JP2011088847A - Tricyclic compound and application thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel compound that has a lipoprotein-related phospholipase A2-inhibiting action and is useful for prevention and treatment of atherosclerosis, coronary syndromes such as myocardial infarction, unstable angina and the like, peripheral arterial obstruction, stroke, cerebral infarction and the like, and a medicine containing the compound. <P>SOLUTION: The compound is represented by formula (I). In the formula, R<SP>1</SP>is an optionally substituted 5 to 10-membered aromatic group; R<SP>2</SP>is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted 1-6C alkoxy group or the like; R<SP>3</SP>is a hydrogen atom or a halogen atom; X<SP>1</SP>is an optionally substituted 1-2C alkylene group; X<SP>2</SP>is an oxygen atom, a sulfur atom or optionally substituted methylene; and Y is an optionally substituted 1-3C alkylene group. A salt of the compound is also provided. The medicine contains the compound. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to a novel tricyclic compound having excellent properties as a pharmaceutical, its production method and use. Specifically, the present invention has a lipoprotein-related phospholipase A ₂ inhibitory action, and prevents coronary syndromes such as atherosclerosis, myocardial infarction, unstable angina, peripheral arterial occlusion, stroke, cerebral infarction, etc. -It relates to a tricyclic compound useful as a therapeutic agent, or a salt thereof, or a prodrug thereof, and a production method and use thereof.

(Background of the Invention)
Lipoprotein-related phospholipase A ₂ (Lp-PLA ₂ ) is known to hydrolyze the sn-2 position of oxidatively modified phosphatidylcholine to produce lysophosphatidylcholine and oxidized fatty acid. These hydrolysates produced by Lp-PLA ₂ function as inflammation-inducing / promoting factors and promote arteriosclerosis by promoting infiltration of circulating monocytes into the intima, damage of vascular endothelial cells, etc. Onset / progress.

In addition, it is known that Lp-PLA ₂ expression increases in blood and atherosclerotic lesions in patients with coronary artery disease (Non-patent Document 3).

Furthermore, an anti-arteriosclerotic effect by a specific inhibitor of Lp-PLA ₂ has been reported in pigs (Non-patent Document 4) and humans (Non-patent Documents 5 and 6).

Therefore, inhibition of Lp-PLA ₂ is considered useful for the treatment of arteriosclerosis.

  In Patent Document 1, there is a formula

Wherein each of R ¹ and R ² independently represents a C _1-6 alkyl or C _2-7 acyl group; X represents an OCH ₂ or group CR ³ R ⁴ where R ³ and R ⁴ Each independently represents a hydrogen atom or a C _1-3 alkyl group); R ⁵ represents a hydrogen atom or a C _1-3 alkyl, C _2-3 alkenyl or C _2-3 alkynyl group; R ⁶ represents a hydrogen atom Or represents a C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, amino, C _1-6 alkylamino, di (C _1-6 ) alkylamino or C _2-7 acylamino group; R ⁷ and Each R ⁸ is independently a hydrogen or halogen atom or hydroxy, trifluoromethyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _2-7 acyl, C _1-6 alkylthio, C _{1 -6} represents an alkoxy or C _3-6 cycloalkyl group; R ⁹ represents a hydrogen or halogen atom or hydroxy, trifluoromethyl, C _1-6 alkyl, C _2-6 Alkenyl, C _2-6 alkynyl, C _2-7 acyl, C _1-6 alkylthio, C _1-6 alkoxy or C _3-6 cycloalkyl group) or a salt thereof is PDE (phosphodiesterase) Examples are disclosed as inhibitors and the examples include formulas
Or a salt thereof (hereinafter abbreviated as Compound A).
Patent Document 2 includes a formula

Is disclosed as having a life-prolonging action on eukaryotes and a cytoprotective action against apoptosis and stress.
Non-Patent Document 1 includes a formula

(Wherein R represents H, O (CH ₂ ) ₃ CH ₃ , OC ₆ H ₅ , SCH ₃ · HI, Cl, NHCH ₃ · HCl · H ₂ O, etc.) It is disclosed as a medicine.

In Patent Documents 3 to 5 and Non-Patent Document 2, Compound A is disclosed as a PDE inhibitor. However, any compound is distinguished from the present compound and there is no description that it has an Lp-PLA ₂ inhibitory action.

So far, compounds having Lp-PLA ₂ inhibitory action have been disclosed in, for example, Patent Documents 6 to 7, Non-Patent Documents 3 to 9 and the like.

International Publication No. 00/58309 Pamphlet US Patent Application Publication No. 2009/0163545 International Publication No. 2009/011893 Pamphlet International Publication No. 2009/011897 Pamphlet International Publication No. 03/105902 Pamphlet International Publication No. 01/60805 Pamphlet International Publication No. 02/30904 Pamphlet

Journal of Medicinal Chemistry, 1984, 27 (11), p.1470-1480 Journal of Pharmacology and Experimental Therapeutics, 2006, 318 (2), p.840-848 Arteriosclerosis Thrombosis Vascular Biology, 2005, 25, p.923-931 Nature Medicine, 2008, 14 (10), p.1059-1166 Circulation, 2008, 118 (11), p.1172-1182 Journal of the American Colledge of Cardiology, 2008 (51), p.1632-1641 Bioorganic & Medicinal Chemistry Letters, 2002, 12 (18), p.2603-2606 Bioorganic & Medicinal Chemistry Letters, 2003, 13 (6), p.1067-1070 Bichemical Journal, 1999, 338, p.479-487

  It is useful for prevention and treatment of coronary syndromes such as atherosclerosis, myocardial infarction, unstable angina, peripheral arterial occlusion, stroke, cerebral infarction, etc., and has excellent pharmacological action, physicochemical properties, etc. Development of the compound which has is desired.

  We have the formula:

[Where
R ¹ represents an optionally substituted 5- to 10-membered aromatic group,
R ² represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkoxy group, or a formula —OCOR ⁴ , —NR ⁴ R ⁵ , —NR ⁵ SO ₂ R ⁴ , —NR ⁵ COR ⁴ or —NR ⁵ CONR ⁴ R ⁶ (wherein R ⁴ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, and R ⁵ and R ⁶ independently represent a hydrogen atom or a C _1-6 alkyl group). R ⁴ and R ⁵ , R ⁴ and R ^6, and R ⁵ and R ⁶ may be bonded to each other to form an optionally substituted ring. Indicate
R ³ represents a hydrogen atom or a halogen atom,
X ¹ represents an optionally substituted C _1-2 alkylene group,
X ² represents an oxygen atom, a sulfur atom or an optionally substituted methylene,
Y represents an optionally substituted C _1-3 alkylene group. ]
Or a salt thereof [hereinafter sometimes referred to as compound (I)] strongly inhibits Lp-PLA ₂ and coronary arteries such as atherosclerosis, myocardial infarction, unstable angina It was found for the first time that it is useful for the prevention and treatment of syndrome, peripheral artery occlusion, stroke, cerebral infarction and the like. Based on this finding, the present inventors have conducted intensive research and have completed the present invention.

That is, the present invention
(1) Compound (I);
(2) X ¹ is a C _1-2 alkylene group which may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, an oxo group and a hydroxy group (1 ) Described compounds;
(3) a prodrug of the compound according to (1) above;
(4) A medicament comprising the compound according to (1) above or a prodrug thereof;
(5) The medicament according to (4) above, which is a lipoprotein-related phospholipase A ₂ inhibitor;
(6) The medicament according to (4) above, which is an agent for preventing or treating arteriosclerosis;
(7) The medicament according to (4) above, which is a cardiovascular event onset inhibitor;
(8) A method for preventing or treating arteriosclerosis in a mammal, which comprises administering an effective amount of the compound according to (1) or a prodrug thereof to the mammal;
(9) A method for suppressing the onset of a cardiovascular event in a mammal, comprising administering an effective amount of the compound or prodrug thereof according to (1) to the mammal;
(10) Use of the compound of the above (1) or a prodrug thereof for producing an agent for preventing or treating arteriosclerosis;
(11) It relates to the use of the compound according to (1) above or a prodrug thereof for producing a cardiovascular event onset inhibitor.

Compound (I) has an Lp-PLA ₂ inhibitory action and is useful for the prevention and treatment of coronary syndromes such as atherosclerosis, myocardial infarction, unstable angina, peripheral arterial occlusion, stroke and cerebral infarction. It is useful and has an excellent medicinal effect.

(Detailed description of the invention)
Hereinafter, the definition of each symbol in formula (I) will be described in detail.
The “halogen atom” in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
Unless otherwise specified, “C _1-6 alkyl group” in the present specification is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

The “C _1-6 alkoxy group” in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
The “C _1-6 alkoxy-carbonyl group” in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
The “C _1-6 alkyl-carbonyl group” in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like unless otherwise specified.

R ¹ represents an optionally substituted 5- to 10-membered aromatic group.

The “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ includes thienyl, furyl, thiazolyl, pyrazolyl, phenyl, pyridyl, pyrimidinyl, naphthyl and the like. Can be mentioned. Preferred are thienyl, phenyl, pyridyl, pyrimidinyl and the like, and more preferred are thienyl, phenyl and the like.

The “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ may have 1 to 3 substituents at substitutable positions. Good.

As such a substituent, for example,
(1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl) _optionally substituted with 1 to 3 halogen atoms;
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a C _6-14 aryl group (eg, phenyl, naphthyl) _optionally substituted with 1 to 3 substituents selected from halogen atoms;
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Oxadiazolyl, thiadiazolyl);
(4) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(5) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) 5- to 10-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(8) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted with 1 to 3 halogen atoms;
(9) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(10) a thiocarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(11) a sulfamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(12) a carboxy group;
(13) a hydroxy group;
(14) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(15) a C _2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(16) C _7-13 aralkyloxy group (eg, benzyloxy);
(17) C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(18) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(19) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(20) A 4- to 14-membered non-aromatic heterocyclic carbonyl optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms A group (eg, pyrrolidinylcarbonyl, morpholinylcarbonyl);
(21) mercapto group;
(22) (a) a halogen atom, and
(b) C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group (e.g., methylthio, ethylthio);
(23) C _7-13 aralkylthio group (eg, benzylthio);
(24) C _6-14 arylthio group (eg, phenylthio, naphthylthio);
(25) a cyano group;
(26) a nitro group;
(27) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(28) a 5- to 10-membered aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (Eg, pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
(29) (a) a halogen atom (eg, a fluorine atom), and
(b) C _1-6 alkoxy group (eg, methoxy)
A C _3-10 cycloalkoxy group (eg, cyclopropoxy, cyclopentyloxy) optionally substituted with 1 to 3 substituents selected from:
(30) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
(31) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _2-6 alkenyl group optionally substituted with 1 to 3 substituents selected from an amino group which may be mono- or di-substituted with a C _1-6 alkyl group (eg, ethenyl, 1 -Propenyl);
(32) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group, and
(d) a C _7-13 aralkyl group (eg, benzyl) _optionally substituted with 1 to 3 substituents selected from a halogen atom;
Etc. When there are two or more substituents, each substituent may be the same or different.

As the “substituent” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ ,
(1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl) _optionally substituted with 1 to 3 halogen atoms;
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(3) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(4) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(5) (a) a halogen atom, and
(b) C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group (e.g., methylthio, ethylthio);
(6) cyano group;
(7) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(8) (a) a halogen atom (eg, fluorine atom), and
(b) C _1-6 alkoxy group (eg, methoxy)
A C _3-10 cycloalkoxy group (eg, cyclopropoxy, cyclopentyloxy) optionally substituted with 1 to 3 substituents selected from:
(9) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
Etc.

R ¹ is preferably
(1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl) _optionally substituted with 1 to 3 halogen atoms;
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(3) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(4) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(5) (a) a halogen atom, and
(b) C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group (e.g., methylthio, ethylthio);
(6) cyano group;
(7) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(8) (a) a halogen atom (eg, fluorine atom), and
(b) C _1-6 alkoxy group (eg, methoxy)
A C _3-10 cycloalkoxy group (eg, cyclopropoxy, cyclopentyloxy) optionally substituted with 1 to 3 substituents selected from:
(9) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
And thienyl, phenyl, pyridyl, pyrimidinyl and the like, each of which may be substituted with 1 to 3 substituents selected from the above.

R ¹ is more preferably
(1) a C _3-10 cycloalkyl group _optionally substituted with 1 to 3 halogen atoms (eg, cyclopropyl, cyclohexyl);
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(3) a cyano group;
(4) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(5) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
And thienyl, phenyl and the like, each of which may be substituted with 1 to 3 substituents selected from the above.

R ² represents a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkoxy group, or a formula —OCOR ⁴ , —NR ⁴ R ⁵ , —NR ⁵ SO ₂ R ⁴ , —NR ⁵ COR ^4. Or —NR ⁵ CONR ⁴ R ⁶ (wherein R ⁴ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, and R ⁵ and R ⁶ independently represent a hydrogen atom or C _1-6 Represents an alkyl group, or R ⁴ and R ⁵ , R ⁴ and R ^6, and R ⁵ and R ⁶ may be bonded to each other to form an optionally substituted ring. Indicates a group.

