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US 11,345,669 B2Granted
Urea derivatives and methods of use thereof
AssigneeNodThera Limited
InventorsDavid Harrison, Alan Paul Watt, Nicolas Boutard, Charles-Henry Fabritius, Michal Galezowski, Piotr Kowalczyk, Oleksandr Levenets, Jakub Woyciechowski
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Abstract
The present disclosure relates to compounds of Formula (I): and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inter alia autoinflammatory and autoimmune diseases and cancers.
Claims20
A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
- wherein:
- R1 is a hexahydroindacene ring:
- wherein # denotes the bond to the nitrogen atom of Formula (I), optionally substituted by 1, 2, 3 or 4 substituents independently selected from (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (1-3C)alkoxy, halo, oxo, hydroxy, cyano, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]-amino, CF3, OCF3, S(O)2CH3, S(O)CH3, S(O)2NH2, S(O)2NHCH3, S(O)2N(CH3)2, NHS(O)2CH3, and N(CH3)S(O)2CH3;
- R2 is H;
- R3 is (1-4C)alkyl R7,
- wherein R7 is selected from a 5 or 6 membered monocyclic aryl or non-aryl ring system comprising 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said heterocyclic R7 ring system is optionally substituted with 1 or more substituents independently selected from (1-6C) alkyl, alkylhydroxy, nitro, OH, COCH3, halo, amino, cyano, and R8,
- or
- wherein R7 is selected from a 5 or 6 membered monocyclic aryl or non-aryl ring system optionally comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system optionally comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, and a 3, 4, 5 or 6 membered saturated or partially unsaturated carbocyclic ring system wherein the R7 ring system is substituted with 1 or more substituents independently selected from (1-6C)alkyl, alkylhydroxy, nitro, OH, COCH3, halo, amino, cyano, and R8,
- wherein R8 is, an optionally N-linked, 5 or 6 membered monocyclic heteroaryl ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, or a 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system comprising 1 heteroatom independently selected from oxygen, nitrogen and sulfur, said ring being optionally substituted with an alkyl, oxo, halo or amino group;
- and
- R4 is H, alkyl, monocyclic saturated carbocyclic ring system, or monocyclic aryl group.
8 more elements
A compound selected from the group consisting of:
- Structure
- Name
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(3- hydroxyphenyl)propanoate);
- (methyl2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(2- hydroxyphenyl)propanoate);
- (methyl 3-(3-acetylphenyl)-2-{[(1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl]amino}propanoate);
- (methyl (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl]amino}propanoate);
- (methyl (2R)-3-(3-cyanophenyl)-2-{[(1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl]amino}propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyridin-2- yl)propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-[3- (hydroxymethyl)phenyl]propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-[3-(1-methyl-1H- imidazol-5- yl)phenyl]propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-[3-(1H-pyrazol-5- yl)phenyl]propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(3- hydroxyphenyl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-[3-(1H-pyrazol-3- yl)phenyl]propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-[3- (hydroxymethyl)phenyl]propanoate);
- (methyl (2R)-3-(3-acetamidophenyl)-2- {[(1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl]amino}propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(1-methyl-1H-pyrazol-4- yl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-[3-(2-oxopyrrolidin-1- yl)phenyl]propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-{3-[(1H-pyrazol-3- yl)amino]phenyl}propanoate);
- ((2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-[3-(1H-pyrazol-3- yl)phenyl]propanoic acid);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(4- hydroxyphenyl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(thiophen-2- yl)propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(1H-imidazol-1- yl)propanoate);
- (methyl (2R)-3-(3-aminophenyl)-2-{[(1,2,3,5,6,7- hexahydro-s-indacen-4- yl)carbamoyl]amino}propanoate);
- (ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-[3-(1H-pyrazol-4- yl)phenyl]propanoate);
- ((2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(pyridin-3-yl)propanoic acid);
- (2-methoxyethyl (2R)-2-{[(1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (cyclobutyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (cyclopropylmethyl (2R)-2-{[(1,2,3,5,6,7- hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (cyclopentyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyridin-3- yl)propanoate);
- (methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(4-methyl-1H-pyrazol-1- yl)propanoate);
- (ethyl (2R)-2-({[2,6-bis(propan-2- yl)phenyl]carbamoyl}amino)-3-(pyridin-3- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(pyrimidin-2- yl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(5- methoxypyridin-3-yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(3-methyl-1,2,4- oxadiazol-5-yl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyridazin-3- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(1,2-oxazol-4- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(1,2-oxazol-3- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(1,3-oxazol-2- yl)propanoate);
- (ethyl (2R)-2-({[6-(propan-2-yl)-2,3-dihydro-1H- inden-5-yl]carbamoyl}amino)-3-(pyridin-3- yl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyrimidin-5- yl)propanoate);
- (methyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4-yl)carbamoyl]amino}-3-(pyrazin-2- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(pyridazin-4- yl)propanoate);
- (ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4- yl)carbamoyl]amino}-3-(pyrimidin-2- yl)propanoate);
- (ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(pyrimidin-4- yl)propanoate);
- (2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)carbamoyl]amino}-3-(pyrimidin-2- yl)propanoic acid).
