CN101928326A

CN101928326A - Substitution five-heterocyclic alkyl aminoacyl compound and application thereof

Info

Publication number: CN101928326A
Application number: CN2009101394885A
Authority: CN
Inventors: 聂爱华; 顾为; 谭祖磊; 李斐; 汤立合; 陶林; 苏瑞斌; 李锦�; 马小根
Original assignee: Institute of Pharmacology and Toxicology of AMMS
Current assignee: Institute of Pharmacology and Toxicology of AMMS
Priority date: 2009-06-24
Filing date: 2009-06-24
Publication date: 2010-12-29
Anticipated expiration: 2029-06-24
Also published as: CN101928326B

Abstract

The invention relates to a substitution five-heterocyclic alkyl aminoacyl compound and application thereof, in particular to a substitution five-heterocyclic alkyl aminoacyl derivative which has IAPs inhibition activity and is expressed by a general formula I and pharmaceutically-acceptable salt or hydrate thereof, wherein the definition of each substitution group in the general formula I is described in the specifications, and a preparation method of the compound expressed by the general formula I, a medicinal composition comprising the compound expressed by the general formula I or the pharmaceutically-acceptable salt or hydrate thereof, the application of the compound expressed by the general formula I or the pharmaceutically-acceptable salt or hydrate thereof to the production of medicaments and the application of the medicaments to the treatment or prevention of solid tumors and relevant rumor diseases derived from hematologic malignancies are all shown in the specifications.

Description

Five-heterocyclic alkyl aminoacyl compound that replaces and uses thereof

Invention field

Five-heterocyclic alkyl aminoacyl derivative, its preparation method that the present invention relates to replace, the pharmaceutical composition that contains them and be used to prepare the purposes of the compound of anti-tumor activity as IAP IAPs (Inhibitor of Apoptosis Proteins) inhibitor.

Background technology

Apoptosis or be called apoptosis usually occurs in the growth and the maintenance stage of health tissues in the multicellular organism.Known apoptotic pathways is at fetal development, viral pathogeny, cancer, autoimmune disorder and neurodegenerative disease, and has important effect in other incident.Found in the apoptosis reaction change and cancer, autoimmune disorder for example systemic lupus erythematous and multiple sclerosis development and with comprise that the virus infection of being correlated with simplexvirus, poxvirus and adenovirus is relevant.

IAP IAPs (Inhibitor of Apoptosis Proteins) is the endogenous inhibition of the main attemperator Caspases of apoptosis (east, half Guang sky enzyme), they optionally combine with Caspase-3, Caspase-7 and/or Caspase-9, the proteolytic activity of the Caspases that blocking-up apoptosis institute must rely on, and then inhibition apoptosis.Up to now, the IAPs that finds in human body has 8 members, comprises NAIP, XIAP, cIAP1, cIAP2, ILP2, Bruce, Survivin and Livin (ML-IAP).Wherein, NAIP, XIAP, cIAP1 and cIAP2 contain three BIR structural domains (BIR1, BIR2, BIR3), and ILP2, Bruce, Survivin and Livin only contain a BIR structural domain.Verified many IAPs unconventionality expression in cancer cells, Survivin has high expression level in multiple malignant tumour, but is not checked through this proteic existence in normal cell.Though other IAPs member exists in multiple healthy tissues, also as Survivin overexpression in multiple malignant tumour.The IAPs inducing tumor cell of overexpression produces resistance to chemotherapy, also suppresses the apoptosis that chemotherapy or radiotherapy cause simultaneously.On the other hand, the Smac/Diablo albumen that discharges in the plastosome can combine with IAPs, and its bonded site is IAPs and Caspase-3 ,-7 and Caspase-9 bonded position just, thereby has suppressed the anti-apoptosis activity of IAPs.According to function and IAPs and Caspases and the Smac interactional mechanism of IAPs family protein in apoptosis pathway, had been found that the multiple compound that can suppress the IAPs function and have anti-tumor activity at present.

Although a series of IAPs inhibitor are developed, also there is not marketed drug at present, many compounds yet relate to the limitation of aspects such as usefulness, stability or toxicity.Therefore, the safe and effective IAPs inhibitor of exploitation different types of structure has positive social effect and good market outlook.

Summary of the invention

The objective of the invention is to seek the inhibitor of the selectivity IAPs acceptor high-affinity of new texture, be used to suppress the activity of IAPs in the human body, and then strengthen the proteolytic activity of Caspases, thereby play the purpose of treatment cancer.

The inventor has found a series ofly to promote apoptotic new compound in conjunction with IAPs and by regulating the IAPs function, and they have acceptable stability of pharmacy and bioavailability.This compounds can be blocked the interaction of IAPs and Caspase-3, Caspase-7 and Caspase-9.Result of the present invention shows that this micromolecular can be before apoptosis regulates IAPs albumen down, and explanation is when with other apoptotic inductor administration thus, and this application of compound can provide useful effect clinically.The inventor has proved that The compounds of this invention combines with Mammals XIAP-BIR3, cIAP-BIR3 structural domain, thereby promotes cancer cell-apoptosis.The compound of Miao Shuing has pro-apoptosis bioactivity in multiple cancerous cell line herein, these clones are bladder cancer, mammary cancer, carcinoma of the pancreas, colorectal carcinoma, leukemia, lung cancer, lymphoma, multiple spinal cord knurl and ovarian cancer cell line for example, and may be used for the disease that other cancerous cell line and cell pair cell apoptosis have resistance.These results show that compound of the present invention will have at solid tumor and the tumor treatment activity that originates from malignant hematologic disease.In addition, compound of the present invention also can be used for preventing in the disease of the transfer, invasion, inflammation of cancer cells and other feature with anti-apoptotic cell.Inventor's process discovers that The compounds of this invention can suppress the activity of IAPs, and then strengthens the proteolytic activity of Caspases, recovers the apoptosis regulating effect of Caspases.Therefore, this compounds can be used for tumor treatment.The present invention is based on above-mentioned discovery and be accomplished.

Summary of the invention:

First aspect present invention provides the compound of general formula I:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein:

X is-CH ₂-or-O-or-S-;

Y is-CH ₂-or-CH ₂CH ₂-or-CO-;

R ¹Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl, it is optional replaced by one or more halogens and

3)-C ₃-C ₈Cycloalkyl, it is chosen wantonly and is replaced by one or more halogens;

R ²Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-(C ₁-C ₆Alkyl)-R ⁷And

5)-Ar ¹，

Wherein,

R ⁷Be selected from:

1)-OR ⁸，

2)-SR ⁸，

3)-NR ⁸R ⁹，

4)-NCONR ⁸R ⁹，

5)-NCNNR ⁸R ⁹，

6)-COOR ⁸，

7)-CONR ⁸R ⁹And

8)-Ar ¹，

Ar ¹Be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optional to be selected from following group and to replace by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

2)-(C ₁-C ₆Alkylidene group) _0-3-phenyl, phenyl wherein is optional by one or more being selected from-C ₁-C ₄The group of alkyl, halogen replaces,

3)-C ₁-C ₆Alkyl, it is chosen wantonly and is replaced by one or more halogens,

4)-C ₃-C ₈Cycloalkyl, it is chosen wantonly and is replaced by one or more halogens,

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

6)-C ₂-C ₆Alkynyl, it is chosen wantonly and is replaced by one or more halogens;

R ³Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-(C ₁-C ₆Alkyl)-R ¹⁰,

5)-Ar ¹，

Wherein,

R ¹⁰Be selected from:

1)-OR ⁸，

2)-SR ⁸，

3)-NR ⁸R ⁹，

4)-NCONR ⁸R ⁹，

5)-NCNNR ⁸R ⁹，

6)-COOR ⁸，

7)-CONR ⁸R ⁹And

8)-Ar ¹，

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

[preferred, R ³Connect carbon atom and can be any optical configuration]

R ⁴And R ⁴⁰⁰Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl and

5)-C ₂-C ₆Alkynyl;

R ⁵And R ⁵⁰⁰Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl and

5)-C ₂-C ₆Alkynyl;

R ⁶Be selected from:

1)-R ¹¹，

2)-OR ¹¹，

3)-NR ¹¹R ¹²，

4)-SOR ¹¹And

5)-SO ₂R ¹¹，

Wherein, R ¹¹And R ¹²Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl,

5)-C ₂-C ₆Alkynyl,

6)-COR ⁸，

7)-Ar ¹，

8)-(C ₁-C ₆Alkyl)-Ar ¹,

9)-CO-Ar ¹And

10)-CO-(C ₁-C ₆Alkyl)-Ar ¹,

Wherein,

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

2)-(C ₁-C ₆Alkylidene group) _0-3-phenyl, phenyl wherein is one or more to be selected from-C ₁-C ₄The group of alkyl, halogen replaces,

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

6)-C ₂-C ₆Alkynyl, it is chosen wantonly and is replaced by one or more halogens.

According to the compound of first aspect present invention, it is a formula Ia compound:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein X, R ¹, R ², R ³, R ⁴, R ⁴⁰⁰, R ⁵, R ⁵⁰⁰, and R ⁶Definition as the compound of first aspect present invention mutual-through type I.

According to the compound of first aspect present invention, it is a formula Ib compound:

According to the compound of first aspect present invention, it is a formula Ic compound:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein R ¹, R ², R ³, R ⁸, and R ⁹Definition as the compound of first aspect present invention mutual-through type I.

According to the compound of first aspect present invention, it is a formula Id compound:

According to the compound of first aspect present invention, it is a formula Ic1 compound:

According to the compound of first aspect present invention, it is a formula Id1 compound:

According to the compound of first aspect present invention, it is a formula Ie compound:

R ¹, R ², R ³, and Ar ¹As the definition of the compound of first aspect present invention mutual-through type I,

Ar ²Be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optional to be selected from following group and to replace by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

2)-(C ₁-C ₆Alkylidene group) _0-3-phenyl, phenyl wherein is optional by one or more choosings

From-C ₁-C ₄The group of alkyl, halogen replaces,

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

According to the compound of first aspect present invention, it is a formula If compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

According to the compound of first aspect present invention, it is a formula Ie1 compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

According to the compound of first aspect present invention, it is a formula If1 compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

According to the compound of first aspect present invention, it is selected from:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate.

Second aspect present invention provides the preparation method of each described compound of first aspect present invention, and it may further comprise the steps:

A) make formula II compound

II (formula for example

The compound of expression) with formula H-R ⁶The compound reaction of expression obtains formula

The compound of expression removes group Z then, obtains formula

The compound of expression;

B) make formula

The compound and the formula of expression

The compound reaction of expression obtains formula

The compound of expression, hydrolysis in the presence of alkali then obtains formula

The compound of expression;

C) in the presence of suitable reagent (for example one or more in isobutyl chlorocarbonate, triethylamine and the N-methylmorpholine), make formula

The compound and the formula of expression

The compound reaction of expression obtains formula The compound of expression removes group-Boc then, obtains formula I compound; With optional,

D) make the product of step c) form pharmacologically acceptable salts;

Wherein, X, Y, R ¹, R ², R ³, R ⁴, R ⁴⁰⁰, R ⁵, R ⁵⁰⁰, and R ⁶As the definition of the compound of each mutual-through type of first aspect present invention I, Z is selected from-H ,-Boc and-Cbz.

