JPH11322748A - Heterocyclic compounds and manufacture of the same and their use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic drug or therapeutic agent having tachykinin receptor antagonistic activity or the like applicable to melancholy, anxiety or the like by utilizing a specific heterocyclic compound. SOLUTION: This heterocyclic compound of formula I (the ring M is a heterocyclic ring having a partial structure comprising X (dotted line) and Y (<), such as -N=C< or the like; R<a> and R<b> bond to form ring A or the like; ring A and ring B are each a homocycle or a heterocycle; ring C is a homocycle or a heterocycle; Z is a nitrogen including heterocycle; n is an integer of 1 to 6) or its salt, for example, (9R)-7-[3,5-bis-(trifluoromethyl)benzyl]-6,7,8,9,10,11- hexahydro-9-methyl-5-(4-methyl-phenyl)-6,13-dioxo-13 H-[1,4]diazocino[2,1-g][1,7]naphthyridine. The compound of formula I is obtained by ring closing the compound of formula II [D and E are each a group forming a ring of formula III (R<1> is an 1 to 6C alkyl) with adjacent N; L is a releasable group; R<2> is an 1 to 6C alkyl or the like; X is H or the like].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel use of a heterocyclic compound having a tachykinin receptor antagonistic action.

[0002]

2. Description of the Related Art Japanese Patent Application Laid-Open No. Hei 9-263585 discloses an equation

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A heterocyclic or heterocyclic ring which may have a group, at least one of which may have a substituent; and a ring Z represents an optionally substituted ring. A ring compound and a method for producing the same are disclosed, and it is described that the compound has a tachykinin receptor antagonistic action, a substance P receptor antagonistic action, a neurokinin A receptor antagonistic action, and the like.

[0003]

An object of the present invention is to provide a novel use of the above heterocyclic compound (I) or a salt thereof.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above problems, and as a result, have found that the above heterocyclic compound (I)
Alternatively, they have found that a salt thereof can exert a therapeutic effect on depression, anxiety, manic depression or mental illness, and completed the present invention based on these. That is, the present invention
Equation (1)

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different, and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
Wherein the ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n represents an integer of 1 to 6] or a salt thereof. A prophylactic / therapeutic agent for depression, anxiety, manic depression or mental illness, wherein (a) ^Ra and ^Rb are each a hydrogen atom or (I) a halogen atom, (II) a (i) hydroxy group, (ii)
C _1-6 alkoxy group, (iii) C _1-6 alkylthio group, (i
v) amino group, (v) C _1-7 acylamino group, (vi) carboxyl group, (vii) nitro group, (viii) mono- or di-C _1-6 alkylamino group, (ix) mono- or di- −C _3-8
A heteroatom selected from the group consisting of an oxygen atom and a sulfur atom in addition to a nitrogen atom, which may be substituted with a cycloalkylamino group, (x) a C _6-10 arylamino group, and (xi) C _1-6 alkyl A 5- to 9-membered cyclic amino group optionally containing 1 to 3 carbon atoms, (xii) a carbon atom, a nitrogen atom,
A 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen and sulfur, (xiii) from the group consisting of nitrogen, oxygen and sulfur other than carbon A 5- to 9-membered non-aromatic heterocyclic group containing 1 to 3 heteroatoms selected, (xiv)
C _1- which may have 1 to 5 substituents selected from the group consisting of a C _1-4 alkylsulfonylamino group, (xv) C _1-6 alkyl-carbonyloxy group and (xvi) halogen atom. ₆ alkyl group, (III) optionally halogenated C _1-6 alkoxy group, (IV) optionally halogenated C _1-6 alkylthio group, (V) C _3-10 cycloalkyl group, VI) C _6-10 aryl group, (VII) C _1-7 acylamino group, (VIII) C _1-3 acyloxy group, (IX) hydroxy group, (X) nitro group, (XI) cyano group, (XII) Amino group, (XIII) mono- or di-C _1-6 alkylamino group, (XIV) _optionally selected from the group consisting of oxygen atom and sulfur atom other than nitrogen atom, which may be substituted with C _1-6 alkyl 5 which may contain 1 to 3 hetero atoms to 9-membered cyclic amino group, (XV) C _1-6 alkyl Carbonylamino group, (XVI) C _1-6 alkyl - sulfonylamino group, (XVII) C _1-6 alkoxy - carbonyl group, (XVII
I) carboxyl group, (XIX) C _1-6 alkylcarbonyl group, (XX) carbamoyl group, (XXI) mono- or di-C
_1-6 or indicating the alkylcarbamoyl group and (XXII) C _1-6 alkylsulfonyl substituent selected from the group consisting of radicals; R ^a and R ^b form a ring A together bonded to, ring A is (I ) Halogen atom, (II) (i) hydroxy group, (ii) amino group, (iii) carboxyl group, (iv) nitro group, (v)
A mono- or di-C _1-6 alkylamino group, (vi) a C _1-6 alkyl-carbonyloxy group and (vii) 1 to 5 substituents selected from the group consisting of a halogen atom. Good C _1-6 alkyl group, (III) optionally halogenated C _1-6 alkoxy group, (IV) optionally halogenated C _1-6 alkylthio group, (V) C _6-10 aryl Group, (VI) C _1-7 acylamino group, (VII) C _1-3 acyloxy group, (VIII) hydroxy group, (IX) nitro group,
(X) a cyano group, (XI) an amino group, (XII) a mono- or di-C _1-6 alkylamino group, and (XIII) one heteroatom selected from the group consisting of an oxygen atom and a sulfur atom in addition to a nitrogen atom. A 5- to 9-membered cyclic amino group optionally containing up to three, (XIV) a C _1-6 alkyl-carbonylamino group,
(XV) C _1-6 alkyl-sulfonylamino group, (XVI) C
_1-6 alkoxycarbonyl group, (XVII) a carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XIX) carbamoyl group, (XX) mono - or di -C _1-6 alkylcarbamoyl group, (XXI) C _1-4 selected from the group consisting of _1-6 alkylsulfonyl groups and (XXII) oxo groups
Containing one to three heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, in addition to the carbon atom which may be substituted with 5 substituents.
Or a 9-membered aromatic heterocyclic ring, other than a carbon atom, selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom
A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered cyclic hydrocarbon containing 1 to 3 kinds or 2 kinds of hetero atoms; ring B is (I) a halogen atom, (II) (i )
A hydroxy group, (ii) an amino group, (iii) a carboxyl group, (iv) a nitro group, (v) a mono- or di-C _1-6 alkylamino group, (vi) a C _1-6 alkyl-carbonyloxy group and (Vii) a C _1-6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of halogen atoms, (III) an optionally halogenated C _1-6 alkoxy group, IV) optionally halogenated C _1-6 alkylthio group, (V) C _6-10 aryl group, (VI) C _1-7 acylamino group, (VII) C _1-3 acyloxy group, (VIII) hydroxy Group, (IX) nitro group, (X) cyano group, (XI) amino group, (XII) mono- or di-C _1-6 alkylamino group, (XIII) oxygen atom and sulfur atom other than nitrogen atom 5 which may contain 1 to 3 heteroatoms selected from the group to 9-membered cyclic amino group, (XIV) C _1-6 Al Le - carbonylamino group, (XV) C _1-6 alkyl - sulfonylamino group, (XVI) C _1-6 alkoxycarbonyl group,
(XVII) a carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XIX) carbamoyl group, (XX) mono - or di -C _1-6 alkylcarbamoyl group, (XXI) C _1-6 alkylsulfonyl and ( XXII) one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, other than a carbon atom, which may be substituted with 1 to 4 substituents selected from the group consisting of an oxo group A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 atoms,
A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered ring containing 1 to 3 or 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom A hydrocarbon; C ring is (I) halogen atom, (II) optionally halogenated C _1-10
Alkyl group, (III) C _1-4 alkyl group substituted by an amino group, (IV) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (V) a carboxyl group in substituted C _1-4 alkyl group, (VI) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group, C _1-4 alkyl group substituted with (VII) hydroxy group, ( VIII) C
_3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxy group, (XII) optionally halogenated C _1-10 alkoxy group, (XIII) halogenated A C _1-4 alkylthio group, a (XIV) amino group,
(XV) mono- or di-C _1-4 alkylamino group, (XVI)
5 to 9 which may contain 1 to 3 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to the nitrogen atom
Membered cyclic amino group, (XVII) C _1-4 alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (X
IX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (X
XI) C _1-4 alkoxy-carbonyl group, (XXII) aralkyloxycarbonyl group, (XXIII) carboxyl group,
(XXIV) C _1-6 alkylcarbonyl group, (XXV) C _3-6 cycloalkyl-carbonyl group, (XXVI) carbamoyl group, (XXVII) mono- or di-C _1-4 alkylcarbamoyl group or (XXVIII) C _A group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, in addition to a carbon atom which may be substituted with a _1-6 alkylsulfonyl group and (XXIX) 1 to 3 optionally halogenated C _1-4 alkyl groups; May be substituted with 1 to 5 substituents selected from the group consisting of a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 one or two heteroatoms selected from ,
A 5- to 9-membered heterocycle containing 1 to 3 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; or (I) a halogen atom, (II ) C _1-10 which may be halogenated
Alkyl group, (III) C _1-4 alkyl group substituted by an amino group, (IV) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (V) a carboxyl group in substituted C _1-4 alkyl group, (VI) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group, C _1-4 alkyl group substituted with (VII) hydroxy group, ( VIII) C
_3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxy group, (XII) optionally halogenated C _1-10 alkoxy group, (XIII) halogenated A C _1-4 alkylthio group, a (XIV) amino group,
(XV) mono- or di-C _1-4 alkylamino group, (XVI)
5 to 9 which may contain 1 to 3 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to the nitrogen atom
Membered cyclic amino group, (XVII) C _1-4 alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (X
IX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (X
XI) C _1-4 alkoxy-carbonyl group, (XXII) aralkyloxycarbonyl group, (XXIII) carboxyl group,
(XXIV) C _1-6 alkylcarbonyl group, (XXV) C _3-6 cycloalkyl-carbonyl group, (XXVI) carbamoyl group, (XXVII) mono- or di-C _1-4 alkylcarbamoyl group, (XXVIII) C _1-6 alkylsulfonyl group and (X
XIX) 1 to 3 optionally halogenated C _1-4
A 5- or 6-membered aromatic unit containing 1 to 4 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom which may be substituted by an alkyl group; A 3- to 10-membered homocyclic ring which may be substituted with 1 to 5 substituents selected from the group consisting of cyclic heterocycles; wherein Z ring is (I) a C _1-6 alkyl group, II) C _2-6 alkenyl group, (III) C _2-6 alkynyl group, (IV) C _3-8 cycloalkyl group, (V) C _3-8 cycloalkyl-C _1-4 alkyl group, (VI) C _6-14 aryl group, (VII) nitro group, (VIII) cyano group, (IX) hydroxy group, (X) C _1-4 alkoxy group, (XI) C _1-4 alkylthio group, (XII) amino group , (XIII) C _1-4 mono - selected from or di -C _1-4 alkylamino group, an oxygen atom in addition to (XIV) nitrogen atom, the group consisting of sulfur atoms 5 which may contain 1 to 3 hetero atoms to 9-membered cyclic amino group, (XV) C _1-4 alkyl - carbonylamino group, (XV
I) C _1-4 alkylsulfonylamino group, (XVII) C _1-4
Alkoxy-carbonyl group, (XVIII) carboxyl group, (XIX) C _1-6 alkylcarbonyl group, (XX) carbamoyl group, (XXI) mono- or di-C _1-4 alkylcarbamoyl group, (XXII) C _{1- 6} alkylsulfonyl group, (XXI
II) from the group consisting of nitrogen, oxygen and sulfur in addition to Y and nitrogen, which may be substituted with 1 to 5 substituents selected from the group consisting of oxo and (XXIV) thioxo The agent according to (1), which represents a 5- to 12-membered heterocyclic ring optionally containing at least one selected heteroatom, (3) R ^a and R ^b are each a hydrogen atom or (I) a halogen atom, (II) (i) hydroxy group, (ii) C _1-6 alkoxy group, (iii) C _1-6 alkylthio group, (iv) amino group, (v) C _1-7 acylamino group,
(Vi) mono- or di-C _1-6 alkylamino group, (vii)
A mono- or di-C _3-8 cycloalkylamino group, (vii
i) a 5- to 9-membered cyclic amino group which may be substituted by C _1-6 alkyl and may contain 1 to 3 heteroatoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to a nitrogen atom , (Ix) a C _1-4 alkylsulfonylamino group,
(X) a C _1-6 alkyl-carbonyloxy group and (xi)
It may have 1 to 5 substituents selected from the group consisting of halogen atom C _1-6 alkyl group may be substituted with (III) C _1-6 alkyl, oxygen in addition to the nitrogen atom A 5- to 9-membered (preferably 6-membered) cyclic amino group which may contain 1 to 3 (preferably 1 or 2) heteroatoms selected from the group consisting of atoms and sulfur atoms,
(IV) carboxyl group, (V) carbamoyl group and (V
I) a substituent selected from the group consisting of a mono- or di-C _1-6 alkylcarbamoyl group; R ^a and R ^b are bonded together to form a ring A, and the ring A is a C _1-6 alkyl A 5- to 9-membered aromatic heterocyclic group which may be substituted with 1 to 3 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom A ring (preferably a pyridine ring); wherein ring B is (i) a C _1-6 alkyl group _optionally substituted with a hydroxy group, (ii) a C _1-6 alkylcarbonyl group (including formyl) and ( iii) a C _6-14 aryl group (preferably a benzene ring) which may be substituted with a substituent selected from the group consisting of a carboxyl group; wherein the C ring is (i) a halogen atom, (ii) halogenated which may be a C _1-10 alkyl group and (iii) C _1-10 A Is (preferably a benzene ring) which may C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from the group consisting of Kokishi group be; Z ring is (i) C _1-6 alkyl group , (Ii) a hydroxy group and (iii) an oxo group, which may be substituted with 1 to 3 substituents, and which, other than Y and nitrogen, comprises nitrogen, oxygen and sulfur The agent according to item (1), which represents a 5- to 12-membered heterocyclic ring optionally containing at least one heteroatom selected from the group;

Embedded image Wherein the R ¹ is C _1-6 alkyl group, R ² is C _1-6 alkoxy groups, optionally substituted C _1-6 alkyl group by a halogen, a halogen atom, a hydroxy group or a C _7-15 In the aralkyloxy group, X represents 1 to 5 groups selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a halogen atom. However, (1) when R ¹ is a methyl group and R ² is a trifluoromethyl group, X represents a halogen atom,
(2) when R ¹ is a methyl group and R ² is a methoxy group, X
Represents a hydrogen atom or a halogen atom.] (5) (9R) -7
-[3,5-bis (trifluoromethyl) benzyl]-
6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1 ,
7] The agent according to item (1), containing naphthyridine or a salt thereof, (6) (9R) -7- (3,5-dimethoxybenzyl) -6,7,8,9,10,11-hexahydro- 9-methyl-5- (4-methylphenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] The agent according to (1), containing [1,7] naphthyridine or a salt thereof, (7) (9R) -7- (3,5-dimethoxybenzyl) -5- (4-fluorophenyl)-
Contains 6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine or a salt thereof. (8) (9S) -7-
[(3,5-bis (trifluoromethyl) benzyl]-
6,7,8,9,10,12-Hexahydro-9-methyl-5- (4-methylphenyl) -6,12-dioxo- [1,4] diazepino [2,1-g] [1,7 ] The agent according to (1), comprising naphthyridine or a salt thereof,
Equation (9)

Embedded image Wherein the R ¹ is C _1-6 alkyl group, R ² is C _1-6 alkoxy groups, optionally substituted C _1-6 alkyl group by a halogen, a halogen atom, a hydroxy group or a C _7-15 In the aralkyloxy group, X represents 1 to 5 groups selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a halogen atom. However, (1) when R ¹ is a methyl group and R ² is a trifluoromethyl group, X represents a halogen atom,
(2) when R ¹ is a methyl group and R ² is a methoxy group, X
Represents a hydrogen atom or a halogen atom] or a salt thereof, (10) wherein R ¹ is a C _1-3 alkyl group, R ²
Made There C _1-3 alkoxy group, halogen optionally substituted C _1-3 also be an alkyl group, a halogen atom, a hydroxyl group or a benzyloxy group, a X is a hydrogen atom or, C _1-3 alkyl group and a halogen atom (11) the compound according to (9), which is one or two groups selected from the group;
R ¹ is a methyl group, R ² is a methoxy group, an ethoxy group, an isopropoxy group, a methyl group, a trifluoromethyl group, a chlorine atom, a hydroxy group or a benzyloxy group, X is a hydrogen atom, a methyl group or one or two (12) (9) The compound according to (9), which is a chlorine atom or a fluorine atom.
R) -7- (3,5-Dimethoxybenzyl) -5- (4
-Fluorophenyl) -6,7,8,9,10,11-
Hexahydro-9-methyl-6,13-dioxo-13
H- [1,4] diazosino [2,1-g] [1,7] naphthyridine or a salt thereof, (13) a prodrug of the compound described in (9), (14)

Embedded image [Wherein D and E together with the nitrogen atom adjacent to E have the formula

Embedded image Wherein L is a leaving group, and other symbols are as defined in the above item (9)] or a salt thereof is subjected to a cyclization reaction. (9) a method for producing the compound according to (9), (15) a medicament comprising the compound according to (9), and (16) a tachykinin receptor comprising the compound according to (9). A body P antagonist, (17) a substance P receptor antagonist comprising the compound according to item (9), and (18) a neuron comprising the compound according to item (9). A kinin A receptor antagonist, (19) a prophylactic / therapeutic agent for dysuria characterized by containing the compound described in (9), and (20) a compound described in (9). Characterized by asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease Or a preventive or therapeutic agent for vomiting.

[0005] The compound described in the item (1) includes R ^a
Formula (Ia) wherein R and R ^b are bonded together to form a ring A

Embedded image [Wherein the symbols have the same meanings as described above], or a salt thereof.

The heterocyclic compound (I) used in the preparation of the present invention is a compound described in JP-A-9-263585.

Embedded image In the above formula, R ^a and R ^b are bonded together to form ring A, or are the same or different and represent a hydrogen atom or a substituent on ring M.

As the substituents R ^a and R ^b in the M ring, for example, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, and a halogenated Good alkylthio group, cycloalkyl group, aryl group, acylamino group, acyloxy group, hydroxy group, nitro group, cyano group, amino group, mono- or di-alkylamino group, cyclic amino group (for example, oxygen atom other than nitrogen atom , A cyclic amino group which may contain a hetero atom such as a sulfur atom), an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group, a carbamoyl group, a mono- or di-alkylcarbamoyl group , An alkylsulfonyl group, an oxo group and the like. The “halogen atom” includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine, and bromine atoms. Examples of the “optionally substituted alkyl group” include, for example, a hydroxy group, a C _1-6 alkoxy group (C ₁ -such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.) ₄ alkoxy group), C _1-6 alkylthio group (methylthio, ethylthio, propylthio, butylthio, isobutylthio,
a C _1-4 alkylthio group such as s-butylthio, t-butylthio, etc.), an amino group, a C _1-7 acylamino group (formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.), an N-alkylamino group Carboxyl group, nitro group, mono- or di-C _1-6 alkylamino group (for example, mono- or di-C _1-4 such as methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino group, etc.)
Alkylamino group), which may have a substituent,
N-substituted amino groups substituted by one or two homologous rings (for example, mono- or di-C _3-8 cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclohexylamino group; phenylamino group and the like) such as C _6-10 arylamino group), Hajime Tamaki which may have a substituent [for example, an oxygen atom in addition to the nitrogen atom, may contain 1 to 3 hetero atoms such as sulfur atom 5 A 9-membered cyclic amino group (e.g. piperidino, 4-methylpiperidino, morpholino, thiomorpholino, piperazinyl, 4-
5- or 6-membered non-aromatic cyclic amino groups such as methylpiperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, imidazolidinyl and pyrazolidinyl; pyridyl, pyrazyl,
5- or 6-membered aromatic cyclic amino groups such as pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl and pyrazolyl), aromatic heterocyclic groups such as thiophenyl, furanyl, thiazole, isothiazole, oxazole and isoxazole groups, tetrahydropyridyl, dihydro Pyridyl, tetrahydropyrazyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
Dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrofuranyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxazolyl, dihydroisoxazolyl, hexahydropyrimidinyl, hexahydropyridazinyl, Non-aromatic heterocyclic groups such as tetrahydropyranyl, pyrazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl groups], alkylsulfonylamino group ( For example, C _1-4 alkylsulfonylamino groups such as methylsulfonylamino and ethylsulfonylamino groups), C
_1-6 alkyl-carbonyloxy group (for example, C _1-4 alkyl- such as acetoxy, ethylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy group, etc.)
A carbonyloxy group or the like and a halogen atom (eg, a fluorine, chlorine, bromine atom, etc.)
A C _1-6 alkyl group _optionally having up to 5 substituents (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl and the like).

The preferred "alkyl group optionally having substituent (s)" includes a C _1-6 alkyl group which may be substituted by about 1 to 4 halogen atoms [particularly, an _optionally substituted alkyl group] C _1-4 alkyl group (for example, methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoro Ethyl, pentafluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 1
-(Trifluoromethyl) ethyl, butyl, 4,4,4
-Trifluorobutyl, isobutyl, sec-butyl, te
rt - C _1-4 alkyl groups and 1-5, such as butyl group C _1-4 (especially 1-3) about a halogen atom has been substituted
Alkyl group etc.]], C _1-6 alkoxy-C _1-6 alkyl group (for example, C _1-4 alkoxy-C _1- such as methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl and the like). ₄ alkyl group), C _1-6 alkylthio-C _1-6 alkyl group (for example,
C such as methylthiomethyl, ethylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl
_1-4 alkylthio-C _1-4 alkyl group), amino-C _1-6
Alkyl groups (for example, amino-C _1-4 alkyl groups such as aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-aminobutyl, 3-aminobutyl, 4-aminobutyl groups), C _1-7 acylamino-
C _1-6 alkyl group (C _1-7 acylamino-C ₁ such as formylaminomethyl, acetylaminomethyl, propionylaminomethyl, formylaminoethyl, acetylaminoethyl, propionylaminoethyl, butyrylaminoethyl, benzoylaminomethyl group) _-4 alkyl group), mono- or di-C _1-6 alkylamino-C _1-6 alkyl group (for example, methylaminomethyl, ethylaminomethyl,
Butylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2- (N-methylamino) ethyl, 2-
(N-ethylamino) ethyl, 2- (N-methylamino) propyl, 3- (N-methylamino) propyl,
-(N-methylamino) butyl, 4- (N-methylamino) butyl, 2- (N-dimethylamino) ethyl, 2-
Mono- or di- such as (N-diethylamino) ethyl group
C _1-4 alkylamino-C _1-4 alkyl group), C _3-10 cycloalkylamino-C _1-6 alkyl group (for example, cyclopropylaminomethyl, cyclobutylaminomethyl,
Cyclohexylaminomethyl, cyclopropylaminoethyl, cyclobutylaminoethyl, cyclohexylaminomethyl group, C _3-10 cycloalkylamino-C _1-4 alkyl group such as phenylaminomethyl group),

A 5- or 6-membered cyclic amino-C _1-6 alkyl group which may contain 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom (for example, piperidinomethyl, 4-methylpiperidyl Nomethyl, morpholinomethyl,
Non-aromatic cyclic amino-C _1-4 alkyl groups such as thiomorpholinomethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, piperidinoethyl, morpholinoethyl, piperazinylethyl; pyridylmethyl, pyrimidinylmethyl, imidazolylmethyl, 5- or 6-membered aromatic cyclic amino-C _1-4 alkyl group such as pyridylethyl),
C _1-6 alkylsulfonylamino -C _1-6 alkyl group (e.g., methylsulfonylamino methyl, ethyl sulfonyl aminomethyl, methylsulfonylamino fall, C _1-6 alkylsulfonylamino -C such ethylsulfonylamino ethyl _{1- 6} alkyl groups), C _1-6 alkyl-carbonyloxy-C _1-6 groups (for example, methylcarbonyloxymethyl, ethylcarbonyloxymethyl, butylcarbonyloxymethyl, methylcarbonyloxyethyl, ethylcarbonyloxyethyl, etc. _1-4 alkyl-carbonyloxy-C _1-4 alkyl group) and the like.

The "optionally halogenated alkoxy group" is, for example, a C _1-6 alkoxy group or a 1 to ₆ alkoxy group.
And a C _1-6 alkoxy group substituted with about 5 halogen atoms. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
Trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy Pentoxy, hexyloxy and the like. Preferred "optionally halogenated alkoxy group" is a C _1-4 alkoxy group, or 1 to
A C _1-4 alkoxy group substituted by about 3 halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec −
Butoxy group and the like. The “optionally halogenated alkylthio group” includes, for example, a C _1-6 alkylthio group and a C _1-6 alkylthio group having 1 to 5 halogen atoms.
_1-6 alkylthio group and the like, such as alkylthio group and halogenated alkylthio group, for example,
Methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.
Preferred is the "even alkylthio group optionally halogenated", C _1-4 alkylthio, or one to three degree C _1-4 alkylthio group halogen atom is substituted, for example, methylthio, difluoromethylthio, trifluoromethyl Examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, and 4,4,4-trifluorobutylthio groups.

Further, the “cycloalkyl group” includes C
_3-10 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl groups, etc.) and the like, and the “aryl group” includes C
_{The 6-10} aryl group (eg, phenyl group, etc.) and the “acylamino group” include, for example, a C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.). It is. The “acyloxy group” includes, for example, C _1-3
An acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.) and the like are included. As the “mono- or di-alkylamino group”, for example, a mono- or di-C _1-4 alkylamino group (for example, a methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like) and the like can be mentioned. . Also,
The “cyclic amino group” includes, for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom (for example, pyrrolidino, piperidino, morpholino, Thiomorpholino group) and the like. The “alkylcarbonylamino group” includes, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the “alkylsulfonylamino group” includes, for example, C _1-4 alkyl. A sulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino group, etc.) and “alkoxycarbonyl group” include, for example, C
_1-4 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Butoxycarbonyl group) and “alkylcarbonyl group” include, for example, C _1-6 alkyl-carbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc.), “mono- or di-alkylcarbamoyl group” "Include, for example, mono- or di-
C _1-4 alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,
The “alkylsulfonyl group” and the “alkylsulfonyl group” include, for example, a C _1-6 alkylsulfonyl group (eg, a methylsulfonyl, ethylsulfonyl, propylsulfonyl group and the like).

In the above formula, ring A and ring B are each
A homocyclic or heterocyclic ring which may have a substituent, at least one of which is a heterocyclic ring which may have a substituent. The "homologous or heterocyclic ring" includes, for example, (i) one or two or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, preferably one to three. An aromatic heterocycle or a non-aromatic heterocycle, or (ii) a cyclic hydrocarbon (homocycle) composed of carbon atoms is included. As the "aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, pyridine , Pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole,
Isothiazole, oxazole and isoxazole rings) and the like. Preferred aromatic heterocycles include, for example, pyridine, pyrazine, thiophene rings and the like, as well as, for example, pyrrole, thiazole rings and the like. In particular, (i) a 6-membered nitrogen-containing heterocycle containing one or two nitrogen atoms other than a carbon atom (for example, a pyridine or pyrazine ring) or (ii) a 5-membered nitrogen-containing heterocycle containing one sulfur atom other than a carbon atom An aromatic heterocycle (for example, a thiophene ring) is preferable.

The "non-aromatic heterocyclic ring" includes, for example, a 5- to 9-membered non-aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. For example, for ring A, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydro Examples include isoxazole ring, and for ring B, in addition to those described above, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, Tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, And La tetrahydroisoquinoline isoxazole ring. As the ring A, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (eg, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring, etc.) is preferable, and a tetrahydropyridine ring is particularly preferable. Are commonly used. As the ring B, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (for example, a piperidine or piperazine ring) is preferable, and a piperazine ring and the like are particularly used.

The "cyclic hydrocarbon (homocycle)" includes, for example, a 3- to 10-membered (for example, 5- to 9-membered) cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. It is. For example, for ring A, benzene, C
_3-10 cycloalkenes (for example, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and the like.
Preferred are _5-6 cycloalkenes (eg, cyclopentene, cyclohexene, etc.). As for the ring B, in addition to the above, C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane,
Cycloheptane, cyclooctane, etc.)
As the cycloalkane, C _5-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) is preferable. As the ring A, for example, a 6-membered homocyclic ring such as a benzene ring and a cyclohexene ring is preferable, and a benzene ring and the like are particularly preferable. As the ring B, for example, a 6-membered homocyclic ring such as a benzene or cyclohexane ring is preferable, and a benzene ring is particularly preferable.

At least one of the ring A and the ring B is
The ring A and the ring B may be each composed of a heterocyclic ring which may have a substituent. One of ring A and ring B is composed of an aromatic ring which may have a substituent, and the other is composed of a heterocyclic ring which may have a substituent (particularly, an aromatic heterocyclic ring). Is preferred. The “aromatic ring” includes, for example, (i) the “aromatic heterocycle”, that is, one or two heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom; An optionally substituted 5- or 6-membered aromatic heterocycle containing 1 to 3 substituents (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, Thiazole,
(Such as isothiazole, oxazole and isoxazole rings) or (ii) an optionally substituted benzene ring.

Examples of the substituent which the "aromatic ring" may have include, for example, the same substituents as those for the ring A and the ring B described later. Examples of the “aromatic heterocycle” of the “good aromatic heterocycle” include the same aromatic heterocycles as the above “5- or 6-membered aromatic heterocycle”. Examples of the substituent which the “aromatic heterocyclic ring which may have a substituent (s)” may have include, for example, the same substituents as those in the ring A and the ring B described below. As the “5- or 6-membered aromatic heterocycle”, the same heterocycle as described in the section of “Aromatic heterocycle” and the like are preferable. More preferably, one of the ring A and the ring B is an aromatic heterocyclic ring which may have a substituent (for example, a 5- or 6-membered aromatic heterocyclic ring), and the other has a substituent. Is a benzene ring which may be substituted.

"Homo- or heterocyclic ring", "aromatic heterocyclic ring", "non-aromatic heterocyclic ring", "cyclic hydrocarbon", "aromatic ring" and "benzene ring" represented by ring A and ring B Examples of the substituent which may be present include, for example, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, and an aryl Group, acylamino group, acyloxy group, hydroxy group, nitro group, cyano group, amino group, mono- or di-alkylamino group, cyclic amino group (for example, including a hetero atom such as an oxygen atom and a sulfur atom in addition to a nitrogen atom Cyclic amino group), alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoy Group, mono - or di - alkylcarbamoyl group, an alkylsulfonyl group, an oxo group. The "halogen atom" which the ring A and the ring B may have include, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine, and bromine atoms (particularly, fluorine, chlorine atoms, etc.).

Examples of the "optionally substituted alkyl group" which the ring A and the ring B may have include, for example,
Hydroxy, amino, carboxyl, nitro,
A mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino group, etc.), a C _1-6 alkyl-carbonyloxy group (eg, acetoxy, ethylcarbonyloxy group, etc.) and A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from a halogen atom (eg, fluorine, chlorine, bromine atom and the like) (eg, methyl, ethyl, propyl, isopropyl, butyl) , Isobutyl, se
c-butyl, tert-butyl group, etc.).
Particularly, an alkyl group which may be halogenated, for example, a C _1-6 alkyl group and a C _1-6 alkyl group substituted with about 1 to 4 halogen atoms are preferable. Such alkyl groups or halogenated alkyl groups include, for example, methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 1- (trifluoromethyl) ethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,
6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like.

Further preferred "optionally substituted alkyl groups" include optionally halogenated C
_1-4 alkyl groups, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,
C _1-4 alkyl groups such as 3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, and tert-butyl; Included are C _1-4 alkyl groups substituted by about three halogen atoms. Examples of the “optionally halogenated alkoxy group” that the ring A and the ring B may have include, for example, a C _1-6 alkoxy group or about 1 to 5 halogen atoms as described above are substituted. And a C _1-6 alkoxy group. Such alkoxy groups or halogenated alkoxy groups include
For example, methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy and the like . Preferred "optionally halogenated alkoxy groups" include C _1-4 alkoxy groups and C _1-4 substituted with about 1 to 3 halogen atoms.
Alkoxy group, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy group, etc. Is included.

The "optionally halogenated alkylthio group" which the ring A and the ring B may have include, for example, a C _1-6 alkylthio group and about 1 to 5 halogen atoms as described above. C _1-6 alkylthio group having an atom and the like. Examples of such an alkylthio group and a halogenated alkylthio group include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
Propylthio, isopropylthio, butylthio, 4,
4,4-trifluorobutylthio, pentylthio, hexylthio and the like. Preferred "optionally halogenated alkylthio group" includes a _C1-4 alkylthio group or _C1-4 substituted with about 1 to 3 halogen atoms.
_1-4 alkylthio groups, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4
A 4-trifluorobutylthio group and the like are included. Further, the aryl group as a substituent includes a C _6-10 aryl group (eg, phenyl group), and the acylamino group includes, for example, a C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, Butyrylamino, benzoylamino group, etc.). The acyloxy group includes, for example, a C _1-3 acyloxy group (eg, formyloxy, acetoxy, propionyloxy group and the like). Examples of the mono- or di-alkylamino group include a mono- or di- _C1-4 alkylamino group (for example, a methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, and the like).
And the like. Further, in the cyclic amino group, for example,
Examples thereof include a 5- to 9-membered cyclic amino group (for example, pyrrolidino, piperidino, morpholino group and the like) which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom. The alkylcarbonylamino group includes, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the alkylsulfonylamino group includes, for example, C
_1-4 alkylsulfonylamino groups (for example, methylsulfonylamino, ethylsulfonylamino groups, etc.) and alkoxycarbonyl groups include, for example, C _1-4 alkoxy-
A carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group and the like) and an alkylcarbonyl group include, for example, C
_1-6 alkyl - carbonyl group (e.g., formyl, methylcarbonyl, ethylcarbonyl, and propyl group), mono - or di - The alkylcarbamoyl group, for example, mono- - or di -C _1-4 alkylcarbamoyl group ( For example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.) and alkylsulfonyl include, for example, C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) and the like. .

Hereinafter, when the term “optionally halogenated” is used in the present specification, the number of halogen atoms is 1
-5, preferably about 1-3. Preferred substituents that ring A and ring B may have include a halogen atom and an optionally halogenated C
_1-4 alkyl group, C _1-4 alkoxy group which may be halogenated, C _1-4 alkylthio group which may be halogenated, C _1-3 acyloxy group, hydroxy group, amino group, mono- or Examples include a di-C _1-4 alkylamino group, a carboxyl group, a C _1-4 alkoxy-carbonyl group and an oxo group. More preferred substituents that the ring A and the ring B may have include a halogen atom, a C _1-4 alkyl group which may be halogenated, a C _1-4 alkoxy which may be halogenated, and hydroxy. Groups, amino groups, mono- or di-C _1-4 alkylamino groups, C _1-3 acyloxy groups, oxo groups and the like. In particular, halogen atoms,
An optionally halogenated C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group are preferred. The substituents on ring A and ring B may be substituted on any substitutable position of the ring, and when there are two or more substituents, the substituents may be the same or different from each other The number may be about 1 to 4.
The number of substituents is preferably about 1 to 3. When the ring A and / or the ring B have a nitrogen atom, they may form a quaternary ammonium salt, for example, a halogen ion (eg, Cl ⁻ , Br ⁻ , I ^−, etc.), a sulfate ion, a hydroxy ion, etc. May form a salt with the anion of

As the preferred homocyclic ring in the ring A, an homocyclic ring consisting of an optionally substituted carbon atom, for example, a compound represented by the formula (A-1)

Embedded image [Wherein A ¹ represents a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, , 2,2-trifluoroethyl, pentafluoroethyl and the like) or an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- Trifluoroethoxy,
A pentafluoroethoxy group) or the formula (A-
2)

[0023]

Embedded image [Wherein A ² and A ³ are the same or different and are each a halogen atom (for example, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (for example, methyl, isopropyl, trifluoro Methyl, trichloromethyl,
Ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like, or an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2 ,
2-trifluoroethoxy, pentafluoroethoxy, etc.)].

More preferred homocyclic rings include, for example, compounds of the formula (A-
3)

Embedded image [Wherein A ⁴ and A ⁵ are the same or different and are each a halogen atom (eg, fluorine, chlorine atom, etc.) or a C _1-4 alkyl group which may be halogenated (eg, methyl, trifluoro Methyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl group, etc.]) (e.g., a benzene ring).

As the homocyclic ring, for example, the following formula (A-4)

Embedded image [Each symbol in the formula is as defined above. A benzene ring which may have a substituent represented by formula (1) is also preferable.

The homocyclic ring represented by the above formula particularly preferably includes an homocyclic ring having the following substituent. (1) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.) or a C _1-4 alkyl group which may be halogenated (eg, methyl, trifluoromethyl, ethyl,
(2) A ² and A ³ are the same or different and each may be a halogenated C _1-4 alkyl group (for example, methyl, trifluoromethyl, ethyl, isopropyl group), or a halogenated which may be C _1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, homocyclic is an ethoxy group), is (3) a ⁴ and a ^5, the same or Differently,
A homocyclic ring which is a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group, etc.), (4) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.), and (5) A ² and A ³ are And the same or different homocyclic rings that are C _1-4 alkoxy groups (eg, methoxy, ethoxy, etc.).

