Pyrazolyl compounds as kv7 channel activators

A compound represented by Formula 1

• wherein:
• R1 is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C1-6 alkyl(C3-8 cycloalkyl), C3-8 cycloalkenyl, C1-6 alkyl(C3-8 cycloalkenyl), C3-8 cycloalkynyl, C1-6 alkyl(C3-8 cycloalkynyl), C3-8 spirocarbocyclyl, C1-6 alkyl(C3-8 spirocarbocyclyl), C5-10 bridged bicycloalkyl, C1-6 alkyl(C5-10 bridged bicycloalkyl), C2-6 heterocycloalkyl, C1-6 alkyl(C2-6 heterocycloalkyl), C2-5 heterocycloalkenyl, C1-6 alkyl(C2-8 heterocycloalkenyl), C2-5 heterocycloalkynyl, C1-6 alkyl(C2-5 heterocycloalkynyl), C2-8 spiroheterocyclyl, C1-6 alkyl(C2-8 spiroheterocyclyl), C5-10 bridged heterobicycloalkyl, C1-6 alkyl(C5-10 bridged heterobicycloalkyl), C5-10 aryl, C1-6 alkyl(C5-10 aryl), C2-8 heteroaryl, C1-6 alkyl(C2-8 heteroaryl), C(O)NHC1-4 alkyl, each optionally substituted with a substituent;
• R2 and R3 are each independently
• H, deuterium, halogen, CN;
• or
• C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C1-6 alkyl(C3-8 cycloalkyl), C3-8 cycloalkenyl, C1-6 alkyl(C3-8 cycloalkenyl), C3-8 cycloalkynyl, C1-6 alkyl(C3-8 cycloalkynyl), C3-8 spirocarbocyclyl, C1-6 alkyl(C3-8 spirocarbocyclyl), C5-10 bridged bicycloalkyl, C1-6 alkyl(C5-10 bridged bicycloalkyl), C2-6 heterocycloalkyl, C1-6 alkyl(C2-6 heterocycloalkyl), C2-5 heterocycloalkenyl, C1-6 alkyl(C2-5 heterocycloalkenyl), C2-5 heterocycloalkynyl, C1-6 alkyl(C2-5 heterocycloalkynyl), C2-8 spiroheterocyclyl, C1-6 alkyl(C2-8 spiroheterocyclyl), C5-10 bridged heterobicycloalkyl, C1-6 alkyl(C5-10 bridged heterobicycloalkyl), C5-10 aryl, C1-6 alkyl(C5-10 aryl), C2-8 heteroaryl, or C1-6 alkyl(C2-8 heteroaryl), each optionally substituted with a substituent;
• provided that (a) and/or (b) is true:
• (a) at least one of R1-R3 and A comprises a non-aromatic cyclic group;
• (b) at least one of R1 and R3 comprises a branched alkyl group or a cyclic group;
• R4 is H, deuterium, optionally substituted C1-3 alkyl, optionally substituted C3-8 cycloalkyl, or optionally substituted C1-4 hydroxyalkyl, wherein the optional substituent is selected from a group consisting of deuterium, halogen, or a combination thereof,
• R5 is
• A is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C1-6 alkyl(C3-8 cycloalkyl), C3-8 cycloalkenyl, C1-6 alkyl(C3-8 cycloalkenyl), C3-8 cycloalkynyl, C1-6 alkyl(C3-8 cycloalkynyl), C3-8 spirocarbocyclyl, C1-6 alkyl(C3-8 spirocarbocyclyl), C5-10 bridged bicycloalkyl, C1-6 alkyl(C5-10 bridged bicycloalkyl), C2-6 heterocycloalkyl, C1-6 alkyl(C2-6 heterocycloalkyl), C2-5 heterocycloalkenyl, C1-6 alkyl(C2-5 heterocycloalkenyl), C2-5 heterocycloalkynyl, C1-6 alkyl(C2-5 heterocycloalkynyl), C2-8 spiroheterocyclyl, C1-6 alkyl(C2-8 spiroheterocyclyl), C5-10 bridged heterobicycloalkyl, C1-6 alkyl(C5-10 bridged heterobicycloalkyl), C5-10 aryl, C1-6 alkyl(C5-10 aryl), C2-8 heteroaryl, or C1-6 alkyl(C2-8 heteroaryl), each optionally substituted with a substituent;
• X is H, halogen, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted —OC1-6 alkyl, optionally substituted C2-5 heterocycloalkyl, or optionally substituted C5-10 aryl, wherein each optional substituent is independently selected from the group consisting of halogen, OH, C1-3 alkyl, C1-3 haloalkyl, —OC1-3 alkyl, C3-8 cycloalkyl, C3-8 halocycloalkyl, and CN;
• Y is H, halogen, OH, optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted —OC1-3 alkyl, optionally substituted C1-3 haloalkyl, or optionally substituted —OC1-3 haloalkyl, wherein each optional substituent is independently selected from the group consisting of halogen, OH, C1-3 alkyl, C1.3 haloalkyl, —OC1-3 alkyl, C3-8 cycloalkyl, C3-8 halocycloalkyl, and CN;
• wherein:
• any carbon-carbon single bond of a C1-6 alkyl is optionally replaced by a carbon-carbon double or triple bond;
• any methylene of the alkyl, alkenyl, and alkynyl groups is optionally replaced by O, S, C═O, C═S, S═O, or NR10, wherein R10 is H, deuterium, C1-C3 alkyl, optionally substituted with deuterium, OH, CN, or C1-C3 haloalkyl, optionally substituted with deuterium;
• Z1 is O or S;
• Z2 is a bond, NR6, O, or S;
• R6 is H, deuterium, C1-3 alkyl, optionally substituted with deuterium, halogen, or a combination thereof, or C1-3 haloalkyl, optionally substituted with deuterium;
• and
• the optional substituents of R1-R3 and A are independently are selected from a group consisting of:
• halogen, deuterium, OH, CN, C1-6 alkyl, OC1-6 alkyl, C1-6 alkyne, NH2, NHR, NR2, C1-4alkyl NH2, C1-4alkyl(NH(R)), C1-4alkyl(NH(R)2), CO2H, C1-3alkyl(CO2H), C(═O)OR, OC(C═O)R, C(═O)NHR, NHC(═O)R, C(═O)NH(R)2, NH(R)C(═O)R, C(═O)R, C1-3alkyl(C(═O)OR), C1-3alkyl(OC(C═O)R), C1-3alkyl(C(═O)NHR), C1-3alkyl(C(═O)NH(R)2), C1-3 alkyl(C(═O)R), di(C1-3alkyl) ether, C3-6 cycloalkyl, OC3-6 cycloalkyl, C3-6 heterocycloalkyl, OC3-6 heterocycloalkyl, C5-10 aryl, C1-3alkyl(C5-10 aryl), C(═O)(C5-10 aryl), C2-8 heteroaryl, C1-3alkyl(C2-8 heteroaryl), wherein each occurrence of R is independently C1-6 alkyl, and any hydrogen may be replaced with a deuterium or a halogen;
• or a pharmaceutically acceptable salt thereof,
• provided that the following compound is excluded: