JP2002201193A - Tricyclic compound, method for producing the same and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine having low-density lipoprotein(LDL) receptor- increasing action and useful as a blood lipid depressing agent, etc. SOLUTION: This compound is represented by the formula (I) [a ring A represents a nitrogen-containing heterocyclic ring which may be substituted; Q ring may have a substituent group; R1 is hydrogen atom, a halogen atom, a hydrocarbon group which may be substituted or an acyl group; Y is a bond or CO-NR2 (R2 is hydrogen atom or a hydrocarbon group which may be substituted or an acyl group); X1 is a bond or a divalent hydrocarbon group which may be substituted; X2 is a bond, O, s or NR4 (R4 is hydrogen atom, a hydrocarbon group which may be substituted or an acyl group); X3 is CO, COO or SO2; X4 is a bond or a divalent hydrocarbon group which may be substituted; R3 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted (with the proviso that when Y is CO-NR2 and X1 is a bond, X2 is a bond) or a salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel condensed imidazopyridine derivative having excellent properties as a medicament, a method for producing the same, and an agent containing the same.

[0002]

2. Description of the Related Art Numerous epidemiological studies have revealed that hypercholesterolemia is a major risk factor for arteriosclerotic diseases such as myocardial infarction, angina pectoris and cerebral infarction, as well as hypertension and smoking. . Therefore, appropriate control of blood cholesterol level is extremely important for prevention or treatment of arteriosclerotic diseases such as ischemic heart disease. Drugs that lower blood cholesterol levels include cholestyramine (Cholestyramine) and colestipol (Colestyramine).
acylcoenzyme A cholesterol acyltransferases such as those that capture and inhibit the absorption of bile acids such as ipol) (eg disclosed in US Pat. No. 4,027,099) and Melinamide (disclosed in French Patent No. 1476569) Inhibiting the intestinal absorption of cholesterol, more recently 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co)
A) Lovastatin which inhibits reductase
(Disclosed in US Pat. No. 4,231,938), Simvastatin (disclosed in US Pat. No. 4,231,938), (disclosed in US Pat. No. 4,444,784), Pravastatin (US Pat. No. 4,346,227).
And the like, which suppress the biosynthesis of cholesterol. However, when HMG-CoA reductase is inhibited, in addition to cholesterol biosynthesis, the biosynthesis of other components necessary for living organisms, such as ubiquinone, dolichol and heme A, is also inhibited. It is not a satisfactory drug.

On the other hand, liver low-density lipoprotein (LDL)
Receptors play a major role in cholesterol homeostasis. Cholesterol circulating in the form of LDL is removed from plasma by the very specific LDL receptor and is taken up by cells via receptor-mediated cellular uptake. When taken up into cells, LDL particles are degraded in the lysosome, thereby releasing cholesterol and increasing the intracellular concentration of free cholesterol. Increased free cholesterol levels signal hepatocytes to reduce the rate of transcription of genes for key enzymes in the cholesterol biosynthetic pathway, resulting in reduced de novo cholesterol synthesis. Also, L
DL receptor mRNA and protein are down-regulated by increased intracellular cholesterol, reducing the liver's ability to remove increased LDL cholesterol from plasma. Therefore, the mechanism of independently up-regulating LDL receptors is expected to greatly reduce plasma cholesterol levels-and drugs that up-regulate LDL receptors could be new blood lipid lowering agents There is.

[0004]

There is a demand for the development of new types of drugs such as blood lipid lowering agents based on the action of increasing low density lipoprotein (LDL) receptors.

[0005]

Means for Solving the Problems The present inventors have synthesized, for the first time, a novel condensed imidazopyridine derivative having the following specific substituent, which has an excellent LDL receptor increasing action,
The present inventors have found that they have a blood lipid lowering effect, and furthermore have a blood glucose lowering effect, a diabetic complication ameliorating effect and the like, and are useful as pharmaceuticals, and have completed this study.

That is, the present invention provides the following equation (1)

Embedded image [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). Or a salt thereof; (2) the compound of the above (1), wherein R ² is a hydrogen atom; (3) the compound of the above (1), wherein X ¹ is a bond or a C _1-4 alkylene group. (4) the compound according to (1), wherein X ² is a bond; (5) the compound according to (1), wherein X ³ is —CO—; (6) X ⁴ is C _1-4. (7) The compound according to the above (1), which is an alkylene group; (7) the above (1), wherein R ³ is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group. (8) ring Q is (i) a halogen atom, (ii) C _1-4 alkyl group, (iii) C _1-4 alkoxy group, (iv) C _1-4 alkylthio group, (v) hydroxyl group , (Vi) a carboxyl group,
(vii) cyano group, (viii) nitro group, (ix) amino group, (x) mono - or di -C _{1 -4} alkyl amino group, (xi) a formyl group, (xii) mercapto group, (xiii) C _1-4 alkyl-
Carbonyl group, (xiv) C _1-4 alkoxy-carbonyl group, (xv) sulfo group (—SO ₃ H), (xvi) C _1-4 alkylsulfonyl group, (xvii) carbamoyl group and (xvii
i) The compound according to the above (1), which may have 1 to 3 substituents selected from a mono- or di- _C1-4 alkyl-carbamoyl group; (9) the ring Q is unsubstituted; (10) R ¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, or a substituted The compound according to the above (1), which is a good aryl group, an alkoxycarbonyl group, an alkylcarbamoyl group or an alkanoyl group; (11) the compound according to the above (1), wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group or a phenyl group. (12) A compound represented by the formula: wherein ring A may be substituted

Embedded image A compound according to the above (1), which is a nitrogen-containing heterocyclic ring represented by the formula:

Embedded image (14) the compound according to (1), wherein Y is —CO—NR ² —; (15) N- [3- [1- [4- (trifluoromethyl) benzoyl]
Piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, N- [2- [1- [4-
(Trifluoromethyl) benzoyl] piperidin-4-yl]
Ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide, N- [4- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] butan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide, N- [4-
[[1- [4- (trifluoromethyl) benzoyl] piperidine-4
-Yl] oxy] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, N- [4-[[1- [4- (trifluoromethyl) benzoyl] piperidine -4-yl] thia] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide, N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Carboxamide, 8-bromo-N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide, 2,8-dimethyl-N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -5 -Thia-1,8b-diazaacenaphthylene-4-carboxamide, 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -3H- 1,4,8b-Triazaacenaphthylene-3,5 (4
(16) The compound according to the above (1), which is H) -dione or a salt thereof;

Embedded image [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). A prodrug of a compound represented by the formula: or a salt thereof;

Embedded image [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). A pharmaceutical composition comprising the compound represented by the formula: or a salt thereof, or a prodrug thereof; (18) the composition according to the above (17), which is a low-density lipoprotein receptor enhancer; (19) lipid lowering (20) The composition according to (17), which is an agent for preventing or treating arteriosclerosis; (21) the composition according to (17), which is a hypoglycemic agent; 22) The aforementioned (17) which is a preventive / therapeutic agent for diabetic complications
A composition as described above;

Embedded image [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group. And a salt thereof and a compound represented by the formula

Embedded image [Wherein, R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group, X ¹ represents a bond or a divalent hydrocarbon group which may be substituted, and X ² represents a bond A hand, —O—, —S— or —NR ⁴ — (R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), and X ³ represents —CO—, —COO— or -S
O 2 _- are shown, X ⁴ represents a bond or optionally substituted by divalent be hydrocarbon radicals, R ³ is a cyclic optionally substituted hydrocarbon group or an optionally substituted heterocyclic group (However, when X ¹ is a bond, X ² is a bond). Characterized by reacting with a compound represented by the formula or a salt thereof,

Embedded image Wherein each symbol is as defined above, or a method for producing a salt thereof.

As used herein, the term “5- to 6-membered nitrogen-containing heterocycle” includes one nitrogen atom as a hetero atom, and further includes a hetero atom (for example, a sulfur atom, an oxygen atom,
A 5- or 6-membered nitrogen-containing heterocyclic ring which may contain 1 or 2 nitrogen atoms or the like. These rings may be saturated or unsaturated rings. Examples of the “optionally substituted 5- to 6-membered nitrogen-containing heterocyclic ring” represented by ring A include, for example, a compound that may be substituted

Embedded image And the like. These “nitrogen-containing heterocyclic ring” may have the same substituent as the “heterocyclic group” in the “optionally substituted heterocyclic group” described below. As the substituent which the “nitrogen-containing heterocyclic ring” may have, oxo, thioxo, optionally halogenated C _1-4 alkyl (eg, trifluoromethyl and the like) and the like are preferable. As the “optionally substituted 5- to 6-membered nitrogen-containing heterocycle” represented by the formula:

Embedded image And a nitrogen-containing heterocycle represented by As used herein, the term “divalent hydrocarbon group” refers to, for example, an alkylene group having 1 to 15 carbon atoms (eg, methylene,
Ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, etc.) and 2 to 16 alkenylene groups (for example, vinylene, propenylene, 1-butenylene, 2-butenylene,
1-pentenylene, 2-pentenylene, 3-pentenylene, etc.) and 2 to 16 alkynylene groups (eg, ethynylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene, etc.) Examples thereof include a divalent chain hydrocarbon group, a phenylene group, and a combination thereof. Examples of the substituent which the “divalent hydrocarbon group” may have include, for example, an alkyl group which may be substituted, an aralkyl group which may be substituted, an aryl group which may be substituted, A hydroxyl group which may be substituted (eg, a hydroxyl group which may be substituted with an optionally substituted hydrocarbon group; preferably a hydroxyl group which may be substituted with an optionally substituted alkyl group, a hydroxyl group, etc.) And the like, and an alkyl group which may be substituted is preferable. The “phenylene group” may have a substituent. Examples of the substituent of the “phenylene group” include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C1-
4-alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, etc.), C1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, etc.), C1-4 alkylthio group (for example, methylthio, ethylthio, propylthio) Isopropylthio, etc.), hydroxy group, carboxyl group, cyano group, nitro group, amino group, mono- or di-C1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), formyl group , A mercapto group, a C1-4 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), a C1-4 alkoxy-carbonyl group (eg, methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, etc.), a sulfo group (—SO ₃ H), a C1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.), a carbamoyl group and a mono- or di-C1-4 alkyl- Carbamoyl group (for example,
N-methylcarbamoyl, N-ethylcarbamoyl,
One to four selected from N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like are used.

[0008] The term "halogen atom" as used herein refers to, for example, fluorine, chlorine, bromine, iodine and the like. As used herein, the term "hydrocarbon group" of the "optionally substituted hydrocarbon group" refers to, for example, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, an alkynyl group, an aralkyl group, an aryl group. The term “cyclic hydrocarbon group” in the term “optionally substituted cyclic hydrocarbon group” as used herein refers to, for example, a cycloalkyl group, a cycloalkenyl group, an aryl group and the like. Examples of the substituent that the “hydrocarbon group” may have include the following “alkyl group”, “cycloalkyl group”, “alkenyl group”, “cycloalkenyl group”, “alkynyl group”, “aralkyl” The same substituents as the substituents that the group and the aryl group may have are used. Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl And the like, such as a “linear or branched C1-15 alkyl group”. As the “cycloalkyl group”, for example, a “C3-8 cycloalkyl group” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl is used.

Examples of the substituent which the “alkyl group” and “cycloalkyl group” may have include, for example, (i) nitro group, (ii) hydroxyl group, oxo group, (iii) cyano group, (iv) ) Carbamoyl group, (v) mono- or di-C
_1-4 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.), (vi) carboxyl group, (vii) _C1-4 alkoxy -Carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (viii) sulfo group, (ix) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (x) halogenation _Optionally substituted C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), (xi) phenoxy group, (xii) optionally halogenated phenoxy group (eg, o-, m -Or p-
Chlorophenoxy, o-, m- or p-bromophenoxy), (xiii) optionally halogenated C
_1-4 alkyl group, optionally halogenated C
_1-4 alkylthio group (for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, etc.), (xiv) mercapto group, thioxo group, (xv) benzyloxy group which may be halogenated, halogenation Benzylthio group, (xvi) optionally halogenated phenylthio group, pyridylthio group, (x
vii) C _1-4 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl and the like), (xviii) C
_1-4 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, etc.), (xix) amino group, aminosulfonyl group, (xx) _C1-3 acylamino group (for example,
Acetylamino, propionylamino, etc.), (xxi) mono- or di- _C1-4 alkylamino group (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xxii) 4- to 6-membered cyclic amino group ( For example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, etc.), (xxiii) C
_1-3 acyl group (for example, formyl, acetyl, etc.),
(xxiv) a benzoyl group and (xxv) a 5- to 10-membered heterocyclic group (for example, 2- or 3-thienyl, 2- or 3-
Furyl, 3-, 4- or 5-pyrazolyl, 2-, 4-
Or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 1,2,
3- or 1,2,4-triazolyl, 1H- or 2
H-tetrazolyl, 2-, 3- or 4-pyridyl, 2
-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, isoquinolyl indolyl) and the like. The “alkyl group” may have 1 to 5 of these substituents at substitutable positions.

As a preferable example of the "alkyl group",
Is, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl,
Linear or branched C such as ethylene, hexyl, etc._1-6
Alkyl group; _1-6Alkyl group "
Examples of the substituent which may be a halogen atom,
C_1-4Alkoxy group, hydroxyl group, C_1-4Al
Coxy-carbonyl group, carboxyl group, carbamoyl
Group, mono- or di-C_1-4Alkyl carbamoyl
Group, a pyridylthio group or the like is used.
Examples of the “alkenyl group” include vinyl, allyl,
Isopropenyl, 3-butenyl, 3-octenyl, 9-
"C" such as octadecenyl_2-18Alkenyl group "
Is used. Examples of the "cycloalkenyl group" include,
For example, cyclopropenyl, cyclobutenyl, cyclopente
Nil, cyclohexenyl, cycloheptenyl, cyclo
C_3-8A cycloalkenyl group, etc.
Used. The "alkenyl group" and "cycloalkenyl"
Examples of the substituent which the ル
The same substituents as the substituents that the "killing group" may have are used.
Can be Preferred examples of the "alkenyl group" include:
For example, vinyl, allyl, 2-butenyl, 3-butenyl
Which C_2-6An alkenyl group and the like can be mentioned. The "C_2
-6Alkenyl group '' may have a substituent
For example, the "C_{1 -6}Alkyl group "
The same substituents may be used. The "Alkini
Examples of the group include, for example, ethynyl, propynyl, 1-
Butynyl, 2-butynyl, 1-pentynyl, 2-pentyne
"C such as nil, 3-pentynyl, etc. _2-18Alkynyl
And the like. The “alkynyl group” has
As the substituent which may be present, the aforementioned “alkyl group” has
The same substituents as those which may be used are used. The "Al
Preferred examples of the `` quinyl group '' include, for example, ethynyl,
C such as propynyl, 1-butynyl and 2-butynyl
<sub>2-6</sub>And alkynyl groups. The "C<sub>2-6</sub>A
Examples of the substituent which the `` rukinyl group '' may have include:
For example, "C_1-6Alkyl group "may have
The same substituents are used.

The "aralkyl group" includes C_7-16
An aralkyl group or the like is used.
Jill, phenethyl, 3-phenylpropyl, 4-phenyl
Phenyl-C such as rubutyl_1-6An alkyl group, and
For example, (1-naphthyl) methyl, 2- (1-naphthyl)
Naphthyl such as ethyl and 2- (2-naphthyl) ethyl;
C_1-6And an alkyl group. The "aralkyl"
Examples of the substituent which the group may have include, for example, halogen
Atoms (eg, fluorine, chlorine, bromine, iodine, etc.),
C_1-4Alkyl groups (eg, methyl, ethyl, propyl
, Isopropyl, butyl, etc.), C_2-6Alkenyl
Groups (eg, vinyl, allyl, 2-butenyl, 3-butene)
Nil, etc.), C_1-3Acyl groups (eg, formyl,
Cetyl), C_1-4Alkoxy groups (eg, methoxy
, Ethoxy, propoxy, isopropoxy, etc.), d
Toro group, cyano group, hydroxyl group, C_1-4Alkoki
Si-carbonyl group (for example, methoxycarbonyl, ethoxy
Xoxycarbonyl, propoxycarbonyl, isopropoxy
Carbamoyl group, mono- or di-
-C_1-4An alkyl-carbamoyl group (for example, N-meth
Tylcarbamoyl, N-ethylcarbamoyl, N, N-
Dimethylcarbamoyl, N, N-diethylcarbamoyl
Etc.), mono- or di-C _1-4Alkenyl-carba
Moyl group (for example, N-vinylcarbamoyl, etc.)
And the “aralkyl group” is located at a substitutable position.
You may have 1 to 4 of these substituents. The "A
Examples of the "reel group" include phenyl, 1-naphthyl,
2-naphthyl, phenanthryl, anthryl
Aromatic monocyclic, bicyclic or tricyclic C_6-14
An aryl group or the like is used. The “aryl group” has
As the substituent which may be, the `` aralkyl group '' is
In addition to the substituents that may be possessed, oxo groups and the like are also used.
And the “aryl group” is substituted at a substitutable position.
Having 1 to 4, preferably 1 or 2, groups
Is also good. As the aryl group having an oxo group, for example,
Benzoquinonyl, naphthoquinolyl, anthraquinonyl
And so on.

As used herein, the term "acyl group"
For example, an acyl group derived from a carboxylic acid is used, and for example, an alkoxycarbonyl group, an alkylcarbamoyl group, an alkanoyl group and the like are used. Examples of the "alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, te
rt-butoxycarbonyl, pentyloxycarbonyl,
C such as isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbonyl
_{A 1-6} alkoxycarbonyl group is used. Examples of the “alkylcarbamoyl group” include mono-C such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl and the like.
_1-6 -N-alkylcarbamoyl group and, for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl and the like A di-C _1-6 -N, N-dialkylcarbamoyl group and a dialkyl moiety together form a 4- to 6-membered cyclic carbamoyl group (eg, 1-azetidinylcarbonyl, morpholinocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinocarbonyl, 1-piperazinylcarbonyl, 1-piperazinylcarbonyl, etc.) are used. As the "alkanoyl group", for example, acetyl,
Propionyl, butyryl, and _{C 2-6} alkanoyl group such as pivaloyl used.

As used herein, the term "heterocyclic group" of the term "optionally substituted heterocyclic group" includes, for example, an oxygen atom,
An aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from a sulfur atom, a nitrogen atom and the like And saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups). Examples of the “aromatic heterocyclic group” include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
5- or 6-membered aromatic monocyclic heterocyclic groups such as 2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, Isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,
2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,
Naphthyridinyl, purinyl, Buterijiniru, carbazolyl, alpha-carbolinyl, beta-carbolinyl, .gamma.-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, Fenatorijiniru, Fenatororiniru, indolizinyl, pyrrolo [1,2-b] Pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1,
2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and the like To a 12-membered aromatic condensed heterocyclic group (preferably, a heterocyclic ring obtained by condensing a 5- or 6-membered aromatic monocyclic heterocyclic group with a benzene ring or a 5- or 6-membered aromatic monocyclic group described above) A heterocyclic ring in which two identical or different heterocyclic groups of a heterocyclic group are fused, more preferably a heterocyclic ring in which a 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring)
And the like. Examples of the "non-aromatic heterocyclic group" include 3- to 8-membered (preferably 5 to 6) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group (aliphatic heterocyclic group) or the like, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4
A non-aromatic heterocyclic group in which part or all of the above-mentioned aromatic monocyclic heterocyclic group or aromatic condensed heterocyclic group is saturated, such as tetrahydroisoquinolyl. As the “heterocyclic group” in the “optionally substituted heterocyclic group”, a 5- or 6-membered aromatic monocyclic heterocyclic group or the like is preferable, and the “optionally substituted heterocyclic group” is preferred. Examples of the substituent which the “heterocyclic group” may have include those similar to the substituents that the “hydrocarbon group” may have in the “optionally substituted hydrocarbon group”. No.

In the above formula, the ring Q may have a substituent. Examples of the substituent which the ring Q may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-4 alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, etc.), a C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy,
Isopropoxy, etc.), C _1-4 alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), hydroxy, carboxyl, cyano, nitro, amino, mono- or di-C _1-4.
An alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), a formyl group, a mercapto group, a C _1-4 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.);
C _{1 -4} alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl), a sulfo group, C _1-4 alkylsulfonyl group (e.g., methylsulfonyl and ethyl sulfonyl propylsulfonyl), carbamoyl group and mono - Or a di-C _1-4 alkyl-carbamoyl group (eg, N
-Methylcarbamoyl, N-ethylcarbamoyl, N,
N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like). One to three of these substituents may be substituted at substitutable positions on the ring Q. Examples of the ring Q include (i) a halogen atom, (ii) a C _1-4 alkyl group, (iii) a C _1-4 alkoxy group, and (iv) a C _1-4
Alkylthio group, (v) hydroxyl group, (vi) carboxyl group, (vii) cyano group, (viii) nitro group, (ix) amino group, (x) mono- or di-C _1-4 alkylamino group,
(xi) a formyl group, (xii) mercapto group, (xiii) C _{1 -4}
Alkyl-carbonyl group, (xiv) C _1-4 alkoxy-
1 to 3 selected from a carbonyl group, (xv) sulfo group, (xvi) _C1-4 alkylsulfonyl group, (xvii) carbamoyl group and (xviii) mono- or di- _C1-4 alkyl-carbamoyl group The ring which may have a substituent is preferable, and the ring Q is preferably unsubstituted.

In the above formula, R ¹ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may be substituted or an acyl group. The halogen atom, the optionally substituted hydrocarbon group and the acyl group represented by R ¹ are the same as the above-mentioned “halogen atom”, “optionally substituted hydrocarbon group” and “acyl group” Is used. R ¹ represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkoxycarbonyl group, an alkylcarbamoyl Or an alkanoyl group, in particular, a hydrogen atom, C
_{A 1-6} alkyl group or a phenyl group is preferred. In the above formula, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group. As the optionally substituted hydrocarbon group and acyl group represented by R ² , those similar to the aforementioned “optionally substituted hydrocarbon group” and “acyl group” can be used. As R ² , a hydrogen atom is preferable.

In the above formula, X ¹ represents a bond or a divalent hydrocarbon group which may be substituted, and X ² represents a bond, —
O -, - S- or -NR ⁴ - shows a. However, when X ¹ is a bond, X ² represents a bond. Substituted of or bivalent also be a hydrocarbon group represented by X ^1, the same as the aforementioned "substituted two may be monovalent hydrocarbon group" is used. X ¹ is a bond or C _1-4
An alkylene group is preferred, and X ² is preferably a bond. In the above formula, R ⁴ represents a hydrogen atom, a hydrocarbon group which may be substituted, or an acyl group. As the optionally substituted hydrocarbon group and acyl group represented by R ⁴ , those similar to the aforementioned “optionally substituted hydrocarbon group” and “acyl group” can be used. As R ⁴ , a hydrogen atom is preferable. In the above formula, X ³ is —CO—,
—COO— or —SO ₂ —, and X ⁴ represents a bond or a divalent hydrocarbon group which may be substituted. X ⁴
As the divalent hydrocarbon group which may be substituted, the same as the above-mentioned "divalent hydrocarbon group which may be substituted" is used. The X ^3, -CO
Is preferred, and X ⁴ is preferably a C _1-4 alkylene group. Examples of the optionally substituted cyclic hydrocarbon group and the optionally substituted heterocyclic group represented by R ³ include the aforementioned “optionally substituted cyclic hydrocarbon group”
And the same as "optionally substituted heterocyclic group". As R ³ , an optionally substituted phenyl group or an optionally substituted 5- to 6-membered aromatic heterocyclic group is preferable.

The salt of the compound represented by the formula (I) of the present invention is preferably a pharmaceutically acceptable salt or a physiologically acceptable acid addition salt. Such salts include:
For example, inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.) or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid) Benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc.). Further, when the compound (I ′) of the present invention has an acidic group such as a carboxylic acid, the compound (I ′) may be, for example, an inorganic base (eg, an alkali metal such as sodium, potassium, calcium, or magnesium or an alkaline earth metal). It may form a salt with a similar metal or ammonia or the like or an organic base (for example, a tri-C _1-3 alkylamine such as triethylamine). As the raw material compound of the compound represented by the formula (I) of the present invention, the same salt as described above is used,
There is no particular limitation as long as the reaction is not hindered. The prodrug of the compound represented by the formula (I) or a salt thereof (hereinafter, may be referred to as compound (I)) of the present invention can be prepared by reacting the compound (I) with an enzyme or gastric acid under physiological conditions in a living body. ), Ie, enzymatically oxidized,
Compounds which are converted to compound (I) by reduction, hydrolysis and the like, and compounds which are converted to compound (I) by hydrolysis and the like by stomach acid and the like. As a prodrug of compound (I), the amino group of compound (I) is acylated,
Alkylated and phosphorylated compounds (for example, when the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxy Carbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
Pivaloyloxymethylated, tert-butylated compounds, etc.), compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, and borated (for example, the hydroxyl group of compound (I) is acetylated) , Palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylated compound, etc.), or a compound in which the carboxyl group of compound (I) is esterified or amidated (for example, ,
The carboxyl group of compound (I) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, phthalidyl-esterified, Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like. These compounds can be produced from compound (I) by a method known per se. The prodrug of compound (I) changes into compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163 to 198. There may be.

The compound (I) may be a hydrate. When an optically active form of compound (I) is required, it can be obtained, for example, using optically active starting materials or by resolving the racemic form of the compound using conventional methods. it can. Compound (I) may have an asymmetric carbon in the molecule, but may have R-coordination or S-coordination.
Where two coordination stereoisomers exist, each of them or a mixture thereof is also included in the present invention.

Preferred specific examples of the compound (I) of the present invention are shown below. N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide, N- [2- [1-
[4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene
-4-carboxamide, N- [4- [1- [4- (trifluoromethyl)
Benzoyl] piperidin-4-yl] butan-1-yl] -5-thia
-1,8b-diazaacenaphthylene-4-carboxamide, N- [4-
[[1- [4- (trifluoromethyl) benzoyl] piperidine-4
-Yl] oxy] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, N- [4-[[1- [4- (trifluoromethyl) benzoyl] piperidine -4-yl] thia] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide, N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Carboxamide, 8-bromo-N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide, 2,8-dimethyl-N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -5 -Thia-1,8b-diazaacenaphthylene-4-carboxamide, 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -3H- 1,4,8b-Triazaacenaphthylene-3,5 (4
H) -Diones and their salts. As the salt, an acid addition salt is preferable, and among them, a hydrochloride and the like are preferably used.

The compound (I) of the present invention can be synthesized according to a reaction known per se, for example, by a method represented by the following reaction formula. Method (A): (Y = CONR ² )

Embedded image [The symbols in the formula are as defined above. ]

Method (B): (Y = CONR ² )

Embedded image [Wherein, P represents an amino-protecting group, and other symbols are as defined above. ]

Method (C): (Y = bond)

Embedded image [Wherein, E is a halogen (eg, chlorine, bromine, iodine, etc.),
A leaving group such as methanesulfonyloxy, p-toluenesulfonyloxy and the like, and other symbols are as defined above. ]

Method (D): (Y = bond)

Embedded image [The symbols in the formula are as defined above. ]

Method (E): (Y = bond)

Embedded image [The symbols in the formula are as defined above. ]

Method (F): (Y = bond)

Embedded image [Wherein, R ⁵ represents a lower alkyl group, and other symbols have the same meanings as described above. ]

The compounds represented by formulas (II) and (III) can be specifically synthesized as compounds (V), (VII), (IX) and (XI) by, for example, the following method. . The compound represented by the formula (V) can be produced, for example, according to the method disclosed in publications such as WO97 / 40051 and WO99 / 20632 or a method analogous thereto. For example, the compound can be produced by the following method.

Embedded image [The symbols in the formula are as defined above. In the formylation reaction of compound (IV), compound (IV)
The formylating agent is used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, per 1 equivalent. Examples of such a formylating agent include N, N-dimethylformamide-phosphorus oxychloride (Vilsmeyer reagent). In this case, the ring closure reaction can proceed under the conditions of formylation. As the solvent used at this time, for example, ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), hydrocarbons (eg,
Hexane, pentane, benzene, toluene, etc.), aprotic polar solvents (for example, N, N-dimethylformamide, dimethylsulfoxide, etc.). The reaction time is 0.5 to 48 hours, preferably 1 to 2 hours.
4 hours. The reaction can be carried out at -20 to + 150 ° C, preferably at +80 to 120 ° C. In the formylation reaction of the compound (IV), for example, 1 equivalent of the compound (IV) is reacted with 1 to 3 equivalents of a base such as sodium hydride, potassium hydride or lithium diisopropylamide, and then the formamides (for example, ,
The reaction can be carried out by reacting 1 to 10 equivalents, preferably 2 to 5 equivalents of N, N-dimethylformamide, N, N-methylformanilide or the like or formate esters (eg, methyl formate, ethyl formate, etc.). . Examples of the solvent for the formylation include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), hydrocarbons (eg, hexane, pentane, benzene, toluene, etc.), aprotic polar solvents (eg, N, N- Dimethylformamide, dimethylsulfoxide, etc.). The reaction time is 0.5 to 48
Hours, preferably 1 to 24 hours. The reaction is-
It can be carried out at 100 to + 50 ° C, preferably at -80 to + 30 ° C. In this case, the obtained formyl compound is further added with 1 to large excess, preferably 1 to 50 equivalents of an acid such as acetic acid, at 0 to + 150 ° C., preferably +
The ring closure reaction can be advanced by treating at 80 to 130 ° C. for 1 to 24 hours, preferably for 10 to 20 hours. At this time, as the solvent used,
For example, carboxylic acids (eg, acetic acid, formic acid, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), hydrocarbons (eg, hexane, pentane, benzene, toluene, etc.), aprotic polar solvents (eg, N, N-dimethylformamide,
Dimethyl sulfoxide). The formylation reaction of compound (IV) can also be carried out by reacting hexamethylenetetramine with 1 to a large excess, preferably 1 to 10 equivalents. In this case, the ring closure reaction can proceed under the conditions of formylation. The acid used at this time is, for example, an inorganic acid (eg, hydrochloric acid, sulfuric acid, boric acid, etc.) or an organic acid (eg, acetic acid, trifluoroacetic acid, formic acid, methanesulfonic acid), and preferably acetic acid, boric acid, etc. use. The amount of the acid used is, for example, 1 to a large excess, preferably 1 to 50 equivalents. The reaction temperature at this time is 0 to 200 ° C., preferably 5 to 200 ° C.
0-150 ° C. Examples of the solvent used at this time include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), and esters (eg, ethyl acetate, methyl acetate, etc.). ), Protic polar solvents (e.g., methanol, ethanol, etc.), aprotic polar solvents (e.g., acetonitrile, N, N-dimethylformamide,
Dimethyl sulfoxide). At this time, water may be contained. Preferably, acetic acid which serves as an acid and a solvent is used. The reaction time is generally 10 minutes to 24 hours, preferably 1 to 15 hours. Hydrolysis of the obtained ester can be performed by treating with an acid or a base. That is, the ester form is converted to an acid (for example, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, iodic acid, etc.),
Alternatively, in a solution of a base (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) in water or a lower alcohol (eg, methinol, ethanol, propanol, etc.), 0 to + 100 ° C., preferably +10 to 50 ° C. For 0.5 to 50 hours, preferably 1 to 5 hours. The strength of the acid or base is 1 to 1
0 is preferred, preferably 2 to 5.

The compound represented by the compound (VII) can be produced according to the method disclosed in publications such as WO97 / 40051 and WO99 / 20632 or a method analogous thereto, for example, by the following method. it can.

Embedded image [Wherein, R ⁶ Represents an optionally substituted hydrocarbon group.
Then E ¹ Indicates halogen (eg, chlorine, bromine, iodine, etc.)
And the symbols are as defined above. Reaction of compound (VI) with thioglycolic acid ester
Represents a 1 to large excess of thioglycolate,
Or 1 to 10 equivalents. Salt used at this time
Examples of the group include inorganic bases (for example, potassium carbonate,
Sodium bicarbonate, etc.), organic bases (eg, trie
Tylamine, pyridine, dimethylamine, 1,8-dia
Zabicyclo [5.4.0] -7-undecene, etc.)
Alcoholates (eg, sodium methylate, sodium
Um ethylate, potassium tert-butoxide),
Organometallic reagents (eg, n-butyllithium), water
Examples include sodium oxide and sodium amide.
The amount used is 1 to a large excess, preferably 1 to 5 equivalents.
use. The reaction temperature is 0 to 200 ° C., preferably
20 to 100 ° C. As the solvent used,
Hydrogenated hydrocarbons (eg, methylene chloride, chloroform
, Dichloroethane, etc.), ethers (for example,
Lahydrofuran, dioxane, diethyl ether
), Esters (eg, ethyl acetate, methyl acetate, etc.)
Etc.), protic polar solvents (eg, methanol, ethanol
Aprotic polar solvents (e.g., aceto
Nitrile, N, N-dimethylformamide, dimethyls
Rufoxide). Reaction time is usually 10 minutes
To 24 hours, preferably 1 to 10 hours.
The ring closure reaction is carried out under the reaction conditions with thioglycolate.
Let it proceed. The reaction temperature is usually +100
The process proceeds by heating to 250 ° C. When reacting
The time is usually 1 to 72 hours, preferably 6 hours to 2 hours
4 hours. The hydrolysis of the obtained ester is as described above.
It can be carried out in the same manner as in the production method of compound (V).
You.

Compound (IX) is, for example, compound (VII)
I) can be produced by trifluoroacetylation, ring closure reaction, and hydrolysis.

Embedded image [The symbols in the formula are as defined above. The trifluoroacetylation reaction of compound (VIII)
1 to large excess, preferably 1 to 3 equivalents of trifluoroacetyl chloride or trifluoroacetic anhydride relative to compound (VIII) is used. In this case, the ring closure reaction can proceed under trifluoroacetylation conditions. At this time, as a base, an inorganic salt (for example, potassium carbonate, potassium hydrogen carbonate, or the like) or an organic base (for example, 4-N, N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline, 1,8-diazabicyclo [5. 4.0] -7-undecene or the like may be used in an amount of 1 to 10 equivalents. Reaction temperature is -50
To 100 ° C. As the solvent used at this time, halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), esters (eg, ethyl acetate, methyl acetate, etc.), An aprotic polar solvent (for example, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide and the like) can be mentioned. The reaction time is generally 10 minutes to 24 hours, preferably 0.5 to 4 hours. Hydrolysis of the obtained ester can be carried out in the same manner as in the method for producing the compound (V).

The compound represented by the compound (XI) can be produced, for example, according to the method disclosed in WO96 / 02543, JP-A-8-81467, or a similar method.

Embedded image [The symbols in the formula are as defined above. ]

Compound (VI) is, for example, compound (XI)
I) can be synthesized through formylation, Grignard reaction and oxidation reaction.

Embedded image [The symbols in the formula are as defined above. The formylation reaction of the compound (XII) is carried out by the above-mentioned compound (I)
It can be carried out in the same manner as in the formylation in the conversion of V) to compound (V). The Grignard reaction of compound (XIII) uses 1 to a large excess (1 to 10 equivalents) of a Grignard reagent relative to compound (XIII).
The reaction can be carried out at a temperature of 0 to 100 ° C. Examples of the solvent used at this time include ethers (for example, tetrahydrofuran, dioxane, diethyl ether and the like). The reaction time is usually from 5 minutes to 2 minutes.
4 hours, preferably 10 minutes to 1 hour. In the oxidation reaction of the obtained alcohol, for example, a metal oxide such as manganese dioxide is used in an amount of 1 to a large excess (1 to 50 equivalents) relative to the alcohol. Examples of the solvent used here include hydrocarbons (eg, hexane, pentane, benzene, toluene, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.) ), Aprotic polar solvents (eg, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.). The reaction time is usually 10
Minutes to 72 hours, preferably 6 to 24 hours.

Compound (VIII) is, for example, compound (X)
IV) can be synthesized through lithiation, reaction with carbon dioxide, and esterification.

Embedded image [The symbols in the formula are as defined above. The carboxyl group can be introduced into the methyl group of compound (XIV) by, for example, lithiation followed by reaction with carbon dioxide. For the lithiation of compound (XIV), for example, a lithium salt such as lithium diisopropylamide, n-butyllithium, tert-butyllithium, or phenyllithium is generally used in an amount of 1 to 5 equivalents based on compound (XIV). Reaction temperature is -100 to 5
It can be performed at 0 ° C. The solvent used at this time is ethers (for example, tetrahydrofuran, dioxane,
Diethyl ether, etc.), and hydrocarbons (eg, hexane, pentane, benzene, toluene, etc.). The reaction time is generally 10 minutes to 6 hours, preferably 10 minutes to 2 hours. The reaction between the obtained lithio compound and carbon dioxide can be carried out usually at −100 to 0 ° C. by blowing carbon dioxide gas or adding dry ice. Reaction time is 10 minutes to 6 minutes
Time, preferably from 10 minutes to 1 hour. The esterification reaction of the obtained carboxylic acid form may be carried out by a method known per se, for example, by treating the carboxylic acid form with a lower alcohol (methanol, ethanol, propanol, etc.) in the presence of an acid, or It can be synthesized by treating a lower alkyl halide (methyl iodide, ethyl iodide, propyl chloride, etc.) in the presence of a base.

Compound (I) obtained by the above method
Can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like. When the compound (I) thus obtained is obtained in a free form, it can be converted to a salt by a method known per se or a method analogous thereto (eg, neutralization, etc.) Can be converted into a free form or another salt by a method known per se or a method analogous thereto. Further, when the compound (I) is an optically active form, it can be separated into d-form and 1-form by ordinary optical resolution means.

The compound (I) of the present invention has excellent LDL receptor increasing action, lipid lowering action and blood glucose lowering action,
And low toxicity. Therefore, these compounds and salts thereof can be used in mammals (eg, mice, rats, hamsters,
Rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.), for example, as preventive / remedy for arteriosclerotic diseases, preventive / remedies for hyperlipidemia, preventive / remedies for diabetes, and preventive / remedies for diabetic complications. Can be used safely. The compound (I) may be in its raw form, but is usually used as a carrier for pharmaceutical preparations, for example, excipients (eg, calcium carbonate, kaolin, sodium bicarbonate, lactose, starches, crystalline cellulose, talc, granulated sugar, porous Substances, etc.), binders (for example,
Dextrin, rubbers, alcoholized starch, gelatin,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), disintegrants (eg, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc.), lubricants (eg, stearin) Magnesium oxide, calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, tar dye, caramel, iron sesquioxide, titanium oxide, riboflavins, etc.), flavoring agents (eg, sweets, flavors, etc.), Stabilizer (eg, sodium sulfite, etc.)
And an appropriate amount of a preservative (eg, parabens, sorbic acid, etc.) and the like, and administered in a form prepared according to a conventional method. The prophylactic / therapeutic agent of the present invention containing the above-mentioned preparation suitably contains Compound (I) in an amount effective for treating and preventing a disease. The content of the compound (I) in the preparation of the present invention is as follows:
Usually, it is 0.1 to 100% by weight of the whole preparation. The preparation used in the present invention may contain other active ingredients other than the compound (I) as an active ingredient, and these ingredients are not particularly limited as long as the object of the present invention is achieved. It can be used at a proper mixing ratio. Specific examples of dosage forms include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, fine granules,
Powders, syrups, emulsions, suspensions, injections, inhalants, ointments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).

Specifically, a tablet is produced by mixing the compound (I) as it is, adding an excipient, a binder, a disintegrant or other suitable additives, and mixing the compound (I) uniformly.
After granulating by an appropriate method, a lubricant or the like is added and compression molding is carried out, or compound (I) is used as it is, or excipients, binders, disintegrants or other suitable additives are added thereto to form a uniform mixture. Can be directly compression-molded, or can be produced by compression-molding the granules prepared beforehand as they are, or after adding an appropriate additive and mixing them uniformly. In addition, the present agent, if necessary, a coloring agent,
Flavoring agents and the like can be added. Further, the agent can be coated with an appropriate coating agent. In the method for producing an injection, a certain amount of compound (I) is prepared by dissolving, suspending or emulsifying a fixed amount of compound (I) in water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, and in a vegetable oil in the case of a non-aqueous solvent. The compound can be produced in a quantity or a fixed amount of the compound (I) and sealed in a container for injection. As the pharmaceutical carrier for oral use, substances commonly used in the field of pharmaceuticals such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As the carrier for injection, for example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added. Further, the preparation of the present invention can be used as a sustained release preparation. The sustained-release preparation of the present invention can be prepared, for example, by a method of drying in water (o / w method, w / w method).
/ O / w method), microcapsules (for example, microspheres / microcapsules, microparticles, etc.) produced by a phase separation method, a spray drying method, or a method analogous thereto, as such, or in the form of microcapsules or spheres, needles The pharmaceutical composition in the form of a pellet, a film, or a cream can be formulated into various dosage forms as a raw material and administered. Examples of the dosage form include parenteral preparations (for example, injections or implants for intramuscular, subcutaneous, organ, etc .; transmucosal preparations for nasal cavity, rectum, uterus, etc.), oral preparations (for example, hard capsules, Soft capsules, granules, powders, suspensions and the like). When the sustained-release preparation of the present invention is an injection, a microcapsule is used as a dispersant (for example, a surfactant such as Tween 80 or HCO-60;
Carboxymethylcellulose, sodium alginate,
Polysaccharides such as sodium hyaluronate; protamine sulfate;
Polyethylene glycol, etc.), preservatives (eg, methyl paraben, propyl paraben, etc.), tonicity agents (eg,
An aqueous suspension with sodium chloride, mannitol, sorbitol, glucose, etc., a local anesthetic (eg, xylocaine hydrochloride, chlorobutanol, etc.), or a vegetable oil (eg, sesame oil, corn oil, etc.) or a phospholipid ( For example, a mixture of lecithin and the like, or a medium-chain fatty acid triglyceride (for example, Miglyol 812)
Etc.) to give a sustained-release injection as an oily suspension. When the sustained-release preparation of the present invention is a microcapsule, its average particle size is about 0.1 to about 300 μm, preferably about 1 to about 150 μm, and more preferably about 2 to about 100 μm. Examples of methods for making the microcapsules into a sterile preparation include a method of sterilizing the whole production process, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.

The preparations of the present invention have low toxicity, are useful as pharmaceuticals, and have excellent LDL receptor increasing, lipid lowering and blood glucose lowering effects. Therefore, the preparation of the present invention is useful as a preventive or therapeutic drug for diseases based on these pharmacological actions. That is, arteriosclerosis, hyperlipidemia, diabetes,
It can be used for the treatment or prevention of diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, peripheral vascular disease, thrombosis, pancreatic disorder, sequela of myocardial infarction, valvular heart disease and the like. Compound (I) and salts thereof have a cholesterol and triglyceride lowering action. Given their biological properties, hyperlipidemia, in particular hypertriglyceridemia, hyperlipoproteinemia and hypercholesterolemia and the atherosclerotic vascular lesions resulting therefrom and their sequelae, for example, Coronary artery disease, cerebral ischemia,
It is particularly suitable for treating and preventing aneurysms, cerebral atherosclerosis, peripheral atherosclerosis, intermittent claudication, gangrene, and the like.

In the treatment of these diseases, compound (I) may be used alone for prophylaxis and / or treatment, or may be used together with other lipid-lowering drugs or cholesterol-lowering drugs. These compounds are preferably administered as an oral preparation, and if necessary, may be administered in the form of suppositories as a rectal preparation. In this case, the components that can be combined include, for example, (1) fibrates (eg, clofibrate, bezafibrate, gemfibrozil, fenofibrate, etc.), nicotinic acid, derivatives and analogs thereof (eg, acipimox, probucol, etc.) , (2)
Bile acid binding resins (eg, cholestyramine, colestipol, etc.), compounds that inhibit cholesterol absorption (eg, sitosterol, neomycin, etc.), (3) compounds that inhibit cholesterol biosynthesis (eg, lovastatin, simvastatin, pravastatin, celivastatin, HMG-C such as atrobatatin, flubatitatin
oA reductase inhibitors), squalene epoxidase inhibitors (e.g., NB-598 and its analogs) and the like. Yet another possible combination component is oxidosqualene-lanosterol cyclase (e.g.,
Decalin derivatives, azadecalin derivatives, indane derivatives, etc.).

The compound (I) has a hypoglycemic effect and exhibits a hypoglycemic effect in obese diabetic rats, thereby improving insulin resistance. Given their biological properties, hyperglycemia and the sequelae resulting therefrom, such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic vascular disorders and insulin resistance and resulting therefrom, such as hypertension Disease, impaired glucose tolerance, and its sequelae, such as heart disease, cerebral ischemia, intermittent claudication,
Particularly suitable for the treatment and prevention of gangrene and the like. In the treatment of these diseases, Compound (I) may be used alone for prophylactic treatment or may be used with other hypoglycemic or antihypertensive drugs, in which case these compounds may be administered in an oral formulation And may be administered as a rectal preparation in the form of a suppository, if necessary.
In this case, the components that can be combined include, for example,
(1) insulin preparations (for example, human insulin etc.),
(2) sulfonylurea agents (eg, glibenclamide, gliclazide, etc.), (3) α-glucosidase inhibitors (eg, voglibose, acarbose, etc.), (4)
Insulin sensitivity enhancers (eg, pioglitazone, troglitazone, etc.), (5) aldose reductase inhibitors (eg, epalrestat, tolrestat, etc.), glycation inhibitors (eg, aminoguanidine, etc.) and the like.

Further, a combination with a hypotensive agent is possible,
For example, (1) diuretics (eg, furosemide, spironolactone, etc.), (2) sympatholytics (eg, atenolol, etc.), (3) angiotensin II antagonists (eg, losartan, candesartan, etc.), (4) angiotensin I-converting enzyme inhibitors (eg, enalapril maleate, delapril hydrochloride, etc.), and (5) calcium antagonists (eg, nifedipine, manidipine hydrochloride, etc.). In addition, compound (I) is suitable for the prophylactic treatment of diseases associated with hyperchylomicronemia, for example, acute pancreatitis. Regarding the mechanism of pancreatitis onset, micro-emboli occur in pancreatic capillaries due to chylomicron, or triglyceride is degraded by pancreatic lipase due to hyperchylomicronemia, increasing the free fatty acids produced and strongly stimulating the local area It is said to happen. Therefore,
Since the compound (I) of the present invention has a triglyceride lowering effect, it can be used alone or in combination with a known therapy for the preventive treatment of pancreatitis. For preventive treatment of this disease,
Compound (I) can be administered orally or topically, and they can be used alone or in combination with known active compounds such as aprotinin, gabexate methanesulfonate, nafamostate methanesulfonate, citicoline and ulinastatin.

A further notable application of compound (I) is secondary hyperlipidemia. These include diabetes, insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome or chronic renal failure, etc. These diseases cause hyperlipidemia, but often hyperlipidemia. Is said to exacerbate these diseases and form a so-called vicious circle. In view of its lipid lowering effect, compound (I) is also suitable for the treatment and prevention of the progress of these diseases, wherein compound (I) is used alone or as a known active compound, ie a therapeutic agent for hypothyroidism In combination with dry thyroid, levothyroxine sodium, liothyronine sodium, etc., and in combination with renal disease drugs, prednisolone, methylprednisolone sodium succinate furosemide, bumetanide, azosemide, etc., preferably orally Can be used with

Further possible uses of the compound (I) of the present invention include suppression of thrombus formation. Blood triglyceride levels are positively correlated with factor VII involved in blood coagulation. Ingestion of omega-3 fatty acids lowers triglycerides and suppresses coagulation, so hypertriglyceridemia promotes thrombus formation It is also considered to be. In addition, since VLDL of hyperlipidemic patients increased plasminogen activator inhibitor secretion from vascular endothelial cells more strongly than normolipidemic patients, it is also considered that triglycerides decrease fibrinolytic ability. Therefore, in view of the triglyceride lowering effect, compound (I) is suitable for preventing and treating thrombus formation. They may be used alone or as a known therapeutic agent such as dipyridamole, dilazep hydrochloride, a thrombolytic agent (eg, sodium heparin, urokinase), an antiplatelet agent (eg, aspirin, sulfinpyrazone, ticlopidine hydrochloride, cilostazol).
And preferably used for oral administration. The dose of the preparation of the present invention varies depending on the administration route, symptoms, age, weight, etc. of the patient, for example, as an arteriosclerosis therapeutic agent, a hypoglycemic agent or a diabetic complication therapeutic agent.
When administered orally to adult patients, 0.2 to 50 mg / day, preferably 1.
It is desirable to administer 5 to 30 mg / day in 1 to several divided doses. The administration route may be oral or parenteral.
The dose of the sustained-release preparation of the present invention varies depending on the administration route, symptoms, age and weight of the patient, and also on the duration of release. There is no particular limitation as long as the effective concentration is maintained in the body.
It can be selected appropriately depending on the situation, such as once a week to three months.

[0041]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, experimental results showing the pharmacological effect of the compound (I) of the present invention will be described. Test Example 1: Transcription promoting activity of LDL receptor gene in HepG2 cells (reporter assay) [Test method] HepG2 cells purchased from ATCC (American Type Culture Collection) were converted to RPMI1640 medium (10%
1.6 × 10 ⁴ cells / we in FCS (without phenol red)
After dilution to a concentration of ll (80 μl / well), the cells were seeded on a 96-well luminescence plate (Corning Costar). After culturing for 24 hours, pGL3 basic / LDLRP 0.3 μg / well, lipid (Superfecttr
ansfection reagent (QIAGEN)) 1 μl / well, RPMI1640 me
dium (FCS, phenol red, no antibiotics) 20μl / we
The mixed solution of II was added and reacted in a 37 ° C. carbon dioxide incubator to transiently introduce the reporter gene. 2
After time, remove the culture supernatant, RPMI1640 mediu containing 10% FCS
m (without phenol red) was changed to 100 ml / well, and the test compound was added at the same time. After further culturing for 22 hours, PicaGene L
100 µl / well of T7.5 (Toyo Ink) was added, and the luciferase activity was measured. In order to remove non-specific transcription promoters, a reporter expressing the luciferase gene under the control of the SV40 promoter (pGL3-basic) was used instead of pGL3 basic / LDLRP.
control (Promega)), and a reporter assay was performed in the same manner. The results are shown in [Table 1], [Table 2] and [Table 3].

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

Test Example 2: Effect of increasing LDL binding on HepG2 cells [Test method] Hep purchased from ATCC (American Type Culture Collection) by the method of JLGoldstein et al.
Eagle's minimum essential medium [MEM] (10%
(FBS), collagen-coated 6-well plate
(Sumitomo Bakelite) and cultured at 37 ° C. for 4 days.
After washing the cells, 25% as a standard compound under MEM (10% FBS)
-Hydroxycholesterol (2.3 µM) was used, and each test compound was added at 5 µM, followed by incubation in a carbon dioxide gas incubator for 20 hours. After washing with PBS, MEM (25 mM HEPBS, 1% BSA-FAF) containing ¹²⁵ I-human LDL (4 μg / ml) was added. For non-specific binding capacity (NSB), LDL 300 μg / m
l was added and allowed to bind for 2 hours at 6 ° C. After dissociation with dextran sulfate, ¹²⁵ I was measured and determined as the total binding ability. The protein amount was measured by dissolving the cells with 0.5% NaOH according to the Lowry method. The specific binding ability (LDL-Binding value) was calculated by subtracting the non-specific binding ability from the total binding ability and correcting the value with the amount of protein, and expressed as a percentage of the control group. The results are shown in [Table 4].

[Table 4] From the results of [Table 1] to [Table 4], the compound (I) of the present invention was obtained.
Has an excellent LDL receptor increasing effect.
Therefore, the compound (I) of the present invention reduces LDL and VLDL in blood, and is therefore useful for cardiovascular diseases such as arteriosclerosis and hyperlipidemia.

[0046]

The present invention will be further described in the following examples and reference examples, which are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. May be changed. ^{The 1} H-NMR spectrum was measured by Varian Gemini 200 (200 MHz) using tetramethylsilane as an internal standard, and all δ values were shown in ppm. The numerical values shown for the mixed solvents are volume mixing ratios of the respective solvents unless otherwise specified. % Means% by weight unless otherwise specified. The elution solvent in silica gel chromatography indicates a volume ratio unless otherwise specified. Room temperature (normal temperature) as used herein refers to a temperature of about 20 ° C to about 30 ° C. In addition, each symbol in an Example and a reference example represents the following meaning. s: singlet, d: doublet, t: triplet, q: quartet, b
r: Wide, J: Coupling constant, dd: Double doublet, m: Multiplet, Hz: Hertz, CDCl3: Deuterated chloroform,%:% by weight.

Reference Example 1 Synthesis of 3- (4-cyanophenyl) propionic acid A 2N aqueous sodium hydroxide solution (80.0 ml, 160 mmol) was added to 3
Ethyl-(4-cyanophenyl) propionate (15.8 g, 7
(7.7 mmol) in ethanol solution (160 ml) and stirred at room temperature for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3- (4-cyanophenyl) propionic acid (11.8 g, 87%) as colorless crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 2.58 (2H, t, J = 7.6 Hz),
2.90 (2H, t, J = 7.6 Hz), 7.45 (2H, d, J = 8.4 H
z), 7.74 (2H, d, J = 8.4 Hz), 12.21 (1H, s).

Reference Example 2 Synthesis of 4-amino-1- (4-methoxyphenylsulfonyl) piperidine hydrochloride 1) Synthesis of 4-tert-butoxycarbonylamino-1- (4-methoxyphenylsulfonyl) piperidine Butoxycarbonylaminopiperidine formate
(2.00 g, 8.12 mmol), 4-methoxyphenylsulfonyl chloride (1.84 g, 8.90 mmol), triethylamine (904
mg, 8.93 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (1.24 g, 8.16 mmol) in acetonitrile (50
ml) was stirred at room temperature for 3 hours. After the reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. Wash the extract with saturated saline,
After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to give 4-tert-
Butoxycarbonylamino-1- (4-methoxyphenylsulfonyl) piperidine (2.11 g, 70%) was obtained as colorless crystals, collected by filtration and washed with hexane. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H, s), 1.60-1.80 (2H,
m), 1.90−2.10 (2H, m), 2.30−2.50 (2H, m), 3.50−
3.80 (2H, m), 3.89 (3H, s), 4.30−4.50 (2H, m), 7.0
0 (2H, d, J = 8.8 Hz), 7.69 (2H, d, J = 8.8 Hz) .2) Synthesis of 4-amino-1- (4-methoxyphenylsulfonyl) piperidine hydrochloride concentrated hydrochloric acid (1.0 ml) To 4-tert-butoxycarbonylamino-1- (4-methoxyphenylsulfonyl) piperidine (1.0
(0 g, 2.70 mmol) in ethanol solution (10 ml) and heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure to give 4-amino-1-
(4-Methoxyphenylsulfonyl) piperidine hydrochloride (80
(0 mg, 97%) as colorless crystals, which were collected by filtration and washed with diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.50−2.20 (4H, m), 2.20−
2.40 (2H, m), 2.80−3.10 (3H, m), 3.86 (3H, s), 7.
16 (2H, d, J = 8.8 Hz), 7.68 (2H, d, J = 8.8 Hz),
8.15−8.30 (2H, m).

The following compounds were synthesized in the same manner. Reference Example 3 4-amino-1- (4-fluorophenylsulfonyl) piperidine hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.50-2.20 (4H, m), 2.30-
2.50 (2H, m), 2.80−3.20 (3H, m), 7.40−7.60 (2H, m
m), 7.75−7.90 (2H, m), 8.20−8.40 (2H, m).

Reference Example 4 Synthesis of 2-benzyl-4-chlorobenzoic acid 1) Synthesis of ethyl 4-chloro-2-hydroxybenzoate 4-chlorosalicylic acid (10.5 g, 60.8 mmol), concentrated sulfuric acid (2.0
ml) of an ethanol solution (100 ml) was heated under reflux for 14 hours.
The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and extracted with ethyl acetate. The extract was washed with a saturated sodium hydrogen carbonate solution, water, and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and ethyl 4-chloro-2-hydroxybenzoate.
(7.63 g, 63%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 4.41
(2H, q, J = 7.2 Hz), 6.86 (1H, dd, J = 8.6 and 2.2
Hz), 7.00 (1H, d, J = 2.2 Hz), 7.78 (1H, d, J =
8.6 Hz), 10.95 (1H, s) .2) Synthesis of ethyl 2-benzyl-4-chlorobenzoate Ethyl 4-chloro-2-hydroxybenzoate (3.00 g, 15.
0 mmol), benzyl bromide (2.82 g, 16.5 mmol), and a suspension of potassium carbonate (2.28 g, 16.5 mmol) in N, N-dimethylformamide (20 ml) were stirred at 80 ° C for 2 hours. After cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. Extract water with water,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
After concentration under reduced pressure, ethyl 2-benzyl-4-chlorobenzoate was added.
(4.35 g, quant.) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 6.8 Hz), 4.35
(2H, q, J = 6.8 Hz), 5.15 (2H, s), 6.99 (1H, dd, J
= 8.4 and 1.8 Hz), 7.02 (1H, d, J = 1.8 Hz), 7.30
−7.55 (5H, m), 7.79 (1H, d, J = 8.4 Hz) .3) Synthesis of 2-benzyl-4-chlorobenzoic acid 2N aqueous sodium hydroxide solution (15.0 ml, 30.0 mmol) was added.
Ethyl 2-benzyl-4-chlorobenzoate (4.35 g, 15.0
mmol) in ethanol (30 ml) and stirred at room temperature for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and 2-benzyl-4
-Chlorobenzoic acid (3.56 g, 91%) was obtained as colorless crystals,
It was collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 5.24 (2H, s), 7.07 (1H, dd,
J = 8.4 and 1.6 Hz), 7.25−7.60 (6H, m), 7.69 (1H,
d, J = 8.4 Hz).

Reference Example 5 Synthesis of 2- (4-cyanobenzylthio) benzoic acid 1) Synthesis of ethyl 2- (4-cyanobenzylthio) benzoate Ethyl thiosalicylate (1.83 g, 10.9 mmol), 4-cyanobenzyl Bromide (2.35 g, 12.0 mmol), potassium carbonate
(1.66 g, 12.0 mmol) of N, N-dimethylformamide suspension (20 ml) was stirred at room temperature for 12 hours. The reaction solution was poured into water, and ethyl 2- (4-cyanobenzylthio) benzoate (3.08
g, quant.) were obtained as colorless crystals, collected by filtration and washed with water. ¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s), 4.19 (2H, s), 7.
15−7.35 (2H, m), 7.35−7.50 (1H, m), 7.51 (2H, d,
J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.97 (1H, d
d, J = 7.6 and 1.4 Hz). 2) Synthesis of 2- (4-cyanobenzylthio) benzoic acid A 2N aqueous sodium hydroxide solution (10.0 ml, 20.0 mmol) was added.
Ethyl 2- (4-cyanobenzylthio) benzoate (3.08 g, 1
(0.9 mmol) in ethanol solution (20 ml) and stirred at room temperature for 4 hours. The reaction solution was neutralized with 1N hydrochloric acid to obtain 2- (4-cyanobenzylthio) benzoic acid (2.33 g, 80%) as colorless crystals, which were collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 4.32 (2H, s), 7.16-7.26 (1
H, m), 7.38−7.52 (3H, m), .60−7.68 (1H, m), 7.74
−7.83 (1H, m), 7.83−7.94 (1H, m), 8.02−8.09 (1
H, m).

Reference Example 6 Synthesis of 2-methylsulfonylnicotinic acid 1) Synthesis of ethyl 2-methylthionicotinate 2-Methylthionicotinic acid (10.0 g, 59.1 mmol), concentrated sulfuric acid
(2.0 ml) of an ethanol solution (100 ml) was heated under reflux for 20 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, made basic with a saturated aqueous solution of sodium hydrogen carbonate, and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue (hexane: ethyl acetate = 5: 1)
And purified with ethyl 2-methylthionicotinate (4.42 g, 38
%) Was obtained as colorless crystals, collected by filtration and washed with hexane. ¹ H-NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7.0 Hz), 2.54
(3H, s), 4.40 (2H, q, J = 7.0 Hz), 7.05 (1H, dd, J
= 8.0 and 4.8 Hz), 8.22 (1H, dd, J = 8.0 and 1.8
Hz), 8.58 (1H, dd, J = 4.8 and 1.8 Hz) .2) Synthesis of ethyl 2-methylsulfonylnicotinate g, 11.9 mmol) in tetrahydrofuran solution (50 ml) and stirred at room temperature for 5 hours.
The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give ethyl 2-methylsulfonylnicotinate (2.71 g, 99%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.0 Hz), 3.34
(3H, s), 4.47 (2H, q, J = 7.0 Hz), 7.62 (1H, dd, J
= 8.0 and 4.8 Hz), 8.10 (1H, dd, J = 8.0 and 2.0
Hz), 8.77 (1H, dd, J = 4.8 and 2.0 Hz) .3) Synthesis of 2-methylsulfonylnicotinic acid
-Ethyl methylsulfonylnicotinate (2.62 g, 11.4 mm
ol) in ethanol solution (25 ml) and stirred at room temperature for 1 hour. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-methylsulfonylnicotinic acid (1.40 g, 61%) as colorless crystals, which were collected by filtration and washed with hexane. ¹ H-NMR (DMSO-d ₆ ) δ: 3.34 (3H, s), 7.82 (1H, dd,
J = 8.0 and 4.8 Hz), 8.21 (1H, dd, J = 8.0 and 1.6
Hz), 8.82 (1H, dd, J = 4.8 and 1.6 Hz).

Reference Example 7 Synthesis of 5-phenylthiofuran-2-carboxylic acid 1) Synthesis of ethyl 5-nitrofuran-2-carboxylate 5-Nitrofuran-2-carboxylic acid (3.10 g, 19.7 mmol)
l) and a solution of concentrated sulfuric acid (0.60 ml) in ethanol (40 ml) were heated under reflux for 14 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 5-nitrofuran-2-carboxylate (3.18 g, 95%) as colorless crystals. It was collected by filtration and washed with hexane. ¹ H-NMR (CDCl ₃ ) δ: 1.42 (3H, t, J = 7.0 Hz), 4.45
(2H, q, J = 7.0 Hz), 7.26−7.32 (1H, m), 7.32−7.3
8 (1H, m). 2) Synthesis of ethyl 5-phenylthiofuran-2-carboxylate Ethyl 5-nitrofuran-2-carboxylate (3.18 g, 18.8
mmol), thiophenol (1.89 g, 17.1 mmol) and potassium carbonate (2.60 g, 18.8 mmol) in N, N-dimethylformamide (30 ml) were stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give ethyl 5-phenylthiofuran-2-carboxylate (3.49 g, 82%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.0 Hz), 4.36
(2H, q, J = 7.0 Hz), 6.67 (1H, d, J = 3.6 Hz), 7.1
8 (1H, d, J = 3.6 Hz), 7.22-7.34 (5H, m). 3) Synthesis of 5-phenylthiofuran-2-carboxylic acid 5N aqueous sodium hydroxide solution (6.00 ml, 12.0 mmol) was added to 5
-Ethyl phenylthiofuran-2-carboxylate (1.47 g,
5.92 mmol) in ethanol solution (12 ml) and stirred at room temperature for 1 hour. The reaction solution was neutralized with 1N hydrochloric acid to give 5-phenylthiofuran-2-carboxylic acid (1.13 g, 87%) as colorless crystals, which were collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 7.04 (1H, d, J = 3.6 Hz),
7.20−7.40 (6H, m).

