JP2007524576A - Macrocyclic hepatitis C serine protease inhibitor - Google Patents

Abstract

ここにおいて、Ｗは置換又は非置換の複素環系である、化合物、又はこれらの薬学的に許容される塩、エステル、若しくはプロドラッグに関する。この化合物は、セリンプロテアーゼ、特にＣ型肝炎ウィルス（ＨＣＶ）ＮＳ３−ＮＳ４Ａプロテアーゼ活性を阻害する。従って、本発明の化合物はＣ型肝炎ウィルスのライフサイクルを妨害するので、抗ウィルス剤としても有用である。本発明は、さらにＨＣＶ感染に罹っている患者に投与するための、上記化合物を含有してなる医薬組成物に関する。本発明は、本発明の化合物含有してなる医薬組成物を投与することによって患者のＨＣＶ感染を治療する方法にも関する。The present invention relates to a compound of formula I, II or III:

Here, W relates to a compound, or a pharmaceutically acceptable salt, ester or prodrug thereof, which is a substituted or unsubstituted heterocyclic ring system. This compound inhibits serine proteases, particularly hepatitis C virus (HCV) NS3-NS4A protease activity. Therefore, since the compound of the present invention interferes with the life cycle of hepatitis C virus, it is also useful as an antiviral agent. The present invention further relates to a pharmaceutical composition comprising the above compound for administration to a patient suffering from HCV infection. The invention also relates to a method of treating HCV infection in a patient by administering a pharmaceutical composition comprising a compound of the invention.

Description

(Related application)
The present application is a US provisional application filed on February 13, 2003 (changed to US10 / 365,854), a US provisional application filed on February 7, 2003 (changed to US10 / 360,947), and 2003 Claims the benefit of the US provisional application filed Mar. 7 (changed to US 10 / 384,120), all of which are incorporated herein by reference for any purpose.

  The present invention relates to a novel macrocycle having activity against hepatitis C virus (HCV) and useful for the treatment of HCV infection. More particularly, the present invention relates to macrocyclic compounds, compositions containing such compounds and methods of using the same, as well as methods for making such compounds.

  HCV is a major cause of non-A, non-B hepatitis and is an increasingly serious public health problem in both developed and developing worlds. The virus infects more than 2 billion people worldwide, far surpassing the number of human immunodeficiency virus (HIV) infections, five times more. HCV-infected patients are at risk of developing cirrhosis followed by hepatocellular carcinoma and end-stage liver disease, as a high percentage of patients suffer from chronic infection. HCV is the largest cause of hepatocellular carcinoma and in the West it is a cause of liver transplantation to patients.

  There are numerous obstacles in the development of anti-HCV therapies, such as the persistence of the virus, the genetic diversity of the virus when it replicates in the host, the high incidence of drug resistance gain mutations in the virus, and These include, but are not limited to, reproducible infection culture systems and small animal models for HCV replication and pathogenesis. In many cases, careful consideration is required for antiviral agents that may cause serious side effects, given the mild course of infection and the complex ecology of the liver.

  There are only two approved treatments for HCV infection currently applicable. The initial treatment method is generally intravenous administration of interferon-α (INF-α) every 3-12 months, and the newly approved second generation treatment methods are INF-α and ribavirin. Combination therapy with common antiviral nucleic acid structural analogs. Both of these treatments have the disadvantages of side effects from interferon and low efficacy against HCV infection. Since conventional therapies are poorly tolerated and can only provide unsatisfactory efficacy, the development of effective antiviral agents for the treatment of HCV infection is required.

  In a patient population where most humans are chronically infected and asymptomatic and the prognosis is unknown, effective drugs should have significantly fewer side effects than currently available therapies. Hepatitis C nonstructural protein-3 (NS3) is a proteolytic enzyme required for viral polyprotein processing and subsequent viral replication. Despite the large number of virus variants associated with HCV infection, inhibiting the active site of NS3 protease remains an highly conserved solution, which is an interesting solution. Recent successful treatment of HIV with protease inhibitors supports the idea that inhibition of NS3 is a major target for HCV strategy.

  HCV is a flaviridae type RNA virus. The HCV genome is an envelope structure and contains a single-stranded RNA molecule consisting of about 9600 base pairs. This encodes a polypeptide of about 3010 amino acids.

  HCV polyprotein is degraded by viruses and host peptidases into 10 separate peptides with various functions. There are three structural proteins, C, E and E2. The P7 protein has an unknown function and a very variable sequence. There are 6 nonstructural proteins. NS2 is a zinc-dependent metalloproteinase that functions in conjunction with part of the NS3 protein. NS3 has two catalytic functions, a serine protease function at the N-terminus (which requires NS4A as a cofactor), and an ATP-ase-dependent helicase function at the C-terminus, without association with NS2. Have. NS4A is closely related but is a non-covalent cofactor of serine proteases.

  NS3.4A protease is involved in cleaving viral polyproteins into four sites. NS3-NS4A cleavage is autocatalytic and is caused in cis. The remaining three hydrolysis, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B are all triggered in trans. NS3 is a serine protease and is structurally classified as a chymotrypsin-like protease. NS serine protease has its own proteolytic activity, whereas HCV protease enzyme is not a sufficient enzyme in catalyzing the cleavage of polyprotein. It was shown that the central hydrophobic site of NS4A protein is required to enhance this. It seems that the NS3 protein forms a complex with NS4A to cause processing, which enhances protein resolution at all sites.

  A common strategy for the development of antiviral agents is to inactivate enzymes encoded by the virus, including NS3, essential for viral replication. Recent results regarding the discovery of NS3 protease inhibitors include Tan, A.M. Pause, Y.M. Shi, N .; Sonenberg's Hepatitis C Therapeutics: Current Status and Emerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002). More relevant patent disclosures describing the synthesis of HCV protease inhibitors are WO00 / 59929 (2000); WO99 / 07733 (1999); WO00 / 09543 (2000); WO99 / 50230 (1999); US5861297 (1999). It is.

  The present invention relates to a novel macrocycle and a method for treating hepatitis C infection in patients in need thereof with this macrocycle. The present invention further relates to a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester or prodrug thereof together with a pharmaceutically acceptable carrier or excipient.

  Formula I:

で表される化合物又はこれらの薬学的に許容される塩、エステル、又はプロドラッグであり、

Or a pharmaceutically acceptable salt, ester, or prodrug thereof,

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , —C (═O) —NH—R ² , —C (═S) —NH—R ^2. , —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (C═NR ¹ ) —NH—R ¹ ,
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ¹ , — (C═O) —R ² , — ( C═O) —O—R ¹ , — (C═O) —NHR ¹ and — (C═O) —NHR ²
L is a chemical _{bond, -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 -, and _{CR x} = _CR x - (wherein, _{R x} is hydrogen or halogen) is selected from the group consisting of,
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

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

R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, OH, CH ₃ , CN, SH, halogen, NO ₂ , NH ₂ , amide, methoxy, trifluoromethoxy, and trifluoromethyl;
E represents either a single bond or a double bond between the carbon atoms bonded thereto,
W is a substituted or unsubstituted heterocyclic ring system.

  In one aspect of the invention, E represents a double bond and has the formula II:

又はこれらの薬学的に許容される塩、エステル又はプロドラッグとなる。ここにおいて、残りの置換基は上述の通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof. Here, the remaining substituents are as described above.

  In one aspect of the invention, E represents a single bond and has the formula III:

又はこれらの薬学的に許容される塩、エステル又はプロドラッグとなる。ここにおいて、残りの置換基は上述の通りである。

Or a pharmaceutically acceptable salt, ester or prodrug thereof. Here, the remaining substituents are as described above.

In one aspect of the invention, compounds of Formula II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof are disclosed.
Where W is

Selected from the group consisting of
Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Chosen from the group,
All other substituents are as defined above.

In one aspect of the invention, compounds of Formula II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof are disclosed,
Where W is

Selected from the group consisting of
X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
All other substituents are as defined above.

In one aspect of the invention, compounds of Formula II and III, or pharmaceutically acceptable salts, esters, or prodrugs thereof are disclosed,
Where W is

And
X, Y, and Z are independently 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, 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, heterocycloalkyl, and substituted heterocycles Selected from the group consisting of alkyl or X and Y or Y and Z together with the carbon atom to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring moiety To do.

Another aspect of the present invention is as follows.
Any of those described herein, wherein W is each independently substituted with one or more substituents selected from (a), (b), (c), (d), and (e) It is a compound represented by the above formula.
(A) Alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylamino, alkylaryl, alkylsulfonyl, alkynyl, amide, amide optionally substituted with C ₁ -C ₆ alkyl, aryl, aryl Alkanoylalkyl, arylalkyl, arylaminoalkyl, aryloxyalkyl, arylsulfonyl, cycloalkoxy, cycloalkyl, dialkylamino, dialkylaminoalkyl, diarylaminoalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl, hetero Cycloalkylalkyl, thioalkyl, monoalkylaminoalkyl, sulfonyl, (lower alkyl) sulfonyl, haloalkyl, carbo Sill, amide, (lower alkyl) _amido, C 1 -C ₆ alkyl optionally substituted heterocyclo, perhaloalkyl, sulfonyl, thioalkyl, ^{urea, C (= O) -R 11} , OC (= O) R 11 , C (═O) O—R ¹¹ , C (═O) N (R ¹¹ ) ₂ , C (═S) N (R ¹¹ ) ₂ , SO ₂ R ¹¹ , NHS (O ₂ ) R ¹¹ , N ( R ¹² ) ₂ , N (R ¹² ) C (═O) R ¹¹ ;
Here, each of the substituents may be substituted with 3 or less substituents selected from halogen, OH, alkoxy, and perhaloalkyl.

(B) C ₇ -C ₁₄ aralkyl, C ₂ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, heterocyclo, (lower alkyl) -heterocyclo;
Here, aralkyl, cycloalkyl, aryl, heterocyclo or (lower alkyl) - heterocyclo may be each substituted with ^{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 where R ⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; or R ⁶ is NH—C (O) —OR ⁸ , where 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;
In which R ⁵ is independently hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl, C ₆ or C ₁₀ aryl, C ₇ -C ₁₄ aralkyl, heterocyclo or (lower alkyl) -heterocyclo. .
(D) NH—C (O) —OR ⁸ ;
Here, R ⁸ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl.

(E) formyl, halogen, _hydroxy, NO 2, OH, SH, halo, CN;
put it here,
Each R ¹¹ is independently hydrogen, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein any of the aforementioned substituents are May be substituted with 3 or less groups selected from halogen, OH, alkoxy and perhaloalkyl,

Each R ¹² is independently hydrogen, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein any of the aforementioned substituents are halogen, OH, alkoxy and It may be substituted with 3 or less groups selected from perhaloalkyl.

W is a compound represented by any formula described herein, selected from the following group:
(A) an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and no more than 4 hetero atoms selected from O, N and S Wherein the ring system may be substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ .

(B) an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and no more than 4 hetero atoms selected from O, N and S. wherein in, the ring system OH, CN, halogen, formyl, and the three may be substituted by the following ring substituents selected from the group consisting of R ^101.

Here, each R ¹⁰ is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, aryl. Alkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein each of the aforementioned groups is Halogen, OH, alkoxy and perhaloalkyl, C (═O) —R ¹¹ , OC (═O) —R ¹¹ , C (═O) O—R ¹¹ , C ( ═O) —N (R ¹¹ ) ₂ , C (═S) —N (R ¹¹ ) ₂ , SO ₂ R ¹¹ , NHSO ₂ R ¹¹ , N (R ¹² ) ₂ and N (R ¹² ) C (═O ) -R ¹¹ may be substituted with 3 or less groups selected from.

Each R ¹¹ is independently hydrogen, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein each of the aforementioned groups is halogen, OH , Substituted with 3 or less groups selected from alkoxy and perhaloalkyl.

Each R ¹² is independently hydrogen, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl, wherein each of the foregoing groups is from halogen, OH, alkoxy, and perhaloalkyl It may be substituted with 3 or less groups selected.

W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and no more than 4 heteroatoms selected from O, N and S (wherein Wherein the ring system may be substituted with up to three ring substituents selected from the group consisting of OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ) A compound of the formula

W is an aliphatic heteromonocyclic ring system having 5 to 7 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, R ^And optionally substituted with 3 or less ring substituents selected from the group consisting of ¹⁰ and R ¹¹ ).

  Any of those described herein, wherein the optionally substituted aliphatic heteromonocyclic ring system has 5 ring atoms and 1 or 2 heteroatoms selected from O, N and S A compound of the formula

  An optionally substituted aliphatic heteromonocyclic ring system from the group consisting of pyrrolidine, pyrazolidine, pyrroline, tetrahydrothiophene, dihydrothiophene, tetrahydrofuran, dihydrofuran, imidazoline, tetrahydroimidazole, dihydropyrazole, tetrahydropyrazole, and oxazoline A selected compound of any formula described herein.

  Any of the herein described wherein the optionally substituted aliphatic heteromonocyclic ring system has 6 ring atoms and one or two heteroatoms selected from O, N and S A compound of the formula

  An optionally substituted aliphatic heteromonocyclic ring system is pyridine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, morpholine, thioxan, and A compound of any formula described herein, selected from the group consisting of thiomorpholine.

  Any of those described herein, wherein the optionally substituted aliphatic heteromonocyclic ring system has 7 ring atoms and 1 or 2 heteroatoms selected from O, N and S A compound of the formula

  A compound of any formula described herein, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and hexamethylene sulfide.

W is an aliphatic heterobicyclic ring system having 5 to 16 ring atoms and no more than 4 hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, and A compound of any formula described herein, which may be substituted with 3 or fewer ring substituents selected from the group consisting of R ¹⁰ .

  As described herein, the optionally substituted aliphatic heterobicyclic ring system has 8 to 12 ring atoms and 1 to 4 heteroatoms selected from O, N and S. A compound of any formula of

  Any of the herein described aliphatic heterocyclic bicyclic ring systems having from 8 to 12 ring atoms and 1 or 2 heteroatoms selected from O and N A compound of the formula

W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring A compound of any formula described herein wherein the system is optionally substituted with up to 3 ring substituents selected from the group consisting of OH, CN, halogen, formyl and R ¹⁰ .

W is an aromatic heteromonocyclic ring system having 5 to 7 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl and A compound of any formula described herein, which may be substituted with 3 or fewer ring substituents selected from the group consisting of R ¹⁰ .

 Any of the herein described wherein the optionally substituted aromatic heteromonocyclic ring system has 5 ring atoms and 1 or 2 heteroatoms selected from O, N and S A compound of the formula

 The optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyrrole, pyrazole, porphyrin, furan, thiophene, pyrazole, imidazole, oxazole, oxadiazole, isoxazole, thiazole, thiadiazole, and isothiazole. A compound of any formula described herein.

  Any of those described herein wherein the optionally substituted aromatic heteromonocyclic ring system has 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, N and S A compound of the formula

  A compound of any formula described herein, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyran, and triazine.

  Any of those described herein, wherein the optionally substituted aromatic heteromonocyclic ring system has 5 ring atoms and 3 or 4 heteroatoms selected from O, N and S A compound of the formula

  A compound of any formula described herein, wherein the optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl.

W is an aromatic heterobicyclic ring system having 8-12 ring atoms and no more than 4 heteroatoms selected from O, N and S (this ring system is OH, CN, halogen, formyl and A compound of any formula described herein, which may be substituted with 3 or fewer ring substituents selected from the group consisting of R ¹⁰ .

  An optionally substituted aromatic heterobicyclic ring system is adenine, azabenzimidazole, azaindole, benzimidazole, benzoisothiazole, benzofuran, benzoisoxazole, benzoxazole, benzothiadiazole, benzothiazole, benzothien ( benzothiene), benzothiophene, benzoxazole, carbazole, cinnoline, guanine, imidazopyridine, indazole, indole, isoindole, isoquinoline, phthalazine, purine, pyrrolopyridine, quinazoline, quinoline, quinoxaline, thianaphthene, and xanthine A compound of any formula described herein.

W is an aromatic heterotricyclic ring system having 10 to 16 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, A compound of any formula described herein, which may be substituted with up to 3 ring substituents selected from the group consisting of R ¹⁰ and R ¹¹ . and,

  Any of the aromatic heterotricyclic ring systems that may be substituted are selected from the group consisting of carbazole, bibenzofuran, psoralen, dibenzothiophene, phenazine, thianthrene, phenanthroline, and phenanthridine. A compound of the formula

の化合物である。 Another embodiment is the formula II:

It is a compound of this.

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ¹ , — (C═S) NH—R ² , Selected from the group consisting of —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (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) —O—R ¹ , And — (C═O) —NH—R ² , L is a chemical bond, —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 —, and —CR _x = CR _x — (where R _x is hydrogen or halogen). Selected from the group
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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, Selected from the group consisting of substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, and R ³ and R ⁴ are each independently hydrogen and Selected from the group consisting of methyl.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula II above which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula II above wherein is hydrogen.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, and W is

A compound of formula II above wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, and W is

A compound of formula II above wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  Another embodiment is a compound of formula III:

の化合物である。

It is a compound of this.

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) NH—R ² , Selected from the group consisting of S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (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) —O—R ¹ , And — (C═O) —NH—R ² , L is a chemical bond, —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 —, and —CR _x = CR _x — (where R _x is hydrogen or halogen). Chosen from the group,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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, Selected from the group consisting of substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, and R ³ and R ⁴ are each independently hydrogen and Selected from the group consisting of methyl.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula III above which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula III above wherein is hydrogen.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, and W is

A compound of formula III above, wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, and W is

A compound of formula III above, wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  Formula II:

の化合物。

Compound.

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ^2. , —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (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) —O—R ¹ , And — (C═O) —NH—R ² , L is a chemical bond, —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 —, and —CR _x = CR _x — (where R _x is hydrogen or halogen). Selected from the group
W is

Selected from the group consisting of:
X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, - 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 are X and Y Together with carbon atoms at the 4 and 5 positions of the triazole ring to which Lumpur, heteroaryl, and part of the ring selected from the group consisting of substituted heteroaryl formed,
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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, Selected from the group consisting of substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and methyl.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula II which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula II wherein is hydrogen.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, and W is

A compound of formula II wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, and W is

A compound of formula II wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  Another embodiment is the formula III:

の化合物である。

It is a compound of this.

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ^2. , —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (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) —O—R ¹ , and -(C = O) -NH-R ² is selected, L is a chemical bond, -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 — (wherein R _x is hydrogen or halogen).
W is

Selected from the group consisting of
Wherein, X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino , -CH ₂ - diarylamino, - (C = O) - alkylamino, - (C = O) - dialkylamino, - (C = O) - arylamino, - (C = O) - diarylamino, aryl, Selected from the group consisting of substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or X and Y are X Together with carbon atoms at the 4 and 5 positions of the triazole ring to which Y and Y are bonded, Le, substituted aryl, to form a cyclic moiety selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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, Selected from the group consisting of substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and methyl.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula III which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula III wherein is hydrogen.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, and W is

A compound of formula III wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, and W is

A compound of formula III wherein j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen.

  Formula IV:

の化合物。

Compound.

put it here,
A is hydrogen, — (C═O) —R ¹ , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) NH—R ² , S (O) ₂ —R ² , — (C═NR ¹ ) —R 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) —O—R ¹ , or - (C = O) a ^{-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 ₂ CH ₂ -, or _{-CR x} = CR x - (wherein, _{R x} is hydrogen or halogen), and

X, Y, and Z are each independently 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, diarylamino, diheteroarylamino, arylalkyl, substituted aryl Alkyl, heteroaryl, substituted heteroaryl, -S-heteroaryl, -S-substituted heteroaryl, -O-heteroaryl, -O-substituted heteroaryl, -NH-heteroaryl, -NH-substituted heteroaryl, heteroaryl Alkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted X and Y or Y and Z, together with the carbon atom to which they are attached, are selected from the group consisting of terocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring Forming part,

j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl, 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

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula IV which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula IV wherein is hydrogen.

  Formula V:

の化合物。

Compound.

put it here,
A is hydrogen, — (C═O) —R ¹ , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) NH—R ² , or ^{_{-S (O) 2 -R 2,}} - (C = NR 1) -R 1, or ^- (C = NR 1) is ^{-NH-R 1,}
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , or - (C = O) a ^{-NH-R 2,}
L is a chemical _{bond, -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} is hydrogen or halogen), and

X, Y, and Z are independently 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, 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, heterocycloalkyl, and substituted hetero Or X and Y or Y and Z, together with the carbon atom to which they are attached, represents an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring moiety. Forming,

j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl, 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.

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula V which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula V wherein is hydrogen.

Other embodiments are as follows.
A compound of formula II or III as shown herein;
put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , and Selected from the group consisting of —S (O) ₂ —R ₂ ;
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ¹ , — (C═O) —O—R ¹ , And — (C═O) —NH—R ¹ , L is a chemical bond, —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 the group consisting of
Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Selected from the group consisting of aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, and R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and methyl.

A compound of formula II,
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
put it here,
A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is-(C = O) -O-tert-butyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

Other embodiments are as follows.
A compound of formula II or III,
put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ^2. And —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) —O—R ¹ , And — (C═O) —NH—R ² .
L is a chemical bond, —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 Selected from the group consisting of-, -CF ₂ CH _2- ,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Selected from the group consisting of aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, and R ³ and R ⁴ are each independently selected from the group consisting of hydrogen and methyl.

A compound of formula II,
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
put it here,
A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II;
put it here,
A is — (C═O) —O—R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
put it here,
A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III;
put it here,
A is-(C = O) -O-R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is-(C = O) -O-R ¹ ;
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
put it here,
A is — (C═O) O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

  Another embodiment is a compound of formula IV or V.

put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) NH—R ² , or a 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) —O—R ¹ , or - (C = O) a ^{-NH-R 2,}
L is a chemical bond, —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 - and is,

X, Y, and Z are independently 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, 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, heterocycloalkyl, and substituted heterocycles Or X and Y or Y and Z together with the carbon atom to which they are attached represent an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring moiety. Forming,

j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl,

R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted hetero Aryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, or substituted heterocycloalkyl,
R ³ and R ⁴ are each independently hydrogen or methyl

A is — (C═O) —O—R ¹ , G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are A compound of formula IV which is hydrogen.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula IV wherein is hydrogen.

Formula V, wherein A is — (C═O) —O—R ¹ , L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ are hydrogen. Compound.

A is — (C═O) —O-tert-butyl, G is hydroxyl, L is a chemical bond, j is 3, m and s are 1, and R ³ and R ⁴ A compound of formula V wherein is hydrogen.

Another embodiment is a compound of formula I,
Where W is

であり、

And

Where V, X, Y, and Z are each independently:
a) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl , -C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from:
b) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkenyl;
c) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkynyl;
d) aryl;
e) substituted aryl;
f) heteroaryl;
g) substituted heteroaryl;
h) heterocycloalkyl; or i) selected from substituted heterocycloalkyl, or V and X, X and Y, or Y and Z together with the carbon atom to which they are attached, aryl, substituted aryl, heteroaryl To form a ring moiety selected from substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl.

Another embodiment is a compound of formula I;
Where W is

であり、

And

Where X, Y, and Z are each independently:
a) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl , -C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from:
b) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkenyl;
c) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkynyl;
d) aryl;
e) substituted aryl;
f) heteroaryl;
g) substituted heteroaryl;
h) heterocycloalkyl; or i) selected from substituted heterocycloalkyl, or Y and Z together with the carbon atom to which they are attached aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, Or form a ring moiety selected from substituted heterocycloalkyl.
The remaining substituents are as shown above.

  Other embodiments include (i) Formula VI:

(Wherein P is a nitrogen protecting group (eg, BOC), L is a leaving group (eg, halide, OMs), R is an optionally substituted alkyl, and an optionally substituted aralkyl. Or an optionally substituted heteroaralkyl) with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to a compound of formula I as shown herein A process for producing a compound of formula I as described herein, comprising the step of:

  Another embodiment is a compound of formula VII:

Wherein L is a leaving group (eg, halide, OMs), A is a nitrogen protecting group (eg, BOC), and the remaining variables are as defined in Formula I) Reacting with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to a compound of formula I as shown herein, comprising formula I as described herein This is a method for producing the compound.

  In other embodiments, the present invention provides (i) a proline derivative as described herein (including those having a mesylate substituent) in a nucleophilic form of a heterocyclic compound (eg, proton And (ii) converting the resulting compound to a compound of any of the formulas shown herein, comprising the steps of: Or a pharmaceutically acceptable salt, ester or prodrug thereof of any formula shown in the document (eg, formulas I to VII having substituents defined elsewhere in this specification) It relates to the manufacturing method. In other embodiments, the method includes the reaction of any one or more of the intermediate compounds described herein, as specifically illustrated in the examples and schemes described herein. It also includes a combination of one or more steps, reagents or transformations.

  In another aspect, the invention includes mixing a compound of any formula described herein or a pharmaceutically acceptable salt, ester or prodrug thereof with a pharmaceutically acceptable carrier. It is related with the manufacturing method of the pharmaceutical composition formed.

Another embodiment is a compound of formula VI or VII, wherein L is OMs and A and the remaining variables are as defined for any of the formulas described herein (eg, I, II, III). is there.
(Detailed description of the invention)

(Detailed description of the invention)
A first aspect of the invention is a compound of formula I as described above, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient It is.

  In certain embodiments, the compound has any of the formulas shown herein (substitution as defined herein), wherein W is selected from the following aromatics (optionally substituted): (Including a variable group).

  In other embodiments, the compound has any of the formulas shown herein (wherein W is selected from the following non-aromatic (optionally substituted) Defined substitution variables).

  Another aspect of the present invention is a compound of formula II as set forth herein or a pharmaceutical thereof, wherein W is tetrazole or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.

  Another aspect of the present invention is a compound of formula III as set forth herein or a pharmaceutical thereof, wherein W is tetrazole or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.

  Examples of tetrazole-based macrocycles and methods related to the present invention are disclosed in a US provisional application filed February 13, 2003 (changed to US 10 / 365,854). Representative examples of the present invention include, but are not limited to, the following.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Where A is-(C = O) -O-tert-butyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ；

Selected from the group consisting of:

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—,
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III;
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

Q is a group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen by
Y is from hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Selected from the group
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

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

  The following additional tetrazole-based macrocycles of the present invention were made by the methods and procedures described herein. Although shown stereochemically, the invention is not limited to these stereochemical representations. One skilled in the art will readily appreciate that other isomers of these compounds are within the scope of the present invention.

  Another aspect of the present invention is a compound of formula II as set forth herein or a pharmaceutical thereof, wherein W is triazole or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.

  Another aspect of the present invention is a compound of formula III as shown herein or a pharmaceutical thereof, wherein W is triazole or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.

  Examples of triazole-based macrocyclic compounds and methods related to the present invention are disclosed in a US provisional application filed on Feb. 7, 2003 (changed to US 10 / 360,947). Representative examples of the present invention include, but are not limited to, the following.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

からなる群より選ばれ、

Selected from the group consisting of

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is — (C═O) —O—R ¹ ,
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 arylalkyl, heteroaryl, substituted heteroaryl, hetero Selected from the group consisting of arylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

A compound of formula III,
Here, A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

であり、

And

X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl, or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, form part of the ring selected from the group consisting of heteroaryl, and substituted heteroaryl,
j is 3,
m and s are 1 and R ³ and R ⁴ are hydrogen.

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

  The following additional triazole-based macrocycles of the present invention have been produced by the methods and procedures described herein. Although shown stereochemically, the invention is not limited to these stereochemical representations. One skilled in the art will readily appreciate that other isomers of these compounds are within the scope of the present invention.

Another aspect of the present invention is a compound of formula II as set forth herein or a pharmaceutical thereof, wherein W is pyridazinone or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.
Another aspect of the present invention is a compound of formula III as shown herein or a pharmaceutical thereof, wherein W is pyridazinone or a derivative thereof, in combination with a pharmaceutically acceptable carrier or excipient. Acceptable salts, esters or prodrugs.

Examples of pyridazinone-based macrocyclic compounds and methods related to the present invention are disclosed in a US provisional application filed on March 7, 2003 (changed to US 10 / 384,120). Representative examples of the present invention include, but are not limited to, the following.
A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
G is hydroxyl,
L is a chemical bond,
J is 3,
m and s are 1,
W is

であり、そして
Ｒ^３及びＲ^４は水素である。

And R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
G is hydroxyl,
L is a chemical bond,
J is 3,
m and s are 1,
W is

であり、そして
Ｒ^３及びＲ^４は水素である。

And R ³ and R ⁴ are hydrogen.

