WO2009123164A1 - Heterocyclic derivative having inhibitory activity on endothelial lipase - Google Patents

Abstract

Disclosed is a compound useful as an endothelial lipase inhibitor. Specifically disclosed is a compound represented by the formula, a pharmaceutically acceptable salt thereof, or a solvate of the compound or the pharmaceutically acceptable salt. [In the formula, Z represents a nitrogenated heterocyclic ring; R¹ represents a halogen, a hydroxy, a cyano or the like; r represents an integer of 0 to 3; Y represents -O-, -S-, -NR²- or =N-; R² represents a hydrogen, a substituted or unsubstituted alkyl or the like; A represents -C(=O)- or -C(OH)₂-; B represents -CF₂-R³ or -CN; R³ represents a hydrogen, a halogen, a substituted or unsubstituted alkyl or the like; D represents a single bond, -O-, -(CR⁴R⁵)m-O-, -O-(CR⁶R⁷)n-, -S-, -(CR⁸R⁹)p-S-, -S-(CR¹⁰R¹¹)q-, -NR¹²- or the like; R⁴ to R¹¹ independently represent a hydrogen, a halogen or the like; R¹² represents a hydrogen or a substituted or unsubstituted alkyl; m, n, p and q independently represent an integer of 1 to 5; and E represents a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl or the like.]

Description

Heterocyclic derivatives having vascular endothelial lipase inhibitory activity

The present invention relates to a compound having a vascular endothelial lipase (Endothelial Lipase, hereinafter referred to as EL) inhibitory activity and useful as a medicine.

It has long been known that a negative correlation is established between coronary artery disease (CAD) and blood HDLc level. HDLc is considered to exhibit an anti-arteriosclerosis action through an antioxidant action, an anti-inflammatory action, a reverse cholesterol transfer action, and the like, and hypoHDLcemia is recognized as one of the risk factors of CAD. Endothelial Lipase (EL) is a Triglyceride Lipase family along with Lipoprotein Lipase (LPL) and Hepatic Lipase (HL), and its strong phospholipase activity is involved in the metabolism of HDLc from the analysis of knockout mice and transgenic mice. It becomes clear and has attracted attention as a factor that defines the amount of blood HDLc. (Non-Patent Document 1)
Therefore, there is a possibility that an EL inhibitor may be a CAD therapeutic agent through an increase in HDLc, and it has been reported that a diseased mouse that actually knocked out EL has an increase in HDLc and a decrease in atherosclerotic lesion sites. (Non-Patent Document 2)
These findings suggest the possibility of EL selective inhibitors as therapeutic agents for dyslipidemia or arteriosclerosis.

Patent Document 1 describes a derivative in which the 2-position of thiazole is substituted with an acetyl group or a secondary alcohol as a compound useful as a therapeutic agent for hyperTGemia, an anti-obesity agent, or a hyperlipidemia. Yes. Examples 57 and 79 of the patent document disclose derivatives in which the 2-position of thiazole is substituted with a trifluoroacetyl group, the 4-position is substituted with a cycloalkyl group, and the 5-position is substituted with an aryl group. . Patent Document 1 discloses the results of a blood triglyceride concentration lowering effect and a body weight gain suppressing effect using rats, but does not describe a vascular endothelial lipase inhibitory action or an HDLc raising action.
Patent Document 2 discloses a derivative in which the 2-position of thiazole is substituted with a trifluoroacetyl group as a compound useful for an anticancer agent.
Patent Document 3 discloses a derivative in which the 2-position of thiazole is substituted with a trifluoroacetyl group as a compound useful as an Alzheimer's therapeutic agent.
Non-Patent Documents 3, 4, 5, and 6 disclose derivatives in which the 2-position of imidazole is substituted with a trifluoroacetyl group or a difluoroacetyl group, but do not describe the vascular endothelial lipase inhibitory action.
Patent Documents 4, 5, 6, 7 and 8 disclose derivatives in which the 2-position of imidazole is substituted with a trifluoroacetyl group as compounds useful as anti-inflammatory agents.
Patent Documents 9, 10 and 11 disclose compounds useful as hepatic lipase and / or endothelial lipase inhibitors, but do not disclose derivatives having a trifluoroacetyl group such as the compounds of the present invention.
Patent Document 12 includes triglyceride lipase, lipoprotein lipase, hepatic lipase,
Compounds useful for pancreatic lipase and endothelial lipase inhibitors are disclosed, but derivatives having a trifluoroacetyl group such as the compound of the present invention are not disclosed.
Patent Documents 13 to 21 disclose compounds useful as EL inhibitors, but do not disclose derivatives having a trifluoroacetyl group such as the compounds of the present invention.

International Publication No. 2001/027094 Pamphlet International Publication No. 2007/029035 Pamphlet International Publication No. 95/33737 Pamphlet International Publication No. 96/03387 Pamphlet JP 63-239274 A U.S. Pat. No. 4,372,964 US Pat. No. 4,348,404 European Patent Application No. 32113 International Publication No. 2004/093872 Pamphlet International Publication No. 2004/094393 Pamphlet International Publication No. 2004/094394 Pamphlet International Publication No. 2006/053250 Pamphlet International Publication No. 2007/042178 Pamphlet International Publication No. 2007/045392 Pamphlet International Publication No. 2007/045393 Pamphlet International Publication No. 2007/110216 Pamphlet International Publication No. 2007/110215 Pamphlet International Publication No. 2006/131231 International Publication No. 2006/131232 Pamphlet International Publication No. 2006/131233 Pamphlet International Publication No. 2006/111132

An object of the present invention is to provide an excellent vascular endothelial lipase inhibitor.

The present invention
(1)
Formula (I):

(Where
Z is a nitrogen-containing heterocycle,
R ¹ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl Substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted Substituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or Unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl,
r is an integer from 0 to 3,
Y is —O—, —S—, —NR ² — or ═N—,
R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted acyl;
A is —C (═O) — or —C (OH) ₂ —,
B is —CF ₂ —R ³ or —CN;
R ³ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
D represents a single bond, —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S—, — S- (CR ¹⁰ R ¹¹ ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl, —C (═O) NR ¹² — ^{, -NR 12 C (= O)} - or ^{-NR 12} - and is,
R ⁴ to R ¹¹ are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
R ¹² is hydrogen or substituted or unsubstituted alkyl;
m, n, p and q are each independently an integer of 1 to 5,
E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyloxycarbonyl. Except that Z is thiazolyl, R ¹ is substituted or unsubstituted cycloalkyl, D is a single bond, and E is substituted or unsubstituted aryl. Except thiazolyl, R ¹ is substituted or unsubstituted aryl, D is a single bond, and E is substituted or unsubstituted cycloalkyl, Z is imidazolyl, and R ¹ is substituted or unsubstituted Except for substituted aryl, D is a single bond, and E is substituted or unsubstituted aryl.

), A pharmaceutically acceptable salt thereof or a solvate thereof,
(2)
R ¹ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted alkyloxycal The compound according to (1), a pharmaceutically acceptable salt thereof or a solvate thereof, which is bonyl;
(3)
The compound according to (1) or (2), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Z is a monocyclic nitrogen-containing heterocycle;
(4)
(1) to (3), wherein E is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle ), A pharmaceutically acceptable salt thereof or a solvate thereof,
(5)
Formula (I):

The compound represented by
Formula (II):

(Where
X is ═N—, ═CH— or ═CR ¹ — (where Y, A, B, D, E and R ¹ have the same meanings as (1) above). ), A pharmaceutically acceptable salt thereof or a solvate thereof, the compound according to any one of the above (1) to (4),
(6)
Formula (I):

The compound represented by
Formula (III):

