JP2976097B2 - Cyclic compounds, their production and agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel cyclic compound having an excellent tachykinin receptor antagonistic activity, a method for producing the same, and an agent containing the cyclic compound.

[0002]

2. Description of the Related Art Capsaicin is a stimulable main component of pepper, and substance P among primary sensory nerves.
(Hereinafter sometimes simply referred to as SP), neurokinin A (NKA), calcitonin gene-related peptide (CG
It is known as a substance that selectively stimulates C-fibers (RP) and the like to release their endogenous neuropeptides. Tachykinin is a general term for a group of neuropeptides, and in mammals, substance P, neurokinin-A, and neurokinin-B are known. By binding to kinin-1, neurokinin-2, neurokinin-3),
It is known to exert various biological activities. Among them, substance P is one of the longest-lasting and well-studied neuropeptides.
It is a peptide consisting of 11 amino acids, which was confirmed in horse intestinal extract for one year and whose structure was determined in 1971. Substance P is known to play an important role as a signal transmitter and the like in the periphery and central nervous system.
Allergies, urinary frequency, urinary incontinence, respiratory illness, mental illness, etc.).

[0003] Substance P is widely distributed in the central and peripheral nervous systems. In addition to its function as a transmitter of primary sensory neurons, it also has a vasodilatory effect, a vascular hyperpermeability effect, a smooth muscle contraction effect, and a nerve cell. It has physiological activities such as an excitatory action, a salivary action, a diuretic enhancement action, and an immune action.
In particular, it is known that SP released from the terminal of the dorsal horn of the spinal cord by pain impulses transmits pain information to secondary neurons, and that SP released from peripheral terminals causes an inflammatory response to its receptor. SP is also thought to be involved in Alzheimer-type dementia [Review: Physiological Reviews,
73, pp. 229-308 (published in 1993), Journal of Autonomic Pharmacology (Jour
nal of Autonomic Pharmacology), 13 volumes, 23-93
Page (issued in 1993)]. At present, compounds having a substance P receptor antagonistic action are disclosed in (1)
No. 7095 discloses a compound represented by the formula: R ¹ -AD-Trp (R ² ) -Phe-R ³ [wherein R ¹ is a hydrogen atom or an amino-protecting group, R ² is a hydrogen atom, an amino-protecting group, carbamoyl A (lower) alkyl group, a carboxy (lower) alkyl group or a protected carboxy (lower) alkyl group, R ³ is an ar (lower) alkyl group,

Embedded image (Wherein R ⁴ and R ⁵ each represent a hydrogen atom, an aryl group or a lower alkyl group optionally having a substituent, or R ⁴ and R ⁵ are bonded to each other to form a benzene-condensed lower alkylene; Or a group represented by the formula: -OR ⁶ (wherein R ⁶ represents a hydrogen atom, an aryl group or a lower alkyl group optionally having a suitable substituent). And the group A represents a single bond or one or two amino acid residues, and when A represents one amino acid residue of -D-Trp-, R ⁴ is not a hydrogen atom. And salts thereof are disclosed.

(2) EP-A-436 and 334 have the formula

Embedded image Are represented by (3) EP-A-429,
366 contains the formula

Embedded image Compounds represented by (4) Journal of
Medicinal chemistry (Journal of MedicinalCh)
emistry), 34, 1751 (issued in 1991)

Embedded image And the like are disclosed.

[0005] Further, (5) WO91 / 09844 includes a formula

Embedded image Compounds represented by the following formula (6): EP-A-522,
In 808, the formula

Embedded image And the like are disclosed. (7) WO
In 93/01169, the formula

Embedded image Compounds represented by the following formula (8): EP-A-532,
In 456, the expression

Embedded image And the like are disclosed.

Further, (9) Bioorganic and Medicinal Chemistry Letters
& Medicinal Chemistry Letters), vol. 4, p. 1903 (issued in 1994) include the formula:

Embedded image Is a compound represented by (10) European Journal of Pharmacology
armacology), 250 volumes, 403 pages (published in 1993)
Has the formula:

Embedded image The compound represented by

(11) EP-A-585,913 describes:
formula:

Embedded image [Wherein, ring A may have a substituent; ring B is a benzene ring which may have a substituent; X and Y are each one of -NR ^1- (R ¹ is A hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent), -O- or -S- , The other being -CO-, -C
S- or ^{-C (R 2) R 2a -} (R 2 and R ^2a represent, respectively, a hydrogen atom or a substituent optionally may hydrocarbon group having a), or one is -N =, the other = C
R ^3- (R ³ has a hydrogen atom, a halogen atom, a hydrocarbon group optionally having a substituent, an amino group optionally having a substituent, a hydroxyl group having a substituent or a substituent; Represents a mercapto group which may be substituted with an optionally substituted hydrocarbon group)

Embedded image D is a C _1-3 alkylene group optionally substituted with an oxo group or a thioxo group, or D and Y together form a 5- to 7-membered ring optionally substituted with an oxo group or a thioxo group. E is -NR ^5- (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent, or R ⁵ and Y together are substituted by an oxo group or a thioxo group; May form a 5- to 7-membered ring), -O- or -S (O) _n- (n represents 0, 1 or 2); G represents a bond or a C _1-3 alkylene group; Ar represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent. However,
(I) -XY- is -O-CO- or -CO-O-,
D is is -CO- and E -NR ⁵ - when it is, (a)
G is a C _1-3 alkylene group, Ar is a substituted aryl group or a substituted heterocyclic group, or (b) G is a bond and R ⁵ is a hydrocarbon group which may have a substituent, and (Ii) when -XY- is -NH-CO-, D is-
CO- is shown. Or a salt thereof, and the like.

At present, as compounds having a neurokinin A receptor antagonistic activity, (1) Life Sciences, vol. 50, p. 101 (issued in 1992)

Embedded image Compounds represented by (2) Bio-Organic and Medicinal Chemistry Letters (Bi
oorganic & Medicinal Chemistry Letters), Volume 4,
On page 1951 (issued in 1994), the formula

Embedded image Compounds represented by the formula (3), AFMC International Medicinal Chemistry Symposium
osium) (Tokyo), P6M page 139 (issued in September 1995)

Embedded image Compounds represented by

(4) Tachykinins (Florence) (Ta
chykinins (Florence)), page 21 (October 1995) has the formula

Embedded image (5) Journal of Medicinal Chemistry
istry), vol. 38, p. 3772 (issued in 1995)

Embedded image (6) Bio-organic
And Medicinal Chemistry Letters (Bioo
rganic & Medicinal Chemistry Letters), Volume 5, 2
On page 879 (issued in 1995), the formula

Embedded image And the like are described. However, in these references, the formula:

[0010]

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 which may have a group, at least one of which is a heterocyclic ring which may have a substituent; and ring Z represents a ring which may be substituted. And the properties thereof as well as the condensed heterocyclic compound having a basic skeleton represented by the formula (1).

[0011]

At present, it has excellent tachykinin receptor antagonism (particularly substance P receptor antagonism) as a therapeutic agent for the above-mentioned various conditions (particularly pollakiuria, urinary incontinence, etc.) and is safe. A compound which is sufficiently satisfactory in terms of properties and sustainability has not yet been found. Therefore,
There is a demand for the development of a compound that has a different chemical structure from the known compounds, has an excellent tachykinin receptor antagonistic action, and is sufficiently satisfactory as the therapeutic agent. Accordingly, an object of the present invention is to provide a novel compound having a high tachykinin receptor antagonistic activity, particularly a substance P receptor antagonistic activity, and a method for producing the same. Another object of the present invention is to provide a pharmaceutical composition having a high tachykinin receptor antagonistic activity, particularly a substance P receptor antagonistic activity, a tachykinin receptor antagonist, and an agent for improving dysuria.

[0012]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above circumstances, and as a result, as a basic skeleton,

Embedded image [The symbols in the formula are as defined above. ] And a fused heterocyclic compound having an unexpectedly excellent tachykinin receptor antagonistic action (particularly substance P Receptor antagonism) and the like, and were found to be sufficiently satisfactory as a medicament, and based on these, the present invention was completed.

That is, the present invention provides (1) the following formula (I)

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
The ring is a homo or heterocyclic ring which may have a substituent; the Z ring is a ring which may be substituted; and n represents an integer of 1 to 6. Or a salt thereof,

(2) R ^a and R ^b are each a hydrogen atom or (I) a halogen atom; (II) (i) a hydroxyl group, (ii) a C _1-6 alkoxy group,
(Iii) C _1-6 alkylthio group, (iv) 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 cycloalkylamino group, (x) C _6-10 arylamino group, (xi) One heteroatom selected from oxygen atom and sulfur atom in addition to nitrogen atom
A 5- to 9-membered cyclic amino group optionally containing up to 3
i) a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom; (xiii) a nitrogen atom and an oxygen other than a carbon atom A 5- to 9-membered non-aromatic heterocyclic group containing 1 to 3 heteroatoms selected from atoms and sulfur atoms,
(Xvi) C _1-4 alkylsulfonylamino group, (xv) C
_A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from a _1-6 alkyl-carbonyloxy group and (xvi) a halogen atom, (III) an 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) hydroxyl group, (X) nitro group, (XI) cyano group, (XII) amino group, (XIII) mono- or di-C _1-6 alkylamino group, (XIV) nitrogen oxygen atom besides atom, a cyclic amino group of 1-3 which may contain 5-9 membered heteroatom selected from nitrogen atom, (XV) C _1-6 alkyl - Carbonylamino group, (XVI) C _1-6 alkyl-sulfonylamino group, (XVII) C _1-6 alkoxy-carboni (XVIII) carboxyl group, (XIX) C _1-6 alkyl-carbonyl group, (XX) carbamoyl group, (XXI) mono- or di-C _1-6 alkylcarbonyl group, (XXII) C _1-6 Represents a substituent selected from alkylsulfonyl and (XXIII) oxo; R ^a and R ^b are bonded together to form a ring A,