A compound of formula II,
Here, A is — (C═O) —O—R ¹ ,
G is hydroxyl,
L is a chemical bond,
J is 3,
m and s are 1,
W is

であり、そして
Ｒ^３及びＲ^４は水素である。及び

And R ³ and R ⁴ are hydrogen. as well as

A compound of formula III,
Here, A is — (C═O) —O—R ¹ ,
G is hydroxyl,
L is a chemical bond,
J is 3,
m and s are 1,
W is

であり、そして

And

R ³ and R ⁴ are hydrogen.

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

  The following additional pyridazinone-based macrocycles of the present invention have been produced by the methods and procedures described herein. Although shown stereochemically, the invention is not limited to these stereochemical representations. One skilled in the art will readily appreciate that other isomers of these compounds are within the scope of the present invention.

  Further compounds of the invention are substituted benzimidazolyls, including those in which W is substituted with one or two heteroaryl groups, each of which is independently substituted with benzimidazole. Of formula I, II or III. Examples of such compounds include:

According to an alternative embodiment, the pharmaceutical composition of the present invention may further contain other anti-HCV agents. Examples of anti-HCV agents include, but are not limited to, α-interferon, β-interferon, ribavirin and amantadine.
According to an alternative embodiment, the pharmaceutical composition of the present invention may further contain an HCV protease inhibitor.
According to yet another aspect, the pharmaceutical composition of the present invention may further contain inhibitors of other targets in the HCV life cycle, including but not limited to helicase, polymerase, metallo Proteases and internal ribosome entry sites (IRES) are included.

  According to a further aspect, the invention includes a method of treating hepatitis C infection in a patient in need of treatment by administering to the patient an anti-HCV virus effective amount of a pharmaceutical compound or composition of the invention. The method can further include administration of additional therapeutic agents, including other antiviral or anti-HCV agents. The additional therapeutic agent can be co-administered, co-administered or sequentially administered with the compounds or compositions provided herein. The method of the present invention may further comprise the step of ascertaining whether the patient requires treatment for a hepatitis C infection. This confirmation can be made by subjective (eg, physician judgment) or objective (eg, diagnostic examination) methods.

  All references disclosed herein, including patents, patent publications, literature, text, etc., are incorporated herein by reference.

(Definition)
The following definitions of various terms and phrases used to describe the present invention are consistent with those commonly used in the art and, unless specifically limited, individually or partially Applies to terms used throughout the specification and claims.

The term “C _x -C _y ] as used herein is used in conjunction with the name of a carbon-containing group to indicate that the group contains from x to y carbon atoms. (Where x and y are 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, tert-butyl, neopentyl, n-hexyl, octyl, decyl, dodecyl groups.

As used herein, the term “substituted alkyl” means that one or more of the hydrogen atoms (eg, 1, 2, or 3) are each independently F, Cl, Br, I, OH. _{, NO 2, CN, C 1} -C 6 - alkyl _{-OH, C (O) -C 1} -C 6 - _{alkyl, OCH 2 - (C 3 -C} 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH- (C 1} -C 6 - alkyl), CONH- aryl, CONH- heteroaryl, OC ( O)-(C ₁ -C ₆ -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO ₂ -alkyl, OCO ₂ -aryl, OCO ₂ -heteroaryl, OCONH ₂ , O CONH- (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 _{, 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, heteroaryl arylalkyl, heterocycloalkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ -Indicates an “alkyl” group substituted with alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or methylthiomethyl.

  As used herein, the term “haloalkyl” refers to an acyclic straight or branched chain alkyl having one or more hydrogens substituted with a halogen selected from fluorine, chlorine, bromine and iodine. Indicates a substituent.

  The term “thioalkyl” as used herein refers to an acyclic linear or branched alkyl substituent containing a thiol group, such as, but not limited to, thiopropyl.

  The term “alkoxy” as used herein refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

  The term “alkenyl” as used herein refers to a monovalent group derived by removing one hydrogen atom from a hydrocarbon moiety having one or more carbon-carbon double bonds. . Examples of the alkenyl group include, but are not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

As used herein, the term “substituted alkenyl” refers to F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C ₆ wherein one or more of its hydrogen atoms are each independently. - 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 - hetero _{aryl, 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 , _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 - alkyl amino, thio, aryl - Indicates an “alkenyl” group substituted with thio, heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or methylthiomethyl.

  The term “alkynyl” as used herein refers to a monovalent group derived by removing one hydrogen atom from a hydrocarbon moiety having one or more carbon-carbon triple bonds. . Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and the like.

As used herein, the term “substituted alkynyl” means that one or more of its hydrogen atoms are each independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C _6. - alkyl _{-OH, C (O) - (} C 1 -C 6 - _{alkyl), OCH 2 - (C 3} -C 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH- (C 1} -C 6 - alkyl), CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C 6 - alkyl), OC (O) - aryl, OC (O) - heteroaryl, OCO ₂ - alkyl, OCO ₂ - aryl, OCO ₂ - _{heteroaryl, OCONH 2, OCONH- (C 1} -C ₆ -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁ -C ₆ -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO ₂ -alkyl, NHCO ₂ - aryl, NHCO ₂ - _{heteroaryl, NHCONH 2, NHCONH- (C 1} -C 6 - alkyl), -NHCONH- aryl, -NHCONH- _{heteroaryl, SO 2 - (C 1 -C} 6 alkyl), SO ₂ - aryl , SO ₂ - _{heteroaryl, SO 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 S _{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 cycloalkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl amino, An “alkynyl” group substituted with thio, aryl-thio, heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or methylthiomethyl is indicated.

  As used herein, the term “aryl” refers to a monocyclic or bicyclic carbocyclic ring system having one or two aromatic rings, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Although it is mentioned, it is not limited to these.

As used herein, the term “substituted aryl” means that one or more of its hydrogen atoms are each independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C _6. - alkyl _{-OH, C (O) - (} C 1 -C 6 - _{alkyl), OCH 2 - (C 3} -C 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH- (C 1} -C 6 - alkyl), CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C 6 - alkyl), OC (O) - aryl, OC (O) - heteroaryl, OCO ₂ - alkyl, OCO ₂ - aryl, OCO ₂ - _{heteroaryl, OCONH 2, OCONH- (C 1} -C 6 -Alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁ -C ₆ -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO ₂ -alkyl, NHCO ₂ - aryl, NHCO ₂ - _{heteroaryl, NHCONH 2, NHCONH- (C 1} -C 6 - alkyl), -NHCONH- aryl, -NHCONH- _{heteroaryl, SO 2 - (C 1 -C} 6 alkyl), SO ₂ - aryl, SO ₂ - _{heteroaryl, SO 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 _{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, heterocyclo alkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl, amino, thio And aryl-thio, heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or methylthiomethyl substituted aryl groups as defined herein.

The term “arylalkyl” as used herein refers to a C ₁ -C ₃ alkyl or C ₁ -C ₆ alkyl residue attached to an aryl ring. Examples include, but are not limited to, benzyl, phenethyl and the like.

As used herein, the term “substituted arylalkyl” refers to one or more of its hydrogen atoms independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C _6. - alkyl _{-OH, C (O) -C 1} -C 6 - _{alkyl, OCH 2 - (C 3 -C} 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH-C 1} -C 6 - alkyl, CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C 6 - alkyl), OC (O) - aryl, OC (O) - heteroaryl, OCO ₂ - alkyl, OCO ₂ - aryl, OCO ₂ - _{heteroaryl, OCONH 2, OCONH- (C 1} -C 6 Alkyl), OCONH- aryl, OCONH- _{heteroaryl, NHC (O) - (C} 1 -C 6 - alkyl), NHC (O) - aryl, NHC (O) - heteroaryl, NHCO ₂ - alkyl, NHCO ₂ - aryl, NHCO ₂ - _{heteroaryl, NHCONH 2, NHCONH- (C 1} -C 6 - alkyl), -NHCONH- aryl, -NHCONH- _{heteroaryl, SO 2 - (C 1 -C} 6 alkyl), SO ₂ - aryl, SO ₂ - _{heteroaryl, SO 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, heterocyclo alkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl, amino, thio , Aryl-thio, heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or an arylalkyl group as defined above, substituted with methylthiomethyl.

  The term “cycloalkyl” as used herein refers to a monovalent group derived by removing one hydrogen atom from a monocyclic or bicyclic saturated 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” means that 1, 2 or 3 of the hydrogen atoms are each independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C ₆ - alkyl _{-OH, C (O) - (} C 1 -C 6 - _{alkyl), OCH 2 - (C 3} -C 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH- (C 1} -C 6 - alkyl), CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C ₆ -alkyl), OC (O) -aryl, OC (O) -heteroaryl, OCO ₂ -alkyl, OCO ₂ -aryl, OCO ₂ -heteroaryl, OCONH ₂ , OCONH- (C ₁ -C ₆ -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁ -C ₆ -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO ₂ -alkyl, NHCO ₂ - aryl, NHCO ₂ - _{heteroaryl, NHCONH 2, NHCONH- (C 1} -C 6 - alkyl), -NHCONH- aryl, -NHCONH- _{heteroaryl, SO 2 - (C 1 -C} 6 alkyl), SO ₂ - aryl , SO ₂ - _{heteroaryl, SO 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 S _{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 cycloalkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl amino, thio, aryl - shows a thio, or substituted with methyl methylthiomethyl, defined cycloalkyl groups herein - thio, heteroarylthio, benzyl - thio, C 1 _-C 6 _- alkyl.

  As used herein, the terms “heterocyclo” and “heterocyclic” are 3-7 membered having 1-4 non-carbocyclic atoms selected from heteroatoms consisting of N, O, and S. A monovalent substituent derived by removing one hydrogen atom from a saturated or unsaturated (including aromatic) ring is shown. Examples of suitable heterocycles include, but are not limited to, tetrahydrofuran, thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine, and pyrimidine. This term also includes a heterocycle as defined herein, wherein a heterocycle as defined herein is fused to one or more heterocycles or carbocycles. One example is thiazolo [4,5-b] -pyridine. The terms “heterocycloalkyl”, “aliphatic heteromonocyclic ring system”, “aliphatic heterobicyclic ring system”, “aliphatic heterotricyclic ring system”, “heteroaryl”, “aromatic” "Heterocyclic monocyclic ring system", "aromatic heterobicyclic ring system", "aromatic heterotricyclic ring system", "heteria reel alkyl" are generally covered by the term "heterocycle" However, the specific meaning is described in more detail below.

  The term “heterocycloalkyl” as used herein is a 5-, 6-, or 7-membered having between 1 and 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen. Or a bicyclic or tricyclic group consisting of a condensed 6-membered ring, wherein (i) the 5-membered ring has 0-1 double bonds each, Each having 0-2 double bonds, (ii) nitrogen and sulfur heteroatoms may be oxidized, (iii) nitrogen heteroatoms may be quaternized, and (iv) Any of the above heterocycles may be condensed with a benzene ring. Exemplary heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. It is not something. .

As used herein, the term “substituted heterocycloalkyl” means that one or more of its hydrogen atoms are each independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C ₆ - alkyl _{-OH, C (O) -C 1} -C 6 - _{alkyl, OCH 2 - (C 3 -C} 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH-C 1} -C 6 - alkyl, CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C 6 - alkyl) , OC (O) - aryl, OC (O) - heteroaryl, OCO ₂ - alkyl, OCO ₂ - aryl, OCO ₂ - _{heteroaryl, OCONH 2, OCONH- (C 1} -C ₆ -alkyl), OCONH-aryl, OCONH-heteroaryl, NHC (O)-(C ₁ -C ₆ -alkyl), NHC (O) -aryl, NHC (O) -heteroaryl, NHCO ₂ -alkyl, NHCO ₂ - aryl, NHCO ₂ - _{heteroaryl, NHCONH 2, NHCONH- (C 1} -C 6 - alkyl), -NHCONH- aryl, -NHCONH- _{heteroaryl, SO 2 - (C 1 -C} 6 alkyl), SO ₂ - aryl , SO ₂ - _{heteroaryl, SO 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 S _{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 cycloalkyl, benzyl, benzyloxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl amino, thio, aryl - shows thio, or substituted with methylthiomethyl, a heterocycloalkyl group, as defined above - thio, heteroarylthio, benzyl - thio, C 1 _-C 6 _- alkyl.

  As used herein, the term “aliphatic heteromonocyclic ring system” refers to a single containing one or more heteroatoms (ie, non-carbon) selected from O, N and S. It means a ring system having a non-aromatic ring. The term “aliphatic heterobicyclic ring system” refers to a non-aromatic group in which at least one ring contains one or more heteroatoms (ie, non-carbon) selected from O, N and S. A ring system comprising two fused rings, which is a ring. The term “aliphatic heterotricyclic ring system” means a non-aromatic group in which at least one ring contains one or more heteroatoms (ie, non-carbon) selected from O, N and S. A ring system comprising three fused rings, which is a ring. Of course, an aliphatic heterocyclic ring system can have several levels of saturation (ie, double or triple bonds), but the heteroatom-containing constituent rings are both aromatic. Must not. Thus, an indole, which contains a non-aromatic ring (ie, a pyrroline ring) fused to an aromatic carbocycle (specifically, a phenyl ring), and a structure such as phthalimide is an “aliphatic An example of a “heterobicyclic ring system”.

  As used herein, the term “aromatic monocyclic heterocyclic ring system” includes one or more hetero ring atoms selected from O, N and S (ie, other than carbon). Means an aromatic ring. An “aromatic bicyclic heterocyclic ring system” is an aromatic ring containing two fused rings containing one or more hetero ring atoms selected from O, N and S (ie, other than carbon) It means a system. An “aromatic tricyclic heterocyclic ring system” is an aromatic ring comprising three fused rings containing one or more hetero ring atoms selected from O, N and S (ie, other than carbon) It means a system. Substituent atoms of an aromatic heterocyclic ring system can form additional non-aromatic fused ring structures with additional atoms. Thus, 5,6,7,8-tetrahydroisoquinoline is an example of an aromatic bicyclic heterocyclic ring system, whereas 1,2,3,4-tetrahydroisoquinoline is an aliphatic bicyclic heterocyclic ring. This is an example of the system.

  As used herein, the term “heteroaryl” is a cyclic aromatic having from 5 to 10 ring atoms, wherein one or more atoms are selected from S, O and N, and the remaining ring atoms are carbon. These groups represent any of ring atoms such as pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, indazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl and the like. Can bind to the residues of the molecule.

As used herein, the term “substituted heteroaryl” refers to F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C wherein 1, 2 or 3 of the hydrogen atoms are each independently 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 , _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 , benzoxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl amino, thio, aryl - thio , Heteroarylthio, benzyl-thio, C ₁ -C ₆ -alkyl-thio, or methylthiomethyl substituted heteroaryl group as defined herein.

The term “heteroarylalkyl” as used herein refers to a C ₁ -C ₃ alkyl or C ₁ -C ₆ alkyl residue attached to a heteroaryl ring. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.

As used herein, the term “substituted heteroarylalkyl” refers to one or more of the hydrogen atoms independently F, Cl, Br, I, OH, NO ₂ , CN, C ₁ -C ₆ - alkyl _{-OH, C (O) -C 1} -C 6 - _{alkyl, OCH 2 - (C 3 -C} 12 - cycloalkyl), C (O) - aryl, C (O) - heteroaryl, CO ₂ - alkyl, CO ₂ - aryl, CO ₂ - _{heteroaryl, CONH 2, CONH- (C 1} -C 6 - alkyl), CONH- aryl, CONH- _{heteroaryl, OC (O) - (C} 1 -C 6 - alkyl), OC (O) - aryl, OC (O) - heteroaryl, OCO ₂ - alkyl, OCO ₂ - aryl, OCO ₂ - _heteroaryl, OCONH _2, OCONH- (C -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 _{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, heterocyclo alkyl, benzyl, benzoxy, aryloxy, _{heteroaryloxy,} C 1 -C ₆ - alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, _{heteroarylamino,} C 1 -C ₃ - alkyl, amino, thio, aryl - shown thio, or substituted with methylthiomethyl, a heteroarylalkyl group as defined before - thio, heteroarylthio, benzyl - thio, C 1 _-C 6 _- alkyl.

Any group indicated herein (eg, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocyclic) is also shown below: -F, -Cl, -Br , —I, —OH, protected hydroxy, aliphatic ether, aromatic ether, oxo, —NO ₂ , —CN, optionally substituted with halogen (such as perhaloalkyl) —C ₁ -C ₁₂ - alkyl, halogen 2 which may _-C be substituted with _{-C 12} - alkenyl, halogen 2 which may _-C be substituted with _{-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} - cycloalk Le, -NH- aryl, -NH- heteroaryl, -NH- heterocycloalkyl, - dialkylamino, - diarylamino, - diheteroarylamino, _-O-C 1 _{-C 12} - alkyl, _{-O-C 2} -C ₁₂ - alkenyl, _-O-C 2 _{-C 12} - alkynyl, _-O-C 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 - alkyl, -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, -O CO ₂ - _{heterocycloalkyl, -OCONH 2, -OCONH-C 1} -C 12 - alkyl, -OC
_ONH-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 Le, -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- Reel, -NHC (S) NH- heteroaryl, -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 N _H-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 NH 2, -CH 2} SO 2 CH 3, - aryl, - arylalkyl, - heteroaryl, - heteroarylalkyl, - _{heterocycloalkyl,} -C 3 _{-C 12} - cycloalkyl, Polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -S , _-S-C 1 _{-C 12} - alkyl, _-S-C 2 _{-C 12} - alkenyl, _-S-C 2 _{-C 12} - alkynyl, _-S-C 3 _{-C 12} - cycloalkyl, -S- aryl , -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It should be understood that aryl, heteroaryl, alkyl, and the like can 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 previously defined. Street. The term “dialkylamino” denotes a group having the structure —N (C ₁ -C ₁₂ -alkyl) ₂ , wherein C ₁ -C ₁₂ -alkyl is as previously defined. Examples of dialkylamino include, but are not limited to, N, N-dimethylamino, N, N-diethylamino, N, N-methylethylamino, piperidino 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 previously defined. Examples of diarylamino include, but are not limited to, N, N-diphenylamino, N, N-dinaphthylamino, N, N-di (toluenyl) 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 previously defined. . Examples of diheteroarylamino include, but are not limited to, N, N-difuranylamino, N, N-dithiazolidinylamino, N, N-di (imidazole) amino and the like.

As used herein, the term “hydroxy protecting group” refers to an unstable chemical site known in the art as protecting the hydroxyl group against undesired reactions during the synthesis process. . After this synthetic step, the hydroxy protecting group can be selectively removed as described herein. Hydroxy protecting groups as known in the art are described in T.W. H. Greene and P.M. G. M.M. Generally described in 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, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t -Butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl Benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, methanesulfonyl, Including paratoluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl and the like. Preferred hydroxy protecting groups in 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 ). .

  As used herein, the term “protected hydroxy” refers to a hydroxy group protected with a hydroxy protecting group as defined above, eg, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, and the like. .

As used herein, the term “nitrogen (or amino) protecting group” refers to a labile known in the art as protecting the nitrogen group against undesired reactions during the synthesis process. Chemical sites are shown. Following this synthetic step, the nitrogen protecting group can be selectively removed as described herein. Nitrogen protecting groups as known in the art include T.I. H. Greene and P.M. G. M.M. Generally described in 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, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl and the like.

  As used herein, the term “protected amino” refers to an amino group protected with an amino protecting group as defined above.

  The term “nucleophilic heterocyclic compound” is a nucleophilic form that can react with another molecule to give a covalent bond between the two molecules (eg, a nucleophile in a nucleophilic substitution reaction). A heterocyclic group in a state (for example, a metal salt state or a protonated state) is shown. Examples of such nucleophilic heterocyclic compounds are known in the art and are also presented herein.

  The term “leaving group” refers to a moiety that can be separated from a molecule during a reaction, particularly during a nucleophilic substitution reaction. Examples of leaving groups include halides, mesyl groups, tosyl groups, alkoxides, hydroxides, and their protonated states. Such leaving groups are known in the art and are also shown herein.

  The term “acyl” refers to residues derived from acids including, but not limited to, carboxylic acids, carbamic acids, carbonic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates and aliphatic phosphates.

As used herein, the term “aprotic solvent” refers to a solvent that is relatively inert to proton activity, ie, does not act as a proton donor. Examples include hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and diethyl ether, bis Examples include ethers such as methoxymethyl ether, but are not limited thereto. Such compounds are well known to those skilled in the art, and based on factors such as reagent solubility, reagent reactivity, and preferred temperature range, individual solvents or mixtures thereof may vary depending on the specific compound and reaction conditions. It is clear to those skilled in the art whether this is preferable. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized research papers, such as Techniques of Chemistry Physic . 4th of Organic Solvents Physical Physics , Chemistry Series , John Wiley & Sons, NY, 1986. , Edited by John A. Riddick et al. , Vol. Can be found in II.

As used herein, the term “protic organic solvent” refers to a solvent that is likely to donate protons, such as, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and based on factors such as reagent solubility, reagent reactivity, and preferred temperature ranges, individual solvents or mixtures thereof may vary depending on the specific compound and reaction conditions. It is clear to those skilled in the art whether this is preferable. Further examination of protic solvents can be found in organic chemistry textbooks or specialized research papers such as Organic Solvents Physical Phys . 4 in the Techniques of Chemistry Series , John Wiley & Sons, NY, 1986. , Edited by John A. Riddick et al. , Vol. Can be found in II.

  Combinations of substituents and variables envisioned by this invention are limited to those that can form stable compounds, and the term "stable" as used herein is sufficient for commercialization. Means a compound that is stable and can retain the effectiveness of the quality of the compound for a sufficient period of time for the purposes detailed herein (eg, administration to a patient for therapeutic or prophylactic purposes). is there.

The synthesized compound is separated from the reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As will be appreciated by those skilled in the art, further methods for synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, various synthetic methods may be performed in alternative procedures or sequences to obtain the desired compound. Synthetic chemical transformations and protecting group procedures (protection and deprotection) useful for the synthesis of the compounds described herein are known in the art, see, eg, R.A. Larock, Comprehensive Organic Transformations , VCH Publishers (1989): W. Greene and P.M. G. M.M. Wuts, Protective Groups in Organic Synthesis , 2d. Ed. John Wiley and Sons (1991); Fieser and M.M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); Paquette, ed. , Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995) and its successors.

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

  The compounds of the present invention can be modified by adding appropriate functionality to enhance selective biological properties. Such modifications are well known in the art and allow for enhanced biological permeability to a given biological system (eg, blood, lymphatic system, central nervous system), enhanced oral availability, and administration by injection. Enhancement of solubility, alteration of metabolism and alteration of excretion rate.

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

  The term “pharmaceutically acceptable salt” as used herein refers to humans and lower animals within the scope of appropriate medical judgment without causing inappropriate toxicity, irritation, allergic reactions, etc. It is suitable for use in contact with other tissues, and the effectiveness / risk ratio is reasonable. Pharmaceutically acceptable salts are known in the art; M.M. Berge, et al. , J. et al. Described in detail in Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Such salts may be prepared naturally during the final separation and purification steps of the compounds of the invention or may be prepared separately by reacting the free base functionality with a suitable organic acid.

  Examples of pharmaceutically acceptable non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid Including, but not limited to, salts of amino groups formed with organic acids such as succinic acid or malonic acid, or formed using other methods used in the art such as ion exchange Is not to be done.

  Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate , Camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glycoheptanoate, glycerophosphate, gluconate, hemisulfate , Heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid, lactate, laurate, lauryl sulfate, malate, maleate, malonate, Methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitic acid , Pamonate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate , Thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like, but are not limited thereto.

Typical alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium and the like. Further pharmaceutically acceptable salts are non-toxic ammonium, quaternary ammonium and halides, hydroxides, carboxylates, sulfates, phosphates, oxalates, C ₁ -C, if appropriate. It encompasses amine cations formed using a ₆ sulfonates and counterions such as arylsulfonic acid salt.

  The term “pharmaceutically acceptable ester” as used herein refers to an ester that is hydrolyzed in vivo and that readily disintegrates in the human body to release the parent compound or salt thereof. Contains. Suitable ester groups are pharmaceutically acceptable aliphatic carboxylic acids, especially alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, wherein the alkyl or alkenyl moieties each have 6 or fewer carbon atoms. But are not limited thereto. Specific examples of the ester include, but are not limited to, formic acid ester, acetic acid ester, propionic acid ester, butyric acid ester, acrylic acid ester and ethyl succinic acid ester.

  The term “pharmaceutically acceptable prodrug” as used herein refers to humans and lower animals within the scope of appropriate medical judgment without causing inappropriate toxicity, irritation, allergic reactions, etc. Suitable for use in contact with other tissues, with a reasonable efficacy / risk ratio, useful for the intended use and, if possible, in the zwitterionic form of the compounds of the invention. The prodrugs of the compounds of the invention that are useful for the intended use are shown. The term “prodrug” refers to a compound that hydrolyzes in blood, for example, and easily converts in vivo to the parent compound represented by the above formula. T. T. et al. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.E. C. S. Symposium Series and Edward B. Roche. ed. Bioreversible Carriers in Drug Design (American Pharmaceutical Association and Pergamon Press, 1987), both of which are incorporated herein by reference.

  The term “effective amount” or “therapeutically effective amount” as used herein refers to an amount capable of inhibiting HCV N33 serine protease and inhibiting the production of viral polyproteins essential for viral replication. I mean. This HCV serine protease inhibition contemplated by the methods of the present invention encompasses both therapeutic and prophylactic treatment suitable for patients in need of therapy. Treatment methods, dosages, and requirements can be selected by those skilled in the art from available methods and techniques. For example, a pharmaceutically acceptable excipient for administering a compound of the present invention to a virus infected patient in a pharmaceutically acceptable manner and in an amount effective to reduce the severity of the viral infection. Can be mixed with. Alternatively, the compounds of the present invention can be used as vaccines in methods of protecting individuals from HCV virus infection over an extended period of time. This compound can be applied in a way that protease inhibitors are commonly used in vaccines. For example, the compounds of the present invention can be mixed with pharmaceutically acceptable excipients commonly used in vaccines to administer a prophylactically effective amount to prevent HCV virus infection over an extended period of time in an individual. can do. Thus, the protease inhibitor of the present invention can be administered as a drug for treating or preventing HCV virus infection in a patient.

  The compounds of the present invention can be modified by adding appropriate functionality to enhance selective biological properties. Such modifications are well known in the art and allow for enhanced biological permeability to a given biological system (eg, blood, lymphatic system, central nervous system), enhanced oral availability, and administration by injection. Enhancement of solubility, alteration of metabolism and alteration of excretion rate.

  Although described herein are compounds having two or more asymmetric centers, they may be enantiomers, diastereomers, and (R)-or (S) -like, or in amino acids. And other stereoisomers as defined in terms of absolute configuration such as (D)-or (L). The present invention encompasses all possible isomers as well as racemates and optically active forms. Optical isomers can be prepared from the respective optically active precursors in the manner described above or by resolution of racemic mixtures. This resolution can be carried out in the presence of a resolving agent by chromatography or by repeated recrystallization, or by a combination of these techniques known in the art. More details on optical resolution can be found in James, et al. , Enantiomers Racemates, and Resolutions (John Wiley & sons, 1981). When a compound described herein contains an olefinic double bond or other geometric asymmetric center, this compound includes the E and Z geometric isomers unless otherwise specified. Is intended. Likewise, all tautomeric forms are also intended to be included. The configuration of the carbon-carbon double bond described herein has been selected for convenience only and is not intended to indicate a particular configuration unless stated otherwise in the specification, The carbon-carbon double bond, optionally denoted herein as trans, may be cis, trans, or a mixture of the two in any ratio.

(Pharmaceutical composition)
The pharmaceutical compositions of the invention consist of a therapeutically effective amount of a compound of the invention formulated with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” refers to a non-toxic, inert solid, semi-solid, or liquid bulking agent, diluent, encapsulating material, or various formulation adjuvants. Means. Examples of substances that can be pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; Powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; propylene glycol Glycols; esters such as ethyl oleate and ethyl laurate; agars; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; saline; Ringer's solution; ethyl alcohol and phosphoric acid Buffer Other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweeteners, flavors and fragrances, preservatives and antioxidants Moreover, it can put in a composition by judgment of the person in charge of a formulation. The pharmaceutical composition of the present invention can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment or instillation), buccal administration to humans or other animals. Yes, or can be administered by oral or nasal spray.

  Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms include, for example, water or other solvents, solubilizers, and ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene. 30 types such as glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor, and sesame oil), glycerol, tetrahydrofuranyl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof Inert diluents commonly used in the art, such as emulsifiers, may be included. In addition to inert diluents, the oral compositions can contain additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and fragrances.

