CN1771050A - Macrocyclic inhibitors of hepatitis C serine protease - Google Patents

Abstract

The present invention relates to compounds of formula I, II or III or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein W is a substituted or unsubstituted heterocyclic ring system. These compounds inhibit serine protease activity, particularly the activity of Hepatitis C Virus (HCV) NS 3-NS 4A protease. Thus, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to pharmaceutical compositions comprising the above compounds for administration to a patient infected with HCV. The invention also relates to methods of treating HCV infected patients by administering pharmaceutical compositions containing the compounds of the present invention.

Description

Macrocyclic inhibitors of hepatitis C serine protease

Cross References to Related Applications

This application claims the benefit of priority from the following applications: U.S. Provisional Application ____ (referred to as US 10/365,854), filed on February 13, 2003; ___ (referred to as US 10/360,947), filed on February 7, 2003; ___ (transferred to US 10/384,120), filed March 7, 2003, each of which is hereby incorporated by reference in its entirety.

                      

The present invention relates to novel macrocyclic compounds which are active against hepatitis C virus (HCV) and are useful in the treatment of HCV infection. More specifically, the present invention relates to macrocyclic compounds, compositions comprising such compounds, methods of using them and methods of making said compounds.

Background of the Invention

HCV is the leading cause of non-A, non-B hepatitis and is a growing public health problem in both developed and developing countries. It is estimated that more than 200 million people worldwide are infected with HCV, almost five times the number infected with human immunodeficiency virus (HIV). Due to the high rate of chronicity in HCV-infected patients, the risk of developing cirrhosis, subsequent development of hepatocellular carcinoma, and end-stage liver disease is high. In Western countries, HCV is the most common cause of hepatocellular carcinoma and of patients requiring liver transplantation.

Considerable obstacles exist in the development of anti-HCV therapies, including but not limited to viral persistence, genetic diversity of the virus as it replicates in the host, high incidence of the virus developing drug-resistant mutants, and lack of reproducible infection culture systems and small animal models of HCV replication and pathogenesis. In most cases, given the mild course of the infection and the complex biology of the liver, the use of antivirals must be carefully considered because of the potential for significant side effects.

Only two treatments for HCV infection are currently approved for use. Whereas previous treatment regimens typically involved intravenous interferon-alpha (IFN-α) for 3–12 months, newly approved second-generation therapies involve administration of IFN-α in combination with conventional antiviral nucleoside mimetics such as Liba Waring) combination therapy. Both treatments suffer from interferon-related side effects and have low efficacy against HCV infection. Because existing therapies are poorly tolerated and have low efficacy, there is a need to develop effective antiviral agents for the treatment of HCV infection.

In a patient population, largely chronically infected and asymptomatic, with an uncertain prognosis, an effective drug must have significantly fewer side effects than those of existing therapies. Hepatitis C nonstructural protein-3 (NS3), a proteolytic enzyme, is required for the processing of viral polyproteins and the resulting viral replication. Despite the large number of viral variants associated with HCV infection, the NS3 protease active site remains highly conserved, making its inhibition an attractive mode of intervention. Recent successful treatment of HIV with protease inhibitors supports the notion that inhibition of NS3 is a key target in the fight against HCV.

HCV is an RNA virus of the family Flaviridae. The HCV genome is enveloped, comprising a single-stranded RNA molecule consisting of approximately 9600 base pairs. It encodes a polypeptide consisting of approximately 3010 amino acids.

The HCV polyprotein is processed by viral and host peptidases into 10 peptides with distinct functions. There are three structural proteins C, El and E2. The function of the P7 protein is unknown and consists of highly unstable sequences. There are 6 nonstructural proteins. NS2 is a zinc-dependent metalloprotease that functions in binding part of the NS3 protein. NS3 includes two catalytic functions (separating it from bound NS2): an N-terminal serine protease function, which requires the cofactor NS4A, and a carboxy-terminal ATP-ase-dependent helicase function. NS4A is a non-covalent tight-binding cofactor of serine proteases.

NS3.4A protease is involved in cleaving four sites of the viral polyprotein. NS3-NS4A cleavage is an autocatalytic cis cleavage. The remaining three hydrolyses NS4A-NS4B, NS4B-NS5A and NS5A-NS5B are trans hydrolysis. NS3 is a serine protease structurally belonging to the chymotrypsin-like proteases. While the NS serine protease itself has proteolytic activity, the HCV protease is not an efficient enzyme in terms of catalyzing polyprotein cleavage. It has been shown that the central hydrophobic region of the NS4A protein is required to enhance this effect. It appears that complex formation of NS3 proteins with NS4A is required for processing events to enhance proteolytic potency at all sites.

A general strategy for developing antiviral drugs is to inactivate virus-encoded enzymes, including NS3, that are required for viral replication. S. Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002) summarizes the existing results. More related patent publications introducing synthesis methods of HCV protease inhibitors include: WO00/59929 (2000); WO99/07733 (1999); WO00/09543 (2000); WO99/50230 (1999); US5861297 (1999).

Summary of Invention

The present invention relates to novel macrocycles, and methods of using said macrocycles to treat hepatitis C-infected patients in need of such treatment. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention or their pharmaceutically acceptable salts, esters or prodrugs and pharmaceutically acceptable carriers or excipients.

A compound of the following formula I or a pharmaceutically acceptable salt, ester or prodrug thereof:

in:

A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ;

G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ¹ , -(C=O)-R ² , - (C=O)-OR ¹ , -(C=O)-NH-R ¹ and -(C=O)-NH-R ² ;

L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen;

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

m is 0, 1 or 2;

s is 0, 1 or 2;

R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, aryl substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R3 and ^R4 are each independently selected from hydrogen, OH, _CH3 , CN, SH, halogen, _NO2 , _NH2 , amide, methoxy, trifluoromethoxy and trifluoromethyl;

E is -CH=CH- or -CH ₂ -CH ₂ -;

W is a substituted or unsubstituted heterocyclic ring system.

In one embodiment of the present invention E is -CH=CH-, resulting in a compound of formula II or a pharmaceutically acceptable salt, ester or prodrug thereof:

The remaining substituents are as defined above.

In one embodiment of the present invention E is -CH ₂ -CH ₂ - to give a compound of formula III or a pharmaceutically acceptable salt, ester or prodrug thereof:

The remaining substituents are as defined above.

In one embodiment of the invention, the disclosed compound is a compound of formula II and III or a pharmaceutically acceptable salt, ester or prodrug thereof:

in

和

W selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-;

Q' is absent or selected from -CH ₂ - and -NH-;

Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

All other substituents are as defined above.

In one embodiment of the invention, the disclosed compound is a compound of formula II and III, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

和 W selected from

and

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl;

All other substituents are as defined above.

In one embodiment of the invention, the disclosed compound is a compound of formula II and III, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein:

和W is

and

X, Y and Z are independently selected from H, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted Alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl radical, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl , -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkane and substituted heterocycloalkyl; or, X and Y or Y and Z together with the carbon atoms to which they are attached constitute aryl, substituted aryl, heteroaryl or substituted heteroaryl;

Other aspects of the invention are:

A compound according to any of the formulas herein, wherein W is substituted by one or more substituents each independently selected from any of the following (a), (b), (c), (d) and (e) :

(a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl; alkylsulfonyl; alkynyl; amide; optionally monosubstituted by C ₁ -C ₆ alkyl Amido; aryl; arylalkanoylalkyl; arylalkyl; arylaminoalkyl; aryloxyalkyl; arylsulfonyl; cycloalkoxy; cycloalkyl; dialkylamino; Dialkylaminoalkyl; Diarylaminoalkyl; Haloalkyl; Heteroaryl; Heteroarylalkyl; Heterocyclyl; Heterocycloalkyl; Heterocycloalkylalkyl; Thioalkyl; Monoalkane (lower alkyl)sulfonyl; haloalkyl; carboxyl; amide; (lower alkyl)amide; heterocyclyl optionally substituted by C ₁ -C ₆ alkyl; perhaloalkyl; Sulfonyl; Thioalkyl; Urea; C(=O)-R ¹¹ ; OC(=O)R ¹¹ ; C(=O)OR ¹¹ ; C(=O)N(R ¹¹ ) ₂ ; S) N(R ¹¹ ) ₂ ; SO ₂ R ¹¹ ; NHS(O ₂ )R ¹¹ ; N(R ¹² ) ₂ ; N(R ¹² )C(=O)R ¹¹ ; Substituted by up to three of the following groups: halogen, OH, alkoxy, perhaloalkyl;

(b) C ₇ -C ₁₄ aralkyl; C ₂ -C ₇ cycloalkyl; C ₆ -C ₁₀ aryl; heterocyclyl; (lower alkyl)-heterocyclyl; Alkyl, aryl, heterocyclyl or (lower alkyl)-heterocyclyl may be optionally substituted by R ⁶ ; R ⁶ is halogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, NO ₂ , N(R ⁷ ) ₂ , NH-C(O)-R ⁷ or NH-C(O)-NHR ⁷ , R ⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; or R ⁶ is NH-C(O)-OR ⁸ , R ⁸ is C ₁ -C ₆ alkyl or C ₃ -C ₆ Cycloalkyl;

(c) N(R ⁵ ) ₂ , NH-C(O)-R ⁵ or NH-C(O)-NH-R ⁵ , wherein R ⁵ is independently H, C ₁ -C ₆ alkyl or C ₃ - C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, C ₇ -C ₁₄ aralkyl, heterocyclyl or (lower alkyl)-heterocyclyl;

(d) NH-C(O)-OR ⁸ , wherein R ⁸ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;

(e) Formyl; Halogen; Hydroxy; NO ₂ ; OH; SH; Halo; CN;

in

Each ^R is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkyl Sulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkyl Aminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and per Haloalkyl;

Each ^R is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkane Sulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylamino Alkyl, arylaminoalkyl or diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl;

Compounds of any of the formulas herein, wherein W is selected from:

(a) Aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring systems containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, wherein the ring system is optionally Substituted by up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ;

(b) an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, wherein the ring system is optionally Substituted by up to three of the following ring substituents: OH, CN, halogen, formyl, and R ¹⁰ ;

in:

Each R ¹⁰ is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkylsulfonyl, aryl Sulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, Dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl; C(=O)-R ¹¹ , OC(=O)R ¹¹ , C(=O)OR ¹¹ , C(=O)N(R ¹¹ ) ₂ , C(=S)N(R ¹¹ ) ₂ , SO ₂ R ¹¹ , NHS(O ₂ )R ¹¹ , N(R ¹² ) ₂ and N(R ¹² )C(=O)R ¹¹ ;

Each ^R is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkyl Sulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkyl Aminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and per Haloalkyl;

Each ^R is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkane Sulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylamino Alkyl, arylaminoalkyl or diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl;

A compound of any of the formulas herein, wherein W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system is optionally substituted by up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ;

A compound of any of the formulas herein, wherein W is an aliphatic heteromonocyclic ring system containing 5-7 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system being optionally surrounded by up to three The following ring substituents are substituted: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ;

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 5 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms;

A compound of any structural formula herein, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from pyrrolidines, pyrazolidines, pyrrolines, tetrahydrothiophenes, dihydrothiophenes, tetrahydrofurans, dihydro Furans, imidazolines, tetrahydroimidazoles, dihydropyrazoles, tetrahydropyrazoles and oxazolines;

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 6 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms;

A compound of any structural formula herein, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from pyridines, piperidines, dihydropyridines, tetrahydropyridines, dihydropyrans, tetrahydropyrans , dioxanes, piperazines, dihydropyrimidines, tetrahydropyrimidines, perhydropyrimidines, morpholines, thioxanes and thiomorpholines;

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 7 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms;

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and thioheptane;

A compound of any of the formulas herein, wherein W is an aliphatic heterobicyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system being optionally surrounded by up to three substituted with the following ring substituents: OH, CN, halogen, formyl and R ¹⁰ .

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heterobicyclic ring system contains 8-12 ring atoms and 1-4 ring atoms are selected from O, N and S heteroatoms;

A compound of any of the formulas herein, wherein the optionally substituted aliphatic heterobicyclic ring system contains 8-12 ring atoms and 1-2 ring atoms are selected from O and N heteroatoms;

A compound of any of the formulas herein, wherein W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system is optionally substituted with up to three of the following ring substituents: OH, CN, halogen, formyl and R ¹⁰ ;

A compound of any of the formulas herein, wherein W is an aromatic heteromonocyclic ring system containing 5-7 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system being optionally surrounded by up to three The following ring substituents are substituted: OH, CN, halogen, formyl and R ¹⁰ ;

A compound of any of the formulas herein, wherein the optionally substituted aromatic heteromonocyclic ring system contains 5 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms;

A compound of any structural formula herein, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyrroles, pyrazoles, porphyrins, furans, thiophenes, pyrazoles, imidazoles, oxazoles, Oxadiazoles, isoxazoles, thiazoles, thiadiazoles and isothiazoles.

A compound of any of the formulas herein, wherein the optionally substituted aromatic heteromonocyclic ring system contains 6 ring atoms and 1-3 ring atoms are selected from O, N and S heteroatoms;

A compound of any structural formula herein, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from pyridines, pyrimidines, pyrazines, pyrans and triazines;

A compound of any of the formulas herein, wherein the optionally substituted aromatic heteromonocyclic ring system contains 5 ring atoms and 3-4 ring atoms are selected from O, N and S heteroatoms;

A compound of any of the formulas herein, wherein the optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl;

A compound of any of the formulas herein, wherein W is an aromatic heterobicyclic ring system containing 8-12 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system being optionally surrounded by up to three The following ring substituents are substituted: OH, CN, halogen, formyl and R ¹⁰ ;

A compound of any structural formula herein, wherein the optionally substituted aromatic heterobicyclic ring system is selected from the group consisting of adenines, azabenzimidazoles, azaindoles, benzimidazoles, benzisothiazoles, Benzofurans, benzoisoxazoles, benzooxazoles, benzothiadiazoles, benzothiazoles, benzothienes, benzothiophenes, benzene Benzoxazoles, carbazoles, carnolines, guanines, imidazopyridines, indazoles, indoles, isoindoles, isoquinolines, phthalazines, purines, Pyrrolopyridines, quinazolines, quinolines, quinoxalines, thiaindenes and xanthines;

A compound of any of the formulas herein, wherein W is an aromatic heterotricyclic ring system containing 10-16 ring atoms and up to 4 heteroatoms selected from O, N and S, said ring system being optionally surrounded by up to three The following ring substituents are substituted: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ;

A compound of any structural formula herein, wherein the optionally substituted aromatic heterotricyclic ring system is selected from the group consisting of carbazoles, bibenzofurans, psoralens, thiofluorenes, phenazines, thianthracenes, Phenanthrolines, phenanthridines.

Other embodiments have compounds of formula II:

Formula II

in:

A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ¹ , -C(=S)-NH--R ² , -S(O) ₂ -R ² , -C(=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ;

G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ;

L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen;

和 W selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-;

Q' is absent or selected from -CH ₂ - and -NH-;

Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

^R3 and ^R4 are each independently selected from hydrogen and methyl.

One or more compounds of formula II, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

A is -(C=O)-OR ¹ ,

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

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

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen.

The following are other implementations:

A compound of the following formula III:

Formula III

in

A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ;

G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ;

L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen;

和W selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-;

Q' is absent or selected from -CH ₂ - and -NH-;

Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

R ^{and R} are each independently selected from hydrogen and methyl;

One or more compounds of formula III, wherein:

A is (C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

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

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

A compound of the following formula II:

Formula II

in

A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ;

G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ;

L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen;

和

其中X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；W selected from

and

Wherein X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Baseamino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C= O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl group, heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl radical, heteroaryl and substituted heteroaryl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

R ^{and R} are each independently selected from hydrogen and methyl;

One or more compounds of formula II, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula II, wherein:

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

G is hydroxyl;

L does not exist;

W is

J=3;

M=s=1;

^R3 and ^R4 are hydrogen.

Other embodiments have the following compounds of formula III:

Formula III

in

A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ;

G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ;

L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -O-, -OCH ₂ - , -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, -CF ₂ CH ₂ -, and -CR _x =CR _x -, where _Rx = H or halogen;

W selected from and

Wherein X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Baseamino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C= O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl group, heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl radical, heteroaryl and substituted heteroaryl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl;

R ^{and R} are each independently selected from hydrogen and methyl;

One or more compounds of formula III, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

A is -(C=O)-OR ¹ ,

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula III, wherein:

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

G is hydroxyl;

L does not exist;

W is

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

A compound of the following formula IV:

in

A is hydrogen, -(C=O)-R ¹ , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ or -(C=NR ¹ )-NH-R ¹ ;

G is -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ or -( C=O)-NH-R ² ;

L is -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, -S(O) CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, -CF _2CH2 -or- _CRx = _CRx- , where _Rx =H or _halogen ;

X, Y and Z are independently selected from hydrogen, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted Alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl radical, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl , -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkane and substituted heterocycloalkyl; or, X and Y or Y and Z together with the carbon atoms to which they are attached constitute aryl, substituted aryl, heteroaryl or substituted heteroaryl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Substituted heterocycloalkyl;

R ³ and R ⁴ are each independently hydrogen or methyl;

One or more compounds of formula IV, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula IV, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

A compound of the following formula V:

in

A is hydrogen, -(C=O)-R ¹ , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ or -(C=NR ¹ )-NH-R ¹ ;

G is -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ or -( C=O)-NH-R ² ;

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

X, Y and Z are independently selected from hydrogen, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted Alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl radical, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl , -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkane and substituted heterocycloalkyl; or, X and Y or Y and Z together with the carbon atoms to which they are attached constitute aryl, substituted aryl, heteroaryl or substituted heteroaryl;

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

m = 0, 1 or 2;

s = 0, 1 or 2;

R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl;

R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Substituted heterocycloalkyl;

R ³ and R ⁴ are each independently hydrogen or methyl;

One or more compounds of formula V, wherein:

A is -(C=O)-OR ¹ ;

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen;

One or more compounds of formula V, wherein:

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

G is hydroxyl;

L does not exist;

j = 3;

m=s=1;

^R3 and ^R4 are hydrogen.

The following are other implementations:

A compound of formula II or III described herein, wherein:

和

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝0、1、2、3或4；m＝0、1或2；s＝0、1或2；R¹选自H、C₁-C₆烷基、C₃-C₁₂环烷基、取代的C₃-C₁₂环烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；R²选自H、C₁-C₆烷基、C₃-C₁₂环烷基、烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；R³和R⁴各自独立选自氢和甲基；A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH--R ² and -S(O) ₂ -R ² ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ¹ , - (C=O)-OR ¹ and -(C=O)-NH-R ¹ ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ - , -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, -S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C =O _{) -CH2-} , -CH( _CH3 ) _CH2- , _-CFHCH2- and _-CF2CH2- ; W is selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=0, 1, 2, 3 or 4; m=0, 1 or 2; s=0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl radical, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, aryl ^R3 and R ⁴ are each independently selected from hydrogen and methyl;

和 Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and Substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

and Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen;

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

和 Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；W is

and Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl Base alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl Base alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

和 Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；式III的化合物，其中A为-(C＝O)-O-叔丁基；G为羟基；L不存在；W为

和 Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

and Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen; A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

and Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O ₂ - and -(C=O)-; Q' is absent Or selected from -CH ₂ - and -NH-; Y selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted Heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl Base alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢。A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen.

The following are other implementations:

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝0、1、2、3或4；m＝0、1或2；s＝0、1或2；R¹选自H、C₁-C₆烷基、C₃-C₁₂环烷基、取代的C₃-C₁₂环烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；R²选自H、C₁-C₆烷基、C₃-C₁₂环烷基、烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；R³和R⁴各自独立选自氢和甲基；A compound of formula II or III, wherein A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S )-NH-R ² and -S(O) ₂ -R ² ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C= O)-R ² , -(C=O)-OR ¹ and -(C=O)-NH-R ² ; L is absent or selected from -S-, SCH ₂ -, -SCH ₂ CH ₂ -, - S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, -S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ - and -CF ₂ CH ₂ -; W is selected from and

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ Alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; R ^is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkane radical, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, Heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; R ^{and R} are each independently selected from hydrogen and methyl;

和

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from

and

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

或

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is selected from

or

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-Ch₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -C ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

和 X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from

and X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is selected from or X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

Other embodiments are compounds of formula IV or V:

where A is H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² or - S(O) ₂ -R ² ; G is -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C =O)-OR ¹ or -(C=O)-NH-R ² ; L is absent or is -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S (O) ₂ CH ₂ CH ₂ -, -S(O)-, -S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O) -CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ - or -CF ₂ CH ₂ -; X, Y and Z are independently selected from H, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted Aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkane radical, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl , -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or, the carbon to which X and Y or Y and Z are attached The atoms together form aryl, substituted aryl, heteroaryl or substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkane radical, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl or substituted heterocycloalkyl; R ² is H, C ₁ -C ₆ alkyl , C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl radical, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; ^R and ^R are each independently hydrogen or methyl;

A compound of formula IV, wherein A is -(C=O)-OR ¹ ; G is a hydroxyl group; L does not exist; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula IV, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula V, wherein A is -(C=O)-OR ¹ ; L is absent; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula V, wherein A is -(C=O)-O-tert-butyl; G is hydroxyl; L is absent; j=3; m=s=1; ^R3 and ^R4 are hydrogen.

Another aspect is a compound of formula I, wherein W is

wherein V, X, Y and Z are each independently selected from:

a) -C ₁ -C ₆ alkyl, which contains 0, 1, 2 or 3 heteroatoms selected from O, S or N, and is optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

b) -C ₂ -C ₆ alkenyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

c) -C ₂ -C ₆ alkynyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

d) aryl;

e) substituted aryl;

f) heteroaryl;

g) substituted heteroaryl;

h) heterocycloalkyl; or

i) substituted heterocycloalkyl;

Alternatively, V and X, X and Y, or Y and Z together with the carbon atoms to which they are attached form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkane or substituted heterocycloalkyl;

Another aspect is a compound of formula I, wherein W is

wherein X, Y and Z are each independently selected from:

a) -C ₁ -C ₆ alkyl, which contains 0, 1, 2 or 3 heteroatoms selected from O, S or N, and is optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

b) -C ₂ -C ₆ alkenyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

c) -C ₂ -C ₆ alkynyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl;

d) aryl;

e) substituted aryl;

f) heteroaryl;

g) substituted heteroaryl;

h) heterocycloalkyl; or

i) substituted heterocycloalkyl; alternatively, Y and Z together with the carbon atoms to which they are attached form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic Alkyl or substituted heterocycloalkyl.

All remaining substituents are listed above.

Another aspect is a method of preparing a compound of formula I herein, the method comprising the steps of:

(i) make following formula VI proline derivative:

in,

P is a nitrogen protecting group (eg BOC);

L is a leaving group (e.g. halogen, OMs);

R is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; reacting with a nucleophilic heterocyclic compound; (ii) converting the resulting compound to a compound of formula I presented herein.

Another aspect is a method of preparing a compound of formula I herein, the method comprising the steps of: (i) making a compound of formula VII:

Formula VII

in,

L is a leaving group (e.g. halogen, OMs);

A is a nitrogen protecting group (such as BOC);

All the other variables are identical to the definitions in formula I;

Reaction with a nucleophilic heterocyclic compound; (ii) conversion of the resulting compound to a compound of formula I presented herein.

In other aspects, the present invention relates to the preparation of any structural formula described herein (for example formula I-VII, each substituent variable is defined anywhere herein) or pharmaceutically acceptable salts, esters or prodrugs thereof, The method comprises the following steps: (i) reacting the proline derivatives described herein (including derivatives containing mesylate substituents) with a nucleophilic form (such as a protonated form or a corresponding metal salt form) of a heterocyclic compound ) reaction; (ii) converting the resulting compound into a compound of any of the formulas presented herein. In other aspects, the method comprises reacting one or more intermediate compounds described herein, or a chemical process comprising any one or more steps or reagents or combinations thereof detailed in the examples and schemes herein.

In another aspect, the invention is directed to a method of preparing a pharmaceutical composition comprising admixing a compound of any formula herein, or a pharmaceutically acceptable salt, ester or prodrug thereof, and a pharmaceutically acceptable carrier.

Another aspect is a compound of formula VI or VII, wherein L is OMs, A and the remaining variables are as defined in any of the formulas herein (eg I, II, III).

Detailed description of the invention

The first embodiment of the present invention is the above compound of formula I or a pharmaceutically acceptable salt, ester or prodrug in combination with a pharmaceutically acceptable carrier or excipient.

In certain embodiments, the compound may be a compound of any of the formulas presented herein (any substituent variable may be defined anywhere herein), wherein W is selected from the following optionally substituted aromatic groups:

Aromatic group

  

    

 

 

   

 

  

    

 

 

   

 

1H-pyrrole 1H-imidazole 1H-pyrazole furan thiophene oxazole thiazole isoxazole isothiazole

 

   

 

 

   

 

   

 

 

 

Pyridine Pyridazine Pyrimidine Pyrazine Phthalazine Quinoxaline Quinazoline Quinoline

    

     

   

       

    

     

   

       

Carnoline 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-benzimidazol-2-one

           

                      

           

           

                      

           

1,3-dihydro-benzimidazole-2-thione 2,3-dihydro-1H-indole 1,3-dihydro-indol-2-one 1H-indole-2,3-dione 1,3-Dihydro-benzimidazol-2-one

                                

                   

1H-Pyrrolo[2,3-c]pyridine Benzofuran Benzo[b]thiophene Benzo[d]isoxazole Benzo[d]isothiazole

   

   

1H-quinolin-2-one 1H-quinolin-4-one 1H-quinazolin-4-one

9H-carbazole

1H-Quinazolin-2-one

In another embodiment, the compound may be a compound of any of the formulas presented herein (any substituent variable may be defined anywhere herein), wherein W is selected from the following optionally substituted non-aromatic groups:

              Non-aromatic groups

       

       

     

     

       

       

     

     

Ethyleneimine Azetidine Pyrrolidine 4,5-Dihydro-1H-pyrazole Pyrazolidine

    

     

     

   

    

     

     

Imidazolidine-2-one Imidazolidine-2-thione Pyrrolidin-2-one Pyrrolidine-2,5-dione Piperidine-2,6-dione

     

      

    

    

     

      

    

Piperidin-2-one Piperazine-2,6-dione Piperazine-2-one Piperazine Morpholine Thiomorpholine 1,1-dioxide

  

  

  

  

Pyrazolidine-3-one Imidazolidine-2,4-dione Piperidine

       

    

          

       

    

          

Tetrahydrofuran Tetrahydropyran [1,4]dioxane 1,2,3,6-tetrahydro-pyridine

Another embodiment of the present invention is the compound of the above formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is tetrazole or its derivative) in combination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is the compound of the above formula III or a pharmaceutically acceptable salt, ester or prodrug thereof (wherein W is tetrazole or a derivative thereof) in combination with a pharmaceutically acceptable carrier or excipient.

Exemplary tetrazolyl macrocycles and related methods of the present invention are disclosed in US Provisional Patent Application ________, filed February 13, 2003 (retransmitted as US 10/365,854). A representative subset of the invention includes, but is not limited to:

和

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；式II的化合物，其中A为-(C＝O)-O-叔丁基；G为羟基；L不存在；W为

和

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen; A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl Base alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl Base alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

和 Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；式III的化合物，其中A为-(C＝O)-O-叔丁基；G为羟基；L不存在；W为

和

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S--S(O)₂-和-(C＝O)-；Q′不存在或选自-CH₂-和-NH-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

and Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' does not present or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen; A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S--S(O) ₂ - and -(C=O)-; Q' is absent Or selected from -CH ₂ - and -NH-; Y selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted Heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢；式III的化合物，其中A为-(C＝O)-O-叔丁基；G为羟基；L不存在；W为

Q不存在或选自-CH₂-、-O-、-NH-、-N(R¹)-、-S-、-S(O)₂-和-(C＝O)-；Y选自H、C₁-C₆烷基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；j＝3；m＝s＝1；R³和R⁴为氢。A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl m=s=1; R ³ and R ⁴ are hydrogen; compounds of formula III, wherein A is -(C=O)-O - tert-butyl; G is hydroxyl; L does not exist; W is

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl alkyl, heterocycloalkyl and substituted heterocycloalkyl; j=3; m=s=1; ^R3 and ^R4 are hydrogen.

Representative compounds of the invention include, but are not limited to, the following compounds:

The following tetrazolyl macrocycles of the invention were prepared by the methods and procedures described herein. Although a stereochemical structure is shown, the invention is not limited to the stereochemical structure shown. Those of ordinary skill in the art will readily understand that other isomers of these compounds also fall within the scope of the present invention.