According to the method for second aspect present invention, it randomly has with the next item down or multinomial feature:

In step a), the reaction conditions of first step wherein can adopt exsiccant tetrahydrofuran (THF), N, dinethylformamide or methylene dichloride are as solvent, preferred tetrahydrofuran (THF) can make up as the reaction auxiliary reagent with DCC+HOBt combination or isobutyl chlorocarbonate+tertiary amine, preferably can use the DCC+HOBt combination, temperature of reaction can be at-15 ℃～25 ℃, preferred 0 ℃～10 ℃, reaction can be 1 hour to 24 hours, preferred 12 hours; The second step deprotection can adopt exsiccant to be dissolved with the organic solvent of 2-4N HCl, for example tetrahydrofuran (THF), ethyl acetate, dioxane, preferably 4N HCl/ ethyl acetate, temperature can be at-15 ℃～25 ℃, preferred 0 ℃, reaction can be 1 hour to 8 hours, preferred 2 hours;

In step b), the reaction conditions of first step wherein can adopt exsiccant tetrahydrofuran (THF), N, dinethylformamide or methylene dichloride are as solvent, preferred tetrahydrofuran (THF) can make up as the reaction auxiliary reagent preferred DCC+HOBt combination with DCC+HOBt combination or isobutyl chlorocarbonate+tertiary amine, temperature of reaction can be at-15 ℃～25 ℃, preferred 0 ℃～10 ℃, reaction can be 1 hour to 24 hours, preferred 12 hours; The second step deprotection can adopt the blended methanol/water solution of 1-4N NaOH or LiOH, 50% methanol solution of preferred 1N NaOH, and temperature of reaction can be at-15 ℃～25 ℃, and preferred 0 ℃～10 ℃, reaction can be 1 hour to 24 hours, preferred 3 hours; With

In step c), the reaction conditions of first step wherein, can adopt exsiccant tetrahydrofuran (THF), N, dinethylformamide or methylene dichloride be as solvent, preferred tetrahydrofuran (THF), and preferred isobutyl chlorocarbonate+N-methylmorpholine is as the reaction auxiliary reagent, temperature of reaction can be at-15 ℃～25 ℃, preferred 0 ℃～10 ℃, reaction can be 1 hour to 24 hours, preferred 12 hours; The second step deprotection can adopt exsiccant to be dissolved with the organic solvent of 2-4N HCl, for example tetrahydrofuran (THF), ethyl acetate, dioxane, preferred 4N HCl/ ethyl acetate; temperature can be at-15 ℃～25 ℃; preferred 0 ℃, reaction can be 1 hour to 8 hours, preferred 2 hours.

According to the method for second aspect present invention, formula wherein

The compound of expression can be used formula

The compound of expression replaces, and obtains the isomer of formula I compound.

Third aspect present invention provides a kind of pharmaceutical composition, and it comprises each described compound of first aspect present invention and optional pharmaceutically acceptable carrier or the vehicle that treats and/or prevents significant quantity.

Fourth aspect present invention provide first aspect present invention each described compound preparation be used for the treatment of and/or the medicine of the disease that prevention is relevant with the IAPs overexpression in purposes.

According to the purposes of fourth aspect present invention, wherein said disease is selected from bladder cancer, mammary cancer, carcinoma of the pancreas, colorectal carcinoma, leukemia, lung cancer, lymphoma, multiple spinal cord knurl, ovarian cancer and cervical cancer, especially for example is ovarian cancer and cervical cancer.

Inhaling the 5th aspect for this provides the method that treats and/or prevents the disease relevant with the IAPs overexpression in the Mammals (for example people) that needs is arranged, and this method comprises each the described compound of first aspect present invention to described Mammals (for example people) administering therapeutic and/or prevention significant quantity.

According to the purposes of fifth aspect present invention, wherein said disease is selected from bladder cancer, mammary cancer, carcinoma of the pancreas, colorectal carcinoma, leukemia, lung cancer, lymphoma, multiple spinal cord knurl, ovarian cancer and cervical cancer, especially for example is ovarian cancer and cervical cancer.

Detailed Description Of The Invention:

In an embodiment of The compounds of this invention, wherein said X is-O-.

In an embodiment of The compounds of this invention, wherein said X is-S-.

In an embodiment of The compounds of this invention, wherein said Y is-CH ₂-.

In an embodiment of The compounds of this invention, wherein said Y is-CO-.

In an embodiment of The compounds of this invention, wherein said R ¹Be selected from :-H, optional by one or more halogens replace-C ₁-C ₆Alkyl.

In an embodiment of The compounds of this invention, wherein said R ¹Be selected from :-H and-C ₁-C ₆Alkyl.

In an embodiment of The compounds of this invention, wherein said R ¹Be selected from :-H and-C ₁-C ₄Alkyl.

In an embodiment of The compounds of this invention, wherein said R ¹Be selected from :-H, methyl, ethyl, propyl group, sec.-propyl.

In an embodiment of The compounds of this invention, wherein said R ¹Be selected from :-H, methyl.

In an embodiment of The compounds of this invention, wherein said R ²Be selected from :-H ,-C ₁-C ₆Alkyl.

In an embodiment of The compounds of this invention, wherein said R ²Be selected from :-H ,-C ₁-C ₄Alkyl.

In an embodiment of The compounds of this invention, wherein said R ²Be selected from :-H, methyl, ethyl, propyl group, sec.-propyl.

In an embodiment of The compounds of this invention, wherein said R ²Be selected from :-H, methyl.

In an embodiment of The compounds of this invention, wherein said R ³Be selected from :-H ,-C ₁-C ₆Alkyl ,-C ₃-C ₈Cycloalkyl ,-(C ₁-C ₆Alkyl)-R ¹⁰, R wherein ¹⁰Be selected from :-OR ⁸,-SR ⁸,-NR ⁸R ⁹,-NCONR ⁸R ⁹,-NCNNR ⁸R ⁹,-COOR ⁸,-CONR ⁸R ⁹, R ⁸And R ⁹Be selected from independently of one another :-H ,-(C ₁-C ₆Alkylidene group) _0-3-phenyl, phenyl wherein is optional by one or more being selected from-C ₁-C ₄The group of alkyl and halogen replaces, optional by one or more halogens replace-C ₁-C ₆Alkyl, optional by one or more halogens replace-C ₃-C ₈Cycloalkyl, optional by one or more halogens replace-C ₂-C ₆Thiazolinyl and optional by one or more halogens replace-C ₂-C ₆Alkynyl.

In an embodiment of The compounds of this invention, wherein said R ³Be selected from :-H ,-C ₁-C ₆Alkyl ,-C ₃-C ₈Cycloalkyl ,-(C ₁-C ₆Alkyl)-OR ⁸, R wherein ⁸Be selected from :-H ,-C ₁-C ₆Alkyl ,-C ₂-C ₆Thiazolinyl and-C ₂-C ₆Alkynyl.

In an embodiment of The compounds of this invention, wherein said R ³Be selected from :-H ,-C ₁-C ₄Alkyl ,-C ₄-C ₆Cycloalkyl ,-(C ₁-C ₄Alkyl)-OR ⁸, R wherein ⁸Be selected from :-C ₂-C ₆Alkynyl.

In an embodiment of The compounds of this invention, wherein said R ³Be selected from :-H, methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, cyclopentyl, cyclohexyl, 2-propynyl oxygen base-ethyl.

In an embodiment of The compounds of this invention, wherein said R ⁴And R ⁴⁰⁰Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl.

In an embodiment of The compounds of this invention, wherein said R ⁴And R ⁴⁰⁰Be selected from independently of one another :-H, methyl, ethyl, propyl group, sec.-propyl.

In an embodiment of The compounds of this invention, wherein said R ⁴And R ⁴⁰⁰Be selected from independently of one another :-H, methyl.

In an embodiment of The compounds of this invention, wherein said R ⁵And R ⁵⁰⁰Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl.

In an embodiment of The compounds of this invention, wherein said R ⁵And R ⁵⁰⁰Be selected from independently of one another :-H, methyl, ethyl, propyl group, sec.-propyl.

In an embodiment of The compounds of this invention, wherein said R ⁵And R ⁵⁰⁰Be selected from independently of one another :-H, methyl.

In an embodiment of The compounds of this invention, wherein said R ⁶Be-NR ¹¹R ¹²

In an embodiment of The compounds of this invention, wherein said R ⁶Be-NR ¹¹R ¹², R wherein ¹¹And R ¹²Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl-C ₄-C ₆Cycloalkyl ,-COR ⁸,-Ar ¹,-(C ₁-C ₄Alkyl)-Ar ¹,-CO-Ar ¹, and-CO-(C ₁-C ₄Alkyl)-Ar ¹

In an embodiment of The compounds of this invention, wherein said R ⁶Be-NR ¹¹R ¹², R wherein ¹¹And R ¹²Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl-C ₄-C ₆Cycloalkyl ,-COR ⁸,-Ar ¹,-(C ₁-C ₄Alkyl)-Ar ¹,-CO-Ar ¹, and-CO-(C ₁-C ₄Alkyl)-Ar ¹, Ar wherein ¹Be optional to be selected from the phenyl that following group replaces by one or more: halogen, nitro, cyano group ,-CF ₃,-R ⁸,-OR ⁸,-NR ⁸R ⁹, and-COOR ⁸

In an embodiment of The compounds of this invention, wherein said R ⁶Be-NR ¹¹R ¹², R wherein ¹¹And R ¹²Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl-C ₄-C ₆Cycloalkyl ,-COR ⁸,-Ar ¹,-(C ₁-C ₄Alkyl)-Ar ¹,-CO-Ar ¹, and-CO-(C ₁-C ₄Alkyl)-Ar ¹, Ar wherein ¹Be optional to be selected from the phenyl that following group replaces by one or more: halogen, nitro, cyano group ,-CF ₃,-R ⁸,-OR ⁸,-NR ⁸R ⁹, and-COOR ⁸, R wherein ⁸And R ⁹Be selected from independently of one another :-H ,-(C ₁-C ₄Alkylidene group) _0-3-phenyl, phenyl wherein is optional by one or more being selected from-C ₁- _C4The group of alkyl and halogen replaces, optional by one or more halogens replace-C ₁-C ₄Alkyl, optional by one or more halogens replace-C ₄-C ₆Cycloalkyl, optional by one or more halogens replace-C ₂-C ₄Thiazolinyl and optional by one or more halogens replace-C ₂-C ₄Alkynyl.

In an embodiment of The compounds of this invention, wherein

X is-O-or-S-;

Y is-CH ₂-or-CO-;

R ¹Be selected from :-H ,-C ₁-C ₄Alkyl;

R ²Be selected from :-H ,-C ₁-C ₄Alkyl;

R ³-H ,-C ₁-C ₆Alkyl ,-C ₃-C ₈Cycloalkyl ,-(C ₁-C ₆Alkyl)-OR ⁸, R wherein ⁸Be selected from :-H ,-C ₁-C ₆Alkyl ,-C ₂-C ₆Thiazolinyl and-C ₂-C ₆Alkynyl;

R ⁴And R ⁴⁰⁰Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl;

R ⁵And R ⁵⁰⁰Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl;

R ⁶Be-NR ¹¹R ¹², R wherein ¹¹And R ¹²Be selected from independently of one another :-H ,-C ₁-C ₄Alkyl-C ₄-C ₆Cycloalkyl ,-COR ⁸,-Ar ¹,-(C ₁-C ₄Alkyl)-Ar ¹,-CO-Ar ¹, and-CO-(C ₁-C ₄Alkyl)-Ar ¹, Ar wherein ¹Be optional to be selected from the phenyl that following group replaces by one or more: halogen, nitro, cyano group ,-CF ₃,-R ⁸,-OR ⁸,-NR ⁸R ⁹, and-COOR ⁸, R wherein ⁸And R ⁹Be selected from independently of one another :-H ,-(C ₁-C ₄Alkylidene group) _0-3-phenyl, phenyl wherein is optional by one or more being selected from-C ₁-C ₄The group of alkyl and halogen replaces, optional by one or more halogens replace-C ₁-C ₄Alkyl, optional by one or more halogens replace-C ₄-C ₆Cycloalkyl, optional by one or more halogens replace-C ₂-C ₄Thiazolinyl and optional by one or more halogens replace-C ₂-C ₄Alkynyl.

All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this more detailed description and interpretation to be made in these terms and phrase, term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.

Term used herein " halogen " or " halo " are meant fluorine, chlorine, bromine and iodine.

The term that is adopted among the present invention " alkyl " comprises alkyl, thiazolinyl and alkynyl.These alkyl, thiazolinyl and alkynyl can be straight chain or can be side chain.

Term used herein " alkyl " is meant and comprises having radical of saturated aliphatic alkyl side chain and straight chain that specifies number carbon atom, for example C ₁-C ₆C in the alkyl ₁-C ₆Be defined as comprising and have 1,2,3,4,5 or 6 group with the carbon of line style or branched chain type arrangement.C as defined above ₁-C ₆The example of alkyl includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group and hexyl.

Term used herein " thiazolinyl " is meant wherein to contain to specify number carbon atom and wherein have at least two carbon atoms to be connected to each other and to have E or Z configuration and its with two keys and makes up the undersaturated straight or branched alkyl of configuration.For example, C ₂-C ₆C in the thiazolinyl ₂-C ₆Be defined as comprising that having 2,3,4,5 or 6 carbon and at least two carbon atoms of arranging with line style or branched chain type passes through a doubly linked group.C ₂-C ₆The example of thiazolinyl comprises vinyl, 1-propenyl, 2-propenyl, 1-butylene base etc.

Term used herein " alkynyl " is meant and wherein contains the undersaturated straight or branched alkyl that specifies number carbon atom and wherein have at least two carbon atoms to link together by a triple bond.C for example ₂-C ₆C in the alkynyl ₂-C ₆Be defined as comprising the group that has 2,3,4,5 or 6 carbon atoms in the chain, has at least two carbon atoms to link together by a triple bond.The example of this alkynyl includes but not limited to: ethynyl, 1-proyl, 2-propynyl etc.

Term used herein " cycloalkyl " is meant and wherein contains the saturated aliphatic hydrocarbyl of monocycle that specifies number carbon atom, for example C ₃-C ₈C in the cycloalkyl ₃-C ₈Be defined as comprising the group that has 3,4,5,6,7 or 8 carbon in the mode of single loop arrangement.Above Ding Yi C ₃-C ₈The example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.

Term used herein " cycloalkenyl group " is meant wherein have the undersaturated aliphatic hydrocarbyl of the monocycle that specifies number carbon atom, for example C ₃-C ₈C in the cycloalkenyl group ₃-C ₈Be defined as comprising the group that has 3,4,5,6,7 or 8 carbon in the mode of single loop arrangement.Above Ding Yi C ₃-C ₈The example of cycloalkenyl group includes but not limited to cyclopentenyl and cyclohexenyl.

Term used herein " halo " or " halogen " are meant fluorine, chlorine, bromine and iodine.

Term used herein " haloalkyl " means a kind of alkyl as defined above, and wherein each hydrogen atom can be replaced by halogen atom in succession.The example of haloalkyl includes, but are not limited to :-CH ₂F ,-CHF ₂With-CF ₃

Term used herein " aryl ", no matter be to be used in combination separately or with another group, be meant a kind of like this carbocyclic aromatic monocyclic groups that contains 6 carbon atoms, this group can further condense in second can be aromatics, on saturated or unsaturated 5 yuan or the 6 yuan of carbon ring groups.Aryl includes but not limited to phenyl, 2,3-indanyl, 1-naphthyl, 2-naphthyl and tetralyl.The condensed aryl can be connected on another group of appropriate position on cycloalkyl ring or the aromatic nucleus.

Term used herein " xenyl " is meant two phenyl groups that are bonded together by any one available site on the benzyl ring.Xenyl can be connected to other group in the mode of covalency from any available position on the phenyl ring.

Term used herein " heteroaryl " is meant to have monocycle or the bicyclic system that is up to ten atoms, and wherein at least one ring is an aromatic ring, and contains 1 to 4 heteroatoms that is selected from O, N and S.The heteroaryl substituting group can connect by one of carbon atom or heteroatoms on the ring.The example of heteroaryl includes but not limited to thienyl, benzimidazolyl-, benzo [b] thienyl, furyl, benzofuryl, pyranyl, isobenzofuran-base, benzopyranyl, the 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, the indolizine base, isoindolyl, the 3H-indyl, indyl, indazolyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, quinoxalinyl, quinazolyl, the cinnolines base, pteridyl, isothiazolyl, the isochroman base, chromanyl, different uh azoles base, furan cluck base, indolinyl, isoindolinyl, thiazole also [4,5-b] pyridine, and fluorescent derivative.

Term used herein " heterocycle ", " heterocyclic " or " heterocyclic radical " mean one and contain 1 to 4 heteroatomic 5,6 or 7 yuan of non-aromatic ring system that are selected from O, N and S.The heterocyclic example includes but not limited to pyrrolidyl, tetrahydrofuran base, piperidyl, pyrrolinyl, piperazinyl, imidazolidyl, morpholinyl, imidazolinyl, pyrazolidone, pyrazolinyl.

Term used herein " assorted bicyclic group " is meant a kind of heterocycle as hereinbefore defined that condenses on another ring, other any ring that described another ring can be a heterocycle, an aryl or defines herein.The example of this assorted dicyclo includes but not limited to tonka bean camphor, benzo [d] [1,3] two

Luxuriant, 2,3-dihydrobenzo [b] [1,4] dioxole and 3,4-dihydro-2H-benzo [b] [1,4] dioxole (dioepine).

The compound of the compound of Formula I and its various preferred or specific embodiment of first aspect is contained in the present invention, also contains the various isomer of these compounds.Part of compounds of the present invention can optical isomer or the form of tautomer exist, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and perhaps synthetic method or the three-dimensional method single-minded or asymmetric synthesis that certain isomer can various routines obtains.Because compound of Formula I of the present invention is purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably at least 75%, better at least 85%, best at least 98% purity (% is meant weight percent).

The invention still further relates to suitable pharmacologically acceptable salts, solvate or the hydrate of The compounds of this invention.

Compound of the present invention can use with the form derived from mineral acid or organic acid drug acceptable salt.Word " pharmacologically acceptable salts " refers in reliable medical judgment scope, be suitable for contacting with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur with the mankind, and with rational effect/risk than the salt that matches.Pharmacologically acceptable salts is well known in the art.For example, S.M.Berge, et al.J.Pharmaceutical Sciences, 1977, among the 66:1 pharmacologically acceptable salts is described in detail.Described salt can be by free alkali functionality and the appropriate organic reaction that makes The compounds of this invention, in final separation and the purge process made acid-stable in situ or the preparation separately of The compounds of this invention.The pharmacologically acceptable salts of The compounds of this invention comprises, but is not limited to the salt that compound of Formula I is become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid; And the salt that become such as compound of Formula I and various organic acids such as toxilic acid, fumaric acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetate, trifluoroacetic acid, propionic acid, oxyacetic acid, pyruvic acid, oxalic acid, lactic acid, methylsulfonic acid, tosic acid, phenylformic acid, styracin, amygdalic acid, palmitinic acid, Whitfield's ointment.In addition, the pharmacologically acceptable salts of The compounds of this invention also includes, but not limited to the salt of compound of Formula I and mineral alkali preparation such as sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc.; Include but not limited to the salt of primary amine, secondary amine and tertiary amine by the salt of organic bases acquisition, wherein the amine of Qu Daiing comprises naturally occurring replacement amine, cyclammonium and deacidite, for example Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, 2-dimethylaminoethanol, 2-DEAE diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming, choline, trimethyl-glycine, quadrol, glycosamine, methylglucosamine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, polyamines resin etc.The free alkali form of The compounds of this invention and they salt form is separately gone up slightly different in some physical properties (as the solubleness in polar solvent), but for the object of the invention, each acid salt and they free alkali form separately is quite (referring to for example S.M.Berge, et al., " Pharmaceutical Salts; " J.Pharm.Sci., 66:1-19 (1977), it incorporates this paper by reference into).

Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, may form various solvates.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of pharmacy acceptable solvent such as water, ethanol etc.

The compounds of this invention and pharmacologically acceptable salts thereof can also be prodrug or the form that discharges described activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.

Term used herein " pharmaceutically acceptable carrier " or " vehicle " are meant and include but not limited to any auxiliary agent, carrier, vehicle, glidant, sweeting agent, thinner, sanitas, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, dispersion agent, suspension agent, stablizer, isotonic agent, solvent, emulsifying agent or encapsulating drug, described encapsulating drug is liposome, cyclodextrin, encapsulate polymerization delivery system or polyoxyethylene glycol matrix for example, and it is acceptable when being used for experimenter, the preferred mankind.

The present invention relates to the purposes that compound, its all possible isomer, prodrug, pharmacologically acceptable salts, solvate or the hydrate of general formula I are used to produce medicine, described medicine can be used for the treatment of and/or prevent the relevant disease that caused by the IAPs overexpression.Described disease is including, but not limited to following disease: bladder cancer, mammary cancer, carcinoma of the pancreas, colorectal carcinoma, leukemia, lung cancer, lymphoma, multiple spinal cord knurl, ovarian cancer and cervical cancer especially for example are ovarian cancer and cervical cancer.

On the other hand; the compound of general formula I of the present invention or its pharmacologically acceptable salts can use separately; or use with the form of pharmaceutical composition with acceptable carrier of pharmacy or vehicle; when using with the form of pharmaceutical composition; usually with the compound of Formula I of the present invention of effective dose or its pharmacologically acceptable salts or hydrate and one or more pharmaceutically acceptable carriers or thinner in conjunction with making suitable administration form or dosage form, this program comprises by suitable manner component mixing, granulation, compression or dissolving.Therefore, the invention provides pharmaceutical composition, it comprises compound, its all possible isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate and the acceptable carrier of at least a pharmacy of general formula I.

The pharmaceutical composition of The compounds of this invention, any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred oral, intramuscular injection, intraperitoneal or intravenously application method.

The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. for example.

Can also contain carrier commonly used in the pharmaceutical composition of the present invention, pharmaceutically acceptable carrier described here is including, but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum protein, buffer substance such as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, wool grease etc.The content of carrier in pharmaceutical composition can be 1 weight %-98 weight %, accounts for 80 weight % usually greatly.For simplicity, local anesthetic, sanitas, buffer reagents etc. can directly be dissolved in the carrier.

Oral tablet and capsule can contain vehicle such as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent is as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil, lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli, disintegrating agent, as yam starch, or acceptable dibutyl phthalate, as bay sodium alkoxide vitriol.Tablet can be with known method dressing on the pharmacopedics.

Oral liquid can be made the suspension of water and oil, solution, and emulsion, syrup or elixir also can be made dry product, with preceding make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, hydrogenant food oils, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may comprise edible oil), as Prunus amygdalus oil, grease such as glycerine, ethylene glycol, or ethanol; Sanitas is as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.Can add seasonings or tinting material as needs.

Suppository can comprise conventional suppository base, and this vehicle at room temperature is solid state, and fusing disengages medicine under body temperature, as theobroma oil, and other glyceryl ester or beeswax.

Stomach is offerd medicine outward, and liquid formulation is made by compound and a kind of disinfectant carrier usually.The first-selected water of carrier.Different according to selected carrier and drug level, compound had both dissolved in and also can be made into aaerosol solution in the carrier, and was earlier that compound is soluble in water when making injection solution, packed into after the filter-sterilized and sealed in bottle or the ampoule.

When topical application, The compounds of this invention can be made suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more the carrier.Wherein the operable carrier of ointment formulation is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion and creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, the n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.

Term used herein " composition " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.

