Inhibitors of interleukin-1B converting enzyme.

07-01-2000 дата публикации

Номер:

AP0000000797A

Автор: BEMIS GUY, GOLEC JULIAN M, LAUFFER DAVID J, MULLICAN MICHAEL D, MURCKO MARK A, LIVINGSTONE DAVID J, BEMIS GUY, GOLEC JULIAN M, LAUFFER DAVID J, MULLICAN MICHAEL D, MURCKO MARK A, LIVINGSTONE DAVID J, BEMIS Guy, GOLEC Julian M, LAUFFER David J, MULLICAN Michael D, MURCKO Mark A, LIVINGSTONE David J

Принадлежит: Vertex Pharma

Контакты:

Номер заявки: 00-00-1997960

Дата заявки: 16-06-1995

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Compounds that are inhibitors of interleuken-lB converting enzyme and are representing by the formula: The ICE inhibitors have specific structural and physicochemical features. The compounds and compositions thereof are suited for inhibiting ICE activity and may be used as agents against interleukin-1 mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases.

An ICE inhibitor comprising:

(a) a first and a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide -NH- group of Arg-341, the carbonyl oxygen of Ser-339 and the amide -NH- group of Ser-339;

(b) a first and a second moderately hydrophobic moiety, said moieties each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding. pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket; and

(c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.

The ICE inhibitor according to claim 1, wherein said inhibitor is characterized by a neutral or favorable enthalpic contribution from the sum of all electrostatic interactions between the inhibitor and ICE when the inhibitor is bound thereto.

The ICE inhibitor according to claim 1, wherein said inhibitor has a molecular weight less than or equal to about 700 Daltons.

The ICE inhibitor according to claim 3, wherein said inhibitor has a molecular weight between about 400 and about 600 Daltons.

The ICE inhibitor according to claim 1, wherein said inhibitor further comprises less than two secondary amide bonds.

The ICE inhibitor according to claim 1, wherein said inhibitor further comprises less than two groups' selected from the set consisting of secondary amide groups and carbamate groups.

The ICE inhibitor according to claim 1, wherein said inhibitor further comprises a polysubstituted cyclic group having between three and seven substituents, said cyclic group not comprising the first or second moderately hydrophobic moiety or the electronegative moiety.

The ICE inhibitor according to claim 1 or 7, wherein said inhibitor is characterized by a strain energy of binding of said inhibitor to ICE less than or equal to about 10 kcal/mole.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE at least two of the following four conditions 1) through 4) are met:

1) one of said moderately hydrophobic moieties associates with the P2 binding pocket of ICE, in such a way that:

a) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 7.1Å and about 12.5Å;

b) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 6.0Å and about 12Å; and

c) the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the carbonyl oxygen- of Ser-339 of ICE is between about 3.7Å and about 9.5Å;

2) one of said moderately hydrophobic moieties associates with the P3 binding pocket of ICE in such a way that:

a) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 3.9Å and about 9.5Å;

b) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 5.4Å and about 11Å; and

c) the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 7.0Å and about 13Å;

3) one of said moderately hydrophobic moieties associates with the P4 binding pocket of ICE in such a way that:

a) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 4.5Å and about 7.5Å;

b) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the amide nitrogen of Arg-341 of ICE is between about 5.5Å and about 8.5Å; and

c) the distance from the center of mass of the moderately hydrophobic moiety in the P4 binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8Å and about 11Å; and

4) one of said moderately hydrophobic moieties associates with the P' binding pocket of ICE in such a way that:

a) the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the carbonyl oxygen of Arg-341 of ICE is between about 11Å and about 16Å;

b) the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the amide nitrogen of Arg-341 of ICE is between about 10Å and about 15Å; and

c) the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the carbonyl oxygen of Ser-339 of ICE is between about 8Å and about 12Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P' binding pocket of ICE and the P2 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the center of mass of the moderately hydrophobic moiety in the P2 binding pocket is between about 6.5Å and about 13Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P' binding pocket of ICE and the P3 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the center of mass of the moderately hydrophobic moiety in the P3 binding pocket is between about 6Å and about 15Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P' binding pocket of ICE and the P4 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P' binding pocket to the center of mass of the moderately hydrophobic moiety in the P4 binding pocket is between about 14Å and about 22Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P2 binding pocket of ICE and the P3 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the center of mass of the moderately hydrophobic moiety in the P3 binding pocket is between about 5.5Å and about 13Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P2 binding pocket of ICE and the P4 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P2 binding pocket to the center of mass of the moderately hydrophobic moiety in the P4 binding pocket is between about 9Å and about 17Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said moderately hydrophobic moieties separately associate with the P3 binding pocket of ICE and the P4 binding pocket of ICE and the distance from the center of mass of the moderately hydrophobic moiety in the P3 binding pocket to the center of mass of the moderately hydrophobic moiety in the P4 binding pocket is between about 7.5Å and about 17Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said first hydrogen bonding moiety forms a hydrogen bond with the carbonyl oxygen of Ser-339 of ICE and said second hydrogen bonding moiety forms a hydrogen bond with the carbonyl oxygen of Arg-341 of ICE and wherein the distance between said hydrogen bonding moieties is between about 5Å and about 7.5Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said first hydrogen bonding moiety forms a hydrogen bond with the carbonyl oxygen of Ser-339 of ICE and said second hydrogen bonding moiety forms a hydrogen bond with the amide -NH- group of Arg-341 of ICE and wherein the distance between said moieties is between about 2.5Å and about 5Å.