44 more elements
A compound of Formula (I), or pharmaceutically acceptable salt thereof:
- wherein:
- R1 is a 12, 13, 15 or 16 membered tricyclic partially unsaturated carbocyclic ring system, wherein said tricyclic ring system is optionally substituted by 1, 2, 3 or 4 substituents independently selected from (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (1-3C)alkoxy, halo, oxo, hydroxy, cyano, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]-amino, CF3, OCF3, S(O)2CH3, S(O)CH3, S(O)2NH2, S(O)2NHCH3, S(O)2N(CH3)2, NHS(O)2CH3, and N(CH3)S(O)2CH3;
- R2 is H;
- R3 is (1-4C)AlkylR7;
- wherein R7 is selected from a 5 or 6 membered monocyclic aryl or non-aryl ring system comprising 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, or 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein said R7 ring system is optionally substituted with 1 or more substituents independently selected from (1-6C)alkyl, alkylhydroxy, nitro, OH, COCH3, halo, amino, cyano, an optionally N-linked 5 or 6 membered monocyclic heteroaryl ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, or an optionally N-linked 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system comprising 1 heteroatom independently selected from oxygen, nitrogen and sulfur, said ring being optionally substituted with an alkyl, oxo, halo, or amino group;
- and
- R4 is H, alkyl, monocyclic saturated carbocyclic ring system, or monocyclic aryl group.
4 more elements
A compound of Formula (I), or pharmaceutically acceptable salt thereof:
- wherein:
- R1 is a 12, 13, 15 or 16 membered tricyclic partially unsaturated carbocyclic ring system, wherein said tricyclic ring system is optionally substituted by 1, 2, 3 or 4 substituents independently selected from (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (3-8C)cycloalkyl, (1-3C)alkoxy, halo, oxo, hydroxy, cyano, amino, (1-3C)alkylamino, di-[(1-3C)alkyl]-amino, CF3, OCF3, S(O)2CH3, S(O)CH3, S(O)2NH2, S(O)2NHCH3, S(O)2N(CH3)2, NHS(O)2CH3, and N(CH3)S(O)2CH3;
- R2 is H;
- R3 (1-4C)AlkylR7,
- wherein R7 is selected from a 5 or 6 membered monocyclic aryl or non-aryl ring system optionally comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur, 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system optionally comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, or a 3, 4, 5 or 6 membered saturated or partially unsaturated carbocyclic ring system and said R7 ring system is substituted with 1 or more substituents independently selected from (1-6C)alkyl, alkylhydroxy, nitro, OH, COCH3, halo, amino, cyano, an optionally N-linked 5 or 6 membered monocyclic heteroaryl ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur, and an optionally N-linked 3, 4, 5 or 6 membered monocyclic heterocyclyl ring system comprising 1 heteroatom independently selected from oxygen, nitrogen and sulfur, said ring being optionally substituted with an alkyl, oxo, halo, or amino group;
- and
- R4 is H, alkyl, monocyclic saturated carbocyclic ring system, or monocyclic aryl group.
4 more elements
Dependencies are inferred from the claim text.