CN101928326B - Substitution five-heterocyclic alkyl aminoacyl compound and application thereof - Google Patents

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 replaced and uses thereof

Invention field

The present invention relates to the five-heterocyclic alkyl aminoacyl derivative of replacement, its preparation method, containing they pharmaceutical composition and as the purposes of IAP IAPs (Inhibitor of ApoptosisProteins) inhibitor for the preparation of the compound of anti-tumor activity.

Background technology

Apoptosis or be called apoptosis, usually occurs in growth and the maintenance stage of health tissues in multicellular organism.Known apoptotic pathways at fetal development, viral pathogeny, cancer, autoimmune disorder and neurodegenerative disease, and has important effect in other event.Find the development of change and cancer, the autoimmune disorder such as systemic lupus erythematous and multiple sclerosis in apoptosis reaction and relevant with the virus infection comprised with simplexvirus, poxvirus and adenovirus are correlated with.

IAP IAPs (Inhibitor of Apoptosis Proteins) is the endogenous inhibitors of the main attemperator Caspases (caspase) of apoptosis, they are optionally combined with Caspase-3, Caspase-7 and/or Caspase-9, block the proteolytic activity of the Caspases that apoptosis must rely on, and then inhibited apoptosis.Up to now, the IAPs found 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 are only containing a BIR structural domain.Verified many IAPs unconventionality expression in cancer cells, Survivin has high expression level in Several Kinds of Malignancy, but in normal cell, be not checked through this albumen.Although other IAPs member exists in multiple healthy tissues, also as Survivin in Several Kinds of Malignancy overexpression.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 discharged in plastosome can be combined with IAPs, and its site combined is IAPs and Caspase-3 ,-7 and the position of Caspase-9 combination just, thus inhibits the anti-apoptotic activities of IAPs.According to the function of IAPs family protein in apoptosis pathway and the interactional mechanism of IAPs and Caspases and Smac, have been found that at present and multiplely can suppress IAPs function and there is the compound of anti-tumor activity.

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

Summary of the invention

The object of the invention is the inhibitor of the selectivity IAPs acceptor high-affinity finding new texture, for suppressing the activity of IAPs in human body, and then strengthen the proteolytic activity of Caspases, thus play the object of Therapeutic cancer.

The present inventor has found a series of in conjunction with IAPs and by regulating IAPs function and promote apoptotic new compound, and they have the acceptable stability of pharmacy and bioavailability.This compounds can block the interaction of IAPs and Caspase-3, Caspase-7 and Caspase-9.Result of the present invention shows that this micromolecular can at apoptosis front lower adjustment IAPs albumen, illustrates that being applied in of this compound can provide useful effect clinically when together with other apoptotic inductor during administration thus.The present inventor has proved that the compounds of this invention is combined with Mammals XIAP-BIR3, cIAP-BIR3 structural domain, thus promotes cancer cell-apoptosis.Compound described herein has pro-apoptosis bioactivity in multiple cancerous cell line, 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 such as, and may be used for other cancerous cell line and cell by cell apoptosis has in the disease of resistance.These results show that compound of the present invention will have for solid tumor and the therapeutic activity of tumour originating from malignant hematologic disease.In addition, compound of the present invention also can be used for preventing the transfer of cancer cells, invasion, inflammation, and other has in the disease of the feature of anti-apoptotic cell.The present inventor finds through research, and 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 may be used for the treatment of tumour.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 optionally by one or more halogen substiuted, and

3)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted;

R ²be selected from:

1)-H，

2)-C ₁-C ₆alkyl,

3)-C ₃-C ₈cycloalkyl,

4)-(C ₁-C ₆alkyl)-R ⁷, and

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 ⁹, and

8)-Ar ¹，

Ar ¹be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

8)-COOR ⁸，

R ⁸and R ⁹be selected from independently of one another:

1)-H，

2)-(C ₁-C ₆alkylidene group) _0-3phenyl, phenyl wherein is optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted;

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 ⁹, and

8)-Ar ¹，

Ar ¹be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted;

[preferred, R ³connect carbon atom can for 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 ¹¹, and

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 ¹, and

10)-CO-(C ₁-C ₆alkyl)-Ar ¹,

Wherein,

Ar ¹be selected from phenyl, aromatic heterocyclic and assorted bicyclic group, it is optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.Compound according to a first aspect of the present invention, it is 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 ⁶as the definition of the compound of first aspect present invention mutual-through type I.

Compound according to a first aspect of the present invention, it is formula Ib 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 ⁶as the definition of the compound of first aspect present invention mutual-through type I.

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

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

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

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

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

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

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

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

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

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein: 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, its optionally by one or more be selected from following

Group replaces:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.

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

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein: 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 optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.

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

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein: 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 optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.

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

And isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate, wherein: 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, its optionally by one or more be selected from following

Group replaces:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃，

5)-R ⁸，

6)-OR ⁸，

7)-NR ⁸r ⁹, and

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 optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.

Compound according to a first aspect of the present invention, it is selected from:

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

Second aspect present invention provides the preparation method of compound described in any one of first aspect present invention, and it comprises the following steps:

A) formula II compound is made

iI (such as formula the compound represented) and formula H-R ⁶the compound reaction represented, obtains formula the compound represented, then removes group Z, obtains formula the compound represented;

B) formula is made the compound represented and formula the compound reaction represented, obtains formula the compound represented, is then hydrolyzed in the presence of a base, obtains formula the compound represented;

C) under suitable reagent (in such as isobutyl chlorocarbonate, triethylamine and N-methylmorpholine one or more) exists, formula is made the compound represented and formula the compound reaction represented, obtains formula the compound represented, then removes group-Boc, obtains formula I; With optional,

D) make step c) product formed 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 any one of first aspect present invention mutual-through type I, Z is selected from-H ,-Boc and-Cbz.