In the same manner, the following compound was synthesized.Reference Example 8 5- (2-chlorophenylthio) furan-2-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 6.84-6.90 (1H, m), 7.16−
7.22 (1H, m), 7.26−7.40 (3H, m), 7.50−7.58 (1H,
Reference Example 9 5- (3-chlorophenylthio) furan-2-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 7.12-7.22 (2H, m), 7.25-
7.46 (4H, m).

Reference Example 10 5- (4-chlorophenylthio) furan-2-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 7.09 (1H, d, J = 3.4 Hz),
7.26 (2H, d, J = 8.8 Hz), 7.31 (1H, d, J = 3.4 H
z), 7.44 (2H, d, J = 8.8 Hz).

Reference Example 11 Synthesis of 6-chloro-1-benzofuran-2-carboxylic acid 1) Synthesis of ethyl 5-chloro-2-formylphenoxyacetate 4-Chloro-2-hydroxybenzaldehyde (4.85 g, 3
1.0 mmol), ethyl bromoacetate (5.68 g, 34.0 mmol), and a suspension of potassium carbonate (4.71 g, 34.1 mmol) in N, N-dimethylformamide (50 ml) were stirred at 70 ° C for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. Extract water with water,
After washing with saturated saline and drying over anhydrous magnesium sulfate,
The mixture was concentrated under reduced pressure to give ethyl 5-chloro-2-formylphenoxyacetate (7.52 g, quant.) As a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.0 Hz), 4.30
(2H, q, J = 7.0 Hz), 4.75 (2H, s), 6.86 (1H, d, J
= 1.6 Hz), 7.08 (1H, dd, J = 8.4 and 1.6 Hz), 7.82
(1H, d, J = 8.4 Hz), 10.48 (1H, s). 2) Synthesis of ethyl 6-chloro-1-benzofuran-2-carboxylate Ethyl 5-chloro-2-formylphenoxyacetate (7.52 g,
34.0 mmol) and a toluene solution (30 ml) of 1,8-diazabicyclo [5.4.0] -7-undecene (5.19 g, 34.1 mmol) were heated under reflux for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and ethyl 6-chloro-1-benzofuran-2-carboxylate (2.57 g, 37
%) As colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.0 Hz), 4.45
(2H, q, J = 7.0 Hz), 7.26−7.34 (1H, m), 7.49 (1H,
s), 7.56-7.64 (2H, m). 3) Synthesis of 6-chloro-1-benzofuran-2-carboxylic acid 6N aqueous sodium hydroxide solution (12.0 ml, 24.0 mmol) was added to 6
Ethyl chloro-1-benzofuran-2-carboxylate (2.5
(7 g, 11.4 mmol) in ethanol solution (25 ml) and stirred at room temperature for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and 6-chloro-1-benzofuran-2-carboxylic acid (1.98 g, 88%)
Was obtained as colorless crystals, collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 7.40 (1H, dd, J = 8.4 and
1.4 Hz), 7.69 (1H, d, J = 1.4 Hz), 7.81 (1H, d, J =
8.4 Hz), 7.92 (1H, s).

The following compounds were synthesized in the same manner. Reference Example 12 5,7-dichloro-1-benzofuran-2-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 7.48 (1H, s), 7.68 (1H, d,
J = 1.8 Hz), 7.82 (1H, d, J = 1.8 Hz).

Reference Example 13 Synthesis of (E) -3- (2-cyanophenyl) acrylic acid 2N aqueous sodium hydroxide solution (35.0 ml, 70.0 mmol)
Ethyl (E) -3- (2-cyanophenyl) acrylate (7.07
g, 35.1 mmol) in ethanol solution (70 ml) and at room temperature.
Stir for 2 hours. The reaction solution was neutralized with 1N hydrochloric acid, and (E) -3-
(2-Cyanophenyl) acrylic acid (5.35 g, 88%) was obtained as colorless crystals, collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 6.79 (1H, d, J = 15.8 Hz),
7.56−7.66 (1H, m), 7.70−7.82 (1H, m), 7.78 (1H, m
d, J = 15.8 Hz), 7.92 (1H, d, J = 7.6 Hz), 8.09 (1
(H, d, J = 8.2 Hz).

Reference Example 14 Synthesis of 4- (trifluoromethyl) phenoxyacetic acid 1) Synthesis of ethyl 4- (trifluoromethyl) phenoxyacetate 4- (trifluoromethyl) phenol (3.00 g, 18.5 mmo)
l), a suspension of ethyl bromoacetate (3.39 g, 20.3 mmol) and potassium carbonate (2.81 g, 20.3 mmol) in N, N-dimethylformamide (30 ml) was stirred at room temperature for 2 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain ethyl 4- (trifluoromethyl) phenoxyacetate (4.59 g, quant.) As a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.0 Hz), 4.28
(2H, q, J = 7.0 Hz), 4.67 (2H, s), 6.97 (2H, d, J
= 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz). 2) Synthesis of 4- (trifluoromethyl) phenoxyacetic acid
-Ethyl (trifluoromethyl) phenoxyacetate (4.59 g,
(18.5 mmol) in ethanol solution (20 ml).
Stirred for hours. The reaction solution was neutralized with 1N hydrochloric acid to obtain 4- (trifluoromethyl) phenoxyacetic acid (5.35 g, 88%) as colorless crystals, which were collected by filtration and washed with water. ¹ H-NMR (DMSO-d ₆ ) δ: 4.80 (2H, s), 7.10 (2H, d,
J = 9.2 Hz, 7.65 (2H, d, J = 9.2 Hz).

The following compounds were synthesized in the same manner. Reference Example 15 3- (trifluoromethyl) phenoxyacetic acid ¹ H-NMR (DMSO-d ₆ ) δ: 4.81 (2H, s), 7.00-7.20 (1
H, m), 7.20-7.45 (2H, m), 7.45-7.60 (1H, m).

Reference Example 16 3-Methyl-5-thia-1,8b-diazaacenaphthylene-4
Synthesis of carboxylic acid 1) Synthesis of 5-chloroimidazo [1,2-a] pyridine-3-carbaldehyde 5-chloroimidazo [1,2-a] pyridine (5.60 g, 29.6 mmo
l), hexamethylenetetramine (8.31 g, 59.2 mmol),
1,8-diazabicyclo [5.4.0] -7-undecene (4.51 g,
A 29.6 mmol) acetic acid solution (50 ml) was stirred at 90 ° C. for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed with water, 2N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 5-chloroimidazo [1,2-a] pyridine-3-carbaldehyde (0.84 g, 16%) as crystals. ¹ H-NMR (CDCl ₃ ) δ: 7.21 (1H, t, J = 7.2 Hz), 7.43
(1H, dd, J = 8.8 and 7.2 Hz), 7.90 (1H, d, J = 8.8
Hz), 10.75 (1H, s) .2) 5-Chloro-3- (1-hydroxyethyl) imidazo [1,2
-A] pyridine Synthesis of methylmagnesium chloride (3.0 M solution in tetrahydrofuran, 1.20 ml, 3.60 mmol) in 5-chloroimidazo [1,2
−a] pyridine-3-carbaldehyde (500 mg, 2.77 mmo
l) in tetrahydrofuran solution (15 ml) and add
Stirred for minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1) to give 5-chloro-3- (1-hydroxyethyl) imidazo [1,
[2-a] pyridine (500 mg, 92%) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.79 (3H, d, J = 6.6 Hz), 5.86
(1H, q, J = 6.6 Hz), 6.88 (1H, d, J = 7.2 Hz), 7.1
3 (1H, dd, J = 9.0 and 8.2 Hz), 7.57 (1H, d, J =
9.0 Hz), 7.71 (1H, s) .3) Synthesis of 3-acetyl-5-chloroimidazo [1,2-a] pyridine Manganese dioxide (4.42 g, 50.8 mmol) was added to 5-chloro-3-
(1-hydroxyethyl) imidazo [1,2-a] pyridine (500
mg, 2.54 mmol) in dichloromethane solution (20 ml).
Stirred at room temperature for 22 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1) to give 3-acetyl-5-
Chloroimidazo [1,2-a] pyridine (185 mg, 37%) was obtained as crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s), 7.13 (1H, dd, J
= 7.4 and 1.0 Hz), 7.46 (1H, dd, J = 8.8 and 7.4 H
z), 7.72 (1H, dd, J = 8.8 and 1.0 Hz) .4) Synthesis of ethyl 3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate 3-acetyl-5- Chloroimidazo [1,2-a] pyridine (830
mg, 4.26 mmol), ethyl thioglycolate (1.89 g, 1
7.1 mmol) of N, N-dimethylformamide solution (10 ml) in 1
Stirred at 20 ° C. for 70 hours. The reaction solution was diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give ethyl 3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (450 mg, 41%). Was obtained as red-purple crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.18
(3H, s), 4.22 (2H, q, J = 7.2 Hz), 5.70−5.85 (1H,
m), 6.55-6.75 (2H, m), 7.20 (1H, s) .5) 3-Methyl-5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxylic acid 2N aqueous sodium hydroxide solution (5.76 ml, 11.5 mmol) was added to 3
-Methyl-5-thia-1,8b-diazaacenaphthylene-4-
To a solution of ethyl carboxylate (1.00 g, 3.84 mmol) in tetrahydrofuran-methanol (1: 1) (30 ml) was added at room temperature.
Stirred for hours. The reaction solution was neutralized with 1N hydrochloric acid to obtain 3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (850 mg, 95%) as crystals, which were collected by filtration and washed with water. Washed. ¹ H-NMR (DMSO-d ₆ -DCl) δ: 2.17 (3H, s), 6.75 (1
H, d, J = 6.8 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.43
(1H, dd, J = 8.4 and 7.4 Hz), 8.01 (1H, s).

The following compounds were synthesized in the same manner. Reference Example 17 2,3-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 2.26 (3H, s), 2.33 (3H, s),
5.92−6.02 (1H, m), 6.50−6.60 (1H, m), 6.65−6.8
0 (1H, m).

Reference Example 18 N- [2- (piperidin-4-yl) ethane-1-yl] -5-thia-1,8b
Synthesis of 1-diazaacenaphthylene-4-carboxamide dihydrochloride 1) 2- (1-tert-butoxycarbonylpiperidin-4-yl)
Synthesis of ethanolDi-tert-butyl dicarbonate (65.5 g, 300 mmo) was added to an ethanol solution (500 ml) of piperidine ethanol (38.8 g, 300 mmol).
l) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2- (1-tert-butoxycarbonylpiperidine-4.
-Yl) ethanol (67.4 g, 98%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.40 (4H, m), 1.45 (9H, s),
1.50-1.90 (4H, m), 2.60-2.80 (2H, m), 3.70 (2H,
t, J = 6.4 Hz), 4.00-4.20 (2H, m). 2) Synthesis of N- [2- (1-tert-butoxycarbonylpiperidin-4-yl) ethyl] phthalimide 2- (1-tert-butoxy) Carbonylpiperidin-4-yl) ethanol (67.4 g, 294 mmol) in tetrahydrofuran (5
To the mixture (00 ml), triethylamine (59.4 g, 587 mmol) and methanesulfonyl chloride (40.4 g, 352 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate.The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 2- (1-tert-butoxycarbonylpiperidin-4-yl) methanesulfonate. Ethyl (75.1 g, 8
3%) as pale yellow crystals. Methanesulfonic acid 2- (1-t
ert-butoxycarbonylpiperidin-4-yl) ethyl (75.
1 g, 244 mmol) in N, N-dimethylformamide (500 m
l) was added potassium phthalimide (45.2 g, 244 mmol),
The mixture was stirred at 100 ° C for 1 hour. The reaction solution was poured into ice water, and the resulting crystals were collected by filtration and washed with water, and N- [2- (1-tert-butoxycarbonylpiperidin-4-yl) ethyl] phthalimide (81.1
g, 93%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.30 (3H, m), 1.45 (9H, s),
1.50-1.85 (4H, m), 2.55-2.80 (2H, m), 3.73 (2H,
t, J = 7.4 Hz), 3.95-4.20 (2H, m), 7.70-7.80 (2H,
m), 7.80-7.90 (2H, m) .3) 2- (1-tert-butoxycarbonylpiperidin-4-yl)
Synthesis of ethylamine N- [2- (1-tert-butoxycarbonylpiperidin-4-yl)
Ethyl] phthalimide (81.1 g, 226 mmol) in ethanol solution (500 ml) was added to hydrazine monohydrate (34.0 g, 679 mmol)
Was added and the mixture was heated under reflux for 1 hour. After water was added to the reaction solution, the mixture was concentrated under reduced pressure. Chloroform and an 8 N aqueous sodium hydroxide solution were added to the residue, and insolubles were filtered. The filtrate was saturated with sodium chloride and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2- (1-t
ert-butoxycarbonylpiperidin-4-yl) ethylamine (48.7 g, 94%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.30 (3H, m), 1.30-1.50 (2
H, m), 1.46 (9H, s), 1.50-1.75 (2H, m), 2.60-2.85
(4H, m), 4.00-4.20 (2H, m). 4) N- [2- (piperidin-4-yl) ethane-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N-hydroxysuccinimide (32.7 g, 284 mmol) was treated with 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (31.0 g). g,
142 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (54.5 g, 284 mmol) in acetonitrile suspension (500 ml), and the mixture was stirred at room temperature for 1 hour. 2-
(1-tert-butoxycarbonylpiperidin-4-yl) ethylamine (48.7 g, 213 mmol), triethylamine (28.8 g,
284 mmol) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N-
[2- (1-tert-Butoxycarbonylpiperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (50.8 g, 83%) Obtained as crystals.
Concentrated hydrochloric acid (97.4 ml) was added to N- [2- (1-tert-butoxycarbonylpiperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide ( (50.8 g, 118 mmol)
Was added to an ethanol solution (500 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and N- [2- (piperidin-4-yl)
Ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide dihydrochloride (38.7 g, 81%) was obtained as orange crystals, which were washed with ethanol and diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.70 (5H, m), 1.70-1.90
(2H, m), 2.70-2.90 (2H, m), 3.10-3.30 (4H, m), 6.59
(1H, d, J = 7.2 Hz), 6.97 (1H, d, J = 8.4 Hz), 7.
16 (1H, s), 7.27 (1H, dd, J = 8.4 and 7.2 Hz), 7.6
4 (1H, s), 8.60-9.10 (2H, m).

The following compounds were synthesized in the same manner. Reference Example 19 N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.65 (7H, m), 1.65-1.85 (2H,
m), 2.65-2.95 (2H, m), 3.05-3.30 (4H, m), 6.10 (1H, dJ =
7.4Hz), 6.97 (1H, d, J = 9.2Hz), 7.16 (1H, s), 7.20-7.35
(1H, m), 7.65 ( 1H, s), 8.84 (2H, br, NH 2 +).

Reference Example 20 Synthesis of N- [2- (piperidin-4-yloxy) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) 4 Synthesis of-(2-tert-butoxycarbonylaminoethane-1-yloxy) pyridine sodium hydride (10.6 g, 440 mmol) was converted to 4-chloropyridine (30.0 g, 200 mmol), 2-aminoethanol (12.2 g, 2
(00 mmol) in a N, N-dimethylformamide solution (300 ml) under ice cooling, and the reaction solution was stirred at 50 ° C. under a nitrogen atmosphere overnight. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (150 ml) and di-tert-butyl dicarbonate (48.0
g, 220 mmol) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.
The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give 4-
(2-tert-Butoxycarbonylaminoethane-1-yloxy) pyridine (18.6 g, 39%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.56 (2H, dt, J =
5.2 and 5.2 Hz), 4.08 (2H, t, J = 5.2 Hz), 4.90-5.1
5 (1H, m), 6.81 (2H, d, J = 6.4 Hz) .2) Synthesis of 4- (2-aminoethane-1-yloxy) pyridine dihydrochloride Concentrated hydrochloric acid (65.4 ml) was added to 4- (2- (tert-butoxycarbonylaminoethane-1-yloxy) pyridine (18.6 g, 79.5 mmol)
Was added to an ethanol solution (200 ml), followed by stirring at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give 4- (2-aminoethane-1-yloxy) pyridine dihydrochloride (13.0 g, 77%) as colorless crystals, which were washed with ethanol and diethyl ether. ¹ H-NMR (D ₂ O) δ: 3.57 (2H, t, J = 5.0 Hz), 4.62 (2
H, t, J = 5.0 Hz), 7.48 (2H, d, J = 7.2 Hz), 8.61
(2H, d, J = 7.2 Hz) .3) Synthesis of 4- (2-aminoethane-1-yloxy) piperidine dihydrochloride 4- (2-aminoethane-1-yloxy) pyridine dihydrochloride (1
3.0 g, 74.4 mmol) in ethanol (50 ml) solution 10% Rh-C (1 g)
, And a hydrogenation reaction was performed at 100 ° C. and 100 atm. The reaction solution was filtered to remove the catalyst, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration to give 4- (2-aminoethane-1-yloxy) piperidine dihydrochloride (13.3 g, 99%). 4) Synthesis of 4- (2-aminoethane-1-yloxy) -1-tert-butoxycarbonylpiperidine Benzaldehyde (6.52 g, 61.4 mmol) was converted to 4- (2-aminoethane-1-yloxy) piperidine dihydrochloride (13.3 g , 61.4
mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (18.7
g, 123 mmol) in toluene solution (150 ml) and Dean-St
The mixture was heated under reflux for 3 hours using ark. After cooling the reaction solution to room temperature, di-tert-butyl dicarbonate (13.4 g, 61.4 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and a 1 N aqueous solution of potassium hydrogen sulfate (67.6 ml, 67.6 mmol) was added to the residue.
Was added and stirred at room temperature overnight. An 8 N aqueous sodium hydroxide solution was added to the reaction solution, sodium chloride was added until saturation, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4- (2-aminoethane-1-
Yloxy) -1-tert-butoxycarbonylpiperidine (1
4.7 g, 98%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.50-1.90 (2H,
m), 2.40-2.60 (2H, m), 2.85 (2H, t, J = 5.4 Hz),
3.00-3.20 (2H, m), 3.20-3.40 (4H, m), 3.49 (2H, t,
J = 5.4 Hz), 3.70-3.85 (1H, m) .5) N- [2- (1-tert-butoxycarbonylpiperidin-4-yloxy) ethane-1-yl] -5-thia-1,8b- Synthesis of diazaacenaphthylene-4-carboxamide 1-hydroxybenzotriazole monohydrate (11.9 g, 75.
0 mmol) with 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (10.9 g, 50.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (14.4 g, 75.0 mmol) ) In acetonitrile suspension (200 ml) and stirred at room temperature for 1 hour. 4- (2-aminoethane-1-yloxy) -1-te
rt-butoxycarbonylpiperidine (18.3 g, 75.0 mmo
l) and triethylamine (10.1 g, 100 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [2- (1-tert-butoxycarbonylpiperidin-4-yloxy) ethane-1-yl] -5.
-Thia-1,8b-diazaacenaphthylene-4-carboxamide (1
5.0 g, 68%) as a red amorphous. 6) N- [2- (piperidin-4-yloxy) ethane-1-yl] -5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (27.8 ml) was added to N- [2- (1-tert-butoxycarbonylpiperidin-4-yloxy) ethane-1-yl ] -5-Thia-1,8b-
Diazaacenaphthylene-4-carboxamide (15.0 g, 33.8
(mmol) in ethanol (100 ml) and stirred at 50 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and N- [2- (piperidin-4-yloxy) ethan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (12.0 g, 85%) were obtained as orange crystals and washed with diethyl ether.

The following compounds were synthesized in the same manner. Reference Example 21 N- [3- (piperidin-4-yloxy) propan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride ¹ H-NMR (D ₂ O) δ: 1.60-1.90 (4H, m), 2.00-2.25 (2H,
m), 3.00-3.20 (2H, m), 3.20-3.50 (4H, m), 3.50-3.65
(2H, m), 3.65-3.80 (1H, m), 5.99 (1H, d, J = 7.4 H
z), 6.59 (1H, d, J = 8.2 Hz), 6.63 (1H, s), 6.78
(1H, dd, J = 8.2 and 7.4 Hz), 6.98 (1H, s).

Reference Example 22 N- [2- (piperidin-4-ylthio) ethane-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Synthesis of 1-tert-butoxycarbonyl-4-hydroxypiperidine Di-tert-butyl dicarbonate (41.5 g, 190 mmol) was converted to 4- Hydroxypiperidine (19.2 g, 190 mmol) in ethanol (200
ml) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 1-tert-butoxycarbonyl-4-hydroxypiperidine (31.2 g, 82%) as crystals, which were collected by filtration and washed with hexane. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.70-1.95 (4H, m),
2.95-3.15 (2H, m), 3.75-3.95 (3H, m) .2) Synthesis of 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethanol Methanesulfonyl chloride (21.3 g, 186 mmol) -tert
-Butoxycarbonyl-4-hydroxypiperidine (31.2 g,
155 mmol) and triethylamine (31.4 g, 310 mmol) in tetrahydrofuran solution (300 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 1-tert-butoxycarbonylpiperidin-4-yl methanesulfonate (43.3 g, quant.) Was obtained as an oil. Methanesulfonic acid 1-tert-butoxycarbonylpiperidine
-4-yl (27.9 g, 100 mmol) in 2-mercaptoethanol
(15.7 g, 200 mmol), cesium fluoride (30.4 g, 200 mmo
l) was added to an acetonitrile solution (300 ml), and the mixture was stirred at 70 ° C for 8 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethanol (19.8 g, 76%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.80-2.00 (2H, m),
2.25-2.40 (1H, m), 2.65-3.00 (6H, m), 3.65-3.80
(2H, m), 3.85-4.05 (2H, m) .3) Synthesis of 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethyl methanesulfonate Methanesulfonyl chloride (10.4 g, 91.1 mmol) -(1-
tert-butoxycarbonylpiperidin-4-ylthio) ethanol (19.8 g, 75.9 mmol), triethylamine (15.4
g, 152 mmol) in tetrahydrofuran (200 ml) and stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethyl methanesulfonate (25.7
g, quant.) as an oil. ¹ H-NMR (DCl ₃ ) δ: 1.45 (9H, s), 1.40-1.60 (2H, m),
1.80-2.00 (2H, m), 2.75-3.00 (5H, m), 3.04 (3H,
s), 3.90-4.05 (2H, m), 4.32 (2H, t, J = 7.2 Hz). 4) Synthesis of N- [2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethane] phthalimide Methane N, N- of 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethyl sulfonate (26.5 g, 78.2 mmol)
To a dimethylformamide solution (300 ml) was added potassium phthalimide (14.5 g, 78.2 mmol), and the mixture was stirred at 100 ° C for 1 hour. The reaction solution was poured into ice water, and the resulting crystals were collected by filtration and washed with water, and N- [2- (1-tert-butoxycarbonylpiperidine-4-
[Ilthio) ethane] phthalimide (23.6 g, 80%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.80-2.10 (3H, m),
2.75-3.00 (6H, m), 3.80-4.20 (4H, m), 7.60-7.80
(2H, m), 7.80-8.00 (2H, m) .5) Synthesis of 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethylamine N- [2- (1-tert-butoxycarbonylpiperidine-4 -Ylthio) ethane] phthalimide (23.6 g, 60.4 mmol) in ethanol (250 ml) was added to hydrazine monohydrate (9.07 g, 181 m
mol), and the mixture was heated under reflux for 1 hour. After water was added to the reaction solution, the mixture was concentrated under reduced pressure. Chloroform and an 8 N aqueous sodium hydroxide solution were added to the residue, and insolubles were filtered. The filtrate was saturated with sodium chloride and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-
(1-tert-Butoxycarbonylpiperidin-4-ylthio) ethylamine (13.2 g, 84%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.40-1.80 (5H, m),
1.80-2.00 (2H, m), 2.60-3.00 (6H, m), 3.70-4.10
(2H, m). 6) Synthesis of N- [2- (piperidin-4-ylthio) ethan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1 -Hydroxybenzotriazole monohydrate (10.7 g, 46.
5 mmol) with 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid monohydrate (10.9 g, 46.5 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (13.4 g, 69.8 m
mol) in acetonitrile (150 ml) and added at room temperature.
Stirred for hours. 2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethylamine (13.2 g, 50.6 mm
ol) and triethylamine (9.41 g, 93.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethane-1-yl] -5.
-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained as an oil. Concentrated hydrochloric acid (27.8 ml) was added to N- [2- (1-tert-butoxycarbonylpiperidin-4-ylthio) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. The mixture was added to an ethanol solution (100 ml) and stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and N- [2- (piperidin-4-ylthio) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (10.2 g, 51%) as orange crystals and washed with diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.80 (2H, m), 1.95-2.20 (2H,
m), 2.60-2.80 (2H, m), 2.80-3.15 (3H, m), 3.15-3.40 (4
H, m), 6.64 (1H, d, J = 7.6Hz), 6.99 (1H, d, J = 8.6Hz), 7.21
(1H, s), 7.30 (1H, t, J = 7.6Hz), 7.70 (1H, s), 9.05-9.20
(1H, m), 9.22 ( 2H, br, NH 2 +).

The following compounds were synthesized in the same manner. Reference Example 23 N- [3- (piperidin-4-ylthio) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.55-1.80 (4H, m), 1.95-2.20 (2H,
m), 2.45-2.65 (2H, m), 2.80-3.10 (3H, m), 3.10-3.35 (4
H, m), 6.63 (1H, d, J = 7.2Hz), 6.98 (1H, d, J = 9.0Hz), 7.21
(1H, s), 7.20-7.40 (1H, m), 7.68 (1H, s), 8.85-9.00 (1H,
m), 9.17 (2H, br , NH 2 +).

Reference Example 24 Synthesis of tert-butyl 2-aminoethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate 1) 1- [4- (trifluoromethyl) benzoyl]- Synthesis of 4-piperidinone 1-hydroxybenzotriazole monohydrate (2.30 g, 15.
0 mmol) with 4- (trifluoromethyl) benzoic acid (1.90 g, 1
0.0 mmol) and a suspension of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.88 g, 15.0 mmol) in acetonitrile (30 ml) and stirred at room temperature for 1 hour. 4-
Piperidone hydrochloride monohydrate (1.54 g, 10.0 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (1.52 g, 10.0 mmo
l) and triethylamine (2.02 g, 20.0 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate) to give 1- [4- (trifluoromethyl) benzoyl] -4-
Piperidinone (1.63 g, 60%) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 2.40-2.70 (4H, m), 3.60-4.20 (4
H, m), 7.59 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J =
8.2 Hz). 2) Synthesis of [4-[(2-hydroxyethyl) amino] piperidin-1-yl] [4- (trifluoromethyl) phenyl] methanone Sodium triacetoxyborohydride (2.55 g, 12.0
mmol) with 1- [4- (trifluoromethyl) benzoyl] -4-piperidinone (1.63 g, 6.01 mmol), ethanolamine (73
4 mg, 12.0 mmol) in methanol solution (20 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution was added to the residue, saturated with sodium chloride, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and [4-[(2-hydroxyethyl) amino] piperidin-1-yl] [4- (trifluoromethyl) phenyl] methanone (1.91 g, quant.) Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.60 (3H, m), 1.70-2.20 (4
H, m), 2.70-2.90 (3H, m), 2.90-3.20 (2H, m), 3.67
(2H, t, J = 5.2 Hz), 4.50-4.70 (1H, m), 7.51 (2H,
d, J = 8.6 Hz), 7.69 (2H, d, J = 8.6 Hz). 3) Tert-butyl 2-hydroxyethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate Synthesis Di-tert-butyl dicarbonate (5.06 g, 23.2 mmol) was converted to [4-[(2-hydroxyethyl) amino] piperidin-1-yl] [4- (trifluoromethyl) phenyl] methanone (7.34 g, 23.2 mmol)
Was added to an ethanol solution (40 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 10:
Purification in 1) gave tert-butyl 2-hydroxyethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate (6.29 g, 65%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H, s), 1.50-1.90 (5H, m),
2.60-3.20 (2H, m), 3.25-3.40 (2H, m), 3.60-3.80
(3H, m), 3.90-4.20 (1H, m), 4.70-4.90 (1H, m), 7.5
2 (2H, d, J = 8.0 Hz), 7.70 (2H, d, J = 8.0 Hz) .4) tert-Butyl 2- (1,3-dioxo-1,3-dihydro-2H-isoindole-2 Synthesis of -yl) ethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate Diethyl azodicarboxylate (5.26 g, 30.2 mmol)
Butyl 2-hydroxyethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate (6.29
g, 15.1 mmol), triphenylphosphine (7.92 g, 30.2
mmol) and phthalimide (4.44 g, 30.2 mmol) in tetrahydrofuran solution (60 ml), and the mixture was stirred at room temperature overnight.
The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the residue.
The resulting precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure.
Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 1: 1) and purified with tert-butyl 2-
(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl) ethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate (8.24 g, quant.) Was obtained as a colorless amorphous. 5) Synthesis of tert-butyl 2-aminoethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate tert-butyl 2- (1,3-dioxo-1,3-dihydro-2H
-Isoindol-2-yl) ethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate (11.
Hydrazine monohydrate (3.10 g, 61.9 mmol) was added to an ethanol solution (500 ml) of 3 g, 20.6 mmol), and the mixture was heated under reflux for 1 hour. After water was added to the reaction solution, the mixture was concentrated under reduced pressure. Chloroform and 8N aqueous sodium hydroxide solution were added to the residue,
Insolubles were filtered. The filtrate is saturated with sodium chloride,
Extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, concentrated under reduced pressure and tert-butyl 2-aminoethyl
[1- [4- (trifluoromethyl) benzoyl] piperidine-4-
[Il] carbamate (5.03 g, 59%) was obtained as an orange oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.35 (2H, m), 1.47 (9H, s),
1.50-1.90 (4H, m), 2.79 (2H, t, J = 7.2 Hz), 3.15
(2H, t, J = 7.2 Hz), 3.60-3.80 (2H, m), 4.00-4.30
(2H, m), 4.70-4.95 (1H, m), 7.52 (2H, d, J = 8.0
Hz), 7.69 (2H, d, J = 8.0 Hz).

The following compounds were synthesized in the same manner. Reference Example 25 tert-butyl 3-aminopropyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.35 (2H, m), 1.46 (9H, s),
1.50-1.90 (6H, m), 2.71 (2H, t, J = 6.8 Hz), 3.00
-3.25 (2H, m), 3.60-3.80 (2H, m), 4.10-4.25 (2H, m
m), 4.70-4.90 (1H, m), 7.52 (2H, d, J = 8.0 Hz),
7.68 (2H, d, J = 8.0 Hz).

