, (^-( ₄ alkyl, a straight or branched alkyl group of dC ₄ substituted by a _3⁄4 atom; K is 1, 2, 3, 4;

 Terms used in this application have the following meanings unless otherwise stated:

 In the present invention, the "amino acid" means an L-form or a D-type amino acid; and the "alkyl" means an aliphatic group which may be a linear or branched chain having from 1 to about 15 carbon atoms. a hydrocarbyl group, especially an alkyl group having from 1 to about 6 carbon atoms, for example from 1 to 4 carbon atoms;

The "alkenyl group" refers to a straight or branched aliphatic hydrocarbon group having a carbon-carbon double bond having from about 2 to about 15 carbon atoms in the same chain; the "branched" used herein and throughout the text is It means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight chain; herein refers to a linear alkenyl chain; exemplary alkenyl groups include ethylenyl, propylalkenyl, n-butyl chain Mercapto, isobutenyl, 3-mercaptobut-2-enyl, n-pentenyl, heptenyl, octyl alkenyl, cyclohexylbutenyl and anthracenyl. The alkenyl group may be independently selected from halogen, nitro, amino, hydroxy, carboxy, dC ₄ alkyl or d-alkoxy or (^-(: ₄ alkylthio) by 1, 2, 3 or 4 independently. Substituent substituent; the "block group" refers to an aliphatic hydrocarbon group having a carbon-carbon oxime bond which may be a linear or branched chain having from about 2 to about 15 carbon atoms. There are 2 to about 12 in the chain a carbon atom; and more preferably a chain having from 2 to about 6 carbon atoms (e.g., 2-4 carbon atoms); exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, 3-decyl But-2-ynyl and n-pentynyl. An alkynyl group may be substituted by 1, 2, 3 or 4 independently from a steroid, a nitro group, an amino group, a hydroxy group, a carboxyl group, a dC ₄ alkyl group or a d-C ₄ alkoxy group or a dC ₄ alkylthio group. Base substitution

The "aryl" is a 6-14 membered monocyclic or bicyclic aryl group, such as phenyl or naphthyl, which is unsubstituted or monosubstituted by a substituent independently selected from a steroid, a nitro group, a carboxy group or an alkyl group. Or di- or tri-substituted; the "heteroaryl" is a 4-10 membered monocyclic or bicyclic aryl group containing from 1 to 5 heteroatoms independently selected from hydrazine, 0 and S, such as pyrrolyl, furan a group, a pyridyl group, an imidazolyl group, a fluorenyl group or the like which is unsubstituted or monosubstituted or disubstituted with a substituent independently selected from the group consisting of a 13-tetracycline, a nitro group, a carboxyl group or a dC ₄ alkyl group;

 The "heterocyclic group" is a compound having one or more (e.g., 2, 3, 4, 5) hetero atoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (0) and sulfur (S). The heterocyclic group may especially be aromatic (i.e., heteroaryl), saturated or partially saturated. Preferred monocyclic heterocyclic groups of the invention include 5- and 6-membered monocyclic heterocyclic groups. These heterocyclic and heteroaromatic compounds may be further substituted by the following groups: 13⁄4, alkyl, decyloxy, alkyl, alkoxy, nitro, cyano, sulfanyl, alkylamino Or phenyl;

 The "alkylthio" refers to an alkyl-S- group, wherein the alkyl group is as described herein; the "halogen" includes fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine, bromine;

The "cycloalkyl" refers to a saturated monocyclic or bicyclic ring system of from about 3 to about 10 carbon atoms, optionally substituted with oxygen. Example monocyclic cycloalkyl rings include C ₃ _ ₈ cycloalkyl ring, such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. a cycloalkyl group may be substituted by 1, 2, 3 or 4 substituents independently selected from halogen, nitro, amino, hydroxy, carboxy, dC ₄ alkyl or dC ₄ alkoxy;

The "cycloalkenyl" refers to a non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and having from 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl and cycloheptenyl. The cycloalkenyl group can be 1, 2, 3 or 4 independent It is selected from the group consisting of a nitro group, a nitro group, an amino group, a hydroxyl group, a carboxyl group, a d-C ₄ alkyl group or a substituent substituted with a ₄ -alkoxy group.

 Among the compounds of the formula (1), preferred A is an amino group; a deletion; or

A is an amino group, a deletion, B ₂ is a deletion, -CH is broad or -CH ₂ -CH ₂ -; or

A is an amino group, a deletion, B ₂ is a deletion, -CH ₂ or -CH ₂ -CH ₂ -, is an isopropyl group, and R ₂ is an isobutyl group or a cyclohexanefluorenyl group, wherein R ₂ is preferably an isobutyl group.

Among the above compounds, preferred D is a deletion, -NHC0- or -NHC0-R ₄ , wherein R ₄ is:

In the above compounds, preferred Q is a natural amino acid residue, or one selected from the group consisting of the structure of the formula (VIII), wherein the configuration of the chiral carbon atom is R or S, wherein 11 ₉ is -OH, -C1, _{-Br, -NO3, - NH 2,} - F , or -I;. Is -OH or -NH ₂ .

VIII

Among the above compounds, preferred G is -Asp, -Asp-Ala, -Asp-Ala-Glu, -Asp-Ala-Glu-Phe, or one selected from the structures of formula (IX), wherein R _u and Ru, for each

-CF ₃ , -N0 ₂ , -C0CF ₃ ,

IX Among the above compounds, particularly preferred G is -Asp, -Asp-Ala, -Asp-Ala-Glu, -A s pA la-Gl u-Phe.

 The invention also relates to a process for the preparation of a compound of the invention.

 Preparation of the compound of the present invention by solid phase synthesis, using Ferrifid resin or Wang resin as carrier, Boc- or Fmoc-protection strategy, DCC/H0BT or BOP/DIEA as condensation reagent, HC1/dioxane or piperidine /DMF is a deprotection reagent, and the peptide derivative is cleaved from the resin after completion of the reaction.

 The invention further relates to a pharmaceutical composition comprising at least one compound of the above formula (I), or a stereoisomer thereof, or a non-physiologically acceptable salt thereof, or a prodrug thereof, and a pharmaceutically acceptable carrier, conventional pharmaceutical excipient or adjuvant.

 "Pharmaceutically acceptable carrier or conventional pharmaceutical excipient or adjuvant" includes any or all solvents, dispersion media, coatings, antibacterial or antifungal agents, isotonic and sustained release agents, and similar physiologically compatible formulations, It is suitable for intravenous, intramuscular, subcutaneous, or other non-digestive administration. The active compound may be coated to protect the compound from acid or other natural conditions, depending on the mode of administration.

 As used herein, the term "physiologically toxic salt" means a salt or a combination thereof which retains the expected physiological activity of the parent compound without causing any unexpected toxic side effects. For example: hydrochloride, hydrobromide, sulfate, phosphate, nitrate, and acetate, oxalate, tartrate, succinate, malate, benzoate, pamoate , alginate, methanesulfonate, naphthalenesulfonate, etc. The cation according to the salt may be: an inorganic salt such as a potassium salt, a lithium salt, a zinc salt, a copper salt, a cerium salt, a cerium salt or a calcium salt, or an organic salt such as a trialkylammonium salt.

 The present invention also relates to the use of a medicament comprising at least one compound of the above formula (I) for inhibiting β-secretase activity in a mammal, preventing or treating a secreted enzyme-related disease such as Alzheimer's disease.

 The invention further relates to the use of a compound comprising at least one of the above formula (I) for the preparation of a sputum secretase inhibitor.

The terms "sputum secretase", "Ρ site amyloid precursor protein cleavage enzyme" and BACE are used interchangeably in the present invention. The compounds of the invention are useful for treating, ameliorating, or managing Alzheimer's disease. For example, the compounds are useful for the prevention of Alzheimer's disease type dementia, as well as for early, intermediate or advanced treatment of Alzheimer's disease type dementia. The compounds are also useful in the treatment, amelioration, and management of diseases mediated by aberrant cleavage of amyloid precursor protein (APP) and other diseases or risks that can be treated or prevented by inhibition of P secretase. The p-secretase-related diseases include mild cognitive decline, Down's syndrome, cerebral amyloid vascular disease dementia, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), and infectious spongiform encephalopathy ( Creutzfe ld- Jakob di sease ), de-viral disease, amyotrophic lateral cord sensation, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion of myositis, other peripheral amyloidosis, diabetes and atherosclerosis hardening.

 A patient receiving a compound of the present invention is generally a human in which it is desired to inhibit P secretase activity in the body, but may also include other mammals such as dogs, cats, mice, rats, cows, horses, sheep, rabbits, A monkey, chimpanzee or other simian or primate that is required to inhibit P-secretase activity or to treat the above diseases.

 The term "stereoisomer of the compound of formula (I)" as used in the present invention means its corresponding D- or L-stereo configuration.

"Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient.

Examples of the combination of the compound of the present invention and other drugs in unit dose or in the form of a kit include Alzheimer's disease drugs, such as other P secretase inhibitors or gamma secretase inhibitors; HMG-CoA reductase inhibitors; NSAID, Such as ibuprofen; vitamin E; anti-amyloid antibody; CB-1 receptor antagonist or inverse agonist; antibiotic; N-methyl-D-aspartate (NMDA) receptor antagonist, such as King Kong; cholinesterase inhibitors, such as galantamine, rivastigmine, tacrine, donepezil; growth hormone secretagogue; histamine H ₃ antagonist; AMPA agonist; PDE IV inhibition Neuronal nicotinic agonist; or other drug that affects a receptor or enzyme; the drug may increase efficacy, safety, convenience, or reduce the side effects and toxicity of the compounds involved in this patent. The above combination is illustrative only and is not intended to limit the invention in any way.

The compound of the formula (I) of the present invention, and a stereoisomer thereof or a pharmaceutical composition containing the same Administration in any manner known, such as oral, intramuscular, subcutaneous, nasal administration, etc., for administration of pharmaceutical forms such as tablets, capsules, buccal tablets, chewable tablets, tinctures, suspensions, transdermal agents, micro嚢 Embedding agents, implants, syrups, etc. It may be a general preparation, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems. In order to form a unit dosage form into tablets, various biodegradable or biocompatible carriers well known in the art can be widely used. Examples of the carrier are, for example, saline and various buffered aqueous solutions, ethanol or other polyols, liposomes, polylactic acid, vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and the like.