Term used herein " treatment significant quantity " is meant a kind of dosage, its be applied to this experimenter for example Mammals for example can produce the physiologic response of expectation behind the people, particularly produce at the relevant physiologic response of disease of the present invention.Term " treatment significant quantity " also has similar implication.

According to the difference of administering mode, can contain weight ratio 0.1% in the composition, or the active ingredient of weight ratio 10-60% more suitably.But when comprising unitary dose in the component, each unit preferably comprises 1-500 milligram activeconstituents.

It may be noted that in addition, The compounds of this invention is decided by all multifactor at different patients' specific using dosage and using method, comprise patient's age, body weight, sex, the natural health situation, nutritional status, the activity intensity of compound, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the person in charge judges.Here preferred using dosage is between the 0.01-100mg/Kg body weight/day.

Must recognize, the best dosage of compound of Formula I and be at interval by compound property with such as the decision of the external conditionss such as form, path and position of administration, and this best dosage can be determined with conventional technology.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is determined.

The present invention relates to prepare the preparation method of compound of Formula I or its pharmacologically acceptable salts, solvate or hydrate.Below the generality of this method described the definition of each variable or substituent concrete definition such as first aspect present invention compound.

The compounds of this invention can form by compound and other fragment couplings of being represented by general formula I I capable of being combined:

Wherein Z be selected from include but not limited to following group :-H ,-Boc ,-Cbz, preferred Z is-Boc.

General formula I I compound preferred but be not limited only to following several structure:

IIa, IIb structure synthetic can directly use commerce can buy L-proline(Pro), 4-S-hydroxyl-L-proline(Pro) and Boc acid anhydrides to synthesize and make.The synthetic route of IIc, IId, IIe, IIf by following scheme 1:

Scheme 1

The general step of above scheme 1 is: choose unsubstituted natural halfcystine, Serine, perhaps by R ₅, R ₅₀₀The natural halfcystine, the Serine that replace are through above-mentioned similar route, with formaldehyde, acetaldehyde, acetone or have R ₄, R ₄₀₀Substituent aldehyde, ketone compounds react, and obtain having the replacement/not substituted five-membered heterocycle alkane of S, O atom.

With the Ie compound is example, the 2 explanation the present invention of following scheme how by general formula I I compound to compound of Formula I.

Scheme 2

The general step of above scheme 2 is: after synthesizing amine fragment 2ii and acid fragment 2iv respectively, again with the condensation of IIc order, obtaining after the 2vii again, the deprotection salify obtains end product Ie.

With the If compound is example, the 3 explanation the present invention of following scheme how by general formula I I compound to compound of Formula I.

Scheme 3

The general step of above scheme 3 and scheme 2 unique differences are, after obtaining intermediate 2v, obtain intermediate 3i by suitable method of reducing, by the order condensation, obtain 3iii again, and the deprotection salify obtains If.

Compound of Formula I can be single synthetic with ordinary method, also mixed-the separating method or the parallel synthetic method of available combination chemistry (contain two at least with the storehouse in each storehouse, or 5-1000,10-100 compound preferably) synthetic for unit, promptly can in liquid phase, synthesize also and can use solid phase synthesis process.The various starting material that react used are that those skilled in the art can prepare according to existing knowledge, or can make by the document known method, or can buy by commerce.Used intermediate, starting material, reagent, reaction conditions etc. all can be made appropriate change according to those skilled in the art existing knowledge in the above reaction scheme.About the preparation compound of Formula I more detailed data embodiment part that can vide infra.

Embodiment:

Further specify the present invention below by concrete intermediate and embodiment, still, should be understood to, these intermediates and embodiment are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.

The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.The fusing point of compound is measured by RY-1 fusing point instrument, and thermometer is calibration not.Mass spectrum is measured by MicromassZabSpec high resolution mass spectrometer (resolving power 1000). ¹H-NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency ¹H-NMR 400MHz.

In the context of the present invention, use following shortenings:

Boc: tert-butoxycarbonyl;

Cbz: benzyloxy carbonyl;

DCM: methylene dichloride;

DIPEA: diisopropylethylamine;

DMF:N, dinethylformamide;

DCC: carbodicyclo hexylimide

The HOBt:1-hydroxybenzotriazole;

TEA: triethylamine;

The NMF:N-methylmorpholine;

THF: tetrahydrofuran (THF);

ClCOOiBu: isobutyl chlorocarbonate;

LiAlH ₄: Lithium Aluminium Hydride;

NaBH ₄: sodium borohydride;

TLC: tlc.

Intermediate preparation example 1: formula IIc compound synthetic

Reaction process:

Step 1)

The L-halfcystine of 12.1g (0.1mol) is dissolved in the middle of the 60ml hot water, and slowly the formalin of impouring 10mL 36% shakes up the back standing over night, filter the crystal of separating out next day, get needle-like white crystal 12.8g with second alcohol and water recrystallization again, yield is 96.2%, m.p:196-197 ℃.

Step 2)

Under the ice bath, the L-thiazolidinecarboxylic acid of 0.10mol is dissolved in the aqueous sodium hydroxide solution (0.10mol) of the 2N of 50mL, stirs following (Boc) 24.4g (0.11mol) ₂The acetone mixing solutions of O and 50mL slowly splashes into, and finishes, and continues to stir 2h.The water dilute reaction solution that adds 200mL, the ethyl acetate extraction of usefulness 80mL * 33 times discards organic phase.The water ice bath is 2 with the salt acid for adjusting pH value of 1mol/L down, uses the ethyl acetate extraction 3 times of 80mL * 3 again, the merging organic phase, and removal of solvent under reduced pressure behind the anhydrous sodium sulfate drying gets white crystal with sherwood oil and re-crystallizing in ethyl acetate.

Intermediate preparation example 2: formula IId compound synthetic

Reaction process:

Step 1)

(12.2g 100mmol) is dissolved in the 100ml anhydrous methanol, and logical HCl all dissolves to raw material, and more than the continuation ventilation 2h, ventilation finishes to stir spends the night with the L-halfcystine.Next day the evaporated under reduced pressure solvent, resistates repeats 2 times to take away HCl with dissolve with methanol evaporate to dryness again.Solvent evaporated obtains crude product, with methyl alcohol-ether recrystallization.Yield 91%.m.p：143-145℃。

Step 2)

3.5g (20mmol) intermediate 1ii mix with 40ml acetone refluxed 10 minutes after, add 10ml methyl alcohol and make that solid all dissolves in the system, continue backflow 0.5h after, cooling crystallization leaches behind the crystal mother liquor and concentrates and continue crystallization.Obtain clear crystal, yield 94%.m.p：165-168℃。

Step 3)

4.03g (19mmol) intermediate 1iii and 1.92g TEA mixed dissolution splash into 4.15g (19mmol) Boc under stirring in the middle of 20ml DCM ₂O is dissolved in the solution in the middle of the 20ml DCM, washs successively with 20ml 10% citric acid, 20ml water after the room temperature reaction 3h, is spin-dried for directly as next step.

Step 4)

Intermediate 1iv is dissolved in the middle of the 25ml methyl alcohol, adds the 25ml 2N NaOH aqueous solution, and methyl alcohol was removed in decompression as far as possible after room temperature reaction 4h, TLC detected the raw material disappearance, was diluted with water to 50ml, with the unnecessary Boc of ether flush away of 20ml * 3 ₂O, phase ice bath are 2 with the salt acid for adjusting pH value of 1mol/L down, have a large amount of white solids to separate out, and filter washing and obtain intermediate II d.

Intermediate preparation example 3: formula IIe compound synthetic

Reaction process:

Step 1)

The formalin 10ml (120mmol) of L-Serine 10.5g (100mmol) and 37% is dissolved in the aqueous solution of 2N NaOH of 50ml, ice bath stirs down and spends the night.Under the next day ice bath with 24.0g (Boc) ₂The solution that O (110mmol) is dissolved in the 40ml acetone splashes in the reaction solution, continue to stir 1h after, with 350ml water with reaction solution towards rare, divide 3 extractions with ethyl acetate 120ml then, discard organic phase, it is 2 that water transfers to pH value with HCl, divides three extractions with the 120ml ether, collect organic phase, evaporated under reduced pressure obtains IIe, colorless oil, placement is spent the night and is become solid, obtains the prismatic crystal with ethyl acetate-sherwood oil recrystallization.Yield 94%.

Intermediate preparation example 4: formula IIf compound synthetic

Reaction process:

Formula IIf compound synthetic can be with reference to formula IIe compound synthetic, just raw material changes the L-Threonine into.

Intermediate preparation example 5: intermediate 2ii synthetic that can be used for preparing embodiment 1 compound

Reaction process:

Step 1)

Phenylethylamine and 11.1g (110mmol) triethylamine of 12.1g (100mmol) are dissolved in the 200mL dry methylene chloride, the careful down 100mL dichloromethane solution that contains 14.5g (100mmol) Benzoyl chloride that drips of ice bath, drip off and slowly rise to room temperature, reacted 2 hours.Reaction solution is collected organic phase, anhydrous Na with ethyl acetate-water dispenser extraction ₂SO ₄The decompression of dry back is spin-dried for, and obtains white solid, need not to separate, and is directly used in next step reaction after the oven dry.

Step 2)

Carefully in the 400mL dry THF, add 5.0g (being roughly equal to 130mmol) LiAlH under the ice bath in batches ₄, finish, treat in system, to drip again behind the temperature-stable to 0 ℃ the previous step product and be dissolved in solution in the middle of the 200mL dry THF, slowly drip steadily with guarantee system heat release venting.Drip off the system backflow is spent the night.Ice bath cooling reaction carefully drips saturated ammonium chloride solution to destroy residue LiAlH ₄Filter, filter cake washs to there not being product with ethyl acetate.Merge organic phase, separate (moving phase is the ethyl acetate-sherwood oil of corresponding proportion) by column chromatography after the removal of solvent under reduced pressure and obtain N-styroyl benzylamine.

Intermediate preparation example 6: intermediate 2iv synthetic that can be used for preparing embodiment 1 compound

Reaction process:

The preparation of Boc-L-Ala-OH is with the preparation of Boc-L-thiazolidinecarboxylic acid.

The preparation of 2S-cyclohexyl-L-glycine methyl ester hydrochloride is with the preparation of L-acthiol-J hydrochloride.

Step 1)

The ice bath temperature control is below 0 ℃, Boc-L-Ala 1.89g (10mmol) is dissolved in the methylene dichloride, carefully add DCC 2.27g successively, HOBt 1.49g, 2S-cyclohexyl-L-glycine methyl ester hydrochloride 2.07g (10mmol), triethylamine 1.01g, room temperature reaction spends the night, remove by filter white precipitate DCU, organic phase is used 10% citric acid, saturated aqueous common salt, 4% sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous Na successively ₂SO ₄Dry, decompression is spin-dried for dichloromethane solvent, gets light yellow oil, adds ethyl acetate solvent then, stand at low temperature, adularescent deposit D CU separates out, and removes by filter DCU, and decompression is spin-dried for ethyl acetate, add the ethyl acetate stand at low temperature again, so remove the DCU of the overwhelming majority repeatedly several times, after silica gel column chromatography gets white solid 2.73, yield 80%.

Step 2)

The about 2.70g of intermediate 2iii is dissolved in 15mL methyl alcohol, adds 2N NaOH 10mL, room temperature reaction 2 hours, TLC detection reaction process, it is closely neutral that 1N HCl regulates pH, and part methyl alcohol is revolved in decompression, thin up, the elimination insoluble impurities, filtrate is 1N HCl acidifying in ice bath, the adularescent solid is separated out immediately, filter and collect, it is closely neutral to be washed to washing lotion, drying, the methanol-water recrystallization obtains colourless needle crystal 2.05g, yield 79%.

