JPH10226689A - Condensed imidazopyridine derivative, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new condensed imidazopyridine derivative having a low density lipoprotein receptor-increasing action and a blood lipid and saccharide- lowering action and useful as an agent for preventing and treating arteriosclerosis and diabetic complications, a hypoglycemic agent, etc. SOLUTION: A new condensed imidazopyrimidine derivative (salt) represented by formula I [the Q ring is a (substituted) pyridine ring; one of R<0> , R<1> , R<2> is a group of the formula: Y<0> -Z<0> (Y<0> is a binding bond, a divalent hydrocarbon group which may be substituted; Z<0> is O, N, CO, CS, etc.), and the other two groups are each H, a halogen, a (substituted) hydroxyl group, a (substituted) hydrocarbon group, an acyl; the dotted line portion is a single bond or a double bond]. The derivative of formula I is useful as a low density lipoprotein receptor-increasing agent, a blood lipid-lowering agent, a hypoglycemic agent, an agent for preventing and treating arteriosclerosis and diabetic complications, etc. The compound is obtained by reacting a compound of formula II (Y is a binding bond, CH=CH, etc.) with a compound of formula III [R<3> , R<4> are each H, a (substituted) hydrocarbon group; A, B are each a (substituted) divalent hydrocarbon group; R is a (substituted) hydrocarbon group; X is a binding bond, O, S, etc.].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a condensed imidazopyridine derivative, 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), colestipol (Colestipol) and the like that captures bile acids and inhibits their absorption (for example, disclosed in US Pat. No. 4,027,099),
Melinamide (France patent 14765)
No. 69), which inhibits intestinal absorption of cholesterol by inhibiting cholesterol acyltransferase (ACAT), and more recently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG
-Lovastati, which inhibits CoA) reductase
n) (disclosed in U.S. Patent No. 4,231,938), Simvastatin (disclosed in U.S. Patent No. 4,231,938), (disclosed in U.S. Patent No. 4,444,784), Pravastatin (U.S. Patent No. 43462).
Drugs that suppress cholesterol biosynthesis, such as those disclosed in No. 27), have attracted attention. However, when HMG-CoA reductase is inhibited, in addition to cholesterol biosynthesis, the biosynthesis of other components required 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 cleared from plasma by the very specific LDL receptor and is taken up into cells by receptor-mediated cellular uptake. Once taken up into cells, the 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 upregulation of LDL receptor independently is expected to lower plasma cholesterol levels by a significant amount, and drugs that upregulate LDL receptor may become new blood lipid lowering agents. Could get. There is no compound known to date as a compound having a structure similar to the compound of the present invention.

[0004]

Under the circumstances described above, it has been desired to develop a new type of blood lipid lowering agent based on the activity of increasing low density lipoprotein (LDL) receptor.

[0005]

Means for Solving the Problems The present inventors have synthesized a variety of novel condensed imidazopyridine derivatives having a substituent, and they have excellent LDL receptor increasing action and blood lipid lowering action. It has been found that it has a blood glucose lowering effect and a diabetic complication ameliorating effect, and further research has been conducted.
We have completed this study. That is, the present invention relates to (1) the general formula (I)

Embedded image (2) R ⁰ is -Y ⁰ -Z ⁰ (Y ⁰ and Z ⁰ are each the above (1)
(3) The compound according to (1), wherein Z ⁰ is a group having a molecular weight of 1,000 or less; (4) the compound represented by the general formula (I) Is the expression

Embedded image Z is -CO -, - COO -, - CON (R 3) -, - SO 2
N (R ³⁾ - or -S (O) m- (m denotes 0, 1 or 2)
R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ⁴ , R ^4a and R ⁵ Each represents a hydrogen atom or a hydrocarbon group which may be substituted, or R ³ and A, R ⁴ and A, R ⁴ and B, R ⁴ and R ⁵ or R ⁴ and R form a ring And R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The compound according to the above (1), which is a compound represented by the formula or a salt thereof,

(5) The compound represented by the general formula (I)

Embedded image R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ⁴ , R ^4a and R ⁵ each represent hydrogen Represents an atom or an optionally substituted hydrocarbon group, or represents R ³ and A, R ⁴ and A, R ⁴ and B, R ⁴ and R ⁵
Alternatively, R ⁴ and R may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. (6) A and B are each an alkylene, X is a bond, and R ³ and R ⁴ are each a hydrogen atom or a substituted group. Alkyl, cycloalkyl, alkenyl,
The compound according to the above (5), which is aralkyl or aryl; (7) ring Q is an unsubstituted pyridine ring, X is a bond,

Embedded image R ¹ and R ² are hydrogen atoms, and R ³ and R ⁴ are each a hydrogen atom, C _1-15 alkyl, C _3-8 cycloalkyl,
_2-18 alkenyl, C _7-16 aralkyl or C _6-14 aryl, the compound according to the above (5), wherein R is C _6-14 aryl,

(8) A compound represented by the general formula (I)

Embedded image R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ^4a and R ⁵ each represent a hydrogen atom or a substituted Indicates a hydrocarbon group which may be
Alternatively, R ³ and A ¹ may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. (9) ring Q is an unsubstituted pyridine ring, R ¹ and R ² are hydrogen atoms, R ³ is a hydrogen atom, C _1-15 alkyl,
_3-8 cycloalkyl, C _2-18 alkenyl, C _7-16 aralkyl or C _6-14 aryl, wherein A ¹ is (i) a bond,
(Ii) 1 selected from a hydroxyl group, an oxo group and a phenyl group
C _1-15 alkylene _optionally having 3 to 3 substituents, (iii) C _2-16 alkenylene or (iv) phenylene, wherein B is selected from (i) a hydroxyl group, an oxo group and a phenyl group C optionally having 1 to 3 substituents
_1-15 alkylene, (ii) C _2-16 alkenylene or (ii)
i) is phenylene, and the Q ₁ ring has the formula

Embedded image Wherein A ² represents ＣC or CH. X is a bond, an oxygen atom, a sulfur atom, or -CO
N (R ⁵ )-, wherein R ⁵ is a hydrogen atom or C _1-15 alkyl;

(10) A compound represented by the general formula (I)

Embedded image R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ^4a and R ⁵ each represent a hydrogen atom or an optionally substituted R represents a hydrocarbon group which may be substituted or an optionally substituted heterocyclic group; ^one of G ¹ and G ² is N, and the other is CH or N
And the ^Ga ring may have a substituent, and g is 0,
Indicates 1 or 2. (11) the ring represented by the formula (1), wherein the ring Q is nitro, hydroxy, cyano, carbamoyl, mono- or di-C _1-4 alkyl-carbamoyl, carboxy, C _1-4 alkoxy-carbonyl, sulfone, halogen, C _1-4 alkoxy, phenoxy, naphthoxy, benzyloxy, halogenophenoxy, C _1-4
Alkylthio, mercapto, phenylthio, pyridylthio, C _1-4 alkylsulfinyl, phenylsulfinyl, C _1-4 alkylsulfonyl, phenylsulfonyl,
Pyridine optionally having 1 to 3 substituents selected from amino, C _1-3 acylamino, mono- or di-C _1-4 alkylamino, C _1-4 alkyl and C _1-4 halogenoalkyl wherein a ring (10) compounds according, (12) a ¹ is a bond or ^{-CON (R 4a) -, -} CO-
Or the compound according to the above (10), which is a C _1-15 alkylene or C _2-16 alkenylene group _optionally via —N (R ^4a ) — (R ^4a has the same meaning as the above (10)). (13) The compound according to the above (10), wherein B is a C _1-15 alkylene or C _2-16 alkenylene group, (14) X is a bond, an oxygen atom, a sulfur atom, —CONH
-Or -CO-, wherein ( ¹ ) R ¹ is (I) a hydrogen atom, (II) a halogen atom,
(III) C _1-6 alkyl, phenyl, C _7-10 aralkyl,
Formyl, C _1-6 alkyl-carbonyl, phenyloxycarbonyl, C _7-10 aralkyloxy-carbonyl,
Hydroxy group optionally substituted with pyranyl, furanyl or silyl, (IV) C _1-15 alkyl, C _3-8 cycloalkyl, C _2-18 alkenyl, C _7-16 aralkyl or C
(10) the above (10), which is a _6-14 aryl group, or (V) a C _1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl or C _1-10 alkanoyl group. a compound according is the (16) R ³ is a hydrogen atom, C _1-15 alkyl group, C _3-8 cycloalkyl group, C _2-18 alkenyl, C _7-16 aralkyl or C _6-14 aryl group (17) R is (I) a C _1-15 alkyl, C _3-8 cycloalkyl or C _2-18 alkenyl group [these groups are (i) nitro, (ii) hydroxy (Iii) cyano, (iv) carbamoyl, (v) mono- or di-C _1-4 alkyl-carbamoyl,
(vi) carboxy, (vii) _C1-4 alkoxy-carbonyl,
(viii) sulfone, (ix) halogen, (x) C _1-4 alkoxy,
(xi) phenoxy, (xii) halogenophenoxy, (xiii) C
_1-4 alkylthio, (xiv) mercapto, (xv) phenylthio, (xvi) pyridylthio, (xvii) C _1-4 alkylsulfinyl, (xviii) C _1-4 alkylsulfonyl, (xix) amino, (xx) C _{1 -3} alkanoylamino, (xxi) mono - or di -C _1-4 alkylamino, (xxii) 4 to 6 membered cyclic amino, (xxiii) C _1-3 alkanoyl, (xxiv) benzoyl and
(xxv) 1 to 5 selected from a 5- to 10-membered heterocyclic group
(II) C _7-16 aralkyl group (this group is (i) halogen, (ii) C _1-4 alkyl,
(iii) C _2-6 alkenyl, (iv) C _1-3 alkanoyl, (v) C
_1-4 alkoxy, (vi) nitro, (vii) cyano, (viii) hydroxy, (ix) C _1-4 alkoxy-carbonyl, (x) carbamoyl, (xi) mono- or di-C _1-4 alkyl- Carbonyl and (xii) mono- or di-C _2-4 alkenyl-carbonyl which may have 1 to 4 substituents], (III) C _6-14 aryl group [this group is (i) halogen, (ii) C _1-4 alkyl, (iii) C _1-4 halogenoalkyl, (iv) C _1-4 halogenoalkoxy, (v) C _1-4 alkoxy, (vi) C _1-4 Alkylthio, (vii) hydroxy, (viii)
Carboxy, (ix) cyano, (x) nitro, (xi) amino, (xi
i) mono- or di-C _1-4 alkylamino, (xiii) formyl, (xiv) mercapto, (xv) C _1-4 alkyl-carbonyl, (xvi) C _1-4 alkoxy-carbonyl, (xvii) sulfone 1 to 4 substituents selected from (xviii) C _1-4 alkylsulfonyl, (xix) carbamoyl, (xx) mono- or di-C _1-4 alkyl-carbamoyl, (xxi) oxo and (xxii) thioxo. Or (IV) 5
Or a 6-membered monocyclic heterocyclic group (as an atom constituting a ring system,
A heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (1 to 6 heteroatoms selected from oxygen, sulfur and nitrogen as atoms constituting a ring system) [These groups include (i) halogen, (ii) C _1-4 alkyl, (iii) C _1-4 halogenoalkyl, (iv) C _1-4 halogenoalkoxy, (v) C _1-4 Alkoxy, (vi) C _1-4 alkylthio, (vii) hydroxy, (viii)
Carboxy, (ix) cyano, (x) nitro, (xi) amino, (xi
i) mono- or di-C _1-4 alkylamino, (xiii) formyl, (xiv) mercapto, (xv) C _1-4 alkyl-carbonyl, (xvi) C _1-4 alkoxy-carbonyl, (xvii) sulfone 1 to 4 substituents selected from (xviii) C _1-4 alkylsulfonyl, (xix) carbamoyl, (xx) mono- or di-C _1-4 alkyl-carbamoyl, (xxi) oxo and (xxii) thioxo. (1) which may have a group
(18) The compound according to (1), wherein the ring Ga is ^a ring optionally having one or two substituents selected from oxo and C _1-6 alkyl.
0) described compound,

[0009] (19) Q ring is unsubstituted pyridine ring, R ¹
And R ³ are both hydrogen atoms, G ¹ is CH, G ² is N, g is 1, R is a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted. compound (20) wherein G ^a ring is an unsubstituted ring (19) the compound according (21) wherein a ¹ is a bond or C _1-6 alkylene group (19) compounds according, ( 22) the compound according to the above (19), wherein A ¹ is a bond; (23) the compound according to the above (19), wherein B is a C _1-6 alkylene group; and (24) the compound according to the above (19), wherein X is a bond. ) the compound according, (25) Q ring is unsubstituted pyridine ring, R ¹ and R ³ are both hydrogen atoms, a ¹ is a bond, G ¹ is CH, G ² is N, G ^a ring oxo and C _A ring which may have one or two substituents selected from _1-6 alkyl, g is 1, B is a C _1-6 alkylene group, X is a bond, and R is an optionally substituted Wherein a sulfonyl group (10) compounds according, (26) G ^a ring wherein an unsubstituted ring (25) compounds according, (27) R is halogen, hydroxy, C _1-4 alkyl,
C _1-4 halogenoalkyl, C _1-4 alkoxy and C _1-4 halogenoalkoxy the 1 to a phenyl group which may have a 3 substituents selected from (25) compounds according,

(28) The compound represented by the general formula (I) is

Embedded image R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ and R ^4a each represent a hydrogen atom or a substituted Or R ³ and A may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. Show. (29) The compound or a salt thereof according to the above (1), wherein the ring Q is an unsubstituted pyridine ring, and R ¹ and R ²
Is a hydrogen atom, R ³ is a hydrogen atom, C _1-15 alkyl,
C _3-8 cycloalkyl, C _2-18 alkenyl, C _7-16 aralkyl or C _6-14 aryl, wherein A is (i) a hydroxyl group,
C _1-15 alkylene _optionally having 1 to 3 substituents selected from oxo and phenyl, (ii) C
_2-16 alkenylene or (iii) phenylene, wherein the ring Q ₂ has the formula

Embedded image Wherein B ¹ represents ＣC, CH or N. A compound represented by the above (28), which is a group represented by the formula (30):

Embedded image R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon And R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ] Compounds represented by or a compound of (1), wherein the salt thereof, (31) Q ring is unsubstituted pyridine ring, R ¹ and R ²
Is a hydrogen atom, A ³ and B ² are each a bond, C
_1-15 alkylene, C _2-16 alkenylene or phenylene,

Embedded image Wherein A ⁵ represents ＝ C or CH. A compound represented by the above (30), which is a group represented by the formula: (32) a compound represented by the general formula (I)

Embedded image R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ and R ^4a each represent a hydrogen atom or a substituted Represents a good hydrocarbon group. And (33) the compound according to the above (1), wherein the ring Q is an unsubstituted pyridine ring, and R ¹ and R ²
Is a hydrogen atom, R ³ is a hydrogen atom, C _1-15 alkyl,
C _3-8 cycloalkyl, C _2-18 alkenyl, C _7-16 aralkyl or C _6-14 aryl, wherein A is (i) C _1-15 alkylene, (ii) C _2-16 alkenylene or (iii) Phenylene, and the ring Q ₅ is a group represented by the formula

Embedded image The compound according to (32), which is a group represented by

(34) (R) -N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4- (35) N- [1- (3-Phenylpropyl) piperidin-4-ylmethyl] -3- (5-thia-carboxyamide or the compound according to the above (1), which is a pharmacologically acceptable salt thereof. 1,8b-diazaacenaphthylene-4-yl) acrylamide or the compound according to the above (1), which is a pharmaceutically acceptable salt thereof; (36) N- [4- (4-phenylpiperidine- 1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide or the compound of the above (1), which is a pharmaceutically acceptable salt thereof; 37) N- [1- (3-phenylpropane 1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide or a compound of the above-mentioned (1), which is a pharmaceutically acceptable salt thereof, 38) General formula (II)

Embedded image [The symbols in the formula have the same meanings as described in the above (5). Or a salt thereof, and a compound represented by the general formula: R ³ —NH—AN (R ⁴ ) —BX—R wherein the symbols have the same meanings as described in the above (5). The method for producing a compound or a salt thereof according to the above (5), wherein the compound or a salt thereof is subjected to a condensation reaction,
(39) General formula (III)

Embedded image [In the formula, R ′ represents a COOH group which may be protected, a CH ₂ OH group which may be protected or a CHO group which may be protected, and other symbols are as defined in the above (4). Is shown. (40) a medicament comprising the compound of (1) or a salt thereof, (41) a low-density lipoprotein receptor enhancer (4)
(42) the medicament according to the above (40), which is a blood lipid lowering agent; (43) the medicament according to the above (40), which is an arteriosclerosis preventive / therapeutic agent; (45) The pharmaceutical according to (40), which is an agent for preventing or treating diabetes complications, and the like.

As used herein, the term "halogen atom" refers to, for example, fluorine, chlorine, bromine, iodine and the like. The term “hydrocarbon group” in the term “optionally substituted hydrocarbon group” as used herein refers to, for example, an alkyl group, an alkenyl group, an aralkyl group, an aryl group and the like. As the "alkyl group", for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
a "linear or branched _C1-15 alkyl group" such as c-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl, pentadecyl, and, for example, cyclopropyl And a “C _3-8 cycloalkyl group” such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of the substituent which the “linear or branched C _1-15 alkyl group” and “C _3-8 cycloalkyl group” may have include, for example, (i) nitro group, (ii) hydroxy 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) carboxy group, (vii) _C1-4 alkoxy −
Carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (viii) sulfone group, (ix) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
(X) a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), (xi) phenoxy group, (xii) halogenophenoxy group (eg, o
-, M- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc., (xiii) _C1-4 alkylthio group (for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and the like) ),
(Xiv) mercapto group, (xv) phenylthio group, (xvi)
Pyridylthio group, (xvii) C _1-4 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), (xviii) _C1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), (xi
x) amino group, (xx) C _1-3 alkanoylamino group (for example, acetylamino, propionylamino, etc.), (xx
i) a mono- or di-C _1-4 alkylamino group (for example,
(Xxii) 4- to 6-membered cyclic amino group (eg, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl), (xxiii) C _1-3 alkanoyl groups (eg, formyl, acetyl, etc.), (xxiv) benzoyl groups and (xxv) 5- to 10-membered heterocyclic groups (eg, 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 2H-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 (preferably 1 to 3) of these substituents at substitutable positions.

Preferred examples of the "alkyl group" include, for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like linear or branched C _1-6 alkyl groups, and even if the `` C _1-6 alkyl group '' has Good substituents include, for example, halogen atoms, C _1-4 alkoxy groups, hydroxy groups, C _1-4 alkoxy-carbonyl groups, carboxy groups, carbamoyl groups, mono- or di-C _1-4 alkylcarbamoyl as described above. Group,
One to three substituents such as a pyridylthio group are used. Examples of the “alkenyl group” include vinyl, allyl, isopropenyl, 3-butenyl, 3-octenyl,
A "C _2-18 alkenyl group" such as 9-octadecenyl is used. As the substituent that the “alkenyl group” may have, 1 to 3 substituents similar to the substituent that the “alkyl group” may have are used. Preferred examples of the “alkenyl group” include C _2-6 such as vinyl, allyl, 2-butenyl and 3-butenyl.
An alkenyl group and the like can be mentioned. As the "C _2-6 alkenyl group" substituent optionally have include to the same substituents as "C _{1 -6} alkyl group" substituents which may be possessed by 1 to 3 Used. As the “aralkyl group”, for example, a C _7-16 aralkyl group and the like are used. Specifically, for example, phenyl- such as benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and the like are used.
C _1-6 alkyl group and, for example, (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, naphthyl -C _1-6 alkyl group such as 2- (2-naphthyl) ethyl.

Examples of the substituent which the "aralkyl group" may have include (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), and (ii) a C _1-4 alkyl group (for example, , Methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) C _2-6 alkenyl group (eg, vinyl, allyl, 2-butenyl, 3-butenyl etc.), (iv) C _1-3 alkanoyl group (eg, , Formyl, acetyl, etc.), (v) C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), (vi) nitro group, (vii) cyano group, (viii)
A hydroxy group, (ix) a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl, etc.), (x) carbamoyl group, (xi) mono- or di-
A C _1-4 alkyl-carbamoyl group (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, etc.), (xii) mono- or di-C _2-4 alkenyl -Carbamoyl group (for example, N-vinylcarbamoyl and the like) and the like. The “aralkyl group” has 1 to 4 (preferably 1 to 3) of these substituents at a substitutable position. Is also good.

The "aryl group" includes, for example, an aromatic monocyclic, bicyclic or tricyclic C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, phenanthryl and anthryl. Are used. Preferably, a phenyl group or the like is widely used. The "aryl group"
Examples of the substituent which may have: (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); (ii) a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl) , Butyl, etc.), (iii)
A C _1-4 halogenoalkyl group (eg, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, etc.), (iv) a C _1-4 halogenoalkoxy group (eg, trifluoromethoxy, trichloromethoxy, ,
(V) C _1-4 alkoxy groups (for example, methoxy, ethoxy, propoxy,
(Vi) C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.) (vii) hydroxy group, (viii) carboxy group, (ix) cyano group, (x) Nitro group, (xi) amino group, (xii) mono- or di-C
_1-4 alkylamino groups (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xi
ii) formyl group, (xiv) mercapto group, (xv) C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, hexanoyl, etc.), (xvi) C _1-4 alkoxy-carbonyl group (eg, methoxy Carbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, etc.), (xvii) sulfone group, (xvii
i) a C _1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), (xix) carbamoyl group, (xx) a mono- or di-C _1-4 alkyl-carbamoyl group (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-
Diethylcarbamoyl, etc.), (xxi) oxo group, (xxi
i) a thioxo group and the like; the "aryl group" may have 1 to 4, preferably 1 or 2 of these substituents at substitutable positions. Examples of the aryl group having an oxo group include benzoquinonyl, naphthoquinolyl, and anthraquinonyl.

The term "acyl group" as used herein
For example, an acyl group derived from a carboxylic acid and the like are used, and for example, an alkoxy-carbonyl group, an alkyl-carbamoyl group, an alkanoyl group and the like are used. Examples of the `` alkoxy-carbonyl group '' include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, C _1-6 alkoxy-carbonyl groups such as neopentyloxycarbonyl and tert-pentyloxycarbonyl are used.
As the “alkyl-carbamoyl group”, for example, N-
Mono-C _1-6 -N-alkylcarbamoyl groups such as methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl and, for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, A di-C _1-6 -N, N-dialkyl-carbamoyl group such as N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, N-ethyl-N-methylcarbamoyl and a dialkyl moiety are formed together 4 To a 6-membered cyclic carbamoyl group (eg, 1-azetidinylcarbonyl, morpholinocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinocarbonyl, 1-piperazinylcarbonyl, 1-piperazinylcarbonyl, etc.)
Is used. Examples of the “alkanoyl group” include a formyl group and a C _1-9 alkyl-carbonyl group (for example,
C _1-10 alkanoyl groups such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and the like are used. The “acyl group” may further have 1 to 3 substituents that the “alkyl group” may have.

As used herein, the term "divalent hydrocarbon group" in the term "optionally substituted divalent hydrocarbon group"
Is an alkylene group having 1 to 15 carbon atoms (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, etc.) and an alkenylene group having 2 to 16 carbon atoms (eg, vinylene, propenylene , 1-butenylene, 2-
Butenylene, 1-pentenylene, 2-pentenylene, 3
A divalent chain hydrocarbon group such as 2 to 16 alkynylene groups (eg, ethinylene, propynylene, 1-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene, 3-pentynylene, etc.); Examples thereof include a phenylene group or a combination thereof. Among them, for example, a C _1-15 alkylene group (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene), C _2-16 Alkenylene groups (for example, vinylene, propenylene, 1-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, etc.) are widely used. The "divalent hydrocarbon group" is -CO-, -CON
(R ^4a ) — and —N (R ^4a ) — (R ^4a is a hydrogen atom or a hydrocarbon group which may be substituted). Examples of the substituent which the “divalent chain hydrocarbon group” may have include, for example, an alkyl group which may be substituted, an aralkyl group which may be substituted, and an aryl group which may be substituted. , A hydroxy group, an oxo group, an amino group, a halogen atom and the like. Among them, an alkyl group which may be substituted is preferable. The “alkyl group” of the “optionally substituted alkyl group”, the “aralkyl group” of the “optionally substituted aralkyl group”, and the “aryl group” of the “optionally substituted aryl group” Are the same as those described above. Examples of the substituent of “alkyl”, “aralkyl” and “aryl” as the substituent of the “divalent chain hydrocarbon group” include the “substituent” of the “optionally substituted hydrocarbon group”. Substituents described above are used, and the number of substituents is 1 to 4. The “phenylene group” may have a substituent. Examples of the substituent include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and (ii) C _1-4.
An alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), (iii) a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), (iv) a C _1-4 alkylthio group ( For example,
Methylthio, ethylthio, propylthio, isopropylthio, etc.), (v) hydroxy group, (vi) carboxy group, (vii) cyano group, (viii) nitro group, (ix) amino group, (x) mono- or di-C _1-4 alkylamino groups (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xi) formyl group, (xi
i) mercapto group, (xiii) C _1-4 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), (xiv) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) ), (Xv) sulfone group, (xvi) C
_1-4 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like),
(Xvii) a carbamoyl group and (xviii) a mono- or di-C _1-4 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-
1 to 4 selected from dimethylcarbamoyl, N, N-diethylcarbamoyl and the like are used.

As used herein, the term "heterocyclic group" of the term "optionally substituted heterocyclic group" includes, for example, 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like. A 5- or 6-membered monocyclic heterocyclic group or a bicyclic heterocyclic group containing 1 to 6 heteroatoms selected from oxygen, sulfur, nitrogen and the like is used. Among the “heterocyclic groups”, the monocyclic heterocyclic group is a 5- or 6-membered member containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as atoms (ring atoms) constituting a ring system. A monocyclic aromatic heterocyclic group or a saturated or unsaturated monocyclic non-aromatic heterocyclic group means, for example, thienyl (for example, 2-thienyl, 3
-Thienyl, etc.), furyl (e.g., 2-furyl, 3-
Furyl, pyranyl, 2H-pyrrolyl, pyrrolyl (eg, 2-pyrrolyl, 3-pyrrolyl, etc.), imidazolyl (eg, 2-imidazolyl, 4-imidazolyl, etc.), pyrazolyl (eg, 3-pyrazolyl, 4-pyrazolyl, etc.) ), Isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, etc.), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, etc.), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, etc.), pyridazinyl (eg, 3-pyridazinyl, 4-
And the like are used. Such a monocyclic heterocyclic group may be saturated or partially saturated, and examples of the saturated or partially saturated monocyclic heterocyclic group include pyrrolidinyl (for example, 2-pyrrolidinyl, 3-pyrrolidinyl and the like), Pyrrolinyl (for example, 2-pyrroline-
3-yl), imidazonyl (eg, 2-imidazolin-4-yl etc.), piperidyl (eg, 2-piperidyl, 3-piperidyl etc.), piperazinyl (eg, 2-piperazinyl etc.), morpholinyl (eg,
3-morpholinyl and the like are used.

Among the above "heterocyclic groups", the bicyclic heterocyclic group includes oxygen,
A bicyclic aromatic heterocyclic group containing 1 to 6 heteroatoms selected from sulfur and nitrogen, or a saturated or unsaturated
A condensed ring group of a cyclic non-aromatic heterocyclic group, for example, benzodioxanyl (for example, 1,4-benzodioxane-
2-yl), isobenzofuranyl (eg, 1-benzofuranyl), chromenyl (eg, 2H-chromen-3-yl), benzothienyl (eg, 2-
Benzothienyl, etc.), indolizinyl (for example, 2-
Indolizinyl, 3-indolizinyl, etc., isoindolyl (eg, 1-isoindolyl), 3H-indolyl (eg, 3H-indol-2-yl), indolyl (eg, 2-indolyl), 1
H-indazolyl (e.g., 1H-indazole-3-
Il), prinyl (for example, 8-purinyl),
Isoquinolyl (for example, 1-isoquinolyl, 3-isoquinolyl and the like), quinolyl (for example, 2-quinolyl, 3-
Quinolyl and the like, phthalazyl (for example, 1-phthalazyl and the like), naphthyridinyl (for example, 1,8-naphthyridin-2-yl and the like), quinoxalinyl (for example, 2-quinoxalinyl and the like), quinazolinyl (for example, 2-quinazolinyl and the like), Cinnolinyl (for example, 3-cinnolinyl and the like) and the like are used. Such a bicyclic heterocyclic group may be partially saturated. As the partially saturated bicyclic heterocyclic ring, for example, isochromanyl (for example, 3-
Isochromanyl), indolinyl (eg, 2-indolinyl), isoindolinyl (eg, 1-isoindolinyl), 1,2,3,4-tetrahydro-
2-quinolyl, 1,2,3,4-tetrahydro-3-isoquinolyl and the like are used. Examples of the substituent that the “heterocyclic group” may have include, for example, the same substituents as the aforementioned “aryl group” as the “optionally substituted hydrocarbon group” may have And the number of substituents is 1 to 4 (preferably 1 to 3). As the substituent of the term “optionally substituted hydroxyl group” used in the present specification, for example, (i) C _1-6 alkyl (for example, methyl, ethyl, propyl , isopropyl, butyl, tert- butyl, etc.), (ii) phenyl, (iii) C _7-10 aralkyl (e.g., benzyl etc.), (iv) formyl, (v) C _1-6 alkyl - carbonyl (e.g., methyl Carbonyl, ethylcarbonyl, etc.), (vi) phenyloxycarbonyl (eg, benzooxycarbonyl, etc.), (vii) C
_7-10 aralkyloxy-carbonyl (such as benzyloxycarbonyl), (viii) pyranyl, (ix) furanyl, (x) silyl and the like are used. Examples of the substituent which these may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.), phenyl, C _7-10 aralkyl (for example, benzyl etc.), nitro group, etc. are used, and the number of substituents is 1
Or about four.

Examples of the “substituent” of the ring Q include (i)
Nitro group, (ii) hydroxy group, (iii) cyano group, (i
v) carbamoyl group, (v) mono- or di-C _1-4 alkyl-carbamoyl group (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like), (Vi)
A carboxy group, (vii) a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
(Viii) sulfone group, (ix) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (x) C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy) , Isopropoxy, etc.), (xi) phenoxy group, naphthoxy group, benzyloxy group, (xii) halogenophenoxy group (for example, o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy and the like) ),
(Xiii) a C _1-4 alkylthio group (for example, methylthio,
Ethylthio, n-propylthio, isopropylthio, n
-Butylthio), (xiv) mercapto group, (xv) phenylthio group, (xvi) pyridylthio group, (xvii) C _1-4
Alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), phenylsulfinyl group, (xviii) C _1-4 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), phenylsulfonyl group, (xix) amino group, xx) a C _1-3 acylamino group (eg, acetylamino, propionylamino, etc.), (xxi) a mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (Xxii) C _1-4 alkyl group (for example, methyl, ethyl, propyl, isopropyl, etc.), (xxiii) C _1-4 halogenoalkyl group (for example, trifluoromethyl, trichloromethyl, 2,2,2-trifluoro Ethyl and the like are used. Ring Q may have one to three of these substituents at substitutable positions, but is preferably unsubstituted.

As used herein, the term “basic group”
As, for example, (i) as an atom (ring atom) constituting an optionally substituted amino group and / or a ring system,
A molecular weight of 1000 or less (preferably a hydrocarbon group having 1 to 10 (preferably 1 to 5) heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur at the terminal or in the chain); A group having a molecular weight of 300 or less), (ii)

Embedded image (Wherein each symbol has the same meaning as described above). As the "optionally substituted amino group",
For example, an N-monosubstituted amino group or an N, N-disubstituted amino group is used. The “N-monosubstituted amino group” means an amino group having one substituent, and examples of the substituent include, for example, an alkyl group as described above (particularly, a C _1-15 alkyl group, _3-8 cycloalkyl group, etc.), aryl group (particularly, C _6-14 aryl group), heterocyclic group (particularly, 5-6
Or a 6-membered monocyclic aromatic heterocycle, etc.), an aralkyl group (especially, a C _7-16 aralkyl group, etc.) and the like. The “N, N-disubstituted amino group” means an amino group having two substituents. One example of the substituent is the same as the substituent in the above “N-monosubstituted amino group”. Examples of the other examples include the above-mentioned alkyl groups (particularly, C _1-15 alkyl groups, C _3-8 cycloalkyl groups, etc.) and aryl groups (particularly, C _6-14 aryl groups). Aralkyl groups (especially _C7-16 aralkyl groups, etc.)
And the like. In some cases, two substituents may form a cyclic amino group together with a nitrogen atom. Examples of such a cyclic amino group include, for example, 1-azetidinyl,
1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, 1-piperazinyl and the above-mentioned alkyl group (particularly, C _1-15 alkyl group, C _3-8 cycloalkyl group and the like) at the 4-position, aryl group (for example, _6-14 ant - Le group etc.), an aralkyl group (e.g., a C _7-16 aralkyl group), 1-piperazinyl having like.
Examples of the “heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur as atoms (ring atoms) constituting a ring system” include, for example, (i) imidazolyl, 2H
-Pyrrolyl, pyrrolyl, pyrazolyl, isoxazolyl,
Frazanil, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyridyl,
5- or 6-membered heterocyclic groups such as pyrimidinyl, pyridazinyl, piperidinyl, pyrazinyl, thiomorpholinyl or morpholinyl and (ii) indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolidinyl, isoquinolyl,
Quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4
A bicyclic or tricyclic fused heterocyclic group such as aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl or isoindolinyl is used. 1 to 10 (preferably 1 to 5) heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur as atoms (ring atoms) constituting the ring system, As the “hydrocarbon group” of the “hydrocarbon group contained therein”, for example, those similar to the aforementioned “optionally substituted hydrocarbon group” can be used. The “basic group” may be directly bonded to Y ⁰ , or may be oxygen (—O—), nitrogen (—N
(R ³ ) —), carbonyl (—CO—), thiocarbonyl (—CS—), —S (O) _n — (n represents 0, 1 or 2) or a combination thereof, —CO—N (R ³⁾ -,
^{-CS-N (R 3) -} , - S (O) n -N (R 3) -, - COO
—, —CS—O— (wherein, R ³ represents a hydrogen atom or a hydrocarbon group which may be substituted) and the like, and may be bonded to Y ⁰ .

As the "hydrocarbon group" and "substituent" of the "optionally substituted hydrocarbon group" as R ³ , those described above for the "optionally substituted hydrocarbon group" can be mentioned. Used. As used herein, the term "alkyl" in the term "optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or aryl"
"Cycloalkyl", "alkenyl", "aralkyl"
And “aryl” and each “substituent” include the groups described above for the “optionally substituted hydrocarbon group”. As the ring formed by combining R ⁴ and A, for example, a heterocyclic group Q ₁ containing 1 to 4 optionally substituted nitrogen atoms is used. As the ring formed by combining R ⁴ and B, for example, a heterocyclic group Q ₂ containing 1 to 4 optionally substituted nitrogen atoms is used. As the ring formed by combining R ³ and A, for example, a heterocyclic group Q ₃ containing 1 to 4 optionally substituted nitrogen atoms is used. As the ring formed by combining R ⁴ and R ⁵ , for example, a heterocyclic group Q ₄ containing 1 to 4 optionally substituted nitrogen atoms is used. As the ring formed by combining R ⁴ and R, for example, a heterocyclic group Q ₅ containing 1 to 4 optionally substituted nitrogen atoms is used.

As the ring Q ₁ , for example,

Embedded image And the like are used. As the Q ₂ ring, for example,

Embedded image And the like are used.

[0024]

Embedded image And the like are used. As the Q ₅ ring, for example,

Embedded image And the like are used. Q ₁ ring, Q ₂ ring, Q
_The “substituent” which the _three rings, the Q ₄ ring and the Q ₅ ring may have is the above-mentioned “optionally substituted heterocyclic group”, respectively.
And the like as described with respect to the “substituent” of the above. The number of substituents is one to four. As the protecting group for the “COOH group which may be protected” as used herein, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl) , Tert-butyl, etc.), phenyl, trityl, silyl and the like. Examples of the substituent include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), a nitro group, and the like. The number of substituents is about 1 to 3. As the protecting group for the “optionally protected CH ₂ OH group” used in the present specification, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl) Butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl), formyl, C _1-6 alkyl-carbonyl (eg, acetyl, propionyl, butyryl, etc.), phenyloxycarbonyl (eg, benzooxy) Carbonyl), C _7-10 aralkyloxy-carbonyl (eg, benzyloxycarbonyl), pyranyl, furanyl, silyl and the like. Examples of these substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl,
Propyl, isopropyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl etc.), nitro group, etc., and the number of substituents is about 1 to 4. As the “optionally protected CHO group” used in the present specification, for example, CHO, di-C _1-6 alkyl acetal (eg, dimethyl acetal, diethyl acetal)
And acetal such as 1,3-dioxolene acetal.

The ring Q is preferably unsubstituted. R represents an optionally substituted C _6-14 aryl group, an optionally substituted C _7-16 aralkyl group or an optionally substituted heteroatom selected from oxygen, sulfur and nitrogen. Preferred are a bicyclic aromatic heterocyclic group containing two or a saturated or unsaturated bicyclic non-aromatic heterocyclic group. As the substituents that the “C _6-14 aryl group”, “bicyclic aromatic heterocyclic group” and “saturated or unsaturated bicyclic non-aromatic heterocyclic group” may have, "Hydrocarbon group" of the "optionally substituted hydrocarbon group"
And the like as described in “Substituents” of aryl as above, and one to five such substituents may be substituted at substitutable positions. The “C _7-16 aralkyl group”
Examples of the substituent include the groups described in the aralkyl "substituent" as the "hydrocarbon group" of the "optionally substituted hydrocarbon group". One to four substitutions may be made at possible positions. X is preferably a bond, an oxygen atom or a sulfur atom. Y is a bond or

Embedded image Is preferred. R ¹ is preferably a hydrogen atom, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) or a phenyl group, and R ² and R ³ are preferably hydrogen atoms. R ⁴ is a C _1-10 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) or R ⁴ and A, R ⁴ and B, or R ³ and R ⁴ form a ring together with an adjacent nitrogen atom It is preferable that
As the ring to be formed, pyrrolidine, piperidine, piperazine and the like are preferable. A and B are each a C _1-10 alkylene group (eg, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene, octamethylene) or a C _2-8 alkenylene group (eg, vinylene, propenylene, etc.) Is preferred. 5-thia-1,8b-diazaacenaphthylene skeleton 3
The bond between the positions 4 and 4 is preferably a double bond.

The compound of the present invention has the formula (I'c)

Embedded image [The symbols in the formula are as defined above. Or a salt thereof is particularly preferred. In the formula (I′c), the ring Q is an unsubstituted pyridine ring, R ¹ and R ³ are both hydrogen atoms,
G ¹ is CH, G ² is N, g is 1, R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group (as defined above), and other symbols are as defined above. Is preferred. Further, at this time, for example, G ^a ring unsubstituted ring, A ¹ is a bond or C _1-6 alkylene (e.g., methylene, ethylene, propylene, butylene, etc. pentamethylene); more preferably A ¹ is a bond , B is a C _1-6 alkylene (eg, methylene, ethylene, propylene, butylene, pentamethylene, etc.), and X is particularly preferably a bond. In the formula (I′c), the ring Q is an unsubstituted pyridine ring, R ¹ and R ³ are both hydrogen atoms, A ¹ is a bond,
G ¹ is CH, G ² is N, B is C _1-6 alkylene (for example,
Methylene, ethylene, propylene, butylene, pentamethylene, etc.), X is a bond, R is a phenyl group which may be substituted (the substituent of the phenyl group may be the aryl group of the hydrocarbon group) Is the same as the substituent). Moreover this time, G ^a ring unsubstituted ring, R is a halogen atom (e.g., fluorine, chlorine, bromine, iodine), hydroxy group, C _1-4 alkyl group (e.g., methyl, ethyl, propyl, isopropyl,
Butyl, etc.), C _1-4 halogenoalkyl group (eg, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, etc.), C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy) And C _1-4 halogenoalkoxy groups (eg, trifluoromethoxy, trichloromethoxy, 2,2,2-
Particularly preferred is a phenyl group substituted with one to three substituents selected from trifluoroethoxy and the like.

The salt of the compound (I) of the present invention is particularly preferably 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 compound (I) of the present invention has an acidic group such as carboxylic acid, compound (I)
Is, for example, an inorganic base (eg, sodium, potassium,
Even if it forms a physiologically acceptable salt with an alkali metal or alkaline earth metal such as calcium or magnesium, or ammonia, or an organic base (eg, tri-C _1-3 alkylamine such as triethylamine). Good. In addition, the same salt as described above is used for the starting compound of the target compound (I), but is not particularly limited as long as the reaction is not hindered. Compound (I) may have a double bond in the molecule, but when two kinds of stereoisomers of Z or E exist, each of them or a mixture thereof is included in the present invention. Compound (I) is
With respect to the oxo group, each of its enol and keto forms or a mixture thereof is included in the present invention. Compound (I) may have an asymmetric carbon in the molecule.
When two kinds of stereoisomers of the coordination or S coordination exist, each of them or a mixture thereof is included in the present invention.

Specific examples of the compound (I) of the present invention and salts thereof are shown below. N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- ( 3- (2-fluorophenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (2-fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (4-fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3-fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3- (2-chlorophenyl) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3- (2-chlorophenyl) propane-1
-Yl) piperidin-4-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (2-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (4-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [2- (1- (2-chlorophenethyl) piperidin-4-yl) ethane-1-yl ] -5-Thia-1,8b-
Diazaacenaphthylene-4-carboxamide and its acid addition salt N- (1-phenethylpiperidin-4-ylmethyl)-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1, 8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- (1-phenethylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition N- [4- (4-benzylpiperidin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [4- (4-Phenylpiperidin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (1,4-benzo) Dioxan-2-ylmethyl Piperidin-4-ylmethyl] -5-thia -1,8b
-Diazaacenaphthylene-4-carboxamide and acid addition salts thereof (S) -N- [1- (1,4-benzodioxane-2-
Ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt (R) -N- [1- (1,4-benzodioxane-2-
Ilmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide and its acid addition salt N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl ] -3- (5-Thia-1,8b-diazaacenaphthylene-4-yl) acrylamide and acid addition salts thereof N- (1-phenethylpiperidin-4-yl) -3-
(5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide and its acid addition salt N- (1-phenethylpiperidin-4-ylmethyl)-
3- (5-thia-1,8b-diazaacenaphthylene-4-
Il) Acrylamide and acid addition salts thereof The compound (I) of the present invention can be synthesized, for example, by the following method.

Embedded image Wherein E ¹ is halogen (eg, chlorine) or R ² C
OO- (R ² has the same meaning as described above), and other symbols have the same meanings as above. ]

The compound (I ') of the present invention can be synthesized, for example, by the following method. (A) method:

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 (B): Z = CON (R ³ )

Embedded image [The symbols in the formula are as defined above. Method (C): Z = CON (R ³ )

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

Method (D): Z = CON (R ³ )

Embedded image Wherein, E ^a及E ^b is a group capable of leaving by both react, for example, when one is a hydrogen atom and the other is halogen (e.g., chlorine, bromine, iodine), methanesulfonyloxy, p- toluene It represents sulfonyloxy, and other symbols have the same meanings as described above. Method (E): Z = CON (R ³ )

Embedded image [The symbols in the formula are as defined above. Method (F): Z = COO

Embedded image [The symbols in the formula are as defined above. In the synthesis of compound (I), compound (II ') and R ² -C
Reaction with O-E ^1, the compound (II ') 1 Compound R ² -CO-E ¹ 1 to large excess per equivalent, preferably 1 to 1
Use 0 equivalents. At this time, potassium carbonate, inorganic bases such as sodium hydrogen carbonate, triethylamine, pyridine,
Dimethylaniline, 1,4-diazabicyclo [2.2.
2] 1 to 10 equivalents of an organic base such as octane (DABCO) may be used. Reaction temperature is -30 to +100
C., preferably at +25 to 80.degree. Examples of the solvent used at this time include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), and esters (eg, methyl acetate, ethyl acetate, etc.). And aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.). The reaction time is generally 10 minutes to 24 hours, preferably 1 to 6 hours.

The ring closure reaction proceeds by heating the acyl compound to 100 to 150 ° C. without a solvent. Alternatively, inorganic salts (eg, sodium hydride, lithium diisopropylamide, potassium carbonate, sodium hydrogen carbonate, etc.) or organic bases (eg, 4-N, N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline, 1,4-diazabicyclo) [2.2.2] octane, etc.)
Can be carried out using 1 to 10 equivalents. The reaction temperature can be from 0 to 150 ° C. As the solvent used at this time, for example, hydrogen halides (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.) ,
Aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.); The reaction time is generally 10 minutes to 24 hours, preferably 1 hour to 6 hours. The reduction of the double bond is carried out by using 1 equivalent to a large excess of the reducing agent, preferably
Use 10 equivalents. Examples of the reducing agent include metal hydride complex compounds such as diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride, and diborane. The solvent used at this time can be appropriately selected depending on the type of the reducing agent, for example, alcohols (eg, methanol, ethanol, etc.), ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, , Methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.) and the like. The reaction time is 0.
It is 5 to 72 hours, preferably 1 to 24 hours. The reaction can be carried out at -80 to + 100 ° C, preferably at -80 to + 30 ° C.

In the synthesis of the compound (I '), the reaction of the compound (V) with the compound (IV) in Method A is carried out in an amount of 1 equivalent to a large excess (1 to 10 equivalents) of the compound (IV) with respect to the compound (V). )use. A basic compound such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo [5.4.0] -7-undecene may be used in an amount of 1 to 10 equivalents. Good. Reaction is from -20 to +
It can be performed at 200 ° C. Examples of the solvent used at this time include water, lower alcohols (eg, methanol, ethanol, propanol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, tetrahydrofuran, etc.), aprotic polar Solvent (eg,
N, N-dimethylformamide, dimethylsulfoxide and the like). In the reaction, 1 equivalent to a large excess (1 to 10 equivalents) of sodium iodide may be added as a reaction accelerator. The reaction time is usually from 10 minutes to 2 minutes.
4 hours, preferably 0.5 to 6 hours.

The dehydration-condensation reaction between compound (II) and compound (VI) in method B is advantageously carried out by a usual amide bond formation reaction. In the present amide bond forming reaction, the reaction can be advantageously performed by using the amide forming reagent alone.
Examples of such amide-forming reagents include 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, dicyclohexylcarbodiimide, 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide
Meso-p-toluenesulfonate, N, N'-carbonyldiimidazole, diphenylphosphoramide, diethyl cyanophosphate, 1-ethyl-3- (3-diethylaminopropyl) carbodiimide hydrochloride and the like are used. The amount of the amide forming reagent to be used is generally 1 equivalent to 3 equivalents relative to 1 equivalent of compound (II). In addition, the amide bond forming reaction is performed by, for example, phenols such as 2,4,5-trichlorophenol, pentachlorophenol, pentafluorophenol, 2-nitrophenol, and 4-nitrophenol, for example, N-hydroxysuccinimide, 1-hydroxybenz Triazole, N-hydroxypiperidine, N-hydroxy-5-norbornene-
An N-hydroxy compound such as 2,3-dicarbodiimide and, for example, dicyclohexylcarbodiimide are added, and the compound (II) is condensed to be converted into an active ester form, which is then advantageously reacted with the compound (VI). be able to. The amount of the phenol or N-hydroxy compound to be used is generally 1 equivalent to 3 equivalents relative to 1 equivalent of compound (II). The amount of dicyclohexylcarbodiimide to be used is generally 1 equivalent to 3 equivalents relative to 1 equivalent of compound (II). In the present amide bond formation reaction, the compound (II) is reacted with an acid chloride such as ethyl chlorocarbonate, isobutyl chlorocarbonate or benzyl chlorocarbonate to be converted into a mixed acid anhydride, and then reacted with the compound (VI). This can also advantageously proceed. Also, oxalyl chloride,
Reaction with an acid chloride such as thionyl chloride, conversion to acid chloride, and then reaction with compound (VI) can also advantageously proceed the reaction. The amount of the acid chloride to be used is generally 1 equivalent to 3 equivalents relative to 1 equivalent of compound (II). In the present amide and ester bond formation reaction, compound (VI) is generally used in an amount of 1 equivalent to 3 equivalents per 1 equivalent of compound (II).
It is better to react in an equivalent amount. This reaction can be promoted by adding an organic base, for example, a tertiary amine (eg, triethylamine, pyridine, dimethylpyridine, N-methylpiperidine, etc.), if necessary. The amount of such a reaction accelerator to be used is generally 1 equivalent to a large excess (preferably 1 equivalent to 10 equivalents) per 1 equivalent of compound (II). The reaction is usually -30 ° C to +5
It is performed in a temperature range of 0 ° C. This reaction can be performed without a solvent or in the presence of a solvent. The solvent used is
There is no particular limitation as long as the reaction is not hindered. For example, ether, toluene, benzene, chloroform, methylene chloride, dioxane, tetrahydrofuran and the like are used. The reaction time is generally 10 minutes to 48 hours, preferably 1 hour to 24 hours.

Compound (VII) and compound (VII) in Method C
The reaction with I) can be performed, for example, under the same conditions as the reaction conditions of compound (V) and compound (IV) in Method A. The reaction between the compound (IX) and the compound (X) in Method D can be performed, for example, under the same conditions as the reaction conditions for the compound (V) and the compound (IV) in Method A. The reaction between compound (XI) and compound (XII) in Method E can be carried out, for example, under the same conditions as the reaction conditions for compound (V) and compound (IV) in Method A. In the method F, the dehydration condensation reaction between the compound (II) and the compound (XIII) is carried out, for example, using B
The reaction can be carried out under the same conditions as the reaction conditions of compound (II) and compound (VI) in the method. Compound (II ′) can be synthesized, for example, by the following method or the like.

Embedded image [The symbols in the formula are as defined above. The reaction of compound (XIV) with E-CH ₂ —R ⁰
The reaction can be carried out under the same conditions as the reaction conditions of compound (V) and compound (IV) in the method. Compound (V) can be synthesized, for example, by the following method or the like.

I) When Z = CON (R ³ )

Embedded image [Wherein, P represents hydrogen or a protecting group for an amino group, and other symbols have the same meanings as described above. The reaction between compound (II) and compound (XV) can be carried out, for example, under the same conditions as the reaction conditions for compound (II) and compound (VI) in Method B. When P is an amino-protecting group, compound (V ') can be synthesized by removing the protecting group after the condensation reaction. The removal of the protecting group for the amino group is a reaction known per se, and can be performed according to those conditions.

Ii) Z is CO, -S (O) n- (n = 0,1,
2), -SO ₂ N (R ³ )-;

Embedded image [Wherein R ⁶ is C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, etc.), C _6-14 aryl (eg, phenyl, etc.) or C _7-16 aralkyl (eg, benzyl, etc.) And R ⁷ has the same meaning as the “protecting group” of the “COOH group which may be protected”, and other symbols have the same meanings as above. In the reduction reaction of compound (V "), the reducing agent is used in an amount of 1 equivalent to a large excess, preferably 2 to 10 equivalents, relative to compound (V"). Examples of the reducing agent include metal hydride complex compounds such as diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride, and diborane. The solvent used at this time can be appropriately selected depending on the type of the reducing agent, for example, alcohols (eg, methanol, ethanol, etc.),
Ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.), etc. Can be The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. The reaction can be carried out at -80 to + 100 ° C, preferably at -80 to + 30 ° C. In the oxidation reaction of the obtained alcohol compound to the aldehyde compound, for example, 1 to 20 equivalents of an oxidizing agent is used for 1 equivalent of the alcohol compound. Such oxidizing agents include activated manganese dioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), dimethyl sulfoxide-anhydride (acetic anhydride, trifluoroacetic anhydride, etc.), dimethyl sulfoxide-thionyl chloride, dimethyl Sulfoxide-sulfuryl chloride, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-chlorine, and dimethylsulfoxide-dicyclohexylcarbodiimide (DCC) in the presence of an acid (phosphoric acid, trifluoroacetic acid, dichloroacetic acid, etc.).
The solvent used at this time can be appropriately selected depending on the type of the oxidizing agent, for example, ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.),
Examples include ketones (eg, acetone, methyl ethyl ketone, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.). The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
Time. The reaction is appropriately selected depending on the type of the oxidizing agent,
It can be carried out at -80 to + 100 ° C, preferably at -70 to + 30 ° C.

The reaction of the obtained aldehyde compound with the compound (XVI) is generally advantageously carried out in a solvent. As the solvent used, for example, methylene chloride, halogenated hydrocarbons such as chloroform, for example, tetrahydrofuran, dimethoxyethane, ethers such as dioxane,
For example, benzene, aromatic hydrocarbons such as toluene, alcohols such as methanol, ethanol, propanol, and the like, aprotic polar solvents such as amides such as N, N-dimethylformamide, and sulfoxides such as dimethyl sulfoxide, And a mixed solvent thereof, and other solvents that do not adversely affect the reaction. The compound (XVI) is preferably reacted in an amount of usually 1 to 3 equivalents to 1 equivalent of the aldehyde compound. Also, 1 to 10 equivalents of a basic compound such as sodium hydride,
Preferably, 1 or 2 equivalents are reacted. The reaction is usually carried out at 0 ° C. to the boiling point of the solvent, preferably at 0 to +
It is performed in a temperature range of 80 ° C. The reaction time is usually 0.5
For about 24 hours, preferably 0.5 to 10 hours. Compound (II) can be synthesized, for example, by the following method or the like.

Embedded image [Wherein, R ⁷ represents a protecting group for a carboxy group, and other symbols have the same meanings as described above. ]

Compound (III) can be produced in the same manner as compound (II). Compound (III), (III-a)
Wherein R ′ is an optionally protected CH ₂ OH group or an optionally protected CHO group,
Is a carboxy group, for example, by subjecting the compound to a reduction reaction known per se. The hydrolysis of compound (XVII) can be performed by treating compound (XVII) with an acid or a base. That is, compound (XVII) is converted to an acid (eg, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid,
Water or lower alcohols (eg, methanol, ethanol, etc.) or bases (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.)
The reaction can be carried out in a solution at 0 to + 100 ° C., preferably +10 to 50 ° C., for 0.5 to 50 hours, preferably for 1 to 5 hours. The strength of the acid or base is 1 to 1
0 is preferred, preferably 2 to 5. Compound (VII) can be synthesized, for example, by the following method or the like.

Embedded image [The symbols in the formula are as defined above. The reaction between compound (II) and compound (XVIII)
The reaction can be carried out under the same conditions as the reaction conditions of compound (II) and compound (VI) in the method. For example, when E is a halogen, the conversion of the hydroxyl group to E is carried out with respect to one equivalent of the alcohol compound, such as phosphorus halides such as phosphorus trichloride, phosphorus oxychloride, and phosphorus pentachloride, and red phosphorus and halogen such as halogen or thionyl chloride. The reaction is carried out by reacting 1 to 10 equivalents, preferably 2 to 5 equivalents of the agent. E
Is a toluenesulfonyloxy group or a methanesulfonyloxy group, the reaction is carried out by reacting 1 to 10 equivalents, preferably 2 to 5 equivalents of toluenesulfonyl chloride or methanesulfonyl chloride with respect to 1 equivalent of the alcohol compound. At this time, inorganic bases such as potassium carbonate and sodium hydrogen carbonate, 4-N, N-
Dimethylaminopyridine, triethylamine, pyridine, dimethylaniline, 1,4-diazabicyclo [2.
2.2] Organic bases such as octane (DABCO)
You may use 10 to 10 equivalents. Examples of the solvent used at this time include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.). ), Aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.). The reaction is carried out at 0 to + 100 ° C, preferably 0 to +
It can be performed at 50 ° C. The reaction time is generally 10 minutes to 100 hours, preferably 3 to 24 hours.
Compound (IX) can be synthesized, for example, by the following method or the like.

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

The conversion reaction from compound (II) to compound (IX) can be carried out, for example, under the same conditions as the conversion reaction from compound (II) to compound (VII). Compound (XI)
Can be synthesized, for example, by the following method.

Embedded image [The symbols in the formula are as defined above. The conversion reaction from compound (II) to compound (XI) can be performed, for example, under the same conditions as the reaction conditions for the conversion reaction from compound (II) to compound (V ′). Compound (XVII) can be synthesized, for example, by the following method or the like.

I) When Y is a bond and R ² is hydrogen

Embedded image [The symbols in the formula are as defined above. The conversion of the compound (XXI) to the compound (XVII) is carried out by converting the compound (X
XI) 1 to 50 equivalents of a formylating agent per 1 equivalent,
Preferably, 1 to 10 equivalents are used. Examples of such a formylating agent include N, N-dimethylformamide-phosphorus oxychloride (Vilsmier reagent). in this case,
The ring closure reaction can proceed under the conditions of formylation. Examples of the solvent used at this time include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), and 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 can be carried out at -20 to + 150 ° C, preferably at +80 to 120 ° C. In the formylation reaction of compound (XXI), for example, 1 to 3 equivalents of a base such as sodium hydride, potassium hydride, lithium diisopropylamide is reacted with 1 equivalent of compound (XXI), and then the formamides ( For example, N, N-dimethylformamide,
N, N-methylformanilide or the like) or formate esters (eg, methyl formate, ethyl formate, etc.) may be reacted in an amount of 1 to 10 equivalents, preferably 2 to 5 equivalents. 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 and the like). The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. Reaction is -10
It can be carried out at 0 to + 50 ° C (preferably -80 to + 30 ° C). In this case, the resulting formyl compound is further treated with 1 to large excess, preferably 1 to 50 equivalents of an acid such as acetic acid, at 0 to + 150 ° C., preferably +80 to 130 ° C., for 1 to 24 hours, preferably 10 to 20 hours. The ring-closing reaction proceeds by the treatment,
Compound (XVII) can be obtained. As the solvent used at this time, 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, dimethylsulfoxide, etc.), etc. Is mentioned.

Ii) When Y is a bond and R ² is a hydrocarbon group which may be substituted

Embedded image (The symbols in the formulas have the same meanings as described above.) The reaction of the compound (XXI) with the compound R ² CO-E ¹ is such that the compound R ² —CO-E ¹ is converted into 1 to 1 equivalents of the compound (XXI). A large excess is used, preferably 1 to 10 equivalents. On this occasion,
Inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, pyridine, dimethylaniline, 1,4
-Diazabicyclo [2.2.2] octane (DABCO)
Such an organic base may be used in an amount of 1 to 10 equivalents. The reaction is from -30 to + 100 ° C, preferably +25 to 80 ° C
Can be done with The solvent used at this time,
For example, halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.). The reaction time is generally 10 minutes to 24 hours, preferably 1 minute.
Or 6 hours. The ring closure reaction proceeds by heating the acyl form to +100 to 150 ° C. without a solvent. Alternatively, inorganic salts (eg, sodium hydride, lithium diisopropylamide, potassium carbonate, sodium hydrogen carbonate, etc.) or organic bases (eg, 4-N, N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline, 1,4-diazabicyclo) [2.2.2] octane, etc.) in an amount of 1 to 10 equivalents. The reaction can be performed at 0 to + 150 ° C. As the solvent used at this time, for example, hydrogen halides (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.) And aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, etc.). The reaction time is generally 10 minutes to 24 hours, preferably 1 hour to 6 hours.

Iii) Y is

Embedded image [The symbols in the formula are as defined above. In the reduction reaction of compound (V "), the reducing agent is used in an amount of 1 equivalent to a large excess, preferably 2 to 10 equivalents, relative to compound (V"). Examples of the reducing agent include metal hydride complex compounds such as diisobutylaluminum hydride, sodium borohydride, sodium cyanoborohydride and lithium aluminum hydride, and diborane. The solvent used at this time can be appropriately selected depending on the type of the reducing agent, for example, alcohols (eg, methanol, ethanol, etc.),
Ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, etc.), etc. Can be The reaction time is 0.5 to 72 hours, preferably 1 to 24 hours. The reaction can be carried out at -80 to + 100 ° C, preferably at -80 to + 30 ° C. In the oxidation reaction of the obtained alcohol compound to the aldehyde compound, for example, 1 to 20 equivalents of an oxidizing agent is used for 1 equivalent of the alcohol compound. Examples of such an oxidizing agent include activated manganese dioxide, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), dimethyl sulfoxide-acid anhydride (eg, acetic anhydride, trifluoroacetic anhydride and the like), dimethyl sulfoxide-thionyl chloride. Dimethylsulfoxide-sulfuryl chloride, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-chlorine, and acids (eg, phosphoric acid, trifluoroacetic acid,
Dimethylsulfoxide-dicyclohexylcarbodiimide (DCC) in the presence of dichloroacetic acid and the like. The solvent used at this time can be appropriately selected depending on the type of the oxidizing agent, and examples thereof include ethers (eg, tetrahydrofuran, dioxane, diethyl ether, etc.), halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ketones (Eg, acetone, methyl ethyl ketone, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, etc.). The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours. The reaction temperature is appropriately selected depending on the type of the oxidizing agent, and is -80 to + 100 ° C, preferably -70.
To + 30 ° C.

The reaction of the obtained aldehyde compound with a Wittig reagent such as phosphonate ylide or alkylidenephosphorane is generally advantageously carried out in a solvent. As the solvent used, for example, halogenated hydrocarbons (eg, methylene chloride, chloroform, etc.), ethers (eg, tetrahydrofuran, dimethoxyethane, dioxane, etc.), aromatic hydrocarbons (eg, benzene, toluene, etc.) , Alcohols (eg, methanol, ethanol, propanol, etc.), amides (eg, N, N-dimethylformamide, etc.), aprotic polar solvents (eg, sulfoxides such as dimethyl sulfoxide, etc.) and mixed solvents thereof, Other solvents that do not adversely affect the reaction are used. The Wittig reagent is preferably reacted in an amount of usually 1 to 3 equivalents to 1 equivalent of the aldehyde compound. The reaction is usually carried out at 0 ° C. to the boiling point of the solvent, preferably at 0 to 80 ° C.
It is performed in a temperature range of ° C. The reaction time is usually 1 to 2
It is about 4 hours, preferably 0.5 to 10 hours.
Compound (XXI) can be synthesized, for example, by the method shown below.

Embedded image [The symbols in the formula are as defined above. The reaction between compound (XIV) and E-CH ₂ COOR ⁷ can be performed, for example, under the same conditions as the reaction conditions for compound (V) and compound (IV) in Method A.

The compound (III-a) or a salt thereof, which is a useful intermediate for producing the target compound (I) or a salt thereof of the present invention, comprises:
For example, it can be manufactured using the method described below.

Embedded image [The symbols in the formula are as defined above. In the above reaction, hexamethylenetetramine is used in an amount of 1 to large excess, preferably 1 to 10 equivalents, relative to compound (XXI-a) or a salt thereof. 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, etc.), preferably acetic acid, boric acid, etc. I do. 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 about 0 ° C to 200 ° C, preferably about 50 ° C to 15 ° C.
0 ° C. Examples of the solvent used at this time include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), and esters (eg, methyl acetate, ethyl acetate, etc.). , Protic solvents (eg, methanol, ethanol, etc.), aprotic polar solvents (eg,
Acetonitrile, etc.). 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.

[0046]

Embedded image [The symbols in the formula are as defined above. In the above reaction, hexamethylenetetramine is used in an amount of 1 to large excess, preferably 1 to 10 equivalents, relative to compound (XIV-a) or a salt thereof. 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, etc.), preferably acetic acid, boric acid, etc. I do. 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 about 0 ° C to 200 ° C, preferably about 50 ° C to 15 ° C.
0 ° C. Examples of the solvent used at this time include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), and esters (eg, methyl acetate, ethyl acetate, etc.). , Protic solvents (eg, methanol, ethanol, etc.), aprotic polar solvents (eg,
Acetonitrile, etc.). 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. Further, the compound (XI
Against V-b) or salts thereof of the general formula: HS-CH ₂ -Y
-R 'or a salt thereof (the symbols in the formula are as defined above.
Preferably thioglycolic acid ethyl ester)
It is used in a large excess, preferably 1 to 10 equivalents.
As the base used at this time, for example, an inorganic base (eg,
Potassium carbonate, sodium carbonate, etc.), organic bases (eg, triethylamine, pyridine, dimethylamine, 1,8-
Diazabicyclo [5.4.0] -7-undecene, etc.),
Alcoholates (e.g., sodium methylate, sodium ethylate, potassium tert-butoxide),
Organic metal reagents (eg, n-butyllithium, etc.), sodium hydride, sodium amide and the like can be mentioned. The amount of the base used is 1 to a large excess, preferably 1 to 5 equivalents. The reaction temperature is about 0 ° C to 200 ° C, preferably about 25 ° C to 100 ° C. Examples of the solvent used include halogenated hydrocarbons (eg, methylene chloride,
Chloroform, dichloroethane, etc.), ethers (eg,
Diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), protic solvents (eg, acetic acid, methanol, ethanol, etc.), aprotic polar solvents (eg, N, N-dimethylformamide,
Dimethyl sulfoxide, acetonitrile, etc.). The reaction time is generally 10 minutes to 24 hours, preferably 1 to 10 hours. Compound (XXI-a) or a salt thereof can be produced in the same manner as in the method for producing compound (XXI) or a salt thereof. Compound (XIV-a) or a salt thereof can be produced by a method known per se or in the same manner as in the production of compound (XIV) or a salt thereof.

The production intermediate (A) of the present invention or a salt thereof is
For example, it can be manufactured using the method described below.

Embedded image [Wherein, R ¹⁰ is a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group;
al is a halogen atom; R ¹¹ is an optionally substituted alkyl group; other symbols are as defined above. ] R ¹⁰ is as defined for the R ^1. R ¹¹ is COOR ¹⁵ (R
¹⁵ represents a lower alkyl group. And the like. A C _1-6 alkyl group which may be substituted with a) is preferable.

In the above reaction for synthesizing the compound (A) or a salt thereof, the compound (C) or a salt thereof has a general formula: HS-R ¹¹ (R ¹¹ has the same meaning as described above). (Preferably ethyl thioglycolate) in 1 to excess, preferably 1 to
Use up to 5 equivalents. This reaction is carried out in the presence or absence of a base, preferably in the presence of a base. Examples of the base used at this time include inorganic bases (eg, potassium carbonate, sodium carbonate, etc.) and organic bases (eg, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene. ), Alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxy), organometallic reagents (eg,
n-butyllithium, etc.), sodium hydride, sodium amide and the like. The "base" is used in an amount of 1 to excess, preferably 1 to 5 equivalents. The reaction temperature is 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
° C. Examples of the solvent used in this reaction include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), and esters (eg, methyl acetate, ethyl acetate, etc.). And aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, toluene, etc.). The reaction time is usually from 10 minutes to 24 hours,
Preferably, it is 1 to 10 hours. In this reaction, Hal is preferably fluorine from the viewpoint of the reaction yield.

Compound (C) or a salt thereof is compound (E)
Alternatively, the compound can be produced by reacting the salt thereof with the compound (H) or a salt thereof, for example, by the following production method.

Embedded image [In the formula, R ¹² is a hydrogen atom or an amino-protecting group; other symbols are as defined above. In the above-mentioned reaction for synthesizing the compound (C) or a salt thereof, the compound (E) or a salt thereof has a general formula:

Embedded image (The symbols in the formula have the same meanings as described above), preferably 1 to large excess, preferably 1 to 5 equivalents of chloroacetaldehyde and the like. The reaction temperature is 0 ° C to 150 ° C, preferably 25 ° C to 8 ° C.
0 ° C. As the solvent to be used, for example, protic solvents (eg, water, methanol, ethanol, n-butanol, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.) and the like Is mentioned. The reaction time is usually 1
0 minutes to 10 hours, preferably 1 to 4 hours.

Compound (A) or a salt thereof is prepared by reacting compound (D)
Alternatively, it can be produced by the following production method by reacting the salt thereof with the compound (H) or a salt thereof.

Embedded image [The symbols in the formula are as defined above. In the above reaction, the compound (D) or a salt thereof has a general formula:

Embedded image (The symbols in the formula have the same meanings as described above.) 1 to a large excess, preferably 1 to 5 equivalents. The reaction temperature is 0 ° C to 150 ° C, preferably 25 ° C to 80 ° C. As the solvent used,
For example, protic solvents (eg, water, methanol, ethanol, n-butanol, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.) and the like can be mentioned. The reaction time is generally 10 minutes to 10 hours, preferably 1 to 4 hours. Compound (D) or a salt thereof can be produced from compound (F) or a salt thereof by the following reaction.

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

In this reaction, the compound: R ¹² NH ₂ (R ¹² is as defined above) is used in 1 to a large excess, preferably 1 to 10 equivalents, relative to the compound (F) or a salt thereof. I do. R ¹² NH ₂ is preferably ammonia, formamide or the like. As the solvent to be used, no solvent or a protic solvent (eg, water, methanol, ethanol, n-butanol, etc.), an aprotic polar solvent (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.) And so on. The reaction temperature is 1 to 250 ° C, preferably 100 to 18 ° C.
Perform at 0 ° C. The pressure in the reaction vessel is from normal pressure to 50 kgcm
⁻² , preferably from normal pressure to 20 kgcm ⁻² . The reaction time is 10 minutes to 24 hours, preferably 1 to 8 hours. Compound (D) or a salt thereof is produced by reacting compound (E) or a salt thereof with compound: R ¹¹ -SH (R ¹¹ has the same meaning as described above), for example, by the following production method. Can be.

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

In this reaction, a compound: R ¹¹ -SH (R ¹¹ has the same meaning as described above), preferably ethyl thioglycolate or the like is added to compound (E) or a salt thereof in an amount of 1 to excess. Preferably, 1 to 5 equivalents are used. The reaction is carried out in the presence or absence of a base, preferably in the presence of a base. As the base used at this time,
For example, inorganic bases (eg, potassium carbonate, sodium carbonate, etc.), organic bases (eg, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0]-)
7-undecene, etc.), alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxy), organometallic reagents (eg, n-butyllithium, etc.), sodium hydride, sodium amide and the like. The "base" is used in an amount of 1 to excess, preferably 1 to 5 equivalents. The reaction temperature is between 0 ° C and 1
00 ° C., preferably 30 ° C. to 80 ° C. Examples of the solvent used include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.), esters (eg, methyl acetate, ethyl acetate, etc.),
Aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, toluene, etc.); The reaction time is usually 1
0 minutes to 24 hours, preferably 1 to 10 hours. Compounds (E) and (F) or salts thereof can be produced from the following compound (G) by the following reaction.

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

In this reaction, a compound: R ¹² NH ₂ (R ¹² has the same meaning as described above, preferably ammonia, formamide, etc.) is added to compound (G) or a salt thereof.
It is used in a large excess, preferably 1 to 10 equivalents.
As the solvent to be used, a non-solvent or a protic solvent (eg, water, methanol, ethanol, n-butanol, etc.), an aprotic polar solvent (eg, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile,
Acetone and the like). The reaction temperature is 1 to 250 ° C,
It is preferably carried out at 100 to 150 ° C. The pressure in the reaction vessel is from normal pressure to 50 kgcm ^-2 , preferably from normal pressure to 2 kgcm ^-2 .
0 kgcm ^-2 . The reaction time is 10 minutes to 24 hours, preferably 1 to 8 hours.

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

[0054] In this reaction, the compound (G) or a salt thereof, compound: (. R ¹¹ is of the same meaning as defined above) R ¹¹ -SH, preferably 1 to excess such as thioglycolic acid ethyl ester And preferably 1 to 2 equivalents. The reaction is carried out in the presence or absence of a base, preferably in the presence of a base. As the base used at this time,
For example, inorganic bases (eg, potassium carbonate, sodium carbonate, etc.), organic bases (eg, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0]-)
7-undecene, etc.), alcoholates (eg, sodium methylate, sodium ethylate, potassium tert-butoxy), organometallic reagents (eg, n-butyllithium, etc.), sodium hydride, sodium amide and the like. The "base" is used in an amount of 1 to excess, preferably 1 to 2 equivalents. The reaction temperature is between 0 ° C and 1
00 ° C, preferably 0 ° C to 50 ° C. Examples of the solvent used include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, etc.),
Esters (eg, methyl acetate, ethyl acetate, etc.), aprotic polar solvents (eg, N, N-dimethylformamide,
Dimethyl sulfoxide, acetonitrile, acetone, toluene, etc.). The reaction time is generally 10 minutes to 24 hours, preferably 1 to 10 hours. Among To the compound obtained in (A) or a salt thereof as described above, compounds wherein R ¹¹ is R ¹⁴ i.e. an alkyl group (A-
2) or a salt thereof can be converted to a compound (B) or a salt thereof by a dealkylation reaction.

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

In this reaction, the base is used in 1 to a large excess with respect to compound (A) or a salt thereof. Examples of the base used at this time include inorganic bases (eg, potassium carbonate, sodium carbonate, etc.) and organic bases (eg, triethylamine, pyridine, dimethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene. Etc.), alcoholates (eg, sodium methylate, sodium ethylate, tert-butoxy potassium, etc.), organometallic reagents (eg, n-butyllithium, etc.), sodium hydride, sodium amide, etc., and preferably hydrogen Sodium bromide, n-butyllithium, potassium tert-butoxide,
And sodium amide. The reaction temperature is between 50 ° C and 2
00 ° C., preferably 100 ° C. to 180 ° C. Examples of the solvent used include halogenated hydrocarbons (eg,
Chloroform, dichloroethane, etc.), ethers (eg,
Tetrahydrofuran, etc.), esters (eg, ethyl acetate, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile,
Toluene, xylene, etc.). The reaction time is generally 10 minutes to 10 hours, preferably 1 to 3 hours.

Compound (B) or a salt thereof can be converted to compound (A-1) contained in compound (A) or a salt thereof by, for example, the following method.

Embedded image [Wherein, R ¹⁵ represents a lower alkyl group such as methyl, ethyl, propyl and the like, and the other symbols have the same meanings as described above. Compound (B) or a salt thereof and compound (J): Hal
The reaction with —CH ₂ COOR ¹⁵ or a salt thereof is performed by adding compound (J) or a salt thereof to compound (B) or a salt thereof.
An equivalent to a large excess (1 to 10 equivalents) is used. Also, sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0]-
A basic compound such as 7-undecene may be used in an amount of 1 to 10 equivalents. The reaction can be performed at -20 to 200 ° C. As the solvent used at this time, for example, water,
Lower alcohols (eg, methanol, ethanol, propanol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), ethers (eg, tetrahydrofuran, etc.), aprotic polar solvents (eg, N, N-dimethylformamide, dimethyl) Sulfoxide) and the like. In the reaction, 1 equivalent to a large excess (1 to 10 equivalents) of sodium iodide may be added as a reaction accelerator. The reaction time is generally 10 minutes to 24 hours, preferably 0.5 to 6 hours.

In each of the above reactions, when the starting compound has an amino group, a carboxy group, or a hydroxy group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include formyl, C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyloxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.) ,
Phenyloxycarbonyl (eg, benzooxycarbonyl, etc.), C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl, etc.), trityl, phthaloyl and the like are used. These may further have a substituent,
For example, a halogen atom (eg, fluoro, chloro, bromo,
Iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like, and the number of substituents is about 1 to 3.

As the protecting group for the carboxy group, for example, C
_1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like are used. These may further have a substituent, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), formyl, C _1-6
Alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxy-protecting group include C _1-6 alkyl (eg,
Methyl, ethyl, propyl, isopropyl, butyl, te
rt-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl, etc.), C _1-6 alkyl-carbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyloxy -Carbonyl (eg, benzyloxycarbonyl, etc.), pyranyl,
Furanyl, silyl and the like are used. These may further have a substituent, for example, a halogen atom (eg, fluoro, chloro, bromo, iodo and the like), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, The number of substituents is about 1 to 4.

As a method for removing the protecting group, a method known per se or a method analogous thereto can be used. A method of treating with fluoride, palladium acetate or the like is used. The compound (I) obtained by the above method can be isolated and purified by a usual 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 compound (I) is an optically active form, S-form,
It can be separated into R-forms. The raw material for producing the compound (I) or a salt thereof of the present invention may form a salt, and the salt is not particularly limited as long as the reaction proceeds. For example, the compound (I) may be formed. A salt similar to a salt may be used.

[0060]

The compound (I) of the present invention and a salt thereof have excellent L
It has a DL receptor increasing action, a lipid lowering action and a blood glucose lowering action, and has 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.), It can be used safely as a preventive / therapeutic agent for lipemia, a preventive / therapeutic agent for diabetes, a preventive / therapeutic agent for diabetic complications, and the like. Compound (I) and a salt thereof may be in an intact powder, but are usually used as carriers for pharmaceutical preparations such as excipients (eg, calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches, crystalline cellulose, talc, granulated sugar). , A porous substance), a binder (for example, dextrin, rubber, alcoholized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), a disintegrant (for example, calcium carboxymethylcellulose, croscarmellose sodium, cloth) Popidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc., lubricants (eg, magnesium stearate, calcium stearate, talc, starch, sodium benzoate, etc.), coloring agents (eg, tar pigment, caramel, Dioxide Iron, titanium oxide, riboflavins, etc.), flavoring agents (eg, sweets, flavors, etc.),
It is administered in a form prepared according to a conventional method using an appropriate amount from a stabilizer (eg, sodium sulfite, etc.) and a preservative (eg, parabens, sorbic acid, etc.). The prophylactic / therapeutic agent of the present invention containing the above-mentioned preparation suitably contains Compound (I) or a salt thereof in an effective amount for treating and preventing a disease. The content of compound (I) or a salt thereof in the preparation of the present invention is usually 0.1 to 100% of the whole preparation.
% By weight. The preparation used in the present invention may contain other pharmaceutical ingredients other than the compound (I) or a salt thereof 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 an appropriate mixing ratio. Specific examples of dosage forms include 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 can be prepared by standard methods (eg, methods described in the Japanese Pharmacopoeia)
It is prepared according to

Specifically, the method for producing a tablet is as follows. Compound (I) or a salt thereof is mixed as it is with an excipient, a binder, a disintegrant or other appropriate additives, and uniformly mixed. After granulating by an appropriate method, a lubricant or the like is added, and compression molding is performed, or compound (I) or a salt thereof is used as it is, or an excipient, a binder, a disintegrant or other appropriate additives is added. In addition, it can be produced by directly compressing and molding the mixture that has been uniformly mixed, or by directly mixing the granules prepared in advance, or by adding appropriate additives and mixing them uniformly, and then compressing and molding. . Also,
The present agent can contain a coloring agent, a flavoring agent, and the like, as necessary. Further, the agent can be coated with an appropriate coating agent. In the method for producing an injection, a certain amount of compound (I) or a salt thereof is dissolved, suspended or emulsified in water for injection, physiological saline, Ringer's solution in the case of an aqueous solvent, and usually in vegetable oil in the case of a non-aqueous solvent. The compound (I) or a salt thereof is taken in a fixed amount and sealed in a container for injection to produce. 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 carriers for injection, for example, distilled water, physiological saline,
A glucose solution, an infusion solution and the like are used. In addition, additives generally used in preparations can be appropriately added.

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, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, arrhythmia, peripheral vascular disease, thrombosis,
It can be used for treatment or prevention of pancreatic disorders, sequelae 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, especially hypertriglyceridemia, hyperlipoproteinemia and hypercholesterolemia, and the atherosclerotic vascular lesions resulting therefrom and their sequelae, for example, Coronary artery disease, cerebral ischemia, aneurysm, cerebral atherosclerosis, peripheral atherosclerosis,
Particularly suitable for the treatment and prevention of intermittent claudication, gangrene, etc.

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

Further, the compound (I) or a salt thereof has a hypoglycemic effect and exhibits a hypoglycemic effect in obese diabetic rats, and therefore improves 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,
Particularly suitable for the treatment and prevention of intermittent claudication, gangrene, etc. In the treatment of these diseases, compound (I) or a salt thereof may be used alone for prophylactic treatment or may be used together with other hypoglycemic or antihypertensive drugs, in which case these compounds Is 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) an insulin preparation (eg, human insulin), (2) a sulfonylurea agent (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) sympathomimetic agents (eg, atenolol, etc.), (3) angiotensin II antagonists (eg, losartan, candesartan, etc.), (4) angiotensin I conversion Enzyme inhibitors (eg, enalapril maleate, delapril hydrochloride, etc.), and (5) calcium antagonists (eg, nifedipine, manidipine hydrochloride, etc.) and the like. In addition, compound (I) or a salt thereof is suitable for the prophylactic treatment of diseases associated with hyperchylomicronemia, for example, acute pancreatitis. Regarding the mechanism of pancreatitis,
It is said that micro-embolism occurs in pancreatic capillaries due to chylomicron, or that triglyceride is degraded by pancreatic lipase due to hyperchylomicronemia, increasing the free fatty acids produced and strongly stimulating the local area. Therefore, since the compound (I) of the present invention or a salt thereof has a triglyceride lowering action, it can be used alone or in combination with a known therapy for the prophylactic treatment of pancreatitis. For the prophylactic treatment of this disease, compound (I) or a salt thereof can be administered orally or topically, and they can be used alone or as known active compounds such as aprotinin, gabexate methanesulfonate, nafamostate methanesulfonate. , Can be used in combination with citicoline, ulinastatin and the like.

A further notable application of compound (I) or a salt thereof is secondary hyperlipidemia. These include diabetes, insulin resistance (syndrome X), hypothyroidism, nephrotic syndrome or chronic renal failure, and these diseases cause hyperlipidemia, but often hyperlipidemia. Exacerbates these diseases,
It is said to form a so-called vicious cycle. In view of the lipid-lowering effect, compound (I) or a salt thereof is also suitable for treating and preventing the progress of these diseases, wherein compound (I) or a salt thereof is used alone or as a known active compound, ie, thyroid In combination with a treatment for hypofunction, dry thyroid, levothyroxine sodium, liothyronine sodium, etc.
It can be used preferably for oral administration in combination with prednisolone, methylprednisolone sodium succinate furosemide, bumetanide, azosemide and the like.

Further possible uses of the compound (I) of the present invention or a salt thereof 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 thought to do. In addition, VLDL of hyperlipidemia patients is higher than that of normolipidemia patients.
Strongly increased plasminogen activator inhibitor secretion from vascular endothelial cells, suggesting that triglyceride may reduce fibrinolytic activity. therefore,
In view of the triglyceride lowering effect, compound (I) or a salt thereof is suitable for prevention and treatment of thrombus formation. They may be used alone or as known therapeutic agents, such as dipyridamole, dilazep hydrochloride, thrombolytic agents (eg, sodium heparin, urokinase), antiplatelet agents (eg, aspirin, sulfinpyrazone, ticlopidine hydrochloride, cilostazol). And preferably used for oral administration. The dose of the preparation of the present invention may vary depending on the administration route, symptoms, age, weight, etc. of the patient. When administered to a subject as a compound (I) or a salt thereof, 0.2 to 50 mg / kg per day, preferably 1.5 to 30 mg / kg
/ Kg in one to several divided doses. The administration route may be oral or parenteral. Hereinafter, experimental results showing the pharmacological effects of the compound (I) of the present invention and a salt thereof will be described.

Test Example 1: LDL in HepG2 cells
-Binding increasing effect [Test method]
(American Type Culture Collection) purchased HepG2 cells from Eagle's minimum essential Me
After dispersion in dium [MEM] (10% FBS), the cells were seeded on a collagen-coated 6-well plate (Sumitomo Bakelite) and cultured at 37 ° C. for 4 days. After washing the cells, MEM
Under (10% LPDS), 25-hydroxycholesterol (2.3 μM) was used as a standard compound, each test compound was added at 10 μM, and the mixture was incubated in a CO ₂ incubator for 20 hours. After washing with PBS,
MEM (25 mM) containing ¹²⁵ I-human LDL (4 μg / ml)
HEPES, 1% BSA-FAF). Furthermore, for non-specific binding ability (NSB), LDL 300 μg / ml
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 was quantified by lysing the cells with 0.5% NaOH and measured according to the Lowry method. Specific binding capacity (LDL-Binding value)
The non-specific binding ability was subtracted from the total binding ability, and the value corrected by the amount of protein was expressed as% of the control group. The results are shown in [Table 1].

[Table 1] The results in Table 1 show that the compound (I) of the present invention or a salt thereof has an excellent LDL receptor increasing effect. Therefore, the compound (I) of the present invention and a salt thereof reduce LDL and VLDL in blood, and thus are useful for cardiovascular diseases such as arteriosclerosis and hyperlipidemia.

Test Example 2: Cholesterol lowering effect in hamsters [Test method] Male Golden Syrian hamsters (body weight 110-130 g) were bred with a normal diet (CE-2, CLEA Japan) and water ad libitum. The body weight is measured, blood is collected from the fundus vein, and the total cholesterol (T
C) and triglyceride (TG) using a Wako Pure Chemicals kit, and HDL-cholesterol (HDL-C) using a Kyowa Medicines kit, using an automatic analyzer (Hitachi 707).
0), and divided into 5 animals per group. A test compound suspended in 0.5% methylcellulose was added at 20 mg / kg / day at 1 mg / kg / day.
Gavage was administered once daily for 4 days. On the morning of the fifth day, body weight was measured, venous blood was collected from the fundus, and total cholesterol, triglyceride and HDL-cholesterol in plasma were measured in the same manner as described above. Note that non-HDL
-Cholesterol (non-HDL-C) was determined by subtracting HDL-cholesterol from total cholesterol.
The results are shown in [Table 2].

[0069]

[Table 2] [Table 2] As shown in Table 2, the total blood cholesterol (TC) increased day by day in the control group, but the blood cholesterol increase was suppressed by about 15 to 30% in the compound-administered group. From these results, [non-HDL-cholesterol level] was lower in the group to which the compound (I) of the present invention and its salt were administered than in the control group. Therefore, the compound (I) of the present invention and a salt thereof reduce LDL and VLDL in blood, and thus are useful for cardiovascular diseases such as arteriosclerosis and hyperlipidemia.

Test Example 3: Blood lipid lowering effect in Wistar fatty rats [Test method] Male Wistar fatty rats were fed a normal diet (CE
-2, Clea Japan) and water. 10
The body weight is measured at the age of week, blood is collected from the fundus vein, and total cholesterol (TC) and triglyceride (T
G), glucose and HDL-cholesterol (HD
LC) using an automatic analyzer (Hitachi 7
070). Non-HDL-cholesterol (no
n-HDL-C) was determined by subtracting HDL-cholesterol from total cholesterol. The rats were divided into two groups of six, and the test compound (Example 22) was added to one group at 30 mg / k.
G / day was administered by gavage once a day as a 0.5% methylcellulose solution for 2 weeks (dose group). The other groups were similarly administered only a 0.5% methylcellulose solution (control group). On the 14th day, body weight was measured, blood was collected from the fundus vein, and total cholesterol, HDL-cholesterol, triglyceride and glucose in plasma were measured in the same manner. The results are shown in [Table 3].

[Table 3] From Table 3, it can be seen that the compound of the present invention is non-HDL-
It was found that not only cholesterol but also triglyceride was significantly reduced. Therefore, the compound of the present invention is useful for, for example, prevention and treatment of hyperlipidemia or arteriosclerosis. In addition, the compounds of the present invention also significantly reduce plasma glucose, and are therefore useful, for example, as therapeutics for diabetes or diabetic complications.