(Where
X is ═N—, ═CH— or ═CR ¹ — (where Y, A, B, D, E and R ¹ have the same meanings as (1) above). ), A pharmaceutically acceptable salt thereof or a solvate thereof, the compound according to any one of the above (1) to (4),
(7)
X is = N- or = CH-;
Y is —O— or —S—;
B is —CF ₂ —R ³ ,
R ³ is hydrogen, halogen or substituted or unsubstituted alkyl;
D is a single ^{bond, -O -, - (CR 4} R 5) m-O -, - O- (CR 6 R 7) n -, - S -, - (CR 8 R 9) p-S -, - S- (CR ¹⁰ R ¹¹ ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl,
E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted The compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(8)
The compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein X is ═CH— and Y is —S—;
(9)
The compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein X is ═CH— and Y is —O—;
(10)
The compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein X is ═N— and Y is —S—;
(11)
The compound according to any one of the above (1) to (10), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein B is —CF ₃ ;
(12)
D is —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S—, —S— ( CR ¹⁰ R ¹¹ ) q- (wherein R ⁴ to R ¹¹ , m, n, p and q are as defined in (1) above), a substituted or unsubstituted alkenylene or a substituted or unsubstituted alkynylene, (1) to (11), a pharmaceutically acceptable salt or solvate thereof,
(13)
The compound according to any one of the above (1) to (12), a pharmaceutically acceptable salt or a solvate thereof, wherein R ⁴ to R ¹¹ are each independently hydrogen;
(14)
m, n, p and q are each independently an integer of 1 to 3, the compound according to any one of the above (1) to (13), a pharmaceutically acceptable salt thereof or a solvate thereof,
(15)
The compound according to any one of the above (1) to (14), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein E is substituted or unsubstituted aryl,
(16)
E is

Where R ^a is halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkyl Silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl , Substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl, b is an integer of 1 to 3, and the compound according to any one of (1) to (15) above, its pharmaceutical Top acceptable salts or solvates thereof,
(17)
E is

Wherein R ^a is as defined in (16) above, the compound according to (16), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(18)
A pharmaceutical composition comprising the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof;
(19)
The pharmaceutical composition according to the above (18), which is a vascular endothelial lipase inhibitor, is included.
In the present invention,
(20)
The pharmaceutical composition according to the above (18) for the treatment and / or prevention of dyslipidemia,
(21)
The pharmaceutical composition according to the above (18) for the treatment and / or prevention of hyperlipidemia,
(22)
The pharmaceutical composition according to the above (18) for the treatment and / or prevention of arteriosclerosis,
(23)
A method for preventing or treating dyslipidemia, comprising administering the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(24)
A method for preventing or treating hyperlipidemia, comprising administering the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(25)
A method for preventing or treating arteriosclerosis, comprising administering the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof,
(26)
Use of the compound according to any one of (1) to (17), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic agent and / or a preventive agent for dyslipidemia,
(27)
Use of the compound according to any one of the above (1) to (17), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic agent for hyperlipidemia and / or a preventive agent,
(28)
Use of the compound according to any one of the above (1) to (17), a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for arteriosclerosis,
(29)
The compound according to any one of (1) to (17), a pharmaceutically acceptable salt or a solvate thereof, for the treatment and / or prevention of dyslipidemia,
(30)
The compound according to any one of (1) to (17), a pharmaceutically acceptable salt or a solvate thereof, for the treatment and / or prevention of hyperlipidemia,
(31)
The compound according to any one of the above (1) to (17), a pharmaceutically acceptable salt or a solvate thereof for the treatment and / or prevention of arteriosclerosis is also included.

Since the compound of the present invention has a vascular endothelial lipase inhibitory action, the pharmaceutical composition containing the compound of the present invention is a pharmaceutical, particularly hyperlipidemia, arteriosclerosis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia. It is very useful as a medicament for the treatment and / or prevention of diabetes, obesity and / or syndrome X. The compound of the present invention selectively inhibits vascular endothelial lipase and has high selectivity for hepatic lipase (Hepatic Lipase) and pancreatic lipase (Pancreatic Lipase). In addition, it is a compound having utility as a medicine. Here, as usefulness as a medicine, it is a compound with high metabolic stability, low induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, and high oral absorbability A point, a point with a small clearance, or a point having a sufficiently long half-life for exhibiting a medicinal effect are included.

The terms used in this specification are explained below. In the present specification, each term has the same meaning whether used alone or in combination with other terms.

“Halogen” includes fluorine, chlorine, bromine and iodine.

“Alkyl” means a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert -Butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. Preferred is alkyl having 1 to 6 or 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Examples include pentyl, neopentyl, n-hexyl, and isohexyl.

“Alkenyl” means a linear or branched alkenyl having 2 to 8 carbon atoms having one or more double bonds to the above “alkyl”, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like can be mentioned.

“Alkynyl” means a linear or branched alkynyl having 2 to 8 carbon atoms having one or more triple bonds to the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Can be mentioned. Furthermore, it may have one or more double bonds.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 15 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon. Groups and the like. Preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and a bridged cyclic hydrocarbon group are used.

“Bridged cyclic hydrocarbon group” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two or more rings share two or more atoms. To do. Specifically, bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl, tricyclo [2.2. 1.0] heptyl and the like.

The “spiro hydrocarbon group” includes a group formed by removing one hydrogen from a ring in which two hydrocarbon rings share one carbon atom. Specific examples include spiro [3.4] octyl.

“Cycloalkenyl” means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 7 carbon atoms, and examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, preferably cyclopropenyl, cyclobutenyl. , Cyclopentenyl and cyclohexenyl. Cycloalkenyl also includes bridged cyclic hydrocarbon groups and spiro hydrocarbon groups having an unsaturated bond in the ring.

“Aryl” means a monocyclic aromatic hydrocarbon group (eg, phenyl) and a polycyclic aromatic hydrocarbon group (eg, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1 -Phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl and the like. Preferable is phenyl or naphthyl (1-naphthyl, 2-naphthyl).

“Heteroaryl” means a monocyclic aromatic heterocyclic group and a condensed aromatic heterocyclic group. The monocyclic aromatic heterocyclic group is a substitutable optional group derived from a 5- to 8-membered aromatic ring which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. Means a group which may have a bond at the position. The fused aromatic heterocyclic group has 1 to 4 5 to 8 5 to 8 membered aromatic rings which may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring. It means a group which may have a bond at any substitutable position which is fused with a member aromatic carbocyclic ring or other 5- to 8-membered aromatic heterocycle.

Examples of the “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl). ), Imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (eg, 1,2,4-triazole-1-) Yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (eg 2- Oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) Lyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (eg 2-pyridyl, 3-pyridyl) 4-pyridyl), pyridazinyl (eg: 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (eg: 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazanyl (eg: 3-furazanyl), pyrazinyl (eg: 2 -Pyrazinyl), oxadiazolyl (eg 1,3,4-oxadiazol-2-yl), benzofuryl (eg 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), benzothi Nyl (eg, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] Thienyl), benzimidazolyl (eg, 1-benzoimidazolyl, 2-benzoimidazolyl, 4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzoxazolyl, benzothiazolyl, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl) ), Cinnolinyl (eg, 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg: 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl) 7-quinazolinyl, 8-quina Zolinyl), quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), phthalazinyl (eg, 1-phthalazinyl, 5-phthalazinyl, 6- Phthalazinyl), isoquinolyl (eg, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), prill, pteridinyl (eg, 2-pteridinyl, 4-pteridinyl, 6-pteridinyl, 7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (eg 1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl), indolyl (eg 1-indolyl, 2 -In-drill, 3-indolyl, 4-indole 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, phenazinyl (eg 1-phenazinyl, 2-phenazinyl) or phenothiazinyl (eg 1-phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4 -Phenothiazinyl) and the like.

“Heterocycle” refers to a non-aromatic group that may contain 1 to 4 oxygen, sulfur and / or nitrogen atoms in the ring, and may have a bond at any substitutable position. Means a heterocyclic group. Further, such a non-aromatic heterocyclic group may be further bridged with an alkyl chain having 1 to 4 carbon atoms, and a cycloalkane (preferably a 5- to 6-membered ring) or a benzene ring may be condensed. Good. If it is non-aromatic, it may be saturated or unsaturated. A 5- to 8-membered ring is preferred. For example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, Examples thereof include 3-morpholinyl, morpholino, tetrahydropyranyl and the like.

“Acyl” refers to formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, By substituted or unsubstituted heteroarylcarbonyl, substituted or unsubstituted heterocyclecarbonyl is meant.

“Alkylene” includes a divalent group of 1 to 6 consecutive methylenes, and specifically includes methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.

