2-(cyclic amino)-pyrimidone derivatives

1. A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutically acceptable salt thereof:

wherein each symbol is defined as below:

R 4 represents a group represented by the following formula (II):

A 14 -A 13 -A 12-   (II)

wherein

A 14 represents hydrogen atom, a C 1 -C 6 alkyl group which may be substituted, a C 2 -C 6 alkenyl group which may be substituted, a C 2 -C 6 alkynyl group which may be substituted, a C 3 -C 7 cycloalkyl group which may be substituted, a C 3 -C 7 cycloalkenyl group which may be substituted, or a heterocyclic group which may be substituted;

A 13 represents bond, or oxygen atom;

A 12 represents bond, or a C 1 -C 3 methylene group, and A 14 and A 13 may combine to each other to form a 5 to 7 membered heterocyclic ring;

X represents oxygen atom;

R 5 represents a hydrogen atom, a C 1 -C 6 alkyl group which may be substituted, or a group represented by the following formula (IV):

wherein n represents 0 or integer of 1 to 3,

A represents a C 6 -C 10 aryl group,

R 7 may be the same or different and represents a halogen atom, or a group represented by the following formula (IV-a):

C 4 —C 3 —C 2 —C 1 —  (IV-a)

wherein C 4 represents hydrogen atom (except when all of C 3 , C 2 , and C 1 represent bond), a C 1 -C 6 alkyl group which may be substituted, a C 6 -C 10 aryl group which may be substituted, a heterocyclic group which may be substituted,

C 3 represents bond, or oxygen atom,

C 2 represents bond, or C═O,

C 1 represents bond;

s represents 0 or an integer of 1 to 5,

R 6 may be the same or different and represents a halogen atom, nitro group, cyano group, or a group represented by the following formula (V):

B 14 —B 13 —B 12 —B 11 —  (V)

wherein B 14 represents hydrogen atom(except when all of B 13 , B 12 , and B 11 represent bond), a C 1 -C 6 alkyl group which may be substituted, a heterocyclic group which may be substituted,

B 13 represents bond,

B 12 represents bond,

B 11 represents bond;

p represents an integer of 0 to 6;

Z represents nitrogen atom, C—H or C—R 20 ;

R 20 may be the same or different and represents a halogen atom, or a group represented by the following formula (VI):

D 4 -D 3 -D 2 -D 1 -  (VI)

wherein D 4 represents a C 1 -C 6 alkyl group which may be substituted,

D 3 represents bond, or oxygen atom,

D 2 represents bond,

D 1 represents bond,

q represents 0 or an integer of 1 to 3;

R 2 represents hydrogen atom, a halogen atom or a C 1 -C 6 alkyl group which may be ubstituted;

R 3 represents a C 1 -C 12 alkyl group;

any one or more of R 5 and R 6 , R 5 and R 4 , R 6 and R 4 , and R 6 and R 6 may combine to each other to form a fused, carbocyclic or heterocyclic ring, together with the ring which contains X, and R 5 , R 4 and R 6 bind to;

and each symbol satisfies the following proviso (1):

(1) when R 4 is a hydrogen atom, at least one of R 5 and R 6 , and R 6 and R 6 combine to each other to form a fused carbocyclic or heterocyclic ring, together with the ring which contains X, and R 5 , R 4 and R 6 bind to.

2. The compound, an optically active isomer thereof, or a pharmaceutical acceptable salt thereof according to claim 1 , wherein the formula (VI), (V), and (IV-a) each independently represents a group represented by the following formula (IIa):

-Q 20a -R 20b   (IIa)

R 20b represents hydrogen atom(except when Q 20a represents bond), a C 1 -C 12 alkyl group, a C 6 -C 10 aryl-C 1 -C 12 alkyl group, and each of said groups may be substituted with a halogen atom, cyano group, nitro group, hydroxyl group, a C 1 -C 12 alkyloxy, a C 6 -C 10 aryloxy, amino group, a C 1 -C 12 alkylamino group, a C 3 -C 12 cycloalkylamino group, a di(C 1 -C 12 alkyl) amino group, or a heterocyclic group;

Q 20a represents bond, or oxygen atom;

X is oxygen atom;

n in the formula (IV) is 0 or 1;

