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US 2026/0167632 A1Published application
Nicotinamide derivatives for use in treating disorders associated with kcnk13 activity
AssigneeCerevance, Inc.
InventorsRoland Bürli, Kevin Doyle, Martin Teall
Life of this patent
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Abstract
The present invention provides compounds of formula (I) and pharmaceutically acceptable salts, N-oxides, solvates and prodrugs thereof: Formula (I) wherein Z, X, R1, R2, R4, R1 R5, R6 and R7 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for use in treating disorders associated with KCNK13 activity.
Claims16
A compound of formula (I):
- or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, wherein:
- X is N or CH;
- Z is —C(O)— or —SO2—;
- R1 is -L-R3;
- R2 is hydrogen or C1-C3 alkyl;
- L is a bond, —CH2—, —CHMe-, or —C(C2H4)—;
- R3 is a 5- to 11-membered cyclic group, wherein the cyclic group is optionally substituted with one or more substituents independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), oxo (═O), or —C(O)O(C1-C3 alkyl);
- or R1 and R2 and the nitrogen atom to which they are attached together form a 5- to 11-membered heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents independently selected from halo, cyano, C1-C3 alkyl, C1-C3 haloalkyl, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), or halophenyl;
- R4 is cyano, —O—(C1-C3 alkyl), —O—(C1-C3 haloalkyl), or —N—(C1-C3 alkyl)2;
- or R4 and X together with the carbon atom to which they are attached form a 5-membered heteroaryl group;
- R5 is hydrogen, halo, C1-C3 alkyl, C1-C3 haloalkyl, or C3-C5 cycloalkyl;
- R6 is hydrogen, methyl or halo;
- and
- R7 is hydrogen, methyl or halo.
11 more elements
The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein:
- (i) R4 is cyano, methoxy, ethoxy, fluoromethoxy, or fluoroethoxy;
- and/or
- (ii) R5 is hydrogen, fluoro, chloro, methyl, fluoromethyl, cyclopropyl, or cyclobutyl;
- and/or
- (iii) R6 is hydrogen, methyl, or fluoro;
- and/or
- (iv) R7 is hydrogen or methyl.
4 more elements
The compound, salt, N-oxide, solvate or prodrug as claimed in any one of the preceding claims, wherein the compound is selected from:
- N-benzyl-5-chloro-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(6-cyano-2,3-dihydro-1H-inden-1-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(7-cyano-2,3-dihydro-1H-inden-1-yl)-2-methoxy-N-methylnicotinamide;
- (5-fluoro-2-methoxypyridin-3-yl)(2-(3-fluorophenyl)piperidin-1-yl)methanone;
- 5-fluoro-N-(1-(2-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(1-(3-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methoxy-N-methylnicotinamide;
- N-(2,4-difluorobenzyl)-2-methoxy-N,6-dimethylnicotinamide;
- 5-chloro-N-(2,3-dihydro-1H-inden-1-yl)-2-ethoxy-N-methylnicotinamide;
- N-(chroman-4-yl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- N-(2, 3-dihydro-1H-inden-1-yl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(chroman-4-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(2,3-dihydro-1H-inden-1-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(8-fluorochroman-4-yl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(8-fluorochroman-4-yl)-2-methoxy-N-methylnicotinamide;
- N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- N-(2-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(1-(3-fluorophenyl)cyclopropyl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(5-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;
- N-(2-cyanobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(2-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- N-(2,3-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- N-(2,4-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(2,3-difluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(3,5-difluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-fluoro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(7-fluorochroman-4-yl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(3-chloro-5-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-2-methoxy-N-methylnicotinamide;
- N-benzyl-5-chloro-N-ethyl-2-methoxynicotinamide;
- 5-chloro-N-ethyl-N-(2-fluorobenzyl)-2-methoxynicotinamide;
- 5-chloro-N-ethyl-N-(3-fluorobenzyl)-2-methoxynicotinamide;
- 5-fluoro-N-(3-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 2-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline;
- 2-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline;
- 7-fluoro-4-((2-methoxy-5-methylpyridin-3-yl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine;
