KR100478324B1 - Interleukin-1beta Converting Enzyme Inhibitor - Google Patents

Abstract

The present invention relates to a novel type of compound that is an iterucine-1β converting enzyme (ICE) inhibitor. The ICE inhibitor of the present invention is characterized by specific structural and physicochemical properties. The present invention also relates to a pharmaceutical composition comprising the compound. The compounds and pharmaceutical compositions of the present invention in particular inhibit ICE activity and consequently can be usefully used as agents for interleukin-1 mediated diseases including inflammatory diseases, autoimmune diseases and neurodegenerative diseases. The present invention also relates to methods of inhibiting ICE activity and methods of treating interleukin-1 mediated diseases using the compounds and compositions of the invention.

Description

Interleukin-1beta Converting Enzyme Inhibitor

The following detailed description is set forth in order that the present invention may be better understood.

Applicants have found that compounds having a combination of the following novel features have surprising effects as ICE inhibitors:

(a) each of the first and second binding moieties can form hydrogen bonds with various backbone bond atoms of the interleukin-1β converting enzyme (ICE), wherein the backbone atoms are carbonyl oxygen of Aur-341, Arg A first hydrogen bond portion and a second bond portion selected from the group consisting of an amide -NH- group of -341, a carbonyl oxygen of Ser-339, and an amide -NH- group of Ser-339;

(b) When the ICE inhibitor is bound to ICE, each of the first intermediate hydrophobic portion and the second intermediate hydrophobic portion may be bound to a separate binding pocket of the ICE, wherein the binding pocket is a P2 binding pocket, a P3 binding pocket, a P4 binding A first intermediate hydrophobic portion and a second intermediate hydrophobic portion selected from the group consisting of a pocket and a P 'binding pocket; And

(c) an electron comprising one or more electronegative atoms, wherein the electronegative atoms are bonded to the same or neighboring atoms in the electronegative moiety and are capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of the ICE Contains the voice part.

Any intermediate hydrophobic moiety that engages the P2 binding pocket of ICE

a) the distance between the carbonyl oxygen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P2 binding pocket is from about 7.1 kPa to about 12.5 kPa,

b) the distance between the amide nitrogen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P2 binding pocket is between about 6.0 kPa and about 12 kPa,

c) The distance between the carbonyl oxygen of Ser-339 of the ICE at the center of mass of the intermediate hydrophobic portion in the P2 binding pocket is preferably between about 3.7 kPa and about 9.5 kPa.

Any intermediate hydrophobic moiety that combines with the P3 binding pocket of ICE

a) the distance between the carbonyl oxygen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P3 binding pocket is from about 3.9 kPa to about 9.5 kPa,

b) the distance between the amide nitrogen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P3 binding pocket is between about 5.4 kPa and about 11 kPa

c) The distance between the carbonyl oxygen of Ser-339 of the ICE at the center of mass of the middle hydrophobic portion in the P3 binding pocket is preferably about 7.0 kPa to about 13 kPa.

Any intermediate hydrophobic moiety that engages the P4 binding pocket of ICE

a) the distance between the carbonyl oxygen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P4 binding pocket is about 4.5 kPa to about 7.5 kPa,

b) the distance between the amide nitrogen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P4 binding pocket is from about 5.5 kPa to about 8.5 kPa,

c) The distance between the carbonyl oxygen of Ser-339 of the ICE at the center of mass of the intermediate hydrophobic portion in the P4 binding pocket is preferably about 8 kPa to about 11 kPa.

Any intermediate hydrophobic portion that engages the P 'binding pocket of the ICE

a) the distance between the carbonyl oxygen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P 'binding pocket is from about 11 kPa to about 16 kPa

b) the distance between the amide nitrogen of Arg-341 of the ICE at the center of mass of the intermediate hydrophobic portion in the P 'binding pocket is from about 10 kPa to about 15 kPa

c) The distance between the carbonyl oxygen of Ser-339 of the ICE at the center of mass of the intermediate hydrophobic portion in the P 'binding pocket is preferably about 8 kPa to about 12 kPa.

More preferably all of the above bonding conditions are suitable for the compounds of the present invention. Those skilled in the art are aware that there are several ways to design the inhibitors of the present invention. Candidate compounds for screening as ICE inhibitors can be selected using the same means as described above. The design or selection can be initiated by selecting various parts to fill the binding pocket.

There are several ways to select the part that fills each joining pocket. Examples include visual inspection of physical or computer models of active sites and manual docking of models of selected portions into various binding pockets. Modeling software known and available in the art can be used. Examples include QUANTA [Molecla simulation, Inc., Burlington, Mass., 1992], SYBYL [Molecla Modeling Software, Triforce Associates, Inc., St. Louis, Missouri, 1992] , AMBER [SJ Weiner, PA kollman, DA Case, UC Singh, C. Ghio, G. Alagona and P. Weiner, J. Am. Chem. Soc. , vol. 106, 765-784 (1984)] or CHARMM [BR Brooks and RE Bruccoleri, BD Olafson, DJ States, S. Swaminathan and M. Karplus, J. Comp. Chem. , vol. 4, pages 187-217 (1983). The modeling step is accomplished by energy minimization using standard molecular dynamic force fields such as CHARMM and AMBER. In addition, there are many more refined computer programs that assist the method of selecting the binding pocket of the present invention. Examples of this are as follows:

GRID [Goodford, PJ A Computational Procedure for Determining Energetlcally Favorable Binding Sites on Biologically Important Macromolecules. J. Med. Chem ., 28, 849-885 (1985). GRID is available from Oxford University in Oxford, UK.

2. MCSS [Miranker, A.; Karplus, M. Functionality Maps of Binding Sites: A Multiple Copy Simultaneous Search Method. Proteins: Structure, Function and Genetics, 11, 29–34 (1991)]. MCSS is available from Molecla Simulations in Burlington, Massachusetts.

3. AUTODOCK [Goodsell, DS; Olsen, AJ Automated Docking of Substrates to Proteins by Simmulated Annealing. PROTEINS; Structure, Function and Genetics, 8, pp. 195-202 (1990)]. AUTODOCK is available from Scripps Research Institute, La Jolla, California.

4. DOCK [Kuntz, ID; Blaney, JM; Oatley, SJ; Langridge, R .; Ferrin, TE A Geometric Approach to Macromolecule-Ligand Interactions. J. Mol. Biol ., 161, pages 269-288 (1982). DOCK is available from the University of California, San Francisco, California.

Once the appropriate binding moiety is selected, it can be assembled into a single inhibitor. The assembly can be accomplished by connecting various parts to the central scaffold. The assembly method can be implemented, for example, by visual modeling followed by manual model building, again by software such as Quanta or Sybyl. You can also choose how to connect the various parts using a number of different programs. Examples of these are:

1. CAVEAT [Bartlett PA; Shea, GT; Telfer, SJ; Waterman, S. CAVEAT: A Program to Facilitate the Structure-Derived Design of Biologically Active Molecules. In "molecular Recognition in Chemical and Biological Problem," Special Publication, Royal Chem. Soc ., 78, 182-196 (1989). CAVEAT is available from the University of California, Berkeley, California.

2. 3D database systems such as MACCS-3D (MDL Information Systems, Inc., Lindo, CA). This area has recently been described by Martin [Martin, YC 3D Database Searchlng in Drug Design, J. Med. Chem ., 35, 2145-2154 (1992)].

3. HOOK [available at Molecla simulation in Burlington, Massachusetts, USA].

In addition to computer-assisted modeling of such inhibitor compounds, the inhibitors of the present invention can be “restructured” using those that additionally comprise a co-active site or a specific site of a known inhibitor. Such methods are known in the art. Examples of these are:

1.Budi, HJ The Computer Program LUDI: A New Method for the De Novo Design of Enzyme Inhibitors. J. Comp. Aid. Molec. Design., 6, pages 61-78 (1992)]. LUDI is available from BioSim Technologies, San Diego, California.

2. LEGEND [Nishibata, Y, Itai, A, Tetrahedron , 47, 8985 (1991)]. LEGEND is available from Molecla Simulations in Burlington, Massachusetts.

3 LeapFrog [available at Triforce Associates, St. Louis, Missouri].

Many techniques commonly used in modeling drugs can be used [Ref. Cohen, NC; Blaney, JM; Humblet, C, Gund, P .; Barry, DC, "Molecular Modeling Software and Methods for Medicinal Chemistry", J. Med, Chem ,, 33, 883-894 (1990)]. Similarly, there are several examples of chemistry references in the technology that can be applied to specific drug design projects. See Navia, MA and Murcko, MA, "The Use of Structural Information in Drug Design", Current Opinions in Structural Biology , 2, 202-210 pages (1992). Some examples of such specific applications are the following references. References [Baldwin, JJ et al., “Thienothiopyran-2-sulfonamides: Novel Topically Active Carbonic Anhydrase Inhibitors for the Treatment of Glaucoma”, J. Med. Chem ., 32, 2510-2513 (1989), Appelt, K. et al., "Design of Enzyme Inhibitors Using Iterative Protein Crystallographic Analysis", J. Med. Chem ., 34, 1925-1934 (1991); And Ealick, SE et al., "Application of Crystallographic and Modeling Methods in the Design of Purine Nucleotide Phosphorylase Inhibitors", Proc. Nat. Acad. Sci USA, 88, 11540-11544 (1991)].

The novel combination of steps of the present invention eliminates the time consuming and expensive experimentation by those skilled in the art to determine the enzyme inhibitory activity of a particular compound. The method is also useful for promoting the rational design of therapeutic and prophylactic agents for ICE inhibitors and IL-1 mediated diseases. Thus, the present invention relates to such inhibitors.

Various conventional techniques can be used to perform the respective assessments as well as the assessments necessary to screen candidate compounds for ICE inhibitory activity. In general, the technique includes determining the position and binding proximity of a given moiety, the filled space of the bound inhibitor, the binding strain energy and the electrostatic interaction energy of a given compound. Dynamics, molecular dynamics, molecular dynamics, Monte Carlo sampling, phylogenetic investigation and distance geometrical methods [GR Marshall, Ann. Ref. Pharmacol. Toxicol, 27, p. 193, (1987). Specific computer software has been developed for use in practicing the method. Examples of programs designed for such applications include Gaussian 92, Revision E.2 [MJ Frisch, Gaushan Incopo, Pittsburgh, Pa.]. Rated, ^© 1993; Amber, version 4.0 [PA Kollman, University of California, San Francisco, USA, ^© 1993]; QUANTA / CHARMM [Molecula Simulations, Inc., Burlington, Mass., ^© 1992]; Insight II / Discover [deer during a bio-Calif San Diego Technologies Inco's Va'a-o-federated, ^ⓒ 1992] a. The program can be executed using, for example, a Silicon Graphics Indigo 2 Workstation or IBM RISC / 6000 Workstation Model 550. Other hardware systems or software packages are known and are readily available to those skilled in the art.

According to the present invention, various types of active ICE inhibitors can interact in a manner similar to the various binding pockets of the ICE active site. The spatial arrangement of this important group is often referred to as the stage of drug action. The concept of drug action-generating action groups is described in D, Mayer, CB Naylor, I. Motoc and GR Marshall, J. Comp. Aided Molec. Design vol. 1, pages 3-16 (1987); A. Hopfinger and BJ Burke, Concepts and Applications of Molecular Similarity, MA Johnson and GM Maggiora, Welly (1990).

In addition, various types of ICE inhibitors of the invention may use different scaffolds or core structures, but all such cores may be located within the active site to obtain the specificity interactions essential for binding. The compound is defined as the term for the occurrence of drug action, ie the ability to harmonize structural confirmation of the shape and properties of the active site of the ICE.

One embodiment of the present invention, an ICE inhibitor comprises first and second hydrogen bonding moieties, first and second intermediate hydrophobic moieties and electronegative moieties covalently bonded to one of the scaffolds selected from formulas (I) to (VI) :

Formula I

Formula I I

Formula I I I

Formula IV

Formula V

Formula VI

Formula VI I

Wherein each X is independently C or N;

Z is CO or SO ₂ ;

Each Wl is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain being bonded two ends covalently bonded to two different atoms via r;

Each W ₂ is a straight chain comprising 3 to 5 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, Two ends covalently bonded to two different atoms via bond r;

Each W ₃ is a straight chain comprising 2 to 4 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, Two ends covalently bonded to two different atoms via bond r;

Each W ₄ is a straight chain comprising 1 to 2 covalent bonds independently selected from the group consisting of C, N, S and O, the covalent bonds between which are independently saturated or unsaturated; Two ends covalently bonded to two different atoms via bond r;

Each W ₅ is a straight chain comprising 4 to 6 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, Two ends covalently bonded to two different atoms via bond r;

each bond represented by r is independently a single bond or a double bond;

H is a first hydrogen bond moiety, Z is a second hydrogen bond moiety, each of the first intermediate hydrophobic portion and the second intermediate hydrophobic portion is covalently bonded to the scaffold, and the electronegative portion is covalently bonded to the scaffold do.

Another embodiment (A) of the present invention, the ICE inhibitor is a compound having the formula

Formula α

Wherein X ₁ is CH or N;

g is 0 or 1;

Each J is independently selected from the group consisting of —H, —OH, and —F, provided that the first and second Js are bonded to C, and wherein the first J is —OH, the second J is -H,

m is 0, 1 or 2;

T is any isoelectronic array replacement in place of -Ar ₃ , -OH, -CF ₃ , -CO-CO ₂ H, -CO ₂ H or -CO ₂ H;

R ₁ is selected from the group consisting of the following formulas (a) to (t) and (v), and any ring is selected from any carbon by Q ₁ and from any nitrogen by R ₅ = O, —OH , -CO ₂ H can be monosubstituted or multiply substituted at any atom with halogen, and any saturation ring can be optionally unsaturated at one or two bonds:

[Formula a]

[Formula b]

[Formula c]

[Formula d]

[Formula e]

[Formula f]

[Formula g]

[Formula h]

[Formula i]

[Formula j]

[Formula k]

[Formula 1]

[Formula m]

[Formula n]

[Formula o]

[Formula p]

[Formula q]

[Formula r]

[Formula s]

[Formula t]

[Formula v]

R ₂₀ is represented by the following formulas (aa1), (aa2), (aa3), (aa4), (aa5), (bb), (cc), (dd), (ee), (ff), (gg), ( gga), (ggb) and (ggc) are selected from the group consisting of:

[Formula aa1]

[Formula aa2]

[Formula aa3]

Formula aa4.

[Formula aa5]

[Formula bb]

[Formula cc]

[Formula dd]

[Formula ee]

Formula ff

[Formula gg]

Formula gga

[Formula ggb]

Formula ggc

Each ring C is independent from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl and cyclohexyl Is selected;

R ₃ is -CN, -CH = CH-R ₉ , -CH = NOR ₉ ,-(CH ₂ ) _1-3 -T ₁ -R ₉ , -CJ ₂ -R ₉ , -CO-R ₁₃ or

Is;

Each R ₄ is independently selected from the group consisting of -H, -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ;

Each R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ , And

Independently selected from the group consisting of;

R ₆ and R ₇ together form a saturated 4-8 membered carbocyclic ring or heterocyclic ring comprising -O-, -S- or -NH- or R ₇ is -H and R ₆ is- H, -Ar ₁ , -R ₉ or-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O, optionally substituted with one or two Ar ₁ ;

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Each R ₁₃ is independently selected from the group consisting of -Ar ₂ and -R ₄ ,

Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzo fused, 5 Containing from 15 ring atoms and from 1 to 3 rings, and containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally comprising one or more aromatic rings, optionally mono- or multi-substituted with ═O, —OH, perfluoroC ₁ -C ₃ alkyl or —Q ₁ Cyclic groups;

Each Ar ₂ is independently selected from formulas (hh)-(kk), wherein any ring may be optionally substituted by -Q ₁ :

[Formula hh]

[Formula ii]

[Formula jj]

[Formula kk]

Ar ₃ is a phenyl ring, a 5-membered heteroaromatic ring and 6 containing 1 to 3 heteroatomic groups selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- A cyclic group selected from the group consisting of -membered heteroaromatic rings and optionally mono- or polysubstituted with = 0, -OH, halogen, perfluoro C ₁ -C ₃ alkyl or -CO ₂ H;

Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ,

However, when -Ar ₁ is substituted with a Q ₁ is a group -Ar ₁ comprising one or more additional, -Ar ₁ of the addition is not substituted with Q _1;

Each X is independently selected from the group consisting of = N- and = CH-;

Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —;

Each X ₃ is independently selected from the group consisting of —CH ₂ —, —S—, —SO—, and —SO ₂ —;

Each X ₄ is independently selected from the group consisting of —CH ₂ — and —NH—;

Each X ₅ is And Independently selected from the group consisting of;

X ₆ is N or -CH-, however, and X ₆ is N in the R ₁ group of display (o), and X ₅ are CH, X ₂ is a CH _2, display (o) ring of the group R ₁ Must be substituted with Q ₁ or benzo fused;

Each Y is independently selected from the group consisting of -O- and -S-;

Each Z is independently CO or SO ₂ ;

Each a is independently 0 or 1;

Each c is independently 1 or 2;

Each d is independently 0, 1 or 2,

Each e is independently 0, 1, 2 or 3;

Another embodiment (B) of the invention is an ICE inhibitor is a compound having the formula

Formula α

X ₁ is -CH;

g is 0 or 1,

Each J is independently selected from the group consisting of —H, —OH, and —F, provided that the first and second Js are bonded to C, and wherein the first J is —OH, the second J is -H;

m is 0, 1 or 2;

T is any isoelectric array substitution instead of -OH, -CO-CO ₂ H, -CO ₂ H or -CO ₂ H;

R ₁ is selected from the group consisting of the following formulas (a) to (t) and (v) to (y), and any ring is selected from any carbon by Q ₁ , from any nitrogen by R ₅ = It may be mono substituted or multi substituted at any atom by O, —OH, —CO ₂ H or halogen, and any saturated ring may be optionally unsaturated at one or two bonds:

[Formula a]

[Formula b]

[Formula c]

[Formula d]

[Formula e]

[Formula f]

[Formula g]

[Formula h]

[Formula i]

[Formula j]

[Formula k]

[Formula l]

[Formula m]

[Formula n]

[Formula o]

[Formula p]

[Formula q]

[Formula r]

[Formula s]

[Formula t]

[Formula v]

[Formula w]

[Formula x]

[Formula y]

R ₂₀ is represented by the following formulas (aa1), (aa2), (aa3), (aa4), (aa5), (bb), (cc), (dd), (ee), (ff), (gg), ( gga), (ggb) and (ggc) are selected from the group consisting of:

[Formula aa1]

[Formula aa2]

[Formula aa3]

Formula aa4.

[Formula aa5]

[Formula bb]

[Formula cc]

[Formula dd]

[Formula ee]

Formula ff

[Formula gg]

Formula gga

[Formula ggb]

Formula ggc

Each ring C is independent from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl and cyclohexyl Is selected;

R ₃ is -CN, -CH = CH-R ₉ , -CH = N-0-R ₉ ,-(CH ₂ ) _1-3 -T ₁ -R ₉ , -CJ ₂ -R ₉ , -CO-R ₁₃ or

Is,

Each R ₄ is independently selected from the group consisting of -H, -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ,

Each R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -CO-NH _2- , -SO ₂ -NH _2- , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ , And

Independently selected from the group consisting of;

R ₆ and R ₇ together form a saturated 4-8 membered carbocyclic ring or heterocyclic ring comprising —O—, —S— or —NH— or R ₇ is —H, and R ₆ is — H, -Ar ₁ , -R ₉ or-(CH ₂ ) _1,2,3 -T ₁ -R ₉ or α-amino acid side chain residues;

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with one or two Ar ₁ groups;

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Each of R ₁₃ is -Ar ₂ , -R ₄ and Independently selected from the group consisting of;

Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzo fused, 5 Containing from 15 to 15 ring atoms and from 1 to 3 rings, at least one heteroatom group selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH-; Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally comprising one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN , = O, -OH, perfluoro C ₁ -C ₃ alkyl, Or a cyclic group optionally substituted with single or multiple substituents with -Q ₁ ;

Each Ar ₂ is independently selected from formulas (hh)-(kk), wherein any ring may be optionally substituted by -Q ₁ and -Q ₂ and optionally substituted by:

[Formula hh]

[Formula ii]

[Formula jj]

[Formula kk]

Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -O-Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each Q ₂ is -OH, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN, -CF ₃ and Independently selected from the group consisting of;

However, when -Ar ₁ is substituted with a Q ₁ group which comprises one or more additional -Ar ₁ of, -Ar ₁ groups of said addition is not substituted with Q _1,

Each X is independently selected from the group consisting of = N- and = CH-,

Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —;

Each X ₃ is independently selected from the group consisting of —CH ₂ —, —S—, —SO—, and —SO ₂ —;

Each X ₄ is independently selected from the group consisting of —CH ₂ — and —NH—;

Each X ₅ is And Independently selected from the group consisting of;

X ₆ is -CH- or N,

However, and X ₆ is (o) N a R _1-flight labeled, X ₅ is CH, X ₂ is a case CH ₂ days, the ring of the R ₁ group labeled (o) is substituted with Q ₁ or benzo be fused To;

Each Y is independently selected from the group consisting of -O-, -S- and -NH;

Each Z is independently CO or SO ₂ ;

Each a is independently 0 or 1;

Each c is independently 1 or 2,

Each d is independently 0, 1 or 2;

Each e is independently 0, 1, 2 or 3;

Provided that when R ₁ is (f), R ₆ is an α-amino acid side chain residue and R ₇ is —H, formulas (aa1) and (aa2) should be substituted with Q ₁ ;

R ₁ is (o), g is 0, J is -H, m is 1, R ₆ is an α-amino acid side chain residue, R ₇ is -H, X ₂ is -CH _2- , X ₅ is Where X ₆ is R ₃ is Or -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar ₁ , -CH ₂ -S-Ar ₁ Or -R ₄ , wherein -R ₄ is -H, the ring of the R ₁ (o) group must be substituted with Q ₁ or benzo fused;

Provided that R ₁ is (w), g is 0, J is -H, m is 1, T is -CO ₂ H or -CO-NH-OH, X ₂ is 0, and R ₅ is When benzyloxycarbonyl is ring C is benzo, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-Ar ₁ , and Ar ₁ is 1-phenyl-3-chloro- or 3-trifluoromethylpyrazol-5-yl, or R ₁₃ is -CH ₂ -O-CO-Ar ₁ , and Ar 2 is 2,6-dichlorophenyl.

Preferred forms (a) of the R ₁ groups for embodiments A and B are of the formulas (a1) and (a2):

[Formula a1]

[Formula a2]

Preferred forms (b) of the R ₁ group are the following formulas (b1) to (b3):

[Formula b1]

[Formula b2]

[Formula b3]

Preferred forms (c) of the R ₁ group are the formulas (c1) and (c2):

[Formula c1]

[Formula c2]

Provided that R ₁ is formula (c1), g is 0, J is -H, m is 1, T is -CO ₂ H, X is N, and R ₅ is benzyloxycarbonyl; When R ₆ is -H, R ₃ is not -CO-R _13, wherein R ₁₃ is -CH ₂ -O-Ar ₁ and Ar ₁ is chlorosubstituted 1-phenyl-3-trifluoromethylpyra Sol-5-yl or R ₁₃ is -CH ₂ -O-CO-Ar ₁ and Ar ₁ is 2,6-dichlorophenyl, and the 2-position of the scaffold ring is substituted with p-fluorophenyl.

Preferred forms (d) of the R ₁ group are the following general formulas (d1) to (d4):

Formula d1]

[Formula d2]

[Formula d3]

[Formula d4]

Preferred forms (e) of the R ₁ group are the following formulas (e1) to (e9):

[Formula e1]

[Formula e2]

[Formula e3]

[Formula e4]

[Formula e5]

[Formula e6]

[Formula e7]

It is optionally benzo fused

[Formula e8]

[Formula e9]

When R ₁ is formula (e4), g is 0; J is -H; m is 1; T is -CO ₂ H and R ₅ is benzyloxycarbonyl; if c is 1,

R ₃ is not —CO—R _13, wherein R ₁₃ is —CH ₂ —O-Ar ₁ and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazol-5-yl, wherein the phenyl is chlorine Optionally substituted with atoms), or R ₁₃ is -CH ₂ -O-CO-Ar ₁ and Ar ₁ is 2,6-dichlorophenyl, and the 2-position of the scaffold ring is substituted with p-fluorophenyl;

R ₁ is formula (e7); g is 0; J is -H; m is 1; T is -CO ₂ H or -CO-NH-OH, R ₅ is a protecting group for the N atom of the amino acid side chain residues, and when each c is 1, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar ₁ or -CH ₂ -S-Ar ₁ .

Preferred forms (g) of the R ₁ group are the formulas (g1) and (g2):

[Formula g1]

[Formula g2]

Preferred forms (h) of the R ₁ group are the following formulas (h1) to (h3):

[Formula h1]

[Formula h2]

[Formula h3]

Preferred forms (i) of the R ₁ group are the following general formulas (i1) to (i4):

[Formula i1]

[Formula i2]

[Formula i3]

[Formula i4]

Preferred forms (j) of the R ₁ group are the following formulas (j1) to (j4):

[Formula j1]

[Formula j2]

[Formula j3]

[Formula j4]

Preferred forms (k) of the R ₁ group are the following formulas (k1) to (k5):

[Formula k1]

[Formula k2]

[Formula k3]

[Formula k4]

[Formula k5]

Preferred forms (L) of the R ₁ group are of the general formula (L1)-(L5):

[Formula 1]

[Formula 1]

[Formula 1]

[Formula 1]

[Formula 1]

Preferred forms (m) of the R ₁ group are the following formulas (m1) to (m6):

[Formula m1]

[Formula m2]

[Formula m3]

[Formula m4]

[Formula m5]

[Formula m6]

Preferred forms (n) of the R ₁ group are the following formulas (nl) to (n6):

[Formula n1]

[Formula n2]

[Formula n3]

[Formula n4]

[Formula n5]

[Formula n6]

Preferred forms (o) of the R ₁ group are the following formulas (o1) to (o5):

[Formula o1]

[Formula o2]

[Formula o3]

[Formula o4]

[Formula o5]

A preferred form (o) of the R ₁ group of embodiment B is of the formula (o6):

[Formula o6]

Wherein X ₂ is —O—, —S—, —SO ₂ — or —NH—.

Preferred forms (p) for embodiments A and B are of the formulas (p1) to (p5):

[Formula p1]

[Formula p2]

[Formula p3]

[Formula p4]

[Formula p5]

Preferred forms (q) of the R ₁ group are the following general formulas (q1) to (q6):

[Formula q1]

[Formula q2]

[Formula q3]

[Formula q4]

[Formula q5]

[Formula q6]

Preferred forms (r) of the R ₁ group are the following formulas (r1) to (r7):

[Formula r1]

[Formula r2]

[Formula r3]

[Formula r4]

[Formula r5]

[Formula r6]

[Formula r7]

Preferred forms (s) of the R ₁ group are the following formulas (s1) to (s4):

[Formula s1]

[Formula s2]

[Formula s3]

[Formula s4]

Preferred forms (t) of the R ₁ group are the following formulas (t1) to (t5):

[Formula t1]

[Formula t2]

[Formula t3]

[Formula t4]

[Formula t5]

Preferred forms (v) of the R ₁ group are the following general formulas (v1) to (v4):

[Formula v1]

[Formula v2]

[Formula v3]

[Formula v4]

Preferred form (w) of the R ₁ group of embodiment B is of the formula (w1):

[Formula w1]

Wherein X ₂ is —O—, —S—, —SO ₂ — or —NH—.

Preferred compounds of embodiments A and B of the present invention are compounds of formula α, X ₁ is CH, g is 0, J is -H, m is 0 or 1, T is -Ar ₃ , -CO Any isoelectronic array substitutions instead of -CO ₂ H, -CO ₂ H, or -CO ₂ H, or

Or m is 1 or 2 and T is -OH, -CF ₃ or -CO ₂ H;

More preferably m is 1 and T is -CO ₂ H;

R ₁ is the following formulas (c) to (g) and (r):

Formula c

Formula d

Chemical formula e

Formula f

Chemical formula g

Formula r

R ₂₀ is of the formula (aa1), (aa2), (aa3) or (dd):

Chemical formula aa1

Chemical formula aa2

Chemical formula aa3

Chemical formula dd

Ring C is benzo;

R ₃ is -CO-R ₁₃ or Is;

Most preferably, R ₃ is 1) -CO-Ar ₂ , 2) -CO-R ₉ , wherein R ₉ is C ₃ -C substituted with one Ar ₁ itself substituted with two Ar ₁ or Ar ₁ groups ₆ alkyl group, -C ₁ -C ₂ -Ar ₁ , -C ₁ , -CH ₃ or -CF ₃ ), or 3)-(CH ₂ ) _1,2 -T ₁ -R ₉ , wherein T ₁ is- is O- or -S-, R ₉ is a two Ar ₁ or Ar ₁ group of the self-one substituted with Ar ₁ substituted C ₁ -C _{2 alkyl, C 1 -C 2 -Ar 1,} -C 1, - CH ₃ or -CF ₃ ;

R ₄ is -H or -R ₉ ,;

T ₁ is —O—, —S—, —CO—, —O—CO—, or —SO ₂ —;

When R ₁ is (a), (b), (k) or (m), R ₅ is preferably -Ar ₁ or C ₁ -C ₄ -Ar ₁ ;

When R ₁ is (c), (e), (f), (o) or (r), R ₅ is -SO ₂ -Ar ₁ , -SO ₂ -R ₉ or -CO-C ₁ -C ₄ Preferably is -Ar ₁ ;

R ₇ is -H and R ₆ is C ₁ -C ₄ -Ar ₁ ;

R ₁₀ is —H or C ₁ -C ₃ straight or branched alkyl;

R ₁₃ is -Ar ₂ ;

Ar ₁ is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzooxazolyl, 2-indanyl or indolyl;

Ar ₂ is preferably substituted with -Ar ₁ or -C ₁ -C ₄ -Ar ₁ ;

Ar ₃ is phenyl, thiophene, thiazole, pyridine or oxazole;

Q ₁ is —R ₉ or — (CH ₂ ) _1,2 -T _1- (CH ₂ ) _1.3 -Ar ₁ , wherein T ₁ -is —O— or —S—.