Reference Example 26 2- [1- [4- (trifluoromethyl) benzoyl] piperidine-
Synthesis of 4-yl] ethylamine hydrochloride 1) Synthesis of 4- (2-chloroethyl) piperidine hydrochloride
50 ml) and heated under reflux for 3 hours. Cool the reaction solution,
The purified precipitate was collected by filtration and washed with tetrahydrofuran and diethyl ether to give 4- (2-chloroethyl) piperidine hydrochloride (30.9 g, 84%) as gray crystals. 2) Synthesis of 4- (2-chloroethyl) -1- [4- (trifluoromethyl) benzoyl] piperidine 1,8-diazabicyclo [5.4.0] -7-undecene (1.52 g, 10.
0 mmol), triethylamine (2.02 g, 20.0 mmol)
(2-Chloroethyl) piperidine hydrochloride (1.84 g, 10.0 mmo
l), 4- (trifluoromethyl) benzoyl chloride (2.29
g, 11.0 mmol) in a dichloromethane suspension (20 ml).
Stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl acetate) to give 4- (2-chloroethyl) -1- [4- (trifluoromethyl) benzoyl] piperidine (2.73 g, 86%) as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.40 (2H, m), 1.65-2.00 (4
H, m), 1.78 (2H, t, J = 6.4 Hz), 2.65-2.90 (1H, m),
2.90-3.15 (1H, m), 3.59 (2H, t, J = 6.4 Hz), 4.60
-4.85 (1H, m), 7.50 (2H, d, J = 8.0 Hz), 7.68 (2H,
d, J = 8.0 Hz). 3) Synthesis of N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] phthalimide phthalimide potassium (1.58 g, 8.55 mmol) with 4- (2-chloroethyl) -1- [4- (trifluoromethyl) benzoyl] piperidine (2.73 g, 8.55 mmol) and sodium iodide (2.56 mmol).
g, 17.1 mmol) in N, N-dimethylformamide (30 ml)
And stirred at 100 ° C. for 2 hours. Pour the reaction solution into ice water,
The resulting precipitate was collected by filtration and dissolved in ethyl acetate.
The ethyl acetate solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1.
[-Yl] phthalimide (3.42 g, 93%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.45 (2H, m), 1.50-2.05 (7
H, m), 2.70-2.90 (1H, m), 2.90-3.10 (1H, m), 3.74
(2H, t, J = 7.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.6
8 (2H, d, J = 8.0 Hz), 7.70-7.76 (2H, m), 7.83-7.8
8 (2H, m). 4) Synthesis of 2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethylamine hydrochloride Hydrazine monohydrate (1.19 g, 23.9 mmol) was converted to N- [2- [1- [4-
(Trifluoromethyl) benzoyl] piperidin-4-yl]
The solution was added to an ethanol solution (40 ml) of [ethane-1-yl] phthalimide (3.42 g, 7.95 mmol), and heated under reflux for 1 hour. After water was added to the reaction solution, the mixture was concentrated under reduced pressure. Chloroform and an 8 N aqueous sodium hydroxide solution were added to the residue, and insolubles were filtered. The filtrate was saturated with sodium chloride and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (40 ml), concentrated hydrochloric acid (1.28 ml) was added, the mixture was concentrated under reduced pressure, and 2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethylamine hydrochloride (2.18 g) , 81%) as colorless crystals, collected by filtration and washed with diethyl ether. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.50 (7H, m), 1.50-1.95 (3
H, m), 2.75 (2H, t, J = 7.4 Hz), 2.85-3.15 (1H, m),
3.40-3.75 (1H, m), 4.60-4.80 (1H, m), 7.50 (2H, d,
J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz).

Reference Example 27 3- [1- [4- (trifluoromethyl) benzoyl] piperidine-
4-yl] propylamine hydrochloride 1) Synthesis of 4- (3-chloropropyl) piperidine hydrochloride Thionyl chloride (26.3 ml, 360 mmol) in tetrahydrofuran solution of piperidine-4-propanol (43.0 g, 300 mmol) at 0 ° C (450 ml) and heated under reflux for 3 hours. The reaction solution was cooled, diethyl ether (200 ml) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether, and washed with 4- (3-chloropropyl) piperidine hydrochloride (54.4 g, 9
2%) as crystals. 2) Synthesis of 4- (2-chloroethyl) -1- [4- (trifluoromethyl) benzoyl] piperidine 4- (3-chloropropyl) piperidine hydrochloride (54.4 g, 273 mm
ol) in tetrahydrofuran suspension (500 ml) at 0 ° C for 1,8-
Diazabicyclo [5.4.0] -7-undecene (40.8 g, 273mmol)
And triethylamine (57 ml, 410 mmol) were added. Then 4
-(Trifluoromethyl) benzoyl chloride (44.5ml, 30
0 mmol) was added dropwise and stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Water (300ml) in the residue
And extracted with ethyl acetate (500 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography (hexane:
Purified with ethyl acetate = 5: 1-1: 1) to give 4- (3-chloropropyl) -1
-[4- (trifluoromethyl) benzoyl] piperidine (84.3
g, 92%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.95 (9H, m), 2..65-3.15 (2
H, m), 3.54 (2H, t, J = 6.6 Hz), 3.50-3.75 (1H, m),
4.60-4.80 (1H, m), 7.50 (2H, d, J = 8.4Hz), 7.68
(2H, d, J = 8.4 Hz). 3) Synthesis of N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] phthalimide Potassium phthalimide (38.5 g, 208 mmol) with 4- (3-chloropropyl) -1- [4- (trifluoromethyl) benzoyl] piperidine (208 mmol), sodium iodide (31.1 g, 208 mmo
l) in N, N-dimethylformamide solution (400 ml), 100
Stirred at C for 2 hours. The reaction solution was poured into water (500 ml) and extracted with ethyl acetate (500 ml × 2). The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The precipitated crystals were collected by filtration and N- [3- [3- [4-
(Trifluoromethyl) benzoyl] piperidin-4-yl]
[Propan-1-yl] phthalimide (84.2 g, 91%) was obtained as pale yellow crystals. Melting point: 113-114 ° C Elemental analysis: As C ₂₄ H ₂₃ F ₃ N ₂ O ₃ Calculated: C, 64.86; H, 5.22; N, 6.30 Found: C, 64.80; H, 5.10; N, 6.37. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.95 (9H, m), 2.65-3.10 (2
H, m), 3.69 (1H, t, J = 7.1Hz), 3.55-3.70 (1H, m), 4.60-
4.80 (1H, m), 7.49 (2H, d, J = 8.0Hz), 7.67 (2H, d, J = 8.0H
z), 7.70-7.80 (2H, m), 7.80-7.90 (2H, m). 4) Synthesis of 3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propylamine hydrochloride Hydrazine monohydrate (14.6 ml, 300 mmol) was added to N- [3- [1- [4-
(Trifluoromethyl) benzoyl] piperidin-4-yl]
The solution was added to an ethanol solution (500 ml) of [propan-1-yl] phthalimide (44.5 g, 100 mmol) and heated under reflux for 2 hours. After water (100 ml) was added to the reaction solution, the mixture was concentrated under reduced pressure. An 8 N aqueous sodium hydroxide solution (100 ml) was added to the residue, and the mixture was extracted with chloroform (300 ml × 3). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Residue is ethanol (200m
l), concentrated hydrochloric acid (33 ml) was added, and the mixture was concentrated under reduced pressure to give 3- [1- [4-
(Trifluoromethyl) benzoyl] piperidin-4-yl]
Propylamine hydrochloride (67.3 g, 96%) was obtained as colorless crystals. 173-174 ° C. Elemental analysis: C ₁₆ H ₂₁ F ₃ N ₂ O · HCl Calculated: C, 54.78; H, 6.32; N, 7.99 Found: C, 54.72; H, 6.08; N, 8.08. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.90 (9H, m), 2.60-2.90 (3H,
m), 2.90-3.15 (1H, m), 3.40-3.60 (1H, m), 4.40-4.60
(1H, m), 7.58 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J =
8.0Hz), 8.01 (3H, br , NH 3 +).

The following compounds were synthesized in the same manner. Reference Example 28 3- [1- [4- (trifluoromethyl) benzenesulfonyl] piperidin-4-yl] propylamine ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.90 (9H, m), 2.20-2.40 ( Two
H, m), 3.49 (2H, t, J = 6.6 Hz), 3.75-3.90 (2H, m),
7.81 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 H)
z).

Reference Example 29 Synthesis of 7-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) Synthesis of 2,6-dichloropyridine-4-methanol 2,6-dichloropyridine -4-carboxylic acid (9.60 g, 50.0 mmo
l) was added to a borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution, 100 ml, 100 mmol) under ice cooling,
Stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2,6-dichloropyridine-4-methanol (7.04 g, 79%) as brown crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.57 (2H, d, J = 5.4 Hz), 5.6
7 (1H, t, J = 5.4 Hz), 7.46 (2H, s) .2) Synthesis of 4-chloromethyl-2,6-dichloropyridine 2,6-dichloropyridine-4-methanol (1.78 g, 10.0 mm
ol) was added to thionyl chloride (3.65 ml, 50.0 mmol) at room temperature, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was poured into ice water, and extracted with ethyl acetate. The extract was washed with 1N aqueous sodium hydroxide solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-chloromethyl-2,6-dichloropyridine (1.78 g, 91%) as brown crystals. As obtained. ¹ H-NMR (CDCl ₃ ) δ: 4.51 (2H, s), 7.32 (2H, s) .3) Synthesis of 2,6-dichloro-4-methylpyridine Sodium borohydride (685 mg, 18.1 mmol) Was added to a solution of 4-chloromethyl-2,6-dichloropyridine (1.78 g, 9.06 mmol) in dimethyl sulfoxide (10 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and 2,6-dichloro-
4-methylpyridine (1.00 g, 68%) was obtained as brown crystals,
It was collected by filtration and washed with water. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 2.35 (3H, s), 7.10 (2
H, s) .4) Synthesis of 2-amino-6-chloro-4-methylpyridine 2,6-dichloro-4-methylpyridine (50.0 g, 0.309 mmol)
And 28% aqueous ammonia (50 ml) at 160 ° C under 12.1 kgcm ^-2
After stirring for 2 hours, 2-amino-6-chloro-4-methylpyridine (43.
(6 g, 99%) were obtained as green crystals, collected by filtration and washed with water. ¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 4.48 (2H, brs),
6.20 (1H, s), 7.52 (1H, s) .5) Synthesis of 5-chloro-7-methylimidazo [1,2-a] pyridine 40% aqueous chloroacetaldehyde solution (100 ml, 600 mmol)
To 2-amino-6-chloro-4-methylpyridine (28.5 g, 200 m
mol) in ethanol (200 ml) and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, adjusted to pH 8-9 with an 8 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-chloro-7-methylimidazo [1,2-a] pyridine (26.6
g, 80%) as brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 6.76 (1H, d, J =
1.4 Hz), 7.36 (1H, s), 7.63 (1H, d, J = 1.4 Hz), 7.6
9 (1H, s) .6) Synthesis of ethyl (7-methylimidazo [1,2-a] pyridin-5-yl) thioacetate Ethyl thioglycolate (18.0 g, 150 mmol)
-7-methylimidazo [1,2-a] pyridine (16.6 g, 100 mmol)
N, N-dimethylformamide solution (100 ml) at 50 ° C
For 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and ethyl (7-methylimidazo [1,2-a] pyridin-5-yl) thioacetate (25.0 g, 99
%) As a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.2 Hz), 2.40
(3H, s), 3.67 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 6.
92 (1H, d, J = 1.6 Hz), 7.40 (1H, s), 7.64 (1H, d,
J = 1.2 Hz), 7.82 (1H, d, J = 0.8 Hz) .7) Synthesis of ethyl 7-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate hexamethylenetetramine (28.0 g, 199 mmol) in ethyl (7-methylimidazo [1,2-a] pyridin-5-yl) thioacetate
(25.0 g, 100 mmol) in acetic acid solution (200 ml) at 90 ° C.
Stir for 18 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with an 8N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and ethyl 7-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (16.2 g , 62%) as red crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.0 Hz), 2.01
(3H, s), 4.22 (2H, q, J = 7.0 Hz), 5.58 (1H, d, J =
1.2 Hz), 6.36 (1H, t, J = 0.2 Hz), 6.83 (1H, s),
6.98 (1H, s) .8) Synthesis of 7-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 2N sodium hydroxide aqueous solution (50.0 ml, 100 mmol, 7
Ethyl solution of ethyl 1-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (13.0 g, 50.0 mmol) (50 m
l) and stirred at room temperature for 30 minutes. The pH of the reaction solution was adjusted to 3-4 by adding concentrated hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to give 7-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ( 7.49 g, 65%) were obtained as orange crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.96 (3H, s), 5.89 (1H, s),
6.42 (1H, s), 6.89 (1H, s), 7.08 (1H, s).

Reference Example 30 Synthesis of 8-bromo-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) Synthesis of 6-chloro-2-pivaloylamino-3-trimethylsilylpyridine n-butyllithium (1.6 mol hexane solution, 197 ml, 315
mmol) with 6-chloro-2-pivaloylaminopyridine (19.1
g, 90.0 mmol) in tetrahydrofuran solution (50 ml).
C. and stirred at -78.degree. C. for 30 minutes and at 0.degree. C. for 45 minutes. The reaction solution was cooled to -78 ° C and chlorotrimethylsilane (286 ml,
225 mmol), and the mixture was stirred at -78 ° C for 1 hour and at 0 ° C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 10: 1-5: 1) to give 6-chloro-2
-Pivaloylamino-3-trimethylsilylpyridine (22.1
g, 86%) as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.30 (9H, s), 1.33 (9H, s), 7.1
6 (1H, d, J = 7.8 Hz), 7.70 (1H, s), 7.80 (1H, d, J
2) Synthesis of 3-bromo-6-chloro-2-pivaloylaminopyridine Bromine (4.00 ml, 77.6 mmol) was converted to 6-chloro-2-pivaloylamino-3-trimethylsilylpyridine (22.1 g, 77.5 mmol)
Was added at room temperature to a carbon tetrachloride solution (150 ml), followed by stirring for 10 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium thiosulfate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 2: 1-1: 2) to give 3-bromo-6-
Chloro-2-pivaloylaminopyridine (16.0 g, 71%) was obtained as pale orange crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 7.04 (1H, d, J =
(8.4 Hz), 7.82 (1H, d, J = 8.0 Hz), 7.96 (1H, s) .3) Synthesis of 2-amino-3-bromo-6-chloropyridine 3-bromo-6-chloro-2-pi Valoylaminopyridine (16.0
g, 54.9 mmol) in 6N hydrochloric acid (250 ml) was stirred at 100 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-amino-3-bromo-6-chloropyridine (11.1
g, 97%) as pale brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 5.22 (2H, s), 6.55 (1H, d, J =
7.8 Hz), 7.56 (1H, d, J = 8.0 Hz). 4) Synthesis of 8-bromo-5-chloroimidazo [1,2-a] pyridine 40% aqueous chloroacetaldehyde solution (10.6 ml, 65.0 mmo)
l) with 2-amino-3-bromo-6-chloropyridine (10.4 g, 50.
(0 mmol) in ethanol solution (150 ml), and the mixture was heated under reflux for 20 hours. The reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1-1: 2) to give 8-bromo-5-chloroimidazo [1,2-a] pyridine (9.63 g, 83%) as pale brown crystals As obtained. ¹ H-NMR (CDCl ₃ ) δ: 6.80 (1H, d, J = 7.8 Hz), 7.44
(1H, d, J = 7.8 Hz), 7.78 (1H, s), 7.86 (1H, s) .5) Synthesis of ethyl (8-bromoimidazo [1,2-a] pyridin-5-ylthio) acetate. Ethyl glycolate (541 mg, 4.50 mmol) was added to 8-bromo-5-chloroimidazo [1,2-a] pyridine (694 mg, 3.00 mm
ol) in N, N-dimethylformamide solution (2.0 ml) at room temperature and stirred at 80 ° C. for 8 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 2: 1-1: 1) and purified with ethyl (8-bromoimidazo [1,2-a] pyridin-5-ylthio) acetate (410 m
g, 44%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.4 Hz), 3.67
(2H, s), 4.13 (2H, q, J = 7.2 HZ), 6.96 (1H, d, J =
7.8 Hz), 7.44 (1H, d, J = 7.6 Hz), 7.78 (1H, d, J
= 1.6 Hz), 8.00 (1H, d, J = 1.4 Hz) .6) Synthesis of ethyl 8-bromo-5-thia-1,8b-diazaacenaphthylene-4-carboxylate Phosphorus oxychloride (2.80 ml , 30.0 mmol) was added to N, N-dimethylformamide (20 ml) at 0 ° C. and stirred for 30 minutes. (8-
Ethyl bromoimidazo [1,2-a] pyridin-5-ylthio) acetate (1.69 g, 5.36 mmol) was added to the reaction solution at room temperature, and 2
Stirred for 0 hours. The reaction solution was poured into an ice-cooled saturated aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-1: 2) to give 8-bromo-5-thia-
Ethyl 1,8b-diazaacenaphthylene-4-carboxylate (1.17
g, 67%) as brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.0 Hz), 4.23
(2H, q, J = 7.0 Hz), 5.61 (1H, d, J = 7.6 Hz), 6.8
2-6.85 (2H, m), 7.08 (1H, s) .7) Synthesis of 8-bromo-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 2N aqueous sodium hydroxide solution (2.20 ml, 4.40 mmol) to 8
Ethanol suspension of ethyl -bromo-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (690 mg, 2.12 mmol) (20
ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid in the reaction solution
(4.40 ml, 4.40 mmol) was added and the mixture was stirred for 2 hours. The precipitated precipitate was collected by filtration, washed with water and diethyl ether to give 8-bromo-5-thia-1,8b-diazaacenaphthylene-4-.
The carboxylic acid (540 mg, 86%) was obtained as red-purple crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 5.98 (1H, d, J = 7.8 Hz), 6.9
6 (1H, s), 7.07 (1H, d, J = 7.6 Hz), 7.21 (1H, s).

Reference Example 31 2-phenyl-3- (trifluoromethyl) imidazo [5,1,2-c
d] Synthesis of indolizine-4-carboxylic acid 1) Synthesis of 5-methyl-2-phenylimidazo [1,2-a] pyridine Sodium hydrogen carbonate (24.0 g, 286 mmol) was added to 2-amino-6
-Picoline (15.4 g, 143 mmol) and 2-bromoacetophenone (28.4 g, 143 mmol) in ethanol (150 ml) were added, and the mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
1: 1) to give 5-methyl-2-phenylimidazo [1,2-a] pyridine (12.2 g, 41%) as brown crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.62 (3H, s), 6.62 (1H, d, J =
7.0 Hz), 7.15 (1H, dd, J = 9.2 and 7.0 Hz), 7.33-7.
48 (3H, m), 7.56 (1H, d, J = 9.2 Hz), 7.75 (1H, s),
7.98-8.03 (2H, m). 2) Synthesis of 2-phenylimidazo [1,2-a] pyridine-5-acetic acid 2.0 M lithium diisopropylamide in tetrahydrofuran (100 ml, 200 mmol) was treated with 5-methyl-2- A solution of phenylimidazo [1,2-a] pyridine (20.0 g, 96.0 mmol) in tetrahydrofuran (200 ml) was added at -78 ° C, and the mixture was stirred at -78 ° C for 1 hour. Dry ice was added until the reaction solution turned yellow. The reaction solution was poured into water (100 ml) and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml) and concentrated hydrochloric acid was added until pH4. The precipitated precipitate was collected by filtration, and ethanol,
After washing with diethyl ether, 2-phenylimidazo [1,2-
a] Pyridine-5-acetic acid (15.0 g, 62%) was obtained as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.15 (2H, s), 6.88 (1H, d, J =
6.4 Hz), 7.22-7.37 (2H, m), 7.37-7.57 (3H, m), 8.0
0-8.30 (2H, m), 8.37 (1H, s). 3) Synthesis of methyl 2-phenylimidazo [1,2-a] pyridine-5-acetate Concentrated sulfuric acid (10 ml) was added to 2-phenylimidazo [1 , 2-a] pyridine-5
-Acetic acid (9.96 g, 39.5 mmol) was added to a methanol solution (100 ml), and the mixture was stirred at 50 ° C for 16 hours. Pour the reaction solution into ice water and add 8
After neutralization with a normal aqueous sodium hydroxide solution, the mixture was concentrated under reduced pressure.
The residue was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-
Phenylimidazo [1,2-a] pyridine-5-methyl acetate (9.04
g, 86%) as colorless crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.72 (3H, s), 3.94 (2H, s), 6.7
2 (1H, d, J = 7.0 Hz), 7.17 (1H, dd, J = 9.2 and 7.
0 Hz), 7.32-7.48 (3H, m), 7.62 (1H, d, J = 9.2 Hz),
7.79 (1H, s), 7.95-8.00 (2H, m) .4) 2-Phenyl-3- (trifluoromethyl) imidazo [5,1,2
Synthesis of methyl [-cd] indolizine-4-carboxylate Trifluoroacetic anhydride (2.80 ml, 20.0 mmol) was treated with methyl 2-phenylimidazo [1,2-a] pyridine-5-acetate (2.66 g,
10.0 mmol), pyridine (1.60 ml, 20.0 mmol), triethylamine (7.00 ml, 50.0 mmol) in dichloromethane
(30 ml) was added dropwise at 0 ° C., and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane.
The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1:
Purified in 1), methyl 2-phenyl-3- (trifluoromethyl) imidazo [5,1,2-cd] indolizine-4-carboxylate (3.04
g, 88%) as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.09 (3H, s), 7.55-7.60 (3H,
m), 7.98-8.03 (2H, m), 8.15-8.18 (2H, m), 8.48-8.5
2 (1H, m) .5) 2-Phenyl-3- (trifluoromethyl) imidazo [5,1,2
Synthesis of -cd] indolizine-4-carboxylic acid 2N aqueous sodium hydroxide solution (25.0 ml, 50.0 mmol)
-Phenyl-3- (trifluoromethyl) imidazo [5,1,2-cd]
Methyl indolizine-4-carboxylate (8.69 g, 25.2 mmol)
Was added to a solution of ethanol-tetrahydrofuran (1: 1) (100 ml), and the mixture was stirred at room temperature for 2 hours. Concentrated hydrochloric acid was added to the reaction solution, and pH 4
The precipitate was collected by filtration, washed with ethanol and diethyl ether, and washed with 2-phenyl-3- (trifluoromethyl) imidazo [5,1,2-cd] indolizine-4-carboxylic acid (7.3
4 g, 88%) were obtained as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 7.48-7.78 (3H, m), 7.80-8.09 (2
H, m), 8.34 (1H, t, J = 7.8 Hz), 8.45 (1H, d, J =
7.6 Hz), 8.57 (1H, d, J = 8.0 Hz).

The following compounds were synthesized in the same manner. Reference Example 32 3- (trifluoromethyl) imidazo [5,1,2-cd] indolizine-4-carboxylic acid ¹ H-NMR (DMSO-d ₆ ) δ: 8.37 (1H, t, J = 8.0 Hz) , 8.54 (1H,
d, J = 8.0Hz), 8.64 (1H, d, J = 8.0Hz), 9.15 (1H, s) .Calculated as C ₁₁ H ₅ F ₃ N ₂ O ₂ Calculated: C, 51.98; H , 1.98; N, 11.02 Found: C, 51.70; H, 2.18; N, 11.07.

Reference Example 33 4-Amino-1- [4- (trifluoromethyl) benzoyl] piperidine hydrochloride 1) 4- (tert-butoxycarbonylamino) -1- [4- (trifluoromethyl)] benzoyl ] Piperidine 4- (tert-butoxycarbonylamino) piperidine formate (2.0 g, 8.12 mmol) and ethyl acetate (50 ml), saturated aqueous sodium bicarbonate (5
0 ml), p- (trifluoromethyl) benzoyl chloride (1.45 ml, 9.74 mmol) was added, and the mixture was stirred for 2 hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 4- (tert-butoxycarbonylamino) -1- [4- (trifluoromethyl)
[Benzoyl] piperidine (1.85 g, 61%) was obtained as crystals. 160-161 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s, Bu ^t ), 1.15-1.80 (2H, m),
1.90-2.20 (2H, m), 2.90-3.25 (2H, m), 3.50-3.85 (2H, m
m), 4.40-4.80 (2H, m), 7.50 (2H, d, J = 8.0Hz), 7.68 (2H, m
d, J = 8.0Hz). 2) 4-Amino-1- [4- (trifluoromethyl) benzoyl]
Concentrated hydrochloric acid (20 ml) was added to a solution of piperidine / hydrochloride 4- (tert-butoxycarbonylamino) -1- [4- (trifluoromethyl) benzoyl] piperidine (1.65 g, 4.43 mmol) in ethanol (20 ml). Stirred for hours. The reaction solution was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to give 4-amino-1- [4- (trifluoromethyl) benzoyl).
Piperidine hydrochloride (1.33 g, 97%) was obtained. Melting point: 344-347 ° C (decomposition). Elemental analysis: C ₁₃ H ₁₅ F ₃ N ₂ OHCl Calculated: C, 50.58; H, 5.22; N, 9.07 Found: C, 50.19; H, 5.06; ^{. N, 9.33 1 H-NMR} (DMSO-d 6) δ: 1.40-1.70 (2H, m), 1.80-2.20 (2H,
m), 2.80-3.70 (4H, m), 4.40-4.60 (1H, m), 7.59 (2H, d, J =
8.2Hz), 7.84 (2H, d, J = 8.2Hz).

Reference Example 34 4-Amino-1- (4-chlorobenzoyl) piperidine hydrochloride 1) 4- (tert-butoxycarbonylamino) -1- (4-chlorobenzoyl) piperidine 4- (tert-butoxycarbonyl) Amino) piperidine formate
(3.0 g, 12.2 mmol) and ethyl acetate (50 ml), saturated aqueous sodium bicarbonate (50
p-chlorobenzoyl chloride (1.86 ml, 1 ml)
4.6 mmol) and stirred for 3 hours. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-2: 1) to give 4- (tert-butoxycarbonylamino) -1- (4-chlorobenzoyl) piperidine (2.
45 g, 59%) were obtained as crystals. . Mp ^{146-147 ℃ 1 H-NMR (CDCl} 3) δ: 1.45 (9H, m, Bu t), 1.20-1.80 (2H, m),
1.90-2.15 (2H, m), 2.85-3.25 (2H, m), 3.60-3.90 (2H, m
m), 4.40-4.70 (2H, m), 7.33 (2H, d, J = 8.4Hz), 7.39 (8.4H
z). 2) 4-Amino-1- (4-chlorobenzoyl) piperidine hydrochloride 4- (tert-butoxycarbonylamino) -1- (4-chlorobenzoyl) piperidine 10 (2.3 g, 6.79 mmol) in ethanol (2
0 ml) solution and concentrated hydrochloric acid (15 ml) was added thereto, followed by stirring for 1 hour. The reaction solution was distilled off under reduced pressure, and the precipitated crystals were collected by filtration to give 4-amino-1.
-(4-Chlorobenzoyl) piperidine hydrochloride (1.65g, 88%)
I got . Melting point 275-277 ° C. as the elemental analysis _{C 12 H 15 ClN 2 O ·} HCl, calcd: C, 52.38; H, 5.86 ; N, 10.18 Found:. C, 52.55; H, 5.87; N, 10.29 1 H-NMR (DMSO-d ₆ ) δ: 1.35-1.65 (2H, m), 1.80-2.10 (2H,
m), 2.80-3.20 (2H, m), 3.20-3.40 (1H, m), 3.40-3.80
(1H, m), 4.20-4.60 (1H, m), 7.40 (2H, d, J = 8.6Hz), 7.53
(2H, d, J = 8.6Hz ), 8.27 (3H, br, NH 3 +).

Reference Example 35 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) 3-acetyl-5-chloro-8-methylimidazo [1,2-a ] Pyridine 5-chloro-3- (1-hydroxyethyl) -8-methylimidazo
[1,2-a] pyridine (7.5 g, 35.7 mmol) in methylene chloride (300 m
l) Active manganese dioxide (61.9 g, 0.71 mol) was added to the solution, and the mixture was stirred at room temperature for 22 hours. The reaction solution was passed through celite to remove insolubles by filtration, washed with acetone, and the product was completely drained. The filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane:
Purification with acetone = 1: 3) yielded 3-acetyl-5-chloro-8-methylimidazo [1,2-a] pyridine (3.10 g, 42%) as crystals. In addition, the starting material 5-chloro-3-
(1-Hydroxyethyl) -8-methylimidazo [1,2-a] pyridine (3.9 g, 52%) was recovered. Mp as 75-76 ° C. Elemental analysis C ₁₀ H ₁₁ ClN ₂ O, Calculated: C, 57.01; H, 5.26 ; N, 13.30 Found:. C, 57.10; H, 5.27; N, 13.13 1 H-NMR (CDCl ₃ ) δ: 2.66 (3H, s), 2.68 (3H, s), 7.03 (1H,
d, J = 7.6Hz), 7.26 (1H, d, J = 7.6Hz), 8.28 (1H, s) .2) 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4
-Carboxylic acid ethyl ester 3-acetyl-5-chloro-8-methylimidazo [1,2-a] pyridine (3.0 g, 14.4 mmol) in N, N-dimethylformamide (30 ml)
Ethyl thioglycolate (4.71 ml, 43.1 mmol) was added to the solution, and the mixture was heated with stirring at 120 ° C. for 48 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate (100 ml × 2).
The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ethyl ester (1.61 g, 41%) as red-purple crystals. . Mp 110-111 ° C. Elemental Analysis _{C 14 H 14 N 2 O 2} S · 0.2H as ₂ O, Calculated: C, 60.50; H, 5.22 ; N, 10.08 Found: C, 60.45; H, 5.15 ; N ^{, 10.08 1 H-NMR (CDCl} 3) δ:. 1.32 (3H, t, J = 7.2Hz), 2.16 (3H, s),
2.20 (3H, s), 4.22 (2H, q, J = 7.2Hz), 5.75 (1H, d, J = 7.2H
z), 6.48 (1H, d, J = 7.2Hz), 7.23 (1H, s) .3) 3,8-Dimethyl-5-thia-1,8b-diazaacenaphthylene-
4-carboxylic acid 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ethyl ester (1.45 g, 5.29 mmol) in ethanol-tetrahydrofuran (10 m-10 ml) solution 2N An aqueous sodium hydroxide solution (7.93 ml, 15.9 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding 2N hydrochloric acid (7.93 ml), and the crystals were collected by filtration, washed with water, and dried to give 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-. Carboxylic acid (1.22g,
94%). Melting point> 300 ° C (decomposition). Elemental analysis: C ₁₂ H ₁₀ N ₂ O ₂ S Calculated: C, 58.52; H, 4.09; N, 11.37 Found: C, 58.11; H, 4.26; N, 11.00 ^{. 1 H-NMR (DMSO-} d 6 -DCl) δ: 2.19 (3H, s), 2.23 (3H, s), 6.7
3 (1H, d, J = 7.6Hz), 7.30 (1H, d, J = 7.6Hz), 8.14 (1H, s).

