2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one and this 1,2,3,4-tetrahydropyrimido{1,2-a}pyrimidin-6-one derivatives comprising a substituted morpholine, preparation thereof and pharmaceutical use thereof

Abstract

The invention relates to the novel products of formula (I): ##STR00001##
with p, q=0, 1 or 2; R1=phenyl, pyridyl; —(CH.sub.2).sub.m—Ra; alkylene; cycloalkyl; heterocycloalkyl; alkyl; —SO.sub.2—Rb; —CO—Re; m=1 or 2; Ra=aryl, heteroaryl, —CO-cycloalkyl, —CO-heterocycloalkyl, —CO—Rb, —C(Rb)═N—ORc, —CO.sub.2Rd, —CONRxRy; Rb=alkyl, aryl, heteroaryl; Rc=H, alkyl; Rd=alkyl, cycloalkyl; Re=alkyl, cycloalkyl, aryl, heteroaryl; NRxRy with Rx,Ry=H, alkyl, cycloalkyl, alkoxy, phenyl, or form with N a ring with optionally O, N; R2, R3=H, alkyl, CF.sub.3, or form with C a ring with optionally O, S and N; R4=H, F, Cl, CH.sub.3 or CN; the morpholine is substituted with Me, and optionally substituted with F, OH; or is ##STR00002##
and the isomer of configuration R,R ##STR00003##
these products being in all the isomer forms and the salts, as medicaments, in particular as anticancer medicaments.

Claims

1. A compound of formula (I): ##STR00413## in which: p is an integer 0, and q is an integer 2; R1 is a —(CH.sub.2).sub.m—Ra radical with m being the integer 1 and Ra an optionally substituted monocyclic heteroaryl radical; R2 and R3, which may be identical or different, are chosen from a hydrogen atom and an alkyl radical optionally substituted with one or more fluorine atoms, it being understood that R2 and R3 are not both CF.sub.3 and R2 and R3 are not both hydrogen; R4 is a hydrogen atom, a fluorine or chlorine atom, a methyl radical or a CN radical; and the morpholine residue is substituted with the radicals R5 to R12, which may be identical or different, chosen from a hydrogen atom and methyl and ethyl radicals optionally substituted with a fluorine atom or a hydroxyl radical, it being understood that at least one of R5 to R12 is not a hydrogen atom, the heteroaryl radicals that Ra represents being, in addition, optionally substituted with one or more alkyl radicals themselves optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and hydroxyl and alkoxy radicals; all the alkyl, alkylene and alkoxy radicals above being linear or branched and containing at most 7 carbon atoms, it being understood that one or more of the hydrogen atoms of said products of formula (I) can be a deuterium atom; said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

2. The compound of formula (I) as defined in claim 1, in which the morpholine residue is chosen from the following radicals: ##STR00414## the radicals p, q, R1, R2, R3 and R4 having the meanings indicated in claim 1, said products of formula (I) being in any of the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

3. The compound of formula (I) as defined in claim 1, corresponding to the following formulae: (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(2-fluoropyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((3R,5R)-3,5-Dimethylmorpholin-4-yl)-9-isoxazol-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Methylisoxazol-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(1-Difluoromethyl-1H-pyrazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Isoxazol-3-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chlorothiazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Chloropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Isoxazol-5-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Fluoro-2-phenylethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-3-Fluoro-9-(2-methoxypyridin-4-yl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chloropyridin-4-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-oxazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-oxazol-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-isoxazol-5-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(6-fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Chloropyridin-3-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(5-fluoropyridin-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(5-fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(2-fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(3-methylisoxazol-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Imidazo[1,2-a]pyridin-2-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(4-Chloropyridin-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Chloropyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-thiazol-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-8,8-dimethyl-2-((R)-3-methylmorpholin-4-yl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 3-Fluoro-9-isoxazol-3-ylmethyl-8,8-dimethyl-2-((R)-3-methylmorpholin-4-yl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-3-fluoro-8,8-dimethyl-2-((R)-3-methylmorpholin-4-yl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chloropyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-thiazol-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Chloropyridin-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-thiazol-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Fluoropyridin-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2,5-Dimethyloxazol-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Chloropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Chlorothiophen-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Methylisoxazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-oxazol-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(5-methyl-[1,3,4]thiadiazol-2-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(4-methyl-[1,2,3]thiadiazol-5-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-8-trifluoromethyl-9-(5-trifluoromethyl-[1,3,4]oxadiazol-2-ylmethyl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Cyclopropyl-[1,3,4]oxadiazol-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-3-Fluoro-9-(3-methylisoxazol-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Chlorothiophen-2-ylmethyl)-2-((3S,5R)-3,5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-(5-Chlorothiophen-2-ylmethyl)-2-((3S,5S)-3,5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-2-((3R,5R)-3,5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((3R,5R)-3,5-Dimethylmorpholin-4-yl)-9-(3-methylisoxazol-5-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Chloropyridin-3-ylmethyl)-2-((3R,5R)-3, 5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chloropyridin-4-ylmethyl)-2-((3R,5R)-3,5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((3R,5R)-3,5-Dimethylmorpholin-4-yl)-9-oxazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Chlorothiophen-2-ylmethyl)-2-(3-hydroxymethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-(5-Chlorothiophen-2-ylmethyl)-2-((S)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Isopropyl-[1,2,4]oxadiazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-tert-Butyl-[1,2,4]oxadiazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-8-Methyl-2-((R)-3-methylmorpholin-4-yl)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-8-methyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Isoxazol-3-ylmethyl-8-methyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-pyridin-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-pyridin-3-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-pyridin-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Fluoropyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Fluoropyridin-2-ylmethyl)-2-((R)-3-methylmorpholin-4-yI)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Isopropoxypyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-tert-Butyl-[1,2,4]oxadiazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Isopropoxypyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Isopropoxypyridin-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-thiazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-thiazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-8-Methyl-2-((R)-3-methylmorpholin-4-yl)-9-oxazol-2-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(5-isopropyl-[1,2,4]oxadiazol-3-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(5-Cyclopropyl-[1,2,4]oxadiazol-3-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-Cyclopropyl-[1,2,4]oxadiazol-5-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-y)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(3-tert-Butyl-[1,2,4]oxadiazol-5-vlmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-9-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Fluoropyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-pyridazin-4-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-9-(4H-[1,2,4]triazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((R)-3-Methylmorpholin-4-yl)-8-trifluoromethyl-9-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-isoxazol-3-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Difluoromethyl-2H-pyrazol-3-ylmethyl)-3-fluoro-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 9-Isoxazol-3-ylmethyl-8,8-dimethyl-2-((R)-3-methylmorpholin-4-yl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(3-methylisoxazol-5-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chlorothiazol-5-ylmethyl)-2-((3R,5R)-3,5-dimethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-2-((3R,5R)-3,5-Dimethylmorpholin-4-yl)-9-isoxazol-3-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and also the addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

4. A pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable addition salt with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

5. A pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 3, or a pharmaceutically acceptable addition salt with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

6. A pharmaceutical composition containing, as an active ingredient, at least one of the products of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt of this product and a pharmaceutically acceptable carrier.

7. A method of treatment of a disease capable of being modulated by inhibiting the Vps34/PIK3C3 pathway wherein the disease is a blood vessel proliferation disorder, fibrotic disorder, “mesangial” cell proliferation disorder, metabolic disorder, allergy, asthma, thrombosis, nervous system disease, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and or cancer, comprising administering to a patient a compound of formula (I) as defined in claim 1.

8. A method of treatment of a cancer capable of being modulated by inhibiting the Vps34/PIK3C3 pathway, comprising administering to a patient a compound of formula (I) as defined in claim 1.

9. A method of treatment of a solid or liquid tumour capable of being modulated by inhibiting the Vps34/PIK3C3 pathway, comprising administering to a patient a compound of formula (I) as defined in claim 1.

10. A method of treatment of cancers capable of being modulated by inhibiting the Vps34/PIK3C3 pathway and resistant to cytotoxic agents, comprising administering to a patient a compound of formula (I) as defined in claim 1.

11. A method of treatment of a primary tumour and/or metastasis capable of being modulated by inhibiting the Vps34/PIK3C3 pathway, wherein the primary tumour or metastasis is gastric, hepatic, renal, ovarian, colon, prostate or lung (NSCLC and SCLC) cancer, glioblastoma, thyroid, bladder, or breast cancer, melanoma, a lymphoid or myeloid haematopoietic tumour, sarcoma, brain, larynx, or lymphatic system cancer, bone or pancreatic cancer, or hamartoma, comprising administering to a patient a compound of formula (I) as defined in claim 1.

12. A method of treatment of a lysosomal disease capable of being modulated by inhibiting the Vps34/PIK3C3 pathway, comprising administering to a patient a compound of formula (I) as defined in claim 1.

13. A method of treatment of X-linked myotubular myopathy or Charcot-Marie-Tooth disease capable of being modulated by inhibiting the Vps34/PIK3C3 pathway, comprising administering to a patient a compound of formula (I) as defined in claim 1.

Description

EXPERIMENTAL SECTION

(1) The nomenclature of the compounds of this present invention was performed with the ACDLABS version 10.0 software.

(2) The microwave oven used is a Biotage, Initiator™ Eight, 400 W max, 2450 MHz apparatus.

(3) The .sup.1H NMR spectra at 400 MHz and .sup.1H NMR spectra at 500 MHz were carried out on a Bruker Avance 250 or Bruker Avance DRX-400 or Bruker Avance DPX-500 spectrometer with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d.sub.6 (DMSO-d.sub.6) referenced at 2.5 ppm at the temperature of 303K.

(4) The mass spectra (MS) were obtained either by method A or by method B.

(5) Method A:

(6) Waters UPLC-SQD apparatus; Ionization: positive and/or negative mode electrospray (ES+/−); Chromatographic conditions: Column: Acquity BEH C18 1.7 μm—2.1×50 mm; Solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); Column temperature: 50° C.; Flow rate: 1 ml/min; Gradient (2 min): from 5% to 50% of B in 0.8 min; 1.2 min: 100% of B; 1.85 min: 100% of B; 1.95 min: 5% of B; Retention time=Tr (min).

(7) Method B:

(8) Waters ZQ apparatus; Ionization: positive and/or negative mode electrospray (ES+/−); Chromatographic conditions: Column: XBridge C18 2.5 μm—3×50 mm; Solvents: A: H.sub.2O (0.1% formic acid) B: CH.sub.3CN (0.1% formic acid); Column temperature: 70° C.; Flow rate: 0.9 ml/min; Gradient (7 min): from 5% to 100% of B in 5.3 min; 5.5 min: 100% of B; 6.3 min: 5% of B; Retention time=Tr (min).

(9) The optical rotations (ORs) were measured on a model 341 polarimeter from Perkin Elmer. Wavelength: sodium α line (589 nm).

(10) The intermediates of type F as defined in the schemes above, i.e. F1 to F9 defined in Table 1 below, resulting in Examples 1 to 295, can be prepared in the following way:

(11) Intermediate F1

(12) (S)-2-Chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(13) ##STR00019##

(14) The separation of the two enantiomers of (8R,8S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one (17 g) is carried out by chiral chromatography: stationary phase: Chiralpak AD; mobile phase: EtOH (20%)/Heptane (80%). The laevorotatory enantiomer is concentrated so as to give 8.52 g of (R)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white powder. The dextrorotatory enantiomer is concentrated so as to obtain 8.21 g of (S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white powder, the characteristics of which are the following:

(15) Mass spectrum (method A), ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.51

(16) [α].sub.D.sup.25 at 589 nm=+21.3+/−0.5 (MeOH)

(17) (8R, 8S)-2-Chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(18) ##STR00020##

(19) 60 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 34 g of (8R,8S)-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 500 ml of 1,2-dichloroethane. The mixture obtained is then heated to 65° C. After three hours of stirring at 65° C., the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 100 ml of cold water and 400 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=6. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give an orange residue. This residue is purified by chromatography on silica (eluent: CH.sub.2Cl.sub.2/MeOH: 97/03) so as to give 20 g of (8R,8S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:

(20) Mass spectrum (method A), ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.51

(21) (8R,8S)-2-Hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(22) ##STR00021##

(23) 10 g of (4R,4S)-4-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride and 10 g of sodium methoxide are added to 50 ml of diethyl malonate. The mixture obtained is brought to 100° C. for 75 minutes. The heterogeneous mixture thickens and becomes yellow, with a slight release of gas. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is triturated with ethyl ether. The solid formed is filtered off through a sintered glass funnel and then taken up with 20 ml of cold water. 12N hydrochloric acid is added to the thick suspension obtained, to pH=5-6. The suspension obtained is filtered through a sintered glass funnel and the insoluble matter is rinsed with ethyl ether so as to give 11.5 g of (8R,8S)-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:

(24) Mass spectrum (method A), ES+/−: [M+H]+: m/z 236; [M−H]−: m/z 234; Tr (min)=0.26

(25) (4R,4S)-4-(Trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride can be prepared in the following way.

