Heteroaryl substituted 2-pyridinyl and 2-pyrimidinyl -6,7,8,9-tetrahydropyrimido[1,2-
View Patent ↗The invention relates to use of a pyrimidone derivative represented by formula (I)or a salt thereof wherein: X, Y, R1, R2, R3, R4, R5, m, n and p are as defined herein. In particular, the invention relates to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β or GSK3β and cdk5/p25, such as Alzheimer disease.
1. A method of inhibiting the activity of glycogen synthase kinase 3-beta (GSK3-β), which comprises administering to a patient in need of said inhibition a therapeuticcally effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom;
Y represents a bond, an ethenylene group, an ethynylene group or a methylene group optionally substituted by one or two groups chosen from a C 1-6 alkyl group, a hydroxy group or a C 1-4 a hydroxy group;
R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a C 3-6 cycloalkyl group, a C 1-4 alkyl group, a C 1-4 alkoxy group, a benzyl group or a halogen atom;
R2 represents a heterocyclic ring having 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5-9 carbon atoms, of formula
wherein A, B, C and D represent, each independently, a carbon atom or a nitrogen atom and W represent a saturated or unsaturated 5, 6 or 7 membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0 heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom; the R2 group being optionally substituted on a carbon atom or, when possible, on a nitrogen atom by one or two atoms or groups chosen from a halogen atom, a C 1-6 alkyl group, a hydroxy group, a C 1-4 alkoxy group, a benzene ring, a pyridine ring or a —NR6R7 group;
R3 represents a hydrogen atom, a C 1-6 alkyl group, a hydroxy group, a C 1-4 alkoxy group or a halogen atom;
R4 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-4 alkoxy group or a halogen atom;
R5 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group or a halogen atom;
R6 and R7 represent, each independently, a hydrogen atom, a C 1-6 alkyl group, a benzyl group, a benzene ring or R6 and R7 represent together with the nitrogen atom, a pyrrolidine ring, a piperidine ring, a hexamethyleneimine ring, a morpholine ring or a piperazine ring, the ring being optionally substituted by one or two C 1-6 alkyl group;
when m equals 0, p equals 1, 2 or 3,
when m equals 1, p equals 0, 1 or 2,
when m equals 2, p equals 0 or 1;
when m equals 3, p equals 0; and
n represents 0 to 3;
with the proviso that the compound of formula (I) is not:
9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;
9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;
1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin -5(1H)-one, or
1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin -5(1H)-one.
2. The method according to claim 1 , wherein R1 represents an unsubstituted pyridinyl group or an unsubstituted 4-pyrimidine ring.
3. The method according to claim 1 , wherein the compound is selected from the group consisting of:
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(+)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(−)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl) -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
9-(furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
9-(benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one;
(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;
(±)7,7-dimethyl-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;
(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyrrolidin-1-yl)-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)7,7-difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one; and
9-((+)-(6-R)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-(±)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;
or a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd 1 eptable salt thereof.
4. The method according to claim 1 , wherein the compound is selected from the group consisting of:
9-chroman-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin -4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin -4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaceutically acceptable salt thereof.
5. The method according to claim 1 , wherein the compound is selected from the group consisting of:
9-(6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one
(±)7,7-dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one
(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(chroman-3-y 1 methyl)-7,7-dimethy 1 -2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(−)-(S)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2-furo[2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-benzofuran-2-ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd 1 eptable salt thereof.
6. The method according to claim 1 , wherein the compound is selected from the group consisting of:
9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(8-methoxy-2,3-dihydro-benzo [1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-diliydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyriniido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or
9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaceutically acceptable salt thereof.