  For example, injectable preparations such as sterile injectable aqueous solutions or oil suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. This sterile injectable preparation may also be a sterile injectable solution, suspension or emulsifier in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. There may be. Acceptable vehicles and solvents that can be used are water, USP Ringer's solution, and saline. In addition, sterile, fixed oils are usually used as the solvent or suspending medium, but any brand of sterile fixed oil, including synthetic mono- or di-glycerides, may be used. In addition, fatty acids such as oleic acid are used to prepare injectables.

  Injectable preparations can be prepared, for example, by filtration through a bacterial-retaining filter, or by incorporating a bactericide in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium prior to use. It can be sterilized.

  In order to prolong the effect of the drug, it is often preferable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a dispersion of crystalline or amorphous material that is difficult to dissolve in water. Therefore, the absorption rate of the drug depends on the dissolution rate, in other words, it depends on the crystal size and crystal form. Also, delayed absorption of a pharmaceutical form for parenteral administration is accomplished by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polyactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Other examples of biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot forms are also made by entrapping the drug in liposomes or microcapsules that are compatible with body tissues.

  A composition for rectal or vaginal administration is preferably dissolved and active in the rectal or vaginal cavity, such as cocoa butter, polyethylene glycol or suppository wax, which is solid at room temperature but liquid at body temperature. Suppositories that can be produced by mixing a compound of the present invention with a suitable nonirritating excipient or carrier that releases the compound.

  Similar solid compositions are also used as fillings for soft and hard capsules using excipients such as lactose or lactose, polymeric polyethylene glycols and the like.

  The active compound can also be microencapsulated with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be manufactured by coating and shelling with enteric coatings, modified release coatings and other coating methods well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound is admixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms also include, as a common practice, additional materials other than inert diluents, such as tableting lubricants, and tableting aids such as magnesium stearate and microcrystalline cellulose. You may do it. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. These can contain opacifiers and can also be compositions that release the active ingredient only at certain sites in the intestine or preferentially (may be delayed release). Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also within the scope of the present invention. Ointments, pastes, creams and gels include animal and vegetable oils, oils, waxes, paraffin, starch, tragacanth gum, cellulose derivatives, polyethylene glycol, silicon, bentonite, silicic acid, in addition to the active compounds of the present invention. Excipients such as talc and zinc oxide, or mixtures thereof can be included.

  Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide, or mixtures of these substances. The spray can further contain conventional high pressure gases such as chlorofluorohydrocarbons.

  Transdermal patches have the advantage that the delivery of the compound in the body can be controlled. Such dosage forms can be made by dissolving or suspending the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. This rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

(Antiviral activity)
According to the method of treatment of the present invention, viral infection in a patient such as a human or lower mammal is administered to the patient in an amount and number of times necessary to achieve the desired result. To be treated or prevented. As used herein, the term “anti-hepatitis C virus effective amount” of a compound of the invention is sufficient to reduce the viral load in a patient and reduce the patient's chronic HCV symptoms. Means the amount of the compound. As is well understood in the medical arts, an anti-hepatitis C virus effective amount of a compound of the present invention is reasonable in that the efficacy / risk ratio applies to any treatment.

  Depending on the improvement in the patient's condition, maintenance doses of the compounds, compositions or combinations thereof of the present invention can be administered as needed. The dose and / or number of doses can then be reduced to a level that, depending on the symptoms, improves the symptoms to a desired level, maintains the condition, and ceases treatment. However, some patients require long-term intermittent treatment due to recurrence of the condition.

  It should be understood, however, that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician's reasonable medical judgment. The specific effective amount of anti-HCV virus for a specific patient is the disease and severity to be treated, the activity of the specific compound used, the activity of the specific composition used, the patient's age, weight, general health status, gender and It depends on a variety of factors such as the diet, the time of administration of the particular compound used, the route of administration and excretion rate, the duration of treatment, the drugs used in combination or simultaneously with the particular compound used, and factors well known in the pharmaceutical art.

  The total daily dose of a compound of the invention administered to a patient in a single or divided dose is, for example, 0.01-50 mg / kg body weight, or more usually 0.1-25 mg / kg body weight. It can be an amount. A single dose composition may be administered in the above amounts, or about a quantity to meet the daily dose. In general, a treatment regimen according to the present invention consists of administering to a patient in need of such treatment from about 10 mg to about 1000 mg of a compound of the present invention in single or multiple doses per day.

(Abbreviation)
Abbreviations used in the schemes and examples herein are as follows.
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) -phosphorus amidite DAST: diethylaminosulfur trifluoride DCM: dichloromethane DIAD: diisopropyl azodicarboxylate DIBAL-H: diisobutylaluminum Halide DIEA: Diisopropylethylamine DMAP; N, N-dimethylaminopyridine DME: Ethylene glycol dimethyl ether DMEM: Dulbe Co modified Eagle's medium DMF: N, N-dimethylformamide DMSO: dimethyl sulfoxide DUPHOS:

EDANS: 5- (2-amino-ethylamino) -naphthalene-1-sulfonic acid EDC1 or EDC: 1- (3-diethylaminopropyl) -3-ethylcarbodiimide hydrochloride EtOAc: ethyl acetate HATU: O- (7-azabenzo Triazol-1-yl) -N, N, N ′, N′-tetramethyleuronium hexafluorophosphoric acid HMBA: 4-hydroxymethylbenzoic acid AM resin hoveyda catalyst: dichloro (o-isopropoxyphenylmethylene) (Tricyclohexylphosphine) ruthenium (II)
KHMDS: potassium bis (trimethylsilyl) amide MS: mesyl NMM: N-4-methylmorpholine Ph: phenyl PuPHOS:
PyBrOP: bromo-tri-pyrrolidino-phosphonium hexafluorophosphate RCM: ring closure substitution RT: room temperature RT-PCR: reverse transcription polymerase chain reaction method tBOC or Boc: tert-butyloxycarbonyl TEA: triethylamine TFA: trifluoroacetic acid THF: tetrahydrofuran TLC: Thin layer chromatography TPP or PPh3: Triphenylphosphine Xantphos: 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthine

  The chemical structures having —NH or —OH groups described herein do not represent these hydrogen atoms bonded to hydrogen or oxygen atoms, and therefore the nitrogen or oxygen atoms of such structures are not valent. Although it seems that the number is insufficient, it should be understood that the existence of such a hydrogen atom is suggested.

(Synthesis method)
The compounds and methods of this invention will be better understood by associating them with the following synthetic schemes that show how to make the compounds of this invention.

1. Substitution Methods The compounds of this invention are generally prepared using the substitution methods described in the following schemes.

  Hydroxyproline or mesylated proline precursor is used. This substitution procedure is suitable for converting a starting hydroxy (or corresponding mesylate) proline compound or derivative to a heterocyclic substituted proline derivative. The following synthetic methods illustrate the various methods and intermediate steps used to make the compounds disclosed herein.

A. Synthesis of Hydroxyproline Cyclic Peptide Precursors Cyclic peptide precursors are used to synthesize the compounds of the present invention. In some embodiments, a cyclic precursor mesylate is used.
In some embodiments, commercially available Boc-hydroxyproline A

をジオキサン中のＨＣｌで処理して出発物質Ｉｂを製造する。

Is treated with HCl in dioxane to produce starting material Ib.

Synthesis of cyclic peptide precursors

  Cyclic peptide precursor Ig is synthesized from Boc-L-2-amino-8-nonenoic acid Ia and cis-L-hydroxyproline methyl ester Ib via steps AD generally shown in Scheme 1. It was done. See US Pat. No. 6,608,027 for further details of the synthetic methods used to produce the cyclic peptide precursor Ig. This is incorporated herein by reference.

Synthesis of mesyl form of macrocyclic peptide precursor

  The cyclic precursor mesyl body was synthesized by forming a mesyl body on the hydroxyproline residue of the cyclic peptide precursor by the synthetic route generally described in Scheme 2 above.

  The compound of the present invention is obtained by synthesizing mesyl of macrocyclic peptide mesyl body IIa by a synthesis route generally described in Scheme 3, and 5-substituted-2H-tetrazole (examples of synthesis of tetrazole derivatives are described in Scheme 5 below. Manufactured) by substituting.

  The compounds of the present invention are prepared by substituting the mesyl of the macrocyclic peptide mesyl IIa with 4,5-substituted-1H-triazoles by the synthetic route generally described in Scheme 4. Synthetic examples of such triazole derivatives are described in Scheme 6 below.

B. Synthesis of Substituents for W W can be any of the substituents already described herein. The synthesis of these various substituents is within the skill of the artisan. Several synthesis examples are presented herein, but are merely illustrative and not limiting. Other substituents are commercially available or are readily synthesized by those skilled in the art.

Synthesis of tetrazole Tetrazoles Va-Vq of various structures were synthesized from commercially available nitrile compounds as described in Scheme 5 below.

  One skilled in the art will recognize that some 5-substituted tetrazole compounds can be prepared by the process using any nitrile-containing compound suitable for the reaction conditions described above.

Synthesis of triazole

  The triazoles of the present invention are prepared by reacting commercially available or alkyne compounds VIa and trimethylsilyl azide, prepared by methods described below, using the synthetic route generally described in Scheme 6. Commercially available alkynes suitable for the formation of triazoles include, but are not limited to:

Alkyne Synthesis Alkynes useful for the synthesis of triazoles are prepared by any suitable method. The following is a synthesis example.

Sonogashira reaction

The alkyne used in the present invention is a synthetic route generally described in Scheme 7, primary alkyne compound VIIa, aryl is a ride (Y-halide), and triethylamine in acetonitrile in PdCl ₂ (PPh ₃ ) _2. And the Sonogashira reaction with Cul.
Commercially available aryl halides suitable for the Sonogashira reaction include, but are not limited to:

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

Synthesis of alkynylamides

  Additional alkynes used in the present invention can be prepared by reacting alkynyl acids Va, BOP, and DIEA with amine VIIIb in DMF by the synthetic route generally described in Scheme 8.

Modification after substitution The obtained macrocyclic compound can be modified after W is bonded thereto. Some examples of modifications are as follows.
1. Synthesis of phenol esters

  Acquisition of various phenolic esters by post-substitutional modification of macrocycle IIIa was performed by the synthetic route generally described in Scheme 9.

2. Hydrolysis of macrocyclic peptide ethyl ester

  Hydrolysis of the macrocyclic peptide ethyl ester of the present invention is carried out by the synthetic route generally described in Scheme 10 by dissolving the macrocyclic peptide ethyl ester IV in dioxane and then adding 1M LiOH.

スキーム１１に一般的に記載されている合成ルートで、ブロモ置換チアゾール大環状エチルエステル（以下の合成実施例２６参照）にＤＭＥ、芳香族ボロン酸、炭酸セシウム及びＫＦを加えるスズキカップリング法を行うことによって、本発明の化合物をさらに多様化することができる。 3. Further bi-aryl compounds are produced using the Suzuki coupling method

The synthetic route generally described in Scheme 11 is a Suzuki coupling method in which DME, aromatic boronic acid, cesium carbonate and KF are added to a bromo-substituted thiazole macrocyclic ethyl ester (see Synthesis Example 26 below). As a result, the compounds of the present invention can be further diversified.

II. Stepwise Synthesis The compounds of the present invention can also be prepared by stepwise synthesis rather than by substitutional means. The following is a synthesis example when W is tetrazole.

A. Synthesis of proline derivatives

  B. Synthesis of linear tripeptides

テトラゾール−置換プロリン誘導体を含有している線状トリペプチドＸＩＩＩｄはスキーム１３に一般的に記載されている合成ルートで製造された。

The linear tripeptide XIIId containing a tetrazole-substituted proline derivative was prepared by the synthetic route generally described in Scheme 13.

C. Synthesis of cyclic peptides by ring-closing substitution (RCM)

  Formation of macrocyclic compound XIVb was performed by the ring-closing substitution reaction generally described in Scheme 14 using linear tripeptide XIIId.

D. Other derivatives The tetrazole substituted proline derivatives of the present invention were prepared by the synthetic route generally described in Scheme 12.

  Additional tetrazole-substituted proline derivatives of the present invention were prepared by the synthetic route generally described in Scheme 15.

2. Suzuki coupling

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

III. Solid Phase Synthesis Some compounds of the present invention are suitable for synthesis by solid phase synthesis. For example, a triazole substituted proline derivative (P2) can be synthesized and used in the construction of a linear tripeptide chain on a resin. Resin-bound tripeptides containing triazole-substituted proline derivatives undergo a ring-closing substitution (RCM) and become cyclic tripeptides that yield the final product upon hydrolysis.
The following synthetic scheme shows a method for preparing triazole substituted proline derivatives and solid phase synthesis of the compounds of the present invention.

A. Synthesis of Proline Derivatives Two methods used for the synthesis of triazole substituted proline derivatives are described in the following schemes.

トリアゾリルプロリン誘導体を生成する環付加法は、スキーム１７に一般的に記載されている合成ルートで、アジドプロリン誘導体ＸＶＩＩａとアルキンＶＩＩｂとの３＋２環付加を包含している。アルキンの合成例は上記スキーム７に記載されている。 1. Ring addition method

The cycloaddition method to produce the triazolyl proline derivative involves the 3 + 2 ring addition of the azidoproline derivative XVIIa and alkyne VIIb in the synthetic route generally described in Scheme 17. Synthetic examples of alkynes are described in Scheme 7 above.

さらなるプロリン誘導体はスキーム１８に一般的に記載されている合成ルートで、メシル体ＸＶＩＩＩａを４，５−置換−１Ｈ−トリアゾールと置換することによって製造された。 2. Mesylation method

Additional proline derivatives were prepared by replacing the mesyl form XVIIIa with 4,5-substituted-1H-triazoles by the synthetic route generally described in Scheme 18.

B. Construction on resin and RCM on resin

Construction on the resin Construction of the linear peptide XIXd on the resin and subsequent acquisition of the resin-bound cyclic peptide precursor XIXe by on-resin RCM was performed via steps AD generally described in Scheme 19.

IV. Other Reactions In some embodiments, the substituent W is well suited to other types of reactions. For example, but not limited to, when W is pyridazinone, the following reaction scheme is used. These methods are used for other substituents, but are discussed herein for pyridazinone.

A. Condensation reaction

  Using the Mitsunobu reaction followed by hydrolysis with LiOH, the simplest method is to condense a commercially available pyridazinone (XXa-1 to XXa-4) with the major intermediate as shown in Scheme 20. It is. Further details of the Mitsunobu reaction can be found in O.D. 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).

  A second method for preparing the pyridazinone analogs of the present invention is to further chemically manipulate the di-bromo intermediate XXIa (Scheme 21). When a commercially available 4,5-dibromopyridazinone is coupled with a hydroxy compound and standard Mitsunobu coupling, the desired macrocycle XXIa is obtained. Coupling XXIa with excess 3-thiopheneboronic acid, cesium carbonate and potassium fluoride yields dithiophene XXIb. Compounds XXIa and XXIb are hydrolyzed with LiOH to give the desired analogs XXId and XXIc, respectively. Many different boronic acids can be used in the same way to produce large quantities of di-substituted pyridazinonyl macrocycles.

B. Bromine differentiation reaction

  Differentiation between bromine on macrocycle XXIa is achieved by Michael addition. As shown in Scheme 22, when commercially available pyrrolidine is coupled with dibromide, compound XXIIa is obtained in 87% yield. The bromine site adjacent to the carbonyl then undergoes Suzuki coupling with 3-thiopheneboronic acid to produce intermediate XXIIb, which is further treated with LiOH to give analog XXIIc. For further details of the Suzuki coupling reaction, see A. Suzuki, Pure Appl. Chem. 63, 419-422 (1991) and A.R. R. Martin, Y .; Yang, Acta Chem. Scand. 47, 221-230 (1993).

C. Sulfur-containing nucleophile

The secondary amine nucleophilic pyrrolidine adds only to the 5-bromine position of macrocycle XXIa, whereas sulfur-containing nucleophiles do not show similar selectivity as shown in Scheme 23. According to the sulfur-containing nucleophile, the addition of XXIa to the two bromines was observed along with the monocoupled product XXIIIa, which is only monovalent mercaptopimidine. Separation of compounds XXIIIa, XXIIIb and starting material XXIa by flash chromatography allows further Suzuki coupling of mono-alkylated form XXIIIa with 3-thiopheneboronic acid, followed by hydrolysis of XXIIId with LiOH to give analog XXIIIe Obtained. Dialkylated form XXIIIb is also hydrolyzed with LiOH to produce analog XXIIIc.
D. Suzuki coupling with boronic acid

  Since only a limited number of boronic acids can be used for Suzuki coupling, other coupling methods such as Still coupling and N-arylation using Buchwald's chemistry. Was also examined (Scheme 24). Coupling of the intermediate XXIa with 2-stannylthiazole according to Stille standard conditions followed by hydrolysis gave the analog XXIVa. As N-arylation, the coupling of imidazole to di-brominated product 6 proceeded smoothly. Unfortunately, hydrolysis with LiOH resulted in substitution of imidazole with methoxy in position 5 (XXIVb). For further details regarding the styrene coupling reaction, see J. Am. K. Stille, Angew. Chem. Int. Ed. 25, 508-524 (1986); Pereyre et al. , Tin in Organic Synthesis (Butterworths, Boston, 1987) pp 185-207 passim. ,; And T. N. See Mitchell, Synthesis 1992, 803-815. For further details of the Buchwald reaction, see J. Am. F. Hartwing, Angew. Chem. Int. Ed. 37, 2046-2067 (1998).

E. Various other pyridazinone analogs

  Other methods for various pyridazinone analogs are outlined in Scheme 25. Michael addition of sodium azide as a nucleophile to di-bromo XXIa produced only the mono-coupled compound XXVa, as in the case of secondary amines. Furthermore, Suzuki coupling with 3-thiopheneboronic acid yielded the azide XXVb. Compound XXVb is hydrolyzed to give analog XXVc. Further, the azide moiety of compound XXVb is converted to tetrazole with sodium cyanide under standard conditions and then hydrolyzed to give analog XXVd.

F. Synthesis of 5,6-pyridazinoyl macrocycle

The synthesis of 5,6-pyridazinoyl macrocycle XXVIb is outlined in Scheme 26. Condensation of commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one with the major intermediate If by Mitsunobu condensation gives compound XXVIa. The product XXVIa is further subjected to Suzuki coupling conditions with 3-thiopheneboronic acid and then hydrolyzed to give the desired analog XXVIb.
(Example)

  The compounds and processes of the present invention will be better understood by considering the following examples, which are illustrative and do not limit the invention in any way. Many variations and modifications to the disclosed examples will be apparent to those skilled in the art and are not limited to, but are limited to, the chemical structures, substituents, derivatives, formulas and / or methods of the present invention. And modifications can be made without departing from the spirit of the invention and the scope of the appended claims.

Synthesis of cyclic peptide precursors

1A.
To a solution of Boc-L-2-amino-8-nonane-enoic acid 1a (1.36 g, 5 mol) and commercially available cis-L-hydroxyproline methyl ester 1b (1.09 g, 6 mol) in DMF (15 ml) , DIEA (4 ml, 4 eq) and HATU (4 g, 2 eq) were added. Coupling was performed at 0 ° C. for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and then 5% citric acid (2 × 20 ml), water (2 × 20 ml), 1M NaHCO ₃ (4 × 20 ml) and brine (2 × 10 ml). Respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off to obtain dipeptide 1c (1.91 g, 95.8%), HPLC (retention time: 8.9 minutes, 30-70%, 90%). B) and MS (found: 421.37, M + Na ⁺ ).

1B.
This dipeptide 1c (1.91 g) was dissolved in dioxane (15 mL) and 1N aqueous LiOH solution (15 ML), and a hydrolysis reaction was performed at room temperature for 4 hours. The reaction mixture was acidified with 5% citric acid, extracted with EtOAc (100 mL) and washed with water (2 × 20 ml), 1M NaHCO ₃ (2 × 20 mL) and brine (2 × 20 ml), respectively. Washed. The organic layer was dried over anhydrous Na ₂ SO ₄ and removed under reduced pressure to give the free carboxylic acid compound 1d (1.79 g, 97%), which was used in the next synthetic step without further purification.

1C.
The free carboxylic acid obtained above (1.77 g, 4.64 mmol) was dissolved in DMF (5 ml) and D-β-vinylcyclopropane amino acid ethyl ester 1e (0.95 g, 5 mmol), DIEA ( 4 ml, 4 eq) and HATU (4 g, 2 eq) were added. Coupling was performed at 0 ° C. for 5 hours. The reaction mixture was diluted with EtOAc (80 mL) and 5% citric acid (2 × 20 ml), water (2 × 20 ml), 1M NaHCO ₃ (4 × 20 ml) and brine (2 × 10 ml). ) Respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated. The residue was purified by flash chromatography on silica gel using different ratios of hexane: EtOAc (5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5) as the eluting layer. The eluate was removed and linear peptide 1f (1.59 g, 65.4%) was isolated as an oil, HPLC (retention time: 11.43 min) and MS (found: 544.84, M + Na ⁺ ).

1D. Ring closure substitution (RCM)
Linear peptide 1f (1.51 g, 2.89 mmol) in dry DCM (200 ml) solution of the foamed to deoxygenated _{N 2.} Hoveyda's first generation catalyst (Hoveyda's 1 ^st catalyst: 5 mol%, 1 equivalent) was added as a solid phase. The reaction was refluxed for 12 hours under N ₂ atmosphere. The solvent was distilled off and the residue was flash chromatographed on silica gel using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2 → 1: 5) as elution layer. Purified. Upon removal of the eluate, cyclic peptide precursor 1 (1.24 g, 87%) was isolated as a white powder, HPLC (retention time: 7.84 min, 30-70%, 90% B) and MS (actual value) : 516.28, M + Na ⁺ ). See US Pat. No. 6,608,027 for further details of the synthetic methods used to produce cyclic peptide precursor 1. This is incorporated herein by reference.

Synthesis of mesylated cyclic peptide precursors.

2A.
To a solution of macrocyclic peptide precursor 1 (500 mg, 1.01 mmol) and DIEA (0.4 ml, 2 mmol) in DCM (2.0 ml) was slowly added mesyl chloride (0,1 ml) at 0 ° C. The reaction was continued for 3 hours. Then added EtOAc (30 ml), (2 x 20ml) 5% citric acid, water (2 x 20ml), respectively of NaHCO ₃ 1M (2 x 20ml) and brine (2 x 10ml) Washed. The organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated to give the title mesylated compound that was used in the next synthetic step without purification.

Tetrazole synthesis Various tetrazole IIIa-IIIq used in the synthesis of the tetrazole macrocycle of the present invention was synthesized from commercially available nitrile compounds as follows.

In a sealed tube containing xylene (5 ml), 3-Cl-4-hydroxy-benzoacetonitrile (0.31 g, 5 mol), NaN3 (0.65 g, 10 mmol) and triethylamine hydrochloride (0.52 g, 3 mmol) Was added. The mixture was stirred vigorously for 20-30 hours. The reaction mixture was cooled and poured into a mixture of EtOAc (30 ml) and aqueous citric acid (20 mL). After washing with water (twice with 10 ml) and brine (twice with 10 ml), the organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was distilled off to obtain a yellow solid. Recrystallization from EtOAc-hexane gave tetrazole compound 3a in good yield (0.4 g, 86%), high purity (90% or higher by HPLC), NMR and MS (found: 197.35 and 199). .38, M + H ⁺ ).

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

  Synthesis of proline derivatives

To a solution of N-Boc-cis-hydroxyproline methyl ester 4a (10 g, 40.8 mmol) and N, N-diisopropylethylamine (DIEA, 12 mL, 60 mmol) in DCM (110 mL) was added mesyl chloride (3.85 mL, 50 mL). Mmol) was added dropwise and the reaction mixture was stirred at 0 ° C. for 3 h. TLC (Hexane ethyl acetate = 1: 1, v / v) showed that all Boc-cis-Hyp-OMe4a was converted to its mesyl form 4b. After the reaction was deemed complete by TLC, the reaction mixture was diluted with EtOAc (100 ml), washed with 5% citric acid (2 x 50 ml) and brine (2 x 30 ml) and the organic layer Was dried over anhydrous Na ₂ SO ₄ . The solvent was removed to give 13 g (98% yield) of N-Boc-cis-4-mesylated-proline methyl ester 4b, which was used in Step B without further purification.

To a solution of mesyl 4b (0.65 g, 2 mmol) in DMF (5 mL), 5-phenyl-1H-tetrazole (4 mmol) and anhydrous sodium carbonate (0.53 g, 5 mmol) were added. The resulting reaction mixture was stirred vigorously at 60 ° C. for 6-12 hours. TLC (ethyl hexane acetate = 1: 1, v / v) showed that mesyl 4b was completely converted to 4-tetrazole-substituted proline derivative 4c. After the reaction was deemed complete by TLC, the reaction mixture was diluted with EtOAc (30 ml) and washed with 1M Na ₂ CO ₃ (3 × 10 ml), water (3 × 10 ml), 5% citric acid. (3 times with 10 ml) and brine (3 times with 10 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 5-phenyltetrazole substituted proline derivative 4c in excellent yield (94%) and high purity (> 90%). 4c: Yield 94%, “M + Na] ⁺ = 396.39

Synthesis of linear tripeptides

A.
(1) N-Boc-trans-4- (3-phenyltetrazolyl) -proline methyl ester 4c (0.22 g, 0.6 mmol) was dissolved in dioxane (6 mL) and (2 mL) 1N aqueous LiOH solution. Dipeptide 4e was prepared. The reaction mixture was stirred at room temperature for 3-8 hours to hydrolyze the methyl ester. The reaction mixture was acidified with 5% citric acid, extracted with EtOAc (40 mL) and washed with water (2 × 20 ml), 1M Na ₂ CO ₃ (2 × 20 ml) and brine (2 × 10 ml). Each was washed. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a free carboxylic acid compound (0.20 g, 92%). This was used in the next step without the need for further purification.
(2) Cooled (0 ° C.) D-β-vinylcyclopropane amino acid ethyl ester 4d (0.1 g, 0) was added to a DMF (2 ml) solution of the free acid (0.20 g, 0.55 mmol) obtained above. .52 mmol), DIEA (0.4 ml, 4 eq) and HATU (0.4 g, 2 eq) were added. The resulting reaction mixture was stirred at 0 ° C. for 0.5-3 hours. The reaction mixture was diluted with EtOAc (40 ml), (2 x 20 ml) 5% citric acid, water (2 x 20 ml), (4 × 20 ml) NaHCO ₃ with 1M and brine (2 × 10ml ) Respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give dipeptide 4e (0.24 g, 94%). Identified by HPLC (retention time: 10.03 min) and MS (found: 519.22, M + Na ⁺ ).

B.
(1) Dipeptide 4e (0.24 g, 0.49 mmol) amine was deprotected in TFA (2 mL) at 0 ° C. for 10 minutes to prepare 4 g of tripeptide. After removing TFA under reduced pressure, the free amine product was directly subjected to the next coupling step.
(2) To a cooled (0 ° C.) solution of the free amine compound obtained above in DMF (2 ml), Boc-2-amino-8-decane-enoic acid 4f (0.136 g, 0.50 mmol), DIEA (0.4 ml, 4 eq) and HATU (0.4 g, 2 eq) were added. Coupling was performed at 0 ° C. for 0.5 (30 minutes) to 3 hours. The reaction mixture was diluted with EtOAc (40 ml), (2 x 20 ml) 5% citric acid, water (2 x 20 ml), (4 × 20 ml) NaHCO ₃ with 1M and brine (2 × 10ml ) Respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 4 g of tripeptide (0.28 g, 88% over 2 steps). Identification by HPLC (retention time: 14.03 min) and MS (found: 672.30, M + Na ⁺ ).

Synthesis of cyclic peptides by ring-closing substitution (RCM)

A.
Linear peptide 4g (71 mg, 0.109 mmol) was deoxygenated by bubbling _{N 2} dry DCM (50 ml) solution of. To the resulting degassed solution, Hoveyda's first generation catalyst (Hoveyda's 1 ^st Cat. 5-10 mol%, equivalent) was added as a solid phase, and the resulting reaction mixture was added for 5-20 hours or more in N Refluxed under ₂ atmospheres. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1 → 1: 2) as the eluting layer. Purified by chromatography. The elution solvent was distilled off to obtain macrocyclic peptide 4i (58 mg, 85.5%) as a white powder, HPLC (retention time: 11.80 minutes, 30-80%, 90% B) and MS (actual value: 640.66, M + Na ⁺ ).