 According to a preferred embodiment of the invention, the compound of the invention is selected from at least one of the following peptide compounds or their stereoisomers or non-physiologically toxic salts or prodrugs:

 (1) G 1 u-Va 1 -Leu-Pr o-A s p-A 1 a-G 1 u-Phe

 (2) G 1 u-Va 1 -Leu-D-P r o-A s p-A 1 a-G 1 u-Phe

 (3) G 1 u-Va 1 -Leu-S e r-A s p-A 1 a-G 1 u-Phe

 (4) Glu-Va l -Leu-D-Ser-A s -Ala-Gl u-Phe

 (5) G 1 u-Va 1 -Leu-Thr-A s p-A 1 a-G 1 u-Phe

 (6) Glu-Va l-Leu-Tyr-Asp-Ala-Glu-Phe

 (7) G 1 u-Va 1 -Leu-H i s-Asp-Ala-G 1 u-Phe

 (8) G 1 u-Va 1 -Leu-Trp-A sp-Ala-Gl u-Phe

 (9) G 1 u-Va 1 -Leu-D-Tr p-As p-A 1 a-G lu-Phe

 (10) Glu-Va l -Leu-Me t -A s p-A 1 a-G 1 u-Phe

 (11) Glu-Va l -Leu-Phe-A sp-Ala-Gl u-Phe

 (12) Glu-Va l -Leu-D-Phe- A sp-Ala-Gl u-Phe

(13) G 1 u- Va 1 -Leu-Phe (4 -N0 ₂ ) - A s pA 1 aG 1 u-Phe

(14) Glu-Va l-Leu-D-Phe (4-N0 ₂ ) -Asp-Ala-Glu-Phe

(15) G 1 u-Va 1 -Leu-Phe (4-NH ₂ ) -A sp-Ala-Gl u-Phe

(16) Glu-Va l -Leu-D-Phe (4-NH ₂ ) -A sp-Ala-Gl u-Phe Gl u- -Va l ί-Leu-Phe (4-C1) -Asp-Ala-Glu-Phe

 Gl u- -Va] L-Leu-D-Phe (4-C1) -Asp-Ala-Glu-Phe

Gl u- -Val -Leu- -Phe (3-N0 ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val -Leu- -Phe (3-NH ₂ ) -Asp-Ala-Glu-Phe

 G] u- -Val -Leu- -Phe (2-F) -Asp-Ala-Glu-Phe

 Gl Lu- -Val ί-Leu- -Phe (3-F) -Asp-Ala-Glu-Phe

 Gl u- -Va] -Leu- -Phe (4-F) -Asp-Ala-Glu-Phe

 Gl u- -Val -Leu- -Phe (2-C1) -Asp-Ala-Glu-Phe

 Gl u- -Va] ί-Leu- -Phe (3-C1) -Asp-Ala-Glu-Phe

 Gl u- -Val ί-Leu- -Phe (2-Br) -Asp-Ala-Glu-Phe

 Gl u- -Val ί-Leu- -Phe (3-Br) -Asp-Ala-Glu-Phe

 Gl u- -Val -Leu- -Phe (4- Br) -Asp-Ala-Glu-Phe

Gl u- -Val ί-Leu- -Phe (2-CH ₃ ) -Asp-Ala-Glu-Phe

 G] u- -Val -Leu- -Phe (3-CHs) -Asp-Ala-Glu-Phe

 G l u- -Val -Leu- -Phe (4-CH3) -Asp-Ala-Glu-Phe

 Gl u- -Val -Leu- -Phe (2, 3-d i f 1 uo r i ne) -A s p-A 1 a-G 1 u-Phe

G] u- -Val -Leu- -Phe (2, 4-dif luor ine) -A s p-A 1 a-G 1 u-Phe

G l u- -Val -Leu- -Phe ( 3, 4-dif luor ine) -Asp-Ala-Glu-Phe

G] u- -Val -Leu- -Phe (2, 4 - d i ch 1 or i ne) -As p-A 1 a-G 1 u-Phe

G] u- -Val -Leu- -Phe (3, 4-dichlor ine) -As p-A 1 a-G 1 u-Phe

G] u- -Val -Leu- -Phe (2, 3-dichlorine) -As p-A 1 a-G 1 u-Phe

G l u- -Va] -Leu- -Phe (2, 4- dibromine) -Asp-Ala-Glu-Phe

G] • u- -Va] -Leu- -Phe (3, 4- dibromine) -Asp-Ala-Glu-Phe

G] .u- -Va] -Leu- -Phe (2, 3-dibromine) -As -Ala-Glu-Phe G] .u- -Val [-Leu-Phe (2, 4- dimethyl) -Asp-Ala-Glu-Phe

 G] u- -Val [-Leu-Phe (3, 4-dimethyl) -Asp-Ala-Glu-Phe

 G] u- -Val [-Leu-Phe (2, 3-dimethyl) -Asp-Ala-Glu-Phe

 Gl u- -Va] [-Leu-Phe (3-Br, 4-C1) -Asp-Ala-Glu-Phe

 G] u- -Va] L -Leu-Phe (2-Br, 4-Cl)-Asp-Al a-G 1 u-Phe

 Gl u- -Va] ί -Leu-Phe (3-C1, 4- Br) -Asp-Ala-Glu-Phe

 Gl Lu- -Val [ -Leu-Phe (3-F, 4-C1) -Asp-Ala-Gl u-Phe

 Gl u- -Val ί-Leu-Phe (2-F, 4-C1) -Asp-Ala-Glu-Phe

 G] u- -Va] ί -Leu-Phe (3-C1, 4-F) -Asp-A 1 a-G 1 u-Phe

 G] u- -Val . -Leu-2-Na 1 -A s p-A 1 a-G 1 u-Phe

 G] u- -Va] [ -Leu-D-2-Na 1 -A s p-A 1 a-G 1 u-Phe

G] u- -Val-Leu- Y - (trans, L) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Val -Leu-Y-( cis, L) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Val -Leu- γ-( trans, D) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Va] ί-Leu- v~( cis,D) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val ί-Leu- (trans, L) - Pro (4-OH) -Asp-Ala-Glu-Phe

G] u- -Val L-Leu- (cis, L )- Pro (4-OH) -Asp-Ala-Glu-Phe

Gl u- -Val [-Leu- (trans, D)- Pro (4-OH) -Asp-Ala-Glu-Phe

G] u- -Val ί-Leu- (cis, D) - Pro (4-OH) -Asp-Ala-Glu-Phe

G] u- -Val l-Leu- (trans, L) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val L-Leu- (cis, L ) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val l-Leu- (trans, D) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Val [-Leu- (ci s, D) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Va] L -Leu-Phe-D-Pr oA s pA 1 aG 1 u-Phe G] u- -Val L -Leu-Phe- (cis, D) -Pro (4-OH) -A sp-Ala-Gl u-Phe

Gl u- -Va l -Leu-Phe- (cis, D) -Pro (4-NH ₂ ) -As -Ala-Glu-Phe

G] u- -Va l -Leu-Phe- (cis, D) - γ - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] u- -Val -Leu-Phe- (trans, D) -Pro (4-OH) -Asp-Ala-Glu-Phe

Gl u- -Val -Leu-Phe- (trans, D) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

G] lu- -Val .-Leu-Phe- (trans, D) - v -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val -Leu-Phe- (cis, D) -Pro (5-OH) -Asp-Ala-Glu-Phe

G] u- -Va l -Leu-Phe- (cis, D) - co -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Va l -Leu-Phe- (ci s, D) -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Val .-Leu-Phe- (trans, D) -Pro (5-OH) -Asp-Ala-Glu-Phe

Gl u- -Val L-Leu-Phe- (trans, ϋ) - ω -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe

G) u- -Va] I -Leu-Phe- (trans, D) -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe

Gl u- -Va] ί-Leu-Tyr-D-Pro-Asp-Ala-Glu-Phe

 Gl u- -Val [-Leu-H i s-D-Pro-Asp-A 1 a-G 1 u-Phe

 G] u- -Val L -Leu-Trp-D-Pro-A sp-Ala-Gl u-Phe

Gl u- -Va l [-Leu-Phe (4-N0 ₂ ) -D-Pro-As pA 1 aG 1 u-Phe

G] u- -Val L -Leu-Phe (4-NH ₂ ) -D-Pr o-As pA 1 aG 1 u-Phe

 Gl u- -Va] L -Leu-Phe (4-Cl) -D-Pro-Asp-A 1 a-G 1 u-Phe

 G] u- -Va] L -Leu-Phe (4-Br) -D-P r o-A s p-A 1 a-G 1 u-Phe

G] .u- -Va ] L -Leu-Phe (3-N0 ₂ ) -DP r oA sp-Ala-Gl u-Phe

Gl .u- -Va] L -Leu-Phe (3-NH ₂ ) -DP r oA sp-Ala-Gl u-Phe

 G] .u- -Va] Bu Leu-Phe (2-F) -D-Pr o-A sp-Ala-Gl u-Phe

 G .u- -Va] Bu Leu-Phe (3-F) -D-Pro-Asp-Ala-Glu-Phe

G • u- -Va] L -Leu-Phe (4-F) -DP r oA sp-Ala-Gl u-Phe (89) Glu-Val-Leu-Phe (2-C 1 ) -D-Pr oA sp-Ala-Gl u-Phe

(90) Glu-Val-Leu-Phe (3-Cl) -D-P r o-A sp-Ala-Gl u-Phe

 (91) Glu-Val-Leu-Phe (2-Br) -D-Pro-Asp-Ala-Glu-Phe

 (92) G 1 u-Va 1 -Leu-Phe (3-Br) -D-Pr o-A sp-Ala-Gl u-Phe

 (93) Glu-Val-Leu-Phe (4-Br) -D-Pr o-A sp-Ala-Gl u-Phe

(94) Glu-Va l -Leu-Phe (2-CH ₃ ) -D-Pr oA sp-Ala-Gl u-Phe

(95) Glu-Val -Leu-Phe ( 3-CH ₃ ) -DP r oA sp-Ala-Gl u-Phe

(96) Glu-Val-Leu-Phe (4-CH ₃ ) -D-Pr o-As pA 1 aG lu-Phe

 (97) Glu-Val-Leu-Phe (2, 3-d i f 1 uo r i ne) -D-Pr o-A sp-Ala-Gl u-Phe

(98) Glu-Val-Leu-Phe (2, 4-d i f 1 uo r i ne) -D-Pr o-A sp-Ala-Gl u-Phe

(99) Glu-Va l-Leu-Phe ( 3 , 4 -d i f 1 uo r i ne) -D-P r o-A s p-A 1 a-G 1 u-Phe

(100) Glu-Val-Leu-Phe (2, 4- d i ch 1 or ine) -D-Pr o-As p-A 1 a-G lu-Phe

(101) G 1 u-Va 1 -Leu-Phe (3, 4-dichlor ine) -D-P r o-A sp-Ala-Gl u-Phe

(102) Glu-Val-Leu-Phe (2, 3-dichlor ine) -D-Pro- Asp-Ala- G lu-Phe

(103) Glu-Val-Leu-Phe (2, 4- d i brom i ne) -D-Pr o-A sp-Ala-Gl u-Phe

(104) Glu-Val-Leu-Phe (3, 4-d i b r om i ne) -D-Pr o-A sp-Ala-Gl u-Phe

(105) Glu-Val-Leu-Phe (2, 3-dibromine) -D-Pro-Asp-Ala-Glu-Phe

(106) Glu-Va l-Leu-Phe (2, 4- d i me t hy 1 ) -D-P r o- A sp-Ala-Gl u-Phe

(107) Glu-Va l-Leu-Phe (3, 4-d i me t hy 1 ) -D-Pro-A s p-A 1 a-G 1 u-Phe

(108) Glu-Val-Leu-Phe (2, 3-d i me t hy 1 ) -D-Pro-A sp-Ala-Gl u-Phe

(109) Glu-Val-Leu-Phe (3-Br, 4-Cl) -D-Pro-As p-A la-Gl u-Phe

 (110) Glu-Val-Leu-Phe (2-Br, 4-Cl) -D-Pro-Asp-Ala-Glu-Phe

 (111) Glu-Va l-Leu-Phe (3-Cl, 4-Br) -D-Pr o-As p-A 1 a-G 1 u-Phe

(112) Glu-Val-Leu-Phe (3-F, 4-Cl) -D-Pro-As -A 1 aG lu-Phe 113) G] .u- -Va] Leu-Phe (2-F, 4-CD-D

114) G] u- -Va] L-Leu-Phe(3-Cl,4-F) -D

115) Gl .u- -Va] L-Leu-2-Nal-D-Pro-Asp

116) G] u- -Va] -Leu-Tyr-Asp

 117) G] u- -Va] a Leu - His-Asp

 118) G] u- -Val -Leu-Trp-Asp

 120) G] u- -Va] -Leu-Met -Asp

 121) G] u- -Val -Leu-Phe-Asp

122) G] u- -Va] L -Leu-Phe (4-N0 ₂ ) -Asp

123) G] u- -Val L -Leu-Phe (4-NH ₂ ) -Asp

124) G] u- -Va] L-Leu-Phe(4-Cl)-Asp

125) G] u- -Val L -Leu-Phe (3-N0 ₂ ) -Asp

126) G] u- -Va] L -Leu-Phe (3-NH2) - Asp

127) Gl u- -Va] l-Leu-Phe (2-F) - Asp

128) G] u- -Va] L -Leu-Phe (3-F) -Asp

129) G] u- -Va] I -Leu-Phe (4-F) -Asp

130) G] u- -Va] L-Leu-Phe (2- CI) -Asp

131) G] u- -Va] L-Leu-Phe(3-Cl)-Asp

132) Gl u- -Val L-Leu-Phe (2- Br) - Asp

133) G] u- -Va] -Leu-Phe (3- Br) - Asp

134) G] u- -Va] L-Leu-Phe (4- Br) -Asp

135) G] u- -Val L-Leu-Phe (2-CH ₃ ) - Asp

136) G] Lu- -Val L-Leu-Phe (3-CH ₃ ) -Asp

137) G] u- -Va] L-Leu-Phe (4-CH ₃ ) -Asp (138) Glu- -Val -Leu- -Phe (2, 3-dif luorine) - Asp

 (139) Glu- -Val -Leu- -Phe (2, 4-dif luorine) -Asp

 (140) Glu- -Val -Leu- -Phe ( 3, 4-dif luorine) -Asp

(141) Glu- -Val .-Leu- -Phe (2, 4- dichlorine) -Asp

(142) Glu- -Val .-Leu- -Phe :3, 4-dichlorine) -Asp

 (143) Glu- -Val .-Leu- -Phe (2, 3- dichlorine) - Asp

 (144) Glu- -Val -Leu- -Phe (2, 4- dibromine) -Asp

 (145) Glu- -Val .-Leu- -Phe (3, 4- dibromine) -Asp

 (146) Glu- -Val .-Leu- -Phe (2, 3- dibromine) -Asp

 (147) Glu- -Val .-Leu- -Phe (2, 4- dimethyl) - Asp

 (148) Glu- -Val .-Leu- -Phe (3, 4- dimethyl) -Asp

 (149) Glu- -Val .-Leu- -Phe (2, 3- dimethyl) -Asp

 (150) Glu- -Val l-Leu- -Phe (3-Br, 4-Cl)-Asp

 (151) Glu- -Val -Leu- -Phe (2-Br,4-Cl)-Asp

 (152) Glu- -Val -Leu- -Phe (3-Cl,4-Br)-Asp

 (153) Glu- -Val -Leu- -Phe (3-F, 4-CD-Asp

 (154) Glu- -Va] -Leu- -Phe (2-F, 4-Cl)-Asp

 (155) Glu- -Va] -Leu- -Phe (3-Cl,4-F) -Asp

 (156) Glu- -Va] -Leu- -2-Nal-Asp

 (157) Glu- -Val L -Leu-Phe-D-P r o-A sp-Ala-Gl u-Phe

(158) Glu- -Val -Leu- -Phe- -(cis,D) -Pro (4-0H) -Asp

(159) Glu- -Va .-Leu- -Phe- -(cis,D) -Pro(4-NH ₂ ) -Asp

(160) Glu- -Va .-Leu- -Phe- -(cis,D)-Y-Pro(4-NH ₂ ) -Asp

(161) Glu- -Va .-Leu- -Phe- - (trans, D) -Pro (4-OH) -Asp 162) Gl u- -Val -Leu-Phe- (trans, D) - Pro (4-NH ₂ ) - Asp

163) Gl u- -Val -Leu-Phe- (trans, D) - γ - Pro (4-NH ₂ ) -Asp

164) G] [u- -Val -Leu-Phe- (cis, D) -Pro (5-OH) -Asp

165) Gl lu- -Val -Leu-Phe- (cis, D) - ω - Pro (5-NH ₂ ) -Asp

166) Gl u- -Val -Leu-Phe- (cis, D) - Pro (5-NH ₂ ) -Asp

167) Gl u- -Val -Leu-Phe- (trans, D) -Pro (5-OH) -Asp

168) Gl u- -Val -Leu-Phe- (trans, D) -ω-Pro (5-NH ₂ ) -Asp

169) Gl u- -Val -Leu-Phe- (trans, D) - Pro (5-NH ₂ ) -Asp

170) Gl u- -Val -Leu-Tyr-D-Pro-Asp

 171) G] u- -Val .-Leu-Hi s-D-Pro-Asp

 172) G] u- -Val .-Leu-Trp-D-Pro-Asp

173) Gl u- -Val -Leu-Phe (4-N0 ₂ ) -D-Pro-Asp

174) G] u- -Val -Leu-Phe (4-NH ₂ ) -D-Pro-Asp

 175) Gl u- -Val L -Leu-Phe (4-Cl) -D- Pro-Asp

 176) Gl u- -Val ί-Leu-Phe (4-Br) -D-Pro-Asp

177) G] u- -Val Bu Leu-Phe (3-N0 ₂ ) -D- Pro-Asp

178) G] u- -Val L -Leu-Phe (3-NH ₂ ) -D-Pro-Asp

 179) Gl u- -Val L -Leu-Phe (2-F) -D-Pro-Asp

 180) G] u- -Val [-Leu-Phe (3-F) -D-Pro-Asp

 181) Gl Lu- -Val ί -Leu-Phe (4-F) -D-Pro-Asp

 182) G] u- -Va] L -Leu-Phe (2-Cl) -D-Pro-Asp

 183) Gl • u- -Va] L-Leu-Phe (3- CI) -D-Pro-Asp

 184) G .u- -Va] L -Leu-Phe (2-Br) -D-Pro-As

185) G -u- -Val L-Leu-Phe (3-Br) -D-Pro-Asp 186) Gl u- -Va] -Leu- -Phe (4-Br)-D-Pro-Asp

187) Gl u- -Va) -Leu- -Phe (2-CH ₃ ) -D-Pro-Asp

 188) Gl u- -Val -Leu- -Phe (3-CH3) -D- Pro-Asp

 189) G] u- -Va]-Leu- -Phe (4-CH3) -D-Pro-Asp

190) Gl u- -Val _t -Leu- -Phe (2, 3-dif luorine) -D-Pro-Asp

191) G] u- -Val ί-Leu- -Phe (2, 4-dif luorine) -D-Pro-Asp

192) G] u- -Va] ί-Leu- -Phe (3 , 4-dif luorine) -D-Pro-Asp

193) G] u- -Val -Leu- -Phe (2, 4- dichlorine) -D— Pro- Asp

194) G] u- -Val -Leu- -Phe (3, 4-dichlorine) -D-Pro-Asp

195) G] u- -Va] -Leu- -Phe (2, 3-dichlorine) -D-Pro-Asp

196) Gl u- -Val -Leu- -Phe (2, 4- dibromine) -D-Pro-Asp

197) Gl .u- -Val -Leu- -Phe (3, 4-dibromine) -D-Pro-Asp

198) G] u- -Val -Leu- -Phe (2, 3-dibromine) -D-Pro-Asp

199) G] u- -Val -Leu- -Phe (2, 4- dimethyl) -D-Pro-Asp

200) G] u- -Va] -Leu- -Phe (3, 4-dimethyl) -D-Pro-Asp

221) G • u- -Va] -Leu- -Phe (2, 3-dimethyl) -D-Pro-Asp

222) G • u- -Va] L-Leu- -Phe (3-Br, 4-Cl)-D-Pro-Asp

 223) G .u- -Va] -Leu- -Phe (2-Br, 4-Cl)-D-Pro-Asp

 224) G .u- -Va] -Leu- -Phe (3-Cl, 4-Br)-D-Pro-Asp

 225) G • u- -Va] -Leu- -Phe (3-F, 4-Cl)-D-Pro-Asp

 226) G .u- -Va] .-Leu- -Phe (2-F, 4-Cl)-D-Pro-Asp

 227) G -u- -Val .-Leu- -Phe (3-Cl,4-F) -D-Pro-Asp

228) G lu- -Val .-Leu- -2-Nal-D-Pro-Asp

dsv-ojj-α-ηοι-ΐΒΛ-ηΐΟ (Oil) dsv-ojd-noq-ΐΒΛ-ηΐΟ (632)

Dsv-ojj-α-ηοι-ΐΒΛ-ηΐΟ (Oil) dsv-ojd-noq-ΐΒΛ-ηΐΟ (632)

SZST00/010ZN3/X3d Ζ9£9 ΪΟΖ OAV Advantageous effects of the invention

 The present invention relates to a class of peptide compounds having the structure of formula (I), and in vitro activity evaluation experiments show that it can inhibit P-secretase activity and provide a new way for prevention or treatment of P-secretase-related diseases. detailed description

 The embodiments of the present invention are described in detail below with reference to the accompanying drawings. If no specific conditions are specified in the examples, they are carried out according to the general conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained commercially. The abbreviations used in the present invention have the following meanings:

 Ala Alanine, Alanine

 Asp Aspart ic acid, aspartic acid

 BACE1 β amyloid cleaving enzyme 1

 Boc tert-butoxycarbonyl

 DCC bicyclohexyl amide

 DCM dichloromethane

 DMSO dimercapto sulfoxide

 Fmoc 芴 曱 carbonyl

 Glu Glutamic acid, glutamic acid

 Hi s Hi s t idine, histidine

 HOBt N-hydroxybenzotriazole

 Hyp 4-hydroxy-proline

 Leu Leucine, leucine

 Merr if ield resin chloromethyl resin

Met Methionine, Melonic Acid Na l naphthyl alanine

 Phe Phenylalanine, phenylalanine

 Pro Prol ine, Proline

 RP-HPLC reversed-phase high performance liquid chromatography

 Ser Serine, Serine

 TFA trifluoroacetic acid

 TFMSA trifluorosulfonate

 Thr Threonine, Threonine

 Trp Tryptophan, tryptophan

 Tyr Tyros ine, acid

 Val Va l ine, proline

 Wang Resin '4-Benzyloxybenzyl alcohol resin Example The solid phase synthesis carrier Wang resin (0. 62 mmol/g, 100-200 mesh) used by Tianjin Resin Co., Ltd.; Merr if ield resin ( 1 40 mmol/g, 200-400 mesh) is Fluka; DCC, H0Bt, DIEA and protected natural amino acids are protected by Shanghai Jill Biochemical Co., Ltd. and Chengdu Chengnuo New Technology Co., Ltd. Provided by the synthesis of this laboratory. Example 1 : Synthesis of Compound (1)

 Using 322.5 mg Wang resin (0.2 mmol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, the solid phase peptide synthesis method according to the standard Fmoc/Bu strategy (Reference: Huang Weide, Chen Changqing, Peptide) Synthesis [M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va l-Leu-Pro -Asp-Ala-Glu-Phe-Wang resin.

The above peptide resin was placed in a cleavage reactor, and 1. OmL of anisole and 1 mL of hydrazine were added. Phenol and 8 mL of trifluoroacetic acid were reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with a 10% aqueous solution of acetic acid until the resin was no longer adhered to each other, and the washing liquid was collected, and lyophilized to obtain 95. 3 mg of white dry powder, which was purified by RP-HPLC to obtain pure product (purity). 6%。 More than 95%) 10. 3mg, pure peptide yield 5.6%. ES I-MS:

 [Μ+ΗΓ 919. 7 (Theoretical value M is 919. 0). Example 2: Synthesis of Compound (3)

 Using 322.5 mg Wang resin (0.2 mmol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/Bu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va Bu Leu- Ser-Asp-Ala-Glu-Phe-Wang resin.

 The above peptide resin was placed in a cleavage reactor, and L OmL of phenylhydrazine ether, 1 mL of m-cresol and 8 mL of trifluoroacetic acid were added, and the mixture was reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with a 10% aqueous solution of acetic acid until the resin was not adhered to each other, and the washing liquid was collected, and lyophilized to obtain 75.2 mg of white dry powder, which was purified by RP-HPLC (purity). 6%。 More than 95%) 6. 5mg, pure peptide yield 3.6%. ES I-MS:

[M+H] ⁺ 909. 5 (Theoretical value M is 909. 0). Example 3: Synthesis of Compound (6)

Using 322.5mg Wang resin (0.2 匪ol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/t strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing) , peptide synthesis [M], Science Press, 1985; Wang Dexin. Principles and application guidelines for solid phase organic synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational synthesis of G lu-Va l- Leu-Tyr-Asp-Ala-G lu-Phe-Wang resin. The above peptide resin was placed in a cleavage reactor, and 1.0 mL of anisole, 1 mL of m-nonylphenol, and 8 mL of trifluoroacetic acid were added at 0. C reaction for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with 10% aqueous acetic acid until the resin no longer adhered to each other, and the washing liquid was collected, and lyophilized to obtain 42.3 mg of white dry powder, which was purified by RP-HPLC to obtain pure product (purity). 0%。 More than 95%) 2mg, pure peptide yield 1. 0%. ES I-MS:

 [Μ+ΗΓ 985. 9 (Theoretical value M is 985. 1). Example 4: Synthesis of Compound (11)

 564. 5mgWang resin (0, 35mmo l) as the solid phase carrier, DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc / iBu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va Bu Leu- Phe-Asp-Ala-G lu-Phe-Wang resin.

The above peptide resin was placed in a cleavage reactor, and 1.0 mL of phenylhydrazine ether, 1 mL of m-nonylphenol and 8 mL of trifluoroacetic acid were added, and the reaction was carried out for OX for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. Wash three times with a small amount of cooled anhydrous ether, then rinse with 10% aqueous acetic acid until the resin no longer adheres to each other, collect the washing liquid, freeze and dry to obtain 60mg white dry powder, purified by RP-HPLC to obtain pure product (purity is greater than 95%) 10%, a pure peptide yield of 3.1%. ES I-MS: [M+H] ⁺ 969. 8 (Theoretical M is 969. 1).

Example 5: Synthesis of Compound (17)

Using 564·5mg Wang resin (0.35mmo l) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/Bu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. Glu-Va l-Leu-Phe (4-C1) -Asp-Ala-Glu-Phe-Wang resin.

 The above peptide resin was placed in a cleavage reactor, and 1. OmL of phenylhydrazine ether, 1 mL of decylphenol and 8 mL of trifluoroacetic acid were added, and reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with 10% aqueous acetic acid until the resin was not adhered to each other. The washing liquid was collected, and lyophilized to obtain 42.3 mg of white dry powder, which was purified by RP-HPLC (purity). 8%。 More than 95%) 6. 3mg, pure peptide yield 1. 8%. ESI-MS: [Μ+ΗΓ 1003. 7 (theoretical value M is 1003. 6).

Example 6: Synthesis of Compound (19)

 806mgWang resin (0.5mol) is used as solid phase carrier, DCC/HOBt is used as condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/iBu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, peptide synthesis [M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95.

Glu-Va l-Leu-Phe (3-N0 ₂ ) -Asp-Ala-Glu-Phe-Wang resin.

 The above peptide resin was placed in a cleavage reactor, and 1. OmL of anisole, 1 mL of m-cresol and 8 mL of trifluoroacetic acid were added, and the mixture was reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with 10% aqueous acetic acid until the resin was no longer adhered to each other. The washing liquid was collected and lyophilized to obtain 85.2 mg of white dry powder, which was purified by RP-HPLC to obtain pure product. 5度/。 The yield of pure peptide is 0. 5 ° /. . ESI-MS: [Μ+ΗΓ 1003. 7 (theoretical value M is 1003. 6). Example 7: Synthesis of Compound (52)

564. 5mgWang resin (0.35mmo l) as the solid phase carrier, DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc / Bu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M], Science Press, 1 985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M] , Beijing, Chemical Industry Press, 2004: 91- 95. ) Operational synthesis of Glu-Va, Leu-Y-(trans,L)-Pro(4-NH ₂ )-Asp-Ala-Glu- Phe-Wang resin, of which Pro (4- The NH ₂ ) residue is introduced as (trans, L) Boc -Pro (4-Fmoc-NH) -OH.

The above peptide resin was placed in a cleavage reactor, and L OmL phenyl hydrazine ether, 1 mL of m-nonyl phenol and 8 mL of trifluoroacetic acid were added, and reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. It was washed three times with a small amount of cooled anhydrous diethyl ether, and then washed with 10% aqueous acetic acid until the resin no longer adhered to each other. The washing liquid was collected, and lyophilized to obtain 48 mg of white dry powder, which was purified by RP-HPLC to obtain a pure product (purity greater than 95). %) 8.2 mg, pure peptide yield 2.5%. ESI-MS: [M+H] ⁺ 935.0 (M.

Example 7: Synthesis of Compound (57)

 806mgWang resin (0.5 ship ol) as the solid phase carrier, DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc / tu strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, peptide synthesis [ M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va Bu Leu- (cis, L ) -Pro (4-0H)- Asp-Ala- Glu-Phe-Wang resin.

 The above peptide resin was placed in a cleavage reactor, and L OmL anisole, 1 mL of m-cresol and 8 mL of trifluoroacetic acid were added, and reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with 10% aqueous acetic acid until the resin was no longer adhered to each other, and the washing liquid was collected, and lyophilized to obtain 78. lmg of white dry powder, purified by RP-HPLC to obtain pure product (purity More than 95%) 10.5 mg, pure peptide yield 2.2%.

ESI-MS: [Μ+ΗΓ 935.6 (theoretical M is 934.0).

Example 8: Synthesis of Compound (63)

357. lmg Merrifield resin (0.50mmol) as solid phase carrier, DCC/HOBt As a condensing agent, according to the amino acid sequence of the compound, the solid phase peptide synthesis method according to the standard Boc/Bz l strategy (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M], Science Press, 1985; Wang Dexin. Solid phase organic synthesis A Principle and Application Guide [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va Bu Leu- (cis, D) -Pro (4-NH ₂ ) -As pA 1 aG 1 u-Phe-Wang resin.

 The above peptide resin was placed in a cleavage reactor, and 1 mL of phenylhydrazine sulfide, 1 mL of m-cresol, 5 mL of trifluoroacetic acid, and 1 mL of trifluoromethanesulfonic acid were added, and the mixture was reacted at 0 for 30 minutes, and reacted at room temperature for 3 hours. The acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. Wash three times with a small amount of cooled anhydrous ether, then rinse with 10% aqueous acetic acid until the resin no longer adheres to each other, collect the washing liquid, and freeze-dry to obtain 44 mg of white dry powder, which is purified by RP-HPLC to obtain pure product (purity greater than 95). 7%。 The yield of pure peptide was 0. 7%. ES I-MS: [Μ+ΗΓ 934. 7 (theoretical value M is 934. 0). Example 9: Synthesis of Compound (64)

 806mgWang resin (0.5mol) is used as the solid phase carrier, DCC/HOBt is used as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, peptide synthesis [ M], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va l-Leu-Phe-D -Pro-Asp-Ala-Glu-Phe-Wang resin.