The ICE inhibitor according to claim 1 or 7, wherein when said inhibitor is bound to ICE, said first hydrogen bonding moiety forms a hydrogen bond with the carbonyl oxygen of Arg-341 of ICE and said second hydrogen bonding moiety forms a hydrogen bond with the amide -NH- group of Arg-341 of ICE and wherein the distance between said hydrogen bonding moieties is between about 2.5Å and about 4Å.

An ICE inhibitor comprising:

(a) a scaffold of formula I: wherein:

each X is independently C or N;

Z i s CO or SO₂;

w₁ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

W₂ is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

each bond labeled r is independently a single or a double bond;

H is a first hydrogen bonding moiety and Z is a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said backbone atom being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide -NH- group of Arg-341, the carbonyl oxygen of Ser-339 and the amide -NH- group of Ser-339;

(b) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket; and

(c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.

The ICE inhibitor according to claim 19, wherein said scaffold has the formula: wherein:

each X is independently C or N;

W₁₄ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 19, wherein said scaffold has the formula: wherein:

X is C or N;

W_1a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

W_2a is a straight chain comprising 3-4 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different atoms to form an aryl or heteroaromatic ring therewith; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 19, wherein said scaffold has the formula: wherein:

each X is independently C or N;

each X₁ is independently C, N, or O; and

W_14a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being saturated or unsaturated and said,chain comprising two ends which are covalently bound to two different X₁ atoms to form a non-aromatic ring therewith.

An ICE inhibitor comprising:

a scaffold of formula II:

wherein:

each X is independently C or N;

Z is CO or SO₂;

W₃ is a straight chain comprising 2-4 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

each bond labeled r is independently a single or a double bond;

(a) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket; and

(b) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.

The ICE inhibitor according to claim 23, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₁₅ is a straight chain comprising 1-2 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms; and

the bond labeled r is a single or a double bond.

The ICE inhibitor according to claim 23, wherein said scaffold has the formula: wherein:

each X is independently C or N; and

Z is CO or SO₂.

The ICE inhibitor according to claim 23, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₁₆ is a straight chain comprising 1-2 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

An ICE inhibitor comprising:

(a) a scaffold of formula III: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₄ is a straight chain comprising 2-4 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms;

W₅ is a direct bond or a straight chain comprising 1-2 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

W₆ is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

each bond labeled r is independently a single or a double bond;

The ICE inhibitor according to claim 27, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₁₇ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 27, wherein: wherein:

each X is independently C or N;

each bond labeled r is independently a single or a double bond.

An ICE inhibitor comprising:

(a) a scaffold of formula IV: wherein:

each X is independently C or N;

Z is CO or SO₂;

W, is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

W₈ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated, and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

each bond labeled r is independently a single or a double bond;

The ICE inhibitor according to claim 30, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₁₈ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently, saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 30, wherein said scaffold has the formula: wherein:

each X is independently C or N; and

Z is CO or SO₂.

The ICE inhibitor according to claim 30, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W_8a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms; and

the bond labeled r is a single or a double bond.

The ICE inhibitor according to claim 30, wherein said scaffold has the formula: wherein:

Z is CO or SO₂;

W_θa is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r;

W₁₉ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 30, wherein said scaffold has the formula: wherein:

Z i s CO or SO₂;

W_7a is a straight chain comprising 3 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different C atoms to form an aryl ring therewith; and

the bond labeled r is a single or a double bond.

An ICE inhibitor comprising:

a) a scaffold of formula V: wherein:

each X is independently C or N;

Z is CO or SO₂;

W₉ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

W₁₀ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms through bonds r;

each bond labeled r is independently a single or a double bond;

b) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket; and

c) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or. salt bridges with residues in the P1 binding pocket of ICE.

The ICE inhibitor according to claim 36, wherein said scaffold has the formula: wherein:

each X is independently C or N; and

Z is CO or SO₂.

The ICE inhibitor according to claim 36, wherein said scaffold has the formula: wherein:

each X is independently C or N;

Z is CO or SO₂;

W_9a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms; and

the bond labeled r is a single or a double bond.

The ICE inhibitor according to claim 36, wherein said scaffold has the formula:

each X is independently C or N;

Z is CO or SO₂;

W_10a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different X atoms; and

the bond labeled r is a single or a double bond.

An ICE inhibitor comprising:

(a) a scaffold of formula VI:

Z is CO or SO₂;

W₁₁ is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms to form a ring which may optionally be benzofused or pyridinofused;

W₁₂ is a straight chain comprising 4-6 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to the indicated X atom through bonds r;

each bond labeled r is independently a single or a double bond;

The ICE inhibitor according to claim 40, wherein said scaffold has the formula: wherein:

each X and X_b is independently C or N;

Z is CO or SO₂;

W_12a, is a straight chain comprising 4-6 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to the indicated X_b atom through bonds r; and

each bond labeled r is independently a single or a double bond.

The ICE inhibitor according to claim 40, wherein said scaffold has the formula:

each X is independently C or N;

Z is CO or SO₂;

W₂₀ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different C atoms through bonds r;

W₂₁ is a straight chain comprising 1-2 covalently bound members independently selected from the group consisting of C, N, S and O, said chain comprising two ends which are covalently bound to two different C atoms to form an aryl ring therewith; and

each bond labeled r is independently a single or a double bond.