- 4-((5-chloro-2-methoxypyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine;
- 7-fluoro-4-((2-methoxypyridin-3-yl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine;
- methyl 4-fluoro-2-((5-fluoro-2-methoxy-N-methylnicotinamido)methyl)benzoate;
- 5-chloro-N-(4-fluoro-2-(trifluoromethyl)benzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(2-cyano-4-fluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(1-(2-cyano-5-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;
- N-(2-cyano-4,6-difluorobenzyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- N-(1-(2-cyano-5-fluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- N-(1-(2-cyano-4-fluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(1-(2-cyano-4-fluorophenyl)ethyl)-2-methoxy-N-methylnicotinamide;
- N-(1-(2,4-difluorophenyl)ethyl)-5-fluoro-2-methoxy-N-methylnicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(1-(2-fluorophenyl)ethyl)-N-methylnicotinamide;
- N-(2,4-difluorobenzyl)-2-methoxy-N,5-dimethylnicotinamide;
- N-(2,4-difluorobenzyl)-2-methoxy-N,4-dimethylnicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(7-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(3-fluoro-5-methylbenzyl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(6-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;
- 5-chloro-N-(3,5-difluorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- 5-chloro-N-(3-chloro-5-fluorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-methylbenzyl)nicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(3-methoxybenzyl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-(trifluoromethyl)benzyl) nicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(1-(3-fluorophenyl)ethyl)-N-methylnicotinamide;
- 5-chloro-N-(3-chlorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- 2-(difluoromethoxy)-N-(2,3-dihydrobenzofuran-3-yl)-5-fluoro-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(1-(3-fluorophenyl)ethyl)-N-methylnicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(1-(3-fluorophenyl)ethyl)-N-methylnicotinamide;
- 5-chloro-N-(3-cyanobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(7-fluoro-2,3-dihydrobenzofuran-3-yl)-N-methylnicotinamide;
- N-(2,3-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylnicotinamide;
- N-(2,4-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylnicotinamide;
- 2-(difluoromethoxy)-5-fluoro-N-(3-fluorobenzyl)-N-methylnicotinamide;
- 2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methyl-5-(trifluoromethyl) nicotinamide;
- 5-cyclobutyl-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(3-(difluoromethoxy)benzyl)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-methyl-N-(3-(trifluoromethoxy)benzyl) nicotinamide;
- 5-chloro-N-(2,4-difluorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methylnicotinamide;
- 5-chloro-N-(2, 3-difluorobenzyl)-2-(difluoromethoxy)-N-methylnicotinamide;
- N-(3,5-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;
- (R)-2-(difluoromethoxy)-5-fluoro-N-(1-(3-fluorophenyl)ethyl)-N-methylpyridine-3-sulfonamide;
- (S)-2-(difluoromethoxy)-5-fluoro-N-(1-(3-fluorophenyl)ethyl)-N-methylpyridine-3-sulfonamide;
- N-(3-cyanobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;
- N-(2,3-difluorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;
- N-(3-chlorobenzyl)-2-(difluoromethoxy)-5-fluoro-N-methylpyridine-3-sulfonamide;
- 2-(difluoromethoxy)-N-ethyl-5-fluoro-N-(3-fluorobenzyl)pyridine-3-sulfonamide;
- 2-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroisoquinoline;
- 2-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline;
- 2-(difluoromethoxy)-5-fluoro-N-(3-fluorobenzyl)-N-methylpyridine-3-sulfonamide;
- 5-chloro-2-(difluoromethoxy)-N-(3-fluorobenzyl)-N-methylpyridine-3-sulfonamide;
- 4-((2-(difluoromethoxy)-5-fluoropyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine;
- 4-((5-chloro-2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine;
- 2-((5-chloro-2-(difluoromethoxy)pyridin-3-yl)sulfonyl)-6,8-difluoro-1,2,3,4-tetrahydroisoquinoline;
- 5-chloro-N-(2,6-difluorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-N-(2,6-dichlorobenzyl)-2-methoxy-N-methylnicotinamide;
- 5-chloro-2-(difluoromethoxy)-N-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-3-yl)-N-methylnicotinamide;
- 5-fluoro-2-((7-fluoro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)sulfonyl)benzonitrile;
- or an enantiomer of any of the foregoing;
- or a pharmaceutically acceptable salt, solvate or prodrug of any of the foregoing.
97 more elements
Dependencies are inferred from the claim text.