INHIBITORS OF TRANSGLUTAMINASES

• US 20190322700A1
• Filed: 01/02/2018
• Published: 10/24/2019
• Est. Priority Date: 12/27/2016
• Status: Active Grant

• Current Assignee: Zedira GmbH
• Original Assignee: Zedira GmbH
• Inventors: Hils, Martin, Pasternack, Ralf, Buchold, Christian
• Granted Patent: US 11,072,634 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 233/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/06165 and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/0819 with the first amino acid being acidic
• CPC Class Codes: C07K 5/0821 with the first amino acid being heterocyclic, e.g. His, Pro, Trp
• CPC Class Codes: C07K 5/1013 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/1019 with the first amino acid being basic
• CPC Class Codes: C07K 5/1021 : with the first amino acid being acidic
• CPC Class Codes: C07K 5/1024 : with the first amino acid being heterocyclic

Abstract

The invention relates to the compound of general formula (I) as novel inhibitors of transglutaminases, to methods for producing the inventive compounds, to pharmaceutical compositions containing said inventive compounds and to their use for the prophylaxis and treatment of diseases associated with transglutaminases.

Claims

1. A compound of the general formula (I):

wherein

2. The compound according to claim 1 having any one of the formulae (II-1)-(II-5):

3. The compound according to claim 1 having any one of the formulae (III-1) (III-5):

4. The compound according to claim 1 having any one of the formulae (VI-1)-(VI-5):

5. The Compound according to claim 1 having any one of the formulae (VII-3) (VII-4):

6. The compounds according to claim 1 of the formula (IX):

7. The compound according to claim 6 having the formula (XI-3):

8. The compound according to claim 1 having the formula (XIII);

9. The compound according to claim 8 having the formula (XIV-1)

10. The compound according to claim 1 selected from the group consisting of:

(S)-methyl 2-((S)-1-((S)-2-((S)-2-acetamido-6-amino-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E01),

(S)-methyl 2-((S)-1-((S)-2-((S)-6-amino-2-(benzyloxycarbonylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E02),

(S)-2-acetamido-N1-((S)-5-amino-1-((2S,3R)-1-((S)-1-amino-3-methyl-1-oxobutan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1,5-dioxopentan-2-yl)-5-oxohexanediamide (E03),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E04),

(S)-2-(2-bromo-4-methylthiazole-5-carboxamido)-N1-(1-(2-(isopentylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E05),

(S)-5-acetamido-6-(4-(2-chlorophenyl)piperazin-1-yl)-2,6-dioxohexanamide (E06),

(S)-1-acetyl-N—

((S)-6-amino-1-(4-(3-methylpyridin-2-yl)piperazin-1-yl)-1,5,6-trioxohexan-2-yl)pyrrolidine-2-carboxamide (E07),

(S)-1-((S)-2-((S)-1-((4R,7S,10S,13S,16S)-7-(4-amino-3,4-dioxobutyl)-10,13-dibutyl-4-(carboxymethyl)-18-methyl-2,5,8,11,14-pentaoxo-3,6,9,12,15-pentaazanonadecanecarbonyl)pyrrolidine-2-carboxamido)-3-(1H-indol-3-yl)propanoyl)pyrrolidine-2-carboxylic acid (E08),

(S)—

N1-((S)-1-((R)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)piperidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-2-(6-hydroxy-5-nitronicotinamido)-5-oxohexanediamide (E09),

3-((2S)-6-amino-1-((2S)-3-cyclopropyl-1-((1R,2S)-2-((2S)-1-((2S)-2-(1-(2,6-dimethylphenoxy)propan-2-ylcarbamoyl)-2-methylpyrrolidin-1-yl)-1-oxopentan-2-ylcarbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-1-oxopropan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)-5-nitrobenzoic acid (E10),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-2-(pyrazine-2-carboxamido)hexanediamide (E11),

(S)-2-benzamido-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E12),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(2-methyl-5-nitrobenzamido)-5-oxohexanediamide (E13),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-methylthiazole-5-carboxamido)-5-oxohexanediamide (E14),

(S)-2-(5-(dimethylamino)naphthalene-1-sulfonamido)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E15),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E16),

(S)—

N1-ethyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E17),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-pentylhexanediamide (E18),

(S)—

N1-cyclopropyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E19),

(S)—

N1-benzyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E20),

(S)—

N1-tert-butyl-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E21),

(S)-2-((S)-1-acetylpyrrolidine-2-carboxamido)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxo-N6-pentylhexanediamide (E22),

(S)-2-benzamido-N6-cyclopropyl-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-oxohexanediamide (E23),