Ring A is (I) a halogen atom, (II) (i) a hydroxyl group, (ii) an amino group, (iii) a carboxyl group, (iv) a nitro group, (v) a mono- or di-C
_1-6 alkylamino group, (vi) C _1-6 alkyl - 1 selected from carbonyl group and (vii) a halogen atom
To five may have a substituent group C _1-6 alkyl group, (III) optionally halogenated a C _1-6 alkoxy group, optionally (IV) halide C _{1- 6} alkylthio group, (V) C _6-10 aryl group, (VI) C _1-7 acylamino group, (VII) C _1-3 acyloxy group, (VIII) hydroxyl group, (IX) nitro group, (X) cyano group, (XI) amino group, (XII) mono - contain one to three or di -C _1-6 alkylamino group, (XIII) other than nitrogen atoms to oxygen atoms, hetero atoms selected from nitrogen atom (XIV) C _1-6 alkyl-carbonylamino group, (XV) C _1-6 alkyl-sulfonylamino group, (XVI) C _1-6 alkoxycarbonyl group, (XVII ) Carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XIX) carbamoyl group, (XX) mono- or Is a carbon atom which may be substituted with a di-C _1-6 alkylcarbamoyl group, (XXI) C _1-6 alkylsulfonyl or (XXII) oxo group, other than a nitrogen atom, a sulfur atom and an oxygen atom. A 5- to 9-membered aromatic or non-aromatic heterocyclic ring containing 1 to 3 kinds or 2 kinds of heteroatoms or a 3 to 10-membered cyclic hydrocarbon consisting of carbon atoms; ) Halogen atom, (II) (i) hydroxyl group, (ii) amino group, (iii) carboxyl group, (iv) nitro group, (v) mono- or di-C
_1-6 alkylamino group, (vi) C _1-6 alkyl - 1 selected from carbonyl group and (vii) a halogen atom
To five may have a substituent group C _1-6 alkyl group, (III) optionally halogenated a C _1-6 alkoxy group, optionally (IV) halide C _{1- 6} alkylthio group, (V) C _6-10 aryl group, (VI) C _1-7 acylamino group, (VII) C _1-3 acyloxy group, (VIII) hydroxyl group, (IX) nitro group, (X) cyano group, (XI) amino group, (XII) mono - contain one to three or di -C _1-6 alkylamino group, (XIII) other than nitrogen atoms to oxygen atoms, hetero atoms selected from nitrogen atom (XIV) C _1-6 alkyl-carbonylamino group, (XV) C _1-6 alkyl-sulfonylamino group, (XVI) C _1-6 alkoxycarbonyl group, (XVII ) Carboxyl group, (XVIII) C _1-6 alkylcarbonyl group, (XIX) carbamoyl group, (XX) mono- or Is a carbon atom which may be substituted with a di-C _1-6 alkylcarbamoyl group, (XXI) C _1-6 alkylsulfonyl or (XXII) oxo group, other than a nitrogen atom, a sulfur atom and an oxygen atom. A 5- to 9-membered aromatic or non-aromatic heterocyclic ring containing 1 to 3 kinds or 2 kinds of heteroatoms or a 3 to 10-membered cyclic hydrocarbon consisting of carbon atoms;

Ring C is (I) halogen atom, (II) optionally halogenated C _1-10 alkyl group, (III) C _1-4 alkyl group substituted with amino group, (IV) mono- or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group, C _1-4 alkyl group substituted with (V) a carboxyl group, (VI) C _1-4 alkoxy - substituted with a carbonyl group Done C
_1-4 alkyl group, (VII) C _1-4 alkyl group substituted with hydroxyl group, (VIII) C _3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxyl group , (XII) optionally halogenated C _1-10 alkoxy, (XIII) optionally halogenated C _1-4 alkylthio, (XIV) amino, (XV) mono- or di-C _1-4 alkylamino group, (XVI) 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from oxygen and sulfur atoms in addition to nitrogen atom, (XVII) C _{1- 4} alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (XIX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (XXI) C _{1 -4} alkoxy - carbonyl group, (XXII) aralkyloxy carbonylation Group, (XXIII) carboxyl group, (XXIV) C _1-6 alkyl - carbonyl group, (XXV) C _3-6 cycloalkyl - carbonyl group, (XXVI) carbamoyl group, (XXVII) mono - or di -C _{1- 4} alkylcarbamoyl group or (XXVIII) C _1-6 alkylsulfonyl group or (XXIX) 1 to 3 optionally halogenated C
5- or 6-membered aromatic containing one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be substituted by _1-4 alkyl groups A 5- to 9-membered group containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be substituted with a group monocyclic heterocycle; Heterocycle; or

(I) a halogen atom, (II) an optionally halogenated C _1-10 alkyl group, (III) a C _1-4 alkyl group substituted with an amino group, (IV) a mono- or di- C _1-4 alkyl group substituted by C _1-4 alkylamino group, (V) C _1-4 alkyl group substituted by carboxyl group, (VI) C substituted by C _1-4 alkoxy-carbonyl group
_1-4 alkyl group, (VII) C _1-4 alkyl group substituted with hydroxyl group, (VIII) C _3-10 cycloalkyl group, (IX) nitro group, (X) cyano group, (XI) hydroxyl group , (XII) optionally halogenated C _1-10 alkoxy, (XIII) optionally halogenated C _1-4 alkylthio, (XIV) amino, (XV) mono- or di-C _1-4 alkylamino group, (XVI) 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from oxygen and sulfur atoms in addition to nitrogen atom, (XVII) C _{1- 4} alkyl-carbonylamino group, (XVIII) aminocarbonyloxy group, (XIX) mono- or di-C _1-4 alkylaminocarbonyloxy group, (XX) C _1-4 alkylsulfonylamino group, (XXI) C _{1 -4} alkoxy - carbonyl group, (XXII) aralkyloxy carbonylation Group, (XXIII) carboxyl group, (XXIV) C _1-6 alkyl - carbonyl group, (XXV) C _3-6 cycloalkyl - carbonyl group, (XXVI) carbamoyl group, (XXVII) mono - or di -C _{1- 4} alkylcarbamoyl group or (XXVIII) C _1-6 alkylsulfonyl group or (XXIX) 1 to 3 optionally halogenated C
5- or 6-membered aromatic containing one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be substituted by _1-4 alkyl groups Group 3 which may be substituted with a monocyclic heterocyclic ring
Or a 10-membered homocyclic ring;

Ring Z is (I) 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) hydroxyl group, (X) C _1-4 alkoxy Group, (XI) C _1-4 alkylthio group (XII) amino group, (XIII) C _1-4 mono- or di-C _1-4 alkylamino group, (XIV) oxygen atom and sulfur atom other than nitrogen atom A 5- to 9-membered cyclic amino group optionally containing 1 to 3 selected heteroatoms, (XV) a C _1-4 alkyl-carbonylamino group, (XVI) a C _1-4 alkylsulfonylamino group, XVII) C _1-4 alkoxy - carbonyl group, (XVIII) a carboxyl group, (XIX) C _1-6 alkyl - carbonyl group, (XX) carbamoyl group, XXI) mono - or di -C _1-4 alkylcarbamoyl group, (XXII) C _1-6 alkylsulfonyl group, in addition to (XXIII) oxo or (XXIV) may be substituted with a thioxo group Y and the nitrogen atom , nitrogen atom, wherein also a heterocyclic contain at least one heteroatom selected from oxygen atom and sulfur atom (1) compounds described, (3) R ^a and R ^b are bonded together a A ring, a C-ring may have a substituent, a benzene ring or a heterocyclic ring which may have a substituent, a Z-ring may be an oxo-containing nitrogen-containing heterocyclic ring, and n is (4) the compound according to (1), wherein the Z ring is a nitrogen-containing heterocyclic ring which may be oxo-modified,

(5) The above (1), wherein one of the rings A and B is an aromatic ring which may have a substituent, and the other is an aromatic hetero ring which may have a substituent. (6) The compound according to the above (1), wherein ring A is an aromatic heterocyclic ring which may have a substituent, and ring B is a benzene ring which may have a substituent. The above (5), wherein the aromatic heterocycle is a 5- or 6-membered aromatic heterocycle containing one or two heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
(8) The compound according to the above (1), wherein the ring C is an optionally substituted benzene ring, (9) the ring C is a halogen atom or an optionally halogenated C _1-6 alkyl. Group and a substituent selected from an optionally halogenated C _1-6 alkoxy group by 1 to 3
(10) The compound according to (1), wherein the Z ring is a 5- to 10-membered ring optionally substituted with one or two oxo groups, (11)

Embedded image The compound according to the above (1), which is

(12) The compound according to the above (1), wherein n is 1; (13) a pyridine ring in which ring A may have a substituent;
A benzene ring in which ring B may have a substituent, a benzene ring in which ring C may have a substituent, a 5- to 10-membered ring in which ring Z may be oxo-modified,

Embedded image (14) The compound according to the above (1), wherein n is 1; (14) R ^a and R ^b are the same or different and are a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, Alkoxy, optionally halogenated alkylthio, cycloalkyl, aryl, acylamino, acyloxy, hydroxyl, nitro, cyano, amino, mono-
Or di-alkylamino group, cyclic amino group, alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoyl group, mono- or di-alkylcarbamoyl group, alkylsulfonyl group, oxo group The compound according to the above (1), which is

(15) R ^a and R ^b are the same or different and each represents 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,
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,

Embedded image The compound according to the above (1), wherein n is 1,

(16) R ^a and R ^b are bonded together to form a pyridine ring optionally having 1 to 3 substituents selected from a halogen atom or a C _1-4 alkyl group;

Embedded image (17) The compound according to (16), wherein the pyridine ring is an unsubstituted pyridine ring, (18) a C _1-4 alkyl group wherein the ring B may be halogenated. 1 to a three benzene ring which may have the (16) the compound according, (19) C ring is halogen atom, a C _1-4 alkyl group or halogenated optionally halogenated (1) which is a benzene ring optionally having 1 to 3 substituents selected from C _1-4 alkoxy groups
(6) the compound according to (6), wherein

Embedded image [Wherein, m and p are the same or different and represent an integer of 1 to 5, Z ₁ and Z ₂ are the same or different and represent a hydrogen atom,
Y represents a C _1-4 alkyl group or a hydroxyl group;
The compound according to the above (16), which has the same meaning as described above,

(21) (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] The compound according to the above (1), which is [1,7] naphthyridine. (22) (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] The compound according to the above (1), which is [1,7] naphthyridine. (23) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9, 10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g]
(1) The compound according to the above (1), which is naphthyridine; (24) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11 -Hexahydro-9-methyl-5- (4-methylphenyl)
The compound according to the above (1), which is -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine,

Equation (25)

Embedded image [In the formula, D and E together with a nitrogen atom adjacent to E form a Z ring described in the above (1), L is a leaving group, and other symbols have the same meanings as in the above (1)] Or a salt thereof, which is subjected to a cyclization reaction, a process for producing the compound according to the above (1), (26) a pharmaceutical composition comprising the compound according to the above (1). (27) a tachykinin receptor antagonist comprising the compound according to (1), (28) a substance P receptor antagonist comprising the compound according to (1) (29) a neurokinin A receptor antagonist characterized by containing the compound of (1), (30) an agent for improving dysuria, characterized by containing the compound of (1); (31) Contains the compound described in (1) above Asthma, wherein, rheumatoid arthritis, osteoarthritis, pain,
It relates to an agent for improving cough, irritable bowel disease or vomiting. The compound according to the above (1), wherein R ^a 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.

