KR100426545B1 - Serine Protease Inhibitors - Google Patents

Abstract

The present invention relates to certain substituted oxadiazole, thiadiazole and triazole peptoids useful as serine protease inhibitors.

Description

Serine Protease Inhibitors

The present invention relates to certain substituted oxadiazole, thiadiazole and triazole peptoids useful as inhibitors of serine proteases.

Serine proteases are enzymes that include elastase, chymotrypsin, cathepsin G, trypsin and thrombin. These proteases commonly have a triad consisting of serine-195, histidine-57 and aspartic acid-102 (chymotrypsin numbering system). Human neutrophil elastase (HNE) is a proteolytic enzyme secreted by polymorphonuclear leukocytes (PMN) in response to various inflammatory stimuli. The release of this HNE and its extracellular protease activity is highly regulated and is a normal beneficial function of PMN. Bunhaeryeok of HNE, under normal circumstances is relatively high concentration of α ₁ in plasma - is controlled by the proteinase inhibitor (α ₁ -PI). Stimulated PMN, however, suddenly produces many free radical metabolites, some of which (eg hypochlorous acid) can oxidize important methionine residues of α ₁ -PI. It has been suggested that oxidized α ₁ -PI has limited efficacy as an HNE inhibitor and that its degradation function is performed in a localized regulatory environment by changing this protease / antiprotease balance.

Despite this balance of protease / antiprotease activity, there are several human diseases in which the failure of this regulatory mechanism has been implicated in the onset. Inadequate regulation of HNE activity has been suggested as a cause of adult respiratory distress syndrome, septic shock and multi-center disorders. A series of studies also showed that PMN and neutrophil elastase are involved in myocardial ischemia / reperfusion disorders. People with lower levels of α ₁ -PI are more likely to develop emphysema. HNE-mediated processes are implicated in the penetration behavior of other diseases, such as arthritis, periodontal disease, hepatitis, dermatitis, psoriasis, cystic fibrosis, chronic bronchitis, atherosclerosis, Alzheimer's disease, organ transplantation, corneal ulcers, and malignant tumors It is. There is a need for effective inhibitors of HNE as therapeutics and prophylactic agents for the treatment and / or prophylaxis of elastase mediated diseases.

Summary of the Invention

The present invention provides compounds useful as serine protease inhibitors, such as human neutrophil elastase. The nature of these compounds is their relatively low molecular weight and good potency and selectivity for HNE. In addition, certain compounds of the present invention have demonstrated higher oral bioavailability due to higher blood concentrations after oral administration. Oral bioavailability allows oral administration for use in chronic diseases, the advantage of which is that self-administration is possible and costs are reduced compared to other methods of administration. The compounds described herein can be effectively used to prevent, alleviate or treat diseases characterized by degradation of connective tissue by proteases in humans.

The present invention provides a compound comprising an oxadiazole, thiadiazole or triazole ring structure and generally

It can be represented as.

Wherein Z is a group comprising a serine protease binding moiety, preferably an elastase binding moiety, most preferably a human neutrophil elastase binding moiety, specifically carbonyl, preferably α-amino carbonyl Wherein the carbonyl carbon is covalently bonded to the carbon of the heterocycle,

R ₁ is optionally one or more, preferably 1 to 3 halo, hydroxyl, cyano, nitro, haloalkyl, alkylamino, dialkylamino, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkyl Alkyl, alkenyl or alkynyl substituted with carboxamide, arylcarboxamide or -O- (C ₅ -C ₆ ) aryl; Hydroxyl, amino, alkylamino or dialkylamino; Or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, Alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, Cycloalkyl substituted with alkylthio or haloalkylthio, alkylcycloalkyl, alkenylcycloalkyl, cycloalkenyl, alkylcycloalkenyl, alkenylcycloalkenyl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, (C ₅ -C ₁₂ ) arylalkenyl, fused (C ₅ -C ₁₂ ) aryl-cycloalkyl or alkyl fused (C ₅ -C ₁₂ ) aryl-cycloalkyl,

X and Y independently represent O, S or N (wherein N is optionally substituted alkyl or alkenyl substituted with 1 to 3 halo atoms; optionally comprises 1 to 3 heteroatoms selected from N, O and S) And optionally, halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide , Optionally substituted with (C ₅ -C ₆ ) aryl, arylalkyl or arylalkenyl substituted with arylcarboxamide, alkylthio or haloalkylthio, preferably at least one X or Y is N X and Y are both N when X or Y is substituted). Preferably the compounds of the invention are 1,2,4-oxadiazoles (ie X is O; Y is N) or 1,3,4-oxadiazole rings (ie X is N; Y Is O).

The compounds of the present invention can be conveniently classified into groups I to VI.

In a preferred embodiment, the present invention is

It provides a compound of (Group I).

Wherein X, Y and R ₁ are as defined above;

R ₂ and R ₃ are independently or together H; Optionally alkyl substituted with 1 to 3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine or Alkenyl; -RCOR ', -RCOOR', -RNR'R "R ⁰ or -RC (O) NR'R" where R is alkyl or alkenyl, and R ', R "and R ⁰ are independently H, alkyl , Alkenyl, cycloalkyl or (C ₅ -C ₆ ) aryl; or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, keto, nitro, Hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy , Cycloalkyl, alkylcycloalkyl, alkenyl substituted with alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, alkylthio or haloalkylthio Cycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl or (C ₅ -C ₁₂ ) arylalkenyl;

A is a direct bond, -C (O)-, -NH-C (O)-, -S (O) _2- , -NH-S (O) ₂ , -OC (O)-, -C- or Proline, isoleucine, cyclohexylalanine, optionally sulfur, halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy Cysteine substituted with alkyl, alkenyl or phenyl substituted with alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; Phenylalanine, homo-phenylalanine, dehydrophenylalanine, indolin-2-carboxylic acid; Optionally alkyl, alkenyl or optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, aryl Tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl substituted with carboxamide, alkylthio or haloalkylthio; Tryptophan, tyrosine, serine or threonine, optionally substituted with alkyl or aryl; Histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; Optionally branched nitrogen is one selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or optionally N, O and S Amino acids selected from asparagine, glutamine, ornithine and lysine substituted with aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl containing at least the above heteroatoms;

R ₄ is absent or H, alkyl, alkenyl or alkynyl; Or optionally at least one heteroatom selected from N, O and S and optionally alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, Dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, cycloalkyl, alkylcycloalkyl substituted with alkylthio or haloalkylthio, (C _5- C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, fused (C ₅ -C ₁₂ ) aryl-cycloalkyl or fused alkyl (C ₅ -C ₁₂ ) aryl-cycloalkyl.

In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. Preferably R ₄ -A is arylalkyloxycarbonyl, for example benzyloxycarbonyl; Alkoxycarbonyl, arylsulfonyl, alkylsulfonyl or alkyl.

Preferably R ₂ and R ₃ are alkyl, for example methyl or isopropyl, or H. In another preferred embodiment, R ₂ is isopropyl and R ₃ is H.

In a preferred embodiment of the invention, R ₁ is optionally substituted aryl or arylalkyl group, for example α, α-dimethylbenzyl, benzyl or phenyl group. According to various preferred embodiments the benzene ring is alkyl, for example methyl; Haloalkyl, for example trifluoromethyl; Or dialkylamino, preferably dimethylamino. In another embodiment, R ₁ is a fused arylalkyl group such as methylenenaphthyl; Or fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, for example 3,4-methylenedioxybenzyl. In another embodiment, R ₁ is a straight or branched chain alkyl group, preferably (C ₁ -C ₈ ) alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. to be.

The present invention is also the following formula

Compound (Group II) is provided.

Wherein X, Y, R ₁ , R ₂ and R ₃ are as defined above;

B is —S (O) ₂ —, —C (O) —, —OC (O) — or —CH ₂ C (O) —;

R ₆ is

Wherein R ₂ ′ and R ₃ ′ are independently or together H; optionally one to three halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkyl Alkyl or alkenyl substituted with guanidinyl, guanidinyl, or amidylguanidine; -RCOR ', -RCOOR', -RNR'R "R ⁰ or -RC (O) NR'R" where R is Alkyl or alkenyl and R ', R "and R ⁰ are independently H, alkyl, alkenyl, cycloalkyl or (C ₅ -C ₆ ) aryl; or optionally 1 selected from N, O and S Containing from 4 heteroatoms and optionally halo, cyano, keto, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, al Kenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcar Cycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C ₅ -C ₁₂ ) aryl, (C substituted with voxamide, alkylthio or haloalkylthio ₅ -C ₁₂ ) arylalkyl or (C ₅ -C ₁₂ ) arylalkenyl;

R ₁₃ comprises at least one heteroatom selected from H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or optionally O, N and S Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, optionally substituted with halo or alkyl;

R ₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; Or optionally one or more heteroatoms selected from O, N and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carbo Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, aryl-cycloalkyl, alkylaryl, aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, aryl substituted with alkylthio or haloalkylthio Alkyl, alkyl fused aryl-cycloalkyl or aryloxycarboxamide;

R ₁₅ is aryl comprising one or more heteroatoms selected from H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or optionally O, N and S , Arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl;

W is O or S; Or optionally C or N substituted with H, alkyl or aryl.

In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. According to various preferred embodiments, R ₁₃ is optionally substituted phenyl or benzyl; Pyridyl, piperidinyl, alkyl or H or fused ring systems such as 3,4-methylenedioxybenzyl; R ₁₄ is optionally substituted amino or arylalkyloxycarboxamide, for example benzyloxycarboxamide; R ₁₅ is H or halo.

Preferably R ₂ is isopropyl and R ₃ is H.

In a preferred embodiment of the invention, R ₁ is optionally substituted aryl or arylalkyl group, for example α, α-dimethylbenzyl, benzyl or phenyl group. According to various preferred embodiments, the benzene ring is alkyl, for example methyl; Haloalkyl, for example trifluoromethyl, or dialkylamino, preferably dimethylamino. In another embodiment, R ₁ is a fused arylalkyl group such as methylenenaphthyl; Or fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, for example 3,4-methylenedioxybenzyl. In another embodiment, R ₁ is a straight or branched chain alkyl group, preferably (C ₁ -C ₈ ) alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. to be.

The present invention is also the following formula

Compound (Group III) is provided.

Wherein X, Y, R ₁ , R ₂ , R ₃ and B are as defined above;

R ₆ is a group of formula (I)

Wherein m is 0 or 1; n is 0 or 1;

D is a direct bond or is not limited to proline, isoleucine, cyclohexylalanine, and optionally sulfur is halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, Cysteine substituted with alkyl, alkenyl or phenyl substituted with haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; Phenylalanine, homo-phenylalanine, dehydrophenylalanine, indolin-2-carboxylic acid; Optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or halo Tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl substituted with alkylthio; Tryptophan, tyrosine, serine or threonine, optionally substituted with alkyl or aryl; Histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; Optionally branched nitrogen is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl, or optionally N, O and S Amino acids selected from asparagine, glutamine, ornithine and lysine substituted with aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl comprising at least two heteroatoms;

A is a direct bond or -C (O)-, -NH-C (O)-, -S (O) _2- , -OC (O)-or -C-;

R ₁₄ is H, alkyl, alkenyl, amino, alkylamino or dialkylamino; Or optionally one or more heteroatoms selected from N, O and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carbo Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl substituted with boalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, alkylthio or haloalkylthio -Cycloalkyl.

Alternatively, R ₆ is a group of formula II.

Wherein W is S or O;

R ₈ is alkylamino, dialkylamino or amino;

R ₉ is H, alkyl or halo.

In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. According to an embodiment, when R ₆ is of formula (I) m is 1 and n is 0. In another embodiment, m and n are one. Preferably R ₁₄ is benzyl, A is -OC (O)-and D is valine.

Preferably R ₂ is isopropyl and R ₃ is H.

In a preferred embodiment of the invention, R ₁ is optionally substituted aryl or arylalkyl group, for example α, α-dimethylbenzyl, benzyl or phenyl group. According to various preferred embodiments the benzene ring is alkyl, for example methyl; Haloalkyl, for example trifluoromethyl; Or dialkylamino, preferably dimethylamino. In another embodiment, R ₁ is a fused arylalkyl group such as methylenenaphthyl; Or fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, for example 3,4-methylenedioxybenzyl. In another embodiment, R ₁ is a straight or branched chain alkyl group, preferably (C ₁ -C ₈ ) alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. to be.

According to an embodiment W is S; R ₈ is amino and R ₉ is H.

In another embodiment of the invention, R ₆ in group III compound is aryl, arylalkyl, cycloalkyl or alkylcycloalkyl. According to one embodiment R ₆ -B is Cbz.

The present invention is also the following formula

Compound (Group IV) is provided.

Wherein X, Y, R ₁ , R ₂ and R ₃ are as defined above;

R ₁₀ optionally contains 1 to 3 heteroatoms selected from N, S and O other than peroxide and optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, al (C ₅ -C ₆ ) aryl, (C ₅ -C ₆ ) arylalkyl, substituted with kenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio, (C ₅ -C ₆ ) arylalkenyl, cycloalkyl, fused aryl-cycloalkyl;

D is a direct bond, or -C (O)-or, but not limited to, proline, isoleucine, cyclohexylalanine, and optionally sulfur is halo, cyano, nitro, haloalkyl, amino, aminoalkyl, Cysteine substituted with alkyl, alkenyl or phenyl substituted with dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; Phenylalanine, homo-phenylalanine, dehydrophenylalanine, indolin-2-carboxylic acid; Optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or halo Tetrahydroisoquinoline-2-carboxylic acid optionally substituted with alkyl, alkenyl or phenyl substituted with alkylthio; Tryptophan, tyrosine, serine or threonine, optionally substituted with alkyl or aryl; Histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; Optionally branched nitrogen is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl, or optionally N, O and S Amino acids selected from asparagine, glutamine, ornithine and lysine substituted with aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl comprising at least two heteroatoms;

A is a direct bond, -C (O)-, -NH-C (O)-, -S (O) _2- , -NH-S (O) _2- , -S (O) ₂ -NH-, -OC (O) NH-, -OC (O)-or -C-; R ₁₄ is as described above.

In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N. Preferably D is valine, A is -OC (O)-and R ₁₄ is aryl or arylalkyl, for example benzyl. In a preferred embodiment, R ₁₀ is (C ₅ -C ₆ ) aryl or (C ₅ -C ₆ ) arylalkyl, preferably benzyl, or fused aryl-cycloalkyl, eg indanyl group. According to another preferred embodiment D is -C (O)-and R ₁₄ -A is pyrrole.

Preferably R ₂ is isopropyl and R ₃ is H.

In a preferred embodiment of the invention, R ₁ is optionally substituted aryl or arylalkyl group, for example α, α-dimethylbenzyl, benzyl or phenyl group. According to various preferred embodiments the benzene ring is alkyl, for example methyl; Haloalkyl, for example trifluoromethyl; Or dialkylamino, preferably dimethylamino. In another embodiment, R ₁ is a fused arylalkyl group such as methylenenaphthyl; Or fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, for example 3,4-methylenedioxybenzyl. In another embodiment, R ₁ is a straight or branched chain alkyl group, preferably (C ₁ -C ₈ ) alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. to be.

The present invention further formula

It provides a compound (Group V).

Wherein X, Y, R ₁ , R ₂ , R ₃ , R ' ₂ and R' ₃ are as defined above;

R ₁₁ , R ₁₂ and E comprise 5 to 10 atoms selected from C, N, S and O; At least one keto group; Optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, Haloalkylthio; Optionally containing at least one heteroatom selected from N, S and O other than peroxide and optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl Cycloalkyl substituted with alkoxy, haloalkoxy, carboxyl, carboalkoxy, -C (O) O (alkyl), -C (O) (alkyl), alkylcarboxamido, alkylthio or haloalkylthio, Alkylcycloalkyl, alkenylcycloalkyl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, ((C ₅ -C ₁₂ ) arylalkyl) OC (O) NH- or (C _5- C ₁₂ ) together form a monocyclic or bicyclic ring substituted with an arylalkenyl.

In a preferred embodiment, X is N and Y is O. In another preferred embodiment, X is O and Y is N.

Preferably R ₂ is isopropyl and R ₃ is H.

In a preferred embodiment of the invention, R ₁ is optionally substituted aryl or arylalkyl group, for example α, α-dimethylbenzyl, benzyl or phenyl group. According to various preferred embodiments the benzene ring is alkyl, for example methyl; Haloalkyl, for example trifluoromethyl; Or dialkylamino, preferably dimethylamino. In another embodiment, R ₁ is a fused arylalkyl group such as methylenenaphthyl; Or fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, for example 3,4-methylenedioxybenzyl. In another embodiment, R ₁ is a straight or branched chain alkyl group, preferably (C ₁ -C ₈ ) alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, etc. to be.

According to one embodiment of the invention, R ₁₁ , R ₁₂ and E combine to form a ring of formula I or la.

<Formula I>

Wherein A is as described for the formula of Group IV compound;

V ₁ , V ₂ , V ₃ and V ₄ are independently or together C or N;

When V ₃ is C; R ₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; Or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl optionally containing one or more heteroatoms selected from O, N and S and optionally substituted with halo or alkyl -Cycloalkyl;

R ₁₄ is H, alkyl, alkenyl, amino, alkylamino, or dialkylamino; Or optionally one or more heteroatoms selected from N, O and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carbo Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, aryl-cycloalkyl, alkylaryl, aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, aryl substituted with alkylthio or haloalkylthio Alkyl, alkyl fused aryl-cycloalkyl, arylalkyloxycarbonyl or arylalkylcarboxamide;

W ₁ , W ₂ and W ₃ are optionally substituted with alkyl; C, S and O.

According to one preferred embodiment, V ₄ is N; V ₁ , V ₂ and V ₃ are C. Preferably R ₁₃ is H or halo; R ₁₄ -A is CbzNH, amino or H; R ' ₂ and R' ₃ are H. Preferably, R ₁₁ , R ₁₂ and E combine to form a ring of formula (I). In certain embodiments, R ₁₃ is H or F; R ₁₄ -A is H or H ₂ N-. When R ₁₁ , R ₁₂ and E combine to form a ring of formula (Ia), W 1 is preferably S and W ₂ and W ₃ are C.

In another embodiment, R ₁₁ , R ₁₂ and E combine to form a ring of formula II.

<Formula II>

In the above formula, A, R ₁₃ and R ₁₄ are as described above.

Preferably R ' ₂ and R' ₃ are H. According to an embodiment, R ₁₃ is 1-piperidinyl; R ₁₄ -A is CbzNH. Alternatively R ₁₃ is H; R ₁₄ -A is amino, alkylamino or dialkylamino. In another preferred embodiment, R ₁₃ is halo; R ₁₄ -A is CH ₃ -OC (O)-. In yet another embodiment, R ₁₃ is H; R ₁₄ -A is CbzNH.

According to another embodiment of the invention, R ₁₁ , R ₁₂ and E form a ring of formula III or IV below.

Wherein A is a direct bond or -C- or -C (O);

R ₁₃ , R ₁₄ and R ₁₅ are as described above.

According to certain embodiments, R ₁₁ , R ₁₂ and E form a ring of Formula III; -AR ₁₃ is -C (O) phenyl; R ₁₄ is H; R ' ₂ and R' ₃ are H.

In another embodiment, R ₁₁ , R ₁₂ and E form a ring of Formula IV; -AR ₁₃ is -C (O) phenyl; R ₁₅ is H; R ' ₂ and R' ₃ are H.

In another embodiment of the invention, R ₁₁ , R ₁₂ and E form a ring of formula (V):

Wherein W is S, SO, SO ₂ or C;

n is 0, 1 or 2;

R ₁₃ and R ₁₄ are as defined above;

G is a direct bond or -NHC (O)-, -OC (O) NH-, -C (O)-, -NHS (O) _2- .

According to one embodiment, preferably n is 0 and W is S when R ₁₄ -G is H. Preferably R ₁₃ is optionally substituted benzyl or phenyl.

In another embodiment n is 1 and W is C. Preferably R ₁₄ -G is arylalkyloxycarboxamide, for example CbzNH-. In a preferred embodiment, R ₁₃ is phenyl substituted with H or halo. Preferably R ' ₂ and R' ₃ are H.

The invention also provides compounds wherein R ₁₁ , R ₁₂ and E form a ring of formula VI, VIa, VII or VIII.

In which R ₁₃ is as described above or CH = R ₁₅ , wherein R ₁₅ is optionally pyridinyl, phenyl or benzyl substituted with halo, dialkylamino or —C (O) OCH ₃ ;

R ₁₄ and R ′ ₁₄ are independently or together H, alkyl, alkenyl, CH ₃ C (O) —; Or optionally at least one heteroatom selected from N, O and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkenyl, alkynyl, haloalkoxy, carbo Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cyclo substituted with alkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio Alkyl, aryloxycarbonyl or arylalkyloxycarbonyl;

R ₁₆ , R ₁₇ , R _'16 and R' ₁₇ are independently or together H, alkyl, alkenyl, alkylthio, alkylthioalkyl; Or cycloalkyl, cycloalkenyl, alkylcycloalkyl, aryl, arylalkyl or arylalkenyl, optionally substituted with guanidine, carboalkoxy, hydroxyl, haloalkyl, alkylthio, alkylguanidine, dialkylguanidine or amidine to be.