(S)-methyl 2-((S)-1-((S)-2-((S)-2-benzamido-6-(cyclopropylamino)-5,6-dioxohexanamido)-3-methylbutanoyl)pyrrolidine-2-carboxamido)-4-methylpentanoate (E24),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E25),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(ethylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E26),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-1,5,6-trioxo-6-(pentylamino)hexan-2-ylcarbamoyl)nicotinic acid (E27),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclo-hexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl-amino)-6-(cyclopropylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E28),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(benzylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E29),

4-((S)-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylamino)-6-(tert-butylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E30),

4-((S)-6-amino-1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxo pyrrolidi n-1-yl)-3,3-di methyl-1-oxo butan-2-ylamino)-1,5,6-trioxohexan-2-ylcarbamoyl)nicotinic acid (E31),

(S)—

N1-((S)-1-((S)-2-((S)-2-((S)-2-amino-1-cyclohexyl-2-oxoethylamino)-1-cyclohexyl-2-oxoethylcarbamoyl)-4-oxopyrrolidin-1-yl)-3,3-di methyl-1-oxobutan-2-yl)-N6-cyclopropyl-2-(2-methylthiazole-4-carboxamido)-5-oxohexanediamide (E32),

(S)—

N1-((S)-1-((2R,3S)-1-((S)-1-((S)-2-((S)-1-((S)-2-carbamoylpyrrolidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidi n-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-4-methyl-1-oxopentan-2-yl)-N6-cyclopropyl-2-(2-methylthiazole-4-carboxamido)-5-oxohexanediamide (E33),

(S)-2-(2-acetamidoacetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxo pro pan-2-ylcarbamoyl)pyrrolidi n-1-yl)-4-methyl-1-oxo pentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E34),

(S)-2-(2-((S)-1-acetylpyrrolidine-2-carboxamido)acetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E35),

(S)-2-(2-((S)-1-(2-acetamidoacetyl)pyrrolidine-2-carboxamido)acetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E36),

(S)-2-(2-((S)-1-(2-((S)-2-acetamido-4-methylpentanamido)acetyl)pyrrolidine-2-carboxamido)acetamido)-N1-((S)-1-((2S,3S)-1-((S)-1-((S)-2-((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-ylcarbamoyl)pyrrolidin-1-yl)-4-methyl-1-oxopentan-2-ylamino)-3-methyl-1-oxopentan-2-ylamino)-1-oxohexan-2-yl)-N6-methyl-5-oxohexanediamide (E37),

(S)-methyl 2-(6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanamido)acetat (E38),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-(methoxymethyl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E39),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-(thiazol-5-yl)hexanediamide (E40),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxo-N6-(tosylmethyl)hexanediamide (E41),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E42),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E43),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E44),

(S)—

N1-(5-chloro-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E45),

(S)—

N1-(5-bromo-1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E46),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E47),

(S)-1-methyl-N-(6-(methylamino)-1,5,6-trioxo-1-(4-(phenylsulfonyl)piperazin-1-yl)hexan-2-yl)-1H-imidazole-5-carboxamide (E48),

(S)—

N1-(1-benzylpiperidin-4-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E49),

(S)—

N1-(1-(2-(diethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E50),

(S)—

N1-methyl-5-(1-methyl-1H-imidazole-5-carboxamido)-N6-(1-(2-(methylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-oxohexanediamide (E51),

(S)-ethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E52),

(S)-2-methoxyethyl 2-(3-(2-(1-methyl-1H-imidazole-5-carboxamido)-6-(methylamino)-5,6-dioxohexanamido)-2-oxopyridin-1(2H)-yl)acetate (E53),

(S)—

N1-(1-(2-(methoxymethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E54),

(S)—

N1-(1-(2-((dimethylamino)methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E55),

(S)—

N1-(1-(2-(ethylsulfonamido)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-5-oxohexanediamide (E56),

(S)-benzyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E57),

(S)-tert-butyl 1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E58),

(S)-4-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylamino)-4-oxobutanoic acid (E59),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-((S)-4-oxopyrrolidine-2-carboxamido)hexanediamide (E60),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-2-(furan-3-carboxamido)-N6-methyl-5-oxohexanediamide (E61),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(oxazole-5-carboxamido)-5-oxohexanediamide (E62),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methylpiperidine-4-carboxamido)-5-oxohexanediamide (E63),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(pyrimidine-5-carboxamido)hexanediamide (E64),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(quinoxaline-2-carboxamido)hexanediamide (E65),

(S)-2-(2,4-dimethylthiazole-5-sulfonamido)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E66),

(S)-2-(6-chloroimidazo[2,1-b]thiazole-5-sulfonamido)-N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxohexanediamide (E67),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-2-(1-methyl-1H-imidazole-2-sulfonamido)-5-oxohexanediamide (E68),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylureido)hexanediamide (E69),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N6-methyl-5-oxo-2-(3-phenylthioureido)hexanediamide (E70),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N7-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-6-oxoheptanediamide (E71),