Hereinafter, the present invention will be described in detail. About "M ring, X and Y"

Embedded image In the general formula for the "R ^a and R ^b" (I) (Ia), or bonded R ^a and R ^b together form a ring A, or the same or different substituents in the hydrogen atom or M ring Show. Examples of the substituents ^Ra and ^Rb in the M ring include a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, and an alkylthio group which may be halogenated. , A cycloalkyl group, an aryl group, an acylamino group, an acyloxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, a mono- or di-alkylamino group, a cyclic amino group (for example, an oxygen atom, a sulfur atom other than a nitrogen atom) Such as a cyclic amino group which may contain a hetero 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, and an alkylsulfonyl group. And oxo groups.

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, hydroxyl group, 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 “optionally substituted alkyl group” includes a C _1-6 alkyl group which may be substituted by about 1 to 4 halogen atoms [particularly optionally halogenated alkyl groups] 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, methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl,
A C _1-4 alkoxy-C _1-4 alkyl group such as ethoxyethyl, a C _1-6 alkylthio-C _1-6 alkyl group (eg, methylthiomethyl, ethylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl _C1-4 alkylthio- _C1-4 alkyl group), amino-C
_1-6 alkyl group (for example, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-
Amino-C _1-4 alkyl group such as aminobutyl, 3-aminobutyl, 4-aminobutyl group, C _1-7 acylamino- _1-6 alkyl group (formylaminomethyl, acetylaminomethyl, propionylaminomethyl, formyl) Aminoethyl, acetylaminoethyl, propionylaminoethyl, butyrylaminoethyl, C _1-7 acylamino- _1-4 alkyl group such as benzoylaminomethyl 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,
3- (N-methylamino) butyl, 4- (N-methylamino) butyl, 2- (N-dimethylamino) ethyl,
Mono- or di-C _1-4 alkylamino-C _1-4 alkyl groups such as-(N-diethylamino) ethyl group), C _3-10
Cycloalkylamino -C _1-6 alkyl group (e.g., cyclopropylamino methyl, cyclobutylmethyl aminomethyl, cyclohexyl aminomethyl, cyclopropylamino ethyl, cyclobutyl aminoethyl, cyclohexyl aminomethyl group, C _3, such as phenyl aminomethyl group _-Ten
Cycloalkylamino-C _1-4 alkyl 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 (for example, methylsulfonylaminomethyl, ethylsulfonylaminomethyl, methylsulfonylaminooctyl,
C _1-6 alkylsulfonylamino -C _1-6 alkyl group such as ethylsulfonyl aminoethyl group), C _1-6 alkyl - carbonyloxy -C _1-6 group (e.g., methyl carbonyloxy methyl, ethyl carbonyl oxymethyl,
C such as butylcarbonyloxymethyl, methylcarbonyloxyethyl and ethylcarbonyloxyethyl groups
_1-4 alkyl-carbonyloxy-C _1-4 alkyl group)
And so on.

Examples of the “optionally halogenated alkoxy group” include, for example, a C _1-6 alkoxy group and
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 1
A C _1-6 alkylthio group having about 5 to about 5 halogen atoms. Examples of such an alkylthio group and a halogenated alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, and isopropylthio. , Butylthio,
4,4,4-trifluorobutylthio, pentylthio,
Hexylthio group 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 Methylthio, ethylthio, propylthio, isopropylthio, butylthio,
It includes a 4,4,4-trifluorobutylthio group and the like.

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), “alkylcarbonyl group” includes, for example, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl group and the like), and “mono- or di-alkylcarbamoyl group”. Is, for example, a mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), and “alkylsulfonyl group” is, for example, C _1-6 alkylsulfonyl. Groups (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl groups, etc.) and the like.

Regarding “Ring A and Ring B” In the above formulas (I) and (Ia), the A ring and the B ring are each an optionally substituted homo- or heterocyclic ring, at least One is a heterocyclic ring which may have a substituent. In the "homologous or heterocyclic", for example,
(i) an aromatic or non-aromatic heterocycle containing preferably 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon, preferably 1 to 3 or ii) Cyclic hydrocarbons (homocycles) composed of carbon atoms are 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). 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) one or two nitrogen atoms other than carbon atoms
A 6-membered nitrogen-containing heterocyclic ring (for example, a pyridine or pyrazine ring) or (ii) a 5-membered aromatic heterocyclic ring containing one sulfur atom in addition to a carbon atom (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 1 to 3 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 in 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, hydroxyl 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 other than a nitrogen atom Cyclic amino group which may be substituted), alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamo 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,
Hydroxyl, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino group (for example,
From methylamino, ethylamino, dimethylamino, diethylamino groups, etc., C _1-6 alkyl-carbonyloxy groups (eg, acetoxy, ethylcarbonyloxy groups, etc.) and halogen atoms (eg, fluorine, chlorine, bromine atoms, etc.) A selected C _1-6 alkyl group _optionally having 1 to 5 substituents (for example, 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.

More 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 groups, 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 rings A and B may have includes, 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 (for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl group and the like),
Mono- or di-alkylcarbamoyl groups include, for example,
Mono - or di -C _1-4 alkylcarbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl group, etc.), the alkylsulfonyl group, e.g., C _1-6 alkylsulfonyl group (e.g., methylsulfonyl , Ethylsulfonyl, and propylsulfonyl groups).

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, optionally halogenated C _1-4 alkoxy group, optionally halogenated C _1-4 alkylthio group, C _1-3 acyloxy group, hydroxyl 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, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy, and hydroxyl. Groups, amino groups, mono- or di-C _1-4 alkylamino groups, C _1-3 acyloxy groups, oxo groups and the like. In particular, a halogen atom, a C _1-4 alkyl group which may be halogenated, a C _1-4 alkoxy group which may be halogenated, and the like are preferable.

The substituents on ring A and ring B may be substituted on any substitutable position of the ring, and the substituent is preferably 2
When the number is more than 3, the substituents may be the same or different, and the number may be about 1 to 4. The number of substituents is preferably about 1 to 3.
When the ring A and / or ring B has a nitrogen atom, it may form a quaternary ammonium salt, for example, a halogen ion (for example, Cl ⁻ , Br ⁻ , I ^{− and the} like), a sulfate ion, a hydroxy ion and the like. May form a salt with the anion of

With regard to “ring A”, preferred homocyclic rings in ring A include homocyclic rings 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)

[0044]

Embedded image [In the formula, A ² and A ³ are the same or different and are each a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl,
Isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl group, or 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 homocycles 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, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, etc.), and the like (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. In the homocyclic ring represented by the above formula, particularly preferably, an homocyclic ring having the following substituent is included. (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.), (5) A ² And an homocycle wherein A ³ is the same or different and is a C _1-4 alkoxy group (eg, methoxy, ethoxy group, etc.).

Preferred aromatic or non-aromatic heterocycles in the ring A are 5- or 6-membered aromatic or non-aromatic heterocycles, 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 and an alkyl group which may have a substituent ( As defined for good substituents), C _6-10
Pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole optionally having one or two substituents selected from an aryl group (eg, phenyl group) and a halogen atom (eg, fluorine, chlorine, bromine atom, etc.) And a thiazole ring, and specifically, for example, an aromatic or non-aromatic heterocyclic ring 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) a 6-membered aromatic nitrogen-containing heterocyclic ring containing one or two nitrogen atoms other than a carbon atom (eg, a pyridine, pyrazine ring, etc.) , (I
i) It is preferably a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (for example, a tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring and the like). Particularly preferred ring A includes an aromatic nitrogen-containing heterocycle, especially a pyridine ring.

Regarding the “ring B”, a preferred homocyclic ring in the ring B is a homocyclic ring composed of an optionally substituted carbon atom, for example, a compound represented by the formula (B-
1)

Embedded image [Wherein B ¹ represents a halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated], and a compound represented by the 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 [In the formula, B ⁴ , B ⁵ and B ⁶ are the same or different and each is a halogen atom, an optionally halogenated C _1-4
Alkyl group and C _1-4 alkoxy group which may be halogenated].

More 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,
A halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated]. Particularly preferred homocyclic rings include the following formula (B-5)

Embedded image [Wherein B ¹⁰ represents a halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated].

In the above formula, halogen atoms in B ^{1 to} B ¹⁰ include, for example, fluorine, chlorine, bromine atoms and the like;
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,
2,3,3-Tetrafluoropropyl, isopropyl group and the like, and optionally halogenated C _1-4 alkoxy group 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 and the like are included.

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)

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 (Eg, fluorine, chlorine atom, etc.) or 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 group, etc.) , (3) B ⁷ , B ⁸ and B ⁹ are a halogen atom (for example, fluorine, chlorine atom, etc.), (4) B ¹⁰
Is a fluorine atom, and (5) B ¹⁰ is a C _1-4 alkyl group (for example, a methyl group). As a benzene ring which may have a more preferable substituent, the following formula (B-9)

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.

Combination of Ring A and Ring B A 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.), a C _1-4 alkyl group which may be halogenated (eg, Methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl, isopropyl, etc.) and optionally halogenated C ₁ Selected from _-4 alkoxy groups (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy, etc.) A benzene ring which may be substituted with one to three substituents.