Intermediate preparation example 6: intermediate 3ii synthetic that can be used for preparing embodiment 1 compound

Reaction process:

Step 1)

Cryosel is bathed temperature control below 0 ℃, in the methylene dichloride that is dissolved with 11.5g (50mmol) Boc-thiazolidinecarboxylic acid, careful 10.6g (50mmol) the N-styroyl benzylamine that adds, 7.4g (55mmol) HOBt, and carefully drip the dichloromethane solution of 11.3g (55mmol) DCC dropwises low-temp reaction half an hour, stirred overnight at room temperature, remove by filter white precipitate DCU, organic phase is used 10% citric acid, saturated aqueous common salt, 4% sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous Na successively ₂SO ₄Dry, decompression is spin-dried for dichloromethane solvent, gets light yellow oil, adds ethyl acetate solvent then, stand at low temperature, adularescent deposit D CU separates out, and removes by filter DCU, and decompression is spin-dried for ethyl acetate, add the ethyl acetate stand at low temperature again, so remove the DCU of the overwhelming majority repeatedly several times, after silica gel column chromatography gets white solid 17.5, yield 83%.

Step 2)

N ₂Under the protective condition, will go up step raw material 12.7g (30mmol) and be dissolved among the anhydrous THF, cryosel is bathed temperature control below 0 ℃, carefully adds NaBH ₄2.4g (30mmol), the careful 3.81g I that drips after half an hour ₂THF solution, after being added dropwise to complete, continue reaction 2 hours, reflux 48 hours, TLC detection reaction process.

Reaction carefully adds saturated NH after finishing ₄The Cl aqueous solution, 50 ℃ of no bubbles are emitted, and add 2N NaOH and dissolve insoluble precipitation, and water layer extracts with methyl tertiary butyl ether, merges organic phase, anhydrous Na ₂SO ₄Drying, silica gel column chromatography get the about 9.2g of white powder intermediate 3i, yield 75%.

Step 3)

Cryosel is bathed temperature control below 0 ℃, and 9.18g is dissolved in a small amount of CH with previous step gained white solid ₂Cl ₂In, carefully add the ice-cold 4N HCl/EtOAc solution of 50mL, 0-4 ℃ of reaction 2 hours, a large amount of white precipitates are separated out, filter the about 7.6g of intermediate 3ii, yield 97%.

Embodiment 1

Reaction process

Step 1)

Below the temperature control-15 ℃, intermediate 2iv 328mg is dissolved among the anhydrous THF of 5mL, carefully adds 110 μ L N-methylmorpholines, add 140 μ L isobutyl chlorocarbonates again.After half an hour, add the 3mL DMF solution of intermediate 3ii 348mg and 110 μ L N-methylmorpholines, continue to stir half an hour at-15 ℃, room temperature reaction 2h, concentrating under reduced pressure desolvates.Residue is dissolved in the 25mL ethyl acetate, uses 5%NaHCO ₃, after water, 1N HCl and each 25mL of water wash successively, anhydrous Na ₂SO ₄Drying, silica gel column chromatography obtain white solid 3iii 321mg, yield 48%.

Step 2)

Intermediate 3iii 440mg is dissolved in the methylene dichloride, the ice bath temperature control is below 0 ℃, add the ice-cold 2N HCl/EtOAc solution of 10mL, low-temp reaction half an hour, room temperature continues to stir about 2 hours, and white solid is separated out, and is complete through the TLC detection reaction, filter and collect white solid 215mg, yield 98%.

More than two the step total recoverys 47%.Below the described yield of all embodiment all refer to two step of condensation and deprotection total recovery.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.13-1.17(8H，m，(CH ₂-CH ₂)×2)，1.28-1.30(2H，m，CH ₂)，1.72(3H，d，J＝6.8Hz，CH ₃)，2.0(1H，m，CH)，2.3-.25(2H，d，J＝4.6Hz，CH ₂)，2.6(2H，t，J＝2Hz，CH ₂)，2.6-2.9(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝7.2Hz，CH ₂)，3.6(2H，s，CH ₂)，3.59(2H，d，J＝7.6Hz，CH ₂)，3.89-3.92(1H，m，CH×2)，4.10(1H，d，J＝4.4Hz，CH)，4.86(1H，s，NH)，7.2-7.5(10H，m，ArH)，8.06(2H，t，J＝7.6Hz，NH ₂)，8.16(2H，s，HCl)，MS?m/e：523.5([M+1] ⁺).

Embodiment 2

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; different (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg that are to use replace 2iv, use (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 67%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.18(3H，d，J＝6.8Hz，CH3)，2.6-2.9(2H，d，J＝4.8Hz，CH2)，2.8(2H，t，J＝2Hz，CH2)，3.5(2H，t，J＝7.6Hz，CH2)，3.6-3.7(2H，d，J＝7.6Hz，CH2)，3.76(2H，d，J＝7.6Hz，CH2)，3.8(1H，m，CH)，3.99(1H，m，CH)，4.5(2H，s，CH2)，6.96(1H，s，NH)，7.2-7.5(10H，m，ArH)8.06(2H，t，J＝7.6Hz，NH2)，8.6(1H，s，HCl)，MSm/e：455.2([M+1] ⁺).

Embodiment 3

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv to different (the R)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 35%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.85(3H，d，J＝6.8Hz，CH ₃)，1.20-1.38(8H，m，(CH ₂-CH ₂)×2)，1.58-1.62(2H，m，CH ₂)，2.79(2H，d，J＝4.8Hz，CH ₂)，2.90-2.92(1H，m，CH)，3.43(2H，t，J＝2Hz，CH ₂)，3.5(2H，t，J＝7.6Hz，CH ₂)，3.63(2H，d，J＝7.6Hz，CH ₂)，3.9(1H，s，CH)，4.11-4.12(1H，m，CH)，4.36(2H，s，CH ₂)，4.75(1H，d，J＝4.4Hz，CH)，5.08(1H，s，NH)，7.28-7.32(10H，m，ArH)，8.25(2H，t，J＝7.6Hz，NH ₂)，8.78(1H，s，HCl)，MSm/e：537.3([M+1] ⁺).

Embodiment 4

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 28%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.86(6H，d，J＝6.4Hz，CH ₃×2)，1.18(3H，d，J＝6.8Hz，CH ₃)，1.96-1.99(1H，m，CH)，2.69(2H，d，J＝4.8Hz，CH ₂)，3.67(2H，d，J＝7.6Hz，CH ₂)，3.88-3.92(1H，m，CH)，4.12(1H，d，J＝4.4Hz，CH)，4.2(2H，d，J＝5.4Hz，CH ₂)，4.96(1H，s，NH)，7.25-7.28(5H，m，ArH)，7.5(1H，t，J＝6.5Hz，NH)，8.86(2H，t，J＝7.6Hz，NH ₂)，9.4(1H，s，HCl)，MS?m/e：407.5([M+1] ⁺).

Embodiment 5

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl-N-(thiazolidine-4-base-methyl) benzamide 326mg to replace 3ii.Yield 36%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.86(6H，d，J＝6.4Hz，CH ₃×2)，1.18(3H，d，J＝6.8Hz，CH ₃)，1.96-1.99(1H，m，CH ₂)，2.72(2H，s，CH ₂)，3.12-3.15(2H，m，CH ₂)，4.55(2H，d，J＝5.4Hz，CH ₂)，3.89-3.91(2H，m，CH×2)，4.21(1H，d，J＝4.4Hz，CH)，4.96(1H，s，NH)，7.46-7.49(10H，m，ArH)，8.06(2H，t，J＝7.6Hz，NH ₂)，9.40(1H，s，HCl)，MS m/e：483.2([M+1] ⁺).

Embodiment 6

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 49%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.83-0.85(2H，m，CH ₂)，1.28-1.30(8H，m，(CH ₂-CH ₂)×2)，1.91(3H，d，J＝6.8Hz，CH ₃)，2.6(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝2Hz，CH ₂)，2.94-2.96(1H，m，CH)，3.2(2H，t，J＝7.6Hz，CH ₂)，3.49-3.51(2H，d，J＝7.6Hz，CH ₂)，4.36-4.39(2H，m，CH×3)，4.5(2H，s，CH ₂)，6.96(1H，s，NH)，7.2-7.5(10H，m，ArH)，8.22(2H，t，J＝7.6Hz，NH ₂)，8.72(1H，s，HCl)，MS?m/e：537.3([M+1] ⁺).

Embodiment 7

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-sec.-propyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl thiazolidine-4-carboxamide 222mg to replace 3ii.Yield 52%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.91(6H，d，J＝6.4Hz，CH ₃×2)，1.19(3H，d，J＝6.8Hz，CH ₃)，1.38(3H，s，CH ₃)，1.98-2.10(1H，m，CH)，2.5(2H，d，J＝4.8Hz，CH ₂)，3.16(2H，d，J＝7.6Hz，CH ₂)，3.35-3.36(2H，m，CH×2)，3.9(1H，d，J＝4.4Hz，CH)，4.2(2H，d，J＝5.4Hz，CH ₂)，4.5(1H，s，NH)，7.5(1H，t，J＝16Hz，NH)，7.28-7.32(5H，m，ArH)，8.06(1H，t，J＝7.6Hz，NH)，9.36(1H，s，HCl)，MS?m/e：407.3([M+1] ⁺).

Embodiment 8

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl the amino)-2-tertiary butyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 49%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.05(9H，d，J＝6.4Hz，CH ₃×3)，1.18(3H，d，J＝6.8Hz，CH ₃)，1.33-1.34(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝2Hz，CH ₂)，2.89-2.91(2H，m，CH×2)，3.5(2H，t，J＝10.4Hz，CH ₂)，3.79(2H，d，J＝7.6Hz，CH ₂)，4.1(1H，d，J＝4.4Hz，CH)，4.36(2H，s，CH ₂)，5.13(1H，s，NH)，7.26-7.35(10H，m，ArH)，8.06(2H，t，J＝7.6Hz，NH ₂)，8.62(1H，s，HCl)，MS?m/e：511.4([M+1] ⁺).

Embodiment 9

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-sec.-propyl-acetate 302mg replaces 2iv in different being to use (S)-2-.Yield 31%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.91(6H，d，J＝6.4Hz，CH ₃×2)，1.36(3H，d，J＝6.8Hz，CH ₃)，1.9(1H，m，CH)，1.99(2H，d，J＝1.6Hz，CH ₂)，2.51(2H，t，J＝2Hz，CH ₂)，3.09(2H，d，J＝4.8Hz，CH ₂)，3.12(2H，t，J＝7.2Hz，CH ₂)，3.19(3H，s，CH ₃)，3.21(1H，s，NH)，3.6(2H，s，CH ₂)，3.39-3.41(1H，m，CH×2)，4.90(1H，d，J＝4.4Hz，CH)，4.39(2H，d，J＝7.6Hz，CH ₂)，7.2-7.5(10H，m，ArH)，7.78(1H，t，J＝7.6Hz，NH)，8.92(2H，s，HCl×2)，MS?m/e：497.4([M+1] ⁺).

Embodiment 10

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl the amino)-2-tertiary butyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 50%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.01(9H，d，J＝6.8Hz，CH ₃×3)，1.18(3H，d，J＝6.8Hz，CH ₃)，1.28(2H，d，J＝7.6Hz，CH ₂)，2.69(2H，t，J＝2Hz，CH ₂)，2.73-2.75(2H，d，J＝4.8Hz，CH ₂)，3.23(2H，d，J＝4.4Hz，CH ₂)，4.11-4.12(2H，m，CH×2)，4.24(1H，t，J＝16Hz，NH)，4.26(1H，d，J＝4.4Hz，CH)，4.53(1H，s，NH)，7.21-7.25(5H，m，ArH)，8.24(2H，t，J＝7.6Hz，NH ₂)，8.46(1H，s，HCl)，MS?m/e：421.2([M+1] ⁺).

