ERAP inhibitors

Patent metadata

Field	Value
Publication number	US-12522592-B2
Application number	US-202118267432-A
Country	US
Kind code	B2
Filing date	Dec 17, 2021
Priority date	Dec 18, 2020
Publication date	Jan 13, 2026
Grant date	Jan 13, 2026

Abstract

The present disclosure relates to novel compounds of formula (I) which are useful as inhibitors of endoplasmic reticulum aminopeptidases (ERAP), in particular as inhibitors of ERAP2. The disclosure also relates to the therapeutic use of these compounds, in particular the use of these compounds in the treatment or prophylaxis of proliferative disorders, autoinflammatory disorders and autoimmune disorders.

First claim

The invention claimed is:

1 . A compound of formula (I):

wherein:
n is 0 or 1;
R 1 is selected from the group consisting of phenyl, naphthalenyl, indolyl and benzodioxolyl, wherein said phenyl, naphthalenyl, indolyl and benzodioxolyl may be substituted by one more substituents selected from the group consisting of hydroxyl, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoalkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, ethynyl, carbamoyl, C 1 -C 6 -alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy;
R 3 is a 5- or 6-membered heteroaryl comprising one sulfur atom and optionally one further nitrogen, sulfur or oxygen atom, wherein said 5- or 6-membered heteroaryl may be substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl may be substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl, phenyl, pyridyl, C 1 -C 6 -aminoalkyl and C 1 -C 6 -alkylcarbamoyl;
R 2 is hydrogen, C 1 -C 6 -alkyl or C 3 -C 6 -cycloalkyl; and
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, —CH 2 —O—R a4 , —CH 2 —C(═O)R b4 and —CH 2 —NH—C(═O)R c4 , wherein R a4 is hydrogen or C 1 -C 6 -alkyl, R b4 is hydroxyl, C 1 -C 6 -alkoxy, amino or C 1 -C 6 -alkylcarbonylamino and R c4 is C 1 -C 6 -alkoxy, or
R 2 and R 4 form together with the nitrogen and carbon atoms to which they are attached a 5- or 6-membered heteroaryl selected from pyrrolidinyl morpholinyl, thiazolidinyl and piperidinyl;
or hydrates, solvates, or salts thereof.

2 . The compound of formula (I) according to claim 1 wherein R 1 is selected from the group consisting of phenyl, indol-3-yl, naphthalen-2-yl and 1,3-benzodioxol-5-yl, wherein said phenyl, indol-3-yl, naphthalen-2-yl and 1,3-benzodioxol-5-yl may be substituted by one more substituents selected from the group consisting of hydroxyl, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoalkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, ethynyl, carbamoyl, C 1 -C 6 -alkylcarbamoyl, polyoxyethylenyl amidoxime and phenoxy.

3 . The compound of formula (I) according to claim 1 wherein R 1 is

wherein R a , R b and R c are independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -halogenoalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -halogenoalkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, ethynyl, carbamoyl, C 1 -C 6 -alkylcarbamoyl, polyoxyethylenyl, amidoxime and phenoxy.

4 . The compound of formula (I) according to claim 1 wherein R 3 is a 5- or 6-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl, isothiazolyl, thiopyranyl, dithiinyl and thiazinyl, wherein said 5- or 6-membered heteroaryl may be substituted as recited in claim 1 .

5 . The compound of formula (I) according to claim 1 wherein R 3 is a 5-membered heteroaryl selected from the group consisting of thiophenyl, thiazolyl and isothiazolyl, wherein said thiophenyl, thiazolyl and isothiazolyl may be substituted as recited in claim 1 .

6 . The compound of formula (I) according to claim 1 wherein R 3 is

wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl may be substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl, phenyl, pyridyl, C 1 -C 6 -aminoalkyl and C 1 -C 6 -alkylcarbamoyl.

7 . The compound of formula (I) according to claim 1 wherein R 3 is

wherein R 5 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 -alkyl, phenyl and pyridyl, wherein said phenyl and pyridyl may be substituted by one or more substituents selected from the group consisting of halogen, C 1 -C 6 -alkyl, phenyl, pyridyl, C 1 -C 6 -aminoalkyl and C 1 -C 6 -alkylcarbamoyl.

8 . The compound of formula (I) according to claim 1 wherein the compound of formula (I) has the following formula:

wherein n, R 1 , R 2 , R 3 and R 4 are as recited in any of the preceding claims .

9 . The compound of formula (I) according to claim 1 which is:
(R)—N-hydroxy-4-(1H-indol-3-yl)-3-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide;
(R)—N-hydroxy-3-(1H-indol-3-yl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-3-(1H-indol-3-yl)-2-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-3-(1H-indol-3-yl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)-2-(4-((5-bromothiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxy-3-(1H-indol-3-yl)propenamide;
(R)—N-hydroxy-4-(naphthalen-2-yl)-3-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide;
(S)—N-hydroxy-4-(4-hydroxyphenyl)-3-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide;
(R)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-4-(4-hydroxyphenyl)-3-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)butanamide;
(S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)-4-(5-(N-((1-(1-(hydroxyamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)sulfamoyl)thiophen-2-yl)-N-methylbenzamide;
(S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((N-methyl-5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)-2-(4-((5-bromothiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxy-3-(4-hydroxyphenyl)propenamide;
(S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(2S)-3-(4-hydroxyphenyl)-2-[4-[(3-thienylsulfonylamino)methyl]triazol-1-yl]propanehydroxamic acid
(2S)-2-[4-[[(3-bromo-2-thienyl)sulfonylamino]methyl]triazol-1-yl]-3-(4-hydroxyphenyl)propanehydroxamic acid;
(2S)-3-(4-hydroxyphenyl)-2-[4-[[[5-(2-pyridyl)-2-thienyl]sulfonylamino]methyl]triazol-1-yl]propanehydroxamic acid;
(R)—N-hydroxy-3-(4-hydroxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propanamide;
(S)—N-hydroxy-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-3-(4-(trifluoromethoxy)phenyl)propanamide;
(S)—N-hydroxy-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)-3-(4-(trifluoromethoxy)phenyl)propenamide;
(S)—N-hydroxy-3-(4-phenoxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-3-(4-methoxyphenyl)-2-(4-((5-phenylthiophene-2-sulfonamido)methyl)-1H-1,2,3-triazol-1-yl)propenamide;
(S)—N-hydroxy-3-(4-methoxyphenyl)-2-(4-((5-(pyridin-2-yl)thiophene-2-sulfonamido)methyl)-1H-1,2,3-triaz

Assignees

• Univ Lille
• Pasteur Institut
• Inst Nat Sante Rech Med

Inventors

• Poulain Rebecca Deprez
• Gealageas Ronan
• Camberlein Virgyl
• Fleau Charlotte Tabey
• Guillaume Valentin
• Bosc Damien
• Deprez Benoit
• Sierocki Pierre

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title