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,
Pyridine, pyrazine, thiophene ring, etc.), the other of the A ring and the 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, etc.) and optionally halogenated C _1-4. Selected from alkoxy groups (eg, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy groups, etc.) A benzene ring optionally substituted with 1 to 3 substituents; In particular, the aromatic heterocycle (for example, a 5- or 6-membered aromatic heterocycle, particularly a pyridine ring or the like) in which the ring A may have a substituent, and the ring B may have a substituent. It is preferably a benzene ring.

Regarding “C ring”, in the above formula, the C ring represents a homocyclic ring which may have a substituent or a heterocyclic ring which may have a substituent. The homocyclic ring or heterocyclic ring has about 1 to 5 identical or different substituents,
Preferably, about 1 to 3 may be provided. 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,
3 such as benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) And a 10-membered cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. 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 on the homocyclic ring such as the 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 hydroxyl group (eg, hydroxymethyl, hydroxy Ethyl group), a C _1-4 alkyl group substituted with a C _1-4 alkoxy-carbonyl group (eg, methoxymethyl, methoxyethyl, ethoxyethyl group, etc.),
_3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.), nitro group, cyano group, hydroxyl 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, A fluorobutoxy, pentyloxy, hexyloxy, octyloxy, decyloxy group, etc., an optionally halogenated C _1-4 alkylthio group (eg, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio) group, etc.), amino group, mono- - or di -C _1-4 alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino group), a cyclic amino group (e.g., nitrogen atom Outside oxygen atom, such as 1 to 3 which may contain 5-9 membered cyclic amino group a hetero atom such as sulfur atoms, specifically, for example, pyrrolidino, piperidino, morpholino group), C _{1- 4} alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkylaminocarbonyloxy group (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy , Dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxy Carbonyl, ethoxyca Boniru, propoxycarbonyl, butoxycarbonyl, etc. isobutoxycarbonyl group), an aralkyloxycarbonyl group (e.g., benzyloxycarbonyl group), a carboxyl group, C _1-6 alkyl - carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butyl Carbonyl group), C _3-6 cycloalkyl-carbonyl group (eg, cyclohexylcarbonyl group), carbamoyl group, mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, Butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.).

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 for substitution on the homocyclic ring (benzene ring or the like) as 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, hydroxyl 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,
Ethylamino, dimethylamino, diethylamino and the like), C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl and the like), carboxyl group and carbamoyl group.

In particular, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C
_1-4 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoro Ethyl, propyl, isopropyl, t-butyl and the like, and optionally halogenated C _1-4 alkoxy (eg, methoxy, trifluoromethoxy, ethoxy, 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 hydroxyl group are preferred. The number of these substituents is
For example, the number is preferably about 1 to 3.

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. Among the heterocycles (1) to (3), for example, a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms 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. Examples of the substituent which the heterocyclic ring may have include the same substituents as those described in the above-mentioned section "Homocyclic ring which may have a substituent".

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. Substituted with 1 to 3 substituents selected from an alkyl group, an optionally halogenated C _1-4 alkoxy group, a di-C _1-4 alkylamino group, a C _1-3 acyloxy group and a hydroxyl group. Benzene ring (particularly, a benzene ring substituted with the substituent). 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 and are each a hydrogen atom, a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C
_1-4 alkoxy group, mono- or di-C _1-4 alkylamino group, C _1-3 acyloxy group or hydroxyl group], or the following formula (C-2)

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

Here, C ¹ , C ² , C ³ , C ⁴ or C ⁵
A halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4
The alkoxy group and the mono- or di-C _1-4 alkylamino group are the aforementioned halogen atom, a C _1-4 alkyl group which may be halogenated, a C _1-4 alkoxy group which may be halogenated and The same ones as the mono- or di-C _1-4 alkylamino group are used. More preferred C
In the ring, for example, in the formulas (C-1) and (C-2),
A benzene ring in which C ^{1 to} C ⁵ are the following substituents is included. (1) When C ¹ , C ² and C ³ are the same or different,
A halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated, (2) wherein C ¹ , C ² and C ³ are the same or different, A halogen atom or an optionally halogenated C _1-4 alkyl group, (3) C ¹ , C ² and C ³ being the same or different, and a halogen atom, (4) C ¹ , C ² and C ³ Is the same or different and may be a halogenated C _1-4 alkyl group,

(5) C ¹ , C ² and C ³ are the same or different, and optionally a halogenated C _1-4 alkoxyl group; and (6) C ⁴ and C ⁵ are the same or different. And halogen atoms, (7) C ⁴ and C ⁵ are the same or different, and optionally a halogenated C _1-4 alkyl group, or (8) C ⁴ and C ⁵ are the same or different A C _1-4 alkoxy group which may be halogenated. In the embodiments (1) to (8), the “optionally halogenated C _1-4 alkyl group”, the “optionally halogenated C _1-4 alkoxy group” and the “halogen atom” The same groups or atoms as described above can be exemplified.

More preferred C ring is, for example, a benzene ring in which C ⁴ and C ^{5 in} the above formula (C-2) are the following substituents. (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 chlorine atoms, (c) C 4
One is a methoxy group of ⁴ and C ^5, the other is an isopropyl group, (d) C one methoxy group of ⁴ and C ^5, the other is 1-methoxy-1-methylethyl or (e) C ⁴ and, C ⁵ is a trifluoromethyl group.

Regarding “Z ring” In the above formula, the Z ring represents a ring which may be substituted. Examples of the substituent on the Z ring include various substituents, for example, an alkyl group (for example, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, etc. linear or branched alkyl groups having 1 to 6 carbon atoms, preferably linear or branched alkyl groups having 1 to 4 carbon atoms),
Alkenyl groups (for example, alkenyl groups having 2 to 6 carbon atoms, preferably alkenyl groups having 2 to 4 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, and sec-butenyl groups); alkynyl groups (for example, ethynyl, C2-C6 alkynyl groups such as propynyl, isopropynyl, butynyl, isobutynyl and sec-butynyl groups, preferably C2-C4 alkynyl groups, cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) C _3-8 cycloalkyl groups such as groups, preferably C _3-6 cycloalkyl group), a cycloalkyl - alkyl group (e.g., cyclopropylmethyl, cyclopropylethyl, C _3-6 cycloalkyl such as cyclohexyl methyl group - C _1-4 alkyl group), an aryl group (e.g., off Cycloalkenyl, 1-naphthyl,
C6-C14 aryl groups such as 2-naphthyl, anthryl and phenanthryl groups, preferably C6-C10
Aryl group, especially phenyl group), nitro group, cyano group, hydroxyl 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, etc.), amino,
Mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like), cyclic amino group (for example, heteroatom such as oxygen atom and sulfur atom other than nitrogen atom) Specific examples include a 5- to 9-membered cyclic amino group optionally containing 1 to 3 atoms, such as pyrrolidino, piperidino,
Morpholino, thiomorpholino group, etc.), C _1-4 alkyl-carbonylamino group (eg, 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 group, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc.) ), Carbamoyl group, mono- or di-C
Examples thereof include a _1-4 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, about 1 to 5 and preferably 1 depending on the size of the Z ring.
Or about two.

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

Embedded image (Wherein D and E together with a nitrogen atom adjacent to E represent a group that forms the Z ring). Z
Examples of D and E that form a ring include an alkylene group, an oxyalkylene group, and an iminoalkylene group, at least one of which may be oxo-modified. 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 _1-7 ) _1-5 oxyalkylene group) and C _1-7 iminoalkylene group (especially C _1-5 imialkylene 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 group having 1 to 1 carbon atoms.
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).

“About n” 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. Regarding the compounds (I) and (Ia), in the compounds represented by the general formula (I) and the general formula (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 compound (I) (Ia) is the “M ring” of the aforementioned preferred embodiment.

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. Examples of the above “5- or 6-membered heterocyclic ring” include pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine, and the like. And the ring B is represented by the formula (B-7) (B-
8), especially the benzene ring represented by the 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-
Examples thereof include butyl and tert-butyl groups, and the “optionally halogenated C _1-6 alkyl group” includes a pentyl, hexyl group and the like in addition to the above-mentioned alkyl group or halogenated alkyl group.

The “optionally halogenated C _1-4 alkoxy group” includes, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, te
Examples of the rt-butoxy group include “optionally halogenated C _1-6 alkoxy group” which includes pentyloxy, hexyloxy group and the like in addition to the above-mentioned alkoxy group or halogenated alkoxy group. Among the compounds represented by the general formula (I), particularly the general formula (Ia), the preferable compound (2) includes the following compounds or pharmaceutically acceptable salts. A ring is, other than carbon atom, 1
5- or 6-membered heterocyclic ring containing one nitrogen atom or one sulfur atom, for example, a heterocyclic ring represented by the following formula (A-7);

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.
"Halogen atom", "optionally halogenated C
" _1-4 alkyl group" and "optionally halogenated C
Examples of the “ _1-4 alkoxy group” include the same atoms or groups as described in the section of the compound (1). 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 which may be substituted 5 or optionally 6-membered cyclic amino group with a group, C _1-6 alkylsulfonylamino group or a C _1-6 alkylcarbonyloxy C optionally substituted with a group
_1-6 alkyl 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, Ring B may have 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. A good benzene ring, wherein the C ring is substituted with a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group, or a C _1-4 alkyl group. A benzene ring optionally having 1 to 3 substituents selected from an amino group, a C _1-3 acyloxy group or a hydroxyl group, wherein the Z ring is substituted with a C _1-4 alkyl group or a hydroxyl group. 5 to 10 members, which may be It is a nitrogen heterocyclic group,

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 (In the formula, D and E are an alkylene group which may be oxo-ized, and other symbols are as defined above.) D and E are each a C _1-3 which may be substituted with one oxo group. It is preferably an alkylene group. More 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 (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. Formulas (I) and (Ia)
When the compound represented by the formula (I) forms a salt, which 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 compounds (I) and (Ia) of the present invention or salts thereof include 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 such as the Z ring, an isomer due to conformation may be generated, and such an isomer is also included in the compounds (I) and (Ia) of the present invention or a salt thereof. .