IV. Hydrolysis of ethyl ester Compound 4i (20 mg) was dissolved in dioxane (2 mL) and 1N aqueous LiOH (1 mL) to prepare the title compound. The resulting reaction mixture was stirred at room temperature for 4-8 hours. The reaction mixture was then acidified with 5% citric acid, extracted with EtOAc (10 mL) and washed with water (2 × 20 ml). The solvent was removed and the residue was purified by HPLC on a YMC AQ12S11-052WT column with a 30-80% (100% acetonitrile) gradient for 20 minutes. Lyophilization gave the title compound as a white amorphous solid.
[M + Na] ⁺ = 616.72

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 2-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

5A. Synthesis of Proline Derivative The proline derivative of this example was prepared from the method described in Example 4 (I) using 5- (2-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a. It was prepared with.
[M + Na] ⁺ = 396.39
5B. Synthesis of Linear Tripeptide Using the linear peptide of this example, the proline derivative prepared in Step 5A, D-β-vinylcyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonane-enoic acid And prepared by the method described in Example 4 (II).
[M + Na] ⁺ = 728.41

5C. Ring closure substitution The macrocyclic peptide ethyl ester of this example was prepared by the method described in Example 4 (III) using the linear peptide of step 5B.
[M + Na] ⁺ = 722.37
5D. Hydrolysis of ethyl ester The title compound was finally obtained from the ethyl ester of step 5C by hydrolysis as described in Example 4 (IV).
[M + H] ⁺ = 672.49

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 3-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

6A. Synthesis of Proline Derivative The proline derivative of this example was prepared from the method described in Example 4 (I) using 5- (3-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a. It was prepared with.
[M + Na] ⁺ = 396.39
6B. Synthesis of Linear Tripeptide Using the linear peptide of this example, the proline derivative prepared in Step 6A, D-β-vinylcyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonane-enoic acid And prepared by the method described in Example 4 (II).
[M + Na] ⁺ = 728.41

6C. Ring closure substitution The macrocyclic peptide ethyl ester of this example was prepared by the method described in Example 4 (III) using the linear peptide of step 6B.
[M + Na] ⁺ = 722.37
6D. Hydrolysis of the ethyl ester The title compound was finally obtained from the ethyl ester of step 6C by hydrolysis as described in Example 4 (IV).
[M + H] ⁺ = 672.49

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 4-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

7A. Synthesis of Proline Derivative The proline derivative of this example was prepared according to the method described in Example 4 (I) using 5- (4-bromophenyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a. It was prepared with.
[M + Na] ⁺ = 396.39
7B. Synthesis of Linear Tripeptide Using the linear peptide of this example, the proline derivative prepared in Step 7A, D-β-vinylcyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonane-enoic acid And prepared by the method described in Example 4 (II).
[M + Na] ⁺ = 728.41

7C. Ring closure substitution The macrocyclic peptide ethyl ester of this example was prepared by the method described in Example 4 (III) using the linear peptide of step 7B.
[M + Na] ⁺ = 722.37
7D. Hydrolysis of the ethyl ester The title compound was finally obtained from the ethyl ester of Step 7C by hydrolysis as described in Example 4 (IV).
[M + H] ⁺ = 672.49

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 5-bromo-2-thienyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

8A. Synthesis of Proline Derivative The proline derivative of this example was prepared in Example 4 (I) using 5- (5-bromo-2-thienyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a. Prepared as described.
[M + Na] ⁺ = 480.23

8B. Synthesis of Linear Tripeptide Using the linear peptide of this example, the proline derivative prepared in Step 8A, D-β-vinylcyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonane-enoic acid And prepared by the method described in Example 4 (II).
[M + Na] ⁺ = 634.29

8C. Ring closure substitution The macrocyclic peptide ethyl ester of this example was prepared by the method described in Example 4 (III) using the linear peptide of step 8B.
[M + Na] ⁺ = 736.21
8D. Hydrolysis of ethyl ester The title compound was finally obtained from the ethyl ester of Step 8C by hydrolysis as described in Example 4 (IV).
[M + H] ⁺ = 678.22

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 2-bromo-4-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

9A. Synthesis of Proline Derivative The proline derivative of this example was prepared in Example 4 (I) using 5- (2-bromo-4-pyridyl) -1H-tetrazole and N-Boc-cis-hydroxyproline methyl ester 4a. Prepared as described.
[M + Na] ⁺ = 453.23

9B. Synthesis of Linear Tripeptide Using the linear peptide of this example, the proline derivative prepared in Step 9A, D-β-vinylcyclopropane amino acid ethyl ester, and Boc-2-amino-8-nonane-enoic acid And prepared by the method described in Example 4 (II).
[M + Na] ⁺ = 629.31

9C. Ring closure substitution The macrocyclic peptide ethyl ester of this example was prepared by the method described in Example 4 (III) using the linear peptide of step 9B.
[M + Na] ⁺ = 723.46

9D. Hydrolysis of the ethyl ester The title compound was finally obtained from the ethyl ester of Step 9C by hydrolysis as described in Example 4 (IV).
[M + H] ⁺ = 673.26

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 2-biphenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

To the deoxygenated solution of the ethyl ester compound of Step 5C obtained above (40 mg), phenylboronic acid (10 mg), KF (100 mg) and Cs ₂ CO ₃ (80 mg) in DME (5 ml), Pd (PPh ₃ ) ₄ (5 mg) was added in solid form. The resulting reaction mixture was heated to 90 ° C. in an oil bath and stirred vigorously for 6-12 hours. The solvent was removed and the residue was purified by flash chromatography on silica gel using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1 → 2: 1) as the eluting layer. The elution solvent was distilled off to give the macrocyclic bi-aryl peptide ethyl ester (31 mg, 78%) as a white powder which was directly hydrolyzed as previously described in Example 4 (IV). And purified by HPLC.
[M + Na] ⁺ = 692.38

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = 3-biphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the ethyl ester from step 6C Prepared by hydrolyzing the ethyl ester using the compound and phenylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 692.38

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , where Q = chemical bond, Y = 4-biphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the ethyl ester from step 7C Prepared by hydrolyzing the ethyl ester using the compound and phenylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 692.38

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = 3- (3-thienyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by hydrolysis of the ethyl ester using the ethyl ester compound from 6C and 3-thienylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 698.32

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II where Q = chemical bond, Y = 3- (p-trifluoromethoxyphenyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H By hydrolyzing the ethyl ester using the ethyl ester compound from step 6C and p-trifluoromethoxyphenylboronic acid according to the method described in Example 10 and then according to the method of Example 4 (IV). Prepared.
[M + Na] ⁺ = 776.35

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 3- (p-cyanophenyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by hydrolysis of the ethyl ester using the ethyl ester compound from Step 6C and p-cyanophenylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 692.38

A = tBOC, G = OH, L = chemical bond, W is

Compound of formula II , where Q = chemical bond, Y = 4- (3-thienyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by hydrolysis of the ethyl ester using the ethyl ester compound from 7C and 3-thienylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 698.32

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II where Q = chemical bond, Y = 4- (p-trifluoromethoxyphenyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H By hydrolyzing the ethyl ester using the ethyl ester compound from step 7C and p-trifluoromethoxyphenylboronic acid according to the method described in Example 10 and then according to the method of Example 4 (IV). Prepared.
[M + Na] ⁺ = 776.35

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 4- (p-cyanophenyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by hydrolysis of the ethyl ester using the ethyl ester compound from Step 7C and p-cyanophenylboronic acid as described in Example 10 and then according to the method of Example 4 (IV).
[M + Na] ⁺ = 692.38

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , where Q = chemical bond, Y = 5-phenyl-2-thienyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is prepared from step 8C Was prepared by hydrolyzing the ethyl ester according to the method described in Example 10 and then according to the method of Example 4 (IV) using the ethyl ester compound from
[M + Na] ⁺ = 698.32

A = tBOC, G = OH, L = chemical bond, W is

The compound of the formula II , where Q = chemical bond, Y = 5-phenyl-3-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is prepared from step 9C Was prepared by hydrolyzing the ethyl ester according to the method described in Example 10 and then according to the method of Example 4 (IV) using the ethyl ester compound from
[M + Na] ⁺ = 708.30

A = tBOC, G = OEt, L = chemical bond, W is

Q = chemical bond, Y = 3-chloro-4-hydroxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Substitution Method The title compound was prepared by substituting mesyl body 2 and tetrazole 3a. The substitution method is by dissolving 0.041 mmol of macrocyclic peptide precursor mesyl body 2 and 0.123 mmol of tetrazole 3a in DMF (3 mL) and adding sodium carbonate (60 mg, 0.246 mmol). Yes. The resulting reaction mixture is stirred at 60 ° C. for 4-10 hours, then cooled and extracted with ethyl acetate. The organic layer is washed with water (2 x 30 ml) and the organic solution is concentrated under reduced pressure for use in the crude form for hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 3-chloro-4-hydroxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by dissolving the compound of Example 4 (20 mg) in dioxane (2 mL) and 1N aqueous LiOH (1 mL). The resulting reaction mixture was stirred at room temperature for 4-8 hours. The reaction mixture was approved with 5% citric acid, extracted with EtOAc (10 mL) and washed with water (2 × 20 ml). The solvent was removed and the residue was purified by HPLC on a YMC AQ12S11-052WT column with a 30-80% (100% acetonitrile) gradient for 20 minutes. Lyophilization gave the title compound as a white amorphous solid.
[M + Na] ⁺ = 666.24

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = 3-bromo-4-hydroxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using tetrazole 3b of 2 and Example 3.
[M + Na] ⁺ = 712.18

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = 2-methoxy-4-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22 using tetrazole 3c of 2 and Example 3.
[M + Na] ⁺ = 708.30

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 3-methoxy-4-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester using the mesyl derivative 2 and tetrazole 3d of Example 3 followed by the method of Example 22.
[M + Na] ⁺ = 708.30

A = tBOC, G = OH, L = chemical bond, W is

The compound of the formula II , wherein Q = chemical bond, Y = n-propyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the mesyl compound 2 and example 3 Was prepared by hydrolysis of the ethyl ester by the substitution method described in Example 21, followed by the method of Example 22.
[M + Na] ⁺ = 582.33

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = n-butyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Was prepared by hydrolysis of the ethyl ester by the method described in Example 21, followed by the method of Example 22.
[M + Na] ⁺ = 596.36

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3 g of tetrazole of 3.
[M + Na] ⁺ = 660.92

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 4-propoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3 tetrazole 3h.
[M + Na] ⁺ = 674.29

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 4-butoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3 tetrazole 3i.
[M + Na] ⁺ = 688.32

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 3-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3 tetrazole 3j.
[M + Na] ⁺ = 646.92

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II in which Q = chemical bond, Y = 3,4-dimethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by tetrazole 3k of Example 3 by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22.
[M + Na] ⁺ = 676.38

A = tBOC, G = OH, L = chemical bond, W is

であり、Ｑ＝化学結合、Ｙ＝４−メトキシ−１−ナフチル、ｊ＝３、ｍ＝ｓ＝１、そしてＲ ^３ ＝Ｒ ^４ ＝Ｈである、式ＩＩの化合物
標題化合物を、メシル体２及び実施例３のテトラゾール３ｌを用いて、実施例２１に記載の置換方法、次いで実施例２２の方法によるエチルエステルの加水分解によって調製した。
［Ｍ＋Ｎａ］^＋＝６９７．００

A compound of the formula II in which Q = chemical bond, Y = 4-methoxy-1-naphthyl, j = 3, m = s = 1 and R ³ = R ⁴ = H And tetrazole 3l of Example 3 was prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22.
[M + Na] ⁺ = 697.00

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 4-phenoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3 tetrazole 3m.
[M + Na] ⁺ = 708.51

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II in which Q = chemical bond, Y = benzyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22 using 3n.
[M + Na] ⁺ = 630.35

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = p-phenylbenzyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22, using 3 tetrazole 3o.
[M + Na] ⁺ = 706.38

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 3-chlorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 3-chlorophenyl) -1H-tetrazole.
[M + Na] ⁺ = 650.33

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 3-fluorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by (3-fluorophenyl) -1H-tetrazole by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22.
[M + Na] ⁺ = 634.37

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II in which Q = chemical bond, Y = 3-methoxyphenyl, j = 3, m = s = 1 and R ³ = R ⁴ = H Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using (3-methoxyphenyl) -1H-tetrazole.
[M + Na] ⁺ = 646.92

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 3-phenoxyphenyl, j = 3, m = s = 1 and R ³ = R ⁴ = H Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using (3-phenoxyphenyl) -1H-tetrazole.
[M + Na] ⁺ = 708.51

A = tBOC, G = OH, L = chemical bond, W is

A compound of the formula II in which Q = chemical bond, Y = 3-benzyloxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H , the mesyl compounds 2 and 5 Prepared by the replacement method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using-(3-benzyloxyphenyl) -1H-tetrazole.
[M + Na] ⁺ = 722.32

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II in which Q = chemical bond, Y = 3-trifluoromethylphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 5- (3-trifluoromethylphenyl) -1H-tetrazole.
[M + Na] ⁺ = 684.32

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using (4-bromophenyl) -1H-tetrazole.
[M + Na] ⁺ = 696.28

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-fluorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using (4-fluorophenyl) -1H-tetrazole.
[M + Na] ⁺ = 634.36

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using (4-methoxyphenyl) -1H-tetrazole.
[M + Na] ⁺ = 646.36

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by (4-ethoxyphenyl) -1H-tetrazole by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22.
[M + Na] ⁺ = 660.92

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II in which Q = chemical bond, Y = 4-trifluoromethylphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 5- (4-trifluoromethylphenyl) -1H-tetrazole.
[M + Na] ⁺ = 684.32

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II wherein Q = chemical bond, Y = 3,5-di (trifluoromethyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H By the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22, using mesyl derivative 2 and 5- (3,5-di (trifluoromethyl) phenyl) -1H-tetrazole. Prepared.
[M + Na] ⁺ = 766.32

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = The title compound of formula II, which is H, is obtained using mesyl 2 and 5- (4- (N, N-dimethylamino) -3,5-di (trifluoromethyl) phenyl) -1H-tetrazole, Prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22.
[M + Na] ⁺ = 695.39

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = 2,4-dichlorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is converted to mesyl compounds 2 and 5 Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using-(2,4-dichlorophenyl) -1H-tetrazole.
[M + Na] ⁺ = 684.27

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = 3,5-dichlorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using-(3,5-dichlorophenyl) -1H-tetrazole.
[M + Na] ⁺ = 684.27

A = tBOC, G = OH, L = chemical bond, W is

The compound of the formula II , wherein Q = chemical bond, Y = 3,4-dichlorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is obtained as mesyl compounds 2 and 5 Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using-(3,4-dichlorophenyl) -1H-tetrazole.
[M + Na] ⁺ = 684.27

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 2-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22 using mesyl 2 and 5- (2-pyridyl) -1H-tetrazole.
[M + Na] ⁺ = 617.60

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 2-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22 using mesyl 2 and 5- (2-pyridyl) -1H-tetrazole.
[M + Na] ⁺ = 617.60

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 3-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by the substitution method described in Example 21, followed by hydrolysis of the ethyl ester by the method of Example 22 using mesyl 2 and 5- (3-pyridyl) -1H-tetrazole.
[M + Na] ⁺ = 645.24

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 4-pyridyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Prepared by the substitution method described in Example 21 followed by hydrolysis of the ethyl ester by the method of Example 22 using 4-pyridyl) -1H-tetrazole.
[M + H] ⁺ = 595.50

A = tBOC, G = OH, L = chemical bond, W is

Q = chemical bond, Y = 4-methoxy-3-bromophenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

57A. Formation of tetrazole The tetrazole of this example was prepared by dissolving 4-hydroxy-3-bromo-4-hydroxy-benzonitrile in DMF, adding methyl iodide and stirring at room temperature for 3-12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic layer was then dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 3-bromo-4-methoxy-benzonitrile. This compound was then used to form the corresponding tetrazole in the manner described in Example 3.
The title compound was prepared using the substitution method described in Example 21 using the mesyl compound 2 and 57A of 5- (3-bromo-4-methoxy-phenyl) -1H-tetrazole, followed by the ethyl ester according to the method of Example 22. Prepared by hydrolysis.
[M + Na] ⁺ = 724.91

A = tBOC, G = OH, L = chemical bond, W is

Compound of formula II 58A. , Wherein Q = chemical bond, Y = 4- (methylcyclopropane) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of tetrazole The tetrazole of this example was prepared by dissolving 4-cyano-phenol in DMF, adding (bromomethyl) cyclopropane and stirring at room temperature for 3-12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic layer was then dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 4- (methylcyclopropane) benzonitrile. This compound was then used to form the corresponding tetrazole in the manner described in Example 3.
The title compound was obtained using the mesyl compound 2 and 58A 5- (4- (methylcyclopropane) -phenyl) -1H-tetrazole as described in Example 21, followed by the ethyl ester according to the method of Example 22. Prepared by hydrolysis.
[M + Na] ⁺ = 686.29

A = tBOC, G = OH, L = chemical bond, W is

であり、Ｑ＝化学結合、Ｙ＝３−クロロ−４−（メチルシクロプロパン）フェニル、ｊ＝３、ｍ＝ｓ＝１、そしてＲ ^３ ＝Ｒ ^４ ＝Ｈである、式ＩＩの化合物
標題の化合物を、実施例２１の標題化合物であるエチルエステルを精製せずに用い、（ブロモメチル）シクロプロパンを加えて、６０℃で３〜１２時間撹拌して調製した。得られた反応混合物を室温まで冷却し、ＥｔＯＡｃ：水の５０：５０混合物に注下し、水で洗浄して、減圧下で濃縮した。得られた粗製のエチルエステル化合物を次いで、実施例２２に記載の方法で遊離酸に加水分解した。
［Ｍ＋Ｎａ］^＋＝７２０．２４

Where Q = chemical bond, Y = 3-chloro-4- (methylcyclopropane) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H The compound was prepared by using the ethyl ester, the title compound of Example 21, without purification, adding (bromomethyl) cyclopropane and stirring at 60 ° C. for 3-12 hours. The resulting reaction mixture was cooled to room temperature, poured into a 50:50 mixture of EtOAc: water, washed with water and concentrated under reduced pressure. The resulting crude ethyl ester compound was then hydrolyzed to the free acid by the method described in Example 22.
[M + Na] ⁺ = 720.24

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , where Q = chemical bond, Y = 3-chloro-4-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared following the method described in Example 59 using the title compound of Example 21 and methyl iodide.
[M + Na] ⁺ = 680.23

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , where Q = chemical bond, Y = 3-chloro-4-ethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared following the method described in example 59 using the title compound of example 21 and ethyl iodide.
[M + Na] ⁺ = 694.28

A = tBOC, G = OH, L = chemical bond, W is

The compound of formula II , where Q = chemical bond, Y = 3-bromo-4-ethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Prepared following the method described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and ethyl iodide.
[M + Na] ⁺ = 740.17

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II wherein Q = chemical bond, Y = 3-chloro-4- (2-hydroxyethoxy) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Was prepared according to the method described in Example 59 using the title compound of Example 21 and 2-iodoethanol.

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II wherein Q = chemical bond, Y = 3-bromo-4- (2-hydroxyethoxy) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H Was prepared according to the method described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and 2-iodoethanol.
[M + Na] ⁺ = 754.27

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 3-chloro-4- (O-allyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H The compound was prepared according to the method described in Example 59 using the title compound of Example 21 and 3-iodopropane.
[M + Na] ⁺ = 706.24

A = tBOC, G = OH, L = chemical bond, W is

Where Q = chemical bond, Y = 3-bromo-4- (O-allyl) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H The compound was prepared according to the method described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and 3-iodopropane.
[M + Na] ⁺ = 752.15

A = tBOC, G = OH, L = chemical bond, W is

Wherein Q = chemical bond, Y = 3-chloro-4- (O—CH ₂ SCH ₃ ) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Compound The title compound was prepared according to the method described in Example 59 using the title compound of Example 21 and Cl—CH ₂ SCH ₃ .

A = tBOC, G = OH, L = chemical bond, W is

Wherein Q = chemical bond, Y = 3-chloro-4- (O—CH ₂ SCH ₃ ) phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Compound The title compound was prepared according to the method described in Example 59 using the ethyl ester precursor of the title compound of Example 23 and Cl—CH ₂ SCH ₃ .
[M + Na] ⁺ = 752.15

A = tBOC, G = OH, L = chemical bond, W is

Q ′ = − CH ₂ -, Y =

, J = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

69A. Preparation of cyanoproline derivative (69b) 1-tert-butyl ester of cis-4-hydroxy-proline-1,2-dicarboxylic acid 2-methyl ester (69a) (3.94 g, 16.06 mmol) in CH ₂ Cl ₂ (40 ml) was added dropwise DIEA (4.3 ml) and methanesulfonyl chloride (1.40 ml) at 0 ° C. After the addition, the mixture was stirred for 1.5 hours. The reaction was complete as confirmed by TLC analysis (50% EtOAc-hexane was used for TLC development). The mixture was diluted with EtOAc, washed with saturated NaHCO ₃ , brine and dried (Na ₂ SO ₄ ). After evaporation of the solvent, the oily residue was used in the next step without further purification.
[M + H] ⁺ = 324

The crude product obtained in the previous step was dissolved in DMF (35 ml) and crushed KCN (2.5 g) was added. The mixture was heated to 90 ° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with H ₂ O and brine, and dried over Na ₂ SO ₄ . The crude product was purified by silica gel column chromatography (20% EtOAc / hexane).
[M + H] ⁺ = 255

69B. Preparation nitrile 69b (669 mg, 2.63 mmol) tetrazolyl proline derivative (69c) in toluene (8 ml) solution _of, NaN 3 _(684mg, 10.53 mmol) and _{Et 3 N · HCl (1.45g,} 10 .53 mmol) was added. The mixture was heated to 115 ° C. for 18 hours. The mixture was diluted with CH ₂ Cl ₂ , washed with 5% aqueous citric acid solution and dried over Na ₂ SO ₄ . The solvent was distilled off to obtain a crude product (660 mg) of 69c · Et ₃ N adduct.
[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 K ₂ CO ₃ (140 mg, 1.01 mmol). The mixture was heated to 65 ° C. overnight, then diluted with EtOAc, washed with brine and dried over Na ₂ SO ₄ . After evaporation of the solvent, the crude product _{THF-MeOH-H 2 O:} ; was dissolved in (2 ml 1 ml 1 ml), was added LiOH (130 mg). The mixture was stirred overnight at room temperature. THF and MeOH were distilled off under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over Na ₂ SO ₄ . The solvent was distilled off to obtain crude organisms 69d and 69e.
[M + Boc + H] ⁺ = 350

69D. Preparation of tripeptide (69 g) To a solution of 69d and 69e (about 0.31 mmol) in DMF (2.0 ml), D-β-vinylcyclopropane amino acid ethyl ester / hydrochloric acid (66 mg), DIEA (0.25 ml) and HATU (164 mg) was added separately. The mixture was stirred for 1 h, then diluted with EtOAc, washed with brine, 5% aqueous citric acid and dried over Na ₂ SO ₄ . After distilling off the solvent, the residue was dissolved in CH ₂ Cl ₂ (2 ml) and 4N HCl dioxane solution (2 ml) was added. The mixture was stirred at room temperature for 1.5 hours and the solvent was distilled off. The residue was dissolved in EtOAc, neutralized with saturated NaHCO ₃ , washed with brine and dried over Na ₂ SO ₄ . After the solvent was distilled off, the residue was dissolved in DMF (2 ml), and P3 (120 mg), DIEA and HATU were added thereto in this order. The resulting mixture was stirred and monitored by TLC analysis. After the reaction was complete, the mixture was diluted with EtOAc and washed again with brine, 5% aqueous citric acid, saturated NaHCO ₃ and brine. The organic solution was dried over Na ₂ SO ₄ and evaporated under reduced pressure to give a crude mixture which was purified by silica gel chromatography (30% to 50% EtOAc-hexane).
[M + H] ⁺ = 740
69E. Ring closure substitution (69k)

A mixture of 69f and 69 g (60 mg) to a concentration of about 0.01 mol was dissolved in dry _CH 2 Cl _2. The solution was carefully degassed with a stream of N ₂ for 15 minutes and 5% molar Hoveyda's reagent was added under an N ₂ atmosphere. The mixture was refluxed overnight. The solvent was distilled off. The residue was applied to a silica gel column and eluted with 10% EtOAc to remove the catalyst. The two positional isomers were eluted with 30-30% EtOAc-hexanes to give the less polar product 69j (37.9 mg) and the more polar product 69k (14.8 mg). The 69j and 69k positional isomers were confirmed by NMR analysis.
[M + H] ⁺ = 712

69F. Hydrolysis of ethyl ester (69)
Ester 69h (37.9 mg) of _{THF-MeOH-H 2 O:} ; was dissolved in (2ml 1ml 1ml), was added LiOH (21 mg). The mixture was stirred overnight at room temperature. THF and MeOH were distilled off under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over Na ₂ SO ₄ . The solvent was distilled off to obtain a crude organism. The crude product was purified by silica gel chromatography (5% MeOH in CH ₂ Cl ₂ ) to give the title compound 69k.
[M + H] ⁺ = 684

A = tBOC, G = OH, L = chemical bond, W is

Q ′ = − CH ₂ -, Y =

, J = 3, m = s = 1, and R ³ = R ⁴ = H, the compound ester 69i of formula II (14.8 mg) dissolved in THF-MeOH-H ₂ O (2 ml: 1 ml; 1 ml) LiOH (21 mg) was added. The mixture was stirred overnight at room temperature. THF and MeOH were distilled off under reduced pressure. The residue was dissolved in EtOAc, washed with 5% citric acid and dried over Na ₂ SO ₄ . The solvent was distilled off to obtain a crude organism. The crude product was purified by silica gel chromatography (5% MeOH in CH ₂ Cl ₂ ) to give the title compound 70.
[M + H] ⁺ = 684

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound 71a-amine deprotection of Formula II , where Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H 0.041 mmol) is dissolved in HCl in 4M dioxane (4 ml) and stirred for 1 hour. The reaction residue 69a is concentrated under reduced pressure.

71b-Chloroformate Reagent Chloroformate reagent 71b is prepared by dissolving cyclopentanol (0.045 mmol) in THF (3 ml) and adding a 20% solution of phosgene (0.09 mmol) in toluene. The resulting reaction mixture is stirred at room temperature for 2 hours and the solvent is removed under reduced pressure. DCM is added to the residue, and then concentrated to dryness under reduced pressure twice to obtain a chloroformate reagent 71b.

Formation of 71c-carbamate The title compound is prepared by dissolving residue 71a in THF (1 ml), adding TEA (0.045 mmol) and cooling the resulting reaction mixture to 0 ° C. To this 0 ° C. reaction mixture is added chloroformate reagent 71b in THF (3 ml). The resulting reaction mixture is reacted at 0 ° C. for 2 hours, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over Na ₂ SO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is then hydrolyzed as described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclobutyl), G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, the title compound of Example 21 and cyclobutanol Is prepared by hydrolysis of the ethyl ester in the manner described in Example 71 and then in the manner described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclohexyl), G = OH, L = chemical bond, W is

A compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, the title compound of Example 21 and cyclohexanol Is prepared by hydrolysis of the ethyl ester in the manner described in Example 71 and then in the manner described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ =

, G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is converted to the title compound of Example 21 with (R ) -3-Hydroxytetrahydrofuran is prepared by hydrolysis of the ethyl ester in the manner described in Example 71 and then in the manner described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ =

, G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is converted to the title compound of Example 21 with (S ) -3-Hydroxytetrahydrofuran is prepared by hydrolysis of the ethyl ester in the manner described in Example 71 and then in the manner described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ =

, G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the title compound of Example 21 as

Is prepared by hydrolysis of the ethyl ester in the manner described in Example 71 and then in the manner described in Example 22.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound is dissolved in the compound of Example 21 (0.041 mmol) in 4M HCl in HCl (4 ml) and stirred for 1 hour. The reaction residue is concentrated under reduced pressure. To this residue THF (4 ml) and TEA (0.045 mmol) are added, the mixture is cooled to 0 ° C. and cyclopentalic acid chloride (0.045 mmol) is added. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. After the crude compound is purified on a column of silica, the ethyl ester is hydrolyzed as described in Example 22.

A =-(C = O) -NH-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is obtained from the compound of Example 21 (0.041 Mmol) in 4M HCl in HCl (4 ml) and stirred for 1 hour. The reaction residue is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To this 0 ° C. solution is added cyclopentyl isocyanate (0.045 mmol) and the resulting reaction mixture is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. After the crude compound is purified on a column of silica, the ethyl ester is hydrolyzed as described in Example 22.