Embodiment 11

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 49%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.16-1.18(8H，m，(CH ₂-CH ₂)×2)，1.30(3H，d，J＝6.8Hz，CH ₃)，1.68-1.71(2H，m，CH ₂)，1.68-1.71(1H，m，CH)，2.68(2H，t，J＝2Hz，CH ₂)，2.86(2H，d，J＝4.8Hz，CH ₂)，3.20-3.22(2H，m，CH ₂)，3.57(2H，d，J＝7.6Hz，CH ₂)，3.76-3.89(2H，m，CH×2)，4.45(1H，d，J＝4.4Hz，CH)，4.56(1H，s，NH)，7.22-7.29(5H，m，ArH)，8.18(1H，t，J＝16Hz，NH)，8.27(2H，t，J＝7.6Hz，NH ₂)，8.62(1H，s，HCl)，MS?m/e：447.3([M+1] ⁺).

Embodiment 12

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv in different being to use (S)-2-.Yield 45%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.91(6H，d，J＝6.4Hz，CH ₃×2)，1.32(3H，d，J＝6.8Hz，CH ₃)，1.91(2H，d，J＝1.6Hz，CH ₂)，2.01-2.03(1H，m，CH)，3.09(2H，t，J＝2Hz，CH ₂)，3.20(2H，t，J＝7.2Hz，CH ₂)，3.42(2H，d，J＝4.8Hz，CH ₂)，3.93(1H，d，J＝4.4Hz，CH)，4.33(2H，s，CH ₂)，4.41(2H，d，J＝7.6Hz，CH ₂)，4.87-4.89(2H，m，CH×2)，7.78(1H，s，NH)，7.29-7.46(10H，m，ArH)，8.29(2H，s，2HCl)，8.69(2H，t，J＝7.6Hz，NH ₂)，MS?m/e：483.3([M+1] ⁺).

Embodiment 13

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-sec.-propyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 52%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.91(6H，d，J＝7.2Hz，CH ₃×2)，1.19(3H，d，J＝6.8Hz，CH ₃)，2.10-2.11(1H，m，CH)，2.75(2H，t，J＝2Hz，CH ₂)，2.89-2.91(2H，d，J＝4.8Hz，CH ₂)，3.34-3.35(2H，m，CH ₂)，3.9(3H，s，CH ₃)，4.15(2H，d，J＝7.6Hz，CH ₂)，4.25-4.27(2H，m，CH×2)，4.56(1H，d，J＝4.4Hz，CH)，5.03(1H，s，NH)，7.23-7.28(5H，m，ArH)，8.82(1H，t，J＝7.6Hz，NH)，9.44(1H，t，NH)，MS?m/e：421.5([M+1] ⁺).

Embodiment 14

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-cyclohexyl-acetate 342mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 37%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.85(3H，d，J＝6.8Hz，CH ₃)，1.13-1.24(8H，m，(CH ₂-CH ₂)×2)，1.32-1.34(2H，m，CH ₂)，1.68(3H，s，CH ₃)，2.0(1H，m，CH)，2.6(2H，t，J＝2Hz，CH ₂)，2.83(2H，d，J＝4.8Hz，CH ₂)，3.2(2H，m，CH ₂)，3.34(2H，d，J＝7.6Hz，CH ₂)，3.83(1H，d，J＝4.4Hz，CH)，4.54-4.63(2H，m，CH×2)，5.07(1H，s，NH)，7.22-7.29(5H，m，ArH)，8.13(1H，t，J＝16Hz，NH)，8.81(1H，t，J＝7.6Hz，NH)，9.25(1H，s，HCl)，MSm/e：461.3([M+1] ⁺).

Embodiment 15

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-cyclohexyl-acetate 342mg replaces 2iv to different (the R)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 53%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.83(3H，d，J＝6.8Hz，CH ₃)，1.07-1.12(8H，m，(CH ₂-CH ₂)×2)，1.38-1.40(2H，m，CH ₂)，2.50(2H，t，J＝2Hz，CH ₂)，2.69-2.71(1H，m，CH)，2.9(2H，d，J＝4.8Hz，CH ₂)，3.24-3.29(2H，m，CH ₂)，3.29(3H，s，CH ₃)，3.6-3.7(2H，d，J＝7.6Hz，CH ₂)，3.85-3.87(2H，m，CH×2)，3.91(1H，d，J＝4.4Hz，CH)，4.61(1H，s，NH)，7.20-7.29(5H，m，ArH)，7.9(1H，t，J＝16Hz，NH)，8.97(1H，t，J＝7.6Hz，NH)，9.26(1H，s，HCl)，MS?m/e：461.3([M+1] ⁺).

Embodiment 15

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-sec.-propyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 43%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.91(6H，d，J＝7.2Hz，CH ₃×2)，1.35(3H，d，J＝6.8Hz，CH ₃)，2.51(3H，s，CH ₃)，2.06-2.08(1H，m，CH)，2.83(2H，d，J＝4.8Hz，CH ₂)，2.9(2H，d，J＝7.6Hz，CH ₂)，3.54(2H，t，J＝2.1Hz，CH ₂)，3.89-3.92(1H，m，CH×2)，4.1(1H，d，J＝4.4Hz，CH)，4.56(2H，t，J＝7.6Hz，CH ₂)，4.89(2H，s，CH ₂)，5.18(1H，s，NH)，7.2-7.5(10H，m，ArH)，8.06(1H，t，J＝7.6Hz，NH)，MS?m/e：511.3([M+1] ⁺).

Embodiment 17

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl the amino)-2-tertiary butyl-acetate 316mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 36%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.85(2H，d，J＝4.8Hz，CH ₂)，1.19(9H，d，J＝6.8Hz，CH ₃×3)，1.38(3H，d，J＝6.8Hz，CH ₃)，1.59(3H，s，CH ₃)，2.50(2H，t，J＝2.0Hz，CH ₂)，2.73(2H，t，J＝7.6Hz，CH ₂)，2.89(2H，d，J＝7.6Hz，CH ₂)，3.53-3.57(1H，m，CH×2)，4.13(1H，d，J＝4.4Hz，CH)，4.36(2H，s，CH ₂)，5.12(1H，s，NH)，7.29-7.32(10H，m，ArH)，8.93(1H，t，J＝7.6Hz，NH)，9.40(1H，s，HCl)，MS?m/e：525.5([M+1] ⁺).

Embodiment 18

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-cyclohexyl-acetate 342mg replaces 2iv to different (the R)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 46%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.93(3H，d，J＝6.8Hz，CH ₃)，1.25-1.29(8H，m，(CH ₂-CH ₂)×2)，1.56-1.59(2H，m，CH ₂)，1.89(1H，s，CH)，2.6(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝2.0Hz，CH ₂)，3.4(3H，s，CH ₃)，3.5(2H，t，J＝7.6Hz，CH ₂)，3.76(2H，d，J＝7.6Hz，CH ₂)，3.89-3.92(1H，m，CH×2)，4.36(1H，d，J＝4.4Hz，CH)，4.57(2H，s，CH ₂)，4.96(1H，s，NH)，7.28-7.35(10H，m，ArH)，8.26(1H，t，J＝7.6Hz，NH)，9.40(1H，s，HCl)，MSm/e：551.7([M+1] ⁺).

Embodiment 19

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl the amino)-2-tertiary butyl-acetate 302mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl thiazolidine-4-carboxamide 222mg to replace 3ii.Yield 56%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.01(9H，d，J＝6.8Hz，CH ₃×3)，1.18(3H，d，J＝6.8Hz，CH ₃)，1.29(2H，d，J＝4.8Hz，CH ₂)，3.02(2H，d，J＝7.6Hz，CH ₂)，3.35-3.46(1H，m，CH×2)，3.02(1H，d，J＝4.4Hz，CH)，4.16-4.19(2H，m，CH ₂)，4.36(1H，s，NH)，7.5-7.8(5H，m，ArH)，8.2(1H，t，J＝16Hz，NH)，8.49(2H，t，J＝7.6Hz，NH ₂)，9.21(1H，s，HCl)，MSm/e：407.2([M+1] ⁺).

Embodiment 20

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) acetylamino)-3 Methylbutanoic acid 274mg replaces 2iv.Yield 41%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.86(6H，d，J＝6.4Hz，CH ₃×2)，1.96-1.98(1H，m，CH)，2.35(2H，d，J＝1.6Hz，CH ₂)，2.6(2H，t，J＝2Hz，CH ₂)，2.67(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝7.2Hz，CH ₂)，3.6(2H，s，CH ₂)，3.67(2H，d，J＝6.4Hz，CH ₂)，3.86-3.90(1H，m，CH)，4.1(1H，d，J＝4.4Hz，CH)，4.96(1H，s，NH)，7.2-7.5(10H，m，ArH)，8.7(2H，t，J＝7.6Hz，NH ₂)，9.40(1H，s，HCl)，MS?m/e：469.3([M+1] ⁺).

Embodiment 21

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and ((S)-2-(2-(t-butoxycarbonyl amino) propionyl the amino)-2-tertiary butyl-acetate 302mg replaces 2iv in different being to use (S)-2-.Yield 40%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.94(9H，d，J＝6.4Hz，CH ₃×3)，1.3(3H，d，J＝6.8Hz，CH ₃)，1.9(2H，d，J＝1.6Hz，CH ₂)，2.87(2H，t，J＝2Hz，CH ₂)，3.11(2H，d，J＝4.8Hz，CH ₂)，3.25(2H，t，J＝7.2Hz，CH ₂)，3.36(2H，d，J＝7.6Hz，CH ₂)，3.48(2H，s，CH ₂)，4.02-4.03(1H，m，CH×2)，4.42(1H，d，J＝4.4Hz，CH)，4.68(1H，s，NH)，7.27-7.31(10H，m，ArH)，7.75(2H，t，J＝7.6Hz，NH ₂)，8.25(2H，s，2HCl)，MS?m/e：497.4([M+1] ⁺).

Embodiment 22

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 47%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.14-1.16(8H，m，(CH ₂-CH ₂)×2)，1.36(3H，d，J＝6.8Hz，CH ₃)，1.65-1.68(4H，m，CH ₂×2)，2.0(1H，m，CH)，2.6(2H，t，J＝2Hz，CH ₂)，2.75(2H，d，J＝7.6Hz，CH ₂)，3.25-3.26(2H，m，CH ₂)，3.91-3.93(2H，m，CH×2)，4.1(1H，d，J＝4.4Hz，CH)，4.3(1H，t，J＝7.2Hz，NH)，4.71(1H，s，NH)，7.22-7.29(5H，m，ArH)，8.06(2H，t，J＝7.6Hz，NH ₂)，8.76(1H，s，HCl)，MS?m/e：447.2([M+1] ⁺).

Embodiment 23

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg replaces 2iv.Yield 46%.

1H-NMR(400MHz，DMSO-d6)，δ(ppm)：1.39(3H，d，J＝6.8Hz，CH ₃)，1.91(2H，d，J＝1.6Hz，CH ₂)，3.10-3.39(6H，m，CH ₂×3)，，3.60(2H，s，CH ₂)，3.94(2H，t，J＝6.3Hz，CH ₂)，4.11(2H，s，CH ₂)，4.50-4.60(3H，m，CH，CH ₂)，4.99(1H，s，CH)，7.26-7.71(10H，m，ArH)，8.25(2H，t，J＝7.6Hz，HCl.NH ₂)，8.75(1H，s，CONH)，MS?m/e：441.5([M+1] ⁺).

Embodiment 24

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg replaces 2iv, uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 40%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.18(3H，d，J＝6.8Hz，CH ₃)，2.6(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝2.0Hz，CH ₂)，3.4(3H，s，CH ₃)，3.5(2H，t，J＝7.2Hz，CH ₂)，3.65(2H，d，J＝7.6Hz，CH ₂)，3.76-3.79(2H，m，CH ₂)，3.89-3.92(1H，m，CH×2)，4.5(2H，s，CH ₂)，6.96(1H，s，NH)，7.25-7.29(10H，m，ArH)，8.76(1H，t，J＝7.6Hz，NH)，9.40(1H，s，HCl)，MSm/e：365.3([M+1] ⁺).

Embodiment 25

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(tertbutyloxycarbonyl methylamino) propionyl amino)-2-cyclohexyl-acetate 342mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield 44%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.18-1.19(8H，m，(CH ₂-CH ₂)×2)，1.33(3H，d，J＝6.8Hz，CH ₃)，1.39-1.41(2H，m，CH ₂)，2.0(1H，m，CH)，2.51(2H，d，J＝4.8Hz，CH ₂)，2.8(2H，t，J＝2.0Hz，CH ₂)，2.95(2H，d，J＝7.6Hz，CH ₂)，3.4(3H，s，CH ₃)，3.5(2H，t，J＝7.2Hz，CH ₂)，3.51-3.53(1H，m，CH)，4.1(1H，d，J＝4.4Hz，CH)，4.38(2H，s，CH ₂)，4.68(1H，s，NH)，7.28-7.30(10H，m，ArH)，8.89(1H，t，J＝7.6Hz，NH)，9.31(1H，br，HCl)，MS?m/e：551.5([M+1] ⁺).

Embodiment 26

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg replaces 2iv, uses (R)-N-benzyl-N-propyl group thiazolidine-4-carboxamide 264mg to replace 3ii.Yield is 35%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.84-0.86(3H，t，J＝7.2Hz，CH ₃)，1.37-1.41(5H，m，CH ₂，CH ₃)，2.91-2.93(2H，m，CH ₂)，3.36-3.37(3H，m，CH ₂，CH)，4.30-4.34(2H，m，CH ₂)，4.55-4.66(2H，m，CH ₂)，4.66-4.93(1H，m，CH)，5.17-5.18(2H，s，CH ₂)，7.21-7.40(5H，m，C ₆H ₅)，8.12-8.16(2H，br，J＝15.6Hz，NH ₂)，8.642-8.671(1H，m，CONH)，MS?m/e：393.1[M+H] ⁺。

Embodiment 27

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-propyl group thiazolidine-4-carboxamide 264mg to replace 3ii.Yield is 32%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.78-1.42(14H，m，CH ₂，CH ₃×4)，2.07(1H，m，CH)，2.95-3.66(3H，t，CH ₂，CH)，3.19-3.32(2H，m，CH ₂)，4.23-4.26(1H，m，CH)，4.38-4.51(3H，m，CH ₂，CH)，4.81-4.82(2H，s，CH ₂)，7.26-7.34(5H，m，C ₆H ₅)，8.30(2H，br，NH ₂)，8.58(1H，s，CONH)，MS?m/e：435.0[M+H] ⁺。

Embodiment 28

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg replaces 2iv, uses (R)-N-benzyl-N-butyl thiazolidine-4-carboxamide 276mg to replace 3ii.Yield is 48%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.81-0.84(3H，t，J＝5.6Hz，CH ₃)，1.09-1.63(7H，m，CH ₂×2，CH ₃)，2.89-2.91(1H，-H)，3.22-3.39(5H，m，CH ₂×2，CH)，3.92-4.03(2H，m，CH ₂)，4.302-4.341(2H，m，CH ₂)，4.68-5.21(2H，m，CH ₂)，7.20-7.40(5H，m，C ₆H ₅)，8.252(2H，br，NH ₂)，8.69(1H，s，CONH)，MS?m/e：407.0[M+H] ⁺。

Embodiment 29

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-butyl thiazolidine-4-carboxamide 276mg to replace 3ii.Yield is 52%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.84-0.91(9H，m，CH ₃×3)，1.17-1.30(7H，m，CH ₂×2，CH ₃)，1.99-2.06(1H，m，CH)，2.954-2.983(1H，m，CH)，3.32-3.35(4H，m，CH ₂×2)，3.59-3.60(1H，m，CH)，4.50-4.54(3H，m，CH ₂，CH)，5.13-5.18(2H，m，CH ₂)，7.21-7.40(5H，m，C ₆H ₅)，8.22(2H，br，NH ₂)，8.68-8.70(1H，m，CONH)，MS?m/e：449.1[M+H] ⁺。

Embodiment 30

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and different being to use (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg replaces 2iv, uses (R)-N-benzyl-N-amyl group thiazolidine-4-carboxamide 288mg to replace 3ii.Yield is 39%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.81-0.84(3H，t，J＝6.8Hz，CH ₃)，1.09-1.66(9H，m，CH ₂×3，CH ₃)，2.91-2.94(1H，m，CH)，3.37-3.39(4H，m，CH ₂×2)，3.93-4.03(2H，m，CH ₂)，4.55-4.57(2H，m，CH ₂)，4.93-4.95(1H，m，CH)，5.12-5.22(2H，m，CH ₂)，7.21-7.40(5H，m，C ₆H ₅)，8.10-8.26(2H，br，NH ₂)，8.69(1H，s，CONH)，MSm/e：421.1[M+H] ⁺。

Embodiment 31

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-amyl group thiazolidine-4-carboxamide 288mg to replace 3ii.Yield is 21%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.81-0.93(9H，m，CH ₃×3)，1.18-1.32(9H，m，CH ₂×4，-CH ₃)，2.06-2.08(1H，m，CH)，2.951-2.980(1H，m，CH ₃)，3.32-3.39(4H，m，CH ₂×2)，4.49-4.55(3H，m，CH，CH ₂)，4.81-4.85(1H，m，CH)，5.12-5.18(2H，m，CH ₂)，7.21-7.40(5H，m，C ₆H ₅)，8.23(2H，br，NH ₂)，8.67-8.68(1H，s，CONH)，MS?m/e：463.1[M+H] ⁺。

Embodiment 32

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; different (S)-2-(2-(t-butoxycarbonyl amino) propionyl amino) acetate 246mg that are to use replace 2iv, use (R)-N-benzyl-N-cyclohexyl thiazolidine-4-carboxamide 304mg to replace 3ii.Yield is 36%.

¹H-NMR?(400MHz，DMSO-d ₆)，δppm：1.15-1.66(13H，m，CH ₃，CH ₂×5)，3.01-3.34(1H，m，CH)，3.63(1H，m，CH)，4.01-4.03(4H，m，CH ₂×2)，4.40-4.56(3H，m，CH ₂，CH)，4.93-4.95(2H，m，CH ₂)，7.17-7.25(5H，m，C ₆H ₅)，8.23(2H，br，NH ₂)，8.67(1H，s，CONH)，MS?m/e：433.1[M+H] ⁺。

Embodiment 33

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-cyclohexyl thiazolidine-4-carboxamide 304mg to replace 3ii.Yield is 27%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.89-2.07(19H，m，CH ₂×5，CH ₃×3)，2.05-2.07(1H，m，CH)，2.98-3.01(1H，m，CH)，3.39-3.40(3H，m，CH ₂，CH)，3.62-3.63(1H，m，CH)，4.48-4.60(3H，m，CH ₂，CH)，5.17-5.19(2H，m，CH ₂)，7.18-7.46(5H，m，C ₆H ₅)，8.22(2H，br，NH ₂)，8.61-8.69(1H，s，CONH)，MS?m/e：475.3[M+H] ⁺。

Embodiment 34

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-sec.-propyl-acetate 288mg replaces 2iv to different (the S)-2-that is to use, and uses (R)-N-benzyl-N-styroyl thiazolidine-4-carboxamide 326mg to replace 3ii.Yield is 31.5%.

¹H-NMR(400MHz，DMSO-d ₆)，δppm：0.91-0.93(6H，m，CH ₃×2)，1.30-1.32(3H，m，CH ₃)，2.05-2.06(1H，m，CH)，2.82-2.96(4H，m，CH ₂×2)，3.31-3.36(1H，m，CH)，3.36(2H，m，CH ₂)，4.01-4.03(1H，m，CH)，4.57-4.59(3H，m，CH ₂，CH)，5.10-5.18(2H，m，CH ₂)，7.26-7.31(10H，m，C ₆H ₅×2)，8.10(2H，br，NH ₂)，8.66-8.68(1H，d，J＝8.4Hz，CONH)，MS?m/e：497.1[M+H] ⁺。

Embodiment 35

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv, uses (R)-N-benzyl-N-styroyl in different being to use (S)-2-

Azoles alkane-4-carboxamide 310mg replaces 3ii.Yield 42%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.85-1.15(5H，m，CH ₂×2，CH)，1.15(3H，d，J＝6.8Hz，CH ₃)，1.55-1.66(6H，m，CH ₂×3)，2.65-2.75(1H，m，CH)，2.80-2.99(1H，m，CH)，3.40-3.51(2H，m，CH ₂)，3.60-3.71(2H，m，CH ₂)，3.97(1H，t，J＝7.2Hz，CH)，4.27-4.33(2H，m，CH ₂)，4.58-4.68(1H，m，CH)，4.89-4.98(1H，m，CH)，5.08(1H，t，J＝5.6Hz，CH)，7.09-7.35(10H，m，ArH)，7.52(1H，d，J＝9.2Hz，CONH)，8.41(3H，br，HCl.NH ₂)，MS?m/e：521.6([M+1] ⁺).

Embodiment 36

Synthetic method with reference to embodiment 1 prepares the present embodiment compound, and ((S)-2-(2-(t-butoxycarbonyl amino) propionyl amino)-2-cyclohexyl-acetate 328mg replaces 2iv, uses (R)-N-benzyl-N-styroyl in different being to use (R)-2-

Azoles alkane-4-carboxamide 310mg replaces 3ii.Yield 47%.

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：0.90-1.18(5H，m，CH ₂×2，CH)，1.37(3H，d，J＝6.8Hz，CH ₃)，1.55-1.68(6H，m，CH ₂×3)，2.66-2.75(1H，m，CH)，2.88-3.00(1H，m，CH)，3.40-3.50(2H，m，CH ₂)，3.60-3.70(2H，m，CH ₂)，3.93(1H，t，J＝7.2Hz，CH)，4.32-4.49(2H，m，CH ₂)，4.67-4.78(1H，m，CH)，4.98-5.05(1H，m，CH)，5.17(1H，t，J＝5.6Hz，CH)，7.10-7.40(10H，m，ArH)，8.18(3H，br，HCl.NH ₂)，8.59(1H，d，J＝9.2Hz，CONH)，MS?m/e：521.6([M+1] ⁺).

Embodiment 37

Synthetic method with reference to embodiment 1 prepares the present embodiment compound; different (the 2S that are to use; 3S)-2-((S)-2-(t-butoxycarbonyl amino) propionyl amino)-3-(propyl group-2-alkynyloxy base) butyric acid 328mg replaces 2iv, uses (R)-N-that methyl-benzyl thiazolidine-4-carboxamide 236mg is replaced 3ii.Yield 35%

¹H-NMR(400MHz，DMSO-d ₆)，δ(ppm)：1.16(3H，d，J＝5.6Hz，CH ₃)，1.31(3H，d，J＝6.8Hz，CH ₃)，2.27(3H，s，CH ₃)，3.01-3.05(1H，m，CH)，3.31-3.44(3H，m，CH ₂，CH)，3.88-3.91(1H，m，CH)，3.97(1H，s，CH)，4.18-4.25(4H，m，CH ₂×2)，4.64(1H，d，J＝9.2Hz，CH)，4.73(2H，t，J＝6.8Hz，CH ₂)，5.08(1H，d，J＝9.2Hz，CH)，7.11-7.15(4H，m，Ar-H)，8.18(3H，br，HCl.NH2)，8.35(1H，s，CONH)，8.71(1H，d，J＝5.6Hz，CONH)MS?m/e：447.1([M+1] ⁺).