Method for producing compound or salt thereof Compounds (I) and (Ia) or a salt thereof of the present invention can be prepared, for example, by the following general formula (II)

Embedded image [Wherein L represents a leaving group, and the other symbols are as defined above] or a salt thereof is subjected to a cyclization reaction to produce a ring. Compound (II)
As the leaving group L, for example, a halogen atom (for example,
Examples thereof include a chlorine, bromine, iodine atom and the like and a substituted sulfonyloxy group (for example, a methanesulfonyloxy, an ethanesulfonyloxy, a benzenesulfonyloxy, a p-toluenesulfonyloxy group and the like). The compound (II) may be used as a free compound, or may be subjected to the reaction in the form of a salt thereof (eg, an alkali metal salt such as lithium, sodium, or potassium). The reaction is usually performed in a solvent inert to the reaction. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile; ethers such as dimethoxyethane and tetrahydrofuran; aprotic polar solvents such as dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide. Is preferably used.

The addition of a base advantageously drives 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.

Among the compounds (I) and (Ia) of the present invention,
A compound in which Ring A is a tetrahydropyridine ring can be produced by subjecting a compound in which Ring A is a pyridine ring to a reduction reaction. This reduction reaction can be performed by various methods, for example, a method of reducing in the presence of a metal catalyst for catalytic reduction is preferable. Examples of the catalyst used in the catalytic reduction method include platinum catalysts such as platinum black, platinum oxide, and platinum carbon; palladium catalysts such as palladium black, palladium oxide, palladium barium sulfate, and palladium carbon; reduced nickel, nickel oxide, and Raney nickel. And nickel catalysts such as Urushibara nickel. The amount of the catalyst used varies depending on the type of the catalyst, and usually, the compounds (I) and (I
It is about 0.1 to 10% (w / w) with respect to a). The reduction reaction is usually performed in a solvent. As the solvent, for example, methanol, ethanol, propanol, alcohols such as isopropanol, tetrahydrofuran,
Examples thereof include ethers such as dioxane and esters such as ethyl acetate. The reaction temperature is, for example, 0 ° C to 2 ° C.
The reaction time is usually 0.5 to 48 hours, preferably 1 to 16 hours.
About an hour. The reaction is usually ordinarily performed under normal pressure, but may be performed under pressure (for example, about 3 to 10 atm), if necessary. Such a reduction reaction can be applied to a method of converting another aromatic heterocycle into a non-aromatic heterocycle.

Further, the compound in which the ring A is a tetrahydropyridine ring is the same as the compound in which the ring A is a pyridine ring,
A quaternary salt by reacting with an alkylating agent represented by QL '(wherein Q is an optionally substituted alkyl group and L' is a leaving group). It can also be produced by subjecting a quaternary salt to a reduction reaction. Examples of the leaving group L ′ include the same leaving groups as those described above for the leaving group L. Examples of the alkylating agent QL ′ used for the conversion to a quaternary salt include alkane halides (eg, chloride, bromide, iodide, etc.), sulfates, or sulfonates (eg, methanesulfonate, p-toluenesulfonate) , Benzenesulfonate, etc.), and alkyl halides are particularly preferably used. The amount of the alkylating agent to be used is, for example, about 1 to 100 equivalents, preferably about 1 to 30 equivalents, per 1 mol of the substrate. The reaction with the alkylating agent is usually performed in a solvent. As the solvent, for example, methanol, ethanol,
Alcohols such as propanol and isopropanol,
Ethers such as tetrahydrofuran and dioxane, esters such as ethyl acetate, dichloromethane, 1,2-
Halogenated hydrocarbons such as dichloroethane can be used, and the alkylating agent itself may be used as a solvent. The reaction temperature is, for example, 10 ° C to 200 ° C, preferably 20 ° C.
C. to about 110 ° C., and the reaction time is usually 0.5 to
It is 24 hours, preferably about 1 to 16 hours.

The reduction reaction of the formed quaternary salt to a tetrahydropyridine ring can be carried out in an inert solvent in the presence of a reducing agent such as a metal hydride. Examples of the metal hydride as the reducing agent include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, lithium cyanoborohydride, lithium aluminum hydride and the like. Preferred metal hydrides include sodium borohydride and the like.
The amount of the reducing agent to be used is, for example, about 1 to 10 equivalents, preferably about 1 to 2 equivalents, based on the quaternary salt. Examples of the reaction solvent include lower alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and hydrocarbons such as benzene and toluene.These solvents may be used alone or as a mixture. Can be used. The reaction temperature is usually about -100C to 40C,
It is preferably about -80 ° C to 25 ° C, and the reaction time is generally 5 minutes to 10 hours, preferably 10 minutes to 5 hours.
About an hour. In the reduction reaction of the quaternary salt, a compound having a dihydropyridine ring, which is one of the compounds of the present invention, may be produced depending on the kind of the compound. This dihydropyridine ring can be converted to a further reduced tetrahydropyridine ring by, for example, the above-described catalytic reduction method. When the ring A is a tetrahydropyridine ring and the nitrogen atom has a hydrogen atom,
A compound in which a Q group has been introduced into a nitrogen atom can be obtained by using an alkylating agent represented by QL '(the symbols in the formula have the same meanings as described above).

By subjecting the compound in which ring A is a quaternary salt of a pyridine ring to an oxidation reaction, a compound in which ring A is a pyridone ring can be produced. This oxidation reaction can be carried out, for example, by a known method [E.A.
A. Prill et al., Organic Synthesis (Organic S)
Syntheses, Vol. 2, p. 419 (issued in 1957)] or a method analogous thereto. The compound in which ring B is an aromatic heterocyclic ring can be converted to a compound in which ring B is a non-aromatic heterocyclic ring by subjecting it to the same reduction reaction as described above.

Embedded image It can be produced by reacting with an appropriate sulfide. As the sulfide, for example, phosphorus pentasulfide, Lawson (Lowesso
n) Reagents and the like. This reaction is usually performed in a solvent such as halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as dioxane and tetrahydrofuran, and hydrocarbons such as benzene and toluene under anhydrous conditions. The amount of the sulfide used is at least equimolar to the compound, preferably about 2 to 5 mol. The reaction temperature is, for example, about 20 ° C. to 120 ° C., and the reaction time varies depending on the starting compound, the type of sulfide, the reaction temperature, and the like, and is, for example, about 1 to 8 hours.

The compounds (I) and (Ia) or salts thereof produced by such a method contain a lower (C _1-6 ) alkoxy group in the benzene ring of the groups A, B and C. In this case, if necessary, the lower alkoxy group can be converted to a hydroxyl group by reacting with a conventional method, for example, by reacting with boron tribromide. This reaction is usually carried out in a solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, and hydrocarbons such as benzene and toluene) in a temperature range of about -20 ° C to 80 ° C, preferably about 0 ° C. C. to about 30.degree. The amount of boron tribromide used is, per lower alkoxy group,
It is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents. The reaction time is generally about 15 minutes to 24 hours, preferably about 30 minutes to 12 hours. In the case where the compounds (I) and (Ia) or salts thereof produced by the above method contain a hydroxyl group in the benzene ring of the group represented by ring A, ring B and ring C, if necessary, alkylation or acylation is performed. The hydroxyl group can be converted into an alkoxy or acyloxy group by subjecting the hydroxyl group to an oxidation reaction.

The alkylation reaction can be carried out by reacting an alkylating agent in a solvent in the presence of a base. Examples of the solvent include alcohols such as methanol, ethanol, and propanol; ethers such as dimethoxyethane, dioxane, and tetrahydrofuran; ketones such as acetone; and amides such as N, N-dimethylformamide. The base includes, for example, organic bases such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide. . Examples of the alkylating agent include, for example, halides of alkanes which may have a substituent (eg, chloride, bromide, iodide, etc.), sulfates or sulfonates (eg, methanesulfonate,
p-toluenesulfonate, benzenesulfonate, etc.). The amount of the alkylating agent to be used is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction temperature is usually
The temperature is about -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C. The reaction time is generally about 15 minutes to 24 hours, preferably about 30 minutes to 12 hours.

The acylation reaction is carried out by reacting a desired carboxylic acid or a reactive derivative thereof. This reaction varies depending on the type of the acylating agent and the type of the starting phenolic derivative, but is usually performed in a solvent, and an appropriate base may be added to promote the reaction. Examples of the solvent include hydrocarbons such as benzene and toluene; ethers such as ethyl ether, dioxane and tetrahydrofuran; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane;
Examples include amides such as N-dimethylformamide and aromatic amines such as pyridine. Examples of the base include hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, carbonates such as sodium carbonate and potassium carbonate, acetates such as sodium acetate, tertiary amines such as triethylamine, and aromatic compounds such as pyridine. Group amines and the like. As the reactive derivative of the carboxylic acid as the acylating agent, for example, an acid anhydride, a mixed acid anhydride, an acid halide (for example, chloride, bromide) and the like can be used. The amount of the acylating agent to be used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of the starting phenolic derivative. The reaction temperature is usually from 0 ° C to 1
The reaction temperature is generally 50 ° C., preferably about 10 ° C. to 100 ° C., and the reaction time is usually 15 minutes to 12 hours, preferably 30 minutes.
Minutes to about 6 hours.

Here, D represents an oxyalkylene group [—O—
(CH _{2) q} -] or iminoalkylene group [-NH- (C
The compound represented by H ₂ ) _q- ] includes a leaving group La substituted on the M ring without the intervention of D (the leaving group L such as a halogen atom, an amide group optionally having a substituent on a nitrogen atom). Etc.) and a reactive group of a substituent attached to the nitrogen atom adjacent to E (eg, hydroxyl, amino, mono-C
_With an active hydrogen atom such as a _1-6 alkylamino group) according to the method described above. As a substituent bonded to the nitrogen atom adjacent to E,
Examples thereof include a linear or branched C _1-6 alkylene group which may have a substituent selected from a C _1-6 alkyl group, a hydroxyl group, a C _1-6 alkoxy group and the like.