Another embodiment of the present invention is the compound of the above formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is a triazole or its derivative) in combination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is the compound of the above formula III or a pharmaceutically acceptable salt, ester or prodrug thereof (wherein W is a triazole or a derivative thereof) in combination with a pharmaceutically acceptable carrier or excipient.

Exemplary triazole macrocycles and related methods of the present invention are disclosed in US Provisional Patent Application ________, filed February 7, 2003 (retransmitted as US 10/360,947). A representative subset of the invention includes, but is not limited to:

和

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from

and

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

和

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is selected from

and

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

和 X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl; substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is selected from

and X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

或

X和Y独立选自H、卤素、C₁-C₆烷基、C₃-C₁₂环烷基、-CH₂-烷基氨基、-CH₂-二烷基氨基、-CH₂-芳基氨基、-CH₂-二芳基氨基、-(C＝O)-烷基氨基、-(C＝O)-二烷基氨基、-(C＝O)-芳基氨基、-(C＝O)-二芳基氨基、芳基、取代的芳基、芳基烷基、取代的芳基烷基、杂芳基、取代的杂芳基、杂芳基烷基、取代的杂芳基烷基、杂环烷基和取代的杂环烷基；或者，X和Y与它们连接的三唑环的4位和5位碳原子一起构成选自以下的环状部分：芳基、取代的芳基、杂芳基和取代的杂芳基；j＝3；m＝s＝1；R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is selected from

or

X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula II, wherein A is -(C=O)-OR ¹ , and R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkane radical, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; G is hydroxyl; L is absent; W is X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=Oalkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O)- Diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl Cycloalkyl and substituted heterocycloalkyl; alternatively, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of aryl, substituted aryl, hetero Aryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen;

A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; W is X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Amino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C=O )-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl , heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl , heteroaryl and substituted heteroaryl; j=3; m=s=1; R ³ and R ⁴ are hydrogen.

Representative compounds of the invention include, but are not limited to, the following compounds:

The following triazole macrocycles of the invention were prepared by the methods and procedures described herein. Although a stereochemical structure is shown, the invention is not limited to the stereochemical structure shown. Those of ordinary skill in the art will readily understand that other isomers of these compounds also fall within the scope of the present invention.

Another embodiment of the present invention is the above-mentioned compound of formula II or its pharmaceutically acceptable salt, ester or prodrug (wherein W is pyridazinone or its derivative) in combination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the present invention is the above-mentioned compound of formula III or its pharmaceutically acceptable salt, ester or prodrug (wherein W is pyridazinone or its derivative) in combination with a pharmaceutically acceptable carrier or excipient.

Exemplary pyridazinone macrocycles and related methods of the present invention are disclosed in US Provisional Patent Application ________, filed March 7, 2003 (transferred as US 10/384,120). A representative subset of the invention includes, but is not limited to:

A compound of formula II, wherein A is -(C=O)-OR ¹ ; G is a hydroxyl group; L does not exist; j=3; m=s=1; ^R3 and ^R4 are hydrogen;

R³和R⁴为氢；A compound of formula II, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; j=3; m=s=1;

^R3 and ^R4 are hydrogen;

R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-OR ¹ ; L is absent; j=3; m=s=1;

^R3 and ^R4 are hydrogen;

R³和R⁴为氢；A compound of formula III, wherein A is -(C=O)-O-tert-butyl; G is a hydroxyl group; L does not exist; j=3; m=s=1;

^R3 and ^R4 are hydrogen;

Representative compounds of the invention include, but are not limited to, the following compounds:

The following pyridazinone macrocycles of the present invention were prepared by the methods and procedures described herein. Although a stereochemical structure is shown, the invention is not limited to the stereochemical structure shown. Those of ordinary skill in the art will readily understand that other isomers of these compounds also fall within the scope of the present invention.

Other compounds of the present invention are compounds of formula I, II or III: wherein W is a substituted benzimidazolyl group, which can be substituted by 1-2 heteroaryl groups, each heteroaryl group can be replaced by independence. Examples of such compounds include:

According to another embodiment, the pharmaceutical composition of the present invention may further comprise other anti-HCV drugs. Examples of anti-HCV drugs include, but are not limited to, alpha-interferon, beta-interferon, ribavirin, and amantadine.

According to another embodiment, the pharmaceutical composition of the present invention may further comprise other HCV protease inhibitors.

According to another embodiment, the pharmaceutical composition of the present invention may also comprise inhibitors of other targets of the HCV life cycle including, but not limited to, helicases, polymerases, metalloproteases, and internal ribosome entry sites (IRES ).

According to yet another embodiment, the invention includes a method of treating a hepatitis C infected patient in need of such treatment by administering to said patient an anti-HCV virally effective amount of a pharmaceutical compound or composition of the invention. The method may further comprise administering other therapeutic agents, including additional antiviral or anti-HCV agents. Other drugs may be administered simultaneously or sequentially in combination with the compounds or compositions of the present invention. The methods herein may further comprise the step of identifying a patient in need of treatment for hepatitis C infection. Identification can be subjective (eg, at the discretion of a healthcare provider) or objective (eg, diagnostic testing).

The entire contents of all references (including patents, patent publications, papers, textbooks, etc.) disclosed throughout this specification are hereby incorporated by reference.

definition

Unless otherwise indicated in a particular instance, the following definitions of the various terms and phrases that describe the invention, whether used alone or as part of a larger group, are consistent with their ordinary usage in the art and apply throughout the specification and claims.

As used herein, the term " _Cx - _Cy " is used in conjunction with the designation of a carbon-containing group to mean that the group contains xy carbon atoms, x and y being integers.

As used herein, the terms "halo" and "halogen" refer to an atom selected from fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon group. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl, n-hexyl, octyl, decyl, dodecyl.

As used herein, the term "substituted alkyl" refers to an "alkyl" whose one or more (eg 1, 2 or 3) hydrogen atoms are independently substituted by: 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 radical, 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 -alk radical), 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 ₂ NH ₂ , SO ₂ NH-( C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF _3. CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl radical, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alk Oxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, hetero Arylthio, benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "haloalkyl" refers to an aliphatic straight or branched chain alkyl group in which one or more hydrogens are replaced by a halogen selected from bromine, chlorine, fluorine or iodine.

As used herein, the term "thioalkyl" refers to an aliphatic straight or branched chain alkyl group comprising a thiol group, such as, but not limited to, thiopropyl.

The term "alkoxy" as used herein refers to an alkyl group as defined above attached to the parent molecule through an oxygen atom. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentyloxy, and n-hexyloxy.

As used herein, the term "alkenyl" refers to a monovalent group obtained by the removal of a hydrogen atom from a hydrocarbon having at least one carbon-carbon double bond. Alkenyl groups include, but are not limited to, eg vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

As used herein, the term "substituted alkenyl" refers to an "alkenyl" in which one or more hydrogen atoms are independently replaced by: F, Cl, Br, I, OH, _NO2 , CN, _C1 - _C6 -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 radical, 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 ₂ NH ₂ , SO ₂ NH-(C ₁ -C ₆ -alk radical), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, Arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy, methoxymethyl Oxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroarylthio, benzylthio , C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "alkynyl" refers to a monovalent group derived from a hydrocarbon having at least one carbon-carbon triple bond by the removal of one hydrogen atom. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.

As used herein, the term "substituted alkynyl" refers to an "alkynyl" in which one or more hydrogen atoms are independently replaced by: F, Cl, Br, I, OH, _NO2 , CN, _C1 - _C6 -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 radical, 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 radical, NHCONH-heteroaryl, SO ₂ -(C ₁ -C ₆ -alkyl), SO ₂ -aryl, SO ₂ -heteroaryl, SO ₂ NH ₂ , SO ₂ NH-(C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl radical, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy, methoxy methoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroarylthio, benzyl Thio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "aryl" refers to a monocarbocyclic or bicarbocyclic ring system having one or two aromatic rings, including but not limited to phenyl, naphthyl, tetrahydronaphthalene, indanyl, indenyl, etc. .

As used herein, the term "substituted aryl" refers to an aryl group as defined above in which one or more hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , CN, _C1 -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 -hetero Aryl, 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 ₂ NH ₂ , SO ₂ NH-(C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy, methyl Oxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroarylthio, Benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "arylalkyl" refers to a C ₁ -C ₃ alkyl or C ₁ -C ₆ alkyl attached to an aryl ring. Including but not limited to, for example, benzyl, phenethyl and the like.

As used herein, the term "substituted arylalkyl" refers to an arylalkyl group as defined above in which one or more hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , 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-hetero Aryl, 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 ₂ NH ₂ , SO ₂ NH-(C ₁ - C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl _2. CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy, Methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroarylthio , benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

The term "cycloalkyl" refers to a single bond group obtained by removing a hydrogen atom from a saturated monocyclic or bicyclic carbocyclic compound. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

As used herein, the term "substituted cycloalkyl" refers to a cycloalkyl group as defined above in which 1, 2 or 3 hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , 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 ₂ NH ₂ , SO ₂ NH-( C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF _3. CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl radical, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alk Oxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, hetero Arylthio, benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "heterocyclyl" refers to a saturated or unsaturated (including aromatic) 3-7 membered ring with 1-4 ring atoms of heteroatoms selected from N, O and S, obtained by removing a hydrogen atom single bond substituent. Examples of suitable heterocycles include, but are not limited to, tetrahydrofuran, thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine and pyrimidine. "Heterocyclyl" also includes a heterocycle as defined herein fused to one or more other rings (heterocycle or carbocycle). An example is thiazolo[4,5-b]-pyridine. Although the term "heterocycle" generally includes the terms "heterocycloalkyl", "aliphatic heteromonocyclic ring system", "aliphatic heterobicyclic ring system", "aliphatic heterotricyclic ring system", "heteroaryl group", "aromatic heteromonocyclic ring system", "aromatic heterobicyclic ring system", "aromatic heterotricyclic ring system", "heteroarylalkyl", but their specific meanings are explained below .

The term "heterocycloalkyl" as used herein means a non-aromatic 5-, 6- or 7-membered ring or a fused six-membered ring containing 1-3 heteroatoms independently selected from oxygen, sulfur and nitrogen A bicyclic or tricyclic group wherein (i) each 5-membered ring has 0-1 double bond and each 6-membered ring has 0-2 double bonds, (ii) nitrogen and sulfur heteroatoms can be optionally oxidized , (iii) nitrogen heteroatoms can be optionally quaternized, (iv) any of the above heterocycles can be fused with a benzene ring. Representative heterocycles include, but are not limited to; pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl , morpholinyl, thiazolidinyl, isothiazolidinyl and tetrahydrofuryl.

As used herein, the term "substituted heterocycloalkyl" refers to a heterocycloalkyl group as defined above in which one or more hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , 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 ₂ NH ₂ , SO ₂ NH-(C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl , substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy radical, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroaryl Thio, benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "aliphatic heteromonocyclic ring system" refers to a ring system comprising a non-aromatic ring containing at least one ring hetero (ie, non-carbon) atom selected from O, N, and S. The term "aliphatic heterobicyclic ring system" refers to a ring system comprising two fused rings, and at least one of the two fused rings is a heterocyclic (i.e., non-carbon) ring containing at least one ring selected from O, N, and S. Atoms in non-aromatic rings. The term "aliphatic heterotricyclic ring system" refers to a ring system comprising three fused rings, and at least one of the three fused rings is a heterocyclic (i.e., non-carbon) ring containing at least one ring selected from O, N, and S. Atoms in non-aromatic rings. It should be understood that the aliphatic heterocyclic ring system may have any degree of saturation (ie, double or triple bonds) as long as the heteroatom-containing ring is not aromatic. Thus, structures such as indoline (which contains a non-aromatic heterocycle (i.e., pyrroline ring) fused to an aromatic carbocycle (i.e., benzene ring)) and phthalimide are "aliphatic heterocycles". An example of a bicyclic ring system".

As used herein, the term "aromatic heteromonocyclic ring system" refers to an aromatic ring containing at least one ring hetero (ie, non-carbon) atom selected from O, N, and S. The term "aromatic heterobicyclic ring system" refers to an aromatic ring system comprising two fused rings, the aromatic ring system comprising at least one ring hetero (ie, non-carbon) atom selected from O, N, and S. The term "aromatic heterotricyclic ring system" refers to an aromatic ring system containing three fused rings, the aromatic ring system comprising at least one ring hetero (ie, non-carbon) atom selected from O, N, and S. The substituent atoms of the aromatic heterocyclic ring system can further form non-aromatic fused ring structures with other atoms. Thus, 5,6,7,8-tetrahydroisoquinoline is an example of an aromatic heterobicyclic ring system, while 1,2,3,4-tetrahydroisoquinoline is an example of an aliphatic heterobicyclic ring system. example.

The term "heteroaryl" as used herein refers to a ring-shaped aromatic group containing 5-10 ring atoms and at least one ring atom selected from S, O, and N, and the remaining ring atoms are carbon, which can be passed through any A ring atom attached to the rest of the molecule, e.g. pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazole base, thienyl, furyl, quinolinyl, isoquinolyl, etc.

As used herein, the term "substituted heteroaryl" refers to a heteroaryl group as defined above in which 1 to 3 hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , CN, _C1 -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 -hetero Aryl, 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 ₂ NH ₂ , SO ₂ NH-(C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted Aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ -alkoxy, methyl Oxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, heteroarylthio, Benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

As used herein, the term "heteroarylalkyl" refers to a C ₁ -C ₃ alkyl or C ₁ -C ₆ alkyl attached to a heteroaryl ring. Including but not limited to, for example, pyridylmethyl, pyrimidinylethyl and the like.

As used herein, the term "substituted heteroarylalkyl" refers to a heteroarylalkyl group as defined above in which one or more hydrogen atoms are independently substituted by: F, Cl, Br, I, OH, _NO2 , 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 -alk radical), NHCONH-aryl, NHCONH-heteroaryl, SO ₂ -(C ₁ -C ₆ -alkyl), SO ₂ -aryl, SO ₂ -heteroaryl, SO ₂ NH ₂ , SO ₂ NH- (C ₁ -C ₆ -alkyl), SO ₂ NH-aryl, SO ₂ NH-heteroaryl, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, CF ₃ , CH ₂ CF ₃ , CHCl ₂ , CH ₂ NH ₂ , CH ₂ SO ₂ CH ₃ H, C ₁ -C ₆ alkyl, haloalkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, Aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C ₁ -C ₆ - Alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C ₁ -C ₃ -alkylamino, thio, arylthio, Heteroarylthio, benzylthio, C ₁ -C ₆ -alkylthio or methylthiomethyl.

Substituents for any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocycle) also include any of the following groups: -F, - Cl, -Br, -I, -OH, protected hydroxyl, aliphatic ether, aromatic ether, oxo, -NO ₂ , -CN, -C ₁ -C ₁₂ -alkyl optionally substituted by halogen (e.g. perhaloalkyl), optionally halogen-substituted C ₂ -C ₁₂ -alkenyl, optionally halogen-substituted -C ₂ -C ₁₂ -alkynyl, -NH ₂ , protected amino, -NH-C ₁ - C ₁₂ -Alkyl, -NH-C ₂ -C ₁₂ -alkenyl, -NH-C ₂ -C ₁₂ -alkynyl, -NH-C ₃ -C ₁₂ -cycloalkyl, -NH-aryl, - NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC ₁ -C ₁₂ -alkyl, -OC ₂ -C ₁₂ - Alkenyl, -OC ₂ -C ₁₂ -alkynyl, -OC ₃ -C ₁₂ -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O) -C ₁ -C ₁₂ -alkyl, -C(O)-C ₂ -C ₁₂ -alkenyl, -C(O)-C ₂ -C ₁₂ -alkynyl, -C(O)-C ₃ -C ₁₂ -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH ₂ , -CONH-C ₁ -C ₁₂ -alk -CONH-C ₂ -C ₁₂ -alkenyl, -CONH-C ₂ -C ₁₂ -alkynyl, -CONH-C ₃ -C ₁₂ -cycloalkyl, -CONH-aryl, -CONH-heteroaryl -CONH-heterocycloalkyl, -CO ₂ -C ₁ -C ₁₂ -alkyl, -CO ₂ -C ₂ -C ₁₂ -alkenyl, -CO ₂ -C ₂ -C ₁₂ -alkynyl, - CO ₂ -C ₃ -C ₁₂ -cycloalkyl, -CO ₂ -aryl, -CO ₂ -heteroaryl, -CO ₂ -heterocycloalkyl, -OCO ₂ -C ₁ -C ₁₂ -alkyl, -OCO ₂ -C ₂ -C ₁₂ -alkenyl, -OCO ₂ -C ₂ -C ₁₂ -alkynyl, -OCO ₂ -C ₃ -C ₁₂ -cycloalkyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocycloalkyl, -OCONH ₂ , -OCONH-C ₁ -C ₁₂ -alkyl, -OCONH-C ₂ -C ₁₂ -alkenyl, -OCONH-C ₂ -C ₁₂ -alkynyl, -OCONH-C ₃ -C ₁₂ -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)-C ₁ -C ₁₂ - Alkyl, -NHC(O)-C ₂ -C ₁₂ -alkenyl, -NHC(O)-C ₂ -C ₁₂ -alkynyl, -NHC(O)-C ₃ -C ₁₂ -cycloalkyl, - NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO ₂ -C ₁ -C ₁₂ -alkyl, -NHCO ₂ -C ₂ -C ₁₂ -alkenyl, -NHCO ₂ -C ₂ -C ₁₂ -alkynyl, -NHCO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -Heterocycloalkyl, -NHC(O)NH ₂ , NHC(O)NH-C ₁ -C ₁₂ -alkyl, -NHC(O)NH-C ₂ -C ₁₂ -alkenyl, -NHC(O) NH-C ₂ -C ₁₂ -alkynyl, -NHC(O)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, - NHC(O)NH-heterocycloalkyl, NHC(S)NH ₂ , NHC(S)NH-C ₁ -C ₁₂ -alkyl, -NHC(S)NH-C ₂ -C ₁₂ -alkenyl, - NHC(S)NH-C ₂ -C ₁₂ -alkynyl, -NHC(S)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-hetero Aryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH ₂ , NHC(NH)NH-C ₁ -C ₁₂ -alkyl, -NHC(NH)NH-C ₂ -C ₁₂ -alkenyl, -NHC(NH)NH-C ₂ -C ₁₂ -alkynyl, -NHC(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)NH-aryl, -NHC( NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, NHC(NH)-C ₁ -C ₁₂ -alkyl, -NHC(NH)-C ₂ -C ₁₂ -alkenyl, - NHC(NH)-C ₂ -C ₁₂ -alkynyl, -NHC(NH)-C ₃ -C ₁₂ -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, - NHC(NH)-heterocycloalkyl, -C(NH)NH-C ₁ -C ₁₂ -alkyl, -C(NH)NH-C ₂ -C ₁₂ -alkenyl, -C(NH)NH-C ₂ -C ₁₂ -alkynyl, -C(NH)NH-C ₃ -C ₁₂ -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH )NH-heterocycloalkyl, -S(O)-C ₁ -C ₁₂ -alkyl, -S(O)-C ₂ -C ₁₂ -alkenyl, -S(O)-C ₂ -C ₁₂ - Alkynyl, -S(O)-C ₃ -C ₁₂ -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl-SO ₂ NH ₂ , -SO ₂ NH-C ₁ -C ₁₂ -alkyl, -SO ₂ NH-C ₂ -C ₁₂ -alkenyl, -SO ₂ NH-C ₂ -C ₁₂ -alkynyl, -SO ₂ NH -C ₃ -C ₁₂ -cycloalkyl, -SO ₂ NH-aryl _{, -SO 2 NH-heteroaryl, -SO 2 NH-heterocycloalkyl, -NHSO 2 -C 1 -C 12} -alkyl , -NHSO ₂ -C ₂ -C ₁₂ -alkenyl, -NHSO ₂ -C ₂ -C ₁₂ -alkynyl, -NHSO ₂ -C ₃ -C ₁₂ -cycloalkyl, -NHSO ₂ -aryl, -NHSO ₂ -Heteroaryl, -NHSO ₂ -heterocycloalkyl, -CH ₂ HH ₂ , -CH ₂ SO ₂ CH ₃ , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl , -heterocycloalkyl, -C ₃ -C ₁₂ -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, - SC ₁ -C ₁₂ -alkyl, -SC ₂ -C ₁₂ -alkenyl, -SC ₂ -C ₁₂ -alkynyl, -SC ₃ -C ₁₂ -cycloalkyl, -S-aryl, -S-hetero Aryl, -S-heterocycloalkyl or methylthiomethyl. It is understood that aryl, heteroaryl, alkyl, etc. may be further substituted.

The term "alkylamino" as used herein refers to a group having the structure -NH(C ₁ -C ₁₂ alkyl), wherein C ₁ -C ₁₂ alkyl is as defined above. The term "dialkylamino" refers to a group having the structure -N(C ₁ -C ₁₂ alkyl) ₂ , wherein C ₁ -C ₁₂ alkyl is as defined above. Examples of dialkylamino include, but are not limited to, N,N-dimethylamino, N,N-diethylamino, N,N-methylethylamino, piperidinyl, and the like.

The term "diarylamino" refers to a group having the structure -N(aryl) ₂ or -N(substituted aryl) ₂ , wherein substituted aryl is as defined above. Examples of diarylamino include, but are not limited to, N,N-diphenylamino, N,N-dinaphthylamino, N,N-di(tolyl)amino, and the like.

The term "diheteroarylamino" refers to a group having the structure -N(heteroaryl) ₂ or -N(substituted heteroaryl) ₂ , wherein heteroaryl and substituted heteroaryl are as defined above . Examples of diheteroarylamino include, but are not limited to, N,N-difurylamino, N,N-dithiazolidinylamino, N,N-bis(imidazole)amino, and the like.

The term "hydroxyl protecting group" as used herein refers to a labile chemical moiety known in the art to protect a hydroxyl group from unwanted reactions during synthetic procedures. After the synthetic procedure, the hydroxyl protecting groups presented here can be selectively removed. Hydroxyl protecting groups known in the art are summarized in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd Edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, Isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, alkenyl Propoxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-tri Chloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, p-methoxy Benzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethyl Oxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, p-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl Base etc. Preferred hydroxyl protecting groups of the present invention are acetyl (Ac or -C(O)CH ₃ ), benzoyl (Bn or -C(O)C ₆ H ₅ ) and trimethylsilyl (TMS or - Si(CH ₃ ) ₃ ).

The term "protected hydroxy" refers to a hydroxy protected by a hydroxy protecting group as defined above, including for example benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl protecting groups group.

The term "nitrogen (or amino) protecting group" as used herein refers to a labile chemical moiety known in the art to protect a nitrogen group from unwanted reactions during synthetic procedures. The nitrogen protecting groups presented here can be selectively removed after the synthetic procedure described. Nitrogen protecting groups known in the art are summarized in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd Edition, John Wiley & Sons, New York (1999). Examples of nitrogen protecting groups include, but are not limited to, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

The term "protected amino" as used herein refers to an amino group protected by an amino protecting group as defined above.

The term "nucleophilic heterocyclic compound" refers to a heterocyclic group in nucleophilic form (e.g. metal salt form, protonated form), such a group is capable of reacting with another molecule to create a covalent bond between the two molecules ( For example, nucleophilic displacement reactions of nucleophiles). Examples of such nucleophilic heterocyclic compounds are known in the art and described herein.

The term "leaving group" refers to a moiety that can be detached from a molecule in a reaction, especially a nucleophilic displacement reaction. Examples of leaving groups include, for example, halo, methanesulfonyl, tosyl, alkoxide, hydroxide, and protonated forms thereof. Examples of such leaving groups are known in the art and described herein.

The term "acyl" includes residues derived from acids including, but not limited to, carboxylic, carbamic, carbonic, sulfonic, and phosphorous acids. Included are, for example, aliphatic carbonyl groups, aromatic carbonyl groups, aliphatic sulfonyl groups, aromatic sulfinyl groups, aliphatic sulfinyl groups, aromatic phosphates, and aliphatic phosphates.

As used herein, the term "protic solvent" refers to a solvent that is relatively inert to proton activity (ie, does not act as a proton donor). Including but not limited to, for example, hydrocarbons (such as hexane and toluene), halogenated hydrocarbons (such as dichloromethane, dichloroethane, chloroform, etc.), heterocyclic compounds (such as tetrahydrofuran and N-methylpyrrolidone), and ethers (such as diethyl ether, bismethoxymethyl ether). Such compounds are well known in the art and the preferred single solvent or solvent mixture for a particular compound and reaction conditions will be apparent to those skilled in the art and will depend on various factors such as: solubility of reagents, reactivity of reagents And the preferred temperature range, etc. For an in-depth explanation of aprotic solvents, refer to organic chemistry textbooks or monographs, for example: Organic Solvents Physical Properties and Methods of Purification , 4th Edition, edited by John A. Riddick, etc., Vol.II, Techniques of Chemistry Series , John Wiley&Sons, NY, 1986.

As used herein, the term "proton-donating organic solvent" refers to a solvent that tends to donate protons, such as alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, and the like. Such solvents are well known in the art and the preferred single solvent or solvent mixture for a particular compound and reaction conditions will be apparent to the skilled artisan and will depend on various factors such as: solubility of reagents, reactivity of reagents And the preferred temperature range, etc. For an in-depth explanation of proton-donating solvents, refer to organic chemistry textbooks or monographs, for example: Organic Solvents Physical Properties and Methods of Purification , 4th Edition, edited by John A. Riddick, etc., Vol.II, Techniques of Chemistry Series , John Wiley&Sons, NY, 1986.

Combinations of substituents and variables contemplated by this invention are only those combinations that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that is sufficiently stable to enable manufacture and maintains the integrity of the compound long enough to be used for the purposes described herein (eg, therapeutic or prophylactic administration to a patient).

The synthesized compound can be isolated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. Those skilled in the art will appreciate that further methods of synthesizing compounds of the formulas herein will be apparent to those of ordinary skill in the art. Furthermore, the individual synthetic steps may be performed in a different order to obtain the desired compounds. Methods of chemical transformation and use of protecting groups (protection and deprotection) useful in the synthesis of the compounds herein are well known in the art and include, for example, those described in: R. Larock, Comprehensive Organic Transformations , VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 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); L. Paquette Editors, Encylopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), and their subsequent editions.

The term "patient" as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A patient also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and the like.

The compounds of the present invention may be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are well known in the art and may include modifications that result in enhanced biopenetration into specific biological systems (e.g., blood, lymphatic system, central nervous system), improved oral availability, increased solubility for injection Drugs, altered metabolism, and altered excretion rates.

The term "patient" as used herein refers to a mammal. Preferably the mammal is a human. Patient also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like.

The term "pharmaceutically acceptable salt" as used herein means a salt which, within the scope of sound medical judgment, is suitable for contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and has Reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. These salts can be prepared in situ during the final isolation and purification steps of the compounds of the invention, or can be prepared separately by reaction of the free base function with a suitable organic acid. Examples of pharmaceutically acceptable non-toxic acid addition salts include, but are not limited to, amino acids with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts prepared by other methods in the art (eg, ion exchange). Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate , camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconic acid Salt, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl Sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, bis Moxamate, Pectinate, Persulfate, 3-Phenylpropionate, Phosphate, Picrate, Pivalate, Propionate, Stearate, Succinate, Sulfate , tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed with counterions such as halides, hydroxides, formates, sulfates, phosphates, nitrates, _C1 -C ₆ sulfonates and aryl sulfonates.

As used herein, the term "pharmaceutically acceptable ester" refers to esters that are hydrolyzable in vivo, including esters that are readily broken down in the human body to yield the parent compound or a salt thereof. Suitable esters include, but are not limited to, esters derived from pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic, alkenoic, naphthenic, and alkanedioic acids, in which each alkyl or alkenyl moiety is most preferred. Preferably no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

As used herein, the term "pharmaceutically acceptable prodrugs" refers to such prodrugs of the compounds of the present invention: within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation effects, allergic reactions, etc., and have a reasonable risk/benefit ratio, are effective for the intended use, and where possible, prodrugs also refer to zwitterions of the compounds of the present invention. The term "prodrug" refers to a compound that is readily transformed in vivo (eg, by hydrolysis in blood) to yield the parent compound of the above formula. Prodrugs are detailed in T.Higuchi and V.Stella, Prodrugs as Novel delivery Systems, A.C.S.Symposium Series, Vol.14 and Bioreversible Carriers in Drug Design edited by Edward B. Roche (American Pharmaceutical Association and Pergamon Press, 1987). For clarification, both documents are incorporated herein by reference.