An ICE inhibitor comprising:

(a) a scaffold of formula VII: wherein:

X is C or N;

Z is CO or SO₂;

W₁₃ is a straight chain comprising 3-5 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms;

the bond labeled r is a single or a double bond;

The ICE inhibitor according to claim 43, wherein said scaffold has the formula: wherein:

each X is independently C or N; and

Z is CO or SO₂.

The ICE inhibitor according to claim 43, wherein said scaffold has the formula: wherein:

X is C or N;

Z is CO or SO₂;

W₂₂ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms; and

the bond labeled r is a single or a double bond.

The ICE inhibitor according to claim 43, wherein said scaffold has the formula: wherein:

X is C or N;

Z is CO or SO₂;

W₂₃ is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms; and

the bond labeled r is a single or a double bond.

The ICE inhibitor according to claim 43, wherein said scaffold has the formula: wherein:

X is C or N;

Z is CO or SO₂;

W_22a is a straight chain comprising 1-3 covalently bound members independently selected from the group consisting of C, N, S and O, said covalent bonds between said members being independently saturated or unsaturated and said chain comprising two ends which are covalently bound to two different atoms through bonds r; and

each bond labeled r is independently a single or a double bond.

An ICE inhibitor comprising:

a) a scaffold comprising any monocyclic, bicyclic or tricyclic system, wherein each ring of said system comprises 5-7 members, said system comprising C, N, O or S, said system being aromatic or non-aromatic and comprising a central ring, wherein the distance between the centroid of said central ring and the alpha carbon of Cys-285 of ICE is between about 5.0Å and about 6.0Å when the inhibitor is bound to ICE and the distance between the centroid of said central ring and the alpha carbon of His-237 of ICE is between about 5.5Å and about 6.5Å when the inhibitor is bound to ICE;

b) a first hydrogen bonding moiety and a second hydrogen bonding moiety, each of said moieties being capable of forming a hydrogen bond with a different backbone atom of ICE, said atoms being selected from the group consisting of the carbonyl oxygen of Arg-341, the amide -NH- group of Arg-341, the carbonyl oxygen of Set-339 and the amide - NH- group of Ser-339;

c) a first and a second moderately hydrophobic moiety, said moieties each being covalently bound to said scaffold and each being capable of associating with a separate binding pocket of ICE when the inhibitor is bound thereto, said binding pocket being selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket; and

d) an electronegative moiety comprising one or more electronegative atoms, said atoms being attached to the same atom or to adjacent atoms in the moiety and said moiety being covalently bound to said scaffold and being capable of forming one or more hydrogen bonds or salt bridges with residues in the P1 binding pocket of ICE.

A compound represented by the formula: wherein:

X₁ 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 when a first and second J are bound to a C and said first J is -OH, said second J is -H;

m is 0, 1, or 2;

T is -Ar₃, -OH, -CF₃, -CO-CO₂H, -CO₂H or any bioisosteric replacement for -CO₂H;

R₁ is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q₁, at any nitrogen by R₅, or at any atom by =O, -OH, - CO₂H, or halogen, and in which any saturated ring may optionally be unsaturated at one or two bonds:

R₂₀ is selected from the group consisting of: and wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;

R₃ is

-CN,

-CH=CH-R₉,

- CH=N-O-R₉,

- (CH₂)_1-3-T₁-R₉,

- CJ₂-R₉,

- CO-R₁₃, or

each R₄ is independently selected from the group consisting of:

- H,

- Ar₁,

- R₉,

- T₁-R₉, and

- (CH₂)_1,2,3-T₁R₉,

each T₁ is independently selected from the group consisting of:

- CH=CH-,

- O-,

- S-,

- SO-,

- SO₂- ,

- NR₁₀- ,

- NR₁₀-CO-,

- CO-,

-O-CO-,

- CO-O-,

- CO-NR₁₀-,

- O-CO-NR₁₀-,

- NR₁₀-CO-O-,

- NR₁₀-CO-NR₁₀-,

-SO₂-NR₁₀-,

- NR₁₀-SO₂-, and

- NR₁₀-SO₂-NR₁₀-,

each R₅ is independently selected from the group consisting of:

-H,

-Ar₁,

-CO-Ar₁,

-SO₂-Ar₁,

-R₉,

-CO-R₉,

-CO-O-R₉,

-SO₂-R₉,

and

R₆ and R₇ taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing -O-, -S- , or -NH- , or R₇ is -H and R₆ is

- H

- Ar₁,

- R₉, or

- (CH₂)_1,2,3-T₁-R₉,

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with one or two Ar₁ groups;

each R₁₀ is independently selected from the group consisting of -H or a C_1-6 straight or branched alkyl group;

each R₁₃ is independently selected from the group consisting of -Ar₂ and -R₄,

each Ar₁ is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO₂-, =N-, and -NH-, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by =O, -OH, perfluoro C_1-3 alkyl, or -Q₁;

each Ar₂ is independently selected from the following group, in which any ring may optionally be substituted by -Q₁:

Ar₃ is a cyclic group selected from the set consisting of a phenyl ring, a 5-membered heteroaromatic ring, and a 6-membered heteroaromatic ring, said heteroaromatic rings comprising 1-3 heteroatom groups selected from -O-, -S-, -SO-, -SO₂-, =N-, and -NH-, said cyclic group optionally being singly or multiply substituted with =O, -OH, halogen, perf luoro C_1-3 alkyl , or -CO₂H;

each Q₁ is independently selected from the group consisting of

- Ar₁

- R₉,

- T₁-R₉, and

- (CH₂)_1,2,3-T₁-R₉,

provided that when -Ar₁ is substituted with a Q₁ group which comprises one or more additional -Ar₁ groups, said additional -Ar₁ groups are not substituted with Q₁;