Reference Example 36 N- [4- (piperidin-4-yl) butan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride 1) 4- [1- (N-tert-butoxycarbonyl) piperidine-4-
Yl] butanoic acid 4- (piperidin-4-yl) butanoic acid ・ hydrochloride (10.4g, 50mmo
To a solution of l) in tert-butanol (50 ml) was added a 2N aqueous sodium hydroxide solution (50.3 ml, 0.105 mol). Then, di-tert-butyl dicarbonate (10.9 g, 50 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was acidified by adding 1 N potassium hydrogen sulfate, and then extracted with ethyl acetate (500 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 4- [1- (N-tert-butoxycarbonyl) piperidine-4-.
[Il] butanoic acid (12.8 g, 94%) was obtained as colorless crystals. 73-74 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s, Bu ^t ), 0.80-1.80 (9H, m),
2.35 (2H, t, J = 7.4Hz), 2.58-2.77 (2H, m), 4.00-4.18 (2H,
m). 2) 4- [1- (N-tert-butoxycarbonyl) piperidine-4-
Yl] butanol 4- [1- (N-tert-butoxycarbonyl) piperidin-4-yl]
Butanoic acid (8.14 g, 30 mmol) in tetrahydrofuran (50 m
l) 1M borane-tetrahydrofuran (45 ml,
45 mmol) was added dropwise over 10 minutes, and the mixture was stirred at room temperature for 1 hour. After cooling again with ice, acetic acid-water (1: 1, 15 ml) was added dropwise, and the mixture was stirred for 5 minutes.Saturated sodium bicarbonate solution (500 ml) was added, and ethyl acetate
0 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 4- [1- (N-tert-butoxycarbonyl) piperidine-4-.
[Ill] butanol (7.66 g, 99%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.20 (2H, m), 1.45 (9H, s, Bu ^t ),
1.20-1.73 (9H, m), 2.66 (2H, td, J = 12.9,2.4Hz), 3.64 (2
H, t, J = 6.4Hz), 4.00-4.18 (2H, m) .3) 1- (N-tert-butoxycarbonyl) -4- (4-methanesulfonyloxybutan-1-yl) piperidine 4- [ 1- (N-tert-butoxycarbonyl) piperidin-4-yl]
Methanesulfonyl chloride (10.8 ml, 0.14 mmol) and triethylamine (19.5 ml, 0.14 mol) were added to a solution of butanol (30.0 g, 0.117 mmol) in ethyl acetate (400 ml), and the mixture was stirred at room temperature for 2 hours. After filtering off the insoluble matter, washing with water, drying over anhydrous magnesium sulfate, and distillation under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2:
Purified in 1), 1- (N-tert-butoxycarbonyl) -4- (4-
Methanesulfonyloxybutan-1-yl] piperidine (3
8.4 g, 98%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.20 (2H, m), 1.45 (9H, s, Bu ^t ),
1.20-1.85 (9H, m), 2.66 (2H, td, J = 12.6,2.2Hz), 3.01 (3
H, s), 4.00-4.18 (2H, m), 4.23 (2H, t, J = 6.4Hz) .4) 1- (N-tert-butoxycarbonyl) -4- (4-phthalimidobutan-1-yl ) Piperidine 1- (N-tert-butoxycarbonyl) -4- (4-methanesulfonyloxybutan-1-yl) piperidine (38.g, 0.113 mol)
To a solution of N, N-dimethylformamide (400 ml) was added potassium phthalimide (23.1 g, 0.125 mol), and the mixture was stirred at 100 ° C. for 2 times. The reaction solution was concentrated to half volume under reduced pressure, diluted with water (500 ml), and extracted with ethyl acetate (500 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:
Purified with ethyl acetate = 5: 1) and crystallized from hexane, 1- (N-tert-butoxycarbonyl) -4- (4-phthalimidobutan-1-yl) -piperidine (37.1 g, 85%) I got As mp 94-95 ° C. Elemental analysis _{C 22 H 30 N 2 O 4} , calcd: C, 68.37; H, 7.82 ; N, 7.25 Found:. C, 68.54; H, 7.67; N, 7.42 1 H- _{NMR (CDCl 3) δ: 1.45} (9H, s, Bu t), 0.65-1.80 (11H, m),
2.65 (2H, td, J = 12.7,2.4Hz), 3.69 (2H, d, J = 7.2Hz), 4.
00-4.15 (2H, m), 6.60-6.80 (1H, m, NH), 7.68-7.80 (2H, m
m), 7.80-7.90 (2H, m) .5) 4- [1- (N-tert-butoxycarbonyl) piperidine-4-
Yl] butylamine 1- (N-tert-butoxycarbonyl) -4- (4-phthalimidobutan-1-yl) piperidine (9.66 g, 25 mmol) in ethanol
Hydrazine monohydrate (4.85 ml, 0.1 mol) was added to the (400 ml) solution, and the mixture was heated under reflux for 3 hours. The reaction solution was distilled off under reduced pressure, 4N aqueous sodium hydroxide solution (200 ml) was added to the residue, and the mixture was extracted with ethyl acetate (150 ml × 3). The extract was washed with an 8N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 4- [1- (N-tert-butoxycarbonyl).
[Piperidin-4-yl] butylamine (6.3 g, 98%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s, But), 0.95-1.58 (9H, m),
1.58-1.75 (2H, m), 2.69 (2H, t, J = 6.6Hz), 2.58-2.75 (2H, m
m), 4.00-4.20 (2H, m) .6) N- [4- (N-tert-butoxycarbonyl) piperidine-4-
Yl] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (4.47
g, 20.5 mmol) and 4- [1- (N-tert-butoxycarbonyl) piperidin-4-yl] butylamine (6.3 g, 24.6 mmol) N, N-
Triethylamine in dimethylformamide (100 ml) solution
(4.29 ml, 30.8 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.28 g, 30.8 mmol), 1-hydroxybenzotriazole monohydrate (4.72 g, 30.8 mmol)
l) was added and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution (5
00 ml) and extracted with ethyl acetate (200 ml × 3). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: acetone = 1: 1) to give N- [4- (N-ter
[t-Butoxycarbonyl) piperidin-4-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (9.0 g, 96%) was obtained as an oil. _{^{1 H-NMR (CDCl 3)}} : 0.94-1.72 (8H, m), 1.85-2.10 (1H, m),
2.66 (2H, t, J = 8.2Hz), 3.29 (2H, q, J = 6.6Hz), 3.98-4.20
(2H, m), 5.78 (1H, dd, J = 6.0,2.0Hz), 5.90-6.05 (1H, m, N
H), 6.57- 6.75 (4H, m), 7.02 (1H, s) .7) N- [4- (piperidin-4-yl) butan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride To a mixture of ethanol (100 ml) and concentrated hydrochloric acid (70 ml), N- [4- (N
-tert-Butoxycarbonyl) piperidin-4-yl] butane-
A solution of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (9.0 g, 19.7 mmol) in ethanol (50 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give N
-[4- (Piperidin-4-yl) butan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide dihydrochloride (8.0
g, 93%) as yellow crystals. Melting point: 184-188 ° C. Elemental analysis: C ₁₉ H ₂₄ N ₄ OS ・ HCl ・ 1 / 2H ₂ O Calculated: C, 52.05; H, 6.21; N, 12.78 Found: C, 52.02; H, 6.34 ; N, 12.65. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.60 (7H, m), 1.68-1.87 (2H,
m), 2.70-2.95 (2H, m), 3.00-3.30 (4H, m), 6.60 (1H, d, J =
7.4Hz), 6.98 (1H, d, J = 9.0Hz), 7.12 (1H, s), 7.32 (1H, d
d, J = 9.0,7.4Hz), 7.65 (1H, s), 8.60-9.10 (3H, m, NH, N
H ₂ ^+).

Reference Example 37 2,8-Dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) 2-pivaloylamino-6-chloro-3-methylpyridine 2-amino-6- Pivaloyl chloride (48.1 ml, 0.345 mol) was added dropwise to a solution of chloropyridine (38.6 g, 0.3 mol) and triethylamine (42.4 ml, 0.345 mol) in ethyl acetate (400 ml) over 15 minutes. After stirring for 4 hours, the mixture was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 2-pivaloylamino-6-chloropyridine (56.1
g, 88%) as crystals. 2-pivaloylamino-6-chloropyridine (5.0 g, 23.5 mmol) in tetrahydrofuran (50 m
l) The solution was cooled to -78 ° C, and a hexane solution of n-butyllithium (1.6 mol / l, 36.7 ml, 58.8 mmol) was added dropwise over 10 minutes. After stirring at 0 ° C. for 45 minutes, the mixture was cooled again to −78 ° C., and methyl iodide (2.20 ml, 35.3 mmol) was added dropwise. Reaction solution at 0 ° C
After stirring for 30 minutes, water (150 ml) was added and ethyl acetate (15 ml) was added.
0 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 2-pivaloylamino-6-chloro-3-methylpyridine (3.10 g, 58%) as needles. Melting point: 132-135 ° C Elemental analysis: C ₁₁ H ₁₅ ClN ₂ O Calculated: C, 58.28; H, 6.67; N, 12.36 Found: C, 58.1
. 9; H, 6.40; N , 12.26 1 H-NMR (CDCl 3) δ: 1.34 (9H, s, Bu t), 2.19 (3H, s), 77.14
(1H, d, J = 8.0Hz), 7.53 (1H, d, J = 8.0Hz), 7.70 (1H, br, N
H). 2) 2-Amino-6-chloro-3-methylpyridine 2-pivaloylamino-6-chloro-3-methylpyridine (1.0 g,
A mixture of 4.41 mmol) and 6N hydrochloric acid (20 ml) was stirred at 100 ° C for 13 hours. The reaction solution was treated with an 8 N aqueous sodium hydroxide solution (30
ml), and extracted with ethyl acetate (100 ml). After washing the extract with water, drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration (hexane) to give 2-
Amino-6-chloro-3-methylpyridine (0.56 g, 88%) was obtained as crystals. As Elemental analysis C ₆ H ₇ ClN _2, Calculated: C, 50.54; H, 4.95 ; N, 19.65 Found:. C, 50.80; H, 4.80; N, 19.41 1 H-NMR (CDCl 3) δ: 2.10 (3H, s), 4.52 (2H, br, NH 2), 6.62
(1H, d, J = 7.6Hz), 7.22 (1H, d, J = 7.6Hz). 3) 5-Chloro-2,8-dimethylimidazo [1,2-a] pyridine 2-amino-6-chloro -3-methylpyridine (1.0 g, 7.01 mmo
l), chloroacetone (0.73 ml, 9.12 mmol) and ethanol (15
ml) was heated at reflux for 18 hours. The reaction solution was saturated aqueous sodium bicarbonate
(100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 10: 1-3: 1) to give 5-chloro
-2,8-Dimethylimidazo [1,2-a] pyridi (0.57 g, 45%) was obtained as crystals. As mp 38-40 ° C. Elemental analysis C ₉ H ₉ ClN _2, Calculated: C, 59.84; H, 5.02 ; N, 15.51 Found:. C, 59.04; H, 5.01; N, 15.50 1 H-NMR ( CDCl ₃ ) δ: 2.51 (3H, s), 2.59 (3H, s), 6.74 (1H,
d, J = 7.4Hz), 6.92 (1H, d, J = 7.4Hz), 7.52 (1H, s) .4) (2,8-Dimethylimidazo [1,2-a] pyridin-5-yl) thio Glycolic acid ethyl ester 5-chloro-2,8-dimethylimidazo [1,2-a] pyridine (10
g, 55.4 mmol) and ethyl thioglycolate (7.9 ml, 72.0 mm
ol) and a mixture of N, N-dimethylformamide (100 ml) at 80 ° C.
For 24 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (200 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:
Ethyl acetate = 2: 1-1: 1) to give (2,8-dimethylimidazo [1,2-a] pyridin-5-yl) thioglycolic acid ethyl ester (12.6 g, 87%) as an oil Obtained as a product. ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, t, J = 7.2Hz), 2.51 (3H, s),
2.61 (3H, s), 3.59 (2H, s), 4.11 (2H, q, J = 7.2Hz), 6.91 (1
H, dd, J = 7.2,1.0Hz), 6.98 (1H, d, J = 7.2Hz), 7.68 (1H, s) .5) 2,8-Dimethyl-5-thia-1,8b-diazaacena Butylene-4
-Carboxylic acid ethyl ester (Method A) (2,8-dimethylimidazo [1,2-a] pyridin-5-yl) thioglycolic acid ethyl ester (0.5 g, 1.91 mmol),
Hexamethylenetetramine (0.54g, 3.83mmol) and acetic acid
(5 ml) was stirred at 80 ° C. for 7 hours. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
(Hexane: ethyl acetate = 3: 2-1: 1) to give 2,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ethyl ester (15 mg, 3% ) Was obtained. (Method B) Phosphorus oxychloride (1.78 ml, 19.1 mmol) was added dropwise to N, N-dimethylformamide (15 ml) under ice cooling, followed by stirring for 30 minutes. (2,8-Dimethylimidazo [1,2-a] pyridin-5-yl) thioglycolic acid ethyl ester (1.0 g, 3.83 mmol)
N, N-dimethylformamide (5 ml) solution was added dropwise at 80 ° C.
For 15 hours. The reaction solution was poured into ice water (150 ml), neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (100 ml × 2). After washing the extract with water, drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane ethyl acetate:
(Acetone = 2: 1) to give 2,8-dimethyl-5-thia-1,8b-
Diazaacenaphthylene-4-carboxylic acid ethyl ester (0.
44 g, 42%) as red-purple crystals. Melting point: 140-142 ° C. Elemental analysis: C ₁₄ H ₁₄ N ₂ O ₅ S Calculated: C, 61.29; H, 5.14; N, 10.21 Found: C, 61.36; H, 5.07; N, 10.05. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 2.09 (3H, s),
2.17 (3H, s), 4.23 (2H, q, J = 7.1Hz), 5.62 (1H, d, J = 7.2H
z), 6.98 (1H, dd, J = 7.2,1.2Hz), 6.82 (1H, s) .6) 2,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4
-Carboxylic acid 2,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ethyl ester (0.5 g, 1.82 mmol) in ethanol-
A 1 N aqueous sodium hydroxide solution (5.47 ml, 5.47 mmol) was added to a tetrahydrofuran (15 ml-15 ml) solution, and the mixture was stirred for 1 hour. 1N hydrochloric acid (5.47 ml, 5.47 mmol) was added for neutralization, and 30
Stirred for minutes. Ethanol and tetrahydrofuran were distilled off under reduced pressure, and the crystals were collected by filtration, washed with water and dried to give 2,8-dimethyl-
5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.42
g, 92%) as orange crystals. As Elemental analysis _{C 12 H 10 N 2 O 2} S, Calculated: C, 58.52; H, 4.09 ; N, 11.37 Found:. C, 58.48; H, 4.13; N, 11.41 1 H-NMR (d 6 -DMSO) δ: 1.97 (3H, s), 2.07 (3H, s), 5.87 (1
H, d, J = 9.2Hz), 6.52 (1H, dd, J = 7.4,1.2Hz), 6.87 (1H, s).

Reference Example 38 8-Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) 5-chloro-8-methylimidazo [1,2-a] pyridine 2-amino- 6-chloro-3-methylpyridine (10 g, 70.1 mmo
l), 40% chloroacetaldehyde aqueous solution (14.9 ml, 91.2 mm
ol) in ethanol (200 ml) was heated to reflux for 24 hours. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate (150 ml), and ethyl acetate was added.
(150 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 10: 1-
1: 1) and crystallized from cold hexane to give 5-chloro
-8-Methylimidazo [1,2-a] pyridine (6.59 g, 56%) was obtained as crystals. Melting point 68-69 ° C. Elemental analysis: C ₈ H ₇ ClN ₂ Calculated: C, 57.67; H, 4.23; N, 16.81 Found: C, 57.73; H, 4.05; N, 16.91. ¹ H-NMR (CDCl ₃ ) δ: 2.62 (3H, s), 6.81 (1H, d, J = 7.2Hz),
6.98 (1H, dd, J = 7.2,1.2Hz), 7.73 (1H, d, J = 14.4Hz), 7.74
(1H, d, J = 14.4Hz). 2) (8-Methylimidazo [1,2-a] pyridin-5-yl) thioacetic acid ethyl ester 5-chloro-8-methylimidazo [1,2-a] Pyridine (9.2 g, 55.
2 mmol) and ethyl thioglycolate (7.84 ml, 71.8 mmol)
A mixture of N, N-dimethylformamide (50 ml) was heated and stirred at 80 ° C. for 48 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (300 ml) and extracted with ethyl acetate (200 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 1-1: 2) gave (8-methylimidazo
[1,2-a] pyridin-5-yl) thioacetic acid ethyl ester (10.8
g, 76%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.1Hz), 2.63 (3H, s),
3.61 (2H, s), 4.10 (2H, q, J = 7.1Hz), 6.96 (1H, d, J = 7.0H
z), 7.05 (1H, d, J = 7.0Hz), 7.70 (1H, s), 7.94 (1H, s) .3) 8-Methyl-5-thia-1,8b-diazaacenaphthylene-4 -Carboxylic acid ethyl ester (8-methylimidazo [1,2-a] pyridin-5-yl) thioacetic acid ethyl ester (1.0 g, 3.87 mmol), hexamethylenetetramine (1.09 g, 7.74 mmol) and acetic acid (10 ml) At 80 ° C for 1
Stirred for 6 hours. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate (100 ml),
Extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-hexane: acetone = 3: 1) to give 8-methyl-5-thia-1,8b-diazaacenaphthylene-4-. The carboxylic acid ethyl ester (0.32 g, 32%) was obtained. Melting point: 117-118 ° C. Elemental analysis: C ₁₃ H ₁₂ N ₂ O ₂ S Calculated: C, 59.98; H, 4.65; N, 10.76 Found: C, 60.03; H, 4.61; N, 10.64. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.1 Hz), 1.60 (3H, s),
4.23 (2H, q, J = 7.1Hz), 5.67 (1H, d, J = 7.2Hz), 6.42 (1H, d
d, J = 7.0,1.2Hz), 6.86 (1H, s), 7.05 (1H, s) .4) 8-Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 8- Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ethyl ester (0.5 g, 1.92 mmol) in ethanol (10 m
l) Add 1N aqueous sodium hydroxide solution (5.76ml, 5.76mm
ol) and stirred for 1 hour. 1N hydrochloric acid (5.76ml, 5.76mm
ol), and the mixture was neutralized and stirred for 30 minutes. Ethanol was distilled off under reduced pressure, and the crystals were collected by filtration, washed with water and dried, to give 8-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.31 g, 6
(8%) as orange crystals. Melting point> 300 ° C. Elemental analysis: C ₁₁ H ₈ N ₂ O ₂ S ・ 1 / 4H ₂ O Calculated: C, 55.80; H, 3.62; N, 11.83 Found: C, 55.85; H, 3.63; ^{. N, 11.87 1 H-NMR} (d 6 -DMSO) δ: 2.01 (3H, s), 5.92 (1H, d, J = 7.4Hz),
6.54 (1H, d, J = 7.4Hz), 6.92 (1H, s), 7.14 (1H, s).

Reference Example 39 6-Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1) Synthesis of 2,6-dichloropyridine-3-methanol 2,6-dichloronicotinic acid ( 9.84 g, 51.3 mmol)
-Tetrahydrofuran complex (0.5 M tetrahydrofuran solution, 200 ml, 100 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 2,6-dichloropyridine-3-methanol
(8.65 g, 95%) was obtained as brown crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 4.53 (2H, d, J = 5.6 Hz), 5.64
(1H, t, J = 5.6Hz), 7.50-7.65 (1H, m), 7.95-8.05
(1H, m) .2) Synthesis of 3-chloromethyl-2,6-dichloropyridine 2,6-dichloropyridine-3-methanol (8.65 g, 48.6 mmo
l) was added to thionyl chloride (28.9 g, 243 mmol) at room temperature, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was poured into ice water, and extracted with ethyl acetate. The extract was washed with a 2N aqueous solution of sodium hydroxide and saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified with 3-chloromethyl-
2,6-Dichloropyridine (8.14 g, 85%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 4.66 (2H, s), 7.32 (1H, d, J = 8.6H
z), 7.82 (1H, d, J = 7.6 Hz) .3) Synthesis of 2,6-dichloro-3-methylpyridine Sodium borohydride (3.13 g, 82.7 mmol) was added to 3-chloromethyl-2,6 -Dichloropyridine (8.14 g, 41.4 mmol) in dimethyl sulfoxide (80 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2,6-dichloro-3-
Methylpyridine (6.59 g, 98%) was obtained as crystals, collected by filtration and washed with hexane. ¹ H-NMR (CDCl ₃ ) δ: 2.36 (3H, s), 7.18 (1H, d, J = 8.0Hz),
7.51 (1H, d, J = 8.0Hz) .4) Synthesis of 5-chloro-6-methylimidazo [1,2-a] pyridine 2,6-dichloro-3-methylpyridine (40.0 g, 0.247 mmol)
If 28% aqueous ammonia (50ml) and 12.1 kgcm ^-2 under 5 at 130 ° C.
Stirred for hours. The reaction was allowed to cool and extracted with ethyl acetate. The extract was dried over water and saturated saline, and evaporated under reduced pressure.
The residue was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1-5: 1) to give 2-amino-6-chloro-5-
A mixture of methylpyridine and 2-amino-6-chloro-3-methylpyridine (12.2 g, 35%) was obtained as crystals. This mixture (1
To a solution of 2.2 g (85.6 mmol) in ethanol (40 ml) was added a 40% aqueous chloroacetaldehyde solution (21.6 g, 257 mmol), and the mixture was heated under reflux for 4 hours. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was chromatographed on silica gel (hexane:
Purification and separation with ethyl acetate (4: 1-ethyl acetate) gave 5-chloro-6-methylimidazo [1,2-a] pyridine (3.54 g, 25%) as crystals. Also, 5-chloro-8-methylimidazo [1,2-
a] Pyridine (9.61 g, 67%) was obtained as crystals. 5-Chloro-6-methylimidazo [1,2-a] pyridine: ¹ H-NMR
(CDCl ₃ ) δ: 2.41 (3H, s), 7.10 (1H, d, J = 9.2Hz), 7.52 (1H,
d, J = 9.2Hz), 7.66 (1H, d, J = 1.0Hz), 7.75 (1H, d, J = 1.0H
z) .5) (6-Methylimidazo [1,2-a] pyridin-5-yl) thioacetic acid ethyl ester Ethyl thioglycolate (2.81 g, 23.3 mmol) was treated with 5-chloro.
-6-methylimidazo [1,2-a] pyridine (3.54 g, 21.2 mmol)
N, N-dimethylformamide solution (10 ml) at 80 ° C
Stirred for 24 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (6-methylimidazoline).
Ethyl [1,2-a] pyridin-5-yl) thioacetate (5.32 g, quan
t.) was obtained as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, t, J = 7.2 Hz), 2.57 (3
H, s), 3.51 (2H, s), 4.03 (2H, q, J = 7.2 Hz), 7.11
(1H, d, J = 9.2Hz), 7.60 (1H, s), 7.67 (1H, d, J = 1.
0Hz), 8.09 (1H, d, J = 1.0Hz) .7) Synthesis of ethyl 6-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate hexamethylenetetramine (5.97g, 42.6 mmol) in ethyl (6-methylimidazo [1,2-a] pyridin-5-yl) thioacetate
(5.97 g, 21.3 mmol) in acetic acid solution (70 ml) and stirred at 90 ° C. for 2 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. Wash the extract with 8N aqueous sodium hydroxide solution,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give 6-methyl
Ethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (3.90 g, 71%) was obtained as red crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.31 (3H, t, J = 7.2 Hz), 2.08 (3H,
s), 4.24 (2H, q, J = 7.2Hz), 6.48 (1H, d, J = 9.4H
z), 6.59 (1H, t, J = 9.4 Hz), 6.80 (1H, s), 6.98 (1H,
8) Synthesis of 6-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 2N aqueous sodium hydroxide solution (15.0 ml, 30.0 mmol, 6
Ethyl solution of ethyl 3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (3.90 g, 15.0 mmol) (30 m
l) and stirred at room temperature for 2 hours. Concentrated hydrochloric acid was added to the reaction solution to adjust the pH to 3-4, and the precipitated crystals were collected by filtration, washed with water, and treated with 6-methyl-5-thia-1,8b-diazaacenaphthylene-4-.
The carboxylic acid (2.59 g, 74%) was obtained as orange crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.67 (3H, s), 6.50-6.70 (2H, m),
6.89 (1H, s), 7.09 (1H, s).

Example 1 N- [1- [3- (4-cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Synthesis of hydrochloride 1) N- [1- [3- (4-cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Synthesis of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (567 mg, 2.96 mmol) in 3- (4-cyanophenyl) propionic acid (259 mg, 1.49 mmol), 1-hydroxybenzotriazo The mixture was added to a suspension of acetonitrile (10 ml) of phenol monohydrate (453 mg, 2.94 mmol) and stirred at room temperature for 1 hour. N- [3- (piperidin-4-yl) propan-1-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (500 mg, 1.34 mmo
l), triethylamine (350 mg, 3.46 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (407 mg, 2.67 mmo
l) Acetonitrile solution (5.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [1- [3- (4-cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5. -Thia-1,8b-diazaacenaphthylene-4-carboxamide (561 mg, 89%) was obtained as purple crystals. Elemental analysis: C ₂₆ H ₂₅ N ₅ O ₂ S · 0.6 H ₂ O Calculated: C, 64.73; H, 5.47; N, 14.52. Found: C, 64.66; H, 5.54; N, 14.77. 2 ) Synthesis of N- [1- [3- (4-cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Hydrochloric acid (0.90 ml) was added to N- [1- [3- (4-cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide.
(522 mg, 1.11 mmol) in ethanol solution (10 ml),
Stirred at room temperature for 30 minutes. The reaction solution was concentrated and N- [1- [3-
(4-Cyanophenyl) propionyl] piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (464 mg, 83%) was obtained as orange crystals. The solution was collected by filtration and washed with diethyl ether. Elemental analysis: C ₂₆ H ₂₆ ClN ₅ O ₂ S.2.5H ₂ O Calculated: C, 56.46; H, 5.65; N, 12.66. Found: C, 56.75; H, 5.57; N, 12.89.

Example 2 Synthesis of N- (1-benzyloxycarbonylpiperidin-4-yl) -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide Benzyl chloroformate (167 mg, 0.981 mmol) with N- (piperidin-4-yl) -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (300 mg, 0.
775 mmol), triethylamine (392 mg, 3.87 mmol), 1,
8-diazabicyclo [5.4.0] -7-undecene (234 mg, 1.
(54 mmol) in acetonitrile solution (20 ml) at room temperature.
Stir for 1.5 hours. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give N- (1-benzyloxycarbonylpiperidin-4-yl) -2-methyl-5-thia-
1,8b-diazaacenaphthylene-4-carboxamide (192 m
g, 55%) as purple crystals. Elemental analysis: C ₂₄ H ₂₄ N ₄ O ₃ S · 0.5H ₂ O Calculated: C, 63.00; H, 5.51; N, 12.24. Found: C, 63.30; H, 5.58; N, 11.98.

Example 3 N- [1- (4-methoxyphenylsulfonyl) piperidine-
Synthesis of 4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [1- (4-methoxyphenylsulfonyl) piperidin-4-yl] Synthesis of 2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (824 mg, 4.30 mmol) was converted to N- (Piperidine-4
-Yl) -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (500 mg, 2.15 mmol), 1-hydroxybenzotriazole monohydrate (659 mg, 4.30 mmo
l) was added to an acetonitrile suspension (15 ml) and stirred at room temperature for 1 hour. 4-amino-1- (4-methoxyphenylsulfonyl) piperidine hydrochloride (791 mg, 2.58 mmol), triethylamine (569 mg, 5.62 mmol), 1,8-diazabicyclo
A solution of [5.4.0] -7-undecene (397 mg, 2.61 mmol) in acetonitrile (5.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 20:
Purified in 1), N- [1- (4-methoxyphenylsulfonyl) piperidin-4-yl] -2-methyl-5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide (240 mg,
23%) as purple crystals. Elemental analysis: C ₂₃ H ₂₄ N ₅ O ₄ S ₂ · 0.4H ₂ O Calculated: C, 56.17; H, 5.08; N, 11.39. Found: C, 56.34; H, 5.05; N, 11.40. 2) Synthesis of N- [1- (4-methoxyphenylsulfonyl) piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride concentrated hydrochloric acid (0.50 ml) with N- [1- (4-methoxyphenylsulfonyl) piperidin-4-yl] -2-methyl-5-thia-1,8
b-diazaacenaphthylene-4-carboxamide (240 mg,
0.495 mmol) in ethanol solution (5.0 ml).
Stir for 30 minutes. The reaction solution was concentrated, and N- [1- (4-methoxyphenylsulfonyl) piperidin-4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (464 mg, 83%) as orange crystals, which were collected by filtration and washed with diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.40-1.60 (2H, m), 1.70−
1.90 (2H, m), 2.17 (3H, s), 2.20−2.40 (2H, m), 3.4
0−3.80 (3H, m), 3.86 (3H, s), 6.40−6.50 (2H, m),
6.80−6.90 (1H, m), 7.10−7.30 (1H, m), 7.16 (2H, m
d, J = 8.8 Hz), 7.68 (2H, d, J = 8.8 Hz), 8.30−8.
40 (1H, m).

The compounds of Examples 4 and 5 were synthesized in the same manner as in Example 3. Example 4 N- [1- (4-fluorophenylsulfonyl) piperidine-
4-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: Calculated for C ₂₂ H ₂₂ ClFN ₄ O ₃ S ₂ .H ₂ O: C, 50.14; H, 4.59; N, 10.63. Found: C, 50.15; H, 4.43; N, 10.70.

Example 5 N- [1- (4-chlorophenylsulfonyl) piperidine-4
- yl] -2-methyl-5-thia -1,8b- diaza acenaphthylene-4-carboxamide hydrochloride Elemental _{analysis: C 22 H 22 Cl 2 N} 4 O 3 S 2 · H 2 O Calculated : C, 48.62; H, 4.45; N, 10.31. Found: C, 48.41; H, 4.31; N, 10.31.

Example 6 N- [1- (3-phenylpropionyl) piperidin-4-yl) methyl-5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide dihydrochloride N- (piperidin-4-yl) methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (0.97
g, 2.5 mmol), 3-phenylpropionic acid (0.45 g, 3.0 mmol)
And diethyl cyanophosphate (0.46 ml, 3.0 mmol) in dichloromethane (50 ml) solution, triethylamine (1.12 ml, 8.0 mmol)
Was added at 0 ° C. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added, the mixture was washed, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 10: 1) to give N-
(1- (3-phenylpropionyl) piperidin-4-yl)
Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.09 g, 98%) was obtained as an oil. This oil was dissolved in an ethanol solution (10 ml) and concentrated hydrochloric acid (1.0 m
l) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified by recrystallization from ethanol-acetone-diethyl ether to give N- [1- (3-phenylpropionyl).
(Piperidin-4-yl) methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (0.99 g,
84%) as orange crystals. Elemental analysis: C ₂₅ H ₂₇ ClN ₄ O ₂ S · 0.5H ₂ O Calculated: C, 61.03; H, 5.74; N, 11.39. Found: C, 60.79; H, 5.88; N, 11.28.

Example 7 N- [3- [1- (2-methoxybenzoyl) piperidine-4-
Synthesis of yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- (2-methoxybenzoyl) piperidine-4
-Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (765 mg, 3.99 was added to a suspension of 2-methoxybenzoic acid (405 mg, 2.66 mmol) and 1-hydroxybenzotriazole monohydrate (611 mg, 3.99 mmol) in acetonitrile (30 ml). Stirred for hours. N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide dihydrochloride (1.00 g, 2.41 mmol), triethylamine (365 mg, 3.60
mmol), 1,8-diazabicyclo [5.4.0] -7-undecene
(736 mg, 4.83 mmol) in acetonitrile (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Concentrate the reaction,
The residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue is purified by silica gel column chromatography.
(Ethyl acetate: methanol = 10: 1) and purified by N- [3- [1
-(2-Methoxybenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (772 mg, 67%) was obtained as purple crystals. . Elemental analysis: C ₂₆ H ₂₈ N ₄ O ₃ S · 0.5H ₂ O Calculated: C, 64.31; H, 6.02; N, 11.54. Found: C, 64.25; H, 6.10; N, 11.77. 2 ) N- [3- [1- (2-methoxybenzoyl) piperidine-4
Synthesis of -yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride concentrated hydrochloric acid (1.5 ml) was added to N- [3- [1- (2-methoxy Benzoyl)
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide (750
mg, 1.57 mmol) in ethanol (15 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated, and N- [3- [1- (2-
Methoxybenzoyl) piperidin-4-yl] propane-1
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide hydrochloride (807 mg, quant.) Was obtained as an orange amorphous substance. Elemental analysis: C ₂₆ H ₂₉ ClN ₄ O ₃ S.3.5 H ₂ O Calculated: C, 54.21; H, 6.30; N, 9.73. Found: C, 54.29; H, 6.10; N, 9.78.

The compounds of Examples 8 to 64 were synthesized in the same manner as in Example 7. Example 8 N- [3- [1- (4-Chloro-2-methoxybenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₆ H ₂₈ Cl ₂ N ₄ O ₃ S · 2H ₂ O Calculated: C, 53.52; H, 5.53; N, 9.60. C, 53.47; H, 5.66; N, 9.74.

Example 9 N- [3- [1- (2-benzyloxy-4-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide hydrochloride Elemental analysis: C ₃₂ H ₃₂ Cl ₂ N ₄ O ₃ S · 2H ₂ O Calculated: C, 58.27; H, 5.50; N, 8.49. Found: C, 58.45; H , 5.58; N, 8.33.