(26) ##STR00022##

(27) A mixture of 1.1 g of 10% Pd/C, 22 g of 2-amino-4-(trifluoromethyl)pyrimidine dissolved in 200 ml of water, 50 ml of methanol and 50 ml of 12N HCl is hydrogenated at 3 bar, at 22° C., for 24 hours in an autoclave. The resulting mixture is then filtered and the filtrate is concentrated under reduced pressure. The residue obtained is oven-dried, in the presence of P.sub.2O.sub.5, so as to give 27 g of (4R,4S)-4-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride, in the form of a grey solid, the characteristics of which are the following:

(28) Mass spectrum (method A), ES+/−: [M+H]+: m/z 168; Tr (min)=0.17

(29) Intermediate F2

(30) (8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(31) ##STR00023##

(32) The separation of the enantiomers of (8R,8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one is carried out by chiral chromatography (Chiralpak AD 20 μm 80×350 mm 250 ml/min 254 nm; 5% EtOH 5% MeOH 90% Heptane+0.1% TEA), using 6.8 g of a racemic mixture. The dextrorotatory enantiomer is concentrated so as to obtain 3.13 g of (8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a white solid, the characteristics of which are the following:

(33) [α].sub.D.sup.25 at 589 nm=+19.6+/−0.6 (c=2.488 mg/0.5 ml MeOH)

(34) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 272; [M−H]−: m/z 270; Tr (min)=0.62

(35) (8R, 8S)-2-Chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(36) ##STR00024##

(37) 8 ml of phosphorus oxychloride are added to a solution of 6.5 g of (8R, 8S)-3-fluoro-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 80 ml of 1,2-dichloroethane. After stirring for 4 hours at a temperature of 65° C. and returning to a temperature of about 20° C., the reaction mixture is concentrated to dryness under reduced pressure. The residue is diluted in 150 ml of ethyl acetate and 10 ml of ice-cold water. At a temperature between 0° C. and 10° C., a concentrated sodium hydroxide solution is added until a pH between 6 and 7 is obtained. The solid form is filtered off so as to give 3.5 g of a beige solid S1. The filtrate is separated by settling out, and the organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. After purification of the residue on a silica column (eluent: 97/03 CH.sub.2Cl.sub.2/MeOH), 3.3 g of a pale yellow solid S2 are obtained. The two solids S1 and S2 are combined so as to give 6.8 g of (8R, 8S)-2-chloro-3-fluoro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a pale yellow powder, the characteristics of which are the following:

(38) Mass spectrum (method B) (ES+/−) [M+H]+: m/z 272; [M−H]−: m/z 270; Tr (min)=2.9

(39) (8R, 8S)-3-Fluoro-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(40) ##STR00025##

(41) 5.6 g of sodium methoxide are added to a suspension of 7 g of (4R,4S)-4-(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-ylamine hydrochloride in 35 ml of dimethyl fluoropropanedioate. After stirring the suspension for 3 hours at a temperature of 100° C., the medium obtained is concentrated to dryness under reduced pressure. The residue is taken up in diethyl ether and then dried with suction under vacuum. The solid obtained is taken up in 14 ml of water, and the resulting mixture is cooled in ice, before acidification to pH 5-6 by addition of concentrated hydrochloric acid (25%). After 2 hours of stirring at a temperature of 0° C. and then overnight at a temperature of about 20° C., the suspension is filtered and then the solid is dried with suction and dried under vacuum over P.sub.2O.sub.5. 6.5 g of (8R, 8S)-3-fluoro-2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of a yellow powder, the characteristics of which are the following:

(42) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.28

(43) Intermediate F3

(44) (R)-8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(45) ##STR00026##

(46) The separation of the two enantiomers of (4R,4S)-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one (4.5 g) is carried out by chiral chromatography: stationary phase: AS 20 μm; mobile phase: 5% MeOH; 10% EtOH; 85% Heptane; 0.1% TEA. The laevorotatory enantiomer is concentrated so as to give 2.07 g of (R)-8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white powder, [α].sub.D.sup.25 at 589 nm=−32.7+/−0.7 (DMSO). The dextrorotatory enantiomer is concentrated so as to obtain 2.19 g of (S)-8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a cream powder, [α].sub.D.sup.25 at 589 nm=+29.2+/−0.8 (DMSO).

(47) 8-Chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(48) ##STR00027##

(49) 16 ml of trifluoromethanesulfonic acid are added, at ambient temperature and under an argon atmosphere, to a solution of 8.1 g of 2-chloro-9-(2,4-dimethoxybenzyl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 200 ml of 1,2-dichloromethane. The mixture obtained is then stirred at ambient temperature for one hour. The reaction is complete according to the verification by LC/MS. The reaction medium is cooled in an ice bath. 32% sodium hydroxide is added dropwise to pH=10. The white solid formed is filtered off so as to give 7 g of the solid S1. After separation of the filtrate by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 0.9 g of the solid S2. The solid S1 is taken up with water and ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure, so as to give 3.5 g of the solid S3. The two solids S2 and S3 are combined for purification by chromatography on silica (eluent: CH.sub.2Cl.sub.2/EtOAc: 90/10) so as to give 4.08 g of 8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, the characteristics of which are the following:

(50) Mass spectrum (method A): ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.56

(51) 2-Chloro-9-(2,4-dimethoxybenzyl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(52) ##STR00028##

(53) 14 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 11.5 g of 9-(2,4-dimethoxybenzyl)-2-hydroxy-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 140 ml of 1,2-dichloroethane. The mixture obtained is then heated to 65° C. After one hour of stirring at 60° C., the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 30 ml of cold water and 200 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=8. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents:

(54) dichloromethane/EtOAc: 97/03, so as to give 8.2 g of 2-chloro-9-(2,4-dimethoxybenzyl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are the following:

(55) Mass spectrum (method B): ES+/−: [M+H]+: m/z 404; Tr (min)=4.54

(56) then CH.sub.2Cl.sub.2/EtOAc: 85/15, so as to give 0.64 g of 8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, the characteristics of which are the following:

(57) Mass spectrum (method A): ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.56

(58) 9-(2,4-Dimethoxybenzyl)-2-hydroxy-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(59) ##STR00029##

(60) 35 ml of methyl malonate and 13 g of anhydrous sodium methoxide are added, at ambient temperature and under an argon atmosphere, to a suspension of 19.1 g of 1-(2,4-dimethoxybenzyl)-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine in 175 ml of methanol. The mixture obtained is then heated at reflux. After six hours of stirring at reflux, the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 20 ml of cold water and 400 ml of ethyl acetate. 36% HCl is added dropwise to pH=5-6. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: dichloromethane/MeOH: 98/02, so as to give 11.6 g of 9-(2,4-dimethoxybenzyl)-2-hydroxy-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are the following:

(61) Mass spectrum (method A): ES+/−: [M+H]+: m/z 386; [M−H]−: m/z 384; Tr (min)=0.78

(62) 1-(2,4-Dimethoxybenzyl)-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine can be prepared in the following way.

(63) ##STR00030##

(64) 5.7 g of cyanogen bromide are added, in small amounts, at ambient temperature and under an argon atmosphere, to a solution of 14.2 g of N1-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutane-1,3-diamine in 150 ml of acetonitrile. At the end of the addition, the mixture obtained is then heated at reflux for three hours in an oil bath preheated to 100° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give 19.11 g of 1-(2,4-dimethoxybenzyl)-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine in the form of a pale yellow foam, which will be used as it is in the next step and the characteristics of which are the following:

(65) Mass spectrum (method B): ES+/−: [M+H]+: m/z 318; Tr (min)=2.67

(66) N1-(2,4-Dimethoxybenzyl)-4,4,4-trifluorobutane-1,3-diamine can be prepared in the following way.

(67) ##STR00031##

(68) 8 g of LiAlH.sub.4 are added, in small portions, at ambient temperature and under an argon atmosphere, to a solution of 10.6 g of 3-amino-N-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutyramide in 500 ml of anhydrous ethyl ether. At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours. The reaction medium is cooled to 4° C. in an ice bath, and then 11 ml of water, followed by 11 ml of 4N NaOH and then 22 ml of water are added dropwise. The white precipitate formed is filtered off. The filtrate is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 9.5 g of N1-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutane-1,3-diamine, in the form of a colourless oil, which is used as it is in the next step.

(69) Mass spectrum (method A): ES+/−: [M+H]+: m/z 293; ES+ base peak: m/z 151; Tr (min)=0.33 3-Amino-N-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutyramide can be prepared in the following way.

(70) ##STR00032##
23.4 g of 2,4-dimethoxybenzylamine are added in one step to a suspension of 20 g of 3-amino-4-trifluorobutyric acid in 120 ml of DMF, followed, dropwise, by 41 g of phenylsilane, said additions being carried out while maintaining the temperature of the reaction medium between 20 and 28° C. At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours. The reaction medium is cooled to 4° C. in an ice bath, and then 200 ml of water, followed by 300 ml of ethyl acetate, are added dropwise. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is taken up with 500 ml of methanol. The white solid formed is filtered off. The filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: dichloromethane/MeOH: 95/05, so as to give 25 g of 3-amino-N-(2,4-dimethoxybenzyl)-4,4,4-trifluorobutyramide, in the form of a pasty white solid, the characteristics of which are the following:

(71) Mass spectrum (method A): ES+/−: [M+H]+: m/z 307; ES+ base peak: m/z 151; Tr (min)=2.38

(72) Alternative intermediate F3: Alternatively, (R)-8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(73) ##STR00033##

(74) 3.7 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 3.2 g of (R)-8-hydroxy-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one in 37 ml of 1,2-dichloroethane. The mixture obtained is then heated to 65° C. After 4 hours of stirring at 60° C., the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 50 ml of cold water and 200 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=10. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: CH.sub.2Cl.sub.2/MeOH: 96/04), so as to give 2.53 g of (R)-8-chloro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.56

(75) (R)-8-Hydroxy-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(76) ##STR00034##

(77) 50 ml of trifluoroacetic acid are added, at ambient temperature and under an argon atmosphere, to a suspension of 7.5 g of (R)-8-hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one in 50 ml of 1,2-dichloromethane. The reaction medium is stirred at ambient temperature for 18 hours. After a verification by LC/MS, 51% of the starting product remains. 25 ml of trifluoroacetic acid are added. After 40 hours of stirring, the reaction is complete according to the verification by LC/MS. The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with 10 ml of ice-cold water. 32% sodium hydroxide is added dropwise to pH=6. The mixture is concentrated to dryness under reduced pressure. The residue obtained is taken up with an 80/20 dichloromethane/MeOH mixture and filtered, and then the filtrate is concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on silica (eluent: CH.sub.2Cl.sub.2/MeOH: 75/25), so as to give 2.4 g of (R)-8-hydroxy-7-fluoro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, the characteristics of which are the following:

(78) OR=−22.5+/−0.6. C=2.702 mg/0.5 ml DMSO. On 589 nm.

(79) (R)-8-hydroxy-1-((S)-1-(4-methoxyphenypethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(80) ##STR00035##

(81) 29 g of methyl malonate and 10 g of anhydrous sodium methoxide are added, at ambient temperature and under an argon atmosphere, to a suspension of 11 g of (S)-1-[(S)-1-(4-methoxyphenyl)ethyl]-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine in 150 ml of methanol. The mixture obtained is then heated at reflux. After 4 hours of stirring at reflux, the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: dichloromethane/MeOH: 95/05, so as to give 11.6 g of (R)-8-hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 370; [M−H]−: m/z 368; Tr (min)=1.06 OR=−96.3+/−1.7 at 589 nm weighed 1.623 mg ds 0.5 ml DMSO

(82) (S)-1-[(S)-1-(4-Methoxyphenyl)ethyl]-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine can be prepared in the following way.

(83) ##STR00036##

(84) 4.6 g of cyanogen bromide are added, in small amounts, at ambient temperature and under an argon atmosphere, to a solution of 11 g of (S)-4,4,4-trifluoro-N1-[(S)-1-(4-methoxyphenyl)ethyl]butane-1,3-diamine in 100 ml of acetonitrile. At the end of the addition, the mixture obtained is then heated at reflux for two hours in an oil bath preheated to 100° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure, so as to give 11 g of a brown foam. 50 ml of water and 200 ml of EtOAc are added to this foam, followed by 32% sodium hydroxide to pH=14. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure, so as to give a residue of 11 g of a thick oil.

(85) This residue is purified on a silica column, eluent: dichloromethane/MeOH/28% NH.sub.4OH: 90/10/0.5 then dichloromethane/MeOH/28% NH.sub.4OH: 60/40/5, so as to give 8 g of (S)-1-[(S)-1-(4-methoxyphenyl)ethyl]-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine, in the form of a pale yellow foam, which will be used as it is in the next step and the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 302; Tr (min)=0.57

(86) (S)-4,4,4-Trifluoro-N1-[(S)-1-(4-methoxyphenyl)ethyl]butane-1,3-diamine can be prepared in the following way.