When the compounds (I) and (Ia) are obtained as free compounds in these methods, for example, inorganic acids (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), organic acids (for example, Methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, calcium,
Alkaline earth metals such as magnesium, aluminum or ammonium, etc.) or organic bases (eg trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N ')
-Dibenzylethylenediamine, etc.), and when compound (I) is obtained in the form of a salt, it can be converted to a free compound or another salt according to a conventional method.

The target compounds (I) and (Ia) or salts thereof produced by these methods can be separated and purified by conventional separation and purification means (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.). can do. When the compounds (I) and (Ia) are optically active, they can be separated into d-form and l-form by a conventional optical resolution method. Among the starting compounds (II) for producing the compounds (I) and (Ia) or salts thereof of the present invention,

Embedded image Compounds wherein D is an ethylene group and E is> C = O (II
a) can be produced, for example, by the method shown in the following reaction scheme 1.

Embedded image [Wherein the symbols have the same meanings as described above.] Step 1 and step 2 of the above reaction scheme 1 are performed by ring A and B
It can be carried out according to a known synthesis method of an isoquinolone skeleton compound (for example, a method described in EP-A-481383) relating to a compound in which both rings are a benzene ring which may be substituted. Step 1 is a step of producing an amide (IV) by reacting a carboxyl group of compound (III) with an amino group of iminodiacetonitrile. This reaction can be carried out usually using a compound (III) or its reactive derivative at the carboxyl group and iminodiacetonitrile in a solvent. Examples of the reactive derivative include an acid halide, a mixed acid anhydride, and an active ester. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane; ethers such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; esters such as ethyl acetate; and hydrocarbons such as benzene and toluene. Hydrogens, pyridine, amides such as N, N-dimethylformamide and the like can be used. The amount of iminodiacetonitrile to be used is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of the reactive derivative of the compound (III).

The reaction may be promoted by carrying out the reaction in the presence of a base. As the base, for example,
Organic bases (alkylamines such as triethylamine,
Cyclic amines such as N-methylmorpholine and pyridine;
Aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline); inorganic bases (carbonates of alkali metals such as sodium carbonate and potassium carbonate; alkali metals such as sodium hydrogencarbonate and potassium hydrogencarbonate) Bicarbonate) can be used. The amount of the base to be used is, for example, about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, per 1 mol of compound (III) or a reactive derivative thereof. Further, the reaction in step 1 may use a solvent that is immiscible with water. In this case, water may be added to the reaction system, and the reaction may be performed in a two-phase system. The reaction time is usually 1 to 48 hours,
Preferably, it is about 1 to 24 hours. The reaction temperature is generally -10C to 120C, preferably about 0C to 100C.
It is about.

In step 2, compound (IV) produced in step 1
Is a step of obtaining a closed-ring form (V) by intramolecular addition dehydration. In this reaction, a base is usually used.
As the base, for example, an organic base (eg, 1,5-diazabicyclo [4.3.0] non-5-ene (DB
N), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N-benzyltrimethylammonium hydroxide (Triton B), etc., inorganic bases (sodium methoxide, sodium ethoxide,
Alkoxides such as potassium t-butoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, etc.). The amount of the base to be used is, for example, 0.5 to 20 equivalents, preferably 1 to 5 equivalents, relative to compound (IV).
It is about equivalent.

This ring closure reaction is usually performed in a solvent. As the solvent, a solvent that can be used in Step 1 can be used. The reaction temperature depends on the type of the base used, and is, for example, about -80 ° C to 200 ° C, preferably about -50 ° C to 150 ° C.
It depends on the type of the base, the reaction temperature and the solvent, and is, for example, about 10 minutes to 24 hours. In the reaction,
An intramolecular adduct is produced as an intermediate, but in order to accelerate the dehydration reaction, a method of reacting in the presence of a dehydrating agent (for example, p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, etc.), or a method using a simple intermediate After release, it may be preferable to obtain compound (V) by a method of reacting in the presence of a dehydrating agent.

In Step 3, the compound (V) produced in Step 2
Is a step of converting the cyano group of the N-cyanomethyl group into a carboxyl group by a hydrolysis reaction to produce a compound (VI). The hydrolysis reaction is carried out in a conventional manner, for example, by converting compound (V) into a solvent (eg, methanol, ethanol,
In the presence of an acid (preferably an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid) in an alcohol such as propanol, an organic acid such as acetic acid or propionic acid, or an ether.
The treatment can be performed at a temperature of about 130C to about 130C. Step 4 is a step of reducing the carboxyl group of compound (V) produced in step 3 and converting it to a hydroxymethyl group to produce compound (VII). This reduction reaction is carried out by a conventional method, for example, by converting the carboxyl group of compound (V) to a reactive derivative thereof (for example,
Acid halides, mixed acid anhydrides, active esters, esters, etc.) in a reducing agent (eg, sodium borohydride, lithium aluminum hydride, etc.) and a solvent (eg, ethers such as tetrahydrofuran, dimethoxyethane, etc.) , At a temperature of about 0 ° C to about 100 ° C.

In step 5, compound (VII) produced in step 4 is treated under acidic conditions to give lactone (VIII)
Is a step of generating This step can be performed under the same conditions as in step 3. Step 6 is a step of reacting the compound (VIII) produced in the above step 5 with an amine to produce an amide (IX). This reaction can be performed in the absence of a solvent or in the presence of a solvent. As the solvent, for example, the solvent used in Step 1 can be used. The amount of the amine used is, for example, the compound (VIII)
The amount is 1 to 50 mol, preferably about 1 to 10 mol, per 1 mol. The reaction can be carried out, for example, at a temperature of about 15C to 200C, preferably about 50C to 180C. In step 6, compound (IX) in which X is a hydroxyl group is produced. Step 7 comprises converting the hydroxyl group X of the compound (IX) produced in the above step 6 into a leaving group L,
This is the step of obtaining a). Examples of the leaving group L include a halogen atom (eg, chlorine, bromine, iodine atom, etc.),
C _1-4 alkanesulfonyloxy group (for example, methanesulfonyloxy group, ethanesulfonyloxy group, etc.),
And a C _6-10 arylsulfonyloxy group (for example, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group and the like). The conversion reaction usually uses a compound (for example, thionyl chloride, thionyl bromide, methanesulfonyl chloride, benzenesulfonyl chloride, etc.) corresponding to the leaving group, and a solvent (for example, hydrocarbons such as benzene and toluene, dichloromethane). , 1,2-dichloroethane, chloroform and the like, ethers such as tetrahydrofuran, esters such as ethyl acetate, etc.). The reaction temperature is, for example, about 0 ° C to 100 ° C.

Some of the starting compound (II) may be prepared by a known method (for example, a method described in EP-585913) relating to a compound in which both ring A and ring B are homologous or a method analogous thereto. It can also be manufactured. Further, the compound of the type represented by the general formula (IIa) can be prepared by a known method (method described in EP-481383A1, etc.)

Embedded image Can also be obtained from the following compound (XII). For example, a compound represented by the following general formula (IIb) can be produced by the method shown in the following reaction scheme 2.

Embedded image [The symbols in the formula are as defined above. In this reaction scheme 2, step 1 to step 4 are carried out by a known method (EP-481383) for a compound in which both ring A and ring B are a benzene ring which may have a substituent.
A1). Steps 5 and 6 are amidating the carboxyl groups of compound (XII) and compound (XIII), respectively.
The reaction can be carried out in the same manner as in the step 1 of the reaction scheme 1. Step 7 is a step of converting the pyran ring of the compound (XIV) generated in Step 5 to a pyridine ring, and is performed in the same manner as in Step 4 (NA Santagati, E. Bousquet, G. Romeo, A. Gar).
uso and A. Prato, Bolletino Chimica Farmaceutico, V
ol. 125, p437, 1986).

Further, among the starting compounds (II),

Embedded image [The symbols in the formula are as defined above. Is a method for synthesizing a quinoquine skeleton compound relating to a compound in which both the A ring and the B ring are benzene rings (for example, EP-354994A2, EP-304063A2
And the compound (IIa) (II
It can be produced by a method combining the synthesis method of b) and the like. In compound (II), the compound in which ring A and / or ring B is a non-aromatic nitrogen-containing heterocyclic ring can be produced by subjecting the corresponding aromatic ring to the above-mentioned reduction reaction. The compound (II) may form a salt. Examples of these salts include salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, etc.), and organic acids (eg, acetic acid). , Formic acid, propionic acid, fumaric acid, maleic acid, succinic acid,
Salts with tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.). Further, when the compound (II) has an acidic group such as a carboxyl group, an inorganic base (eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, ammonia or the like) or an organic base (eg. , trimethylamine, tri -C _1-3 alkylamine such as triethylamine) and it may form a salt.

The compounds (I) and (Ia) of the present invention can also be produced, for example, by a method (alkylation reaction) represented by the following reaction formula.

Embedded image [Wherein the symbols have the same meanings as described above. The alkylation reaction can be carried out by reacting an alkylating agent in a solvent in the presence of a base. More specifically, the alkylation reaction can be carried out usually by reacting about 1 to 3 mol of a base with 1 mol of the compound (XV) and an alkylating agent. Examples of the solvent include 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.

The addition of a base advantageously drives 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. Examples of the alkylating agent include halides of alkanes which may have a substituent (for example, chloride, bromide, iodide and the like), sulfates and sulfonates (for example, methanesulfonate, p-toluenesulfonate, benzenesulfonate) Etc.) are included. The reaction time varies depending on the type of the base and the alkylating agent, but is usually from 0 ° C. to room temperature. The reaction time is usually about 1 to 10 hours.