The above peptide resin was placed in a cleavage reactor, and 1.0 mL of phenylhydrazine ether, 1 mL of m-nonylphenol and 8 mL of trifluoroacetic acid were added, and the mixture was reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with 10% aqueous acetic acid until the resin was no longer adhered to each other. The washing liquid was collected and lyophilized to obtain 259. 2 mg of white dry powder, which was purified by RP-HPLC (purity) 8%。 More than 95%) 15. lmg, pure peptide yield 2.8%. ESI-MS: [Μ+ΗΓ 1067. 0 (theoretical value M is 1066. 2). Example 10: Synthesis of Compound (65)

 Using 806mgWang resin (0.5mmol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, the solid phase peptide synthesis method according to the standard Fmoc/iBu strategy (Reference: Huang Weide, Chen Changqing, Peptide Synthesis [M ], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va Bu Leu-Phe- (cis, D)-Pro(4-0H)-Asp-Ala-Glu-Phe- Wang resin.

 The above peptide resin was placed in a cleavage reactor, and 1.0 mL of phenyl hydrazine ether, 1 mL of decyl phenol and 8 mL of trifluoroacetic acid were added, and the mixture was reacted at 0 ° C for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, and the reaction was carried out. The solid was precipitated from chilled anhydrous ether, and the suspension was transferred to a sand core funnel. Washed three times with a small amount of cooled anhydrous diethyl ether, and then washed with 10% aqueous acetic acid until the resin no longer adhered to each other, and the washing liquid was collected. After lyophilization, 257.5 mg of white dry powder was obtained, which was purified by RP-HPLC (purity of more than 95%), 10.4 mg, pure peptide yield: 1.9% ESI-MS: [Μ+ΗΓ 1083.0 (theoretical value M is 1082.2).

Example 11: Synthesis of Compound (67)

Using 806mgWang resin (0.5mmol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, according to the standard Fmoc/t strategy solid phase peptide synthesis method (Reference: Huang Weide, Chen Changqing, peptide synthesis [M ], Science Press, 1985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Val-Leu-Phe- (cis, D) - v "Pro (4-NH ₂ ) - Asp-Ala-Glu-Phe-Wang resin, in which the Pro (4-NH ₂ ) residue is (trans, L) Boc-P ro (4-Fmoc-NH ) -OH introduction.

The above peptide resin was placed in a cleavage reactor, and 1.0 mL of phenylhydrazine ether, 1 mL of m-cresol and 8 mL of trifluoroacetic acid were added, and the mixture was reacted at 0 for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. Wash three times with a small amount of cooled anhydrous ether, then rinse with 10% aqueous acetic acid until the resin no longer adheres to each other, collect the washing liquid, freeze-dry to obtain 267.7mg white dry powder, purified by RP-HPLC to obtain pure product (purity is greater than 95%) 12.6 mg, pure peptide yield 2.3%. ESI-MS: [M+H] ⁺ 1081. 7 (Theoretical value M is 1081. 2)

Example 12: Synthesis of Compound (230)

 Using 322.5mg Wang resin (0.2 匪ol) as the solid phase carrier and DCC/HOBt as the condensing agent, according to the amino acid sequence of the compound, the solid phase peptide synthesis method according to the standard Fmoc/iBu strategy (Reference: Huang Weide, Chen Changqing) , Peptide Synthesis [M], Science Press, 1 985; Wang Dexin. Principles and Application Guidelines for Solid Phase Organic Synthesis [M], Beijing, Chemical Industry Press, 2004: 91-95. ) Operational Synthesis of Glu-Va l- Leu-Phe-D-Pro-Asp- Wang resin.

 The above peptide resin was placed in a cleavage reactor, and 1. OmL of phenylhydrazine ether, 1 mL of m-cresol and 8 mL of trifluoroacetic acid were added, and reacted at OX for 40 minutes. The trifluoroacetic acid was removed under reduced pressure, the reactor was removed, solidified by the addition of chilled anhydrous diethyl ether, and the suspension was transferred to a core funnel. After washing with a small amount of anhydrous ethyl ether, the mixture was washed with a 10% aqueous solution of acetic acid until the resin was not adhered to each other, and the washing liquid was collected, and lyophilized to obtain 54.7 mg of white dry powder, which was purified by RP-HPLC (purity). 1%。 More than 95%) 5. 8mg, pure peptide yield 5.1%. ESI-MS: [Μ+ΗΓ 572. 4 (theoretical value M is 571. 6).

Example 13: Evaluation of in vitro activity

 In vitro activity evaluation method: β-secretase activity assay kit (AD0258, PerkinElmer)

 Instruments and reagents: TruPointTM beta-secretase activity assay kit (AD0258, PerkinElmer); multifunctional enzyme analyzer (VICT0R3, PerkinElmer).

EGCG (99.6%, 070512), Chengdu Purifa Technology Development Co., Ltd.; DMS0 (99.7%), ACR0S Company; Human Recombinant BACE1 (P2947, invi trogen); Substrate is Eu-CEVNLDAEFK-Qsy (PerkinElmer The company, TruPointTM beta-secretase activity assay kit comes with).

Experimental principle: The peptide containing the cleavage site of the enzyme in the BACE1 substrate was coupled to a fluorescent ruthenium (Eu) at one end and a ruthenium fluorescence quencher (QSY7) at the other end; the substrate was After BACEl cleavage, the ruthenium complex is separated from its quencher, and the signal of ruthenium is enhanced. The degree of enhancement can be determined by instrument; if the sample to be tested inhibits BACE1, the mixed system after the interaction between the two interacts with the substrate. The fluorescence signal is changed and the fluorescence signal is measured, and the intensity of inhibition of BACE1 by the sample to be tested can be calculated.

 Each of the test compounds (1)-(230) prepared according to the methods described in Examples 1-12 was dissolved in DMS0 to prepare a desired concentration; BACE1 and the substrate were separately dissolved in a buffer and water to prepare The solutions were in a concentration of 0.67 mU/mL and 400 nmol/L, respectively. Black 384-well plate, double well; Add 15//L BACE1 solution, test compound solution, incubate at room temperature for 30 min in the dark, add 15/L substrate solution, incubate at room temperature for 6 h in the dark, and terminate with 10/L stop solution. reaction. The fluorescence value was measured by a multi-functional enzyme analyzer (Ex 34 Onm, Em615nm), and the inhibition rate of BACE1 was calculated.

 Calculated indicator: percentage of inhibition

 EGCG is a known BACE1 inhibitor, which is used as a positive control drug. In this experiment, only buffer is added, BACE1 is not added, and the fluorescence inhibition value corresponding to the inhibition is 100%; only DMS0 is added, no addition is added. For BACE1 inhibitors, the measured fluorescence value corresponds to a percent inhibition of 0%; the test compound (containing the positive control drug) is added, and the measured fluorescence value is calculated by the formula attached to the kit to obtain the corresponding inhibition rate; It indicates that the inhibitory effect of the drug on p secretase is stronger. For specific experimental methods and calculation methods, refer to the instructions of the TruPointTM β-secretase activity assay kit. The results are shown in Table 1: Table 1 ESI-MS data of some compounds and in vitro activity evaluation results Test concentration (M) against BACE1 inhibition rate (%), Ms ESI-MS

 Compound (, Ca lc, ) [M+H] '

Ι χ Ι ^{-6 -6} 1 10" ⁵ 1 x 10

EGCG 20. 9 93. 3 100. 0

(1) 919. 0 919. 7 23. 3 32. 2 61. 8

(2) 919. 0 919. 4 12. 6 24. 3 65. 0

(3) 909. 0 909. 5 -3. 3 9. 7 59. 5 9 ΊΙ ·1ί S 'ΙΙΛ 9 '" S {ill) ΐ Ή ^ '9ί 8 1 L Ί80Ι 1 ·ΐ80ΐ U9)

^ ·96 6 'U 6 ·9Ζ 0 ·£80Ι ι 'z (S9)

£ 'L6 9 ·8 ΐ '91 0 " 90Τ I "990T (^9)

6ΐ 'ί Τ8 "6- 66 Ί- L Ή6 0 Ή6 (£9)

9Ζ ΊΙ ΐ£ ·6- οε 'ζ L Ή6 0 £6 (29)

 10 L Ή6 0 Ή6 (19)

L U 'l- . L Ήβ 0 £6 (09) π ·ο οε Ί 9 '9ί6 0 £6 (6S) π ·εε ·9 9 '9ί6 0 £6 (8S)

^ ·" ξ£ ·8 ιο ,π 9 'ξίβ 0 £6 US)

0L 'Ι 29 ·0- ε9 'ΐ- 9 ' 6 0 Ή6 (9S)

 61 Ί 0271- 8 £6 0 "5£6 ( )

11 ·εΐ ΖΙ Ί 01 ·9- L Ή6 0 "S£6 ( ) frO "82 ΟΖ, S2 "8- 9 £6 0 "S£6

 Ζ9 'ξΖ 1 'ί- L6 ·8- L Ή6 0 "S£6 s)

9L 'Π ^ 'L 19 Ί L ·6ΐ0ΐ 6 "8Ι0Ϊ as)

8 "S8 6 ·08 0 ΌΙ ·6ΐ0ΐ S ·8ΐ0ΐ (OS)

L ·£6 S 'ί£ L ·6 0 "^Οΐ (82)

L 'L6 ε ·9δ 0 '9Ζ 8 ΐΟΐ ^ 'εΐθΐ (6ΐ)

8ε Ι OS ·0 u ·ο- A TOOT 9 'εοοΐ (8ΐ)

^ ·66 S 'LL I ΊΖ L TOOT 9 "ΖΟΟΤ (Π)

 98 83 'Τ- 0 'S86 ΐ 86 (9ΐ)

81 "03 il ·9 ZL 9 ΤΟΙ I Τ0Ι (Η)

6 ·86 0 '8S ε "ετ ·6Τ0Τ S ·8ΐΟΙ (ευ

9 "Sfr 1 t · ε 8 "696 0 "696

 S9 "38 9τ ·?ε 19 'Μ 8 "696 0 '696 (π)

9 ·08 Τ ·0ΐ 6 Ό- L '£ 6 Τ S6 (Οΐ)

9 '9i ^ ,0 ^ "0- L '8001 I "8001 (6)

8 ·£6 0 'ί^ ε Ί L "8001 I ·800Ι (8)

S Ζ S "I ε 'ζ- L "656 0 '656 ω

 9 '26 1 ·6 Ζ 'L 6 ·586 Τ "586 (9)

0 8 ε ·χ L 'ίΖ6 0 'ίΖ6 (S)

L 'ίί 1 ·0 - s 5 '606 0 '606 卜Οΐ χ ΐ _S- 0T I _9- 0Ι I

 (oi^D)

 Bell W

(%) THDV9 W) ^-W-

SZSlOO/OlOZSlD/lDd Ζ9£9 ΪΟΖ OAV Test concentration (M) for BACE1 inhibition rate (%), Ms ESI -MS

 Compound

 (Calc) [Μ+ΗΓ

1 10" ⁶ 1 x 10" ⁵ 1 x 10"

(230) 571.6 572

It can be seen from the experimental results that all the compounds in Table 1 have a certain degree of inhibition on BACE1, among which compounds (6), (8), (11), (13), (17), (19), (50 ), (64), (65) and (67) have a strong inhibitory effect on BACE1. Although specific embodiments of the invention have been described in detail, those skilled in the art will understand. Various modifications and alterations may be made to those details in accordance with the teachings of the invention, which are within the scope of the invention. The full scope of the invention is indicated by the appended claims and any equivalents thereof.