“Alkenylene” includes a divalent group in which 2 to 6 methylenes are continuous and at least one carbon-carbon bond is a double bond.

“Alkynylene” includes a divalent group in which 2 to 6 methylenes are continuous and at least one of carbon-carbon bonds is a triple bond.

“Heterocyclic diyl” includes a divalent group formed by removing one hydrogen atom from the above “heteroaryl”.

"Substituted or unsubstituted arylalkyl", "Substituted or unsubstituted alkyloxycarbonyl", "Substituted or unsubstituted alkoxy", "Substituted or unsubstituted alkylsulfonyl", "Substituted or unsubstituted alkyloxycarbamoyl" The alkyl part of “substituted or unsubstituted alkylcarbonyl” and “substituted or unsubstituted alkylsilyloxy” means the above “alkyl”.
The alkenyl part of “substituted or unsubstituted alkenylcarbonyl” means the above “alkenyl”.
The cycloalkyl part of “substituted or unsubstituted cycloalkylcarbonyl” means the above “cycloalkyl”.
The cycloalkenyl part of “substituted or unsubstituted cycloalkenylcarbonyl” means the above “cycloalkenyl”.
The aryl part of “substituted or unsubstituted arylalkyl”, “substituted or unsubstituted arylsulfonyl”, “substituted or unsubstituted arylcarbonyl” and “substituted or unsubstituted aryloxy” means the above “aryl” To do.
The heteroaryl part of “substituted or unsubstituted heteroarylcarbonyl” means the above “heteroaryl”.
The heterocycle part of “substituted or unsubstituted heterocyclecarbonyl” means the above “heterocycle”.

The “nitrogen-containing heterocyclic ring” means a ring having at least one N in the ring and further may have O, S, N (R ² ). The ring includes a single ring or a condensed ring, and may be an aromatic heterocyclic ring or a non-aromatic heterocyclic ring. For example, the following are mentioned.

(Here, R ² has the same meaning as described above.)

“Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted aryl”, “substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted "Substituted cycloalkenyl", "substituted or unsubstituted heteroaryl", "substituted or unsubstituted heterocycle", "substituted or unsubstituted alkylene", "substituted or unsubstituted alkenylene", "substituted or unsubstituted “Alkynylene”, “substituted or unsubstituted heterocyclic diyl”, “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkylcarbonyl”, “substituted or unsubstituted alkenylcarbonyl”, “substituted or unsubstituted cyclohexane” Alkylcarbonyl "," substituted or unsubstituted cycloalkene “Carbonyl”, “substituted or unsubstituted arylcarbonyl”, “substituted or unsubstituted heteroarylcarbonyl”, “substituted or unsubstituted heterocyclecarbonyl”, “substituted or unsubstituted aryloxy”, “substituted or unsubstituted” Alkylsilyloxy "," substituted or unsubstituted alkylsulfonyl "," substituted or unsubstituted arylsulfonyl "," substituted or unsubstituted alkyloxycarbamoyl "," substituted or unsubstituted sulfamoyl "or" substituted or unsubstituted Examples of the substituent in “substituted alkyloxycarbonyl” include, for example, hydroxy, carboxy, halogen, alkyl halide (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl ₃ ), nitro, nitroso, cyano, alkyl (eg, Methyl, ethi , Isopropyl, tert-butyl), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl, adamantyl), cycloalkylalkyl (eg, cyclohexylmethyl, adamantylmethyl), cycloalkenyl (eg, : Cyclopropenyl), aryl (eg: phenyl, naphthyl), arylalkyl (eg: benzyl, phenethyl), heteroaryl (eg: pyridyl, furyl), heteroarylalkyl (eg: pyridylmethyl), heterocycle (eg: piperidyl) ), Heterocycle alkyl (eg morpholylmethyl), alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogenated alkyloxy (eg OCF ₃ ), alkenyloxy (eg vinyloxy, allyloxy), ali Alkyloxy (eg: phenyloxy), alkyloxycarbonyl (eg: methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), arylalkyloxy (eg: benzyloxy), amino (eg: alkylamino (eg: methylamino, ethylamino) Dimethylamino), acylamino (eg, acetylamino, benzoylamino), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, alkylaminoalkyl (eg, diethylaminomethyl), sulfamoyl, and the like. The It may be substituted with 1 to 4 such substituents.

The substituent of the alkyl moiety and the substituent of the aryl moiety in the “substituted or unsubstituted arylalkyl” are the same as the substituents of the above “substituted or unsubstituted alkyl” and “substituted or unsubstituted aryl”.

The substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, and “substituted or unsubstituted sulfamoyl” include alkyl, alkenyl, aryl, heteroaryl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl , Heterocyclecarbonyl, alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocycleoxycarbonyl, sulfamoyl, alkylsulfonyl, carbamoyl, cycloalkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclesulfonyl, hydroxy, sulfonyl, sulfinyl , Amino and the like.

The aryl part of “aryloxycarbonyl” means the above “aryl”.
The heteroaryl part of “heteroaryloxycarbonyl” means the above “heteroaryl”.
The heterocycle part of “heterocycleoxycarbonyl” means the above “heterocycle”.
“Alkylsilyloxy” means a silyloxy group substituted with 1 to 3 alkyl groups. For example, tert-butyldimethylsilyloxy and the like are included.

Of the compounds of the present invention, the compounds of the following embodiments are preferred.
Examples of Z include nitrogen-containing heterocycles. For example, the following rings are mentioned.

(Here, R ² has the same meaning as described above.)
The following rings are preferable.

(Here, R ² has the same meaning as described above.)
More preferably, the following rings are mentioned.

(Here, R ² has the same meaning as described above.)

Examples of r include an integer of 0 to 3.
Preferably, it is 0 or 1. Particularly preferred is 0.

R ¹ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted Or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted Or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl.
Preferably, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted alkyloxy It is a carbonyl.
More preferred is halogen, hydroxy, carboxy, substituted or unsubstituted alkyl.

Y includes —O—, —S—, —NR ² — or ═N—.
Preferred is —O— or —S—.

R ² includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted acyl.
Preferably, it is hydrogen or substituted or unsubstituted alkyl.

B includes —CF ₂ —R ³ or —CN.
Preferred is —CF ₂ —R ³ .

R ³ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Examples include alkenyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle.
Preferably, it is hydrogen, halogen or substituted or unsubstituted alkyl.
Halogen is particularly preferable, and fluorine is used.

D is a single bond, —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S— , —S— (CR ¹⁰ R ¹¹ ) q—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl, —C (═O) NR ^{12 -, - NR 12 C (} = O) - or ^{-NR 12} - and the like.
Preferably, a single bond, —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S—, -S- (CR ¹⁰ R ¹¹ ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, or substituted or unsubstituted heterocyclic diyl.
In particular, — (CR ⁴ R ⁵ ) m—O—, — (CR ⁸ R ⁹ ) p—S—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene are preferable.

R ⁴ to R ¹¹ each independently include hydrogen, halogen, or substituted or unsubstituted alkyl.
Preferably, it is hydrogen.

R ¹² includes hydrogen or substituted or unsubstituted alkyl.
Preferably, it is hydrogen.

m, n, p and q each independently represents an integer of 1 to 5.
Preferably, each is independently 1 to 3.

E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or Examples include unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyloxycarbonyl.
Preferably, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or Unsubstituted amino, substituted or unsubstituted alkoxy or substituted or unsubstituted alkyloxycarbonyl.
In particular, E is preferably the following substituents.

Here, R ^a has the same meaning as in the above (16), and b is an integer of 1 to 3. b is preferably an integer of 1 or 2.
More preferably, E includes the following substituents.

(Here, ^Ra is as defined in (16) above.)

R ^a is halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted Or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted Or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl.
Preferably, halogen, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted silyloxy, hydroxy, substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted heterocycle.
In particular, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted silyloxy, hydroxy or substituted or unsubstituted Substituted alkyloxycarbonyl is preferred.
Here, particularly preferable substituents of “substituted or unsubstituted alkyl” in R ^a include halogen. Particularly preferred substituents for “substituted or unsubstituted aryl” for R ^a include cyano. Particularly preferred substituents of “substituted or unsubstituted amino” in R ^a include acyl, arylsulfonyl, alkyloxycarbonyl, and alkylsulfonyl. Particularly preferred substituents of “substituted or unsubstituted alkoxy” in R ^a include aryl, heterocycle, cycloalkyl, arylthio, and alkoxy.