(87) ##STR00037##

(88) 11.7 g of LiAlH.sub.4 are added, in small portions, at ambient temperature and under an argon atmosphere, to a solution of 15 g of (S)-3-amino-4,4,4-trifluoro-N—[(S)-1-(4-methoxyphenyl)ethyl]butyramide in 600 ml of anhydrous ethyl ether. At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 72 hours. The reaction medium is cooled to 4° C. in an ice bath, and then 9.7 ml of water, followed by 9.7 ml of 4N NaOH and then 19.4 ml of water, are added dropwise. The white precipitate formed is filtered off. The filtrate is dried over MgSO.sub.4 and then concentrated under reduced pressure, so as to give 11.2 g of (S)-4,4,4-trifluoro-N1-[(S)-1-(4-methoxyphenyl)ethyl]butane-1,3-diamine, in the form of a colourless oil, which is used as it is in the next step and the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 277; Tr (min)=0.32

(89) (S)-3-Amino-4,4,4-trifluoro-N—[(S)-1-(4-methoxyphenyl)ethyl]butyramide and (R)-3-amino-4,4,4-trifluoro-N—[(S)-1-(4-methoxyphenyl)ethyl]butyramide can be prepared in the following way.

(90) ##STR00038##
32.8 g of (S)-(−)-1-(4-methoxyphenyl)ethylamine are added in one step to a suspension of 31 g of 3-amino-4-trifluorobutyric acid in 300 ml of DMF, followed, dropwise, by 64 g of phenylsilane, said additions being carried out while maintaining the temperature of the reaction medium between 25 and 35° C. At the end of the addition, the reaction medium, a suspension, is stirred at ambient temperature for 48 hours. The reaction medium is cooled to 4° C. in an ice bath, and then 200 ml of water, followed by 400 ml of ethyl acetate, are added dropwise. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is taken up with 500 ml of methanol. The white solid formed is filtered off. The filtrate is concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: 90/10 dichloromethane/EtOAc, so as to give 15 g of (S)-3-amino-4,4,4-trifluoro-N—[(S)-1-(4-methoxyphenyl)ethyl]butyramide, in the form of a white solid, the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 291; [M−H]−: m/z 289; ES+ base peak: m/z 135; Tr (min)=0.46 [α].sub.D.sup.25 at 589 nm=−31.8+/−0.9 (DMSO)

(91) Then eluent with 50/50 dichloromethane/EtOAc, so as to give 12 g of (R)-3-amino-4,4,4-trifluoro-N—[(S)-1-(4-methoxyphenyl)ethyl]butyramide, in the form of a white solid, the characteristics of which are the following: Mass spectrum (method A): ES+/−: [M+H]+: m/z 291; ES+ base peak: m/z 135; Tr (min)=0.47 [α].sub.D.sup.25 at 589 nm=−78+/−1.5 (DMSO)

(92) Intermediate F4:

(93) (R)-8-Chloro-7-fluoro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(94) ##STR00039##

(95) 30 ml of trifluoroacetic acid are added, at ambient temperature and under an argon atmosphere, to a solution of 4 g of (R)-8-chloro-7-fluoro-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one in 30 ml of 1,2-dichloromethane. The reaction medium is stirred at ambient temperature for 18 hours. The reaction medium turns a dark violet colour. The reaction is complete according to the verification by LC/MS. The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with 100 ml of dichloromethane and 50 ml of ice-cold water. 32% sodium hydroxide is added dropwise to pH=10. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is taken up with ethyl ether and the white solid formed is filtered off, so as to give 2.1 g of the solid S1. The filtrate is concentrated to dryness under reduced pressure and the residue obtained is purified by chromatography on silica (eluent: CH.sub.2Cl.sub.2/EtOAc: 97/03), so as to give 0.35 g of the solid S2. The two solids S1 and S2 are combined so as to give 2.45 g of (R)-8-chloro-7-fluoro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid, used as it is in the next step.

(96) (R)-8-Chloro-7-fluoro-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(97) ##STR00040##

(98) 10.8 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 15 g of (R)-7-fluoro-8-hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one in 100 ml of 1,2-dichloroethane. The mixture obtained is then heated to 65° C. After 3 hours of stirring at 60° C., the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 100 ml of cold water and 300 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=10. The resulting organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica, eluents: dichloromethane/EtOAc: 98/02, so as to give 4 g of (R)-8-chloro-7-fluoro-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, used in the next step. CH.sub.2Cl.sub.2/EtOAc: 95/05, so as to give 2.5 g of (R)-8-chloro-7-fluoro-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, in the form of a white solid.

(99) (R)-7-Fluoro-8-hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one can be prepared in the following way.

(100) ##STR00041##

(101) 30 g of methyl fluoromalonate and 10.8 g of anhydrous sodium methoxide are added, at ambient temperature and under an argon atmosphere, to a suspension of 12 g of (S)-1-[(S)-1-(4-methoxyphenyl)ethyl]-4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine in 150 ml of methanol. The mixture obtained is then heated at reflux. After one hour of stirring at reflux, the reaction is complete according to the verification by LC/MS. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up with 100 ml of cold water. 36% HCl is added dropwise to pH=6. The solid formed is filtered off and then washed three times with ethyl ether. The solid is oven-dried under vacuum in the presence of P.sub.2O.sub.5, so as to give 15 g of (R)-7-fluoro-8-hydroxy-1-((S)-1-(4-methoxyphenyl)ethyl)-4-(trifluoromethyl)-3,4-dihydro-1H-pyrimido[1,2-a]pyrimidin-6(2H)-one, which is used as it is in the next step.

(102) Intermediate F5:

(103) (8S)-2-Chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one and (8R)-2-chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(104) ##STR00042##

(105) A suspension of 410 mg (1.645 mmol) of 2-hydroxy-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 22 ml of 1,2-dichloroethane is treated at ambient temperature with 0.767 ml of phosphorus trichloride. The reaction medium is heated at 65° C. for 7 h 15 min. It is then evaporated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up with 3 ml of water and 30 ml of ethyl acetate, cooled in an ice bath and basified to pH 9 with 32% aqueous NaOH, and then the organic phase is separated. The aqueous phase is extracted with 20 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa). The crude obtained is purified by flash chromatography on silica [eluent: dichloromethane/1-propanol/acetonitrile (100/0/0 then 96/2/2 by volume)]. After evaporation of the fractions under reduced pressure, 217 mg of 2-chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a white solid (mixture of enantiomers).

(106) Mass spectrum (method A): ES+/−: [M+H]+: m/z 268; [M−H]−: m/z 266; Tr (min)=0.58

(107) The mixture of enantiomers is purified by preparative chromatography on a chiral column under the following conditions:

(108) Technique: Prochrom

(109) Chiral stationary phase: AD 20 μm, lot CFB03

(110) Mobile phase: 85% Heptane—15% EtOH

(111) Flow rate: 260 ml/min

(112) Detection: UV 254 nm

(113) After evaporation of the fractions under reduced pressure, 93 mg of (8R)-2-chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a white solid.

(114) ##STR00043##

(115) The characteristics of this product are the following:

(116) Mass spectrum (method A): ES+/−: [M+H]+: m/z 268; [M−H]−: m/z 266; Tr (min)=0.59

(117) Retention time by chiral phase HPLC: 6.6 minutes

(118) Conditions used for the chiral phase HPLC:

(119) Technique: Gilson

(120) Chiral stationary phase: AD-H 5 μm 250×4.6 mm

(121) Mobile phase: 85% Heptane—15% EtOH

(122) Flow rate: 1 ml/min

(123) Detection: UV 254 nm After evaporation of the fractions, 104 mg of (8S)-2-chloro-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are also obtained, in the form of a white solid.

(124) ##STR00044##

(125) The characteristics of this product are the following:

(126) Mass spectrum (method A): ES+/−: [M+H]+: m/z 268; [M−H]−: m/z 266; Tr (min)=0.59

(127) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.45 (q, J=0.5 Hz, 3H); 2.00 (m, 1H); 2.35 (td, J=4,4 and 14.7 Hz, 1H); 3.45 (m, 1H); 4.11 (m, 1H); 5.81 (s, 1H); 9.16 (broad s, 1H).

(128) Retention time by chiral phase HPLC: 15.6 minutes

(129) Conditions used for the chiral phase HPLC:

(130) Technique: Gilson

(131) Chiral stationary phase: AD-H 5 μm 250×4.6 mm

(132) Mobile phase: 85% Heptane—15% EtOH

(133) Flow rate: 1 ml/min

(134) Detection: UV 254 nm

(135) 2-Hydroxy-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(136) ##STR00045##

(137) 44 mg (1.927 mmol) of sodium are dissolved in 4 ml of methanol under argon and then 101 mg (0.385 mmol) of 4-methyl-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-imine hydrobromide in 2 ml of methanol are added, followed by 305 mg (2.312 mmol) of methyl malonate at ambient temperature. The reaction medium is heated at reflux for 5 h 45 min. After cooling, the reaction medium is evaporated to dryness under reduced pressure. The residue obtained is taken up in 0.5 ml of water and then, after cooling in a water-ice bath, 0.1 ml of an aqueous 8N hydrochloric acid solution is added to approximately pH=5. The reaction medium is stirred in the cold bath for approximately 15 minutes and then, after having added approximately 3 ml of ethyl ether to the reaction medium, the latter is filtered through a sintered glass funnel. After drying under vacuum, 92 mg of 2-hydroxy-8-methyl-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a beige solid.

(138) Mass spectrum (method A): ES+/−: [M+H]+: m/z 250; [M−H]−: m/z 248; Tr (min)=0.32

(139) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.40 (s, 3H); 1.92 (m, 1H); 2.22 (m, 1H); 3.45 (m, 1H); 3.95 (m, 1H); 4.61 (broad s, 1H); 10.30 (broad m, 2H).

(140) 4-Methyl-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-imine hydrobromide can be prepared in the following way.

(141) ##STR00046##

(142) A solution of 458 mg (2.933 mmol) of 2-methyl-2-(trifluoromethyl)butane-1,4-diamine in 4 ml of acetonitrile is treated at ambient temperature with 311 mg (2.933 mmol) of cyanogen bromide. 12 ml of acetonitrile are then added and the solution is heated at reflux for 2 h 30 min. After evaporation to dryness under reduced pressure, 695 mg of 4-methyl-4-(trifluoromethyl)tetrahydropyrimidin-2(1H)-imine hydrobromide are obtained in the form of a yellow solid.

(143) Mass spectrum (method A): ES+/−: [M+H]+: m/z 182; Tr (min) (ELSD)=0.24

(144) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.45 (s, 3H); 1.94 (m, 1H); 2.17 (m, 1H); 3.11 to 3.44 (partially masked m, 2H); 6.97 (broad s, 2H); 8.17 (broad s, 1H); 8.60 (broad s, 1H).

(145) 2-Methyl-2-(trifluoromethyl)butane-1,4-diamine can be prepared in the following way.

(146) ##STR00047##

(147) A suspension of 1.17 g (4.751 mmol) of N.sup.1-benzyl-4,4,4-trifluoro-3-methylbutane-1,3-diamine and 758 mg (0.713 mmol) of palladium-on-carbon (10%) in 55 ml of ethanol and 2.090 ml (10.45 mmol) of an aqueous 5N hydrochloric acid solution is hydrogenated at 50° C. under 10 bar of hydrogen for 68 h. The reaction medium is then filtered through celite and the filtrate is then evaporated to dryness. Toluene is added to the residue obtained and then the resulting product is evaporated to dryness, so as to give 1.231 g of a yellow solid. This yellow solid is dissolved in 5 ml of water and then the solution is basified with approximately 2 ml of an aqueous 32% sodium hydroxide solution to pH=12. The aqueous phase is extracted with ethyl ether, then the organic phases are combined, dried over magnesium sulfate and then filtered through a sintered glass funnel, and the filtrate is evaporated in a rotary evaporator under reduced pressure (the bath temperature is maintained below 25° C. and the pump vacuum is maintained above 100 mbar). 469 mg of 2-methyl-2-(trifluoromethyl)butane-1,4-diamine are obtained, in the form of a yellow liquid.

(148) Mass spectrum (method A): ES+/−: [M+H]+: m/z 157; Tr (min)=0.11

(149) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.11 (s, 3H); 1.55 (m, 2H); 1.87 (broad m, 4H); 2.68 (m, 2H).

(150) N.sup.1-benzyl-4,4,4-trifluoro-3-methylbutane-1,3-diamine can be prepared in the following way.

(151) ##STR00048##

(152) A solution of 2.494 g (9.583 mmol) of 3-amino-N-benzyl-4,4,4-trifluoro-3-methylbutanamide in 80 ml of ethyl ether is treated at ambient temperature, under a light argon stream, with 2.182 g (57.500 mmol) of powdered lithium aluminium hydride. The reaction medium is stirred at ambient temperature for 72 h and is then diluted with 80 ml of ethyl ether and 15 ml of THF and cooled to approximately 0° C., and 2.18 ml of water, 2.18 ml of an aqueous 15% sodium hydroxide solution and 6.54 ml of water are successively added slowly, and the mixture is filtered through a sintered glass funnel. The filtrate is dried over magnesium sulfate and then, after filtration through a sintered glass funnel, the filtrate obtained is evaporated to dryness under reduced pressure (2.7 kPa). The crude is purified by flash chromatography on silica [eluent: dichloromethane/methanol/acetonitrile (90/5/5 to 80/10/10 by volume)]. After evaporation of the fractions under reduced pressure, 1.176 g of N.sup.1-benzyl-4,4,4-trifluoro-3-methylbutane-1,3-diamine are obtained, in the form of a yellow oil.