The preferred aromatic or non-aromatic heterocyclic ring in the ring A is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, for example, pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole, thiazole And the like. Specifically, for example, a heterocyclic ring represented by the formula (A-5) is preferable.

Embedded image

Preferred examples of the aromatic or non-aromatic heterocyclic ring which may have a substituent include, for example, an oxo group,
An alkyl group which may have a substituent (having the same meaning as the substituent which ring A and ring B may have), a C _6-10 aryl group (for example, a phenyl group) and the like. Specific examples include pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole, and thiazole rings which may have one or two substituents selected from halogen atoms (for example, fluorine, chlorine, and bromine atoms). For example, an aromatic or non-aromatic heterocycle represented by the following formula (A-6) is preferable.

Embedded image [Wherein, D ¹ represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), E ¹ represents a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), compounds having a partial structure represented by (ii) a halogen ion ^{(e.g., Cl -, Br -, I} -
Quaternary ammonium salts with sulfate ions or hydroxy ions. G is a hydrogen atom or C
_1-4 alkyl groups (eg, methyl, ethyl, propyl,
J represents a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.) or a C _6-10 aryl group (eg, phenyl group, etc.). ]

Ring A is a 5- or 6-membered nitrogen-containing heterocyclic ring, for example, (i) 6-membered ring containing one or two nitrogen atoms other than carbon atoms.
(Ii) a 6-membered non-aromatic heterocycle containing one or two nitrogen atoms in addition to a carbon atom (eg, tetrahydropyridine, tetrahydropyrimidine) , A tetrahydropyridazine ring, etc.). Particularly preferred ring A includes an aromatic nitrogen-containing heterocycle, especially a pyridine ring.

As the preferred homocyclic ring in the ring B, an homocyclic ring consisting of an optionally substituted carbon atom, for example, a compound represented by the formula (B-1)

Embedded image Wherein B ¹ is a halogen atom, a C _1-4 alkyl group optionally substituted or halogenated with hydroxy, a C _1-4 alkoxy group optionally halogenated, a C _1-6 alkylcarbonyl group or Indicates a carboxyl group),

Formula (B-2)

Embedded image [Wherein, B ² and B ³ are the same or different and each represent a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group] Or

Formula (B-3)

Embedded image Wherein B ⁴ , B ⁵ and B ⁶ are the same or different,
A halogen atom, a C _1-4 alkyl group which may be halogenated, and a C _1-4 alkoxy group which may be halogenated].

Further, preferred homocyclic rings include those represented by the formula (B-4)

Embedded image [Wherein B ⁷ , B ⁸ and B ⁹ are the same or different and are each a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group; And the like) are included.

Particularly preferred homocyclic rings include those represented by the following formula (B-
Five)

Embedded image [In the formula, B ¹⁰ is a halogen atom, a C _1-4 alkyl group optionally substituted or halogenated with hydroxy, an optionally halogenated C _1-4 alkoxy group, a C _1-6 alkylcarbonyl group. Or a carboxyl group].

In the above formula, the halogen atoms in B ^{1 to} B ¹⁰ include, for example, fluorine, chlorine, bromine atoms, etc.
Examples of the optionally halogenated C _1-4 alkyl group include, for example, methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,
2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl, 2,
Examples of the optionally halogenated _C1-4 alkoxy group which include 2,3,3-tetrafluoropropyl, isopropyl group and the like include, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2 2-trifluoroethoxy, 2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, propoxy, 2,2,3,3-tetrafluoropropoxy, isopropoxy group, etc. included. In the above formula, the C _1-6 alkylcarbonyl group represented by B ¹ or B ¹⁰ includes formyl, acetyl, and the like.

It is also preferred that ring B is a benzene ring which may have a substituent. Such a benzene ring has, for example, the formula (B-6)

Embedded image Is more preferable, and more preferably, formula (B-7)

[0037]

Embedded image

In particular, the formula (B-8)

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

Among the substituents in the above formula, particularly preferred substituents are (1) B ¹ , B ² , B ³ , B ⁴ , B ⁵ and B ^{6, which} are the same or different and each have a halogen atom (For example,
A fluorine or chlorine atom), an optionally halogenated C _1-4 alkyl group (eg, methyl, trifluoromethyl, ethyl, isopropyl group, etc.), (2) B ¹ , B ² ,
B ³ , B ⁴ , B ⁵ and B ⁶ are the same or different and each may be a halogenated C _1-4 alkoxy group (for example,
Methoxy, trifluoromethoxy, ethoxy, etc.),
(3) B ⁷ , B ⁸ and B ⁹ are each a halogen atom (for example,
Fluorine, such as chlorine atom), (4) B ¹⁰ is a fluorine atom,
(5) B ¹⁰ is a C _1-4 alkyl group (eg, a methyl group), (6) B ¹ or B ¹⁰ is a C _1-6 alkyl group optionally substituted with hydroxy (eg, hydroxymethyl) , C _1-6 alkylcarbonyl (eg, formyl, acetyl, etc.), carboxyl group and the like. As a benzene ring which may have a more preferable substituent, the following formula (B-9)

[0040]

Embedded image And a phenyl group represented by

Preferred examples of the aromatic or non-aromatic hetero ring in the ring B include 5- or 6-membered aromatic or non-aromatic hetero rings such as pyridine, thiophene and piperidine rings. May have the same preferable substituents as those exemplified in the section of the ring A. When the ring B is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, particularly preferred aromatic heterocyclic rings or non-aromatic heterocyclic rings include, for example, those represented by the formula (B-10)

Embedded image And the like. When both or one of the ring A and the ring B is a heterocyclic ring, the heterocyclic ring is also preferably an unsubstituted heterocyclic ring.

The preferred combination (1) of ring A and ring B is as follows. (1) Any one of ring A and ring B: selected from a nitrogen atom and a sulfur atom other than a carbon atom which may be substituted with a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group, etc.) 5- or 6-membered heterocycle containing one or two heteroatoms (eg, pyridine, pyrazine,
Thiophene, tetrahydropyridine, piperidine, piperazine ring, etc.), the other of A ring and B ring: a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, Methyl,
Trifluoromethyl, trichloromethyl, ethyl, 2,
2,2-trifluoroethyl, pentafluoroethyl,
2,2,2-trichloroethyl, propyl, isopropyl group and the like, and optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trioxy) Fluoroethoxy, pentafluoroethoxy, 2,2
A benzene ring which may be substituted with 1 to 3 substituents selected from 2-trichloroethoxy, propoxy, isopropoxy and the like.

A more preferred combination (2) of the ring A and the ring B is as follows. (2) Any one of ring A and ring B: a 5- or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom and a sulfur atom other than a carbon atom (for example,
A pyridine, pyrazine, thiophene ring, etc.) and the other of the A ring and the B ring: a halogen atom (eg, fluorine, chlorine,
A C _1-4 alkyl group which may be halogenated (for example, methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2 2-trichloroethyl, propyl, isopropyl groups and the like; and optionally halogenated C _1-4 alkoxy groups (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentane) 1-3 selected from fluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy, etc.)
A benzene ring which may be substituted with two substituents. Especially,
The aromatic heterocycle (for example, a 5- or 6-membered aromatic heterocycle, particularly a pyridine ring, etc.) in which ring A may have a substituent, and the benzene ring in which ring B may have a substituent. It is preferred that

In the above formula, the ring C represents a homocyclic ring which may have a substituent or a heterocyclic ring which may have a substituent.
The homocyclic ring or heterocyclic ring may have the same or different substituents as 1
It may have about 5 to 5, preferably about 1 to 3. Further, these substituents may be substituted at any position of the homocyclic ring or the heterocyclic ring. The homocyclic ring includes the same “cyclic hydrocarbon (homocyclic ring)” as described in the section “A ring and B ring”, for example, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, 3- to 10-membered cyclic hydrocarbons such as cyclohexene, cycloheptene, cyclooctene, etc., C _3-10 cycloalkanes (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.), preferably 5- or 6-membered hydrocarbons And cyclic hydrocarbons. Preferred homocyclic rings include a 6-membered homocyclic ring such as a benzene, cyclohexene, and cyclohexane ring, and a benzene ring is particularly preferred.

Examples of the substituent of the above-mentioned homocyclic ring such as a benzene ring include a halogen atom (for example, fluorine, chlorine,
Bromine, iodine atom), optionally halogenated C
_1-10 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3 , 3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl, decyl group, etc.), and a C _1-4 alkyl group substituted with an amino group (for example, aminomethyl,
A 2-aminoethyl group), mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group (e.g.,
Methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, etc.),
A C _1-4 alkyl group substituted with a carboxyl group (for example, a carboxymethyl, carboxyethyl group, etc.);
A C _1-4 alkyl group substituted with a _1-4 alkoxy-carbonyl group (eg, methoxycarbonylethyl, ethoxycarbonylethyl group, etc.), a C _1-4 alkyl group substituted with a hydroxy group (eg, hydroxymethyl, hydroxy An ethyl group), a C _1-4 alkyl group substituted with a C _1-4 alkoxy-carbonyl group (eg, methoxymethyl, methoxyethyl, ethoxyethyl group, etc.), C _3-10
Cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.), nitro group, cyano group,
Hydroxy group, optionally halogenated C _1-10 alkoxy group (for example, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy,
2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, octyloxy, decyloxy, etc.), halogenated C _1-4 alkylthio group (for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio group, etc.), amino group, mono- or di-C _1-4 alkylamino group (for example,
A methylamino, ethylamino, propylamino, dimethylamino, diethylamino group or the like, a cyclic amino group (for example, a 5- to 9-membered member which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom) Cyclic amino group, specifically, for example, pyrrolidino, piperidino, morpholino group, etc., C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, — Or di-C _1-4 alkylaminocarbonyloxy group (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C
_1-4 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.), _C1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxy) A carbonyl group), an aralkyloxycarbonyl group (eg, a benzyloxycarbonyl group),
Carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), C _3-6 cycloalkyl-carbonyl group (eg, cyclohexylcarbonyl group, etc.), carbamoyl group, mono- or Di-C _1-4 alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C
_1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl group and the like) and the like.

Further, the homocyclic ring as the ring C is, for example,
One 5- or 6-membered aromatic monocyclic heterocyclic group (for example, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.), and these aromatic monocyclic heterocyclic groups are It may be substituted by about C _1-4 alkyl groups which may be halogenated (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, isopropyl groups, etc.).

Preferred substituents to be substituted on the homocyclic ring (such as a benzene ring) as the ring C include, for example, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.) and optionally halogenated C _{1-. 6} alkyl groups (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, s-butyl, t-butyl, perfluorobutyl group, etc.), nitro group, hydroxy group An optionally halogenated C _1-6 alkoxy group (for example,
Methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy,
3,3,3-trifluoro propoxy and butoxy group), an amino group, a mono - or di -C _1-4 alkylamino C _1-4 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl , 2-methylaminoethyl, 2-dimethylaminoethyl, etc.), mono- or di-C _1-4 alkylamino (eg, methylamino,
Examples thereof include an ethylamino, dimethylamino, and diethylamino group), a _C1-4 alkoxy-carbonyl group (for example, a methoxycarbonyl and ethoxycarbonyl group), a carboxyl group, and a carbamoyl group. Among them, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl,
Trichloromethyl, trifluoromethyl, ethyl, 2-
Bromoethyl, 2,2,2-trichloroethyl, 2,
2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t-butyl, etc.), and optionally halogenated C _1-4 alkoxy (eg, methoxy, trifluoromethoxy, ethoxy, 2,2
2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy group, etc., di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.), C _1-3 An acyloxy group (for example, an acetoxy group) and a hydroxy group are preferred. The number of these substituents is preferably, for example, about 1 to 3. In particular, a halogen atom (for example,
A fluorine, chlorine, bromine atom or the like, a C _1-4 alkyl group which may be halogenated (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2) 2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t-butyl group, etc., optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoro Methoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2
-Trifluoroethoxy, perfluoroethoxy, propoxy group and the like).

The “heterocycle” of the “heterocycle optionally having substituent (s)” includes, for example, a nitrogen atom,
It includes a 5- to 10-membered heterocyclic ring containing 1 to 4 kinds of one or two kinds of hetero atoms such as an oxygen atom and a sulfur atom.
Specific examples of the heterocycle include (1) furyl,
Thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
5- or 6-membered aromatic monocyclic heterocycle such as pyrazinyl and triazinyl;

(2) Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2- Benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , Thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
9- or 10-membered fused aromatic heterocycle such as 1,2,4-triazolo [4,3-b] pyridazinyl; or

(3) 5- to 10-membered non-aromatic heterocycles such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and pyrazinyl. The heterocycle (1) to
Among (3), for example, a 5- or 6-membered heterocycle containing 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom is widely used. Such heterocycles include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl, and the like. As the substituent which the heterocyclic ring may have,
Substituents similar to those described in the above-mentioned section “Homocyclic ring optionally having substituent (s)” can be mentioned.

A more preferred ring C is a benzene ring which may have a substituent (particularly, a benzene ring substituted by a substituent), for example, a halogen atom or an optionally halogenated C _1-4. An alkyl group, an optionally halogenated C _1-4 alkoxy group, a di-C _1-4 alkylamino group,
A benzene ring which may be substituted with one to three substituents selected from a C _1-3 acyloxy group and a hydroxy group (particularly, a benzene ring substituted with the substituent) is included. Specifically, preferred C ring includes, for example, the following formula (C-1)

Embedded image Wherein C ¹ , C ² and C ³ are the same or different,
A hydrogen atom, a halogen atom, a C _1-4 alkyl group which may be halogenated, a C _1-4 alkoxy group which may be halogenated, a mono- or di-C _1-4 alkylamino group,
C _{1-3 represents an} acyloxy group or a hydroxy group], or

The following formula (C-2)

Embedded image [Wherein C ⁴ and C ⁵ are the same or different and are each a hydrogen atom, a halogen atom, an optionally halogenated C _1-4
An alkyl group or a C _1-4 alkoxy group which may be halogenated].

Here, a halogen atom represented by C ¹ , C ² , C ³ , C ⁴ or C ⁵ , an optionally halogenated C
_{The 1-4} alkyl group, the optionally halogenated C _1-4 alkoxy group and the mono- or di-C _1-4 alkylamino group may be the aforementioned halogen atom, the optionally halogenated C _1-4 Alkyl group, optionally halogenated C _1-4
The same as the alkoxy group and the mono- or di-C _1-4 alkylamino group are used. More preferred C ring, for example, the formula (C-1) and in (C-2), C ¹
-C ⁵ can include a benzene ring a substituent described below. (1) wherein C ¹ , C ² and C ³ are the same or different and are each a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, (2) C ¹ , C ² and C ³ are the same or different and are each a halogen atom or a halogenated C
_1-4 alkyl groups, (3) C ¹ , C ² and C ³ are the same or different and are halogen atoms, (4) C ¹ , C ² and C ³
Is the same or different and may be a halogenated C _1-4 alkyl group, and (5) C ¹ , C ² and C ³ may be the same or different and may be a halogenated C _{1 -4} alkoxyl group, (6) C ⁴ and C ⁵ are the same or different and a halogen atom, (7) C ⁴ and C ⁵ are the same or different and may be halogenated C _{1- 4} alkyl groups, or (8) C _1-4 alkoxy groups in which C ⁴ and C ⁵ are the same or different and may be halogenated.
In the above embodiments (1) to (8), “optionally halogenated C _1-4 alkyl group”, “optionally halogenated C _1-4 alkoxy group” and “halogen atom”
Can be exemplified by the same groups or atoms as described above. As a more preferred C ring, for example, a benzene ring in which C ⁴ and C ⁵ are the following substituents in the above formula (C-2) can be mentioned. (A) one of C ⁴ and C ⁵ is a hydrogen atom, the other is a methoxy group, (b) C ⁴ and C ⁵ are a chlorine atom, (c) one of C ⁴ and C ⁵ is a methoxy group, the other is isopropyl (D) one of C ⁴ and C ⁵ is a methoxy group, the other is a 1-methoxy-1-methylethyl group, or (e) C 4
⁴ and C ⁵ is a trifluoromethyl group.

In the above formula, the Z ring represents a nitrogen-containing heterocyclic ring which may be substituted. Examples of the substituent on the Z ring include various substituents, for example, an alkyl group (for example, a linear group having 1 to 6 carbon atoms such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl group and the like). Carbon atoms such as linear or branched alkyl groups, preferably linear or branched alkyl groups having 1 to 4 carbon atoms, alkenyl groups (for example, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl groups) An alkynyl group having 2 to 6 carbon atoms, preferably an alkenyl group having 2 to 4 carbon atoms), an alkynyl group (for example, an alkynyl group having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl group) , Preferably having 2 to 2 carbon atoms
4 alkynyl groups), cycloalkyl groups (for example, C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, preferably C _{3-8
3- 6} cycloalkyl group), a cycloalkyl - alkyl group (e.g., cyclopropylmethyl, cyclopropylethyl, C _3-6 cycloalkyl -C _1-4 alkyl group such as cyclohexylmethyl group), an aryl group (e.g., phenyl , A 1-naphthyl, 2-naphthyl, anthryl, phenanthryl group or other aryl group having 6 to 14 carbon atoms, preferably an aryl group having 6 to 10 carbon atoms, particularly a phenyl group),
Nitro group, cyano group, hydroxy group, C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, etc.), C _1-4 alkylthio group (for example, methylthio, ethylthio, propylthio group, etc.), Amino group, mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group, etc.), cyclic amino group (for example, oxygen atom, sulfur atom other than nitrogen atom) And a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, such as, for example, pyrrolidino, piperidino, morpholino, thiomorpholino group, etc., C _1-4 alkyl-carbonyl Amino group (for example,
Acetylamino, propionylamino, butyrylamino group, etc., C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino group, etc.), C _1-4 alkoxy-carbonyl group (eg,
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl, C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), carbamoyl, mono- or di-C _1-4. Examples thereof include an alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.), a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.), an oxo group, a thioxo group, and the like. The number of these substituents is, for example, 1 to 3 depending on the size of the Z ring.
It is about 5 pieces, preferably about 1 or 2 pieces.

The ring Z may be a heterocyclic ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur atoms in addition to Y and nitrogen atom N. It is preferably a nitrogen-containing heterocyclic ring which may be substituted. In the Z ring, the following formula (Z-1)

Embedded image (Wherein, D and E each represent a group that forms the Z ring together with the nitrogen atom adjacent to E).

As D and E forming the Z ring, at least one of which may be an oxo group,
An oxyalkylene group, an iminoalkylene group and the like can be mentioned. Desirable D and E are often an alkylene group or an oxyalkylene group which may be oxo-modified. The optionally oxoalkylene group, oxyalkylene group, and iminoalkylene group represented by D and E are such that the Z ring has a carbon number that forms a 5- to 12-membered ring, preferably a 5- to 9-membered ring. Is preferred. In addition, the carbon number of the alkylene group represented by D and E may be the same or different. Preferred D includes, for example, a C _1-7 alkylene group which may be oxo-modified (particularly a C _1-5 alkylene group which may be oxo- _modified ), a C _1-7 oxyalkylene group (particularly C _1-5 Oxyalkylene group) and C _1-7 iminoalkylene group (especially C _1-5 iminoalkylene group). More preferred D, the formula - (CH _{2) m} - (wherein, m is 1-7) alkylene group represented by the formula -O-
An oxyalkylene group represented by (CH ₂ ) _p- (where p is an integer of 1 to 7), a formula -NH- (CH ₂ ) _q-
q is an integer of 1 to 7). In the above formula, m and p are each 1 to
5, particularly preferably 2 to 5. A preferred E is
For example, it includes a C _1-3 alkylene group which may be oxo-modified, particularly an alkylene group having 1 or 2 carbon atoms which may be oxo-modified, and among them, a methylene group which may be oxo-modified. The number of oxo groups that can be substituted on the Z ring is not particularly limited, and can be selected from a range of about 1 to 3 depending on the size of the Z ring. The number is about one or two. The oxo group may be substituted on at least one of D and / or E. In a preferred Z ring, the oxo group is substituted with E.

In a preferred Z ring, D is a C 1 -C
5, particularly an alkylene or oxyalkylene group having 2 to 5 carbon atoms, and E is an oxo-modified alkylene group having 1 or 2 carbon atoms, particularly> C = O. Preferred Z rings include
For example, the following formula (Z-2)

Embedded image (Wherein m and p each represent an integer of 1 to 5). In the above formula, n
Represents an integer of 1 to 6, and is preferably an integer of 1 to 3, particularly 1 or 2. More preferably, n is 1.

In the compounds represented by formulas (I) and (Ia), the "M ring"

Embedded image The combination is not particularly limited, and the compounds (I) and (Ia) can be constructed by appropriately combining.

Preferred compounds (I) and (Ia) are the “M ring” of the preferred embodiment described above.

Embedded image It is constructed by combining.

Among the compounds represented by the general formula (I), particularly the general formula (Ia), preferred compounds (1) include the following compounds or pharmaceutically acceptable salts. One of the ring A and the ring B is a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom and a sulfur atom other than a carbon atom, and the other is a benzene ring , A ring and B ring are each selected from a halogen atom and an optionally halogenated C _1-4 alkyl group.
Or ring C may have a halogen atom, an optionally halogenated C _1-6 alkyl group (preferably a C _1-4 alkyl group) and a halogenated ring. A benzene ring optionally having 1 to 3 substituents selected from a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group); and D constituting the Z ring is-(CH ₂ ) _M
- (m is an integer of 1 to 7) or -O- (CH ₂₎ p-
(P represents an integer of 1 to 7);

E constituting the Z ring is> C = O;

Embedded image A compound wherein n is 1 or a pharmaceutically acceptable salt thereof.

The “5- or 6-membered heterocycle” includes, for example, pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine and the like. -5), and the B ring includes, for example, the benzene ring represented by the above formula (B-7) and (B-8), particularly the above formula (B-10). . The “halogen atom” includes, for example, fluorine, chlorine, bromine atom and the like. As the “optionally halogenated C _1-4 alkyl group”, for example, methyl, chloromethyl, difluoromethyl, trichloro Methyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl,
Butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl and the like,
The “optionally halogenated C _1-6 alkyl group” includes pentyl, hexyl group and the like in addition to the above-mentioned alkyl group or halogenated alkyl group. As the “optionally halogenated C _1-4 alkoxy group”, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, Butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, tert-butoxy group and the like. The “optionally halogenated C _1-6 alkoxy group” includes the above-mentioned alkoxy group or halogen group. And a pentyloxy, hexyloxy group and the like in addition to the functionalized alkoxy group.

Among the compounds represented by the above general formula (I), particularly the general formula (Ia), the preferred compound (2) includes the following compounds or pharmaceutically acceptable salts. Ring A is a 5- or 6-membered heterocyclic ring containing one nitrogen atom or one sulfur atom other than a carbon atom, for example, the following formula (A-7)
A heterocyclic ring represented by;

Embedded image Ring B is a benzene ring which may have 1 to 3 substituents selected from a halogen atom and an optionally halogenated C _1-4 alkyl group; A benzene ring optionally substituted by 1 to 3 substituents selected from an optionally substituted C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group; constituting a Z ring D to the _{- (CH 2) m - (} m is an integer of 1-7) (shown represents an integer of 1 to 7 p) or -O- (CH ₂₎ p-;

E constituting the Z ring is> C = O;

Embedded image A compound wherein n is 1 or a pharmaceutically acceptable salt thereof.

The “halogen atom”, “optionally halogenated C _1-4 alkyl group” and “optionally halogenated C _1-4 alkoxy group” are the same as those described in the above compound (1). The same atoms or groups as described above can be exemplified. More preferably, R ^a and R ^b are the same or different and are a hydrogen atom or a C _1-6 alkoxy group, a C _1-6 alkylthio group, an amino group, a C _1-7 acylamino group, a mono-
Or di -C _1-6 alkylamino group, C _3-10 cyclic amino group, C _1-6 alkyl group optionally substituted by 5 or even six-membered cyclic amino group, C _1-6 alkylsulfonylamino group, or A C _1-6 alkyl group which may be substituted with a C _1-6 alkylcarbonyloxy group, or R ^a and R ^b
Are bonded together to form a pyridine ring which may have 1 to 3 substituents selected from a halogen atom or a C _1-4 alkyl group, and the ring B may be a halogen atom or halogenated. A benzene ring optionally having 1 to 3 substituents selected from a good C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, wherein the C ring is a halogen atom, Optionally halogenated C _1-4 alkyl group, optionally halogenated C _1-4 alkoxy group, amino group optionally substituted with C _1-4 alkyl group, C _1-3 acyloxy group Or a benzene ring optionally having 1 to 3 substituents selected from a hydroxyl group, wherein the Z ring may be substituted with a C _1-4 alkyl group or a hydroxyl group or may be oxo-modified. 5
A 10-membered nitrogen-containing heterocyclic group,

[0066]

Embedded image Compounds wherein n is 1 or salts thereof are included.

Preferred compounds among the compounds (I) and (Ia) include, for example, a compound represented by the following general formula or a salt thereof.

Embedded image (Wherein D and E are alkylene groups which may be oxoated, and other symbols are as defined above)
Is a group of C
_It is preferably a _1-3 alkylene group.

More preferable compounds among the compounds (I) and (Ia) include, for example, a compound represented by the following general formula or a salt thereof.

Embedded image (In the formula, m is an integer of 1 to 7, and other symbols are as defined above.) M is preferably an integer of 2 to 5.

In the above formula, R ^a and R ^b each represent a hydrogen atom or (I) a halogen atom, (II) (i) a hydroxy group, (ii) a C _1-6 alkoxy group, and (iii) a C _1-6 alkylthio group. Group, (iv) amino group, (v) C _1-7 acylamino group,
(Vi) mono- or di-C _1-6 alkylamino group, (vii)
A mono- or di-C _3-8 cycloalkylamino group, (vii
i) optionally substituted by C _1-6 alkyl, nitrogen oxygen atom in addition to atoms, 1 to 3 which may contain 5-9 membered cyclic amino group a hetero atom selected from the group consisting of sulfur atoms , (Ix) C _1-4 alkylsulfonylamino group, (x) C
_A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from the group consisting of _1-6 alkyl-carbonyloxy group and (xi) halogen atom, and (III) C _1-6 alkyl. A substituted or unsubstituted hetero atom selected from the group consisting of an oxygen atom and a sulfur atom other than a nitrogen atom,
(Preferably 1 or 2)
9-membered (preferably 6-membered) cyclic amino group, (IV) carboxyl group, (V) carbamoyl group and (VI) mono-
Or a substituent selected from the group consisting of a di-C _1-6 alkylcarbamoyl group; R ^a and R ^b are bonded together to form a ring A, and the ring A is substituted with a C _1-6 alkyl group; A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom (preferably A pyridine ring); wherein the ring B is (i) a C _1-6 alkyl group _optionally substituted with a hydroxy group,
i) a C _1-6 alkylcarbonyl group (including formyl) and (iii) a C _6-14 aryl group (preferably a benzene ring) which may be substituted with a substituent selected from the group consisting of a carboxyl group. A ring C is (i) a halogen atom,
C _6-14 optionally substituted with 1 to 3 substituents selected from the group consisting of (ii) an optionally halogenated C _1-10 alkyl group and (iii) a C _1-10 alkoxy group.
An aryl group (preferably a benzene ring); wherein the Z ring is composed of (i) a C _1-6 alkyl group, (ii) a hydroxy group and (ii)
i) in addition to Y and a nitrogen atom, which may be substituted with 1 to 3 substituents selected from the group consisting of oxo groups,
5 which may contain at least one hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom
It is preferable to show a to 12-membered heterocyclic ring.

In particular, as the heterocyclic compound (I), for example, (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro- 9-methyl-5- (4-methylphenyl)-
6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine, (9R)-
7- (3,5-dimethoxybenzyl) -6,7,8,
9,10,11-Hexahydro-9-methyl-5- (4
-Methylphenyl) -6,13-dioxo-13H-
[1,4] diazosino [2,1-g] [1,7] naphthyridine, (9R) -7- (3,5-dimethoxybenzyl) -5- (4-fluorophenyl) -6,7,8,
9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] naphthyridine and the like are preferred.

Of the compounds represented by the above formulas,

Embedded image Wherein the R ¹ is C _1-6 alkyl group, R ² is C _1-6 alkoxy groups, optionally substituted C _1-6 alkyl group by a halogen, a halogen atom, a hydroxy group or a C _7-15 In the aralkyloxy group, X represents 1 to 5 groups selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a halogen atom. However, (1) when R ¹ is a methyl group and R ² is a trifluoromethyl group, X represents a halogen atom,
(2) when R ¹ is a methyl group and R ² is a methoxy group, X
Represents a hydrogen atom or a halogen atom.] Is a novel compound.

Examples of the C _1-6 alkyl group represented by R ¹ , R ² or X include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. And a C _1-3 alkyl group, and a methyl group is particularly preferable. As the halogen atom which is a substituent of the C _1-6 alkyl group represented by R ² , for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are used, and among them, a chlorine atom is preferable. As the C _1-6 alkyl group _optionally substituted with halogen represented by R ² , for example, a trichloromethyl group, a trifluoromethyl group and the like are preferable, and a trifluoromethyl group is particularly preferable. As the C _7-15 aralkyloxy group represented by R ² , for example, a benzyloxy group, a phenylethyloxy group and the like are used, and among them, a benzyloxy group is preferable. As the halogen atom represented by R ² or X, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like are used, and among them, a chlorine atom is preferable. As the C _1-6 alkoxy group represented by R ² , for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group and the like are used. _{A 1-3} alkoxy group is preferred, and a methoxy group is particularly preferred.

The number of X substituted on the phenyl group is 1 to 5
When X is a C _1-6 alkyl group or a halogen atom, the number is usually 1 to 3, preferably 1 or 2. When X is a C _1-6 alkyl group or a halogen atom, the position of substitution of X is not limited.
_1-6 alkyl groups and / or 1 halogen atom
In the case of 2, the phenyl group is preferably in the 4-position, and in the case of 2, the 3- and 4-positions of the phenyl group are preferred.
Is preferably a halogen atom (particularly, a chlorine atom). Among the above, as R ¹ , a C _1-3 alkyl group such as a methyl group, an ethyl group, a propyl group, and an isopropyl group is preferable, and a methyl group is particularly preferable. R ² is preferably a C _1-3 alkoxy group (eg, methoxy group, ethoxy group, isopropoxy group, etc.), methyl group, trifluoromethyl group, chlorine atom, hydroxy group, benzyloxy group and the like. X represents a hydrogen atom, a methyl group, 1
Alternatively, two chlorine atoms or two fluorine atoms are preferable. Particularly, as the heterocyclic compound (I), for example, (9
R) -7- (3,5-Dimethoxybenzyl) -5- (4
-Fluorophenyl) -6,7,8,9,10,11-
Hexahydro-9-methyl-6,13-dioxo-13
H- [1,4] diazosino [2,1-g] [1,7] naphthyridine and the like are preferred.

When the heterocyclic compound (I) forms a salt and is used as a pharmaceutical, the salt is preferably a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid, or acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, Examples thereof include salts with organic acids such as succinic acid, citric acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid, salicylic acid and stearic acid. The heterocyclic compound (I) or a salt thereof includes stereoisomers such as cis and trans isomers, racemic forms, and optically active forms such as R form and S form. Further, depending on the size of the ring containing Q or the Z ring in the heterocyclic compound (I), an isomer due to conformation may be formed, and such an isomer is also present in the heterocyclic compound (I) or a derivative thereof. Included in salt. Further, the heterocyclic compound (I) or a salt thereof may be a hydrate or a non-hydrate.

The prodrug of the heterocyclic compound (I ′) or a salt thereof is a compound which can be converted into the heterocyclic compound (I ′) or a salt thereof by a reaction with an enzyme or gastric acid under physiological conditions in a living body, that is, an enzyme A compound which changes into a heterocyclic compound (I ') or a salt thereof by causing oxidation, reduction, hydrolysis or the like, and a compound which changes to a heterocyclic compound (I') or a salt thereof by causing hydrolysis or the like by gastric acid or the like Say. As a prodrug of the heterocyclic compound (I ′) or a salt thereof, a compound in which the amino group of the heterocyclic compound (I ′) is acylated, alkylated, or phosphorylated (for example, an amino group of the heterocyclic compound (I ′)) The group is eicosanoylated, alanylated,
Pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated Compounds, etc.), and compounds in which the hydroxyl group of the heterocyclic compound (I ') is acylated, alkylated, phosphorylated, and borated (the hydroxyl group of the heterocyclic compound (I') is acetylated, palmitoylated, propanoylated, pivaloylated) , Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.), and compounds in which the carboxyl group of the heterocyclic compound (I ′) is esterified or amidated (eg, the heterocyclic compound (I ′) Carboxyl group of ethyl ester, phenyl ester, carboxyoxymethyl ester, dimethyl Mino methyl esterification,
Pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, etc.). These prodrugs can be produced according to a method known per se or a method analogous thereto. Further, a prodrug of the heterocyclic compound (I ′) or a salt thereof can be prepared under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pp. 163-198, under physiological conditions. I ′) or a salt thereof may be used.

Heterocyclic compound (I), heterocyclic compound (I ')
Alternatively, the salt thereof can be produced according to the production method described in JP-A-9-263585, particularly the method described in Examples or a method analogous thereto. Specifically, the heterocyclic compound (I ′) or a salt thereof is, for example, a compound represented by the following general formula (II)

Embedded image [Wherein D and E are represented by the formula

Embedded image Wherein L represents a leaving group, and the other symbols are as defined above.) Or a salt thereof, which is subjected to a cyclization reaction to produce a ring. it can.

D, E and R ¹ in the compound (II) are as defined above. As the leaving group L of the compound (II), for example, a halogen atom (eg, chlorine, bromine, iodine atom or the like) or a substituted sulfonyloxy group (eg,
Methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.). Compound (II) may be used as a free compound, but its salt (for example, lithium,
(Eg, alkali metal salts such as sodium and potassium). The reaction is usually performed in a solvent inert to the reaction. As the solvent, for example,
Halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide are preferably used. Addition of a base favors the reaction. Examples of such a base include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and alkali metals such as sodium carbonate and potassium carbonate). Metal carbonates, alkali metal hydrides such as sodium hydride, potassium hydride, alkoxides such as sodium amide, sodium methoxide, and sodium ethoxide; organic bases (amines such as trimethylamine, triethylamine, and diisopropylethylamine);
Preferred are cyclic amines such as pyridine. In addition,
In the cyclization reaction, instead of using a base, a compound (I
I) may be converted into a salt with a base (for example, the above-mentioned alkali metal salt, alkaline earth metal salt, etc.) and reacted. The amount of the base depends on the type of the compound (II) and the solvent used,
Usually, compound (II) 1
It is about 1 to 10 mol, preferably about 1 to 5 mol, per mol. The reaction temperature is, for example, about -50 ° C to 200 ° C,
The reaction time is preferably in the range of about −20 ° C. to 150 ° C., and the reaction time varies depending on the type of compound (II) or the type of the salt thereof, the reaction temperature, and the like. is there. Starting compound (II)
Can be produced according to the method described in JP-A-9-263585.

The heterocyclic compound (I) or a salt thereof has an effect of inhibiting capsaicin-induced increase in tracheal vascular permeability as well as an excellent tachykinin receptor antagonistic effect, particularly SP
Has receptor antagonism. Cathepsins, the major components of the intense taste of red pepper, stimulate their C-fiber primary sensory nerves, including extracellular neuropeptides such as SP, NKA and the calcitonin gene-related peptide (CGRP), to produce these neuropeptides. It is known as a substance that liberates Thus, the vascular permeability inhibitory effect of the heterocyclic compound (I) or a salt thereof is considered to be based on an antagonistic effect on the tachykinin receptor. The heterocyclic compound (I) or a salt thereof has low toxicity,
It is safe. Therefore, a heterocyclic compound (I) or a salt thereof having excellent tachykinin receptor antagonism (eg, SP receptor antagonism) can be used for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, Depression, anxiety (anxi, sheep, monkeys, humans, etc.)
ety), safe prophylactic and therapeutic agents such as manic depression or mental illness, and also have Down syndrome, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diabetic neuropathy, peripheral neuropathy, Bronchospasm, chronic obstructive airway disease,
Opposing immune reactions such as rejection of transplanted tissues, extravasation of plasma caused by cytokine chemotherapy, etc., impaired blood flow due to vasodilation and angina, fibrotitis, spring catarrh, stimulus-induced miosis, dry eyes, Proliferative vitreoretinopathy, eczema, measles, sunburn, addictive disorders such as atopic dermatitis, alcoholism, ataxia (food intake inhibition), stress-related disability, shoulder / hand syndrome Reflex exchange dystrophy, systemic lupus erythematosus, fibrosis and collagen diseases such as scleroderma and eosinophilic fluke, small cell carcinomas such as small cell lung cancer, Sjogren's sindrome, IV and Type V hyperlipoproteinosis, hemochromatosis, sarcoidosis, amyloidosis, bladder detrusor hyperreflexia, arteriosclerosis, irritating symptoms of benign prostatic hyperplasia, cancer Continuous pain, chronic lower back pain, cluster headache, herpetic neuralgia, phantom limb pain, toothache, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone damage pain, pain during delivery and childbirth, burns It is also useful as a safe prophylactic and therapeutic agent for pain associated with urinary recruitment including pain, postpartum pain, angina pain, cystitis, spinal cord trauma, stroke, stroke, renal failure, Huntington's chorea. The heterocyclic compound (I ′) of the present invention may be, for example, an inflammatory or allergic disease (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple occurrences) Sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia, pruritus,
Cough, and diseases of the central nervous system (eg, schizophrenia, Parkinson's disease, psychosomatic disease, dementia (eg, Alzheimer's disease) etc.), gastrointestinal diseases [eg, irritable bowel disease (eg, diarrhea, constipation, mucus) Abnormal bowel movements such as stool, abdominal pain, abdominal distension, etc.), ulcerative colitis, Crohn's disease, urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori, etc.) (eg, gastritis, gastric ulcer, etc.) Etc.), vomiting (nausea, nausea, acute vomiting, delayed vomiting, precursor vomiting, empty vomiting, epidemic vomiting, early morning vomiting, malignant vomiting, pregnancy vomiting, spurting vomiting, psychogenic vomiting, retention vomiting, etc.), urination Abnormalities (eg, urinary frequency, urinary incontinence, etc.), cardiovascular diseases (eg, angina, hypertension, heart failure, thrombosis, etc.)
It is also useful as a safe preventive and therapeutic agent for immune abnormalities. In particular, the heterocyclic compound (I ′) or a salt thereof is useful as a tachykinin receptor antagonist, an agent for improving dysuria such as pollakiuria and urinary incontinence, and a therapeutic agent for these dysuria.