The “C _1-6 alkoxy group” in the “optionally substituted C _1-6 alkoxy group” represented by R ² may have 1 to 3 substituents at substitutable positions.
As such a substituent, for example,
(1) a C _3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl) _optionally substituted with 1 to 3 halogen atoms;
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a C _6-14 aryl group (eg, phenyl, naphthyl) _optionally substituted with 1 to 3 substituents selected from halogen atoms;
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Oxadiazolyl, thiadiazolyl);
(4) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(5) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) 5- to 10-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(8) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted with 1 to 3 halogen atoms;
(9) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(10) a thiocarbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(11) a sulfamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(12) a carboxy group;
(13) a hydroxy group;
(14) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(15) a C _2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(16) C _7-13 aralkyloxy group (eg, benzyloxy);
(17) C _6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(18) C _1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(19) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(20) A 4- to 14-membered non-aromatic heterocyclic carbonyl optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms A group (eg, pyrrolidinylcarbonyl, morpholinylcarbonyl);
(21) mercapto group;
(22) (a) a halogen atom, and
(b) C _1-6 alkoxy - one to three optionally substituted with a substituent C _1-6 alkylthio group selected from a carbonyl group (e.g., methylthio, ethylthio);
(23) C _7-13 aralkylthio group (eg, benzylthio);
(24) C _6-14 arylthio group (eg, phenylthio, naphthylthio);
(25) a cyano group;
(26) a nitro group;
(27) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(28) a 5- to 10-membered aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from a C _1-6 alkyl group _optionally substituted with 1 to 3 halogen atoms (Eg, pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
Etc. When there are two or more substituents, each substituent may be the same or different.

R ⁴ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group.

The “C _1-6 alkyl group” in the “ _optionally substituted C _1-6 alkyl group” represented by R ⁴ may have 1 to 3 substituents at substitutable positions.
As such substituents, for example, those similar to the substituent group of the "C _1-6 alkoxy group" in the "optionally substituted C _1-6 alkoxy group" represented by R ^2.
When there are two or more substituents, each substituent may be the same or different.

R ⁵ and R ⁶ independently represent a hydrogen atom or a C _1-6 alkyl group.

Examples of the “ring” in the “optionally substituted ring” formed by R ⁴ and R ⁵ , R ⁴ and R ⁶ and R ⁵ and R ⁶ bonded to each other include, for example, other than carbon atoms as ring constituent atoms Includes a 4- to 14-membered nitrogen-containing non-aromatic heterocyclic ring which contains at least one nitrogen atom and may further contain one or two heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Specific examples of the nitrogen-containing non-aromatic heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.

The “ring” in the “optionally substituted ring” formed by R ⁴ and R ⁵ , R ⁴ and R ⁶ and R ⁵ and R ⁶ bonded to each other has 1 to 3 substituents at substitutable positions. It may have a substituent. Examples of such a substituent include a substituent that the “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ may have The same thing, an oxo group, etc. are mentioned.
When there are two or more substituents, each substituent may be the same or different.

R ² is preferably
(1) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Oxadiazolyl, thiadiazolyl);
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) 5- to 10-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(4) a C _1-6 alkyl-carbonyl group _optionally substituted with 1 to 3 halogen atoms;
(5) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(6) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(7) a sulfamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(8) hydroxy group;
(9) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(10) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(11) A 4- to 14-membered non-aromatic heterocyclic carbonyl optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms A group (eg, pyrrolidinylcarbonyl, morpholinylcarbonyl);
(12) a cyano group;
(13) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(14) a 5- to 10-membered aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (Eg, pyrazolylcarbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
A C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from the above;

R ² is more preferably
(1) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Oxadiazolyl, thiadiazolyl);
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) 5- to 10-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(4) a C _1-6 alkyl-carbonyl group _optionally substituted with 1 to 3 halogen atoms;
(5) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(6) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(7) hydroxy group;
(8) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(9) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(10) a cyano group;
A C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from the above;

R ³ represents a hydrogen atom or a halogen atom.

X ¹ represents an optionally substituted C _1-2 alkylene group.

As "C _1-2 alkylene group" in the "optionally substituted C _1-2 alkylene group" represented by X ^1, include methylene or ethylene.

The “C _1-2 alkylene group” in the “ _optionally substituted C _1-2 alkylene group” represented by X ¹ may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a substituent that the “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ may have The same thing, an oxo group, etc. are mentioned.
When there are two or more substituents, each substituent may be the same or different.

X ¹ is preferably
(1) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(2) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted with 1 to 3 halogen atoms;
(4) hydroxy group;
(5) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(6) cyano group;
(7) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(8) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
(9) an oxo group;
And methylene and ethylene, each of which may be substituted with 1 to 3 substituents selected from the above.

X ¹ is more preferably
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(2) a C _1-6 alkyl group;
(3) an oxo group;
(4) hydroxy group;
And methylene and ethylene, each of which may be substituted with 1 to 3 substituents selected from the above.

X ² represents an oxygen atom, a sulfur atom or an optionally substituted methylene.
The “methylene” in the “optionally substituted methylene” represented by X ² may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a substituent that the “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ may have The same thing, an oxo group, etc. are mentioned.
When there are two or more substituents, each substituent may be the same or different.
Preferable examples of the substituent of “methylene” in the “optionally substituted methylene” represented by X ² include, for example,
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(2) a C _1-6 alkyl group;
(3) an oxo group;
(4) hydroxy group;
Etc.

X ² is preferably an oxygen atom, a sulfur atom or the like.

Y represents an optionally substituted C _1-3 alkylene group.
As "C _1-3 alkylene group" in the "optionally substituted C _1-3 alkylene group" represented by Y, methylene, ethylene, propylene, isopropylene, and the like.
The “C _1-3 alkylene group” in the “ _optionally substituted C _1-3 alkylene group” represented by Y may have 1 to 2 substituents at substitutable positions. Examples of such a substituent include a substituent that the “5- to 10-membered aromatic group” in the “optionally substituted 5- to 10-membered aromatic group” represented by R ¹ may have The same thing, an oxo group, etc. are mentioned.
When there are two or more substituents, each substituent may be the same or different.

Y is preferably
(1) a C _1-6 alkyl-carbonyl group which may be substituted with 1 to 3 halogen atoms;
(2) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(3) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl) optionally substituted with 1 to 3 halogen atoms;
(4) hydroxy group;
(5) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(6) cyano group;
(7) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(8) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
And methylene, ethylene, propylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.

Y is more preferably
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
And methylene, ethylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.

Preferable examples of compound (I) include the following compounds.
R ¹ is
(1) a C _3-10 cycloalkyl group _optionally substituted with 1 to 3 halogen atoms (eg, cyclopropyl, cyclohexyl);
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(3) a cyano group;
(4) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(5) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
Thienyl and phenyl each optionally substituted by 1 to 3 substituents selected from:
R ² is
(1) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and
(d) a 5- to 10-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Oxadiazolyl, thiadiazolyl);
(2) (a) a C _1-6 alkyl group _optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C _1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a halogen atom, and
(e) a 4- to 14-membered non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups (eg, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, Piperazinyl);
(3) (a) a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C _1-6 alkyl-carbonyl group _optionally substituted by 1 to 3 halogen atoms,
(c) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or disubstituted with a C _1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and
(f) 5- to 10-membered aromatic heterocyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(4) a C _1-6 alkyl-carbonyl group _optionally substituted with 1 to 3 halogen atoms;
(5) (a) a halogen atom,
(b) a C _1-6 alkoxy group,
(c) a C _6-14 aryl group (eg, phenyl), and
(d) 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl)
A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(6) a carbamoyl group which may be mono- or di-substituted with a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(7) hydroxy group;
(8) (a) a halogen atom,
(b) a carboxy group,
(c) a C _1-6 alkoxy group,
(d) a C _1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C _6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C _1-6 alkyl group and a C _1-6 alkoxy-carbonyl group,
(f) a 4- to 14-membered heterocyclic group (eg, tetrahydrofuryl), and
(g) a C _1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a C _3-10 cycloalkyl group;
(9) (a) a halogen atom, and
(b) a C _6-14 aryl-carbonyl group _optionally substituted with 1 to 3 substituents selected from C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms (eg, Benzoyl);
(10) a cyano group;
A C _1-6 alkoxy group, each optionally substituted by 1 to 3 substituents selected from:
R ³ is
A hydrogen atom or a halogen atom;
X ¹ is
(1) hydroxy group;
(2) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(3) a C _1-6 alkyl group;
(4) an oxo group;
Methylene or ethylene, each optionally substituted by 1 to 3 substituents selected from
X ² is,
An oxygen atom or a sulfur atom;
Y is
(1) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C _1-6 alkoxy-carbonyl group,
(e) a C _1-6 alkoxy group, and
(f) a C _1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C _1-6 alkyl group;
Methylene or ethylene, each optionally substituted with 1 to 3 substituents selected from
Compound (I).

  The salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. And a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.

  Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.

  Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.

  Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

  Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.

  Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.

  Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I) or the like.
Compound (I) may be a solvate (for example, an anhydride) or a solvate (for example, a hydrate).
Further, a deuterium converter obtained by converting ¹ H into ² H (D) is also encompassed in compound (I).

  The prodrug of the compound (I) is a compound that is converted to the compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, the compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).

Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylated compounds);
Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated or dimethylaminomethylcarbonylated compounds);
Compounds in which the carboxyl group of compound (I) is esterified or amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation Compound) and the like. These compounds can be produced from compound (I) by a method known per se.

  In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.

Hereafter, the manufacturing method of compound (I) is demonstrated.
Compound (I) can be produced by a method known per se (for example, a method described in Katritzky, AR, COMPREHENSIVE HETEROCYCLIC CHEMISTRY, PERGAMON PRESS, 1984, Vol. 3, pp. 106-142, etc.) or a method analogous thereto. it can. Compound (I) can be produced, for example, by the method shown below or a method analogous thereto.
In the following reaction formula, each raw material compound may form a salt as long as it does not inhibit the reaction. Examples of such salts include those exemplified as the salts of the compound represented by the aforementioned formula (I). Used.

In the case where a specific production method is not described, the raw material compounds can be easily obtained commercially, or can be produced according to a method known per se or a method analogous thereto.
The compound (I) can be converted to another compound (I) represented by the formula (I) by functional group conversion using a method known in the art. For example, it can be converted to another compound (I) represented by the formula (I) by alkylating, acylating, or converting the hydroxyl group as R ² in the formula (I) to an amino group.
In addition, the compound obtained in each step can be used in the next reaction as a crude product (for example, as it is in the reaction solution), but may be isolated from the reaction mixture according to a conventional method, and further recrystallized. Alternatively, it may be purified by a separation means such as distillation or chromatography.

(In the formula, L ¹ , L ² and L ³ each represent a leaving group, and X ² represents an oxygen atom or a sulfur atom in the case of step 1, step 2, step 4, step 5, step 6 and step 7; 3 represents methylene which may be substituted, and the other symbols are as defined above.)
Examples of the leaving group represented by L ¹ , L ² or L ³ include a halogen atom, trifluoromethanesulfonate, methanesulfonate, trifluoroacetate and the like.

[Step 1]

(The symbols in the formula are as defined above.)
Compound (I) can be produced by condensing compound (II) and compound (III).

This condensation reaction can be performed in the presence of a base in an inert solvent.
Examples of the solvent include toluene, benzene, xylene, methanol, ethanol, propanol, isopropanol, n-butanol, acetone, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, dimethyl. Examples thereof include sulfoxide, pyridine, water and the like, or a mixed solvent thereof.

Examples of the base include sodium hydride, sodium methoxide, tert-butoxypotassium, pyridine, 4-dimethylaminopyridine, triethylamine, potassium carbonate, sodium acetate and the like.
Compound (III) is generally used in an amount of about 1 to 3 to 5 mol with respect to 1 mol of compound (II).
The base is generally used in an amount of about 1/5 to 5 mol with respect to 1 mol of compound (III).
The reaction temperature is usually about 0 ° C. to 200 ° C., and the reaction time is usually about 10 minutes to about 50 hours.

[Step 2]

(The symbols in the formula are as defined above.)
Compound (I) can be produced by condensing compound (IV) and compound (V).
This condensation reaction can be performed in the presence of a base in an inert solvent.
Examples of the solvent include toluene, benzene, xylene, methanol, ethanol, propanol, isopropanol, n-butanol, acetone, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, dimethyl. Examples thereof include sulfoxide, pyridine, water and the like, or a mixed solvent thereof.