Method according to a second aspect of the present invention, it optionally has following one or more feature:

Step a) in, the reaction conditions of first step wherein can adopt dry tetrahydrofuran (THF), N, dinethylformamide or methylene dichloride are as solvent, preferred tetrahydrofuran (THF), can combine using DCC+HOBt or isobutyl chlorocarbonate+tertiary amine combinations is as reacting auxiliary reagent, and DCC+HOBt preferably can be used to combine, temperature of reaction can at-15 DEG C ~ 25 DEG C, preferably 0 DEG C ~ 10 DEG C, reaction can be 1 hour to 24 hours, preferably 12 hours; Second step deprotection can adopt the dry organic solvent being dissolved with 2-4 N HCl, such as tetrahydrofuran (THF), ethyl acetate, dioxane, can preferred 4N HCl/ ethyl acetate, temperature can at-15 DEG C ~ 25 DEG C, preferably 0 DEG C, reaction can be 1 hour to 8 hours, preferably 2 hours;

In step b) in, the reaction conditions of first step wherein can adopt dry tetrahydrofuran (THF), N, dinethylformamide or methylene dichloride are as solvent, preferred tetrahydrofuran (THF), can combine using DCC+HOBt or isobutyl chlorocarbonate+tertiary amine combinations is as reacting auxiliary reagent, and preferred DCC+HOBt combines, temperature of reaction can at-15 DEG C ~ 25 DEG C, preferably 0 DEG C ~ 10 DEG C, reaction can be 1 hour to 24 hours, preferably 12 hours; Second step deprotection can adopt the methanol/water solution of the mixing of 1-4N NaOH or LiOH, 50% methanol solution of preferred 1N NaOH, and temperature of reaction can at-15 DEG C ~ 25 DEG C, preferably 0 DEG C ~ 10 DEG C, and reaction can be 1 hour to 24 hours, preferably 3 hours; With

In step c) in, the reaction conditions of first step wherein, dry tetrahydrofuran (THF), N can be adopted, dinethylformamide or methylene dichloride as solvent, preferred tetrahydrofuran (THF), preferred isobutyl chlorocarbonate+N-methylmorpholine as reaction auxiliary reagent, temperature of reaction can at-15 DEG C ~ 25 DEG C, preferably 0 DEG C ~ 10 DEG C, reaction can be 1 hour to 24 hours, preferably 12 hours; Second step deprotection can adopt the dry organic solvent being dissolved with 2-4 N HCl, such as tetrahydrofuran (THF), ethyl acetate, dioxane, preferred 4N HCl/ ethyl acetate; temperature can at-15 DEG C ~ 25 DEG C; preferably 0 DEG C, reaction can be 1 hour to 8 hours, preferably 2 hours.

Method according to a second aspect of the present invention, formula wherein the compound represented can use formula the compound represented replaces, and obtains the isomer of formula I.

Third aspect present invention provides a kind of pharmaceutical composition, and it comprises the compound described in any one of first aspect present invention and optional pharmaceutically acceptable carrier or vehicle that treat and/or prevent significant quantity.

Fourth aspect present invention provides compound described in any one of first aspect present invention for the preparation of the purposes treated and/or prevented in the medicine of the disease relevant to IAPs overexpression.

Purposes according to a fourth aspect of the 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, is especially such as ovarian cancer and cervical cancer.

This inhale the 5th aspect provide the method treating and/or preventing the disease relevant to IAPs overexpression in Mammals in need (such as people), the method comprise to described Mammals (such as people) administering therapeutic and/or prevention significant quantity any one of first aspect present invention described in compound.

Purposes according to a fifth aspect of the 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, is especially such as 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, optionally by the-C of one or more halogen substiuted 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, wherein R 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 optionally selected from-C by one or more ₁-C ₄the group of alkyl and halogen replaces, optionally by the-C of one or more halogen substiuted ₁-C ₆alkyl, optionally by the-C of one or more halogen substiuted ₃-C ₈cycloalkyl, optionally by the-C of one or more halogen substiuted ₂-C ₆thiazolinyl and optionally by the-C of one or more halogen substiuted 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, wherein R 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, wherein R 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 ⁶-NR ¹¹r ¹².

In an embodiment of the compounds of this invention, wherein said R ⁶-NR ¹¹r ¹², wherein R 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 ⁶-NR ¹¹r ¹², wherein R 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, wherein Ar ¹optionally by one or more phenyl being selected from following group and replacing: 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 ⁶-NR ¹¹r ¹², wherein R 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, wherein Ar ¹optionally by one or more phenyl being selected from following group and replacing: halogen, nitro, cyano group ,-CF ₃,-R ⁸,-OR ⁸,-NR ⁸r ⁹, and-COOR ⁸, wherein R ⁸and R ⁹be selected from independently of one another :-H ,-(C ₁-C ₄alkylidene group) _0-3-phenyl, phenyl wherein is optionally selected from-C by one or more ₁-C ₄the group of alkyl and halogen replaces, optionally by the-C of one or more halogen substiuted ₁-C ₄alkyl, optionally by the-C of one or more halogen substiuted ₄-C ₆cycloalkyl, optionally by the-C of one or more halogen substiuted ₂-C ₄thiazolinyl and optionally by the-C of one or more halogen substiuted 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, wherein R 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 ⁶-NR ¹¹r ¹², wherein R 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, wherein Ar ¹optionally by one or more phenyl being selected from following group and replacing: halogen, nitro, cyano group ,-CF ₃,-R ⁸,-OR ⁸,-NR ⁸r ⁹, and-COOR ⁸, wherein R ⁸and R ⁹be selected from independently of one another :-H ,-(C ₁-C ₄alkylidene group) _0-3-phenyl, phenyl wherein is optionally selected from-C by one or more ₁-C ₄the group of alkyl and halogen replaces, optionally by the-C of one or more halogen substiuted ₁-C ₄alkyl, optionally by the-C of one or more halogen substiuted ₄-C ₆cycloalkyl, optionally by the-C of one or more halogen substiuted ₂-C ₄thiazolinyl and optionally by the-C of one or more halogen substiuted ₂-C ₄alkynyl.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