The preparation containing the heterocyclic compound (I) or a salt thereof may be any of solid preparations such as powders, granules, tablets and capsules, and liquid preparations such as syrups, emulsions and injections. The prophylactic / therapeutic preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulating, tableting, coating, sterilizing treatment, emulsification, etc., depending on the form of the preparation.
In addition, regarding the production of the preparation, for example, each section of the Japanese Pharmacopoeia Act general provisions of the preparation can be referred to. In the preparation of the present invention, the content of the heterocyclic compound (I) or a salt thereof varies depending on the form of the preparation, but is usually 0.01 to 10% based on the whole preparation.
It is about 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight. When the heterocyclic compound (I) or a salt thereof is used as the above-mentioned drug, it may be used as it is or as an appropriate pharmacologically acceptable carrier such as an excipient (eg, starch, lactose, sucrose,
Calcium carbonate, calcium phosphate, etc.), binders (eg, starch, arabic gum, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium talc talc) Disintegrants (eg, carboxymethylcellulose calcium,
Talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and as needed, additives (stabilizers, preservatives, coloring agents, flavors, dissolution aids, emulsifiers, buffers, isotonic agents, etc.) )
Can be administered orally or parenterally in the form of a solid such as powders, fine granules, granules, tablets, capsules or a liquid such as injection.
The dose varies depending on the type of the heterocyclic compound (I) or a pharmaceutically acceptable salt thereof, the route of administration, symptoms, age of the patient, and the like. For example, when administered orally to an adult patient with depression, About 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, of the heterocyclic compound (I) or a salt thereof per kg of body weight per day can be divided and administered in 1 to 3 times.

Further, the prophylactic / therapeutic agent of the present invention may contain, in addition to the heterocyclic compound (I) or a salt thereof, other antidepressants, anxiolytics, antimanic depressants or antipsychotics. You may use together. As the antidepressant, for example, fluoxetine, sertraline, paroxetine and the like are used. As the anxiolytic, for example, diazepam, buspirone, lorazepam, alprazocam and the like are used. As the anti-manic depressant, for example, lithium carbonate, sultopride, carbamazepine, levomepromazine and the like are used. As the antipsychotic, for example, risperidone, olanzapine, quetiapine and the like are used.

The heterocyclic compound (I) or a salt thereof can also be used by appropriately mixing it with another pharmaceutically active ingredient in an appropriate amount. Examples of such active ingredients include central nervous system drugs (eg, imipramine), anticholinergic drugs (eg, oxybutynin), α ₁ −
Receptor blockers (eg, tamsulosin), muscle relaxants (eg, baclofen), potassium channel openers (eg, nicorandil), calcium channel blockers (eg, nifedipine), and the like. The content of the drug other than the heterocyclic compound (I) or a salt thereof to be incorporated in the preparation of the present invention varies depending on the form of the preparation, but is usually 0.01 to 80% by weight, preferably 0.01 to 80% by weight based on the whole preparation. It is about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.

[0082]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to examples and reference examples. However, the present invention is not limited by the examples, and May be changed. Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise specified. In the TLC observation, Merck was used as a TLC plate.
The solvent used as the elution solvent in the column chromatography was used as the developing solvent using 60F ₂₅₄ manufactured by the company. A UV detector was used for detection. Silica gel 60 (70-230 mesh) manufactured by Merck was used as silica gel for column chromatography. Room temperature usually means a temperature of about 10 ° C to 35 ° C. Further, sodium sulfate or magnesium sulfate was used for drying the extract. The meanings of the abbreviations in Examples and Reference Examples are as follows. NMR: nuclear magnetic resonance spectrum EI-MS: electron impact mass spectrometry spectrum SI-MS: secondary electron ion mass spectrometry spectrum DMF: dimethylformamide, THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, Hz: hertz, J: coupling constant, m: multiplet, q:
Quartet, t: triplet, d: doublet,
s: singlet, b: broad, like: approximation.

[0083]

EXAMPLES Reference Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (2-hydroxyethyl)-
5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Magnesium (2.4 g) in THF (30 m
l) Iodine (catalytic amount) was added to the suspension while stirring at room temperature under a nitrogen atmosphere, and then a solution of 4-bromotoluene (17.1 g) in THF (20 ml) was added dropwise.
Stirred for hours. This mixture was added to a solution of 2,3-pyridinedicarboxylic anhydride (12.7 g) in THF (50 ml) with stirring while maintaining the temperature at 0 to 5 ° C.
Stirred for 0 minutes and then at room temperature for 1 hour. The solvent was distilled off from the reaction mixture, water (30 ml) was added to the residue, and the pH was adjusted to 1.0 using hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried, and the solvent was distilled off. Dichloromethane (about 10 ml) is added to the residue,
Then isopropyl ether (about 70 ml) was added,
After stirring at room temperature for 16 hours, 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid was obtained as colorless crystals (5.0.
g). Melting point: 168-170 ° C (recrystallized from dichloromethane-ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.41 (3H, s), 7.24 (2H, d, J =
8.4Hz), 7.62 (2H, d, J = 8.4Hz), 7.70 (1H, dd, J = 8.0,
4.8Hz), 7.85 (1H, dd, J = 8.0, 1.5Hz), 8.77 (1H, dd, J
= 4.8, 1.5Hz).

(Step 2) The compound (6.
0g), DMF (catalytic amount), thionyl chloride (10m
l), THF (50 ml), dichloroethane (50 m
The mixture of 1) was refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane (100 ml). Iminodiacetonitrile (3.0 g) and triethylamine (10 ml) were added to this solution, and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was washed successively with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, then dried, and the solvent was distilled off.
N, N-bis (cyanomethyl) -3- (4-methylbenzoyl) -2-pyridinecarboxamide was obtained as light brown crystals (4.3 g). Melting point: 166-168 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.55 (2H, s),
4.69 (2H, s), 7.31 (2H, d, J = 8.1Hz), 7.56 (1H, dd, J =
7.9, 4.9Hz), 7.69 (2H, d, J = 8.1Hz), 7.94 (1H, dd, J
= 7.9, 1.6Hz), 8.78 (1H, dd, J = 4.9, 1.6Hz) Elemental analysis: C ₁₈ H ₁₄ N ₄ O ₂ Calculated (%): C 67.92, H 4.43, N 17.60 Actual measurement ( %): C 67.76, H 4.54, N 17.62.

(Step 3) The compound (0.
86g), 1,8-diazabicyclo [5.4.0] -7
-Undecene (DBU) (1 ml) and toluene (4
0 ml) was heated at reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water, dilute acid, aqueous sodium hydrogen carbonate and water, dried and evaporated to remove 7-cyanomethyl-7,8-dihydro-5-.
(4-Methylephenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarbonitrile was obtained as pale brown crystals (765 mg). Melting point: 229-231 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.48 (3H, s), 5.28 (2H, s),
7.31 (2H, d, J = 8.2Hz), 7.40 (2H, d, J = 8.2Hz), 7.64 (1
H, dd, J = 8.2, 4.4Hz), 7.80 (1H, dd, J = 8.2, 1.4Hz),
9.06 (1H, dd, J = 4.4, 1.4Hz) Elemental analysis: C ₁₈ H ₁₂ N ₄ O · 0.2H ₂ O Calculated (%): C 71.14, H 4.11, N 18.43 Actual (%) : C 71.20, H 4.26, N 18.20.

(Step 4) The compound (2.
A mixture of 35 g), hydrochloric acid (25 ml) and acetic acid (25 ml) was heated under reflux for 1.5 hours. After evaporating the solvent, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and evaporated to remove 7-carboxymethyl-7,8-dihydro-5-.
(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarbonitrile was obtained as colorless crystals (1.62 g). Melting point: 253-254 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.46 (3H, s), 5.22 (2H, s),
6.64 (1H, bs, -CO ₂ H), 7.32 (2H, d, J = 8.2Hz), 7.37 (2H,
d, J = 8.2Hz), 7.62 (1H, dd, J = 8.4, 4.4Hz), 7.82 (1H,
d, J = 8.4 Hz), 9.09 (1H, d, J = 4.4 Hz) Elemental analysis: C ₁₈ H ₁₃ N ₃ O ₃ · 0.1 H ₂ O Calculated (%): C 67.33, H 4.14, N 13.09 Found (%): C 67.28, H 4.19, N 13.00.

(Step 5) The compound (1.
Hydroxybenzotriazole (770 mg) and 1,3-dicyclohexylcarbodiimide (1.23 g) were added to a THF (50 ml) solution of 54 g), and the solution was added at room temperature.
Stirred for hours. Next, sodium borohydride (550 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried, and the solvent was distilled off. Dichloromethane was added to the residue, the insoluble portion was removed by filtration, and the solvent was distilled off. Hydrochloric acid (50 ml) was added to the residue, and the mixture was heated under reflux for 16 hours. The solvent was distilled off, ice water was added to the residue, the mixture was made alkaline with aqueous potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to remove the solvent.
8,9,11-tetrahydro-5- (4-methylphenyl) -6,11-dioxo [1,4] oxazino [3
4-g] [1,7] naphthyridine is a colorless crystal (0.86
g). Melting point: 247-249 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.48-4.72 (4H,
m), 7.12 (2H, d, J = 8.0Hz), 7.32 (2H, d, J = 8.0Hz), 7.
55 (1H, dd, J = 8.4, 4.4Hz), 7.68 (1H, dd, J = 8.4, 1.6
Hz), 9.01 (1H, dd, J = 4.4, 1.6Hz) Elemental analysis: C ₁₈ H ₁₄ N ₂ O ₃ .0.2H ₂ O Calculated (%): C 69.76, H 4.68, N 9.04 Actual measurement Value (%): C 69.64, H 4.86, N 8.95.

(Step 6) Compound (41) obtained in Step 5
0 mg) and 3,5-bis (trifluoromethyl) benzylamine (1.2 g) under an argon atmosphere.
Heated at 50 ° C. for 2.5 hours. After cooling to room temperature, isopropyl ether was added to give the title compound as colorless crystals (441 mg). Melting point: 123-125 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.28 (3H, s), 3.71 (2H, m),
3.97 (2H, m), 4.46 (2H, d, J = 5.2Hz), 7.00-7.20 (4H,
m), 7.37 (1H, dd, J = 8.4, 4.2Hz), 7.52 (1H, dd, J = 8.4,
1.6Hz), 7.66 (2H, s), 7.76 (1H, s), 8.51 (1H, bs),
8.61 (1H, dd, J = 4.2, 1.6 Hz) Elemental analysis: C ₂₇ H ₂₁ N ₃ O ₃ F ₆ Calculated (%): C 59.02, H 3.85, N 7.65 Actual (%): C 58.95 , H 3.95, N 7.52.

Reference Example 2 N- [3,5-bis (trifluoromethyl) benzyl]
-7- (3-chloropropyl) -7,8-dihydro-5
-(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid (13.9 g), bromomalonic acid Diethyl ester (15.4 g), triethylamine (9.1 m
A mixture of 1) and THF (120 ml) was heated at reflux for 6 hours. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, diluted hydrochloric acid and saturated saline, dried, and the solvent was distilled off. Residue (oil) (20.5 g)
In a THF (120 ml) solution at −78 ° C. with DBU
(4.2 ml) was added. After the mixture was stirred at 0 ° C. for 15 minutes, the solvent was concentrated. The concentrated solution is 2N-HCl
And the pH is adjusted to about 10 with sodium bicarbonate.
And extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off to give 5,6-dihydro-5-hydroxy-5- (4-methylphenyl) -8-.
Oxo-8H-pyrano [3,4-b] pyridine-6,6
-Dicarboxylic acid diethyl ester is a colorless crystal (14.
1g). Melting point: 148-149 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.06 (3H, t, J = 7.1 Hz), 1.21
(3H, t, J = 7.1Hz), 2.31 (3H, s), 3.95-4.30 (4H, m),
4.65 (1H, s), 7.15 (2H, d, J = 8.3Hz), 7.55 (1H, dd, J =
8.0, 4.8Hz), 7.65 (2H, d, J = 8.3Hz), 8.47 (1H, dd, J =
8.0, 1.4Hz), 8.86 (1H, dd, J = 4.8, 1.4Hz) Elemental analysis: C ₂₁ H ₂₁ NO ₇ Calculated (%): C 63.15, H 5.30, N 3.51 Actual (%): C 63.09, H 5.16, N 3.47.

This compound was also obtained by the method described below. A mixture of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid (3.0 g), DMF (1 drop), thionyl chloride (4.5 ml) and THF (30 ml) was added to a mixture of 2
Heated to reflux for an hour. The solvent was evaporated and the crystalline residue obtained was dissolved in THF (50 ml). -10
While stirring at <RTIgt;
% Oil) (646 mg) was added in small portions. The reaction mixture was stirred at −10 ° C. for 30 minutes, and then ethyl acetate (10%).
0 ml) and water (100 ml). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and brine, dried and evaporated to give the compound as colorless crystals (4.0 g). The physicochemical data for this compound was consistent with the data for the above compound.

(Step 2) Compound (1) obtained in Step 1
4.1 g), acetic acid (100 ml) and hydrochloric acid (100 m
The mixture of 1) was heated at reflux for 3 hours. The solvent was distilled off, and water was added to the residue to give 5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxylic acid as colorless crystals (8. 45 g). Melting point: 274 to 277 ° C. (changed from around 240 ° C. to brown) (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) ppm: 2.43 (3H, s), 6.10 (1
H, bs, -CO ₂ H), 7.16 (2H, d, J = 8.0Hz), 7.29 (2H, d, J
= 8.0Hz), 7.50-7.70 (2H, m), 8.94 (1H, m) Elemental analysis: C ₁₆ H ₁₁ NO ₄ · 0.1H ₂ O Calculated (%): C 67.89, H 3.99, N 4.95 Found (%): C 67.70, H 4.06, N 4.83.

(Step 3) 3-bromopropylamine hydrobromide (1.5 g), triethylamine (2.0 m
l) and methanol (5 ml) to a mixture of 5- (4
-Methylphenyl) -8-oxo-8H-pyrano [3
4-b] pyridine-6-carboxylic acid (150 mg) T
An HF (5 ml) solution was added dropwise, and after stirring at room temperature for 2 hours, the solvent was distilled off. Hydrochloric acid (10 ml) was added to the residue, and the mixture was stirred at room temperature for 14 hours, concentrated, and concentrated with 1N-NaO
The pH of the concentrate was adjusted to 1 using H. The precipitated crystals were collected by filtration and washed with water to give 7- (3-bromopropyl) -7,8-dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b The pyridinecarboxylic acid was obtained as colorless crystals (131 mg). Melting point: 194 ° -196 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) ppm: 2.30-2.60 (2H, m),
2.42 (3H, s), 3.54 (2H, t, J = 6.8Hz), 4.29 (2H, t, J = 7.
2Hz), 5.42 (1H, bs, -CO ₂ H), 7.20-7.40 (4H, m), 7.50
(1H, m), 7.64 (1H, d, J = 8.0 Hz), 8.88 (1H, m).

(Step 4) Compound (11) obtained in Step 3
0 mg), DMF (catalytic amount), thionyl chloride (0.3 m
l), 1,2-dichloromethane (3 ml) and THF
(3 ml) was heated under reflux for 40 minutes, and then the solvent was distilled off. THF (5 ml), 3,5-bis (trifluoromethyl) benzylamine (82 mg) were added to the residue,
Triethylamine (0.12 ml) and THF (2 m
1) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, washed sequentially with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried, and then the solvent was distilled off to give the title compound as colorless crystals (79 mg).
As obtained. Melting point: 227-229 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.10-2.40 (2H, m), 2.27 (3H,
s), 3.4-3.7 (4H, m), 4.49 (2H, d, J = 5.8Hz), 7.07 (2H,
d, J = 7.6Hz), 7.24 (2H, d, J = 7.6Hz), 7.40 (1H, dd, J =
8.4, 4.2Hz), 7.54 (1H, dd, J = 8.4, 1.4Hz), 7.67 (2H,
s), 7.78 (1H, s), 8.06 (1H, bt), 8.70 (1H, dd, J = 4.2,
1.4 Hz) Elemental analysis: C ₂₈ H ₂₂ N ₃ O ₂ ClF ₆ .0.2 H ₂ O Calculated (%): C 57.43, H 3.86, N 7.18 Actual (%): C 57.29, H 3.98, N 7.07.

Reference Example 3 N- [3,5-bis (trifluoromethyl) benzyl]
-5- (4-Methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide The compound obtained in Step 2 of Reference Example 2 and 3,5-bis (trifluoro The reaction and treatment were carried out using methyl) benzylamine in the same manner as in Step 4 of Reference Example 2, whereby the title compound was obtained as colorless crystals. Melting point: 182-183 ° C. (recrystallized from ethyl acetate-ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.63 (2H, d, J =
6.4Hz), 7.17 (2H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.1Hz),
7.50-7.65 (3H, m), 7.73 (2H, s), 7.80 (1H, s), 8.96 (1
H, m) Elemental analysis: C ₂₅ H ₁₆ N ₂ O ₃ F ₆ Calculated (%): C 59.30, H 3.18, N 5.53 Found (%): C 59.42, H 3.30, N 5.45.

Reference Example 4 N- (2-methoxybenzyl) -5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide In Step 2 of Reference Example 2, The obtained compound was reacted with 2-methoxybenzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give the title compound as colorless crystals. Melting point: 189-190 ° C (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 3.90 (3H, s),
4.48 (2H, d, J = 5.8Hz), 6.85-6.95 (2H, m), 7.10-7.35 (6
H, m), 7.43 (1H, bt), 7.50-7.63 (2H, m), 8.93 (1H,
m).

Reference Example 5 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (4-hydroxybutyl)-
5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide THF (5 m) of the compound (200 mg) obtained in Reference Example 3
l) To a solution of -methanol (10 ml) was added 4-amino-1-butanol (0.5 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture, hydrochloric acid (15 ml) was added to the residue, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into aqueous potassium carbonate-ice and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (144 mg). Melting point: 187-188 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.5 (2H, m), 1.6-1.9 (2
H, m), 2.29 (3H, s), 2.82 (1H, bs), 3.55 (2H, t, J = 5.7
Hz), 3.69 (2H, m), 4.48 (2H, d, J = 5.8Hz), 7.08 (2H,
d, J = 8.1Hz), 7.21 (2H, d, J = 8.1Hz), 7.29 (1H, dd, J =
8.4, 4.2Hz), 7.52 (1H, dd, J = 8.4, 1.4Hz), 7.68 (2H,
s), 7.78 (1H, s), 8.39 (1H, bt), 8.61 (1H, dd, J = 4.2,
1.4Hz).

Reference Example 6 7,8-dihydro-7- (3-hydroxypropyl)-
N- (2-methoxybenzyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 4 and 3-amino-1-propanol were used. The reaction was carried out and treated in the same manner as in Reference Example 5 to give the title compound. This compound was used for the reaction of Reference Example 58 without purification.

Reference Example 7 7,8-dihydro-7- (4-hydroxybutyl) -N
-(2-methoxybenzyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 4 and 4-amino-1
Using butanol, reacting in the same manner as in Reference Example 5,
Upon treatment, the title compound was obtained as colorless crystals. Melting point: 205-206 ° C (recrystallized from methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.57 (2H, m), 1.95 (2H, m),
2.33 (3H, s), 2.71 (1H, bs), 3.66 (2H, t, J = 6.0Hz),
3.75 (3H, s), 4.00-4.15 (2H, m), 4.29 (2H, d, J = 6.2H
z), 6.59 (1H, bt), 6.71-6.92 (3H, m), 7.04-7.30 (5H,
m), 7.41 (1H, dd, J = 8.4, 4.4Hz), 7.62 (1H, dd, J = 8.
4, 1.4Hz), 8.82 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 8 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (5-hydroxypentyl)
-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and 5-amino-1-pentanol, The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 136-137 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.10-1.35 (2H, m), 1.35-1.
55 (2H, m), 1.6-1.9 (2H, m), 2.28 (3H, s), 3.50-3.70
(4H, m), 4.47 (2H, d, J = 5.8Hz), 7.06 (2H, d, J = 8.0H
z), 7.19 (2H, d, J = 8.0Hz), 7.35 (1H, dd, J = 8.3, 4.4H
z), 7.50 (1H, d, J = 8.3, 1.4Hz), 7.69 (2H, s), 7.78 (1
H, s), 8.29 (1H, bt), 8.64 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 9 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (3-hydroxypropyl)
-8-oxo-5-phenyl-6-pyrido [3,4-
b] Pyridinecarboxamide (Step 1) The procedure of Reference Example 2 was repeated using 3-benzoyl-2-pyridinecarboxylic acid instead of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2. Reacts in the same manner as 1, and when treated, gives 5,6-dihydro-5
-Hydroxy-8-oxo-5-phenyl-8H-pyrano [3,4-b] pyridine-6,6-dicarboxylic acid diethyl ester was obtained as colorless crystals. Melting point: 146-147 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.07 (3H, t, J = 7.2 Hz), 1.1
8 (3H, t, J = 7.2Hz), 4.00-4.25 (4H, m), 4.70 (1H, s),
7.30-7.40 (3H, m), 7.56 (1H, dd, J = 8.0, 4.8Hz), 7.74
-7.85 (2H, m), 8.48 (1H, dd, J = 8.0, 1.5Hz), 8.87 (1H,
dd, J = 4.8, 1.5Hz). (Step 2) Using the compound obtained in Step 1, acetic acid and hydrochloric acid, reacting and treating in the same manner as in Step 2 of Reference Example 2, 8-
Oxo-5-phenyl-8H-pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. Melting point: 288-290 ° C (recrystallized from THF-methanol-ether) NMR (200 MHz, DMSO-d ₆ ) ppm: 7.28-7.60 (6H, m), 7.81
(1H, dd, J = 8.2, 4.4Hz), 8.95 (1H, dd, J = 4.4, 1.6Hz)
.

(Step 3) The compound obtained in Step 2 and 3,5-
Using bis (trifluoromethyl) benzylamine,
The reaction and treatment were carried out in the same manner as in Reference Example 3 to give N- [3,5-bis (trifluoromethyl) benzyl] -8-oxo-5.
-Phenyl-8H-pyrano [3,4-b] pyridine-6
-Carboxamide was obtained as colorless crystals. Melting point: 182-183 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.61 (2H, t, J = 6.2 Hz), 7.2
4-7.34 (2H, m), 7.49-7.67 (6H, m), 7.72 (2H, s), 7.79
(1H, s), 8.96 (1H, dd, J = 4.2, 1.6 Hz). (Step 4) The compound obtained in step 3 was reacted with 3-amino-1-propanol in the same manner as in Reference Example 5 to give the title compound as colorless crystals. Melting point: 129-130 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.91 (2H, m), 3.45 (2H, t,
J = 5.4Hz), 3.70 (2H, m), 4.46 (2H, d, J = 6.0Hz), 7.2-
7.4 (5H, m), 7.44 (1H, dd, J = 8.4, 4.4Hz), 7.59 (1H, d
d, J = 8.4, 1.6Hz), 7.61 (2H, s), 7.78 (1H, s), 8.25 (1
H, bt), 8.70 (1H, dd, J = 4.4, 1.6Hz).

Reference Example 10 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (4-hydroxybutyl)-
8-oxo-5-phenyl-6-pyrido [3,4-b]
Pyridinecarboxamide When the compound obtained in Step 3 of Reference Example 9 and 4-amino-1-butanol were reacted and treated in the same manner as in Reference Example 5, the title compound was obtained as colorless crystals. Melting point: 155-157 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45 (2H, m), 1.83 (2H, m),
3.58 (2H, t, J = 5.8Hz), 3.73 (2H, m), 4.44 (2H, d, J =
5.8Hz), 7.2-7.4 (6H, m), 7.54 (1H, dd, J = 8.1, 1.1H
z), 7.60 (2H, s), 7.77 (1H, s), 8.05 (1H, bt), 8.66 (1
H, dd, J = 4.1, 1.1 Hz).

Reference Example 11 N- [3,5-bis (trifluoromethyl) benzyl]
-1,2-dihydro-2- (4-hydroxybutyl)-
4- (4-methylphenyl) -1-oxo-3-pyrido [3,4-c] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid of Step 1 of Reference Example 2 In place of 4- (4-methylbenzoyl) -3-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Step 1 of Reference Example 2 to give 3,4-dihydro-4-hydroxy-4- (4-methyl Phenyl)
-1-oxo-1H-pyrano [3,4-c] pyridine-
3,3-Dicarboxylic acid diethyl ester was obtained as a yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.08 (3H, t, J = 7.1 Hz), 1.2
1 (3H, t, J = 7.2Hz), 2.31 (3H, s), 4.00-4.40 (4H, m),
4.72 (1H, bs), 7.14 (2H, d, J = 8.4Hz), 7.64 (2H, d, J =
8.4Hz), 8.05 (1H, d, J = 5.3Hz), 8.85 (1H, d, J = 5.3H
z), 9.12 (1H, s). (Step 2) Using the compound obtained in Step 1, acetic acid and hydrochloric acid, reacting and treating in the same manner as in Step 2 of Reference Example 2, 4-
(4-Methylphenyl) -1-oxo-1H-pyrano [3,4-c] pyridine-3-carboxylic acid was obtained as colorless crystals. Melting point: 254-256 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ + d ₆ -DMSO) ppm: 2.43 (3H, s), 5.3
1 (1H, bs, COOH), 7.04 (1H, d, J = 5.5Hz), 7.16 (2H, d,
J = 7.8Hz), 7.29 (2H, d, J = 7.8Hz), 8.81 (1H, d, J = 5.5H
z), 9.54 (1H, s).

(Step 3) The compound obtained in Step 2 and 3,5-
Using bis (trifluoromethyl) benzylamine,
The reaction was carried out in the same manner as in Reference Example 3, and N- [3,5-bis (trifluoromethyl) benzyl] -4- (4-methylphenyl) -1-oxo-1H-pyrano [3,4-
c] Pyridine-3-carboxamide was obtained as colorless crystals. Melting point: 188-189 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.61 (2H, d,
J = 6.2Hz), 7.05 (1H, d, J = 5.3Hz), 7.15 (2H, d, J = 8.1H
z), 7.32 (2H, d, J = 8.1Hz), 7.43 (1H, bt), 7.7.0 (2H,
s), 7.80 (1H, s), 8.85 (1H, d, J = 5.3Hz), 9.56 (1H,
s). (Step 4) The compound obtained in Step 3 was reacted with 4-amino-1-butanol in the same manner as in Reference Example 5 to give the title compound as colorless crystals. Melting point: 128-131 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45-1.70 (2H, m), 1.75-2.
05 (2H, m), 2.31 (3H, s), 3.65 (2H, t, J = 5.9Hz), 3.98
(2H, m), 4.36 (2H, d, J = 6.0Hz), 7.00 (1H, d, J = 5.7H
z), 7.12 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.
56 (2H, s), 7.80 (1H, s), 8.47 (1H, d, J = 5.7Hz), 9.41
(1H, s).

Reference Example 12 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide (Step 1) TH of 2-aminoethanol (3.6 ml)
3,5-Bis (trifluoromethyl) benzyl bromide (1.1 ml) was added to the F (30 ml) solution under ice cooling. After stirring this mixture at room temperature for 1 hour, ethyl acetate (30 ml) was added, and the mixture was washed with water and saturated aqueous sodium chloride. After drying the organic layer, the solvent was distilled off to give N-
[3,5-bis (trifluoromethyl) benzyl] -N
-(2-Hydroxyethyl) amine is a colorless crystal (1.3
8g). Melting point: 107-108 ° C (recrystallized from ethanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.83 (2H, t, J = 5.4 Hz), 3.72
(2H, t, J = 5.4Hz), 3.96 (2H, s), 7.78 (1H, s), 7.82 (2
H, s). (Step 2) To a solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (318 mg) in THF (10 ml),
Thionyl chloride (0.7 ml) and DMF (catalytic amount) were added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off and the residue was
Dissolved in F (5 ml). This solution was cooled in ice under step 1
N- [3,5-bis (trifluoromethyl) obtained in
Benzyl] -N- (2-hydroxyethyl) amine (3
91 mg), triethylamine (0.57 ml) and T
It was added to a mixture of HF (10 ml) and stirred at room temperature for 2 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was separated and purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) to give the title compound as an oil (551 mg) (about 2: 1 cis-trans isomer ratio for the amide bond). Obtained. NMR (200 MHz, CDCl ₃ ) ppm: 2.82-3.92 (4H, m), 4.16 (1H
× 1/3, d, J = 16.0Hz), 4.41 (1H × 1/3, d, J = 16.0Hz), 4.
73 (1H × 2/3, d, J = 15.0Hz), 4.87 (1H × 2/3, d, J = 15.0H
z), 7.20-8.85 (9H, m), 8.43 (1H, m).

Reference Example 13 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -5- (4-methylphenyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide THF (10 m) of the compound (1.0 g) obtained in Reference Example 3
l) (S) -3-Amino-2-methyl-1-propanol (307 mg) was added to a -methanol (7.5 ml) solution, and the mixture was stirred at room temperature for 14 hours. After adding dilute hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and the solvent was distilled off. Acetonitrile (3 ml), toluene (21 ml) and DB were added to the residue.
U (0.42 ml) was added, and the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate, and washed with water, diluted hydrochloric acid, and saturated saline in this order. After the organic layer was dried, the solvent was distilled off to obtain the title compound as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
15-216 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) [α] _D : + 11.1 ° (C = 0.350, CHC
l ₃ ) NMR (200 MHz, CDCl ₃ ) ppm: 0.79 (3H, d, J = 7.0 Hz), 2.1
3 (1H, m), 2.28 (3H, s), 3.10-3.70 (4H, m), 4.48 (2H,
d, J = 6.2Hz), 7.00-7.25 (4H, m), 7.43 (1H, dd, J = 8.4,
4.2Hz), 7.59 (1H, dd, J = 8.4, 1.6Hz), 7.69 (2H, s),
7.79 (1H, s), 8.38 (1H, bt), 8.70 (1H, dd, J = 4.2, 1.6
Hz) Elemental analysis: C ₂₉ H ₂₅ N ₃ O ₃ F ₆ .0.5H ₂ O Calculated (%): C 59.39, H 4.47, N 7.16 Actual (%): C 59.64, H 4.31, N 7.01.

Reference Example 14 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -8-oxo-5-phenyl-6
-Pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 and (R) -3-amino-
The reaction was carried out in the same manner as in Reference Example 13 using 2-methyl-1-propanol, and the title compound was obtained as colorless crystals. Melting point: 101-103 ° C (recrystallized from ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.77 (3H, d, J = 6.6 Hz), 2.1
4 (1H, m), 3.10-3.70 (4H, m), 4.47 (2H, d, J = 5.8Hz),
7.1-7.4 (5H, m), 7.45 (1H, dd, J = 8.4, 4.2Hz), 7.60 (1
H, d, J = 8.4Hz), 7.65 (2H, s), 7.78 (1H, s), 8.60 (1H,
bt), 8.69 (1H, d, J = 4.2 Hz) [α] _D : -5.4 ° (C = 0.512, CHC
l ₃ ).

Reference Example 15 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -5- (4-methylphenyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (R) -3-amino-2-methyl-1-propanol, in the same manner as in Reference Example 13 After reaction and treatment, the title compound was obtained as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
15-216 ° C. (remelting (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 13 [α] _D : -9.0 ° (C = 0. 346, CHCl
₃ ).

Reference Example 16 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrid [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 was reacted with 4-amino-2-methyl-1-butanol in the same manner as in Reference Example 13 and treated. The title compound was obtained as colorless crystals. Melting point: 217-219 ° C (recrystallized from ethyl acetate-isopropyl ether).

Reference Example 17 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and 4-amino-2-methyl-1-
The reaction was carried out in the same manner as in Reference Example 13 using butanol,
Upon treatment, the title compound was obtained as colorless crystals. Melting point: 129-130 ° C (once melted and solidified again), 1
88-190 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.79 (3H, d, J = 6.6 Hz), 1.4
-1.8 (3H, m), 2.28 (3H, s), 3.03 (1H, t, J = 6.6Hz, -O
H), 3.2-3.7 (4H, m), 4.49 (2H, d, J = 5.8Hz), 7.0-7.3
(4H, m), 7.30 (1H, dd, J = 8.4, 4.4Hz), 7.53 (1H, dd,
J = 8.4, 1.4Hz), 7.68 (2H, s), 7.78 (1H, s), 8.48 (1H,
t, J = 6.0Hz), 8.61 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 18 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 and (R) -4-amino-
The reaction was carried out using 2-methyl-1-butanol tetrahydropyranyl (THP) ether in the same manner as in Reference Example 13, and the title compound THP ether was obtained as a pale orange oil. This compound is reacted with p-toluenesulfonic acid in methanol at room temperature to give T
Removal of the HP group gave the title compound as colorless crystals. Melting point: 213-215 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: Same as the spectrum of the compound of Reference Example 16 [α] _D : + 1.0 ° (C = 0.519, CHCl
₃ ). In addition, (R) -4-amino-2-methyl-1-butanol THP ether was prepared by the following method. (S)-
Using (+)-3-hydroxy-2-methylpropionic acid methyl ester as a starting material, the method described in the literature [Kenji Mori, Tetrahedron 39, 31
07-3109 (1983): describes a synthesis method for enantiomers. Or etch. Mattes (H, Matte
s) et al., Journal of Medicinal Chemistry, 30, 194.
8-1951 (1987)].
(R) -4-hydroxy-3-methylbutanenitrile T
An HP ether was prepared. [Colorless oil, NMR (200 MHz, CDCl ₃ ) ppm:
1.09 (3H × 1/2, d, J = 6.8 Hz), 1.1
0 (3H × 1/2, d, J = 6.8 Hz), 1.5-1.9
(6H, m), 2.1-2.6 (3H, m), 3.17-3.
88 (4H, m), 4.60 (1H, b)]. Ethyl ether (100m) of this compound (22.7g)
l) Bring the solution to lithium aluminum hydride (3.7
g) was slowly added to a suspension of ethyl ether (200 ml) with vigorous stirring. Then, the reaction mixture was stirred at room temperature for 1 hour, cooled again with ice water, and water (3 ml), 15 ml
Aqueous sodium hydroxide solution (3 ml) and water (10 ml) were added with stirring. The precipitate was filtered off using Celite and washed with ethyl acetate. The filtrate and washing solution were combined, washed with aqueous potassium carbonate and brine, dried, and the solvent was distilled off to give (R) -4-amino-2-methyl-1-butanol THP ether as a colorless oil (21.7 g). )
Was obtained as NMR (200 MHz, CDCl ₃ ) ppm: 0.94 (3
H × 1/2, d, J = 6.8 Hz), 0.95 (3H × 1 /
2, d, J = 6.8 Hz), 1.2-1.9 (11 H, m),
3.13-3.90 (6H, m), 4.57 (1H, b).

Reference Example 19 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (R) -4-amino-2-methyl-1-butanol THP ether, Reference Example 1
Reaction and treatment in a manner similar to 3 gave the title compound THP ether as a pale orange oil. This compound was reacted with p-toluenesulfonic acid in methanol at room temperature to remove the THP group to give the title compound as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
05-206 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 17 [α] _D : + 1.2 ° (C = 0. 471, CHCl ₃ )
.

Reference Example 20 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrido [3,4-b] pyridinecarboxamide (R) -4-amino-2-methyl- in Reference Example 18
(S) -4 instead of 1-butanol THP ether
The reaction was carried out using -amino-2-methyl-1-butanol THP ether in the same manner as in Reference Example 18 to give the title compound as colorless crystals. Melting point: 213-214 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 16 [α] _D : -1.5 ° (C = 0.492) , CHC
l ₃ ).

Reference Example 21 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide (R) -4-amino-2-methyl- in Reference Example 19
(S) -4 instead of 1-butanol THP ether
The reaction and treatment with -amino-2-methyl-1-butanol THP ether in the same manner as in Reference Example 19 were carried out, whereby the title compound was obtained as colorless crystals. Melting point: 213 to 215 ° C (once melted and solidified again), 2
07-208 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 17 [α] _D : -2.7 ° C (C = 0) .391, CHC
l ₃ ).

