WO2000006578A1 - Pyridobenzoxazine derivatives and process for producing the same - Google Patents

Abstract

Pyridobenzoxazine derivatives having tachykinin antagonism, in particular, substance P receptor antagonism. Namely, pyridobenzoxazine derivatives represented by general formula (1) and salts thereof and medicinal compositions containing these compounds or pharmaceutically useful salts thereof: wherein R?1, R2 and R3¿ are the same or different and each represents hydrogen or C¿1-6? alkyl; the ring A is a homocycle or a heterocycle optionally having 1 to 3 substituents selected independently (wherein 2 substituents adjacent to each other may be bonded together to form a ring); the ring B is a benzene ring optionally having 1 to 5 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring); and the ring C is a benzene ring optionally having 1 to 3 substituents (wherein 2 substituents adjacent to each other may be bonded together to form a ring).

Description

 Satsuki Itoda β pyridobenzoxazine derivative and method for producing the same

Technical field

 TECHNICAL FIELD The present invention relates to a novel pyridobenzoxazine derivative or a pharmacologically acceptable salt thereof having an evening kinkinin receptor antagonistic activity, a method for producing the same, and a pharmaceutical composition containing the pyridobenzoxazine derivative. It is.

Background art

 Evening kikinin (substance Ρ, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors in the body (neurokinin 1 (NK1), neurokinin 2 (NK2), It is known that various biological activities are expressed by binding to neurokinin 3 (NK3)). Among them, substance P acts as a transmitter of central and peripheral primary sensory neurons, and also enhances diuresis, excites nerve cells, enhances vascular permeability, expands blood vessels, smoothens muscles, and immunizes. Various physiological conditions

(Urinary frequency, urinary incontinence, vomiting, inflammation, allergy, respiratory tract disease, pain, central nervous system disease, etc.). Accordingly, compounds having excellent tachykinin receptor antagonism, particularly substance P receptor antagonism, and excellent safety and long-lasting properties as preventive and therapeutic agents for the various disease states as described above. Development is desired.

At present, the following compounds and the like are disclosed as compounds having a substance P receptor antagonistic action.

(1) In Japanese Patent Application Laid-Open No. 1-28795, formula: R ¹ -AD-Trp (R ² ) -Phe-R ³

(Wherein, R ¹ is hydrogen or an amino protecting group, R ² is hydrogen, an amino protecting group, a carbamoyl (lower) alkyl group, a carboxy (lower) alkyl group, or a protected carboxy (lower) alkyl group, R ³ Is an alk (lower) alkyl group, one N (R ⁴ ) (R ⁵ ) group (wherein R ⁴ and R ⁵ are each independently a hydrogen, aryl group or a lower alkyl which may have a suitable substituent) R ⁴ and R ⁵ are linked to each other to form a benzene-condensed lower alkylene group), or —OR ⁶ group, wherein R ⁶ is hydrogen, aryl, or a suitable substituent. Wherein A represents a single bond or one or two amino acid residues, and A represents one amino acid residue of D—T rp. R ⁴ is not hydrogen when this is meant.) The compound represented by) and a salt thereof are disclosed. Have been.

 (2) E P — A — 4 2 9 3 6 6 Formula:

Are disclosed.

(3) Formula in W09 1/0 9 8 4 4:

Are disclosed.

(4) Ε Ρ— Α— 5 3 2 4 5 6 Formula

(5) EP—A— is a compound represented by the formula

And the like are disclosed.

 (6) WO 93/0 1 1 69 No. formula:

And the like are disclosed.

 (7) In Japanese Patent Application Laid-Open No. Hei 8-67676, the formula is as follows:

(Wherein, ring A and ring B are homo or hetero rings, at least one of which is heterocyclic; ring C is a benzene ring; R is H or a hydrocarbon residue; one of X and Y is one NR ¹ - (R ¹ is H or a hydrocarbon residue) or one 0 and the other one C_〇 one or one CS-, or one one N =, the other = CR ² one (R iH, Nono androgenic, hydrocarbons N represents 1 or 2.) or a salt thereof is disclosed.

