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US 2026/0193170 A1Published application
Noncovalent Keap1-Nrf2 Small-Molecule Inhibitors
AssigneeUniversity of Copenhagen
InventorsChunyu Lin, Jie Zang, Dilip Narayanan, Anders Bach
Life of this patent
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Abstract
The present invention relates to a series of noncovalent Keap1-Nrf2 small-molecule inhibitors and their use as medicaments. The series comprises novel small-molecule analogues with strong affinity for the Keap1 Kelch domain and ability to inhibit the Keap1-Nrf2 interaction.
Claims24
A compound of Formula (XI):
- wherein
- X1 is CH or N;
- X2 is CH or N;
- X3 is CH or N;
- X4 is CH or N;
- X5 is CH or N;
- X6 is CH or N;
- R1 is phenyl, pyridinyl or H, wherein the phenyl or pyridinyl is optionally substituted with one or more, identical or different, substituents R6, wherein two of the substituents R6 optionally are linked together to form a ring;
- R2 is selected from the group consisting of C5-7 cycloalkyl, C5-7 cycloalkenyl, C5-7 heterocycloalkyl, phenyl, C5-8 bicycloalkyl, C3-6 alkyl, and C9-12 tricycloalkyl, wherein said C5-7 cycloalkyl, C5-7 cycloalkenyl, C5-7 heterocycloalkyl, phenyl, C5-8 bicycloalkyl, C3-6 alkyl, and C9-12 tricycloalkyl is optionally substituted with one or more, identical of different substituents R28;
- R5 is H or CH3;
- or R2 is C3-6 alkanediyl optionally substituted with R28, R5 is a bond, and R2 and R5 are linked together to form a ring;
- R3 is H or CH3;
- R4 is H or CH3;
- R6 is selected from the group consisting of C1-5 alkyl, halogen, —OH, —OC1-5 alkyl and C2-5 alkenyl,
- wherein said C1-5 alkyl, —OC1-5 alkyl and C2-5 alkenyl are optionally substituted with one or more substituents individually selected from C1-3 alkyl and halogen;
- wherein one or more methylene group of the C1-5 alkyl, —OC1-5 alkyl, or C2-5 alkenyl is optionally replaced with O or N(R7);
- and/or
- wherein one or more methine group of the C2-5 alkenyl is optionally replaced with N;
- R7 is H or C1-3 alkyl;
- R23 is selected from the group consisting of —OH;
- —OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R26;—OC2-5 alkenyl optionally substituted with one or more, identical or different, substituents R26;
- —OC2-5 alkynyl optionally substituted with one or more, identical or different, substituents R26;
- —OC3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R26;
- —O-phenyl optionally substituted with one or more, identical or different, substituents R27;
- and —O-benzyl optionally substituted with one or more, identical or different, substituents R27;
- and —NH(CH3);
- R24 is H or CH3;
- R25 is H or CH3;
- R26 is independently selected from the group consisting of H, deuterium, F, Cl and —OC1-3 alkyl;
- R27 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;
- and
- R28 is individually selected from C1-3 alkyl, —OC1-3 alkyl, halogen, and deuterium, wherein said C1-3 alkyl is optionally substituted with one or more halogens;
- or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.
30 more elements
The compound according to any one of the preceding claims, wherein X1, X2, X3, X4, X5 and X6 are CH, and R3, R4 and R5 are H.
The compound according to any one of the preceding claims, wherein R1 is of Formula (II):
- wherein
- X7 is C(R11) or N;
- R7 is H or C1-3 alkyl;
- R8 is H or C1-5 alkyl;
- R9 is selected from the group consisting of H, C1-5 alkyl, halogen, —OH, —OC1-5 alkyl and C2-5 alkenyl,
- wherein said C1-5 alkyl, —OC1-5 alkyl and C2-5 alkenyl are optionally substituted with one or more substituents individually selected from C1-3 alkyl and halogen;
- wherein one or more methylene group of the C1-5 alkyl, —OC1-5 alkyl, or C2-5 alkenyl is optionally replaced with O or N(R7);
- and/or
- wherein one or more methine group of the C2-5 alkenyl is optionally replaced with N;
- R10 is selected from the group consisting of H, C1-5 alkyl, halogen, —OH, —OC1-5 alkyl and C2-5 alkenyl,
- wherein said C1-5 alkyl, —OC1-5 alkyl and C2-5 alkenyl are optionally substituted with one or more substituents individually selected from C1-3 alkyl and halogen;
- wherein one or more methylene group of the C1-5 alkyl, —OC1-5 alkyl, or C2-5 alkenyl is optionally replaced with O or N(R7);
- and/or
- wherein one or more methine group of the C2-5 alkenyl is optionally replaced with N;
- R11 is H or —OC1-5 alkyl;
- R12 is selected from the group consisting of H, C1-5 alkyl, —OC1-5 alkyl, and halogen;
- and
- R9 and R10 are optionally linked together to form a ring.
15 more elements
The compound according to any one of the preceding claims, wherein R1 is of Formula (III):
- wherein
- R8 is H or C1-3 alkyl;
- R9 is selected from the group consisting of H, C1-3 alkyl, halogen, —OH and —OC1-3 alkyl;
- R10 is selected from the group consisting of H, halogen, —OH and —OC1-3 alkyl;
- R11 is H;
- and
- R12 is selected from the group consisting of H, C1-3 alkyl and halogen.
4 more elements
The compound according to any one of the preceding claims, wherein R2 is of Formula (VIII):
- wherein
- X13 is C(H) or N;
- X14 is (1) C(H) and b is a double bond;
- (2) C(R21)(R22) and b is a single bond;
- or (3) O and a is a single bond;
- R21 is selected from the group consisting of H, deuterium, halogen and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more halogens;
- R22 is selected from the group consisting of H, deuterium, halogen and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more halogens;
- a is a double bond or a single bond;
- b is a double bond or a single bond;
- and
- m is 1 or 2,
- with the proviso that no more than one of a and b is a double bond.
9 more elements
The compound according to any one of the preceding claims, wherein R2 is of Formula (IX):
- wherein
- X13 is C(R29) or N;
- X14 is C(R21)(R22) or O;
- R21 is selected from the group consisting of H, deuterium, halogen and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more halogens;
- R22 is selected from the group consisting of H, deuterium, halogen and C1-3 alkyl, wherein said C1-3 alkyl is optionally substituted with one or more halogens;
- R29 is H or C1-3 alkyl;
- and
- m is 0, 1 or 2.
5 more elements
A pharmaceutical composition comprising the compound according to any one of the preceding claims.
Dependencies are inferred from the claim text.