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

each X₂ is independently selected from the group consisting of -O-, -CH₂-, -NH-, -S-, -SO-, and -SO₂-;

each X₃ is independently selected from the group consisting of -CH₂-, -S-, -SO-, and -SO₂-;

each X₄ is independently selected from the group consisting of -CH₂- and -NH-;

each X₅ is independently selected from the group consisting of

X₆ is CH or N, provided that when X₆ is N in the R₁ group labeled (o) and X₅ is CH and X₂ is CH₂ the ring of the R₁ group labeled (o) must be substituted by Q₁ or benzofused;

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

each Z is independently CO or SO₂,

each a is independently 0 or 1,

each c is independently 1. or 2,

each d is independently 0, 1, or 2, and

each e is independently 0, 1, 2, or 3.

The compound according to claims 49 or 80, wherein R₁ is:

The compound according to claims 49 or 80 , wherein R₁ is:

The compound according to claims 49 or 80, wherein R₁ is:

The compound according to claims 49 or 80, wherein Ri is:

The compound according to claims 49 or 80, wherein R₁ is:

The compound according to claims 49 or 8 0 , wherein R₁ is:

The compound according to claims 49 or 80, wherein R₁ is:

The compound according to claims 49 or 80 , wherein R₁ is:

The compound according to claims 49 or 80, wherein R₁ is:

The compound according to claims 49 or 80 , wherein R₁ is:

The compound according to claims 49 or 80, wherein R₁ is:

A pharmaceutical composition for treating or preventing an IL-1 mediated disease comprising a pharmaceutically effective amount of an ICE inhibitor according to any one of claims 1-70 and 80-124 and a pharmaceutically acceptable carrier.

A pharmaceutical composition for treating or preventing an autoimmune disease comprising a pharmaceutically effective amount of an ICE inhibitor according to any one of claims 1-70 and 80-124 and a pharmaceutically acceptable carrier.

A pharmaceutical composition for treating or preventing an inflammatory disease comprising a pharmaceutically effective amount of an ICE inhibitor according to any one of 1-70 and 80-124 and a pharmaceutically acceptable carrier.

A pharmaceutical composition for treating or preventing a neurodegenerative disease comprising a pharmaceutically effective amount of an ICE inhibitor according to any one of claims 1-70 and 80-124 and a pharmaceutically acceptable carrier.

A pharmaceutical composition for inhibiting an ICE-mediated function comprising a pharmaceutically effective amount of an ICE inhibitor according to any one of claims 1-70 and 80-124 and a pharmaceutically acceptable carrier.

A method for treating or preventing a disease selected from the group consisting of IL-1 mediated disease, autoimmune disease, inflammatory disease and neurodegenerative disease in a patient comprising the step of administering to said patient a pharmaceutical composition according to any one of claims 71 to 75.

A method for selecting an ICE inhibitor comprising the steps of:

a) selecting a candidate compound of defined chemical structure comprising at least two hydrogen bonding moieties, at least two moderately hydrophobic moieties and one electronegative moiety comprising one or more electronegative atoms attached either to the same atom or to adjacent atoms in the electronegative moiety;

b) determining a low-energy conformation for binding of said compound to the active site of ICE;

c) evaluating the capability of said compound in said conformation to form at least two hydrogen bonds with the non-carbon backbone atoms of Arg-341 and Ser-339 of ICE;

d) evaluating the capability of said compound in said conformation to associate with at least two of the binding pockets of ICE selected from the group consisting of the P2 binding pocket, the P3 binding pocket, the P4 binding pocket and the P' binding pocket;

e) evaluating the capability of said compound in said conformation to interact with the P1 binding pocket of ICE; and

f) accepting or rejecting said candidate compound as an ICE inhibitor based on the determinations and evaluations carried out in the preceeding steps.

The method of claim 77, additionally comprising the following steps which follow step e) and proceed step f):

g) evaluating the deformation energy of binding of said compound to ICE; and

h) evaluating the contribution of the sum of all electrostatic interactions between said compound and ICE when said compound is bound thereto in said conformation.

An ICE inhibitor selected by either of the methods according to claims 77 or 78.

A compound represented by the formula: wherein;

X₁ is -CH;

g is 0 or 1;

each J is independently selected from the group consisting of -H, -OH, and -F, provided that when a first and second J are bound to a C and said first J is -OR, said second J is -H;

m is 0, 1, or 2;

T is -OH, -CO-CO₂H, -CO₂H, or any bioisosteric replacement for -CO₂H;

R₁ is selected from the group consisting of the following formulae, in which any ring may optionally be singly or multiply substituted at any carbon by Q_1' at any nitrogen by R₅, or at any atom by =O, -OH, -CO₂H, or halogen; any saturated ring may optionally be unsaturated at one or two bonds; and wherein R₁ (e) and R₁ (y) are optionally benzofused;

R₂₀ is selected from the group consisting of: wherein each ring C is independently chosen from the group consisting of benzo, pyrido, thieno, pyrrolo, furano, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrimido, imidazolo, cyclopentyl, and cyclohexyl;

R₃ is:

-CN,

- CH=CH-R₉,

-CH=N-O-R₉,

- (CH₂)_1-3-T₁-R₉,

- CJ₂-R₉,

- CO-R₁₃, or

each R₄ is independently selected from the group consisting of:

- H,

- Ar₁,

- R₉,

- T₁-R₉, and

-(CH₂)_1,2,3-T₁-R₉;

each T₁ is independently selected from the group consisting of:

CH=CH-,

-O-,

- S-,

- SO-,

- SO₂-,

- NR₁₀-,

- NR₁₀-CO- ,

- CO-,

- O-CO-,

- CO-O-,

- CO-NR₁₀-,

- O-CO-NR₁₀-,

- NR₁₀-CO-O-,

- NR₁₀-CO-NR₁₀-,

- SO₂-NR₁₀-,

- NR₁₀-SO₂-, and

- NR₁₀-SO₂-NR₁₀-;

each R₅ is independently selected from the group consisting of:

- H,

- Ar₁,

- CO-Ar₁,

- SO₂-Ar₁,

- CO-NH₂,

- SO₂-NH₂,

- R₉,

- CO-R₉,

- CO-O-R₉ ,

- SO₂-R₉,

and

R₆ and R₇ taken together form a saturated 4-8 member carbocyclic ring or heterocyclic ring containing -O-, -S-, or -NH-; or R₇ is -H and R₆ is

-H

- Ar₁,

- R₉,

- (CH₂)_1,2,3-T₁-R₉, or

an α-amino acid side chain residue;

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with one or two Ar₁ groups;

each R₁₀ is independently selected from the group consisting of -H or a C_1-6 straight or branched alkyl group;

each R₁₃ is independently selected from the group consisting of -Ar₂, -R₄ and

each Ar₂ is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by -Q₁ and -Q₂: and

each Q₁ is independently selected from the group consisting of:

- Ar₁

- O-Ar₁

- R₉,

- T₁-R₉, and

-(CH₂)_1,2,3-T₁-R₉;

each Q₂ is independently selected from the group consisting of -OH, -NH₂, -CO₂H, -Cl, -F, -Br, -I, -NO₂, -CN, -CF₃, and provided that when -Ar₁ is substituted with a Q₁ group which comprises one or more additional -Ar₁ groups, said additional -Ar₁ groups are not substituted with Q₁;

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

each X₂ is independently selected from the group consisting of -O-, -CH₂-, -NH-, -S-, -SO-, and -SO₂-;

each X₃ is independently selected from the group consisting of -CH₂-, -S-, -SO-, and -SO₂-;

each X₄ is independently selected from the group consisting of -CH₂- and -NH-;

each X₅ is independently selected from the group consisting of

X₆ is -CH- or -N-;

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

each Z is independently CO or SO₂;

each a is independently 0 or 1;

each c is independently 1 or 2;

each d is independently 0, 1, or 2; and

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

provided that when

R₁ is (f),

R₆ is an α-amino acid side chain residue, and

R₇ is -H,

then (aa1) and (aa2) must be substituted with Q₁; also provided that when

R₁ is (o),

g is 0,

J is -H,

m is 1,

R₆ is an α-amino acid side chain residue,

R₇ is -H,

X₂ is -CH₂-,

X₆ is and

R₃ is or -CO-R₁₃, when

R₁₃ is :

- CH₂-O-CO-Ar₁,

- CH₂-S-CO-Ar₁,

- CH₂-O-Ar₁,

-CH₂-S-Ar₁, or

- R₄ when -R₄ is -H;

then the ring of the R₁(O) group must be substituted with Q₁ or benzofused; and provided that when

R₁ is (w),

g is 0,

J is -H,

m is 1,

T is -CO₂H,

X₂ is O,

R₅ is benzyloxycarbonyl, and ring C is benzo,

then R₃ cannot be -CO-R₁₃, when:

R₁₃ is -CH₂-O-Ar₁ and

Ar₁ is 1-phenyl-3-trifluoromethylpyrazole-5-yl wherein the phenyl is optionally substituted with a chlorine atom;

or when

R₁₃ is -CH₂-O-CO-Ar₁, wherein

Ar₁ is 2,6-dichlorophenyl.

The compound according to claim 80, wherein R₁ is:

The compound according to claim 80,

The compound according to claim 80, wherein R₁ is:

The compound according to claim 80, wherein:

X₁ is -CH;

g is 0;

J is -H;

m is 0 or 1 and T is -CO-CO₂H, or any bioisosteric replacement for -CO₂H, or

m is 1 and T is -CO₂H;

R₂₀ is : or

and c is 1;

ring C is benzo optionally substituted with - C_1-3 alkyl, -O-C_1-3 alkyl, -Cl, -F or -CF₃;

when R₁ is (a) or (b) , R₅ is preferably -H, and

when R₁ is (c) , (e), (f) , (o) , (r) , (w) , (x) or (y), R₅ is preferably:

- CO-Ar₁

- SO₂-Ar₁,

-CO-NH₂,

- CO-NH-Ar₁

- CO-R₉,

- CO-O-R₉,

- SO₂-R₉, or

-CO-NH-R₉,

R₇ is -H and R₆ is:

-H,

-R₉, or

- Ar₁;

R₉ is a C_1-6 straight or branched alkyl group optionally substituted with =O and optionally substituted with -Ar₁;

R₁₀ is -H or a -C_1-3 straight or branched alkyl group;

Ar₁ is phenyl, naphthyl, pyridyl, benzothiazolyl, thienyl, benzothienyl, benzoxazolyl, 2-indanyl, or indolyl substituted with -O-C_1-3 alkyl, -NH-C_1-3 alkyl, -N-(C_1-3 alkyl)₂, -C1, -F, -CF₃, - C_1-3 alkyl, or

Q₁ is R₉ or -(CH₂)_0,1,2-T₁-(CH₂)_0,1,2-Ar₁, wherein T₁ is -O- or -S-;

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

each X₂ is independently selected from the group consisting of -O-, -CH₂-, -NH-, -S-, -SO-, and -SO₂-;

each X₅ is independently selected from the group consisting of

X₆ is provided that when:

R₁ is R₁(o),

X₂ is -CH₂-,

X₅ is and

X₆ is

then the ring of the R₁(o) group must be substituted with Q₁ or benzofused; and

Z is C=O.