Example 10 N- [3- [1- (2-chloro-6-fluorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₅ H ₂₅ Cl ₂ FN ₄ O ₂ S · H ₂ O Calculated: C, 54.25; H, 4.92; N, 10.12. C, 54.34; H, 5.11; N, 10.45.

Example 11 N- [3- [1- (2-cyanobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Hydrochloride Elemental analysis: C ₂₆ H ₂₆ ClN ₅ O ₂ S.H ₂ O Calculated: C, 59.36; H, 5.36; N, 13.31. Found: C, 59.09; H, 5.33; N, 13.19.

Example 12 N- [3- [1- (3-cyanobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Hydrochloride Elemental analysis: C ₂₆ H ₂₆ ClN ₅ O ₂ S · 0.3 H ₂ O Calculated: C, 60.82; H, 5.22; N, 13.64. Found: C, 60.78; H, 5.13; N, 13.56 .

Example 13 N- [3- [1- (4-cyanobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.85 (9H, m), 2.60-
2.90 (2H, m), 2.90−3.20 (1H, m), 3.30−3.50 (2H, m
m), 4.40−4.60 (1H, m), 6.58 (1H, d, J = 7.4Hz),
6.90−7.05 (2H, m), 7.20−7.30 (1H, m), 7.55 (2H, m
d, J = 8.4 Hz), 7.55--7.65 (1H, m), 7.91 (2H, d, J
= 8.4 Hz), 8.60−8.70 (1H, m).

Example 14 N- [3- [1- (4-Sulfamoylbenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Carboxamide hydrochloride Elemental analysis: C ₂₅ H ₂₈ ClN ₅ O ₄ S ₂ .H ₂ O Calculated: C, 51.76; H, 5.21; N, 12.07. Found: C, 51.76; H, 5.04; N , 11.94.

Example 15 N- [3- [1- (4-dimethylaminobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Carboxamide dihydrochloride Elemental analysis: C ₂₇ H ₃₃ Cl ₂ N ₅ O ₂ S · 2H ₂ O Calculated: C, 54.18; H, 6.23; N, 11.70. Found: C, 53.97; H, 6.31; N, 11.63.

Example 16 N- [3- [1- (4-methylthiobenzoyl) piperidine-4
−yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: Calculated as C ₂₆ H ₂₉ ClN ₄ O ₂ S ₂ .1.5H ₂ O Values: C, 56.15; H, 5.80; N, 10.07. Found: C, 55.88; H, 5.79; N, 9.89.

Example 17 N- [3- [1- (2-methylthiobenzoyl) piperidine-4
−yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: Calculated as C ₂₆ H ₂₉ ClN ₄ O ₂ S ₂ .1.5H ₂ O Values: C, 56.38; H, 5.86; N, 10.45. Found: C, 56.15; H, 5.80; N, 10.07.

Example 18 N- [3- [1- (2-Methylsulfonylbenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Carboxamide hydrochloride Elemental analysis: C ₂₆ H ₂₉ ClN ₄ O ₄ S ₂ .H ₂ O Calculated: C, 53.92; H, 5.40; N, 9.67. Found: C, 53.82; H, 5.72; N, 9.67.

Example 19 N- [3- [1- (2-benzylthiobenzoyl) piperidine-
4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: Calculated as C ₃₂ H ₃₃ ClN ₄ O ₂ S ₂ .H ₂ O Values: C, 61.67; H, 5.66; N, 8.99. Found: C, 61.58; H, 5.79; N, 9.19.

Example 20 N- [3- [1- [2- (4-Chlorophenylmethylthio) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide
Hydrochloride Elemental _{analysis: C 32 H 32 Cl 2 N} 4 O 2 S 2 · 2H 2 O Calculated:. C, 56.88; H, 5.37; N, 8.29 Found: C, 57.15; H, 5.29 ; N , 8.56.

Example 21 N- [3- [1- [2- (4-cyanophenylmethylthio) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Butylene-4-carboxamide
Hydrochloride Elemental analysis: as C ₃₃ H ₃₂ ClN ₅ O ₂ S ₂ .3.5H ₂ O Calculated: C, 57.17; H, 5.67; N, 10.10. Found: C, 57.22; H, 5.61; N, 10.23.

Example 22 N- [3- [1- (2-chloropyridin-3-ylcarbonyl)]
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₂₅ Cl ₂ N ₅ O ₂ S · 0.7 H ₂ O Calculated: C, 54.28; H, 5.01; N, 13.19 Found: C, 54.25; H, 5.35; N, 13.14.

Example 23 N- [3- [1- (2-chloropyridin-5-ylcarbonyl)
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₂₅ Cl ₂ N ₅ O ₂ S Calculated: C, 55.60; H, 4.86; N, 13.51. , 55.39; H, 5.15; N, 13.92.

Example 24 N- [3- [1- (2-chloropyridin-4-ylcarbonyl)]
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₂₅ Cl ₂ N ₅ O ₂ S · 1.5 H ₂ O Calculated: C, 52.84; H, 5.17; N, 12.84 Found: C, 53.11; H, 5.33; N, 13.08.

Example 25 N- [3- [1- (2-Methylthiopyridin-3-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide dihydrochloride Elemental analysis: C ₂₅ H ₂₉ Cl ₂ N ₅ O ₂ S ₂ .1.5H ₂ O Calculated: C, 50.58; H, 5.43; N, 11.80. 50.85; H, 5.27; N, 11.81.

Example 26 N- [3- [1- (2-Methylsulfonylpyridin-3-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₅ H ₂₈ ClN ₅ O ₄ S ₂ .1.5H ₂ O Calculated: C, 50.97; H, 5.30; N , 11.89. Found: C, 51.33; H, 5.56; N, 12.00.

Example 27 N- [3- [1- (pyrazin-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₅ ClN ₆ O ₂ S · 0.5H ₂ O Calculated: C, 55.92; H, 5.30; N, 17.01. Found: C, 55.70; H, 5.27; N , 17.10.

Example 28 N- [3- [1- (5-Methylpyrazin-2-ylcarbonyl)]
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Elemental analysis: C ₂₄ H ₂₈ Cl ₂ N ₆ O ₂ S · H ₂ O Calculated: C, 52.08; H, 5.46; N, 15.18 Found: C, 52.26; H, 5.65; N, 15.26.

Example 29 N- [3- [1- (Pyrazol-4-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene 4-carboxamide hydrochloride elemental _{analysis: C 22 H 25 ClN 6 O} 2 S · 0.7H 2 O calculated:. C, 54.41; H, 5.48; N, 17.31 Found: C, 54.12; H, 5.60 ; N, 17.03.

Example 30 N- [3- [1- (furan-2-ylcarbonyl) piperidine-
4-yl] propan-1-yl] -5-thia -1,8b- diaza acenaphthylene-4-carboxamide hydrochloride Elemental _{analysis: C 23 H 25 ClN 4 O} 3 S · 1.3H calculated as ₂ O Values: C, 55.65; H, 5.60; N, 11.29. Found: C, 55.71; H, 5.59; N, 11.20.

Example 31 N- [3- [1- (furan-3-ylcarbonyl) piperidine-
4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: Calculated as C ₂₃ H ₂₅ ClN ₄ O ₃ S.H ₂ O : C, 56.26; H, 5.54; N, 11.41. Found: C, 56.03; H, 5.43; N, 11.69.

Example 32 N- [3- [1- (2-Nitrofuran-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₄ ClN ₅ O ₅ S · 0.7H ₂ O Calculated: C, 52.06; H, 4.83; N, 13.20. C, 52.00; H, 4.82; N, 13.29.

Example 33 N- [3- [1- (2-Bromofuran-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₄ BrClN ₄ O ₃ S.H ₂ O Calculated: C, 48.47; H, 4.60; N, 9.83. , 48.65; H, 4.60; N, 9.87.

Example 34 N- [3- [1- (2-Phenylthiofuran-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Butylene-4-carboxamide hydrochloride Elemental analysis: C ₂₉ H ₂₉ ClN ₄ O ₃ S ₂ .0.5H ₂ O Calculated: C, 59.02; H, 5.12; N, 9.49. Found: C, 58.86; H, 5.40; N, 9.43.

Example 35 N- [3- [1- [2- (2-chlorophenylthio) furan-5-
Ilcarbonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₉ H ₂₈ Cl ₂ N ₄ O ₃ S ₂ · 2.5H ₂ O calculated:. C, 52.72; H, 5.03; N, 8.48 Found: C, 52.53; H, 4.95 ; N, 8.78.

Example 36 N- [3- [1- [2- (3-chlorophenylthio) furan-5-
Ylcarbonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₉ H ₂₈ Cl ₂ N ₄ O ₃ S ₂ · 1.5H ₂ O Calculated: C, 54.20; H, 4.86; N, 8.72. Found: C, 54.25; H, 4.92; N, 9.02.

Example 37 N- [3- [1- [2- (4-chlorophenylthio) furan-5-
Ilcarbonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₉ H ₂₈ Cl ₂ N ₄ O ₃ S ₂ · 2H ₂ O calculated:. C, 53.45; H, 4.95; N, 8.60 Found: C, 53.63; H, 5.01 ; N, 8.59.

Example 38 N- [3- [1- (4-Oxo-4H-pyran-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-dia Zaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₂₅ ClN ₄ O ₄ S.H ₂ O Calculated: C, 55.54; H, 5.24; N, 10.79. Found: C, 55.53; H, 5.09; N, 10.69.

Example 39 N- [3- [1- (thiophen-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₅ ClN ₄ O ₂ S ₂ .0.2H ₂ O Calculated: C, 56.07; H, 5.20; N, 11.46. Found: C, 56.09; H, 5.09; N, 11.46.

Example 40 N- [3- [1- (2-chlorothiophen-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₄ Cl ₂ N ₄ O ₂ S ₂ .H ₂ O Calculated: C, 51.01; H, 4.84; N, 10.35. Found: C, 51.19; H, 4.86; N, 10.37.

Example 41 N- [3- [1- (2-phenylthiothiophen-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₉ H ₂₉ ClN ₄ O ₂ S ₃ .0.5H ₂ O Calculated: C, 57.46; H, 4.99; N, 9.24. Found: C, 57.63; H, 5.08; N, 9.35.

Example 42 N- [3- [1- (2,3-dibromothiothiophen-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₃ H ₂₃ Br ₂ ClN ₄ O ₂ S ₂ Calculated: C, 42.71; H, 3.58; N, 8.66. Found: C, 42.83; H, 3.57; N, 8.67.

Example 43 N- [3- [1- (5-Bromo-1-benzofuran-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₇ H ₂₆ BrClN ₄ O ₃ S.H ₂ O Calculated: C, 52.31; H, 4.55; N, 9.04 Found: C, 52.60; H, 4.79; N, 9.23.

Example 44 N- [3- [1- (6-Chloro-1-benzofuran-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₇ H ₂₆ Cl ₂ N ₄ O ₃ S · 0.5H ₂ O Calculated: C, 57.24; H, 4.80; N, 9.89. Found: C, 57.15; H, 4.69; N, 9.85.

Example 45 N- [3- [1- (5,7-Dichloro-1-benzofuran-2-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b - diaza acenaphthylene-4-carboxamide hydrochloride elemental _{analysis: C 27 H 25 Cl 3 N} 4 O 3 S calculated:. C, 54.78; H, 4.26; N, 9.47 Found: C, 54.68; H, 4.28; N, 9.39.

Example 46 N- [3- [1- (2-Phenylthiazol-4-ylcarbonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Butylene-4-carboxamide hydrochloride Elemental analysis: C ₂₈ H ₂₈ ClN ₅ O ₂ S ₂ .1.5H ₂ O Calculated: C, 56.70; H, 5.27; N, 11.81. Found: C, 56.62; H, 5.43; N, 11.83.

Example 47 N- [3- [1- [2- (pyridin-3-yl) thiazol-4-]
Ilcarbonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Elemental analysis: C ₂₇ H ₂₈ Cl ₂ N ₆ O ₂ Calculated as S ₂ · 0.5H ₂ O: C, 52.94; H, 4.77; N, 13.72. Found: C, 52.98; H, 4.86; N, 13.87.

Example 48 N- [3- [1- [2- (pyridin-4-yl) thiazol-4-]
Ilcarbonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Elemental analysis: C ₂₇ H ₂₈ Cl ₂ N ₆ O ₂ Calculated as S ₂ · H ₂ O: C, 52.17; H, 4.86; N, 13.52. Found: C, 52.35; H, 4.62; N, 13.27.

Example 49 N- [3- (1-Cyclobutylcarbonylpiperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Element Analytical value: C ₂₃ H ₂₉ ClN ₄ O ₂ S.H ₂ O Calculated: C, 57.67; H, 6.52; N, 11.70. Found: C, 57.71; H, 6.45; N, 11.87.

Example 50 N- [3- (1-cyclopentylcarbonylpiperidin-4-
Yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₃₁ ClN ₄ O ₂ S.H ₂ O Calculated: C , 58.46; H, 6.75; N, 11.36. Found: C, 58.38; H, 6.73; N, 11.46.

Example 51 N- [3- (1-cyclohexylcarbonylpiperidin-4-
Yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₅ H ₃₃ ClN ₄ O ₂ S.H ₂ O Calculated: C , 59.21; H, 6.96; N, 11.05. Found: C, 59.01; H, 6.93; N, 10.97.

Example 52 N- [3- [1- (3-Cyclohexen-1-ylcarbonyl)]
Piperidin-4-yl] propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.80 (11H, m), 1.85-
2.25 (3H, m), 2.65−2.85 (1H, m), 2.85−3.20 (3H,
m), 3.80−4.00 (2H, m), 4.35−4.45 (2H, m), 5.66 (2
H, s), 6.61 (1H, d, J = 7.0 Hz), 6.85−7.10 (2H,
m), 7.15−7.30 (1H, m), 7.50−7.70 (1H, m), 8.55−
8.75 (1H, m).

Example 53 N- [3- (1-cycloheptylcarbonylpiperidin-4-
Yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.80 (20H, m), 2.35 −
2.55 (2H, m), 2.60−2.80 (1H, m), 2.80−3.20 (3H,
m), 3.80−4.00 (1H, m), 4.30−4.50 (1H, m), 6.68 (1
H, d, J = 7.4 Hz), 7.01 (1H, d, J = 9.2 Hz), 7.14
(1H, s), 7.34 (1H, dd, J = 9.2 and 7.4 Hz), 7.71
(1H, s), 8.70−8.85 (1H, m).

Example 54 N- [3- [1-[(E) -3- (2-cyanophenyl) -2-propenoyl] piperidin-4-yl] propan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₈ H ₂₈ ClN ₅ O ₂ S.H ₂ O Calculated: C, 60.91; H, 5.48; N, 12.69. Found: C, 60.87; H, 5.34; N, 12.61.

Example 55 N- [3- [1-[(E) -3- (3-cyanophenyl) -2-propenoyl] piperidin-4-yl] propan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₈ H ₂₈ ClN ₅ O ₂ S.H ₂ O Calculated: C, 60.91; H, 5.48; N, 12.69. Found: C, 60.68; H, 5.44; N, 12.60.

Example 56 N- [3- [1-[(E) -3- (4-cyanophenyl) -2-propenoyl] piperidin-4-yl] propan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₈ H ₂₈ ClN ₅ O ₂ S · 0.5 H ₂ O Calculated: C, 61.92; H, 5.38; N, 12.90 Found: C, 61.62; H, 5.39; N, 12.92.

Example 57 N- [3- [1-[(E) -3- [4- (trifluoromethyl) phenyl] -2-propenoyl] piperidin-4-yl] propan-1-yl] -5 -Thia-1,8b-diazaacenaphthylene-4
-Carboxamide hydrochloride Elemental analysis: C ₂₈ H ₂₈ ClF ₃ N ₄ O ₂ S · 2.5H ₂ O Calculated: C, 54.06; H, 5.35; N, 9.01. Found: C, 54.04; H, 5.07 ; N, 9.31.

Example 58 N- [3- [1-[(E) -3- [3- (trifluoromethyl) phenyl] -2-propenoyl] piperidin-4-yl] propan-1-yl] -5 -Thia-1,8b-diazaacenaphthylene-4
- carboxamide hydrochloride Elemental _{analysis: C 28 H 28 ClF 3 N} 4 O 2 S · 1.5H 2 O Calculated:. C, 55.67; H, 5.17; N, 9.27 Found: C, 55.68; H, 5.02 ; N, 9.43.

Example 59 N- [3- [1- [4- (trifluoromethyl) phenoxy] acetylpiperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide
Hydrochloride Elemental analysis: C ₂₇ H ₂₈ ClF ₃ N ₄ O ₃ S · 4.5H ₂ O Calculated: C, 48.98; H, 5.63; N, 8.46. Found: C, 48.70; H, 5.88; N , 8.74.

Example 60 N- [3- [1- [3- (trifluoromethyl) phenoxy] acetylpiperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Ren-4-carboxamide
Hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 0.80-1.25 (4H, m), 1.40−
1.60 (3H, m), 1.60-1.80 (2H, m), 2.45-2.65 (2H,
m), 2.90−3.20 (2H, m), 3.70−3.90 (1H, m), 4.20−
4.40 (1H, m), 4.93 (2H, s), 6.65 (1H, d, J = 7.4 H
z), 6.99 (1H, d, J = 9.0 Hz), 7.05--7.60 (6H, m),
7.69 (1H, s), 8.70−8.85 (1H, m).

Example 61 N- [3- [1- [3- [4- (trifluoromethyl) phenyl] propionyl] piperidin-4-yl] propan-1-yl]
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 0.75-1.00 (2H, m), 1.05-
1.25 (2H, m), 1.30-1.55 (2H, m), 1.55-1.70 (2H, m
m), 2.50−2.70 (2H, m), 2.80−3.00 (3H, m), 3.00−
3.20 (2H, m), 3.75−3.90 (2H, m), 4.30−4.45 (2H, m
m), 6.55−6.65 (1H, m), 6.90−7.05 (2H, m), 7.20−
7.35 (1H, m), 7.46 (2H, d, J = 8.4 Hz), 7.62 (2H,
d, J = 8.4 Hz), 7.55-7.65 (1H, m), 8.55-8.70 (1
H, m).

Example 62 N- [3- [1- [3- [3- (trifluoromethyl) phenyl] propionyl] piperidin-4-yl] propan-1-yl]
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₈ H ₃₀ ClF ₃ N ₄ O ₂ S.H ₂ O Calculated: C, 56.32; H, 5.40 N, 9.38. Found: C, 56.20; H, 5.57; N, 9.65.

Example 63 N- [3- [1- (2-Chlorothiophen-5-ylcarbonyl) piperidin-4-yl] propan-1-yl] -3-methyl-5-thia-1,8b- Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₄ H ₂₆ Cl ₂ N ₄ O ₂ S ₂ .1.5H ₂ O Calculated: C, 51.06; H, 5.18; N, 9.92. : C, 50.76; H, 5.17; N, 10.28.

Example 64 N- [3- [1- (4-Cyanobenzoyl) piperidin-4-yl] propan-1-yl] -3-methyl-5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₇ H ₂₈ ClN ₅ O ₂ S ₂ .H ₂ O Calculated: C, 58.11; H, 5.78; N, 12.55. 57.92; H, 5.67; N, 12.66.

Example 65 N- [3- [1- (2,4-dichlorobenzoyl) piperidine-4
Synthesis of -yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- (2,4-dichlorobenzoyl) piperidine Synthesis of -4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl]- Five
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg, 1.93 mmol), 2,4-dichlorobenzoyl chloride (450 mg, 2.15 mmol), 1,8-diazabicyclo [5.4. 0] -7-undecene (595 mg, 3.91 mmol),
A solution of triethylamine (292 mg, 2.88 mmol) in acetonitrile (40 ml) was stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1), and N- [3
-[1- (2,4-dichlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (684 mg, 69%). Obtained as purple crystals. Elemental analysis: C ₂₅ H ₂₄ Cl ₂ N ₄ O ₂ S · 0.6 H ₂ O Calculated: C, 57.05; H, 4.83; N, 10.64. Found: C, 56.90; H, 4.87; N, 10.42 .2) N- [3- [1- (2,4-dichlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Synthesis of salt Concentrated hydrochloric acid (1.0 ml) was added to N- [3- [1- (2,4-dichlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Butylene-4-carboxamide (67
(5 mg, 1.31 mmol) in ethanol solution (10 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated, and N- [3- [1- (2,
4-dichlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide hydrochloride (675 mg, 93%) was obtained as orange amorphous. Elemental analysis: C ₂₅ H ₂₅ Cl ₃ N ₄ O ₂ S · 0.7H ₂ O Calculated: C, 53.19; H, 4.71; N, 9.92. Found: C, 53.42; H, 5.03; N, 9.94 .

In the same manner as in Example 65, Examples 66 to 70
Was synthesized. Example 66 N- [3- [1- (2,6-dichlorobenzoyl) piperidine-4
-Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-2.00 (9H, m), 2.60−
2.90 (2H, m), 2.90−3.30 (2H, m), 4.40−4.60 (2H, m
m), 6.58 (1H, d, J = 7.0 Hz), 6.85−7.05 (2H, m),
7.15−7.30 (1H, m), 7.40−7.60 (4H, m), 8.55−8.70
(1H, m).

Example 67 N- [3- [1- (3,5-dichlorobenzoyl) piperidine-4
-Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: as C ₂₅ H ₂₅ Cl ₃ N ₄ O ₂ S · 0.5H ₂ O Calculated: C, 53.53; H, 4.67; N, 9.99. Found: C, 53.63; H, 4.88; N, 9.67.

Example 68 N- [3- [1- (3,4-dichlorobenzoyl) piperidine-4
-Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: as C ₂₅ H ₂₅ Cl ₃ N ₄ O ₂ S · 0.5H ₂ O Calculated: C, 53.53; H, 4.67; N, 9.99. Found: C, 53.29; H, 4.86; N, 10.05.

Example 69 N- [3- [1- (2,4,6-trichlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene -4-Carboxamide hydrochloride Elemental analysis: C ₂₅ H ₂₄ Cl ₄ N ₄ O ₂ S · 0.9H ₂ O Calculated: C, 49.83; H, 4.32; N, 9.30. Found: C, 50.11; H , 4.59; N, 9.00.

Example 70 N- [3- [1-[(E) -3-phenyl-2-propenoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b
- diaza acenaphthylene-4-carboxamide hydrochloride ^{1 H-NMR (DMSO-d} 6) δ: 0.90-1.35 (4H, m), 1.40-
1.60 (3H, m), 1.65-1.80 (2H, m), 3.00-3.20 (3H,
m), 4.20−4.60 (4H, m), 6.65 (1H, d, J = 6.6Hz),
6.95−7.10 (2H, m), 7.20−7.50 (6H, m), 7.65−7.80
(3H, m), 8.65−8.80 (1H, m).

Example 71 N- [3- [1- (4-cyanophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Synthesis of carboxamide hydrochloride 1) N- [3- [1- (4-cyanophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (1.00 g, 2.41 mmol), 4-cyanophenylsulfonyl chloride (535 mg, 2.65 mmol), 1,8-diazabicyclo [5.4.0 ] -7-undecene (736 mg, 4.83 mmo
l) and a solution of triethylamine (365 mg, 3.60 mmol) in acetonitrile (30 ml) were stirred at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give N- [3
-[1- (4-cyanophenylsulfonyl) piperidine-4-
[Ill] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (261 mg, 21%) was obtained as purple crystals. Elemental analysis: C ₂₅ H ₂₅ N ₅ O ₃ S ₂ Calculated: C, 59.15; H, 4.96; N, 13.80. Found: C, 58.94; H, 5.01; N, 13.73. 2) N− [ 3- [1- (4-cyanophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide hydrochloride Concentrated hydrochloric acid (0.5 ml) was added to N- [3- [1- (4-cyanophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-.
To a solution of thia-1,8b-diazaacenaphthylene-4-carboxamide (245 mg, 0.483 mmol) in ethanol (5.0 ml) was stirred at room temperature for 30 minutes. The reaction solution was concentrated and N- [3-
[1- (4-Cyanophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (247 mg, 94%) Obtained as orange crystals, collected by filtration and washed with diisopropyl ether. Elemental analysis: C ₂₅ H ₂₆ ClN ₅ O ₃ S ₂ .H ₂ O Calculated: C, 53.42; H, 5.02; N, 12.46. Found: C, 53.17; H, 5.07; N, 12.41.

Example 72 N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -2-methyl-5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- [4- [trifluoromethyl) benzoyl]
Synthesis of piperidin-4-yl] propan-1-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (824 mg, 4.30 mmol) was added to 2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (500
mg, 2.15 mmol) and 1-hydroxybenzotriazole monohydrate (659 mg, 4.30 mmol) in acetonitrile (15%).
ml) and stirred at room temperature for 1 hour. 4- (3-aminopropan-1-yl) -1- [4- (trifluoromethyl) benzoyl] piperidine hydrochloride (905 mg, 2.58 mmol), triethylamine (569 mg, 5.62 mmol), 1,8-diazabicyclo
A solution of [5.4.0] -7-undecene (397 mg, 2.61 mmol) in acetonitrile (5.0 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, the residue was dissolved in water and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 20:
Purified in 1), N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -2
-Methyl-5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide (867 mg, 76%) was obtained as red-purple crystals. Elemental analysis: C ₂₇ H ₂₇ F ₃ N ₄ O ₂ S · 0.6H ₂ O Calculated: C, 60.12; H, 5.27; N, 10.39. Found: C, 59.97; H, 5.29; N, 10.55 .2) N- [3- [1- (4-trifluoromethylbenzoyl) piperidin-4-yl] propan-1-yl] -2-methyl-5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Concentrated hydrochloric acid (1.6 ml) was added to N- [3- [1- [4- [trifluoromethyl) benzoyl] piperidin-4-yl ] Propan-1-yl] -2-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (854 mg, 1.62 mmol) in ethanol
And stirred at room temperature for 30 minutes. The reaction solution is concentrated and N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -2-
Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (780 mg, 85%) was obtained as an orange amorphous. Elemental analysis: C ₂₇ H ₂₈ ClF ₃ N ₄ O ₂ S.H ₂ O Calculated: C, 55.62; H, 5.19; N, 9.61. Found: C, 55.76; H, 5.26; N, 9.84.

Compounds of Examples 73 to 77 were synthesized in the same manner as in Example 72. Example 73 N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -6-methyl-5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₇ H ₂₈ ClF ₃ N ₄ O ₂ S Calculated: C, 57.39; H, 4.99; N, 9.92. : C, 57.08; H, 4.96; N, 9.73.

Example 74 N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -2,3-dimethyl-5-thia-1,8b -Diazaacenaphthylene-4-carboxamide hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.80 (9H, m), 1.97 (3
H, s), 2.44 (3H, s), 2.65−2.90 (2H, m), 3.00−3.2
0 (2H, m), 4.20−4.60 (2H, m), 6.74 (1H, d, J = 7.4
Hz), 7.07 (1H, d, J = 9.2 Hz), 7.39 (1H, dd, J =
9.2 and 7.4 Hz), 7.59 (2H, d, J = 8.0 Hz), 7.80 (2
H, d, J = 8.0 Hz), 8.60−8.75 (1H, m).

Example 75 N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -2-methyl-5-thia-1,8b- Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₆ H ₂₈ ClF ₃ N ₄ O ₃ S ₂ .H ₂ O Calculated: C, 50.44; H, 4.88; N, 9.05. C, 50.72; H, 4.84; N, 9.06.

Example 76 N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -6-methyl-5-thia-1,8b- Diazaacenaphthylene-4-carboxamide hydrochloride Elemental analysis: C ₂₆ H ₂₈ ClF ₃ N ₄ O ₃ S ₂ .0.5H ₂ O Calculated: C, 51.18; H, 4.79; N, 9.18. : C, 51.42; H, 4.90; N, 8.98.

Example 77 N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -2,3-
Dimethyl-5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide hydrochloride Elemental analysis: C ₂₇ H ₃₀ ClF ₃ N ₄ O ₃ S ₂ .0.5H ₂ O Calculated: C, 51.96; H, 5.01; N, 8.98. Found: C, 51.94; H, 5.13 ; N, 9.07.

Example 78 N- [3- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene -4-carboxamide hydrochloride 1) N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Synthesis of butylene-4-carboxamide (Method A) 4- (trifluoromethyl) benzoyl chloride
(1.00 g, 4.80 mmol) was added to N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (1.66 g , 4.00 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (1.22 g, 8.00 mmo
l) and triethylamine (810 mg, 8.00 mmol) in dichloromethane solution (25 ml), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 10: 1) and purified with N- [3- [1-
[4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.74 g, 84.5%) Obtained as crystals. (Method B) To a suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (15.3 g, 70 mmol) in acetonitrile (500 ml) was added 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (20.1 g, 105 mmol) and 1-hydroxybenzotriazole monohydrate (16.1 g, 105 mmol) were added, and the mixture was stirred for 1 hour. The reaction mixture was added to 3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propylamine hydrochloride (29.5 g, 84
mmol) and 1,8-diazabicyclo [5.4.0] unde-7-cene (12.5
ml, 84 mmol) in acetonitrile (50 ml) was added dropwise. Then, triethylamine (14.6 ml, 105 mmol) was added dropwise, and the mixture was stirred for 3 hours. Chloroform (700 ml) was added to the reaction solution, washed with saturated aqueous sodium hydrogen carbonate (200 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 10: 1), and N-
[3- [1- [4- (trifluoromethyl) benzoyl] piperidine
-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (31.2 g, 87%) was obtained as a red amorphous. 2) N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Synthesis of hydrochloride N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Concentrated hydrochloric acid (21.4 ml) was added to a solution of carboxamide (88.1 g, 171 mmol) in ethanol (700 ml), and the mixture was added at room temperature.
Stir for 30 minutes. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were added with diethyl ether and collected by filtration to give N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (92 g, 94%) was obtained as orange crystals. Melting point 196-202 ° C Elemental analysis: C ₂₆ H ₂₆ ClF ₃ N ₄ O ₂ S.H ₂ O Calculated: C, 54.88; H, 4.96; N, 9.85. Found: C, 54.99; H, 4.94 ; N, 9.96.

Example 79 N- [1- [4- (trifluoromethyl) benzoyl] piperidine-
4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-
Synthesis of carboxamide hydrochloride 4- (trifluoromethyl) benzoyl chloride (1.00 g,
4.80 mmol) with N-[(piperidin-4-yl) methyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(1.55 g, 4.00 mmol), 1,8-diazabicyclo [5.4.0] -7-
Undecene (1.22 g, 8.00 mmol), triethylamine (810
mg, 8.00 mmol) in dichloromethane solution (25 ml).
Stirred at room temperature for 30 minutes. Water was added to the reaction solution, and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol =
10: 1) and purified by N- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (2.09 g, quant.) as a red amorphous. Concentrated hydrochloric acid (0.71 ml) was added to N- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] methyl
-5-thia-1,8b-diazaacenaphthylene-4-carboxamide
(2.09 g, 4.00 mmol) in ethanol solution (20 ml),
Stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and N- [1- [4-
(Trifluoromethyl) benzoyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (1.18 g, 51%) was obtained as orange crystals and was treated with 2-propanol. Washed. Elemental analysis: C ₂₄ H ₂₂ ClF ₃ N ₄ O ₂ S.H ₂ O Calculated: C, 53.28; H, 4.47; N, 10.36. Found: C, 52.99; H, 4.46; N, 10.24.

The following compounds were synthesized in the same manner.