Preferred compounds are those in which R ₁₃ is CH = R ₁₅ or R ₁₅ ; Cbz or benzyl, wherein R ₁₄ is substituted with H, alkyl, CH ₃ C (O) —, or optionally alkyl, halo or alkylamino; Or 3,4-methylenedioxybenzyl or 3,4-ethylenedioxybenzyl; Is a compound of Formula VI or Formula VIa wherein R ' ₂ and R' ₃ are H; Preferably R ₁₃ is = CHR ₁₅ , wherein R ₁₅ is optionally phenyl or benzyl substituted with halo or -C (O) CH ₃ .

In another embodiment, R ₁₁ , R ₁₂ and E form a ring of formula IX or IXa.

Wherein U, V, W and Y are independently or together N, C, C (O), N (R ₁₃ ), wherein R ₁₃ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl , Alkylthio, amino, alkylamino, dialkylamino; or aryl, arylalkyl, cycloalkyl, alkyl, optionally containing one or more heteroatoms selected from O, N and S and optionally substituted with halo or alkyl Cycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl); NR ₁₄ , wherein R ₁₄ comprises one or more heteroatoms selected from H, alkyl, alkenyl; or optionally N, O and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkyl Aryl, arylalkyl, cycloalkyl, substituted with amino, carboxyl, alkenyl, alkynyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamide, alkylthio or haloalkylthio, Alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl; Or C (R ₁₆ ) (R ₁₇ ) wherein R ₁₆ and R ₁₇ are independently or together H, alkyl, alkylthio, alkylthioalkyl; carboxylic acid of the formula-(CH ₂ ) _m C (O) OR N-substituted alkylamides of the formula or formula-(CH ₂ ) _m C (O) NRR 'wherein m is 1 to 6 and R and R' are independently or together H or alkyl; or optionally N At least one heteroatom selected from O, not S, and peroxide and optionally amino, alkylamino, dialkylamino, guanidine, carboalkoxy, keto, hydroxy, alkyl, haloalkyl, alkylthio, alkylguanidine , Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl substituted with dialkylguanidine or amidine; together 4 to 8 selected from C, N, O and S To form a cyclic ring structure comprising two atoms.

In one preferred embodiment, U is C (R ₁₆ ) (R ₁₇ ), V is N, W is N (R14) and Y is C (O), wherein preferably R ′ ₂ and R ′ ₃ is H; R ₁₆ is phenyl or benzyl; R ₁₇ is H; R ₁₄ is H or benzyl optionally substituted with alkyl, halo, or alkylamine.

In another preferred embodiment, U is C (O), V is N, W is N, N (R ₁₃ ) or N (R ₁₄ ); Y is C (R ₁₆ ) (R ₁₇ ), preferably R ' ₂ and R' ₃ are H; R ₁₄ is H; R ₁₆ is H, alkyl, optionally substituted aryl or arylalkyl Benzyl or phenyl, preferably substituted with dialkylamino or hydroxyl; pyridinyl, methylene pyridinyl; fused aryl such as indolyl; or carboxylic ester or N-substituted alkyl as defined above Amide, R ₁₇ is H, alkyl, succinimidyl, aryl or arylalkyl.

In another embodiment, U is C (O), V is N, W is N, N (R ₁₃ ) or N (R ₁₄ ); Y is N (R ₁₃ ) (preferably R ′ ₂ and R ′ ₃ are H; W is NH; R ₁₃ is arylalkyl; R ₁₄ is H).

In another embodiment, U is C (R ₁₆ ) (R ₁₇ ); V is N; W is N or N (R ₁₃ ); Y is C (O). Preferably R ₁₃ and R ₁₆ are aryl; R ₁₇ is H.

When R ₁₁ , R ₁₂ and E form a ring of formula IXa, W is typically N (R ₁₃ ), where R ₁₃ is aryl or cycloalkyl, for example piperidinyl.

In other embodiments, R ₁₆ and R ₁₇ form a cyclic ring structure, such as a cyclopentyl or cyclohexyl group.

The present invention is also the following formula

It provides a compound (Group VI).

Wherein X, Y, R ₁ , R ₂ , and R ₃ are as defined above and R ₁₁ , R ₁₂ and E combine to form a ring of formula (X).

Wherein U and V are independently or together N, C, N (R ₁₃ ) wherein R ₁₃ is H, alkyl, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkyl Amino, or optionally aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl comprising one or more heteroatoms selected from O, N and S; Or C (R ₁₆ ) (R ₁₇ ), wherein R 16 and R 17 are as described above;

n is 1 or 2.

The invention also

(a) reacting a compound of formula B with an aldehyde of formula C;

(b) removing the protecting group from the alcohol (D) produced;

(c) coupling the alcohol obtained in step (b) with an acid of formula E; And

(d) oxidizing the product obtained, further removing protecting groups if necessary to obtain the final compound

It provides a method for synthesizing a compound of the formula (A) consisting of.

Z'-COOH

Wherein Z 'is as defined below;

R ₁ is optionally alkyl or alkenyl substituted with one to three halo or hydroxyl; -Alkyl-C (O) OCH ₃ ; Alkylamino, dialkylamino, alkyldialkylamino; Or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, Alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, Cycloalkyl substituted with alkylthio or haloalkylthio, alkylcycloalkyl, alkenylcycloalkyl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, (C ₅ -C ₁₂ ) arylalkenyl , Fused (C ₅ -C ₁₂ ) aryl-cycloalkyl or fused (C ₅ -C ₁₂ ) aryl-cycloalkylalkyl,

X and Y independently represent O, S or N (wherein N is optionally substituted alkyl or alkenyl substituted with 1 to 3 halo atoms; optionally comprises 1 to 3 heteroatoms selected from N, O and S) And optionally, halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide Or (substituted or unsubstituted with (C ₅ -C ₆ ) aryl, arylalkyl or arylalkenyl substituted with arylcarboxamide, alkylthio or haloalkylthio);

R ₂ and R ₃ are independently or together H; Optionally alkyl substituted with 1 to 3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine or Alkenyl; -RCOR ', -RCOOR', -RNR'R "R ⁰ or -RC (O) NR'R" where R is alkyl or alkenyl, and R ', R "and R ⁰ are independently H, alkyl , Alkenyl, cycloalkyl or (C ₅ -C ₆ ) aryl; or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, keto, nitro, Hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy , Cycloalkyl, alkylcycloalkyl, alkenyl substituted with alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, alkylthio or haloalkylthio Cycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl or (C ₅ -C ₁₂ ) arylalkenyl.

According to one embodiment the protecting group [PGR ₁ ] is removed from alcohol (D) by reacting aldehyde of formula C with hydrochloric acid in dioxane. The protecting group [PGr ₁ ] may be any suitable group, preferably Boc.

According to another embodiment, the oxidation step of (d) is performed using Dess Martin reagent.

In another embodiment, the compound of formula B is

(e) treating the acid of formula (R ₁ ) COOH with thionyl chloride or oxalyl chloride;

(f) treating the resulting acid chloride with hydrazine to obtain a hydrazide of formula (R ₁ ) CONHNH ₂ ;

(g) reacting hydrazide with triethyl orthoformate or trimethyl orthoformate and TsOH to obtain an oxadiazole of Formula F; And

(h) treating oxadiazole with butyllithium and further reacting with MgBr.OEt2 if necessary to obtain Compound B

To synthesize.

In one embodiment, Z 'is

Wherein A is a direct bond, -C (O)-, -NH-C (O)-, -S (O ₂ )-, -NH-S (O) _2- , -OC (O) -, -C- or proline, isoleucine, cyclohexylalanine, optionally sulfur with halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy Cysteine, unsubstituted or substituted with alkyl, alkenyl, or phenyl substituted with alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; phenylalanine, homo-phenylalanine, dehydrophenylalanine, indolin-2-car Acids; optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkyl Tet optionally substituted with alkyl, alkenyl or phenyl substituted with thio or haloalkylthio Hydroisoquinoline-2-carboxylic acid; tryptophan, tyrosine, serine or threonine, optionally substituted with alkyl or aryl; histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; At least one branched nitrogen is alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonyl alkyl or optionally at least one selected from N, O and S Amino acids selected from asparagine, glutamine, ornithine and lysine substituted with aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl containing heteroatoms;

R ₄ is absent or H, alkyl, alkenyl or alkynyl; Or optionally at least one heteroatom selected from N, O and S and optionally alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, alkoxy, amino, alkylamino, Dialkylamino, carboxyl, haloalkoxy, carboalkoxy, alkylcarboxamide, aryl, arylalkyl, arylcarboxamido, cycloalkyl, alkylcycloalkyl substituted with alkylthio or haloalkylthio, (C _5- C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, fused (C ₅ -C ₁₂ ) aryl-cycloalkyl or fused (C ₅ -C ₁₂ ) aryl-cycloalkylalkyl);

The following groups are of the formulas

Wherein R ' ₂ and R' ₃ are independently or together H; Optionally alkyl substituted with 1 to 3 halo, hydroxyl, thio, alkylthio, amino, alkylamino, dialkylamino, alkylguanidinyl, dialkylguanidinyl, guanidinyl, or amidylguanidine or Alkenyl; -RCOR ', -RCOOR', -RNR'R "R ⁰ or -RC (O) NR'R" where R is alkyl or alkenyl, and R ', R "and R ⁰ are independently H, alkyl , Alkenyl, cycloalkyl or (C ₅ -C ₆ ) aryl; or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, keto, nitro, Hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, amidine, alkylamidine, dialkylamidine, alkyl, alkenyl, alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy , Cycloalkyl, alkylcycloalkyl, alkenyl substituted with alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, alkylthio or haloalkylthio Cycloalkyl, alkyl-oxyaryl, alkyl-thioaryl, alkyl-aminoaryl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl or (C ₅ -C ₁₂ ) arylalkenyl;

R ₁₃ comprises at least one heteroatom selected from H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino, or optionally O, N and S Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, optionally substituted with halo or alkyl;

R ₁₄ is H, alkyl, alkenyl, amino, alkylamino, dialkylamino; Or optionally one or more heteroatoms selected from O, N and S and optionally alkyl, halo, alkoxy, amino, alkylamino, dialkylamino, carboxyl, alkenyl, alkynyl, haloalkoxy, carbo Aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, aryl-cycloalkyl, alkylaryl, aryl, arylalkyl, arylcarboxamide, arylalkylcarboxamide, aryl substituted with alkylthio or haloalkylthio Alkyl, alkyl fused aryl-cycloalkyl or aryloxycarboxamide;

R ₁₅ is H, alkyl, halo, alkoxy, carboalkoxy, carboxyl, alkylthio, amino, alkylamino, dialkylamino; Or aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl, optionally comprising one or more heteroatoms selected from O, N and S.

In yet another embodiment, Z 'is a group of formula (1).

<Formula 1>

In which m is 0 or 1; n is 0 or 1;

D is a direct bond or proline, isoleucine, cyclohexylalanine, optionally sulfur is halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, Cysteine substituted with alkyl, alkenyl or phenyl substituted with carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or haloalkylthio; Phenylalanine, homo-phenylalanine, dehydrophenylalanine, indolin-2-carboxylic acid; Optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, arylcarboxamide, alkylthio or halo Tetrahydroisoquinoline-2-carboxylic acid, optionally substituted with alkyl, alkenyl or phenyl substituted with alkylthio; Tryptophan, tyrosine, serine or threonine, optionally substituted with alkyl or aryl; Histidine, methionine, valine, norvaline, norleucine, octahydroindole-2-carboxylic acid; Optionally branched nitrogen is selected from alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, or optionally N, O and S Amino acids selected from aryl, arylalkyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or fused aryl-cycloalkyl containing at least two heteroatoms, araspragine, glutamine, ornithine and lysine;

A 'is a direct bond or -C (O)-, -NH-C (O)-, -S (O) _2- , -NH-S (O) _2- , -OC (O)-or -C -to be.

In another embodiment, Z 'is represented by the formula

<Formula 2>

Wherein W is S or O; R ₈ is alkylamino, dialkylamino or amino; R ₉ is H, alkyl or halo; expression

Wherein R ₁₀ optionally comprises one or more heteroatoms selected from N, S and O other than peroxide and optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino (C ₅ -C ₆ ) aryl substituted with alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio or haloalkylthio, (C ₅ -C ₆ ) Arylalkyl, (C ₅ -C ₆ ) arylalkenyl, cycloalkyl, alkylcycloalkyl, fused aryl-cycloalkyl or alkyl fused aryl-cycloalkyl).

In a preferred embodiment, Z 'is the following formula

Wherein R ₁₁ , R ₁₂ and E together comprise 5 to 10 atoms selected from C, N, S and O; and at least one keto group; optionally halo, cyano, nitro , Haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, alkylthio, haloalkylthio, or optionally N At least one heteroatom selected from O and not peroxide, and optionally halo, cyano, nitro, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, alkynyl, alkoxy, halo Alkoxy, carboxyl, carboalkoxy, -C (O) O (alkyl), -C (O) (alkyl), alkylcarboxamide, cycloalkyl, alkylcycloalkyl substituted with alkylthio or haloalkylthio, al Kenylcycloalkyl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, ((C ₅ -C ₁₂ ) arylalkyl) OC And form a monocyclic or bicyclic ring which is optionally substituted with (O) NH- or (C ₅ -C ₁₂ ) arylalkenyl.

In a preferred embodiment, the present invention

(a) reacting a compound of formula B with an aldehyde of formula C;

(b) removing the protecting group from the alcohol (D) produced;

(c) coupling the alcohol obtained in step (b) with an acid of formula (H); And

(d) oxidizing the product obtained to obtain a ketone of formula J;

Additionally if T ₁ is [PGr ₂ ] NH

(e) removing the protecting group [PGr 2] to afford the compound of formula G

It provides a method for synthesizing a compound of the formula (G) consisting of.

<Formula B>

<Formula C>

Wherein T is H or NH ₂ ;

R ₁ is optionally alkyl or alkenyl substituted with one to three halo or hydroxyl; Carboxylic acid esters such as -alkyl-C (O) OCH ₃ ; Alkylamino, dialkylamino, alkyldialkylamino; Or optionally 1 to 4 heteroatoms selected from N, O and S and optionally halo, cyano, nitro, hydroxyl, haloalkyl, amino, aminoalkyl, dialkylamino, alkyl, alkenyl, Alkylenedioxy, alkynyl, alkoxy, haloalkoxy, carboxyl, carboalkoxy, alkylcarboxamide, (C ₅ -C ₆ ) aryl, -O- (C ₅ -C ₆ ) aryl, arylcarboxamide, Cycloalkyl substituted with alkylthio or haloalkylthio, alkylcycloalkyl, alkenylcycloalkyl, (C ₅ -C ₁₂ ) aryl, (C ₅ -C ₁₂ ) arylalkyl, (C ₅ -C ₁₂ ) arylalkenyl , Fused (C ₅ -C ₁₂ ) aryl-cycloalkyl or fused (C ₅ -C ₁₂ ) aryl-cycloalkylalkyl;

Ar is aryl or arylalkyl optionally substituted with H, alkyl, amino, alkylamino, dialkylamino, halo or hydroxyl;

M is Li or MgBr;

[PrG ₁ ] is a protecting group;

T 'is H or [PGr ₂ ] NH, where [PGr ₂ ] is a protecting group. Preferably [PGr ₂ ] is Cbz.

As used herein, the term " optionally substituted " means that when substituted, both monosubstituted and substituted.

The term "independently" as used herein, means that the substituents may be the same or different.

The term "alkyl" as used herein means C ₁ -C ₁₅ but preferably means C ₁ -C ₈ .

The term "alkenyl" as used herein means C ₁ -C ₁₅ but preferably means C ₁ -C ₈ .

As used herein, the term "alkynyl" means C ₁ -C ₁₅ but preferably C ₁ -C ₈ .

It will be appreciated that alkyl, alkenyl and alkynyl groups may be substituted or unsubstituted or straight or branched.

The term "aryl" as used herein, unless otherwise indicated, means an aryl group having preferably 5 to 12 carbon atoms, more preferably 5 or 6 carbon atoms. Unless otherwise indicated, the term includes both monocyclic and bicyclic fused ring systems.

When the term "arylalkyl" is defined herein as the formula (Cx-Cy) arylalkyl, x and y represent the number of carbons making up an aryl group. Alkyl groups are as defined above. The term includes monocyclic alkyl groups (eg benzyl), and disubstituted alkyl groups such as -alkyl (aryl) ₂ (eg CH (phenyl) ₂ )). The term arylalkyl and alkyl fused arylcycloalkyl refers to (α, α) -disubstituted groups such as (α, α) -disubstituted benzyl and (α, α) -disubstituted 3,4-methylenedioxybenzyl groups (where , α substituents preferably comprise an alkyl group, for example methyl, ethyl or propyl. Specific examples include (α, α) -dimethylbenzyl and (α, α) -dimethyl-3,4-methylenedioxybenzyl.

The term "arylalkenyl" as used herein includes aryl groups in which the alkenyl group contains one to three or more double bonds. Examples of arylalkenyl groups are = CH-CH ₂ -aryl and -CH = CH-aryl, where aryl is preferably phenyl.

As used herein, the term "cycloalkyl" means a cycloalkyl group having 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms, unless stated otherwise. Unless otherwise indicated, the term includes both mono-, non- and tricyclic fused ring systems.

As used herein, the term "Cbz" refers to benzyloxycarbonyl.

The term "carboxamide" as used herein has the same meaning as an amide, ie a group of the formula -NHC (O)-.

As used herein, the term "oxycarboxamide" refers to a group of the formula -O-C (O) -NH-.

The term "oxycarbonyl" as used herein, means a group of the formula -OC (O)-.

Pharmaceutically acceptable salts of the foregoing compounds are included within the scope of the present invention.

1 schematically shows a method for synthesizing compounds of Group I.

2 schematically shows a method for synthesizing a compound of Group I.

Figure 3 schematically shows a method for synthesizing a compound of Group I.

4 schematically shows a method for synthesizing a compound of Group I.

5 schematically shows the synthesis of compounds of Group II.

6 schematically shows a method for synthesizing a compound of Group II.

7 schematically shows a method for synthesizing a compound of Group II.

8 schematically shows the synthesis of compounds of Group III.

9 schematically shows a method for synthesizing a compound of Group III.

10 schematically shows the synthesis of compounds of group IV.

11 schematically shows the synthesis of compounds of group V. FIG.

12 schematically shows the synthesis of compounds of group V. FIG.

FIG. 13 schematically shows the synthesis of compounds of Group V. FIG.

Figure 14 schematically shows the synthesis of compounds of group V.

15 schematically shows a method for synthesizing a compound of Group V. FIG.

16 schematically shows a method for synthesizing a compound of Group V. FIG.

17 schematically shows a method for synthesizing a compound of Group V. FIG.

18 schematically shows a method for synthesizing a compound of Group V. FIG.

19 schematically shows a method for synthesizing a compound of Group V. FIG.

20 schematically shows a method for synthesizing a compound of Group V. FIG.

FIG. 21 schematically shows a method for synthesizing a compound of Group V. FIG.

22 schematically shows a method for synthesizing a compound of Group V. FIG.

23 shows the activity of certain compounds in Group I.

24 shows the activity of certain compounds in Group I.

25 shows the activity of certain compounds in Group I.

26 shows the activity of certain compounds in Group I.

27 shows the activity of certain compounds in Group I.

28 shows the activity of certain compounds in Groups II and III.

FIG. 29 shows the activity of certain compounds in Groups II, III, and IV.

30 shows the activity of certain compounds in Group V.

FIG. 31 shows the activity of certain compounds in Group V.

32 shows the activity of certain compounds in Group V.

33 shows the activity of certain compounds in group V.

34 shows the activity of certain compounds in group V. FIG.

35 shows the activity of certain compounds in Group V.

36 shows the activity of certain compounds in Group V.

37 shows the activity of certain compounds in Group V.

38 shows the activity of certain compounds in Group V.

39 schematically illustrates a method for synthesizing certain compounds of the present invention.

Compounds of the invention have been found to be potent inhibitors of the human neutrophil elastase (HNE), a serine protease. The compounds of the present invention are probably reversible inhibitors that form intermediates in the transition state with active sites of serine residues. The property of this compound is that it has high selectivity and high stability with respect to HNE given the low molecular weight and physiological conditions. Thus, the compounds can be used to prevent, alleviate and / or treat diseases mediated by the degradation effects associated with the presence of HNE. The use of the compounds of the present invention is particularly important because they relate to the treatment of various humans in vivo, but can also be used as diagnostic tools in vitro.

The present invention provides specific embodiments shown in the following examples, but is not limited thereto.

