CN1771050A

CN1771050A - Macrocyclic hepatitis c serine protease inhibitors

Info

Publication number: CN1771050A
Application number: CNA2004800092686A
Authority: CN
Inventors: 苗振伟; 孙颖; 吴新和; S·纳卡吉马; 许国友; 柯日新; 王喆
Original assignee: Enanta Pharmaceuticals Inc
Current assignee: Enanta Pharmaceuticals Inc
Priority date: 2003-02-07
Filing date: 2004-02-06
Publication date: 2006-05-10
Also published as: WO2004072243A2; KR20050111585A; CA2515216A1; AU2004211637B2; KR100940619B1; JP2007524576A; EP1590442A4; EP1590442A2; AU2004211637A1; AU2004211637C1; WO2004072243A3

Abstract

The present invention relates to compounds of Formula (I, II or III), or a pharmaceutically acceptable salt, ester, or prodrug, thereof: (I), (II), (III), wherein W is a substituted or unsubstituted heterocyclic ring system. The compounds inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

The macrocyclic hcv inhibitors of hepatitis C serine protease

The cross reference of related application

The application requires the benefit of priority of following application: U.S. Provisional Application _ _ (transferring US 10/365,854 to), apply on February 13rd, 2003; _ _ (transfers US10/360 to, and 947), apply on February 7th, 2003; _ _ (transfers US 10/384,120 to), on March 7th, 2003 application, more than full content of each application be attached to this paper by reference.

Technical field

The present invention relates to novel macrocyclic compound, they have anti-hepatitis c virus (HCV) activity, and can be used for treating the HCV infection.More particularly, the method that the present invention relates to macrocyclic compound, comprises such compound compositions, utilizes their method and prepare described chemical compound.

Background of invention

HCV is the main cause of non-A non-B hepatitis, all is a serious day by day public health problem in developed country and developing country.Estimating that the whole world surpasses 200 million people's HCV infection, almost is 5 times of infected person immunodeficiency virus (HIV) number.Because the chronicity rate height of HCV infected patient, thus form liver cirrhosis, subsequently develop into hepatocarcinoma and latter stage hepatopathy risk very high.In western countries, HCV is the common cause of hepatocarcinoma and needs of patients liver transplantation.

In the exploitation of anti-HCV therapy, there is considerable obstacle, the genetic diversity of the persistence, virus that includes but not limited to virus when the host duplicates, high rate that virus forms the drug resistance mutant, lacks reproducible infection cultivating system and HCV duplicates and pathogenetic small animal model.As a rule, in view of the infection of the gentle course of disease and the complex biological feature of liver, carefully whether consideration uses antiviral agents, because produce very big side effect probably.

The Therapeutic Method that has only two kinds of HCV to infect at present goes through to use.Original therapeutic scheme is usually directed to intravenous and gives interferon-' alpha ' (IFN-α) 3-12 month, and newly approved second filial generation therapy relates to IFN-α and conventional anti-viral nucleoside analogies (as ribavirin) therapeutic alliance.All there is the relevant side effect of interferon in these two kinds of treatments, and the effect that anti-HCV infects is low.Because existing therapy toleration difference and usefulness are very low, so be necessary to develop the effective antiviral that treatment HCV infects.

In patient crowd, major part is chronic infection and asymptomatic, acatalepsia, and the side effect of active drug must significantly be less than the side effect of existing therapy.A kind of proteolytic enzyme of hepatitis C non-structural protein-3 (NS3) is that viral polyprotein of processing and the virus replication that causes thus are necessary.Although exist a large amount of HCV to infect relevant virus variation body, still highly preserve in NS3 proteinase activity site, thus its inhibition is become a kind of attractive intervention pattern.Recently such viewpoint has been supported in the successful treatment of HIV: in anti-HCV, be a crucial target to the inhibition of NS3 with protease inhibitor.

HCV is a kind of flaviviridae (flaviridae) RNA viruses.The HCV genome is comprised the single stranded RNA molecule of being made up of about 9600 base pairs by peplos.Its coding is by about 3010 polypeptide that aminoacid is formed.

The HCV polyprotein is processed as 10 peptides with difference in functionality by virus and host's peptidase.Three kinds of structural protein C, E1 and E2 are arranged.The proteic Unknown Function of P7 is made up of highly unstable sequence.6 kinds of non-structural proteins are arranged.NS2 is a kind of zinc dependency metalloproteases, works in bound fraction NS3 albumen.NS3 comprises two kinds of catalysiss (it and bonded NS2 are divided to be opened): the serine protease function of N-end, it needs cofactor NS4A, the ATP-ase-dependency helicase function of carboxyl terminal.NS4A is a kind of non-covalent cofactor of combining closely of serine protease.

NS3.4A protease participates in four sites of the viral polyprotein of cutting.The NS3-NS4A cracking is the cracking of autocatalysis type cis.Its excess-three kind hydrolyzing N S4A-NS4B, NS4B-NS5A and NS5A-NS5B are trans hydrolysis.NS3 is the serine protease that belongs to chymotrypsin-like proteinase on a kind of structure.Though the NS serine protease itself has proteolytic activity, with regard to the cracking of catalysis polyprotein, HCV protease is not a kind of effective enzyme.Confirmed must NS4A albumen center hydrophobic region to strengthen this effect.As if NS3 albumen and NS4A formation complex is that the processing incident is necessary, renders a service with the Proteolytic enzyme that strengthens all sites.

The exploitation antiviral drugs general strategy be enzyme (the comprising NS3) inactivation that makes encoding viral, and these enzymes virus replication is necessary just.S.Tan, A.Pause, Y.Shi, N.Sonenberg, Hepatitis C Therapeutics:Current Status and EmergingStrategies, Nature Rev.Drug Discov., 1,867-881 (2002) has summed up the on going result of exploitation NS3 protease inhibitor.The relevant patent disclosure of the HCV of introduction protease inhibitor synthetic methods has more: WO00/59929 (2000); WO99/07733 (1999); WO00/09543 (2000); WO99/50230 (1999); US5861297 (1999).

Summary of the invention

The present invention relates to new macrocyclic compound, and the method that needs the infection hepatitis C patients of this treatment with described macrocyclic compound treatment.The invention further relates to Pharmaceutical composition, said composition comprises The compounds of this invention or their pharmaceutically acceptable salt, ester or prodrug and pharmaceutically acceptable carrier or excipient.

A kind of chemical compound of following formula I or its pharmaceutically acceptable salt, ester or prodrug:

Wherein:

A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ²,-C (=S)-NH-R ²,-S (O) ₂-R ²,-(C=NR ¹)-R ¹With-(C=NR ¹)-NH-R ¹

G is selected from-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ¹,-(C=O)-R ²,-(C=O)-O-R ¹,-(C=O)-NH-R ¹With-(C=O)-NH-R ²

L do not exist or be selected from-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-,-CF ₂CH ₂-and-CR _x=CR _x-, R wherein _x=H or halogen;

J is 0,1,2,3 or 4;

M is 0,1 or 2;

S is 0,1 or 2;

R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement;

R ²Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement;

R ³And R ⁴Independently be selected from hydrogen, OH, CH separately ₃, CN, SH, halogen, NO ₂, NH ₂, amide, methoxyl group, trifluoromethoxy and trifluoromethyl;

E is-CH=CH-or-CH ₂-CH ₂-;

W replaces or unsubstituted heterocycle ring system.

E is-CH=CH-in an embodiment of the present invention, obtains formula II chemical compound or its pharmaceutically acceptable salt, ester or prodrug:

The same definition above of all the other substituent groups.

E is-CH in an embodiment of the present invention ₂-CH ₂-, obtain formula III chemical compound or its pharmaceutically acceptable salt, ester or prodrug:

The same definition above of all the other substituent groups.

In an embodiment of the present invention, disclosed chemical compound is chemical compound or its pharmaceutically acceptable salt, ester or the prodrug of formula II and III:

Wherein

W is selected from

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-;

Q ' does not exist or is selected from-CH ₂-and-NH-;

Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement;

The same definition above of all other substituent groups.

In an embodiment of the present invention, disclosed chemical compound is chemical compound or its pharmaceutically acceptable salt, ester or the prodrug of formula II and III, wherein

W is selected from

With

X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement;

The same definition above of all other substituent groups.

In an embodiment of the present invention, disclosed chemical compound is chemical compound or its pharmaceutically acceptable salt, ester or the prodrug of formula II and III, wherein:

W is

With

X, Y and Z independently are selected from H, N ₃, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl, alkyl amino, dialkyl amido, C ₁-C ₆Alkynyl, the alkynyl that replaces, aryl, the aryl that replaces,-S-aryl, the aryl that-S-replaces,-O-aryl, the aryl that-O-replaces, the NH-aryl, the aryl that NH-replaces, ammonia diaryl base, two heteroaryl aminos, aryl alkyl, the aryl alkyl that replaces, heteroaryl, the heteroaryl that replaces,-S-heteroaryl, the heteroaryl that-S-replaces,-O-heteroaryl, the heteroaryl that-O-replaces,-NH-heteroaryl, the heteroaryl that-NH-replaces, heteroaryl alkyl, the heteroaryl alkyl that replaces, the Heterocyclylalkyl of Heterocyclylalkyl and replacement; Perhaps, X and Y or Y and the carbon atom that Z is connected with them constitute the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement;

Others of the present invention have:

According to the chemical compound of this paper any structure formula, wherein W is replaced by one or more substituent groups, and described substituent group independently is selected from following (a) and (b), (c), (d) and any group (e) separately:

(a) thiazolinyl; Alkoxyl; Alkoxyalkyl; Alkyl; Alkyl amino; Alkylaryl; Alkyl sulphonyl; Alkynyl; Amide; Optional by C ₁-C ₆The mono-substituted acylamino-of alkyl; Aryl; The aromatic yl silane terephthalamide yl alkyl; Aryl alkyl; The arylamino alkyl; Aryloxy alkyl; Aryl sulfonyl; Cycloalkyloxy; Cycloalkyl; Dialkyl amido; Dialkyl aminoalkyl; The ammonia diaryl base alkyl; Haloalkyl; Heteroaryl; Heteroaryl alkyl; Heterocyclic radical; Heterocyclylalkyl; The Heterocyclylalkyl alkyl; Alkylthio; The alkyl monosubstituted amino alkyl; Sulfonyl; (low alkyl group) sulfonyl; Haloalkyl; Carboxyl; Amide; (low alkyl group) amide; Optional by C ₁-C ₆The heterocyclic radical that alkyl replaces; Whole haloalkyl; Sulfonyl; Alkylthio; Urea; C (=O)-R ¹¹OC (=O) R ¹¹C (=O) O-R ¹¹C (=O) N (R ¹¹) ₂C (=S) N (R ¹¹) ₂SO ₂R ¹¹NHS (O ₂) R ¹¹N (R ¹²) ₂N (R ¹²) C (=O) R ¹¹Wherein above-mentioned each substituent group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl, whole haloalkyl;

(b) C ₇-C ₁₄Aralkyl; C ₂-C ₇Cycloalkyl; C ₆-C ₁₀Aryl; Heterocyclic radical; (low alkyl group)-heterocyclic radical; Wherein each aralkyl, cycloalkyl, aryl, heterocyclic radical or (low alkyl group)-heterocyclic radical can be chosen wantonly by R ⁶Replace; R ⁶Be halogen, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, C ₁-C ₆Alkoxyl, C ₃-C ₆Cycloalkyloxy, NO ₂, N (R ⁷) ₂, NH-C (O)-R ⁷Or NH-C (O)-NHR ⁷, R ⁷Be H, C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl; Perhaps R ⁶Be NH-C (O)-OR ⁸, R ⁸Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

(c) N (R ⁵) ₂, NH-C (O)-R ⁵Or NH-C (O)-NH-R ⁵, R wherein ⁵Independent is H, C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl, C ₆Or C ₁₀Aryl, C ₇-C ₁₄Aralkyl, heterocyclic radical or (low alkyl group)-heterocyclic radical;

(d) NH-C (O)-OR ⁸, R wherein ⁸Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

(e) formoxyl; Halogen; Hydroxyl; NO ₂OH; SH; Halogen; CN;

Wherein

Each R ¹¹Independent is H, OH, alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl, heteroaryl alkyl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl amino, dialkyl amido, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl, ammonia diaryl base alkyl, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl;

Each R ¹²Independent is H, formoxyl, alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl alkyl, heteroaryl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl or ammonia diaryl base alkyl, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl;

The chemical compound of this paper any structure formula, wherein W is selected from:

(a) contain 5-16 annular atoms and maximum 4 annular atomses and be selected from the assorted monocycle of heteroatomic aliphatic of O, N and S, assorted bicyclo-or assorted three ring ring systems, wherein said ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

(b) contain 5-16 annular atoms and maximum 4 annular atomses and be selected from the assorted monocycle of heteroatomic aromatics of O, N and S, assorted bicyclo-or assorted three ring ring systems, wherein said ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

Wherein:

Each R ¹⁰Independent is alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl, heteroaryl alkyl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl amino, dialkyl amido, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl, ammonia diaryl base alkyl, heteroaryl or urea, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl; C (=O)-R ¹¹, OC (=O) R ¹¹, C (=O) O-R ¹¹, C (=O) N (R ¹¹) ₂, C (=S) N (R ¹¹) ₂, SO ₂R ¹¹, NHS (O ₂) R ¹¹, N (R ¹²) ₂And N (R ¹²) C (=O) R ¹¹

The chemical compound of this paper any structure formula; wherein W contains 5-16 annular atoms and maximum 4 annular atomses to be selected from the assorted monocycle of heteroatomic aliphatic of O, N and S, assorted bicyclo-or assorted three ring ring systems, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

The chemical compound of this paper any structure formula; wherein W contains the assorted monocycle ring system of heteroatomic aliphatic that 5-7 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 5 annular atomses and 1-2 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement is selected from pyrrolidines, pyrazoles alkanes, pyrrolin class, Tetramethylene sulfide class, dihydro-thiophene class, tetrahydrofuran derivatives, dihydrofuran class, imidazolines, imidazolidine class, pyrazoline class, tetrahydro-pyrazole class and oxazoline class;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 6 annular atomses and 1-2 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement is selected from pyridines, piperidines, dihydropyridines, tetrahydropyridine class, dihydropyran class, Pentamethylene oxide. class, dioxane, piperazines, dihydropyridine, tetrahydropyrimidine class, perhydrogenate pyrimidine, morpholine, thioxane and thiomorpholine;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 7 annular atomses and 1-2 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aliphatic of wherein said optional replacement are selected from methylene imine and thiophene ring in heptan;

The chemical compound of this paper any structure formula; wherein W contains the assorted bicyclo-ring system of heteroatomic aliphatic that 5-16 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

The chemical compound of this paper any structure formula, the assorted bicyclo-ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 8-12 annular atoms and 1-4 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted bicyclo-ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 8-12 annular atoms and 1-2 annular atoms are selected from O and N;

The chemical compound of this paper any structure formula; wherein W contains 5-16 annular atoms and maximum 4 annular atomses to be selected from the assorted monocycle of heteroatomic aromatics of O, N and S, assorted bicyclo-or assorted three ring ring systems, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

The chemical compound of this paper any structure formula, wherein W contains the assorted monocycle ring system of heteroatomic aromatics that 5-7 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 5 annular atomses and 1-2 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement is selected from pyroles, pyrazoles, porphyrin class, furans, thiophene-based, pyrazoles, imidazoles, oxazole Lei, oxadiazole class, isoxazole, thiazoles, thiadiazole and isothiazole class.

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 6 annular atomses and 1-3 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement is selected from pyridines, miazines, pyrazine class, pyrans class and triazines;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 5 annular atomses and 3-4 annular atoms are selected from O, N and S;

The chemical compound of this paper any structure formula, the assorted monocycle ring system of the aromatics of wherein said optional replacement is triazolyl or tetrazole radical;

The chemical compound of this paper any structure formula; wherein W contains the assorted bicyclo-ring system of heteroatomic aromatics that 8-12 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

The chemical compound of this paper any structure formula, the assorted bicyclo-ring system of the aromatics of wherein said optional replacement is selected from adenine kind, Azabenzimidazole-based, Azaindoles, benzimidazole, benzo isothiazole, benzofurans, benzo-isoxazole Benzooxazole kind (benzooxazoles), the diazosulfide class, benzothiazoles, benzothiophene kind (benzothienes), benzothiophene kind (benzothiophenes) Benzooxazole kind (benzoxazoles), carbazoles, the cinnoline class, the guanine class, imidazopyridine, the indazole class, indoles, isoindoles, iloquinoline derivative, the phthalazines class, the purine class, Pyrrolopyridine, quinazoline ditosylate salt, quinolines, quinoxaline, benzo-thiophene class and xanthine;

The chemical compound of this paper any structure formula; wherein W contains the assorted three ring ring systems of heteroatomic aromatics that 10-16 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

The chemical compound of this paper any structure formula, the assorted three ring ring systems of the aromatics of wherein said optional replacement are selected from carbazoles, biphenyl benzofuran, psoralen class, dibenzothiophen class, azophenlyene class, thianthrene class, phenanthroline class, phenanthridines class.

Other embodiment has formula II chemical compound:

Formula II

Wherein:

A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ¹,-C (=S)-NH--R ²,-S (O) ₂-R ²,-C (=NR ¹)-R ¹With-(C=NR ¹)-NH-R ¹

G is selected from-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ²,-(C=O)-O-R ¹With-(C=O)-NH-R ²

W is selected from

With

Q ' does not exist or is selected from-CH ₂-and-NH-;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ²Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement;

R ³And R ⁴Independently be selected from hydrogen and methyl separately.

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and O-R ¹,

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

Below be other embodiment:

The chemical compound of a kind of Formula Il I:

Formula III

Wherein

A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹, C (=O)-NH-R ²,-C (=S)-NH-R ²,-S (O) ₂-R ²,-(C=NR ¹)-R ¹With-(C=NR ¹)-NH-R ¹

W is selected from

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-, N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-;

Q ' does not exist or is selected from-CH ₂-and-NH-;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately;

The chemical compound of more than one formula IIIs, wherein:

A is (C=O)-O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O) the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

A kind of chemical compound of Formula Il:

Formula II

Wherein

W is selected from

With

Wherein X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas II, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

J＝3；

M＝s＝1；

R ³And R ⁴Be hydrogen.

Other embodiment has following formula III chemical compound:

Formula III

Wherein

L do not exist or be selected from-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-,-CF ₂CH ₂-and-CR _x=CR _x-, R wherein _x=H or halogen;

W is selected from With

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and O-R ¹,

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formula IIIs, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of a kind of following formula I V:

Wherein

A be hydrogen ,-(C=O)-R ¹,-(C=O)-O-R ¹,-C (=O)-NH-R ²,-C (=S)-NH-R ²,-S (O) ₂-R ²,-(C=NR ¹)-R ¹Or-(C=NR ¹)-NH-R ¹

G is-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ²,-(C=O)-O-R ¹Or-(C=O)-NH-R ²

L is-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-,-CF ₂CH ₂-or-CR _x=CR _x-, R wherein _x=H or halogen;

X, Y and Z independently are selected from hydrogen, N ₃, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl, alkyl amino, dialkyl amido, C ₁-C ₆Alkynyl, the alkynyl that replaces, aryl, the aryl that replaces,-S-aryl, the aryl that-S-replaces,-O-aryl, the aryl that-O-replaces, the NH-aryl, the aryl that NH-replaces, ammonia diaryl base, two heteroaryl aminos, aryl alkyl, the aryl alkyl that replaces, heteroaryl, the heteroaryl that replaces,-S-heteroaryl, the heteroaryl that-S-replaces,-O-heteroaryl, the heteroaryl that-O-replaces,-NH-heteroaryl, the heteroaryl that-NH-replaces, heteroaryl alkyl, the heteroaryl alkyl that replaces, the Heterocyclylalkyl of Heterocyclylalkyl and replacement; Perhaps, X and Y or Y and the carbon atom that Z is connected with them constitute the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ¹Be hydrogen, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl or replacement;

R ²Be hydrogen, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl or replacement;

R ³And R ⁴Independent separately is hydrogen or methyl;

The chemical compound of more than one formulas IV, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas IV, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of a kind of following formula V:

Wherein

L do not exist or for-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-,-CF ₂CH ₂-or-CR _x=CR _x-, R wherein _x=H or halogen-;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independent separately is hydrogen or methyl;

The chemical compound of more than one formulas V, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen;

The chemical compound of more than one formulas V, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

Below be other embodiment:

Formula II that this paper introduces or the chemical compound of III, wherein:

A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ²,-C (=S)-NH--R ²With-S (O) ₂-R ²G is selected from-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ¹,-(C=O)-O-R ¹With-(C=O)-NH-R ¹L do not exist or be selected from-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-and-CF ₂CH ₂-; W is selected from

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=0,1,2,3 or 4; M=0,1 or 2; S=0,1 or 2; R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; R ²Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; R ³And R ⁴Independently be selected from hydrogen and methyl separately;

Formula II chemical compound, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is

With Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

Formula II chemical compound, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist;

W is

The chemical compound of formula II, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is

With Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen; The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is

With Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen.

Below be other embodiment:

The chemical compound of formula II or III, wherein A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ²,-C (=S)-NH-R ²With-S (O) ₂-R ²G is selected from-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ²,-(C=O)-O-R ¹With-(C=O)-NH-R ²L does not exist or is selected from-S-, SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-and-CF ₂CH ₂-; W is selected from With

X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=0,1,2,3 or 4; M=0,1 or 2; S=0,1 or 2; R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; R ²Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; R ³And R ⁴Independently be selected from hydrogen and methyl separately;

The chemical compound of formula II, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is selected from

With

X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is selected from

Or

The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is

The chemical compound of formula III, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is selected from

With X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is selected from Or X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

Other embodiment has the chemical compound of formula IV or V:

Wherein A be H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ²,-C (=S)-NH-R ²Or-S (O) ₂-R ²G is-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ²,-(C=O)-O-R ¹Or-(C=O)-NH-R ²L do not exist or for-S-,-SCH ₂-,-SCH ₂CH ₂-,-S (O) ₂-,-S (O) ₂CH ₂CH ₂-,-S (O)-,-S (O) CH ₂CH ₂-,-O-,-OCH ₂-,-OCH ₂CH ₂-,-(C=O)-CH ₂-,-CH (CH ₃) CH ₂-,-CFHCH ₂-or-CF ₂CH ₂-; X, Y and Z independently are selected from H, N ₃, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl, alkyl amino, dialkyl amido, C ₁-C ₆Alkynyl, the alkynyl that replaces, aryl, the aryl that replaces,-S-aryl, the aryl that-S-replaces,-O-aryl, the aryl that-O-replaces, the NH-aryl, the aryl that NH-replaces, ammonia diaryl base, two heteroaryl aminos, aryl alkyl, the aryl alkyl that replaces, heteroaryl, the heteroaryl that replaces,-S-heteroaryl, the heteroaryl that-S-replaces,-O-heteroaryl, the heteroaryl that-O-replaces,-NH-heteroaryl, the heteroaryl that-NH-replaces, heteroaryl alkyl, the heteroaryl alkyl that replaces, the Heterocyclylalkyl of Heterocyclylalkyl and replacement; Perhaps, X and Y or Y and the carbon atom that Z is connected with them constitute the heteroaryl of aryl, heteroaryl or the replacement of aryl, replacement; J=0,1,2,3 or 4; M=0,1 or 2; S=0,1 or 2; R ¹Be H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl or replacement; R ²Be H, C ₁-C ₆Alkyl, C ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, alkyl amino, dialkyl amido, arylamino, ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl or replacement; R ³With and R ⁴Independent separately is hydrogen or methyl;

The chemical compound of formula IV, wherein A be-(C=O)-O-R ¹G is a hydroxyl; L does not exist; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula IV, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula V, wherein A be-(C=O)-O-R ¹L does not exist; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula V, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; J=3; M=s=1; R ³And R ⁴Be hydrogen.

Be the chemical compound of formula I on the other hand, wherein W is

Wherein V, X, Y and Z independently are selected from separately:

A)-C ₁-C ₆Alkyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

B)-C ₂-C ₆Thiazolinyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

C)-C ₂-C ₆Alkynyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

D) aryl;

E) aryl of Qu Daiing;

F) heteroaryl;

G) heteroaryl of Qu Daiing;

H) Heterocyclylalkyl; Or

I) Heterocyclylalkyl of Qu Daiing;

Perhaps, V and X, X and Y or Y constitute with carbon atom that Z is connected with them and are selected from following annulus: the Heterocyclylalkyl of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

Be the chemical compound of formula I on the other hand, wherein W is

Wherein X, Y and Z independently are selected from separately:

D) aryl;

E) aryl of Qu Daiing;

F) heteroaryl;

G) heteroaryl of Qu Daiing;

H) Heterocyclylalkyl; Perhaps

I) Heterocyclylalkyl of Qu Daiing; Perhaps, Y constitutes with carbon atom that Z is connected with them and is selected from following annulus: the Heterocyclylalkyl of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement.

All the other all substituent groups are listed hereinbefore.

Be the method for preparing this paper formula I chemical compound on the other hand, this method may further comprise the steps:

(i) make following formula VI proline derivative:

Wherein,

P is nitrogen-protecting group group (for example BOC);

L is leaving group (for example halogen, OMs);

R is the optional alkyl that replaces, the optional aralkyl that replaces or the optional heteroarylalkyl that replaces; React with the nucleophilic heterocyclic chemical compound; (ii) the gained chemical compound is converted into the formula I chemical compound that this paper introduces.

Be the method for preparing this paper formula I chemical compound on the other hand, this method may further comprise the steps: (i) make following formula VII chemical compound:

Formula VII

Wherein,

L is leaving group (for example halogen, OMs);

A is nitrogen-protecting group group (for example BOC);

Remaining variables is identical with the definition among the formula I;

React with the nucleophilic heterocyclic chemical compound; (ii) the gained chemical compound is converted into the formula I chemical compound that this paper introduces.

In others, the present invention relates to prepare any structure formula that this paper introduces (formula I-VII for example, each substituent group variable is the definition of any position of this paper) chemical compound or the method for its pharmaceutically acceptable salt, ester or prodrug, this method may further comprise the steps: (i) make nucleophilic form (for example protonated form or the corresponding metal salt form) reaction of proline derivative (comprise and contain the substituent derivant of methanesulfonates) that this paper introduces and heterocyclic compound; (ii) the gained chemical compound is converted into the chemical compound of any structure formula of this paper introduction.In others, described method comprises the midbody compound reaction that one or more this paper are introduced, and perhaps comprises detailed any one that introduce of this paper embodiment and flow process or the dress method of a plurality of step or reagent or combination.

On the other hand, the present invention relates to prepare the method for Pharmaceutical composition, this method comprises mixes the chemical compound of this paper any structure formula or its pharmaceutically acceptable salt, ester or prodrug with pharmaceutically acceptable carrier.

Be the chemical compound of formula VI or VII on the other hand, wherein L is OMs, and A and remaining variables are the definition of (for example I, II, III) in this paper any structure formula.

Detailed Description Of The Invention

First embodiment of the present invention is that above-mentioned formula I chemical compound or its pharmaceutically acceptable salt, ester or prodrug are in conjunction with pharmaceutically acceptable carrier or excipient.