Examples of the base include sodium hydride, sodium methoxide, tert-butoxypotassium, pyridine, 4-dimethylaminopyridine, triethylamine, potassium carbonate, sodium acetate and the like.
Compound (V) is generally used in an amount of about 1/3 to 5 mol with respect to 1 mol of compound (IV).
The base is generally used in an amount of about 1/5 to 5 mol with respect to 1 mol of compound (IV).
The reaction temperature is usually about 0 ° C. to 200 ° C., and the reaction time is usually about 10 minutes to about 50 hours.

[Step 3]

(In the formula, M represents an atom such as boron, tin, silicon, zinc, magnesium, etc .; Z represents a hydroxy group, a C _1-8 alkyl group, a C _1-6 alkoxy group, a halogen atom, etc .; or It indicates bicyclic leaving group MZN; X ² represents an optionally methylene optionally substituted; n is an integer of 1 to 3; and other symbols are as defined above).

Here, examples of the C _1-8 alkyl group include methyl, ethyl, propyl, propyl, butyl and the like.

  Examples of the bicyclic leaving group include borabicyclo [3.2.2] nonyl.

Compound (I) can be produced by condensing compound (II) with compound (VI) in the presence of a catalyst and reducing the product as necessary.
This condensation reaction can be carried out without a solvent or in an inert solvent.
Examples of such solvents include tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, acetone, acetonitrile, ethyl acetate, methanol, ethanol, hexane, toluene, benzene, xylene, pyridine, dichloromethane, chloroform, dichloroethane, dimethylformamide, Examples thereof include dimethyl sulfoxide, water and the like, or a mixed solvent thereof.
The reaction temperature is usually about 0 ° C. to about 200 ° C., and the reaction time is usually about 5 minutes to about 50 hours.
Compound (VI) is generally used in an amount of about 0.3 to about 5 mol, preferably about 0.5 to about 2 mol, per 1 mol of compound (II).
Examples of the catalyst include tetrakistriphenylphosphine palladium, dichlorobis- (triphenylphosphine) palladium, bis-tri-ortho-tolylphosphine-palladium chloride, dichloro- (bis-diphenylphosphino) ferrocenyl) palladium, and palladium acetate. And nickel catalysts such as nickel chloride, dichlorobis (triphenylphosphine) nickel, 1,2- (bis (diphenylphosphino) ethane) -dichloronickel, and the like.

The catalyst is generally used in an amount of about 0.05 to about 1 mol, preferably about 0.1 to about 0.25 mol, per 1 mol of compound (II).
In addition, when an appropriate ligand, additive, and / or base are used as necessary, the reaction can be smoothly advanced.
Examples of such a ligand include triphenylphosphine, tris- (dimethylamino) -phosphine, tris- (ortho-tolyl) phosphine, and the like.
Examples of the additive include lithium chloride, tetraethylammonium chloride, potassium fluoride, cesium fluoride, and tetrabutylammonium fluoride.
Examples of the base include potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, sodium tert-butoxide, triethylamine and the like.

The ligand, additive, or base is generally used in an amount of about 0.05 to about 10 mol, preferably about 0.1 to about 3 mol, per 1 mol of compound (II).
The reduction reaction can be performed by a method known per se. For example, it is carried out by a method of hydrogenation in the presence of a catalyst such as palladium.
This hydrogenation reaction can be carried out in an inert solvent.
Examples of such solvents include tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, acetone, acetonitrile, ethyl acetate, methanol, ethanol, hexane, toluene, benzene, xylene, pyridine, dichloromethane, chloroform, dichloroethane, dimethylformamide, Examples thereof include dimethyl sulfoxide, acetic acid, water, and a mixed solvent thereof.
The reaction temperature is usually about 0 ° C. to about 120 ° C., and the reaction time is usually about 5 minutes to about 50 hours.
Examples of the catalyst include a palladium catalyst such as palladium-carbon, a platinum catalyst such as platinum-carbon, a nickel catalyst such as Raney nickel, and a rhodium catalyst.
The catalyst is generally used in an amount of about 0.05 to about 1 mol, preferably about 0.1 to about 1 mol, per 1 mol of compound (II).
This reduction reaction is preferably performed in a hydrogen atmosphere at 1 to 10 atm.

[Step 4]

(The symbols in the formula are as defined above.)
Compound (I) can be produced by ring-closing compound (VII).
This ring-closing reaction can be carried out in the presence of a base in an inert solvent.
Examples of the solvent include toluene, benzene, xylene, methanol, ethanol, propanol, isopropanol, n-butanol, acetone, chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, hexane, ethyl acetate, dimethylformamide, dimethyl. Examples thereof include sulfoxide, pyridine, water and the like, or a mixed solvent thereof.
Examples of the base include sodium hydride, sodium methoxide, tert-butoxypotassium, pyridine, 4-dimethylaminopyridine, triethylamine, potassium carbonate, sodium acetate and the like.
The base is generally used in an amount of about 1/5 to 5 mol with respect to 1 mol of compound (VII).
The reaction temperature is usually about 0 ° C. to 200 ° C., and the reaction time is usually about 10 minutes to about 50 hours.

Compounds (II) and (IV) can be produced by known methods, but can also be produced, for example, as follows.
[Step 5]
Compound (VIII) is cyclized by heating with a chlorinating agent (eg, phosphorus oxychloride, etc.) in the absence of solvent or in an inert solvent such as 1,4-dioxane to produce compound (II) can do.
[Step 6]
Compound (II) can be produced by reacting compound (IX) with phosphorus oxychloride or thionyl chloride in a solventless or inert solvent (eg, chloroform, pyridine). At this time, the reaction can be smoothly advanced by adding dimethylformamide or the like.

[Step 7]
Compound (IV) can be produced by treating compound (IX) with a sulfurization reagent (eg, phosphorus pentasulfide, Lawesson's reagent, etc.) in an inert solvent (eg, pyridine, 1,4-dioxane). it can.

  In each of the above reactions, when the raw material compound has an amino group, carboxyl group, hydroxy group, carbonyl group or mercapto group as a substituent, a protective group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.

Examples of the protecting group for the amino group include a formyl group, a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a benzoyl group, a C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C _7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the protecting group for the carboxyl group include a C _1-6 alkyl group, a C _7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C _2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkoxy group and a nitro group.

Examples of the protective group for the hydroxy group include a C _1-6 alkyl group, a phenyl group, a trityl group, a C _7-10 aralkyl group (eg, benzyl), a formyl group, a C _1-6 alkyl-carbonyl group, a benzoyl group, C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), a _C2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group.

Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C _1-6 alkylacetal) and the like.

Examples of the mercapto group-protecting group include a C _1-6 alkyl group, a phenyl group, a trityl group, a C _7-10 aralkyl group (eg, benzyl), a C _1-6 alkyl-carbonyl group, a benzoyl group, and a C _7- group. ₁₀ aralkyl-carbonyl group (eg, benzylcarbonyl), C _1-6 alkoxy-carbonyl group, C _6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C _7-14 aralkyloxy-carbonyl group (eg, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl group, C _1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a nitro group.

  The protecting group removal method described above can be carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980), and the like. . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.

  Compound (I) obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.

  When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by a known synthesis method and separation method, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).

Compound (I) may be a crystal.
Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I).
In the present specification, the melting point is measured using, for example, a trace melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
In general, the melting point may vary depending on measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.

  Compound (I) or a prodrug thereof (hereinafter, sometimes simply abbreviated as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition. Thus, it can be used as a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).

  Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.

  Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.

  Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

  Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.

  Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

  Preferable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

  Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.

  Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.

  Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
A preferred example of the soothing agent is benzyl alcohol.

Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfite and ascorbate.

  Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (E.g., the aluminum salt of the water-soluble edible tar dye) and natural dyes (e.g., [beta] -carotene, chlorophyll, bengara).

  Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

  Examples of the dosage form of the pharmaceutical composition include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, and lozenges. Oral preparations such as syrup, emulsion, suspension, film (eg, orally disintegrating film); and injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, Intravenous preparations, external preparations (eg, transdermal preparations, ointments), suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc. Oral preparations are mentioned. These can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration).

  These preparations may be controlled-release preparations such as immediate-release preparations or sustained-release preparations (eg, sustained-release microcapsules).

  The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.

  The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.

  When producing an oral preparation, it may be coated for the purpose of taste masking, enteric properties or sustainability, if necessary.

  Examples of the coating base used for coating include a sugar coating base, a water-soluble film coating base, an enteric film coating base, and a sustained-release film coating base.

  As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

  Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.

  Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ], Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], and natural products such as shellac.

  Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].

  Two or more of the coating bases described above may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.

  The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats, guinea pigs, rabbits, etc.) can be used as preventive or therapeutic agents for various diseases described later, or diagnostic agents.

Since the compound (I) of the present invention is low in toxicity and safe and has a strong Lp-PLA ₂ inhibitory action, it is useful for, for example, prevention or treatment of arteriosclerosis, suppression of onset of cardiovascular events, and the like.
Here, as “arteriosclerosis”, for example, arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), vascular thickening, intervention (percutaneous coronary artery formation) Surgery, stent placement, coronary endoscopy, intravascular ultrasound, coronary thrombolysis, etc.) Vascular thickening or occlusion and organ damage, vascular re-occlusion / restenosis after bypass surgery, atherothrombosis, etc. It is done.
Examples of the “cardiovascular event” include ischemic heart disease (unstable angina, acute myocardial infarction, acute heart failure, heart death, etc.), stroke, cerebral infarction (including transient cerebral ischemia), and the like. It is done.
In addition, the compound (I) of the present invention can be used for cardiac diseases (cardiac hypertrophy, chronic heart failure including acute heart failure and congestion, cardiomyopathy, angina pectoris, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc.), myocardial ischemia , Venous dysfunction, heart failure transition after myocardial infarction, pulmonary heart, respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus / pulmonary embolism, etc.), inflammatory diseases (retinopathy, nephropathy, nerve Diabetic complications such as disorders, macrovascular disorders; rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, arthritis such as periosteitis, inflammation after surgery / trauma, swelling relief, pharyngitis, cystitis, pneumonia, Inflammatory bowel diseases such as atopic dermatitis, Crohn's disease, necrotizing enterocolitis, ischemic bowel necrosis, ulcerative colitis, meningitis, inflammatory eye disease, pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis Lung disease, etc.), allergic diseases (allergic rhinitis, conjunctivitis, digestion) Allergies, hay fever, anaphylaxis, etc.), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.) Head injury, spinal cord injury, brain edema, etc.), schizophrenia, dementia, memory impairment, consciousness disorder, amnesia, anxiety symptoms, tension symptoms, uncomfortable mental state, mental illness (depression, epilepsy, alcoholism, etc.) ), Ischemic peripheral circulatory disorder, deep vein thrombosis, obstructive peripheral circulatory disorder, obstructive arteriosclerosis, obstructive thrombotic vasculitis, diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), diabetic complications (Neuropathy, nephropathy, retinopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmotic coma, infection, diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder Etc.), bill Xie / nutrition disorders (obesity, hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose tolerance, etc.), insulin resistance syndrome, syndrome X, visceral obesity syndrome, cerebrovascular disorder (asymptomatic cerebrovascular disorder, one Transient cerebral ischemic attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disorder, recurrence of cerebrovascular disorder and sequelae (neurological symptoms, psychiatric symptoms, subjective symptoms, activities of daily living) Disorders), renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, immunoglobulin A nephropathy, nephrotic syndrome, hypertensive nephrosclerosis, dialysis complications, Radiation-induced organ damage including nephropathy), eye disease, thrombosis, multiple organ failure, endothelial dysfunction, other cardiovascular diseases (ischemic cerebral circulation disorder, Raynaud's disease, Buerger disease, etc.), chronic obstructive lung Disease, tumor (malignant melanoma, malignant lymphoma, gastrointestinal (eg, stomach, intestine, etc.) cancer) and associated cachexia, endocrine disease, urinary / male genital disease, gynecological disease, toxemia (sepsis, Septic shock, endotoxic shock, gram-negative sepsis, toxin shock syndrome, etc.), respiratory distress syndrome, exudative otitis media, femoral popliteal bypass graft patency, stomatitis, periodontal disease, oral inflammation, respiratory tract inflammation and It is useful for the prevention or treatment of hyperresponsiveness, HIV infection and the onset of AIDS, etc., especially the prevention and treatment of arteriosclerosis including atherosclerosis that has been pointed out to be related to Lp-PLA ₂ , and the breakdown of arteriosclerotic plaque It is desirable to use it for the suppression of the onset of cardiovascular events caused by.

  The content of the compound of the present invention in the pharmaceutical composition is usually about 0.01 to about 99.9% by weight, preferably about 0.1 to about 50% by weight, based on the entire preparation.

The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, and the like. -100 mg / kg body weight, preferably 0.05-30 mg / kg body weight, more preferably 0.5-10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
Further, since the compound of the present invention is excellent in safety, it can be administered over a long period of time.

