Novel 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.mRa; alkylene; cycloalkyl; heterocycloalkyl; alkyl; SO.sub.2Rb; CORe; m=1 or 2; Ra=aryl, heteroaryl, CO-cycloalkyl, CO-heterocycloalkyl, CORb, C(Rb)NORc, 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): ##STR00071## in which: p and q are the integers 0 or 1 or 2 such that, if p=0, then q=1 or 2 and, if p=1 or 2, then q=0; R1 is a (CH.sub.2).sub.mRa radical with m being the integer 1 and Ra an optionally substituted 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; or else R2 and R3 form, together with the carbon atom to which they are bonded, a cyclic radical containing from 3 to 6 ring members and optionally one or more other heteroatoms chosen from O, S and NRz, this cyclic radical being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and oxo, Rz, ORz and NRzRz radicals; with Rz and Rz, which may be identical or different, being a hydrogen atom or an alkyl, cycloalkyl or heterocycloalkyl radical; R4 is a hydrogen atom, a fluorine or chlorine atom, a methyl radical or a CN radical; 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, either at least one of R5 to R12 is not a hydrogen atom, or this morpholine residue contains a bridge defined as follows: R7 or R8 can form an ethylene bridge with R9 or R10, or else R7 or R8 can form a methylene bridge of absolute configuration R,R with R11 or R12, or else R5 or R6 can form a methylene bridge of absolute configuration R,R with R9 or R10 so as to give the following radicals: ##STR00072## and the isomer of configuration R,R ##STR00073## the aryl and heteroaryl radicals that Ra, Rb and Re may represent, and also the alkyl radicals that Rb and Re may represent, being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cycloalkyl, heterocycloalkyl, heteroaryl and alkoxy radicals, the latter heteroaryl and alkoxy radicals being themselves optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and hydroxyl, alkyl and alkoxy radicals; 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 cycloalkyl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from a fluorine atom and alkyl radicals themselves optionally substituted with one or more fluorine atoms; all the heterocycloalkyl radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from a fluorine atom and alkyl radicals themselves optionally substituted with one or more fluorine atoms; all the heterocycloalkyl radicals being, in addition, optionally substituted with a CO.sub.2alk radical, where appropriate on a nitrogen atom; all the alkyl (alk), 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; it being understood that, when p=0 and one of R2 and R3 is an alkyl radical and the other an alkyl radical substituted with one or more fluorine atoms, then R1 is not a phenyl or pyridyl radical as defined in a) above, 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: ##STR00074## 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, in which p is the integer 0 and q is the integer 2 or else p is the integer 2 and q is the integer 0; the radicals R1, R2, R3 and R4 and the morpholine residue 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).

4. The compound of formula (I) as defined in claim 1, in which p is the integer 0 and q is the integer 1 or else p is the integer 1 and q is the integer 0; the radicals R1, R2, R3 and R4 and the morpholine residue 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).

5. 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 (R)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-2-ylmethyl-6-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 (R)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-6-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 (R)-2-((R)-3-Methylmorpholin-4-yl)-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-9-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-6-Fluoro-2-methyl-7-((R)-3-methylmorpholin-4-yl)-1-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-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 (R)-9-Isoxazol-5-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-9-Isoxazol-3-ylmethyl-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-4-ylmethyl-6-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 (R)-9-(2-Chloropyridin-4-ylmethyl)-2-((R)-3-methylmorpholin-4-yl)-6-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (R)-2-((R)-3-Methylmorpholin-4-yl)-9-oxazol-5-ylmethyl-6-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 (R)-3-Fluoro-2-((R)-3-methylmorpholin-4-yl)-9-oxazol-2-ylmethyl-6-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)-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)-2-((R)-3-Methylmorpholin-4-yl)-6-trifluoromethyl-9-(3-trifluoromethyl-[1,2,4]oxadiazol-5-ylmethyl)-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 (R)-3-Fluoro-2-((R)-3-Methylmorpholin-4-yl)-9-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-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-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Isoxazol-5-ylmethyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(2-Chlorothiazol-5-ylmethyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (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-tetrahydropyrimido[1,2-a]pyrimidin-4-one (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-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-(6-Chloropyridin-3-ylmethyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Isoxazol-3-ylmethyl-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-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)-1-(2-Chloropyridin-4-ylmethyl)-2-methyl-7-((R)-3-methylmorpholin-4-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (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 (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 (S)-1-(2-Chloropyridin-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 (S)-9-Benzyl-2-(2-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-Benzyl-2-(2-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-Benzyl-2-(2-fluoromethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-9-Benzyl-2-(2-fluoromethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-Benzyl-2-(2-fluoromethylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (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)-6-Fluoro-2-methyl-7-((R)-3-methylmorpholin-4-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one (S)-2-Methyl-7-((R)-3-methylmorpholin-4-yl)-1-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-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-Hydroxy-2-pyridin-2-ylethyl)-2-((R)-3-methylmorpholin-4-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, single stereoisomer (S)-9-(2-Hydroxy-2-pyridin-2-ylethyl)-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)-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-yl)-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)-2-((R)-3-Methylmorpholin-4-yl)-9-(2-oxo-2-piperidin-1-ylethyl)-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)-2-Methyl-7-((R)-3-methylmorpholin-4-yl)-1-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-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-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)-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)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (S)-3-Fluoro-9-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-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).