In certain embodiments, chemical compound can be the chemical compound (any substituent group variable can be the definition of any position of this paper) of any structure formula introduced of this paper, and wherein W is selected from following optional substituted aromatic group:

Aromatic group

1H-pyrroles 1H-imidazoles 1H-pyrazoles furan Sai Fen oxazole thiazole isoxazole isothiazole

Pyridine pyridazine pyrimidine pyrazine phthalazines quinoxaline quinazoline quinoline

Cinnoline 1H-pyrrolo-[2,3-b] pyridine 1H-indole 1H-benzimidazole 1H-indazole 7H-purine

Benzothiazole benzoxazole 1H-imidazo [4,5-c] pyridine 1H-imidazo [4,5-b] pyridine 1,3-dihydro-benzimidazolyl-2 radicals-ketone

1,3-dihydro-benzimidazolyl-2 radicals-thioketone 2,3-dihydro-1H-indole 1,3-dihydro-indol-2-one 1H-indole-2,3-diketone 1,3-dihydro-benzimidazolyl-2 radicals-ketone

1H-pyrrolo-[2,3-c] pyridine benzofuran benzos [b] thiophene benzo [d] isoxazole benzo [d] isothiazole

1H-quinoline-2-one-1H-quinoline-4-ketone 1H-quinazoline-4-one

The 9H-carbazole

1H-quinazoline-2-ketone

In another embodiment, described chemical compound can be the chemical compound (any substituent group variable can be the definition of any position of this paper) of any structure formula introduced of this paper, and wherein W is selected from following optional substituted non-aromatic group:

Non-aromatic group

Azacyclopropane azetidine pyrrolidine 4,5-dihydro-1 h-pyrazole pyrazolidine

Imidazolidin-2-one imidazolidine-2-thioketone pyrrolidin-2-one pyrrolidine-2,5-diketone piperidines-2,6-diketone

Piperidines-2-ketone piperazine-2,6-diketopiperazine-2-ketone piperazine morpholine thiomorpholine 1,1-dioxide

Pyrazolidine-3-ketone imidazolidine-2,4-diketone piperidines

Oxolane Pentamethylene oxide. [1,4] diox 1,2,3,6-tetrahydrochysene-pyridine

Another embodiment of the present invention is that the chemical compound of above-mentioned formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the tetrazolium or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is that the chemical compound of above-mentioned formula III or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the tetrazolium or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

The tetrazole radical macrocyclic compound of example and correlation technique of the present invention the US temporary patent application of on February 13rd, 2003 application _ _ open in (transferring US 10/365,854 to).Representative subset of the present invention includes but not limited to:

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen; The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

With

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S--S (O) ₂-and-(C=O)-; Q ' does not exist or is selected from-CH ₂-and-NH-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

Q does not exist or is selected from-CH ₂-,-O-,-NH-,-N (R ¹)-,-S-,-S (O) ₂-and-(C=O)-; Y is selected from H, C ₁-C ₆The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of alkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen; The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is

Representative compounds of the present invention includes but not limited to following chemical compound:

Method and step preparation that following tetrazole radical macrocycle molecule of the present invention is introduced by this paper.Though showed stereochemical structure, the present invention is not limited to illustrated stereochemical structure.Those of ordinary skills are readily appreciated that is that other isomers of these chemical compounds also belongs to the scope of the invention.

Another embodiment of the present invention is that the chemical compound of above-mentioned formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the triazole or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is that the chemical compound of above-mentioned formula III or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the triazole or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

The triazole macrocycle chemical compound of example and correlation technique of the present invention the US temporary patent application of on February 7th, 2003 application _ _ open in (transferring US 10/360,947 to).Representative subset of the present invention includes but not limited to:

With

With

The chemical compound of formula III, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl; The Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl that replaces, heteroaryl alkyl, replacement; G is a hydroxyl; L does not exist; W is selected from

The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is selected from

Or

The chemical compound of formula II, wherein A be-(C=O)-O-R ¹, R ¹Be selected from H, C ₁-C ₆Alkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The Heterocyclylalkyl of the heteroaryl alkyl of the heteroaryl of the aryl alkyl of the aryl of cycloalkyl, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement, Heterocyclylalkyl and replacement; G is a hydroxyl; L does not exist; W is X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(the C=O alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; W is X and Y independently are selected from H, halogen, C ₁-C ₆Alkyl, C ₃-C ₁₂Cycloalkyl ,-CH ₂-alkyl amino ,-CH ₂-dialkyl amido ,-CH ₂-arylamino ,-CH ₂-ammonia diaryl base ,-(C=O)-alkyl amino ,-(C=O)-dialkyl amido ,-(C=O)-arylamino ,-(C=O)-Heterocyclylalkyl of heteroaryl alkyl, Heterocyclylalkyl and the replacement of the heteroaryl of the aryl alkyl of the aryl of ammonia diaryl base, aryl, replacement, aryl alkyl, replacement, heteroaryl, replacement, heteroaryl alkyl, replacement; Perhaps, 4 of the triazole ring that is connected with them of X and Y and 5 carbon atoms constitute and are selected from following annulus: the heteroaryl of the aryl of aryl, replacement, heteroaryl and replacement; J=3; M=s=1; R ³And R ⁴Be hydrogen.

Method and step preparation that following triazole macrocycle molecule of the present invention is introduced by this paper.Though showed stereochemical structure, the present invention is not limited to illustrated stereochemical structure.Those of ordinary skills are readily appreciated that is that other isomers of these chemical compounds also belongs to the scope of the invention.

Another embodiment of the present invention is that the chemical compound of above-mentioned formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the 2H-Pyridazin-3-one or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is that the chemical compound of above-mentioned formula III or its pharmaceutically acceptable salt, ester or prodrug (wherein W is the 2H-Pyridazin-3-one or derivatives thereof) are in conjunction with pharmaceutically acceptable carrier or excipient.

The 2H-Pyridazin-3-one macrocyclic compound of example and correlation technique of the present invention the US temporary patent application of on March 7th, 2003 application _ _ open in (transferring US 10/384,120 to).Representative subset of the present invention includes but not limited to:

The chemical compound of formula II, wherein A be-(C=O)-O-R ¹G is a hydroxyl; L does not exist; J=3; M=s=1; R ³And R ⁴Be hydrogen;

The chemical compound of formula II, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; J=3; M=s=1;

R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-O-R ¹L does not exist; J=3; M=s=1;

R ³And R ⁴Be hydrogen;

The chemical compound of formula III, wherein A be-(C=O)-the O-tert-butyl group; G is a hydroxyl; L does not exist; J=3; M=s=1;

R ³And R ⁴Be hydrogen;

Method and step preparation that following 2H-Pyridazin-3-one macrocycle molecule of the present invention is introduced by this paper.Though showed stereochemical structure, the present invention is not limited to illustrated stereochemical structure.Those of ordinary skills are readily appreciated that is that other isomers of these chemical compounds also belongs to the scope of the invention.

Other chemical compound of the present invention is such formula I, II or the chemical compound of III: the benzimidazolyl of W wherein for replacing, and described benzimidazolyl can be by 1-2 heteroaryl replacement, and each heteroaryl again can be by independent replacement.Such examples for compounds comprises:

According to another embodiment, Pharmaceutical composition of the present invention can further comprise other anti-HCV medicament.The example of anti-HCV medicament includes but not limited to alpha-interferon, beta-interferon, ribavirin and amantadine.

According to another embodiment, Pharmaceutical composition of the present invention can further comprise other HCV protease inhibitor.

According to another embodiment, Pharmaceutical composition of the present invention also can comprise the inhibitor of other target of HCV biocycle, and described target includes but not limited to helicase, polymerase, metalloproteases and internal ribosome entry site (IRES).

According to another embodiment, the present invention includes the method that treatment needs the hepatitis C infection patient of this treatment, the medicinal compound of the present invention or the compositions of the anti-HCV virus of the described patient of this method afford effective dose.Described method may further include and gives other medicine, comprises other antiviral agents or anti-HCV medicine.Other medicines can be united The compounds of this invention or compositions while or sequential administration.Method herein may further include the step that discriminating need be treated the patient of hepatitis C infection.Can subjective (for example health care provider judgement) or objective method discriminating (for example diagnostic test).

The full content of disclosed all lists of references of whole description (comprising patent, patent disclosure, paper, textbook etc.) is attached to this paper by reference.

Definition

Unless explanation is arranged under specific circumstances in addition, otherwise no matter be to use separately or as the part of macoradical more, it is consistent describing using with they routines in the art to give a definition of various term of the present invention and phrase, and is applicable to whole description and claims.

Term " C used herein _x-C _y" use in conjunction with the title of carbon-containing group, being meant that this group comprises x-y carbon atom, x and y are integers.

Term used herein " halogen " and " halogen " are meant the atom that is selected from fluorine, chlorine, bromine and iodine.

Term used herein " alkyl " is meant saturated straight or branched alkyl.For example include but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, neopentyl, n-hexyl, octyl group, decyl, dodecyl.

Term used herein " alkyl of replacement " is meant independent " alkyl " that is replaced by following group of its one or more (for example 1,2 or 3) hydrogen atom: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-C ₁-C ₆-alkyl, OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆Alkyl), SO ₂Aryl, SO ₂Heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " haloalkyl " is meant that one or more hydrogen are selected from the aliphatic straight or branched alkyl of the halogen replacement of bromine, chlorine, fluorine or iodine.

Term used herein " alkylthio " is meant the aliphatic straight or branched alkyl that comprises thiol group, for example (is not limited to) the sulfo-propyl group.

Term " alkoxyl " used herein is meant that alkyl defined above is connected to parent molecule by oxygen atom.The example of alkoxyl includes but not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, tert-butoxy, neopentyl oxygen and positive hexyloxy.

Term used herein " thiazolinyl " is meant that the hydrocarbon with at least one carbon-carbon double bond sloughs the monoradical that a hydrogen atom obtains.Thiazolinyl includes but not limited to for example vinyl, acrylic, cyclobutenyl, 1-methyl-2-butene-1-base etc.

Term used herein " thiazolinyl of replacement " is meant independent " thiazolinyl " that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-(C ₁-C ₆-alkyl), OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-C ₁-C ₆-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " alkynyl " refers to have the triple-linked hydrocarbon of at least one carbon carbon and sloughs the monoradical that a hydrogen atom obtains.Representative alkynyl includes but not limited to for example acetenyl, 1-propinyl, ethyl acetylene base etc.

Term used herein " alkynyl of replacement " is meant independent " alkynyl " that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-(C ₁-C ₆-alkyl), OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " aryl " is meant monocyclic carbocyclic ring or the bicyclic carbocyclic ring ring system with one or two aromatic ring, includes but not limited to phenyl, naphthyl, naphthane, indanyl, indenyl etc.

Term used herein " aryl of replacement " is meant the aryl of the independent above definition that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-(C ₁-C ₆-alkyl), OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " aryl alkyl " is meant the C that connects aryl rings ₁-C ₃Alkyl or C ₁-C ₆Alkyl.Include but not limited to for example benzyl, phenethyl etc.

Term used herein " aryl alkyl of replacement " is meant the aryl alkyl of the independent above definition that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-C ₁-C ₆-alkyl, OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂Aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term " cycloalkyl " is meant from saturated monocycle or bicyclo-carbocyclic compound sloughs the singly-bound group that a hydrogen atom obtains.Include but not limited to for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, dicyclo [2.2.1] heptyl and dicyclo [2.2.2] octyl group.

Term used herein " cycloalkyl of replacement " is meant the cycloalkyl of the independent above definition that is replaced by following group of 1,2 or 3 hydrogen atom: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-(C ₁-C ₆-alkyl), OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " heterocyclic radical " is meant that 1-4 annular atoms is selected from the 3-7 unit ring of N, O and S heteroatomic saturated or unsaturated (comprising aromatics) and sloughs the singly-bound substituent group that a hydrogen atom obtains.Suitable heterocycle example includes but not limited to that oxolane, thiophene, diaza heptan is because of, isoxazole, piperidines, diox, morpholine and pyrimidine." heterocyclic radical " also comprises and the condensed heterocycle of definition herein of one or more other rings (heterocycle or carbocyclic ring).An example is also [4,5-b]-pyridine of thiazole.Although term " heterocycle " has comprised term " Heterocyclylalkyl ", " aliphatic mix monocycle ring system ", " aliphatic mix bicyclo-ring system ", " the assorted three ring ring systems of aliphatic ", " heteroaryl ", " aromatics mix monocycle ring system ", " aromatics mix bicyclo-ring system ", " aromatics mix three encircle ring systems ", " heteroaryl alkyl " usually, but their concrete implication is described hereinafter.

Term used herein " Heterocyclylalkyl " is meant and contains 1-3 bicyclo-or three cyclic groups that independently are selected from heteroatomic non-aromatics 5-, 6-or the 7-unit ring of oxygen, sulfur and nitrogen or contain condensed hexatomic ring, wherein (i) each 5 yuan of rings have 0-1 two key, each 6 yuan of rings have 0-2 two key, (ii) nitrogen and sulfur heteroatom can be chosen wantonly oxidized, (iii) nitrogen heteroatom can be chosen wantonly by quaternized, and (iv) above any heterocycle can fused benzene rings.Representational heterocycle includes but not limited to; Pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl, oxazolidinyl, isoxazole alkyl, morpholinyl, thiazolidinyl, isothiazole alkyl and tetrahydrofuran base.

Term used herein " Heterocyclylalkyl of replacement " is meant the independent Heterocyclylalkyl defined above that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-C ₁-C ₆-alkyl, OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Be meant term used herein " aliphatic mix monocycle ring system " ring system that comprises a non-aromatic ring, non-aromatic ring contain assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.Term " aliphatic mix bicyclo-ring system " is meant the ring system that comprises two fused rings, and one of at least two fused rings are the non-aromatic rings that contains assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.Term " aliphatic assorted three ring ring systems " is meant the ring system that comprises three fused rings, and one of at least three fused rings are the non-aromatic rings that contains assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.As long as should be understood that containing heteroatomic ring is not aromatic ring, then described aliphatic heterocycle ring system can have any saturation (promptly two keys or triple bond).Thus, such as the indoline (it comprises the non-aromatic heterocyclic (being the pyrrolin ring) of fused aromatic carbocyclic ring (being phenyl ring)) and the structure of phthalimide be the example of " aliphatic mix bicyclo-ring system ".

Term used herein " aromatics mix monocycle ring system " is meant an aromatic ring that contains assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.Term " aromatics mix bicyclo-ring system " is meant that the aromatics ring system that contains two fused rings, aromatics ring system comprise assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.Term " the assorted three ring ring systems of aromatics " is meant that the aromatics ring system that contains three fused rings, aromatics ring system comprise assorted (the being non-carbon) atom of at least one ring that is selected from O, N and S.The substituent group atom of aromatic heterocycle ring system can further constitute the fused rings structure of non-aromatics with other atom.Thus, 5,6,7, the 8-tetrahydroisoquinoline is the example of the assorted bicyclo-ring system of aromatics, and 1,2,3, the 4-tetrahydroisoquinoline is the example of the assorted bicyclo-ring system of aliphatic.

Term used herein " heteroaryl " is meant and contains 5-10 annular atoms and at least one annular atoms is selected from S, O and N, all the other annular atomses are the ring-type aromatic group of carbon, this group can be connected to the remainder of molecule by any annular atoms, for example pyridine radicals, pyrazinyl, pyrimidine radicals, pyrrole radicals, pyrazolyl, imidazole radicals, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl group, oxadiazole base, thienyl, furyl, quinolyl, isoquinolyl etc.

Term used herein " heteroaryl of replacement " is meant the heteroaryl of the independent above definition that is replaced by following group of 1-3 hydrogen atom: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-C ₁-C ₆-alkyl, OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆)-alkyl, OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Term used herein " heteroaryl alkyl " is meant the C that connects hetero-aromatic ring ₁-C ₃Alkyl or C ₁-C ₆Alkyl.Include but not limited to for example pyridylmethyl, pyrimidinylethyl etc.

Term used herein " heteroaryl alkyl of replacement " is meant the independent heteroaryl alkyl defined above that is replaced by following group of one or more hydrogen atoms: F, Cl, Br, I, OH, NO ₂, CN, C ₁-C ₆-alkyl-OH, C (O)-C ₁-C ₆-alkyl, OCH ₂-(C ₃-C ₁₂-cycloalkyl), C (O)-aryl, C (O)-heteroaryl, CO ₂-alkyl, CO ₂-aryl, CO ₂-heteroaryl, CONH ₂, CONH-(C ₁-C ₆-alkyl), CONH-aryl, CONH-heteroaryl, OC (O)-(C ₁-C ₆-alkyl), OC (O)-aryl, OC (O)-heteroaryl, OCO ₂-alkyl, OCO ₂-aryl, OCO ₂-heteroaryl, OCONH ₂, OCONH-(C ₁-C ₆-alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁-C ₆-alkyl), NHC (O)-aryl, NHC (O)-heteroaryl, NHCO ₂-alkyl, NHCO ₂-aryl, NHCO ₂-heteroaryl, NHCONH ₂, NHCONH-(C ₁-C ₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl, SO ₂-(C ₁-C ₆-alkyl), SO ₂-aryl, SO ₂-heteroaryl, SO ₂NH ₂, SO ₂NH-(C ₁-C ₆-alkyl), SO ₂NH-aryl, SO ₂NH-heteroaryl, C ₁-C ₆-alkyl, C ₃-C ₆-cycloalkyl, CF ₃, CH ₂CF ₃, CHCl ₂, CH ₂NH ₂, CH ₂SO ₂CH ₃H, C ₁-C ₆Alkyl, haloalkyl, C ₃-C ₁₂The C of cycloalkyl, replacement ₃-C ₁₂The aryl of cycloalkyl, aryl, replacement, aryl alkyl, heteroaryl, heteroaryl alkyl, Heterocyclylalkyl, benzyl, benzyloxy, aryloxy group, heteroaryloxy, C ₁-C ₆-alkoxyl, methoxymethoxy, methoxy ethoxy, amino, benzylamino, arylamino, heteroaryl amino, C ₁-C ₃-alkyl amino, sulfo-, arylthio, heteroarylthio, benzylthio, C ₁-C ₆-alkylthio group or methylthiomethyl.

Should be understood that aryl, heteroaryl, alkyl etc. can further be substituted.

Term used herein " alkyl amino " is meant to have-NH (C ₁-C ₁₂Alkyl) group of structure, wherein C ₁-C ₁₂Alkyl is definition above.Term " dialkyl amido " is meant to have-N (C ₁-C ₁₂Alkyl) ₂The group of structure, wherein C ₁-C ₁₂Alkyl is definition above.Examples of dialkylamino includes but not limited to N, N-dimethylamino, N, N-diethylamino, N, N-Methylethyl amino, piperidyl etc.

Term " ammonia diaryl base " is meant to have-N (aryl) ₂Or-N (aryl of replacement) ₂The group of structure, wherein the aryl of Qu Daiing is definition above.The example of ammonia diaryl base includes but not limited to N, N-diphenyl amino, N, N-dinaphthyl amino, N, N-two (tolyl) amino etc.

Term " two heteroaryl aminos " is meant to have-N (heteroaryl) ₂Or-N (heteroaryl of replacement) ₂The group of structure, wherein the heteroaryl of heteroaryl and replacement is definition above.The example of two heteroaryl aminos includes but not limited to N, N-difuryl amino, N, N-dithiazole alkyl amino, N, N-two (imidazoles) amino etc.

Term used herein " hydroxy-protective group " is meant that the hydroxyl of protecting known in the art is to avoid the unstable chemical part of unwanted reaction in building-up process.After described building-up process, the hydroxy-protective group of Jie Shaoing can be sloughed by selectivity herein.Hydroxy-protective group known in the art is in following document summarized introduction: T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley﹠amp; Sons, New York (1999).The example of hydroxy-protective group comprises benzyloxycarbonyl; 4-nitro benzyloxycarbonyl; 4-bromo-benzyloxy-carbonyl; 4-methoxyl group benzyloxy base carbonyl; methoxycarbonyl; tert-butoxycarbonyl; isopropoxy carbonyl; diphenyl methoxy base carbonyl; 2; 2; 2-trichlorine ethoxy carbonyl; 2-(trimethyl silyl) ethoxy carbonyl; 2-bran oxygen base carbonyl; allyloxy carbonyl; acetyl group; formoxyl; chloracetyl; trifluoroacetyl group; the methoxyl group acetyl group; the phenoxy group acetyl group; benzoyl; methyl; the tert-butyl group; 2; 2; 2-three chloroethyls; 2-trimethyl silyl ethyl; 1; 1-dimethyl-2-acrylic; 3-methyl-3-cyclobutenyl; pi-allyl; benzyl; to the methoxy-benzyl diphenyl methyl; trityl group (trityl); tetrahydrofuran base; methoxy; methylthiomethyl; benzyloxymethyl; 2; 2,2-trichlorine ethoxyl methyl; 2-(trimethyl silyl) ethoxyl methyl; mesyl; p-toluenesulfonyl; trimethyl silyl; triethylsilyl; triisopropyl silicyl etc.Preferred hydroxy-protective group of the present invention have acetyl group (Ac or-C (O) CH ₃), benzoyl (Bn or-C (O) C ₆H ₅) and trimethyl silyl (TMS or-Si (CH ₃) ₃).

Term " hydroxyl of protection " is meant by the hydroxyl of the hydroxy-protective group of above definition protection, comprises for example benzoyl, acetyl group, trimethyl silyl, triethylsilyl, methoxy blocking group.

Term used herein " nitrogen (or amino) blocking group " is meant that the nitrogen groups of protecting known in the art is to avoid the unstable chemical part of unwanted reaction in building-up process.After described building-up process, the nitrogen-protecting group group of Jie Shaoing can be sloughed by selectivity herein.Nitrogen-protecting group known in the art is rolled into a ball in following document summarized introduction: T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley﹠amp; Sons, New York (1999).The example of nitrogen-protecting group group includes but not limited to tert-butoxycarbonyl, 9-fluorenyl methoxy carbonyl, benzyloxycarbonyl etc.

Term used herein " amino of protection " is meant by the amino of the amido protecting group of above definition protection.

Term " nucleophilic heterocyclic chemical compound " is meant the heterocyclic group of nucleophilic form (for example metallic salt form, protonated form), such group can with another molecular reaction, at two intermolecular generation covalent bonds (for example nucleophilic displacement reaction of nucleopilic reagent).The example of such nucleophilic heterocyclic chemical compound is known in the art, and introduces in this article.

Term " leaving group " is meant the part that can break away from from molecule in reaction (especially nucleophilic displacement reaction).The example of leaving group comprises for example halogen, mesyl, tosyl, alkoxide, hydroxide and protonated form thereof.The example of such leaving group is known in the art, and introduces in this article.

Term " acyl group " comprises the residue derived from acid (including but not limited to carboxylic acid, carbamic acid, carbonic acid, sulfonic acid and phosphorous acid).Comprise for example aliphatic carbonyl, aromatics carbonyl, aliphatic sulfonyl, aromatics sulfinyl, aliphatic sulfinyl, aromatic phosphate acid ester and aliphatic phosphate ester.

Term used herein " aprotic solvent " is meant the solvent to the active relative inertness of proton (promptly not as proton donor).Include but not limited to for example hydro carbons (for example hexane and toluene), halogenated hydrocarbons (for example dichloromethane, dichloroethanes, chloroform etc.), heterocyclic compound (for example oxolane and N-Methyl pyrrolidone) and ether (for example ether, bi-methoxy methyl ether).Such chemical compound is well known in the art, to those skilled in the art, the preferred single solvent or the solvent mixture of specific compound and reaction condition are conspicuous, and depend on for example following various factors: the dissolubility of reagent, the reactivity of reagent and preferred temperature range etc.The in-depth explanation of relevant aprotic solvent can be referring to organic chemistry textbook or monograph, for example: Organic Solvents Physical Properties and Methods of Purification, the 4th edition, chief editor John A.Riddick etc., Vol.II, Techniques of Chemistry Series, John Wiley﹠amp; Sons, NY, 1986.

Term used herein " protogenic organic solvent " is meant that trend provides the solvent of proton, for example alcohol, for example methanol, ethanol, propanol, isopropyl alcohol, butanols, the tert-butyl alcohol etc.Such solvent is well known in the art, to those skilled in the art, the preferred single solvent or the solvent mixture of specific compound and reaction condition are conspicuous, and depend on for example following various factors: the dissolubility of reagent, the reactivity of reagent and preferred temperature range etc.The in-depth explanation of relevant protogenic solvent can be referring to organic chemistry textbook or monograph, for example: Organic Solvents Phyical Properties and Methods of Purification, the 4th edition, chief editor John A.Riddick etc., Vol.II, Techniques of Chemistry Series, John Wiley﹠amp; Sons, NY, 1986.

The substituent group of the present invention's expection and the combination of variable only are those combinations that cause forming stable compound.Term used herein " is stablized " and is meant such chemical compound: have enough stability and make it possible to preparation, and keep the time long enough of chemical compound integrity, the purpose of introducing for use in this paper (for example therapeutic or preventative give the patient).

Synthetic chemical compound can be separated from reactant mixture, uses such as column chromatography, high pressure lipuid chromatography (HPLC) or recrystallize method and further purifies.Those skilled in the art can be understood that the more multi-method of the chemical compound of synthetic this paper structural formula is conspicuous for those of ordinary skills.In addition, the order that each synthesis step can be different is carried out to obtain required chemical compound.The chemical conversion process and the blocking group application process (protection and deprotection) that can be used for synthetic this paper chemical compound are well known in the art, comprise the method that for example following document is introduced: R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 2nd edition, John Wiley and Sons (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); The L.Paquette chief editor, Encylopedia Of Reagents for Organic Synthesis, John Wiley and Sons (1995), and their later release.

Term used herein " patient " is meant animal.Preferred animal is a mammal.More preferably mammal is behaved.The patient also refers to for example Canis familiaris L., cat, horse, cattle, pig, Cavia porcellus, fish, bird etc.

The compounds of this invention can be learned characteristic to strengthen selectivity organism by adding suitable modified with functional group.Such modification is well known in the art, can comprise the modification that can produce following effect: strengthen the biological penetration capacity enter particular organisms system (for example blood, lymphsystem, central nervous system), improve oral utilization rate, improve dissolubility so that drug administration by injection, change metabolism and change excretion rate.

Term used herein " patient " is meant mammal.Preferred mammal is behaved.The patient also refers to for example Canis familiaris L., cat, horse, cattle, pig, Cavia porcellus etc.

Term used herein " pharmaceutically acceptable salt " is meant such salt: in rational medical judgment scope, be fit to contact with people and zootic tissue and do not have excessive toxicity, stimulation, anaphylaxis etc., and have reasonably benefited/risk ratio.Pharmaceutically acceptable salt is well known in the art.For example S.M.Berge etc. is at J.PharmaceuticalSciences, and 1977,66, describe pharmaceutically acceptable salt among the 1-19 in detail, by reference the document is attached to this paper.These salt can perhaps can prepare separately with the reaction of suitable organic acid by free alkali functional group in the final separation of The compounds of this invention and purification step in in-situ preparing.The example of pharmaceutically acceptable non-toxic acid addition salts includes but not limited to the amino salt that forms with mineral acid (for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid) or organic acid (for example acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), perhaps uses the salt of other method (for example ion exchange) preparation of this area.Other pharmaceutically acceptable salt includes but not limited to adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluconate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxyl-esilate, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, Pivalate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, tosilate, the hendecane hydrochlorate, valerate etc.Representational alkaline or alkaline-earth salts comprises sodium salt, lithium salts, potassium salt, calcium salt, magnesium salt etc.Under the suitable situation, other pharmaceutically acceptable salt comprises with counter ion counterionsl gegenions and forms nontoxic ammonium, quaternary ammonium and amine cation, for example halogenide, hydroxide, formic acid esters, sulfate, phosphate, nitrate, C ₁-C ₆Sulfonate and arylsulphonate.

Term used herein " pharmaceutically acceptable ester " but be meant the ester of hydrolysis in the body, comprise being easy in human body, decompose the ester that obtains parent compound or its salt.Suitable ester includes but not limited to that by the deutero-ester of pharmaceutically acceptable aliphatic carboxylic acid (especially alkanoic acid, alkenoic acid, aphthenic acids and alkanedioic acid) wherein each alkyl or alkenyl part preferably is no more than 6 carbon atoms.The example of concrete ester includes but not limited to formic acid esters, acetas, propionic ester, butyrate, acrylate and ethyl succinate.

Term used herein " pharmaceutically acceptable prodrug " is meant such prodrug of The compounds of this invention: in rational medical judgment scope, be fit to contact and do not have excessive toxicity, stimulation, an anaphylaxis etc. with people and zootic tissue, and has rational risk/beneficiary proportion, for intended purpose is effective, under the possibility situation, prodrug also refers to the amphion of The compounds of this invention.Term " prodrug " is meant and is easy to transform fast in vivo the chemical compound that (for example by hydrolysis in the blood) obtains the parent compound of above structural formula.T.Higuchi and V.Stella, Prodrugs as Novel deliverySystems, A.C.S.Symposium Series, Vol.14 and Edward B.Roche chief editor's Bioreversible Carriers in Drug Design (American PharmaceuticalAssociation and Pergamon Press, 1987) in prodrug has been carried out detailed elaboration, two documents have been attached to this paper by reference.