  The compound of the present invention is, for example, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an antihyperlipidemic agent, an antiarteriosclerotic agent, an antihypertensive agent, an antiobesity agent, a diuretic agent, an antigout agent, an antithrombotic agent, an anti-inflammatory agent. Drugs, heart failure treatment agents, arrhythmia treatment agents, HDL increase agents, chemotherapeutic agents, immunotherapy agents, osteoporosis treatment agents, anti-dementia agents, erectile dysfunction improvement agents, urinary incontinence treatment agents, dysuria treatment agents, etc. (Abbreviated as a concomitant drug). These concomitant drugs may be low molecular weight compounds, or may be high molecular weight proteins, polypeptides, antibodies, vaccines, or the like.

Examples of the “diabetes therapeutic agent” include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragments or derivatives (eg, INS-1), oral insulin preparations), insulin resistance improvers (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Netoglitazone (MCC-555), Rivoglitazone (CS-011), FK-614, compounds described in WO01 / 38325, Tesaglitazar (AZ-242), Ragaglitazar (NN- 622), Muraglitazar (B S-298585), Edaglitazone (BM-13-1258), Metaglidasen (MBX-102), Naveglitazar (LY-519818), MX-6054, LY-510929, AMG131 (T- 131) or a salt thereof, THR-0921), an α-glucosidase inhibitor (eg, voglibose, acarbose, miglitol, emiglitate), a biguanide agent (eg, phenformin, metformin, buformin or a salt thereof (eg, hydrochloride, fumarate) Acid salt, succinate)), insulin secretagogue [sulfonylurea (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole) Repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof], dipeptidyl peptidase IV inhibitor (eg, Vidagliptin (LAF237), P32 / 98, Sitagliptin (MK-431), alogliptin (alogliptin) SYR-322), SYR-472, P93 / 01, PT-100, Saxagliptin (BMS-477118), T-6666, TS-021), β3 agonist (eg, AJ-9679), GPR40 agonist, GLP -1 receptor agonist [eg, GLP-1, GLP-1 MR agent, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH ₂ , CJC-1131], amylin agonist (eg, pramlintide), phosphotyros Phosphatase inhibitors (eg, sodium vanadate), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), SGLUT (sodium-glucose cotransporter) inhibitors (eg, T -1095, dapagliflozin, remogliflozin), 11β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improvers, somatostatin receptor agonists Drugs (eg, compounds described in WO01 / 25228, WO03 / 42204, WO98 / 44921, WO98 / 45285, WO99 / 22735, etc.), glucokinase activators (eg, Ro-28-1675), ACC2 (acetyl-CoA Carbo Xylase 2) inhibitors and the like.

  Examples of the “diabetic complication therapeutic agent” include aldose reductase inhibitors (eg, torrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112, ranirestat (AS-3201)), neurotrophic Factors and their increasing agents (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoters described in WO01 / 14372 (for example, 4- (4-chlorophenyl) -2- (2-methyl-1- Imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole)), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, pimagedin, N-Fe Nasyl thiazolium bromide (ALT766), EXO-226, Pyridorin, pyridoxamine), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiopride, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis signal regulating kinase-1 ( ASK-1) inhibitors.

  Examples of the “antihyperlipidemic agent” include, for example, statins that are cholesterol synthesis inhibitors (eg, cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, or salts thereof (eg, sodium salt). Etc.), squalene synthase inhibitors (eg, TAK-475 etc.) or fibrate compounds having a triglyceride lowering action (eg, bezafibrate, clofibrate, simfibrate, clinofibrate etc.), cholesterol absorption inhibitors (eg, Zetia), anion exchange resin (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), plant sterols (eg, soysterol), gamma oryzanol (γ -oryzanol)) EPA, DHA, PPARa agonists, PPARy agonists, PPAR [delta agonists, LXR agonists, FXR antagonists, DGAT inhibitors, MGAT inhibitors include MTP inhibitors like.

  Examples of the “anti-arteriosclerotic agent” include acylcoenzyme A cholesterol acyltransferase (ACAT) inhibitors (eg, merinamide, (eg, Avasimibe, Eflucimibe, etc.), lipid rich plaque reductive drugs ( Examples, compounds described in WO 02/06264 pamphlet, WO 03/069900 pamphlet and the like), 5-lipoxygenase inhibitor, FLAP inhibitor, sPLA2 inhibitor, CTEP inhibitor, MMP inhibitor, Examples include chymase inhibitors, ApoA-1 and related molecules.

  Examples of the “hypertensive agent” include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, TAK-491, TAK-536, losartan, losartan potassium , Eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine etc.), β-blockers (eg, pullranolol, nadolol, timolol, Nipradilol, bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolo , Metoprolol, labetalol, amosulalol, arotinolol, etc.), clonidine and the like.

    The above-mentioned “anti-obesity agents” include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor Body, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban), ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylating enzyme Inhibitors, opioid receptor antagonists (eg, GSK-1521498), orexin receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (eg, AZD-4017), pancreatic lipase inhibitors (eg, , Orlistat, cetilistat), β3 agonists (eg, N-5984) , Diacylglycerol acyltransferase 1 (DGAT1) inhibitor, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (eg, R-256918), Na-glucose cotransport carrier inhibitor Drugs (eg, JNJ-28431754, remogliflozin), NFκ inhibition (eg, HE-3286), PPAR agonists (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (eg, sodium vanadate, Trodusquemin) ), GPR119 agonist (eg, PSN-821), glucokinase activator (eg, AZD-1656), leptin, leptin derivative (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived) Neurotrophic factor), cholecystokinin agonist, glucagon-like peptide-1 (GLP-1) formulation (eg, animal GL extracted from bovine and porcine pancreas) P-1 preparation; human GLP-1 preparation genetically engineered using E. coli and yeast; GLP-1 fragment or derivative (eg, exenatide, liraglutide)), amylin preparation (eg, pramlintide, AC-2307) ), Neuropeptide Y agonists (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparations: FGF21 preparations (eg, animals extracted from bovine, porcine pancreas) FGF21 preparation; human FGF21 preparation synthesized by genetic engineering using Escherichia coli and yeast; FGF21 fragment or derivative)), antifeedant (eg, P-57)

  Examples of the “diuretic agent” include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide). , Penfluthiazide, poly-5thiazide, methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, eplerenone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, chlorthalidone) And azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

  Examples of the “anti-gout agent” include febuxostat, allopurinol, probenecid, colchicine, benzbromarone, febuxostat, citrate and the like.

  Examples of the above-mentioned “antithrombotic agents” include anticoagulants (eg, heparin sodium, heparin calcium, warfarin calcium (warfarin), antithrombin drugs (eg, argatroban, dabigatran), activated blood coagulation Factor Xa inhibitors (eg, rivaroxaban, apixaban, Du-176b, YM-150, TAK-442, compounds described in WO 2004/048363 pamphlet, etc.), thrombolytic agents [Eg, tPA, urokinase], antiplatelet drug (eg, aspirin, sulfinpyrazone (antulan), dipyridamole (persantin), ticlopidine (panaldin), cilostazol (pretal), GPIIb / IIIa antagonist (eg, leopro, etc.), Clopidogrel, prasugrel, etc.) It is.

  Examples of the above “anti-inflammatory agents” include acetaminophen, phenacetin, ethenamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin , Flurbiprofen, fenbufen, pranoprofen, fructophenine, epirisol, tiaramid hydrochloride, zaltoprofen, gabexate mesylate, camostat mesilate, urinastatin, colchicine, probenade, sulfinpyrazone, benzbromarone, allopurinol, gold sodium thiomalate, Sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, Ropin, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, non-steroidal anti-inflammatory agents such as oxymorphone or a salt thereof.

  Examples of the “heart failure treatment agent” include cardiotonic drugs (eg, digitoxin, digoxin, methyldigoxin, lanatoside C, prossilaridin, etc.), α, β stimulants (eg, epinephrine, norepinephrine, isoproterenol, dopamine, Docarpamine, dobutamine, denopamine, etc.), phosphodiesterase inhibitors (eg, amrinone, milrinone, olprinone hydrochloride, etc.), calcium channel sensitivity enhancers (eg, pimobentan, etc.), nitrate drugs (eg, nitroglycerin, isosorbide nitrate, etc.), angiotensin conversion Enzyme inhibitors (such as the aforementioned angiotensin converting enzyme inhibitors), angiotensin II antagonists (such as the aforementioned angiotensin II antagonists), β blockers (such as the aforementioned β blockers), diuretics (such as the aforementioned diuretics, etc.) ), ANP, sGC activity Agents, myosin sensitivity enhancer, carperitide, ubidecarenone, vesnarinone, aminophylline, and the like.

  Examples of the above-mentioned “arrhythmic therapeutic agent” include sodium channel blockers (eg, quinidine, procainamide, disopyramide, ajmarin, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide, pildicinide, phenytoin), β-blockers (Eg, propranolol, alprenolol, bufetrol, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotilolol, etc.), potassium channel blockers (eg, amiodarone, etc.), calcium channel blockers ( Examples, verapamil, diltiazem, etc.).

  Examples of the “HDL increasing agent” include squalene synthase inhibitors, CETP inhibitors, LPL activators, endothelial lipase inhibitors and the like.

  Examples of the “chemotherapeutic agent” include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), anticancer antibiotics (eg, mitomycin, Adriamycin, etc.), plant-derived anticancer agents (eg, vincristine, vindesine, taxol, etc.), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furtulon or neoflutulon are preferred.

  Examples of the above-mentioned “immunotherapy agent” include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil, etc.), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin, etc.), genetic engineering techniques. Examples include cytokines obtained (eg, interferon, interleukin (IL), etc.), colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin, etc.), among which IL-1, IL-2, IL-12, etc. preferable.

  Examples of the above `` osteoporosis therapeutic agent '' include, for example, alfacalcidol, calcitriol, elcaltonin, salmon calcitonin, caltritonin, estriol, ipriflavone, and pamidronate. Examples include sodium (pamidronate disodium), alendronate sodium hydrate, incadronate disodium, and the like.

  Examples of the above “anti-dementia agent” include tacrine, donepezil, rivastigmine, galantamine and the like.

  Examples of the “erectile dysfunction ameliorating agent” include apomorphine, PDE5 (phosphodiesterase 5) inhibitor (eg, sildenafil citrate) and the like.

Examples of the “urine incontinence therapeutic agent” include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the above “difficulty to urinate” include acetylcholinesterase inhibitors (eg, distigmine) and the like.

  Furthermore, as a concomitant drug, nerve regeneration promoting drugs (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), α2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.

  The administration time of the aforementioned concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or may be administered with a time difference. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

  In addition, these concomitant drugs may be combined in an appropriate ratio of two or more. In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be combined at the time of administration.

  Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) formulating the compound of the present invention and the concomitant drug separately. Simultaneous administration of the two obtained preparations by the same administration route, (3) administration of the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different times in the same administration route, (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug through different administration routes, (5) 2 obtained by formulating the compound of the present invention and the concomitant drug separately Administration of different types of preparations at different time intervals (for example, administration in the order of the compound of the present invention → concomitant drug or administration in the reverse order) and the like. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

The present invention will be described in more detail with reference to the following Reference Examples, Examples, Test Examples and Formulation Examples, which are not intended to limit the present invention, and may be changed without departing from the scope of the present invention. Also good.
The gene manipulation method described below was in accordance with the method described in the book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or the method described in the protocol attached to the reagent.

  In the following Reference Examples and Examples, “%” indicates mol / mol% unless otherwise specified, and indicates% by weight for others. “Room temperature” indicates a temperature of 1 to 30 ° C. unless otherwise specified.

In Reference Examples and Examples, the melting point, mass spectrum (MS) and nuclear magnetic resonance spectrum (NMR) were measured under the following conditions.
Melting point measuring device: Yanagimoto trace melting point measuring device or Buchi melting point measuring device type B-545 was used.

MS measuring apparatus: Waters ZMD, Waters ZQ2000, Micromass Platform II or Waters Waters MUX 4-ch LC / MS system
Ionization method: Electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Unless otherwise noted, ESI was used.

  NMR measurement apparatus: Varian Mercian-300 (300 MHz), Varian INOVA-400 (400 MHz), Bruker Biospin AVANCE 300 or Bruker Biospin AV400. Chemical shifts are expressed in ppm using tetramethylsilane as an internal standard, and coupling constants (J) are expressed in hertz (Hz).