[0071]

The present invention will be described in more detail with reference to the following examples and reference examples, but the present invention is not limited to these examples. In the following Reference Examples and Examples, “room temperature” indicates 0 to + 30 ° C., and the ratio of solvents used for purification by silica gel column chromatography is a volume ratio (vol./vol.). Indicates the following meaning. s: singlet d: doublet (doublet) t: triplet quint: quintet m: multiplet br: broad (broad) Hz: Hertz (CD) ₃ : heavy chloroform CD ₃ OD: heavy methanol DMSO-d ₆ : heavy dimethyl sulfoxide

Reference Example 1 Synthesis of N- [2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl] phthalimide 1) 4- (2-hydroxyethylidene) piperidine-1
Synthesis of tert-butyl carboxylate 4- (ethoxycarbonylmethylene) piperidine-1-
19.901 g of tert-butyl carboxylate (73.8)
(88 mmol) in 100 ml of toluene at -78 DEG C. and 123 ml of 1.5 M diisobutylaluminum hydride.
(185 mmol) and the mixture was stirred at -78 ° C for 1 hour. Methanol was added thereto at -78 ° C, and the mixture was stirred for 0.5 hour to decompose excess diisobutylaluminum hydride. Then, water was added under ice cooling, and the mixture was stirred for 2 hours. The resulting precipitate was filtered using Celite, the Celite was washed with ethyl acetate, the solvent of the collected filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1) to obtain the desired product. Colorless liquid Yield 15.292 g (91% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.469 (9H, s), 1.735 (1H, b
rs), 2.174 (2H, s, 5.9Hz), 2.260 (2H, t, 5.9Hz), 3.383-
3.462 (4H, m), 4.172 (2H, d, 7.0Hz), 5.493 (1H, t, 7.0Hz). 2) Synthesis of tert-butyl 4- (2-bromoethylidene) piperidine-1-carboxylate 4- 15.292 g of tert-butyl (2-hydroxyethylidene) piperidine-1-carboxylate (67.27
To a solution of 74.5 mmol) and 24.5 g (74.0 mmol) of carbon tetrabromide in 150 ml of acetonitrile was added 19.4 g (74.0 mmol) of triphenylphosphine at -78 ° C, and the mixture was heated to room temperature and stirred for 2 hours. . The solvent of the reaction solution was distilled off under reduced pressure, diethyl ether was added and the mixture was stirred, and the resulting precipitate was filtered and washed with diethyl ether. The filtrate was collected, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1 to 9/1) to obtain the desired product. Colorless liquid Yield 11.283 g (58% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.471 (9H, s), 2.203 (2H, t,
6.0Hz), 2.297 (2H, t, 5.7Hz), 3.405-3.478 (4H, m), 4.00
7 (2H, d, 8.4Hz), 5.621 (1H, t, 8.4Hz). 3) Synthesis of N- [2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl] phthalimide 4- ( A solution of 5.775 g (19.900 mmol) of tert-butyl 2-bromoethylidene) piperidine-1-carboxylate and 4.05 g (21.9 mmol) of potassium phthalimide in 100 ml of N, N-dimethylformamide at 100 ° C. for 1 hour Stirred. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1 to 3/1) to obtain the desired product. 5.473 g (77% yield) of pale yellow solid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.469 (9H, s), 2.143 (2H, t,
5.2Hz), 2.458 (2H, t, 5.6Hz), 3.401 (2H, t, 5.9Hz), 3.48
0 (2H, t, 5.7Hz), 4.294 (2H, d, 7.4Hz), 5.367 (1H, t, 7.3H
z), 7.693-7.759 (2H, m), 7.801-7.885 (2H, m)

Reference Example 2 N- [2- [1- (tert-butoxycarbonyl)-
Synthesis of 1,2,3,6-tetrahydropyridin-4-yl] ethyl] phthalimide 1) Synthesis of tert-butyl 4- (2-hydroxyethyl) -3,6-dihydro-2H-pyridine-1-carboxylate To a suspension of 0.66 g (17.5 mmol) of lithium aluminum hydride in 100 ml of diethyl ether was added 4- (ethoxycarbonylmethyl) -3,6-dihydro-2H-.
Tert-Butyl pyridine-1-carboxylate 4.719
g (17.521 mmol) of tetrahydrofuran 50
The resulting solution was added dropwise under ice-cooling and stirred at room temperature for 1 hour. Ethyl acetate was added thereto under ice cooling to decompose excess lithium aluminum hydride, and water was further added until a white precipitate was formed. The resulting precipitate was filtered using Celite, the Celite was washed with ethyl acetate, the solvent of the collected filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1 /
1) The desired product was obtained. Colorless liquid Yield 3.259 g (82% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.467 (9H, s), 1.663 (1H, br
s), 2.086 (2H, br s), 2.282 (2H, t, 6.0Hz), 3.502 (2H, t,
5.7Hz), 3.709 (2H, t, 6.4Hz), 3.879 (2H, brs), 5.480 (1
H, brs). 2) 4- (2-bromoethyl) -3,6-dihydro-
Synthesis of tert-butyl 2H-pyridine-1-carboxylate In the same manner as in 2) of Reference Example 1, the desired product was obtained as a pale yellow liquid. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.469 (9H, s), 2.071 (2H, br
s), 2.573 (2H, t, 7.3Hz), 3.443 (2H, t, 7.3Hz), 3.500 (2H, t, 7.3Hz)
t, 5.8 Hz), 3.884 (2H, brs), 5.476 (1H, brs) 3) N- [2- [1- (tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine-4 Synthesis of -yl] ethyl] phthalimide In the same manner as in 3) of Reference Example 1, the desired product was obtained as a pale yellow liquid. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.456 (9H, s), 2.152 (2H, br
s), 2.376 (2H, t, 6.8Hz), 3.475 (2H, t, 5.7Hz), 3.757 (2H
H, s), 3.793 (2H, t, 7.0Hz), 5.347 (1H, br s), 7.689-7.7
55 (2H, m), 7.796-7.895 (2H, m).

Reference Example 3 Synthesis of tert-butyl 4-amino-1-piperidinecarboxylate 1) Synthesis of N- (1-benzylpiperidin-4-yl) trifluoroacetamide 25.94 g of 4-amino-1-benzylpiperidine (1
36.3 mmol), 22.1 ml of pyridine (27.3)
(Mmol) was added dropwise to a solution of 21.2 ml (43.9 mmol) of trifluoroacetic anhydride in 250 ml of tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature overnight. The solvent of this reaction solution was distilled off under reduced pressure, water was added, and the mixture was extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1), and the obtained solid was washed with diethyl ether to obtain the desired product. White solid Yield 39.23 g (100% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.045-2.330 (4H, m), 2.675-
2.804 (2H, m), 3.515-3.573 (2H, m), 3.987-4.074 (1H, m),
4.150 (2H, s), 7.371-7.479 (5H, m), 7.957-7.806 (1H,
m). 2) Synthesis of tert-butyl 4-trifluoroacetamido-1-piperidinecarboxylate A solution of 11.431 g (39.927 mmol) of N- (1-benzylpiperidin-4-yl) trifluoroacetamide in 100 ml of methanol was prepared. 10% palladium /
Using 4 g of carbon (containing 50% water) as a catalyst, hydrogenation was performed at room temperature and normal pressure until the raw materials disappeared (2 hours). The catalyst in the reaction solution was separated by filtration using Celite, and the catalyst was washed with methanol. The solvent of the collected filtrate was distilled off under reduced pressure to obtain crude N- (piperidin-4-yl) trifluoroacetamide. The obtained crude product was used for the next reaction without purification. The obtained crude N- (piperidin-4-yl) trifluoroacetamide, triethylamine 6.68 ml (47.9 mmol) in tetrahydrofuran 50 ml-methanol 2
0-ml solution at room temperature in di-tert-butyl dicarbonate 9.5
9 g (43.9 mmol) was added dropwise, and the mixture was stirred overnight. The solvent of this reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain the desired product. 8.505 g (72% yield) of white solid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.321-1.555 (2H, m), 1.456
(9H, s), 1.921-1.995 (2H, m), 2.786-2.923 (2H, m), 3.89
0-4.140 (3H, m), 6.528 (1H, brd, 7.0Hz). 3) 4-amino-1-piperidinecarboxylic acid tert-
Synthesis of butyl A solution of 7.35 g (24.8 mmol) of tert-butyl 4-trifluoroacetamido-1-piperidinecarboxylate and 5.71 g (41.3 mmol) of potassium carbonate in 50 ml of methanol was stirred at 60 ° C. for 8 hours. . The reaction solution was poured into an aqueous sodium hydrogen carbonate solution, saturated with sodium chloride, and then extracted ten times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a light yellow liquid target product. The obtained target product was used for the next reaction without purification. ¹ H-NMR (CDCl ₃ , 200MHz) δ: 1.076-1.358 (4H, m), 1.456
(9H, s), 1.725-1.822 (2H, m), 2.703-2.855 (3H, m), 3.99
3-4.077 (2H, m).

Reference Example 4 N- [2- [1- (tert-butoxycarbonyl)-
Synthesis of 2,5-dihydro-1H-pyrrol-3-yl] ethyl] phthalimide 1) 3-oxopyrrolidine-1-carboxylic acid tert-
Synthesis of butyl 3-pyrrolidinol 25.63 g (0.2942 mol)
150ml of tetrahydrofuran and 50ml of ethanol
To a mixed solvent solution of di-tert-butyl dicarbonate.
6 g (0.324 mol) was added dropwise at room temperature.
Stirred for hours. The solvent of the reaction solution was distilled off under reduced pressure to obtain crude tert-butyl 3-hydroxypyrrolidine-1-carboxylate. 56.0 g (0.441 mol) of oxalyl chloride
62.6 ml (0.883 mol) of dimethyl sulfoxide was added dropwise to a solution of the above in 400 ml of tetrahydrofuran at -78 ° C. After stirring for 5 minutes, a solution of the crude tert-butyl 3-hydroxypyrrolidine-1-carboxylate obtained above in 150 ml of tetrahydrofuran was added dropwise, and the solution was added at -78 ° C for 15 minutes.
Stirred for minutes. This is mixed with triethylamine 24 at -78 ° C.
6 ml (1.77 mol) was added, and the temperature was raised to room temperature. The reaction mixture was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1).
~ 3/1) to obtain the desired product. Yellow liquid Yield 50.44 g (93% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.487 (9H, s), 2.588 (2H, t,
7.9Hz), 3.756 (2H, s), 3.777 (2H, t, 7.8Hz). 2) Synthesis of tert-butyl 3- (ethoxycarbonylmethyl) -2,5-dihydropyrrole-1-carboxylate 60% hydrogen Liquid paraffin suspension of sodium chloride 3.4
1 g (85.2 mmol) was washed with hexane three times, then suspended in 50 ml of toluene, and a solution of 33.8 g (151 mmol) of ethyl diethylphosphonoacetate in 50 ml of toluene was added dropwise under ice-cooling, and the mixture was allowed to stand at room temperature for 30 minutes. Stirred. This was converted to 1- (tert-butoxycarbonyl) pyrrolidine-
A solution of 25.42 g (137.2 mmol) of 3-one in 200 ml of toluene was added dropwise at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Diethyl ether was added to the reaction solution, which was washed with water, and the aqueous layer was extracted twice with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified twice by silica gel column chromatography (hexane / ethyl acetate = 6/1).
~ 3/1) to obtain the desired product. Yellow liquid Yield 8.201 g (23% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.280 (3H, t,
7.1 Hz), 1.472 (9H, s), 3.14
6 (2H, s), 4.119-4.226 (6H,
m), 5.613-5.651 (1H, m). 3) Synthesis of tert-butyl 3- (2-hydroxyethyl) -2,5-dihydropyrrole-1-carboxylate A suspension of 1.22 g (32.1 mmol) of lithium aluminum hydride in 150 ml of tetrahydrofuran was added.
8.201 g of tert-butyl (ethoxycarbonylmethyl) -2,5-dihydropyrrole-1-carboxylate
(32.122 mmol) of tetrahydrofuran 50 m
The solution was added dropwise under ice-cooling and stirred at room temperature for 1 hour. Ethyl acetate was added thereto under ice cooling to decompose excess lithium aluminum hydride, and water was further added until a white precipitate was formed. The resulting precipitate was filtered using Celite, the Celite was washed with ethyl acetate, and the solvent of the collected filtrate was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1).
1) The desired product was obtained. 4.826 g (70% yield) of colorless liquid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.47
3 (9H, s), 1.767 (1H, br s), 2.387 (2H, br t, 6.2Hz), 3.7
69 (2H, t, 6.3Hz), 4.083-4.139 (4H, m), 5.499-5.537 (1H,
m). 4) N- [2- [1- (tert-butoxycarbonyl) -2,5-dihydro-1H-pyrrol-3-yl]
Synthesis of ethyl] phthalimide 4.818 g of tert-butyl 3- (2-hydroxyethyl) -2,5-dihydropyrrole-1-carboxylate
(22.590 mmol), triethylamine 4.72
100 ml of diethyl ether (33.9 mmol)
methanesulfonyl chloride 2.10 ml under ice-cooling
(27.1 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 0.5 hour. Pour this reaction solution into aqueous sodium hydrogen carbonate solution,
Extracted three times with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 100 ml of N, N-dimethylformamide, 4.60 g (24.8 mmol) of potassium phthalimide was added, and the mixture was stirred at 100 ° C. for 5 hours. The reaction solution was poured into water, stirred, and the resulting precipitate was collected by filtration, washed with water, and dried to obtain the desired product. Light brown solid Yield 5.522 g (yield 71%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.482 (9H,
s), 2.498 (2H, t, 6.9 Hz), 3.
848 (2H, t, 7.1 Hz), 4.075 (4
H, s), 5.504 (1H, s), 7.702
7.744 (2H, m), 7.832-7.874
(2H, m).

Reference Example 5 1- (3-phenylpropan-1-yl) piperidine-
Synthesis of 3-ylmethylamine dihydrochloride 1) Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-3-ylmethyl] phthalimide 10.07 g (87.43 mmol) of 3-piperidinemethanol , 1-bromo-3-phenylpropane 19.1
To a solution of g (96.2 mmol) in 150 ml of acetonitrile was added 18.1 g (131 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 1 day. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude 1- (3-phenylpropan-1-yl) piperidine-3-methanol. The obtained crude product was used for the next reaction without purification. The obtained crude 1- (3-phenylpropan-1-yl) piperidine-3-methanol, triethylamine 1
4.6 ml (105 mmol) of tetrahydrofuran 1
11.0 g of methanesulfonyl chloride (9
(6.2 mmol) in 50 ml of tetrahydrofuran was added dropwise under ice-cooling, and the mixture was stirred for 0.5 hour. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with N, N-dimethylformamide 500 m
17.8 g of potassium phthalimide (96.
2 mmol) and stirred at 100 ° C. overnight. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate) to obtain the desired product. Yellow liquid Yield 25.905 g (82% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.95
4-1.123 (1H, m), 1.437-2.153 (8H, m), 2.336 (2H, t, 7.9H
z), 2.595 (2H, t, 7.7Hz), 2.752-2.807 (2H, m), 3.542 (1
H, dd, 7.0Hz, 13.6Hz), 3.624 (1H, dd, 6.9Hz, 13.7Hz), 7.1
05-7.295 (5H, m), 7.666-7.769 (2H, m), 7.804-7.871 (2H, m
m). 2) N-tert-butoxycarbonyl- [1- (3-
Synthesis of phenylpropan-1-yl) piperidin-3-ylmethyl] amine 10.770 g of N- [1- (3-phenylpropan-1-yl) piperidin-3-ylmethyl] phthalimide
To a solution of (29.713 mmol) in 50 ml of ethanol was added 1.44 ml (29.7 mmol) of hydrazine monohydrate.
Was added and the mixture was heated under reflux for 2 hours. After the reaction solution was cooled to room temperature, 7.78 g (35.7 g) of di-tert-butyl dicarbonate was used.
Mmol) and stirred at room temperature for 1 hour. The reaction solution was poured into an aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate =
1/1 to ethyl acetate) to obtain the desired product. 8.914 g (90% yield) of pale yellow liquid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.846-1.117 (1H, m), 1,434
(9H, s), 1.568-1.960 (8H, m), 2.339 (2H, t, 7.5Hz), 2.61
6 (2H, t, 7.9Hz), 2.757-2.835 (2H, m), 3.009 (2H, brs),
4.607 (1H, brs), 7.133-7.318 (5H, m). 3) Synthesis of 1- (3-phenylpropan-1-yl) piperidin-3-ylmethylamine dihydrochloride N-tert-butoxycarbonyl 8.902 g of-[1- (3-phenylpropan-1-yl) piperidin-3-ylmethyl] amine was dissolved in 50 ml of methanol, 10 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours. This was concentrated to obtain the desired product. Pale yellow foamy substance 8.200 g (100% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.212-1.434 (1H, m), 1.785-
2.438 (6H, m), 2.728 (2H, t, 7.6Hz), 2.776-3.032 (4H, m),
3.153 (2H, t, 8.6Hz), 3.538-3.690 (2H, m), 7.161-7.347
(5H, m).

Reference Example 6 1- (3-phenylpropan-1-yl) -4,4'-
Synthesis of bipiperidine dihydrochloride 1) 1-tert-butoxycarbonyl-1 ′-(3-
Synthesis of phenylpropan-1-yl) -4,4′-bipiperidine 10.98 g (45.52 mmol) of 4,4′-bipiperidine, 9.06 g of 1-bromo-3-phenylpropane
To a solution of (45.5 mmol) in 150 ml of ethanol was added 18.9 g (137 mmol) of potassium carbonate, and the mixture was stirred at room temperature for 1 day. The reaction solution was filtered, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue is treated with tetrahydrofuran 100
dissolved in 1 ml of di-tert-butyl dicarbonate.
(54.6 mmol) and stirred at room temperature for 6 hours.
The reaction solution was poured into an aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1 / 1-ethyl acetate) to obtain the desired product. Yellow solid Yield 3.597 g (20% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.009-1.381 (6H, m), 1.451
(9H, s), 1.628-1.683 (4H, m), 1.744-1.896 (4H, m), 2.33
3 (2H, t, 7.7Hz), 2.575-2.689 (4H, m), 2.946 (2H, brd, 11.
8Hz), 4.064-4.169 (2H, m), 7.127-7.305 (5H, m). 2) 1- (3-Phenylpropan-1-yl) -4,
Synthesis of 4′-bipiperidine dihydrochloride 1-tert-butoxycarbonyl-1 ′-(3-phenylpropan-1-yl) -4,4′-bipiperidine 3.425 g (8.860 mmol) was added to methanol 20.
The resulting mixture was dissolved in 5 ml of the mixture, 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 6 hours. After concentrating this, it was crystallized from methanol-diethyl ether to obtain the desired product. Light yellow solid Yield 2.965 g (93% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.413-1.659 (6H, m), 1.945-
2.170 (6H, m), 2.715 (2H, t, 7.5Hz), 2.860-3.131 (6H, m),
3.413 (2H, br d, 12.6Hz), 3.595 (2H, br d, 12.4Hz), 7.1
57-7.335 (5H, m).

Reference Example 7 N- [2- (3-phenylpropan-1-yl) -2,
Synthesis of 3-dihydro-1H-isoindol-5-ylmethyl] phthalimide 1) (7,7-dimethyl-5,9-dihydro-6,8-
Synthesis of dioxabenzocyclohepten-2-yl) methanol A suspension of 25.1 g (661 mmol) of lithium aluminum hydride in 1,300 ml of tetrahydrofuran was added with 1,3.
-Dioxo-1,3-dihydroisobenzofuran-5-
50.77 g of carboxylic acid (trimellitic anhydride) (26
(4.2 mmol) was slowly added under ice-cooling, and the mixture was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture under ice cooling to decompose excess lithium aluminum hydride, and water was further added until a white precipitate was formed. The resulting precipitate was filtered using Celite, the Celite was washed with ethyl acetate and ethanol, and the solvent in the collected filtrate was distilled off under reduced pressure. The obtained crude [2,4-bis (hydroxymethyl) phenyl] methanol was dissolved in 100 ml of N, N-dimethylformamide, and 100 ml of acetone, 70 ml of 2,2-dimethoxypropane and 5 g of DL-10-camphorsulfonic acid were added. Stirred overnight at room temperature. To this was added an aqueous sodium hydroxide solution, and the mixture was extracted six times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1).
1) The desired product was obtained. White solid Yield 20.20 g (37% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.502 (6H, s), 1.654 (1H, br
s), 4.630 (2H, s), 4.839 (4H, s), 7.044 (1H, d, 7.8Hz),
7.063 (1H, s), 7.152 (1H, d, 7.8 Hz). 2) tert-butyl- (7,7-dimethyl-5,9-
Dihydro-6,8-dioxabenzocycloheptene-2
Synthesis of (-yl) methoxydiphenylsilane (7,7-dimethyl-5,9-dihydro-6,8-dioxabenzocyclohepten-2-yl) methanol
227 g (15.495 mmol), imidazole 1.
To a solution of 27 g (18.6 mmol) of N, N-dimethylformamide in 20 ml was added 4.69 g (17.0 mmol) of tert-butylchlorodiphenylsilane at room temperature, and the mixture was stirred for 2 hours. The reaction solution was poured into water and extracted three times with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1) to obtain the desired product. Colorless liquid Yield 6.504 g (94% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.079 (9H, s), 1.511 (6H, s),
4.720 (2H, s), 4.837 (2H, s), 4.853 (2H, s), 7.011 (1H,
s), 7.031 (1H, d, 8.0Hz), 7.157 (1H, d, 7.8Hz), 7.326 (6
H, m), 7.659-7.718 (4H, m).

3) Synthesis of [4- (tert-butyldiphenylsiloxymethyl) -2-hydroxymethylphenyl] methanol Tert-butyl- (7,7-dimethyl-5,9-dihydro-6,8-dioxabenzo 6.175 g (13.8 g of cyclohepten-2-yl) methoxydiphenylsilane
25 mmol) tetrahydrofuran-water (4: 1) 5
2 ml of trifluoroacetic acid was added to the 0 ml solution under ice cooling,
Stirred at room temperature for 4 hours. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product. Colorless liquid Yield 5.720 g (100% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.090 (9H, s), 2.973 (2H, br
s), 4.663 (4H, s), 4.749 (2H, s), 7.257-7.459 (14H, m),
7.656-7.702 (4H, m). 4) 5- (tert-butyldiphenylsiloxymethyl) -2- (3-phenylpropan-1-yl) -2,
Synthesis of 3-dihydro-1H-isoindole [4- (tert-butyldiphenylsiloxymethyl)
-2-hydroxymethylphenyl] methanol 5.86
To a solution of 7 g (14.429 mmol) and 12.6 ml (72.1 mmol) of N, N-diisopropylethylamine in 100 ml of acetonitrile was added dropwise a solution of 3.47 g (30.3 mmol) of methanesulfonyl chloride in 10 ml of acetonitrile under ice cooling. Then, the mixture was stirred at 0 ° C. for 0.5 hour.
2.15 g of 3-phenylpropylamine was added to the reaction solution.
(15.9 mmol) and stirred at 80 ° C. overnight.
The solvent was distilled off under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added.
Extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1 to 3/1) to obtain the desired product. Brown liquid Yield 3.710 g (51% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.080 (9H, s), 1.845-1.995
(2H, m), 2.739 (2H, t, 7.7Hz), 2.754 (2H, t, 7.3Hz), 3.91
9 (4H, s), 4.747 (2H, s), 7.155-7.469 (14H, m), 7.668-7.
727 (4H, m). 5) 2- (3-Phenylpropan-1-yl) -2,3
Synthesis of -dihydro-1H-isoindol-5-ylmethanol 5- (tert-butyldiphenylsiloxymethyl)-
3.699 g of 2- (3-phenylpropan-1-yl) -2,3-dihydro-1H-isoindole (7.31 g)
To a solution of 6 mmol) in 50 ml of tetrahydrofuran at room temperature was added 8.78 ml (8.78 mmol) of a 1.0 N solution of tetrabutylammonium fluoride in tetrahydrofuran at room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate =
1/1 to ethyl acetate) to obtain the desired product. Brown liquid 1.840 g (94% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.846-1.998 (2H, m), 2.414
(1H, brs), 2.720 (2H, t, 7.7Hz), 2.736 (2H, t, 7.5Hz),
3.854 (2H, s), 3.894 (2H, s), 4.597 (2H, s), 7.078 (1H,
s), 7.123 (2H, s), 7.154-7.336 (5H, m).

6) N- [2- (3-phenylpropane-
Synthesis of 1-yl) -2,3-dihydro-1H-isoindol-5-ylmethyl] phthalimide 2- (3-phenylpropan-1-yl) -2,3-dihydro-1H-isoindol-5-yl To a solution of 1.835 g (6.863 mmol) of methanol and 1.43 ml (10.3 mmol) of triethylamine in 50 ml of tetrahydrofuran was added 0.1 ml of methanesulfonyl chloride under ice cooling.
64 ml (8.24 mmol) was added dropwise at 0 ° C. for 0.5 minute.
Stirred for hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted three times with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude 2- (3-phenylpropan-1-yl) -2,3-dihydro-1H-isoindol-5-ylmethyl methanesulfonate was converted into N, N-dimethylformamide 6
Dissolve in 0ml and add potassium phthalimide 1.40g
(7.55 mmol) and stirred at 100 ° C. for 4 hours. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane / ethyl acetate = 3/1 to 2/1) to obtain the desired product as a mixture with phthalimide. This was dissolved in ethyl acetate, washed sequentially with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain the desired product. Yellow liquid Yield 0.401 g (Yield 15%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.806-1.953 (2H, m), 2.705
(4H, t, 7.6Hz), 3.876 (4H, s), 4.817 (2H, s), 7.112-7.31
9 (8H, m), 7.673-7.755 (2H, m), 7.794-7.873 (2H, m).

Reference Example 8 Synthesis of N- [4- [4- (2-chlorobenzylidene) piperidino] butyl] phthalimide 1) 1- (tert-butoxycarbonyl) -4- (2
Synthesis of 1- (tert-butoxycarbonyl) -4-piperidone 9.199 g (46.168 mmol), 19.5 g (4-chlorobenzyltriphenylphosphonium chloride) of 4-chlorobenzylidene) piperidine
6.2 mmol) in methanol (50 ml) at room temperature in a methanol solution of 28% sodium methoxide (8.91).
g (46.2 mmol) was added and the mixture was heated under reflux for 36 hours. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the obtained residue, and the resulting precipitate (triphenylphosphine oxide) was filtered.
Washed with diethyl ether. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to 1).
6/1) and crystallized from cold hexane to give the desired product. White solid Yield 1.473 g (10% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.474 (9H, s), 2.277-2.396
(4H, m), 3.405 (2H, t, 5.8Hz), 3.531 (2H, t, 5.7Hz), 6.35
6 (1H, s), 7.193 (3H, s), 7.354-7.402 (1H, m). 2) Synthesis of N- [4- [4- (2-chlorobenzylidene) piperidino] butyl] phthalimide 1.428 g of 1- (tert-butoxycarbonyl) -4- (2-chlorobenzylidene) piperidine (4.63)
3 ml of concentrated hydrochloric acid was added to a solution of 9 mmol) in 20 ml of methanol at room temperature, followed by stirring at 50 ° C. for 2 hours. The solvent was distilled off under reduced pressure to obtain crude 4- (2-chlorobenzylidene) piperidine.
The hydrochloride was obtained. The obtained crude product was used for the next reaction without purification. The obtained crude 4- (2-chlorobenzylidene) piperidine hydrochloride, 1.31 g (4.64 mmol) of 4-bromobutylphthalimide and 1.28 g (9.28 mmol) of potassium carbonate were treated with N, N-dimethylformamide. Stirred at 100 ° C. in 20 ml overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1).
1) The desired product was obtained. Yellow liquid Yield 1.560 g (yield 82%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.477-1.799 (4H, m), 2.341-
2.438 (8H, m), 2.537 (2H, t, 5.5Hz), 3.715 (2H, t, 6.8Hz),
6.265 (1H, s), 7.098-7.197 (3H, m), 7.345-7.378 (1H,
m), 7.682-7.748 (2H, m), 7.796-7.862 (2H, m).

Reference Example 9 Synthesis of N- [4- (4-hydroxy-4-phenylpiperidino) butyl] phthalimide 2.501 g of 4-hydroxy-4-phenylpiperidine
(14.110 mmol), 3.98 g (14.1 mmol) of 4-bromobutylphthalimide, and 3.90 g (28.2 mmol) of potassium carbonate were stirred at 100 ° C. for 1 day in 30 ml of N, N-dimethylformamide. . Water was added to the reaction solution and the mixture was stirred. The resulting precipitate was collected, washed with water and dried to obtain the desired product. 3.835 g (72% yield) of pale yellow solid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.507-1.768 (7H, m), 2.137
(2H, dt, 4.3Hz, 13.0Hz), 2.361-2.476 (4H, m), 2.773-2.8
30 (2H, m), 3.727 (2H, t, 6.9Hz), 7.209-7.389 (3H, m), 7.
488-7.532 (2H, m), 7.686-7.748 (2H, m), 7.801-7.863 (2
H, m).

Reference Example 10 Synthesis of N- [2-hydroxy-3- (4-phenylpiperidino) propan-1-yl] phthalimide 1.980 g of N- (2,3-epoxypropan-1-yl) phthalimide (9.744 mmol) and a solution of 1.73 g (10.7 mmol) of 4-phenylpiperidine in 50 ml of ethanol were heated under reflux for 1 hour, and then the solvent of the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1), and crystallized from diethyl ether-hexane to obtain the desired product. White solid Yield 2.113 g (60% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.560-1.835 (4H, m), 2.083
(1H, dt, 2.8Hz, 11.6Hz), 2.335-2.579 (4H, m), 2.910-3.0
88 (2H, m), 3.730 (1H, dd, 5.0Hz, 13.8Hz), 3.841 (1H, dd,
6.7Hz, 13.7Hz), 4.004-4.130 (1H, m), 7.149-7.332 (5H,
m), 7.700-7.763 (2H, m), 7.830-7.911 (2H, m).

Reference Example 11 Synthesis of N- [2-[(4-phenylpiperidino) methyl] benzyl] phthalimide 1) Synthesis of 2- (tert-butyldimethylsilyloxymethyl) benzyl alcohol 1,2-benzenedi 14.074 g of methanol (10
1.86 mmol) of 1,2-dimethoxyethane 100
To the ml solution at room temperature was added 4.07 g (102 mmol) of a 60% sodium hydride liquid paraffin suspension,
The mixture was stirred for 1 hour. To this mixture was added 15.4 g (102 mmol) of tert-butylchlorodimethylsilane.
Was added dropwise and stirred at room temperature overnight. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate = 9/1 to 3/1) to obtain the desired product. Colorless liquid Yield 22.792 g (89% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.127 (6H, s), 0.921 (9H, s),
3.219 (1H, brt, 5.9Hz), 4.681 (2H, d, 5.2Hz), 4.807 (2H,
s), 7.258-7.405 (4H, m). 2) Synthesis of N- [2- (tert-butyldimethylsilyloxymethyl) benzyl] phthalimide

11.413 g of 2- (tert-butyldimethylsilyloxymethyl) benzyl alcohol (4
5.213 mmol), 7.56 ml of triethylamine
(54.3 mmol) of diethyl ether in 150 ml of ice-cooled methanesulfonyl chloride 5.70 g (49.
(7 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 0.5 hour. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 150 ml of N, N-dimethylformamide, and potassium phthalimide (9.21) was dissolved.
g (49.7 mmol) was added and the mixture was stirred at 100 ° C. for 3 hours. The reaction solution was poured into water and extracted three times with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 /
1) The desired product was obtained. Colorless liquid Yield 15.021 g (Yield 87%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.112 (6H, s), 0.938 (9H, s),
4.929 (2H, s), 4.971 (2H, s), 7.189-7.426 (4H, m), 7.69
3-7.755 (2H, m), 7.818-7.880 (2H, m). 3) Synthesis of N- [2- (hydroxymethyl) benzyl] phthalimide N- [2- (tert-butyldimethylsilyloxymethyl) benzyl] 15.021 g of phthalimide (39.
To a solution of 368 mmol) in 50 ml of methanol was added 5 ml of concentrated hydrochloric acid at room temperature, followed by stirring for 10 minutes.
The reaction solution was poured into a mixture of water and diethyl ether, and the resulting precipitate was collected and washed sequentially with water and diethyl ether.
After drying, the desired product was obtained. 8.743 g (83% yield) of white solid ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 3.033 (1H, brs), 4.891 (2H,
s), 5.004 (2H, s), 7.219-7.310 (2H, m), 7.362-7.418 (2
H, m), 7.699-7.761 (2H, m), 7.809-7.871 (2H, m).

4) Synthesis of N- [2-[(4-phenylpiperidino) methyl] benzyl] phthalimide 2.704 g (10.117 mmol) of N- [2- (hydroxymethyl) benzyl] phthalimide, triethylamine 1 To a solution of 0.69 ml (12.1 mmol) in 50 ml of tetrahydrofuran was added dropwise 0.86 ml (11.1 mmol) of methanesulfonyl chloride under ice cooling, followed by stirring at 0 ° C for 0.5 hour. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue is washed with N, N-dimethylformamide 5
Dissolved in 0 ml, and 1.79 g of 4-phenylpiperidine
(11.1 mmol) and 2.80 g of potassium carbonate
(20.2 mmol) and stirred at 100 ° C. overnight. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1).
~ 3/1) to obtain the desired product. White solid Yield 2.722 g (66% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.506-1.791 (4H, m), 2.080
(2H, dt, 2.3Hz, 11.5Hz), 2.482 (1H, tt, 3.9Hz, 11.9Hz),
2.989 (2H, br d, 11.4Hz), 3.716 (2H, s), 5.123 (2H, s),
7.134-7.376 (9H, m), 7.671-7.759 (2H, m), 7.819-7.882
(2H, m).

Reference Example 12 Synthesis of 4- (4-phenylpiperidinomethyl) piperidine dihydrochloride 1) Synthesis of tert-butyl 4- (bromomethyl) piperidine-1-carboxylate 4-piperidinylmethanol 792 g (50.28
To a solution of 7 mmol) in 150 ml of dichloromethane was added dropwise 12.1 g (55.3 mmol) of di-tert-butyl dicarbonate at room temperature, and the mixture was stirred overnight. The solvent of the reaction solution was distilled off under reduced pressure to obtain crude tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate. The obtained crude product was used for the next reaction without purification. To a solution of the obtained crude tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate and 18.3 g (55.3 mmol) of carbon tetrabromide in 100 ml of acetonitrile was added 14.5 g (55.50 g) of triphenylphosphine at room temperature. 3 mmol)
Was added and stirred as it was for 3 hours. The solvent of this reaction solution was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred, and the resulting precipitate (triphenylphosphine oxide) was removed by filtration, and further washed with diethyl ether. The collected filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 30/1 to 15/1 to 9/1) to obtain the desired product. Colorless liquid Yield: 12.126 g (82% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.075-1.284 (2H, m), 1.454
(9H, s), 1.702-1.854 (3H, m), 2.693 (2H, brt, 12.5Hz),
3.294 (2H, d, 5.8 Hz), 4.135 (2H, brd, 12.8 Hz). 2) Synthesis of tert-butyl 4- (4-phenylpiperidinomethyl) piperidine-1-carboxylate 4- (bromomethyl) Piperidine-1-carboxylic acid te
3.081 g (11.075 mmol) of rt-butyl,
1.96 g (12.2 mmol) of 4-phenylpiperidine and 3.06 g (22.2 mmol) of potassium carbonate were stirred in 20 ml of N, N-dimethylformamide at 110 ° C. for 4 hours. The reaction solution was poured into water and extracted twice with diethyl ether. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / hexane).
Ethyl acetate (3/1) afforded the desired product. Yellow liquid Yield 3.550 g (89% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.989-1.189 (2H, m), 1.460
(9H, s), 1.557-1.830 (7H, m), 1.949-2.077 (2H, m), 2.19
3 (2H, d, 6.6Hz), 2.403-2.559 (1H, m), 2.696 (2H, brt, 11.
9Hz), 2.970 (2H, br d, 11.2Hz), 4.068-4.174 (2H, m), 7.
153-7.339 (5H, m). 3) Synthesis of 4- (4-phenylpiperidinomethyl) piperidine dihydrochloride 4- (4-phenylpiperidinomethyl) piperidine-1
-3.550 g of tert-butyl carboxylate (9.90 g)
5 mmol of concentrated hydrochloric acid in a solution of 2 mmol) in 30 ml of methanol
Was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized from ethanol-diethyl ether to obtain the desired product. Light yellow solid Yield 2.972 g (91% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.478-1.692 (2H, m), 2.051-
2.390 (7H, m), 2.835-3.233 (7H, m), 3.455 (2H, br d, 12.8
Hz), 3.752 (2H, br d, 12.8Hz), 7.180-7.369 (5H, m).

Reference Example 13 Synthesis of N-[[4- (4-phenylpiperidino) cyclohexyl] methyl] phthalimide 1) Synthesis of 1,5-dibromo-3-phenylpentane 9.10 g of lithium aluminum hydride (240 Mmol) in a suspension of 500 ml of tetrahydrofuran in 200 ml of diethyl ether.
A solution of 60 g (119.9 mmol) in 100 ml of tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight.
Water was slowly added dropwise to the reaction mixture under ice cooling until precipitation occurred. The resulting precipitate was filtered using Celite,
The precipitate was washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure to obtain crude 3-phenylpentane-1,5-diol. The obtained crude product was used for the next reaction without purification. (Brown liquid yield 19.19 g) The obtained crude 3-phenylpentane-1,5-diol,
To a solution of 74.2 g (224 mmol) of carbon tetrabromide in 300 ml of acetonitrile was added 58.7 g (224 mmol) of triphenylphosphine under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred, and the formed precipitate was removed by filtration. The precipitate was washed with diethyl ether, and the solvent of the collected filtrate was distilled off under reduced pressure. Hexane was added to the obtained residue, and the mixture was stirred. The resulting precipitate was removed by filtration, and the precipitate was washed with hexane. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-hexane / ethyl acetate = 20 /
1) The desired product was obtained. Colorless liquid Yield 25.963 g (71% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 2.119-2.223 (4H, m), 2.983-
3.337 (5H, m), 7.176-7.386 (5H, m). 2) Synthesis of methyl 4-aminocyclohexanecarboxylate hydrochloride 5.109 g of 4-aminocyclohexanecarboxylic acid (3.
5.680 mmol) was added with about 10% of a methanol solution of hydrogen chloride (50 ml), and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was crystallized from methanol-diethyl ether to obtain the desired product. White solid Yield 6.624 g (96% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.460-1.936 (6H, m), 2.073-
2.187 (3H, m), 2.639-2.702 (1H, m), 3.187 (1H, br s), 3.
696 (3H, s).

3) Synthesis of methyl 4- (4-phenylpiperidino) cyclohexanecarboxylate 3.896 g (20.117 mmol) of methyl 4-aminocyclohexanecarboxylate hydrochloride, 1,5-dibromo-3-phenyl 6.77 g (22.1 mmol) of pentane, N, N-diisopropylethylamine 14.0
100 ml of acetonitrile (80.5 mmol)
The solution was heated at reflux for one day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/1).
1) The desired product was obtained. Yellow liquid Yield 2.825 g (47% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.294-1.811 (10H, m), 2.046
-2.609 (7H, m), 3.034 (2H, d, 11.4Hz), 3.668 (0.6H, s),
3.691 (2.4H, s), 7.150-7.336 (5H, m). 4) Synthesis of 4- (4-phenylpiperidino) cyclohexylmethanol 0.36 g (9.37 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran Add 4- (4
A solution of 2.825 g (9.372 mmol) of methyl (phenylpiperidino) cyclohexanecarboxylate in 50 ml of tetrahydrofuran was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added thereto under ice cooling to decompose excess lithium aluminum hydride, and water was further added until a white precipitate was formed. The resulting precipitate was filtered using Celite, the precipitate was washed with ethyl acetate, and the solvent in the collected filtrate was distilled off under reduced pressure. The obtained solid was washed with diethyl ether-hexane to obtain the desired product. White solid Yield 2.160 g (84% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.885-2.007 (15H, m), 2.108
-2.553 (4H, m), 3.013-3.123 (2H, m), 3.460 (0.4H, d, 6.2H
z), 3.611 (1.6H, d, 6.6 Hz), 7.140-7.341 (5H, m). 5) Synthesis of N-[[4- (4-phenylpiperidino) cyclohexyl] methyl] phthalimide 4- (4 To a solution of 1.986 g (7.264 mmol) of triphenylamine and 1.21 ml (8.72 mmol) of triethylamine in 50 ml of tetrahydrofuran was added 0.62 ml (7.99 mmol) of methanesulfonyl chloride under ice-cooling. The mixture was added dropwise and stirred at 0 ° C. for 0.5 hour. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained is N,
Dissolve in 50 ml of N-dimethylformamide, add 1.48 g (7.99 mmol) of potassium phthalimide,
Stirred at 100 ° C. overnight. After the reaction solution was cooled to room temperature, it was poured into water and stirred. The resulting precipitate was collected by filtration, washed with water and dried to obtain the desired product. Light brown solid Yield 0.567 g (19% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.000-1.368 (2H, m), 1.669-
1.958 (12H, m), 2.238-2.517 (3H, m), 2.885-3.150 (2H,
m), 3.545 (1.6H, d, 6.6Hz), 3.699 (0.4H, d, 7.6Hz), 7.140
-7.325 (5H, m), 7.695-7.757 (2H, m), 7.808-7.873 (2H,
m).

Reference Example 14 Synthesis of N- (1-benzhydrylpiperidin-4-ylmethyl) phthalimide 1) Synthesis of 1-benzhydrylpiperidin-4-ylmethanol 2.291 g of 4-piperidinylmethanol hydrochloride (1
5.108 mmol), bromodiphenylmethane 4.4
8 g (18.1 mmol), potassium carbonate 6.26 g
(45.3 mmol) was stirred in 20 ml of N, N-dimethylformamide at 100 ° C. for 3.5 days and at 150 ° C. for 2 hours. After the reaction solution was cooled to room temperature, it was poured into water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 2/1 to 1/1) to obtain the desired product. White solid Yield 0.347 g (8.2% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.209-1.696 (6H, m), 1.841
(2H, t, 11.7Hz), 2.910 (2H, d, 12.2Hz), 3.500 (2H, br s),
4.235 (1H, s), 7.127-7.305 (6H, m), 7.385-7.426 (4H,
m). 2) Synthesis of N- (1-benzhydrylpiperidin-4-ylmethyl) phthalimide 1-benzhydrylpiperidin-4-ylmethanol 0.450 g (1.599 mmol), triethylamine 0.33 ml (2.40 mmol) Of methanesulfonyl chloride in a 30 ml solution of tetrahydrofuran under ice-cooling.
15 ml (1.92 mmol) were added dropwise at 0 ° C.
Stirred for hours. The reaction solution was poured into water, and extracted with ethyl acetate.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 25 ml of N, N-dimethylformamide, and 0.36 g (1.92 mmol) of potassium phthalimide was added.
Stirred at C overnight. After cooling the reaction solution to room temperature, pour it into water,
Extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1 to 3/1), and crystallized from diethyl ether-hexane to obtain the desired product. White solid Yield 0.178 g (27% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.291-1.496 (2H, m), 1.596
(2H, br d, 13.0Hz), 1.683-1.846 (3H, m), 2.868 (2H, d, 1
1.8Hz), 3.595 (2H, d, 7.0Hz), 4.222 (1H, s), 7.101-7.28
6 (6H, m), 7.345-7.456 (4H, m), 7.643-7.735 (2H, m), 7.7
82-7.867 (2H, m).

Reference Example 15 Synthesis of 1- (4-aminobutan-1-yl) -4-phenylpiperidine 1) Synthesis of 4- (4-phenylpiperidin-1-yl) butan-1-ylphthalimide 4-phenylpiperidine 5.00 g (31 mmol),
8.75 g of N- (4-bromobutyl) -phthalimide
(31 mmol) and 6.5 ml of triethylamine
(46.6 mmol) in acetonitrile (30 ml) was heated to reflux under a nitrogen atmosphere for 62 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 5-10%) to obtain the desired product. White solid Yield 10.38 g (yield 92%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.49-1.88 (m, 8H), 1.95-2.1
4 (m, 2H), 2.32-2.57 (m, 3H), 3.04 (br d, J = 11.4Hz, 2H),
3.73 (d, J = 6.8Hz, 2H) 7.11-7.35 (m 5H) 7.65-7.76 (m 2
H) 7.78-7.90 (m2H). 2) Synthesis of 1- (4-aminobutan-1-yl) -4-phenylpiperidine 4- (4-phenylpiperidin-1-yl) butane-1
-To a solution of 10.38 g (28.64 mmol) of ylphthalimide in 160 ml of ethanol was added 4.2 ml (86.58 mmol) of hydrazine monohydrate at room temperature, and the mixture was heated under reflux for 1.5 hours. After removing the white solid by filtration, the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydroxide was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain the desired product. Light yellow solid Yield 6.49 g (98% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.39-1.63 (m, 4H), 1.72-1.
90 (m, 6H), 2.35-2.58 (m, 3H), 2.73 (t, J = 6.6Hz, 2H), 3.
07 (br d, J = 11.6Hz, 2H), 7.15-7.35 (m, 5H).

Reference Example 16 Synthesis of 1- (3-aminopropan-1-yl) -4-phenylpiperidine 1) A white solid 3-
(4-phenylpiperidin-1-yl) propane-1-
Ilphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40-1.79 (m, 4H), 1.83-2.0
4 (m, 4H), 2.30-2.51 (m, 1H), 2.45 (t, J = 6.9Hz, 2H), 2.90
-3.05 (m, 2H), 3.79 (t, J = 7.0Hz, 2H), 7.03-7.32 (m, 5H),
7.66-7.76 (m, 2H), 7.80-7.90 (m, 2H). 2) In the same manner as in Reference Example 15-2), a white solid 1-
(3-Aminopropan-1-yl) -4-phenylpiperidine was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.61-1.90 (m, 6H), 1.94-2.1
2 (m, 2H), 2.29-2.59 (m, 5H), 2.81 (t, J = 6.8Hz, 2H), 3.0
0-3.15 (m, 2H), 7.07-7.38 (m, 5H).

Reference Example 17 Synthesis of 1- (4-aminobutan-1-yl) -4-benzylpiperidine dihydrochloride 1) In the same manner as in 1) of Reference Example 15, the yellow oil 4-
(4-Benzylpiperidin-1-yl) butan-1-ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17-1.96 (m, 11H), 2.26-2.
38 (m, 2H), 2.51 (d, J = 6.6Hz, 2H), 2.83-2.96 (m, 2H), 3.
70 (t, J = 6.8Hz, 2H), 7.10-7.31 (m, 5H), 7.67-7.73 (m, 2
H), 7.78-7.86 (m, 2H). 2) Synthesis of 1- (4-aminobutan-1-yl) -4-benzylpiperidine dihydrochloride 4- (4-benzylpiperidine-1-) butane-1 To a solution of 9.66 g (25.7 mmol) of ylphthalimide in 30 ml of ethanol was added 1.9 ml (39.2 mmol) of hydrazine monohydrate at room temperature, and the mixture was refluxed for 2 hours. After removing the white solid by filtration, the solvent was distilled off under reduced pressure. Add aqueous sodium hydroxide solution to the residue,
Extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (free form). Free body (6.39
To a solution of g) in ethanol (30 ml) was added 12N hydrochloric acid (10 ml) at room temperature, and the mixture was stirred for several minutes. After evaporating the solvent under reduced pressure, diethyl ether was added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. White crystals Yield 5.84 g (yield 71%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.50-1.88 (m, 9H), 2.68-
3.50 (m, 10H), 7.14-7.36 (m, 5H), 7.92-8.24 (m, 2H).

Reference Example 18 Synthesis of 1- (3-aminopropan-1-yl) -4-benzylpiperidine dihydrochloride 1) In the same manner as in Reference Example 1) 1),
(4-benzylpiperidin-1-yl) propane-1-
Ilphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94-1.19 (m, 2H), 1.29-1.9
5 (m, 7H), 2.30-2.47 (m, 4H), 2.76-2.89 (m, 2H), 3.74 (t,
J = 6.8Hz, 2H), 7.04-7.32 (m, 5H), 7.65-7.77 (m, 2H), 7.8
0-7.90 (m, 2H). 2) Synthesis of 1- (3-aminopropan-1-yl) -4-benzylpiperidine dihydrochloride 3- (4-benzylpiperidin-1-yl) propane-
9.22 g (25.4 mmol) of 1-ylphthalimide
Hydrazine at room temperature in ethanol (50 ml) solution
1.8 ml (37.1 mmol) of monohydrate was added, and the mixture was heated under reflux for 3 hours. After removing the white solid by filtration,
12.0 ml (52.2 mmol) of di-tert-butyl dicarbonate was added, and the mixture was stirred at room temperature for 14 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the crude product was subjected to column chromatography (methanol / ethyl acetate 10-20%).
And purified. 12N hydrochloric acid (8 ml) was added to the obtained free form at room temperature, and the mixture was stirred for several minutes. After adding ethanol to the reaction system, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the resulting crystals were collected by filtration.
The crystals were washed with ethanol and diethyl ether to obtain the desired product. White crystals Yield 3.11 g (40% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.44-1.85
(M, 4H), 1.93-2.11 (m, 2H),
2.70-2.96 (m, 4H), 3.01-3.4
7 (m, 6H), 7.13-7.37 (m, 5H),
8.02-8.36 (m, 2H).

Reference Example 19 Synthesis of 1- (4-aminobutan-1-yl) -4-phenylpiperazine trihydrochloride 1) In the same manner as 1) of Reference Example 15, 4-yellow-green
(4-Phenylpiperazin-1-yl) butan-1-ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.49
-1.83 (m, 4H), 2.44 (t, J = 7.3Hz, 2H), 2.57 (m, 4H), 3.13-
3.25 (m, 4H), 3.73 (t, J = 6.9Hz, 2H), 6.81-6.97 (m, 3H),
7.18-7.32 (m, 2H) 7.66-7.78 (m, 2H), 7.78-7.90 (m, 2H). 2) In the same manner as in Reference Example 17-2), white crystal 1-
(4-Aminobutan-1-yl) -4-phenylpiperazine trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.54-1.95 (m, 4H), 2.70-
2.91 (m, 2H), 2.98-3.31 (m, 6H), 3.45-3.60 (m, 2H), 3.69
-3.1 (m, 2H), 5.65-6.03 (m, 3H), 6.84-6.91 (m, 1H), 7.00-
7.04 (m, 2H), 7.24-7.32 (m, 2H).

Reference Example 20 Synthesis of 1- (3-aminopropan-1-yl) -4-phenylpiperazine trihydrochloride 1) In the same manner as in Reference Example 1) 1),
(4-phenylpiperazin-1-yl) -propane-1
-Ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.82-1.98 (m, 2H), 2.43-2.5
9 (m, 6H), 2.99-3.10 (m, 4H), 3.80 (t, J = 7.0Hz, 2H), 6.78
-6.91 (m, 3H), 7.17-7.30 (m, 2H), 7.64-7.75 (m, 2H), 7.7
9-7.90 (m, 2H). 2) In the same manner as in 2) of Reference Example 17, 1-
(3-Aminopropan-1-yl) -4-phenylpiperazine.trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.00 to 2.21
(M, 2H), 2.82-3.02 (m, 2H),
3.02-3.35 (m, 6H), 3.44-3.6
1 (m, 2H), 3.72-3.90 (m, 2H),
5.86-6.25 (m, 3H), 6.81-6.
93 (m, 1H), 6.95-7.06 (m, 2
H), 7.20-7.32 (m, 2H), 8.12.
-8.38 (m, 2H).

Reference Example 21 Synthesis of 1- (4-aminobutan-1-yl) -4-benzylpiperazine trihydrochloride 1) In the same manner as in Reference Example 15-1), the brown oily 4-
(4-benzylpiperazin-1-yl) -butane-1-
Ilphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45
-1.79 (m, 4H), 2.31-2.57 (m, 10H), 3.49 (s, 2H), 3.70 (t, J
= 6.9Hz, 2H), 7.22-7.35 (m, 5H), 7.68-7.76 (m, 2H), 7.80
-7.87 (m, 2H). 2) In the same manner as in 2) of Reference Example 17, the white crystal 1-
(4-Aminobutan-1-yl) -4-benzylpiperazine trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.50-1.88 (m, 4H), 2.66-
2.87 (m, 2H), 2.95-3.77 (m, 10H), 4.17-4.52 (m, 2H), 7.3
5-7.51 (m, 3H), 7.55-7.72 (m, 2H), 7.92-8.25 (m, 2H).

Reference Example 22 Synthesis of 1- (3-aminopropan-1-yl) -4-benzylpiperazine trihydrochloride 1) In the same manner as in Reference Example 15-1), a brown oily 3-
(4-benzylpiperazin-1-yl) -propane-1
-Ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.78-1.93 (m, 2H), 2.23-2.5
3 (m, 10H), 3.40 (s, 2H), 3.75 (t, J = 6.8Hz, 2H), 7.19-7.31
(m, 5H), 7.65-7.76 (m, 2H), 7.78-7.88 (m, 2H). 2) In the same manner as in 2) of Reference Example 17, 1-
(3-Aminopropan-1-yl) -4-benzylpiperazine trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.93 to 2.13 (m, 2H), 2.80-
3.01 (m, 2H), 3.11-3.93 (m, 10H), 4.29-4.52 (m, 2H), 7.4
1-7.52 (m, 3H), 7.59-7.73 (m, 2H), 8.00-8.28 (m, 2H).

Reference Example 23 2- (4-aminobutan-1-yl) -1,2,3,4
-Synthesis of tetrahydroisoquinoline dihydrochloride 1) In the same manner as in 1) of Reference Example 15, 4-yellow solid
(1,2,3,4-tetrahydroisoquinolin-2-yl) -butan-1-ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.54-1.93 (m, 4H), 2.54 (t, J
= 7.4Hz, 2H), 2.69-2.74 (m, 2H), 2.86-2.92 (m, 2H), 3.61
(s, 2H), 3.70 (t, J = 7.0Hz, 2H), 6.94-7.14 (m, 4H), 7.64-
7.75 (m, 2H), 7.78-7.89 (m, 2H). 2) The white crystals of 2-
(4-Aminobutan-1-yl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.52-1.75 (m, 2H), 1.79-
2.01 (m, 2H), 2.71-3.75 (m, 8H), 4.17-4.35 (m, 1H), 4.40
-4.58 (m, 1H), 7.13-7.32 (m, 4H), 7.98-8.29 (m, 3H), 11.
10-11.32 (m, 1H).

Reference Example 24 2- (3-Aminopropan-1-yl) -1,2,3
Synthesis of 4-tetrahydroisoquinoline dihydrochloride 1) In the same manner as in 1) of Reference Example 15, 3-
(1,2,3,4-tetrahydroisoquinolin-2-yl) -propan-1-ylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.88-2.05 (m, 2H), 2.60 (t, J
= 7.0Hz, 2H), 2.64-2.72 (m, 2H), 2.73-2.83 (m, 2H), 3.57
(s, 2H), 3.82 (t, J = 7.0Hz, 2H), 6.92-7.12 (m, 4H), 7.58-
7.67 (m, 2H), 7.72-7.81 (m, 2H). 2) The white crystals of 2-
(3-aminopropan-1-yl) -1,2,3,4-
Tetrahydroisoquinoline dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.03-2.26 (m, 2H), 2.82-
3.13 (m, 2H), 3.17-3.75 (m, 6H), 4.18-4.36 (m, 1H), 4.44
-4.61 (m, 1H), 7.12-7.38 (m, 4H), 8.02-8.45 (m, 3H).

Reference Example 25 Synthesis of 3- (1-tert-butoxycarbonyl-4-piperidinyl) -1-propylamine 1) Synthesis of 3- (1-tert-butoxycarbonyl-4-piperidinyl) -1-propanol -(4-Piperidinyl) -1-propanol 35.8
g (250 mmol) in 500 ml of ethanol was added to 54.6 g of di-tert-butyl dicarbonate.
(250 mmol) was added dropwise. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: hexane = 1: 1 → ethyl acetate) to give the target compound (50) as a pale yellow oil. .2
g, 82%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96-1.41 (m, 5H), 1.45 (s, 9
H), 1.49-1.78 (m, 4H), 2.61-2.74 (m, 2H), 3.62 (t, J = 6.4
Hz, 2H), 4.04-4.10 (m, 2H). 2) Synthesis of 3- (1-tert-butoxycarbonyl-4-piperidinyl) -1-propylphthalimide 3- (1-tert-butoxycarbonyl-4-piperidinyl) ) A solution of 4.87 g (20.0 mmol) of 1-propanol and 5.6 ml (40.0 mmol) of triethylamine in 50 ml of diethyl ether was added at 0 ° C.
Then, 1.86 ml (24.0 mmol) of methanesulfonyl chloride was added thereto, and the mixture was stirred at 0 ° C. for 30 minutes. After the reaction, the reaction solution was poured into ice water and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3- (1-tert-butoxycarbonyl-4-piperidinyl) -1-propyl mesylate. To a solution of the obtained mesylate in 100 ml of N, N-dimethylformamide was added 3.70 g (20.0 mmol) of potassium phthalimide, and the reaction mixture was diluted with 10 ml of potassium phthalimide.
Heated at 0 ° C. for 90 minutes. After the reaction, the reaction solution was cooled at room temperature, then poured into ice water, and the resulting precipitate was collected by filtration, washed with water,
Drying under reduced pressure gave the desired product as a white solid (20.24
g, 90%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.94-1.37 (m, 5H), 1.45 (s, 9
H), 1.57-1.80 (m, 4H), 2.61-2.73 (m, 2H), 3.68 (t, J = 7.2
Hz, 2H), 4.04-4.10 (m, 2H), 7.70-7.87 (m, 4H). 3) Synthesis of 3- (1-tert-butoxycarbonyl-4-piperidinyl) -1-propylamine 3- (1 -Tert-butoxycarbonyl-4-piperidinyl) -1-propylphthalimide 20.24 g (5
To a solution of 4.34 mmol) in 350 ml of ethanol, 7.9 ml (163 mmol) of hydrazine monohydrate was added, and the reaction solution was heated to reflux for 1 hour. After the reaction,
The reaction solution was cooled to room temperature, and the resulting precipitate (phthalide) was filtered off. The precipitate was washed with a small amount of ethanol, and the filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, and the organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product. 13.08 g (99% yield) of pale yellow oily substance ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96-1.95 (m, 18H), 2.61-2.
72 (m, 4H), 4.04-4.10 (m, 2H).

Reference Example 26 Synthesis of tert-butyl 4-[(methylamino) methyl] piperidine-1-carboxylate 1) Synthesis of N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) trifluoroacetamide -Aminomethylpiperidine-1-carboxylic acid-ter
To a solution of 5.07 g (23.7 mmol) of t-butyl and 5.0 ml (35.9 mmol) of triethylamine in acetonitrile (40 ml) was added 5.6 ml (47.1 mmol) of ethyl trifluoroacetate at room temperature. For 1.5 hours. After evaporating the solvent under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline. The solvent was distilled off under reduced pressure to give the desired product (6.40) as a pale yellow solid.
g, about 87%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.04-1.30 (m, 2H), 1.45 (s, 9
H), 1.60-1.82 (m, 3H), 2.62-2.76 (m, 2H), 2.78 (t, J = 6.4
Hz, 2H), 4.07-4.18 (m, 2H), 6.33-6.48 (m, 1H). 2) Synthesis of N-methyl-N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) trifluoroacetamide Nitrogen Under an atmosphere, a solution of 1.51 g (4.87 mmol) of N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) trifluoroacetamide in 10 ml of N, N-dimethylformamide was added at 0 ° C. with sodium hydride. 0.21 g of a 60% liquid paraffin suspension (5.
25 mmol) and stirred at that temperature for 40 minutes. 0.5 ml of methyl methanesulfonate in the reaction system
(5.90 mmol) was added and stirred at room temperature for 112 hours. After further stirring at 100 ° C. for 2.5 hours, the reaction was quenched with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (ethyl acetate / hexane 40%) to obtain the desired product. 1.32 g (84% yield) of colorless oily substance ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10-1.30 (m, 2H), 1.46 (s, 9)
H), 1.50-1.96 (m, 3H), 2.56-2.77 (m, 2H), 3.04 (s, 0.78
H), 3.15 (s, 2.22H), 3.26-3.40 (m, 2H), 4.04-4.25 (m, 2
H). 3) 4-[(Methylamino) methyl] piperidine-1-
Synthesis of tert-butyl carboxylate To a solution of 1.32 g (4.07 mmol) of N-methyl-N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) trifluoroacetamide in ethanol was added sodium borohydride at room temperature. .23 g (6.08 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. 0.27 g (7.1 mmol) of sodium borohydride was further added to the reaction system, and the mixture was stirred at room temperature for 20 hours.
Stirred at 1.5 ° C for 1.5 hours. Water was added to the reaction system to stop the reaction, and extracted with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give the target compound as a colorless oil (1.00 g, quan).
t. ) Got. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96-1.24 (m, 2H), 1.45 (s, 9
H), 1.50-1.78 (m, 3H), 2.44 (s, 3H), 2.47 (d, J = 6.2Hz, 2
H), 2.63-2.76 (m, 2H), 3.98-4.21 (m, 2H).

Reference Example 27 Synthesis of tert-butyl 4-[(benzylamino) methyl] piperidine-1-carboxylate 1) In the same manner as in Reference Example 26-2), N-
Benzyl-N- [1-tert-butoxycarbonylpiperidin-4-ylmethyl] trifluoroacetamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.02-1.30 (m, 2H), 1.44 (s, 9
H), 1.50-1.63 (m, 2H), 1.69-1.99 (m, 1H), 2.52-2.74 (m,
2H), 3.98-4.24 (m, 2H), 4.59-4.72 (m, 2H), 7.16-7.42
(m, 5H). 2) In the same manner as in 3) of Reference Example 26, the colorless oil 4-
(Benzylamino) methylpiperidine-1-carboxylate-tert-butyl was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96-1.23 (m, 2H), 1.45 (s, 9
H), 1.47-1.78 (m, 3H), 2.51 (d, J = 6.4Hz, 2H), 2.54-2.78
(m, 2H), 3.79 (s, 2H), 3.95-4.18 (m, 2H), 7.19-7.44 (m, 5
H).

Reference Example 28 2- [N-tert-butoxycarbonyl-N- (3-
Phenylpropan-1-yl)] aminoethylamine 1) 2- [N-tert-butoxycarbonyl-N-
Synthesis of (3-phenylpropan-1-yl)] aminoethanol A solution of 7.6 ml (50 mmol) of 3-bromo-1-phenylpropane and 17.1 g (280 mmol) of 2-aminoethanol in 100 ml of acetonitrile was added to 16 Heated to reflux for an hour. After evaporating the solvent under reduced pressure, chloroform was added to the residue, and the mixture was washed with water and saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform (100 ml).
11.5 ml (50 mmol) of di-tert-butyl was added and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane 50%) to obtain the desired product. Yield 14.07 g (quant.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45 (s, 9H), 1.73-1.95 (m, 2
H), 2.61 (t, J = 7.8Hz, 2H), 3.15-3.44 (m, 4H), 3.67-3.80
(m, 2H), 7.12-7.35 (m, 5H). 2) 2- [N-tert-butoxycarbonyl-N-
Synthesis of (3-phenylpropan-1-yl)] aminoethylphthalimide 2- [N-tert-butoxycarbonyl-N- (3-
Phenylpropan-1-yl)] aminoethanol 1
4.07 g (50 mmol), 26.23 g (100 mmol) of triphenylphosphine and phthalimide 1
To a suspension of 4.71 g (100 mmol) in tetrahydrofuran (100 ml) at 0 ° C. was added 15.8 ml (100 mmol) of diethyl azodicarboxylate.
Stir for 4.5 hours. After evaporating the solvent under reduced pressure, diethyl ether was added to the residue and the mixture was ice-cooled. The generated crystals were removed by filtration, and the solvent was distilled off under reduced pressure. Separation and purification by column chromatography (ethyl acetate / hexane 20-30%) gave the desired product. 13.34 g (65% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.24-1.30 (s, 9H), 1.74-1.9
5 (m, 2H), 2.59 (t, J = 7.8Hz, 2H), 3.13-3.36 (m, 2H), 3.41
-3.55 (m, 2H), 3.76-3.90 (m, 2H), 7.09-7.32 (m, 5H), 7.6
3-7.92 (m, 4H). 3) 2- [N-tert-butoxycarbonyl-N-
Synthesis of (3-phenylpropan-1-yl)] aminoethylamine 2- [N-tert-butoxycarbonyl-N- (3-
To a solution of 13.34 g (32.5 mmol) of aminoethylphthalimide in 200 ml of ethanol at room temperature was added 4.8 ml (99 mmol) of hydrazine monohydrate for 1.5 hours. Heated to reflux. After cooling to room temperature, remove the precipitate by filtration,
The solvent was distilled off under reduced pressure. Water was added to the residue, extracted with chloroform, and the organic layer was washed with saturated saline. The solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil as a crude product. Yield 9.84 g (quant.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (s, 9H), 1.74-1.94 (m, 2
H), 2.60 (t, J = 7.8Hz, 2H), 2.81 (t, J = 6.6Hz, 2H), 3.11-
3.35 (m, 4H), 7.13-7.35 (m, 5H).

Reference Example 29 3- [N-tert-butoxycarbonyl-N- (3-
Phenylpropan-1-yl)] aminopropylamine 1) In the same manner as in 1) of Reference Example 28, 3- [N-ter
[t-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminopropanol was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45 (s, 9H),
1.55-1.94 (m, 4H), 2.54-2.6
6 (m, 2H), 3.06-3.22 (m, 2H),
3.29-3.43 (m, 2H), 3.46-3.
62 (m, 2H), 7.12-7.33 (m, 5
H). 2) In the same manner as in 2) of Reference Example 28, 3- [N-ter
[t-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminopropylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.
41 (s, 9H), 1.78-1.96 (m, 4H), 2.55-2.63 (m, 2H), 3.13-3.
31 (m, 4H), 3.68 (t, J = 7.4Hz, 2H), 7.12-7.31 (m, 5H), 7.6
8-7.87 (m, 4H). 3) In the same manner as in 3) of Reference Example 28, 3
-[N-tert-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminopropylamine was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (s, 9H), 1.52-1.95 (m, 4
H), 2.56-2.72 (m, 4H), 3.10-3.35 (m, 4H), 7.14-7.35 (m,
5H).

Reference Example 30 4- [N-tert-butoxycarbonyl-N- (3-
Phenylpropan-1-yl)] aminobutylamine 1) In the same manner as in 1) of Reference Example 28, 4- [N-ter
[t-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminobutanol was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.44 (s, 9H), 1.47-1.65 (m, 4
H), 1.74-1.95 (m, 2H), 2.60 (t, J = 7.8Hz, 2H), 3.11-3.29
(m, 4H), 3.60-3.72 (m, 2H), 7.12-7.33 (m, 5H). 2) In the same manner as in 2) of Reference Example 28, 4- [N-ter
[t-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminobutylphthalimide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.42 (s 9H) 1.47-1.92 (m
6H) 2.54-2.62 (m 2H) 3.09-3.27 (m 4H) 3.70 (t J = 6.
8 Hz 2H) 7.10-7.32 (m 5H) 7.68-7.89 (m 4H). 3) In the same manner as in 3) of Reference Example 28, 4
-[N-tert-butoxycarbonyl-N- (3-phenylpropan-1-yl)] aminobutylamine was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.43 (s 9H)
1.35-1.62 (m4H) 1.72-1.9
0 (m2H) 2.20-2.93 (m4H)
3.08-3.31 (m4H) 7.13-7.
34 (m5H).

Reference Example 31 3- [N-methyl-N- (3-phenylpropane-1-
Synthesis of yl) amino] propan-1-ylamine 1) Synthesis of N- (3-phenylpropan-1-yl) trifluoroacetamide 9.37 g (69.3 mmol) of 3-phenylpropylamine and 14 ml (100.4 mmol) of triethylamine (Mmol) in acetonitrile (70 ml) at room temperature was added with 16.4 ml (122.7 mmol) of ethyl trifluoroacetate, and the mixture was stirred at the same temperature for 2 hours. After evaporating the solvent under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water and saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the desired product. White crystals Yield 15.95 g (quant.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.86
-2.04 (m 2H) 2.69 (t J = 7.5 Hz 2H) 3.39 (ddJ = 6.6,
6.6 Hz 2H) 6.16-6.43 (m1H) 7.09-7.41 (m5H). 2) Synthesis of N-methyl-N- (3-phenylpropan-1-yl) trifluoroacetamide N- (3 -Phenylpropan-1-yl) trifluoroacetamide (8.0 g, 34.6 mmol) in N, N-dimethylformamide (70 ml) at 0 ° C. in 60% liquid paraffin suspension (1.5 g). (37.5 mmol) was added and the mixture was stirred at the same temperature for 40 minutes. To the reaction system was added 3.5 ml (41.3 mmol) of methyl methanesulfonate at 0 ° C.
Stir at room temperature for 1.5 hours. Water was added to the reaction system to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. Separation and purification by column chromatography (ethyl acetate / hexane 15%) gave the desired product. 7.48 g (88% yield) of pale yellow oily substance ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.83-2.02 (m 2H) 2.61-2.6
9 (m 2H) 3.00 (s 1.17H) 3.09 (s 1.83H) 3.35-3.52
(m 2H) 7.14-7.37 (m 5H).

3) Synthesis of 3- [N-methyl-N- (3-phenylpropan-1-yl) amino] propan-1-ylphthalimide N-methyl-N- (3-phenylpropan-1-yl)
To a solution of 4.0 g (16.3 mmol) of trifluoroacetamide in 30 ml of ethanol was added 1.23 g (32.5 mmol) of sodium borohydride at room temperature, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction system, extracted with methylene chloride, and the organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (3-phenylpropan-1-yl) methylamine (2.5 g) as a pale yellow oil. 2.6 g (<16.3 mmol) of this (3-phenylpropan-1-yl) methylamine, 4.81 g (17.9 mmol) of N- (3-bromopropyl) phthalimide
And 3.0 ml (21.5 mmol) of triethylamine
The solution was heated at reflux for 20 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 20%)
And the desired product was obtained. Colorless oily substance 3.49 g (yield 64%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.07-1.96 (m 4H) 2.24 (s
3H) 2.37-2.47 (m 4H) 2.62 (t J = 7.7 Hz 2H) 3.74 (t
J = 7.3 Hz 2H) 7.12-7.33 (m 5H) 7.66-7.77 (m 2H) 7.7
9-7.88 (m2H). 4) 3- [N-methyl-N- (3-phenylpropane-
Synthesis of 1-yl) amino] propan-1-ylamine 3- [N-methyl-N- (3-phenylpropan-1-
Yl) amino] propane-1-ylphthalimide 3.4
9 g (10.37 mmol) of ethanol (50 ml)
1.5 ml of hydrazine monohydrate (3
0.92 mmol) and heated to reflux for 40 minutes. The resulting solid was removed by filtration, and the filtrate was concentrated. The residue was made strongly alkaline by adding water and sodium hydroxide, and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product. Colorless oily substance Yield 2.09 g (98% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.55-1.87 (m 4H) 2.22 (s
3H) 2.34-2.43 (m 4H) 2.59-2.67 (m 2H) 2.75 (s J = 7.
0 Hz 2H) 7.13-7.36 (m5H).

Reference Example 32 Synthesis of 4-[(3-phenylpropan-1-yl) aminomethyl] piperidine 1) N- (3-phenylpropan-1-yl) -N-
(1-tert-butoxycarbonylpiperidine-4-
Synthesis of ylmethyl) trifluoroacetamide Under a nitrogen atmosphere, a solution of 1.73 g (5.57 mmol) of N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) trifluoroacetamide in N, N-dimethylformamide (20 ml) was added. 0.25 g of a 60% liquid paraffin suspension of sodium hydride at 0 ° C. (6.
(25 mmol) and stirred at 0 ° C. for 30 minutes. 1.0 ml (6.58 mmol) of 1-bromo-3-phenylpropane was added, and the mixture was stirred at room temperature for 2.5 hours and further at 60 ° C. for 1 hour. Then, water was added to the reaction system to stop the reaction. Extracted with ethyl. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (ethyl acetate / hexane 30%) gave the desired product. Colorless liquid Yield 1.49 g (yield 62%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.99-1.33 (m 2H) 1.46 (s
9H) 1.43-1.67 (m 3H) 1.82-2.03 (m 2H) 2.51-2.72 (m
4H) 3.17-3.46 (m 4H) 4.00-4.22 (m 2H) 7.12-7.37
(m5H). 2) Synthesis of 4-[(3-phenylpropan-1-yl) aminomethyl] piperidine N- (3-phenylpropan-1-yl) -N- [1-
tert-butoxycarbonylpiperidin-4-ylmethyl] trifluoroacetamide 1.49 g (3.48)
1.0 ml (12 mmol) of 12N hydrochloric acid was added to ethanol (10 ml) at room temperature, and the mixture was stirred for 20 minutes. After distilling off the solvent under reduced pressure, the residue was 3 ml of 12N hydrochloric acid.
(36 mmol) and stirred at room temperature for 20 minutes. After ethanol was added to the reaction system, the solvent was distilled off under reduced pressure to obtain 1.29 g (quant) of a crude product as a white solid. To a solution of 0.33 g (0.90 mmol) of this crude product in ethanol (4 ml) was added 4 ml (4 mmol) of a 1N aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 30 minutes. After distilling off the ethanol under reduced pressure, the residue was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product. Colorless liquid Yield 0.1858 g (89% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.96-1.24 (m 2H) 1.45-4.9
2 (m 5H) 2.46 (d J = 6.6Hz 2H) 2.50-2.72 (m 6H) 2.98
-3.16 (m 2H) 7.10-7.33 (m 5H).

Reference Example 33 Synthesis of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate Preparation of ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate (11.8 g) Hexamethylenetetramine (14.0 g) was added to an acetic acid (120 ml) solution, and 90 ° C.
For 10 hours. After cooling, add ethyl acetate (3
60 ml) and washed with water. The obtained organic layer was neutralized with a 30% aqueous sodium hydroxide solution under ice-cooling, and further washed with water. The obtained organic layer was concentrated, n-hexane (100 ml) was added to the precipitated crystals, and the mixture was stirred at room temperature for 1 hour. The obtained crystals are collected by filtration, dried, and dried.
6g, 78% yield). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.30 (t, J = 7.1 Hz, 3H),
4.22 (q, J = 7.1Hz, 2H), 5.70 (m, 1H), 6.55-6.64 (m, 2
H), 6.80 (s, 1H), 7.01 (s, 1H).

Reference Example 34 Synthesis of 5-chloro-3-formylimidazo [1,2-a] pyridine 5-chloro-imidazo [1,2-a] pyridine (997
mg) and hexamethylenetetramine (1.8 g) in acetic acid (10 ml) were stirred at 90 ° C for 5 hours. After cooling down,
Ethyl acetate / tetrahydrofuran (4/1; 2
00 ml) and washed with saturated saline. After neutralizing the obtained organic layer with a 2N aqueous solution of sodium hydroxide,
Dried over anhydrous magnesium sulfate and concentrated. After the precipitated crystals were washed with diethyl ether, the target product (440 m
g, yield 37%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20 (d, J =
7.4 Hz, 1H), 7.44 (dd, J = 7.
4, 8.9 Hz, 1H), 7.76 (d, J =
8.9 Hz, 1H), 8.50 (s, 1H),
10.71 (s, 1H).

Reference Example 35 Synthesis of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate Imidazo [1,2-a] pyridine-5-thiol (44
8 mg), ethyl thioglycolate (0.36
ml) and a solution of sodium ethylate (210 mg) in ethanol (10 ml) were stirred under reflux for 3 hours. After allowing to cool, it was concentrated. Ethyl acetate (10 ml) was added to the residue, and the mixture was extracted with 1N aqueous hydrochloric acid. The obtained aqueous layer is 1N-
Neutralized with aqueous sodium hydroxide and extracted with ethyl acetate. The obtained organic layer was washed with water and concentrated. After washing the precipitated crystals with diisopropyl ether (20 ml),
Drying yielded the desired product (430 mg, 65% yield).

Reference Example 36 Synthesis of 6-tert-butyldimethylsiloxy-2- (2-hydroxyethyl) -2,5,7,8-tetramethylchroman 1) 6-Hydroxy-2,5,7,8- Synthesis of methyl tetramethylchroman-2-acetate A suspension of 10.0 g (37.83 mmol) of 6-hydroxy-2,5,7,8-tetramethylchroman-2-acetic acid in methanol (50 ml) was concentrated at room temperature. 0.5 ml of sulfuric acid
(6 mmol) and stirred for 3 days. 0 ° C for the reaction system
After adding saturated aqueous sodium hydrogen carbonate until the pH became 5-7, the solvent was distilled off under reduced pressure. Water was added to the residue and extracted with diethyl ether. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a brown oil. Yield 7.69 g (75%) ¹ H-NMR (CDCl ₃ ) δ: 1.41 (s 3H), 1.82-2.06 (m 2H), 2.09
(s 3H), 2.11 (s 3H), 2.16 (s 3H), 2.60-2.68 (m 4H),
3.69 (s 3H) .IR (neat): 3494, 2933, 1730, 1450, 1329, 1252, 1165,
1092, 1028, 924 cm ^-1

2) Synthesis of methyl 6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-acetate Under a nitrogen atmosphere, 6-hydroxy-2,5,7,8-tetramethylchroman 7.69 g of methyl acetate (27.
63 mmol) and 2.82 g of imidazole (41.4)
Mmol) in DMF (54 ml) at room temperature.
tert-butyldimethylsilane5.41 g (35.9)
Mmol) and stirred at 0 ° C. for 20 hours. The reaction mixture was added to vigorously stirred saturated aqueous sodium bicarbonate-diethyl ether to terminate the reaction, and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (ethyl acetate / hexane: 10%) to obtain the desired product as a yellow oil. Yield 11.35 g (quant) ¹ H-NMR (CDCl ₃ ) δ: 0.11 (s 6H), 1.04 (s 9H), 1.41 (s 3
H), 1.85-2.03 (m 2H), 2.05 (s 6H), 2.09 (s 3H), 2.55-
2.64 (m 4H), 3.69 (s 3H). IR (neat): 2937, 2858, 1740, 1460, 1254, 1092, 941,
887, 837, 779 cm ^-1

3) 6-tert-butyldimethylsiloxy-2- (2-hydroxyethyl) -2,5,7,8-
Synthesis of tetramethylchroman Lithium aluminum hydride 1.1 g under nitrogen atmosphere
(28.99 mmol) in diethyl ether (50 m
l) A solution of 11.35 g (28.91 mmol) of methyl 6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-acetate in diethyl ether (10 ml) was added to the suspension at 0 ° C. The mixture was stirred at the same temperature for 1 hour. Water (1.1 ml), 15%
An aqueous solution of sodium hydroxide (1.1 ml) and water (1.1
ml) were added in this order and stirred at room temperature for 30 minutes. Magnesium sulfate was added to the mixture, the precipitate was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate / hexane:
20-30%) to give the desired product (9.65 g, yield 92%) as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.12 (s 6H), 1.05 (s 9H), 1.28 (s 3H
H), 1.70-2.02 (m 4H), 2.06 (s 6H), 2.10 (s 3H), 2.50-
2.67 (m2H), 3.83-4.03 (m2H).

Reference Example 37 Synthesis of 1- (trans-4-aminomethyl-1-cyclohexylmethyl) -4-phenylpiperidine dihydrochloride 1) trans-4- [N- (tert-butoxycarbonyl) aminomethyl] Synthesis of cyclohexane-1-carboxylic acid 47.16 g (300 mmol) of trans-4-aminomethylcyclohexane-1-carboxylic acid was purified with 30 parts of purified water.
To a suspension added to a mixed solvent consisting of 0 ml and 300 ml of THF, 41.8 ml (300 mmol) of triethylamine and 65.48 g of di-tert-butyl dicarbonate (3.
00 mmol) and the reaction was stirred at room temperature for 2 hours. After the reaction, 12N hydrochloric acid was added until the pH of the aqueous layer became 2, followed by extraction with 200 ml of ethyl acetate. The organic layer was washed with saturated saline (300 ml), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product (67.3).
g (87.2% yield) as a white solid. The crude product was used for the next reaction without purification. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.74-0.98 (m, 2H), 1.09-1.
47 (m, 12H), 1.61-1.79 (m, 2H), 1.79-1.98 (m, 2H), 1.98-
2.19 (m, 1H), 2.76 (t, 2H, J = 6.2Hz), 6.78 (t, 1H, J = 5.4H
z). IR (KBr): 3375,1694,1529cm ^-1 .

2) trans-4- [N- (tert-
Butoxycarbonyl) aminomethyl] cyclohexane-
Synthesis of 1-Methanol The trans-4 was added to 400 ml of a 1.0 M borane THF solution.
-[N- (tert-butoxycarbonyl) aminomethyl] cyclohexane-1-carboxylic acid 51.7 g (20
(0 mmol) was added in small portions at 0 ° C. and the reaction was
Stirred for hours. After the reaction, the reaction solution was poured into ice water, the mixture was stirred well, and extracted with 200 ml of ethyl acetate. The organic layer was washed with 250 ml of saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 47.06 g of a crude product (yield 96.7%) as a white solid. The crude product was used for the next reaction without purification. ¹ H-NMR (200 MHz; DMSO-d ₆ ) δ: 0.74-0.96 (m, 4H), 1.14-1.
45 (m, 11H), 1.62-1.81 (m, 4H), 2.76 (t, 2H, J = 6.2Hz), 3.
20 (t, 2H, J = 6.0Hz), 4.31 (t, 1H, OH, J = 6.0Hz), 6.72 (t, 1
H, J = 5.4Hz). IR (KBr): 3376,1698,1533cm ^-1 .