Term used herein " effective dose " or " treatment effective dose " are meant such dosage: can suppress HCV NS3 serine protease, and the viral interference generation of duplicating necessary viral polyprotein thus.When being fit to the patient of this treatment of needs, the HCV serine stretch protein enzyme inhibition of the inventive method expection comprises therapeutic and prophylactic treatment.Those of ordinary skills can use existing method and choice of technology Therapeutic Method, dosage level and requirement.By way of example, The compounds of this invention can give the viral infection patient with pharmaceutically acceptable mode and effective dosage that reduces the viral infection order of severity in conjunction with pharmaceutically acceptable excipient.Perhaps, The compounds of this invention can be used in the protection individual vaccine and method, prevents the HCV viral infection for a long time.Can use chemical compound according to the conventional same way as of using protease inhibitor in vaccine.For example, The compounds of this invention can combine with the pharmaceutically acceptable excipient that uses in vaccine usually, gives individuality with the prevention effective dose, thereby protects individuality to avoid the HCV viral infection for a long time.Equally, protease inhibitor of the present invention can be used as medicine and gives, treatment or prevention patient's HCV viral infection.

The compounds of this invention comprises two or more asymmetric centers, produce enantiomer, diastereomer and other stereoisomer thus, can be defined as according to the absolute stereo chemistry (R)-or (S)-, perhaps for aminoacid be defined as (D)-or (L)-.The present invention includes all so possible isomers and their racemic modification and the pure form of optically-active.Optical isomer can perhaps prepare by resolving racemic mixtures with the method preparation of their optically active precursors separately by above introduction.Can in the presence of resolving agent, some combination by chromatography, repeated crystallization or technology well known by persons skilled in the art split.The further data of relevant fractionation is referring to Jacques etc., Enantiomers Racemates andResolutions (John Wiley﹠amp; Sons, 1981).When The compounds of this invention comprised olefinic double bonds or other how much asymmetric centers, except as otherwise noted, otherwise this chemical compound comprised E type and Z type geometric isomer.Equally, in all tautomeric forms are also included within.Except as otherwise noted, otherwise any carbon-carbon double bond configuration that this paper occurs only is to select such configuration for convenience, is not to specify the fixed configuration of tool; Therefore arbitrarily be illustrated as trans carbon-carbon double bond can for cis, trans or two kinds of configurations arbitrarily than mixture.

Pharmaceutical composition

Pharmaceutical composition of the present invention comprises The compounds of this invention and one or more pharmaceutically acceptable carriers for the treatment of effective dose.Term used herein " pharmaceutically acceptable carrier " is meant the formulation aid of nontoxic inert solid, semisolid or liquid filling agent, diluent, coating material or any kind.Can sugar be arranged as the part example of pharmaceutically acceptable carrier, for example lactose, Fructus Vitis viniferae and sucrose; Starch, for example corn starch and potato starch; Cellulose and derivant thereof, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Pulvis Talci; Excipient, for example cupu oil and suppository wax; Oil, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; Alcohol, for example propylene glycol; Ester, for example ethyl oleate and ethyl laurate; Agar; Buffer agent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; Ringer's mixture; Ethanol and phosphate buffered solution; According to recipe design person's judgement, other nontoxic compatible lubricant (for example sodium lauryl sulfate and magnesium stearate), coloring agent, antitack agent, coating materials, sweeting agent, flavoring agent, aromatizing agent, antiseptic and antioxidant also can add in the compositions.Pharmaceutical composition of the present invention can per os, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (as powder, ointment or drop), buccal, mouthspray or intranasal spraying administration of human or other animal.

The liquid oral dosage form comprises pharmaceutically acceptable Emulsion, microemulsion, solution, suspensoid, syrup and elixir.Remove the active ingredient beyond the region of objective existence, liquid dosage form can also comprise this area inert diluent (for example water or other solvent), solubilizing agent and emulsifying agent commonly used, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (especially Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol, the fatty acid ester of sorbitan and their mixture.Except that inert diluent, Orally administered composition also can comprise adjuvant, for example wetting agent, emulsifying agent, suspending agent, sweeting agent, flavoring agent and aromatizing agent.

Ejection preparation (for example aseptic injection aqueous or oiliness suspensoid) can be prepared according to known technology with suitable dispersant or wetting agent and suspending agent.Aseptic injection preparation can also be nontoxic parenteral acceptable diluent or aseptic injectable solution agent, suspensoid or the Emulsion in the solvent, for example solution in the 1,3 butylene glycol.In acceptable solvent and solvent, can make water, Ringer's mixture, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic expressed oi is usually as solvent or suspension media.For this purpose, can use the expressed oi of any gentleness, comprise synthetic monoglyceride or diglyceride.In addition, fatty acid (for example oleic acid) also uses in ejection preparation.

Ejection preparation can followingly be sterilized: keep filter by antibacterial and filter, perhaps biocide is added in the aseptic solid composite, aseptic solid composite can face with preceding dissolving be distributed to sterilized water or other aseptic injection medium in.

In order to prolong drug effect, wish to slow down absorption subcutaneous or the intramuscular injection medicine usually.Can use the crystal of poorly water-soluble or the liquid suspension of amorphous substance to reach this purpose.The drug absorption rate depends on rate of dissolution like this, and this depends on crystal size and crystal form.Perhaps, thus with medicine dissolution or be suspended in the oiliness solvent absorption that postpones the parenteral administered agents.Make injection storage storehouse dosage form by the microcapsule that in biodegradable polymer (for example polyactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester), forms medicine.Rely on the character of the concrete polymer of drug/polymer ratio and use, can control release rate of drugs.The example of other biodegradable polymer comprises poly-(ortho esters) and poly-(anhydride).Also pharmaceutical pack can be embedded in liposome or the microemulsion compatible and preparation storage storehouse ejection preparation with bodily tissue.

The compositions of rectum or vagina administration is preferably suppository, suppository can be mixed with by The compounds of this invention and suitable non-stimulated excipient or carrier, for example (they are solids in room temperature with cupu oil, Polyethylene Glycol or suppository wax, and be liquid under body temperature, therefore in rectum or vaginal canal fusing, discharge reactive compound) mix.

The solid composite of similar type can also be as the filler of soft and hard filled capsules, for example uses lactose and high component Polyethylene Glycol etc. as excipient.

Reactive compound also can constitute microencapsulation form with one or more above-mentioned excipient.Solid dosage forms tablet, dragee, capsule, pill and granule can be used coating and shell, for example enteric coating, release control coating and known other coating of pharmacy formulation art.In such solid dosage forms, reactive compound can for example sucrose, lactose or starch be mixed with at least a inert diluent.As conventional practice, such preparation also can comprise other material except that inert diluent, for example film-making lubricant and other film-making auxiliary agent (for example magnesium stearate and microcrystalline Cellulose).When being capsule, tablet and pill, these dosage forms also can comprise buffer agent.They also can be chosen wantonly and comprise opacifier, only also can be or preferably in the compositions of some part release of active ingredients of intestinal, optionally discharge with delayed mode.The example of operable embedding composition comprises polymer and wax.

The dosage form of part or transdermal administration The compounds of this invention comprises ointment, paste, emulsifiable paste, lotion, gel, powder, solution, spray, inhalant or patch.Under aseptic condition, active component and pharmaceutically acceptable carrier and any antiseptic that may need or buffer agent are mixed.Eye preparation, ear drop, eye ointment, powder and solution are also included within the scope of the invention.Remove active ingredient beyond the region of objective existence of the present invention, ointment, paste, emulsifiable paste and gel also can comprise excipient, for example animal and plant fat, oil, wax, paraffin, starch, Tragacanth, cellulose derivative, Polyethylene Glycol, silicone, bentonite, silicic acid, Pulvis Talci, zinc oxide or their mixture.

Except that The compounds of this invention, powder and spray also can comprise excipient, for example the mixture of lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates, polyamide powder or these materials.Spray also can comprise cast charge, for example chloro-fluoro-carbon kind usually.

Transdermal patch has extra advantage, and the may command chemical compound is administered to health.Can or be assigned to the such dosage form of preparation in the suitable medium with compound dissolution.Also can use absorption enhancer to improve the flux that chemical compound passes skin.Use rate controlling membranes or chemical compound is distributed to may command rate of release in polymeric matrix or the gel.

Antibacterial activity

The Therapeutic Method according to the present invention, by giving the The compounds of this invention of patient's effective dose, treatment or prevention patient's (for example people or low wait mammal) viral infection, and dosage and administration time length are that the required result of realization is necessary." the anti-hepatitis c virus effective dose " of term The compounds of this invention used herein is meant the chemical compound of q.s, makes patient's viral load reduce, and alleviates described patient's chronic hcv symptom thus.As medical domain was well-known, in any therapeutic treatment, the anti-hepatitis c virus effective dose of The compounds of this invention was to obtain the dosage of benefited/risk ratio rationally.

After improving patient's the state of an illness, if desired, can give The compounds of this invention, compositions or the combination medicine of maintenance dose.Subsequently, along with the improvement of symptom, dosage or frequency can reduce, and perhaps the both reduces, and up to keeping the dosage level that the state of an illness is improved, to desired level, should stop treatment in remission.But in case disease symptoms has any recurrence, the patient may need to carry out for a long time the intermittence treatment.

But, should be understood that total daily dose of The compounds of this invention and compositions will reasonably determined in the medical judgment scope by the attending doctor.Multiple factor be will depend on to the effectively concrete dosage level of the anti-HCV virus of particular patient, the disease of being treated, the order of severity of disease comprised; The activity of the particular compound of using; The concrete compositions of using; Patient's age, body weight, general health situation, sex and diet; The discharge rate of administration time, route of administration and the chemical compound that uses; The time that treatment continues; With compound used therefor associating or the medicine that uses simultaneously; And the known similar factor of medical domain.

Total daily dose of The compounds of this invention gives the patient with single agent or multi-agent, and total daily dose is for example 0.01-50mg/kg body weight, 0.1-25mg/kg body weight more commonly used.The potion compositions can comprise such dosage or its approximate number dosage is to constitute daily dose.Usually, therapeutic scheme of the present invention comprises that the about 10mg of the patient who needs this treatment is to about 1000mg The compounds of this invention/sky, with single agent or multi-agent administration.

Abbreviation

In the explanation of flow process and embodiment, use following abbreviation:

The ACN acetonitrile;

The BME 2 mercapto ethanol;

BOP benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus hexafluorophosphate;

The COD cyclo-octadiene;

DABCYL 6-(N-4 '-carboxyl-4-(dimethylamino) diphenyl diimide)-amino hexyl-1-O-(2-

Cyano ethyl)-(N, N-diisopropyl)-amino phosphite ester;

DAST diethylamino sulfur trifluoride;

The DCM dichloromethane;

The DIAD diisopropyl azodiformate;

The DIBAL-H diisobutyl aluminium hydride;

The DIEA diisopropylethylamine;

DMAP N, the N-dimethyl aminopyridine;

The DME glycol dimethyl ether;

DMEM Dulbecco′s Modified Eagles Media；

DMF N, dinethylformamide;

The DMSO dimethyl sulfoxine;

DUPHOD

EDANS 5-(2-amino-ethyl amino)-naphthalene-1-sulfonic acid;

EDCI or EDC 1-(3-diethylamino propyl group)-3-ethyl-carbodiimide hydrochloride;

The EtOAc ethyl acetate;

HATU O (7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea six

Fluorophosphate;

HMBA 4-hydroxymethyl benzoic acid AM resin;

Hoveyda ' s Cat. dichloro (o-isopropoxy benzene methylene) (tricyclohexyl phosphine) ruthenium (II);

Two (trimethyl silyl) potassamides of KHMDS;

The Ms mesyl;

NMM N-4-methyl morpholine

The Ph phenyl;

PuPHOS

PyBrOP bromo-three-pyrrolidinyl-phosphorus hexafluorophosphate;

RCM closed loop displacement reaction;

The RT room temperature;

The RT-PCR RT-polymerase chain reaction;

TBOC or Boc tert-butoxycarbonyl;

The TEA triethylamine;

The TFA trifluoroacetic acid;

The THF oxolane;

The TLC thin layer chromatography;

TPP or PPh3 triphenylphosphine;

Xantphos 4, and 5-pair-diphenylphosphino-9,9-dimethyl-9H-xanthene.

This paper some have-NH or-chemical constitution of OH do not depict the hydrogen atom that connects oxygen or nitrogen-atoms.Therefore as if, nitrogen-atoms in such structure or oxygen atom do not have normal quantivalence, but actual these hydrogen atoms that comprises.

Synthetic method

In conjunction with following synthesis flow, will understand The compounds of this invention and preparation method better, these flow example explanations can be used for preparing the method for The compounds of this invention.

I. displacement method

The compounds of this invention can prepare in order to the displacement method of following flow process general description:

Can use hydroxyproline or methylsulfonyl proline precursor.This replacement scenario is fit to any hydroxyl (or corresponding methanesulfonates) proline compounds or deutero-precursor compound are converted into the proline derivative of heterocyclic substituted.The explanation of subsequently synthetic method can be used for preparing this paper the come into the open the whole bag of tricks and the intermediate steps of compound.

A. synthesis of hydroxy proline cyclic peptide precursor

The cyclic peptide precursor can be used for synthetic The compounds of this invention.In certain embodiments, can use the cyclic precursor of methylsulfonylization.

In certain embodiments, with commercially available Boc-hydroxyproline A

Handle acquisition initial feed Ib with HCl De dioxane solution.

The synthetic cyclic peptide precursor

Flow process 1

Cyclic peptide precursor I g summarizes the steps A-D that lists with Boc-L-2-amino-8-nonenoic acid Ia and suitable-L-L-Hydroxyproline methyl ester Ib according to flow process 1 and synthesizes.The more detailed synthetic method of relevant preparation cyclic peptide precursor I g is attached to this paper with its full content by reference referring to United States Patent (USP) 6,608,027.

The methanesulfonates precursor of synthetic Macrocyclic peptides

Flow process 2

Following synthesis of cyclic precursor methanesulfonates: form methanesulfonates on the hydroxyl according to route of synthesis hydroxyproline residue in the cyclic peptide precursor of above flow process 2 summary descriptions.

Flow process 3

According to the concise and to the point route of synthesis of describing of flow process 3 with 5-replace-methanesulfonates of 2H-tetrazolium displacement Macrocyclic peptides methanesulfonates IIa prepares The compounds of this invention, following flow process 5 has been introduced the exemplary synthetic method of such tetrazolium.

Flow process 4

With 4,5-replaces-methanesulfonates that the 1H-triazole is replaced Macrocyclic peptides methanesulfonates IIa prepares The compounds of this invention according to the concise and to the point route of synthesis of describing of flow process 4.Following flow process 6 has been introduced the exemplary synthetic method of such triazole.

B. synthetic substituent group W

W can be any substituent group mentioned above.Those of ordinary skills can synthesize these different substituent groups.Embodiment has introduced the partial synthesis method, but these embodiment and nonrestrictive.Other substituent group is commercially available or those of ordinary skills are easy to synthetic.

Synthetic tetrazolium

The tetrazolium Va-Vq that structure is different is synthetic according to the method for following flow process 5 with commercially available nitrile compounds:

Flow process 5

The tetrazole compound that those skilled in the art can understand multiple 5-replacement can prepare according to the method with any nitrile compound that contains that is fit to above-mentioned reaction condition.

Synthetic triazole

Flow process 6

Be prepared as follows triazole of the present invention: alkine compounds VIa (commercially available or with following method preparation) and nitrine trimethyl silicane are reacted according to the route of synthesis of flow process 6 summary descriptions.The commercially available alkynes that is fit to the preparation triazole includes but not limited to:

Synthetic alkynes

The alkynes that is used for synthetic triazole can be by any suitable method preparation.It below is the exemplary synthetic method of part.

The Sonogashira reaction

Flow process 7

The alkynes that the present invention uses can pass through the Sonogashira prepared in reaction: the acetonitrile solution of using uncle's alkine compounds VIIa, aryl halide (Y-halogen) and triethylamine is at PdCl ₂(PPh ₃) ₂React according to the route of synthesis of flow process 7 summary descriptions down with the CuI existence.

The commercially available aryl halide that is fit to the Sonogashira reaction includes but not limited to:

The commercially available uncle's alkynes that is fit to the Sonogashira reaction includes but not limited to:

Synthetic alkynyl amide

Flow process 8

Other alkynes that the present invention uses can be prepared as follows: the DMF solution of alkynyl acid Va, BOP and DIEA and amine VIIIb are reacted according to the route of synthesis of flow process 8 summary descriptions.

Modification after the displacement

Can after connecting W, modify the gained macrocyclic compound.It below is the exemplary modification of part.

1. synthesizing phenol ester

Flow process 9

R=methyl, ethyl, pi-allyl, 2-hydroxyethyl, isopropyl, methylthiomethyl (methiomethyl)

The displacement back is modified macrocyclic compound IIIa and is obtained different phenol esters, and this modification is carried out according to the route of synthesis of flow process 9 summary descriptions.

2. hydrolysis Macrocyclic peptides ethyl ester

Flow process 10

Following hydrolysis Macrocyclic peptides ethyl ester of the present invention: according to the route of synthesis of flow process 10 summary descriptions, reaction is dissolved in diox with Macrocyclic peptides ethyl ester IV, adds 1M LiOH.

3. with the more multi-joint aryl compound of Suzuki coupling reaction preparation

Flow process 11

The compounds of this invention can be undertaken more changeableization by the Suzuki coupling reaction: according to the route of synthesis of flow process 11 summary descriptions, and adding DME, aromatics boric acid, cesium carbonate and KF in the triazole macrocycle ethyl ester (relevant preparation method is referring to following examples 26) that bromo-replaces.

II. synthetic method progressively

The compounds of this invention also can be by progressively synthetic method rather than the preparation of displacement mechanism.Below be exemplary synthetic method, wherein W is a tetrazolium.

A. proline biosynthesis derivant

Flow process 12

B. synthesizing linear tripeptides

Flow process 13

The linear tripeptides of proline derivative XIIc that contains tetrazolium-replacement is according to the preparation of the route of synthesis of flow process 12 summary descriptions.

C. closed loop displacement reaction (RCM) synthetic cyclic peptide

Flow process 14

Prepare macrocyclic compound Xb with linear tripeptides XIIId according to the closed loop displacement reaction of flow process 14 summary descriptions.

Other derivant of D

1. the proline derivative that tetrazolium of the present invention replaces is according to the route of synthesis preparation of flow process 12 summary descriptions.

Flow process 15

The proline derivative that other tetrazolium of the present invention replaces is according to the route of synthesis preparation of flow process 15 summary descriptions.

2.Suzuki coupling reaction

Flow process 16

Suzuki coupling reaction with flow process 16 summary descriptions prepares more derivant.

III. solid-phase synthesis

Part of compounds of the present invention can be prepared by solid-phase synthesis.For example the proline derivative (P2) of triazole replacement can be used for the linear tripeptides chain of assembling on the resin after synthetic.Resin in conjunction with tripeptides (contain triazole replace proline derivative) obtains the ring-type tripeptides through closed loop displacement reaction (RCM), obtains end-product by hydrolysis cracking from the resin.

Following synthesis flow is introduced the preparation method of the proline derivative that triazole replaces and the solid-phase synthesis of The compounds of this invention.

A. proline biosynthesis derivant

Two kinds of methods of following flow process summary description can be used for the proline derivative of synthetic triazole-replacement:

1. cycloaddition method

Flow process 17

The cycloaddition method of preparation triazolyl proline derivative relates to the 3+2 cycloaddition of nitrine proline derivative XVIIb and alkynes VIIb, according to the route of synthesis reaction of flow process 17 summary descriptions.The example synthetic method of alkynes is introduced in above flow process 7.

2. methanesulfonates method

Flow process 18

According to the route of synthesis of flow process 18 summary descriptions, by methanesulfonates XVIIIa and 4,5-replaces-synthetic other proline derivative of displacement reaction of 1H-triazole.

B. on the resin assembling and resin on RCM

Flow process 19

On resin, assemble

According to the steps A-D of flow process 19 summary descriptions, on resin, carrying out the cyclic peptide precursor XIXe that RCM obtains binding resin behind the assembling linear peptides XIXd on the resin.

IV. other reaction

In certain embodiments, substituent group W is fit to the reaction of other type very much.For example (but non-limiting) uses following reaction process when W is 2H-Pyridazin-3-one.These methods can be used for other substituent group, but illustrate with 2H-Pyridazin-3-one in this paper context.

A. condensation reaction

Flow process 20

The simplest method (shown in the flow process 20) is with commercially available 2H-Pyridazin-3-one (XXa-1-XXa-4) and key intermediate If condensation, uses the Mitsunobu condition earlier, uses the LiOH hydrolysis then.The more particulars of relevant Mitsunobu reaction is referring to O.Mitsunobu, and Synthesis 1981,1-28; D.L.Hughes, Org.React.29,1-162 (1983); D.L.Hughes, OrganicPreparations and Procedures Int.28,127-164 (1996); J.A.Dodge, S.A.Jones, Recent Res.Dev.Org.Chem.1,273-283 (1997).

Flow process 21

The second method for preparing 2H-Pyridazin-3-one analog of the present invention is further chemical treatment dibromo intermediate X XIa (flow process 21).Commercially available 4, the standard Mitsunobu coupling reaction of 5-dibromo 2H-Pyridazin-3-one and hydroxyl If obtains required macro ring XXIa.The coupling in the presence of cesium carbonate and potassium fluoride of XXIa and excessive 3 thienylboronic acid obtains two thiophene XXIb.Compounds X XIa and XXIb and LiOH hydrolysis obtain required analog XXId and XXIc respectively.Can obtain many dibasic pyridazine ketone group macro ring with similar method with a lot of different boric acid.

B. bromide differentiation reaction

Flow process 22

The differentiation that macro ring XXIa goes up bromide realizes by the Michael addition.Shown in flow process 22, commercially available pyrrolidine and dibromide coupling are obtained compounds X XIIa, 87% yield.Then, the bromide part adjacent with carbonyl carried out the Suzuki coupling reaction with 3 thienylboronic acid and obtained intermediate X XIIb, it further handled obtaining analog XXIIc with LiOH.Being described in more detail of relevant Suzuki coupling reaction referring to A.Suzuki, Pure Appl.Chem.63,419-422 (1991) and A.R.Martin, Y.Yang, Acta Chem.Scand.47,221-230 (1993).

C. sulfur-bearing nucleopilic reagent

Flow process 23

Though secondary amine nucleopilic reagent pyrrolidine carries out the exclusiveness addition in the 5-of macro ring XXIa bromine position, the sulfur-bearing nucleopilic reagent does not have identical selectivity, shown in flow process 23.Use the sulfur-bearing nucleopilic reagent, additive reaction all takes place in two bromine positions of XXIa in part, and part is only had single coupling product XXIIa of 1 equivalent mercaptopyrimidine.Compounds X XIIIa, XXIIIb can separate by flash column chromatography with initial feed XXIa, and the XXIIIa of monoalkylation can carry out the Suzuki coupling reaction with 3 thienylboronic acid like this, obtain analog XXIIIe with LiOH hydrolysis XXIIId then.The also available LiOH hydrolysis of dialkyl group product X XIIIb obtains analog XXIIIc.

D. with the Suzuki coupling reaction of boric acid

Flow process 24

Owing to have only a small amount of boric acid to can be used for the Suzuki coupling reaction, to for example Stille coupling and utilize the N-arylation of Buchwald chemical reaction also to do research (flow process 24) of other couling process.Intermediate X XIa and the coupling under the Stille standard conditions of 2-stannyl thiazole, hydrolysis obtains analog XXIVa then.For the N-arylation, imidazoles and dibromide 6 coupling successfully.Unfortunately, cause 5 imidazoles part and methoxyl group generation displacement reaction (XXIVb with the hydrolysis of LiOH.The more details of relevant Stille coupling reaction are referring to J.K.Stille, Angew.Chem.Int.Ed.25,508-524 (1986); M.Pereyre etc., Tin inOrganic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim., T.N.Mitchell, Synthesis 1992,803-815.The more details of relevant Buchwald reaction are referring to J.F.Hartwig, Angew.Chem.Int.Ed.37,2046-2067 (1998).

E. other different 2H-Pyridazin-3-one analog

Flow process 25

Flow process 25 has been introduced the method for another kind of diversified 2H-Pyridazin-3-one analog.Michael additive reaction as the Hydrazoic acid,sodium salt of nucleopilic reagent and dibromide XXIa only obtains the compounds X XVa of (under the situation of secondary amine) single coupling.Further carry out the Suzuki coupling reaction with 3 thienylboronic acid and obtain azide XXVb.Compounds X XVb hydrolysis obtains analog XXVc.In addition under standard conditions, with Cyanogran. the azide part of compounds X XVb further is converted into tetrazolium, obtain analog XXVd with posthydrolysis.

F. synthesize 5,6-pyridazine ketone group macro ring

Flow process 26

Flow process 26 has introduced 5, the synthetic method of 6-pyridazine ketone group macro ring XXVIb.Make commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one and key intermediate If condensation under the Mitsunobu condition obtain compounds X XVIa.Make product X XVIa under Suzuki coupling condition with the 3 thienylboronic acid coupling, hydrolysis obtains required analog XXVb then.

Embodiment

With the following Examples, will understand The compounds of this invention and preparation method better, these embodiment are only as illustration purpose, rather than limitation of the scope of the invention.For those skilled in the art, the various changes and modifications of disclosed embodiment are conspicuous.Under the situation that does not break away from essence of the present invention and claims scope, can make such changes and improvements (including but not limited to the changes and improvements of relevant chemical constitution of the present invention, substituent group, derivant, preparation and/or method).

Embodiment 1. synthetic cyclic peptide precursors

1A.Boc-L-2-amino-8-nonenoic acid 1a (1.36g, 5mol) and commercially available suitable-L-L-Hydroxyproline methyl ester 1b (1.09g, add in 15ml DMF solution 6mmol) DIEA (4ml, 4eq.) and HATU (4g, 2eq).This coupling reaction is carried out 1h under 0 ℃.Reactant mixture is used 5% citric acid, 2 * 20ml, water 2 * 20ml, 1MNaHCO respectively then with 100mL EtOAc dilution ₃4 * 20ml and saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄Drying, evaporation obtains dipeptides 1c (1.91g, 95.8%) then, with HPLC (retention time=8.9min, 30-70%, 90%B) and MS (measured value 421.37, M+Na ⁺) identify.

1B. dipeptides 1c (1.91g) is dissolved in 15mL diox and 15mL 1N LiOH aqueous solution, and hydrolysis carries out 4h in room temperature.Reactant mixture with 100mL EtOAc extraction, is distinguished water 2 * 20ml, 1M NaHCO with 5% citric acid acidify then ₃2 * 20ml and saline 2 * 20ml washing.The organic facies anhydrous Na ₂SO ₄Drying, vacuum is removed then, obtains free carboxy acid's chemical compound 1d (1.79g, 97%), it is directly used in next synthesis step need not to purify again.

1C. the free acid of above acquisition (1.77, add in 5ml DMF solution 4.64mmol) D-β-vinyl cyclopropane aminoacid ethyl ester 1e (0.95g, 5mmol), DIEA (4ml, 4eq.) and HATU (4g, 2eq).This coupling reaction is carried out 5h under 0 ℃.Reactant mixture dilutes with 80mLEtOAc, uses 5% citric acid, 2 * 20ml, water 2 * 20ml, 1M NaHCO then respectively ₃4 * 20ml and saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄Drying, evaporation then.Residue flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5)).After removing eluting solvent, isolate the linear tripeptides 1f (1.59g, 65.4%) of grease, with HPLC (retention time=11.43min) and MS (measured value 544.84, M+Na ⁺) identify.

1D. closed loop displacement reaction (RCM).Feed nitrogen to remove linear tripeptides 1f (1.51g, the oxygen in the anhydrous DCM solution of 200ml 2.89mmol).Be incorporated as the first generation catalyst (5mol%eq.) of solid Hoveyda then.Make the reactant 12h that under blanket of nitrogen, refluxes.Evaporating solvent, residue flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5)).After removing eluting solvent, isolate white powder cyclic peptide precursor 1 (1.24g, 87%), with HPLC (retention time=7.84min, 30-70%, 90%B) and MS (measured value 516.28, M+Na ⁺) identify.The more detailed synthetic method of relevant preparation cyclic peptide precursor 1 is attached to this paper with its full content by reference referring to United States Patent (USP) 6,608,027.

Embodiment 2. synthetic cyclic peptide precursor methanesulfonates

2A. at 0 ℃, to Macrocyclic peptides precursor 1 (500mg, 1.01mmol) and DIEA (0.4ml slowly adds mesyl chloride (0.1ml) in 2.0ml DCM solution 2mmol), 3h is carried out in reaction.Add 30mL EtOAc then, use 5% citric acid, 2 * 10ml, water 2 * 10ml, 1M NaHCO respectively ₃2 * 10ml and saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄The evaporation of dry back obtains the title compound methanesulfonates, it is directly used in next synthesis step need not to purify again.