The compound according to claim 84, wherein the R₁ group is optionally substituted with Q₁, wherein

R₅ is -H;

R₇ is -H; and

Z is C=O.

The compound according to claim 84, wherein the R₁ group is optionally substituted with Q₁, wherein

R₅ is -H;

R₇ is -H; and

Z is C=O.

The compound according to claim 84, wherein the R₁ group is which is optionally substituted with Q₁; provided that when R₁ is (cl),

g is 0,

J is -H,

m is 1,

T is -CO₂H,

X is N,

R₅ is benzyloxycarbonyl, and

R₆ is -H,

then R₃ cannot be -CO-R₁₃ when

R₁₃ is -CH₂-O-Ar₁ and

Ar₁ is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, wherein the phenyl is optionally substituted with a chlorine atom; or when

R₁₃ is -CH₂-O-CO-Ar₁, wherein

Ar₁ is 2,6-dichlorophenyl,

and when the 2-position of the scaffold ring is substituted with para-fluoro-phenyl.

The compound according to claim 84,' wherein the R₁ group is: which is optionally substituted with Q₁.

The compound according to claim 84, wherein the R₁ group is: and c is 2; or which is optionally benzofused, and c is 1 or 2; provided that when R₁ is (e4),

g is 0,

J is -H,

m is 1,

T is -CO₂H,

R₅ is benzyloxycarbonyl, and

c is 1,

then R₃ cannot be -CO-R₁₃ when

R₁₃ is -CH₂-O-Ar₁ and

Ar₁ is 1-phenyl-3-trifluoromethyl-pyrazole-5-yl, wherein the phenyl is optionally substituted with a chlorine atom; or when

R₁₃ is -CH₂-O-CO-Ar₁, wherein

Ar₁ is 2,6-dichlorophenyl,

and when the 2-position of the scaffold ring is substituted with para-fluoro-phenyl; and

also provided that when

R₁ is (e7) ,

g is 0,

J is -H,

m is 1,

T is -CO₂H or -CO-NH-OH,

R₅ is a protective group for the N atom of an amino acid side chain residue, and

each c is 1,

then R₃ cannot be -CO-R₁₃ when

R₁₃ is :

- CH₂-O-CO-Ar₁,

- CH₂-S-CO-Ar₁,

- CH₂-O-Ar₁, or

- CH₂-S-Ar₁.

The compound according to claim 84, wherein the R₁ group is

The compound according to claim 84, wherein the R₁ group is , wherein

R₂₀ is (aa1) optionally substituted singly or multiply with Q₁; and

Z is C=O.

The compound according to claim 84, wherein the R₁ group is wherein

R₂₀ is (aa1) optionally substituted singly or multiply with Q₁; and

Z is C=O.

The compound according to claim 84, wherein the R₁ group is: and optionally substituted with Q₁.

The compound according to claim 84, wherein the R₁ group is wherein

X₂ is:

-O-,

-S-,

- SO₂-, or

-NH-;

optionally substituted with R₅ or Q₁ at X₂ when X₂ is -NH-; and

ring C is benzo substituted with -C_1-3 alkyl, - O-C_1-3 alkyl, -Cl, -F or -CF₃.

The compound according to claim 84, wherein

R₃ is:

-CO-R₁₃, or

T₁ is:

-O- or

-S-;

R₉ is a C_1-6 straight or branched alkyl group optionally substituted with =O and optionally substituted with Ar₁; and

R₁₃ is:

- H,

- R₉,

- Ar₂, or

-CH₂-T₁-R₉.

The compound according to claim 95, wherein -Ar₂ is: optionally substituted singly or multiply with - C_1-6 alkyl , -O-C_1-6 alkyl , -NH-C_1-6 alkyl , -N-(C_1-6 alkyl)₂, -S-C_1-6 alkyl, -Cl, -F, -CF₃, or

The compound according to claim 95, wherein -Ar₂ is: or

The compound according to claim 95, wherein:

R₁₃ is -CH₂-O-R₉; wherein:

R₉ is a C_1-6 straight or branched alkyl group optionally substituted with =O and optionally substituted with Ar₁.

The compound according to claim 95, wherein:

R₁₃ is -CH₂-S-R₉; wherein:

R₉ is a C_1-6 straight or branched alkyl group optionally substituted with Ar₁.

The compound according to claim 98, wherein:

R₁₃ is -CH₂-O-R₉; wherein:

R₉ is a C_1-6 straight or branched alkyl group optionally substituted with Ar₁.

The compound according to claim 95, wherein:

R₁₃ is H.

