Compound having KDM5 inhibitory activity and pharmaceutical use thereof
The compound disclosed is a KDM5 inhibitor represented by the general formula (Z): wherein all symbols have the same meanings as the definitions described in the specification, or a salt thereof, and is useful as a prophylactic and/or therapeutic agent for cancer, Huntington's disease, or Alzheimer's disease and the like.
1 . A compound of the following formula (II-1-1):
wherein
R 1-1Y represents
in the group, the arrow indicates a binding to the carbon atom of carbonyl;
R 6-1 represents a C1-4 alkyl which is optionally substituted with 1 to 4 R 8-1 , C3-8 cycloalkyl, C3-8 cycloalkyl which is substituted with C1-4 alkyl, C1-4 haloalkyl, or halogen atom;
R 8-1 represents a hydroxy, halogen atom, nitrile, benzyloxy, or 5- or 6-membered monocyclic carbocycle;
R 2-1Y represents a 3- to 8-membered monocyclic carbocycle which is optionally substituted with 1 to 4 R 13-1 or 4- to 15-membered bicyclic carbocycle which is optionally substituted with 1 to 4 R 14-1 ;
R 13-1 represents a C1-4 alkyl, C3-8 cycloalkyl, halogen atom, or C1-4 haloalkyl;
R 14-1 represents a C1-4 alkyl, C3-8 cycloalkyl, halogen atom, or C1-4 haloalkyl;
when being substituted with a plurality of R 8-1 , R 13-1 or R 14-1 , R 8-1 , R 13-1 or R 14-1 are the same or different from each other;
R 3-1 represents a hydrogen atom, C1-4 alkyl, C1-4 haloalkyl, or halogen atom;
R 9-1 represents a hydrogen atom, or C1-4 alkyl; and
represents α-configuration, β-configuration or a mixture of α-configuration and β-configuration,
or a salt thereof.
2 . The compound according to claim 1 , wherein the compound is N-(1-(5-isopropyl-1H-pyrazole-3-carbonyl) azetidin-3-yl) cyclopropanecarboxamide or a salt thereof.
3 . A pharmaceutical composition comprising the compound or the salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.
4 . The pharmaceutical composition according to claim 3 , which is a KDM5 inhibitor.
5 . The pharmaceutical composition according to claim 3 , further comprising one or more drug selected from the group consisting of donepezil hydrochloride, galantamine hydrobromide, huperzine A, idebenone, levacecarnine hydrochloride, memantine hydrochloride, memantine hydrochloride/donepezil hydrochloride, proteolytic peptide fraction from porcine brain protein, rivastigmine tartrate, tacrine hydrochloride, and aducanumab.
6 . A method for inhibiting KDM5 in a subject in need thereof, comprising administering to the subject an effective amount of the compound or the salt thereof according to claim 1 .
7 . The method according to claim 6 , wherein the subject has cancer or Alzheimer's disease.