Claims

Rights request a compound of the formula (I), a stereoisomer thereof, a salt thereof which is not physiologically toxic or

among them, A is an amino group, a substituted amino group, and the substituent is (^-( ₆ acyl group, benzyl group; 8 ₁ and 8 ₂ are a deletion or a 1, 2, 3 position dC ₃ alkane substituted by R ₃ partially or wholly) Base or alkenyl group; 11 ₃ is halogen, -(: ₆ alkyl, ("( ₆ ene-^ or alkynyl, c ₃ -c ₇ cycloalkyl, aryl, heteroaryl, heteroaryl substituted or unsubstituted at any position) a ring group, the substituents are each independently a dC ₆ alkyl group, a c ₂ - c ₆ alkenyl or alkynyl group, a c ₃ -c ₇ cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group; D is a deletion, -NHC0- or -NHC0-R ₄ -; R ₄ is C "C ₆ alkyl, C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, aryl, heterocyclic or heteroaryl substituted or unsubstituted at any position. , the substituents are each independently halogen, C-C ₆ alkyl, c ₂ -c ₆ alkenyl or alkynyl, c ₃ -c ₇ cycloalkyl, aryl, heterocyclyl or heteroaryl; E is a bioelectronic isosteric structure of a deletion, halogen, -H, -OH, -NH ₂ , -C00H, - C00CH ₃ , a tetrazole ring, or -C00H; ^ and R ₂ are each independently -C00H, -C00H bioisosteric structure, substituted or unsubstituted d- ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₇ naphthenic Or a heterocyclic group; the substituent is phenyl, benzyl, phenylthio, phenylmethanethio, phenylsulfonyl substituted d- ₆ alkyl, arylhetero and cycloalkyl structures, - 0H, -N0 ₂ , halogen, -C00H, and its non-physiological salts Or prodrug;  n is 1, 2, 3;  Q is a natural amino acid residue, or a formula ( Π ), or a formula (ΙΠ):

 among them, 1\ is -0-, -S-, -NH-, -NR ₆ -, - CH ₂ -, - CHR ₆ - or -CR ₆ R ₆ ,-; R ₆ and R ₆ are each independently H, C "C ₆ linear or branched alkyl, C ₂ -C ₆ alkenyl or alkynyl, CrC: cycloalkyl, substituted at all or in part Or unsubstituted aryl, heteroaryl, heterocyclic, substituents are each independently halogen, linear or branched fluorenyl group of dC ₆ , C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C _{a 7} cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group;  i is 0, 1, 2; R ₅ is an alkyl group substituted or unsubstituted at a partial or total position, (polyalkenyl or blocked, C ₃ -C ₇ cycloalkyl, ( _3- ( _7- cycloalkenyl, aryl, heterocyclyl or a heteroaryl group; the substituents are independently a linear or branched alkyl group of dC ₆ , a C ₂ -C ₆ alkenyl or alkynyl group, a C ₃ -C ₇ cycloalkyl group, a heterocyclic group, an aryl group, an aromatic group a hetero group, - OH, -NH ₂ , - N0 ₂ , halogen, -CN, -C00H, and a salt or prodrug thereof which is not physiologically toxic; W is a C ₃ -C ₇ cycloalkyl, aryl, C ₃ -C ₇ cycloalkenyl, heteroaryl or heterocyclic group which is substituted or unsubstituted at any position, and the substituent is halogen, -0H, -NH ₂ , - C00H, - C00H bioisosteric structure, linear or branched alkyl group of dC ₆ , C ₂ -C ₆ alkenyl or alkynyl, C ₃ -C ₇ cycloalkyl, cyclic, heteroaryl Base, or formula (IV);

among them, T ₂ is - 0-, -S-, - NH -, -NR ₇ -, -CH ₂ -, -CHR or - CR ₇ R ₇ ,-; R ₇ and R ₇ are each independently -H, a linear or branched alkyl group of dC ₆ which is wholly or partially substituted or unsubstituted at any position, C ₂ -C ₆ alkenyl or alkynyl, Cs- . a cycloalkyl group, an aryl group, a heteroaryl group or a heterocyclic group; the substituents are each independently halogen, a straight or branched alkyl group of dC ₆ , a C ₂ -C ₆ alkenyl group or an alkynyl group, and a C "C ₇ ring An alkyl group, an aryl group, a heteroaryl group or a heterocyclic group; Is a linear or branched alkyl group of dC ₆ , C ₂ -C ₆ alkenyl or alkynyl. a cycloalkyl group, c ₃ -c, cycloalkenyl group, an aryl group, a heteroaryl group or a heterocyclic group which is wholly or partially substituted or unsubstituted at any position; the substituent is a linear or branched group of each independently dC ₆ Alkenyl, C ₂ -C ₆ alkenyl or blocked, 0 ₃ -( ₇ cycloalkyl, heterocyclyl, aryl, aryl, - 0H, -NH ₂ , -N0 ₂ , halogen, -CN , -C00H, and its non-physiological salts or prodrugs;  G is -0H, an amino acid residue, a peptide fragment consisting of 2-4 amino acid residues, or a structure of formula (V):

among them, Z is -NH -, -Asp-Ala-NH- -Asp-Ala-, -NH-CZt (Z ₂ ) -, -Asp-ΝΗ-, -Asp- CZ ZJ -or- NH-CZ ZJ -CZ ZJ -, wherein Zi ^ Z ₂ are each independently -H, -OH, -NH ₂ , -CN, an alkyl or halogen of gas dC ₆ (here Parentheses mean that Z ₂ is connected to the same carbon atom, not z, z _{2 is} connected; L ₂ is. A cycloalkyl group, a C ₅ containing a double bond at any position –! . a cycloalkenyl group, an aryl group, a heteroaryl group or a heterocyclic group; X is a bioelectron isosteric structure of -H, -C00H, -C00H, -C0NHR ₈ , -OCH ₂ COOR ₈ , -OCH ₂ CONHR ₈ , -OH, -P0 ₄ H, - S0 ₃ H or -CZ ₃ ( Z ₄ ) X, (here the brackets mean that Z ₃ and Z ₄ are all connected to the same carbon atom, not Z ₃ and Z _{4 are} connected), wherein ^ and Z ₄ are independent -H, -OH, -NH ₂ , -CN, gas C "C ₆ alkyl, halogen, or formula (VI);

X, is H, -COOH, -C0NHR ₈ , -OCH ₂ COOR ₈ , - OCH ₂ CONHR ₈ , -OH, - P0 ₄ H or -S0 ₃ H, Y and Y are each independently -H, -COOH, -C0NHR ₈ , -0R ₈ , -P0 ₄ H, - S0 ₃ H, halogen or methyl; R ₈ ^ H, (^-( ₄ alkyl, a straight or branched alkyl group of d- substituted by a _3⁄4 atom; K is 1, 2, 3, 4. 2. The compound according to claim 1, wherein  A is amino, missing; or A is an amino group, a deletion, B ₂ is a deletion, -CH ₂ - or -CH ₂ -CH ₂ -; or A is an amino group, a deletion, B ₂ is a deletion, -CH "or - CH ₂ -CH ₂ -, an isopropyl group, and R ₂ is an isobutyl group or a cyclohexanemethyl group, wherein R ₂ is preferably an isobutyl group. 3. A compound according to claim 1, wherein, D is missing, -NHC0- or - NHC0-R _4, wherein one kind of R is selected from structural formulas (Vn of) of:

4. The compound according to claim 1, wherein Q is a natural amino acid residue, or one selected from the group consisting of a structure (Vin) wherein the chiral carbon atom has a configuration of R or S, wherein R is -0H, -CI, -Br, -N0 ₃ , -NH ₂ , -F or -I; R _1Q is -OH or -NH ₂ :

VIII. 5. The compound according to claim 1, wherein G is -Asp, -Asp-Ala, -Asp-Ala-Glu, -Asp-Ala-Glu-Phe, or one selected from the formula (IX), wherein 1 (" and R„' are independent -C00H, -C0NH ₂ , -OH, -CI, -F, -Br, -I, -CF ₃ , -N0 ₂ , -C0CF ₃ , -CONHS0 ₂ CF ₃ , -NH ₂ ,