The names of the above embodiments are as follows (although most of the disclosed embodiments show stereochemistry of 2-methylpropyl groups having the (S) configuration, both (R) -configuration and racemic (R, S) To be within the scope of the invention):

CE-2157: 2-oxo-5- (phenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2158: 3- (S)-[(benzyloxycarbonyl) amino- (5,6-phenyl-ε-lactam] -N- [1, (3- [5- (3-trifluoromethylbenzyl ) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2159: 2- (R, S)-[6- (methylene-4-pyridyl) piperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2160: 3- (R, S)-[(benzyloxycarbonyl) amino-δ-lactam] -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2161: (pyridyl-3-carbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl)- 2- (S) -methylpropyl] -L-prolineamide

CE-2162: 4- [1- (2-N-morpholino) ethyl-3- (R) -benzyl piperazine-2,5-dione] -N- [1- (2- [5- (3 -Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -acetamide

CE-2163: methylsulfonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide

CE-2164: (pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] -amide

CE-2165: N-acetyl-2- (L)-(2,3-dihydro-1H-indole) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] amide

CE-2166: 1-phenyl-1,2,4-triazolidine-3,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2168: Phenylsulfonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide

CE-2170: [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] -2- (S)-[(benzyloxycarbonyl) amino] -3-methyl Butan-1-one

CE-2171: (3-pyridylcarbonyl) -L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] -L-prolineamide

CE-2172: methylsulfonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- ( S) -methylpropyl] -L-prolineamide

CE-2173: 1- (3-morpholinoethyl) -5- (R) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2174: 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide

CE-2176: 1-benzyl-1,2,4-triazolidine-3,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2177: (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide

CE-2178: (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (4-methylenedioxybenzyl) -1,2,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] -L-prolineamide

CE-2179: 5- (R, S) -phenyl-1-methyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2180: 1- (N-morpholinoethyl) -5- (R) -benzyl-2,4-imidazolidinedione-N- [1- (3- [5- (3trifluoromethyl Benzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2181: 1- (N-morpholinoethyl) -5- (S) -benzyl-2,4-imidazolidinedione-N- [1- (3- [5- (3trifluoromethyl Benzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2182: 5- (R, S) -phenyl-1-methyl-2,4-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1 , 2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2183: benzyloxycarbonyl-L-valyl- (1,2,3,4-tetrahydroisoquinoline) -3-N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] amide

CE-2184: 1- (N-morpholinoethyl) -5- (S) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2185: 4-pyridylmethyleneoxycarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] -L-florinamide

CE-2186: 4-pyridylmethyleneoxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] -L-florinamide

CE-2187: 4- [1- (3,4-ethylenedioxybenzyl) -3- (S) -benzyl-piperazine-2,5-dione-N- [1- (3- [5- (3 -Trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2188: 1-benzyl-4- (S) -benzyl-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-1289: 1-benzyl-2,4-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carr Carbonyl) -2- (S) -methylpropyl] acetamide

CE-2190: [1-benzyloxycarbonyl-5- (R) -benzylpiperazin-3-one] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2191: 1-benzyl-4- (S) -benzyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4- Oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2192: 1- (N-morpholinoethyl) -5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2193: 1- (N-morpholinoethyl) -5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (3- [5- (3-tri Fluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2194: [4- (R, S)-(4-Dimethylaminophenyl)]-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2195: (pilol-2-carbonyl) -N- (1- (R, S) -indanyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] amide

CE-2196: (6- (R) -benzylpiperazin-2-one) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (R, S) -methylpropyl] acetamide

CE-2197: 4- [1- (3,4-ethylenedioxybenzyl) -3- (R) -benzylpiperazine-2,5-dione] -N- [1- (2- [5- (3 -Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2198: 4- (R, S) -phenyl-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2200: [4- (R, S)-(4-dimethylaminophenyl)]-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethyl Benzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2202: isopropyloxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] -L-prolineamide

CE-2203: [4- (R)-(3-pyridylmethylene)]-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2204: 1-benzyloxycarbonyl- (2- (R) -phenylpiperazin-5-one) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2205: [4- (R)-(3-pyridylmethyl)]-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2206: [4- (R, S)-(4-pyridyl) -4- (R, S) -N-succinimidyl] -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2207: isopropyloxycarbonyl-L-valyl-N- [1- (3- [5- (3-triblueuromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] -L-prolineamide

CE-2208: (2- (R) -phenylpiperazin-5-one) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (R, S) -methylpropyl] acetamide

CE-2209: [4- (R, S)-(4-pyridyl) -4- (R, S) -N-succinimidyl] -2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2210: (N-benzylaminocarbonyl) -N- (benzyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] amide

CE-2211: (R, S) -3-amino-2-oxo-5-phenyl-1,4- (6-2'-chlorobenzodiazepine) -N- [1- (2- [5-phenyl-1 , 3,4-oxadiazolyl] carbonyl) -2- (R, S) -propyl] acetamide

CE-2212: 3- [1- (4-piperidine)]-benzimidazolidin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2213: methyloxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -Methylpropyl] -L-prolineamide

CE-2214: methyloxycarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide

CE-2215: 1,4-quinazolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- ( S) -methylpropyl] acetamide

CE-2216: [4- (R, S)-(2-pyridyl) -4- (R, S) -methyl] -2,5-imidazolidinedione-N- [1- (2- [ 5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2217: 2-oxo-5- (2-pyridyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide

CE-2218: (R, S) -3-amino-2-oxo-5- (2-pyridyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylpropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2219: 1,4-quinazolin-2-one-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl)- 2- (S) -methylpropyl] acetamide

CE-2220: (2S, 5S) -5-Amino-1,2,4,5,6,7-hexahydroazino- [3.2.1] -indol-4-one-carbonyl-N- [1 -(3- [5- (3-methylpropyl) -1,2,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] amide

CE-2221: (R, S) -3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (3- [5- (3-methylbenzyl) -1,2, 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2223: (R, S) -3-amino-2-oxo-5-phenyl-1,4- (2'-chlorobenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2224: (R, S) -3-amino-2-oxo-5- (4-chlorophenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2225: (R, S) -3-Amino-2-oxo-5-methyl-1,4- (2 ', 3'-methylenedioxy) benzodiazepine) -N- [1- (2- [5 -(3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2226: (R, S) -3-amino-2-oxo-5-methyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2227: 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2228: 3- (R, S) -amino-2-oxo-4,5-dihydro-1-benzoazine-N- [1- (2- [5- (3-methylbenzyl) -1 , 3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2229: (R, S) -3-amino-2-oxo-5- (2-chlorophenyl) -1,4- (2'-chlorobenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2230: (R, S) -3-benzyloxycarbonylamino-2-oxo-5- (2-chlorophenyl) -1,4- (2'-chlorobenzodiazepine) -N- [1- (2 -[5- (3-methylbenzyl) -1,3,4-oxadiazolylcarbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2231: 4-spirocyclopentane-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide

CE-2232: benzyloxycarbonyl-L-valyl-N- (phenyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] amide

CE-2233: 2-oxo-5- (4-piperidinyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2234: 2- (2-pyridyl) -benzimidazole-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] acetamide

CE-2235: (R, S) -3-amino-2-oxo-5-methyl-1,4- (2 ', 3'-dimethooxybenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

CE-2236: (R, S) -3-amino-2-oxo-5-methyl-1,4- (1-thiophenodiazepine) -N- [1- (2- [5- (3- Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2237: 2-oxo-5- (4-trifluoromethylphenyl) -1,4benzodiazepene-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2238: 2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] acetamide

CE-2239: 4,4-dimethyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide

CE-2240: 4- (S)-(2-isopropyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2241: 4-spirocyclohexane-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide

CE-2242: 2-oxo-5-phenyl-1,4- (4'-methylbenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2243: 4- (R)-(3-indolylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2244: 2-oxo-5-methyl-1,4- (1-thiophenodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4- Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2245: 2-oxo-5-methyl-1,4- (2-phenyl-1-thiophenodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2246: 4- (R)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2247: 4- (R)-(N, N-dimethylaminocarbonylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2248: 2-oxo-5- (3,4-methylenedioxyphenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2249: 4- (R)-(2-methoxycarbonylethyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2250: 2-oxo-5- (2-methooxyphenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2251: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyridinyl] -N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2252: 4,4-diphenyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] acetamide

CE-2253: 4-spiro- (2-indanyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxa Diazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2254: 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2255: 4- (R)-(4-hydroxybenzyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2256: 4- (R)-(4-hydroxybenzyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3,4-methylenedioxybenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2257: 4- (R) -2-imidazolylmethyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2258: 2-oxo-5-phenyl-1,4- (2'-dimethylaminobenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxa Diazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2259: 4,4-diphenyl-2,5-imidazolidinedione-N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxa Diazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2260: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2261: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2262: 2- [5-amino-6-oxo-2-thiophenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

CE-2263: 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-690: 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-691: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-692: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethyl-3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-693: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-694: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-phenyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-695: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (3-pyridyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-696: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- tert -butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-697: 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-phenyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-698: 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- tert -butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-699: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (4-methoxyphenyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-700: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-701: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethyl-3,4-dihydroxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-702: 2- [5- (methylsulfonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1 -(2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-703: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-benzyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-704: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-methyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-705: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-isopropyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-706: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-707: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-708: 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- tert -butyl-1,3,4- Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-709: 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- (α, α-dimethylbenzyl) -1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-710: Methylsulfonyl-L-valyl-N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide

ONO-PO-711: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-712: 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5 tert -butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-713: Methylsulfonyl-L-valyl-N- [1- (2- [5- (tert-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide

ONO-PO-714: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (1-methylcyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-715: 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5 -(α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-716: 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- ( tert -Butyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-717: 2-oxo-5- (4-chlorophenyl) -1,4-benzodiazepine-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-718: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- ( tert -butyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-719: 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5-tert - butyl-1,3,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-720: 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5- (α, α - dimethylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-721: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-722: 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α , α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-723: 4- (R)-(3-indolylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5- tert -butyl-1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-724: 4- (R)-(3-indolylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5- (α, α-dimethylbenzyl-1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-725: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-726: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-727: 2- [ 6- oxo-2- (4-fluorophenyl) -l, 6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert - Butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-728: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methyl Cyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-729: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl- 1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-730: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl-1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-731: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-α, α-dimethylbenzyl-1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-732: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl-1,3, 4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide

ONO-PO-733: 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- tert -butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

ONO-PO-734: 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1 -Methylcyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-735: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methylcyclopropyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

ONO-PO-736: 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl- 1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

ONO-PO-737: 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- tert -butyl-1,3, 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide

The compounds of the present invention are not limited to those used for the inhibition of human elastase. Elastase is a member of the class of enzymes known as serine proteases. Such enzymes also include, for example, chymotrypsin, cathepsin G, trypsin and thrombin enzymes. The proteases commonly include a catalyst terpolymer consisting of serine-195, histidine-57 and aspartic acid-102 (chymotrypsin numbering system). The exact hydrogen bonding network present between these amino acid residues causes the hydroxyl of serine-195 to form tetrahedral intermediates with carbonyl based amides. Degradation of the intermediate releases free amines and acylating enzymes. In subsequent steps, the newly formed ester is hydrolyzed to produce natural protein and carboxylic acid. Characterizing the specificity of the enzyme is the carboxyl component. In the example where the carboxyl component is a peptide, the alpha substituent of the amino acid primarily determines the specificity for the enzyme. Using partial nomenclature by Schechter and Berger, which is predominantly acceptable (see Biochem. Biophy. Res. Commun., 27: 157 (1967)), amino acid residues in the substrate to be degraded are P ₁ on the N-terminus. ... P _n , and on the C-terminal side, P ' ₁ ... P' _n , so that the cleaved bond is between the P ₁ and P ′ ₁ residues of the peptide subunit. Similar nomenclature is used for the amino acid residues of the enzymes that make up the binding pocket, which is named S ₁ ... S _n , as opposed to P ₁ ... P _n for the substrate.

The properties of the P ₁ residues that determine the specificity of the serine protease are well known. Proteinases can be separated into three subclasses of elastase, kinase and tryptase based on this difference in P1 residues. Elastases favor small aliphatic residues, such as valine, while kinases and tryptases prefer large aromatic hydrophobic residues and positively charged residues, respectively.

One further proteinase not classified in any of the above categories is propyl endopeptidase. The P ₁ residue that determines specificity is proline. The enzyme is associated with the progression of memory loss in Alzheimer's disease patients. It has recently been found that inhibitors consisting of α-keto heterocycles inhibit propyl endopeptidase (see Tsutsumi et al., J. Med. Chem., 37: 3492-3502 (1994)). Incidentally, the α-keto heterocycle as defined herein allows for an increase in binding at the P ₁ site of this enzyme.

Proteinases Representative Enzyme Characteristics of P ₁ Elastase Human neutrophil elastase Small aliphatic residues Kimase Alpha-chymotrypsin, cathepsin G Aromatic residues or large hydrophobic residues Tryptase Thrombin, trypsin, urokinase, plasma kallikrein, plasminogen activator, plasmin Positively charged residues Etc Prolyl Endopeptidase Proline

Since P ₁ residues predominantly define substrate specificity, the present invention provides a P ₁ -P _n 'modification, specifically 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4 To specific alpha-substituted keto-heterocycles consisting of thiadiazole, 1,2,4-thiadiazole, 1-substituted 1,2,4-triazole and 4-substituted 1,2,4-triazole will be. By changing the alpha substituents and substituents on the heterocycle, the compound can be made specific for the desired proteinase (for example a small aliphatic group for elastase).

The efficacy of a compound for the treatment of various diseases can be measured by scientific methods known in the art. The following diseases are known as examples of HNE mediated diseases:

In the case of acute respiratory distress syndrome according to the human neutrophil elastase (HNE) model [AARD, 141: 227-677 (1990)]; Acute lung disorder model induced by endotoxin in minipig [AARD, 142: 782-788 (1990)]; Or a method according to the human polymorphonuclear elastase-induced pulmonary bleeding model in hamsters (European Patent Application Publication No. 0769498) can be used;

-Canine Model of Reperfusion Disorders in Ischemia / Reperfusion [J. Clin. Invest., 81: 624-629 (1988)] can be used.

The compounds of the present invention, their salts and intermediates thereof may be prepared or formulated according to the methods described herein or according to various known methods present in the chemical field (see International Patent Application Publication No. 96/16080). have. For example, compounds of group I can be synthesized according to the methods shown in FIGS. 1-2 (1,3,4-oxadiazole) and 3-4 (1,2,4-oxadiazole). 5 to 7 show the synthesis of compounds of Group II. 8-9 show the synthesis of compounds of group III and FIG. 10 shows the synthesis of compounds of group IV. Various classes of compounds of Group V are described in FIGS. 11-12.

Alternatively, the compounds of the present invention can be prepared as described in FIG. The 2-substituted 1,3,4-oxadiazoles (3) can be prepared by forming hydrazide (eg, thionyl chloride or oxalyl chloride) by forming an acid chloride from acid (1) and then treating with hydrazine in a suitable solvent. 2) can be produced. Reaction of the compound of (2) with triethyl orthoformate or trimethyl orthoformate and TsOH affords the necessary 2-substituted 1,3,4-oxadiazole (3).

Compound (3 ') is formed using standard conditions (i.e., reacted with butyllithium at low temperature in a polar aprotic solvent, and optionally MgBR.OEt ₂ if necessary), followed by addition of aldehyde (4) to alcohol (5) is obtained.

Dehydroprotection of the protected amine of the compound of (5) with dichloric acid in dioxane yields amino hydrochloride (6) which is then coupled with acid (7) by methods known to those skilled in the art to obtain intermediates (8). Get) Ketones (9) are obtained by oxidation using Periodinane from Dess-Martin or by other methods described in Oxidation in Organic Chemistry by Milos Hudlicky, ACS Monograph 186 (1990).

In the final step, the protecting group must be removed from the amine. This can be done in a number of ways. The final compound (10) can be obtained using, for example, aluminum chloride, anisole and nitromethane in a suitable solvent such as dichloromethane. Compound (10) is then treated with an electrophile (for example methanesulfonyl chloride) and a base is added to give the compound of (14).

Aldehyde (4) can be prepared by any of the three methods described. Weinreb amide (12) is prepared from amino acid (11), which is then reduced to aldehyde using hydrogenated diisobutylaluminum (DIBAL). Alternatively, aldehyde (4) can be obtained by producing an ester of amino acid (13) followed by reduction with DIBAL. Also alcohol (13-1) is produced and then oxidized to SO ₃ -Py in DMSO.

The activity of this compound is shown in FIGS. 23-28 as K _i value (nM). K _i values were measured essentially as described in WO 96/16080, which is incorporated herein by reference unless otherwise indicated.

Although the compounds and / or salts thereof described herein may be administered as pure chemicals, it is preferred to administer the active ingredients in pharmaceutical compositions. Accordingly, the present invention provides the use of a pharmaceutical composition containing together one or more compounds and / or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic components. To provide. The carrier (s) should be "acceptable" in the sense that it must be compatible with the other ingredients of the composition and not toxic to its receptor.

Pharmaceutical compositions include those suitable for oral or parenteral (intramuscular, subcutaneous and intravenous) administration. The compositions may conveniently be presented in discrete unit dosage forms if desired and may be prepared by any method known in the art of pharmacy. The method comprises the step of bringing into association the active compound with the liquid carrier, solid matrix, semisolid carrier, micronized solid carrier or combination thereof, and then forming the product into the desired delivery system, if necessary.

Pharmaceutical compositions suitable for oral administration include discrete unit dosage forms such as hard or soft gelatin capsules, cassettes or tablets each containing a predetermined amount of the active ingredient; Powder or granules; It can be provided as a solution, suspension or emulsion. The active ingredient may also be provided as a bolus, soft or paste. Tablets and capsules for oral administration may contain conventional excipients such as binders, fillers, lubricants, disintegrants, or wetting agents. Tablets may be coated, for example with enteric coatings, according to methods known in the art.

Oral liquid formulations may be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or may be provided as a dry product for constitution with water or other suitable vehicle before use. These liquid formulations may contain conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible fats), or preservatives.

The compounds may also be formulated for parenteral administration (eg injection, eg bolus injection or continuous infusion), with the addition of ampoules, prefilled syringes, unit dosage forms or preservatives in small bolus infusion containers. It may be provided in the form of a multi-dose container. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, eg pyrogen-free sterile water, before use.

The compounds may be formulated with the active ingredients of ointments, creams or lotions, or transdermal patches for topical administration to the epidermis. Suitable transdermal delivery systems are disclosed, for example, in US Pat. No. 4,788,603 to Fisher et al. Or US Pat. Nos. 4,931,279 to Bawas et al., 4,668,504 and 4,713,224. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will generally contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or coloring agents. The active ingredient may also be delivered by iontophoresis as disclosed, for example, in US Pat. No. 4,140,122, US Pat. No. 4,383,529, or 4,051,842.

Compositions suitable for topical administration in the oral cavity include lozenges containing the active ingredient in a sweet base, generally sucrose and gum arabic or tragacanth; Lozenge tablets containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and gum arabic; Unit dosage forms such as mucoadhesive gels and mouthwashes containing the active ingredient in a suitable liquid carrier.

If desired, the composition can be modified, for example, by combining it with a specific hydrophilic polymer matrix such as natural gels, synthetic polymer gels or mixtures thereof such that the active ingredient used is continuously released.

Pharmaceutical compositions according to the invention may also contain other adjuvants, for example sweetening, coloring, antibacterial, or preservatives.

It is also understood that the amount of compound or active salt or derivative thereof required for treatment depends on the particular salt selected and the route of administration, the nature of the disease to be treated and the age and condition of the patient and ultimately the judgment of the attending physician or clinician. Will be.

Generally, however, suitable dosages are from about 0.5 to about 100 mg, for example from about 1 to about 75 mg, for example from 3 to about 50 mg, preferably from 6 to 90 mg, most preferred per kilogram body weight of recipient per day. Preferably from 15 to 60 mg.

The compounds are conveniently administered in unit dosage form, eg, in unit dosage forms containing 0.5 to 1000 mg of active ingredient, conveniently 5 to 750 mg, most conveniently 10 to 500 mg per unit dosage form.

Ideally the active ingredient should be administered such that peak concentrations in the plasma of the active ingredient of about 0.5 to about 75 μM, more preferably about 1 to 50 μM, most preferably about 2 to about 30 μM are obtained. This can be achieved, for example, by intravenous injection of the active ingredient, optionally 0.05 to 5% solution in saline, or by oral administration as a bolus containing about 0.5 to 500 mg of the active ingredient. Preferred blood concentrations may be from about 0.01 to 5.0 mg / kg / hour in continuous infusions or maintained in discontinuous infusions containing from about 0.4 to 15 mg per kg of active ingredient (s).

The desired dosage may conveniently be provided in a single dose or in divided doses, eg administered twice, three times, four or more sub-doses at appropriate intervals. The sub dose itself may be further divided into roughly spaced multiple discrete doses, eg, multiple inhalations or multiple drops from a quarter.