In Reference Examples and Examples, purification by preparative HPLC was performed under the following conditions.
Preparative HPLC apparatus: Waters, UV purification apparatus Column: Develosil ODS-UG-10
Solution: Solution A; Water containing 0.1% trifluoroacetic acid Solution B: Acetonitrile gradient containing 0.1% trifluoroacetic acid: 10 minute gradient, 5-100% gradient gradient cycle: 0.00 minute (A / B = 95/5), 1.00 min (A / B = 95/5), 2.00 min (A / B = 80/20), 5.00 min (A / B = 5/95), 5.10 Minutes (A / B = 0/100), 7.00 minutes (A / B = 100/0)
Flow rate: 150 mL / min,
Detection method: UV 220 nm

Or
Preparative HPLC apparatus: Gilson High-throughput purification system column: CombiPrep, Pro C18 RS S-5 μm, 20 × 50 mm (YMC)
Solution: Solution A; 0.1% trifluoroacetic acid-containing aqueous solution B; 0.1% trifluoroacetic acid in acetonitrile gradient cycle: 0.00 min (A / B = 98/2), 1.10 min (A / B = 98/2), 5.00 minutes (A / B = 0/100), 6.40 minutes (A / B = 0/100), 6.50 minutes (A / B = 98/2)
Flow rate: 20 mL / min Detection method: UV 220, 254 nm

The abbreviations in the reference examples and examples follow the examples currently used in the present technical field, and have the following meanings, for example.
s: singlet
d: Doublet
t: triplet
q: quartet
dd—Double doublet
dt—Double triplet
dq—Double quartet
ddd—Double double doublet
td—triple doublet
tt—triple triplet
m: multiplet
br: Broad
brs: Broad singlet
J: coupling constant
WSC: water-soluble carbodiimide THF: tetrahydrofuran DMF: dimethylformamide DMSO: dimethyl sulfoxide DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene EDCI: 1-ethyl-3- (3-dimethylaminopropyl) Carbodiimide HOBt: 1-hydroxybenzotriazole IPE: diisopropyl ether DMAP: 4- (dimethylamino) pyridine DCM: dichloromethane DCE: dichloroethane IPA: isopropyl alcohol TFA: trifluoroacetic acid TEA: triethylamine RP-HPLC: reverse phase high performance liquid chromatography EtOAc : Ethyl acetate NBS: N-bromosuccinimide NIS: N-iodosuccinimide dppf: 1,1′-bis (diphenylphosphino Ferrocene Pd ₂ dba ₃ :( tris (dibenzylideneacetone) dipalladium (0)
NCS: N-chlorosuccinimide

Reference example 1
6,7-Dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione

To a mixed solution of 2- (3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide (0.44 g) and 5% sodium ethoxide-ethanol solution (12.6 ml) was added diethyl carbonate (1.6 g). Added at room temperature. The reaction solution was stirred under reflux for 8 hours, and the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added, and the resulting solid was collected by filtration, and washed with water and then diisopropyl ether to give the title compound (0.40 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.98 (t, J = 6.3 Hz, 2 H), 3.92-4.02 (m, 2 H), 6.20 (d, J = 1.9 Hz, 1 H) , 7.36-7.45 (m, 2 H), 7.45-7.60 (m, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 11.34 (br. S., 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 215.

Reference example 2
2-Chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

To 6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione (0.50 g), phosphorus oxychloride (5.3 mL) was added, and 105 ° C. under an argon atmosphere. For 5 hours. The mixture was concentrated under reduced pressure, diluted with ethyl acetate and added to a cooled saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.42 g) as a brown amorphous solid.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 3.06 (t, J = 6.6 Hz, 2 H), 4.02-4.21 (t, J = 6.6 Hz, 2 H), 7.25 (s, 1 H), 7.45 (dd, J = 7.2, 4.5 Hz, 2 H), 7.59 (d, J = 7.2 Hz, 1 H), 8.08 (d, J = 7.6 Hz, 1 H).
LCMS (ESI ⁺ ), M + H ⁺ : 233.

Reference example 3
tert-Butyl 5-methoxy-3,4-dihydroisoquinoline-2 (1H) -carboxylate

To a solution of tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2 (1H) -carboxylate (4.0 g), DMF (40 mL) at 0 ° C., 60% sodium hydride (0.64 g) was added. The mixture was stirred for 30 minutes while warming to room temperature, then added to a mixed solution of methyl iodide (1.0 mL) in DMF (30 mL) at 0 ° C., and stirred for 12 hours while warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (2.6 g) as a yellow oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.49 (s, 9 H), 2.57-2.71 (m, 2 H), 3.53 (t, J = 6.1 Hz, 2 H), 3.79 (s, 3 H), 4.46 (s, 2 H), 6.66-6.91 (m, 2 H), 7.08-7.23 (m, 1 H).

Reference example 4
(2Z) -2- (5-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide

To a solution of tert-butyl 5-methoxy-3,4-dihydroisoquinoline-2 (1H) -carboxylate (2.6 g) in ethyl acetate (10 mL) was added 4N hydrogen chloride (ethyl acetate solution, 10 mL). Stir for hours. The produced solid was collected by filtration, 1N aqueous sodium hydroxide solution was added to the collected solid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A solution of the obtained residue (2.6 g) and tungsten (VI) sodium dihydrate (0.30 g) in methanol (20 mL) was ice-cooled to 0 ° C. under an argon atmosphere, and 30% aqueous hydrogen peroxide (1 6 mL) was added dropwise, followed by stirring for 3 hours while raising the temperature to room temperature. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with THF. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. A solution of the residue (1.3 g) in DME (10 mL) in a mixed solution of diethyl cyanomethylphosphonate (1.2 mL), sodium hydride (0.36 g) and DME (10 mL) previously stirred at 0 ° C. for 10 minutes. Added to. The reaction mixture was stirred at room temperature for 6 hours, water was added, and the mixture was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. A mixture of the obtained residue (1.3 g) and polyphosphoric acid (7.9 g) was stirred at 100 ° C. for 3 hours. The reaction mixture was cooled to room temperature, neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (0.72 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.73 (t, J = 6.2 Hz, 2 H), 3.21-3.31 (m, 2 H), 3.81 (s, 3 H), 5.14 (s, 1 H), 6.37 (br. S., 2 H), 6.99-7.09 (m, 1 H), 7.14-7.21 (m, 1 H), 7.21-7.31 (m, 1 H), 9.45 (br. S ., 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 219.

Reference Example 5
8-Methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione

To a mixed solution of (2Z) -2- (5-methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide (0.72 g) and 5% sodium ethoxide ethanol solution (18 mL) was added diethyl carbonate (2 4 mL) was added at room temperature, and the mixture was stirred at 90 ° C. for 3 hours, and then the solvent was distilled off under reduced pressure. The residue was treated with 1N hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to give the title compound (0.70 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.90 (t, J = 6.4 Hz, 2 H), 3.85 (s, 3 H), 3.88 (t, J = 6.4 Hz, 2 H), 6.17 (d, J = 2.3 Hz, 1 H), 7.13-7.20 (m, 1 H), 7.31-7.40 (m, 1 H), 7.47-7.56 (m, 1 H), 11.34 (br. s., 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 245.

Reference Example 6
2-Chloro-8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 8-methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione (0.2 g) and phosphorus oxychloride (1.9 mL) at 110 ° C. After stirring for 30 minutes, the mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was ice-cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.19 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.98 (t, J = 6.8 Hz, 2 H), 3.87 (s, 3 H), 4.05 (t, J = 6.8 Hz, 2 H), 7.21 (s, 1 H), 7.25-7.32 (m, 1 H), 7.38-7.48 (m, 1 H), 7.61-7.73 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 263.

Reference Example 7
2-[(E) -2-Phenylethenyl] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.5 g), [(E) -2-phenylethenyl] boronic acid (0.38 g), A mixture of sodium carbonate (0.8 g), tetrakis (triphenylphosphine) palladium (0) (0.015 g), water (1.5 mL), and THF (10 mL) was microwave irradiated at 150 ° C. for 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (0.12 g) was added to the reaction mixture, and microwave irradiation was further performed at 150 ° C. for 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. Crystallization using ethyl acetate / n-hexane gave the title compound (0.093 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.06 (t, J = 6.6 Hz, 2 H), 4.12 (t, J = 6.6 Hz, 2 H), 7.14 (d, J = 16.2 Hz, 1 H), 7.25-7.66 (m, 7 H), 7.68-7.78 (m, 2 H), 7.95 (d, J = 16.2 Hz, 1 H), 8.04-8.27 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 301.

Reference Example 8
(2Z) -2- (8-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide

Under argon atmosphere, a mixture of 8-methoxy-1,2,3,4-tetrahydroisoquinoline (1.8 g), sodium tungstate dihydrate (0.073 g) and methanol (40 mL) was cooled to 0 ° C. with ice. 30% hydrogen peroxide (3.7 g) was added dropwise. Thereafter, the ice bath was removed and the reaction solution was gradually warmed to room temperature and stirred for 4 hours. To the reaction solution was added brine and extracted with THF. The organic layer was washed with an aqueous sodium thiosulfate solution and then with brine, and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DME (10 mL) and added into a mixed solution of diethyl cyanomethylphosphonate (1.7 g), 60% sodium hydride (0.46 g) and DME (10 mL) previously stirred at 0 ° C. for 10 minutes. . The reaction solution was stirred at room temperature for 12 hours, brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue was added polyphosphoric acid (10 g) and the mixture was stirred at 110 ° C. for 12 hours. The reaction solution was cooled to room temperature, neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (0.31 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.67-2.83 (m, 2 H), 3.11-3.27 (m, 2 H), 3.81 (s, 3 H), 5.53 (s, 1 H) , 6.36 (br. S, 2 H), 6.79-6.86 (m, 1 H), 6.93-7.02 (m, 1 H), 7.19-7.31 (m, 1 H), 9.77 (br. S., 1 H ).
LCMS (ESI ⁺ ) M + H ⁺ : 219.

Reference Example 9
11-methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione

2- (8-methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide (0.31 g), diethyl carbonate (1.03 g) and ethanol (10 mL) were mixed with 20% sodium ethoxide- Ethanol solution (0.39 g) was added at room temperature. The reaction solution was stirred under reflux for 12 hours, cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (0.22 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.91 (t, J = 6.1 Hz, 2 H), 3.81-3.88 (m, 2 H), 3.90 (s, 3 H), 6.47 (d, J = 2.3 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 7.10 (d, J = 8.0 Hz, 1 H) 7.40-7.48 (m, 1 H) 11.28 (br. S., 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 245.

Reference Example 10
2-Chloro-11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 11-methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione (0.22 g) and phosphorus oxychloride (1.8 mL) For 3 hours. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether to give the title compound (0.21 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.89-3.08 (m, 2 H), 3.94 (s, 3 H), 3.99-4.13 (m, 2 H), 6.88-7.11 (m, 1 H), 7.12-7.23 (m, 1 H), 7.30 (s, 1 H), 7.48-7.64 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 263.

Reference Example 11
(6-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanenitrile

Reference Example 11a)
6-methoxy-3,4-dihydroisoquinoline 2-oxide under argon atmosphere, 6-methoxy-1,2,3,4-tetrahydroisoquinoline (5.8 g), sodium tungstate dihydrate (0.4 g) and A mixture of methanol (270 mL) was ice-cooled to 0 ° C., and 30% aqueous hydrogen peroxide (20 mL) was added dropwise. Thereafter, the ice bath was removed and the reaction solution was gradually warmed to room temperature and stirred for 3 hours. To the reaction solution was added brine and extracted with THF. The organic layer was washed with aqueous sodium thiosulfate solution and then with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (6.4 g) as an oil.
LCMS (ESI ⁺ ) M + H ⁺ : 178.

Reference Example 11b) (Reference Example 11)
(6-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanenitrile
6-Methoxy-3,4-dihydroisoquinoline 2-oxide (18.6 g) was stirred for 10 minutes at 0 ° C. with diethyl cyanomethylphosphonate (19.2 g), 60% sodium hydride (5.4 g) and DME. (150 mL) was added into the mixed solution. The reaction solution was stirred at room temperature for 12 hours, cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (7.1 g) as pale yellow crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.80 (t, J = 6.2 Hz, 2 H), 3.25 (td, J = 6.2, 3.0 Hz, 2 H), 3.79 (s, 3 H) , 4.40 (s, 1 H), 6.82-6.86 (m, 2 H), 7.29 (br.s, 1H), 7.62-7.64 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 201.

Example 1
2- (Benzyloxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

To a solution of 2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.10 g) and benzyl alcohol (134 μL) in DMF (5.0 mL) was added potassium carbonate (0. 18 g) was added and the mixture was stirred at 85 ° C. for 8 hours under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, followed by recrystallization from ethyl acetate / n-hexane to give the title compound (0.030 g) as crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 6.4 Hz, 2 H), 4.04 (t, J = 6.4 Hz, 2 H), 5.38 (s, 2 H), 6.68 (s, 1 H), 7.24-7.75 (m, 8 H), 8.00 (d, J = 7.6 Hz, 1 H).
LCMS (ESI ⁺ ), M + H ⁺ : 305.