A =-(C = S) -NH-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is obtained from the compound of Example 21 (0.041 Mmol) in 4M HCl in HCl (4 ml) and stirred for 1 hour. The reaction residue is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To this 0 ° C. solution is added cyclopentyl isothiocyanate (0.045 mmol) and the resulting reaction mixture is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. After the crude compound is purified on a column of silica, the ethyl ester is hydrolyzed as described in Example 22.

A = -S (O) ₂ -NH-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is obtained from the compound of Example 21 (0.041 Mmol) in 4M HCl in HCl (4 ml) and stirred for 1 hour. The resulting concentrated residue is dissolved in THF (4 ml), TEA (0.045 mmol) is added and cooled to 0 ° C. To this 0 ° C. solution is added cyclopentylsulfonyl chloride (0.045 mmol) and the resulting reaction mixture is stirred at 0 ° C. for 2 h. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. After the crude compound is purified on a column of silica, the ethyl ester is hydrolyzed as described in Example 22.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -O-phenethyl, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by adding PyBrOP (1.2 eq), (4 eq) DIEA (4 eq), and a catalytic amount of DMAP to a solution of the title compound of Example 71 and phenethyl alcohol 81a in DCM (0.5 ml) at 0 ° C. In addition, prepare. The resulting reaction mixture is stirred at 0 ° C. for 1 hour and then warmed to room temperature over 4-12 hours. 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 and isolated as phenethyl ester 81b A compound is obtained.
Other esters can be prepared using the same method.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NH-phenethyl, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

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

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NHS (O) ₂ -Phenethyl, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was added to a solution of the title compound of Example 71 and α-toluenesulfonamide 83a (10 mg) in DCM (0.5 ml) at 0 ° C. with PyBrOP (1.2 eq), DIEA (4 eq) and a catalytic amount of DMAP. Add in to prepare. The resulting reaction mixture is stirred for 1 hour and allowed to warm to room temperature over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to give the title compound sulfonamide 83c.
Other sulfonamides can be prepared using the same method.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -OH, L = chemical bond, W is

Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

  The title compound is prepared by adding a solution of the title compound of Example 71 in THF (0.5 ml) and α-hydroxy-α-methyl-propionitrile (0.1 ml) and a catalytic amount of TFA at 0 ° C. . The resulting reaction mixture is warmed from 0 ° C. to room temperature over 4-12 hours and then hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction is then extracted with EtOAc and washed with water and brine to give the α-hydroxy compound 83a as a crude product. When this crude compound 84a is subjected to Dess-Martin oxidation in THF (0.5 ml), the α-carbonyl compound 84b is obtained as a crude product. The 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 elution layer and isolated as keto acid 84b A compound is obtained.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -O-phenethyl, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the title compound of Example 84, keto Prepared according to the method described in example 81 using acid and phenetanol.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -NH-phenethyl, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the title compound of Example 84, keto Prepared according to the method described in example 82 using acid and phenethylamine.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -NH-S (O) ₂ -Benzyl, L = chemical bond, W is

The compound of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, is the title compound of Example 84, keto Prepared according to the method described in example 83 using acid and α-toluenesulfonamide.

A = tBOC, G = OH, L =-(C = O) CH ₂ -, W is

Q = chemical bond, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Synthesis of (2S) -N-Boc-amino-5-oxo-nonane-8-enoic acid 88A.
The above amino acids are prepared by adding n-Bu ₂ Mg to a dry THF solution of malonic monoallyl ester in N 2 atmosphere at −78 ° C. over 5 minutes. The resulting suspension is then stirred at room temperature for 1 hour and evaporated to dryness. The solid 88b Mg salt is dried under reduced pressure.

  The glutamic acid derivative 88a is first mixed with 1,1-carbonyldiimidazole in anhydrous THF and the mixture is stirred at room temperature to activate the free acid portion. Subsequently, the activated glutamic acid derivative is cannulated into the solution of the 88b Mg salt and the reaction mixture is stirred at room temperature for 16 hours. The mixture was then extracted with ethyl acetate, and the organic solution was added to 0. Wash with N HCl and brine (at 0 ° C.), dry and evaporate. The resulting residue is separated by silica chromatography using an elution system of 35-40% ethyl acetate in hexane to give diester 88c.

88B.
The diester is added while stirring a solution of tetrakis (triphenylphosphine) PD (0) in anhydrous DMF. The mixture is stirred at room temperature for 3.5 hours. DMF is distilled off under reduced pressure and the residue is diluted with EtOAc. The EtOAc solution is washed with 0.5 N HCl, brine at 0 ° C., dried and evaporated. The residue is chromatographed on silica using 15-20% ethyl acetate in hexane as eluent to give the methyl ester intermediate.

This methyl ester intermediate is dissolved in THF and water, LiOH.H ₂ O is added and the mixture is stirred at room temperature for 25 hours. At this time, completion of hydrolysis is monitored by TLC. The reaction mixture is concentrated under reduced pressure to remove most of the THF and further diluted with methylene chloride. The resulting solution is washed with 1N HCl, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. To remove trace impurities and excess Boc ₂ O, the crude product is purified by flash chromatography using a solvent gradient from 100% hexane to 100% EtOAc as eluent. (2S) -N-Boc-amino-5-oxo-nonane-8-enoic acid 88d is obtained. Details of the amino acid synthesis method are described in Tsuda et al. , J .; Am. Chem. Soc. 1980, 102, 6381-6384 and WO 00/59929. These are incorporated herein by reference.

88C. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was synthesized by using (2S) -N-Boc-amino-5-oxo- instead of Boc-L-2-amino-8-nonane-enoic acid 1a. Prepared using the nonane-8-enoic acid 88d using the synthetic route detailed in Example 1 and then converting to the corresponding mesyl form in the manner described in Example 2.

  The title compound is described in the substitution method described in Example 21, using the modified cyclic peptide precursor mesyl form formed at 88C and 5-phenyl-1H-tetrazole, and then described in Example 22. Prepare by hydrolyzing the ethyl ester in the process.

A = tBOC, G = OH, L = -CH (CH ₃ ) CH ₂ -, W is

Q = chemical bond, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

(2S, 5R) -N-Boc-amino-5-methyl-nonane-8-enoic acid (89h)
89A.
Solid ethyl 2-acetamidomalonate 89b is added to a solution of (R)-(+)-citronellal 89a in pyridine over 1 minute. The resulting solution is cooled in a 10 ° C. bath and acetic anhydride is added over 4 minutes. The resulting solution is stirred at room temperature for 3 hours and a second portion of ethyl 2-acetamidomalonate 89a is added. The resulting mixture is stirred for an additional 11 hours at room temperature. Ice is added and the solution is stirred for 1.5 hours, then the mixture is diluted with water (250 ml) and extracted twice with water. The organic layer is washed with 1N HCl, saturated NaHCO ₃ , dried over Na ₂ SO ₄ , concentrated, and purified by flash chromatography (40% EtOAc / hexane) to give compound 89c.

89B.
(S, S) -Et-PUPHOSRh (COD) OTf is added to the degassed 89c ethanol solution. Pass 30 psi of hydrogen through the mixture and stir on a Parr shaker for 2 hours. The resulting mixture is evaporated to dryness to give the crude compound 59d, which is used in the next step without purification.

89C.
Compound 89d is dissolved in a (1: 1: 1) mixture of tBuOH / acetone / H ₂ O and set in an ice bath (0 ° C.). NMMO and OsO ₄ are added in succession and the reaction mixture is stirred at room temperature for 4 hours. Most of the acetone is distilled off under reduced pressure and the mixture is extracted with ethyl acetate. The solid phase is further washed with water and brine, dried over MgSO ₄ and evaporated to dryness. Flash chromatography using 1% acetic acid in ethanol as the eluent yields diol 50e in high purity.

89D.
To a THF / H ₂ O (1: 1) solution of diol 89e is added NaIO ₄ at 0 ° C. and the reaction mixture is stirred at room temperature for 3.5 hours. Most of the THF is then distilled off under reduced pressure and the remaining mixture is extracted with EtOAc. The combined organic layers are further washed with 5% aqueous citric acid solution, 5% aqueous NaHCO ₃ solution and brine, the organic layer is dried over MgSO ₄ and evaporated to dryness under reduced pressure. The aldehyde intermediate 89f is used in crude form in the following steps.

89E.
To an anhydrous toluene solution of Ph ₃ PCH ₃ Br, KHMDS is added to form a suspension, which is stirred for 30 minutes at room temperature under N ₂ atmosphere. After stirring, the suspension is cooled to 0 ° C., a solution of aldehyde intermediate 89f in THF is added and the mixture is warmed to room temperature and stirred for 1 hour. Most of the THF is distilled off under reduced pressure, EtOAc is added to the mixture, and the organic layer is washed with water, 5% aqueous NaHCO ₃ and brine. The organic layer is dried over MgSO ₄ and evaporated to dryness under reduced pressure. Purify by silica gel flash chromatography using hexane: EtOAc (3: 2) as eluent to isolate 89 g of pure compound.

89F.
To the crude 89 g THF solution, Boc ₂ O and DMAP are added and the reaction mixture is heated to reflux for 2.5 hours. Subsequently, most of the THF is distilled off and the crude mixture is diluted with methylene chloride and washed with 1N HCl to remove DMAP. The organic layer is further washed with saturated aqueous NaHCO ₃ solution, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product is diluted with THF and water, LiOH.H ₂ O is added and the resulting mixture is stirred at room temperature for 25 hours. Completion of hydrolysis is observed by TLC. The reaction mixture is concentrated under reduced pressure to remove most of the THF and further diluted with methylene chloride. The resulting solution is washed with 1N HCl, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. To remove small amounts of impurities and excess Boc ₂ O, the crude product is purified by flash chromatography using a solvent gradient of 100% hexane to 100% EtOAc as eluent. (2S, 5R) -N-Boc-2-amino-5-methyl-nonane-8-enoic acid 89h is obtained. See WO00 / 59929 for details of the amino acid synthesis. This is incorporated herein by reference in its entirety.

89G. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was synthesized by using (2S, 5R) -N-Boc-2-amino- instead of Boc-L-2-amino-8-nonane-enoic acid 1a. Prepared by using the synthetic route detailed in Example 1 using 5-methyl-nonane-8-enoic acid 89h and then converting to the corresponding mesyl form in the manner described in Example 2. To do.
The title compound was converted by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed at 89G and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -O-, W is

Q = chemical bond, Y = phenyl, j = 0, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Synthesis of N-Boc-O-allyl- (L) -threonine (90d) 90A.
Dissolve a portion of Boc- (L) -threonine 90a in methylene chloride / methanol at 0 ° C. Add a solution of diazomethane in diethyl ether until yellow, indicating the presence of diazomethane. The solvent is distilled off to give the crude methyl ester 90b.

90B.
Intermediate 90b is dissolved in anhydrous diethyl ether and Ag ₂ O and freshly activated 4M molecular sieves are added. Finally, allyl iodide is added after 20 and 30 hours and stirring is continued for a total of 36 hours. The mixture is filtered through celite and purified by flash chromatography on silica gel using EtOAc / hexane (1: 4) as eluent to give compound 90c.

90C.
Compound 90c is dissolved in a mixture of THF / MeOH / H ₂ O (2: 1: 1) and LiOH.H ₂ O is added. The solution is stirred at room temperature for 2 hours, acidified with 1N HCl to pH˜3, and then the solvent is removed under reduced pressure to give crude compound 90d. See WO00 / 59929 for details of the amino acid synthesis. This is incorporated herein by reference in its entirety.

90D. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body is converted to N-Boc-O-allyl- (L) -threonine 90d instead of Boc-L-2-amino-8-nonane-enoic acid la. By using the synthetic route detailed in Example 1 and then converting to the corresponding mesyl form by the method described in Example 2.
The title compound was converted by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed in 90D and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -S-, W is

Q = chemical bond, Y = phenyl, j = 0, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Synthesis of (2S, 3S) -N-Boc-2-amino-3- (mercaptoallyl) butanoic acid (91e) 91A.
Compound 91a is dissolved in pyridine, the solution is cooled to 0 ° C. in an ice bath, tosyl chloride is added in portions and the reaction mixture is partitioned between diethyl ether and H ₂ O. The ethyl ether layer is further washed with 0.2N HCl and brine, dried over anhydrous MgSO ₄ , filtered and concentrated to dryness under reduced pressure. Purify the crude material by flash chromatography on silica gel using hexane / EtOAc (8: 2 to 7: 3 gradient) as eluent to isolate tosyl derivative 91b.

91B.
To a solution of tosyl derivative 91b in anhydrous DMF is added potassium thioacetate and the reaction mixture is stirred at room temperature for 24 hours. Most of the DMF is distilled off under reduced pressure and the remaining mixture is partitioned between EtOAc and H ₂ O. The aqueous layer is re-extracted with EtOAc and the combined organic layers are washed with brine, dried over anhydrous MgSO ₄ and evaporated to dryness. Purify the crude material by flash chromatography on silica gel using hexane / EtOAc (4: 1 ratio) as eluent to give thioester 91c.

91C.
To a solution of thioester 91c in H ₂ O / EtOH (3: 5 ratio) is added 0.2 M aqueous NaOH and the mixture is stirred at room temperature for 1.5 hours. Allyl iodide is then added and stirring is continued for another 30 minutes at room temperature. The reaction mixture is concentrated to half of the initial volume and extracted with EtOAc. Acidify the aqueous layer to pH 3 with chilled 0.5 N aqueous HCl and re-extract with EtOAc. The combined organic layers are dried over anhydrous MgSO ₄ and evaporated to dryness under reduced pressure. The crude reaction mixture contains at least 4 products, all of which are isolated by flash chromatography on silica gel using hexane / EtOAc (9: 1 to 3: 1 gradient). . The desired product 91d is the least polar compound.

91D.
A solution of compound 91d in MeOH / H ₂ O (3: 1) is mixed with aqueous NaOH (0.3N) for 24 hours at room temperature and 1 hour at 40 ° C. The reaction mixture is acidified with chilled 0.5N aqueous HCl, MeOH is removed under reduced pressure and the remaining aqueous mixture is extracted with EtOAc. The organic layer is dried over anhydrous MgSO ₄ and evaporated to dryness to give compound 91e. See WO00 / 59929 for details of the amino acid synthesis. Which is incorporated herein by reference in its entirety.

91E. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was synthesized by using (2S, 3S) -N-Boc-2-amino- instead of Boc-L-2-amino-8-nonane-enoic acid 1a. Prepare by using the synthetic route detailed in Example 1 using 3- (mercaptoallyl) butanoic acid 52e and then converting to the corresponding mesyl form by the method described in Example 2.
The title compound was modified by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed in 91E and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -S (O)-, W is

A compound- modified amino acid of formula II, wherein Q = chemical bond, Y = phenyl, j = 2, m = s = 1, R ³ = methyl, and R ⁴ = hydrogen

Formation of (92a) 92A.
This modified amino acid is prepared by dissolving sodium metaperiodate (1.1 eq) in water, cooling to 0 ° C. in an ice bath and adding a dioxane solution of compound 91d dropwise. The resulting reaction mixture is stirred at 0 ° C. for 1 hour and at 40 ° C. for 4 hours. The reaction mixture is concentrated, water is added and the mixture is extracted twice with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. Reduction of this methyl ester by the method described in Example 91D yields the modified amino acid 92a. Details of the amino acid synthesis method are described in T.W. Tsuda et al. , J .; Am. Chem. Soc. 1980, 102, 6381-6384 and WO 00/59929. All of which are incorporated herein by reference.

92B. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was described in detail in Example 1 using the modified amino acid 92a in place of Boc-L-2-amino-8-nonane-enoic acid 1a. And then converted to the corresponding mesyl form by the method described in Example 2.
The title compound was modified by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed in 92B and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -S (O) ₂ -, W is

A compound- modified amino acid of formula II, wherein Q = chemical bond, Y = phenyl, j = 2, m = s = 1, R ³ = methyl, and R ⁴ = hydrogen

Formation of (93a) 93A.
This modified amino acid is prepared by dissolving sodium metaperiodate (1.1 eq) in water, cooling to 0 ° C. in an ice bath and adding a dioxane solution of compound 92d dropwise. The resulting reaction mixture is stirred at 0 ° C. for 1 hour and at 40 ° C. for 4 hours. The reaction mixture is concentrated, water is added and the mixture is extracted twice with methylene chloride. The combined organic layers are washed with water and brine, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. Reduction of this methyl ester by the method described in Example 91D yields the modified amino acid 92a. Details of the amino acid synthesis method are described in T.W. Tsuda et al. , J .; Am. Chem. Soc. 1980, 102, 6381-6384 and WO 00/59929. All of which are incorporated herein by reference.

93B. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was described in detail in Example 1 using the modified amino acid 93a instead of Boc-L-2-amino-8-nonane-enoic acid 1a. And then converted to the corresponding mesyl form by the method described in Example 2.
The title compound was modified by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed in 93B and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -S (O) ₂ -, W is

Q = chemical bond, Y = phenyl, j = 2, m = s = 1, R ³ = Methyl and R ⁴ = A compound of formula II, where hydrogen

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). Subsequently, bromopentene and CsOH.H ₂ O are added to the mixture and stirring is continued for another 12 hours. DMF is substantially removed under reduced pressure and the remaining mixture is diluted with 0.5 N HCl (0 ° C.) to adjust the pH to 4-5 and extracted twice with EtOAc. The organic layer is extracted with brine (twice), dried over MgSO ₄ and evaporated to dryness to give the crude carboxylic acid 94a. See WO00 / 59929 for details of the amino acid synthesis. This is incorporated herein by reference in its entirety.

94B. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was described in detail in Example 1 using the modified amino acid 94a in place of Boc-L-2-amino-8-nonane-enoic acid 1a. And then converted to the corresponding mesyl form by the method described in Example 2.
The title compound was modified by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed in 94B and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -CF ₂ CH ₂ -, W is

Q = chemical bond, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Synthesis of (2S) -N-Boc-amino-5-difluoro-nonane-8-enoic acid (95b) 95A.
To a solution of ketone compound 88d (0.30 g, 1 mmol) in DCM (5 ml) is added DAST (diethylamino-sulfur trifluoride, 0.2 g, 1.2 eq). The reaction is held at room temperature for 2-3 days. The solvent was distilled off and the residue was purified and purified by flash chromatography on silica gel using different ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) hexane / EtOAc as eluent. The methyl ester 95a is obtained. Details regarding the synthesis can be found in Tius, Marcus et al. Tetrahedron, 1993, 49, 16; 3291-3304. Which is incorporated herein by reference in its entirety.

95B.
The methyl ester 95a THF / MeOH / H2O and water (2: 1: 1), added LiOH · _{H 2} O. The solution was stirred for 2 hours at room temperature, acidified to pH 3 with 1N HCl, and then the solvent was removed under reduced pressure to give crude (2S) -N-Boc-amino-5-difluoro-nonane-8. -The enoic acid 95b is obtained.

95C. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was prepared by using crude (2S) -N-Boc-amino-5 instead of Boc-L-2-amino-8-nonane-enoic acid 1a. Prepared by using the synthetic route detailed in Example 1 using difluoro-nonane-8-enoic acid 95b and then converting to the corresponding mesyl form in the manner described in Example 2.
The title compound was modified by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed with 95B and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = -CFHCH ₂ -, W is

Q = chemical bond, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Synthesis of (2S) -N-Boc-amino-5-fluoro-nonane-8-enoic acid (96c) 96A.
To a solution of ketone compound 88d in methanol (5 ml), NaBH ₄ (2.2 eq) is added. The reaction mixture is stirred at room temperature for 2-6 hours, triturated with 1M ammonium chloride and extracted with EtOAc (30 ml). The solvent is distilled off to obtain the crude hydroxy compound 96a.

96B.
Hydroxy compound 96a is dissolved in DCM (5 ml), to which DAST (0.2 g, 1.2 eq) is added and stirred at −45 ° C. for 1 hour. The reaction mixture is warmed to room temperature and stirred for 2-3 days. The solvent was distilled off and the residue was purified and purified by flash chromatography on silica gel using different ratios (9: 1 → 5: 1 → 3: 1 → 1: 1) hexane / EtOAc as eluent. The monofluoro compound methyl ester 95b is obtained. For details on this synthesis, see Bist, Peter H et al. Tetrahedron Lett. 1987, 28, 3891-3894. This is incorporated herein by reference in its entirety.

96B.
Dissolve methyl ester 96b in THF / MeOH / H ₂ O (2: 1: 1) and add LiOH.H ₂ O. The solution was stirred for 2 hours at room temperature, acidified to pH 3 with 1N HCl, and then the solvent was removed under reduced pressure to give crude (2S) -N-Boc-amino-5-difluoro-nonane- 8-Enoic acid 96c is obtained.

96C. Synthesis of Modified Cyclic Peptide Precursor Mesyl Body The modified cyclic peptide precursor mesyl body was prepared by using crude (2S) -N-Boc-amino-5 instead of Boc-L-2-amino-8-nonane-enoic acid 1a. Prepared by using the synthetic route detailed in Example 1 using monofluoro-nonane-8-enoic acid 96b and then converting to the corresponding mesyl form in the manner described in Example 2. .
The title compound was converted by the substitution method described in Example 21 using the modified cyclic peptide precursor mesyl form formed at 96C and 5-phenyl-1H-tetrazole, followed by the method described in Example 22. Prepared by hydrolysis of the ethyl ester.

A = tBOC, G = OH, L = chemical bond, W is

Compound 97A. Of formula II , wherein Q = chemical bond, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H.
The saturated cyclic peptide precursor mesylate is prepared by catalytic reduction in the presence of H ₂ from the Pd / C mesylation cyclic peptide precursor 2 in MeOH.
The title compound is substituted with the saturated cyclic peptide precursor mesyl form formed with 97A and 5-phenyl-1H-tetrazole using the substitution method shown in Example 21 and then the method described in the Example. It is prepared by hydrolysis of the ethyl ester.
The compounds of the present invention exhibit potent inhibitory properties against HCV NS3 protease. The following examples illustrate the evaluation that the light compounds of the present invention were tested for anti-HCV effects.

Synthesis of Triazoles Typical triazole derivatives used in the preparation of the light compounds of the present invention can be prepared as described in the following examples.

  The triazole of the present invention is 4 mmol of alkylene compound 98a, which is commercially available or can be prepared as described below, and 8 mmol of trimethylsilyl azide in 2 ml of xylene at 140 ° C. in a pressure tube. It can be prepared by reacting for 24-27 hours. The resulting reaction mixture is directly separated on a silica gel column to give triazole 98b in 30-90% yield.

Synthesis of alkylene 99A. Sonogashira reaction

The alkylene used in the present invention is a primary alkyne compound 99a (4 mmol), aryl is a degassed solution of a ride (Y-halide, 4 mmol), triethylamine (1 ml) and acetonitrile (10 ml), PdCl ₂ ( It can be prepared by the Sonogashira reaction in which PPh ₃ ) ₂ (140 mg, 0.2 mmol) and CuI (19 mg, 0.1 mmol) are reacted. The reaction mixture is degassed and stirred at room temperature for 5 hours. The reaction mixture is then heated to 90 ° C. for 12 hours. Subsequently, the reaction mixture is concentrated under reduced pressure and purified on a silica gel column to give the substituted alkyne 98a in 60-90% yield.
99B. Synthesis of alkynylamides

Further alkynes used in the present invention were prepared by reacting a solution of alkynyl acid 99b (10 mmol), BOP (11 mmol), and DIEA (22 mmol) in DMF (15 ml) and amine 99b (11 mmol) for 3 hours at room temperature. It can be prepared by stirring. The reaction mixture was extracted with ethyl acetate (2 × 50 ml); 1M NaHCO ₃ (2 × 30 ml), water (2 × 30 ml), 5% citric acid (2 × 50 ml) and brine (30 ml). Dried over anhydrous sodium sulfate; concentrated under reduced pressure to give alkyne 99d in 90% yield.

A = tBOC, G = OH, L = chemical bond, W is

X = H, Y = 4-t-butylphenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

The title compound was prepared by the following method. Boc-azidoproline methyl ester 100a (0.54 g, 2 mmol) and 4-tert-butylphenylacetylene 100b ((2.5 mmol) were dissolved in xylene (2 ml) and stirred at 110 ° C. for 12 hours. The resulting reaction mixture was directly separated on a silica gel column to separate isomers 100c and 100d in 90% yield.
The title compound was then formed by hydrolysis of the ethyl ester by the RCM method described in Example 1 using 100b instead of hydroxyproline, followed by the method described in Example 106.
[M + Na] ⁺ = 671.72

A = tBOC, G = OH, L = chemical bond, W is

In Example 1 using 100c instead of the compound hydroxyproline of formula II where X = H, Y = H, j = 3, m = s = 1, and R ³ = R ⁴ = H. The title compound was prepared by the RCM method described, followed by hydrolysis of the ethyl ester as described in Example 106.
[M + Na] ⁺ = 649.44

A = tBOC, G = OH, L = chemical bond, W is

X and Y together are phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Triazole-substituted proline corresponding to the title compound was dissolved in hydroxyproline mesyl 102a (0.5 g, 1.5 mmol) and benzotriazole 102b (4.5 mmol) in DMF (5 ml), and cesium carbonate (2 0.9 g, 9 mmol) was added and the resulting reaction mixture was prepared by stirring at 70 ° C. for 12 hours. The reaction mixture was extracted with EtOAc and washed with 1M sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The target isomers 102c and 102d were separated by silica gel column chromatography.
The title compound was prepared by the RCM method described in Example 1 followed by hydrolysis of the ethyl ester by the method described in Example 106 using 102d instead of hydroxyproline.
[M + Na] ⁺ = 588.46

A = tBOC, G = OH, L = chemical bond, W is

Wherein X and Y together are phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, using 102c instead of the compound hydroxyproline of formula II The title compound was prepared by the RCM method described in 1, followed by hydrolysis of the ethyl ester by the method described in Example 106.
[M + Na] ⁺ = 588.50

A = tBOC, G = OH, L = chemical bond, W is

A triazole-substituted proline corresponding to the title compound of formula II , wherein X = Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, the mesyl form of hydroxyproline 102a (0.5 g, 1.5 mmol) and benzotriazole 102b (4.5 mmol) are dissolved in DMF (5 ml), cesium carbonate (2.9 g, 9 mmol) is added, and the resulting reaction mixture is stirred. Prepared by stirring at 70 ° C. for 12 hours. The reaction mixture was extracted with EtOAc and washed with 1M sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure.
Using the triazole-substituted proline of this example instead of hydroxyproline, the title compound was obtained by the RCM method described in Example 1, followed by hydrolysis of the ethyl ester by the method described in Example 106. Prepared.
[M + Na] ⁺ = 690.42

A = tBOC, G = OEt, L = chemical bond, W is

X = Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

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

A = tBOC, G = OOH, L = chemical bond, W is

Compound of Formula II Example 105 (0.041 mmol) is dioxane (3 ml) , wherein X = Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. 1M LiOH (2 ml) was added and reacted at room temperature for 8 hours to prepare the title compound. The pH of the reaction mixture was then adjusted to 3 with citric acid, extracted with EtOAc, and washed with brine and water. The organic solution was concentrated under reduced pressure and purified by HPLC.
[M + Na] ⁺ = 690.42

A = tBOC, G = OOH, L = chemical bond, W is

X = Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Azidoproline 100a (0.25 g, 0.93 mmol) and diphenylacetylene (1 mmol) are dissolved in xylene (2 ml), heated to 110 ° C. and stirred for 12 hours to give the triazole-substituted proline precursor of the title compound. Was prepared. The reaction mixture was separated directly on a silica gel column to give 107a (0.27 g, 90%).
[M + H] ⁺ = 499.05
The hydrolysis method shown in Example 105 gave 107b (0.26 g, 99%).
The title compound was obtained by the RCM method described in Example 1 using 107b instead of hydroxyproline.
[M + Na] ⁺ = 691.99

A = tBOC, G = OOH, L = chemical bond, W is

With the compound of formula II n-propyl phenylacetylene and sodium azide where X = n-propyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H 4- (n-propyl) -5-phenylthiazole was prepared by the method of Example 98.
The title compound of Example 2 and 4- (n-propyl) -5-phenylthiazole 108a were used according to the method described in Example 105, followed by hydrolysis of the ethyl ester by the method of Example 106 to give the title Was prepared.
[M + Na] ⁺ = 657.99