Embodiment 3. synthetic tetrazoliums

Tetrazolium IIIa-IIIq (being used to prepare tetrazole radical macro ring of the present invention) different on the structure is following synthetic with commercially available nitrile compound:

Be equipped with add in the sealed tube of 5ml dimethylbenzene 3-Cl-4-hydroxyl-benzonitrile (benzoacetonitile) (0.31g, 5mol), NaN ₃(0.65g, 10mmol) and triethylamine hydrochloride (0.52g, 3mmol).At 140 ℃ of vigorous stirring mixture 20-30h.Reaction mixture then is in impouring EtOAc (30ml) and aqueous citric acid solution (20mL) mixture.After water 2 * 10ml and saline 2 * 10ml washing, the organic facies anhydrous Na ₂SO ₄Drying is evaporated to light yellow solid.After with EtOAc-hexane recrystallization, (＞90%, HPLC) acquisition tetrazole compound 3a is with NMR and MS (measured value 197.35 and 199.38, M+H with higher yields (0.4g, 86%%), high-purity ⁺) identify.

Embodiment 4. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The proline biosynthesis derivant

(10g, 40.8mmol) and N, (DIEA, 12mL drip 3.85mL mesyl chloride (50mmol) to the N-diisopropylethylamine to N-Boc-cis-L-Hydroxyproline methyl ester 4a in 110mL DCM solution 60mmol), the gained reactant mixture is stirred 3h at 0 ℃.(hexane: ethyl acetate=1: 1 v/v) confirms that Boc-cis-Hyp-OMe 4a adorns the methanesulfonates 4b that turns to it fully to TLC.After TLC confirmed to react completely, reactant mixture with 5% citric acid, 2 * 50ml and saline 2 * 30ml washing, was used anhydrous sodium sulfate drying with 100ml EtOAc dilution.Removing desolvates obtains 13g (98% yield) N-Boc-cis-4-methanesulfonates-proline methyl ester 4b, it is directly used among the step B need not to purify again.

Methanesulfonates 4b (0.65g, and adding 4mmol 5-phenyl-1H-tetrazolium and natrium carbonicum calcinatum in 5mL DMF solution 2mmol) (0.53g, 5mmol).At 60 ℃ of vigorous stirring gained reactant mixture 6-12h.(hexane: ethyl acetate=1: 1 v/v) confirms that methanesulfonates 4b is converted into the proline derivative 4c that trans 4-tetrazolium replaces fully to TLC.After TLC confirmed to react completely, reactant mixture was used 1M Na respectively with 30ml EtOAc dilution ₂CO ₃(3 * 10ml), water (3 * 10ml), 5% citric acid (3 * 10ml) and saline (3 * 10ml) washing.The organic facies anhydrous sodium sulfate drying, vacuum concentration obtains the proline derivative 4c that the 5-phenyltetrazole replaces with high yield (94%) and high-purity (＞90%).The 4c:94% yield,

[M+Na] ⁺＝396.39。

The synthesizing linear tripeptides

Dipeptides 4e is prepared as follows: with 0.22g (0.6mmol) N-Boc-trans-4-(3-phenyltetrazole base)-proline methyl ester 4c is dissolved in 6mL diox and 2mL 1N LiOH aqueous solution.The gained reactant mixture at stirring at room 3-8h, is made the methyl ester hydrolysis.Reactant mixture is with 5% citric acid acidify, with 40mL EtOAc extraction, water 2 * 20ml, 1M NaHCO respectively ₃2 * 20ml and saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄Drying, vacuum concentration obtains free carboxy acid's chemical compound (0.20g, 92%), it is directly used in next synthesis step need not to purify again.(2) the above free acid that obtains (0.20g, add in 2ml DMF 0.55mmol) cold (0 ℃) solution D-β-vinyl cyclopropane aminoacid ethyl ester 4d (0.1g, 0.52mmol), DIEA (0.4ml, 4eq.) and HATU (0.4g, 2eq).The gained reactant mixture is stirred 0.5-3h at 0 ℃.Reactant mixture is used 5% citric acid, 2 * 20ml, water 2 * 20ml, 1M NaHCO respectively with 40mL EtOAc dilution ₃4 * 20ml, saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄Drying, vacuum concentration obtains dipeptides 4e (0.24g, 94%), with HPLC (retention time=10.03min) and MS (measured value 519.22, M+Na ⁺) identify.

B. (1) tripeptides 4g is prepared as follows: slough dipeptides 4e (0.24g, the 10min of amine protecting group group 0.49mmol) in 0 ℃, 2mLTFA.After vacuum is removed TFA, the unhindered amina product is directly used in subsequently coupling reaction.(2) add in 2mlDMF cold (0 ℃) solution of the above unhindered amina chemical compound that obtains Boc-2-amino-8-nonenoic acid 4f (0.136g, 0.50mmol), DIEA (0.4ml, 4eq.) and HATU (0.4g, 2eq).This coupling reaction is carried out 0.5-3h under 0 ℃.Reactant mixture is used 5% citric acid, 2 * 20ml, water 2 * 20ml, 1M NaHCO respectively with 40mL EtOAc dilution ₃4 * 20ml and saline 2 * 10ml washing.The organic facies anhydrous Na ₂SO ₄Drying, vacuum concentration obtains tripeptides 4g (0.28g, two steps 88%), with HPLC (retention time=14.03min) and MS (measured value 672.30, M+Na ⁺) identify.

By closed loop displacement reaction (RCM) synthetic cyclic peptide

A. (71mg feeds nitrogen to remove oxygen to linear tripeptides 4g in the anhydrous DCM solution of 50ml 0.109mmol).Be incorporated as solid Hoveyda ' sCat. (5-10mol%eq.) in the gained de gassed solution, with the gained reactant mixture 5-20h that under blanket of nitrogen, refluxes.Vacuum concentration reactant mixture then, residue is with flash chromatography on silica gel method purify (with the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2)).Isolate white powder Macrocyclic peptides 4i (58mg, 85.5%) by the evaporation eluting solvent, with HPLC (retention time=11.80min, 30-80%, 90%B) and MS (measured value 644.66, M+Na ⁺) identify.

IV. hydrolysis ethyl ester

Title compound is prepared as follows: chemical compound 4i (20mg) is dissolved in 2mL diox and 1mL 1N LiOH aqueous solution.With the gained reactant mixture at stirring at room 4-8h.Then with reactant mixture with 5% citric acid acidify, with 10mL EtOAc extraction, water 2 * 20ml washing.Evaporating solvent, residue with HPLC purify (YMC AQ12S11-0520WT post, 30-80% (100% acetonitrile) gradient, 20min).Behind lyophilization, obtain white amorphous solid title compound.

[M+Na] ⁺＝616.72。

Embodiment 5. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

5A. proline biosynthesis derivant

The proline derivative of present embodiment wherein uses 5-(2-bromophenyl)-1H-tetrazolium and N-Boc-cis-L-Hydroxyproline methyl ester 4a according to the method preparation of embodiment 4 (I).

[M+Na] ⁺＝396.39。

5B. synthesizing linear tripeptides

The linear peptides of present embodiment wherein uses proline derivative, D-β-vinyl cyclopropane aminoacid ethyl ester and the Boc-2-amino-8-nonenoic acid of step 5A preparation according to the method preparation that embodiment 4 (II) introduces.

[M+H] ⁺＝728.41

5C. closed loop displacement reaction

The method preparation that the Macrocyclic peptides ethyl ester of present embodiment is introduced according to embodiment 4 (III) with the linear peptides of step 5B.

[M+Na] ⁺＝722.37。

5D. hydrolysis ethyl ester

Title compound finally obtains by the hydrolysis that embodiment 4 (IV) introduces with the ethyl ester of step 5C.

[M+H] ⁺＝672.49。

Embodiment 6. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

6A. proline biosynthesis derivant

The proline derivative of present embodiment wherein uses 5-(3-bromophenyl)-1H-tetrazolium and N-Boc-cis-L-Hydroxyproline methyl ester 4a according to the method preparation that embodiment 4 (I) introduces.

[M+Na] ⁺＝396.39。

6B. synthesizing linear tripeptides

The linear peptides of present embodiment wherein uses proline derivative, D-β-vinyl cyclopropane aminoacid ethyl ester, the Boc-2-amino-8-nonenoic acid of step 6A preparation according to the method preparation that embodiment 4 (II) introduces.

[M+H] ⁺＝728.41。

6C. closed loop displacement reaction

The method preparation that the Macrocyclic peptides ethyl ester of present embodiment is introduced according to embodiment 4 (III) with the linear peptides of step 6B.

[M+Na] ⁺＝722.37。

6D. hydrolysis ethyl ester

Title compound finally obtains by the hydrolysis that embodiment 4 (IV) introduces with the ethyl ester of step 6C.

[M+H] ⁺＝672.49。

Embodiment 7. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

7A. proline biosynthesis derivant

The proline derivative of present embodiment wherein uses 5-(4-bromophenyl)-1H-tetrazolium and N-Boc-cis-L-Hydroxyproline methyl ester 4a according to the method preparation that embodiment 4 (I) introduces.

[M+Na] ⁺＝396.39。

7B. synthesizing linear tripeptides

The linear peptides of present embodiment wherein uses proline derivative, D-β-vinyl cyclopropane aminoacid ethyl ester and the Boc-2-amino-8-nonenoic acid of step 7A preparation according to the method preparation that embodiment 4 (II) introduces.

[[M+Na]+H] ⁺＝728.41。

7C. closed loop displacement reaction

The method preparation that the Macrocyclic peptides ethyl ester of present embodiment is introduced according to embodiment 4 (III) with the linear peptides of step 7B.

[M+Na] ⁺＝722.37。

7D. hydrolysis ethyl ester

Title compound finally obtains by the hydrolysis that embodiment 4 (IV) introduces with the ethyl ester of step 7C.

[M+H] ⁺＝672.49。

Embodiment 8. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=5-bromo-2-thienyl, j=3, m=s=1 and R ³ =R ⁴ =H

8A. proline biosynthesis derivant

The proline derivative of present embodiment wherein uses 5-(5-bromo-2-thienyl)-1H-tetrazolium and N-Boc-cis-L-Hydroxyproline methyl ester 4a according to the method preparation that embodiment 4 (I) introduces.

[M+Na] ⁺＝480.23。

8B. synthesizing linear tripeptides

The linear peptides of present embodiment wherein uses proline derivative, D-β-vinyl cyclopropane aminoacid ethyl ester and the Boc-2-amino-8-nonenoic acid of step 8A preparation according to the method preparation that embodiment 4 (II) introduces.

[M-Boc+H] ⁺＝634.29。

8C. closed loop displacement reaction

The method preparation that the Macrocyclic peptides ethyl ester of present embodiment is introduced according to embodiment 4 (III) with the linear peptides of step 8B.

[M+Na] ⁺＝736.21。

8D. hydrolysis ethyl ester

Title compound finally obtains by the hydrolysis that embodiment 4 (IV) introduces with the ethyl ester of step 8C.

[M+H] ⁺＝678.22。

Embodiment 9. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2-bromo-4-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

9A. proline biosynthesis derivant

The proline derivative of present embodiment wherein uses 5-(2-bromo-4-pyridine radicals)-1H-tetrazolium and N-Boc-cis-L-Hydroxyproline methyl ester 4a according to the method preparation that embodiment 4 (I) introduces.

[M+Na] ⁺＝453.23。

9B. synthesizing linear tripeptides

The linear peptides of present embodiment wherein uses proline derivative, D-β-vinyl cyclopropane aminoacid ethyl ester and the Boc-2-amino-8-nonenoic acid of step 9A preparation according to the method preparation that embodiment 4 (II) introduces.

[M-Boc+H] ⁺＝629.31。

9C. closed loop displacement reaction

The method preparation that the Macrocyclic peptides ethyl ester of present embodiment is introduced according to embodiment 4 (III) with the linear peptides of step 9B.

[M+Na] ⁺＝723.36。

9D. hydrolysis ethyl ester

Title compound finally obtains by the hydrolysis that embodiment 4 (IV) introduces with the ethyl ester of step 9C.

[M+H] ⁺＝673.26。

Embodiment 10. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2-xenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Ethyl ester compound (40mg), phenylboric acid (10mg), KF (100mg) and Cs with step 5C acquisition ₂CO ₃5ml DME solution (80mg) is removed oxygen, to the Pd (PPh that wherein adds solid form ₃) ₄(5mg).Heating gained reactant mixture to 90 ℃ in oil bath, vigorous stirring 6-12h.Evaporating solvent, residue is purified with the flash chromatography on silica gel method, and use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1 → 2: 1).Isolate white powder macro ring biaryl peptide ethyl ester (31mg, 78%) by the evaporation eluting solvent then,, purify with HPLC with its hydrolysis that is directly used in the foregoing description 4 (IV).

[M+Na] ⁺＝692.38。

Embodiment 11. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-xenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the phenylboric acid of step 6C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝692.38。

Embodiment 12. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-xenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the phenylboric acid of step 7C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝692.38。

Embodiment 13. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=3-(3-thienyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the 3-thienyl boric acid of step 6C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝698.32。

Embodiment 14. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-(to Trifluoromethoxyphen-l) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is with the ethyl ester compound of step 6C and the method preparation that Trifluoromethoxyphen-l boric acid is introduced according to embodiment 10, then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝776.35。

Embodiment 15. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-(to cyano-phenyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is with the ethyl ester compound of step 6C and the method preparation that cyano-phenyl boric acid is introduced according to embodiment 10, then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝692.38。

Embodiment 16. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-(3-thienyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the 3-thienyl boric acid of step 7C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝698.32。

Embodiment 17. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-(to Trifluoromethoxyphen-l) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is with the ethyl ester compound of step 7C and the method preparation that Trifluoromethoxyphen-l boric acid is introduced according to embodiment 10, then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝776.35。

Embodiment 18. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-(to cyano-phenyl) phenyl, j=3, m=s=1 and R3 =R ⁴ =H

Title compound is with the ethyl ester compound of step 7C and the method preparation that cyano-phenyl boric acid is introduced according to embodiment 10, then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝692.38。

Embodiment 19. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=5-phenyl-2-thienyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the phenylboric acid of step 8C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝698.32。

Embodiment 20. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=5-phenyl-3-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 10 with ethyl ester compound and the phenylboric acid of step 9C is then according to the method hydrolysis ethyl ester of embodiment 4 (IV).

[M+Na] ⁺＝708.30。

Embodiment 21. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, W For Q=does not exist; Y=3-chloro-4-hydroxy phenyl, j=3, m=s=1 andR ³=R ⁴ =H

Method of replacing

Title compound is by the displacement reaction preparation of methanesulfonates 2 and tetrazolium 3a.Method of replacing is as follows: 0.041mmol Macrocyclic peptides precursor methanesulfonates 2 and 0.123mmol tetrazolium 3a are dissolved in 3ml DMF, add 0.246mmol sodium carbonate (60mg).Stir gained reactant mixture 4-10h at 60 ℃, ethyl acetate extraction is used in cooling then.Organic extract liquid water (2 * 30ml) washings, vacuum concentration organic solution, the crude product of hydrolysis ethyl ester.

Embodiment 22. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-hydroxy phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound (20mg) of embodiment 4 is dissolved in 2mL diox and 1mL 1N LiOH aqueous solution.With the gained reactant mixture at stirring at room 4-8h.Reactant mixture extracts with 10mL EtOAc with 5% citric acid acidify, water 2 * 20ml washing.Evaporating solvent, residue with HPLC purify (YMC AQ12S11-0520WT post, 30-80% (100% acetonitrile) gradient, 20min).Behind lyophilization, obtain white amorphous solid title compound.

[M+Na] ⁺＝666.24。

Embodiment 23. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-bromo-4-hydroxy phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3b of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝712.18。

Embodiment 24. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=2-methyl-4-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3c of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝708.30。

Embodiment 25. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-methyl-4-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3d of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝708.30。

Embodiment 26. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=n-pro-pyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3e of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝582.33。

Embodiment 27. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=normal-butyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3f of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝596.36。

Embodiment 28. formula II chemical compounds, A=tBOG wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-ethoxyl phenenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: carry out the displacement reaction that embodiment 21 introduces with the tetrazolium 3g of methanesulfonates 2 and embodiment 3, then according to the method hydrolysis ethyl ester of embodiment 22.

[M+H] ⁺＝660.92。

Embodiment 29. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-propoxyl group phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3h of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝674.29。

Embodiment 30. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-butoxy phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3i of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.[M+Na] ⁺＝688.32。

Embodiment 31. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3j of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝646.92。

Embodiment 32. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3, the 4-Dimethoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3k of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝676.38。

Embodiment 33. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-methoxyl group-1-naphthyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 31 of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝697.00。

Embodiment 34. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

Q=does not exist, Y=4-Phenoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3m of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝708.51。

Embodiment 35. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=benzyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3n of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝630.35。

Embodiment 36. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, and Y=is to phenylbenzyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with the tetrazolium 3o of methanesulfonates 2 and embodiment 3, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝706.38。

Embodiment 37. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chlorphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-chlorphenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝650.33。

Embodiment 38. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=3-fluorophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-fluorophenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝634.37。

Embodiment 39. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-methoxyphenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝646.92。

Embodiment 40. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-Phenoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-Phenoxyphenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝708.51。

Embodiment 41. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-benzyloxy phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-benzyloxy phenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝722.32。

Embodiment 42. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=3-trifluoromethyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-trifluoromethyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝684.32。

Embodiment 43. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-bromophenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.[M+Na] ⁺＝696.28。

Embodiment 44. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-fluorophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-fluorophenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝634.36。

Embodiment 45. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-methoxyphenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝646.36。

Embodiment 46. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-ethoxyl phenenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-ethoxyl phenenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+H] ⁺＝660.92。

Embodiment 47. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-trifluoromethyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-trifluoromethyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝684.32。

Embodiment 48. formula II chemical compound, wherein A=tBOC G=OH , L=does not exist, and W is

Q=does not exist, Y=3,5-two (trifluoromethyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3,5-two (trifluoromethyl) phenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝766.32。

Embodiment 49. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-(N, N-dimethylamino)-3,5-two (trifluoromethyl) benzene Base, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-(N, N-dimethylamino)-3,5-two (trifluoromethyl) phenyl)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝695.39。

Embodiment 50. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2,4-Dichlorobenzene base, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(2, the 4-Dichlorobenzene base)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝684.27。

Embodiment 51. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

Q=does not exist, Y=3,5-Dichlorobenzene base, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3, the 5-Dichlorobenzene base)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝684.27。

Embodiment 52. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3,4-Dichlorobenzene base, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3, the 4-Dichlorobenzene base)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝684.27。

Embodiment 53. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(2-pyridine radicals)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝617.60。

Embodiment 54. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=2-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

[M+Na] ⁺＝617.60。

Embodiment 55. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=3-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(3-pyridine radicals)-1H-tetrazolium, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝645.24。

Embodiment 56. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-pyridine radicals, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with methanesulfonates 2 and 5-(4-pyridine radicals)-1H-tetrazolium class, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+H] ⁺＝595.50

Embodiment 57. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=4-methoxyl group-3-bromophenyl, j=3, m=s=1 and R ³ =R ⁴ =H

57A. preparation tetrazolium

The tetrazolium of present embodiment is prepared as follows: 4-hydroxyl-3-bromo-4-hydroxyl-phenylcyanide is dissolved in DMF, adds methyl iodide, at stirring at room 3-12h.The gained reactant mixture dilutes with EtOAc, water and salt water washing.Gained organic facies dried over sodium sulfate, vacuum concentration obtain 3-bromo-4-methoxyl group-benzonitrile.The method of introducing according to embodiment 3 is used to prepare corresponding tetrazolium with this chemical compound then.

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with 5-(3-bromo-4-methoxyl group-phenyl)-1H-tetrazolium of methanesulfonates 2 and 57A, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝724.91。

Embodiment 58. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=4-(methyl cyclopropane) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

58A. preparation tetrazolium

The tetrazolium of present embodiment is prepared as follows: 4-cyano group-phenol is dissolved in DMF, adds (bromomethyl) cyclopropane, at stirring at room 3-12h.The gained reactant mixture dilutes with EtOAc, water and salt water washing.Gained organic facies dried over sodium sulfate, vacuum concentration obtains 4-(methyl cyclopropane) benzonitrile.The method of introducing according to embodiment 3 is used to prepare corresponding tetrazolium with this chemical compound then.

Title compound is prepared as follows: the method for replacing reaction of introducing according to embodiment 21 with 5-(4-(methyl cyclopropane)-phenyl)-1H-tetrazolium of methanesulfonates 2 and 58A, and then according to the method hydrolysis ethyl ester of embodiment 22.

[M+Na] ⁺＝686.29。

Embodiment 59. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is Q=does not exist, Y=3-chloro-4-(methyl cyclopropane) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: directly use the ethyl ester title compound of embodiment 21 to need not to handle again, add (bromomethyl) cyclopropane, stir 3-12h at 60 ℃.The gained reactant mixture is cooled to room temperature, impouring 50: 50EtOAc: in the mixture of water, wash vacuum concentration with water.The rough ethyl ester compound of gained is hydrolyzed to free acid according to the method that embodiment 22 introduces.

[M+Na] ⁺＝720.24。

Embodiment 60. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with title compound and the methyl iodide of embodiment 21.

[M+Na] ⁺＝680.23。

Embodiment 61. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-ethoxyl phenenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with title compound and the ethyl iodide of embodiment 21.

[M+Na] ⁺＝694.28。

Embodiment 62. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-bromo-4-ethoxyl phenenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with the ethyl ester precursor and the ethyl iodide of embodiment 23 title compounds.

[M+Na] ⁺＝740.17。

Embodiment 63. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-(2-hydroxyl-oxethyl) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with title compound and the ethylene iodohydrin of embodiment 21.

Embodiment 64. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-bromo-4-(2-hydroxyl-oxethyl) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with the ethyl ester precursor and the ethylene iodohydrin of embodiment 23 title compounds.

[M+Na] ⁺＝754.27。

Embodiment 65. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-(O-pi-allyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with title compound and the 3-iodopropylene of embodiment 21.

[M+Na] ⁺＝706.24。

Embodiment 66. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-bromo-4-(O-pi-allyl) phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 59 with the ethyl ester precursor and the 3-iodopropylene of preparation embodiment 23 title compounds.

[M+Na] ⁺＝752.15。

Embodiment 67. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Q=does not exist, Y=3-chloro-4-(O-CH ₂SCH ₃) phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound title compound and the Cl-CH of embodiment 21 ₂SCH ₃The method of introducing according to embodiment 59 prepares.

Embodiment 68. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

The title compound ethyl ester precursor and the Cl-CH of embodiment 23 title compounds ₂SCH ₃The method of introducing according to embodiment 59 prepares.

[M+Na] ⁺＝752.15。

Embodiment 69. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Wherein Q '=-CH ₂- ,

J=3, m=s=1 and R ³ =R ⁴ =H

69A. preparation cyano group proline derivative (69b)

At 0 ℃, to suitable-4-hydroxyl-pyrrolidine-1,2-dioctyl phthalate 1-tert-butyl ester 2-methyl ester (69a) (3.94g, CH 16.06mmol) ₂Cl ₂(40ml) drip DIEA (4.3ml) and mesyl chloride (1.40ml) in the solution.After adding, 1.5h stirs the mixture.The TLC analysis confirmation reacts completely (the 50%EtOAc-hexane is used to the TLC that develops).Mixture dilutes with EtOAc, uses saturated NaHCO ₃, salt water washing after drying (Na ₂SO ₄).Behind the evaporating solvent, the oily residue is directly used in next step and need not to purify again.[M+H] ⁺＝324。

The crude product that previous step is rapid is dissolved in DMF (35ml), adds the KCN (2.5g) that grinds.With mixture 90 ℃ of heated overnight.After being cooled to room temperature, mixture dilutes with EtOAc, uses H ₂Dried over sodium sulfate is used in O and salt water washing.Crude product is with silica gel chromatography purify (20%EtOAc/ hexane).

[M+H] ⁺＝255。

69B. preparation tetrazole radical proline derivative (69c)

(669mg adds NaN in toluene 2.63mmol) (8ml) solution to nitrile 69b ₃(684mg, 10.53mmol) and Et ₃NHCl (1.45g, 10.53mmol).At 115 ℃ of heating blends 18h.Mixture CH ₂Cl ₂Dilution with the washing of 5% aqueous citric acid solution, is used dried over sodium sulfate.Evaporating solvent obtains crude product 69cEt ₃N auxiliary agent (660mg).

[M+H] ⁺＝298。

69C. preparation 5-xenyl methyl-tetrazole radical proline (69e)

69c (92.8mg, add in THF 0.31mmol) (2ml) solution 4-phenylbenzyl bromine (90.4mg, 0.37mmol) and K ₂CO ₃(140mg, 1.01mmol).Spend the night at 65 ℃ of heating blends, with the EtOAc dilution, use the salt water washing then, use dried over sodium sulfate.Behind evaporating solvent, crude product is dissolved in THF-MeOH-H ₂O (2ml: 1ml: 1ml), add LiOH (130mg).In the stirring at room mixture overnight.Reduction vaporization THF and MeOH.Residue is dissolved in EtOAc,, uses dried over sodium sulfate with the washing of 5% citric acid.Evaporating solvent obtains crude product 69d and 69e.

[M+Boc+H] ⁺＝350。

69D. preparation tripeptides (69g)

Add D-β-vinyl cyclopropane aminoacid ethyl ester HCl (66mg), DIEA (0.25ml) and HATU (164mg) successively in DMF (2.0ml) solution of 69d and 69e (about 0.31mmol).The 1h that stirs the mixture then with the EtOAc dilution, with saline, the washing of 5% citric acid, uses dried over sodium sulfate.Behind evaporating solvent, residue is dissolved in 2ml CH ₂Cl ₂, add 2ml4N HCl De dioxane solution.At stirring at room mixture 1.5h, evaporating solvent.Residue is dissolved in EtOAc, uses saturated NaHCO ₃The salt water washing is used in neutralization, uses dried over sodium sulfate.Behind evaporating solvent, residue is dissolved in DMF (2ml), add P3 (120mg), DIEA and HATU successively to it.Stir the gained mixture, analyze monitoring by TLC.After reacting completely, mixture dilutes with EtOAc, uses saline, 5% citric acid, saturated sodium bicarbonate, salt water washing successively.Organic solution dried over sodium sulfate, vacuum evaporation obtain the mixture of crude product, with it with silica gel chromatography purify (30%-50%EtOAc-hexane).

[M+H] ⁺＝740

69E. closed loop displacement reaction (69k)

The mixture (60mg) of 69f and 69g is dissolved in anhydrous CH ₂Cl ₂, make concentration reach about 0.01mol.With solution with the nitrogen current 15min that outgases carefully.Under blanket of nitrogen, add the 5%molHoveyda catalyst.Mixture is refluxed to spend the night.Evaporating solvent.Residue is filled into silicagel column, removes catalyst with the 10%EtOAc eluting.Separate that two kinds of position isomers obtain less polar product 69j (37.9mg) and than the product 69k (14.8mg) of high polarity with 30-40%EtOAc-hexane eluting.The position chemical constitution of 69j and 69k is by the NMR analysis confirmation.

[M+H] ⁺＝712。

69F. hydrolysis ethyl ester (69)

Ester 69h (37.9mg) is dissolved in THF-MeOH-H ₂O (2ml: 1ml: 1ml), add LiOH (21mg).In the stirring at room mixture overnight.Reduction vaporization THF and MeOH.Residue is dissolved in EtOAc,, uses dried over sodium sulfate with the washing of 5% citric acid.Evaporating solvent obtains crude product.Crude product is with the silica gel chromatography (5%MeOH/CH that purifies ₂Cl ₂) obtain title compound 69k.

[M+H] ⁺＝684。

Embodiment 70. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, and W is

Wherein Q '=-CH ₂- ,

J=3, m=s=1 and R ³ =R ⁴ =H

Ester 69i (14.8mg) is dissolved in THF-MeOH-H ₂O (2ml: 1ml: 1ml), add LiOH (21mg).In the stirring at room mixture overnight.Reduction vaporization THF and MeOH.Residue is dissolved in EtOAc,, uses dried over sodium sulfate with the washing of 5% citric acid.Evaporating solvent obtains crude product.Crude product is with the silica gel chromatography (5%MeOH/CH that purifies ₂Cl ₂) obtain title compound 70.