Example 2
2- (Benzylsulfanyl) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

To a solution of 2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.15 g) and phenylmethanethiol (227 μL) in DMF (3.0 mL) was added potassium carbonate (0 .27 g) was added and the mixture was stirred at 85 ° C. overnight under an argon atmosphere. Water and 1N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC followed by recrystallization from ethyl acetate / n-hexane to give the title compound (0.026 g) as yellow crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.03 (t, J = 6.6 Hz, 2 H), 4.05 (d, J = 6.6 Hz, 2 H), 4.44 (s, 2 H), 7.04 (s, 1 H), 7.21-7.47 (m, 7 H), 7.50-7.58 (m, 1 H), 8.00 (d, J = 7.5 Hz, 1 H).
LCMS (ESI ⁺ ), M + H ⁺ : 321.

Example 3
2- (Pyridin-3-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

To a solution of 2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.015 g) and 3-pyridinemethanol (190 μL) in DMF (3.0 mL) was added potassium carbonate ( 0.27 g) was added and the mixture was stirred at 85 ° C. for 6 hours under an argon atmosphere. Water and 1N hydrochloric acid were added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC, and then recrystallized from ethyl acetate / n-hexane to give the title compound (0.011 g) as crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 6.4 Hz, 2 H), 4.05 (t, J = 6.4 Hz, 2 H), 5.43 (s, 2 H), 6.69 (s, 1 H), 7.31-7.57 (m, 4 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 8.57 (d, J = 3.4 Hz, 1 H), 8.70 (d, J = 1.5 Hz, 1 H).
LCMS (ESI ⁺ ), M + H ⁺ : 306.

Example 4
2-[(4-Fluorobenzyl) oxy] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.15 g) in DMF (2 mL) was previously stirred at 0 ° C. for 30 minutes (4-fluoro A mixture of phenyl) methanol (0.21 mL), 60% sodium hydride (0.077 g) and DMF (2 mL) was added, and the mixture was stirred for 4 hours while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.022 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 6.3 Hz, 2 H), 4.05 (t, J = 6.3 Hz, 2 H), 5.36 (s, 2 H), 6.67 (s, 1 H), 7.11-7.31 (m, 2 H), 7.35-7.48 (m, 2 H), 7.48-7.61 (m, 3 H), 7.93-8.05 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 323.
Anal.Calcd for C19H15N2O2F: C, 70.80; H, 4.69; N, 8.69.Found: C, 70.66; H, 4.71; N, 8.74.

Example 5
2- (2-Phenylethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Phenylethanol stirred in a DMF (2 mL) solution of 2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.15 g) at 0 ° C. for 30 minutes in advance. (0.232 mL), 60% sodium hydride (0.077 g) and DMF (2 mL) were added, and the mixture was stirred for 5 hours while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.049 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.94-3.09 (m, 4 H), 3.96-4.07 (m, 2 H), 4.42-4.57 (m, 2 H), 6.57 (s, 1 H), 7.16-7.44 (m, 8 H), 7.47-7.58 (m, 1 H), 7.93-8.05 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 319.

Example 6
2-[(4-Fluorobenzyl) sulfanyl] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-chloro-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.15 g), (4-fluorophenyl) methanethiol (0.28 g), potassium carbonate (0. 54 g) and DMF (2 mL) were stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography followed by preparative HPLC. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.10 g) as yellow crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.03 (t, J = 6.4 Hz, 2 H), 4.05 (t, J = 6.4 Hz, 2 H), 4.43 (s, 2 H), 7.03 (s, 1 H), 7.09-7.33 (m, 2 H), 7.29-7.62 (m, 5 H), 7.85-8.08 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 339.
Anal.Calcd for C19H15N2OSF: C, 67.44; H, 4.47; N, 8.28.Found: C, 67.23; H, 4.49; N, 8.27.

Example 7
2- (Pyridin-2-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.15 g) in DMF (2 mL) was previously stirred at 0 ° C. for 30 minutes with pyridine-2- A mixture of ilmethanol (0.19 mL), 60% sodium hydride (0.077 g), and DMF (2 mL) was added, and the mixture was stirred for 7 hours while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.035 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 6.4 Hz, 2 H), 4.04 (t, J = 6.4 Hz, 2 H), 5.45 (s, 2 H), 6.75 (s, 1 H), 7.19-7.71 (m, 5 H), 7.73-7.96 (m, 1 H), 7.96-8.21 (m, 1 H), 8.41-8.79 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 306.

Example 8
2- (2-Phenylethyl) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

Under hydrogen atmosphere, 2-[(E) -2-phenylethenyl] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.05 g), 10% Pd / C A mixture of (0.01 g) and methanol / THF (2 mL / 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate / n-hexane to give the title compound as white crystals (0.006 g).
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.84-2.96 (m, 2 H), 2.96-3.12 (m, 4 H), 4.07 (t, J = 6.6 Hz, 2 H), 7.05 ( s, 1 H), 7.14-7.25 (m, 1 H), 7.24-7.36 (m, 4 H), 7.37-7.50 (m, 2 H), 7.50-7.62 (m, 1 H), 7.97-7.99 ( m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 303.

Example 9
2- (3-Phenylpropoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Phenyl-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.15 g) in DMF (2 mL) previously stirred at 0 ° C. for 30 minutes A mixture of -1-ol (0.25 mL), 60% sodium hydride (0.077 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC followed by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.041 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.92-2.12 (m, 2 H), 2.70-2.75 (m, 2 H), 2.98-3.03 (m, 2 H), 4.00-4.05 (m , 2 H), 4.25-4.30 (m, 2 H), 6.62 (s, 1 H), 7.13-7.36 (m, 5 H), 7.35-7.46 (m, 2 H), 7.46-7.61 (m, 1 H), 7.94-8.07 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 333.
Anal.Calcd for C21H20N2O2: C, 75.88; H, 6.06; N, 8.43.Found: C, 75.93; H, 6.19; N, 8.47.

Example 10
2- (1,3-Thiazol-2-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

1,3-chloro-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.15 g) in DMF (2 mL) was stirred at 0 ° C. for 30 minutes in advance. A mixture of thiazol-2-ylmethanol (0.22 g), 60% sodium hydride (0.077 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.077 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.03 (t, J = 6.4 Hz, 2 H), 4.06 (t, J = 6.4 Hz, 2 H), 5.67 (s, 2 H), 6.74 (s, 1 H), 7.35-7.47 (m, 2 H), 7.49-7.59 (m, 1 H), 7.79-7.81 (m, 1 H), 7.85-7.86 (m, 1 H), 7.97-8.09 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 312.
Anal.Calcd for C16H13N3O2S: C, 61.72; H, 4.21; N, 13.50.Found: C, 61.81; H, 4.25; N, 13.53.

Example 11
2- (Thiophen-2-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.15 g) in DMF (2 mL) was previously stirred at 0 ° C. for 30 minutes for thiophene-2- A mixture of ilmethanol (0.22 g), 60% sodium hydride (0.077 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.027 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.96-3.08 (m, 2 H), 3.99-4.11 (m, 2 H), 5.56 (s, 2 H), 6.63 (s, 1 H) , 7.01-7.08 (m, 1 H), 7.22-7.31 (m, 1 H), 7.36-7.45 (m, 2 H), 7.48-7.61 (m, 2 H), 7.97-8.00 (m, 1H).
LCMS (ESI ⁺ ) M + H ⁺ : 311.
Anal.Calcd for C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03.Found: C, 65.62; H, 4.52; N, 8.97.

Example 12
2- (1,3-Thiazol-5-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

1,3-chloro-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.10 g) in DMF (2 mL) was stirred at 0 ° C. for 30 minutes in advance. A mixture of thiazol-5-ylmethanol (0.15 g), 60% sodium hydride (0.052 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.059 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.02 (t, J = 6.4 Hz, 2 H), 4.06 (t, J = 6.4 Hz, 2 H), 5.64 (s, 2 H), 6.64 (s, 1 H), 7.32-7.46 (m, 2 H), 7.47-7.62 (m, 1 H), 7.97-8.00 (m, 1 H), 8.05 (s, 1 H), 9.12 (s, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 312.
Anal.Calcd for C16H13N3O2S: C, 61.72; H, 4.21; N, 13.50.Found: C, 61.57; H, 4.28; N, 13.39.

Example 13
2-[(1-Phenylethyl) sulfanyl] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

1-phenylethane stirred in a DMF (2 mL) solution of 2-chloro-6,7-dihydro-4H-pyrimido [6,1-A] isoquinolin-4-one (0.10 g) at 0 ° C. for 30 minutes in advance. A mixture of thiol (0.071 g), 60% sodium hydride (0.021 g) and DMF (2 mL) was added, and the mixture was stirred for 2 days while warming to room temperature. To the reaction solution was added potassium carbonate (0.059 g), and the mixture was stirred at 50 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative HPLC to give the title compound (0.045 g) as an amorphous solid.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.70-1.73 (m, 3 H), 3.02 (t, J = 6.4 Hz, 2 H), 4.00-4.09 (m, 2 H), 5.17 ( m, 1 H), 6.95 (s, 1 H), 7.21-7.58 (m, 8 H), 7.92-8.00 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 335.

Example 14
2- (Benzylsulfanyl) -8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.09 g) in DMF (2 mL) was previously stirred at 0 ° C. for 15 minutes. A mixture of phenylmethanethiol (0.14 mL), 60% sodium hydride (0.041 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.073 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.92-2.97 (m, 2 H), 3.86 (s, 3 H), 3.99-4.03 (m, 2 H), 4.44 (s, 2 H) , 7.00 (s, 1 H), 7.17-7.47 (m, 7 H), 7.57-7.60 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 351.
Anal.Calcd for C20H18N2O2S: C, 68.55; H, 5.18; N, 7.99.Found: C, 68.45; H, 5.17; N, 7.98.

Example 15
2-[(4-Fluorobenzyl) sulfanyl] -8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.09 g) in DMF (2 mL) was previously stirred at 0 ° C. for 15 minutes. A mixture of (4-fluorophenyl) methanethiol (0.15 mL), 60% sodium hydride (0.041 g) and DMF (2 mL) was added, and the mixture was stirred for 1 hour while warming to room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.076 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.94 (t, J = 6.7 Hz, 2 H), 3.86 (s, 3 H), 4.01 (t, J = 6.7 Hz, 2 H), 4.43 (s, 2 H), 7.00 (s, 1 H), 7.10-7.25 (m, 3 H), 7.35-7.41 (m, 1 H), 7.43-7.51 (m, 2 H), 7.57-7.60 (m , 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 369.
Anal.Calcd for C20H17N2O2SF: C, 65.20; H, 4.65; N, 7.60.Found: C, 65.17; H, 4.64; N, 7.62.

Example 16
2- (Benzylsulfanyl) -8-hydroxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.22 g) and hydrobromic acid (18 mL) For 10 minutes. The reaction solution was concentrated under reduced pressure. A part of the residue (0.09 g) was purified by silica gel column chromatography. The obtained solid was crystallized from THF / n-hexane to give the title compound (0.0098 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.90 (t, J = 6.6 Hz, 2 H), 4.01 (t, J = 6.6 Hz, 2 H), 4.43 (s, 2 H), 6.95 (s, 1 H), 7.01-7.04 (m, 1 H), 7.15-7.38 (m, 4 H), 7.39-7.47 (m, 3 H), 10.02 (s, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 337.

Example 17
2- (Benzylsulfanyl) -8-ethoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.22 g) and hydrobromic acid (18 mL) For 10 minutes. The reaction solution was concentrated under reduced pressure. To a solution of a part of the residue (0.090 g) in DMF (4 mL) was added iodoethane (0.051 mL) and potassium carbonate (0.15 g) in this order, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.015 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.35-1.40 (m, 3 H), 2.93-2.97 (m, 2 H), 3.99-4.04 (m, 2 H), 4.07-4.14 (m , 2 H), 4.44 (s, 2 H), 7.00 (s, 1 H), 7.16-7.47 (m, 7 H), 7.56-7.59 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 365.

Example 18
2- (Benzylsulfanyl) -8-butoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -8-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.22 g) and hydrobromic acid (18 mL) For 10 minutes. The reaction solution was concentrated under reduced pressure. To a solution of a part of the residue (0.090 g) in DMF (4 mL), iodobutane (0.051 mL) and potassium carbonate (0.15 g) were sequentially added, and the mixture was stirred at 80 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography. The obtained solid was crystallized from ethyl acetate / n-hexane to give the title compound (0.015 g) as white crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.92-0.97 (m, 3 H), 1.37-1.56 (m, 2 H), 1.65-1.82 (m, 2 H), 2.93-2.97 (m , 2 H), 3.91-4.12 (m, 4 H), 4.44 (s, 2 H), 6.99 (s, 1 H), 7.16-7.47 (m, 7 H), 7.56-7.58 (m, 1 H) .
LCMS (ESI ⁺ ) M + H ⁺ : 393.