6. Process for preparing the compound of formula (I) as defined in claim 1, according to scheme 2 as defined hereinafter: ##STR00075## in which the substituents n, p, q, PG, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and alkyl have the meanings indicated for the compound of formula (I) in claim 1.

7. Pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 1, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

8. Pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 5, and also the pharmaceutically acceptable addition salts with inorganic and organic acids or with inorganic and organic bases of said products of formula (I).

9. Pharmaceutical compositions containing, as active ingredient, at least one of the products of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt of this product or a prodrug of this product and a pharmaceutically acceptable carrier.

10. Method of treatment or prevention of a disease chosen from the following group: blood vessel proliferation disorders, fibrotic disorders, mesangial cell proliferation disorders, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers, comprising administering to a patient a compound of formula (I) as defined in claim 1.

11. Method of treatment of cancers comprising administering to a patient a compound of formula (I) as defined in claim 1.

12. Method of treatment of solid or liquid tumours, comprising administering to a patient a compound of formula (I) as defined in claim 1.

13. Method of treatment of cancers resistant to cytotoxic agents, comprising administering to a patient a compound of formula (I) as defined in claim 1.

14. Method of treatment of primary tumours and/or of metastases, in particular in gastric, hepatic, renal, ovarian, colon, prostate and lung (NSCLC and SCLC) cancers, glioblastomas, thyroid, bladder and breast cancers, in melanoma, in lymphoid or myeloid haematopoietic tumours, in sarcomas, in brain, larynx and lymphatic system cancers, bone and pancreatic cancers, and in hamartomas, comprising administering to a patient a compound of formula (I) as defined in claim 1.

15. Method of treatment of lysosomal diseases such as glycogenosis type II (or Pompe's disease) or Danon disease, comprising administering to a patient a compound of formula (I) as defined in claim 1.

16. Method of treatment of X-linked myotubular myopathies and Charcot-Marie-Tooth disease, comprising administering to a patient a compound of formula (I) as defined in claim 1.

17. As novel industrial products, the starting products or synthesis intermediates as defined in claim 6 as follows: of formulae A, B, G and N: ##STR00076## in which n=1, one of R2 and R3 is alkyl and the other is alkyl substituted with one or more fluorine atoms, and PG is a protective group for amine; of formulae E, F, I and J: ##STR00077## in which q=0, one of R2 and R3 is alkyl and the other is alkyl substituted with one or more fluorine atoms, and the substituents p, PG, R1 and R4 have the definitions indicated in claim 6; of formulae P and H: ##STR00078## in which the substituents n, p, q, PG, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 have the definitions indicated in claim 6; of formula Q: ##STR00079## in which either q=0, one of R2 and R3 is alkyl and the other is alkyl substituted with one or more fluorine atoms, and the substituents p, PG, R1 and R4 have the definitions indicated in claim 6, or R1 is (CH.sub.2).sub.mRa with Ra being CO-cycloalkyl, CO-heterocycloalkyl, CORb, C(Rb)NORc, CO.sub.2Rd or CONRxRy, and the substituents p, q, R2, R3 and R4 have the definitions indicated in claim 6.

Description

EXAMPLE 334

Pharmaceutical Composition

[1095] Tablets corresponding to the following formula were prepared:

TABLE-US-00010 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).

[1096] 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.

[1097] Pharmacological Section:

[1098] Experimental Protocols

[1099] Study of the Phosphorylation of Phosphatidylinositol (PI) by Vps34 In Vitro

[1100] 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 resolvedFluorescence Resonance Energy transfer) using the Transcreener kit sold by Cisbio (HTRF Transcreener ADP, reference 62ADPPEB).

[1101] 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 l of molecules are added to 96-well plates (Corning Costar 3694), followed by 8 l 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 l 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 M ATP, 55 g/ml PI, approximately 3 nM of Vps34 and between 0.51 nM and 10 M for the molecules. The amount of enzyme is adapted to each batch so as to form approximately 2 M 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 l 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 (1signal 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.

TABLE-US-00011 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

TABLE-US-LTS-00001 LENGTHY TABLES The patent application 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).