Reference Example 22 N- (2-aminoethyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2-chloro-4-phenyl-3-pyridinecarboxamide (Step 1) 2-chloro To a solution of -4-phenyl-3-pyridinecarboxylic acid (145 mg) in THF (5 ml) was added thionyl chloride (0.15 ml) and DMF (catalytic amount).
The mixture was heated under reflux for 2 hours. The solvent was distilled off, and the residue was washed with THF.
(5 ml). This solution was cooled under ice-cooling with N- [3,
5-bis (trifluoromethyl) benzyl] -N'-te
rt-butoxycarbonylethylenediamine (240m
g), triethylamine (0.26 ml) and THF
(10 ml) and stirred at room temperature for 3 hours. In addition, N- [3,5-bis (trifluoromethyl)
[Benzyl] -N'-tert-butoxycarbonylethylenediamine is a mixture of ethylenediamine and methanesulfonic acid 3,
5-bis (trifluoromethyl) benzyl ester is converted to T
After reacting in HF to give N- [3,5-bis (trifluoromethyl) benzyl] ethylenediamine as an oil, this compound is reacted with di-tert-butyl dicarbonate in THF in the presence of triethylamine. To give an oil. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (tert.
-Butoxycarbonylamino) ethyl] -2-chloro-
4-Phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.20-1.60 (total 9H, m), 2.7
0-4.90 (total 7H, m), 7.20-8.00 (total 9H, m), 8.46 (1
H, d, J = 5.2Hz). (Step 2) To the compound obtained in step 1 was added a 4N-HCl ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as a pale yellow oil (34
9 mg). NMR (200 MHz, CDCl ₃ ) ppm: 2.30-3.70 (4H, m), 4.15 (1H ×
2/5, d, J = 16.2Hz), 4.38 (1H × 2/5, d, J = 16.2Hz), 4.6
5 (1H × 3/5, d, J = 15.2Hz), 4.84 (1H × 3/5, d, J = 15.2H
z), 7.20-7.60 (6H, m), 7.65-7.80 (6H, m), 8.47 (1H,
m).

Reference Example 23 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (3-hydroxypropyl) -4-
Phenyl-3-pyridinecarboxamide (Step 1) The reaction and treatment were carried out in the same manner as in Step 1 of Reference Example 12 using 3-amino-1-propanol instead of 2-aminoethanol in Step 1 of Reference Example 12. However, N- [3,5-bis (trifluoromethyl) benzyl] -N- (3-hydroxypropyl) amine was obtained as colorless crystals. Melting point: 57-58 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 1.77 (2H, quintet, J = 5.8 Hz),
2.89 (2H, t, J = 5.8Hz), 3.82 (2H, t, J = 5.8Hz), 3.93
(2H, s), 7.89 (3H, s) Elemental analysis: C ₁₂ H ₁₃ NOF ₆ Calculated (%): C 47.85, H 4.35, N 4.65 Actual (%): C 47.76, H 4.32, N 4.65.

(Step 2) N in Step 2 of Reference Example 12
-[3,5-bis (trifluoromethyl) benzyl]-
Step 1 instead of N- (2-hydroxyethyl) amine
The reaction was carried out using the amine obtained in Step 2 in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained as colorless crystals (cis-trans isomer ratio about amino bond: about 3: 1). . Melting point: 121-122 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.00-1.70 (2H, m), 2.75-3.20
(2H, m), 3.35-3.55 (3H, m), 4.06 (1H × 1/4, d, J = 16.2
Hz), 4.31 (1H × 1/4, d, J = 16.2Hz), 4.65 (1H × 3/4, d,
J = 15.2Hz), 4.76 (1H × 3/4, d, J = 15.2Hz), 7.20-7.55 (6
H, m), 7.72 (2H, s), 7.80 (1H, s), 8.47 (1H, d, J = 5.2
Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₂ F ₆ Cl Calculated (%): C 55.77, H 3.71, N 5.42 Found (%): C 55.65, H 3.70, N 5.57.

Reference Example 24 N- [3,5-bis (trifluoromethyl) benzyl]
2-chloro-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide 2 in place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12. -Chloro-5-
The reaction was carried out using methyl-4-phenyl-3-pyridinecarboxylic acid in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained as colorless crystals. Melting point: 146-148 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.09 (3H, s), 3.02 (1H, dt, J)
= 15.0, 5.6Hz), 3.25 (1H, dt, J = 15.0, 5.6Hz), 3.60 (2
H, m), 4.57 (1H, d, J = 15.2Hz), 4.79 (1H, d, J = 15.2H
z), 7.05-7.50 (5H, m), 7.62 (2H, s) 7.76 (1H, s), 8.3
3 (1H, s).

Reference Example 25 N- [3,5-bis (trifluoromethyl) benzyl]
-2-chloro-N- (3-hydroxypropyl) -5
Methyl-4-phenyl-3-pyridinecarboxamide Instead of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12, 2-chloro-5-
Using methyl-4-phenyl-3-pyridinecarboxylic acid, obtained in Step 1 of Reference Example 23 instead of N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine. The reaction was carried out using N- [3,5-bis (trifluoromethyl) benzyl] -N- (3-hydroxypropyl) amine in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained. Obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.10-1.80 (2H, m), 2.06 (3H
× 1/2, s), 2.08 (3H × 1/2, s), 2.80-3.30 (3H, m), 3.3
5-3.70 (1H, m), 4.08 (1H × 1/2, d, J = 16.4Hz), 4.39 (1H
× 1/2, d, J = 15.0Hz), 4.47 (1H × 1/2, d, J = 16.4Hz),
4.70 (1H × 1/2, d, J = 15.0Hz), 6.90-7.62 (7H, m), 7.72
(1H × 1/2, s), 7.77 (1H × 1/2, s), 8.28 (1H × 1/2, s),
8.31 (1H x 1/2, s).

Reference Example 26 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (2,3-dihydroxypropyl) -5- (4-methylphenyl ) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and (±) -3-amino-1,2-
The reaction and treatment were carried out using propanediol in the same manner as in Reference Example 13, and the title compound was obtained as a pale yellow foam. NMR (200 MHz, CDCl ₃ ) ppm: 2.20 (3H, s), 3.50 (2H, m),
4.02-4.30 (5H, m), 4.75 (1H, b), 5.35 (1H, b), 6.92-
7.46 (6H, m), 7.55 (2H, s), 7.70 (1H, s), 8.63 (1H,
m), 8.83 (1H, b).

Reference Example 27 N-benzyl-8-oxo-5-phenyl-8H-pyrano- [3,4-b] pyridine-6-carboxamide Using the compound obtained in Step 2 of Reference Example 9 and benzylamine Then, when the reaction and treatment were carried out in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals. Melting point: 188-189 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.48 (2H, d, J = 5.4 Hz), 7.2
-7.4 (8H, m), 7.49-7.65 (5H, m), 8.95 (1H, dd, J = 4.4,
2.0Hz).

Reference Example 28 N- (3,4-dichlorobenzyl) -8-oxo-5
Phenyl-8H-pyrano [3,4-b] pyridine-6-
Carboxamide When the compound obtained in Step 2 of Reference Example 9 and 3,4-dichlorobenzylamine were reacted and treated in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals. Melting point: 198-200 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.44 (2H, d, J = 6.0 Hz), 7.1
0 (1H, dd, J = 8.2, 2.0Hz), 7.25-7.70 (10H, m), 8.96 (1
H, dd, J = 4.3, 1.7Hz).

Reference Example 29 N- [3,5-bis (trifluoromethyl) benzyl]
-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -5-methyl-4-phenyl-3-pyridinecarboxamide 3,5-bis (trifluoromethyl) benzylmethanesulfonate and (S ) -3-Amino-2-methylpropanol is reacted in THF to give N- [3,5-bis (trifluoromethyl) benzyl] -N-[(S) -3-hydroxy-2-methylpropyl] amine Was obtained as a colorless oil. NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.8 Hz), 1.9
8 (1H, m), 2.63 (1H, dd, J = 9.4, 11.8Hz), 2.70-2.90 (3
H, m), 3.56 (1H, dd, J = 8.6, 10.6Hz), 3.71 (1H, ddd,
J = 1.4, 4.0, 10.6Hz), 3.87 (1H, d, J = 13.8Hz), 3.98 (1
H, d, J = 13.8 Hz), 7.79 (3H, s) 2-chloro-4-phenyl-3-pyridinecarboxylic acid and N- [3,5-bis (trifluoromethyl) in Step 2 of Reference Example 12. In place of benzyl] -N- (2-hydroxyethyl) amine, 2-chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid and the above N-
[3,5-bis (trifluoromethyl) benzyl] -N
The reaction was carried out in the same manner as in Step 2 of Reference Example 12 using-[(S) -3-hydroxy-2-methylpropyl] amine to give the title compound as a colorless oil. NMR (200 MHz, CDCl ₃ ) ppm: 0.60-0.82 (3H, m), 1.50-2.
00 (1H, m), 2.00-2.15 (3H, m), 2.15-3.92 (4H, m), 4.05
-4.92 (2H, m), 7.00-7.85 (8H, m), 8.34 (1H, m).

Reference Example 30 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N-[(R) -3-hydroxy-2-methylpropyl] -5-methyl-4-phenyl-3-pyridinecarboxamide N- [3,5-bis (trifluoromethyl) of Reference Example 29 ) Benzyl] -N-[(S) -3-hydroxy-2-
N- [3,5-bis (trifluoromethyl) benzyl] -N-[(R) -3 instead of methylpropyl] amine
-Hydroxy-2-methylpropyl] amine was reacted and treated in the same manner as in Reference Example 29 to give the title compound as a colorless oil. NMR spectrum of this product (2
00MHz, CDCl ₃ ) was identical to the spectrum of the compound obtained in Reference Example 29.

Reference Example 31 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -6-methyl-4-phenyl-3-pyridinecarboxamide (Step 1) 2-Chloro-6-methyl-4-phenyl-3
-Pyridinecarboxylic acid ethyl ester (15.43
g), a mixture of ethanol (70 ml) and a 4N aqueous solution of sodium hydroxide (70 ml) was heated under reflux for 2.5 hours. The reaction solution was concentrated, the concentrated solution was made acidic (pH 3) using hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated saline, dried, and the solvent was distilled off.
Chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid was obtained as colorless crystals (11.2 g). Melting point: 191-194 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.59
(3H, s), 7.16 (1H, s), 7.45 (5H, s), 9.53 (1H, b). (Step 2) 2-chloro-4 in Step 2 of Reference Example 12
Instead of -phenyl-3-pyridinecarboxylic acid, 2-chloro-6-methyl-4-phenyl- obtained in step 1
Step 3 of Reference Example 12 using 3-pyridinecarboxylic acid
The title compound was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.95-3.80 (4H, m), 2.58 (3H,
s), 4.15 (1H × 2/5, d, J = 16.2Hz), 4.41 (1H × 2/5, d,
J = 16.2Hz), 4.75 (1H × 3/5, d, J = 15.0Hz), 4.85 (1H × 3 /
5, d, J = 15.0Hz), 7.15 (1H × 3/5, s), 7.17 (1H × 2/5,
d, J = 15.0Hz), 7.23-7.58 (5H, m), 7.74 (2H, s), 7.78
(1H, s).

Reference Example 32 N- [3,5-bis (trifluoromethyl) benzyl]
-2-chloro-N- (3-hydroxypropyl) -6
Methyl-4-phenyl-3-pyridinecarboxamide 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12 and N- [3,5-bis (trifluoromethyl) benzyl] -N- ( Instead of 2-hydroxyethyl) amine, 2-chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid and N- [3,
5-bis (trifluoromethyl) benzyl] -N- (3
The reaction was carried out using -hydroxypropyl) amine in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.15-1.65 (2H, m), 2.59 (3H,
s), 2.75-3.20 (2H, m), 4.06 (1H × 2/5, d, J = 15.4Hz),
4.31 (1H × 2/5, d, J = 15.4Hz), 4.65 (1H × 3/5, d, J = 15.
2Hz), 4.74 (1H × 3/5, d, J = 15.2Hz), 7.16 (1H, s), 7.2
0-7.60 (5H, m), 7.72 (2H, s), 7.78 (1H, s).

Reference Example 33 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (2-hydroxyethyl) -5-methyl-2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) 5 prepared according to the method described in JP-A-62-160881. -Methyl-4-phenyl-2,3
-Pyridinedicarboxylic acid diethyl ester [13.0
g, melting point 73-74 ° C. (recrystallized from ethyl ether-isopropyl ether)], potassium hydroxide (20
g) and a 70% aqueous ethanol solution (200 ml) were heated to reflux for 3 hours. After evaporation of the solvent, the residue was diluted with water and washed with ethyl ether. 2N water layer
-The pH was adjusted to 2-3 using hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried, and the solvent was distilled off to give 5-methyl-4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals (3.06 g). Melting point: 187-188 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, DMSO-d ₆ ) ppm: 2.10 (3H, s), 7.20-7.30
(2H, m), 7.40-7.55 (3H, m), 8.65 (1H, s). (Step 2) The compound (2.9 g) obtained in Step 1 was heated and refluxed in acetic anhydride (50 ml) for 2 hours. After the solvent was distilled off, ethanol (50 ml) was added to the residue, and the mixture was stirred at room temperature for 4 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with a saturated saline solution, dried, and the solvent was distilled off to give 5-methyl-4-phenyl-.
A mixture (about 3: 2) of 2-ethyl ester and 3-ethyl ester of 2,3-pyridinedicarboxylic acid was obtained as a pale brown oil (3.39 g).

(Step 3) The oily substance obtained in Step 2 (1.
DMF (3 drops) in a solution of 94 g) in THF (30 ml)
And oxalyl chloride (2.0 ml).
Stirred for 0 minutes. After the solvent was distilled off, the residue was washed with THF.
(40 ml). N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine (2.2 g) and triethylamine (2.0 ml) were added to this solution, and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, aqueous potassium carbonate solution and saturated saline solution in that order, and dried. After the solvent was distilled off, the residue was subjected to column chromatography using silica gel (hexane-ethyl acetate =
1: 2), followed by purification, to give N- [3,5-bis (trifluoromethyl) benzyl] -2-ethoxycarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl -3-Pyridinecarboxamide was obtained as colorless crystals (1.31 g). Melting point: 138-139 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45 (3
H × 1/4, t, J = 7.1Hz), 1.46 (3H × 3/4, t, J = 7.1Hz), 2.
18 (3H × 3/4, s), 2.19 (3H × 1/4, s), 2.82 (1H, m), 3.2
-3.7 (3H, m), 4.15-4.62 (4H, m), 7.05-7.80 (8H, m), 8.
65 (1H x 3/4, s), 8.68 (1H x 1/4, s). (Step 4) T of the compound (377 mg) obtained in Step 3
A 40% methylamine-methanol solution (15 ml) was added to the HF (5 ml) solution, and the mixture was stirred at room temperature for 16 hours.
Evaporation of the solvent gave the title compound as a pale yellow oil (370
mg). NMR (200 MHz, CDCl ₃ ) ppm: 2.12 (3H × 2/3, s), 2.14 (3H
× 1/3, s), 2.83 (1H, m), 3.03 (3H × 1/3, d, J = 5.2Hz),
3.04 (3H × 2/3, d, J = 4.8Hz), 3.25-3.80 (3H, m), 4.30
(1H × 2/3, d, J = 15Hz), 4.36 (1H × 1/3, d, J = 15Hz), 4.
59 (1H × 1/3, d, J = 15Hz), 4.86 (1H × 2/3, d, J = 15Hz),
7.0-7.9 (8H, m), 8.02 (1H × 2/3, bd), 8.17 (1H × 1/3, b
d), 8.46 (1H, s).

Reference Example 34 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (2-hydroxyethyl) -2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) 5-methyl-4 in Step 1 of Reference Example 33
4-phenyl-2,3-pyridinedicarboxylic acid diethyl ester instead of -phenyl-2,3-pyridinedicarboxylic acid diethyl ester [Japanese Patent Laid-Open No. 62-1060]
No. 81] and treated in the same manner as in Step 1 of Reference Example 33 to give 4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals. Melting point: 146-148 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) ppm: 7.3-7.6 (6H, m),
8.69 (1H, d, J = 5.0Hz). (Step 2) Reference example 33 using the compound obtained in step 1
Reacting and treating in the same manner as in Step 2 of 4-phenyl-
A mixture of 2,3-pyridinedicarboxylic acid 2-ethyl ester and 3-ethyl ester (about 3: 2) was obtained as a light brown oil.

(Step 3) The oily substance obtained in Step 2 was reacted in the same manner as in Step 3 of Reference Example 33 to give N-
[3,5-bis (trifluoromethyl) benzyl] -2
-Ethoxycarbonyl-N- (2-hydroxyethyl)
-4-Phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.48 (3H, t, J = 7.1 Hz), 2.71
(1H, m), 3.1-3.7 (3H, m), 4.1-4.9 (4H, m), 7.18-7.52
(6H, m), 7.65-7.82 (3H, m), 8.78 (1H × 3/4, d, J = 4.8H
z), 8.80 (1H × 1/4, d, J = 4.8Hz)). (Step 4) Reference example 33 using the compound obtained in step 3
The title compound was obtained as a pale-yellow oil upon treatment. NMR (200 MHz, CDCl ₃ ) ppm: 2.73 (1H, m), 3.05 (3H × 1/3,
d, J = 5.0Hz), 3.06 (3H × 2/3, d, J = 5.0Hz), 3.1-3.9 (3
H, m), 4.29 (1H × 1/3, d, J = 16Hz), 4.52 (1H × 2/3, d,
J = 15Hz), 4.54 (1H × 1/3, d, J = 16Hz), 4.93 (1H × 2/3,
d, J = 15Hz), 7.0-7.9 (9H, m), 7.95 (1H × 2/3, bd), 8.1
9 (1H × 1/3, bd), 8.59 (1H, d, J = 5.2Hz).

Reference Example 35 N-benzyl-2-ethoxycarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide The oil obtained in Step 2 of Reference Example 33 and N -Benzyl-
Reference Example 3 using N- (2-hydroxyethyl) amine
Reaction and treatment as in step 3 of 3 gave the title compound as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.44 (3H × 1/4, t, J = 7.2 Hz),
1.46 (3H × 3/4, t, J = 7.1Hz), 2.15 (3H × 3/4, s), 2.19
(3H × 1/4, s), 2.6-3.7 (4H, m), 3.96 (1H × 3/4, d, J = 1
5Hz), 4.00 (1H × 1/4, d, J = 15Hz), 4.4-4.6 (2H + 1H × 1 /
4, m), 5.37 (1H × 3/4, d, J = 15Hz), 6.48 (2H × 3/4, m),
6.82 (2H x 1/4, m) 7.0-7.6 (8H, m), 8.65 (1H x 3/4,
s), 8.66 (1H x 1/4, s).

Reference Example 36 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (3-hydroxypropyl) -5-methyl-2-
Methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) The oil obtained in Step 2 of Reference Example 33 and N-
[3,5-bis (trifluoromethyl) benzyl] -N
Reference Example 3 using-(3-hydroxypropyl) amine
Reaction and treatment in the same manner as in Step 3 of Step 3 gave N- [3,5
-Bis (trifluoromethyl) benzyl] -2-ethoxycarbonyl-N- (3-hydroxypropyl) -5
Methyl-4-phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.44 (3H × 1/4, t, J = 7.1 Hz),
1.45 (3H × 3/4, t, J = 7.1Hz), 1.60 (2H, m), 2.17 (3H ×
3/4, s), 2.18 (3H x 1/4, s), 2.7-3.7 (4H, m), 3.96 (1H
× 1/4, d, J = 16Hz), 4.35-4.60 (3H + 1H × 3/4, m), 7.10
-7.80 (8H, m), 8.64 (1H x 3/4, s), 8.68 (1H x 1/4, s). (Step 2) Reference example 33 using the compound obtained in step 1
The title compound was obtained as a pale-yellow oil upon treatment. NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.9 (2H, m), 2.11 (3H × 3
/ 5, s), 2.14 (3H × 2/5, s), 2.7-3.8 (4H, m), 3.02 (3H
× 3/5, d, J = 5.2Hz), 3.03 (3H × 2/5, d, J = 5.2Hz), 4.0
4 (1H × 2/5, d, J = 16Hz), 4.28 (1H × 3/5, d, J = 15Hz),
4.46 (1H × 2/5, d, J = 16Hz), 4.82 (1H × 3/5, d, J = 15Hz),
7.0-7.6 (5H, m), 7.63 (2H × 3/5, s), 7.67 (2H × 2/5,
s), 7.73 (1H, s), 7.96 (1H × 3/5, bd), 8.06 (1H × 2/5,
bd), 8.45 (1H × 3/5, s), 8.48 (1H × 2/5, s).

The compound of Reference Example 37-45 was 2-chloro-
4-phenyl-3-pyridinecarboxylic acid and N-substituted-N
-(Substituted) benzylamines, each of which is N- (2-hydroxyethyl) -N- (3,4,5-trimethoxybenzyl) amine, N- (3,4-dichlorobenzyl) -N
-(2-hydroxyethyl) amine, N- (3,4-
Dimethoxybenzyl) -N- (2-hydroxyethyl)
Amine, N-benzyl-N- (2-hydroxyethyl) amine, N- (2-hydroxypropyl) -N-
(3,4,5-trimethoxybenzyl) amine, N-
Benzyl-N-[(S) -3-hydroxy-2-methylpropyl] amine, N-benzyl-N-[(R) -3
-Hydroxy-2-methylpropyl] amine, N-
[3,5- (Bistrifluoromethyl) benzyl] -N
-[(S) -3-hydroxy-2-methylpropyl] amine, and N- [3,5- (bistrifluoromethyl) benzyl] -N-[(R) -3-hydroxy-2-
Reference Example 12 Step 2 using [methylpropyl] amine}
The reaction was carried out in substantially the same manner as described above, and each was treated to give a pale yellow oil. The physicochemical data is described below.

Reference Example 37 2-Chloro-N- (2-hydroxyethyl) -4-phenyl-N- (3,4,5-trimethoxybenzyl) -3
- pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 2.05-2.50 (2H, m), 2.80-4.0
0 (12H, m), 4.00-4.40 (1H × 3/2, m), 4.93 (1H × 1/2, d,
J = 14.2Hz), 6.22 (2H × 1/2, s), 6.55 (2H × 1/2, s), 7.
25-7.70 (6H, m), 8.42 (1H × 1/2, d, J = 6.2Hz), 8.48 (1H
× 1/2, d, J = 5.8Hz). (1: 1 mixture of amide rotamers).

Reference Example 38 2-Chloro-N- (3,4-dichlorobenzyl) -N-
(2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 1.80-3.85 (5H, m), 3.96 (1H
× 4/9, d, J = 16.0Hz), 4.24 (1H × 4/9, d, J = 16.0Hz), 4.
44 (1H × 5/9, d, J = 15.2Hz), 4.92 (1H × 5/9, d, J = 15.2H
z), 6.50-6.85 (2H, m), 7.10-7.70 (7H, m), 8.46 (1H,
m). (A mixture of amide rotamers 5: 4).

Reference Example 39 2-Chloro-N- (3,4-dimethoxybenzyl) -N
- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 2.70-4.30 (12H, m), 4.53 (1H
× 1/2, d, J = 14.8Hz), 4.74 (1H × 1/2, d, J = 14.8Hz), 6.
30-7.00 (3H, m), 7.20-7.65 (6H, m), 8.39 (1H × 1/2, d,
J = 5.0Hz), 8.46 (1H × 1/2, d, J = 5.2Hz). (1: 1 mixture of amide rotamers).

Reference Example 40 N-benzyl-2-chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.27 (1H × 1/2, b) , 2.60 (1H
× 1/2, b), 2.75-3.15 (1H, m), 3.25-3.65 (3H, m), 3.9
0 (1H × 1/2, d, J = 15.4Hz), 4.26 (1H × 1/2, d, J = 15.4H
z), 4.49 (1H × 1/2, d, J = 15.0Hz), 4.95 (1H × 1/2, d, J
= 15.0Hz), 6.74 (2H × 1/2, m), 6.92 (2H × 1/2, m), 7.10
-7.65 (9H, m), 8.42 (1H, m). (Amide rotamer 1:
1).

Reference Example 41 2-chloro-N- (2-hydroxypropyl) -4-phenyl-N- (3,4,5-trimethoxybenzyl)-
3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 1.10-2.30 (3H, m), 2.70-4.3
0 (14H + 1H × 3/7, m), 4.88 (1H × 4/7, d, J = 14.8Hz), 6.1
8 (2H × 4/7, s), 6.52 (2H × 3/7, s), 7.20-7.60 (6H, m),
8.47 (1H, m). (A mixture of amide rotamers 4: 3).

Reference Example 42 N-benzyl-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 0.50- 0.85 (3H, m), 1.40-1.8
5 (1H, m), 2.20-3.75 (5H, m), 3.80-5.15 (2H, m), 6.60
-7.65 (11H, m), 8.42 (1H, m). (Amide rotamer 2:
1).

Reference Example 43 N-Benzyl-2-chloro-N-[(R) -3-hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: Reference Example Same as spectrum of compound 42.

Reference Example 44 N- [3,5- (bistrifluoromethyl) benzyl]
2-chloro -N - [(S) -3- hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 0.53 (3H × 1/4, d, J = 7.0Hz),
0.63 (3H × 1/4, d, J = 7.0Hz), 0.75 (3H × 1/4, d, J = 6.8
Hz), 0.81 (3H × 1/4, d, J = 6.8Hz), 1.50-1.90 (1H, m),
2.42-3.80 (5H, m), 4.00-4.95 (2H, m), 7.10-7.90 (9H,
m), 8.42 (1H, m). (1: 1 mixture of amide rotamers).

Reference Example 45 N- [3,5- (bistrifluoromethyl) benzyl]
2-chloro -N - [(R) -3- hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : same as the spectrum of the compound of Reference Example 44.

Reference Example 46 N-benzyl-7,8-dihydro-7- (4-hydroxybutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Reference Example 2 The compound obtained in Step 2 was reacted with benzylamine in substantially the same manner as in Step 4 of Reference Example 2 to give N-benzyl-5- (4-methylphenyl). ) -8-Oxo-8H-pyrano [3,4-b]
Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 208-209 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.48 (2H, d, J)
= 5.6Hz), 7.10-7.40 (10H, m), 7.58 (2H, m), 8.94 (1H,
dd, J = 3.6, 2.2Hz). (Step 2) The compound obtained in Step 1 was reacted with 4-amino-1-butanol in substantially the same manner as in Reference Example 13 to give the title compound as colorless crystals. Melting point: 205-207 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.48 (2H, m), 1.83 (2H, m),
2.45 (3H, s), 2.86 (1H, b), 3.57 (2H, t, J = 5.9Hz), 3.
85 (2H, m), 4.34 (2H, d, J = 6.0Hz), 6.8-7.1 (2H, m),
7.10-7.35 (8H, m), 7.50 (1H, m), 7.55 (1H, dd, J = 8.4,
1.4Hz), 8.60 (1H, dd, J = 4.0, 1.4Hz).

Reference Example 47 (R) -N-benzyl-7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Reference Example 46 The compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 226-227 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 6.6 Hz), 1.5-
2.0 (3H, m), 2.44 (3H, s), 3.20-3.55 (3H, m), 3.93 (2H,
m), 4.31 (2H, d, J = 5.4Hz), 6.75-6.90 (2H, m), 7.1-7.
3 (8H, m), 7.39 (1H, dd, J = 8.2, 4.2Hz), 7.61 (1H, d,
J = 8.2Hz), 8.68 (1H, d, J = 4.2Hz).

Reference Example 48 (S) -N-benzyl-7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Reference Example 46 The compound obtained in Step 1 and (S) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 226-227 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: Same as the spectrum of the compound of Reference Example 47.

Reference Example 49 (R) -7,8-dihydro-7- (4-hydroxy-3
-Methylbutyl) -5- (4-methylphenyl) -8-
Oxo-N- (3,4,5-trimethoxybenzyl)-
6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Reference Example 2 The compound obtained in Step 2 and 3,4,5-
Reference Example 2 Step 4 using trimethoxybenzylamine
And treated in substantially the same manner as
(4-methylphenyl) -8-oxo-N- (3,4,
5-trimethoxybenzyl) -8H-pyrano [3,4-
b] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 195-196 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 3.84 (3H, s),
3.85 (6H, s), 4.40 (2H, d, J = 5.8Hz), 6.50 (2H, s), 7.
17 (2H, d, J = 8.0Hz), 7.27 (1H, b), 7.32 (2H, d, J = 8.0H
z), 7.58 (2H, m), 8.94 (1H, dd, J = 4.0, 2.2Hz). (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 194-195 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 6.8 Hz), 1.5-
2.0 (3H, m), 2.38 (3H, s), 3.2-3.6 (3H, m), 3.65-3.95
(2H, m), 3.80 (6H, s), 3.82 (3H, s), 4.23 (2H, d, J =
6.0Hz), 6.40 (2H, s), 7.05-7.40 (4H, m), 7.32 (1H, d
d, J = 8.2, 4.2Hz), 7.56 (1H, dd, J = 8.2, 1.6Hz), 7.80
(1H, m), 8.63 (1H, dd, J = 4.2, 1.6Hz).

Reference Example 50 (S) -7,8-dihydro-7- (4-hydroxy-3
-Methylbutyl) -5- (4-methylphenyl) -8-
Oxo-N- (3,4,5-trimethoxybenzyl)-
6-pyrido [3,4-b] pyridinecarboxamide Reference Example 49 The compound obtained in Step 1 and (S) -4-amino-
The reaction and treatment were carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, whereby the title compound was obtained as colorless crystals. Mp: 194-195 ° C. (acetone - recrystallized from ethyl _{ether) NMR (200MHz, CDCl 3)} ppm: same as the spectrum of the compound of Reference Example 49.

Reference Example 51 (R) -N- (3,5-dimethoxybenzyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-
Pyrid [3,4-b] pyridinecarboxamide (Step 1) Using the compound obtained in Step 2 and 3,5-dimethoxybenzylamine in substantially the same manner as in Step 4 of Reference Example 2, After processing, N- (3,5
-Dimethoxybenzyl) -5- (4-methylphenyl)
-8-oxo-8H-pyrano [3,4-b] pyridine-
6-carboxamide was obtained as colorless crystals. Melting point: 154-155 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 3.78 (6H, s),
4.41 (2H, d, J = 5.4Hz), 6.41 (3H, m), 7.17 (2H, d, J =
8.0Hz), 7.23 (1H, b), 7.33 (2H, d, J = 8.0Hz), 7.58 (2H,
m), 8.94 (1H, dd, J = 4.0, 2.2Hz). (Step 2) Compound (R) -4-amino-2 obtained in Step 1
Using the THP ether of -methyl-1-butanol,
The reaction and treatment were conducted in substantially the same manner as in Reference Example 19 to give the title compound as colorless crystals. Melting point: 169-172 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 6.8 Hz), 1.62
(1H, m), 1.79 (2H, m), 2.40 (3H, s), 3.11 (1H, b), 3.
25-3.60 (2H, m), 3.76 (6H, s), 3.86 (2H, m), 4.23 (2H,
d, J = 5.6Hz), 6.25 (2H, d, J = 2.2Hz), 6.35 (1H, t, J =
2.2Hz), 7.15-7.35 (4H, m), 7.30 (1H, dd, J = 8.4, 4.2H
z), 7.44 (1H, m), 7.56 (1H, dd, J = 8.4,1.6Hz), 8.65 (1
H, dd, J = 4.2, 1.6Hz).

The compounds of Reference Examples 52-54 and 144 were 2-chloro-4- (4-methylphenyl) -3-
Pyridine carboxylic acid [2-cyano-3-methyl-3-
(4-Methylphenyl) propenoic acid Ethyl ester is condensed with N, N-dimethylacetamide dimethylacetal, then cyclized with hydrogen chloride, and the ester group is alkali-hydrolyzed. Decomposition)] and N-substituted-N- (substituted) benzylamine {N-benzyl-N- (2-hydroxyethyl) amine, N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine, N-benzyl-N-[(S) -3-hydroxy-2-methylpropyl] amine, and N- [3,5-bis (trifluoromethyl) benzyl] -N- [ Reference Example 12 using (S) -3-hydroxy-2-methylpropyl] amine
The reaction was carried out in substantially the same manner as in Step 2, and each was obtained as a pale yellow oily substance after treatment. The physicochemical data is described below.

Reference Example 52 N-benzyl-2-chloro-N- (2-hydroxyethyl) -4- (4-methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H × 1) / 2, s), 2.46 (3H
× 1/2, s), 2.70-3.80 (total 4H, m), 3.90 (1H × 1/2,
d, J = 15.4Hz), 4.24 (1H × 1/2, d, J = 15.4Hz), 4.51 (1H
× 1/2, d, H = 15.2Hz), 4.94 (1H × 1/2, d, J = 15.2Hz),
6.74 (1H, m), 6.97 (1H, m), 7.10-7.55 (8H, m), 8.40 (1
H, m). (1: 1 mixture of amide rotamers).

Reference Example 53 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-
(4-methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.36 (3H × 7/11, s), 2.44 (3H
× 4/11, s), 2.80-3.80 (total 4H, m), 4.16 (1H × 4/11,
d, J = 16.2Hz), 4.41 (1H × 4/11, d, J = 16.2Hz), 4.77 (1H
H × 7/11, d, H = 15.0Hz), 4.90 (1H × 7/11, d, J = 15.0H
z), 7.10-7.50 (6H, m), 7.76 (2H, m), 8.42 (1H, m).
(A mixture of amide rotamers 7: 4).

Reference Example 54 N-benzyl-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -4- (4-methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 0.59 (3H × 1/4, d, J = 7.0Hz),
0.66 (3H × 1/4, d, J = 7.0Hz), 0.77 (3H × 1/4, d, J = 3.8H
z), 0.80 (3H × 1/4, d, J = 3.8Hz), 1.40-1.90 (1H, m),
2.30-2.50 (3H, m), 2.50-3.80 (total 5H, m), 3.80-4.4
2 (2H × 3/4, m), 5.05 (2H × 1/4, m), 6.60-7.50 (total 10
H, m), 8.40 (1H, m). (1: 1 mixture of amide rotamers).

Reference Example 55 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9-Tetrahydro-5- (4-methylphenyl) -6,11-dioxo-11H-pyrazino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 1 ( 200 mg), triethylamine (0.20 ml), methanesulfonyl chloride (0.10
ml) and dichloromethane (10 ml) in 0 ml.
Stirred at C for 2 hours. Ethyl acetate was added to the reaction mixture,
After washing with water and drying and evaporating the solvent, N- [3,5-
Bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (2-methanesulfonyloxyethyl) -5
-(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide was formed. After dissolving this compound in DMF (5 ml), sodium hydride (60% oil) (30 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, diluted hydrochloric acid and water, dried, and evaporated to give the title compound as colorless crystals (109 mg). Melting point: 270-271 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.46 (3H, s), 3.67 (2H, tlik)
e, J = 5.4Hz), 4.51 (2H, t like, J = 5.4Hz), 4.81 (2H,
s), 7.13 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 7.
52 (1H, dd, J = 8.4, 4.4Hz), 7.64 (1H, dd, J = 8.4, 1.6H
z), 7.70 (2H, s), 7.84 (1H, s), 8.97 (1H, dd, J = 4.4,
1.6 Hz) Elemental analysis: C ₂₇ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 61.02, H 3.60, N 7.91 Found (%): C 61.07, H 3.50, N 7.85.

Reference Example 56 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,12-Hexahydro-5-
(4-methylphenyl) -6,12-dioxo [1,
4] Diazepino [2,1-g] [1,7] naphthyridine N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloropropyl) -7,8 obtained in Reference Example 2.
-Dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (66 mg), sodium hydride (60% oil) (84
mg) and THF (3 ml) was stirred at room temperature for 14 hours. After adding 2N-HCl to the reaction mixture, the mixture was made alkaline with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to obtain the title compound as colorless crystals (35 mg). Melting point: 194-195 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.16 (2H, m), 2.42 (3H, s),
3.25-3.70 (3H, m), 4.12 (1H, d, J = 15Hz), 5.34 (1H, d,
J = 15Hz), 5.52 (1H, m), 6.93 (1H, d, J = 8.2Hz), 7.20
(1H, d, J = 8.2Hz), 7.30-7.45 (2H, m), 7.51 (1H, dd, J
= 8.4, 4.4Hz), 7.62 (2H, s), 7.70 (1H, dd, J = 8.4, 1.6
Hz), 7.84 (1H, s), 8.93 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 61.65, H 3.88, N 7.70 Found (%): C 61.29, H 4.06, N 7.61.

Reference Example 57 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-5-
(4-methylphenyl) -6,13-dioxo-13H
-[1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 5 was reacted and treated in the same manner as in Reference Example 55 to give the title compound as colorless crystals Was obtained as Melting point: 192-193 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.5 (4H, m), 2.37 (3H,
s), 3.25 (1H, m), 3.40-3.72 (2H, m), 4.01 (1H, d, J = 1
5Hz), 5.13 (1H, dd, J = 14, 5.4Hz), 5.46 (1H, d, J = 15H
z), 6.85 (1H, d, J = 7.9Hz), 7.05 (1H, d, J = 7.9Hz), 7.
26 (1H, d, J = 7.8Hz), 7.34 (1H, d, J = 7.8Hz), 7.42-7.6
0 (2H, m), 7.47 (2H, s), 7.81 (1H, s), 8.92 (1H, m).