Examples of the pharmaceutically acceptable salt of the compound of the present invention include the following salts.
Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt , Triethanolamine salt, procaine salt, meglumine salt, diethanolamine salt or ethylenediamine salt or other aliphatic amine salt; N, N-dibenzylethylenediamine, venetamine salt or other aralkylamine salt; pyridine salt, picoline salt, quinoline salt, isoquinoline Heterocyclic aromatic amine salts such as salts; tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyl Examples include quaternary ammonium salts such as trioctylammonium salt and tetrabutylammonium salt; basic amino acid salts such as arginine salt and lysine salt.
Examples of the acid salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogen carbonate, perchlorate; acetate, propionate, lactate, maleate, Organic acid salts such as fumarate, tartrate, malate, citrate and ascorbate; sulfonates such as methanesulfonate, isethionate, benzenesulfonate and p-toluenesulfonate; Examples include acidic amino acids such as aspartate and glutamate.

The solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include alcohol (eg, ethanol) solvate and hydrate. Examples of the hydrate include monohydrate, dihydrate and the like.

The general production method of the compound of the present invention is exemplified below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
(When Z is a monocyclic nitrogen-containing heterocycle)

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II′-1) may be a known compound or a compound derived from a known compound by a conventional method. “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc. Here, “Ms” is a methanesulfonyl group, “Ts” is a paratoluenesulfonyl group, “Tf” represents a trifluoromethanesulfonyl group, “Ns” represents an orthonitrobenzenesulfonyl group, and “ak” represents an alkyl having 1 to 3 carbon atoms.)

First Step This is a step for producing an isothiocyanate represented by the formula (II′-2) from a compound represented by the formula (II′-1).
It can be synthesized according to the method described in WO96 / 17850.
Second Step The second step is a step for producing a compound represented by the formula (II′-3) by hydrolyzing a compound represented by the formula (II′-2).
Reaction solvents include N, N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons ( Examples, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), alcohols (eg, methanol, ethanol, t-butanol, etc.), water and a mixed solvent thereof.
Examples of the base include metal hydrides (eg, sodium hydride), metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), metal carbonates (eg, sodium carbonate) , Calcium carbonate, cesium carbonate, etc.), metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium hydrogen carbonate, metallic sodium, organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2, 6-lutidine, etc.), pyridine, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) and the like.
Preferably, an ether (eg, tetrahydrofuran, diethyl ether, dioxane, etc.) is used as a reaction solvent, and a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.) is used as a base. Just do it. The reaction may be performed at −78 to 30 ° C. for 0.5 to 24 hours.

Third Step In this step, the compound represented by the formula (II′-3) is reacted with the compound represented by the formula (E-LG) to produce the compound represented by the formula (II′-4).
As the reaction solvent, the solvent described in Step 2 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) and N, N-dimethylformamide may be used.
As the base, the base described in Step 2 can be used. Preferably, a metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) may be used.
The reaction may be performed at −10 to 30 ° C. for 0.5 to 24 hours.
Examples of the compound represented by the formula (E-LG) include benzyl bromide.

Fourth Step A compound represented by the formula (II′-4) and a compound represented by the formula: AB—O-ak or a compound represented by the formula: A—B—O—B—A in the presence of a base This is a step of reacting to produce a compound represented by the formula (II-1).
As the solvent, the solvent described in Step 2 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
As the base, alkyl lithium (n-BuLi, sec-BuLi, tert-BuLi) may be used.
The reaction may be performed at −78 to 30 ° C. for 0.5 to 12 hours.
Examples of the compound represented by the formula: AB—O-ak include ethyl trifluoroacetate. Examples of the compound represented by the formula: AB—O—B—A include (CF ₃ CO) ₂ O.

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (II′-5) may be a known compound or a compound derived from a known compound by a conventional method. (The above scheme is another method for synthesizing the compound represented by the formula (II′-2).)

Fifth step is a step of producing a compound represented by the formula (II'-6) from a compound represented by the formula (II'-5).
It can be synthesized according to the method described in WO96 / 17850.

Sixth step is a step of producing a compound represented by the formula (II'-2) from a compound represented by the formula (II'-6).
It can be synthesized according to the method described in WO2004 / 067532.

(Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II′-7) may be a known compound or a compound derived from a known compound by a conventional method) “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc. Here, “Ms” is a methanesulfonyl group, “Ts” is a paratoluenesulfonyl group, “Tf” represents a trifluoromethanesulfonyl group, and “Ns” represents an orthonitrobenzenesulfonyl group.)

Seventh Step: A compound represented by the formula (II′-7) is reacted with a compound represented by the formula: EDH or a compound represented by the formula: EDB (OH) ₂ in the presence of a palladium catalyst. In this step, the compound represented by the formula (II′-8) is produced.
As the reaction solvent, the solvent described in Step 2 can be used. Preferably, aromatic hydrocarbons (eg, toluene, benzene, xylene, etc.), water, and a mixed solvent thereof may be used. When the reaction is performed using a microwave, the reaction can be performed under conditions that do not use a solvent.
As the base, the base described in Step 2 can be used. Preferably, a metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) or an organic amine (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.) may be used.
The reaction is carried out at the temperature at which the solvent used refluxes in the presence of a palladium catalyst (eg Pd (PPh ₃ ) ₄ , PdCl ₂ , Pd (dba) ₂ etc.) and a phosphine ligand (eg PPh ₃ , BINAP etc.). For 0.5 to 12 hours. When the reaction is performed using a microwave, the reaction may be performed at 80 to 150 ° C. for 5 minutes to 1 hour. The solvent described above may be used as the solvent, but it may not be used.
Examples of the compound represented by the formula: EDH include ethynylacetylene. Examples of the compound represented by the formula: EDB (OH) ₂ include styrylboronic acid.

Eighth step is a step of producing a compound represented by the formula (II-2) from a compound represented by the formula (II′-8).
The reaction may be performed under the conditions described in Step 4.

(Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II′-9) may be a known compound or a compound derived from a known compound by a conventional method) (The above scheme is an alternative method when Z is an oxazole ring.)

Ninth step The ninth step is a step of reacting a compound represented by the formula (II′-9) with Tosmic (tosylmethyl isocyanide) to produce a compound represented by the formula (II′-10).
As the solvent, the solvent described in Step 2 can be used. Preferably, alcohols (eg, methanol, ethanol, t-butanol, etc.) may be used.
As the base, the base described in Step 2 can be used. Preferably, a metal carbonate (eg, sodium carbonate, calcium carbonate, cesium carbonate, etc.) may be used.
The reaction may be carried out at a temperature from 30 ° C. to the reflux temperature of the solvent used for 0.5 to 12 hours.

Tenth step The tenth step is a step of producing a compound represented by the formula (II-3) from a compound represented by the formula (II'-10).
The reaction may be performed under the conditions described in Step 4.

(In the formula, each symbol is as defined above, and the compound represented by the formula (III′-1) may be a known compound, or a compound derived from a known compound by a conventional method may be used. “Ak” means alkyl having 1 to 3 carbon atoms.)

Eleventh step is a step of producing a compound represented by the formula (III'-2) from a compound represented by the formula (III'-1) by Horner-Wadsworth-Emmons reaction.
As the reaction solvent, the solvent described in Step 2 can be used. Preferably, ethers (eg, tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) may be used.
As the base, the base described in Step 2 can be used. Preferably, metal alkoxide (eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), metal hydride (eg, sodium hydride, etc.) may be used.
The reaction may be performed at −20 to 40 degrees for 0.5 to 12 hours.

Twelfth step is a step of producing a compound represented by the formula (III-1) from a compound represented by the formula (III'-2).
The reaction may be performed under the conditions described in Step 4.
(When Z is a bicyclic nitrogen-containing heterocyclic ring)

(In the formula, each symbol is as defined above, and the compound represented by the formula (I′-1) may be a known compound, or a compound derived from a known compound by a conventional method may be used. “Ak” means alkyl having 1 to 3 carbon atoms.)