The term "effective amount" or "therapeutically effective amount" as used herein refers to a dose capable of inhibiting the HCV NS3 serine protease and thereby interfering with the production of viral polyproteins necessary for viral replication. Inhibition of the HCV serine protease contemplated by the methods of the invention includes both therapeutic and prophylactic treatments, as appropriate for patients in need of such treatment. Methods of treatment, dosage levels and requisites can be selected by one of ordinary skill in the art using known methods and techniques. For example, the compounds of the present invention can be combined with pharmaceutically acceptable excipients and administered to patients with viral infection in a pharmaceutically acceptable manner and at a dosage effective to reduce the severity of viral infection. Alternatively, the compounds of the present invention may be used in vaccines and methods for protecting individuals against HCV viral infection for long periods of time. Compounds can be used in the same manner as protease inhibitors are routinely used in vaccines. For example, the compounds of the present invention can be combined with pharmaceutically acceptable excipients commonly used in vaccines, and administered to individuals in a prophylactically effective amount, thereby protecting individuals from HCV virus infection for a long period of time. Likewise, the protease inhibitors of the present invention can be administered as a drug to treat or prevent HCV viral infection in a patient.

The compounds of the present invention may be modified by adding appropriate functional groups to enhance selective biological properties. Such modifications are well known in the art and may include modifications that result in enhanced biopenetration into specific biological systems (e.g., blood, lymphatic system, central nervous system), improved oral availability, increased solubility for injection Drugs, altered metabolism, and altered excretion rates.

The compounds of the present invention contain two or more asymmetric centers, thereby giving rise to enantiomers, diastereomers and other stereoisomers, which can be defined as (R)- or ( S)-, or (D)- or (L)- for amino acids as defined. The present invention includes all such possible isomers as well as their racemates and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the methods described above, or by resolution of racemic mixtures. Resolution can be carried out by chromatography in the presence of a resolving agent, repeated crystallization, or some combination of techniques known to those skilled in the art. For further information on resolution see Jacques et al., Enantiomers Racemates and Resolutions (John Wiley & Sons, 1981). When the compounds of the present invention contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, the compounds include E and Z geometric isomers. Likewise, all tautomeric forms are included. Unless otherwise stated, any carbon-carbon double bond configuration that appears herein is only to select such a configuration for convenience, and is not to specify a specific configuration; therefore, the carbon-carbon double bond that is freely shown as trans can be Cis, trans or any mixture of the two configurations.

pharmaceutical composition

The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples that can be used as pharmaceutically acceptable carriers include sugars such as lactose, grape and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and Cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut, cottonseed, safflower, sesame, olive, corn, and soybean oils Alcohols, such as propylene glycol; Esters, such as ethyl oleate and ethyl laurate; Agar; Buffers, such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethanol and phosphate buffered saline; at the judgment of the formulator, other nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, detackifying agents, coating agents, sweeteners, flavorings Additives, flavoring agents, preservatives and antioxidants can also be added to the composition. The pharmaceutical composition of the present invention may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powder, ointment or drops), buccally, by oral spray or intranasal spray .

Oral liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents (such as water or other solvents), solubilizers and emulsifiers commonly used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerin, tetrahydro Fatty acid esters of furfuryl alcohol, polyethylene glycol, sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations (such as sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable preparations can be sterilized by filtration through bacteria-retaining filters, or by adding sterilizing agents to sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just before use middle.

In order to prolong the action of the drug, it is often desirable to slow the absorption of the subcutaneously or intramuscularly injected drug. Liquid suspensions of poorly water soluble crystalline or amorphous materials can be used for this purpose. The rate of drug absorption thus depends upon the rate of dissolution which, in turn, depends upon crystal size and crystalline form. Alternatively, the drug is dissolved or suspended in an oil vehicle to delay the absorption of a parenterally administered drug. Injectable depot forms are made by microencapsulating the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the drug/polymer ratio, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

Compositions for rectal or vaginal administration are preferably suppositories, which may be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax (which are solid at room temperature and liquid at body temperature and therefore melts in the rectum or vaginal cavity, releasing the active compound).

Solid compositions of a similar type can also be used as fillers in soft and hard-filled capsules using, for example, lactose as well as high content polyethylene glycols and the like as excipients.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms tablets, dragees, capsules, pills, and granules can employ coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such formulations may also include substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose, as is conventional practice. In the case of capsules, tablets and pills, these dosage forms may also comprise buffering agents. They may also optionally contain opacifying agents and may also be of a composition to release the active ingredients only, or preferably, in certain parts of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for the topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives or buffers that may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also included within the scope of this invention. Ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol Glycols, silicones, bentonite, silicic acid, talc, zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays also generally contain propellants, such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of allowing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or distributing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of release can be controlled using rate controlling membranes or by dispersing the compound in polymer matrices or gels.

Antibacterial activity

According to the treatment method of the present invention, viral infection in a patient (such as a human or a lower mammal) is treated or prevented by administering to the patient an effective amount of the compound of the present invention, and the dosage and duration of administration are necessary to achieve the desired result. As used herein, the term "anti-HCV effective amount" of a compound of the present invention refers to a sufficient amount of the compound such that the viral load in a patient is reduced, thereby alleviating chronic HCV symptoms in said patient. As is well known in the medical arts, an anti-HCV effective amount of a compound of the present invention is that amount which yields a reasonable benefit/risk ratio in any medical treatment.

After improving the condition of the patient, if necessary, a maintenance dose of the compound, composition or combination of the present invention can be administered. Subsequently, as symptoms improve, the dose or frequency of administration, or both, may be reduced until the dose level at which the improvement is maintained is maintained, and treatment should be discontinued after symptoms have resolved to the desired level. However, patients may require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

It should be understood, however, that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific dosage level effective in a particular patient against the HCV virus will depend on a variety of factors, including the disease being treated, the severity of the disease; the activity of the specific compound being used; the specific composition being used; the age, weight, general health of the patient Condition, sex, and diet; time of administration, route of administration, and rate of excretion of the compound used; duration of treatment; drugs used in conjunction or concomitantly with the compound used; and similar factors well known in the medical arts.

A total daily dose of the compound of the invention is administered to the patient in single or multiple doses, for example 0.01-50 mg/kg body weight, more usually 0.1-25 mg/kg body weight. A dose of the composition may contain such doses or submultiples thereof to constitute the daily dose. Typically, the treatment regimen of the present invention comprises administering to a patient in need of such treatment from about 10 mg to about 1000 mg of a compound of the present invention per day, in single or multiple doses.

abbreviation

The following abbreviations are used in the description of the schemes and examples:

ACN Acetonitrile;

BME 2-mercaptoethanol;

BOP benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate;

COD Cyclooctadiene;

DABCYL 6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-

   cyanoethyl)-(N,N-diisopropyl)-phosphoramidate;

DAST Diethylaminosulfur trifluoride;

DCM dichloromethane;

DIAD Diisopropyl azodicarboxylate;

DIBAL-H Diisobutylaluminum hydride;

DIEA Diisopropylethylamine;

DMAP N, N-dimethylaminopyridine;

DME Ethylene glycol dimethyl ether;

DMEM Dulbecco's Modified Eagles Media;

DMF N, N-dimethylformamide;

DMSO Dimethyl sulfoxide;

DUPHOD

EDANS 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;

EDCI or EDC 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

EtOAc Ethyl acetate;

HATU O(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexa

fluorophosphate;

HMBA 4-Hydroxymethylbenzoic acid AM resin;

Hoveyda's Cat. Dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium(II);

KHMDS Potassium bis(trimethylsilyl)amide;

Ms methanesulfonyl;

NMM N-4-Methylmorpholine

Ph phenyl;

PuPHOS

PyBrOP Bromo-tris-pyrrolidinyl-phosphonium hexafluorophosphate;

RCM closed-loop replacement reaction;

RT room temperature;

RT-PCR Reverse transcription polymerase chain reaction;

tBOC or Boc tert-butoxycarbonyl;

TEA Triethylamine;

TFA Trifluoroacetic acid;

THF Tetrahydrofuran;

TLC thin layer chromatography;

TPP or PPh3 triphenylphosphine;

Xantphos 4,5-bis-diphenylphosphino-9,9-dimethyl-9H-xanthene.

Certain chemical structures herein having -NH or -OH do not depict a hydrogen atom attached to an oxygen or nitrogen atom. Thus, nitrogen or oxygen atoms in such structures appear to have no normal valence, but actually contain these hydrogen atoms.

resolve resolution

The compounds of the invention and methods of preparation will be better understood in conjunction with the following synthetic schemes, which illustrate methods that can be used to prepare the compounds of the invention.

I. Replacement method

Compounds of the present invention can be prepared by the displacement methods outlined in the following schemes:

Hydroxyproline or mesylated proline precursors can be used. This displacement scheme is suitable for converting any hydroxy (or corresponding mesylate) proline compound or derived starting compound into a heterocyclic substituted proline derivative. The synthetic methods that follow illustrate various methods and intermediate steps that can be used to prepare the compounds disclosed herein.

A. Synthesis of Hydroxyproline Cyclic Peptide Precursors

Cyclic peptide precursors can be used in the synthesis of compounds of the invention. In certain embodiments, mesylated cyclic precursors may be used.

In certain embodiments, commercially available Boc-hydroxyproline A

Treatment with HCl in dioxane affords starting material Ib.

Synthetic cyclic peptide precursor

Process 1

Cyclic peptide precursor Ig was synthesized following steps A-D outlined in Scheme 1 using Boc-L-2-amino-8-nonenoic acid Ia and cis-L-hydroxyproline methyl ester Ib. More detailed synthetic methods for preparing cyclic peptide precursor Ig are found in US Patent 6,608,027, the entire contents of which are incorporated herein by reference.

Synthesis of Mesylate Precursors of Macrocyclic Peptides

Process 2

The cyclic precursor mesylate was synthesized as follows: The mesylate was formed on the hydroxyl group of the hydroxyproline residue in the cyclic peptide precursor following the synthetic pathway outlined in Scheme 2 above.

Process 3

Compounds of the invention were prepared following the synthetic route briefly described in Scheme 3 by substituting a 5-substituted-2H-tetrazole for the mesylate of the macrocyclic peptide mesylate IIa, an exemplary synthesis of such a tetrazole is described in Scheme 5 below method.

Process 4

The compounds of the invention were prepared following the synthetic route briefly described in Scheme 4 by replacing the mesylate of the macrocyclic peptide mesylate IIa with a 4,5-substituted-1H-triazole. Scheme 6 below presents an exemplary synthesis of such triazoles.

B. Synthesis of Substituent W

W may be any of the substituents described above. Those of ordinary skill in the art are able to synthesize these different substituents. The examples describe some synthetic methods, but these examples are not limiting. Other substituents are commercially available or readily synthesized by one of ordinary skill in the art.

synthetic tetrazole

Tetrazoles Va-Vq with different structures are synthesized according to the method of following scheme 5 with commercially available nitrile compounds:

Process 5

Those skilled in the art will appreciate that a wide variety of 5-substituted tetrazole compounds can be prepared in this way from any nitrile-containing compound suitable for the reaction conditions described above.

Synthetic triazole

Process 6

The triazoles of the present invention are prepared by reacting alkyne compounds VIa (commercially available or prepared as follows) and trimethylsilyl azide following the synthetic route outlined in Scheme 6. Commercially available alkynes suitable for the preparation of triazoles include, but are not limited to:

synthetic alkyne

Alkynes for the synthesis of triazoles can be prepared by any suitable method. The following are some exemplary synthetic methods.

Sonogashira reaction

Process 7

The alkynes used in the present invention can be prepared by the Sonogashira reaction: using the primary alkyne compound VIIa, aryl halide (Y-halogen) and triethylamine in acetonitrile in the presence of _PdCl2 ( _PPh3 ) ₂ and CuI as outlined in Scheme 7 synthetic pathway reactions.

Commercially available aryl halides suitable for the Sonogashira reaction include, but are not limited to:

Commercially available acetylenes suitable for the Sonogashira reaction include, but are not limited to:

Synthesis of Alkynyl Amides

Process 8

Other alkynes used in the present invention can be prepared by reacting alkynyl acids Va, BOP and DIEA in DMF with amines VIIIb following the synthetic pathway outlined in Scheme 8.

modification after replacement

The resulting macrocycle can be modified after attachment of W. The following are some exemplary modifications.

1. Synthesis of phenolic esters

Process 9

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

Post-displacement modification of the macrocycle IIIa to give different phenolic esters followed the synthetic pathway outlined in Scheme 9.

2. Hydrolysis of macrocyclic peptide ethyl ester

Process 10

The macrocyclic peptide ethyl ester of the present invention is hydrolyzed as follows: according to the synthetic route outlined in Scheme 10, the macrocyclic peptide ethyl ester IV is dissolved in dioxane, and 1M LiOH is added.

3. Preparation of more biaryl compounds by Suzuki coupling reaction

Process 11

Compounds of the present invention can be further varied by Suzuki coupling reactions: following the synthetic route outlined in Scheme 11, to bromo-substituted triazole macrocyclic ethyl esters (see Example 26 below for the preparation) add DME, aromatic boronic acids , cesium carbonate and KF.

II. Step-by-step synthesis

The compounds of the present invention may also be prepared by stepwise synthetic methods rather than displacement mechanisms. The following are exemplary synthetic methods where W is tetrazole.

A. Synthesis of Proline Derivatives

Process 12

B. Synthesis of Linear Tripeptides

Process 13

Linear tripeptides containing tetrazole-substituted proline derivatives XIIc were prepared following the synthetic route outlined in Scheme 12.

C. Cyclic peptide synthesis by ring-closing displacement reaction (RCM)

Process 14

The macrocycle Xb is prepared following the ring-closing displacement reaction outlined in Scheme 14 using the linear tripeptide XIIId.

D other derivatives

1. The tetrazole-substituted proline derivatives of the present invention are prepared according to the synthetic route outlined in Scheme 12.

Process 15

Other tetrazole-substituted proline derivatives of the present invention were prepared following the synthetic route outlined in Scheme 15.

2.Suzuki coupling reaction

Process 16

Further derivatives were prepared using the Suzuki coupling reaction outlined in Scheme 16.

III. Solid Phase Synthesis

Some compounds of the present invention can be prepared by solid-phase synthesis. For example, triazole-substituted proline derivatives (P2) can be used to assemble linear tripeptide chains on resin after synthesis. A resin bound to a tripeptide (containing a triazole-substituted proline derivative) undergoes a ring-closing displacement reaction (RCM) to obtain a cyclic tripeptide, which is cleaved from the resin by hydrolysis to obtain the final product.

The following synthetic scheme introduces the preparation method of triazole-substituted proline derivatives and the solid-phase synthesis method of the compound of the present invention.

A. Synthesis of Proline Derivatives

Two methods outlined in the following schemes can be used for the synthesis of triazole-substituted proline derivatives:

1. Cycloaddition method

Process 17

The cycloaddition method for the preparation of triazolylproline derivatives involves the 3+2 cycloaddition of azidoproline derivatives XVIIb and alkynes VIIb, following the synthetic pathway outlined in Scheme 17. An exemplary synthesis of alkynes is presented in Scheme 7 above.

2. Mesylate method

Process 18

Following the synthetic route outlined in Scheme 18, other proline derivatives were synthesized by displacement reactions of mesylate XVIIIa with 4,5-substituted-1H-triazoles.

B. Assembly on Resin and RCM on Resin

Process 19

Assembly on resin

Following steps A-D outlined in Scheme 19, linear peptide XIXd was assembled on the resin followed by RCM on the resin to obtain the resin-bound cyclic peptide precursor XIXe.

IV. Other reactions

In certain embodiments, the substituent W is well suited for other types of reactions. For example, but not limitation, when W is pyridazinone, the following reaction scheme is used. These methods can be used for other substituents, but are illustrated with pyridazinones in this context.

A. Condensation reaction

Process 20

The simplest approach (shown in Scheme 20) is the condensation of commercially available pyridazinones (XXa-1-XXa-4) with the key intermediate If, using Mitsunobu conditions followed by LiOH hydrolysis. For more detailed information about the Mitsunobu reaction, refer to O.Mitsunobu, Synthesis 1981, 1-28; D.L.Hughes, Org.React.29, 1-162 (1983); D.L.Hughes, Organic Preparations and Procedures Int.28, 127-164 (1996 ); J.A. Dodge, S.A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997).

Process 21

A second approach to the preparation of the pyridazinone analogs of the present invention is the further chemical treatment of the dibromo intermediate XXIa (Scheme 21). Standard Mitsunobu coupling of commercially available 4,5-dibromopyridazinone with hydroxyl If affords the desired macrocycle XXIa. Coupling of XXIa with excess 3-thiopheneboronic acid in the presence of cesium carbonate and potassium fluoride affords dithiophene XXIb. Hydrolysis of compounds XXIa and XXIb with LiOH gave the desired analogs XXId and XXIc, respectively. Many disubstituted pyridazinonyl macrocycles can be obtained in a similar manner with many different boronic acids.

B. Bromide Differentiation Reaction

Process 22

Bromide differentiation on the macrocycle XXIa is achieved by Michael addition. As shown in Scheme 22, coupling of commercially available pyrrolidine with dibromide afforded compound XXIIa in 87% yield. Suzuki coupling of the bromide moiety adjacent to the carbonyl group with 3-thiopheneboronic acid then afforded intermediate XXIIb, which was further treated with LiOH to afford analog XXIIc. For a more detailed description of Suzuki coupling reactions see A. Suzuki, Pure Appl. Chem. 63, 419-422 (1991) and A. R. Martin, Y. Yang, Acta Chem. Scand. 47, 221-230 (1993).

C. Sulfur-containing nucleophiles

Process 23

While the secondary amine nucleophile pyrrolidine undergoes exclusive addition at the 5-bromo position of the macrocycle XXIa, the sulfur-containing nucleophile does not have the same selectivity, as shown in Scheme 23. Using a sulfur-containing nucleophile, some addition reactions occurred at both bromine positions of XXIa, and some of them gave the single-coupling product XXIIa with only 1 equivalent of mercaptopyrimidine. Compounds XXIIIa, XXIIIb and starting material XXIa can be separated by flash column chromatography, so that monoalkylated XXIIIa can be subjected to Suzuki coupling reaction with 3-thiophene boronic acid, followed by hydrolysis of XXIIId with LiOH to give analog XXIIIe. The dialkylated product XXIIIb can also be hydrolyzed with LiOH to give the analog XXIIIc.

D. Suzuki Coupling Reaction with Boronic Acid

Process 24

Since only small amounts of boronic acid are available for Suzuki coupling, other coupling methods such as Stille coupling and N-arylation using Buchwald chemistry were also investigated (Scheme 24). Coupling of intermediate XXIa with 2-stannylthiazole under Stille's standard conditions followed by hydrolysis affords analog XXIVa. For N-arylation, imidazole was smoothly coupled with dibromide 6. Unfortunately, hydrolysis with LiOH resulted in a displacement reaction of the imidazole moiety at position 5 with the methoxy group (XXIVb. For more details on the Stille coupling reaction see J.K.Stille, Angew.Chem.Int.Ed.25, 508-524( 1986); M.Pereyre et al., Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim., T.N.Mitchell, Synthesis 1992, 803-815. For more detailed information on the Buchwald reaction see J.F.Hartwig, Angew.Chem. Int. Ed. 37, 2046-2067 (1998).

E. Other Different Pyridazinone Analogs

Process 25

Scheme 25 describes another approach to diversify pyridazinone analogs. Michael addition of sodium azide as nucleophile to dibromide XXIa gives only (in the case of secondary amine) monocoupled compound XXVa. Further Suzuki coupling reaction with 3-thiophene boronic acid afforded the azide XXVb. Compound XXVb is hydrolyzed to give analog XXVc. Alternatively, the azide moiety of compound XXVb was further converted to the tetrazole with sodium cyanide under standard conditions, followed by hydrolysis to give the analog XXVd.

F. Synthesis of 5,6-pyridazinonyl macrocycles

Process 26

Scheme 26 describes the synthesis of 5,6-pyridazinonyl macrocycle XXVIb. The commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one was condensed with the key intermediate If under Mitsunobu conditions to obtain compound XXVIa. The product XXVIa is coupled with 3-thiopheneboronic acid under Suzuki coupling conditions followed by hydrolysis to give the desired analogue XXVb.

Example

The compounds and methods of preparation of the present invention will be better understood with reference to the following examples, which are provided for illustrative purposes only and not to limit the scope of the present invention. Various changes and modifications to the disclosed embodiments will become apparent to those skilled in the art. Such changes and improvements (including but not limited to changes and improvements related to the chemical structure, substituents, derivatives, formulations and/or methods of the present invention) can be made without departing from the essence of the present invention and the scope of the appended claims ).

Example 1. Synthesis of cyclic peptide precursors

1A. Add DIEA ( 4ml, 4eq.) and HATU (4g, 2eq). The coupling reaction was carried out at 0 °C for 1 h. The reaction mixture was diluted with 100 mL EtOAc, then washed with 5% citric acid 2 x 20 ml, water 2 x 20 ml, 1M NaHCO ₃ 4 x 20 ml and brine 2 x 10 ml, respectively. The organic phase was dried over _{anhydrous Na2SO4} and evaporated to give dipeptide 1c (1.91 g, 95.8%), which was analyzed by HPLC (retention time = 8.9 min, 30-70%, 90% B) and MS (found 421.37 , M+Na ⁺ ) identification.

1B. Dipeptide 1c (1.91 g) was dissolved in 15 mL of dioxane and 15 mL of 1N LiOH aqueous solution, and the hydrolysis reaction was carried out at room temperature for 4 h. The reaction mixture was acidified with 5% citric acid, extracted with 100 mL EtOAc, then washed with water 2 x 20 ml, 1M NaHCO ₃ 2 x 20 ml and brine 2 x 20 ml, respectively. The organic phase was dried over anhydrous Na ₂ SO ₄ and removed in vacuo to give free carboxylic acid compound 1d (1.79 g, 97%), which was directly used in the next synthetic step without further purification.

1C. Add D-β-vinylcyclopropane amino acid ethyl ester 1e (0.95g, 5mmol), DIEA (4ml, 4eq.) and HATU (4g, 2eq). The coupling reaction was carried out at 0 °C for 5 h. The reaction mixture was diluted with 80 mL of EtOAc, then washed with 5% citric acid 2 x 20 ml, water 2 x 20 ml, 1M NaHCO ₃ 4 x 20 ml and brine 2 x 10 ml, respectively. The organic phase was dried over _{anhydrous Na2SO4} and evaporated. The residue was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc as eluent phase (5:1→3:1→1:1→1:2→1:5)). After removal of the elution solvent, linear tripeptide 1f (1.59 g, 65.4%) was isolated as an oil and identified by HPLC (retention time = 11.43 min) and MS (found 544.84, M+Na ⁺ ).

1D. Ring Closing Metathesis (RCM). Nitrogen was sparged to remove oxygen from a solution of the linear tripeptide If (1.51 g, 2.89 mmol) in 200 ml dry DCM. Hoveyda's first generation catalyst (5 mol % eq.) was then added as a solid. The reaction was refluxed for 12h under nitrogen atmosphere. The solvent was evaporated and the residue was purified by silica gel flash chromatography (using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1→1:2→1:5)) . After removal of the elution solvent, the cyclic peptide precursor 1 (1.24 g, 87%) was isolated as a white powder, which was analyzed by HPLC (retention time = 7.84 min, 30-70%, 90% B) and MS (found 516.28, M+Na ⁺ ) identification. A more detailed synthetic method for the preparation of cyclic peptide precursor 1 is found in US Patent 6,608,027, which is hereby incorporated by reference in its entirety.

Example 2. Synthesis of cyclic peptide precursor mesylate

2A. Methanesulfonyl chloride (0.1 ml) was slowly added to a solution of macrocyclic peptide precursor 1 (500 mg, 1.01 mmol) and DIEA (0.4 ml, 2 mmol) in 2.0 ml DCM at 0° C., and the reaction was carried out for 3 h. Then 30 mL of EtOAc was added and washed with 5% citric acid 2 x 10 ml, water 2 x 10 ml, 1M NaHCO ₃ 2 x 10 ml and brine 2 x 10 ml, respectively. The organic phase was dried over anhydrous _Na2SO4 and evaporated to give the title compound mesylate, which was used directly in _the next synthetic step without further purification.

Embodiment 3. synthetic tetrazole

Structurally distinct tetrazoles IIIa-IIIq (used in the preparation of the tetrazolyl macrocycles of the present invention) were synthesized from commercially available nitrile compounds as follows:

3-Cl-4-hydroxyl-benzonitrile (benzoacetonitrile) (0.31g, 5mol), NaN ₃ (0.65g, 10mmol) and triethylamine hydrochloride (0.52g, 3 mmol). The mixture was stirred vigorously at 140 °C for 20-30 h. The reaction mixture was then cooled and poured into a mixture of EtOAc (30 mL) and aqueous citric acid (20 mL). After washing with water 2 x 10 _ml and brine 2 x 10 ml, the organic phase was dried over anhydrous _Na2SO4 and evaporated to a pale yellow solid. After recrystallization from EtOAc-hexane, tetrazole compound 3a was obtained in higher yield (0.4 g, 86%), high purity (>90%, HPLC), and was obtained by NMR and MS (found values 197.35 and 199.38, M+H ⁺ ) identification.

Embodiment 4. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

Synthetic Proline Derivatives

3.85 mL of methanesulfonyl chloride ( 50 mmol), the resulting reaction mixture was stirred at 0 °C for 3 h. TLC (hexane:ethyl acetate=1:1, v/v) confirmed that Boc-cis-Hyp-OMe 4a was completely converted to its mesylate 4b. After the completion of the reaction was confirmed by TLC, the reaction mixture was diluted with 100ml EtOAc, washed with 5% citric acid 2×50ml and brine 2×30ml, and dried over anhydrous sodium sulfate. Removal of solvent afforded 13 g (98% yield) of N-Boc-cis-4-mesylate-proline methyl ester 4b, which was used directly in Step B without further purification.

To a solution of mesylate 4b (0.65 g, 2 mmol) in 5 mL of DMF was added 4 mmol of 5-phenyl-1H-tetrazole and anhydrous sodium carbonate (0.53 g, 5 mmol). The resulting reaction mixture was stirred vigorously at 60 °C for 6-12 h. TLC (hexane:ethyl acetate=1:1, v/v) confirmed the complete conversion of mesylate 4b to trans 4-tetrazole substituted proline derivative 4c. After the completion of the reaction was confirmed by TLC, the reaction mixture was diluted with 30ml EtOAc and washed with 1M Na ₂ CO ₃ (3×10ml), water (3×10ml), 5% citric acid (3×10ml) and brine (3×10ml) respectively. washing. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 5-phenyltetrazolium-substituted proline derivative 4c in high yield (94%) and high purity (>90%). 4c: 94% yield,

[M+Na] ⁺ = 396.39.

Synthetic linear tripeptide

Dipeptide 4e was prepared as follows: 0.22 g (0.6 mmol) of N-Boc-trans-4-(3-phenyltetrazolyl)-proline methyl ester 4c was dissolved in 6 mL of dioxane and 2 mL of 1N aqueous LiOH. The resulting reaction mixture was stirred at room temperature for 3-8 h to allow hydrolysis of the methyl ester. The reaction mixture was acidified with 5% citric acid, extracted with 40 mL EtOAc, washed with water 2 x 20 ml, 1M NaHCO ₃ 2 x 20 ml and brine 2 x 10 ml, respectively. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give the free carboxylic acid compound (0.20 g, 92%), which was directly used in the next synthetic step without further purification. (2) Add D-β-vinylcyclopropane amino acid ethyl ester 4d (0.1g, 0.52mmol), DIEA (0.4ml , 4eq.) and HATU (0.4g, 2eq). The resulting reaction mixture was stirred at 0 °C for 0.5-3 h. The reaction mixture was diluted with 40 mL EtOAc, washed with 5% citric acid 2×20 ml, water 2×20 ml, 1M NaHCO ₃ 4×20 ml, brine 2×10 ml, respectively. The organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to afford dipeptide 4e (0.24 g, 94%), which was identified by HPLC (retention time = 10.03 min) and MS (found 519.22, M+Na ⁺ ).