(S)—

N1-methyl-6-(1-methyl-1H-imidazole-5-carboxamido)-N7-(4-(4-methylpiperazin-1-ylsulfonyl)phenyl)-2-oxoheptanediamide (E72),

(S)—

N1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-N8-methyl-2-(1-methyl-1H-imidazole-5-carboxamido)-7-oxooctanediamide (E73),

(S)—

N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxoheptan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E74),

(S)—

N-(6-cyclopropyl-1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E75),

(S)—

N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-1,5,6-trioxo-6-phenylhexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E76),

(S)-methyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E77),

(S)-2-methoxyethyl 6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-5-(1-methyl-1H-imidazole-5-carboxamido)-2,6-dioxohexanoate (E78),

(S)—

N1-(cyclopentylmethoxy)-N6-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-(1-methyl-1H-imidazole-5-carboxamido)-2-oxohexanediamide (E79),

(S)—

N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-8-methyl-1,5,6-trioxononan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E80),

(S)—

N-(1-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridin-3-ylamino)-6-(1-methyl-1H-imidazol-4-yl)-1,5,6-trioxohexan-2-yl)-1-methyl-1H-imidazole-5-carboxamide (E81),

(2S)-N1-((S)-1-((S)-1-((S)-3-carbamoyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl)-2-(2-(5,5-dimethyl-2-oxotetrahydrofuran-3-yl)acetamido)-N6-methyl-5-oxohexanediamide (E82),

(S)—

N1-(3-((S)-3-(biphenyl-4-yl)-1-((2S,4R)-2-carbamoyl-4-phenoxypyrrolidin-1-yl)-1-oxopropan-2-ylcarbamoyl)phenyl)-2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)acetamido)-N6-methyl-5-oxohexanediamide (E83), and

isopropyl (S)-1-((S)-1-(1-((2S,4R)-2-carbamoyl-4-hydroxypyrrolidin-1-yl)-2-methyl-1-oxopropan-2-ylamino)-5-guanidino-1-oxopentan-2-ylamino)-6-(methylamino)-1,5,6-trioxohexan-2-ylcarbamate (E84).

12. A method for treatment or prophylaxis of atherosclerosis, coeliac disease, Duhring-Brocq-disease, gluten ataxia, tissue fibrosis, cystic fibrosis, kidney fibrosis and diabetic nephropathy, liver fibrosis, thrombosis, Huntington'"'"'s disease, Parkinson'"'"'s disease, Alzheimer'"'"'s disease, cataract, ichthyosis, acne, psoriasis, skin aging, and candidosis comprising administering the compound of claim 1 to a subject.

13. A method for producing a compound according to claim 1 comprising:

Step (0);

providing a protected amino acid having a chemical warhead;

Step 1C;

deprotecting an amino protecting group PG² and a carboxyl protecting group PG³;

Step 1C′

;

(a) performing coupling reaction of a resulting compound of Step 1C with a corresponding C-terminal amino acid building block H₂AS^Ci-OPG⁴;

(b) deprotecting the protecting group PG⁴;

(c) repeating the steps (a) and (b) i times, wherein i is 1-8

Step 2C;

performing coupling reaction with a C-terminal building block E^C-H;

Step 3C;

deprotecting an amino protecting group PG¹;

Step 4C;

performing coupling reaction with a N-terminal building block E^N-AG¹;

to produce the compound of the formula (I).

14. The method according to claim 13 further comprising the Step 3C′

between the step 3B and the step 4C;

Step 3C′

;

(d) performing coupling reaction of a resulting compound of Step 3C with a corresponding N-terminal amino acid building block (PG⁵)HAS^Nj-OH;

(e) deprotecting the protecting group PG⁵;

(f) repeating the steps (a) and (b) j times, wherein j is 1-4.

15. A method for producing a compound according to claim 1 comprising:

Step (0);

providing a protected amino acid (1C′

) having a chemical warhead precursor (W′

);

Step 1 D;

performing coupling reaction of the protected amino acid (1C′

) with a C-terminal peptide building block (C-P) or a C-terminal building block (E^C-H) to obtain a compound 1D-1 or 1D-2;

Step 2D;

deprotecting an amino protecting group PG¹;

to obtain a compound 2D-1 or 2D-2;

Step 3D;

performing coupling reaction of the compound 2D-1 or 2D-2 with a N-terminal peptide building block (N-P) or a N-terminal building block (E^N-H);

to obtain a compound 3D-1, 3D-2, 3D-3, or 3D-4;

Step 4D;

converting the chemical warhead precursor (W′

) of the compound 3D-1, 3D-2, 3D-3, or 3D-4 to a chemical precursor (W)

to produce a compound 4D-1, 4D-2, 4D-3, or 4D-4 as compound of the formula (I).

11. (canceled)