(153) Mass spectrum (method B): ES+/−: [M+H]+: m/z 247; Tr (min)=7.74 (ELSD).

(154) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.10 (q, J=0.6 Hz, 3H); 1.52 to 1.74 (m, 2H); 2.02 (broad m, 3H); 2.53 to 2.76 (m, 2H); 3.68 (s, 2H); 7.15 to 7.39 (m, 5H).

(155) 3-Amino-N-benzyl-4,4,4-trifluoro-3-methylbutanamide can be prepared in the following way.

(156) ##STR00049##

(157) A suspension of 3.100 g (14.93 mmol) of 3-amino-4,4,4-trifluoro-3-methylbutanoic acid hydrochloride, 2.862 g (14.93 mmol) of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 2.017 g (14.93 mmol) of 1-hydroxybenzotriazole in 100 ml of methylene chloride is treated at ambient temperature with 4.363 ml (31.350 mmol) of triethylamine and then with 1.631 ml (14.93 mmol) of benzylamine. The reaction medium is stirred at ambient temperature for 62 h and then 3.26 ml (29.86 mmol) of benylamine are added. The reaction medium is stirred at ambient temperature for 27 h and then evaporated to dryness under reduced pressure (2.7 kPa). The crude obtained is purified by flash chromatography on silica [eluent: dichloromethane/1-propanol/acetonitrile (96/2/2 then 90/5/5 by volume)]. After evaporation of the fractions under reduced pressure, 2.504 g of 3-amino-N-benzyl-4,4,4-trifluoro-3-methylbutanamide are obtained, in the form of a brown oil.

(158) Mass spectrum (method A): ES+/−: [M+H]+: m/z 261; [M−H]−: m/z 259; Tr (min)=0.38

(159) .sup.1H NMR spectrum (300 MHz, δ in ppm, DMSO-d6): 1.23 (broad s, 3H); 2.27 (s, 2H); 2.31 (d, J=13.8 Hz, 1H); 2.43 (d, J=13.8 Hz, 1H); 4.30 (d, J=5.7 Hz, 2H); 7.18 to 7.38 (m, 5H); 8.53 (broad t, J=5.7 Hz, 1H).

(160) 3-Amino-4,4,4-trifluoro-3-methylbutanoic acid hydrochloride can be prepared in the following way.

(161) ##STR00050##

(162) A mixture of 4.460 g (22.393 mmol) of ethyl 3-amino-4,4,4-trifluoro-3-methylbutanoate and 1.776 g (9.592 mmol) of methyl 3-amino-4,4,4-trifluoro-3-methylbutanoate is treated at ambient temperature with an aqueous 5N hydrochloric acid solution. The reaction medium is heated at 90° C. for 4 h. A mixture of acetonitrile and toluene is added and then the mixture is evaporated to dryness under reduced pressure. 4.61 g of 3-amino-4,4,4-trifluoro-3-methylbutanoic acid hydrochloride are obtained, in the form of a beige solid.

(163) Mass spectrum (method A): ES+/−: [M+H]+: m/z 172; [M−H]−: m/z 170; Tr (min)=0.13

(164) .sup.1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 1.60 (s, 3H); 2.93 (m, 2H); 10.11 (broad m, 3H).

(165) Ethyl 3-amino-4,4,4-trifluoro-3-methylbutanoate and methyl 3-amino-4,4,4-trifluoro-3-methylbutanoate can be prepared in the following way.

(166) ##STR00051##

(167) A solution of 1.5 g (8.235 mmol) of ethyl 3-(trifluoromethyl)crotonate in 6 ml of acetonitrile and 11.76 ml (82.350 mmol) of 7N aqueous ammonia in methanol is microwave-heated at 130° C. for 1 h 20 min. The reaction medium is diluted with 20 ml of methylene chloride and then evaporated to dryness under reduced pressure (the bath temperature is maintained below 25° C. and the pump vacuum is maintained above 100 mbar). A mixture of 969 mg (4.865 mmol) of ethyl 3-amino-4,4,4-trifluoro-3-methylbutanoate and 386 mg (2.085 mmol) of methyl 3-amino-4,4,4-trifluoro-3-methylbutanoate (70% ethyl ester—30% methyl ester ratio) is obtained, in the form of a yellow liquid, the characteristics of which are the following:

(168) Mass spectrum (method A): ES+/−: [M+H]+: m/z 200; Tr (min)=0.32 (ethyl ester).

(169) Mass spectrum (method A): ES+/−: [M+H]+: m/z 186; Tr (min)=0.21 (methyl ester).

(170) .sup.1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 1.19 (t, J=7.1 Hz, 3H); 1.28 (s, 3H); 2.19 (broad m, 2H); 3.17 (m, 2H); 4.08 (q, J=7.1 Hz, 2H) (ethyl ester).

(171) .sup.1H NMR spectrum (400 MHz, δ in ppm, DMSO-d6): 1.28 (s, 3H); 2.19 (broad m, 2H); 3.17 (m, 2H); 3.61 (s, 3H) (methyl ester).

(172) Intermediate F6

(173) 2-Chloro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(174) ##STR00052##

(175) 1.7 g of 2-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are placed in suspension in 24 ml of 1,2-dichloroethane. 2.4 ml of POCl.sub.3 are added and then the medium is heated at 65° C. for 2 h. The medium is concentrated to dryness. The residue is taken up in 50 ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. 32% NaOH is added to pH=7. The aqueous phase is extracted with ethyl acetate and then the organic phase is dried over magnesium sulfate. After the solvent has been evaporated off, 0.9 g (yield=55%) of 2-chloro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a brown solid, the characteristics of which are the following:

(176) Mass spectrum (method A) ES+/−: Tr: 2.14 min, m/z=214.

(177) 2-Hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(178) ##STR00053##

(179) A mixture of 2 g of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide, 10 ml of ethyl malonate and 2.6 g of sodium methoxide is heated to 100° C. After 4 h of heating, the reaction medium is concentrated to dryness. The oil obtained is taken up in ethyl ether. The precipitate is filtered off and then the residue is taken up in 7 ml of water and acidified with 25% HCl to pH 6. The precipitate formed is filtered off, washed with ethyl ether and oven-dried under vacuum. 1.7 g (yield=90%) of 2-hydroxy-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained, in the form of a beige solid, the characteristics of which are the following:

(180) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 196; [M−H]−: m/z 194; Tr (min)=0.22

(181) 4,4-Dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide can be prepared in the following way.

(182) ##STR00054##

(183) 1.95 g of 3-methylbutane-1,3-diamine dihydrobromide are placed in suspension in 20 ml of MeOH and 1.2 g of sodium methanolate are added.

(184) The mixture is stirred at ambient temperature for 2 h. The mixture is filtered and then evaporated to dryness. The reaction crude is solubilised in 20 ml of water, cooled with an ice bath. 0.78 g of CNBr is added and the mixture is stirred at ambient temperature for 12 h. The mixture is evaporated to dryness, and 3 g (yield=quantitative) of 4,4-dimethyl-1,4,5,6-tetrahydropyrimidin-2-amine hydrobromide are obtained, in the form of a translucent oil, which will subsequently be used as it is.

(185) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 128; Tr (min)=0.12

(186) 3-Methylbutane-1,3-diamine dihydrobromide can be prepared in the following way.

(187) ##STR00055##

(188) 2.8 g of ethyl (3-amino-1,1-dimethylpropyl)carbamate are cooled using an ice bath. 9.9 ml of HBr at 33% in acetic acid are added dropwise and then the mixture is heated at reflux for 2 h. After a return to ambient temperature, the product is precipitated with ethyl ether and filtration is carried out. The powder obtained is oven-dried at 70° C. 2.34 g (yield=55%) of 3-methylbutane-1,3-diamine dihydrobromide are obtained, in the form of a white powder, the characteristics of which are the following:

(189) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 103; Tr (min)=0.12

(190) Ethyl (3-amino-1,1-dimethylpropyl)carbamate can be prepared in the following way.

(191) ##STR00056##

(192) 5.12 g of ethyl [3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1,1-dimethylpropyl]carbamate are placed in solution in 47 ml of ethanol. 4 ml of hydrazine hydrate are added and then the mixture is heated at reflux for 30 minutes. After a return to ambient temperature, the reaction medium is filtered and then the solvent is evaporated off. 2.8 g (yield=88%) of ethyl (3-amino-1,1-dimethylpropyl)carbamate are obtained in the form of a brown gum, the characteristics of which are the following:

(193) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 175; Tr (min)=0.22

(194) Ethyl [3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1,1-dimethylpropyl]carbamate can be prepared in the following way.

(195) ##STR00057##

(196) 34.2 g of ethyl carbamate are placed in solution in toluene, 22 ml of BF.sub.3.Et.sub.2O are added and the mixture is heated for 1 h 30 min at 70° C. 11 g of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are added and the mixture is heated at reflux for 12 h. After a return to ambient temperature, the mixture is evaporated to dryness and then taken up in an H.sub.2O/EtOAc mixture. The organic phase is separated by settling out, washed with a saturated NaCl solution and then dried over magnesium sulfate. The crude is purified by flash chromatography on silica gel (CH.sub.2Cl.sub.2/MeOH, 99/1). 5.12 g (yield=31%) of ethyl [3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1,1-dimethylpropyl]carbamate are obtained, in the form of a brown powder, the characteristics of which are the following:

(197) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 305; Tr (min)=0.86

(198) 2-(3-Methylbut-2-en-1-yl)-1H-isoindole-1,3-dione can be prepared in the following way.

(199) ##STR00058##

(200) 20 g of 1-bromo-3-methylbut-2-ene and 26.1 g of phthalimide are placed in suspension in anhydrous DMF and then the mixture is heated at reflux for 12 h. After a return to ambient temperature, the reaction medium is filtered and then taken up with a saturated aqueous NH.sub.4Cl solution. The aqueous phase is extracted with ethyl acetate, washed with an NaCl solution, then dried over magnesium sulfate and evaporated to dryness. The solid obtained is placed in suspension in 100 ml of water and stirred. The precipitated product is filtered off, rinsed with ether and then oven-dried under vacuum at 65° C. 18.3 g (yield=63%) of 2-(3-methylbut-2-en-1-yl)-1H-isoindole-1,3-dione are obtained, in the form of a white powder, the characteristics of which are the following:

(201) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 216; Tr (min)=0.99

(202) Intermediate F7

(203) 2-Chloro-3-fluoro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(204) ##STR00059##

(205) 3.15 g of 2-hydroxy-3-fluoro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are placed in suspension in 42 ml of 1,2-dichloroethane. 4.15 ml of POCl.sub.3 are added and then the medium is heated at 65° C. for 3 h. The medium is concentrated to dryness. The residue is taken up in 150 ml of ethyl acetate and 10 ml of water and then cooled in an ice bath. Concentrated NaOH is added to pH 10. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue obtained is triturated from ethyl ether and the solid is filtered and then dried, so as to give 2.23 g of 2-chloro-3-fluoro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in the form of a brown solid, the characteristics of which are the following:

(206) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 214; [M−H]−: m/z 212; Tr (min)=0.42

(207) 2-Hydroxy-3-fluoro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one can be prepared in the following way.

(208) ##STR00060##

(209) A suspension of 5 g of 4,4-dimethyl-1,4,5,6-tétrahydropyrimidin-2-amine, 29 g of dimethyl fluoromalonate and 3.9 g of sodium methoxide is heated at 100° C. for 3 hours. The reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up with ethyl ether. The solid formed is filtered off and then dried. 10 ml of water are added to the solid obtained, and the resulting mixture is cooled on ice, before acidification to pH 5-6 by adding concentrated hydrochloric acid (25%). The suspension is filtered and then the solid is washed with 5 ml of water and then dried under vacuum over P.sub.2O.sub.5, so as to give 3.15 g of 2-Hydroxy-3-fluoro-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, in the form of a yellow powder, the characteristics of which are the following:

(210) Mass spectrum (method A) (ES+/−) [M+H]+: m/z 232; [M−H]−: m/z 230; Tr (min)=0.86

(211) Intermediate F8: (S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one can be prepared in the following way.

(212) ##STR00061##

(213) 11 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 5.6 g of (S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one in 100 ml of 1,2-dichloroethane. The resulting mixture is then heated to 70° C. After two hours of stirring and after verification by LC/MS, the reaction is complete. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 5 ml of cold water and 200 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=6. The organic phase is then separated and then dried over magnesium sulfate, filtered and concentrated under reduced pressure, so as to give 6 g of (S)-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one, the characteristics of which are the following:

(214) Mass spectrum (method A), ES+/−: [M+H]+: m/z 254; [M−H]−: m/z 252; Tr (min)=0.51

(215) [α].sub.D.sup.25 at 589 nm=−64.8+/−1.1 (c=2.2 mg/0.5 ml DMSO)

(216) (S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one can be prepared in the following way.