A compound represented by the formula: wherein the ring is optionally substituted with one or more R groups, preferably 0, 1 or 2; and wherein:

R₁ is R₅-(A)_p-;

R₅ is selected from the group consisting of:

- H,

- Ar₁,

- CO-Ar₁,

- SO₂-Ar₁,

- R₉,

- CO-R₉,

- CO-O-R₉,

- SO₂-R₉,

and

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; and

R is:

- H,

-O-C_1-6 alkyl,

-NH (C_1-6 alkyl),

-N(C_1-6 alkyl)₂,

-S-C_1-6 alkyl,

- C_1-6 alkyl, or

- Q₂;

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with one Ar₁ group;

each R₁₀ is independently selected from the group consisting of -H or a C_1-6 straight or branched alkyl group;

each T₁ is independently selected from the group consisting of:

- CH=CH-,

- O-,

- S-,

- SO-;

- SO₂-,

- NR₁₀-,

-NR₁₀-CO-,

- CO-,

-O-CO-,

- CO-O-,

- CO-NR₁₀-,

- O-CO-NR₁₀-,

- NR₁₀-CO-O-,

- NR₁₀-CO-NR₁₀-,

- SO₂-NR₁₀-,

- NR₁₀-SO₂-, and

-NR₁₀-SO₂-NR₁₀-,

each Q₁ is independently selected from the group consisting of:

- Ar₁

- R₉.

- T₁-R₉, and

- (CH₂)_1,2,3-T₁-R₉;

each Q₂ is independently selected from the group consisting of -OH, -NH₂, -CO₂H, -Cl, -F, -Br, -I, -NO₂, -CN, -CF₃, and

provided that when -Ar₁ is substituted with a Q₁ group which comprises one or more additional -Ar₁ groups, said additional -Ar₁ groups are not substituted with Q₁.

A compound according to claim 102 selected from the group consisting of: and

A compound according to claim 102 wherein each A is independently selected from the group consisting of the α-amino acids:

alanine,

histidine,

lysine,

phenylalanine,

proline,

tyrosine,

valine,

leucine,

isoleucine,

glutamine,

methionine,

homoproline,

3-(2-thienyl) alanine, and

3-(3-thienyl) alanine.

A compound represented by the formula:

Z wherein:

R₁ is R₅-(A)_P-;

each T₁ is independently selected from the group consisting of:

-CH=CH-,

-O-,

- S-,

-SO-,

- SO₂-,

-NR₁₀-,

-NR₁₀-CO-,

-CO-,

- O-CO-,

- CO-O-,

-CO-NR₁₀-,

-O-CO-NR₁₀-,

- NR₁₀-CO-O-,

-NR₁₀-CO-NR₁₀-,

- SO₂-NR₁₀-,

- NR₁₀-SO₂-,and

- NR₁₀-SO₂-NR₁₀-;

R₅ is selected from the group consisting of:

- H,

- Ar₁,

- CO-Ar₁,

- SO₂-Ar₁,

- R₉,

-CO-R₉,

- CO-O-R₉ ,

- SO₂-R₉,

and

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

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

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with an Ar₁ group;

each R₁₀ is independently selected from the group consisting of -H or a C_1-6 straight or branched alkyl group;

Ar₁ is a cyclic group independently selected from the set consisting of an aryl group which contains 6, 10, 12, or 14 carbon atoms and between 1 and 3 rings, a cycloalkyl group which contains between 3 and 15 carbon atoms and between 1 and 3 rings, said cycloalkyl group being optionally benzofused, and a heterocycle group containing between 5 and 15 ring atoms and between 1 and 3 rings, said heterocycle group containing at least one heteroatom group selected from -O-, -S-, -SO-, -SO₂-, =N-, and -NH-, said heterocycle group optionally containing one or more double bonds, said heterocycle group optionally comprising one or more aromatic rings, and said cyclic group optionally being singly or multiply substituted by -NH₂, -CO₂H, -Cl, -F, -Br, -I, -NO₂, -CH, =O, -OH, -perfluoro C_1-3 alkyl, - R₉, or - T₁-R₉.

A compound according to claim 105 selected from the group consisting of: and

A compound according to claim 105 wherein each A is independently selected from the group consisting of the α-amino acids:

alanine,

histidine,

lysine,

phenylalanine,

proline,

tyrosine,

valine,

leucine,

isoleucine,

glutamine,

methionine,

homoproline,

3-(2-thienyl) alanine, and

3-(3-thienyl) alanine.

The compound according to claim 85, selected from the group consisting of: and

The compound according to claim 88, selected from the group consisting of

The compound according to claim 89, wherein:

R₁ is: or and c is 2;

m is 1;

T is -CO₂H; and

R₃ is -CO-R₁₃.

The compound according to claim 110, selected from the group consisting of: and

The compound according to claim 90, selected from the group consisting of:

The compound according to claim 91, selected from the group consisting of: and

The compound according to claim 84, wherein:

R₁ is:

X₂ is -NH-;

m is 1;

T is -CO₂H;

R₃ is -CO-R₁₃.

The compound according to claim 114, selected from the group consisting of: and

The compound according to claim 93, selected from the group consisting of: and

The compound according to claim 94, selected from the group consisting of: and

The compound according to claim 105:

A compound represented by the formula: wherein:

m is 0, 1, or 2

T is -CO₂H, or any bioisosteric replacement for - CO₂H

R₃ is

-CN,

- CO-R₁₃, or

R₅ is selected from the group consisting of:

- H,

- Ar₁,

- CO-Ar₁,

- SO₂-Ar₁,

- R₉,

- CO-R₉,

- CO-O-R₉,

- SO₂-R₉,

and

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

p is 2 or 3;

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with one Ar₁ group;

each T₁ is independently selected from the group consisting of:

-CH=CH-,

-O-,

- S-,

- SO-,

-SO₂-_,

-NR₁₀-,

- NR₁₀-CO-,

- CO-,

- O-CO-,

- CO-O-,

-CO-NR₁₀-,

-O-CO-NR₁₀-.