Reference Example 58 6,7,8,9,10,12-Hexahydro-7- (2
-Methoxybenzyl) -5- (4-methylphenyl)-
6,12-dioxo [1,4] diazepino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 6 was reacted and treated in the same manner as in Reference Example 55, whereby the title compound was obtained as colorless crystals. Melting point: 264-266 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.1 (2H, m), 2.43 (3H,
s), 3.25-3.52 (3H, m), 3.84 (3H, s), 4.67 (2H, s), 5.
39 (1H, dd, J = 14, 5.8Hz), 6.85-7.00 (3H, m), 7.10-7.2
2 (2H, m), 7.22-7.44 (3H, m), 7.48 (1H, dd, J = 8.4, 4.
4Hz), 7.72 (1H, dd, J = 8.4, 1.4Hz), 8.90 (1H, dd, J =
4.4, 1.4Hz).

Reference Example 59 6,7,8,9,10,11-Hexahydro-7- (2
-Methoxybenzyl) -5- (4-methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 7 was reacted and treated in the same manner as in Reference Example 55. However, the title compound was obtained as colorless crystals. Melting point: 235-236 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.3 (4H, m), 2.46 (3H,
s), 3.15-3.30 (1H, m), 3.38-3.65 (2H, m), 3.80 (3H,
s), 4.24 (1H, d, J = 15Hz), 5.04 (1H, d, J = 15Hz), 5.13
(1H, dd, J = 15, 6.4Hz), 6.25 (1H, dd, J = 7.6, 1.4Hz),
6.63 (1H, dt, J _d = 0.5Hz, J _t = 7.6Hz), 6.82 (1H, d, J =
7.4Hz), 6.96 (1H, dd, J = 7.6, 2.0Hz), 7.11-7.34 (3H,
m), 7.38-7.47 (1H, m), 7.47 (1H, dd, J = 8.3, 4.3Hz),
7.62 (1H, dd, J = 8.3, 1.7Hz), 8.90 (1H, dd, J = 4.3, 1.
7Hz).

Reference Example 60 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11,12,14-Octahydro-5- (4-methylphenyl) -6,14-dioxo [1,4] diazonino [2,1-g] [1,7 Naphthyridine The compound obtained in Reference Example 8 was reacted and treated in the same manner as in Reference Example 55, and the title compound was obtained as colorless crystals. Melting point: 177-179 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45-1.95 (4H, m), 2.10 (2
H, m), 2.33 (3H, s), 3.06-3.24 (1H, m), 3.32-3.56 (2
H, m), 3.86 (1H, d, J = 15Hz), 4.95 (1H, dt, Jd = 15Hz,
Jt = 4.8Hz), 5.38 (1H, d, J = 15Hz), 6.86 (1H, dd, J = 8.
0, 1.5Hz), 7.00 (1H, d, J = 8.0Hz), 7.17 (1H, d, J = 8.2
Hz), 7.29 (1H, dd, J = 8.2, 1.5Hz), 7.40-7.54 (2H, m),
7.44 (2H, s), 7.79 (1H, s), 8.89 (1H, dd, J = 3.8, 2.0
Hz).

Reference Example 61 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,12-Hexahydro-6,1
2-Dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 9 was reacted and treated in the same manner as in Reference Example 55. The title compound was obtained as colorless crystals. Melting point: 244-245 ° C. (recrystallized from ethyl acetate-THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.00-2.25 (2H, m), 3.25-3.
70 (3H, m), 4.15 (1H, d, J = 15Hz), 5.30 (1H, d, J = 15H
z), 5.52 (1H, m), 7.05 (1H, d, J = 7.4Hz), 7.3-7.7 (6H,
m), 7.62 (2H, s), 7.84 (1H, s), 8.93 (1H, dd, J = 4.2,
1.6Hz).

Reference Example 62 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-6,1
3-Dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 10, reacted in the same manner as in Reference Example 55, Upon treatment, the title compound was obtained as colorless crystals. Melting point: 205-206 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.70-2.35 (4H, m), 3.18-3.
36 (1H, m), 3.4-3.7 (2H, m), 3.98 (1H, d, J = 15Hz), 5.
14 (1H, dd, J = 14, 5.8Hz), 5.43 (1H, d, J = 15Hz), 6.94
(1H, d, J = 7.3Hz), 7.19 (1H, t, J = 7.3Hz), 7.3-7.6 (5
H, m), 7.44 (2H, s), 7.79 (1H, s), 8.91 (1H, dd, J = 4.
0, 1.8Hz).

Reference Example 63 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-5-
(4-methylphenyl) -6,13-dioxo-13H
-[1,4] diazosino [1,2-b] [2,7] naphthyridine The compound obtained in Reference Example 11 was reacted and treated in the same manner as in Reference Example 55, and the title compound was found to be colorless crystals Was obtained as Melting point: 231-233 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.3 (4H, m), 2.37 (3H,
s), 3.2-3.7 (3H, m), 4.00 (1H, d, J = 15Hz), 5.05 (1H, d
d, J = 15, 6.2Hz), 5.44 (1H, d, J = 15Hz), 6.83 (1H, dd,
J = 7.8, 1.6Hz), 6.98 (1H, d, J = 5.4Hz), 7.04 (1H, d,
J = 7.8Hz), 7.25 (1H, d, J = 7.8Hz), 7.33 (1H, dd, J = 7.
8, 1.6Hz), 7.46 (2H, s), 7.81 (1H, s), 8.64 (1H, d, J =
5.4Hz), 9.68 (1H, s).

Reference Example 64 7- [3,5-bis (trifluoromethyl) benzyl]
-1,2,3,4,6,7,8,9,10,11-Decahydro-2-methyl-5- (4-methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [1,2-b] [2,7] naphthyridine A mixture of the compound obtained in Reference Example 63 (250 mg), iodomethane (3 ml) and ethyl acetate (6 ml). 1.
The mixture was refluxed for 5 hours. After evaporating the solvent, the residue was dissolved in methanol (15 ml). To this solution was added sodium borohydride (50 mg) at 0 ° C with stirring, and the mixture was added at 0 ° C.
After stirring for 1 hour, the mixture was concentrated. . Ethyl acetate was added to the concentrate, washed with water and dried, and the solvent was distilled off. The residue was dissolved in methanol (15 ml), and 10% palladium / carbon (50% water-containing) (100 mg) was added.
Stir at room temperature for 3 hours. The catalyst was filtered off, and the solvent was distilled off from the filtrate. The residue was subjected to column chromatography using silica gel (ethyl acetate → ethyl acetate: methanol =
4: 1) gave the title compound as pale yellow crystals (150 m
g). Melting point: 233-235 ° C. (recrystallized from THF-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.6 (8H, m), 2.31 (3H,
s), 2.47 (3H, s), 3.1-3.8 (5H, m), 3.95 (1H, d, J = 15H
z), 4.93 (1H, dd, J = 14, 6.2Hz), 5.41 (1H, d, J = 15Hz),
6.72 (1H, d, J = 7.8Hz), 6.98 (1H, d, J = 7.8Hz), 7.19
(2H, s), 7.42 (2H, s), 7.78 (1H, s).

Reference Example 65 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide (Reference Example 12)
To a solution of (348 mg) in THF (15 ml) was added sodium hydride (60% oil) (60 mg), and the mixture was stirred under reflux with heating for 2 hours. Ethyl acetate was added to the reaction mixture,
After washing with water and drying, the solvent was distilled off to give the title compound as colorless crystals (278 mg). Melting point: 200-201 ° C (recrystallized from ethanol-hexane) NMR (200MHz, CDCl ₃ ) ppm: 3.70 (2H, t, J = 5.8Hz), 4.4
7 (2H, t, J = 5.8Hz), 4.88 (2H, s), 7.24 (1H, d, J = 5.2H
z), 7.25-7.55 (5H, m), 7.80 (2H, s), 7.86 (1H, s), 8.
44 (1H, d, J = 5.2 Hz) EI-MS m / z: 466 (M ⁺ ) [(C ₂₃ H ₁₆ N ₂ O ₂ F ₆ )
⁺ ].

Reference Example 66 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
2-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine Compound (7
00mg), triethylamine (0.41 ml), methanesulfonyl chloride (0.224 ml) and THF (1
After stirring the mixture at room temperature for 30 minutes, saturated aqueous sodium hydrogencarbonate (15 ml) was added, and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate,
The extract was washed with diluted hydrochloric acid and saturated saline, dried, and the solvent was distilled off. After the residue was dissolved in THF (15 ml), sodium hydride (60% oil) (76 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium carbonate and saturated saline, dried and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol = 9: 1) to give the title compound as colorless crystals (408 mg). Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.05 (3H × 2/3, d, J = 7.0 Hz),
1.22 (3H × 1/3, d, J = 7.0Hz), 2.39 (3H × 1/3, s), 2.42
(3H × 2/3, s), 2.52 (1H, m), 3.0-3.3 (2H, m), 3.48 (1H
× 2/3, dd, J = 14, 4.6Hz), 3.71 (1H × 1/3, dd, J = 16,
5.2Hz), 4.06 (1H × 1/3, d, J = 15Hz), 4.12 (1H × 2/3, d,
J = 15Hz), 5.28-5.65 (2H, m), 6.83 (1H × 1/3, d, J = 7.4
Hz), 6.96 (1H × 2/3, d, J = 7.6Hz), 7.09 (1H × 1/3, d, J
= 7.4Hz), 7.20 (1H × 2/3, d, J = 7.6Hz), 7.35 (2H, m), 7.
42-7.75 (4H, m), 7.83 (1H, s), 8.92 (1H, d, J = 3.6 Hz) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25 , H 4.14, N 7.51 Actual value (%): C 62.00, H 4.08, N 7.24 [α] _D : -60.2 ° (C = 0.348, MeO
H).

Reference Example 67 (9S) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine Reference When the compound obtained in Example 14 was reacted and treated in the same manner as in Reference Example 66, the title compound was obtained as colorless crystals. Melting point: 150-152 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.06 (3H × 2/3, d, J = 7.0 Hz),
1.21 (3H × 1/3, d, J = 7.0Hz), 2.50 (1H, m), 3.05-3.30
(2H, m), 3.49 (1H × 2/3, dd, J = 14, 4.6Hz), 3.72 (1H ×
1/3, dd, J = 16, 5.4Hz), 4.07 (1H × 1/3, d, J = 15Hz),
4.14 (1H × 2/3, d, J = 15Hz), 5.25-5.62 (2H, m), 6.94 (1H
× 1/3, d, J = 7.6Hz), 7.08 (1H × 2/3, d, J = 7.4Hz), 7.2-
7.7 (8H, m), 7.83 (1H, s), 8.93 (1H, dd, J = 4.3, 1.7H
z) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 61.65, H 3.88, N 7.70 Actual (%): C 61.33, H 3.89, N 7.51 [α] _D : + 69.8 ° (C = 0.353, MeO
H).

Reference Example 68 (9S) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
2-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 15 was reacted and treated in the same manner as in Reference Example 66, whereby the title compound was obtained as colorless crystals. Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 66 Elemental analysis: calculated as C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Value (%): C 62.25, H 4.14, N 7.51 Actual value (%): C 61.94, H 4.16, N 7.24 [α] _D : + 58.2 ° (C = 0.353, MeO
H).

Reference Example 69 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo- 5-phenyl-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine To a solution of the compound (830 mg) obtained in Reference Example 16 and triethylamine (0.56 ml) in THF (15 ml) was added methanesulfonyl chloride (0.29 m
l) was added. The mixture was stirred for 50 minutes under ice-cooling, then saturated aqueous sodium hydrogen carbonate (15 ml) was added, and the mixture was further stirred at room temperature for 40 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with diluted hydrochloric acid and saturated saline,
After drying, the solvent was distilled off. After the residue was dissolved in THF (25 ml), sodium hydride (60% oil) (90 m
g) was added, and the mixture was stirred for 1 hour while heating under reflux. The reaction mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium carbonate, and saturated saline, dried, and evaporated to give the title compound as colorless crystals (460 mg). Melting point: 257-258 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.92 (3H, d, J = 6.6 Hz), 1.73
(1H, m), 1.95-2.40 (2H, m), 2.98 (1H, d, J = 15Hz), 3.
30-3.65 (2H, m), 3.97 (1H, d, J = 15Hz), 5.11 (1H, dd,
J = 14, 5.9Hz), 5.43 (1H, d, J = 15Hz), 6.93 (1H, d, J =
7.6Hz), 7.19 (1H, dd, J = 7.6, 7.0Hz), 7.3-7.6 (7H, m),
7.81 (1H, s), 8.91 (1H, dd, J = 4.0, 2.0 Hz) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Value (%): C 61.93, H 4.05, N 7.57.

Reference Example 70 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methyl Phenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 17 was reacted and treated in the same manner as in Reference Example 69, whereby the title compound was obtained as colorless crystals. Melting point: 280-281 ° C. (recrystallized from ethyl acetate-THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3H, d, J = 6.8 Hz), 1.73
(1H, m), 1.95-2.40 (2H, m), 2.37 (3H, s), 2.97 (1H,
d, J = 15Hz), 3.35-3.62 (2H, m), 3.99 (1H, d, J = 15Hz),
5.10 (1H, dd, J = 14, 5.3Hz), 5.46 (1H, d, J = 15Hz),
6.83 (1H, dd, J = 7.8, 1.6Hz), 7.05 (1H, d, J = 7.8Hz),
7.25 (1H, d, J = 7.8Hz), 7.34 (1H, dd, J = 7.8, 1.6Hz),
7.46 (1H, dd, J = 8.4, 4.2Hz), 7.47 (2H, s), 7.55 (1H,
dd, J = 8.4,1.8Hz), 7.81 (1H, s), 8.91 (1H, dd, J = 4.2,
1.8 Hz) Elemental analysis: Calculated _{C 30 H 25 N 3 O 2} F 6 (%): C 62.83, H 4.39, N 7.33 Found (%): C 62.61, H 4.21, N 7.12.

Reference Example 71 (9R) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-funyl-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The compound obtained in Reference Example 18 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 245-247 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 69 [α] _D : + 133.8 ° (C = 0.51) MeOH) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Found (%): C 62.13, H 4.13, N 7.40.

Reference Example 72 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine The compound obtained in Reference Example 19 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 226-228 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 70 [α] _D : + 109.4 ° (C = 0.541, MeO
H) Elemental analysis: C ₃₀ H ₂₅ N ₃ O ₂ F ₆ Calculated (%): C 62.83, H 4.39, N 7.33 Actual (%): C 62.55, H 4.56, N 7.10.

Reference Example 73 (9S) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-funyl-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The compound obtained in Reference Example 20 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 242-244 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 69 [α] _D : -130.4 ° (C = 0.496) , MeO
H) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Actual (%): C 62.07, H 4.15, N 7.36.

Reference Example 74 (9S) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine The compound obtained in Reference Example 21 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 227-228 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 70 [α] _D : -107.1 ° (C = 0.521) , MeO
H) Elemental analysis: Calculated _{C 30 H 25 N 3 O 2} F 6 (%): C 62.83, H 4.39, N 7.33 Found (%): C 62.55, H 4.40, N 7.13.

Reference Example 75 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenyl-1H-pyrido [2,3-e] [1,4] diazepine The compound obtained in Reference Example 22 (370 mg), anhydrous potassium carbonate ( A mixture of 200 mg) and xylene (10 ml) was stirred for 9 hours while heating under reflux. After cooling the reaction mixture, water was added and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals. Melting point: 242-243 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.60-3.80 (4H, m), 4.81 (2H,
s), 4.86 (1H, s), 6.87 (1H, d, J = 5.2Hz), 7.30-7.50 (6
H, m), 7.79 (2H, s), 7.85 (1H, s), 8.21 (1H, d, J = 5.2H
z) Elemental analysis: Calculated _{C 23 H 17 N 3 OF 6} (%): C 59.36, H 3.68, N 9.03 Found (%): C 59.24, H 3.66, N 9.06 EI-MS m / z: 465 (M ⁺ ) [(C ₂₃ H ₁₇ N ₃ OF ₆ )
⁺ ].

Reference Example 76 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 23, The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 188-189 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.65-1.88 (1H, m), 2.18-2.
45 (1H, m), 3.36 (1H, dd, J = 15.2Hz), 3.73 (1H, m), 4.1
7 (1H, d, J = 15.2Hz), 4.32 (1H, dt, J = 12.6,3.6Hz), 4.
67 (1H, ddd, J = 12.6, 5.6, 2.4Hz), 5.50 (1H, d, J = 15.
2Hz), 7.16 (1H, d, J = 5.2Hz), 7.20-7.45 (5H, m), 7.71
(2H, s), 7.83 (1H, s), 8.41 (1H, d, J = 5.2 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₂ F ₆ Calculated (%): C 60.00, H 3.78 , N 5.83 Found (%): C 59.92, H 3.76, N 5.89.

Reference Example 77 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-7-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Using the compound obtained in Reference Example 24, Reference Example 65 The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 179-181 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.13 (3H, s), 3.57 (2H, t,
J = 5.8Hz), 4.42 (2H, t, J = 5.8Hz), 4.80 (2H, s), 7.16
(2H, m), 7.47 (3H, m), 7.65 (2H, s), 7.81 (1H, s), 8.3
2 (1H, s).

Reference Example 78 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin The compound obtained in Reference Example 25 was reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. Melting point: 180-182 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.71 (1H, m), 2.07 (3H, m),
2.28 (1H, m), 3.24 (1H, dd, J = 15.2, 3.8Hz), 3.64 (1
H, dd, J = 15.2, 12.0Hz), 4.05 (1H, d, J = 15.6Hz), 4.2
7 (1H, dt, J = 12.6, 3.8Hz), 4.63 (1H, ddd, J = 12.6, 5.
4, 2.0Hz), 5.45 (1H, d, J = 15.6Hz), 7.38 (5H, m), 7.5
4 (2H, s), 7.78 (1H, s), 8.29 (1H, s)

Reference Example 79 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-9-hydroxy-5- (4-methyl Phenyl) -6
12-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 26 was reacted and treated in the same manner as in Reference Example 56, and the title compound was obtained as colorless crystals. Melting point: 282-283 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H, s), 3.35-3.63 (3H,
m), 4.02 (1H × 3/8, d, J = 3.5Hz, -OH), 4.21 (1H × 3/8,
d, J = 15Hz), 4.30 (1H × 5/8, d, J = 3.5Hz, -OH), 4.38 (1
H × 5/8, d, J = 15Hz), 4.60 (1H, m), 5.24 (1H × 3/8, d,
J = 15Hz), 5.61 (1H × 5/8, d, J = 15Hz), 5.68 (1H, m), 6.
92 (1H, t-like, J = 3.8Hz), 7.19-7.86 (8H, m), 8.95 (1
(H, d, J = 4 Hz) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₃ F ₆ .1 / 4H ₂ O Calculated (%): C 59.42, H 3.83, N 7.42 Actual (%): C 59.45, H 3.74, N 7.39 EI-MS m / z: 561 (M ⁺ ) [(C ₂₈ H ₂₁ N ₃ O ₃ F ₆
) ⁺ ].

Reference Example 80 7-benzyl-6,7,8,9,10,12-hexahydro-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7 Naphthyridine The compound obtained in Reference Example 27 was reacted with 3-amino-1-propanol in the same manner as in Reference Example 13 and treated to give 7-benzyl-7,8-dihydro-7-.
(3-Hydroxypropyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared. When this compound was reacted and treated in the same manner as in Reference Example 12, the title compound was obtained as colorless crystals. Melting point: 210-212 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.2 (2H, m), 3.2-3.6 (3
H, m), 4.30 (1H, d, J = 14Hz), 4.89 (1H, d, J = 14Hz),
5.43 (1H, dd, J = 14, 5.7Hz), 7.0-7.7 (11H, m), 7.70 (1
H, dd, J = 8.4, 1.6Hz), 8.92 (1H, dd, J = 4.4, 1.6Hz).

Reference Example 81 7-benzyl-6,7,8,9,10,11-hexahydro-6,13-dioxo-5-phenyl-13H-
[1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 27 and 4-amino-1-butanol were reacted and treated in the same manner as in Reference Example 16. 7-
Benzyl-7,8-dihydro-7- (4-hydroxybutyl) -8-oxo-5-phenyl-6-pyrido [3,
4-b] Pyridinecarboxamide was prepared, reacted with this compound in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. Melting point: 243-244 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.3 (4H, m), 3.15 (1H,
m), 3.35-3.65 (2H, m), 3.76 (1H, d, J = 15Hz), 5.15 (1
H, dd, J = 14, 5.7Hz), 5.42 (1H, d, J = 15Hz), 6.64 (2H,
d, J = 6.2Hz), 7.0-7.3 (4H, m), 7.3-7.7 (6H, m), 8.91
(1H, dd, J = 4.2,1.8Hz).

Reference Example 82 7-benzyl-6,7,8,9,10,11,12,1
4-octahydro-6,14-dioxo-5-phenyl [1,4] diazonino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 27 and 5-amino-1-pentanol And reacted and treated in the same manner as in Reference Example 16
-Benzyl-7,8-dihydro-7- (5-hydroxypentyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, and this compound was used in Reference Example 69. The title compound was obtained as colorless crystals after treatment. Melting point: 224-226 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.9 (4H, m), 2.09 (2H,
m), 2.85-3.05 (1H, m), 3.15-3.40 (1H, m), 3.50 (1H, d
t, Jd = 15Hz, Jt = 6.4Hz), 3.64 (1H, d, J = 15Hz), 4.97 (1
H, dt, Jd = 15Hz, Jt = 4.8Hz), 5.48 (1H, d, J = 15Hz), 6.
43 (2H, d, J = 7.2Hz), 7.05-7.25 (4H, m), 7.3-7.7 (6H,
m), 8.91 (1H, dd, J = 4.2, 1.8Hz).

Reference Example 83 7- (3,4-Dichlorobenzyl) -6,7,8,9,
10,12-hexahydro-6,12-dioxo-5-
Phenyl [1,4] diazepino [2,1-g] [1,
7] Naphthyridine Using the compound obtained in Reference Example 28 and 3-amino-1-propanol, reacting and treating in the same manner as in Reference Example 13
-(3,4-dichlorobenzyl) -7,8-dihydro-
7- (3-Hydroxypropyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, reacted with this compound and treated in the same manner as in Reference Example 66. The title compound was obtained as colorless crystals. Melting point: 224-226 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.9-2.3 (2H,
m), 3.2-3.6 (3H, m), 4.01
(1H, d, J = 15 Hz), 5.05 (1H,
d, J = 15 Hz), 5.49 (1H, dd,
J = 13, 5.0 Hz), 6.9-7.1 (2
H, m), 7.25 (1H, m), 7.38 (1
H, d, J = 8.6 Hz), 7.3-7.8 (6
H, m), 8.93 (1H, d, J = 4.0H)
z).

Reference Example 84 7- (3,4-Dichlorobenzyl) -6,7,8,9,
10,11-Hexahydro-6,13-dioxo-5-
Phenyl-13H- [1,4] diazosino [2,1-
g] [1,7] naphthyridine The compound obtained in Reference Example 28 and 4-amino-1-butanol were reacted and treated in the same manner as in Reference Example 16 to give 7-.
(3,4-dichlorobenzyl) -7,8-dihydro-7
-(4-Hydroxybutyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, and reacted with this compound in the same manner as in Reference Example 15 to give the title compound. The compound was obtained as colorless crystals. Melting point: 236-238 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.
7-2.3 (4H, m), 3.14 (1H, m), 3.39-3.60 (2H, m) 3.70 (1
H, d, J = 15Hz), 5.14 (1H, dd, J = 15, 5.9Hz), 5.35 (1H,
d, J = 15Hz), 6.35 (1H, dd, J = 8.4, 2.0Hz), 7.02 (2H,
m), 7.18 (1H, d, J = 8.4Hz), 7.3-7.6 (6H, m), 8.91 (1H,
dd, J = 4.0, 1.8Hz).

Reference Example 85 (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl- 6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 29, reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. . Melting point: 147-148 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 7.4 Hz), 2.0
7 (3H, s), 2.39 (1H, m), 2.97 (1H, d, J = 15.4Hz), 3.48
(1H, m), 3.87 (1H, dd, J = 10.4, 12.4Hz), 4.06 (1H, d,
J = 15.6Hz), 4.59 (1H, dd, J = 5.2, 12.4Hz), 5.44 (1H,
d, J = 15.4Hz), 7.37 (5H, s), 7.53 (2H, s), 7.78 (1H,
s), 8.29 (1H, s) Elemental analysis: C ₂₆ H ₂₂ N ₂ O ₂ F ₆ Calculated (%): C 61.42, H 4.36, N 5.51 Actual (%): C 61.30, H 4.52, N 5.70 [α] _D ²⁰ : -106.8 ° (C = 0.257, CHC
l ₃ ).

Reference Example 86 (R) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl- 6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 30, reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. . Melting point: 147-149 ° C. (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of Reference Example 85 Elemental analysis: C ₂₆ H ₂₂ N ₂ O ₆ Calculated (%): C 61.42, H 4.36, N 5.51 Actual measured value (%): C 61.26, H 4.33, N 5.69 [α] _D ²⁰ : + 102.5 ° (C = 0.573, CHC
l ₃ ).

Reference Example 87 4- [3,5-bis (trifluoromethyl) benzyl]
Reference Example 6 using the compound obtained in Reference Example 31, -2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine
The reaction and reaction were conducted in a similar manner to 5 to give the title compound as colorless crystals. Melting point: 151-153 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.58 (3H, s), 3.69 (2H, t,
J = 5.4Hz), 4.47 (2H, t, J = 5.4Hz), 4.87 (2H, s), 7.11
(1H, s), 7.17-7.56 (5H, m), 7.80 (2H, s), 7.86 (1H,
s) Elemental _{analysis: C 24 H 18 N 2 O} 2 F 6 · 1/4 H 2 O Calculated (%): C 59.44, H 3.85, N 5.78 Found (%): C 59.42 , H 3.82, N 5.84.

Reference Example 88 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin The compound obtained in Reference Example 32 was reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. Melting point: 164-165 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.79 (1H, m), 2.30 (1H, m),
2.56 (3H, s), 3.35 (1H, m), 3.77 (1H, m), 4.14 (1H,
d, J = 15.2Hz), 4.31 (1H, m), 4.65 (1H, m), 5.49 (1H,
d, J = 15.2Hz), 7.02 (1H, s), 7.20-7.50 (5H, m), 7.72
(2H, s), 7.83 (1H, s) Elemental analysis: C ₂₅ H ₂₀ N ₂ O ₂ F ₆ Calculated (%): C 60.73, H 4.08, N 5.67 Actual (%): C 60.43, H 4.04, N 5.74.

Reference Example 89 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-Tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine 9-oxide Compound obtained in Reference Example 87 (1.20 g) M-chloroperbenzoic acid (870 m
g) was added and the mixture was stirred at room temperature for 20 hours. Evaporate the solvent,
Aqueous potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium carbonate, dried, and the solvent was distilled off to give the title compound as colorless crystals (1.1
0 g). Melting point: 181-183 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.62 (3H, s),
3.72 (2H, m), 4.65 (2H,
m), 4.89 (2H, s), 7.18 (1H,
s), 7.20-7.50 (5H, m), 7.
79 (2H, s), 7.87 (1H, s) Elemental _analysis: Calculated _{C 24 H 18 N 2 O 3} F 6 (%): C 57.03, H 3.79, N 5.54 Found (%): C 57.15, H 3.77, N 5.16

Reference Example 90 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5, -tetrahydro-9-methyl-6-
Oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin 10-oxide Using the compound obtained in Reference Example 88, the reaction was carried out in the same manner as in Reference Example 89, and the title compound was obtained as colorless crystals (727 mg). Melting point: 116-118 ° C (recrystallized from ethanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60-1.82 (1H, m), 2.42 (1H,
m), 2.61 (3H, s), 3.43 (1H, dd, J = 6.0, 17.0Hz), 3.8
1 (1H, m), 4.18 (1H, d, J = 15.4Hz), 4.25 (1H, m), 4.78
(1H, dd, J = 5.2, 12.6Hz), 5.52 (1H, d, J = 15.4Hz), 7.
16 (1H, s), 7.18-7.50 (5H, m), 7.72 (2H, s), 7.84 (1H,
s) Elemental analysis: C ₂₅ H ₂₀ N ₂ O ₃ .1 / 4 H ₂ O Calculated (%): C 58.31, H 4.01, N 5.44 Actual (%): C 58.17, H 4.38, N 5.31 .

Reference Example 91 8-acetoxymethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido- [3,2- f]
[1,4] oxazepine A mixture of the compound (939 mg) obtained in Reference Example 89 and acetic anhydride (25 ml) was heated under reflux for 20 minutes. The solvent was distilled off, an aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (740 mg). Melting point: 122-124 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.18 (3H, s), 3.71 (2H, t, J
= 5.6Hz), 4.50 (2H, t, J = 5.6z), 4.88 (2H, s), 5.21 (2H,
s), 7.18-7.50 (6H, m), 7.79 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₀ N ₂ O ₄ F ₆ Calculated (%): C 58.00, H 3.74, N 5.20 Found (%): C 57.60, H 4.02, N 5.09.

Reference Example 92 9-acetoxymethyl-5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido [2 , 3
-B] [1,5] oxazosin Using the compound obtained in Reference Example 90, the reaction was carried out in the same manner as in Reference Example 91, and the title compound was obtained as colorless crystals (479 mg). Melting point: 156-157 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60-1.95 (1H, m), 2.00-2.2
0 (1H, m), 2.17 (3H, s), 3.36 (1H, m), 3.75 (1H, m),
4.14 (1H, d, J = 15.2Hz), 4.31 (1H, m), 4.61 (1H, m),
5.20 (2H, s), 5.48 (1H, d, J = 15.2Hz), 7.18 (1H, s),
7.20-7.50 (5H, m), 7.70 (2H, s), 7.83 (1H, s) Elemental analysis: C ₂₇ H ₂₂ N ₂ O ₄ F ₆ Calculated (%): C 58.70, H 4.01, N 5.07 Found (%): C 58.81, H 4.11, N 5.17.

Reference Example 93 4- [3,5-bis (trifluoromethyl) benzyl]
-8-Chloromethyl-2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine Phosphorus oxychloride (1.24 ml) and triethylamine (1.85 m) were added to a solution of the compound (4.40 g) obtained in Reference Example 89 in dichloromethane (100 ml) at room temperature with stirring.
l) was added dropwise at the same time. After the mixture was refluxed for 1 hour, the solvent was distilled off. Aqueous potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate-THF. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (1.
44g). Melting point: 183-184 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.73 (2H, t, J = 5.4 Hz), 4.51
(2H, t, J = 5.4Hz), 4.66 (2H, s), 4.89 (2H, s), 7.27 (1
H, s), 7.30-7.55 (5H, m), 7.81 (2H, s), 7.88 (1H, s) Elemental analysis: C ₂₄ H ₁₇ N ₂ O ₂ F ₆ Cl Calculated (%): C 55.99, H 3.33, N 5.44 Found (%): C 55.75, H 3.53, N 5.27.

Reference Example 94 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine The compound (151 mg) obtained in Reference Example 93, THF (2 m
l), a mixture of methanol (1 ml) and a 28% sodium methoxide-methanol solution (1 ml) was stirred at room temperature for 2 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (118 mg). Melting point: 139-140 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.51 (3H, s), 3.71 (2H, t, J =
5.6Hz), 4.49 (2H, t, J = 5.6Hz), 4.58 (2H, s), 4.89 (2H,
s), 7.27 (1H, s), 7.30-7.52 (5H, m), 7.81 (2H, s),
7.87 (1H, s) Elemental _{analysis: C 25 H 20 N 2 O} 3 F 6 Calculated (%): C 58.83, H 3.95, N 5.49 Found (%): C 58.73, H 3.95, N 5.57.

Reference Example 95 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- (1-methylethyloxy) -5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine The compound obtained in Reference Example 93 (150 mg), THF (1 m
l), a mixture of isopropanol (10 ml) and sodium hydride (60% oil) (120 mg) was stirred at room temperature for 3 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-ethyl acetate = 1: 1),
Purification provided the title compound as colorless crystals (74 mg). Melting point: 134-136 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 1.26 (6H, d, J = 6.0 Hz), 3.60-
3.90 (3H, m), 4.48 (2H, t, J = 5.4Hz), 4.63 (2H, s), 4.
89 (2H, s), 7.27 (1H, s), 7.30-7.55 (5H, m), 7.81 (2H,
s), 7.87 (1H, s) Elemental analysis: C ₂₇ H ₂₄ N ₂ O ₃ F ₆ Calculated (%): C 60.22, H 4.49, N 5.20 Actual (%): C 60.00, H 4.61, N 5.07.

Reference Example 96 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methylthiomethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine A mixture of the compound obtained in Reference Example 93 (125 mg), methanol (5 ml), and a 15% aqueous solution of sodium methylmercaptan (1 ml) was stirred at room temperature for 10 minutes.
The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (103 mg). Melting point: 165-166 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.14 (3H, s),
3.72 (2H, t, J = 5.4 Hz), 3.7
9 (2H, s), 4.49 (2H, t, J = 5.
4Hz), 4.89 (2H, s), 7.30-
7.50 (5H, m), 7.34 (1H, s),
7.81 (2H, s), 7.87 (1H, s) Elemental _{analysis: C 25 H 20 N 2 O} 2 SF 6 · 1/6 H 2 O Calculated (%): C 56.71, H 3.87 , N 5.29 Found (%): C 56.67, H 3.87, N 5.23.

Reference Example 97 8-Aminomethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine The compound obtained in Reference Example 93 (500 mg), THF (10
mixture) and 25% aqueous ammonia (10 ml) were heated in a sealed tube at 120 ° C. for 1 hour. After cooling, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (443 mg). Melting point: 188-191 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.71 (2H, t, J = 5.6 Hz), 4.00
(2H, s), 4.50 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.20-7.
60 (6H, m), 7.81 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₄ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 58.19, H 3.87, N 8.48 Value (%): C 58.36, H 3.81, N 8.00.

Reference Example 98 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methylaminomethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine A mixture of the compound (150 mg) obtained in Reference Example 93 and a 40% methylamine-methanol solution (10 ml) was stirred at room temperature for 30 minutes. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with water and dried,
The solvent was distilled off to give the title compound as colorless crystals (115 m
g). Melting point: 152-154 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.50 (3H, s), 3.70 (2H, t, J =
5.6Hz), 3.89 (2H, s), 4.48 (2H, t, J = 5.6Hz), 4.88 (2H, s)
s), 7.22-7.50 (6H, m), 7.80 (2H, s), 7.86 (1H, s) Elemental analysis: C ₂₅ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 58.94, H 4.15, N 8.25 Found (%): C 58.71, H 4.25, N 8.35.

Reference Example 99 4- [3,5-bis (trifluoromethyl) benzyl]
-8-dimethylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine THF (3m) of the compound (150 mg) obtained in Reference Example 93
l) Dimethylamine (1 ml) was added to the solution,
Stirred for 0 minutes. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (128 mg). Melting point: 186-188 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.33 (6H, s), 3.60 (2H, s),
3.71 (2H, t, J = 5.6Hz), 4.49 (2H, t, J = 5.6Hz), 4.89 (2
H, s), 7.26 (1H, s), 7.30-7.50 (5H, m), 7.81 (2H, s),
7.86 (1H, s) Elemental analysis: C ₂₆ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 59.66, H 4.43, N 8.03 Found (%): C 59.43, H 4.49, N 7.84.

Reference Example 100 4- [3,5-bis (trifluoromethyl) benzyl]
-8-Cyclopropylaminomethyl-2,3,4,5-
Tetrahydro-5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine THF (10 mg) of the compound (155 mg) obtained in Reference Example 93
ml) solution, cyclopropylamine (0.5 ml) was added, and the mixture was heated under reflux with stirring for 15 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography on silica gel (ethyl acetate: methanol = 9: 1), separated and purified to give the title compound as colorless crystals (127 mg). Melting point: 129-131 ° C. (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 0.44 (4H, m), 2.19 (1H, m),
3.69 (2H, t, J = 5.6Hz), 3.97 (2H, s), 4.48 (2H, t, J =
5.6Hz), 4.87 (2H, s), 7.25 (1H, s), 7.26-7.55 (5H,
m), 7.79 (2H, s), 7.86 (1H, s). Elemental analysis: C ₂₇ H ₂₃ N ₃ O ₂ F ₆ .1 / 6 H ₂ O Calculated (%): C 60.22, H 4.37, N 7.80 Actual (%): C 59.98, H 4.40, N 7.85 .

Reference Example 101 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-Tetrahydro-8- (N-methylpiperazinomethyl) -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine The compound obtained in Reference Example 93 (150 mg) in THF (1 m
l) N-Methylpiperazine (1 ml) was added to the solution, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract is washed with water and dried,
The solvent was distilled off to give the title compound as colorless crystals (105 m
g). Melting point: 181-182 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.30 (3H, s), 2.48 (4H, br),
2.59 (4H, br), 3.68 (2H, s), 3.71 (2H, t, J = 5.6Hz),
4.48 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.27 (1H, s), 7.
30-7.50 (5H, m), 7.81 (2H, m), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₈ N ₄ O ₂ F ₆ Calculated (%): C 60.20, H 4.88, N 9.68 Found (%): C 59.96, H 5.00, N 9.51.

Reference Example 102 8-Acetylaminomethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine Compound (150 mg) obtained in Reference Example 97 was treated with pyridine (3
Acetic anhydride (1 ml) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with 1N hydrochloric acid and water, then dried,
The solvent was distilled off to give the title compound as colorless crystals (113 m
g). Melting point: 223-224 ° C. (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.07 (3H, s), 3.72 (2H, t, J)
= 5.4Hz), 4.49 (2H, t, J = 5.4Hz), 4.56 (2H, d, J = 5.4H)
z), 4.88 (2H, s), 6.62 (1H, br), 7.21 (1H, s), 7.22-
7.55 (5H, m), 7.80 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₁ N ₃ O ₃ F ₆ Calculated (%): C 58.10, H 3.94, N 7.82 Values (%): C 58.06, H 3.97, N 7.99.