3) Synthesis of N- (trans-4-bromomethyl-1-cyclohexylmethyl) -N- (tert-butoxycarbonyl) amine trans-4- [N- (tert-butoxycarbonyl) aminomethyl] cyclohexane-1 13.0 g of carbon tetrabromide in a methylene chloride (30 ml) solution of 5.00 g (20.55 mmol) of methanol and 6.42 g (24.48 mmol) of triphenylphosphine at 0 ° C.
(41.1 mmol) and stirred at room temperature for 20 hours. The reaction mixture was separated and purified by column chromatography (ethyl acetate / hexane: 10%) to obtain the desired product as a white solid. Yield 2.53 g (40% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.83-1.14 (m, 4H), 1.44 (s,
9H), 1.49-1.70 (m, 2H), 1.71-2.01 (m, 4H), 2.98 (t,
J = 6.4Hz, 2H), 3.28 (d, J = 6.2Hz, 2H), 4.47-4.66
(m, 1H). IR (KBr): 3390, 2921, 1685, 1524, 1257, 1174, 613 c
m ^-1

4) 1- [trans-4- [N- (te
Synthesis of rt-butoxycarbonyl) aminomethyl] -1-cyclohexylmethyl] -4-phenylpiperidine N- (trans-4-bromomethyl-1-cyclohexylmethyl) -N- (tert-butoxycarbonyl)
A solution of 2.51 g (8.20 mmol) of amine, 1.32 g (8.19 mmol) of 4-phenylpiperidine and 2.3 ml (16.5 mmol) of triethylamine in ethanol (10 ml) was heated to reflux under a nitrogen atmosphere for 64 hours. did. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (methanol / ethyl acetate: 10%) to obtain the desired product as a pale yellow solid. Yield 1.02 g (yield 32%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.85-0.99 (m, 4H), 1.45 (s,
9H), 1.61-2.15 (m, 12H), 2.22 (d, J = 6.8Hz, 2H), 2.
39-2.56 (m, 1H), 2.90-3.10 (m, 4H), 4.51-4.64 (m, 1
H), 7.13-7.39 (m, 5H). IR (KBr): 3386, 2937, 1691, 1522, 1443, 1279, 1250,
1171, 698 cm ^-1

5) Synthesis of 1- (trans-4-aminomethyl-1-cyclohexylmethyl) -4-phenylpiperidine dihydrochloride 1- [trans-4- [N- (tert-butoxycarbonyl) aminomethyl] -1-cyclohexylmethyl] -4-phenylpiperidine (1.02 g, 2.64 mmol) in ethanol (10 ml) at room temperature.
10 ml (120 mmol) of 2N hydrochloric acid was added and stirred for 1 hour. After concentration under reduced pressure (crystals precipitated), diethyl ether was added, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as pale purple crystals. Yield 0.81 g (yield 85%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.85-1.11 (m, 4H), 1.68-
2.08 (m, 6H), 2.14-2.40 (m, 2H), 2.55-3.17 (m, 7H),
3.40-3.64 (m, 4H), 7.18-7.41 (m, 5H), 7.92-8.16 (m, 3
H), 10.17-10.44 (m, 1H). IR (neat): 1603, 1504, 1433, 9985, 945, 754, 702 cm
^-1

Reference Example 38 Synthesis of 1- [4- (aminomethyl) benzyl] -4-phenylpiperidine dihydrochloride 1) Synthesis of 4- [N- (tert-butoxycarbonyl) aminomethyl] benzoic acid To a suspension of 15 g (99.2 mmol) of (aminomethyl) benzoic acid in 100 ml of THF was added 100 ml (100 mmol) of a 1N aqueous sodium hydroxide solution at room temperature, and 23.8 g of di-tert-butyl dicarbonate (1
09 mmol) and stirred for 20 hours. 6 in the reaction system
N hydrochloric acid was added until the pH reached 4, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and washed with magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with hexane to obtain the desired product as white crystals. Yield: 22.23 g (89% yield) Melting point: 161 ° -162 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40 (9H, s), 4.19 (2H,
d, J = 6.4 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.39-7.50
(1H, m), 7.89 (2H, d, J = 8.2 Hz). IR (KBr): 3357, 2982, 1686, 1510, 1431, 1292, 1246,
1171 cm ^-1

2) Synthesis of 4- [N- (tert-butoxycarbonyl) aminomethyl] -1-phenylmethanol 1M borane-THF complex 100 ml (100 mmol)
At 0 ° C with 4- [N- (tert-butoxycarbonyl)
[Aminomethyl] benzoic acid (25.13 g, 100 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to ice water to stop the reaction, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The crystals formed by evaporating the solvent under reduced pressure were collected by filtration. The crystals were washed with hexane to obtain the desired product as white crystals. Yield 11.07 g (47% yield) Melting point 88-90 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 4.31 (2H, d,
J = 6.0 Hz), 4.68 (2H, s), 4.76-5.06 (1H, s), 7.23-
7.38 (m, 4H). IR (KBr): 3347, 2980, 1686, 1514, 1248, 1171 cm ^-1

3) Synthesis of 1- [4- [N- (tert-butoxycarbonyl) aminomethyl] benzyl] -4-phenylpiperidine 4- [N- (tert-butoxycarbonyl) aminomethyl] -1-phenylmethanol 5.0 g (21.07
Mmol) and 5.9 ml of triethylamine (42.3).
To a solution of 3 mmol) in THF (42 ml) was added 2.5 ml (32.3 mmol) of methanesulfonyl chloride at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and washed with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product as a pale brown solid (6.72 g, 21.07 mmol). To a solution of 6.72 g (21.07 mmol) of crude mesylate in ethanol (42 ml) was added 5.9 ml (4.
2.33 mmol) and 4-phenylpiperidine 3.4
0 g (21.09 mmol) was added, and the mixture was heated under reflux for 18 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (ethyl acetate / hexane: 50%) to obtain the desired product as a single yellow solid. Yield 5.77 g (yield 72%) Melting point 73-74 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.73-1.88
(4H, m), 1.99-2.19 (1H, m), 2.94-3.08 (2H, m), 3.54
(2H, s), 4.31 (2H, d, J = 5.8 Hz), 4.73-4.96 (1H,
m), 7.13-7.36 (4H, m). IR (KBr): 3389, 1690, 1518, 1269, 1171 cm ^-1

4) Synthesis of 1- [4- (aminomethyl) benzyl] -4-phenylpiperidine dihydrochloride 1- [4- [N- (tert-butoxycarbonyl) aminomethyl] benzyl] -4-phenyl Piperidine5.
77 g (15.16 mmol) of 12N hydrochloric acid 10 at room temperature.
ml (120 mmol) was added, and the mixture was stirred for 2 hours. Ethanol was added to the reaction system and concentrated under reduced pressure. Ethanol and diethyl ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 4.72 g (88% yield) Melting point 257-260 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82-2.01 (2H, m), 2.05
-2.32 (2H, m), 2.68-2.88 (1H, m), 2.91-3.15 (2H, m
m), 3.28-3.56 (2H, m), 3.99-4.12 (2H, m) 4.32 (2H,
d, J = 5.0 Hz), 7.12-7.44 (5H, m), 7.59 (2H, d, J = 8.
0 Hz), 7.73 (2H, d, J = 8.0 Hz) 8.34-8.74 (3H, m), 1
1.25-11.50 (1H, m). IR (KBr): 2091, 1601, 1530, 14
50, 1533, 1422, 1399, 93
9,746,700 cm ^-1

Reference Example 39 Synthesis of 1- [4- (aminomethyl) benzyl] -4-benzylpiperidine dihydrochloride 1) 1- [4- [N- (tert-butoxycarbonyl) aminomethyl] benzyl]- Synthesis of 4-benzylpiperidine 4- [N- (tert-butoxycarbonyl) aminomethyl] -1-phenylmethanol 5.0 g (21.07)
Mmol) and 5.9 ml of triethylamine (42.3).
To a solution of 3 mmol) in THF (42 ml) was added 2.5 ml (32.3 mmol) of methanesulfonyl chloride at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and washed with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product as a pale brown solid (7.21 g, 21.07 mmol). To a solution of 7.21 g (21.07 mmol) of crude mesylate in 42 ml of ethanol, 5.9 g of triethylamine (42.
33 mmol) and 4-69-phenylpiperidine 3.69
(21.05 mmol) was added and the mixture was refluxed for 18 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (ethyl acetate / hexane: 50%) to obtain the desired product as a single yellow oil. Yield 5.77 g (69% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.46
(9H, s), 1.85-2.01 (2H, m), 2.53 (2H, d, J = 6.2 Hz),
2.78-2.93 (2H, m), 3.48 (2H, s), 4.29 (2H, d, J = 6.
0 Hz), 4.70-4.88 (1H, m) 7.07-7.34 (9H, m). IR (neat): 3350, 2924, 1709, 1508, 1452, 1365, 125
2, 1173 cm ^-1

2) Synthesis of 1- [4- (aminomethyl) benzyl] -4-benzylpiperidine dihydrochloride 1- [4- [N- (tert-butoxycarbonyl) aminomethyl] benzyl] -4-benzyl Piperidine5.
77 g (14.6 mmol) of 12N hydrochloric acid at room temperature in 10 m
1 (120 mmol) was added and the mixture was stirred for 1 hour. Ethanol was added to the reaction system, and the mixture was concentrated under reduced pressure. Ethanol and diethyl ether were added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 4.25 g (79% yield) Melting point 245-250 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.50-1.88 (5H, m), 2.65
-2.98 (2H, m), 3.16-3.41 (4H, m), 3.98-4.14 (2H, m
m), 4.17-4.28 (2H, m), 7.12-7.36 (5H, m) 7.55 (2H,
d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4Hz) 8.29-8.62 (3H,
m) 10.70-10.98 (1H, m). IR (KBr): 3395, 2980, 2500, 1593, 1512, 1454, 1078,
881, 860, 748, 700cm ^-1

Reference Example 40 Synthesis of tert-butyl 4-[(dimethoxyphosphoryl) acetyl] piperidine-1-carboxylate 1) Synthesis of ethyl 1- (tert-butoxycarbonyl) piperidine-4-carboxylate Piperidine-4-carboxylate 16.377 g of ethyl acid (1
04.17 mmol) in 150 ml of tetrahydrofuran
25.0 g of di-tert-butyl dicarbonate at room temperature
(115 mmol) in 50 ml of tetrahydrofuran was added dropwise, and the mixture was stirred as it was for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 9/1).
~ 6/1) to obtain the desired product. Colorless liquid Yield 26.631 g (99% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.258 (3H, t, 7.1 Hz), 1.456
(9H, s), 1.518-1.718 (2H, m), 1.880 (2H, br d, 13.3Hz),
2.434 (1H, tt, 4.0Hz, 11.0Hz), 2.832 (2H, brt, 13.9Hz),
4.031 (2H, brd, 13.4Hz), 4.145 (2H, q, 7.1Hz). IR (neat): 2976, 1732, 1695, 14
21, 1367, 1313, 1240, 116
7, 1041 cm ^-1

2) Synthesis of tert-butyl 4-[(dimethoxyphosphoryl) acetyl] piperidine-1-carboxylate To a solution of 10.1 g (81.3 mmol) of dimethyl methylphosphonate in 100 ml of tetrahydrofuran was added at -78 ° C.
53.2 hexane solution of 1.6 Mn-butyllithium in 53.2
ml (85.2 mmol) was added dropwise, and the mixture was stirred as it was for 10 minutes. Thereto 9.964 g of ethyl 1- (tert-butoxycarbonyl) piperidine-4-carboxylate
(38.721 mmol) of tetrahydrofuran 50 m
The solution was added at -78 ° C, and the temperature was raised to room temperature with stirring. The reaction solution was poured into an aqueous ammonium chloride solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 1/1 to ethyl acetate) to obtain the desired product. Colorless liquid Yield 11.487 g (88% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.45
3 (9H, s), 1.299-1.700 (2H, m), 1.865 (2H, br d, 11.0Hz),
2.661-2.850 (3H, m), 3.147 (2H, d, 22.8Hz), 3.793 (6H, m
d, 11.4Hz), 4.109 (2H, br d, 12.8Hz). IR (neat): 3475, 2931, 1691, 1423, 1242, 1169, 103
0, 810 cm ^-1

Reference Example 41 Synthesis of tert-butyl 4- [4- (dimethoxyphosphoryl) -3-oxobutyl] piperidine-1-carboxylate 1) (E) -4- (2-Ethoxycarbonylvinyl) piperidine-1- Synthesis of tert-butyl carboxylate To a solution of 10.7 g (84.4 mmol) of oxalyl chloride in 100 ml of tetrahydrofuran, 12.0 ml (169 mmol) of dimethyl sulfoxide was added dropwise at -78 ° C. After stirring for 5 minutes, a solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate in 100 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at -78 ° C for 15 minutes. This was added at -78 ° C with triethylamine 47.0.
ml (338 mmol) was added and the temperature was raised to room temperature. The reaction mixture was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude tert-butyl 4-formylpiperidine-1-carboxylate was used for the next reaction without purification. 2.48 g (61.9 mmol) of a 60% sodium hydride liquid paraffin suspension was washed twice with hexane, then suspended in 50 ml of toluene, and 15.1 g of ethyl diethylphosphonoacetate (67. (5 mmol) in 50 ml of toluene was added dropwise and stirred at room temperature for 30 minutes. The crude tert-butyl 4-formylpiperidine-1-carboxylate obtained above was treated with toluene 100
The solution was added dropwise at room temperature and stirred at room temperature overnight (after about 1 hour, a gummy precipitate appeared and could not be stirred).
The reaction solution was poured into water and extracted twice with diethyl ether.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (hexane / ethyl acetate: 6
/ 1) to obtain the desired product. Yellow liquid Yield 14.281 g (90% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.236-1.420 (2H, m), 1.293
(3H, t, 7.0Hz), 1.460 (9H, s), 1.737 (2H, br d, 13.8Hz),
2.205-2.383 (1H, m), 2.762 (2H, brt, 11.9Hz), 4.121 (2
H, br d, 12.4Hz), 4.193 (2H, q, 7.1Hz), 5.801 (1H, dd, 1.2
Hz, 16.0Hz), 6.897 (1H, dd, 6.6Hz, 15.8Hz). IR (neat): 2978, 1718, 1693, 1421, 1275, 1169 cm ^-1

2) (E) -4- [4- (Dimethoxyphosphoryl) -3-oxo-1-butenyl] piperidine-1
Synthesis of tert-butyl carboxylate To a solution of 13.1 g (106 mmol) of dimethyl methylphosphonate in 100 ml of tetrahydrofuran was added -78 ° C.
1.6 Mn-butyllithium hexane solution 69.2
ml (111 mmol) was added dropwise and the mixture was stirred for 10 minutes. To this, a solution of 14.271 g (50.362 mmol) of tert-butyl (E) -4- (2-ethoxycarbonylvinyl) piperidine-1-carboxylate in 100 ml of tetrahydrofuran was added at -78 ° C, and the temperature was raised to room temperature with stirring. Warmed. The reaction solution was poured into an aqueous ammonium chloride solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 1/1 to ethyl acetate),
The desired product was obtained. Yellow liquid Yield 11.768 g (65% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.115-1.403 (2H, m), 1.462
(9H, s), 1.559-1.832 (2H, m), 2.271-2.394 (1H, m), 2.76
9 (2H, brt, 12.1Hz), 3.228 (2H, d, 22.6Hz), 3.786 (6H, d,
11.4Hz), 3.962-4.189 (2H, m), 6.212 (1H, dd, 1.3Hz, 15.9
Hz), 6.862 (1H, dd, 6.5Hz, 15.7Hz). IR (neat): 3479, 2958, 1689, 1425, 1250, 1171, 103
2, 970, 814 cm ^-1

3) 4- [4- (dimethoxyphosphoryl)
-3-oxobutyl] piperidine-1-carboxylic acid te
Synthesis of rt-butyl (E) -4- [4- (dimethoxyphosphoryl) -3-oxo-1-butenyl] piperidine-1-carboxylic acid te
A solution of 5.443 g (15.062 mmol) of rt-butyl in 50 ml of methanol was added to 10% palladium / carbon (5%).
Using 3 g of a catalyst (containing 0% water), hydrogenation was performed at room temperature and normal pressure until the raw materials disappeared. The catalyst in the reaction solution was separated by filtration using Celite, and the catalyst was washed with methanol. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 1/1 to ethyl acetate) to obtain the desired product. Colorless liquid Yield 4.732 g (87% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.994-1.691 (9H, m), 1.449
(9H, s), 2.659 (2H, brt, 12.1Hz), 3.094 (2H, d, 22.6Hz),
3.789 (6H, d, 11.4Hz), 3.962-4.185 (2H, m). IR (neat): 3479, 2927, 1689, 1423, 1246, 1167, 103
0, 812 cm ^-1

Reference Example 42 Synthesis of tert-butyl 4- (diethoxyphosphorylmethylthiomethyl) piperidine-1-carboxylate 1) Synthesis of S- (diethoxyphosphorylmethyl) thioacetate 17.527 g of diethyl chloromethylphosphonate (9.
To a solution of 3.938 mmol) in N, N-dimethylformamide (50 ml) was added 12.9 g (113) of potassium thioacetate.
Mmol) and stirred at 100 ° C. for 3 hours. The reaction solution was poured into water, saturated with sodium chloride, and then extracted with ethyl acetate.
Extracted times. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 3/1 to 1/1) to obtain the desired product. Orange liquid Yield 13.059 g (61% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.330 (6H, t, 7.2 Hz), 2.398
(3H, s), 3.231 (2H, d, 14.0Hz), 4.141 (4H, quint, 7.4Hz). IR (neat): 2983, 1701, 1252, 1051, 1024, 968, 623 c
m ^-1

2) Synthesis of tert-butyl 4- (diethoxyphosphorylmethylthiomethyl) piperidine-1-carboxylate S- (diethoxyphosphorylmethyl) thioate 1.52
Under ice-cooling, 1.30 g (6.76 mmol) of a 28% sodium methoxide methanol solution was added to a 9 g (6.759 mmol) methanol 30 ml solution, and
Stirred for 0 minutes. To this reaction solution was added crude tert-butyl 4- (mesyloxymethyl) piperidine-1-carboxylate (4- (hydroxymethylthiomethyl) piperidine-1.
-A solution of 1.75 g (8.11 mmol) of tert-butyl carboxylate and 1.51 ml (10.8 mmol) of triethylamine in 30 ml of tetrahydrofuran was cooled with ice.
0.73 ml (9.46 mmol) of methanesulfonyl chloride was added, the mixture was stirred for 0.5 hour as it was, poured into water, extracted twice with ethyl acetate, and the collected organic layer was dried over magnesium sulfate and concentrated. The mixture was heated under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure, poured into water, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 3/1 to ethyl acetate) to obtain the desired product. Yellow liquid Yield 2.325 g (yield 90%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.042-1.256 (2H, m), 1.353
(6H, t, 6.9Hz), 1.454 (9H, s), 1.552-1.730 (1H, m), 1.80
4 (2H, br d, 13.8Hz), 2.629-2.778 (6H, m), 4.060-4.130
(2H, m), 4.181 (4H, quint, 7.4Hz). IR (neat): 2978, 2929, 1691, 1423, 1246, 1163, 105
3, 1026, 966, 827 cm ^-1

Reference Example 43 4- (Diethoxyphosphorylmethanesulfonylmethyl)
Synthesis of tert-butyl piperidine-1-carboxylate 2.325 g of tert-butyl 4- (diethoxyphosphorylmethylthiomethyl) piperidine-1-carboxylate
(6.095 mmol), 30% hydrogen peroxide 2.76
g (24.4 mmol) and a solution of 0.2 g of sodium tungstate in 50 ml of methanol were stirred at room temperature overnight. The reaction solution was poured into water and extracted four times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography (hexane / ethyl acetate: 1/1).
To ethyl acetate) to obtain the desired product. Colorless liquid Yield 2.041 g (81% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.224-1.410 (2H, m), 1.376
(6H, t, 7.1Hz), 1.452 (9H, s), 1.943 (2H, br d, 13.2Hz),
2.203-2.335 (1H, m), 2.768 (2H, brt, 12.3Hz), 3.325 (2
H, d, 6.6Hz), 3.567 (2H, d, 16.4Hz), 4.090 (2H, br d, 12.4
Hz), 4.234 (4H, qd, 7.1Hz, 8.3Hz). IR (neat): 2976, 1689, 1425, 1311, 1250, 1165, 105
1, 1022, 972, 835, 798cm ^-1

Reference Example 44 Synthesis of tert-butyl 4- (diphenoxyphosphorylmethanesulfonylaminomethyl) piperidine-1-carboxylate Phenyl diphenoxyphosphorylmethanesulfonate
A solution of 405 g (5.947 mmol) and 1.66 g (7.73 mmol) of 1- (tert-butoxycarbonyl) piperidin-4-ylmethylamine in 50 ml of toluene was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate: 2/1 to 1/1).
The desired product was obtained. Yellow liquid Yield 2.245 g (yield 72%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.000-1.181 (2H, m), 1.449
(9H, s), 1.524-1.724 (3H, m), 2.636 (2H, t, 13.0Hz), 2.9
73 (2H, t, 6.4Hz), 3.883 (2H, d, 16.0Hz), 4.087 (2H, br d,
11.0Hz), 5.409 (1H, t, 6.4Hz), 7.186-7.264 (6H, m), 7.3
32-7.405 (4H, m). IR (neat): 3207, 2934, 1687, 1489, 1425, 1338, 127
7, 1213, 1182, 1163, 951, 766 cm ^-1

Reference Example 45 Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 3.00 g of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid ( To a solution of 12.18 mmol) in methanol (9 ml) was added at room temperature 18 ml (18 mmol) of a 1N aqueous sodium hydroxide solution,
Stirred for 2.5 hours. The reaction was cooled to 0 ° C., 1N hydrochloric acid was added until the pH reached 5, and the resulting crystals were collected by filtration. The crystals were washed with water, ethanol and diethyl ether to give the desired product as an orange solid (yield 1.98 g,
Yield 69%). Elemental analysis (as C ₁₀ H ₆ N ₂ O ₂ S · 1.0H ₂ O) Calculated: C, 50.84; H, 3.41; N, 11.86. Found: C, 50.59; H, 3.41; N, 11.62.

Reference Example 46 1-aminoacetyl-4- (3-phenylpropane-1
Synthesis of -yl) piperazine dihydrochloride 1) Synthesis of tert-butyl 4- (3-phenylpropyl) piperazine-1-carboxylate 1-tert-butoxycarbonylpiperazine 7.06
g (37.9 mmol) in a solution of ethanol (50 ml) at room temperature in 8.0 ml (57.4 mmol) of triethylamine and 7.09 g of 1-bromo-3-phenylpropane.
(39.7 mmol), and the mixture was heated and refluxed for 16 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction system, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography (ethyl acetate / hexane = 25-50%), and the solvent was distilled off under reduced pressure to obtain the target compound as a pale yellow liquid. Yield 8.69 g (75%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.46 (9H, s), 1.75-1.90
(2H, m), 2.30-2.42 (6H, m), 2.64 (2H, t, J = 7.6 H
z), 3.43 (4H, t, J = 5.2 Hz), 7.11-7.30 (5H, m) .IR (neat) 1699, 1456, 1419, 1365, 1288, 1238, 117
3, 1126, 1007, 866, 748, 700cm ^-1

2) Synthesis of 1- (3-phenylpropyl) -piperazine dihydrochloride 4-phenylpropylpiperazine-1-carboxylic acid-t
To 8.45 g (27.8 mmol) of tert-butyl was added 10 ml (120 mmol) of 12N hydrochloric acid at room temperature, followed by stirring for 1 hour. After adding ethanol to the reaction system, it was concentrated under reduced pressure. Diethyl ether was added to the precipitated white crystals,
The crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Further, crystallization was performed from the mother liquor to obtain a target substance as white crystals. Yield First crystal 5.41 g (70%) Second crystal 1.77 g (23%) Melting point 182-189 ° C. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.91-2.13 (2H, m), 2.65
(2H, t, J = 7.8 Hz), 3.02-3.86 (10H, m), 7.15-7.37
(5H, m), 9.46-9.96 (2H, m) .IR (KBr) 3500, 3410, 3026, 2939, 2403, 1554, 1443,
1385, 966, 762, 706 cm ^-1 3) Synthesis of 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (3-phenylpropan-1-yl) piperazine N-tert-butoxycarbonylglycine 1 .90g
(10.8 mmol) and 2.48 g (16.2 mmol) of 1-hydroxybenzotriazole monohydrate in acetonitrile (20 ml) were stirred at room temperature with N-ethyl-.
N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride (3.11 g, 16.2 mmol) was added, and the mixture was stirred for 1 hour. 1- (3-phenylpropyl)-
3.00 g (10.8 mmol) of piperazine dihydrochloride, 1,8-diazabicyclo [5.4.0] unde-
3.29 g (21.6 mmol) of 7-cene (DBU),
And 1.5 ml of triethylamine (10.8 mmol)
Acetonitrile (15 ml) solution was added to the reaction system, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the crude product was separated and purified by column chromatography (ethyl acetate → methanol / ethyl acetate 10%), and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil. Yield 3.63 g (93%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.73-1.90
(2H, m), 2.30-2.48 (6H, m), 2.65 (2H, t, J = 7.6 H
z), 3.32-3.43 (2H, m), 3.59-3.69 (2H, m), 3.95 (2H,
d, J = 4.4 Hz), 5.46-5.58 (1H, m), 7.12-7.34 (5H,
m) .IR (KBr) 3417, 2937, 1713, 1655, 1462, 1242, 1171,
1026, 752, 702 cm ^-1 4) Synthesis of 1-aminoacetyl-4- (3-phenylpropan-1-yl) piperazine dihydrochloride 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4 To 3.48 g (9.63 mmol) of-(3-phenylpropan-1-yl) piperazine was added 12 at room temperature.
7 ml (84 mmol) of N hydrochloric acid was added, and the mixture was stirred for 30 minutes. When ethanol was added to the reaction system, crystals precipitated. After concentration under reduced pressure, diethyl ether and ethanol were added, and the crystals were collected by filtration. The crystals were washed with diethyl ether to obtain the desired product as white crystals. Yield 2.81 g (87%) Melting point 223-227 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.97-2.20
(2H, m), 2.65 (2H, t, J =
7.8 Hz), 2.79-3.74 (8H,
m), 3.78-4.09 (3H, m), 4.
32-4.51 (1H, m), 7.15-7.3
8 (5H, m) 8.12-8.49 (3H,
m), 11.61-11.84 (1H, m). IR (KBr) 3423, 3361, 299
5, 2931, 2559, 2465, 167
0, 1498 cm ^-1

Reference Example 47 Synthesis of 1-aminoacetyl-4- (2-phenethyl) piperazine dihydrochloride 1) Synthesis of tert-butyl 4- (2-phenethyl) piperazine-1-carboxylate 1-tert- Butoxycarbonylpiperazine 7.00
To a solution of g (37.6 mmol) in ethanol (50 ml) were added 8.0 ml (57.4 mmol) of triethylamine and 8.42 g (45.4 mmol) of phenethyl bromide at room temperature, and the mixture was refluxed for 16 hours under a nitrogen atmosphere. . Further, 2 ml of triethylamine (14.3) was added to the reaction system.
Mmol) and 2 ml of phenethyl bromide (14.6).
Mmol), and the mixture was further heated under reflux for 4 hours. Ethyl acetate was added to the reaction system, washed with water and saturated saline, and then washed with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate / hexane 30-
(50%), and the solvent was distilled off under reduced pressure to obtain the target compound as white crystals. Yield 8.03 g (74%) Melting point 62-65 ° C ¹ HNMR (200 MHz, CDCl ₃ ) δ 1.47 (9H, s), 2.44-2.49
(4H, m), 2.55-2.66 (2H, m), 2.74-2.88 (2H, m), 3.44
-3.49 (2H, m) 7.15-7.36 (5H, m) .IR (KBr) 2976, 1687, 2868, 2818, 1414, 1252, 1174,
1120, 1001, 711, 735,696 cm ^-1

2) 1- (2-phenethyl) piperazine
Synthesis of dihydrochloride 4- (2-phenethyl) piperazine-1-carboxylic acid-
To 7.94 g (27.34 mmol) of tert-butyl was added 10 ml (120 mmol) of 12N hydrochloric acid at room temperature.
Stir for 30 minutes. Ethanol was added to the reaction system, diethyl ether was further added to the precipitated white crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 6.96 g (97%) Melting point 206-210 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.96-3.88 (12H, m), 7.
17-7.42 (5H, m), 9.65-10.11 (2H, m) .IR (KBr) 3542, 3141, 2931, 2764, 2359, 1434, 1084
^{cm -1 3) 1- [N- (} tert- butoxycarbonyl) amino acetyl] -4- (2-phenethyl) Synthesis N-tert-butoxycarbonyl glycine 2.00g of piperazine
(11.4 mmol) and 2.62 g (17.1 mmol) of 1-hydroxybenzotriazole monohydrate in acetonitrile (20 ml) were stirred at room temperature with N-ethyl-.
3.28 g (17.1 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1 hour. 1- (2-phenethyl) piperazine dihydrochloride 3.00 g (11.4 mmol), 1,8
-Diazabicyclo [5.4.0] unde-7-cene (D
A solution of 3.47 g (22.8 mmol) of BU) and 1.6 ml (11.5 mmol) of triethylamine in acetonitrile (20 ml) was added to the reaction system, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the crude product was separated and purified by column chromatography (methanol / ethyl acetate 5%). The desired product was obtained. Yield 3.01 g (76%) Melting point 109-110 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 2.45-2.56
(4H, m), 2.56-2.70 (2H, m), 2.74-2.87 (2H, m), 3.3
5-3.47 (2H, m), 3.60-3.73 (2H, m), 3.96 (2H, d, J =
4.2 Hz), 5.45-5.60 (1H, m) 7.14-7.36 (5H, m) .IR (KBr) 3263, 2968, 2929, 1718, 1656, 1543, 1452,
1240, 1163, 1038, 739cm ^-1

4) Synthesis of 1-aminoacetyl-4- (2-phenethyl) piperazine dihydrochloride 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (2-phenethyl) piperazine 2.98
g (8.58 mmol) at room temperature in 4 ml of 12N hydrochloric acid (4 ml).
8 mmol) and stirred for 30 minutes. When ethanol was added to the reaction system, crystals precipitated. More diethyl ether was added and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 2.67 g (97%) Melting point 237-247 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.88-3.47 (8H, m), 3.5
1-3.76 (2H, m), 3.83-4.11 (3H, m), 4.36-4.53 (1H,
m), 7.21-7.42 (5H, m), 8.16-8.38 (3H, m) .IR (KBr) 3412, 2995, 2931, 2549, 1666, 1500, 1452
cm ^-1

Reference Example 48 1- (aminoacetyl) -4- (3-phenylpropan-1-yl) -2,3,5,6-tetrahydro-7H-
Synthesis of 1,4-diazepine dihydrochloride 1) 4- (3-phenylpropan-1-yl) -2,
Synthesis of 3,5,6-tetrahydro-7H-1,4-diazepine-1-carboxylate-tert-butyl 1-tert-butoxycarbonyl-2,3,5,6-
4.50 g of tetrahydro-7H-1,4-diazepine
(22.47 mmol) in a solution of ethanol (50 ml) at room temperature in 4.7 ml (33.72 mmol) of triethylamine and 4.47 of 1-bromo-3-phenylpropane.
g (22.45 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 8 hours. 3. Add triethylamine to the reaction system.
7 ml (33.72 mmol) and 4.47 g (22.45 mmol) of 1-bromo-3-phenylpropane were added, and the mixture was heated under reflux for 16 hours. After cooling to room temperature, ethyl acetate was added to the reaction system, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate / hexane 30%-
The solvent was distilled off under reduced pressure to obtain the target product as a yellow liquid. Yield 5.41 g (76
%) ¹ HNMR (200 MHz, CDCl ₃ ) δ 1.46 (9H,
s), 1.68-1.89 (4H, m), 2.
46-2.53 (2H, m), 2.54-2.70
(6H, m), 3.36-3.55 (4H,
m), 7.12-7.34 (5H, m). IR (neat) 2937, 1693, 146
4, 1412, 1365, 1173, 746,
700 cm- ¹ 2) 1- (3-phenylpropan-1-yl) -2,
Synthesis of 3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 4- (3-phenylpropan-1-yl) -2,3
5,6-tetrahydro-7H-1,4-diazepine-1
-5.41 g of tert-butyl-carboxylate (16.9)
(9 mmol) was added 5 ml (60 mmol) of 12N hydrochloric acid at room temperature and stirred for 2 hours. After adding ethanol to the reaction system, the solvent was distilled off under reduced pressure to obtain the target product as a pale yellow amorphous substance. Yield 5.65 g (100%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.91-2.33 (4H, m), 2.63
(2H, t, J = 7.8 Hz), 3.02-3.84 (10H, m), 7.10-7.39
(5H, m), 9.38-10.08 (2H, m), 11.42-11.74 (1H, m)

3) 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (3-phenylpropan-1-yl) -2,3,5,6-tetrahydro-7H
Synthesis of -1,4-diazepine 2.8 g of N-tert-butoxycarbonylglycine
(15.98 mmol) and 3.67 g (23.96 mmol) of 1-hydroxybenzotriazole monohydrate
4.6 g (24.0 mmol) of N-ethyl-N'-3- (N, N-dimethylamino) propyl carbodiimide hydrochloride was added to a suspension of acetonitrile (30 ml) at room temperature, and the mixture was stirred for 1 hour. 1- (3-phenylpropane-1
-Yl) -2,3,5,6-tetrahydro-7H-1,
5.65 g (16.99 mmol) of 4-diazepine dihydrochloride, 5.17 g (33.96 mmol) of 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU), and triethylamine 2 0.3 ml (16.5 mmol) of acetonitrile solution (20 ml) was added to the reaction system, and the mixture was further stirred for 2 hours. After distilling off the solvent under reduced pressure,
Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product is subjected to column chromatography (methanol / ethyl acetate 10
-20%), and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil. Yield 5.64 g (94%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.68-1.97
(4H, m), 2.42-2.55 (2H, m), 2.55-2.74 (6H, m), 3.3
6-3.49 (2H, m), 3.58-3.72 (2H, m), 3.90-3.99 (2H, m
m), 5.50-5.62 (1H, m ), 7.12-7.35 (5H, m). IR (neat) 3415, 2935, 1711, 1651, 1456, 1168 cm -1 4) 1- ( aminoacetyl) -4- (3-phenylpropan-1-yl) -2,3,5,6-tetrahydro-7
Synthesis of H-1,4-diazepine dihydrochloride 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (3-phenylpropan-1-yl)-
To 5.64 g (15.02 mmol) of 2,3,5,6-tetrahydro-7H-1,4-diazepine was added 12
5 ml (60 mmol) of N hydrochloric acid was added and stirred for 20 minutes. Ethanol was added to the reaction system, and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow amorphous. This compound was used for the next reaction without purification. Yield 4.69 g (90%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.94-2.18 (4H, m), 2.5
6-2.71 (2H, m), 2.90-4.15 (12H, m), 7.15-7.37 (5H, m
m), 8.14-8.42 (3H, m) .IR (KBr) 3353, 2949, 1661, 1470 cm ^-1

Reference Example 49 1- (aminoacetyl) -4- (2-phenethyl)-
Synthesis of 2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 1) 4- (2-phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepine -1-carboxylic acid-
Synthesis of tert-butyl 1-tert-butoxycarbonyl-2,3,5,6-
4.61 g of tetrahydro-7H-1,4-diazepine
To a solution of (20.0 mmol) in ethanol (50 ml) were added 6.5 ml (46.6 mmol) of triethylamine and 6.3 g (34.0 mmol) of phenethyl bromide at room temperature, and the mixture was refluxed for 16 hours under a nitrogen atmosphere.
Further, 3.0 ml of triethylamine (21.5
Mmol) and phenethyl bromide (1.0 ml, 7.3).
(2 mmol) and heated to reflux for 3 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added to the reaction system, washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified by column chromatography (ethyl acetate / hexane 50% -ethyl acetate). The solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil. Yield 5.63 g (80%) ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.46 (9H, s), 1.75-1.94
(2H, m), 2.63-2.87 (8H, m), 3.37-3.58 (4H, m), 7.13
-7.36 (5H, m). IR (neat) 1691 cm ^-1 2) Synthesis of 1- (2-phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 4 -(2-phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepine-1-carboxylic acid-te
To 5.63 g (18.5 mmol) of rt-butyl, 5 ml (60 mmol) of 12N hydrochloric acid was added at room temperature, and the mixture was stirred for 1 hour. Ethanol was added to the reaction system, the mixture was concentrated under reduced pressure, and ethanol and diethyl ether were added to the precipitated white crystals.
The crystals were collected by filtration and washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 4.7 g (92%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.07-2.28 (2H, m), 2.9
0-3.90 (12H, m), 7.18-7.20 (5H, m), 9.36-10.09 (2
H, m), 11.55-11.89 (m, 1H) .IR (KBr) 2973, 2593, 1580, 1441, 1111, 1030, 1020,
747, 696 cm ^-1

3) 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (2-phenethyl)-
Synthesis of 2,3,5,6-tetrahydro-7H-1,4-diazepine 2.71 g of N-tert-butoxycarbonylglycine
(15.47 mmol) and 3.55 g (23.2 mmol) of 1-hydroxybenzotriazole monohydrate in acetonitrile (30 ml) were stirred at room temperature with N-ethyl-N′-3- (N, N -Dimethylamino) propyl carbodiimide hydrochloride (4.45 g, 23.2 mmol) was added and stirred for 1 hour. 1- (2-phenethyl) -2,
3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 4.5 g (16.23 mmol), 1,8-
Diazabicyclo [5.4.0] unde-7-cene (DB
U) 4.94 g (32.45 mmol) of triethylamine and 2.2 ml (15.78 mmol) of triethylamine in acetonitrile were added to the reaction system, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. Wash the organic layer with saturated aqueous sodium bicarbonate and saturated saline,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 10 → 40%), and the solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow oil. Yield 5.18 g (93%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.79-2.00
(2H, m), 2.61-2.82 (8H, m), 3.36-3.50 (2H, m), 3.5
9-3.74 (2H, m), 3.89-3.99 (2H, m), 5.50-5.63 (1H,
m), 7.13-7.35 (5H, m) .IR (neat) 3415, 2974, 2935, 1712, 1651, 1493, 145
8, 1365, 1250, 1171, 1053, 750, 702 cm ^-1 4) 1- (Aminoacetyl) -4- (2-phenethyl)
Synthesis of -2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 1- [N- (tert-butoxycarbonyl) aminoacetyl] -4- (2-phenethyl) -2,3 , 5,6-
5.18 g of tetrahydro-7H-1,4-diazepine
(14.3 mmol) and 5 ml of 12N hydrochloric acid (60
Mmol) and stirred for 1 hour. After adding ethanol to the reaction system, the solvent was distilled off under reduced pressure. Ethanol and diethyl ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 4.64 g (97%) Melting point 257-260 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.97-2.22 (2H, m), 2.9
3-4.14 (14H, m), 7.20-7.41 (5H, m), 8.15-8.42 (3H,
m). IR (KBr) 3374, 2948, 1661, 1470 cm ^-1

Reference Example 50 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -aminoacetamide dihydrochloride 1) N- [1- (3-phenylpropane-1) Synthesis of -yl) piperidin-4-yl]-(N-tert-butoxycarbonylamino) acetamide 4.21 g of N-tert-butoxycarbonylglycine
(24.03 mmol) and 5.51 g (35.98 mmol) of 1-hydroxybenzotriazole monohydrate in acetonitrile (30 ml) at room temperature with N-.
6.90 g (36.0 mmol) of ethyl-N′-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1 hour. Next, 7.00 g (24.03 mmol) of 4-amino-1- (3-phenylpropan-1-yl) piperidine dihydrochloride was added to the reaction system.
-Bicyclo [5.4.0] unde-7-cene (DBU)
A solution of 7.32 g (48.08 mmol) and triethylamine (3.4 ml, 24.4 mmol) in acetonitrile (20 ml) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, chloroform was added to the residue, washed with water and saturated saline, and then washed with magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was separated and purified by column chromatography (methanol / ethyl acetate 30%), and the solvent was distilled off under reduced pressure to obtain the target compound as a yellow-orange liquid. Yield 5.35 g (59%) ¹ H NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 1.61-1.97
(6H, m), 2.03-2.20 (2H, m), 2.32-2.43 (2H, m), 2.63
(2H, t, J = 7.6 Hz), 2.74-2.93 (2H, m), 3.66-3.87
(1H, m), 3.75 (2H, d, J = 6.0 Hz), 4.99-5.15 (1H,
m), 5.92-6.06 (1H, m), 7.12-7.33 (5H, m) .IR (neat) 3413, 3305, 2937, 1713, 1670, 1539, 136
9, 1250, 1169 cm ^-1

2) N- [1- (3-phenylpropane-
Synthesis of 1-yl) piperidin-4-yl] -aminoacetamide dihydrochloride N- [1- (3-phenylpropan-1-yl) piperidin-4-yl]-(N-tert-butoxycarbonylamino) To 5.35 g (14.25 mmol) of acetamide was added 10 ml (120 mmol) of 12N hydrochloric acid at room temperature, followed by stirring for 1 hour. After adding ethanol to the reaction system, it was concentrated under reduced pressure. 2-Propanol and diethyl ether were added to the residue, and the resulting crystals were collected by filtration.
Wash the crystals with 2-propanol and diethyl ether,
The desired product was obtained as pale yellow crystals. Yield 4.20 g
(85%) Melting point 258-261 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.67-2.21 (6H, m), 2.5
6-2.62 (2H, m), 2.64-3.12 (4H, m), 3.24-4.13 (5H,
m), 7.11-7.37 (m, 5H), 8.04-8.30 (3H, m), 8.65-8.7
6 (1H, m) .IR (KBr) 3175, 3054, 2996, 1690, 1568, 1505, 1437,
1269, 912, 764, 706 cm ^-1

Reference Example 51 Synthesis of 4- (4-aminobutan-1-yl) -1-bensoylpiperazine dihydrochloride 1) Synthesis of 1-benzoyl-4-benzylpiperazine 25.72 g of 1-benzylpiperazine (145) .92 mmol) and 31 ml of triethylamine (222.4).
Mmol) in acetonitrile (250 ml).
21.44 g (152.5 mmol) of benzoyl chloride
Was added and stirred at room temperature for 16 hours. After evaporating the solvent under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and washed with magnesium sulfate. After concentration, the residue was separated and purified by column chromatography (ethyl acetate / hexane 50% → ethyl acetate), the solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain the desired product as pale brown crystals. Yield 38.41 g (94%) ¹ H NMR (200 MHz, CDCl ₃ ) δ 2.28-2.62 (4H, m), 3.31-
3.58 (2H, m), 3.54 (2H, s), 3.65-3.89 (2H, m), 7.18
-7.36 (5H, m), 7.40 (5H, s). IR (KBr) 1628, 1437, 1279, 997, 739, 704 cm ^-1 2) Synthesis of 1-benzoylpiperazine formate 1-benzoyl-4- Benzyl piperazine 20.02 g
(71.4 mmol) and 10% palladium on carbon 1.
9.9 g (215 mmol) of formic acid was slowly added dropwise to a suspension of 0 g of methanol (200 ml) at room temperature, followed by stirring for 6 hours. The catalyst was removed by filtration, concentrated under reduced pressure,
Ethyl acetate was added to the residue, and the mixture was further concentrated. Ethyl acetate and hexane were added to the precipitated crystals, and the crystals were collected by filtration. The crystals were washed with ethyl acetate and hexane to give the desired product as white crystals. Yield 15.97 g (95%) Melting point 88-90 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.74-2.95 (4H, m), 3.2
4-3.73 (4H, m), 7.34-7.49 (5H, m), 8.29 (1H, s) .IR (KBr) 3433, 2937, 1660, 1626, 1446, 1249, 1404,
1282, 1242, 1007, 781, 739, 708 cm ^-1

3) 4- (4-aminobutan-1-yl)
Synthesis of 1-Bensoylpiperazine dihydrochloride 5.0 g of 1-benzoylpiperazine formate (21.1
6 mmol), 4-bromobutylphthalimide 5.97
g (21.16 mmol) and triethylamine 9.0
ml (64.57 mmol) of ethanol (50 ml)
The solution was heated at reflux for 40 hours. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 5 → 10%), and the solvent was distilled off under reduced pressure to give N- [4- (4-benzoylpiperazin-1-yl) as a yellow oil. (Butan-1-yl) phthalimide (6.99 g) was obtained. To a solution of 6.99 g of this compound in ethanol (50 ml) was added 1.34 g (26.8 mmol) of hydrazine monohydrate at room temperature, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, a white solid was removed by filtration and concentrated under reduced pressure. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 4- (4
-Aminobutan-1-yl) -1-bensoylpiperazine was obtained. To an ethanol solution of this compound was added 5 ml (60 mmol) of 12N hydrochloric acid at room temperature, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, diethyl ether was added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 2.92 g (41%) Melting point 257-260 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.51-1.88 (4H, m), 2.7
1-2.92 (2H, m), 2.94-3.20 (4H, m), 3.27-3.65 (6H,
m), 7.41-7.55 (5H, m), 7.88-8.13 (3H, m) .IR (KBr) 2931, 1632, 1460, 1429, 1284, 714 cm ^-1

Reference Example 52 Synthesis of 4- (3-aminopropan-1-yl) -1-bensoylpiperazine dihydrochloride 5.0 g of 1-benzoyl, piperazine formate (21.
16 mmol), 3-bromopropylphthalimide5.
67 g (21.15 mmol) and 9.0 ml (64.57 mmol) of triethylamine in ethanol (50
ml) The solution was heated to reflux for 18 hours under a nitrogen atmosphere. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 5%), and the solvent was distilled off under reduced pressure to give N- [3- (4-
(Benzoylpiperazin-1-yl) propan-1-yl] phthalimide (6.22 g) was obtained. 1.24 g (24.8 mmol) of hydrazine monohydrate was added to a solution of this compound (6.22 g) in ethanol (50 ml) at room temperature.
Was added and the mixture was heated under reflux for 2 hours. After cooling to room temperature, a white solid was removed by filtration and concentrated under reduced pressure. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude 4- (3-aminopropan-1-yl) -1
-Bensoylpiperazine was obtained. To a solution of the crude 4- (3-aminopropan-1-yl) -1-bensoylpiperazine in ethanol at room temperature, 3 ml of 12N hydrochloric acid (36 mmol).
Was added and stirred at room temperature for 1 hour. After concentration under reduced pressure, diethyl ether was added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as white crystals. Yield 1.80 g (27%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.94-2.11 (2H, m), 2.8
3-3.64 (12H, m), 7.42-7.54 (5H, m) .IR (KBr) 3433, 2997, 2929, 1630, 1458, 1429, 1284
cm ^-1

Reference Example 53 Synthesis of Cis-4- (1-benzyl-2,6-dimethyl-piperazin-1-yl) butan-1-ylamine 1) Cis-1-tert-butoxycarbonyl-3,
Synthesis of 5-dimethylpiperazine 5.0 g of Cis-3,5-dimethylpiperazine (21.
(07 mmol) in ethanol (42 ml) at room temperature was added with 2.5 ml (32.3 mmol) of di-tert-butyl dicarbonate and stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain the desired product as a pale yellow solid. Yield 5.77 g (72%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.06 (6H, d, J = 6.4 Hz),
1.46 (9H, s), 2.21-2.40 (2H, m), 2.68-2.86 (2H,
m), 3.79-4.09 (2H, m) .IR (KBr) 3319, 2972, 1680, 1425, 1367, 1315, 1267,
1173, 1144, 1072, 895, 866, 797 cm ^-1 2) Cis-1-tert-butoxycarbonyl-3,
Synthesis of 5-dimethyl-4-benzylpiperazine Cis-1-tert-butoxycarbonyl-3,5-
N, N of 10 g (46.66 mmol) of dimethylpiperazine and 12.90 g (93.3 mmol) of potassium carbonate
-To a suspension of dimethylformamide (100 ml) at room temperature was added 11.97 g (70 mmol) of benzyl bromide,
Stirred at 120 ° C. for 16 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. Column chromatography of the residue (ethyl acetate / hexane 30%)
The desired product was obtained as a pale yellow oil. Yield 13.56 g (95%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.04 (6H, d, J = 5.8 Hz),
1.45 (9H, s), 2.45-2.75 (4H, m), 3.67-3.92 (2H,
m), 3.81 (2H, s), 7.15-7.39 (5H, m) .IR (neat) 2980, 1693, 1423, 1136, 1061, 924, 883,
766, 729, 700 cm ^-1

3) Synthesis of Cis-1-benzyl-2,6-dimethylpiperazine Cis-1-tert-butoxycarbonyl-3,5-
13.56 g of dimethyl-4-benzylpiperazine (4
4.54 mmol) at room temperature in 15 ml of 12N hydrochloric acid (1
80 mmol) and stirred for 1 hour. 0 ° C for the reaction system
Then, the mixture was made alkaline with an 8N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a yellow oil. This compound was used for the next reaction without purification. Yield 7.67 g (95%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.02 (6H, d, J = 5.8 Hz),
2.39-2.63 (4H, m), 2.88 (2H, d, J = 9.8 Hz), 3.83 (2
H, s), 7.15-7.41 (5H, m) .IR (KBr) 3271, 2970, 2816, 1460, 1379, 1315, 1200,
1158, 1140, 1603, 729 cm ^-1 4) Synthesis of N-cis- [4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-yl] phthalimide Cis-1-benzyl-2 3.5 g (17.13 mmol) of 3,6-dimethylpiperazine and 5.0 ml (35.87 mmol) of triethylamine in ethanol (30
ml) solution was added at room temperature with 4-bromobutylphthalimide (4.83 g, 17.12 mmol), and the mixture was heated under reflux under a nitrogen atmosphere for 18 hours. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane 75% → ethyl acetate) to obtain the desired product as an orange oil. Yield 5.86 g (84%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.02 (6H, d, J = 6.4 Hz),
1.44-1.87 (6H, m), 2.23-2.35 (2H, m), 2.55-2.78 (4
H, m), 3.70 (2H, t, J = 7.2 Hz), 3.81 (2H, s), 7.16
7.37 (5H, m), 7.66-7.75 (2H, m), 7.78-7.86 (2H,
m) .IR (neat) 2939, 2812, 1772, 1714, 1396, 1369, 115
5, 1076, 1047, 721 cm ^-1

5) Cis-4- (1-benzyl-2,6
Synthesis of -dimethylpiperazin-1-yl) butan-1-ylamine 5.86 g of N-cis- [4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-yl] phthalimide .45 mmol) of ethanol (2
0 ml) solution at room temperature with hydrazine monohydrate 1.08
g (21.57 mmol) was added and the mixture was refluxed for 2 hours. After cooling to room temperature, the white solid was removed by filtration,
The solvent was distilled off under reduced pressure. An aqueous solution of sodium hydroxide and common salt were added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product as an orange oil.
This compound was used for the next reaction without purification. Yield 3.64 g (91%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.04 (6H, d, J = 6.2 Hz),
1.36-1.63 (4H, m), 1.78-1.89 (2H, m), 2.22-2.33 (2
H, m), 2.57-2.82 (6H, m), 3.83 (2H, s), 7.14-7.40
(5H, m) .IR (neat) 3359, 2936, 2812, 1468, 1323, 1153, 107
6, 729, 698 cm ^-1

Reference Example 54 Cis-4- (3-aminopropyl) -1-benzyl-
Synthesis of 2,6-dimethylpiperazine 1) Synthesis of N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl] phthalimide Cis-1-benzyl-2, 4.06 g (19.87 mmol) of 6-dimethylpiperazine and 5.6 ml (40.18 mmol) of triethylamine in ethanol (4
(0 ml) solution, 5.33 g (19.88 mmol) of 3-bromopropylphthalimide was added to the solution at room temperature, and the mixture was refluxed for 20 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate /
(Hexane 50 → 75%) to give the desired product as a yellow oil. Yield 6.59 g (85%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.99 (6H, d, J = 5.8 Hz),
1.71-1.93 (4H, m), 2.31-2.38 (2H, m), 2.41-2.55 (2
H, m), 2.65-2.76 (2H, m), 3.71-3.78 (2H, m), 3.73
(2H, s), 7.13-7.37 (5H, m), 7.65-7.74 (2H, m), 7.7
8-7.86 (2H, m) .IR (neat) 2964, 2937, 2812, 1772, 1714, 1466, 139
6, 1369, 1329, 1200, 1155, 1090, 1038, 721 cm ^-1

2) Cis-4- (3-aminopropyl)
Synthesis of -1-benzyl-2,6-dimethylpiperazine N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl] phthalimide 6.59 g (16.8) Mmol) of ethanol (3
0 ml) solution at room temperature with hydrazine monohydrate 1.26
g (25.2 mmol) was added and the mixture was refluxed for 1 hour.
After cooling to room temperature, a white solid was removed by filtration, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydroxide was added to the residue, and extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then distilled off under reduced pressure.
The desired product was obtained as a yellow oil. This compound was used for the next reaction without purification. Yield 3.85 g (88%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.04 (6H, d, J = 6.2 Hz),
1.57-1.70 (2H, m), 1.83 (2H, t, J = 10.8 Hz), 2.29-
2.37 (2H, m), 2.61-2.83 (6H, m), 3.83 (2H, s), 7.1
8-7.32 (5H, m) .IR (neat) 3361, 3284, 2937, 2812, 1603, 1493, 146
7, 1375, 1323, 1153, 1076, 727, 698 cm ^-1

Reference Example 55 Synthesis of Cis-1- (2-aminoethyl) -4- (3-phenylpropan-1-yl) -3,5-dimethylpiperazine 1) Cis-1-tert-butoxycarbonyl-3 ,
Synthesis of 5-dimethyl-4- (3-phenylpropan-1-yl) piperazine Cis-1-tert-butoxycarbonyl-3,5-
10 g (46.66 mmol) of dimethylpiperazine and 12.90 g (93.3 mmol) of potassium carbonate in N,
To a suspension of N-dimethylformamide (50 ml) was added 11.15 g of 1-bromo-3-phenylpropane (5.
6 mmol), and the mixture was stirred at 120 ° C. for 40 hours under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, reduced, and evaporated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate / hexane 20 → 3
0%) to give the desired product as a yellow oil. Yield 12.21 g (79%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.00 (6H, d, J = 5.8 Hz),
1.45 (9H, s), 1.57-1.69 (2H, m), 2.43-2.62 (6H,
m), 2.67-2.85 (2H, s), 3.68-3.96 (2H, m), 7.13-7.3
5 (5H, m) .IR (neat) 2974, 2931, 2856, 1695, 1454, 1427, 127
3, 1248, 1174, 1142, 748, 700 cm ^-1 2) Cis-1- (3-phenylpropan-1-yl)
Synthesis of -2,6-dimethyl-piperazine Cis-1-tert-butoxycarbonyl-3,5-
To 11.76 g (35.4 mmol) of dimethyl-4- (3-phenylpropan-1-yl) piperazine was added 10 ml (120 mmol) of 12N hydrochloric acid at room temperature, followed by stirring for 1 hour. Water was added to the reaction system, and impurities were removed by extraction with ethyl acetate. Next, it was made alkaline by adding an aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a yellow oil. This compound was used for the next reaction without purification. Yield 5.51 g (67%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.98 (6H, d, J = 5.8 Hz),
1.66-1.84 (2H, m), 2.43-2.59 (6H, m), 2.74-2.88 (4
H, s), 7.13-7.35 (5H, m) .IR (neat) 3267, 2962, 2937, 2818, 1689, 1454, 137
3, 1319, 1205, 1157, 1074, 924, 748, 700 cm ^-1 3) N-cis- [2- [4- (3-phenylpropan-1-yl) -3,5-dimethylpiperazine-1- 4. Synthesis of yl] ethane-1-yl] phthalimide phthalimidoacetaldehyde diethyl acetal
To a solution of 67 g (21.5 mmol) of acetic acid (18 ml) was added 2.1 ml (25.2 mmol) of 12N hydrochloric acid at room temperature, followed by stirring at 60 ° C. for 2 hours. After cooling to room temperature, hydrochloric acid was neutralized with 2.54 g (30.2 mmol) of sodium hydrogen carbonate. The reaction system was cis-1- (3-phenylpropan-1-yl) -2,6-dimethylpiperazine 5.00.
g (21.5 mmol) of methanol (40 ml) was added and stirred for 1 hour. 6.84 g (32.27 mmol) of sodium triacetoxyborohydride was added to the reaction system in 3 portions.
It was added in three portions at 0 minute intervals and stirred for 18 hours. After evaporating the solvent under reduced pressure, acetic acid was neutralized with sodium hydrogen carbonate. After extraction with ethyl acetate, the organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (methanol / ethyl acetate 5%) to give the desired product as a pale brown oil. Yield 7.37 g (85%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.99 (6H, d, J = 6.2 Hz),
1.54-1.74 (2H, m), 1.81-1.93 (2H, m), 2.44-2.63 (6
H, m), 2.68-2.86 (2H, m), 3.79 (2H, t, J = 6.8Hz),
7.11-7.32 (5H, m), 7.64-7.74 (2H, m), 7.80-7.87 (2
H, m) .IR (neat) 2945, 2814, 1774, 1713, 1394, 1327, 124
2, 1159, 1076, 1026, 721 cm -1 4) Cis-1- ( Synthesis N-cis-2-aminoethyl) -4- (3-phenyl-1-yl) -3,5-dimethylpiperazine [2- [4- (3-phenylpropane-1)
-Yl) -3,5-dimethylpiperazin-1-yl] ethane-1-yl] phthalimide 7.28 g (17.95
Hydrazine monohydrate (1.3 ml, 26.8 mmol) was added to an ethanol (50 ml) solution of ethanol (50 mmol) at room temperature, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, a white solid was removed by filtration, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydroxide was added to the residue, and extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain the desired product as a yellow oil. This compound was used for the next reaction without purification. Yield 4.35 g (88%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.00 (6H, d, J = 6.2 Hz),
1.65-1.90 (4H, m), 2.34 (2H, t, J = 6.3 Hz), 2.54 (2
H, t, J = 7.5 Hz), 2.61-2.85 (8H, m), 7.13-7.34 (5H,
m). IR (neat) 3359, 3262, 2960, 2810, 1691, 1603, 145
6, 1371, 1323, 1153, 1076, 748, 700 cm ^-1

Reference Example 56 Synthesis of Trans-1- (4-aminobutyl) -4-benzyl-2,5-dimethylpiperazine 1) Trans-1-tert-butoxycarbonyl-
Synthesis of 2,5-dimethylpiperazine Trans-2,5-dimethylpiperazine 25.18 g
(220.5 mmol) in a solution of ethanol (200 ml) at room temperature in 9.63 g of di-tert-butyl dicarbonate (4.
4.1 mmol) and stirred for 2 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a pale brown oil. Yield 9.36 g (99%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.17 (3H, d, J = 7.0 Hz),
1.21 (3H, d, J = 6.6 Hz), 1.46 (9H, s), 2.48 (1H, d
d, J = 12.8, 3.0 Hz), 3.05-3.26 (3H, m), 3.55 (1H, d
d, J = 13.2, 1.6 Hz), 4.03-4.19 (1H, m). 2) Trans-1-tert-butoxycarbonyl-
Synthesis of 2,5-dimethyl-4-benzylpiperazine Trans-1-tert-butoxycarbonyl-2,
4.5 g (21.0 mmol) of 5-dimethylpiperazine
And 5.9 ml (42.3 mmol) of triethylamine
Was added at room temperature to acetonitrile (40 ml) solution, and the mixture was refluxed for 24 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / hexane 10%) to give the desired product as a pale yellow oil. Yield 5.17 g (81%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.98 (3H, d, J = 6.6 Hz),
1.23 (3H, d, J = 7.0 Hz), 1.46 (9H, s), 2.19 (1H, d,
J = 13.0 Hz), 2.70 (1H, dd, J = 12.0, 4.4 Hz), 2.85-3.
04 (1H, m), 3.31 (1H, dd, J = 12.8, 3.8 Hz), 3.46 (1
H, d, J = 13.6 Hz), 3.62 (1H, d, J = 13.6 Hz), 3.65 (1
H, dd, J = 13.0, 0.8 Hz), 4.10-4.28 (1H, m), 7.18-7.
42 (5H, m) .IR (neat) 2929, 2819, 1691, 1417, 1367, 1317, 126
7, 1163, 1059, 864, 756, 708 cm ^-1 3) Synthesis of Trans-1-benzyl-2,5-dimethylpiperazine dihydrochloride Trans-1-tert-butoxycarbonyl-2,
9.76 g of 5-dimethyl-4-benzylpiperazine (3
2.06 mmol) and 10 ml of 12N hydrochloric acid (1
20 mmol) and stirred for 1 hour. The solvent was distilled off under reduced pressure, 2-propanol was added to the residue, and the mixture was further concentrated. Diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with 2-propanol and diethyl ether to obtain the desired product as white crystals. Yield 7.97 g (90%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.22 (3H, d, J = 6.6 H)
z), 1.59 (3H, d, J = 5.4 Hz), 2.84-3.83 (6H, m), 3.9
6-4.29 (1H, m), 4.57-4.74 (1H, m), 7.36-7.52 (3H,
m), 7.56-7.72 (2H, m), 9.93-10.25 (2H, m) IR (KBr) 2767, 2694, 2507, 2266, 1454, 1333, 1186,
1061, 991, 928, 766,706 cm ^- 14) N-trans- [4- (4-benzyl-2,5-
Synthesis of dimethylpiperazin-1-yl) butan-1-yl] phthalimide Trans-1-benzyl-2,5-dimethylpiperazine dihydrochloride 4.00 g (14.43 mmol), 4-
To a suspension of 4.88 g (17.3 mmol) of bromobutylphthalimide and 8.0 ml (57.4 mmol) of triethylamine in 50 ml of acetonitrile was added 2.59 g (17.3 mmol) of sodium iodide at room temperature. The mixture was refluxed for 20 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate → methanol / ethyl acetate 5%) to give the desired product as a brown oil. Yield 3.97 g (68%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, d, J = 5.8 Hz),
1.15 (3H, d, J = 6.0 Hz), 1.43-1.77 (4H, m), 1.82-1.
93 (2H, m), 2.08 (2H, t, J = 10.8 Hz), 2.16-2.51 (3
H, m), 2.59 (1H, dd, J = 11.4, 2.8 Hz), 2.70-2.79 (1
H, m), 2.82 (1H, dd, J = 11.4, 2.8 Hz), 3.06 (1H, d,
J = 13.2 Hz), 3.70 (2H, t, J = 7.0 Hz), 4.08 (1H, d, J
= 13.2 Hz), 7.16-7.34 (5H, m), 7.65-7.76 (2H, m),
7.78-7.89 (2H, m) .IR (neat) 2939, 2800, 1770, 1713, 1441, 1396, 137
1, 1336, 1182, 1066, 1041, 719 cm ^-15 ) 5) Synthesis of Trans-1- (4-aminobutyl) -4-benzyl-2,5-dimethyl-piperazine N-trans- [4- (4- To a solution of 3.97 g (9.79 mmol) of benzyl-2,5-dimethyl-piperazin-1-yl) butan-1-yl] phthalimide in ethanol (20 ml) at room temperature was added hydrazine monohydrate 0.
74 g (14.8 mmol) was added, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, a white solid was removed by filtration, and the solvent was distilled off under reduced pressure. An aqueous solution of sodium hydroxide was added to the residue, and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a yellow oil. This compound was used for the next reaction without purification. Yield 2.31 g (86%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.95 (3H, d, J = 6.2 Hz),
1.16 (3H, d, J = 5.8 Hz), 1.34-1.55 (4H, m), 1.81-1.
91 (1H, m), 2.02-2.13 (1H, m), 2.14-2.52 (4H, m),
2.60 (1H, dd, J = 11.4, 2.6 Hz), 2.65-2.76 (2H, m),
2.83 (1H, dd, J = 11.0, 3.0 Hz), 3.07 (1H, d, J = 13.6
Hz), 4.08 (1H, d, J = 13.2 Hz), 7.19-7.36 (5H, m) .IR (neat) 3363, 3280, 2935, 2802, 1603, 1450, 137
7, 1336, 1178, 1153, 1068, 833, 739, 700 cm ^-1

Reference Example 57 Synthesis of 1- (2-aminoethane-1-yl) -2,6-dioxo-4- (3-phenylpropan-1-yl) piperazine dihydrochloride 1) 1-tert-butoxy Synthesis of carbonyl ethylenediamine A solution of 18 g (299.5 mmol) of ethylenediamine in 300 ml of tetrahydrofuran was added at room temperature with
21.8 g (99.9 mmol) of tert-butyl was added, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure,
Water was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration under reduced pressure, 1N hydrochloric acid was added, washed with ethyl acetate, made alkaline with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired product as a colorless oil. This compound was used for the next reaction without purification. Yield 7.43 g (46%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.45 (9H, s), 2.77-2.83
(2H, m), 3.13-3.22 (2H, m), 4.76-4.96 (1H, m) .IR (neat) 3361, 2976, 1713, 1522, 1454, 1276, 125
5, 1173, 955, 879, 771 cm ^-1 2) Synthesis of 4-benzyl-1- [2- (tert-butoxycarbonylamino) ethane-1-yl] -2,6-dioxopiperazine Benzyl imino under nitrogen atmosphere 9.75 g of diacetate (4
3.68 mmol) of tetrahydrofuran (129 m
1) Add carbonyldiimidazole to the suspension at room temperature
58 g (96.08 mmol) was added, and the mixture was heated under reflux for 1 hour. To the reaction system was added 7.00 g (43.69 mmol) of 1-tert-butoxycarbonylethylenediamine in tetrahydrofuran (20 ml), and the mixture was further refluxed for 21 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate, and twice with 0.5N hydrochloric acid (200 ml, 50 ml).
ml). After washing with water and saturated saline, the mixture was dried over magnesium sulfate. After concentration, the residue was washed by column chromatography (ethyl acetate / hexane 50%) to obtain the desired product as colorless crystals. Yield 8.65 g (57%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.41 (9H, s), 3.26-3.45
(2H, m), 3.41 (4H, s), 3.62 (2H, s), 3.91 (2H, t, J
= 5.6 Hz), 4.66-4.81 (1H, m), 7.24-7.41 (5H, m) .IR (KBr) 3404, 2976, 1768, 1687, 1680, 1516, 1352,
1228, 1164, 704 cm ^-1 3) Synthesis of 1- [2- (tert-butoxycarbonylamino) ethane-1-yl] -2,6-dioxopiperazine 4-benzyl-1- [2- (tert- Butoxycarbonylamino) ethane-1-yl] -2,6-dioxopiperazine 4.0 g (11.5 mmol) and 10% palladium on carbon 0.37 g in methanol (100 ml) were stirred under a hydrogen atmosphere for 20 hours. . After removing palladium carbon by filtration, the solvent was distilled off under reduced pressure to obtain the target compound as colorless crystals. Yield 3.4 g (100%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.41 (9H, s), 3.26-3.40
(2H, m), 3.68 (4H, s), 3.95 (2H, t, J = 5.4 Hz), 4.74
-4.90 (1H, m) .IR (KBr) 3369, 2981, 1730, 1687, 1664, 1537, 1367,
1340, 1267, 1254, 1180, 868 cm ^-1 4) 1- (tert-butoxycarbonylamino)-
2,6-dioxo-4- (3-phenylpropane-1-
Synthesis of yl) piperazine 1- [2- (tert-butoxycarbonylamino) ethan-1-yl] -2,6-dioxopiperazine 3.0
To a solution of 1 g (11.7 mmol) and 1.57 g (11.7 mmol) of dihydrocinnamic aldehyde in 50 ml of tetrahydrofuran was added 3.72 g (17.6 mmol) of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 18 hours. Stirred. The reaction mixture was added to water to stop the reaction, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, column chromatography (ethyl acetate / hexane 30-50%)
The product was obtained as colorless crystals by recrystallization (ethyl acetate-hexane). Yield 2.77 g (63%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.42 (9H, s), 1.73-1.88
(2H, m), 2.41-2.49 (2H, m), 2.65 (2H, t, J = 7.5 Hz),
3.20-3.42 (2H, m), 3.39 (4H, m), 3.92 (2H, t, J = 5.
7Hz), 4.68-4.82 (1H, m), 7.10-7.35 (5H, m) .IR (KBr) 3365, 2983, 1740, 1689, 1682, 1672, 1531,
1365, 1348, 1265, 1228, 1174, 1138, 964, 748, 69
6, 642 cm ^-1 5) Synthesis of 1- (2-aminoethane-1-yl) -2,6-dioxo-4- (3-phenylpropan-1-yl) piperazine dihydrochloride 1- (tert- Butoxycarbonylamino) -2,6
-Dioxo-4- (3-phenylpropan-1-yl)
To a solution of 2.67 g (7.11 mmol) of piperazine in 30 ml of ethanol was added 5 ml of 12N hydrochloric acid (60 ml) at room temperature.
Mmol) and stirred for 16 hours. Concentrate under reduced pressure,
The resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as colorless crystals. Yield 2.41 g (97%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.91-2.11 (2H, m), 2.6
1-2.68 (2H, m), 2.88-3.05 (2H, m), 3.08-3.26 (2H, m
m), 3.96 (2H, t, J = 5.9 Hz), 4.25 (4H, br s), 7.13-
7.38 (5H, m), 8.05-8.32 (3H, m) .IR (KBr) 2974, 1751, 170, 1379, 1261, 1165, 962, 7
60, 702 cm ^-1

[0159] Reference Example 58 2-Amino-6-Synthesis of fluoro pyridine 2,6-difluoro-pyridin 30.0g of 28% aqueous ammonia 150mL sealed container and dissolved in (4.6 eq) (pressure 12.1Kgcm ^{- 2} ), and stirred at 130 ° C. for 5 hours. This was cooled to 0 ° C., allowed to stand for 2 hours, and then crude crystals (plate-like crystals) were collected by a glass filter and dried under reduced pressure at 40 ° C. for 2 hours (24.2 g, yield 82.6%). ). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 4.33-4.74 (2H, brs), 6.2
0 (1H, m), 6.30 (1H, m), 7.48 (1H, m) Elemental analysis (C ₅ H ₅ H ₂ as F) Calculated:. C, 53.57; H, 4.50; N, 24.97; F , 16.95. Found: C, 53.44; H, 4.45; N, 24.97; F, 17.25.

Reference Example 59 Synthesis of ethyl 6- (2-fluoropyridinyl) thioacetate 2,6-Difluoropyridine (5 mL) was added to DMF (10 mL).
mL), potassium carbonate (1 equivalent) and thioglycolic acid ethyl ester (1 equivalent) were added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL three times) and water (100 mL) were added to the reaction solution, and an extraction operation was performed from the aqueous layer.
After combining the ethyl acetate solutions, the mixture was washed with saturated saline (100 mL three times). After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain oily ethyl 6- (2-fluoropyridinyl) thioacetate (10 g, yield 84%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.28 (3H, t, J = 7.1 Hz),
3.93 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 6.60 (1H, ddd,
J = 2.6, 7.9, 7.9 Hz), 7.11 (1H, ddd, J = 2.3, 7.9, 7.
9 Hz), 7.59 (1H, ddd, J = 7.9, 7.9, 7.9 Hz).

Reference Example 60 Synthesis of 2-fluoro-6- (formylamino) pyridine 0.63 g of 2,6-difluoropyridine was dissolved in 0.2 mL of formamide and stirred at 150 ° C. for 3 hours. The reaction solution was cooled to room temperature, and water (100 mL) and ethyl acetate (100 mL three times) were added for extraction. When the extract was dried over anhydrous magnesium sulfate and concentrated, a white powder of 2-fluoro-6- (formylamino) pyridine was precipitated. The powder is collected by filtration with a glass filter and
Drying was performed at 0 ° C. for 2 hours (0.4 g). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 6.64 to 6.73 (128 / 93H, m),
7.72-7.88 (1H, m), 8.11 (58 / 93H, m), 8.51 (58/93
H, s), 8.77 (1H, br s), 9.32 (35 / 93H, d, J = 10.6 H
z).

Reference Example 61 Synthesis of 5-fluoroimidazo [1,2-a] pyridine 12 g of 2-amino-6-fluoropyridine was dissolved in distilled water 12
The solution was completely dissolved in 0 mL at 60 ° C., 35 mL (2 equivalents) of 40% chloroacetaldehyde was added, and the mixture was stirred at 60 ° C. for 3 hours. The reaction solution was gradually cooled to room temperature, and 1N HCl was added.
An aqueous solution (50 mL) and ethyl acetate (150 mL) were added. The ethyl acetate solution was added to a 1N aqueous HCl
After extraction with L), the aqueous solutions were mixed. NaH is added to this aqueous solution.
CO ₃ was added to neutralize the solution (pH 0.35 to 7.3).
0). Ethyl acetate: THF = 4: 1 (15
0 mL three times) and the product was extracted. The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-fluoroimidazo [1,2-a] pyridine as a black liquid (9.5 g, 65% yield). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 6.52 (1H, m), 7.26 (1H,
m), 7.49 (2H, d, J = 9.1 Hz), 7.66 (2H, m). MS (SIMS), 137 (MH ⁺ ).

Reference Example 62 Synthesis of 5-fluoroimidazo [1,2-a] pyridine 5 g of 2-fluoro-6-formylaminopyridine was dissolved in 50 mL of ethanol, and 23.5 mL (4 equivalents) of 40% chloroacetaldehyde was added. The mixture was stirred under reflux for 1 hour. The reaction solution was gradually cooled to room temperature and 1N-HC
l Aqueous solution (100 mL) and ethyl acetate (100 mL) were added. The ethyl acetate solution was added to a 1N aqueous HCl solution (100
(2 × mL) and the aqueous solution was mixed. NaHCO ₃ was added to the aqueous solution to neutralize the solution (pH 0.35 to 7.30). Ethyl acetate (100 mL
Times) to extract the product. The combined extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
-Fluorimidazo [1,2-a] pyridine was obtained as a black liquid (1.5 g, 31% yield).

Reference Example 63 Synthesis of 5-fluoroimidazo [1,2-a] pyridine monohydrochloride Concentrated hydrochloric acid (5 mL) was added to black liquid 5-fluoroimidazo [1,2-a] pyridine (650 mg) and the mixture was concentrated under reduced pressure. And then ethanol: THF: ethyl acetate (10 mL: 5
(0 mL: 200 mL) to give 5-fluoroimidazo [1,2-a] pyridine monohydrochloride powder (6
90 mg, 84% yield). ¹ H-NMR (D ₂ O, 300 MHz) δ: 7.24 (1H, m), 7.78 (1H, d, J
= 9.1 Hz), 7.98-8.10 (2H, m), 8.15 (1H, m).

REFERENCE EXAMPLE 64 Synthesis of ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate 1.2 g of 5-fluoroimidazo [1,2-a] pyridine was dissolved in 10 mL of dimethylformamide, and potassium 1.8 g and thioglycolic acid ethyl ester 1.5 m
L was added and stirred at room temperature for 4 hours. Add 1N-HCl to the reaction solution
An aqueous solution (100 mL) and ethyl acetate (100 mL) were added. Ethyl acetate solution was added to 1N-HCl aqueous solution (100m
L was extracted twice), and the aqueous solution was mixed. NaHCO ₃ was added to this aqueous solution to neutralize the solution (pH 0.35 to 7.3).
0). Ethyl acetate (100 mL three times) was added to the neutralized aqueous solution to extract the product. The combined extracts were washed with saturated saline (100 mL three times), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (imidazo [1,2
-A] Pyridin-5-ylthio) ethyl acetate was obtained as a black liquid (1.7 g, 80%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.17 (3H, t, J = 7.2 Hz),
3.68 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 7.07 (1H, dd, J
= 1.0, 7.0 Hz), 7.16 (1H, dd, J = 7.0, 8.9 Hz), 7.65 (1
H, d, J = 8.9 Hz), 7.71 (1H, s), 7.91 (1H, s).

Reference Example 65 From 5-chloroimidazo [1,2-a] pyridine monohydrochloride (imidazo [1,2-a] pyridin-5-ylthio)
Synthesis of ethyl acetate In a 50 mL reaction vessel under an argon atmosphere, 1 g of 5-chloroimidazo [1,2-a] pyridine monohydrochloride was suspended in 10 mL of dimethylformamide. 1.5 mL of triethylamine is added to the reaction vessel, and the mixture is stirred for 15 minutes.
The mixture was stirred at 80 ° C. for 2 hours. After allowing the reaction solution to cool, a 1N-HCl aqueous solution (50 mL) and ethyl acetate (100 mL) were added to the reaction solution. Ethyl acetate layer is 1N-HCl
Extracted with an aqueous solution (50 mL twice). An acidic aqueous solution was mixed, and NaHCO ₃ was added to the aqueous solution to neutralize the solution (p
H 0.35 to 7.30). Ethyl acetate (5
0 mL three times) and the product was extracted. The combined extract was washed with saturated saline (50 mL three times), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (imidazo [1,2-a] pyridin-5-ylthio) acetic acid. Ethyl was obtained as a black liquid (1.8 g, quantitative yield 62.1%, HPLC 87.5%).

Reference Example 66 Synthesis of ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate from 5-bromoimidazo [1,2-a] pyridine 5-bromoimidazo in a 50 mL reaction vessel under an argon atmosphere. 103.2 mg of [1,2-a] pyridine was dissolved in 1 mL of dimethylformamide. 0.11 mL of triethylamine is added to the reaction vessel, and then 0.085 mL of ethyl thioglycolate is added, and the mixture is added at 60 ° C. for 1.5 hours at room temperature.
For 2 hours and at 80 ° C. for 9 hours. After allowing the reaction solution to cool, 1N-HCl aqueous solution (50 mL) and ethyl acetate (100 mL) were added to the reaction solution. 1N-ethyl acetate layer
Extract with aqueous HCl (50 mL twice). An acidic aqueous solution was mixed, and NaHCO ₃ was added to the aqueous solution to neutralize the solution (pH 0.35 to 7.30). Ethyl acetate (50 mL three times) was added to the neutralized aqueous solution to extract the product. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate as a black liquid (1).
50 mg, quantitative yield 56.9%, HPLC 79.1
%).

Reference Example 67 Synthesis of 2-fluoro-6-methylthiopyridine 2,6-difluoropyridine (1 g) was added to THF (10 m
L), sodium thiomethoxide (731 mg, 1.2 equivalents) was added at 0 ° C under an argon atmosphere, and the mixture was stirred at room temperature overnight. Add ethyl acetate (30 mL
Times) and water (30 mL), and extraction was performed from the aqueous layer. After combining the ethyl acetate solutions, the mixture was washed with water (20 mL twice). After drying over anhydrous sodium sulfate, the mixture was filtered and then concentrated under reduced pressure to give 2-fluoro-6-methylthiopyridine (1.09 g, yield 8) as a pale yellow oil.
8%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.55 (3H, s), 3.93 (2H,
s), 3.57 (1H, m), 7.05 (1H, m), 7.56 (1H, m).

Reference Example 68 Synthesis of 2-amino-6-methylthiopyridine 900 mg of 2-fluoro-6-methylthiopyridine was added to 2
Dissolve in 5 mL of 8% aqueous ammonia and in a closed container (internal pressure 1
2.1 kgcm ^-2 ), 1 hour at 150 ° C, 6 hours at 180 ° C
Stirred for hours. After cooling to room temperature, ethyl acetate (50 mL) and water (50 mL) were added. The water was extracted with ethyl acetate (50 mL) and the combined ethyl acetate was washed with water (2 x 50 mL). After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain a yellow oil. (Crystallized on standing overnight) (873 g, 99% yield). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.49 (3H, s), 4.40 (2H, br
s), 6.18 (1H, dd, J = 0.5, 8.1 Hz), 6.53 (1H, dd, J =
0.5, 7.7 Hz), 7.26 (1H, dd, J = 7.7, 8.1 Hz).

Reference Example 69 Synthesis of 2-amino-6-methylthiopyridine Aqueous sodium thiomethoxide (13 mL, 10 equivalents) was added to 2-amino-6-fluoropyridine (300 mg).
Was added and the suspension was stirred at 80 ° C. for 1 hour and at 100 ° C. for 5 hours. After cooling the reaction solution to room temperature, ethyl acetate (4
0 mL twice) and water (30 mL) were added, and an extraction operation was performed from the aqueous layer. After combining the ethyl acetate solutions, the mixture was washed with water (40 mL). After drying over anhydrous sodium sulfate, the mixture was filtered and concentrated under reduced pressure to obtain an oily substance (crystallized by standing overnight) (237 mg, yield 63%).

Reference Example 70 Synthesis of 5-methylthioimidazo [1,2-a] pyridine 3.094 g of 2-amino-6-methylthiopyridine was dissolved in 31 mL of ethanol and heated to 60 ° C. 40%
14.6 mL of chloroacetaldehyde was added dropwise and stirred for 1 hour. After cooling, the mixture was concentrated, 1N-HCl (60 mL) was added, and the mixture was washed with ethyl acetate (20 mL twice). 2N for water layer
-Sodium hydroxide (50 mL) was added, followed by extraction with ethyl acetate (30 mL three times). Wash the ethyl acetate layer with water (20m
L twice). Dry over sodium sulfate and concentrate by filtration to give a brown oil (5.01 g, 83.0% yield). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 2.61 (3H, s), 6.76 (1H,
m), 7.18 (1H, m), 7.55 (1H, m), 7.73 (2H, m)

Reference Example 71 Synthesis of imidazo [1,2-a] pyridine-5-thiol Xylene (2 mL), hexamethylphosphoric triamide (0.1 mL), sodium hydride (24.4 mg) under an argon atmosphere Was placed in a flask. Heat to 45 ° C. and add diethylamine (0.06 mL). The mixture was stirred for 20 minutes as it was. 5-methylthioimidazo [1,2-
a] A solution of pyridine (57 mg) in xylene (1 mL) was added, and the mixture was heated to 150 ° C. and stirred for 2 hours and 30 minutes. After cooling,
Water (5 mL), 1N-HCl (10 mL) were added, and the mixture was washed with ethyl acetate (20 mL). The aqueous layer was adjusted to pH 8.5 with 2N-NaOH, extracted with ethyl acetate, dried over Na ₂ SO ₄ , filtered and concentrated. Brown oily imidazo [1,2-
a] Pyridine-5-thiol (10 mg, 19%) was obtained. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ: 6.93 (2H, m), 7.30 (1H,
m), 7.85 (1H, m), 8.32 (1H, m).

Reference Example 72 Imidazo [1,2-a] pyridine-5-thiol (12
0.02 g: 0.7911 mol), triethylamine (1
34 mL: 0.959 mol) of an ethanol solution (500
Ethyl bromoacetate (88.6 mL: 0.
799 mol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent of the reaction solution under reduced pressure, ethyl acetate was added to the residue.
The resulting precipitate (mainly triethylamine hydrochloride) was filtered and washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure to obtain ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate as a crude product. This was used for the next reaction without purification. Brown liquid Yield 199.7 g Acetic acid solution of crude ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate (199.7 g) and hexamethylenetetramine (224 g: 1.60 mol) (5
00 mL) was stirred at 90 ° C. for 1 day. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to give 5-
Ethyl thia-1,8b-diazaacenaphthylene-4-carboxylate was obtained as a crude product. This was used for the next reaction without purification. Black purple solid Yield 193.69 g 5-thia-1,8b-diazaacenaphthylene- obtained
Sodium hydroxide (62.9 g: 1.57) was added to an ethanol solution (1 L) of ethyl 4-carboxylate (193.69 g).
Mol) was added and stirred at room temperature for 0.5 hour. Concentrated hydrochloric acid (130 mL) was added with stirring until the pH of the reaction solution reached 4 to 5, and the resulting precipitate was filtered, washed with ethanol, acetone, and diethyl ether in this order to give 5-thia-1,8b-diaza. Acenaphthylene-4-carboxylic acid was obtained. Orange solid Yield 96.3 g (55% yield) ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 5.97 (1H, dd, J = 6.6, 1.
2Hz), 6.57-6.73 (2H, m), 6.88 (1H, s), 7.12 (1H, s). IR (KBr): 3413, 1632, 1338 cm ^-1

Reference Example 73 Production of 4-amino-1- (3-phenylpropyl) piperidine 1- (3-Phenylpropyl) -4-aminopyridinium bromide (50 g) was dissolved in methanol (467 mL) to give 5% Palladium carbon (2.5 g), 28
% -Sodium methylate (32.9 g) was added. Catalytic reduction was performed at a hydrogen pressure of 6 to 8 atm and a reaction temperature of 40 ° C for 5 hours. After cooling, the catalyst was removed by filtration, and the filtrate was concentrated. Ethyl acetate (1 L) and water (200 mL) were added, and 2N was added under ice cooling.
-Sodium hydroxide was added. Liquid separation and water (300m
L). After drying over sodium sulfate, the mixture was concentrated. Acetonitrile (476 mL) was added, and under ice-cooling,
3.5N hydrochloric acid / ethyl acetate (195 mL) was added.
After stirring at room temperature for 40 minutes, the mixture was filtered and acetonitrile (70 m
L), dried under reduced pressure, and dried with 4-amino-1- (3-phenylpropyl) piperidine dihydrochloride (42.86).
g, yield 86.3%). ¹ H-NMR (D ₂ O, 300 MHz) δ: 1.7-2.0 (m, 6H), 2.5 (t, 2H,
J = 7.5Hz), 2.8-3.2 (m, 4H), 7.1-7.3 (m, 5H).

Reference Example 74 Production of 4-amino-1- (3-phenylpropyl) piperidine 1- (3-phenylpropyl) -4-aminopyridinium bromide (10 g), 2-propanol (200 m
L), sodium methylate (1.84 g) and sodium borohydride (10 g) were mixed and heated to reflux. Methanol (50 mL) was added dropwise thereto, and the mixture was refluxed for 2 hours. After cooling, water (150 mL) and concentrated hydrochloric acid (35 m
L) was added and the mixture was stirred at room temperature for 1.5 hours. 30% on this
Sodium hydroxide (53 mL) was added. After concentration, the mixture was extracted with ethyl acetate (100 mL three times), and further washed with water (5 mL).
0 mL twice), dried over sodium sulfate, filtered, and concentrated. Under ice cooling, methanol-denatured alcohol (2
3 mL). To this, 3.96 N hydrochloric acid / methanol denatured alcohol (17 mL) was added dropwise. After stirring for 30 minutes under ice cooling, the mixture was stirred at room temperature for 1 hour. Diisopropyl ether (60 mL) was added dropwise thereto, and the mixture was further stirred at room temperature for 2 hours and then under ice cooling for 1 hour. The crystals were collected by filtration under reduced pressure, and washed with isopropyl ether (twice with 20 mL). This was dried under reduced pressure, and 4-amino-1- (3-phenylpropyl) piperidine dihydrochloride (8.54 g,
Yield 86%). ¹ H-NMR (D ₂ O, 300 MHz) δ: 1.7-2.0 (m, 6H), 2.5 (t, 2
(H, J = 7.5Hz), 2.8-3.2 (m, 4H), 3.3-3.6 (m, 3H), 7.1-7.
3 (m, 5H).

Reference Example 75 1- (3-Aminopropan-1-yl) -4-tert
Synthesis of -butoxycarbonyl-2-oxopiperazine 1) Synthesis of 4-tert-butoxycarbonyl-2-oxopiperazine Di-tert-butyl dicarbonate (10.4 g, 47.6 m)
mol) with 2-oxopiperazine (4.77 g, 47.
(6 mmol) in ethanol solution (100 ml) at room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the desired product as white crystals, which were washed with hexane (8.00).
g, 84%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 6.90-6.56 (1H, m), 4.0
9 (2H, s), 3.64 (2H, t, J = 5.2 Hz), 3.44-3.34 (2H,
m), 1.48 (9H, s) .IR (KBr): 3265, 3195, 2981, 1691, 1666, 1635, 141
9, 1398, 1365, 1338, 1243, 1176, 1131, 1002 cm -1. 2) 4-tert- butoxycarbonyl-1- (3-
Synthesis of phthaloylpropan-1-yl) -2-oxopiperazine Sodium hydride (60% oily, 1.78 g, 44.
5 mmol) with 4-tert-butoxycarbonyl-2
-Oxopiperazine (8.00 g, 40.0 mmol)
Was slowly added at room temperature to an N, N-dimethylformamide solution (100 ml), followed by stirring for 1 hour. Then N-
(3-bromopropyl) phthalimide (12.5 g, 4
6.6 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. 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 (silica gel 150 g, hexane / ethyl acetate = 1/1) to obtain the desired product as a colorless oil (9.02 g, 55%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.90-7.80 (2H, m), 7.8
0-7.68 (2H, m), 4.07 (2H, s), 3.72 (2H, t, J = 5.2 H
z), 3.67 (2H, t, J = 5.2 Hz), 3.50 (2H, t, J = 7.2 H
z), 3.37 (2H, t, J = 5.2 Hz), 1.98 (2H, tt, J = 7.2 an
d 7.2 Hz), 1.47 (9H, s) .IR (neat): 2976, 2935, 1772, 1714, 1652, 1398, 13
67, 1239, 1170, 1126,722 cm ^-1 .3) 1- (3-Aminopropan-1-yl) -4-t
-Butoxycarbonyl-2-oxopiperazine hydrazine monohydrate (1.75 g, 46.6 mmol) was added to 4-
tert-butoxycarbonyl-1- (3-phthaloylpropan-1-yl) -2-oxopiperazine (9.0
2 g, 23.3 mmol) in ethanol (50 m
l) and heated to reflux for 1 hour. The generated insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. A 2N aqueous sodium hydroxide solution 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 to obtain the desired product as a colorless oil (5.
43 g, 91%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 4.29 (2H, m), 4.07 (2
H, s), 3.69-3.60 (2H, m), 3.51-3.20 (4H, m), 2.71
(2H, t, J = 7.0 Hz), 2.03-1.92 (2H, m), 1.47 (9H,
s) .IR (neat): 2977, 1695, 1652, 1419, 1367, 1326, 12
47, 1168 cm ^-1 .

Reference Example 76 Synthesis of 3- (4-tert-butoxycarbonylaminophenyl) propyl methanesulfonate 1) Synthesis of ethyl (E) -3- (4-nitrophenyl) acrylate Sodium hydride (60% oil-based) , 2.22 g, 55.5
mmol) with 4-nitrobenzaldehyde (8.00).
g, 52.9 mmol), triethyl phosphonoacetate (1
(2.4 g, 55.5 mmol) in N, N-dimethylformamide solution (50 ml), and the mixture was stirred at 0 ° C. for 30 minutes. The reaction solution was poured into water to obtain crystals as a target substance. The crystals were collected by filtration, and washed with water and hexane (11.7 g, quant.). 133-135 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.26 (2H, d, J = 8.8 H
z), 7.72 (1H, d, J = 16.0Hz), 7.68 (2H, d, J = 8.8H
z), 6.57 (1H, d, J = 16.0 Hz), 4.30 (2H, q, J = 7.0H
z), 1.36 (3H, t, J = 7.0 Hz) .IR (KBr): 3107, 3080, 2985, 2908, 1714, 1646, 159
4, 1517, 1342, 1313, 1180, 979, 844 cm -1. 2) 3- (4- amino-phenyl) ethyl propionate (E)-3-(4-nitrophenyl) ethyl acrylate (11. 7g, 52.9 mmol), a suspension of 10% palladium-carbon (1.20 g) in tetrahydrofuran (1
00 ml) was stirred at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product as a yellow oil (9.66 g, 95%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 6.99 (2H, d, J = 8.4 H
z), 6.62 (2H, d, J = 8.4 Hz), 4.12 (2H, q, J = 7.0 H
z), 3.60-3.00 (2H, m), 2.84 (2H, t, J = 7.6 Hz), 2.5
5 (2H, t, J = 7.6 Hz), 1.23 (3H, t, J = 7.0 Hz) .IR (neat): 3371, 2981, 2925, 1729, 1627, 1519, 13
72, 1282, 1180, 1155,1037, 825 cm -1. 3) 3- (4-tert- butoxycarbonylamino phenyl) propionate 3- (4-aminophenyl) propionate (9.
66 g, 50.0 mmol), a solution of di-tert-butyl dicarbonate (13.1 g, 60.0 mmol), and a solution of triethylamine (6.07 g, 60.0 mmol) in tetrahydrofuran (50 ml) were stirred at room temperature for 17 hours. 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,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 150 g, hexane / ethyl acetate = 5).
/ 1) to give the desired product as a yellow oil (14.
7g, quant. ). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.27 (2H, d, J = 8.6 H
z), 7.12 (2H, d, J = 8.6 Hz), 6.42 (1H, brs), 4.12
(2H, q, J = 7.0 Hz), 2.90 (2H, t, J = 8.0 Hz), 2.58 (2
H, t, J = 8.0 Hz), 1.53 (9H, s), 1.23 (3H, t, J = 7.0
Hz) .IR (neat): 3344, 2981, 1808, 1729, 1527, 1372, 13
15, 1215, 1160, 1118, 1072 cm ^- 1.4) Synthesis of 3- (4-tert-butoxycarbonylaminophenyl) propanol Dibutylaluminum hydride (1.5 M toluene solution,
30.5 ml, 45.8 mmol) in 3- (4-ter
A solution of ethyl t-butoxycarbonylaminophenyl) propionate (6.10 g, 20.8 mmol) in tetrahydrofuran (60 ml) was added dropwise at 0 ° C, and 0 ° C for 1 hour.
And stirred. After gradually adding 2N hydrochloric acid to the reaction solution,
Extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (silica gel 100 g, hexane /
Purification with ethyl acetate = 3/2) gave the desired product as a colorless oil (2.66 g, 51%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.34-7.00 (4H, m), 6.4
4 (1H, brs), 3.67 (2H, t, J = 6.4 Hz), 2.80-2.60 (2H,
m), 2.00-1.80 (2H, m), 1.43 (9H, s) .IR (neat): 3311, 2979, 2933, 1726, 1521, 1369, 12
43, 1158, 1116, 1054 cm -1. 5) Synthesis of methanesulfonic acid 3- (4-tert-butoxycarbonylamino-phenyl) propyl 3- (4-tert-butoxycarbonylamino-phenyl) propanol (2.66 g, 10 .6 mmol),
Methanesulfonyl chloride (1.33 g, 11.6 mm
ol), triethylamine (1.18 g, 11.7 mm)
ol) in ethyl acetate (10 ml) 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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 50 g, hexane / ethyl acetate = 3/1) to obtain the desired product as colorless crystals (2.75 g, 79).
%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.35-7.00 (4H, m), 6.4
4 (1H, brs), 4.21 (2H, t, J = 6.4 Hz), 2.99 (3H, s),
2.70 (2H, t, J = 7.4 Hz), 2.15-1.95 (2H, m), 1.52 (9
H, s) .IR (KBr): 3381, 2979, 1706, 1529, 1349, 1237, 116
8, 952 cm ^-1 .

Reference Example 77 Synthesis of 3- (3-tert-butoxycarbonylaminophenyl) propyl methanesulfonate 1) Synthesis of ethyl (E) -3- (3-nitrophenyl) acrylate Sodium hydride (60% oil-based) , 2.22 g, 55.5
mmol) with 3-nitrobenzaldehyde (8.00).
g, 52.9 mmol), triethyl phosphonoacetate (1
2.4 g, 55.5 mmol) in N, N-dimethylformamide solution (50 ml).
Stirred for hours. The reaction solution was poured into water to obtain crystals as a target substance. The crystals were collected by filtration, and washed with water and hexane (11.7 g, quant.). Melting point 65-66 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 8.42-8.35 (1H, m), 8.2
4 (1H, dd, J = 8.0 and 2.2 Hz), 7.88-7.80 (1H, m),
7.73 (1H, d, J = 15.6 Hz), 7.59 (1H, dd, J = 8.0and 8.
0 Hz), 6.57 (1H, d, J = 15.6 Hz), 4.30 (2H, q, J = 6.0
Hz), 1.36 (3H, t, J = 6.0 Hz). 2) Synthesis of ethyl 3- (3-aminophenyl) propionate Ethyl (E) -3- (3-nitrophenyl) acrylate (11.7 g, 52.9 mmol), a suspension of 10% palladium-carbon (2.80 g) in tetrahydrofuran (1
00 ml) was stirred at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 100 g, hexane / ethyl acetate = 3/1) to obtain the desired product as a yellow oil (6.21 g, 61%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.12-7.00 (1H, m), 6.6
5-6.50 (3H, m), 4.13 (2H, q, J = 7.0 Hz), 3.62 (2H, b
rs), 2.86 (2H, t, J = 7.0 Hz), 2.58 (2H, t, J = 7.0 H
z), 1.24 (3H, t, J = 7.0 Hz). 3) Synthesis of ethyl 3- (3-tert-butoxycarbonylaminophenyl) propionate Ethyl 3- (3-aminophenyl) propionate (6.
21 g, 32.1 mmol), a solution of di-tert-butyl dicarbonate (8.41 g, 38.5 mmol), and a solution of triethylamine (3.90 g, 38.5 mmol) in tetrahydrofuran (30 ml) were stirred at room temperature for 19 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 (silica gel 100 g, hexane / ethyl acetate = 8/1) to obtain the desired product as a yellow oil (9.35 g, 99%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-7.10 (3H, m), 6.9
0-6.80 (1H, m), 6.44 (1H, brs), 4.13 (2H, q, J = 7.2
Hz), 2.92 (2H, t, J = 7.8 Hz), 2.60 (2H, t, J = 7.8 H
z), 1.51 (9H, s), 1.24 (3H, t, J = 7.2 Hz) .IR (neat): 3346, 2981, 2933, 1733, 1612, 1594, 15
38, 1494, 1442, 1369,1236, 1162, 1056, 871, 788 cm
^-1.4 ) Synthesis of 3- (3-tert-butoxycarbonylaminophenyl) propanol dibutylaluminum hydride (1.5 M toluene solution,
57.0 ml, 85.5 mmol) with 3- (3-ter
A solution of ethyl t-butoxycarbonylaminophenyl) propionate (9.35 g, 31.9 mmol) in tetrahydrofuran (100 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 24 hours. After 2N hydrochloric acid was gradually added to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 100 g, hexane / ethyl acetate = 2/1) to obtain the desired product as a colorless oil (3.24 g, 40%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.30-7.05 (3H, m), 7.0
0-6.80 (1H, m), 6.47 (1H, brs), 3.66 (2H, t, J = 6.4
Hz), 2.68 (2H, t, J = 7.6 Hz), 2.00-1.80 (2H, m), 1.
52 (9H, s) .IR (neat): 3317, 2979, 2933, 1699, 1610, 1592, 15
38, 1490, 1442, 1369,1245, 1160, 1056, 778 cm -1. 5) Synthesis of methanesulfonic acid 3- (3-tert-butoxycarbonylamino-phenyl) propyl 3- (3-tert-butoxycarbonylamino-phenyl ) Propanol (3.24 g, 12.9 mmol),
Methanesulfonyl chloride (1.63 g, 14.2 mm
ol), triethylamine (1.44 g, 14.2 mm)
ol) in ethyl acetate (50 ml) 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, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 50 g, hexane / ethyl acetate = 3/1) to obtain the desired product as colorless crystals (3.50 g, 82).
%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-7.00 (3H, m), 6.8
6 (1H, d, J = 6.6 Hz), 6.46 (1H, brs), 4.22 (2H, t,
J = 6.0 Hz), 3.01 (3H, s), 2.73 (2H, t, J = 7.6Hz), 2.
20-1.98 (2H, m), 1.51 (9H, s).