Thirteenth step is a step of producing a compound represented by formula (I'-2) from a compound represented by formula (I'-1).
In the same manner as when Z is a monocyclic nitrogen-containing heterocyclic ring, a substituent represented by the formula: -DE may be introduced.

Step 14 This is a step for producing a compound of formula (I-1) from a compound of formula (I′-2).
The reaction may be performed under the conditions described in Step 4.

As another method of the general synthesis method of the compound of the present invention, the group represented by the formula: -AB can be introduced before the group represented by the formula: -DE is introduced.
For example, it demonstrates below using a 7th process and an 8th process.

(Wherein each symbol has the same meaning as described above, and the compound represented by the formula (II′-7) may be a known compound or a compound derived from a known compound by a conventional method) “LG” means a leaving group, and includes halogen, —OMs, —OTs, —OTf, —ONs, etc. Here, “Ms” is a methanesulfonyl group, “Ts” is a paratoluenesulfonyl group, “Tf” represents a trifluoromethanesulfonyl group, and “Ns” represents an orthonitrobenzenesulfonyl group.)

Step 7 ′ This is a step of producing a compound represented by the formula (II′-8 ′) from a compound represented by the formula (II′-7).
The reaction may be performed under the conditions described in Step 8.

Step 8 ′ This is a step of producing a compound represented by the formula (II-2) from a compound represented by the formula (II′-8 ′).
The reaction may be performed under the conditions described in Step 7.

In addition, when a group represented by the formula: -AB is introduced, it can be produced according to the scheme shown below.

(In the formula, each symbol has the same meaning as described above, and the compound represented by the formula (I′-3) may be a known compound or a compound derived from a known compound by a conventional method. .)

Fifteenth step is a step of producing a compound represented by the formula (I'-4) from a compound represented by the formula (I'-3).
A substituent represented by the formula: -B may be introduced into the formyl group (carbonyl group) of the compound represented by the formula (I'-3) by a nucleophilic reaction.

Sixteenth step is a step of producing a compound represented by the formula (I-1) by oxidizing a compound represented by the formula (I′-4).
For example, it may be performed under conditions such as Jones oxidation, Collins oxidation, PCC oxidation, MnO ₂ oxidation, and Swern oxidation.

The compound of the present invention includes the following carbonyl compounds and hydrates. The carbonyl compound may be partially or wholly hydrated after synthesis to form a hydrate. In some cases, the compound of the present invention is present as a carbonyl compound.

Various substituents of the compounds of the present invention are (1) Alan R.Katriszly et al., Comprehensive Heterocyclic Chemistry (2) Alan R.Katriszly etKaal., Comprehensive Heterocyclic Chemistry II (3) RODD'S CH It can be introduced with reference to COMPOUNDS.

The compound of the present invention has excellent vascular endothelial lipase inhibitory activity. Therefore, it can be used for the treatment or prevention of diseases involving vascular endothelial lipase, particularly diseases such as hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis and / or syndrome X. In particular, it is useful in the treatment or prevention of hyperlipidemia, arteriosclerosis and dyslipidemia.

The compound used in the present invention can be administered orally or parenterally. In the case of oral administration, the compound used in the present invention is a usual preparation, for example, solid preparations such as tablets, powders, granules, capsules; liquid preparations; oil suspensions; or liquid preparations such as syrups or elixirs. It can be used also as any dosage form. In the case of parenteral administration, the compound used in the present invention can be used as an aqueous or oily suspension injection or nasal solution. In the preparation, conventional excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifiers, suspending agents, preservatives, stabilizers and the like can be arbitrarily used. In particular, it is preferable to use it as an oral preparation.
Formulations of the compounds used in the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of a compound used in the present invention with a pharmaceutically acceptable carrier or diluent. The preparation of the compound used in the present invention is produced by a known method using well-known and readily available components.
The dose of the compound used in the present invention varies depending on the administration method, the patient's age, weight, condition, and type of disease, but usually about 0.05 mg to 3000 mg per day for an adult when administered orally, preferably May be administered in an amount of about 0.1 mg to 1000 mg divided if necessary. In the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg is administered per day for an adult. In administration, it can be used in combination with other therapeutic agents.

The present invention will be described in more detail with reference to the following examples, but these are not intended to limit the present invention.
The NMR spectrum or LC / MS data of the compound of the present invention and its intermediate were shown. LC / MS was measured under either of the following two conditions.
method A:
Luna 5μ C18 (2) 100A, 50x4.6mm (manufactured by Phenomenex) was used for the measurement, and a linear gradient of acetonitrile / water (0.1% formic acid) 10:90 to 100: 0/3 min at a flow rate of 3 ml / min. After application, acetonitrile was flowed for 1 minute for measurement.
method C:
Shim-pack XR-ODS 50Lx3.0 (manufactured by Shimazu) was used for measurement, and a linear gradient of acetonitrile / water (0.1% formic acid) 10:90 to 100: 0/3 min at a flow rate of 1.6 ml / min. After applying, acetonitrile was allowed to flow for 30 seconds for measurement.

Compound 2 was synthesized from 2-aminothiazole 1 according to the method described in WO96 / 17850.
Compound 3 was synthesized from 2-amino-5-thiocyanate thiazole 2 according to the method described in WO2004 / 067532.
A solution of 1.00 g (7.03 mmol) of 5-thiocyanate thiazole 3 in anhydrous THF was ice-cooled, 1.41 ml (7.03 mmol) of 5M NaOH aqueous solution was added, and the mixture was stirred for 15 minutes under ice cooling. After the solvent was distilled off and azeotroped with toluene, 1.11 ml (8.44 mmol) of 3-chlorobenzyl bromide, 2.33 g (16.9 mmol) of potassium carbonate and 20 ml of anhydrous DMF were added, and the mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 545 mg (32%) of Compound 4 as a yellow oily liquid.
Compound 4; ¹ H-NMR (CDCl ₃ ) δ: 3.90 (2H, s), 7.00-7.03 (1H, m), 7.17-7.24 (3H, m), 7.68 (1H, s), 8.79 (1H, s ).
Compound 4 80.0 mg (0.331 mmol) in anhydrous THF 1.6 ml was cooled to −78 ° C., n-butyllithium n-hexane solution 0.256 ml (0.397 mmol) was added dropwise, and the mixture was stirred at −78 ° C. for 30 minutes. Further, 0.079 ml (0.662 mmol) of ethyl trifluoroacetate was added, and the mixture was heated at −78 ° C. for 1 hour, then heated up and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 69.4 mg (59%) of Compound (II-1-1) as a pale yellow solid. .
Compound (II-1-1); ¹ H-NMR (DMSO-d ₆ ) δ: 4.15 (2H, s), 7.17-7.19 (1H, m), 7.30-7.33 (3H, m), 7.71 (1H, s), 8.32 (2H, s).

In a 30 mL eggplant-shaped flask, 5-bromothiazole 5 (400 mg, 2.439 mmol), boronic acid 6 (397 mg, 2.68 mmol), triphenylphosphine (44.8 mg, 0.171 mmol), sodium carbonate (775 mg, 7.32 mmol) Was added and degassed in toluene (2 mL) and H ₂ O (2 mL). Tetrakistriphenylphosphine palladium (0) (141 mg, 0.122 mmol) was added here, and it stirred under heating-reflux conditions for 5.5 hours.
The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine. The organic layer is dried over magnesium sulfate and filtered, and then the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (n-hexane: ethyl acetate = 87: 13) to give a white powder compound. 163 mg (36%) of 7 was obtained.
Compound 7; ¹ H-NMR (DMSO-d6) δ: 7.02 (d, J = 16.5 Hz, 1H), 7.29 (m, 1H), 7.39 (t, J = 7.2 Hz, 2H), 7.54 (d, J = 16.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.99 (s, 1H), 9.01 (s, 1H).
In a 20 mL round bottom flask, 7 (70 mg, 0.374 mmol) was dissolved in THF (2 mL), cooled to −78 ° C., n-butyllithium (0.284 ml, 0.449 mmol) was added dropwise, and −78 Stir at 15 ° C. for 15 minutes. Ethyl trifluoroacetate (0.054 ml, 0.449 mmol) was added here, and it stirred at -78 degreeC for 20 minutes. After quenching with 10 mL of saturated aqueous ammonium chloride, ethyl acetate was added for extraction. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 52 mg (46%) of a yellow solid compound (II-1-2).
Compound (II-1-2); ¹ H-NMR (DMSO-d6) δ: 7.07 (d, J = 16.5 Hz, 1H), 7.30 (t, J = 6.9 Hz, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.49 (d, J = 16.5 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.91 (s, 1H), 8.30 (s, 2H).