Reference Example 103 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methanesulfonylaminomethyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine THF of the compound (150 mg) obtained in Reference Example 97 (5m
l) Triethylamine (0.085 ml) and methanesulfonyl chloride (0.050 ml) were added to the solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with aqueous potassium carbonate and water, dried, and evaporated to give the title compound as colorless crystals (108 mg). Melting point: 194-195 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.99 (3H, s), 3.72 (2H, t, J)
= 5.4Hz), 4.44 (2H, d, J = 6.0Hz), 4.48 (2H, t, J = 5.4H)
z), 4.88 (2H, s), 5.55 (1H, t, J = 6.0Hz), 7.26 (1H,
s), 7.27-7.50 (5H, m), 7.80 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₅ H ₂₁ N ₃ O ₄ SF ₆ · 1/2 H ₂ O Calculated ( %): C 51.55, H 3.80, N 7.21 Actual values (%): C 51.43, H 3.78, N 7.07.

Reference Example 104 6- [3,5-bis (trifluoromethyl) benzyl]
-5,6,7,8,9,10-Hexahydro-3,9-
Dimethyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazosin THF (15 mg) of the compound (370 mg) obtained in Reference Example 33
ml) solution and triethylamine (0.42 m
l) and methanesulfonyl chloride (0.24 ml) were added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (15 ml) was added to the reaction solution, and the mixture was further stirred at room temperature for 40 minutes, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and saturated saline, dried, and the solvent was distilled off. The residue was dissolved in THF (30 ml), sodium hydride (60% oil) (84 mg) was added, and the mixture was heated under reflux for 40 minutes. The reaction mixture was diluted with ethyl acetate, diluted with hydrochloric acid,
The extract was washed with aqueous sodium carbonate and saturated saline, dried and evaporated to give the title compound as colorless crystals (213 mg). Melting point: 203-205 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.72 (1H, dd, J = 15, 7.2Hz),
2.18 (3H, s), 2.75 (1H, m), 3.04 (3H, s), 3.54 (3H,
m), 4.09 (1H, dd, J = 14, 7.2Hz), 7.2-7.6 (5H, m), 7.48
(2H, s), 7.74 (1H, s), 8.69 (1H, s) Elemental analysis: C ₂₆ H ₂₁ N ₃ O ₂ F ₆ .0.2 H ₂ O Calculated (%): C 59.48, H 4.11 , N 8.00 Found (%): C 59.39, H 4.13, N 7.83 EI-MS m / s: 521 (M ⁺ ) [(C ₂₆ H ₂₁ N ₃
O ₂ F ₆₎ ^+].

Reference Example 105 6- [3,5-bis (trifluoromethyl) benzyl]
-5,6,7,8,9,10-Hexahydro-9-methyl-5,10-dioxo-4-phenylpyrido [2,3
-F] [1,4] diazocine Using the compound obtained in Reference Example 34, and reacting and treating in the same manner as in Reference Example 104, the title compound was obtained as colorless crystals. Melting point: 167-169 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.05 (1H, m), 2.87 (1H, m),
3.10 (3H, s), 3.36 (1H, d, J = 14Hz), 3.48 (1H, d, J = 1
4Hz), 3.97 (1H, m), 4.26 (1H, dd, J = 15, 7.1Hz), 7.35
(3H, m), 7.53 (5H, m), 7.71 (1H, s), 8.81 (1H, d, J =
5.0 Hz) Elemental analysis: C ₂₅ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 59.18, H 3.77, N 8.28 Actual (%): C 58.90, H 3.81, N 8.05.

Reference Example 106 6-benzyl-5,6,7,8,9,10-hexahydro-3,9-dimethyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4 Diazosin Using the compound obtained in Reference Example 35 and methylamine, reacting and treating in the same manner as in Step 4 of Reference Example 33 to give N-benzyl-N- (2-hydroxyethyl) -5-methyl-2- Methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide was prepared and this compound was used to prepare Reference Example 10.
Reaction and treatment as in 4 gave the title compound as colorless crystals. Melting point: 183-184 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.46 (1H, dd, J = 15, 8.1H)
z), 2.17 (3H, s), 2.69 (1H, m), 3.02 (3H, s), 3.27 (1
H, d, J = 13Hz), 3.44 (1H, d, J = 13Hz), 3.56 (1H, m), 4.
00 (1H, m), 7.01 (2H, m), 7.2-7.6 (8H, m), 8.68 (1H, m
s) Elemental analysis: calculated as C ₂₄ H ₂₃ N ₃ O ₂ Calculated (%): C 74.78, H 6.01, N 10.90 Found (%): C 74.52, H 6.13, N 10.82.

Reference Example 107 6- [3,5-bis (trifluoromethyl) benzyl]
-9-ethyl-5,6,7,8,9,10-hexahydro-3-methyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazocine Step of Reference Example 33 Using the compound obtained in Step 3 and ethylamine, the reaction was carried out in the same manner as in Step 4 of Reference Example 33, followed by treatment to give N-
[3,5-bis (trifluoromethyl) benzyl] -2
-Ethylaminocarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide was prepared, reacted with this compound in the same manner as in Reference Example 104, and treated to give the title compound. Obtained as colorless crystals. Melting point: 228-229 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.33 (3H, t, J = 7.0Hz), 1.5
1 (1H, dd, J = 15, 7.6Hz), 2.18 (3H, s), 2.72 (1H, m),
3.39 (1H, m), 3.42 (1H, d, J = 14Hz), 3.57 (1H, d, J = 14H
z), 3.57 (1H, m), 3.77 (1H, m), 4.03 (1H, dd, J = 15,
7.6Hz), 7.2-7.6 (5H, m), 7.48 (2H, s), 7.74 (1H, s),
8.69 (1H, s) Elemental analysis: C ₂₇ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 60.56, H 4.33, N 7.85 Found (%): C 60.28, H 4.51, N 7.65.

Reference Example 108 6- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-3,1
0-dimethyl-5,11-dioxo-4-phenyl-5
H-pyrido [2,3-g] [1,5] diazonine The compound obtained in Reference Example 36 was reacted and treated in the same manner as in Reference Example 104, and the title compound was obtained as colorless crystals. Melting point: 247-249 ° C. (recrystallized from THF-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.2-1.4 (1H, m), 1.8-2.3 (1
H, m), 2.15 (3H, s), 3.0-3.6 (4H, m), 3.04 (3H, s), 3.
91 (1H, d, J = 15Hz), 5.32 (1H, d, J = 15Hz), 7.0-7.5 (7
H, m), 7.75 (1H, s), 8.59 (1H, s) Elemental analysis: C ₂₇ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 60.56, H 4.33, N 7.85 Actual measurement ( %): C 60.41, H 4.46, N 7.87 EI-MS m / s: 535 (M ⁺ ) [(C ₂₇ H ₂₃ N ₃
O ₂ F ₆₎ ^+].

Reference Example 109 4- [3,5-bis (trifluoromethyl) benzyl]
-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine 8-acetoxymethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f ]
[1,4] oxazepine (Reference Example 91) (4.51)
g), ethanol (50 ml) and 4N-NaOH
(50 ml) was stirred at room temperature for 1.5 hours. The solvent was distilled off, and water was added to the residue. The pH of the mixture was adjusted to about 8 using dilute hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (4.10 g). Melting point: 199-201 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.10 (1H, b), 3.71 (2H, t, J
= 5.6Hz), 4.50 (2H, t, J = 5.6Hz), 4.78 (2H, s), 4.88 (2
H, .s), 7.20-7.50 (6H, m), 7.80 (2H, m), 7.87 (1H, s)

Reference Example 110 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8-carboxylic acid 4- [3,5-bis (trifluoromethyl) Benzyl] -8-hydroxymethyl-2,
3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (Reference Example 109) (3.49 g), 2N-NaOH (100 m
l) and a mixture of potassium permanganate (2.22 g) was stirred at room temperature for 45 hours. A saturated aqueous solution of sodium thiosulfate (10 ml) was added to the reaction mixture, and the pH was adjusted to about 3 using hydrochloric acid, followed by extraction with ethyl acetate-THF (1: 2). The extract was washed with brine, dried, and evaporated to give the title compound as colorless crystals (2.74 g). Melting point: 199-123 ° C (recrystallized from methanol-ethyl ether) NMR (200 MHz, DMSO-d6) ppm: 3.94 (2H, b), 4.46 (2H,
b), 4.91 (2H, s), 7.25-7.55 (5H, m), 7.90 (1H, s), 8.
06 (2H, s), 8.12 (1H, s)

Reference Example 111 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
8-carboxamide 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
8-carboxylic acid (Reference Example 110) (220 mg), TH
A mixture of F (15 ml), DMF (catalytic amount) and thionyl chloride (0.087 ml) was stirred under superheated reflux for 2.5 hours. The solvent was distilled off, and the residue was washed with THF (10 ml).
Was dissolved. Aqueous ammonia (2 ml) was added to the solution, the mixture was stirred at room temperature for 1 hour, and the solvent was concentrated. Water was added to the concentrate and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (163 mg). Melting point: 221-222 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.74 (2H, t, J = 5.6 Hz), 4.50
(2H, t, J = 5.6Hz), 4.92 (2H, s), 5.80 (1H, b), 7.30-
7.55 (6H, m), 7.83 (2H, s), 7.89 (1H, s), 8.20 (1H, s)

The compound of Reference Example 112-117 was 4-
[3,5-bis (trifluoromethyl) benzyl]-
2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8-carboxylic acid (Reference Example 110) is converted to a substituted amine via an acid chloride. (Methylamine, dimethylamine, n-butylamine, piperidine, morpholine, 1-methylpiperazine)
And a reaction was carried out in the same manner as in Reference Example 111, and the mixture was treated. The physicochemical data is described below. Reference Example 112 4- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8-carboxamide Melting point: 145 ° C. (decomposition) (THF-ethyl Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.04 (3H, d, J = 5.2 Hz), 3.73
(2H, t, J = 5.4Hz), 4.48 (2H, t, J = 5.4Hz), 4.09 (2H,
s), 7.25-7.60 (5H, m), 7.65-7.95 (1H, b), 7.81 (2H,
s), 7.87 (1H, s), 8.17 (1H, s)

Reference Example 113 4- [3,5-bis (trifluoromethyl) benzyl]
-N, N-dimethyl-2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine-8-carboxamide Melting point: 235-236 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.11 (3H, s), 3.15 (3H, s),
3.72 (2H, t, J = 5.6Hz), 4.47 (2H, t, J = 5.6Hz), 4.90 (2
H, s), 7.25-7.50 (5H, m), 7.60 (1H, s), 7.82 (2H, s),
7.88 (1H, s)

Reference Example 114 4- [3,5-bis (trifluoromethyl) benzyl]
-N-n-butyl-2,3,4,5-tetrahydro-5
-Oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine-8-carboxamide Melting point: 194-196 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.96 (3H, t, J
= 7.2 Hz), 1.20-1.80 (6H,
m), 4.78 (2H, m), 3.73 (2H,
t, J = 5.6 Hz), 4.49 (2H, t,
J = 5.6 Hz), 4.91 (2H, s),
7.30-7.58 (5H, m), 7.82 (2
H, s), 7.88 (1H, s), 8.18
(1H, s)

Reference Example 115 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenyl-8-piperidinocarbonylpyrido [3,2-
f] [1,4] oxazepine Melting point: 218-220 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60
(2H, b), 1.69 (4H, b), 3.44 (2H, t, J = 5.6Hz), 3.72 (4
H, m), 4.46 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.20-7.6
0 (6H, m), 7.81 (2H, s), 7.87 (1H, s)

Reference Example 116 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-morpholinocarbonyl-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine Melting point: 265-266 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.55-3.90 (10H, m), 4.46 (2
(H, t, J = 5.6Hz), 4.89 (2H, s), 7.25-7.52 (5H, m), 7.5
9 (1H, s), 7.81 (2H, s), 7.88 (1H, s)

Reference Example 117 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- [1- (4-methylpiperazinyl) carbonyl] -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 196 -198 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.35 (3H, s), 2.45 (2H, m),
2.54 (2H, m), 3.61 (2H, m), 3.72 (2H, t, J = 5.6Hz), 3.
84 (2H, m), 4.46 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.25-
7.50 (5H, m), 7.54 (1H, s), 7.81 (2H, s), 7.88 (1H, s)

The compounds of Reference Examples 118 to 126 were reacted with the compounds of Reference Examples 37 to 45 in substantially the same manner as in Reference Example 65 (in THF in the presence of sodium hydride). To give colorless crystals. The respective physicochemical data are shown below. Reference Example 118 2,3,4,5-tetrahydro-5-oxo-6-phenyl-4- (3,4,5-trimethoxybenzyl) pyrido "3,2-f] [1,4] oxazepine Melting point: 177-179 ° C (recrystallized from acetone-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.70 (2H, t, J = 5.6Hz), 3.85
(6H, s), 3.87 (3H, s), 4.34 (2H, t, J = 5.6Hz), 4.72 (2H,
s), 6.60 (2H, s), 7.24 (1H, d, J = 5.2Hz), 7.30-7.55
(5H, m), 8.42 (1H, d, J = 5.2Hz)

Reference Example 119 4- (3,4-dichlorobenzyl) -2,3,4,5-
Tetrahydro-5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine Melting point: 189-192 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.67 (2H, t, J = 5.4 Hz), 4.42
(2H, t, J = 5.4Hz), 4.71 (2H, s), 7.10-7.70 (9H, m),
8.43 (1H, d, J = 5.2Hz)

Reference Example 120 4- (3,4-dimethoxybenzyl) -2,3,4,5
-Tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 175-176 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.67 (2H , t, J = 5.4Hz), 3.85
(3H, s), 3.91 (3H, s), 4.29 (2H, t, J = 5.4Hz), 4.72 (2
H, s), 6.80-7.00 (3H, m), 7.22 (1H, d, J = 5.2Hz), 7.3
0-7.50 (5H, m), 8.40 (1H, d, J = 5.2Hz)

Reference Example 121 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 209-211 ° C. (methanol-ethyl Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.64 (2H, t, J = 5.6Hz), 4.33
(2H, t, J = 5.6Hz), 4.77 (2H, s), 7.22 (1H, d, J = 5.2H
z), 7.30-7.55 (5H, m), 8.39 (1H, d, J = 5.2Hz)

Reference Example 122 2,3,4,5-tetrahydro-6-oxo-7-phenyl-5- (3,4,5-trimethoxybenzyl) -6
H-pyrido [2,3-b] [1,5] oxazosin Melting point: 155-156 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.65-1.85 (1H, m), 2.29 (1H,
m), 3.40-3.75 (2H, m), 3.77 (6H, s), 3.87 (3H, s),
4.07 (1H, d, J = 14.2Hz), 4.27 (1H, m), 4.66 (1H, m),
5.22 (1H, d, J = 14.2Hz), 6.53 (2H, s), 7.15 (1H, d, J =
5.2Hz), 7.35 (5H, m), 8.40 (1H, d, J = 5.2Hz)

Reference Example 123 (S) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5 Oxazosin melting point: 139-141 ° C (ethyl acetate-isopropyl
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 7.0Hz), 2.43
(1H, m), 3.12 (1H, d, J = 14.8Hz), 3.39 (1H, dd, J = 15.
4, 10.2Hz), 3.72-4.00 (2H, m), 4.60 (1H, dd, J = 12.4,
5.2Hz), 5.51 (1H, d, J = 14.8Hz), 7.16 (1H, d, J = 5.0H
z), 7.20-7.50 (10H, m), 8.39 (1H, dd, J = 5.0Hz)

Reference Example 124 (R) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5 Oxazosin melting point: 139-141 ° C (ethyl acetate-isopropyl
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: the same as the spectrum of the compound of Reference Example 123.

Reference Example 125 (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H- Pyrido [2,3-
b] [1,5] oxazosin Melting point: 142-143 ° C (ethyl acetate-isopropyl)
Recrystallization from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d, J = 7.0 Hz), 2.46
(1H, m), 3.10 (1H, d, J = 15.4Hz), 3.59 (1H, dd, J = 15.
0, 10.6Hz), 3.92 (1H, dd, .J = 12.6, 10.4Hz), 4.20 (1
H, d, J = 15.4Hz), 4.63 (1H, dd, J = 12.6, 5.2Hz), 5.50
(1H, d, J = 15.4Hz), 7.18 (1H, d, J = 5.0Hz), 7.20-7.50
(5H, m), 7.72 (2H, s), 7.84 (1H, s), 8.43 (1H, d, J =
5.0Hz)

Reference Example 126 (R) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H- Pyrido [2,3-
b] [1,5] oxazosin Melting point: 142-143 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: the same as the spectrum of the compound of Reference Example 125.

Reference Example 127 7-Benzyl-6,7,8,9,10,11-hexahydro-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,7 1-g]
[1,7] Naphthyridine Using the compound obtained in Reference Example 46, reacted in the same manner as in Reference Example 69, and treated to obtain the title compound as colorless crystals. Melting point: 239-241 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.1 (4H,
m), 2.50 (3H, s), 3.14 (1H,
dd, J = 15, 3.8 Hz), 3.3-3.
7 (2H, m), 3.77 (1H, d, J = 1
5 Hz), 5.14 (1H, dd, J = 14,
5.9 Hz), 5.42 (1H, d, J = 15H)
z), 6.67 (2H, d, J = 7.0 Hz),
6.92 (1H, dd, J = 7.6, 1.8H
z), 7.1-7.5 (6H, m), 7.46
(1H, dd, J = 8.4, 4.4 Hz),
7.60 (1H, dd, J = 8.4, 1.8H
z), 8.90 (1H, dd, J = 4.4,
1.8Hz)

Reference Example 128 (9R) -7-benzyl-6,7,8,9,10,11
-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 47 And the reaction was carried out in the same manner as in Reference Example 69 to give the title compound as colorless crystals. Melting point: 218-220 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 7.0 Hz),
1.50-1.75 (1H, m), 1.90-2.35 (2H, m), 2.50 (3H, s),
2.89 (1H, d, J = 15Hz), 3.26 (1H, dd, J = 14, 10Hz), 3.59
(1H, dd, J = 14, 11Hz), 3.75 (1H, d, J = 15Hz), 5.10 (1
H, dd, J = 14, 6.1Hz), 5.42 (1H, d, J = 15hz), 6.69 (2H,
d, J = 6.8Hz), 6.91 (1H, dd, J = 7.8, 1.8Hz), 7.1-7.5
(6H, m), 7.46 (1H, dd, J = 8.4, 4.2Hz), 7.60 (1H, dd,
J = 8.4, 1.8Hz), 8.90 (1H, dd, J = 4.2, 1.8Hz)

Reference Example 129 (9S) -7-benzyl-6,7,8,9,10,11
-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 47 The reaction was carried out in the same manner as in Reference Example 69 and treated to give the title compound as colorless crystals. Melting point: 218-220 ° C (ethyl acetate-isopropyl)
NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 74.

Reference Example 130 (9R) -6,7,8,9,10,11-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13
-Dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 49 was reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. White powder NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3H, d, J = 6.6 Hz), 1.5
-1.8 (1H, m), 1.9-2.5 (2H, m), 2.41 (3H, s), 3.11 (1H,
d, J = 15Hz), 3.35 (1H, dd, J = 15, 11Hz), 3.56 (1H, d
d, J = 14, 11Hz), 3.7-3.9 (1H, m), 3.75 (6H, s), 3.87
(3H, s), 5.07 (1H, dd, J = 14, 5.9Hz), 5.19 (1H, d, J =
15Hz), 6.30 (2H, s), 6.77 (1H, d, J = 8.0Hz), 6.97 (1H,
d, J = 8.0Hz), 7.29 (1H, d, J = 8.2Hz), 7.37 (1H, d, J =
8.2Hz), 7.45 (1H, dd, J = 8.4, 4.0Hz), 7.58 (1H, dd, J
= 8.4, 1.4Hz), 8.89 (1H, dd, J = 4.0, 1.4Hz)

Reference Example 131 (9S) -6,7,8,9,10,11-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13
-Dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 50 was reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. White powder NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 76.

Reference Example 132 (9R) -7- (3,5-dimethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine Using the compound obtained in Reference Example 51, reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. Melting point: 206-208 ° C (ethanol-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d, J = 7.0 Hz), 1.6
7 (1H, m), 1.9-2.4 (2H, m), 2.42 (3H, s), 3.05 (1H, d,
J = 15Hz), 3.24-3.40 (1H, m), 3.45-3.85 (2H, m), 3.74
(6H, s), 5.08 (1H, dd, J = 14, 5.8Hz), 5.26 (1H, d, J =
14Hz), 6.12 (2H, d, J = 2.0Hz), 6.38 (1H, t, J = 2.0Hz),
6.84 (1H, d, J = 7.0Hz), 7.09 (1H, d, J = 7.0Hz), 7.29
(1H, d, J = 9.2Hz), 7.38 (1H, d, J = 9.2Hz), 7.46 (1H, d
d, J = 8.2,4.2Hz), 7.62 (1H, dd, J = 8.2, 1.6Hz), 8.89
(1H, dd, J = 4.2, 1.6Hz)

The compounds of Reference Examples 133 to 136 were obtained from Reference Examples 52 to 54 and Reference Example 14, respectively.
The compound (4) was subjected to a reaction (cyclization reaction in THF in the presence of sodium hydride) and treatment substantially in the same manner as in Reference Example 65 to give colorless crystals. Each physicochemical data is described below. Reference Example 133 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6- (4-methylphenyl) pyrido [3,2-
f] [1,4] oxazepine Melting point: 203-204 ° C (recrystallized from methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.41 (3H, s), 3.64 (2H, t,
J = 5.4Hz), 4.32 (2H, t, J = 5.4Hz), 4.78 (2H, s), 7.21
(1H, d, J = 5.2Hz), 7.25 (4H, s), 7.38 (5H, s), 8.37 (1
(H, d, J = 5.2Hz)

Reference Example 134 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-
(4-methylphenyl) pyrido [3,2-f] [1,
4] Oxazepine Melting point: 212-213 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.40 (3H, s), 3.70 (2H, t,
J = 5.6Hz), 4.47 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.24
(total 5H, m), 7.81 (2H, s), 7.87 (1H, s), 8.41 (1H,
d, J-5.2Hz)

Reference Example 135 (S) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-7- (4-methylphenyl) -6-oxo-6H-pyrido [2,3-b ] [1,5] oxazosin Melting point: 148-149 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 7.4 Hz), 2.3
0-2.60 (1H, b), 2.42 (3H, s), 3.11 (1H, d, J = 15.4Hz),
3.40 (1H, dd, J = 15.4, 10.4Hz), 3.75-4.00 (2H, m),
4.59 (1H, dd, J = 12.4, 4.8Hz), 5.50 (1H, d, J = 15.0H
z), 7.15 (1H, d, J = 4.8Hz), 7.20-7.40 (total 9H, m),
8.37 (1H, d, J = 4.8Hz)

Reference Example 136 (S) -5- [3,5-bis (trifluoromethyl) benzyl-2,3,4,5-tetrahydro-3-methyl-
7- (4-Methylphenyl) -6-oxo-6H-pyrido [2,3-b] [1,5] oxazosin Melting point: 159-160 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃₎ ) Ppm: 0.86 (3H, d, J = 7.0Hz), 2.2
0-2.60 (1H, b), 2.37 (3H, s), 3.09 (1H, d, J = 15.4Hz),
3.58 (1H, dd, J = 15.4, 10.4Hz), 3.89 (1H, t, J = 11.6H
z), 4.18 (1H, d, J = 15.4Hz), 4.62 (1H, dd, J = 12.2, 5.
2Hz), 5.53 (1H, d, J = 15.4Hz), 7.17 (total 5H, m), 7.7
2 (2H, s), 7.84 (1H, s), 8.40 (1H, d, J = 5.2Hz)

Reference Example 137 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-5-
(4-hydroxymethylphenyl) -9-methyl-6,1
3-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine yeast extract 0.4%, malt extract 1%, glucose 0.4
%, Agar 2% (ISP Medium No. 2), pH 7.
28 Streptomyces subrutilus IFO 13388 on agar slant 3
C. for 14 days. Separately, 0.5% glucose, 5% dextrin, 3.5% defatted soy bean meal,
Prepare a medium containing 0.7% calcium carbonate and add 200ml
40 ml was placed in a conical flask and steam sterilized at 120 ° C. for 20 minutes. One platinum loop of the above-mentioned cultured cells was inoculated into this medium, and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further transferred to 13 flasks each containing the same medium in an amount of 1 ml, and cultured at 28 ° C. for 48 hours with shaking. The (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl- obtained in Reference Example 72 was added to each culture. 5- (4-methylphenyl)-
6,13-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] Naphthyridine (104 mg) in DMSO
(5.2 ml) The solution was added in 0.4 ml portions and added at 28 ° C.
For 48 hours to react. After the reaction, p with 2N sulfuric acid
Adjusted to H4 and extracted with 500 ml of ethyl acetate. The extract was concentrated, and the concentrate was separated and purified by column chromatography using silica gel (ethyl acetate-methanol = 9: 1) to give the title compound as colorless crystals (30 mg).
Was obtained as 240-241 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.6 Hz), 1.5-1.9 (2H, m),
1.95-2.40 (2H, m), 2.98 (1H, d, J
= 15 Hz), 3.35-3.65 (2H, m), 4.02
(1H, d, J = 15Hz), 4.75 (2H, s), 5.
10 (1H, dd, J = 15, 5.5 Hz), 5.46 (1
H, d, J = 15 Hz), 6.97 (1 H, d, J = 8.0)
Hz), 7.26 (1H, d, J = 8.0Hz), 7.4-
7.6 (6H, m), 7.81 (1H, s), 8.93 (1
H, dd, J = 4.0, 1.8 Hz) Elemental analysis: Calculated as C ₃₀ H ₂₅ N ₃ O ₃ F ₆ Calculated (%): C 61.12, H 4.27, N 7.13 Measured Value (%): C 61.15, H 4.21, N 7.03 EI-MS m / z: 589 (M ⁺ ) [(C ₃₀ H ₂₅ N ₃ O)
₃ F ₆₎ ^+].

Reference Example 138 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,8,9,10,
11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Yeast extract 0.4%, malt extract 1%, glucose 0. 4
%, Agar agar 2% (ISP Medium No. 2), pH 7.
Streptomyces tanaciensis subsp. Cephalomyceticas (Streptomyc
es tanashiensis subsp. cephalomyceticus) IFO 1
3929 was cultured at 28 ° C. for 14 days. Separately, glucose 0.5%, dextrin 5%, defatted soy flour (soy bean me
al) A medium containing 3.5% and 0.7% calcium carbonate was prepared, placed in a 200 ml Erlenmeyer flask, and sterilized with steam at 120 ° C. for 20 minutes. The above culture cells are added to this medium for 1 hour.
A platinum loop was inoculated and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further added to 25 flasks containing the same medium.
Each ml was transferred and shake-cultured at 28 ° C. for 48 hours. The (9R) -7- [3,5-bis) obtained in Reference Example 72 was added to each of the culture solutions.
(Trifluoromethyl) benzyl] -6,7,8,9,10,1
DM of 1-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
SO (10 ml) solution was added in 0.4 ml portions, and 2
The mixture was shaken at 8 ° C for 48 hours to react. After the reaction, the pH was adjusted to 4 with 2N sulfuric acid and extracted with 1 L of ethyl acetate. The extract was concentrated, and the concentrate was separated and purified by column chromatography using silica gel (ethyl acetate-methanol = 9: 1) to give colorless crystals containing the title compound. The structure of this product was determined by comparing the NMR spectrum with the compound separately prepared in Reference Example 139.

Reference Example 139 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,8,9,10,
11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (9R) -7- [3 obtained in Reference Example 137 , 5-Bis (trifluoromethyl) benzyl] -6,7,8,9,10,11
-Hexahydro-5- (4-hydroxymethylphenyl)
-9-Methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (109 m
g), a mixture of manganese dioxide (1.3 g) and dichloromethane (13 ml) was stirred at room temperature for 2 hours, and then the precipitate was filtered off using Celite. The filtrate was concentrated to give the title compound as colorless crystals (70 mg). Mp 213-214 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 1.60-1.85 (1H,
m), 1.95-2.40 (2H, m), 3.05 (1H,
d, J = 15 Hz), 3.35-3.65 (2H, m), 4.
00 (1H, d, J = 15 Hz), 5.11 (1H, dd,
J = 14, 5.7 Hz), 5.38 (1 H, d, J = 15 H)
z), 7.12 (1H, d, J = 8.4Hz), 7.40-
7.55 (4H, m), 7.60-7.75 (2H, m),
7.78 (1H, s), 7.96 (1H, d, J = 8.0H)
z), 8.94 (1H, m ), 10.03 (1H, s) Elemental analysis: Calculated _{C 30 H 23 N 3 O 3} F 6 (%): C 61.33, H 3.95 , N 7.15 Found (%): C 61.25, H 4.04, N 7.11 EI-MS m / z: 587 (M ⁺ ) [(C ₃₀ H ₂₃ N ₃ O
₃ F ₆₎ ^+].

Reference Example 140 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine yeast extract 0.4%, malt extract 1%, glucose 0.4
%, Agar 2% (ISP Medium No. 2), pH 7.
Streptomyces lavenduligriseus IFO 13 on agar slant 3
405 was cultured at 28 ° C. for 14 days. Separately, glucose 0.5%, dextrin 5%, defatted soy flour (soy bean me
al) A medium containing 3.5% and 0.7% calcium carbonate was prepared, placed in a 200 ml Erlenmeyer flask, and sterilized with steam at 120 ° C. for 20 minutes. The above culture cells are added to this medium for 1 hour.
A platinum loop was inoculated and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further added to 25 flasks containing the same medium.
Each ml was transferred and shake-cultured at 28 ° C. for 48 hours. The (9R) -7- [3,5-bis) obtained in Reference Example 72 was added to each of the culture solutions.
(Trifluoromethyl) benzyl] -6,7,8,9,10,1
DM of 1-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
SO (10 ml) solution was added in 0.4 ml portions, and 2
The mixture was shaken at 8 ° C for 48 hours to react. After the reaction, the pH was adjusted to 4 with 2N sulfuric acid and extracted with 1 L of ethyl acetate. The extract was concentrated, and the concentrate was extracted with 1N aqueous sodium hydroxide. The extract was adjusted to pH 3-4 using 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline and dried, and the solvent was distilled off. The residue was separated and purified by column chromatography on silica gel (ethyl acetate-methanol = 9: 1) to give the title compound as colorless crystals (58 mg). 300-301 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.96 (3
H, d, J = 6.6 Hz), 1.76 (1H, m), 1.95
-2.40 (2H, m), 3.09 (1H, d, J = 15H
z), 3.40-3.65 (2H, m), 4.02 (1H,
d, J = 15 Hz), 5.12 (1H, dd, J = 14,5.
6 Hz), 5.36 (1 H, d, J = 15 Hz), 7.04
(1H, dd, J = 8.0, 1.6Hz), 7.45-7.6
5 (5H, m), 7.83 (1H, s), 7.91 (1
H, d, J = 8.4 Hz), 8.20 (1 H, dd, J = 8.
4,1.8 Hz), 8.97 (1H, dd, J = 3.6, 2.
2Hz) EI-MS m / z : 603 (M +) [(C 30 H 23 N 3 O
₄ F ₆₎ ^+].

Reference Example 141 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methyl (Phenyl) -6,13-dioxo-
13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine N-oxide (9R) -7- [3,5-bis (trifluoromethyl) benzyl] obtained in Reference Example 72 -6,7,8,9,10,11-
Hexahydro-9-methyl-5- (4-methylphenyl)
-6,13-Dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine (1.60 g), m-chloroperbenzoic acid (1.2 g) and dichloromethane (20 m
After the mixture of l) was stirred at room temperature for 3 hours, the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate and saturated saline, and dried. Evaporation of the solvent gave the title compound as pale yellow crystals (0.73 g). 237-239 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.6 Hz), 1.73 (1H, m), 1.9−
2.4 (2H, m), 2.36 (3H, s), 2.97 (1
H, d, J = 15 Hz), 3.3-3.5 (2H, m), 3.
97 (1H, d, J = 15 Hz), 4.97 (1H, dd,
J = 14, 5.2Hz), 5.41 (1H, d, J = 15H)
z), 6.82 (2H, m), 7.04 (1H, d, J = 7.
4Hz), 7.15-7.35 (3H, m), 7.44 (2
H, s), 7.81 (1H, s), 8.31 (1H, dd, J
= 5.4,0.8Hz) Elemental analysis: Calculated _{C 30 H 25 N 3 O 3} F 6 (%): C 61.12, H 4.27, N 7.13 Found (%): C 60.77, H 4.55, N 7.00

Reference Example 142 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-5- (4
-Hydroxymethylphenyl) -9-methyl-6,13-
Dioxo-13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine N-oxide (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11 obtained in Reference Example 137
-Hexahydro-5- (4-hydroxymethylphenyl)
-9-Methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (100 m
After stirring a mixture of g), 4-dimethylaminopyridine (catalytic amount), acetic anhydride (0.1 ml) and pyridine (3 ml) at room temperature for 16 hours, the solvent was distilled off. Ethyl acetate was added to the residue, washed with dilute hydrochloric acid and saturated saline, dried, and the solvent was distilled off. The residue was diluted with dichloromethane (10 ml).
Was dissolved. To this solution was added m-chloroperbenzoic acid (102
mg) and stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and washed with 0.1N aqueous sodium hydroxide.
It was dried and the solvent was distilled off. Methanol (10m
l) and 1N aqueous sodium hydroxide (2 ml) were added, the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and evaporated to give the title compound as pale yellow crystals (28 mg). 240-243 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.2 Hz), 1.5-2.4 (4H, m),
2.98 (1H, d, J = 15 Hz), 3.44 (2H,
m), 4.00 (1 H, d, J = 15 Hz), 4.74 (2
H, s), 4.98 (1H, m), 5.40 (1H, d, J
= 15 Hz), 6.88 (1H, m), 7.26 (1H,
d, J = 7.4 Hz), 7.45 (6H, m), 7.81 (1
H, s), 8.32 (1H, m)

Reference Example 143 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine N-oxide (9R) obtained in Reference Example 140 -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,10,11-hexahydro-9-
TH of methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
Ethyl ether (10 ml) of diazomethane (adjusted using N-nitrosomethylurea and potassium hydroxide) was added to the F (20 ml) solution, and the mixture was stirred at room temperature for 30 minutes. After evaporation of the solvent, the residue was dissolved in dichloromethane (20 ml). To this solution, m-chloroperbenzoic acid (0.6 g) was added little by little, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with 1N aqueous sodium hydroxide and water, dried, and the solvent was distilled off. Methanol (2
0 ml) and 1N aqueous sodium hydroxide (5 ml) were added,
The mixture was heated under reflux for 30 minutes. After the solvent was distilled off, water was added to the residue, and the mixture was adjusted to pH 2-3 with 2N hydrochloric acid. The solution was extracted with ethyl acetate, and the extract was washed with saturated saline, dried, and evaporated to give the title compound as pale yellow crystals (88 mg). NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 1.75 (1H, m), 1.9−
2.4 (2H, m), 3.08 (1H, d, J = 15H
z), 3.47 (2H, m), 4.00 (1H, d, J = 1)
5Hz), 5.00 (1H, dd, J = 14, 6.0Hz),
5.29 (1H, d, J = 15 Hz), 6.80 (1H,
d, J = 8.4 Hz), 7.02 (1 H, d, J = 7.3 H)
z), 7.28 (1H, dd, J = 7.0, 6.6Hz), 7.
46 (2H, s), 7.54 (1H, d, J = 7.0H)
z), 7.81 (1H, s), 7.88 (1H, d, J = 7.
3 Hz), 8.16 (1 H, d, J = 8.4 Hz), 8.39
(1H, d, J = 6.6Hz).

Reference Example 144 N- [3,5-bis (trifluoromethyl) benzyl]
2-chloro -N - [(S) -3-hydroxy-2-methylpropyl] -4- (4-methylphenyl) -3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 0.54 (3H × 1 / 4, d, J = 7.0Hz),
0.63 (3H × 1/4, d, J = 7.0Hz), 0.79 (3H × 1/4, d, J = 7.0H
z), 0.84 (3H × 1/4, d, J = 7.0Hz), 1.50-1.90 (1H, m),
2.25-2.45 (3H, m), 2.45-3.90 (total 5H, m), 4.05-4.4
5 (1H, m), 4.50-4.95 (1H, m), 7.00-7.20 (1H, m), 7.20
-7.50 (total 5H, m), 7.70-7.85 (2H, m), 8.42 (1H, m). (1: 1 mixture of amide rotamers).