Reference Example 78 Synthesis of 3- (4-tert-cyanophenyl) propyl methanesulfonate 1) Synthesis of ethyl (E) -3- (4-cyanophenyl) acrylate Sodium hydride (60% oily, 3 .20 g, 80.0
mmol) with 4-cyanobenzaldehyde (10.0
g, 76.3 mmol), triethyl phosphonoacetate (1
(8.0 g, 80.1 mmol) in N, N-dimethylformamide (80 ml) and stirred at 0 ° C. for 1 hour. The reaction solution was poured into water to obtain crystals as a target substance,
The crystals were collected by filtration and washed with water and hexane (1).
3.9 g, 91%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.74-7.54 (4H, m), 7.63
(1H, d, J = 16.2 Hz), 6.52 (1H, d, J = 16.2 Hz), 4.29
(2H, q, J = 7.0 Hz), 1.34 (3H, t, J = 7.0 Hz) .IR (KBr): 3402, 2987, 2227, 1706, 1641, 1560, 147
. 3, 1369, 1166, 1002 , 850 cm -1 2) 3- (4- cyano-phenyl) propionate (E) -3- (4- cyanophenyl) - ethyl acrylate (13.9 g, 69 .1 mmol), and a suspension of 10% palladium-carbon (4.00 g) in tetrahydrofuran (100 ml) was stirred at room temperature under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the desired product as a yellow oil (13.7 g, 98%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.59 (2H, d, J = 8.2 H
z), 7.33 (2H, d, J = 8.2 Hz), 4.13 (2H, q, J = 7.0 H
z), 3.01 (2H, t, J = 7.6 Hz), 2.64 (2H, t, J = 7.6 H)
z), 1.23 (3H, t, J = 7.0 Hz) .IR (neat): 2981, 2933, 2229, 1733, 1608, 1506, 14
46, 1417, 1374, 1297, 1185, 1041, 827 cm ^-1 .3) Synthesis of 3- (4-cyanophenyl) propionic acid ethyl 3- (4-cyanophenyl) propionate (6.
A 2N aqueous solution of sodium hydroxide (30.0 ml, 60.0 mmol) in ethanol (60 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as colorless crystals (4.40 g, 85%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.60 (2H, d, J = 8.0 H
z), 7.33 (2H, d, J = 8.0 Hz), 3.02 (2H, t, J = 7.6 H
z), 2.71 (2H, t, J = 7.6 Hz) .IR (KBr): 3060, 2922, 2227, 1710, 1608, 1434, 141
1, 1330, 1309, 1224, 935, 840 cm ^- 1.4) Synthesis of 3- (4-cyanophenyl) propanol A borane-tetrahydrofuran complex salt (1.0 M solution in tetrahydrofuran, 33.0 ml, 33.0 mmol) was added in 0%.
3- (4-cyanophenyl) propionic acid (4.4
(0 g, 25.1 mmol) in a tetrahydrofuran solution (50 ml). After the reaction solution was stirred at room temperature for 14 hours, water (50 ml) and potassium carbonate (10.0 g, 7 g) were added.
2.4 mmol) was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as a colorless oil (3.20 g, 79%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.58 (2H, d, J = 8.2 H
z), 7.31 (2H, d, J = 8.2 Hz), 3.68 (2H, t, J = 6.2 H
z), 2.79 (2H, t, J = 7.8 Hz), 2.00-1.75 (2H, m) .IR (neat): 3319, 2943, 2229, 1608, 1505, 1415, 10
^{54, 854, 817 cm -1.} 5) Methanesulfonic acid 3- (4-cyanophenyl)
Synthesis of propyl 3- (4-cyanophenyl) propanol (3.77
g, 23.4 mmol), methanesulfonyl chloride (2.96 g, 25.8 mmol), and a solution of triethylamine (2.60 g, 25.7 mmol) in ethyl acetate (100 ml) were stirred at room temperature for 30 minutes. 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 (silica gel 60 g, hexane / ethyl acetate = 1/1) to obtain the desired product as a colorless oil (4.79 g, 86%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.61 (2H, d, J = 8.4 H
z), 7.31 (2H, d, J = 8.4 Hz), 4.24 (2H, t, J = 6.2 H
z), 3.02 (3H, s), 2.83 (2H, t, J = 7.8 Hz), 2.09 (2
H, tt, J = 7.8 and 6.2 Hz) .IR (neat): 3028, 2941, 2227, 1608, 1506, 1351, 11
72, 975, 929, 836, 815cm ^-1 .

Reference Example 79 Synthesis of 4- (3-aminopropan-1-yl) -1- (3-phenylpropan-1-yl) -2-oxopiperazine 1) 4-tert-butoxycarbonyl-1- ( 3-
Synthesis of phenylpropan-1-yl) -2-oxopiperazine Sodium hydride (60% oily, 630 mg, 15.8)
mmol) with 4-tert-butoxycarbonyl-2-
A solution of oxopiperazine (3.00 g, 15.0 mmol) in N, N-dimethylformamide (40 ml) was gradually added at room temperature, followed by stirring for 30 minutes. Then, 1-
Bromo-3-phenylpropane (3.29 g, 16.5)
mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. Extract water with water,
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 (silica gel 50 g, hexane / ethyl acetate =
1/1) to give the desired product as colorless crystals (3.
85 g, 81%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.35-7.15 (5H, m), 4.0
4 (2H, s), 3.57 (2H, t, J = 5.4 Hz), 3.46 (2H, t, J =
7.2 Hz), 3.28 (2H, t, J = 5.4 Hz), 2.65 (2H, t, J = 7.
2 Hz), 1.90 (2H, tt, J = 7.2 and 7.2 Hz), 1.46 (9H,
s) .IR (KBr): 2975, 2916, 1699, 1656, 1419, 1367, 123
9, 1170, 1128, 992, 701 cm- ^1.2 ) 1- (3-phenylpropan-1-yl) -2-
Synthesis of oxopiperazine Concentrated hydrochloric acid (4.2 ml) was added to 4-tert-butoxycarbonyl-1- (3-phenylpropan-1-yl) -2-
The mixture was added to oxopiperazine (3.85 g, 12.1 mmol) and stirred at room temperature for 1 hour. The reaction solution was made basic by adding an 8N aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the desired product as a colorless oil (2.49 g, 94%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.30-7.05 (5H, m), 3.4
8 (2H, s), 3.44 (2H, t, J = 7.6 Hz), 3.25 (2H, t, J =
5.4 Hz), 3.01 (2H, t, J = 5.4 Hz), 2.65 (2H, t, J = 7.
6 Hz), 1.91 (2H, tt, J = 7.6 and 7.6 Hz) .IR (neat): 3290, 2927, 1635, 1496, 1454, 1344, 13
15, 751, 701 cm ^-1 .3) 1- (3-phenylpropan-1-yl) -4-
Synthesis of (3-phthaloylpropan-1-yl) -2-oxopiperazine 1- (3-phenylpropan-1-yl) -2-oxopiperazine (2.49 g, 11.4 mmol), N-
(3-bromopropyl) phthalimide (3.67 mmol
1,13.7 mmol), potassium carbonate (1.89 g,
13.7 mmol) and a mixture of N, N-dimethylformamide (20 ml) were stirred at room temperature for 4 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 subjected to silica gel column chromatography (silica gel 60 g, hexane / ethyl acetate = 1 /
4) to give the desired product as a colorless oil (2.0%).
5 g, 44%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.82 (2H, dd, J = 5.2 an
d 3.2 Hz), 7.64 (2H, dd, J = 5.2 and 3.2 Hz), 7.35-
7.10 (5H, m), 3.77 (2H, t, J = 6.6 Hz), 3.30 (2H, t,
J = 7.6 Hz), 3.16 (2H, t, J = 5.4 Hz), 3.07 (2H, s),
2.70-2.52 (4H, m), 2.45 (2H, t, J = 6.6 Hz), 2.00-1.
70 (4H, m). 4) 4- (3-Aminopropan-1-yl) -1-
Synthesis of (3-phenylpropan-1-yl) -2-oxopiperazine Hydrazine monohydrate (382 mg, 7.63 mmol)
To 1- (3-phenylpropan-1-yl) -4- (3
-Phthaloylpropan-1-yl) -2-oxopiperazine (2.05 g, 5.05 mmol) in ethanol (10 ml) and heated under reflux for 1 hour. The generated insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. 2 for residue
A normal aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the desired product as a colorless oil (1.38 g, 99%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.35-7.15 (5H, m), 3.4
3 (2H, t, J = 7.6 Hz), 3.30 (2H, t, J = 5.4 Hz), 3.13
(2H, s), 2.78 (2H, t, J = 6.8 Hz), 2.71-2.58 (4H,
m), 2.46 (2H, t, J = 7.2 Hz), 2.05-1.75 (2H, m), 1.6
5 (2H, tt, J = 6.8 and 6.8 Hz).

Example 1 (R) -N- [1- (1,4-benzodioxane-2-
Synthesis of ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) (imidazo [1,2-a] pyridin-5-ylthio) acetic acid Synthesis of ethyl imidazo [1,2-a] pyridine-5-thiol 10
0.55 g (669.4 mmol), 112 ml of triethylamine (803 mmol) and 500 ml of ethanol
The solution was added at room temperature with 81.7 ml of ethyl bromoacetate (736
Mmol) and stirred at room temperature for 2 hours. After evaporating the solvent of the reaction solution under reduced pressure, ethyl acetate was added, and the resulting precipitate (triethylamine / hydrochloride) was filtered and washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate) to obtain the desired product. Brown liquid Yield 132.34 g (84% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.169 (3H, t, 7.1 Hz), 3.678
(2H, s), 4.122 (2H, q, 7.1Hz), 7.066 (1H, dd, 1.5Hz, 6.9H
z), 7.160 (1H, dd, 7.0Hz, 8.8Hz), 7.642 (1H, ddd, 0.7Hz,
1.5Hz, 8.8Hz), 7.724 (1H, d, 1.0Hz), 7.919 (1H, d, 0.6H
z); IR (neat) 3390, 2983, 1734, 1487, 1294, 1180,
1147, 1026, 783, 739 cm ^-1

2) Synthesis of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate Method A With stirring in 250 ml of N, N-dimethylformamide at 0 ° C., 93.2 ml of phosphorus oxychloride (1 (0.0mol) was added dropwise over 10 minutes, and the reaction solution was stirred at 0 ° C for 1 hour. To this solution was added (imidazo [1,2-a] pyridine-5
A solution of 47.26 g (0.2 mol) of ethyl (-ylthio) acetate in 50 ml of N, N-dimethylformamide was added over 5 minutes, and the reaction solution was stirred at 80 ° C for 16 hours. After the reaction, the reaction solution was poured into 1 liter of ice water, mixed well, and 1 liter of ethyl acetate was added. A 50% aqueous sodium hydroxide solution was added to the mixture with stirring under ice cooling to neutralize the aqueous layer. The organic layer was washed three times with 500 ml of water, further washed with 500 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a dark purple residue. The residue was washed with 250 ml of diethyl ether to obtain the desired product as a crude product. The obtained crude product was used for the reaction of 3) without further purification. Dark purple solid Yield 11.58 g (23.5% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.299 (3H, t, 7.1 Hz), 4.224
(2H, q, 7.1Hz), 5.629-5.731 (1H, m), 6.506-6.609 (2H,
m), 6.807 (1H, s), 7.006 (1H, s); IR (nujol) 1693,161
4, 1267, 1227, 1043, 773, 735 cm ^-1

Method B 60% liquid paraffin suspension of sodium hydride
4 g (560 mmol) was washed twice with 100 ml of hexane, 60 ml of N, N-dimethylformamide was added thereto and suspended in 500 ml of tetrahydrofuran. While cooling the reaction vessel with a water bath, at room temperature (imidazo [1,2
-A] pyridin-5-ylthio) ethyl acetate 132.3
4 g (560.1 mmol) of tetrahydrofuran 20
0 ml of the solution was added dropwise, and the mixture was stirred for 2 hours. Subsequently, while cooling the reaction vessel with a water bath, ethyl formate was added.
9 ml (840 mmol) was added, and the mixture was stirred overnight. The resulting precipitate was collected by filtration, washed successively with ethyl acetate and diethyl ether, dried and dried to give 2- (imidazo [1,
2-a] pyridin-5-ylthio) -3-oxo-2-
Ethyl sodiopropionate was obtained. Yellow solid Yield 114.37 g (yield 71%) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.222 (3H, t, 7.1 Hz), 4.119
(2H, q, 7.1Hz), 6.676 (1H, d, 6.6Hz), 7.207 (1H, dd, 7.0H
z, 8.8Hz), 7.291 (1H, d, 8.4Hz), 7.590 (1H, s), 7.933 (1
H, s), 9.400 (1H, s). IR (nujol): 1662, 1558, 1273, 1065, 771, 732, 692
cm ^-1 Elemental analysis _{(C l2 H 11 N 2 O} 3 SNa · 0.3H as ₂ O) Calculated:. C, 49.41; H, 4.01; N, 9.60 Found: C, 49.55; H, 4.14 ; N , 9.35.

Heat 500 ml of acetic acid to 120 to 130 ° C., and stir the above 2- (imidazo [1,2-a]
106.64 g (372.5 mmol) of ethyl pyridin-5-ylthio) -3-oxo-2-sodipropionate were added in portions. The reaction was stirred at 100 ° C. overnight. After evaporating the solvent of the reaction solution under reduced pressure, water was added, the mixture was carefully neutralized with potassium carbonate, and extracted four times with chloroform. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to ethyl acetate), and the resulting solid was washed with diethyl ether to obtain the desired product. Dark purple solid Yield 50.33 g (55% yield) 3) 5-Thia-1,8b-diazaacenaphthylene-4-
Synthesis of carboxylic acid To a solution of 64.047 g (260.0 mmol) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate in 400 ml of ethanol was added 156 ml (312 mmol) of a 2N aqueous sodium hydroxide solution. Stirred at room temperature for 1 hour. Concentrated hydrochloric acid was added to the reaction solution with stirring until the pH reached 4 to 5, and the resulting precipitate was filtered and washed sequentially with ethanol and diethyl ether to obtain the desired product. Red solid Yield 61.16 g (100% yield) ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 5.97 (1 H, dd, 6.6 Hz, 1.2 H)
z), 6.57-6.73 (2H, m), 6.88 (1H, s), 7.12 (1H, s). IR (KBr) 3413, 1632, 1338 cm ^-1

4) (Piperidin-4-ylmethyl) -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 26.48 g (121.3 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid While stirring 15.4 g (133 mmol) of N-hydroxysuccinimide in 250 ml of acetonitrile, 25.6 g (133 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added thereto. Stirred for hours. Triethylamine 2
0.3 ml (146 mmol), 1- (tert-butoxycarbonyl) piperidin-4-ylmethylamine 2
7.3 g (127 mmol) was added and stirred at room temperature overnight. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 9/1) to give crude N- [1-
(Tert-Butoxycarbonyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. The obtained crude N- [1-
30 ml of concentrated hydrochloric acid was added to (tert-butoxycarbonyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide, and the mixture was stirred at room temperature for 1 hour. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid Yield 33.347 g (71% yield) ¹ H-NMR (DMSO-d ₆ , 200 Mz) δ: 1.19-1.54 (2H, m), 1.58-1.
92 (3H, m), 2.66-2.96 (2H, m), 2.96-3.15 (2H, m), 3.16-
3.35 (2H, m), 6.65 (1H, d, 7.4Hz), 7.01 (1H, d, 9.2Hz), 7.
26 (1H, s), 7.32 (1H, dd, 9.2Hz, 7.4Hz), 7.70 (1H, s), 8.7
0-9.28 (3H, m, NH). IR (KBr) 3358, 1641, 1535 cm ^-1

5) (R) -N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide A solution of 0.410 g (2.467 mmol) of (R) -2-hydroxymethyl-1,4-benzodioxane and 0.52 ml (3.70 mmol) of triethylamine in 30 ml of diethyl ether was cooled with ice. 0.21 ml (2.71 mmol) of methanesulfonyl chloride was added dropwise, and the mixture was stirred for 0.5 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to short silica gel column chromatography (hexane / ethyl acetate = 3/1 to 2/1) to give crude (S) -2-methanesulfonyloxymethyl-1,4-
Benzodioxane was obtained. The obtained crude (S) -2-methanesulfonyloxymethyl-1,4-benzodioxane, N- (piperidin-4-ylmethyl) -5-thia-
A solution of 1.05 g (2.71 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.20 ml (8.64 mmol) of triethylamine in 30 ml of ethanol was heated to reflux for 3 days. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 4/1).
３3/1) to obtain the desired product as a mixture with triethylamine.hydrochloride. Ethyl acetate was added thereto, and the mixture was washed with an aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Red foamy substance Yield 0.452 g (40% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.222. 1.368 (2H, m), 1.493-
1.702 (3H, m), 2.011-2.187 (2H, m), 2.543 (1H, dd, 6.4Hz,
13.0Hz), 2.663 (1H, dd, 5.4Hz, 13.2Hz), 2.885-3.035 (2
H, m), 3.182 (2H, t, 6.1Hz), 3.957 (1H, dd, 7.7Hz, 11.7H
z), 4.249-4.317 (2H, m), 5.759 (1H, dd, 2.5Hz, 5.5Hz),
6.371 (1H, brt, 5.9Hz), 6.600-6.654 (3H, m), 6.788-6.8
96 (4H, m), 6.990 (1H, s). IR (neat) 3313, 2924, 1618, 1549, 1491, 1265, 115
3, 731 cm ^-1

6) (R) -N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride (R) -N- [1- (1,4-benzodioxane-2-
0.452 g of [ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was dissolved in 1 ml of methanol, and an excess amount of a methanol solution of hydrogen chloride was added and stirred. This was concentrated to obtain the desired product. Orange foamy substance Yield 0.530 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.641-2.042 (5H, m), 3.114-
3.588 (6H, m), 3.687-3.881 (2H, m), 4.037 (1H, dd, 6.6Hz,
11.8Hz), 4.346 (1H, dd, 2.3Hz, 11.5Hz), 4.828-4.905 (1
H, m), 6.636 (1H, d, 7.2Hz), 6.827-6.904 (3H, m), 6.931-
6.992 (1H, m), 7.038 (1H, d, 9.2Hz), 7.098 (1H, s), 7.401
(1H, dd, 7.6Hz, 8.8Hz), 7.563 (1H, s) .IR (nujol): 3228, 2650, 1630, 1493, 1294, 1263, 756
cm ^-1 Elemental analysis _{(C 25 H 28 Cl 2 N} 4 O 3 S · 2.5H as ₂ O) Calculated:. C, 51.72; H, 5.73; N, 9.65 Found: C, 51.66; H, 5.97 N, 9.62.

Example 2 (S) -N- [1- (1,4-benzodioxan-2-
Synthesis of ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in Example 1, 5), a red foam (S ) -N
-[1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.245-1.395 (2H, m), 1.468-
1.719 (3H, m), 2.018-2.210 (2H, m), 2.561 (1H, dd, 5.8Hz,
13.4Hz), 2.679 (1H, dd, 5.7Hz, 13.3Hz), 2.901-3.059 (2
H, m), 3.211 (2H, t, 6.2Hz), 3.973 (1H, dd, 7.7Hz, 11.7H
z), 4.253-4.350 (2H, m), 5.798 (1H, brt, 6.2Hz), 5.800
(1H, dd, 1.8Hz, 6.2Hz), 6.594-6.719 (3H, m), 6.801-6.90
9 (4H, m), 7.062 (1H, s). IR (neat): 3311, 2924, 1618, 1549, 1491, 1265, 115
3,735 cm ^{-1 Using the} above compound, an orange foam-like target product was obtained in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.643-2.040 (5H, m), 3.116-
3.238 (4H, m), 3.418-3.594 (2H, m), 3.685-3.879 (2H, m),
4.037 (1H, dd, 6.6Hz, 11.8Hz), 4.349 (1H, dd, 2.2Hz, 11.4
Hz), 4.832-4.907 (1H, m), 6.638 (1H, d, 7.2Hz), 6.829-
6.905 (3H, m), 6.933-6.995 (1H, m), 7.040 (1H, d, 9.2Hz),
7.105 (1H, s), 7.404 (1H, dd, 7.6Hz, 9.0Hz), 7.569 (1H,
s). IR (nujol): 3230, 2667, 1630, 1493, 1298, 1263, 75
6 cm ^-1 elemental analysis (as C ₂₅ H ₂₈ Cl ₂ N ₄ O ₃ S · 2.0 H ₂ O) Calculated: C, 52.54; H, 5.64; N, 9.80. Found: C, 52.53; H, 5.86; N, 9.75.

Example 3 N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in 5) of Example 1, red foamy N- [1-
(1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.273-1.396 (2H, m), 1.478-
1.713 (3H, m), 2.015-2.204 (2H, m), 2.553 (1H, dd, 5.8Hz,
13.6Hz), 2.674 (1H, dd, 5.8Hz, 13.6Hz), 2.894-3.066 (2
H, m), 3.204 (2H, t, 6.1Hz), 3.968 (1H, dd, 7.8Hz, 11.6H
z), 4.242-4.348 (2H, m), 5.788 (1H, dd, 1.6Hz, 6.0Hz),
5.865 (1H, brt, 6.2Hz), 6.583-6.711 (3H, m), 6.794-6.9
02 (4H, m), 7.047 (1H, s). IR (neat): 3313, 2926, 1618, 1549, 1491, 1267, 115
3, 731 cm ^-1 An orange foam was obtained in the same manner as in 6) of Example 1 using the above compound. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.577-2.042 (5H, m), 3.083-
3.246 (4H, m), 3.403-3.530 (2H, m), 3.656-3.845 (2H, m),
4.034 (1H, dd, 6.5Hz, 11.5Hz), 4.326 (1H, dd, 2.4Hz, 11.4
Hz), 4.832-4.907 (1H, m), 6.615 (1H, dd, 0.8Hz, 7.6Hz),
6.861-6.896 (3H, m), 6.929-6.973 (1H, m), 7.007 (1H, dd,
0.8Hz, 9.2Hz), 7.045 (1H, s), 7.393 (1H, dd, 7.5Hz, 8.9H
z), 7.539 (1H, s). IR (nujol): 3217, 2663, 1629, 1493, 1294, 1261, 75
6 cm ^-1 Elemental analysis (as C ₂₅ H ₂₈ Cl ₂ N ₄ O ₃ S · 3.0 H ₂ O) Calculated: C, 50.93; H, 5.81; N, 9.50. Found: C, 51.11; H, 5.86; N, 9.55.

Example 4 N- [1- (3-Phenylpropan-1-yl) piperidin-3-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-3-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1, 0.46 g (1.860 mmol) of 8b-diazaacenaphthylene-4-carboxylic acid, 1- (3
-Phenylpropan-1-yl) piperidin-3-ylmethylamine dihydrochloride 0.62 g (2.05 mmol), triethylamine 1.04 ml (7.44 mmol) in N, N-dimethylformamide 10 ml solution,
0.34 ml (2.23 mmol) of diethyl cyanophosphate was added at room temperature, and the mixture was stirred overnight. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate / methanol = 4/1 to 2/1) to obtain the desired product. Red foamy substance Yield 0.300 g (37% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.072-1.187 (1H, m), 1.497-
2.045 (8H, m), 2.188 (1H, t, 9.0Hz), 2.390 (2H, t, 7.8Hz),
2.628 (2H, t, 7.7Hz), 2.708-2.901 (3H, m), 3.202 (1H, d
d, 5.2Hz, 13.6Hz), 3.324 (1H, dd, 6.1Hz, 13.3Hz), 5.702
(1H, dd, 1.6Hz, 6.2Hz), 6.537-6.679 (3H, m), 6.859 (1H, b
rs), 6.975 (1H, s), 7.144-7.325 (5H, m). IR (neat): 3278, 2931, 1618, 1549, 1481, 1281, 115
5, 1053, 773, 733, 700 cm ^-1 2) N- [1- (3-Phenylpropan-1-yl) piperidin-3-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4 -Synthesis of carboxamide dihydrochloride In the same manner as in 6) of Example 1, an orange foam was obtained. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.145-1.350 (1H, m), 1.830-
2.214 (6H, m), 2.709 (2H, t, 7.5Hz), 2.784-2.964 (2H, m),
3.108-3.372 (4H, m), 3.509-3.559 (2H, m), 6.627 (1H, d,
7.2Hz), 7.035 (1H, d, 8.8Hz), 7.120-7.325 (6H, m), 7.39
1 (1H, dd, 7.7Hz, 9.1Hz), 7.556 (1H, s). IR (neat): 3390, 2949, 2679, 1633, 1566, 1537, 145
0, 1296, 1215, 754, 702 cm -1 Elemental analysis _{(C 25 H 30 Cl 2 N} 4 OS · 2.5H as ₂ O) Calculated:. C, 54.54; H, 6.41; N, 10.18 Found: C, 54.52; H, 6.40; N, 9.96.

Example 5 4- [1 ′-(3-Phenylpropan-1-yl)-
4,4'-Bipiperidin-1-ylcarbonyl] -5
Synthesis of thia-1,8b-diazaacenaphthylene dihydrochloride In the same manner as in Example 4, 1), red foam 4- [1 ′] was obtained.
-(3-Phenylpropan-1-yl) -4,4'-bipiperidin-1-ylcarbonyl] -5-thia-1,8
b-Diazaacenaphthylene was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.049-1.382 (6H, m), 1.644-
1.903 (8H, m), 2.346 (2H, t, 7.6Hz), 2.619 (2H, t, 7.7Hz),
2.817 (2H, brd, 12.3Hz), 2.964 (2H, brd, 11.2Hz), 4.3
54 (2H, br d, 13.4Hz), 5.705 (1H, dd, 1.5Hz, 6.3Hz), 6.04
5 (1H, s), 6.587 (1H, dd, 9.2Hz, 16.8Hz), 6.607 (1H, dd, 9.
2Hz, 12.0Hz), 6.921 (1H, s), 7.127-7.312 (5H, m). IR (neat): 2937, 1618, 1483, 1439, 1279, 1149, 731
cm- ¹ The target compound was obtained as an orange foam in the same manner as in 6) of Example 1 using the above compound. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.145-2.194 (12H, m), 2.707
(2H, t, 7.7Hz), 2.903-3.154 (6H, m), 3.587 (2H, br d, 11.
8Hz), 4.342 (2H, br d, 12.8Hz), 6.521 (1H, s), 7.666 (1
H, d, 7.4Hz), 7.096 (1H, d, 8.8Hz), 7.140-7.330 (5H, m),
7.424 (2H, dd, 7.6Hz, 9.2Hz), 7.499 (1H, s). IR (neat): 2947, 2721, 1630, 1500, 1448, 1390, 127
5, 1215, 972, 754, 702cm -1 Elemental analysis _{(C 29 H 36 Cl 2 N} 4 OS · 2.5H as ₂ O) Calculated:. C, 57.61; H, 6.83; N, 9.27 Found: C H, 7.10; N, 8.88.

Example 6 N- [2- [1- (3-phenylpropan-1-yl)]
Piperidine-4-ylidene] ethyl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [2- (piperidin-4-ylidene) ethyl]
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl] phthalimide 2.5
To a solution of 55 g (7.169 mmol) in 30 ml of ethanol was added 0.38 ml (7.89 mmol) of hydrazine monohydrate, and the mixture was heated under reflux for 1 hour. After the reaction solution was cooled to room temperature, it was poured into an aqueous sodium hydroxide solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude 2- [1- (t
[ert-butoxycarbonyl) piperidine-4-ylidene] ethylamine was used in the next reaction without purification. 5-thia-1,8b-diazaacenaphthylene-4-
1.56 g (7.17 mmol) of carboxylic acid and 0.83 g (7.17 mmol) of N-hydroxysuccinimide
Was stirred in 50 ml of acetonitrile, 1.51 g (7.89 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 2 hours. 1.50 ml (10.8 mmol) of triethylamine was added to the reaction mixture, and the resulting crude 2-
[1- (tert-butoxycarbonyl) piperidine-
4-Ylidene] ethylamine in acetonitrile 20 ml
The solution was added and stirred at room temperature for 2 hours. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate.
The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 9/1) to give crude N- [2- [1- (tert-butoxycarbonyl) piperidine-4-ylidene] ethyl].
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. The obtained crude N- [2- [1- (t
ert-butoxycarbonyl) piperidin-4-ylidene] ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was added with 4 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 0.5 hour. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid Yield 1.117 g (39% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.460 (2H, t, 5.8 Hz), 2.614
(2H, t, 5.8Hz), 3.169-3.248 (4H, m), 3.856-3.909 (2H,
m), 5.427 (1H, t, 7.2Hz), 6.607 (1H, d, 7.2Hz), 6.927 (1
H, s), 6.987 (1H, d, 9.2Hz), 7.384 (1H, dd, 7.8Hz, 9.2Hz),
7.503 (1H, s). IR (nujol): 3498, 3446, 3251, 3190, 3064, 2792-247
6, 1626, 1564, 1500, 1281, 1213, 775 cm ^-1

2) N- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylidene] ethyl]
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- [2- (piperidin-4-ylidene) ethyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 0.508 g (1.272 mmol), 1-bromo-3-phenylpropane 0.38 g
(1.91 mmol), 0.62 ml of triethylamine
A solution of (4.45 mmol) in 20 ml of ethanol was heated to reflux overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 4/1) to obtain the desired product as a mixture with triethylamine / hydrochloride. Ethyl acetate was added thereto, and the mixture was washed with an aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Red liquid Yield 0.395 g (70% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.749-1.901 (2H, m), 2.196-
2.467 (10H, m), 2.630 (2H, t, 7.7Hz), 3.870 (2H, t, 6.2H
z), 5.178 (1H, t, 7.2Hz), 5.737 (1H, dd, 2.2Hz, 5.8Hz),
6.171 (1H, t, 5.2Hz), 6.534-6.698 (3H, m), 6.968 (1H, s),
7.133-7.308 (5H, m) .IR (neat): 3300, 2941, 1616, 1543, 1510, 1481, 127
9, 1155, 773, 731, 700 cm ^-1 3) N- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylidene] ethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride The target product was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.026-2.183 (2H, m), 2.310-
2.590 (3H, m), 2.724 (2H, t, 7.5Hz), 2.936-3.019 (3H, m),
3.097-3.182 (2H, m), 3.539-3.645 (2H, m), 3.805 (1H, d
d, 7.0Hz, 15.4Hz), 3.922 (1H, dd, 7.8Hz, 15.2Hz), 5.431
(1H, t, 7.3Hz), 6.605 (1H, d, 7.2Hz), 6.949 (1H, s), 6.99
1 (1H, d, 8.8Hz), 7.160-7.305 (5H, m), 7.386 (1H, dd, 7.5H
z, 8.9Hz), 7.508 (1H, s) .IR (nujol): 3331, 3250, 3064, 2705-2460, 1632, 156
2, 1529, 1498, 1275, 1215, 775, 727 cm -1 Elemental analysis _{(C 26 H 30 Cl 2 N} 4 OS · 2.0H 2 O ) Calculated values: C, 56.41; H, 6.19 ; N, 10.12 Found: C, 56.39; H, 6.12; N, 10.10.

Example 7 N- [1- (3-Phenylpropan-1-yl) piperidin-2-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- (piperidin-2-ylmethyl) -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 3.605 g (16.519 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and N-hydroxy While stirring 2.09 g (18.2 mmol) of succinimide in 100 ml of acetonitrile, 1
3.48 g (18.2 mmol) of -ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 2 hours. To this reaction solution, 3.45 ml (24.8 mmol) of triethylamine and 2.83 g (24.8 mmol) of 2-aminomethylpiperidine were added, and the mixture was stirred at room temperature for 1 hour. In addition, di-carbonate di-ter
5.41 g (24.8 mmol) of t-butyl was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 9 /
1), crude N- [1- (tert-butoxycarbonyl)
Piperidin-2-ylmethyl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide was obtained. The obtained crude N- [1- (tert-butoxycarbonyl)
Piperidin-2-ylmethyl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide and concentrated hydrochloric acid 5
Then, the mixture was stirred at room temperature for 0.5 hour. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid Yield 3.476 g (54% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.476-1.909 (6H, m), 2.898-
3.022 (1H, m), 3.290-3.504 (4H, m), 6.615 (1H, d, 7.6Hz),
6.993 (1H, d, 8.8Hz), 7.068 (1H, s), 7.390 (1H, dd, 7.6H
z, 8.8Hz), 7.547 (1H, s). IR (nujol): 3300, 3199, 3032
2713, 1633, 1564, 1539, 1
500, 1294, 795 cm ^-1

2) N- [1- (3-phenylpropane-
1-yl) piperidin-2-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide The target compound was obtained in the same manner as in Example 6-2). Red liquid Yield 0.164 g (Yield 15%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.25
6-1.909 (7H, m), 2.218-2.819 (7H, m), 2.980-3.042 (1H,
m), 3.367 (2H, t, 4.3Hz), 5.705 (1H, dd, 1.4Hz, 6.2Hz),
6.532-6.689 (4H, m), 7.001 (1H, s), 7.149-7.318 (5H,
m). IR (neat): 3319, 2935, 1618, 1545, 1483, 1281, 115
3,773,733,700 cm ^-1 3) N- [1- (3-phenylpropan-1-yl) piperidin-2-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4- Synthesis of carboxamide dihydrochloride The target compound was obtained as an orange foam in the same manner as in 7) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.558-2.261 (8H, m), 2.627-
2.862 (2H, m), 3.012-3.747 (7H, m), 6.621 (1H, dd, 0.8Hz,
7.6Hz), 7.010 (1H, dd, 0.8Hz, 9.2Hz), 7.147-7.301 (6H,
m), 7.399 (1H, dd, 7.6Hz, 9.2Hz), 7.550 (1H, s). IR (nujol): 3392, 3061-2545, 1633, 1566, 1537, 150
0, 1450, 1294, 1215, 785, 752, 702 cm -1 Elemental analysis _{(C 25 H 30 Cl 2 N} 4 OS · 2.0H as ₂ O) Calculated: C, 55.45; H, 6.33 ; N, 10.35 Found: C, 55.61; H, 6.35; N, 10.14.

Example 8 N- [2- [1- (3-phenylpropan-1-yl)]
-1,2,3,6-tetrahydropyridin-4-yl]
Synthesis of ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in Example 6, 1), an orange solid N- [2-
(1,2,3,6-tetrahydropyridin-4-yl)
Ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.271-2.392 (4H, m), 3.193-
3.429 (4H, m), 3.639 (2H, br s), 5.529 (1H, br s), 6.606
(1H, d, 7.8Hz), 6.988 (1H, d, 8.6Hz), 6.991 (1H, s), 7.38
3 (1H, dd, 8.0Hz, 8.8Hz), 7.513 (1H, s). IR (nujol): 3516, 3454, 3244, 3061, 2791-2339, 163
3, 1566, 1533, 1498, 1304, 1263, 1213, 829, 773, 7
35 cm ^{-1 In the same} manner as in Example 6-2) using the above compound, N- [2- [1- (3-phenylpropane-1) as a red foam was obtained.
-Yl) -1,2,3,6-tetrahydropyridine-4
-Yl] ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.797-1.951 (2H, m), 2.143-
2.227 (4H, m), 2.467 (2H, t, 7.7Hz), 2.573 (2H, d, 5.4Hz),
2.650 (2H, t, 7.5Hz), 2.986 (2H, brs), 3.385 (2H, q, 6.4
Hz), 5.455 (1H, s), 5.720 (1H, dd, 1.8Hz, 6.2Hz), 6.259
(1H, t, 5.5Hz), 6.524-6.609 (2H, m), 6.651 (1H, s), 6.97
5 (1H, s), 7.133-7.323 (5H, m). IR (neat): 3277, 2939, 1618, 1549, 1481, 1281, 115
5, 773, 731, 700 cm ^{-1 Using the} above compound, the desired product was obtained as an orange foam in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.061-2.220 (3H, m), 2.269-
2.379 (2H, m), 2.606 (1H, brs), 2.738 (2H, t, 7.7Hz), 3.
176-3.350 (4H, m), 3.407-3.661 (3H, m), 3.880 (1H, br d,
15.4Hz), 5.493 (1H, brs), 6.606 (1H, d, 7.6Hz), 7.027
(1H, d, 9.2Hz), 7.145-7.294 (6H, m), 7.381 (1H, dd, 7.7H
z, 8.7Hz), 7.537 (1H, s). IR (neat): 3390, 3060-2602, 1633, 1566, 1535, 150
0, 1446, 1296, 1215, 785, 754, 702 cm -1 Elemental analysis _{(C 26 H 30 Cl 2 N} 4 OS · 2.5H 2 O ) Calculated values: C, 55.51; H, 6.27 ; N, 9.96 Found: C, 55.37; H, 6.42; N, 9.94.

Example 9 N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethyl] -3- (5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-yl) acrylamide dihydrochloride 1) 5-thia-1,8b-diazaacenaphthylene-4-
Synthesis of methanol 10.757 g (43.676 mmol) of ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate
In 1.5 ml of dichloromethane at -78 ° C.
Diisobutylaluminum hydride in toluene 8
About 20 ml of 7.4 ml (131 mmol) was added, and the temperature was raised to about 0 ° C. The mixture was cooled again to -78 ° C, and about 30 ml of a 1.5 M solution of diisobutylaluminum hydride in toluene was added thereto. The reaction solution was further cooled to -78 ° C, and the remaining 1.5 M solution of diisobutylaluminum hydride in toluene was added, followed by stirring for 0.5 hour. Methanol was added to the reaction solution at -78 ° C to decompose excess diisobutylaluminum hydride, and then water was carefully added under ice cooling until precipitation occurred. The resulting precipitate was filtered using celite, and the precipitate was washed with aqueous dimethyl sulfoxide. The solvent of the collected filtrate was distilled off under reduced pressure, and the resulting solid was washed with diethyl ether to obtain the desired product. Yellow solid Yield 7.777 g (87% yield) ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 3.804 (2H, s), 5.330 (1 H, b
rs), 5.945 (1H, dd, 2.2Hz, 5.6Hz), 6.123 (1H, s), 6.596
-6.706 (2H, m), 6.883 (1H, s). IR (nujol): 3429, 3084, 1481, 1090, 1028, 851, 76
7,727 cm ^-1 2) Synthesis of 3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylic acid 5-thia-1,8b-diazaacenaphthylene-4-methanol 7.777 g (38.076 mmol) of ethyl acetate 50 ml-N, N-dimethylformamide 50 ml
23 g of activated manganese dioxide was added to the solution, and the mixture was stirred at room temperature for 4 hours. The insolubles in the reaction solution were filtered and washed with N, N-dimethylformamide. The solvent of the collected filtrate was distilled off under reduced pressure. The obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde was used for the next reaction without purification. 9.39 g of ethyl diethylphosphonoacetate
(41.9 mmol) in 50 ml toluene solution
1.68 g of liquid paraffin suspension of sodium hydride
(41.9 mmol) was added at room temperature, and the mixture was stirred as it was for 0.5 hour. The crude 5-thia-1,8b-
N, N- of diazaacenaphthylene-4-carbaldehyde
A solution of 50 ml of dimethylformamide-200 ml of toluene was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained ethyl 3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylate was used for the next reaction without purification. The resulting crude 3- (5-thia-1,8b-
To a 300 ml solution of ethyl diazaacenaphthylene-4-yl) acrylate in ethanol was added 60 ml (120 mmol) of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid was added (about 10 ml) with stirring until the reaction solution reached pH 4-5, and the resulting precipitate was filtered and washed sequentially with ethanol and diethyl ether to obtain the desired product. Red solid Yield 7.777 g (84% yield) ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 5.529 (1H, d, 15.8 Hz), 6.2
62 (1H, dd, 1.4Hz, 6.6Hz), 6.795-6.939 (3H, m), 7.226 (1H,
d, 16.0Hz), 7.266 (1H, s). IR (nujol): 2521, 1711, 1587, 1309, 1255, 1136, 11
07, 947, 970 cm ^-1

3) N- (piperidin-4-ylmethyl)
-3- (5-Thia-1,8b-diazaacenaphthylene-
Synthesis of 4-yl) acrylamide dihydrochloride 3- (5-thia-1,8b-diazaacenaphthylene-4
0.708 g (2.898 mmol) of -yl) acrylic acid, 0.68 g (3.19 mmol) of 1- (tert-butoxycarbonyl) piperidin-4-ylmethylamine, 0.48 ml (3.48 mmol) of triethylamine While stirring in 10 ml of N, N-dimethylformamide in 0.53 ml of diethyl cyanophosphate (3.4
(8 mmol) was added dropwise at room temperature, and the mixture was stirred as it was overnight.
The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was passed through silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 9/1) to give crude N- [1- (te
(rt-Butoxycarbonyl) piperidin-4-ylmethyl] -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide was obtained. The obtained crude N-
[1- (tert-butoxycarbonyl) piperidine-
4-ylmethyl] -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide and concentrated hydrochloric acid 1
Then, the mixture was stirred at room temperature for 0.5 hour. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid Yield 1.099 g (92% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.335-1.635 (2H, m), 1.794-
2.072 (3H, m), 2.907-3.035 (2H, m), 3.227-3.438 (4H, m),
6.173 (1H, d, 15.4Hz), 6.743 (1H, s), 6.751 (1H, d, 7.4H
z), 7.141 (1H, d, 8.8Hz), 7.195 (1H, d, 15.4Hz), 7.504 (1
H, dd, 7.8Hz, 9.2Hz), 7.546 (1H, s). IR (nujol): 3373, 2735, 1666, 1637, 1606, 1552, 13
81, 1344, 1302, 1261, 1215, 962, 777 cm- ¹ 4) N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethyl] -3- (5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-yl) acrylamide N- (piperidin-4-ylmethyl) -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide dihydrochloride 0.502 g (1.214 mmol) of salt, 0.36 g of 1-bromo-3-phenylpropane
(1.82 mmol), 0.59 ml of triethylamine
A solution of (4.25 mmol) in 20 ml of ethanol was heated to reflux for 1 day. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (from ethyl acetate to
Ethyl acetate / methanol = 4/1) to obtain the target product as a mixture with triethylamine / hydrochloride. Ethyl acetate was added thereto, and the mixture was washed with an aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product. Red foamy substance Yield 0.305 g (55% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.229-1.401 (2H, m), 1.482-
1.958 (7H, m), 2.354 (2H, t, 7.7Hz), 2.612 (2H, t, 7.7Hz),
2.896-2.954 (2H, m), 3.231 (2H, t, 6.0Hz), 5.659 (1H, d,
15.2Hz), 5.859 (1H, dd, 1.2Hz, 6.6Hz), 6.222 (1H, brt,
5.8Hz), 6.255 (1H, s), 6.598-6.746 (2H, m), 7.048-7.30
5 (7H, m). IR (neat): 3273, 2926, 1651, 1
614, 1585, 1554, 1344, 12
65, 1213, 1142, 964, 773,
731, 700 cm ^-1

5) N- [1- (3-phenylpropane-
1-yl) piperidin-4-ylmethyl] -3- (5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-yl) acrylamide dihydrochloride N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -3- (5- Chia-1,8b-
Diazaacenaphthylene-4-yl) acrylamide 0.
305 g was dissolved in 2 ml of methanol, and an excess amount of a methanol solution of hydrogen chloride was added and stirred. This was concentrated and crystallized from ethanol-diethyl ether to obtain the desired product. Orange solid Yield 0.342 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.40
5-2.610 (2H, m), 1.790-2.140 (5H, m), 2.711 (2H, t, 7.5H
z), 2.868-3.244 (6H, m), 3.553-3.616 (2H, m), 6.149 (1
H, d, 15.4Hz), 6.735 (1H, s), 6.792 (1H, d, 7.2Hz), 7.109
-7.334 (7H, m), 7.496 (1H, dd, 7.8Hz, 9.2Hz), 7.537 (1H, m
s). IR (nujol): 3255, 2669, 1637, 1601, 1545, 1301, 12
63, 1215, 1159, 970, 777, 752, 727, 700 cm -1 Elemental analysis _{(C 27 H 32 C l2 N} 4 OS · 2.0H as ₂ O) Calculated: C, 57.14; H, 6.39 ; N , 9.87. Found: C, 57.44; H, 6.27; N, 9.80.

Example 10 N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide -Synthesis of dihydrochloride In the same manner as in Example 9-3), orange solid N- (piperidin-4-yl) -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) ) Acrylamide dihydrochloride was obtained. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.641-1.844 (2H, m), 2.123-
2.174 (2H, m), 3.072-3.466 (4H, m), 3.978-4.132 (1H, m),
6.138 (1H, d, 15.4Hz), 6.741 (1H, s), 6.789 (1H, d, 7.4H
z), 7.128 (1H, d, 8.4Hz), 7.211 (1H, d, 15.8Hz), 7.494 (1
H, dd, 7.8Hz, 9.2Hz), 7.536 (1H, s). IR (nujol): 3485, 3413, 3230, 2725, 1664, 1639, 16
05, 1549, 1302, 1263, 1213, 993, 781 cm ^{-1 A} red foam N- [1- (3-phenylpropane-1-) was obtained in the same manner as in Example 6-2) using the above compound. Yl) piperidin-4-yl] -3- (5-thia-1,8
b-diazaacenaphthylene-4-yl) acrylamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.423-1.597 (2H, m), 1.731-
2.147 (6H, m), 2.366 (2H, t, 7.7Hz), 2.616 (2H, t, 7.7Hz),
2.834-2.892 (2H, m), 3.799-3.944 (1H, m), 5.665 (1H, d,
15.0Hz), 5.845 (1H, d, 6.6Hz) 6.171 (1H, d, 8.0Hz), 6.253
(1H, s), 6.590-6.737 (2H, m), 7.043 (1H, s), 7.118-7.30
7 (6H, m). IR (neat): 3265, 2943, 1649, 1614, 1585, 1551, 134
8, 1267, 1213, 1142, 1113, 960, 910, 773, 731, 700
cm- ¹ The target compound was obtained as an orange solid in the same manner as in 6) of Example 1 using the above compound. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.711-1.908 (2H, m), 2.048-
2.218 (4H, m), 2.720 (2H, t, 7.5Hz), 3.011-3.222 (4H, m),
3.590-3.654 (2H, m), 3.929-4.205 (1H, m), 6.113 (0.8H, m
d, 15.4Hz), 6.321 (0.2H, d, 16.0Hz), 6.737 (1H, s), 6.79
0 (1H, d, 7.2Hz), 7.109-7.339 (7H, m), 7.495 (1H, dd, 7.6H
z, 9.2Hz), 7.539 (1H, s). IR (nujol): 3369, 3184, 1486, 1655, 1637, 1597, 15
52, 1215, 1159, 980, 837, 783, 758, 727 cm -1 Elemental analysis _{(C 26 H 30 Cl 2 N} 4 OS · 1.4H as ₂ O) Calculated: C, 57.54; H, 6.09 ; N , 10.32. Found: C, 57.74; H, 6.07; N, 10.17.

Example 11 N- [2- (3-phenylpropan-1-yl) -2,
3-dihydro-1H-isoindol-5-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride 1) N- [2- (3-phenylpropan-1-yl)-
2,3-dihydro-1H-isoindol-5-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- [2- (3-phenylpropan-1-yl) -2,
0.401 g (1.011 mmol) of 3-dihydro-1H-isoindol-5-ylmethyl] phthalimide
Hydrazine monohydrate in 20 ml ethanol solution
5 ml (1.11 mmol) was added, and the mixture was heated under reflux for 2 hours. After cooling the reaction to room temperature, the resulting precipitate was filtered,
Washed with ethanol. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained crude N- [2- (3-phenylpropane-1) was obtained.
-Yl) -2,3-dihydro-1H-isoindole-
[5-yl] methylamine was used in the next reaction without purification. 5-thia-1,8b-diazaacenaphthylene-
0.22 g (1.21 mmol) of 4-carboxylic acid, crude N- [2- (3-phenylpropan-1-yl) obtained
-2,3-dihydro-1H-isoindol-5-yl] methylamine, triethylamine 0.17 ml
To a solution of (1.21 mmol) in 20 ml of N, N-dimethylformamide was added dropwise 0.18 ml (1.21 mmol) of diethyl cyanophosphate at room temperature with stirring, and the mixture was stirred for 3 days. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol = 9).
/ 1) to obtain the desired product. Red liquid Yield 0.109 g (23% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.870-1.985 (2H, m), 2.714
(2H, t, 8.0Hz), 2.751 (2H, t, 7.3Hz), 3.913 (4H, s), 4.39
9 (2H, d, 5.8Hz), 5.715 (1H, dd, 2.9Hz, 4.9Hz), 6.571 (1H,
dd, 9.2Hz, 11.2Hz), 6.591 (1H, s), 6.664 (1H, s), 6.672
(1H, brt, 5.3Hz), 6.907 (1H, s), 7.058-7.332 (8H, m). IR (neat): 3275, 2935, 1618, 1545, 1481, 1281, 115
3, 1032, 771, 731, 700 cm ^-1 2) N- [2- (3-phenylpropan-1-yl)-
2,3-dihydro-1H-isoindol-5-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride The target compound was obtained as a brown solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.070-2.227 (2H, m), 2.764
(2H, t, 7.7Hz), 3.401-3.482 (2H, m), 4.427 (2H, s), 4.48
2-4.553 (2H, m), 4.836-4.878 (2H, m), 6.587 (1H, d, 7.4H
z), 6.991 (1H, d, 8.8Hz), 6.995 (1H, s), 7.149-7.415 (9
H, m), 7.512 (1H, s) .IR (neat): 3251, 3131, 2924, 2515, 1633, 125, 1498,
1443, 1296, 1219 cm ^-1 Elemental analysis _{(C 28 H 28 Cl 2 N} 4 OS · 4.5H as ₂ O) Calculated:. C, 54.19; H, 6.01; N, 9.03 Found: C, 53.99; H, 5.63; N, 9.38.

Example 12 N- [2- [1- (3-Phenylpropan-1-yl)]
-2,5-Dihydro-1H-pyrrol-3-yl] ethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride In the same manner as in 1) of Example 6, N- [2-
(2,5-dihydro-1H-pyrrol-3-yl) ethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide dihydrochloride was obtained. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.445 (2H, t, 6.4 Hz), 3.440
(2H, t, 6.8Hz), 4.048 (4H, s), 5.645 (1H, s), 6.614 (1H,
d, 7.8Hz), 6.996 (1H, d, 8.4Hz), 7.006 (1H, s), 7.389 (1
H, dd, 7.6Hz, 9.2Hz), 7.528 (1H, s). IR (nujol): 3358, 3226, 2665, 1657, 1633, 1564, 15
35, 1498, 1282, 1209, 777 cm ^{-1 A} red liquid N- [2- [1- (3-phenylpropane-1) was obtained in the same manner as in Example 6-2) using the above compound.
-Yl) -2,5-dihydro-1H-pyrrol-3-yl] ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.742-1.894 (2H, m), 2.291
(2H, t, 6.2Hz), 2.645 (2H, t, 7.5Hz), 2.667 (2H, t, 7.7H
z), 3.367-3.460 (6H, m), 5.489 (1H, s), 5.721 (1H, dd, 2.
2Hz, 5.4Hz), 6.524 (1H, t, 5.1Hz), 6.570-6.627 (3H, m),
6.960 (1H, s), 7.134-7.327 (5H, m). IR (neat): 3242, 2937, 1618, 1549, 1510, 1481, 128
1, 1153, 910, 773, 731, 700 cm ^{-1 Using the} above compound, the desired product was obtained as an orange foam in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.991-2.149 (2H, m), 2.421
(2H, t, 6.2Hz), 2.747 (2H, t, 7.7Hz), 3.290-3.513 (4H, t
m), 3.914-4.052 (2H, m), 4.240-4.334 (2H, m), 5.634 (1
H, s), 6.598 (1H, d, 7.4Hz), 6.993 (1H, d, 9.0Hz), 7.043
(1H, s), 7.144-7.299 (5H, m), 7.385 (1H, dd, 7.4Hz, 9.2H
z), 7.517 (1H, s). IR (neat): 3062, 2945, 2675, 2486, 1633, 1566, 153
7, 1500, 1448, 1296, 1215, 785, 756, 702 cm -1 Elemental analysis _{(C 25 H 28 Cl 2 N} 4 OS · 2.0H 2 O ) Calculated values: C, 55.66; H, 5.98 ; N , 10.38. Found: C, 55.88; H, 6.33; N, 10.32.

Example 13 Synthesis of N- [4- [4- (2-chlorobenzylidene) piperidino] butyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Example In the same manner as 11-1), the red liquid N- [4
-[4- (2-chlorobenzylidene) piperidino] butyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.565-1.628 (4H, m), 2.377-
2.500 (8H, m), 2.598 (2H, t, 5.2Hz), 3.282-3.339 (2H, m),
5.759 (1H, dd, 2.0Hz, 6.0Hz), 6.307 (1H, s), 6.551-6.68
9 (4H, m), 7.007 (1H, s), 7.116-7.247 (3H, m), 7.352-7.4
08 (1H, m). IR (neat): 3304, 2941, 1618, 1549, 1510, 1479, 128
1, 1155, 910, 773, 731 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.577-1.705 (2H, m), 1.764-
1.916 (2H, m), 2.469-3.103 (6H, m), 3.193 (2H, brt, 8.1H
z), 3.317 (2H, t, 6.6Hz), 3.552-3.762 (2H, m), 6.556 (1
H, s), 6.609 (1H, d, 7.4Hz), 6.997 (1H, d, 8.8Hz), 7.037
(1H, s), 7.239-7.448 (5H, m), 7.526 (1H, s). IR (nujol): 3213, 2721, 1632, 1498, 1292, 1215, 75
0, 725 cm ^-1 Elemental analysis (as C ₂₆ H ₂₉ Cl ₃ N ₄ OS · 3.5 H ₂ O) Calculated: C, 50.78; H, 5.90; N, 9.11. Found: C, 51.04; H, 5.74; N, 9.30.

Example 14 Synthesis of N- [4- (4-hydroxy-4-phenylpiperidino) butyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in 1) of Example 11, N- [4
-(4-hydroxy-4-phenylpiperidino) butyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.584-1.826 (7H, m), 2.186
(2H, dt, 4.1Hz, 13.1Hz), 2.392-2.546 (4H, m), 2.812-2.8
67 (2H, m), 3.260-3.337 (2H, m), 5.716 (1H, dd, 1.8Hz, 5.8
Hz), 6.539-6.656 (4H, m), 6.942 (1H, s), 7.213-7.402 (3
H, m), 7.501-7.548 (2H, m). IR (neat): 3305, 2943, 1618, 1547, 1510, 1481, 128
2, 1153, 910, 770, 731, 700 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.593-2.012 (6H, m), 2.425
(2H, dt, 4.8Hz, 13.7Hz), 3.218 (2H, t, 8.2Hz), 3.292-3.5
76 (6H, m), 6.616 (1H, d, 7.6Hz), 6.999 (1H, d, 10.4Hz),
7.025 (1H, s), 7.231-7.436 (4H, m), 7.507-7.584 (3H,
m). IR (nujol): 3211, 2673, 1630, 1497, 1292, 1213, 97
6, 766, 725, 700 cm -1 Elemental analysis _{(C 25 H 30 Cl 2 N} 4 O 2 S · 1.5H as ₂ O) Calculated:. C, 54.74; H, 6.06; N, 10.21 Found: C, 54.42; H, 6.44; N, 10.10.

Example 15 N- [2-hydroxy-3- (4-phenylpiperidino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis of Salt In the same manner as in Example 11-1), a red foam N- [2
-Hydroxy-3- (4-phenylpiperidino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.623-1.890 (4H, m), 2.126
(1H, dt, 2.4Hz, 11.5Hz), 2.293-2.620 (5H, m), 2.919-3.1
31 (2H, m), 3.236 (1H, td, 6.0Hz, 13.7Hz), 3.558 (1H, ddd,
3.7Hz, 5.6Hz, 13.7Hz), 3.813-3.932 (1H, m), 5.759 (1H, d
d, 1.6Hz, 6.2Hz), 6.525 (1H, brt, 5.0Hz), 6.561-6.684
(3H, m), 7.031 (1H, s), 7.172-7.352 (5H, m). IR (neat): 3311, 2933, 2808, 1618, 1543, 1506, 148
3, 1281, 1155, 910, 773, 731, 700 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.092 (4H, brs), 2.820-2.9
70 (1H, m), 3.147-3.425 (6H, m), 3.724-3.786 (2H, m), 4.
190-4.300 (1H, m), 6.619 (1H, d, 7.Hz), 7.000 (1H, d, 9.2H
z), 7.078 (1H, s), 7.221-7.437 (6H, m), 7.550 (1H, s). IR (nujol): 3242, 2723, 1633, 1498, 1296, 1215, 11
13, 783, 702 cm ^-1 Elemental analysis value (as C ₂₄ H ₂₈ Cl ₂ N ₄ O ₂ S · 2.0 H ₂ O) Calculated value: C, 53.04; H, 5.93; N, 10.31. 53.09; H, 6.11; N, 10.31.

Example 16 N- [2-oxo-3- (4-phenylpiperidino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis of Salt 1) Synthesis of N- [2-oxo-3- (4-phenylpiperidino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Oxalyl chloride To a solution of 0.39 g (3.05 mmol) in 20 ml of dichloromethane was added dropwise 0.43 ml (6.11 mmol) of dimethyl sulfoxide at -78 ° C. 5
After stirring for minutes, N- [2-hydroxy-3- (4-phenylpiperidino) propan-1-yl] -5-thia-
A solution of 0.88 g (2.037 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide in 20 ml of dichloromethane was added, and the mixture was stirred at -78 ° C for 15 minutes. 1.70 ml (12.2 mmol) of triethylamine was added thereto, and the temperature was raised to room temperature. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (ethyl acetate to ethyl acetate / methanol = 9/1 to 4 /
1) The desired product was obtained. Red foamy matter Yield 0.652 g (74% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.812-1.903 (4H, m), 2.195-
2.324 (2H, m), 2.423-2.580 (1H, m), 2.910-2.967 (2H, m),
3.278 (2H, s), 4.354 (2H, d, 4.6Hz), 5.789 (1H, dd, 1.9H
z, 6.1Hz), 6.581-6.722 (4H, m), 7.063 (1H, s), 7.166-7.
357 (5H, m). IR (neat): 3257, 2935, 1731, 1616, 1539, 1504, 148
3, 1282, 1153, 910, 773, 731, 700 cm ^-1 2) N- [2-oxo-3- (4-phenylpiperidino) propan-1-yl] -5-thia-1,8b- Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride The target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.050-2.150 (4H, m), 2.841-
3.000 (1H, m), 3.180-3.321 (2H, m), 3.629-3.691 (2H, m),
4.215 (2H, s), 4.444 (2H, s), 6.625 (1H, d, 7.2Hz), 7.00
7 (1H, d, 9.2Hz), 7.039 (1H, s), 7.195-7.442 (6H, m), 7.5
57 (1H, s) .IR (nujol): 3234, 2723, 1743, 1633, 1498, 1300, 121
5, 968, 779, 725, 700 cm ^-1 Elemental analysis value (as C ₂₄ H ₂₆ Cl ₂ N ₄ O ₂ S · 2.5H ₂ O) Calculated value: C, 52.36; H, 5.68; N, 10.18. : C, 52.65; H, 5.72; N, 10.08.

Example 17 N- [2-[(4-phenylpiperidino) methyl] benzyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride A red solid N- [2-
[(4-phenylpiperidino) methyl] benzyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.787-2.030 (4H, m), 2.207
(2H, dt, 2.3Hz, 11.8Hz), 2.619 (1H, tt, 3.9Hz, 12.0Hz),
3.109 (2H, br d, 11.6Hz), 3.549 (2H, s), 4.484 (2H, d, 5.0
Hz), 5.418 (1H, dd, 0.8Hz, 6.8Hz), 6.460 (1H, dd, 6.8Hz,
9.2Hz), 6.535 (1H, s), 6.598 (1H, dd, 0.9Hz, 9.2Hz), 6.7
68 (1H, s), 7.154-7.453 (9H, m), 8.127 (1H, brs). IR (nujol): 3296, 1647, 1597, 1516, 1485, 1244, 11
40, 741 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 2.053-2.125 (4H, m), 2.883-
3.044 (1H, m), 3.224-3.367 (2H, m), 3.585-3.667 (2H, m),
4.566 (4H, s), 6.584 (1H, d, 7.6Hz), 7.017 (1H, d, 8.8H
z), 7.182-7.631 (12H, m). IR (nujol): 3392, 2698, 1610, 1572, 1311, 1207, 76
0 cm ^-1 elemental analysis (C ₂₉ H ₃₀ Cl ₂ N ₄ OS · 1.0 H ₂ O) Calculated: C, 60.94; H, 5.64; N, 9.80. Found: C, 60.67; H, 5.78; N, 9.74.

Example 18 N- (1-phenethylpiperidin-4-yl) -3-
Synthesis of (5-thia-1,8b-diazaacenaphthylene-4-yl) acrylamide dihydrochloride 1) N- (1-phenethylpiperidin-4-yl) -3
-(5-thia-1,8b-diazaacenaphthylene-4-
Synthesis of yl) acrylamide N- (piperidin-4-yl) -3- (5-thia-1,
998 g (2.5 mmol) of 8b-diazaacenaphthylene-4-yl) acrylamide dihydrochloride and 0.703 g (3.8 mmol) of phenethyl bromide are suspended in 10 ml of ethanol, and 1.74 ml of triethylamine is suspended.
(12.5 mmol) was added and the mixture was refluxed for 5 hours. Further, phenethyl bromide (0.070 g, 0.38 mmol) was added and the mixture was refluxed overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The product was crystallized from to give the desired product. Red solid Yield 0.544 (51% yield) ¹ H-NMR (CDCl ₃ ) δ: 1.45-1.80 (4H, m), 1.90-2.10 (2H,
m), 2.15-2.35 (2H, m), 2.60-2.75 (2H, m), 2.80-2.90
(2H, m), 2.93-3.10 (2H, m), 3.83-4.05 (1H, m), 5.44-
5.48 (1H, m), 5.61 (1H, d, 15.0Hz), 5.88 (1H, d, 6.2H
z), 6.29 (1H, s), 6.63-6.78 (2H, m), 7.08 (1H, s), 7.
15-7.35 (4H, m). IR (KBr): 3392, 3224, 3035, 2941, 1647, 1614, 157
8, 1363, 1263, 1142, 1111, 995, 966, 750, 702 cm ^-1 2) N- (1-phenethylpiperidin-4-yl) -3
-(5-thia-1,8b-diazaacenaphthylene-4-
Il) Synthesis of acrylamide dihydrochloride In the same manner as in 7) of Example 1, an orange solid target product was obtained. ¹ H-NMR (CD ₃ OD) δ: 1.75-2.00 (2H, m), 2.05-2.35 (4H,
m), 3.00-3.25 (4H, m), 3.30-3.50 (2H, m), 3.65-3.80
(2H, m), 3.90-4.30 (1H, m), 6.12 (0.8H, d, 15.4Hz),
6.33 (0.2H, d, 15.0Hz), 6.94 (1H, s), 6.77 (1H, d, 7.
4Hz), 7.10-7.48 (6H, m), 7.53 (1H, s). IR (KBr): 3425, 3240, 3052, 2947, 2684, 1659, 160
5, 1551, 1504, 1394, 1360, 1217, 1151, 966, 764 cm
^-1 Elemental analysis _{(C 25 H 28 N 4 OSCl} 2 · 0.5H 2 O ) Calculated values:. C, 58.59; H, 5.70; N, 10.93 Found: C, 58.65; H, 5.81 ; N, 11.11 .

Example 19 N- (1-phenethylpiperidin-4-ylmethyl)-
3- (5-thia-1,8b-diazaacenaphthylene-4
Synthesis of -yl) acrylamide dihydrochloride In the same manner as in Example 18-1), a red solid N- (1-
Phenethylpiperidin-4-ylmethyl) -3- (5-
Thia-1,8b-diazaacenaphthylene-4-yl) acrylamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.50 (2H, m), 1.50-1.80 (3H,
m), 1.95-2.20 (4H, m), 2.56-2.64 (2H, m), 2.78-2.86
(2H, m), 3.04 (2H, brd, 11.8Hz), 3.27 (2H, t, 6.1H
z), 5.61 (1H, d, 15.2Hz), 5.80-5.95 (2H, m), 6.63-6.
77 (2H, m), 7.08 (1H, s), 7.15-7.32 (4H, m). IR (KBr): 3427, 3292, 2924, 1641, 1614, 1587, 154
3, 1344, 1267, 1144, 951, 770, 702 cm ^-1 . An orange solid was obtained in the same manner as in Example 1, 6) using the above compound. ¹ H-NMR (CD ₃ OD) δ: 1.40-1.70 (2H, m), 1.80-2.10 (3H,
m), 2.90-3.50 (8H, m), 3.69 (2H, brd, 12.8Hz), 6.17
(1H, d, 15.4Hz), 6.74 (1H, s), 6.80 (1H, d, 7.4Hz),
7.11-7.40 (5H, m), 7.45-7.50 (1H, m), 7.55 (1H, s). IR (KBr): 3427, 3230, 3059, 2943, 2681, 1657, 163
9, 1603, 1552, 1500, 1456, 1392, 1358, 1304, 1267,
1217, 1157, 968, 839, 783, 702 cm -1 Elemental analysis _{(C 26 H 30 N 4 OSCl} 2 · 0.5H as ₂ O) Calculated:. C, 59.31; H, 5.93; N, 10.64 Found : C, 59.29; H, 5.88; N, 10.59.

Example 20 Synthesis of 4- (4-phenylpiperidinomethyl) -1- (5-thia-1,8b-diazaacenaphthylene-4-ylcarbonyl) piperidine dihydrochloride Example 4 In the same manner as in 1), 4- (4-
Phenylpiperidinomethyl) -1- (5-thia-1,8
b-diazaacenaphthylene-4-ylcarbonyl) piperidine was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.061-1.240 (2H, m), 1.672-
2.103 (9H, m), 2.222 (2H, d, 6.6Hz), 2.409-2.566 (1H, m),
2.826-2.995 (4H, m), 4.338 (2H, br d, 13.6Hz), 5.714 (1
H, dd, 1.4Hz, 6.2Hz), 6.061 (1H, s), 6.530-6.669 (2H, m),
6.926 (1H, s), 7.158-7.343 (5H, m). IR (neat): 2933, 1616, 1483, 1435, 1281, 1265, 114
9, 910, 771, 729, 700 cm ^{-1 Using the} above compound, the desired product was obtained as an orange foam in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.280-1.449 (2H, m), 2.002-
2.321 (7H, m), 2.870-3.238 (7H, m), 3.752 (2H, br d, 12.0
Hz), 4.383 (2H, br d, 13.2Hz), 6.528 (1H, s), 6.658 (1H,
d, 7, 2 Hz), 7.069 (1H, d, 9.2 Hz), 7.173-7.473 (7H, m). IR (nujol): 2669, 1624 , 1498, 1213, 970 cm -1 Elemental analysis _{(C 27 H 32 C l2 N} 4 OS · 2.0H as ₂ O) Calculated: C, 57.14; H, 6.39 ; N, 9.87. Found: C, 57.02; H, 6.45; N, 9.98.

Example 21 Synthesis of N-[[4- (4-phenylpiperidino) cyclohexyl] methyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Example In the same manner as 11-1), red foam N-
[[4- (4-phenylpiperidino) cyclohexyl]
Methyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 0.842-1.071 (2H, m), 1.214-
1.987 (12H, m), 2.144-2.535 (3H, m), 2.991-3.316 (4H,
m), 5.716-5.771 (1H, m), 6.542-6.676 (4H, m), 6.976 (1
H, s), 7.138-7.330 (5H, m). IR (neat): 3307, 2927, 1616, 1551, 1510, 1483, 127
9, 1153, 910, 771, 731, 700 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.048-1.246 (2H, m), 1.501-
2.227 (12H, m), 2.824-2.972 (1H, m), 3.108-3.344 (4H,
m), 3.533-3.675 (2H, m), 6.618 (1H, d, 8.4Hz), 6.903-7.
015 (2H, m), 7.195-7.434 (6H, m), 7.516 (1H, s). IR (nujol): 3379, 3215, 2644, 1633, 1500, 1286, 12
19 cm ^-1

Example 22 N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis In the same manner as in Example 18-1), a red foam N- [1
-(3-phenylpropan-1-yl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (CDCl ₃ , 200 Mz) δ: 1.32-1.81 (5H, m), 1.81-1.97
(2H, m), 1.97-2.18 (2H, m), 2.41-2.56 (2H, m), 2.64 (2H, m
t, 7.6Hz), 2.98-3.14 (2H, m), 3.19 (2H, t, 5.8Hz), 5.76 (1
H, dd, 5.6Hz, 3.4Hz), 6.44 (1H, t, 5.6Hz), 6.55-6.68 (2H,
m), 6.77 (1H, s), 7.02 (1H, s), 7.11-7.34 (5H, m). IR (KBr): 3289, 1620, 1546, 1279 cm ^{-1 Using the} above compound, the target compound was obtained as an orange solid in the same manner as in 6) of Example 1. ¹ H-NMR (DMSO-d ₆ , 200 Mz) δ: 1.42-1.70 (3H, m), 1.72-1.
92 (2H, m), 2.01-2.22 (2H, m), 2.62-2.78 (2H, m), 2.78-
2.97 (2H, m), 2.97-3.33 (4H, m), 3.44-3.60 (2H, m), 6.66
(1H, d, 7.2Hz), 7.03 (1H, d, 8.8Hz), 7.20-7.46 (2H, m),
7.71 (1H, s), 8.97 (1H, t, 5.4Hz). IR (KBr): 3379, 1641, 1535, 1294 cm ^-1 Elemental analysis value (as C ₂₅ H _{3 0} N ₄ OSCl ₂ .2H ₂ O) Calculated value: C, 55.45; H, 6.33; N, 10.35; Cl, 13.09. Found: C, 55.18; H, 6.29; N, 10.35; Cl, 13.05.

Example 23 N- [1- (3,3'-bithiophen-5-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in Example 18-1), a red-brown solid N- [1
-(3,3'-Bithiophen-5-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.85 (5H, m), 1.90-2.15 (2H,
m), 2.98 (2H, brd, 11.2Hz), 3.21 (2H, t, 6.2Hz), 3.7
1 (2H, s), 5.79 (1H, dd, 1.7, 6.3Hz), 5.80-5.90 (1H,
m), 6.58-6.71 (3H, m), 7.05 (1H, s), 7.14 (1H, s), 7.
20-7.40 (4H, m). IR (KBr): 3332, 3093, 2922, 2796, 1618, 1539, 1506,
1481, 1367, 1340, 1277, 1155, 968, 840, 771, 737,
The desired product was obtained as a pale orange solid in the same manner as in 6) of Example 1 using the above compound at 594 cm ^-1 . ¹ H-NMR (CD ₃ OD) δ: 1.45-1.70 (2H, m), 1.80-2.10 (3H,
m), 2.95-3.40 (4H, m), 3.50-3.70 (2H, m), 4.57 (2H,
s), 6.60 (1H, d, 7.4Hz), 6.99 (2H, t, 4.3Hz), 7.30-
7.80 (7H, m). IR (KBr): 3388, 3064, 2927, 2729, 1633, 1566, 153
7, 1502, 1452, 1394, 1296, 939, 839, 777, 600 cm -1 Elemental analysis _{(C 25 H 26 N 4 OS} 3 Cl 2 · 2.8H as ₂ O) Calculated: C, 48.74; H, 5.17; N, 9.09. Found: C, 49.10; H, 5.40; N, 8.70.

Example 24 N- [1- (benzo [b] furan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride In the same manner as in Example 18-1), a dark red foam N-
[1- (Benzo [b] furan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25-1.80 (5H, m), 1.95-2.15 (2H,
m), 2.90-3.05 (2H, m), 3.20 (2H, t, 6.0Hz), 3.68 (2H,
s), 5.79 (1H, dd, 1.7Hz, 6.1Hz), 5.80-5.90 (1H, m),
6.59-6.72 (4H, m), 7.05 (1H, s), 7.16-7.30 (2H, m),
7.46-7.55 (2H, m). IR (KBr): 3429, 3062, 2924, 1618, 1543, 1510, 145
4, 1282, 1155, 1105, 970, 773, 752 cm ^-1 . An orange solid was obtained in the same manner as in 6) of Example 1 using the above compound. ¹ H-NMR (CD ₃ OD) δ: 1.40-1.60 (2H, m), 1.80-2.10 (3H,
m), 3.00-3.40 (4H, m), 3.50-3.70 (2H, m), 4.57 (2H,
s), 6.60 (1H, d, 7.8Hz), 6.96-7.00 (2H, m), 7.16 (1H,
s), 7.26-7.42 (3H, m), 7.51-7.58 (2H, m), 7.68 (1H,
d, 8.2Hz). IR (KBr): 3429, 3061, 2926, 2
719, 2667, 1633, 1564, 15
39, 1502, 1452, 1392, 129
0, 1215, 1107, 939, 787,
756 cm ^-1 Elemental analysis _{(C 25 H 26 N 4 O} 2 SCl 2 · 1.3H 2 O ) Calculated values:. C, 55.51; H, 5.33; N, 10.36 Found: C, 55.75; H, 5.32 N, 10.36.

Example 25 N- (1-Benzhydrylpiperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride In the same manner as in Example 11-1), N- (1
-Benzhydrylpiperidin-4-ylmethyl) -5
Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.216-1.629 (5H, m), 1.809
(2H, t, 11.0Hz), 2.882 (2H, d, 11.4Hz), 3.175 (2H, t, 6.1H
z), 4.224 (1H, s), 5.723 (1H, dd, 2.0Hz, 6.0Hz), 6.301 (1
H, t, 5.7Hz), 6.522-6.650 (3H, m), 6.967 (1H, s), 7.112-
7.294 (6H, m), 7.361-7.455 (4H, m). IR (neat): 3313, 2922, 1616, 1549, 1483, 1281, 115
3, 908, 731, 704 cm ^-1 An orange foam was obtained in the same manner as in Example 1, 6) using the above compound. ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.711-1.970 (5H, m), 3.051
(2H, brt, 12.1Hz), 3.219 (2H, d, 5.4Hz), 3.413 (2H, br
d, 12.2Hz), 4.910 (1H, s), 6.600 (1H, d, 7.6Hz), 6.961-
7.029 (2H, m), 7.337-7.512 (8H, m), 7.725-7.773 (4H,
m). IR (nujol): 3352, 3194, 2719-2530, 1630, 1562, 153
3, 1290, 1213, 754, 708 cm -1 Elemental analysis _{(C 29 H 30 C l2 N} 4 OS · 1.5H as ₂ O) Calculated:. C, 60.00; H, 5.73; N, 9.65 Found: C, 60.00; H, 6.11; N, 9.43.

Example 26 N- [4- (4-Phenylpiperidin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [4- (4-phenylpiperidin-1-yl)
Synthesis of butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.0 g of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (4. 58 mmol) and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (10 ml) at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 2 hours. 1- (4
-Aminobutan-1-yl) -4-phenylpiperidine 1.60 g (6.89 mmol) and 1.3 ml (9.33 mmol) of triethylamine in acetonitrile (5
ml) solution was added and stirred for another hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 20-50-80%) to obtain the desired product as a purple-red solid. Yield 1.76 g (89% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.50-1.68 (m 4H) 1.73-1.9
2 (m 4H) 1.99-2.18 (m2H) 2.36-2.57 (m 3H) 3.03-3.1
6 (m 2H) 3.25-3.39 (m 2H) 5.73 (dd J = 1.6, 6.0 1H)
6.50-6.72 (m 4H) 6.98 (s 1H) 7.10-7.29 (m 5H). 2) N- [4- (4-phenylpiperidin-1-yl)
Synthesis of butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (4-phenylpiperidin-1-yl) butan-1-yl ] To a solution of 1.76 g (4.07 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (15 ml) was added 6 ml (24 mmol) of a 4N hydrogen chloride / methanol solution at room temperature. Stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with diethyl ether to obtain the desired product as orange crystals. Yield 1.78 g (81% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.61 (m 2H) 1.65-
1.86 (m 2H) 1.87-2.26 (m 4H) 2.73-3.31 (m 7H) 3.28
-3.61 (m 2H) 6.61 (d J = 7.2 Hz 1H) 6.98 (d J = 8.4 Hz
1H) 7.17-7.40 (m 7H) 7.65 (s 1H) 8.84-8.97 (m 1
H). IR (KBr): 1635, 1568, 1533, 1500, 1294, 1217, 787
cm ^-1 Elemental analysis _{(C 25 H 30 N 4 OSCl} 2 · 2.3H 2 O ) Calculated values:. C, 54.90; H, 6.38; N, 10.24 Found: C, 54.97; H, 6.37 ; N, 10.16.

Example 27 N- [3- (4-Phenylpiperidin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) In the same manner as in 1) of Example 26, N-
[3- (4-Phenylpiperidin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.63-12.19 (m 8H) 2.55-2.
60 (m 3H) 3.10-3.23 (m2H) 3.37-3.49 (m 2H) 5.57 (d
d J = 1.2, 6.6 Hz 1H) 6.47-6.65 (m 3H) 6.67 (s 1H)
6.91 (s 1H) 7.16-7.35 (m 5H). 2) In the same manner as in 2) of Example 26, N-
[3- (4-Phenylpiperidin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82-2.23 (m 6H) 2.72-
3.34 (m 7H) 3.46-3.61 (m 2H) 6.58 (d J = 7.2 Hz 1H)
6.96 (d J = 8.8 Hz 1H) 7.16-7.40 (m 7H) 7.63 (s1H)
8.92-9.04 (m 1H). IR (KBr): 1635, 1566, 1533, 1500, 1294, 1213, 785
cm ^-1 elemental analysis (as C ₂₄ H ₂₈ N ₄ OSCl ₂ · 3.0 H ₂ O) Calculated: C, 52.84; H, 6.28; N, 10.27. Found: C, 52.78; H, 6.08; N, 10.05.

Example 28 N- [4- (4-benzylpiperidin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [4- (4-benzylpiperidin-1-yl)
Synthesis of butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.0 g of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (4. 58 mmol) and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (10 ml) at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 2 hours. 1- (4
-Aminotan-1-yl) -4-benzylpiperidine dihydrochloride (2.19 g, 6.86 mmol) and 3.87 ml (27.8 mmol) of triethylamine in acetonitrile (5 ml) were added thereto, and further added for 1 hour. Stirred. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 30-50%) gave the desired product as a red-purple amorphous substance. Yield: 2.00 g (98% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.51-1.92 (m 9H) 2.23-2.4
3 (m 2H) 2.53-2.78 (m4H) 3.22-3.42 (m 4H) 5.72 (dd
J = 2.2, 5.8 Hz 1H) 6.52-6.62 (m 2H) 6.94 (s1H) 7.0
4 (s 1H) 7.10-7.48 (m 6H). 2) N- [4- (4-benzylpiperidin-1-yl)
Synthesis of butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (4-benzylpiperidin-1-yl) butan-1-yl ] To a solution of 2.00 g (4.48 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (20 ml) was added 10 ml (40 mmol) of a 4N hydrogen chloride / methanol solution at room temperature. Stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, the mixture was cooled to 0 ° C, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.76 g (70% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.34-1.86 (m 9H) 2.61-
3.50 (m 10H) 6.64 (d J = 7.4 Hz 1H) 6.99 (d J = 9.0 Hz
1H) 7.17-7.35 (m 7H) 7.67 (s 1H) 8.89-9.02 (m 1
H). IR (KBr): 1635, 1566, 1533, 1500, 1294, 1215, 787
cm ^-1 Elemental analysis _{(C 26 H 32 N 4 OSCl} 2 · 2.3H 2 O ) Calculated values:. C, 55.67; H, 6.58; N, 9.99 Found: C, 55.75; H, 6.74 ; N, 9.84.

Example 29 N- [3- (4-benzylpiperidin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [3- (4-benzylpiperidin-1-yl)
Synthesis of propane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.0 g of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (4. 58 mmol) and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (10 ml) at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 2 hours. 1- (3
-Aminopropan-1-yl) -4-benzylpiperidine dihydrochloride (2.09 g, 6.85 mmol) and triethylamine, 3.87 ml (27.8 mmol), in acetonitrile (5 ml) were added. Stirred for minutes. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Separation and purification were performed by column chromatography (methanol / ethyl acetate 20-40-60%) to obtain the target compound as a purple-red amorphous substance. Yield 1.84 g (93% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.22-2.05 (m 9H) 2.45-2.
57 (m 4H) 2.93-3.10 (m2H) 3.34-3.46 (m 2H) 5.75 (d
d J = 2.0, 6.0 Hz 1H) 6.54-6.67 (m 3H) 7.03 (s 1H)
7.06-7.34 (m5H) 8.32-8.46 (m1H). 2) N- [3- (4-benzylpiperidin-1-yl)
Synthesis of propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [3- (4-benzylpiperidin-1-yl) propan-1-yl To a solution of 1.84 g (4.25 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 10 ml of ethanol was added 6 ml (24 mmol) of a 4N hydrogen chloride / methanol solution at room temperature. Stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, ethanol and diethyl ether were added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.81 g (yield 84%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.37-1.96 (m 7H) 2.59-
3.47 (m 10H) 6.56 (d J = 6.8 Hz 1H) 6.94 (d J = 8.4 Hz
1H) 7.14-7.37 (m 7H) 7.61 (s 1H) 8.90-9.04 (m 1
H). IR (KBr): 1633, 1568, 1300, 1217, 787 cm ^-1

Example 30 Synthesis of N- [4- (4-phenyl-1-piperazinyl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) Synthesis of N- [4- (4-phenyl-1-piperazinyl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b- N-ethyl-N 'was added to a suspension of 1.0 g (4.58 mmol) of diazaacenaphthylene-4-carboxylic acid and 0.90 g (7.82 mmol) of N-hydroxysuccinimide in acetonitrile (10 ml) at room temperature.
1.51 g (7.88 mmol) of -3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 2 hours. A solution of 2.02 g (5.89 mmol) of 1- (4-aminobutan-1-yl) -4-phenylpiperazine trihydrochloride and 4.1 ml (29.4 mmol) of triethylamine in ethanol (10 ml) was added to the reaction system. The mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 50% → methanol / chloroform 1:10)
And purified. After concentration, ethanol was added and the resulting crystals were collected by filtration to give the desired product as red crystals. Yield 1.37 g (yield 69%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.48-1.67 (m 4H) 2.36-2.
48 (m 2H) 2.57-2.66 (m4H) 3.17-3.40 (m 6H) 5.73 (d
d J = 1.6, 6.4 Hz 1H) 6.28-6.40 (m 1H) 6.56-6.69 (m
3H) 6.82-6.99 (m 4H) 7.22-7.33 (m 2H). IR (KBr): 3267, 3054, 3949, 2816, 1612, 1547, 149
5, 1279, 1232, 1147, 761 cm ^-1 2) N- [4- (4-phenyl-1-piperazinyl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4 Synthesis of -carboxamide trihydrochloride N- [4- (4-phenyl-1-piperazinyl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.37 g ( To a solution of 3.16 mmol) in ethanol (20 ml) was added 10 ml (40 mmol) of a 4N hydrogen chloride / methanol solution at room temperature, and the mixture was stirred at room temperature for 3 hours. (The crystals were deposited.) The solvent was distilled off under reduced pressure, and ethanol and diethyl ether were added to the residue. The resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 1.7252 g (97% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.62 (m 2H) 1.64-
1.87 (m 2H) 2.96-3.28 (m 8H) 3.46-3.59 (m 2H) 3.70-
3.89 (m 2H) 6.69 (d J = 7.0 Hz 1H) 6.87 (d J = 7.2 Hz
1H) 6.99-7.04 (m 3H) 7.23-7.40 (m 4H) 7.72 (s 1H)
8.92-9.07 (m 1H) 10.90-11.11 (m 1H). IR (KBr): 3404, 2914, 2503, 1635, 1566, 1533, 149
7, 1441, 1288, 1215, 779 cm ^-1 Elemental analysis (as C ₂₄ H ₃₀ N ₅ OSCl ₃ .1.0 H ₂ O) Calculated: C, 51.39; H, 5.75; N, 12.48. H, 5.86; N, 12.23.

Example 31 Synthesis of N- [3- (4-phenyl-1-piperazinyl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as in 1) of Example 30, red-violet solid N-
[3- (4-phenyl-1-piperazinyl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.58-1.84 (m 2H) 2.54-2.66 (m 2H) 2.66-2.77 (m4H)
3.26-3.38 (m 4H) 3.38-3.53 (m 2H) 5.37 (d J = 7.0 Hz
1H) 6.42 (dd J = 7.0, 9.2 Hz 1H) 6.60 (dd J = 0.8, 9.
2 Hz 1H) 6.72 (s 1H) 6.86 (s 1H) 6.87-6.99 (m 3H)
7.20-7.35 (m 2H) 8.10-8.23 (m 1H). IR (KBr): 3177, 2949, 2831, 1643, 1606, 1495, 127
9, 1238, 1149, 768,687 cm ^-1 2) In the same manner as in 2) of Example 30, N-
[3- (4-phenyl-1-piperazinyl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82-2.03 (m 2H) 2.98-
3.30 (m 8H) 3.44-3.60 (m 2H) 3.71-3.90 (m 2H) 6.59
(d J = 7.0 Hz 1H) 6.81-7.04 (m 4H) 7.15-7.33 (m 4H)
7.64 (m 1H) 8.94-9.07 (m 1H) 10.86-11.02 (m 1H). IR (KBr): 3248, 3035, 2673, 2565, 1639, 1531, 150
2, 1446, 1394, 1296, 1215 cm ^-1

Example 32 Synthesis of N- [4- (4-benzyl-1-piperazinyl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as in 1) of Example 30, red amorphous N-
[4- (4-benzyl-1-piperazinyl) butane-1
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.48-1.65 (m 4H) 2.31-2.
63 (m 10H) 3.23-3.36 (m 2H) 3.51 (s 2H) 5.77 (dd J
= 1.2, 6.2 Hz 1H) 6.43-6.53 (m 1H) 6.56-6.71 (m 3H)
7.02 (s 1H) 7.23-35 (m 5H). IR (KBr): 3415, 2937, 2812, 1624, 1549, 1281, 115
1, 739 cm ^-1 2) In the same manner as in 2) of Example 30, N-
[4- (4-benzyl-1-piperazinyl) butane-1
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.41-1.79 (m 4H) 3.01-
4.41 (m 14H) 6.56 (d J = 7.4 Hz 1H) 6.94 (d J = 8.8 Hz
1H) 7.12 (br s 1H) 7.16-7.28 (m 1H) 7.38-7.65 (m
6H) 8.72-8.86 (m 1H). IR (KBr): 3253, 2951, 2519, 1630, 1529, 1450, 130
4, 1217, 791 cm ^-1 Elemental analysis (as C ₂₅ H ₃₂ N ₅ OSCl ₃ · 1.0 H ₂ O) Calculated: C, 52.22; H, 5.96; N, 12.18. Found: C, 52.07; H , 6.05; N, 11.88.