[M+H] ⁺＝684。

Embodiment 71. formula II chemical compound, wherein A=-(C=O)-O-R ¹, R ¹ =cyclopenta, G=OH , L=does not exist, W is Q=does not exist, the Y=phenyl; J=3, m=s=1 and R ³ =R ⁴ =H

71a-sloughs the protection of amine.

The title compound of 0.041mmol embodiment 21 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration reaction residue 69a.

71b-chloro-formate reagent

Chloro-formate reagent 71b is prepared as follows: the 0.045mmol cyclopentanol is dissolved in THF (3ml), adds the toluene solution (20%) of 0.09mmol phosgene.In stirring at room gained reactant mixture 2h, solvent removed in vacuo.Add DCM in the residue, vacuum concentration obtains chloro-formate reagent 71b to doing twice then.

71c-prepares carbamate

The title carbamate is prepared as follows: residue 71a is dissolved in 1ml THF, adds 0.045mmol TEA, cooling gained reactant mixture to 0 ℃.The 3ml THF solution that in this 0 ℃ of reactant mixture, adds chloro-formate reagent 71b.The gained reactant mixture with the EtOAc extraction, with 1M sodium bicarbonate, water and salt water washing, is used dried over mgso at 0 ℃ of reaction 2h, and vacuum concentration is to doing.Crude compound is purified with silica column, then the method hydrolysis ethyl ester of introducing according to embodiment 22.

Embodiment 72. formula II chemical compound, wherein A=-(C=O)-O-R ¹, R ¹ =cyclobutyl, G=OH , L=does not exist, and W is Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound wherein uses title compound and the cyclobutanol of embodiment 21, then the method hydrolysis ethyl ester of introducing according to embodiment 22 according to the method preparation that embodiment 71 introduces.

Embodiment 73. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclohexyl, G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound wherein uses title compound and the Hexalin of embodiment 21, then the method hydrolysis ethyl ester of introducing according to embodiment 22 according to the method preparation that embodiment 71 introduces.

Embodiment 74. formula II chemical compound, wherein A=-(C=O)-O-R ¹ ,

G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is according to the method preparation that embodiment 71 introduces, and wherein uses the title compound of embodiment 21 and (R)-3-hydroxyl tetrahydrofuran, method hydrolysis ethyl ester of introducing according to embodiment 22 then.

Embodiment 75. formula II chemical compound, wherein A=-(C=O)-O-R ¹ ,

G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is according to the method preparation that embodiment 71 introduces, and wherein uses the title compound of embodiment 21 and (S)-3-hydroxyl tetrahydrofuran, method hydrolysis ethyl ester of introducing according to embodiment 22 then.

Embodiment 76. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is according to the method preparation that embodiment 71 introduces, wherein use embodiment 21 title compound and The method hydrolysis ethyl ester of introducing according to embodiment 22 then.

Embodiment 77. formula II chemical compound, wherein A=-(C=O)-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 21 is dissolved in 4ml 4M HCl De dioxane solution, stirred reaction mixture 1h.The vacuum concentration reaction residue.Add 4ml THF and 0.045mmol TEA in residue, cooling mixture to 0 ℃ is to wherein adding 0.045mmol ring valeryl chlorine.Stir gained reactant mixture 2h at 0 ℃.Then reactant mixture is extracted with EtOAc, with 1M sodium bicarbonate, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 22.

Embodiment 78. formula II chemical compound, wherein A=-(C=O)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 21 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isocyanates in 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Then solution is extracted with EtOAc, with 1%HCl, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 22.

Embodiment 79. formula II chemical compound, wherein A=-(C=S)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 21 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isothiocyanate in 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Then solution is extracted with EtOAc, with 1%HCl, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 22.

Embodiment 80. formula II chemical compound, wherein A=-S (O) ₂-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

Q=does not exist, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 21 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.The spissated reaction residue of gained is dissolved in 4ml THF, adds 0.045mmol TEA, be cooled to 0 ℃ to it.Add the 0.045mmol cyclopentyl sulfonyl chloride in 0 ℃ of solution, stir gained reactant mixture 2h at 0 ℃.Then solution is extracted with EtOAc, with 1M sodium bicarbonate, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 22.

Embodiment 81. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-O- Phenethyl, L does not exist, and W is

Q=does not exist, Y=phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: at 0 ℃, add 1.2eq.PyBrOP, 4eq.DIEA, catalytic amount DMAP in the 0.5ml DCM solution of the title compound of embodiment 71 and phenethanol 81a.Stir gained reactant mixture 1h at 0 ℃, then at the 4-12h internal heating to room temperature.Reactant mixture obtains independent phenethyl ester 81b title compound with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1)).

Other ester can prepare with identical method.

Embodiment 82. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-NH- Phenethyl, L=does not exist, and W is

Q=does not exist, the Y=phenyl, and j=3, M=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: add EDC (1.2eq.) and DIEA (4eq.) at 0 ℃ in the 0.5ml DMF solution of the title compound of embodiment 71 and phenethylamine 82a (0.05ml).Stir gained reactant mixture 1h.Subsequently, with reactant at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound phenethyl amide 82b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1)).Other amide can prepare with identical method.

Embodiment 83. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-NHS (O) ₂-phenethyl, L=does not exist, and W is

Q=does not exist, Y=benzene Base, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: at 0 ℃, add 1.2eq.PyBrOP, 4eq.DIEA and catalytic amount DMAP in the 0.5ml DCM solution of the title compound of embodiment 71 and α-toluenesulfonamide 83a (10mg).Stir gained reactant mixture 1h, then at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound sulfonamide 83c with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1)).

Other sulfonamide can prepare with identical method.

Embodiment 84. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-OH , L=does not exist, and W is Q=does not exist, the Y=phenyl, and j=3, M=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: at 0 ℃, add Alpha-hydroxy-Alpha-Methyl-propionitrile (0.1ml) and catalytic amount TFA in the 0.5mlTHF solution of the title compound of embodiment 71.In 4-12h, the gained reactant mixture is heated to room temperature from 0 ℃, uses the hydrolysis of concentrated hydrochloric acid De dioxane solution then.Reactant extracts with EtOAc, water and salt water washing, the crude product of acquisition 'alpha '-hydroxylation compound 83a.Crude compound 84a carries out the Dess-Marin oxidation reaction in THF (0.5ml), obtain the crude product of alpha-carbonyl chemical compound 84b.Rough 84b obtains title compound keto acid 84b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Embodiment 85. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- (C=O)-and the O-phenethyl, L=does not exist, and W is

Q=does not exist, Y=benzene Base, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 81 with title compound keto acid and the phenethanol of embodiment 84.

Embodiment 86. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta.G=- (C=O)-and the NH-phenethyl, L=does not exist, and W is

Q=does not exist, Y-benzene Base, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 82 with title compound keto acid and the phenethylamine of embodiment 84.

Embodiment 87. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-NH-S (O) ₂-benzyl, L=does not exist, and W is Q=does not exist, Y= Phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 83 with title compound keto acid and the α-toluenesulfonamide of embodiment 84.

Embodiment 88. formula II chemical compounds, A=tBOC wherein, G=OH , L=-(C=O) CH ₂- , W is

Q=does not exist, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Synthetic (2S)-N-Boc-amino-5-oxo-ninth of the ten Heavenly Stems-8-olefin(e) acid

88A. above-mentioned aminoacid is prepared as follows: under blanket of nitrogen ,-78 ℃, in 5min, in the anhydrous THF solution of the monoene propyl ester of malonic acid, drip n-Bu ₂Mg.Behind stirring at room gained suspension 1h, be evaporated to dried then.Vacuum drying solid Mg salt 88b.

With glutamate derivatives 88a at first with 1,1 '-the anhydrous THF of carbonyl dimidazoles mixes, at stirring at room mixture 1h with activation free acid part.Subsequently, activatory glutamate derivatives imports in the solution of Mg salt 88b, at stirring at room gained reactant mixture 16h with conduit.Mixture dilutes with ethyl acetate, and organic solution is evaporated with 0.5NHCl (0 ℃) and salt water washing, dry back.The gained residue splits (with 35-40% ethyl acetate/hexane eluant system) by the silicon dioxide chromatography and obtains diester 88c.

88B. add the DMF solution of diester in the dry DMF agitating solution of four (triphenylphosphine) PD (0).At stirring at room mixture 3.5h.Reduction vaporization DMF, residue dilutes with EtOAC.EtOAc solution evaporates with 0 ℃ of HCl of 0.5N, salt water washing, dry back.Residue obtains methyl ester intermediate with silica gel chromatography purification (using the 15%-20%EtOAc/ hexane as eluant).

Methyl ester intermediate adds LiOHH with THF and water dilution ₂O is at stirring at room gained mixture 25h, by the performance of TLC monitoring hydrolysis.The vacuum concentration reactant mixture further dilutes with dichloromethane to remove most of THF.Gained solution is used anhydrous sodium sulfate drying, vacuum concentration with 1N HCl washing.In order to remove a spot of impurity and excessive Boc ₂O, crude product with flash chromatography purify (with 100% hexane to the solvent gradient of 100%EtOAc as eluant).Obtain (2S)-N-Boc-amino-5-oxo-ninth of the ten Heavenly Stems-8-olefin(e) acid 88d.The details of relevant aforementioned aminoacid synthetic method can be referring to T.Tsuda etc., J.Am.Chem.Soc., and 1980,102,6381-6384 and WO 00/59929, the full content with them is attached to herein by reference.

88C. the cyclic peptide precursor methanesulfonates of synthetic modification

The route of synthesis preparation that the cyclic peptide precursor methanesulfonates of modifying is introduced according to embodiment 1, and substitute Boc-L-2-amino-8-nonenoic acid 1a with (2S)-N-Boc-amino-5-oxo-ninth of the ten Heavenly Stems-8-olefin(e) acid 88d, the method for introducing by embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with synthetic modification among the 88C react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 89. formula II chemical compounds, A=tBOC wherein, G=OH , L=CH (CH ₃) CH ₂- , W is Q=does not exist, Y=phenyl, j=1, m=s=1, R ³ =methyl and R ⁴ =H

Synthetic (2S, 5R)-N-Boc-2-amino-5-methyl-ninth of the ten Heavenly Stems-8-olefin(e) acid (89h).

89A. in 1min, in solid 2-acetylamino malonic ester 89b, add the pyridine solution of (R)-(+)-citronellal 89a.Cooling gained solution adds acetic anhydride in 4min in 10 ℃ of cooling baths.At stirring at room gained solution 3h, add part 2-acetylamino malonic ester 89a in addition.At stirring at room gained mixture 11h.Add ice then, agitating solution 1.5h, mixture is with the dilution of 250ml water, with two parts of extracted with diethyl ether.Organic facies 1NHCl, saturated NaHCO ₃Dried over sodium sulfate is used in washing, concentrates, and obtains chemical compound 89C by flash chromatography purification (40%EtOAc/ hexane).

89B.89c the dehydrated alcohol de gassed solution in add (S, S)-Et-PUPHOSRh (COD) OTf.Mixture is placed the 30psi nitrogen atmosphere, stir 2h with the Parr agitator.The gained mixture is evaporated to the dried crude compound 50d that obtains, its step that is directly used in subsequently be need not to purify again.

89C. chemical compound 89d is dissolved in tBuOH/ acetone/H ₂The mixture of O (1: 1: 1) places ice bath (0 ℃).Add NMMO and OsO continuously ₄, at stirring at room reactant mixture 4h.Most of acetone is removed in vacuum evaporation, the mixture ethyl acetate extraction.Organic layer water and salt water washing, dried with being evaporated to behind the anhydrous magnesium sulfate drying.Handle the back at flash column chromatography (with 1% ethanol/ethyl acetate as eluant) and obtain high-purity diols 50e.

89D. THF/H at 0 ℃ of glycol 89e ₂Add NaIO in O (1: the 1) solution ₄, at stirring at room reactant mixture 3.5h.Most of THF solvent is removed in vacuum evaporation subsequently, and remaining mixture extracts with EtOAc.The organic layer that merges is with 5% aqueous citric acid solution, 5%aq.NaHCO ₃With the salt water washing, organic facies is evaporated to dried with the dried over mgso final vacuum.Aldehyde intermediate 89f directly uses crude product in next step.

89E.Ph ₃PCH ₃Add KHMDS in the anhydrous toluene solution of Br and form suspension, at blanket of nitrogen, stirring at room 30min.After stirring, cooling suspension to 0 ℃ adds the THF solution of aldehyde intermediate 89f, and mixture heated to room temperature, is stirred 1h.The most of THF of vacuum evaporation adds mixture with EtOAc, organic facies water, 5%aq.NaHCO ₃With the salt water washing.With the organic facies dried over mgso, vacuum evaporation is to doing then.After purifying, isolate neat compounds 89g with flash chromatography on silica gel method (using hexane: EtOAc (3: 2)) as eluant.

89F. add Boc in the THF solution of rough 89g ₂O, DMAP are heated to backflow 2.5h with reactant mixture.Subsequently, evaporate most of THF, crude mixture is diluted with dichloromethane, removes DMAP with 1N HCl washing.The saturated NaHCO of organic layer ₃Aqueous solution extraction is used anhydrous sodium sulfate drying, vacuum concentration.Crude product adds LiOHH with THF and water dilution ₂O is at stirring at room gained mixture 25h, by the performance of TLC monitoring hydrolysis.The vacuum concentration reactant mixture further dilutes with dichloromethane to remove most of THF.Gained solution is used anhydrous sodium sulfate drying, vacuum concentration with 1N HCl washing.In order to remove a spot of impurity and excessive Boc ₂O, crude product with flash chromatography purify (with 100% hexane to the solvent gradient of 100%EtOAc as eluant).Obtain (2S, 5R)-N-Boc-2-amino-5-methyl-ninth of the ten Heavenly Stems-8-olefin(e) acid 89h.The detailed introduction of relevant above-mentioned aminoacid synthetic method is attached to this paper with its full content by reference referring to WO 00/59929.

89G. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is according to the route of synthesis preparation of embodiment 1, wherein use (2S, 5R)-and N-Boc-2-amino-5-methyl-ninth of the ten Heavenly Stems-8-olefin(e) acid 89h substitutes Boc-L-2-amino-8-nonenoic acid 1a, and the method for introducing by embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 89G react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 90. formula II chemical compounds, A=tBOC wherein, G=OH , L=-O- , W is

Q=does not exist, Y=phenyl, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Synthetic N-Boc-O-pi-allyl-(L)-threonine (90d)

90A. Boc-(L)-threonine 90a is partially soluble in methylene chloride at 0 ℃.The diethyl ether solution that adds Azimethylene. illustrates to have Azimethylene. up to the solution flavescence.Behind the evaporating solvent, obtain rough methyl ester 90b.

90B. 90b is dissolved in absolute ether with intermediate, adds Ag ₂O and new activatory 4_ molecular sieve.At last, allyl iodide is added in the reactant mixture, under refluxing, stir.Behind 20h and 30h, add allyl iodide in the reactant mixture once more respectively, continuous stirring amounts to 36h.Then by the diatomite filtration mixture, by the flash chromatography on silica gel method purify (with EtOAc/ hexane 1: 4 as eluant) obtain chemical compound 90C.

90C. 90c is dissolved in THF/MeOH/H with chemical compound ₂O mixture (2: 1: 1) adds LiOHH ₂O.At stirring at room solution 2h, be acidified to pH～3, solvent removed in vacuo then with 1N HCl.Obtain crude compound 90d.The details of relevant aforementioned aminoacid synthetic method are attached to this paper with its full content by reference referring to WO 00/59929.

90D. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute Boc-L-2-amino-8-nonenoic acid 1a reaction according to the route of synthesis of embodiment 1 with N-Boc-O-pi-allyl-(L)-threonine 90d, the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 90D react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 91. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S- , W is

Q=does not exist, Y=phenyl, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Synthetic (2S, 3S)-N-Boc-2-amino-3-(sulfydryl pi-allyl) butanoic acid (91e).

91A. 91a is dissolved in pyridine with chemical compound, cooling solution to 0 ℃ in ice bath is divided into small lot and adds toluene sulfochloride, and reactant mixture is at ether and H ₂Distribute between O.Ether layer is further used 0.2N HCl and salt water washing, uses anhydrous magnesium sulfate drying, filters, and vacuum concentration is to doing.Purify (with 8: 2 to 7: 3 hexanes/EtOAc gradient as eluant) with the flash chromatography on silica gel method, thereby isolate tosyl radical derivative 91b.

91B. add thioacetic acid potassium in the anhydrous DMF solution of tosyl radical derivative 91b, at stirring at room reactant mixture 24h.The most of DMF of vacuum evaporation, remaining mixture is at EtOAc and H ₂Distribute between O.Water layer reuse EtOAc extraction, the salt water washing of the organic layer of merging, dried with being evaporated to behind the anhydrous magnesium sulfate drying.With the flash chromatography on silica gel method purify (with hexane/EtOAc 4: 1 as eluant) obtain thioesters 91c.

91C. add H in the thioesters 91c solution ₂O/EtOH (3: 5) adds 0.2M NaOH aqueous solution, at stirring at room mixture 1.5h.Add allyl iodide then, continue at stirring at room 30min.Reactant mixture is concentrated into half of original volume, extracts with EtOAc then.With 0.5N HCl cold water solution water layer is acidified to pH～3, extracts with EtOAc once more.The organic layer salt water washing that merges is evaporated to dried with the anhydrous magnesium sulfate drying final vacuum.Crude reaction mixture contains at least four kinds of products; After handling, isolate all products with flash chromatography on silica gel method (with 9: 1 to 3: 1 hexanes/EtOAc gradient).Required product 91d is the chemical compound of polarity minimum.

91D. MeOH/H with chemical compound 91d ₂O (3: 1) solution and NaOH aqueous solution (0.3N) mix 1h at mixed at room temperature 24h at 40 ℃.Reactant mixture 0.5N HCl cold water solution acidify, vacuum is removed MeOH, and the residue aqueous mixture extracts with EtOAc.The organic facies dried over mgso is evaporated to and does to obtain chemical compound 91e.The details of relevant above-mentioned aminoacid synthetic method are attached to this paper with its full content by reference referring to WO 00/59929.

91E. the cyclic peptide precursor methanesulfonates of synthetic modification

Cyclic peptide-precursor methanesulfonates of modifying is prepared as follows: with (2S, 3S)-and N-Boc-2-amino-3-(sulfydryl pi-allyl) butanoic acid 52e substitutes the route of synthesis reaction that Boc-L-2-amino-8-nonenoic acid 1a introduces according to embodiment 1, and the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 91E react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 92. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O)- , W is

Q=does not exist, Y=phenyl, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

The aminoacid that preparation is modified

92A. the aminoacid of modifying is prepared as follows: (1.1eq.) is water-soluble with sodium metaperiodate, is cooled to 0 ℃ in ice bath, drips chemical compound 91d De dioxane solution then.Stir gained reactant mixture 1h at 0 ℃, stir 4h at 40 ℃.Concentrated reaction mixture adds entry, twice of dichloromethane extraction of mixture.The organic layer water, the salt water washing that merge are used anhydrous magnesium sulfate drying, vacuum concentration.The aminoacid 92a that the method reduction that methyl ester is introduced by embodiment 91D obtains modifying.The details of relevant above-mentioned aminoacid synthetic method can be referring to T.Tsuda etc., J.Am.Chem.Soc., and 1980,102,6381-6384 and WO 00/59929, the full content with them is attached to herein by reference.

92B. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute the route of synthesis reaction of Boc-L-2-amino-8-nonenoic acid 1a according to embodiment 1 with the aminoacid 92a that modifies, the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 92B react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 93. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O) ₂- , W For

Q=does not exist, Y=phenyl, j=2, m=s=1, R ³ =methyl and R ⁴ =H

The aminoacid that preparation is modified

93A. the aminoacid of modifying is prepared as follows: (1.1eq.) is water-soluble with sodium metaperiodate, is cooled to 0 ℃ in ice bath, drips chemical compound 92d De dioxane solution then.Stir gained reactant mixture 1h at 0 ℃, stir 4h at 40 ℃.Concentrated reaction mixture adds entry, twice of dichloromethane extraction of mixture.The organic layer water, the salt water washing that merge are used anhydrous magnesium sulfate drying, vacuum concentration.The aminoacid 92a that the method reduction that methyl ester is introduced according to embodiment 91D obtains modifying.The details of relevant above-mentioned aminoacid synthetic method can be referring to T.Tsuda etc., J.Am.Chem.Soc., and 1980,102,6381-6384 and WO00/59929, the full content with them is attached to herein by reference.

93B. the cyclic peptide precursor methanesulfonates of synthetic modification

Be prepared as follows the cyclic peptide precursor methanesulfonates of modification: substitute the route of synthesis reaction that Boc-L-2-amino-8-nonenoic acid 1a introduces according to embodiment 1 with the aminoacid 93a that modifies, the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 93B react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 94. formula II chemical compounds, A=tBOC wherein, G=OH , L=-SCH ₂CH ₂- , W is

Q=does not exist, Y=phenyl, j=0, m=s=1 and R ³ =R ⁴ =CH ₃

94A. synthetic (S)-N-Boc-2-amino-3-methyl-3-(1-sulfydryl-4-cyclobutenyl) butanoic acid (94b)

L-penicillamine 94a is dissolved in DMF/DMSO (5: 1), subsequently with 4-bromine amylene and CsOHH ₂O adds mixture, continuous stirring 12h again.Remove DMF with final vacuum, remaining mixture is diluted to pH～4-5 with 0.5N HCl (0 ℃), uses the EtOAC extracting twice then.Organic facies is used dried over mgso with salt water washing (2x), is evaporated to do to obtain rough carboxylic acid 94a.The details of relevant above-mentioned aminoacid synthetic method are attached to this paper with its full content by reference referring to WO 00/59929.

94B. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute the route of synthesis reaction of Boc-L-2-amino-8-nonenoic acid 1a according to embodiment 1 with the aminoacid 94a that modifies, the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 94B react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 95. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CF ₂CH ₂- , W For

Q=does not exist, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Synthetic (2S)-N-Boc-amino-5-two fluoro-ninth of the ten Heavenly Stems-8-olefin(e) acid (95b).

95A. ketonic compound 88d (0.30g, add in 5ml DCM solution 1mmol) DAST (the diethylamino sulfur trifluoride, 0.2g, 1.2eq).At room temperature reaction 2-3 days.Evaporating solvent, residue with the flash chromatography on silica gel method purify (with the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluant) obtain isolating methyl ester 95a.Relevant above synthetic more details are referring to Tius, Marcus A etc., Tetrahedron, 1993,49,16; 3291-3304 is attached to this paper with its full content by reference.

95B. 95a is dissolved in THF/MeOH/H with methyl ester ₂O (2: 1: 1) adds LiOHH ₂O.At stirring at room solution 2h, be acidified to pH～3 with 1N HCl, solvent removed in vacuo obtains rough (2S)-N-Boc-amino-5-two fluoro-ninth of the ten Heavenly Stems-8-olefin(e) acid 95b then.

95C. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute Boc-L-2-amino-8-nonenoic acid 1a reaction according to the route of synthesis of embodiment 1 with rough (2S)-N-Boc-amino-5-two fluoro-ninth of the ten Heavenly Stems-8-olefin(e) acid 95b, the method according to embodiment 2 introductions is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 95C react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 96. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CFHCH ₂- , W is Q=does not exist, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Synthetic (2S)-N-Boc-amino-5-fluoro-ninth of the ten Heavenly Stems-8-olefin(e) acid (96c).

96A. add NaBH in the 5ml methanol solution of ketonic compound 88d ₄(2.2eq).Reactant mixture at stirring at room 2-6h, is used the quencher of 1M ammonium chloride then, with EtOAc extraction (30ml).Evaporating solvent obtains rough hydroxy compounds 96a.

96B. hydroxy compounds 96a is dissolved in 5ml DCM, and (0.2g 1.2eq), stirs 1h at-45 ℃ to add DAST to it.Then reactant mixture is heated to room temperature, stirred 2-3 days.Evaporating solvent, residue with the flash chromatography on silica gel method purify (with the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluant) obtain isolating single fluoric compound methyl ester 95b.Relevant this synthetic further information is referring to Buist, Peter H etc., and Tetrahedron Lett., 1987,28,3891-3894 is attached to this paper with its full content by reference.

96B. 96b is dissolved in THF/MeOH/H with methyl ester ₂O (2: 1: 1) adds LiOHH ₂O.At stirring at room solution 2h, be acidified to pH～3 with 1N HCl then, solvent removed in vacuo obtains rough (2S)-N-Boc-amino-5-two fluoro-ninth of the ten Heavenly Stems-8-olefin(e) acid 96C then.

96C. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute Boc-L-2-amino-8-nonenoic acid 1a reaction according to the route of synthesis of embodiment 1 with the single fluoro-of rough (2S)-N-Boc-amino-5-ninth of the ten Heavenly Stems-8-olefin(e) acid 96b, the method according to embodiment 2 introductions is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: cyclic peptide precursor methanesulfonates and 5-phenyl-1H-tetrazolium with the modification that generates among the 96C react according to the method for replacing that embodiment 21 introduces, then the method hydrolysis ethyl ester of introducing by embodiment 22.

Embodiment 97. formula III chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For Q=does not exist, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

97A. saturated cyclic peptide precursor methanesulfonates is prepared as follows: with the MeOH catalytic reduction methanesulfonates cyclic peptide precursor 2 in the presence of hydrogen that contains Pd/C.

Title compound is prepared as follows: react according to the method for replacing that embodiment 21 introduces with the saturated cyclic peptide precursor methanesulfonates that generates among the 97A and 5-phenyl-1H-tetrazolium, then the method hydrolysis ethyl ester of introducing by embodiment 22.

The compounds of this invention has effective HCV NS3 protease rejection characteristic.Embodiment hereinafter will illustrate the method for test The compounds of this invention anti-hcv activity.

Embodiment 98. synthetic triazoles

The exemplary triazole derivative that is used to prepare The compounds of this invention can prepare according to following examples.

Triazole of the present invention can be prepared as follows: make the 4mmol alkine compounds 98a (commercially available or with following method preparation) and the 2ml xylene solution of 8mmol nitrine trimethyl silicane react 24-72h in 140 ℃ in manometer tube.The gained reactant mixture directly separates by silica column, obtains triazole 98b, the 30-90% yield.

Embodiment 99. synthetic alkynes

99A.Sonogashira reaction

The alkynes that the present invention uses can be by the de gassed solution and 140mg (0.2mmol) PdCl of Sonogashira prepared in reaction: 4mmol uncle alkine compounds 99a, 4mmol aryl halide (Y-halogen), 1ml triethylamine and 10mol acetonitrile ₂(PPh ₃) ₂And 19mg (0.1mmol) CuI reaction.With the degassing of gained reactant mixture, at stirring at room 5min.Reactant is heated to 90 ℃ then, stirs 12h.Subsequently, the vacuum concentration reactant mixture is by the alkynes 98a that silica column purification acquisition replaces, 60-90% yield.

99B. synthetic alkynyl amide

Other alkynes that the present invention uses can be prepared as follows: make 15ml DMF solution and the 11mmol amine 99b reaction of the acid of 10mmol alkynyl 99b, 11mmol BOP, 22mmol DIEA, at stirring at room 3h.Use ethyl acetate (2 * 50ml) extractive reaction mixture then; Use 1M NaHCO ₃(2 * 30ml), water (2 * 30ml), 5% citric acid (2 * 50ml) and saline (2 * 30ml) washing; Use anhydrous sodium sulfate drying; Vacuum concentration obtains alkynes 99d, 90% yield.

Embodiment 100. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For X=H , Y=4-tert-butyl-phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound prepares in accordance with the following methods: 2mmol (0.54g) Boc methyl ester azido proline 100a and 2.5mmol 4-tert-butyl benzene ethyl-acetylene 100b are dissolved in 2ml dimethylbenzene, stir 12h at 110 ℃.The gained reactant mixture directly separates by silica column, splits out 100c and 100d, yield 90%.

Title compound is prepared as follows: the RCM method of introducing according to embodiment 1 substitutes the hydroxyproline reaction with 100b, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 106.

[M+Na] ⁺＝671.72。

Embodiment 101. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=4-tert-butyl-phenyl, Y=H , j=3, m=s=1 and R ³ =R ⁴ =H

Be prepared as follows title compound: the RCM method of introducing according to embodiment 1 substitutes the hydroxyproline reaction with 100c, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 106.

[M+H] ⁺＝649.44。

Embodiment 102. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

X and Y combine=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The proline that the corresponding triazole of title compound replaces is prepared as follows: 1.5mmol (0.5g) hydroxyproline methanesulfonates 102a and 4.5mmol benzotriazole 102b are dissolved in 5ml DMF, add 9mmol (2.9g) cesium carbonate, stir gained reactant mixture 12h at 70 ℃.Reactant mixture extracts with EtOAc, with 1M sodium bicarbonate and salt water washing.The organic layer dried over mgso, vacuum concentration.Split the isomer 102c and the 102d of expection by the silicon dioxide column chromatography.

Title compound is prepared as follows: the RCM method of introducing according to embodiment 1 substitutes the hydroxyproline reaction with 102d, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 106.[M+Na] ⁺＝588.46。

Embodiment 103. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For X and Y combine=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the RCM method of introducing according to embodiment 1 substitutes the hydroxyproline reaction with 102c, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 106.

[M+Na] ⁺＝588.50。

Embodiment 104. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The proline that the corresponding triazole of title compound replaces is prepared as follows: 1.5mmol (0.5g) hydroxyproline methanesulfonates 102a and 4.5mmol benzotriazole 102b are dissolved in 5mlDMF, add 9mmol (2.9g) cesium carbonate, stir gained reactant mixture 12h at 70 ℃.Reactant mixture extracts with EtOAc, with 1M sodium bicarbonate and salt water washing.The organic layer dried over mgso, vacuum concentration.

Title compound is prepared as follows: use the proline of the triazole replacement of present embodiment to substitute hydroxyproline according to the RCM method that embodiment 1 introduces, subsequently the method hydrolysis ethyl ester of introducing according to embodiment 106.

[M+Na] ⁺＝690.42。

Embodiment 105. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, W For

The X=Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: with title compound and the 0.123mmol 4 of 0.041mmol embodiment 2, the 5-diphenyl triazole is dissolved in 3ml DMF, adds 0.246mmol cesium carbonate (80mg), at 70 ℃ of reaction 12h.Reactant mixture extracts with EtOAc, with the 1M sodium bicarbonate (2 * 30ml) and water (2 * 30ml) wash.Gained organic solution vacuum concentration is extremely done.

Embodiment 106. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For The X=Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 105 is dissolved in the 3ml diox, adds 2ml1M LiOH, at room temperature reaction 8h.Subsequently, with citric acid conditioned reaction mixture pH to 3,, use saline and water washing then with the EtOAc extraction.Vacuum concentration organic solution is purified with HPLC.

[M+Na] ⁺＝690.42。

Embodiment 107. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

The proline precursor that the triazole of title compound replaces is prepared as follows: 0.93mmol (0.25g) azido proline 100a and 1mmol dibenzenyl are dissolved in 2ml dimethylbenzene, are heated to 110 ℃, stir 12h.Reactant mixture directly separates acquisition 0.27g107a (90%) by silica column.[M+H] ⁺：449.05。The method for hydrolysis of introducing by embodiment 105 obtains 0.26g 107b (99%).

Title compound is prepared as follows: the RCM method of introducing according to embodiment 1 substitutes the hydroxyproline reaction with 107b.

[M+Na] ⁺＝691.99。

Embodiment 108. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For The X=n-pro-pyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

108a prepares triazole

Prepare 4-(n-pro-pyl)-5-Phenyltriazole with n-propylbenzene ethyl-acetylene and Hydrazoic acid,sodium salt according to the method for embodiment 98.

Title compound is prepared as follows: title compound and 4-(n-pro-pyl)-5-Phenyltriazole 108a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+Na] ⁺＝657.99。

Embodiment 109. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=m-methoxyphenyl, the Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

109a prepares alkynes

Method according to embodiment 99A prepares 2-(m-methoxyphenyl)-4-methoxybenzene ethyl-acetylene with 4-methoxybenzene ethyl-acetylene and 3-bromoanisole.

109b prepares triazole

Method according to embodiment 3 prepares 4-(m-methoxyphenyl)-5-(p-methoxyphenyl) triazole with alkynes 109a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(m-methoxyphenyl)-5-(p-methoxyphenyl)-triazole 109a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+Na] ⁺＝752.08。

Embodiment 110. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For Bromophenyl between X=, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

110a prepares alkynes

Method according to embodiment 99A prepares 2-(bromophenyl)-4-methoxybenzene ethyl-acetylene with 4-methoxybenzene ethyl-acetylene and 3-iodo-5-bromobenzene.

110b prepares triazole

Method according to embodiment 3 prepares 4-(bromophenyl)-5-(p-methoxyphenyl) triazole with alkynes 110a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(bromophenyl)-5-(p-methoxyphenyl) triazole 110a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+Na] ⁺＝800.05。

Embodiment 111. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=1-naphthyl, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

111a prepares alkynes

Method according to embodiment 99A prepares 2-(1-naphthyl)-4-methoxybenzene ethyl-acetylene with 1-iodine naphthalene and 4-methoxybenzene ethyl-acetylene.

111b prepares triazole

Method according to embodiment 3 prepares 4-(bromophenyl)-5-(p-methoxyphenyl) triazole with 2-(1-naphthyl)-4-methoxybenzene ethyl-acetylene 113a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(1-naphthyl)-5-(p-methoxyphenyl) triazole 113d with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+Na] ⁺＝772.11。

Embodiment 112. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=2-thienyl, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

112a prepares alkynes

Method according to embodiment 99A prepares 2-(2-thienyl)-4-methoxybenzene ethyl-acetylene with 2-iodo-thiophene and 4-methoxybenzene ethyl-acetylene.

112b prepares triazole

Method according to embodiment 3 prepares 4-(2-thienyl)-5-(p-methoxyphenyl) triazole with 2-(2-thienyl)-4-methoxybenzene ethyl-acetylene 112a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(2-thienyl)-5-(p-methoxyphenyl) triazole 112a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝705.31。

Embodiment 113. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=3-thienyl, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

113a prepares alkynes

Method according to embodiment 99a prepares 2-(3-thienyl)-4-methoxybenzene ethyl-acetylene with 2-iodo-thiophene and 4-methoxybenzene ethyl-acetylene.

113b prepares triazole

Method according to embodiment 3 prepares 4-(3-thienyl)-5-(p-methoxyphenyl) triazole with 2-(3-thienyl)-4-methoxybenzene ethyl-acetylene 113a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(3-thienyl)-5-(p-methoxyphenyl) triazole 113a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+Na] ⁺＝727.21。

Embodiment 114. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=4-pyrazolyl, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

114a prepares alkynes

Method according to embodiment 99A prepares 2-(4-pyrazolyl)-4-methoxybenzene ethyl-acetylene with 4-iodine pyrazoles and 4-methoxybenzene ethyl-acetylene.

114b prepares triazole

Method according to embodiment 3 prepares 4-(4-pyrazolyl) 5-(p-methoxyphenyl) triazole with 2-(4-pyrazolyl)-4-methoxybenzene ethyl-acetylene 114a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(4-pyrazolyl)-5-(p-methoxyphenyl) triazole 114a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝700.82。

Embodiment 115. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For The X=3-pyridine radicals, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

115a prepares alkynes

Method according to embodiment 99A prepares 2-(3-pyridine radicals)-4-methoxybenzene ethyl-acetylene with 3-iodine pyridine and 4-methoxybenzene ethyl-acetylene.

115b prepares triazole

Method according to embodiment 3 prepares 4-(3-pyridine radicals)-5-(p-methoxyphenyl) triazole with 2-(3-pyridine radicals)-4-methoxybenzene ethyl-acetylene 115a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(3-pyridine radicals)-5-(p-methoxyphenyl) triazole 115a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝700.36。

Embodiment 116. formula II chemical compounds. A=tBOC wherein, G=OH , L=does not exist, and W is

The X=2-pyridine radicals, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

116a prepares alkynes

Method according to embodiment 99A prepares 2-(2-pyridine radicals)-4-methoxybenzene ethyl-acetylene with 2-iodine pyridine and 4-methoxybenzene ethyl-acetylene.

116b prepares triazole

Method according to embodiment 3 prepares 4-(2-pyridine radicals)-5-(p-methoxyphenyl) triazole with 2-(2-pyridine radicals)-4-methoxybenzene ethyl-acetylene 116a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(2-pyridine radicals)-5-(p-methoxyphenyl) triazole 116a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.[M+H] ⁺＝700.82。

Embodiment 117. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=2-thiazolyl, Y=p-methoxyphenyl, j=3, m=s=1 and R ³ =R ⁴ =H

117A. preparation alkynes

The alkynes 2-of present embodiment (2-thiazolyl)-4-methoxybenzene ethyl-acetylene is prepared as follows: add 140mg (0.2mmol) PdCl in the 10ml acetonitrile de gassed solution of 4mmol4-acetylenylbenzene methyl ether, 4mmol 2-bromo thiazole and 1ml triethylamine ₂(PPh ₃) ₂And 19mg (0.1mmol) CuI.With the mixture degassing,, be heated to 90 ℃ of 12h at stirring at room 5min.The vacuum concentration reactant mixture obtains 0.61g brown liquid, 70% yield with the silica column purification.

[M+H] ⁺：216.17， ¹HNMR(CDCl ₃，500MHz)δ7.765(d，J＝3Hz，1H)，7.472-7.455(m，2H)，7.277(d，J＝3.5Hz，1H)，6.837-6.820(m，2H)，3.768(s，3H)。

117B. preparation triazole

4-(2-thiazolyl)-5-(p-methoxyphenyl) triazole 117d is prepared as follows: add 0.3g 117c, 0.74ml nitrine trimethyl silicane and 4ml dimethylbenzene, heating blends to 140 ℃ 48h in the manometer tube.Reactant mixture directly separates by silica column, obtains brown liquid (117d) (0.18g, 50%) after purification.

[M+H] ⁺：259.27， ¹H NMR(DMSO-d ₆)，500MHz)δ8.016(d，J＝8.5Hz，2H)，7.929(d，J＝3Hz，1H)，7.817(d，J＝3Hz，1H)，7966(d，J＝8.5Hz，2H)，3.824(s，3H)。

117C. ethyl ester 117e is prepared as follows:

0.041mmol methanesulfonates macro ring precursor 117d and 0.123mmol 117d are dissolved in 3ml DMF, add the 0.24mmol cesium carbonate, at 70 ℃ of reaction 12h.Reactant mixture extracts with EtOAc, with the 1M sodium bicarbonate (2 * 30ml) and water (2 * 30ml) wash, and vacuum concentration obtains ethyl ester 117e.

[M+H] ⁺：734.34

The preparation title compound

Following hydrolysis ethyl ester 117c: 117e is dissolved in the 3ml diox, adds 2ml 1MLiOH, at stirring at room gained reactant mixture 8h.With citric acid with reactant mixture pH regulator to 3; Then reactant mixture is extracted with EtOAc, with saline and water washing.Vacuum concentration organic solution is purified by HPLC, obtains yellow powder (10mg, yield 34%) after lyophilization.

[M+H] ⁺: 706.33, ¹H NMR (DMSO-d ₆, 500MHz) δ 12.283 (s, broad peak, 1H), 8.750 (s, broad peak, 1H), 8.014 (d, J=9Hz, 2H), 7.938 (d, J=3.5Hz, 1H), 7.852 (d, J=3.5Hz, 1H), 6.997 (d, J=8Hz, 2H), 6.927 (d, J=7,1H), 5.555 (s, broad peak, 1H), 5.499 (m, 1H), 5.298 (t, J=18Hz and 9Hz, 1H), 4.643 (t, J=16Hz and 8Hz, 1H), 4.558 (d, J=11.5Hz, 1H), 4.125-4.093 (m, 2H), 3.802 (s, 3H), 2.890-2.847 (m, 1H), 2.542-2.497 (m, 2H), 2.123-2.106 (m, 1H), 1.806 (s, broad peak, 1H), 1.701-1.663 (m, 1H), 1.519 (s, broad peak, 1H), 1.460-1.435 (m, 1H), 1.314-1.074 (m, 16H).

Embodiment 118. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=benzyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

118a prepares alkynes

Method according to embodiment 117A prepares 2-(benzyl)-4-methoxybenzene ethyl-acetylene with 4-iodobenzene and 3-phenyl-propine.

118b prepares triazole

Method according to embodiment 3 prepares 4-(benzyl)-5-(p-methoxyphenyl) triazole with 2-(benzyl)-4-methoxybenzene ethyl-acetylene 118a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(2-benzyl)-5-(p-methoxyphenyl) triazole 118a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝700.82。

Embodiment 119. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=normal-butyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

119a prepares triazole

Method according to embodiment 3 prepares 4-(normal-butyl)-5-Phenyltriazole with normal-butyl-1-phenylacetylene and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(normal-butyl)-5-Phenyltriazole 119a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝649.44。

Embodiment 120. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=n-pro-pyl, Y=n-pro-pyl, j=3, m=s=1 and R ³ =R ⁴ =H

120a prepares triazole

Method according to embodiment 3 prepares 4,5-(n-pro-pyl) triazole with 4-octene and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: with the title compound and 4 of embodiment 2,5-(n-pro-pyl) triazole 120a passes through the method hydrolysis ethyl ester of embodiment 106 subsequently according to the method reaction of embodiment 105.

[M+H] ⁺＝601.46。

Embodiment 121. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

X=4-(N, N-dimethylamino) phenyl, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

121A. bromination reaction

The Phenyltriazole 121b that bromine replaces is prepared as follows: 1mmol 121a (preparing triazole 121a according to the method that embodiment 2 introduces with commercially available phenylacetylene and Hydrazoic acid,sodium salt) is dissolved in 16ml1: 15MeOH/CHCl ₃, add 0.28mol TEA, drip the 0.128ml bromine.Stir gained reactant mixture 2h.Add 10% cold Na in the reactant mixture ₂S ₂O ₅, up to the mixture bleach.Mixture extracts with EtOAc, with saline and water washing, uses dried over sodium sulfate, and vacuum concentration obtains 0.216g 121b (97%) after silica column is purified.

[M+H] ⁺：224.19。

121B. methanesulfonates displacement reaction.The method of introducing according to embodiment 3 prepares 0.2g 121c with the 121b of purification and the title compound of embodiment 2.

[M+Na] ⁺：721.00。

121C.Suzuki coupling reaction.Ethyl ester 121d is prepared as follows: 0.07mmol (50mg) 121c is dissolved in 3ml DME, adds 0.21mmol (35mg) 4-dimethylaminophenyl boric acid, 137mg cesium carbonate, 100mg KF in this solution.With the reactant mixture degassing, add 5mg Pd (PPh subsequently to it ₃) ₄The gained reactant mixture is heated to 90 ℃, stirs 12h.Reactant mixture extracts with EtOAc then, with saline and water washing, uses dried over sodium sulfate, and vacuum concentration obtains 40mg (78% yield) 121d with the silica column purification.

121D. hydrolysis ethyl ester.React with 121d according to 106 methods of introducing, after HPLC purifies, obtain 12mg 121e (30%).

[M+H] ⁺：712.33。

Embodiment 122. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

X=(N, N-diethylamino) methyl, the Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

122a prepares triazole

Method according to embodiment 3 prepares 4-(N, N-diethylamino methyl)-5-Phenyltriazole with 3-diethylamino-1-phenyl propine and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(N, N-diethylamino methyl)-5-Phenyltriazole 122a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝678.44。

Embodiment 123. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

X=N, N-diethylamino carbonyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

123A. preparation alkynes

Alkynes 123a is prepared as follows: 10mmol phenyl acetylenecarboxylic acid, 11mmol BOP, 22mmolDIEA are dissolved in 15ml DMF, add the 11mmol diethylamine to it.Then with the gained reactant mixture at stirring at room 3h.(1MNaHCO is used in 2 * 50ml) extractions to reactant mixture with EtOAc ₃(2 * 30ml), water (2 * 30ml), 5% citric acid (2 * 50ml), saline (2 * 30ml) washing.The organic extract liquid anhydrous Na ₂SO ₄Drying, vacuum concentration obtains 1.8g (90%) 123a[M+H] ⁺: 202.09.

123B. preparation triazole

Method according to embodiment 3 prepares 4-(N, N-diethylamino carbonyl)-5-Phenyltriazole 123b with 123a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(N, N-diethylamino carbonyl)-5-Phenyltriazole 123b with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 then.

[M+H] ⁺：692.47。

Embodiment 124. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

Chlorphenyl between X=, Y=4-ethoxyl phenenyl, j=3, m=s=1 and R ³ =R ⁴ =H

124a prepares alkynes

Method according to embodiment 99 prepares 2-(chlorphenyl)-4-methoxybenzene ethyl-acetylene with 3-chloro-bromobenzene and 4-methoxybenzene ethyl-acetylene.

124b prepares triazole

Method according to embodiment 3 prepares 4-(chlorphenyl)-5-(p-methoxyphenyl) triazole with 2-(chlorphenyl)-4-methoxybenzene ethyl-acetylene 124a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(chlorphenyl)-5-(p-methoxyphenyl) triazole 124a with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

[M+H] ⁺＝747.37.

Embodiment 125. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=2-phenyl vinyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: carry out the Suzuki reaction that embodiment 121 introduces, the method hydrolysis of introducing according to embodiment 106 subsequently with 121c and phenyl vinyl boric acid.

[M+H] ⁺＝695.30。

Embodiment 126. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W Be 5,6-methylbenzotrazole, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: with the title compound and 5 of embodiment 2, the 6-methylbenzotrazole passes through the method hydrolysis ethyl ester of embodiment 106 subsequently according to the method reaction of embodiment 105.

[M+H] ⁺＝595.42。

Embodiment 127. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For X=N-ethylamino carbonyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

127a. preparation alkynes

Alkynes 127a is prepared as follows: 10mmol phenyl acetylenecarboxylic acid, 11mmol BOP, 22mmolDIEA are dissolved in 15ml DMF, add 11mmol ethamine to it.Then with the gained reactant mixture at stirring at room 3h.(1MNaHCO is used in 2 * 50ml) extractions to reactant mixture with EtOAc ₃(2 * 30ml), water (2 * 30ml), 5% citric acid (2 * 50ml), saline (2 * 30ml) washing.The organic extract liquid anhydrous Na ₂SO ₄Drying, vacuum concentration obtains 1.8g (90%) 127a.[M+H] ⁺：177.09。

127b prepares triazole

Method according to embodiment 3 prepares 4-(N-ethylamino carbonyl)-5-Phenyltriazole with 127a and Hydrazoic acid,sodium salt.

Title compound is prepared as follows: title compound and 4-(N-ethylamino carbonyl)-5-Phenyltriazole 127b with embodiment 2 react according to the method for embodiment 105, pass through the method hydrolysis ethyl ester of embodiment 106 subsequently.

Embodiment 128. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

128a-sloughs the protection of amine

The title compound of 0.041mmol embodiment 105 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration reaction residue 128a.

128b-chloro-formate reagent

Chloro-formate reagent 128b is prepared as follows: the 0.045mmol cyclopentanol is dissolved in THF (3ml), adds the toluene solution (20%) of 0.09mmol phosgene.In stirring at room gained reactant mixture 2h, solvent removed in vacuo.Add DCM in the residue, vacuum concentration obtains chloro-formate reagent 128b to doing twice subsequently.

128c-prepares carbamate

The title carbamate is prepared as follows: residue 128a is dissolved in 1ml THF, adds 0.045mmol TEA, cooling gained reactant mixture to 0 ℃.The 3ml THF solution that adds chloro-formate reagent 128b to 0 ℃ of reactant mixture.The gained reactant mixture with the EtOAc extraction, with 1M sodium bicarbonate, water and salt water washing, is used dried over mgso at 0 ℃ of reaction 2h, and vacuum concentration is to doing.Crude compound is purified with silica column, then according to the method hydrolysis ethyl ester of embodiment 106.

Embodiment 129. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclobutyl, G=OH , L=does not exist, and W is The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: use the title compound of embodiment 105 and cyclobutanol to react according to the method that embodiment 33 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 130. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclohexyl, G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: use the title compound of embodiment 105 and Hexalin to react according to the method for embodiment 33, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 131. formula II chemical compound, wherein A=-(C=O)-O-R ¹ ,

G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the method for introducing according to embodiment 33 with the title compound of embodiment 105 and (R)-reaction of 3-hydroxyl tetrahydrofuran, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 132. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: according to the method for embodiment 33 with the title compound of embodiment 105 and (S)-reaction of 3-hydroxyl tetrahydrofuran, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 133. formula II chemical compound, wherein A=-(C=O)-O-R ¹ ,

G=OH , L=does not exist, and W is The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: according to the method for embodiment 33 with the title compound of embodiment 105 and

Reaction, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 134. formula II chemical compound, wherein A=-(C=O)-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 105 is dissolved in 4ml 4M HCl De dioxane solution, stirred reaction mixture 1h.The vacuum concentration reaction residue.Add 4ml THF and 0.045mmol TEA in this residue, cooling mixture to 0 ℃ adds 0.045mmol ring valeryl chlorine to it.Stir gained reactant mixture 2h at 0 ℃.Reactant mixture extracts with EtOAc, with 1M sodium bicarbonate, water and salt water washing, uses dried over mgso, and vacuum concentration is to doing.Crude compound is purified by silica column, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 135. formula II chemical compound, wherein A=-(C=O)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 105 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isocyanates to 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Then solution is extracted with EtOAc, with 1%HCl, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 136. formula II chemical compound, wherein A=-(C=S)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 105 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isothiocyanate to 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Then solution is extracted with EtOAc, with 1%HCl, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 137. formula II chemical compound, wherein A=-S (O) ₂-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, and W is The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: the title compound of 0.041mmol embodiment 105 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.The spissated reaction residue of gained is dissolved in 4ml THF, adds 0.045mmol TEA, be cooled to 0 ℃ to it.Add the 0.045mmol cyclopentyl sulfonyl chloride to 0 ℃ of solution, stir gained reactant mixture 2h at 0 ℃.Then solution is extracted with EtOAc, with 1M sodium bicarbonate, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, then according to the method hydrolysis ethyl ester of embodiment 106.

Embodiment 137. formula II chemical compound, wherein A=-(C=0)-O-R ¹ , R ¹ =cyclopenta, G=- The O-phenethyl, L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: add 1.2eq.PyBrOP, 4eq.DIEA, catalytic amount DMAP at 0 ℃ in the 0.5ml DCM solution of the title compound of embodiment 128 and phenethanol 138a.Stir gained reactant mixture 1h at 0 ℃, then at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound phenethyl ester 138b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc is as eluting phase (9: 1 → 5: 1 → 3: 1 → 1: 1)).

Other ester can prepare with identical method.

Embodiment 139. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-NH- Phenethyl, L=does not exist, and W is

The X=phenyl, Y=phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: add EDC (1.2eq.) and DIEA (4eq.) at 0 ℃ in the 0.5ml DMF solution of the title compound of embodiment 128 and phenethyl amine 139a (0.05ml).Stir gained reactant mixture 1h.Subsequently, with reactant at the 4-12h internal heating to room temperature.The purification of reactant mixture usefulness flash chromatography on silica gel method (hexane of usefulness different proportion: EtOAc (9: 1 → ⁵: 1 → 3: 1 → 1: 1 as the eluting phase)) acquisition title compound phenethyl amide 139b.

Other amide can prepare with identical method.

Embodiment 140. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-O-NHS (O) ₂-phenethyl, L=does not exist, and W is

The X=phenyl, the Y=phenyl, j=3, M=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: add 1.2eq.PyBrOP, 4eq.DIEA, catalytic amount DMAP at 0 ℃ in the 0.5ml DCM solution of the title compound of embodiment 128 and α-toluenesulfonamide 140a (10mg).Stir gained reactant mixture 1h, then at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound sulfonamide 140b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Other sulfonamide can prepare with identical method.

Embodiment 141. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-OH , L=does not exist, and W is The X=phenyl, Y=phenyl, j=3, m=s=1 And R ³ =R ⁴ =H

Title compound is prepared as follows: add Alpha-hydroxy-Alpha-Methyl-propionitrile (0.1ml) and catalytic amount TFA at 0 ℃ in the 0.5mlTHF of the title compound of embodiment 128 solution.The gained reactant mixture is heated to room temperature from 0 ℃ in 4-12h, uses the hydrolysis of concentrated hydrochloric acid De dioxane solution then.Reactant extracts with EtOAc, water and salt water washing, the crude product of acquisition 'alpha '-hydroxylation compound 141a.Crude compound 46b carries out the Dess-Martin oxidation reaction in THF (0.5ml), obtain the crude product of alpha-carbonyl chemical compound 46b.Rough 141b obtains title compound keto acid 141c with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Embodiment 142. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- (C=O)-and phenethyl, L=does not exist, and W is

The X=phenyl, the Y=phenyl, j=3, M=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 138 with title compound keto acid and the phenethanol of embodiment 141.

Embodiment 143. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- (C=O)-and the NH-phenethyl, L=does not exist, and W is The X=phenyl, the Y=phenyl, j=3, M=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 139 with title compound keto acid and the phenethylamine of embodiment 141.

Embodiment 144. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-NH-S (O) ₂-benzyl, L=does not exist, and W is

The X=phenyl, the Y=phenyl, J=3, m=s=1 and R ³ =R ⁴ =H

The method preparation that title compound is introduced according to embodiment 140 with title compound keto acid and the α-toluenesulfonamide of embodiment 141.

Embodiment 145. formula II chemical compounds, A=tBOC wherein, G=OH , L=-(C=O) CH ₂- , W is

The X=phenyl, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 88C, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 146. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CH (CH ₃) CH ₂- , W is

The X=phenyl, Y=phenyl, j=1, m=s=1 and R ³ =methyl and R ⁴ =H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 89G, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 147. formula II chemical compounds, A=tBOC wherein, G=OH , L=-O- , W is

The X=phenyl, Y=phenyl, j=0, m=s=1, R ³ =methyl and R ⁴ =H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 90D, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 148. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S- , W is The X=phenyl, Y=phenyl, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 91E, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 149. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O)- , W is

The X=phenyl, Y=phenyl, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 92B, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 150. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O) ₂- , W For

The X=phenyl, Y=phenyl, j=2, m=s=1, R ³ =methyl and R ⁴ = ^H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 93B, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 151. formula II chemical compounds, A=tBOC wherein, G=OH , L=-SCH ₂CH ₂-, W is The X=phenyl, Y=phenyl, j=0, m=s=1 and R ³ =R ⁴ =CH ₃

151A. synthetic (S)-N-Boc-2-amino-3-methyl-3 (1-sulfydryl-4-cyclobutenyl) butanoic acid (151b)

L-penicillamine 151a is dissolved in DMF/DMSO (5: 1), subsequently, with 4-bromine amylene and CsOHH ₂O adds mixture, continuous stirring 12h again.Remove DMF with final vacuum, remaining mixture 0 ℃ of dilution, reaches～4-5 pH with 0.5N HCl, uses the EtOAC extracting twice then.Organic facies is used dried over mgso with saline (2x) washing, is evaporated to do to obtain rough carboxylic acid 151a.

151B. the cyclic peptide precursor methanesulfonates of synthetic modification

The cyclic peptide precursor methanesulfonates of modifying is prepared as follows: substitute the route of synthesis reaction of Boc-L-2-amino-8-nonenoic acid 1a according to embodiment 1 with the amino acid/11 51a that modifies, the method for introducing according to embodiment 2 is converted into corresponding methanesulfonates then.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 151B, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 152. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CF ₂CH ₂- , W is The X=phenyl, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 95C, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 153. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CHFCH ₂- , W is

The X=phenyl, Y=phenyl, j=1, m=s=1 and R ³ =R ⁴ =H

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the embodiment 96C, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 154. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

The X=phenyl, Y=phenyl, j=3, m=s=1 and R ³ =R ⁴ =H

154A. with the MeOH that contains Pd/C saturated cyclic peptide precursor methanesulfonates of catalytic reduction methanesulfonates cyclic peptide precursor 2 preparations in the presence of hydrogen.

Title compound is prepared as follows: with the saturated cyclic peptide precursor methanesulfonates and 4 that generates among the 154A, and the method for replacing reaction that the 5-diphenyl triazole is introduced according to embodiment 105, the method hydrolysis ethyl ester of introducing according to embodiment 106 then.