- NR₁₀-CO-O-,

- NR₁₀-CO-NR₁₀-,

-SO₂-NR₁₀-,

- NR₁₀-SO₂-, and

-NR₁₀-SO₂-NR₁₀-;

each R₁₀ is independently selected from the group consisting of -H or a -C_1-6 straight or branched alkyl group;

each R₁₃ is independently selected from the group consisting of H, R₉, Ar₂, and -CH₂-T₁-R_9;

each Ar₂ is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by -Q₁ and -Q₂: and

each Q₁ is independently selected from the group consisting of:

- Ar₁

-O-Ar₁

-R₉,

-T₁-R₉, and

-(CH₂)_1,2,3-T₁-R₉;

each Q₂ is independently selected from the group consisting of -OH, -NH₂, -CO₂H, -Cl, -F, -Br, -I, -NO₂, -CN, -CF₃, and

provided that when -Ar₁ is substituted with a Q₁ group which comprises one or more additional -Ar₁ groups, said additional -Ar₁ groups are not substituted with Q₁.

The compound according to claim 119, selected from the group consisting of: and

The compound acording to claim 119, wherein each A is independently selected from the group consisting of the α-amino acids:

alanine,

histidine,

lysine,

phenylalanine,

proline,

tyrosine,

valine,

leucine,

isoleucine,

glutamine,

methionine,

homoproline,

3-(2-thienyl) alanine, and

3-(3-thienyl) alanine.

A compound represented by the formula:

R₁ is R₅-(A)_p-;

R₅ is selected from the group consisting of:

- H,

-Ar₁,

-CO-Ar₁,

-SO₂-Ar₁,

- R₉,

-CO-R₉,

- CO-O-R₉,

-SO₂-R₉,

and

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

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

each R₉ is a C_1-6 straight or branched alkyl group optionally singly or multiply substituted by -OH, -F, or =O and optionally substituted with one Ar₁ group;

each R₁₀ is independently selected from the group consisting of -H or a C_1-6 straight or branched alkyl group;

each T₁ is independently selected from the group consisting of:

-CH=CH-,

- O-,

-S-,

- SO-,

each Ar₂ is independently selected from the following group, in which any ring may optionally be singly or multiply substituted by -Q₁ and -Q₂: and

each Q₁ is independently selected from the group consisting of:

-Ar₁

-O-Ar₁

- R₉;

-T₁-R₉, and

- (CH₂)_1,2,3-T₁-R₉;

each Q₂ is independently selected from the group consisting of -OH, -NH₂, -CO₂H, -Cl, -F, -Br, -I, - NO₂, -CN, -CF₃, and provided that when -Ar₁ is substituted with a Q₁ group which comprises one or more additional -Ar₁ groups, said additional -Ar₁ groups are not substituted with Q₁;

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

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

The compound according to claim 122, selected from the group consisting of: and

The compound according to claim 122, wherein each A is independently selected from the group consisting of the α-amino acids:

alanine,

histidine,

lysine,

phenylalanine,

proline,

tyrosine,

valine,

leucine,

isoleucine,

glutamine,

methionine,

homoproline,

3-(2-thienyl) alanine, and

3-(3-thienyl) alanine.

CPC - классификация

A A6 A61 A61K A61K3 A61K38 A61K38/A61K38/0 A61K38/00 A61P A61P2 A61P25 A61P25/A61P25/0 A61P25/00 A61P29 A61P29/A61P29/0 A61P29/00 A61P3 A61P37 A61P37/A61P37/0 A61P37/00 A61P4 A61P43 A61P43/A61P43/0 A61P43/00 C C0 C07 C07K C07K5 C07K5/C07K5/0 C07K5/02 C07K5/020 C07K5/0202

IPC - классификация

A A6 A61 A61K A61K3 A61K31 A61K31/A61K31/4 A61K31/42 A61K31/421 A61K38 A61K38/A61K38/0 A61K38/00 A61K4 A61K45 A61K45/A61K45/0 A61K45/00 A61P A61P2 A61P25 A61P25/A61P25/0 A61P25/00 A61P29 A61P29/A61P29/0 A61P29/00 A61P3 A61P37 A61P37/A61P37/0 A61P37/00 A61P4 A61P43 A61P43/A61P43/0 A61P43/00 C C0 C07 C07C C07C2 C07C22 C07C229 C07C229/C07C229/2 C07C229/22 C07C23 C07C233 C07C233/C07C233/4 C07C233/41 C07C233/8 C07C233/83 C07C3 C07C31 C07C311 C07C311/C07C311/3 C07C311/30 C07C317 C07C317/C07C317/2 C07C317/26 C07D C07D2 C07D26 C07D263 C07D263/C07D263/2 C07D263/24 C07D5 C07D52 C07D521 C07D521/C07D521/0 C07D521/00 C07K C07K5 C07K5/C07K5/0 C07K5/02 C07K5/023 C07K5/04

Цитирование НПИ

EP0519748 A2
EP0529713 A1
WO9309135 A1
WO9314777 A1
WO9316710 A1

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