In connection with a CIP application, the applicant prefers the compound of embodiment B of the compound of the invention using the general formula α, wherein X ₁ is -CH, g is 0, J is -H, and m is 0 or 1, T is any isoelectronic array substitution instead of -CO-CO ₂ H or -CO ₂ H or m is 1 and T is -CO ₂ H;

R ₁ is selected from the group consisting of the following formulas (a) to (h), (o), (r), (w), and any ring is selected from any carbon by Q ₁ , and optionally selected from R ₅ In nitrogen, it may be mono-substituted or multi-substituted at any atom with ═O, —OH, —CO ₂ H or halogen, and (e) is optionally benzo fused:

Formula a

Formula b

Formula c

Chemical formula e

Formula f

Chemical formula g

Formula h

Formula 0

 Formula r

Chemical formula w

R ₂₀ is of the formula (aa1) or (aa2), wherein C is 1:

Chemical formula aa1

Chemical formula aa2

Ring C is banjo optionally substituted with -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -C ₁ , -F or -CF ₃ ;

R ₃ is -CO-R ₁₃ or Is;

More preferably, R ₃ is 1) -CO-Ar ₂ , 2) -CO-R ₉ , wherein R ₉ is C ₁ -C ₅ alkyl substituted with Ar ₁ or 3) -CH ₂ -T ₁ -R ₉ , wherein T ₁ is -O- or -S- and R ₉ is C ₁ -C ₂ alkyl substituted with one Ar ₁ group;

R ₄ is -H or -R ₉ ;

T ₁ is —O—, —S—, —CO—, —O—CO—, or —SO ₂ —;

When R ₁ is (a) or (b), R ₅ is preferably -H;

When R ₁ is (c), (e), (f), (o), (r), (w), (x) or (y), R ₅ is -CO-Ar ₁ , -SO _2- Ar ₁ , -CO-NH ₂ , -CO-NH-Ar ₁ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ or -CO-NH-R ₉ is preferable;

R ₇ is -H and R ₆ is -H, -R ₉ or -Ar ₁ ;

R ₉ is a C ₁ -C ₆ straight or branched chain alkyl group optionally substituted with ═O and optionally substituted with —Ar ₁ group;

R ₁₀ is —H or a C ₁ -C ₃ straight or branched alkyl group;

R ₁₃ is -H, -R ₉ , -Ar ₂ or -CH ₂ -T ₁ -R ₉ ;

When -Ar ₂ is formula (hh) and formula (hh) is -C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -NH-C ₁ -C ₆ alkyl, -N- (C ₁ -C ₆ alkyl) ₂ , -SC ₁ -C ₆ alkyl, -C ₁ , -F, -CF ₃ or More preferably, mono- or polysubstituted;

Ar ₁ is —OC ₁ -C ₃ alkyl, -NH-C ₁ -C ₃ alkyl, -N- (C ₁ -C ₃ alkyl) ₂ , -Cl, -F, -CF ₃ , -C ₁ -C ₃ Alkyl or Substituted phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzooxazolyl, 2-indanyl or indolyl;

Ar ₂ is preferably of formula (ii), (ii) or (kk):

Formula ii

Chemical formula jj

Chemical formula kk

Each X is independently selected from the group consisting of = N- and = CH-;

Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —;

Each X ₅ is And Independently selected from the group consisting of;

X ₆ is or Is,

Z is C═O;

Provided that when R ₁ is (f), R ₆ is an α-amino acid side chain residue and R ₇ is —H, formulas (aa1) and (aa2) should be substituted with Q ₁ ;

R ₁ is (o), g is 0, J is -H, m is 1, R ₆ is an α-amino acid side chain residue, R ₇ is -H, X ₂ is -CH _2- , X ₅ is Where X ₆ is R ₃ is

Or -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar ₁ , -CH ₂ -S- When Ar ₁ or —R ₄ , wherein —R ₄ is —H, the ring of the R ₁ (o) group must be substituted with Q ₁ or benzo fused;

R ₁ is (w), g is 0, J is -H, m is 1, T is -CO ₂ H, X ₂ is 0, R ₅ is benzyloxycarbonyl, and ring C is If benzo, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-Ar ₁ , and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazol-5-yl ( Wherein phenyl is optionally substituted with a chlorine atom) or R ₁₃ is -CH ₂ -O-CO-Ar ₁ and Ar ₁ is 2,6-dichlorophenyl.

Preferred form of R ₁₃ is —CH ₂ —OR ₉ , wherein R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with ═O and optionally substituted with Ar ₁ ;

Another preferred form of R ₁₃ is CH ₂ -SR ₉ , wherein R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with Ar ₁ ;

Another preferred form of R ₁₃ is CH ₂ -OR ₉ , wherein R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with Ar ₁ ;

Another preferred form of R ₁₃ is H.

A more preferred form (a) of the R ₁ group is of formula a ₂ , optionally substituted with Q ₁ , and is of formula a2

Wherein R ₅ is -H and R ₇ is -H; Z is C═O;

A more preferred form (b) of the R ₁ group is the formula b, optionally substituted with Q ₁ :

Formula b

Wherein R ₅ is -H and R ₇ is -H; Z is C═O;

More preferred forms (c) of the R ₁ group are of the formulas c1 and c2:

Chemical Formula c1

Chemical formula c2

Provided that R ₁ is (c1); g is 0, J is -H and m is 1; T is -CO ₂ H and X is N; R ₅ is benzyloxycarbonyl; When R ₆ is -H, R ₃ is not -CO-R _13, wherein R ₁₃ is -CH ₂ -O-Ar ₁ , and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazole- 5-yl, wherein the phenyl is optionally substituted with a chlorine atom, or R ₁₃ is -CH ₂ -O-CO-Ar ₁ , Ar ₁ is 2,6-dichlorophenyl, and 2- of the scaffold ring The position is substituted with p-fluorophenyl.

More preferred forms (e) of the R ₁ group are of the formulas e1, e2, e4 and e7:

Chemical formula e1

Chemical formula e2

Where c is 2.

Chemical formula e4

Chemical formula e7

Optionally benzo fused,

Where c is 1 or 2,

Provided that R ₁ is (e4); g is 0; J is -H; m is 1 and T is —CO ₂ H; R ₅ is benzyloxycarbonyl; when c is 1, R ₃ is not -CO-R _13, wherein R ₁₃ is -CH ₂ -O-Ar ₁ , and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazole-5- Is either phenyl optionally substituted with a chlorine atom, or R ₁₃ is -CH ₂ -O-CO-Ar ₁ , Ar ₁ is 2,6-dichlorophenyl, and the 2-position of the scaffold ring is P -Substituted with fluorophenyl;

And R ₁ is (e7); g is 0; J is -H; m is 1; T is any isoelectronic array substitution instead of -CO ₂ H, -CO-NH-OH or -CO ₂ H; R ₅ is a protecting group for the N atom of the α-amino acid side chain moiety, and when each c is 1, R ₃ is not -CO-R _13, wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar _1, and -CH ₂ -S-Ar ₁ .

A more preferred form (f) of the R ₁ group is of the formula f1:

[Formula f1]

A more preferred form (g) of the R ₁ group is of the formula g2:

Chemical formula g2

Wherein R ₂₀ is of formula (aa1) optionally substituted with single or multiple substituents with Q ₁ ; Z is C═O;

A more preferred form (h) of the R ₁ group is of the formula h:

Formula h

Wherein R ₂₀ is of formula (aa1) optionally substituted with single or multiple substituents with Q ₁ ; Z is C═O;

A more preferred form (o) of the R ₁ group is of the formula o 1, wherein d is 1 or 2 or o 6:

Chemical formula o1

Chemical formula o6

More preferred forms (r) of the R ₁ group are of the formulas r5, r4 and r3, optionally substituted with Q ₁ :

Chemical formula r3

Chemical formula r4

Chemical formula r5

A more preferred form (w) of the R ₁ group is of the formula w1:

Formula w1

Wherein X ₂ is —NH—, —S—, —O— or —SO ₂ —, where X ₂ is —N—, is optionally substituted with R ₅ or Q ₁ in X ₂ ;

Ring C is benzo substituted with —C ₁ -C ₃ alkyl, —OC ₁ -C ₃ alkyl, —Cl, —F or —CF ₃ when R ₁ is the formula a2:

Formula a2

Non-limiting examples of preferred compounds of the present invention are compounds having the formulas 20d and 142:

[Formula 20d]

[Formula 142]

Preferred compounds of embodiment B of the present invention are compounds having the formula α wherein R ₁ is the formula c2.

Chemical formula c2

Non-limiting examples of preferred compounds of this embodiment are compounds having the formulas 54a, 54b, 54 g, 54j, 54k, 57b, 88, 90, 91, 125a, 126, 127, 128, 129, 130, and 131:

[Formula 54a]

[Formula 54b]

[Formula 54 g]

[Formula 54j]

[Formula 54k]

[Formula 57b]

[Formula 88]

[Formula 90]

[Formula 91]

[Formula 125a]

[Formula 126]

[Formula 127]

[Formula 128]

Formula 129]

[Formula 130]

[Formula 131]

When R ₁ is of formula e, non-limiting examples of preferred compounds of the invention include the following formulas 132a, 132b, 133, 140, 141 and the like:

Chemical formula e

[Formula 132a]

[Formula 132b]

[Formula 133]

[Formula 140]

Formula 141

Preferred compounds of embodiment B of the invention are those wherein R ₁ is of the formula e1 or e2 (wherein C is 2), m is 1, T is -CO ₂ H, and R ₃ is -CO-R ₁₃ Is a compound having the formula α:

Chemical formula e1

Chemical formula e2

Non-limiting examples of preferred compounds of this embodiment are compounds having the formulas 47a, 47b, 125b, 135a, 135b, 136, 137, 138, and 139:

[Formula 47a]

[Formula 47b]

[Formula 125b]

[Formula 135a]

[Formula 135b]

[Formula 136]

[Formula 137]

[Formula 138]

[Formula 139]

When R ₁ is the formula f1, a non-limiting example of a preferred compound of the present invention is a compound having the formulas 86, 87, 158 and 160, which is formula g2.

Formula f1

[Formula 86]

[Formula 87]

[Formula 158]

[Formula 160]

When R ₁ is g2, non-limiting examples of preferred compounds of the present invention are compounds having the formulas 21d, 21e, 21f, 22e and 157:

Chemical formula g2

[Formula 21d]

[Formula 21e]

[Formula 21f]

[Formula 22e]

[Formula 157]

When R ₁ is of the formula o, non-limiting examples of preferred compounds of the invention are compounds:

Formula o

[Formula 92]

Preferred compounds of embodiment B of the present invention are those in which R ₁ is of formula o6 (X ₂ is -NH-), m is 1, T is -CO ₂ H, and R ₃ is -CO-R ₁₃ It is a compound which has (alpha).

Chemical formula o6

Non-limiting examples of preferred compounds of this embodiment are compounds having the formulas 114a, 114b, 115, and 121:

Formula 114a]

Formula 114b]

[Formula 115]

[Formula 121]

Non-limiting examples of preferred compounds of embodiment B of the invention wherein R ₁ is optionally substituted with Q ₁ are the compounds having formulas 98, 102a, 102b and 102c:

Chemical formula r3

Chemical formula r4

Chemical formula r5

[Formula 98]

[Formula 102a]

[Formula 1O2b]

[Formula 102c]

When R ₁ is w1, non-limiting examples of preferred compounds of the present invention are compounds having the formulas 106a, 106b, 106c, 108a, 108b and 108c:

Formula w1

Formula 106a]

Formula 106b]

Formula 106c]

[Formula 108a]

[Formula 108b]

[Formula 108c]

An ICE inhibitor of another embodiment (C) of the present invention is a compound represented by the formula

Chemical formula σ

Wherein the ring is optionally substituted with one or more, preferably 0, 1 or 2 R groups;

R ₁ is R _5- (A) _p- ;

R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ ,

, , And Is;

Each A is independently selected from the group consisting of any α-amino acid;

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

Y is -O-, -S- or -NH,

R is -H, -OC ₁ -C ₆ alkyl, -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) ₂ , -SC ₁ -C ₆ alkyl, -C ₁ -C ₆ Alkyl or -Q ₂ ;

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with one Ar ₁ group;

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-HR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ;

Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1-3 rings and optionally benzo fused, 5 Containing from 15 ring atoms and from 1 to 3 rings, and containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally containing one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN , = 0, -OH, perfluoro C ₁ -C ₃ alkyl, Or a cyclic group optionally substituted with single or multiple substituents with -Q ₁ ;

Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each Q ₂ is -OH, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN, -CF ₃ and Independently selected from the group consisting of;

However, when -Ar ₁ is substituted with a Q ₁ group which comprises one or more additional -Ar ₁ of, -Ar ₁ of the sub-groups are not substituted with Q _1.

Non-limiting examples of preferred compounds of embodiment C of the present invention are compounds selected from the group consisting of the following formulas (9), (R), (S), (T) and (V):

[Formula Q]

[Formula R]

[Formula S]

[Formula T]

[Formula V]

In addition, preferred compounds of embodiment C of the present invention are those wherein each A is alanine, histidine, lysine, phenylalanine, proline, tyrosine, valine, leucine, isoleucine, glutamine, methionine, homoproline, 3- (2-thienyl) alanine And α-amino acids of 3- (3-thienyl) alanine.

ICE inhibitor of another embodiment (D) of the present invention is a compound represented by the following formula (π).

Formula π

In which R ₁ is R _5- (A) _P- ;

Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ;

R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ ,

, , And Is;

Each A is independently selected from the group consisting of any α-amino acid;

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

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with an Ar ₁ group;

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzo fused, 5 to 15 Containing one or more ring atoms and one or more heteroatoms selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- and containing one or more double bonds Optionally selected from the group consisting of heterocycle groups optionally comprising one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CH, = O, —OH, perfluoro C ₁ -C ₃ alkyl, , -R ₉ or -T ₁ -R ₉ is a cyclic group optionally mono- or multisubstituted.

Preferred compounds of embodiment (D) of the present invention are compounds wherein R ₉ is C ₁ -C ₄ straight or branched chain alkyl wherein Ar ₁ is substituted with Ar ₁ being phenyl.

Non-limiting examples of preferred compounds of embodiment (D) of the present invention are compounds having the following formulas

[Formula W]

[Formula X]

[Formula Y]

[Formula Z]

Formula 89

In addition, preferred compounds of embodiment D of the invention are those wherein A is alanine, histidine, lysine, phenylalanine, proline, tyrosine, valine, leucine, isoleucine, glutamine, methionine, homoproline, 3- (2-thienyl) alanine and 3 And a compound independently selected from the group consisting of α-amino acids of-(3-thienyl) alanine.

An ICE inhibitor of another embodiment (E) of the present invention is a phosphorus compound represented by the following formula (v):

Chemical formula v

m is 0, 1 or 2;

T is any isoelectronic array substitution instead of —CO ₂ H or —CO ₂ H;

R ₃ is -CN, -CO-R ₁₃ or Is;

R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-0-R ₉ , -SO ₂ -R ₉ , , , And Is;

Each A is independently selected from the group consisting of any α-amino acid;

p is 2 or 3;

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with one Ar ₁ group;

Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ,

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Each R ₁₃ is independently selected from the group consisting of H, R ₉ , Ar ₂ and CH ₂ -T ₁ -R ₉ ;

Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzo fused, 5 Containing from 15 ring atoms and from 1 to 3 rings, and containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally comprising one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN , = O, -OH, perfluoro C ₁ -C ₃ , Or a cyclic group optionally mono- or polysubstituted with -Q ₁ ;

Each Ar ₂ is independently selected from formulas (hh)-(kk), wherein any ring may be optionally substituted by -Q ₁ and -Q ₂ and optionally substituted by:

Chemical formula hh

Formula ii

Chemical formula jj

Chemical formula kk

Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -O-Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each Q ₂ is -OH, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN, -CF ₃ and Independently selected from the group consisting of;

However, when -Ar ₁ is substituted with a Q ₁ group which comprises one or more additional -Ar ₁ of, -Ar ₁ of the sub-groups are not substituted with Q _1.

Non-limiting compounds of the preferred compounds of another embodiment (E) of the present invention are the following formulas (I), (K), (85), (156), (159), (161) and (162):

[Formula I]

[Formula K]

[Formula 85]

[Formula 156]

[Formula 159]

[Formula 161]

[Formula 162]

In addition, preferred compounds of embodiment E of the present invention are those wherein A is alanine, histidine, lysine, phenylalanine, proline, tyrosine, valine, leucine, isoleucine, glutamine, methionine, homoproline, 3- (2-thienyl) alanine and 3 And a compound independently selected from the group consisting of α-amino acids of-(3-thienyl) alanine.

An ICE inhibitor of another embodiment (F) of the present invention is a compound represented by the following formula (δ):

Formula δ

R ₁ is R _5- (A) _P- ;

R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ , , , And Is,

Each A is independently selected from the group consisting of any α-amino acid;

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

Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with one Ar ₁ group;

Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups;

Each T ₁ is independently selected from the group consisting of —CH═CH—, —O—, —S—, and —SO—;

Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzo fused, 5 Containing from 15 ring atoms and from 1 to 3 rings, and containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally comprising one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, NO ₂ , -CN, = O, -OH, perfluoro C ₁ -C ₃ alkyl, Or a cyclic group optionally substituted with single or multiple substituents with -Q ₁ ;

Each Ar ₂ is independently selected from formulas (ii)-(kk), wherein any ring may be optionally substituted by -Q ₁ and -Q ₂ and optionally substituted by:

Formula ii

Chemical formula jj

Chemical formula kk

Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -O-Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ;

Each Q ₂ is -OH, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN, -CF ₃ and Independently selected from the group consisting of;

However, when -Ar ₁ is substituted with a Q ₁ is a group -Ar ₁ comprising one or more additional, -Ar ₁ of the sub-groups are not substituted with Q _1;

Each X is independently selected from the group consisting of = N- and = CH-;

Each Y is independently selected from the group consisting of -O-, -S- and -NH.

Non-limiting compounds of the preferred compounds of another embodiment (F) of the present invention are the compounds of formulas (144) to (155) and (163):

[Formula 144]

[Formula 145]

Formula 146

[Formula 147]

[Formula 148]

[Formula 149]

[Formula 150]

[Formula 151]

[Formula 152]

[Formula 153]

Formula 154

[Formula 155]

[Formula 163]

In addition, preferred compounds of embodiment F of the present invention are those wherein A is alanine, histidine, lysine, phenylalanine, proline, tyrosine, valine, leucine, isoleucine, glutamine, methionine, homoproline, 3- (2-thienyl) alanine and 3 And a compound independently selected from the group consisting of α-amino acids of-(3-thienyl) alanine.

The compound of the present invention preferably has a molecular weight of about 700 Daltons or less, and more preferably about 400 to 600 Daltons. Said preferred compounds can be readily absorbed by the bloodstream of the patient upon oral administration. The oral availability makes the compounds excellent formulations for the treatment and prophylaxis of oral administration for IL-1 mediated diseases.

The ICE inhibitors of the present invention can be synthesized using conventional techniques. Advantageously, the compounds are readily synthesized as starting materials that are readily available.

Compounds of the present invention are most readily synthesized among known ICE inhibitors. The already disclosed ICE inhibitors comprise four or more chiral centers and include various peptide bonds. The relative ease of synthesizing the compounds of the present invention has great forgetfulness in mass production of such compounds.

It should be borne in mind that the compounds of the present invention may exist in various equilibrium forms, depending on conditions including the choice of solvents, pH and others known to those skilled in the art. All forms of the compounds are specifically included in the present invention. In particular, many of the compounds of the present invention, particularly those containing aldehyde or ketone groups of R ₃ , carboxylic acid groups of T, are in the form of hemi-ketals (or hemi-acetals) or hydrates, as shown in Scheme 1 described below. Can take:

Scheme 1

In addition, depending on the choice of solvents and other conditions known to those skilled in the art, the compounds of the present invention may take the form of acyloxy ketals, acyloxy acetals, ketals or acetals, as shown in Scheme 2:

Scheme 2

In addition, equilibrium forms of the compounds of the present invention may include tautomeric forms. All forms of the compounds are specifically included in the present invention.

Compounds of the present invention can be modified by appropriate functionality to enhance selective biological properties. Such modifications are known in the art, examples of which include increased biological penetration into certain biological systems (eg, bloodstream, lymphatic system, central nervous system), increased oral availability, and increased solubility to enable injection administration. And altering metabolism and altering secretion rate. In addition, the compound is changed into the drug precursor form such that certain compounds are produced in the patient's body to have metabolic or other biochemical effects on the drug precursor. Examples of drug precursors are the ketal, acetal, oxime and hydrazone forms of the compounds formed in particular the R ₃ groups of the compounds of the invention, including ketone or aldehyde groups.

Compounds of the present invention are excellent ligands for ICE. Thus, the compounds are capable of targeting and inhibiting IL-1 mediated diseases that convert precursor IL-1β to mature IL-1β, and then the final activity of the protein in inflammatory diseases, autoimmune diseases and neurodegenerative diseases. Will have For example, the compounds of the present invention can inhibit the conversion of precursor IL-1β to mature IL-1β by inhibiting ICE. Since ICE is essential for the production of mature IL-1, inhibition of this enzyme blocks IL-1 mediated physiological effects and symptoms such as inflammation by inhibiting the production of mature IL-1. Thus, by inhibiting IL-1β precursor activity, the compounds of the present invention effectively act as IL-1 inhibitors.

The compounds of the present invention can be used in conventional methods for the treatment of diseases mediated by IL-1. The method of treatment, its amount of use and requirements can be selected by one skilled in the art from conventional methods and techniques. For example, the compounds of the present invention may be combined in a pharmaceutically acceptable manner and with a pharmaceutically acceptable adjuvant for administration to a patient suffering from an IL-1 mediated disease in an amount effective to alleviate the pain of the disease. .

In some cases, the compounds of the present invention may be used in compositions and in methods of protecting and treating an individual against IL-1 mediated diseases over long periods of time. The compound may be used alone in the composition or in combination with a compound different from the compound of the present invention in a manner consistent with the conventional use of ICE inhibitors in pharmaceutical compositions. For example, the compounds of the present invention can be used in combination with pharmaceutically acceptable adjuvants commonly used in vaccines and are administered in prophylactically effective amounts to protect individuals against IL-1 mediated diseases over long periods of time.

Compounds of the invention are co-administered with other ICE inhibitors to increase the effect of treatment or prevention against various IL-1 mediated diseases.

In addition, the compounds of the present invention can be used in combination with conventional anti-inflammatory or matrix metalloproteinase inhibitors, lipoxygenase inhibitors and antagonists of cytokines other than IL-1β.

Compounds of the invention include immunomodulators (eg, bropyrimin, anti-human alpha interferon antibodies, IL-2, GM-CSF, methionine enkephalins, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexone and rEPO) or prostaglandins can be administered in combination to prevent or treat symptoms of IL-1 mediated diseases such as infections.

When the compounds of the invention are administered in combination therapy with other agents, they may be administered sequentially or simultaneously to the patient. In some cases, the pharmaceutical or prophylactic compositions according to the invention may differ from the ICE inhibitors of the invention. It may be in combination with a therapeutic or prophylactic agent.

The pharmaceutical composition of the present invention comprises any compound of the present invention, and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. Pharmaceutically acceptable carriers, adjuvants and excipients which may be used in the pharmaceutical compositions of the present invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g. human serum albumin), buffers (e.g. phosphate, glycine, sorbent). Partial glyceride mixtures of hydrobromic acid, potassium sorbate, saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrroli Money, cellulosic materials, polyethylene glycols, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycols and wool fats, but are not limited to these.

The pharmaceutical compositions of the present invention can be administered orally, parenterally, inhalationally sprayed, topically, rectally, intranasally, buccal, intravaginal, or through a transplant reservoir. Oral administration is preferred. The pharmaceutical composition of the present invention may comprise any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or excipient. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intramuscular, intrasternal, intra-secondary, intra-lesional and intracranial injection or infusion techniques.

The pharmaceutical composition may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. Such suspensions may be prepared using suitable dispersing or wetting agents (eg, Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations may be sterile injectable solutions or suspensions dissolved in non-toxic orally-acceptable diluents or solvents, such as solutions dissolved in 1,3-butanediol. Among the acceptable excipients and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils can be conventionally employed as a solvent or suspending medium. For this purpose, any non-volatile mixed oil can be used including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives are useful as injectable preparations, natural pharmaceutically acceptable oils such as olive oil or castor oil, in particular polyoxyethylated variants thereof. These oil solutions or suspensions may be formulated as long chain alcohol diluents or dispersants such as Ph. Helv or similar alcohols.

The pharmaceutical compositions of the present invention may be orally administrable dosage forms, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of oral tablets, carriers that can be used commonly include lactose and corn starch. Lubricants, such as magnesium stearate, are usually added. For oral administration in a capsule formulation, useful diluents include lactose and anhydrous corn starch. In the case of oral administration of an aqueous suspension, the active ingredient is combined with emulsifiers and suspending agents. If desired, any sweetener and / or fragrance and / or colorant may be added.

The pharmaceutical compositions of the present invention may be administered in suppository formulations for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients, which are solid at room temperature but are liquid at rectal temperature and therefore melt in the rectum to release the active ingredient. Examples of such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions of the present invention is particularly useful where certain treatments are desired at sites or organs that are easily accessible by topical administration. For topical administration to the skin, the pharmaceutical composition should be formulated with a suitable ointment comprising the active ingredients dissolved or suspended in a carrier. Non-limiting examples of carriers for topical administration of a compound of the invention include mineral oil, Liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compounds, emulsifying waxes and water. Alternatively, the pharmaceutical composition may be formulated with lotions or creams comprising the active compound dissolved or suspended in a carrier. Non-limiting examples of suitable carriers include mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, stearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of the present invention may be administered topically under the intestine by rectal suppository formulations or by suitable enema formulations. Topical-transdermal patches also belong to the present invention.

The pharmaceutical composition of the present invention can be administered by nasal aerosol or inhalation. These compositions may be prepared according to techniques known in the art of pharmaceutical formulations, and may be benzyl alcohol or other suitable preservatives, absorption accelerators to enhance bioavailability, fluorocarbons, and / or other solubilizers known in the art. Or a solution in brine using a dispersant.

IL-1 mediated diseases that can be treated or prevented by the compounds of the invention include, but are not limited to, inflammatory diseases, autoimmune diseases and neurodegenerative diseases.

Examples of inflammatory diseases that can be treated or prevented include septic shock, sepsis, and respiratory disease symptoms in adults. Examples of target autoimmune diseases include rheumatoid, arthritis, systemic lupus erythematosus, scleroderma, chronic thyroidism, Graves' disease, autoimmune gastritis, insulin-dependent diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic Active hepatitis, myasthenia gravis and multiple sclerosis. Examples of target neurodegenerative diseases include amyotrophic lateral sclerosis, Alzheimer's disease, Parkin's disease, and primary lateral sclerosis. The ICE inhibitor of the present invention can also be used to promote wound healing. The ICE inhibitors of the invention can be used to treat infectious diseases.

While the present invention focuses on using the compounds described herein to prevent and treat IL-1 mediated diseases, the compounds of the present invention can also be used as inhibitors for other cysteine proteases.

The compounds of the present invention may be useful as commercial agents that are effectively bound to ICE or other cysteine proteases. Commercially available medicaments and derivatives thereof can be used to block or induce proteolysis of target peptides to bind to stable resins as bond substrates for affinity chromatography applications. These and other uses characterized by commercial cystine protease inhibitory properties will be apparent to those of ordinary skill in the art.

In order to facilitate a more complete understanding of the present invention, the following examples are presented. These examples are for illustrative purposes only, and the scope of the present invention should not be limited by them.

Example 1

The following examples illustrate drug design methods embodying the present invention.

Step 1) Take the two hydrogen bonding moieties of the ICE, namely the backbones C═O and N—H of Arg-341.

Step 2) Choose a scaffold, ie a pyridone derivative, and confirm that the hydrogen bond portion of the scaffold can form a satisfactory hydrogen bond with the hydrogen bond portion selected in step 1. The identification is carried out using molecular dynamics techniques that minimize scaffold fragments in the context of the active site of the ICE.

Chemical Formula Z1

Step 3) The next goal is to take hydrophobic pockets, ie S2 and hydrophobic moieties, benzene. Verify that a significant amount of hydrophobic overlap can be obtained by minimizing the benzene groups in the S2 pockets.

Chemical Formula Z2

Step 4) The next goal is to take another hydrophobic pocket, ie S4 and a hydrophobic moiety, benzene. Verify that a significant amount of hydrophobic overlap can be obtained by minimizing the benzene group in the S4 pocket.

Chemical Formula Z3

Step 5) Fill the S1 polar pocket with the carboxylate side chain provided by the aspartic acid in which the electronegative portion, ie the C-terminus is aldehyde reduced. Make sure the carboxylate side chains have an electrostatic interaction advantageously with the S1 polar pocket.

Chemical Formula Z4

Step 6) Connect the scaffolds with the parts in steps 3, 4 and 5 using a minimum number of bonds, preferably matching the chemically relevant structure. The total complex molecule in the active site of ICE is minimized.

Chemical Formula Z5

Step 7) Evaluate the energy of the molecule if it has the structure necessary to bind to ICE. Thereafter, the free form energy is minimized and reassessed. The strain energy for the binding of a potential inhibitor to ICE is the difference between the free form energy and the bond form energy. The strain energy should be about 10 mA / mol or less. In this case, the bond form energy is -1.6 kW / mol, the free form energy is -11.7 kW / mol, and the strain energy is 10.1 kW / mol.

Step 8) An inhibitor designed using the above step was prepared and found to have a Ki of 150 nM or less.

Example 2

Applicants obtained the inhibition constants (K _i ) and IC ₅₀ values for the various compounds of the invention using the three methods described below.

1. Enzyme analysis using UV-visible substrate

This assay is performed using a succinyl-Tyr-Val-Ala-Asp-pnitroanilide substrate. Synthesis of analogous substrates is described in LA Reiter, Int. J. .Peptide Proteinn Res. 43, 87-96 (1994). The assay mixture consisted of 65 μl of buffer solution (10 mM Tris, 1 mM DTT, 0.1% CHAPS pH ca. 8.1), 10 μl of ICE (50 nM final concentration giving a rate of −1 mOD per minute), 5 μl of DMSO / inhibitor mixture and 20 μl of 400 μM substrate (80 μM final concentration) contains 100 μl total reaction volume.

Visible ICE analysis was performed on 96 well microtiter plates. Buffer, ICE and DMSO (if inhibitor is present) are added to the wells in the order presented. The components are left to start when all components are in all wells and incubated for 15 minutes at room temperature. Microtiter plate readers are adjusted and incubated at 37 ° C. After incubation for 15 minutes, the substrate was added directly to the wells and monitored after release of chromophores (pNA) at 405-603 nm for 20 minutes at 37 ° C. The linear summation of the data was performed and the rate was calculated in mOD / min. During the experiment, only DMSO with inhibitor was present and the buffer was used to make 100 μL of volume in the other experiments.

2. Enzyme Analysis Using Fluorescent Substrate

This analysis was performed using Substrate 17 cited above by Thornberry et al., Nature 356: 768-774 (1992). The substrate is acetyl-Tyr-Val-Alα-Asp-amino-4-methylcoumarin (AMC). 65 μl buffer solution (10 mM Tris, 1 mM DTT, 0.1% CHAPS pH ca. 8.1), 10 μl ICE (2-10 nM final concentration), 5 μl DMSO / inhibitor solution and 20 μl 150 μM substrate (30 μM final concentration) Mix 100 μl total reaction volume with.

This analysis was performed on 96 well microtiter plates. Buffer and ICE are added to the wells. The components are left to incubate at 37 ° C. for 15 minutes on a temperature controlled plate. After incubation for 15 minutes, the substrate was added directly to the wells to initiate the reaction and the reaction was monitored after release of the AMC chromophore using an excitation wavelength at 380 nm and an emission wavelength of 460 nm for 30 minutes at about 37 ° C. The linear addition of was performed for each well and the rate was calculated in fluorescence units per second.

For determination of enzyme inhibition constant (K _i ) or type of inhibition (competitive, non-competitive), rate data measured in enzyme assays at various inhibitor concentrations are computerized into standard enzyme kinetics equations [Ref: IH Segel, Enzyme Kinetics , Willie-Interscience, 1975].