(8) In JP-A-9-1104674, the formula is as follows:

(In the formula, X represents a hydrogen atom or an oxygen atom, Y represents a nitrogen atom or an oxygen atom which may be alkylated or acylated, and R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkanol group, or a nitrogen atom. alkyl group, a force Rubamoiru group containing, lower alkylthio group, a lower alkyl sulfide El group, a lower alkylsulfonyl group, a (4-phenylene Rubiperajin one 1-I) methyl group, R ² represents a hydrogen atom, a lower alkyl group, a hydroxyl group And a lower alkenyl group, a lower alkanol group and a lower alkoxy group, and the ring A and the ring B each represent a benzene ring which may have a substituent.

 (9) In Japanese Patent Application Laid-Open No. 9-2636587, the formula is as follows:

(Wherein, the M ring is a heterocyclic ring having a partial structure of 1 X = Y, 1 N = C, 1 C〇1 N <or 1 CS—N <; R a and R b are bonded together Form a ring A, or the same or different hydrogen atom or M ring Ring A and ring B are each an optionally substituted homo- or heterocyclic ring, at least one of which may have a substituent. Heterocyclic ring; ring C is substituted A homocyclic or heterocyclic ring which may have a group; a ring Z which may be substituted; and n represents an integer of 1 to 6. ) Is disclosed.

 At present, it has an excellent antagonistic activity against tachykinin receptor (particularly, a substance P receptor antagonistic activity) as a preventive or therapeutic agent for the above-mentioned various disease states, and in view of safety, sustainability and the like. However, no compound has been found that can be a sufficiently satisfactory drug. An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism to tachykinin receptor, particularly a substance P receptor antagonist, which has a different chemical structure from known compounds including the above-mentioned compounds, a tachykinin receptor antagonist, An object of the present invention is to provide an agent for preventing or treating dysuria, an agent for preventing or treating gastrointestinal disorders, and an agent for preventing or treating vomiting. Disclosure of the invention

 The present inventors have the following general formula (1)

(Wherein R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C t -C ₆ alkyl group, and the A ring is independently selected from one to three substituents (adjacent Even if two substituents are bonded to each other to form a ring A homo- or heterocyclic ring which may have 1 or 5 ring (s) may have 1 to 5 substituents (two adjacent substituents may be bonded to each other to form a ring); The optionally substituted benzene ring and the C ring may have a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). Show. And a salt, hydrate and solvate thereof.

 We have:

A ring is a halogen atom, an optionally substituted C i -C ₆ alkyl group-an optionally substituted aryl group, a hydroxy group, an optionally substituted C ₁ -C ₆ alkoxy group, _{3 to} Ci. , An optionally substituted C ₁ -C ₆ alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted aryloxy group, C ₃ .- C. A cycloalkanoyloxy group, an optionally substituted C i -C ₆ alkylthio group, an optionally substituted C i Ce alkylsulfinyl group, an optionally substituted C i -C ₆ Alkylsulfonyl group, amino group, mono- or di-substituted CtCe alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, CiCe An alkylcarbonylamino group, an alkoxycarbonylamino group of CiCs, an alkylsulfonylamino group of CiCe, an optionally substituted arylsulfonylamino group, C! Alkylcarbonyl group ~ C _6, a formyl group, a force Rupokishiru group, alkoxy force Lupo sulfonyl group C i C e, alkyl force Rubamoiru group C i to C ₆ mono- or di-substitution from 1 to 3 of the 1 to 3 substituents independently selected from a 4- to 9-membered cyclic rubamoyl group, a cyano group or a nitro group which may contain a terrorist atom (when two adjacent substituents are Which may combine with each other to form a ring), Ring B is a halogen atom, an optionally substituted C i -C ₆ alkyl group. C ₃ -C i. Cycloalkyl groups, optionally substituted Ariru group arsenide Dorokishiru group, an optionally substituted C i to C ₆ alkoxy group, alkanoyloxy Noi Ruo alkoxy group ~ C ₆ optionally C ₁ may be substituted, optionally substituted § Li also be Roiruokishi group, an optionally substituted Ariru Mechiruokishi group, C ₃ -C _{1 0} cycloalkoxy group, cycloalkadienyl Noi Ruo alkoxy group of C ₃ ~ C i _0, optionally substituted C i Ce alkylthio group, optionally substituted C i Ce alkylsulfinyl group, optionally substituted C i Cs alkylsulfonyl group, amino group, mono or di A substituted C i C alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a C t to C ₆ alkylcarbonylamino group, C i C e alkoxycarbonylamino group, C to C ₆ Le Kill sulfonyl § Mi amino group, optionally substituted § Li one also be Rusuruhoniruami amino group, an alkylcarbonyl group C. 1 to C _6, a carboxyl group, an alkoxycarbonyl two Le group C. 1 to C 6, mono- or di-substituted Each independently represents a C i -C ₆ alkyl group, a 4- to 9-membered cyclic group, which may contain 1 to 3 heteroatoms, a cyano group or a nitro group. A benzene ring which may have 1 to 3 selected substituents (two adjacent substituents may be bonded to each other to form a ring),