[0243] Reference Example ^{145 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -8,9.1
0,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine-6,13-dione (d ₄ form of the compound of Reference Example 72) (Step 1) (S)-(+)-3-hydroxy-2-methylpropionic acid methyl ester THP ether (3
9.5 g) (prepared according to the method described in the literature [Kenji Mori, Vol. 39, Tetrahedron 39, 3107-3109 (1983): Synthetic method is described for enantiomers)]. 60 ml) solution at 0 ° C. with lithium aluminum deuteride (5.80 g) in ethyl
It was slowly added to a suspension of ether (200 ml) with vigorous stirring. Then, the reaction mixture was stirred at room temperature for 1 hour, cooled again with ice water, and 1N aqueous sodium hydroxide (24%).
ml) and THF (24 ml) were added with stirring. After the precipitate was filtered off through celite, and the filtrate was dried and the solvent was evaporated ^{(S) - [1,1- 2 H} 2] -2
-Methyl-1,3-propanediol mono THP ether was obtained as a colorless oil (35.6 g). NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3
H × 1/2, d, J = 7.0 Hz), 0.91 (3H × 1 /
2, d, J = 7.0 Hz), 1.4-1.9 (6 H, m), 2.
01 (1H, m), 2.74 (1H, bs), 3.3-3.6
(3H, m), 3.89 (1H, m), 4.58 (1H,
b). (Step 2) While stirring under cooling with a solution of the compound obtained in Step 1 (35.6 g) in pyridine (150 ml), p-chloride was added.
Toluenesulfonyl (39 g) was added. The mixture was stirred overnight at room temperature, diluted with ethyl ether, washed with water, dilute hydrochloric acid and brine, dried, and the solvent was distilled off. The residue was dissolved in DMSO (150 ml), sodium cyanide (13 g) was added, and the mixture was stirred at room temperature for 6 hours. After diluting with hexane, washing with water and drying, and evaporating the solvent, (R)
- [2,2- _² H ^2] -4- hydroxy-3-methyl butane nitrile THP ether pale yellow oil (19.1
g). NMR (200 MHz, CDCl ₃ ) ppm: 1.09 (3
H × 1/2, d, J = 6. Hz, 1.10 (3H × 1 /
2, d, J = 6.8 Hz), 1.5-1.9 (6 H, m),
2.16 (1H, m), 3.16-3.88 (4H, m),
4.60 (1H, b).

(Step 3) Compound (19.1) obtained in Step 2
A solution of g) in ethyl ether (80 ml) was added slowly at 0 ° C. to a suspension of lithium aluminum deuteride (4.85 g) in ethyl ether (200 ml) with vigorous stirring. The reaction mixture was then stirred at room temperature for 1 hour,
After cooling again with ice water, 1N aqueous sodium hydroxide solution (20 ml)
And a mixture of THF (20 ml) was added with stirring. After the precipitate was filtered off through celite, and the filtrate was dried and the solvent was evaporated ^{(R) - [3,3,4,4- 2 H} 4]
-4-Amino-2-methyl-1-butanol THP ether was obtained as a pale yellow oil (19.3 g). NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3
H × 1/2, d, J = 6.8 Hz), 0.94 (3H × 1 /
2, d, J = 6.8 Hz), 1.2-1.9 (9 H, m), 3.
13-3.27 (1H, m), 3.45-3.64 (2H,
m), 3.86 (1H, m), 4.57 (1H, b).

(Step 4) Compound obtained in Step 3 and Reference Example 3
The compound obtained in was treated by reacting in the same manner as in Reference Example 5 to give (R) -N- [3,5- (bistrifluoromethyl) benzyl] -7,8-dihydro-7-([ One,
1,2,2- ² H _4] -4- hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo - 1,
7-Naphthyridine-6-carboxamide was obtained as colorless crystals. Melting point: 205-207 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.78 (3
H, d, J = 7.0 Hz), 1.55 (1H, m), 2.28
(3H, s), 3.14 (1H, b, OH), 3.2-3.
5 (2H, m), 4.50 (2H, d, J = 6.0 Hz),
7.0-7.3 (4H, m), 7.29 (1H, dd, J =
8.4, 4.4 Hz), 7.54 (1H, dd, J = 8.4,
1.6Hz), 7.69 (2H, s), 7.78 (1H,
s), 8.55 (1 H, t, J = 6.0 Hz), 8.61 (1
H, dd, J = 4.4, 1.6 Hz). Elemental analysis: C ₃₀ H ₂₃ D ₄ F ₆ N ₃ O ₃ .1 / 2H ₂ O Calculated (%): C, 59.60 H, 4.00 D, 1.33 N, 6.95 Value (%): C, 59.94 H, 3.82 D, 1.29 N, 7.13.

(Step 5) The compound obtained in Step 4 was reacted and treated in the same manner as in Reference Example 69 to give the title compound as colorless crystals. Melting point: 227-229 ° C (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 7.0 Hz), 2.08 (1 H, m), 2.3
7 (3H, s), 2.97 (1H, dd, J = 15, 1.4
Hz), 3.45 (1H, dd, J = 15, 11 Hz), 3.
99 (1H, d, J = 15 Hz), 5.46 (1H, d, J
= 15Hz), 6.83 (1H, dd, J = 7.8, 1.8H)
z), 7.05 (1H, d, J = 7.8Hz), 7.26 (1
H, d, J = 7.8 Hz, 7.34 (1H, dd, J = 7.3)
8, 1.8 Hz), 7.47 (1H, dd, J = 8.6, 4.4)
Hz), 7.48 (2H, s), 7.56 (1H, dd, J =
8.6, 1.8 Hz), 7.82 (1H, s), 8.91 (1
H, dd, J = 4.1, 1.8 Hz). Elemental analysis: C ₃₀ H ₂₁ D ₄ F ₆ N ₃ O ₂ Calculated (%): C, 62.39 H, 3.66 D, 1.39 N, 7.28 Actual (%): C , 62.41 H, 3.65 D, 1.35 N, 7.21. EI-MS m / z: 577 (M ⁺ ), 558, 35
0, 313 [α] _D : + 116.6 ° (c = 0.541, MeOH).

[0247] Reference Example ^{146 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -8,9.1
0,11-tetrahydro-5- (4-hydroxymethylphenyl) -9-methyl-7H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-dione (Reference Example) using the compound obtained in d ₄ body) reference example 145 compound 137, was treated by the same reaction as in reference example 137, the title compound was obtained as colorless crystals. Melting point: 241-242 ° C. (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 7.0 Hz), 1.85 (1H, m), 2.09
(1H, m), 2.98 (1H, dd, J = 15, 1.4H
z), 3.47 (1H, dd, J = 15, 11 Hz), 4.0
2 (1H, d, J = 15 Hz), 4.75 (2H, d, J
= 4.4 Hz), 5.45 (1 H, d, J = 15 Hz), 6.
97 (1H, d, J = 8.0 Hz), 7.25 (1H, d,
J = 8.0 Hz), 7.4-7.6 (6 H, m), 7.81
(1H, s), 8.91 (1H, dd, J = 4.0, 2.2H
z). Elemental analysis: C ₃₀ H ₂₁ D ₄ F ₆ N ₃ O ₃ .1 / 2H ₂ O Calculated (%): C, 59.80 H, 3.68 D, 1.34 N, 6.97 Value (%): C, 59.76 H, 3.78 D, 1.40 N, 6.73. EI-MS m / z: 593 (M ⁺ ), 554, 51
9,366,313 [α] _D : + 94.2 ° (c = 0.538, MeOH).

[0248] Reference Example ^{147 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -5- (4
-Formylphenyl) -8,9,10,11-tetrahydro-9-methyl-7H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine-6,13-dione (d ₄ form of the compound of Reference Example 138) The compound obtained in Reference Example 146 was reacted and treated in the same manner as in Reference Example 138 or Reference Example 139. The title compound was obtained as colorless crystals. Mp: 215-216 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 7.0 Hz), 2.10 (1H, m), 3.05
(1H, dd, J = 15, 1.4 Hz), 3.47 (1H, d
d, J = 15, 11 Hz), 4.00 (1H, d, J = 15)
Hz), 5.39 (1H, d, J = 15Hz), 7.12
(1H, dd, J = 8.0, 1.8Hz), 7.40-7.5
5 (4H, m), 7.62-7.74 (2H, m), 7.7
9 (1H, s), 7.97 (1H, dd, J = 8.0, 1.8
Hz), 8.94 (1H, dd, J = 4.0, 1.8Hz),
10.04 (1H, s). Elemental analysis: C ₃₀ H ₁₉ D ₄ F ₆ N ₃ O ₃ Calculated (%): C, 60.91 H, 3.24 D, 1.36 N, 7.10 Actual (%): C , 60.89 H, 3.31 D, 1.36 N, 6.99. EI-MS m / z: 591 (M ⁺ ), 572, 51
7,364,313 [α] _D : + 106.1 ° (c = 0.510, MeOH).

[0249] Reference Example ^{148 (9S) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -5- (4
-Carboxyphenyl) -8,9,10,11-tetrahydro-9-methyl-7H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine-6,13-dione (d ₄ form of the compound of Reference Example 140) The compound obtained in Reference Example 146 (2.0 g), t-butanol (80 ml), 0.3N water Aqueous sodium oxide (55 ml)
While stirring at 0 ° C., potassium permanganate (1.7 g) was added little by little to the mixture. After stirring at room temperature for 1 hour, ethanol (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was separated by filtration using Celite and washed with ethanol. The filtrate and the washing were combined, the solvent was distilled off, and the residue was dissolved in 1N aqueous sodium hydroxide. After washing this solution with a mixture of ethyl ether and THF,
The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried, and evaporated to give the title compound as colorless crystals (1.71 g). Melting point: 302-303 ° C (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 2.09 (1H, m), 3.09
(1H, d, J = 14 Hz), 3.49 (1H, dd, J =
14, 9.4Hz), 4.02 (1H, d, J = 15Hz),
5.36 (1H, d, J = 15 Hz), 7.04 (1H, d,
J = 8.0 Hz), 7.50 (4H, m), 7.59 (1H,
d, J = 8.4 Hz), 7.82 (1H, s), 7.91 (1
H, d, J = 8.4 Hz, 8.20 (1H, d, J = 8.0)
Hz), 8.97 (1H, dd, J = 3.6, 2.2 Hz). Elemental analysis: C ₃₀ H ₁₉ D ₄ F ₆ N ₃ O ₄ .1 / 2H ₂ O Calculated (%): C, 58.44 H, 3.27 D, 1.31 N, 6.82 Value (%): C, 58.47 H, 3.21 D, 1.32 N, 6.89. EI-MS m / z: 607 (M ⁺ ), 568, 53
3,380,313 [α] _D : + 123.2 ° (c = 0.545, MeOH).

Reference Example 149 (R) -N- [3,5-di (benzyloxy) benzyl] -7,8-dihydro-7- (4-hydroxy-3-
(Methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Di (benzyloxy) benzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N-
[3,5-di (benzyloxy) benzyl] -5- (4
-Methylphenyl) -8-oxo-8H-pyrano [3
4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 177-179 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H, s), 4.40 (2H,
d, J = 5.8 Hz), 5.01 (4H, s), 6.51 (3H, m), 7.1-7.5
(15H, m), 7.57 (2H, m), 8.94 (1H, dd, J = 3.6, 2.2
Hz) Elemental analysis: C ₃₇ H ₃₀ N ₂ O ₅ Calculated (%): C 76.27, H 5.19, N 4.81 Found (%): C 76.36, H 5.11, N 4.78. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 168-170 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 2.30 (3H, s), 2.99 (1H, m),
3.2-3.6 (2H, m), 3.75-3.95 (2H, m), 4.21 (2H, d, J
= 6.0 Hz), 4.98 (4H, s), 6.33 (2H, d, J = 1.8 Hz),
6.50 (1H, bt), 7.1-7.5 (16H, m), 7.58 (1H, d, J =
8.4 Hz), 8.67 (1H, dd, J = 4.4, 1.2 Hz) Elemental analysis: C ₄₂ H ₄₁ N ₃ O ₅ .0.3 H ₂ O Calculated (%): C 74.93, H 6.23, N 6.24 Found (%): C 74.80, H 6.25, N 6.28.

Reference Example 150 (R) -N- (3,5-dimethoxybenzyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -8-oxo-5-phenyl-6-pyrido [3,4
-B] pyridinecarboxamide (Step 1) Compound obtained in Step 2 of Reference Example 9 and 3,5
Step 4 of Reference Example 2 using -dimethoxybenzylamine
When the reaction and treatment were carried out in the same manner as described above, N- (3,5-
Dimethoxybenzyl) -8-oxo-5-phenyl-8
H-Pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 126-127 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.40 (2H,
d, J = 5.8 Hz), 6.41 (3H, m), 7.20-7.35 (3H, m), 7.
45-7.65 (5H, m), 8.95 (1H, dd, J = 4.0, 1.4 Hz) Elemental analysis: C ₂₄ H ₂₀ N ₂ O ₅ Calculated (%): C 69.22, H 4.84, N 6.73 Value (%): C 69.27, H 4.72, N 6.83. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 150-151 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 3.09 (1H, m), 3.2-3.6 (2H,
m), 3.6-3.9 (2H, m), 3.76 (6H, s), 4.20 (2H, d, J
= 5.8 Hz), 6.27 (2H, d, J = 2.2 Hz), 6.35 (1H, t,
J = 2.2 Hz), 7.2-7.7 (8H, m), 8.61 (1H, dd, J = 4.
Elemental analysis: C ₂₉ H ₃₁ N ₃ O ₅ Calculated (%): C 69.44, H 6.23, N 8.38 Found (%): C 69.11, H 6.04, N 8.51.

Reference Example 151 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-chlorophenyl) -7,8-dihydro-7- (4-hydroxy-3-methylbutyl ) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Instead of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2, 3- (4-
Using (chlorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (4-chlorophenyl) -8-oxo-8H.
-Pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) ppm: 7.24 (2H, d, J =
8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J
= 8.0 Hz), 7.63 (1H, dd, J = 8.0, 4.4 Hz), 8.96 (1
H, d, J = 4.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-bis (trifluoromethyl) benzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N-
[3,5-bis (trifluoromethyl) benzyl] -5
-(4-Chlorophenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 217-219 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.63 (2H, d, J = 6.2 H)
z), 7.23 (2H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.2
Hz), 7.53 (1H, dd, J = 8.4, 1.6 Hz), 7.65 (1H, d
d, J = 8.4, 4.4 Hz), 7.6-7.8 (1H, m), 7.73 (2H,
s), 7.80 (1H, s), 8.98 (1H, dd, J = 4.4, 1.6 Hz). (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 259-261 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.78 (3H, d, J = 6.2 H)
z), 1.4-1.8 (3H, m), 3.02 (1H, m), 3.2-3.7 (4H,
m), 4.48 (2H, m), 7.1-7.4 (5H, m), 7.46 (1H, d, J
= 8.0 Hz), 7.72 (2H, s), 7.85 (1H, s), 8.60 (2H,
m).

Reference Example 152 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) of Step 1 of Reference Example 2 3- (3,3) instead of 2-pyridinecarboxylic acid
Using 4-dichlorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (3,4-dichlorophenyl) -8-oxo-8H-pyrano [ [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200MHz, DMSO-d ₆ ) ppm: 7.34 (1H, dd, J = 8.2,
1.8 Hz), 7.50 (1H, dd, J = 8.4, 1.4 Hz), 7.66 (1H,
d, J = 1.8 Hz), 7.72-7.85 (2H, m), 8.96 (1H, dd, J
= 4.4, 1.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-bis (trifluoromethyl) benzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N-
[3,5-bis (trifluoromethyl) benzyl] -5
-(3,4-dichlorophenyl) -8-oxo-8H-
Pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 220-221 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.64 (2H, d, J = 6.2 H)
z), 7.15 (1H, dd, J = 8.4, 1.8 Hz), 7.39 (1H, d, J
= 1.8 Hz), 7.5-7.8 (4H, m), 7.75 (2H, s), 7.81 (1
H, s), 8.99 (1H, dd, J = 4.4, 1.4 Hz). (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound. This compound was prepared in Example 7 without purification.
Was used for the reaction.

Reference Example 153 (R) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- (4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 1 of Reference Example 152 and 3,5-dimethoxybenzyl The reaction and treatment were carried out in the same manner as in Step 4 of Reference Example 2 using an amine.
(3,4-dichlorophenyl) -N- (3,5-dimethoxybenzyl) -8-oxo-8H-pyrano [3,4-
b] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 220-221 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 6.0 Hz), 6.38-6.48 (3H, m), 7.15 (1H, dd, J
= 8.4, 1.8 Hz), 7.34-7.82 (5H, m), 8.96 (1H, dd,
J = 4.2, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₅ Cl ₂ Calculated (%): C 59.40, H 3.74, N 5.77 Actual (%): C 59.13, H 3.81, N 5.77 . (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound. This compound was prepared in Example 8 without purification.
Was used for the reaction.

Reference Example 154 (R) -N- (3,5-dimethylbenzyl) -7,8-
Dihydro-7- (4-hydroxy-3-methylbutyl)
-5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Dimethylbenzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N- (3,5-dimethylbenzyl) -5- (4-methylphenyl) -8-
Oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 201-202 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.30 (6H, s), 2.45 (3H,
s), 4.39 (2H, d, J = 5.8 Hz), 6.88 (2H, s), 6.93 (1
H, s), 7.17 (2H, d, J = 8.0 Hz), 7.19 (1H, m), 7.3
3 (2H, d, J = 8.0 Hz), 7.57 (2H, m), 8.93 (1H, dd,
J = 4.0, 2.2 Hz) Elemental analysis: C ₂₅ H ₂₂ N ₂ O ₃ Calculated (%): C 75.36, H 5.57, N 7.03 Found (%): C 74.93, H 5.58, N 7.00. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 193 ° -194 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.6 H)
z), 1.5-2.0 (3H, m), 2.25 (6H, s), 2.42 (3H, s),
3.14 (1H, m), 3.2-3.4 (2H, m), 3.89 (2H, m), 4.20
(2H, d, J = 5.4 Hz), 6.61 (2H, s), 6.87 (1H, s),
7.1-7.4 (6H, m), 7.58 (1H, dd, J = 8.4, 1.4 Hz),
8.62 (1H, dd, J = 4.4, 1.4 Hz) Elemental analysis: C ₃₀ H ₃₃ N ₃ O ₃ · 0.3 H ₂ O Calculated (%): C 73.69, H 6.93, N 8.59 Actual measured (% ): C 73.85, H 6.95, N 8.52.

Reference Example 155 (R) -N- (3,5-dichlorobenzyl) -7,8-
Dihydro-7- (4-hydroxy-3-methylbutyl)
-5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Dichlorobenzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N- (3,5-dichlorobenzyl) -5- (4-methylphenyl) -8-
Oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 232-233 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.44 (2H,
d, J = 6.4 Hz), 7.1-7.3 (5H, m), 7.34 (2H, d, J =
7.6 Hz), 7.43 (1H, bt), 7.59 (2H, m), 8.95 (1H, dd,
J = 4.0, 2.2 Hz) Elemental analysis: C ₂₃ H ₁₆ N ₂ O ₃ Cl ₂ Calculated (%): C 62.89, H 3.67, N 6.38 Actual (%): C 62.62, H 3.70, N 6.36 . (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 123-125 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 7.0 H)
z), 1.5-2.0 (3H, m), 2.39 (3H, s), 3.17 (1H, m),
3.2-3.8 (4H, m), 4.34 (2H, d, J = 6.2 Hz), 6.95 (2
H, d, J = 2.0 Hz), 7.1-7.4 (5H, m), 7.31 (1H, dd,
J = 8.2, 4.4 Hz), 7.56 (1H, dd, J = 8.2, 1.6 Hz),
8.31 (1H, bt), 8.62 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₈ H ₂₇ N ₃ O ₃ Cl ₂ Calculated (%): C 64.13, H 5.19, N 8.01 Value (%): C 63.82, H 5.01, N 7.96.

Reference Example 156 (R) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethylbenzyl) -7,8-dihydro-7
-(4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 1 of Reference Example 152 and 3,5-dimethylbenzylamine Was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give 5- (3,
4-Dichlorophenyl) -N- (3,5-dimethylbenzyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 210-211 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.30 (6H, s), 4.40 (2H,
d, J = 5.6 Hz), 6.89 (2H, s), 6.94 (1H, s), 7.16 (1
H, dd, J = 8.2, 2.2 Hz), 7.30 (1H, bt), 7.39 (1H,
d, J = 2.2 Hz), 7.50 (1H, dd, J = 8.4, 1.6 Hz), 7.
60 (1H, d, J = 8.2 Hz), 7.65 (1H, dd, J = 8.4, 4.4
Hz), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₃ Cl ₂ .0.2 H ₂ O Calculated (%): C 63.09, H 4.06, N 6.13 Found (%): C 63.13, H 3.94, N 6.14. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as a colorless foam. NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 5.8 H
z), 1.4-1.9 (3H, m), 2.29 (6H, s), 2.90 (1H, m),
3.25-3.85 (4H, m), 4.29 (2H, d, J = 5.6 Hz), 6.72
(2H, s), 6.93 (1H, s), 7.25-7.55 (5H, m), 7.75 (1
H, m), 8.60 (1H, m).

Reference Example 157 (R) -N- (3,5-dimethoxybenzyl) -5
(4-fluorophenyl) -7,8-dihydro-7-
(4-hydroxy-3-methylbutyl) -8-oxo-
6-pyrido [3,4-b] pyridinecarboxamide (Step 1) In place of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2, 3- (4-
Using (fluorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (4-fluorophenyl) -8-oxo-8.
H-Pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200MHz, DMSO-d ₆ ) ppm: 7.25-7.50 (5H, m), 7.8
1 (1H, dd, J = 8.4,4.4 Hz), 8.95 (1H, dd, J = 4.4,
1.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-dimethoxybenzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N- (3,5-dimethoxybenzyl)- 5- (4-Fluorophenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 193 ° -194 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 6.0 Hz), 6.42 (3H, m), 7.2-7.4 (5H, m), 7.52
(1H, dd, J = 8.4, 1.6 Hz), 7.64 (1H, dd, J = 8.4,
4.497), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₅ F Calculated (%): C 66.36, H 4.41, N 6.45 Actual (%) : C 66.07, H 4.55, N 6.27. (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 170-171 ° C. (recrystallized from ethyl acetate-ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 3.06 (1H, m), 3.2-3.6 (2H,
m), 3.65-3.85 (2H, m), 3.78 (6H, s), 4.27 (2H, d, J
= 6.2 Hz), 6.26 (2H, d, J = 2.2 Hz), 6.36 (1H, t,
J = 2.2 Hz), 7.07 (2H, t, J = 8.6 Hz), 7.28 (1H,
dd, J = 8.4, 4.0 Hz), 7.35-7.50 (2H, m), 7.46 (1H,
dd, J = 8.4, 1.4 Hz), 7.91 (1H, bt), 8.59 (1H, d
d, J = 4.0, 1.4 Hz) Elemental analysis: C ₂₉ H ₃₀ N ₃ O ₅ F Calculated (%): C 67.04, H 5.82, N 8.09 Actual (%): C 66.87, H 5.73, N 8.04.

Reference Example 158 (R) -5- (4-Chlorophenyl) -N- (3,5-
Dimethoxybenzyl) -7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Using the compound obtained in Step 1 of Reference Example 151 and 3,5-dimethoxybenzylamine, The reaction and treatment were carried out in the same manner as in Step 4 of Example 2.
-Chlorophenyl) -N- (3,5-dimethoxybenzyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 5.8 Hz), 6.42 (3H, m), 7.23 (2H, d, J = 8.4
Hz), 7.34 (1H, bt), 7.51 (2H, d, J = 8.4Hz), 7.52
(1H, dd, J = 8.2, 1.6 Hz), 7.63 (1H, dd, J = 8.2,
4.4 Hz), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₅ Cl Calculated (%): C 63.93, H 4.25, N 6.21 Actual measured (%) : C 63.70, H 4.37, N 6.11. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 181-182 ° C (recrystallized from ethyl acetate-ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.4-1.8 (3H, m), 2.98 (1H, m), 3.2-3.4 (2H, m),
3.60-3.85 (2H, m), 3.78 (6H, s), 4.27 (2H, d, J =
5.8 Hz), 6.29 (2H, d, J = 2.2 Hz), 6.38 (1H, t, J
= 2.2 Hz), 7.22-7.45 (5H, m), 7.45 (1H, dd, J = 8.
4, 1.8 Hz), 7.82 (1H, bt), 8.60 (1H, dd, J = 4.0,
1.8 Hz) Elemental analysis: C ₂₉ H ₃₀ N ₃ O ₅ Cl Calculated (%): C 64.98, H 5.64, N 7.84 Found (%): C 64.79, H 5.58, N 7.73.

Reference Example 159 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl) -7,8-dihydro-7- (4-hydroxy-3- Methylbutyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Using the compound obtained in Step 1 of Reference Example 157 and 3,5-bis (trifluoromethyl) benzylamine, Reference Example 2 The reaction and treatment were carried out in the same manner as in step 4 of the above, and N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl) -8-oxo-8H-pyrano [3,4 -B] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 166-167 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 4.63 (2H, d, J = 6.2H)
z), 7.1-7.3 (4H, m), 7.54 (1H, dd, J = 8.4, 1.6 H
z), 7.6-7.8 (1H, m), 7.65 (1H, dd, J = 8.4, 4.4 H
z), 7.73 (2H, s), 7.80 (1H, s), 8.98 (1H, dd, J =
(4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₃ N ₂ O ₃ F ₇ Calculated (%): C 56.48, H 2.57, N 5.49 Found (%): C 56.52, H 2.68, N 5.47. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 212-213 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.77 (3H, d, J = 7.0 H)
z), 1.4-1.8 (3H, m), 3.1-3.7 (5H, m), 4.51 (2H,
m), 6.84-7.00 (2H, m), 7.25-7.48 (3H, m), 7.48 (1H,
dd, J = 8.4, 1.8 Hz), 7.69 (2H, s), 7.82 (1H, s),
8.60 (1H, dd, J = 4.2, 1.8 Hz), 8.76 (1H, bt) Elemental analysis: C ₂₉ H ₂₄ N ₃ O ₃ F ₇ Calculated (%): C 58.49, H 4.06, N 7.06 Value (%): C 58.28, H 4.06, N 7.02.

Reference Example 160 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-ethylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (±) -4-amino-2-ethyl-1-butanol, reacting in the same manner as in Reference Example 5. After treatment, the title compound was obtained as a colorless oil. NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, t, J = 7.0 H
z), 1.0-1.4 (3H, m), 1.5-1.9 (2H, m), 2.28 (3H,
s), 3.0-3.6 (5H, m), 4.50 (2H, d, J = 6.2 Hz), 7.07
(2H, d, J = 8.6 Hz), 7.1-7.3 (2H, m), 7.31 (1H, d
d, J = 8.0, 4.2 Hz), 7.55 (1H, dd, J = 8.0, 1.4 H
z), 7.68 (2H, s), 7.78 (1H, s), 8.43 (1H, bt), 8.6
5 (1H, m).

Reference Example 161 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- [4-hydroxy-
3- (1-Methylethyl) butyl] -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and (±) -4- Amino-2- (1
Reference Example 5 using -methylethyl) -1-butanol
The title compound was obtained as a colorless oil upon treatment. NMR (200MHz, CDCl ₃ ) ppm: 0.82 (6H, d, J = 6.6 H
z), 1.3-2.0 (4H, m), 2.27 (3H, s), 3.30 (1H, m),
3.52 (4H, m), 4.50 (2H, d, J = 5.8 Hz), 7.07 (2H,
d, J = 8.6 Hz), 7.20-7.35 (3H, m), 7.54 (1H, dd, J
= 8.4, 1.6 Hz), 7.67 (2H, s), 7.78 (1H, s), 8.51
(1H, bt), 8.63 (1H, dd, J = 4.4, 1.6 Hz).

Reference Example 162 (±) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- (4-hydroxy-3-ethylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 1 of Reference Example 153 and (±) -4-amino-2-ethyl The reaction was carried out in the same manner as in Reference Example 5 using -1-butanol to give the title compound.
This compound was used for the reaction of Example 17 without purification.

Reference Example 163 (±) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- [4-hydroxy-3- (1-methylethyl) butyl] -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 1 of Reference Example 153 and (±) -4 The reaction was carried out using -amino-2- (1-methylethyl) -1-butanol in the same manner as in Reference Example 5, and the title compound was obtained as a colorless oil upon treatment. This compound was used for the reaction of Example 18 without purification.

Reference Example 164 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-10-methyl-5- (4-methyl Phenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine (Step 1) The compound obtained in Reference Example 3 was reacted with (±) -4-amino-3-methyl-1-butanol in the same manner as in Reference Example 5, Upon treatment, (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-2-methylbutyl) -5
(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide was obtained as a colorless foam. NMR (200MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 7.0 H
z), 1.3-2.4 (3H, m), 2.30 (3H, s), 2.95 (1H, m),
3.4-3.9 (4H, m), 4.46 (2H, m), 7.0-7.4 (5H, m), 7.
52 (1H, d, J = 7.0 Hz), 7.71 (2H, s), 7.78 (1H,
s), 8.56 (1H, bt), 8.64 (1H, d, J = 3.0 Hz). (Step 2) The compound obtained in Step 1 was reacted and treated in the same manner as in Reference Example 69 to give the title compound as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 1.18 (3H, d, J = 7.0 H
z), 1.4-2.5 (3H, m), 2.37 (3H, s), 3.1-3.8 (3H,
m), 4.02 (1H, d, J = 15 Hz), 4.81 (1H, d, J = 14 H
z), 5.46 (1H, d, J = 15 Hz), 6.84 (1H, d, J = 7.2
Hz), 7.06 (1H, d, J = 7.2 Hz), 7.2-7.6 (4H, m), 7.4
8 (2H, s), 7.81 (1H, s), 8.90 (1H, m).

Example 1 (9R) -7- [3,5-di (benzyloxy) benzyl] -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 149 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H
z), 1.65 (1H, m), 1.8-2.4 (2H, m), 2.15 (3H, s),
3.02 (1H, d, J = 15 Hz), 3.32 (1H, dd, J = 15, 10
Hz), 3.52 (1H, dd, J = 14, 10 Hz), 3.81 (1H, d, J
= 14 Hz), 4.97 (4H, s), 5.04 (1H, dd, J = 14, 5.6
Hz), 5.24 (1H, d, J = 14 Hz), 6.28 (2H, d, J = 2.2
Hz), 6.55 (1H, bt), 6.86 (1H, d, J = 8.0 Hz), 7.03
(1H, d, J = 8.0 Hz), 7.2-7.5 (13H, m), 7.60 (1H, d
d, J = 8.4, 1.2 Hz), 8.88 (1H, dd, J = 4.4, 1.2 Hz) Elemental analysis: C ₄₂ H ₃₉ N ₃ O ₄ .0.5H ₂ O Calculated value (%): C 76.57 , H 6.12, N 6.38 Found (%): C 76.19, H 6.33, N 6.25.

Example 2 (9R) -7- (3,5-dihydroxybenzyl)-
6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1 ,
7] Naphthyridine A mixture of the compound obtained in Example 1 (2.3 g), 10% palladium-carbon (50% water content) (3.0 g) and methanol (70 ml) was heated under reflux in a hydrogen atmosphere for 15 hours. After the catalyst was removed by filtration using Celite, the filtrate was concentrated to give the title compound as a colorless powder (1.08 g). NMR (200MHz, DMSO-d ₆ ) ppm: 0.78 (3H, d, J = 6.2 H
z), 1.1-1.6 (1H, m), 1.9-2.5 (2H, m), 2.38 (3H, s),
2.90 (1H, d, J = 15 Hz), 3.0-3.6 (2H, m), 3.87 (1
H, d, J = 14 Hz), 4.7-4.9 (1H, m), 4.84 (1H, d, J
= 14 Hz), 5.88 (2H, d, J = 1.8 Hz), 6.17 (1H, bt),
6.9-7.3 (4H, m), 7.5-7.7 (2H, m), 8.84 (1H, m), 9.
21 (2H, s).

Example 3 (9R) -7- (3,5-diethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The compound obtained in Example 2 (200 mg), sodium hydride (60% oil) (70 mg) and DMF (7 ml)
After stirring the mixture at room temperature for 30 minutes, ethyl iodide was added thereto under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was diluted with ethyl acetate, it was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline. After drying the organic layer, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give the title compound as a colorless powder (66.5 mg). . NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.6 H
z), 1.43 (6H, t, J = 6.9 Hz), 1.66 (1H, m), 1.9-2.
4 (2H, m), 2.42 (3H, s), 3.06 (1H, d, J = 15Hz),
3.33 (1H, dd, J = 15, 11 Hz), 3.56 (1H, dd, J = 1
4, 11 Hz), 3.81 (1H, d, J = 14 Hz), 3.95 (4H, q, J
= 6.9 Hz), 5.06 (1H, dd, J = 14, 5.6 Hz), 5.23 (1
H, d, J = 14 Hz), 6.17 (2H, d, J = 2.2 Hz), 6.38
(1H, t, J = 2.2 Hz), 6.88 (1H, dd, J = 7.8, 1.6 H
z), 7.15 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 7.8
Hz), 7.36 (1H, dd, J = 7.8, 1.6 Hz), 7.46 (1H, dd,
J = 8.4, 4.4 Hz), 7.63 (1H, dd, J = 8.4, 1.4 Hz),
8.90 (1H, dd, J = 4.4, 1.4Hz).

Example 4 (9R) -7- [3,5-Di (1-methylethyloxy) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4 -Methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Reaction was carried out in the same manner as in Example 3 using the compound obtained in Example 2 and 2-iodopropane. Upon treatment, the title compound was obtained as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 7.0 Hz),
1.34 (12H, d, J = 6.0 Hz), 1.65 (1H, m), 1.9-2.4
(2H, m), 2.44 (3H, s), 3.06 (1H, d, J = 15Hz), 3.3
5 (1H, dd, J = 15, 10 Hz), 3.55 (1H, dd, J = 14, 1
1 Hz), 3.88 (1H, d, J = 14 Hz), 4,48 (2H, m), 5.05
(1H, dd, J = 14, 5.7 Hz), 5.19 (1H, d, J = 14 H
z), 6.18 (2H, d, J = 2.2 Hz), 6.37 (1H, t, J = 2.2
Hz), 6.95 (1H, d, J = 7.4 Hz), 7.23 (1H, d, J =
7.6 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.36 (1H, d, J
= 7.4 Hz), 7.47 (1H, dd, J = 8.4, 4.2 Hz), 7.65 (1
H, dd, J = 8.4, 1.6 Hz), 8.90 (1H, dd, J = 4.2, 1.
6 Hz).

Example 5 (9R) -7- (3,5-Dimethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
6,13-dioxo-5-phenyl-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 150 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 199-201 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d, J = 7.0 H)
z), 1.70 (1H, m), 1.90-2.29 (2H, m), 3.05 (1H, d,
J = 15 Hz), 3.33 (1H, dd, J = 15, 10 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.73 (6H, s), 3.80 (1H, d,
J = 14 Hz), 5.08 (1H, dd, J = 14, 5.7 Hz), 5.23 (1
H, d, J = 14 Hz), 6.12 (2H, d, J = 2.2 Hz), 6.37 (1
H, t, J = 2.2 Hz), 6.97 (1H, d, J = 7.2 Hz), 7.23-
7.55 (5H, m), 7.59 (1H, dd, J = 8.2, 1.4 Hz), 8.90
(1H, dd, J = 4.2, 1.4 Hz) Elemental analysis: C ₂₉ H ₂₉ N ₃ O ₄ Calculated (%): C 72.03, H 6.04, N 8.69 Actual (%): C 71.94, H 6.09 , N 8.93.

Example 6 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (4-chlorophenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine The compound obtained in Reference Example 151 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 226-227 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.92 (3H, d, J = 6.6 H)
z), 1.73 (1H, m), 1.9-2.4 (2H, m), 3.02 (1H, d, J
= 16 Hz), 3.35-3.65 (2H, m), 4.01 (1H, d, J = 15 H
z), 5.10 (1H, dd, J = 14, 5.2 Hz), 5.39 (1H, d, J
= 15 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.19 (1H, d, J
= 8.4 Hz), 7.4-7.6 (6H, m), 7.85 (1H, s), 8.93 (1
H, t, J = 3.0 Hz).

Example 7 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (3,4-dichlorophenyl) -6
7,8,9,10,11-hexahydro-9-methyl-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 152 was reacted and treated in the same manner as in Reference Example 69. However, the title compound was obtained as colorless crystals. Melting point: 280-282 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3H × 5/9, d, J = 6)
6 Hz), 0.96 (3H × 4/9, d, J = 6.2 Hz), 1.67 (1H,
m), 1.9-2.4 (2H, m), 3.02 (1H × 5/9, d, J = 15 Hz),
3.13 (1H × 4/9, d, J = 15 Hz), 3.35-3.65 (2H, m),
4.04 (1H × 5/9, d, J = 15 Hz), 4.05 (1H × 4/9, d, J
= 15 Hz), 5.00-5.18 (1H, m), 5.26 (1H × 4/9, d, J =
15 Hz), 5.41 (1H × 5/9, d, J = 15 Hz), 6.79 (1H × 5
/ 9, dd, J = 8.2, 2.0 Hz), 6.98 (1H × 4/9, d, J = 2.0
Hz), 7.25-7.65 (6H, m), 7.85 (1H, s), 8.94 (1H,
m).