3. Cell analysis

IL-1β using a Mixed Population of Human Peripheral Blood Mononuclear Cells (PBMC) or Enriched Adhesive Monocytes

Treatment of pre-IL-1β by ICE can be measured in cell culture using a variety of cell sources. Human PBMCs from healthy donors provide a mixed population of mononuclear and lymphoid cell subspecies that produce interleukin and cytokine spectra in response to various types of physiological stimuli. Adherent monocytes from PBMCs provide a normal monocyte-rich cell source that is selective for the study of cytokine production by activated cells.

Experimental procedure:

Initial starting dilutions of a series of test compounds in DMSO or ethanol were prepared by diluting in RPMI-10% FBS medium (2 mM L-glutamine, 10 mM HEPES, 50 U and 50 μg / ml pen / strep), respectively, to 0.4% DMSO or 0.4 Drugs were generated at four times the final test concentration with% ethanol. The final concentration of DMSO is 0.1% for all drug dilutions. The apparent density measured titers enclosed in parentheses, the K _i for a test compound measured in ICE inhibition assay is generally used for the primary compound search.

Applicants tested 5 to 6 dilutions and the cellular components of the analytes were subjected to duplicate ELISA measurements on each cell culture supernatant.

PMBC Isolation and IL-1 Analysis:

Dilute the pale yellow coat cells isolated from 1 pint of human blood (producing a final volume of plasma + cells of 40-45 ml) to 80 ml with medium and leuco PREP separation tubes (Becton Dickinson), respectively. Nested in 10 ml cell suspension. The plasma / medium layer was aspirated by centrifugation at 1500-1800 × g for 15 minutes, then the mononuclear cell layer was collected with a Pasteur pipette and transferred to a 15 ml conical centrifuge tube (Corning). Medium is added to bring the volume to 15 ml, the cells are mixed gently by inversion and centrifuged at 300 × g for 15 minutes. PBMC pellets were resuspended in a small amount of medium and adjusted to 6 × 10 ⁶ cells / ml.

For cell analysis, 1.0 ml of cell suspension was added to each 24 well plate tissue culture plate (Corning), and 0.5 ml of test compound dilution and 0.5 ml of LPS solution (Sigma # L-3012; in complete RPMI medium). 20 ng / ml solution prepared; final LPS concentration 5 ng / ml) is added. 0.5 ml of test compound additive and LPS are sufficient to mix the components of the well. Three control mixtures, LPS alone, solvent excipient control, and / or additional medium for adjusting the final culture volume to 2.0 ml are run in each experiment. Cell cultures were incubated in the presence of 5% CO ₂ at 37 ° C. for 16-18 hours.

At the end of the incubation cycle, cells were harvested and transferred to 15 ml conical centrifuge tubes. After centrifugation at 200 x g for 10 minutes, the supernatant was collected and transferred to 1.5 ml Eppendorf tubes. Cell pellets can be used for biochemical evaluation of preliminary IL-1β and / or mature IL-1β contents in citazole extracts by ELISA using western blotting or preliminary IL-1β specific antiserum.

Isolation of Adhesive Mononuclear Cells:

The PBMCs are separated and prepared as described above. The medium (1.0 mL) is first added to the wells and then to 0.5 mL PBMC suspension. After incubation for 1 hour, shake the plate gently to aspirate non-adhesive cells from each well. The wells are washed three times with 1.0 ml of medium and finally resuspended in 1.0 ml of medium. Adhesion cell enrichment usually produces 2.5-3.0 × 10 ⁵ cells per gel. Test compounds, LPS, cell culture conditions and supernatant treatments are performed as described above.

ELISA:

Applicants used Quintikin kit (R & D Systems) for the measurement of mature IL-1β. The analysis was carried out according to the manufacturer's instructions. Approximately 1-3 ng / ml of mature IL-1β was observed in both PBMC and adherent mononuclear cell positive controls. ELISA analysis was performed with 1: 5, 1:10 and 1:20 dilutions of the supernatant from the LPS positive control to select the optimal dilution for the supernatant in the test panel.

The inhibitory potency of a compound can be expressed as an IC ₅₀ value, which is the concentration of inhibitor in which 50% of mature IL-1β for the positive control is detected in the supernatant.

The following K _i and IC ₅₀ values were determined for Compounds A-N using the assays shown. The structures for Compounds A-N are shown after the table below.

TABLE 1

Structure of Compounds A to N

[Formula A]

[Formula B]

[Formula C]

[Formula D]

[Formula E]

Formula F]

[Formula G]

[Formula H]

[Formula I]

[Formula J]

[Formula K]

[Formula L]

[Formula M]

[Formula N]

Example 3

The compound of Example 2 was synthesized as follows.

H. N- (N-acetyl-tyrosinyl-valynyl-pipecolyl) -3-amino-4-oxobutanoic acid

Step A: N- (N-t-butoxycarbonylpipecolyl) -4-amino-5-benzyloxy-2-oxotetrahydrofuran

See reaction of Nt-butoxycarbonylpipecolic acid (460 mg, 2.0 mmol) and N-allyloxycarbonyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (530 mg, 1.82 mmol). Chapman, Bioorg. & Med. Chem. Lett., 1992, 2, 613-618, was carried out in a similar manner to give 654 mg of the title compound.

Step B: N-Pipecolyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran

N- (Nt-butoxycarbonylpipecolyl) -4-amino-5-benzyloxy-2-oxotetrahydrofuran (654 mL) was dissolved in 25% trifluoroacetic acid in 15 mL of dichloromethane and at room temperature Stirred at. The mixture was concentrated to give a gum-like residue. The residue was dissolved in dichloromethane and washed with 10% sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 422 mg of the title compound as a beige solid.

Step C. N- (N-Acetyl-Tyrosinyl-Valinyl-Pipecolyl) -4-Amino-5-benzyloxy-2-oxotetrahydrofuran

5 ml of N-acetyl-tyrosinyl-valine (464 mg, 1.44 mmol) and N-pipecolyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (412 mg, 1.3 mmol) each Dissolved in dimethylformamide and dichloromethane and cooled to 0 ° C. To the cooled solution was added 1-hydroxybenzotriazole (HOBT; 210 mg, 1.56 mmol), followed by 1- (3-dimethylaminopropyl)- 3-ethyl carbodiimide hydrochloride (EDC; 326 mg, 1.7 mmol) was added. After stirring for 18 hours, the mixture was diluted with ethyl acetate and washed with water, 10% sodium hydrogen sulfate, 10% sodium bicarbonate and water. The organic layer was concentrated to give a crude solid which was purified by flash chromatography eluting with 94: 6: 1 of dichloromethane: isopropanol: pyridine to give 370 mg of the title compound.

Step D: 100 mg of N- (N-acetyl-tyrosinyl-valine in 10 mL of N- (N-acetyl-tyrosinyl-valinyl-pipecolyl) -3-amino-4-oxobutanoic acid methanol 60 mg of Pd (OH) ₂ on carbon was added to the Neyl-Pipecolyl) -4-amino-5-benzyloxy-2-oxotetrahydrofuran solution and the mixture was placed under hydrogen atmosphere via the apparatus. Filtration with light and concentration gave a white solid. The crude solid was dissolved in 2 ml of methanol and dispersed in diethyl ether to give 26 mg of the title compound.

The following compounds were prepared in a similar manner as reported in H.

J. N- [N-acetyl-tyrosinyl-valinyl- (4-hydroxypyrrolinyl)]-3-amino-4-oxobutanoic acid

N-t-butoxycarbonyl-4-benzyloxyproline is used instead of N-t-butoxycarbonylpipecolic acid

L. N- [2- (N-acetyl-tyrosinyl-valinyl)-(S) -1,2,3,4-tetrahydroisoquinoline-3-carbonyl] -3-aminooxobutanoic acid

(S) -N-t-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is used instead of N-t-butoxycarbonylpipecolic acid

I. N- (N-acetyl-tyrosinyl-valynyl- (4-phenoxyprolinyl))-3-amino-4-oxobutanoic acid

Step A: N-t-butoxycarbonyl-4-phenoxyproline methyl ester

Cool solution of Nt-butoxy-cis-4-hydroxyproline (2.0 g, 8.15 mmol), phenol (0.77 g, 8.15 mmol) and triphenylphosphine (2.14 g, 8.15 mmol) in 20 mL tetrahydrofuran Diethyl azodicarboxylate (1.4 mL, 9 mmol) was added dropwise to (0 ° C.) over 30 minutes. The reaction was stirred at rt for 16 h, then concentrated to give a viscous residue The crude residue was purified by flash chromatography (SiO 2) eluting with 3: 7 ethyl acetate: hexanes to give 1.89 g of the title compound. .

Step B: 4-phenoxyproline methyl ester hydrochloride

Anhydrous hydrogen chloride was bubbled until saturated in a cold solution (ice bath) of N-t-butoxycarbonyl-4-phenoxyproline methyl ester (0.6 g) in 20 mL of ethyl acetate. The mixture was allowed to warm to rt, stirred for 3 h and then concentrated to give 480 mg of the title compound.

Step C: N-acetyl-tyrosinyl-valinyl- (4-phenoxy) proline methyl ester

N-acetyl-tyrosinyl-valine (0.524 g, 1.63 mmol) and 4-phenoxyproline methyl ester (0.381 g, 1.48 mnol) were each dissolved in 4 ml of dimethylformamide and dichloromethane and cooled to 0 ° C. I was. To the cooled solution was added diisopropylethylamine (258 μl, 1.86 mmol), HOBT (0.24 g, 1.78 mmol) and EDC (0.37 g, 1.92 mmol) and the reaction was stirred for 18 hours. The mixture was diluted with 400 ml of ethyl acetate, washed with water, washed with 10% sodium hydrogen sulfate, 10% sodium bicarbonate and water. The organic layer was concentrated to give a residue, which was purified by flash chromatography (SiO ₂ ) eluting with 94: 6: 1 CH ₂ Cl ₂ : i-PrOH: pyridine to afford 360 mg of the title compound.

Step D: N-acetyl-tyrosinyl-valinyl- (4-phenoxy) proline

Lithium hydroxide (57 mg, 1.37 munol) dissolved in 8 ml of tetrahydrofuran / water (1: 1) N-acetyl-tyrosinyl-valinyl- (4-phenoxy) proline methyl ester (360 mg, 0.685 mmol) was added to the solution and stirred at room temperature for 1 hour. The mixture was acidified with 10% hydrochloric acid to give a white precipitate, which was collected to yield 175 mg of the title compound.

Step E: N- [N-acetyl-tyrosinyl-valynyl- (4-phenoxy) prolinyl] -4-amino-5-benzyloxy-2-oxotetrahydrofuran

By reaction of N-acetyl-tyrosinyl-valynyl- (4-phenoxy) proline and N-allyloxycarbonyl-4-amino-5-benzyloxytetrahydrofuran by the method reported in Step A The title compound was prepared.

Step F: N- [N-acetyl-tyrosinyl-valinyl- (4-phenoxy) prolinyl] -3-amino-4-oxobutanoic acid

Compound H, the title compound was prepared by the hydrogenolysis reaction reported in step D.

All.

K. N- [N-acetyl-tyrosinyl-valinyl- (4-benzyloxy) prolinyl]

3-Amino-4-oxobutanoic acid

Step A: N- (N-allyloxycarbonyl-4-benzyloxyprolinyl) -3-amino-4-oxobutanoic acid t-butyl ester semicarbazone

N-allyloxycarbonyl-4-benzyloxyproline and 3-amino-4-oxobutanoic acid t-butyl ester semicarbazone [Ref. L. Grayville, Abstracts of papers, 206th National Meeting of the American Chemical Society, Abstract MEDI-235, Illinois, Chicago (1993)], as reported above (Compound H, Step C) under similar peptide coupling conditions. Reaction gave the title compound.

Step B: N- (N-acetyl-tyrosinyl-valinyl- (4-benzyloxyprolinyl))-3-amino-4-oxobutanoic acid t-butyl ester semicarbazone

N-acetyl-tyrosinyl-valine and N- (N-allyloxycarbonyl-4-benzyloxyprolinyl) -3-amino-4-oxobutanoic acid t-buntyl ester semicarbazone Compound H, step Reaction under the reaction conditions reported in A provided the title compound.

Step C: N- (N-acetyl-tyrosinyl-valinyl- (4-benzyloxyprolinyl))-3-amino-4-oxobutanoic acid

N- (N-acetyl-tyrosinyl-valinyl- (4-benzyloxyprolinyl) -3-amino-4-oxobutanoic acid t-butyl ester semicarbazone (270 mg) in 10 ml of dichloromethane Dissolved in 25% trifluoroacetic acid and stirred at room temperature for 3 hours The mixture was concentrated to give a solid residue The residue was 10 mL of methanol: acetic acid: 37% formaldehyde (3: 1: 1). Was dissolved in a mixture of and stirred for 1 hour at room temperature The mixture was concentrated and the resulting residue was purified by flash chromatography (SiO ₂ ), eluting with dichloromethane / methanol / formic acid (100: 5: 0.5). 37 mg of the title compound were obtained.

Example 4

Applicants used enzyme and cell assays with UV-visible substrates as described in Example 2 to obtain inhibition constants (K _i ) and IC ₅₀ values of various compounds of the invention. The following K _i and IC ₅₀ values are given for the compounds 7a, 7b, 20a-20d, 21c-21f, 22e, 25, 28, 33a-33c, 36a, 36b, 39, 43, 47a, 47b, 54a- using the analysis shown. Measurements were made for 54 L, 63, 69 a, 69 b, 84 a and 84 b. The compound structure is shown in Examples 2 and 5.

TABLE 2a

TABLE 2b

Example 5

The compound of Example 4 was synthesized as in Scheme 3 below.

Scheme 3

3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidinone-carboxylic acid methyl ester (3)

(4S) -2-Amino-1-pyrroline-5-carboxylic acid ethyl ester hydrochloride in ethanol (10 mL) (1, 0.44 g, 2.38 mmol; see Li and Row, J. Org. Chem., 52, 5717-21 (1987) prepared in a similar manner as the methyl ester); A mixture of 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (2, 0.50 g, 2.31 mmol) and sodium methoxide (0.12 g, 2.22 mmol) was refluxed for 2 hours. The reaction was cooled to rt and concentrated in vacuo. The residue was suspended in water and 1N sulfuric acid was added until pH was 1. The aqueous mixture was extracted with dichloromethane, the organic layer was separated and concentrated in vacuo to give 0.6 g of an orange solid. Chromatography (flash, SiO ₂ , 60% ethyl acetate / hexanes after step gradient of 100% ethyl acetate, 10 g methanol / dichloromethane) gave 0.5 g of an orange solid. An orange solid and potassium cyanide (0.03 g, 0.5 mmol) mixture in methanol (10 mL) was refluxed overnight. The cooled reaction was concentrated in vacuo to yield a yellow solid. Chromatography (flash, SiO ₂ , step gradient of 40% ethyl acetate / hexanes to 100% ethyl acetate) gave 0.22 g (31.6%) of the title compound.

(3S)-[(3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-6-carbonyl) amino] -4-oxo- Butanoic acid t-butyl ester semicarbazone (5a and 5b)

3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo- [1,2-a] pyrimidine-6-carrol in methanol (5 mL) and tetrahydrofuran (5 mL) A mixture of acid ethyl ester (3, 0.22 g, 0.70 mmol) and lithium hydroxide hydrate (0.032 g, 0.76 mmol) was stirred at rt for 18 h. The reaction was concentrated to give 3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-6-lithium carboxylic acid salt (4) as a white solid. Got it. This was used without further purification in subsequent reactions.

(3S) -Amino-4-oxo-butanoic acid t-butyl ester semicarbazone (0.163 g, 0.71 mmol; Grayville et al., Int. J. Protein) in dimethylformamide (5 mL) and dichloromethane (5 mL) Res., 44, pages 173-82 (1994)) and 3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-6-carboxyl Treatment of a 0 ° C. mixture of lithium acid salt (4) with hydroxybenzotriazole (0.104 g, 0.77 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrogen chloride (0.148 g, 0.37 mmol) It was. The reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was poured into water (50 mL) and extracted with ethyl acetate (2 x 50 mL) and washed with combined organic aqueous 1M aqueous sodium hydrogen sulfate solution, dilute aqueous sodium hydrogen carbonate solution (50 mL) and saturated sodium chloride. The organic layer was concentrated in vacuo to yield 0.43 g of a yellow solid. Chromatography (flash, SiO ₂ , ammonium hydroxide / methanol / dichloromethane (1: 1: 99 to 1:10:90 step gradient)) of 0.11 g (30.9%) of _Rf high diastereomer (5a) and 0.11 g (30.9%) of _Rf having a low diastereomer (5b) was obtained. Diastereomers 5a and diastereomers 5b were taken separately.

Diastereomer (5a) with high R _f

Diastereomers with Low R _f (5b)

(3S)-[(3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-6-carbonyl) amino] -4-oxo moiety Carbonic acid (7a)

(3S)-[(3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo- [1, in dichloromethane (7,5 mL) and trifluoroacetic acid (2.5 mL) 2-a] pyrimidine-carbonyl) amino] -4-oxobutanoic acid t-butyl ester semicarbazone (5a, 0.11 g, 0.22 mmol) suspension was stirred for 5 hours The reaction was concentrated in vacuo and the residue Water was taken up in dichloromethane, concentrated in vacuo, suspended in toluene and concentrated in vacuo to afford the white solid (3S)-[(3-benzoylamino-4-oxo-4,6,7,8-tetrahydro- Pyrrolo [1,2-a] pyrimidine-6-carbonyl) amino] -4-oxobutanoic acid semicarbazone (6a) was obtained. The solid was suspended in a 37% aqueous formaldehyde / acetic acid / methanol (1: 1: 5) mixture and stirred at room temperature for 18 hours. The reaction was concentrated in vacuo, the residue suspended in acetonitrile and concentrated in vacuo. 0.1 g of a white solid was obtained. Chromatography (HPLC, reverse phase C18, gradient elution of 1% to 75% acetonitrile / water (buffered with 0.1% trifluoroacetic acid)) gave 0.05 g (60%) of a white solid 7a: RT = 7.9 Minutes (HPLC, C18 reverse phase, 1-100% acetonitrile / water (0.1% trifluoroacetic acid buffer); 20 min gradient elution)

(3S)-[(3-benzoylamino-4-oxo-4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine-6-carbonyl) amino] -4-oxo- Butanoic acid (7b) was prepared as described for diastereomer (7a) to yield 0.03 g (35%) of white solid (7b): RT = 8.1 min (HPLC, C18 reversed phase, 1-100% aceto) Nitrile / water (0.1% trifluoroacetic acid buffer); 20 min gradient elution)

[Banungsik 4]

Imidazole-2-carboxylic acid (13), see Yamanaka et al., Chem. Pharm. Bull. , 31, 4549-53 (1983), Suzuki et al., J. Org. Chem., 38, pages 3571-75 (1973); And Oliver et al., J. Org. Chem. , 38, pages 1437-38 (1973).

Imidazole-2-carboxylic acid (13a), see Curtis and Brown, J. Org. Chem. , 45, pages 4038-40 (1980).

4-benzylimidazole-2-carboxylic acid (13b) was isolated as off-white solid.

4- (2-phenylethyl) imidazole-2-carboxylic acid (13c) was isolated as a pale yellow solid.

4- (3-phenylpropyl) imidazole-2-carboxylic acid (13d) was isolated as a pale yellow solid.

4- [3- (4-methoxyphenyl) propyl] imidazole-2-carboxylic acid (13e) was isolated as a white crystalline solid.

Elemental Analysis for C ₁₄ H ₁₆ N ₂ O ₃

Theoretical: C, 64.60; H, 6. 20; N, 10.76

Found: C, 64.45; H, 6. 21; N, 10.70

4- [3- (4-hydroxyphenyl) propyl] imidazole-2-carboxylic acid (13f)

A 13e (1.15 g, 4.0 mmol) ethyl ester solution in anhydrous dichloromethane (50 mL) was treated with boron tribromide (16 mL, 1.0 M solution in CH ₂ Cl ₂ , 16.0 mmol) at 0 ° C. After 15 minutes at 0 ° C., the mixture was warmed to 25 ° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath and the reaction was terminated by dropwise addition of water (20 mL). The resulting mixture was stirred gently at 25 ° C. and filtered. Solid NaHCO ₃ was added to the filtrate and carefully neutralized to give compound 13f (700 mg, 71%) as a white solid: mp 186-187 ° C. (decomposition) (recrystallized from MeOH).

Elemental Analysis for C ₁₃ H ₁₄ N ₂ O ₃

Theoretical: C, 63.40; H, 5.73; N, 11.38

Found: C, 62.96; H, 5. 70; N, 11.27

(2R, S, 3S) N ² -t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L-alanineamide (14)

Tri-n-butyl tin hydride (4.0 mL, 14.9 mmol) was dissolved in (2R, S, 3S) 3- (N-allyloxycarbonyl) -amino-2-benzyloxy-5-oxo in dichloromethane (75 mL). Tetrahydrofuran [Chapman, Biorg. Med. Chem. Lett., 2, pages 613-18 (1992), 2,91 g, 10 mmol]; To a solution of Nt-butoxycarbonyl-L-alanine (2.08 g, 11 mmol) and bis (triphenylphosphine) palladium (11) (150 mg) was added dropwise until the color of the solution became dark orange. Hydroxybenzotriazole (2.70 g, 20 mmol) was added and the mixture was cooled to 0 ° C. After addition of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride (2.30 g, 12 mmol), the mixture was slowly warmed to room temperature for 4 hours. The mixture was diluted with ethyl acetate (250 mL), washed with 1N hydrochloric acid (3 × 150 mL), saturated aqueous sodium bicarbonate solution (3 × 150 mL) and brine (2 × 15O mL), then dried (MgSO ₄ ) , Filtered and concentrated. The crude product was purified by column chromatography (50-70% ethyl acetate / hexanes) to yield 3.17 g (84%) diastereomeric mixture. Colorless crystals were obtained by recrystallization (ethyl acetate-nucleic acid). mp 132-145 ° C.

Elemental Analysis for C ₁₉ H ₂₆ N ₂ O ₆

Theoretical: C, 60.31; H, 6.92; N, 7.40

Found: C, 60.30; H, 6.91; N, 7.38

(2R, S, 3S) t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L-prolineamide (15) was prepared by the method described in compound 14. To give 1.64 g (81%) of a colorless glass material.

(2R, S, 3S) N- (Nt-butoxycarbonyl- (4 (R) -phenoxy-L-prolinyl) -3-amino-2-benzyloxy-5-oxotetrahydrofuran (16 ) Was prepared by the method described in compound 14 to yield 530 mg (84%) of a colorless amorphous solid.

(2R, S, 3S) N ^2- [4- (3-phenylpropyl) imidazole-2-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L Alanineamide (17d)

Trifluoroacetic acid (7 mL) was added (2R, S, 3S) N ² -t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3- in dichloromethane (7 mL). To a solution of furanyl) -L-alanineamide (14) (1.00 g, 2,64 mmol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 75 minutes. The mixture was concentrated and the residue was treated with diethyl ether, then ether was removed in vacuo. The above procedure was repeated twice to give a pale yellow glass material. The solid was dissolved in DMF (20 mL). Diisopropylethylamine (1.38 mL, 7.92 mmol) followed by 4- (3-phenylpropyl) imidazole-2-carboxylic acid (13d) (0.67 g, 290 mmol), 1- (3-dimethylaminopropyl ) -3-ethyl carbodiimide hydrochloride (0.56 g, 2.90 mmol) and hydroxybenzotriazole (0.71 g, 5.28 mmol) were added to the solution. The mixture was stirred at rt for 20 h and then poured into brine. The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (2 × 100 mL), then brine (2 × 100 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by column chromatography (ethyl acetate) to give 0.99 g (76%) of compound 17d as a diastereomeric mixture.

The following compounds were prepared in a similar manner.

(2R, S, 3S) N 2 - light yellow to (imidazole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- alaninamide (17a) Separate as a solid (74%).

(2R, S, 3S) N ^2- (4-benzylimidazole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L-alanineamide ( 7b) was isolated as pale yellow glassy (75%).

(2R, S, 3S) N 2 - [4- (2- phenylethyl) imidazole-2-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L Alanineamide (17c) was isolated as pale yellow glassy (79%).

(2R, S, 3S) 1- [4- (2-phenylethyl) imidazole-2-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- Prolineamide (18c) was isolated as pale yellow glassy (79%).

(2R, S, 3S) 1- [4- (3-phenylpropyl) imidazole-2-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- Prolineamide (18d) was isolated as colorless glass (87%).

(2R, S, 3S) 1- {4- [3- (4-methoxyphenyl) propyl] imidazole-2-carbonyl} -N- (tetrahydro-2-benzyloxy-5-oxo-3- Furanyl) -L-prolineamide (18e) was isolated as a colorless glassy solid (72%).

(2R, S, 3S) 1- {4- [3- (4-hydroxyphenyl) propyl] imidazole-2-carbonyl} -N- (tetrahydro-2-benzyloxy-5-oxo-3- Furanyl) -L-prolineamide (18f) was isolated as a pale yellow glassy solid (70%).

1- {5- [3- (4-methoxyphenyl) propyl] -1 H-imidazole-2-carbonyl} -4 (R) -phenoxypyrrolidine-2 (S) -carbonyl- (tetra Hydro-2 (R, S) -benzyloxy-5-oxofuran-3 (S) -yl) amide (19e) was isolated as a clear colorless amorphous solid (77%).

(3S) 3- {N- [4- (3-phenylpropyl) imidazole-2-carbonyl] -L-alaninyl} amino-4-oxo-butanoic acid (20d)

(2R, S, 3S) N ^2- [4- (3-phenylpropyl) imidazole-2-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3 in methanol (100 mL) -Furanyl) -L-alanineamide (0.93 g, 1.90 mmol) and a mixture of 10% palladium (0.93 g) on activated carbon were stirred under hydrogen atmosphere for 5 hours. The resulting mixture was filtered and concentrated to give a colorless glassy. Recrystallization from methanol-diethyl ether gave 401 mg (53%) of compound (20d) as a colorless solid.

The following compounds were prepared in a similar manner.

(3S) 3- [N- (imidazole-2-carbonyl) -L-alaninyl] amino-4-oxobutanoic acid (20a, E) was isolated as a colorless solid (83%).

(3S) 3- [N- (4-benzylimidazole-2-carbonyl) -L-alaninyl] amino-4-oxobutanoic acid (20b) was isolated as a colorless solid (56%).

Elemental Analysis for C ₁₈ H ₂₀ N ₄ O ₅

Theoretic value: C, 56.69; H, 5.55; N, 14,69

Found: C, 57.07; H, 5.54: N, 14.41

(3S) 3- {N- [4- (2-phenylethyl) imidazole-2-carbonyl] -L-alaninyl} amino-4-oxobutanoic acid (20c, N) colorless glassy (53% ).

Elemental Analysis for _{C 19 H 22 N 4 O 5} · H 2 O

Theoretic value: C, 56.43; H, 5.98; N, 13.85

Found: C, 56.65; H, 5. 84; N, 13.91

(3S) 3- {N- [4- (2-phenylethyl) imidazole-2-carbonyl] -L-prolinyl} amino-4-oxobutanoic acid (21c) as colorless glass (85%) Separated.

Elemental Analysis for _{C 21 H 24 N 4 O 5} · H 2 O

Theoretical: C, 58.60; H, 6.09; N, 13.02

Found: C, 58.34; H, 5.96; N, 12.67

(3S) 3- {N- [4- (3-phenylpropyl) imidazole-2-carbonyl] -L-prolinyl} amino-4-oxobutanoic acid (21d) as colorless glass (81%) Separated. mp 91-94 ℃

Elemental Analysis for _{C 22 H 26 N 4 O 5} · H 2 O

Theoretical: C, 59.45; H, 6. 35; N, 12.60

Found: C, 59.75; H, 6. 21; N, 12.41

(3S) 3- {N- [4- [3- (4-methoxyphenyl) propyl] imidazole-2-carbonyl] -L-prolinyl} amino-4-oxobutanoic acid (21e) white Separated as glassy solid (65%): mp 101-105 ° C.

Elemental Analysis for _{C 23 H 28 N 4 O 6} · H 2 O

Theoretical: C, 58.22; H, 6. 37; N, 11.81

Found: C, 58.39; H, 6. 34; N, 11.45

FABMS m / e 457 (M ⁺ ), 405, 312, 243, 215, 176, 154 (100%)

(3S) 3- {N- [4- [3- (4-hydroxyphenyl) propyl] imidazole-2-carbonyl] -L-prolinyl} amino-4-oxobutanoic acid (21f) white Separate as a glassy solid (43%). mp 114-118 ° C .;

Elemental Analysis for _{C 22 H 26 N 4 O 6} · H 2 O

Theoretic value: C, 57,38; H, 6, 13; N, 12.17

Found: C, 57.68; H, 6. 25; N, 11.66

FABMS m / e 443 (M ⁺ ), 298, 229, 154 (100%)

3 (S)-[(1- {5- [3- (4-methoxyphenyl) propyl] -1 H-imidazole-2-carbonyl} -4 (R) -phenoxy pyrrolidine-2 (S ) -Carbonyl) amino] -4-oxobutanoic acid (22e) was isolated as a beige solid (43%).

[Bungungsik 5]

{Phenethyl- [5- (3-propyl) -1H-imidazole-2-carbonyl] amino} acetic acid t-butyl ester (23)

4- (3-phenylpropyl) imidazole-2-carboxyl (13d) (150 mg, 0.65 mmol) and N- (2-phenethyl) glycine t-butyl ester (140 mg, in 5 ml anhydrous dimethylformamide) 0.59 mmol) of the 0 ° C. solution was diluted with diisopropylethylamine (154 μl, 0.89 mmol), hydroxybenzotriazole (160 mg, 1.18 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide Treated with hydrochloride (136 mg, 0.71 mmol). After stirring for 36 hours, the reaction was poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed twice with saturated aqueous sodium bicarbonate solution (twice) and saturated aqueous sodium chloride solution (once), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a brown oil. Chromatography (flash, SiO ₂ , 30% ethyl acetate / hexanes) afforded 160 mg (61%) of compound (23) as a white solid.

(3S)-(2-phenethyl- [5- (3-phenylpropyl) -1H-imidazole-2-carbonyl] amino} acetylamino) 4-oxobutanoic acid t-butyl ester semicarbazone (24)

The ester compound 23 (160 mg, 0.357 mmol) was treated with 25% trifluoroacetic acid / dichloromethane (7 mL) for 4 hours. The reaction was concentrated in vacuo to yield 180 mg of the acid. Acid (180 mg, 0.357 mmol) was converted to (3S) -3-amino-4-oxobutanoic acid t-butyl ester semicarbazone (161 mg, 0.357 mmol) as described for the preparation of compounds (5a) and (5b). ) To 86 mg (33%) of Compound (24) (one diastereomer) as a white solid.

(3S)-(2- {phenethyl- [5- (3-phenylpropyl) -1H-imidazole-2-carbonyl] amino} acetylamino) -4-oxobutanoic acid trifluoroacetic acid salt (25) Was prepared by the method described for compound (7a) to give 32 mg (82%) as a white solid.

7- [5- (3-phenylpropyl) -1H-imidazole-2-carbonyl] -1,4-dithia-7-azaspiro [4,4] nonan-8 (S) -methyl carboxylic acid Ester (26)

4- (3-phenylpropyl) imidazole-2-carboxylic acid (13d) was converted to 1,4-dithia-7-azaspiro [4.4] nonan-8 (S) -carboxylic acid methyl ester hydrobromide [ REFERENCES: Smith Smith, J. Med. Chem., 31, 875-85 (1988)] by the method described for compound (23) above to give 140 mg (65%) as a yellow gum.