B. (1) Tripeptide 4g was prepared as follows: remove the amine protecting group of dipeptide 4e (0.24g, 0.49mmol) in 2mL TFA at 0°C for 10min. After removal of TFA in vacuo, the free amine product was used directly in the subsequent coupling reaction. (2) Boc-2-amino-8-nonenoic acid 4f (0.136g, 0.50mmol), DIEA (0.4ml, 4eq.) and HATU ( 0.4g, 2eq). The coupling reaction was carried out at 0 °C for 0.5-3 h. The reaction mixture was diluted with 40 mL EtOAc and washed with 5% citric acid 2 x 20 ml, water 2 x 20 ml, 1M NaHCO ₃ 4 x 20 ml and brine 2 x 10 ml, respectively. The organic phase was dried over _{anhydrous Na2SO4} and concentrated in vacuo to obtain tripeptide 4g (0.28g, 88% for two steps) by HPLC (retention time = 14.03min) and MS (found 672.30, M+Na ⁺ ) Identification.

Synthesis of Cyclic Peptides by Ring-Closing Metathesis Reactions (RCM)

A. A solution of 4 g (71 mg, 0.109 mmol) of linear tripeptide in 50 ml of anhydrous DCM was bubbled with nitrogen to remove oxygen. Hoveyda's Cat. (5-10 mol% eq.) was added as a solid to the resulting degassed solution, and the resulting reaction mixture was refluxed for 5-20 h under a nitrogen atmosphere. The reaction mixture was then concentrated in vacuo and the residue was purified by flash chromatography on silica gel using different ratios of hexane:EtOAc as eluent (9:1→5:1→3:1→1:1→1:2)). The macrocyclic peptide 4i (58 mg, 85.5%) was isolated as a white powder by evaporation of the elution solvent, and was analyzed by HPLC (retention time = 11.80 min, 30-80%, 90% B) and MS (found value 644.66, M+Na ⁺ ) identification.

IV. Hydrolysis of Ethyl Ester

The title compound was prepared by dissolving compound 4i (20 mg) in 2 mL of dioxane and 1 mL of 1N aqueous LiOH. The resulting reaction mixture was stirred at room temperature for 4-8 h. The reaction mixture was then acidified with 5% citric acid, extracted with 10 mL EtOAc, washed 2 x 20 ml with water. The solvent was evaporated and the residue was purified by HPLC (YMC AQ12S11-0520WT column, 30-80% (100% acetonitrile) gradient, 20 min). After freeze-drying, the title compound was obtained as a white amorphous solid.

[M+Na] ⁺ = 616.72.

Q＝不存在，Y＝2-溴苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 5. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 2-bromophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

5A. Synthesis of Proline Derivatives

The proline derivative of the present embodiment is prepared according to the method of embodiment 4 (I), wherein 5-(2-bromophenyl)-1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a are used .

[M+Na] ⁺ = 396.39.

5B. Synthesis of linear tripeptides

The linear peptide of this example was prepared according to the method described in Example 4 (II), wherein the proline derivative prepared in step 5A, D-β-vinylcyclopropane amino acid ethyl ester and Boc-2-amino-8- nonenoic acid.

[M+H] ⁺ ＝728.41

5C. Ring-closing displacement reaction

The macrocyclic peptide ethyl ester of this example was prepared using the linear peptide in Step 5B according to the method introduced in Example 4 (III).

[M+Na] ⁺ = 722.37.

5D. Hydrolysis of ethyl ester

The title compound was finally obtained by the hydrolysis described in Example 4(IV) using the ethyl ester of Step 5C.

[M+H] ⁺ = 672.49.

Q＝不存在，Y＝3-溴苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 6. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 3-bromophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

6A. Synthesis of Proline Derivatives

The proline derivative of the present embodiment is prepared according to the method described in Example 4 (I), wherein 5-(3-bromophenyl)-1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester are used 4a.

[M+Na] ⁺ = 396.39.

6B. Synthesis of linear tripeptides

The linear peptide of this example was prepared according to the method described in Example 4 (II), wherein the proline derivative prepared in step 6A, D-β-vinylcyclopropane amino acid ethyl ester, Boc-2-amino-8- nonenoic acid.

[M+H] ⁺ = 728.41.

6C. Ring-closing displacement reaction

The macrocyclic peptide ethyl ester of this example was prepared using the linear peptide in Step 6B according to the method introduced in Example 4 (III).

[M+Na] ⁺ = 722.37.

6D. Hydrolysis of ethyl ester

The title compound was finally obtained by the hydrolysis described in Example 4(IV) using the ethyl ester of Step 6C.

[M+H] ⁺ = 672.49.

Q＝不存在，Y＝4-溴苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 7. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 4-bromophenyl, j = 3, m = s = 1 and ^R3 = ^R4 = H.

7A. Synthesis of Proline Derivatives

The proline derivative of the present embodiment is prepared according to the method described in Example 4 (I), wherein 5-(4-bromophenyl)-1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester are used 4a.

[M+Na] ⁺ = 396.39.

7B. Synthesis of linear tripeptides

The linear peptide of this example was prepared according to the method described in Example 4 (II), wherein the proline derivative prepared in step 7A, D-β-vinylcyclopropane amino acid ethyl ester and Boc-2-amino-8- nonenoic acid.

[[M+Na]+H] ⁺ = 728.41.

7C. Ring-closing displacement reaction

The macrocyclic peptide ethyl ester of this example was prepared using the linear peptide in Step 7B according to the method introduced in Example 4 (III).

[M+Na] ⁺ = 722.37.

7D. Hydrolysis of ethyl ester

The title compound was finally obtained by hydrolysis described in Example 4(IV) using the ethyl ester in Step 7C.

[M+H] ⁺ = 672.49.

Q＝不存在，Y＝5-溴-2-噻吩基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 8. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 5-bromo-2-thienyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

8A. Synthesis of Proline Derivatives

The proline derivatives of this embodiment are prepared according to the method described in Example 4 (I), wherein 5-(5-bromo-2-thienyl)-1H-tetrazole and N-Boc-cis-hydroxyproline are used Acid methyl ester 4a.

[M+Na] ⁺ = 480.23.

8B. Synthesis of linear tripeptides

The linear peptide of this example was prepared according to the method described in Example 4 (II), wherein the proline derivative prepared in step 8A, D-β-vinylcyclopropane amino acid ethyl ester and Boc-2-amino-8- nonenoic acid.

[M-Boc+H] ⁺ = 634.29.

8C. Loop-closing displacement reaction

The macrocyclic peptide ethyl ester of this example was prepared using the linear peptide in Step 8B according to the method introduced in Example 4 (III).

[M+Na] ⁺ = 736.21.

8D. Hydrolysis of ethyl ester

The title compound was finally obtained by the hydrolysis described in Example 4(IV) using the ethyl ester of Step 8C.

[M+H] ⁺ = 678.22.

Q＝不存在，Y＝2-溴-4-吡啶基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 9. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 2-bromo-4-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

9A. Synthesis of Proline Derivatives

The proline derivative of the present embodiment is prepared according to the method described in Example 4 (I), wherein 5-(2-bromo-4-pyridyl)-1H-tetrazole and N-Boc-cis-hydroxyproline are used Acid methyl ester 4a.

[M+Na] ⁺ = 453.23.

9B. Synthesis of linear tripeptides

The linear peptide of this example was prepared according to the method described in Example 4 (II), wherein the proline derivative prepared in step 9A, D-β-vinylcyclopropane amino acid ethyl ester and Boc-2-amino-8- nonenoic acid.

[M-Boc+H] ⁺ = 629.31.

9C. Ring-closing displacement reaction

The macrocyclic peptide ethyl ester of this example was prepared using the linear peptide in Step 9B according to the method introduced in Example 4 (III).

[M+Na] ⁺ = 723.36.

9D. Hydrolysis of ethyl esters

The title compound was finally obtained by the hydrolysis described in Example 4(IV) using the ethyl ester of Step 9C.

[M+H] ⁺ = 673.26.

Q＝不存在，Y＝2-联苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 10. The compound of formula II, wherein A=tBOC, G= OH , L=absence, W is

Q = absent, Y = 2-biphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

A 5 ml DME solution of the ethyl ester compound (40 mg), phenylboronic acid (10 mg), KF (100 mg) and Cs ₂ CO ₃ (80 mg) obtained in Step 5C was deoxygenated, and Pd(PPh ₃ ) ₄ was added in solid form thereto (5 mg). The resulting reaction mixture was heated to 90 °C in an oil bath and stirred vigorously for 6-12 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1→2:1). The macrocyclic biaryl peptide ethyl ester (31 mg, 78%) was then isolated as a white powder by evaporating the eluted solvent, which was directly used in the hydrolysis reaction of the above Example 4 (IV) and purified by HPLC.

[M+Na] ⁺ = 692.38.

Q＝不存在，Y＝3-联苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 11. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-biphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 6C and phenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 692.38.

Embodiment 12. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is Q = absent, Y = 4-biphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 7C and phenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 692.38.

Embodiment 13. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is Q = absent, Y = 3-(3-thienyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 6C and 3-thienylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 698.32.

Q＝不存在，Y＝3-(对三氟甲氧基苯基)苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 14. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 3-(p-trifluoromethoxyphenyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 6C and p-trifluoromethoxyphenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 776.35.

Q＝不存在，Y＝3-(对氰基苯基)苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 15. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 3-(p-cyanophenyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 6C and p-cyanophenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 692.38.

Q＝不存在，Y＝4-(3-噻吩基)苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 16. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-(3-thienyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 7C and 3-thienylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 698.32.

Q＝不存在，Y＝4-(对三氟甲氧基苯基)苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 17. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-(p-trifluoromethoxyphenyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 7C and p-trifluoromethoxyphenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 776.35.

Q＝不存在，Y＝4-(对氰基苯基)苯基，j＝3，m＝s＝1且 R3 ＝R ⁴ ＝H。 Embodiment 18. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-(p-cyanophenyl)phenyl, j = 3, m = s = 1 and R 3 =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 7C and p-cyanophenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 692.38.

Q＝不存在，Y＝5-苯基-2-噻吩基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 19. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 5-phenyl-2-thienyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 8C and phenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 698.32.

Embodiment 20. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is Q = absent, Y = 5-phenyl-3-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by using the ethyl ester compound in Step 9C and phenylboronic acid according to the method described in Example 10, and then the ethyl ester was hydrolyzed according to the method in Example 4 (IV).

[M+Na] ⁺ = 708.30.

Embodiment 21. The compound of formula II, wherein A=tBOC, G= OEt , L=absent, W is Q = absent; Y = 3-chloro-4-hydroxyphenyl, j = 3, m = s = 1 and ^R3 = ^R4 = H.

replacement method

The title compound was prepared by displacement of mesylate 2 and tetrazole 3a. The replacement method was as follows: 0.041 mmol of macrocyclic peptide precursor mesylate 2 and 0.123 mmol of tetrazole 3a were dissolved in 3 ml of DMF, and 0.246 mmol of sodium carbonate (60 mg) was added. The resulting reaction mixture was stirred at 60 °C for 4-10 h, then cooled and extracted with ethyl acetate. The organic extract was washed with water (2 x 30ml), the organic solution was concentrated in vacuo, and the crude ethyl ester was hydrolyzed.

Q＝不存在，Y＝3-氯-4-羟基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 22. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 3-chloro-4-hydroxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by dissolving the title compound of Example 4 (20 mg) in 2 mL of dioxane and 1 mL of 1N aqueous LiOH. The resulting reaction mixture was stirred at room temperature for 4-8 h. The reaction mixture was acidified with 5% citric acid, extracted with 10 mL EtOAc, washed 2 x 20 mL with water. The solvent was evaporated and the residue was purified by HPLC (YMC AQ12S11-0520WT column, 30-80% (100% acetonitrile) gradient, 20 min). After freeze-drying, the title compound was obtained as a white amorphous solid.

[M+Na] ⁺ = 666.24.

Q＝不存在，Y＝3-溴-4-羟基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 23. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 3-bromo-4-hydroxyphenyl, j = 3, m = s = 1 and ^R3 = ^R4 = H.

The title compound was prepared by reacting mesylate 2 with tetrazole 3b of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 712.18.

Embodiment 24. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is Q = absent, Y = 2-methyl-4-bromophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with tetrazole 3c of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 708.30.

Q＝不存在，Y＝3-甲基-4-溴苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 25. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 3-methyl-4-bromophenyl, j = 3, m = s = 1 and ^R3 = ^R4 = H.

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3d of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 708.30.

Q＝不存在，Y＝正丙基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 26. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = n-propyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3e of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 582.33.

Q＝不存在，Y＝正丁基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 27. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = n-butyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3f of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 596.36.

Q＝不存在，Y＝4-乙氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 28. The compound of formula II, wherein A = tBOG, G = OH , L = absent, W is

Q = absent, Y = 4-ethoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by carrying out the metathesis reaction described in Example 21 with mesylate 2 and tetrazole 3 g of Example 3, followed by hydrolysis of the ethyl ester as in Example 22.

[M+H] ⁺ = 660.92.

Q＝不存在，Y＝4-丙氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 29. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is

Q = absent, Y = 4-propoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3h of Example 3 according to the displacement method described in Example 21, and then hydrolyzing the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 674.29.

Q＝不存在，Y＝4-丁氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 30. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-butoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3i of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22. [M+Na] ⁺ = 688.32.

Q＝不存在，Y＝3-甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 31. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3j of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 646.92.

Q＝不存在，Y＝3，4-二甲氧基苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 32. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3,4-dimethoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3k of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 676.38.

Q＝不存在，Y＝4-甲氧基-1-萘基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 33. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-methoxy-1-naphthyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with tetrazole 31 of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 697.00.

Q＝不存在，Y＝4-苯氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 34. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-phenoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with tetrazole 3m of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 708.51.

Embodiment 35. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = benzyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with tetrazole 3n of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 630.35.

Q＝不存在，Y＝对苯基苄基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 36. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = p-phenylbenzyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the mesylate 2 with the tetrazole 3o of Example 3 according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 706.38.

Q＝不存在，Y＝3-氯苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 37. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chlorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-chlorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 650.33.

Embodiment 38. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 3-fluorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-fluorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 634.37.

Q＝不存在，Y＝3-甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 39. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-methoxyphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 646.92.

Q＝不存在，Y＝3-苯氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 40. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-phenoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-phenoxyphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 708.51.

Q＝不存在，Y＝3-苄氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 41. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-benzyloxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-benzyloxyphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 722.32.

Embodiment 42. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 3-trifluoromethylphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-trifluoromethylphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 684.32.

Embodiment 43. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-bromophenyl, j = 3, m = s = 1 and ^R3 = ^R4 = H.

The title compound was prepared by reacting mesylate 2 with 5-(4-bromophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22. [M+Na] ⁺ = 696.28.

Embodiment 44. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-fluorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(4-fluorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 634.36.

Q＝不存在，Y＝4-甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 45. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(4-methoxyphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 646.36.

Embodiment 46. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-ethoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(4-ethoxyphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+H] ⁺ = 660.92.

Embodiment 47. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-trifluoromethylphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(4-trifluoromethylphenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 684.32.

Q＝不存在，Y＝3，5-二(三氟甲基)苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 48. The compound of formula II wherein A = tBOC G = OH , L = absent, W is

Q = absent, Y = 3,5-bis(trifluoromethyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3,5-bis(trifluoromethyl)phenyl)-1H-tetrazole according to the displacement procedure described in Example 21, followed by the procedure described in Example 22 Methods Hydrolysis of ethyl esters.

[M+Na] ⁺ = 766.32.

Q＝不存在，Y＝4-(N，N-二甲基氨基)-3，5-二(三氟甲基)苯 基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 49. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-(N,N-dimethylamino)-3,5-bis(trifluoromethyl) phenyl , j = 3, m = s = 1 and R ³ =R ⁴ = H.

The title compound was prepared by using mesylate 2 and 5-(4-(N,N-dimethylamino)-3,5-bis(trifluoromethyl)phenyl)-1H-tetrazole according to example 21 introduced the replacement method reaction, and then according to the method of Example 22 to hydrolyze the ethyl ester.

[M+Na] ⁺ = 695.39.

Q＝不存在，Y＝2，4-二氯苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 50. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 2,4-dichlorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(2,4-dichlorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 684.27.

Q＝不存在，Y＝3，5-二氯苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 51. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3,5-dichlorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3,5-dichlorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 684.27.

Q＝不存在，Y＝3，4-二氯苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 52. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3,4-dichlorophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3,4-dichlorophenyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 684.27.

Q＝不存在，Y＝2-吡啶基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 53. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 2-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(2-pyridyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 617.60.

Q＝不存在，Y＝2-吡啶基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H Embodiment 54. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 2-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H

The title compound was prepared by reacting mesylate 2 with 5-(2-pyridyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 617.60.

Embodiment 55. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 3-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(3-pyridyl)-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester according to the method of Example 22.

[M+Na] ⁺ = 645.24.

Embodiment 56. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-pyridyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting mesylate 2 with 5-(4-pyridyl)-1H-tetrazole according to the displacement procedure described in Example 21, followed by hydrolysis of the ethyl ester as in Example 22.

[M+H] ⁺ ＝595.50

Q＝不存在，Y＝4-甲氧基-3-溴苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 57. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 4-methoxy-3-bromophenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

57A. Preparation of Tetrazoles

The tetrazole of this example was prepared as follows: 4-hydroxy-3-bromo-4-hydroxy-benzocyanide was dissolved in DMF, methyl iodide was added, and stirred at room temperature for 3-12 hours. The resulting reaction mixture was diluted with EtOAc, washed with water and brine. The resulting organic phase was dried over sodium sulfate and concentrated in vacuo to obtain 3-bromo-4-methoxy-benzonitrile. This compound was then used to prepare the corresponding tetrazole as described in Example 3.

The title compound was prepared by reacting mesylate 2 with 5-(3-bromo-4-methoxy-phenyl)-1H-tetrazole of 57A according to the displacement procedure described in Example 21, followed by Example 22 method for the hydrolysis of ethyl esters.

[M+Na] ⁺ = 724.91.

Embodiment 58. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = 4-(methylcyclopropane)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

58A. Preparation of tetrazole

The tetrazole of this example was prepared as follows: 4-cyano-phenol was dissolved in DMF, (bromomethyl)cyclopropane was added, and stirred at room temperature for 3-12 h. The resulting reaction mixture was diluted with EtOAc, washed with water and brine. The resulting organic phase was dried over sodium sulfate and concentrated in vacuo to obtain 4-(methylcyclopropane)benzonitrile. This compound was then used to prepare the corresponding tetrazole as described in Example 3.

The title compound was prepared by reacting mesylate 2 with 5-(4-(methylcyclopropane)-phenyl)-1H-tetrazole of 58A according to the displacement procedure described in Example 21, followed by the procedure described in Example 22 Methods Hydrolysis of ethyl esters.

[M+Na] ⁺ = 686.29.

Embodiment 59. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is Q=absent, Y=3-chloro-4-(methylcyclopropane)phenyl, j=3, m=s=1 and R3 ⁼ R4 ⁼ H .

The title compound was prepared as follows: directly use the ethyl ester title compound of Example 21 without further treatment, add (bromomethyl)cyclopropane, and stir at 60° C. for 3-12 h. The resulting reaction mixture was cooled to room temperature, poured into a 50:50 EtOAc:water mixture, washed with water and concentrated in vacuo. The obtained crude ethyl ester compound was hydrolyzed into free acid according to the method described in Example 22.

[M+Na] ⁺ = 720.24.

Q＝不存在，Y＝3-氯-4-甲氧基苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 60. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chloro-4-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 59 using the title compound of Example 21 and methyl iodide.

[M+Na] ⁺ = 680.23.

Q＝不存在，Y＝3-氯-4-乙氧基苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 61. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chloro-4-ethoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 59 using the title compound of Example 21 and ethyl iodide.

[M+Na] ⁺ = 694.28.

Q＝不存在，Y＝3-溴-4-乙氧基苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 62. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q ⁼ absent, Y = 3-bromo-4-ethoxyphenyl, j = 3, m = s = 1 and R3 = ^R4 = H.

The title compound was prepared as described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and ethyl iodide.

[M+Na] ⁺ = 740.17.

Q＝不存在，Y＝3-氯-4-(2-羟基乙氧基)苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 63. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q=absent, Y=3-chloro-4-(2-hydroxyethoxy)phenyl, j=3, m=s=1 and ^R3 =R4 ⁼ H .

The title compound was prepared as described in Example 59 using the title compound of Example 21 and 2-iodoethanol.

Q＝不存在，Y＝3-溴-4-(2-羟基乙氧基)苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 64. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-bromo-4-(2-hydroxyethoxy)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and 2-iodoethanol.

[M+Na] ⁺ = 754.27.

Q＝不存在，Y＝3-氯-4-(O-烯丙基)苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 65. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chloro-4-(O-allyl)phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 59 using the title compound of Example 21 and 3-iodopropene.

[M+Na] ⁺ = 706.24.

Q＝不存在，Y＝3-溴-4-(O-烯丙基)苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 66. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q ⁼ absent, Y=3-bromo-4-(O-allyl)phenyl, j=3, m=s=1 and R3 = R4 ⁼ H .

The title compound was prepared as described in Example 59 using the ethyl ester precursor of the title compound in Preparation Example 23 and 3-iodopropene.

[M+Na] ⁺ = 752.15.

Q＝不存在，Y＝3-氯-4-(O-CH₂SCH₃)苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 67. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chloro-4-(O- _CH2SCH3 )phenyl, j = 3, _m = s = 1 and ^R3 = ^R4 = H.

The title compound was prepared by the method described in Example ₅₉ using the title compound of Example 21 and Cl- _CH2SCH3 .

Q＝不存在，Y＝3-氯-4-(O-CH₂SCH₃)苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 68. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

Q = absent, Y = 3-chloro-4-(O- _CH2SCH3 )phenyl, j = 3, _m = s = 1 and ^R3 = ^R4 = H.

The title compound was prepared by the method described in Example 59 using the ethyl ester precursor of the title compound from Example 23 and Cl—CH ₂ SCH ₃ .

[M+Na] ⁺ = 752.15.

其中Q′＝-CH₂-，

j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 69. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

where Q' = -CH ₂ - ,

j=3, m=s=1 and R ³ =R ⁴ = H .

69A. Preparation of cyanoproline derivatives (69b)

At 0°C, drop into a solution of cis-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl 2-methyl ester (69a) (3.94g, 16.06mmol) in CH ₂ Cl ₂ (40ml) DIEA (4.3ml) and methanesulfonyl chloride (1.40ml) were added. After the addition, the mixture was stirred for 1.5 h. TLC analysis confirmed the completion of the reaction (50% EtOAc-hexane for developing TLC). The mixture was diluted with EtOAc, washed with saturated _NaHCO3 , brine and _dried ( _Na2SO4 ). After evaporation of the solvent, the oily residue was used directly in the next step without further purification. [M+H] ⁺ =324.

The crude product from the previous step was dissolved in DMF (35ml) and ground KCN (2.5g) was added. The mixture was heated at 90°C overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with _H2O and brine, dried over sodium sulfate. The crude product was purified by silica gel chromatography (20% EtOAc/hexanes).

[M+H] ⁺ =255.

69B. Preparation of tetrazolylproline derivatives (69c)

To a solution of nitrile 69b (669 mg, 2.63 mmol) in toluene (8 ml) was added NaN ₃ (684 mg, 10.53 mmol) and Et ₃ N·HCl (1.45 g, 10.53 mmol). The mixture was heated at 115 °C for 18 h. The mixture was diluted with _CH2Cl2 , washed with 5% aqueous citric acid and dried _over sodium sulfate. Evaporation of the solvent afforded the crude product 69c·Et ₃ N adjuvant (660 mg).

[M+H] ⁺ =298.

69C. Preparation of 5-biphenylmethyl-tetrazolylproline (69e)

To a solution of 69c (92.8 mg, 0.31 mmol) in THF (2 ml) was added 4-phenylbenzyl bromide (90.4 mg, 0.37 mmol) and _K2CO3 (140 _mg , 1.01 mmol). The mixture was heated at 65 °C overnight, then diluted with EtOAc, washed with brine and dried over sodium sulfate. After evaporation of the solvent, the crude product was dissolved in THF-MeOH- _H2O (2ml:1ml:1ml) and LiOH (130mg) was added. The mixture was stirred overnight at room temperature. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over sodium sulfate. Evaporation of the solvent afforded crude products 69d and 69e.

[M+Boc+H] ⁺ =350.

69D. Preparation of tripeptide (69g)

To a solution of 69d and 69e (about 0.31 mmol) in DMF (2.0 ml) was added D-β-vinylcyclopropaneamino acid ethyl ester·HCl (66 mg), DIEA (0.25 ml) and HATU (164 mg) in sequence. The mixture was stirred for 1 h, then diluted with EtOAc, washed with brine, 5% citric acid and dried over Na2SO4. After evaporation of _the solvent, the residue was dissolved in 2 ml _CH2Cl2 and 2 ml 4N HCl in dioxane was added. The mixture was stirred at room temperature for 1.5 h and the solvent was evaporated. The residue was dissolved in EtOAc, neutralized with saturated NaHCO ₃ , washed with brine, dried over sodium sulfate. After evaporating the solvent, the residue was dissolved in DMF (2 ml), to which P3 (120 mg), DIEA and HATU were sequentially added. The resulting mixture was stirred and monitored by TLC analysis. After the reaction was complete, the mixture was diluted with EtOAc, washed successively with brine, 5% citric acid, saturated sodium bicarbonate, and brine. The organic solution was dried over sodium sulfate and evaporated in vacuo to give a mixture of crude products which were purified by silica gel chromatography (30%-50% EtOAc-hexanes).

[M+H] ⁺ ＝740

69E. Ring-closing displacement reactions (69k)

The mixture of 69f and 69g (60 mg) was dissolved in _{anhydrous CH2Cl2} to a concentration of about 0.01 mol. The solution was carefully degassed with nitrogen flow for 15 min. 5% mol Hoveyda catalyst was added under nitrogen atmosphere. The mixture was refluxed overnight. The solvent was evaporated. The residue was packed into a silica gel column and eluted with 10% EtOAc to remove the catalyst. The two positional isomers were separated by eluting with 30-40% EtOAc-hexanes to give the less polar product 69j (37.9 mg) and the more polar product 69k (14.8 mg). The positional chemical structures of 69j and 69k were confirmed by NMR analysis.

[M+H] ⁺ =712.

69F. Hydrolysis of ethyl esters (69)

The ester 69h (37.9mg) was dissolved in THF-MeOH- _H2O (2ml:1ml:1ml), and LiOH (21mg) was added. The mixture was stirred overnight at room temperature. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over sodium sulfate. The solvent was evaporated to obtain crude product. _The crude product was purified by silica gel chromatography (5% MeOH/ _CH2Cl2 ) to afford the title compound 69k.

[M+H] ⁺ =684.

其中Q′＝-CH₂-，

j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 70. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

where Q' = -CH ₂ - ,

j=3, m=s=1 and R ³ =R ⁴ = H .

Ester 69i (14.8 mg) was dissolved in THF-MeOH-H ₂ O (2ml:1ml:1ml), and LiOH (21mg) was added. The mixture was stirred overnight at room temperature. THF and MeOH were evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over sodium sulfate. The solvent was evaporated to obtain crude product. _The crude product was purified by silica gel chromatography (5% MeOH/ _CH2Cl2 ) to afford the title compound 70.

[M+H] ⁺ =684.

Embodiment 71. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is Q = absent, Y = phenyl; j = 3, m = s = 1 ^and R3 = ^R4 = H.

71a - Deprotection of the amine.

0.041 mmol of the title compound of Example 21 was dissolved in 4 ml of 4M HCl in dioxane, and stirred for 1 h. The reaction residue 69a was concentrated in vacuo.

71b-chloroformate reagent

Chloroformate reagent 71b was prepared by dissolving 0.045 mmol cyclopentanol in THF (3 ml) and adding 0.09 mmol phosgene in toluene (20%). The resulting reaction mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo. DCM was added to the residue, then concentrated to dryness in vacuo twice to afford chloroformate reagent 71b.

71c - Preparation of carbamates

The title carbamate was prepared by dissolving the residue 71a in 1 ml THF, adding 0.045 mmol TEA, and cooling the resulting reaction mixture to 0 °C. To this 0°C reaction mixture was added a solution of chloroformate reagent 71b in 3 ml THF. The resulting reaction mixture was reacted at 0 °C for 2 h, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified on a silica column and then the ethyl ester was hydrolyzed as described in Example 22.

Embodiment 72. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclobutyl, G = OH , L = absent, W is Q = absent, Y = phenyl, j = 3, m = s = 1 and ^R3 = R4 ⁼ H

The title compound was prepared as described in Example 71 using the title compound of Example 21 and cyclobutanol, followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 73. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclohexyl, G = OH , L = absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 71 using the title compound of Example 21 and cyclohexanol, followed by hydrolysis of the ethyl ester as described in Example 22.

G＝OH， L＝不存在，W为

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 74. The compound of Formula II wherein A= -(C=O)-OR ¹ ,

G = OH , L = not present, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 71 using the title compound of Example 21 and (R)-3-hydroxytetrahydrofuran, followed by hydrolysis of the ethyl ester as described in Example 22.

G＝OH， L＝不存在，W为

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 75. The compound of Formula II wherein A= -(C=O)-OR ¹ ,

G = OH , L = not present, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 71 using the title compound of Example 21 and (S)-3-hydroxytetrahydrofuran, followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 76. The compound of Formula II wherein A= -(C=O)-OR ¹ , G = OH , L = not present, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared according to the method described in Example 71, wherein the title compound of Example 21 and The ethyl ester was then hydrolyzed as described in Example 22.

Embodiment 77. The compound of formula II wherein A = -(C=O)-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 21 was dissolved in 4 ml of 4M HCl in dioxane and the reaction mixture was stirred for 1 h. The reaction residue was concentrated in vacuo. 4 ml of THF and 0.045 mmol of TEA were added to the residue, the mixture was cooled to 0°C, and 0.045 mmol of cyclopentanoyl chloride was added thereto. The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 78. The compound of formula II wherein A = -(C=O)-NH-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 21 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. 0.045 mmol cyclopentyl isocyanate was added to the solution at 0° C., and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was then extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 79. The compound of formula II wherein A = -(C=S)-NH-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 21 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. 0.045 mmol cyclopentyl isothiocyanate was added to the solution at 0° C., and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was then extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 80. The compound of formula II wherein A = -S(O) ₂ -R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 21 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting concentrated reaction residue was dissolved in 4 ml of THF, 0.045 mmol of TEA was added thereto, and cooled to 0°C. 0.045 mmol cyclopentylsulfonyl chloride was added to the solution at 0°C, and the resulting reaction mixture was stirred at 0°C for 2h. The solution was then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as described in Example 22.

Q＝不存在，Y＝苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 81. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -O- phenethyl, L is absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by adding 1.2 eq. PyBrOP, 4 eq. DIEA, a catalytic amount of DMAP to a solution of the title compound of Example 71 and phenylethyl alcohol 81a in 0.5 ml DCM at 0°C. The resulting reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to room temperature over 4-12 h. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1) to afford the title compound of phenethyl ester 81b alone.

Other esters can be prepared in the same way.

Q＝不存在，Y＝苯基，j＝3， m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 82. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -NH- phenethyl, L = absent, W is

Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by adding EDC (1.2 eq.) and DIEA (4 eq.) to a solution of the title compound of Example 71 and phenethylamine 82a (0.05 ml) in 0.5 ml DMF at 0°C. The resulting reaction mixture was stirred for 1 h. Subsequently, the reaction was warmed to room temperature over 4-12 h. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1) to afford the title compound phenethylamide 82b. Other amides can be prepared in the same way.

Q＝不存在，Y＝苯 基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 83. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -NHS(O) ₂ -phenethyl, L = absent, W is

Q = absent, Y = phenyl , j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by adding 1.2eq. The resulting reaction mixture was stirred for 1 h, then allowed to warm to room temperature over 4-12 h. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1) to afford the title compound sulfonamide 83c.

Other sulfonamides can be prepared in the same way.

Embodiment 84. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -(C=O)-OH , L = absent, W is Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by adding α-hydroxy-α-methyl-propionitrile (0.1 ml) and a catalytic amount of TFA to a solution of the title compound of Example 71 in 0.5 ml THF at 0°C. The resulting reaction mixture was warmed from 0 °C to room temperature over 4-12 h, then hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction was extracted with EtOAc, washed with water and brine to obtain the crude product of α-hydroxy compound 83a. Crude compound 84a was subjected to Dess-Marin oxidation in THF (0.5 ml) to give the crude product of α-carbonyl compound 84b. Crude 84b was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound ketoacid 84b.

Q＝不存在，Y＝苯 基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 85. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-O-phenethyl, L=absent, W is

Q = absent, Y = phenyl , j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 81 using the title compound ketoacid from Example 84 and phenylethyl alcohol.

Q＝不存在，Y-苯 基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 86. The compound of formula II wherein A= -(C=O) ^-OR1 , R1 ⁼ cyclopentyl. G=- (C=O)-NH-phenethyl, L=absent, W is

Q = absent, Y- phenyl , j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 82 using the title compound ketoacid from Example 84 and phenethylamine.

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

The title compound was prepared as described in Example 83 using the title compound ketoacid from Example 84 and α-toluenesulfonamide.

Q＝不存在，Y＝苯基，j＝1，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 88. The compound of formula II wherein A=tBOC, G= OH , L= -(C=O) _CH2- , W is

Q = absent, Y = phenyl, j = 1, m = s = 1 and R ³ =R ⁴ = H .

Synthesis of (2S)-N-Boc-amino-5-oxo-non-8-enoic acid

88A. The above amino acid was prepared by adding n-Bu ₂ Mg dropwise to a solution of monoallyl malonate in anhydrous THF under a nitrogen atmosphere at -78° C. within 5 min. The resulting suspension was then stirred for 1 h at room temperature and then evaporated to dryness. The solid Mg salt 88b was dried in vacuo.

The glutamic acid derivative 88a was first mixed with 1,1'-carbonyldiimidazole in anhydrous THF, and the mixture was stirred at room temperature for 1 h to activate the free acid moiety. Subsequently, the activated glutamate derivative was cannulated into a solution of Mg salt 88b and the resulting reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and the organic solution was washed with 0.5N HCl (0°C) and brine, dried and evaporated. The resulting residue was resolved by chromatography on silica (using a 35-40% ethyl acetate/hexanes eluent system) to afford diester 88c.

88B. A solution of diester in DMF was added to a stirred solution of tetrakis(triphenylphosphine)PD(0) in anhydrous DMF. The mixture was stirred at room temperature for 3.5 h. DMF was evaporated under reduced pressure and the residue was diluted with EtOAC. The EtOAc solution was washed with 0.5N 0°C HCl, brine, dried and evaporated. The residue was purified by silica gel chromatography (15%-20% EtOAc/hexanes as eluent) to afford the methyl ester intermediate.

The methyl ester intermediate was diluted with THF and water, LiOH·H ₂ O was added, the resulting mixture was stirred at room temperature for 25 h, and the completion of hydrolysis was monitored by TLC. The reaction mixture was concentrated in vacuo to remove most of the THF and further diluted with dichloromethane. The resulting solution was washed with 1N HCl, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (solvent gradient from 100% hexane to 100% EtOAc as eluent) in order to remove minor impurities and excess _Boc2O . (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 88d is obtained. Detailed information on the aforementioned amino acid synthesis methods can be found in T. Tsuda et al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929, the entire contents of which are incorporated herein by reference.

88C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared according to the synthesis route introduced in Example 1, and (2S)-N-Boc-amino-5-oxo-non-8-enoic acid 88d was used to replace Boc-L-2 -Amino-8-nonenoic acid 1a, then converted to the corresponding mesylate by the method described in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate synthesized in 88C with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, and then hydrolyzing B by the method described in Example 22. ester.

Embodiment 89. Compounds of Formula II Where A=tBOC, G= OH , L= CH(CH ₃ )CH ₂ − , W is Q = absent, Y = phenyl, j = 1, m = s = 1, R3 ⁼ methyl and ^R4 = H.

Synthesis of (2S,5R)-N-Boc-2-amino-5-methyl-non-8-enoic acid (89h).

89A. To solid ethyl 2-acetamidomalonate 89b was added a solution of (R)-(+)-citronellal 89a in pyridine over 1 min. The resulting solution was cooled in a 10 °C cooling bath and acetic anhydride was added within 4 min. The resulting solution was stirred at room temperature for 3 h and an additional portion of ethyl 2-acetamidomalonate 89a was added. The resulting mixture was stirred at room temperature for 11 h. Ice was then added, the solution was stirred for 1.5 h, the mixture was diluted with 250 mL of water and extracted with two portions of ether. The organic phase was washed with 1N HCl, saturated NaHCO ₃ , dried over Na2SO4, concentrated, and purified by flash chromatography (40% EtOAc/Hexanes) to afford compound 89C.

Add (S,S)-Et-PUPHOSRh(COD)OTf to the degassed solution of 89B.89c in absolute ethanol. The mixture was placed under 30 psi hydrogen atmosphere and stirred with a Parr shaker for 2 h. The resulting mixture was evaporated to dryness to afford crude compound 5Od, which was used directly in subsequent steps without further purification.

89C. Compound 89d was dissolved in a mixture of tBuOH/acetone/ _H2O (1:1:1) and placed in an ice bath (0°C). NMMO and _OsO4 were added continuously and the reaction mixture was stirred at room temperature for 4h. Most of the acetone was removed by evaporation in vacuo and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Diol 50e was obtained in high purity after flash column chromatography (1% ethanol/ethyl acetate as eluent).

89D. To a solution of diol 89e in THF/ _H2O (1:1) at 0°C was added _NaIO4 , and the reaction mixture was stirred at room temperature for 3.5 h. Most of the THF solvent was then evaporated in vacuo and the remaining mixture was extracted with EtOAc. The combined organic layers were washed with 5% aqueous citric acid, 5% aq. NaHCO ₃ and brine, the organic phase was dried over magnesium sulfate and evaporated to dryness in vacuo. Aldehyde intermediate 89f The crude product was used directly in the next step.

89E. Add KHMDS to anhydrous toluene solution of _{Ph 3} PCH ₃ Br to form a suspension, and stir at room temperature for 30 min under nitrogen atmosphere. After stirring, the suspension was cooled to 0 °C, a THF solution of aldehyde intermediate 89f was added, the mixture was warmed to room temperature and stirred for 1 h. Most of the THF was evaporated in vacuo, EtOAc was added to the mixture, the organic phase was washed with water, 5% aq. NaHCO ₃ and brine. The organic phase was then dried over magnesium sulfate and evaporated to dryness in vacuo. Pure compound 89 g was isolated after purification by silica gel flash chromatography using hexane:EtOAc (3:2) as eluent.

89F. Boc ₂ O and DMAP were added to the crude 89 g THF solution, and the reaction mixture was heated to reflux for 2.5 h. Subsequently, most of the THF was evaporated and the crude mixture was diluted with dichloromethane and washed with 1N HCl to remove DMAP. The organic layer was extracted with saturated aqueous NaHCO ₃ , dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was diluted with THF and water, LiOH·H ₂ O was added, the resulting mixture was stirred at room temperature for 25 h, and the completion of hydrolysis was monitored by TLC. The reaction mixture was concentrated in vacuo to remove most of the THF and further diluted with dichloromethane. The resulting solution was washed with 1N HCl, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by flash chromatography (solvent gradient from 100% hexane to 100% EtOAc as eluent) in order to remove minor impurities and excess _Boc2O . (2S,5R)-N-Boc-2-amino-5-methyl-non-8-enoic acid 89h was obtained. For a detailed description of the above amino acid synthesis methods see WO 00/59929, the entire contents of which are incorporated herein by reference.

89G. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared according to the synthetic route of Example 1, wherein (2S, 5R)-N-Boc-2-amino-5-methyl-non-8-enoic acid 89h was used instead of Boc- L-2-Amino-8-nonenoic acid 1a is then converted to the corresponding mesylate by the method described in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate formed in 89G with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝0，m＝s＝1，R ³ ＝甲基且R ⁴ ＝氢。 Embodiment 90. The compound of formula II wherein A = tBOC, G = OH , L = -O- , and W is

Q = absent, Y = phenyl, j = 0, m = s = 1, R3 ⁼ methyl and R4 ⁼ hydrogen.

Synthesis Synthesis of N-Boc-O-allyl-(L)-threonine (90d)

90A. Boc-(L)-threonine 90a was partially dissolved in dichloromethane/methanol at 0°C. Diazomethane in ether was added until the solution turned yellow, indicating the presence of diazomethane. After evaporation of the solvent, the crude methyl ester 90b was obtained.

90B. Intermediate 90b was dissolved in anhydrous ether, _Ag2O and freshly activated 4-molecular sieves were added. Finally, allyl iodide was added to the reaction mixture and stirred at reflux. After 20 h and 30 h respectively, allyl iodide was added to the reaction mixture again, and stirring was continued for a total of 36 h. The mixture was then filtered through celite and purified by flash chromatography on silica gel (EtOAc/Hexane 1:4 as eluent) to afford compound 90C.

90C. Compound 90c was dissolved in THF/MeOH/ _H2O mixture (2:1:1), and LiOH· _H2O was added. The solution was stirred at room temperature for 2 h, acidified to pH~3 with 1N HCl, then the solvent was removed in vacuo. Crude compound 90d was obtained. Details on the aforementioned amino acid synthesis methods are found in WO 00/59929, the entire contents of which are incorporated herein by reference.

90D. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: According to the synthetic route of Example 1, N-Boc-O-allyl-(L)-threonine 90d was used to replace Boc-L-2-amino-8- Nonenoic acid 1a was reacted and then converted to the corresponding mesylate as described in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 90D with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝0，m＝s＝1，R ³ ＝甲基且R ⁴ ＝氢。 Embodiment 91. The compound of formula II wherein A = tBOC, G = OH , L = -S- , and W is

Q = absent, Y = phenyl, j = 0, m = s = 1, R3 ⁼ methyl and R4 ⁼ hydrogen.

Synthesis of (2S,3S)-N-Boc-2-amino-3-(mercaptoallyl)butanoic acid (91e).

91A. Dissolve compound 91a in pyridine, cool the solution to 0°C in an ice bath, add tosyl chloride in small portions, and partition the reaction mixture between diethyl ether and H ₂ O. The ether layer was further washed with 0.2N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness in vacuo. Purification by flash chromatography on silica gel (gradient 8:2 to 7:3 hexane/EtOAc as eluent) isolated the tosyl derivative 91b.

91B. Potassium thioacetate was added to anhydrous DMF solution of tosyl derivative 91b, and the reaction mixture was stirred at room temperature for 24 h. Most of the DMF was evaporated in vacuo and the remaining mixture was partitioned between EtOAc and _H2O . The aqueous layer was extracted again with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. Purification by flash chromatography on silica gel (hexane/EtOAc 4:1 as eluent) afforded the thioester 91c.

91C. Add H ₂ O/EtOH (3:5) to the thioester 91c solution, add 0.2M NaOH aqueous solution, and stir the mixture at room temperature for 1.5 h. Allyl iodide was then added and stirring was continued for 30 min at room temperature. The reaction mixture was concentrated to half its original volume, then extracted with EtOAc. The aqueous layer was acidified to pH~3 with cold aqueous 0.5N HCl and extracted again with EtOAc. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The crude reaction mixture contained at least four products; all were isolated after silica gel flash chromatography (gradient with 9:1 to 3:1 hexane/EtOAc). The desired product 91d is the least polar compound.

91D. A solution of compound 91d in MeOH/ _H2O (3:1) was mixed with aqueous NaOH (0.3 N) at room temperature for 24 h and at 40 °C for 1 h. The reaction mixture was acidified with cold aqueous 0.5N HCl, MeOH was removed in vacuo and the remaining aqueous mixture was extracted with EtOAc. The organic phase was dried over magnesium sulfate and evaporated to dryness to obtain compound 91e. For details on the methods of amino acid synthesis described above see WO 00/59929, the entire contents of which are incorporated herein by reference.

91E. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide-precursor mesylate was prepared by substituting (2S,3S)-N-Boc-2-amino-3-(mercaptoallyl)butanoic acid 52e for Boc-L-2-amino-8 - Nonenoic acid 1a was reacted according to the synthesis route introduced in Example 1, and then converted into the corresponding mesylate according to the method introduced in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 91E with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝2，m＝s＝1，R ³ ＝甲基且R ⁴ ＝氢。 Embodiment 92. The compound of formula II wherein A=tBOC, G= OH , L= -S(O)- , and W is

Q = absent, Y = phenyl, j = 2, m = s = 1, R3 ⁼ methyl and R4 ⁼ hydrogen.

Preparation of Modified Amino Acids

92A. Modified amino acids were prepared by dissolving sodium metaperiodate (1.1 eq.) in water, cooling to 0° C. in an ice bath, and then adding compound 91d in dioxane dropwise. The resulting reaction mixture was stirred at 0 °C for 1 h and at 40 °C for 4 h. The reaction mixture was concentrated, water was added, and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Reduction of the methyl ester by the method described in Example 91D yields the modified amino acid 92a. Detailed information on the above amino acid synthesis methods can be found in T. Tsuda et al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929, the entire contents of which are incorporated herein by reference.

92B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: replace Boc-L-2-amino-8-nonenoic acid 1a with modified amino acid 92a according to the synthetic route of Example 1, and then according to the method described in Example 2 Conversion to the corresponding mesylate.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 92B with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝2，m＝s＝1，R ³ ＝甲基且R ⁴ ＝H。 Embodiment 93. The compound of Formula II wherein A=tBOC, G= OH , L= -S(O) ₂ - , and W is

Q = absent, Y = phenyl, j = 2, m = s = 1, R3 ⁼ methyl and ^R4 = H.

Preparation of Modified Amino Acids

93A. The modified amino acid was prepared by dissolving sodium metaperiodate (1.1 eq.) in water, cooling to 0° C. in an ice bath, and then adding compound 92d in dioxane dropwise. The resulting reaction mixture was stirred at 0 °C for 1 h and at 40 °C for 4 h. The reaction mixture was concentrated, water was added, and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Modified amino acid 92a was obtained by reducing the methyl ester as described in Example 91D. Detailed information on the above amino acid synthesis methods can be found in T. Tsuda et al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO00/59929, the entire contents of which are incorporated herein by reference.

93B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: Substitute Boc-L-2-amino-8-nonenoic acid 1a with modified amino acid 93a according to the synthesis route described in Example 1, and then according to the method described in Example 2 Method conversion to the corresponding mesylate.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 93B with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝0，m＝s＝1且R ³ ＝R ⁴ ＝CH₃ 。 Embodiment 94. The compound of formula II wherein A=tBOC, G= _OH , L= _-SCH2CH2- , W is

Q = absent, Y = phenyl, j = 0, m = s = 1 and R ³ =R ⁴ = CH ₃ .

94A. Synthesis of (S)-N-Boc-2-amino-3-methyl-3-(1-mercapto-4-butenyl)butanoic acid (94b)

L-penicillamine 94a was dissolved in DMF/DMSO (5:1), then 4-bromopentene and CsOH·H ₂ O were added to the mixture, and stirring was continued for another 12 h. DMF was then removed in vacuo and the remaining mixture was diluted with 0.5N HCl (0°C) to pH~4-5, then extracted twice with EtOAC. The organic phase was washed with brine (2x), dried over magnesium sulfate and evaporated to dryness to give crude carboxylic acid 94a. For details on the methods of amino acid synthesis described above see WO 00/59929, the entire contents of which are incorporated herein by reference.

94B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: replace Boc-L-2-amino-8-nonenoic acid 1a with modified amino acid 94a according to the synthetic route of Example 1, and then according to the method described in Example 2 Conversion to the corresponding mesylate.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 94B with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Q＝不存在，Y＝苯基，j＝1，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 95. The compound of formula II wherein A=tBOC, G= _OH , L= _-CF2CH2- , W is

Q = absent, Y = phenyl, j = 1, m = s = 1 and R ³ =R ⁴ = H .

Synthesis of (2S)-N-Boc-amino-5-difluoro-non-8-enoic acid (95b).

95A. Add DAST (diethylaminosulfur trifluoride, 0.2 g, 1.2 eq) to a solution of ketone compound 88d (0.30 g, 1 mmol) in 5 ml of DCM. React at room temperature for 2-3 days. The solvent was evaporated and the residue was purified by flash chromatography on silica gel using various ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent to give the isolated methyl ester 95a. For more detailed information on the above synthesis see Tius, Marcus A et al., Tetrahedron, 1993, 49, 16; 3291-3304, the entire contents of which are incorporated herein by reference.

95B. The methyl ester 95a was dissolved in THF/MeOH/ _H2O (2:1:1) and LiOH· _H2O was added. The solution was stirred at room temperature for 2 h, acidified to pH~3 with 1 N HCl, then the solvent was removed in vacuo to afford crude (2S)-N-Boc-amino-5-difluoro-non-8-enoic acid 95b.

95C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: The crude (2S)-N-Boc-amino-5-difluoro-non-8-enoic acid 95b was substituted for Boc-L- 2-Amino-8-nonenoic acid 1a was reacted and then converted to the corresponding mesylate as described in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 95C with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B ester.

Embodiment 96. The compound of formula II wherein A = tBOC, G = OH , L = -CFHCH ₂ - and W is Q = absent, Y = phenyl, j = 1, m = s = 1 and R ³ =R ⁴ = H .

Synthesis of (2S)-N-Boc-amino-5-fluoro-non-8-enoic acid (96c).

96A. To a solution of ketone compound 88d in 5 ml of methanol was added NaBH ₄ (2.2 eq). The reaction mixture was stirred at room temperature for 2-6 h, then quenched with 1M ammonium chloride and extracted with EtOAc (30 ml). Evaporation of solvent afforded crude hydroxy compound 96a.

96B. The hydroxyl compound 96a was dissolved in 5ml DCM, and DAST (0.2g, 1.2eq) was added thereto, and stirred at -45°C for 1h. The reaction mixture was then warmed to room temperature and stirred for 2-3 days. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (using various ratios of hexane:EtOAc (9:1 → 5:1 → 3:1 → 1:1) as eluent) to give the isolated monofluoro compound A Ester 95b. For further information on this synthesis see Buist, Peter H et al., Tetrahedron Lett., 1987, 28, 3891-3894, the entire contents of which are hereby incorporated by reference.

96B. The methyl ester 96b was dissolved in THF/MeOH/ _H2O (2:1:1) and LiOH- _H2O was added. The solution was stirred at room temperature for 2 h, then acidified with 1N HCl to pH~3, then the solvent was removed in vacuo to afford crude (2S)-N-Boc-amino-5-difluoro-non-8-enoic acid 96C.

96C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared by replacing Boc-L- 2-Amino-8-nonenoic acid 1a was reacted and then converted to the corresponding mesylate as described in Example 2.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate formed in 96C with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of B by the method described in Example 22. ester.

Embodiment 97. The compound of formula III wherein A=tBOC, G= OH , L=absent, W is Q = absent, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

97A. Saturated cyclic peptide precursor mesylate was prepared by catalytic reduction of mesylate cyclic peptide precursor 2 with Pd/C in MeOH in the presence of hydrogen.

The title compound was prepared by reacting the saturated cyclic peptide precursor mesylate formed in 97A with 5-phenyl-1H-tetrazole according to the displacement method described in Example 21, followed by hydrolysis of the ethyl ester as described in Example 22 .

The compounds of the present invention have potent HCV NS3 protease inhibitory properties. The following examples illustrate methods for testing the anti-HCV effects of the compounds of the present invention.

Example 98. Synthesis of triazoles

Exemplary triazole derivatives useful in preparing compounds of the invention can be prepared according to the following examples.

The triazole of the present invention can be prepared by reacting 4 mmol of alkyne compound 98a (commercially available or prepared by the following method) and 8 mmol of trimethylsilyl azide in 2 ml of xylene in a pressure tube at 140° C. for 24-72 h. The resulting reaction mixture was directly separated by silica column to afford triazole 98b in 30-90% yield.

Example 99. Synthesis of alkynes

99A. Sonogashira reaction

The alkyne used in the present invention can be prepared by the Sonogashira reaction: 4 mmol of the primary alkyne compound 99a, 4 mmol of the aryl halide (Y-halogen), 1 ml of triethylamine and 10 mol of acetonitrile in a degassed solution with 140 mg (0.2 mmol) of PdCl ₂ (PPh ₃ ) ₂ was reacted with 19 mg (0.1 mmol) CuI. The resulting reaction mixture was degassed and stirred at room temperature for 5 min. The reactant was then heated to 90 °C and stirred for 12 h. Subsequently, the reaction mixture was concentrated in vacuo and purified by silica column to obtain the substituted alkyne 98a in 60-90% yield.

99B. Synthesis of alkyne amides

Other alkynes used in the present invention can be prepared by reacting 10 mmol alkynyl acid 99b, 11 mmol BOP, 22 mmol DIEA in 15 ml DMF with 11 mmol amine 99b and stirring at room temperature for 3 h. The reaction mixture was then extracted with ethyl acetate (2×50ml); washed with 1M NaHCO ₃ (2×30ml), water (2×30ml), 5% citric acid (2×50ml) and brine (2×30ml); Dry over anhydrous sodium sulfate; concentrate in vacuo to give alkyne 99d in 90% yield.

Embodiment 100. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is X = H , Y = 4-tert-butylphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 2 mmol (0.54 g) of Boc methyl ester azidoproline 100a and 2.5 mmol of 4-tert-butylphenylacetylene 100b were dissolved in 2 ml of xylene and stirred at 110°C for 12 h. The resulting reaction mixture was directly separated by a silica column, and 100c and 100d were separated with a yield of 90%.

The title compound was prepared by following the RCM method described in Example 1, substituting 100b for hydroxyproline, followed by hydrolysis of the ethyl ester as described in Example 106.

[M+Na] ⁺ = 671.72.

X＝4-叔丁基苯基，Y＝H，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 101. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X = 4-tert-butylphenyl, Y = H , j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by following the RCM method described in Example 1, substituting 100c for hydroxyproline, followed by hydrolysis of the ethyl ester as described in Example 106.

[M+H] ⁺ = 649.44.

X和Y结合在一起＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 102. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X and Y taken together = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The corresponding triazole-substituted proline of the title compound was prepared as follows: 1.5 mmol (0.5 g) of hydroxyproline mesylate 102a and 4.5 mmol of benzotriazole 102b were dissolved in 5 ml DMF and 9 mmol (2.9 g) of carbonic acid cesium, and the resulting reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The expected isomers 102c and 102d were resolved by silica column chromatography.

The title compound was prepared by following the RCM method described in Example 1, substituting 102d for hydroxyproline, followed by hydrolysis of the ethyl ester as described in Example 106. [M+Na] ⁺ = 588.46.

Embodiment 103. The compound of Formula II wherein A=tBOC, G= OH , L=absent, W is X and Y taken together = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by following the RCM method described in Example 1, substituting 102c for hydroxyproline, followed by hydrolysis of the ethyl ester as described in Example 106.

[M+Na] ⁺ = 588.50.

X＝Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 104. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X=Y=phenyl, j=3, m=s=1 and R3 ⁼ R4 ⁼ H .

The corresponding triazole-substituted proline of the title compound was prepared by dissolving 1.5 mmol (0.5 g) of hydroxyproline mesylate 102a and 4.5 mmol of benzotriazole 102b in 5 ml DMF and adding 9 mmol (2.9 g) of cesium carbonate , and the resulting reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo.

The title compound was prepared by substituting the triazole-substituted proline of this example for hydroxyproline according to the RCM method described in Example 1, followed by hydrolysis of the ethyl ester as described in Example 106.

[M+Na] ⁺ = 690.42.

X＝Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 105. The compound of formula II wherein A=tBOC, G= OEt , L=absent, W is

X=Y=phenyl, j=3, m=s=1 and R3 ⁼ R4 ⁼ H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 2 and 0.123 mmol of 4,5-diphenyltriazole were dissolved in 3 ml of DMF, 0.246 mmol of cesium carbonate (80 mg) was added, and reacted at 70°C for 12 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate (2 x 30ml) and water (2 x 30ml). The resulting organic solution was concentrated to dryness in vacuo.

Embodiment 106. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is X=Y=phenyl, j=3, m=s=1 and R3 ⁼ R4 ⁼ H .

The title compound was prepared as follows: dissolve 0.041 mmol of the title compound of Example 105 in 3 ml of dioxane, add 2 ml of 1M LiOH, and react at room temperature for 8 h. Subsequently, the reaction mixture was adjusted to pH 3 with citric acid, extracted with EtOAc, and washed with brine and water. The organic solution was concentrated in vacuo and purified by HPLC.

[M+Na] ⁺ = 690.42.

X＝Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 107. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X=Y=phenyl, j=3, m=s=1 and R3 ⁼ R4 ⁼ H .

The triazole-substituted proline precursor of the title compound was prepared as follows: 0.93 mmol (0.25 g) azidoproline 100a and 1 mmol diphenylacetylene were dissolved in 2 ml xylene, heated to 110° C., and stirred for 12 h. The reaction mixture was directly isolated by silica column to obtain 0.27 g of 107a (90%). [M+H] ⁺ : 449.05. 0.26 g of 107b (99%) was obtained by the hydrolysis procedure described in Example 105.

The title compound was prepared by following the RCM method described in Example 1, substituting 107b for hydroxyproline.

[M+Na] ⁺ = 691.99.

Embodiment 108. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is X = n-propyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

108a Preparation of triazoles

4-(n-Propyl)-5-phenyltriazole was prepared according to the method of Example 98 using n-propylphenylacetylene and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(n-propyl)-5-phenyltriazole 108a according to the method of Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106.

[M+Na] ⁺ = 657.99.

X＝间甲氧基苯基，Y＝对甲氧基苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 109. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

109a Preparation of alkynes

2-(m-Methoxyphenyl)-4-methoxyphenylacetylene was prepared according to the method of Example 99A using 4-methoxyphenylacetylene and 3-bromoanisole.

109b Preparation of Triazoles

4-(m-methoxyphenyl)-5-(p-methoxyphenyl)triazole was prepared according to the method of Example 3 using alkyne 109a and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 and 4-(m-methoxyphenyl)-5-(-p-methoxyphenyl)-triazole 109a according to the method of Example 105, followed by implementing The method of Example 106 hydrolyzed the ethyl ester.

[M+Na] ⁺ = 752.08.

Embodiment 110. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is X = m-bromophenyl, Y = p-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

110a Preparation of alkynes

2-(m-Bromophenyl)-4-methoxyphenylacetylene was prepared by the method of Example 99A using 4-methoxyphenylacetylene and 3-iodo-5-bromobenzene.

110b Preparation of triazoles

4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole was prepared according to the method of Example 3 using alkyne 110a and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole 110a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+Na] ⁺ = 800.05.

X＝1-萘基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 111. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

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

111a Preparation of alkynes

2-(1-Naphthyl)-4-methoxyphenylacetylene was prepared using 1-iodonaphthalene and 4-methoxyphenylacetylene according to the method of Example 99A.

111b Preparation of Triazoles

According to the method of Example 3, 4-(m-bromophenyl)-5-(p-methoxyphenyl) was prepared with 2-(1-naphthyl)-4-methoxyphenylacetylene 113a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(1-naphthyl)-5-(p-methoxyphenyl)triazole 113d according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+Na] ⁺ = 772.11.

X＝2-噻吩基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H Embodiment 112. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

112a Preparation of alkynes

2-(2-Thienyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 99A using 2-iodo-thiophene and 4-methoxyphenylacetylene.

112b Preparation of triazoles

According to the method of Example 3, 4-(2-thienyl)-5-(p-methoxyphenyl) was prepared with 2-(2-thienyl)-4-methoxyphenylacetylene 112a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(2-thienyl)-5-(p-methoxyphenyl)triazole 112a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+H] ⁺ = 705.31.

X＝3-噻吩基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 113. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

113a Preparation of alkynes

2-(3-Thienyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 99a using 2-iodo-thiophene and 4-methoxyphenylacetylene.

113b Preparation of Triazoles

According to the method of Example 3, 4-(3-thienyl)-5-(p-methoxyphenyl) was prepared with 2-(3-thienyl)-4-methoxyphenylacetylene 113a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(3-thienyl)-5-(p-methoxyphenyl)triazole 113a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+Na] ⁺ = 727.21.

X＝4-吡唑基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 114. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

114a Preparation of alkynes

2-(4-Pyrazolyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 99A using 4-iodopyrazole and 4-methoxyphenylacetylene.

114b Preparation of Triazoles

Prepare 4-(4-pyrazolyl) 5-(p-methoxyphenyl) with 2-(4-pyrazolyl)-4-methoxyphenylacetylene 114a and sodium azide according to the method of Example 3 ) triazole.

The title compound was prepared by reacting the title compound of Example 2 and 4-(4-pyrazolyl)-5-(p-methoxyphenyl)triazole 114a according to the method of Example 105, followed by the reaction of Example 106 Methods Hydrolysis of ethyl esters.

[M+H] ⁺ = 700.82.

Embodiment 115. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is X = 3-pyridyl, Y = p-methoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

115a Preparation of alkynes

2-(3-Pyridyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 99A using 3-iodopyridine and 4-methoxyphenylacetylene.

115b Preparation of Triazoles

According to the method of Example 3, 4-(3-pyridyl)-5-(p-methoxyphenyl) was prepared with 2-(3-pyridyl)-4-methoxyphenylacetylene 115a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(3-pyridyl)-5-(p-methoxyphenyl)triazole 115a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+H] ⁺ = 700.36.

X＝2-吡啶基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Example 116. Compound of Formula II. Wherein A=tBOC, G= OH , L=absent, W is

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

116a Preparation of alkynes

2-(2-Pyridyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 99A using 2-iodopyridine and 4-methoxyphenylacetylene.

116b Preparation of Triazoles

According to the method of Example 3, 4-(2-pyridyl)-5-(p-methoxyphenyl) was prepared with 2-(2-pyridyl)-4-methoxyphenylacetylene 116a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(2-pyridyl)-5-(p-methoxyphenyl)triazole 116a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters. [M+H] ⁺ = 700.82.

X＝2-噻唑基，Y＝对甲氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 117. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

117A. Preparation of alkynes

The alkyne 2-(2-thiazolyl)-4-methoxyphenylacetylene of this example is prepared as follows: in 10 ml of acetonitrile degassed solution of 4 mmol 4-ethynyl anisole, 4 mmol 2-bromothiazole and 1 ml triethylamine 140 mg (0.2 mmol) PdCl ₂ (PPh ₃ ) ₂ and 19 mg (0.1 mmol) CuI were added. The mixture was degassed, stirred at room temperature for 5 min, and heated to 90 °C for 12 h. The reaction mixture was concentrated in vacuo and purified by silica column to obtain 0.61 g of brown liquid, 70% yield.

[M+H] ⁺ : 216.17, ¹ HNMR (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 of triazoles

4-(2-Thiazolyl)-5-(p-methoxyphenyl)triazole 117d was prepared by adding 0.3 g of 117c, 0.74 ml of trimethylsilyl azide and 4 ml of xylene to a pressure tube and heating the mixture to 140 ℃ 48h. The reaction mixture was directly separated by a silica column to obtain a brown liquid (117d) (0.18 g, 50%) after purification.

[M+H] ⁺ : 259.27, ¹ H NMR (DMSO-d ₆ ), 500 MHz) 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 was prepared as follows:

Dissolve 0.041 mmol mesylate macrocyclic precursor 117d and 0.123 mmol 117d in 3 ml DMF, add 0.24 mmol cesium carbonate, and react at 70°C for 12 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate (2x30ml) and water (2x30ml), concentrated in vacuo to give ethyl ester 117e.

[M+H] ⁺ : 734.34

Preparation of the title compound

Ethyl ester 117c was hydrolyzed as follows: 117e was dissolved in 3 ml of dioxane, 2 ml of 1M LiOH was added, and the resulting reaction mixture was stirred at room temperature for 8 h. The pH of the reaction mixture was adjusted to 3 with citric acid; the reaction mixture was then extracted with EtOAc, washed with brine and water. The organic solution was concentrated in vacuo and purified by HPLC to obtain a yellow powder (10 mg, yield 34%) after lyophilization.

[M+H] ⁺ : 706.33, ¹ H NMR (DMSO-d ₆ , 500MHz) δ12.283(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).

X＝苄基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 118. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

118a Preparation of alkynes

2-(Benzyl)-4-methoxyphenylacetylene was prepared following the procedure of Example 117A using 4-iodobenzene and 3-phenyl-propyne.

118b Preparation of Triazoles

4-(benzyl)-5-(p-methoxyphenyl)triazole was prepared according to the method of Example 3 using 2-(benzyl)-4-methoxyphenylacetylene 118a and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(2-benzyl)-5-(p-methoxyphenyl)triazole 118a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+H] ⁺ = 700.82.

X＝正丁基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 119. The compound of formula II, wherein A=tBOC, G= OH , L=absent, W is

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

119a Preparation of triazoles

According to the method of Example 3, 4-(n-butyl)-5-phenyltriazole was prepared from n-butyl-1-phenylacetylene and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(n-butyl)-5-phenyltriazole 119a according to the method of Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106.

[M+H] ⁺ = 649.44.

X＝正丙基，Y＝正丙基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 120. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X = n-propyl, Y = n-propyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

120a Preparation of triazoles

According to the method of Example 3, 4,5-(n-propyl)triazole was prepared with 4-octene and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4,5-(n-propyl)triazole 120a according to the method of Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106.

[M+H] ⁺ = 601.46.

X＝4-(N，N-二甲基氨基)苯基，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 121. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

121A. Bromination reaction

Bromine-substituted phenyltriazole 121b was prepared as follows: 1 mmol of 121a (triazole 121a was prepared by the method described in Example 2 using commercially available phenylacetylene and sodium azide) was dissolved in 16 ml of 1:15 MeOH/CHCl ₃ , and 0.28 mol of TEA, add dropwise 0.128ml of bromine. The resulting reaction mixture was stirred for 2 h. 10% cold _Na2S2O5 was added to the reaction _mixture until the mixture became _colorless . The mixture was extracted with EtOAc, washed with brine and water, dried over sodium sulfate and concentrated in vacuo to afford 0.216 g of 121b (97%) after purification on a silica column.

[M+H] ⁺ : 224.19.

121B. Mesylate displacement reaction. Purified 121b and the title compound of Example 2 were used to prepare 0.2 g of 121c as described in Example 3.

[M+Na] ⁺ : 721.00.

121C. Suzuki coupling reaction. Ethyl ester 121d was prepared as follows: 0.07 mmol (50 mg) 121c was dissolved in 3 ml DME, and 0.21 mmol (35 mg) 4-dimethylaminophenylboronic acid, 137 mg cesium carbonate, 100 mg KF were added to this solution. The reaction mixture was subsequently degassed, to which 5 mg of Pd(PPh ₃ ) ₄ was added. The resulting reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was then extracted with EtOAc, washed with brine and water, dried over Na2SO4, concentrated in vacuo and purified with silica column to obtain 40 mg (78% yield) of 121d.

121D. Hydrolysis of ethyl esters. Reaction with 121d as described in 106 gave 12 mg of 121e (30%) after HPLC purification.

[M+H] ⁺ : 712.33.

X＝(N，N-二乙基氨基)甲基，Y＝苯基，j＝3，m＝s＝1且 R ³ ＝R ⁴ ＝H。 Embodiment 122. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

122a Preparation of triazoles

According to the method of Example 3, 4-(N,N-diethylaminomethyl)-5-phenyltriazole was prepared by using 3-diethylamino-1-phenylpropyne and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(N,N-diethylaminomethyl)-5-phenyltriazole 122a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+H] ⁺ = 678.44.

X＝N，N-二乙基氨基羰基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 123. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

123A. Preparation of alkynes

Alkyne 123a was prepared by dissolving 10 mmol phenylpropiolic acid, 11 mmol BOP, 22 mmol DIEA in 15 ml DMF, to which 11 mmol diethylamine was added. The resulting reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was extracted with EtOAc (2x50ml), washed with 1M _NaHCO3 (2x30ml), water (2x30ml), 5% citric acid (2x50ml), brine (2x30ml). The organic extract was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to obtain 1.8 g (90%) of 123a[M+H] ⁺ : 202.09.

123B. Preparation of triazoles

4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b was prepared according to the method of Example 3 using 123a and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b according to the method of Example 105, followed by hydrolysis by the method of Example 106 ethyl ester.

[M+H] ⁺ : 692.47.

X＝间氯苯基，Y＝4-乙氧基苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 124. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

X = m-chlorophenyl, Y = 4-ethoxyphenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

124a Preparation of Alkynes

2-(m-Chlorophenyl)-4-methoxyphenylacetylene was prepared according to the method of Example 99 using 3-chloro-bromobenzene and 4-methoxyphenylacetylene.

124b Preparation of Triazoles

According to the method of Example 3, 4-(m-chlorophenyl)-5-(p-methoxyphenyl) was prepared with 2-(m-chlorophenyl)-4-methoxyphenylacetylene 124a and sodium azide triazole.

The title compound was prepared by reacting the title compound of Example 2 with 4-(m-chlorophenyl)-5-(p-methoxyphenyl)triazole 124a according to the method of Example 105, followed by the method of Example 106 Hydrolysis of ethyl esters.

[M+H] ⁺ ＝747.37.

X＝2-苯基乙烯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 125. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

The title compound was prepared by the Suzuki reaction described in Example 121 using 121c and phenylvinylboronic acid, followed by hydrolysis as described in Example 106.

[M+H] ⁺ = 695.30.

Example 126. Compound of Formula II Where A=tBOC, G= OH , L=absent, W is 5,6-methylbenzotriazole, j=3, m=s=1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the title compound of Example 2 with 5,6-methylbenzotriazole according to the method of Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106.

[M+H] ⁺ = 595.42.

Embodiment 127. The compound of formula II, wherein A = tBOC, G = OH , L = absent, W is X = N-ethylaminocarbonyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

127a. Preparation of alkynes

Alkyne 127a was prepared by dissolving 10 mmol phenylpropiolic acid, 11 mmol BOP, 22 mmol DIEA in 15 ml DMF, to which 11 mmol ethylamine was added. The resulting reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was extracted with EtOAc (2x50ml), washed with 1M _NaHCO3 (2x30ml), water (2x30ml), 5% citric acid (2x50ml), brine (2x30ml). The organic extract was dried over _{anhydrous Na2SO4} and concentrated in vacuo to afford 1.8 g (90%) of 127a. [M+H] ⁺ : 177.09.

127b Preparation of Triazoles

4-(N-ethylaminocarbonyl)-5-phenyltriazole was prepared according to the method of Example 3 using 127a and sodium azide.

The title compound was prepared by reacting the title compound of Example 2 with 4-(N-ethylaminocarbonyl)-5-phenyltriazole 127b according to the method of Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106.

Embodiment 128. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

128a-deprotection of amine

0.041 mmol of the title compound of Example 105 was dissolved in 4 ml of 4M HCl in dioxane, and stirred for 1 h. The reaction residue 128a was concentrated in vacuo.

128b-chloroformate reagent

Chloroformate reagent 128b was prepared by dissolving 0.045 mmol cyclopentanol in THF (3 ml) and adding 0.09 mmol phosgene in toluene (20%). The resulting reaction mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo. DCM was added to the residue, followed by concentration to dryness in vacuo twice to afford the chloroformate reagent 128b.

128c - Preparation of carbamates

The title carbamate was prepared by dissolving the residue 128a in 1 ml THF, adding 0.045 mmol TEA, and cooling the resulting reaction mixture to 0 °C. To the 0°C reaction mixture was added a solution of chloroformate reagent 128b in 3 ml THF. The resulting reaction mixture was reacted at 0 °C for 2 h, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified by silica column, and then the ethyl ester was hydrolyzed according to the method of Example 106.

Embodiment 129. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclobutyl, G = OH , L = absent, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the title compound of Example 105 with cyclobutanol as described in Example 33, followed by hydrolysis of the ethyl ester as described in Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 130. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclohexyl, G = OH , L = absent, W is

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

The title compound was prepared by reacting the title compound of Example 105 with cyclohexanol as described in Example 33, followed by hydrolysis of the ethyl ester as described in Example 106.

G＝OH， L＝不存在，W为

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 131. The compound of Formula II wherein A= -(C=O)-OR ¹ ,

G = OH , L = not present, W is

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

The title compound was prepared by reacting the title compound of Example 105 with (R)-3-hydroxytetrahydrofuran as described in Example 33, followed by hydrolysis of the ethyl ester as described in Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 132. The compound of Formula II wherein A= -(C=O)-OR ¹ , G = OH , L = not present, W is

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

The title compound was prepared by reacting the title compound of Example 105 with (S)-3-hydroxytetrahydrofuran according to the method of Example 33, followed by hydrolysis of the ethyl ester as described in Example 106.

G＝OH， L＝不存在，W为 X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 133. The compound of Formula II wherein A= -(C=O)-OR ¹ ,

G = OH , L = not present, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

反应，然后按照实施例106介绍的方法水解乙酯。The title compound was prepared by following the method of Example 33 using the title compound of Example 105 and

reaction, followed by hydrolysis of the ethyl ester as described in Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 134. The compound of formula II wherein A = -(C=O)-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

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

The title compound was prepared by dissolving 0.041 mmol of the title compound of Example 105 in 4 ml of 4M HCl in dioxane and stirring the reaction mixture for 1 h. The reaction residue was concentrated in vacuo. To this residue were added 4 ml of THF and 0.045 mmol of TEA, the mixture was cooled to 0°C, and 0.045 mmol of cyclopentanoyl chloride was added thereto. The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified by silica column and then the ethyl ester was hydrolyzed as described in Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 135. The compound of formula II wherein A = -(C=O)-NH-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

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

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 105 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. To the solution at 0 °C was added 0.045 mmol of cyclopentyl isocyanate, and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was then extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column, followed by hydrolysis of the ethyl ester as described in Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 136. The compound of formula II wherein A = -(C=S)-NH-R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is

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

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 105 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. To the solution at 0 °C was added 0.045 mmol of cyclopentyl isothiocyanate, and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was then extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column, followed by hydrolysis of the ethyl ester as described in Example 106.

Embodiment 137. The compound of formula II wherein A = -S(O) ₂ -R ¹ , R ¹ = cyclopentyl, G = OH , L = absent, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as follows: 0.041 mmol of the title compound of Example 105 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The resulting concentrated reaction residue was dissolved in 4 ml of THF, 0.045 mmol of TEA was added thereto, and cooled to 0°C. To the 0 °C solution was added 0.045 mmol of cyclopentylsulfonyl chloride, and the resulting reaction mixture was stirred at 0 °C for 2 h. The solution was then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified by silica column, and then the ethyl ester was hydrolyzed according to the method of Example 106.

X＝苯基，Y＝苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 137. The compound of formula II wherein A= -(C=0)-OR ¹ , R ¹ =cyclopentyl, G=-O -phenethyl, L=absent, W is

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

The title compound was prepared by adding 1.2eq. The resulting reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to room temperature over 4-12 h. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexane:EtOAc as eluent phase (9:1→5:1→3:1→1:1) to afford the title compound phenethyl ester 138b.

Other esters can be prepared in the same way.

X＝苯基，Y＝苯基，j＝3，m＝s＝1 且R ³ ＝R ⁴ ＝H。 Embodiment 139. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -NH- phenethyl, L = absent, W is

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

The title compound was prepared by adding EDC (1.2 eq.) and DIEA (4 eq.) to a solution of the title compound of Example 128 and phenethylamine 139a (0.05 ml) in 0.5 ml DMF at 0°C. The resulting reaction mixture was stirred for 1 h. Subsequently, the reaction was warmed to room temperature over 4-12 h. The reaction mixture was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→ ⁵ :1→3:1→1:1 as eluent phase)) to afford the title compound phenethylamide 139b.

Other amides can be prepared in the same way.

X＝苯基，Y＝苯基，j＝3， m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 140. The compound of formula II wherein A = -(C=O)-OR ¹ , R ¹ = cyclopentyl, G = -O -NHS(O) ₂ -phenethyl, L = absent, W is

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

The title compound was prepared by adding 1.2eq. The resulting reaction mixture was stirred for 1 h, then allowed to warm to room temperature over 4-12 h. The reaction mixture was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound sulfonamide 140b.

Other sulfonamides can be prepared in the same way.

Embodiment 141. The compound of Formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G= -(C=O)-OH , L=absent, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by adding α-hydroxy-α-methyl-propionitrile (0.1 ml) and a catalytic amount of TFA to a solution of the title compound of Example 128 in 0.5 ml THF at 0°C. The resulting reaction mixture was heated from 0° C. to room temperature over 4-12 h, then hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction was extracted with EtOAc, washed with water and brine to obtain the crude product of α-hydroxy compound 141a. Crude compound 46b was subjected to Dess-Martin oxidation in THF (0.5 ml) to give the crude product of α-carbonyl compound 46b. Crude 141b was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound ketoacid 141c.

X＝苯基，Y＝苯基，j＝3， m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 142. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-phenethyl, L=absent, W is

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

The title compound was prepared as described in Example 138 using the title compound ketoacid from Example 141 and phenylethyl alcohol.

Embodiment 143. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-NH-phenethyl, L=absent, W is X = phenyl, Y = phenyl, j = 3, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared as described in Example 139 using the title compound ketoacid from Example 141 and phenethylamine.

X＝苯基，Y＝苯基， j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 144. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-NH-S(O) ₂ -benzyl, L= does not exist, W is

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

The title compound was prepared by the method described in Example 140 using the title compound ketoacid from Example 141 and α-toluenesulfonamide.

X＝苯基，Y＝苯基，j＝1，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 145. The compound of Formula II wherein A=tBOC, G= OH , L= -(C=O)CH ₂ - and W is

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

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 88C with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝1，m＝s＝1且R ³ ＝甲基且R ⁴ ＝H。 Embodiment 146. The compound of Formula II wherein A=tBOC, G= OH , L= -CH(CH ₃ )CH ₂ - , and W is

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

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 89G with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝0，m＝s＝1，R ³ ＝甲基且R ⁴ ＝H。 Embodiment 147. The compound of Formula II wherein A=tBOC, G= OH , L= -O- , and W is

X=phenyl, Y=phenyl, j=0, m=s=1, R ³ =methyl and R ⁴ = H .

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 90D with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

Embodiment 148. The compound of formula II wherein A=tBOC, G= OH , L= -S- , and W is X = phenyl, Y = phenyl, j = 0, m = s = 1, R ³ = methyl and R ⁴ = hydrogen.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 91E with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝2，m＝s＝1，R ³ ＝甲基且R ⁴ ＝氢。 Embodiment 149. The compound of Formula II wherein A=tBOC, G= OH , L= -S(O)- , and W is

X = phenyl, Y = phenyl, j = 2, m = s = 1, R ³ = methyl and R ⁴ = hydrogen.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 92B with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝2，m＝s＝1，R ³ ＝甲基且R ⁴ ＝ ^H 。 Embodiment 150. The compound of Formula II wherein A=tBOC, G= OH , L= -S(O) ₂ - , and W is

X = phenyl, Y = phenyl, j = 2, m = s = 1, R ³ = methyl and R ⁴ = ^H .

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 93B with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

Embodiment 151. The compound of Formula II wherein A=tBOC, G= _OH , L= _-SCH2CH2- , W is X = phenyl, Y = phenyl, j = 0, m = s = 1 and R ³ =R ⁴ = CH ₃ .

151A. Synthesis of (S)-N-Boc-2-amino-3-methyl-3(1-mercapto-4-butenyl)butanoic acid (151b)

L-penicillamine 151a was dissolved in DMF/DMSO (5:1), then, 4-bromopentene and CsOH·H ₂ O were added to the mixture, and stirring was continued for another 12 h. DMF was then removed in vacuo and the remaining mixture was diluted with 0.5N HCl at 0°C to bring the pH to ~4-5, then extracted twice with EtOAC. The organic phase was washed with brine (2x), dried over magnesium sulfate and evaporated to dryness to give crude carboxylic acid 151a.

151B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate was prepared as follows: use the modified amino acid 151a to replace Boc-L-2-amino-8-nonenoic acid 1a according to the synthetic route of Example 1, and then follow the method described in Example 2 Conversion to the corresponding mesylate.

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in 151B with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by hydrolysis of ethanol as described in Example 106 ester.

Embodiment 152. The compound of Formula II wherein A=tBOC, G= _OH , L= _-CF2CH2- , W is X = phenyl, Y = phenyl, j = 1, m = s = 1 and R ³ =R ⁴ = H .

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 95C with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝1，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 153. The compound of Formula II wherein A=tBOC, G= OH , L= -CHFCH ₂ - and W is

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

The title compound was prepared by reacting the modified cyclic peptide precursor mesylate generated in Example 96C with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by the method described in Example 106 Hydrolysis of ethyl esters.

X＝苯基，Y＝苯基，j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 154. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

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

154A. Preparation of saturated cyclic peptide precursor mesylate by catalytic reduction of mesylate cyclic peptide precursor 2 with Pd/C-containing MeOH in the presence of hydrogen.

The title compound was prepared by reacting the saturated cyclic peptide precursor mesylate formed in 154A with 4,5-diphenyltriazole according to the displacement method described in Example 105, followed by hydrolysis of the ethyl ester as described in Example 106 .

j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 155. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

j=3, m=s=1 and R ³ =R ⁴ = H .

155A. Preparation of Substituted Benzotriazoles

The bromine-substituted benzotriazole 155b of this example was prepared as follows: 2.15 g (10 mmol) of 5-bromo-3,4-dimethylbenzene-1,2-diamine, 1.15 mol (20 mmol) of glacial acetic acid and 10 ml Water was mixed and the resulting mixture was heated to obtain a clear solution. The clear solution was then cooled to 5 °C, a cold solution of 0.83 g (12 mmol) sodium nitrite in 5 ml water was added and the reaction mixture was heated to 70-80 °C for 2 h. The reaction mixture was extracted with EtOAc, washed with brine and water, dried over sodium sulfate and concentrated in vacuo. The crude product was purified with a silica column.

155B. Displacement reactions

Ethyl ester 155c was prepared following the displacement procedure described in Example 105 using the title compound of Example 2 and bromo-substituted benzotriazole 155b.

The title compound was finally prepared by hydrolysis as described in Example 106 using ethyl ester 155c.

j＝3，m＝s＝1且R ³ ＝R ⁴ ＝H。 Embodiment 156. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is

j=3, m=s=1 and R ³ =R ⁴ = H .

156A.Suzuki reaction

Compound 156a of this example was prepared using 155c and 3-thienylboronic acid following the Suzuki coupling described in Example 26C.

156B. Hydrolysis reactions

The title compound was prepared following the hydrolysis procedure described in Example 106 using ethyl ester 156a.

Embodiment 157. The compound of formula II wherein A=tBOC, G= OH , L=absent, W is j=3, m=s=1 and R ³ =R ⁴ = H .

157a. Preparation of bicyclic compounds

Bicyclic compounds of this invention were prepared using 2,3-diaminopyridine following the procedure described in Example 157A.

The title compound was prepared by reacting the bicyclic compound prepared from 157a with the title compound of Example 2 following the displacement procedure described in Example 105, followed by hydrolysis of the ethyl ester as described in Example 106.

Embodiment 158. The compound of formula II wherein A=tBOC, G= OEt , L=absent, X=Y= bromine, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R4 ⁼ hydrogen.

Macrocycle 1 (185 mg, 0.38 mmol), 4,5-dibromo-2H-pyridazin-3-one (95 mg, 0.38 mmol) and triphenylphosphine (197 mg, 0.75 mmol) in THF ( 5 mL) to the mixture was added dropwise DIAD (148 μL, 0.75 mmol). After stirring at 0 °C for 15 min, the solution was warmed to room temperature and stirred for a further 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (eluting with 40% ethyl acetate-hexanes) to give 235 mg (86%) of the title compound.

¹ H-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.

Example 159. Compound of Formula II Where A=tBOC, G= OEt , L=absent, X=Y= thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

A mixture of the title compound of Example 162 (40 mg, 0.055 mmol), 3-thiophene boronic acid (35 mg, 0.28 mmol), cesium carbonate (71 mg, 0.22 mmol), potassium fluoride monohydrate (41 mg, 0.44 mmol) was added to the circle The bottom flask was purged twice with nitrogen. To this mixture was added DME, nitrogen was bubbled again into the resulting solution, and then tetrakis(triphenylphosphine)palladium (7 mg, 10 mol%) was added. Nitrogen was bubbled in two more times, and the mixture was heated to reflux for 20 h. The mixture was then cooled, diluted with water and extracted three times with EtOAc. The combined EtOAc layers were washed once with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluting with 20-40% EtOAc-hexanes) to give the title compound (24 mg, 60%) as a clear film.

¹ H-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. Compound of Formula II Where A=tBOC, G= OH , L=absent, X=Y= thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

Lithium hydroxide (14 mg, 0.33 mmol) was added to a solution of the title compound of Example 2 (24 mg, 0.033 mmol) in THF/MeOH/H ₂ O (2/1/0.5 mL). After stirring at room temperature for 16 h, the mixture was acidified to pH 4 with citric acid and extracted three times with EtOAc. The combined organic extracts were washed once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (eluting with 5-10% methanol-chloroform) to give the title compound (13 mg, 56%).

[M+H] ⁺ = 708.3.

Embodiment 161. Compounds of Formula II Where A=tBOC, G= OH , L=absent, X=Y= phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen .

The title compound was prepared by double Suzuki coupling with phenylboronic acid and the title compound from Example 158 as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ ＝696.40

Embodiment 162. The compound of formula II, wherein A=tBOC, G= OH , L=absence, X=Y=4-(N,N-dimethylamino)phenyl, Z=hydrogen, j=3, m =s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by double Suzuki coupling reaction with 4-(N,N-dimethylamino)phenylboronic acid and the title compound of Example 158 as described in Example 159, followed by hydrolysis as described in Example 160 ethyl ester.