(217) ##STR00062##

(218) 8.4 g of (S)-4-methyl-4-(trifluoromethyl)imidazolidin-2-ylideneamine hydrobromide and 2.16 g of sodium methoxide are added to a mixture of 5.4 g of diethyl malonate in 50 ml of methanol. The resulting mixture is refluxed for 18 hours. After cooling, the mixture obtained is concentrated to dryness under reduced pressure. 20 ml of cold water are added to the residue obtained, so as to obtain a thick suspension, to which is added 25% hydrochloric acid to pH=5. The resulting suspension is stirred in an ice bath for two hours and then filtered through a sintered glass funnel. The insoluble matter obtained is rinsed with water (twice 4 ml) and then dried so as to give 5.6 g of (S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one in the form of a white solid, the characteristics of which are the following:

(219) Mass spectrum (method A), ES+/−: [M+H]+: m/z 236; [M−H]−: m/z 234; Tr (min)=0.32

(220) [α].sub.D.sup.25 at 589 nm=−5.6+/−0.6 (c=1.789 mg/0.5 ml DMSO)

(221) (S)-4-methyl-4-(trifluoromethyl)imidazolidin-2-ylideneamine hydrobromide can be prepared in the following way.

(222) ##STR00063##

(223) 1.7 g of cyanogen bromide are added, in small amounts, to a solution, cooled to 5° C., of 2.3 g of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in 10 ml of water, while maintaining the temperature between 5 and 10° C. At the end of the addition, the reaction mixture is stirred at 5° C. for 30 minutes. The ice bath is then withdrawn and the mixture obtained is stirred at ambient temperature for 3 hours. The resulting mixture is then concentrated under reduced pressure. The residue obtained is taken up twice with 100 ml of ethanol and then twice with 100 ml of toluene, and evaporated to dryness each time. The solid obtained is triturated with ethyl ether and then filtered off, so as to give 4.5 g of (S)-4-methyl-4-(trifluoromethyl)imidazolidin-2-ylideneamine hydrobromide, in the form of a white solid, the characteristics of which are the following:

(224) Mass spectrum (method A), ES+/−: [M+H]+: m/z 168; Tr (min)=0.14

(225) [α].sub.D.sup.25 at 589 nm: −5.2+/−0.3 (c=4.909 mg/0.5 ml DMSO)

(226) (S)-3,3,3-Trifluoro-2-methylpropane-1,2-diamine can be prepared in the following way.

(227) ##STR00064##

(228) 4.8 g of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine hydrochloride, 2.5 ml of water and 100 ml of ethyl ether are placed in a round-bottomed flask. 4.5 ml of 32% sodium hydroxide are added, dropwise, to the resulting mixture, to pH=12. The aqueous phase is subsequently separated by settling out and then extracted with 4 times 200 ml of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure (300 mbar/bath temperature=25° C.), so as to give 2.3 g of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine, in the form of a pale yellow oil, the characteristics of which are the following:

(229) Mass spectrum (method B), ES+/−: [M+H]+: m/z 143; base peak: m/z 126; Tr (min)=0.34

(230) [α].sub.D.sup.25 at 589 nm=−4.3+/−0.6 (c=1.778 mg/0.5 ml DMSO)

(231) (S)-3,3,3-Trifluoro-2-methylpropane-1,2-diamine dihydrochloride can be prepared in the following way.

(232) ##STR00065##

(233) A mixture of 7 g of (2R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol in 40.5 ml of methanol, 23.5 ml of 3N hydrochloric acid and 0.94 g of Pd(OH).sub.2/C (20%) is hydrogenated at 22° C. in an autoclave, under a hydrogen pressure of 5 bar, for 18 hours. The mixture obtained is then filtered and the filtrate is evaporated to dryness. The oil obtained is taken up with a 3N hydrochloric acid solution (50 ml). The mixture obtained is extracted with diethyl ether (3×50 ml). The aqueous phase is then evaporated to dryness, taken up with methanol, and then again evaporated to dryness. The yellowish solid obtained is dried under vacuum, so as to give 5.54 g (yield 79%) of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine dihydrochloride, in the form of an off-white solid, the characteristics of which are the following:

(234) .sup.1H NMR spectrum (400 MHz, D.sub.2O): 1.55 (s, 3H), 3.40 (d, J=14.6 Hz, 1H), 3.51 (d, J=14.6 Hz, 1H).

(235) .sup.19F NMR spectrum (400 MHz, D.sub.2O): −81.08 (not calibrated with C.sub.6F.sub.6)

(236) [α].sub.D.sup.25 at 589 nm=+4.65+/−0.6 (c=2.2; MeOH)

(237) (2R)-2-((S)-1-Aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol can be prepared in the following way.

(238) ##STR00066##

(239) 1.6 g of lithium aluminium hydride are added, in small portions, to a solution, cooled to 4° C., of 2.5 g of (2S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile in 250 ml of anhydrous ethyl ether, in a three-necked flask under argon. Substantial evolution of gas and a temperature rise to 8° C. are observed. At the end of the addition, the temperature is left to come back up to ambient temperature, and then the reaction mixture is left stirring for 18 h. The mixture obtained is cooled to 4° C., followed by very slow dropwise addition of 2 ml of water. Substantial evolution of gas and a temperature rise to 12° C. are observed. 2 ml of 15% potassium hydroxide are added, dropwise and very slowly, to the resulting mixture, maintained at 4° C., followed, still dropwise and very slowly, by 4 ml of water. The white precipitate formed is filtered off and the filtrate obtained is dried over magnesium sulfate and then concentrated under reduced pressure, so as to give 2.2 g of (2R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol, the characteristics of which are the following:

(240) Mass spectrum (method A), ES+/−: [M+H]+: m/z 263; Tr (min)=0.43

(241) [α].sub.D.sup.25 at 589 nm=−51.2+/−1.3 (c=1.576 mg/0.5 ml DMSO)

(242) (2S)-3,3,3-Trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile can be prepared in the following way.

(243) ##STR00067##

(244) 3.4 g of trimethylsilyl cyanide are added, dropwise, to a solution, cooled to 0° C., of 5.3 g of (2R,2S)-2-methyl-4-(R)-phenyl-2-(trifluoromethyl)oxazolidine in 100 ml of dichloromethane in a three-necked flask under argon, followed by dropwise addition of 4.9 g of boron trifluoride etherate. The cold bath is then withdrawn to allow the mixture to warm up to ambient temperature. The resulting mixture is stirred at ambient temperature for 18 hours, followed by addition of a saturated sodium bicarbonate solution to pH=8. The organic phase is separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica (eluent: cyclohexane/EtOAc: 80/20), so as to give 3 g of (2R)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile, in the form of a colourless oil, and 2.5 g of (2S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropionitrile, in the form of a white solid, the characteristics of which are:

(245) Mass spectrum (method A), ES+/−: [M+H]+: m/z 259; [M−H+HCO.sub.2H]−: m/z 303; Tr (min)=0.86

(246) [α].sub.D.sup.25 at 589 nm=−89.0+/−1.4 (c=2.444 mg/0.5 ml CHCl.sub.3)

(247) [α].sub.D.sup.25 at 589 nm=−77.6+/−1.4 (c=1.818 mg/0.5 ml DMSO)

(248) (2R,2S)-2-Methyl-4-(R)-phenyl-2-(trifluoromethyl)oxazolidine can be prepared in the following way.

(249) ##STR00068##

(250) 4.8 g of (R)-phenylglycinol and then, in one step, 0.8 g of pyridinium para-toluenesulfonate are added to a solution of 5 g of trifluoroacetone in 180 ml of toluene in a three-necked flask on which is mounted a Dean-Stark apparatus. The mixture obtained is then heated at reflux for 18 hours, during which time 0.3 ml of water is collected. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by filtration on silica (eluent: dichloromethane), so as to give 5.3 g of (2R,2S)-2-methyl-4-(R)-phenyl-2-(trifluoromethyl)oxazolidine, in the form of a colourless liquid, the characteristics of which are the following:

(251) Mass spectrum (method A), ES+/−: [M+H]+: m/z 232; Tr (min)=0.96

(252) [α].sub.D.sup.25 at 589 nm=−23.4+/−0.8 (c=1.794 mg/0.5 ml MeOH)

(253) Intermediate F9:

(254) (S)-6-Fluoro-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one can be obtained in the following way.

(255) ##STR00069##

(256) 9 ml of phosphorus oxychloride are added, at ambient temperature and under an argon atmosphere, to a suspension of 8.20 g of (S)-6-fluoro-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one in 90 ml of 1,2-dichloroethane. The resulting mixture is then heated to 70° C. After 3 hours of stirring and after verification by LC/MS, the reaction is complete. After cooling, the reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up in 50 ml of cold water and 200 ml of ethyl acetate. 32% sodium hydroxide is added to the mixture obtained, to pH=10. The organic phase is then separated and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue obtained is purified by silica column chromatography (eluent: 98.5/1.5 dichloromethane/methanol), so as to give 4 g of (S)-6-fluoro-7-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo [1,2-a]pyrimidin-5(1H)-one, the characteristics of which are the following:

(257) Mass Spectrometry: Method B:

(258) Retention time Tr (min)=2.92, [M+H]+: m/z 272; [M−H]−: m/z 270 (S)-6-Fluoro-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one can be obtained in the following way.

(259) ##STR00070##

(260) 11 g of (S)-4-methyl-4-(trifluoromethyl)imidazolidin-2-ylideneamine hydrobromide and 4.79 g of sodium methoxide are added to a mixture of 6.7 g of diethyl fluoromalonate in 110 ml of methanol. The resulting mixture is refluxed for 3 hours. After cooling, the mixture obtained is concentrated to dryness under reduced pressure. 15 ml of cold water are added to the residue obtained, so as to obtain a thick suspension, to which is added 25% hydrochloric acid to pH=5-6. The reaction mixture is evaporated to dryness under reduced pressure. The residue obtained is taken up with an 80/20 dichloromethane/MeOH mixture and then filtered. The filtrate is concentrated under reduced pressure and the residue obtained is purified by chromatography on silica (eluent: 70/30 dichloromethane/MeOH), so as to give 8.14 g of (2S)-7-hydroxy-2-methyl-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, in the form of a pale orange foam, which is used as it is in the next step.

(261) TABLE-US-00001 TABLE 1 Starting intermediates of type F Intermediate of type F Structure Substituents F1 R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) F2 R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) F3 R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) F4 R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) F5 R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) F6 R4 = H; p = 0; q = 2; R2 = Me; R3 = Me F7 R4 = F; p = 0; q = 2; R2 = Me; R3 = Me F8 R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) F9 R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S)