(3S)-({7- [5- (3-phenylpropyl) -1H-imidazole-2-carbonyl] -1,4-dithia-7-azas

Fatigue [4.4] nonane-8 (S) -carbonyl} -amino) -4-oxobutanoic acid t-butyl ester semicarbazone (27)

Following the procedure described in compound (4), ester (26) is converted to its acid, followed by (3S) -3-amino-4-oxobutanoic acid t-butylester semicarr as described in compound (24). Coupling to vazone gave 70 mg (33%) as a brown solid.

(3S)-({7- [5- (3-phenylpropyl) -1H-imidazole-2-carbonyl] -1,4-dithia-7-azaspiro [4.4] nonane-8 (S)- Carbonyl} -amino) -4-oxobutanoic acid (28) was prepared by the procedure described for compound (7a) to yield 17 mg (26%) as a light brown solid.

Scheme 6

4,5-dihydroimidazole-4-carboxylic acid ester (29) was prepared by modifying the procedure described in Jones et al., Tetrahedron Lett., 29, pages 3853-56 (1988).

(4R, S) methyl 2- (2-phenylethyl) -4,5-dihydroimidazole-4-carboxylate (29a)

Anhydrous hydrogen chloride was bubbled into a solution of hydrocinnamononitrile (3.28 mL, 25 mmol) in methanol (125 mL) at 0 ° C. for 45 min. The solvent was removed to give the imidate salt, which was dissolved in methanol (125 mL) with methyl 2,3-diaminopropionate (25 mmol) [Ref .: Jones D., homology]. The mixture was kept at room temperature for 2.5 hours and then concentrated to give a yellow oil The crude product was purified by column chromatography (10-20% methanol / dichloromethane) to give 3.52 g (61%) of a colorless glass material.

(4R, S) Methyl 2- [2- (4-trifluoromethylphenyl) ethyl] -4,5-dihydroimidazole-4-carboxylate (29b) was prepared by the method described for compound (29a). 6.80 g (78%) of a colorless solid were obtained.

Imidazole-4-carboxylic acid ester (30), see Martin et al., J. Org . Chem ., 33, pages 3758-61 (1968).

Methyl 2- (2-phenylethyl) imidazole-4-carboxylate (30a)

(4R, S) methyl 2- (2-phenylethyl) -4,5-dihydroimidazole-4-carboxylate (29a) (3.40 g, 14.64 mmol), chloroform (75 mL) and manganese oxide (IV ) (13.0 g, 150 mmol) was heated at reflux for 21 h and then filtered at high temperature. The solid was washed with chloroform and methanol. The combined filtrates were concentrated to give a tan solid, which was purified by column chromatography (2-5% methanol / dichloromethane) to give 1.46 g (43%) of a pale yellow solid.

Elemental Analysis for C ₁₃ H ₁₄ N ₂ O ₂

Theoretical: C, 67.81; H, 6. 13; N, 12.16

Found: C, 67.70; H, 6. 15; N, 12.16

Methyl 2- [2- (4-trifluoromethylphenyl) ethyl] imidazole-4-carboxylate (30b) was prepared by the method described in compound (30a). It was recrystallized in ethyl acetate to give 1.88 g (33%) of cream crystals.

Elemental Analysis for C ₁₄ H ₁₃ F ₃ N ₂ O ₂

Theoretic value: C, 56.38; H, 4. 39; N, 9.39; F, 19.11

Found: C, 56.23, H, 4.44, N, 9.33, F, 19.08

2- (2-phenylethyl) imidazole-4-carboxylic acid (31a)

A mixture of methyl 2- (2-phenylethyl) imidazole-4-carboxylate (30a) (1.38 g, 6 mmol), methanol (30 mL) and 1M aqueous sodium hydroxide solution (30 mL) was heated to reflux for 16 hours. It was. Methanol was removed under reduced pressure and the resulting aqueous solution was neutralized with 4M hydrochloric acid to precipitate a pale yellow solid. The precipitate was collected, washed with water and dried to give 1.18 g (91%) as a pale yellow solid.

Elemental Analysis for _{C 12 H 12 N 2 O 2} · 0.25H 2 O

Theoretical: C, 65.29; H, 5.71, N, 12.69

Found: C, 65.00; H, 5. 64; N, 12.58

2- [2- (4-trifluoromethylphenyl) ethyl] imidazole-4-carboxylic acid (3Ib) was prepared by the method described in compound 31a to obtain 1.09 g (76%) of a pale yellow solid.

(2R, S, 3S) N 2 - [2- (2- phenylethyl) imidazole-4-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L Alanineamide (32a)

(2R, S, 3S) N ² -t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-in dichloromethane (15 mL) cooled to 0 ° C. L-alanineamide (14) [1.59 g, 4.20 mmol; References: Chapman, Biorg. Med. Chem. Lett. , 2, pp. 613-18 (1992)] was added trifluoroacetic acid (15 mL). The mixture was stirred at 0 ° C. for 1 h and concentrated. After the residue was treated with ether, the ether was removed in vacuo. The procedure was repeated twice to obtain a pale yellow glass material. The solid was dissolved in DMF (20 mL) and diisopropylethylamine (2.19 mL, 12.6 mmol), 2- (2-phenylethyl) imidazole-4-carboxylic acid (31a) (1.0 g, 4.62 mmol) , 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (0.89 g, 4.62 mmol) and hydroxybenzotriazole (1.14 g, 8.40 mmol) were added to the solution. The reaction mixture was stirred at rt for 20 h and then poured into brine. The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (3 × 100 mL), then brine (3 × 100 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by column chromatography (isopropane in 2-10% dichloromethane, isopropanol in 0-6% ethyl acetate) to give 1.10 g (55%) of compound 32a as a diastereomeric mixture.

(2R, S, 3S) N 2 - {2- [2- (4- trifluoromethylphenyl) ethyl] imidazole-4-carbonyl} -N- (tetrahydro-2-benzyloxy-5-oxo- 3-furanyl) -L-alanineamide (32b) was prepared by the method described for compound 32a to give 1.08 g (62%) of a pale yellow glass material.

(2R, S, 3S) N 2 - (2- benzyl-imidazole-4-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- alaninamide ( 32c) to 2-benzylimidazole-4-carboxylic acid [see: Ger. Offen. DE 3427136] was prepared by the method described for compound 32a to give 1.13 g (83%) of a yellow glass material.

(3S) 3- {N- [2- (2-phenylethyl) -imidazole-4-carbonyl] -L-alaninyl} amino 4-oxo butanoic acid (33a; A)

Methanol (2R, S, 3S) in the ^{(50 ㎖) N 2 - [} 2- (2- phenylethyl) be charged with a-4-carbonyl] -N- (tetrahydro-2-benzyloxy-5-oxo- A mixture of 3-furanyl) -L-alanineamide (32a) (1.0 g, 2.10 mmol) and 10% palladium on activated carbon (1.0 g) was stirred under hydrogen atmosphere for 4.5 hours. The resulting mixture was filtered and concentrated to A colorless glass material was obtained. Recrystallization from methanol-diethyl ether gave 510 mg (63%) left colorless solid.

Elemental Analysis for _{C 19 H 22 N 4 O 5} · H 2 O

Theoretic value: C, 56.43; H, 5.98; N, 13.85

Found: C, 56.78; H, 5. 70; N, 13.77

(3S) 3- {N- [2- (2- [4-trifluorometalphenyl] ethyl) imidazole-4-carbonyl] -L-alaninyl} -amino-4-oxobutanoic acid (33b C) was prepared by the method described in compound 33a to yield 612 mg (73%) of a colorless solid.

Elemental Analysis for _{C 20 H 21 F 3 N 4} O 5 · 0.5H 2 O

Theoretical: C, 51.84; H, 4.78; N, 12.09; F, 12.30

Found: C, 51.83; H, 4 72; N, 12.14; F, 12.36

(3S) 3- [N- (2-benzylimidazole-4-carbonyl) -L-alaninyl] amino-4-oxobutanoic acid (33c; B) was prepared by the method described in compound 33a, and 426. mg (64%) of a colorless solid were obtained.

Elemental Analysis for _{C 18 H 20 N 4 O 5} · H 2 O

Theoretical: C, 55.37; H, 5.68; N, 14.35

Found: C, 55.83; H, 5.75; N, 13.96

MS (FAB, m / z): 373 (M ⁺ ), 228, 185, 91

Scheme 7

(a) R = H

(b) R-CH ₂ Ph

5-benzylpyrrole-2-carboxylic acid (34b)

Ethyl 5-benzylpyrrole-2-zacarboxylate [0.7 g, 3.05 mmol; References: Elder et

al., Synthetic Communications , 19, 763-767 (1989)], a mixture of ethanol (20 mL) and 1M sodium hydroxide (9.2 mL, 9.2 mmol) was stirred and heated to reflux for 3 hours. Most of the ethanol was removed and the remaining liquid was diluted with water, washed with ether, cooled with ice and acidified with concentrated hydrochloric acid. The mixture was extracted with ether. The combined extracts were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to yield 0.567 g (92%) of an off-white solid.

(2R, S, 3S) N 2 - ( pyrrole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- alaninamide (35a)

(2R, S, 3S) N ² -t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L in 0 ° C. anhydrous dichloromethane (8 mL) Alanineamide (14) (756 mg, 2.0 mmol) solution was treated with trifluoroacetic acid (8 mL) for 1 hour and then evaporated to dryness. Anhydrous ether was added to the residue and the mixture was concentrated to give a viscous oil. The oil was dissolved in anhydrous DMF (10 mL). Pyrrole-2-carboxylic acid (34a) (244 mg, 2.20 mmol) was added and the solution was cooled in an ice bath, then N, N-diisopropylamine (0.78 g, 6.0 mmol), 1-hydroxy Benzotriazole (0.54 g, 4.0 mmol) and ethyl dimethylaminopropyl carbodiimide hydrochloride (0.42 g, 2.2 mmol) were added. The resulting mixture was stirred at 25 ° C. for 17 h and then saturated aqueous sodium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (3 × 20 mL) and the combined organic extracts were washed with 5% aqueous sodium bicarbonate solution (3 × 10 mL) and brine (10 mL), dried (MgSO ₄ ) and concentrated. Flash chromatography (25% hexane-ethyl acetate) gave 557 mg (75%) of a 1: 1 diastereomeric mixture as a white, glassy solid.

(2R, S, 3S) N 2 - (5- benzyl-pyrrole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L- alaninamide (35b) Was prepared in 5-benzylpyrrole-2-carboxylic acid (34b) by the method described for compound 35a. Data is provided for single diastereomers.

(3S) 3- [N- (pyrrolyl-2-carbonyl) -L-alaninyl] amino-4-oxobutanoic acid (36a, D) compound 35a (612 mg, 1.65 mmol), methanol (40 mL ) And 10% palladium on carbon (500 mg) was vigorously stirred under hydrogen atmosphere for 4 hours. The mixture was filtered through a 0.2 μM nylon membrane and then concentrated. The residue was purified by flash chromatography (methanol in 5-10% methylene chloride) to give hemihydrate (223 mg, 48%) of compound 36a as a white solid, which was then precipitated in an ethyl acetate-ether mixture. Traces of solvent were present in the product.

(3S) 3- [N- (5-benzylpyrrole-2-carbonyl) -L-alaninyl] amino-4-oxobutanoic acid (36b) was prepared from compound 35b by the method described in compound 36a to yield an off-white solid. (41%) was obtained.

Elemental Analysis for _{C 19 H 21 N 3 O 5} · 1.75H 2 O

Theoretic value: C, 56.64; H, 6. 13; N, 10.43

Found: C, 56.34; H, 5.72; N, 10.00

Scheme 8

(2R, S, 3S) 1- (Indole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L-prolineamide (38)

Trifluoroacetic acid (4 mL) was added (2R, S, 3S) 1-t-butoxycarbonyl-N- (tetrahydro-2-benzyloxy-5-oxo-3-fura in dichloromethane (4 mL). Neil) -L-prolineamide (15) (0.6 07 g, 1.5 mmol) solution was added at 0 ° C. The mixture was stirred at 0 ° C. for 75 minutes. The mixture was concentrated and the residue was treated with diethyl ether and then ether was removed in vacuo. The procedure was repeated twice to give a yellow oil which was dissolved in DMF (12 mL). Diisopropylethylamine (0.78 mL, 4.5 mmol) followed by indole-2-carboxylic acid (266 mg, 1.65 mmol), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (316 mg, 1.65 mmol) and hydroxybenzotriazole (405 mg, 3 mmol) were added to the solution. The mixture was stirred at rt for 20 h and then poured into brine. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (2 × 60 mL) followed by brine (2 × 60 mL), dried (MgSO ₄ ), filtered and concentrated. The residue was purified by column chromatography (ethyl acetate) to give 518 mg (77%) of the diastereomer mixture.

(3S) 3- [1- (indole-2-carbonyl) -L-prolinyl] amino-4-oxobutanoic acid (39)

(2R, S, 3S) 1- (Indole-2-carbonyl) -N- (tetrahydro-2-benzyloxy-5-oxo-3-furanyl) -L-prolineamide (38) (478 mg, 1.07 mmol), 10% palladium on carbon (475 mg) and methanol (150 mL) mixture was stirred under hydrogen atmosphere for 6 hours. The resulting mixture was filtered and concentrated to give a colorless glassy material. Methane was recrystallized from and diethyl ether mixture to give 202 mg (53%) of a colorless solid.

Scheme 9

Methyl 2- (3,5-dihydro-7-methyl-4-oxo-4H-pyrrolo [3,2-d] pyrimidin-3-yl) acetate (40)

Freshly prepared methyl glycinate (1.25 g, 14 mmol) was added ethyl 3- [N- (dimethylamino) methylene] amino-4-methylpyrrole-2-carboxylate [1.56 g, in anhydrous methanol (60 mL), 7.0 mmol; Rim Ildong, J Org. Chem., 44, pages 3826-29 (1979)]. The resulting mixture was kept at 70 ° C. Two additional batches of methyl glycinate (1.25, 14.0 mmol) were cooled and filtered 24 hours after the last addition. The filtrate was concentrated and the residue was purified by flash chromatography (2-5% methanol / chloroform) to yield 0.54 g (35%) of white crystalline solid. mp 233-235 ° C. (recrystallized from ethyl acetate)

_{C 10 H 11 N 3 O 3} · 0.1H ₂ O Elemental Analysis for

Theoretical: C, 53.85; H, 5.07; N, 18.84

Found: C, 53.85; H, 4.96; N, 18.81

MS (70eVE.I.) M / e 222, 221 (M ⁺ , 100%), 189, 162, 133, 105

2- (3,5-Dihydro-7-methyl-4-oxo-4H-pyrrolo [3,2-d] pyrimidin-3-yl) acetic acid, sodium salt (41)

A suspension of compound (354 mg, 1.6 mmol) in methanol (l 5 mL) was treated with 0.5 N sodium hydroxide (4.8 mL) and the resulting mixture was stirred at 25 ° C. for 1 h. The reaction mixture was filtered to give hemihydrate (354 mg, 97%) of compound 41 as a white crystalline solid. mp> 340 ° C (recrystallized from methanol)

Elemental Analysis for C ₉ H ₈ N ₃ O ₃ Na · 0.5H ₂ O

Theoretical: C, 45.39; H, 3.81; N, 17.64

Found: C, 45.57; H, 4.05; N, 17.39

(2R, S, 3S) 2- (3,5-Dihydro-7-methyl-4-oxo-chae-pyrrolo [3,2-d] pyrimidin-3-yl) -N- (tetrahydro- 2-benzyloxy-5-oxo-3-furanyl) acetamide (42)

A suspension of sodium salt 41 (344 mg, 1,5 mmol) in anhydrous DMF (15 mL) was added to ethyl dimethylaminopropylcarbodiimide hydrochloride (373 mg, 1.95 mmol) and 1-hydroxybenzotriazole (405 mg, 3.0 mmol). Dealt with. The mixture was kept at 25 ° C. for 1 hour and then (2R, S, 3S) N-allyloxycarbonyl-3-amino-2-benzyloxy-5-oxotetrahydrofuran (437 mg, 1.5 mmol; Chapman, Bioorg Med. Chem. Lett, 2, pages 613-18 (1992)] and (Ph ₃ P) ₂ PdCl ₂ (25 mg) were added followed by the dropwise addition of hydrogenated n-tributyltin (0.6 mL, 2.25 mmol). The resulting mixture was stirred for 1 h at 25 ° C. and water (20 mL) was added The mixture was extracted with ethyl acetate (3 × 15 mL) and the combined organic extracts were washed with water (5 mL), Dry (MgSO ₄ ) and concentrate to give the diastereomeric mixture, evaporate the aqueous phase and purify the residue by flash chromatography (5% methanol / chloroform) to add an additional content of 182 mg of compound 42 (31%). Mp 240-244 ° C.

(3S) -3- [2- (3,5-Dihydro-7-methyl-4-oxo-4H-pyrrolo [3,2-d] pyrimidin-3-yl) -1-oxo-ethylamino ] -4-oxobutanoic acid (43)

Compound 42 (131 mg, 0.33 mmol) and 10% palladium on carbon (100 mg) mixture in methanol (50 mL) was vigorously stirred under hydrogen atmosphere for 2 hours. Additional content of catalyst (100 mg) was added and the mixture was hydrogenated for an additional 2 hours. The mixture was filtered through a 0.2 μM nylon membrane and concentrated. The residue was recrystallized in methanol / diethyl ether to give 79 mg (78%) of compound 43 as a hygroscopic white solid.

Elemental Analysis for _{C 13 H 14 N 4 O 5} · 1.4H 2 O

Theoretical: C, 47.10; H, 5. 12; N, 16.90

Found: C, 47.00; H, 4.79; N, 16.59

FABMS m / e 307, 306 (M ⁺ ), 244, 207, 190, 152, 115 (100%)

Scheme 10

(1S, 9S) t-Butyl 6,10-dioxo-octahydro-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1 Carboxylate (44a)

(1S, 9S) t-butyl 9-amino-6,10-dioxo-octahydro-6H-pyridazino [1,2-a] [1,2 in dioxane (16 mL) and water (4 mL) 2] Sodium bicarbonate (292 mg, 3.48 mmol) was added to a solution of diazepine-1-carboxylate (690 mg, 2.32 mmol; GB 2128984), followed by 3-phenylpropionyl chloride (470 mg, 2.78 mmol). I dropped it. After the mixture was stirred at room temperature for 2 hours, more sodium bicarbonate (200 mg, 2.38 mmol) and 3-phenylpropionyl chloride (100 mg, 0.6 mmol) were added. The mixture was stirred for an additional 2 h at rt, diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution (2 × 25 mL), dried (mgSO ₄ ) and concentrated. The residue was purified by flash chromatography (0-50% ethyl acetate / chloroform) and finally dispersed in ether to crystallize to yield 860 mg (86%) of a white solid. mp 137-138 ℃

(1S, 9S) t-butyl octahydro-10-oxo-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxyl Rate (44b) was converted to (1S, 9S) t-butyl 9-amino-octahydro-10-oxo-6H-pyridazino [1,2-a] [1,2] diazepine- by the method described in compound 44a. 1-carboxylate [Atwood et al., J. Chem. Soc. Perkin 1, pages 1101-19 (1986), yielded 810 mg (81%) of a colorless oil.

(1S, 9S) 6,10-dioxo-octahydrogol- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid (45a)

(1S, 9S) t-butyl 6,10-dioxo-octahydro-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [in anhydrous dichloromethane (5 mL) [ To the solution of 1,2] diazepine-1-carboxylate (44a) (800 mg, 1.863 mmol) trifluoroacetic acid (5 mL) was added at 0 ° C. The solution was stirred at rt for 3 h and then concentrated. Anhydrous ether (10 mL) was added to the residue and then removed in vacuo. The method was repeated three times to obtain a crystalline solid. The solid was dispersed with ether and filtered to yield 590 mg (85%) of white crystalline solid.

(1S, 9S) octahydro-10-oxo-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid (45b ) (1S, 9S) t-butyl octahydro-10-oxo-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1) by the method described for compound 45a , 2] produced in diazepine-1-carboxylate (44b) to give 657 mg (96%) of compound 45b as a crystalline solid.

[3S, 2R, S, (1S, 9S)] N- (2-Benzyloxy-5-oxotetrahydrofuran-3-yl) -6,10-dioxo-octahydro-9- (3-phenylpropy Onylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxamide (46a)

(1S, 9S) 6,10-dioxo-octahydro-9- (3-phenylpropionylamino) -6H-pyridazino [1 in anhydrous dichloromethane (9 mL) and anhydrous dimethyl formamide (3 mL) Bis (triphenylphosphine) palladium chloride (30 mg) and (3S, 2R) in a ,, 2-a] [1,2] diazepine-1-carboxyl (45a) (662 mg, 1.773 mmol) solution at room temperature , S) -3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran [chapman, Biorg. Med Chem. Lett., 2, pages 613-18 (1992)] (568 mg, 1.95 mmol), followed by the dropwise addition of hydrogenated tri-n-butyl tin (1.19 g, 4.09 mmol). 1-hydroxybenzotriazole (479 mg, 3.546 mmol) was added to the mixture and the mixture was cooled to 0 ° C., followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (408 mg, 2.128 mmol) was added. The mixture was stirred at rt for 3.25 h, diluted with ethyl acetate (50 mL), twice with dilute hydrochloric acid (20 mL), twice with saturated sodium bicarbonate (20 mL), once with brine, and dried ( MgSO ₄ ) and concentrated. The resulting oil was purified by flash chromatography (0-100% ethyl acetate / chloroform) to yield 810 mg (81%) of compound 46a as an anomer mixture.

[3S, 2R, S (1S, 9S)] N- (2-Benzyloxy-5-oxotetrahydrofuran-3-yl) -octahydro-10-oxo-9- (3-phenylpropionylamino)- 6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxamide (46b) was prepared in compound 45b by the method described for compound 46a to give 790 mg (96%) of glass Obtained the material.

[3S, (1S, 9S)] 3- (6,10-Dioxo-octahydro-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] Diazepine-1-carboxamido) -4-oxobutanoic acid (47a)

[3S, 2R, S, (1S, 9S)] N- (2-Benzyloxy-5-oxotetrahydrofuran-3-yl) -6,10-dioxo-octahydro-9- (3-phenylpropy Onylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxamide (46a) (205 mg, 0.364 mmol), 10% palladium on carbon (200 mg) and The methanol (20 mL) mixture was stirred under atmospheric hydrogen for 5 hours. The mixture was filtered and then concentrated to give 154 mg (90%) of glass.

Elemental Analysis for _{C 23 H 27 N 4 O 7} · H 2 O

Theoretical: C, 56.32; H, 6. 16; N, 11.42

Found: C, 56.29; H, 6. 11; N, 11.25

MS (FAB, m / z) 473 (M ⁺ +1), 176, 149, 105, 91

[3S, (1S, 9S)] 3- (Otahydro-10-oxo-9- (3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine- 1-Carboxamido) -4-oxobutanoic acid (47b) was prepared in compound 46b by the method described for compound 47a. The residue was purified by flash chromatography (0-10% methanol / chloroform) to give 65 mg (52%) of glass.

Elemental Analysis for _{C 23 H 30 N 4 O 6} · 0.5H 2 O

Theoretical: C, 59.09; H, 6.68; N, 11.98

Found: C, 58.97; H, 6.68; N, 11 73

MS (FAB, m / z) 459 (M ⁺ + l), 310, 149, 105, 91

Scheme 11

Pyridone 48, see Damwood et al., J. Med. Chem., 37, pages 3303-12 (1994). Compound 48d is novel.

3-benzyloxycarbonylamino-6-butyl-pyrid-2-one (48d) was isolated as a cream solid.

Elemental Analysis for C ₁₇ H ₂₀ N ₂ O ₃

Theoretical: C, 67.98; H, 6. 71; N, 9.33

Found: C, 67.69; H, 6.68; N, 9.20

MS CI M ⁺ = 300 (m) 28%

(2S) methyl 2- [3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl] propionate (49a)

Sodium hydride (80%, oil dispersion) (0.35 g, 11.64 mmol) was added 3- (benzyloxycarbonylamino) pyrid-2-one (48a) (2,58 g, 10.58 mmol) and tetrahydrofuran ( 100 ml) was added to the stirred mixture. The mixture was stirred for 10 minutes. The resulting solution was diluted with 2 (R) methyl-2-((trifluoromethane) sulfonyloxy) propionate [2.5 g, 10.58 mmol in tetrahydrofuran (5 mL); Reference: Pinstra Illon, Tetrahedron Lett., 28, pages 1215-18 (1987)] were added to the solution for 10 minutes at room temperature. The mixture was stirred at rt for 80 min and then poured into ethyl acetate. The mixture was washed twice with 1M HCl and twice with aqueous sodium bicarbonate solution followed by brine. It was dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (30% ethyl acetate / hexanes) to yield 2.945 g (84%) of a colorless solid.

Elemental Analysis for C ₁₇ H ₁₈ N ₂ O ₅

Theoretical: C, 61.81; H, 5.49; N, 8.48

Found: C, 61.49; H, 5.51; N, 8.41

MS (FAB, m / z) 331 (M ⁺ +1), 299, 223, 196, 163, 91

Methyl [6-benzyl-3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl] acetate (49b)

Sodium hydride (80%, oil dispersion) (0.65 g, 26.2 mmol) was added 6-benzyl-3- (benzyloxycarbonylamino) pyrid-2-one (48b) (7.3 g, 2.18 mmol) and tetra at room temperature. To a stirred mixture of hydrofuran (150 mL) was added. The mixture was stirred for 10 minutes, treated with methyl bromoacetate (2.5 mL, 26.2 mmol) and maintained for 3 hours. The resulting solid is filtered off and dissolved in dichloromethane. The resulting solution was dried (MgSO ₄ ), bleached with activated charcoal and concentrated. The residue was purified by flash chromatography (2-5% ethyl acetate / dichloromethane) to give 7.2 g (81%) of colorless crystals.

The following compounds were prepared in a similar manner.

Methyl [3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-6-phenethyl-1-pyridyl] acetate (49c) yield 97%

Methyl [3-benzyloxycarbonylamino-6-butyl-1,2-dihydro-2-oxo-1-pyridyl] acetate (49d) yield 90%

Yield of methyl [3-benzyloxycarbonylamino-1,2-dihydro-6-methyl-2-oxo-1-pyridyl] acetate (49e) 84%, colorless solid

Yield of methyl [3-benzyloxycarbonylamino-1,2-dihydro-6-phenyl-1-pyridyl] acetate (49f) 67%, colorless oil

Methyl [3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl] acetate (49 g) yield 80%, colorless crystalline solid

Elemental Analysis for C ₁₆ H ₁₆ N ₂ O ₅

Theoretical: C, 60 75; H, 5. 10; N, 8.85

Found: C, 60.65; H, 5. 15; N, 8.85

MS FAB (+) M + = 317 (M + 1)

Preparation of Compound 49a by 2 (S) methyl 2-methyl- [6-benzyl- (3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl] Arthur 1tate (49h) Prepared by the method used for the yield of 58% oil.

Methyl [6-benzyl-1,2-dihydro-2-oxo- (2-phenylethoxy) carbonylamino-1-pyridyl] acetate (49i) was isolated as a 88% colorless solid.

Scheme 12

(2S) methyl 2- [3-amino-1, 2-dihydro-2-oxo-1-pyridyl] propionate (50a)

2 (S) methyl-2- [3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl] propionate (49a) (2.75 g, 8.33 mmol), methanol (100 ML) and 10% palladium on carbon (300 mg) mixture was stirred under hydrogen atmosphere for 30 minutes. The mixture was filtered and concentrated to yield 1.63 g (100%) of a colorless solid.

The following compounds were prepared in a similar manner.

Methyl [3-amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl] acetate (50b) yield 100%, gray solid

Methyl [3-amino-1, 2-dihydro-2-oxo-6-phenethyl-1-pyridyl] acetate (50c) yield 99%, viscous oil

Methyl [3-amino-6-butyl-1,2-dihydro-2-oxo-1-pyridyl] acetate (50d) yield 97%, brown solid

Methyl [3-amino-1, 2-dihydro-6-methyl-2-oxo-1-pyridyl] acetate (50e) was isolated as a colorless crystalline solid (100%).

Methyl [3-amino-1, 2-dihydro-2-oxo-6-phenyl-1-pyridyl] acetate (50f) was isolated as a gray solid (86%).

Methyl [3-amino-1, 2-dihydro-2-oxo-1-pyridyl] acetate (50 g) was obtained as a colorless oil which was used directly in the next step.

2 (S) Methyl 2-methyl- [3-amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl] acetate (50 h) was isolated as a colorless oil (69%).

Scheme 13

2 (S) Methyl 2- [1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] propionate (51a)

3-phenylpropionyl chloride (1.5 g, 9 mmol) was added to 2 (S) methyl-2- [3-amino-1, 2-dihydro-2-oxo-1-pyridyl] propionate (50a) ( 1.63 g, 8.33 mmol), dioxane (60 mL), water (15 mL) and sodium bicarbonate (1.54 g, 16.7 mmol) were added dropwise to a stirred mixture. The mixture was kept for 1 h and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and concentrated. The resulting red oil was purified by flash chromatography to yield 2.54 g (93%) of oil.

The following compounds were prepared in a similar manner.

Methyl [6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51b) was isolated as crystals (93%).

Methyl [1,2-rihydro-2-oxo-6-phenethyl-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51c) was isolated as colorless crystals (81%).

Methyl [6-butyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51d) was isolated as colorless crystals (88%).

Methyl [1,2-dihydro-6-methyl-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51e) was isolated as pale yellow oil (100%).

Methyl [1,2-dihydro-2-oxo-6-phenyl-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51f) was isolated as pale yellow oil (99%).

Methyl [1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51 g) was isolated as an oil (8 l%).

2 (S) methyl 2-methyl- [6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetate (51h) was colorless oil (93 %).

Methyl [3- (N-acetyl-0-benzyl-L-tyrosine) amino-6-benzyl-1,2-dihydro-2-oxo-pyridyl] acetate (51i)

Methyl [3-amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl] acetate (100 mg,

0.367 mmol), Boc-Tyr (Bn) -OH (136 mg, 0.367 mmol), dimethylformamide (1 mL), diisopropylethylamine (0.25 mL, 1.468 mmol) and 2- (1H-benzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (118 ms, 0.367 mmol) was maintained at room temperature overnight The mixture was diluted with ethyl acetate and twice with 1M hydrochloric acid, sodium bicarbonate Washed twice with aqueous solution and once with brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (10% ethyl acetate / dichloromethane) to give 162 mg (70%) of a colorless oil. Oil (160 mg, 0.255 mmol) was dissolved in dichloromethane (1 mL) and treated with trifluoroacetic acid (1 mL) at 0 ° C. The resulting solution was allowed to come to room temperature for 40 minutes and evaporated to dryness at 30 ° C. The residue was dissolved in dichloromethane and then evaporated to dryness. The procedure was repeated three times. The residue was dissolved in pyridine (0.5 mL) and treated with acetic anhydride (0.03 mL, 0.3 mmol) at 0 ° C. The resulting mixture was allowed to come to room temperature and held for 3.5 hours. It was diluted with ethyl acetate, washed twice with 1M hydrochloric acid and twice with aqueous sodium bicarbonate solution, dried (MgSO ₄ ) and concentrated to give 128 mg (86%) of a colorless oil.