C ring is a halogen atom, optionally substituted C! -C ₆ alkyl group, hydroxy group, optionally substituted C ₆ -C ₆ alkoxy group, optionally substituted C 1 -C 6 alkanoyloxy group, optionally substituted § Li Roiruokishi group, substituted optionally may be Ari Rumechiruokishi group, C ₃ -C i ₀ cycloalkoxy group, C ₃ ~ C _{1 0} cycloalkadienyl Noi Ruo alkoxy group, amino group, ~ a mono- or di-substituted C ₆ alkylamino group, even containing 1-3 heteroatoms Good 4- to 9-membered cyclic amino group, C! Alkylcarbonyl amino group ~ C _6, C ₁ alkoxycarbonyl § Mi amino group of ~ C _6, C i C g of § Le Kill sulfonyl § Mi amino group, optionally substituted § Li one also be Rusuruho Niruamino group, Shiano Has one to three substituents independently selected from a group or a two-port group (two adjacent substituents may be bonded to each other to form a ring) 3. The pyridobenzoxazine derivative according to claim 1, which represents a benzene ring that may be substituted. I will provide a.

 The present inventors have the following general formula (2)

(In the formula, R ³ is a hydrogen atom or a C-C ₆ alkyl group, R ⁴ is a hydroxyl group, a C j Ce alkoxy group, a benzyloxy group or a reactive residue, even if the A ring is a halogen atom, Good C i -C ₆ alkyl group, optionally substituted aryl group, hydroxy group, optionally substituted C t Ce alkoxy group, C ₃ -C 10 cycloalkoxy group, substituted Optionally substituted Ci to C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ to C i _Q cycloalkano An aryloxy group, an optionally substituted CCe alkylthio group, an optionally substituted C i -C ₆ alkylsulfiel group, an optionally substituted C i -C ₆ alkylsulfonyl group, Amino group, mono- or di-substituted C i C g alkyl Amino groups, even containing 1-3 heteroatoms A 4- to 9-membered cyclic amino group, a C i -C ₆ alkylcarbonylamino group, a C i Cs alkoxycarbonylamino group,

C e § Le kills sulfonyl § Mi amino group of, optionally substituted § Li one also be Rusuruho Niruami amino group, an alkylcarbonyl group of C i to C _6, a formyl group, a force Rupokishiru group, alkoxycarbonyl C i~C ₆ group, mono- or alkyl force Rubamoiru group C i to C ₆ di substitution, 1 of 3 may contain heteroatoms of 4-9 membered cyclic force Rubamoiru group, the Shiano group or a Toro group A homo- or heterocyclic ring which may have 1 to 3 substituents independently selected from each other (two adjacent substituents may combine with each other to form a ring) And the ring C is a halogen atom, an optionally substituted C i -C 6 alkyl group, a hydroxyl group, an optionally substituted (丄-^^ alkoxy group, an optionally substituted

6 Arca Noi Ruo alkoxy group, an optionally substituted § Li Roiruoki shea group, optionally substituted § reel also be methyl O alkoxy group, cycloalkoxy group of _{C 3 ~ C 1 0, C} g C i. Cycloalkanols Noi Ruo alkoxy group. Amino, mono- or di-substituted alkylamino amino group of C 1~ C _6, 1~ 3 or may contain heteroatoms of 4-9 membered cyclic Amino groups, C ! Alkylcarbonyl § amino group ~C _6, Arukokishikaru Boniruami amino group of the C i C e, C! 1 to 3 substituents each independently selected from an alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, a cyano group and a nitro group of C ₆ to C ₆ ( Two adjacent substituents may be bonded to each other to form a ring). )

Or a salt, hydrate and solvate thereof.