(262) TABLE-US-00002 Experimental section: Table 2: Examples from 1 to 295, starting intermediates of type F and amount of each example isolated Amount Intermediate isolated EXAMPLE Example name of type F Example structure (mg) EXAMPLE-1 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 1300 EXAMPLE-2 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(5- methyl- [1,2,4]oxadiazol-3-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 109 EXAMPLE-3 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(3- methyl-2-oxobutyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 151 EXAMPLE-4 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(3-methyl-2-oxo- butyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 65 EXAMPLE-5 (S)-3-Fluoro-9-(2- fluoropyridin-4-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 1200 EXAMPLE-6 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 1450 EXAMPLE-7 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxopropyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 45 EXAMPLE-8 (S)-3-Fluoro-9-((S)-2- hydroxypropyl)-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 181 EXAMPLE-9 (S)-2-((3R,5R)-3,5- Dimethylmorpholin-4- yl)-9-isoxazol-5-yl- methyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 95 EXAMPLE-10 (S)-9-[2-(2-Chloro- pyridin-4-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 35 EXAMPLE-11 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-3-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 35 EXAMPLE-12 (S)-9-(3-Methyl- isoxazol-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 186 EXAMPLE-13 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-2-ylmethyl-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 120 EXAMPLE-14 [(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid ethyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 134 EXAMPLE-15 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(5-methyl- [1,2,4]oxadiazol-3-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 75 EXAMPLE-16 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxobutyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 25 EXAMPLE-17 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(3- methyl- [1,2,4]oxadiazol-5-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 50 EXAMPLE-18 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-oxo-2-(tetrahydro- pyran-4-yl)ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 140 EXAMPLE-19 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(3-methyl- [1,2,4]oxadiazol-5-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 95 EXAMPLE-20 (S)-3-Fluoro-9-(2- methoxy-ethyl)-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 38 EXAMPLE-21 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(5-methyl- [1,2,4]oxadiazol-3-yl- methyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 00 86 EXAMPLE-22 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxobutyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 01 62 EXAMPLE-23 2-[(S)-7-Fluoro-8-((R)- 3-methylmorpholin-4- yl)-6-oxo-2- trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]-N- methoxy-N-methyl- acetamide R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 02 550 EXAMPLE-24 (S)-9-(6-Fluoropyridin- 3-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 03 84 EXAMPLE-25 (S)-9-[2-(2-Fluoro- pyridin-4-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 04 46 EXAMPLE-26 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxobutyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 05 98 EXAMPLE-27 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(5- methyl- [1,2,4]oxadiazol-3-yl- methyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 06 77 EXAMPLE-28 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl-9-(3- trifluoromethyl- [1,2,4]oxadiazol-5-yl- methyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 07 139 EXAMPLE-29 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxobutyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 08 44 EXAMPLE-30 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-(5- methyl- [1,2,4]oxadiazol-3-yl- methyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 09 87 EXAMPLE-31 (S)-1-(2-Cyclopropyl- 2-oxoethyl)-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 0 45 EXAMPLE-32 (S)-9-(1- Difluoromethyl-1H- pyrazol-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-33 (S)-9-Isoxazol-3-yl- methyl-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 50 EXAMPLE-34 (S)-9-(2-Chloro- thiazol-5-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 25 EXAMPLE-35 (S)-9-(6-Chloro- pyridin-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 45 EXAMPLE-36 (S)-9-Isoxazol-5-yl- methyl-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 45 EXAMPLE-37 (S)-9-(2- Difluoromethyl-2H- pyrazol-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-38 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-pyridin-2- ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 20 EXAMPLE-39 (S)-9-(2-Fluoro-2- phenylethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]yrimidin- 4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 46 EXAMPLE-40 (S)-3-Fluoro-9-(2- methoxypyridin-4-yl)- 2-((R)-3-Methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 98 EXAMPLE-41 (S)-9-(2-Chloro- pyridin-4-ylmethyl)-3- fluoro-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 48 EXAMPLE-42 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-oxazol-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 85 EXAMPLE-43 (S)-9-(6-Cyclopropyl- pyridin-3-yl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-44 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-oxazol-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 46 EXAMPLE-45 (S)-9-(2-Chloro- pyridin-4-yl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 62 EXAMPLE-46 (S)-3-Fluoro-9- isoxazol-5-ylmethyl-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 68 EXAMPLE-47 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-pyridin-3-yl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 21 EXAMPLE-48 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-(2,2,2-trifluoro- ethoxy)ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 17 EXAMPLE-49 (S)-3-Fluoro-9-(2- hydroxy-2-methyl- propyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-50 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-pyridin-3- ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 16 EXAMPLE-51 (S)-3-Fluoro-9-(6- fluoropyridin-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 80 EXAMPLE-52 (S)-9-(6-Chloro- pyridin-3-ylmethyl)-3- fluoro-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 73 EXAMPLE-53 (S)-9-(6- Difluoromethylpyridin- 3-yl)-3-fluoro-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-54 (S)-9-(5-tert-Butyl- [1,2,4]oxadiazol-3-yl- methyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 70 EXAMPLE-55 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-pyridin-4-yl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-56 (S)-3-Fluoro-9-(5- fluoropyridin-2-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 65 EXAMPLE-57 (S)-3-Fluoro-9-(5- fluoropyridin-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 62 EXAMPLE-58 (S)-3-Fluoro-9-(2- fluoropyridin-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 65 EXAMPLE-59 (S)-3-Fluoro-9-[2-(3- fluoropyridin-2-yl)-2- oxoethyl]-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 80 EXAMPLE-60 (S)-9-[2-(3-Fluoro- pyridin-2-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 130 EXAMPLE-61 (S)-9-[2-(2-Methoxy- pyridin-4-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 18 EXAMPLE-62 (S)-3-Fluoro-9-(3- methylisoxazol-4-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 104 EXAMPLE-63 (S)-9-[2-(6-Fluoro- pyridin-2-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-64 (S)-9-Imidazo[1,2-a]- pyridin-2-ylmethyl-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 62 EXAMPLE-65 (S)-9-(4-Chloro- pyridin-2-ylmethyl)-2- ((R)-3-methyl- mopholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 87 EXAMPLE-66 (S)-9-(3-Chloro- pyridin-4-ylmethyl)-2- ((R)-3-methyl- mopholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 81 EXAMPLE-67 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-3-pyridin-2-yl- propyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 20 EXAMPLE-68 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-thiazol-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-69 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-thiazol-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 48 EXAMPLE-70 (S)-9-[2-(5-Fluoro- pyridin-2-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 24 EXAMPLE-71 3-Fluoro-8,8-dimethyl- 2-((R)-3-methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = Me; R3 = Me 0 60 EXAMPLE-72 9-(2-Difluoromethyl- 2H-pyrazol-3-yl- methyl)-8,8-dimethyl- 2-((R)-3-methyl- morpholin-4-yl)- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = Me 50 EXAMPLE-73 3-Fluoro-9-isoxazol-3- ylmethyl-8,8-dimethyl- 2-((R)-3-methyl- morpholin-4-yl)- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = Me; R3 = Me 80 EXAMPLE-74 9-(2-Difluoromethyl- 2H-pyrazol-3-yl- methyl)-3-fluoro-8,8- dimethyl-2-((R)-3- methylmorpholin-4-yl)- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = Me; R3 = Me 60 EXAMPLE-75 (S)-9-(3-Fluoro- phenyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 96 EXAMPLE-76 (S)-9-(2-Chloro- pyridin-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 29 EXAMPLE-77 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 80 EXAMPLE-78 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- thiazol-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 94 EXAMPLE-79 (S)-9-(2-Chloro- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 66 EXAMPLE-80 (S)-9-(2-Methoxy- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 25 EXAMPLE-81 (S)-2-((R)-3-Methyl- morpholin-4-yl)-8- trifluoromethyl-9-(6- trifluoromethylpyridin- 3-yl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 147 EXAMPLE-82 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- (2,2,2-trifluoro- ethoxy)ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 74 EXAMPLE-83 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(6- methylpyridin-3-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 20 EXAMPLE-84 (S)-9-(2-Hydroxy-2- methylpropyl)-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 42 EXAMPLE-85 (S)-9-(6-Isopropoxy- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 25 EXAMPLE-86 (S)-9-(5-Chloro- pyridin-2-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 105 EXAMPLE-87 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- thiazol-5-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 96 EXAMPLE-88 (S)-9-(6-Cyclobutyl- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 128 EXAMPLE-89 (S)-9-(2-Cyclopropyl- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 96 EXAMPLE-90 (S)-9-(2-Methoxy- ethyl)-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 69 EXAMPLE-91 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-5-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 40 EXAMPLE-92 (S)-9-(5-Fluoropyridin- 2-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-93 (S)-9-(2,5-Dimethyl- oxazol-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 66 EXAMPLE-94 (S)-9-(5-Fluoropyridin- 3-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 95 EXAMPLE-95 (S)-9-(5-Chloro- pyridin-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 6 EXAMPLE-96 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(5- methyl- [1,3,4]oxadiazol-2-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 90 EXAMPLE-97 (S)-9-(3,3-Dimethyl-2- oxobutyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 104 EXAMPLE-98 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 29 EXAMPLE-99 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-phenylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 128 EXAMPLE-100 (S)-9-((S)-2-Methoxy- 2-phenylethyl)-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 39 EXAMPLE-101 (S)-9-(3-Methyl- isoxazol-5-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 350 EXAMPLE-102 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 15 EXAMPLE-103 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 1000 EXAMPLE-104 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- (toluene-4-sulfonyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 277 EXAMPLE-105 (R)-9-Isoxazol-5-yl- methyl-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 34 EXAMPLE-106 (R)-9-Isoxazol-3-yl- methyl-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 39 EXAMPLE-107 (R)-9-(6-Cyclopropyl- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 60 EXAMPLE-108 (R)-9-(2-Chloro- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 106 EXAMPLE-109 (R)-9-(2-Methoxy- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 208 EXAMPLE-110 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-4-ylmethyl-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 54 EXAMPLE-111 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-oxazol-5-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 34 EXAMPLE-112 (R)-9-(2-Chloro- pyridin-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 82 EXAMPLE-113 (R)-9-(2-Hydroxy-2- methylpropyl)-2-((R)- 3-methylmorpholin-4- yl)-6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 51 EXAMPLE-114 (R)-9-(2-Isopropoxy- pyridin-4-yl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 95 EXAMPLE-115 (R)-9-(6-Chloro- pyridin-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 96 EXAMPLE-116 (R)-9-(6-Isopropoxy- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 68 EXAMPLE-117 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxazol-5-ylmethyl-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 57 EXAMPLE-118 (R)-9-(2-Cyclopropyl- 2-oxoethyl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 90 EXAMPLE-119 (R)-3-Fluoro-9-(2- methoxypyridin-4-yl)- 2-((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 55 EXAMPLE-120 (R)-9-(2-Cyclopropyl- 2-oxoethyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 70 EXAMPLE-121 (R)-9-(6- Difluoromethylpyridin- 3-yl)-3-fluoro-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 00 41 EXAMPLE-122 (R)-9-(2-Chloro- pyridin-4-yl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 01 52 EXAMPLE-123 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(5- methyl- [1,3,4]thiadiazol-2-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 02 198 EXAMPLE-124 (S)-9-(6- Difluoromethoxy- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 03 53 EXAMPLE-125 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(4- methyl- [1,2,3]thiadiazol-5-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 04 42 EXAMPLE-126 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-pyridin-3- ylethyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 05 131 EXAMPLE-127 (R)-9-(6- Difluoromethoxy- pyridin-3-yl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 06 55 EXAMPLE-128 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(3-methyl-2-oxo- butyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 07 74 EXAMPLE-129 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-oxazol-2-ylmethyl-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 08 44 EXAMPLE-130 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(3- methyl-2-oxobutyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 09 53 EXAMPLE-131 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- oxo-2-(tetrahydro- pyran-4-yl)ethyl]-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 0 133 EXAMPLE-132 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-oxo-2-(tetrahydro- pyran-4-yl)ethyl]-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 133 EXAMPLE-133 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- oxetan-3-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-134 9-(6-Difluoromethyl- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 23 EXAMPLE-135 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-pyridin-2- ylethyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 17 EXAMPLE-136 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[1- (tetrahydro-furan-2- yl)methyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 56 EXAMPLE-137 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[1- (tetrahydrofuran-2- yl)methyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 62 EXAMPLE-138 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[1- (tetrahydropyran-2- yl)methyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 74 EXAMPLE-139 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[1- (tetrahydropyran-2- yl)methyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 94 EXAMPLE-140 (S)-2-((R)-3-Methyl- morpholin-4-yl)-8- trifluoromethyl-9-(5- trifluoromethyl- [1,3,4]oxadiazol-2-yl- methyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 33 EXAMPLE-141 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-3-yl- ethyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 0 86 EXAMPLE-142 (S)-9-(5-Cyclopropyl- [1,3,4]oxadiazol-2-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 211 EXAMPLE-143 (R)-9-(3-Methyl- isoxazol-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 99 EXAMPLE-144 (R)-2-((R)-3-Methyl- morpholin-4-yl)-6- trifluoromethyl-9-(3- trifluoromethyl- [1,2,4]oxadiazol-5-yl- methyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 183 EXAMPLE-145 (R)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxopropyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 2; q = 0; R2 = H; R3 = CF3 (R) 93 EXAMPLE-146 (R)-3-Fluoro-9-(3- methylisoxazol-4-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 6-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 86 EXAMPLE-147 (R)-9-(3-Cyclopropyl- [1,2,4]oxadiazol-5-yl- methyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 78 EXAMPLE-148 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxopropyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 64 EXAMPLE-149 (R)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(3-methyl- [1,2,4]oxadiazol-5-yl- methyl)-6- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 2; q = 0; R2 = H; R3 = CF3 (R) 36 EXAMPLE-150 (S)-2-(3,3-Dimethyl- morpholin-4-yl)-9-(2- oxo-2-phenylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 26 EXAMPLE-151 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-((3S,5R)-3,5- dimethylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one Single stereoisomer. R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 57 EXAMPLE-152 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-((3S,5S)-3,5- dimethylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 73 EXAMPLE-153 (S)-2-((3S,5S)-3,5- Dimethylmorpholin-4- yl)-9-(2-oxo-2-phenyl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 57 EXAMPLE-154 (S)-9-(2- Difluoromethyl-2H- pyrazol-3-ylmethyl)-2- ((3R,5R)-3,5-dimethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 99 EXAMPLE-155 (S)-2-((3R,5R)-3,5- Dimethylmorpholin-4- yl)-9-(3-methyl- isoxazol-5-ylmethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 55 EXAMPLE-156 (S)-9-(6-Chloro- pyridin-3-ylmethyl)-2- ((3R,5R)-3,5-dimethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 42 EXAMPLE-157 (S)-9-(2-Chloro- pyridin-4-ylmethyl)-2- ((3R,5R)-3,5-dimethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 53 EXAMPLE-158 (S)-2-((3R,5R)-3,5- Dimethylmorpholin-4- yl)-9-oxazol-2-yl- methyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 121 EXAMPLE-159 (S)-9-(2-Chloro- pyridin-4-yl)-2- ((3R,5R)-3,5-dimethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 116 EXAMPLE-160 (S)-2-((3R,5R)-3,5- Dimethylmorpholin-4- yl)-9-pyridin-3-yl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 93 EXAMPLE-161 (S)-9-(3,5-Difluoro- phenyl)-2-(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 20 EXAMPLE-162 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-(8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 86 EXAMPLE-163 (S)-2-(8-Oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 9-(2-oxo-2-phenyl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 127 EXAMPLE-164 (S)-9-Isoxazol-5-yl- methyl-2-(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 56 EXAMPLE-165 (S)-9-(2-Chloro- thiazol-5-ylmethyl)-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 95 EXAMPLE-166 (S)-9-(2- Difluoromethyl-2H- pyrazol-3-ylmethyl)-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 103 EXAMPLE-167 (S)-9-(1- Difluoromethyl-1H- pyrazol-3-ylmethyl)-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 75 EXAMPLE-168 (S)-9-(6-Chloro- pyridin-3-ylmethyl)-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 76 EXAMPLE-169 (S)-9-Isoxazol-3-yl- methyl-2-(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 88 EXAMPLE-170 (S)-2-(8-Oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 9-(2-oxo-2-pyridin-3- ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 16 EXAMPLE-171 (S)-2-(8-Oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 9-(2-oxo-2-pyridin-2- ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 41 EXAMPLE-172 (S)-2-(-2-Ethyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 42 EXAMPLE-173 (S)-2-(-2-Ethyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-174 (S)-2-(-2-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 41 EXAMPLE-175 (S)-2-(-2-Methyl- morpholin-4-yl)-9-(2- oxo-2-pyridin-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 38 EXAMPLE-176 (S)-9-(3,5-Difluoro- phenyl)-2-(3- hydroxymethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 32 EXAMPLE-177 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-(-3-hydroxymethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-178 (S)-9-(5-Chloro- thiophen-2-ylmethyl)- 2-((S)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 54 EXAMPLE-179 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-(2-oxo-2-pyridin-2- ylethyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 