Methyl [6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethanesulfonyl) amino-1-pyridyl] acetate (51j)

2-phenylethanesulfonyl chloride [Reference: Jong Il, J. Am. Chem. Soc., 113, 2259-63 (1991)] methyl [3-amino-6-benzyl-2-oxo-1,2-dihydro-1-pyridyl] acetate (49b) (1.0 g, 3.67 mmol) To a stirred mixture of dichloromethane (15 mL) and triethylamine (1.0 mL, 7.34 mmol). The mixture was left overnight and poured into ethyl acetate. The resulting mixture was washed twice with aqueous sodium bicarbonate solution, twice with 1M hydrochloric acid and brine. It was dried (MgSO ₄ ) and concentrated. The resulting light brown solid was purified by flash chromatography (10% ethyl acetate / dichloromethane) to yield 1.25 g (77%) of a pale yellow solid.

Methyl [6-benzyl-1,2-dihydro-2-oxo-3- (4-phenylbutyryl) amino-1-pyridyl] acetate (51 L) was isolated as colorless crystals (74%).

Scheme 14

2 (S) 2- [1,2-dihydro-2-oxozin- (3-phenylpropionyl) amino-1-pyridyl] propionic acid (52a)

1 M sodium hydroxide (15 mL, 15 mmol) was dissolved in 2 (S) methyl 2- [1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyri in methanol (30 mL). To a stirred solution of dill] propionate 51a (2.39 g, 7.3 mmol) was added at 0 ° C. The mixture was kept at this temperature for 2 hours, acidified with 1M hydrochloric acid (15.1 mL) and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated to yield 1.98 g (87%) of a colorless solid.

The following compounds were prepared in a similar manner.

[6-Benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52b) was obtained as a light amber oil (100%).

[1,2-Dihydro-2-oxo-6-phenethyl-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52c) was obtained as a beige solid (94%).

[6-Butyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52d) was obtained as a light brown solid (99%).

[1,2-Dihydro-6-methyl-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52e) was obtained as a solid (100%).

[1,2-Dihydro-2-oxo-6-phenyl-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52f) was obtained as a pale yellow foam (100%).

[1,2-Dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] acetic acid (52 g) was obtained as a colorless solid (94%).

2 (R, S) 2- [6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] propionic acid (52h) was used at 40 DEG C for 5 hours. Was prepared by hydrolysis reaction of compound 51h in aqueous tetrahydrofuran at to give as a pale yellow oil (95%).

[3- (acetyl-Tyr (Bn)) amino-6-benzyl-1,2-dihydro-2-oxo-1-pyridyl] acetic acid (52i) was isolated as a foam (93%).

[6-Benzyl-1,2-dihydro-2-oxo-3- (2-phenylethanesulfonyl) amino-1-pyridyl] acetic acid (52j) was isolated as a colorless solid (100%).

Hydrolysis of Compound 49i with [6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethoxy) carbonylamino-1-pyridyl] acetic acid (52k) at 60 ° C. for 1 hour Prepared by reaction. 70%)

[6-Benzyl-1,2-dihydro-2-oxo-3- (4-phenylbutyryl) amino-1-pyridyl] acetic acid (52 L) was isolated as a white foam (100%).

Scheme 15

2 (S) N-3 (S) 2- [1,2-dihydro-2-oxolett- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy-5- Oxotetrahydrofuran-3-yl) propionamide (53a)

Hydrogenated tri-n-butyltin (1.7 mL, 6.3 mmol) to 2 (S) -2- [1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] Propionic acid (52a) (1.1 g, 3.49 mmol), 3 (S), 2 (R, S) 3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran (1.02 g, 3.49 mmol); Chapterman, Biorg. Med, Chem. Lett., 2, pages 613-18 (1992)], in a stirred mixture of bis (triphenylphosphine) palladium (II) chloride (55 mg), dichloromethane (35 mL) and dimethylformamide (1 mL). I dropped it. The resulting mixture was stirred for 5 minutes and 1-hydroxybenzotriazole (946 mg, 7 mmol) was added. After the mixture was cooled to 0 ° C., 1- (3-dimethylaminopropyl) -2-ethylcarbodiimide hydrochloride (740 mg, 3.84 mmol) was added. The mixture was kept at room temperature overnight and then poured into ethyl acetate. The mixture was washed twice with 1M hydrochloric acid, twice with sodium bicarbonate and brine. The mixture was dried (MgSO ₄ ) and concentrated. The residue was triturated with pentane and the remaining solids were purified by flash chromatography (40-60% ethyl acetate / hexanes) to yield 1.28 g (73%) of a colorless solid.

The following compounds were prepared in a similar manner.

N (3 (S)) 2- [6-Benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy- 5-oxotetrahydrofuran-3-yl) acetamide (53b) was obtained as a foam (86%).

N (3 (S)) 2- [1,2-dihydro-2-oxo-6-phenethyl-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy -5-oxotetrahydrofuran-4-yl) acetamide (53c) was obtained as anomer mixture (74%).

N (3 (S)) 2- [6-Butyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy- 5-oxotetrahydrofuran-3-yl) acetamide (53d) was obtained as anomer mixture (74%).

N (3 (S)) 2- [1,2-Dihydro-6-methyl-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy- 5-oxotetrahydrofuran-3-yl) acetamide (53e) was obtained as anomer mixture (67%).

N (3 (S)) 2- [1,2-Dihydro-2-oxo-6-phenyl-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy- 5-oxotetrahydrofuran-3-yl) acetamide (53f) was obtained as anomer mixture (73%).

N (3 (S)) 2- [1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy-5-oxotetra Hydrofuran-3-yl) acetamide (53 g) was obtained as anomer mixture (70%).

Elemental Analysis for _{C 27 H 27 N 3 O 6} · H 2 O

Theoretical: C, 63.90; H, 5. 76; N, 8,28

Found: C, 63.70; H, 5.68; N, 8.22

MS FAB M ⁺ = 490 (M + 1)

2 (R, S) N (3 (S)) 2- [6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy-5-oxotetrahydrofuran-3-yl) propionamide (53h) was obtained as a mixture of diastereomers (89%). Data is for single diastereomers.

N (3 (S)) 2- [6-Benzyl-1,2-dihydro-2-oxo-3- (N-acetyl-O-benzyltyrosinyl) amino-1-pyridyl] -N- (2-benzyloxy-5-oxotetrahydrofuran-3-yl) acetamide (53i) was obtained as anomer mixture (76%).

N (3 (S)) 2- [6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethanesulfonyl) amino-1-pyridyl] -N- (2-benzyloxy -5-oxotetrahydrofuran-3-yl) acetamide (53j) was obtained as anomer mixture (78%).

N (3 (S)) 2- [6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethoxy) carbonylamino-1-pyridyl] -N- (2-benzyl Oxy-5-oxotetrahydrofuran-3-yl) acetamide (53k) was obtained as anomer mixture (78%).

N (3 (S)) 2- [6-benzyl-1,2-dihydro-2-oxo-3- (4-phenylbutyryl) amino-1-pyridyl] -N- (2-benzyloxy- 5-Oxotetrahydrofuran-3-yl) acetamide (53 L) was obtained as a colorless oil (86%).

Scheme 16

3 (S), N (2 (S)) 3- (2- (1,2-dihydro-2-oxo-3- (3-phenylpropionylamino-1-pyridyl) propionylamino) -4 Oxobutanoic acid (54a; F)

2 (S), N (3 (S)) 2- [1,2-dihydro-2-oxozin- (3-phenylpropionyl) amino-1-pyridyl] -N- (2-benzyloxy- A mixture of 5-oxotetrahydrofuran-3-yl) propionamide (53a) (1.28 g, 2.5 mmol), methanol (140 mL), ethyl acetate (60 mL) and 10% palladium on carbon (1.4 g) was hydrogenated. Stirred under atmosphere. After 2.5 hours, catalyst (300 mg) was added and hydrogenation continued for 1 hour. The mixture was filtered through Celite ™, refiltered again to 0.2 μM nylon fibers and concentrated. The residual oil was triturated with methane and ether mixtures to give 916 mg (87%) of colorless crystals.

Elemental Analysis for C ₂₁ H ₂₃ N ₃ O ₆ · 0.75H ₂ O

Theoretical: C, 59.08; H, 5.78; N, 9.84

Found: C, 59.24; H, 5.96; N, 9.84

FAB M ⁺ = 414 (M + 1), 297, 165, 91

The following compounds were prepared in a similar manner.

3 (S) 3- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54b; M ) Was separated into colorless crystals (59%).

Elemental Analysis for C ₂₇ H ₂₇ N ₃ O ₆ · 0.7H ₂ O

Theoretic value: C, 64.58; H, 5. 70; N, 8.37

Found. C, 64.51; H, 5.63; N, 8.38

MS FAB + M ⁺ = 490 (M + 1)

3 (S) 3- (1,2-dihydro-2-oxo-6-phenethyl-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54c) Was separated into a white solid (46%).

3 (S) 3- (6-butyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54d) Separated as colorless crystals (90%).

Elemental Analysis for _{C 24 H 29 N 3 O 6} · 0.5H 2 O

Theoretical: C, 62.06; H, 6.51; N, 9.05

Found: C, 62.08; H, 6. 43; N, 9.01

MS FAB + M ⁺ = 456 (M + 1)

3- (S) 3- (1,2-dihydro-group-methyl-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54e) colorless Separated as a solid (85%).

Elemental Analysis for _{C 21 H 22 N 3 O 6} · H 2 O

Theoretic value: C, 58.46; H, 5. 84; N, 9.74

Found: C, 58.82; H, 60.5; N, 9.42

3 (S) 3- (1,2-dihydro-2-oxo-6-phenyl-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54f) off-white Solid (73%)

Foamed 3 (S) 3- (1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54 g, G) (73%).

Elemental analysis for C ₂₀ H ₂₁ N ₃ O ₆ · 0.6H ₂ O

Theoretical: C, 58.50; H, 5. 45; N, 10.24

Found: C, 58 43; H, 5. 35; N, 9.85

MS FAB + M ⁺ = 400 (M + 1)

3 (S), N (2 (R, S)) 3- (2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl ) Propionylamino) -4-oxobutanoic acid (54h) was obtained as a colorless foam (69%).

Elemental analysis for C ₂₈ H ₂₉ N ₃ O ₆ · 1.25H ₂ 0

Theoretic value: C, 63.93; H, 6.03; N, 7.99

Found: C, 63,98; H, 5.85; N, 7.86

MS FAB (+) M ⁺ = 504 (M + 1)

3 (S) 3- (3- (2-acetyl-L-tyrosinyl) amino-6-benzyl-1,2-dihydro-2-oxo-1-pyri

Dyl) acetylamino-4-oxobutanoic acid (54i) was obtained as colorless crystals (79%).

Elemental Analysis for C ₂₉ H ₃₀ N ₄ O ₈ · 2H ₂ O

Theoretic value: C, 58.19; H, 5.72; N, 9.36

Found: C, 58.11; H, 5.63; N, 9.29

MS FAB + M ⁺ = 563 (M + 11)

3 (S) 3- (6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethanesulfonyl) amino-1-pyridyl) acetylamino-4-oxobutanoic acid (54j) Was separated as a colorless solid (85%).

Elemental Analysis for C ₂₆ H ₂₇ N ₃ O ₇ S · 1.7H ₂ O

Theoretical: C, 56.14; H, 5.51; N, 7.55

Found: C, 56.20; H, 5.49; N, 7.29

MS FAB (+) M ⁺ = 526 (M + 1)

3 (S) 3- (6-benzyl-1,2-dihydro-2-oxo-3- (2-phenylethoxy) carbonylamino-1-pyridyl) acetylamino-4-oxobutanoic acid (54k ) Was isolated as off-white solid (54%).

3 (S) 3- (6-benzyl-1,2-dihydro-2-oxo-3- (4-phenylbutyryl) carbonylamino-1-pyridyl) acetylamino-4-oxobutanoic acid (54 L ) Was isolated as a white solid (50%).

Elemental Analysis for _{C 28 H 29 N 3 O 6} · 1.5H 2 0

Theoretic value: C, 63.39; H, 6.08; N, 7.92

Found: C, 63.69; H, 5. 74; N, 7.83

Scheme 17

t-butyl N-2- (3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl) acetyl-3-amino-5- (2,6-dichlorobenzoyloxy)- 4-oxopentanoate (56a)

Acetic acid (55a) (WO93 / 21213) in THF (2 mL) was stirred at room temperature, 1-hydroxybenzotriazole (60 ms, 0.448 mmol) and dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (47 mg , 0.246 mmol). After 5 minutes, water (2 drops) was added and stirring continued for 20 minutes. Bis (triphenylphosphine) palladium (II) chloride (6 mg) was added, followed by t-butyl 3- (allyloxycarbonylamino) -4-oxo-5- (2,6) in THF (1 mL). A solution of dichlorobenzoyloxy) pentanoate (WO93 / 16710) (103 mg, 0.224 mmol) was added. Hydrogenated tributyl tin (0.09 mL, 0.336 mmol) was added dropwise at room temperature over 1 hour. The mixture was stirred for an additional 3 hours, poured into ethyl acetate, washed with 1M HCl, aqueous NaHCO ₃ , brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dispersed with pentane and the supernatant was discarded. The remaining solid was purified by flash chromatography (50% ethyl acetate / hexanes) to give 92 mg (63%) of a colorless oil of the title compound.

t-butyl N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetyl-3-amino-5- (2, 6-dichlorobenzoyloxy) -4-oxopentanoate (56b) was prepared by the method described for compound 56a to give the title compound (66%) as a colorless oil.

Scheme 18

N-2- (3-benzyloxycarbonylamino-1,2-dihydro-2-oxo-1-pyridyl) acetyl-3-amino-5- (2,6-dichlorobenzoyloxy) -4-oxo Pentanic Acid (57a; O)

Ester 56a (210 mg, 0.356 mmol) in dichloromethane (0.5 mL) was cooled to 0 ° C., treated with trifluoroacetic acid (0.5 mL), stirred and warmed to 20 ° C. over 30 minutes. The solution was evaporated to dryness under reduced pressure, redissolved in dichloromethane and concentrated three times. The residue was triturated with ethyl acetate and diluted with ether to give 162 mg (85%) of the title compound as a colorless solid.

Elemental Analysis for C ₂₇ H ₂₃ N ₃ O ₉ Cl ₂

Theoretical: C, 53.66; H, 3.84; N, 6.95

Found: C, 53.36; H, 3. 90; N, 6.81

MS FAB (+) M ⁺ = 604 (M ⁺ + l), 285, 241, 195, 173, 149, 91

N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionylamino1-pyridyl) acetyl-3-amino-5- (2,6-dichlorobenzoyloxy ) -4-oxopentanoic acid (57b; P) was prepared by the method described for compound 57a to give the title compound (78%) as colorless crystals.

Elemental Analysis for _{C 35 H 31 N 3 O 8} Cl 2 · H 2 O

Theoretical: C, 59.16; H, 4.68; N, 5.91

Found: C, 59.38; H, 4.53; N, 5.84

MS (+ FAB) 694 (Cl = 35, 37), (M ⁺ +1), 692 (Cl = 35, 35) (M ⁺ + l).

Scheme 19

(3S, 4R, S) t-butyl N- (benzyloxycarbonyl) -3-amino-4- (2-benzoxazolyl) -4-hydroxybutanoate (59)

To a stirred solution of benzoxazole (250.2 mg, 2.1 mmol) in dry THF (10.5 mL) was added dropwise 2.3 M n-butyl lithium in hexane (0.96 mL, 2.2 mmol) under N ₂ atmosphere at −78 ° C. After 20 min stirring at -78 ° C, anhydrous MgBr ₂ OEt ₂ (594.0 mg, 2.3 mmol) was added as a solid. The resulting heterogeneous mixture was warmed to -45 ° C and stirred for 15 minutes.

The reaction mixture was again cooled to -78 ° C and aldehyde 58 [Grayville et al., Int. In THF (10.5 mL). J. Peptide Protein Res., 44, pages 173-182 (1993)] (644.6 mg, 2.1 mmol) was added dropwise. The reaction was stirred at −78 ° C. for 30 minutes, warmed to 0 ° C. for 1 hour and then at room temperature for 16 hours. The reaction was terminated with 5% sodium bicarbonate (2.0 mL) and THF was removed in vacuo. The resulting aqueous residue was extracted four times with methylene chloride. The combined extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford 880.0 mg of crude product. Flash chromatography (45:55 ethyl acetate / hexanes) gave 567.2 mg (63%) of the title compound as an oil as a mixture of diastereomers in C-4.

(3S, 4R, S) t-Butyl 3-amino-4- (2-benzoxazolyl) -4-hydroxybutanoate (60)

The solution of ester 59 in ethanol (5.0 mL) was treated with 10% palladium on carbon (20.5 mg) and stirred for 21 h under H ₂ atmosphere. The mixture was filtered through Celite ^® and the solvent was evaporated to yield 125.0 mg (98%) of crude amine 60 as an oil. This was used without further purification.

(3S, 4R, S) t-Butyl N- (H-benzyloxycarbonyl- (S) -valinyl- (S) -alanyl) -3-amino-4- (2-benzoxazolyl) -4 -Hydroxybutanoate (61)

Amine 60 (261.4 mg, 0.89 mmol), Z-Val-Ala-OH (286.9 mg, 0.89 mmol) in DMF (3.0 mL) (prepared by standard peptide synthesis procedure) and hydroxybenzotriazole (120.3 mg, 0.89 mmol) solution was treated with 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (179.2 mg, 0.93 mmol). The reaction was allowed to warm to rt and stirred for 16 h. The reaction was diluted with ethyl acetate and washed twice with 1 M sodium hydrogen sulfate, twice with saturated sodium bicarbonate, and with water and brine. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo to yield 494.8 mg of crude product. Flash chromatography (95: 5 methylene chloride / methanol) gave 480.9 mg (91%) of the title compound as a yellow solid.

Elemental Analysis for _{C 31 H 40 N 4 O 8} · H 2 O

Theoretical: C, 60.57; H, 6.89; N, 9.11

Found: C, 60.84; H, 6. 64; N, 9.09

MS (+ FAB); 597 (M ⁺ + 1); 541, 91

(3S) t-butyl N- (N-benzyloxycarbonyl- (S) -valinyl- (S) -alanyl) -3-amino-4- (2-benzoxazolyl) -4-oxobutano Eight (62)

Alcohol 61 (100.3 mg, 0.17 mmol) was dissolved in methylene chloride (2.0 mL) and Dess-Martin formulation (142.6 mg, 0.34 mmol) was added [Ref .: I. Ireland, J. Org. Chem., 58, pages 2899 (1993), Death Ilul, J. Org, Chem., 48, pages 4155-4156 (1983). The resulting mixture was stirred for 22 minutes and partitioned between saturated sodium thiosulfate: saturated sodium bicarbonate (1: 1, 10 mL) and ethyl acetate (10 mL). The resulting organic phase was washed with saturated sodium thiosulfate, saturated sodium bicarbonate (1: 1), saturated sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to yield 111.3 mg of crude product. Flash chromatography (95: 5 methylene chloride / methanol) gave 97.3 mg (96%) of the title compound as an oil.

(3S) N- (N-benzyloxycarbonyl- (S) -valinyl- (S) -alaninyl) -3-amino-4- (2-benzoxazolyl) -4-oxobutanoate ( 63, 0)

A solution of ester 62 (95.0 mg, 0.16 mmol) in a 1: 1 methylene chloride and trifluoroacetic acid (10.0 mL) mixture was stirred for 1 h in N ₂ anhydrous atmosphere. The solution was concentrated in vacuo, taken up in ether and concentrated again. The above procedure was repeated six times to give an off-white solid crude product. Flash chromatography (95: 5 methylene chloride / methanol) gave 60.0 mg (69%) of the title compound as a white solid. The product was present as a mixture of three isomers in CD ₃ OD consisting of the ketone form (one isomer, c 44%) and its acyloxy ketal form (two isomers in C-4, c 56%).

Elemental Analysis for _{C 27 H 30 N 4 O 8} · 0.5H 2 O

Theoretical: C, 59.22; H, 5.71; N, 10.23

Found: C, 59.48; H, 5. 36; N, 10.17

MS (+ FAB); 539 (M ⁺ + l), 91

Scheme 20

7-methoxybenzoxazole (65a)

A mixture of 2-nitro-6-methoxyphenol (2.62 g, 15.5 mmol) (EP 333176) and 10% palladium on carbon (130 mg) in ethanol (50.0 mL) was stirred in H ₂ atmosphere for 75 minutes. The mixture was filtered through Celite ^® and immediately treated with P-toluenesulfonic acid (32.0 mg) and triethylorthoformate (6.45 mL, 38.3 mmol) and then heated to reflux under N ₂ atmosphere. After 20 hours, P-toluenesulfonic acid (30.0 mg) and triethylorthoformate (6.45 mL, 38.8 mmol) were added. After heating for a total of 44 hours, the reaction was cooled and concentrated in vacuo. The resulting residue was purified by flash chromatography (25:75 ethyl acetate / hexanes) to give 1,97 g (85%) of the title compound as a yellow solid.

Elemental Analysis for _{C 8 H 7 N 1 O 2} · 0.1H 2 O

Theoretical: C, 63.65; H, 4.81; N, 9.29

Found: C, 63.43; H, 4.88; N, 9.05

MS (+ FAB); 150 (M ⁺ + l)

4-methoxybenzoxazole (65b)

4-hydroxybenzoxazole (2.00 g, 14 8 mmol) in acetone (80.0 mL) [Musser et al., J. med. Chem. , 30, 62-67 (1987)] to the suspension was added anhydrous K ₂ CO ₃ (2.25 g, 16.3 mmol) followed by iodomethane (1.38 mL, 22.2 mmol). The reaction was heated to reflux for 4.5 h in N ₂ atmosphere, then filtered and concentrated in vacuo to afford the crude product. The resulting residue was purified by flash chromatography (25:75 ethyl acetate / hexanes) to yield 2.0 g (91%) of the title compound as a white crystalline solid.

Elemental Analysis for C ₈ H ₇ NO ₂

Theoretical: C, 64.42; H, 4.73; N, 9.39

Found: C, 64.40; H, 4. 84; N, 9.31

m / z (EI) 149 (M ⁺ + l, 100%)

(3S, 4R, S) t-butyl N- (allyloxycarbonyl) -3-amino-4-hydroxy-4- (2- (7-methoxybenzoxazolyl)) butanoate (66a)

To a stirred solution of 7-methoxybenzoxazole 65a (548.6 mg, 3.68 mmol) in anhydrous THF (18.5 mL) was added dropwise 1.56 M n-butyl lithium in hexane (2.47 mL, 3.86 mmol) at -78 ° C. under N ₂ atmosphere. To give a yellow colored solution. After stirring at −78 ° C. for 20 minutes, anhydrous MgBr ₂ OEt ₂ (1.045 g, 4.05 mmol) was added as a solid. The resulting heterogeneous mixture was warmed to -45 ° C and stirred for 15 minutes. The reaction mixture was again cooled to -78 ° C and a solution of (S) -Alloc-Asp (t-Bu) H ^1b (946.4 mg, 3.68 mmol) in THF (18.5 mL) was added dropwise. The reaction was stirred at −78 ° C. for 30 minutes, warmed to 0 ° C. and stirred for 1 hour. The resulting homogeneous reaction was allowed to warm to room temperature and stirred for 16 hours. After the reaction was terminated with 5% sodium bicarbonate (3.5 mL), THF was removed under vacuum. The resulting aqueous residue was extracted with methylene chloride (6 times). The combined extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford 1.8 g of crude. Flash chromatography (40:60 ethyl acetate / hexanes) afforded 1.21 g (81%) of the title compound as a mixture as a diastereomer at C-4.

Elemental analysis for C ₂₀ H ₂₆ N ₂ O ₇ · 0.6H ₂ O

Theoretic value: C, 57.57; H, 6.57; N, 6.72

Found: C, 57.49; H, 6. 34; N, 6.60

MS (+ FAB); 407 (M ⁺ + l); 351, 307, 154

(3S, 4R, S) t-butyl N- (allyloxycarbonyl) -3-amino-4-hydroxy-4- (2- (4-methoxybenzoxazolyl)) butanoate (66b) Prepared according to the method described for compound 66a to afford 1.29 g (26%, 68% based on recovered starting material) as an oil as a mixture which is a diastereomer in C-4.

Elemental analysis for C ₂₀ H ₂₆ N ₂ O ₇ · 0.4H ₂ O

Theoretical: C, 58.07; H, 6.53; N, 6 77

Found: C, 58.09; H, 6. 41; N, 6.63

MS (+ FAB); 407 (M ⁺ +1, 88%); 351 (100)

(3S, 4R, S) t-Butyl N- (N-acetyl- (S)-(Ot-butyl-tyrosinyl)-(S) -valinyl- (S) -alaninyl) -3-amino 4-hydroxy-4- (2- (7-methoxybenzoxazolyl)) butanoate (67a)

Bis chloride in a stirred solution of benzoxazole 66a (481.9 mg, 1.19 mmol) and Ac-Tyr ( ^t Bu) -Val-Ala-OH (586.3 ms, 1.30 mmol) in methylene chloride (3.5 mL) and DMF (3.5 mL) (Triphenylphosphine) palladium (II) (18.0 mg) and tributyltin hydride (0.80 mL, 2.96 mmol) were added dropwise in this order. Hydroxybenzotriazole (320.4 mg, 2.37 mmol) was added and the mixture was cooled to 0 ° C. 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide hydrochloride (278.2 mg, 1.42 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 16.5 hours. The reaction was diluted with ethyl acetate and washed twice with 1M sodium hydrogen sulfate, twice with saturated sodium bicarbonate, with water and brine. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo to yield 2.0 g of crude product. Flash chromatography (95: 5 methylene chloride / methanol) gave 844.0 mg (94%) of the title compound as a white solid.

Elemental Analysis for _{C 39 H 55 NO 10 · 0.5H} 2 O

Theoretical: C, 61.40; H, 7. 40; N, 9.18

Found: C, 61.43, H, 7.31; N, 9.07

MS (+ FAB) 754 (M ⁺ + 1), 698, 338, 267

(3S, 4R, S) t-Butyl N- (N-acetyl- (S)-(Ot-butyl-tyrosinyl)-(S) -valinyl- (S) -alaninyl) -3-amino 4-hydroxy-4- (2- (4-methoxybenzoxazolyl) butanoate (67b) was prepared by the method described for compound 67a to give 1.05 g (94%) of the title compound as a pure white powder. Got it.

Elemental Analysis for _{C 39 H 55 N 5 O 10} · 0.5H 2 O

Theoretical: C, 61.40; H, 7. 40; N, 9.18

Found: C, 61.58; H, 7. 38; N, 8.91

MS (+ FAB) 754 (M ⁺ + 1, 30%); 72 (100)

(3S) t-Butyl N- (N-acetyl- (S)-(Ot-butyl-tyrosinyl)-(S) -valinyl- (S) -alaninyl) -3-amino-4- ( 2- (7-methoxybenzoxazolyl))-4-oxobutanoate (68a)

Dess-Martin preparation (1.082 g, 2.55 mmol) [Republic of Ireland et al., J. Org . Chem, 58, 2899 page (1993); Dess et al, J. Org Chem., 48, pages 4155-4156 (1983), were added to a stirred suspension of alcohol 67a (641.0 mg, 0.85 mmol) in methylene chloride (46.0 mL). The resulting mixture was stirred for 1 hour and then partitioned between saturated sodium thiosulfate: saturated sodium bicarbonate (1: 1, 86.0 mL) and ethyl acetate (86.0 mL). The resulting organic phase was washed with saturated sodium thiosulfate's saturated sodium bicarbonate (1: 1), saturated sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 660.0 mg of crude product. Flash chromatography (94: 6 methylene chloride / methanol) then gave 636.0 mg (100%) of the title compound as a white solid.

(3S) t-butyl N- (N-acetyl- (S)-(O) -t-butyl-tyrosinyl)-(S) -valinyl- (S) -alaninyl) -3-amino- 4- (2- (4-methoxybenzoxazolyl))-4-oxobutanoate (68b) was prepared by the method described for ketone 68a to give 420 mg (55%) of the title compound as a white solid. .

(3S) N- (N-acetyl- (S) -tyrosinyl- (S) -valinyl- (S) -alaninyl) -3-amino-4- (2- (7-methoxybenzone company Zolyl))-4-oxobutanoate (69a, R)

A solution of ester 68a (600.0 mg, 0.80 mmol) in a 1: 1 methylene chloride and trifluoroacetic acid (65.0 mL) mixture was stirred for 1 h in anhydrous N ₂ atmosphere. The solution was concentrated in vacuo, taken in ether and concentrated again. The procedure was repeated six times to give the crude product as an off-white solid. Flash chromatography (gradient 95: 5 to 80:20 methylene chloride / methanol) gave 420.8 mg (83%) of the title compound as a hygroscopic white solid. The product was present as a mixture of three isomers in CD ₃ OD consisting of the keto form (c 50%) and its acyloxy keto form (two isomers at C-4, c 50%): mp decomposes at 150 ° C .;

Elemental Analysis for C ₃₁ H ₃₇ N ₅ O ₁₀ 3H ₂ O

Theoretical: C, 53.67; H, 6. 25; N, 10.10

Found: C, 53.76; H, 5.56; N, 10.28

MS (+ FAB); 640 (M ⁺ + l); 435, 147

(3S) t-butyl N- (N-acetyl- (S) -tyrosinyl- (S) -valinyl- (S) -alaninyl) -3-amino-4- (2- (4-meth Oxybenzoxazolyl))-4-oxobutanoate (69b, S) was prepared by the method described for acid 69a to yield 252 mg (96%) of the hygroscopic title compound. The product was present as a mixture of three isomers in the CD ₃ OD consisting of the keto form and its acyloxy ketal form (two isomers in C-4). The product was present as a single isomer in d-6 DMSO.

Elemental Analysis for _{C 31 H 37 N 5 O 10} · 1.5H 2 O

Theoretical: C, 55.85; H, 6.05; N, 10.51

Found: C, 55.21; H, 5.69; N, 10.13

MS (+ FAB); 640 (M ⁺ +1, 22%); 107 (100)

Scheme 21

(3S) t-butyl N- (allyloxycarbonyl) -3-amino-4-oxo-5- (1,2-dioxo-2-phenylethyloxy) pentanoate (80)

Potassium fluoride (792 mg, 13.6 mmol) and benzoyl formic acid (1.02 g, 6.82 mmol) were added (3S) t-butyl N- (allyloxycarbonyl) -3-amino-5-bro in dimethylformamide (30 mL). To a stirred solution of parent-4-oxo-pentanoate (WO93 / 16710) (2.17 g, 6.20 mmol). The mixture was stirred for 140 minutes, the reaction was terminated with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (4 x 50 mL) and then brine (50 mL). It was dried (MgSO ₄ ), concentrated to an oil, and purified by flash chromatography (20-45% ethyl acetate / hexanes) to give 2.44 g (94%) of a colorless oil.

(3S) t-butyl N- (allyloxycarbonyl) -3-amino-5-hydroxy-4-oxo-pentanoate (81)

A mixture of the ester 80 (2.40 g, 5,71 mmol), tetrahydrofuran (200 mL) and 1M aqueous potassium bicarbonate solution (200 mL) was vigorously stirred at room temperature for 18 hours. The layers were separated and the aqueous portion was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO ₅ ) and concentrated. The residue was purified by flash chromatography (10-60% ethyl acetate / hexanes) to yield 1.48 g (90%) of pale yellow oil.