Pharmacology test example 1:XIAP-BIR3 and cIAP1-BIR3 suppress determination of activity

With the fluorescent tracer (SM-F2, IAPs inhibitor) and target proteins matter composition mixture of fixed concentration, wherein protein concn constantly increases until saturated.By monitoring, thereby measure SM-F2 respectively in conjunction with the equilibrium dissociation constant (K of XIAP-BIR3 (residue 241-356) and cIAP1-BIR3 (residue 253-363) to the total fluorescence polarization intensity of this mixture _d).The fluorescence polarization intensity level uses super microplate reader in 96-hole fluoroscopic examination microwell plate (Mierofluor 2, the extremely low background of black, round bottom) (Thermo Scientific) (TecanU.S., Research Triangle Park NC) measure.Test damping fluid to each hole (contains 100mM dipotassium hydrogen phosphate, pH 7.5,100 μ gml bovines, 0.02% Sodium Azide, 4%DMSO, Invitrogen company) add concentration in and be respectively the constantly target proteins of rising of 2nM (mensuration combines with XIAP-BIR3's) and 1nM (mensuration combines with cIAP1-BIR3's) SM-F2 and corresponding concentration, the final volume of system is 125 μ L.With the 96-orifice plate incubated at room temperature 3 hours and shaking gently to guarantee to reach balance.In excitation wavelength is that 485nm and emission wavelength are that the 530nm place measures polarizability, with the milli unit of polarization (mP) expression measured value.(Graphpad Software, San Diego is CA) by the function calculation equilibrium dissociation constant (K of match S type (sigmoidal) dosage-dependence FP increased value as protein concentration to use Graphpad Prism 5.0 softwares _d).

Dosage by inhibitor-dependence competition is in conjunction with the K of measuring inhibitor _iValue.In this experiment, the concentration of diluting inhibitor gradually, the inhibitor of different concns (is said determination K with the fluorescent tracer (SM-F2) of fixed concentration to fixed concentration respectively _dThe 2-3 of value is doubly) the combination of competing property of target proteins.The DMSO solution of the test-compound of 5 μ L different concns and the buffered soln that 120 μ L contain the target proteins/SM-F2 mixture of hatching in advance (are contained 100mM dipotassium hydrogen phosphate, pH 7.5,100 μ g/ml bovines, 0.02% Sodium Azide, 4%DMSO, Invitrogen company) join in the 96-orifice plate, incubated at room 3 hours is also shaken gently.Combine with the competitiveness of XIAP-BIR3 with SM-F2 for measuring test-compound, the ultimate density of XIAP-BIR3 and SM-F2 is respectively 10nM and 2nM in the system; And for the combination with cIAP1-BIR3, the ultimate density of cIAP1-BIR3 and SM-F2 is respectively 3nM and 1nM in the system.In each piece 96-orifice plate, all contain negative control group and positive controls, negative control group only contains target proteins/SM-F2 mixture (inhibiting rate is equivalent to 0%), and positive controls only contains free SM-F2 (inhibiting rate is equivalent to 100%).The mensuration of FP value is identical with the method for foregoing description.Tried makes the IC of thing ₅₀Nonlinear regression and fitting by competition curve is determined.The Ki of competitive inhibitor obtains by following Equation for Calculating:

K _i＝[I] ₅₀/([L] ₅₀/K _d+[P] ₀/K _d+1)

In the formula, [I] ₅₀Inhibitor concentration when expression 50% suppresses, [L] ₅₀Tagged ligand (SM-F2) concentration when being 50% inhibition, [P] ₀Protein concentration when being 0% inhibition, K _dIt is equilibrium dissociation constant.

XIAP-BIR3 and cIAP1-BIR3 suppress determination of activity and the results are shown in Table 1.

Table 1:XIAP-BIR3 and cIAP1-BIR3 suppress the determination of activity result

Pharmacology test example 2: adopt tetrazolium bromide (MTT) method to determine that various synthetic target compounds are external Survival restraining effect to ovarian cancer and cervical cancer cell

1. to the survival restraining effect of ovarian cancer:The ovarian cancer SKOV3 cell of taking the logarithm vegetative period, concentration are 1 * 10 ⁵Individual/hole, join 96 orifice plates, every hole adds celliferous nutrient solution 200 μ l, puts 37 ℃, 5%CO ₂After incubator is hatched 16h, add the various synthetic target compounds of 100 μ M successively, the while as the blank group, adds MTT (5mg/ml) 20 μ l/ holes with the DMEM substratum behind dosing 48h, and 37 ℃, 5%CO ₂After incubator is hatched 4h, abandon supernatant, every hole adds DMSO 150 μ l and measures absorbancy OD value, each concentration replicate(determination) 4 hole in 490nm wavelength place.

2. to the survival restraining effect of cervical cancer cell:Collect the logarithmic phase cell, adjust concentration of cell suspension, every hole adds 200ul, and bed board makes cell to be measured transfer density to 10000/ hole, (marginal pore is filled with aseptic PBS).Blank is set, positive control and negative control.5%CO ₂, hatch for 37 ℃, be paved with the hole to cell monolayer at the bottom of (96 hole flat underside), add the finite concentration medicine.5%CO ₂, to hatch 48 hours for 37 ℃, inverted microscope is observed down.Every hole adds 20ul MTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4h.Stop cultivating, the careful suction removed nutrient solution in the hole.Every hole adds 150 μ l dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on the shaking table, and crystallisate is fully dissolved.Measure the light absorption value in each hole at enzyme-linked immunosorbent assay instrument OD 490nm place.Zeroing hole (substratum, MTT, dimethyl sulfoxide (DMSO)) is set simultaneously, control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, dimethyl sulfoxide (DMSO)).

By above-mentioned raw data, calculate growth inhibition ratio (IR) by following formula.

Inhibiting result shows to the survival of ovarian cancer, all compounds to the inhibiting rate (100 μ m) of ovarian cancer cell all between 10%-70%.The results are shown in Table 2 to the survival of cervical cancer cell is inhibiting, wherein in the table 2 unlisted other compounds to the inhibiting rate (100 μ m) of cervical cancer cell all between 10%-70%.

Table 2: embodiment is to cervical cancer cell inhibiting rate (100 μ m)

Claims

1. the compound of general formula I:

X is-CH ₂-or-O-or-S-;

Y is-CH ₂-or-CH ₂CH ₂-or-CO-;

R ¹Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl, it is optional replaced by one or more halogens and

R ²Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-(C ₁-C ₆Alkyl)-R ⁷And

5)-Ar ¹，

Wherein,

R ⁷Be selected from:

1)-OR ⁸，

2)-SR ⁸，

3)-NR ⁸R ⁹，

4)-NCONR ⁸R ⁹，

5)-NCNNR ⁸R ⁹，

6)-COOR ⁸，

7)-CONR ⁸R ⁹And

8)-Ar ¹，

Ar ¹Be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optional by one or more

Being selected from following group replaces:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

R ³Be selected from:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-(C ₁-C ₆Alkyl)-R ¹⁰,

5)-Ar ¹，

Wherein,

R ¹⁰Be selected from:

1)-OR ⁸，

2)-SR ⁸，

3)-NR ⁸R ⁹，

4)-NCONR ⁸R ⁹，

5)-NCNNR ⁸R ⁹，

6)-COOR ⁸，

7)-CONR ⁸R ⁹And

8)-Ar ¹，

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

[preferred, R ³Connect carbon atom and can be any optical configuration]

R ⁴And R ⁴⁰⁰Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl and

5)-C ₂-C ₆Alkynyl;

R ⁵And R ⁵⁰⁰Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl and

5)-C ₂-C ₆Alkynyl;

R ⁶Be selected from:

1)-R ¹¹，

2)-OR ¹¹，

3)-NR ¹¹R ¹²，

4)-SOR ¹¹And

5)-SO ₂R ¹¹，

Wherein, R ¹¹And R ¹²Be selected from independently of one another:

1)-H，

2)-C ₁-C ₆Alkyl,

3)-C ₃-C ₈Cycloalkyl,

4)-C ₂-C ₆Thiazolinyl,

5)-C ₂-C ₆Alkynyl,

6)-COR ⁸，

7)-Ar ¹，

8)-(C ₁-C ₆Alkyl)-Ar ¹,

9)-CO-Ar ¹And

10)-CO-(C ₁-C ₆Alkyl)-Ar ¹,

Wherein,

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is chosen wantonly and is replaced by one or more halogens,

With

2. the compound of claim 1, it is a formula Ia compound:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein X, R ¹, R ², R ³, R ⁴, R ⁴⁰⁰, R ⁵, R ⁵⁰⁰, and R ⁶Definition as the compound of claim 1 mutual-through type I.

3. the compound of claim 1, it is a formula Ib compound:

4. the compound of claim 1, it is a formula Ic compound:

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein R ¹, R ², R ³, R ⁸, and R ⁹Definition as the compound of claim 1 mutual-through type I.

5. the compound of claim 1, it is a formula Id compound:

6. the compound of claim 1, it is a formula Ic1 compound:

7. the compound of claim 1, it is a formula Id1 compound:

8. the compound of claim 1, it is a formula Ie compound:

R ¹, R ², R ³, and Ar ¹As the definition of the compound of claim 1 mutual-through type I,

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

9. the compound of claim 1, it is a formula If compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

10. the compound of claim 1, it is a formula Ie1 compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

11. the compound of claim 1, it is a formula If1 compound:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸R ⁹And

8)-COOR ⁸，

Wherein, R ⁸And R ⁹Be selected from independently of one another:

1)-H，

From-C ₁-C ₄The group of alkyl, halogen replaces,

5)-C ₂-C ₆Thiazolinyl, it is optional replaced by one or more halogens and

12. the compound of claim 1, wherein

X is-O-or-S-;

Y is-CH ₂-or-CO-;

R ¹Be selected from :-H ,-C ₁-C ₄Alkyl;

R ²Be selected from :-H ,-C ₁-C ₄Alkyl;

13. each compound of claim 1-12, it is selected from:

With

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate.

14. the preparation method of each described compound of claim 1-13, it may further comprise the steps:

A) make formula II compound

II (formula for example

The compound of expression removes group Z then, obtains formula

The compound of expression;

B) make formula

The compound and the formula of expression

The compound reaction of expression obtains formula

The compound of expression, hydrolysis in the presence of alkali then obtains formula The compound of expression;

The compound and the formula of expression

The compound reaction of expression obtains formula

The compound of expression removes group-Boc then, obtains formula I compound; With optional,

D) make the product of step c) form pharmacologically acceptable salts;

Wherein, X, Y, R ¹, R ², R ³, R ⁴, R ⁴⁰⁰, R ⁵, R ⁵⁰⁰, and R ⁶As the definition of the compound of each mutual-through type of claim 1-12 of the present invention I, Z is selected from-H ,-Boc and-Cbz.

15. a pharmaceutical composition, its comprise treat and/or prevent significant quantity claim 1-13 each compound and optional pharmaceutically acceptable carrier or vehicle.

16. claim 1-13 each compound preparation be used for the treatment of and/or the medicine of the disease that prevention is relevant with the IAPs overexpression in purposes.

17. the purposes of claim 16, wherein said disease are selected from bladder cancer, mammary cancer, carcinoma of the pancreas, colorectal carcinoma, leukemia, lung cancer, lymphoma, multiple spinal cord knurl, ovarian cancer and cervical cancer, especially for example are ovarian cancer and cervical cancer.