29 EXAMPLE-180 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-(2-oxo-2-pyridin-3- ylethyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 66 EXAMPLE-181 (S)-1-(2-Chloro- pyridin-4-ylmethyl)-2- methyl-7-((R)-3- methylmorpholin-4-yl)- 2-trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 0 77 EXAMPLE-182 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-oxazol-5-ylmethyl-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 25 EXAMPLE-183 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-oxazol-4-ylmethyl-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 56 EXAMPLE-184 (S)-1-(2-Chloro- pyridin-4-ylmethyl)-6- fluoro-2-methyl-7-((R)- 3-methylmorpholin-4- yl)-2-trifluoromethyl- 2,3-dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 117 EXAMPLE-185 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-(3- methyl-2-oxobutyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 45 EXAMPLE-186 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-[2- oxo-2-(tetrahydro- pyran-4-yl)ethyl]-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 360 EXAMPLE-187 (S)-1-(2-Cyclopropyl- 2-oxoethyl)-6-fluoro-2- methyl-7-((R)-3- methylmorpholin-4-yl)- 2-trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 63 EXAMPLE-188 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-(3-methyl-2-oxo- butyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 15 EXAMPLE-189 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-(2- oxo-2-pyridin-3-yl- ethyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 172 EXAMPLE-190 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-[2-oxo-2-(tetrahydro- pyran-4-yl)ethyl]-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 188 EXAMPLE-191 (S)-9-Benzyl-2-(2- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 83 EXAMPLE-192 (S)-9-Benzyl-2-(2- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 70 EXAMPLE-193 (S)-9-Benzyl-2-(2- fluoromethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 227 EXAMPLE-194 (S)-9-Benzyl-2-(2- fluoromethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 88 EXAMPLE-195 (S)-9-Benzyl-2-(2- fluoromethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 89 EXAMPLE-196 N-Methoxy-N-methyl- 2-[(S)-8-((R)-3-methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]- acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 127 EXAMPLE-197 N-Methoxy-2-[(S)-8- ((R)-3-methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]- acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-198 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- pyridin-4-yl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 17 EXAMPLE-199 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-(2- oxo-2-pyridin-2-yl- ethyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 1112 EXAMPLE-200 (S)-9-(2-Hydroxy-2- methylpropyl)-8- methyl-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 62 EXAMPLE-201 (S)-9-(5-Isopropyl- [1,2,4]oxadiazol-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 103 EXAMPLE-202 (S)-9-(5-Cyclopropyl- [1,2,4]oxadiazol-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 112 EXAMPLE-203 (S)-9-(5-tert-Butyl- [1,2,4]oxadiazol-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 108 EXAMPLE-204 (S)-3-Fluoro-9-(2- hydroxyethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 107 EXAMPLE-205 (S)-9-((S)-2-Hydroxy- propyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 114 EXAMPLE-206 (S)-9-((S)-2-Methoxy- 2-phenylethyl)-2- (1R,5S)-8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 87 EXAMPLE-207 (S)-6-Fluoro-2-methyl- 7-((R)-3-methyl- morpholin-4-yl)-1-(3- methyl- [1,2,4]oxadiazol-5-yl- methyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 47 EXAMPLE-208 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-(3-methyl- [1,2,4]oxadiazol-5-yl- methyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = F; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 147 EXAMPLE-209 (S)-9-(2-Hydroxy-2- pyridin-3-ylethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 44 EXAMPLE-210 (S)-9-(2-Hydroxy-2- pyridin-3-ylethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 67 EXAMPLE-211 (S)-8-Methyl-2-((R)-3- methylmorpholin-4-yl)- 9-(5-methyl- [1,2,4]oxadiazol-3-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 0 43 EXAMPLE-212 (S)-9-(2-Hydroxy-2- pyridin-2-ylethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 75 EXAMPLE-213 (S)-9-(2-Hydroxy-2- pyridin-2-ylethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 38 EXAMPLE-214 (S)-9-(2- Difluoromethyl-2H- pyrazol-3-ylmethyl)-8- methyl-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 140 EXAMPLE-215 (S)-9-Isoxazol-3-yl- methyl-8-methyl-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 35 EXAMPLE-216 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- pyridin-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 43 EXAMPLE-217 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- pyridin-3-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-218 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- pyridin-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-219 (S)-9-[2-(4-Fluoro- phenyl)ethyl]-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-220 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- pyridin-2-ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 6 EXAMPLE-221 (S)-9-(2-Fluoropyridin- 3-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 00 110 EXAMPLE-222 N,N-Dimethyl-2-[(S)-8- ((R)-3-methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]- acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 01 150 EXAMPLE-223 N-Methyl-2-[(S)-8-((R)- 3-methylmorpholin-4- yl)-6-oxo-2- trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]- acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 02 90 EXAMPLE-224 (S)-9-(6-Fluoropyridin- 2-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 03 135 EXAMPLE-225 (S)-9-(2-Isopropoxy- pyridin-4-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 04 65 EXAMPLE-226 (S)-9-(3-Isopropyl- [1,2,4]oxadiazol-5-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 05 46 EXAMPLE-227 (S)-9-(3-Cyclopropyl- [1,2,4]oxadiazol-5-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 06 130 EXAMPLE-228 (S)-9-(3-tert-Butyl- [1,2,4]oxadiazol-5-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 07 130 EXAMPLE-229 (S)-9-(6-Isopropoxy- pyridin-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 08 165 EXAMPLE-230 (S)-9-(2-Isopropoxy- pyridin-3-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 09 100 EXAMPLE-231 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- thiazol-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 69 EXAMPLE-232 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-thiazol-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 40 EXAMPLE-233 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-piperidin-1-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 153 EXAMPLE-234 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- morpholin-4-yl-2-oxo- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 125 EXAMPLE-235 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-morpholin-4-yl-2- oxoethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 170 EXAMPLE-236 2-[(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]-N- phenyl-acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 136 EXAMPLE-237 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxo-2-piperidin-1- ylethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 89 EXAMPLE-238 (S)-9-Acetyl-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-239 (S)-8-Methyl-2-((R)-3- methylmorpholin-4-yl)- 9-oxazol-2-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 106 EXAMPLE-240 (S)-2-Methyl-7-((R)-3- methylmorpholin-4-yl)- 1-(5-methyl- [1,2,4]oxadiazol-3-yl- methyl)-2- trifluoromethyl-2,3- dihydro-1H- imidazo[1,2-a]- pyrimidin-5-one R4 = H; p = 0; q = 1; R2 = Me; R3 = CF3 (S) 120 EXAMPLE-241 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 600 EXAMPLE-242 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-thiazol-2-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 55 EXAMPLE-243 [(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid cyclopentyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 145 EXAMPLE-244 (S)-9-(2-Cyclopentyl- 2-oxoethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 165 EXAMPLE-245 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- oxo-2-(tetrahydro- pyran-4-yl)ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 200 EXAMPLE-246 (S)-3-Fluoro-9-(5- isopropyl- [1,2,4]oxadiazol-3-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-247 (S)-9-(5-Cyclopropyl- [1,2,4]oxadiazol-3-yl- methyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-248 (S)-3-Fluoro-9-(3- isopropyl- [1,2,4]oxadiazol-5-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-249 (S)-9-(3-Cyclopropyl- [1,2,4]oxadiazol-5-yl- methyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 125 EXAMPLE-250 (S)-9-(3-tert-Butyl- [1,2,4]oxadiazol-5-yl- methyl)-3-fluoro-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-251 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl-9-(3- trifluoromethyl- [1,2,4]oxadiazol-5-yl- methyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 77 EXAMPLE-252 (S)-8-Methyl-2-((R)-3- methylmorpholin-4-yl)- 9-(3-methyl-2-oxo- butyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 35 EXAMPLE-253 (S)-9-[2-(1-Methyl- cyclopentyl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 165 EXAMPLE-254 [(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid isopropyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 103 EXAMPLE-255 (S)-9-(3,3-Dimethyl-2- oxobutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 144 EXAMPLE-256 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxopropyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 129 EXAMPLE-257 (S)-9-(2-Fluoropyridin- 4-ylmethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 150 EXAMPLE-258 (S)-9-(2-Cyclohexyl-2- oxoethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 114 EXAMPLE-259 (S)-2-((R)-3-methyl- morpholin-4-yl)-9- pyridazin-4-ylmethyl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 86 EXAMPLE-260 [(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid tert-butyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 112 EXAMPLE-261 2-{2-[(S)-8-((R)-3- Methylmorpholin-4-yl)- 6-oxo-2- trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetyl}- pyrrolidine-1- carboxylic acid tert- butyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 137 EXAMPLE-262 [(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid methyl ester R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-263 2-[(S)-8-((R)-3-Methyl- morpholin-4-yl)-6-oxo- 2-trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]- acetamide R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 88 EXAMPLE-264 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(4H- [1,2,4]triazol-3-yl- methyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-265 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- oxo-2-piperidin-4-yl- ethyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 48 EXAMPLE-266 (S)-9-(3-Methyl-but-2- enyl)-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 16 EXAMPLE-267 (S)-9-(3-Fluoro-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 11 EXAMPLE-268 (S)-9-[2-(3-Methyl- isoxazol-4-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 30 EXAMPLE-269 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- oxo-2-(tetrahydro- furan-3-yl)ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 57 EXAMPLE-270 (S)-9-(5-Methyl- [1,2,4]oxadiazol-3-yl- methyl)-2-(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 133 EXAMPLE-271 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-2-(8-oxa- 3-azabicyclo[3.2.1]oct- 3-yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 197 EXAMPLE-272 (S)-9-(3-Methyl-2-oxo- butyl)-2-(8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 200 EXAMPLE-273 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-3-fluoro-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 200 EXAMPLE-274 (S)-3-Fluoro-9-(3- methyl-2-oxobutyl)-2- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 160 EXAMPLE-275 (S)-3-Fluoro-9-(5- methyl- [1,2,4]oxadiazol-3-yl- methyl)-2-(8-oxa-3- azabicyclo[3.2.1]oct-3- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 157 EXAMPLE-276 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(4- methyl-2-oxo-pentyl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 106 EXAMPLE-277 (S)-2-((S)-3-Methyl- morpholin-4-yl)-9-(3- methyl-2-oxobutyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 245 EXAMPLE-278 (S)-3-Fluoro-2-((S)-3- methylmorpholin-4-yl)- 9-(3-methyl-2-oxo- butyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 191 EXAMPLE-279 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(5-methyl-2-oxo- hexyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 45 EXAMPLE-280 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(4-methyl-2-oxo- pentyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 109 EXAMPLE-281 (S)-9-(3-Ethyl-2-oxo- pentyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 138 EXAMPLE-282 (S)-9-(3-Ethyl-2-oxo- pentyl)-3-fluoro-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 144 EXAMPLE-283 [(S)-7-Fluoro-8-((R)-3- methylmorpholin-4-yl)- 6-oxo-2- trifluoromethyl-3,4- dihydro-2H,6H- pyrimido[1,2-a]- pyrimidin-1-yl]acetic acid methyl ester R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 4320 EXAMPLE-284 (S)-9-sec-Butyl-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 15 EXAMPLE-285 (S)-9-sec-Butyl-2-((R)- 3-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 14 EXAMPLE-286 (S)-9-(2-Hydroxy-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 7 EXAMPLE-287 (S)-9-(2-Hydroxy-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 150 EXAMPLE-288 (S)-9-(2-Methoxy-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 110 EXAMPLE-289 (S)-9-(2-Methoxy-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one single stereoisomer R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 14 EXAMPLE-290 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(5- methyl-2-oxo-hexyl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 172 EXAMPLE-291 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(3- methyl-2-oxo-pentyl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 150 EXAMPLE-292 (S)-2-((R)-3-Methyl- morpholin-4-yl)-8- trifluoromethyl-9-(3- trifluoromethyl- [1,2,4]oxadiazol-5-yl- methyl)-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 80 EXAMPLE-293 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-(2-oxa-6-aza- spiro[3.3]hept-6-yl)-2- oxoethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 59 EXAMPLE-294 (S)-3-Fluoro-9-[2-(5- methylisoxazol-3-yl)-2- oxoethyl]-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 19 EXAMPLE-295 (S)-9-(2-Fluoro-2- phenylethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 45 EXAMPLE-296 (S)-3-Fluoro-9- isoxazol-3-ylmethyl-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-297 (S)-9-(2- Difluoromethyl-2H- pyrazol-3-ylmethyl)-3- fluoro-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 160 EXAMPLE-298 9-Isoxazol-3-ylmethyl- 8,8-dimethyl-2-((R)-3- methylmorpholin-4-yl)- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = CH3; R3 = CH3 27 EXAMPLE-299 (S)-3-Fluoro-9-(3- methylisoxazol-5-yl- methyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 67 EXAMPLE-300 (S)-9-(2-Isopropoxy- ethyl)-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 90 EXAMPLE-301 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9- pyridin-3-yl-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 107 EXAMPLE-302 (S)-9-(6-Cyclopropyl- pyridin-3-yl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 155 EXAMPLE-303 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-{2- [2-((R)-3-methyl- morpholin-4-yl)pyridin- 4-yl]-2-oxoethyl}-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 6.3 EXAMPLE-304 (S)-9-{2-Cyclopropyl- 2-[(Z)-hydroxyim ino]- ethyl}-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, isomer 1 of undetermined configuration Z or E R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 70.4 EXAMPLE-305 (S)-9-{2-Cyclopropyl- 2-[(E)-hydroxyimino]- ethyl}-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, isomer 2 of undetermined configuration Z or E R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 106.9 EXAMPLE-306 (S)-9-{2-Cyclopropyl- 2-[(E)-methoxyimino]- ethyl}-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, isomer 1 of undetermined configuration Z or E R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 72 EXAMPLE-307 (S)-9-{2-Cyclopropyl- 2-[(Z)-methoxyimino]- ethyl}-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, isomer 2 of undetermined configuration Z or E R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 48 EXAMPLE-308 (S)-9-(2-Cyclopropyl- oxetan-2-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the side chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 84.5 EXAMPLE-309 (S)-9-(2-Cyclopropyl- oxetan-2-ylmethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido[1,2- a]pyrimidin-4-one, diastereoisomer 2 of undetermined absolute configuration on the asymmetric carbon of the side chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 131.4 EXAMPLE-310 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- (4-methyl-tetrahydro- pyran-4-yl)-2-oxo- ethyl]-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 138.5 EXAMPLE-311 (S)-9-[2-(5-Methyl- isoxazol-3-yl)-2-oxo- ethyl]-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 9 EXAMPLE-312 (S)-9-(2-Chloro- thiazol-5-ylmethyl)-2- ((3R,5R)-3,5-dimethyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 73 EXAMPLE-313 (S)-2-((3R,5R)-3,5- Dimethylmorpholin-4- yl)-9-isoxazol-3-yl- methyl-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 90 EXAMPLE-314 (S)-3-Fluoro-9-(2- isoxazolidin-2-yl-2- oxoethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 95 EXAMPLE-315 (S)-9-(2-Hydroxy- ethyl)-2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 100 EXAMPLE-316 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-(6-oxa-1-aza- spiro[3.3]hept-1-yl)-2- oxoethyl]-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 72 EXAMPLE-317 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-(2-[1,2]oxazinan-2- yl-2-oxoethyl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 46 EXAMPLE-318 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-(2- [1,2]oxazinan-2-yl-2- oxoethyl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 39 EXAMPLE-319 (S)-9-(2-Isoxazolidin- 2-yl-2-oxoethyl)-2- ((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 59 EXAMPLE-320 (S)-2-(2-Methyl- morpholin-4-yl)-9-(3- methyl-2-oxobutyl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the morpholine R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 118 EXAMPLE-321 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-3-fluoro-2- ((S)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 00 113 EXAMPLE-322 (S)-9-(2-Cyclopropyl- 2-oxoethyl)-3-fluoro-2- (2-methylmorpholin-4- yl)-8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the morpholine R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 01 114 EXAMPLE-323 (S)-9-(2-Fluoro-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the 2-fluoro- 3-methylbutyl chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 02 30 EXAMPLE-324 (S)-9-(2-Fluoro-3- methylbutyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, diastereoisomer 2 of undetermined absolute configuration on the asymmetric carbon of the 2-fluoro- 3-methylbutyl chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 03 21 EXAMPLE-325 (S)-9-(2-Cyclopropyl- 2-fluoroethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the 2-cyclo- propyl-2-fluoroethyl chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 04 73 EXAMPLE-326 (S)-9-(2-Cyclopropyl- 2-fluoroethyl)-2-((R)-3- methylmorpholin-4-yl)- 8-trifluoromethyl- 6,7,8,9-tetrahydro- pyrimido[1,2-a]- pyrimidin-4-one, diastereoisomer 2 of undetermined absolute configuration on the asymmetric carbon of the 2-cyclo- propyl-2-fluoroethyl chain R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 05 73 EXAMPLE-327 (S)-8-Methyl-2-((R)-3- methylmorpholin-4-yl)- 9-(2-oxopropyl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = Me; R3 = CF3 (S) 06 47 EXAMPLE-328 (S)-3-Fluoro-9-(2- fluoro-3-methylbutyl)- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the 2-fluoro- 3-methylbutyl chain R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 07 68 EXAMPLE-329 (S)-3-Fluoro-9-(2- fluoro-3-methylbutyl)- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one, diastereoisomer 2 of undetermined absolute configuration on the asymmetric carbon of the 2-fluoro- 3-methylbutyl chain R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 08 63 EXAMPLE-330 (S)-2-((R)-3-Methyl- morpholin-4-yl)-9-[2- (1-oxa-6-aza- spiro[3.3]hept-6-yl)-2- oxoethyl]-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = H; p = 0; q = 2; R2 = H; R3 = CF3 (S) 09 28 EXAMPLE-331 (S)-9-(2-Cyclopropyl- 2-fluoroethyl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one, diastereoisomer 1 of undetermined absolute configuration on the asymmetric carbon of the 2-cyclo- propyl-2-fluoroethyl chain R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 0 98 EXAMPLE-332 (S)-9-(2-Cyclopropyl- 2-fluoroethyl)-3-fluoro- 2-((R)-3-methyl- morpholin-4-yl)-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one, diastereoisomer 2 of undetermined absolute configuration on the asymmetric carbon of the 2-cyclo- propyl-2-fluoroethyl chain R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 96 EXAMPLE-333 (S)-3-Fluoro-2-((R)-3- methylmorpholin-4-yl)- 9-[2-(1-oxa-6-aza- spiro[3.3]hept-6-yl)-2- oxoethyl]-8- trifluoromethyl-6,7,8,9- tetrahydropyrimido- [1,2-a]pyrimidin-4-one R4 = F; p = 0; q = 2; R2 = H; R3 = CF3 (S) 12

