# US 8,569,294 B2 · 2-(cyclic amino)-pyrimidone derivatives

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- Number: US 8,569,294 B2
- Document ID: US8569294B2
- Status: Granted
- Kind: B2
- Application number: 12/282,396
- Filed: 2007-03-14
- Published: 2009-09-17
- Granted: 2013-10-29
- Earliest claimed: 2006-03-15
- Assignees: Mitsubishi Tanabe Pharma Corporation; Sanofi
- Applicants: Kenji Fukunaga; Toshiyuki Kohara; Kazutoshi Watanabe; Yoshihiro Usui; Fumiaki Uehara; Satoshi Yokoshima; Daiki Sakai; Shin-ichi Kusaka; Kazuki Nakayama
- Inventors: Kenji Fukunaga; Toshiyuki Kohara; Kazutoshi Watanabe; Yoshihiro Usui; Fumiaki Uehara; Satoshi Yokoshima; Daiki Sakai; Shin-ichi Kusaka; Kazuki Nakayama
- Web page: https://patentgrep.com/patent/US8569294B2

## CPC

- C07D 413/14: containing three or more hetero rings
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/14: for baldness or alopecia
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 453/06: containing isoquinuclidine ring systems
- C07D 493/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof: wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).

## Claims

### Claim 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:
R4 represents a group represented by the following formula (II):
A14-A13-A12- (II)
wherein
A14 represents hydrogen atom, a C1-C6 alkyl group which may be substituted, a C2-C6 alkenyl group which may be substituted, a C2-C6 alkynyl group which may be substituted, a C3-C7 cycloalkyl group which may be substituted, a C3-C7 cycloalkenyl group which may be substituted, or a heterocyclic group which may be substituted;
A13 represents bond, or oxygen atom;
A12 represents bond, or a C1-C3 methylene group, and A14 and A13 may combine to each other to form a 5 to 7 membered heterocyclic ring;
X represents oxygen atom;
R5 represents a hydrogen atom, a C1-C6 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 C6-C10 aryl group,
R7 may be the same or different and represents a halogen atom, or a group represented by the following formula (IV-a):
C4—C3—C2—C1— (IV-a)
wherein C4 represents hydrogen atom (except when all of C3, C2, and C1 represent bond), a C1-C6 alkyl group which may be substituted, a C6-C10 aryl group which may be substituted, a heterocyclic group which may be substituted,
C3 represents bond, or oxygen atom,
C2 represents bond, or C═O,
C1 represents bond;
s represents 0 or an integer of 1 to 5,
R6 may be the same or different and represents a halogen atom, nitro group, cyano group, or a group represented by the following formula (V):
B14—B13—B12—B11— (V)
wherein B14 represents hydrogen atom(except when all of B13, B12, and B11 represent bond), a C1-C6 alkyl group which may be substituted, a heterocyclic group which may be substituted,
B13 represents bond,
B12 represents bond,
B11 represents bond;
p represents an integer of 0 to 6;
Z represents nitrogen atom, C—H or C—R20;
R20 may be the same or different and represents a halogen atom, or a group represented by the following formula (VI):
D4-D3-D2-D1- (VI)
wherein D4 represents a C1-C6 alkyl group which may be substituted,
D3 represents bond, or oxygen atom,
D2 represents bond,
D1 represents bond,
q represents 0 or an integer of 1 to 3;
R2 represents hydrogen atom, a halogen atom or a C1-C6 alkyl group which may be ubstituted;
R3 represents a C1-C12 alkyl group;
any one or more of R5 and R6, R5 and R4, R6 and R4, and R6 and R6 may combine to each other to form a fused, carbocyclic or heterocyclic ring, together with the ring which contains X, and R5, R4 and R6 bind to;
and each symbol satisfies the following proviso (1):
(1) when R4 is a hydrogen atom, at least one of R5 and R6, and R6 and R6 combine to each other to form a fused carbocyclic or heterocyclic ring, together with the ring which contains X, and R5, R4 and R6 bind to.

### Claim 2 (depends on 1)

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):
-Q20a-R20b (IIa)
R20b represents hydrogen atom(except when Q20a represents bond), a C1-C12 alkyl group, a C6-C10 aryl-C1-C12 alkyl group, and each of said groups may be substituted with a halogen atom, cyano group, nitro group, hydroxyl group, a C1-C12 alkyloxy, a C6-C10 aryloxy, amino group, a C1-C12 alkylamino group, a C3-C12 cycloalkylamino group, a di(C1-C12 alkyl) amino group, or a heterocyclic group;
Q20a 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 R5 and R6, R5 and R4, R6 and R4, and R6 and R6 combine to each other to form a fused, carbocyclic or heterocyclic ring, together with the ring which contains X, and R5, R4 and R6 bind to, the one or more of R5 and R6, R5 and R4, R6 and R4, and R6 and R6 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 C6-C10 aryl group which may be substituted or a heterocyclic group which may be substituted.

### Claim 3 (depends on 1)

The compound, an optically active isomer thereof, or a pharmaceutical acceptable salt thereof according to claim 1, wherein R3 is methyl group.

### Claim 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.

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 4)

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.

### Claim 8 (depends on 4)

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.