Term used herein " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.

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

Term used herein " alkyl " refer to comprise that there is the side chain that specifies number carbon atom with radical of saturated aliphatic alkyl that is straight chain, such as C ₁-C ₆c in alkyl ₁-C ₆be defined as comprising the group with the carbon that 1,2,3,4,5 or 6 arranges with line style or branched chain type.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 " refers to wherein containing specifying number carbon atom and wherein having at least two carbon atoms to be connected to each other with a double bond and have the undersaturated straight or branched alkyl of E or Z configuration and its combination configuration.Such as, C ₂-C ₆c in thiazolinyl ₂-C ₆be defined as comprising have 2,3,4,5 or 6 with line style or branched chain type arrangement carbon and at least two carbon atoms by 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 " refers to wherein containing specifying number carbon atom and wherein having the undersaturated straight or branched alkyl that two carbon atoms are linked together by a triple bond at least.Such as C ₂-C ₆c in alkynyl ₂-C ₆be defined as comprising in chain the group that there are 2,3,4,5 or 6 carbon atoms, have at least two carbon atoms to be linked 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 " refers to wherein saturated containing the monocycle specifying number carbon atom aliphatic hydrocarbyl, such as C ₃-C ₈c in cycloalkyl ₃-C ₈be defined as comprising the group in the mode of single loop arrangement with 3,4,5,6,7 or 8 carbon.C defined above ₃-C ₈the example of cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.

Term used herein " cycloalkenyl group " refers to wherein have the undersaturated aliphatic hydrocarbyl of the monocycle specifying number carbon atom, such as C ₃-C ₈c in cycloalkenyl group ₃-C ₈be defined as comprising the group in the mode of single loop arrangement with 3,4,5,6,7 or 8 carbon.C defined above ₃-C ₈the example of cycloalkenyl group includes but not limited to cyclopentenyl and cyclohexenyl.

Term used herein " halo " or " halogen " refer to 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 independent or be combined with another group, refer to a kind of like this carbocyclic aromatic monocyclic groups containing 6 carbon atoms, it can be on aromatics, saturated or unsaturated 5 yuan or 6 yuan of carbon ring groups that this group can condense in second further.Aryl includes but not limited to phenyl, 2,3-indanyls, 1-naphthyl, 2-naphthyl and tetralyl.The aryl condensed can be connected on another group of appropriate position on cycloalkyl ring or aromatic nucleus.

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

Term used herein " heteroaryl " refers to the monocycle or bicyclic system that have and be up to ten atoms, and wherein at least one ring is aromatic ring, and is selected from the heteroatoms of O, N and S containing 1 to 4.Heteroaryl substituent connects by one of carbon atom or heteroatoms on a ring.The example of heteroaryl includes but not limited to thienyl, benzimidazolyl-, benzo [b] thienyl, furyl, benzofuryl, pyranyl, isobenzofuran-base, benzopyranyl, 2H-pyrryl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, indolizine base, isoindolyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl, 2, 3-phthalazinyl, 1, 5-phthalazinyl, quinoxalinyl, quinazolyl, cinnolines base, pteridyl, isothiazolyl, 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 ", " heterocycle " or " heterocyclic radical " mean one is selected from O, N and S heteroatomic 5,6 or 7 yuan of non-aromatic ring system containing 1 to 4.The example of heterocycle includes but not limited to pyrrolidyl, tetrahydrofuran base, piperidyl, pyrrolinyl, piperazinyl, imidazolidyl, morpholinyl, imidazolinyl, pyrazolidone, pyrazolinyl.

Term used herein " assorted bicyclic group ", refers to and a kind ofly condenses the heterocycle as hereinbefore defined on another ring, other any ring that another ring described 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] bis-Evil are luxuriant, 2,3-dihydrobenzos [b] [Isosorbide-5-Nitrae] dioxole and 3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] dioxole (dioepine).