Although the invention has been described in connection with specific embodiments thereof, the invention can be further modified and such variations are generally in accordance with the principles of the invention and within known or customary practice in which the invention is included, and as described above. It will be understood that it encompasses any variation, use or modification of the invention which may be adapted to essential features and which includes variations of the invention which are within the scope of the appended claims.

The following examples are intended to illustrate the invention and are not intended to limit the invention in any way.

The following abbreviations are used as follows: TFA-trifluoroacetic acid; HOBT-hydroxybenzotriazole; DIEA-diisopropylethylamine; NMM-4-methylmorpholine; DMF-N, N-dimethylformamide; TEA-triethylamine; EDCI-1- (3-dimethylaminopropyl-3-ethylcarbodiimide; BOPCl-bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride; FMOC-9-fluorenylmethoxycarbonyl; BTD-bicy Clicked Dipeptide (see, eg, Tetrathedron, 49: 3577-3592 (1993)); THF-tetrahydrofuran

Example 1 (CE-2072) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] -L-prolineamide

0.65 mL (8.85 mmol) of dimethyl sulfide was added to a mixture containing 0.79 g (5.94 mmol) of N-chlorosuccinimide in 40 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The reaction was cooled to −25 ° C. using carbon tetrachloride / dry ice bath and then (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) in 17 mL of anhydrous toluene. A solution containing) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] -L-prolineamide (0.90 g, 1.49 mmol) was added dropwise. The reaction was stirred at −25 ° C. for 2 hours and then 1.0 mL (7.17 mmol) triethylamine were added. The cold bath was removed and the mixture was allowed to warm to room temperature and held for 20 minutes. The reaction mixture was mixed with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel with 70% ethyl acetate / hexanes to give 0.90 g of material which was then further purified by preparative HPLC to give 665 mg (73.9%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 604. Measured value: 604.

Intermediate (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -Methylpropyl] -L-prolineamide was prepared as follows.

a. 3- (S) -Amino-2- (R, S) -hydroxy-4-methyl pentanic acid

Solution of 3- (S)-[(benzyloxycarbonyl) amino] -2-acetoxy-4-methylpentannitrile (15.2 g, 50.0 mmol) in 183 mL of dioxane (e.g. 183 mL of concentrated hydrochloric acid and 7.45 ?? of anisole were added to (see Example 1 of 96/16080). The reaction mixture was heated to reflux overnight. The hydrolysis reaction was cooled to room temperature and then concentrated in vacuo. The resulting aqueous solution was extracted twice with ether. The aqueous phase was added to a Dowex 50x8-100 column (H ⁺ form, pre-eluted with deionized water to pH 7). The column was eluted with 2.0 N ammonium hydroxide and the pure fractions were concentrated to give 5.53 g (75%) of 3- (S) -amino-2- (R, S) -hydroxy-4-methylpentanoic acid as a pale yellow solid. It was.

FAB MS [M + H] m / z; Theoretical: 148. Found: 148.

b. 3- (S)-[(benzyloxycarbonyl) amino] -2- (R, S) -hydroxy-4-methylpentanoic acid

1.43 in 1.0 g (6.8 mmol) of 3- (S) -amino-2- (R, S) -hydroxy-4-methylpentanoic acid solution in 9.5 mL of 1 N NaOH and 10 mL of dioxane under nitrogen atmosphere. g (8.4 mmol) benzyl chloroformate was added. If necessary, pH was maintained above 8 with 1 N NaOH. The reaction mixture was stirred at rt overnight. The reaction was diluted with water and washed with ether. The aqueous phase was acidified to pH 2 with 1 N HCl and extracted twice with ether. The combined organic layers were dried over magnesium sulfate, filtered and evaporated under vacuum to afford 1.75 g (92) of 3- (S)-[(benzyloxycarbonyl) amino] -2- (R, S) -hydroxy-4-methylpentanoic acid. %) Was obtained as a light yellow viscous oil.

FAB MS [M + H] m / z; Theoretical: 282. Found: 282.

c. 3- (S)-[(benzyloxycarbonyl) amino] -2- (R, S) -acetoxy-4-methylpentanoic acid

Anhydrous in a solution of 3- (S)-[(benzyloxycarbonyl) amino-2- (R, S) -hydroxy-4-methylpentanoic acid (1.70 g, 6.04 mmol) and pyridine (4.9 mL) at room temperature Acetic acid (5.7 mL, 6.17 g, 60.4 mmol) was added dropwise. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed twice with water. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a dark oil. The residue was purified by column chromatography on silica gel using 15% methanol / dichloromethane to give 3- (S)-[(benzyloxycarbonyl) amino] -2- (R, S) -acetoxy-4- 1.56 g (80%) of methylpentanoic acid were obtained as a light yellow viscous oil.

FAB MS [M + H] m / z; Theoretical: 324. Found: 324.

d. 1-[(3-methylphenylacetyl) -2- (2- (R, S) -acetoxy) -3- (S)-[(benzyloxycarbonyl) amino] -4-methylpentanoyl] hydrazine

3- (S)-[(benzyloxycarbonyl) amino] -2- (R, S) -acetoxy-4-methylpentanoic acid (2.3 g, 7.11 mmol) in 40 mL of DMF at 0 ° C. under nitrogen atmosphere. ) Was added 1.31 g (9.69 mmol) of HOBT and 1.36 g (7.09 mmol) of EDCI. Prepared similarly to 1.20 g (7.31 mmol) of 3-methylphenyl acetate hydrazide (H. hydrazide, described in Rabis et al., J. Org. Chem., 30: 2486 (1965)) after stirring for 30 minutes. ) And 1.0 mL (9.10 mmol) of NMM were added. The reaction was allowed to warm to rt and stirred overnight. The reaction was diluted with ethyl acetate and washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate, brine and water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 10% methanol / dichloromethane to give 2.31 g (89.0%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 470. Measured value: 470.

e. 1- [2- (5- [3-methylbenzyl) -1,3,4-oxadiazolyl] -1-acetoxy-2- (S)-[(benzyloxycarbonyl) amino] amino] -3 -Methylbutane

2.31 g (4.92 mmol) of 1-[(3-methylphenylacetyl) -2- (2- (R, S) -acetoxy) -3- (S)-[(benzyloxy in 25 mL of pyridine under nitrogen atmosphere Carbonyl) amino] -4-methyl pentanoyl] hydrazine solution and 1.88 g (9.86 mmol) of toluene sulfonyl chloride were heated to reflux for 72 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 5% ethyl acetate / hexanes to give 1.41 g (63.5%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 452. Found: 452.

f. 1- [2- (5- [3-methylbenzyl) -1,3,4-oxadiazolyl] -2- (S)-[(benzyloxycarbonyl) amino] -3-methylbutan-1-ol

1.80 g (3.99 mmol) of 1- [2- (5- [3-methylbenzyl] -1,3,4-oxadiazolyl)]-1-acetoxy-2 in 30 mL of methanol and 8 mL of water A solution of-(S)-[(benzyloxycarbonyl) amino] -3-methylbutane and 0.72 g (5.21 mmol) potassium carbonate was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 50% ethyl acetate / hexanes to give 1.46 g (89.3%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 410, Measured value: 410.

g. 1- [2- (5- [3-methylbenzyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride

1.31 g (3.20 mmol) of 1- [2- (5- [3-methylbenzyl] -1,3,4-oxadiazolyl)]-2 in 25 mL of trifluoroacetic acid at 0 ° C. under a nitrogen atmosphere. To a solution of-(S)-[(benzyloxycarbonyl) amino] -3-methylbutan-1-ol was added 0.43 mL (3.94 mmol) of thioanisole. The reaction was warmed to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ether and cooled to -78 ° C under nitrogen atmosphere. To the solution was added 3 mL (3 mmol) of 1 N hydrochloric acid in ether. The resulting white solid was allowed to settle and the ether was drained off. Additional ether was decanted (3 times). The solid was dried under vacuum to give 0.92 g (92.2%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 276, Found: 276.

h. (Benzyloxycarbonyl) -L-valyl-N-1- [2- (5- [3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl-2- (S) -methylpropyl -L-prolineamide

To a solution of 1.30 g (3.38 mmol) of Cbz-Val-Pro-OH in 25 mL of anhydrous dichloromethane at 0 ° C. under nitrogen atmosphere, 0.90 g (3.54 mmol) of BOPCl and 0.60 g (3.44 mmol) of DIEA were added. It was. After stirring for 30 minutes 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- (S in 15 mL of dichloromethane and 0.6 mL (3.94 mmol) ) -Amino-3-methyl butan-1-ol hydrochloride was added. The reaction was stirred at 0 ° C overnight. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using 5% methanol / dichloromethane to give 1.0 g (57.3%) of the title compound as a tan solid.

FAB MS [M + H] m / z; Theoretical: 606. Measured: 606.

Example 2 (CE-2074) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (methyl) -1,3,4-oxadiazolyl] carbonyl)] -2- (S) -methylpropyl] -L-prolineamide

Prepared in a similar manner to Example 1.

FAB MS [M + H] m / z; Theoretical: 514. Measured: 514.

Example 3 (CE-2075) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-trifluoromethylbenzyl) -1,3,4-oxadia Zolyl] carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

Prepared in a similar manner to Example 1.

FAB MS [M + H] m / z; Theoretical value: 658, Found: 658.

Example 4 (CE-2100) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (4-dimethylaminobenzyl) -1,3,4-oxadiazolyl] Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

Prepared in a similar manner to Example 1.

FAB MS [M + H] m / z; Theoretical value: 633. Measured value: 633.

Example 5 (CE-2124) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (1-naphthylmethylene) -1,3,4-oxadiazolyl] Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

Prepared in a similar manner to Example 1.

FAB MS [M + H] m / z; Theoretical value: 640. Measured value: 640.

Example 6 (CE-2177) (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxa Diazolyl] carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

Prepared in a similar manner to Example 1.

FAB MS [M + H] m / z; Theoretical value: 634. Measured value: 634.

Example 7 (CE-2178) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,4-methylenedioxybenzyl) -1,2,4-oxa Diazolyl] carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 634. Measured value: 634.

Example 8 (CE-2052) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-dimethylbenzyl) -1,2,4-oxadiazolyl ] Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 618. Measured value: 618.

Example 9 (CE-2053) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-dimethoxybenzyl) -1,2,4-oxadia Zolyl] carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 650. Measured value: 650.

Example 10 (CE-2054) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-ditrifluoromethylbenzyl) -1,2,4 -Oxadiazolyl] carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 726. Found: 726.

Example 11 (CE-2055) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-methylbenzyl) -1,2,4-oxadiazolyl] carb Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 604. Measured value: 604.

Example 12 (CE-2057) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5-biphenylmethine-1,2,4-oxadiazolyl] carbonyl)] -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 666. Measured value: 666.

Example 13 (CE-2058) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (4-phenylbenzyl) -1,2,4-oxadiazolyl] carb Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 666. Measured value: 666.

Example 14 (CE-2062) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-phenylbenzyl) -1,2,4-oxadiazolyl] carb Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 666. Measured value: 666.

Example 15 (CE-2066) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-phenoxybenzyl) -1,2,4-oxadiazolyl] Carbonyl)]-2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical: 682. found: 682.

Example 16 (CE-2069) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5-cyclohexylmethylene) -1,2,4-oxadiazolyl] carbonyl) ] -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 596, Measured value: 596.

Example 17 (CE-2073) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (α, α-dimethyl-3-trifluoromethylbenzyl) -1, 2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical: 686. Measured: 686.

Example 18 (CE-2077) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (1-naphthylmethylene) -1,2,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 640. Measured value: 640.

Example 19 (CE-2078) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-pyridylmethyl) -1,2,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 591, Found: 591.

Example 20 (CE-2096) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-diphenylbenzyl) -1,2,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 742. Found: 742.

Example 21 (CE-2115) (benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (4-dimethylaminobenzyl) -1,2,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] -L-prolineamide

It was prepared by a method similar to Example 1 of WO 96/16080.

FAB MS [M + H] m / z; Theoretical value: 633. Measured value: 633.

Example 22 (CE-2089) 2- [5- (benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl ] -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl)-(S) -2-methylpropyl] acetamide

0.95 mL (12.9 mmol) of dimethyl sulfide was added to a mixture of 1.15 g (8.60 mmol) of N-chlorosuccinimide in 43 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The reaction was cooled to −25 ° C. using carbon tetrachloride / dry ice bath and then 2- [5- (benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) in 15 mL of anhydrous toluene. -1,6-dihydro-1-pyrimidinyl] -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] hydroxymethyl) A solution of-(S) -2-methylpropyl] acetamide (1.52 g, 2.15 mmol) was added dropwise. The reaction was stirred at -25 [deg.] C. for 2 hours and then 1.2 mL (8.60 mmol) triethylamine were added. The cold bath was removed and the mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient elution of 2-10% methanol / dichloromethane to give 1.19 g of material which was further purified by preparative HPLC to give 629 mg (41%) of the title compound as a white. Obtained as a solid.

FAB MS [M + H] m / z; Theoretical value: 707. Measured value: 707.

Intermediate 2- [5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- ( 3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] hydroxymethyl)-(S) -2-methylpropyl] acetamide was prepared as follows: 10 mL 1.35 g (3.7 mmol) of 1- [3- [5- (3-methylbenzyl) -1,2,4-oxadiazolyl] -2- (S) -amino-3-methylbutane- in anhydrous DMF Solution of 1-ol hydrochloride and [5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid [J . Med. Chem., 38: 98-108 (1995)] added 1.0 mL (7.44 mmol) of TEA and 0.76 g (4.94 mmol) of HOBT. The mixture was cooled to 0 ° C. and 0.95 g (4.94 mmol) EDC were added and the reaction mixture was stirred overnight. An additional 1.0 mL (7.44 mmol) of TEA was added and again the reaction was stirred overnight. The reaction mixture was diluted with dichloromethane and washed twice with saturated ammonium chloride solution and with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 2% methanol / dichloromethane to give 1.52 g (87%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 709. Measured value: 709.

Example 23 (CE-2090) 2- [5-Amino-6-oxo-2- (4-fluorophenyl) -1, 6-dihydro-1-pyrimidinyl] -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

0.41 g (0.56 mmol) of 2- [5-[(benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1 in 4 mL of trifluoroacetic acid at room temperature under nitrogen atmosphere , 6-dihydro-1-pyrimidinyl] -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl)-(S 87 mg (0.70 mmol) of thioanisole was added to the mixture of) -2-methylpropyl] acetamide. The reaction mixture was stirred for 3 days and concentrated in vacuo. The residue was purified by preparative HPLC to give 269 mg (47%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 573, Found: 573.

Example 24 (CE-2095) 2- [5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidy Nil] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl)-(S) -2-methylpropyl] acetamide

To a mixture of 0.83 g (6.23 mmol) of N-chlorosuccinimide in 32 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 0.7 mL (9.35 mmol) of dimethyl sulfide. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 2- [5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) in 12 mL of anhydrous toluene. ) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl)-( S) -2-methylpropyl] acetamide (1.02 g, 1.56 mmol) was added dropwise. The reaction was stirred at −25 ° C. for 2 hours before 0.9 mL (6.23 mmol) of triethylamine were added. The cold bath was removed and the mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using 1% methanol / dichloromethane to give 1.37 g of the material which was further purified by preparative HPLC to give 368 mg (36%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 653, Found: 653.

Intermediate 2- [5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- ( 2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl)-(S) -2-methylpropyl] acetamide was prepared as follows: 10 mL of anhydrous DMF. 1.35 g (3.7 mmol) of 1- [2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutane hydrochloride and [5 A solution of [[benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid [J. Med. Chem., 38: 98-108 (1995)] added 0.73 mL (6.6 mmol) NMM and 0.46 g (3.0 mmol) HOBT. The mixture was cooled to 0 ° C. and 0.50 g (2.6 mmol) EDCI was added and the reaction mixture was stirred for 2 days. The reaction was diluted with dichloromethane and washed twice with saturated ammonium chloride solution and with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography, eluting with a 2-5% gradient of methanol / dichloromethane on silica gel to give 1.02 g (77%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 655, Measured value: 655.

Example 25 (CE-2101) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

0.219 g (0.335 mmol) of 2- [5-[(benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1 in 3 mL of trifluoroacetic acid at room temperature under nitrogen atmosphere , 6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl)-(S) -2 To a mixture of -methylpropyl] acetamide was added 0.05 mL (0.402 mmol) of thioanisole. The reaction mixture was stirred for 3 days and concentrated in vacuo. The residue was purified by preparative HPLC to give 187 mg (88%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical: 519. Found: 519.

Example 26 (CE-2164) (pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl-2- (S) -methylpropyl] acetamide

To a mixture of 1.97 g (14.7 mmol) of N-chlorosuccinimide in 60 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 1.54 mL (21.0 mmol) of dimethyl sulfide. The mixture was stirred for 1 hour. The reaction was cooled to -25 [deg.] C. using a carbon tetrachloride / dry ice bath and then (pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (2- [5 in 30 mL of anhydrous toluene. A solution of-(3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl)]-2- (S) -methylpropyl] amide (0.90 g, 1.49 mmol) was added dropwise. The reaction was stirred at -25 [deg.] C. for 1 hour before the addition of 2.16 mL (15.5 mmol) triethylamine. The cold bath was removed and the mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 4: 1 ethyl acetate / hexanes. This material was further purified by preparative HPLC to yield 1.20 g (63.4%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical: 514. Measured: 514.

Intermediate (pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) ] -2- (S) -methylpropyl] amide was prepared by the following method.

a. (Pyrrole-2-carbonyl) -N- (benzyl) glycine-t-butyl ester

To a suspension of 3.00 g (27.0 mmol) of pyrrole-2-carboxylic acid in 75 mL of anhydrous dichloromethane at 0 ° C. under nitrogen atmosphere, 6.96 g (27.0 mmol) of BOPCl and 14.1 mL (81.0 mmol) of DIEA were added. It was. After stirring for 30 minutes 5.97 g (27.0 mmol) of N- (benzyl) glycine-t-butyl ester were added and the reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 100% hexanes to 60% hexanes / ethyl acetate to give 2.92 g (34.4%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 315, Found: 315.

b. (Pyrrole-2-carbonyl) -N- (benzyl) glycine

25 mL of TFA was added dropwise to a solution of 2.85 g (9.01 mmol) of (pyrrole-2-carbonyl) -N- (benzyl) glycine-t-butyl ester in chloromethane cooled to 0 ° C. After 90 minutes an additional 25 mL of TFA was added and stirred for 30 minutes. The mixture was dried under vacuum to give 2.19 g of (pyrrole-2-carbonyl) -N- (benzyl) glycine as a tan solid.

FAB MS [M + H] m / z; Theoretical: 259. Found: 259.

c. (Pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl)] -(S) -2-methylpropyl] amide

To a solution of 1.90 g (7.35 mmol) of (pyrrole-2-carbonyl) -N- (benzyl) glycine in 75 mL of anhydrous DMF was added 2.4 mL (22.1 mmol) of NMM and 1.29 g (9.56 mmol) of HOBT. It was. The mixture was cooled to 0 ° C. and 1.69 g (8.82 mmol) of EDCI were added and the reaction mixture was stirred. After 30 minutes 2.17 g (6.99 mmol) of 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- (S) -amino in 25 mL of anhydrous DMF 3-Methyl butan-1-ol hydrochloride was added and the mixture was warmed to room temperature overnight. The reaction was diluted with ethyl acetate and washed with 5% potassium hydrogen sulfate and water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with 20-80% gradient ethyl acetate / hexanes on silica gel to give 2.02 g (56%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 516. Measured value: 516.

Example 27 (CE-2097) (Pyrrole-2-carbonyl) -N- (benzyl) glycyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1, 2,4-oxadiazolyl] carbonyl- (S) -methylpropyl] amide was prepared in a similar manner to Example 25.

FAB MS [M + H] m / z; Theoretical: 568. Found: 568.

Example 28 (CE-2130) (2S, 5S) -5-Amino-1,2,4,5,6,7-hexahydroazino- [3,2,1] -indol-4-one -Carbonyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl- (R, S) -2-methylpropyl] amide

0.93 g (1.28 mmol) of (2S, 5S) -Fmoc-5-amino-1,2,4,5,6,7-hexahydroazino- [3,2, in 4.5 mL of anhydrous DMF under nitrogen atmosphere 1] -indol-4-one-carbonyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl- (S) -2-methyl 0.45 mL of diethylamine was added to a solution of propyl] amide The mixture was stirred at room temperature for 15 minutes and concentrated under high vacuum The residue was purified by preparative HPLC to give 0.57 g (72%) of the title compound as a white. Obtained as a solid.

FAB MS [M + H] m / z; Theoretical value: 502, Measured value: 502.

