Iminotetrahydropyrimidinone derivatives as plasmepsin V inhibitors
A series of 2-imino-6-methyltetrahydropyrimidin-4(1H)-one derivatives, substituted in the 6-position by a phenyl moiety which in turn is meta-substituted by an optionally substituted unsaturated fused bicyclic ring system containing at least one nitrogen atom, being selective inhibitors of plasmepsin V activity, are beneficial as pharmaceutical agents, especially in the treatment of malaria.
1. A compound represented by formula (IIA), or a pharmaceutically acceptable salt thereof:
wherein
R 1 represents hydrogen; or R 1 represents C 1-6 alkyl, optionally substituted by hydroxy;
R 2 , R 3 and R 4 independently represent hydrogen or halogen;
ring X represents a benzene or pyridine ring;
W represents N or C—R 13- ;
Y represents N or C—R 14- ;
R 13 represents hydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, pyrrolidinyl, morpholinyl, hydroxymethyl, hydroxyisopropyl, methoxy, amino, methylamino, dimethylamino or benzylamino;
R 14 represents hydrogen, cyano or C 1-4 alkyl;
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoromethyl, methylpyrazolyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, di(C 1-6 )alkylamino(C 1 - 6 )alkyl, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylamino-carbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 )alkylaminosulfonyl.
2. A compound as claimed in claim 1 represented by formula (IIA-1a), or a pharmaceutically acceptable salt thereof:
3. A pharmaceutical composition comprising a compound of formula (IIA) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
4. A method for the treatment of malaria, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IIA) as defined in claim 1 or a pharmaceutically acceptable salt thereof.
5. A compound as claimed in claim 1 wherein R 1 represents hydrogen, methyl, ethyl or 2-hydroxyethyl.
6. A compound as claimed in claim 2 wherein R 1 represents hydrogen, methyl, ethyl or 2-hydroxyethyl.
7. A compound according to claim 1 , wherein the compound is of formula (IIA-1b)
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , wherein the compound is of formula (IIA-1c)
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 , wherein the compound is of formula (IIA-2a)
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 , wherein the compound is of formula (IIA-3a)
or a pharmaceutically acceptable salt thereof.