Elemental analysis for C ₁₈ H ₂₁ N ₁ O ₆ · 0.25H ₂ O

Theoretical: C, 53.51; H, 7. 43; N, 4.80

Found: C, 53.61; H, 7. 18; N, 4.71

MS (CI); 280 (M ⁺ +1, 87%); 232 (100)

(3S) t-butyl N- (allyloxycarbonyl) -3-amino-5- (2,6-dichlorophenyl-methoxy) -4-oxo-pentanoate (82)

The alcohol 81 (1.44 g, 5.01 mmol), 2,6-dichlorobenzyl iodide (Abraham et al., J. Chem, Soc ., Pages 1605-1607 (1936)) (4.31 g, 15.0 mmol), A stirred mixture of silver oxide (2.32 g, 10.0 mmol) and dichloromethane (25 mL) was heated to reflux for 45 hours. The mixture was cooled to rt, diluted with water (50 mL) and then extracted with ethyl acetate (50 mL, 25 mL). The organic layer was washed with water (50 mL), then brine (50 mL), dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (10-100% ethyl acetate / hexanes) to 1.65. g (74%) of a colorless oil was obtained.

Elemental analysis for C ₂₀ H ₂₅ Cl ₂ N ₁ O ₆ · 0.25H ₂ O

Theoretical: C, 53.28; H, 5. 70; N, 3.11

Found: C, 53.15; H, 5.52; N, 2,98

MS (CI); 446 (M ⁺ , 27%); 390 (100)

(3R, S) t-Butyl N- [N-phenylmethyloxycarbonylvalanylalanalanyl] -3-amino-5- (2,6-dichlorophenylmethyloxy) -4-oxo-pentanoate ( 83a)

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (379 g, 1.98 mmol) and 1-hydroxybenzotriazole (486 mg, 3.60 mmol) were added with tetrahydrofuran (40 mL) and water ( To a stirred solution of N-phenyl-methyloxycarbonylvalinylalanine (637 mg, 1.98 mmol) in 1 mL). After the mixture was stirred for 15 minutes, ether 82 (802 mg, 1.80 mmol) and bis (triphenylphosphine) palladium (II) chloride (about 5 mg) were added. Hydrogenated tributyl tin (785 mg, 725 1, 2.70 mmol) was added dropwise for 20 minutes, the resulting solution was stirred for 3.75 hours and the reaction was terminated with 1M hydrochloric acid (50 mL). The mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with 1M hydrochloric acid, aqueous sodium bicarbonate solution (twice), water, brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography (10-30% ethyl acetate-dichloromethane) to give 941 mg (79%) of a pale yellow solid.

Elemental Analysis for _{C 32 H 41 Cl 2 N 3} O 8 · 0.25H 2 O

Theoretic value: C, 57.25; H, 6, 23; Cl, 10.57; N, 6.26

Found: C, 57.18; H, 6. 23; Cl, 10.58; N, 5.95

MS (+ FAB); 667 (M ⁺ 1, 1%); 666 (3), 159 (25), 91 (100)

(3R, S) t-Butyl N-[(N-acetyl-Ot-butyl-tyrosinyl) -balaninyl-alaninyl] -3-amino-5- (2,6-dichlorophenylmethyloxy)- 4-oxo-pentanoate (83b) was prepared by the method described for compound 83a to yield 554 mg (64%) of a colorless solid.

(R, S) N- [N- (phenylmethyloxy) carbonyl-valinyl-alaninyl] -3-amino-5- (2,6-dichlorophenylmethyloxy) -4-oxo-pentanoic acid ( 84a; V)

Trifluoroacetic acid (5 mL) was added to a stirred solution of ester 83a (918 mg, 1,38 mmol) in dichloromethane (20 mL). The mixture was stirred for 2.5 hours and then evaporated to dryness. The residue was treated with ether (25 mL) and evaporated to dryness. The procedure was repeated three times. The resulting product was distributed with ether (10 mL) and then dried to give 730 mg (87%) of a light brown powder.

Elemental Analysis for _{C 28 H 33 Cl 2 N 3} O 8 · 0.5H 2 O

Theoretical: C, 54.27; H, 5.53; Cl, 11.45; N, 6.78

Found: C, 54.49; H, 5.39; Cl, 11.33; N, 6.73

MS (+ FAB); 610 (M ⁺ 1, 10%), 91 (100)

(R, S) N- [N- (acetyl) tyrosinyl-valynyl-alaninyl] -3-amino-5- (2,6-dichlorophenylmethyloxy) -4-oxo-pentanoic acid (84b W) was obtained as a colorless solid by 95% by the method described for compound 84a.

Elemental Analysis for _{C 31 H 38 Cl 2 N 4} O 9 · H 2 O

Theoretical: C, 53.22; H, 5. 76; Cl, 10.14; N, 8.09

Found: C, 53.33; H, 5.54; Cl, 10.02; N, 7.85

MS (+ FAB); 682 (M ⁺ 2, 30%); 681 (67), 158 (100)

(-FAB); 680 (45); 679 (100)

Example 6

Applicants obtained inhibition constants (K _i ) and IC ₅₀ values of the various compounds of the present invention using UV-visible substrates, enzyme assays and cell assays using fluorescent substrates as described in Example 2. The following K _i and IC ₅₀ values are calculated using the assays presented for compounds 22e, 54b, 54j, 54k, 57b, 85, 86, 87, 88, 89, 90, 91, 92, 98, 102a-102c, 106a-106c, 108a to 108c, 114a, 114b, 115, 121, 125a, 125b, 126, 127, 128, 129, 130, 131, 132a, 132b, 133, 135a, 135b, 136, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162 and 163. The structures of compounds 22e, 54b, 54j, 54k and 57b are shown in Example 5. Other compound structures are shown in Example 7.

TABLE 3a

TABLE 3b

TABLE 3c

Example 7

Compounds 126, 127, 128, 129, 135a, 135b, 137, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155 in a similar manner to those used for the synthesis of compound 69a , 156, 157, 159, 160, 162 and 163 were synthesized.

[Formula 126]

[Formula 127]

[Formula 128]

Formula 129]

[Formula 135a]

[Formula 135b]

[Formula 137]

[Formula 144]

[Formula 145]

Formula 146

[Formula 147]

[Formula 148]

[Formula 149]

[Formula 150]

[Formula 151]

[Formula 152]

[Formula 153]

Formula 154

[Formula 155]

[Formula 156]

[Formula 157]

[Formula 159]

[Formula 160]

[Formula 162]

[Formula 163]

The compound of formula 158 was synthesized in a similar manner to the method used for the synthesis of compound K.

[Formula 158]

The compound of formula 130 was synthesized in a similar manner to that used for the synthesis of compound 56b.

[Formula 130]

The compounds of formulas 131, 136, 138 and 142 were synthesized in a similar manner to the method used for the synthesis of compound 57b.

[Formula 131]

[Formula 136]

[Formula 138]

[Formula 142]

The compounds of formulas 132a, 132b, 139, 140 and 141 were synthesized in a similar manner to the method used for the synthesis of compound 47a. Starting materials for compound 140 are described in Robl, et al., J. Am. Chem. Soc ., 116, 2348-2355 (1994). Starting materials for compound 141 are described in Wyvratt, et al., Pept. Struct: Funct. Proc . ( 8th Am. Pept. Symp .), (1983) or US Pat. No. 4415496.

[Formula 132a]

[Formula 132b]

[Formula 139]

[Formula 140]

Formula 141

The compound of formula 133 was synthesized in a similar manner to the method used for the synthesis of compound 47b.

[Formula 133]

The compound of formula 161 was synthesized in a similar manner to the method used for the synthesis of compound 125a.

[Formula 161]

The compounds of formulas 22e, 54b, 54j, 54k and 57b were synthesized as described in Example 5.

Formulas 85, 86, 87, 88, 89, 90, 91, 92, 98, 102a, 102b, 102c, 106a, 106b, 106c, 108a, 108b, 108c, 114a, 114b, 115, 121, 125a and 125b It was synthesized as follows.

[Formula 85]

N- (N-acetyl-tyrosinyl-valinyl- (4 (R) -allyloxyprolinyl))-3 (S) -amino-4-oxobutanoic acid (85)

Step A N-t-butoxycarbonyl-4 (R) -allyloxyproline

To a solution of 60% sodium hydride (3.36 g, 84 mmol) in 100 ml anhydrous tetrahydrofuran is added Nt-butoxycarbonyl (4R) -hydroxyproline (9.25 g, 40 mmol) and at room temperature for 2 hours. Stirring Allyl bromide (6.9 mL, 80 mmol) was added to the mixture and refluxed for 6 hours. The reaction of the mixture was terminated by addition of the hot flakes, then additional water was added and the mixture was washed with hexane. The aqueous layer was acidified with 10% sodium hydrogen sulfate and extracted with ethyl acetate (2 x 150 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to afford 5 g of the title product which was no longer purified.

Step B 4 (R) -allyloxyproline methyl ester hydrochloride

N-t-butoxycarbonyl-4 (R) -allyloxyproline (5 g, 18.4 mmol) was refluxed in 50 ml of saturated methanolic hydrogen chloride for 6 hours. The mixture was evaporated in vacuo to yield 3.78 g of the title compound as a yellow gum.

Step C N-acetyl-tyrosinyl-valynyl- (4 (R) -allyloxyproline) methyl ester

4 (R) -allyloxyproline methyl ester hydrochloride (1.05 g, 4.75 mmol) and N-acetyl-Tyr-Val-OH (1.68 g, 5.21 mmol) in a 1: 1 mixture of 10 mL of dichloromethane and dimethylformamide Dissolved in and cooled to 0 ° C. Diisopropylethylamine (1 mL, 5.93 mmol) was added to the cooled mixture, followed by N-hydroxybenzotriazole (0.769 g, 5.69 mmol) and 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride (1.18 g, 6.2 mmol) was added. After stirring for 2 hours, the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was poured into 150 ml of ethyl acetate and washed with 50 ml of each water, 10% sodium hydrogen sulfate and 10% sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and neutralized to give a pale yellow solid which was purified by flash chromatography eluting with dichloromethane / methanol / pyridine (100: 3: 0.5) to give 780 mg of the title compound.

Step D

N- (N-acetyl-tyrosinyl-valinyl- (4 (R) -allyloxyprolinyl) -3 (S) -amino-4-oxobutanoic acid t-butyl ester semicarbazone

N-acetyl-tyrosinyl-valynyl- (4-allyloxyproline) methyl ester (770 mg, 1.57 mmol) was dissolved in 20 ml of tetrahydrofuran and 4 ml of methanol. Lithium hydroxide (145 mg, 3.46 mmol) was added to the mixture and stirred at room temperature. After 2 hours, 1 ml of 10% hydrogen chloride is added and the mixture is evaporated under vacuum to give a solid residue, partitioned between 5 ml of water and 50 ml of ethyl acetate, the organic layer is separated and evaporated under vacuum 430 mg of acid were obtained and used immediately in the next step.

N-acetyl-tyrosinyl-bilinyl-4-allyloxyproline (420 mg, 0.88 mmol) and 3-amino-4-oxobutyric acid t-butyl ester semicarbazone [184 mg, 0.8 mol; Graybill et al., Int. J. Protein Res., 44, pages 173-82 (1994)] gave 100 mg (20%) of the title compound as a white amorphous solid.

Step E N- (N-acetyl-tyrosinyl-valinyl- (4 (R) -allyloxyprolinyl))-3 (S) -amino-4-oxobutanoic acid (85)

N- (N-acetyl-tyrosinyl-valinyl- (4 (R) -allyloxyprolinyl) -3 (S) -amino-4-oxobutanoic acid t-butyl ester semicarbazone (100 mg) Was deprotected as described above (Example 3, Compound K, Step C) to give 44.2 mg (53%) of the title compound.

Compounds 86 and 87 were prepared in a similar manner as described for the synthesis of compound 69a of Example 5.

[Formula 86]

N-acetyl- (S) -valinyl- (4- (S) -phenoxy) -prolinyl-3 (S) -amino-4- (7-methoxybenzoxazol-2-yl) -4- Oxo-Butanoic Acid (86)

N-acetyl- (S) -valinyl- (S)-(4- (S) -phenoxy) proline was converted to the compound of formula 302 above as a white powder.

[Formula 87]

N-acetyl (4- (R) -phenoxy) prolinyl-3 (S) -amino-4- (7-methoxybenzoxazol-2-yl) -4-oxo-butanoic acid (87)

N-acetyl- (S)-(4- (S) -phenoxy) proline was converted to the compound of formula 87 above as a white powder.

[Formula 88]

N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetyl-3 (S) -amino-5-hydroxy- 4-Oxopentanoic acid (88)

N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino- by the method described for the synthesis of compounds of formula 83a from compounds of formulas 52b and 81 1-pyridyl) acetyl-3 (S) -amino-5-hydroxy-4-oxo-pentanoic acid t-butyl ester was prepared to obtain a white solid (45%).

The resulting product was converted to the compound of formula 88 by the method described in Example 5, compound 84a to give the title compound (42%) as a white solid.

Compounds 89 and 90 were prepared by a similar method as described for the preparation of the compound of Formula 84a of Example 5.

[Formula 89]

N-acetyl- (S) -tyrosinyl- (S) -valinyl- (S) -alaninyl-3 (S) -amino-5- (2-chlorobenzyloxy) -4-oxo-pentanoic acid (89) to Ac-Tyr-Val-Ala-OH and (3S) t-butyl N- (allyloxycarbonyl) -3-amino-5- (2-chlorophenylmethoxy) -4-oxo-pentano Prepared from Eate (produced in the same manner as Compound 82) to obtain a white solid.

[Formula 90]

N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetyl-3-amino-5- (2-chlorobenzyloxy ) -4-oxopentanoic acid (90) to compound 52b and (3S) t-butyl N- (allyloxycarbonyl) -3-amino-5- (2-chlorophenylmethoxy) -4-oxo-pentano Prepared from Eate (produced in the same manner as Compound 82) to obtain a white solid.

[Formula 91]

N-2- (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionyl) amino-1-pyridyl) acetyl-3 (S) -amino-5- (5- (2,6-Dichlorophenyl) thiazol-2-yl) -4-oxopentanolic acid (91) was added to compound 52b and 3- (allyloxycarbonyl) -amino-4-[(2,6-dichloro-phenyl ) Thiazol-2-yl] -4-hydroxy-butyric acid t-butyl ester (99) as described for the preparation of compound 69a to give an off-white powder.

[Formula 92]

3- (S)-(2- (3 [3- (S)-(4-hydroxy-phenyl) -propionylamino] -2-oxo-azpan-1-yl) -acetylamino) -4- Oxobutyric acid (92) is 2- (3 [3- (S)-(4-hydroxy-phenyl) propionylamino] -2-oxo-azpan-1-yl) acetic acid and N-allyloxycarbonyl- 4-amino-5-benzyloxy-2-oxotetrahydrofuran [see Chapman, Biorg. Med. Chem. Lett., 2, pages 613-18 (1992), was prepared in a similar manner to that described for the synthesis of compound 54a to give the title compound as a white solid.

Scheme 22

4-ethoxymethylene-2-styryl-4H-oxazol-5-one (94), see Cornforth, The Chemistry of Penicillin , Clark, Johnson, Robinson (ed.), Princeton University Press, page 804 (1949). )].

4-oxo-3- (3-phenyl-acryloylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carboxylic acid ethyl ester (95 ) Was prepared by the procedure of Example 5 for compound 3 from compound 94 to give 4.5 g (30%) of the title compound.

4-Oxolett- (3-phenyl-acryloylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carboxylic acid (96)

4-oxo-3- (3-phenyl-acryloylamino) -4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine- (6S)-in methanol (10 mL) A mixture of carboxylic acid ethyl ester (95, 3.1 g, 8.8 mmol) and aqueous 1N lithium hydroxide (8.8 mL, 8.8 mmol) was stirred for 18 hours at room temperature. The reaction was diluted with water and washed with ethyl ether (1 × 20 m). The aqueous layer was acidified with concentrated hydrochloric acid. The solid was collected by filtration and washed with water. The solid was dried in a vacuum oven at 50 ° C. for 18 hours to give 2.2 g (75%) of the title compound as a tan solid.

4-Oxo-3- (3-phenyl-acryloylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carboxylic acid (2-benzyl Oxy-5-oxo-tetrahydrofuran- (3S) -yl) amide (97) was prepared from compound 96 by the method described in Example 3 for compound H, step A to give 0.52 g (as a mixture of diastereomers) 75%) of the title compound.

4-oxo- (3S)-{[4-oxo-3- (3-phenylpropionylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -Carbonyl] -amino} butyric acid (98) was prepared by the method described in Example 3 for compound H, step D to afford 0.13 g (45%) of the title compound.

Scheme 23

3 (S)-(allyloxycarbonyl) -amino-4-[(2,6-dichlorophenyl) -oxazol-2-yl] -4 (R, S) -hydroxybutyric acid t-butyl ester (99 )

5- (2,6-dichlorophenyl) oxa in tetrahydrofuran (65 mL) [2.71 g, 12.7 mmol, references: Tet. Lett . Prepared by a method analogous to that described on page 23, page 2369 (1972). The solution was cooled at −78 ° C. under a nitrogen atmosphere. To the solution was added n-butyllithium (1.5M solution in hexane, 8.5 mL, 13.3 mmol) and stirred at -78 ° C for 30 minutes. Magnesium bromide etherate (3.6 g, 13.9 mmol) was added and the solution warmed to -45 ° C. for 15 minutes. The reaction was cooled to -78 ° C. and aldehyde 58 [3.26] in tetrahydrofuran (65 mL). g, 12.7 mmol; Graybill et al., Int. J. Prorein Res. , 44, pages 173-82 (1993), were added dropwise. The reaction was stirred for 25 minutes, then warmed to -40 ° C, stirred for 3 hours, and then stirred at room temperature for 1 hour. The reaction was stopped with 5% NaHCO ₃ (12 mL) and stirred for 3 hours. Tetrahydrofuran was removed under vacuum and the resulting residue was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered to give 6.14 g of the title compound. The purification gave 4.79 g (80%) of compound 99.

4-oxo-3- (3-phenyl-propionylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carboxylic acid (100)

4-oxo-3- (3-phenyl-acryloylamino) -4,6,7,8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carrol in methanol (50 mL) A mixture of acid (96; 2.1 g, 6.5 mmol) and 20% palladium hydroxide on carbon (0.5 g) was stirred under hydrogen atmosphere for 4 hours. The resulting mixture was filtered and concentrated to give 2.1 g (100%) of the title compound as a white solid.

Scheme 24

2,6-dichloro-benzoic acid 4-t-butoxycarbonyl-2-oxo- (3S)-{[4-oxo-3- (3-phenyl-propionylamino) -4,6,7,8- Tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] amino} butyl ester (101a) was prepared by the procedure of Example 5 for compound 56a to give 0.16 g (20%) of the title The compound was obtained.

4- (7-methoxy-benzoxazol-2-yl) -4-oxo- (3S)-{[4-oxo-3- (3-phenyl-1-propionylamino) -4,6,7, 8-tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] -amino} butyric acid t-butyl ester (101b)

4-hydroxy-4- (7-methoxy-benzoxazol-2-yl)-(3S)-{[4-oxo-3- (from Compound 100 and 66a by the procedure of Example 5 for compound 67a 3-phenyl-propionylamino) -4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] -amino} butyric acid t-butyl ester 0.95 g (quantitative content) of a diastereomeric mixture were obtained.

The resulting product was converted to compound 101b by the method of Example 5 for compound 68a to yield 0.36 g (50%) of the title compound.

4- [5- (2,6-dichlorophenyl) -oxazol-2-yl] -4-oxo- (3S)-{[4-oxo-3- (3-phenyl-propionylamino) -4, 6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] amino} butyric acid t-butyl ester (101C)

4- [5- (2,6-dichloro-phenyl) -oxazol-2-yl] -4-hydroxy- (3S)-{from Compounds 100 and 99 using the method described in Example 5, compound 67a [4-oxo-3- (3-phenyl-propionylamiro) -4,6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] amino} Butyric acid t-butyl ester was obtained as a product of 0.09 g (60%) as a diastereomeric mixture.

The resulting product was converted to compound 101c by the method of Example 5 for compound 68a to afford 0.04 g (45%) of the title compound.

2,6-dichloro-benzoic acid 4-carboxy-2-oxo- (3S)-{[4-oxo-3- (3-phenyl-propionylamino) -4,6,7,8-tetrahydropyrrolo [ 1,2-a] pyrimidine- (6S) -carbonyl] -amino} butyl ester (102a) was prepared by the procedure of Example 5 for compound 57a to afford 0.12 g (80%) of the title compound.

4- (7-methoxy-benzoxazol-2-yl) -4-oxo- (3S)-{[4-oxo-3- (3-phenyl-propionylamino) -4,6,7,8- Tetrahydropyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] amino} butyric acid (102b) was prepared from compound 101b by the procedure of Example 5 for compound 69a to give 0.12 g (35%) The title compound was obtained.

4- [5- (2,6-Dichloro-phenyl) -oxazol-2-yl] -4-oxo- (3S)-{[4-oxo-3- (3-phenyl-propionylamino) -4 , 6,7,8-tetrahydro-pyrrolo [1,2-a] pyrimidine- (6S) -carbonyl] amino} butyric acid (102c)

Prepared from compound 101c using the method described in Example 5, compound 69a to afford 0.01 g (40%) of the title compound.

Scheme 25

(3-t-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] diazepan-1-yl) acetic acid methyl ester (103)

Step A

2 (S) -t-butoxycarbonylamino-3- (2-nitrophenyl-amino) propionic acid

2-t-butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoro nitrobenzene (5.7 mL, 54 mmol) and sodium bicarbonate (8.25 g, 98 mmol) are 130 mL of dimethyl Placed in formamide and heated at 80 ° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue which was dissolved in 300 mL of water and extracted with diethyl ether (3x15O mL). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3 × 250 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated to afford 12.64 g (83%) of the title compound as an orange amorphous solid.

Step B

2 (S) -t-butoxycarbonylamino-3- (2-aminophenylamino) propionic acid

2-t-butoxycarbonylamino-3- (2-nitrophenylamiro) propionic acid (12.65 g, 40.5 mmol) and 0.5 g of 10% Pd / C mixture in 100 mL methanol were added at 1 atm under hydrogen atmosphere for 4 hours. Was stirred. The solution was filtered through Celite 545 and the filtrate was evaporated in vacuo to give 11.95 g of the title compound as a quantitative yield of a dark brown solid which was used without further purification.

Step C

3 (S) -t-butoxycarbonylamino-1,3,4,5-tetrahydro-benzo [b] [1,4] diazepin-2-one

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) in 2-ml-butoxycarbonylamino-3- (2-aminophenylamino in dimethylformamide in 100 ml ) Was added to a low temperature (0 ° C.) solution of propionic acid (11.95 g, 40.5 mmol) and stirred for 18 hours. The reaction was poured into 700 ml of ethyl acetate and washed four times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to afford a brown solid which was purified by flash chromatography eluting with 3: 7 ethyl acetate / hexanes to give 8 g (71%) of the title compound.

Step D (3 (S) -t-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl) acetic acid methyl ester ( 103)

A 1.0M solution of lithium bis (trimethylsilyl) amide (3.4 mL, 3.4 mmol) in THF was added 3-t-butoxycarbonylamino-1,3,4,5-tetrahydro in 20 mL of anhydrous tetrahydrofuran. To the -78 ° C solution of benzo [b] [1,4] diazepin-2-one (0.94 g, 3.38 mmol) was added dropwise and stirred for 30 minutes. Methyl bromoacetate (0.44 mL, 4 mmol) was added dropwise to the reaction mixture and then warmed to room temperature. The reaction was diluted with 100 mL of ethyl acetate and washed with 0.3 N potassium hydrogen sulfate (50 mL), water (2 × 50 mL) and brine. The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to give a gum which was purified by flash chromatography eluting with 3: 7 EtOAC / hexanes to give 0.98 g (83%) of the title compound as a white solid.

Scheme 26

[2-Oxogle (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydro-benzo [b] [1,4] diazepin-1-yl] acetic acid methyl ester (104a )

Anhydrous hydrogen chloride was added to (3 (S) -t-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepine- in 25 ml of ethyl acetate. The solution of 1-yl) acetic acid methyl ester (103, 1 g, 2.86 mmol) was bubbled for 2 minutes and then stirred at room temperature for 1 hour. The reaction was evaporated to afford 2-oxo-3 (S) -amino-2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl acetic acid methyl ester hydrochloride as a white solid. Hydrochloride and hydrocinnamic acid (0.47 g, 3.15 mmol) were dissolved in 20 mL of dimethylformamide and cooled to 0 ° C. Diisopropylethylamine (1 mL, 5.72 mmol) was added to the solution, followed by N-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. After stirring for 18 hours at room temperature, the mixture was diluted with 150 ml of ethyl acetate and washed with 10% sodium hydrogen sulfate, 10% sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated to a crude solid, which was purified by flash chromatography eluting with 7: 3 ethyl acetate / dichloromethane to give 600 mg (55%) of the title compound as a white solid.

(3 (S)-(3-phenylpropionylamino) -2-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetic acid (105a)

(3 (S)-(3-phenylpropionylamino) -2-oxo-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepin-1-yl) in 90% methanol Acetic acid methyl ester 104a was dissolved. Lithium hydroxide hydrate was added to the reaction and the reaction was stirred at room temperature for 4 hours. The reaction was evaporated in vacuo to yield a white solid. It was dissolved in 20 mL of water, acidified to pH 5 and extracted with ethyl acetate to give 304 mg (88%) of the title compound as a white solid.

4-oxo-3 (S)-{2- [2-oxo-2 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydro-benzo [b] [1,4 ] Diazepin-1-ylacetylamino} butyric acid (106a)

Example 3, N- [1- (2-benzyloxy-5-oxotetrahydrofuran-3-carbamoylmethyl) -2-oxo-2,3 from compound 105a by the procedure of compound H (step A) , 4,5-tetrihydro-1H-benzo [b] [1,4] diazepin-3-yl] -3-phenylpropionamide was prepared to give 390 mg (93%) of the product as a diastereomer. .

The resulting product was converted to the compound of formula 106a by the method described in Example 3, compound H (step D) to give the title compound (17%) as a white solid.

[2-oxo-5- (3-phenylpropionyl) -3 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepine -1-yl] acetic acid methyl ester (104b)

Anhydrous hydrogen chloride was added to (3 (S) -t-butoxycarbonylamino-2-oxo-2,3,4,5-tetrahydro-benzo [b] [1,4] diazepine- in 25 ml of ethyl acetate. The solution of 1-yl) acetic acid methyl ester (103, 1 g, 2.86 mmol) was bubbled for 2 minutes and then stirred at room temperature for 1 hour. The reaction was evaporated to afford 2-oxo-3 (S) -amino-2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl acetic acid methyl ester hydrochloride as a white solid. Was suspended in 20 mL of dichloromethane and cooled to 0 ° C. Triethylamine (1.6 mL, 11.5 mmol) was added to the suspension followed by the dropwise addition of dihydrocinnamoyl chloride (0.9 mL, 6 mmol). The mixture was allowed to warm to rt and stirred for 18 h. The mixture was diluted with 25 mL of dichloromethane and washed twice with 50 mL of water and once with 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a viscous yellow oil which was purified by flash chromatography eluting with 1: 1 ethyl acetate / dichloromethane to give 1.35 g (92%) of the title product as a white solid. Got

[2-oxo-5- (3-phenylpropionyl) -3- (3 (S) -phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepine -1-yl] acetic acid (105b)

Procedure of compound 105a was carried out as described in [2-oxo-5- (3-phenylpropionyl) -3- (3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] Diazepin-1-yl] acetic acid methyl ester (104b, 680 mg, 1.32 mmol) was hydrolyzed to yield 645 mg (98%) of the title compound as a white solid.

2-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 (S)-(3-phenyl-propionyl-amino) -2,3,4,5 Tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid (106b)

Example 3, the procedure of Compound K (Step A), [2-oxo-5- (3-phenylpropionyl) -3- (3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetic acid and 3-amino-4-oxobutyric acid t-butylester semicarbazone were coupled to give 350 mg (85%) of a white solid.

4-oxo-3- {2- [2-oxo-5- (3-phenylpropionyl) -3- (3-phenylpropionylamino) -2 as described in Example 3, compound K (step C) Of 118 mg (47%) as a white solid by deprotection of 3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid t-butyl ester semicarbazone The title compound was obtained.

[5-benzyl-2-oxolett (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydro-benzo [b] [1,4] diazepin-1-yl] acetic acid Methyl ester (104c)

[2-Oxolett- (3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetic acid methyl ester (104a, 500 mg, 1.31 mmol), calcium carbonate (155 mg, 1.58 mmol) and benzyl bromide (170 μl, 1.44 mmol) were added to 10 mL of dimethylformamide and heated to 80 ° C. for 8 hours. The mixture was diluted with 150 ml of ethyl acetate and washed four times with 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a viscous yellow oil which was purified by flash chromatography eluting with dichloromethane / ethyl acetate (8: 2) to give 460 mg (75%) of the title as a white solid. The compound was obtained.

[5-benzyl-2-oxo-3 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydro-benzo [b] [1,4] diazepin-1-yl] Acetic acid (105c) was prepared by hydrolysis of the ester (102c) using the procedure reported for compound 105a to give 450 mg (98%) of the title compound as a white solid.

3 (S)-{2- [5-benzyl-2-oxozin- (3 (S) -phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] dia Zepin-1-yl] acetylamino} -4-oxobutyric acid (106c)

[5-Benzylnic-oxo-kin (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetic acid and 3 (S) -Amino-4-oxobutyric acid t-butylester semicarbazone was coupled in the procedure of Example 3, compound K (step A) to give 260 mg (85%) of a white solid.

3 (S)-{2- [5-benzyl-2-oxo-3 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] Diazepin-1-yl] acetylamino} -4-oxobutyric acid t-butyl ester semicarbazone was deprotected by the procedure of Example 3, compound K (step C) to give 168 mg (81%) of the title as a white solid. The compound was obtained.

Scheme 27

2,6-dichlorobenzoic acid 4-t-butoxy-carbonyl-2-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 (S)-(3 -Phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetyl-amino} butyl ester (107a)

The resulting semicarbazone was converted to compound 105b and t-butyl-3- (allyloxycarbonylamino) -4-oxo-5- (2,6-dichlorobenzoyloxy) pentanoate (WO93 / 16710) to compound 56a. Coupling as described in afforded 256 mg (58%) of the title compound as a white solid.

2,6-dichlorobenzoic acid 4-carboxy-2-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyl ester (108a) was prepared from compound 107a by the method described in compound 57a to give a white solid. 156 mg (68%) of the title compound were obtained.

4- (7-methoxybenzoxazol-2-yl) -4-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 (S)-(3- Phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid t-butyl ester (107b)

4 (R, S) -hydroxy-4- (7-methoxybenzoxazol-2-yl) -3 (S)-{2- (2-oxo-5- (3-phenylpropionyl) -3 ( S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydro [b] [1,4] diazepin-1-yl-acetylamino} butyric acid t-butyl ester with compound 105b and 66a Was prepared by the method described in Example 5, compound 67 to give 56% white solid.

The resulting product was converted to the compound of formula 107b by the method described in Example 5, compound 68a to give the title compound (56%) as a white solid.

4- (7-methoxybenzoxazol-2-yl) -4-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 (S)-(3- Phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid (108b) was added to the method described in Example 5, compound 69a. To yield 50% of the title compound as a white solid.

4- [5- (2,6-dichlorophenyl) oxazol-2-yl] -4-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 ( S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid t-butyl ester (107c)

4- [5- (2,6-dichlorophenyl) oxazol-2-yl] -4 (R, S) -hydroxy-3 (S)-{2- [2-oxo-5- (3-phenyl Propionyl) -3 (S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepen-1-yl] acetylamino} butyric acid t- Butyl esters were prepared from compounds 106c and 99 by a similar method described in compound 67a to yield 72% white solids.

The resulting product was converted to the compound of formula 107c by a similar method described in Example 5, compound 68a to give quantitative yield of a white solid.

4- [5- (2,6-dichlorophenyl) oxazol-2-yl] -4-oxo-3 (S)-{2- [2-oxo-5- (3-phenylpropionyl) -3 ( S)-(3-phenylpropionylamino) -2,3,4,5-tetrahydrobenzo [b] [1,4] diazepin-1-yl] acetylamino} butyric acid (108c) in Example 5, Prepared from compound 107c by the method described in compound 69a to give 72% of the title compound as a white solid.

Scheme 28

3 (S)-{2 (R, S)-[4-benzyl-7-oxo-6 (S)-(N-benzyloxycarbonylamino)-[1,4] diazepane-1-yl]- Propionylamino} -4-oxo-butyric acid trifluoroacetic acid salt (114a)

Step A

T-butyl-2-N-benzyloxycarbonyl-3-N-benzyl- (S) -2,3-diaminopropionate (110; 0.85 g, 2,2 mmol) in methanol (45 mL), 3- (Nt-butoxycarbonyl) amino-2-methyl-5-oxo-pentanoic acid methyl ester (109a; 0.65 g, 2.7 mmol), acetic acid (0.1 mL, 1.8 mmol), sodium acetate (0.36 g, 2 mmol) and 4 'molecular sieve (1 g) were added sodium cyanoborohydride (0.33 g, 5.3 mmol). The mixture was stirred at 25 ° C. overnight, then filtered through celite and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and extracted with ethyl acetate (3 × 40 mL). The organic layer was dried (MgSO ₄ ), filtered and concentrated to give an oil. Chromatography (silica gel, 4: 1 hexanes: ethyl acetate as eluent) gave 0.92 g (68% yield) of compound 111a as an oil.

Step B

The material was dissolved in dichloromethane (3 mL) cooled to 0 ° C., treated with a 25% trifluoroacetic acid (20 mL) solution in dichloromethane, then warmed to 25 ° C. and TLC (4: 1 hexanes: Ethyl acetate) and stir until the reaction is judged complete. The solvent was removed under reduced pressure, the residue was removed in vacuo, then dissolved in dichloromethane (40 mL), 4-methylmorpholine (1 mL, 9 mmol), HOBT (0.2 g, 1.5 mmol) and EDC (0.61). g, 3.2 mmol). The resulting mixture was stirred overnight at 25 ° C., then diluted with dichloromethane and washed with water. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give an oil. Chromatography (silica gel, 3: 2 hexanes: ethyl acetate) gave 0.49 g (74% yield) of compound 112a as a viscous oil.

Step C

2 (R, S)-[4-Benzyl-7-oxo-6 (S)-(N-benzyloxycarbonylamino)-[1,4] diazepane-1-yl] -propionic acid methyl ester (112a; 0.15 g, 0.32 mmol) was dissolved in methanol, treated with 1M LiOH (0.32 mL), stirred at 25 ° C. for 5,5 hours and then evaporated to dryness. The residue was azeotropic with ethanol (2 × 10 mL), acetonitrile (2 × 10 mL), benzene (2 × 10 mL) and then dried under vacuum. The resulting residue is converted to the compound of formula 114a by Example 3, compound K (steps A, B and C) and by a similar method, and converted to reverse phase (C18 column) HFLC with 0.1% TFA: water as eluent. Purification with /0.1% TFA: acetonitrile gave 17 mg (10% yield) of viscous oil.

3 (S)-{2- [4-benzyl-7-oxo-6 (S)-(N-benzyloxycarbonylamino)-[1,4] diazepan-1-yl] acetylamino} -4- Oxo-butyric acid trifluoroacetic acid salt (114b) was prepared from compound 109b in a similar manner as described for the synthesis of compound 114a to give 85 mg of viscous oil.

4-oxo-3 (S)-{2 (R, S)-[7-oxo-4- (3-phenylpropionyl) -6 (S)-(3-phenyl-propionylamino)-[1, 4] diazepan-1-yl] propionylamino1-butyric acid (115)

Step D 2 (R, S)-[4-Benzyl-7-oxo-6 (S)-(N-benzyloxycarbonylamino)-[1,4] diazepane-1-yl] -methyl propionate in ethanol A suspension of ester (112b, 0.22 g, 0.49 mmol) and Pd (OH) ₂ (50 mg) on 20% carbon was stirred under hydrogen atmosphere for 7 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (20 mL) and treated with triethylamine (1 mL) and dihydrocinnamoyl chloride (170 ms, 1 mmol). The resulting mixture was stirred overnight. Then diluted with ethyl acetate and washed with 1N NaOH. The organic phase was dried (MgSO ₄ ), filtered and evaporated to give an oil. Chromatography (silica gel, 4: 1 nucleic acid: ethyl acetate) gave 0.175 g (75% yield) of compound 113 as an oil.

Step C 0.15 g of a sample of Compound 113 (0.32 mmol) was dissolved in methanol, treated with 1MLiOH (0.32 mL), stirred at 40 ° C. overnight, and evaporated to dryness. The residue was azeotropic with ethanol (2 × 10 mL), acetonitrile (2 × 10 mL), benzene (2 × 10 mL) and then dried under vacuum. The resulting residue was converted to the compound of Formula 115 by a method similar to that described in Example 3, Compound K (Steps A, B and C).

Scheme 29

3- {2- [2,4-Dibenzyl-3,7-dioxo-6- (N-benzyloxycarbonylamino)-[1,4] diazepane-1-yl] -acetylahino}- 4-oxo-butyric acid (121)

Step E t-butyl-2-N-carbobenzoxy-3-N-benzyl- (S) -2,3-diaminopropionate (110, 1.77 g, 4.6 mmol) in dichloromethane (50 mL) 25 ° C. solution of N-allyl-Nt-butoxycarbonyl- (S) -phenylalanine (116; 1.04 g, 4.8 mmol), HOBT (0.74 g, 5.5 mmol) and EDC (1.33 g, 6.9 mmol) After stirring for 16 h, it was diluted with dichloromethane (100 mL) and washed with water. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give an oil. Chromatography (silica gel, 85:15 hexanes.ethyl acetate) gave 1.34 g (43% yield) of compound 117 as a colorless viscous oil.

Step F 1.34 g of a sample of Compound 117 was dissolved in dichloromethane (3 mL) and treated with a 50% trifluoroacetic acid (20 mL) solution in dichloromethane. After 1.5 h, the solvent was removed under reduced pressure, and the residue was dried under vacuum, then dissolved in dichloromethane (50 mL), 4-methylmorpholine (0.2 mL, 2 mmol), HOBT (0.27 g, 2 mmol). ) And Em (0.8 g, 4 mmol). The mixture was stirred overnight at 25 ° C., then diluted with dichloromethane and washed with water. The organic layer was dried (MgSO ₄ ), filtered and evaporated to give an oil. Chromatography (silica gel, 7: 3 hexanes: ethyl acetate) gave 0.8 g (80% yield) of compound 118 as a viscous oil.

Step G 0.8 g of Compound 118 was dissolved in methanol (40 mL), cooled to -78 ° C and saturated with ozone until the color of the solution became blue. After excess ozone was removed with argon purge, dimethylsulfide (5 mL) was added and the mixture was warmed to 25 ° C. and stirred for 3 h. The solvent was removed and chromatography (silica gel, 1: 1 hexane: ethyl acetate) gave 0.74 g (74% yield) of compound 119 as a white solid.

Step H 0.2 g (0.4 mmol) of a sample of Compound 119 was dissolved in acetone (25 mL), cooled to 0 ° C. and treated dropwise with Jones formulation solution until orange color was maintained. 2-propanol (5 mL) was added to the mixture and the resulting solution was filtered through celite and washed with acetone. Removal of the solvent gave a greenish white solid which was dried under vacuum to give compound 120. The resulting residue was subjected to compound of formula 121 by a method analogous to that described in Example 3, compound K (steps A, B and C). Switched to Chromatography (SiO ₂ , 95: 4.5: 0.5 dichloromethane: methanol: acetic acid eluent) gave 85 mg (53% yield) of a cream solid, which was based on the spectral data as follows. 2,4-Dibenzyl-3,7-dioxo-6- (N-benzyloxycarbonylamino)-[1,4] diazepane-1-yl-acetylamino) -4-oxo-butyric acid (121) Was found to be.

Scheme 30

t-butyl (3S) N- (allyloxycarbonyl) -3-amino-5- (2-chlorophenylmethylthio) -4-oxo-pentanoate (123)

Potassium fluoride (273 mg, 4.70 mmol) followed by 2-chlorophenylmethyl thiol (373 mg, 2.35 mmol) was added (3S) t-butyl N- (allyloxycarbonyl)-in dimethylformamide (20 mL). To a stirred solution of 3-amino-5-bromo-4-oxo-pentanoate (122; 749 mg, 2.14 mmol; WO93 / 16710) was added. The mixture was stirred for 3.5 h, the reaction was terminated with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (4 x 50 mL) and then brine (50 mL). It was dried (MgSO ₄ ), concentrated to give an oil, and purified by flash chromatography (10-35% ethyl acetate / hexanes) to give 832 mg (91%) of a colorless solid.

Elemental Analysis for C ₂₀ H ₂₆ ClNO ₅ S

Theoretic value: C, 56.13, H, 6.12; N, 3.27; S, 7.49

Found: C, 56. days; H, 6. 11; N, 3.26; S, 7,54

MS (CI) 430/28 (M ⁺ + l, 3%), 374/2 (100)

t-butyl (3S) 3 (2 (6-benzyl-1,2-dihydro-2-oxo-kin (3-phenylpropionylamino) -1-pyridyl) acetylamino-5- (2-chlorophenylmethyl Thio) -4-oxo-pentanoate (124a)

6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionylamino) -pyridylacetic acid (52b; 300 mg, 0.76 mmol) in THF (7 mL) was diluted with 1-hydroxybenzone. Stir with triazole (205 mg, 1.52 mmol) and 1- (3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride). After 3 minutes, water (12 drops) is added and the mixture is stirred for 10 minutes and t-butyl (3S) N- (allyloxycarbonyl) -3-amino-5- (2-chlorophenylmethylthio) Treated with -4-oxopentanoate (123) (325 mg, 0.76 mmol), bis (triphenylphosphine) palladium (II) (20 mg) and tributyltin hydride (0.6 mL, 2.28 mmol) mixture. Was stirred at rt for 5 h, poured into ethyl acetate, washed twice with aqueous 1M HCl, aqueous sodium bicarbonate, brine, dried (MgSO ₄ ) and concentrated. The residue was dispersed with pentane and the supernatant was discarded. Chromatography (silica gel, 50% ethyl acetate / hexanes) gave 439 mg (81%) of a colorless foam.

Elemental Analysis for C ₃₉ H ₄₂ ClN ₃ O ₆ S

Theoretic value: C, 65.39; H, 5.91; N, 5.87

Found: C, 65.51; H, 5.99; N, 5.77

t-butyl [3S (1S, 9S)]-3- (6,10-dioxo-1,2,3,4,7,8,9,10-octahydro) -9- (3-phenylpropionyl Amino) -6H-pyridazine [1,2-a] [1,2] diazepine-1-carboxamido-5- (2-chlorophenylmethylthio) -4-oxopentanoate (124b) Thioether 123 and [3S (1S, 9S)]-3- (6,10-dioxo-1,2,3,4,7,8,9,10-octahydro) -9 in a similar manner to compound 124a 452 mg (50%) of colorless foam prepared from-(3-phenylpropionylamino) -6H-pyridazino [1,2-a] [1,2] diazepine-1-carboxylic acid (45a) Got water.

Elemental Analysis for C ₃ H ₄₃ ClN ₄ O ₇ S · 0.25H ₂ O

Theoretical: C, 59.73; H, 6. 23; Cl, 5.04; N, 7.96; S, 4.56

Found: C, 59.73; H, 6. 19; Cl, 5.10; N, 7.79; S, 4.58

MS (-FAB) 697 (M-1,100)

(3S) 3 (2 (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionylamino) -1-pyridyl) acetylamino-5- (2-chlorophenylmethylthio ) -4-oxopentanoic acid (125a)

T-butyl-3 (2 (6-benzyl-1,2-dihydro-2-oxo-3- (3-phenylpropionylamino) -1-pyridyl) acetyl-amino- in dichloromethane (3 mL) 5- (2-Chlorophenylmethylthio) -4-oxo-pentanoate (124a) (400 mg, 0.56 mmol) was treated with trifluoroacetic acid (3 mL) at 0 ° C. and 1 hour at 0 ° C. Stir and stir for 0.5 h at rt The solution was concentrated, then dissolved in dichloromethane and concentrated again The procedure was repeated three times The residue was stirred in ether for 1 h and filtered A colorless solid (364 mg, 99%) was obtained.

[3S (1S, 9S)]-3- (6,10-Dioxo-1,2,3,4,7,8,9,10-octahydro) -9- (3-phenylpropionylamino)- 6H-pyridazine [1,2-a] [1,2] diazepine-1-carboxamido-5- (2-chlorophenyl-methylthio) -4-oxopentanoic acid (125b) with compound 125a In a similar manner, 362 mg (93%) of a colorless powder was prepared from t-butyl ester 124b.

Elemental Analysis for C ₃₁ H ₃₅ Cl ₂ N ₄ O ₇ S · 0.25H ₂ O

Theoretic value: C, 57.49; H, 5.53; N, 8.65; S, 4.95

Found: C, 57.35; H, 5. 43; N, 8.45; S, 4.88

MS (-FAB) 641 (M-1,100)

The data of the above examples illustrate that the compounds of the present invention exhibit inhibitory activity against IL-1β converting enzymes.

To date, it has been found that the compounds of the present invention can inhibit ICE ex vivo and, in addition, can be delivered orally to mammals, and they have been found to be clinically useful in the treatment of IL-1 mediated diseases. The test illustrates that the compound is capable of inhibiting ICE in vivo.

The Applicant has described various embodiments of the invention, and it is possible to modify the basic concept of the Applicant to provide other embodiments using the products and methods of the invention. Therefore, it is to be understood that the scope of the invention is defined by the appended claims rather than by the specific embodiments presented for purposes of illustration.

Detailed description of the invention

[Purpose of invention]

[Technical Field to which the Invention belongs and Prior Art in the Field]

The present invention relates to a new class of compounds that are inhibitors of interleukin-1β converting enzyme (“ICE”). The ICE inhibitor of the present invention is characterized by specific structure and physicochemical properties. The present invention also relates to a pharmaceutical composition comprising the compound. Since the compound and the pharmaceutical composition of the present invention are very suitable for inhibiting ICE activity, , Interleukin-1 (“IL-1”) mediated diseases such as inflammatory diseases, autoimmune diseases and neurodegenerative diseases. The invention also relates to methods of inhibiting ICE activity using the compounds and compositions of the invention and to methods of treating interleukin-1 mediated diseases.

[Technical problem to be achieved]

Interleukin-1 ("IL-1") promotes fibroblast differentiation and proliferation, production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophilic granule depletion and neutrophil activation Pre-inflammatory and immunomodulatory proteins. See, Oppenheim, JH et al., Immunology Today , 7, 45-56 (1986). As such, IL-1 is included in the pathogenesis of chronic and acute inflammation and autoimmune diseases. IL-1 is produced primarily by peripheral blood mononuclear cells as part of an inflammatory response and exists in two distinct forms of agonists: IL-1α and IL-1β. See, eg , Moses , BS, et al., Pror. Nat Acad . Sci ., 84, 4572-4576 (1987), Lonnemann, G. et al., Eur. J. Immunol ., 19, 1531-1536 (1989).

IL-1β is synthesized as a biologically inactive precursor, pIL-1β. pIL-1β has no conventional leader sequence and is not processed by signal peptidase. See, March, CJ, Nature , 315, 641-647 (1985). Instead, pIL-1β is cleaved between Asp-116 and Ala-117 by interleukin-1β converting enzyme ("ICE") to produce the biologically active C-terminal segments found in human serum and synovial fluid. References Sleath, PR et al., J. Biol. Chem , 265, 14526-14528 (1992); AD Howard et al, J. Immunol. , 147, 2964-2969 (1991). Treatment with ICE is also essential for transporting mature IL-1β through cell membranes.

ICE is a cysteine protease predominantly ubiquitous in monocytes. This converts the precursor IL-1β into a mature form. See Black, RA et al., FEBS Lett ., 247, pages 386-390 (1989); Kostura, MJ et al., Proc Nat l. Acad. Sci. USA, 86, 5227-5231 (1989). ICE or its analogs are also involved in the regulation of cell death or apoptosis. See, Yuan, J. et al., Cell , 75, 641-652 (1993); Miura, M, et al., Cell , 75, pages 653-660 (1993); Nett-Fiordalisi MA et al., J. Cell Biochem ., 17B, page 117 (1993). Specifically, ICE or ICE homologues are thought to be involved in the regulation of apoptosis in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. References Marx, J. and M. Baringa, Scienre , 259, pages 760-762 (1993); Gagliardini, V. et al., Science, 263, 826-828 (1994).

ICE is already described in the literature as a heterodimer consisting of two subunits, p20 and p10 (molecular weight 20 kDa and 10 kDa, respectively). These subunits are derived from the 45 kDa preenzyme (p45) via the p30 form via an autocatalytic activation mechanism. Thornberry, NA et al., Nature , pages 356, 768-774 (1992). ICE preenzymes may have several functional domains: prodomains (p14), p22 / 20 subunits, polypeptide linkers and p10. It is divided into subunits. References Thornberry et al., Homology; CaSano et al., Genomics , 20, pages 474-481 (1994).

Full length p45 is characterized by its cDNA and amino acid sequences. (PCT patent applications WO91 / 15577 and WO94 / 00154). p20 and P10 cDNA and amino acid sequences are also known. See, Thornberry et al., Homology. Mouse and rat ICEs have also been sequenced and replicated. They have amino acid and nucleic acid sequences that have a high degree of homology to the human ICE. References [Miller, DK et al., Ann. NY Acad . Sci ., 696, 133-148 (1993); Molineaux, SM et al., Proc. Nat. Acad. Sci ., 90, pages 1809-1813 (1993). However, knowledge of the basic structure of ICE cannot predict its tertiary structure at all. In addition, knowledge of such basic structures does not understand the structural, morphological and chemical interactions of ICE and its substrate pIL-1β or other substrates or inhibitors.

ICE inhibitors represent a class of compounds useful for controlling inflammation or apoptosis, or both. Peptide and peptidyl inhibitors of ICE have been disclosed. Examples include PCT patent application WO91 / 15577; WO 93/05071; WO93 / 09135; WO 93/14777 and WO93 / 16710; And European Patent Application No. 0,547,699. However, such inhibitors, due to their peptide properties, usually have undesirable pharmacological properties such as inferior oral absorption, inferior stability and rapid metabolic reactions. References Plattner, JJ and DW Norbeck, Drug Discovery Technologies, CR Clark and WH Moos, edited by Ellis Howwood, Clychester, UK, pages 92-126. This limited the development of such inhibitors into effective drugs.

Therefore, there is a need for a compound capable of effectively inhibiting the action of ICE and operating as a prophylactic and therapeutic agent for chronic and acute forms of IL-1 mediated diseases, including various cancers as well as inflammation, autoimmune diseases or neurodegenerative diseases. I'm doing it.

[Invention Composition]

Summary of the Invention

The present invention provides a new class of compounds useful as inhibitors of ICE, and pharmaceutically acceptable derivatives thereof. The compounds of the present invention can be used alone or in combination with antibiotics, immunomodulators or other anti-inflammatory agents for the treatment or prevention of diseases mediated by IL-1. According to a preferred embodiment, the compounds of the present invention can bind to the active site of ICE and inhibit the activity of the enzyme.

It is a primary object of the present invention to provide a new class of ICE inhibitors. This new class of ICE inhibitors is characterized by the following structural and physicochemical properties:

a) a first hydrogen bond moiety and a second hydrogen bond moiety, each of which may form a hydrogen bond with a different backbone atom of the ICE, the backbone atom being a carbonyl oxygen atom of Arg-341, an amide of Arg-341 -NH- group, a carbonyl oxygen atom of Ser-339 and an amide -NH- group of Ser-339);

b) a first intermediate hydrophobic portion and a second intermediate hydrophobic portion, each of which may bind to separate binding pockets when the inhibitor is bound to ICE, the binding pocket being a P2 binding pocket, a P3 binding pocket , Selected from the crowd consisting of P4 bond pockets and P 'bond pockets); And

c) an electronegative moiety comprising at least one electronegative atom, said atom being bonded to the same atom or an adjacent atom in said moiety, said moiety forming one or more hydrogen bonds or salt bridges with a residue in the P1 binding pocket of the ICE; Can be).

It is also an object of the present invention to provide a method for identifying, designing or predicting an ICE inhibitor comprising the following steps a) to f):

a) with a specific chemical structure comprising at least two hydrogen bonding moieties, at least two intermediate hydrophobic moieties, and one electronegative moiety comprising at least one electronegative atom bonded to the same atom or an adjacent atom in the electronegative moiety; Selecting the candidate compounds;

b) determining a low energy form for binding of said compound to the active site of ICE;

c) evaluating the ability of said compound to form two or more hydrogen bonds with non-carbon backbone atoms of Arg-341 and Ser-339 of ICE;

d) evaluating the ability of said compound to bind to at least two of the binding pockets of an ICE selected from a crowd consisting of P2 binding pockets, P3 binding pockets, P4 binding pockets, and P 'binding pockets;

e) evaluating the ability of said compound to interact with the P1 binding pocket of ICE in said form; And

f) accepting or rejecting the candidate compound as an ICE inhibitor based on the measurements and evaluations performed in the steps described above.

Another object of the present invention is to provide a new class of ICE inhibitors represented by the formulas a, σ, π, ν, and δ:

Formula α

Chemical formula σ

Formula π

Formula ν

Formula δ

Definition of abbreviations and terms

Definition of Terms

The following terms are used in this specification:

"Active site" refers to any or all of the following sites in the ICE: a substrate binding site, a site to which an inhibitor binds, and a site where degradation of the substrate occurs. The active site is at least one amino acid residue 173, 176, 177, 178, 179, 180, 236, 237, 238, 239, 244, 248, 283, using the sequence and numbering scheme according to Thornberry et al, supra. 284, 285, 290, 338, 339, 340, 341, 342, 343, 344, 345, 348, 352, 381, 383.

The terms "P binding pocket", "S subsite", "S pocket" and the like refer to the subsite or portion of the substrate binding site on the ICE molecule. Amino acid residues of the substrate are indicated according to their relative position to cleavable bonds, ie, bonds degraded by proteases. The residue is represented by P1, P2, or the like, for residues extending toward the N-terminus of the substrate, and P1 ', P2', or the like, for residues extending toward the C-terminus of the substrate. The portion of the inhibitor corresponding to the P or P 'residue of the substrate is also labeled P1, P1' by analogy with the substrate. The binding subsite of an ICE molecule containing a residue labeled with P1, P1 ', or the like may be labeled S1, S1', or the like, or alternatively, "P1 binding pocket", "P1 'binding pocket", or the like. [I. Schechter and A. Berger, "On the Size of the Active Site in Proteases", Biochem. Biophys. Res. Commun ., Vol. 27, pp. 157-162 (1967).

The term "P2 binding pocket" or "S2 subsite" of the ICE active site is of equivalent meaning and is defined as the space surrounded by amino acid residues Pro-290, Val-338 or Trp-340.

The term "P3 binding pocket" or "S3 subsite" of an ICE active site is of equivalent meaning and defined as the space surrounded by amino acid residues Pro-177, Arg-178, Thr-180, Arg-341 or Pro-343. do.

The terms "P4 binding pocket" or "S4 subsite" of the ICE active site have the same meaning, and the amino acid residues His-342, Met-345, Val-348, Arg-352, Asp-381, Arg-383 or Trp It is defined as the space surrounded by -340.

The terms "P1 binding pocket" or "S1 subsite" of the ICE active site are of equivalent meaning and are defined as the space surrounded by amino acid residues Arg-179, His-237, Gln-283 or Arg-341.

The terms "P 'binding pocket" or "S' subsite" of the ICE active site have the same meaning, and the amino acid residues Phe-173, Ile-176, His-237, Gly-238, Ile-239, Cys-244 Or as a space surrounded by His-248.

The term "hydrophobic" means a portion that tends to be insoluble in water or is fat-soluble. Non-limiting examples of hydrophobic moieties include hydrocarbons such as alkanes, alkenes, alkynes, cycloalkanes, cycloalkenes, cycloalkynes, and aromatic compounds such as aryl and certain saturated and unsaturated heterocycles and natural or unnatural α-amino acids, Examples include parts substantially similar to the side chains of valine, leucine, isoleucine, methionine, phenylalanine, α-aminoisobutyric acid, alloisoleucine, tyrosine and tryptophan.

The term "intermediate hydrophobic" refers to a hydrophobic moiety in which one or more carbon atoms are replaced with atoms of higher polarity such as oxygen or nitrogen.

The term "heterocycle" or "heterocyclic" refers to a stable monocyclic or polycyclic compound which may optionally comprise one or two double bonds or optionally contain one or more aromatic rings. Each heterocycle consists of 1 to 4 heteroatoms selected from the group consisting of carbon atoms and nitrogen, oxygen and sulfur, respectively. As used herein, the terms “nitrogen heteroatoms” and “sulfur heteroatoms” also include tetravalent forms of nitrogen or sulfur atoms and any basic nitrogen atoms in any oxidized form. Examples of the heterocycles defined above include pyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, purinyl, pyrimidyl, indolinyl, benzimidazolyl, imidazolyl, imidazolinoyl, imidazolidinyl , Quinolyl, isoquinolyl, indolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl , Thiazolyl, β-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinyl sulfone, benzooxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazinyl, azepinyl, Isooxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazolyl, benzodioxolyl, benzothienyl, tetrahydrothiophenyl and sulfolanyl. Other heterocycles are described in: AR katritzky and CW Rees, compilation, Comprehensive Heterocyclic Chemistry; The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Volumes 1-8, Pergamon Press, New York (1984).

The term "cycloalkyl" refers to a monocyclic or polycyclic group containing 3 to 15 carbon atoms and optionally containing one or two double bonds. Examples include cyclohexyl, adamantyl and norbornyl. Can be mentioned.

The term "aryl" refers to monocyclic or polycyclic groups containing 6, 10, 12, or 14 carbon atoms and at least one ring is aromatic. Examples thereof include phenyl, naphthyl and biphenyl.

The term “heteroaromatic” contains from 1 to 15 carbon atoms and from 1 to 4 heteroatoms independently selected from the group comprising sulfur, nitrogen and oxygen, further comprising 1 to 3 5 or 6 membered rings. Wherein at least one of the rings refers to a monocyclic or polycyclic group which is aromatic.

The term “alpha-amino acid” (α-amino acid) refers to other “non-protein” α-amino acids commonly used in the peptide chemistry art when making synthetic analogs of naturally occurring amino acids and naturally occurring peptides. All means, including D and L forms. Naturally occurring amino acids include glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, γ-carboxyglutamic acid, arginine, ornithine And lysine. Examples of “non-protein” alpha-amino acids are hydroxylysine, homoserine, homotyrosine, homophenylalanine, citrulline, kynurenine, 4-amino-phenylalanine, 3- (2-naphthyl) -alanine, 3- (1- Naphthyl) -alanine, methionine sulfone, t-butyl alanine, t-butylglycine, 4-hydroxyphenylglycine, aminoalanine, phenylglycine, vinylalanine, propargyl-glycine, 1,2,4-triazolo- 3-alanine, 4,4,4-trifluorothreonine, tyronyl, 6-hydroxytryptophan, 5-hydroxytryptophan, 3-hydroxykynurenine, 3-aminotyrosine, trifluoromethylalanine, 2- Thienylalanine, (2- (4-pyridyl) ethyl) -cysteine, 3,4-dimethoxy-phenylalanine, 3- (2-thiazolyl) alanine, ivohenic acid, 1-amino-1-cyclopentanecar Acids, 1-amino-1-cyclohexanecarboxylic acid, quiscuolinic acid, 3-trifluoromethylphenylalanine, 4-trifluoromethylphenylalanine, cyclohexylalanine, Chlohexylglycine, thiohistidine, 3-methoxytyrosine, elastatinal, norleucine, norvaline, alloleucine, homoarginine, thioproline, dihydroproline, hydroxyproline, isonipetotinic acid, homoproline, cyclohexyl Glycine, α-amino-n-butyric acid, cyclohexylalanine, aminophenylbutyric acid, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy in the ortho, meta or para position of the phenyl moiety Phenylalanine, β-2- and 3-thienylalanine, β-2- and 3-furanylalanine, β-2-, 3- and 4-pyridylalanine, substituted by one or two or substituted with methylenedioxy groups, O-alkylated derivatives of β- (benzothienyl-2- and 3-yl) alanine, β- (1- and 2-naphthyl) alanine, serine, threonine or tyrosine, S-alkylated cysteines, S-alkylated Homocysteine, O-sulfate, O-phosphate and O-carboxylate esters of cysteine, 3-sulfo- Tyrosine, 3-carboxycyrosine, 3-phosphotyrosine, 4-methanesulfonic acid ester of tyrosine, 4-methane phosphate ester of tyrosine, 3,5-diiotyrosine, 3-nitrotyrosine, ε-alkyl lysine, and Delta-alkyl ornithine. These α-amino acids may be substituted with a methyl group at the alpha position, with a halogen at any aromatic residue on the α-amino acid side chain, or with an appropriate protecting group at the O, N or S atoms of the side chain residue. Suitable protecting groups are disclosed in Protective Groups In Organic Synthesis, TW Greene and PGM Wuts, John Welly and Sons, 1991, New York, NY.

The term “α-amino acid side chain residues” refers to the chemical moiety bound to the α-carbon atom of the alpha amino acid.

The term "bioisotope substitutions instead of -CO ₂ H" means a group that can be substituted for a carboxylic acid group in a biologically active molecule. Examples of such groups are described in ChristoPher A. Lipinski "Bioisosteres in Drug". Design ", Annual Reports In Medical Chemistry , 21, pages 286-88 (1986), and CW Thornber," Isosterism and Molecular Modification in Drug Design ", Chemical Society Reviews , pages 563-580 (1979).

The term "binding" is used to denote a proximal state in which the parallelism is kinematically promoted by electrostatic interaction or van der Waals interaction between the inhibitor or a portion thereof and the ICE molecule or portions thereof.

The term "hydrogen bond" refers to a preferred interaction that occurs at any time when a suitable donor atom X with proton H and a suitable acceptor atom Y are separated by 2.5 kPa to 3.5 kPa and the angle XH --- Y is greater than 90 degrees. will be. Suitable donors and acceptor atoms are well known in the medical chemistry art. References GC Pimentel and AL McClellan, The Hydrogen Bond , Freeman, San Francisco, 1960; R. Taylor and O. Kennard, "Hydrogen Bond Geometry in Organic Crystals", Accounts of Chemical Research , 17, 320-326 (1984).