Intermediate (2S, 5S) -Fmoc-5-amino-1,2,4,5,6,7-hexahydroazino- [3,2,1] -indol-4-one-carbonyl-N- [ 1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl- (S) -2-methylpropyl] amide was prepared as follows:

a. (2S, 5S) -Fmoc-5-amino-1,2,4,5,6,7-hexahydroazino- [3,2,1] -indol-4-one-carbonyl-N- [1 -(2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl- (S) -2-methylpropyl] amide

1.25 g (2.67 mmol) of (2S, 5S) -Fmoc-5-amino-1,2,4,5,6,7 in 200 mL of anhydrous dichloromethane and 1 mL of anhydrous DMF at 0 ° C. under nitrogen atmosphere. To a solution of hexahydroazino- [3,2,1] -indol-4-one-carboxylic acid was added 0.71 g (2.80 mmol) of BOPCl and 0.6 mL (3.45 mmol) of DIEA. After stirring for 1 hour, 1.14 g (3.66 mmol) of 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- () in 10 mL of anhydrous dichloromethane S) -amino-3-methylbutan-1-ol hydrochloride was added and the reaction mixture was stirred at 4 ° C. overnight. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with 3% methanol / dichloromethane to give the title FAB MS [M + H] m / z; Theoretical value: 315, Found: 315.

b. (2S, 5S) -Fmoc-5-amino-1,2,4,5,6,7-hexahydroazino- [3,2,1] -indol-4-one-carbonyl-N- [1 -(2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl- (S) -2-methylpropyl] amide

0.79 mL (10.7 mmol) of dimethyl sulfide was added to a mixture of 0.95 g (7.16 mmol) of N-chlorosuccinimide in 150 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 1.30 g (1.79 mmol) of (2S, 5S) -Fmoc-5-amino-1,2,4,5, in 10 mL of anhydrous toluene. 6,7-hexahydroazino- [3,2,1] -indol-4-one-carbonyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4- A solution of oxadiazolyl] hydroxymethyl)]-(S) -2-methylpropyl] amide was added dropwise. The reaction was stirred at -25 [deg.] C. for 2 hours before the addition of 1.17 mL (8.4 mmol) triethylamine. The cold bath was removed and the mixture was allowed to warm to room temperature over 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. The residue was purified by column chromatography on silica gel with 10% ethyl acetate / hexanes to give 0.93 g (72%) of a tan foam.

Example 29 (CE-2126) BTD- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl-2- (S) -2-methyl Propyl] amide

0.41 g (0.59 mmol) of FMOC-BTD- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazole] carbonyl)-in 4.5 mL of anhydrous DMF under a nitrogen atmosphere- To a solution of 2- (S) -methylpropyl] amide 0.5 mL of diethylamine was added. The mixture was stirred at rt for 30 min and then concentrated under high vacuum. The residue was purified by preparative HPLC to give 0.23 g (66%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical: 472. Measured: 472.

Intermediate Fmoc-BTD- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl-2- (S) -methylpropyl] amide was prepared as follows. :

a. (2S, 5S) -Fmoc-BTD- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl-2- (S) -methylpropyl] amide

0.76 g (2.99 mmol) of BOPCl and 0.6 mL (3.45 mmol) of DIEA in a solution of 1.25 g (2.85 mmol) of FMOC-BTD in 80 mL of anhydrous dichloromethane and 2.5 mL of anhydrous DMF at 0 ° C. under nitrogen atmosphere. Was added. After stirring for 30 minutes 1.14 g (3.66 mmol) of 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- () in 10 mL of anhydrous dichloromethane S) -amino-3-methylbutan-1-ol hydrochloride and 0.6 mL of DIEA were added and the reaction mixture was stirred at 0 ° C. overnight. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with 3% methanol / dichloromethane to give 1.13 g (55%) of the title compound as a tan foam.

b. Fmoc-BTD- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl-2- (S) -methylpropyl] amide

0.67 mL (9.1 mmol) of dimethyl sulfide was added to a mixture of 0.81 g (6.09 mmol) of N-chlorosuccinimide in 110 mL of 1: 1 anhydrous dichloromethane / toluene at 0 ° C. under nitrogen atmosphere. The mixture was stirred for 30 minutes. The reaction was cooled to −25 ° C. using carbon tetrachloride / .dry ice bath and then 1.06 g (1.52 mmol) of Fmoc-BTD- [1- (2- [5- (3-methylbenzyl) in 10 mL of anhydrous toluene. A solution of -1,3,4-oxadiazolyl] hydroxymethyl-2- (S) -methylpropyl] amide was added dropwise The reaction was stirred at -25 [deg.] C. for 2 hours and then 1.0 mL (7.6 mmol) of Triethylamine was added The cold bath was removed and the mixture was allowed to warm to room temperature over 40 minutes The reaction mixture was diluted with ethyl acetate and washed with water The organic phase was dried over magnesium sulfate The resulting mixture was filtered and under reduced pressure Concentration and purification by column chromatography on silica gel with 70% ethyl acetate / hexanes gave 0.53 g of the product as a yellow oil which was further purified by preparative HPLC to give 0.41 g (38.8%) of the title compound as a white solid. It was.

Example 30 (CE-2134) (R, S) -3-Amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl-2- (R, S) -2-methylpropyl] acetamide

0.93 g (1.19 mmol) of (R, S) -FMOC-3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- in 6.0 mL of anhydrous DMF under nitrogen atmosphere. 0.45 mL of diethylamine was added to a solution of [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. After stirring for 2.5 hours at room temperature the mixture was concentrated under high vacuum. The residue was purified by preparative HPLC to give 0.030 g (4.5%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 565, Measured value: 565.

Intermediate (R, S) -FMOC-3-Amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl-2- (S) -methylpropyl] acetamide was prepared as follows:

a. (R, S) -FMOC-3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4- Oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide

0.75 g (1.41 mmol) of (R, S) -FMOC-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1, in 30 mL of anhydrous dichloromethane at 0 ° C. under a nitrogen atmosphere. To a solution of 4-benzodiazepine 0.36 g (1.41 mmol) BOPCl and 0.25 mL (1.41 mmol) DIEA were added. After stirring for 1 hour, 0.48 g (1.55 mmol) of 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- () in 10 mL of anhydrous dichloromethane S) -amino-3-methylbutan-1-ol hydrochloride and 0.49 mL (2.82 mmol) DIEA were added and the reaction mixture was stirred at 4 ° C. overnight. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel with 2-6% gradient methanol / dichloromethane to give 1.00 g (89%) of the title compound as a yellow solid.

b. (R, S) -FMOC-3-amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4- Oxadiazolyl] carbonyl-2- (S) -methylpropyl] acetamide

To a mixture of 0.71 g (7.6 mmol) of N-chlorosuccinimide in 40 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 0.84 mL (11.4 mmol) of dimethyl sulfide. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 1.50 g (1.90 mmol) of (R, S) -FMOC-3-amino-2-oxo-5-phenyl- in 10 mL of anhydrous toluene. Of 1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl-2- (S) -methylpropyl] acetamide The solution was added dropwise The reaction was stirred at -25 [deg.] C. for 2 hours before 1.0 mL (7.6 mmol) of triethylamine was added The cold bath was removed and the mixture was allowed to warm to room temperature over 1 hour. Diluted with acetate and washed with water The organic phase was dried over magnesium sulfate The residue was filtered and concentrated under reduced pressure to spoon 0.94 g (62%) of material which was used without further purification.

FAB MS [M + H] m / z; Theoretical value: 787. Measured value: 787.

Example 31 (CE-2145) (benzyloxycarbonyl) -L-valyl-2-L- (2,3-dihydro-1H-indole) -N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl-2- (S) -methylpropyl] amide

0.40 mL (5.41 mmol) of dimethyl sulfide was added to a mixture of 0.48 g (3.67 mmol) of N-chlorosuccinimide in 30 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The reaction mixture was stirred for 1 hour and then cooled to -25 ° C using a carbon tetrachloride / dry ice bath and then 0.95 g (1.90 mmol) of (benzyloxycarbonyl) -L-valyl-2 in 20 mL of anhydrous toluene. -L- (2,3-dihydro-1H-indole) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2 -(S) -methylpropyl] amide was added dropwise. The reaction was stirred at -25 [deg.] C. for 2 hours and then 0.50 mL (3.6 mmol) triethylamine was added. The cold bath was removed and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with dichloromethane and washed twice with 1 N HCl, twice with saturated sodium bicarbonate, and with water. The organic phase was dried over magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to give 0.61 g. The residue was purified by column chromatography on silica gel with 50% ethyl acetate / hexanes to give 0.27 g of material which was further purified by preparative HPLC to give 196 mg (33.4%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 652, Found: 652.

Intermediate (benzyloxycarbonyl) -L-valyl-2-L- (2,3-dihydro-1H-indole) -N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] hydroxymethyl-2- (S) -methylpropyl] amide was prepared by the following method.

a. 2-L-methyl (2,3-dihydroindole) carboxylate

To a suspension of 5.00 g (30.6 mmol) of 2-L- (2,3-dihydroindole) carboxylic acid in 100 mL of anhydrous MeOH cooled to 0 ° C. was slowly added over 20 minutes. The resulting homogeneous solution was stirred overnight while warming to room temperature. The mixture was evaporated and the residue was crystallized from methanol / ether and dried to give 5.58 g (85%) of L-methyl (2,3-dihydroindole) carboxylate.

b. 2-methyl [(S) -1- (N- [benzyloxycarbonyl) -L-valyl-2,3-dihydro-1H-indole) carboxylate

7.15 g (28.8 mmol) of BOPCl in a solution of 3.00 g (14.0 mmol) of methyl (2,3-dihydroindole) -L-2-carboxylate in 60 mL of anhydrous dichloromethane at 0 ° C. under nitrogen atmosphere And 7.72 mL (70.2 mmol) of DIEA. A solution of 7.06 g (28.08 mmol) of Cbz-Val-OH in 40 mL of anhydrous dichloromethane and 3 mL of DMF. The mixture was stirred at 5 ° C. for 3 days then diluted with ethyl acetate and washed twice with 1 N HCl and brine. The mixture was filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a hexane / ethyl acetate gradient of 9: 1 to 1: 1 to give 4.85 g (87%) of the title compound as a white foam.

c. 2-[(S) -1- (N- [benzyloxycarbonyl) -L-valyl-2,3-dihydro-1H-indole) carboxylic acid

4.85 g (12.17 mmol) of 2-methyl [(S) -1- (N- [benzyloxycarbonyl) -L-valyl-2,3-dihydro in 45 mL of THF and 15 mL of MeOH at 0 ° C. 15.8 mL of 1 N LiOH was added dropwise to a solution of -1H-indole) carboxylate. After 30 minutes 1 N HCl was added to bring the pH to 2 and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4.51 g (93%) of the title compound as a white solid.

d. (Benzyloxycarbonyl) -L-valyl-2-L- (2,3-dihydro-1H-indole) -N- {1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] hydroxymethyl) -2 (S) -methylpropyl] amide.

1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol 1.09 in 30 mL anhydrous dichloromethane g (3.96 mmol) and 1.31 g (3.3 mmol) 2-[(S) -1- (N- {benzyloxycarbonyl] -L-valyl) -2,3-dihydro-1H-indole] carboxylic acid To the solution containing 1.21 mL (6.93 mmol) DIEA and 0.49 g (3.63 mmol) HOBT were added. The mixture was cooled to 0 ° C, 0.70 g (3.63 mmol) of EDCI was added and the reaction mixture was stirred halfway. Additional 1.0 mL (7.44 mmol) of TEA was added and the reaction stirred again overnight. The reaction was diluted with dichloromethane and washed with 1N HCl (2X), saturated sodium bicarbonate (2X) and water. The organic phase was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica using 80% ethyl acetate / hexanes to give 0.66 g (30%) of the title compound.

Example 32-(CE-2125) (benzyloxycarbonyl) -L-Vanyl-2-L- (2,3-dihydro-1H-idol) -N- [1-3- [5- (3- Trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] amide. Prepared in a similar manner to Example 30.

FAB MS [M + H] m / z; Theoretical value: 706. Measured value: 706.

Example 33-(CE-2143) acetyl-2L- (2,3-dihydro-1H-indole) -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2 , 4-oxadiazol] carbonyl) -2- (S) -methylpropyl] amide. Prepared in a similar manner to Example 30.

FAB MS [M + H] m / z; Theoretical: 515. Found: 515.

Example 34-(CE-2165) N-acetyl-2- (L)-) 2,3-dihydro-1H-indole) -N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2 (S) -methylpropyl] amide. Prepared in a similar manner to Example 30.

FAB MS [M + H] m / z; Theoretical value: 461, Found: 461.

Example 35-(CE-2104) (morpholino-N-carbonyl) -L-valyl-N- [1-2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2 (S) -methylpropyl] -L-prolineamide.

0.60 mL (8.17 mmol) of dimethyl sulfide was added to a mixture containing 0.69 g (5.17 mmol) of N-chlorosuccinimide in 60 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere. The reaction was cooled to -25 [deg.] C. using carbon tetrachloride / drying bath and then (morpholino-N-carbonyl) -L-valyl-N- [1-2- [5- (3- in 10 mL of anhydrous toluene. A solution containing methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 (S) -methylpropyl] -L-prolineamide (0.75 g, 1.28 mmol) was added. The reaction was stirred at −25 ° C. for 2 hours and then 1.1 mL of additional triethylamine (0.83 g, 7.89 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature over 20 minutes. The reaction was diluted with ethyl acetate and water. The organic phase was dried over magnesium sulphate and filtered. The solvent was evaporated in vacuo and purified by column chromatography using 70% ethyl acetate / hexanes on silica. Final purification by preparative HPLC gave 405 mg (54.3%) of the title compound as a white solid. FAB MS [M + H] m / z; Theoretical value: 583, Measured value: 583.

Intermediate (morpholino-N-carbonyl) -L-valyl-N- [1-2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 (S ) -Methylpropyl] -L-prolineamide was prepared as follows.

a. (Morpholino-N-carbonyl) -L-valyl-L-proline-O-t-butyl ester

(Morpholino-N-carbonyl) -L-valyl-L-proline-Ot-butyl-ester (1.80 g, 5.87 mmol) in 80 mL of anhydrous methylene chloride and 1.5 mL of N-methyl morpholine at 0 ° C. under nitrogen atmosphere. Morpholine carboline chloride was added dropwise to the solution containing). The mixture was allowed to warm to room temperature overnight. The reaction was diluted with methylene chloride and washed with water. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified by column chromatography on silica gel using 10% methanol / dichloromethane to give 1.98 g (88%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 384. Measured value: 384.

b. (Morpholino-N-carbonyl) -L-valyl-L-proline

A. In 80 mL of anhydrous methylene chloride at 0 ° C. under a nitrogen atmosphere. Trifluoroacetic acid (13 mL, 130 mmol) was added to a solution which antimuxed (morpholino-N-carbonyl) -L-valyl-L-proline-O-t-butyl ester. The mixture was obtained g (88%) to room temperature overnight.

FAB MS [M + H] m / z; Theoretical value: 384. Measured value: 384.

c. (Morpholino-N-carbonyl) -L-valyl-N- [1-2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 (S) -Methylpropyl] -L-prolineamide.

To a solution containing (morpholino-N-carbonyl) -L-valyl-L-proline in 25 mL of anhydrous dichloromethane under nitrogen atmosphere at 0 ° C, 0.80 g (3.14 mmol) of BOPCI and 1.5 mL (8.61 g) DIEA Was added. After 30 minutes [1-2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] -2 (S) -amino-3-methylbutan-1-ol 0.75 in 10 mL of dichloromethane g (2.41 mmol) and 1.1 mL (6.31 mmol) DIEA were added. The reaction was stirred to 0 ° C. The reaction was diluted with dichloromethane and washed with saturated NaHCO ₃ solution. The organic phase was dried over magnesium sulphate and filtered. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel using 6% methanol / dichloromethane to give 0.77 g (54.84%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical value: 585, Measured value: 585.

Example 36-(CE-2079) 3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2 (S) -methylpropyl] acetamide.

1.94 mL (2.64 mmol) of dimethyl sulfide was added to a mixture containing 2.37 g (17.75 mmol) of N-chlorosuccinimide in 60 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere. The reaction was cooled to −25 ° C. using carbon tetrachloride / drying bath and then 3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-N- [5- (3-methyl in 20 mL of anhydrous toluene A solution containing 2.5 g (4.44 mmol) of benzyl) -1,3,4-oxadiazolyl] carbonyl) -2 (S) -methylpropyl] acetamide was added. After the addition was completed, the reaction was stirred at −25 ° C. for 2 hours and then 3.0 mL of additional triethylamine 21.52 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature over 30 minutes. The reaction was diluted with ethyl acetate and water. The organic phase was dried over magnesium sulfate. The solvent was filtered off and purified by column chromatography using 5% methanol / dichloromethane on silica to give 1.8 g of a pale yellow solid. Final purification was then carried out by preparative HPLC to give 1.8 g (38.1%) of the title compound as a white solid.

FAB MS [M + H] m / z; Theoretical: 562. found: 562.

Intermediate 3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxy Methyl) -2 (S) -methylpropyl] acetamide was prepared as follows.

a. 3- (S)-[(benzyloxycarbonyl) amino] -ε-lactam

78 mL (369.70 mmol) of hexamethylenedisilazane was added to a mixture containing 9.9 g (37.18 mmol) Cbz-ornatrine in 150 mL acetonitrile under a nitrogen atmosphere. The reaction was heated at reflux for 78 hours. The reaction mixture was cooled to room temperature and poured into 250 mL of cold methanol. The solvent was removed under reduced pressure. Chloroform was added and the mixture passed through celite. The filtrate was concentrated under reduced pressure to dissolve the residue in ethyl acetate. Hexane was added until the solution became slightly cloudy and left overnight. The resulting solid was filtered and dried to give 8.37 g (90.7%) of the title compound.

b. N- [3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-t-butyl acetate

1.50 mL of bromo-t-butyl acetate (10.16 mmol) in a solution containing 1.0 g (4.03 mmol) of 3- (S)-(benzyloxycarbonyl) amino) -ε-lactam in 20 mL of anhydrous DMF under nitrogen atmosphere. And 1.17 g of silver oxide (5.05 mmol) was added. The reaction was warmed to 45 ° C. for 5 hours, diluted with acetonitrile and passed through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate and washed with radish. The organic phase was dried over magnesium sulfate. The solvent was filtered off and the residue was column chromatographed on silica gel using 60% ethyl acetate / hexanes to give 1.18 g (80.79%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 363, Measured value: 363.

c. N- [3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-carboxymethane.

To a solution containing 0.55 g of N- [3- (S)-(benzyloxycarbonyl) amino) -ε-lactam-t-butyl acetate (1.52 mmol) in 20 mL of trifluoroacetic acid (15.58 mmol) was added. . The reaction was allowed to warm up to room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. The solvent was filtered off to give 0.50 g of the title compound.

FAB MS [M + H] m / z; Theoretical value: 307, Measured value: 307.

d. 3- (S)-[benzyloxycarbonyl) amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl ) -2- (S) -methylpropyl] acetamide

2.37 g (in a solution of 2.72 g (8.88 mmol) of N- [3- (S)-(benzyloxycarbonyl) amino] -ε-lactam-carboxymethane in 80 mL of dichloromethane at 0 ° C. under nitrogen atmosphere. 9.31 mmol) BOPCI and 1.60 mL (9.91 mmol) DIEA were added. The reaction was stirred at 0 ° C. for 30 min and then 2.37 g (7.60 mmol) of 1- [3- [5- (3-methylbenzyl) -1, in 20 mL of dichloromethane and 1.60 mL (9.19 mmol) of DIEA. 3,4-oxadiazolyl] -2- (S) -amino-3-methyl butan-1-ol hydrochloride was added. The reaction was stirred at 0 ° C overnight. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filter and remove the solvent and residue was column chromatographed on silica gel with 10% methanol / dichloromethane to give 2.58 g (50.23%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 564. Measured: 564.

Example 37 (CE-2080) 3- (S- (amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide trifluoroacetic acid salt

The compound is 3- (S)-[benzyloxycarbonyl) amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1 under conditions standard to those skilled in the art. , 3,4-oxadiazolyl] carbonyl-2- (S) -methylpropyl] acetamide was prepared to deprotect to afford the title compound.

FAB MS [M + H] m / z; Theoretical: 428. Found: 428.

Example 38 (CE-2091) 3- (S)-[2- (4-morpholinocarbonyl) ethylcarbonylamino] -ε-lactam-N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl-2- (S) -methylpropyl] acetamide

0.127 g (0.498 mmol) of BOPCI and 0.09 mL (0.492 mmol) in a solution of 0.089 g (0.475 mmol) of 4-morpholino 4-oxo-butanoic acid in 10 mL of dichloromethane at 0 ° C. under nitrogen atmosphere. DIEA was added. The reaction was stirred for 30 minutes before 0.22 g (0.406 mmol) of 3- (S- (amino) -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide trifluoroacetic acid salt was added The reaction was stirred overnight at 0 ° C. The reaction was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulphate, filtered and the solvent removed and purified by preparative HPLC to afford 0.044 g (18%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 597, Measured value: 597.