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

Example 100 N- [2- [tert-butoxycarbonyl- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl]] amino] ethane
-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N-hydroxysuccinimide (1.39 g, 12.0 mmol)
Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.31
g, 6.00 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (2.30 g, 12.0 mmol) in acetonitrile suspension (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added with tert-butyl 2-aminoethyl [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] carbamate (4.9
9 g, 12.0 mmol), triethylamine (1.21 g, 12.0 mmo
l) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and N- [2- [t
ert-butoxycarbonyl- [1- [4- (trifluoromethyl)
Benzoyl] piperidin-4-yl]] amino] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (3.04 g, 82%) was obtained as a red amorphous. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 1.60-2.00 (4H,
m), 2.70-3.20 (2H, m), 3.20-3.40 (4H, m), 3.60-4.00
(2H, m), 4.70-4.95 (1H, m), 5.74 (1H, d, J = 5.6 a
nd 1.6 Hz), 6.50-6.70 (3H, m), 6.97 (1H, s), 7.53
(2H, d, J = 8.2Hz), 7.70 (2H, d, J = 8.2Hz)

The following compounds were synthesized in the same manner. Example 101 N- [3- [tert-butoxycarbonyl- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl]] amino] propan-1-yl] -5-thia-1,8b -Diazaacenaphthylene-4-carboxamide ¹ H-NMR (CDCl ₃ ) δ: 1.50 (9H, s), 1.60-2.00 (6H,
m), 2.70-3.20 (2H, m), 3.20-3.40 (4H, m), 3.60-4.00
(2H, m), 4.70-5.00 (1H, m), 5.74 (1H, d, J = 5.6 a
nd 2.2 Hz), 6.60 (1H, d, J = 5.6 Hz), 6.61 (1H,
s), 6.67 (1H, s), 6.98 (1H, s), 7.52 (2H, d, J = 8.
2 Hz), 7.70 (2H, d, J = 8.2 Hz)

Example 102 N- [2- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] amino] ethane-1-yl] -5-thia-1,8b-diazaacena Butylene-4-carboxamide dihydrochloride concentrated hydrochloric acid (0.67 ml) was added to N- [2- [tert-butoxycarbonyl- [1-
[4- (Trifluoromethyl) benzoyl] piperidin-4-yl]] amino] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.02 g, 1.62 mmol) Was added to an ethanol solution (20 ml), and the mixture was stirred at 50 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give N- [2- [tert-butoxycarbonyl- [1-
[4- (Trifluoromethyl) benzoyl] piperidin-4-yl]] amino] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride as orange crystals Obtained and washed with ethanol. Elemental analysis: C ₂₅ H ₂₆ Cl ₂ F ₃ N ₅ O ₂ S · 0.2H ₂ O Calculated: C, 50.72; H, 4.49; N, 11.83. Found: C, 50.60; H, 4.26; N , 11.84.

The following compounds were synthesized in the same manner. Example 103 N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] amino] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene- 4-Carboxamide dihydrochloride Elemental analysis: C ₂₆ H ₂₈ Cl ₂ F ₃ N ₅ O ₂ S · 1.1H ₂ O Calculated: C, 50.18; H, 4.89; N, 11.25. Found: C, 50.36 ; H, 5.00; N, 10.93.

Example 104 N- [2- [1- [4- (trifluoromethyl) benzyloxycarbonyl] piperidin-4-yloxy] ethane-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride triphosgene (594 mg, 2.00 mmol) was converted to 4- (trifluoromethyl) benzyl alcohol (1.06 g, 6.00 mmol), pyridine (633 mg, 8.00 mmol). mmol) in acetonitrile (20 ml)
And stirred at room temperature for 3 hours. N- [2- (piperidin-4-yloxy) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (1.67 g,
4.00 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene
(3.05 g, 20.0 mmol), triethylamine (4.05 g, 40.0
(mmol) in acetonitrile (20 ml) and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [2- [1- [4- (trifluoromethyl) benzyloxycarbonyl] piperidin-4-yloxy] ethane-1-yl]. -5-thia-1,8b-diazaacenaphthylene
4-Carboxamide (720 mg, 34%) was obtained as a red amorphous. Concentrated hydrochloric acid (0.22 ml) was added to N- [2- [1- [4- (trifluoromethyl) benzyloxycarbonyl] piperidin-4-yloxy] ethane-1-yl] -5-thia-1,8b-diaza Acenaphthylene-4-carboxamide (720 mg, 1.32 mmol) was added to an ethanol solution (20 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give N- [2- [1- [4- (trifluoromethyl) benzyloxycarbonyl] piperidin-4-yloxy] ethane-1
[-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (650 mg, 85%) was obtained as orange crystals, which were washed with ethanol and diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.90-2.00 (4H, m), 2.80-4.00
(9H, m), 4.40-4.50 (2H, m), 6.50 (1H, d, J = 8.4 H
z), 6.90 (1H, d, J = 9.4 Hz), 7.03 (1H, s), 7.10-
7.25 (1H, m), 7.56 (1H, s), 7.80-8.00 (4H, m), 8.6
0-8.80 (1H, m).

The following compounds were synthesized in the same manner.

[Table 10]

[Table 11]

Example 110 N- [1- [4- (Trifluoromethyl) phenylsulfonyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 4- (Trifluoromethyl) phenylsulfonyl chloride
(1.17 g, 4.80 mmol) in N- (piperidin-4-ylmethyl) -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (1.55 g, 4.00 mmol), 1,8-diazabicyclo [5.4.
[0] -7-undecene (1.22 g, 8.00 mmol) and triethylamine (810 mg, 8.00 mmol) in acetonitrile (25 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: methanol = 10: 1) to give N- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidine-4-
[Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.94 g, 93%) was obtained as a red amorphous substance.
Concentrated hydrochloric acid (0.61 ml) was added to N- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-ylmethyl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide (1.94 g, 3.
(71 mmol) in ethanol solution (20 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and N- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride ( 1.79 g, 86%) was obtained as orange crystals, which were washed with ethanol and diethyl ether. Elemental analysis: C ₂₃ H ₂₂ ClF ₃ N ₄ O ₃ S ₂ Calculated: C, 49.42; H, 3.97; N, 10.02. Found: C, 49.51; H, 3.96; N, 10.12.

The following compounds were synthesized in the same manner.

[Table 12]

[Table 13]

[Table 14]

[Table 15]

Example 124 N- [2- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -3-methyl-5-thia-1,8b-dia Zaacenaphthylene-4-carboxamide hydrochloride N-hydroxysuccinimide (691 mg, 6.00 mmol)
Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (697 mg, 3.00 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.15 g, 6.00 mmol) Acetonitrile (15 ml) and N, N-dimethylformamide (20 m
l) Added to the suspension and stirred at room temperature for 1 hour. Add 2- [1
-[4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethylamine hydrochloride (1.52 g, 4.50 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (685 mg, 4.50 mmo
l) and triethylamine (607 mg, 6.00 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-
Yl] -3-methyl-5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide (1.10 g, 72%) was obtained as a red amorphous. Concentrated hydrochloric acid (0.35 ml) was added to N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] ethane-1-yl] -3-
Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.10 g, 2.16 mmol) was added to an ethanol solution (15 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure and N- [2
-[1- [4- (trifluoromethyl) benzoyl] piperidine-4
-Yl] ethane-1-yl] -3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (880 mg, 72%)
Was obtained as orange crystals and washed with diethyl ether. Elemental analysis: C ₂₆ H ₂₆ ClF ₃ N ₄ O ₂ S.H ₂ O Calculated: C, 54.88; H, 4.96; N, 9.85. Found: C, 54.77; H, 4.97; N, 9.86.

The following compounds were synthesized in the same manner.

[Table 16]

[Table 17]

Example 132 N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl]
Piperidin-4-yl] propan-1-yl] -3-methyl-5-thia
-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride N-hydroxybenzotriazole monohydrate (1.23 g, 8.0
0 mmol) in 3-methyl-5-thia-1,8b-diazaacenaphthylene
-4-carboxylic acid (930 mg, 4.00 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.53 g, 8.00 m
mol) in N, N-dimethylformamide (20 ml) and stirred at room temperature for 1 hour. Add 3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] to the reaction mixture.
Propylamine hydrochloride (1.86 g, 4.80 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (731 mg, 4.80 mmol),
Add triethylamine (810 mg, 8.00 mmol) and add 1
Stirred for hours. The reaction solution was concentrated under reduced pressure, water was added to the residue,
Extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl]-. 3-Methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (2.01 g, 89%) was obtained as a red amorphous. Concentrated hydrochloric acid (0.60 ml) was added to N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -3-methyl-5-thia-1,8b -Diazaacenaphthylene-4-carboxamide (2.01 g, 3.56 mmol) in ethanol solution (20 ml) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -3-methyl-5-thia-1,8b -Diazaacenaphthylene-4-carboxamide hydrochloride (1.69 g, 73%) was obtained as orange crystals, which were washed with diethyl ether. Elemental analysis: C ₂₆ H ₂₈ ClF ₃ N ₄ O ₃ S ₂ .C ₂ H ₅ OH Calculated: C, 51.97; H, 5.30; N, 8.66. Found: C, 51.69; H, 5.49; N , 8.65.

The following compounds were synthesized in the same manner.

[Table 18]

[Table 19]

Example 137 3-Methyl-1- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -1,4,7b-triazacyclo Penta [cd] indene-2 (1H) -one hydrochloride 4- (trifluoromethyl) benzoyl chloride (918 mg,
4.40 mmol) was converted to 3-methyl-1- [3- (piperidin-4-yl) propan-1-yl] -1,4,7b-triazacyclopenta [cd] indene-2 (1H) -one Hydrochloride (1.49 g, 4.00 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (1.22 g, 8.00 mmo
l) and triethylamine (810 mg, 8.00 mmol) in acetonitrile solution (20 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give 3-methyl-1- [3- [1- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propane- 1-yl] -1,4,7b-
Triazacyclopenta [cd] indene-2 (1H) -one (1.40
g, 74%) as an amorphous solid. Concentrated hydrochloric acid (0.50 ml)
-Methyl-1- [3- [1- [4- (trifluoromethyl) benzoyl]
Piperidin-4-yl] propan-1-yl] -1,4,7b-triazacyclopenta [cd] indene-2 (1H) -one (1.40 g, 2.98 m
mol) in ethanol (20 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give 3-methyl-1- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -1,4,7b-triaza Cyclopenta [cd] indene-2 (1H) -one hydrochloride (1.26 g, 87%) was obtained as colorless crystals, which were washed with diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.20 (2H, m), 1.20-1.40
(2H, m), 1.40-1.90 (6H, m), 2.77 (3H, s), 2.90-3.20
(1H, m), 3.30-3.60 (1H, m), 4.07 (2H, t, J = 6.8 H
z), 4.35-4.55 (1H, m), 7.40-7.60 (3H, m), 7.65-7.8
5 (3H, m), 8.00-8.20 (1H, m).

The following compounds were synthesized in the same manner. Example 138 3-Methyl-1- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -1,4,7b
-Triazacyclopenta [cd] indene-2 (1H) -one hydrochloride ¹ H-NMR (DMSO-d ₆ ) δ: 1.10-1.40 (5H, m), 1.60-1.80
(4H, m), 2.15-2.35 (2H, m), 2.77 (3H, s), 3.60-3.75
(2H, m), 4.02 (2H, t, J = 7.0 Hz), 7.49 (1H, d, J
= 8.0 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.90-8.20 (5
H, m).

Example 139 4- [3- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -3H-1,4,8b-triazaacenaphthylene Ethyl -3,5 (4H) -dione hydrochloride 3- (2,2,2-trichloroacetyl) imidazo [1,2-a] pyridine-5-carboxylate (1.68 g, 5.00 mmol) was added to 3- [ 1-
[4- (trifluoromethyl) benzoyl] piperidin-4-yl] propylamine hydrochloride (2.11 g, 6.00 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (913 mg, 6.00 mmo
l) and triethylamine (1.01 g, 10.0 mmol) in acetonitrile solution (20 ml), and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl]. -3H-1,4,8b-Triazaacenaphthylene-3,5 (4H) -dione (1.98 g, 82%) was obtained as crystals. Concentrated hydrochloric acid (0.67 ml) was added to 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propane-1
[-Yl] -3H-1,4,8b-triazaacenaphthylene-3,5 (4H) -dione (1.98 g, 4.09 mmol) in ethanol (20 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give 4- [3-
[1- [4- (trifluoromethyl) benzoyl] piperidine-4-
Yl] propan-1-yl] -3H-1,4,8b-triazaacenaphthylene-3,5 (4H) -dione hydrochloride (1.53 g, 72%) as colorless crystals, which was treated with 2-propanol. Washed. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.25 (2H, m), 1.25-1.45
(2H, m), 1.45-1.85 (5H, m), 2.65-3.15 (2H, m), 3.40
-3.60 (1H, m), 4.01 (2H, t, J = 7.2 Hz), 4.40-4.60
(1H, m), 7.58 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J
= 8.0 Hz), 7.92 (1H, dd, J = 8.0 and 6.6 Hz), 8.14
(1H, d, J = 6.6 Hz), 8.30 (1H, d, J = 8.0 Hz), 8.6
8 (1H, s).

The following compounds were synthesized in the same manner.

[Table 20]

Example 143 4- [3- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -4,5-dihydro-3H-1,4,8b -
Triazaacenaphthylene-3-one hydrochloride 5-chloromethylimidazo [1,2-a] pyridine-3-carboxylate ethyl sulfate (1.68 g, 5.00 mmol), sodium iodide (7
49 mg, 5.00 mmol), 3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propylamine hydrochloride (1.
93 g, 5.50 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (2.29 g, 15.0 mmol), triethylamine (1.01
g, 10.0 mmol) in acetonitrile (30 ml) was heated to reflux for 3 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give 4- [3- [1- [4- (trifluoromethyl)
Benzoyl] piperidin-4-yl] propan-1-yl] -4,5-
Dihydro-3H-1,4,8b-triazaacenaphthylene-3-one
(1.73 g, 74%) was obtained as crystals. 4 concentrated hydrochloric acid (0.60 ml)
-[3- [1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -4,5-dihydro-3H-1,4,8b-
Triazaacenaphthylene-3-one (1.73 g, 3.68 mmol) was added to an ethanol solution (20 ml), and the mixture was stirred at room temperature for 30 minutes.
The reaction mixture was concentrated under reduced pressure to give 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl]-.
4,5-Dihydro-3H-1,4,8b-triazaacenaphthylene-3-one hydrochloride (1.39 g, 75%) was obtained as pale yellow crystals, which were washed with 2-propanol and diethyl ether. ¹ H-NMR (DMSO-d ₆ ) δ: 1.00-1.85 (5H, m), 2.60-2.85
(2H, m), 2.85-3.15 (2H, m), 3.40-3.60 (2H, m), 4.01
(2H, t, J = 7.2 Hz), 4.40-4.60 (2H, m), 5.25 (2H,
s), 7.42 (1H, d, J = 7.0 Hz), 7.50-7.65 (2H, m),
7.75-8.40 (4H, m), 8.60-8.70 (1H, m).

The following compounds were synthesized in the same manner.

[Table 21]

Example 147 2-Phenyl-3- (trifluoromethyl) -N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] imidazo [5,1,2- cd] Indolizine-4-carboxamide hydrochloride N-hydroxybenzotriazole monohydrate (919 mg, 6.0
0 mmol) with 2-phenyl-3- (trifluoromethyl) imidazo
[5,1,2-cd] indolizine-4-carboxylic acid (1.32 g, 4.00 m
mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.15 g, 6.00 mmol) in acetonitrile suspension (30 ml), and stirred at room temperature for 1 hour. To the reaction solution
3- [1- [4- (trifluoromethyl) benzoyl] piperidine-
4-yl] propylamine hydrochloride (1.54 g, 4.40 mmol), 1,
8-diazabicyclo [5.4.0] -7-undecene (670 mg, 4.40
mmol) and triethylamine (810 mg, 8.00 mmol).
Stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give 2-phenyl-3- (trifluoromethyl) -N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidine -4-yl] Imidazo [5,1,2-cd] indolidin-4-carboxamide (2.16 g, 86%) was obtained as crystals. Concentrated hydrochloric acid (0.57 ml) was added to 2-phenyl-3- (trifluoromethyl) -N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] imidazo [5,1,2 [cd] -Indolizine-4-carboxamide (2.16 g, 3.45 mmol) in ethanol solution (25 ml) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to give 2-phenyl-3- (trifluoromethyl) -N- [3-
[1- [4- (trifluoromethyl) benzoyl] piperidine-4-
[Ill] imidazo [5,1,2-cd] indolizine-4-carboxamide hydrochloride (1.30 g, 57%) was obtained as pale yellow crystals, and washed with diethyl ether. Elemental analysis: C ₃₃ H ₂₈ ClF ₆ N ₄ O ₂ Calculated: C, 59.87; H, 4.26; N, 8.46. Found: C, 59.78; H, 4.37; N, 8.47.

The following compounds were synthesized in the same manner.

[Table 22]

Example 151 N- [1- (4-Chlorophenylsulfonyl) piperidin-4-yl] -3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3-methyl-5 -Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.3 g, 1.29 mmol), 4-amino-1- (4-chlorophenylsulfonyl) piperidine hydrochloride (0.52 g, 1.68 mmol), triethylamine (0.23 ml, 1.68 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g,
2.58 mmol), 1-hydroxybenzotriazole monohydrate
(0.40 g, 2.58 mmol) and N, N-dimethylformamide (10 ml)
Was stirred at room temperature for 5 hours. The reaction solution was treated with aqueous sodium bicarbonate (100 m
1) and extracted with dichloromethane (50 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue
(Chloroform: acetone = 1: 1) to give N- [1- (4-chlorophenylsulfonyl) piperidin-4-yl] -3-methyl-5-thia-1,8b-diazaacenaphthylene- 4-Carboxamide (0.59 g, 93%) was obtained as crystals. . Mp 261-262 ° C. as the elemental analysis _{C 22 H 21 ClN 4 O 3} S 2, Calculated: C, 54.03; H, 4.33 ; N, 11.46 Found: C, 53.88; H, 4.14 ; N, 11.42. ¹ H-NMR (CDCl ₃ ) δ: 1.45-1.70 (2H, m), 2.01 (3H, s), 1.95
-2.10 (2H, m), 2.40-2.60 (2H, m), 3.70-3.85 (3H, m), 5.7
5-5.92 (2H, m), 6.65-6.80 (2H, m), 7.17 (1H, s), 7.50-7.
60 (2H, m), 7.65-7.78 (2H, m).

Example 152 3-Methyl-N- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-
4-carboxamide 3-methyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.3 g, 1.29 mmol), 4-amino-1- [4- (trifluoromethyl) benzoyl] piperidine・ Hydrochloride (0.52g, 1.68mmo
l), triethylamine (0.23 ml, 1.68 mmol), 1-ethyl-3
-(3-Dimethylaminopropyl) carbodiimide hydrochloride (0.
44 g, 2.58 mmol), 1-hydroxybenzotriazole monohydrate (0.40 g, 2.58 mmol) and N, N-dimethylformamide
(10 ml) was stirred at room temperature for 2 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 3-methyl-N- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] -5- Thia-1,8b-diazaacenaphthylene-4-carboxamide (0.52 g, 83%) was obtained as crystals. Melting point: 192-194 ° C. Elemental analysis: C ₂₄ H ₂₁ F ₃ N ₄ O ₃ S Calculated: C, 59.25; H, 4.35; N, 11.52 Found: C, 58.98; H, 4.31; N, 11.54 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.20-1.75 (2H, m), 2.01 (3H, s), 1.90
-2.20 (2H, m), 2.90-3.30 (2H, m), 3.55-3.85 (1H, m), 3.9
8-4.20 (1H, m), 4.50-4.80 (1H, m), 5.85 (1H, dd, J = 6.4,1.
4Hz), 6.00-6.15 (1H, m, NH), 6.63-6.82 (2H, m), 7.18 (1
H, s), 7.52 (2H, d, J = 8.0Hz), 7.69 (2H, d, J = 8.0Hz).

Example 153 3-Methyl-N- [1- (4-chlorobenzoyl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3-methyl-5 -Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.3 g, 1.29 mmol), 4-amino-1- (4-chlorobenzoyl) piperidine hydrochloride (0.46 g, 1.68 mmol), triethylamine ( 0.23 ml, 1.68 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g, 2.58 mmo
l), 1-hydroxybenzotriazole monohydrate (0.40 g,
A mixture of 2.58 mmol) and N, N-dimethylformamide (10 ml) was stirred at room temperature for 3 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give 3-methyl-N- [1- (4-
Chlorobenzoyl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.56 g, 94%) was obtained as crystals. . Mp 135-138 ° C. as the elemental analysis _{C 23 H 21 ClN 4 O 2} S · 0.4H 2 O, Calculated: C, 60.03; H, 4.77 ; N, 12.18 Found: C, 59.95; H, 4.81 ; ^{. N, 12.23 1 H-NMR} (CDCl 3) δ: 1.30-1.75 (2H, m), 2.04 (3H, s), 1.95
-2.15 (2H, m), 2.90-3.25 (2H, m), 3.60-4.20 (2H, m), 4.2
0-4.60 (1H, m), 5.86 (1H, dd, J = 6.4,1.4Hz), 5.85-6.00 (1
H, m, NH), 6.65-6.82 (2H, m), 7.19 (1H, s), 7.30-7.58 (4
H, m).

Example 154 3,8-Dimethyl-N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.5 g, 2.01 mmol) and 4- (3-aminopropane -1-yl) -1- [4- (trifluoromethyl) benzoyl] piperidine.
Hydrochloride (0.92 g, 2.62 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.69 g, 4.03 mmol)
l), 1-hydroxybenzotriazole monohydrate (0.62 g,
4.03 mmol), triethylamine (0.73 ml, 5.24 mmol) and N,
A mixture of N-dimethylformamide (10 ml) was stirred at room temperature for 3 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (100 ml) and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 3,8-dimethyl-N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl ] Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.99 g, 91%) was obtained as reddish purple crystals. Melting point: 190-191 ° C. Elemental analysis: C ₂₈ H ₂₉ F ₃ N ₄ O ₂ S Calculated: C, 62.09; H, 5.21; N, 10.34 Found: C, 62.11; H, 5.56; N, 10.41 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.00-1.44 (4H, m), 1.48-1.97 (5H, m),
2.04 (3H, s), 2.22 (3H, s), 2.68-2.90 (1H, m), 2.90-3.1
5 (1H, m), 3.31 (2H, q, J = 6.4Hz), 3.58-3.76 (1H, m), 4.66
-4.83 (1H, m), 5.82 (1H, d, J = 6.0Hz), 6.08-6.20 (1H, m, N
H), 6.53 (1H, d, J = 6.6Hz), 7.18 (1H, s), 7.50 (2H, d, J =
8.0Hz), 7.68 (2H, d, J = 8.0Hz).

Example 155 N- [3- [1- (4-Chlorophenylsulfonyl) piperidine-4-
Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- (4-chlorophenylsulfonyl) piperidine-
Synthesis of 4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5 -Cheer-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4 mmol) in acetonitrile (20 ml) was added 4-chlorophenylsulfonyl chloride (0.51 g, 2.4 m
mol) and triethylamine (0.56 ml, 4 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (100 ml) was added to the reaction solution,
Extracted with ethyl acetate (200,100ml). After washing the extract with water,
It was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:
Acetone = 2: 1-chloroform: acetone: methanol = 25: 2
5: 1) to give N- [3- [1- (4-chlorophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide (0.92g, 89%)
Was obtained as red-purple crystals. Melting point 165-167 ° C. Elemental analysis: C ₂₄ H ₂₅ ClN ₄ O ₃ S ₂ Calculated: C, 55.75; H, 4.87; N, 10.84 Found: C, 55.82; H, 5.10; N, 10.54. ¹ H-NMR (CDCl ₃ ) δ: 1.10-1.83 (9H, m), 2.15-2.32 (2H, m),
3.26 (2H, q, J = 6.2Hz), 3.70-3.88 (2H, m), 5.66-5.80 (1
H, m), 5.89 (1H, dd, J = 6.0,1.6Hz), 6.59-6.75 (3H, m), 7.
05 (1H, s), 7.48-7.60 (2H, m), 7.67-7.78 (2H, m) .2) N- [3- [1- (4-chlorophenylsulfonyl) piperidine-
Synthesis of 4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride N- [3- [1- (4-chlorophenylsulfonyl) piperidine-4 -
[Il] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.82 g) in chloroform-methanol (10-20 ml) was added with concentrated hydrochloric acid (2 ml) and shaken. mixed.
The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (4-chlorophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5-thia. -1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.70 g, 80
%) Were obtained as yellow crystals. Melting point 210-214 ° C. Elemental analysis: C ₂₄ H ₂₅ ClN ₄ O ₃ S ₂・ HCl ・ 1 / 2H ₂ O Calculated: C, 51.24; H, 4.84; N, 9.96 Found: C, 51.41; . H, 4.55; N, 9.98 1 H-NMR (DMSO-d 6) δ: 1.0-1.3 (5H, m), 1.30-1.50 (2H, m),
1.60-1.80 (2H, m), 2.10-2.30 (2H, m), 3.00-3.18 (2H, m
m), 3.50-3.70 (2H, m), 6.56 (1H, d, J = 7.2Hz), 6.94 (1H,
d, J = 9.2Hz), 7.01 (1H, s), 7.24 (1H, dd, J = 9.2,7.4Hz),
7.60 (1H, s), 7.67-7.83 (4H, m), 8.58-8.70 (1H, m).

Example 156 N- [3- [1- (4-bromophenylsulfonyl) piperidine-4-
Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- (4-bromophenylsulfonyl) piperidine-
Synthesis of 4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5 -Cheer-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4 mmol) in acetonitrile (20 ml) was added 4-bromophenylsulfonyl chloride (0.61 g, 2.4 mmol).
mmol) and triethylamine (0.56 ml, 4 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (100 ml) was added to the reaction solution,
Extracted with ethyl acetate (200ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give N- [3- [1- (4-bromophenylsulfonyl) piperidin-4-yl] propan-1-yl] -5. -Cheer-
1,8b-diazaacenaphthylene-4-carboxamide (0.87 g,
78%) as red-purple crystals. Melting point: 173-175 ° C. Elemental analysis: C ₂₄ H ₂₅ BrN ₄ O ₃ S ₂ Calculated: C, 51.34; H, 4.49; N, 9.98 Found: C, 51.44; H, 4.56; N, 9.56. ¹ H-NMR (CDCl ₃ ) δ: 1.1-1.8 (9H, m), 2.10-2.32 (2H, m),
3.25 (2H, q, J = 6.2Hz), 3.70-3.86 (2H, m), 5.68-5.82 (1H,
m), 5.79 (1H, dd, J = 6.2,1.6Hz), 6.58-6.80 (3H, m), 7.05
(1H, s), 7.58-7.77 (4H, m). 2) N- [3- [1- (4-bromophenylsulfonyl) -piperidin-4-yl] propan-1-yl] -5-thia- 1,8b-diazaacenaphthylene-4-carboxamide hydrochloride N- [3- [1- (4-bromophenylsulfonyl) piperidine-4-
Il] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.77 g) in chloroform-methanol (10-20 ml) was added with concentrated hydrochloric acid (2 ml) and shaken. mixed.
The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (4-bromophenylsulfonyl)-
Piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.73 g,
88%) as yellow crystals. Melting point: 198-202 ° C. Elemental analysis: as C ₂₄ H ₂₅ BrN ₄ O ₃ S ₂・ HCl ・ 1 / 2H ₂ O Calculated: C, 47.49; H, 4.48; N, 9.23 Found: C, 47.77; . H, 4.21; N, 9.34 1 H-NMR (DMSO-d 6) δ: 1.0-1.3 (5H, m), 1.30-1.53 (2H, m),
1.60-1.80 (2H, m), 2.10-2.35 (2H, m), 3.00-3.20 (2H, m
m), 3.55-3.75 (2H, m), 6.58 (1H, d, J = 7.2Hz), 6.95 (1H,
d, J = Hz), 7.02 (1H, s), 7.26 (1H, dd, J = 9.2,7.2Hz), 7.65
(2H, d, J = 8.6Hz), 7.85 (2H, d, J = 8.6Hz), 8.60-8.73 (1H,
m).

Example 157 N- [3- [1- [4- (Trifluoromethoxy) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide hydrochloride 1) N- [3- [1- [4- (trifluoromethoxy) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -5-thia- 1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
In a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (30 ml), 4- (trifluoromethoxy) phenylsulfonyl chloride (0.41 ml, 2.4 mmol) and triethylamine (0.56 ml, 4.
0 mmol) and stirred at room temperature for 3 hours. Water (100m
l) was added, and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1) to give N- [3- [1- [4- (trifluoromethoxy) benzenesulfonyl] piperidine-4.
[-Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.76 g, 67%) was obtained as reddish purple crystals. Melting point 161-162 ° C. Elemental analysis: C ₂₅ H ₂₅ F ₃ N ₄ O ₄ S2 Calculated: C, 52.99; H, 4.45; N, 9.89 Found: C, 52.67; H, 4.65; N, 9.54 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.15-1.82 (9H, m), 2.25 (2H, t, J = 10.6
Hz), 3.25 (2H, q, J = 6.6Hz), 3.70-3.90 (2H, m), 5.79 (1H,
(dd, J = 6.2,1.8Hz), 5.70-5.83 (1H, m), 6.58-6.77 (3H, m),
7.05 (1H, s), 7.36 (2H, d, J = 8.8Hz), 7.78-7.88 (2H, m) .2) N- [3- [1- [4- (trifluoromethoxy) benzenesulfonyl] piperidine -4-yl] propan-1-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide hydrochloride N- [3- [1- [4- (trifluoromethoxy) phenylsulfonyl] piperidin-4-yl] propan-1-yl] -5- Chia-1,8b-
Concentrated hydrochloric acid (2 ml) was added to a methanol (20 ml) solution of diazaacenaphthylene-4-carboxamide (0.66 g), and the mixture was shaken.
The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether), and N- [3- [1- [4- (trifluoromethoxy) benzenesulfonyl] piperidin-4-yl] propan-1-yl ]-Five-
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.65 g, 93%) was obtained as yellow crystals. Melting point 210-213 ° C. Elemental analysis: C ₂₅ H ₂₅ F ₃ N ₄ O ₄ S ₂・ HCl ・ H ₂ O Calculated: C, 49.79; H, 4.68; N, 9.29 Found: C, 49.75; . H, 4.30; N, 9.29 1 H-NMR (DMSO-d 6) δ: 1.0-1.60 (5H, m), 1.60-1.85 (2H,
m), 2.15-2.35 (2H, m), 3.00-3.20 (2H, m), 3.50-3.80 (2
H, m), 6.63 (1H, d, J = 7.2Hz), 6.98 (1H, d, J = 9.0Hz), 7.05
(1H, s), 7.30 (1H, dd, J = 9.0,7.2Hz), 7.58-7.78 (3H, m),
7.89 (2H, d, J = 9.0Hz), 8.63-8.78 (1H, m, NH).