A = tBOC, G = OOH, L = chemical bond, W is

Compound 109a. Of formula II wherein X = m-methoxyphenyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkylene 2- (m-methoxyphenyl) -4-methoxyphenylacetylene was prepared from 4-methoxyphenylphenylacetylene and 3-bromoanisole by the method of Example 99A.
109b. Triazole formation 4- (m-methoxyphenyl) -5- (p-methoxyphenyl) trial was prepared by the method of Example 3 using alkyne 109a and sodium azide.
Using the title compound of Example 2 and 4- (m-methoxyphenyl) -5- (p-methoxyphenyl) trial 109a, following the procedure described in Example 105, the ethyl ester was then prepared by the procedure of Example 106. Hydrolysis yielded the title compound.
[M + Na] ⁺ = 752.08

A = tBOC, G = OOH, L = chemical bond, W is

A compound of Formula II wherein X = m-bromophenyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkylene 2- (m-bromophenyl) -4-methoxyphenylacetylene was prepared from 4-methoxyphenylphenylacetylene and 3-iodo-5-bromobenzene by the method of Example 99A.
110b. Triazole Formation 4- (m-Bromophenyl) -5- (p-methoxyphenyl) trial was prepared by the method of Example 3 using alkyne 110a and sodium azide.
Using the title compound of Example 2 and 4- (m-bromophenyl) -5- (p-methoxyphenyl) trial 110a, following the procedure described in Example 105, then the ethyl ester was prepared by the procedure of Example 106. Hydrolysis yielded the title compound.
[M + Na] ⁺ = 800.05

A = tBOC, G = OOH, L = chemical bond, W is

A compound of formula II , wherein X = 1-naphthyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkylene 2- (1-naphthyl) -4-methoxyphenylacetylene was prepared from 1-iodonaphthalene and 4-methoxyphenylphenylacetylene by the method of Example 99A.
111b. Formation of triazole 4- (m-bromophenyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (1-naphthyl) -4-methoxyphenylacetylene 113a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (1-naphthyl) -5- (p-methoxyphenyl) triazole 113a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + Na] ⁺ = 772.11

A = tBOC, G = OH, L = chemical bond, W is

Compound of Formula II, wherein X = 2-thienyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. 112a. Formation of alkyne 2- (2-thienyl) -4-methoxyphenylacetylene was prepared from 2-iodo-thiophene and 4-methoxyphenylphenylacetylene by the method of Example 99A.
112b. Formation of triazole 4- (2-thienyl) -5- (p-methoxyphenyl) thiazole was prepared by the method of Example 3 using 2- (2-thienyl) -4-methoxyphenylacetylene 112a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (2-thienyl) -5- (p-methoxyphenyl) triazole 112a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 705.31

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II 113a. Wherein X = 3-thienyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (3-thienyl) -4-methoxyphenylacetylene was prepared from 2-iodo-thiophene and 4-methoxyphenylphenylacetylene by the method of Example 99a.
113b. Formation of triazole 4- (3-thienyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (3-thienyl) -4-methoxyphenylacetylene 113a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (3-thienyl) -5- (p-methoxyphenyl) triazole 113a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + Na] ⁺ = 727.21

A = tBOC, G = OH, L = chemical bond, W is

Compound 114a. Of formula II , wherein X = 4-pyrazolyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (4-pyrazolyl) -4-methoxyphenylacetylene was prepared from 4-iodotipyrazole and 4-methoxyphenylphenylacetylene by the method of Example 99A.
114b. Formation of triazole 4- (4-pyrazolyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (4-pyrazolyl) -4-methoxyphenylacetylene 114a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (4-pyrazolyl) -5- (p-methoxyphenyl) triazole 114a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 700.82

A = tBOC, G = OH, L = chemical bond, W is

Compound of Formula II , wherein X = 3-pyridyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (3-pyridyl) -4-methoxyphenylacetylene was prepared from 3-iodopyridine and 4-methoxyphenylphenylacetylene by the method of Example 99A.
115b. Formation of triazole 4- (3-pyridyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (3-pyridyl) -4-methoxyphenylacetylene 115a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (3-pyridyl) -5- (p-methoxyphenyl) triazole 115a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 700.36

A = tBOC, G = OH, L = chemical bond, W is

Compound 116a of formula II , wherein X = 2-pyridyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (2-pyridyl) -4-methoxyphenylacetylene was prepared from 2-iodopyridine and 4-methoxyphenylphenylacetylene by the method of Example 99A.
116b. Formation of triazole 4- (2-pyridyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (2-pyridyl) -4-methoxyphenylacetylene 116a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (2-pyridyl) -5- (p-methoxyphenyl) triazole 116a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 700.82

A = tBOC, G = OH, L = chemical bond, W is

X = 2-thiazolyl, Y = p-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

117a. Alkyne Formation To a degassed solution of 4-ethynylanisole (4 mmol), 2-bromothiazole (4 mmol), and triethylamine (1 ml) in acetonitrile (10 ml) was added PdCl ₂ (PPh ₃ ) ₂ (140 mg, 0.2 mmol). ) And CuI (19 mg, 0.1 mmol) were added to prepare the alkyne of this example, 2- (2-thiazolyl) -4-methoxyphenylacetylene. The mixture was degassed, stirred at room temperature for 5 minutes and heated to 90 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified with a silica gel column to obtain 0.61 g of a brown liquid in a yield of 70%.
[M + H] ⁺ : 216.17
¹ HNMR (CDCl ₃ , 500 MHz): δ 7.765 (d, J = 3 Hz, 1H), 7.472-7.455 (m, 2H), 7.277 (d, J = 3.5 Hz, 1H), 6.837-6.820 (m, 2H), 3.768 (s, 3H).

117B. Formation of triazole 117c (0.3 g), trimethylsilyl azide (0.74 ml) and xylene (4 ml) were placed in a pressure tube and the mixture was heated to 140 ° C. for 48 hours to give 4- (2-thiazolyl)- 5- (p-methoxyphenyl) triazole 117d was prepared. The reaction mixture was separated directly on a silica gel column and then purified to give a brown liquid (117d) (0.18 g, 50% yield).
[M + H] ⁺ : 259.27
1H NMR (DMSO-d ₆ , 500 MHz): δ 8.016 (d, J = 8.5 Hz, 2H), 7.929 (d, J = 3 Hz, 1H), 7.817 (d, J = 3 Hz, 1H) 7.066 (d, J = 8.5 Hz, 1H), 3.824 (s, 3H).

117c.
Macrocyclic precursor mesyl bodies 117d (0.041 mmol) and 117d (0.123 mmol) were dissolved in DMF (3 ml), cesium carbonate (0.246 mmol) was added, and the mixture was reacted at 70 ° C. for 12 hours. The ethyl ester 117e was prepared. The reaction mixture was extracted with EtOAc, washed with 1M sodium bicarbonate (2 × 30 ml) and water (2 × 30 ml) and concentrated under reduced pressure to give ethyl ester 117e.
[M + H] ⁺ : 734.34

Preparation of title compound

  117e was dissolved in dioxane (3 ml), 1M LiOH (2 ml) was added and the reaction mixture was stirred at room temperature for 8 hours to hydrolyze the ethyl ester 117c. The pH of the reaction mixture was adjusted to 3 with citric acid, then the reaction mixture was extracted with EtOAc and washed with brine and water. The organic solution was concentrated under reduced pressure, purified by HPLC and lyophilized to give a yellow powder (10 mg, 34% yield).

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

A = tBOC, G = OH, L = chemical bond, W is

Compound 118a. Of formula II , wherein X = benzyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (Benzyl) -4-methoxyphenylacetylene was prepared from 4-iodobenzene and 3-phenyl-propyne by the method of Example 117A.
118b. Triazole Formation 4- (Benzyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (2-benzyl) -4-methoxyphenylacetylene 118a and sodium azide. .
Using the title compound of Example 2 and 4- (2-benzyl) -5- (p-methoxyphenyl) triazole 118a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 700.82

A = tBOC, G = OH, L = chemical bond, W is

Compound 119a of formula II , wherein X = n-butyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of triazole 4- (n-butyl))-5-phenyltriazole was prepared by the method of Example 3 using n-butyl-1-phenylacetylene and sodium azide.
Hydrolysis of the ethyl ester using the title compound of Example 2 and 4- (n-butyl) -5-phenyltriazole 119a according to the method described in Example 105 and then by the method of Example 106 gave the title Was prepared.
[M + H] ⁺ = 649.44

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II wherein X = n-propyl, Y = n-propyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of triazole 4,5- (n-propyl) triazole was prepared by the method of Example 3 using 4-octyne and sodium azide.
The title compound of Example 2 was hydrolyzed using the title compound of Example 2 and 4,5- (n-propyl) triazole 120a according to the method described in Example 105 and then by the method of Example 106 to give the title compound. Was prepared.
[M + H] ⁺ = 601.46

A = tBOC, G = OH, L = chemical bond, W is

X = 4- (N, N-dimethylamino) phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

121A. Brominated 121a (1 mmol; triazole 121a was prepared as described in Example 2 using commercially available phenylacetylene and sodium azide) was dissolved in a 1:15 solution of MeOH / CHCl ₃ (16 ml) and TEA (0.28 ml) was added and bromine (0.128 ml) was added dropwise to prepare bromine substituted phenyltriazole, 121b. The resulting reaction mixture was stirred for 2 hours. Cooled 10% Na ₂ S ₂ O ₅ was added to the reaction mixture until the mixture turned colorless. The mixture was extracted with EtOAc, washed with brine and water, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and purified on a silica gel column to give 0.216 g (97%) of 121b.
[M + H] ⁺ : 224.19
121B. Substitution with mesyl 0.2 g of 121c was prepared from the purified 121b and the title compound of Example 2 as described in Example 3.
[M + H] ⁺ : 721.00

121C. Suzuki coupling reaction 121c (50 mg, 0.07 mmol) was dissolved in DME (3 ml) and 4-dimethylaminophenylboronic acid (35 mg, 0.21 mmol), cesium carbonate (137 mg), and KF ( 100 mg) was added to prepare ethyl ester 121d. Thereafter, Pd (PPh ₃ ) ₄ (5 mg) was added to the degassed reaction mixture. The resulting reaction mixture was stirred at 90 ° C. for 12 hours. The reaction mixture was then extracted with EtOAc, washed with brine and water, dried over _Na 2 SO _4, and concentrated under reduced pressure and purified by silica gel column to give 121d of 40 mg (78% yield) .
121D. Hydrolysis of the ethyl ester From 121d by the method described in Example 106 and then purified by HPLC, 12 mg (30% yield) of 121e was prepared.
[M + H] ⁺ : 712.33

A = tBOC, G = OH, L = chemical bond, W is

Compound 122a. Of formula II wherein X = (N, N-diethylamino) methyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Triazole Formation 4- (N, N-diethylaminomethyl) -5-phenyltriazole was prepared by the method of Example 3 using 3-diethylamino-1-phenylpropyne and sodium azide.
Hydrolysis of the ethyl ester using the title compound of Example 2 and 4- (N, N-diethylaminomethyl) -5-phenyltriazole 122a according to the method described in Example 105 followed by the method of Example 106. To prepare the title compound.
[M + H] ⁺ = 678.44

A = tBOC, G = OH, L = chemical bond, W is

Compound of Formula II , wherein X = N, N-diethylaminocarbonyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Alkyne formation

Phenylpropionic acid (10 mmol), BOP (11 mmol), and DIEA (22 mmol) were dissolved in DMF (15 ml), and diethylamine (11 mmol) was added thereto to prepare alkyne 123a. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc (2 × 50 ml) and washed with 1M NaHCO ₃ (2 × 30 ml), water (2 × 30 ml), 5% citric acid (2 × 50 ml), and brine (2 × 30 ml). The organic extract was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 1.8 g (90%) of 123a.
[M + H] ⁺ : 202.09

123B. Formation of triazole 4- (N, N-diethylaminocarbonyl) -5-phenyltriazole 123b was prepared by the method of Example 3 using 123a and sodium azide.
Hydrolysis of the ethyl ester using the title compound of Example 2 and 4- (N, N-diethylaminocarbonyl) -5-phenyltriazole 123b according to the method described in Example 105 and then by the method of Example 106. To prepare the title compound.
[M + H] ⁺ : 692.47

A = tBOC, G = OH, L = chemical bond, W is

Compound 124a. Of formula II wherein X = m-chlorophenyl, Y = 4-ethoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of alkyne 2- (m-chlorophenyl) -4-methoxyphenylacetylene was prepared by the method of Example 99 from 3-chloro-bromobenzene and 4-methoxyphenylacetylene.
124b. Formation of triazole 4- (m-chlorophenyl) -5- (p-methoxyphenyl) triazole was prepared by the method of Example 3 using 2- (m-chlorophenyl) -4-methoxyphenylacetylene 124a and sodium azide. Prepared.
Using the title compound of Example 2 and 4- (m-chlorophenyl) -5- (p-methoxyphenyl) triazole 124a, the ethyl ester was hydrolyzed according to the method described in Example 105 and then by the method of Example 106. Decomposed to prepare the title compound.
[M + H] ⁺ = 747.37

A = tBOC, G = OH, L = chemical bond, W is

Examples from compound 121c of formula II and phenylethenylboronic acid , where 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 121 followed by hydrolysis by the method described in Example 106.
[M + H] ⁺ = 695.30

A = tBOC, G = OH, L = chemical bond, W is 5,6-methylbenzotriazole, j = 3, m = s = 1, and R ³ = R ⁴ = H. according to the method described in example 105 using the title compound of compound example 2 and 5,6-methylbenzotriazole, subsequent hydrolysis of the ethyl ester by the method of example 106, was prepared the title compound.
[M + H] ⁺ = 595.42

A = tBOC, G = OH, L = chemical bond, W is

A compound of formula II wherein X = N-ethylaminocarbonyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Alkyne formation

Phenylpropionic acid (10 mmol), BOP (11 mmol) and DIEA (22 mmol) were dissolved in DMF (15 ml), and ethylamine (11 mmol) was added thereto to prepare alkyne 127a. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with EtOAc (2 × 50 ml) and washed with 1M NaHCO ₃ (2 × 30 ml), water (2 × 30 ml), 5% citric acid (2 × 50 ml), and brine (2 × 30 ml). The organic extract was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain 1.8 g of 127a (90% yield).
[M + H] ⁺ : 177.09

127b. Triazole formation 4- (N-ethylaminocarbonyl) -5-phenyltriazole was prepared by the method of Example 3 using 127a and sodium azide.
Hydrolysis of the ethyl ester using the title compound of Example 2 and 4- (N-ethylaminocarbonyl) -5-phenyltriazole 127b according to the method described in Example 105 followed by the method of Example 106. The title compound was prepared.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound of Formula II , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. -Deprotection of the amine The title compound of Example 105 (0.041 mmol) is dissolved in a 4M solution of HCl in dioxane (4 ml) and stirred for 1 hour. The reaction residue 128a is concentrated under reduced pressure.
128b. Chloroformate reagent Cyclopentanol (0.045 mmol) is dissolved in THF (3 ml) and phosgene (0.09 mmol, in toluene (20%)) is added to prepare the chloroformate reagent 128b. The resulting reaction mixture is stirred at room temperature for 2 hours and the solvent is removed under reduced pressure. DCM is added to the residue and concentrated to dryness under reduced pressure twice to give the chloroformate reagent 128b.

128c. -Carbamate formation Dissolve residue 128a in THF (1 ml), add TEA (0.045 mmol) and cool the resulting reaction mixture to 0 ° C to prepare the title carbamate. To the reaction mixture at 0 ° C. is added chloroformate reagent 128b in THF (3 ml). The resulting reaction mixture is reacted at 0 ° C. for 2 hours, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 106.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclobutyl), G = OH, L = chemical bond, W is

A compound of formula II , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, using the title compound of example 105 and cyclobutanol The title compound is prepared by hydrolysis of the ethyl ester by the method described in 33 followed by the method described in Example 106.

A =-(C = O) -O-R ¹ (Where R ¹ = Cyclohexyl), G = OH, L = chemical bond, W is

A compound of formula II , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H, using the title compound of example 105 and cyclohexanol. The title compound is prepared by hydrolysis of the ethyl ester by the method described in 33 followed by the method described in Example 106.

A =-(C = O) -O-R ¹ (Where R ¹ =

), G = OH, L = chemical bond, W is

The title compound of Example II and (R) -3-hydroxy where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. The title compound is prepared by hydrolysis of the ethyl ester using tetrahydrofuran in the manner described in Example 33 followed by the method described in Example 106.

A =-(C = O) -O-R ¹ (Where R ¹ =

), G = OH, L = chemical bond, W is

The title compound of Example II and (S) -3-hydroxy where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. The title compound is prepared by hydrolysis of the ethyl ester using tetrahydrofuran in the manner described in Example 33 followed by the method described in Example 106.

A =-(C = O) -O-R ¹ (Where R ¹ =

), G = OH, L = chemical bond, W is

The compound of Formula II, Example 105 , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H

Is used to prepare the title compound by hydrolysis of the ethyl ester by the method described in Example 33 followed by the method described in Example 106.

A =-(CO) -R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound of Formula II Example 105 (0.041 mmol) is HCl , where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Is dissolved in 4M dioxane solution (4 ml) and stirred for 1 hour to prepare the title compound. The reaction residue is concentrated under reduced pressure. To this residue is added THF (4 ml) and TEA (0.045 mmol), cooled to 0 ° C., and cyclopentanoic acid chloride (0.045 mmol) is added thereto. The resulting reaction mixture is stirred at 0 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 106.

A =-(C = O) -NH-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound of Formula II Example 105 (0.041 mmol) is HCl , where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Is dissolved in 4M dioxane solution (4 ml) and stirred for 1 hour to prepare the title compound. The reaction residue obtained is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To the solution cooled to 0 ° C., cyclopentyl isocyanate (0.045 mmol) is added and the resulting reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 106.

A =-(C = S) -NH-R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound of Formula II Example 105 (0.041 mmol) is HCl , where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Is dissolved in 4M dioxane solution (4 ml) and stirred for 1 hour to prepare the title compound. The reaction residue obtained is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To the solution cooled to 0 ° C., cyclopentyl isothiocyanate (0.045 mmol) is added and the resulting reaction mixture is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 106.

A = -S (O) ₂ -R ¹ (Where R ¹ = Cyclopentyl), G = OH, L = chemical bond, W is

Compound of Formula II Example 105 (0.041 mmol) is HCl , where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. Is dissolved in 4M dioxane solution (4 ml) and stirred for 1 hour to prepare the title compound. TEA (0.045 mmol) is added to the resulting residual concentrate dissolved in THF (4 ml) and cooled to 0 ° C. To the 0 ° C. solution is added cyclopentylsulfonyl chloride (0.045 mmol) and cooled to 0 ° C. Cyclopentylsulfonyl chloride (0.045 mmol) is added to the 0 ° C. solution and the resulting reaction mixture is stirred at 0 ° C. for 2 hours. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 106.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = O-phenethyl, L = chemical bond, W is

X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

To a solution of the title compound of Example 128 and phenethyl alcohol 138a in DCM (0.5 ml), PyBrOP (1.2 eq), DIEA (4 eq) and DMAP (catalytic amount) were added at 0 ° C. to prepare the title compound. To do. The resulting reaction mixture is stirred at 0 ° C. for 1 hour and allowed to warm to room temperature over 4-12 hours. The reaction mixture was purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to give the title compound isolated as phenethyl ester 138b. obtain.
Other esters can be prepared using similar methods.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NH-phenethyl, L = chemical bond, W is

X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

Prepare the title compound by adding EDC (1.2 eq) and DIEA (4 eq) at 0 ° C. to a solution of the title compound of Example 128 and phenethylamine 139a (0.05 ml) in DMF (0.5 ml). The resulting reaction mixture is stirred for 1 hour. The reaction is then warmed to room temperature over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to give the title compound phenethylamide 139b.
Other amides can be prepared using similar methods.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NHS (O) ₂ -Phenethyl, L = chemical bond, W is

X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

To a solution of the title compound of Example 128 and α-toluenesulfonamide 140a (10 mg) in DCM (0.5 ml) was added PyBrOP (1.2 eq), DIEA (4 eq) and DMAP (catalytic amount) at 0 ° C. To prepare the title compound. The resulting reaction mixture is stirred for 1 hour and allowed to warm to room temperature over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent to give the title compound sulfonamide 140b.
Other sulfonamides can be prepared using similar methods.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -OH, L = chemical bond, W is

X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ A compound of formula II, wherein = H

To a solution of the title compound of Example 128 in THF (0.5 ml), α-hydroxy-α-methyl-propionitrile (0.1 ml) and TFA (catalytic amount) are added at 0 ° C. to prepare the title compound. . The resulting reaction mixture is warmed from 0 ° C. to room temperature over 4-12 hours and hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction is extracted with EtOAc and washed with water and brine to give the α-hydroxy compound 141a in crude form. This crude compound 46b is des-martin oxidized in THF (0.5 ml) to give the α-carbonyl compound 46b in crude form. The crude 141b is purified by silica gel flash chromatography using different ratios of hexane: EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as elution layer and the title compound isolated as keto acid 141c Get.
Other sulfonamides can be prepared using similar methods.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -O-phenethyl, L = chemical bond, W is

Wherein ketoic acid and phenetanol, which are the title compounds of Example 141 , are X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H. The title compound is prepared by the method described in Example 138.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -NH-phenethyl, L = chemical bond, W is

With keto acid and phenethylamine which are the title compounds of compound Example 141 of formula II where X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H The title compound is prepared by the method described in Example 139.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -NH-S (O) ₂ -Benzyl, L = chemical bond, W is

Keto acid and α-toluene which are the title compounds of compound Example 141 of formula II , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H The title compound is prepared by the method described in Example 140 using the sulfonamide.

A = tBOC, G = OH, L =-(C = O) CH ₂ -, W is

A precursor mesyl derivative of the modified cyclic peptide formed in compound Example 88c of formula II , wherein X = phenyl, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ = H The title compound is prepared by hydrolyzing the ethyl ester with 4,5-diphenyltriazole and by the substitution method shown in Example 105, followed by the method shown in Example 106.

A = tBOC, G = OH, L = -CH (CH ₃ ) CH ₂ -, W is

A precursor of the modified cyclic peptide formed in compound Example 89G of formula II where X = phenyl, Y = phenyl, j = 1, m = s = 1, R ³ = methyl, and R ⁴ = H The title compound is prepared by hydrolyzing the ethyl ester using the mesyl and 4,5-diphenyltriazole by the substitution method shown in Example 105 and then in the method shown in Example 106.

A = tBOC, G = OH, L = -O-, W is

A precursor of the modified cyclic peptide formed in compound Example 90D of formula II , wherein X = phenyl, Y = phenyl, j = 0, m = s = 1, R ³ = methyl, and R ⁴ = hydrogen The title compound is prepared by hydrolyzing the ethyl ester using the mesyl and 4,5-diphenyltriazole by the substitution method shown in Example 105 and then in the method shown in Example 106.

A = tBOC, G = OH, L = -S-, W is

A precursor of the modified cyclic peptide formed in compound Example 91E of formula II , where X = phenyl, Y = phenyl, j = 0, m = s = 1, R ³ = methyl, and R ⁴ = hydrogen The title compound is prepared by hydrolyzing the ethyl ester using the mesyl and 4,5-diphenyltriazole by the substitution method shown in Example 105 and then in the method shown in Example 106.

A = tBOC, G = OH, L = -S (O)-, W is

A precursor of the modified cyclic peptide formed in compound Example 92B of formula II where X = phenyl, Y = phenyl, j = 2, m = s = 1, R ³ = methyl, and R ⁴ = hydrogen The title compound is prepared by hydrolyzing the ethyl ester using the mesyl and 4,5-diphenyltriazole by the substitution method shown in Example 105 and then in the method shown in Example 106.

A = tBOC, G = OH, L = -S (O) ₂ -, W is

A precursor of the modified cyclic peptide formed in compound Example 93B of formula II where X = phenyl, Y = phenyl, j = 2, m = s = 1, R ³ = methyl, and R ⁴ = H The title compound is prepared by hydrolyzing the ethyl ester using the mesyl and 4,5-diphenyltriazole by the substitution method shown in Example 105 and then in the method shown in Example 106.

A = tBOC, G = OH, L = -SCH ₂ CH ₂ -, W is

X = phenyl, Y = phenyl, j = 0, m = s = 1, and R ³ = R ⁴ = CH ₃ A compound of formula II

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 are added to the mixture and stirring is continued for another 12 hours. The DMF is then removed under reduced pressure and the remaining mixture is diluted with 0.5 N HCl (at 0 ° C.) to adjust the pH to ˜4-5 and extracted with 2 × EtOAc. The organic layer is washed twice with brine, dried over MgSO ₄ and evaporated to dryness to give crude carboxylic acid 151a.

151B. Synthesis of Precursor Mesyl Form of Modified Cyclic Peptide Using the modified amino acid 151a instead of Boc-L-2-amino-8-nonenoic acid, the synthetic route detailed in Example 1 and then in Example 2 Precursor mesyl forms of modified cyclic peptides are prepared by conversion to the corresponding mesyl form by the methods described.
The modified cyclic peptide precursor mesyl formed in 151B and 4,5-diphenyltriazole were used to hydrolyze the ethyl ester by the substitution method shown in Example 105 and then by the method described in Example 106. Decompose to prepare the title compound.

A = tBOC, G = OH, L = CF ₂ CH ₂ , W

A precursor mesyl derivative of the modified cyclic peptide formed of compound Example 95C of formula II , wherein X = phenyl, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ = H The title compound is prepared by hydrolyzing the ethyl ester with 4,5-diphenyltriazole and by the substitution method shown in Example 105, followed by the method shown in Example 106.

A = tBOC, G = OH, L = -CHFCH ₂ -, W is

A precursor mesyl derivative of the modified cyclic peptide formed of compound Example 96C of formula II , wherein X = phenyl, Y = phenyl, j = 1, m = s = 1, and R ³ = R ⁴ = H The title compound is prepared by hydrolyzing the ethyl ester with 4,5-diphenyltriazole and by the substitution method shown in Example 105, followed by the method shown in Example 106.

A = tBOC, G = OH, L = chemical bond, W is

Compound 154A. Of Formula III , wherein X = phenyl, Y = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = H.
Cyclic peptide precursor mesylate body 2 is catalytically reduced with Pd / C in MeOH in the presence of H ₂ to prepare a saturated cyclic peptide precursor mesylate body.
The ethyl ester was hydrolyzed by the substitution method shown in Example 105 using the precursor mesylate of saturated cyclic peptide formed with 154A and 4,5-diphenyltriazole and then by the method shown in Example 106. Decompose to prepare the title compound.

A = tBOC, G = OH, L = chemical bond, W is

Compound 155A. Of formula II , wherein j = 3, m = s = 1, and R ³ = R ⁴ = H. Formation of substituted benzotriazoles

5-Bromo-3,4-dimethylbenzene-1,2-diamine (2.15 g, 10 mmol), glacial acetic acid (1.15 ml, 20 mmol), and water (10 ml) were mixed and the mixture was heated. A clear solution is obtained to prepare the bromine substituted benzotriazole 155b of this example. The clear solution is cooled to 5 ° C., a solution of sodium nitrite (0.83 g, 12 mmol) in water (5 ml) is added and the reaction mixture is heated to 70-80 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc, washed with brine and water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product is purified on a silica gel column.
155B. Replace

The ethyl ester 155c is prepared by the substitution method described in Example 105 using the title compound of Example 2 and the bromine substituted benzotriazole 155b.
The ethyl ester 155c is hydrolyzed as described in Example 106 to finally prepare the title compound.

A = tBOC, G = OH, L = chemical bond, W is

Compound 156A. Of formula II , wherein j = 3, m = s = 1, and R ³ = R ⁴ = H. Suzuki reaction

Compound 156a of this example is prepared by Suzuki coupling reaction of 155c and 3-thienylboronic acid as described in Example 26C.
156B. Hydrolysis Ethyl ester 156a is hydrolyzed as described in Example 106 to prepare the title compound.

A = tBOC, G = OH, L = chemical bond, W is

Compound 157a. Of formula II , wherein j = 3, m = s = 1, and R ³ = R ⁴ = H. Bicyclic Compound Formation The bicyclic compound of the present invention is prepared by the method described in Example 157A using 2,3-diaminopyridine.
Prepare the title compound using the bicyclic compound prepared in 157a and the title compound of Example 2 by the substitution method described in Example 105 and then hydrolyzing the ethyl ester by the method described in Example 106. .

A compound of formula II in which A = tBOC, G = OEt, L = chemical bond, X = Y = bromo, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = 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 5 mL). To this mixture, DIAD (148 μL, 0.75 mmol) is added dropwise at 0 ° C. After stirring at 0 ° C. for 15 minutes, the solution is warmed to room temperature and stirred for an additional 16 hours. The mixture is then concentrated under reduced pressure and the residue is purified by column chromatography eluting with 40% ethyl acetate-hexanes to give the title compound (235 mg, 86% yield).