Example 39 (CE-2087) 6- [4-fluorophenyl] -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide

To a solution of 0.70 g (5.24 mmol) of N-chlorosuccinimide in 30 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 0.60 mL (8.17 mmol) of dimethyl sulfide. The reaction was carbon tetrachloride / dry ice bath. After cooling to −25 ° C., 0.67 g (1.32 mmol) of 6- [4-fluorophenyl] -ε-lactam-N- [1- (2- [5- (3) in 15 mL of anhydrous toluene A solution of -methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was added dropwise. After the addition was complete the reaction was stirred at -25 [deg.] C. for 2 hours and then 0.90 mL (6.46 mmol) triethylamine was added. The cold bath was removed and the reaction was allowed to warm to room temperature and held for 20 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure and column chromatography of the residue on silica gel with 10% methanol / dichloromethane gave 0.61 g of a pale yellow solid. Preparative HPLC was then performed to give 338 mg (50.5%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 507. Found: 507.

Intermediate 6- [4-fluorophenyl] -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] amide was prepared by the following method:

a. 6- [4-fluorophenyl] -6-carboxymethylene-2-piperidinone

2.15 g (8.11 mmol) of 6- [4-fluoro in 70 mL of methanol and 20 mL of water prepared by a similar method as reported in Compernolle in Tetrahedron, 49: 3193 (1993) under a nitrogen atmosphere. To the phenyl] -1-carbomethoxymethylene-2-piperidinone solution was added 0.55 g (13.11 mmol) of lithium hydroxide. The reaction was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent gave 2.0 g (98.2%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 252. Found: 252.

b. 6- [4-fluorophenyl] -ε-lactam-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- ( S) -methylpropyl] amide

1.10 g (4.32 mmol) in a solution of 1.04 g (4.14 mmol) of 6- [4-fluorophenyl] -6-carboxymethylene-2-piperidinone in 25 mL of anhydrous dichloromethane at 0 ° C. under nitrogen atmosphere. BOPCI and 0.80 mL (4.59 mmol) DIEA were added. After stirring for 30 minutes 1.1 g (3.53 mmol) of 1- [2- (5- [3-methylbenzyl])-1,3,4- in 10 mL of dichloromethane and 1.10 mL (6.31 mmol) of DIEA Solution of oxadiazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride. The reaction was stirred at 0 ° C overnight. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate. Filter and remove the solvent under reduced pressure and residue residue was column chromatographed on silica gel with 10% methanol / dichloromethane to give 736 mg (41.0%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 509, Measured value: 509.

Example 40 (C2-2121) 2- [2- (R, S) -phenyl-4-oxothiazolidin-3-yl] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

To a mixture of 2.05 g (15.38 mmol) of N-chlorosuccinimide in 250 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 1.70 mL (23.06 mmol) of dimethyl sulfide. The reaction was cooled to −25 ° C. using carbon tetrachloride / dry ice bath and then 1.90 g (3.84 mmol) of 2- [2- (R, S) -phenyl-4-oxothiazolidine- in 20 mL of anhydrous toluene. 3-yl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide Added dropwise. The reaction was stirred at −25 ° C. for 2 hours before 2.52 mL (18.07 mmol) triethylamine was added. The cold bath was removed and the reaction was allowed to warm to room temperature over 40 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and column chromatography of the residue on silica gel using 60% ethyl acetate / hexanes gave 1.10 g of a yellow oil. This was further purified by preparative HPLC to give 0.45 g (24%) of the title compound as an off-white solid.

FAB MS [M + H] m / z; Theoretical value: 493, Measured value: 493.

Intermediate 2- [2- (R, S) -phenyl-4-oxothiazolidin-3-yl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4- Oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was prepared as follows: Holmes [J. Org. Chem., 60: 7328 (1995)] 1.78 g (7.51 mmol) of 2- (2-phenyl-4-oxothiazolidin-3-yl) acetic acid in 80 mL of dichloromethane prepared according to the method described in. To a solution of 2.04 g (8.02 mmol) BOPCl and 1.35 mL (7.76 mmol) DIEA were added. After stirring for 30 minutes 2.0 g (6.41 mmol) of 1- [3- (5- [3-methylbenzyl)]-1,3,4- in 50 mL of dichloromethane and 1.35 mL (7.76 mmol) of DIEA Oxadiazolyl] -2- (S) -amino-3-methyl-butan-1-ol hydrochloride was added. The reaction was stirred at 0 ° C overnight. The reaction mixture was diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was column chromatographed on silica gel with 4% methanol / dichloromethane to give 2.30 g of yellow foam. Preparative HPLC then performed 1.9 g of the title compound.

FAB MS [M + H] m / z; Theoretical: 495. Found: 495.

Example 41 (CE-2122) 2- [2- (R, S) -Benzyl-4-oxothiazolidin-3-yl] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner to Example 39.

FAB MS [M + H] m / z; Theoretical: 507. Found: 507.

Example 42 (CE-2136) 2-[(2- (R, S) -benzyl-4-oxothiazolidin-3-yl oxide] -N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

1.31 g (2.59 mmol) of 2- [2- (R, S) -benzyl-4-oxothiazolidin-3-yl] -N- [1- (2- [5 in 15 mL of methanol under a nitrogen atmosphere To a solution of-(3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide 0.51 mL (5.17 mmol) of 30% hydrogen peroxide was added. The reaction was stirred overnight at room temperature and then partitioned between brine and dichloromethane. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure and column chromatography on silica gel with 85% ethyl acetate / hexanes gave 0.73 g of a tan oil. Preparative HPLC was then performed to afford 0.54 g (48%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 523. Found: 523.

Example 43 (CE-2137) 2-[(2- (R, S) -benzyl-4-oxothiazolidin-3-yl oxide] -N- [1- (3- [5- ( 3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 41.

FAB MS [M + H] m / z; Theoretical: 577, Found: 577.

Example 44 (CE-2118) 2-[(2- (R, S) -phenyl-4-oxomeththiazan-3-yl] -N- [1- (2- [5- (3- Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 39.

FAB MS [M + H] m / z; Theoretical: 507. Found: 507.

Example 45 (CE-2140) (1-benzoyl-3,8-phthalazinedione) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxa Diazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

To the mixture containing 1.70 g (2.74 mmol) of N-chlorosuccinimide in 75 mL of anhydrous toluene at 0 ° C. under nitrogen atmosphere was added 1.70 mL (23.15 mmol) of dimethyl sulfide. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 1.90 g (3.27 mmol) of (1-benzoyl-3,8-phthalazinedione) -N- [1- in 10 mL of anhydrous toluene. (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide solution was added dropwise. The reaction was stirred at -25 [deg.] C. for 2 hours and then 3.20 mL (22.96 mmol) triethylamine were added. The cold bath was removed and the reaction was allowed to warm to room temperature and held for 15 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica gel with 5% methanol / dichloromethane to give a brown oil. This was further purified by preparative HPLC to give 450 mg (40.1%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 580. Measured value: 580.

Intermediate (1-benzoyl-3,8-phthalazinedione) -N- [1- (2- [5- (3-methylbenzyl) -1,2,4-oxadiazolyl] hydroxymethyl) -2 -(S) -methylpropyl] acetamide was prepared as follows.

a. 1-benzoyl-3,8-phthalazinedione-2-t-butyl acetate

Under a nitrogen atmosphere, 5.0 g (18.78 mmol) of 1-benzoyl-3,8-phthalazinedione in 100 mL of DMF in a similar manner as reported in Melnyk et al., Tetrahedron Lett., 37: 4145 (1996). To a solution of 4.30 mL (29.12 mmol) bromo-t-butylacetate and 5.4 g (23.30 mmol) of silver oxide were added. The reaction was heated to 50 ° C. overnight, diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filter and remove the solvent under reduced pressure and residue was column chromatographed on silica gel with 40% ethyl acetate / hexanes to give 5.25 g (73.49%) of product.

FAB MS [M + H] m / z; Theoretical: 381, Found: 381.

b. 1-benzoyl-2-carboxymethylene-3,8-phthalazinedione

21.0 mL (211.44 mmol) of a tree in a solution of 5.20 g (13.67 mmol) of 1-benzoyl-3,8-phthalazinedione-2-t-butyl acetate in 300 mL of dichloromethane at 0 ° C. under nitrogen atmosphere. Fluoroacetic acid was added. The reaction was warmed to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent gave 4.32 g (97.45%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 325, found: 325.

c. (1-benzoyl-3,8-phthalazinedione) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide

1.90 g (7.46 mmol) of BOPCI and 1.40 in a solution of 1.80 g (5.55 mmol) of carboxymethylene-3,8-phthalazinedione in 100 mL of anhydrous dichloromethane and 5 mL of DMF at 0 ° C. under nitrogen atmosphere. mL (8.05 mmol) of DIEA was added. After stirring for 30 minutes 1.70 g (5.45 mmol) of 1- (2- [5- (3-methylbenzyl) -1,3,4-oxa in 20 mL of dichloromethane and 3.80 mL (21.84 mmol) DIEA Diazolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride was added The reaction was stirred overnight at 0 ° C., diluted with dichloromethane and washed with water The organic phase was dried over magnesium sulfate. It was filtered and the solvent was removed under reduced pressure and the residue was column chromatographed on silica gel with 10% methanol / dichloromethane to give 1.93 g (60.9%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 582, Measured value: 582.

Example 46 (CE-2138) (1-Benzoyl-perhydropyridazine-3,6-dione) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 44.

FAB MS [M + H] m / z; Theoretical: 532, Found: 532.

Example 47 (CE-2147) (1-phenyl-perhydropyridazine-3,6-dione) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 44.

FAB MS [M + H] m / z; Theoretical value: 504, Measured value: 504.

Example 48 (CE-2148) (1-phenyl-perhydropyridazine-3,6-dione) -N- [1- (3- [5- (3-trifluoromethylbenzyl) -1, 2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 44.

FAB MS [M + H] m / z; Theoretical value: 558, Found: 558.

Example 49 (CE-2108) 3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

0.13 mL (1.77 mmol) of dimethyl sulfide was added to a mixture containing 0.16 g (1.18 mmol) of N-chlorosuccinimide in 20 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 0.18 g (0.30 mmol) of 3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N- in 20 mL of methylene chloride. A solution of [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was added dropwise. The reaction was stirred at −25 ° C. for 2 hours before 0.19 mL (1.38 mmol) triethylamine was added. The cold bath was removed and the reaction was allowed to warm to room temperature and held for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was column chromatographed on silica gel with 3% methanol / dichloromethane to give oil 0.23. This was further purified by preparative HPLC to give 100 mg of the title compound.

FAB MS [M + H] m / z; Theoretical value: 608. Measured value: 608.

3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide intermediate was prepared as follows:

a. 3-[(benzyloxycarbonyl) amino] -quinolin-2-one

Under a nitrogen atmosphere, Anderson et al. Heterocyclic Chem., 30: 1533 (1993)] in a solution of 0.5 g (3.10 mmol) of 3-amino-quinolin-2- (1H) -one in 40 mL of dioxane in 14 mL of water. 0.14 g (3.4 mmol) sodium hydroxide was added. The reaction mixture was cooled to 0 ° C. and then 0.50 mL (3.4 mmol) benzylchloroformate was added. The pH of the reaction was maintained above 8.0 with additional 1 N sodium hydroxide. The reaction was warmed to rt and stirred for 2 h. The reaction mixture was diluted with methylene chloride and washed with water. The organic phase was dried over magnesium sulfate. Filtration and the solvent removed under reduced pressure and the residue was column chromatographed on silica gel with 2% methanol / dichloromethane to give 0.32 g (35%) of the product as a white solid.

FAB MS [M + H] m / z; Theoretical value: 295. Measured value: 295.

b. 3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N-t-butyl-acetate

0.15 mL (1.02 mmol) of t-butyl bromoacetate and 0.24 in a solution of 0.30 g (1.02 mmol) of 3-[(benzyloxycarbonyl) amino] -quinolin-2-one in 20 mL of DMF under nitrogen atmosphere g (1.02 mmol) of silver oxide was added. The reaction was heated to 70 ° C. and maintained at this temperature overnight. The reaction mixture was diluted with acetonitrile and filtered through a layer of celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate. Filtration and the solvent removed under reduced pressure and the residue was column chromatographed on silica gel with dichloromethane to give 0.20 g (48%) of the product as a white solid.

FAB MS [M + H] m / z; Theoretical value: 409, Found: 409.

c. 3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide

A solution of 1.09 g (3.09 mmol) of 3-[(benzyloxycarbonyl) amino] -1-carboxymethylene-quinolin-2-one in 50 mL of anhydrous dichloromethane and 3 mL of DMF at 0 ° C. under nitrogen atmosphere. To this was added 0.84 g (3.31 mmol) of BOPCI and 1.10 mL (6.31 mmol) of DIEA. After stirring for 30 minutes, 0.82 g (2.65 mmol) of 1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia in 8 mL of dichloromethane and 0.56 mL (3.20 mmol) of DIEA Zolyl] -2- (S) -amino-3-methylbutan-1-ol hydrochloride was added The reaction was stirred at 0 ° C. overnight, diluted with dichloromethane and washed with water The organic phase was dried over magnesium sulfate. It was filtered and the solvent was removed under reduced pressure and the residue was column chromatographed on silica gel with 5% methanol / dichloromethane to give 0.37 g (30.3%) of product.

FAB MS [M + H] m / z; Theoretical value: 610, Measured value: 610.

Example 50 (CE-2107) 3-[(benzyloxycarbonyl) amino] -7-piperidinyl-quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 48.

FAB MS [M + H] m / z; Theoretical value: 691, Found: 691.

Example 51 (CE-2117) 3-Carbomethoxy-7-fluoro-quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Prepared in a similar manner to Example 48.

FAB MS [M + H] m / z; Theoretical value: 535. Measured value: 535.

Example 52 (CE-2113) 3- (Amino-quinolin-2-one) -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] acetamide

2.30 g (3.79 mmol) of 3-[(benzyloxycarbonyl) amino] -quinolin-2-one-N- [1- (2- [5 in 60 mL of trifluoroacetic acid at 0 ° C. under nitrogen atmosphere. To a solution of-(3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide 0.53 mL (4.54 mmol) of thioanisole was added. The reaction was warmed to room temperature overnight. The solvent was removed under reduced pressure. Preparative HPLC was then performed to give 0.61 g (27%) of the title compound.

FAB MS [M + H] m / z; Theoretical: 474. Found: 474.

Example 53 (CE-2116) 3-[(4-morpholino) aceto] amino-quinolin-2-one-N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

To a solution of 0.32 g (1.22 mmol) of 4-morpholino acetic acid in 18 mL of dichloromethane at 0 ° C. was added 0.33 g (1.30 mmol) of BOPCI and 0.22 mL (1.26 mmol) of DIEA. After stirring for 1.5 hours, 0.61 g (1.04 mmol) of 3- (amino-quinolin-2-one) -N- [1- (2- [5- (3-methylbenzyl) -1 in 20 mL of dichloromethane A solution of, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was added followed by 0.22 mL (1.26 mmol) DIEA. The reaction mixture was stirred at 0 ° C. overnight, diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filtration and the solvent removed under reduced pressure and preparative HPLC gave 0.20 g (27%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 602. Measured value: 602.

Example 54 (CE-2088) 3,4-dihydro-quinolin-2-one-N- [1- (from commercially available 3,4-dihydro-2 (1H) -quinolin-2-one 2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2-S-methylpropyl] acetamide

Prepared in a similar manner to Example 52.

FAB MS [M + H] m / z; Theoretical value: 461, Found: 461.

Example 55 (CE-2099) 1-Acetyl-3-benzylidene piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

0.46 mL (6.22 mmol) of dimethyl sulfide was added to a solution of 0.55 g (4.15 mmol) of N-chlorosuccinimide in 35 mL of anhydrous toluene at 0 ° C. under a nitrogen atmosphere. The reaction was cooled to −25 ° C. using a carbon tetrachloride / dry ice bath and then 0.58 g (1.04 mmol) of 1-acetyl-3-benzylidene piperazine-2,5-dione-N- [1 in 8 mL of toluene. A solution of-(2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] -L-prolineamide was added. The reaction was stirred at -25 [deg.] C. for 2 hours before 0.68 mL (4.87 mmol) of triethylamine was added. The cold bath was removed and the mixture was allowed to warm to room temperature and held for 40 minutes. The reaction was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The residue was column chromatographed with 60% ethyl acetate / hexanes on silica gel to give 0.54 g of brown oil which was further purified by preparative HPLC to give 1.46 mg (25%) of the title compound.

FAB MS [M + H] m / z; Theoretical value: 558, Found: 558.

Intermediate 1-acetyl-3-benzylidene piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was prepared as follows.

a. 1-acetyl-3-benzylidene piperazine-2,5-dione-N-t-butyl acetate

6.36 g (26.00 mmol) of 1-acetyl-3-benzylidene piperazine-2,5-dione described in D.Villemn, et al. (Synthetic Communications, 20: 3325 (1990)) in 100 mL of DMF. To a solution containing was added 9.62 mL (65.10 mmol) of t-butyl bromoacetate and 7.55 g (32.60 mmol) of silver oxide under nitrogen atmosphere The reaction was heated overnight to 45 ° C. The reaction was filtered through a plug of celite The filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with water The organic phase was dried over magnesium sulfate, filtered, removal of solvent under reduced pressure and residue on silica gel using 1% methanol / dichloromethane. Column chromatography gave 5.37 g of a tan solid, which was further purified via preparative HPLC to give 2.5 g (27%) of the title compound FAB MS [M + H] m / z; Theoretical: 359, Found: 359 .

b. 1-acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione.

5.40 mL (69.80) trifluoroacetic acid in a solution containing 2.50 g (6.98 mmol) of 1-acetyl-3-benzylidene piperazine-2,5-dione-Nt-butyl acetate in 100 mL of dichloromethane under a nitrogen atmosphere of 0 ° C. mmol) was added. The reaction was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous phase was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure gave 1.96 g (96%) of product as a tan solid. FAB MS [M + H] m / z; Theoretical value: 303, Found: 303.

c. 1-acetyl-3-benzylidene piperazine 2,5-dione-N- [1- (2 [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide

BOPCI 0.57 under a nitrogen atmosphere of 0 ° C. in a solution containing 0.65 g (2.14 mmol) of 1-acetyl-3-benzylidene-4-carboxymethylene-piperazine-2,5-dione in 40 mL of anhydrous dichloromethane and 3 mL of DMF. g (1.83 mmol) and 0.39 mL (2.21 mmol) DIEA were added. After stirring for 30 minutes, 1- (2 [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2 in 10 mL of dichloromethane and 0.39 mL (2.21 mmol) of DIEA. 0.57 g (1.83 mmol) of-(S) -amino-3-methylbutan-1-ol hydrochloride. The reaction was warmed at 0 ° C. overnight, diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filter, remove solvent under reduced pressure and column chromatography on silica gel with 5% methanol / dichloromethane to give 0.13 g (58%) of product. FAB MS [M + H] m / z; Theoretical value: 560, Found: 560.

Example 56 (CE-2105) 1-acetyl-3- (4-fluorobenzylidene) piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 54. FAB MS [M + H] m / z; Theoretical value: 576. Found: 576.

Example 57 (CE-2111) 1-acetyl-3- (4-dimethylaminobenzylidene) piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 54. FAB MS [M + H] m / z; Theoretical value: 601, Found: 601.

Example 58 (CE-2112) 1-acetyl-3- (4-carbomethoxybenzylidene) piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 54. FABMS [M + H] m / z; Theoretical value: 616. Found: 616.

Example 59 (CE-2114) 1-acetyl-3-[(4-pyridyl) methylene] piperazine-2,5-dione-N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 54. FAB MS [M + H] m / z; Theoretical Value: 559, Found: 559.

Example 60 (CE-2144) 4- [1-benzyl-3- (R) -benzyl-piperazine-2,5-dione] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.

2.1 mL (28.59 mmol) of dimethyl sulfide was added to a mixture containing 2.20 g (16.48 mmol) of N-chlorosuccinamide in 10 mL of anhydrous toluene under a nitrogen atmosphere of 0 ° C. The reaction was cooled to −25 ° C. using carbon tetrachloride / anhydrous ice bath and 4- [1-benzyl-3- (R) -benzyl piperazine-2,5-dione] -N- [1- in 15 ml of toluene. A solution containing (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was added. The reaction was stirred for 2 h at −25 ° C. and 4.0 mL (28.70 mmol) of triethylamine were added. The cold bath was removed and the reaction was allowed to warm to room temperature and held for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filter, remove the solvent under reduced pressure and column chromatograph the residue on silica gel with 5% methanol / dichloromethane to give 2.27 g of a light brown solid, which was further purified by preparative HPLC to give 350 mg of the title compound ( 14.4%). FAB MS [M + H] m / z; Theoretical value: 608, Found: 608.