Example 158 N- [3- [1- [4- (Trifluoromethoxy) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene -4-carboxamide hydrochloride 1) N- [3- [1- [4- (trifluoromethoxy) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacena Synthesis of butylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 4- (trifluoromethoxy) benzoic acid
(0.54 g, 2.6 mmol) in a solution of N, N-dimethylformamide (20 ml) in triethylamine (0.56 ml, 4 mmol), 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide hydrochloride (0.52
g, 3.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.46 g, 3.0 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction solution was added with saturated aqueous sodium hydrogen carbonate (100 ml), and ethyl acetate (100 ml x 2)
Extracted. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 1: 1-chloroform: acetone: methanol = 25: 25: 1) to give N- [3
-[1- [4- (trifluoromethoxy) benzoyl] piperidine
-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.90 g, 85%) was obtained as red-purple crystals. Melting point: 184-185 ° C. Elemental analysis: C ₂₆ H ₂₅ F ₃ N ₄ O ₃ S Calculated: C, 58.86; H, 4.75; N, 10.56 Found: C, 58.63; H, 4.70; N, 10.34 _{^{. 1 H-NMR (CDCl 3}} ) δ: 1.0-1.9 (9H, m), 2.65-3.20 (2H, m),
3.30 (2H, q, J = 6.6Hz), 3.60-3.80 (1H, m), 4.55-4.80 (1H,
m), 5.75-5.90 (2H, m), 6.40-6.80 (3H, m), 7.05 (1H, s),
7.20-7.35 (2H, m), 7.40-7.50 (2H, m). 2) N- [3- [1- [4- (trifluoromethoxy) benzoyl] piperidin-4-yl] propan-1-yl] Of N-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride N- [3- [1- [4- (trifluoromethoxy) benzoyl] piperidin-4-yl] propane-1 -Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.8 g) in chloroform-
Concentrated hydrochloric acid (2 ml) was added to a methanol (15-15 ml) solution and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) and N- [3- [1- [4- (trifluoromethoxy)
Benzoyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.80 g, 91%) was obtained as yellow crystals. Melting point: 196-199 ° C. Elemental analysis: C ₂₆ H ₂₅ F ₃ N ₄ O ₃ S.HCl.H ₂ O Calculated: C, 53.38; H, 4.82; N, 9.58 Found: C, 53.22; H ^{, 4.71; N, 9.65 1 H} -NMR (DMSO-d 6) δ:. 0.90-1.85 (9H, m), 2.60-2.95 (2H,
m), 3.00-3.20 (2H, m), 3.30-3.70 (1H, m), 4.35-4.65 (1
H, m), 6.57 (1H, d, J = 7.2Hz), 6.95 (1H, d, J = 7.2Hz), 7.03
(1H, s), 7.25 (1H, t, J = 8.2Hz), 7.41 (2H, d, J = 8.8Hz), 7.
52 (2H, d, J = 8.8Hz), 8.60-8.72 (1H, m).

Example 159 N- [3- [1- [4- (Trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenafti Len-4-carboxamide hydrochloride 1) N- [3- [1- [4- (trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
N, N-dimethylformamide of (0.83 g, 2.0 mmol) and 4- (trifluoromethyl) phenylbenzoic acid (0.53 g, 2.6 mmol)
(20 ml) solution in triethylamine (0.56 ml, 4 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.52 g, 3.0 mmol), 1-hydroxybenzotriazole monohydrate (0.46 g, 3.0 mmol) and stirred at room temperature for 3 hours. The reaction solution was added with saturated aqueous sodium hydrogen carbonate (100 ml), and ethyl acetate was added.
(100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: acetone = 1: 1).
-Chloroform: acetone: methanol = 15: 15: 1) to give N- [3- [1- [4-trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl] -5. -Cheer-1,8b-
Diazaacenaphthylene-4-carboxamide (0.94 g, 89%)
Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.80-1.80 (9H, m), 2.47-2.66 (1H, m),
2.87-3.08 (1H, m), 3.27 (2H, q, J = 6.4Hz), 3.77 (3H, s),
3.70-3.90 (1H, m), 4.55-4.70 (1H, m), 5.79 (1H, dd, J = 6.
6,1.6Hz), 6.58-6.77 (3H, m), 7.05 (1H, s), 6.36 (2H, d, J
= 8.0Hz), 7.58 (2H, d, J-8.0Hz). 2) N- [3- [1- [4- (trifluoromethyl) phenylacetyl) piperidin-4-yl] propan-1-yl] -5-Thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide hydrochloride N- [3- [1- [4-trifluoromethyl] phenylacetyl] piperidin-4-yl] propan-1-yl] -5-thia-1 Concentrated hydrochloric acid (2 ml) was added to a solution of 8,8-diazaacenaphthylene-4-carboxamide (0.94 g) in ethanol (20 ml) and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether-
Ethanol) to give N- [3- [1- [4- (trifluoromethyl) phenylacetyl) piperidin-4-yl] propan-1-yl]-
5-thia-1,8b-diazaacenaphthylene-4-carboxamide
The hydrochloride (0.92 g, 90%) was obtained as crystals. Melting point: 188-193 ° C. Elemental analysis: C ₂₇ H ₂₇ F ₃ N ₄ O ₂ S ・ HCl ・ 1 / 2H ₂ O Calculated: C, 56.49; H, 5.09; N, 9.76 Found: C, 56.37 ; H, 5.14; N, 9.83 1 H-NMR (DMSO-d 6) δ:. 0.80-1.30 (5H, m), 1.30-1.75 (4H,
m), 2.40-2.65 (1H, m), 2.88-3.20 (3H, m), 3.81 (2H, s),
3.80-4.05 (2H, m), 4.30-4.48 (2H, m), 6.61 (1H, d, J = 7.6
Hz), 6.97 (1H, d, J = 9.0Hz), 7.06 (1H, s), 7.20-7.36 (1
H, m), 7.44 (2H, d, J = 8.0Hz), 7.64 (1H, s), 7.65 (2H, d, J
= 8.0Hz), 8.60-8.80 (1H, m, NH).

Example 160 N- [4- [1- [4- (Trifluoromethyl) benzoyl) piperidin-4-yl] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene -4-carboxamide hydrochloride 1) N- [4- [1- [4- (trifluoromethyl) benzoyl) piperidin-4-yl] butan-1-yl] -5-thia-1,8b-diaza Synthesis of acenaphthylene-4-carboxamide N- [4- (piperidin-4-yl) butan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride
(0.88 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (20 ml) was added 4- (trifluoromethyl) benzoyl chloride (0.3
6 ml, 2.4 mmol) and triethylamine (0.56 ml, 4.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone: methanol = 50: 50: 1) to give N- [4-
(1- [4- (trifluoromethyl) benzoyl) piperidine-4-
[Ill] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.00 g, 94%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.95 (11H, m), 2.60-3.15 (2H,
m), 3.31 (2H, q, J = 6.6Hz), 3.55- 3.75 (1H, m), 4.60-4.80
(1H, m), 5.80 (1H, dd, J = 6.2,1.8Hz), 5.68-5.90 (1H, m),
6.60-6.80 (3H, m), 7.06 (1H, s), 7.50 (2H, d, J = 8.4Hz),
7.68 (2H, d, J = 8.4Hz). 2) N- [4- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] butan-1-yl] -5-thia-1 Of 8,8b-diazaacenaphthylene-4-carboxamide hydrochloride N- [4- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] butan-1-yl] -5- Thia-1,8b-diazaacenaphthylene-4-carboxamide (1.0 g) in methanol (20 ml)
Concentrated hydrochloric acid (2 ml) was added to the solution and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N-
[4- [1- [4- (trifluoromethyl) benzoyl] piperidine
-4-yl] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (1.04 g, 97%) was obtained as orange crystals. . As mp 197-202 ° C. Elemental analysis _{C 27 H 27 F 3 N 4} O 2 S · HCl, calcd:. C, 57.39; H, 4.99; N, 9.92 Found: C, 57.20; H, 5.07 ; ^{. N, 9.77 1 H-NMR} (DMSO-d 6) δ: 0.90-1.85 (11H, m), 2.65-3.25 (4H,
m), 3.35-3.55 (1H, m), 4.40-4.60 (1H, m), 6.59 (1H, d, J
= 7.6Hz), 6.96 (1H, d, J = 9.0Hz), 7.05 (1H, s), 7.25 (1H, d
d, J = 9.2,7.6 Hz), 7.58 (2H, d, J = 8.4Hz), 7.63 (1H, s),
7.80 (2H, d, J = 8.4Hz), 8.40-8.75 (1H, m, NH).

Example 161 N- [4- [1- (4-Chlorobenzoyl) piperidin-4-yl] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide・ Hydrochloride 1) N- [4- [1- (4-chlorobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [4- (piperidin-4-yl) propan-1-yl] -5-thia-
Acetonitrile of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-7-cene (0.60 ml, 4.0 mmol) ( 15ml) solution, 4-chlorobenzoyl chloride (0.31ml, 2.4mmo
l) and triethylamine (0.56 ml, 4.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (100 ml) was added to the reaction solution,
Extracted with chloroform (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone: methanol = 15: 15: 1) to give N- [4- [1- (4-
Chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.83 g, 86%) was obtained as crystals. . Mp 198-199 ° C. as the elemental analysis _{C 25 H 25 ClN 4 O 2} S, Calculated: C, 62.42; H, 5.24 ; N, 11.65 Found:. C, 62.23; H, 5.32; N, 11.47 1 H-NMR (CDCl ₃ ) δ: 1.00-1.90 (9H, m), 2.60-3.20 (2H, m),
3.29 (2H, q, J = 6.4Hz), 3.60-3.85 (1H, m), 4.50-4.80
(1H, m), 5.79 (1H, dd, J = 6.0,1.6Hz), 5.80-5.95 (1H, m),
6.60-6.80 (3H, m), 7.04 (1H, s), 7.20-7.50 (4H, m) .2) N- [4- [1- (4-chlorobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [4- [1- (4-chlorobenzoyl) piperidin-4-yl] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Concentrated hydrochloric acid (2m) in a solution of carboxamide (0.73g) in methanol (30ml)
l) was added and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [4- [1- (4-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-.
Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.76 g, 94%) was obtained as orange crystals. Melting point: 194-198 ° C. Elemental analysis: C ₂₅ H ₂₅ ClN ₄ O ₂ S.HCl.H ₂ O Calculated: C, 56.07; H, 5.27; N, 10.40 Found: C, 56.07; H, 5.10 ; N, 10.64. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.88 (9H, m), 2.60-3.20 (4H,
m), 4.30-4.60 (2H, m), 6.20-6.50 (2H, m), 6.70-7.20 (4
H, m), 7.39 (2H, d, J = 8.4Hz), 7.49 (2H, d, J = 8.4Hz), 8.48-
8.68 (2H, m).

Example 162 N- [4- [1- (4-Bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide hydrochloride 1) N- [4- [1- (4-bromobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [4- (piperidin-4-yl) propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (0.73 g, 1.76 mmol) and 1,8-diazabicyclo [5.4.0] unde-7-cene (0.52 ml, 3.51 mmol) in acetonitrile ( 15m
l) In solution, 4-bromobenzoyl chloride (0.46 g, 2.11 mm
ol) and triethylamine (0.49 ml, 3.51 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate (100 ml) was added to the reaction solution, and the mixture was extracted with chloroform (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone: methanol = 15: 15: 1) to give N- [4-
[1- (4-bromobenzoyl) piperidin-4-yl] butane-1-
[Ill] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.81 g, 88%) was obtained as crystals. Melting point: 196-197 ° C. Elemental analysis: C ₂₅ H ₂₅ BrN ₄ O ₂ S Calculated: C, 57.14; H, 4.80; N, 10.66 Found: C, 56.74; H, 4.65; N, 10.56. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.95 (9H, m), 2.60-3.15 (2H, m),
3.30 (1H, q, J = 6.0Hz), 3.55- 3.85 (1H, m), 4.55-4.85 (1
H, m), 5.80 (1H, dd, J = 6.2,1.8Hz), 6.60-6.78 (3H, m), 7.
05 (1H, s), 7.28 (2H, d, J = 8.2Hz), 7.54 (2H, d, J = 8.2Hz) .2) N- [4- [1- (4-bromobenzoyl) piperidine-4 -Ill]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [4- [1- (4-bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -
Carboxamide (0.71 g) methanol-chloroform (15 m
l-15ml) solution, concentrated hydrochloric acid (2ml) was added and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [4- [1- (4-bromobenzoyl) piperidin-4-yl].
Butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-
Carboxamide hydrochloride (0.71 g, 92%) was obtained as orange crystals. Melting point: 166-169 ° C. Elemental analysis: C ₂₅ H ₂₅ BrN ₄ O ₂ S ・ HCl ・ 1 / 2H ₂ O Calculated: C, 52.59; H, 4.77; N, 9.81 Found: C, 52.88; H , 4.52; N, 9.99. ¹ H-NMR (DMSO-d ₆ ) δ: 0.90-1.90 (9H, m), 2.60-3.20 (4H,
m), 4.30-4.60 (2H, m), 6.59 (1H, d, J = 7.2Hz), 6.96 (1H,
d, J = 9.0Hz), 7.05 (1H, s), 7.27 (1H, dd, J = 9.0,7.2Hz),
7.32 (2H, d, J = 8.4Hz), 7.63 (2H, d, J = 8.4Hz), 7.64 (1H,
s), 8.60-8.74 (1H, m).

Example 163 N- [4- [1- [α-hydroxy-4- (trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide
Hydrochloride 1) N- [4- [1- [α-hydroxy-4- (trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl]
Of N-5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [4- (piperidin-4-yl) propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide hydrochloride
(0.88 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (15 ml) was added 4- (trifluoromethyl) mandelic acid (0.57 g, 2.6 mm
ol) and triethylamine (0.56 ml, 4.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (100 ml) was added to the reaction solution,
Extracted with ethyl acetate (100ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: acetone = 1: 1-chloroform: acetone: methanol = 15: 15: 1)
And purified by N- [4- [1- [α-hydroxy-4- (trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl] -5-thia-1,8b-dia Zaacenaphthylene-4-carboxamide (0.96 g, 88%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.85 (9H, m), 2.50-2.80 (2H, m),
2.80-3.03 (1H, m), 3.15-3.37 (2H, m), 3.53-3.70 (1H,
m), 4.55-4.72 (1H, m), 5.26 (1H, d, J = 3.6Hz), 5.70-5.90
(2H, m), 6.60-6.80 (3H, m), 7.05 (1H, s), 7.40-7.55 (2H, m
m), 7.55-7.73 (2H, m). 2) N- [4- [1- [α-hydroxy-4- (trifluoromethyl) phenylacetyl] piperidin-4-yl] propan-1-yl]
Of N-5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride N- [4- [1- [α-hydroxy-4- (trifluoromethyl) phenylacetyl] piperidine-4- Il] propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide
(0.86 g) in methanol (20 ml) was added with concentrated hydrochloric acid (2 ml) and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration.
(Diethyl ether) to give N- [4- [1- [α-hydroxy-4-
(Trifluoromethyl) phenylacetyl] piperidine-4-
[Ill] butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.77 g, 84%) was obtained as an orange amorphous powder. Elemental analysis: C ₂₇ H ₂₇ F ₃ N ₄ O ₂ S ・ HCl ・ 1 / 2H ₂ O Calculated: C, 54.96; H, 4.95; N, 9.50 Found: C, 54.82; H, 5.02; N ^{, 9.13 1 H-NMR (DMSO} -d 6) δ:. 0.70-1.75 (9H, m), 2.40-2.93 (3H,
m), 3.00-3.20 (2H, m), 3.80-4.10 (2H, m), 4.30-4.50 (2
H, m), 5.51 (1H, d, J = 5.8Hz), 6.59 (1H, d, J = 7.4Hz), 6.96
(1H, s), 7.63 (1H, s), 7.72 (2H, d, J = 8.2Hz), 8.58-8.70
(1H, m).

Example 164 3,8-Dimethyl-N- [4- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] butan-1-yl] -5-thia-1, 8b-diazaacenaphthylene-4-carboxamide hydrochloride 1) 3,8-dimethyl-N- [4- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] butane-1 -Il]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3,8-dimethyl-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (0.37 g, 1.50 mmol) And 4- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] butylamine hydrochloride (0.70 g, 1.08 mmol) in N, N-dimethylformamide (30 ml) -3- (3-Dimethylaminopropyl) carbodiimide hydrochloride (0.39 g, 2.25 mmol) and 1-
Hydroxybenzotriazole monohydrate (0.35g, 2.25mm
ol) and triethylamine (0.25 ml, 4.06 mmol), and the mixture was stirred at room temperature for 15 hours. Water (200 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1-chloroform: acetone = 2: 1) to give 3,8
-Dimethyl-N- [4- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] butan-1-yl] -5-thia
-1,8b-diazaacenaphthylene-4-carboxamide (0.74
g, 85%) as crystals. Melting point 109-112 ° C. Elemental analysis: C ₂₇ H ₂₉ F ₃ N ₄ O ₃ S ₂ Calculated: C, 56.04; H, 5.05; N, 9.68 Found: C, 55.86; H, 5.01; N, 9.78. ¹ H-NMR (CDCl ₃ ) δ: 1.15-1.85 (9H, m), 2.03 (3H, s), 2.22
(3H, s), 2.20-2.40 (2H, m), 3.26 (2H, q, J = 6.6Hz), 3.75-
3.90 (2H, m), 5.81 (1H, d, J = 7.0Hz), 6.00-6.15 (1H, m, N
H), 6.53 (1H, dd, J = 7.0,1.2Hz), 7.18 (1H, s), 7.81 (2H,
d, J = 8.4Hz), 7.90 (2H, d, J = 8.4Hz) .2) 3,8-Dimethyl-N- [4- [1- [4- (trifluoromethyl) benzoyl)] piperidine-4 -Ill] butan-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide hydrochloride 3,8-dimethyl-N- [4- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] butane- 1-yl] -5-thia-1,8b-
Concentrated hydrochloric acid (2 ml) was added to a solution of diazaacenaphthylene-4-carboxamide (0.64 g) in ethanol (20 ml), and the mixture was shaken.
The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give 3,8-dimethyl-N- [4- [1- [4- (trifluoromethyl) benzoyl)] piperidin-4-yl. ] Butan-1-yl]-
5-thia-1,8b-diazaacenaphthylene-4-carboxamide
The hydrochloride (0.67 g, 98%) was obtained as orange crystals. . Mp 202-206 ° C. as the elemental analysis _{C 27 H 29 F 3 N 4} O 3 S 2 · HCl, calcd: C, 52.72; H, 4.92 ; N, 9.11 Found: C, 52.46; H, 4.94 ; ^{. N, 9.12 1 H-NMR} (DMSO-d 6) δ: 1.00-1.60 (7H, m), 1.60-1.80 (2H,
m), 1,87 (3H, s), 2.22 (3H, s), 2.18-2.40 (2H, m), 3.00
-3.20 (2H, m), 3.60-3.80 (2H, m), 6.67 (1H, d, J = 7.6Hz),
7.23 (1H, d, J = 7.6Hz), 7.87 (1H, s), 7.95 (2H, d, J = 8.6H
z), 8.02 (2H, d, J = 8.6Hz).

Example 165 N- [3- [1- (2-Chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide・ Hydrochloride 1) N- [3- [1- (2-chlorobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (15 ml) were added 2-chlorobenzoyl chloride (0.30 ml, 2.4 mmol) and triethylamine (0.56 ml, 4.0 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (50 ml), and the mixture was extracted with dichloromethane (50 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Silica gel column chromatography of the residue (chloroform: acetone = 1: 1-chloroform: acetone: methanol = 15: 15: 1)
And purified with N- [3- [1- (2-chlorobenzoyl) piperidine
-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.83 g, 86%) was obtained as a red-purple oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.95 (9H, m), 2.67-3.20 (2H, m),
3.29 (2H, q, J = 6.6Hz), 3.20-3.50 (1H, m), 4.70-4.90 (1
H, m), 5.75-5.90 (2H, m), 6.60-6.80 (3H, m), 7.04 (1H,
s), 7.20-7.50 (4H, m). 2) N- [3- [1- (2-chlorobenzoyl) piperidin-4-yl]-
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [3- [1- (2-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Concentrated hydrochloric acid in a solution of carboxamide (0.70 g) in methanol (20 ml)
(2 ml) and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (2-chlorobenzoyl) piperidin-4-yl] -propan-1-yl].
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.70 g, 77%) was obtained as yellow crystals. Melting point 172-175 ° C. Elemental analysis: C ₂₅ H ₂₅ ClN ₄ O ₂ S ・ HCl ・ H ₂ O Calculated: C, 56.08; H, 5.27; N, 10.46 Found: C, 56.24; H, 5.03 ; N, 10.43. ¹ H-NMR (DMSO-d ₆ ) δ: 0.95-1.88 (9H, m), 2.60-3.20 (4H,
m), 3.35-3.65 (1H, m), 4.30-4.60 (1H, m), 6.60 (1H, d, J =
7.4Hz), 6.98 (1H, d, J = 9.2Hz), 7.08 (1H, s), 7.20-7.60
(5H, m), 7.65 (1H, s), 8.65-8.80 (1H, m).

Example 166 N- [3- [1- (2-Bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide・ Hydrochloride 1) N- [3- [1- (2-bromobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (20 ml) was added 2-bromobenzoyl chloride (0.31 ml, 2.4 mmol)
And triethylamine (0.56 ml, 4.0 mmol).
Stirred for hours. A saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1) to give N- [3- [1- (2-bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-. Thia-1,8b-diazaacenaphthylene-4-carboxamide (1.00 g, 95%) was obtained as a red-purple oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.00 (9H, m), 2.45-3.20 (2H, m),
3.29 (2H, q, J = 6.2Hz), 3.30-3.50 (1H, m), 4.65-4.90 (1
H, m), 5.77-5.90 (2H, m), 6.60-6.80 (3H, m), 7.05 (1H,
s), 7.15-7.70 (4H, m). 2) N- [3- [1- (2-bromobenzoyl) piperidin-4-yl]-
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [3- [1- (2-bromobenzoyl) piperidin-4-yl] -propan-1-yl] -5-thia-1,8b-diazaacenaphthylene- Four-
Concentrated hydrochloric acid (2 ml) was added to a solution of carboxamide (0.90 g) in ethanol (10 ml) and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (2-
Bromobenzoyl) piperidin-4-yl] -propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide hydrochloride (0.87 g, 90%) was obtained as yellow crystals. . Melting point: 175-180 ° C. Elemental analysis: C ₂₅ H ₂₅ BrN ₄ O ₂ S ・ HCl Calculated: C, 53.44; H, 4.66; N, 9.97 Found: C, 53.32; H, 4.87; N, 9.83 ^{. 1 H-NMR (DMSO-} d 6) δ: 0.85-1.86 (9H, m), 2.65-3.30 (5H,
m), 4.33-4.60 (1H, m), 6.60 (1H, d, J = 7.4Hz), 6.96 (1H,
d, J = 7.4Hz), 7.20-7.52 (4H, m), 7.60-7.72 (2H, m), 8.62-
8.78 (1H, m).

Example 167 N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide・ Hydrochloride 1) N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamidihydrochloride (0.
83g, 2.0mmol) and 1,8-diazabicyclo [5.4.0] unde-7-
3-chlorobenzoyl chloride (0.30 ml, 2.4 mmol) in a solution of sen (0.60 ml, 4.0 mmol) in acetonitrile (15 ml)
And triethylamine (0.56 ml, 4.0 mmol).
Stirred for hours. To the reaction solution was added a saturated aqueous sodium hydrogen carbonate solution (50 ml), and the mixture was extracted with dichloromethane (50 ml × 2). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: acetone = 1: 1-chloroform: acetone: methanol = 15: 15:
Purified in 1) to give N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4- Carboxamide (0.84 g, 87%) was obtained as red-purple crystals. 139-140 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.00-1.95 (9H, m), 2.60-3.15 (4H, m),
3.30 (2H, q, J = 6.6Hz), 3.60-3.80 (1H, m), 4.60-4.80 (1
H, m), 5.70-5.85 (2H, m), 6.58-6.78 (3H, m), 7.05 (1H,
s), 7.20-7.45 (4H, m). 2) N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -
Carboxamide (0.73 g) chloroform-methanol (10 m
concentrated hydrochloric acid (2 ml) was added to the solution and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (3-chlorobenzoyl) piperidin-4-yl].
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide hydrochloride (0.77 g, 98%) was obtained as yellow crystals. Melting point 185-190 ° C. Elemental analysis: C ₂₅ H ₂₅ ClN ₄ O ₂ S · HCl · 1 / 2H ₂ O Calculated: C, 57.03; H, 5.17; N, 10.64 Found: C, 56.78; H ^{, 5.10; N, 10.54 1 H} -NMR (DMSO-d 6) δ:. 0.90-1.86 (9H, m), 2.60-3.50 (5H,
m), 4.42-4.60 (1H, m), 6.55 (1H, d, J = 7.4Hz), 6.94 (1H,
d, J = 9.2Hz), 7.01 (1H, s), 7.18-7.58 (5H, m), 7.59 (1H,
s), 8.58- 8.70 (1H, m).

Example 168 N- [3- [1- (3-Bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide・ Hydrochloride 1) N- [3- [1- (3-bromobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [3- (piperidin-4-yl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride
(0.83 g, 2.0 mmol) and 1,8-diazabicyclo [5.4.0] unde-
To a solution of 7-cene (0.60 ml, 4.0 mmol) in acetonitrile (20 ml) was added 3-bromobenzoyl chloride (0.31 ml, 2.4 mmol)
And triethylamine (0.56 ml, 4.0 mmol).
Stirred for hours. A saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone = 2: 1) to give N- [3- [1- (3-bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-. Thia-1,8b-diazaacenaphthylene-4-carboxamide (0.87 g, 83%) was obtained as red-purple crystals. As mp 155-157 ° C. Elemental analysis _{C 25 H 25 BrN 4 O 2} S, Calculated: C, 57.15; H, 4.80 ; N, 10.66 Calcd:. C, 57.08; H, 4.94; N, 10.73 1 H -NMR (CDCl ₃ ) δ: 1.00-1.95 (9H, m), 2.60-3.15 (2H, m),
3.29 (2H, q, J = 6.0Hz), 3.60-3.85 (1H, m), 4.55-4.80 (1
H, m), 5.80 (1H, dd, J = 6.2,1.8Hz), 5.75-5.95 (1H, m), 6.
60-6.80 (3H, m), 7.04 (1H, s), 7.20-7.40 (2H, m), 7.50-
7.60 (2H, m). 2) N- [3- [1- (3-bromobenzoyl) piperidin-4-yl]
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide hydrochloride N- [3- [1- (3-bromobenzoyl) piperidin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Carboxamide (0.77 g) in chloroform-methanol (10 ml-
10 ml) solution, concentrated hydrochloric acid (2 ml) was added and shaken. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration (diethyl ether) to give N- [3- [1- (3-bromobenzoyl) piperidin-4-yl].
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide / hydrochloride (0.78 g, 95%) was obtained as yellow crystals. Melting point: 157-162 ° C. Elemental analysis: C ₂₅ H ₂₅ BrN ₄ O ₂ S.HCl: Calculated: C, 53.44; H, 4.66; N, 9.97 Found: C, 53.05; H, 4.66; N, 9.84 ^{. 1 H-NMR (DMSO-} d 6) δ: 0.90-1.85 (9H, m), 2.60-3.20 (5H,
m), 3.40-3.70 (1H, m), 4.30-4.60 (1H, m), 6.60 (1H, d, J =
7.4Hz), 6.96 (1H, d, J = 7.4Hz), 7.05 (1H, s), 7.20-7.50
(3H, m), 7.50-7.70 (3H, m), 8.60-8.75 (1H, m).

[0203]

The compound (I) of the present invention has excellent LDL
Since it has a receptor increasing effect, a lipid lowering effect and a blood glucose lowering effect, pharmaceutical preparations containing these compounds include, for example, atherosclerotic disease preventive and therapeutic agents, hyperlipidemic preventive and therapeutic agents,
It can be used safely and advantageously as a drug for preventing and treating diabetes, a drug for preventing and treating diabetic complications, and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 43/00 111 43/00 111 C07D 513/16 C07D 513/16 ( 72) Inventor Tetsuji Kawamoto F-term (reference) 4B065 AA07 BB06 CC06 DD03 EE03 HH01 JJ01 KK09 LL04 PP13 4C072 AA02 BB03 CC02 CC16 EE16 FF05 GG09 HH08 AU01A0C86A86C CB29 MA01 MA04 NA14 ZA36 ZA45 ZC33 ZC35 ZC41

Claims (23)

[Claims] (1) Formula (1) [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). Or a salt thereof. 2. The compound according to claim 1, wherein R ² is a hydrogen atom. 3. The compound according to claim 1, wherein X ¹ is a bond or a C _1-4 alkylene group. 4. The compound according to claim 1, wherein X ² is a bond. 5. The compound according to claim 1, wherein X ³ is —CO—. 6. The compound according to claim 1, wherein X ⁴ is a C _1-4 alkylene group. 7. The compound according to claim 1, wherein R ³ is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered aromatic heterocyclic group. 8. The ring Q is (i) a halogen atom, (ii) C_1-4
Alkyl group, (iii) C _1-4Alkoxy group, (iv) C
_1-4Alkylthio group, (v) hydroxyl group, (vi)
Boxyl group, (vii) cyano group, (viii) nitro group, (ix)
Amino group, (x) mono- or di-C_1-4Alkylamino
Group, (xi) formyl group, (xii) mercapto group, (xiii) C
_1-4Alkyl-carbonyl group, (xiv) C_1-4Arco
Xy-carbonyl group, (xv) sulfo group, (xvi) C_1-4A
Alkylsulfonyl, (xvii) carbamoyl and (xvi
ii) mono- or di-C_1-4Alkyl-carbamoyl
May have from 1 to 3 substituents selected from
The compound of claim 1. 9. The compound according to claim 1, wherein ring Q is unsubstituted. 10. R ¹ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkoxycarbonyl group. The compound according to claim 1, which is an alkylcarbamoyl group or an alkanoyl group. 11. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group or a phenyl group. 12. A compound of the formula wherein each ring A is optionally substituted. The compound according to claim 1, which is a nitrogen-containing heterocyclic ring represented by the formula: 13. The ring A is of the formula The compound according to claim 1, which is a nitrogen-containing heterocyclic ring represented by the formula: 14. The method according to claim 1, wherein Y is —CO—NR ² —.
A compound as described. 15. N- [3- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] propan-1-yl] -5-thia
-1,8b-diazaacenaphthylene-4-carboxamide, N- [2-
[1- [4- (trifluoromethyl) benzoyl] piperidine-4-
Yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, N- [4- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl ] Butan-1-yl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide, N
-[4-[[1- [4- (Trifluoromethyl) benzoyl] piperidin-4-yl] oxy] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [4-[[1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] thia] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 -Carboxamide, N- [3- [1- [4- (trifluoromethyl) phenylsulfonyl] piperidin-4-yl] propane-1
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, 8-bromo-N- [2- [1- [4- (trifluoromethyl) benzoyl] piperidin-4-yl] Ethane-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide, 2,8-dimethyl-N- [2- [1- [4- (trifluoromethyl) benzoyl]
Piperidin-4-yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, 4- [3- [1- [4- (trifluoromethyl) benzoyl] piperidine -4-yl] propan-1-yl] -3H-1,4,8b-triazaacenaphthylene-3,5
The compound according to claim 1, which is (4H) -dione or a salt thereof. 16. The formula: [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). And a prodrug of the compound or a salt thereof. 17. A compound of the formula [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, and Y represents a bond or -CO
—NR ² — (R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ¹ represents a bond or a divalent hydrocarbon group which may be substituted,
X ² is a bond, —O—, —S—, or —NR ⁴ — (R ⁴
Represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group), X ³ represents —CO—, —COO— or —SO ₂ —, and X ⁴ represents a bond or substituted R ³ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group (provided that Y is -CO-NR ² -and X ¹
Is a bond, X ² represents a bond). Or a salt thereof, or a prodrug thereof. 18. The composition according to claim 17, which is a low-density lipoprotein receptor enhancer. 19. The composition according to claim 17, which is a lipid-lowering agent. 20. The method according to claim 1, which is an agent for preventing or treating arteriosclerosis.
A composition according to claim 7. 21. The composition according to claim 17, which is a hypoglycemic agent. 22. The composition according to claim 17, which is an agent for preventing or treating diabetic complications. 23. The formula [In the formula, ring A represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may be substituted, ring Q may have a substituent, and R ¹
Represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group. And a salt thereof and a compound represented by the formula: [Wherein, R ² represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl group, X ¹ represents a bond or a divalent hydrocarbon group which may be substituted, and X ² represents a bond A hand, —O—, —S— or —NR ⁴ — (R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), and X ³ represents —CO—, —COO— or -S
O 2 _- are shown, X ⁴ represents a bond or optionally substituted by divalent be hydrocarbon radicals, R ³ is a cyclic optionally substituted hydrocarbon group or an optionally substituted heterocyclic group (However, when X ¹ is a bond, X ² is a bond). A compound represented by the formula: or a salt thereof. [Wherein the symbols have the same meanings as described above], or a method for producing a salt thereof.