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

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 within the scope of reliable medical judgment, is suitable for not occurring excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue, and the salt matched with rational effect/Hazard ratio.Pharmacologically acceptable salts is well known in the art.Such as, S.M.Berge, et al.J.Pharmaceutical Sciences, has been described in detail pharmacologically acceptable salts in 1977,66:1.Described salt, by making the free alkali functionality of the compounds of this invention and suitable organic acid reaction, is prepared at the final abstraction and purification process situ of the compounds of this invention or prepares separately.The pharmacologically acceptable salts of the compounds of this invention comprises, but is not limited to, salt formed by compound of Formula I and mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid; And compound of Formula I and various organic acid salt as formed in toxilic acid, fumaric acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetic acid, 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 etc.In addition, the pharmacologically acceptable salts of the compounds of this invention also includes, but not limited to salt prepared by compound of Formula I and mineral alkali as sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc., the salt obtained by organic bases includes but not limited to primary amine, the salt of secondary amine and tertiary amine, the amine wherein replaced comprises naturally occurring replacement amine, cyclammonium and deacidite, such as Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, thanomin, DMAE, 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 their respective salt forms upper slightly different in some physical properties (solubleness as in polar solvent), but for the object of the invention, each acid salt and their respective free alkali forms are quite (see such as S.M.Berge, et al., " Pharmaceutical Salts; " J.Pharm.Sci., 66:1-19 (1977), it is incorporated to herein by reference).

Some compounds in the present invention with water or various organic solvent crystallization or recrystallization, in this case, may may form all kinds of SOLVENTS compound.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound comprising variable water gaging formed when preparing with lyophylization.In general, for object of the present invention, as suitable with non solvate form in the solvate form thereof of water, ethanol etc. with the acceptable solvent of pharmacy.

The compounds of this invention and pharmacologically acceptable salts thereof can also be prodrug or the form that can discharge described activeconstituents in vivo after 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 " refer to 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 aggregated delivery system or polyoxyethylene glycol matrix such as, and it is for being acceptable when experimenter, the preferably mankind.

The present invention relates to the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate for the production of the purposes of medicine, described medicine may be used for treating and/or preventing the relevant disease caused by 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 are especially such as ovarian cancer and cervical cancer.

On the other hand; compound or its pharmacologically acceptable salts of general formula I of the present invention can be used alone; or use with the form of pharmaceutical composition together with the carrier acceptable with pharmacy or vehicle; when using with the form of pharmaceutical composition; usually 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 are combined and make suitable administration form or dosage form, this program comprise by suitable mode, component is mixed, granulation, compression or dissolve.Therefore, the invention provides pharmaceutical composition, it comprises the acceptable carrier of the compound of general formula I, its all possible isomer, prodrug, pharmacologically acceptable salts, solvate or hydrate and at least one pharmacy.

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

The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit.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. such as.

Can also containing conventional carrier in 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 is as human serum protein, buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures 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 % by weight-98 % by weight, usually accounts for greatly 80 % by weight.For simplicity, local anesthetic, sanitas, buffer reagent etc. can directly be dissolved in carrier.

Oral tablet and capsule can contain vehicle as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone, weighting agent, 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 with method dressing known in pharmacopedics.

Oral liquid can make the suspension of water and oil, and solution, emulsion, syrup or elixir, also can make dry product, with front 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, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, Sudan Gum-arabic; Or nonaqueous carrier (may edible oil be comprised), as Prunus amygdalus oil, grease as glycerine, ethylene glycol, or ethanol; Sanitas, as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.As needs can add seasonings or tinting material.

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

Offer medicine outward to stomach, liquid forms is made up of the carrier of compound and a kind of sterilization usually.The first-selected water of carrier.According to the difference of selected carrier and drug level, compound had both dissolved in carrier and also can be made into aaerosol solution, first that compound is soluble in water when making injection solution, loaded in sealed bottle or ampoule after filter-sterilized.

When topical application, the compounds of this invention can make suitable ointment, lotion, or the form of creme, and wherein activeconstituents suspends or is dissolved in one or more 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; Lotion and the spendable carrier of creme include but not limited to: mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, and cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.

Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.

Term used herein " treatment significant quantity " refers to a kind of dosage, and it can produce the physiologic response of expectation after being applied to this experimenter such as Mammals such as people, particularly produce for 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, in composition, can weight ratio 0.1% be contained, or the active ingredient of more suitably weight ratio 10-60%.But when comprising unitary dose in component, each unit preferably comprises 1-500 milligram activeconstituents.

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

Must recognize, the best dosage of compound of Formula I and interval are determined by external conditionss such as the form of compound property and such as administration, path and positions, and this best dosage can be determined by the technology of routine.Also must recognize, the best course for the treatment of, i.e. the dosage of compound of Formula I every day within the specified time, available method well known in the art is determined simultaneously.

The present invention relates to the preparation method of preparation compound of Formula I or its pharmacologically acceptable salts, solvate or hydrate.In describing the generality of the method below, each variable or substituent concrete definition are as the definition of first aspect present invention compound.

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

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

Compounds of formula II preferably but be not limited only to following several structure:

The synthesis of IIa, IIb structure can directly use business can buy L-PROLINE, 4-S-OH-L-proline and Boc acid anhydrides to synthesize obtained.The synthesis of IIc, IId, IIe, IIf is by the route of following scheme 1:

scheme 1

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

For Ie compound, following scheme 2 illustrates that the present invention is how by Compounds of formula II 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, then with the condensation of IIc order, after obtaining 2vii, deprotection salify obtains end product Ie again.

For If compound, following scheme 3 illustrates that the present invention is how by Compounds of formula II to compound of Formula I.

scheme 3

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

Compound of Formula I can use the single synthesis of ordinary method, also the method for available combination chemistry mixed-point method or parallel projects with storehouse (at least containing two in each storehouse, or 5-1000, preferably 10-100 compound) be unit synthesis, namely can synthesize in the liquid phase and also can use solid phase synthesis process.The various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Can to vide infra embodiment part about the more detailed data of preparation compound of Formula I.

Embodiment:

Further illustrate the present invention below by concrete intermediate and embodiment, but should be understood to, these intermediates and embodiment are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.