Intermediate 4- [1-benzyl-3- (R) -benzyl piperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxa Diazolyl] hydroxymethyl-2- (S) -methylpropyl] acetamide was prepared as follows.

a. 1-benzyl-3- (R) -benzylpiperazine-2,5-dione-4-t-butyl acetate

1-benzyl-3- (R) -benzylpiperazine-2,5-dione in 125 mL of DMF under a nitrogen atmosphere (Steel, et al., J. Biorg, Med. Chem. Lett., 5:47 ( 1995)] was added 5.30 mL (35.89 mmol) of t-butyl bromoacetate and 6.80 g (29.34 mmol) of silver oxide to a solution containing 7.0 g (23.78 mmol). The reaction was heated to 50 ° C. overnight, diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filter, remove solvent under reduced pressure and column chromatograph the residue on silica gel using 50% ethyl acetate / hexanes to yield 7.74 g (79.7%) of the title compound as a white solid. FAB MS [M + H] m / z; Theoretical value: 409, Found: 409.

b. 1-benzyl-3- (R) -benzyl-4-carboxymethylene-piperazine-2,5-dione

Trifluoro in a solution containing 7.70 g (18.85 mmol) of 1-benzyl-3- (R) -benzyl piperazine-2,5-dione-4-t-butyl acetate in 300 ml of dichloromethane under nitrogen at 0 ° C. 19.0 mL (191.30 mmol) of acetic acid were added. The reaction was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure gave 6.69 g of product. FAB MS [M + H] m / z; Theoretical value: 353, Found: 353.

c. 4- [1-benzyl-3 (R) -benzyl piperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Hydroxymethyl) -2- (S) -methylpropyl] acetamide

A solution containing 2.0 g (5.68 mmol) of 1-benzyl-3- (R) -benzyl-4-carboxymethylene-piperazine-2,5-dione in 100 ml of dichloromethane and 2 ml of DMF under a nitrogen atmosphere at 0 ° C. To 2.0 g (7.86 mmol) of BOPCI and 1.50 mL (8.62 mmol) of DIEA were added. After stirring for 30 min, 1- [2- (5- [3-methylbenzyl])-1,3,4-oxadiazolyl] -2- (S in 10 mL of dichloromethane and 4.0 mL (22.99 mmol) of DIEA. A solution containing 1.80 g (5.7 mmol) of) -amino-3-methylbutan-1-ol hydrochloride was added. The reaction was stirred at 0 ° C. overnight, diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filter, remove solvent under reduced pressure and column chromatography on silica gel with 7% methanol / dichloromethane to give 2.69 g (77.7%) of product. FAB MS [M + H] m / z; Theoretical value: 610, Found: 610.

Example 61 (CE-2128) 4- [1-benzyl-3- (S) -phenylpiperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 608, Found: 608.

Example 62 (CE-2146) 4- [1-Methyl-3- (R) -benzylpiperazine-2,5-dione] -N- [1- (3- [5- (3-trifluoro Romethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 662. Found: 662.

Example 63 (CE-2129) 4- [1-methyl-3- (S) -benzylpiperazine-2,5-dione] -N- [1- (3- [5- (3-trifluoro Romethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 662. Found: 662.

Example 64 (CE-2133) 4- [1-benzyl-3- (S) -benzylpiperazine-2,5-dione] -N- [1- (3- [5- (3-dimethylamino Ethyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that described in Example 59. FAB MS [M + H] m / z; Theoretical value: 575, Found: 575.

Example 65 (CE-2084) 4- [1-Methyl-3- (R, S) -phenylpiperazine-2,5-dione] -N- [1- (3- [5- (3- Trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 572, Found: 572.

Example 66 (CE-2106) 4- [1-Methyl-3- (R, S) -phenylpiperazine-2,5-dione] -N- [1- (2- [5- (3- Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 518, Found: 518.

Example 67 (CE-2162) 4- [1- (2-N-morpholino ethyl) -3- (R) -benzyl piperazine-2,5-dione] -N- [1- (2 -[5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 59. FAB MS [M + H] m / z; Theoretical value: 631, Found: 631.

Example 68 (CE-2149) 5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.

To a mixture containing 0.28 g (2.10 mmol) of N-chlorosuccinimide in 50 mL of anhydrous toluene under a nitrogen atmosphere of 0 ° C., 0.23 mL (3.13 mmol) of dimethyl sulfide was added. The reaction mixture was cooled to -25 DEG C using carbon tetrachloride / anhydrous ice bath, and 5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2 in 10 ml of toluene. A solution containing 0.26 g (0.52 mmol) of-[5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was added. . The reaction was stirred for 2 h at -25 &lt; 0 &gt; C and 0.30 mL (2.15 mmol) of triethylamine was added. The cooling bath was removed and the reaction was left at room temperature and held for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration, the solvent was removed under reduced pressure and the residue was column chromatographed on silica gel using 10% methanol / dichloromethane, and preparative HPLC gave 120 mg (47.2%) of the title compound. FAB MS [M + H] m / z; Theoretical value: 490, Found: 490.

Intermediate 5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydride Roxymethyl) -2- (S) -methylpropyl] acetamide was prepared as follows.

a. (R) -N- (ethoxy carbonylmethyl) -N '-(1-methoxy carbonyl-2-phenyl) urea

10 ml of ethyl isocyanatoacetate in a solution containing 18.45 g (91.49 mmol) of (R) -2-phenylglycine methyl ester in 250 ml of ethyl acetate and 13.4 ml (96.12 mmol) of triethylamine under nitrogen at 0 ° C 91.49 mmol) was added. After stirring for 1 hour, the reaction was diluted with ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. Filtration and removal of the solvent under reduced pressure gave 29.28 g (97.6%) of a product as a white solid. FAB MS [M + H] m / z; Theoretical value: 235, Found: 235.

b. (R) -5-phenyl-3-carboxymethyl hydantoin

A mixture containing 29.28 g (99.49 mmol) of (R) -N- (ethoxycarbonylmethyl) -N '-(1-methoxycarbonyl-2-phenyl) urea in 500 mL concentrated hydrochloric acid was heated to reflux overnight. It was. The reaction mixture was cooled to rt and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent under reduced pressure gave 14.01 g (60%) of the title compound. FAB MS [M + H] m / z; Theoretical value: 295. Found: 295.

c. 5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] hydroxy Methyl) -2- (S) -methylpropyl] acetamide

EDCI 2.30 g (12.00 mmol) and HOBT 1.62 in a solution containing 2.55 g (10.89 mmol) of (R) -5-phenyl-3-carboxymethyl hydantoin in 100 mL of dichloromethane and 10 mL of DMF under a nitrogen atmosphere at 0 ° C. g (11.99 mmol) was added. After stirring for 30 minutes, 1- [2- (5- [3-methylbenzyl) -1,3,4-oxadiazolyl] -2- (S) in 20 mL of dichloromethane and 4.78 mL (43.50 mmol) of NMM. A solution containing 4.43 g (14.21 mmol) of -amino-3-methylbutan-1-ol hydrochloride was added. The reaction was warmed to room temperature overnight, diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate. Filtration, the solvent was removed under reduced pressure and the residue was column chromatographed on silica gel with 50% acetone / dichloromethane to give 1.90 g (35.5%) of the title compound. FAB MS [M + H] m / z; Theoretical value: 490, Found: 490.

Example 69 (CE-2154) 5- (S) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 504, Found: 504.

Example 70 (CE-2142) 5- (R) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 504, Found: 504.

Example 71 (CE-2141) 5- (R) -benzyl-2,4-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1 , 2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 558, Found: 558.

Example 72 (CE-2155) 5- (S) -benzyl-2,4-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1 , 2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 558, Found: 558.

Example 73 (CE-2151) 1-benzyl-4- (R) -benzyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 594. Found: 594.

Example 74 (CE-2150) 1-benzyl-4- (R) -benzyl-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethyl Benzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. Prepared in a similar manner to that shown in Example 67. FAB MS [M + H] m / z; Theoretical value: 648. Found: 648.

Example 75 (ONO-PO-698) 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidy Nil] -N- [1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

Dess-Martin Reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3- (1H) -one) in 4 ml of dichloromethane 410 mg To a mixture containing (0.744 mmol, 77% purity) 2-[(5-benzyloxycarbonyl) -amino-6-oxo-2- (4-fluorophenyl) -1,6- in 5 ml of dichloromethane Dihydro-1-pyrimidinyl] -N- [1- (2- [5-t-butyl-1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acet A solution containing 410 mg (0.676 mmol) of amide was added dropwise. The reaction mixture was stirred for 1 hour. The reaction was quenched by addition of water and extracted twice with ethyl acetate. The extract was washed with water and saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 33% ethyl acetate / hexane as eluent to yield 372 mg of the title compound. APCI, Pox, 40 V [M + H] m / z; Theoretical value: 605. Found: 605.

Intermediate 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-pyrimidinyl] -N- [1- (2- [5 -t-butyl-1,3,4-oxadiazolyl] hydroxymethyl) -2- (S) -methylpropyl] acetamide was prepared as follows. [1- [5-t-butyl-1,3,4-oxadiazol-2-yl] -2- (S) -amino-1-hydroxy-3-methylbutane hydrochloride 265 in 2 ml of anhydrous DMF. Mg (1.01 mmol) and 5-[(benzyloxycarbonyl) amino] -6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] acetic acid (see [J Med. Chem., 38: 98-108 (1995)] were added 155 mg (1.01 mmol) of HOBT and 231 mg (1.01 mmol) of EDCl. The mixture was cooled to 0 ° C., 0.11 mL (1.0 mmol) of NMM was added dropwise and the reaction mixture was stirred for 3 hours. The reaction was quenched by addition of water and extracted three times with ethyl acetate. The extract was washed with 10% aqueous citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 0-1% methanol / chloroform gradient eluent to yield 418 mg of the title compound. APCI, Pos, 40 V [M + H] m / z; Theoretical value: 607, Found: 607.

Example 80 (ONO-PO-690) 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidy Nil] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide Prepared in a similar manner to Example 75. APCI, Pos, 40 V [M + H] m / z; Theoretical value: 667, Found: 667.

Example 81 (ONO-PO-697) 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidy Nyl] -N- [1- (2- [5-phenyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner to Example 75. It was. El, Pos, [M + H] m / z; Theoretical value: 624, Found: 624.

Example 82 (ONO-PO-716) 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2 -[5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner as in Example 75. APCI, Neg, 40 V [M + H] m / z; Theoretical value: 454, Found: 454.

Example 83 (ONO-PO-722) 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2 -[5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolylcarbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner to Example 75. APCI, Neg, 40 V [M + H] m / z; Theoretical value: 516. Found: 516.

Example 84 (ONO-PO-727) 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2 -[5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared in a similar manner as in Example 75. APCI, Pos, 40 V [M + H] m / z; Theoretical value: 456, Found: 456.

Example 85 (ONO-PO-730) 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-t- Butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner to Example 75. APCI, Neg, 40 V [M + H] m / z; Theoretical value: 436, Found: 436.

Example 86 (ONO-PO-731) 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α , α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared in a similar manner to Example 75. APCI, Neg, 40 V [M + H] m / z; Theoretical value: 498, Found: 498.

<Example 87>

In a similar manner to Example 75 (ONO-PO-732) 2- [6-oxo-2-phenyl-1.6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-t- Butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calc. 438. found: 438.

<Example 88>

In a similar manner as in Example 75 (ONO-PO-734) 2- [6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [1- (2 -[5- (1-methylcyclopropyl) -1,3,4-oxadiazolylcarbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated: 454, found: 454.

<Example 89>

In a similar manner as in Example 75 (ONO-PO-735) 2- [6-oxo-2-phenyl-1,6-dihydro-pyrimidinyl] -N- [1- (2- [5- (1 -Methylcyclopyrophyll) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 436, Found: 436.

<Example 90>

In a similar manner to Example 75 (ONO-PO-737) 2- [6-oxo-2-phenyl-1.6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-t- Butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calc. 438. found: 438.

<Example 91>

(ONO-PO-732) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [1- (2- [5 -t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide.

2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N in 8 mL of dichloromethane at 0 ° C. 296 mg (0.49 mmol) and anisole 0.32 of [1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl} -2- (S) -methylprofil] acetamide To a mixture containing mL (2.9 mmol) was added dropwise a solution containing 392 mg (2.9 mmol) of aluminum chloride in 4 mL of nitromethane The reaction mixture was stirred for 1.5 h, quenched by the addition of ice water and extracted with ethyl acetate. (3 times) The extract was extracted with water and saturated sodium chloride solution The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure The residue was purified on silica gel using 66% ethyl acetate / hexane as eluent. Purification by column chromatography gave 175 mg of the title compound as a white solid: APCI, Pos. 40 V [M + H] m / z: calc. 471. found: 471.

<Example 92>

In a similar manner as in Example 91 (ONO-PO-691) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 533, Found: 533.

<Example 93>

In a similar manner as in Example 91 (ONO-PO-692) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethyl-3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 547, Found: 547.

<Example 94>

In a similar manner as in Example 91 (ONO-PO-693) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R-methylpropyl] acetamide was prepared FAB, Pos. M + H] m / z; calculated: 519, found: 519.

<Example 95>

In a similar manner as in Example 91 (ONO-PO-694) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-phenyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 491, Found: 491.

<Example 96>

In a similar manner as in Example 91 (ONO-PO-695) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (3-pyridyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 492, Found: 492.

<Example 97>

In a similar manner as in Example 91 (ONO-PO-699) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (4-methoxyphenyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calc. 521. found: 521.

<Example 98>

In a similar manner as in Example 91 (ONO-PO-701) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethyl) -3,4-dihydroxybenzyl) 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide Was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated value: 565, Found: 565.

<Example 99>

In a similar manner as in Example 91 (ONO-PO-692) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-benzyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 505, Found: 505.

<Example 100>

In a similar manner as in Example 91 (ONO-PO-704) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-methyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 429, Found: 429.

<Example 101>

In a similar manner as in Example 91 (ONO-PO-705) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-isopropyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 457, Found: 457.

<Example 102>

In a similar manner as in Example 91 (ONO-PO-706) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 471. Found: 471.

<Example 103>

In a similar manner as in Example 91 (ONO-PO-707) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 453, Found: 453.

<Example 104>

In a similar manner as in Example 91 (ONO-PO-711) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. FAB, Pos. 40 V [M + H] m / z; Calculated Value: 515, Found: 515.

<Example 105>

In a similar manner as in Example 91 (ONO-PO-712) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated: 454, found: 454.

<Example 106>

In a similar manner as in Example 91 (ONO-PO-714) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (1-methylcyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 469. Found: 469.

<Example 107>

In a similar manner as in Example 91 (ONO-PO-715) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 516, Found: 516.

<Example 108>

In a similar manner as in Example 91 (ONO-PO-718) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 471. Found: 471.

<Example 109>

In a similar manner as in Example 91 (ONO-PO-721) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 533, Found: 533.

<Example 110>

In a similar manner as in Example 91 (ONO-PO-728) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5- (1-methylcyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 449 Found: 559.

<Example 111>

In a similar manner as in Example 91 (ONO-PO-729) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 453, Found: 453.

<Example 112>

In a similar manner as in Example 91 (ONO-PO-733) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [ 1- (2- [5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 471. Found: 471.

<Example 113>

In a similar manner to Example 91 (ONO-PO-736) 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2 -[5-t-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide was prepared. APCI, Pos. 40 V [M + H] m / z; Calculated Value: 453, Found: 453.

<Example 114>

(ONO-PO-700) 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [1- (2- [5 -(α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1 in 8 mL of dichloromethane. -(2- [5- (α, α-dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl} -2- (S) -methylprruphyll] acetamide 66 mg (0.093 mmol) were added to 2.5 mL of 30% hydrobromic acid in acetic acid solution.The reaction mixture was stirred for 1 hour, quenched by adding ice water, ethyl Extracted with acetate (3 times) The extract was extracted with water (2 times) and saturated sodium chloride solution The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. Purification by column chromatography on silica gel using an elution gradient of methanol / chloroform gave 41 mg of the title compound as a white solid. [M + H] m / z: calc. 576. Found: 576.

<Example 115>

(ONO-PO-702) 2- [5- (methylsulfonyl) amino-6-oxo-2- (4-fluorophenyl) -1.6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide

187 mg (0.36 mmol) of 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyri in 187 mg (0.36 mmol) in 3.5 mL of pyridine under argon atmosphere. Midinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide (Example To the mixture containing 25) was added 0.028 mL (0.36 mmol) mesyl chloride. The reaction mixture was stirred for 17 hours at room temperature, 15 hours at 50 ° C and 1 hour at 70 ° C. Ice reaction was added to quench the reaction and extracted with dichloromethane. The extract was washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient elution of 50-66% ethyl acetate / hexanes to give 60 mg of the title compound APCI, Pos, 40V [M + H] m / z; Theoretical value: 597, Measured value: 597.

Biological Example 1 In Vitro Inhibition of Elastase

The inhibitory activity of the ONO-PO family compounds was measured using the following protocol. The elastase used in the protocol was from human saliva (HSE). The mother liquor of the HSE enzyme was prepared by diluting commercially available HSE (875 U / mg protein, SE-563, Elastin Product Co., Inc, Missouri, USA) with brine to 1,000 U / ml, using 0 ° C. before use. Further diluted to 2 U / ml at.

100 μl 0.2 M HEPES-NaOH buffer (pH 8.0), 40 μl 2.5 M NaCl, 20 μl 1% polyethylene glycol 6000, 8 μl distilled water, 10 μl DMSO solution of inhibitor and N-methoxysuccinyl-Ala-Ala-Pro The solution was prepared by mixing 2 μl of a -Val-p-nitroaniline solution (concentrations 100, 200 and 400 μM). This solution was incubated at 37 ° C. for 10 minutes. To this was added a solution of HSE (elastase derived from human saliva) enzyme. The next rate analysis was performed using the resulting mixture.

To measure the rate of enzymatic reaction, the optical density at 405 nm (SPECTRA MAX 250, Molecular Devices) attributable to the p-nitroaniline produced by the enzymatic reaction is defined as the period during which the rate of production of p-nitroaniline remains linear. Was measured at 37 ° C. This rate mO.D./min was measured for 10 minutes at 30 second intervals immediately after the addition of the enzyme solution. IC ₅₀ values were measured by log-logging method and converted to K _i values by Dickson plot method. The values are shown in Table 1 below.

CE compounds were tested as described in WO 96/16080. The results are shown in Table 2 below. As can be seen from the table, the compounds of the present invention are potent elastase inhibitors, of which certain compounds show sub-molar levels of inhibitory activity.

Biological Example 2 Blood Concentration Screening

Inhibitors were dissolved or suspended in polyethylene glycol (PEG), PEG-400 or PEG: H ₂ O: EtOH at a concentration of 10 mg / ml. This solution oral dose was administered via gavage to an unstarved male Sprague-Dawley rat. Mice received a 10 mg inhibitor / kg body weight at a 1 ml / kg dose. After 1, 3 or 6 hours, rats were overdosed with urethane (2.5 g / kg intraperitoneal) and blood was collected in heparinized tubes via cardiac puncture. Erythrocytes were separated from plasma by centrifugation.

Depending on the type of inhibitor, compounds were extracted from the plasma using one of four organic materials (ethyl acetate, toluene, isopropyl ether or methyl t-butyl ether). Inhibitor concentrations were determined by HPLC or LC / MS analysis. The results are shown in Table 2 below. Certain compounds of the present invention exhibited high oral bioavailability as revealed by blood levels over time.

Biological Example 3 Extracellular Matrix (ECM) Analysis Procedure

A 48-well plate containing an extracellular matrix was provided by Simon's team at New York State University in Storybrook, USA. In summary, the preparation of this plate is as follows: R22 rat cardiac smooth muscle cells were seeded in the wells at 2.5 × 10 ⁴ cells / cm. Cells were fed with Eagle minimum essential medium supplemented with fetal bovine serum, tryptic phosphate broth, cytotaxime and streptomycin every 4 days. Once congenital growth was made, 50 μg / ml of ascorbic acid was supplemented daily for 8 to 10 days while the ECM layer was synthesized. [ ³⁵ S] sulphate and [ ³ H] proline were also added to the culture medium to introduce radiolabels into the matrix. The cells were later lysed with 25 mM NH ₄ OH. The plates were washed three times with water and once with phosphate buffered saline containing 0.02% NaN ₃ . Plates were stored at 4 ° C. until use.

Matrix degradation assay was performed as follows: 0.40 ml of Hanks Balanced Salt Solution (HBSS) containing 1 or 5 μM of test inhibitor (final concentration; diluted in DMSO mother liquor; <2% DMSO final concentration) was added to the wells. Was added. After 30 minutes, 50 μl of neutrophil (PMN) suspension was added to give 5 × 10 ⁵ cells / well. PMN was stimulated with opsonized geosmoic acid. The zymosan particles were washed and suspended in 0.5 ml of human serum, vortexing every 15 minutes at 37 ° C. for 1 hour. The particles were then washed three times with HBSS and added to the wells in a volume of 50 μl, at a rate of 10 particles / PMN. After incubation at 37 ° C. for 4 hours, 100 μl of supernatant was aliquoted and scintillation counted. After removal of the remaining supernatant, the residual ECM was solubilized with 0.5 ml of 2M NaOH. The amount of tritium in this solubilized ECM was calculated by scintillation. ECM decomposition data is expressed as (Emitted Soluble Count / Total ECM Count)-(Basic Count / Total ECM Count Released without PMN). The results are shown in Table 2 below.