When the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent in each reaction of the target compound and the starting material synthesis, these groups are protected as commonly used in peptide chemistry and the like. May be protected by a group. In this case, after the reaction, the desired compound can be obtained by removing the protecting group, if necessary. Examples of the amino-protecting group include, for example,
C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl group, etc.), phenylcarbonyl group, C _1-6 alkyl-oxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl group, etc.), aryloxycarbonyl group (E.g., phenyloxycarbonyl group), _C7-10 aralkyl-carbonyl group (e.g., benzyloxycarbonyl group),
Examples include a trityl group and a phthaloyl group, and these protecting groups may have a substituent. As these substituents, for example, a halogen atom (for example, fluorine, chlorine,
Bromine, iodine atom), C _1-6 alkyl - carbonyl group (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl and the like groups), a nitro group and the like, the number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, n-
Propyl, i-propyl, n-butyl, tert-butyl, etc.), a phenyl group, a trityl group, a silyl group and the like, and these protecting groups may have a substituent. Examples of these substituents include a halogen atom (fluorine, chlorine, bromine, iodine atom), a C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), a nitro group and the like. And the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl group, etc.), a phenyl group,
C _7-10 aralkyl group (for example, benzyl group), C
_1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl group, etc.), aryloxycarbonyl group (eg, phenyloxycarbonyl group, etc.), C _7-10 aralkyl-carbonyl group (eg, benzyloxycarbonyl group, etc.) ), A pyranyl group, a furanyl group, a silyl group and the like, and these protecting groups may have a substituent. Examples of these substituents include a halogen atom (fluorine, chlorine, bromine, and iodine atom), a C _1-6 alkyl group, a phenyl group, a C _7-10 aralkyl group, a nitro group, and the like. Is about 1 to 4.

The protective group can be removed by a known method or a method analogous thereto, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method of treating with palladium acetate or the like can be used. Compounds (I) and (Ia) produced by such a method
For example, it can be isolated and purified by ordinary separation means such as recrystallization, distillation and chromatography. Also,
When the compound (I) thus obtained is in a free form, it can be converted into a salt by a known method or a method analogous thereto (for example, neutralization or the like), and conversely, the compound (I) ) Is obtained in the form of a salt,
It can be converted to a free form or another salt by a known method or a method analogous thereto.

The compounds (I) and (Ia) of the present invention or salts thereof have excellent tachykinin receptor antagonism, in addition to capsaicin-induced increase in tracheal vascular permeability.
In particular, it has an SP receptor antagonistic effect. Further, the compounds (I) and (Ia) of the present invention or salts thereof have low toxicity and are safe. Therefore, the compounds (I) and (Ia) of the present invention having excellent SP receptor antagonistic activity or a salt thereof can be used for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, Humans)
Inflammatory or allergic diseases (eg, atopy, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum, rhinitis,
Rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, conjunctivitis, cystitis, etc.), pain, migraine, neuralgia,
Pruritus, cough, 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, ulcerative colitis, Crohn's disease, abnormalities (eg, gastritis, gastric ulcer, etc.) caused by urease-positive spiral gram-negative bacteria (eg, Helicobacter pylori, etc.), vomiting, urination abnormalities (eg, pollakiuria, urinary incontinence, etc.),
It is useful as a safe preventive or therapeutic agent for cardiovascular diseases (eg, angina, hypertension, heart failure, thrombosis, etc.) and immune disorders. In particular, the compounds (I) and (Ia) of the present invention or salts thereof are useful as tachykinin receptor antagonists, dysuria agents such as pollakiuria and urinary incontinence, and therapeutic agents for these dysuria.

The preparation containing the compounds (I) and (Ia) or a salt thereof of the present invention may be any of solid preparations such as powders, granules, tablets and capsules, and liquid preparations such as syrups, emulsions and injections. You may. The prophylactic / therapeutic preparation of the present invention is
Depending on the form of the preparation, it can be produced by a conventional method such as mixing, kneading, granulating, tableting, coating, sterilizing treatment, emulsification and the like. 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 compounds (I) and (Ia) or a salt thereof varies depending on the form of the preparation, but is usually 0.01 to 100% by weight, preferably 0.1 to 100% by weight, based on the whole preparation. ~ 5
0 wt%, more preferably about 0.5 to 20 wt%.

When the compounds (I) and (Ia) or salts thereof of the present invention are used as the above-mentioned pharmaceuticals, they may be used as they are or as appropriate pharmacologically acceptable carriers such as excipients (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, Disintegrators (eg, calcium carboxymethylcellulose, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), and if necessary, additives (stabilizers, preservatives, coloring agents, fragrances) , Dissolution aid, emulsifier, buffer, isotonic Agents, etc.) and by a conventional method by mixing, powders, fine granules, granules, tablets, can be administered orally or parenterally in the form of a liquid, such as a solid, or injectable preparations such capsules. The dosage varies depending on the type of compound (I) and (Ia) or a pharmaceutically acceptable salt thereof, the administration route, symptoms, age of the patient, etc., for example, oral administration to an adult patient with dysuria In this case, about 0.005 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 m, as compounds (I) and (Ia) or a salt thereof per kg of body weight per day.
g can be divided and administered in 1 to 3 times.

The compounds (I) and (Ia) or a salt thereof of the present invention can be used by being appropriately mixed with other pharmaceutically active ingredients in an appropriate amount. Such active ingredients include, for example,
Central nervous system acting drugs (such as imipramine), anticholinergic drugs (such as oxybutynin), α ₁
-Receptor blockers (such as tamsulosin), muscle relaxants (such as baclofen), potassium channel openers (such as nicorandil), calcium channel blockers (such as nifedipine) and the like.

[0106]

Industrial Applicability The compounds (I) and (Ia) of the present invention or salts thereof have high tachykinin receptor antagonism, in particular, substance P receptor antagonism and NKA receptor antagonism, have low toxicity and are safe as pharmaceuticals. is there. Therefore, the compounds (I) and (Ia) or a salt thereof is a pharmaceutical composition,
It is useful as a tachykinin receptor antagonist and an agent for improving dysuria.

[0107]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to examples and reference examples, but the present invention is not limited by the examples and does not depart from the scope of the present invention. May be changed.

Elution by column chromatography in Reference Examples and Examples was performed by TLC (Thin) unless otherwise specified.
It was performed under observation by Layer Chromatography (thin layer chromatography). In TLC observation, TLC
Using 60F ₂₅₄ Merck (Merck) manufactured as a plate, it was used as a developing solvent, the solvent used as an elution solvent in column chromatography. In addition, U
A V detector was employed. As silica gel for column chromatography, silica gel 60 (70 manufactured by Merck) is used.
-230 mesh). Room temperature is usually about 1
Meaning a temperature between 0 ° C and 35 ° C. Further, sodium sulfate or magnesium sulfate was used for drying the extract.

The meanings of the abbreviations in the 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.

[0110]

【Example】

Example 1 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.

Example 2 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.

Example 3 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 treated by reacting in the same manner as in Example 1 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).

Example 4 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 Example 1 to give the title compound 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).

Example 5 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 Example 1. 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).

Example 6 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 Example 1, 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).

Example 7 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 Example 1. 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).

Example 8 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 Example 1, 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).

Example 9 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 Example 1 to give the title compound as 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).

Example 10 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 Example 9 (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).

Example 11 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 )
⁺ ].

Example 12 (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).

Example 13 (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 Example 12, 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).

Example 14 (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 Example 12, and 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 Example 12 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).

Example 15 (±) -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.

Example 16 (±) -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 Example 15 to give the title compound 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.

Example 17 (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 reaction was carried out using the compound obtained in Reference Example 18 in the same manner as in Example 15, 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 Example 15 [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.

Example 18 (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 Example 15, 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: the same as the spectrum of the compound of Example 16 [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.

Example 19 (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 Using the compound obtained in Reference Example 20, reacted and treated in the same manner as in Example 15, 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 Example 15 [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.

Example 20 (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 Example 15, 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 Example 16 [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.

Example 21 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: C ₂₃ H ₁₇ N ₃ OF ₆ Calculated (%): C 59.36, H 3.68, N 9.03 Actual (%): C 59.24, H 3.66, N 9.06 EI-MS m / z: 465 (M ⁺ ) [(C ₂₃ H ₁₇ N ₃ OF ₆ )
⁺ ].

Example 22 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.

Example 23 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, 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).

Example 24 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 Using the compound obtained in Reference Example 25, the reaction was carried out in the same manner as in Example 11, 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)

Example 25 (±) -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 Example 2, 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
) ⁺ ].

Example 26 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 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).

Example 27 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 Example 15, 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).

Example 28 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 Example 15 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).

Example 29 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 in the same manner as in Example 12, and treated. 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 (3
H, m), 4.01 (1H, d, J = 15Hz), 5.05 (1H, d, J = 15Hz),
5.49 (1H, dd, J = 13, 5.0Hz), 6.9-7.1 (2H, m), 7.25 (1H,
m), 7.38 (1H, d, J = 8.6Hz), 7.3-7.8 (6H, m), 8.93 (1
H, d, J = 4.0Hz).

Example 30 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 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 (1H, d, J = 15Hz), 5.14 (1H,
dd, J = 15, 5.9Hz), 5.35 (1H, d, J = 15Hz), 6.35 (1H, d
d, J = 8.4, 2.0Hz), 7.02 (2H, m), 7.18 (1H, d, J = 8.4H
z), 7.3-7.6 (6H, m), 8.91 (1H, dd, J = 4.0, 1.8Hz).

Example 31 (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 Example 11, 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 ).

Example 32 (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 in the same manner as in Example 11, and treated to obtain the title compound as colorless crystals. . Melting point: 147-149 ° C. (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: Same as the spectrum of Example 31 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 ).

Example 33 4- [3,5-Bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Using the compound obtained in Example 31, The reaction and treatment were carried out in the same manner 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 Actual (%): C 59.42, H 3.82, N 5.84.

Example 34 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 Using the compound obtained in Reference Example 32, the reaction was carried out in the same manner as in Example 11, 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.

Example 35 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 32 (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: C ₂₄ H ₁₈ N ₂ O ₃ F ₆ Calculated (%): C 57.03, H 3.79, N 5.54 (%): C 57.15, H 3.77, N 5.16

Example 36 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 34, the reaction was carried out in the same manner as in Example 35, 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 .

Example 37 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 34 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.

Example 38 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 36, the reaction was carried out in the same manner as in Example 37, 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.

Example 39 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 (1.24ml) and triethylamine (1.85m) were added to a solution of the compound (4.40g) obtained in Reference Example 34 in dichloromethane (100ml) 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.

Example 40 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine Compound (151 mg) obtained in Reference Example 39, 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.

Example 41 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- (2-methylethyl) -5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine Compound (150 mg) obtained in Reference Example 39, 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.

Example 42 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 (125 mg) obtained in Reference Example 39, 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 =
5.4Hz), 3.79 (2H, s), 4.49 (2H, t, J = 5.4Hz), 4.89 (2H, s)
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.