The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, 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 melting point apparatus, the non-calibration of thermometer.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, following shortenings is used:

Boc: tert-butoxycarbonyl;

Cbz: Benzyloxycarbonyl;

DCM: methylene dichloride;

DIPEA: diisopropylethylamine;

DMF:N, dinethylformamide;

DCC: carbodicyclo hexylimide

HOBt:1-hydroxybenzotriazole;

TEA: triethylamine;

NMF:N-methylmorpholine;

THF: tetrahydrofuran (THF);

ClCOOiBu: isobutyl chlorocarbonate;

LiAlH ₄: Lithium Aluminium Hydride;

NaBH ₄: sodium borohydride;

TLC: tlc.

intermediate Preparation example 1: the synthesis of formula IIc compound

reaction process:

step 1)

The Cys of 12.1g (0.1mol) is dissolved in the middle of 60ml hot water, the formalin of slow impouring 10mL 36%, shake up rear hold over night, filter institute's crystallize out next day, needle-like white crystals 12.8g is obtained again with second alcohol and water recrystallization, yield is 96.2%, m.p:196-197 DEG C.

step 2)

Under ice bath, the L-thiazolidinecarboxylic acid of 0.10mol is dissolved in the aqueous sodium hydroxide solution (0.10mol) of the 2N of 50mL, by (Boc) of 24.4g (0.11mol) under stirring ₂the acetone mixing solutions of O and 50mL slowly instills, and finishes, and continues to stir 2h.Add the water dilute reaction solution of 200mL, with the extraction into ethyl acetate 3 times of 80mL × 3, discard organic phase.Be 2 with the salt acid for adjusting pH value of 1mol/L under aqueous phase ice bath, then use the extraction into ethyl acetate 3 times of 80mL × 3, merge organic phase, removal of solvent under reduced pressure after anhydrous sodium sulfate drying, obtains white crystal by sherwood oil and re-crystallizing in ethyl acetate.

intermediate Preparation example 2: the synthesis of formula IId compound

reaction process:

step 1)

Be dissolved in by Cys (12.2g, 100mmol) in 100ml anhydrous methanol, logical HCl all dissolves to raw material, continues ventilation more than 2h, and ventilation terminates stirring and spends the night.Next day evaporated under reduced pressure solvent, resistates dissolve with methanol evaporate to dryness again, repeats 2 times to take away HCl.Solvent evaporated obtains crude product, uses methanol-diethyl ether recrystallization.Yield 91%.m.p：143-145℃。

step 2)

3.5g (20mmol) intermediate 1ii and 40ml acetone mixing backflow, after 10 minutes, add 10ml methyl alcohol and solid in system are all dissolved, and after continuing backflow 0.5h, cooling crystallization, after leaching crystal, mother liquor concentrations continues crystallization.Obtain clear crystal, yield 94%.m.p：165-168℃。

step 3)

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

step 4)

Intermediate 1iv is dissolved in the middle of 25ml methyl alcohol, adds the 25ml 2N NaOH aqueous solution, and room temperature reaction 4h, TLC reduce pressure after detecting raw material disappearance and remove methyl alcohol as far as possible, are diluted with water to 50ml, wash away unnecessary Boc with the ether of 20ml × 3 ₂o, is 2 with the salt acid for adjusting pH value of 1mol/L under phase ice bath, has a large amount of white solid to separate out, and filters washing and obtains intermediate II d.

intermediate Preparation example 3: the synthesis of formula IIe compound

reaction process:

step 1)

The formalin 10ml (120mmol) of Serine 10.5g (100mmol) and 37% is dissolved in the aqueous solution of 2N NaOH of 50ml, stirs under ice bath and spend the night.By 24.0g (Boc) under next day ice bath ₂o (110mmol) is dissolved in the solution instillation reaction solution in 40ml acetone, after continuing to stir 1h, is rushed by reaction solution rare with 350ml water, then 3 extractions are divided with ethyl acetate 120ml, discard organic phase, it is 2 that aqueous phase HCl is adjusted to pH value, divides three extractions with 120ml ether, collect organic phase, evaporated under reduced pressure, obtains IIe, colorless oil, placement is spent the night and is become solid, obtains prismatic crystals with ethyl acetate-light petrol recrystallization.Yield 94%.

intermediate Preparation example 4: the synthesis of formula IIf compound

reaction process:

The synthesis of formula IIf compound can with reference to the synthesis of formula IIe compound, and just raw material changes L-threonine into.

intermediate Preparation example 5: the synthesis that can be used for the intermediate 2ii preparing embodiment 1 compound

reaction process:

step 1)

The phenylethylamine of 12.1g (100mmol) and 11.1g (110mmol) triethylamine are dissolved in 200mL dry methylene chloride, the careful 100mL dichloromethane solution dripped containing 14.5g (100mmol) Benzoyl chloride under ice bath, drip off and slowly rise to room temperature, react 2 hours.Reaction solution ethyl acetate-water dispenser extraction, collects organic phase, anhydrous Na ₂sO ₄after dry, decompression is spin-dried for, and obtains white solid, without the need to being separated, is directly used in next step reaction after oven dry.

step 2)

Carefully in 400mL dry THF, add 5.0g (being roughly equal to 130mmol) LiAlH under ice bath in batches ₄, finish, after temperature-stable to 0 DEG C, in system, drip previous step product be again dissolved in solution in the middle of 200mL dry THF, slowly drip with guarantee system heat release venting steadily.Drip off and system backflow is spent the night.Ice bath cooling reaction, the careful saturated ammonium chloride solution that drips is to destroy residue LiAlH ₄.Filter, filter cake ethyl acetate is washed extremely without product.Merge organic phase, after removal of solvent under reduced pressure, obtain N-styroyl benzylamine by pillar layer separation (moving phase is the ethyl acetate-light petrol of corresponding proportion).