¹ N-NMR (500 MHz, 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.

A = tBOC, G = OEt, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II The title compound of Example 162 (40 mg, 0.055 mmol), 3-thiopheneboronic acid (35 mg, 0.28 mmol), cesium carbonate (71 mg, 0.22 mmol), potassium fluoride monohydrate (41 mg, 0.44 mmol) of the mixture is placed in a round bottom flask and washed twice with nitrogen. To this mixture is added DME, the solution is again washed with nitrogen and palladium tetrakis (triphenylphosphine) (7 mg, 10 mol%) is added. After washing twice with nitrogen, the mixture is heated to reflux for 20 hours. Cool the mixture, then dilute with water and extract three times with EtOAc. The combined EtOAc layers are washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue is purified by column chromatography eluting with 20-40% ethyl acetate-hexanes to give the title compound (24 mg, 60% yield) as a clear film.

¹ N-NMR (500 MHz, CDCl ₃ ) δ (PPM): 7.9 (s, 1 H), 7.6 (s, 1 H), 7.3 (s, 1 H), 7.3 (m, 1 H) , 7.0 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.7 (m, 1H), 5.5 (m, 1H), 5.4 ( 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), 1.4 (s, 9H), 1.2 (t, 3H), M + H] ⁺ = 758. 63.

A = tBOC, G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II 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) is added lithium hydroxide (14 mg, 0.33 mmol). After stirring at room temperature for 16 hours, the mixture is acidified to pH 4 with citric acid and extracted three times with EtOAc. The combined organic extracts are washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue is purified by column chromatography eluting with 5-10% methanol-chloroform to give the title compound (13 mg, 56% yield).
[M + H] ⁺ = 708.3

A compound phenylboron of formula II wherein A = tBOC, G = OH, L = chemical bond, X = Y = phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen The title compound is prepared by double Suzuki coupling the acid and the title compound of Example 158 according to the method described in Example 159 and then hydrolyzing the ethyl ester as described in Example 160.
[M + H] ⁺ = 696.40

A = tBOC, G = OH, L = chemical bond, X = Y = 4- (N, N-dimethylamino) phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = Double Suzuki coupling of compound 4- (N, N-dimethylamino) phenylboronic acid of formula II and the title compound of Example 158, which is hydrogen, according to the method described in Example 159, followed by ethyl ester Hydrolyze as described in Example 160 to prepare the title compound.
[M + H] ⁺ = 782.30

A = tBOC, G = OH, L = chemical bond, X = Y = 4- (trifluoromethoxy) phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of formula II, 4- (trifluoromethoxy) phenylboronic acid and the title compound of Example 158 are double Suzuki coupled according to the method described in Example 159 and then the ethyl ester is prepared as described in Example 160. To give the title compound.
[M + H] ⁺ = 864.09

A = tBOC, G = OH, L = chemical bond, X = Y = 4- (methanesulfonyl) phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of formula II 4- (methanesulfonyl) phenylboronic acid and the title compound of Example 158 are double Suzuki coupled according to the method described in Example 159 and then the ethyl ester is hydrolyzed by the method described in Example 160. Decompose to prepare the title compound.

A = tBOC, G = OH, L = chemical bond, X = Y = 4- (cyano) phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound II of 4-Cyanophenylboronic acid and the title compound of Example 158 are double Suzuki coupled according to the method described in Example 159, then the ethyl ester is hydrolyzed as described in Example 160, Prepare the title compound.
[M + H] ⁺ = 746.14

A = tBOC, G = OH, L = chemical bond, X = Y = pyridin-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II The compound 3-pyridylboronic acid and the title compound of Example 158 were double Suzuki coupled according to the method described in Example 159, and then the ethyl ester was hydrolyzed as described in Example 160 to yield the title compound. To prepare.
[M + H] ⁺ = 698.3

A = tBOC, G = OH, L = chemical bond, X = Y = 4- (morpholino-4-yl-methanonyl) phenyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = Hydrogen compound 4-carboxyphenylboronic acid of formula II and the title compound of example 158 according to the method described in example 159, then double Suzuki coupled and then subjected to standard amide bond formation conditions, eg The title compound is prepared by amide formation with morpholine with PyBrOP, DIEA and DMAP with DMF in DMF. The ethyl ester of the resulting compound is hydrolyzed by the method described in Example 160.

A compound of formula II wherein A = tBOC, G = OH, L = chemical bond, X = bromo, Y = methoxy, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen The title compound is prepared from the title compound of Example 158 by hydrolysis of the ethyl ester according to the method described in Example 160. However, methoxy addition to the 5-position is observed in addition to the hydrolysis of the ethyl ester.
[M + H] ⁺ = 652.2, 654.2

A = tBOC, G = OH, L = chemical bond, X and Y (together) = phenyl, Z = 4-methoxyphenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen The compound of formula II is commercially available 4- (4-methoxy-phenyl) -2H-phthalazin-1-one using the Mitsunobu conditions described in Scheme 20 and then the ethyl ester as described in Example 160. To give the title compound.
[M + H] ⁺ = 700.1

A = tBOC, G = OH, L = chemical bond, X and Y (together) = phenyl, Z = 4-chlorophenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen A compound of formula II, using commercially available 4- (4-chloro-phenyl) -2H-phthalazin-1-one, under the Mitsunobu conditions described in Scheme 20, and then the ethyl ester in the manner described in Example 160. Hydrolyze to prepare the title compound.
[M + H] ⁺ = 704.2

A = tBOC, G = OH, L = chemical bond, X = 4-fluorophenyl, Y = hydrogen, Z = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. The compound of II using the commercially available 4- (4-fluoro-phenyl) -6-phenyl-2H-pyridazin-3-one under the Mitsunobu conditions described in Scheme 20 and then the ethyl ester as described in Example 160 To give the title compound.
[M + H] ⁺ = 704.2

A = tBOC, G = OH, L = chemical bond, X = hydrogen, Y = 1-piperidyl, Z = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II using compounds commercially available 6-phenyl-5-piperidyl-1-yl -2H- pyridazin-3-one, under Mitsunobu conditions described in scheme 20, and then hydrolyzed by the method described ethyl ester example 160 To prepare the title compound.
[M + H] ⁺ = 702.3

A compound of formula II wherein A = tBOC, G = OEt, L = chemical bond, X = hydrogen, Y = bromo, Z = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen The title compound is prepared using commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one under the Mitsunobu conditions described in Scheme 20.
[M + H] ⁺ = 726.3, 728.3

A = tBOC, G = OH, L = chemical bond, X = hydrogen, Y = thiophen-3-yl, Z = phenyl, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of Formula II Using the title compound of Example 173 and thiophen-3-ylboronic acid, following the Suzuki coupling conditions described in Example 159, the ethyl ester was then hydrolyzed as described in Example 160, Prepare the title compound.
[M + H] ⁺ = 730.3

A compound of formula II wherein A = tBOC, G = OH, L = chemical bond, X = bromo, Y = pyrrolidyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen A mixture of the title compound of Example 158 (45 mg, 0.062 mmol), pyrrolidine (21 mL, 0.25 mmol) and potassium carbonate (34 mg, 0.25 mmol) in acetonitrile (2 mL) is heated to reflux for 3 hours. . After cooling to room temperature, the mixture is filtered through a glass filter and the filtrate is concentrated under reduced pressure. The residue is redissolved in ethyl acetate and then washed once with saturated sodium carbonate, once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a yellow residue. This is subjected to silica gel column chromatography eluting with 3% methanol-chloroform to give the title compound (37 mg, 83% yield).
[M + H] ⁺ = 719.22.71.2

A = tBOC, G = OEt, L = chemical bond, X = thiophen-3-yl, Y = pyrrolidyl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of Formula II Using the title compound of Example 175 and thiophen-3-ylboronic acid under the Suzuki conditions described in Example 159 and then hydrolyzing the ethyl ester as described in Example 160, the title compound To prepare.
[M + H] ⁺ = 694.3

A compound of formula II wherein A = tBOC, G = OEt, L = chemical bond, X = bromo, Y = azide, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen A mixture of the title compound of Example 158 (45 mg, 0.062 mmol), sodium azide (16 mg, 0.25 mmol), and potassium carbonate (34 mg, 0.25 mmol) in acetonitrile (2 mL) for 3 hours. Heat to reflux. After cooling to room temperature, the mixture is filtered through a glass filter and the filtrate is concentrated under reduced pressure. The residue is redissolved in ethyl acetate and then washed once with saturated sodium carbonate and once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a yellow residue. This is subjected to silica gel column chromatography eluting with 3% methanol-chloroform to give the title compound (37 mg, 83% yield).

A = tBOC, G = OEt, L = chemical bond, X = thiophen-3-yl, Y = azide, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of Formula II The title compound is prepared using the Suzuki compound described in Example 159 with the title compound of Example 177 and thiophen-3-ylboronic acid.

A = tBOC, G = OH, L = chemical bond, X = thiophen-3-yl, Y = azide, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. Compound of Formula II The title compound is prepared by hydrolysis of the ethyl ester of the title compound of Example 178 by the hydrolysis method of Example 160.

A = tBOC, G = OH, L = chemical bond, X = thiophen-3-yl, Y = tetrazol-2-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = To a solution of the title compound of Example II 178 (2.63 mmol) in toluene (8 ml) that is hydrogen , KCN (10.53 mmol) and Et ₃ N.HCl (10.53 mmol) are added. The mixture was heated to 115 ° C. for 18 hours, diluted with DVM, washed with 5% citric acid (aq), dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to give the title compound crude. Get as a thing. The ethyl ester is hydrolyzed as described in Example 160 to give the title compound.

A = tBOC, G = OH, L = chemical bond, X = Y = mercapto-2-pyrimidine, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = A compound of formula II, where hydrogen

A mixture of the title compound of Example 158 (45 mg, 0.062 mmol), pyrimidine-2-thiol (0.25 mmol), and potassium carbonate (34 mg, 0.25 mmol) in acetonitrile (2 mL) for 3 hours. Heat to reflux. After cooling to room temperature, the mixture is filtered through a glass filter and the filtrate is concentrated under reduced pressure. The residue is redissolved in ethyl acetate and then washed once with saturated sodium carbonate and once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a yellow residue. This is subjected to silica gel column chromatography eluting with 3% methanol-chloroform to obtain 181b in 19% yield. The ethyl ester of compound 181b is then hydrolyzed as described in Example 160 to give the title compound.
[M + H] ⁺ = 764.3

A = tBOC, G = OH, L = chemical bond, X = bromo, Y = mercapto-2-pyrimidine, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. The title compound is prepared by hydrolysis of the ethyl ester of Compound 181a, formed in Compound Example 181 of Formula II, as described in Example 160.
[M + H] ⁺ = 732.2, 734.2

A = tBOC, G = OH, L = chemical bond, X = thiophen-3-yl :, Y = mercapto-2-pyrimidine, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = Compound of formula II, wherein hydrogen is used according to Suzuki coupling conditions described in example 159 using compound 181a of example 181 and thiophen-3-ylboronic acid, and then the ethyl ester is prepared as described in example 160. To give the title compound.

A = tBOC, G = OEt, L = chemical bond, X = Y = thiazol-2-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II To a degassed solution of the title compound of Example 158 (1 mmol) and thiazol-2-ylstannane (2 mmol) is added Pd (PPh ₃ ) ₄ (10 mol%). The mixture is degassed twice more with nitrogen and heated to 100 ° C. for 3 hours. Concentrate the cooled mixture under reduced pressure and purify the residue by column chromatography eluting with 30% EtOAc / hexane, then hydrolyze the ethyl ester by the method of Example 160 to give the title compound.
[M + H] ⁺ = 710.3

A = tBOC, G = OH, L = chemical bond, X = Y = imidazol-1-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula II To a dry mixture of the title compound of Example 158 (0.068 mmol), imidazole (2 eq), Cs ₂ CO ₃ (3 eq), xanthphos (Xantphos; 30 mol%), and Pd (OAc) ₂ Dioxane is added under a nitrogen atmosphere to prepare the title compound. The reaction mixture is degassed and stirred at 75 ° C. for 18 hours. When the reaction is complete as observed by TLC, the reaction mixture is diluted with DCM, filtered and concentrated under reduced pressure. The reaction mixture is then purified by silica gel chromatography using 5% MeOH / CHCl ₃ to give the ethyl ester of the title compound. The ethyl ester is then hydrolyzed under the conditions described in Example 160 to give the title compound.

A = tBOC, G = OH, L = chemical bond, X = 2- (cyclopropylamino) -thiazol-4-yl, Y = 4-methoxyphenyl, Z = hydrogen, j = 3, m = s = 1, And R ³ = R ⁴ = A compound of formula II, where hydrogen
Formation of 4- (2-cyclopropylamino-thiazol-4-yl) -5- (4-methoxy-phenyl) -2H-pyridazin-3-one (186h)

186A.
A mixture of 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). Is heated to reflux for 1 hour. After cooling, the solvent is evaporated under reduced pressure. The residue is applied to a small silica gel column and purified by eluting with 10% EtOAc / hexanes to give compound 186a as a white powder (81% yield).
[M + H] ⁺ = 256.3

186B.
While stirring a solution of 186a (4.5 mmol) in dry dioxane (20 mL) magnetically, a 21% solution of sodium methoxide (1.0 mL) is added at room temperature. After 1 hour, the mixture is poured into water / ethyl acetate and the organic layer is dried over MgSO ₄ and concentrated to an oil. The oily residue is purified by column chromatography eluting with 10% EtOAc / hexanes to give 186b (85% yield).
[M + H] = 251.7
Alternative substitution of pyridazinone 186b can be performed by using methanol instead of dioxane as a solvent, where methoxy is located at the 5-position of pyridazinone and chloro is located at the 4-position.

186C.
Pyridazinone 186b (1 mmol) is dissolved in DME. To this mixture was added Pd (PPh ₃ ) ₄ (10 mol%) and the mixture was stirred at room temperature for 10 minutes before adding 4-methoxybenzeneboronic acid (2 mmol) and a 10% aqueous solution of Na ₂ CO ₃ (1 mL). Add. The reaction mixture is subsequently heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The combined organic layers are dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography eluting with 15% EtOAc / hexanes to give compound 186c.
[M + H] ⁺ = 323.3

186D.
To a solution of 186c (3 mmol) in DME is added 2N KOH and the mixture is heated to reflux for 1 hour. The cooled mixture is diluted with water, acidified with solid citric acid to pH˜5 and extracted three times with CH ₂ Cl ₂ . The organic layer is washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give compound 186d.
[M + H] ⁺ = 309.3

186E.
A solution of compound 186d (2 mmol) and triethylamine (0.4 mL) in dichloromethane (10 mL) is cooled (ice-acetone bath) and trifluoromethanesulfonic anhydride (0.4 mL) is added dropwise. The resulting solution is stirred at −5 ° C. for 30 minutes. The reaction mixture is poured into dilute HCl (0.5 M) and extracted with CH ₂ Cl ₂ . The combined organic layers are washed with 1% NaOH ₃ , brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give a brown oil. Compound 186e is used immediately without further purification.
[M + H] ⁺ = 441.4

186F.
Commercially available 2,4-dibromothiazole (2 mmol) is dissolved in cyclopropylamine (3 mL) and the reaction mixture is heated to 50 ° C. for 8 hours. The cooled mixture is poured into water and extracted twice with ether. After the combined organic fractions were dried (MgSO ₄ ), the solvent was evaporated and purified by flash column chromatography (silica gel, 15% EtOAc / hexane) to give 2-cyclopropylamine-4-bromothiazole. This is further converted to the corresponding stannane 186f. A degassed DME solution of 2-cyclopropylamine-4-bromothiazole is treated with hexamethyldistin and Pd (PPh ₃ ) ₄ and heated to 80 ° C. for 18 hours. The cooled mixture is concentrated under reduced pressure and the residue is purified by column chromatography eluting with 20% EtOAc / hexane / 2% Et ₃ N to give stannane 186f.
[M + H] ⁺ = 304.1

188G.
To a degassed solution of compound 186e (1 mmol) and stannane 186f (2 mmol) is added Pd (PPh ₃ ) ₄ (10 mol%). The mixture is degassed twice more with nitrogen and then heated to 100 ° C. for 3 hours. The cooled mixture is concentrated under reduced pressure and the residue is purified by column chromatography eluting with 30% EtOAc / hexanes to give 186 g of compound.
[M + H] ⁺ = 431.6

186H.
A hydrogen balloon is attached to a solution of compound 186 g and 10% Pd / C (wet) in methanol for 2 hours. The mixture is filtered through a pad of celite and the filtrate is concentrated under reduced pressure to give compound 186h.
[M + H] ⁺ = 341.4
The title compound is prepared from pyridazinone 186h and cyclic peptide precursor 1 of Example 1 according to Mitsunobu conditions as described in Example 158 and then hydrolyzing the ethyl ester as described in Example 159.

A = tBOC, G = OH, L = chemical bond, X and Y (together) = 6-methoxyisoquinolin- (3,4) -yl, Z = hydrogen, j = 3, m = s = 1, And R ³ = R ⁴ = A compound of formula II, where hydrogen

187A.
Pyridazinone 186b (2 mmol) is dissolved in DME. To this mixture is added Pd (PPh ₃ ) ₄ and the mixture is stirred at room temperature for 10 minutes before adding an aqueous solution (10% by weight) of 2-formyl-4-methoxybenzeneboronic acid and Na ₂ CO ₃ . The reaction mixture is subsequently heated to reflux for 18 hours. The cooled reaction mixture is diluted with water and extracted three times with ethyl acetate. The combined organic layers are dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with 20% EtOAc / hexanes to give compound 187a.
[M + H] ⁺ = 351.4
187B.
A mixture of pyridazinone 187a (1 mmol), MeOH (20 mL) and NH ₄ OH (10 mL; 28-30 wt%) is heated to 60 ° C. for 30 minutes. After cooling, the precipitate, compound 187b, is filtered and washed with MeOH (15 mL).
[M + H] ⁺ = 317.4

187C.
A mixture of pyridazinoisoquinolinone 187b (0.5 mmol), AlCl ₃ and toluene is stirred and heated to 70 ° C. for 1 hour. After cooling, water is added and the mixture is filtered and rinsed with water. The residue is purified by column chromatography on silica gel eluting with 50% EtOAc / hexanes to give compound 187c.
[M + H] ⁺ = 227.3
The title compound was prepared from pyridazinoisoquinolinone 187c and cyclic peptide precursor 1 of Example 1 by Mitsunobu conditions as described in Example 162 and then by hydrolysis of the ethyl ester as described in Example 159. To do.

A = — (C═O) —O—R ¹ (where R ¹ = cyclopentyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, compound 188a. Of formula II wherein m = s = 1 and R ³ = R ⁴ = hydrogen . Deprotection of the amine The title compound of Example 159 (0.041 mmol) is dissolved in HCl in 4M dioxane (4 ml) and stirred for 1 hour. The reaction residue 188a is concentrated under reduced pressure.
188b. Chloroformate reagent Cyclopentanol (0.045 mmol) is dissolved in THF (3 ml) and a solution of phosgene (0.09 mmol) in toluene (20%) is added to prepare chloroformate reagent 188b. The reaction mixture is stirred at room temperature for 2 hours and the solvent is removed under reduced pressure. DCM is added to the residue followed by concentration to dryness under reduced pressure twice to give the chloroformate reagent 188b.

188c. Carbamate Formation Residue 188a is dissolved in THF (1 ml), TEA (0.045 mmol) is added and the reaction mixture is cooled to 0 ° C. to prepare the title compound. To this 0 ° C. reaction mixture is added chloroformate reagent 188b in THF (3 ml). The resulting reaction mixture is reacted at 0 ° C. for 2 hours, extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 160.

A = — (C═O) —O—R ¹ (where R ¹ = cyclobutyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = The title compound is prepared in the manner described in Example 188 using the title compound of Example II and cyclobutanol for the compound of Formula II , where m = s = 1 and R ³ = R ⁴ = hydrogen .

A = — (C═O) —O—R ¹ (where R ¹ = cyclohexyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = The title compound is prepared in the manner described in Example 188 using the title compound of Example II 159 and cyclohexanol , wherein m = s = 1 and R ³ = R ⁴ = hydrogen .

A =-(C = O) -O-R ¹ (Here, R ¹ =

), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. The title compound is prepared by the method described in Example 188 using the title compound of Example 159 and (R) -3-hydroxytetrahydrofuran.

A =-(C = O) -O-R ¹ (Here, R ¹ =

), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. The title compound is prepared by the method described in Example 188 using the title compound of Example 159 and (S) -3-hydroxytetrahydrofuran.

A =-(C = O) -O-R ¹ (Here, R ¹ =

), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen. The title compound of Example 159 and

Is used to prepare the title compound as described in Example 188.

A = — (C═O) —O—R ¹ (where R ¹ = cyclopentyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3. Compound of Formula II , where m = s = 1 and R ³ = R ⁴ = hydrogen The title compound of Example 159 is dissolved in HCl in 4M dioxane (4 ml) and the reaction mixture is stirred for 1 hour. To prepare the title compound. The reaction residue is concentrated under reduced pressure. To this residue is added THF (4 ml) and TEA (0.045 mmol), the mixture is cooled to 0 ° C., and to this is added cyclopentylic acid chloride (0.045 mmol). The resulting reaction mixture is stirred at 0 ° C. for 2 hours. The reaction mixture is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 160.

A = — (C═O) —NH—R ¹ (where R ¹ = cyclopentyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3. Compound of Formula II , where m = s = 1 and R ³ = R ⁴ = hydrogen The title compound of Example 159 is dissolved in 4M HCl in HCl (4 ml) and stirred for 1 hour to give the title A compound is prepared. The reaction residue is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To this 0 ° C. solution is added cyclopentyl isocyanate (0.045 mmol) and the reaction mixture is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 160.

A = — ( C═S ) —NH—R ¹ (where R ¹ = cyclopentyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3. Compound of Formula II , where m = s = 1 and R ³ = R ⁴ = hydrogen The title compound of Example 159 is dissolved in 4M HCl in HCl (4 ml) and stirred for 1 hour to give the title A compound is prepared. The reaction residue is concentrated under reduced pressure, dissolved in THF (4 ml) and cooled to 0 ° C. To this 0 ° C. solution is added cyclopentyl isothiocyanate (0.045 mmol) and the reaction mixture is stirred at room temperature for 4 hours. The solution is then extracted with EtOAc, washed with 1% HCl, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 160.

A = —S (O) ₂ —R ¹ (where R ¹ = cyclopentyl), G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, Compound of Formula II, where m = s = 1 and R ³ = R ⁴ = hydrogen The title compound of Example 159 is dissolved in HCl in 4M dioxane (4 ml) and stirred for 1 hour to give the title compound Prepare. TEA (0.045 mmol) is added to the concentrated reaction residue dissolved in THF (4 ml) and cooled to 0 ° C. To the 0 ° C. solution is added cyclopentylsulfonyl chloride (0.045 mmol) and the reaction mixture is stirred at 0 ° C. for 2 h. The solution is then extracted with EtOAc, washed with 1M sodium bicarbonate, water and brine, dried over MgSO ₄ and concentrated to dryness under reduced pressure. The crude compound is purified on a silica gel column and the ethyl ester is subsequently hydrolyzed as described in Example 160.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -O-phenethyl, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = A compound of formula II, where hydrogen

To a solution of the title compound of Example 194 and phenethyl alcohol 198a in DCM (0.5 ml) at 0 ° C. was added PyBrOP (1.2 eq), DIEA (4 eq), and DMAP (catalytic amount) to give the title compound. Prepare. The reaction mixture is stirred at 0 ° C. for 1 hour and then allowed to warm to room temperature over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography using different ratios of hexane / EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as eluent and isolated as phenethyl ester 198b A compound is obtained.
Other esters can be prepared in a similar manner.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NH-phenethyl, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = A compound of formula II, where hydrogen

Prepare the title compound by adding EDC (1.2 eq) and DIEA (4 eq) at 0 ° C. to a solution of the title compound of Example 194 and phenethylamine 199a (0.05 ml) in DMF (0.5 ml). The reaction mixture is stirred for 1 hour. The reaction is then warmed to room temperature over 4-12 hours. 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 to give the title compound phenethylamide 199b. obtain.
Other amides can be prepared in a similar manner.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G = -NHS (O) ₂ -Phenethyl, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = A compound of formula II, where hydrogen

To a solution of the title compound of Example 194 and α-toluenesulfonamide 200a (10 mg) in DCM (0.5 ml) at 0 ° C. was added PyBrOP (1.2 eq), DIEA (4 eq), and DMAP (catalytic amount). In addition, the title compound is prepared. The reaction mixture is stirred for 1 hour and then allowed to warm to room temperature over 4-12 hours. 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 elution layer to give the title compound sulfonamide 200b. obtain.
Other sulfonamides can be prepared in a similar manner.

A =-(C = O) -O-R ¹ , R ¹ = Cyclopentyl, G =-(C = O) -OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = A compound of formula II, where hydrogen

Prepare the title compound by adding EDC (1.2 eq) and DIEA (4 eq) at 0 ° C. to a solution of the title compound of Example 194 in DMF (0.5 ml). The reaction mixture is stirred for 1 hour. The reaction is then warmed to room temperature over 4-12 hours. The reaction mixture is purified by silica gel flash chromatography to give the hydroxyamide.
This hydroxyamide is treated with DIBAL-H in THF at −78 ° C. for 2 hours. The reaction mixture is then diluted with EtOAc (8 ml), washed with water and brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give aldehyde 201a.
To a solution of aldehyde 39a in THF (0.5 ml) at 0 ° C. is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and TFA (catalytic amount). The reaction mixture is warmed from 0 ° C. to room temperature over 4-12 hours and then hydrolyzed with concentrated hydrochloric acid in dioxane. The reaction solution is then extracted with EtOAc and washed with water and brine to give the α-hydroxy compound 201b in crude form.
When this crude compound 201b is subjected to Dess-Martin oxidation in THF (0.5 ml), an α-carbonyl compound 201c is obtained in a crude form. The crude 201c is purified by silica gel flash chromatography using different ratios of hexane / EtOAc (9: 1 → 5: 1 → 3: 1 → 1: 1) as the eluting layer and isolated as keto acid 201c. The title compound is obtained.

A = — (C═O) —O—R ¹ , R ¹ = cyclopentyl, G = — (C═O) —O-phenethyl, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen J = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, using the title compound keto acid and phenetanol of Example 201 according to the method described in Example 198. The title compound is prepared.

A = — (C═O) —O—R ¹ , R ¹ = cyclopentyl, G = — (C═O) —NH-phenethyl, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen J = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, using the title compound keto acid and phenethylamine of Example 201, according to the method described in Example 199, Prepare the title compound.

A = — (C═O) —O—R ¹ , R ¹ = cyclopentyl, G = — (C═O) —NH—S (O) ₂ -benzyl, L = chemical bond, X = Y = thiophene-3 Using keto acid and α-toluenesulfonamide, the title compound of compound Example 201 of formula II, wherein -yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen The title compound is prepared according to the method described in Example 200.

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 As shown in Example 158, using the precursor mesyl form of a modified cyclic peptide formed with compound 88C of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one The ethyl ester is then hydrolyzed in the manner described in Example 160 according to the Mitsunobu conditions described to give the title compound.

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 Example 158 using a precursor mesyl derivative of a modified cyclic peptide formed with compound 89G of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one, wherein R ⁴ = hydrogen The ethyl ester is then hydrolyzed in the manner described in Example 160 using the Mitsunobu conditions shown in to give the title compound.

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. Mitsunobu as shown in Example 158 using a precursor mesyl of a modified cyclic peptide formed with compound 90D of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one Depending on the conditions, the ethyl ester is then hydrolyzed as described in Example 160 to give the title compound.

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. Mitsunobu as shown in Example 158, using a precursor mesyl of a modified cyclic peptide formed with compound 91E of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one Depending on the conditions, the ethyl ester is then hydrolyzed as described in Example 160 to give the title compound.

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 = As shown in Example 158, using a modified cyclic peptide precursor mesyl form formed with compound 92B of formula II, which is hydrogen, and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one. According to the existing Mitsunobu conditions, this ethyl ester is then hydrolyzed as described in Example 160 to give the title compound.

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 As shown in Example 158, using a precursor mesyl derivative of a modified cyclic peptide formed with compound 93B of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one The ethyl ester is then hydrolyzed in the manner described in Example 160 according to the Mitsunobu conditions described to give the title compound.