(263) TABLE-US-00003 Lengthy table referenced here US11739100-20230829-T00001 Please refer to the end of the specification for access instructions.

(264) TABLE-US-00004 Lengthy table referenced here US11739100-20230829-T00002 Please refer to the end of the specification for access instructions.

(265) TABLE-US-00005 Lengthy table referenced here US11739100-20230829-T00003 Please refer to the end of the specification for access instructions.

(266) TABLE-US-00006 Lengthy table referenced here US11739100-20230829-T00004 Please refer to the end of the specification for access instructions.

(267) TABLE-US-00007 Lengthy table referenced here US11739100-20230829-T00005 Please refer to the end of the specification for access instructions.

(268) TABLE-US-00008 Lengthy table referenced here US11739100-20230829-T00006 Please refer to the end of the specification for access instructions.

(269) TABLE-US-00009 Lengthy table referenced here US11739100-20230829-T00007 Please refer to the end of the specification for access instructions.

(270) TABLE-US-00010 Lengthy table referenced here US11739100-20230829-T00008 Please refer to the end of the specification for access instructions.

Example 334: Pharmaceutical Composition

(271) Tablets corresponding to the following formula were prepared:

(272) TABLE-US-00011 Product of Example 42 . . . 0.2 g Excipient for a tablet with a final weight of . . . 1 g (details of the excipient: lactose, talc, starch, magnesium stearate).

(273) Example 42 is taken by way of example of a pharmaceutical preparation, it being possible for this preparation to be carried out, if desired, with other products in examples in the present application.

(274) Pharmacological Section:

(275) Experimental Protocols

(276) Study of the Phosphorylation of Phosphatidylinositol (PI) by Vps34 In Vitro

(277) This test is based on the detection of the ADP produced during the phosphorylation of PI by Vps34 in the presence of ATP. The ADP is detected by TR-FRET (Time resolved—Fluorescence Resonance Energy transfer) using the Transcreener kit sold by Cisbio (HTRF® Transcreener® ADP, reference 62ADPPEB).

(278) The molecules are diluted 3-fold in pure dimethyl sulfoxide (DMSO, Sigma Fluka 41647), and then diluted, in a second step, in 10% DMSO in water. 2 μl of molecules are added to 96-well plates (Corning Costar 3694), followed by 8 μl of a PI (Sigma P5766)/recombinant Vps34 (Invitrogen PV5126 or produced by Sanofi) mixture in buffer A: 50 mM Hepes, 5 mM MnCl.sub.2, 0.1% CHAPS, 2 mM TCEP, pH 7.1. The reaction is initiated with 10 μl of a solution of ATP (Sigma A7699) in buffer A and lasts 1 hour at ambient temperature. The concentrations during the reaction are 1% DMSO, 10 μM ATP, 55 μg/ml PI, approximately 3 nM of Vps34 and between 0.51 nM and 10 μM for the molecules. The amount of enzyme is adapted to each batch so as to form approximately 2 μM of ADP during the reaction. In parallel, a range of ADP and of ATP for calibrating the results is prepared according to the indications of the kit. Controls not containing enzyme (negative control) or not containing molecules (positive control) are also prepared in parallel. The reaction is then blocked and visualised with the transcreener kit using 10 μl of each of the two reagents and according to the indications of the kit. The fluorescence emission is detected on a Rubystar instrument at 620 and 665 nm. The signal ratio is calculated by dividing the 665 nm signal by the 620 nm signal and then multiplying by 10 000. The signal ratios are converted into ADP concentration using the calibration range and according to the instructions of the kit. The percentages of inhibition by the molecules are calculated relative to the positive controls according to the formula (1−signal ratio of the molecule/signal ratio of the positive control)×100. The absolute IC50s (inhibitory concentration which gives 50% inhibition) are calculated according to a 4-parameter logistical model. Two independent experiments make it possible to calculate the mean of the IC50s. The IC50 results, in nM, obtained for the products in examples of the present invention are given in the table below.

(279) TABLE-US-00012 Table of pharmacological results obtained by means of the above test IC50 activity range in nM Examples <10 nM 42, 152, 163, 98, 153, 206, 32, 33, 36, 35, 37, 1, 11, 100, 99, 75, 76, 78, 38, 179, 79, 80, 101, 102, 180, 103, 71, 81, 40, 9, 154, 41, 214, 82, 215, 199, 181, 44, 84, 43, 83, 107, 85, 109, 108, 45, 86, 46, 89, 88, 87, 183, 69, 111, 255, 14, 90, 91, 93, 49, 92, 239, 94, 48, 112, 10, 50, 95, 217, 218, 284, 285, 155, 157, 114, 115, 3, 219, 257, 184, 116, 241, 258, 243, 96, 7, 6, 97, 242, 259, 260, 2, 254, 220, 158, 262, 244, 245, 221, 264, 160, 159, 118, 209, 119, 121, 122, 200, 210, 198, 120, 12, 51, 53, 52, 5, 124, 4, 224, 127, 126, 196, 128, 225, 15, 54, 16, 211, 17, 129, 204, 226, 212, 213, 18, 201, 202, 203, 19, 246, 247, 20, 248, 249, 250, 130, 251, 55, 21, 56, 131, 132, 57, 58, 227, 228, 252, 134, 135, 133, 22, 287, 286, 23, 229, 24, 59, 186, 185, 266, 267, 230, 253, 25, 189, 60, 187, 141, 231, 288, 289, 136, 137, 61, 62, 138, 139, 140, 31, 30, 232, 63, 233, 70, 65, 66, 142, 67, 26, 27, 190, 143, 28, 237, 276, 68, 144, 290, 29, 8, 146, 279, 280, 149, 147, 281, 282, 291, 283, 240, 205, 207, 294, 292, 295, 39, 293, 296, 297, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 313, 314, 315, 317, 318, 319, 323, 324, 325, 326, 327, 328, 329, 331, 332, 333 10-100 nM 191, 192, 161, 162, 177, 151, 178, 167, 166, 165, 164, 168, 169, 34, 150, 170, 171, 77, 174, 72, 73, 74, 106, 105, 110, 182, 47, 13, 216, 256, 156, 113, 104, 261, 117, 236, 123, 223, 222, 125, 265, 197, 188, 269, 270, 271, 273, 274, 275, 145, 234, 235, 148, 208, 298, 312, 316, 320, 321, 322, 330 >100 nM 193, 194, 195, 176, 172, 173, 175, 263, 268, 64, 272, 277, 278, 238

(280) TABLE-US-LTS-00001 LENGTHY TABLES The patent contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).