5-Brothiazole 5 (100 mg, 0.610 mmol), ethynylacetylene 8 (149 mg, 1.463 mmol), PdCl2 (PPh3) 2 (21.40 mg, 0.030 mmol), copper iodide (9.29) in a 5 mL vial for microwave reaction mg, 0.049 mmol) and triethylamine (3 ml, 21.64 mmol) were added. This was stirred at 100 ° C. for 30 minutes under microwave irradiation.
The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 87: 13) to give a brown solid 9 78 mg (70%) was obtained.
Compound 9; ¹ H-NMR (DMSO-d6) δ: 7.45-7.47 (m, 3H), 7.57-7.60 (m, 2H), 8.23 (s, 1H), 9.18 (s, 1H).
In a 20 mL round bottom flask, 9 (75 mg, 0.405 mmol) was dissolved in THF (3 mL), cooled to −78 ° C., n-butyllithium (0.307 ml, 0.486 mmol) was added dropwise, and −78 Stir at 20 ° C. for 20 minutes. Ethyl trifluoroacetate (0.116 ml, 0.972 mmol) was added thereto at −78 ° C., and the mixture was stirred for 45 minutes while gradually warming to room temperature. After quenching with 10 mL of a 10% citric acid aqueous solution, ethyl acetate was added for extraction. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 75: 25) and recrystallized from hexane to give 40 mg (33% of white powder of compound (II-1-3)). ) Obtained.
Compound (II-1-3); ¹ H-NMR (DMSO-d6) δ: 7.46-7.48 (m, 3H), 7.58-7.61 (m, 2H), 8.17 (s, 1H), 8.49 (s, 2H ).

To a mixed solution of Compound 10 (3 g, 11.5 mmol), Compound 5 (1.03 mL, 11.53 mmol) Toluene (9 mL), and Water (6 mL), Pd (PPh3) 4 (0.67 g, 0.58 mmol) and Na2CO3 (3.67 g, 34.6 mmol) was added. The mixture was heated and stirred at 150 degrees for 30 minutes using a microwave. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 5: 1) to obtain a yellow oil 11 (1.24 g, 5.71 mmol, 49.5%).
Compound 11; ¹ H-NMR (DMSO-d ₆ ) δ: 3.80 (3H, s), 6.87 (1H, dd, J = 8.34, 1.52 Hz), 7.00 (1H, d, J = 16.17 Hz), 7.17 ( 2H, d, J = 8.84 Hz), 7.29 (1H, t, J = 7.83 Hz), 7.56 (1H, d, J = 16.17 Hz), 7.99 (1H, s), 9.01 (1H, s).
n-BuLi (7.1 mL, 11.4 mmol, 1.5M solution in nHexane) was added to a solution of dodecane-1-thiol (2.72 mL, 11.4 mmol) in HMPA (4 mL). After stirring at room temperature for 10 minutes, Compound 11 (1.24 g, 5.71 mmol) was added, and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, and the temperature was raised to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was roughly purified by silica gel chromatography (nHexane: AcOEt = 4: 1) to obtain yellow oil (E) -3- (2- (thiazol-5-yl) vinyl) phenol. It was. IMIDAZOLE (40 mg, 0.59 mmol) and TBSCl (650 mg, 4.31 mmol) were added to a solution of (E) -3- (2- (thiazol-5-yl) vinyl) phenol in DMF (4.0 mL) at room temperature. Stirred for a day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / toluene. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 2: 1) to give yellow oil 12 (743.7 mg, 2.342 mmol, 41.0%).
Compound 12; LC / MS Rt: 3.17 min, mass: 317.90 (M + 1), method: C
N-BuLi (2.126 mL, 3.40 mmol, 1.5M solution in nHexane) was added to a THF (10 ml) solution of Compound 12 (720 mg, 2.268 mmol) cooled to −78 degrees. After stirring at -78 degrees for 30 minutes, Compound 13 (0.55 mL, 4.54 mmol) was added, and the mixture was stirred at -78 degrees for 30 minutes. Water was added to the reaction solution, and the temperature was raised to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 4: 1) to obtain a yellow solid (II-1-4) (655 mg, 1.52 mmol, 67.0%).
Compound (II-1-4); LC / MS Rt: 2.98 min, mass: 432.25 (M + 1), method: C
TBAF (2 mL, 2.0 mmol, 1M solution in THF) was added to a solution of compound (II-1-4) (665 mg, 1.52 mmol) in THF (6 mL), and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 2: 1) to obtain a yellow solid (II-1-5) (189.1 mg, 0.60 mmol, 39%).
Compound (II-1-5); Rt: 1.66 min, mass: 317.95 (M + 1), method: C
To a solution of compound (II-1-5) (20 mg, 0.06 mmol) in CH2Cl2 (1.5 mL), compound 14 (8.1 mg, 0.06 mmol), DIAD (66.4 mL, 0.13 mmol, 1.9M solution in toluene) and PPh3 (33.1 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 2: 1) to obtain a yellow solid (II-1-6) (1.5 mg, 0.003 mmol, 6%).
Compound (II-1-6); ¹ H-NMR (DMSO-d ₆ ) δ: 0.97 (2H, dt, J = 16.00, 3.85 Hz), 1.20 (4H, dt, J = 23.66, 6.06 Hz), 1.48 (1H, dd, J = 3.79, 2.53 Hz), 1.61-1.76 (8H, m), 4.02 (2H, t, J = 6.32 Hz), 6.85 (1H, t, J = 3.92 Hz), 7.02 (1H, d, J = 16.17 Hz), 7.12-7.17 (2H, m), 7.27 (1H, t, J = 8.08 Hz), 7.50 (1H, d, J = 16.17 Hz), 7.90 (1H, s), 8.30 ( (2H, d, J = 7.07 Hz).

Tosmic (4 g, 20.5 mmol) and K2CO3 (2.83 g, 20.49 mmol) were added to a solution of compound 15 (3.3 g, 20.5 mmol) in MeOH (50 mL), and the mixture was stirred at 60 degrees for 2 hours. After evaporating the solvent under reduced pressure, water was added to the residue. After extraction with ethyl acetate, the organic layer was washed with water and saturated brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 2: 1) to obtain a yellow solid 16 (1.5 g, 7.5 mmol, 36%).
Compound 16; ¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (3H, s), 6.95 (2H, d, J = 8.84 Hz), 7.04 (2H, s), 7.20 (1H, s), 7.54 ( 2H, d, J = 8.84 Hz), 8.33 (1H, s).
N-BuLi (0.34 mL, 0.68 mmol, 1.5M solution in nHexane) was added to a THF (10 mL) solution of compound 16 (91.5 mg, 0.46 mmol) cooled to −78 degrees. After stirring at −78 ° C. for 30 minutes, 2,2,2-trifluoroacetic anhydride (0.5 mL, 3.6 mmol) was added, and the mixture was gradually warmed to room temperature and stirred for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (nHexane: AcOEt = 3: 1) to obtain a yellow solid (II-1-7) (16 mg, 0.05 mmol, 11%).
Compound (II-1-7); ¹ H-NMR (DMSO-d6) δ: 3.78 (3H, s), 6.96 (2H, d, J = 8.59 Hz), 7.05 (1H, s), 7.26 (1H, s), 7.56 (2H, d, J = 8.34 Hz), 8.28 (2H, s).