A = tBOC, G = OH, L = —SCH ₂ CH ₂ —, X = Y = thiophen-3-yl, Z = hydrogen, j = 0, m = s = 1, and R ³ = R ⁴ = CH ₃ As shown in Example 158, using a precursor mesyl of a modified cyclic peptide formed with compound 94B of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one Depending on the Mitsunobu conditions, this ethyl ester is then hydrolyzed as described in Example 160 to give the title compound.

A = tBOC, G = OH, L = —CF ₂ CH ₂ —, X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1, and R ³ = R ⁴ = hydrogen As shown in Example 158, using a precursor mesyl of a modified cyclic peptide formed with compound 95C of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one Depending on Mitsunobu conditions, the ethyl ester is then hydrolyzed as described in Example 160 to give the title compound.

A = tBOC, G = OH, L = —CHFCH ₂ —, X = Y = thiophen-3-yl, Z = hydrogen, j = 1, m = s = 1, and R ³ = R ⁴ = hydrogen. Mitsunobu conditions as shown in Example 158 using the precursor mesyl of a modified cyclic peptide formed with compound 96C of formula II and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one The ethyl ester is then hydrolyzed in the manner described in Example 160 to give the title compound.

A = tBOC, G = OH, L = chemical bond, X = Y = thiophen-3-yl, Z = hydrogen, j = 3, m = s = 1, and R ³ = R ⁴ = hydrogen, Formula III Compound 214A.
A saturated cyclic peptide precursor mesyl body is prepared by catalytic reduction of the mesylated cyclic peptide precursor of Example 2 with Pd / C in the presence of H ₂ in MeOH.
Using the saturated cyclic peptide precursor mesyl form formed in 214A and 4,5-di (thiophen-3-yl) -2H-pyridazin-3-one, this was followed by Mitsunobu conditions as shown in Example 158. The ethyl ester is hydrolyzed as described in Example 160 to give the title compound.

  The compounds of the present invention exhibit potent inhibitory properties against HCV NS3 protease. The following examples illustrate typical tests in which compounds of the present invention were evaluated for anti-HCV effects.

NS3 / NS4a Protease Enzyme Test Intramolecular quencher- fluorinated fluorogenic substrates are used to test HCV protease activity and inhibition. The DABCYL and EDANS groups are attached to both ends of the short peptide. Quenching of EDANS fluorescence by the DABCYL group alleviates proteolytic cleavage. Fluorescence was measured with a Molecular Devices Fluoromax or equivalent instrument using an excitation wavelength of 335 nm and an emission wavelength of 485 nm.

The test is performed in full length NS3 HCV protease 1b linked to NS4A coenzyme (final enzyme concentration 1 to 15 nM) in Corning 96 well half area plates, white, (VWR29444-312 [Corning3693]). The test buffer is supplemented with 10 μM NS4A coenzyme Pep4A (Anaspec 25446 or in-house MW1424.8). RET S1 (Ac-Asp-Glu-Asp (EDANS) -Glu-Glu-Abu- [COO] Ala-Ser-Lys- (DABCYL) -NH ₂ ; AnaSpec 29991, MW 1548.6) is used as a fluorogenic peptide substrate . The test buffer contains 50 mM Hepes, 30 mM NaCl and 10 mM BME at pH 7.5. The enzymatic reaction is followed over a time course of 30 minutes at room temperature in the presence and absence of inhibitors.

Peptide inhibitors HCV Inh1 (Anaspec 2345, MW 796.8); Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [−20 ° C.] and HCV Inh2 (Anaspec 25346, MW 913.1); Ac-Asp-Glu -Dif-Cha-Cys-OH was used as a reference compound.
IC50 value was calculated by the formula 205: y = A + ((BA) / 1 + ((C / x) ^ D))) using XLFit in ActivityBasa (IDBS).

Cell-based replicon test
Quantification of HCV replicon RNA in cell lines (HCV cell line test)
Cell lines containing Huh-17 or Huh9-13, infested with HCV replicon (Lohmann et al. Science 285: 110-113, 1999), were seeded in 96-well plates at 5 × 10 ³ cells / well and DMEM ( High glucose) Add medium containing 10% fetal bovine serum, penicillin-streptomycin and non-essential amino acids. Cells are cultured at 37 ° C. in a 5% CO ₂ incubator. At the end of the culture, total RNA is extracted and purified from the cells using a Qiagen Rneasy 96 Kit (Catalog No. 74182). In amplifying HCV RNA to allow a sufficient amount of material to be detected by an HCV specific probe (shown below), primers specific to HCV (shown below) can be used for reverse transcription of HCV RNA and Tuckman One Step. It mediates both amplification of cDNA by polymerase chain reaction (PCR) using a PT-PCR master mix kit (TaqMan One-Step PT-PCR Master Mix Kit; Applied Biosystems Catalog No. 4329169). The nucleic acid sequence of the PT-PCR primer present in the NS5B site of the HCV genome is as follows.

HCV Forward Primer “RBNS5bfor”
5 'GCTGCGGCCCGTCGAGCT;
HCV reverse primer "RBNS5Brev"
5'CAAGGTCGTCTCCCCATAC

  Detection of PT-PCR products is performed with an Applied Biosystem (ABI) Prism 7700 Sequence Detection System (SDS), which is labeled with a fluorescent reporter dye and quencher dye and detects the fluorescence emitted by the probe during the PCR reaction. It was performed using. The increase in fluorescence is measured during each PCR cycle and reflects the increase in RT-PCR product. In particular, quantification is based on a threshold cycle where the amplification plot crosses the established fluorescence threshold. Comparison of threshold cycles between samples and known standards provides a sensitive measurement of relative template concentration in different samples (ABI User Manual # 2, December 11, 1997). This data is analyzed using the ABI SDS program version 1.7. Relative template concentrations can be converted to RNA transcription numbers using a standard curve of HCV RNA standards and known copy numbers (ABI User Manual # 2, December 11, 1997).

RT-PCR products were detected using the following labeled probes.
5'-FAM-CGAAGCTCCAGGAACTGCACGATGCT-TAMRA
FAM = fluorescent reporter dye TAMRA = quencher dye

  The RT reaction is performed at 48 ° C. for 30 minutes and then by PCR. The thermal cycler parameters used for the PCR reaction in the ABI prism 7700 sequence detection system are as follows. One cycle is 10 minutes at 95 ° C, then 35 cycles, each cycle comprising a first culture at 95 ° C for 15 seconds and a second culture at 60 ° C for 1 minute.

  To normalize the internal control molecule data with cellular RNA, RT-PCR is performed on the cellular messenger RNA, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The number of GAPDH copies is constant for the cell line used. GAPDH RT-PCR is performed on the exact same RNA sample from which the HCV copy number was determined. GAPDH primers and probes are included in the ABI Pre-Developed TaqMan measurement kit (Catalog No. 431086E) as well as the standard for determining copy number. The RNA ratio of HCV / GAPDH is used to calculate the activity of a compound that evaluates HCV RNA replication inhibition.

Activity of compounds as HCV transcription inhibitors in replicon-containing Huh-7 cell lines (cell-based tests)
The effect of a specific antiviral compound on the HCV replicon RNA level of Huh-11-7 or Huh-9-13 cells is to determine the amount of HCV RNA normalized by GAPDH (eg, the ratio of HCV / GAPDH). It was measured by comparing that of the added cells with that of cells that had 0% inhibition and 100% inhibition. Specifically, cells are seeded in a 96-well plate at 5 × 10 ³ cells / well,
1) Medium containing 1% DMSO (0% inhibition control),
2) 1% DMSO broth containing 100 International Units (IU) / ml interferon-alpha 2b, or 3) 1% DMSO broth containing a certain concentration of compound,
Cultured with any of the above. (Measurement of _{1C 50)} above 96-well plates for 3 days at 37 ° C. (initial screening test) or 4 days and cultured. The inhibition rate is defined as follows.

Inhibition (%) = [100 − ((S−C2) / (C1−C2))] × 100
put it here,
S = ratio of HCV RNA copy number / GAPDH RNA copy number in the sample;
C1 = Ratio of HCV RNA copy number / GAPDH RNA copy number in 0% inhibition control (1% DMSO medium); and C2 = HCV RNA in 100% inhibition control (100 IU / ml interferon-alpha 2b). It is the ratio of copy number / GAPDH RNA copy number.

Inhibitor dose-response curves were generated by sequentially adding compounds to wells in 3-fold dilutions over 3 logarithms, starting with a maximum concentration of 10 μM for a particular compound and ending with a minimum concentration of 0.01 μM. Additional dilution systems (eg, 1 μM to 0.01 μM) were made when IC ₅₀ values were not within the linear region of this curve. IC ₅₀ was measured based on the IDBS Activity Base program using Microsoft Excel's “XL Fit”. Here, A = 100% inhibition value (100 IU / ml interferon-alpha 2b), B = 0% inhibition control value (1% DMSO medium) and C is C = (B−A / 2) It is defined as + A and is the midpoint of this curve. The values of A, B and C are shown as the ratio of HCV RNA / GAPDH RNA measured for each sample in each well of the above 96 well plate. On average, 4 wells were used for each plate to determine 100% and 0% inhibition values.

  While the invention has been described in terms of various preferred embodiments, it is not intended to be limited thereto, but rather to be within the spirit of the invention and the scope of the appended claims to be within the scope of the person skilled in the art. It is a place to recognize.

Claims (77)

Formula I:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , —C (═O) —NH—R ² , —C (═S) —NH—R ^2. , —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (C═NR ¹ ) —NH—R ¹ ;
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ¹ , — (C═O) —O—R ¹ , And — (C═O) —NHR ¹ ;
L is a chemical _{bond, -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 Selected from the group consisting of-, -CF ₂ CH _2- , and CR _x = CR _x-, where R _x is hydrogen 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 hydrogen, 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, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R ² is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl , Heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R ³ and R ⁴ are each independently selected from the group consisting of hydrogen, OH, CH ₃ , CN, SH, halogen, NO ₂ , NH ₂ , amide, methoxy, trifluoromethoxy, and trifluoromethyl;
E is selected from —CH═CH— or —CH ₂ —CH ₂ —; and W is a substituted or unsubstituted heterocyclic ring system),
A compound represented by W is substituted with one or more substituents, each of which is (a), (b), (c), (d) and (e):
(A) alkenyl, alkoxy, alkoxyalkyl, alkyl, alkylamino, alkylaryl, alkylsulfonyl, alkynyl, amido, C ₁ -C ₆ alkyl mono - Good amide substituted, aryl, aryl alkanoyl, arylalkyl , Arylaminoalkyl, aryloxyalkyl, arylsulfonyl, cycloalkoxy, cycloalkyl, dialkylamino, dialkylaminoalkyl, diarylaminoalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocyclo, heterocycloalkyl, heterocycloalkylalkyl, thioalkyl , Monoalkylaminoalkyl, sulfonyl, (lower alkyl) sulfonyl, haloalkyl, carboxyl, amide, (lower Kill) _amide, C 1 -C ₆ alkyl optionally substituted heterocyclo, perhaloalkyl, sulfonyl, thioalkyl, ^{urea, C (= O) -R 11} , OC (= O) -R 11, OC (= O ) O—R ¹¹ , C (═O) N (R ¹¹ ) ₂ , C (═S) N (R ¹¹ ) ₂ , SO ₂ (R ¹¹ ) ₂ , NHS (O ₂ ) R ¹¹ , N (R ¹²⁾ ) ₂ , N (R ¹² ) C (═O) R ¹¹ (wherein each of the above groups may be substituted with 3 or less groups selected from halogen, OH, alkoxy and perhaloalkyl);
(B) C ₇ -C ₁₄ aralkyl, C ₂ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, heterocyclo, (lower alkyl) -heterocyclo (where aralkyl, cycloalkyl, aryl, heterocyclo, or (lower alkyl)) -Heterocyclo may each be substituted with 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, wherein R ⁷ is hydrogen, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; or R ⁶ is NH—C (O) —OR ⁸ where 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 (R 5 wherein is independently _hydrogen, C 1 -C ₆ alkyl or _C 3 -C ₆ cycloalkyl, aryl _{C 6} or _{C 10, C} 7 _{-C 14} aralkyl, heterocyclo or (lower alkyl) - heterocyclo);
(D) NH—C (O) —OR ⁸ (where R ⁸ is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl);
(E) formyl, halogen, _hydroxy, NO 2, OH, SH, halo, CN;
(put it here,
Each R ¹¹ is independently hydrogen, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl. Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl (wherein each of the above groups is halogen, OH , alkoxy and optionally substituted with up to three groups selected from perhaloalkyl); and R ¹² are each independently hydrogen, formyl, Alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl , Aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or dialkylaminoalkyl, wherein each group is substituted with up to 3 groups selected from halogen, OH, alkoxy and perhaloalkyl May be)),
The compound according to claim 1, which is independently selected from any one of the above. W:
(A) an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and no more than 4 heteroatoms selected from O, N and S (this The ring system may be substituted with up to 3 ring substituents selected from the group consisting of OH, CN, halogen, formyl, R ¹⁰ and R ¹¹ ): and (b) 5-16 ring atoms and Aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring systems having up to 4 heteroatoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, And optionally substituted with 3 or less ring substituents selected from the group consisting of R ¹⁰ );
Each R ¹⁰ is independently alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, arylalkanoylalkyl , Heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea (wherein each of the above groups is halogen, OH, alkoxy and ^{perhaloalkyl, C (= O) -R 11} , OC (= O) -R 11, C (= O) O-R 11, C (= O) -N (R 11 _{^{2, C (= S) -N}} (R 11) 2, SO 2 R 11, NHSO 2 R 11, N (R 12) 2 and ^{N (R 12) C (=} O) 3 or selected from ^{-R 11} Optionally substituted with the following groups:
R ¹¹ is independently hydrogen, OH, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl, heteroarylalkyl. , Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl (wherein each of the above groups is halogen, OH, Optionally substituted with up to 3 groups selected from alkoxy and perhaloalkyl);
Each R ¹² is independently hydrogen, formyl, alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl, heteroaryl, Arylalkanoylalkyl, heterocycloalkylalkyl, aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, or diarylaminoalkyl (wherein each of the foregoing groups is selected from halogen, OH, alkoxy and perhaloalkyl) Which may be substituted with up to 3 groups).
The compound according to claim 1, which is selected from the group consisting of: W is an aliphatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and no more than 4 heteroatoms selected from O, N and S ring systems OH, CN, halogen, formyl, may also be) optionally substituted with up to three ring substituents selected from the group consisting of R ¹⁰ and R ^11, the compound according to claim 3. W is an aliphatic heteromonocyclic ring system having 5 to 7 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, The compound according to claim 3, which may be substituted with 3 or less ring substituents selected from the group consisting of R ¹⁰ and R ¹¹ .   6. A compound according to claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system has 5 ring atoms and 1 or 2 heteroatoms selected from O, N and S. .   The optionally substituted aliphatic heteromonocyclic ring system comprises pyrrolidine, pyrazolidine, pyrroline, tetrahydrothiophene, dihydrothiophene, tetrahydrofuran, dihydrofuran, imidazoline, tetrahydroimidazole, dihydropyrazole, tetrahydropyrazole, and oxazoline The compound according to claim 6, which is selected from:   6. A compound according to claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system has 6 ring atoms and 1 or 2 heteroatoms selected from O, N and S. .   An optionally substituted aliphatic heteromonocyclic ring system is pyridine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, morpholine, thioxan, 9. The compound of claim 8, selected from the group consisting of and thiomorpholine.   6. A compound according to claim 5, wherein the optionally substituted aliphatic heteromonocyclic ring system has 7 ring atoms and 1 or 2 heteroatoms selected from O, N and S. .   9. The compound of claim 8, wherein the optionally substituted aliphatic heteromonocyclic ring system is selected from the group consisting of hexamethyleneimine and hexamethylene sulfide. W is an aliphatic heterobicyclic ring system having 5 to 16 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl, And the compound according to claim 3, which may be substituted with 3 or less ring substituents selected from the group consisting of R ¹⁰ and R ¹⁰ .   The optionally substituted aliphatic heterobicyclic ring system has 8 to 12 ring atoms and 1 to 4 heteroatoms selected from O, N and S. The described compound.   The optionally substituted aliphatic heterobicyclic ring system has 8 to 12 ring atoms and one or two heteroatoms selected from O and N. Compound. W is an aromatic heteromonocyclic, heterobicyclic or heterotricyclic ring system having 5 to 16 ring atoms and not more than 4 heteroatoms selected from O, N and S (this ring systems OH, CN, halogen, optionally substituted with up to three ring substituents selected from the group consisting of formyl and R ¹⁰ is may also be) a compound according to claim 3. W is an aromatic heteromonocyclic ring system having 5 to 7 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl And the compound according to claim 3, which may be substituted with 3 or less ring substituents selected from the group consisting of R ¹⁰ and R ¹⁰ .   16. A compound according to claim 15, wherein the optionally substituted aromatic heteromonocyclic ring system has 5 ring atoms and 1 or 2 heteroatoms selected from O, N and S. .   The optionally substituted aromatic heteromonocyclic ring system is from the group consisting of pyrrole, pyrazole, porphyrin, furan, thiophene, pyrazole, imidazole, oxazole, oxadiazole, isoxazole, thiazole, thiadiazole, and isothiazole. 18. A compound according to claim 17, which is selected.   17. The optionally substituted aromatic heteromonocyclic ring system has 6 ring atoms and 1, 2 or 3 heteroatoms selected from O, N and S. Compound.   20. A compound according to claim 19, wherein the optionally substituted aromatic heteromonocyclic ring system is selected from the group consisting of pyridine, pyrimidine, pyrazine, pyran and triazine.   17. A compound according to claim 16, wherein the optionally substituted aromatic heteromonocyclic ring system has 5 ring atoms and 3 or 4 heteroatoms selected from O, N and S. .   24. The compound of claim 21, wherein the optionally substituted aromatic heteromonocyclic ring system is triazolyl or tetrazolyl. W is an aromatic heterobicyclic ring system having 8 to 12 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl And the compound according to claim 3, which may be substituted with 3 or less ring substituents selected from the group consisting of R ¹⁰ and R ¹⁰ .   An optionally substituted aromatic heterobicyclic ring system is adenine, azabenzimidazole, azaindole, benzimidazole, benzoisothiazole, benzofuran, benzoisoxazole, benzoxazole, benzothiazole, benzothiazole, From the group consisting of benzothienes, benzothiophene, benzoxazole, carbazole, cinnoline, guanine, imidazopyridine, indazole, indole, isoindole, isoquinoline, phthalazine, purine, pyrrolopyridine, quinazoline, quinoline, quinoxaline, thianaphthene, and xanthine 24. The compound of claim 23, which is selected. W is an aromatic heterotricyclic ring system having 10 to 16 ring atoms and 4 or less hetero atoms selected from O, N and S (this ring system is OH, CN, halogen, formyl , R ¹⁰ and R ¹¹ , which may be substituted with 3 or less ring substituents selected from the group consisting of R ¹¹ and R ¹¹ ).   The optionally substituted aromatic heterotricyclic ring system is selected from the group consisting of carbazole, bibenzofuran, psoralen, dibenzothiophene, phenazine, thianthrene, phenanthroline, and phenanthridine. Compound. Formula II:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ¹ , — (C═S) —NH—R ² , Selected from the group consisting of —S (O) ₂ —R ² , — (C═NR ¹ ) —R ¹ , and — (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) —O—R ¹ , and Selected from the group consisting of — (C═O) —NH—R ² ;
L is a chemical _{bond, -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 —, and —CR _x = CR _x — (wherein R _x is hydrogen or halogen);
W is

Selected from the group consisting of:
Q is selected from the group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen;
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—;
Y is hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Chosen from the group;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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 Selected from the group consisting of arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R ³ and R ⁴ are each independently from hydrogen and methyl Selected from the group)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
28. The compound of claim 27. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
28. The compound of claim 27. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
28. The compound of claim 27. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s is 1, and R ³ and ^{R 4} are hydrogen, A compound according to claim 27.

28. The compound of claim 27, selected from the group consisting of:

28. The compound of claim 27, selected from the group consisting of:

28. The compound of claim 27, selected from the group consisting of:

28. The compound of claim 27, selected from the group consisting of: Formula III:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , ^{_{S (O) 2 -R 2,}} - (C = NR 1) -R 1, and ^- (C = NR 1) selected from the group consisting of ^{-NH-R 1;}
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , and Selected from the group consisting of — (C═O) —NH—R ² ;
L is a chemical _{bond, -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 —, and —CR _x = CR _x — (wherein R _x is hydrogen or halogen);
W is

Selected from the group consisting of:
Q is selected from the group consisting of a chemical bond, —CH ₂ —, —O—, —NH—, —N (R ¹ ) —, —S—, —S (O) ₂ —, and — (C═O) —. Chosen;
Q ′ is selected from the group consisting of a chemical bond, —CH ₂ —, and —NH—;
Y is hydrogen, C ₁ -C ₆ alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl Chosen from the group;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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 Selected from the group consisting of arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R ³ and R ⁴ are each independently from hydrogen and methyl Selected from the group)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
37. The compound of claim 36. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
37. The compound of claim 36. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
37. The compound of claim 36. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
37. The compound of claim 36. Formula II:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , ^{_{S (O) 2 -R 2,}} - (C = NR 1) -R 1, and ^- (C = NR 1) selected from the group consisting of ^{-NH-R 1;}
G represents —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , — Selected from the group consisting of (C═O) —NH—R ² ;
L is a chemical _{bond, -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 —, and —CR _x = CR _x — (wherein R _x is hydrogen or halogen);
W is

Selected from the group consisting of:
And X and Y are each independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, - 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 are X and Y Together with carbon atoms at the 4 and 5 positions of the triazole ring to which Conversion aryl, heteroaryl, and part of the ring selected from the group consisting of substituted heteroaryl form;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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 Selected from the group consisting of arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R ³ and R ⁴ are each independently from hydrogen and methyl Selected from the group)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
42. The compound of claim 41. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
42. The compound of claim 41. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
42. The compound of claim 41. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
42. The compound of claim 41.

42. The compound of claim 41, selected from the group consisting of:

42. The compound of claim 41, selected from the group consisting of:

42. The compound of claim 41, selected from the group consisting of:

42. The compound of claim 41, selected from the group consisting of: Formula III:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , ^{_{S (O) 2 -R 2,}} - (C = NR 1) -R 1, and ^- (C = NR 1) selected from the group consisting of ^{-NH-R 1;}
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , and Selected from the group consisting of — (C═O) —NH—R ² ;
L represents a chemical bond, —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 In which R _x is hydrogen or halogen);
W is

Selected from the group consisting of:
X and Y are independently hydrogen, _halogen, C 1 -C _{6 alkyl,} C 3 _{-C 12} cycloalkyl, -CH ₂ - alkylamino, -CH ₂ - dialkylamino, -CH ₂ - arylamino, -CH ₂ -diarylamino,-(C = O) -alkylamino,-(C = O) -dialkylamino,-(C = O) -arylamino,-(C = O) -diarylamino, aryl, substituted aryl, Selected from the group consisting of arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or X and Y are such that X and Y are Together with carbon atoms at the 4 and 5 positions of the attached triazole ring, Le, heteroaryl, and forms part of the ring selected from the group consisting of substituted heteroaryl;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Selected from the group consisting of alkyl, substituted heteroarylalkyl, heterocycloalkyl, and 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 Selected from the group consisting of arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; and R ³ and R ⁴ are each independently from hydrogen and methyl Selected from the group)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
51. A compound according to claim 50. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
51. A compound according to claim 50. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
51. A compound according to claim 50. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
W is

And
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
51. A compound according to claim 50. Formula IV:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , ^{_{-S (O) 2 -R 2,}} - (C = NR 1) -R 1, or ^- (C = NR 1) be a ^{-NH-R 1;}
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , or -(C = O) -NH-R ² ;
L are _{-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 - a is (wherein, _{R x} is hydrogen or halogen);
X, Y, and Z are each independently 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, 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 hetero Arylalkyl, heterocycloalkyl, and substituted hetero Selected from the group consisting of chloroalkyl; or X and Y or Y and Z together with the carbon atom to which they are attached, an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring moiety Forming;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Alkyl, 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; and R ³ and R ⁴ are each independently hydrogen or methyl)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s is 1, and R ³ and ^{R 4} are hydrogen, A compound according to claim 55. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
56. The compound of claim 55.

56. The compound of claim 55, selected from the group consisting of:

56. The compound of claim 55, selected from the group consisting of:

56. The compound of claim 55, selected from the group consisting of:

56. The compound of claim 55, selected from the group consisting of: Formula IV:

(put it here,
A is hydrogen, — (C═O) —R ² , — (C═O) —O—R ¹ , — (C═O) —NH—R ² , — (C═S) —NH—R ² , or ^{_{-S (O) 2 -R 2,}} - (C = NR 1) -R 1, or ^- (C = NR 1) be a ^{-NH-R 1;}
G is —OH, —O— (C ₁ -C ₁₂ alkyl), —NHS (O) ₂ —R ¹ , — (C═O) —R ² , — (C═O) —O—R ¹ , or -(C = O) -NH-R ² ;
L is a chemical _{bond, -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} is hydrogen or halogen); and
X, Y, and Z are each independently 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, 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, heterocycloalkyl, and substituted Or X and Y or Y and Z, together with the carbon atom to which they are attached, are attached to the ring of aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Forming a part;
j is 0, 1, 2, 3, or 4;
m is 0, 1, or 2;
s is 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 arylalkyl, heteroaryl, substituted heteroaryl, heteroaryl Alkyl, 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; and R ³ and R ⁴ are each independently hydrogen or methyl)
Compound. A is-(C = O) -O-R ¹ ;
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
64. The compound of claim 62. A is-(C = O) -O-tert-butyl,
G is hydroxyl,
L is a chemical bond,
j is 3,
m and s are 1, and R ³ and R ⁴ are hydrogen,
64. The compound of claim 62.   An anti-hepatitis C virus effective amount of a compound according to claim 1, 27, 36, 41, 50, 55, or 62 or a pharmaceutically acceptable salt, ester, or prodrug thereof is pharmaceutically acceptable. A pharmaceutical composition comprising a carrier or excipient.   66. A method of treating hepatitis C virus infection in a patient, comprising administering to the patient an effective amount of an anti-hepatitis C virus of the pharmaceutical composition of claim 65.   66. A method of inhibiting hepatitis C virus replication comprising providing a hepatitis C virus NS3 protease inhibitory amount of the pharmaceutical composition of claim 65.   68. The method of claim 66, further comprising administering an additional anti-hepatitis C virus agent simultaneously.   69. The method of claim 68, wherein the additional anti-hepatitis C virus agent is selected from the group consisting of [alpha] -interferon, [beta] -interferon, ribavirin, and adamantine.   69. The method of claim 68, wherein the additional anti-hepatitis C virus agent is an inhibitor of other targets in the hepatitis C virus life cycle selected from helicases, polymerases, metalloprofesases, and IRES.

A compound selected from the group consisting of: pharmaceutically acceptable salts and isomers thereof.

And a pharmaceutically acceptable salt and isomer thereof.

And a pharmaceutically acceptable salt and isomer thereof. (I) Formula VI

(put it here,
P is a nitrogen protecting group;
L is a leaving group,
R is an optionally substituted alkyl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
Reacting with a nucleophilic heterocyclic compound; and (ii) converting the resulting compound to the compound of formula I of claim 1;
A process for preparing a compound of formula I according to claim 1. (I) Formula VII

(put it here,
L is a leaving group,
A is a nitrogen protecting group, and the remaining variables are as defined in claim 1)
Reacting with a nucleophilic heterocyclic compound; and (ii) preparing the compound of formula I of claim 1 comprising converting the resulting compound to the compound of formula I of claim 1. how to. W is

(Where V, X, Y and Z are each independently:
j) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl , -C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from:
k) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkenyl;
l) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkynyl;
m) aryl;
n) substituted aryl,
o) heteroaryl;
p) substituted heteroaryl;
q) heterocycloalkyl; or r) selected from substituted heterocycloalkyl: or V and X, X and Y, or Y and Z together with the carbon atom to which they are attached, aryl, substituted aryl, heteroaryl , Forming a ring moiety selected from substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl)
The compound of claim 1, wherein W is

(Where X, Y and Z are each independently:
a) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl , -C ₁ -C ₆ alkyl optionally substituted with one or more substituents selected from:
b) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkenyl;
c) containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, halogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl it may be substituted with one or more substituents selected from, -C ₂ -C ₆ alkynyl;
d) aryl;
e) substituted aryl,
f) heteroaryl;
g) substituted heteroaryl;
h) heterocycloalkyl; or i) selected from substituted heterocycloalkyl: or Y and Z together with the carbon atom to which they are attached are aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, Or form a ring moiety selected from substituted heterocycloalkyl)
The compound of claim 1, wherein