Example 33 Synthesis of N- [3- (4-benzyl-1-piperazinyl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as in 1) of Example 30, red amorphous N-
[3- (4-benzyl-1-piperazinyl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.57-1.78 (m 2H) 2.38-2.
71 (m 10H) 3.35-3.46 (m 2H) 3.50 (s 2H) 5.76 (dd J
= 2.0, 6.0 Hz 1H) 6.56-6.68 (m 3H) 7.04 (s 1H) 7.23
-7.36 (m 5H) 8.15-8.27 (m 1H). IR (KBr): 3346, 2941, 2812, 1622, 1545, 1279, 114
9, 739 cm ^-1 2) In the same manner as in 2) of Example 30, N-
[3- (4-benzyl-1-piperazinyl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.80-2.01 (m 2H) 3.03-
3.32 (m 2H) 3.32-3.82 (m 10H) 4.35-4.51 (m 2H) 6.64
(d J = 7.4 Hz 1H) 6.99 (d J = 9.2 Hz 1H) 7.20 (br s 1
H) 7.31 (dd J = 7.4, 9.2 Hz 1H) 7.42-7.55 (m 3H) 7.6
1-7.76 (m 3H) 8.93-9.09 (m 1H). IR (KBr): 3396, 3053, 2649, 2561, 1635, 1444, 129
6, 1213,945, 791 cm ^-1 Elemental analysis _{(C 24 H 30 N 5 OSCl} 3 · 2.0H as ₂ O) Calculated:. C, 49.79; H, 5.92; N, 12.10 Found: C, 49.66 H, 5.80; N, 12.09.

Example 34 N- [4- (1,2,3,4-tetrahydroisoquinolin-2-yl) butan-1-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [4- (1,2,3,4-tetrahydroisoquinolin-2-yl) butan-1-yl] -5-thia −
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1.0 g (4.58 mmol) and N-hydroxysuccinimide 1 To a suspension of 0.055 g (9.12 mmol) in acetonitrile (10 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at the same temperature for 2 hours. 2- (4)
A solution of 1.90 g (6.85 mmol) of 1,2-aminobutan-1-yl) -1,2,3,4-tetrahydroisoquinoline dihydrochloride and 4.0 ml (28.7 mmol) of triethylamine in ethanol (10 ml) was added. And further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. After washing the organic layer with saturated saline,
Dried over magnesium sulfate. Separation and purification were performed by column chromatography (methanol / ethyl acetate 30%) to obtain the target substance as a red-purple amorphous substance. Yield 1.76 g (95% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.57-1.92 (m 4H) 2.58 (t
J = 6.2 Hz 2H) 2.73-2.79 (m 2H) 2.95 (t J = 5.8 Hz 2
H) 3.25-3.37 (m 2H) 3.69 (s 2H) 5.55 (dd J = 2.0, 6.
2 Hz 1H) 6.30 (s 1H) 6.48-6.60 (m 3H) 6.97-7.16 (m
4H) 7.41-7.55 (m1H). 2) N- [4- (1,2,3,4-tetrahydroisoquinolin-2-yl) butan-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (1,2,3,4-tetrahydroisoquinolin-2-yl) butan-1-yl] -5-thia -1, 8
b-diazaacenaphthylene-4-carboxamide 1.7
To a solution of 6 g (4.35 mmol) of ethanol (10 ml) at room temperature was added 6 ml of a 4N hydrogen chloride / methanol solution (24 ml).
Mmol) and stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, ethanol was added to the residue, and the mixture was further concentrated. Diethyl ether was added to the resulting crystals, and the crystals were collected by filtration. Washing the crystals with ethanol and diethyl ether,
The desired product was obtained. Orange crystal Yield 1.65 g (78% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.62 (m 2H) 1.70-1.
93 (m 2H) 2.91-3.39 (m7H) 3.56-3.77 (m 1H) 4.18-4.3
5 (m 1H) 4.43-4.59 (m 1H) 6.57 (d J = 6.8 Hz1H) 6.95
(d J = 8.4 Hz 1H) 7.09-7.32 (m 6H) 7.61 (s 1H) 8.83
-8.95 (m 1H). IR (KBr): 3400, 3045, 2939, 1635, 1562, 1535, 150
0, 1440, 1292, 1211, 756 cm ^-1 Elemental analysis (as C ₂₃ H ₂₆ N ₄ OSCl ₂ · 0.5 H ₂ O) Calculated: C, 56.79; H, 5.59; N, 11.52. H, 5.73; N, 11.40.

Example 35 N- [3- (1,2,3,4-tetrahydroisoquinolin-2-yl) propan-1-yl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 34, red-purple amorphous N
-[3- (1,2,3,4-tetrahydroisoquinolin-2-yl) propan-1-yl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.65-1.90 (m 2H) 2.67-2.
83 (m 4H) 2.93-3.03 (m2H) 3.39-3.52 (m 2H) 3.71 (s
2H) 5.23 (dd J = 1.6, 6.6 Hz 1H) 6.13 (s 1H) 6.31 (s
1H) 6.44-6.53 (m 2H) 6.97-7.13 (m 4H) 8.71-8.94
(m 1H). 2) In the same manner as in 2) of Example 34, N-
[3- (1,2,3,4-tetrahydroisoquinoline-
2-yl) propan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.88-2.12 (m 2H) 2.88-
3.36 (m 7H) 3.56-3.75 (m 1H) 4.17-4.37 (m 1H) 4.45-
4.60 (m 1H) 6.59 (d J = 7.4 Hz 1H) 6.96 (d J = 9.0 Hz
1H) 7.14-7.35 (m 6H) 7.64 (s 1H) 8.96-9.11 (m 1H) .IR (KBr): 3390, 3047, 295 ,, 2684, 2600, 1637, 1531,
1442, 1294, 1211 cm ^-1

Example 36 N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- (1-ethoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 10.76 g (38.45 mmol) of acid / hydrochloride and 11.35 g (98.6) of N-hydroxysuccinimide
2 mmol) in acetonitrile (150 ml) was added to 18.9 g of N-ethyl-N′-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride (9).
8.59 mmol) and stirred at room temperature for 2 hours. Further, at room temperature, 10 ml (58.3 mmol) of ethyl 4-aminopiperidine-1-carboxylate and 13 ml (92.3 mmol) of triethylamine in acetonitrile (30 ml) were added.
ml) solution was added and stirred for 2 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The obtained crude product was separated and purified by column chromatography (methanol / ethyl acetate 20%) to obtain the desired product. Red amorphous substance Yield 19.47 g (quant.) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.16-1.46 (m 2H), 1.26 (t
J = 7.0 Hz 3H), 1.93-2.02 (m 2H), 2.84-2.97 (m 2H),
3.87-4.21 (m 3H), 4.13 (q J = 7.0 Hz 2H), 5.67 (br
d J = 8.0 Hz 1H), 5.80 (dd J = 1.8, 6.2 Hz 1H), 6.59-
6.71 (m3H), 7.05 (s1H). 2) Synthesis of N- (1-tert-butoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide Under argon atmosphere, 19.47 g of N- (1-ethoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide (<38.45
(Mmol) in acetonitrile (350 ml) at room temperature was added with 21 ml (147.6 mmol) of trimethylsilane iodide and stirred for 84 hours. Methanol was added to the reaction system to stop the reaction, and 30 ml of triethylamine was added at room temperature.
(215 mmol) and 9.8 ml (42.7 mmol) of di-tert-butyl dicarbonate were added and stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. The obtained crude product was separated and purified by column chromatography (methanol / ethyl acetate 20%) to give the desired product (14.59 g,
95%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.13-1.99 (m 2H), 1.46
(s 9H), 1.73-1.98 (m 2H), 2.74-2.95 (m 2H), 3.84-
4.18 (m 3H), 5.70-5.85 (m 1H), 5.79 (dd J = 1.9,5.7
Hz 1H), 6.58-6.72 (m3H), 7.04 (s1H). 3) N- (piperidin-4-yl) -5-thia-1,8
Synthesis of b-diazaacenaphthylenecarboxamide dihydrochloride N- (1-tert-butoxycarbonylpiperidine-
20 ml (240 mmol) of 12N hydrochloric acid was added to 14.59 g (36.4 mmol) of 4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide at room temperature.
Stirred at room temperature for 1 hour. Ethanol was added to the reaction system, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 10.08 g (74% yield) ¹ H-NMR (200 MHz, D ₂ O) δ: 1.64-1.87 (m 2H), 2.03-2.1
9 (m 2H), 3.03-3.21 (m2H), 3.42-3.58 (m 2H), 3.82-
4.02 (m 1H), 5.98 (d J = 7.0 Hz 1H), 6.60 (dJ = 9.2Hz
1H), 6.67 (s 1H), 6.78 (dd J = 7.2, 9.2 Hz 1H), 6.98
(s 1H). IR (KBr): 3481, 3223, 2935, 2798, 2717, 1633, 152
9, 1302, 1257, 1211, 787 cm ^-1

4) N- [1- (3-phenylpropane-
1-yl) piperidin-4-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-yl) -5-thia-1,8b-
Diazaacenaphthylenecarboxamide dihydrochloride 0.4
0 g (1.07 mmol) and 0.7 of triethylamine
To a solution of 5 ml (5.38 mmol) in ethanol (5 ml) at room temperature was added 1-bromo-3-phenylpropane 0.20.
ml (1.32 mmol), and the mixture was heated under reflux for 15 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. After washing the organic layer with saturated saline,
Dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 20-40%) gave the desired product. Red purple amorphous substance Yield 356.2 mg (80% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.41-1.64 (m 2H), 1.75-
2.21 (m 6H), 2.31-2.47 (m 2H), 2.63 (t J = 7.7 Hz 2
H), 7.79-2.96 (m 2H), 3.72-3.92 (m 1H), 5.75-5.80
(m 2H), 6.57-6.69 (m 3H), 7.03 (s 1H), 7.16-7.32
(m5H). 5) N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 356.2 mg (0.8
5 mmol) in 4 ml of ethanol (6 ml) at room temperature.
2.0 ml (8.0 mmol) of a hydrogen chloride / methanol solution was added, and the mixture was stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 399 mg (96% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.80-2.14 (m 6H), 2.63
(t J = 7.5 Hz 2H), 2.82-3.11 (m 4H), 3.38-3.56 (m 2
H), 3.72-3.93 (m 1H), 6.64 (d J = 6.6 Hz 1H), 6.99 (d
J = 9.2 Hz 1H), 7.15-7.38 (m 7H), 7.67 (s 1H), 8.80
-8.90 (m 1H). IR (KBr): 3412, 3051, 1635, 1564, 1535, 1495, 130
4 cm ^-1 Elemental analysis (as C ₂₄ H ₂₈ N ₄ OSCl ₂ .2.5H ₂ O) Calculated: C, 53.73; H, 6.20; N, 10.44. Found: C, 54.03; H, 5.96; N , 10.46.

Example 37 Synthesis of N- (1-phenethylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Example 36-4) In the same manner as described above, N-
(1-phenethylpiperidin-4-yl) -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. Melting point: 216.0-217.0 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40-1.70 (2H, m), 1.80-2.
20 (4H, m), 2.50-3.10 (6H, m), 3.70-4.00 (1H, m), 5.6
0-5.90 (2H, m), 6.50-6.80 (3H, m), 7.04 (1H, s), 7.10
-7.40 (5H, m). IR (KBr): 3292, 2947, 1612, 1537, 1279, 1159, 771,
735, 696 cm ⁻¹ . 2) In the same manner as in 5) of Example 36, N-
(1-phenethylpiperidin-4-yl) -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.80-2.30 (m 6H) 3.00-3.6
0 (m 4H) 3.73 (br d J = 12.8 Hz 2H) 3.90-4.20 (m 1H)
6.61 (d J = 7.0Hz 1H) 6.90-7.10 (m 2H) 7.20-7.50 (m
6H) 7.53 (s 1H). IR (KBr): 3427, 3244, 3030, 2935, 2727, 1632, 156
. 2, 1537, 1502, 1458 , 1308, 791, 758, 704cm -1 Elemental analysis _{(C 23 H 26 N 4 OSCl} 2 · 1.0H 2 O ) Calculated values: C; 55.76, H; 5.70 , N; 11.31. Found: C; 56.06, H; 5.47, N; 1
1.51.

Example 38 N- [1- [3- (2-fluorophenyl) propane-
1-yl] piperidin-4-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (2-Fluorophenyl) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 3- (2-fluorophenyl) propanol 616.7
mg (4.0 mmol) and triethylamine 809.5
mg (8.0 mmol) in ether (20 ml) solution under ice-cooling was methanesulfonyl chloride 687.3 mg (6.0).
Mmol) and stirred for 5 minutes.
Stirred at room temperature for 1 hour. Furthermore, triethylamine 405
mg (4.0 mmol), methanesulfonyl chloride 344
mg (3.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. After the organic layer was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. N- (piperidin-4-yl) -5-thia- was added to the obtained mesyl form.
1,8b-diazaacenaphthylenecarboxamide dihydrochloride 746.6 mg (2.0 mmol), triethylamine 1.15 g (10 mmol) in ethanol (10 m
l) The solution was added and the mixture was refluxed overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. After washing the organic layer with water and drying over sodium sulfate,
The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (ethyl acetate: methanol = 3: 3).
After separation and purification in 1), concentration was performed, ether was added, and the precipitated crystals were collected by filtration to give the desired product (55
(3.6 mg, 63.4%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35
-1.57 (2H, m), 1.70-2.15 (6H, m), 2.40 (2H, t, J = 7.5H
z), 2.66 (2H, t, J = 8.0Hz), 2.85 (2H, brd, J = 12.0Hz),
3.70-3.90 (1H, m), 5.67 (1H, d, J = 7.8Hz), 5.78 (1H, d
d, J = 1.5, 6.1Hz), 6.58-6.70 (3H, m), 6.95-7.22 (5H,
m). IR (KBr): 3429, 3394, 3217, 3049, 2939, 2804, 2771,
1632, 1614, 1552, 1512, 1479, 1454, 1311, 1281, 1
. 246, 1228, 1140, 1099 , 781, 758, 735cm -1 2) N- [1- [3- (2- fluorophenyl) propan-1-yl] piperidin-4-yl] -5-thia -
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (2-fluorophenyl) propane-
1-yl] piperidin-4-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide 55
3.6 mg (1.3 mmol) of ethanol (20 m
l) 2 ml of 4N hydrogen chloride / ethyl acetate solution (8.
0 mmol) and stirred for several minutes. Ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration to give orange crystals (666.6 mg, 94%).
I got ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.80-2.20 (m 6H) 2.77 (t
J = 7.4 Hz 2H) 3.00-3.22 (m 3H) 3.40-3.50 (m 1H) 3.63
(br d J = 12.4 Hz 2H) 3.90-4.10 (m 1H) 6.61 (d J = 7.6
Hz 1H) 6.98-7.43 (m 7H) 7.53 (s 1H). IR (KBr): 3427, 3390, 3062, 2940, 2717, 1633, 1564,
1539, 1504, 1456, 1304, 1217, 771cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ OSCl ₂ F · 2H ₂ O) Calculated: C; 52.84, H; 5.73, N; 10.27. : C; 52.66, H; 5.83, N; 10.20.

Example 39 N- [1- [3- (2-chlorophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
-Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 38, N-
[1- [3- (2-Chlorophenyl) propan-1-yl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.39-1.59 (2H, m), 1.73-2.
16 (6H, m), 2.40 (2H, t, J = 7.5Hz), 2.75 (2H, t, J = 7.7H
z), 2.86 (2H, brd, J = 12.2Hz), 3.70-3.95 (1H, m), 5.64
(1H, d, J = 7.6Hz), 5.79 (1H, dd, J = 1.8, 6.2Hz), 6.58
-6.70 (3H, m), 7.05 (1H, s), 7.10-7.36 (4H, m). IR (KBr): 3230, 2949, 1633, 1614, 1541, 1508, 1479,
1311, 1281, 1246, 1140, 779, 758 cm ^-1 2) In the same manner as in Example 38-2), N-
[1- [3- (2-Chlorophenyl) propan-1-yl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.80-2.20 (6H, m), 2.82-
2.90 (2H, m), 3.03-3.22 (3H, m), 3.40-3.50 (1H, m),
3.65 (2H, brd, J = 12.2Hz), 3.90-4.10 (1H, m), 6.61
(1H, d, J = 7.2Hz), 6.97-7.04 (2H, m), 7.19-7.43 (5
H, m), 7.53 (1H, s). IR (KBr): 3400, 3066, 2945, 2717, 1633, 1568, 1539,
. 1504, 1473, 1456, 1302 , 1215, 758cm -1 Elemental analysis _{(C 24 H 27 N 4 OSCl} 3 · 2H 2 as O) Calculated:. C; 51.30, H; 5.56, N; 9.97 Found: C; 51.47, H; 5.69, N; 9.87.

Example 40 N- [1- [2- (thiophen-3-yl) ethane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
-Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 38, N-
[1- [2- (thiophen-3-yl) ethane-1-yl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40-1.60 (2H, m), 1.90-2.
05 (2H, m), 2.12-2.23 (2H, m), 2.58-2.65 (2H, m), 2.7
9-2.95 (4H, m), 3.75-3.95 (1H, m), 5.60-5.80 (2H, m),
6.58-6.70 (3H, m), 6.94-7.04 (3H, m), 7.23-7.25 (1H,
m). IR (KBr): 3292, 2949, 1608, 1539, 1508, 1481, 1308,
1279, 1236, 1161, 1119, 771, 737, 646 cm ^-1 .2) In the same manner as in Example 38-2), orange crystal N-
[1- [2- (thiophen-3-yl) ethane-1-yl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. . ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.85-2.25 (4H, m), 3.05-
3.20 (4H, m), 3.23-3.50 (2H, m), 3.60-3.75 (2H, m),
3.90-4.15 (1H, m), 6.61 (1H, d, J = 7.2Hz), 6.96-7.
10 (3H, m), 7.10-7.45 (3H, m), 7.52 (1H, s). IR (KBr): 3392, 3059, 2910, 2721, 2675, 2551, 1633,
1564, 1529, 1502, 1458, 1394, 1304, 1263, 1215, 7
87cm ^-1 .

Example 41 N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis of Salt 1) In the same manner as in 1) of Example 38, red amorphous N-
[1- (1,4-benzodioxan-2-ylmethyl)
Piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.38-1.53 (m 2H) 1.86-2.
02 (m 2H) 2.18-2.21 (m2H) 2.52-2.76 (m 2H) 2.80-3.
02 (m 2H) 23.72-3.91 (m 1H) 3.98 (dd J = 7.6,11.6 Hz
1H) 4.22-4.35 (m 2H) 5.48-5.60 (m 1H) 5.80 (dd J =
1.6, 6.4 Hz 1H) 6.59-6.72 (m 3H) 6.80-6.91 (m 4H)
7.06 (s 1H). IR (KBr): 1620, 1543, 1493, 1267, 1149, 782 cm ^-1 2) In the same manner as in Example 38-2), orange crystal N-
[1- (1,4-benzodioxan-2-ylmethyl)
Piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.81-2.09 (m 4H) 2.95-
4.39 (m 9H) 4.85-5.00 (m 1H) 6.48-6.53 (m 1H) 6.77-
6.98 (m 5H) 7.10-7.23 (m 2H) 7.55 (s 1H) 8.71-8.79
(m 1H). IR (KBr): 1637, 1497, 1304, 1263, 762 cm ^-1 Elemental analysis value (as C ₂₄ H ₂₆ N ₄ O ₃ SCl ₂ · 2.0 H ₂ O) Calculated value: C, 51.71; H, 5.42; N, 10.05. Found: C, 51.74; H, 5.34; N, 9.91.

Example 42 N- [2- (1- (3-phenylpropan-1-yl)]
Synthesis of piperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [2- (1-tert-butoxycarbonyl) −
Synthesis of 4-piperidinyl) ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 4.37 g of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (20. 0 mmol) and 4.60 g (40.0 mmol) of N-hydroxysuccinimide were suspended in 50 ml of acetonitrile.
7.67 g (40.0 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained active ester compound was treated with chloroform 100
5.6 ml of triethylamine (40.0 ml).
Mmol) and 4- (2-aminoethyl) piperidine3.
After adding 08 g (24.0 mmol) and stirring at room temperature for 30 minutes, di-tert-butyl dicarbonate 4.37 g (20.
(0 mmol) was added dropwise, and the mixture was further stirred at room temperature for 1 hour.
After the reaction, water was added to the reaction solution for washing, and then the organic layer was washed with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: ethanol = 10: 1).
The desired product was obtained. Red oily substance Yield 3.37 g (39% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.01-1.28 (m 2H) 1.41-1.5
8 (m 12H) 1.62-1.76 (m2H) 2.62-2.74 (m 2H) 3.34 (m
2H) 4.04-4.11 (m 2H) 5.79 (dd J = 2.0, 6.0 Hz 1H)
5.85 (t J = 5.6 Hz 1H) 6.62-6.71 (m 3H) 7.04 (s 1H). IR (KBr): 1684, 1622, 1547, 1281, 1159 cm ^-1

2) N- [2- (4-Piperidinyl) ethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride N- [2- (1-tert-butoxycarbonyl-4-)
3.37 g (piperidinyl) ethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (7.
86 mmol) in ethanol (100 ml) solution.
N hydrochloric acid (3.2 ml, 39.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The generated crystals are collected by filtration,
The desired product was obtained by washing with a small amount of ethanol and ether. Orange crystal Yield 2.52 g (Yield 80.0%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.22-1.68 (m 5H) 1.78-1.
85 (m 2H) 2.68-2.91 (m2H) 3.10-3.31 (m 4H) 6.63 (d
J = 6.8 Hz 1H) 7.00 (d J = 9.2 Hz 1H) 7.24 (s1H) 7.31
(dd J = 6.8, 9.2 Hz 1H) 7.68 (s 1H) 8.91 (t J = 5.6 H
z 1H) 9.08 (brs 2H). IR (KBr): 1643, 1533, 1290 cm ^-13 ) N- [2- (1- (3-Phenylpropan-1-yl) piperidin-4-yl) ethane- 1-yl] -5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide N- [2- (4-piperidinyl) ethyl] -5-thia-
To a solution of 0.60 g (1.49 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.17 mmol) of triethylamine in ethanol (6 ml) was added 3-phenyl- at room temperature. 0.27 ml (1.78 mmol) of 1-bromopropane was added, and the mixture was heated and refluxed for 24 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 30-50)
(−80%) separation and purification to obtain the desired product. Red-purple amorphous substance Yield 514 mg (77% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.08-2.01 (m 11H) 2.31-
2.39 (m 2H) 2.62 (t J = 7.7 Hz 2H) 2.92 (br d J = 11.2
Hz 2H) 3.28-3.38 (m 2H) 5.55-5.68 (m 1H) 5.78 (dd
J = 1.7, 6.5 Hz 1H) 6.58-6.70 (m 3H) 7.05 (s 1H) 7.
12-7.33 (m5H). 4) N- [2- (1- (3-Phenylpropan-1-yl) piperidin-4-yl) ethan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [2- (1- (3-phenylpropan-1-yl)
Piperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (10 ml) containing 0.5142 g (1.15 mmol) of 4N chloride at room temperature. 4 ml (16 mmol) of a hydrogen / methanol solution was added, and the mixture was stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 546 mg (88% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.31-1.61 (m 5H) 1.70-
2.14 (m 4H) 2.63 (t J = 7.5 Hz 2H) 2.70-3.23 (m 6H)
3.36-3.52 (m 2H) 6.59 (d J = 7.4 Hz 1H) 6.96 (d J = 8.
8 Hz 1H) 7.16 (s 1H) 7.19-7.37 (m 6H) 7.63 (s 1H)
8.74-9.88 (m 1H) .IR (KBr) 1639, 1560, 1537, 1500,
1444, 1290, 1217, 831, 785 cm ^-1 Elemental analysis (as C ₂₆ H ₃₂ N ₄ OSCl ₂ .1.0 H ₂ O) Calculated: C, 58.09; H, 6.38; N, 10.42. , 58.22; H, 6.12; N, 10.45.

Example 43 N- [2- (1-Phenethylpiperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Similar to 3) of Example 42, magenta N
-[2- (1-Phenethylpiperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.32-1.58 (m 4H) 1.69-2.
20 (m 5H) 2.63-2.71 (m2H) 2.84-2.92 (m 2H) 3.04-3.
18 (m 2H) 3.31-3.41 (m 2H) 5.71-5.85 (m 1H) 5.79 (d
d J = 1.8, 6.2 Hz 1H) 6.59-6.67 (m 2H) 6.71 (s 1H)
7.06 (s 1H) 7.16-7.39 (m 5H). 2) In the same manner as in 4) of Example 42, N-
[2- (1-Phenethylpiperidin-4-yl) ethan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.31-1.62 (m 5H) 1.77.
-1.96 (m 2H) 2.72-3.30 (m 8H) 3.46-3.60 (m 2H) 6.61
(d J = 7.4 Hz 1H) 6.97 (d J = 9.2 Hz 1H) 7.17 (s 1H)
7.20-7.42 (m 6H) 7.65 (s 1H) 8.80-8.90 (m 1H). IR (KBr): 1632, 1564, 1535, 1441, 1290, 1211, 79
5, 770 cm ^-1

Example 44 N- [2- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) ethane-1-yl] -5-thia-1,8b-dia Zaacenaphthylene-4
Synthesis of carboxamide dihydrochloride 1) N- [2- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) ethane-1
Synthesis of -yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3- (2-chlorophenyl) propanol 409.5 m
g (2.4 mmol) and 0.7 ml of triethylamine
To a solution of (4.8 mmol) in ether (20 ml) was slowly added methanesulfonyl chloride (412.4 mg, 3.6 mmol) under ice-cooling, followed by stirring at room temperature for 2 hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2- (piperidin-4-yl) ethane-1- was added to the obtained mesyl form.
Yl-5-thia-1,8b-diazaacenaphthylene-4
-A solution of 481.6 mg (1.2 mmol) of carboxamide dihydrochloride and 0.85 ml (6.0 mmol) of triethylamine in ethanol (10 ml) was added, and the mixture was heated under reflux overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography (ethyl acetate: methanol = 3: 1), concentrated, and concentrated in ether. Was added to obtain the desired product (327.9 mg, 56.8%) as a dark red amorphous substance. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10-1.55 (5H, m), 1.60-2.
10 (6H, m), 2.37-2.44 (2H, m), 2.74 (2H, t, J = 7.6Hz),
2.95 (2H, brd, J = 11.0Hz), 3.28-3.38 (2H, m), 5.65-5.
80 (1H, m), 5.78 (1H, dd, J = 1.9, 6.3Hz), 6.60-6.70 (3
H, m), 7.05 (1H, s), 7.10-7.20 (4H, m). IR (KBr): 3286, 3057, 2926, 1618, 1545, 1512, 1479,
1442, 1280, 1153, 1053, 970, 870, 754, 677, 650cm
^-1

2) N- [2- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) ethane-1-yl] -5-thia-1,8b-diaza Synthesis of acenaphthylene-4-carboxamide dihydrochloride N- [2- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) ethane-1-yl] -5 Thia-1,8b-diazaacenaphthylene-4
327.9 mg (0.68 mmol) of carboxamide
Of ethanol (10 ml) was added with 4 ml of a 4N hydrogen chloride / ethyl acetate solution (8.0 mmol), and the mixture was stirred for several minutes. After evaporating the solvent under reduced pressure, ether was added to the residue,
The precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give the desired product as orange crystals (364.0 mg, 91%). ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.30-1.80 (5H, m), 1.90-2.
10 (4H, m), 2.90-3.40 (8H, m), 3.50-3.70 (2H, m), 6.6
0 (1H, d, J = 6.8Hz), 6.96-7.00 (2H, m), 7.10-7.45 (5H,
m), 7.51 (1H, s). IR (KBr): 3427, 3057, 2939, 2727, 1632, 1566, 1535,
1502, 1473, 1439, 1390, 1292, 1215, 1051, 951, 76
2cm ^-1 . Elemental analysis value (as C ₂₆ H ₃₁ N ₄ OSCl ₃ .2.0H ₂ O) Calculated value: C; 52.93, H; 5.98, N; 9.50. Found: C; 52.95, H; 5.75, N 9.41.

Example 45 N- [2- (1- (2-Chlorophenethyl) piperidin-4-yl) ethane-1-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as 1) of Example 44, dark red amorphous N
-[2- (1- (2-chlorophenethyl) piperidine-
4-yl) ethane-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.55 (5H, m), 1.60-1.
85 (2H, m), 1.95-2.15 (2H, m), 2.54-2.62 (2H, m), 2.9
1-3.06 (4H, m), 3.30-3.40 (2H, m), 6.60-6.75 (1H, m),
5.79 (1H, dd, J = 1.6, 6.0Hz), 6.59-6.71 (3H, m), 7.0
5 (1H, s), 7.10-7.36 (4H, m). IR (KBr): 3334, 3062, 2927, 1618, 1543, 1512, 1479,
1441, 1371, 1342, 1281, 1211, 1153, 1111, 1051, 9
70, 771, 752, 729 cm ⁻¹ . 2) In the same manner as in 2) of Example 44, N-
[2- (1- (2-chlorophenethyl) piperidine-4
-Yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.40-1.90 (5H, m), 1.95-2.
20 (2H, m), 3.00-3.40 (8H, m), 3.60-3.80 (2H, m), 6.6
1 (1H, d, J = 7.4Hz), 6.97-7.01 (2H, m), 7.25-7.50 (5H,
m), 7.52 (1H, s). IR (KBr): 3425, 2941, 2665, 2532, 1632, 1566, 1537,
1502, 1473, 1394, 1338, 1286, 1215, 1111, 783c
. m ^-1 Elemental analysis _{(C 25 H 29 N 4 OSCl} 3 · 1.0H 2 O ) Calculated values: C; 53.82, H; 5.60 , N; 10.04 Found:. C; 54.06, H; 5.66, N 9.97.

Example 46 N- [3- (1- (3-Phenylpropan-1-yl)]
Synthesis of piperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [3- (1-tert-butoxycarbonyl) −
4-piperidinyl) propan-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (6.55 g, 30.0 mmol) and N-hydroxysuccinimide 6.91 g (60.0 mmol) were suspended in acetonitrile (120 ml), and N-
Ethyl-N'-3- (N, N-dimethylamino) propyl carbodiimide hydrochloride (11.50 g, 60.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an active ester. To a chloroform (100 ml) solution of the obtained active ester compound, 8.4 ml (60.0 mmol) of triethylamine and 3- (1
-Tert-butoxycarbonyl-4-piperidinyl)
8.72 g (36.0 mmol) of propylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, purified water was added to the reaction solution for washing, and then the organic layer was washed with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: ethanol = 10: 1) to obtain the desired product. Red solid Yield 10.16 g (76% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.95-1.41 (m 4H) 1.45 (s
9H) 1.48-1.72 (m 5H) 2.61-2.73 (m 2H) 3.28 (m 2H)
4.05-4.14 (m 2H) 5.79 (dd J = 2.2, 5.8 Hz 1H) 6.02 (t
J = 5.6 Hz 1H) 6.63-6.70 (m 3H) 7.02 (s 1H). IR (KBr): 1684, 1624, 1278, 1161 cm ^-1

2) Synthesis of N- [3- (4-piperidinyl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [3- (1-tert-butoxycarbonyl-4-
Piperidinyl) propan-1-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide 1
0.12 g (22.87 mmol) of ethanol 100
9.4 ml of 12N hydrochloric acid (114.
33 mmol) and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with a small amount of ethanol and ether to obtain 8.79 g (yield: 92.5%) of the desired product as orange crystals. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.13-1.59 (m 7H) 1.74-
1.80 (m 2H) 2.68-2.93 (m 2H) 3.04-3.30 (m 4H) 6.62
(d 1H) 7.00 (d J = 9.2 Hz 1H) 7.18 (s 1H) 7.30 (dd J
= 7.4, 9.2 Hz 1H) 7.67 (s 1H) 8.84 (t J = 5.6 Hz 1H)
. 8.88-9.15 br s2H) IR (KBr ): 1637, 1564, 1518 cm -1 3) N- [3- (1- (3- phenylpropan-1-yl) piperidin-4-yl) propan-1 Il] -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide N- [3- (4-piperidinyl) propan-1-yl]
-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1.0 g (2.41 mmol)
And 1.7 ml of triethylamine (12.2 mmol)
To a solution of ethanol (10 ml) at room temperature in 1-bromo-3.
0.45 ml (2.96 mmol) of phenylpropane
And heated under reflux in a nitrogen atmosphere for 20 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 30-50-100%) gave the desired product. Red-purple amorphous substance Yield 811 mg (yield 73%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17-1.38 (m 4H) 1.44-2.0
3 (m 9H) 2.34-2.41 (m2H) 2.62 (t J = 7.7 Hz 2H) 2.86
-3.02 (m 2H) 3.29 (q J = 6.6 Hz 2H) 5.61-5.73 (m 1H)
5.79 (dd J = 1.6, 6.4 Hz 1H) 6.58-6.70 (m 3H) 7.05
(s 1H) 7.11-7.33 (m 5H).

4) N- [3- (1- (3-Phenylpropan-1-yl) piperidin-4-yl) propane-1
Synthesis of -yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [3- (1- (3-phenylpropan-1-yl)
Piperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (0.813 g, 1.76 mmol) in ethanol (10 ml) at room temperature with 4N chloride. 6 ml (24 mmol) of a hydrogen / methanol solution was added, and the mixture was stirred at room temperature for several minutes. Diethyl ether was added to the crystals formed by evaporating the solvent under reduced pressure, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystals Yield 821 mg (85% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.04-1.28 (m 2H) 1.32-
1.62 (m 5H) 1.65-1.88 (m 2H) 1.93-2.12 (m 2H) 2.37
-2.68 (m 2H) 2.72-3.20 (m 6H) 3.31-3.51 (m 2H) 6.5
3 (d J = 7.2 Hz 1H) 6.93 (d J = 8.8 Hz 1H) 7.07 (s 1H)
7.12-7.38 (m 6H) 7.58 (s 1H) 8.61-8.77 (m 1H). IR (KBr): 1635, 1562, 1529, 1446, 1300, 1217 cm ^-1 Elemental analysis (C ₂₇ H ₃₄ N ₄ OSCl ₂ · 1.0H ₂ O) calculated values:. C, 58.79; H, 6.58; N, 10.16 Found: C, 58.66; H, 6.74 ; N, 10.12.

Example 47 N- [3- (1-Phenethylpiperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [3- (1-Phenethylpiperidin-4-yl) propan-1-yl] -5-thia-1,8b- as a magenta amorphous substance in the same manner as 3) of Example 46. Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-2.16 (m 11H) 2.57-
2.66 (m 2H) 2.81-2.89 (m 2H) 2.92-3.12 (m 2H) 3.24
-3.34 (m 2H) 5.66-5.77 (m 1H) 5.80 (dd J = 1.7,6.3 H
(z 1H) 6.58-6.73 (m 3H) 7.06 (s 1H) 7.14-7.37 (m 5
H). 2) In the same manner as in 4) of Example 46, N-
[3- (1-Phenethylpiperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.94-2.21 (m 2H) 2.66
(br t J = 7.7 Hz 2H) 3.09-3.90 (m 14H) 6.60 (d J = 7.4
Hz 1H) 6.97 (d J = 9.0 Hz 1H) 7.16-7.37 (m 7H) 7.65
(s 1H) 9.03-9.16 (m 1H). IR (KBr): 1639, 1564, 1535, 1500, 1446, 1292, 121
7 cm ^-1 elemental analysis (as C ₂₆ H ₃₂ N ₄ OSCl ₂ .0.5H ₂ O) Calculated: C, 59.08; H, 6.29; N, 10.60. Found: C, 59.03; H, 6.21; N , 10.52.

Example 48 N- [3- (1- (3- (2-Chlorophenyl) propan-1-yl) piperidin-4-yl) propane-1-
Yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride 1) N- [3- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) propane-
Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3- (2-chlorophenyl) propanol 682.6 m
g (4.0 mmol) and triethylamine 809.5 m
To a solution of g (8.0 mmol) in ether (20 ml) was slowly added 687.3 mg (6.0 mmol) of methanesulfonyl chloride under ice-cooling, followed by stirring for 5 minutes and then for 30 minutes at room temperature. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. After the organic layer was washed with water and dried over sodium sulfate, the solvent was distilled off under reduced pressure. N- [3- (4-Piperidinyl) propan-1-yl] -5-thia-1,8b- was added to the obtained mesyl form.
830.8 mg (2.0 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride, 1.15 g (10 mmol) of triethylamine in ethanol (10 ml)
The solution was added and heated to reflux overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The target substance (580.
0 mg, 58.6%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10-1.40 (4H, m), 1.40-2.
00 (9H, m), 2.38 (2H, t, J = 7.5Hz), 2.69 (2H, t, J = 7.8H
z), 2.93 (2H, br d, J = 11.0Hz), 3.22-3.32 (2H, m), 5.7
8 (1H, dd, J = 1.8, 6.2Hz), 5.80-5.90 (1H, m), 6.57-6.
70 (3H, m), 7.03 (1H, s), 7.05-7.35 (4H, m). IR (neat): 3307, 2927, 1618, 15
56, 1477, 1443, 1281, 115
1, 1055, 754 cm ^-1 .

2) N- [3- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) propan-1-yl] -5-thia-1,8b-diaza Synthesis of acenaphthylene-4-carboxamide dihydrochloride N- [3- (1- (3- (2-chlorophenyl) propan-1-yl) piperidin-4-yl) propane-1-
Yl] -5-thia-1,8b-diazaacenaphthylene-
580.0 mg (1.2 mmol) of 4-carboxamide
Of ethanol (10 ml) was added with 4 ml of a 4N hydrogen chloride / ethyl acetate solution (8.0 mmol), and the mixture was stirred for several minutes. Ether was added to the residue obtained by evaporating the solvent under reduced pressure, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give the desired product as orange crystals (605.4 mg, 91%). ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.25
-1.80 (8H, m), 1.90-2.20 (4H, m), 2.75-3.05 (4H, m),
3.05-3.35 (3H, m), 3.54-3.60 (2H, m), 6.60 (1H, d, J =
7.4Hz), 6.92-7.00 (2H, m), 7.15-7.45 (5H, m), 7.50 (1
H, s). IR (KBr): 3464, 3215, 3049, 2939, 2656, 1635, 1568,
1539, 1502, 1473, 1437, 1298, 1219, 781, 756 cm ^-1 . Elemental analysis (as C ₂₇ H ₃₃ N ₄ OSCl ₃ .0.5H ₂ O) Calculated: C; 56.20, H; 5.94, N; 9.71. Found: C; 56.29, H; 5.80, N; 9.61.

Example 49 N- [3- (1- (2-chlorophenethylpiperidine-
4-yl) propan-1-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide dihydrochloride 1) As in Example 48 1), a dark red solid N-
[3- (1- (2-chlorophenethyl) piperidine-4
-Yl) propan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10-1.40 (2H, m), 1.40-1.
80 (4H, m), 1.90-2.30 (3H, m), 2.50-2.65 (2H, m), 2.8
0-3.15 (4H, m), 3.20-3.40 (2H, m), 3.43-3.54 (2H, m),
5.75-6.00 (2H, m), 6.55-6.80 (3H, m), 7.04 (1H, s),
7.05-7.40 (4H, m). IR (KBr): 3390, 3265, 2927, 1740, 1697, 1643, 1618,
1558, 1514, 1481, 1371, 1286, 1153, 1119, 889, 77
1, 727, 675 cm ⁻¹ . 2) In the same manner as in 2) of Example 48, N-
[3- (1- (2-chlorophenethyl) piperidine-4
-Yl) propan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.25-1.70 (7H, m), 1.90-2.
10 (2H, m), 2.95-3.40 (8H, m), 3.60-3.75 (2H, m), 6.6
0 (1H, d, J = 7.8Hz), 6.90 (1H, s), 6.98 (1H, d, J = 9.2H
z), 7.25-7.55 (6H, m). IR (KBr): 3427, 3053, 2937, 2856, 2652, 1635, 1564,
1537, 1504, 1292, 1217, 771 cm ^-1 . Elemental analysis (as C ₂₆ H ₃₁ N ₄ OSCl ₃ .0.5H ₂ O) Calculated: C; 55.47, H; 5.73, N; 9.95. 55.72, H; 5.79, N; 9.96.

Example 50 N- [3- (1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-yl) propan-1-yl] -5-thia-1,8b-diazaacena Butylene-4
-Synthesis of carboxamide dihydrochloride 1) In the same manner as in 1) of Example 48, N- [3- (1- (1,4-benzodioxan-2-ylmethyl) piperidine-4) as a red-orange amorphous substance -Yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.10-1.40 (4H, m), 1.40-
1.80 (5H, m), 1.90-2.20 (2H, m), 2.49-2.71 (2H, m),
2.86-2.30 (2H, m), 3.23-3.33 (2H, m), 3.92-4.01 (1H,
m), 4.20-4.40 (2H, m), 5.79 (1H, dd, J = 1.8, 6.0Hz),
5.80-5.95 (1H, m), 6.58-6.72 (3H, m), 6.75-6.98 (4H,
m), 7.04 (1H, s). IR (KBr): 3321, 2926, 1616, 15
43, 1495, 1265, 1155, 108
2, 1041, 750 cm ^-1 . 2) In the same manner as in 2) of Example 48, N-
[3- (1- (1,4-Benzodioxan-2-ylmethyl) piperidin-4-yl) propan-1-yl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.25
-1.80 (7H, m), 1.85-2.10 (2H, m), 3.05-3.32 (5H, m),
3.35-3.40 (2H, m), 3.60-3.85 (2H, m), 4.03 (1H, dd, J
= 6.3, 11.3Hz), 4.32 (1H, dd, J = 2.4, 11.6Hz), 6.61 (1
H, d, J = 7.6Hz), 6.80-7.05 (6H, m), 7.34-7.43 (1H,
m), 7.51 (1H, s). IR (KBr): 3425, 3062, 2933, 1632, 1564, 1537, 1495,
1265, 758 cm ^-1 . Elemental analysis (as C ₂₇ H ₃₂ N ₄ O ₃ SCl ₂ .0.5H ₂ O) Calculated: C; 56.20, H; 5.94, N; 9.71. Found: C; 56.29, H 5.80, N; 9.61.

Example 51 N-methyl-N- [1- (3-phenylpropane-1-)
Il) piperidin-4-ylmethyl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N-methyl-N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide 5-thia-1, synthesized in the same manner as 1) of Example 42
0.58 g (1.84) of 8b-diazaacenaphthylene-4-carboxylic acid-N-hydroxysuccinimide ester
Tert-butyl 4-[(methylamino) methyl] piperidine-1-carboxylate (0.50 g, 2.19 mmol) and triethylamine (1.0 ml, 7.2 mmol) in an acetonitrile (6 ml) solution at room temperature. ) In acetonitrile (3 ml), and
Stir for 3 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 30%) gave the desired product. Red purple solid Yield 771 mg (98% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.06-1.31 (m 2H) 1.45 (s
9H) 1.51-1.98 (m 3H) 2.58-2.78 (m 2H) 3.11 (br s 3
H) 3.21-3.40 (m 2H) 4.01-4.22 (m 2H) 5.74 (dd J = 1.
8, 6.1 Hz 1H) 6.06 (s 1H) 6.55-6.68 (m 2H) 6.94 (s
1H).

2) N-methyl-N- (piperidine-4-
Synthesis of ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N-methyl-N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) -5-thia- 1,8b-
Diazaacenaphthylene-4-carboxamide 0.771
To a solution of 6 g (1.8 mmol) of ethanol (5 ml) was added 0.8 ml (9.6 mmol) of 12N hydrochloric acid at room temperature, and the mixture was stirred for 18 hours. After evaporating the solvent under reduced pressure, 2 ml (24 mmol) of 12N hydrochloric acid was added to the residue, and the mixture was stirred for 5 minutes. After adding ethanol to the reaction system, the solvent was distilled off under reduced pressure. Ethanol was further added to the residue, and ethanol was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with ethanol, acetone and diethyl ether to obtain the desired product. Orange solid Yield 494.1 mg (68% yield) ¹ H-NMR (200 MHz, D ₂ O) δ: 1.30-1.61 (m 2H) 1.70-1.96
(m 2H) 2.02-2.23 (m 1H) 2.86-3.08 (m 3H) 3.15-3.5
3 (m 6H) 6.13 (d J = 7.4 Hz 1H) 6.37 (s 1H) 6.75 (d
J = 9.2 Hz 1H) 6.94 (dd J = 7.4, 9.2 Hz 1H) 7.07 (s 1
H). 3) N-methyl-N- [1- (3-phenylpropane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide N-methyl-N- (piperidin-4-ylmethyl) -5
1-bromo-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride in ethanol solution of 464.3 mg (1.16 mmol) and 0.8 ml (5.74 mmol) of triethylamine at room temperature. 0.21 ml (1.38 mmol) of 3-phenylpropane was added, and the mixture was heated and refluxed under a nitrogen atmosphere for 15 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 20-
(50%) Separation and purification gave the desired product. Red purple solid Yield 346 mg (67% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (m 2H) 1.50-1.
98 (m 7H) 2.32-2.39 (m2H) 2.62 (t J = 7.7 Hz 2H) 2.8
4-3.00 (m 2H) 3.06 (br s 3H) 3.35 (d J = 7.0Hz 2H)
5.71 (dd J = 1.6, 6.4 Hz 1H) 6.04 (s 1H) 6.53-6.67
(m 2H) 6.93 (s 1H) 7.13-7.32 (m 5H).

4) N-methyl-N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl]
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N-methyl-N- [1- (3-phenylpropane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide 34
6.1 mg (0.77 mmol) of ethanol (4 m
l) Add 4N hydrogen chloride / methanol solution 2.0 at room temperature
ml (8.0 mmol) was added and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure to obtain the desired product. Orange amorphous substance Yield 397 mg (90% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.18 (m 7H) 2.63
(t J = 7.7 Hz 2H) 2.73-3.55 (m 11H) 6.65 (d J = 7.6 Hz
1H) 6.60 (br s 1H) 7.03 (d J = 9.2 Hz 1H) 7.21-7.35
(m 6H) 7.50 (s 1H). IR (KBr): 3417, 2935, 2721, 1628, 1498, 1448 cm ^-1 Elemental analysis (calculated as C ₂₆ H ₃₂ N ₄ OSCl ₂・ 3.0H ₂ O) : C, 54.44; H, 6.68; N, 9.77. Found: C, 54.32; H, 6.62; N, 9.64.

Example 52 N-benzyl-N- [1- (3-phenylpropane-1)
-Yl) pyyridin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene dihydrochloride 1) N-benzyl-N- (1-tert-butoxycarbonylpiperidin-4-ylmethyl) -5-thia-1,
Synthesis of 8b-diazaacenaphthylene 5-thia-1, synthesized in the same manner as 1) of Example 42
To a solution of 1.26 g (4.0 mmol) of 8b-diazaacenaphthylene-4-carboxylic acid-N-hydroxysuccinimide ester in 12 ml of acetonitrile at room temperature was added 4- (benzylaminomethyl) piperidine-1-. 1.40 g (4.79 mmol) of tert-butyl carboxylate
And a solution of 1.2 ml (8.6 mmol) of triethylamine in acetonitrile (6 ml) were added, and the mixture was stirred at room temperature for 17 hours and further at 40 ° C. for 3 days. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate.
Column chromatography (methanol / ethyl acetate 2
(0% → methanol / chloroform 1:15), but could not be purified, and a crude product (0.5162 g) was obtained. 2) Synthesis of N-benzyl-N- (piperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene dihydrochloride Crude N-benzyl-N- (1-tert-butoxycarbonylpiperidine -4-ylmethyl) -5-thia-1,8
To a solution of b-diazaacenaphthylene (0.5162 g) in ethanol (2 ml) was added 1.0 ml of 12N hydrochloric acid (1 ml) at room temperature.
2 mmol) and stirred for 15 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was washed with chloroform. Under reduced pressure, water was distilled off to obtain a crude product (0.451 as an orange solid).
g) was obtained.

3) Synthesis of N-benzyl-N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene Crude N-benzyl -N- (piperidin-4-ylmethyl)
-5-thia-1,8b-diazaacenaphthylene dihydrochloride (0.451 g) and 0.7 ml of triethylamine
0.15 ml of 1-bromo-3-phenylpropane at room temperature in a solution of (5.0 mmol) in ethanol (4 ml).
(1.1 mmol), and the mixture was heated and refluxed for 15 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / chloroform 1: 50-1: 15: 1: 2
Separation and purification were attempted in 0), but the purification could not be performed, and a crude product (245 mg) was obtained as a reddish purple solid as a crude product. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.14-1.44 (m 2H) 1.51-2.
01 (m 7H) 2.32-2.39 (m2H) 2.61 (t J = 7.7 Hz 2H) 2.9
3 (br d J = 11.4 Hz 2H) 3.25 (d J = 6.6 Hz 2H) 4.69 (br
s 2H) 5.70 (dd J = 1.4, 6.4 Hz 1H) 6.04 (s 1H) 6.52
-6.65 (m2H) 6.88 (s1H) 7.09-7.42 (m10H). 4) N-benzyl-N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia Synthesis of -1,8b-diazaacenaphthylene dihydrochloride Crude N-benzyl-N- [1- (3-phenylpropane-
1-yl) piperidin-4-ylmethyl] -5-thia-
To a solution of 245.4 mg (about 0.47 mmol) of 1,8b-diazaacenaphthylene in ethanol (4 ml) was added 1.0 ml (4.0 mmol) of a 4N hydrogen chloride / methanol solution at room temperature, followed by stirring for 20 minutes. . The solvent was distilled off under reduced pressure, and diethyl ether was added to the resulting crystals, followed by filtration to obtain the desired product as an orange solid. Orange crystal Yield 174 mg (7%, 4 steps) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.78 (m 4H) 1.89-
2.13 (m 3H) 2.63 (t J = 7.7 Hz 2H) 2.71-3.53 (m 8H)
4.66-4.87 (m 2H) 6.64 (d J = 7.4 Hz 1H) 6.69 (s 1H)
. 7.02 (d J = 9.2 Hz 1H) 7.16-7.50 (m 12H) IR (KBr): 3425, 2937, 2667, 1630, 1498, 1439 cm -1 Elemental analysis _{(C 32 H 36 N 4 OSCl} 2 · 2.5 H ₂ O) calculated values:. C, 59.99; H, 6.45; N, 8.75 Found: C, 60.26; H, 6.59 ; N, 8.53.

Example 53 N- [2- (3-phenylpropan-1-ylamino)
Synthesis of ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 09 g (about 3.2 mmol) and 1.15 g (10 mmol) of N-hydroxysuccinimide in acetonitrile (15 ml) were stirred at room temperature with N-ethyl-
1.92 g (10 mmol) of N'-3- (N, N-dimethylamino) propyl carbodiimide hydrochloride was added,
Stir for 2 hours. After evaporating the solvent under reduced pressure, water and water were added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude active ester (1.63 g). Crude active ester (1.63 g) and triethylamine 1.4 ml (1
0 mmol) in acetonitrile (15 ml) at room temperature was added with 1.67 g (6.00 mmol) of tert-butyl N- (2-aminoethane-1-yl) -3-phenylpropan-1-ylaminecarboxylate, Stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. After washing with a saturated saline solution, it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product. Perform column chromatography (methanol / ethyl acetate 10%) to give a crude product (2.13 g containing impurities)
I got 1 in 413 mg (0.80 mmol) of crude product
1.5 ml (18 mmol) of 2N hydrochloric acid was added and stirred for several minutes. Ethanol and diethyl ether were added to the reaction system, and the resulting crystals were collected by filtration. After washing with ethanol, acetone and diethyl ether, the desired product was obtained. Orange crystal Yield 329 mg (91% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.84-2.03 (m 2H) 2.67
(t J = 7.7 Hz 2H) 2.84-3.09 (m 4H) 3.39-3.51 (m 2H)
6.60 (d J = 6.8 Hz 1H) 6.96 (d J = 8.4 Hz 1H) 7.16-7.3
7 (m 7H) 7.65 (s 1H) 9.00-9.18 (m 2H). IR (KBr): 3431, 3236, 1636, 1568, 1502, 1292, 785
cm ^-1 Elemental analysis (as C ₂₁ H ₂₄ N ₄ OSCl ₂ · 0.1H ₂ O) Calculated: C, 55.65; H, 5.38; N, 12.36. Found: C, 55.44; H, 5.19; N, 12.35.

Example 54 In the same manner as in Example 53, N- [3- (3-
Phenylpropan-1-ylamino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.73-2.01 (m 4H) 2.67
(t J = 7.7 Hz 2H) 2.81-2.97 (m 4H) 3.15-3.26 (m 2H)
6.61 (d J = 7.4 Hz 1H) 6.97 (d J = 9.0 Hz 1H) 7.20-7.
33 (m 7H) 7.65 (s 1H) 8.95-9.15 (m 1H). IR (KBr): 3436, 2947, 2792, 1635, 1294 cm ^-1

Example 55 In the same manner as in Example 53, N- [4- (3-
Phenylpropan-1-ylamino) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d3) δ: 1.32-1.70 (m 4H) 1.86-
2.01 (m 2H) 2.66 (t J = 7.7 Hz 2H) 2.77-2.93 (m 4H)
3.06-3.19 (m 2H) 6.60 (d J = 6.8 Hz 1H) 6.97 (d J = 8.
4 Hz 1H) 7.15-7.34 (m 7H) 7.64 (s 1H) 8.82-9.10
. (m 1H) IR (KBr ): 3411, 2944, 2786, 1637, 1565, 1292 cm -1 Elemental analysis (C ₂₃ H ₂₈ N ₄ as oSCL ₂₎ Calculated: C, 57.62; H, 5.89 ; N , 11.69. Found: C, 57.32; H, 5.91; N, 11.57.

Example 56 N- [3- (N-methyl-N- (3-phenylpropan-1-yl) amino) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene Synthesis of -4-carboxamide dihydrochloride 1) N- [3- (N-methyl-N- (3-phenylpropan-1-yl) amino) propan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1, synthesized in the same manner as 1) of Example 42
0.50 g (1.59 g) of 8b-diazaacenaphthylene-4-carboxylic acid-N-hydroxysuccinimide ester
Mmol) in acetonitrile (6 ml) at room temperature [3- (N-methyl-N- (3-phenylpropane-1).
-Yl) amino) propan-1-yl] amine 0.39
g (1.89 mmol) and 0.5 m of triethylamine
l (3.59 mmol) in acetonitrile (4 ml) was added and stirred for 5 minutes. After distilling off the solvent under reduced pressure,
Water was added to the residue and extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 80-
(100%) to obtain the desired product. Red-purple oily substance Yield 577 mg (89% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.57-1.73 (m 2H) 1.77-1.
95 (m 2H) 2.25 (s 3H) 2.40-2.55 (m 4H) 2.66 (t J = 7.
(7 Hz 2H) 3.37-3.45 (m 2H) 5.58 (d J = 6.4 Hz1H) 6.49
-6.64 (m 3H) 6.89 (s 1H) 7.12-7.3 (m 5H) 8.37-8.60
(m 1H).

2) N- [3- (N-methyl-N- (3-
Phenylpropan-1-yl) amino) propane-1-
Yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride N- [3- (N- (3-phenylpropan-1-yl)
Amino) propan-1-yl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide 577.3
mg (1.42 mmol) in ethanol (6 ml) at room temperature in 4N hydrogen chloride / methanol 2.0 ml
(8.0 mmol) and stirred for several minutes. The solvent was distilled off under reduced pressure to obtain the desired product. Orange amorphous substance Yield 670 mg (87% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.71-2.07 (m 4H) 2.60-
2.73 (m 5H) 2.89-3.25 (m 6H) 6.62 (d J = 7.4 Hz 1H)
6.98 (d J = 9.2 Hz 1H) 7.16-7.36 (m 7H) 7.66 (s 1H)
8.92-9.03 (m 1H). IR (KBr): 3433, 3059, 2951, 2715, 1637, 1296 cm ^-1 Elemental analysis (calculated as C ₂₃ H ₂₈ N ₄ O ₂ SCl ₂・ 2.5H ₂ O) : C, 52.67; H, 6.34; N, 10.68. Found: C, 52.40; H, 6.25; N, 10.39.

Example 57 Synthesis of 4- [4- (3-phenylpropan-1-yl) piperazino-1-carbonyl] -5-thia-1,8b-diazaacenaphthylene dihydrochloride 1) 4 Synthesis of-(4-tert-butoxycarbonylpiperazino-1-carbonyl) -5-thia-1,8b-diazaacenaphthylene 5-thia-1, synthesized in the same manner as in Example 42-1)
0.28 g (3.25 mmol) of piperazine and triethylamine in a solution of 0.85 g (2.7 mmol) of 8b-diazaacenaphthylene-4-carboxylic acid-N-hydroxysuccinimide ester in acetonitrile (10 ml) at room temperature A suspension of 0.75 ml (5.38 mmol) of acetonitrile (3 ml) was added, and the mixture was stirred at room temperature for 30 minutes. 1.0 ml of di-tert-butyl dicarbonate in the reaction system
(4.3 mmol) and stirred at room temperature for 2.5 hours. After evaporating the solvent under reduced pressure, water was added to the reaction system, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Purification was attempted by column chromatography (methanol / ethyl acetate 10%),
The crude product could not be purified and was obtained as a red-purple amorphous substance. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.48 (s 9H) 3.25-3.73 (m
8H) 5.74 (dd J = 1.8, 5.8 Hz 1H) 6.12 (s 1H) 6.56-
6.67 (m 2H) 6.95 (s 1H).

2) 4- (piperazino-1-carbonyl)
Synthesis of -5-thia-1,8b-diazaacenaphthylene dihydrochloride Crude 4- (4-tert-butoxycarbonylpiperazino-1-carbonyl) -5-thia-1,8b-diazaacena 0.54 ml of 12N hydrochloric acid was added at room temperature to a solution of 0.5092 g (about 1.3 mmol) of butylene in ethanol (4 ml).
(6.48 mmol) and stirred for 15 hours. The precipitated crystals were removed by filtration, and the filtrate was concentrated to give a crude product (333 mg) as an orange solid as a crude product. ¹ H-NMR (200 MHz, D ₂ O) δ: 3.20-3.48 (m 4H) 3.90-4.03
(m 4H) 6.17 (d J = 7.0 Hz 1H) 6.43 (s 1H) 6.78 (d J
= 9.4 Hz 1H) 6.94-7.02 (m1H) 7.11 (s1H). 3) 4- [4- (3-Phenylpropan-1-yl) piperazino-1-carbonyl] -5-thia-1,8b- Synthesis of diazaacenaphthylene 4- (piperazino-1-carbonyl) -5-thia-1,
333 mg (about 0.927 mmol) of 8b-diazaacenaphthylene dihydrochloride and 0.65 m of triethylamine
l (4.66 mmol) in ethanol (6 ml) was added at room temperature to 1-bromo-3-phenylpropane 0.17.
ml (1.1 mmol) was added, and the mixture was heated and refluxed under a nitrogen atmosphere for 48 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 20-40%) gave the desired product. Red purple amorphous substance Yield 160 mg (15%, 3 steps) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.78-1.90 (m 2H) 2.40-2.
47 (m 6H) 2.65 (t J = 7.7 Hz 2H) 3.63-3.68 (m 4H) 5.
71 (dd J = 1.6, 6.2 Hz 1H) 6.01 (s 1H) 6.53-6.66 (m
2H) 6.93 (s 1H) 7.15-7.34 (m 5H). IR (KBr): 3425, 2595, 1632, 1498, 1431, 1273, 121
1, 966 cm ^-1

4) 4- [4- (3-phenylpropane-
1-yl) piperazino-1-carbonyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene dihydrochloride 4- [4- (3-phenylpropan-1-yl) piperazino-1-carbonyl] -5-thia-1,8b-diazaacenaphthylene To a solution of (160 mg, 0.40 mmol) in ethanol (2 ml) was added 0.5 ml (2.0 mmol) of a 4N hydrogen chloride / methanol solution. The solvent was distilled off under reduced pressure to obtain the desired product. Orange amorphous substance Yield 183 mg (90% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.96 to 2.13 (m 2H) 2.65
(t J = 7.8 Hz 2H) 2.94-3.16 (m 4H) 3.42-3.63 (m 4H)
4.20-4.36 (m 2H) 6.65 (d J = 8.6 Hz 1H) 6.67 (s 1H)
7.03 (d J = 9.2 Hz 1H) 7.17-7.36 (m 6H) 7.52 (s 1H). IR (KBr): 3439, 3060, 2942, 1637, 1329, 1120, 791
cm ^-1 Elemental analysis _{(C 23 H 26 N 4 OSCl} 2 · 1.5H 2 O ) Calculated values:. C, 54.76; H, 5.79; N, 11.11 Found: C, 54.72; H, 6.03 ; N, 10.87.

Example 58 N- [2- (4- (3-Phenylpropan-1-yl)
Synthesis of piperazin-1-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) N- [2- (4-tert-butoxycarbonyl) −
1-piperazinyl) ethane-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 5.27 g (15.0 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and N-hydroxysuccinimide 3 .45 g (30.0 mmol) was suspended in 50 ml of acetonitrile, and 5.75 g (30.0 mmol) of N-ethyl-N′-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added thereto. Was added and stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with 150 ml of chloroform. The organic layer was washed with 100 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an active ester.
A solution of the obtained active ester in 100 ml of chloroform was added to 4.2 ml (30.0 ml) of triethylamine.
Mmol) and 1- (2-aminoethyl) piperazine
After adding 94 g (15.0 mmol) and stirring at room temperature for 30 minutes, di-tert-butyl dicarbonate 3.28 g (1
(5.0 mmol) was added dropwise, and the mixture was further stirred at room temperature for 1 hour. After the reaction, 100 ml of purified water was added to the reaction solution for washing, and then the organic layer was washed with 150 ml of saturated saline.
After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: ethanol = 10: 1) to give 3.64 g of the desired product (56. 5%, red liquid). ¹ H-NMR (200 MHz; CDCl ₃ ) δ: 1.47 (s, 9H), 2.42 (m, 4H), 2.53
(t, 2H, J = 6.0Hz), 3.35-3.48 (m, 6H), 5.80 (dd, 1H, J = 6.2Hz,
4.4Hz), 6.42 (brs, 1H, NH), 6.62-6.70 (m, 3H), 7.05 (s, 1H) .IR (KBr): 1687,1622,1280,1161cm ^-1 .

2) Synthesis of N- [2- (1-piperazinyl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride N- [2- (4-tert-butoxycarbonyl-1-
Piperazinyl) ethane-1-yl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide 3.6
To a solution of 0 g (8.38 mmol) in 100 ml of ethanol was added 3.4 ml (41.90 mmol) of 12N hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration, and washed with a small amount of ethanol and ether.
36 g (91.4%, orange crystals) were obtained. ¹ H-NMR (200 MHz; DMSO-d ₆ ) δ: 3.30-3.59 (m, 12H), 6.64 (d,
1H, J = 7.0Hz), 7.01 (d, 1H, J = 8.2Hz), 7.28-7.36 (m, 2H), 7.6
9 (s, 1H), 9.18 (t, 1H, NH, J = 5.6Hz), 9.90 (brs, 2H, NH). IR (KBr): 1641, 1568, 1298cm- ¹ . 3) N- [2- (4- (3-Phenylpropan-1-yl) piperazin-1-yl) ethane-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide N- [2- (1-piperazinyl) ethane-1-yl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1.63 g (3.71 mmol)
And 3.0 ml (21.5 mmol) of triethylamine
In a solution of ethanol (16 ml) at room temperature.
0.68 ml of phenylpropane (4.47 mmol)
And heated under reflux in a nitrogen atmosphere for 20 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 20-50%) separation and purification gave the desired product. Red-purple amorphous substance Yield 1.15 g (69% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.73-1.93 (m 2H) 2.36-2.
68 (m 14H) 3.33-3.42 (m2H) 5.78 (dd J = 1.8, 6.2 Hz 1
H) 6.46-6.66 (m 4H) 7.04 (s 1H) 7.15-7.31 (m 5H).

4) N- [2- (4- (3-Phenylpropan-1-yl) piperazin-1-yl) ethane-1-
Yl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide trihydrochloride N- [2- (4- (3-phenylpropan-1-yl)
Piperazin-1-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.15 g (2.57 mmol) of ethanol (10
4 ml of 4N hydrogen chloride / methanol solution at room temperature
1 (16 mmol) was added and the mixture was stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 1.27 g (yield 85%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.94-2.21 (m 2H) 2.66
(br t J = 7.7 Hz 2H) 3.09-3.90 (m 14H) 6.60 (d J = 7.4
Hz 1H) 6.97 (d J = 9.0 Hz 1H) 7.16-7.37 (m 7H) 7.65
(s 1H) 9.03-9.16 (m 1H). IR (KBr): 1641, 1560, 1535, 1497, 1443, 1288, 121
5, 1107, 958, 794 cm -1 Elemental analysis _{(C 25 H 32 N 5 OSCl} 3 · 1.5H 2 O ) Calculated values:. C, 51.42; H, 6.04; N, 11.99 Found: C, 51.51 H, 5.79; N, 11.81.

Example 59 N- [3- (4- (3-Phenylpropan-1-yl)
Piperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as 1) of Example 58, red Oil N-
[3- (4-tert-butoxycarbonyl-1-piperazinyl) propan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.47 (s 9H) 1.62-1.80 (m 2
H) 2.33-2.59 (m 6H) 3.35-3.48 (m 2H) 3.48-3.59 (m
4H) 5.74 (dd J = 1.4, 6.4 Hz 1H) 6.57-6.71 (m3H) 7.0
2 (s 1H) 7.70 (t J = 5.4 Hz 1H). IR (KBr): 3327, 1695, 1626 cm ^-1 2) In the same manner as in Example 58-2), orange N-
[3- (1-Piperazinyl) propan-1-yl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.83-2.05 (m 2H) 3.04-
3.32 (m 6H) 3.32-3.77 (m 6H) 6.68 (d J = 7.2 Hz 1H)
7.03 (d J = 8.8 Hz 1H) 7.27 (s 1H) 7.35 (dd J = 7.2,
(8.8 Hz 1H) 7.73 (s 1H) 9.06 (t J = 5.6 Hz 1H) 9.94
(brs 2H). IR (KBr): 3363, 1639, 1556 cm ^-1

3) In the same manner as in 3) of Example 58, N- [3- (4- (3-phenylpropane-1) as a red oily substance was obtained.
-Yl) piperazin-1-yl) propan-1-yl]
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.51-1.92 (m 4H) 2.29-2.
71 (m 14H) 3.37-3.45 (m 2H) 5.69 (dd J = 1.2, 6.4 Hz
1H) 6.51-6.66 (m 3H) 6.98 (s 1H) 7.12-7.35 (m 5H)
8.07-8.24 (m 1H). IR (KBr): 3255, 2939, 2814, 1620, 1545, 1279, 115
1 cm ^-1 4) In the same manner as in 4) of Example 58, N-
[3- (4- (3-Phenylpropan-1-yl) piperazin-1-yl) propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.78-2.10 (m 4H) 2.56-
2.72 (m 2H) 2.98-4.09 (m 14H) 6.51 (d J = 7.4 Hz 1H)
6.91 (d J = 9.2 Hz 1H) 7.04-7.38 (m 7H) 7.57 (s 1H)
8.76-8.89 (m 1H). IR (KBr): 3174, 3035, 2366, 1630, 1441, 1296, 121
1, 795 cm ^-1 Elemental analysis (as C ₂₆ H ₃₄ N ₅ OSCl ₃ .0.5H ₂ O) Calculated: C, 53.84; H, 6.08; N, 12.07. Found: C, 53.84; H, 5.80 N, 12.29.

Example 60 N- [1- (3-Phenylpropan-1-yl) pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [3- (1-tert-butoxycarbonyl)
Synthesis of [pyrrolidinyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5.27 g (15.0 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 3.45 g (30.0 mmol) of N-hydroxysuccinimide were suspended in 50 ml of acetonitrile, and N-ethyl-N′-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added thereto. 75 g (30.0 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with 150 ml of chloroform. The organic layer was washed with 100 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an active ester.
A solution of the obtained active ester in 100 ml of chloroform was added to 4.2 ml (30.0 ml) of triethylamine.
Mmol) and 1.55 g of 3-aminopyrrolidine (15.
0 mmol) and stirred at room temperature for 30 minutes.
3.28 g (15.0 mmol) of di-tert-butyl
Was added dropwise, and the mixture was further stirred at room temperature for 1 hour. After the reaction, 100 ml of purified water was added to the reaction solution for washing, and then the organic layer was washed with 150 ml of saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate: ethanol = 10: 1) to obtain 3.22 g of the desired product (5.
5.5%, red solid). ¹ H-NMR (200 MHz; CDCl ₃ ) δ: 1.46 (s, 9H), 1.81-2.02 (m, 1
H), 2.08-2.28 (m, 1H), 3.43-3.88 (m, 4H), 4.12-4.27 (m, 1
H), 4.74 (d, 1H, NH, J = 6.0Hz), 5.73 (dd, 1H, J = 5.6Hz, 3.2H
z), 6.23 (s, 1H), 6.58-6.66 (m, 2H), 6.95 (s, 1H) .IR (KBr): 1697,1608,1163cm ^-1 .

2) Synthesis of N- (3-pyrrolidinyl) -5-thia-1,8b-diazaacephthylene-4-carboxamide dihydrochloride N- [3- (1-tert-butoxycarbonyl) pyrrolidinyl ] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3.2 g (8.28 mmol)
Was dissolved in 100 ml of ethanol, 3.4 ml (41.40 mmol) of 12N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. The generated crystals were collected by filtration and washed with a small amount of ethanol and ether to obtain 2.12 g (89.4%, orange crystals) of the desired product. ¹ H-NMR (200 MHz; DMSO-d ₆ ) δ: 2.04-2.32 (m, 2H), 3.61-3.8
4 (m, 5H), 6.65 (d, 1H, J = 7.4Hz), 6.87 (s, 1H), 7.04 (d, 1H, J =
9.2Hz), 7.32 (t, 1H, J = 7.6Hz), 7.59 (s, 1H), 8.51 (brs, 2H, N
H). IR (KBr): 1605,1497,1427cm ^-1 .3) N- [1- (3-Phenylpropan-1-yl) pyrrolidin-3-yl] -5-thia-1,8b-diaza Synthesis of acenaphthylene-4-carboxamide N- (3-pyrrolidinyl) -5-thia-1,8b-diazaacephthylene-4-carboxamide dihydrochloride 0.5
0 g (1.39 mmol) and triethylamine 1.0
0.25 m of 1-bromo-3-phenylpropane at room temperature in a solution of ethanol (5 ml) in 0.1 ml (7.17 mmol).
l (1.64 mmol) was added and the mixture was heated under reflux under a nitrogen atmosphere for 18 hours. Further, 0.2 ml (1.32 mmol) of 1-bromo-3-phenylpropane was added to the reaction system, and 3
Heated to reflux for an hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 20-30%) was separated and purified, and N- [1- (3-phenylpropan-1-yl) was purified.
Pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. Red purple amorphous substance Yield 242 mg (43% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.67-2.20 (m 4H) 2.61-2.
71 (m 4H) 3.24-3.41 (m2H) 3.49-3.83 (m 3H) 5.71 (d
d J = 2.2, 5.8 Hz 1H) 6.22 (s 1H) 6.51-6.62 (m 2H)
6.93 (s 1H) 7.16-7.32 (m 6H).

4) N- [1- (3-phenylpropane-
1-yl) pyrrolidin-3-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (3-phenylpropan-1-yl) pyrrolidin-3-yl] -5-thia-1,8b-diazaacena 242.4 mg of butylene-4-carboxamide (0.6
0 mmol) in ethanol (2 ml) at room temperature with 4N
1.5 ml (6.0 mmol) of a hydrogen chloride / methanol solution was added and the mixture was stirred at room temperature for several minutes. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and the resulting crystals were collected by filtration. The crystals are washed with diethyl ether,
The desired product was obtained. Orange crystals Yield 253 mg (88% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.88-2.09 (m 2H) 2.14-2.
31 (m 2H) 2.69 (t J = 7.6 Hz 2H) 2.88-3.03 (m 2H) 3.
46-4.07 (m 5H) 6.62 (d J = 7.4 Hz 1H) 6.86 (s1H) 7.0
9 (d J = 9.2 Hz 1H) 7.15-7.37 (m 6H) 7.55 (s 1H) 9.4
1-9.82 (m 1H). IR (KBr): 1624, 1498, 1437, 1390, 1211, 785 cm ^-1 .

Example 61 N-[(3R) -1- (3-phenylpropan-1-yl) pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. Synthesis of dihydrochloride 1) In the same manner as in 1) of Example 60, a red solid N-
[(3R) -1-tert-butoxycarbonylpyrrolidinyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (s 9H) 1.78-1.98 (m
1H) 2.04-2.28 (m 1H) 3.36-3.92 (m 4H) 4.12-4.30 (m
1H) 4.56-4.72 (m 1H) 5.72 (dd J = 2.2, 5.6 Hz1H) 6.
23 (s 1H) 6.58-6.71 (m 2H) 6.95 (s 1H). IR (KBr): 1697, 1608, 1163 cm ^-1 2) In the same manner as in Example 60-2), orange N-
((3R) -Pyrrolidinyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.07-2.29 (m 1H) 2.34-
2.55 (m 1H) 3.39-4.16 (m 5H) 6.08 (d J = 7.3 Hz 1H)
6.53 (s 1H) 6.70 (d J = 8.9 Hz 1H) 6.89 (dd 7.3, 8.
9 Hz 1H) 7.08 (s 1H). IR (KBr): 1603, 1500, 1433 cm ^-1

3) In the same manner as in 3) of Example 60, a red-purple amorphous substance N-[(3R) -1- (3-phenylpropan-1-yl) pyrrolidin-3-yl] -5- Cheer
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.67-2.20 (m 4H) 2.61-2.
71 (m 4H) 3.24-3.41 (m2H) 3.49-3.83 (m 3H) 5.71 (d
d J = 2.2, 5.6 Hz 1H) 6.22 (s 1H) 6.51-6.62 (m 2H)
6.93 (s 1H) 7.16-7.32 (m 6H). 4) In the same manner as in 4) of Example 60, N-
[(3R) -1- (3-phenylpropan-1-yl)
Pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.87-2.07 (m 2H) 2.12-2.3
3 (m 2H) 2.69 (t J = 7.6Hz 2H) 2.88-3.04 (m 2H) 3.46
-4.07 (m 5H) 6.58 (d J = 7.2 Hz 1H) 6.83 (s 1H) 6.98
(d J = 9.2 Hz 1H) 7.16-7.38 (m 6H) 7.51 (s 1H) 9.31
-9.70 (m 1H). IR (KBr): 1624, 1498, 1437, 1390, 1211, 785 cm ^-1 Elemental analysis value (as C ₂₃ H ₂₆ N ₄ OSCl ₂ · 1.6H ₂ O) Calculated value: C, 54.56; H, 5.81; N, 11.07. Found: C, 54.44; H, 6.09; N, 11.04.

Example 62 N-[(3S) -1- (3-phenylpropan-1-yl) pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. Synthesis of dihydrochloride 1) In the same manner as in 1) of Example 60, a red solid N-
[(3s)-(1-tert-butoxycarbonyl) pyrrolidinyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.46 (s 9H) 1.78-1.91 (m
1H) 2.04-2.28 (m 1H) 3.36-3.92 (m 4H) 4.12-4.30 (m
1H) 4.56-4.72 (m 1H) 5.72 (dd J = 2.2, 5.6 Hz1H) 6.
23 (s 1H) 6.53-6.71 (m 2H) 6.95 (s 1H). IR (KBr): 1697, 1608, 1163 cm ^-1 2) In the same manner as in 2) of Example 60, N-
((3s) -Pyrrolidinyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 2.07-2.29 (m 1H) 2.34-
2.55 (m 1H) 3.39-4.16 (m 5H) 6.08 (d J = 7.3 Hz 1H)
6.53 (s 1H) 6.70 (d J = 8.9 Hz 1H) 6.89 (dd 7.3, 8.
9 Hz 1H) 7.08 (s 1H). IR (KBr): 1606, 1496, 1425 cm ^-1

3) In the same manner as in 3) of Example 60, a red-purple amorphous substance N-[(3S) -1- (3-phenylpropan-1-yl) pyrrolidin-3-yl] -5- Cheer
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.67-2.20 (m 4H) 2.61-2.
71 (m 4H) 3.24-3.41 (m2H) 3.49-3.83 (m 3H) 5.71 (d
d J = 2.2, 5.6 Hz 1H) 6.22 (s 1H) 6.51-6.62 (m 2H)
6.93 (s 1H) 7.16-7.32 (m 6H). 4) In the same manner as in 4) of Example 60, N-
[(3S) -1- (3-phenylpropan-1-yl)
Pyrrolidin-3-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.88-2.08 (m 2H) 2.14-2.
33 (m 2H) 2.68 (t J = 7.6 Hz 2H) 2.88-3.05 (m 2H) 3.
28-4.32 (m 5H) 6.56 (d J = 7.0 Hz 1H) 6.82 (s1H) 6.9
6 (d J = 9.2 Hz 1H) 7.16-7.37 (m 6H) 7.50 (s 1H) 9.2
2-9.63 (m 1H). IR (KBr): 1624, 1498, 1437, 1390, 1211, 785 cm ^-1 Elemental analysis value (as C ₂₃ H ₂₆ N ₄ OSCl ₂ · 1.5H ₂ O) Calculated value: C , 54.76; H, 5.79; N, 11.11. Found: C, 54.46; H, 5.83; N, 11.01.

Example 63 4- [4- (3-Phenylpropan-1-ylaminomethyl) piperidino-1-carbonyl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene dihydrochloride 1) 4- [4- (3-Phenylpropan-1-ylaminomethyl) piperidino-1-carbonyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene 5-thia-1, synthesized in the same manner as in 1) of Example 42
0.21 g (0.67 g) of 8b-diazaacenaphthylene-4-carboxylic acid-N-hydroxysuccinimide ester
Mmol) in acetonitrile (2 ml) at 0 ° C. in 0.1858 g (0.8 mmol) of 4-[(3-phenylpropan-1-yl) aminomethyl] piperidine and 0.15 ml (1.08 mmol) of triethylamine. Acetonitrile (2 ml) solution was added, and the mixture was stirred at the same temperature for 4 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 20-50-100
%) To obtain the desired product. Red-purple amorphous substance Yield 180 mg (62% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.02-1.30 (m 2H) 1.57-1.91
(m 5H) 2.50 (d J = 6.2Hz 2H) 2.59-2.70 (m 4H) 2.81-
2.93 (m 2H) 4.30-4.37 (m 2H) 5.71 (dd J = 1.6, 6.2 H
(z 1H) 6.05 (s 1H) 6.53-6.66 (m 2H) 6.92 (s 1H) 7.1
5-7.32 (m 5H).

2) 4- [4- (3-phenylpropane-
1-ylaminomethyl) piperidino-1-carbonyl]
Synthesis of -5-thia-1,8b-diazaacenaphthylene dihydrochloride 4- [4- (3-phenylpropan-1-ylaminomethyl) piperidino-1-carbonyl] -5-thia-1,
8b-diazaacenaphthylene 180.9 mg (0.42
1.0 ml (4 mmol) of a 4N hydrogen chloride / methanol solution was added to a solution of ethanol (2 mmol) in ethanol (2 ml) at room temperature and stirred for several minutes. The solvent was distilled off under reduced pressure to obtain the desired product. Orange amorphous substance Yield 201 mg (86% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.09-1.28 (m 2H) 1.77-
2.08 (m 5H) 2.58-3.04 (m 8H) 4.06-4.24 (m 2H) 6.52
(s 1H) 6.65 (d J = 7.2 Hz 1H) 7.03 (d J = 9.2 Hz 1H)
7.15-7.37 (m 6H) 7.50 (s 1H) 8.93-9.19 (m 1H). IR (KBr): 3421, 2945, 2794, 1628, 1500, 1444, 138
7, 1281, 1215 cm ^-1 Elemental analysis (as C ₂₅ H ₃₀ N ₄ OSCl ₂ · 3.0 H ₂ O) Calculated: C, 53.66; H, 6.48; N, 10.01. Found: C, 53.88; H , 6.59; N, 10.04.

Example 64 N- [3- (4-benzyl-1,4-diazepine-1-)
Synthesis of yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) N- [3- (1-tert-butoxycarbonyl-)
2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-
Synthesis of 1,8-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 2619 mg (12 mmol) and N-hydroxysuccinimide 2762 mg (24 mmol) Was suspended in acetonitrile (50 ml), and N-ethyl-
N′-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride (4601 mg, 24 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an active ester. To a solution of the obtained active ester in chloroform (100 ml) was added 4.2 ml (30 mmol) of triethylamine and 1-tert-butoxycarbonyl-4- (3-aminopropyl) -2,3,3.
5,6-Hexahydro-7H-1,4-diazepine 37
10 mg (14 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction, purified water was added to the reaction solution for washing, and then the organic layer was washed with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate: ethanol = 10: 1).
And 4291 mg of the desired product as a red solid (78.
2%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.47 (s 9H) 1.62-1.83 (m
2H) 1.83-2.16 (m 2H) 2.51-2.83 (m 6H) 3.29-3.55 (m
6H) 5.71 (dd 1H J = 5.8Hz, 2.2 Hz) 6.54-6.77 (m 3H)
7.03 (d 1H J = 4.0 Hz) 7.76 (d 1H J = 14.8 Hz).

2) N- [3- (hexahydro-1,4-
Synthesis of diazepin-1-yl) propan-1-yl] -5-thia-1,8-diazaacenaphthylene-4-carboxamide trihydrochloride N- [3- (4-tert-butoxycarbonyl-2) ,
3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-1,8
-Diazaacenaphthylene-4-carboxamide 4250
To a solution of mg (9.29 mmol) in 100 ml of ethanol was added 3.8 ml (46.44 mmol) of 12N hydrochloric acid, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration and washed with a small amount of ethanol and ether to obtain 4020 mg (yield: 92.8%) of the desired product as orange crystals. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.82-2.06 (m 2H) 2.09-
2.31 (m 2H) 3.02-3.42 (m 6H) 3.46-3.82 (m 6H) 6.65
(d 1H J = 7.4 Hz) 7.02 (d 1H J = 9.2 Hz) 7.28 (s1H)
7.32 (dd 1H J = 9.2 Hz, 7.4 Hz) 7.70 (s 1H) 9.07 (t
1H J = 5.6 Hz). 3) N- [3- (4-benzyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5 Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide N- [3- (hexahydro-1,4-diazepine-1-
Yl) propan-1-yl] -5-thia-1,8-diazaacenaphthylene-4-carboxamide.trihydrochloride 60
6.9 mg (1.3 mmol) and benzyl bromide 3
42.1 mg (2.0 mmol) in ethanol 10 ml
, And 0.91 ml (6.5 mmol) of triethylamine was added, and the mixture was heated under reflux overnight. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate: methanol =
2: 3) and purified as dark red liquid.
20.0 mg, 55.0%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.60-1.75 (2H, m), 1.75-1.
95 (2H, m), 2.60-2.85 (10H, m), 3.37-3.45 (2H, m), 3.
63 (2H, s), 5.71 (1H, dd, J = 1.7, 6.1Hz), 6.54-6.66 (3
H, m), 6.96 (1H, s), 7.20-7.35 (5H, m), 8.40 (1H, br
s). IR (neat): 3286, 3059, 2933, 2818, 1618, 1547, 150
8, 1481, 1452, 1348, 1281, 1213, 1155, 1120, 773,
733, 700, 650cm ^-1 .

4) N- [3- (4-benzyl-2,3,
5,6-tetrahydro-7H-1,4-diazepine-1
-Yl) propan-1-yl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide trihydrochloride N- [3- (4-benzyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propane-1 -Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide in a solution of 320.0 mg (0.71 mmol) of ethanol (10 ml) in 2 ml of a 4N hydrogen chloride / ethyl acetate solution (8.0 mmol) ) Was added and the mixture was heated and stirred for 2 hours. Ether was added to the ethanol solution in which the crystals were precipitated, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give the desired product (390.9 mg, 94%) as pale orange crystals. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.90-2.20 (2H, m), 2.20-2.5
0 (2H, m), 3.15-4.10 (12H, m), 4.40-4.60 (2H, m), 6.5
0-6.70 (1H, m), 6.90-7.10 (2H, m), 7.30-7.70 (7H, m). IR (KBr): 3425, 3064, 2949, 2603, 1633, 1566, 1535,
1500, 1454, 1389, 1296, 1215, 785, 700, 631, 59
9, 525 cm ^-1 . Elemental analysis (as C ₂₅ H ₃₂ N ₅ OSCl ₃ · 1.5 H ₂ O) Calculated: C; 51.42, H; 6.04, N; 11.99. Found: C; 51.20, H; 5.96 , N; 11.75.

Example 65 N- [3- (4-Phenethyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-1 , 8b-Diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as in 3) of Example 64, N-
[3- (4-phenethyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.60-1.75 (2H, m), 1.80-1.
95 (2H, m), 2.60-2.90 (14H, m), 3.35-3.50 (2H, m), 5.
71 (1H, d, J = 6.6Hz), 6.50-6.70 (3H, m), 6.97 (1H, s),
7.10-7.35 (5H, m), 8.25-8.35 (1H, m). IR (KBr): 3269, 3055, 2933, 2806, 1643, 1620, 1556,
1514, 1481, 1454, 1369, 1282, 1225, 1151, 1117, 7
^{77, 750, 700, 669cm -1} . 2) in the same manner as in 4) of Example 64, an orange crystalline N-
[3- (4-phenethyl-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propane-
1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.95-2.20 (2H, m), 2.30-2.
50 (2H, m), 3.10-3.25 (2H, m), 3.25-4.10 (14H, m), 6.
62 (1H, d, J = 7.6Hz), 6.97-7.03 (2H, m), 7.20-7.45 (6
H, m), 7.54 (1H, s). IR (KBr): 3425, 3062, 2945, 2659, 2727, 1632, 1564,
1537, 1502, 1456, 1392, 1296, 1215, 1107, 785, 7
. 02cm ^-1 Elemental analysis _{(C 26 H 34 N 5 OSCl} 3 · 2.0H 2 O ) Calculated values: C; 51.44, H; 6.31 , N; 11.54 Found:. C; 51.48, H; 6.24, N 11.62.

Example 66 N- [3- (4- (3-phenylpropan-1-yl)
-2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) As in 3) of Example 64, N
-[3- (4- (3-phenylpropan-1-yl)-
2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.60-1.95 (6H, m), 2.45-2.
80 (14H, m), 3.37-3.45 (2H, m), 5.72 (1H, dd, J = 1.4,
6.4Hz), 6.52-6.66 (3H, m), 6.98 (1H, s), 7.10-7.35 (5
H, m), 8.36 (1H, brs). IR (neat): 3280, 3059, 3024, 2937, 2818, 1616, 154
5, 1481, 1342, 1281, 1215, 1155, 1120, 1034, 966,
868, 752, 700, 652, 606, 503, 473 cm ⁻¹ . 2) In the same manner as in 4) of Example 64, N-
[3- (4- (3-phenylpropan-1-yl)-
2,3,5,6-tetrahydro-7H-1,4-diazepin-1-yl) propan-1-yl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.95-2.55 (6H, m), 2.65-2.
90 (2H, m), 3.20-4.20 (14H, m), 6.50-6.70 (1H, m), 6.
90-7.15 (2H, m), 7.15-7.45 (6H, m), 7.50-7.60 (1H,
m). IR (KBr): 3394, 3061, 2947, 2659, 1633, 1564, 1537,
1502, 1456, 1392, 1296, 1215, 1107, 787, 756, 70
2cm ^-1 . Elemental analysis value (as C ₂₇ H ₃₆ N ₅ OSCl ₃ .1.0H ₂ O) Calculated value: C; 52.98, H; 6.42, N; 11.44. Found: C; 52.79, H; 6.61, N 11.37.

Example 67 N- [1- (3- (2-fluorophenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- (3- (2-fluorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5 Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide Under a nitrogen atmosphere, 2-fluorophenylpropanol 49
9 mg (3.24 mmol) and triethylamine 0.2.
90 ml (6.47 mmol) of methylene chloride (6 m
l) 0.38 ml of methanesulfonyl chloride at 0 ° C.
(4.90 mmol) was added and stirred at that temperature for 20 minutes. Saturated aqueous sodium bicarbonate was added to the reaction system to stop the reaction,
Extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.722 g (3.24 mmol) of 2-fluorophenylpropyl mesylate. N- (piperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride
58 g (1.5 mmol) and triethylamine 1.0
ml (7.2 mmol) of ethanol solution at room temperature.
-Fluorophenylpropyl mesylate 0.60 g
(2.69 mmol), and the mixture was heated and refluxed for 16 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 20-50%) gave the desired product. Red-purple amorphous substance Yield 347 mg (54% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-2.05 (m 9H) 2.38 (t
J = 7.7 Hz 2H) 2.65 (tJ = 7.5 Hz 2H) 2.94 (br d J = 11.
8 Hz 2H) 3.20 (t J = 6.1 Hz 2H) 5.78 (dd J = 1.8, 6.0
Hz 1H) 5.89-6.03 (m 1H) 6.57-6.69 (m 3H) 6.92-7.2
1 (m 5H).