Example 8 (9R) -7- (3,5-Dimethoxybenzyl) -5
(3,4-dichlorophenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 153 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 207-208 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H × 1/2, d, J = 6)
8 Hz), 0.89 (3H × 1/2, d, J = 6.8 Hz), 1.65 (1H,
m), 1.9-2.4 (2H, m), 3.00-3.38 (2H, m), 3.44-3.90
(2H, m), 3.75 (3H, s), 3.77 (3H, s), 5.07 (1H, dd,
J = 14, 6.2 Hz), 5.25 (1H, dd, J = 15, 7.4 Hz),
5.99 (1H, d, J = 2.2 Hz), 6.12 (1H, d, J = 2.2 Hz),
6.36 (1H × 1/2, t, J = 2.2 Hz), 6.40 (1H × 1/2, t,
J = 2.2 Hz), 6.79 (1H × 1/2, dd, J = 8.0, 2.2 Hz),
7.11 (1H × 1/2, d, J = 1.8 Hz), 7.25-7.65 (4H, m),
8.91 (1H, m) Elemental analysis: C ₂₉ H ₂₇ N ₃ O ₄ Cl ₂ Calculated (%): C 63.05, H 4.93, N 7.61 Found (%): C 62.73, H 5.07, N 7.64.

Example 9 (9R) -7- (3,5-dimethylbenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 154 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 200-202 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 6.6 H)
z), 1.67 (1H, m), 1.9-2.4 (2H, m), 2.25 (6H, s),
2.44 (3H, s), 2.97 (1H, d, J = 15 Hz), 3.27 (1H, d
d, J = 15, 10 Hz), 3.58 (1H, dd, J = 14, 11 Hz),
3.73 (1H, d, J = 15 Hz), 5.08 (1H, dd, J = 14, 5.7
Hz), 5.38 (1H, d, J = 15 Hz), 6.50 (2H, s), 6.92
(2H, m), 7.15 (1H, d, J = 8.0 Hz), 7.35 (1H, d, J
= 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 7.46 (1H, dd,
J = 8.2, 4.2 Hz), 7.58 (1H, dd, J = 8.2, 1.6 Hz),
8.90 (1H, dd, J = 4.2, 1.6 Hz) Elemental _{analysis: C 30 H 31 N 3 O} 2 Calculated (%): C 77.39, H 6.71, N 9.03 Found (%): C 77.01, H 6.75, N 8.95.

Example 10 (9R) -7- (3,5-Dichlorobenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 155 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 139-141 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3H, d, J = 6.6 H)
z), 1.70 (1H, m), 1.9-2.4 (2H, m), 2.43 (3H, s),
2.95 (1H, d, J = 15 Hz), 3.38 (1H, dd, J = 15, 11
Hz), 3.52 (1H, dd, J = 15, 11 Hz), 3.74 (1H, d, J
= 15 Hz), 5.08 (1H, dd, J = 15, 5.6 Hz), 5.39 (1H,
d, J = 15 Hz), 6.79 (2H, d, J = 1.8 Hz), 6.88 (1
H, dd, J = 7.6, 1.8 Hz), 7.21 (1H, d, J = 7.6 Hz),
7.29 (1H, s), 7.31 (1H, d, J = 7.6 Hz), 7.38 (1H,
dd, J = 7.6, 1.8 Hz), 7.47 (1H, dd, J = 8.4, 4.4
Hz), 7.59 (1H, dd, J = 8.4, 1.8 Hz), 8.90 (1H, dd,
J = 4.4, 1.8 Hz) Elemental analysis: C ₂₈ H ₂₅ N ₃ O ₂ Cl ₂ · 0.3 H ₂ O Calculated (%): C 65.71, H 5.04, N 8.21 Actual (%): C 65.40 , H 4.90, N 8.17.

Example 11 (9R) -5- (3,4-Dichlorophenyl) -7-
(3,5-dimethylbenzyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 156 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as a colorless powder. Melting point: 137-139 ° C NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H × 1/2, d, J = 6.
2 Hz), 0.89 (3H × 1/2, d, J = 6.0 Hz), 1.5-2.3 (3H,
m), 2.25 (3H, s), 2.28 (3H, s), 2.90-3.84 (4H, m),
5.07 (1H, dd, J = 14, 5.8 Hz), 5.31 (1H, dd, J =
14, 9.2 Hz), 6.50 (1H, s), 6.57 (1H, s), 6.78 (1H ×
1/2, dd, J = 8.0, 1.8 Hz), 6.93 (1H, d, J = 6.0 H
z), 7.12 (1H × 1/2, d, J = 1.8 Hz), 7.30 (1H, d, J
= 8.8 Hz), 7.4-7.7 (3H, m), 8.92 (1H, m) Elemental analysis: C ₂₉ H ₂₇ N ₃ O ₂ Cl ₂ .0.3 H ₂ O Calculated (%): C 66.24, H 5.29, N 7.99 Found (%): C 66.21, H 5.49, N 7.70.

Example 12 (9R) -7- (3,5-Dimethoxybenzyl) -5
(4-Fluorophenyl) -6,7,8,9,10,1
1-hexahydro-9-methyl-6,13-dioxo-
13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine The compound obtained in Reference Example 157 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 192-193 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H, d, J = 6.8 H)
z), 1.5-1.8 (1H, m), 1.9-2.4 (2H, m), 3.03 (1H, d,
J = 15 Hz), 3.36 (1H, dd, J = 15, 10 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.75 (1H, d, J = 15 Hz), 3.
76 (6H, s), 5.08 (1H, dd, J = 14, 5.6 Hz), 5.27 (1
H, d, J = 15 Hz), 6.03 (2H, d, J = 2.2 Hz), 6.37 (1
H, t, J = 2.2 Hz), 6.9-7.1 (2H, m), 7.19 (1H, m),
7.45-7.60 (3H, m), 8.91 (1H, dd, J = 4.2, 2.0 Hz) [a] _D = + 109.4 ° (c = 0.497%, methanol) Elemental analysis: C ₂₉ H ₂₈ N Calculated for ₃ O ₄ F (%): C 69.45, H 5.63, N 8.38 Found (%): C 69.32, H 5.57, N 8.31.

Example 13 (9R) -5- (4-Chlorophenyl) -7- (3,5
-Dimethoxybenzyl) -6,7,8,9,10,11
-Hexahydro-9-methyl-6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 158 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 229-230 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H, d, J = 7.0 H)
z), 1.5-1.8 (1H, m), 1.9-2.4 (2H, m), 3.06 (1H, d,
J = 15 Hz), 3.29 (1H, dd, J = 15, 9.8 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.76 (1H, d, J = 15 Hz), 3.
77 (6H, s), 5.07 (1H, dd, J = 14, 5.6 Hz), 5.27 (1
H, d, J = 15 Hz), 6.08 (2H, d, J = 2.2 Hz), 6.39
(1H, t, J = 2.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.2
8 (1H, d, J = 8.4 Hz), 7.46 (2H, m), 7.48 (1H, dd,
J = 8.4, 4.0 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz),
8.91 (1H, dd, J = 4.0, 1.8 Hz) Elemental analysis: C ₂₉ H ₂₈ N ₃ O ₄ Cl.0.2 H ₂ O Calculated (%): C 66.78, H 5.49, N 7.99 Actual measurement ( %): C 66.78, H 5.54, N 7.88.

Example 14 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (4-fluorophenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine The compound obtained in Reference Example 159 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 234-236 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3H, d, J = 6.8 H)
z), 1.73 (1H, m), 2.0-2.4 (2H, m), 3.00 (1H, d, J
= 15 Hz), 3.34-3.62 (2H, m), 3.97 (1H, d, J = 15 H
z), 5.10 (1H, dd, J = 15, 5.2 Hz), 5.42 (1H, d, J
= 15 Hz), 6.85-6.95 (2H, m), 7.13 (1H, dt, J _d = 2.
2, J _t = 9.0 Hz), 7.40-7.52 (3H, m), 7.45 (2H, s),
7.83 (1H, s), 8.92 (1H, t, J = 2.9 Hz) Elemental analysis: C ₂₉ H ₂₂ N ₃ O ₂ F Calculated (%): C 60.31, H 3.84, N 7.28 Actual (% ): C 60.43, H 3.98, N 7.13.

Example 15 (±) -7- [3,5-Bis (trifluoromethyl) benzyl] -9-ethyl-6,7,8,9,10,11-
Hexahydro-5- (4-methylphenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 160 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 258-260 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3H, t, J = 7.1 H)
z), 1.0-1.4 (2H, m), 1.5-1.9 (2H, m), 2.28 (1H,
m), 2.39 (3H, s), 3.04 (1H, d, J = 15 Hz), 3.39 (1
H, dd, J = 15, 9.6 Hz), 3.52 (1H, dd, J = 15, 11 H
z), 3.97 (1H, d, J = 15 Hz), 5.11 (1H, dd, J = 15,
6.6 Hz), 5.48 (1H, d, J = 15 Hz), 6.82 (1H, d, J =
7.6 Hz), 7.06 (1H, d, J = 7.6 Hz), 7.2-7.6 (4H,
m), 7.48 (2H, s), 7.82 (1H, s), 8.91 (1H, dd, J =
4.0, 1.8 Hz) Elemental analysis: C ₃₁ H ₂₇ N ₃ O ₂ F ₆ Calculated (%): C 63.37, H 4.63, N 7.15 Found (%): C 63.24, H 4.67, N 7.29.

Example 16 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9- (1-methylethyl) -5 -(4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 161, reference Example 69 was carried out. The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 228-229 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H)
z), 0.87 (3H, d, J = 7.0 Hz), 1.5-2.4 (4H, m), 2.
39 (3H, s), 3.06 (1H, d, J = 15 Hz), 3.38 (1H, dd,
J = 15, 9.0 Hz), 3.50 (1H, dd, J = 14, 10 Hz), 3.
95 (1H, d, J = 15 Hz), 5.14 (1H, dd, J = 14, 5.6 H
z), 5.49 (1H, d, J = 15 Hz), 6.83 (1H, dd, J = 7.8,
1.4 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J
= 8.0 Hz), 7.35 (1H, dd, J = 8.0, 1.4 Hz), 7.47
(1H, dd, J = 8.4, 4.4 Hz), 7.48 (2H, s), 7.56 (1H,
dd, J = 8.4, 1.8 Hz), 7.82 (1H, s), 8.91 (1H, dd,
J = 4.4, 1.8 Hz) Elemental analysis: Calculated _{C 32 H 29 N 3 O 2} F 6 (%): C 63.89, H 4.86, N 6.98 Found (%): C 63.82, H 4.70, N 7.13 .

Example 17 (±) -5- (3,4-dichlorophenyl) -7-
(3,5-dimethoxybenzyl) -9-ethyl-6
7,8,9,10,11-Hexahydro-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 162 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 260-262 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 0.85-1.00 (3H, m), 1.0-
1.4 (2H, m), 1.5-1.9 (2H, m), 2.23 (1H, m), 3.19 (2
H, m), 3.47-3.80 (2H, m), 3.75 (3H, s), 3.77 (3H,
s), 5.09 (1H, dd, J = 14, 6.2 Hz), 5.28 (1H, dd, J
= 14, 7.6 Hz), 5.99 (1H, d, J = 2.2 Hz), 6.13 (1
H, d, J = 2.2 Hz), 6.36 (1H × 1/2, t, J = 2.2 Hz),
6.40 (1H × 1/2, t, J = 2.2 Hz), 6.76 (1H × 1/2, dd,
J = 8.2, 2.2 Hz), 7.09 (1H × 1/2, d, J = 2.2 Hz), 7.
25-7.62 (4H, m), 8.91 (1H, m) Elemental analysis: C ₃₀ H ₂₉ N ₃ O ₄ Cl ₂ Calculated (%): C 63.61, H 5.16, N 7.42 Actual (%): C 63.20, H 5.15, N 7.58.

Example 18 (±) -5- (3,4-dichlorophenyl) -7-
(3,5-dimethoxybenzyl) -6,7,8,9,1
0,11-hexahydro-9- (1-methylethyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 163 was reacted and treated in the same manner as in Reference Example 69. However, the title compound was obtained as colorless crystals. Melting point: 202-205 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (6H, m), 1.4-2.0 (3
H, m), 2.15 (1H, m), 3.18 (2H, m), 3.4-3.8 (2H, m),
3.75 (3H, s), 3.77 (3H, s), 5.11 (1H, dd, J = 14,
6.4 Hz), 5.28 (1H, dd, J = 14, 6.2 Hz), 5.9-6.8
(3.5H, m), 7.0-7.6 (4.5H, m), 8.91 (1H, m).

Example 19 (1) Compound of Reference Example 72 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl methylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg Reference 10.0 mg of the compound obtained in Example 72 and lactose
A mixture of 0 mg and 35.0 mg of corn starch was granulated using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), dried at 40 ° C. and sieved. The obtained granules were mixed with 2.0 mg of magnesium stearate and compressed. The obtained uncoated tablet,
It was coated with sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 20 (1) Compound of Reference Example 72 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Reference example After granulating 10.0 mg of the compound obtained in 72 and 3.0 mg of magnesium stearate with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), drying, 70.0 mg of lactose and 50.0 mg of corn starch And mixed. The mixture was compressed to give tablets.

Example 21 (1) Compound of Example 12 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl methylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg 10.0 mg of the compound obtained in Example 12 and lactose
A mixture of 0 mg and 35.0 mg of corn starch was granulated using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), dried at 40 ° C. and sieved. The obtained granules were mixed with 2.0 mg of magnesium stearate and compressed. The obtained uncoated tablet,
It was coated with sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 22 (1) Compound of Example 12 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg After granulating 10.0 mg of the compound obtained in 12 and 3.0 mg of magnesium stearate with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), drying, drying, 70.0 mg of lactose and 50.0 mg of corn starch And mixed. The mixture was compressed to give tablets.

[Radioligand Receptor Binding Inhibitory Activity] Binding Inhibitory Activity Using Receptor from Human Lymphoblast Cells (IM-9) MA Cascieri [Molecular Pharmacology] 42
Vol., P. 458 (issued in 1992)]. Receptors were prepared from human lymphoblast cells (IM-9). After IM-9 cells (2 × 10 ⁵ cells / ml) were cultured for 3 days (1 liter) after inoculation, they were centrifuged at 500 × G for 5 minutes to obtain cell pellets. The obtained pellet was added to a phosphate buffer (Flow Laboratories, CAT. N).
o. 28-103-05), and then washed 3 times.
0 mM 120 mM sodium chloride, 5 mM potassium chloride, 2 μg / ml chymostatin, 40 μg / ml bacitracin, 5 μg / ml phosphoramidone, 0.5 mM phenylmethylsulfonyl fluoride, 1 mM ethylenediaminetetraacetic acid in 50 mM Tris-HCl buffer (pH
Crushed in 7.4) using a Polytron homogenizer (Kinematika, Germany),
Centrifuged at 000 × G for 20 minutes. The separated product was washed twice with 30 ml of the above buffer solution, and then stored frozen (−80 ° C.) as a receptor sample.

This sample was treated with a reaction buffer [50 mM Tris / hydrochloric acid buffer (pH 7.4), 0.02% bovine serum albumin, 1 m) to a protein concentration of 0.5 mg / ml.
M phenylmethylsulfonyl fluoride, 2 μg / m
1 chymostatin, 40 μg / ml bacitracin, 3 mM
Manganese chloride], and a 100 μl volume was used for the reaction. Sample, ¹²⁵ I-BHSP (0.46 KBq)
At 25 ° C. in 0.2 ml of reaction buffer.
Minutes. The amount of non-specific binding was determined by adding substance P to 2 × 10 ⁻⁶ M. After the reaction, the cell harvester [290PHD, Cambridge Technology, Incorporated.
c.) Company, USA], using a glass filter [GF /
B, Whatman, USA] to stop the reaction, and to stop the reaction, 250 μl of 50 mM Tris-HCl buffer (pH 7.4) containing 0.02% bovine serum albumin.
And the radioactivity remaining on the filter was measured with a gamma counter. Filter before use 0.1
% Polyethyleneimine for one day and then air-dried before use.

The antagonistic activity of each of the compounds obtained in Reference Examples and Examples was 50% under the above conditions, respectively.
The following results were obtained when the concentration was determined as the drug concentration (IC ₅₀ value) required to show inhibition.

[Table 1] Radioligand refers to substance P labeled with ¹²⁵ I. From this, it can be seen from Table 1 that the heterocyclic compound (I) or a salt thereof has excellent substance P receptor antagonism.

Human NK ₂ Receptor Binding Inhibitory Activity A. Graham, B. Hopkins, SJ Powel
l, P. Danks and I. Briggs) [Biochemical and Biophysical Research Communica
tions) 177 Volume 8-16 pp (3 was prepared according to the 1991 issue)] et al nucleotide sequence of the human NK ₂ receptor cDNA reported 'primer (5'-CTAACCCCT
ACCTCCCAACACTGCCACATTGGG-
3 ′, 20 pmol), human gastric poly A ⁺ RNA (2 μg, Clo
ntech Laboratories, Inc., USA) and Superscri
ptRNase H ^- reverse transcriptase (GIBCO
Reverse transcriptase reaction was performed at 48 ° C. for 1 hour using BRL Life Technologies Inc., USA. Then, 3 'primer, 5', prepared according to the base sequence of the human NK ₂ receptor cDNA which the Agent Graham et al reported primers (5'-GAGCCAGGTCCTTTGTTCCA
GACCCAGAAGCAG-3 ') and Taq DN
A at 95 ° C using A polymerase (Takara Shuzo, Shiga)
Polymerase chain reaction (PCR) was performed for 50 minutes at 55 ° C. for 2 minutes and at 72 ° C. for 3 minutes for 50 cycles.
The 1.3 kbp PCR product was converted to pBluescript II SK ⁺
(Stratagene, USA). The nucleotide sequence was analyzed, it was confirmed to be consistent with the nucleotide sequence of the human NK ₂ receptor cDNA which the Agent Graham et al reported. 1.3k to construct the expression vector
Incorporating human NK ₂ receptor cDNA base pairs downstream of the SRα promoter [Y. Takebe, M. Seiki, J. Fuji
sawa, P. Hoy, K. Yokota, K. Arai, M. Yoshida, and
N. Arai “Molecular and Cellular Biology 8, p 466-
472 (1988)].

COS-7 cells were seeded in a 175 cm ² flask (Nunc, Denmark) (3 × 10 ⁶ cells / flask), and DMEM medium (I) containing 10% fetal bovine serum.
After overnight culture in CN Biomedicals, Inc., USA, 30 μg of the above expression vector, 150 μg of transfectam (Bi
oSepra Inc., USA) at 37 ° C. for 5 hours. After culturing for 3 days, a phosphate buffer containing 0.1% ethylenediaminetetraacetic acid (ICN Biomedicals, Inc., Ca.
t. No. 2810305, USA), and after removing cells, 17
Centrifugation was performed at 0 × g for 5 minutes to obtain a cell pellet. The obtained cells were treated with 120 mM sodium chloride, 5 mM potassium chloride,
0.5 mM phenylmethylsulfonyl fluoride, 2 μm
g / ml chymostatin, 40 μg / ml bacitracin, 5 μg
/ Ml phosphoramidone, 50 mM Tris-HCl buffer (pH 7.4) containing 1 mM ethylenediaminetetraacetic acid and a homogenizer (Physicotron Handy Micro Homo).
(generator NS-310E, Nichion Medical Science Instrument Co., Ltd., Chiba) and centrifuged at 40,000 × g for 60 minutes. After the pellet was washed twice with the above buffer, it was frozen and stored at -80 ° C as a receptor sample.

This sample was treated with a reaction buffer (50 mM Tris / HCl buffer (pH 7.4): 0.02% bovine serum albumin, 1 mM) so as to obtain a protein concentration of 0.6 mg / ml.
Phenylmethylsulfonyl fluoride, containing 2 μg / ml chymostatin, 40 μg / ml bacitracin and 3 mM manganese chloride), and 0.1 ml was used for the reaction.
Test compound (2- [ ¹²⁵ I] iodohistidyl ¹ ) Neurokinin
A (manufactured by Amersham, UK) (74 TBq / mmol, 1.
(48 kBq, 0.1 nM final concentration) to a final volume of 0.2 ml and left standing at room temperature for 60 minutes in a 96-well plate. Glass fiber filter (UniFilter-96, GF / B,
Packard Instrument
CO., Inc.), the United States) and cell harvesters (Filter
After suction filtration using Mate Cell Harvester, Packard Instrument CO., Inc. (USA), and washing three times with 0.3 ml of the above reaction buffer,
The radioactivity of the filter is measured by a scintillation counter (TopCount Microplate Scintillation Counter, manufactured by Packard Instrument C)
O., Inc.), USA). For non-specific binding, neurokinin A (Peptide Institute, Osaka) was used at a final concentration of 10 × 1.
It was determined by adding at 0 ^-6 M. Before use, glass fiber filters are 0.5% bovine serum albumin (Sigma,
(US) for one day. Then, the drug concentration (IC ₅₀ value, n) required to exhibit 50% inhibition of the binding antagonistic activity of the compounds obtained in Reference Examples under the above conditions, respectively.
M), the following results were obtained.

[0294]

[Table 2] Table 2 shows that the heterocyclic compound (I) or a salt thereof exhibits excellent NK ₂ receptor antagonistic activity.

Capsaicin in guinea pig trachea
cin) Inhibitory activity of induced vascular hyperpermeability reaction Pentobarbital (Pentobarbital) 35 mg / kg was intraperitoneally (ip) administered to anesthetize guinea pigs (Hartley white male guinea pigs) (n = 6), and the test compound was intravenously administered. (Iv.) Administration. After 5 minutes, capsaic
in) (150μg / kg) and Evans'blu
e) The reaction was induced by iv administration of a mixture of (20 mg / kg). Ten minutes later, the thoracotomy was performed to cut the vena cava, and then perfused with 50 ml of saline from the pulmonary artery. After removal of the trachea, the wet weight was measured. And acetone-
Add 1 ml of 0.3% sodium sulfate (7: 3) solution and add 1 ml.
After standing overnight, Evans'blue was extracted from the trachea. After the extract was centrifuged at 1500 rpm for 5 minutes, the Evans'blue
_Was quantified by measuring _A620 . The vascular hyperpermeability reaction was determined by the amount of Evans'blue (μ) per unit weight (g) of the trachea.
g), and the drug effect is calculated as the inhibition rate (% inh
ibition) was calculated and evaluated [Table 3].

[0296]

(Equation 1)

[Results]

[Table 3] Table 3 shows that the heterocyclic compound (I) or a salt thereof has an excellent inhibitory effect on the capsaicin-induced vascular hyperpermeability reaction.

[0298]

EFFECTS OF THE INVENTION The heterocyclic compound (I) or a salt thereof has a tachykinin receptor antagonistic activity and is useful as a preventive / therapeutic agent for depression, anxiety, manic depression or mental illness.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/435 606 A61K 31/435 606 31/55 601 31/55 601

Claims (20)

[Claims] (1) Formula (1) A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different, and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
A ring is a homo- or heterocyclic ring which may have a substituent; a ring Z is a nitrogen-containing heterocyclic ring which may be substituted; and n represents an integer of 1 to 6] or a salt thereof. A prophylactic / therapeutic agent for depression, anxiety, manic depression or mental illness, comprising: 2. ^Ra and ^Rb are each a hydrogen atom or (I) a halogen atom, (II) (i) a hydroxy group, (ii) C
_1-6 alkoxy group, (iii) C _1-6 alkylthio group, (i
v) amino group, (v) C _1-7 acylamino group, (vi) carboxyl group, (vii) nitro group, (viii) mono- or di-C _1-6 alkylamino group, (ix) mono- or di- −C _3-8
A heteroatom selected from the group consisting of an oxygen atom and a sulfur atom in addition to a nitrogen atom, which may be substituted with a cycloalkylamino group, (x) a C _6-10 arylamino group, and (xi) C _1-6 alkyl A 5- to 9-membered cyclic amino group optionally containing 1 to 3 carbon atoms, (xii) a carbon atom, a nitrogen atom,
A 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen and sulfur, (xiii) from the group consisting of nitrogen, oxygen and sulfur other than carbon A 5- to 9-membered non-aromatic heterocyclic group containing 1 to 3 heteroatoms selected, (xiv)
C _1- which may have 1 to 5 substituents selected from the group consisting of a C _1-4 alkylsulfonylamino group, (xv) C _1-6 alkyl-carbonyloxy group and (xvi) halogen atom. ₆ alkyl group, (III) optionally halogenated C _1-6 alkoxy group, (IV) optionally halogenated C _1-6 alkylthio group, (V) C _3-10 cycloalkyl group, VI) C _6-10 aryl group, (VII) C _1-7 acylamino group, (VIII) C _1-3 acyloxy group, (IX) hydroxy group, (X) nitro group, (XI) cyano group, (XII) Amino group, (XIII) mono- or di-C _1-6 alkylamino group, (XIV) _optionally selected from the group consisting of oxygen atom and sulfur atom other than nitrogen atom, which may be substituted with C _1-6 alkyl 5 which may contain 1 to 3 hetero atoms to 9-membered cyclic amino group, (XV) C _1-6 alkyl Carbonylamino group, (XVI) C _1-6 alkyl - sulfonylamino group, (XVII) C _1-6 alkoxy - carbonyl group, (XVII
I) carboxyl group, (XIX) C _1-6 alkylcarbonyl group, (XX) carbamoyl group, (XXI) mono- or di-C
_1-6 or indicating the alkylcarbamoyl group and (XXII) C _1-6 alkylsulfonyl substituent selected from the group consisting of radicals; R ^a and R ^b form a ring A together bonded to, ring A is (I ) A halogen atom, (II) a hydroxy group, (i)
i) amino group, (iii) carboxyl group, (iv) nitro group, (v) mono- or di-C _1-6 alkylamino group, (v
i) a C _1-6 alkyl-carbonyloxy group and (vii)
C _1-6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of halogen atoms, (III) C _1-6 alkoxy group optionally halogenated, (IV) halogen _Optionally substituted C _1-6 alkylthio group, (V) C
_6-10 aryl group, (VI) C _1-7 acylamino group, (VII)
C _1-3 acyloxy group, (VIII) hydroxy group, (IX)
Nitro group, (X) cyano group, (XI) amino group, (XII) mono- or di-C _1-6 alkylamino group, (XIII) hetero atom selected from the group consisting of oxygen atom and sulfur atom other than nitrogen atom A 5- to 9-membered cyclic amino group optionally containing 1 to 3 atoms, (XIV) a C _1-6 alkyl-carbonylamino group, (XV) a C _1-6 alkyl-sulfonylamino group,
(XVI) C _1-6 alkoxycarbonyl group, (XVII) carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XI
1 to 4 substituents selected from the group consisting of X) carbamoyl group, (XX) mono- or di-C _1-6 alkylcarbamoyl group, (XXI) C _1-6 alkylsulfonyl group and (XXII) oxo group A 5- to 9-membered aromatic heterocycle containing 1 to 3 one or two heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom which may be substituted with A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered ring containing 1 to 3 or 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom Represents a hydrocarbon; ring B is (I) a halogen atom, (II)
(i) hydroxy group, (ii) amino group, (iii) carboxyl group, (iv) nitro group, (v) mono- or di-C _1-6 alkylamino group, (vi) C _1-6 alkyl-carbonyl A C _1-6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of an oxy group and (vii) a halogen atom, (III) a C _1-6 alkoxy optionally halogenated Group, (IV) a C _1-6 alkylthio group which may be halogenated, (V) a C _6-10 aryl group, (VI) a C _1-7 acylamino group, (VII) a C _1-3 acyloxy group, VIII) hydroxy group, (IX) nitro group, (X) cyano group, (XI) amino group, (XII) mono- or di-C _1-6 alkylamino group, (XIII) nitrogen atom, oxygen atom, sulfur 5 which may contain 1 to 3 heteroatoms selected from the group consisting of atoms to 9-membered cyclic amino group, (XIV) C _1-6 a Kill - carbonylamino group, (XV) C _1-6 alkyl - sulfonylamino group, (XVI) C _1-6 alkoxycarbonyl group,
(XVII) a carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XIX) carbamoyl group, (XX) mono - or di -C _1-6 alkylcarbamoyl group, (XXI) C _1-6 alkylsulfonyl and ( XXII) one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, other than a carbon atom, which may be substituted with 1 to 4 substituents selected from the group consisting of an oxo group A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 atoms,
A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered ring containing 1 to 3 or 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom A hydrocarbon; C ring is (I) halogen atom, (II) optionally halogenated C _1-10
Alkyl group, (III) C _1-4 alkyl group substituted by an amino group, (IV) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (V) a carboxyl group in substituted C _1-4 alkyl group, (VI) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group, C _1-4 alkyl group substituted with (VII) hydroxy group, ( VIII) C
_3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxy group, (XII) optionally halogenated C _1-10 alkoxy group, (XIII) halogenated A C _1-4 alkylthio group, a (XIV) amino group,
(XV) mono- or di-C _1-4 alkylamino group, (XVI)
5 to 9 which may contain 1 to 3 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to the nitrogen atom
Membered cyclic amino group, (XVII) C _1-4 alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (X
IX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (X
XI) C _1-4 alkoxy-carbonyl group, (XXII) aralkyloxycarbonyl group, (XXIII) carboxyl group,
(XXIV) C _1-6 alkylcarbonyl group, (XXV) C _3-6 cycloalkyl-carbonyl group, (XXVI) carbamoyl group, (XXVII) mono- or di-C _1-4 alkylcarbamoyl group or (XXVIII) C _A group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, in addition to a carbon atom which may be substituted with a _1-6 alkylsulfonyl group and (XXIX) 1 to 3 optionally halogenated C _1-4 alkyl groups; May be substituted with 1 to 5 substituents selected from the group consisting of a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 one or two heteroatoms selected from ,
A 5- to 9-membered heterocycle containing 1 to 3 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; or (I) a halogen atom, (II ) C _1-10 which may be halogenated
Alkyl group, (III) C _1-4 alkyl group substituted by an amino group, (IV) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (V) a carboxyl group in substituted C _1-4 alkyl group, (VI) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group, C _1-4 alkyl group substituted with (VII) hydroxy group, ( VIII) C
_3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxy group, (XII) optionally halogenated C _1-10 alkoxy group, (XIII) halogenated A C _1-4 alkylthio group, a (XIV) amino group,
(XV) mono- or di-C _1-4 alkylamino group, (XVI)
5 to 9 which may contain 1 to 3 hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to the nitrogen atom
Membered cyclic amino group, (XVII) C _1-4 alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (X
IX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (X
XI) C _1-4 alkoxy-carbonyl group, (XXII) aralkyloxycarbonyl group, (XXIII) carboxyl group,
(XXIV) C _1-6 alkylcarbonyl group, (XXV) C _3-6 cycloalkyl-carbonyl group, (XXVI) carbamoyl group, (XXVII) mono- or di-C _1-4 alkylcarbamoyl group, (XXVIII) C _1-6 alkylsulfonyl group and (X
XIX) 1 to 3 optionally halogenated C _1-4
A 5- or 6-membered aromatic unit containing 1 to 4 one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom which may be substituted by an alkyl group; A 3- to 10-membered homocyclic ring which may be substituted with 1 to 5 substituents selected from the group consisting of cyclic heterocycles; wherein Z ring is (I) a C _1-6 alkyl group, II) C _2-6 alkenyl group, (III) C _2-6 alkynyl group, (IV) C _3-8 cycloalkyl group, (V) C _3-8 cycloalkyl-C _1-4 alkyl group, (VI) C _6-14 aryl group, (VII) nitro group, (VIII) cyano group, (IX) hydroxy group, (X) C _1-4 alkoxy group, (XI) C _1-4 alkylthio group, (XII) amino group , (XIII) C _1-4 mono - selected from or di -C _1-4 alkylamino group, an oxygen atom in addition to (XIV) nitrogen atom, the group consisting of sulfur atoms 5 which may contain 1 to 3 hetero atoms to 9-membered cyclic amino group, (XV) C _1-4 alkyl - carbonylamino group, (XV
I) C _1-4 alkylsulfonylamino group, (XVII) C _1-4
Alkoxy-carbonyl group, (XVIII) carboxyl group, (XIX) C _1-6 alkylcarbonyl group, (XX) carbamoyl group, (XXI) mono- or di-C _1-4 alkylcarbamoyl group, (XXII) C _{1- 6} alkylsulfonyl group, (XXI
II) from the group consisting of nitrogen, oxygen and sulfur, in addition to Y and nitrogen, which may be substituted with 1 to 5 substituents selected from the group consisting of oxo and (XXIV) thioxo The agent according to claim 1, which represents a 5- to 12-membered heterocycle optionally containing at least one selected heteroatom. 3. R ^a and R ^b are each a hydrogen atom or (I) a halogen atom, (II) (i) a hydroxy group, (ii) C
_1-6 alkoxy group, (iii) C _1-6 alkylthio group, (i
v) amino group, (v) C _1-7 acylamino group, (vi) mono- or di-C _1-6 alkylamino group, (vii) mono- or di-C _3-8 cycloalkylamino group, (viii ) C _1-6 alkyl optionally substituted, an oxygen atom in addition to the nitrogen atom, a hetero atom selected from the group consisting of sulfur atoms 1
A 5- to 9-membered cyclic amino group optionally containing three,
(Ix) C _1-4 alkylsulfonylamino group, (x) C _1-6
A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from the group consisting of an alkyl-carbonyloxy group and (xi) a halogen atom, and (III) a C _1-6 alkyl group. A 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to a nitrogen atom, (IV) a carboxyl group, and (V) carbamoyl groups and (VI) mono - or di -C _1-6 or a substituent selected from the group consisting of an alkylcarbamoyl group; R ^a and R ^b are joined together to form a ring a, ring a is C _{1 -6-} membered 5- to 9-membered group which may be substituted with an alkyl group and contains 1 to 3 or 1 or 2 hetero atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom An aromatic heterocyclic ring; ring B is (i) Proxy C _1-6 alkyl group optionally substituted with a group, (ii) C _1-6 alkylcarbonyl group and (iii)
A C _6-14 aryl group which may be substituted with a substituent selected from the group consisting of a carboxyl group;
Halogen atom, (ii) optionally halogenated C
_A C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from the group consisting of a _1-10 alkyl group and (iii) a C _1-10 alkoxy group; C _1-6
An alkyl group, (ii) a hydroxy group and (iii) an oxo group, which may be substituted with 1 to 3 substituents selected from the group consisting of a nitrogen atom,
5 to 12 which may contain at least one hetero atom selected from the group consisting of an oxygen atom and a sulfur atom
The agent according to claim 1, which represents a membered heterocycle. 4. A compound of the formula Wherein the R ¹ is C _1-6 alkyl group, R ² is C _1-6 alkoxy groups, optionally substituted C _1-6 alkyl group by a halogen, a halogen atom, a hydroxy group or a C _7-15 In the aralkyloxy group, X represents 1 to 5 groups selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a halogen atom. However, (1) when R ¹ is a methyl group and R ² is a trifluoromethyl group, X represents a halogen atom,
(2) when R ¹ is a methyl group and R ² is a methoxy group, X
Represents a hydrogen atom or a halogen atom]. (5) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11
-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine or a salt thereof. Item 7. The agent according to Item 1. 6. (9R) -7- (3,5-dimethoxybenzyl) -6,7,8,9,10,11-hexahydro-
9-methyl-5- (4-methylphenyl) -6,13-
Dioxo-13H- [1,4] diazosino [2,1-
g] The agent according to claim 1, comprising [1,7] naphthyridine or a salt thereof. (9) (9R) -7- (3,5-dimethoxybenzyl) -5- (4-fluorophenyl) -6,7,8,
9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] The agent according to claim 1, comprising [1,7] naphthyridine or a salt thereof. 8. (9S) -7-[(3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,1
A composition comprising 2-hexahydro-9-methyl-5- (4-methylphenyl) -6,12-dioxo- [1,4] diazepino [2,1-g] [1,7] naphthyridine or a salt thereof. The agent according to 1. 9. A compound of the formula Wherein the R ¹ is C _1-6 alkyl group, R ² is C _1-6 alkoxy groups, optionally substituted C _1-6 alkyl group by a halogen, a halogen atom, a hydroxy group or a C _7-15 In the aralkyloxy group, X represents 1 to 5 groups selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group and a halogen atom. However, (1) when R ¹ is a methyl group and R ² is a trifluoromethyl group, X represents a halogen atom,
(2) when R ¹ is a methyl group and R ² is a methoxy group, X
Represents a hydrogen atom or a halogen atom] or a salt thereof. 10. R ¹ is C _1-3 alkyl group, R ² is C _1-3 alkoxy group, an optionally C _1-3 alkyl group optionally substituted by halogen, halogen atom, hydroxy group or a benzyl group, 10. The compound according to claim 9, wherein X is a hydrogen atom or one or two groups selected from the group consisting of a _C1-3 alkyl group and a halogen atom. 11. R ¹ is a methyl group, R ² is methoxy, ethoxy, isopropoxy, methyl, trifluoromethyl, chlorine, hydroxy or benzyloxy, X is hydrogen, methyl or methyl. The compound according to claim 9, which is one or two chlorine atoms or fluorine atoms. (9) (9R) -7- (3,5-dimethoxybenzyl) -5- (4-fluorophenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine or a salt thereof. (13) a prodrug of the compound according to the above (9); 14. A compound of the formula [Wherein D and E together with the nitrogen atom adjacent to E have the formula Wherein L is a leaving group, and other symbols are as defined in claim 9.] or a salt thereof is subjected to a cyclization reaction. The method for producing a compound according to claim 9, wherein [15] A pharmaceutical comprising the compound according to [9]. 16. A tachykinin receptor antagonist comprising the compound according to claim 9. (17) A substance P receptor antagonist comprising the compound according to the above (9). (18) A neurokinin A receptor antagonist, comprising the compound according to (9). (19) A preventive / therapeutic agent for urinary abnormalities, comprising the compound according to (9). (20) A preventive / therapeutic agent for asthma, rheumatoid arthritis, osteoarthritis, pain, cough, irritable bowel disease or vomiting, comprising the compound according to (9).