Under ice cooling, 438 mg (3.91 mmol) of potassium t-butoxide was added to 823 mg (3.61 mmol) of benzylphosphonic acid diester in 6 ml of anhydrous tetrahydrofuran and stirred for 10 minutes. And stirred at the same temperature for 15 minutes. 2N Hydrochloric acid, water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine, saturated sodium bicarbonate, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain 450 mg (80%) of Compound 18 as a colorless solid.
Compound 18; ¹ H-NMR (CDCl 3) δ; 7.17 (1H, d, J = 16.0 Hz), 7.21-7.39 (4H, m), 7.50-7.55 (3H, m), 8.82 (1H, d, J = 1.8Hz)
Under a nitrogen stream, compound 18 (100 mg, 0.534 mmol) was dissolved in 6 ml of anhydrous tetrahydrofuran, 1.55N n-butyllithium / n-hexane solution (0.413 ml, 1.282 mmol) was added at −78 ° C., and the same temperature was maintained for 10 minutes. After stirring, 2,2,2-trifluoroacetic acid ethyl ester (0.153 ml, 1.282 mmol) was added, stirred at the same temperature for 10 minutes, and further stirred at room temperature for 15 minutes. The reaction mixture was extracted with 2N hydrochloric acid, saturated sodium bicarbonate and ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), crystallized from n-hexane, and 78.5 mg (49%) of a yellow solid compound (III-1 -1) was obtained.
Compound (III-1-1); ¹ H-NMR (DMSO-d6) δ: 7.25-7.42 (5H, m), 7.59-7.7.36 (2H, m), 7.76 (1H, s), 8.31 (2H , s).

Compound (III-1-2) was synthesized in the same manner as Example 6.

According to the above scheme, 519 mg (yield 79%) of Compound 19 colorless oil was obtained.
Compound 19; ¹ H-NMR (CDCl 3) δ: 3.81 (3H, s), 6.82-6.88 (1H, m), 7.06-7.31 (5H, m), 7.47 (1H, d, J = 16.0 Hz), 8.24 (1H, d, J = 2.1 Hz).
According to the above scheme, 53.7 mg (yield 35%) of compound (III-1-2) was obtained as a yellow solid.
Compound (III-1-2); ¹ H-NMR (DMSO-d6) δ: 3.79 (3H, s,), 6.83-1.87 (1H, m), 7.12-7.35 (5H, m), 7.76 (1H, s), 8.31 (2H, s).

To a suspension of compound 20 1.9 g (9.99 mmol) and potassium carbonate 1.66 g (12.010 mmol) synthesized in the method described in JP 52048666 in 10 ml of anhydrous dimethylformamide was added 2.16 g (10.512 mmol) of 4-chlorobenzyl bromide at room temperature. Stirred for 2 hours. 30 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.91 g (93%) of colorless solid (Compound 21).
Compound 21; ¹ H-NMR (CDCl 3): δ (ppm) 1.44 (3H, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 4.59 (2H, s), 7.30 (2H, d, J = 8.4Hz), 7.39 (2H, d, J = 8.4Hz).
A solution of 315 mg (1.00 mmol) of Compound 21 in 10 ml of methylene chloride was cooled in a refrigerant at -78 ° C. (acetone-dry ice), and 1.1 ml of a DIBAL toluene solution (1.01 mol / L) was added dropwise. After stirring at the same temperature for 3 hours, the temperature was raised to 0 ° C. Saturated aqueous ammonium chloride solution, water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with water and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 3: 1 → 1: 1) to obtain 78 mg (29%) of Compound 22.
Compound 22; ¹ H-NMR (CDCl 3): δ (ppm) 4.63 (2H, s), 7.32 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.7 Hz), 10.13 (1H, s).
To a solution of compound 22 75 mg (0.277 mmol) in tetrahydrofuran 2 ml were added trifluoromethyltrimethylsilane 49 μl (0.331 mmol) and cesium fluoride 4.2 mg (0.028 mmol) under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 0.28 ml of 5N hydrochloric acid under ice cooling, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Water and ethyl acetate were added to the reaction solution for extraction, and the organic layer was washed with saturated brine and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1 → 4: 1 → 1: 1) to obtain 35 mg (36%) of Compound 23.
Compound 23; ¹ H-NMR (CDCl 3): δ (ppm) 3.72 (1H, brs), 4.55 (2H, s), 5.46 (1H, br), 7.31 (2H, d, J = 8.4 Hz), 7.37 ( (2H, d, J = 8.4Hz).
To a solution of compound 23 32 mg (0.094 mmol) in tetrahydrofuran 1.5 ml was added manganese dioxide 82 mg (0.944 mmol) at room temperature, and the mixture was stirred at the same temperature for 5 hours. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1 → 3: 1) to give 30 mg of compound (II-1-8). (88%) obtained.
Compound (II-1-8); ¹ H-NMR (CDCl3): δ (ppm) 4.54 (2H, s), 5.00 (1H, brs), 7.31 (2H, d, J = 8.7 Hz), 7.37 (2H , d, J = 8.7Hz).

Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate 24 (E) -styrylboronic acid 77 mg (0.52 mmol), sodium carbonate 55 mg (0.52 mmol), Pd (PPh3 4) 60 mg (0.05 mmol) was added, and the mixture was reacted at 120 ° C. for 20 minutes using a microwave reactor. After adding ethyl acetate and filtering through Presep, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 25 mg (27%) of yellow oily substance 25.
Compound 25 Trimethyl (trifluoromethylsilane) 77 mg (0.24 mmol) and a catalytic amount of cesium fluoride (about 10 mg) were added to a solution of 30 mg (0.12 mmol) of diglyme and stirred at room temperature for 2 hours. Water was added to the reaction solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to give 3 mg (II-1-9) of a yellow oil (II-1-9) 8%).
Compound (II-1-9); ¹ H-NMR (DMSO-d6) δ: 7.43 (q, J = 8.08 Hz, 2H), 7.63 (s, 1H), 7.75 (d, J = 7.07 Hz, 1H) , 8.69 (s, 1H).

Ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate 24 Ethylylbenzene 69mg (0.68mmol), PdCl2 (PPh3) 2 36.4mg (0.05mmol), Copper iodide in 100ml (0.52mmol) DMF 1ml solution 14.8 mg (0.078 mmol) and triethylamine 220 μl (1.56 mmol) were added, and the mixture was reacted at 100 ° C. for 20 minutes using a microwave reactor. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 26 79 mg (59%) of yellow crystals.
Compound 26 95 mg (0.24 mmol) of trimethyl (trifluoromethylsilane) and 51 mg (0.33 mmol) of cesium fluoride were added to a 1 ml solution of 79 mg (0.30 mmol) of diglyme and stirred at room temperature for 2 hours. After adding water to the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 18.5 mg (18%) of compound (II-1-10) )
Compound (II-1-10) ¹ H-NMR (DMSO-d6) δ: 7.50-7.57 (m, 3H), 7.72 (d, J = 7.58 Hz, 2H), 8.91 (s, 2H).

The compounds shown below were synthesized in the same manner. About each compound, the measurement result of NMR or LC / MS was shown.

(Test Example 1)
Evaluation method using human high density lipoprotein (HDL) of human Endothelial Lipase (EL) 20 mM Tris-HCl buffer (pH 7.4), bovine serum albumin (0.5%), calcium chloride (4 mM), sodium chloride ( 150 mM), an inhibitor dissolved in DMSO and added to a reaction solution composed of human HDL (2 mg / ml) was added to 0.5% DMSO, followed by addition of EL enzyme (total amount: 20 μl).
After reacting at 37 ° C. for 4 hours, free fatty acid (NEFA) produced from HDL by EL was measured with a commercially available assay kit, and the amount of NEFA was used as an enzyme activity index. Using the enzyme activity when no inhibitor was included as a control value, the inhibition rate relative to the control value at each concentration of the inhibitor was calculated, and the 50% inhibitory concentration (IC50 value) of the inhibitor was determined from the inhibition curve.