intermediate Preparation example 6: the synthesis that can be used for the intermediate 2iv 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 Cys methyl ester hydrochloride.

step 1)

Ice bath temperature control less than 0 DEG C, Boc-L-Ala 1.89g (10mmol) is dissolved in methylene dichloride, carefully add DCC2.27g successively, HOBt1.49g, 2S-cyclohexyl-L-glycine methyl ester hydrochloride 2.07g (10mmol), triethylamine 1.01g, room temperature reaction spends the night, cross and filter white precipitate DCU, organic phase use successively 10% citric acid, saturated aqueous common salt, 4% sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous Na ₂sO ₄dry, decompression is spin-dried for dichloromethane solvent, give light yellow oil, then adds ethyl acetate solvent, stand at low temperature, adularescent precipitation DCU separates out, and cross and filter DCU, decompression is spin-dried for ethyl acetate, add ethyl acetate stand at low temperature again, so repeatedly remove the DCU of the overwhelming majority several times, obtain white solid 2.73 finally by silica gel column chromatography, yield 80%.

step 2)

Intermediate 2iii is about 2.70g and is dissolved in 15mL methyl alcohol, add 2N NaOH 10mL, room temperature reaction 2 hours, TLC detection reaction process, 1N HCl regulates pH weakly acidic pH, and part methyl alcohol is revolved in decompression, thin up, elimination insoluble impurities, filtrate is 1N HCl acidifying in ice bath, adularescent solid is separated out immediately, collecting by filtration, is washed to washing lotion weakly acidic pH, dry, methanol-water recrystallization obtains colorless needle crystals 2.05g, yield 79%.

intermediate Preparation example 6: the synthesis that can be used for the intermediate 3ii preparing embodiment 1 compound

reaction process:

step 1)

Cryosel bath temperature control less than 0 DEG C, to in the methylene dichloride being dissolved with 11.5g (50mmol) Boc-thiazolidinecarboxylic acid, carefully add 10.6g (50mmol) N-styroyl benzylamine, 7.4g (55mmol) HOBt, and carefully drip the dichloromethane solution of 11.3g (55mmol) DCC, dropwise low-temp reaction half an hour, stirred overnight at room temperature, cross and filter white precipitate DCU, organic phase use successively 10% citric acid, saturated aqueous common salt, 4% sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous Na ₂sO ₄dry, decompression is spin-dried for dichloromethane solvent, give light yellow oil, then adds ethyl acetate solvent, stand at low temperature, adularescent precipitation DCU separates out, and cross and filter DCU, decompression is spin-dried for ethyl acetate, add ethyl acetate stand at low temperature again, so repeatedly remove the DCU of the overwhelming majority several times, obtain white solid 17.5 finally by silica gel column chromatography, yield 83%.

step 2)

N ₂under protective condition, be dissolved in anhydrous THF by upper step raw material 12.7g (30mmol), cryosel bath temperature control less than 0 DEG C, carefully adds NaBH ₄2.4g (30mmol), careful dropping 3.81g I after half an hour ₂tHF solution, after being added dropwise to complete, continue reaction 2 hours, reflux 48 hours, TLC detection reaction process.

After reaction terminates, carefully add saturated NH ₄the Cl aqueous solution, 50 DEG C of bubble-free are released, and add 2N NaOH and dissolve insoluble precipitation, water layer methyl tertiary butyl ether extracts, and merge organic phase, anhydrous Na ₂sO ₄drying, silica gel column chromatography obtains white powder intermediate 3i and is about 9.2g, yield 75%.

step 3)

Cryosel bath temperature control less than 0 DEG C, is dissolved in a small amount of CH by previous step gained white solid 9.18g ₂cl ₂in, carefully add the 4N HCl/EtOAc solution that 50mL is ice-cold, 0-4 DEG C is reacted 2 hours, and a large amount of white precipitate is separated out, and filters intermediate 3ii is about 7.6g, yield 97%.

embodiment 1

reaction process

step 1)

Temperature control less than-15 DEG C, is dissolved in intermediate 2iv 328mg in the anhydrous THF of 5mL, carefully adds 110 μ L N-methylmorpholines, then adds 140 μ L isobutyl chlorocarbonates.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, room temperature reaction 2h, concentrating under reduced pressure desolventizing at-15 DEG C.Residue is dissolved in 25mL ethyl acetate, uses 5%NaHCO ₃, after water, 1NHCl and each 25mL of water wash successively, anhydrous Na ₂sO ₄drying, silica gel column chromatography obtains white solid 3iii321mg, yield 48%.

step 2)

Intermediate 3iii 440mg is dissolved in methylene dichloride, ice bath temperature control less than 0 DEG C, add the 2N HCl/EtOAc solution that 10mL is ice-cold, low-temp reaction half an hour, room temperature continues stirring 2 hours, and white solid is separated out, complete through TLC detection reaction, collecting by filtration white solid 215mg, yield 98%.

Above two step total recoverys 47%.Yield described in all embodiments all refers to condensation and deprotection two step total recovery below.

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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, 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; unlike the use of (R)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, uses (R)-N-styroyl thiazolidine-4-carboxamide 236mg to replace 3ii.Yield 28%.