A in the formula (IV) is phenyl group, naphthyl group, a heteroaryl group; and

when any one or more of R 5 and R 6 , R 5 and R 4 , R 6 and R 4 , and R 6 and R 6 combine to each other to form a fused, carbocyclic or heterocyclic ring, together with the ring which contains X, and R 5 , R 4 and R 6 bind to, the one or more of R 5 and R 6 , R 5 and R 4 , R 6 and R 4 , and R 6 and R 6 are a part of an optionally substituted 5 to 7 membered ring optionally containing 1 or 2 hetero atoms selected from the group consisting of nitrogen atoms oxygen atoms and sulfur atoms, and said 5 to 7 membered ring may be substituted and/or be condensed with a C 6 -C 10 aryl group which may be substituted or a heterocyclic group which may be substituted.

3. The compound, an optically active isomer thereof, or a pharmaceutical acceptable salt thereof according to claim 1 , wherein R 3 is methyl group.

4. A compound selected from the group consisting of:

2-((3S)-3-Benzyl-morpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-((4aRS,10bRS)-trans-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-((4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho [1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-((4aRS,10bRS)-trans-3,4,4a,5,6,10b-Hexahydro-2H-naphtho[1,2-b][1,4]oxazin-4-yl) -3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one;

2-(8-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(8-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(8-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-(7-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(7-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(7-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-(9-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(9-methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one,

2-(9-Methoxy-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-((4aRS,10bSR)-cis-2,3,4a,5,6,10b-Hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,10bRS)-trans-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(8-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(6-methoxy-(4aRS,10aRS)-trans-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3-methyl-3H-pyrimidin-4-one;

2-(9-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(9-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(9-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-(7-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-2-(7-methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(7-Methoxy-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

3-Methyl-6-pyridin-4-yl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3H-pyrimidin-4-one;

1-Methyl-2-((4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-1H-[4,4′]bipyrimidinyl-6-one;

6-(3-Fluoro-pyridin-4-yl)-2-(6-methoxy-(4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-3-methyl-3H-pyrimidin-4-one;

2-(6-Methoxy-(4aRS,10aRS)-cis-2,3,10,10a-tetrahydro-4aH-4,9-dioxa-1-aza-phenanthren-1-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(9-Fluoro-(4aRS,10bRS)-trans-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one;

2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-(9-Fluoro-(4aRS,10bSR)-cis-2,3,4a,5,6,10b-hexahydro-naphtho[1,2-b][1,4]oxazin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

3-Methyl-2-((3R)-3-methyl-morpholin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((3R)-3-methyl-morpholin-4-yl)-3H-pyrimidin-4-one;

1-Methyl-2-((3R)-3-methyl-morpholin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one;

6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((3S)-3-methyl-morpholin-4-yl)-3H-pyrimidin-4-one;

3-Methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-6-pyridin-4-yl-3H-pyrimidin-4-one;

6-(3-Fluoro-pyridin-4-yl)-3-methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-3H-pyrimidin-4-one;

1-Methyl-2-((4aRS,8aRS)-trans-octahydro-benzo[1,4]oxazin-4-yl)-1H-[4,4′]bipyrimidinyl-6-one;

2-((3R)-3-Ethyl-morpholin-4-yl)-6-(3-fluoro-pyridin-4-yl)-3-methyl-3H-pyrimidin-4-one;

2-((3R)-3-Ethyl-morpholin-4-yl)-1-methyl-1H-[4,4′]bipyrimidinyl-6-one;

6-(3-Fluoro-pyridin-4-yl)-2-((3R)-3-isopropyl-morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one; and

6-(3-Fluoro-pyridin-4-yl)-2-((3R)-3-isobutyl-morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one; and an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

5. A medicament composition comprising as an active ingredient a substance selected from the compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

6. A tau protein kinase 1 inhibitor composition comprising as an active ingredient a substance selected from the compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 .

7. A medicament composition comprising as an active ingredient the compound according to claim 4 , an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.

8. A tau protein kinase 1 inhibitor composition comprising as an active ingredient the compound according to claim 4 , an optically active isomer thereof, or a pharmaceutically acceptable salt thereof.