[M+H] ⁺ ＝782.30

Embodiment 163. The compound of formula II, wherein A=tBOC, G= OH , L=absence, X=Y=4-(trifluoromethoxy)phenyl, Z=hydrogen, j=3, m=s= 1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by double Suzuki coupling reaction with 4-(trifluoromethoxy)phenylboronic acid and the title compound of Example 158 as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ ＝864.09

Embodiment 164. The compound of formula II wherein A=tBOC, G= OH , L=absent, X=Y=4-(methylsulfonyl)phenyl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by double Suzuki coupling with 4-(methylsulfonyl)phenylboronic acid and the title compound of Example 158 as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

Example 165. Compound of Formula II Where A=tBOC, G= OH , L=absent, X=Y=4-(cyano)phenyl, Z=hydrogen, j=3, m=s=1 and R ³ = R ⁴ = hydrogen.

The title compound was prepared by double Suzuki coupling reaction with 4-cyanophenylboronic acid and the title compound of Example 158 as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ ＝746.14

Example 166. Compound of Formula II Where A=tBOC, G= OH , L=absent, X=Y= pyridin-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

The title compound was prepared by double Suzuki coupling reaction with 3-pyridylboronic acid and the title compound of Example 158 as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ = 698.3.

Embodiment 167. The compound of formula II, wherein A=tBOC, G= OH , L=absence, X=Y=4-(morpholin-4-yl-formyloxy)phenyl, Z=hydrogen, j= 3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by double Suzuki coupling reaction with 4-carboxyphenylboronic acid and the title compound of Example 158 as described in Example 159, followed by morpholine under standard amide bond forming conditions (e.g. PyBrOP, DIEA, DMAP DMF solution) to form amides. The ethyl ester of the resulting compound was then hydrolyzed by the method of Example 160.

Example 168. Compound of Formula II Where A=tBOC, G= OH , L=absent, X= bromo, Y=methoxy, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R ⁴ = Hydrogen.

The title compound was prepared by hydrolysis of the ethyl ester using the title compound of Example 158 following the procedure of Example 160, but in addition to the hydrolysis of the ethyl ester, addition of the methoxy group at the 5-position was observed.

[M+H] ⁺ = 652.2, 654.2.

Example 169. The compound of formula II wherein A=tBOC, G= OH , L=absent, X and Y taken together=phenyl, Z=4-methoxyphenyl, j=3, m=s= 1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by reaction with commercially available 4-(4-methoxy-phenyl)-2H-phthalazin-1-one according to the Mitsunobu conditions described in Scheme 20, followed by hydrolysis of the ethyl ester by the method of Example 160.

[M+H] ⁺ = 700.1.

Embodiment 170. The compound of formula II, wherein A=tBOC, G= OH , L=absent, X and Y taken together=phenyl, Z=4-chlorophenyl, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by reaction with commercially available 4-(4-chloro-phenyl)-2H-phthalazin-1-one according to the Mitsunobu conditions described in Scheme 20, followed by hydrolysis of the ethyl ester by the method of Example 160.

[M+H] ⁺ = 704.2.

Embodiment 171. Compounds of Formula II Where A=tBOC, G= OH , L=absent, X=4- fluorophenyl, Y=hydrogen, Z=phenyl, j=3, m=s=1 and R ³ = R ⁴ = hydrogen.

The title compound was prepared by reacting commercially available 4-(4-fluoro-phenyl)-6-phenyl-2H-pyridazin-3-one according to the Mitsunobu conditions described in Scheme 20, followed by hydrolysis of ethanol by the method of Example 160 ester.

[M+H] ⁺ = 704.2.

Example 172. Compounds of Formula II Where A=tBOC, G= OH , L=absent, X= hydrogen, Y=1-piperidinyl, Z=phenyl, j=3, m=s=1 and R ³ = R ⁴ = hydrogen.

The title compound was prepared by reaction with commercially available 6-phenyl-5-piperidin-1-yl-2H-pyridazin-3-one according to the Mitsunobu conditions described in Scheme 20, followed by hydrolysis of the ethyl ester by the method of Example 160.

[M+H] ⁺ = 702.3.

Embodiment 173. Compounds of Formula II Where A=tBOC, G= OEt , L=absent, X= hydrogen, Y=bromine, Z=phenyl, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

The title compound was prepared according to the Mitsunobu conditions described in Scheme 20 using commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one.

[M+H] ⁺ = 726.3, 728.3.

Example 174. Compound of Formula II Where A=tBOC, G= OH , L=absent, X= hydrogen, Y=thiophen-3-yl, Z=phenyl, j=3, m=s=1 and R ³ = R ⁴ = hydrogen.

The title compound was prepared by reacting the title compound of Example 173 with thiophen-3-ylboronic acid under the Suzuki coupling conditions described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ ＝730.3

Example 175. Compound of Formula II Where A=tBOC, G= OEt , L=absent, X= bromo, Y=1-pyrrolidinyl, Z=hydrogen, j=3, m=s=1 and ^R3 =R ⁴ =hydrogen.

A mixture of the title compound of Example 158 (45mg, 0.062mmol), pyrrolidine (21mL, 0.25mmol), potassium carbonate (34mg, 0.25mmol) and 2ml of acetonitrile was heated to reflux for 3h, and after cooling to room temperature, the Filter the mixture through a funnel, and concentrate the filtrate in vacuo. The residue was redissolved in ethyl acetate, then washed once with saturated sodium carbonate, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue, which was purified by silica gel chromatography (washed with 3% methanol-chloroform de) yielded 37 mg (83%) of the title compound.

[M+H] ⁺ = 719.2, 721.2.

Embodiment 176. The compound of formula II, wherein A = tBOC, G = OH , L = absent, X = thiophen-3-yl, Y = 1-pyrrolidinyl, Z = hydrogen, j = 3, m = s = 1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by reacting the title compound of Example 175 with thiophen-3-ylboronic acid under Suzuki conditions as described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

[M+H] ⁺ = 694.3.

Example 177. Compound of Formula II Where A=tBOC, G= OEt , L=absent, X= bromo, Y=azido, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R ⁴ = Hydrogen.

A mixture of the title compound of Example 158 (45 mg, 0.062 mmol), sodium azide (16 mg, 0.25 mmol), potassium carbonate (34 mg, 0.25 mmol) and 2 mL of acetonitrile was heated to reflux for 3 h. After cooling to room temperature, the mixture was filtered through a fritted glass funnel, and the filtrate was concentrated in vacuo. The residue was redissolved in ethyl acetate, then washed once with saturated sodium carbonate, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue, which was purified by silica gel chromatography (washed with 3% methanol-chloroform de) yielded 37 mg (83%) of the title compound.

Embodiment 178. The compound of formula II wherein A=tBOC, G= OEt , L=absence, X= thiophen-3-yl, Y=azido, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared under the Suzuki conditions described in Example 159 using the title compound of Example 177 and thiophen-3-ylboronic acid.

Embodiment 179. The compound of formula II wherein A=tBOC, G= OH , L=absent, X= thiophen-3-yl, Y=azido, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by hydrolyzing the ethyl ester of the title compound in Example 178 according to the method of Example 160.

Example 180. Compound of Formula II Wherein A=tBOC, G= OH , L=absent, X= thiophen-3-yl, Y=tetrazol-2-yl, Z=hydrogen, j=3, m=s =1 and R ³ =R ⁴ =hydrogen.

To a solution of the title compound of Example 178 (2.63 mmol) in toluene (8 ml) were added KCN (10.5 ³ mmol) and Et ₃ N·HCl (10.53 mmol). The mixture was heated at 115 °C for 18 h, diluted with DCM, washed with 5% citric acid (aq), dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product of the ethyl ester of the title compound. The ethyl ester was hydrolyzed according to the method of Example 160 to obtain the title compound.

Example 181. Compound of Formula II Where A=tBOC, G= OH , L=absent, X=Y= mercapto-2-pyrimidine, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R ⁴ = Hydrogen.

A mixture of the title compound of Example 158 (45 mg, 0.062 mmol), pyrimidine-2-thiol (0.25 mmol), potassium carbonate (34 mg, 0.25 mmol) and 2 mL of acetonitrile was heated to reflux for 3 h. After cooling to room temperature, the mixture was filtered through a fritted glass funnel, and the filtrate was concentrated in vacuo. The residue was redissolved in ethyl acetate, then washed once with saturated sodium carbonate, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a yellow residue, which was purified by silica gel chromatography (washed with 3% methanol-chloroform off) to obtain 181b in 19% yield. The ethyl ester of compound 181b was hydrolyzed as described in Example 160 to give the title compound.

[M+H] ⁺ = 764.3.

Example 182. Compound of Formula II Where A=tBOC, G= OH , L=absent, X= bromine, Y=mercapto-2-pyrimidines, Z=hydrogen, j=3, m=s=1 and R ³ = R ⁴ = hydrogen.

The ethyl ester of compound 181a prepared in Example 181 was hydrolyzed by the method described in Example 160 to obtain the title compound.

[M+H] ⁺ = 732.2, 734.2.

Example 183. Compound of Formula II Wherein A=tBOC, G= OH , L=absent, X= thiophen-3-yl, Y=mercapto-2-pyrimidine, Z=hydrogen, j=3, m=s= 1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by reacting compound 181a of Example 181 with thiophen-3-ylboronic acid under the Suzuki coupling conditions described in Example 159, followed by hydrolysis of the ethyl ester as described in Example 160.

Example 184. Compound of Formula II Where A=tBOC, G= OEt , L=absent, X=Y= thiazol-2-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

To a degassed solution of the title compound of Example 158 (1 mmol) and thiazol-2-ylstannane (2 mmol) was added Pd( _PPh3 ) ₄ (10 mol%). The mixture was degassed two more times with nitrogen and heated to 100 °C for 3 h. The cooled mixture was concentrated in vacuo, the residue was purified by column chromatography (eluting with 30% EtOAc/hexanes), and the ethyl ester was hydrolyzed as in Example 160 to afford the title compound.

[M+H] ⁺ = 710.3.

Example 185. Compound of Formula II Where A=tBOC, G= OH , L=absent, X=Y= imidazol-1-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = Hydrogen.

The title compound was prepared from a dry mixture of the title compound _of Example 158 (0.068 mmol), imidazole (2 eq.), _Cs2CO3 (3 eq.), Xantphos (30 mol%) and Pd(OAc) ₂ under nitrogen atmosphere Dioxane was added. The reaction mixture was then degassed and stirred at 75 °C for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM, filtered and concentrated in vacuo. The reaction mixture was purified by silica column chromatography (5% MeOH/ _CHCl3 ) to obtain the ethyl ester of the title compound. The ethyl ester was then hydrolyzed under the conditions described in Example 160 to afford the title compound.

Example 186. Compound of Formula II Wherein A=tBOC, G= OH , L=absent, X=2-( cyclopropylamino)-thiazol-4-yl, Y=4-methoxyphenyl, Z =hydrogen, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

Preparation of 4-(2-cyclopropylamino-thiazol-4-yl)5-(4-methoxy-phenyl-2H-pyridazin-3-one (186h)

186A. Mix commercially available 4,5-dichloropyridazin 3(2H)-one (18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol), tetrabutylammonium bromide (1 mmol) and acetonitrile (45 mL) The mixture was stirred and heated at reflux for 1 h. After cooling, the solvent was evaporated under reduced pressure. The residue was filtered through a small silica gel plug (eluting with 10% EtOAc/hexanes) to afford compound 186a (81%) as a white powder. [M+H] ⁺ = 256.3.

186B. To a magnetically stirred solution of 186a (4.5 mmol) in anhydrous dioxane (20 mL) was added 1.0 mL of a 21 wt% sodium methoxide solution at room temperature. After 1 h, the mixture was poured into water/ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated to an oil. The oily residue was purified by column chromatography (eluting with 10% EtOAc/Hex) to give 85% 186b.

[M+H] ⁺ = 251.7.

Alternatively, the substitution reaction of pyridazinone 186b can be achieved by this procedure using MeOH instead of dioxane as solvent with the methoxy group at the 5-position of the pyridazinone ring and the chloro group at the 4-position.

186C. Pyridazinone 186 (1 mmol) was dissolved in DME. To this mixture was added Pd(PPh ₃ ) ₄ (10 mol%), the mixture was stirred at room temperature for 10 min, then 4-methoxyphenylboronic acid (2 mmol) and 1 mL of Na ₂ CO ₃ aqueous solution (10 wt %) were added. Subsequently, the reaction mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 15% EtOAc/hexanes) to afford compound 186c.

[M+H] ⁺ = 323.3.

186D. To a solution of 186c (3 mmol) in DME was added 2N KOH and the resulting mixture was heated to reflux for 1 h. The cooled mixture was diluted with water _, acidified to pH-5 with solid citric acid and extracted 3 times with _CH2Cl2 . The organic layer was washed once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford compound 186d. [M+H] ⁺ = 309.3.

186E. To a cold solution of compound 186d (2 mmol), triethylamine (0.4 mL) in dichloromethane (10 mL) (ice-acetone bath) was added trifluoromethanesulfonic anhydride (0.4 mL) dropwise. The resulting solution was stirred at -5°C for 30 min. _The reaction mixture was then poured into dilute HCl (0.5M) and extracted with _CH2Cl2 . The combined organic layers were washed with 1% _NaHCO3 , brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. Compound 186e was used without further purification.

[M+H] ⁺ = 441.4.

186F. Commercially available 2,4-dibromothiazole (2 mmol) was dissolved in cyclopropylamine (3 mL), and the reaction mixture was heated to 50° C. for 8 h. The cooled mixture was then poured into water and extracted twice with ether. After drying the combined organic fractions (MgSO ₄ ), evaporation of the solvent and purification by flash column chromatography (silica gel, 15% EtOAc/hexanes) afforded 2-cyclopropylamine-4-bromothiazole, which was converted to the corresponding Stannane 186f. A degassed DME solution of 2-cyclopropylamine-4-bromothiazole was treated with hexamethylditin and Pd(PPh ₃ ) ₄ and heated at 80° C. for 18 h. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography (eluting with 20% EtOAc/Hexanes/2% _Et3N ) to give stannane 186f.

[M+H] ⁺ = 304.1.

186G. To a degassed solution of compound 186e (1 mmol) and stannane 186f (2 mmol) was added Pd(PPh ₃ ) ₄ (10 mol%). The mixture was degassed two more times with a nitrogen purge and then heated to 100° C. for 3 h. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography (eluting with 30% EtOAc/hexanes) to give compound 186g. [M+H] ⁺ = 431.6.

186H. Compound 186g and 10% Pd/C (wet) in MeOH were used for 2h using a hydrogen tank. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo to afford compound 186h.

[M+H] ⁺ = 341.4.

The title compound was prepared by reacting pyridazinone 186h with cyclic peptide precursor 1 from Example 1 under the Mitsunobu conditions described in Example 158, followed by hydrolysis of the ethyl ester under the conditions described in Example 159.

Example 187. The compound of formula II wherein A=tBOC, G= OH , L=absent, X and Y taken together=6-methoxy-isoquinolin-(3,4)-yl, Z=hydrogen , j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

187A. Pyridazinone 186b (2 mmol) was dissolved in DME. To this mixture was added Pd(PPh ₃ ) ₄ , the mixture was stirred at room temperature for 10 min, then 2-formyl-4-methoxyphenylboronic acid and aqueous Na ₂ CO ₃ (10 wt %) were added. Subsequently, the reaction mixture was heated to reflux for 18 h. The cooled reaction mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried ( _MgSO4 ), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 20% EtOAc/hexanes) to afford compound 187a. [M+H] ⁺ = 351.4.

187B. A mixture of pyridazinone 187a (1 mmol), MeOH (20 mL) and _NH4OH (10 mL, 28-30 wt%) was heated at 60 °C for 30 min. After cooling, the precipitated compound 187b was filtered off, rinsing with MeOH (15 mL). [M+H] ⁺ = 317.4.

187C. A mixture of pyridazinoisoquinolinone 187b (0.5 mmol), AlCl ₃ and toluene was stirred and heated at 70 °C for 1 h. After cooling, water was added and the mixture was filtered, rinsing with water. The residue was purified by silica gel column chromatography (eluting with 50% EtOAc/Hex) to afford compound 187c. [M ⁺ H] ⁺ = 227.3.

The title compound was prepared by reacting pyridazinoisoquinolinone 187c with cyclic peptide precursor 1 from Example 1 under the Mitsunobu conditions described in Example 162, followed by hydrolysis of the ethyl ester under the conditions described in Example 159.

Example 188. Compound of Formula II Where A = -(C=O)-OR ¹ , R ¹ = Cyclopentyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z = Hydrogen , j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

188a-Deprotection of the amine.

0.041 mmol of the title compound of Example 159 was dissolved in 4 ml of 4M HCl in dioxane and stirred for 1 h. The reaction residue 188a was concentrated in vacuo.

188b-chloroformate reagent

Chloroformate reagent 188b was prepared by dissolving 0.045 mmol cyclopentanol in THF (3 ml) and adding 0.09 mmol phosgene in toluene (20%). The resulting reaction mixture was stirred at room temperature for 2 h and the solvent was removed in vacuo. DCM was added to the residue, followed by concentration to dryness in vacuo twice to afford the chloroformate reagent 188b.

188c - Preparation of carbamates

The title carbamate was prepared by dissolving the residue 188a in 1 ml THF, adding 0.045 mmol TEA, and cooling the resulting reaction mixture to 0 °C. To the 0°C reaction mixture was added a solution of chloroformate reagent 188b in 3 ml THF. The resulting reaction mixture was reacted at 0 °C for 2 h, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as in Example 160.

Example 189. Compound of Formula II Where A = -(C=O)-OR ¹ , R ¹ = Cyclobutyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z = Hydrogen , j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared as described in Example 188 using the title compound of Example 159 and cyclobutanol.

Embodiment 190. Compounds of Formula II Where A = -(C=O)-OR ¹ , R ¹ = Cyclohexyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z = Hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared as described in Example 188 using the title compound of Example 159 and cyclohexanol.

G＝OH，L＝不存在，X＝Y＝噻吩-3-基，Z＝氢，j＝3， m＝s＝1且R ³ ＝R ⁴ ＝氢。 Embodiment 191. The compound of Formula II wherein A= -(C=O)-OR ¹ ,

G= OH , L=absent, X=Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R4 ⁼ hydrogen.

The title compound was prepared as described in Example 188 using the title compound of Example 159 and (R)-3-hydroxytetrahydrofuran.

Embodiment 192. The compound of Formula II wherein A= -(C=O)-OR ¹ , G= OH , L=absent, X=Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R4 ⁼ hydrogen.

The title compound was prepared as described in Example 188 using the title compound of Example 159 and (S)-3-hydroxytetrahydrofuran.

Embodiment 193. The compound of Formula II wherein A= -(C=O)-OR ¹ , G = OH , L = absent, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1 and R ³ = R ⁴ = hydrogen, carried out according to the method described in Example 188 The title compound of Example 159 and Preparation of the title compound.

Embodiment 194. Compound of Formula II Where A = -(C=O)-R ¹ , R ¹ = Cyclopentyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z = Hydrogen , j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared from the title compound of Example 159 in 4 ml 4M HCl/dioxane and the reaction mixture was stirred for 1 h. The reaction residue was concentrated in vacuo. To this residue were added 4 ml of THF and 0.045 mmol of TEA, the mixture was cooled to 0°C, and 0.045 mmol of cyclopentyl acid chloride was added thereto. The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as in Example 160.

Example 195. Compound of Formula II Where A = -(C=O)-NH-R ¹ , R ¹ = Cyclopentyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z =hydrogen, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

The title compound was prepared from a solution of the title compound from Example 159 in 4 ml of 4M HCl/dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. To the solution at 0 °C was added 0.045 mmol of cyclopentyl isocyanate, and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was then extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as in Example 160.

Example 196. Compound of Formula II Where A = -(C=S)-NH-R ¹ , R ¹ = Cyclopentyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z =hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared from a solution of the title compound from Example 159 in 4 ml of 4M HCl/dioxane and stirred for 1 h. The resulting reaction residue was concentrated in vacuo, dissolved in 4 ml THF, and cooled to 0°C. To the solution at 0 °C was added 0.045 mmol of cyclopentyl isothiocyanate, and the resulting reaction mixture was stirred at room temperature for 4 h. The solution was extracted with EtOAc, washed with 1% HCl, water and brine, dried over magnesium sulfate, and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as in Example 160.

Embodiment 197. Compound of Formula II Where A = -S(O) ₂ -R ¹ , R ¹ = Cyclopentyl, G = OH , L = Absent, X = Y = Thiophen-3-yl, Z = Hydrogen , j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared from a solution of the title compound from Example 159 in 4 ml of 4M HCl/dioxane and stirred for 1 h. The resulting concentrated reaction residue was dissolved in 4 ml of THF, 0.045 mmol of TEA was added thereto, and cooled to 0°C. To the 0 °C solution was added 0.045 mmol of cyclopentylsulfonyl chloride, and the resulting reaction mixture was stirred at 0 °C for 2 h. The solution was then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over magnesium sulfate and concentrated to dryness in vacuo. The crude compound was purified on a silica column followed by hydrolysis of the ethyl ester as in Example 160.

Example 198. Compound of Formula II Where A= -(C=O)-OR ¹ , R ¹ =Cyclopentyl, G=-O -Phenylethyl, L=Absent, X=Y=thiophene-3- radical, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

The title compound was prepared by adding 1.2eq. The resulting reaction mixture was stirred for 1 h. Then warm to room temperature within 4-12h. The reaction mixture was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound phenethyl ester 198b.

Other esters can be prepared in the same way.

Embodiment 199. The compound of formula II wherein A= -(C=O) ^-OR1 , R1 ⁼ cyclopentyl, G=-NH- phenethyl, L=absent, X=Y=thiophene-3. radical, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

The title compound was prepared by adding EDC (1.2 eq.) and DIEA (4 eq.) to a solution of the title compound of Example 194 and phenethylamine 199a (0.05 ml) in 0.5 ml DMF at 0°C. The resulting reaction mixture was stirred for 1 h. Subsequently, the reaction was warmed to room temperature over 4-12 h. The reaction mixture was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound phenethylamide 199b.

Other amides can be prepared by the same method.

Embodiment 200. The compound of formula II, wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G= -NHS(O) ₂ -phenethyl, L=absent, X=Y= Thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared by adding 1.2eq. The resulting reaction mixture was stirred for 1 h, then allowed to warm to room temperature over 4-12 h. The reaction mixture was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound sulfonamide 200b.

Other sulfonamides can be prepared by the same method.

Embodiment 201. Compounds of Formula II Where A = -(C=O)-OR ¹ , R ¹ =Cyclopentyl, G = -(C=O)-OH , L = Absent, X = Y = Thiophene- 3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ = hydrogen.

The title compound was prepared by adding EDC (1.2 eq.) and DIEA (4 eq.) to a solution of the title compound of Example 194 in 0.5 ml DMF at 0°C. The resulting reaction mixture was stirred for 1 h. Subsequently, the reaction was warmed to room temperature over 4-12 h. The reaction mixture was purified by silica gel flash chromatography to obtain the hydroxyamide. The hydroxyamide was treated with DIBAL-H at -78 °C in THF for 2 h. The reaction mixture was diluted with 8 ml EtOAc, _washed with water and brine, dried over _Na2SO4 , concentrated in vacuo to afford aldehyde 201a. To a solution of aldehyde 39a in 0.5 ml THF at 0°C was added α-hydroxy-α-methyl-propionitrile (0.1 ml) and a catalytic amount of TFA. The resulting reaction mixture was heated from 0° C. to room temperature over 4-12 h, then hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction was extracted with EtOAc, washed with water and brine to obtain the crude product of α-hydroxy compound 201b. Crude compound 201b was subjected to Dess-Martin oxidation in THF (0.5ml) to give the crude product of α-carbonyl compound 201c. Crude 201c was purified by flash chromatography on silica gel (using different ratios of hexane:EtOAc (9:1→5:1→3:1→1:1) as eluent phase) to afford the title compound ketoacid 201c.

Embodiment 202. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-O-phenethyl, L=absent, X= Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared according to the method of Example 198 using the title compound ketoacid of Example 201 and phenylethyl alcohol.

Embodiment 203. The compound of formula II wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-NH-phenethyl, L=absent, X= Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared as described in Example 199 using the title compound ketoacid from Example 201 and phenethylamine.

Embodiment 204. Compound of Formula II Wherein A= -(C=O)-OR ¹ , R ¹ =cyclopentyl, G=- (C=O)-NH-S(O) ₂ -benzyl, L= Absent, X=Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R4 ⁼ hydrogen.

The title compound was prepared according to the method described in Example 200 using the title compound ketoacid from Example 201 and α-toluenesulfonamide.

Example 205. Compound of Formula II Where A=tBOC, G= OH , L= -(C=O)CH ₂ - , X=Y=thiophen-3-yl, Z=hydrogen, j=1, m=s =1 and R ³ =R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 88C and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Example 206. Compound of Formula II Where A=tBOC, G= OH , L= -CH(CH ₃ )CH ₂ - , X=Y=thiophen-3-yl, Z=hydrogen, j=1, m=s =1, R ³ =methyl and R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 89G and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Example 207. Compound of Formula II Where A=tBOC, G= OH , L= -O- , X=Y= thiophen-3-yl, Z=hydrogen, j=0, m=s=1, R ³ = Methyl and R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 90D and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Example 208. Compound of Formula II Where A=tBOC, G= OH , L= -S- , X=Y=thiophen -3-yl, Z=hydrogen, j=0, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 91E and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Embodiment 209. The compound of formula II wherein A=tBOC, G= OH , L= -S(O)- , X=Y= thiophen-3-yl, Z=hydrogen, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 92B and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Embodiment 210. The compound of formula II, wherein A=tBOC, G= OH , L= -S(O) ₂ , X=Y= thiophen-3-yl, Z=hydrogen, j=2, m=s=1, R ³ =methyl and R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 93B and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Embodiment 211. The compound of formula II wherein A=tBOC, G= OH , L= _-SCH2CH2- , X=Y=thiophen-3-yl, Z=hydrogen, j=0, m=s=1 _and R ³ =R ⁴ = CH ₃ .

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 94B and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Embodiment 212. Compounds of Formula II Where A=tBOC, G= _OH , L= _CF2CH2 , X=Y= thiophen-3-yl, Z=hydrogen, j=1, m=s=1 and ^R3 =R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 95C and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Embodiment 213. Compound of Formula II Where A=tBOC, G= OH , L= -CHFCH ₂ - , X=Y=thiophen-3-yl, Z=hydrogen, j=1, m=s=1 and ^R3 =R ⁴ =hydrogen.

The title compound was prepared using the modified cyclic peptide precursor mesylate generated in 96C and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 The following reaction was followed by hydrolysis of the ethyl ester as described in Example 160.

Example 214. Compound of Formula III Where A=tBOC, G= OH , L=absent, X=Y= thiophen-3-yl, Z=hydrogen, j=3, m=s=1 and R3 ⁼ R ⁴ = Hydrogen.

214A. Preparation of saturated cyclic peptide precursor mesylate by catalytic reduction of the mesylate cyclic peptide precursor of Example 2 with Pd/C-containing MeOH in the presence of hydrogen.

The title compound was prepared by using the saturated cyclic peptide precursor mesylate formed in 214A and 4,5-bis(thiophen-3-yl)-2H-pyridazin-3-one under the Mitsunobu conditions described in Example 158 reaction, followed by hydrolysis of the ethyl ester as described in Example 160.

The compounds of the present invention have potent HCV NS3 protease inhibitory properties. The following examples illustrate methods for testing the anti-HCV effects of compounds of the present invention.

Example 215. NS3/NS4a protease analysis

HCV protease activity and inhibition were assayed with an internally quenched fluorogenic substrate. DABCYL and EDANS groups are attached to opposite ends of the short peptide. After protein cleavage, the fluorescence quenching of EDANS by the DABCYL group is reduced. Fluorescence was measured with a Molecular Devices Fluoromax (or equivalent device) with an excitation wavelength of 355 nm and an emission wavelength of 485 nm.