¹H-NMR(400 MHz，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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-sec.-propyl-acetic acid 302mg replaces 2iv, uses (R)-N-substituted benzylthiazolidine-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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) the propanoylamino)-2-tertiary butyl-acetic acid 302mg replaces 2iv, 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 unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-sec.-propyl-acetic acid 302mg replaces 2iv.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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) the propanoylamino)-2-tertiary butyl-acetic acid 302mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, 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 unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv.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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-sec.-propyl-acetic acid 302mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-cyclohexyl-acetic acid 342mg replaces 2iv, 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; unlike the use of (R)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-cyclohexyl-acetic acid 342mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-sec.-propyl-acetic acid 302mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) the propanoylamino)-2-tertiary butyl-acetic acid 316mg replaces 2iv, 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; unlike the use of (R)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-cyclohexyl-acetic acid 342mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) the propanoylamino)-2-tertiary butyl-acetic acid 302mg replaces 2iv, uses (R)-N-substituted benzylthiazolidine-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, replaces 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) acetylamino)-3 Methylbutanoic acid 274mg.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 unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) the propanoylamino)-2-tertiary butyl-acetic acid 302mg replaces 2iv.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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, 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, replaces 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg.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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, use (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; unlike the use of (S)-2-, ((S)-2-(2-(tert-Butoxycarbonylmethyl is amino) propanoylamino)-2-cyclohexyl-acetic acid 342mg replaces 2iv, 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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, use (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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, 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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, use (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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, 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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, use (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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, 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; replace 2iv unlike the use of (S)-2-(2-(t-butoxycarbonyl amino) propanoylamino) acetic acid 246mg, use (R)-N-benzyl-N-Cyclohexylthiazolidine-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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, uses (R)-N-benzyl-N-Cyclohexylthiazolidine-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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-sec.-propyl-acetic acid 288mg replaces 2iv, 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; unlike the use of (S)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, uses (R)-N-benzyl-N-Ben Yi Ji oxazolidine-4-carboxamide 310mg to replace 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; unlike the use of (R)-2-, ((S)-2-(2-(t-butoxycarbonyl amino) propanoylamino)-2-cyclohexyl-acetic acid 328mg replaces 2iv, uses (R)-N-benzyl-N-Ben Yi Ji oxazolidine-4-carboxamide 310mg to replace 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; unlike the use of (2S; 3S)-2-((S)-2-(t-butoxycarbonyl amino) propanoylamino)-3-(propyl group-2-alkynyloxy base) butyric acid 328mg replaces 2iv, uses (R)-N-to replace 3ii to methyl-benzyl thiazolidine-4-carboxamide 236mg.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 inhibit activities measures

By the fluorescent tracer (SM-F2, IAPs inhibitor) of fixed concentration and target proteins matter composition mixture, wherein protein concn constantly increases until saturated.By the monitoring to the total fluorescence polarization intensity of this mixture, thus measure SM-F2 respectively in conjunction with the equilibrium dissociation constant (K of XIAP-BIR3 (residue 241-356) and cIAP1-BIR3 (residue 253-363) _d).Fluorescence polarization intensity level is at 96-hole fluoroscopic examination microwell plate (Mierofluor 2, the extremely low background of black, round bottom) the super microplate reader (TecanU.S. of (Thermo Scientific) middle use, Research Triangle Park, NC) measure.To the test damping fluid in each hole (containing 100mM dipotassium hydrogen phosphate, pH 7.5,100 μ g/ml bovineγ-globulins, 0.02% Sodium Azide, 4%DMSO, Invitrogen company) in add concentration and be respectively the target proteins that the 2nM combination of XIAP-BIR3 (measure with) and the 1nM combination of cIAP1-BIR3 (measure and) SM-F2 and corresponding concentration constantly raises, the final volume of system is 125 μ L.By the shake incubated at room temperature 3 hours and gently of 96-orifice plate to guarantee to reach balance.In excitation wavelength, to be 485nm and emission wavelength be that 530nm place measures polarizability, represents measured value with the milli unit (mP) that polarizes.Use Graphpad Prism 5.0 software (Graphpad Software, San Diego, CA) by the function calculated equilibrium dissociation constant (K of matching S type (sigmoidal) dose-dependant FP increased value as protein concentration _d).

The K of inhibitor is measured by the dose-dependant competion experiment of inhibitor _ivalue.In this experiment, dilute the concentration of 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) competing property of target proteins combine.The DMSO solution of the test-compound of 5 μ L different concns and 120 μ L are contained the buffered soln of the target proteins/SM-F2 mixture of hatching in advance (containing 100mM dipotassium hydrogen phosphate, pH 7.5,100 μ g/ml bovineγ-globulins, 0.02% Sodium Azide, 4%DMSO, Invitrogen company) join in 96-orifice plate, incubated at room 3 hours is also shaken gently.For measuring test-compound and the SM-F2 competitive binding with XIAP-BIR3, in system, the ultimate density of XIAP-BIR3 and SM-F2 is respectively 10nM and 2nM; And for the combination of same cIAP1-BIR3, in system, the ultimate density of cIAP1-BIR3 and SM-F2 is respectively 3nM and 1nM.In each block 96-orifice plate, all containing negative control group and positive controls, negative control group is only containing target proteins/SM-F2 mixture (inhibiting rate is equivalent to 0%), and positive controls is only containing free SM-F2 (inhibiting rate is equivalent to 100%).The mensuration of FP value is identical with the method for foregoing description.The IC of test-compound ₅₀determined by the nonlinear regression and fitting of competition curve.The K of competitive inhibitor _iobtained by Equation for Calculating below:

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

In formula, [I] ₅₀represent inhibitor concentration during 50% suppression, [L] ₅₀tagged ligand (SM-F2) concentration when being 50% suppression, [P] ₀protein concentration when being 0% suppression, K _dit is equilibrium dissociation constant.