2) N- [1- (3- (2-Fluorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride N- [1- (3- (2-fluorophenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
347 mg (0.8 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide in ethanol (4 ml)
1.0 ml of a 4N hydrogen chloride / methanol solution (4.
0 mmol) was added. After evaporating the solvent under reduced pressure, ethanol and diethyl ether were added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield: 360 mg (86% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.36-2.09 (m 7H) 2.66
(t J = 7.9 Hz 2H) 2.72-3.48 (m 8H) 6.57 (d J = 7.4 Hz
1H) 6.95 (d J = 8.8 Hz 1H) 7.11-7.39 (m 6H) 7.61 (s
1H) 8.83-8.90 (m 1H). IR (KBr): 3462, 3057, 2951, 2696, 1643, 1535, 149
7, 1443, 1290, 1221,800 cm -1 Elemental analysis _{(C 25 H 29 N 4 OSCl} 2 F · 1.0H 2 O ) Calculated values:. C, 55.45; H, 5.77; N, 10.35 Found: C, 55.60; H, 5.80; N, 10.13.

Example 68 N- [1- (2-Fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 67 1), a red solid N-
[1- (2-Fluorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20
-1.45 (2H, m), 1.45-1.80 (3H, m), 1.95-2.15 (2H, m),
2.50-2.65 (2H, m), 2.82-2.90 (2H, m), 3.04 (2H, brd,
J = 11.8Hz), 3.22 (2H, t, J = 6.0Hz), 5.79 (1H, dd, J = 1.
8, 6.2Hz), 5.85-5.95 (1H, m), 6.59-6.71 (3H, m), 6.9
6-7.24 (5H, m). IR (KBr): 3250, 3086, 2927, 1639, 1618, 1558, 1485,
1286, 1153, 760 cm ^-1 . 2) In the same manner as in 2) of Example 67, N-
[1- (2-Fluorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.45-1.70 (2H, m), 1.80-
2.10 (3H, m), 2.95-3.50 (8H, m), 3.71 (2H, brd, J = 12.
4Hz), 6.60 (1H, d, J = 7.6Hz), 6.99 (1H, d, J = 7.8Hz),
7.01 (1H, s), 7.07-7.20 (2H, m), 7.27-7.43 (3H, m),
7.52 (1H, s). IR (KBr): 3427, 3250, 2933, 2688, 1635, 1566, 1539,
1497, 1439, 1390, 1284, 1209, 779, 761 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ OSFCl ₂ .0.5H ₂ O) Calculated: C; 55.60, H; 5.44, N; 10.81. Found: C; 55.42, H; 5.40, N; 10.73.

Example 69 N- [1- (3-Fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 67 1), a red solid N-
[1- (3-Fluorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (2H, m), 1.45-
1.80 (3H, m), 1.90-2.10 (2H, m), 2.55-2.63 (2H, m),
2.77-2.85 (2H, m), 3.01 (2H, brd, J = 11.4Hz), 3.21 (2
H, t, J = 6.0Hz), 5.78 (1H, dd, J = 2.2, 5.5Hz), 6.20 (1
H, brt, J = 5.5Hz), 6.57-6.69 (3H, m), 6.85-7.02 (4H,
m), 7.18-7.25 (1H, m). IR (KBr): 3315, 2924, 1618, 1547, 1483, 1281, 1148,
775, 733, 692 cm ^-1 . 2) In the same manner as in 2) of Example 67, N-
[1- (3-Fluorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.45-1.70 (2H, m), 1.75-
2.10 (3H, m), 2.90-3.50 (8H, m), 3.60-3.75 (2H, m),
6.62 (1H, d, J = 7.6Hz), 6.95-7.20 (5H, m), 7.30-7.43
(2H, m), 7.53 (1H, s). IR (KBr): 1633, 1566, 1539, 1292, 785cm ^-1 . Elemental analysis (calculated as C ₂₄ H ₂₇ N ₄ OSFCl ₂ · 1.5H ₂ O) Value: C; 53.73, H; 5.64, N; 10.44. Found: C; 53.54, H; 5.91, N; 10.36.

Example 70 N- [1- (4-fluorophenethyl) piperidine-4
Synthesis of -ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1 -(4-fluorophenethyl) piperidine-4
-Ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (2H, m), 1.45-
1.80 (3H, m), 1.90-2.10 (2H, m), 2.50-2.59 (2H, m),
2.74-2.82 (2H, m), 3.01 (2H, brd, J = 11.8Hz), 3.21 (2
H, t, J = 6.0Hz), 5.78 (1H, dd, J = 2.0, 5.6Hz), 6.09 (1
H, brt, J = 5.6Hz), 6.58-6.69 (3H, m), 6.91-7.03 (3H,
m), 7.11-7.27 (2H, m). IR (KBr): 3352, 2927, 1618, 15
456, 1510, 1481, 1282, 12
19, 1153, 827, 773, 731 cm
^-1 . 2) In the same manner as in 2) of Example 67, N-
[1- (4-Fluorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.4
5-1.75 (2H, m), 1.75-2.10 (3H, m), 2.90-3.45 (8H, m),
3.60-3.75 (2H, m), 6.61 (1H, d, J = 7.8Hz), 6.97-7.11
(4H, m), 7.29-7.42 (3H, m), 7.52 (1H, s). IR (KBr): 3431, 3246, 3061, 2935, 2690, 1632, 1566,
1541, 1510, 1439, 1389, 1288, 1215, 831, 783 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ OSFCl ₂ · 0.5 H ₂ O) Calculated: C; 55.60, H; 5.44, N; 10.81. Found: C; 55.83, H; 5.27, N; 11.02.

Example 71 N- [1- (2-chlorophenethyl) piperidine-4-
Synthesis of ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (2-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.47 (2H, m), 1.47-
1.80 (3H, m), 2.00-2.20 (2H, m), 2.56-2.64 (2H, m),
2.90-3.09 (4H, m), 3.23 (2H, t, J = 5.8Hz), 5.79 (1H, d
d, J = 1.8, 6.0Hz), 5.94 (1H, brt, J = 5.5Hz), 6.59-6.7
1 (3H, m), 7.05 (1H, s), 7.10-7.40 (4H, m). IR (KBr): 3309, 2924, 1618, 1543, 1510, 1479, 1282,
1155, 771, 754, 732 cm ⁻¹ . 2) In the same manner as in 2) of Example 67, N-
[1- (2-Chlorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.45-1.75 (2H, m), 1.80-
2.10 (3H, m), 2.95-3.45 (8H, m), 3.65-3.80 (2H, m),
6.61 (1H, d, J = 7.8Hz), 6.99 (1H, d, J = 7.8Hz), 7.01 (1
H, s), 7.25-7.50 (5H, m), 7.53 (1H, s). IR (KBr): 3429, 2945, 2710, 1653, 1635, 1564, 1537,
1502, 1282, 773, 754 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ OSCl ₃ .0.5H ₂ O) Calculated: C; 53.89, H; 5.28, N; 10.47. Found: C; 53.74 , H; 5.09, N; 10.52.

Example 72 N- [1- (3-Chlorophenethyl) piperidine-4-
Synthesis of ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) As in 1) of Example 67, N- [1- (3-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (2H, m), 1.45-
1.80 (3H, m), 1.90-2.15 (2H, m), 2.53-2.60 (2H, m),
2.74-2.82 (2H, m), 3.00 (2H, brd, J = 11.8Hz), 3.21 (2
H, t, J = 6.0Hz), 5.78 (1H, dd, J = 1.8, 6.0Hz), 5.95-
6.05 (1H, m), 6.58-6.69 (3H, m), 7.03-7.09 (2H, m),
7.10-7.20 (3H, m). IR (KBr): 3327, 2926, 1618, 1545, 1481, 1282, 1153,
687 cm ⁻¹ . 2) In the same manner as in 2) of Example 67, N-
[1- (3-Chlorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.45-1.75 (2H, m), 1.75-
2.10 (3H, m), 2.90-3.50 (8H, m), 3.60-3.75 (2H, m),
6.62 (1H, d, J = 7.6Hz), 6.97-7.02 (2H, m), 7.20-7.45
(5H, m), 7.53 (1H, s). IR (KBr): 1633, 1566, 1537, 1504, 1292, 1215, 785cm
. ^-1 Elemental analysis _{(C 24 H 27 N 4 OSCl} 3 · 1.5H as ₂ O) Calculated: C; 52.13, H; 5.47 , N; 10.13 Found:. C; 52.47, H; 5.53, N; 10.23.

Example 73 N- [1- (4-chlorophenethyl) piperidine-4-
Synthesis of ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (4-chlorophenethyl) piperidine-4-
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.2
0-1.45 (2H, m), 1.45-1.80 (3H, m), 1.90-2.10 (2H, m),
2.50-2.60 (2H, m), 2.70-2.85 (2H, m), 3.00 (2H, brd,
J = 11.4Hz), 3.22 (2H, t, J = 6.1Hz), 5.79 (1H, dd, J =
1.9, 6.1Hz), 5.94 (1H, brt, J = 5.9Hz), 6.59-6.72 (3H,
m), 7.05-7.14 (3H, m), 7.22-7.27 (2H, m). IR (KBr): 3282, 3055, 2924, 2806, 1616, 1549, 1485,
1282, 1153, 1119, 1092, 970, 773, 731 cm- ¹ . 2) In the same manner as in 2) of Example 67, N-
[1- (4-Chlorophenethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.40-1.75 (2H, m), 1.75-
2.10 (3H, m), 2.90-3.50 (8H, m), 3.60-3.75 (2H, m), 6
6.1 (1H, d, J = 7.4Hz), 6.99 (1H, d, J = 8.8Hz), 7.00 (1
H, s), 7.25-7.45 (5H, m), 7.53 (1H, s). IR (KBr): 3425, 3061, 2935, 2731, 1633, 1566, 1537,
1498, 1292, 1215, 785 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ OSCl ₃ .1.5 H ₂ O) Calculated: C; 52.13, H; 5.47, N; 10.13. Found: C; 51.90 , H; 5.54, N; 10.10.

Example 74 N- [1- (3- (3-fluorophenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Similar to 1) of Example 67, N- [1- (3- (3-fluoro) Phenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.30-1.97 (m 9H) 2.31-2.
38 (m 2H) 2.62 (t J = 7.5 Hz 2H) 2.93 (br d J = 11.8 H
z 2H) 3.21 (t J = 6.0 Hz 2H) 5.79 (dd J = 1.7, 6.1 Hz
1H) 5.77-5.85 (m 1H) 6.58-6.70 (m 3H) 6.81-6.96
(m 3H) 7.05 (s 1H) 7.11-7.25 (m 1H). 2) In the same manner as in Example 67-2), orange N-
[1- (3- (3-fluorophenyl) propane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-2.13 (m 7H) 2.66
(t J = 7.6 Hz 2H) 2.70-3.28 (m 8H) 6.62 (d J = 7.2 Hz
1H) 6.93-7.40 (m 7H) 7.66 (s 1H) 8.86-8.97 (m 1H). IR (KBr): 3417, 3064, 2941, 1635, 1574, 1535, 129
4,787 cm ^-1

Example 75 N- [1- (3- (4-fluorophenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (4-fluoro) Phenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.30-2.47 (m 11H) 2.61
(t J = 7.7 Hz 2H) 3.02 (br d J = 12Hz 2H) 3.21 (t J = 5.9
Hz 2H) 5.76-5.80 (m 1H) 6.04-6.20 (m 1H) 6.57-6.6
8 (m 2H) 6.74 (s 1H) 6.92-7.17 (m 5H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (4-fluorophenyl) propane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.04 (m, 6H), 2.53
-3.10 (m 11H) 6.55 (dJ = 7.6 Hz 1H) 6.94 (d J = 9.2 H
(z 1H) 7.08-7.31 (m 6H) 7.57 (d J = 1.2 Hz 1H) 8.78-8.
. 88 (m 1H) IR ( KBr): 1639, 1508, 1294, 1221 cm -1 Elemental analysis _{(C 25 H 29 N 4 OSCl} 2 F · 0.5H 2 O ) Calculated values: C, 56.39; H, 5.68; N, 10.52. Found: C, 56.47; H, 5.85; N, 10.61.

Example 76 N- [1- (3- (2,4-difluorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (2 , 4-Difluorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.16 to 2.05 (m 8H) 2.34 (t
(J = 7.7 Hz 2H) 2.60 (tJ = 7.7 Hz 2H) 2.69 (m 1H) 2.91
(br d J = 12 Hz 2H) 3.18 (t J = 6.1 Hz 2H) 5.76 (dd J
= 2.8, 5.0 Hz 1H) 6.39 (m 1H) 6.56-6.82 (m 5H) 6.98
(s 1H) 7.07-7.18 (m 1H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (2,4-Difluorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride is obtained. Was. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-2.06 (m 7H) 2.60-
3.49 (m 10 H) 6.56 (dJ = 7.6 Hz 1H) 6.95 (d J = 8.8 Hz
1H) 7.00-7.46 (m 5H) 7.60 (s 1H) 8.82-8.90 (m 1H). IR (KBr): 3415, 3056, 2943, 2700, 1635, 1504, 128
8 cm ^-1 Elemental analysis value (as C ₂₅ H ₂₈ N ₄ OSCl ₂ F ₂ · 1.0 H ₂ O) Calculated value: C, 53.67; H, 5.40; N, 10.01. Actual value: C, 53.97; H, 5.28 N, 10.11.

Example 77 N- [1- (3- (2-chlorophenyl) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In a manner similar to 1) of Example 67, N- [1- (3- (2-chlorophenyl) ) Propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17-
2.05 (m 9H) 2.39 (t J = 7.6 Hz 2H) 2.74 (t J = 7.7 Hz
2H) 2.94 (br d J = 11.4 Hz 2H) 3.20 (t J = 6.1 Hz 2H)
5.78 (dd J = 1.8,6.0 Hz 1H) 5.97 (m 1H) 6.57-6.70
(m 3H) 7.03 (s 1H) 7.06-7.37 (m 4H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (2-Chlorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.23 (m 7H) 2.65
-3.70 (m 10 H) 6.49-6.53 (d J = 7.4 Hz 1H) 6.92 (d J
= 9.4 Hz 1H) 7.08-7.46 (m 6H) 7.55 (s 1H) 8.75-8.80
(m 1H). IR (KBr): 3452, 3375, 3055, 2951,2690, 1641, 153
1, 1439, 1288, 1217, 800 cm -1 Elemental analysis _{(C 25 H 29 N 4 OSCl} 3 · 0.6H as ₂ O) Calculated:. C, 54.51; H, 5.52; N, 10.17 Found: C H, 5.71; N, 9.90.

Example 78 N- [1- (3- (3-chlorophenyl) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (3-chlorophenyl) ) Propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18-2.00 (m 9H) 2.29-2.
37 (m 2H) 2.59 (t J = 7.5 Hz 2H) 2.91 (br d J = 11.4 H
z 2H) 3.18 (t J = 6.1 Hz 2H) 5.76 (dd J = 2.4, 5.4 Hz
1H) 6.29 (br t J = 5.9 Hz 1H) 6.59-6.66 (m 3H) 7.00
(s 1H) 7.03-7.07 (m 1H) 7.12-7.24 (m 3H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (3-chlorophenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.12 (m 7H) 2.65
(t J = 7.7 Hz 2H) 2.72-3.26 (m 6H) 3.38-3.50 (m 2H)
6.61 (d J = 7.4 Hz 1H) 6.97 (d J = 9.2 Hz 1H) 7.21-7.
. 39 (m 6H) 7.65 ( s 1H) 8.89-8.99 (m 1H) IR (KBr): 3442, 1637, 1292, 1213, 793 cm -1 Elemental analysis _{(C 25 H 29 N 4 OSCl} 3 · 1.0H ₂ O) calculated values:. C, 53.82; H, 5.60; N, 10.04 Found: C, 54.07; H, 5.80 ; N, 9.79.

Example 79 N- [1- [3- (4-chlorophenyl) propane-1
-Yl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) As in 1) of Example 67, N-
[1- [3- (4-Chlorophenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.45-1.83 (5H, m), 1.85-
2.03 (2H, m), 2.15-2.30 (2H, m), 2.53-2.67 (4H, m), 3.1
0-3.24 (4H, m), 5.754 (1H, dd, J = 2.4, 5.3Hz), 6.50-6.7
0 (3H, m), 6.822 (1H, s), 7.05-7.15 (3H, m), 7.22-7.30
(2H, m). 2) In the same manner as in 2) of Example 67, N-
[1- [3- (4-Chlorophenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.95 (4H, m), 1.90
-2.15 (2H, m), 2.58-2.70 (2H, m), 2.70-3.30 (5H, m),
3.40-3.55 (2H, m), 6.685 (1H, d, J = 7.6Hz), 7.017 (1H,
d, J = 7.6Hz), 7.017 (1H, d, J = 9.2Hz), 7.24-7.39 (5H, m),
7.720 (1H, s), 8.90-9.10 (1H, m), 10.588 (1H, br s). IR (KBr): 3420, 3250, 3050, 2950, 2850, 2720, 267
0, 2600, 2550, 1650, 1630, 1560, 1530, 1500, 1440,
1280, 1220, 1090, 780 cm ^-1 . Elemental analysis (as C ₂₅ H ₂₉ N ₄ OSCl ₃ .1.5 H ₂ O) Calculated: C, 52.96; H, 5.69; N, 9.88. 53.43; H, 5.71; N, 9.59.

Example 80 N- [1- (3- (2-methoxyphenyl) propane-
1-yl) piperidin-4 | ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (2-methoxy) Phenyl) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-2.00 (m 9H) 2.35-2.
43 (m 2H) 2.61 (t J = 7.7 Hz 2H) 2.96 (br d J = 11.4 H
z 2H) 3.18 (t J = 5.9 Hz 2H) 3.81 (s 3H) 5.74-5.78
(m 1H) 6.16-6.30 (m 1H) 6.55-6.67 (m 3H) 6.78-6.8
9) (m 2H) 6.99-7.20 (m 3H). 2) In the same manner as in Example 67-2), orange N-
[1- (3- (2-methoxyphenyl) propane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-2.00 (m 7H) 2.53-
3.26 (m 8H) 3.38-3.47 (m 2H) 3.79 (s 3H) 6.56 (d J =
7.2 Hz 1H) 6.83-6.98 (m 3H) 7.13-7.27 (m 4H) 7.60
(s 1H) 8.80-8.92 (m 1H). IR (KBr): 3463, 3390, 2948, 2
702, 1638, 1533, 1498, 14
^{41, 1290, 802, 764 cm} -1 Elemental analysis _{(C 26 H 32 N 4 OSCl} 2 · 1.0H 2 O ) Calculated values:. C, 56.41; H, 6.19; N, 10.12 Found: C, 56.69 H, 6.24; N, 10.07.

Example 81 N- [1- [3- (4-methoxyphenyl) propane-
1-yl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) As in 1) of Example 67, N-
[1- [3- (4-methoxyphenyl) propane-1-
Yl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.95 (9H, m), 2.29-
2.36 (2H, m), 2.52-2.60 (2H, m), 2.86-2.96 (2H, m), 3.20
4 (2H, t, J = 6.2Hz), 3.786 (3H, s), 5.791 (1H, dd, J = 1.8,
6.2Hz), 5.70-5.82 (1H, m), 6.632-6.692 (3H, m), 6.818
(2H, d, J = 8.6), 7.054 (1H, s), 7.093 (2H, d, J = 8.8 Hz). 2) In the same manner as in Example 67-2), orange N-
[1- [3- (4-methoxyphenyl) propane-1-
Yl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ^{1 H-NMR (200MHz, DMSO} -d 6) δ: 1.45-2.10 (7H, m), 2.50-
2.60 (2H, m), 2.70-3.30 (6H, m), 3.37-3.51 (2H, m), 3.7
28 (3H, s), 6.604 (1H, d, J = 7.4Hz), 6.867 (2H, d, J = 8.0),
6.973 (1H, d, J = 9.2), 7.13-7.32 (4H, m), 7.643 (1H, s),
8.90-8.96 (1H, m). IR (KBr): 3420, 3280, 2980, 2930, 2670, 1635, 156
0, 1530, 1510, 1460, 1280, 1260, 1240, 1220, 1030,
780 cm ^-1 . Elemental analysis (as C ₂₆ H ₃₂ N ₄ O ₂ SCl ₂ .1H ₂ O) Calculated: C, 56.41; H, 6.19; N, 10.12. Actual: C, 56.09; H, 6.36 N, 10.00.

Example 82 N- [1- (3- (2,3-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (2 , 3-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.15-1.98 (m 9H) 2.34-2.
42 (m 2H) 2.54-2.69 (m2H) 2.85-2.99 (m 2H) 3.17 (t
J = 6.0 Hz 2H) 3.81 (s 3H) 3.85 (s 3H) 5.73-5.78 (m
1H) 6.52-6.65 (m 4H) 6.75-6.79 (m 2H) 6.92-6.99
(m 2H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (2,3-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride is obtained. Was. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-2.03 (m 7H) 2.55-
3.07 (m 8H) 3.38-3.49 (m 2H) 3.73 (s 3H) 3.80 (s 3
H) 6.58 (d J = 7.8 Hz 1H) 6.78-7.03 (m 4H) 7.14-7.29
(m 2H) 7.61 (s 1H) 8.81-8.90 (m 1H). Elemental analysis (calculated as C ₂₇ H ₃₄ N ₄ O ₃ SCl ₂ .2.0H ₂ O) Calculated: C, 53.91; H, 6.37; N , 9.31. Found: C, 53.98; H, 6.66; N, 9.06.

Example 83 N- [1- (3- (2,4-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (2 , 4-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.97 (m 9H) 2.33-2.
41 (m 2H) 2.53 (t J = 7.6 Hz 2H) 2.95 (br d J = 11.4 H
z 2H) 3.18 (t J = 6.0 Hz 2H) 3.78 (s 3H) 3.79 (s 3H)
5.76 (dd J = 2.4, 5.6 Hz 1H) 6.26-6.43 (m 3H) 6.60-
6.68 (m 3H) 6.99-7.03 (m 2H). 2) In the same manner as in Example 67-2), orange N-
[1- (3- (2,4-Dimethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride is obtained. Was. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39-1.95 (m 7H) 2.65-
3.25 (m 8H) 3.37-3.45 (m 2H) 3.74 (s 3H) 3.78 (s 3
H) 6.43-6.55 (m 3H) 6.92 (d J = 9.0 Hz 1H) 7.04-7.24
(m 3H) 7.57 (s 1H) 8.77-8.84 (m 1H). IR (KBr): 3429, 1633, 1508, 1292, 1209, 787 cm ^-1 Elemental analysis (C ₂₇ H ₃₄ N ₄ O ₃ SCl ₂・ As 2.5H ₂ O) Calculated: C, 53.11; H, 6.44; N, 9.18. Found: C, 53.30; H, 6.65; N, 9.18.

Example 84 N- [1- [3- (4-ethylphenyl) propane-1
-Yl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) As in 1) of Example 67, N-
[1- [3- (4-Ethylphenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.220 (3H, t, J = 7.6 Hz), 1.2
5-1.38 (1H, m), 1.40-2.05 (8H, m), 2.32-2.39 (2H, m),
2.54-2.67 (4H, m), 2.88-2.95 (2H, m), 3.196 (2H, t, J = 6.1
Hz), 5.778 (1H, dd, J = 1.8, 6.1Hz), 5.85-5.93 (1H, m),
6.573-6.695 (3H, m), 7.034 (1H, s), 7.097 (4H, s). 2) In the same manner as in Example 67-2), orange crystal N-
[1- [3- (4-Ethylphenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.159 (3H, t, J = 7.5 Hz),
1.43-1.85 (5H, m), 1.90-2.10 (2H, m), 2.45-2.65 (4H, m),
2.75-3.25 (5H, m), 3.35-3.55 (3H, m), 6.603 (1H, d, J =
7.4Hz), 6.970 (1H, d, J = 9.2Hz), 7.14-7.31 (5H, m), 7.64
3 (1H, s), 8.85-9.00 (1H, m), 10.47 (1H, br s). IR (KBr): 3400, 3250, 3050, 2950, 2920, 2730, 163
0, 1560, 1530, 1500, 1440, 1390, 1290, 1110, 1045,
. 945, 780 cm ^-1 Elemental analysis _{(C 27 H 34 N 4 O} 2 SCl 2 · 1H 2 as O) Calculated:. C, 58.79; H, 6.58; N, 10.16 Found: C, 58.64; H , 6.62; N, 9.62.

Example 85 N- [1- (3- (2-trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as 1) of Example 67, N- [1- (3- (2-trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18-2.05 (m 9H) 2.30-2.
38 (m 2H) 2.68 (t J = 7.5 Hz 2H) 2.85-3.01 (m 2H) 3.
21 (t J = 6.2 Hz 2H) 5.79 (dd J = 1.8, 6.0 Hz 1H) 5.65
-5.90 (m 1H) 6.59 -6.71 (m 3H) 7.05 (s 1H) 7.28 (d
J = 8.0 Hz 2H) 7.53 (d J = 8.0 Hz 2H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (2-trifluoromethylphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.30-2.10 (m 7H) 2.68-
3.52 (m 10H) 6.51 (d J = 7.4 Hz 1H) 6.91 (d J = 8.8 Hz
1H) 7.08 (s 1H) 7.14-7.22 (m 1H) 7.41-7.73 (m 5H)
8.72-8.86 (m 1H). IR (KBr): 3425, 3250, 3059, 2947, 2710, 1637, 130
8, 1115, 779 cm ^-1 Elemental analysis (as C ₂₆ H ₂₉ N ₄ OSCl ₂ F ₃ .1.5H ₂ O) Calculated: C, 52.00; H, 5.37; N, 9.33. Found: C, 51.77 H, 5.28; N, 9.10.

Example 86 N- [1- (3- (3-trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as 1) of Example 67, N- [1- (3- (3-trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18-2.03 (m 9H) 2.30-2.
37 (m 2H) 2.68 (t J = 7.6 Hz 2H) 2.88-2.94 (m 2H) 3.
20 (t J = 6.0 Hz 2H) 5.78 (dd J = 1.9, 5.9 Hz 1H) 6.07
(br t J = 5.9 Hz 1H) 6.62-6.68 (m 3H) 7.02 (s 1H)
7.35-7.48 (m 4H). 2) In the same manner as in 2) of Example 67, N- [1- (3- (3-trifluoromethylphenyl) propan-1-yl) piperidin-4- of orange crystals was obtained.
Ilmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.19-2.08 (m 7H) 2.68-
3.52 (m 10H) 6.60 (d J = 7.2 Hz 1H) 6.96 (d J = 8.6 Hz
1H) 7.17-7.31 (m 2H) 7.58-7.64 (m 5H) 8.86-8.97
(m 1H). IR (KBr): 3423, 3060, 2942, 1637, 1329, 1120, 791
cm ^-1 Elemental analysis _{(C 26 H 29 N 4 OSCl} 2 F 3 · 2.0H 2 O ) Calculated values:. C, 51.23; H, 5.46; N, 9.19 Found: C, 51.25; H, 5.45 ; N, 9.17.

Example 87 N- [1- (3- (4-trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as 1) of Example 67, N- [1- (3- (4 -Trifluoromethylphenyl)
Propan-1-yl) piperidin-4-ylmethyl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18-2.05 (m 9H) 2.30-2.
38 (m 2H) 2.68 (t J = 7.5 Hz 2H) 2.85-3.01 (m 2H) 3.
21 (t J = 6.2 Hz 2H) 5.79 (dd J = 1.8, 6.0 Hz 1H) 5.65
-5.90 (m 1H) 6.59 -6.71 (m 3H) 7.05 (s 1H) 7.28 (d
J = 8.0 Hz 2H) 7.53 (d J = 8.0 Hz 2H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (4-trifluoromethylphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.36-2.18 (m 7H) 2.74
(t J = 7.6 Hz 2H) 2.70-3.23 (m 6H) 3.41-3.53 (m 2H)
6.64 (d J = 7.0 Hz 1H) 6.99 (d J = 8.4 Hz 1H) 7.16-7.
23 (m 1H) 7.30 (dd J = 7.0, 8.4 Hz 1H) 7.49 (d J = 8.0
Hz 2H) 7.677 (s1H) 2.782 (d J = 8.0 Hz 2H) 8.87-9.0
0 (m 1H). IR (KBr): 3398, 3057, 2941, 2673, 1635, 1327, 111
9, 785 cm ^-1 Elemental analysis (as C ₂₆ H ₂₉ N ₄ OSCl ₂ F ₃ .1.5H ₂ O) Calculated: C, 52.00; H, 5.37; N, 9.33. Found: C, 51.87; H , 5.16; N, 9.47.

Example 88 N- [1- (3- (3-trifluoromethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N-
[1- (3- (3-trifluoromethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.38 (2H, m), 1.42-
1.60 (1H, m), 1.62-2.00 (6H, m), 2.335 (2H, t, J = 7.5Hz),
2.645 (2H, t, J = 7.7Hz), 2.915 (2H, d, J = 11.8Hz), 3.207
(2H, t, J = 6.1Hz), 5.790 (1H, dd, J = 1.8, 6.2Hz), 5.78-
5.85 (1H, m), 6.58-6.71 (3H, m), 7.00-7.13 (4H, m), 7.2
3-7.339 (1H, m). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (3-trifluoromethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.95 (5H, m), 1.95
-2.15 (2H, m), 2.61-3.23 (8H, m), 3.451 (2H, d like, J = 1
1.4Hz), 6.685 (1H, d, J = 7.6Hz), 7.020 (1H, d, J = 9.2H
z), 7.15-7.50 (6H, m), 7.719 (1H, s), 9.065 (1H, t lik
e, J = 5.5Hz), 10.5 (1H, brs). IR (KBr): 3420, 2950, 2720, 2550, 1635, 1565, 153
5, 1500, 1440, 1395, 1280, 1220, 1150, 790, 740,
700, 630, 600 cm ^-1 . Elemental analysis (as C ₂₆ H ₂₉ N ₄ O ₂ SCl ₂ F ₃ .1.5H ₂ O) Calculated: C, 50.65; H, 5.23; N, 9.09. C, 50.32; H, 5.63; N, 8.81.

Example 89 N- [1- (3- (4-Trifluoromethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Synthesis of carboxamide dihydrochloride 1) N- [1- (3- (4-trifluoromethoxyphenyl) propan-1-yl) piperidine of magenta amorphous substance in the same manner as 1) of Example 67 -4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.32-2.21 (m
9H) 2.44-2.52 (m2H) 2.6
4 (tJ = 7.6 Hz 2H) 3.03-3.
09 (m2H) 3.19 (tJ = 5.5H
z 2H) 5.75 (dd J = 2.6, 5.4
Hz 1H) 6.41-6.69 (m3H)
6.77 (s1H) 7.01-7.22 (m
5H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (4-Trifluoromethoxyphenyl) propan-1-yl) piperidin-4-ylmethyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ )
δ: 1.38-2.16 (m 7H) 2.67 (t J = 7.6 Hz 2H) 2.70-3.2
6 (m 6H) 3.38-3.52 (m 2H) 6.62 (d J = 7.4 Hz 1H) 6.9
8 (d J = 9.0 Hz 1H) 7.19-7.41 (m 6H) 7.65 (s 1H) 8.
90-8.96 (m 1H) .IR (KBr): 3375, 3062, 2942, 2710, 1637, 1506, 1269,
1217, 1161, 787 cm ^-1 Elemental analysis value (as C ₂₆ H ₂₉ N ₄ O ₂ SCl ₂ F ₃ .1.5H ₂ O) Calculated value: C, 50.65; H, 5.23; N, 9.09. H, 5.20; N, 8.87.

Example 90 N- [1- [3- (4-hydroxyphenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -Synthesis of dihydrochloride 1) In the same manner as in 1) of Example 67, N-
[1- [3- (4-tert-Butyldimethylsiloxyphenyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.178 (6H, s), 0.978 (9H,
s), 1.20-1.42 (2H, m), 1.42-2.05 (7H, m), 2.28-2.90 (2
H, m), 2.544 (2H, t like, J = 7.5Hz), 2.88-3.00 (2H, m),
3.202 (2H, t like, J = 6.0Hz), 5.785 (1H, d, J = 6.6Hz), 5.
80-5.95 (1H, m), 6.59-6.76 (5H, m), 6.90-7.05 (3H, m). 2) In the same manner as in Example 67-2), orange N-
[1- [3- (4-hydroxyphenyl) propane-1
-Yl] piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.10 (7H, m), 2.65
-3.20 (7H, m), 3.33-353 (3H, m), 6.61-6.78 (3H, m), 6.90
-7.05 (3H, m), 7.15-7.35 (2H, m), 7.671 (1H, s), 8.85-9.0
3 (1H, m), 10.4 (1H, brs). IR (KBr): 3420, 3250, 2950, 2930, 1650, 1635, 161
0, 1560, 1540, 1520, 1500, 1290, 1220, 800 cm ^-1 . Elemental analysis (as C ₂₅ H ₃₀ N ₄ O ₂ SCl ₂ · 1.0 H ₂ O) Calculated: C, 55.66; H, 5.98 N, 10.38. Found: C, 55.81; H, 5.91 N, 10.07.

Example 91 N- [1- (3- (4-biphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
b) Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3- (4-biphenyl) propane -1-yl) piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33-2.16 (m 9H) 2.49-2.
56 (m 2H) 2.68 (t J = 7.7 Hz 2H) 3.08 (br d J = 11.8 H
z 2H) 3.19 (t J = 5.9 Hz 2H) 5.73 (dd J = 2.2, 5.6 Hz
1H) 6.53-6.72 (m 3H) 6.77 (s 1H) 7.01 (s 1H) 7.23
-7.60 (m 9H). 2) In the same manner as in 2) of Example 67, the orange amorphous substance N
-[1- (3- (4-biphenyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-2.17 (m 7H) 2.60-
3.52 (m 10H) 6.52 (d J = 7.4 Hz 1H) 6.92 (d J = 8.2 Hz
1H) 7.10-7.66 (m 12H) 8.72-8.84 (m 1H). IR (KBr): 3425, 1635, 1292, 1213, 775 cm ^-1 Elemental analysis (C ₃₁ H ₃₄ N ₄ OSCl ₂・ 2.0H ₂ Calculated: C, 60.28; H, 6.20; N, 9.07. Found: C, 60.10; H, 6.28; N, 8.79.

Example 92 N- [1- (1-Naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Example 67 In the same manner as 1), the dark red amorphous substance N- [1- (1-naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide is used. Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.15-1.40 (2H, m), 1.45-1.
80 (3H, m), 1.90-2.10 (2H, m), 2.96 (2H, brd, J = 11.0H
z), 3.19 (2H, t, J = 6.1Hz), 3.88 (2H, s), 5.77 (1H, d
d, J = 1.5, 6.3Hz), 5.75-5.90 (1H, m), 6.57-6.70 (3H,
m), 7.04 (1H, s), 7.35-7.65 (4H, m), 7.70-7.90 (2H,
m), 8.20-8.350 (1H, m). IR (KBr): 3319, 3049, 2922, 2806, 2764, 1618, 1541,
1510, 1481, 1367, 1281, 1151, 1113, 970, 773, 73
3, 652 cm ^-1 . 2) In the same manner as in 2) of Example 67, N-
[1- (1-Naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.35-1.65 (2H, m), 1.80-2.
05 (3H, m), 3.10-3.40 (4H, m), 3.50-3.65 (2H, m), 4.8
3 (2H, s), 6.60 (1H, d, J = 7.6Hz), 6.95-7.00 (2H, m),
7.34-7.81 (6H, m), 7.98-8.08 (2H, m), 8.26 (1H, d, J =
8.0Hz). IR (KBr): 3427, 3062, 2935, 2729, 1633, 1564, 1537,
. 1504, 1394, 1296, 1217 , 779, 602cm -1 Elemental analysis _{(C 27 H 28 N 4 OSCl} 2 · 4.0H 2 O ) Calculated values:. C; 54.09, H; 6.05, N; 9.34 Found : C; 54.15, H; 5.79, N; 9.38.

Example 93 Synthesis of N- [1- (2-naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Implementation In the same manner as in Example 67-1), a red-orange solid N-
[1- (2-Naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide was obtained. ¹ H-NMR (CDC) δ: 1.20-1.45 (2H, m), 1.45-1.75 (3H, m),
1.80-2.15 (2H, m), 2.95 (2H, brd, J = 11.4Hz), 3.20 (2H
H, t, J = 5.9Hz), 3.66 (2H, s), 5.77 (1H, d, J = 6.2Hz),
5.80-5.95 (1H, m), 6.57-6.70 (3H, m), 7.03 (1H, s),
7.40-7.55 (3H, m), 7.70-7.90 (4H, m). IR (KBr): 3292, 3257, 3051, 2912, 2800, 1630, 1545,
1512, 1481, 1365, 1335, 1279, 1146, 771, 730 cm ^-1 . 2) In the same manner as in Example 67-2), orange-colored N-
[1- (2-Naphthylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.40-1.70 (2H, m), 1.80-2.
05 (3H, m), 2.95-3.30 (4H, m), 3.45-2.65 (2H, m), 4.4
8 (2H, s), 6.59 (1H, d, J = 7.0Hz), 6.96 (1H, s), 6.97 (1H
(H, d, J = 8.4Hz), 7.33-7.41 (1H, m), 7.50 (1H, s), 7.5
0-7.65 (3H, m), 7.90-8.05 (3H, m), 8.07 (1H, s). IR (KBr): 3427, 3228, 3055, 2933, 2669, 2530, 1632,
1566, 1537, 1502, 1433, 1389, 1290, 1213, 781, 5
98, 478 cm ^-1 . Elemental analysis (as C ₂₇ H ₂₈ N ₄ OSCl ₂ · 1.0 H ₂ O) Calculated: C; 59.45, H; 5.54, N; 10.27. Found: C; 59.52, H; 5.54 , N; 10.27.

Example 94 N- [1- (3- (2-Naphthyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
b) Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- (3- (2-naphthyl) propane, a red-purple amorphous substance, in the same manner as 1) of Example 67 -1-yl) piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.35-1.81 (m
5H) 1.97-2.21 (m4H) 2.5
5-2.64 (m2H) 3.03-3.22 (m
6H) 5.73 (dd J = 2.0, 6.0
Hz 1H) 6.51-6.63 (m3H)
6.79 (s 1H) 7.01 (s 1H)
7.27-7.54 (m4H) 7.71 (br
d J = 8.0 Hz 1H) 7.82-7.87
(M1H) 7.97-8.04 (m1H). 2) In the same manner as in 2) of Example 67, N-
[1- (3- (2-Naphthyl) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ )
δ: 1.39-1.71 (m 5H) 2.03-2.23 (m 2H) 2.70-3.28 (m
8H) 3.37-3.50 (m 2H) 6.60 (d J = 7.2 Hz 1H) 6.97 (d
J = 8.8 Hz 1H) 7.20-7.31 (m 2H) 7.40-7.58 (m 4H) 7.6
5 (s 1H) 7.78-7.83 (m 1H) 7.91-7.96 (m 1H) 8.09-8.1
3 (m 1H) 8.90-9.01 (m 1H) .IR (KBr): 3489, 3394, 3253, 2951, 2698, 1637, 1535,
1292, 1211, 793 cm ^-1 Elemental analysis (as C ₂₉ H ₃₂ N ₄ OSCl ₂ · 1.5 H ₂ O) Calculated: C, 59.79; H, 6.06; N, 9.62. Found: C, 59.65; H , 6.06; N, 9.46.

Example 95 N- [1- [2- (thiophen-2-yl) ethane-1
-Yl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N-
[1- [2- (thiophen-2-yl) ethane-1-yl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23-1.41 (2H, m), 1.45-1.
8 (3H, m), 1.95-2.13 (2H, m), 2.58-2.68 (2H, m), 2.96-
3.08 (4H, m), 3.212 (2H, t, J = 6.1Hz), 5.789 (1H, dd, J = 1.
9, 5.9Hz), 5.95-6.09 (1H, m), 6.58-6.71 (3H, m), 6.81
-6.94 (1H, m), 7.035 (1H, s), 7.129 (1H, dd, J = 1.0, 5.0
2) In the same manner as in 2) of Example 67, N-
[1- [2- (thiophen-2-yl) ethane-1-yl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (5H, m), 2.80-
3.10 (4H, m), 3.15-3.40 (4H, m), 3.549 (2H, d like, J = 1
2.2), 6.633 (1H, d, J = 7.4Hz), 6.96-7.03 (3H, m), 7.227
(1H, s), 7.22-7.34 (1H, m), 7.420 (1H, d, J = 4.8Hz), 7.6
72 (1H, s), 8.95-9.00 (1H, m), 10.83 (1H, br s). IR (KBr): 3430, 3250, 3050, 2930, 2700, 1635, 158
5, 1540, 1500, 1440, 1390, 1290, 1280, 1210, 780,
700 cm ^-1 . Elemental analysis (as C ₂₂ H ₂₆ N ₄ OS ₂ Cl ₂ .0.5H ₂ O) Calculated: C, 52.17; H, 5.37; N, 11.06. Found: C, 52.05; H, 5.56; N, 10.88.

Example 96 N- [1- [2- (thiophen-3-yl) ethane-1
-Yl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N-
[1- [2- (thiophen-3-yl) ethane-1-yl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-1.45 (2H, m), 1.45-1.
68 (1H, m), 1.68-1.88 (2H, m), 1.93-2.08 (2H, m), 2.56
-2.68 (2H, m), 2.80-2.88 (2H, m), 3.011 (2H, d like, J = 1
1.6Hz), 3.224 (2H, t like, J = 6.0Hz), 5.800 (1H, dd, J =
1.8, 6.2Hz), 5.75-6.85 (1H, m), 6.59-6.72 (3H, m), 6.
94-7.00 (2H, m), 7.064 (1H, s), 7.23-7.26 (1H, m). 2) In the same manner as in 2) of Example 67, N-
[1- [2- (thiophen-3-yl) ethane-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
This gave b-diazaacenaphthylene-4-carboxamide dihydrochloride. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.90 (5H, m), 2.78-
2.95 (2H, m), 3.00-3.18 (4H, m), 3.18-3.35 (2H, m), 3.4
8-3.60 (2H, m), 6.576 (1H, d, J = 7.4Hz), 6.953 (1H, d, J =
8.4Hz), 7.056 (1H, dd, J = 1.2, 5.0Hz), 7.17-7.32 (3H,
m), 7.52-7.56 (1H, m), 7.621 (1H, s), 8.87-8.93 (1H, m),
10.53 (1H, brs). IR (KBr): 3430, 3250, 3050, 2930, 2680, 1635, 156
5, 1540, 1500, 1440, 1390, 1290, 1280, 1220, 780cm
. ^-1 Elemental analysis _{(C 22 H 26 N 4 OS} 2 Cl 2 · 0.5H 2 O ) Calculated values:. C, 52.17; H, 5.37; N, 11.06 Found: C, 52.52; H, 5.16 ; N, 10.98.

Example 97 N- [1- [2- (furan-3-yl) ethane-1-yl] piperidin-4-ylmethyl] -5-thia-1,
8b-Diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N-
[1- [2- (furan-3-yl) ethane-1-yl]
Piperidin-4-ylmethyl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23-1.40 (2H, m), 1.43-1.
60 (1H, m), 1.62-1.78 (2H, m), 1.985 (2H, J = 1.6, 11.6H
z), 2.48-2.66 (4H, m), 2.991 (2H, d like, J = 11.4Hz),
3.216 (2H, t, J = 6.1Hz), 5.792 (1H, dd, J = 1.7,6.1Hz),
5.78-5.90 (1H, m), 6.284 (1H, s), 6.58-6.72 (3H, m), 7.
052 (1H, s), 7.255 (1H, s), 7.347 (1H, t, J = 1.6Hz). 2) In the same manner as in Example 67-2), orange N-
[1- [2- (furan-3-yl) ethane-1-yl]
Piperidin-4-ylmethyl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.90 (5H, m), 2.80-
2.95 (4H, m), 3.00-3.10 (2H, m), 3.15-3.30 (2H, m), 3.
43-3.60 (2H, m), 6.42-6.45 (1H, m), 6.590 (1H, d, J = 7.2H
z), 6.964 (1H, d, J = 8.8Hz), 7.19-7.31 (2H, m), 7.56-7.6
4 (3H, m), 8.85-9.00 (1H, m), 10.6 (1H, brs). IR (KBr): 3420, 3250, 3070, 3000, 2940, 2680, 264
0, 1635, 1585, 1540, 1500, 1470, 1440, 1395, 1310,
1300, 1280, 1220, 1160, 1020, 940, 875, 800, 78
0, 630, 600 cm ^-1 . Elemental analysis (as C ₂₂ H ₂₆ N ₄ O ₂ SCl ₂ · 1.0 H ₂ O) Calculated: C, 52.91; H, 5.65; N, 11.22. 53.27; H, 5.38; N, 11.22.

Example 98 Synthesis of N- [1-[(thiazol-4-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride ) Synthesis of N- [1-[(thiazol-4-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 4-chloromethylthiazole 255 mg (1.5 mg) Mmol), N- (piperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 387 mg (1 mmol) and 697 ml (5 mmol) of triethylamine in ethanol (10
225 mg (1.5 mmol) of sodium iodide was added to the solution at room temperature, and the mixture was heated under reflux in a 90 ° C. oil bath overnight. Water was added to the reaction solution, and the product was extracted with ethyl acetate.The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The target product (150 mg) was obtained as a red oil from the fraction eluted with ethyl acetate-ethanol-triethylamine (20: 20: 1). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25
-1.45 (2H, m), 1.45-1.60 (1H, m), 1.60-1.72 (2H, m), 2.
049 (2H, t like, J = 11.4Hz), 2.966 (2H, d like, J = 11.8H
z), 3.206 (2H, t like, J = 6.0Hz), 3.722 (2H, s), 5.791
(1H, dd, J = 1.8, 6.2Hz), 5.75-5.90 (1H, m), 6.59-6.71 (3
H, m), 7.050 (1H, s), 7.184 (1H, d, J = 2.2Hz), 8.786 (1H,
d, J = 2.0Hz).

2) Synthesis of N- [1-[(thiazol-4-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 2 ml of a 4N hydrogen chloride / ethyl acetate solution was added to an ethanol solution of [1-[(thiazol-4-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide ( (8.0 mmol), the solvent was distilled off under reduced pressure, ether was added to the residue obtained, and the precipitated crystals were collected by filtration.
The crystals were washed with ethanol and diethyl ether to give the desired product (150 mg, 28%) as orange crystals. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-1.90 (5H, m), 2.80-
3.25 (4H, m), 3.30-3.45 (2H, m), 4.431 (2H, d, J = 4.6Hz),
6.674 (1H, d, J = 6.8Hz), 7.010 (1H, d, J = 9.2Hz), 7.21-7.
38 (2H, m), 7.707 (1H, s), 8.052 (1H, d, J = 1.8Hz), 8.90
-9.10 (1H, m), 9.232 (1H, d, J = 2.0Hz), 10.6 (1H, brs). IR (KBr): 3400, 2950, 1635, 1560, 1540, 1500, 129
0, 1220, 1110, 940, 890, 820, 780 cm ^-1 . Elemental analysis (as C ₂₀ H ₂₄ N ₅ OS ₂ Cl ₃ .0.5H ₂ O) Calculated: C, 45.33; H, 4.75; N , 13.22. Found: C, 45.31; H, 5.07; N, 13.09.

Example 99 N- [1- (3-cyclohexylpropan-1-yl)
Piperidin-4-ylmethyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, N- [1- (3-cyclohexylpropan-1-yl) as a red-purple amorphous substance
Piperidin-4-ylmethyl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.75-1.87 (m 20H) 2.30
(t J = 11.0 Hz 2H) 2.53-2.62 (m 2H) 3.13-3.25 (m 4H)
5.75 (dd J = 2.6, 5.4 Hz 1H) 6.52-6.64 (m 2H) 6.90
(s 1H) 7.02 (m 2H). 2) In the same manner as in 2) of Example 67, N-
[1- (3-Cyclohexylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.75-1.82 (m 20H) 2.63
-3.48 (m 8H) 6.60 (d J = 7.2 Hz 1H) 6.97 (d J = 8.6 Hz
1H) 7.19-7.31 (m 2H) 7.64 (s 1H) 8.85-8.94 (m 1
H). IR (KBr): 3438, 2924, 1635, 1
535, 1298, 788 ^{cm -1} Elemental analysis _{(C 25 H 36 N 4 OSCl} 2 · 2.1H as ₂ O) Calculated:. C, 54.65; H, 7.38; N, 10.20 Found: C, 54.41; H , 7.37; N, 10.11.

Example 100 N- [1-[(Quinolin-2-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride Synthesis 1) The red oily N-
[1-[(Quinolin-2-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23-1.44 (2H, m), 1.45-1.
72 (3H, m), 2.128 (2H, t like, J = 11.5Hz), 2.940 (2H, d li
ke, J = 11.6Hz), 3.222 (2H, t like, J = 6.0Hz), 3.823 (2H,
s), 5.781 (1H, dd, J = 1.8, 6.2Hz), 5.78-5.90 (1H, m),
6.57-6.70 (3H, m), 7.037 (1H, s), 7.47-7.82 (4H, m), 8.05
-8.14 (2H, m). 2) In the same manner as in Example 98-2), orange crystals of N-
[1-[(Quinolin-2-yl) methyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.90 (5H, m), 3.00-
3.25 (4H, m), 3.45-3.60 (2H, m), 4.654 (2H, br s), 6.672
(1H, d, J = 6.8Hz), 7.008 (1H, d, J = 9.0Hz), 7.245 (1H, s),
7.336 (1H, dd, J = 7.6, 9.1Hz), 7.16-7.22 (2H, m), 7.8
0-7.88 (2H, m), 8.02-8.12 (2H, m), 8.523 (1H, d, J = 8.4H
z), 8.98-9.05 (1H, m), 10.6 (1H, brs). IR (KBr): 3420, 2620, 1630, 1550, 1530, 1500, 139
0, 1300, 1210, 940, 790 cm ^-1 . Elemental analysis (as C ₂₆ H ₂₈ N ₅ OSCl ₃ .2.0 H ₂ O) Calculated: C, 51.96; H, 5.37; N, 11.65. C, 52.12; H, 5.47; N, 11.81.

Example 101 N- [1- [3- (4-Pyridyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) In the same manner as 1) of Example 98, N-
[1- [3- (4-Pyridyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23-1.38 (2H, m), 1.42-1.
60 (1H, m), 1.60-1.78 (2H, m), 1.80-1.98 (3H, m), 2.05-
2.13 (1H, m), 2.341 (2H, t like, J = 7.5Hz), 2.627 (2H, t, J
= 7.7Hz), 2.911 (2H, d like, J = 11.8Hz), 3.200 (2H, t, J =
6.2Hz), 5.783 (1H, dd, J = 2.0, 6.2Hz), 5.92-6.05 (1H,
m), 6.58-6.69 (3H, m), 7.030 (1H, s), 7.114 (2H, dd, J = 1.
4, 4.8 Hz), 8.481 (2H, dd, J = 1.4, 4.4 Hz). 2) In the same manner as in Example 98-2), orange N-
[1- [3- (4-Pyridyl) propan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.90 (5H, m), 2.08-
2.20 (2H, m), 2.70-3.28 (8H, m), 3.471 (2H, d like), 6.5
30 (1H, d, J = 7.2Hz), 6.928 (1H, d, J = 9.0Hz), 7.12-7.25
(2H, m), 7.575 (1H, s), 7.944 (2H, d, J = 5.8Hz), 8.851 (2
H, d, J = 5.4Hz), 8.80-8.91 (1H, m), 10.6 (1H, brs). IR (KBr): 3420,2920, 2700, 1635, 1500, 1295, 122
0, 790, 780 cm ^-1 . Elemental analysis: (as C ₂₄ H ₃₀ N ₅ OSCl ₃ .1.5 H ₂ O) Calculated: C, 50.57; H, 5.84; N, 12.29. Found: C, 50.59 H, 5.89; N, 12.10.

Example 102 N- [1- (2- (3-Indol) ethane-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 67, a dark red amorphous substance N- [1- (2- (3-indole) ethane -1-yl) piperidin-4-ylmethyl] -5-thia-1,8
b-Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (2H, m), 1.45-
1.90 (3H, m), 1.95-2.15 (2H, m), 2.60-2.80 (2H, m),
2.90-3.15 (4H, m), 3.23 (2H, t, J = 6.0Hz), 5.79 (1H, d
d, J = 1.7, 6.1Hz), 5.91 (1H, brt, J = 6.1Hz), 6.58-6.7
5 (3H, m), 7.00-7.25 (4H, m), 7.36 (1H, d, J = 7.2Hz),
7.62 (1H, d, J = 7.2Hz), 8.14 (1H, brs). IR (KBr): 3334, 2922, 1618, 1541, 1510, 1481, 1456,
1342, 1281, 1153, 744 cm ⁻¹ . 2) In the same manner as in 2) of Example 67, N-
[1- (2- (3-Indol) ethane-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, CD ₃ OD) δ: 1.40-1.70 (2H, m), 1.70-
2.10 (3H, m), 2.90-3.15 (2H, m), 3.15-3.50 (6H, m),
3.60-3.80 (2H, m), 6.59 (1H, d, J = 7.8Hz), 6.95-7.23
(5H, m), 7.34-7.41 (2H, m), 7.51 (1H, s), 7.61 (1H,
d, J = 7.0Hz). IR (KBr): 3392, 3062, 2935, 2727, 1633, 1564, 1539,
1504, 1456, 1292, 1216, 1105, 748 cm ^-1 . Elemental analysis (calculated as C ₂₆ H ₂₉ N ₅ OSCl ₂ · 2.0 H ₂ O) Calculated: C; 55.12, H; 5.87, N; 12.36. : C; 55.16, H; 6.03, N; 12.01.

Example 103 N- (1-benzylpiperidin-4-ylmethyl) -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- (1-benzylpiperidin-4-ylmethyl)
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-ylmethyl) -5-thia-1,
To a solution of 0.58 g (1.5 mmol) of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mmol) of triethylamine in ethanol solution at room temperature was added 0.19 ml (1%) of benzyl bromide. (0.6 mmol) and heated to reflux for 6 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with methylene chloride. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol /
Separation and purification with ethyl acetate (40%) gave the desired product. Yield 479 mg (79% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.17-1.69 (m 5H) 1.94 (t
J = 11.0 Hz 2H) 2.88 (br d J = 11.6 Hz 2H) 3.17 (t J =
(5.9 Hz 2H) 3.48 (s 2H) 5.72-5.76 (m 1H) 6.35-6.50
(m 1H) 6.59-6.64 (m 3H) 6.96-6.97 (m 1H) 7.18-7.3
8 (m5H). 2) N- (1-benzylpiperidin-4-ylmethyl)
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- (1-benzylpiperidin-4-ylmethyl) -5
To a solution of 479 mg (1.18 mmol) of thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (4 ml) was added a 4N hydrogen chloride / methanol solution of 1.0%.
ml (4 mmol) was added and stirred at room temperature for several minutes. After evaporating the solvent under reduced pressure, ethanol and diethyl ether were added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 424. mg (73% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.87 (m 5H) 2.79-
3.35 (m 6 H) 4.25 (brs 2H) 6.59 (d J = 7.2 Hz 1H) 6.
96 (d J = 9.0 Hz 1H) 7.17-7.30 (m 2H) 7.44-7.47 (m 3
H) 7.59-7.65 (m 3H) 8.83-8.89 (m 1H). Elemental analysis (as C ₂₃ H ₂₆ N ₄ OSCl ₂ · 1.0H ₂ O) Calculated: C, 55.76; H, 5.70; N, 11.31 Found: C, 55.71; H, 5.70; N, 11.57.

Example 104 N- (1-Phenethylpiperidin-4-ylmethyl)-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) A red-purple amorphous substance N- (1-phenethylpiperidine- 4-ylmethyl)
-5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.23-2.10 (m 5H) 2.01 (t
J = 11.3 Hz 2H) 2.54-2.62 (m 2H) 2.77-2.85 (m 2H)
3.02 (br d J = 11.2 Hz 2H) 3.22 (t J = 5.3 Hz 2H) 5.76
5.81 (m 1H) 5.92-6.13 (m 1H) 6.56-6.69 (m 3H) 7.0
2-7.05 (s 1H) 7.16-7.32 (m 5H). 2) In the same manner as in 2) of Example 103, N-
(1-phenethylpiperidin-4-ylmethyl) -5
Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.87 (m 7H) 2.79-
3.59 (m 8 H) 6.55 (d J = 7.0 Hz 1H) 6.94 (d J = 9.2 Hz
1H) 7.15-7.39 (m 7H) 7.60 (s 1H) 8.80-8.91 (m 1H). IR (KBr): 3415, 3057, 2941, 2702, 1637, 1535, 129
4, 1215, 789 cm ^-1 Elemental analysis (as C ₂₄ H ₂₈ N ₄ OSCl ₂ · 0.5 H ₂ O) Calculated: C, 57.60; H, 5.84; N, 11.19. Found: C, 57.52; H , 5.75; N, 11.00.

Example 105 N- [1- (4-Phenylbutan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) N- [1- (4-Phenylbutan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b- as a magenta amorphous substance in the same manner as 1) of Example 103. Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.18-1.94 (m 11H) 2.32
(t J = 7.4 Hz 2H) 2.62 (tJ = 7.2 Hz 2H) 2.91 (br d J = 1
1.2 Hz 2H) 3.20 (t J = 6.2 Hz 2H) 5.79 (dd J = 1.6, 6.
2 Hz 1H) 5.75-5.90 (m 1H) 6.56-6.70 (m 3H) 7.04-7.
30 (m 6H). 2) In the same manner as in 2) of Example 103, N-
[1- (4-Phenylbutan-1-yl) piperidine-
4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.30-1.85 (m 9H), 2.53-
3.20 (m 10H) 6.53 (d J = 7.6 Hz 1H) 6.93 (d J = 9.2 H
(z 1H) 7.11-7.32 (m 7H) 7.57 (s 1H) 8.75-8.86 (m 1
H). IR (KBr): 1635, 1566, 1533, 1502, 1294, 1217,787
cm ^-1 Elemental analysis _{(C 26 H 32 N 4 OSCl} 2 · 2.1H 2 O ) Calculated values:. C, 56.03; H, 6.55; N, 10.05 Example: C, 55.78; H, 6.55 ; N, 10.05.

Example 106 Synthesis of N- [1- (5-phenylpentan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- (5-Phenylpentan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-dia as a red-purple amorphous substance in the same manner as 1) of Example 103 Zaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.90 (m 10H) 2.34-
3.31 (m 11H) 5.74 (dd J = 2.2, 5.8 Hz 1H) 6.51-6.63
(m2H) 6.90-7.31 (m7H). IR (KBr): 3440, 1628, 1551, 1281, 1151 cm ^-1 2) In the same manner as in Example 103-2), orange crystal N-
[1- (5-Phenylpentan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.25-1.85 (m 11H), 2.65
-3.20 (m 10H) 2.59 (tJ = 7.5 Hz 2H) 6.55 (d J = 8.0 Hz
1H) 6.95 (d J = 8.8 Hz 1H) 7.13-7.32 (m 7H) 7.60 (s
1H) 8.75-8.86 (m 1H). IR (KBr): 1635, 1566, 1535, 1500, 1444, 1294, 121
7 cm ^-1 Elemental analysis (as C ₂₇ H ₃₄ N ₄ OSCl ₂ · 1.8 H ₂ O) Calculated: C, 57.30; H, 6.70; N, 9.90. Found: C, 57.51; H, 9.96; N , 9.96.

Example 107 N- [1- (3-Phenyl-2-propen-1-yl)
Piperidin-4-ylmethyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- (3-Phenyl-2-propen-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-ylmethyl) -5-thia-1,
0.58 g (1.5 mmol) of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mmol) of triethylamine in ethanol (6 m
l) 0.355 g of cinnamyl bromide at room temperature
(1.8 mmol), and the mixture was heated and refluxed for 24 hours under a nitrogen atmosphere. Furthermore, cinnamyl bromide 0.1 was added to the reaction system.
29 g (1.47 mmol) was added, and the mixture was heated under reflux for 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / chloroform 1: 19-1: 10-1: 5) gave the desired product. Red-purple amorphous substance Yield 379 mg (59% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.27-1.80 (m 5H) 2.03 (b
rt J = 10.9 Hz 2H) 2.90-3.25 (m 6H) 5.75 (dd J = 2.5,
5.3 Hz 1H) 6.28 (dt J = 6.7, 15.8 Hz 1H) 6.49-6.65
(m 4H) 6.69 (s 1H) 6.99 (s 1H) 7.23-7.41 (m 5H). 2) N- [1- (3-Phenyl-2-propen-1-yl) piperidin-4-ylmethyl] -5 -Cheer-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (3-phenyl-2-propen-1-yl)
Piperidin-4-ylmethyl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide 0.391
To a solution of 9 g (0.84 mmol) of ethanol (4 ml) was added 1.0 ml (4 mmol) of a 4N hydrogen chloride / methanol solution. After evaporating the solvent under reduced pressure, ethanol and diethyl ether were added, and the resulting crystals were collected by filtration. Wash the crystals with ethanol and diethyl ether,
The desired product was obtained. Orange crystal Yield 330.2 mg (77% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.38-1.91 (m 5H) 2.81-
3.10 (m 4H) 3.41-3.53 (m 2H) 3.84 (br d J = 6.8 Hz 2
H) 6.32-6.49 (m 1H) 6.57 (d J = 7.2 Hz 1H) 6.82 (d J
= 16 Hz 1H) 6.95 (d J = 8.8 Hz 1H) 7.15-7.53 (m 7H)
7.61 (s 1H) 8.80-8.93 (m 1H). IR (KBr): 3452, 1639, 1292, 1215 cm ^-1 Elemental analysis (calculated as C ₂₅ H ₂₈ N ₄ OSCl ₂ .0.5H ₂ O) Calculated: C, 58.59; H, 5.70; N, 10.93. Actual location: C, 58.37; H, 5.84; N, 10.66.

Example 108: N- [1- (2-Phenoxyethane-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [1- (2-phenoxyethane-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide Phenoxyethanol 0 under nitrogen atmosphere .44 g (3.
18 mmol) and 0.89 ml of triethylamine
To a solution of (6.39 mmol) in methylene chloride (6 ml) was added 0.37 ml (4.78 mmol) of methanesulfonyl chloride at 0 ° C., and the mixture was stirred at the same temperature for 35 minutes.
Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with diethyl ether. After washing the organic layer with water and saturated saline,
Dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 0.6989 g of phenoxyethyl mesylate (<3.18)
Mmol). N- (piperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4
0.6989 g (<3.18) of phenoxyethyl mesylate in a solution of 0.58 g (1.5 mmol) of carboxamide dihydrochloride and 1.0 ml (7.2 mmol) of triethylamine in ethanol (6.0 ml) at room temperature. Mmol), and the mixture was refluxed for 17 hours under a nitrogen atmosphere.
After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 30-40%) gave the desired product. Red-purple amorphous substance Yield 414 mg (63% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-2.18 (m 7H) 2.80 (t
J = 5.9 Hz 2H) 3.02 (brd J = 11.6 Hz 2H) 3.20 (t J = 6.
1 Hz 2H) 4.10 (t J = 5.9Hz 2H) 5.78 (dd J = 2.0, 6.0 H
z 1H) 6.01 (br t J = 5.8 Hz 1H) 6.57-6.70 (m 3H) 6.8
6-6.98 (m 3H) 7.03 (s 1H) 7.24-7.32 (m 2H).

2) N- [1- (2-phenoxyethane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (2-phenoxyethane-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-dia 414 mg of Zaacenaphthylene-4-carboxamide (0.
To a suspension of 95 mmol) in ethanol (9 ml) was added 1.0 ml (4 mmol) of a 4N hydrogen chloride / methanol solution, and the mixture was stirred at room temperature for 30 minutes. The resulting crystals were collected by filtration and washed with ethanol and ether to obtain the desired product. Orange crystals Yield 363 mg (70% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.41-1.90 (m 5H) 2.93-
3.60 (m 8H) 4.36-4.45 (m 2H) 6.60 (d J = 6.8 Hz 1H)
6.94-7.02 (m 4H) 7.21-7.37 (m 4H) 7.64 (s 1H) 8.91
-8.97 (m 1H). IR (KBr): 3388, 3238, 3057, 2638, 2514, 1639, 129
4, 1230, 797, 764 cm ^-1 Elemental analysis value (as C ₂₄ H ₂₈ N ₄ O ₂ SCl ₂ .0.5H ₂ O) Calculated value: C, 55.81; H, 5.66; N, 10.85. H, 5.69; N, 10.69.

Example 109: N- [1- (4-Phenoxybutan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [1- (4-phenoxybutan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidine-4 -Ylmethyl) -5-thia-1,
0.58 g (1.5 mmol) of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (27.5 mmol) of triethylamine in ethanol (6
ml) solution at room temperature was added with 0.45 g (1.96 mmol) of 4-phenoxybutyl bromide, and the mixture was refluxed for 14 hours under a nitrogen atmosphere. Further, 0.23 g (1.0 mmol) of 4-phenoxy-butyl bromide was added, and the mixture was refluxed for 6 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / chloroform 1: 15-1: 10-1:
The desired product was obtained by separation and purification in 5). Red-purple amorphous substance Yield: 324 mg (47% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.40-1.92 (m 9H) 2.15-2.
28 (m 2H) 2.53-2.67 (m2H) 3.12-3.22 (m 4H) 3.97 (b
(rt J = 5.3 Hz 2H) 5.74 (dd J = 2.4, 5.6 Hz 1H) 6.58-6.
61 (m 2H) 6.65-6.76 (m 1H) 6.81-6.97 (m 3H) 7.02
(s 1H) 7.23-7.31 (m 3H).

2) N- [1- (4-phenoxybutane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (4-phenoxybutan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacena 0.3241 g of futhylene-4-carboxamide
(0.70 mmol) in ethanol (4 ml)
1.0 ml (4 mmol) of N hydrogen chloride / methanol solution
Was added. After evaporating the solvent under reduced pressure, ethanol and ether were added, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product. Orange crystal Yield 270 mg (70% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-1.93 (m 9H) 2.65-
3.21 (m 6H) 3.43-3.49 (m 2H) 3.99 (t J = 5.6 Hz 2H)
6.58 (d J = 7.4 Hz 1H) 6.89-6.98 (m 4H) 7.19-7.33 (m
4H) 7.63 (s 1H) 8.89-8.94 (m 1H). IR (KBr): 3435, 3051, 2943, 1635, 1294, 1241, 764
cm ^-1 elemental analysis value (as C ₂₆ H ₃₂ N ₄ O ₂ SCl ₂ · 1.0 H ₂ O) Calculated value: C, 56.41; H, 6.19; N, 10.12. N, 10.19.

Example 110: N- [1- (3-Phenoxypropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) A red-purple amorphous substance N- [1- (3-phenoxypropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b- Diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.73 (m 5H) 1.90-2.
08 (m 4H) 2.50-2.57 (m2 H) 2.98 (br d J = 11.2 Hz 2
H) 3.18 (t J = 6.1 Hz 2H) 3.99 (t J = 6.2 Hz 2H) 5.74
(dd J = 3.0, 5.0 Hz 1H) 6.52-6.68 (m 4H) 6.82-6.97
(m 4H) 7.17-7.32 (m 2H). 2) In the same manner as in Example 109-2), orange crystal N-
[1- (3-Phenoxypropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.95 (m 5H) 2.10-
2.28 (m 2H) 2.81-3.29 (m 6H) 3.43-3.56 (m 2H) 4.05
(t J = 6.0 Hz 2H) 6.61 (d J = 7.4 Hz 1H) 6.91-6.9 (m 4
H) 7.21-7.34 (m 4H) 7.65 (s 1H) 8.87-9.00 (m 1H). IR (KBr): 3421, 3236,3049,2941, 2642, 2532, 1635,
1295, 1294, 1240, 762cm ^-1 Elemental analysis _{(C 25 H 30 N 4 O} 2 SCl 2 · 0.5H 2 O ) Calculated values:. C, 56.60; H, 5.89; N, 10.56 Found Location: C, 56.38; H, 5.79; N, 10.56.

Example 111 N- [1- (3- (2-Fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -Synthesis of dihydrochloride 1) N- [1- (3- (2-fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-ylmethyl) -5-thia-1,
To a solution of 0.58 g (1.5 mmol) of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mmol) of triethylamine in ethanol was added 3- (2-fluorophenoxy) at room temperature. 0.37 g (2.0 mmol) of -propyl chloride and 0.28 g (1.9 mmol) of sodium iodide were added, and the mixture was refluxed for 20 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography (methanol / ethyl acetate 30-
(50%) to obtain the desired product. Red-purple amorphous substance yield 244 mg (35% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.16-2.06 (m 9H) 2.48-2.
55 (m 2H) 2.94 (br dJ = 11.6 Hz 2H) 3.19 (t J = 6.2 H
z 2H) 4.07 (t J = 6.4 Hz 2H) 5.77 (dd J = 2.5,5.3 Hz 1
H) 6.25 (br t J = 5.8 Hz 1H) 6.61-6.67 (m 3H) 6.84
-7.14 (m5H).

2) N- [1- (3- (2-Fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride N- [1- (3- (2-fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene- 244 mg (0.52 mmol) of 4-carboxamide in ethanol (4 m
l) 1.0 ml of 4N hydrogen chloride / methanol solution
(4.0 mmol) was added. After evaporating the solvent under reduced pressure, the residue was purified by recrystallization to obtain the desired product. Orange crystal Yield 218 mg (75% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-1.90 (m 5H) 2.13-
2.30 (m 2H) 2.80-3.60 (m 8H) 4.14 (t J = 5.8 Hz 2H)
6.57 (d J = 7.4 Hz 1H) 6.93-7.02 (m 2H) 7.10-7.28
(m 5H) 7.61 (s 1H) 8.87 (m 1H). IR (KBr): 3429, 1635, 1506, 1290 cm ^-1 Elemental analysis (C ₂₅ H ₂₉ N ₄ O ₂ SCl ₂ F ・ 1.0H ₂ O Calculated: C, 53.86; H, 5.60; N, 10.05. Geodetic: C, 53.91; H, 5.46; N, 10.00.

Example 112 N- [1- (3- (3-Fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -Synthesis of dihydrochloride 1) A red-purple amorphous substance N- [1- (3- (3-fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl as in 1) of Example 111 ] -5-Thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-2.13 (m 9H) 2.56 (b
rt J = 6.8 Hz 2H) 3.00 (br d J = 11.0 Hz 2H) 3.19 (t J
= 5.7Hz 2H) 3.98 (t J = 6.0 Hz 2H) 5.60-5.71 (m 1H)
6.35-6.83 (m 7H) 6.98-7.05 (m 1H) 7.13-7.29 (m 1
H). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (3-fluorophenoxy) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.36-1.87 (m 5H) 2.10-
2.25 (m 2H) 2.78-3.80 (m 8H) 4.07 (t J = 5.9 Hz 2H)
6.57 (d J = 6.8 Hz 1H) 6.72-6.85 (m 3H) 6.95 (d J = 9.
0 Hz 1H) 7.14-7.37 (m 3H) 7.61 (s 1H) 8.80-8.90 (m
1H). IR (KBr): 3413, 2948, 2648, 1635, 1491, 1288, 113
6, 779 cm ^-1 Elemental analysis (as C ₂₅ H ₂₉ N ₄ O ₂ SCl ₂ F · 1.5 H ₂ O) Calculated: C, 53.00; H, 5.69; N, 9.89. H, 5.72; N, 9.65.

Example 113 N- [1- (3- (4-Fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -Synthesis of dihydrochloride 1) In the same manner as in 1) of Example 111, N- [1- (3- (4-fluorophenoxy) propan-1-yl) piperidin-4-ylmethyl as a magenta amorphous substance ] -5-Thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-2.13 (m 7H) 2.55-2.
62 (m 2H) 3.00-3.06 (m4H) 3.19 (t J = 5.9 Hz 2H) 3.9
6 (t J = 6.2 Hz 2H) 5.75 (dd J = 3.0, 5.0 Hz 1H) 6.58-
6.65 (m 3H) 6.72 (s 1H) 6.77-7.00 (m 5H). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (4-fluorophenoxy) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-2.22 (m 7H) 2.77-
3.54 (m 8H) 4.03 (t J = 6.1 Hz 2H) 6.54 (d J = 7.8 Hz
1H) 6.89-7.24 (m 7H) 7.58 (s 1H) 8.78-8.86 (m 1H). IR (KBr): 3461, 3400, 2711, 1637, 1504, 1294, 121
1, 835, 790 cm ^-1 Elemental analysis value (as C ₂₅ H ₂₉ N ₄ O ₂ SCl ₂ F · 1.0 H ₂ O) Calculated value: C, 53.86; H, 5.60; N, 10.05. 53.65; H, 5.57; N, 9.81.

Example 114 N- [1- (2- (2-fluorophenoxy) ethane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 108 1), the red oil N
-[1- (2- (2-fluorophenoxy) ethane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25 to 2.21 (7
H, m), 2.847 (2H, t like, J =
6.0 Hz), 3.00-3.10 (2H, d like)
e), 3.217 (2H, t, J = 6.0), 4.
10-4.20 (2H, m), 5.799 (1H, d
d, J = 1.8, 6.2 Hz), 5.75-5.
88 (1H, m), 6.60-6.73 (2H,
m), 6.85-7.15 (6H, m). 2) In the same manner as in 2) of Example 108, N-
[1- (2- (2-fluorophenoxy) ethane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ )
δ: 1.40-1.95 (4H, m), 2.90-3.35 (5H, m), 3.40-3.65
(4H, m), 4.45-4.55 (2H, m), 6.645 (1H, d, J = 7.6Hz), 6.9
5-7.08 (2H, m), 7.13-7.35 (5H, m), 7.678 (1H, s), 8.85-
8.98 (1H, m), 10.70 (1H, br s). IR (KBr): 3420, 3050, 2950, 1635, 1560, 1535, 128
0, 1260, 1220, 1150, 780, 760 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ O ₂ SCl ₂ F · 2.5 H ₂ O) Calculated: C, 50.53; H, 5.65; N, 9.82. Actual location: C, 50.81; H, 5.68; N, 9.65.

Example 115 N- [1- (2- (3-fluorophenoxy) ethane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 108 1), the red oil N
-[1- (2- (3-fluorophenoxy) ethane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.45 (2H, m), 1.45-
1.63 (1H, m), 1.63-1.78 (2H, m), 2.05-2.18 (2H, m), 2.7
98 (2H, t, J = 6.0Hz), 3.017 (2H, d like, J = 11.8Hz), 3.
212 (2H, t, J = 6.0Hz), 4.080 (2H, t, J = 5.7Hz), 5.800 (1H, d
d, J = 1.8, 6.1Hz), 5.75-5.90 (1H, m), 6.58-6.73 (6H,
m), 7.054 (1H, s), 7.16-7.27 (1H, m). 2) In the same manner as in 2) of Example 108, N-
[1- (2- (3-fluorophenoxy) ethane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.95 (4H, m), 2.92
-3.15 (4H, m), 3.18-3.35 (1H, m), 3.42-3.65 (4H, m),
4.38-4.52 (2H, m), 6.603 (1H, d, J = 7.2Hz), 6.78-6.99 (4
H, m), 7.20-7.42 (3H, m), 7.647 (1H, s), 8.90-9.00 (1H,
m), 10.70 (1H, brs). IR (KBr): 3420, 3250, 3050, 2950, 1635, 1610, 159
0, 1560, 1540, 1500, 1490, 1290, 1260, 1220, 1170,
1140, 780 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₄ O ₂ SCl ₂ F · 1.0 H ₂ O) Calculated: C, 53.04; H, 5.38; N, 10.31. H, 5.59; N, 10.32.

Example 116 N- [1- (2- (4-Fluorophenoxy) ethane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 108 1), the red oil N
-[1- (2- (4-fluorophenoxy) ethane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.42 (2H, m), 1.45-
1.65 (1H, m), 1.63-1.77 (2H, m), 2.03-2.16 (2H, m), 2.7
83 (2H, t, J = 5.9Hz), 3.015 (2H, d like, J = 11.8Hz), 3.
214 (2H, t, J = 6.2Hz), 4.055 (2H, t, J = 5.9Hz), 5.798 (1H, d
d, J = 1.6, 6.2Hz), 5.75-5.85 (1H, m), 6.59-6.72 (3H,
m), 6.80-6.88 (2H, m), 6.89-7.01 (2H, m), 7.058 (1H,
s). 2) In the same manner as in 2) of Example 108, N-
[1- (2- (4-fluorophenoxy) ethane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.90 (5H, m), 2.90
-3.15 (3H, m), 3.15-3.30 (1H, m), 3.40-3.60 (4H, m),
4.33-4.42 (2H, m), 6.599 (1H, d, J = 7.4Hz), 6.94-7.06 (3
H, m), 7.13-7.31 (4H, m), 7.644 (1H, s), 8.85-8.95 (1H,
m), 10.56 (1H, brs). IR (KBr): 3420, 3250, 3050, 2950, 1635, 1560, 154
. 0, 1500, 1290, 1250 , 1210, 830, 780, 760 cm -1 Elemental analysis _{(C 24 H 27 N 4 O} 2 SCl 2 F · 1.5H 2 O ) Calculated values: C, 52.17; H, 5.47; N, 10.14. Actual location: C, 52.28; H, 5.53; N, 10.06.

Example 117 N- [1- (3- (2,4-difluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Similarly to 1) of Example 111, N- [1- (3- ( 2,4-difluorophenoxy)
Propan-1-yl) piperidin-4-ylmethyl]-
5-Thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.21-1.73 (m 4H) 1.90-2.
08 (m 5H) 2.54 (t J = 7.4 Hz 2H) 2.96 (br d J = 12.2 H
z 2H) 3.21 (t J = 6.2 Hz 2H) 4.04 (t J = 6.3 Hz2H) 5.7
9 (dd J = 1.8, 6.2 Hz 1H) 5.82-5.89 (m 1H) 6.58-6.93
(m 6H) 7.05 (s1H). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (2,4-Difluorophenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride is obtained. Was. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.95 (m 5H) 2.14-
2.29 (m 2H) 2.80-3.26 (m 6H) 3.46-3.55 (m 2H) 4.12
(t J = 5.9 Hz 2H) 6.60 (d J = 7.2 Hz 1H) 6.96 (d J = 8.8
Hz 1H) 6.96-7.05 (m 1H) 7.15-7.42 (m 4H) 7.64 (s
1H) 8.86-8.97 (m 1H) .IR (KBr): 3460, 3381, 3246, 2951, 2702, 1639, 1510,
1294, 1215, 798 cm ^-1 Elemental analysis value (as C ₂₅ H ₂₈ N ₄ O ₂ SCl ₂ F ₂ · 1.0H ₂ O) Calculated value: C, 52.18; H, 5.25; N, 9.74. H, 5.29; N, 9.67.

Example 118 N- [1- (3- (4-chlorophenoxy) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Similar to 1) of Example 111, N- [1- (3- (4-chloro) Phenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.19-2.01 (m 9H) 2.50 (t
J = 7.5 Hz 2H) 2.95 (brd J = 11.4 Hz 2H) 3.20 (t J = 6.
2 Hz 2H) 3.97 (t J = 6.4 Hz 2H) 5.78 (dd J = 2.2, 5.8
Hz 1H) 6.07 (br t J = 5.9 Hz 1H) 6.63-6.68 (m 3H)
6.80-6.85 (m 2H) 7.02 (s 1H) 7.20-7.26 (m 2H). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (4-chlorophenoxy) propane-1-
Il) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.39-1.90 (m 5H) 2.10-
2.26 (m 2H) 2.76-3.31 (m 6H) 3.43-3.58 (m 2H) 4.05
(t J = 6.0 Hz 2H) 6.57 (d J = 7.4 Hz 1H) 6.92-7.01 (m
3H) 7.16-7.37 (m 4H) 7.61 (s 1H) 8.87 (m 1H). IR (KBr): 3404, 1635, 1495, 1292, 1242 cm ^-1 Elemental analysis (C ₂₅ H ₂₉ N ₄ O ₂ SCl ₃ · 0.5H ₂ as O) calculated:. C, 53.15; H, 5.35; N, 9.92 Found Location: C, 53.40; H, 5.23 ; N, 9.92.

Example 119 N- [1- (3- (2-Methoxyphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenat-tylene-4-carboxamide-2 Synthesis of hydrochloride 1) In the same manner as in 1) of Example 111, N
-[1- (3- (2-methoxyphenoxy) propane-
1-yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.26-2.15 (9H, m), 2.630
(2H, t, J = 7.3Hz), 3.02-3.08 (2H, m), 3.218 (2H, t, J = 6.1H
z), 3.861 (3H, s), 4.079 (2H, t, J = 6.4Hz), 5.786 (1H, dd,
J = 1.8, 6.2Hz), 5.90-6.05 (1H, m), 6.60-6.75 (3H, m),
6.907 (4H, s), 7.056 (1H, s). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (2-methoxyphenoxy) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.85 (5H, m), 2.10
-2.30 (2H, m), 2.80-3.30 (6H, m), 3.45-3.60 (2H, m), 3.7
62 (3H, s), 4.00-4.06 (2H, m), 6.571 (1H, d, J = 6.6Hz),
6.86-7.01 (5H, m), 7.16-7.28 (2H, m), 7.611 (1H, s), 8.8
2-8.90 (1H, m). IR (KBr): 3420,2920, 1630, 1500, 1285, 1250, 122
0, 1120, 780, 740 cm ^-1 . Elemental analysis (as C ₂₆ H ₃₂ N ₄ O ₃ SCl ₂ · 1.5 H ₂ O) Calculated: C, 53.98; H, 6.10; N, 9.68. C, 53.86; H, 6.14; N, 9.51.

Example 120 N- [1- (3- (4-Methoxyphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -Synthesis of dihydrochloride 1) A red-purple amorphous substance N- [1- (3- (4-methoxyphenoxy) propan-1-yl) piperidin-4-ylmethyl as in Example 111 1) ] -5-Thia-1,8b-diazaacenaphthylene-4-carboxamide. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.38-2.25 (m 9H) 2.63-2.
71 (m 2H) 3.11 (br d J = 11.4 Hz 2H) 3.17-3.26 (m 2
H) 3.77 (s 3H) 3.97 (t J = 6.1 Hz 2H) 5.77 (ddJ = 2.0,
(5.8 Hz 1H) 6.15-6.27 (m 1H) 6.60-6.67 (m 2H) 6.77
-6.83 (m 5H) 7.05 (s 1H). 2) In the same manner as in 2) of Example 111, N-
[1- (3- (4-methoxyphenoxy) propane-1
-Yl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (m 5H) 2.11-
2.24 (m 2H) 2.78-3.30 (m 6H) 3.43-3.53 (m 2H) 3.70
(s 3H) 3.98 (t J = 5.9 Hz 2H) 6.56 (d J = 7.3 Hz 1H)
6.87-6.97 (m 5H) 7.15-7.28 (m 2H) 7.61 (s 1H) 8.80
-8.92 (m 1H). IR (KBr): 3425, 3051, 2947, 2708, 2507, 1635, 150
6, 1227 cm ^-1

Example 121 N- [1- (3- (4-tert-butylphenoxy)
Propan-1-yl) piperidin-4-ylmethyl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Similarly to 1) of Example 111, N- [1- (3- (4-tert-butylphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.29 (s 9H) 1.40-2.36 (m
9H) 2.62-2.70 (m 2H) 3.04-3.13 (m 2H) 3.21 (t J = 6.
2 Hz 2H) 3.99 (t J = 6.0 Hz 2H) 5.74 (dd J = 2.2, 5.8
Hz 1H) 6.36-6.67 (m 3H) 6.79-6.84 (m 2H) 6.90 (s
1H) 7.05 (s 1H) 7.26-7.31 (m 2H). 2) In the same manner as in 2) of Example 111, an orange solid N-
[1- (3- (4-tert-butylphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-
Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.25 (s 9H) 1.35-1.92
(m 5H) 2.06-2.23 (m 2H) 2.80-3.56 (m 8H) 4.02 (t J
= 6.0 Hz 2H) 6.56 (d J = 7.4 Hz 1H) 6.83-6.89 (m 2H)
6.94 (d J = 9.0 Hz 1H) 7.10 (s 1H) 7.19-7.32 (m 3H)
7.60 (s 1H) 8.72-8.82 (m 1H). IR (KBr): 3429, 2954, 1635, 1510, 1294, 1244, 83
1, 785 cm ^-1

Example 122 N- [1- (3- (2,4,6-Trimethylphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene -4
-Synthesis of carboxamide dihydrochloride 1) N- [1- (3- (2,4,6-trimethylphenoxy) propan-1-yl) of a magenta amorphous substance in the same manner as in 1) of Example 111. ) Piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.37-1.86 (m 4H) 2.00-2.
30 (m 5H) 2.21 (s 9H) 2.75-2.83 (m 2H) 3.12-3.19 (m
4H) 3.76 (t J = 5.8 Hz 2H) 5.69-5.73 (m 1H) 6.56-6.
58 (m 2H) 6.80 (s 2H) 6.89 (s 1H) 6.99 (s 1H) 7.14
-7.29 (m1H). 2) In the same manner as in 2) of Example 111, an orange solid N-
[1- (3- (2,4,6-trimethylphenoxy) propan-1-yl) piperidin-4-ylmethyl] -5
-Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (m 4H) 2.05-
2.40 (m 3H) 2.17 (s 9H) 2.80-3.36 (m 6H) 3.52 (br
d J = 12.4 Hz 2H) 3.74 (t J = 5.7 Hz 2H) 6.60 (dJ = 7.0
Hz 1H) 6.82 (s 2H) 6.97 (d J = 9.2 Hz 1H) 7.20-7.31
(m 2H) 7.65 (s1H) 8.87-8.95 (m 1H). IR (KBr): 3392, 2947, 2715, 1635, 1492, 1294, 121
5 cm ^-1

Example 123 N- [1- [2- (Phenylthio) ethan-1-yl]
Piperidin-4-ylmethyl] -5-thia-1,8b
-Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as 1) of Example 108, N-
[1- [2- (Phenylthio) ethan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.40 (2H, m), 1.40-
1.60 (1H, m), 1.60-1.75 (2H, m), 1.92-2.08 (2H, m), 2.
58-2.66 (2H, m), 2.945 (2H, d like, J = 11.2Hz), 3.02-3.1
0 (2H, m), 3.201 (2H, t, J = 6.1Hz), 5.791 (1H, dd, J = 1.7,
6.2Hz), 6.58-6.71 (3H, m), 7.053 (1H, s), 7.10-7.37 (5
H, m). 2) In the same manner as in 2) of Example 108, N-
[1- [2- (Phenylthio) ethan-1-yl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.30-1.90 (5H, m), 2.75
-3.30 (7H, m), 3.38-3.60 (3H, m), 6.600 (1H, d, J = 6.8H
z), 6.966 (1H, d, J = 9.2Hz), 7.17-7.46 (7H, m), 7.641 (1
H, s), 8.83-8.93 (1H, m), 10.84 (1H, br s). IR (KBr): 3420, 3250, 3050, 2680, 1650, 1635, 156
5, 1540, 1500, 1440, 1390, 1290, 1220, 750 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₈ N ₄ OS ₂ Cl ₂ .0.5H ₂ O) Calculated: C, 54.13; H, 5.49; N, 10.52. Found: C, 53.68; H, 5.83; N, 10.22.

Example 124 Synthesis of N- [1- (phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N Synthesis of-[1- (phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N-
(Piperidin-4-ylmethyl) -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride (581 mg, 1.5 mmol) and triethylamine (759 mg, 7.5 mmol) in ethanol (30 m
l) Add 254 mg of chloroacetylaniline to the solution at room temperature
(1.5 mmol) and heated under reflux for 18 hours. After evaporating the solvent under reduced pressure, water was added, and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated saline solution and dried over sodium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate 1: 2) gave the desired product as a red oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.45 (2H, m), 1.45-
2.68 (1H, m), 1.70-1.80 (2H, m), 2.246 (2H, dt, J = 2.2, 1
1.65Hz), 2.936 (2H, br d, J = 11.8), 3.109 (2H, s), 3.2
48 (2H, t, J = 6.4Hz), 5.791 (1H, dd, J = 1.6, 6.0Hz), 5.88
-5.95 (1H, m), 6.59-6.71 (3H, m), 7.05-7.15 (2H, m), 7.2
9-7.38 (2H, m), 7.52-7.58 (2H, m), 9.117 (1H, br s).