7. A method of inhibiting the activity of cdk5/p25 enzyme, which comprises administering to a patient in need of said inhibition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2 alkyl group and a hydrogen atom;
Y represents a bond, an ethenylene group, an ethynylene group or a methylene group optionally substituted by one or two groups chosen from a C 1-6 alkyl group, a hydroxy group or a C 1-4 alkoxy group;
R1 represents a 2,3 or 4-pyridine ring or a 2,4 or 5-pyrimidine ring, the ring being optionally substituted by a C 3-6 cycloalkyl group, a C 1-4 alkyl group, a C 1-4 alkoxy group, a benzyl group or a halogen atom;
R 2 represents a heterocyclic bicyclic ring having 1-4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and having 5-9 carbon atoms, of formula
wherein A, B, C and D represent, each independently, a carbon atom or a nitrogen atom and W represent a saturated or unsaturated 5,6 or 7 membered cyclic ring having from 3 to 7 carbon atoms and 2 to 0 heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom; the R2 group being optionally substituted on a carbon atom or, when possible, on a nitrogen atom by one or two atoms or groups chosen from a halogen atom, a C 1-6 alkyl group, a hydroxy group, a C 1-4 alkoxy group, a benzene ring, a pyridine ring or a —NR6R7 group;
R3 represents a hydrogen atom, a C 1-6 alkyl group, a hydroxy group, a C 1-4 alkoxy group or a halogen atom;
R4 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-4 alkoxy group or a halogen atom;
R5 represents a hydrogen atom, a C 1-6 alkyl group, a C 1-2 perhalogenated alkyl group, a C 1-3 halogenated alkyl group or a halogen atom;
R6 and R7 represent, each independently, a hydrogen atom, a C 1-6 alkyl group, a benzyl group, a beuzene ring or R6 and R7 represent together with the nitrogen atom, a pyrrolidine ring, a piperidine ring, a hexamethyleneimine ring, a morpholine ring or a piperazine ring, the ring being optionally substituted by one or two C 1-6 alkyl group;
when m equals 0, p equals 1, 2 or 3,
when m equals 1, p equals 0, 1 or 2,
when m equals 2, p equals 0 or 1;
when m equals 3, p equals 0; and
n represents 0 to 3;
with the proviso that the compound of formula (I)is not:
9-[2-(1H-indol-3-yl)ethyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;
9-[3-(1H-indol-3-yl)propyl]-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-α]pyrimidin-4-one;
1-[2-(1H-Indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin -5(1H)-one, or
1-[3-(1H-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-α]pyrimidin -5(1H)-one.
8. The method according to claim 7 , wherein R1 represents an unsubstituted pyridinyl group or an unsubstituted 4-pyrimidine ring.
9. The method according to claim 7 , wherein the compound is selected from the group consisting of:
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(+)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one;
(−)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]-pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl) -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
9-(furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
9-(benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one;
(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyridin-4-yl)-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;
(±)7,7-dimethyl-9-(2-phenyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one;
(±)7,7-dimethyl-2-(pyridin-4-yl)-9-[2-(pyrrolidin-1-yl)-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl]-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one;
(±)7,7-difluoro-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidine-4-one; and
9-((+)-(6-R)-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-(±)-7-methyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidine-4-one;
or a pharmaC hd 1 eutiC hd 1 ally aC hd 1 C hd 1 eptable salt thereof.
10. The method according to claim 7 , wherein the compound is selected from the group consisting of:
9-chroman-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin -4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyridin -4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8,8-dimethyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyridin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaceutically acceptable salt thereof.
11. The method according to claim 7 , wherein the compound is selected from the group consisting of:
9-(6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)7,7-dimethyl-2-(pyrimidin-4-yl)-9-(2-phenyl-6,7-dihydro-5H -[1]pyrindin-6-ylmethyl)-6,7,8,9-tetrahydro-pyrimido[1,2-]pyrimidine-4-one
(±)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(chroman-3-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(−)-(S)-9-(2,3-dihydro-benzofuran-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)9-(2,3-dihydro-benzo [1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin -4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(±)-9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(−)-(6S)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
(+)-(6R)-9-(6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2-furo [2,3-b]pyridin-3-yl-ethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one
9-benzofuran-2- ylmethyl-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
(±)-7,7-dimethyl-9-(2-methyl-6,7-dihydro-5H-[1]pyrindin-6ylmethyl)-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaceutically acceptable salt thereof.
12. The method according to claim 7 , wherein the compound is selected from the group consisting of:
9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-fluoro-8-methoxy-chroman-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-chroman-2-ylmethyl-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(5-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido [1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(R)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8,8-dimethyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
9-furo[3,2-b]pyridin-2-ylmethyl-8-methyl-2-pyrimidin-4-yl-6,7,8,9-tetrahydro -pyrimido[1,2-α]pyrimidin-4-one
9-(6,7-dihydro-5H-[1]pyrindin-6-(S)-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one or
9-(6,7-dihydro-5H-[2]pyrindin-6-ylmethyl)-8-methyl-2-pyrimidin-4-yl -6,7,8,9-tetrahydro-pyrimido[1,2-α]pyrimidin-4-one
or a pharmaceutically acceptable salt thereof.