The results of Test Example 1 are shown below.
Compound (III-1-2): IC50 = 2.29 μM
Compound (II-2-82): IC50 = 1.83 μM
Compound (II-3-10): IC50 = 2.15 μM

(Formulation example 1)
Hard gelatin capsules are manufactured using the following ingredients:
Dose (mg / capsule)
Active ingredient 250
Starch (dried) 200
Magnesium stearate 10
Total 460mg

(Formulation example 2)
Tablets are manufactured using the following ingredients:
Dose (mg / tablet)
Active ingredient 250
Cellulose (microcrystal) 400
Silicon dioxide (fume) 10
Stearic acid 5
665mg total
The ingredients are mixed and compressed into tablets each weighing 665 mg.

(Formulation example 3)
An aerosol solution is prepared containing the following ingredients:
weight
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (chlorodifluoromethane) 74.00
Total 100.00
The active ingredient and ethanol are mixed and this mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required amount is then fed into a stainless steel container and diluted with the remaining propellant. Attach the bubble unit to the container.

(Formulation example 4)
A tablet containing 60 mg of active ingredient is prepared as follows:
Active ingredient 60mg
45mg starch
Microcrystalline cellulose 35mg
Polyvinylpyrrolidone (10% solution in water) 4mg
Sodium carboxymethyl starch 4.5mg
Magnesium stearate 0.5mg
Talc 1mg
150mg total
The active ingredients, starch, and cellulose are no. 45 mesh U.F. S. And mix well. An aqueous solution containing polyvinylpyrrolidone was mixed with the obtained powder, and the mixture was 14 mesh U.S. S. Pass through a sieve. The granules thus obtained were dried at 50 ° C. 18 mesh U.F. S. Pass through a sieve. No. 60 mesh U.S. S. Sodium carboxymethyl starch, magnesium stearate, and talc passed through a sieve are added to the granules, mixed and then compressed on a tablet press to obtain tablets each weighing 150 mg.

(Formulation example 5)
Capsules containing 80 mg of active ingredient are prepared as follows:
Active ingredient 80mg
Starch 59mg
Microcrystalline cellulose 59mg
Magnesium stearate 2mg
Total 200mg
Mix the active ingredient, starch, cellulose and magnesium stearate; 45 mesh U.F. S. Through the sieve and filled into hard gelatin capsules 200 mg each.

(Formulation Example 6)
A suppository containing 225 mg of active ingredient is prepared as follows:
Active ingredient 225mg
Saturated fatty acid glyceride 2000mg
Total 2225mg
The active ingredient is No. 60 mesh U.S. S. And suspended in a saturated fatty acid glyceride that has been heated and melted to the minimum necessary. The mixture is then cooled in an apparent 2 g mold.

(Formulation example 7)
A suspension containing 50 mg of active ingredient is prepared as follows:
Active ingredient 50mg
Sodium carboxymethylcellulose 50mg
Syrup 1.25ml
Benzoic acid solution 0.10ml
Fragrance q. v.
Dye q. v.
5ml in total with purified water
The active ingredient is No. 45 mesh U.F. S. And is mixed with sodium carboxymethylcellulose and syrup to form a smooth paste. Add the benzoic acid solution and perfume diluted with a portion of the water and stir. Then add a sufficient amount of water to the required volume.

(Formulation Example 8)
The intravenous formulation is manufactured as follows:
Active ingredient 100mg
Saturated fatty acid glyceride 1000ml
Solutions of the above components are usually administered intravenously to the patient at a rate of 1 ml per minute.

As is clear from the above test examples, the compound according to the present invention exhibits vascular endothelial lipase inhibitory action. Therefore, the compound according to the present invention is very useful as a therapeutic agent for dyslipidemia, a therapeutic agent for hyperlipidemia, and a therapeutic agent for arteriosclerosis.

Claims (19)

1. Formula (I):
   

   

   
   (Where
   Z is a nitrogen-containing heterocycle,
   R ¹ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl Substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted Substituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or Unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl,
   r is an integer from 0 to 3,
   Y is —O—, —S—, —NR ² — or ═N—,
   R ² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted acyl;
   A is —C (═O) — or —C (OH) ₂ —,
   B is —CF ₂ —R ³ or —CN;
   R ³ is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycle,
   D represents a single bond, —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S—, — S- (CR ¹⁰ R ¹¹ ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl, —C (═O) NR ¹² — ^{, -NR 12 C (= O)} - or ^{-NR 12} - and is,
   R ⁴ to R ¹¹ are each independently hydrogen, halogen or substituted or unsubstituted alkyl;
   R ¹² is hydrogen or substituted or unsubstituted alkyl;
   m, n, p and q are each independently an integer of 1 to 5,
   E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, or substituted or unsubstituted alkyloxycarbonyl. Except that Z is thiazolyl, R ¹ is substituted or unsubstituted cycloalkyl, D is a single bond, and E is substituted or unsubstituted aryl. Except thiazolyl, R ¹ is substituted or unsubstituted aryl, D is a single bond, and E is substituted or unsubstituted cycloalkyl, Z is imidazolyl, and R ¹ is substituted or unsubstituted Except for substituted aryl, D is a single bond, and E is substituted or unsubstituted aryl.
   

   

   
   ), A pharmaceutically acceptable salt thereof, or a solvate thereof.
2. R ¹ is halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkylsilyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted Acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted alkyloxycal The compound according to claim 1, which is bonyl, a pharmaceutically acceptable salt thereof, or a solvate thereof.
3. The compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein Z is a monocyclic nitrogen-containing heterocyclic ring.
4. Any of claims 1-3, wherein E is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle Or a pharmaceutically acceptable salt or solvate thereof.
5. Formula (I):
   

   

   
   The compound represented by
   Formula (II):
   

   

   
   (Where
   X is ═N—, ═CH— or ═CR ¹ — (where Y, A, B, D, E and R ¹ are as defined in claim 1). The compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a solvate thereof.
6. Formula (I):
   

   

   
   The compound represented by
   Formula (III):
   

   

   
   (Where
   X is ═N—, ═CH— or ═CR ¹ — (where Y, A, B, D, E and R ¹ are as defined in claim 1). The compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, or a solvate thereof.
7. X is = N- or = CH-;
   Y is —O— or —S—;
   B is —CF ₂ —R ³ ,
   R ³ is hydrogen, halogen or substituted or unsubstituted alkyl;
   D is a single ^{bond, -O -, - (CR 4} R 5) m-O -, - O- (CR 6 R 7) n -, - S -, - (CR 8 R 9) p-S -, - S- (CR ¹⁰ R ¹¹ ) q-, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heterocyclic diyl,
   E is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a solvate thereof.
8. The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, wherein X is = CH- and Y is -S-.
9. The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, wherein X is = CH- and Y is -O-.
10. The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 7, wherein X is = N- and Y is -S-.
11. The compound, pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 10, wherein B is -CF ₃ .
12. D is —O—, — (CR ⁴ R ⁵ ) m—O—, —O— (CR ⁶ R ⁷ ) n—, —S—, — (CR ⁸ R ⁹ ) p—S—, —S— ( CR ¹⁰ R ¹¹ ) q-, wherein R ⁴ to R ¹¹ , m, n, p and q are as defined in claim 1, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene. The compound according to any one of 1 to 11, a pharmaceutically acceptable salt thereof or a solvate thereof.
13. The compound according to any one of claims 1 to 12, wherein R ⁴ to R ¹¹ are hydrogen, a pharmaceutically acceptable salt thereof, or a solvate thereof.
14. The compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m, n, p and q are each independently an integer of 1 to 3.
15. The compound according to any one of claims 1 to 14, its pharmaceutically acceptable salt, or a solvate thereof, wherein E is substituted or unsubstituted aryl.
16. E is
    

    

    
    Where R ^a is halogen, hydroxy, carboxy, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted alkyl Silyloxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted acyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted alkyloxycarbamoyl , Substituted or unsubstituted sulfamoyl or substituted or unsubstituted alkyloxycarbonyl, b is an integer of 1 to 3, and a pharmaceutically acceptable compound thereof Salts or solvates thereof.
17. E is
    

    

    
    Wherein R ^a is as defined in claim 16, the compound according to claim 16, a pharmaceutically acceptable salt thereof, or a solvate thereof.
18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17, a pharmaceutically acceptable salt thereof, or a solvate thereof.
19. The pharmaceutical composition according to claim 18, which is a vascular endothelial lipase inhibitor.