Example 19
2- (Benzylsulfanyl) -11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-Chloro-11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.1 g), potassium carbonate (0.1 g), phenylmethanethiol (0.047 g ) And DMF (2 mL) were stirred at 50 ° C. for 2 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (0.074 g) was obtained as colorless crystals by crystallization from ethyl acetate / n-hexane.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.95 (t, J = 6.2 Hz, 2 H), 3.89 (s, 3 H), 3.94-4.06 (m, 2 H), 4.43 (s, 2 H), 6.94-7.02 (m, 1 H), 7.08-7.13 (m, 1 H), 7.15 (s, 1 H), 7.21-7.37 (m, 3 H), 7.38-7.51 (m, 3 H ).
LCMS (ESI ⁺ ) M + H ⁺ : 351.

Example 20
2-[(4-Fluorobenzyl) sulfanyl] -11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2-chloro-11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.1 g), potassium carbonate (0.1 g), (4-fluorophenyl) methane A mixture of thiol (0.054 g) and DMF (2 mL) was stirred at 50 ° C. for 2 hours. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (0.065 g) was obtained as colorless crystals by crystallization from ethyl acetate / n-hexane.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.85-3.03 (m, 2 H), 3.89 (s, 3 H), 3.94-4.04 (m, 2 H), 4.42 (s, 2 H) , 6.86-7.03 (m, 1 H), 7.06-7.21 (m, 4 H), 7.40-7.58 (m, 3 H).
LCMS (ESI ⁺ ) M + H ⁺ : 369.

Example 21
2- (Benzylsulfanyl) -11-butoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -11-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.24 g) and 48% hydrobromic acid (10 mL) Microwave irradiation at 150 ° C. for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was dissolved in DMF (3 mL), and potassium carbonate (0.29 g) and butyl iodide (0.13 g) were added at room temperature. The mixture was stirred at 50 ° C. for 3 hours, cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (0.008 g) as an oil.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.00 (t, J = 7.4 Hz, 3 H), 1.47-1.59 (m, 2 H), 1.76-1.90 (m, 2 H), 2.87- 3.03 (m, 2 H), 4.03-4.10 (m, 2 H), 4.13-4.21 (m, 2 H), 4.52 (s, 2 H), 6.74-6.96 (m, 2 H), 7.20-7.37 ( m, 5 H), 7.36-7.50 (m, 2 H).
LCMS (ESI ⁺ ) M + H ⁺ : 393.

Example 22
2- (Benzylsulfanyl) -9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

Example 22a)
2- (6-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide
A mixture of (6-methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanenitrile (1.2 g) and polyphosphoric acid (15 g) was stirred at 100 ° C. for 3 hours. The reaction solution was neutralized with 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.2 g) as an amorphous solid.
LCMS (ESI ⁺ ) M + H ⁺ : 219.

Example 22b)
9-Methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione
2- (6-Methoxy-3,4-dihydroisoquinoline-1 (2H) -ylidene) ethanamide (1.2 g), diethyl carbonate (4.0 g) and ethanol (40 mL) were mixed with 20% sodium ethoxide- Ethanol solution (7.8 mL) was added at room temperature. The reaction solution was stirred under reflux for 12 hours and cooled to room temperature, and 1N hydrochloric acid (45 mL) was added. The yellow precipitate was collected by filtration, washed with water and dried to give the title compound (1.1 g) as an amorphous solid.
LCMS (ESI ⁺ ) M + H ⁺ : 245.

Example 22c)
2-Chloro-9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one
A mixture of 9-methoxy-6,7-dihydro-2H-pyrimido [6,1-a] isoquinoline-2,4 (3H) -dione (0.5 g) and phosphorus oxychloride (7.7 g) For 1 hour. The reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.43 g) as an amorphous solid.
LCMS (ESI ⁺ ) M + H ⁺ : 263.

Example 22d) (Example 22)
2- (Benzylsulfanyl) -9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one
2-Chloro-9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.43 g), potassium carbonate (1.1 g), phenylmethanethiol (0.4 g ) And DMF (25 mL) were stirred at 90 ° C. for 15 h. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (0.45 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.00 (t, J = 6.5 Hz, 2 H), 4.01-4.06 (m, 3 H), 4.43 (s, 2 H), 6.93-6.98 ( m, 3 H), 6.99 (d, J = 2.4 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.30-7.35 (m, 3 H), 7.41-7.45 (m, 2 H), 7.95 (d, J = 8.9 Hz, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 351.

Example 23
2- (Benzylsulfanyl) -9-ethoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.30 g) and 48% hydrobromic acid (30 mL) Microwave irradiation at 150 ° C. for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was washed with THF to obtain a solid (0.41 g). A mixture of the obtained solid (0.2 g), ethyl iodide (0.22 g), potassium carbonate (0.33 g) and DMF (5 mL) was stirred at 110 ° C. for 3 hours. To the reaction solution was added brine and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography, and the obtained crude crystals were washed with acetonitrile to give the title compound (0.035 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.35 (t, J = 7.0 Hz, 3 H), 2.99 (t, J = 6.5 Hz 2 H), 4.03 (t, J = 6.7 Hz, 2 H) 4.12 (q, J = 7.0 Hz, 2 H), 4.43 (s, 2 H), 6.92-6.95 (m, 2 H), 6.97 (d, J = 2.3 Hz, 1 H), 7.26 (d, J = 7.2 Hz, 1 H), 7.30-7.35 (m, 2 H), 7.43 (d, J = 7.2 Hz, 2 H). 7.93 (d, J = 8.9 Hz, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 365.

Example 24
2- (Benzylsulfanyl) -9-butoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 2- (benzylsulfanyl) -9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (0.30 g) and 48% hydrobromic acid (30 mL) Microwave irradiation at 150 ° C. for 10 minutes. The solvent was distilled off under reduced pressure, and the residue was washed with THF to obtain a solid (0.41 g). A mixture of the obtained solid (0.2 g), butyl iodide (0.26 g), potassium carbonate (0.33 g) and DMF (5 mL) was stirred at 110 ° C. for 3 hours. To the reaction solution was added brine and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography, and the obtained crude crystals were washed with acetonitrile to give the title compound (0.031 g) as colorless crystals.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.93 (t, J = 7.4 Hz, 3 H), 1.40-1.47 (m, 2 H), 1.68-1.74 (m, 2 H), 2.99 ( t, J = 6.4 Hz, 2 H), 4.01-4.09 (m, 4 H), 4.43 (s, 2 H), 6.92-6.96 (m, 2 H), 6.98 (d, J = 2.4 Hz, 1 H ), 7.23-7.28 (m, 1 H), 7.30-7.35 (m, 2 H), 7.43 (d, J = 7.2 Hz, 2 H), 7.93 (d, J = 8.9 Hz, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 393.

Example 25
2- (Benzylsulfanyl) -9- (2-methoxyethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

2- (Benzylsulfanyl) -9-hydroxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (23.5 mg) in DMF solution (1.0 mL) was added potassium carbonate (69 mg ), 2-bromoethyl methyl ether (29.2 mg) was added, and the mixture was stirred at 60 ° C. for 3 hours. After completion of the reaction, water (3 mL) and ethyl acetate (2 mL) were added and stirred for a while. Only the organic layer was passed through a phase separation filter. After the filtrate was concentrated, the residue was dissolved in DMSO (1 mL), purified by preparative HPLC, and concentrated to give the title compound (14.3 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 395, purity 100%.

Example 26
2- (Benzylsulfanyl) -9- (cyclohexylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using (bromomethyl) cyclohexane (37.2 mg) in the same manner as in Example 25 to obtain the title compound (11.7 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 0.97-1.10 (m, 2 H), 1.12-1.32 (m, 3 H), 1.60-1.84 (m, 6 H), 2.99 (t, J = 6.3 Hz, 2 H), 3.87 (d, J = 6.1 Hz, 2 H), 4.03 (t, J = 6.1 Hz, 2 H), 4.44 (s, 2 H), 6.93-7.00 (m, 3 H) , 7.23-7.29 (m, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.43 (d, J = 7.3 Hz, 2 H), 7.94 (d, J = 8.8 Hz, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 433 [M + H], purity 100%.

Example 27
3-{[2- (Benzylsulfanyl) -4-oxo-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-9-yl] oxy} propanamide

2- (Benzylsulfanyl) -9-hydroxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (23.5 mg) in DMF solution (1.0 mL) was added potassium carbonate (69 mg ), 3-bromopropionamide (31.9 mg) was added, and the mixture was stirred at 60 ° C. for 3 hours. 3-Bromopropionamide (31.9 mg), potassium t-butoxide (12.0 mg) and sodium iodide (15.0 mg) were further added to the reaction solution, and the mixture was stirred at 70 ° C. for 15 hours. After completion of the reaction, water (3 mL) and ethyl acetate (2 mL) were added and stirred for a while, and only the organic layer was passed through a phase separation filter. After the filtrate was concentrated, the residue was dissolved in DMSO (1 mL), purified by preparative HPLC, and concentrated to obtain the title compound (2.6 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 408, purity 100%.

Example 28
{[2- (Benzylsulfanyl) -4-oxo-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-9-yl] oxy} ethyl acetate

Reaction was carried out using ethyl bromoacetate (35.1 mg) in the same manner as in Example 25 to obtain the title compound (13.7 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 423, purity 100%.

Example 29
2- (Benzylsulfanyl) -9- (2-pyrrolidin-1-ylethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one trifluoroacetate

In the same manner as in Example 27, reaction was performed using N- (2-chloroethyl) pyrrolidine hydrochloride (71.4 mg) to obtain the title compound (8.2 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 434, purity 100%.

Example 30
(±) -2- (Benzylsulfanyl) -9- (tetrahydro-2H-pyran-2-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was conducted using 2- (bromomethyl) tetrahydro-2H-pyran (37.6 mg) in the same manner as in Example 25 to obtain the title compound (10.7 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 435, purity 100%.

Example 31
2- (Benzylsulfanyl) -9- (2-phenylethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using 2- (bromoethyl) benzene (38.9 mg) in the same manner as in Example 25 to obtain the title compound (17.0 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 441, purity 100%.

Example 32
2- (Benzylsulfanyl) -9- (2-morpholin-4-ylethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one trifluoroacetate

The reaction was conducted using 4- (2-chloroethyl) morpholine hydrochloride (39.1 mg) in the same manner as in Example 25 to obtain the title compound (23.9 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 450, purity 100%.

Example 33
2- (Benzylsulfanyl) -9- (pyridin-2-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using 2- (bromomethyl) pyridine hydrobromide (106.2 mg) in the same manner as in Example 27 to obtain the title compound (11.1 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 428, purity 100%.

Example 34
2- (Benzylsulfanyl) -9-[(4-fluorobenzyl) oxy] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was conducted using 4-fluorobenzyl bromide (39.7 mg) in the same manner as in Example 25 to obtain the title compound (18.2 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 445, purity 100%.

Example 35
2- (Benzylsulfanyl) -9- (2-oxobutoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using 1-bromo-2-butanone (31.7 mg) in the same manner as in Example 25 to obtain the title compound (9.2 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 407, purity 100%.

Example 36
(±) -2- (Benzylsulfanyl) -9- (2-hydroxypropoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using 1-bromo-2-propanol (29.2 mg) in the same manner as in Example 27 to obtain the title compound (1.6 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 395, purity 100%.

Example 37
2- (Benzylsulfanyl) -9- (pyridin-3-ylmethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one trifluoroacetate

The reaction was conducted using 3- (bromomethyl) pyridine hydrobromide (53.1 mg) in the same manner as in Example 25 to obtain the title compound (6.8 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 428, purity 100%.

Example 38
2- (Benzylsulfanyl) -9- [2- (4-fluorophenyl) -2-oxoethoxy] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was performed using 4-fluorophenacyl bromide (45.6 mg) in the same manner as in Example 25 to obtain the title compound (11.0 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 473 [M + H], purity 100%.

Example 39
2- (Benzylsulfanyl) -9- (2-hydroxyethoxy) -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

The reaction was carried out using 2-bromoethanol (26.2 mg) in the same manner as in Example 25 to obtain the title compound (12.0 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 381 [M + H], purity 100%.

Example 40
{[2- (Benzylsulfanyl) -4-oxo-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-9-yl] oxy} acetonitrile

Reaction was carried out using bromoacetonitrile (25.2 mg) in the same manner as in Example 25 to obtain the title compound (10.7 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 3.03 (t, J = 6.6 Hz, 2 H), 4.05 (t, J = 6.6 Hz, 2 H), 4.44 (s, 2 H), 5.28 ( s, 2 H), 7.00 (s, 1 H), 7.08-7.15 (m, 2 H), 7.21-7.29 (m, 1 H), 7.33 (t, J = 7.6 Hz, 2 H), 7.43 (d , J = 7.1 Hz, 2 H), 8.04 (d, J = 8.5 Hz, 2 H). LCMS (ESI ⁺ ) M + H ⁺ : 376 [M + H], purity 100%.

Example 41
2- (Benzylsulfanyl) -9- [2- (diethylamino) ethoxy] -6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one trifluoroacetate

The reaction was conducted using 2-bromo-N, N-diethylethylamine hydrobromide (54.8 mg) in the same manner as in Example 27 to obtain the title compound (2.2 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 436, purity 100%.