The term "salt bridge" refers to non-covalent attraction interaction when the distance between the center of mass of P and N is between 2 and 6Å between the positively charged portion (P) and the negatively charged portion (N). do. The calculation of the center of mass also includes atoms that may contain formal charges and atoms immediately adjacent to them. For example, a salt bridge may be formed between the positively charged guanidinium side chain and the negatively charged carboxylate side chain of the glutamate residue. Salt bridges are well known in the field of medicinal chemistry. References [L. Stryer, Biochemistry , Freeman, San Francisco, (1975); KA Dill, "Dominant Forces in Protein Folding", Biochemistry , 29, 31, 7133-7155, pages (1990)].

The term "center of mass" refers to a point in stereoscopic space that represents the weight average position of the materials that make up an object.

The term "backbone" means a portion of a polypeptide comprising a repeat unit -CO-CH-NH-.

The term "scaffold" refers to a structural composition block which forms the basis of an ICE inhibitor according to the invention. Various parts and functional groups can be attached to the scaffold. Thus the scaffolds of the present invention are shown to have open valences. Various scaffolds of ICE inhibitors according to the invention comprise the following parts:

or

In the scaffold, the NH and CO or SO ₂ moieties represent the first and second hydrogen bond moieties, the fractions may each form a hydrogen bond with the main chain atom of the ICE, and the main chain atom is a carbon of Arg-341. It is selected from the group consisting of carbonyl oxygen atom, amide -NH- of Arg-341, carbonyl oxygen atom of Ser-339 and amide -NH- of Ser-339.

The term "substituent" means substituting a substituent group for a hydrogen atom in a compound. In the present invention, hydrogen atoms that form part of the hydrogen bond moiety capable of forming hydrogen bonds with carbonyl oxygen atoms of Arg-341 of ICE or Ser-339 of ICE are excluded from substitution. Examples of the hydrogen atoms excluded in this way include hydrogen atoms constituting the -NH- group in the α position with respect to the Z or -CO- group, and formulas (a) to (t), (v) to (y), and (I). ) Is represented by -NH- or other symbol, not X group.

The term "straight chain" refers to a covalently bonded member that forms part of a ring, ie a continuous unbranched chain of atoms. The straight chain and rings in which the straight chain forms part can be substituted, but the substituents are not part of the straight chain.

The term "K _i " refers to a measure of the efficacy of a compound in inhibiting the activity of a target enzyme, such as ICE. Smaller K _i values mean greater efficacy. K _i values are derived by incorporating experimentally measured rate data into the standard enzyme kinetics. References [IH Segel, Enzyme Kinetics , Welly-Interscience, 1975].

The term "minimize" refers to the systematic change of the atomic conformation of a molecule or molecular complex such that additional small disturbances of the atomic conformation increase the total energy of the system as measured by molecular mechanical force fields. Minimization and molecular dynamic force fields are known in the field of computer language chemistry (Ref. U. Burkert and NL Allinger, Molecular Mechanics , ACS MonograPh 177, American Chemical Society, Washington, DC 1982, pages 59-78).

The term "strain energy" as used herein refers to the difference between the free arrangement energy of a compound and the binding arrangement energy when the compound is bound to ICE. The strain energy can be measured by the following steps: When the molecule has the energy necessary to bind to the ICE, the energy of the molecule is evaluated. The energy, that is, the free array energy, is then minimized and reassessed. The strain energy for the binding of a potential inhibitor to ICE is the difference between the free and energetic binding energy. In a preferred embodiment, the strain energy of the inhibitor of the invention is about 10 kcal / mol or less.

The term "patient" as used herein refers to animals, especially humans.

The term "pharmaceutically effective amount" means an amount effective for treating or alleviating an IL-1 mediated disease in a patient. The term “prophylactically effective amount” refers to an amount effective to prevent or substantially reduce IL-1 mediated disease in a patient.

The term "pharmaceutically acceptable carrier or adjuvant" means a nontoxic carrier or adjuvant that can be administered to a patient with a compound of the invention and does not destroy the pharmacological activity of the compound of the invention.

The term "pharmaceutically acceptable derivative" refers to any pharmaceutically acceptable compound of the present invention that can provide a compound of the present invention or an anti-ICE active metabolite or moiety thereof (directly or indirectly) when administered to a recipient. Acceptable salts, esters or salts of esters thereof.

Examples of pharmaceutically acceptable salts of the compounds of this invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid: nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, by themselves are not pharmaceutically acceptable, but can be used to prepare salts useful as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from suitable bases include alkali metals such as sodium, alkaline earth metals such as magnesium, ammonium and N- (C _1-4 alkyl) ₄ ⁺ salts.

The present invention also encompasses “quadylated” forms of any basic nitrogen-containing groups of the compounds disclosed herein. Basic nitrogen atoms include reagents known in the art, such as lower alkyl halides such as methyl, ethyl , Propyl and butyl chlorides, bromide and iodide; Dialkyl sulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; And aralkyl halides including benzyl and phenethyl bromide. Water soluble or oil soluble or dispersible products can be obtained by the tetravalent.

ICE inhibitors of the present invention may contain one or more "asymmetric" carbon atoms and may therefore occur as racemates, racemic mixtures, single stereoisomers, diastereomeric mixtures and individual diastereomers. All isomeric forms of such compounds are also included in the present invention. Each stereoisomeric carbon atom may be in the R or S configuration. Certain compounds and scaffolds exemplified herein are shown as specific stereochemical forms, but also include compounds and scaffolds or mixtures thereof having opposing stereochemistry at any given chiral center.

The ICE inhibitor of the present invention may comprise a ring structure which may be optionally substituted by various substituents on carbon, nitrogen or other atoms. Such ring structures may be single substituted or multiple substituted. It is preferable to contain a ring structure which has 0-3 substituents. In the case of multiple substitutions, each substituent may be independently selected from any other substituent as long as the combination of substituents forms a stable compound.

Combinations of substituents and variables included in the present invention are limited to those capable of forming stable compounds. As used herein, the term "stable" is intended to be prepared by methods known in the art and having sufficient stability for administration to a mammal. Reference is made to the compound. Typically, such compounds are stable for a period of at least one week under moisture or other chemically reactive conditions at temperatures up to 40 ° C.

Claims (12)

Compounds of the general formula Formula α Where a) X ₁ is CH or N; g is 0 or 1, Each J is independently selected from the group consisting of —H, —OH, and —F, provided that the first and second Js are bonded to C, and wherein the first J is —OH, the second J is -H, m is 0, 1 or 2; T is any isoelectronic array substitution instead of -Ar ₃ , -OH, -CF ₃ , -CO-CO ₂ H, -CO ₂ H or -CO ₂ H; R ₁ is selected from the group consisting of the following formulas (a) to (t) and (v), and any ring is selected from any carbon by Q ₁ and from any nitrogen by R ₅ = O, —OH , May be mono-substituted or multi-substituted at any atom with -CO ₂ H or halogen, and any saturated ring may be optionally unsaturated at one or two bonds: Formula a Formula b Formula c Formula d Chemical formula e Formula f Chemical formula g Formula h Formula i Formula j Formula k Formula l Chemical formula m Formula n Formula o Chemical formula p Formula q Formula r Chemical formula s Formula t Chemical formula v R ₂₀ is represented by the following formulas (aa1), (aa2), (aa3), (aa4), (aa5), (bb), (cc), (dd), (ee), (ff), (gg), ( gga), (ggb) and (ggc) are selected from the group consisting of:  Chemical formula aa1 Chemical formula aa2 Chemical formula aa3 Chemical formula aa4 Chemical formula aa5 Chemical formula bb Chemical formula cc Chemical formula dd Chemical formula ee Chemical formula ff Chemical formula gg Chemical formula gga Chemical formula ggb Chemical formula ggc ; Each ring C is independent from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl and cyclohexyl Is selected; R ₃ is -CN, -CH = CH-R ₉ , -CH = NOR ₉ ,-(CH ₂ ) _1-3 -T ₁ -R ₉ , -CJ ₂ -R ₉ , -CO-R ₁₃ or Is; Each R ₄ is independently selected from the group consisting of -H, -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ; Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ; Each R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ , , , And Independently selected from the group consisting of; R ₆ and R ₇ together form a saturated 4-8 membered carbocyclic ring or heterocyclic ring containing -O-, -S- or -NH- or R ₇ is -H and R ₆ is- H, -Ar ₁ , -R ₉ or-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ; Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O, optionally substituted with one or two Ar ₁ groups; Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups; Each R ₁₃ is independently selected from the group consisting of -Ar ₂ and -R ₄ ; Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzofused, 5 At least one heteroatom containing from 15 ring atoms and from 1 to 3 rings and selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally containing one or more aromatic rings, optionally mono- or multi-substituted with ═O, —OH, perfluoro C ₁ -C ₃ alkyl or —Q ₁ Cyclic group; Each Ar ₂ is independently selected from formulas (hh)-(kk), wherein any ring may be optionally substituted by -Q ₁ : Chemical formula hh Formula ii Chemical formula jj Chemical formula kk Ar ₃ is selected from the group consisting of phenyl ring, 5-membered heteroaromatic ring and 6-membered heteroaromatic ring, wherein these heteroaromatic rings are -O-, -S-, -SO-, -SO _2- , A cyclic group comprising 1 to 3 heteroatoms selected from = N- and -NH-, wherein the cyclic group is optionally selected from = O, -OH, halogen, perfluoro C ₁ -C ₃ alkyl or -CO as ₂ H, and when cyclic group is mono-substituted or multi-substituted; Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ , provided that -Ar ₁ when substituted with a Q ₁ which comprises one or more additional group of -Ar _1, -Ar ₁ of the further group is not substituted with Q _1; Each X is independently selected from the group consisting of = N- and = CH-; Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —; Each X ₃ is independently selected from the group consisting of —CH ₂ —, —S—, —SO—, and —SO ₂ —; Each X ₄ is independently selected from the group consisting of —CH ₂ — and —NH—, Each X ₅ is And Independently selected from the group consisting of; X ₆ is N in the R ₁ group represented by N or -CH-, with the proviso that, X ₆ is (o), and X ₅ is CH, if X ₂ is CH _2, the R ₁ group represented by (o) The ring should be substituted with Q ₁ or benzo fused; Each Y is independently selected from the group consisting of -O- and -S-; Each Z is independently CO or SO ₂ ; Each a is independently 0 or 1; Each c is independently 1 or 2; Each d is independently 0, 1 or 2, Each e is independently 0, 1, 2 or 3, b) X ₁ is -CH; g is 0 or 1; Each J is independently selected from the group consisting of -H, -OH and -F, provided that the first and second Js are bonded to C, and wherein said first J is -OH, said second J is -H; m is 0, 1 or 2; T is any isoelectronic array substitution instead of —OH, —CO—CO ₂ H, —CO ₂ H or —CO ₂ H; R ₁ is selected from the group consisting of the following formulas (a) to (t) and (v) to (y), wherein any ring is selected from any carbon by Q ₁ , from any nitrogen by R ₅ , Or mono- or multi-substituted at any atom by ═O, —OH, —CO ₂ H or halogen, any saturated ring may be optionally unsaturated at one or two bonds, and R ₁ (e) And R ₁ (y) is optionally benzo fused, Formula a Formula b Formula c Formula d Chemical formula e Formula f Chemical formula g Formula h Formula i Formula j Formula k Formula l Chemical formula m Formula n Formula o Chemical formula p Formula q Formula r Chemical formula s Formula t Chemical formula v Chemical formula w Chemical formula x Chemical formula y R ₂₀ is represented by the following formulas (aa1), (aa2), (aa3), (aa4), (aa5), (bb), (cc), (dd), (ee), (ff), (gg), ( gga), (ggb) and (ggc). Chemical formula aa1 Chemical formula aa2 Chemical formula aa3 Chemical formula aa4 Chemical formula aa5 Chemical formula bb Chemical formula cc Chemical formula dd Chemical formula ee Chemical formula ff Chemical formula gg Chemical formula gga Chemical formula ggb Chemical formula ggc Each ring C is independent from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl and cyclohexyl Is selected, R ₃ is -CN, -CH = CH-R ₉ , -CH = NOR ₉ ,-(CH ₂ ) _1-3 -T ₁ -R ₉ , -CJ ₂ -R ₉ , -CO-R ₁₃ or Is; Each R ₄ is independently selected from the group consisting of -H, -Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ; Each T ₁ is -CH = CH-, -O-, -S-, -SO-, -SO _2- , -NR _10- , -NR ₁₀ -CO-, -CO-, -O-CO-, -CO-O-, -CO-NR _10- , -O-CO-NR _10- , -NR ₁₀ -CO-O-, -NR ₁₀ -CO-NR _10- , -SO ₂ -NR ₁₀ -,- Independently selected from the group consisting of NR ₁₀ -SO ₂ -and -NR ₁₀ -SO ₂ -NR _10- ; Each R ₅ is -H, -Ar ₁ , -CO-Ar ₁ , -SO ₂ -Ar ₁ , -CO-NH _2- , -SO ₂ -NH _2- , -R ₉ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ , , And Independently selected from the group consisting of; R ₆ and R ₇ together form a saturated 4-8 membered carbocyclic ring or heterocyclic ring comprising -O-, -S- or -NH- or R ₇ is -H and R ₆ is- H, -Ar ₁ , -R ₉ or-(CH ₂ ) _1,2,3 -T ₁ -R ₉ or α-amino acid side chain residues; Each R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally mono- or multi-substituted with —OH, —F or ═O and optionally substituted with one or two Ar ₁ groups; Each R ₁₀ is independently selected from the group consisting of —H or C ₁ -C ₆ straight or branched alkyl groups, Each of R ₁₃ is -Ar ₂ , -R ₄ and Independently selected from the group consisting of; Each Ar ₁ is an aryl group containing 6, 10, 12 or 14 carbon atoms and 1 to 3 rings, a cycloalkyl group containing 3 to 15 carbon atoms and 1 to 3 rings and optionally benzofused, 5 At least one heteroatom containing from 15 ring atoms and from 1 to 3 rings and selected from -O-, -S-, -SO-, -SO _2- , = N- and -NH- Independently selected from the group consisting of heterocycle groups optionally comprising a bond and optionally containing one or more aromatic rings, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN , = O, -OH, perfluoro C ₁ -C ₃ alkyl, Or a cyclic group optionally mono- or polysubstituted with -Q ₁ ; Each Ar ₂ is independently selected from formulas (hh) to (kk), wherein any ring may be optionally substituted by single- or multiple-substituted by -Q ₁ and -Q ₂ and: Chemical formula hh Formula ii Chemical formula jj Chemical formula kk ; Each Q ₁ is independently selected from the group consisting of -Ar ₁ , -O-Ar ₁ , -R ₉ , -T ₁ -R ₉ and-(CH ₂ ) _1,2,3 -T ₁ -R ₉ ; Each Q ₂ is -OH, -NH ₂ , -CO ₂ H, -Cl, -F, -Br, -I, -NO ₂ , -CN, -CF ₃ and Independently selected from the group consisting of; However, -Ar ₁ in this case be substituted with a Q ₁ group which comprises one or more additional -Ar ₁ of, -Ar ₁ of the further group is not substituted with Q _1; Each X is independently selected from the group consisting of = N- and = CH-; Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —; Each X ₃ is independently selected from the group consisting of —CH ₂ —, —S—, —SO—, and —SO ₂ —; Each X ₄ is independently selected from the group consisting of —CH ₂ — and —NH—; Each X ₅ is And Independently selected from the group consisting of; X ₆ is -CH- or -N-; Each Y is independently selected from the group consisting of -O-,-S- and -NH; each Z is independently CO or SO ₂ , Each a is independently 0 or 1; Each c is independently 1 or 2; Each d is independently 0, 1 or 2, Each e is independently 0, 1, 2 or 3; Provided that when R ₁ is formula f, R ₆ is an α-amino acid side chain residue, and R ₇ is —H, formulas (aa1) and (aa2) should be substituted with Q ₁ ; R ₁ is formula o, g is 0, J is -H, m is 1, R ₆ is an α-amino acid side chain residue, R ₇ is -H, X ₂ is -CH _2- , X ₅ is Is, X ₆ is R ₃ is Or -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar ₁ , -CH ₂ -S-Ar ₁ or -R ₄ , wherein- When R ₄ is -H, the ring of the R ₁ (o) group must be substituted with Q ₁ or benzo fused; Provided that R ₁ is a chemical formula w, g is 0, 1 is -H, m is 1, T is -CO ₂ H, X ₂ is O, R ₅ is benzyloxycarbonyl, and ring C Is a benzo, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-Ar ₁ , and Arl is 1-phenyl-3-trifluoromethylpyrazol-5-yl, wherein , Phenyl may be optionally substituted with a chlorine atom) or R ₁₃ is -CH ₂ -O-CO-Ar ₁ and Ar ₁ is 2,6-dichlorophenyl. The compound of claim 1, wherein R ₁ is selected from the group consisting of the following formulas (a) to (t) and (v) to (y): Formula a Formula b Formula c Formula d Chemical formula e Formula f Chemical formula g Formula h Formula i Formula j Formula k Formula l Chemical formula m Formula n Formula o Chemical formula p Formula q Formula r Chemical formula s Formula t Chemical formula v Chemical formula w Chemical formula x Chemical formula y The compound of claim 1, wherein X ₁ is —CH; g is 0; J is -H; m is 0 or 1 and T is any isoelectronic array substitution instead of -CO-CO ₂ H or -CO ₂ H or m is 1 and T is -CO ₂ H; R ₁ is selected from the group consisting of the following formulas (a) to (c), (e) to (h), (o), (r) and (w), and any ring is any carbon by Q ₁ In any nitrogen by R ₅ , it may be monosubstituted or multiply substituted at any atom by ═O, —OH, —CO ₂ H or halogen, (e) is optionally benzo fused: Formula a Formula b Formula c Chemical formula e Formula f Chemical formula g Formula h Formula o Formula r Chemical formula w R ₂₀ is of the formula (aa1) or (aa2): Chemical formula aa1 Chemical formula aa2 Where c is 1; Ring C is benzo optionally substituted with -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -Cl, -F or -CF ₃ ; When R ₁ is formula (a) or (b), R ₅ is preferably -H, When R ₁ is of formula (c), (e), (f), (o), (r), (w), (x) or (y), R ₅ is -CO-Ar ₁ , -SO ₂ Preferred is -Arl, -CO-NH ₂ , -CO-NH-Ar ₁ , -CO-R ₉ , -CO-OR ₉ , -SO ₂ -R ₉ or -CO-NH-R ₉ ; R ₇ is -H, R ₆ is -H, -R ₉ or -Ar ₁ , R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with ═O, optionally substituted with —Ar ₁ ; R ₁₀ is —H or —C ₁ -C ₃ straight or branched alkyl group; Ar ₁ is —OC ₁ -C ₃ alkyl, -NH-C ₁ -C ₃ alkyl, -N- (C ₁ -C ₃ alkyl) ₂ , -Cl, -F, -CF ₃ , C ₁ -C ₃ alkyl or Optionally mono- or polysubstituted phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzooxazolyl, 2-indanyl or indolyl; Q ₁ is R _{9 or-} (CH ₂ ) _0,1,2 -T _1- (CH ₂ ) _0,1,2 -Ar ₁ , wherein T ₁ is -O- or -S-; Each X is independently selected from the group consisting of = N- and = CH-; Each X ₂ is independently selected from the group consisting of —O—, —CH ₂ —, —NH—, —S—, —SO—, and —SO ₂ —; Each X ₅ is And Independently selected from the group consisting of; X ₆ is or Is, Provided that R ₁ is R ₁ (o) and X ₂ is —CH ₂ —; X ₅ is Where X ₆ is In which case the ring of the R ₁ (o) group should be substituted with Q ₁ or benzo fused; Z is C = O. According to claim 3, wherein the R ₁ group is represented by the formula (a2), formula (b), formula (c1), formula (c2), formula (e1), formula (e2), formula (e4), formula (e7) , Formula (f1), formula (g2), formula (h), formula (r3), formula (r4), formula (r5), formula (w1) and formula (o6). Formula a2 It is optionally substituted with Q ₁ , wherein R ₅ is -H; R ₇ is -H; Z is C═O; Formula b It is optionally substituted with Q ₁ , wherein R ₅ is -H; R ₇ is -H; Z is C═O; Chemical Formula c1 It is optionally substituted with Q ₁ ; Chemical formula c2 Which is optionally substituted by Q ₁ , Chemical formula e1 Chemical formula e2 And c is 2; Chemical formula e4 ; Chemical formula e7 It is optionally benzo fused and c is 1 or 2; Formula f1 ; Chemical formula g2 Wherein R ₂₀ is of formula (aa1) optionally substituted with Q ₁ or monosubstituted, and Z is C═O; Formula h Wherein R ₂₀ is formula (aa1) optionally substituted with single or multiple substituted with Q ₁ , and Z is C═O]; Chemical formula r3 ; Chemical formula r4 ; Chemical formula r5 It is optionally substituted with Q ₁ ; Formula w ₁ Wherein X ₂ is —O—, —S—, —SO ₂ —, or —NH—, and when X ₂ is —NH—, is optionally substituted with R ₅ or Q ₁ in X ₂ , Ring C is benzo substituted with -C ₁ -C ₃ alkyl, -OC ₁ -C ₃ alkyl, -Cl, -F or -CF ₃ ; Chemical formula o6 X ₂ is -NH-, m is 1, T is -CO ₂ H, R ₃ is -CO-R ₁₃ , Provided that R ₁ is formula (c1), g is 0, J is -H, m is 1, T is -CO ₂ H, X is N, R ₅ is benzyloxycarbonyl, and R is _{When 6} is -H, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-Ar ₁ and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazole-5 Or- ₁₃ , wherein phenyl is optionally substituted with a chlorine atom, or R ₁₃ is -CH ₂ -O-CO-Ar ₁ , Ar ₁ is 2,6-dichlorophenyl, and the 2-position of the scaffold ring is substituted with p-fluorophenyl, When R ₁ is formula (e4), g is 0, J is -H, m is 1, T is -CO ₂ H, R ₅ is benzyloxycarbonyl, and c is 1, R ₃ Is not -CO-R ₁₃ , where R ₁₃ is -CH ₂ -O-Ar ₁ , and Ar ₁ is 1-phenyl-3-trifluoromethylpyrazol-5-yl, wherein phenyl is a chlorine atom Optionally substituted), or R ₁₃ is -CH ₂ -O-CO-Ar ₁ , Ar ₁ is 2,6-dichlorophenyl, the 2-position of the scaffold ring is substituted with p-fluorophenyl, R ₁ is formula (e7), g is 0, J is -H, m is 1, T is -CO ₂ H or -CO-NH-OH, and R ₅ is at the N atom of the amino acid side chain residue And each c is 1, R ₃ is not -CO-R ₁₃ , wherein R ₁₃ is -CH ₂ -O-CO-Ar ₁ , -CH ₂ -S-CO-Ar ₁ , -CH ₂ -O-Ar ₁ or -CH ₂ -S-Ar ₁ . The compound of claim 4, wherein R ₁ is of formula (e1) or (e2), and C is 2, m is 1, T is —CO ₂ H, and R ₃ is —CO—R ₁₃ . Chemical formula e1 Chemical formula e2 The compound of claim 3, wherein R ₃ is —CO—R ₁₃ or Is; T ₁ is -O- or -S-; R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with ═O and optionally substituted with Ar ₁ ; R ₁₃ is -H, -R ₉ , -Ar ₂ or -CH ₂ -T ₁ -R ₉ . The compound of claim 6, wherein -Ar ₂ is the following formula (hh), formula (ii), formula (jj) or formula (kk): Chemical formula hh It is -C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -NH-C ₁ -C ₆ alkyl, -N- (C ₁ -C ₆ alkyl) ₂ , -SC ₁ -C ₆ alkyl, -Cl , -F, -CF ₃ or Optionally mono- or multi-substituted with; Formula ii ; Chemical formula jj ; or Chemical formula kk The method of claim 6, a) R ₁₃ is -CH ₂ -OR ₉ wherein r ₉ is optionally substituted with = O and is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with Ar ₁ , or b) R ₁₃ is -CH ₂ -SR ₉ , wherein R ₉ is a C ₁ -C ₆ straight or branched chain alkyl group optionally substituted with Ar _1; or c) a compound in which R ₁₃ is H. The compound of claim 8, wherein R ₁₃ is —CH ₂ —OR ₉ , wherein R ₉ is a C ₁ -C ₆ straight or branched alkyl group optionally substituted with Ar ₁ . The formula (20d), formula (142), formula (54a), formula (54b), formula (54g), formula (54j), formula (54k), formula (57b), and formula (88). ), Formula (90), formula (91), formula (125a), formula (126), formula (127), formula (128), formula (129), formula (130), formula (131), formula (47a) ), Formula (47b), formula (125b), formula (135a), formula (135b), formula (136), formula (137), formula (138), formula (139), formula (86), formula (87 ), Formula (158), formula (160), formula (21d), formula (21e), formula (21f), formula (22e), formula (157), formula (114a), formula (114b), formula (115) ), Formula (121), formula (98), formula (102a), formula (102b), formula (102c), formula (106a), formula (106b), formula (106c), formula (108a), formula (108b) ) And formula (108c). Formula 20d Formula 142 Formula 54a Formula 54b Chemical Formula 54g Chemical Formula 54j Chemical Formula 54k Formula 57b Formula 88 Formula 90 Formula 91 Formula 125a Formula 126 Formula 127 Formula 128 Formula 129 Formula 130 Formula 131 Formula 47a Formula 47b Formula 125b Formula 135a Formula 135b Formula 136 Formula 137 Formula 138 Formula 139 Formula 86 Formula 87 Formula 158 Formula 160 Chemical Formula 21d Formula 21e Formula 21f Formula 22e Formula 157 Formula 114a Formula 114b Formula 115 Formula 121 Formula 98 Formula 102a Formula 102b Formula 102c Formula 106a Formula 106b Formula 106c Formula 108a Formula 108b Formula 108c a) a candidate for a given chemical structure comprising at least two hydrogen bonding moieties, at least two intermediate hydrophobic moieties and one electronegative moiety comprising at least one electronegative atom bonded to the same atom or to a neighboring atom in the electronegative part Selecting a compound; b) determining a low energy form for binding the compound to the active site of the ICE; c) assessing the ability of the compound in the form to form two or more hydrogen bonds with the non-carbon backbone atoms of Arg-341 and Ser-339 of ICE; d) assessing the ability of said compound in said form to bind to at least two binding pockets of an ICE selected from the group consisting of P2 binding pockets, P3 binding pockets, P4 binding pockets, and P 'binding pockets; e) assessing the ability of a compound in said form to interact with the P1 binding pocket of ICE; And f) A method for selecting an ICE inhibitor comprising accepting or rejecting the candidate compound as an ICE inhibitor based on the measurements and evaluations performed in the preceding step, wherein the chemical structure comprising two or more hydrogen bond moieties is A method of selecting an ICE inhibitor selected from the group consisting of structural formulas. Wherein each X is independently C or N; Each Z is CO or SO ₂ ; W ₁ is a straight chain comprising 1 to 3 covalent members independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the members are independently saturated or unsaturated, and the straight chain is bonded r Two ends covalently bonded to two different X atoms through; W 2 is a straight chain comprising 3 to 5 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chains represent Two ends covalently bonded to two different X atoms through; each bond represented by r is independently a single bond or a double bond; W ₁₄ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different C atoms through; W _1a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different X atoms through; W _2a is a straight chain comprising 3 to 4 covalent bonds independently selected from the group consisting of C, N, S and O, said straight chain comprising two ends covalently bonded to two different atoms aryl or To form a heteroaromatic ring; Each X ₁ is independently C, N or O; W _14a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between said circles are saturated or unsaturated, said straight chain being two different X Two terminals covalently bonded to _one atom to form a non-aromatic ring; W ₃ is a straight chain comprising 2 to 4 covalent members independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the members are independently saturated or unsaturated, and the straight chain is bonded r Two ends covalently bonded to two different X atoms through; W ₁₅ is a straight chain comprising 1 to 2 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Two ends covalently bonded to different X atoms; W ₁₆ is a straight chain comprising 1 to 2 covalent bonds independently selected from the group consisting of C, N, S, and O, wherein the covalent bonds between said circles are independently saturated or unsaturated, and said straight chain is bonded r Comprising two ends covalently bonded to two different C atoms via W ₄ is a straight chain comprising 2 to 4 covalent members independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the groups are independently saturated or unsaturated, and the straight chain is Two ends covalently bonded to different atoms; Each W ₅ is a straight chain comprising 1 to 2 covalent bonds independently selected from the group consisting of a direct bond or C, N, S and O, wherein the covalent bonds between the groups are independently saturated or unsaturated, The straight chain comprises two ends covalently bonded to two different atoms via bond r; W ₆ is a straight chain comprising 3 to 5 covalent members independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is bonded r Two ends covalently bonded to two different X atoms through; Each W ₁₇ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, Two ends covalently bonded to two different C atoms via the bond r; W ₇ is a straight chain comprising 3 to 5 covalent members independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the members are independently saturated or unsaturated, and the straight chain is bonded r Two ends covalently bonded to two different X atoms through; W ₈ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different X atoms through; W ₁₈ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S, and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different C atoms through; W _8a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Includes two ends covalently bonded to different C atoms, W ₁₉ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different C atoms through; W _7a is a straight chain comprising three covalent members independently selected from the group consisting of C, N, S and O, said straight chain comprising two ends covalently bonded to two different C atoms to form an aryl ring Form; W ₉ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Includes two ends that are bonded to two different X atoms via W ₁₀ is a straight chain comprising one to three covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different X atoms through; W _9a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Two ends covalently bonded to different C atoms; W _10a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain being two Two ends covalently bonded to different X atoms; W ₁₁ is a straight chain comprising 3 to 5 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Two terminals covalently bonded to different atoms to form a ring, which may optionally be benzofused or pyridino fused; W ₁₂ is a straight chain comprising 4 to 6 covalent bonds independently selected from the group consisting of C, N, S, and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to the X atom indicated through; Each X _b is independently C or N, W _12a is a straight chain comprising 4 to 6 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is a bond r Two ends covalently bonded to the X _b atom indicated through; W ₂₀ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain is a bond r Two ends covalently bonded to two different C atoms through; W ₂₁ is a straight chain comprising 1 to 2 covalent bonds independently selected from the group consisting of C, N, S and O, said straight chain comprising two ends covalently bonded to two different C atoms To form a ring; W ₁₃ is a straight chain comprising 3 to 5 covalent bonds independently selected from the group consisting of C, N, S, and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, the straight chain being two Includes two ends covalently bonded to different atoms, W ₂₂ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Two ends covalently bonded to different atoms; W ₂₃ is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is Two ends covalently bonded to different atoms; In addition W _22a is a straight chain comprising 1 to 3 covalent bonds independently selected from the group consisting of C, N, S and O, wherein the covalent bonds between the circles are independently saturated or unsaturated, and the straight chain is a bond r It includes two ends covalently bonded to two different atoms through. 12. The method of claim 11, wherein between step e) and step f) g) assessing the strain energy of the binding of the compound to ICE; And h) assessing the contribution of the sum of all electrostatic interactions between the compound and ICE when the compound is bound to ICE in the form.