2) N- [1- (phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene -4-Carboxamide chloroform-
After 2 ml (8.0 mmol) of a 4N hydrogen chloride / ethyl acetate solution was added to a methanol (1: 1) solution, the solvent was distilled off under reduced pressure, and ethanol-ether (1: 1) was added to the residue.
10) was added, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give the desired product (506 mg, 60%) as orange crystals. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.80 (5H, m), 3.00
-3.30 (4H, m), 3.45-3.60 (2H, m), 4.152 (2H, s), 6.618
(1H, d, J = 7.2Hz), 6.977 (1H, d, J = 8.8Hz), 7.114 (1H, t, J
= 7.5Hz), 7.24-7.39 (4H, m), 7.627 (1H, s), 7.666 (2H,
s), 8.95-9.10 (1H, m), 10.00 (1H, br s), 11.016 (1H, s) .IR (KBr): 3400, 3250, 3050, 2950, 1690, 1630, 160
0, 1560, 1540, 1500, 1440, 1390, 1300, 1210, 1110,
940, 780, 760 cm ^-1 . Elemental analysis (as C ₂₄ H ₂₇ N ₅ O ₂ SCl ₂ .2.5H ₂ O) Calculated: C, 50.97; H, 5.70; N, 12.38. 51.17; H, 5.68; N, 12.13.

Example 125 N- [1-[[3,5-Bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide dihydrochloride 1) N- [1-[[3,5-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidine-
Synthesis of 4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 3,5-bis (trifluoromethyl) aniline 709m
g (3 mmol) and 455 mg of triethylamine (4.
386 mg (3.3 mmol) of chloroacetyl chloride was slowly added to a dichloromethane solution (20 ml) of 5 mmol) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature for 1 hour. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution, the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crystals (830 mg). This chloride was dissolved in ethanol (30 ml), and triethylamine 75 was dissolved.
9 mg (7.5 mmol), N- (piperidin-4-ylmethyl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 581 mg (1.5 mg)
(Mmol) was added and the mixture was heated under reflux at 90 ° C overnight. Excess ethanol was distilled off, the amount of the reaction solution was concentrated to about half, water (20 ml) was added, and the product was extracted with dichloromethane. The organic layer was washed with water, dried, and the solvent was distilled off. The residue obtained was separated and purified by column chromatography (methanol / ethyl acetate 1: 2) to give the desired product as a red oil (570 mg, 0.98 mmol). I got ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.33-1.49 (2H, m), 1.50-1.
70 (1H, m), 1.73-1.85 (2H, m), 2.22-2.38 (2H, m), 2.85-
3.00 (2H, m), 3.161 (2H, s), 3.282 (2H, t, J = 6.4Hz), 5.
75-5.85 (2H, m), 6.60-6.73 (3H, m), 7.081 (1H, s), 7.616
(1H, s), 8.081 (2H, s), 9.458 (1H, br s).

2) N- [1-[[3,5-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4 -Synthesis of carboxamide dihydrochloride N- [1-[[3,5-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenafti 2 ml of 4N hydrogen chloride / ethyl acetate solution in chloroform-methanol (1: 1) solution of len-4-carboxamide
(8.0 mmol), the solvent was distilled off under reduced pressure, ether was added to the residue obtained, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give the desired product as orange crystals (404 mg, 41%).
I got ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.45-1.95 (5H, m), 3.00
-3.40 (4H, m), 3.50-3.68 (2H, m), 4.268 (2H, s), 6.647
(1H, d, J = 7.4Hz), 6.996 (1H, d, J = 9.2Hz), 7.24-7.35 (2
H, m), 7.698 (1H, s), 7.854 (1H, s), 8.392 (2H, s), 9.017
(1H, brs), 10.179 (1H, brs), 12.225 (1H, s). IR (KBr): 3420, 3230, 3050, 2950, 1700, 1635, 156
0, 1540, 1500, 1470, 1440, 1380, 1280, 1215, 1180,
1130, 940, 890, 840, 780, 700, 680 cm ^-1 . Elemental analysis (as C ₂₆ H ₂₅ N ₅ O ₂ SCl ₂ F ₆ .0.2H ₂ O) Calculated: C, 47.31; H, 3.88 N, 10.61. Found: C, 47.59; H, 4.19; N, 10.45.

Example 126 N- [1-[[2,6-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide dihydrochloride 1) In the same manner as in Example 125 1), a red solid N-
[1-[[2,6-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.25-1.45 (2H, m), 1.55-
1.85 (3H, m), 2.26-2.40 (2H, m), 2.88-2.90 (2H, m), 3.1
72 (2H, s), 3.266 (2H, t, J = 6.1Hz), 5.75-5.80 (1H, m),
5.809 (1H, dd, J = 6.3,1.8Hz), 6.61-6.75 (3H, m), 7.075
(1H, s), 7.452 (1H, dlike), 7.744 (1H, d like), 8.896 (1
H), 10.20 (1H, br s). 2) In the same manner as in Example 125-2), yellow N-
[1-[[2,6-bis (trifluoromethyl) phenyl] aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-
4-Carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.70 (3H, m), 1.70-
1.95 (3H, m), 3.00-3.20 (2H, m), 3.50-3.65 (2H, m), 4.1
5-4.40 (3H, m), 6.564 (1H, d, J = 7.6Hz), 6.950 (1H, d, J =
9.2Hz), 7.18-7.28 (2H, m), 7.616 (1H, s), 7.928 (1H, dl
ike), 8.85-9.00 (1H, m), 10.04 (1H, br s), 10.80 (1H, b
rs). IR (KBr): 3400, 3230, 3050, 2950, 1700, 1630, 158
0, 1560, 1540, 1500, 1430, 1390, 1330, 1315, 1600,
1210, 1180, 1130, 1080, 1040, 940, 840, 780, 74
0, 630 cm ^-1 . Elemental analysis (as C ₂₆ H ₂₅ N ₅ O ₂ SCl ₂ F ₆ · 1.0 H ₂ O) Calculated: C, 46.30; H, 4.03; N, 10.38. 46.16; H, 3.91; N, 10.40.

Example 127 N- [1-[(4-Fluorophenyl) aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 125 1), N
-[1-[(4-Fluorophenyl) aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-1.45 (2H, m), 1.50-
1.70 (1H, m), 1.70-1.95 (2H, m), 2.18-2.35 (2H, m), 2.8
5-3.00 (2H, m), 3.107 (2H, s), 3.20-3.35 (2H, m), 5.797
(1H, dd, J = 2.2, 5.5Hz), 5.98-6.15 (1H, m), 6.59-6.77 (3
H, m), 6.98-7.15 (3H, m), 7.45-7.65 (2H, m), 9.123 (1H, b
rs). 2) In the same manner as in 2) of Example 125, N-
[1-[(4-fluorophenyl) aminocarbonylmethyl] piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (6H, m), 2.9
8-3.30 (3H, m), 3.48-3.60 (2H, m), 4.157 (2H, s), 6.63
9 (1H, d, J = 6.8Hz), 6.990 (1H, d, J = 9.2Hz), 7.15-7.35
(3H, m), 7.63-7.75 (3H, m), 8.96-9.08 (1H, m), 10.026 (1
H, br s), 11.162 (1H, s). IR (KBr): 3400, 3230, 3050, 2
950, 1695, 1630, 1560, 15
35, 1500, 1300, 1210, 840,
780, 700, 620 cm ^-1 . Elemental analysis _{(C 24 H 26 N 5 O} 2 SCl 2 F · 2.2H 2 O
Calculated: C, 49.86; H, 5.30; N, 12.11. Found: C, 50.29; H, 5.31; N, 11.65.

Example 128 Synthesis of N- [1- (benzylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Implementation As in Example 125 1), the red oily N
-[1- (Benzylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.05-1.30 (2H, m), 1.40-
1.60 (1H, m), 1.655 (2H, br d like, J = 12.8), 2.127 (2
H, t like, J = 10.7Hz), 2.828 (2H, br d, J = 11.4Hz), 3.0
20 (2H, s), 3.152 (2H, t, J = 6.4Hz), 4.468 (2H, d, J = 5.8H
z), 5.741 (1H, dd, J = 3.0, 5.2Hz), 6.490 (1H, t, J = 5.9H
z), 6.59-6.65 (3H, m), 6.949 (1H, s), 7.239-7.385 (5
H, m), 7.526-7.58 (1H, t, J = 5.9 Hz). 2) In the same manner as in Example 125-2), orange N-
[1- (Benzylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.90 (4H, m), 2.95
-3.51 (7H, m), 3.983 (2H, brs), 4.352 (2H, d, J = 5.8H
z), 6.649 (1H, d, J = 7.4Hz), 7.003 (1H, d, J = 9.2Hz), 7.20
-7.39 (6H, m), 7.693 (1H, s), 9.05-9.15 (1H, m), 9.316
(1H, t, J = 5.9Hz), 10.00 (1H, br s). IR (KBr): 3420, 3220, 3050, 2930, 1680, 1630, 156
0, 1540, 1500, 1450, 1430, 1390, 1285, 1210, 1110,
950, 780, 740, 700 cm ^-1 . Elemental analysis (as C ₂₅ H ₂₉ N ₅ O ₂ SCl ₂ · 0.5 H ₂ O) Calculated: C, 55.25; H, 5.56; N, 12.89. C, 55.02; H, 6.29; N, 12.22.

Example 129 N- [1- (N-methyl-N-phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in Example 125 1), N
-[1- (N-methyl-N-phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-
1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ:
1.18-1.53 (3H, m), 1.55-1.68 (2H, m), 1.88-2.05 (2H, m
m), 2.78-2.95 (2H, m), 2.912 (2H, s), 3.150 (2H, t lik
e, J = 5.9Hz), 3.266 (3H, s), 5.763 (1H, dd, J = 2.8, 5.4H
z), 6.433 (1H, br s), 6.60-6.63 (2H, m), 6.700 (1H, s),
6.991 (1H, s), 7.16-7.22 (2H, m), 7.29-7.48 (3H, m). 2) In the same manner as in Example 125-2), orange N-
[1- (N-methyl-N-phenylaminocarbonylmethyl) piperidin-4-ylmethyl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide dihydrochloride was obtained. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.40-1.95 (4H, m), 2.8
2-3.10 (3H, m), 3.10-3.55 (4H, m), 3.243 (3H, s), 3.80
-3.91 (2H, m), 6.651 (1H, d, J = 7.6Hz), 7.003 (1H, d, J =
9.2Hz), 7.25-7.60 (6H, m), 7.694 (1H, s), 9.00-9.15 (1
H, m), 9.632 (1H, brs). IR (KBr): 3400, 3230, 3050, 2950, 1650, 1630, 159
0, 1560, 1535, 1500, 1455, 1435, 1360, 1290, 1210,
1130, 1110, 1040, 950, 780, 700, 620 cm ^-1

Example 130 N- [1- (3,3-Diphenylpropan-1-yl)
Piperidin-4-ylmethyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) In the same manner as in 1) of Example 38, N
-[1- (3,3-Diphenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.75 (5H, m), 1.90-2.05 (2
H, m), 2.20-2.60 (4H, m), 2.98 (2H, brd, 11.4Hz), 3.
19 (2H, t, 5.9Hz), 3.95 (1H, brt, 6.6Hz), 5.78 (1H, d
d, 1.8, 5.8Hz), 5.95-6.05 (1H, m), 6.57-6.70 (2H,
m), 6.72 (1H, s), 7.04 (1H, s), 7.10-7.35 (10H, m). IR (KBr): 3359, 3059, 3026, 2927, 2810, 1618, 154
3,1510,1481,1452,1282,1155,970,771,752,73
5,702 cm ^-1 . 2) N- [1- (3,3-diphenylpropan-1-yl) piperidin-4-ylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride The target compound was obtained as an orange solid in the same manner as in 6) of Example 1 using the above compound. ¹ H-NMR (CD ₃ OD) δ: 1.40-1.70 (2H, m), 1.80-2.00 (3
H, m), 2.50-2.65 (2H, m), 2.80-3.10 (4H, m), 3.19 (2
H, d, 5.8Hz), 3.50-3.65 (2H, m), 4.02 (1H, t, 7.7H
z), 6.60 (1H, d, 7.6Hz), 6.96-7.01 (2H, m), 7.15-7.4
5 (11H, m), 7.51 (1H, s). IR (KBr): 3388, 3061, 2933, 2694, 1635, 1564, 153
5, 1498, 1454, 1394, 1290, 1215, 1103, 781, 704 cm
^-1 Elemental analysis _{(C 31 H 34 N 4 OSCl} 2 · 1.5H 2 O ) Calculated values: C, 61.18; H, 6.13 ; N, 9.21. Found: C, 61.15; H, 6.21; N, 9.32.

Example 131 N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1 ) N-[(1-ethoxycarbonyl) piperidine-4
Synthesis of 5-thia-1,8b-diazaacenaphthylenecarboxylic acid 2.02 g (9.26 mmol) of acetonitrile (3
0 ml) N-hydroxysuccinimide 2.1 in solution
3 g (18.51 mmol) and N-ethyl-N'-3
3.55 g (18.52 mmol) of-(N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. To a solution of the residue in acetonitrile (27 ml) was added a mixture of 1.9 ml (11.08 mmol) of ethyl-4-aminopiperidinecarboxylate and 2.5 ml (17.9 mmol) of triethylamine in acetonitrile (5 ml). And stirred at room temperature for 2 hours.
The solvent was distilled off under reduced pressure, and the residue was extracted with water and methylene chloride. The organic layer was washed with saturated saline and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / ethyl acetate 20%) to give N-[(1-ethoxycarbonyl) piperidine-4- as a red amorphous substance.
Ill] -5-Thia-1,8b-diazaacenaphthylenecarboxamide, 3.12 g (91%). ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.46 (m, 2H), 1.26 (t, J = 7.0H
z, 3H), 1.93-2.02 (m, 2H), 2.84-2.97 (m, 2H), 3.87-
4.21 (m, 2H), 4.13 (q, J = 7.0Hz, 2H), 5.67 (brd, J = 8.0
Hz, 1H), 5.80 (dd, J = 1.8, 6.2Hz, 1H), 6.59-6.71 (m,
3H), 7.05 (s, 1H).

2) Synthesis of N- (1-tert-butoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide N-[(N-ethoxycarbonyl) under an argon atmosphere
1.58 g of piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylenecarboxamide (4.24 g)
Mmol) in acetonitrile (35 ml) at room temperature in 1.8 ml of trimethylsilane iodide (12.65).
Mmol) and stirred for 16 hours. Further, 1.2 ml (8.43 mmol) of trimethylsilane iodide was added, and the mixture was stirred at room temperature for 2 days. Methanol was added to the reaction solution to stop the reaction, and the mixture was stirred at room temperature for 2 hours. At room temperature, 4 ml (28.7 mmol) of triethylamine and 1.07 ml (4.66 mmol) of di-tert-butyl dicarbonate were added to the mixture, and the mixture was stirred for 10 minutes. After evaporating the solvent under reduced pressure, water and methylene chloride were added for extraction. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / ethyl acetate 10%) to give N- (1-tert-butoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene. 2.12 g of carboxamide were obtained as a red amorphous substance. ¹ H-NMR (CDCl ₃ ) δ: 1.13-1.99 (m, 2H), 1.46 (s, 9H),
1.73-1.98 (m, 2H), 2.74-2.95 (m, 2H), 3.84-4.18 (m, 3
H), 5.70-5.85 (m, 1H), 5.79 (dd, J = 1.9, 5.7Hz, 1H),
6.58-6.72 (m, 3H), 7.04 (s, 2H). 3) N- (piperidin-4-yl) -5-thia-1,8
Synthesis of b-diazaacenaphthylenecarboxamide dihydrochloride N- (1-tert-butoxycarbonylpiperidine-
10 ml of concentrated hydrochloric acid was added to 2.12 g of 4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide, and the mixture was stirred at room temperature for 2 hours. The solid was removed by filtration and ethanol was added to the mother liquor. After evaporating the solvent under reduced pressure, ethanol was added again, and the mixture was further concentrated. This operation was repeated several times, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give N- (piperidin-4-yl) -5-thia-1,3 as an orange solid.
0.95 g (60%) of 8b-diazaacenaphthylenecarboxamide dihydrochloride was obtained. ¹ H-NMR (D ₂ O) δ: 1.64-1.87 (m, 2H), 2.03-2.19 (m, 2H),
3.03-3.21 (m, 2H), 3.42-3.58 (m, 2H), 3.82-4.02 (m,
1H), 5.98 (d, J = 7.0Hz, 1H), 6.60 (d, J = 9.2Hz, 1H), 6.
67 (s, 1H), 6.78 (dd, J = 7.2, 9.2Hz, 1H), 6.98 (s, 1H
H).

4) N- [1- (3-phenylpropane-
1-yl) piperidin-4-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride N- (piperidin-4-yl) -5-thia-1,8b-
Diazaacenaphthylenecarboxamide dihydrochloride 3.0
g (8.84 mmol) and 4.1 m of triethylamine
l (29.4 mmol) in ethanol (40 ml) at room temperature in 1.6 ml of 3-phenyl-1-bromopropane.
1 (10.53 mmol) was added and the mixture was heated and refluxed for 16 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, water was added,
Extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Separation and purification by silica gel column chromatography (methanol / ethyl acetate 20-40%), N- [1- (3-phenylpropane-1) was obtained as a red-purple amorphous substance.
-Yl) piperidin-4-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide 2.91
g (86%). ¹ H-NMR (CDCl ₃ ) δ: 1.41-1.64 (m, 2H), 1.75-2.21 (m, 6
H), 2.31-2.47 (m, 2H), 2.63 (t, J = 7.7Hz, 2H), 7.79-
2.96 (m, 2H), 3.72-3.92 (m, 1H), 5.75-5.80 (m, 2H),
6.57-6.69 (m, 1H), 7.03 (s, 1H), 7.16-7.32 (m, 5H). 5) N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -5 Synthesis of -Thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1, 10 ml (40 mmol) of a 4N hydrogen chloride / methanol solution in a solution of 2.91 g (6.95 mmol) of 8b-diazaacenaphthylene-4-carboxamide in ethanol (10 ml) at room temperature
Was added and stirred at room temperature for several minutes. The solvent is distilled off under reduced pressure,
Ethanol and diethyl ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give N- [1
-(3-phenylpropan-1-yl) piperidine-4
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 3.08 g (90%)
I got ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.14 (m, 6H), 2.63 (t, J = 7.5
Hz, 2H), 2.82-3.11 (m, 4H), 3.38-3.56 (m, 2H), 3.72-
3.93 (m, 1H), 6.64 (d, J = 6.6Hz, 1H), 6.99 (d, J = 9.2H
z, 1H), 7.15-7.38 (m, 7H), 7.67 (s, 1H), 8.80-8.90
(m, 1H). Elemental analysis (as C ₂₄ H ₂₈ N ₄ OSCl ₂ .2.5H ₂ O) Calculated: C, 53.73; H, 6.20; N, 10.44. Found: C, 53.84; H, 6.06 N, 10.28.

Example 132 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1) 4 Synthesis of tert-butyl-aminopiperidine-1-carboxylate 1/2 hydrogensulfate potassium 50 g of 4-amino-1-benzylpiperidine (262.
5 mmol of 5% palladium-carbon (water-containing) was added to a 500 ml solution of methanol (8 mmol), and the hydrogen pressure was 5 kg / c.
Catalytic reduction at 35 ° C. for 15 hours at m ² . After removing the catalyst palladium-carbon by filtration, the mixture was concentrated under reduced pressure to give 4
-Aminopiperidine was obtained. To a solution of 4-aminopiperidine in toluene (500 ml) was added benzaldehyde (27.89 g, 262.8 mmol), and Dea was added.
The mixture was heated under reflux for 3 hours while removing water generated by the n-stark trap. After cooling to room temperature, di-tert-butyl dicarbonate (63.08 g, 289 mmol) was slowly added dropwise in about 1 hour, and the mixture was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, 1N aqueous potassium hydrogen sulfate solution (290 ml) was added to the residue at room temperature, and the mixture was stirred for 2 hours. The resulting crystals were collected by filtration and washed with water, ethanol and diethyl ether to give colorless crystals of tert-butyl 4-aminopiperidine-1-carboxylate · 1/2 bisulfate potassium salt (49.02 g, 71
%). ¹ H-NMR (200 MHz, CD ₃ CO ₂ D) δ: 1.47 (s, 9H), 1.52-1.73
(m, 2H), 2.01-2.18 (m, 2H), 2.75-2.98 (m, 2H), 3.41-
3.59 (m, 1H), 4.10-4.32 (m, 2H). IR (KBr): 1689, 1621, 1543, 1429, 1369, 1252, 115
1, 1065, 862, 766, 617 cm ^-1 2) Synthesis of N- (1-tert-butoxycarbonylpiperidin-4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide dihydrochloride 5 To a suspension of 12.88 g (53.8 mmol) of thia-1,8b-diazaacenaphthylene carboxylic acid in 27 ml of acetonitrile was added 12.38 g (107.6 mmol) of N-hydroxysuccinimide and N -Ethyl-
N'-3- (N, N-dimethylamino) propyl carbodiimide hydrochloride 20.63 g (107.6 mmol)
Was added and stirred at room temperature for 2 hours. Then, 17.3 g (64.5 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate 1/2 hydrogensulfate potassium salt,
8-diazabicyclo [5.4.0] -7-undecene 1
9.6 g (128.7 mmol) and 7.5 ml (53.8 mmol) of triethylamine in acetonitrile (8
0 ml) solution and stirred for 64 hours. After distilling off the solvent under reduced pressure, a small amount of ethanol and ethyl acetate were added,
The organic layer was washed with water and saturated saline, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / ethyl acetate 10%).
-(1-tert-butoxycarbonylpiperidine-4
-Yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide (22.48 g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.16-1.46 (m, 2H), 1.26 (t, J = 7.0 H
z, 3H), 1.93-2.02 (m, 2H), 2.84-2.97 (m, 2H), 3.87-
4.21 (m, 2H), 4.13 (q, J = 7.0Hz, 2H), 5.67 (brd, J = 8.0
Hz, 1H), 5.80 (dd, J = 1.8, 6.2Hz, 1H), 6.59-6.71 (m,
3H), 7.05 (s, 1H).

3) N- (piperidin-4-yl) -5
Synthesis of thia-1,8b-diazaacenaphthylenecarboxamide dihydrochloride N- (1-tert-butoxycarbonylpiperidine-
To 22.48 g of 4-yl) -5-thia-1,8b-diazaacenaphthylenecarboxamide was added 40 ml of concentrated hydrochloric acid, followed by stirring at room temperature for 2 hours. Ethanol was added to the reaction solution, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to give N- (piperidin-4-yl) -5-thia-1,8 as orange crystals.
b-diazaacenaphthylenecarboxamide dihydrochloride 1
4.68 g (73%) were obtained. ¹ H-NMR (D ₂ O) δ: 1.64-1.87 (m, 2H), 2.03-2.19 (m, 2H),
3.03-3.21 (m, 2H), 3.42-3.58 (m, 2H), 3.82-4.02 (m,
1H), 5.98 (d, J = 7.0Hz, 1H), 6.60 (d, J = 9.2Hz, 1H), 6.
67 (s, 1H), 6.78 (dd, J = 7.2, 9.2Hz, 1H), 6.98 (s, 1H
H). 4) Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidine -4-yl) -5-thia-1,8b-
11. diazaacenaphthylenecarboxamide dihydrochloride
0 g (32.1 mmol) and triethylamine 22.4
ml (160.7 mmol) of ethanol (160 m
l) At room temperature, 5.9 ml (38.8 mmol) of 3-phenyl-1-bromopropane was added to the solution, and the mixture was heated and refluxed under a nitrogen atmosphere for 20 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / ethyl acetate 20-40%). The obtained crystals were ethanol (100 ml),
It was dissolved in chloroform (100 ml), and chloroform was distilled off by heating under normal pressure. After concentrating to a liquid volume of about 80 ml, the mixture was allowed to stand at room temperature, and the resulting crystals were collected by filtration to give N- [1- (3-phenylpropan-1-yl) piperidin-4-yl as red crystals. ] -7-Thia-1,8b-diazaacenaphthylene-4-carboxamide (7.04 g, 52%) was obtained. Melting point: 187-188 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.41-1.64 (m, 2H), 1.75-2.21 (m, 6
H), 2.31-2.47 (m, 2H), 2.63 (t, J = 7.7Hz, 2H), 7.79-
2.96 (m, 2H), 3.72-3.92 (m, 1H), 5.75-5.80 (m, 2H),
6.57-6.69 (m, 1H), 7.03 (s, 1H), 7.16-7.32 (m, 5H). Elemental analysis (as C ₂₄ H ₂₆ N ₄ OS) Calculated: C, 68.87; H, 6.26; N , 13.39. Found: C, 68.62; H, 6.25; N, 13.42.

Example 133 N- [1- [2- (6-hydroxy-2,5,7,8-
Synthesis of tetramethylchroman-2-yl) ethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [2- (6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2
-Yl) ethyl] piperidin-4-ylmethyl] -5-
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 6-tert-butyldimethylsiloxy-2- (2-hydroxyethyl) -2,5,7,8-tetramethylchroman 1 under a nitrogen atmosphere .46 g (4.00 mmol)
To a solution of 1.11 ml (7.96 mmol) of triethylamine and diethyl ether (8 ml) was added 0.46 ml (5.94 mmol) of methanesulfonyl chloride at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude mesylate (1.76 g) as a pale yellow oil. N-
(Piperidin-4-ylmethyl) -5-thia-1,8b
-The above-mentioned crude mesylate (1) was added at room temperature to a solution of 0.77 g (1.99 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mmol) of triethylamine in ethanol (7 ml). .76
g, 3.98 mmol) under a nitrogen atmosphere.
Heated to reflux for an hour. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (methanol / ethyl acetate: 20-40%) to obtain the target compound as a red amorphous substance. Yield 1.00 g (76% yield) ¹ H-NMR (CDCl ₃ ) δ: 0.11 (s, 6H), 1.04 (s, 9H), 1.24 (s, 3
H), 1.42-2.01 (m, 11H), 2.04 (s, 3H), 2.06 (s, 3H), 2.09
(s, 3H), 2.45-2.61 (m, 4H), 2.84-3.00 (m, 2H), 3.17-3.2
3 (m, 2H), 5.72-5.84 (m, 1H), 5.80 (dd, J = 1.6,6.2Hz, 1H),
6.59-6.74 (m, 3H), 7.06 (s, 1H). IR (KBr): 3442, 2929, 1622, 1545, 1468, 1257, 1153,
1092, 837, 773 cm ^-1

2) N- [1- [2- (6-hydroxy-
2,5,7,8-tetramethylchroman-2-yl) ethyl] piperidin-4-ylmethyl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [2- (6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl) Ethyl] piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.00 g (1.51 mmol) in ethanol (4
ml) solution to a 4.0N hydrogen chloride / methanol solution 4.0m
1 (16 mmol) was added and the mixture was stirred at room temperature for 63 hours.
After evaporating the solvent under reduced pressure, ethanol was added and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 789.4 mg (yield 84%) ¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (s, 3H), 1.36-2.08 (m, 11H),
1.99 (s, 3H), 2.02 (s, 3H), 2.05 (s, 3H), 2.76-3.55 (m, 8
H), 6.58 (d, J = 7.0Hz, 1H), 6.96 (d, J = 8.4Hz, 1H), 7.17-
7.30 (m, 2H), 7.63 (s, 1H), 8.84-8.96 (m, 1H), 10.07-10.
32 (m, 1H). IR (KBr): 3392, 1635, 1564, 1450, 1294, 1253, 1161,
1088, 995, 789 cm ^-1 Elemental analysis _{(C 31 H 40 N 4 O} 3 SCl 2 · 2.0H 2 O ) Calculated values:. C, 56.79; H, 6.76; N, 8.54 Found: C, 56.93 ; H, 6.79; N, 8.35.

Example 134 N- [1- [2- (6-hydroxy-2,5,7,8-
Synthesis of tetramethylchroman-2-yl) ethyl] piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [2- (6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2
-Yl) ethyl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide Under a nitrogen atmosphere, 6-tert-butyldimethylsiloxy-2- (2-hydroxyethyl) -2,5,7,8-tetramethylchroman 1.46 g (4.00 mmol)
To a solution of 1.11 ml (7.96 mmol) of triethylamine and diethyl ether (8 ml) was added 0.46 ml (5.94 mmol) of methanesulfonyl chloride at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude mesylate (1.75 g) as a pale yellow oil. N- (piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 0.93
g (2.4 mmol) and triethylamine 1.7 m
To a solution of 1 (12.2 mmol) in ethanol (10 ml) was added the above mesylate (1.75 g) at room temperature, and the mixture was heated under reflux under a nitrogen atmosphere for 16 hours. Water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (methanol / ethyl acetate: 20-30%) to obtain the target compound as a red amorphous substance. Yield 1.17 g (74% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.11 (s, 6H), 1.04 (s, 9H),
1.25 (s, 3H), 1.68-2.22 (m, 8H), 2.05 (s, 6H), 2.09 (s, 3
H), 2.24-2.90 (m, 6H), 3.03-3.22 (m, 2H), 3.79-4.02 (m,
2H), 5.79 (dd, J = 1.8,5.8Hz, 1H), 5.97-6.09 (m, 1H), 6.5
7-6.69 (m, 2H), 6.73 (s, 1H), 7.06 (s, 1H). IR (KBr): 3444, 2943, 1624, 1251, 1153, 1092, 837,
773 cm ^-1

2) N- [1- [2- (6-hydroxy-
2,5,7,8-Tetramethylchroman-2-yl) ethyl] piperidin-4-yl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [2- (6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-yl) ethyl] Piperidin-4-yl] -5-thia-1,
8b-diazaacenaphthylene-4-carboxamide
17 g (1.78 mmol) of ethanol (5 ml)
5.0 ml of a 4N hydrogen chloride / methanol solution (20 ml) was added to the solution.
Mmol) and stirred at room temperature for 90 hours. After evaporating the solvent under reduced pressure, ethanol and diethyl ether were added, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 867.3 mg (80% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.19 (s, 3H), 1.62-2.13 (m,
8H), 2.00 (s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.43-2.65
(m, 2H), 2.80-3.59 (m, 6H), 3.71-4.08 (m, 1H), 6.62 (d, J
= 7.8Hz, 1H), 6.98 (d, J = 8.8Hz, 1H), 7.22 (s, 1H), 7.29 (d
d, J = 7.6,8.8Hz, 2H), 7.65 (s, 1H), 8.72-8.91 (m, 1H), 1
0.37-10.79 (m, 1H). IR (KBr): 3396, 1635, 1533, 1450, 1306, 1257, 1219
cm ^-1

Example 135 N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethyl] -3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4- Synthesis of carboxamide dihydrochloride 1) Synthesis of ethyl 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylate Imidazo [1,2-a] pyridine-5-thiaacetic acid 11.8 g (50 mmol) of ethyl acetonitrile (250
13.9 g (75 mmol) of N, N-dimethylmethyleneammonium iodide was added to the solution at room temperature, and the mixture was refluxed for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was separated and purified by column chromatography (hexane / ethyl acetate: 10-20%) to obtain the desired product as a red-purple oil. Yield 5.13 g (yield 41%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.19 (t, 3H, J = 7.2 Hz), 3.63-
3.80 (m, 2H), 4.05-4.22 (m, 3H), 6.78 (d, J = 7.0Hz, 1H),
7.09-7.17 (m, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.53 (s, 1H).

2) N-[(1-tert-butoxycarbonyl-4-piperidin-4-yl) methyl] -3,4
Synthesis of -dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5.13 g of ethyl 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylate (20.7
Mmol) in ethanol (20 ml) at room temperature
12 ml (24 mmol) of an aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour. 4 ml (24 mmol) of 6N hydrochloric acid was added to the reaction system, and the precipitated crystals were collected by filtration.
The crystals were washed with ethanol and diethyl ether to give 3,4-dihydro-5-thia-1,8b-
Diazaacenaphthylene-4-carboxylic acid was obtained. This carboxylic acid was used for the next reaction without purification. 661 mg (3.0 mmol) of the above 3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid was added to 2.2 ml (30.0 mmol) of thionyl chloride, and the mixture was heated at 60 ° C. For 1 hour. After the reaction, excess thionyl chloride was distilled off under reduced pressure.
After adding and mixing well, the solvent was distilled off under reduced pressure.
-Dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid chloride / hydrochloride was obtained. To a solution of the obtained acid chloride in 30 ml of THF was added, at 0 ° C, 2.5 ml (40.0 mmol) of triethylamine and 1-
1286 mg (6.0 mmol) of (tert-butoxycarbonyl) -4-aminomethylpiperidine were added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, add 50 ml of ice water to the reaction solution.
The mixture was poured on top, and the mixture was extracted with 100 ml of ethyl acetate. The organic layer was washed with 100 ml of saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent;
Purification with ethyl acetate: ethanol = 10: 1) gave 801 mg (yield: 64.1%) of the desired product as a brown amorphous substance. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.72-1.01 (m, 2H), 1.25-1.38
(m, 3H), 2.38-2.61 (m, 2H), 2.83-3.02 (m, 1H), 3.08-3.2
7 (m, 1H), 3.62 (dd, 1H, J = 17.4Hz, 7.0Hz), 3.87-4.09 (m, 4
H), 6.66 (t, 1H, NH, J = 5.8Hz), 6.77 (d, 1H, J = 7.2Hz), 7.1
1 (dd, 1H, J = 9.2Hz, 7.2Hz), 7.45 (d, 1H, J = 9.2Hz), 7.51
(s, 1H). IR (KBr): 1666,1385,1188cm ^-1 .

3) Synthesis of N- (4-piperidin-4-yl) methyl-3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [ (1-tert-butoxycarbonyl-4-piperidin-4-yl) methyl] -3,4-dihydro-5-
0.47 ml of 12N hydrochloric acid was added to a solution of 480 mg (1.15 mmol) of thia-1,8b-diazaacenaphthylene-4-carboxamide dissolved in 20 ml of 2-propanol.
(5.76 mmol) was added and stirred at room temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with a small amount of ether to obtain 404 mg of the desired product (yield 90.2%).
Was obtained as white crystals. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.18-1.53 (m, 2H), 1.58-1.
85 (m, 3H), 2.64-2.88 (m, 2H), 3.12-3.36 (m, 4H), 3.63-
3.75 (m, 2H), 4.65 (t, 1H, J = 5.8Hz), 7.51 (dd, 1H, J = 6.4H
z, 2.2Hz), 7.77-7.92 (m, 2H), 8.18 (s, 1H), 9.04 (t, 1H, N
H, J = 5.4 Hz), 9.20 (brs, 2H, NH). IR (KBr): 1649, 1554, 1504 cm ^-1 .

4) N- [1- (3-phenylpropane-
1-yl) piperidin-4-ylmethyl] -3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide N- (4-piperidin-4-yl) methyl-3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-
746.4 mg of 4-carboxamide dihydrochloride (1.9
1 mmol) and 1.4 ml of triethylamine (10.
0 mmol) in ethanol (5 ml) at room temperature.
-Bromo-3-phenylpropane 0.35 ml (2.3
(0 mmol), and the mixture was heated and refluxed under a nitrogen atmosphere for 64 hours. Water was added to the reaction system, and extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. Separation and purification by column chromatography (methanol / ethyl acetate: 20-30-50%) gave the desired product as a red amorphous. Yield 583.9 mg (70% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.06
-1.38 (m, 4H), 1.70-1.92 (m, 3H), 1.96-2.25 (m, 2H), 2.3
3-2.41 (m, 2H), 2.56-2.64 (m, 2H), 2.79-3.00 (m, 3H), 3.
08-3.26 (m, 1H), 3.57-3.72 (m, 1H), 3.97-4.10 (m, 2H), 6.
53-6.69 (m, 1H), 6.78 (dd, J = 7.0,1.0Hz, 1H), 7.03-7.34
(m, 6H), 7.45 (dd, J = 9.2,1.0Hz, 1H), 7.53 (s, 1H). IR (KBr): 3304, 2926, 1657, 1620, 1556, 1481, 1306,
1140 cm ^-1

5) N- [1- (3-phenylpropane-
1-yl) piperidin-4-ylmethyl] -3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-
Synthesis of 4-carboxamide dihydrochloride N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -3,4-dihydro-5-thia-1,8b-diazaacenaphthylene -4-Carboxamide 583.9 mg (1.34 mmol) in ethanol (5 ml) was added to a 4N hydrogen chloride / methanol solution 10 m.
1 (40 mmol) was added and stirred at room temperature for several minutes. After evaporating the solvent under reduced pressure, 2-propanol was added, and the resulting crystals were removed by filtration. The mother liquor was concentrated to obtain the desired product as a light brown amorphous substance. Yield 542.5 mg (80% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.35-1.86 (m, 3H), 1.94-2.
20 (m, 2H), 2.44-3.23 (m, 10H), 3.32-4.00 (m, 4H), 4.51-
4.68 (m, 1H), 7.10-7.41 (m, 5H), 7.43-7.59 (m, 1H), 7.72
-7.92 (m, 2H), 8.16 (s, 1H), 8.87-9.08 (m, 1H), 10.53-1
0.82 (m, 1H) .IR (KBr): 3421, 3064, 2933, 2721, 1662, 1551, 1502,
1441, 1365, 1215 cm ^-1

Example 136 N- [trans-4- (4-phenylpiperidine-1)
Synthesis of -ylmethyl) -1-cyclohexylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [trans-4- (4-phenylpiperidine-1- Ylmethyl) -1-cyclohexylmethyl] -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 0.41 g (1.88 mmol) and N-hydroxyamber To a solution of 0.37 g (3.21 mmol) of acid imide in acetonitrile (5 ml) was added N-ethyl- at room temperature.
0.62 g (3.23 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide was added, and the mixture was stirred for 1 hour. In the reaction system, 0.70 g (1.95 mmol) of 1- (trans-4-aminomethyl-1-cyclohexylmethyl) -4-phenylpiperidine dihydrochloride and 1.0 ml (7.17 mmol) of triethylamine in chloroform ( 10 ml) suspension and stirred for a further 2 hours. After evaporating the solvent under reduced pressure, water and a small amount of ethanol were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (methanol / ethyl acetate: 30-50%), and further recrystallized from ethyl acetate to obtain the desired product as magenta crystals. Yield 576.9 mg (63% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.78-1.03 (m, 4H), 1.62-2.03
(m, 12H), 2.20 (d, J = 7.0Hz, 2H), 2.39-2.59 (m, 1H), 2.94
-3.08 (m, 2H), 3.11-3.23 (m, 2H), 5.72-5.84 (m, 1H), 5.7
9 (dd, J = 6.2,1.6Hz, 1H), 6.58-6.74 (m, 3H), 7.06 (s, 1H),
7.12-7.36 (m, 5H). IR (KBr): 3336, 2922, 1618, 1533, 1277, 1161 cm ^-1

2) N- [trans-4- (4-phenylpiperidin-1-ylmethyl) -1-cyclohexylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis of N- [trans-4- (4-phenylpiperidine-1
-Ylmethyl) -1-cyclohexylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide A solution of 549.7 mg (1.13 mmol) of ethanol (5 ml) in 1.0 ml of 12N hydrochloric acid ( 12.0 mmol) and stirred at room temperature for several minutes. After concentration under reduced pressure, diethyl ether was added, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 541.1 mg (86% yield) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 0.80-1.12 (m, 4H), 1.29-
2.09 (m, 8H), 2.14-2.41 (m, 2H), 2.65-3.17 (m, 7
H), 3.44-3.62 (m, 2H), 6.63 (d, J = 6.8 Hz, 1H), 6.99
(d, J = 8.2 Hz, 1H), 7.19 (s, 1H), 7.21-7.42 (m, 6
H), 7.67 (s, 1H), 8.81 (t, J = 5.6 Hz, 1H), 10.14-10.
40 (m, 1H). IR (KBr): 3417, 2924, 1635, 1564, 1535, 1500, 144
1, 1292 cm ^-1 Elemental analysis (as C ₂₉ H ₃₆ N ₄ OSCl ₂ · 1.5 H ₂ O) Calculated: C, 59.38; H, 6.70; N, 9.55. Found: C, 59.10; H, 6.65 ; N, 9.55.

Example 137 N- [1- (4-Phenylbutan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [1- (4-phenylbutan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4) -Yl) -5-thia-1,8b-
72.5 mg (1.94 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride, 1.4 ml (10.0 mmol) of triethylamine in ethanol (7 m
l) Add 1-iodo-4-phenylbutane to solution at room temperature.
61 g (2.33 mmol) were added under nitrogen atmosphere.
Heated to reflux for an hour. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was subjected to column chromatography (methanol / ethyl acetate:
30%), and recrystallized from ethyl acetate to obtain the desired product as pale purple crystals. Yield 495.2 mg (59% yield) Melting point 183-185 ° C. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.47-1.68 (6H, m), 1.86-
2.03 (2H, m), 2.12-2.29 (2H, m), 2.39-2.51 (2H, m),
2.57-2.72 (2H, m), 2.89-3.05 (2H, m), 3.74-3.97
(1H, m), 5.78 (1H, dd, J = 6.2, 1.8 Hz), 5.81-5.92
(1H, m), 6.58-6.70 (3H, m), 7.05 (1H, s), 7.11-7.3
5 (5H, m). IR (KBr): 3298, 2941, 1612, 1535, 1277, 1159 cm ^-1

2) N- [1- (4-phenylbutane-1)
-Yl) piperidin-4-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- (4-phenylbutan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenafti 437.4 mg of len-4-carboxamide (1.01
0.5 mmol (6 mmol) of 12N hydrochloric acid was added to a solution of (mmol) in ethanol (10 ml), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, a small amount of ethanol was added, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 431.1 mg (84% yield) Melting point 232-237 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.48-2.02 (8H, m), 2.54
-2.67 (2H, m), 2.77-3.15 (4H, m), 3.24-3.53 (2H, m
m), 3.70-4.08 (1H, m), 6.54 (1H, d, J = 7.4Hz), 6.93
(1H, d, J = 9.2Hz), 7.10-7.36 (7H, m), 7.58 (1H, s),
8.64-8.71 (0.2H, m), 8.78 (0.8H, d, J = 7.2Hz), 10.
06-10.25 (0.2H, m), 10.38-10.60 (0.8H, m). IR (KBr): 3415, 2939, 1632, 1566, 1535, 1500, 1304,
1213 cm ^-1 Elemental analysis (as C ₂₅ H ₃₀ N ₄ OSCl ₂ · 2.0 H ₂ O) Calculated: C, 55.45; H, 6.33; N, 10.35. Found: C, 55.46; H, 6.21; N , 10.56.

Example 138 N- [1- [3- (4-Fluorophenyl) propane-
1-yl] piperidin-4-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (4-Fluorophenyl) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide Under nitrogen atmosphere, 0.62 g (4.02 mmol) of 3- (4-fluorophenyl) propanol, 1.1 ml (7.89 mmol) of triethylamine in diethyl 0.47 methanesulfonyl chloride in ether (8 ml) solution at 0 ° C.
ml (6.07 mmol) were added and 1
Stirred for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction system to stop the reaction, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude mesylate, which was used for the next reaction without purification. N- (piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 0.75 g (2.00 mmol), triethylamine 1.4 ml (10.0 mmol) ) In ethanol (8 ml) at room temperature in 0.94 g of crude mesylate (<
4.02 mmol) and heated to reflux for 16 hours under a nitrogen atmosphere. After cooling, water was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the crude product was separated and purified by column chromatography (methanol / ethyl acetate: 20-30-40%), and further recrystallized with ethyl acetate-ethanol to obtain the desired product as red purple crystals. Yield 405.2 mg (46% yield) Melting point 117-119 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.35-1.65 (2H, m), 1.70-
2.21 (6H, m), 2.31-2.42 (2H, m), 2.60 (2H, t, J = 7.
6 Hz), 2.72-2.96 (2H, m), 3.71-3.92 (1H, m), 5.66
(1H, br d, J = 8.8 Hz), 5.78 (1H, dd, J = 5.8, 1.6 H
z), 6.58-6.71 (3H, m), 6.91-7.16 (5H, m) IR (KBr) 3284, 2941, 1614, 1535, 1508, 1281, 1160
cm ^-1

2) N- [1- [3- (4-Fluorophenyl) propan-1-yl] piperidin-4-yl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1-[(4-fluorophenyl) butan-1-yl] piperidin-4-yl] -5- Thia-1,8b-diazaacenaphthylene-4-carboxamide 378.4 m
To a solution of g (0.86 mmol) in 5 ml of ethanol was added 0.5 ml (6.0 mmol) of 12N hydrochloric acid at room temperature, followed by stirring for several minutes. After evaporating the solvent under reduced pressure, 2-propanol and ethanol were added, and the mixture was concentrated. Then, diethyl ether was added, and the resulting crystals were collected by filtration. The crystals were washed with 2-propanol and diethyl ether to obtain the desired product as orange crystals. The crystals were further dissolved in ethanol, concentrated, and added with diethyl ether. The resulting crystals were collected by filtration. The crystals were washed with ethanol / diethyl ether to obtain the desired product as orange crystals. Yield 433.5 mg (65% yield) Melting point 164-174 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.75-2.13 (6H, m), 2.54
-2.70 (2H, m), 2.82-3.10 (4H, m), 3.23-3.57 (2H,
m), 3.71-4.06 (1H, m), 6.58 (1H, d, J = 7.0 Hz), 6.9
6 (1H, d, J = 9.2 Hz), 7.05-7.36 (6H, m), 7.62 (1H,
s), 8.68-8.78 (0.14H, m), 8.81 (0.86H, d, J = 7.8H
. z), 10.45-10.62 (0.14H, m), 10.68-10.94 (0.86H, m) IR (KBr): 3412, 1633, 1506, 1217 cm -1 Elemental analysis _{(C 24 H 27 N 4 OSCl} 2 F · 1.0H as ₂ O) calculated:. C, 54.65; H, 5.54; N, 10.62 Found: C, 54.29; H, 5.83 ; N, 10.37.

Example 139 Synthesis of N- [4- (4-phenylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N Synthesis of-[4- (4-phenylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8bdiazaacenaphthylene-4 To a suspension of 1.0 g (4.58 mmol) of carboxylic acid and 0.90 g (7.82 mmol) of N-hydroxysuccinimide in 10 ml of acetonitrile at room temperature was added N-ethyl-
1.51 g (7.88 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1 hour. 1.67 g (4.73 mmol) of 1- [4- (aminomethyl) benzyl] -4-phenylpiperidine dihydrochloride was added to the reaction system, and 1.44 g of DBU.
(9.46 mmol) and 0.55 m of triethylamine
1 (3.95 mmol) of acetonitrile (20 ml)
The solution was added and stirred for another 4 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with brine and dried over magnesium sulfate. The crude product was separated and purified by column chromatography (methanol / ethyl acetate: 20-30%) to obtain the target compound as a red amorphous substance. Yield 1.59 g (72% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.68-1.89 (4H, m), 20.3-
2.21 (2H, m), 2.39-2.60 (1H, m), 2.93-3.10 (2H, m),
3.56 (2H, s), 4.47 (2H, d, J = 6.0 Hz), 5.77 (1H, d
d, J = 6.2, 1.8 Hz), 5.95-6.08 (1H, m), 6.62-6.70 (3
H, m), 7.03 (1H, s), 7.17-7.21 (9H, m). IR (KBr): 3295, 1615, 1543, 1481, 1281, 1155 cm ^-1

2) N- [4- (4-Phenylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (4-phenylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide To a solution of 1.59 (3.31 mmol) in ethanol (10 ml) was added 1 ml (12 mmol) of 12N hydrochloric acid at room temperature, followed by stirring for several minutes. After concentrating under reduced pressure, ethanol and diethyl ether were added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.26 g (69% yield) Melting point 269-275 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.83-2.00 (2H, m), 2.02
-2.29 (2H, m), 2.69-2.87 (1H, m), 2.90-3.14 (2H, m
m), 3.30-3.46 (2H, m), 4.29 (2H, d, J = 4.8 Hz), 4.3
7 (2H, d, J = 6.0 Hz), 6.59 (1H, d, J = 7.4 Hz), 6.96
(1H, d, J = 8.8 Hz), 7.13-7.22 (9H, m), 7.55-7.69 (3
H, m) 9.35-9.47 (1H, m) 11.00-11.22 (1H, m). IR (KBr): 3391, 1642, 15001, 1298, 770 cm ^-1 Elemental analysis (C ₂₉ H ₃₀ N ₄ OSCl ₂・ As 1.0H ₂ O) Calculated: C, 60.94; H, 5.64; N, 9.80. Found: C, 60.84; H, 5.73; N, 9.71.

Example 140 Synthesis of N- [4- (4-benzylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N Synthesis of-[4- (4-benzylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8bdiazaacenaphthylene-4 -1.0 g (4.58 mmol) of carboxylic acid / hydrochloride and 0.90 g (7.82 mmol) of N-hydroxysuccinimide
1.51 g (7.88 mmol) of N-ethyl-N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added to a suspension of acetonitrile (10 ml) at room temperature, and the mixture was stirred for 2 hours. . To the reaction system, 1.88 g (5.12 mmol) of 1- [4- (aminomethyl) benzyl] -4-benzylpiperidine dihydrochloride and DBU1.5
6 g (10.25 mmol) and 0.1 g of triethylamine.
55 ml (3.95 mmol) of acetonitrile (20
ml) solution was added and stirred for another 4 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with brine and dried over magnesium sulfate. Column chromatography of the crude product (methanol / ethyl acetate: 20%)
The desired product was obtained as a red amorphous substance. Yield 1.73 g (77% yield) ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.20-20.3 (7H, m), 2.53
(2H, d, J = 6.4 Hz), 2.79-2.93 (2H, m), 3.49 (2H,
s), 4.46 (2H, d, J = 5.4 Hz), 5.77 (1H, dd, J = 6.2,
1.8 Hz), 5.93-6.08 (1H, m), 6.56-6.71 (3H, m), 7.0
3 (1H, s), 7.07-7.37 (9H, m). IR (KBr): 3204, 1643, 1615, 1537, 1481, 1281, 115
5, 772, 700 cm ^-1

2) N- [4- (4-benzylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (4-benzylpiperidin-1-ylmethyl) benzyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide To a solution of 1.73 (3.50 mmol) in ethanol (12 ml) was added 1 ml (12 mmol) of 12N hydrochloric acid at room temperature and stirred for several minutes (crystal precipitation). After concentration under reduced pressure, ethanol and diethyl ether were added, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.48 g (75% yield) Melting point 164-172 ° C (dec.) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 1.42-1.87 (5H, m), 2.68
-2.95 (3H, m), 3.02-3.17 (1H, m), 3.18-3.33 (2H, m
m), 4.12-4.25 (2H, m), 4.35 (2H, d, J = 4.6 Hz), 6.5
7 (1H, d, J = 7.4 Hz), 6.96 (1H, d, J = 9.2 Hz), 7.11-
7.39 (9H, m), 7.50-7.65 (3H, m), 9.31-9.43 (1H, m)
10.49-10.79 (1H, m). IR (KBr): 3217, 1634, 1566, 1537, 1505, 1298, 1217,
774, 700 cm ^-1 Elemental analysis _{(C 30 H 32 N 4 OSCl} 2 · 0.5C 2 H 5 OH · 1.5H 2 O ) Calculated values:. C, 60.28; H, 6.20; N, 9.07 Found: C, 60.27; H, 5.89; N, 9.08.

Example 141 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1) 5 -Thia-1,8b-diazaacenaphthylene-4-
Synthesis of carboxylic acid imidazo [1,2-a] pyridine-5-thiol 12
0.02 g (0.7991 mol), triethylamine 1
Ethyl bromoacetate (88.6 ml, 0.79 ml) was added to 34 ml (0.959 mol) of a ethanol (500 ml) solution at room temperature.
9 mol), and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent of the reaction solution under reduced pressure, ethyl acetate was added to the residue, and the resulting precipitate (mainly triethylamine / hydrochloride) was filtered and washed with ethyl acetate. The solvent of the collected filtrate was distilled off under reduced pressure to obtain ethyl (imidazo [1,2-a] pyridin-5-ylthio) acetate as a crude product. This was used for the next reaction without purification. Brown liquid Yield: 199.7 g A solution of the obtained crude (imidazo [1,2-a] pyridin-5-ylthio) acetate (199.7 g) and hexamethylenetetramine (224 g, 1.60 mol) in acetic acid (500 ml) at 90 ° C. Stirred for days. The reaction solution was poured into water and extracted twice with ethyl acetate. The collected organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was washed with diethyl ether to give 5-thia-1, 1
Ethyl 8b-diazaacenaphthylene-4-carboxylate was obtained as a crude product. This was used for the next reaction without purification. Black purple solid Yield 193.69 g 5-thia-1,8b-diazaacenaphthylene- obtained
193.69 g of ethyl 4-carboxylate in 1 liter of ethanol
A solution of 62.9 g (1.57 mol) of sodium hydroxide in 500 ml of water was added to the solution, and the mixture was stirred at room temperature for 0.5 hour.
About 130 ml of concentrated hydrochloric acid was added to the reaction solution with stirring until the pH reached 4 to 5, and the resulting precipitate was filtered, and ethanol,
Washing with acetone and diethyl ether sequentially gave the desired product. Orange solid Yield 96.3 g (55% yield) ¹ H-NMR (DMSO-d ₆ , 200 MHz) δ: 5.97 (1 H, dd, J = 6.6,1.2H)
z), 6.57-6.73 (2H, m), 6.88 (1H, s), 7.12 (1H, s). IR (KBr): 3413, 1632, 1338 cm ^-1

2) N- [1- (3-phenylpropane-
1-yl) piperidin-4-yl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide 39.11 g (0.1792 mol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 21.7 g of N-hydroxysuccinimide (0 .188 mol) in acetonitrile (500 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide.hydrochloride (36.1 g, 0.188 mol) was added, and the mixture was stirred at room temperature overnight. Triethylamine 30.0
ml (0.215 mol) was added and 4-amino-
1- (3-phenylpropan-1-yl) piperidine 3
9.1 g (0.179 mol) of acetonitrile 100 m
A 50 ml solution of l-chloroform was added, and the mixture was stirred at room temperature for 1 hour. The resulting orange precipitate was collected by filtration and washed with acetonitrile (yield 55.75 g). The obtained crude product was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 4/1/1).
1) Further recrystallization from chloroform-ethanol gave the desired product. Red crystals Yield 49.5 g (66% yield) Melting point 189.5-191.0 ° C ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.350-1.568 (2H, m), 1.760-
2.134 (6H, m), 2.359 (2H, t, J = 7.7Hz), 2.623 (2H, t, J = 7.7
Hz), 2.804-2.865 (2H, m), 3.720-3.920 (1H, m), 5.584 (1
(H, d, J = 8.4Hz), 6.787 (1H, dd, J = 1.6,6.0Hz), 6.578-6.70
. 2 (3H, m) 7.045 (1H, s), 7.156-7.325 (5H, m) IR (KBr): 2995, 1622, 1545, 1479, 1282 cm -1 Elemental analysis (C ₂₄ H ₂₆ N ₄ OS Calculated: C, 68.87; H, 6.26; N, 13.39. Found: C, 68.83; H, 6.39;
N, 13.39.

Example 142 (E) -1- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -3- (5-thia-1,8
b-diazaacenaphthylene-4-yl) propene-1-
Synthesis of on-dihydrochloride 1) (E) -1- (piperidin-4-yl) -3- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of propen-1-one dihydrochloride 5-thia-1,8b-diazaacenaphthylene-4-methanol 2.541 g (12.441 mmol) of N, N
6 g of active manganese dioxide (Aldrich) was added to 30 ml of dimethylformamide solution, and the mixture was stirred at room temperature overnight. The insolubles in the reaction solution were filtered and washed with N, N-dimethylformamide. The solvent of the collected filtrate was distilled off under reduced pressure.
The obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde was used for the next reaction without purification. 5.30 g of tert-butyl 4-[(dimethoxyphosphoryl) acetyl] piperidine-1-carboxylate
(14.9 mmol) in 50 ml toluene solution
0.55 g of liquid paraffin suspension of sodium hydride
(13.7 mmol) was added at room temperature, and the mixture was stirred for 2.5 hours. The crude 5-thia-1,8b-
N, N- of diazaacenaphthylene-4-carbaldehyde
A solution of dimethylformamide (50 ml) was added at room temperature, and the mixture was stirred for 2 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude (E) -1-
[1- (tert-butoxycarbonyl) piperidine-
4-yl] -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) propen-1-one was used for the next reaction without purification. The obtained crude (E) -1- [1
-(Tert-butoxycarbonyl) piperidine-4-
Il] -3- (5-Thia-1,8b-diazaacenaphthylene-4-yl) propen-1-one was added with 5 ml of concentrated hydrochloric acid and stirred at room temperature for 10 minutes. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid Yield 2.596 g (54% yield) ¹ H-NMR (CD ₃ OD-DMSO-d ₆ , 200)
MHz) δ: 1.672-1.881 (2H, m), 2.050-2.123 (2H, m),
3.017-3.158 (3H, m), 3.422 (2H, td, J = 4.0,13.2Hz), 6.38
1 (1H, d, J = 15.8Hz), 6.787 (1H, d, J = 7.4Hz), 6.876 (1H,
s), 7.133 (1H, d, J = 8.8Hz), 7.354 (1H, d, J = 15.8Hz), 7.49
4 (1H, dd, J = 7.8,9.2Hz), 7.594 (1H, s) .IR (nujol): 3431,2686,1680,1635,1587,1215,102
7, 785 cm ^-1

2) (E) -1- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -3- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of propen-1-one (E) -1- (piperidin-4-yl) -3- (5-thia-1,8b-diazaacenaphthylene-4-yl) propen-1-one dihydrochloride 0.675 g (1.756 mmol) of salt, 1-bromo-3-phenylpropane 0.52
g (2.63 mmol), triethylamine 0.86 m
1 (6.15 mmol) in 30 ml of acetonitrile was heated to reflux for 1 day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue is purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 4.
/ 1) to obtain the desired product. Dark purple liquid Yield 0.159 g (21% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.619-2.110 (8H, m), 2.339-
2.526 (3H, m), 2.634 (2H, t, J = 7.7Hz), 2.962 (2H, td, J = 3.
2,11.3Hz), 5.894 (1H, dd, J = 1.8,6.4Hz), 6.050 (1H, d, J =
15.0Hz), 6.345 (1H, s), 6.651-6.786 (2H, m), 7.028-7.3
25 (7H, m). IR (neat): 2941, 1676, 1564, 1498, 1340, 1261, 114
4, 1066, 773, 750, 700cm ^-1

3) (E) -1- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -3- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of propen-1-one dihydrochloride (E) -1- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -3- (5-thia-1,8
b-diazaacenaphthylene-4-yl) propene-1-
0.159 g of ON was dissolved in 2 ml of methanol, and an excess amount of a methanol solution of hydrogen chloride was added, followed by stirring for 10 minutes.
This was concentrated and crystallized from ethanol-diethyl ether to obtain the desired product. Orange solid Yield 0.151 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.722-1.921 (2H, m), 2.008-
2.171 (4H, m), 2.726 (2H, t, J = 7.5Hz), 3.006-3.178 (5H,
m), 3.449 (0.4H, brd, J = 12.4Hz), 3.648 (1.6H, brd, J = 1
1.4Hz), 6.367 (0.8H, d, J = 15.4Hz), 6.420 (0.2H, d, J = 15.
8Hz), 6.794 (1H, d, J = 7.4Hz), 6.883 (1H, s), 7.134 (1H,
d, J = 9.0Hz), 7.199-7.418 (6H, m), 7.499 (1H, dd, J = 7.6,
9.2Hz), 7.592 (1H, s) .IR (nujol): 2457, 1678, 1635, 1581, 1209, 1126, 108
2, 972, 783, 754, 725cm -1 Elemental analysis _{(C 26 H 29 Cl 2 N} 3 OS · 1.28H as ₂ O) Calculated:. C, 59.42; H, 6.05; N, 8.00 Found: C , 59.05; H, 5.65; N, 7.93.

Example 143 (E) -5- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -1- (5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-yl) -1-penten-3-one dihydrochloride 1) (E) -5- (piperidin-4-yl) -1- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of -1-penten-3-one dihydrochloride 2.234 g (10.938 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-methanol of N, N
-25 g of dimethylformamide solution was added with 6 g of active manganese dioxide (Aldrich) and stirred at room temperature overnight. The insolubles in the reaction solution were filtered and washed with N, N-dimethylformamide. The solvent of the collected filtrate was distilled off under reduced pressure.
The obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde was used for the next reaction without purification. 4.77 g (13.1 mmol) of tert-butyl 4- [4- (dimethoxyphosphoryl) -3-oxobutyl] piperidine-1-carboxylate in 50 ml of toluene
0.48 g (12.0 mmol) of a 60% sodium hydride liquid paraffin suspension was added to the solution at room temperature, and the mixture was stirred for 2 hours. This was combined with the crude 5-thia-1, obtained above.
8b-Diazaacenaphthylene-4-carbaldehyde N, N-dimethylformamide 30 ml-toluene 50
The solution was added to the ml solution under ice-cooling, and the mixture was stirred as it was for 3 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 9/1) to give (E) -5- [1- (tert-butoxycarbonyl) piperidin-4-yl]-. 1- (5-thia-1,8b-diazaacenaphthylene-4-yl) -1
-Penten-3-one was obtained as a crude product. The obtained crude product was used for the next reaction without further purification. The obtained crude (E) -5- [1- (tert-butoxycarbonyl) piperidin-4-yl] -1- (5-thia-1,8b-diazaacenaphthylene-4-yl) -1
-Concentrated hydrochloric acid (5 ml) was added to penten-3-one, and the mixture was added at room temperature for 1 hour.
Stir for 5 minutes. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid yield 0.673 g (yield 15%) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.294-1.479 (2H, m), 1.583-
1.646 (3H, m), 1.967 (2H, d, J = 13.6Hz), 2.756 (2H, t, J = 7.
1Hz), 2.961 (2H, t, J = 13.1Hz), 3.381 (2H, d, J = 12.6Hz),
6.270 (1H, d, J = 15.8Hz), 6.803 (1H, d, J = 7.4Hz), 6.848 (1
H, s), 7.138 (1H, d, J = 9.2Hz), 7.296 (1H, d, J = 15.8Hz),
7.507 (1H, dd, J = 7.6,9.0Hz), 7.588 (1H, s) .IR (nujol): 3413,2717,1680,1635,1579,1211,107
4, 972, 792 cm ^-1

2) (E) -5- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -1- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of -1-penten-3-one (E) -5- (piperidin-4-yl) -1- (5-thia-1,8b-diazaacenaphthylene-4-yl) -1
-Penten-3-one dihydrochloride 0.362 g (0.8
78 mmol), 0.26 g (1.32 mmol) of 1-bromo-3-phenylpropane, 0.43 ml (3.07 mmol) of triethylamine in 30 m of ethanol
The solution was heated to reflux for one day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 9/1) to obtain the desired product. Dark purple liquid Yield 0.2
81 g (yield 70%) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.158-1.366 (2H, m), 1.524-
1.987 (9H, m), 2.345 (2H, t, J = 7.7Hz), 2.561 (2H, t, J = 7.7
Hz), 2.617 (2H, t, J = 7.7Hz), 2.913 (2H, d, J = 11.0Hz), 5.
898 (1H, dd, J = 1.8,6.2Hz), 5.948 (1H, d, J = 15.4Hz), 6.33
4 (1H, s), 6.649-6.785 (2H, m), 7.003 (1H, d, J = 15.4Hz),
7.107 (1H, s), 7.127-7.319 (5H, m). IR (neat): 2923, 1570, 1500, 1342, 1261, 1144, 107
6, 964, 773, 733,700 cm ^-1

3) (E) -5- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -1- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Synthesis of -1-penten-3-one dihydrochloride (E) -5- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -1- (5-thia-1,8
Dissolve 0.281 g of b-diazaacenaphthylene-4-yl) -1-penten-3-one in 2 ml of methanol,
An excess amount of a methanol solution of hydrogen chloride was added and stirred for 10 minutes. This was concentrated and crystallized from ethanol-diethyl ether to obtain the desired product. Orange solid Yield 0.309 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.403-1.733 (5H, m), 1.952-
2.148 (4H, m), 2.672-2.780 (4H, m), 2.910 (2H, t, J = 12.1H
z), 3.041-3.125 (2H, m), 3.555 (2H, d, J = 13.2Hz), 6.254
(1H, d, J = 16.2Hz), 6.791 (1H, d, J = 7.6Hz), 6.841 (1H, s),
7.130 (1H, d, J = 9.2Hz), 7.171-7.336 (6H, m), 7.496 (1H,
dd, J = 7.5,8.9Hz), 7.579 (1H, s) .IR (nujol): 3408, 3165, 2679, 1668, 1641, 1184, 97
2, 762, 723 cm ^-1 Elemental analysis _{(C 28 H 33 Cl 2 N} 3 OS · 1.0H as ₂ O) Calculated: C, 61.31; H, 6.43 ;
N, 7.66. Found: C, 61.01; H, 6.53;
N, 7.58.

Example 144 (E) -4- [2- [1- (3-Phenylpropane-1)
-Yl) piperidin-4-ylmethanesulfonyl] vinyl] -5-thia-1,8b-diazaacenaphthylene dihydrochloride 1) (E) -4- [2- (piperidin-4-yl) Synthesis of [methanesulfonyl) vinyl] -5-thia-1,8b-diazaacenaphthylene dihydrochloride 0.904 g (4.426 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-methanol N), N-
2 g of active manganese dioxide (Aldrich) was added to a 30 ml solution of dimethylformamide, and the mixture was stirred at room temperature for 4 hours. The insolubles in the reaction solution were filtered, washed with N, N-dimethylformamide, and the solvent in the collected filtrate was distilled off under reduced pressure. The obtained crude 5-thia-1,8b-diazaacenaphthylene-
4-Carbaldehyde was used for the next reaction without purification. 1. tert-butyl 4- (diethoxyphosphorylmethanesulfonylmethyl) piperidine-1-carboxylate
Liquid paraffin suspension 0.1 of 60% sodium hydride in a solution of 01 g (4.87 mmol) in 30 ml of toluene.
8 g (4.43 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The crude 5-thia-1,8b-
N, N- of diazaacenaphthylene-4-carbaldehyde
The solution was added to a solution of dimethylformamide (10 ml) -toluene (30 ml) at room temperature, followed by stirring for 0.5 hour. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 9 /
1), (E) -4- [2- [1- (tert-butoxycarbonyl) piperidin-4-ylmethanesulfonyl]
Vinyl] -5-thia-1,8b-diazaacenaphthylene was obtained as a crude product. The obtained crude product was used for the next reaction without further purification. The crude (E) obtained
-4- [2- [1- (tert-butoxycarbonyl)
Piperidin-4-ylmethanesulfonyl] vinyl] -5
-Thia-1,8b-diazaacenaphthylene and concentrated hydrochloric acid 3m
was added and stirred at room temperature for 10 minutes. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Orange solid: 1.398 g (73% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.520-1.734 (2H, m), 2.189
(2H, br d, J = 15.4Hz), 2.278-2.410 (1H, m), 3.068 (2H, t,
J = 12.6Hz), 3.226 (2H, d, J = 6.6Hz), 3.398 (2H, d, J = 12.4H
z), 6.801 (1H, d, J = 7.2Hz), 6.805 (1H, d, J = 15.4Hz), 6.9
20 (1H, s), 7.149 (1H, d, J = 8.8Hz), 7.274 (1H, d, J = 15.4H
z), 7.514 (1H, dd, J = 7.6,9.0Hz), 7.625 (1H, s) .IR (nujol): 2715, 1633, 1597, 1308, 1201, 1134, 94
5, 854, 785, 737 cm ^-1

2) (E) -4- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethanesulfonyl] vinyl] -5-thia-1,8b-diazaacenafti Synthesis of Ren (E) -4- [2- (Piperidin-4-ylmethanesulfonyl) vinyl] -5-thia-1,8b-diazaacenaphthylene dihydrochloride 0.402 g (0.925 mmol) 0.28 g of 1-bromo-3-phenylpropane
(1.39 mmol), 0.45 ml of triethylamine
A solution of (3.24 mmol) in 20 ml of ethanol was heated to reflux for 1 day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 9 / 1-
1/1) to obtain the desired product. Red liquid Yield 0.373 g (94% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.681-1.822 (2H, m), 1.887-
2.311 (7H, m), 2.542 (2H, t, J = 7.8Hz), 2.653 (2H, t, J = 7.6
Hz), 2.977 (2H, d, J = 6.2Hz), 3.072-3.182 (2H, m), 5.929
(1H, dd, J = 1.8,6.2Hz), 6.060 (1H, d, J = 15.0Hz), 6.396 (1
H, s), 6.692-6.814 (2H, m), 7.023 (1H, d, J = 15.0Hz), 7.1
61-7.326 (6H, m). IR (neat): 2939, 1581, 1498, 12
94, 1126, 837, 777, 731 c
m ^-1

3) (E) -4- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethanesulfonyl] vinyl] -5-thia-1,8b-diazaacenafti Synthesis of len dihydrochloride (E) -4- [2- [1- (3-phenylpropane-1)
-Yl) piperidin-4-ylmethanesulfonyl] vinyl] -5-thia-1,8b-diazaacenaphthylene.
418 g was dissolved in 2 ml of methanol, an excess amount of a methanol solution of hydrogen chloride was added, and the mixture was stirred for 10 minutes. This was concentrated and crystallized from ethanol-diethyl ether.
The desired product was obtained. Orange solid Yield 0.373 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.58
4-1.799 (2H, m), 2.000-2.258 (5H, m), 2.711 (2H, t, J = 7.5
Hz), 2.962-3.141 (4H, m), 3.218 (2H, d, J = 6.2Hz), 3.550
-3.619 (2H, m), 6.800 (1H, d, J = 7.6Hz), 6.802 (1H, d, J = 1
5.0Hz), 6.924 (1H, s), 7.125-7.307 (7H, m), 7.510 (1H, d
d, J = 7.4,9.0Hz), 7.627 (1H, s) .IR (nujol): 2638-2360, 1633, 1591, 1306, 1269, 112
2, 847, 816, 768 cm -1 Elemental analysis _{(C 26 H 31 Cl 2 N} 3 O 2 S 2 · 3.0H 2 O ) Calculated values:. C, 51.48; H, 6.15; N, 6.93 Found For: C, 51.69; H, 6.20; N, 6.55.

Example 145 (E) -4- [2- [1- (3-Phenylpropane-1)
-Yl) piperidin-4-ylmethylthio] vinyl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene dihydrochloride 1) (E) -4- [2- (piperidin-4-ylmethylthio) vinyl] -5-thia-1,8b-dia Synthesis of zaacenaphthylene dihydrochloride To a solution of 1.073 g (5.253 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in 30 ml of chloroform was added 3 g of active manganese dioxide (Aldrich). The mixture was stirred at room temperature for 4 hours. The insolubles in the reaction solution were filtered and washed with chloroform. The solvent of the collected filtrate was distilled off under reduced pressure, and the obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde was used for the next reaction without purification. 4- (diethoxyphosphorylmethylthiomethyl) piperidine-1-carboxylic acid tert
2.20 g (5.78 mmol) of butyl, 10 ml of N, N-dimethylformamide of the obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde
0.59 g (5.25 mmol) of potassium tert-butoxide was added to a 50 ml solution of toluene, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 4 ml of concentrated hydrochloric acid was added to the obtained residue, and the mixture was stirred at room temperature for 10 minutes. Ethanol was added thereto and the mixture was stirred, and the resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Yellow solid Yield 0.667 g (yield 32%) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.409-1.612 (2H, m), 1.859-
2.017 (1H, m), 2.098 (2H, d, J = 13.6Hz), 2.894 (2H, d, J = 6.
2Hz), 3.004 (2H, t, J = 12.4Hz), 3.418 (2H, d, J = 13.2Hz),
6.318 (1H, d, J = 15.4Hz), 6.321 (1H, s), 6.644 (1H, d, J = 1
5.4Hz), 6.767 (1H, d, J = 7.6Hz), 7.119 (1H, d, J = 9.2Hz),
7.405 (1H, s), 7.473 (1H, dd, J = 7.8,8.8Hz). IR (nujol): 2706, 1637, 1500, 1207, 937, 773 cm ^-1

2) (E) -4- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethylthio] vinyl] -5-thia-1,8b-diazaacenaphthylene Synthesis of (E) -4- [2- (piperidin-4-ylmethylthio) vinyl] -5-thia-1,8b-diazaacenaphthylene dihydrochloride 0.314 g (0.780 mmol),
0.19 g of 1-bromo-3-phenylpropane (0.9
4 mmol), 0.38 ml of triethylamine (2.7)
(3 mmol) in 20 ml of ethanol was heated to reflux for 1 day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol: 4/1) to obtain the desired product. Red liquid Yield 0.233 g (67% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.255-1.614 (3H, m), 1.795-
2.004 (6H, m), 2.381 (2H, t, J = 7.7Hz), 2.584-2.683 (4H,
m), 2.956 (2H, d, 11.6Hz), 5.862 (1H, dd, J = 1.0Hz, 6.8H
z), 5.891 (1H, s), 5.986 (1H, d, J = 15.4Hz), 6.113 (1H, d,
J = 15.4Hz), 6.625 (1H, dd, J = 6.8Hz, 9.4Hz), 6.737 (1H, d
d, J = 1.1Hz, 9.1Hz), 6.951 (1H, s), 7.134-7.317 (5H, m). IR (neat): 2933, 1610, 1475, 1290, 1246, 1136, 916,
851, 771, 700 cm ^-1

3) (E) -4- [2- [1- (3-Phenylpropan-1-yl) piperidin-4-ylmethylthio] vinyl] -5-thia-1,8b-diazaacenaphthylene -Synthesis of dihydrochloride (E) -4- [2- [1- (3-phenylpropane-1)
-Yl) piperidin-4-ylmethylthio] vinyl]-
5-thia-1,8b-diazaacenaphthylene 0.233
g was dissolved in 2 ml of methanol, an excess amount of a methanol solution of hydrogen chloride was added, and the mixture was stirred for 10 minutes. This was concentrated to obtain the desired product. Orange foamy substance Yield 0.253 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.504-1.700 (2H, m), 1.840-
2.167 (5H, m), 2.713 (2H, t, J = 7.1Hz), 2.882 (2H, d, J = 6.6
Hz), 2.969-3.141 (4H, m), 3.552-3.654 (2H, m), 6.312 (1
H, d, J = 15.4Hz), 6.321 (1H, s), 6.632 (1H, d, J = 15.8Hz),
6.765 (1H, d, J = 7.4Hz), 7.121 (1H, d, J = 9.2Hz), 7.167-7.
340 (5H, m), 7.405 (1H, s), 7.470 (1H, dd, J = 7.8,9.2Hz). IR (neat): 2949, 2717-2553, 1635, 1574, 1498, 1448,
1304, 1213, 783, 752,702 cm -1 Elemental analysis _{(C 26 H 31 Cl 2 N} 3 S 2 · 2.0H as ₂ O) Calculated:. C, 56.10; H, 6.34; N, 7.55 Found: C , 55.99; H, 6.50; N, 7.57.

Example 146 (E) -N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -2- (5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-yl) vinylsulfonamide dihydrochloride 1) (E) -N- (piperidin-4-ylmethyl) -2
-(5-thia-1,8b-diazaacenaphthylene-4-
Il) Synthesis of vinylsulfonamide dihydrochloride To a solution of 0.800 g (3.917 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in 30 ml of chloroform, 3 g of active manganese dioxide (Aldrich) Was added and stirred at room temperature for 4 hours. The insoluble matter of the reaction solution was filtered, washed with chloroform, and the solvent of the collected filtrate was distilled off under reduced pressure. The obtained crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde was used for the next reaction without purification. Tert-Butyl 4- (diphenoxyphosphorylmethanesulfonylaminomethyl) piperidine-1-carboxylate 2.16 g (4.11 mmol) in toluene 20 ml-tetrahydrofuran 20 ml
0.33 g (8.23 mmol) of a 60% sodium hydride liquid paraffin suspension was added to the solution at room temperature, and the mixture was stirred for 1 hour. This was combined with the crude 5-thia-1,
10 ml of N, N-dimethylformamide of 8b-diazaacenaphthylene-4-carbaldehyde-toluene 50
The solution was added to the solution at room temperature and stirred for 0.5 hours.
The reaction solution was poured into water and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is passed through silica gel column chromatography (ethyl acetate-ethyl acetate / methanol:
9/1), crude (E) -N- [1- (tert-butoxycarbonyl) piperidin-4-ylmethyl] -2- (5
-Thia-1,8b-diazaacenaphthylene-4-yl)
Vinyl sulfonamide was obtained. 1 ml of concentrated hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethanol was added to this mixture, and the mixture was stirred. The resulting precipitate was collected and washed sequentially with ethanol and diethyl ether to obtain the desired product. Yellow solid Yield 0.384 g (22% yield) ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.339-1.631 (2H, m), 1.727-
2.186 (3H, m), 2.910-3.063 (4H, m), 3.360-3.452 (2H, m),
6.546 (1H, d, J = 14.8Hz), 6.809 (1H, d, J = 7.6Hz), 6.840 (1
H, s), 7.119 (1H, d, J = 14.6Hz), 7.151 (1H, d, J = 9.2Hz),
7.516 (1H, dd, J = 7.6,9.2Hz), 7.594 (1H, s) .IR (nujol): 3064,2727-2505,1637,1601,1138,106
1, 851, 787 cm ^-1

2) (E) -N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -2
-(5-thia-1,8b-diazaacenaphthylene-4-
Synthesis of (yl) vinylsulfonamide (E) -N- (piperidin-4-ylmethyl) -2-
(5-thia-1,8b-diazaacenaphthylene-4-yl) vinylsulfonamide dihydrochloride 0.285 g
(0.634 mmol), 0.15 g (0.76 mmol) of 1-bromo-3-phenylpropane, 0.31 ml (2.22 mmol) of triethylamine in ethanol 2
The 0 ml solution was heated to reflux for 1 day. The reaction solution was poured into an aqueous solution of sodium hydrogen carbonate, and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate / methanol:
9/1), the desired product was obtained. Red foamy substance Yield 0.217 g (69% yield) ¹ H-NMR (CDCl ₃ , 200 MHz) δ: 1.230-1.623 (3H, m), 1.726-
2.036 (6H, m), 2.333-2.496 (2H, m), 2.624 (2H, t, 7.7Hz),
2.875-3.029 (4H, m), 5.130 (1H, br s), 5.895 (1H, dd, 1.
4Hz, 6.6Hz), 6.003 (1H, d, 15.0Hz), 6.322 (1H, s), 6.638
-6.800 (2H, m), 6.901 (1H, d, 15.0Hz), 7.120-7.315 (6H,
m). IR (neat): 3030, 2931, 1585, 1329, 1140, 731 cm ^-1

3) (E) -N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -2
-(5-thia-1,8b-diazaacenaphthylene-4-
Synthesis of yl) vinylsulfonamide dihydrochloride (E) -N- [1- (3-phenylpropan-1-yl) piperidin-4-ylmethyl] -2- (5-thia-
0.217 g of 1,8b-diazaacenaphthylene-4-yl) vinylsulfonamide was dissolved in 2 ml of methanol, an excess amount of a methanol solution of hydrogen chloride was added, and the mixture was stirred for 10 minutes. This was concentrated to obtain the desired product. Orange foamy substance Yield 0.247 g ¹ H-NMR (CD ₃ OD, 200 MHz) δ: 1.434-1.628 (2H, m), 1.714-
2.165 (5H, m), 2.709 (2H, t, J = 7.5Hz), 2.911 (2H, d, J = 6.6
Hz), 3.008-3.141 (4H, m), 3.522-3.621 (2H, m), 6.536 (1
H, d, J = 15.4Hz), 6.803 (1H, d, J = 7.2Hz), 6.838 (1H, s),
7.106 (1H, d, J = 15.4Hz), 7.150 (1H, d, J = 9.2Hz), 7.155-
7.332 (5H, m), 7.506 (1H, dd, J = 7.8,9.0Hz), 7.590 (1H,
. s) IR (nujol): 3351, 2667, 1632, 2331, 1144, 725 cm -1 Elemental analysis _{(C 26 H 32 Cl 2 N} 4 O 2 S 2 · 1.0H as ₂ O) Calculated: C, 53.33; H, 5.85; N, 9.57. Found: C, 53.24; H, 5.59; N, 9.64.

Example 147 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1) 5 -Thia-1,8b-diazaacenaphthylene-4-
Synthesis of carboxylic acid Ethyl 5-thia-1,8b-diazaacenaphthylene-4-carboxylate (2.2 g) in methanol (6.6 ml)
A 1N aqueous sodium hydroxide solution (13 ml) was added to the suspension, and the mixture was stirred at room temperature for 2 hours. PH 5 with 1N hydrochloric acid under ice-cooling
, And returned to room temperature and stirred for 1 hour. The precipitated crystals were collected by filtration, dried, and then dried with 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.8 g, yield 94).
%). ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 5.97 (1 H, d, J = 7.0 Hz),
6.60 (2H, d, J = 9.1Hz), 6.67 (1H, dd, J = 7.0, 9.1Hz),
6.89 (1H, s), 7.12 (1H, s). 2) N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenafti Synthesis of len-4-carboxamide (i) Production method A 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.2 g), 4-amino-1- (3-phenylpropane-1) -Yl) piperidine dihydrochloride (1.5
g), triethylamine (1.5 ml), 1-hydroxy-1H-benzotriazole monohydrate (0.8 g)
And 1-ethyl-3- (3-diethylaminopropyl) carbodiimide hydrochloride (1.0 g) of N,
A suspension of N-dimethylformamide (15 ml) at 50 ° C
For 2 hours. After cooling, the mixture was extracted with ethyl acetate / tetrahydrofuran (4/1: 90 ml). The obtained organic layer was washed with a 1N aqueous solution of sodium hydroxide (10 ml) and water (3 mL).
0 ml) and concentrated. The precipitated crystals were washed with diisopropyl ether (20 ml) and then dried to obtain the desired product (2.0 g, yield 95%).

(Ii) Production method B A suspension of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (10 g) and N, N-dimethylformamide (1.8 ml) in tetrahydrofuran (100 ml) Then, oxalyl chloride (8 ml) was added dropwise to the mixture under water cooling, and the mixture was returned to room temperature and stirred for 24 hours. The reaction solution was concentrated, and this was concentrated in N, N-dimethylformamide (40 ml).
Was dissolved. 4-amino-1- (3-phenylpropyl) piperidine dihydrochloride (13.4 g), 1,8-diazabicyclo [5.4.0] -7-undecene (13.
7ml), triethylamine (25.6ml) and N, N
The above solution was added to a dimethylformamide (60 ml) solution under ice-cooling so as not to exceed 10 ° C., and further stirred at room temperature for 1.5 hours. Add water (400ml) to this,
Ethyl acetate / tetrahydrofuran (4/1: 200 m
Extracted in l). The obtained organic layer was washed with a 1N aqueous solution of sodium hydroxide (100 ml) and water (300 ml) and concentrated. The precipitated crystals were treated with diisopropyl ether (2
0ml) and dried to obtain the desired product (12.9 g, yield 67%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45-1.53 (2H, m), 1.69-
1.83 (2H, m), 1.85-1.92 (2H, m), 1.96-2.08 (2H, m),
2.33-2.38 (2H, m), 2.60-2.65 (2H, m), 2.81-2.85 (2H, m
m), 3.79-3.82 (1H, m), 5.53 (1H, d, J = 7.8Hz), 5.78 (1H
(H, d, J = 6.6Hz), 6.59-6.69 (3H, m), 7.05 (1H, s), 7.1
6-7.19 (3H, m), 7.25-7.30 (2H, m).

Example 148 N- [4- (3-Phenylpropan-1-yl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [4- (3-Phenylpropan-1-yl) piperazin-1-ylcarbonylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1.0 g (4.58 mmol) and N-hydroxysuccinimide 1 To a suspension of 0.055 g (9.12 mmol) in acetonitrile (20 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1.5 hours. In the reaction system, 1.68 g (5.03 mmol) of 1-aminoacetyl-4- (3-phenylpropan-1-yl) piperazine dihydrochloride, 1,8-
Diazabicyclo [5.4.0] unde-7-cene (DB
U) A solution of 1.53 g (10.05 mmol) and 0.7 ml (5.02 mmol) of triethylamine in acetonitrile (15 ml) was added, and the mixture was further stirred for 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 30-50%) to give the target compound as a red amorphous substance. Yield 1.32 g (62%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.71-1.91 (2H, m), 2.31-
2.51 (6H, m), 2.65 (2H, t, J = 7.6 Hz), 3.36-3.45 (2
H, m), 3.59-3.73 (2H, m), 4.06 (2H, d, J = 3.8Hz),
5.78 (1H, dd, J = 6.0, 1.8 Hz), 6.58-6.72 (3H, m),
6.90-7.00 (1H, m), 7.05 (1H, s), 7.13-7.35 (5H,
m). IR (KBr) 1637, 1622, 1481, 1282, 1238, 1155, 73, 7
31,700 cm ^-1 2) N- [4- (3-phenylpropan-1-yl) piperazin-1-ylcarbonylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (3-phenylpropan-1-yl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8
b-diazaacenaphthylene-4-carboxamide 1.3
06 g (2.83 mmol) of ethanol (10 ml)
1.5 ml (18 mmol) of 12N hydrochloric acid at room temperature
Was added and stirred for several minutes. After concentrating under reduced pressure, ethanol and diethyl ether were added to the crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.26 g (83%) Melting point 189-196 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.93-2.17 (2H, m), 2.6
5 (2H, t, J = 7.6 Hz), 2.80-3.29 (6H, m), 3.39-3.68
(2H, m), 3.91-4.48 (4H, m), 6.59 (1H, d, J = 7.0 H
z), 6.96 (1H, d, J = 8.4 Hz), 7.17 (1H, s), 7.19-7.3
6 (6H, m), 7.66 (1H, s), 8.81-8.91 (1H, m) 11.18-1
1.45 (1H, m). IR (KBr) 3260, 1667, 1638, 1503 cm ^-1 Elemental analysis C ₂₅ H ₂₉ N ₅ O ₂ SCl ₂ 1.5H ₂ O Calculated: C, 53.47; H, 5.74 N, 12.47 Found: C, 53.47; H, 5.65; N, 12.46.

Example 149 Synthesis of N- [4- (2-phenethyl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) Synthesis of N- [4- (2-phenethyl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenafti A suspension of 1.0 g (4.58 mmol) of len-4-carboxylic acid and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (20 ml) was treated with N-ethyl-
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. 1-aminoacetyl-4 was added to the reaction system.
1.76 g of-(2-phenethyl) piperazine dihydrochloride
(5.50 mmol), 1,8-diazabicyclo [5.
4.0] 1.67 g of unde-7-cene (DBU) (1
0.97 mmol) and 0.64 ml of triethylamine
(4.59 mmol) in acetonitrile (15 ml) was added and stirred for an additional hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution and dried over magnesium sulfate. The crude product was subjected to column chromatography (methanol / ethyl acetate 30-4).
0%) and crystallized from ethyl acetate to give the desired product as purple crystals. Yield 1.18 g (57%) Melting point 137-139 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 2.46-2.58 (4H, m), 2.58-
2.71 (2H, m), 2.75-2.87 (2H, m), 3.38-3.49 (2H,
m), 3.63-3.75 (2H, m), 4.07 (2H, d, J = 4.0Hz), 5.78
(1H, dd, J = 6.0, 1.8 Hz), 6.55-6.67 (2H, m), 6.71
(1H, s), 6.92-7.01 (1H, m), 7.05 (1H, s) 7.16-7.36
(m 5H) .IR (KBr) 3423, 3255, 1632, 1618, 1556, 1481, 1282,
1246, 1157 cm ^-1 2) Synthesis of N- [4- (2-phenethyl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1.13 g (2.52 mmol) of N- [4- (2-phenethyl) piperazin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (10 ml) Add the solution at room temperature to 12
1.5 ml (18 mmol) of N hydrochloric acid was added and stirred for several minutes. After concentrating under reduced pressure, ethanol and diethyl ether were added to the crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.20 g (91%) Melting point 165-175 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 2.84-3.42 (8H, m), 3.4
9-3.73 (2H, m), 3.92-4.52 (4H, m), 6.61 (1H, d, J =
7.2 Hz), 6.98 (1H, d, J = 9.2 Hz), 7.19 (1H, s), 7.2
0-7.42 (6H, m), 7.68 (1H, s), 8.85-8.96 (1H, m), 1
1.42-11.72 (1H, m) .IR (KBr) 3260, 1669, 1634 cm ^-1 Elemental analysis Calculated as C ₂₄ H ₂₇ N ₅ O ₂ SCl ₂ .2.0H ₂ O: C, 51.80; H , 5.61;
N, 12.58 Found: C, 51.86; H, 5.34;
N, 12.54.