XIAP-BIR3 and cIAP1-BIR3 inhibit activities measurement result is in table 1.

Table 1:XIAP-BIR3 and cIAP1-BIR3 inhibit activities measurement result

pharmacology test example 2: adopt tetrazolium bromide (MTT) method to determine the target compound of various synthesis in vitro to the survival restraining effect of 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 is 1 × 10 ⁵individual/hole, joins 96 orifice plates, and every hole adds celliferous nutrient solution 200 μ l, puts 37 DEG C, 5%CO ₂after incubator hatches 16h, add the target compound of the various synthesis of 100 μMs successively, simultaneously using DMEM substratum as blank group, after dosing 48h, add MTT (5mg/ml) 20 μ l/ hole, 37 DEG C, 5%CO ₂after incubator hatches 4h, abandon supernatant, every hole adds DMSO 150 μ l and measures absorbancy OD value in 490nm wavelength place, each concentration replicate(determination) 4 hole.

2. to the survival restraining effect of cervical cancer cell:collect logarithmic phase cell, adjustment concentration of cell suspension, every hole adds 200ul, and bed board makes cell to be measured adjust density to 10000/ hole, (the aseptic PBS of marginal pore fills).Blank is set, positive control and negative control.5%CO ₂, hatch for 37 DEG C, be paved with (96 hole flat underside) at the bottom of hole to cell monolayer, add finite concentration medicine.5%CO ₂, hatch 48 hours for 37 DEG C, observe under inverted microscope.Every hole adds 20ul MTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4h.Stop cultivating, carefully suck nutrient solution in hole.Every hole adds 150 μ l dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on shaking table, crystallisate is fully dissolved.The light absorption value in each hole is measured 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, by following formulae discovery growth inhibition ratio (IR).

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

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

Claims (8)

1. the compound of general formula I:

And isomer, pharmacologically acceptable salts, wherein:

X is-S-;

Y is-CH ₂-;

R ¹be selected from:

1)-H，

2)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted;

R ²be selected from:

1)-H，

2)-C ₁-C ₆alkyl,

R ³be selected from:

1)-H，

2)-C ₁-C ₆alkyl,

3)-C ₃-C ₈cycloalkyl,

R ⁴and R ⁴⁰⁰be selected from independently of one another:

1)-H，

R ⁵and R ⁵⁰⁰be selected from independently of one another:

1)-H，

R ⁶be selected from:

1)-NR ¹¹R ¹²，

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 ₁-C ₆alkyl)-Ar ¹,

Wherein,

Ar ¹be phenyl, it is optionally selected from following group gets by one or more

Generation:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃。

2. the compound of claim 1, wherein, R ³connect carbon atom can for any optical configuration.

3. formula Id compound:

And isomer, pharmacologically acceptable salts, wherein R ¹, R ², R ³as the definition of the compound of claim 1 mutual-through type I, R ⁸and R ⁹be selected from independently of one another:

1)-H，

2)-(C ₁-C ₆alkylidene group) _0-3-phenyl, phenyl wherein is optionally selected from-C by one or more ₁-C ₄the group of alkyl, halogen replaces,

3)-C ₁-C ₆alkyl, it is optionally by one or more halogen substiuted,

4)-C ₃-C ₈cycloalkyl, it is optionally by one or more halogen substiuted,

5)-C ₂-C ₆thiazolinyl, it is optionally by one or more halogen substiuted, and

6)-C ₂-C ₆alkynyl, it is optionally by one or more halogen substiuted.

4. formula If compound:

And isomer, pharmacologically acceptable salts, wherein:

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

Ar ²be phenyl, it is optionally selected from following group replaces by one or more:

1) halogen,

2) nitro,

3) cyano group,

4)-CF ₃。

5. the compound of general formula I:

And isomer, pharmacologically acceptable salts, wherein:

X is-S-;

Y is-CH ₂-;

R ¹be selected from :-H ,-C ₁-C ₄alkyl;

R ²be selected from :-H ,-C ₁-C ₄alkyl;

R ³be selected from :-H ,-C ₁-C ₆alkyl ,-C ₃-C ₈cycloalkyl ,-(C ₁-C ₆alkyl)-OR ⁸, wherein R 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 ⁶-NR ¹¹r ¹², wherein R 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, wherein Ar ¹optionally by one or more phenyl being selected from following group and replacing: halogen, nitro, cyano group ,-CF ₃, wherein R ⁸be selected from :-H ,-(C ₁-C ₄alkylidene group) _0-3-phenyl, phenyl wherein is optionally selected from-C by one or more ₁-C ₄the group of alkyl and halogen replaces, optionally by the-C of one or more halogen substiuted ₁-C ₄alkyl.

6. compound, it is selected from:

And isomer, pharmacologically acceptable salts.

7. a pharmaceutical composition, it comprises the compound of any one of claim 1-6 treating and/or preventing significant quantity and optional pharmaceutically acceptable carrier or vehicle.

8. the compound of any one of claim 1-6 is for the preparation of the purposes treated and/or prevented in the medicine of the disease relevant to XIAP-BIR3 or cIAP1-BIR3 overexpression, and wherein said disease is selected from ovarian cancer and cervical cancer.