This assay uses Corning white half-area 96-well plate (VWR 29444-312 [Corning 3693]) using full-length NS3 HCV protease 1b complexed with the NS4A cofactor (final enzyme concentration 1-15 nM ). Assay buffer was supplemented with 10 [mu]M NS4A cofactor Pep 4A (Anaspec 25336 or in-house, MW1424.8). RET S1 (Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser-Lys-(DABCYL) _-NH2 , AnaSpec 22991, MW 1548.6) was used as fluorescent peptide substrate. Assay buffer contained 50 mM Hepes pH 7.5, 30 mM NaCl and 10 mM MBME. Enzyme reactions were carried out at room temperature for 30 min in the presence or absence of inhibitors.

Peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [-20°C] and HCV Inh 2 (Anaspec 25346, MW 913.1) Ac-Asp-Glu -Dif-Cha-Cys-OH effect control compound.

IC50 was calculated with XLFit in ActivityBase (IDBS), using equation 205: y=A+((B-A)/(1+((C/x)^D))).

Example 216. Cell-based replicon analysis

Quantification of HCV Replicon RNA in Cell Lines (HCV Cell Typing Analysis)

Cell lines carrying HCV replicons (including Huh-11-7 or Huh 9-13) (Lohmann et al., Science 285:110-113, 1999) were seeded into 96-well plates at 5×10 ³ cells/well, providing Medium of DMEM (high glucose), 10% fetal calf serum, penicillin-streptomycin and non-essential amino acids. Cells were incubated at 37 °C in a 5% _CO2 incubator. At the end of the incubation period, total RNA was extracted and purified from the cells using the Qiagen RNeasy 96 Kit (Catalog #74182). To amplify HCV RNA such that sufficient material is detected by HCV-specific probes (see below), HCV-specific primers (see below) mediate reverse transcription of HCV RNA and amplification of cDNA by polymerase chain reaction (PCR), Wherein the kit TaqMan One-Step RT-PCR Master Mix Kit (Applied Biosystems catalog number 4309169) was used. The following are the nucleotide sequences of RT-PCR primers (located in the NS5B region of the HCV genome):

HCV forward primer "RBNS5bfor"

5'GCTGCGGCCTGTCGAGCT:

HCV reverse primer "RBNS5Brev":

5′CAAGGTCGTCTCCGCATAC

RT-PCR products were detected with an Applied Biosystems (ABI) Prism 7700 Sequence Detection System (SDS), which detects fluorescence emitted during the processing of probes labeled with fluorescent reporter and quencher dyes during the PCR reaction. An increase in fluorescence is detected at each PCR cycle, which reflects an increase in RT-PCR product. Specifically, quantification is based on the number of valve cycles where the amplification curve crosses a defined fluorescence threshold. Comparing the valve cycle number of a sample to a known standard provides a highly sensitive measure of the relative template concentration in different samples (ABI User Bulletin #2, December 11, 1997). Data were analyzed with the program ABI SDS 1.7. Relative template concentrations can be converted to RNA copy numbers using a standard curve of HCV RNA standards of known copy number (ABI User Bulletin #2, December 11, 1997).

RT-PCR products were detected with the following labeled probes:

5′FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA

FAM = fluorescent reporter dye.

TAMRA:=quencher dye.

The RT reaction was performed at 48°C for 30 min, followed by PCR. Thermal cycler parameters for PCR reaction on ABI Prism 7700 Sequence Detection System: one cycle: 95°C, 10min; then cycle 35 times, each cycle includes an incubation at 95°C for 15s, and then incubation at 60°C for 1min.

To normalize the data to the cellular RNA internal control molecule, RT-PCR was performed with the cellular messenger RNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH). GAPDH copy number was very stable in the cell lines used. GAPDH RT-PCR was performed on the exact same RNA samples for HCV copy number determination. The ABI Pre-Developed TaqMan Assay Kit (Catalog #4310884E) contains GAPDH primers, probes, and standards for copy number determination. The ratio of HCV/GAPDH RNA was used to calculate the compound activity and evaluate the inhibitory effect on HCV RNA replication.

Activity of Compounds as Inhibitors of HCV Replication (Cell-Based Assays) in the Replicon-Containing Huh-7 Cell Line

The effect of specific antiviral compounds on Huh-11-7 was determined by comparing the amount of HCV RNA (normalized to GAPDH (e.g. HCV/GAPDH ratio)) in cells exposed to the compound to cells exposed to 0% inhibition and controls exposed to 100% inhibition. or the effect of HCV replicon RNA concentration in 9-13 cells. Specifically, cells were seeded into 96-well plates at 5×10 ³ cells/well, and incubated with one of the following media: 1) media containing 1% DMSO (0% inhibition control), 2) media containing 100 International units, IU/ml α-interferon 2b in medium/1% DMSO, or 3) medium containing a fixed concentration of compound/1% DMSO. The above 96-well plates were then incubated at 37°C for 3 days (primary screening assay) or 4 days (IC50 determination). The percent inhibition is defined as:

Inhibition percentage = [100-((S-C2)/C1-C2)]×100, where:

S=the ratio of HCV RNA copy number/GAPDH RNA copy number in the sample;

The ratio of HCV RNA copy number/GAPDH RNA copy number in C1=0% inhibition control (medium/1%DMSO);

C2=100% inhibits the ratio of HCV RNA copy number/GAPDH RNA copy number in the control (100IU/ml α-interferon 2b).

Dose response curves for inhibitors were obtained by adding three-fold serial dilutions of compound to individual wells over a 3-log concentration range, starting with the highest concentration of the specific compound, 10 μM, and ending with the lowest concentration, 0.01 μM. If the IC50 values are not in the linear range of the curve, further dilution series (eg 1 μM to 0.001 μM) are used. IC50 was determined based on the IDBS Activity Base program, using Microsoft Excel "XL Fit", where A = 100% inhibition value (1001U/ml α-interferon 2b), B = 0% inhibition control value (medium/1% DMSO), C = midpoint of the curve, defined as C=(B-A/2)+A. A, B and C values are expressed as the ratio of HCV RNA/GAPDH RNA of each sample in each well of the above-mentioned 96-well plate. For each plate, the average value of 4 wells was used to define 100% and 0% inhibition values.

Although the present invention has described many different preferred embodiments, it is not limited thereto, and those skilled in the art will appreciate that changes and improvements can be made thereto without departing from the essence of the present invention and the scope of the appended claims.

Claims (77)

1. A compound of the following formula I: in: A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ¹ , -(C=O)-OR ¹ and - (C=O)-NH-R ¹ ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen; j is 0, 1, 2, 3 or 4; m is 0, 1 or 2; s is 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, aryl substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R3 and ^R4 are each independently selected from hydrogen, OH, _CH3 , CN, SH, halogen, _NO2 , _NH2 , amide, methoxy, trifluoromethoxy and trifluoromethyl; E is selected from -CH=CH- or -CH ₂ -CH ₂ -; W is a substituted or unsubstituted heterocyclic ring system. 2. The compound of claim 1, wherein W is substituted by one or more substituents, each of which is independently selected from any of the following (a), (b), (c), (d) and (e) group: (a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl; alkylsulfonyl; alkynyl; amide; optionally monosubstituted by C ₁ -C ₆ alkyl Amido; aryl; arylalkanoylalkyl; arylalkyl; arylaminoalkyl; aryloxyalkyl; arylsulfonyl; cycloalkoxy; cycloalkyl; dialkylamino; Dialkylaminoalkyl; Diarylaminoalkyl; Haloalkyl; Heteroaryl; Heteroarylalkyl; Heterocyclyl; Heterocycloalkyl; Heterocycloalkylalkyl; Thioalkyl; Monoalkane (lower alkyl)sulfonyl; haloalkyl; carboxyl; amide; (lower alkyl)amide; heterocyclyl optionally substituted by C ₁ -C ₆ alkyl; perhaloalkyl; Sulfonyl; Thioalkyl; Urea; C(=O)-R ¹¹ ; OC(=O)R ¹¹ ; C(=O)OR ¹¹ ; C(=O)N(R ¹¹ ) ₂ ; S) N(R ¹¹ ) ₂ ; SO ₂ R ¹¹ ; NHS(O ₂ )R ¹¹ ; N(R ¹² ) ₂ ; N(R ¹² )C(=O)R ¹¹ ; Each of the above-mentioned substituents can be optionally substituted by up to three of the following groups: halogen, OH, alkoxy, perhaloalkyl; (b) C ₇ -C ₁₄ aralkyl; C ₂ -C ₇ cycloalkyl; C ₆ -C ₁₀ aryl; heterocyclyl; (lower alkyl)-heterocyclyl; Wherein each aralkyl, cycloalkyl, aryl, heterocyclyl or (lower alkyl)-heterocyclyl can be optionally substituted by R ⁶ ; R ⁶ is halogen, C ₁ -C ₆ alkyl, C ₃ - C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy, NO ₂ , N(R ⁷ ) ₂ , NH-C(O)-R ⁷ or NH-C(O )-NHR ⁷ , R ⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; or R ⁶ is NH-C(O)-OR ⁸ , R ⁸ is C ₁ -C ₆ alkane group or C ₃ -C ₆ cycloalkyl; (c) N(R ⁵ ) ₂ , NH-C(O)-R ⁵ or NH-C(O)-NH-R ⁵ , wherein R ⁵ is independently H, C ₁ -C ₆ alkyl or C ₃ - C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, C ₇ -C ₁₄ aralkyl, heterocyclyl or (lower alkyl)-heterocyclyl; (d) NH-C(O)-OR ⁸ , wherein R ⁸ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; (e) Formyl; Halogen; Hydroxy; NO ₂ ; OH; SH; Halo; CN; in Each ^R is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkyl Sulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkyl Aminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and per Haloalkyl; each ^R is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkane radical, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, di Alkylaminoalkyl, arylaminoalkyl or diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl. 3. The compound of claim 1, wherein W is selected from: (a) Aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring systems containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, wherein the ring system is optionally Substituted by up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ; (b) an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S, wherein the ring system is optionally Substituted by up to three of the following ring substituents: OH, CN, halogen, formyl, and R ¹⁰ ; in: Each R ¹⁰ is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkylsulfonyl, aryl Sulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, Dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl; C(=O)-R ¹¹ , OC(=O)R ¹¹ , C(=O)OR ¹¹ , C(=O)N(R ¹¹ ) ₂ , C(=S)N(R ¹¹ ) ₂ , SO ₂ R ¹¹ , NHS(O ₂ )R ¹¹ , N(R ¹² ) ₂ and N(R ¹² )C(=O)R ¹¹ ; Each ^R is independently H, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkyl Sulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkyl Aminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and per Haloalkyl; Each ^R is independently H, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclyl, heterocycloalkyl, alkane Sulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylamino Alkyl, arylaminoalkyl or diarylaminoalkyl, wherein any of the above groups may be optionally substituted with up to three of the following groups: halogen, OH, alkoxy and perhaloalkyl. 4. The compound of claim 3, wherein W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and up to 4 heteroatoms selected from O, N and S , the ring system is optionally substituted with up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ . 5. The compound of claim 3, wherein W is an aliphatic heteromonocyclic ring system containing 5-7 ring atoms and up to 4 ring atoms selected from heteroatoms of O, N and S, said ring system being optionally Substitution by up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ . 6. The compound of claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 5 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms. 7. The compound of claim 6, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of pyrrolidines, pyrazolidines, pyrrolines, tetrahydrothiophenes, dihydrothiophenes, tetrahydrofurans, Dihydrofurans, imidazolines, tetrahydroimidazoles, dihydropyrazoles, tetrahydropyrazoles and oxazolines. 8. The compound of claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 6 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms. 9. The compound of claim 8, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of pyridines, piperidines, dihydropyridines, tetrahydropyridines, dihydropyrans, tetrahydropyridines Furans, dioxanes, piperazines, dihydropyrimidines, ectoines, perhydropyrimidines, morpholines, thioxanes and thiomorpholines. 10. The compound of claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system contains 7 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms. 11. The compound of claim 8, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and thiaheptane. 12. The compound of claim 3, wherein W is an aliphatic heterobicyclic ring system containing 5-16 ring atoms and up to 4 ring atoms selected from heteroatoms of O, N and S, said ring system being optionally Substitution by up to three of the following ring substituents: OH, CN, halogen, formyl and R ¹⁰ . 13. The compound of claim 12, wherein the optionally substituted aliphatic heterobicyclic ring system contains 8-12 ring atoms and 1-4 ring atoms are selected from O, N and S heteroatoms. 14. The compound of claim 13, wherein the optionally substituted aliphatic heterobicyclic ring system contains 8-12 ring atoms and 1-2 ring atoms are selected from O and N heteroatoms. 15. The compound of claim 3, wherein W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system containing 5-16 ring atoms and a maximum of 4 ring atoms selected from O, N and S heteroatoms , the ring system is optionally substituted with up to three of the following ring substituents: OH, CN, halogen, formyl, and R ¹⁰ . 16. The compound of claim 3, wherein W is an aromatic heteromonocyclic ring system containing 5-7 ring atoms and up to 4 ring atoms selected from heteroatoms of O, N and S, said ring system being optionally Substitution by up to three of the following ring substituents: OH, CN, halogen, formyl and R ¹⁰ . 17. The compound of claim 15, wherein the optionally substituted aromatic heteromonocyclic ring system contains 5 ring atoms and 1-2 ring atoms are selected from O, N and S heteroatoms. 18. The compound of claim 17, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyrroles, pyrazoles, porphyrins, furans, thiophenes, pyrazoles, imidazoles, oxazoles Classes, oxadiazoles, isoxazoles, thiazoles, thiadiazoles and isothiazoles. 19. The compound of claim 16, wherein the optionally substituted aromatic heteromonocyclic ring system contains 6 ring atoms and 1-3 ring atoms are selected from O, N and S heteroatoms. 20. The compound of claim 19, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridines, pyrimidines, pyrazines, pyrans and triazines. 21. The compound of claim 16, wherein the optionally substituted aromatic heteromonocyclic ring system contains 5 ring atoms and 3-4 ring atoms are selected from O, N and S heteroatoms. 22. The compound of claim 21, wherein the optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl. 23. The compound of claim 3, wherein W is an aromatic heterobicyclic ring system containing 8-12 ring atoms and up to 4 ring atoms selected from heteroatoms of O, N and S, said ring system being optionally Substitution by up to three of the following ring substituents: OH, CN, halogen, formyl and R ¹⁰ . 24. The compound of claim 23, wherein the optionally substituted aromatic heterobicyclic ring system is selected from the group consisting of adenines, azabenzimidazoles, azaindoles, benzimidazoles, benzisothiazoles benzofurans, benzoisoxazoles, benzoxazoles, benzothiadiazoles, benzothiazoles, benzothienes, benzothiophenes, benzoxazoles , carbazoles, carnolines, guanines, imidazopyridines, indazoles, indoles, isoindoles, isoquinolines, phthalazines, purines, pyrrolopyridines, quinazoles Phenolines, quinolines, quinoxalines, thiadenes, and xanthines. 25. The compound of claim 3, wherein W is an aromatic heterotricyclic ring system containing 10-16 ring atoms and up to 4 ring atoms selected from heteroatoms of O, N and S, said ring system being optionally Substitution by up to three of the following ring substituents: OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ . 26. The compound of claim 25, wherein the optionally substituted aromatic heterotricyclic ring system is selected from the group consisting of carbazoles, bibenzofurans, psoralens, thiofluorenes, phenazines, thianthrenes Classes, phenanthrolines, phenanthridines. 27. A compound of the following formula II Formula II in: A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ¹ , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen; W selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, -N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' is absent or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; ^R3 and ^R4 are each independently selected from hydrogen and methyl. 28. The compound of claim 27, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 29. The compound of claim 27, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 30. The compound of claim 27, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 31. The compound of claim 27, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; W is

j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 32. The compound of claim 27, selected from the group consisting of:

33. The compound of claim 27, selected from the group consisting of:

34. The compound of claim 27, selected from the group consisting of: 35. The compound of claim 27, selected from the group consisting of:

36. A compound of formula III:

Formula III in A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen; W selected from

and

Q is absent or selected from -CH ₂ -, -O-, -NH-, N(R ¹ )-, -S-, -S(O) ₂ - and -(C=O)-; Q' is absent or selected from -CH ₂ - and -NH-; Y is selected from H, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; ^R3 and ^R4 are each independently selected from hydrogen and methyl. 37. The compound of claim 36, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 38. The compound of claim 36, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 39. The compound of claim 36, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; W is

j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 40. The compound of claim 36, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; W is j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 41. A compound of the following formula II: Formula II in A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, - S(O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, _-CF2CH2- and _{-CRx = CRx-} , where _Rx =H or halogen; W selected from

and

Wherein X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Baseamino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C= O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl group, heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl radical, heteroaryl and substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; ^R3 and ^R4 are each independently selected from hydrogen and methyl. 42. The compound of claim 41, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 43. The compound of claim 41, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 44. The compound of claim 41, wherein: A is -(C=O)-OR ¹ , G is hydroxyl; L does not exist; W is j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 45. The compound of claim 41, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; W is J=3; M=s=1; ^R3 and ^R4 are hydrogen. 46. The compound of claim 41 selected from the group consisting of:

47. The compound of claim 41 selected from the group consisting of:

48. The compound of claim 41 selected from the group consisting of:

49. The compound of claim 41 selected from the group consisting of: 50. A compound of formula III:

Formula III in A is selected from H, -(C=O)-R ² , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , - S(O) ₂ -R ² , -(C=NR ¹ )-R ¹ and -(C=NR ¹ )-NH-R ¹ ; G is selected from -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ and - (C=O)-NH-R ² ; L is absent or selected from -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -O-, -OCH ₂ - , -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, -CF ₂ CH ₂ -, and -CR _x =CR _x -, where _Rx = H or halogen; W selected from and

Wherein X and Y are independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, -CH ₂ -alkylamino, -CH ₂ -dialkylamino, -CH ₂ -aryl Baseamino, -CH ₂ -diarylamino, -(C=O)-alkylamino, -(C=O)-dialkylamino, -(C=O)-arylamino, -(C= O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl group, heterocycloalkyl and substituted heterocycloalkyl; or, X and Y together with the 4- and 5-position carbon atoms of the triazole ring to which they are attached constitute a cyclic moiety selected from the group consisting of: aryl, substituted aryl radical, heteroaryl and substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; ^R is selected from H, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diaryl Amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl and substituted heterocycloalkyl; ^R3 and ^R4 are each independently selected from hydrogen and methyl. 51. The compound of claim 50, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 52. The compound of claim 50, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 53. The compound of claim 50, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; W is

j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 54. The compound of claim 50, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; W is

j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 55. A compound of formula IV: in A is hydrogen, -(C=O)-R ¹ , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ or -(C=NR ¹ )-NH-R ¹ ; G is -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ or -( C=O)-NH-R ² ; L is -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, -S(O) CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ -, -CF _2CH2 -or- _CRx = _CRx- , where _Rx =H or _halogen ; X, Y and Z are independently selected from hydrogen, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted Alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl radical, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl , -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkane and substituted heterocycloalkyl; or, X and Y or Y and Z together with the carbon atoms to which they are attached constitute aryl, substituted aryl, heteroaryl or substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Substituted heterocycloalkyl; ^R3 and ^R4 are each independently hydrogen or methyl. 56. The compound of claim 55, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 57. The compound of claim 55, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 58. The compound of claim 55, selected from the group consisting of: A G L X, Y Z j m,s R ³ , R ⁴ tBO OEt does not exist X=Y=bromine hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO OEt does not exist X=Y=thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=Phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=4-(N,N-dimethylamino)phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=4-(trifluoromethoxy)phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=4-(methylsulfonyl)phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=4-(cyano)phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=3-pyridyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=4-(morpholin-4-yl-formyloxy)phenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=bromine hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X and Y together form phenyl 4-methoxyphenyl 3 m=s=1 R ³ =R ⁴ =H A G L X, Y Z j m,s R ³ , R ⁴ tBO Oh does not exist X and Y together form phenyl 4-Chlorophenyl 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X = 4-fluorophenyl Y = hydrogen Phenyl 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist Y=1-piperidinyl Phenyl 3 m=s=1 R ³ =R ⁴ =H tBO OEt does not exist X = hydrogen Y = bromine Phenyl 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X = hydrogen Y = thiophen-3-yl Phenyl 3 m=s=1 R ³ =R ⁴ =H tBO OEt does not exist X = bromo Y = pyrrolidin-1-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=thiophen-3-yl Y=pyrrolidin-1-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO OEt does not exist X = Bromine Y = Azido hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO OEt does not exist X = thiophen-3-yl Y = azido hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X = thiophen-3-yl Y = azido hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=thiophen-3-yl Y=tetrazol-2-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=Mercapto-2-pyrimidine hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X = bromine Y = mercapto-2-pyrimidine hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X = thiophen-3-yl Y = mercapto-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 tBO Oh does not exist X=Y=thiazol-2-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=Y=imidazol-1-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X=2-(cyclopropylamino)-thiazol-4-yl Y=4-methoxyphenyl hydrogen 3 m=s=1 R ³ =R ⁴ =H tBO Oh does not exist X and Y together form 6-methoxy-isoquinolinyl hydrogen 3 m=s=1 R ³ =R ⁴ =H 59. The compound of claim 55, selected from the group consisting of:

60. The compound of claim 55, selected from the group consisting of: A G L x Y Z j m,s R ³ , R ⁴ tBO Oh -(C＝O) _CH2- Thiophen-3-yl Thiophen-3-yl hydrogen 1 m=s=1 R ³ =R ⁴ =H tBO Oh -CH(CH ₃ )CH ₂ - Thiophen-3-yl Thiophen-3-yl hydrogen 1 m=s=1 R ³ =methyl R ⁴ =H tBO Oh -O- Thiophen-3-yl Thiophen-3-yl hydrogen 0 m=s=1 R ³ =methyl R ⁴ =H tBO Oh -S- Thiophen-3-yl Thiophen-3-yl hydrogen 0 m=s=1 R ³ =methyl R ⁴ =H tBO Oh -S(O)- Thiophen-3-yl Thiophen-3-yl hydrogen 2 m=s=1 R ³ =methyl R ⁴ =H tBO Oh -S(O) ₂ - Thiophen-3-yl Thiophen-3-yl hydrogen 2 m=s=1 R ³ =methyl R ⁴ =H tBO Oh -SCH ₂ CH ₂ - Thiophen-3-yl Thiophen-3-yl hydrogen 0 m=s=1 R ³ =R ⁴ =CH ₃ tBO Oh -CF ₂ CH ₂ - Thiophen-3-yl Thiophen-3-yl hydrogen 1 m=s=1 R ³ =R ⁴ =H tBO Oh -CFHCH ₂ - Thiophen-3-yl Thiophen-3-yl hydrogen 1 m=s=1 R ³ =R ⁴ =H 61. The compound of claim 55, selected from the group consisting of: A G L x Y Z j m,s R ³ , R ⁴ -(C=O)-OR ¹ R ¹ =cyclopentyl -O-phenethyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -NH-phenethyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -NHS(O) ₂ -phenethyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -(C=O)-OH does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -(C=O)-O-phenethyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -(C=O)-NH-phenethyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H -(C=O)-OR ¹ R ¹ =cyclopentyl -(C=O)-NH-S(O) ₂ -benzyl does not exist Thiophen-3-yl Thiophen-3-yl hydrogen 3 m=s=1 R ³ =R ⁴ =H 62. A compound of formula IV:

in A is hydrogen, -(C=O)-R ¹ , -(C=O)-OR ¹ , -C(=O)-NH-R ² , -C(=S)-NH-R ² , -S (O) ₂ -R ² , -(C=NR ¹ )-R ¹ or -(C=NR ¹ )-NH-R ¹ ; G is -OH, -O-(C ₁ -C ₁₂ alkyl), -NHS(O) ₂ -R ¹ , -(C=O)-R ² , -(C=O)-OR ¹ or -( C=O)-NH-R ² ; L does not exist or is -S-, -SCH ₂ -, -SCH ₂ CH ₂ -, -S(O) ₂ -, -S(O) ₂ CH ₂ CH ₂ -, -S(O)-, -S (O)CH ₂ CH ₂ -, -O-, -OCH ₂ -, -OCH ₂ CH ₂ -, -(C=O)-CH ₂ -, -CH(CH ₃ )CH ₂ -, -CFHCH ₂ - , -CF ₂ CH ₂ -or -CR _x ＝CR _x -, wherein R _x ＝H or halogen-; X, Y and Z are independently selected from hydrogen, N ₃ , halogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, C ₁ -C ₆ alkynyl, substituted Alkynyl, aryl, substituted aryl, -S-aryl, -S-substituted aryl, -O-aryl, -O-substituted aryl, NH-aryl, NH-substituted aryl radical, diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl , -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkane and substituted heterocycloalkyl; or, X and Y or Y and Z together with the carbon atoms to which they are attached constitute aryl, substituted aryl, heteroaryl or substituted heteroaryl; j = 0, 1, 2, 3 or 4; m = 0, 1 or 2; s = 0, 1 or 2; R ¹ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl; R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, substituted C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino , aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or Substituted heterocycloalkyl; ^R3 and ^R4 are each independently hydrogen or methyl. 63. The compound of claim 62, wherein: A is -(C=O)-OR ¹ ; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 64. The compound of claim 62, wherein: A is -(C=O)-O-tert-butyl; G is hydroxyl; L does not exist; j = 3; m=s=1; ^R3 and ^R4 are hydrogen. 65. A pharmaceutical composition comprising an anti-hepatitis C virus effective amount of the compound of claim 1, 27, 36, 41, 50, 55 or 62 or their pharmaceutically acceptable salts, esters or precursors Drugs and pharmaceutically acceptable carriers or excipients. 66. A method of treating a patient infected with hepatitis C virus, the method comprising administering to the patient an anti-hepatitis C virus effective amount of the pharmaceutical composition of claim 65. 67. A method of inhibiting hepatitis C virus replication, the method comprising providing a hepatitis C virus NS3 protease inhibiting effective amount of the pharmaceutical composition of claim 65. 68. The method of claim 66, further comprising concurrently administering other anti-HCV drugs. 69. The method of claim 68, wherein said other anti-HCV drug is selected from the group consisting of alpha-interferon, beta-interferon, ribavirin and amantadine. 70. The method of claim 68, wherein said other anti-hepatitis C virus drug is an inhibitor of other targets in the life cycle of the hepatitis C virus selected from the group consisting of helicase, polymerase, metalloprotease and IRES . 71. A compound selected from the group consisting of:

And their pharmaceutically acceptable salts and isomers. 72. A compound selected from the group consisting of:

And their pharmaceutically acceptable salts and isomers. 73. A compound selected from the group consisting of:

And their pharmaceutically acceptable salts and isomers. 74. A method for preparing a formula I compound of claim 1, the method comprising the steps of: (i) making the following formula VI proline derivatives:

in, P is a nitrogen protecting group; L is a leaving group; R is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl; reacting with a nucleophilic heterocyclic compound; (ii) converting the formed compound into the formula I of claim 1 compound. 75. A method for preparing a compound of formula I according to claim 1, the method comprising the steps of: (i) making the compound of formula VII:

Formula VII in, L is a leaving group; A is a nitrogen protecting group; The rest of the variables are as defined in claim 1; reacting with a nucleophilic heterocyclic compound; (ii) converting the resulting compound into a compound of formula I according to claim 1. 76. The compound of formula I of claim 1, wherein W is wherein V, X, Y and Z are each independently selected from: j) -C ₁ -C ₆ alkyl, which contains 0, 1, 2 or 3 heteroatoms selected from O, S or N, and is optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; k) -C ₂ -C ₆ alkenyl, which contains 0, 1, 2 or 3 heteroatoms selected from O, S or N, and is optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; l) -C ₂ -C ₆ alkynyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; m) aryl; n) substituted aryl; o) heteroaryl; p) substituted heteroaryl; q) heterocycloalkyl; or r) substituted heterocycloalkyl; alternatively, V and X, X and Y, or Y and Z together with the carbon atoms to which they are attached form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, Substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl. 77. The compound of formula I according to claim 1, wherein W is

wherein X, Y and Z are each independently selected from: a) -C ₁ -C ₆ alkyl, which contains 0, 1, 2 or 3 heteroatoms selected from O, S or N, and is optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; b) -C ₂ -C ₆ alkenyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; c) -C ₂ -C ₆ alkynyl containing 0, 1, 2 or 3 heteroatoms selected from O, S or N, and optionally substituted by one or more of the following substituents: halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl or substituted heterocycloalkyl; d) aryl; e) substituted aryl; f) heteroaryl; g) substituted heteroaryl; h) heterocycloalkyl; or i) substituted heterocycloalkyl; alternatively, Y and Z together with the carbon atoms to which they are attached form a cyclic moiety selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic Alkyl or substituted heterocycloalkyl.