Example 42
2-{[2- (benzylsulfanyl) -4-oxo-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-9-yl]}-N, N-diethylacetamide

The reaction was conducted using 2-bromo-N, N-diethylacetamide (40.7 mg) in the same manner as in Example 25 to obtain the title compound (11.1 mg).
LCMS (ESI ⁺ ) M + H ⁺ : 450, purity 100%.
Example 43
2- (Benzylsulfanyl) -9-hydroxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one
2- (Benzylsulfanyl) -9-methoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one (1.65 g) in methylene chloride (12 mL) under ice-cooling Boron bromide (1.0 M methylene chloride solution, 14 ml) was added and stirred at room temperature for 5 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was stirred for 1 hr. The resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (1.47 g) as pale-yellow crystals.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 2.93 (t, J = 6.4 Hz, 2 H), 4.01 (t, J = 6.6 Hz, 2 H), 4.42 (s, 2 H), 6.72- 6.80 (m, 2 H), 6.85 (s, 1 H), 7.21-7.46 (m, 5 H), 7.83 (d, J = 8.3 Hz, 1 H), 10.27-10.52 (m, 1 H).
LCMS (ESI ⁺ ) M + H ⁺ : 337.

Example 1
(1) Preparation of expression vector A vector for expressing human Lp-PLA ₂ was prepared as follows. First, PCR was performed using two primers, Primer 1 and Primer 2, using pTriEx-3 (Novagen) as a template.
Primer 1: 5'-CCTATTAATAGTAATCAATTACGGGGTCATTAG-3 '(SEQ ID NO: 1)
Primer 2: 5'-CGCATGCTTTCAGCAAAAAACCCCTCAAGACC-3 '(SEQ ID NO: 2)
The reaction was treated with Pyrobest DNA Polymease (Takara Bio) for 1 minute at 98 ° C, followed by repeating 10 times at 98 ° C for 10 seconds and 67 ° C for 1 minute 35 times, followed by treatment at 72 ° C for 5 minutes. The 1.6 kbp PCR product was recovered by agarose gel electrophoresis. This DNA fragment was inserted into pFastBac1 (Invitrogen) cut with Sna BI and Avr II (both Takara Bio) and blunt-ended using Blunting High (Toyobo), cloned into Escherichia coli JM109 (Nippon Gene), and the expression vector pFastTriEx Was made.
Next, tags were introduced using synthetic DNA. Primer 3 and Primer 4 were annealed to obtain double-stranded DNA fragments HPA-F / HPA-R.
Primer 3: 5'-TAAAATACTATACTGTAAATTACATTTTATTTACAATCAAAGGAGGTTAAC-3 '(SEQ ID NO: 3)
Primer 4: 5'-CATGGTTAACCTCCTTTGATTGTAAATAAAATGTAATTTACAGTATAGTATTTTAAT-3 '(SEQ ID NO: 4)
Similarly, anneal Primer 5 and Primer 6, Primer 7 and Primer 8, Primer 9 and Primer 10, respectively.FNCONHE-F / NCONHE-R ・ FNHENOT-F / NHENOT-R ・ PBGLNHE-F / PBGLNHE-R Got.
Primer 5: 5'-CATGGACTACAAGGACGACGATGACAAGGGATCCG-3 '(SEQ ID NO: 5)
Primer 6: 5'-CTAGCGGATCCCTTGTCATCGTCGTCCTTGTAGTC-3 '(SEQ ID NO: 6)
Primer 7: 5'-CTAGCGACTACAAGGACGACGATGACAAGTGAGC-3 '(SEQ ID NO: 7)
Primer 8: 5'-GGCCGCTCACTTGTCATCGTCGTCCTTGTAGTCG-3 '(SEQ ID NO: 8)
Primer 9: 5'-GATCTCTGGAAGTTCTGTTCCAGGGGCCCGGATCCG-3 '(SEQ ID NO: 9)
Primer 10: 5'-CTAGCGGATCCGGGCCCCTGGAACAGAACTTCCAGA-3 '(SEQ ID NO: 10)
Of these, three double-stranded DNA fragments, HPA-F / HPA-R, FNCONHE-F / NCONHE-R, FNHENOT-F / NHENOT-R, were obtained with Pac I (New England Biolabs) and Not I (Takara Bio). It was inserted into the cut pFastTriEx and cloned into E. coli JM109 to prepare the expression vector pFTF (-). In addition, pFTF (-) was cleaved with BamHI (Takara Bio) and Nhe I (Takara Bio), and double-stranded DNA fragments PBGLNHE-F / PBGLNHE-R were inserted to prepare an expression vector pFTF (+). Further, Primer 11 and Primer 12, Primer 13 and Primer 14 were annealed to obtain double-stranded DNA fragments HNCONHE-F / HNCONHE-R and HNHENOT-F / HNHENOT-R.
Primer 11: 5'-CATGGCACACCATCACCACCATCACGGATCCG-3 '(SEQ ID NO: 11)
Primer 12: 5'-CTAGCGGATCCGTGATGGTGGTGATGGTGTGC-3 '(SEQ ID NO: 12)
Primer 13: 5'-CTAGCCATCACTATCATCATCACTGAGC-3 '(SEQ ID NO: 13)
Primer 14: 5'-GGCCGCTCAGTGATGATGATAGTGATGG-3 '(SEQ ID NO: 14)
Three double-stranded DNA fragments HPA-F / HPA-R, HNCONHE-F / HNCONHE-R, HNHENOT-F / HNHENOT-R were similarly inserted into pFastTriEx cut with Pac I and Not I, and cloned. An expression vector pFTH (-) was prepared. In addition, pFTH (-) was cleaved with BamHI and NheI, and double-stranded DNA fragments PBGLNHE-F / PBGLNHE-R were inserted to prepare an expression vector pFTH (+).

(2) human Lp-PLA ₂ gene intracellular subcloned region human Lp-PLA ₂ gene intracellular full-length human subcloning regions were purchased from Invitrogen Lp-PLA ₂ cDNA gene (Invitrogen, Cat No.FL1002) to 10ng a template The PCR was performed using the primer set Primer 15 and Primer 16 prepared with reference to the gene base sequence information.
Primer 15: 5'-AGGAGGTTAACCATGTTTGACTGGCAATAC-3 '(SEQ ID NO: 15)
Primer 16: 5'-CTTGTAGTCGCTAGCATTGTATTTCTCTAT-3 '(SEQ ID NO: 16)
To the reaction tube for PCR so that the total volume is 50 μL, KOD DNA Polymerase (Toyobo) 2.5 U / reaction, template amount 10 ng, each primer 25 pmoles, dNTP concentration 0.2 mM, MgCl2 concentration 1 mM, 10 × buffer 1 for KOD DNA Polymerase After adding 5 minutes of denaturation at 96.0 ° C using Gene Amp PCR System 9700 (Applied Biosystems), 25 cycles of 96.0 ° C for 30 seconds, 50.0 ° C for 30 seconds, and 72.0 ° C for 40 seconds Performed under conditions. The obtained PCR fragment was digested with restriction enzymes Hpa I (Takara Bio) and Nhe I (Takara Bio), and then subjected to agarose gel electrophoresis to recover the DNA fragment. The DNA fragment was mixed with baculovirus expression plasmid pFTF (+) digested with restriction enzymes Hpa I (Takara Bio) and Nhe I (Takara Bio) and ligated with DNA Ligation Kit Ver.2 (Takara Bio). Plasmid pFTF (+) / hLpPLA2-2 was obtained by transforming competent cells of E. coli JM109.

(3) Preparation of plasmid for expression of human Lp-PLA ₂ and preparation of recombinant baculovirus Recombinant baculovirus using the above plasmid pFTF (+) / hLpPLA2-2 and BAC-to-BAC Baculovirus Expression System (Invitrogen) Virus stocks were prepared.

(4) Preparation of human Lp-PLA ₂
After seeding 5 L of High Five cells (Invitrogen) at 0.3 × 10 ⁶ cells / mL in Express Five medium (Invitrogen) containing 10% (v / v) FBS, the cells were cultured at 27 ° C. for 3 days.
Add 5 L of Express Five medium (Invitrogen) containing 10% (v / v) FBS to a cell density of 2 × 10 ⁶ cells / mL, add 36 mL of baculovirus stock of human Lp-PLA ₂ and culture for 3 days did. The cells were separated from the culture solution by centrifugation (4,000 rpm, 10 min), and then washed with PBS. 2 L of cells are suspended in 150 mL of Lysis buffer (TBS + 163 mM NaCl + 10% (v / v) Glycerol + 0.1% w / v CHAPS), then treated with a homogenizer (Polytron) at 20,000 rpm for 2 seconds The cells were disrupted by performing the treatment once. The supernatant obtained by centrifugation (40,000 rpm, 40 min) was adsorbed on Anti-FLAG M2 agarose gel and washed (Lysis buffer), and then eluted with Lysis buffer containing 0.1 mg / mL FLAG peptide.
Further Purification by TBS + 163mMNaCl + 10% (v / v) Superdex200 column equilibrated with Glycerol, to prepare a recombinant human Lp-PLA _2.

(5) Measurement of recombinant human Lp-PLA ₂ enzyme inhibitory activity
3 μL of enzyme solution (100 mM Tris-HCl, 1 mM EGTA, 0.1% (w / v) BSA (pH 7.2)) containing 300 ng / mL recombinant human Lp-PLA ₂ in 3% (v / v) 3 μL of the example compound of Table 1 dissolved in DMSO was mixed and incubated at room temperature for 10 minutes. Next, 3 μL of 6 μM Red / Green BODIPY PC-A2 (Invitrogen) was added and mixed to start the reaction. Furthermore, after reacting at room temperature for 30 minutes, the reaction was stopped by adding and mixing 3 μL of 0.4N phosphoric acid solution. Two kinds of fluorescence values (Excitation485nm / Emission535nm, Excitation485nm / Emission590nm) were measured at Envision (PerkinElmer), and enzyme activity was calculated from these ratios ((Excitation485nm / Emission535nm) / (Excitation485nm / Emission590nm)). Effects on human Lp-PLA ₂ enzyme activity of the example compounds was expressed by inhibition ratio (%). This is defined as 100-100X (t, where t is the value when no example compound is added and the enzyme is added, b is the value when the example compound and the enzyme are not added, and t 'is the value when the example compound and the enzyme are added. It was calculated from the formula '-b) / (tb). The results are shown in Table 1.

As is clear from Table 1, the compound of the present invention showed excellent Lp-PLA ₂ inhibitory activity.

Formulation Example 1 (Manufacture of capsules)
1) Compound of Example 1 30 mg
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.

Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

The compound of the present invention has Lp-PLA ₂ action and is useful for the prevention and treatment of coronary syndromes such as atherosclerosis, myocardial infarction, unstable angina, peripheral arterial occlusion, stroke, cerebral infarction, etc. is there.

Claims (11)

formula


[Wherein, R ¹ represents an optionally substituted 5- to 10-membered aromatic group,
R ² is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C _1-6 alkoxy group, or a formula —OCOR ⁴ , —NR ⁴ R ⁵ , —NR ⁵ SO ₂ R ⁴ , —NR ⁵ COR ⁴ or —NR ⁵ CONR ⁴ R ⁶ (wherein R ⁴ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, R ⁵ and R ⁶ independently represent a hydrogen atom or a C _1-6 alkyl group) R ⁴ and R ⁵ , R ⁴ and R ^6, and R ⁵ and R ⁶ may be bonded to each other to form an optionally substituted ring. Indicate
R ³ represents a hydrogen atom or a halogen atom,
X ¹ represents an optionally substituted C _1-2 alkylene group,
X ² represents an oxygen atom, a sulfur atom or an optionally substituted methylene,
Y represents an optionally substituted C _1-3 alkylene group. ]
Or a salt thereof. 2. The compound according to claim 1, wherein X ¹ is a C _1-2 alkylene group which may be substituted with 1 to 3 substituents selected from a halogen atom, a C _1-6 alkyl group, an oxo group and a hydroxy group. A prodrug of the compound of claim 1. A medicament comprising the compound according to claim 1 or a prodrug thereof. A lipoprotein-associated phospholipase A ₂ inhibitor, according to claim 4 medicament according. The medicament according to claim 4, which is an agent for preventing or treating arteriosclerosis. The medicament according to claim 4, which is a cardiovascular event onset inhibitor. A method for preventing or treating arteriosclerosis in a mammal, comprising administering an effective amount of the compound according to claim 1 or a prodrug thereof to the mammal. A method for inhibiting the onset of cardiovascular events in a mammal, comprising administering an effective amount of the compound according to claim 1 or a prodrug thereof to the mammal. Use of the compound according to claim 1 or a prodrug thereof for producing an agent for preventing or treating arteriosclerosis. Use of the compound according to claim 1 or a prodrug thereof for producing a cardiovascular event onset inhibitor.