 IX. 6. A compound according to claim 5, wherein G is -Asp, -Asp-Ala, -Asp-Ala-Glu or -Asp-Ala-Glu-Phe. The compound according to any one of claims 1 to 6, which is selected from at least one of the following compounds, stereoisomers thereof, physiologically nontoxic salts or prodrugs thereof:  ( 1 ) G 1 u-Va 1 -Leu-P r 0- A s p-A 1 a-G 1 u-Phe  (2) G 1 u-Va 1 -Leu-D-Pro-A s p-A 1 a-G 1 u-Phe  (3) G 1 u-Va 1 -Leu-S e r -A s p-A 1 a-G 1 u-Phe  (4) G lu-Va l -Leu-D-Ser-A sp-Ala-Gl u-Phe  (5) G 1 u-Va 1 -Leu-Thr-Asp-A la-Gl u-Phe  (6) G 1 u-Va 1 -Leu-Ty r-A sp-Ala-Gl u-Phe  (7) Glu-Va l -Leu-H i s -A s p-A 1 a-G 1 u-Phe  (8) Glu-Va l -Leu-Tr p-A s p-A 1 a-G 1 u-Phe  (9) Glu-Va l -Leu-D-T r -A s p-A 1 a-G 1 u-Phe  (10) Glu-Va l -Leu-Me t -A s p-A 1 a-G 1 u-Phe  (11) G 1 u-Va 1 -Leu-Phe- A s p-A 1 a-G 1 u-Phe  (12) Glu-Va l -Leu-D-Phe-A s p-A 1 a-G 1 u-Phe (13) Glu-Va l -Leu-Phe (4-N0 ₂ ) -A sp-Ala-Gl u-Phe G 1 u-Va 1 -Leu-D-Phe (4-N0 ₂ ) - A sp-Ala-Gl u-Phe Glu-Val -Leu-Phe (4-NH ₂ ) -A sp-Ala-Gl u-Phe Glu-Val -Leu-D-Phe (4-NH ₂ ) -A sp-Ala-Gl u-Phe  G 1 u-Va 1 -Leu-Phe (4-C1) -Asp-A 1 a-G 1 u-Phe  Glu-Va l -Leu-D-Phe (4-C1) -Asp-A la-Gl u-Phe G 1 u-Va 1 -Leu-Phe (3-N0 ₂ ) -Asp-A 1 aG 1 u-Phe G 1 u-Va 1 -Leu-Phe (3-NH ₂ ) -A sp-Ala-Gl u-Phe  Glu-Val -Leu-Phe (2-F) -A sp-Ala-Gl u-Phe  G 1 u-Va 1 -Leu-Phe (3-F) -A sp-Ala-Gl u-Phe  Glu-Val -Leu-Phe (4-F) -Asp-Ala-Glu-Phe  Glu-Va 1-Leu-Phe (2-C1) -Asp-A 1 a-Glu-Phe  Glu-Va l -Leu-Phe (3-C1) -Asp-Ala-Gl u-Phe  Glu-Val -Leu-Phe (2-Br) -Asp-Ala-Glu-Phe  G 1 u-Va 1 -Leu-Phe (3-Br) -As p-A la-Gl u-Phe  G 1 u-Va 1 -Leu-Phe (4-Br) -As p-A la-Gl u-Phe Glu-Va 1-Leu-Phe (2-CH ₃ ) -Asp-Ala-Glu-Phe Glu-Va l -Leu-Phe (3-CH ₃ ) -A s pA 1 aG 1 u-Phe Glu-Va 1-Leu-Phe (4-CH ₃ ) -Asp-Ala-Glu-Phe  G 1 u-Va 1 -Leu-Phe (2, 3-dif luor i ne) -A s p-A 1 a-G 1 u-Phe G 1 u-Va 1 -Leu-Phe (2, 4-dif luorine) -Asp-Ala-Gl u-Phe Glu-Val-Leu-Phe ( 3, 4-dif luor ine) -Asp-Ala-Glu-Phe Glu-Va 1-Leu-Phe (2, 4- d i ch 1 or i ne) -As p-A 1 a-G 1 u-Phe Glu-Va 1-Leu-Phe (3, 4- dichlorine) -Asp-Ala-Glu-Phe Glu-Val -Leu-Phe (2, 3-dichlor ine) -Asp-Ala-Gl u-Phe Gl u- -Val .-Leu-Phe (2, 4- dibromine) -Asp-Ala-Glu-Phe G] u- -Val _L -Leu-Phe (3, 4- dibromine) -Asp-Ala-Glu-Phe  G] u- -Val ί-Leu-Phe (2, 3- dibromine) -Asp-Ala-Glu-Phe  G] u- -Val -Leu-Phe (2, 4- dimethyl) -Asp-Ala-Glu-Phe  Gl u- -Val L-Leu-Phe (3, 4- dimethyl) -Asp-Ala-Glu-Phe  Gl u- -Val ί -Leu-Phe (2, 3- dimethyl) -Asp-Ala-Glu-Phe  Gl u- -Val ί -Leu-Phe (3-Br, 4-C1) -Asp-Ala-Glu-Phe  Gl u- -Va] L -Leu-Phe (2-Br, 4-C1) -Asp-Ala-Glu-Phe  Gl u- -Val Bu Leu-Phe (3-C1, 4- Br) -Asp-Ala-Glu-Phe  Gl u- -Val l-Leu-Phe (3-F, 4-C1) -Asp-Ala-Glu-Phe  Gl u- -Val L -Leu-Phe (2-F, 4-C1) -Asp-Ala-Glu-Phe  Gl u- -Val L-Leu-Phe (3-C1, 4-F) -Asp-Ala-Glu-Phe  G] u- -Val [ -Leu-2-Na 1 -A s p-A 1 a-G 1 u-Phe  G] u- -Va] L -Leu-D-2-Na 1-Asp-Ala-Gl u-Phe G] u- -Va] L-Leu- Y - (trans, L) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Val L-Leu-Y-( cis, L) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Val L-Leu- γ-( trans, D) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Val I -Leu- v-( cis,D) -Pro (4-NH ₂ ) -As pA 1 aG 1 u-Phe G] u- -Va] L-Leu- (trans, L) - Pro (4- OH) -Asp-Ala-Glu-Phe G] u- -Va] L-Leu- (cis, L )- Pro (4-OH) -Asp-Ala-Glu-Phe G] .u- -Va] L-Leu- (trans, D)- Pro (4-OH) -Asp-Ala-Glu-Phe G Lu- -Va] L-Leu- (cis,D)- Pro (4-OH) -Asp-Ala-Gl u-Phe G • u- -Va] L-Leu- (trans, L) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G .u- -Va L-Leu- (cis, L ) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] Lu- -Va] L-Leu- (trans, D) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Va]Bu Leu- (cis, D)- Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe  G] u- -Va] L -Leu-Phe-D-Pro-A sp-Ala-Gl u-Phe  G] u- -Va] L -Leu-Phe- (cis,D) -Pro (4-OH) -Asp-Ala-Glu-Phe G] u- -Va] L -Leu-Phe- (cis, D) -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe Gl u- -Val L -Leu-Phe- (cis, D)- γ -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Va] L -Leu-Phe- (trans, D) - Pro (4-OH) -Asp-Ala-Glu-Phe Gl u- -Va] L -Leu-Phe- (trans, D) - Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe Gl u- -Val L -Leu-Phe- (trans, D)- γ -Pro (4-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Va] L -Leu-Phe- (cis, D) -Pro (5-OH) -Asp-Ala-Glu-Phe Gl u- -Val L -Leu-Phe- (cis, D) - ω -Pro (5-NH ₂ ) -Asp-A 1 aG 1 u-Phe Gl u- -Val L -Leu-Phe- (cis,D) -Pro (5-NH ₂ ) -Asp-A 1 aG 1 u-Phe Gl u- -Va] L -Leu-Phe- (trans, D) -Pro (5-OH) -Asp-A 1 a-G 1 u-Phe G] u- -Val L-Leu-Phe- (trans, D) -ω -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe G] u- -Val ί -Leu-Phe- (trans, D) -Pro (5-NH ₂ ) -Asp-Ala-Glu-Phe Gl u- -Val -Leu-Tyr-D-Pro-A s p-A 1 a - G 1 u-Phe  Gl u- -Val [ -Leu-H i s -D-Pro-A sp-Ala-Gl u-Phe  Gl u- -Val L -Leu-Trp-D-Pro-A s p-A 1 a-G 1 u-Phe Gl u- -Val [-Leu-Phe (4-N0 ₂ ) -D-Pro-As pA 1 aG 1 u-Phe G] u- -Val L -Leu-Phe (4-NH ₂ ) -D- Pro- Asp-Ala- Glu-Phe  Gl u- -Val L-Leu-Phe (4-C1) -D-Pr o-A sp-Ala-Gl u-Phe  G] u- -Va] L -Leu-Phe (4-Br) -D-Pr o-A sp-Ala-Gl u-Phe G] u- -Val L-Leu-Phe (3-N0 ₂ ) -DP r oA s pA 1 aG 1 u-Phe Gl u- -Val L-Leu-Phe (3-NH ₂ ) -DP r oA s pA 1 aG 1 u-Phe (86) Glu- -Val -Leu- -Phe (2-F) -DP r oA s pA 1 aG 1 u-Phe [87) Glu- -Va l -Leu- -Phe (3-F) -D-Pro-A sp-Ala-Gl u-Phe  (88) Glu- -Va l -Leu- -Phe (4-F) -D-P r o-A s p-A 1 a-G 1 u-Phe  (89) Glu- -Va l -Leu- -Phe (2-Cl) -D-P r o-A s p-A 1 a-G 1 u-Phe  (90) Glu- -Val -Leu- -Phe (3-Cl) -D-P r o-A sp-Ala-Gl u-Phe  [91) Glu- -Va l -Leu- -Phe (2-Br) -D-P r o-A s p-A 1 a-G 1 u-Phe  (92) Glu- -Val -Leu- -Phe (3- Br) -D-Pro-A s p-A 1 a-G 1 u-Phe  [93) Glu- -Va l -Leu- -Phe (4-Br) -D-Pro-A s p-A 1 a-G 1 u-Phe [94) Glu- -Val -Leu- -Phe (2-CH ₃ ) -D-Pro-As pA 1 aG 1 u-Phe  (95) Glu- -Va l -Leu- -Phe (3-CH3) -D-Pro-As p-A 1 a-G lu-Phe  (96) Glu- -Val -Leu- -Phe (4-CH3) -D-P r o-A s p-A 1 a-G 1 u-Phe  [97) Glu- -Val -Leu- -Phe (2, 3-dif luor ine) -D-Pro-A sp-Ala-Gl u-Phe [98) Glu- -Val -Leu- -Phe (2, 4-dif luorine) -D-Pro-A s p-A 1 a-G 1 u-Phe (99) Glu- -Val -Leu- -Phe ( 3, 4-dif luor ine) -D-Pro-Asp-Ala-Glu-Phe (100) Glu- -Val- -Leu-Phe (2 4- dichlor ine) -D-Pr o-As p-A 1 a-G 1 u-Phe (101) Glu- -Val- -Leu-Phe (3 4-d i ch 1 or i ne) -D-Pr o-As -A 1 a-G 1 u-Phe (102) Gl u-Va 1 -Leu-Phe (2 3- d ichlor ine) -D-P r o-A s p-A la-Gl u-Phe (103) Glu- -Val- -Leu-Phe (2 4- dibromine) -D-Pr o-A s p-A la-Gl u-Phe (104) Glu- -Val- -Leu-Phe (3 4-dibromine) -D-P r o-A s p-A la-Gl u-Phe (105) Glu- -Va l- -Leu-Phe (2 3- dibromine) -D-Pr o-As p-A 1 a-G 1 u-Phe (106) Glu- -Val- -Leu-Phe (2 4- dimethyl) -D-Pro-A s p-A la-Gl u-Phe (107) Glu- -Val- -Leu-Phe (3 4-dimethyl) -D-P r o-A sp-Ala-Gl u-Phe (108) Glu- -Val- -Leu-Phe (2 3-dimethyl) -D-P r o-A sp-Ala-Gl u-Phe (109) Glu- -Va l- -Leu-Phe (3 Br, 4 -C 1 ) -DP r oA s pA 1 aG 1 u-Phe (110) Glu- -Val -Leu-Phe (2-Br, 4-Cl) -DP r oA s pA 1 aG 1 u-Phe (111) Glu- -Val- -Leu-Phe (3-Cl, 4-Br) -D-Pr o-A s p-A 1 a-G 1 u-Phe (112) Glu- -Va l- -Leu-Phe (3-F, 4-Cl) -D-P r o-A s p-A 1 a-G 1 u-Phe (113) Glu- -Va l- -Leu-Phe (2-F, 4-Cl) -D-P r o-A s p-A 1 a-G 1 u-Phe (114) Glu- -Va l- -Leu-Phe (3-Cl, 4-F) -D-P r o-A s p-A 1 a-G 1 u-Phe (115) Glu- -Val- -Leu-2-Na 1 -D-Pro-Asp-A 1 a-G 1 u-Phe  (116) Glu- -Va l- -Leu-Tyr-Asp  (117) Glu- -Val- -Leu-Hi s-Asp  (118) Glu- -Val- -Leu-Trp-Asp  (120) Glu- -Val- -Leu-Met -Asp  (121) Glu- -Val- -Leu-Phe-Asp (122) Glu- -Val- -Leu- -Phe (4-N0 ₂ ) -Asp (123) Glu- -Val- -Leu- -Phe (4-NH ₂ ) -Asp  (124) Glu- -Val- -Leu- -Phe (4-Cl) -Asp (125) Glu- -Val- -Leu- -Phe (3-N0 ₂ ) -Asp (126) Glu- -Val- -Leu- -Phe (3-NH ₂ ) -Asp  (127) Glu- -Val- -Leu- -Phe (2-F) -Asp  (128) Glu- -Val- -Leu- -Phe (3-F) -Asp  (129) Glu- -Val- -Leu- -Phe (4-F) -Asp  (130) Glu- -Val- -Leu- -Phe (2-CD -Asp  (131) Glu- -Va l- -Leu- -Phe (3-Cl) -Asp  (132) Glu- -Va l -Leu- -Phe (2-Br) -Asp  (133) Glu- -Val -Leu- -Phe (3- Br) - Asp (134) Glu- -Val -Leu- -Phe (4-Br) -Asp (135) Gl u- -Va] -Leu- -Phe (2-CH ₃ ) -Asp  (136) G] Lu- -Va] -Leu- -Phe (3-CH3) -Asp  (137) Gl Lu- -Va] -Leu- -Phe (4-CH3) -Asp  (138) Gl u- -Va] -Leu- -Phe (2, 3-dif luorine) -Asp (139) G] Lu- -Val -Leu- -Phe (2, 4-dif luorine) -Asp (140) G] u- -Val -Leu- -Phe ( 3, 4-dif luorine) -Asp (141) G] Lu- -Val -Leu- -Phe (2, 4- dichlorine) -Asp (142) Gl u- -Val -Leu- -Phe (3, 4-dichlorine) -Asp (143) G] u- -Va] l-Leu- -Phe (2, 3-dichlorine) -Asp (144) G] u- -Val l-Leu- -Phe (2, 4- dibromine) -Asp (145) G] iu- -Val -Leu- -Phe (3, 4-dibromine) -Asp (146) Gl u- -Val -Leu- -Phe (2, 3-dibromine) -Asp (147) G] u- -Va] L-Leu- -Phe (2, 4- dimethyl) -Asp (148) G] u- -Val L-Leu- -Phe (3, dimethyl) -Asp (149) Gl u- -Val -Leu- -Phe (2, 3-dimethyl) - Asp (150) Gl lu- -Val -Leu- -Phe (3-Br, 4-CD-Asp  (151) G] u- -Va] -Leu- -Phe (2-Br, 4-Cl)-Asp  (152) G] u- -Va] -Leu- -Phe (3-Cl,4-Br)-Asp  (153) Gl u- -Va] -Leu- -Phe (3-F, 4-CD-Asp  (154) Gl u- -Va] -Leu- -Phe (2-F, 4-Cl)-Asp  (155) G] Lu- -Val -Leu- -Phe (3-Cl,4-F) -Asp  (156) G Lu- -Va] -Leu- -2-Nal-Asp  (157) G u- -Va] ί -Leu-Phe-D-P r o - A sp-Ala-Gl u-Ph (158) G .u- -Va] .-Leu- -Phe- -(cis,D) -Pro (4-OH) -As 159) G .u- -Va] L -Leu-Phe- (ci s, D) - Pro (4-NH ₂ ) -Asp 160) G .u- -Val L -Leu-Phe- (cis, D) - γ -Pro (4-NH ₂ ) - Asp 161) G u- -Val L -Leu-Phe- (trans, D) -Pro (4-0H) -Asp 162) G] • u- -Val [-Leu-Phe- (trans, D) -Pro (4-NH ₂ ) -Asp 163) G] u- -Val l-Leu-Phe- (trans, D)- γ - Pro (4-NH ₂ ) -Asp 164) G] u- -Val L-Leu-Phe- (cis, D) -Pro (5 - OH) -Asp 165) G] u- -Val ί -Leu-Phe- (cis, D) -ω-Pro (5-NH ₂ ) -Asp 166) G] u- -Val -Leu-Phe- (cis, D) - Pro (5-NH ₂ ) - Asp 167) G] u- -Val .-Leu-Phe- (trans, D) -Pro (5- OH) -Asp 168) G] u- -Val .-Leu-Phe- (trans, D) -ω-Pro (5-NH ₂ ) -Asp 169) G] u- -Val -Leu-Phe- (trans, D) -Pro (5-NH ₂ ) - Asp 170) G] u- -Val .-Leu-Tyr-D-Pro-Asp  171) G] u- -Val L -Leu-Hi s-D-Pro-Asp  172) G] u- -Val -Leu-Trp-D-P ro-Asp 173) G] u- -Val .-Leu-Phe (4-N0 ₂ ) -D-Pro-Asp 174) G] Lu- -Val -Leu-Phe (4-NH ₂ ) -D-Pro-Asp  175) G] u- -Val .-Leu-Phe (4- CI) -D-Pro-Asp  176) Gl Lu- -Val .-Leu-Phe (4- Br) -D-Pro-Asp 177) G] u- -Val -Leu-Phe (3-N0 ₂ ) -D- Pro-Asp 178) G] u- -Val -Leu-Phe (3-NH ₂ ) -D-Pro-Asp  179) G] .u- -Val L-Leu-Phe (2-F) -D-Pro-Asp  180) G] .u- -Val .-Leu-Phe (3-F) -D-Pro-Asp  181) G] u- -Val ί -Leu-Phe (4-F) -D-Pro-Asp 182) G] u- -Val ί -Leu-Phe (2-C1) -DP ro-Asp 183) G -u- -Va] L-Leu- -Phe 3-Cl)-D-Pro-Asp  184) G • u- -Va] -Leu- -Phe 2- Br)-D-Pro-Asp  185) G .u- -Va] -Leu- -Phe 3- Br)-D-Pro-Asp  186) G] .u- -Va] -Leu- -Phe 4- Br)-D-Pro-Asp 187) G] u- -Va] -Leu- -Phe 2- CH ₃ ) -D-Pro-Asp  188) G] u- -Va] -Leu- -Phe 3- CH3) -D-Pro-Asp  189) G] u- -Va] -Leu- -Phe 4- CH3) -D- Pro-Asp  190) G] u- -Val -Leu- -Phe 2, 3-dif luorine) -D-Pro-Asp 191) G] .u- -Va] -Leu- -Phe 2, 4-dif luorine) -D-Pro-Asp 192) G] u- -Val -Leu- -Phe 3, 4-dif luorine) -D-Pro-Asp 193) G] u- -Val -Leu- -Phe 2, 4- dichlorine) -D-Pro-Asp 194) G] u- -Val -Leu- -Phe 3, 4-di chlorine) -D-Pro-Asp 195) G] u- -Val -Leu- -Phe 2.3- dichlorine) -D-Pro-Asp 196) G] u- -Val -Leu- -Phe 2.4- dibromine) -D-Pro-Asp 197) G] u- -Val -Leu- -Phe 3, 4-dibromine) -D-Pro-Asp 198) G] u- -Val -Leu- -Phe 2, 3-dibromine) - D- Pro- Asp 199) G] u- -Val -Leu- -Phe 2, 4- dimethyl) -D-Pro-Asp 200) Gl u- -Val l-Leu- -Phe 3, 4-dimethyl) -D-Pro-Asp 221) Gl u- -Val-Leu- -Phe 2, 3-dimethyl) -D-Pro-Asp 222) Gl u- -Val L-Leu- -Phe 3-Br, 4-Cl)-D-Pro-Asp  223) Gl u- -Val l-Leu- -Phe 2- Br, 4-C -D- Pro-Asp  224) G] u- -Val -Leu- -Phe 3-Cl,4-Br)- D-Pro-Asp  225) Gl u- -Val -Leu- -Phe 3-F, 4-Cl)-D-Pro-Asp 226) G] u- -Val -Leu- -Phe 2-F, 4-Cl)-D-Pro-Asp

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 Dsy-ojj-a- ( —t7 'ΐθ-ε) siid-ngq- ■Ι3⁄4Λ- SZSl00/0T0ZN3/X3d Z9£9 Ϊ0 OAV 8. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7 together with a pharmaceutically acceptable carrier or excipient or adjuvant. The use of the compound according to any one of claims 1 to 7 for the preparation of a medicament for inhibiting P-secretase activity in a mammal, preventing or treating a P-secretase-related disease such as Alzheimer's disease. 10. Use of a compound according to any one of claims 1 to 7 for the preparation of a p-secretase inhibitor.