Example 43 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 39 (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.

Example 44 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 39 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.

Example 45 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 39
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.

Example 46 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 39
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 using 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 .

Example 47 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- (N-methylpiperazinomethyl) -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Compound obtained in Reference Example 39 (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.

Example 48 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 43 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.

Example 49 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 43 (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.

Example 50 6- [3,5-bis (trifluoromethyl) benzyl]
-5,6,7,8-Hexahydro-3,9-dimethyl-
5,10-dioxo-4-phenylpyrido [2,3-
f] [1,4] diazocine The compound (370 mg) obtained in Reference Example 33 in THF (15
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₎ ^+].

Example 51 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 in the same manner as in Example 50, 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.

Example 52 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 in Example 50.
The title compound was obtained as colorless crystals after treatment. 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.

Example 53 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 Example 50, 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.

Example 54 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 Example 50 to give the title compound 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₎ ^+].

Example 55 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 (Example 37) (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)

Example 56 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
4-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 (Example 55) (3.49)
g) A mixture of 2N-NaOH (100 ml) and 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)

Example 57 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 (Example 66) (220 mg), THF
(15 ml), a mixture of DMF (catalytic amount) and thionyl chloride (0.087 ml) were stirred under 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 Examples 58-63 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 (Example 56) is converted to a substituted amine (methylamine) via acid chloride. , Dimethylamine, n-butylamine, piperidine, morpholine, 1-methylpiperazine)
And a reaction and treatment in the same manner as in Example 57. The physicochemical data is described below. Example 58 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)

Example 59 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) Example 60 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 (200MHz, CDCl ₃ ) ppm: 0.96 (3H, t, J = 7.2Hz), 1.20
-1.80 (6H, m), 4.78 (2H, m), 3.73 (2H, t, J = 5.6Hz),
4.49 (2H, t, J = 5.6Hz), 4.91 (2H, s), 7.30-7.58 (5H,
m), 7.82 (2H, s), 7.88 (1H, s), 8.18 (1H, s)

Example 61 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 (4H, m), 4.46 (2H, t, J =
5.6Hz), 4.89 (2H, s), 7.20-7.60 (6H, m), 7.81 (2H,
s), 7.87 (1H, s) Example 62 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)

Example 63 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 Examples 64 to 72 are referred to in Reference Example 3 respectively.
The compound of Reference Example 7 to Reference Example 45 was reacted (cyclization reaction in the presence of sodium hydride in THF) and treated in substantially the same manner as in Example 11 to obtain colorless crystals. The respective physicochemical data are shown below. Example 64 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)

Example 65 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 = 5.2 Hz) Example 66 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)

Example 67 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 = 5.2 Hz) Example 68 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)

Example 69 (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 = 5.0 Hz) Example 70 (R) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-6-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 Example 69.

Example 71 (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 =
5.0 Hz) Example 72 (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 Example 71.

Example 73 7-benzyl-6,7,8,9,10,11-hexahydro-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,2 1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 46 was reacted in the same manner as in Example 15 and treated to give 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, 3.8Hz), 3.3-3.7 (2H, m), 3.7
7 (1H, d, J = 15Hz), 5.14 (1H, dd, J = 14, 5.9Hz), 5.42
(1H, d, J = 15Hz), 6.67 (2H, d, J = 7.0Hz), 6.92 (1H, d
d, J = 7.6, 1.8Hz), 7.1-7.5 (6H, m), 7.46 (1H, dd, J =
8.4, 4.4Hz), 7.60 (1H, dd, J = 8.4, 1.8Hz), 8.90 (1H,
(dd, J = 4.4, 1.8Hz)

Example 74 (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 Example 15 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), 1.5
0-1.75 (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 (1H, d
d, 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)

Example 75 (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 Example 15 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: Same as the spectrum of the compound of Example 74. Example 76 (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 Example 15 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)

Example 77 (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 Example 15 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 Example 76. Example 78 (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 Example 15, and treated to obtain 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, 1.6 Hz) The compounds of Examples 79 to 82 were each prepared in Reference Example 5
The compound of Reference Example 2 to Reference Example 55 was reacted (cyclization reaction in THF in the presence of sodium hydride) and treated in substantially the same manner as in Example 11 to obtain colorless crystals. Each physicochemical data is described below.

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 = 5.2 Hz) Example 80 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)

Example 81 (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 = 4.8 Hz) Example 82 (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 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 obtained in Step 1 (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.

(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 Example 4 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 Using the compound obtained in Reference Example 4 and 3-amino-1-butanol. Then, the reaction and treatment were carried out in the same manner as in Reference Example 5, whereby 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) Using the compound obtained in Step 2 and 3,5-bis (trifluoromethyl) benzylamine to react in the same manner as in Reference Example 3, and treating with 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 was reacted with 3,5-bis (trifluoromethyl) benzylamine in the same manner as in Reference Example 3 to give 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-
Pyrido [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 ).

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- [3,5-
The reaction was carried out in the same manner as in Step 2 of Reference Example 12 using the amine obtained in Step 1 instead of bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine, and the title compound was obtained. Was obtained as colorless crystals (cis-trans isomer ratio for 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, Reaction and treatment as in Example 3 yielded the title compound 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) T of the oily substance (1.94 g) obtained in Step 2
DMF (3 drops) and oxalyl chloride (2.0 ml) were added to the HF (30 ml) solution, and the mixture was stirred at room temperature for 30 minutes. After evaporation of the solvent, the residue was dissolved in THF (40 ml). To this solution is added N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl)
Amine (2.2 g) and triethylamine (2.0 m
l) was added 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 separated and purified by column chromatography using silica gel (hexane-ethyl acetate = 1: 2) to give N- [3,5-bis (trifluoromethyl) benzyl. ] -2-ethoxycarbonyl-N-
(2-Hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide is a colorless crystal (1.31).
g). Melting point: 138-139 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.45 (3H × 1/4, t, J = 7.1Hz),
1.46 (3H × 3/4, t, J = 7.1Hz), 2.18 (3H × 3/4, s), 2.19
(3H x 1/4, s), 2.82 (1H, m), 3.2-3.7 (3H, m), 4.15-4.6
2 (4H, m), 7.05-7.80 (8H, m), 8.65 (1H × 3/4, s), 8.68
(1H × 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) Reference Example 33 using the oil obtained in step 2
And then treated to give N- [3,5-bis (trifluoromethyl) benzyl] -2-ethoxycarbonyl-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide. 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: Compound of Reference Example 42 The same as the spectrum.

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 and benzylamine were reacted and treated in substantially the same manner as in Reference Example 2, Step 4, 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 compound of Reference Example 52-55 was obtained by converting 2-chloro-4- (4-methylphenyl) -3-pyridinecarboxylic acid [2-cyano-3-methyl-3- (4-methylphenyl) propenoic acid ethyl ester to N , N-dimethylacetamide
Condensed with dimethyl acetal, cyclized with hydrogen chloride, and alkali-hydrolyzed the ester group, prepared: melting point 20
5-208 ° C (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-[(S)-
Using [3-hydroxy-2-methylpropyl] amine}, the reaction was carried out in substantially the same manner as in Step 2 of Reference Example 12 to give each product as a pale yellow oil. 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 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).

Formulation Example 1 (1) 10.0 mg of the compound of Example 2 (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 2 and 60.0 lactose
mg and 35.0 mg of corn starch,
After granulation using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), the mixture was dried at 40 ° C. and sieved. The obtained granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting uncoated tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain coated tablets.

Formulation Example 2 (1) Compound of Example 1 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 10.0 mg of the compound obtained in 2 and 3.0 mg of magnesium stearate were added to an aqueous solution of soluble starch in 0.
After granulation with 07 ml (7.0 mg as soluble starch), it was dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give tablets.

[Radioligand Receptor Binding Inhibitory Activity] A receptor from human lymphoblastoid cells (IM-9) was used.
Binding Inhibitory Activity MA Cascieri [Molecular Pharmacology 42]
Vol., P. 458 (issued in 1992)]. Receptors were prepared from human lymphoblast cells (IM-9). IM-9 cells (2 × 10 ⁵ cells / ml) were cultured for 3 days (1 liter) after inoculation, and then centrifuged at 500 × G for 5 minutes to obtain a cell pellet. 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 the compounds obtained in the examples was determined as the drug concentration (IC ₅₀ value) required to exhibit 50% inhibition under the above-mentioned conditions, and the following results were obtained. Was.

[Table 1] Example No. The IC ₅₀ values (nM) Example No. IC ₅₀ value (nM) 2 0.28 24 1.6 3 0.76 25 0.18 1.231 0.36 10 0.66 35 0.44 13 0.17 37 0.28 14 0.28 38 0.74 15 0.88 39 0.42 16 0.17 40 0.17 17 0.23 45 0.12 18 0.43 47 0.223 1.1 The radio ligand is labeled with ¹²⁵ I. FIG. From this, it can be seen from Table 1 that the compounds (I) and (Ia) of the present invention or salts thereof have 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 was used.
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).
genizer 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 that the protein concentration was 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 Maye 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 the examples under the above conditions, respectively.
M), the following results were obtained.

[Table 2] Example No. IC ₅₀ value (nM) 22 7.5 27 6.2 33 9.5 From Table 2, the NK ₂ receptor in which the compounds (I) and (Ia) of the present invention or their salts are excellent It turns out that it shows an antagonistic action.

Capsaicin in guinea pig trachea
cin) Inhibitory activity of induced vascular hyperpermeability response Pentobarbital (Pentobarbital) 35 mg / kg was intraperitoneally (ip) administered to anesthetize guinea pig (Hartley white male guinea pig) (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].

Embedded image 〔result〕

[Table 3] Table 3 shows that the compounds (I) and (Ia) of the present invention or salts thereof have an excellent inhibitory effect on capsaicin-induced vascular hyperpermeability.

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 471/04 121 C07D 471/04 121 498/04 116 498/04 116 (31) Priority claim number Japanese Patent Application No. Hei 8-30033 (32) Priority Japan, Japan (JP) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 471/14 102 CA (STN)

Claims (1)

(57) [Claims] (1) (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.