Example 150 N- [4- (3-Phenylpropan-1-yl) -2,
3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b-
Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [4- (3-phenylpropan-1-yl)-
2,3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide 1.0 g (4.58 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g of N-hydroxysuccinimide (9.12 mmol) in acetonitrile (20 ml) was added to a suspension of N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1 hour. 1- (aminoacetyl) in the reaction system
-4- (3-Phenylpropan-1-yl) -2,3,
1.91 g (5.48 mmol) of 5,6-tetrahydro-7H-1,4-diazepine dihydrochloride, 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU)
1.67 g (10.97 mmol) and 0.7 ml (5.0 mmol) of triethylamine in acetonitrile (2
0 ml) solution and stirred for an additional hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was subjected to column chromatography (methanol / ethyl acetate 30-50).
%) To obtain the desired product as a red amorphous substance. Yield 1.00 g (46%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.66-1.97
(4H, m), 2.42-2.55 (2H,
m), 2.55-2.75 (6H, m), 3.
39-3.50 (2H, m), 3.60-3.7
2 (2H, m), 4.03-4.08 (2H,
m), 5.77 (1H, dd, J = 6.2,
1.8 Hz), 6.55-6.65 (2H,
m), 6.70 (1H, s), 6.95-7.
06 (1H, m), 7.04 (1H, s),
7.13-7.34 (5H, m). IR (KBr) 3243, 1644, 162
2, 1454, 1283, 1157, 772
702 cm ^<-1 > 2) N- [4- (3-phenylpropan-1-yl)-
2,3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8
Synthesis of b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (3-phenylpropan-1-yl) -2,
3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b-
Diazaacenaphthylene-4-carboxamide 1.00 g
(2.1 mmol) in ethanol (10 ml)
At room temperature, 1 ml (12 mmol) of 12N hydrochloric acid was added and stirred for several minutes. The mixture was concentrated under reduced pressure, diethyl ether was added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 0.996 g (86%) Melting point 269-275 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.90-2.19 (4H, m), 2.5
4-2.70 (2H, m), 2.85-3.36 (4H, m), 3.38-3.65 (5H,
m), 3.77-4.19 (3H, m), 6.63 (1H, d, J = 7.4 Hz), 6.9
9 (1H, d, J = 8.2 Hz), 7.15-7.38 (7H, m), 7.69 (1H,
s), 8.83-8.96 (1H, m), 11.04-11.31 (1H, m) .IR (KBr) 3268, 1661, 1638, 1501 cm ^-1 Elemental analysis C ₂₆ H ₃₁ N ₅ O ₂ SCl ₂・ 1.0H _{As 2} O, Calculated: C, 55.12; H, 5.87; N, 12.36 Found: C, 54.82; H, 5.59; N, 12.54.

Example 151 N- [4- (2-Phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b- Synthesis of diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [4- (2-phenethyl) -2,3,5,6-
Synthesis of tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8bdiazaacenaphthylene-4 To a suspension of 1.0 g (4.58 mmol) of carboxylic acid and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (20 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 1 hour. 1- (aminoacetyl) in the reaction system
-4- (2-phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride 1.84 g
(5.50 mmol), 1,8-diazabicyclo [5.
4.0] Unde-7-cene (DBU) 1.68 g (1
1.0 mmol) and 0.7 ml of triethylamine
(5.0 mmol) in acetonitrile (20 ml) was added, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 20-50%) to obtain the target product as a red amorphous substance. Yield 0.91 g (43%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.78-1.99 (2H, m), 2.64-
2.85 (8H, m), 3.40-3.50 (2H, m), 3.61-3.76 (2H,
m), 4.01-4.09 (2H, m), 5.78 (1H, dd, J = 5.8, 1.8 H
z), 6.55-6.68 (2H, m), 6.72 (1H, s), 6.96-7.05 (1
H, m), 7.05 (1H, s), 7.13-7.34 (5H, m). 2) N- [4- (2-phenethyl) -2,3,5,6-
Synthesis of tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [4- (2-phenethyl) -2,3,5,6-tetrahydro-7H-1,4-diazepin-1-ylcarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 0.91 g (1.97 1 mmol (12 mmol) of 12N hydrochloric acid at room temperature, and stirred for 1 hour. Diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 0.918
1 g (87%) Melting point 269-275 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.99-2.23 (2H, m), 2.9
6-4.21 (14H, m), 6.59 (1H, d, J = 7.4 Hz), 6.96 (1H,
d, J = 9.0 Hz), 7.14-7.41 (7H, m), 7.65 (1H, s), 8.80
-8.90 (1H, m), 10.99-11.23 (1H, m) .IR (KBr) 3425, 1633, 1566, 1500, 1458, 1296, 1121,
783 cm ^-1 Elemental analysis C ₂₅ H ₂₉ N ₅ O ₂ SCl ₂ · 1.5 H ₂ O Calculated: C, 53.47; H, 5.74; N, 12.47 Found: C, 53.37; H, 5.65; N, 12.69.

Example 152 N- [1- (3-Phenylpropan-1-yl) piperidin-4-ylaminocarbonylmethyl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide, synthesis of dihydrochloride 1) N- [1- (3-phenylpropan-1-yl) piperidin-4-ylaminocarbonylmethyl] -5 Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 0.5 g (2.29 mmol) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and N-hydroxysuccinic acid To a suspension of 0.53 g (4.61 mmol) of imide in acetonitrile (10 ml) was added N-ethyl- at room temperature.
0.88 g (4.59 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. N- [1- (3-Phenylpropan-1-yl) piperidin-4-yl] -aminoacetamide dihydrochloride 0.96 g (2.76 mmol), 1,8-diazabicyclo [5.4] were added to the reaction system. .0] unde-
A solution of 0.84 g (5.52 mmol) of 7-cene (DBU) and 0.4 ml (2.87 mmol) of triethylamine in acetonitrile (10 ml) was added, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was subjected to column chromatography (methanol / ethyl acetate 1:
(3 → 1: 1 → 3: 1), and recrystallized from ethyl acetate to obtain the desired product as purple crystals. Yield 303.
2 mg (28%) Melting point 202-205 ° C ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.36-2.00 (6H, m), 2.00-
2.17 (2H, m), 2.30-2.42 (2H, m), 2.63 (2H, t, J = 7.
6 Hz), 2.76-2.92 (2H, m), 3.66-3.87 (1H, m), 3.91
(2H, d, 4.8 Hz), 5.78 (1H, dd, J = 6.0, 1.8 Hz), 5.8
0-5.90 (1H, m), 6.56-6.74 (4H, m), 7.05 (1H, s), 7.
13-7.33 (5H, m) .IR (KBr) 3281, 3065, 2946, 1649, 1622, 1553, 1483,
1287, 1267, 1159, 775 cm ^-1 2) N- [1- (3-Phenylpropan- ¹ -yl) piperidin-4-ylaminocarbonylmethyl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide, synthesis of dihydrochloride N- [1- (3-phenylpropan-1-yl) piperidin-4-ylaminocarbonylmethyl] -5-thia-
303.2 mg (0.64 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide in ethanol (5
0.5 ml (6.0 mmol) of 12N hydrochloric acid was added to the solution at room temperature, followed by stirring for 1 hour. After concentration under reduced pressure, ethanol and diethyl ether were added to the residue, and the resulting crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 257.5 mg (73%) Melting point. 178-183 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.61-2.11 (6H, m), 2.5
4-2.71 (2H, m), 2.77-3.87 (9H, m), 6.54 (1H, d, J =
7.4 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.09 (1H, s), 7.1
0-7.36 (6H, m), 7.61 (1H, s), 8.16-8.25 (1H, m),
8.80-8.95 (1H, m) .IR (KBr) 3220, 3059, 1649, 1636, 1566, 1535, 1501,
1298 cm ^-1 Elemental analysis As C ₂₆ H ₂₁ N ₅ O ₂ SCl ₂ .1.5H ₂ O Calculated: C, 54.26; H, 5.95; N, 12.17 Found: C, 54.01; H, 5.74; N, 12.18.

Example 153 N- [4- (4-Benzoylpiperazin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [4- (4-benzoylpiperazin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1, To a suspension of 1.0 g (4.58 mmol) of 8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mmol) of N-hydroxysuccinimide in acetonitrile (15 ml) was added N. -Ethyl-
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. 1.68 g (5.5 mmol) of 4- (4-aminobutan-1-yl) -1-bensoylpiperazine dihydrochloride and 1,8-diazabicyclo [5.4.0] undecene (DBU) were added to the reaction system. 1.68g (1
1.04 mmol) and 1.5 ml of triethylamine
(10.76 mmol) of acetonitrile (10 ml)
The solution was added and stirred for another 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (methanol / ethyl acetate 20-
30%) to obtain the desired product as a red amorphous substance. Yield 1.25 g (59%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.42-1.63 (4H, m), 2.24-
2.56 (6H, m), 3.19-3.55 (4H, m), 3.63-3.88 (2H,
m), 5.76-5.80 (1H, m), 5.96-6.08 (1H, m), 6.55-6.6
9 (3H, m), 7.02 (1H, s), 7.34-7.45 (5H, m) .IR (KBr) 3309, 1616, 1547, 1437, 1281, 1155, 1012,
775,733,712 cm ^-1 2) N- [4- (4-benzoylpiperazin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide. Synthesis of dihydrochloride N- [4- (4-benzoylpiperazin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.16 g (2. 51 mmol) in ethanol (10 ml) at room temperature.
1 ml (12 mmol) of N hydrochloric acid was added and the mixture was stirred for several minutes, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 0.918 g (69%) Melting point 247-253 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.40-1.58 (2H, m), 1.6
2-1.84 (2H, m), 2.96-3.24 (8H, m), 3.31-3.64 (4H,
m), 6.61 (1H, d, J = 6.8 Hz), 6.97 (1H, d, J = 8.6 H
z), 7.22 (1H, s), 7.28 (1H, dd, J = 7.6, 9.2 Hz), 7.
42-7.55 (5H, m), 7.64 (1H, s), 8.85-8.97 (1H, m) .IR (KBr) 3398, 1632, 1568, 1533, 1500, 1429, 1288
cm ^-1 as elemental analysis _{C 25 H 29 N 5 O 2} SCl 2 · 1.5H 2 O, Calculated: C, 53.47; H, 5.74 ; N, 12.47 Found: C, 53.28; H, 5.74 ; N, 12.73 .

Example 154 N- [3- (4-Benzoylpiperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Synthesis 1) Synthesis of N- [3- (4-benzoylpiperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1, 8b To a suspension of 0.8 g (3.67 mmol) of diazaacenaphthylene-4-carboxylic acid and 0.84 g (8.8 mmol) of N-hydroxysuccinimide in acetonitrile (15 ml) at room temperature was added N- Ethyl-N '
1.41 g (7.36 mmol) of -3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added,
Stir for 2 hours. In the reaction system, 4- (3-aminopropane-
1-yl) -1-bensoylpiperazine dihydrochloride
41 g (4.4 mmol), 1.34 g of 1,8-diazabicyclo [5.4.0] unde-7-cene (DBU)
(8.8 mmol) and 1.0 ml of triethylamine
(7.17 mmol) in acetonitrile (15 ml) was added and stirred for a further 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate (a small amount of ethanol was also used). The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography (methanol / ethyl acetate 30-4).
0%), and the solvent was distilled off under reduced pressure to obtain the desired product as red-purple crystals. Yield 0.738 g (45%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.68-1.81 (2H, m), 2.43-
2.63 (6H, m), 3.37-3.49 (2H, m), 3.55-3.92 (4H,
m), 5.77 (1H, dd, J = 1.8, 6.6 Hz), 6.60-6.69 (1H,
m), 6.73 (1H, s), 7.05 (1H, s), 7.25-7.35 (1H, m),
7.35-7.47 (5H, m). IR (KBr) 3319, 1612, 1545, 1444, 1273, 1153 cm- ¹ 2) N- [3- (4-Benzoylpiperazin-1-yl) propan-1-yl] Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [3- (4-benzoylpiperazin-1-yl) propan-1-yl] -5-thia- 0.715 g of 1,8b-diazaacenaphthylene-4-carboxamide (1.6
To a solution of 0 mmol) in ethanol (10 ml) was added 10 ml (120 mmol) of 12N hydrochloric acid at room temperature and stirred for 16 hours. After concentration under reduced pressure, ethanol and diethyl ether were added, and the precipitated crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 0.715 g (86%) Melting point 277-282 ° C (decomposition) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.82-2.01 (2H, m), 2.9
6-3.28 (8H, m), 3.34-3.61 (4H, m), 6.55 (1H, d, J =
(7.8 Hz), 6.93 (1H, d, J = 9.2 Hz), 7.13 (1H, s), 7.1
8-7.26 (1H, m), 7.41-7.51 (5H, m), 7.60 (1H, s),
8.84-8.96 (1H, m). IR (KBr) 3344, 1632, 1529, 1423, 1302, 800 cm ^-1 Elemental analysis C ₂₄ H ₂₇ N ₅ O ₂ SCl ₂・ 1.5H ₂ O Calculated value: C , 52.65; H, 5.52; N, 12.79 Found: C, 52.95; H, 5.30; N, 12.95.

Example 155 N-cis- [4- (4-Benzyl-3,5-dimethylpiperazin-1-yl) butan-1-yl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide trihydrochloride 1) N-cis- [4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1.0 g (4.58 mmol) and N-hydroxysuccinic acid To a suspension of 1.05 g (9.12 mmol) of imide in acetonitrile (15 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. 1.64 g (5.95 mmol) of cis-4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-ylamine and 1.5 ml (10.76 mmol) of triethylamine in acetonitrile were added to the reaction system. (15 ml) solution was added and stirred for another 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product is subjected to column chromatography (methanol / ethyl acetate 30
%) To obtain the desired product as a red amorphous substance. Yield 1.55 g (91%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.05 (6H, d, J = 6.0 Hz),
1.47-1.63 (4H, m), 1.73-1.93 (2H, m), 2.24-2.36 (2
H, m), 2.61-2.82 (4H, m), 3.23-3.36 (2H, m), 3.83
(2H, m), 5.74 (1H, dd, J = 6.2, 1.8 Hz), 6.56 (1H,
s), 6.57-6.69 (3H, m), 6.97 (1H, s), 7.13-7.39 (5
H, m) .IR (KBr) 3319, 1618, 1549, 1479, 1281, 1153, 773,
729 cm ^-1 2) N-cis- [4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride N-cis- [4- (1-benzyl-2,6-dimethylpiperazin-1-yl) butan-1-yl] -5-thia-
1.55 g (3.21 mmol) of 1,8b-diazaacenaphthylene-4-carboxamide in ethanol (10 m
l) To the solution, 3.0 ml (36 mmol) of 12N hydrochloric acid was added and stirred for several minutes. After evaporating the solvent under reduced pressure, 2-
Propanol was added, and the precipitated crystals were collected by filtration. The crystals were washed with 2-propanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.274g
(67%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.35-1.84 (10H, m), 3.
00-3.45 (6H, m), 3.56-3.84 (4H, m), 4.42-4.64 (2H,
m), 6.62 (1H, d, J = 7.4 Hz), 6.98 (1H, d, J = 9.2 H
z), 7.22 (1H, s), 7.29 (1H, dd, J = 9.2, 7.6 Hz), 7.
38-7.62 (5H, m), 7.65 (1H, s), 8.82-8.95 (1H, m) .IR (KBr) 3423, 1635, 1537, 1498, 1448, 1296, 1215,
783, 746 cm ^-1 as elemental analysis _{C 27 H 36 N 5 OSCl 3} · 1.0H 2 O, Calculated: C, 53.78; H, 6.39 ; N, 11.61 Found: C, 53.54; H, 6.39 ; N, 11.48.

Example 156 N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide trihydrochloride 1) N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl] -5
Synthesis of -Thia-1,8b-diazaacenaphthylene-4-carboxamide 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.0 g, 4.58 mmol) and N-hydroxyamber To a suspension of 1.05 g (9.12 mmol) of acid imide in acetonitrile (30 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. A solution of cis-4- (3-aminopropyl) -1-benzyl-2,6-dimethylpiperazine (1.56 g, 5.97 mmol) and triethylamine (2.0 ml, 14.3 mmol) in acetonitrile (15 ml) was added to the reaction system. Was added, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product is subjected to column chromatography (methanol / ethyl acetate 3
0%) to obtain the desired product as a red amorphous substance. Yield 1.00 g (48%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.03 (6H, d, J = 6.2 Hz),
1.58-1.79 (2H, m), 1.83-1.94 (2H, m), 2.45-2.50 (2
H, m), 2.62-2.93 (4H, m), 3.32-3.45 (2H, m), 3.77
(2H, s), 5.69 (1H, dd, J = 6.2, 1.8 Hz), 6.55-6.67
(3H, m), 6.98 (1H, s), 7.13-7.42 (5H, m), 8.03-8.1
4 (1H, m) .IR (KBr) 3283, 2960, 2810, 1618, 1543, 1479, 1279,
1151, 729 cm ^-1 2) N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride N-cis- [3- (4-benzyl-3,5-dimethylpiperazin-1-yl) propan-1-yl ] -Thia-1,8b-diazaacenaphthylene-4-carboxamide 1.00 g (2.17 mmol) in ethanol (1
0 ml) solution, 2.0 ml (36 mmol) of 12N hydrochloric acid was added, and the mixture was stirred for 1 hour. After evaporating the solvent under reduced pressure, 2-propanol and diethyl ether were added, and the precipitated crystals were collected by filtration. The crystals were washed with 2-propanol and diethyl ether to obtain the desired product as orange crystals. Yield 0.8489 g (69%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.41-1.70 (6H, m), 1.7
8-1.98 (2H, m), 2.97-3.43 (6H, m), 3.55-3.82 (4H,
m), 4.42-4.62 (2H, m), 6.61 (1H, d, J = 7.4 Hz), 6.9
8 (1H, d, J = 8.8 Hz), 7.19 (1H, s), 7.28 (1H, dd, J
= 9.2, 7.2 Hz), 7.41-7.63 (5H, m), 7.66 (1H, s), 8.
92-9.04 (1H, m) .IR (KBr) 3435, 3390, 1633, 1566, 1535, 1500, 1452,
1390, 1298, 1213, 785 cm ^-1 elemental analysis C ₂₆ H ₃₄ N ₅ OSCl ₃ .1.5H ₂ O, calculated: C, 52.22; H, 6.24;
N, 11.71 found: C, 52.41; H, 6.40;
N, 11.59.

Example 157 N-cis- [2- [4- (3-phenylpropane-1)
-Yl) -3,5-dimethylpiperazin-1-yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride 1) N-cis -[2- [4- (3-Phenylpropan-1-yl) -3,5-dimethylpiperazin-1-yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene- Synthesis of 4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid 1.0 g (4.58 mmol) and N-hydroxysuccinimide 1.05 g (9.12 mmol) of acetonitrile (15 ml) at room temperature with N-ethyl-
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. Cis-1- (2-aminoethyl) -4- (3-phenylpropan-1-yl) was added to the reaction system.
A solution of 1.89 g (6.86 mmol) of -3,5-dimethylpiperazine and 2.0 ml (14.3 mmol) of triethylamine in acetonitrile (15 ml) was added, and the mixture was further stirred for 2 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 30%) to obtain the desired product as a red amorphous substance. Yield 1.33 g (61%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.03 (6H, d, J = 5.8 Hz),
1.63-2.01 (4H, m), 2.44 (2H, t, J = 5.6 Hz), 2.55 (2
H, t, J = 7.6 Hz), 2.61-2.88 (6H, m), 3.28-3.42 (2H,
m), 5.74 (1H, dd, J = 6.4, 1.6 Hz), 6.40-6.49 (1H,
m), 6.52-6.69 (3H, m), 7.03 (1H, s), 7.13-7.35 (5
H, m) .IR (KBr) 3325, 2939, 2812, 1618, 1547, 1483, 1281,
1153, 773, 733, 700 cm ^-1 2) N-cis- [2- [4- (3-phenylpropan-1-yl) -3,5-dimethylpiperazin-1-yl] ethane-1-yl] Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride N-cis- [2- [4- (3-phenylpropane-1-
Yl) -3,5-dimethylpiperazin-1-yl] ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.32 g (2.78 mmol) of ethanol ( To the solution (10 ml) was added 2.0 ml (24 mmol) of 12N hydrochloric acid, and the mixture was stirred for 1 hour.
The precipitated crystals were collected by filtration and washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.41 g (87%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.32 (6H, d, J = 5.8 H)
z), 1.79-2.04 (2H, m), 2.64-2.76 (2H, m), 3.07-3.3
9 (6H, m), 3.48-3.62 (2H, m), 3.72-4.06 (4H, m),
6.61 (1H, d, J = 7.2 Hz), 6.96 (1H, d, J = 9.2 Hz), 7.
17-7.40 (7H, m), 7.64 (1H, s), 9.02-9.15 (1H, m) .IR (KBr) 2419, 2426, 1637, 1566, 1498, 1444, 1290,
1213 cm ^-1 Elemental analysis As C ₂₇ H ₃₆ N ₅ OSCl ₃ Calculated: C, 55.43; H, 6.20; N, 11.97 Found: C, 55.39; H, 6.23; N, 11.97.

Example 158 N-trans- [4- (4-benzyl-2,5-dimethylpiperazin-1-yl) butan-1-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride) N-trans- [4- (4-benzyl-2,5-dimethylpiperazin-1-yl) butan-1-yl ] -5
Synthesis of -Thia-1,8b-diazaacenaphthylene-4-carboxamide 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.0 g, 4.58 mmol) and N-hydroxyamber To a suspension of 1.05 g (9.12 mmol) of acid imide in acetonitrile (15 ml) was added N-ethyl- at room temperature.
1.76 g (9.18 mmol) of N'-3- (N, N-dimethylamino) propylcarbodiimide hydrochloride was added, and the mixture was stirred for 2 hours. In the reaction system, trans-1- (4-
A solution of 1.64 g (5.95 mmol) of (aminobutyl) -4-benzyl-2,5-dimethyl-piperazine and 2.0 ml (14.3 mmol) of triethylamine in 15 ml of acetonitrile was added, and the mixture was further stirred for 2 hours.
After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by column chromatography (methanol / ethyl acetate 30%) to obtain the desired product as a red amorphous substance. Yield 1.797 g (83%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 0.97 (3H, d, J = 6.2 Hz),
1.17 (3H, d, J = 5.8 Hz), 1.47-1.63 (4H, m), 1.83-2.
52 (4H, m), 2.61 (1H, dd, J = 11.0, 2.8 Hz), 2.71-2.
80 (1H, m), 2.84 (1H, dd, J = 11.4, 3.0 Hz), 3.05 (1
H, d, J = 13.2 Hz), 3.24-3.37 (2H, m), 4.09 (1H, d,
J = 13.2 Hz), 5.77 (1H, dd, J = 6.4, 1.8 Hz), 6.21-6.3
3 (1H, m), 6.57-6.70 (3H, m), 7.03 (1H, s), 7.17-
7.36 (5H, m) .IR (KBr) 3325, 3253, 2935, 2800, 161
8, 1547, 1279, 1151, 734 cm ^-1 2) N-trans- [4- (4-benzyl-2,5-
Dimethyl-piperazin-1-yl) butan-1-yl]
Synthesis of -5-thia-1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride N-trans- [4- (4-benzyl-2,5-dimethyl-piperazin-1-yl) butane- 1-yl] -5
To a solution of 1.65 g (3.47 mmol) of -thia-1,8b-diazaacenaphthylene-4-carboxamide in 10 ml of ethanol was added 2.0 ml (24 mmol) of 12N hydrochloric acid and stirred for 1 hour. After evaporating the solvent under reduced pressure, 2-propanol was added, and the precipitated crystals were collected by filtration. The crystals were washed with 2-propanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.844 g (91%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.30 (3H, d, J = 5.6 H)
z), 1.43-1.78 (7H, m), 2.93-3.90 (10H, m), 4.03-4.
28 (1H, m), 4.55-4.73 (1H, m), 6.60 (1H, d, J = 7.4
Hz), 6.96 (1H, d, J = 8.8 Hz), 7.13-7.32 (2H, m), 7.
39-7.50 (3H, m), 7.56-7.69 (3H, m), 8.77-8.92 (1H,
m) .IR (KBr) 3453, 3223, 2611, 2463, 2353, 1633, 1497,
1443, 1298, 777, as 746cm ^-1 elemental analysis _{C 27 H 36 N 5 OSCl 3} , Calculated: C, 55.43; H, 6.20 ; N, 11.97 Found: C, 55.37; H, 6.23 ; N, 11.96.

Example 159 N- [2- (2,6-Dioxo-4- (3-phenylpropan-1-yl) piperazin-1-yl) ethane-1
Synthesis of -yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [2- (2,6-dioxo-4- (3-phenylpropane-1) -Yl) piperazin-1-yl) ethane-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 5-thia-1,8b-diazaacenaphthylene-4 To a suspension of 0.8 g (3.67 mmol) of ethyl carboxylate and 0.84 g (7.30 mmol) of N-hydroxysuccinimide in 10 ml of acetonitrile at room temperature was added
Ethyl-N′-3- (N, N-dimethylamino) propyl carbodiimide (1.41 g, 7.36 mmol) was added and the mixture was stirred for 2 hours. 1.66 g of 1- (2-aminoethane-1-yl) -2,6-dioxo-4- (3-phenylpropan-1-yl) piperazine dihydrochloride was added to the reaction system.
(4.77 mmol) and 2.7 ml of triethylamine
(19.4 mmol) of chloroform (5 ml) was added, and the mixture was further stirred for 1 hour. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over magnesium sulfate. After concentration, the residue was subjected to column chromatography (methanol / ethyl acetate 20
%) To obtain the desired product as a red amorphous substance. Yield 1.56 g (89%) ¹ H-NMR (200 MHz, CDCl ₃ ) δ 1.72-1.92 (2H, m), 2.40-
2.54 (2H, m), 2.60-2.73 (2H, m), 3.24-3.59 (6H,
m), 3.97-4.06 (2H, m), 5.73 (1H, dd, J = 6.2, 1.4 H
z), 6.23-6.35 (1H, m), 6.54-6.66 (3H, m), 7.01 (1
H, s), 7.11-7.35 (5H, m) .IR (KBr) 3350, 2941, 1736, 1682, 1620, 1545, 1346,
1279, 1234, 1182, 1151, 748, 700, 644 cm ^-1 2) N- [2- (2,6-dioxo-4- (3-phenylpropan-1-yl) piperazin-1-yl) ethane- Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [2- (2,6-dioxo-4- (3-phenylpropane-1-) Il) piperazin-1-yl) ethane-1
-Yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1.56 g (3.28 mmol)
2N hydrochloric acid at room temperature in ethanol (10 ml) solution
1 (24 mmol) was added and stirred for several minutes. After concentration under reduced pressure, ethanol was added to the resulting crystals, and the crystals were collected by filtration. The crystals were washed with ethanol and diethyl ether to obtain the desired product as orange crystals. Yield 1.20 g (66%) ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.87-2.08 (2H, m), 2.6
1-2.68 (2H, m), 2.96-3.13 (2H, m), 3.20-3.36 (2H, m
m), 3.72-3.85 (2H, m), 4.13 (4H, br s), 6.64 (1H,
d, J = 7.2 Hz), 6.97 (1H, d, J = 9.2 Hz), 7.12 (1H,
s), 7.14-7.37 (6H, m), 7.64 (1H, s), 8.81-8.92 (1H,
m) .IR (KBr) 3260,2952,2590,1745,1697,1633,1562,1529,
1500,1438,1345,1293,1212,780,630Cm ^-1 and elemental analysis _{C 25 H 27 N 5 O 3} SCl 2 · 2.0H 2 O, Calculated: C, 51.37; H, 5.35 ; N, 11.98 Found: C, 51.69; H, 5.28; N, 12.05.

Example 160 N- [1- [3- (4-Ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (4-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl ]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-yl) -5-thia-1,8b-
At room temperature, a solution of 0.80 g (2.14 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride, 1.5 ml (10.76 mmol) of triethylamine and 0.38 g of sodium iodide in ethanol (20 ml) was added.
Ethyl-(3-chloro-1-propoxy) benzoate
62 g (2.55 mmol) were added under nitrogen atmosphere.
Heated to reflux for days. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. Wash the organic layer with saturated saline,
Washed with magnesium sulfate. After concentration, the residue was subjected to column chromatography (methanol / ethyl acetate 20 to 40).
%, And purified as a red solid (758.%).
4 mg, 75%). The target substance was obtained as red crystals by recrystallization (ethanol). ¹ HNMR (200MHz, CDCl ₃ ) δ 1.38 (3H, t, J = 7.2 Hz),
1.37-1.55 (2H, m), 1.87-2.03 (4H, m), 2.06-2.22 (2
H, m), 2.49-2.56 (2H, m), 2.79-2.94 (2H, m), 3.74-
3.94 (1H, m), 4.07 (2H, t, J = 6.2 Hz), 4.35 (2H, q,
J = 7.2 Hz), 5.47-5.58 (1H, m), 5.80 (1H, dd, J = 6.
2, 1.6 Hz), 6.59-6.71 (3H, m), 6.91 (2H, d, J = 8.8 H
z), 7.07 (1H, s), 7.99 (2H, d, J = 8.8 Hz) .IR (KBr) 3280,2945,1706,1608,1536,1511,1482,1280,1
257,1172,1056,954,883,844,771 cm ^-1 2) N- [1- [3- (4-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (4-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
To a solution of 329.7 mg (0.65 mmol) of thia-1,8b-diazaacenaphthylene-4-carboxamide in 5 ml of ethanol at room temperature was added 2 ml of 24N hydrochloric acid at room temperature.
Mmol) and stirred for 1 hour. The precipitated crystals were collected by filtration, and the crystals were washed with ethanol and diethyl ether to give the desired product as orange crystals (369.8 m
g, 98%). Melting point 162-166 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.31 (6H, t, J = 7.0 H
z), 1.83-2.10 (4H, m), 2.15-2.32 (2H, m), 2.89-3.2
4 (4H, m), 3.44-3.60 (2H, m), 3.74-3.96 (1H, m),
4.08-4.21 (2H, m), 4.28 (2Hm q, J = 7.0 Hz), 6.58 (1
H, d, J = 7.4 Hz), 6.95 (1H, d, J = 8.8 Hz), 7.05 (2H,
d, J = 9.2 Hz), 7.20-7.29 (2H, m), 7.62 (1H, s), 7.
92 (2H, d, J = 9.2 Hz), 8.79-8.87 (1H, m) .IR (KBr) 3265,2945,2636,1697,1633,1605,1534,1511,
1255,1216,1170,1128,1112,852,771Cm ^-1 as elemental analysis _{C 27 H 32 N 4 O 4} SCl 2 · 2.0H 2 O, Calculated: C, 52.68; H, 5.89 ; N, 9.10 Found: C, 52.96; H, 5.68; N, 8.94.

Example 161 N- [1- [3- (3-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (3-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl ]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-yl) -5-thia-1,8b-
At room temperature, a solution of 0.80 g (2.14 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride, 1.5 ml (10.76 mmol) of triethylamine and 0.38 g of sodium iodide in ethanol (20 ml) was added.
Ethyl-(3-chloro-1-propoxy) benzoate
62 g (2.55 mmol) were added under nitrogen atmosphere.
Heated to reflux for days. After cooling to room temperature, water was added to the reaction system, and extracted with ethyl acetate. Wash the organic layer with saturated saline,
Washed with magnesium sulfate. After concentration, the residue was subjected to column chromatography (methanol / ethyl acetate 30-40).
%) And purified as red crystals (636.%).
2 mg, 59%). ¹ HNMR (200MHz, CDCl ₃ ) δ 1.40 (3H, t, J = 7.2 Hz),
1.41-1.58 (2H, m), 1.88-2.04 (4H, m), 2.06-2.21 (2
H, m), 2.49-2.56 (2H, m), 2.80-2.94 (2H, m), 3.73-
3.94 (1H, m), 4.01 (2H, t, J = 6.2 Hz), 4.38 (2H, q,
J = 7.2 Hz), 5.57 (1H, d, J = 8.2Hz), 5.80 (1H, dd, J =
6.2, 1.6 Hz), 6.59-6.71 (3H, m), 7.06 (1H, s), 7.04
-7.12 (1H, m), 7.30-7.38 (1H, m), 7.53-7.67 (2H,
m) .IR (KBr) 3275,2952,1720,1610,1540,1278,1232,1162,
873,771 cm ^-1 2) N- [1- [3- (3-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (3-ethoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
To a solution of 473.3 mg (0.93 mmol) of thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (5 ml) at room temperature was added 2 ml of 12N hydrochloric acid (24 ml).
Mmol) and stirred for several minutes. After concentration under reduced pressure, ethanol was added, and the precipitated crystals were collected by filtration. Wash the crystals with ethanol and diethyl ether,
The desired product (425.4 mg, 79%) was obtained as orange crystals. Melting point 140-145 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.32 (3H, t, J = 7.0 H
z), 1.84-2.08 (4H, m), 2.14-2.31 (2H, m), 2.94-3.2
8 (4H, m), 3.47-3.61 (2H, m), 3.79-3.96 (1H, m),
4.08-4.20 (2H, m), 4.31 (2H, q, J = 7.0 Hz), 6.59 (1
H, d, J = 7.4 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.18-7.30
(3H, m), 7.42-7.63 (4H, m), 8.85 (1H, d, J = 7,2 H
z) .IR (KBr) 3370,3053,2607,1699,1635,1565,1540,1444,
1290,1233,1203,1124,813,751Cm ^-1 as elemental analysis _{C 27 H 32 N 4 O 4} SCl 2 · 2.0H 2 O, Calculated: C, 52.68; H, 5.89 ; N, 9.10 Found: C, 52.80; H, 5.76; N, 9.17.

Example 162 N- [1- [3- (2-Methoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (2-methoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl ]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide N- (piperidin-4-yl) -5-thia-1,8b-
0.80 g (2.14 mmol) of diazaacenaphthylene-4-carboxamide dihydrochloride, 1.5 ml (10.76 mmol) of triethylamine and 1,8-diazabicyclo [5.4.0] unde-7- Sen (DBU)
0.65 g (4.27 mmol) of acetonitrile (2
(0 ml) solution, 0.38 g of sodium iodide and 0.59 g (2.58 mmol) of methyl 2- (3-chloro-1-propoxy) benzoate were added to the solution at room temperature, and the mixture was heated under reflux under a nitrogen atmosphere for 3 days. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with chloroform. The organic layer was washed with a saturated saline solution and washed with magnesium sulfate. After concentration, the residue was subjected to column chromatography (methanol / ethyl acetate 30).
-50%), and the solvent was distilled off under reduced pressure to obtain the desired product (0.81 g, 77%) as a red amorphous substance. ¹ HNMR (200MHz, CDCl ₃ ) δ 1.37-1.61 (2H, m), 1.87-
2.23 (4H, m), 2.57 (2H, t, J = 7.4 Hz), 2.80-2.95 (2
H, m), 3.89 (3H, s), 4.09 (2H, t, J = 6.2 Hz), 5.51-
5.62 (1H, m), 5.80 (1H, dd, J = 6.2, 1.8 Hz), 6.59-
6.71 (3H, m), 6.94-7.02 (2H, m), 7.05 (1H, s), 7.4
0-7.49 (1H, m), 7.76-7.80, 1H, m) .IR (KBr) 3230,2949,1727,1617,1540,1482,1454,1286,
1249,1151,1085,772,757 cm ^-1 2) N- [1- [3- (2-methoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl]-
Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (2-methoxycarbonylphenoxy) propan-1-yl] piperidin-4-yl] -5
To a solution of 0.81 g (1.64 mmol) of thia-1,8b-diazaacenaphthylene-4-carboxamide in 5 ml of ethanol was added 1 ml (12 mmol) of 12N hydrochloric acid at room temperature and stirred for several minutes. After concentration, acetonitrile was added to the residue, and the precipitated crystals were collected by filtration.
The crystals were washed with ethanol and diethyl ether to give the desired product as orange crystals (809.1 mg, 87%). Melting point 164-168 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ 1.82-2.07 (4H, m), 2.1
5-2.32 (2H, m), 2.94-3.26 (4H, m), 3.43-3.58 (2H, m
m), 3.78-3.99 (1H, m), 3.83 (3H, s), 4.10-4.20 (2
H, m), 6.60 (1H, d, J = 7.4 Hz), 6.95-7.07 (2H, m),
7.14-7.32 (3H, m), 7.50-7.71 (3H, m), 8.87 (1H, d,
J (6.8 Hz). IR (KBr) 3159,2643,1687,1629,1314,1247,764 cm ^-1 Elemental analysis C ₂₆ H ₃₀ N ₄ O ₄ SCl ₂ .0.5H ₂ O Calculated value: C, 54.36 H, 5.44; N, 9.75 Found: C, 54.30; H, 5.72; N, 9.80.

Example 163 2- [3- [4- (5-Thia-1,8b-diazaacenaphthylene-4-carbonylamino) piperidin-1-yl] propan-1-yloxy] benzoic acid · 2 Synthesis of hydrochloride N- [1- [3- (2-methoxycarbonylphenoxy) -propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (400 m
g) and 6N hydrochloric acid (20 ml).
Stirred for hours. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration and washed with isopropyl ether to give the desired compound (37).
9 mg, 97%). Melting point 180-183 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 10.70-10.40 (1H, brs),
8.89 (1H, d, J = 7.4 Hz), 7.75-7.60 (2H, m), 7.60-7.40
(1H, m), 7.40-7.20 (2H, m), 7.20-6.90 (3H, m), 6.64 (1
H, d, J = 7.4 Hz), 4.20-2.80 (9H, m), 2.40-1.80 (6H,
m) IR (KBr) ν: 3000, 1695, 1635, 1538, 1496, 1436, 139
4, 1230, 1087, 1016, 753 cm ^-1 Elemental analysis C ₂₅ H ₂₈ N ₄ O ₄ SCl ₂ · 3.5 H ₂ O Calculated: C 48.86, H 5.74, N 9.12 Found: C 48.62, H 5.51, N9.
13.

Example 164 3- [3- [4- (5-Thia-1,8b-diazaacenaphthylene-4-carbonylamino) piperidin-1-yl] propan-1-yloxy] benzoic acid · 2 Synthesis of hydrochloride N- [1- [3- (3-ethoxycarbonylphenoxy) -propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (400 m
g) and 6N hydrochloric acid (20 ml) were mixed and stirred at 80 ° C. for 4 hours. The resulting crystals were collected by filtration and washed with water to give the desired product (255 mg). The filtrate was concentrated under reduced pressure, and the resulting crystals were collected by filtration and washed with isopropyl ether to give the desired product (122 mg) (total 377 mg, 8
7%). 224-230 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.90-8.75 (1H, m), 7.64
-7.36 (4H, m), 7.30-7.15 (2H, m), 6.95 (1H, d, J = 9.2
Hz), 6.58 (1H, d, J = 7.8 Hz), 4.20-3.00 (9H, m), 2.35
-2.10 (2H, m), 2.10-1.80 (4H, m) IR (KBr) ν: 3000, 1706, 1635, 1565, 1538, 1500, 144
8, 1388, 1212, 1112, 952, 786, 763cm- ¹ Elemental analysis C ₂₅ H ₂₈ N ₄ O ₄ SCl ₂・ 4.5H ₂ O Calculated: C 47.47, H 5.90, N 8.86 Observed: C 47.39 , H 5.62, N 9.10.

Example 165 4- [3- [4- (5-Thia-1,8b-diazaacenaphthylene-4-carbonylamino) piperidin-1-yl] propan-1-yloxy] benzoic acid • 2 Synthesis of hydrochloride N- [1- [3- (4-ethoxycarbonylphenoxy) -propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (400 m
g) and 6N hydrochloric acid (20 ml) were mixed and stirred at 80 ° C. for 5 hours. The resulting crystals were collected by filtration and washed with water to give the desired product (397 mg, 91%). 277-280 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 7.90 (2H, d, J = 8.8 Hz),
7.58 (1H, s), 7.15-7.26 (2H, m), 7.03 (2H, d, J = 8.8
Hz), 6.92 (1H, d, J = 9.6 Hz), 6.53 (1H, d, J = 8.0 Hz),
4.05-4.20 (1H, m), 3.15-4.00 (8H, m), 2.10-2.30 (2H, m
m), 1.80-2.00 (4H, m) IR (KBr) ν: 3051, 1683, 1633, 1606, 1569, 1502, 14
40, 1316, 1259, 1212,1168, 773cm- ¹ Elemental analysis C ₂₅ H ₂₈ N ₄ O ₄ SCl ₂・ 4.0H ₂ O Calculated: C 48.16, H 5.82, N 8.99 Actual: C 48.18, H 5.73, N 9.08.

Example 166 N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5 Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide 2- (3-chloropropan-1-yl) oxybenznitrile (503 mg) was converted to N- (piperidin-4-yl)
-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8-diazabicyclo [5.4.0] -7-undecene (662 m
g), triethylamine (1.09 g), sodium iodide (285 mg) in acetonitrile (20 ml)
At room temperature and heated to reflux for 7.5 hours under a nitrogen atmosphere. 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 chromatographed on silica gel (ethyl acetate / methanol =
2/1) to give the desired product as a reddish purple oil (816 mg, 83%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.55 (2H, d, J = 8.0 Hz),
7.06-6.95 (3H, m), 6.78 (1H, s), 6.63 (1H, d, J = 5.8
Hz), 6.10-5.80 (1H, m), 5.78 (1H, dd, J = 1.8 and 5.8
Hz), 4.16 (2H, t, J = 6.0 Hz), 4.00-3.80 (1H, m), 3.
60-3.40 (2H, m), 3.10-2.90 (2H, m), 2.83-2.65 (2H, m
m), 2.20-1.90 (6H, m), 1.85-1.60 (2H, m) 2) N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidin-4-yl]- Synthesis of 5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5-thia-
Concentrated hydrochloric acid (3.0 ml) was added to an ethanol solution (8.0 ml) of 1,8b-diazaacenaphthylene-4-carboxamide (565 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting crystals were collected by filtration and washed with ethanol to give the desired product (462 mg, 70%). Melting point 234-240 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.90-8.78 (1H, m), 7.80
-7.58 (3H, m), 7.34-7.06 (4H, m), 6.96 (1H, d, J = 8.8
Hz), 6.59 (1H, d, J = 7.2 Hz), 4.40-4.20 (2H, m), 4.00
-2.80 (7H, m), 2.40-2.20 (2H, m), 2.20-1.80 (4H, m) IR (KBr) ν: 3290, 3031, 2638, 2225, 1644, 1633, 15
69, 1540, 1498, 1450,1291, 1263, 1218, 1112, 796cm
^-1 Elemental analysis As C ₂₅ H ₂₇ N ₅ O ₂ SCl ₂・ 2.0H ₂ O Calculated: C 52.82, H 5.50, N 12.32 Observed: C 52.89, H 5.24, N 12.29.

Example 167 N- [1- [3- (3-cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (3-cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5 Synthesis of -thia-1,8b-diazaacenaphthylene-4-carboxamide 3- (3-chloropropan-1-yl) oxybenznitrile (503 mg) was converted to N- (piperidin-4-yl)
-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8-diazabicyclo [5.4.0] -7-undecene (662 m
g), triethylamine (1.09 g), sodium iodide (285 mg) in acetonitrile (20 ml)
At room temperature and heated under reflux in a nitrogen atmosphere for 6.5 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 chromatographed on silica gel (ethyl acetate / methanol =
2/1) and purified as reddish purple crystals (565).
mg, 57%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.48-7.00 (4H, m), 6.80-
6.58 (3H, m), 5.90-5.70 (2H, m), 4.04 (2H, t, J = 6.1
Hz), 3.95-3.70 (1H, m), 3.00-2.81 (2H, m), 2.55 (2H, m
t, J = 7.0 Hz), 2.30-1.80 (6H, m), 1.70-1.40 (2H, m) 2) N- [1- [3- (3-cyanophenyloxy) propan-1-yl] piperidine- Synthesis of 4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidine -4-yl] -5-thia-
Concentrated hydrochloric acid (3.0 ml) was added to an ethanol solution (8.0 ml) of 1,8b-diazaacenaphthylene-4-carboxamide (565 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting crystals were collected by filtration and washed with ethanol (462).
mg, 70%). Melting point 169-172 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.90-8.80 (1H, m), 7.62
-7.39 (4H, m), 7.38-7.18 (3H, m), 6.95 (1H, d, J = 8.6
Hz), 6.58 (1H, d, J = 7.2 Hz), 4.20-4.10 (2H, m), 4.00
-2.90 (7H, m), 2.20-2.10 (2H, m), 2.10-1.80 (4H, m) IR (KBr) ν: 3224, 3055, 2549, 2227, 1635, 1565, 150
2, 1432, 1317, 1301, 1264, 1214, 784 cm ^-1 Elemental analysis C ₂₅ H ₂₇ N ₅ O ₂ SCl ₂ · 2.0 H ₂ O Calculated: C 52.82, H 5.50, N 12.32 Actual value: C 52 .92, H 5.34, N 1
2.28.

Example 168 N- [1- [3- (4-Cyanophenyloxy) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) 4- (3-Chloropropan-1-yl) oxybenznitrile (503 mg) was added to N- (piperidin-4-yl) -5. -Thia-1,8b-diazaacenaphthylene-4
-Carboxamide dihydrochloride (800 mg), 1,8-
Diazabicyclo [5.4.0] -7-undecene (66
2mg), triethylamine (1.09g), sodium iodide (285mg) in acetonitrile (20m
l) at room temperature and heated under reflux in a nitrogen atmosphere for 19 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 chromatography (ethyl acetate / methanol = 2/1) to give the desired product (73) as red-purple crystals.
(3 mg, 74%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.
58 (2H, d, J = 8.8 Hz), 7.05 (1H, s), 6.94 (2H, d, J =
8.8 Hz), 6.96-6.58 (3H, m), 5.88-5.74 (1H, m), 5.79
(1H, dd, J = 1.8 and 6.2 Hz), 4.07 (2H, t, J = 5.8 H
z), 4.00-3.75 (1H, m), 3.05-2.90 (2H, m), 2.61 (2H, t,
J = 7.0 Hz), 2.35-1.90 (6H, m), 1.80-1.50 (2H, m) 2) N- [1- [3- (4-cyanophenyloxy) propan-1-yl] piperidin-4- Synthesis of yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride N- [1- [3- (2-cyanophenyloxy) propan-1-yl] piperidine-4 -Yl] -5-thia-
Concentrated hydrochloric acid (3.0 ml) was added to an ethanol solution (8.0 ml) of 1,8b-diazaacenaphthylene-4-carboxamide (621 mg), and the mixture was stirred at room temperature for 15 minutes. The resulting crystals were collected by filtration and washed with ethanol to give the desired product (572 mg, 79%). Melting point 268-272 ° C ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.86 (1 H, d, J = 7.8 Hz),
7.78 (2H, d, J = 9.2 Hz), 7.68-7.58 (1H, m), 7.34-7.1
8 (2H, m), 7.11 (2H, d, J = 9.2 Hz), 6.97 (1H, d, J = 8.0
Hz), 6.60 (1H, d, J = 7.6 Hz), 4.30-4.10 (2H, m), 4.00
-2.94 (7H, m), 2.40-2.15 (2H, m), 2.15-1.80 (4H, m) IR (KBr) ν: 3212, 3055, 2219, 1631, 1604, 1569, 15
38, 1506, 1297, 1263, 1168, 1126, 834, 792cm ^-1 Elemental analysis C ₂₅ H ₂₇ N ₅ O ₂ SCl ₂ · 0.8H ₂ O Calculated: C 54.90, H 5.27, N 12.81 Found: C 54.91, H 5.06, N 12.96.

Example 169 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide -1,8b-diazaacenaphthylene-4-carboxylic acid (5.00 g) was added to tetrahydrofuran (40 m
l) and dimethylformamide (0.89 ml), oxalyl chloride (4.00 ml) was added dropwise over 10 minutes under ice cooling, and the mixture was stirred at room temperature for 2 hours. The obtained reaction solution was concentrated by an evaporator (the obtained solution is referred to as “concentrate 1”). On the other hand, 4-amino-1-
(3-Phenylpropyl) piperidine dihydrochloride (7.34
g) is suspended in dimethylformamide (20 ml),
Triethylamine (19.80 ml) was added dropwise, the mixture was stirred for 30 minutes, and the insolubles were removed by filtration (the resulting solution is referred to as "amine solution 1"). The concentrate 1 obtained above was suspended in dimethylformamide (20 ml), the amine solution 1 obtained above was added dropwise at an internal temperature of 50 ° C. over 1 hour, and further the internal temperature was adjusted to 5 mL.
Stirred at 0 ° C. for 1 hour. Add water (200ml), 1
N sodium hydroxide solution (20 ml) was added, and the mixture was washed three times with ethyl acetate: tetrahydrofuran = 4: 1 (100 ml). The organic layer was concentrated, ethyl acetate: isopropyl ether = 1: 1 (20 ml) was added to the remaining crystals, and the mixture was stirred at room temperature for 2 hours and then filtered. The obtained product was dried under reduced pressure to obtain the title compound (7.45 g, yield: 77.7%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45-1.50 (m, 2H), 1.77-
1.85 (m, 2H), 1.91-1.95 (d, J = 12.68Hz, 2H), 2.04-2.11
(t, J = 9.62Hz, 2H), 2.33-2.38 (t, J = 7.89Hz, 2H), 2.60-2.
65 (t, J = 7.79Hz, 2H), 2.81-2.85 (d, J = 11.94Hz, 2H), 3.79
-3.81 (m, 1H), 5.68-5.70 (d, J = 7.73Hz, 1H), 5.76-5.78
(m, 1H), 6.58-6.68 (m, 3H), 7.03 (s, 1H), 7.16-7.20 (m, 3
H), 7.25-7.30 (m, 2H).

Example 170 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 4-amino -1- (3-Phenylpropyl) piperidine dihydrochloride (7.01 g) was added to dimethylformamide (40
ml) and triethylamine (6.71 ml)
Was added dropwise and stirred for 10 minutes. In addition, 5-thia-1,
8b-diazaacenaphthylene-4-carboxylic acid (5.0
0g), 1-hydroxy-1H-benzotriazole
Monohydrate (0.70 g), 1-ethyl-3- (3
-Dimethylaminopropyl) -carbodiimide (4.61
g) was added. The mixture was stirred at an internal temperature of 68 ° C to 70 ° C for 2 hours. Ethyl acetate: tetrahydrofuran = 4: 1
(380 ml), 1N sodium hydroxide (50 ml),
Water (80 ml) was added and the mixture was separated. The aqueous layer was further extracted twice with ethyl acetate: tetrahydrofuran = 4: 1 (120 ml). The organic layers were combined and washed three times with water (130 ml). The organic layer was concentrated, and the residue was treated with ethyl acetate (15 m
l) was added and the mixture was stirred at room temperature for 2 hours, and then filtered. Dry under reduced pressure to obtain the title compound (8.87 g, yield: 92.5%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45-1.50 (m, 2H), 1.77-
1.85 (m, 2H), 1.91-1.95 (d, J = 12.68Hz, 2H), 2.04-2.11
(t, J = 9.62Hz, 2H), 2.33-2.38 (t, J = 7.89Hz, 2H), 2.60-2.
65 (t, J = 7.79Hz, 2H), 2.81-2.85 (d, J = 11.94,2H), 3.79-
3.81 (m, 1H), 5.68-5.70 (d, J = 7.73Hz, 1H), 5.76-5.78 (m,
1H), 6.58-6.68 (m, 3H), 7.03 (s, 1H), 7.16-7.20 (m, 3H),
7.25-7.30 (m, 2H).

Example 171 Synthesis of N- [1- (3-phenylpropan-1-yl) piperidin-4-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 4-amino -1- (3-Phenylpropyl) piperidine dihydrochloride (1.40 g) was added to dimethylformamide (10
ml), and triethylamine (1.34 ml) was added dropwise, followed by stirring for 10 minutes. 5-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1.00 g) and diethyl cyanophosphate (0.81 ml) were added. The mixture was stirred for 1 hour under ice cooling, 1 hour at room temperature, and 2 hours at 55 ° C. Ethyl acetate: tetrahydrofuran = 4: 1 (75 ml), 1N
Sodium hydroxide (30 ml) was added and the layers were separated. The organic layer was washed three times with 1N sodium hydroxide (30 ml) and water (30 ml).
ml) twice. After concentration, ethyl acetate (4 ml) was added to the residual crystals, and the mixture was stirred at room temperature for 1 hour, filtered, and dried under reduced pressure to obtain the title compound (1.07 g, yield: 63.6%). ¹ H-NMR (CDCl ₃ , 300 MHz) δ: 1.45-1.50 (m, 2H), 1.77-1.
85 (m, 2H), 1.91-1.95 (d, J = 12.68Hz, 2H), 2.04-2.11 (t, J
= 9.62Hz, 2H), 2.33-2.38 (t, J = 7.89HZ, 2H), 2.60-2.65
(t, J = 7.79Hz, 2H), 2.81-2.85 (d, J = 11.94Hz, 2H), 3.79-
3.81 (m, 1H), 5.68-5.70 (d, J = 7.73Hz, 1H), 5.76-5.78 (m,
1H), 6.58-6.68 (m, 3H), 7.03 (s, 1H), 7.16-7.20 (m, 3H),
7.25-7.30 (m, 2H).

Example 172 N- [3- (4-Phenylmethyl-2-oxopiperazin-1-yl) propan-1-yl] -5-thia-1,
Synthesis of 8b-diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [3- (4-tert-butoxycarbonyl-2-oxopiperazin-1-yl) propan-1-yl] -5-thia -1,8b-diazaacenaphthylene-4
Synthesis of -carboxamide N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (4.22 g, 22.0 mmol) was added to 5
-Thia-1,8b-diazaacenaphthylene-4-carboxylic acid (2.40 g, 11.0 mmol), N-hydroxysuccinimide (2.53 g, 22.0 mmol) in acetonitrile suspension (30 ml) at room temperature Add below,
The mixture was stirred at room temperature for 1.5 hours. 1- (3-aminopropan-1-yl) -4-tert-butoxycarbonyl-
2-oxopiperazine (3.67 g, 14.3 mmol)
l), triethylamine (4.45 g, 44.0 mmol)
l) Acetonitrile solution (15 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 19 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 subjected to silica gel column chromatography (silica gel 50 g, ethyl acetate / methanol = 10 /
Purification in 1) gave the desired product as a purple amorphous (1.5
3g, 30%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.45-7.30 (1H, m), 7.0
3 (1H, s), 6.70-6.55 (3H, m), 5.75 (1H, dd, J = 6.0
and 1.8 Hz), 4.13 (2H, s), 3.75-3.60 (2H, m), 3.60
-3.40 (2H, m), 3.40-3.30 (2H, m), 3.30-3.15 (2H,
m), 1.85-1.60 (2H, m), 1.48 (9H, s) .IR (KBr): 3269, 2977, 2931, 1695, 1644, 1482, 141
9, 1284, 1164 cm ^-1 .2) N- [3- (2-oxopiperazin-1-yl)
Synthesis of propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (4.0 ml) was added to N- [3- (4-tert-butoxycarbonyl-). 2-oxopiperazin-1-yl)
Propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (1.53 g, 3.
34 mmol) and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the target compound as an orange amorphous substance (1.
53 g, quant. ). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 10.00-9.60 (1H, m),
8.85-8.70 (1H, m), 7.68 (1H, s), 7.36-7.25 (1H,
m), 7.14 (1H, s), 6.99 (1H, d, J = 8.6 Hz), 6.65 (1H,
d, J = 7.4 Hz), 4.00-2.80 (6H, m), 2.40-2.10 (2H,
m), 1.80-1.55 (4H, m). 3) N- [3- (4-Phenylmethyl-2-oxopiperazin-1-yl) propan-1-yl] -5-thia-1,8b-dia Synthesis of Zaacenaphthylene-4-carboxamide Benzyl chloride (187 mg, 1.48 mmol) was converted to N- [3- (2-oxopiperazin-1-yl) propan-1-yl] -5-thia-1,8b- Diazaacenaphthylene-4-carboxamide dihydrochloride (518 mg,
1.20 mmol), triethylamine (605 mg,
5.98 mmol), sodium iodide (216 mg,
1.44 mmol), 1,8-diazabicyclo [5.
4.0] Undecene (366 mg, 2.41 mmol)
To acetonitrile solution (20 ml) at room temperature.
The mixture was heated and refluxed under a nitrogen atmosphere for days. 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 (silica gel 20 g, ethyl acetate / methanol = 8/1) to obtain the desired product as a purple amorphous substance (303 mg, 56%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.62-7.45 (1H, m), 7.4
0-7.20 (5H, m), 7.00 (1H, s), 6.65 (1H, s), 6.60-
6.50 (2H, m), 5.73 (1H, dd, J = 5.6 and 2.4 Hz), 3.5
8 (2H, s), 3.52-3.38 (2H, m), 3.38-3.10 (4H, m),
3.20 (2H, s), 2.70 (2H, t, J = 5.2 Hz), 1.80-1.60 (2
H, m) .IR (KBr): 3242, 2937, 1627, 1505, 1482, 1282, 115
6, 913, 734 cm ^-1 .4) N- [3- (4-phenylmethyl-2-oxopiperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenafti Synthesis of len-4-carboxamide dihydrochloride Concentrated hydrochloric acid (0.8 ml) was converted to N- [3- (4-phenylmethyl-2-oxopiperazin-1-yl) propane-1-
Yl] -5-thia-1,8b-diazaacenaphthylene-
4-carboxamide (300 mg, 0.670 mmol
l) in ethanol solution (5.0 ml),
Stirred for hours. The reaction solution was concentrated under reduced pressure to obtain the target compound as an orange amorphous substance (345 mg, 98%). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.80-8.60 (1H, m),
7.80-7.40 (6H, m), 7.40-7.15 (1H, m), 7.05 (1H,
s), 6.95 (1H, d, J = 8.4 Hz), 6.56 (1H, d, J = 6.6 Hz),
4.38 (2H, s), 4.00-3.20 (8H, m), 3.20-3.00 (2H,
m), 1.80-1.50 (2H, m) .IR (KBr): 3240, 3058, 2941, 1635, 1565, 1538, 150
2, 1293, 1214, 759, 705 cm ^-1 . Elemental analysis: As C ₂₆ H ₃₁ Cl ₂ N ₅ O ₂ S.2.5 H ₂ O Calculated: C 50.97; H 5.70; N 12.38. C 50.90; H 5.71; N 1
2.08.

Example 173 N- [3- [4- (2-phenylethane-1-yl)-
2-oxopiperazin-1-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
Synthesis of -carboxamide dihydrochloride 1) N- [3- [4- (2-phenylethan-1-yl) -2-oxopiperazin-1-yl] propane-1
-Yl] -5-Thia-1,8b-diazaacenaphthylene-4-carboxamide 2-bromoethylbenzene (312 mg, 1.68 mm)
ol) is converted to N- [3- (2-oxopiperazin-1-yl) propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (6
10 mg, 1.42 mmol), triethylamine (7
22 mg, 7.13 mmol), sodium iodide (2
55 mg, 1.70 mmol), 1,8-diazabicyclo [5.4.0] undecene (438 mg, 2.88 m)
mol) of acetonitrile (20 ml) at room temperature and heated to reflux for 2 days under a nitrogen atmosphere. 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 (silica gel 20 g, ethyl acetate / methanol = 8/1) to obtain the desired product as a purple amorphous substance (288 mg, 44%). ¹ H-NMR (200 MHz, CDCl ₃ )
δ: 7.65-7.45 (1H, m), 7.40-7.15 (5H, m), 7.01 (1
H, s), 6.60-6.50 (2H, m), 5.74 (1H, dd, J = 6.0 and
2.2 Hz), 3.60-3.40 (2H, m), 3.40-3.00 (6H, m), 3.0
0-2.60 (6H, m), 1.80-1.60 (2H, m) .IR (KBr): 3286, 2935, 1714, 1635, 1506, 1482, 128
2,1156,732 cm ^-1 .2) N- [3- [4- (2-Phenylethane-1-yl) -2-oxopiperazin-1-yl] propane-1
Synthesis of -yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (0.8 ml) was added to N- [3- [4- (2-phenylethane-1-) Yl) -2-oxopiperazin-1-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (369 mg,
0.799 mmol) in ethanol solution (5.0 ml)
And stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure,
The desired product was obtained as an orange amorphous substance (424 mg, 99
%). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.80-8.65 (1H, m),
7.62 (1H, s), 7.60-7.20 (6H, m), 7.08 (1H, s), 7.00
-6.90 (1H, m), 6.62-6.50 (1H, m), 4.20-3.20 (10H,
m), 3.20-3.00 (4H, m), 1.85-1.55 (2H, m) .IR (KBr): 3242, 2935, 1652, 1635, 1565, 1538, 150
0, 1455, 1361, 1293, 1214, 784, 703 cm ^-1 . Elemental analysis: C ₂₅ H ₂₉ Cl ₂ N ₅ O ₂ S ・ 0.7C ₂ H ₅ OH ・ 2.0H ₂ O Calculated: C 52.60 ; H 6.22; N 11.62. Found: C 52.74; H 5.96; N 11.68.

Example 174 N- [3- [4- (3-phenylpropan-1-yl)
-2-oxopiperazin-1-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
Synthesis of carboxamide dihydrochloride 1) N- [3- [4- (3-Phenylpropane-1-)
Yl) -2-oxopiperazin-1-yl] propane-
Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide 1-bromo-3-phenylpropane (210 mg, 1.
05 mmol) with N- [3- (2-oxopiperazine-
1-yl) propan-1-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide dihydrochloride (389 mg, 0.904 mmol), triethylamine (459 mg, 4.53 mmol), sodium iodide (163 mg, 1.09 mmol), 1,8-diazabicyclo [5.4 .0] undecene (275 mg,
1.81 mmol) in acetonitrile (10 ml)
At room temperature and heated to reflux under a nitrogen atmosphere for 2 days.
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 (silica gel 15 g, ethyl acetate / methanol = 8/1) to obtain the desired product as a purple amorphous substance (285 mg, 66%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.62-7.50 (1H, m), 7.4
0-7.15 (5H, m), 7.01 (1H, s), 6.66 (1H, s), 6.62-
6.50 (2H, m), 5.74 (1H, dd, J = 6.0 and 2.2 Hz), 3.5
4-3.40 (1H, m), 3.36-3.26 (2H, m), 3.26-3.12 (2H,
m), 3.18 (2H, s), 2.67 (4H, t, J = 7.4 Hz), 1.95-1.40
(4H, m) .IR (KBr): 3294, 2935, 1714, 1635, 1506, 1282, 115
6, 732 cm ⁻¹ .2) N- [3- [4- (3-phenylpropane-1-)
Yl) -2-oxopiperazin-1-yl] propane-
Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (0.8 ml) was added to N- [3- [4- (3-phenylpropane-1). -Yl) -2-oxopiperazine-1-
Il] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (261 m
g, 0.549 mmol) in an ethanol solution (5.0 m
l) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the desired product as an orange amorphous substance (295 mg, 98
%). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.82-8.70 (1H, m),
7.67 (1H, s), 7.40-7.15 (6H, m), 7.10 (1H, s), 6.98
(1H, d, J = 7.4 Hz), 6.63 (1H, d, J = 7.4 Hz), 4.00-2.
70 (8H, m), 2.64 (2H, t, J = 7.2 Hz), 2.20-1.85 (4H,
m), 1.80-1.50 (4H, m) .IR (KBr): 3219, 2937, 1652, 1538, 1500, 1455, 129
1, 1216, 786, 757 cm ^-1 .Calculated elemental value: C ₂₆ H ₃₁ Cl ₂ N ₅ O ₂ S ・ 2.5H ₂ O Calculated value: C 52.61; H 6.11; N 11.80. Actual value: C 52.88; H 6.18; N 11.58.

Example 175 N- [1- [3- (4-aminophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide trihydrochloride 1) N- [1- [3- (4-tert-butoxycarbonylaminophenyl) propan-1-yl] piperidin-4-yl] -5- Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 3- (4-tert-butoxycarbonylaminophenyl) propyl methanesulfonate (423 mg, 1.2
8 mmol) with N- (piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol),
1,8-diazabicyclo [5.4.0] undecene (3
26 mg, 2.14 mmol), sodium iodide (1
92 mg, 1.28 mmol) in an acetonitrile solution (20 ml), and the mixture was heated and refluxed for one day under a nitrogen atmosphere.
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 (silica gel 20 g, ethyl acetate / methanol = 3/1) to obtain the desired product as a purple amorphous substance (350 mg, 61%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-7.00 (4H, m), 6.8
0-6.58 (3H, m), 6.45-6.38 (1H, m), 5.79 (1H, dd, J
= 5.8 and 1.4 Hz), 5.65-5.55 (1H, m), 3.90-3.70 (1
H, m), 2.95-2.78 (2H, m), 2.70-2.50 (2H, m), 2.45-
2.30 (2H, m), 2.20-1.58 (8H, m), 1.43 (9H, s). 2) N- [1- [3- (4-aminophenyl) propan-1-yl] piperidin-4-yl ] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride Concentrated hydrochloric acid (1.5 ml) was added to N- [1- [3- (4-ter
(t-butoxycarbonylaminophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide (350
mg, 0.656 mmol) and stirred at room temperature for 2 hours. Ethanol was added to the reaction solution, and the orange crystals formed as the target product were collected by filtration and washed with ethanol (25
1 mg, 71%). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.80-8.70
(1H, m), 7.59 (1H, s),
7.40-7.15 (6H, m), 6.94 (1
H, d, J = 9.6 Hz), 6.54 (1
H, d, J = 7.8 Hz), 4.00-3.2.
0 (3H, m), 3.20-2.80 (6H,
m), 2.80-2.60 (2H, m), 2.
20-1.80 (6H, m). IR (KBr): 3000, 2557, 16
53, 1631, 1515, 1498, 129
9, 1216, 1116, 823, 782 c
m ^-1 . Elemental analysis value C ₂₄ H ₃₀ Cl ₃ N ₅ OS · 1.5H ₂
As O, Calc: C 50.57; H 5.84; N 12.29. Found: C 50.60; H 5.77; N 12.33.

Example 176 N- [1- [3- (3-aminophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide trihydrochloride 1) N- [1- [3- (3-tert-butoxycarbonylaminophenyl) propan-1-yl] piperidin-4-yl] -5- Synthesis of thia-1,8b-diazaacenaphthylene-4-carboxamide 3- (3-tert-butoxycarbonylaminophenyl) propyl methanesulfonate (423 mg, 1.2
8 mmol) with N- (piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol),
1,8-diazabicyclo [5.4.0] undecene (3
26 mg, 2.14 mmol), sodium iodide (1
92 mg, 1.28 mmol) in an acetonitrile solution (20 ml), and the mixture was refluxed for 16 hours under a nitrogen atmosphere. 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 (silica gel 15 g, ethyl acetate / methanol = 3/1) to obtain the desired product as a purple amorphous (413 mg, 72%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.23-7.00 (3H, m), 6.8
5 (1H, d, J = 7.4 Hz), 6.70-6.50 (4H, m), 5.90-5.75
(1H, m), 5.78 (1H, dd, J = 5.8 and 1.8 Hz), 4.00-3.7
5 (1H, m), 3.00-2.80 (2H, m), 2.62 (2H, t, J = 7.2 H
z), 2.43 (2H, t, J = 7.4 Hz), 2.30-1.55 (8H, m), 1.51
(9H, s). 2) N- [1- [3- (3-aminophenyl) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide trihydrochloride Concentrated hydrochloric acid (1.5 ml) was treated with N- [1- [3- (3-ter
(t-butoxycarbonylaminophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
-Diazaacenaphthylene-4-carboxamide (392
mg, 0.735 mmol) and stirred at room temperature for 1 hour. Ethanol was added to the reaction solution, and orange crystals formed as the target product were collected by filtration and washed with ethanol (26).
5 mg, 66%). ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 8.85-8.75 (1H, m), 7.
63 (1H, s), 7.50-7.36 (1H, m), 7.32-7.16 (5H, m),
6.96 (1H, d, J = 9.2 Hz), 6.59 (1H, d, J = 7.4 Hz), 4.
20-3.20 (4H, m), 3.20-2.80 (5H, m), 2.68 (2H, t, J
= 6.8 Hz), 2.20-1.80 (6H, m). IR (KBr): 3050, 1633, 1567, 1540, 1498, 1307, 122
0, 1112, 782 cm ^-1 Elemental analysis: C ₂₄ H ₃₀ Cl ₃ N ₅ OS 1.5 H ₂ O Calculated: C, 50.57; H, 5.84; N, 12.29. Found: C, 50.27; H , 5.92; N, 12.05.

Example 177 N- [1- [3- (4-cyanophenyl) propane-1
-Yl] piperidin-4-yl] -5-thia-1,8b
Synthesis of -diazaacenaphthylene-4-carboxamide dihydrochloride 1) N- [1- [3- (4-cyanophenyl) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide 3- (4-tert-butoxycarbonylaminophenyl) propyl methanesulfonate (307 mg, 1.2
8 mmol) with N- (piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (400 mg, 1.07 mmol), triethylamine (539 mg, 5.33 mmol),
1,8-diazabicyclo [5.4.0] undecene (3
26 mg, 2.14 mmol), sodium iodide (1
92 mg, 1.28 mmol) in an acetonitrile solution (20 ml), and the mixture was refluxed for 14 hours under a nitrogen atmosphere. 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 (silica gel 20 g, ethyl acetate / methanol = 2/1) to obtain the desired product as a purple oil (298 mg, 63%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.57 (2H, d, J = 8.0 H
z), 7.28 (2H, d, J = 8.0 Hz), 7.06 (1H, s), 6.75-6.5
5 (3H, m), 5.79 (1H, dd, J = 6.0 and 1.6 Hz), 5.56
(1H, d, J = 7.8 Hz), 3.92-3.70 (1H, m), 2.92-2.75 (2
H, m), 2.69 (2H, t, J = 7.8 Hz), 2.36 (2H, t, J = 7.4 H
z), 2.20-2.02 (2H, m), 2.02-1.88 (2H, m), 1.88-1.7
6 (2H, m), 1.60-1.40 (2H, m) .IR (neat): 3209, 2943, 2227, 1615, 1540, 1508, 14
82, 1286, 1156, 734 cm ^-1 .2) N- [1- [3- (4-cyanophenyl) propan-1-yl] piperidin-4-yl] -5-thia-
Synthesis of 1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (1.5 ml) was converted to N- [1- [3- (4-cyanophenyl) propan-1-yl] piperidin-4- Yl] -5-thia-1,8b-diazaacenaphthylene-4
-Carboxamide (298 mg, 0.672 mmol)
Was added to an ethanol solution (4.0 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the desired product as orange crystals (324 mg, 93%). ^{1 H-NMR (200MHz, DMSO} -d 6): 8.85-8.75 (1H, m), 7.79 (2
H, d, J = 7.8Hz), 7.62 (1H, s), 7.47 (2H, d, J = 7.8Hz),
7.32-7.10 (2H, m), 6.96 (1H, d, J = 9.2Hz), 6.59 (1H,
d, J = 7.6Hz), 4.00-3.20 (3H, m), 3.15-2.90 (2H, m),
2.80-2.65 (2H, m), 2.20-1.90 (4H, m), 1.90-1.80 (2H, m
m) IR (KBr): 3037, 2939, 2223, 1633, 1500, 1307, 1220,
1114, 776 cm ^-1

Example 178 N- [3- [1- (3-Phenylpropan-1-yl)
-2-oxopiperazin-4-yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4
Synthesis of -carboxamide dihydrochloride 1) N- [3- [1- (3-phenylpropane-1-)
Yl) -2-oxopiperazin-4-yl] propane-
Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (1.58 g, 8.24 mmol)
-(Piperidin-4-yl) -5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (900 mg,
4.12 mmol) and a suspension of N-hydroxysuccinimide (948 mg, 8.24 mmol) in acetonitrile (10 ml) were added at room temperature and stirred at room temperature for 2 hours. 4- (3-aminopropan-1-yl) -1-
(3-Phenylpropan-1-yl) -2-oxopiperazine (1.38 g, 5.01 mmol), triethylamine (459 mg, 4.54 mmol), 1,8-diazabicyclo [5.4.0] undecene (1. 25g,
8.24 mmol) in acetonitrile (20 ml)
Was added to the reaction solution, followed by stirring at room temperature for 1 day. 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 (silica gel 60 g, ethyl acetate / methanol = 5/1) to obtain the desired product as a purple amorphous substance (978 mg, 50%). ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-7.10 (5H, m), 7.0
2 (1H, s), 6.67 (1H, s), 6.66-6.50 (2H, m), 5.72
(1H, d, J = 7.0 Hz), 3.60-3.20 (6H, m), 3.17 (2H,
s), 2.75-2.60 (4H, m), 2.53 (2H, t, J = 5.8 Hz), 2.0
0-1.78 (2H, m), 1.78-1.60 (2H, m) .IR (KBr): 3248, 2941, 1639, 1544, 1504, 1482, 128
2, 1155, 734 cm ^-1 .2) N- [3- [1- (3-phenylpropane-1-)
Yl) -2-oxopiperazin-4-yl] propane-
Synthesis of 1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride Concentrated hydrochloric acid (4.5 ml) was added to N- [3- [1- (3-phenylpropane-1). -Yl) -2-oxopiperazine-4-
Yl] propan-1-yl] -5-thia-1,8b-diazaacenaphthylene-4-carboxamide (954 m
g, 2.01 mmol) in ethanol (12.0 m
l) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the desired product as an orange amorphous substance (1.08 g, 98
%). ¹ H-NMR (DMSO-d ₆ ): δ 9.02-8.90 (1H, m), 7.66 (1H, s),
7.40-7.10 (6H, m), 6.97 (1H, d, J = 9.2Hz), 6.62 (1H,
d, J = 7.2Hz), 4.20-3.00 (8H, m), 2.65-2.50 (2H, m), 2.
00-1.70 (8H, m) IR (KBr): 3226, 3028, 2931, 1633, 1565, 1500, 1454,
1444, 1359, 1297, 1216, 782, 703 cm ^-1

[0424]

The compound (I) of the present invention or a salt thereof has excellent LDL receptor increasing action, blood lipid lowering action, blood glucose lowering action, diabetic complication ameliorating action and the like. The pharmaceutical preparation can be a safe and useful prophylactic / therapeutic agent for diseases such as arteriosclerosis, hyperlipidemia, diabetes, and diabetic complications.

Claims (45)

[Claims] 1. A compound of the general formula (I) 2. The compound according to claim 1, wherein R ⁰ is -Y ⁰ -Z ⁰ (Y ⁰ and Z ⁰ each have the same meaning as described in claim 1). 3. The compound according to claim 1, wherein Z ⁰ is a group having a molecular weight of 1,000 or less. 4. A compound represented by the general formula (I): Z is -CO -, - COO -, - CON (R 3) -, - SO 2
N (R ³⁾ - or -S (O) m- (m denotes 0, 1 or 2)
R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ⁴ , R ^4a and R ⁵ Each represents a hydrogen atom or a hydrocarbon group which may be substituted, or R ³ and A, R ⁴ and A, R ⁴ and B, R ⁴ and R ⁵ or R ⁴ and R form a ring And R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 5. A compound represented by the general formula (I): R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ⁴ , R ^4a and R ⁵ each represent hydrogen Represents an atom or an optionally substituted hydrocarbon group, or represents R ³ and A, R ⁴ and A, R ⁴ and B, R ⁴ and R ⁵
Alternatively, R ⁴ and R may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 6. A and B are each an alkylene;
Is a bond, and R ³ and R ⁴ are each a hydrogen atom or an optionally substituted alkyl, cycloalkyl, alkenyl, aralkyl or aryl. (7) ring Q is an unsubstituted pyridine ring, X is a bond, R ¹ and R ² are hydrogen atoms, and R ³ and R ⁴ are each a hydrogen atom, C _1-15 alkyl, C _3-8 cycloalkyl,
The compound according to claim 5, wherein the compound is _2-18 alkenyl, _C7-16 aralkyl or _C6-14 aryl, and R is _C6-14 aryl. 8. A compound represented by the general formula (I): R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ^4a and R ⁵ each represent a hydrogen atom or a substituted Indicates a hydrocarbon group which may be
Alternatively, R ³ and A ¹ may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The compound according to claim 1, wherein 9. The ring Q is an unsubstituted pyridine ring, R ¹ and R ² are hydrogen atoms, R ³ is a hydrogen atom, C _1-15 alkyl, C _3-8 cycloalkyl, C _2-18 Alkenyl, C _7-16
Aralkyl or C _6-14 aryl, A ¹ is (i) a bond, (ii) hydroxyl, to 1 selected from oxo group and a phenyl group which may have a three substituents C _1-15 Alkylene, (iii) C _2-16 alkenylene or (iv) phenylene, wherein B is (i) C _1- which may have 1 to 3 substituents selected from a hydroxyl group, an oxo group and a phenyl group; ₁₅ alkylene, (ii) C _2-16 alkenylene or (iii) phenylene, wherein the ring Q ₁ has the formula Wherein A ² represents ＣC or CH. X is a bond, an oxygen atom, a sulfur atom, or -CO
N (R ⁵⁾ - a is The compound of claim 8 wherein R ⁵ is a hydrogen atom or a C _1-15 alkyl. 10. A compound represented by the general formula (I): R ¹ represents a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ , R ^4a and R ⁵ each represent a hydrogen atom or an optionally substituted R represents a hydrocarbon group which may be substituted or an optionally substituted heterocyclic group; ^one of G ¹ and G ² is N, and the other is CH or N
And the ^Ga ring may have a substituent, and g is 0,
Indicates 1 or 2. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 11. The ring Q is nitro, hydroxy, cyano,
Carbamoyl, mono- or di-C _1-4 alkyl-carbamoyl, carboxy, C _1-4 alkoxy-carbonyl,
Sulfone, halogen, C _1-4 alkoxy, phenoxy,
Naphthoxy, benzyloxy, halogenophenoxy, C
_1-4 alkylthio, mercapto, phenylthio, pyridylthio, C _1-4 alkylsulfinyl, phenylsulfinyl, C _1-4 alkylsulfonyl, phenylsulfonyl, amino, C _1-3 acylamino, mono- or di-C _1-4
Alkylamino, C _1-4 alkyl and C _1-4 halogenoalkyl compound of claim 10, wherein 1 is selected from alkyl to a three pyridine ring optionally having a substituent. 12. A ¹ is a bond or -CON (R ^4a )-,-
C _1-15 alkylene or C 1 -CO— or —N (R ^4a ) — (R ^4a has the same meaning as described in claim 10)
The compound according to claim 10, which is a _2-16 alkenylene group. 13. The compound according to claim 10, wherein B is a C _1-15 alkylene or C _2-16 alkenylene group. 14. X is a bond, an oxygen atom, a sulfur atom, -C
The compound according to claim 10, which is ONH- or -CO-. 15. R ¹ is (1) hydrogen atom, (2) halogen atom, (3) C _1-6 alkyl, phenyl, C _7-10 aralkyl, formyl, C _1-6 alkyl-carbonyl, phenyloxycarbonyl , C _7-10 aralkyloxy-carbonyl, pyranyl, furanyl or silyl-substituted hydroxy group, (4) C _1-15 alkyl, C _3-8 cycloalkyl, C _2-18 alkenyl, C _{7- 16} aralkyl or C _6-14 aryl group, or (5) C _1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-
C _1-6 alkyl - carbamoyl or C _1-10 10. A compound according alkanoyl group. 16. R ³ is a hydrogen atom, a C _1-15 alkyl group,
The compound according to claim 10, which is a _3-8 cycloalkyl group, a _C2-18 alkenyl group, a _C7-16 aralkyl group or a _C6-14 aryl group. 17. R is (1) a C _1-15 alkyl, C _3-8 cycloalkyl or C _2-18 alkenyl group (these groups are represented by (i)
Nitro, (ii) hydroxy, (iii) cyano, (iv) carbamoyl, (v) mono- or di-C _1-4 alkyl-carbamoyl, (vi) carboxy, (vii) C _1-4 alkoxy-carbonyl, ( viii) sulfone, (ix) halogen, (x) C _1-4 alkoxy, (xi) phenoxy, (xii) halogenophenoxy, (xii
i) C _1-4 alkylthio, (xiv) mercapto, (xv) phenylthio, (xvi) pyridylthio, (xvii) C _1-4 alkylsulfinyl, (xv
iii) C _1-4 alkylsulfonyl, (xix) amino, (xx) C
_1-3 alkanoylamino, (xxi) mono- or di- _C1-4 alkylamino, (xxii) 4- to 6-membered cyclic amino, (xxii
i) may have 1 to 5 substituents selected from C _1-3 alkanoyl, (xxiv) benzoyl and (xxv) 5- to 10-membered heterocyclic group], (2) C _7-16 aralkyl Group (this group is (i) halogen, (i
i) C _1-4 alkyl, (iii) C _2-6 alkenyl, (iv) C _1-3 alkanoyl, (v) C _1-4 alkoxy, (vi) nitro, (vii)
Cyano, (viii) hydroxy, (ix) C _1-4 alkoxy-carbonyl, (x) carbamoyl, (xi) mono- or di-C _1-4
Alkyl-carbonyl and (xii) mono- or di-C _2-4 alkenyl-carbonyl which may have 1 to 4 substituents], (3) C _6-14 aryl group [this group Are (i) halogen, (ii)
C _1-4 alkyl, (iii) C _1-4 halogenoalkyl, (iv) C
_1-4 halogenoalkoxy, (v) C _1-4 alkoxy, (vi) C
_1-4 alkylthio, (vii) hydroxy, (viii) carboxy, (ix) cyano, (x) nitro, (xi) amino, (xii) mono-
Or di-C _1-4 alkylamino, (xiii) formyl, (xiv)
Mercapto, (xv) C _1-4 alkyl-carbonyl, (xvi) C
_1-4 alkoxy-carbonyl, (xvii) sulfone, (xviii)
Having 1 to 4 substituents selected from C _1-4 alkylsulfonyl, (xix) carbamoyl, (xx) mono- or di-C _1-4 alkyl-carbamoyl, (xxi) oxo and (xxii) thioxo Or (4) a 5- or 6-membered monocyclic heterocyclic group (including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen as atoms constituting the ring system) or bicyclic Formula-condensed heterocyclic group (as a ring system atom, one selected from oxygen, sulfur and nitrogen
From 6 to 6 heteroatoms) [these radicals being (i)
Halogen, (ii) C _1-4 alkyl, (iii) C _1-4 halogenoalkyl, (iv) C _1-4 halogenoalkoxy, (v) C _1-4 alkoxy, (vi) C _1-4 alkylthio, vii) hydroxy, (v
iii) carboxy, (ix) cyano, (x) nitro, (xi) amino, (xii) mono- or di-C _1-4 alkylamino, (xiii)
Formyl, (xiv) mercapto, (xv) _C1-4 alkyl-carbonyl, (xvi) _C1-4 alkoxy-carbonyl, (xvii) sulfone, (xviii) _C1-4 alkylsulfonyl, (xix) carbamoyl, xx) mono- or di-C _1-4 alkyl-carbamoyl, (xxi) oxo and (xxii) thioxo, which may have 1 to 4 substituents). Compound. 18. The compound according to claim 10, wherein the ring Ga is ^a ring optionally having one or two substituents selected from oxo and C _1-6 alkyl. 19. A pyridine ring wherein the ring Q is unsubstituted, R ¹ and R ³
Is a hydrogen atom, G ¹ is CH, G ² is N, g is 1, R is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. 20. The compound of claim 19, wherein G ^a ring is unsubstituted ring. 21. The compound according to claim 19, wherein A ¹ is a bond or a C _1-6 alkylene group. 22. The compound according to claim 19, wherein A ¹ is a bond. 23. The method according to claim 1, wherein B is a C _1-6 alkylene group.
9. The compound according to 9. 24. The compound according to claim 19, wherein X is a bond. 25. A ring wherein Q is an unsubstituted pyridine ring, R ¹ and R ³
There are both hydrogen atoms, A ¹ is a bond, which may have 1 or 2 substituents G ¹ is CH, G ² is N, G ^a ring selected from oxo and C _1-6 alkyl ring , G is 1, B is C
The compound according to claim 10, wherein _{1-6 is an} alkylene group, X is a bond, and R is a phenyl group which may be substituted. 26. The compound according to claim 25, wherein the ^Ga ring is an unsubstituted ring. 27. R is halogen, hydroxy, C _1-4 alkyl, C _1-4 halogenoalkyl, C _1-4 alkoxy and C
26. The compound according to claim 25, which is a phenyl group optionally having 1 to 3 substituents selected from _1-4 halogenoalkoxy. 28. A compound represented by the general formula (I): R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ and R ^4a each represent a hydrogen atom or a substituted Or R ³ and A may be bonded to form a ring, and R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. Show. The compound or a salt thereof according to claim 1, which is a compound represented by the formula: or a salt thereof. 29. Q ring is unsubstituted pyridine ring, R ¹
And R ² are hydrogen atoms, R ³ is a hydrogen atom, C _1-15 alkyl, C _3-8 cycloalkyl, C _2-18 alkenyl, C 2
_7-16 aralkyl or C _6-14 aryl, wherein A is (i)
A C _1-15 alkylene _optionally having 1 to 3 substituents selected from a hydroxyl group, an oxo group and a phenyl group;
(Ii) C _2-16 alkenylene or (iii) phenylene, wherein the ring Q ₂ has the formula Wherein B ¹ represents ＣC, CH or N. 29. The compound according to claim 28, which is a group represented by the formula: 30. A compound represented by the general formula (I): R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ⁵ represents a hydrogen atom or an optionally substituted hydrocarbon And R represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 31. Q ring is unsubstituted pyridine ring, R ¹
And R ² is a hydrogen atom, and A ³ and B ² are each a bond, C _1-15 alkylene, C _2-16 alkenylene or phenylene, and Wherein A ⁵ represents ＝ C or CH. 31. The compound according to claim 30, which is a group represented by the formula: 32. A compound represented by the general formula (I): R ¹ and R ² each represent a hydrogen atom, a halogen atom, an optionally substituted hydroxyl group, an optionally substituted hydrocarbon group or an acyl group, and R ³ and R ^4a each represent a hydrogen atom or a substituted Represents a good hydrocarbon group. The compound according to claim 1, which is a compound represented by the formula: or a salt thereof. 33. Q ring is unsubstituted pyridine ring, R ¹
And R ² are hydrogen atoms, R ³ is a hydrogen atom, C _1-15 alkyl, C _3-8 cycloalkyl, C _2-18 alkenyl, C 2
_7-16 aralkyl or C _6-14 aryl, wherein A is (i)
C _1-15 alkylene, (ii) C _2-16 alkenylene or (ii)
i) phenylene, wherein the ring Q ₅ has the formula 33. The compound according to claim 32, which is a group represented by: 34. (R) -N- [1- (1,4-benzodioxan-2-ylmethyl) piperidin-4-ylmethyl] -5-thia-1,8b-diazaacenaphthylene-4
The compound according to claim 1, which is -carboxamide or a pharmacologically acceptable salt thereof. 35. N- [1- (3-phenylpropyl) piperidin-4-ylmethyl] -3- (5-thia-1,8
2. The compound according to claim 1, which is b-diazaacenaphthylene-4-yl) acrylamide, or a pharmaceutically acceptable salt thereof. 36. N- [4- (4-phenylpiperidine-
1-yl) butan-1-yl] -5-thia-1,8b-
The compound according to claim 1, which is diazaacenaphthylene-4-carboxamide, or a pharmaceutically acceptable salt thereof. 37. N- [1- (3-phenylpropane-1)
-Yl) piperidin-4-yl] -5-thia-1,8b
The compound according to claim 1, which is -diazaacenaphthylene-4-carboxamide, or a pharmaceutically acceptable salt thereof. 38. A compound of the general formula (II) [The symbols in the formula are as defined in claim 5.] Or a salt thereof, and a compound represented by the general formula: R ³ -NH-AN (R ⁴ ) -BXR wherein the symbols have the same meanings as in claim 5. 6. The method for producing a compound or a salt thereof according to claim 5, wherein the compound or a salt thereof is subjected to a condensation reaction. 39. A compound of the general formula (III) [In the formula, R 'represents a COOH group which may be protected, a CH ₂ OH group which may be protected or a CHO group which may be protected, and other symbols have the same meanings as in claim 4. Show. Or a salt thereof. [40] a pharmaceutical comprising the compound or a salt thereof according to the above [1]; (41) the pharmaceutical according to (40), which is a low-density lipoprotein receptor enhancer; 42. The medicament according to claim 40, which is a blood lipid lowering agent. 43. An agent for preventing or treating arteriosclerosis.
The medicament according to claim. 44. The medicament according to claim 40, which is a hypoglycemic agent. (45) the medicament according to the above (40), which is an agent for preventing or treating diabetic complications;