Biological Example 4 In Vitro Inhibition of Elastase

Sixty minutes after oral administration of the inhibitor with the appropriate vehicle, blood samples (0.9 ml) were collected through the abdominal aorta using a syringe containing 0.1 ml of 3.8% sodium citrate solution.

Blood samples were treated as follows: 60 [mu] l (final 0.1-1 mg / ml) of suspension solution of opsonized gimosane in Hank's buffer was added to preincubated whole blood (540 [mu] l) for 5 min at 37 [deg.] C. The mixture was incubated at the same temperature for 30 minutes. The reaction was terminated by dipping the test tube in ice water. The reaction mixture was then centrifuged at 4 ° C., 3,000 rpm for 10 minutes. Elastase activity was measured using 20 µl of the supernatant obtained as a sample (below 'sample').

The mixture consisting of the following components was incubated at 37 ° C. for 24 hours and then the optical density was measured at 405 nm.

100 μl 0.2 M Tris-HCl buffer (pH 8.0)

2.5 μl 2.5 M NaCl

36 μl of distilled water

50 mM substrate solution ( ^* ) 4 μl

20 μl sample

N-methylsuccinyl-Ala-Ala-Pro-Val-p-nitroanilide

The test sample mixed with 1-methyl-2-pyrrolidone instead of the substrate is treated as the substrate (-). The test sample mixed with saline instead of 'sample' is treated as blank. Residual elastase activity in the 'sample' is calculated according to the following equation:

Optical Density of Substrate (+)-(Optical Density of Substrate (-) + Optical Density of Blank)

This value is taken as the total production of p-nitroaniline over 24 hours based on a standard curve for the amount of p-nitroaniline.

Average activity is calculated based on test samples of 5-6 animals. A 3, 10 or 30 mg / kg medicament is forcibly administered orally to hungry animals 60 minutes prior to blood collection. Optical density was measured by SPECTRA MAX 250 (Molecular Devices).

Claims (304)

delete delete delete delete (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-dimethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-dimethoxybenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-ditrifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-methylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (4-phenylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-phenylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-phenoxybenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,5-diphenylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (4-dimethylaminobenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (biphenylmethine) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl ] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (α, α-dimethyl- [3-trifluoromethyl] benzyl) -1,2,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (1-naphthylmethylene) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (2-naphthylmethylene) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3,4-methylenedioxybenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- ( S) -methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (3-pyridylmethylene) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, or (Benzyloxycarbonyl) -L-valyl-N- [1- (3- [5- (cyclohexylmethylene) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl ] -L-prolineamide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete 3-pyridylcarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] -L-prolineamide, Methyloxycarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, Isopropyloxycarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -Methylpropyl] -L-prolineamide, 4-pyridylmethyleneoxycarbonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide, or Methylsulfonyl-L-valyl-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide. delete delete delete delete delete delete delete delete delete delete delete Compounds of the formula In the above formula, X is N and Y is O; R ₁ is (C ₁ -C ₆ ) alkyl-phenyl in which phenyl is unsubstituted or substituted with CH ₃ or CF ₃ , or R ₁ is 3,4-methylenedioxybenzyl; One of R ₂ and R ₃ is H and the other is (C ₁ -C ₆ ) alkyl; A is -C (O)-, -S (O) _2- , or -OC (O)-; R ₄ is (C ₁ -C ₆ ) alkyl-phenyl or (C ₁ -C ₆ ) alkyl-pyridyl. delete delete delete delete The method of claim 70, wherein (benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] car Carbonyl) -2- (S) -methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5-methyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L- Prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5-dimethylamino-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L Prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -1-methylethyl] -L Prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (3-trifluoromethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (4-dimethylaminobenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, (Benzyloxycarbonyl) -L-valyl-N- [1- (2- [5- (1-naphthylmethylene) -1,3,4-oxadiazolyl] carbonyl) -2- (S)- Methylpropyl] -L-prolineamide, 3-pyridylcarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methyl Propyl] -L-prolineamide, Methyloxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-prolineamide, Isopropyloxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl ] -L-prolineamide, 4-pyridylmethyleneoxycarbonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -Methylpropyl] -L-prolineamide, Methylsulfonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl]- L-prolineamide, Phenylsulfonyl-L-valyl-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl]- L-prolineamide, Methylsulfonyl-L-valyl-N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl ] -L-prolineamide, or Methylsulfonyl-L-valyl-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] -L-proline A compound that is an amide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete Compounds of the formula In the above formula, X is O and Y is N or X is N and Y is O; R ₁ is (C ₁ -C ₆ ) alkyl, phenyl, or phenyl- (C ₁ -C ₄ ) alkyl unsubstituted or substituted with CH ₃ or CF ₃ ; One of R ₂ and R ₃ is H and the other is (C ₁ -C ₆ ) alkyl; B is -C (O)-; R ₆ is represented by Formulas I to VI Wherein R ' ₂ and R' ₃ are H; R ₁₃ is H, (C ₁ -C ₄ ) alkyl, unsubstituted or monosubstituted phenyl, (C ₁ -C ₄ ) alkoxy, pyridyl, piperidinyl, or 3,4-methylenedioxybenzyl ; R ₁₄ is H, amino or benzyloxycarboxamide; R ₁₅ is H, (C ₁ -C ₄ ) alkyl, halo, (C ₁ -C ₄ ) alkoxy, or di (C ₁ -C ₄ ) alkylamino; W is S). delete delete 124. The composition of claim 124 (2S, 5S) -5-amino-1, 2,4,5,6,7-hexahydroazino- [3,2,1] -indol-4-one-carbonyl- N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S ) -Methylpropyl] acetamide, 2-oxo-5- (4-chlorophenyl) -1,4-benzodiazepine-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2-oxo-5- (4-trifluoromethylphenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] car Carbonyl) -2- (S) -methylpropyl] acetamide, 3- (R, S) -amino-2-oxo-5-phenyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 3- (R, S) -amino-2-oxo-5-phenyl-1,4- (2'-chlorobenzodiazepine) -N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 2-oxo-5-phenyl-1,4- (2'-dimethylaminobenzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide, (R, S) -3-amino-2-oxo-5- (4-chlorophenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, (R, S) -3-amino-2-oxo-5- (2-chlorophenyl) -1,4- (2'-chlorobenzodiazepine) -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, (R, S) -3-benzyloxycarbonylamino-2-oxo-5- (2-chlorophenyl) -1,4- (2'-chlorobenzodiazepine-N- [1- (2- [5- ( 3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 3- (R, S) -amino-2-oxo-5- (2-chlorophenyl) -1,4- (2'-chlorobenzodiazepine-N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 3- (R, S) -amino-2-oxo-5- (2-pyridyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 2-oxo-5- (2-pyridyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2-oxo-5- (4-piperidinyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide, 3- (R, S) -amino-2-oxo-5-methyl-1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, 2-oxo-5- (3,4-methylenedioxyphenyl) -1,4-benzodiazepine-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide, 3- (R, S) -Amino-2-oxo-5-methyl-1, 4- (2 ', 3'-methylenedioxy) -benzodiazepine-N- [1- (2- [5- (3- Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide, or 3- (R, S) -Amino-2-oxo-5-methyl-1, 4- (1-thiophenodiazepine) -N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete Compounds of the formula In the above formula, X is N and Y is O; R ₁ is phenyl- (C ₁ -C ₄ ) alkyl wherein phenyl is unsubstituted or substituted with CH ₃ ; One of R ₂ and R ₃ is H and the other is (C ₁ -C ₆ ) alkyl; B is -C (O)-; R ₆ is represented by the following Chemical Formula 1 <Formula 1> Wherein m is 1 and n is 1; D is valine; A 'is a direct bond; R ₁₄ is phenyl- (C ₁ -C ₄ ) alkyl. delete delete delete 167. The method of claim 167, wherein benzyloxycarbonyl-L-valyl- (1,2,3,4-tetrahydroisoquinoline) -3-N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] amide. delete delete delete Compounds of the formula In the above formula, X is N and Y is O or X is O and Y is N; R ₁ is (C ₁ -C ₆ ) alkyl; Cyclopropyl unsubstituted or substituted with (C ₁ -C ₄ ) alkyl; Phenyl unsubstituted or substituted with (C ₁ -C ₄ ) alkoxy; Pyridyl; Phenyl- (C ₁ -C ₆ ) alkyl wherein phenyl is unsubstituted or substituted by one or more substituents selected from CH ₃ , CF ₃ and OH; Or 3,4-methylenedioxybenzyl unsubstituted or substituted with (C ₁ -C ₄ ) alkyl; One of R ₂ and R ₃ is H and the other is (C ₁ -C ₈ ) alkyl; R ' ₂ and R' ₃ are H; R ₁₁ , R ₁₂ and E together represent a ring structure of Formula I or Ia <Formula I> <Formula Ia> (In the above formula, A is a direct bond or -S (O) ₂ -NH- or -OC (O) NH-; V ₁ and V ₃ are C; V ₂ and V ₄ are independently N or C; R ₁₃ is H or halo; R ₁₄ is H, (C ₁ -C ₄ ) alkyl, amino, or benzyl; W ₁ is S; W ₂ and W ₃ are C); or R ₁₁ , R ₁₂ and E together represent a ring of formula VI or VIa <Formula VI> <Formula VIa> (In the above formula, R ₁₃ is phenyl or benzyl; R ₁₄ is 3,4-ethylenedioxybenzyl or benzyloxycarbonyl); or R ₁₁ , R ₁₂ and E together represent a ring corresponding to formula (IX) <Formula IX> (In the above formula, V is N; U is C (O); Y is NR ₁₃ or C (R ₁₆ ) (R ₁₇ ); R ₁₃ is H or morpholino - (C ₁ -C ₄₎ alkyl; R ₁₆ and R ₁₇ are independently H; (C ₁ -C ₆ ) alkyl; (CH ₂ ) ₂ C (O) OCH ₃ ; Unsubstituted or di (C ₁ -C ₄₎ alkylamino, benzyl or -CH ₂ -C ₁₈ (here, C ₁₈ is a pyridyl or benzo pyrrolidinyl nilim) or substituted by phenyl, or R ₁₆ and R ₁₇ together represent a structure (Wherein Y is C); or R ₁₁ , R ₁₂ and E together are a bicyclic ring corresponding to (In the above formula, W is NR ₁₃ and R ₁₃ is piperidinyl. 175. The compound of claim 175, wherein R ₁₁ , R ₁₂ and E form a ring structure of formula I or Ia. <Formula I> <Formula Ia> In the above formula, A is a direct bond or -S (O) ₂ -NH- or -OC (O) NH-; V ₁ and V ₃ are C; V ₂ and V ₄ are independently N or C; R ₁₃ is H or halo; R ₁₄ is H, (C ₁ -C ₄ ) alkyl, amino or benzyl; W ₁ is S; W ₂ and W ₃ are C. 176. The compound of claim 176, wherein R ₁₁ , R _12, and E combine to form a ring of formula (I). 181. The compound of claim 177, wherein R ₁₄ -A is benzyloxycarboxamide, H ₂ N- or H. 178. The compound of claim 178, wherein R ₁₃ is H or halo. 181. The compound of claim 179, wherein V ₁ , V ₂ and V ₃ are C. 179. 181. The compound of claim 180, wherein V ₄ is N. 182. The method of claim 181, 2-[(6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-pyrid Dill) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-phenyl-1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-phenyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (4-meth Methoxyphenyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-benzyl-1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methyl Benzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethyl-3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethyl-3,4-dihydroxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide; 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4 -Oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α -Dimethyl-3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5- (benzyloxycarbonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [ 5-tert-butyl-1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-methyl-1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-isopropyl-1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-butyl-1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3,4- Oxdiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (tert-butyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3, 4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (tert-butyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] Carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] Carbonyl) -2- (R) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (tert-butyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1,3,4- Oxdiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (tert-butyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (tert-butyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (R) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methyl Cyclopropyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methylcyclopropyl-1,3 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methylcyclopropyl)- 1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (1-methylcyclopropyl) -1,3,4- Oxdiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyridinyl] -N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyridinyl] -N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] carb Carbonyl) -2- (S) -methylpropyl] acetamide; 2- [6-oxo-2-phenyl-1,6-dihydro-1-pyridinyl] -N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4- Oxdiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyridinyl] -N- [1- (2- [5- (3,4- Methylenedioxybenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2-thienyl-1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl) -1, 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (3-methylbenzyl ) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5-tert-butyl-1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; or 2- [5-amino-6-oxo-2- (3-pyridyl) -1,6-dihydro-1-pyrimidinyl] -N- [1- (2- [5- (α, α- Dimethylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. delete delete 177. The compound of claim 177, wherein R ₁ is (α, α) -disubstituted phenyl- (C ₁ -C ₆ ) alkyl; Or 3,4-methylenedioxybenzyl unsubstituted or substituted with (C ₁ -C ₄ ) alkyl. 185. The compound of claim 185, wherein R ₁ is unsubstituted or (α, α) -dimethylbenzyl substituted with CH ₃ , CF ₃ or OH. 186. The compound of claim 186, wherein R ₁₃ is H or halo. 187. The compound of claim 187, wherein R ₁₄ -A is benzyloxycarboxamide, H ₂ N- or H. delete 185. The compound of claim 185, wherein R ₁ is (α, α) -dimethyl-3,4-methylenedioxybenzyl. delete 177. The compound of claim 177, wherein R ₁ is (C ₁ -C ₆ ) alkyl. 192. The compound of claim 192, wherein R ₁ is methyl, isopropyl, isobutyl, n-butyl or tert-butyl. 194. The compound of claim 193, wherein R ₁₃ is H or halo. 204. The compound of claim 194, wherein R ₁₄ -A is benzyloxycarboxamide, H ₂ N- or H. delete 182. The compound of claim 177, wherein A is -S (O) ₂ -NH-. 197. The compound of claim 197, wherein R ₁₄ is (C ₁ -C ₈ ) alkyl. 200. The compound of claim 198, wherein R ₁ is unsubstituted or substituted with (C ₁ -C ₄ ) alkoxy; Pyridyl; And phenyl is phenyl- (C ₁ -C ₆ ) alkyl unsubstituted or substituted by CH ₃ . 201. The composition of claim 199, wherein 2- [5- (methylsulfonyl) amino-6-oxo-2- (4-fluorophenyl) -1,6-dihydro-1-pyrimidinyl] -N- [1 -(2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. 182. The compound of claim 180, wherein V ₄ is C. 182. 178. The compound of claim 177, wherein V ₄ is N. 182. The compound of claim 180, wherein R ₁ is (C ₁ -C ₄ ) alkylcyclopropyl. 203. The compound of claim 203, wherein R ₁ is methylcyclopropyl. 204. The compound of claim 204, wherein R ₁₃ is H or halo. 205. The compound of claim 205, wherein R ₁₄ -A is benzyloxycarboxamide, H ₂ N- or H. delete delete 182. The compound of claim 177, wherein R ₁₁ , R ₁₂ and E form a ring of formula la. 209. The compound of claim 209, wherein W ₁ is S. delete 181. The compound of claim 177, wherein V ₂ is N. 213. The compound of claim 212, wherein V ₁ and V ₃ are C and V ₄ is N. 213. The compound of claim 213, wherein R ₁₄ -A is H or H ₂ N. delete 175. The compound of claim 175, wherein R ₁₁ , R ₁₂ and E form a ring of formula V: <Formula V> Wherein W is S, SO, SO ₂ or C; n is 0 or 1; R ₁₃ is H, (C ₅ -C ₆ ) aryl or (C ₁ -C ₈ ) alkyl, unsubstituted or substituted with halo; R ₁₄ is H, amino, or (C ₁ -C ₈ ) alkylcarboxyamide; G is —NHC (O) —, —OC (O) NH—, —C (O), —S (O) ₂ —NH— or a direct bond. delete delete delete delete 175. The compound of claim 175, wherein R ₁₁ , R ₁₂ and E form a ring of formula VI or VIa. <Formula VI> <Formula VIa> In the above formula, R ₁₃ is phenyl or benzyl; R ₁₄ is 3,4-ethylenedioxybenzyl or benzyloxycarbonyl. delete delete delete 222. The compound of claim 221, wherein 4- [1- (3,4-ethylenedioxybenzyl) -3- (R) -benzylpiperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide, or 2- (R, S)-[6- (methylene-4-pyridyl) piperazine-2,5-dione] -N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide. delete delete delete delete delete delete delete delete delete delete 175. The ring of claim 175, wherein R ₁₁ , R ₁₂ and E are of the formula (IX) <Formula IX> (In the above formula, V is N; U is C (O); Y is NR ₁₃ or C (R ₁₆ ) (R ₁₇ ); R ₁₃ is H or morpholino - (C ₁ -C ₄₎ alkyl; R ₁₆ and R ₁₇ are independently H; (C ₁ -C ₆ ) alkyl; (CH ₂ ) ₂ C (O) OCH ₃ ; Unsubstituted or di (C ₁ -C ₄₎ alkylamino, benzyl or -CH ₂ -C ₁₈ (here, C ₁₈ is a pyridyl or benzo pyrrolidinyl nilim) or substituted by phenyl, or R ₁₆ and R ₁₇ together represent a structure (Wherein Y is C); or R ₁₁ , R ₁₂ and E together are a bicyclic ring corresponding to (In the above formula, W is NR ₁₃ and R ₁₃ is piperidinyl. delete delete delete delete delete delete delete delete 236. 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- (α, α-dimethylbenzyl) -1 , 3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide; 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4-oxadiazolyl] carr Carbonyl) -2- (S) -methylpropyl] acetamide; 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 4- (S)-(2-isobutyl) -2,5-imidazolidinedione-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] carbonyl ) -2- (S) -methylpropyl] acetamide; 4- (R) -isopropyl-2,5-imidazolidinedione-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazazolyl] carbonyl) -2 -(S) -methylpropyl] acetamide; [4- (R, S)-(4-dimethylaminophenyl)]-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3, 4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 4- (R, S) -phenyl-2,5-imidazolidinedione-N- [1- (3- [5- (3-trifluoromethylbenzyl) -1,2,4-oxadiazolyl ] Carbonyl) -2- (S) -methylpropyl] acetamide; [4- (R, S)-(4-pyridyl) -4- (R, S) -N-succinimidyl] -2,5-imidazolidinedione-N- [1- (2- [ 5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; [4- (R, S)-(2-Pyridyl) -4- (R, S) -methyl] -2,5-imidazolidinedione-N- [1- (2- [5- (3 -Methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 4,4-diphenyl-2,5-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadiazolyl] carbonyl) -2 -(S) -methylpropyl] acetamide; 4,4-diphenyl-2,5-imidazolidinedione-N- [1- (2- [5- (3,4-methylenedioxybenzyl) -1,3,4-oxadiazolyl] carr Carbonyl) -2- (S) -methylpropyl] acetamide; 4- (R)-(3-Indolylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5-tert-butyl-1,3,4-oxadiazolyl] carr Carbonyl) -2- (S) -methylpropyl] acetamide; 4- (R)-(3-Indolylmethyl) -2,5-imidazolidinedione-N- [1- (2- [5- (α, α-dimethylbenzyl) -1,3,4- Oxdiazolyl] carbonyl) -2- (S) -methylpropyl] acetamide; 1- (N-morpholinoethyl) -5- (R) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; 1- (N-morpholinoethyl) -5- (R, S) -phenyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1 , 3,4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; 1- (N-morpholinoethyl) -5- (S) -benzyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3 , 4-oxadiazolyl] carbonyl) -2- (R, S) -methylpropyl] acetamide; or 5- (R, S) -phenyl-1-methyl-2,4-imidazolidinedione-N- [1- (2- [5- (3-methylbenzyl) -1,3,4-oxadia Zolyl] carbonyl) -2- (S) -methylpropyl] acetamide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete A pharmaceutical composition comprising an effective amount of a compound of claims 5, 58, 70, 124, 167 or 175 is administered to a host, except a person in need of inhibiting one or more serine proteases. Method of inhibiting the serine protease comprising a. 299. The method of claim 298, wherein the at least one serine protease is elastase. 299. The method of claim 299, wherein the at least one elastase is human neutrophil elastase. delete A pharmaceutical composition for inhibiting at least one serine protease comprising at least one compound of claims 5, 58, 70, 124, 167 or 175 and a pharmaceutically acceptable carrier. 302. The pharmaceutical composition of claim 302, wherein the at least one serine protease is elastase. 303. The pharmaceutical composition of claim 303, wherein the at least one elastase is human neutrophil elastase.