Embodiment 155. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

J=3, m=s=1 and R ³ =R ⁴ =H

155A. the benzotriazole that preparation replaces

The benzotriazole 155b that the bromine of present embodiment replaces is prepared as follows: with 2.15g (10mmol) 5-bromo-3, and 4-dimethyl benzene-1,2-diamidogen, 1.15mol (20mmol) glacial acetic acid and 10ml water mix, and heating gained mixture obtains settled solution.Settled solution is cooled to 5 ℃ then, adds the cold soln of 0.83g (12mmol) sodium nitrite and 5ml water, reactant mixture is heated to 70-80 ℃ of 2h.Reactant mixture extracts with EtOAc, with saline and water washing, uses dried over sodium sulfate, vacuum concentration.Crude product is purified with silica column.

155B. displacement reaction

The method of replacing of introducing according to embodiment 105 prepares ethyl ester 155c with the title compound of embodiment 2 and the benzotriazole 155b of bromo-replacement.

The method for hydrolysis preparation that title compound is finally introduced according to embodiment 106 with ethyl ester 155c.

Embodiment 156. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For

J=3, m=s=1 and R ³ =R ⁴ =H

156A.Suzuki reaction

The chemical compound 156a for preparing present embodiment with 155c and 3-thienyl boric acid according to the Suzuki coupling reaction of embodiment 26C introduction.

156B. hydrolysis

Prepare title compound with ethyl ester 156a according to the method for hydrolysis that embodiment 106 introduces.

Embodiment 157. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, W For J=3, m=s=1 and R ³ =R ⁴ =H

157a. preparation dicyclic compound

With 2, the 3-diamino-pyridine prepares dicyclic compound of the present invention according to the method that embodiment 157A introduces.

Title compound is prepared as follows: react according to the method for replacing that embodiment 105 introduces with the dicyclic compound of 157a preparation and the title compound of embodiment 2, then the method hydrolysis ethyl ester of introducing according to embodiment 106.

Embodiment 158. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X=Y= Bromine, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

0 ℃ to macrocyclic compound 1 (185mg, 0.38mmol), 4,5-two bromo-2H-pyridazin-3-ones (95mg, 0.38mmol) and triphenylphosphine (197mg, drip in THF 0.75mmol) (5mL) mixture DIAD (148 μ L, 0.75mmol).Behind 0 ℃ of stirring 15min, solution is heated to room temperature, further stir 16h.Vacuum concentrated mixture, residue obtains 235mg (86%) title compound by column chromatography purification (with 40% ethyl acetate-hexane eluting).

¹H-NMR(500MHz，CDCl ₃)δ(ppm)：7.8(s，1H)，7.1(brs，1H)，5.5(m，2H)，5.2(m，2H)，5.0(m，1H)，4.4(brt，1H)，4.0-4.2(m，4H)，2.9(m，1H)，2.6(m，1H)，1.8-2.3(m，5H)，1.4(s，9H)，1.2(t，3H)。[M+H] ⁺＝730.6。

Embodiment 159. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X=Y= Thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

With the title compound of embodiment 162 (40mg, 0.055mmol), 3 thienylboronic acid (35mg, 0.28mmol), cesium carbonate (71mg, 0.22mmol), (41mg, mixture 0.44mmol) adds round-bottomed flask to the potassium fluoride monohydrate, purifies twice with nitrogen.Add DME to this mixture, feed nitrogen in the gained solution once more, add then tetrakis triphenylphosphine palladium (7mg, 10mol%).Feed nitrogen twice again, with mixture heated to the 20h that refluxes.Cooling mixture then, dilute with water is with EtOAc extraction three times.The EtOAc layer that merges with the salt water washing once use dried over mgso, and it is concentrated to filter final vacuum.Residue is purified (with 20-40%EtOAc-hexane eluting) by column chromatography, obtains transparent membranaceous title compound (24mg, 60%).

¹H-NMR(500MHz，CDCl ₃)，δ(ppm)：7.9(s，1H)，7.6(s，1H)，7.3(s，1H)，7.3(m，1H)，7.0(s，1H)，6.9(d，1H)，6.8(d，1H)，5.7(m，1H)，5.5(m，1H)，54(brd，1H)，5.2(t，1H)，5.0(m，1H)，4.6(brt，1H)，4.0-4.2(m，4H)，2.9(m，1H)，2.6(m，1H)，2.0-2.3(m，5H)，14(s，9H)，1.2(t，3H)。[M+Na] ⁺＝758.63。

Embodiment 160. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound of embodiment 2 (24mg, THF/MeOH/H 0.033mmol) ₂Add in O (2/1/0.5mL) solution Lithium hydrate (14mg, 0.33mmol).Behind stirring at room 16h, to pH 4, extract three times with EtOAc with citric acid acidify mixture.The organic extract liquid that merges with the salt water washing is once used dried over mgso, filters vacuum concentration.Residue obtains title compound (13mg, 56%) by column chromatography purification (with 5-10% methanol-chloroform eluting).

[M+H] ⁺＝708.3。

Embodiment 161. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the method for introducing according to embodiment 159 is carried out dual Suzuki coupling with the title compound of phenylboric acid and embodiment 158, then according to the method hydrolysis ethyl ester of embodiment 160 introductions.

[M+H] ⁺＝696.40

Embodiment 162. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y=4-(N, N-dimethylamino) phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: use the title compound of 4-(N, N-dimethylamino) phenylboric acid and embodiment 158 to carry out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝782.30

Embodiment 163. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y=4-(trifluoromethoxy) phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the title compound with 4-(trifluoromethoxy) phenylboric acid and embodiment 158 carries out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝864.09

Embodiment 164. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y=4-(mesyl) phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the title compound with 4-(mesyl) phenylboric acid and embodiment 158 carries out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 165. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y=4-(cyano group) phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the title compound with 4-cyano-phenyl boric acid and embodiment 158 carries out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝746.14

Embodiment 166. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Pyridin-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the title compound with 3-pyridine radicals boric acid and embodiment 158 carries out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝698.3。

Embodiment 167. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y=4-(morpholine-4-base-formyloxy) phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the title compound with 4-carboxyl phenyl boric acid and embodiment 158 carries out dual Suzuki coupling reaction according to the method that embodiment 159 introduces, and uses morpholine (for example DMF solution of PyBrOP, DIEA, DMAP) under standard amide key formation condition to form amide then.Pass through the ethyl ester of the method hydrolysis gained chemical compound of embodiment 160 then.

Embodiment 168. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Bromine, Y=methoxyl group, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: use the method hydrolysis ethyl ester of the title compound of embodiment 158 according to embodiment 160, but except the hydrolysis of ethyl ester, also observe the methoxyl group addition at 5.

[M+H] ⁺＝652.2，654.2。

Embodiment 169. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X Combine=phenyl Z=4-methoxyphenyl, j=3, m=s=1 and R with Y ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the Mitsunobu condition of introducing according to flow process 20 is passed through the method hydrolysis ethyl ester of embodiment 160 subsequently with commercially available 4-(4-methoxyl group-phenyl)-2H-phthalazines-1-reactive ketone.

[M+H] ⁺＝700.1。

Embodiment 170. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X Combine=phenyl Z=4-chlorphenyl, j=3, m=s=1 and R with Y ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: the Mitsunobu condition of introducing according to flow process 20 is passed through the method hydrolysis ethyl ester of embodiment 160 subsequently with commercially available 4-(4-chloro-phenyl)-2H-phthalazines-1-reactive ketone.

[M+H] ⁺＝704.2。

Embodiment 171. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=4- Fluorophenyl, Y=hydrogen, Z=phenyl, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: react with commercially available 4-(4-fluoro-phenyl)-6-phenyl-2H-pyridazin-3-one according to the Mitsunobu condition that flow process 20 is introduced, pass through the method hydrolysis ethyl ester of embodiment 160 subsequently.

[M+H] ⁺＝704.2。

Embodiment 172. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Hydrogen, Y=1-piperidyl, Z=phenyl, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: react with commercially available 6-phenyl-5-piperidines-1-base-2H-pyridazin-3-one according to the Mitsunobu condition that flow process 20 is introduced, pass through the method hydrolysis ethyl ester of embodiment 160 subsequently.

[M+H] ⁺＝702.3。

Embodiment 173. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X= Hydrogen, Y=bromine, Z=phenyl, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The Mitsunobu condition of introducing according to flow process 20 prepares title compound with commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one.

[M+H] ⁺＝726.3，728.3。

Embodiment 174. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Hydrogen, Y=thiene-3-yl-, Z=phenyl, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: title compound and thiene-3-yl-boric acid with embodiment 173 react under the Suzuki coupling condition that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝730.3

Embodiment 175. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X= Bromine, Y=1-pyrrolidinyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

With the title compound of embodiment 158 (45mg, 0.062mmol), pyrrolidine (21mL, 0.25mmol), potassium carbonate (34mg, 0.25mmol) and the mixture heated of 2ml acetonitrile to the 3h that refluxes, after being cooled to room temperature, by cellular glass funnel filtering mixt, vacuum concentrated filtrate.Residue is dissolved in ethyl acetate again, then once with the saturated sodium carbonate washing, with the salt water washing once, use dried over mgso, filter, vacuum concentration obtains yellow residue, obtains 37mg (83%) title compound with silica gel chromatography purification (with 3% methanol-chloroform eluting).

[M+H] ⁺＝719.2，721.2。

Embodiment 176. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Thiene-3-yl-, Y=1-pyrrolidinyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: title compound and thiene-3-yl-boric acid with embodiment 175 react under the Suzuki condition that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

[M+H] ⁺＝694.3。

Embodiment 177. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X= Bromine, Y=azido, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

With the title compound of embodiment 158 (45mg, 0.062mmol), Hydrazoic acid,sodium salt (16mg, 0.25mmol), potassium carbonate (34mg, 0.25mmol) and the mixture heated of 2mL acetonitrile to the 3h that refluxes.After being cooled to room temperature, mixture filters by the cellular glass funnel, vacuum concentrated filtrate.Residue is dissolved in ethyl acetate again, then once with the saturated sodium carbonate washing, with the salt water washing once, use dried over mgso, filter, vacuum concentration obtains yellow residue, obtains 37mg (83%) title compound with silica gel chromatography purification (with 3% methanol-chloroform eluting).

Embodiment 178. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X= Thiene-3-yl-, Y=azido, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound and thiene-3-yl-boric acid with embodiment 177 prepare title compound under the Suzuki condition that embodiment 159 introduces.

Embodiment 179. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Thiene-3-yl-, Y=azido, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Ethyl ester according to method hydrolysis embodiment 178 title compounds of embodiment 160 prepares title compound.

Embodiment 180. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Thiene-3-yl-, Y=tetrazolium-2-base, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Add KCN (10. in toluene (8ml) solution of the title compound of embodiment 178 (2.63mmol) ⁵3mmol) and Et ₃NHCl (10.53mmol).Mixture at 115 ℃ of heating 18h, with the DCM dilution, with 5% citric acid (aq) washing, is used anhydrous sodium sulfate drying, and vacuum concentration obtains the crude product of ethyl ester title compound.Method hydrolysis ethyl ester according to embodiment 160 obtains title compound.

Embodiment 181. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Sulfydryl-2-pyrimidine, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

With the title compound of embodiment 158 (45mg, 0.062mmol), pyrimidine-2-mercaptan (0.25mmol), potassium carbonate (34mg, 0.25mmol) and the mixture heated of 2mL acetonitrile to the 3h that refluxes.After being cooled to room temperature, mixture filters by the cellular glass funnel, vacuum concentrated filtrate.Residue is dissolved in ethyl acetate again, then once with the saturated sodium carbonate washing, with the salt water washing once, use dried over mgso, filter, vacuum concentration obtains yellow residue, obtain 181b, 19% yield with silica gel chromatography purification (with 3% methanol-chloroform eluting).The ethyl ester of chemical compound 181b obtains title compound according to the method hydrolysis that embodiment 160 introduces.

[M+H] ⁺＝764.3。

Embodiment 182. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Bromine, Y=sulfydryl-2-miazines, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

According to the ethyl ester of the chemical compound 181a of preparation among the method hydrolysis embodiment 181 of embodiment 160 introductions, thus title compound.

[M+H] ⁺＝732.2，734.2。

Embodiment 183. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X= Thiene-3-yl-, Y=sulfydryl-2-pyrimidine, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: chemical compound 181a and thiene-3-yl-boric acid with embodiment 181 react under the Suzuki coupling condition that embodiment 159 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 184. formula II chemical compounds, A=tBOC wherein, G=OEt , L=does not exist, X=Y= Thiazol-2-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Add Pd (PPh in the de gassed solution of the title compound of embodiment 158 (1mmol) and thiazol-2-yl stannane (2mmol) ₃) ₄(10mol%).Mixture is outgased twice again with nitrogen, be heated to 100 ℃ of 3h.The refrigerative mixture of vacuum concentration, residue is purified (with 30%EtOAc/ hexane eluting) by column chromatography, and the method hydrolysis ethyl ester according to embodiment 160 obtains title compound then.

[M+H] ⁺＝710.3。

Embodiment 185. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Imidazoles-1-base, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: under blanket of nitrogen, and the title compound of embodiment 158 (0.068mmol), imidazoles (2eq.), Cs ₂CO ₃(3eq.), Xantphos (30mol%) and Pd (OAc) ₂Drying composite in add diox.With the reactant mixture degassing, stir 18h then at 75 ℃.After reaction is finished (by the TLC monitoring), reactant mixture dilutes with DCM, filters vacuum concentration.Reactant mixture silica column chromatographic purification (5%MeOH/CHCl ₃) obtain the ethyl ester of title compound.The hydrolysis ethyl ester obtains title compound under the condition that embodiment 160 introduces then.

Embodiment 186. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=2-(ring Propyl group amino)-and thiazole-4-base, Y=4-methoxyphenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Preparation 4-(2-cyclopropyl amino-thiazolyl--4-yl) 5-(4-methoxyl group-phenyl-2H-pyridazin-3-one (186h)

186A. with commercially available 4, the mixture of 5-dichloro-pyridazine 3 (2H)-ketone (18mmol), benzyl bromide a-bromotoluene (19mmol), potassium carbonate (45mmol), tetrabutyl ammonium bromide (1mmol) and acetonitrile (45mL) stirs, and heats 1h under refluxing.After cooling, solvent evaporated under reduced pressure.Residue filters (with 10%EtOAc/ hexane eluting) by little silicagel column and obtains white powder chemical compound 186a (81%).[M+H] ⁺＝256.3。

186B. in no Shui diox (20mL) magnetic agitation solution of 186a (4.5mmol), add 1.0mL 21wt% sodium methoxide solution in room temperature.Behind 1h, in mixture impouring water/ethyl acetate, organic layer dried over mgso, simmer down to grease.The oily residue obtains 85%186b by column chromatography purification (using the 10%EtOAc/Hex eluting).

[M+H] ⁺＝251.7。

Perhaps, the substitution reaction of 2H-Pyridazin-3-one 186b can realize by this step, uses MeOH rather than diox as solvent, and wherein methoxyl group is at 5 of the 2H-Pyridazin-3-one ring, and chloro is at 4.

186C. (1mmol) is dissolved in DME with 2H-Pyridazin-3-one 186.Add Pd (PPh to this mixture ₃) ₄(10mol%), at stirring at room mixture 10min, add 4-methoxyphenylboronic acid (2mmol) and 1mL Na then ₂CO ₃Aqueous solution (10wt%).Subsequently, reactant mixture is heated to backflow 18h.Refrigerative reactant mixture dilute with water is used ethyl acetate extraction 3 times.Dry organic layer (the MgSO that merges ₄), filter vacuum concentration.Residue obtains chemical compound 186c by silica gel column chromatography purification (with 15%EtOAc/ hexane eluting).

[M+H] ⁺＝323.3。

186D.186c add 2N KOH in the DME solution (3mmol), with the gained mixture heated to the 1h that refluxes.Refrigerative mixture dilute with water is acidified to pH-5 with solid citric acid, uses CH ₂Cl ₂Extract 3 times.Organic layer with the salt water washing is once used dried over mgso, filters, and vacuum concentration obtains chemical compound 186d.[M+H] ⁺＝309.3。

186E. (ice-acetone bath) drips Trifluoromethanesulfonic anhydride (0.4mL) in dichloromethane (10mL) cold soln of chemical compound 186d (2mmol), triethylamine (0.4mL).Stir gained solution 30min at-5 ℃.With among the rare HCl of reactant mixture impouring (0.5M), use CH then ₂Cl ₂Extraction.The organic layer 1%NaHCO that merges ₃, the salt water washing, use dried over mgso, filter, vacuum concentration obtains brown oil.The direct use of chemical compound 186e be need not to purify again.

[M+H] ⁺＝441.4。

186F. with commercially available 2,4-two bromo thiazoles (2mmol) are dissolved in cyclopropylamine (3mL), and reactant mixture is heated to 50 ℃ of 8h.With in the refrigerative mixture impouring water, use extracted with diethyl ether 2 times then.Organic moiety (MgSO in the drying merging ₄) after, evaporating solvent obtains 2-cyclopropylamine-4-bromo thiazole with flash column chromatography purification (silica gel, 15%EtOAc/ hexane), is translated into corresponding stannane 186f.The degassing DME solution of 2-cyclopropylamine-4-bromo thiazole hexa methyl ditin and Pd (PPh ₃) ₄Handle, at 80 ℃ of heating 18h.With refrigerative mixture vacuum concentration, residue (is used 20%EtOAc/ hexane/2%Et by column chromatography ₃The N eluting) purification obtains stannane 186f.

[M+H] ⁺＝304.1。

186G. add Pd (PPh in the de gassed solution of chemical compound 186e (1mmol) and stannane 186f (2mmol) ₃) ₄(10mol%).With the mixture reuse nitrogen body degassing twice, be heated to 100 ℃ of 3h subsequently.The refrigerative mixture of vacuum concentration, residue obtains chemical compound 186g by column chromatography purification (with 30%EtOAc/ hexane eluting).[M+H] ⁺＝431.6。

186H. the MeOH solution to chemical compound 186g and 10%Pd/C (moistening) uses hydrogen jar 2h.Mixture filters by Celite pad, and vacuum concentrated filtrate obtains chemical compound 186h.

[M+H] ⁺＝341.4。

Title compound is prepared as follows: the cyclic peptide precursor 1 with 2H-Pyridazin-3-one 186h and embodiment 1 reacts under the Mitsunobu condition that embodiment 158 introduces, then hydrolysis ethyl ester under the condition that embodiment 159 introduces.

Embodiment 187. formula II chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X Combine with Y=6-methoxyl group-isoquinolin-(3,4)-Ji, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

187A. 2H-Pyridazin-3-one 186b (2mmol) is dissolved in DME.Add Pd (PPh to this mixture ₃) ₄,, add 2-formoxyl-4-methoxyphenylboronic acid and Na then at stirring at room mixture 10min ₂CO ₃Aqueous solution (10wt%).Subsequently, reactant mixture is heated to backflow 18h.Refrigerative reactant mixture dilute with water is used ethyl acetate extraction 3 times.Dry organic layer (the MgSO that merges ₄), filter vacuum concentration.Residue obtains chemical compound 187a by silica gel column chromatography purification (with 20%EtOAc/ hexane eluting).[M+H] ⁺＝351.4。

187B. with 2H-Pyridazin-3-one 187a (1mmol), MeOH (20mL) and NH ₄(10mL, mixture 28-30wt%) is at 60 ℃ of heating 30min for OH.After cooling, leach precipitation chemical compound 187b, with MeOH (15mL) flushing.[M+H] ⁺＝317.4。

187C. with pyridazine and isoquinolines 187b (0.5mmol), AlCl ₃Stir with the mixture of toluene, at 70 ℃ of heating 1h.After cooling, add entry, filtering mixt, water flushing.Residue obtains chemical compound 187c by silica gel column chromatography purification (using the 50%EtOAc/Hex eluting).[M ⁺H] ⁺＝227.3。

Title compound is prepared as follows: the cyclic peptide precursor 1 with pyridazine and isoquinolines 187c and embodiment 1 reacts under the Mitsunobu condition that embodiment 162 introduces, then hydrolysis ethyl ester under the condition that embodiment 159 introduces.

Embodiment 188. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

188a-sloughs the protection of amine.

The title compound of 0.041mmol embodiment 159 is dissolved in 4ml 4M HCl De dioxane solution, stirs 1h.Vacuum concentration reaction residue 188a.

188b-chloro-formate reagent

Chloro-formate reagent 188b is prepared as follows: the 0.045mmol cyclopentanol is dissolved in THF (3ml), adds the toluene solution (20%) of 0.09mmol phosgene.In stirring at room gained reactant mixture 2h, solvent removed in vacuo.Add DCM in the residue, vacuum concentration obtains chloro-formate reagent 188b to doing twice subsequently.

188c-prepares carbamate

The title carbamate is prepared as follows: residue 188a is dissolved in 1ml THF, adds 0.045mmol TEA, cooling gained reactant mixture to 0 ℃.The 3ml THF solution that adds chloro-formate reagent 188b to 0 ℃ of reactant mixture.The gained reactant mixture with the EtOAc extraction, with 1M sodium bicarbonate, water and salt water washing, is used dried over mgso at 0 ℃ of reaction 2h, and vacuum concentration is to doing.Crude compound is purified with silica column, subsequently according to the method hydrolysis ethyl ester of embodiment 160.

Embodiment 189. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclobutyl, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The method of introducing according to embodiment 188 prepares title compound with title compound and the cyclobutanol of embodiment 159.

Embodiment 190. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclohexyl, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The method of introducing according to embodiment 188 prepares title compound with title compound and the Hexalin of embodiment 159.

Embodiment 191. formula II chemical compound, wherein A=-(C=O)-O-R ¹ ,

G=OH , L=does not exist, the X=Y=thiene-3-yl-, and Z=hydrogen, j=3, M=s=1 and R ³ =R ⁴ =hydrogen.

The method of introducing according to embodiment 188 with the title compound of embodiment 159 with (R)-the 3-hydroxyl tetrahydrofuran prepares title compound.

Embodiment 192. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The method of introducing according to embodiment 188 with the title compound of embodiment 159 with (S)-the 3-hydroxyl tetrahydrofuran prepares title compound.

Embodiment 193. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen,The method of introducing according to embodiment 188 with the title compound of embodiment 159 and The preparation title compound.

Embodiment 194. formula II chemical compound, wherein A=-(C=O)-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound prepares stirred reaction mixture 1h with the 4ml 4M HCl/ dioxane solution of the title compound of embodiment 159.The vacuum concentration reaction residue.Add 4ml THF and 0.045mmol TEA in this residue, cooling mixture to 0 ℃ adds 0.045mmol cyclopenta acid chloride to it.Stir gained reactant mixture 2h at 0 ℃.Reactant mixture extracts with EtOAc, with 1M sodium bicarbonate, water and salt water washing, uses dried over mgso, and vacuum concentration is to doing.Crude compound is purified with silica column, subsequently according to the method hydrolysis ethyl ester of embodiment 160.

Embodiment 195. formula II chemical compound, wherein A=-(C=O)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Title compound stirs 1h with the 4ml 4M HCl/ dioxane solution preparation of the title compound of embodiment 159.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isocyanates to 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Then solution is extracted with EtOAc, with 1%HCl, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently according to the method hydrolysis ethyl ester of embodiment 160.

Embodiment 196. formula II chemical compound, wherein A=-(C=S)-NH-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound stirs 1h with the 4ml 4M HCl/ dioxane solution preparation of the title compound of embodiment 159.Vacuum concentration gained reaction residue is dissolved in 4ml THF, is cooled to 0 ℃.Add 0.045mmol cyclopenta isothiocyanate to 0 ℃ of solution, at stirring at room gained reactant mixture 4h.Solution extracts with EtOAc, with 1%HCl, water and salt water washing, uses dried over mgso, and vacuum concentration is to doing.Crude compound is purified with silica column, subsequently according to the method hydrolysis ethyl ester of embodiment 160.

Embodiment 197. formula II chemical compound, wherein A=-S (O) ₂-R ¹ , R ¹ =cyclopenta, G=OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound stirs 1h with the 4ml 4M HCl/ dioxane solution preparation of the title compound of embodiment 159.The spissated reaction residue of gained is dissolved in 4ml THF, adds 0.045mmol TEA, be cooled to 0 ℃ to it.Add the 0.045mmol cyclopentyl sulfonyl chloride to 0 ℃ of solution, stir gained reactant mixture 2h at 0 ℃.Then solution is extracted with EtOAc, with 1M sodium bicarbonate, water and salt water washing, use dried over mgso, vacuum concentration is to doing.Crude compound is purified with silica column, subsequently according to the method hydrolysis ethyl ester of embodiment 160.

Embodiment 198. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- The O-phenethyl, L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Title compound is prepared as follows: add 1.2eq.PyBrOP, 4eq.DIEA and catalytic amount DMAP at 0 ℃ in the 0.5ml DCM of embodiment 194 title compounds and phenethanol 198a solution.Stir gained reactant mixture 1h.Then at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound phenethyl ester 198b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Other ester can prepare with identical method.

Embodiment 199. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-NH- Phenethyl, L=does not exist, X=Y=thiophene-3.Base, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Title compound is prepared as follows: add EDC (1.2eq.) and DIEA (4eq.) at 0 ℃ in the 0.5ml DMF solution of the title compound of embodiment 194 and phenethyl amine 199a (0.05ml).Stir gained reactant mixture 1h.Subsequently, with reactant at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound phenethyl amide 199b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Other amide can be by identical method preparation.

Embodiment 200. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-NHS (O) ₂-phenethyl, L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 And R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: add 1.2eq.PyBrOP, 4eq.DIEA and catalytic amount DMAP at 0 ℃ in the 0.5ml DCM solution of the title compound of embodiment 194 and α-toluenesulfonamide 200a (10mg).Stir gained reactant mixture 1h, then at the 4-12h internal heating to room temperature.Reactant mixture obtains title compound sulfonamide 200b with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Other sulfonamide can be by identical method preparation.

Embodiment 201. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-OH , L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Title compound is prepared as follows: add EDC (1.2eq.) and DIEA (4eq.) at 0 ℃ in the 0.5mlDMF of the title compound of embodiment 194 solution.Stir gained reactant mixture 1h.Subsequently, with reactant at the 4-12h internal heating to room temperature.Reactant mixture is purified with the flash chromatography on silica gel method and is obtained hydroxy amide.Hydroxy amide is handled 2h with DIBAL-H at-78 ℃ in THF.Reactant mixture dilutes with 8ml EtOAc, and Na is used in water and salt water washing ₂SO ₄Drying, vacuum concentration obtains aldehyde 201a.In the 0.5ml of aldehyde 39a THF solution, add Alpha-hydroxy-Alpha-Methyl-propionitrile (0.1ml) and catalytic amount TFA at 0 ℃.The gained reactant mixture is heated to room temperature from 0 ℃ in 4-12h, uses the hydrolysis of concentrated hydrochloric acid De dioxane solution then.Reactant extracts with EtOAc, and water and salt water washing obtain the crude product of 'alpha '-hydroxylation compound 201b.Crude compound 201b carries out the Dess-Martin oxidation reaction in THF (0.5ml), obtain the crude product of alpha-carbonyl chemical compound 201c.Rough 201c obtains title compound keto acid 201c with flash chromatography on silica gel method purification (use the hexane of different proportion: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) is as the eluting phase).

Embodiment 202. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- (C=O)-and the O-phenethyl, L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 And R ³ =R ⁴ =hydrogen.

Prepare title compound with the title compound keto acid of embodiment 201 and phenethanol according to the method for embodiment 198.

Embodiment 203. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=- (C=O)-and the NH-phenethyl, L=does not exist, X=Y=thiene-3-yl-, Z=hydrogen, j=3, m=s=1 And R ³ =R ⁴ =hydrogen.

Title compound keto acid and phenethylamine with embodiment 201 prepare title compound according to the method that embodiment 199 introduces.

Embodiment 204. formula II chemical compound, wherein A=-(C=O)-O-R ¹ , R ¹ =cyclopenta, G=-(C=O)-NH-S (O) ₂-benzyl, L=does not exist, the X=Y=thiene-3-yl-, Z=hydrogen, j=3, M=s=1 and R ³ =R ⁴ =hydrogen.

Title compound keto acid and α-toluenesulfonamide with embodiment 201 prepare title compound according to the method that embodiment 200 introduces.

Embodiment 205. formula II chemical compounds, A=tBOC wherein, G=OH , L=-(C=O) CH ₂- , The X=Y=thiene-3-yl-, Z=hydrogen, j=1, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 88C, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 206. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CH (CH ₃) CH ₂- , The X=Y=thiene-3-yl-, Z=hydrogen, j=1, m=s=1, R ³ =methyl andR ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 89G, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 207. formula II chemical compounds, A=tBOC wherein, G=OH , L=-O- , X=Y= Thiene-3-yl-, Z=hydrogen, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 90D, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 208. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S- , the X=Y=thiophene Fen-3-base, Z=hydrogen, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 91E, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 209. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O)- , X=Y= Thiene-3-yl-, Z=hydrogen, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 92B, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 210. formula II chemical compounds, A=tBOC wherein, G=OH , L=-S (O) ₂ , X=Y= Thiene-3-yl-, Z=hydrogen, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 93B, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 211. formula II chemical compounds, A=tBOC wherein, G=OH , L=-SCH ₂CH ₂- , The X=Y=thiene-3-yl-, Z=hydrogen, j=0, m=s=1 and R ³ =R ⁴ =CH ₃

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 94B, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 212. formula II chemical compounds, A=tBOC wherein, G=OH , L=CF ₂CH ₂ , X=Y= Thiene-3-yl-, Z=hydrogen, j=1, m=s=1 and R ³ =R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 95C, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 213. formula II chemical compounds, A=tBOC wherein, G=OH , L=-CHFCH ₂- , The X=Y=thiene-3-yl-, Z=hydrogen, j=1, m=s=1 and R ³=R ⁴ =hydrogen.

Title compound is prepared as follows: with the cyclic peptide precursor methanesulfonates and 4 of the modification that generates among the 96C, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

Embodiment 214. formula III chemical compounds, A=tBOC wherein, G=OH , L=does not exist, X=Y= Thiene-3-yl-, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

214A. the saturated cyclic peptide precursor of methanesulfonates cyclic peptide precursor preparation methanesulfonates with the MeOH that contains Pd/C catalytic reduction embodiment 2 in the presence of hydrogen.

Title compound is prepared as follows: with the saturated cyclic peptide precursor methanesulfonates and 4 that generates among the 214A, 5-two (thiene-3-yl-)-2H-pyridazin-3-one reacts under the Mitsunobu condition that embodiment 158 introduces, then the method hydrolysis ethyl ester of introducing according to embodiment 160.

The compounds of this invention has effective HCV NS3 protease rejection characteristic.Following examples will illustrate the method for test The compounds of this invention anti-hcv activity.

Embodiment 215.NS3/NS4a protease is analyzed

Fluorogenic substrate with inner quencher is analyzed HCV proteinase activity and inhibitory action.DABCYL and EDANS group are connected the opposite two ends of small peptide.Behind protein cleavage, the DABCYL group reduces EDANS fluorescent quenching.Measure fluorescence, excitation wavelength 355nm, emission wavelength 485nm with Molecular DevicesFluoromax (or equivalent of the apparatus).

This analyze to use Corning white half regional 96 orifice plates (Corning white half-area96-well plate) (VWR 29444-312[Corning 3693]), uses the total length NS3 HCV protease 1b (final enzyme concentration 1-15nM) of compound NS4A cofactor.Additional 10 μ M NS4A cofactor Pep 4A in the analysis buffer (Anaspec 25336 or inside, MW1424.8).RET S1 (Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-[COO] Ala-Ser-Lys-(DABCYL)-NH ₂, AnaSpec 22991, and MW 1548.6) as the fluorescence peptide substrates.Analysis buffer comprises Hepes, 30mM NaCl and the 10mMBME of 50mM pH7.5.In the inhibitor existence or not, carry out enzyme reaction 30min in room temperature.

Inhibitor peptides HCV Inh 1 (Anaspec 25345, and MW 796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [20 ℃] and HCV Inh 2 (Anaspec 25346, and MW 913.1) Ac-Asp-Glu-Dif-Cha-Cys-OH effect control compound.

In ActivityBase (IDBS), calculate IC50, use equation 205:y=A+ ((B-A)/(1+ ((C/x) ^D))) with XLFit.

Embodiment 216. is based on the replicon analysis of cell

HCV replicon rna (analysis of HCV cellular type) in the quantitative cell line

To carry the cell line (comprising Huh-11-7 or Huh 9-13) (Lohmann etc., Science 285:110-113,1999) of HCV replicon with 5 * 10 ³Cells/well is inoculated into 96 orifice plates, provides to comprise DMEM (high glucose), 10% hyclone, penicillin-streptomycin and nonessential amino acid whose culture medium.With cell at 5%CO ₂In the incubator in 37 ℃ of incubations.When incubation period finishes, use Qiagen Rneasy 96 Kit (catalog number 74182) from cell extraction and the total RNA of purification.For the HCV RNA that increases makes have enough raw materials to detect (seeing below) by the HCV specific probe, the Auele Specific Primer of HCV (seeing below) mediated reverse transcription HCV RNA and by polymerase chain reaction (PCR) amplification cDNA wherein uses test kit TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog number 4309169).Below be the nucleotide sequence (being positioned at the genomic NS5B of HCV zone) of RT-PCR primer:

HCV forward primer " RBNS5bfor "

5′GCTGCGGCCTGTCGAGCT：

HCV reverse primer " RBNS5Brev ":

5′CAAGGTCGTCTCCGCATAC

Detect the RT-PCR product with Applied Biosystems (ABI) Prism 7700 Sequence DetectionSystem (SDS), detect emitted fluorescence when PCR processes probe between the reaction period, described probe fluorescent reporter dye and quencher dye marker.At each PCR cycle detection fluorescence increment, its reflection RT-PCR product increment.Specifically, quantitatively be based on the valve period, wherein amplification curve intersects with the fluorescence thresholding of regulation.Valve period and known standard contrast with sample can detect relative template concentrations (ABI User Bulletin #2, on December 11st, 1997) in the different samples highly delicately.With program ABI SDS 1.7 analytical data.Utilize the standard curve of the HCV RNA standard substance of known copy number, relative template concentrations can be converted into RNA copy number (ABI User Bulletin #2, on December 11st, 1997).

The RT-PCR product is in order to descend the probe in detecting of labelling:

5′FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA

The FAM=fluorescent reporter dye.

TAMRA:=quencher dyestuff.

RT is reflected at 48 ℃ and carries out 30min, carries out PCR then.The thermo cycler parameter that is used for PCR reaction on the ABI Prism 7700Sequence Detection System a: circulation: 95 ℃, 10min; Circulate then 35 times, each circulation is included in 15s of 95 ℃ of incubations, 60 ℃ of incubation 1min then.

For the data of standardization cell RNA internal contrast molecule, carry out RT-PCR with cell messenger RNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH).The GAPDH copy number is highly stable in employed cell line.GAPDH RT-PCR carries out on the RNA sample of identical mensuration HCV copy number.The standard substance that ABI Pre-Developed TaqMan Assay Kit (catalog number 4310884E) comprises GAPDH primer, probe and measures copy number.HCV/GAPDH RNA ratio is used to calculate compound activity, estimates the inhibitory action to the HCV rna replicon.

The activity of chemical compound (based on the analysis of cell) in containing the Huh-7 cell line of replicon as the HCV replication inhibitors

The cell of contrast contact chemical compound with contact 0% inhibiting cell and contact 100% inhibiting contrast in HCV RNA quantity (being standardized as GAPDH (for example HCV/GAPDH ratio)), determine of the influence of specificity antivirus chemical compound to HCV replicon rna concentration in Huh-11-7 or the 9-13 cell.Specifically, with cell with 5 * 10 ³Cells/well is inoculated into 96 orifice plates, with a kind of following culture medium incubation: 1) comprise the culture medium (contrast of 0% inhibitory action) of 1%DMSO, 2) contain 100 ius, culture medium/1%DMSO of IU/ml alpha-interferon 2b, perhaps 3) contain the culture medium/1%DMSO of fixed concentration chemical compound.Then with above-mentioned 96 orifice plates at 37 ℃ of incubations 3 days (Preliminary screening analysis) or 4 days (determining IC50).Suppressing percent is defined as:

Inhibition percent=[100-((S-C2)/C1-C2)] * 100, wherein:

The ratio of HCV RNA copy number in the S=sample/GAPDH RNA copy number;

C1=0% suppresses the contrast (ratio of HCV RNA copy number/GAPDH RNA copy number in the culture medium/1%DMSO);

C2=100% suppresses the ratio of HCV RNA copy number in the contrast (100IU/ml alpha-interferon 2b)/GAPDH RNA copy number.

The dose-effect curve of following acquisition inhibitor: in 3 logarithm concentration ranges, in each hole, add the chemical compound of three times of serial dilutions, begin, finish with least concentration 0.01 μ M with the maximum concentration 10 μ M of specific compound.If the IC50 value, is used further dilution series (for example 1 μ M to 0.001 μ M) not in the range of linearity of curve.Determine IC50 based on IDBSActivity Base program, use Microsoft Excel " XL Fit ", A=100% inhibiting value (1001U/ml alpha-interferon 2b) wherein, B=0% inhibitory action control value (culture medium/1%DMSO), the mid point of C=curve is defined as C=(B-A/2)+A.A, B and C value are expressed as the ratio of the HCV RNA/GAPDH RNA of each sample in each holes of above-mentioned 96 orifice plates.For each plate, use meansigma methods definition 100% and 0% inhibiting value in 4 holes.

Although the present invention by the agency of many different preferred embodiments, be not limited to this, those skilled in the art can understand and can make the changes and improvements that do not break away from essence of the present invention and claims scope to it.

Claims

1. the chemical compound of a following formula I:

Wherein:

G is selected from-OH ,-O-(C ₁-C ₁₂Alkyl) ,-NHS (O) ₂-R ¹,-(C=O)-R ¹,-(C=O)-O-R ¹With-(C=O)-NH-R ¹

J is 0,1,2,3 or 4;

M is 0,1 or 2;

S is 0,1 or 2;

E is selected from-CH=CH-or-CH ₂-CH ₂-;

W replaces or unsubstituted heterocycle ring system.

2. the chemical compound of claim 1, wherein W is replaced by one or more substituent groups, and described substituent group independently is selected from following (a) and (b), (c), (d) and any group (e) separately:

(a) thiazolinyl; Alkoxyl; Alkoxyalkyl; Alkyl; Alkyl amino; Alkylaryl; Alkyl sulphonyl; Alkynyl; Amide; Optional by C ₁-C ₆The mono-substituted acylamino-of alkyl; Aryl; The aromatic yl silane terephthalamide yl alkyl; Aryl alkyl; The arylamino alkyl; Aryloxy alkyl; Aryl sulfonyl; Cycloalkyloxy; Cycloalkyl; Dialkyl amido; Dialkyl aminoalkyl; The ammonia diaryl base alkyl; Haloalkyl; Heteroaryl; Heteroaryl alkyl; Heterocyclic radical; Heterocyclylalkyl; The Heterocyclylalkyl alkyl; Alkylthio; The alkyl monosubstituted amino alkyl; Sulfonyl; (low alkyl group) sulfonyl; Haloalkyl; Carboxyl; Amide; (low alkyl group) amide; Optional by C ₁-C ₆The heterocyclic radical that alkyl replaces; Whole haloalkyl; Sulfonyl; Alkylthio; Urea; C (=O)-R ¹¹OC (=O) R ¹¹C (=O) O-R ¹¹C (=O) N (R ¹¹) ₂C (=S) N (R ¹¹) ₂SO ₂R ¹¹NHS (O ₂) R ¹¹N (R ¹²) ₂N (R ¹²) C (=O) R ¹¹

Wherein above-mentioned each substituent group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl, whole haloalkyl;

(b) C ₇-C ₁₄Aralkyl; C ₂-C ₇Cycloalkyl; C ₆-C ₁₀Aryl; Heterocyclic radical; (low alkyl group)-heterocyclic radical;

Wherein each aralkyl, cycloalkyl, aryl, heterocyclic radical or (low alkyl group)-heterocyclic radical can be chosen wantonly by R ⁶Replace; R ⁶Be halogen, C ₁-C ₆Alkyl, C ₃-C ₆Cycloalkyl, C ₁-C ₆Alkoxyl, C ₃-C ₆Cycloalkyloxy, NO ₂, N (R ⁷) ₂, NH-C (O)-R ⁷Or NH-C (O)-NHR ⁷, R ⁷Be H, C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl; Perhaps R ⁶Be NH-C (O)-OR ⁸, R ⁸Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

(d) NH-C (O)-OR ⁸, R wherein ⁸Be C ₁-C ₆Alkyl or C ₃-C ₆Cycloalkyl;

(e) formoxyl; Halogen; Hydroxyl; NO ₂OH; SH; Halogen; CN;

Wherein

Each R ¹¹Independent is H, OH, alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl, heteroaryl alkyl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl amino, dialkyl amido, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl, ammonia diaryl base alkyl, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl; Each R ¹²Independent is H, formoxyl, alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl alkyl, heteroaryl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl or ammonia diaryl base alkyl, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl.

3. the chemical compound of claim 1, wherein W is selected from:

Wherein:

Each R ¹²Independent is H, formoxyl, alkyl, thiazolinyl, alkynyl, whole haloalkyl, alkoxyl, aryl, aryl alkyl, alkylaryl, heterocyclic radical, Heterocyclylalkyl, alkyl sulphonyl, aryl sulfonyl, heteroaryl alkyl, heteroaryl, aromatic yl silane terephthalamide yl alkyl, Heterocyclylalkyl alkyl, aryloxy alkyl, alkyl monosubstituted amino alkyl, dialkyl aminoalkyl, arylamino alkyl or ammonia diaryl base alkyl, and wherein any above-mentioned group can be chosen wantonly by maximum three following groups and replace: halogen, OH, alkoxyl and whole haloalkyl.

4. the chemical compound of claim 3; wherein W contains 5-16 annular atoms and maximum 4 annular atomses to be selected from the assorted monocycle of heteroatomic aliphatic of O, N and S, assorted bicyclo-or assorted three ring ring systems, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

5. the chemical compound of claim 3, wherein W contains the assorted monocycle ring system of heteroatomic aliphatic that 5-7 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

6. the chemical compound of claim 5, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 5 annular atomses and 1-2 annular atoms are selected from O, N and S.

7. the chemical compound of claim 6, the assorted monocycle ring system of the aliphatic of wherein said optional replacement is selected from pyrrolidines, pyrazoles alkanes, pyrrolin class, Tetramethylene sulfide class, dihydro-thiophene class, tetrahydrofuran derivatives, dihydrofuran class, imidazolines, imidazolidine class, pyrazoline class, tetrahydro-pyrazole class and oxazoline class.

8. the chemical compound of claim 5, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 6 annular atomses and 1-2 annular atoms are selected from O, N and S.

9. the chemical compound of claim 8, the assorted monocycle ring system of the aliphatic of wherein said optional replacement is selected from pyridines, piperidines, dihydropyridines, tetrahydropyridine class, dihydropyran class, Pentamethylene oxide. class, dioxane, piperazines, dihydropyridine, tetrahydropyrimidine class, perhydrogenate pyrimidine, morpholine, thioxane and thiomorpholine.

10. the chemical compound of claim 5, the assorted monocycle ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 7 annular atomses and 1-2 annular atoms are selected from O, N and S.

Methylene imine and thiophene ring in heptan 11. the chemical compound of claim 8, the assorted monocycle ring system of the aliphatic of wherein said optional replacement are selected oneself.

12. the chemical compound of claim 3; wherein W contains the assorted bicyclo-ring system of heteroatomic aliphatic that 5-16 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

13. the chemical compound of claim 12, the assorted bicyclo-ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 8-12 annular atoms and 1-4 annular atoms are selected from O, N and S.

14. the chemical compound of claim 13, the assorted bicyclo-ring system of the aliphatic of wherein said optional replacement contain the hetero atom that 8-12 annular atoms and 1-2 annular atoms are selected from O and N.

15. the chemical compound of claim 3; wherein W contains 5-16 annular atoms and maximum 4 annular atomses to be selected from the assorted monocycle of heteroatomic aromatics of O, N and S, assorted bicyclo-or assorted three ring ring systems, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

16. the chemical compound of claim 3, wherein W contains the assorted monocycle ring system of heteroatomic aromatics that 5-7 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

17. the chemical compound of claim 15, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 5 annular atomses and 1-2 annular atoms are selected from O, N and S.

18. the chemical compound of claim 17, the assorted monocycle ring system of the aromatics of wherein said optional replacement is selected from pyroles, pyrazoles, porphyrin class, furans, thiophene-based, pyrazoles, imidazoles, oxazole Lei, oxadiazole class, isoxazole, thiazoles, thiadiazole and isothiazole class.

19. the chemical compound of claim 16, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 6 annular atomses and 1-3 annular atoms are selected from O, N and S.

20. the chemical compound of claim 19, the assorted monocycle ring system of the aromatics of wherein said optional replacement is selected from pyridines, miazines, pyrazine class, pyrans class and triazines.

21. the chemical compound of claim 16, the assorted monocycle ring system of the aromatics of wherein said optional replacement contain the hetero atom that 5 annular atomses and 3-4 annular atoms are selected from O, N and S.

22. the chemical compound of claim 21, the assorted monocycle ring system of the aromatics of wherein said optional replacement is triazolyl or tetrazole radical.

23. the chemical compound of claim 3, wherein W contains the assorted bicyclo-ring system of heteroatomic aromatics that 8-12 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl and R ¹⁰

24. the chemical compound of claim 23, the assorted bicyclo-ring system of the aromatics of wherein said optional replacement is selected from adenine kind, Azabenzimidazole-based, Azaindoles, benzimidazole, benzo isothiazole, benzofurans, benzo-isoxazole Benzooxazole kind, the diazosulfide class, benzothiazoles, benzothiophene kind (benzothienes), benzothiophene kind Benzooxazole kind, carbazoles, the cinnoline class, the guanine class, imidazopyridine, the indazole class, indoles, isoindoles, iloquinoline derivative, the phthalazines class, the purine class, Pyrrolopyridine, quinazoline ditosylate salt, quinolines, quinoxaline, benzo-thiophene class and xanthine.

25. the chemical compound of claim 3, wherein W contains the assorted three ring ring systems of heteroatomic aromatics that 10-16 annular atoms and maximum 4 annular atomses are selected from O, N and S, and described ring system is optional to be replaced by maximum three following ring substituents: OH, CN, halogen, formoxyl, R ¹⁰And R ¹¹

26. the chemical compound of claim 25, the assorted three ring ring systems of the aromatics of wherein said optional replacement are selected from carbazoles, biphenyl benzofuran, psoralen class, dibenzothiophen class, azophenlyene class, thianthrene class, phenanthroline class, phenanthridines class.

27. the chemical compound of a Formula Il

Formula II

Wherein:

A be selected from H ,-(C=O)-R ²,-(C=O)-O-R ¹,-C (=O)-NH-R ¹,-C (=S)-NH-R ²,-S (O) ₂-R ²,-(C=NR ¹)-R ¹With-(C=NR ¹)-NH-R ¹

W is selected from

With

Q ' does not exist or is selected from-CH ₂-and-NH-;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately.

28. the chemical compound of claim 27, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

29. the chemical compound of claim 27, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

30. the chemical compound of claim 27, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

31. the chemical compound of claim 27, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

32. the chemical compound of claim 27, it is selected from following chemical compound:

33. the chemical compound of claim 27, it is selected from following chemical compound:

34. the chemical compound of claim 27, it is selected from following chemical compound:

35. the chemical compound of claim 27, it is selected from following chemical compound:

36. the chemical compound of a Formula Il I:

Formula III

Wherein

W is selected from

With

Q ' does not exist or is selected from-CH ₂-and-NH-;

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately.

37. the chemical compound of claim 36, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

38. the chemical compound of claim 36, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

39. the chemical compound of claim 36, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

40. the chemical compound of claim 36, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

41. the chemical compound of a Formula Il:

Formula II

Wherein

W is selected from

With

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately.

42. the chemical compound of claim 41, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

43. the chemical compound of claim 41, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

44. the chemical compound of claim 41, wherein:

A is-(C=O)-and O-R ¹,

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

45. the chemical compound of claim 41, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

J＝3；

M＝s＝1；

R ³And R ⁴Be hydrogen.

46. the chemical compound of claim 41, it is selected from following chemical compound:

47. the chemical compound of claim 41, it is selected from following chemical compound:

48. the chemical compound of claim 41, it is selected from following chemical compound:

49. the chemical compound of claim 41, it is selected from following chemical compound:

50. the chemical compound of a Formula Il I:

Formula III

Wherein

W is selected from With

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independently be selected from hydrogen and methyl separately.

51. the chemical compound of claim 50, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

52. the chemical compound of claim 50, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

53. the chemical compound of claim 50, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

54. the chemical compound of claim 50, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

W is

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

55. the chemical compound of a following formula I V:

Wherein

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independent separately is hydrogen or methyl.

56. the chemical compound of claim 55, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

57. the chemical compound of claim 55, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

58. the chemical compound of claim 55, it is selected from following chemical compound: A G L X，Y Z j m，s R ³，R ⁴ tBOC OEt Do not exist The X=Y=bromine Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OEt Do not exist The X=Y=thiene-3-yl- Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist The X=Y=thiene-3-yl- Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist The X=Y=phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=4-(N, N-dimethylamino) phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=4-(trifluoromethoxy) phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=4-(mesyl) phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=4-(cyano group) phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist The X=Y=3-pyridine radicals Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=4-(morpholine-4-base-formyloxy) phenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist The X=Y=bromine Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X and Y constitute phenyl together The 4-methoxyphenyl 3 m＝s＝1 R ³＝R ⁴＝H

A G L X，Y Z j m，s R ³，R ⁴ tBOC OH Do not exist X and Y constitute phenyl together The 4-chlorphenyl 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=4-fluorophenyl Y=hydrogen Phenyl 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist The Y=1-piperidyl Phenyl 3 m＝s＝1 R ³＝R ⁴＝H tBOC OEt Do not exist X=hydrogen Y=bromine Phenyl 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=hydrogen Y=thiene-3-yl- Phenyl 3 m＝s＝1 R ³＝R ⁴＝H tBOC OEt Do not exist X=bromine Y=pyrrolidine-1-base Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=thiene-3-yl-Y=pyrrolidine-1-base Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OEt Do not exist X=bromine Y=azido Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OEt Do not exist X=thiene-3-yl-Y=azido Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=thiene-3-yl-Y=azido Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=thiene-3-yl-Y=tetrazolium-2-base Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=sulfydryl-2-pyrimidine Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=bromine Y=sulfydryl-2-pyrimidine Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=thiene-3-yl-Y=sulfydryl-2-pyrimidine Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H

A G L X，Y Z j m，s R ³，R ⁴ tBOC OH Do not exist The X=Y=thiazol-2-yl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=Y=imidazoles-1-base Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X=2-(cyclopropyl amino)-thiazole-4-base Y=4-methoxyphenyl Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H tBOC OH Do not exist X and Y constitute 6-methoxyl group-isoquinolyl together Hydrogen 3 m＝s＝1 R ³＝R ⁴＝H

59. the chemical compound of claim 55, it is selected from following chemical compound:

60. the chemical compound of claim 55, it is selected from following chemical compound: A G L X Y Z j m，s R ³，R ⁴ tBOC OH -(C＝O)CH ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 1 m＝s＝1 R ³＝R ⁴＝H tBOC OH -CH(CH ₃)CH ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 1 m＝s＝1 R ³=methyl R ⁴＝H tBOC OH -O- Thiene-3-yl- Thiene-3-yl- Hydrogen 0 m＝s＝1 R ³=methyl R ⁴＝H tBOC OH -S- Thiene-3-yl- Thiene-3-yl- Hydrogen 0 m＝s＝1 R ³=methyl R ⁴＝H tBOC OH -S(O)- Thiene-3-yl- Thiene-3-yl- Hydrogen 2 m＝s＝1 R ³=methyl R ⁴＝H tBOC OH -S(O) ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 2 m＝s＝1 R ³=methyl R ⁴＝H tBOC OH -SCH ₂CH ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 0 m＝s＝1 R ³＝R ⁴ ＝CH ₃ tBOC OH -CF ₂CH ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 1 m＝s＝1 R ³＝R ⁴＝H tBOC OH -CFHCH ₂- Thiene-3-yl- Thiene-3-yl- Hydrogen 1 m＝s＝1 R ³＝R ⁴＝H

61. the chemical compound of claim 55, it is selected from following chemical compound: A G L X Y Z j m，s R ³，R ⁴ -(C＝O)-O-R ¹ R ¹=cyclopenta -O-phenethyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s ＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -NH-phenethyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s ＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -NHS(O) ₂-phenethyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s ＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -(C＝O)-OH Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -(C=O)-the O-phenethyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s ＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -(C=O)-the NH-phenethyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s＝1 R ³＝R ⁴ ＝H -(C＝O)-O-R ¹ R ¹=cyclopenta -(C＝O)-NH- S(O) ₂-benzyl Do not exist Thiophene-3-base Thiophene-3-base Hydrogen 3 m＝s ＝1 R ³＝R ⁴ ＝H

62. the chemical compound of a following formula I V:

Wherein

J=0,1,2,3 or 4;

M=0,1 or 2;

S=0,1 or 2;

R ³And R ⁴Independent separately is hydrogen or methyl.

63. the chemical compound of claim 62, wherein:

A is-(C=O)-and O-R ¹

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

64. the chemical compound of claim 62, wherein:

A is-(C=O)-and the O-tert-butyl group;

G is a hydroxyl;

L does not exist;

j＝3；

m＝s＝1；

R ³And R ⁴Be hydrogen.

65. a Pharmaceutical composition, it comprises the claim 1,27,36,41,50 of anti-hepatitis c virus effective dose, 55 or 62 chemical compound or their pharmaceutically acceptable salt, ester or prodrug and pharmaceutically acceptable carrier or excipient.

66. a method for the treatment of the infection with hepatitis C virus patient, this method comprise the Pharmaceutical composition of the claim 65 that gives patient's anti-hepatitis c virus effective dose.

67. the Pharmaceutical composition that provides hepatitis C virus NS protease to suppress the claim 65 of effective dose is provided for a method that suppresses hepatitis c viral replication, this method.

68. also comprising, the method for claim 66, this method give other anti-hepatitis c virus medicine simultaneously.

69. the method for claim 68, wherein said other anti-hepatitis c virus medicine is selected from alpha-interferon, beta-interferon, ribavirin and amantadine.

70. the method for claim 68, wherein said other anti-hepatitis c virus medicine thing is the inhibitor of other target in the hepatitis C virus biocycle, and described target is selected from helicase, polymerase, metalloproteases and IRES.

71. one kind is selected from following chemical compound:

And their pharmaceutically acceptable salt and isomer.

72. one kind is selected from following chemical compound:

And their pharmaceutically acceptable salt and isomer.

73. one kind is selected from following chemical compound:

And their pharmaceutically acceptable salt and isomer.

74. a method for preparing the formula I chemical compound of claim 1, this method may further comprise the steps: (i) make following formula VI proline derivative:

Wherein,

P is a nitrogen-protecting group group;

L is a leaving group;

R is the optional alkyl that replaces, the optional aralkyl that replaces or the optional heteroarylalkyl that replaces; React with the nucleophilic heterocyclic chemical compound; (ii) formed chemical compound is converted into the formula I chemical compound of claim 1.

75. a method for preparing the formula I chemical compound of claim 1, this method may further comprise the steps: (i) make following formula VII chemical compound:

Formula VII

Wherein,

L is a leaving group;

A is a nitrogen-protecting group group;

Remaining variables is identical with the definition in the claim 1; React with the nucleophilic heterocyclic chemical compound; (ii) the gained chemical compound is converted into the formula I chemical compound of claim 1.

76. the formula I chemical compound of claim 1, wherein W is Wherein V, X, Y and Z independently are selected from separately:

J)-C ₁-C ₆Alkyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

K)-C ₂-C ₆Thiazolinyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

L)-C ₂-C ₆Alkynyl wherein contains 0,1,2 or 3 hetero atom that is selected from O, S or N, and optional by one or more following substituent groups replacements: the Heterocyclylalkyl of the heteroaryl of the aryl of halogen, aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement;

M) aryl;

N) aryl of Qu Daiing;

O) heteroaryl;

P) heteroaryl of Qu Daiing;

Q) Heterocyclylalkyl; Or

R) Heterocyclylalkyl of Qu Daiing; Perhaps, V and X, X and Y or Y constitute with carbon atom that Z is connected with them and are selected from following annulus: the Heterocyclylalkyl of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, Heterocyclylalkyl or replacement.

77. the formula I chemical compound of claim 1, wherein W is

Wherein X, Y and Z independently are selected from separately:

D) aryl;

E) aryl of Qu Daiing;

F) heteroaryl;

G) heteroaryl of Qu Daiing;

H) Heterocyclylalkyl; Perhaps