The present inventors have the following general formula (3)

(Wherein, R ³ is a hydrogen atom or an alkyl group of C, (6, R ⁵ is

(R ¹ and R ² are the same or different and each is a hydrogen atom or a C i C s alkyl group; ring B is 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring have also may) have been showing a benzene ring.) or a reactive residue, X is a halogen atom or a 0 S_〇 ₂ R ⁶ (R ⁶ is an optionally halogen-substituted C i to C ₆ alkyl group, optionally substituted aryl group), ring C is halogen atom, optionally substituted C t -C ₆ alkyl group, hydroxy group, optionally substituted C i C e, an alkoxy group, an optionally substituted (^-. (^ an alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylylmethyloxy group, C ₃ ~ C,. the consequent opening alkoxy group, C ₃ ~ C i. cycloalkadienyl Noi Ruo alkoxy group, amino group, Mo Or di-alkylamino amino group substitution C i C e, 1~ 3 ring-shaped § Mi Roh group which may 4-9 membered contain a hetero atom, an alkylcarbonyl amino group of C ~ C _6, C 1 ~ C 6 alkoxycarbonylamino group, C i Ce alkylsulfonylamino group, substituted 1 to 3 substituents each independently selected from an arylsulfonylamino group, a cyano group, and a nitro group (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have The present invention provides a pyridobenzoxazine derivative represented by the formula or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (4)

(Wherein, R ³ is a hydrogen atom or a C i Ce alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, the C ring is a halogen atom, an optionally substituted C i -C ₆ alkyl group, a hydroxy group, but it may also be substituted alkoxy group C. 1 to C 6, optionally substituted C ₁ -C ₆ of § Rukanoiruokishi group, optionally substituted § Li Roiruokishi group, an optionally substituted § reel methyl O alkoxy group, C ₃ ~C _1. The alkoxy group of the mouth, C to C,. A cycloalkanoyloxy group of Amino group, mono- or di-substituted alkylamino amino group of C ~ C _6, 1~ 3 ring-shaped § Mi amino group of may 4-9 membered optionally containing a heteroatom, alkylcarbonyl § of C. 1 to C ₆ Mi amino group, an alkoxycarbonylamino group of C i to C _6, alkylsulfonyl § Mi amino group of C i to C _6, optionally substituted § Li one even if Le sulfonyl § amino group, a Shiano group or two Toro group Represents a benzene ring which may have 1 to 3 substituents independently selected from each other (two adjacent substituents may be bonded to each other to form a ring) . The present invention provides a pyridobenzoxazine derivative represented by the following formula: or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Cs alkyl group, R ⁴ is a hydroxyl group, a C i C alkoxy group, a benzyloxy group or a reactive residue, and the A ring is independently selected. A homo- or heterocyclic ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring); A benzene ring which may have two or more substituents (adjacent two substituents may be bonded to each other to form a ring).

And a salt, hydrate and solvate thereof. The following general formula (5)

(Five)

R ²

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom or a C! To C ₆ alkyl group, and ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other A benzene ring which may have a) or a salt, hydrate, or solvate thereof represented by the formula: And a method for producing a compound, a salt thereof, a hydrate and a solvate thereof.

 The present inventors have the following general formula (6)

(Wherein, R ³ is a hydrogen atom or an alkyl group C i C e, R ⁷ is hydroxyl. Alkoxy C i to C _6, Benjiruokishi group,

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of C! Ce; ring B has 1 to 5 substituents. Which may form a ring together). ) Or a reactive residue, X is a halogen atom or a ^{_{0 S 0 2 R 6 (R}} 6 is an alkyl group optionally C i to C ₆ be halogen-substituted, optionally substituted Ariru group), C ring Represents a benzene ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring). ) And pyridobenzoxazine derivatives or their salts, hydrates and solvates

The following general formula (Ί)

(In the formula, Y is a halogen atom, 〇 S_〇 ₂ R ⁶ (R ⁶ is as defined ^{above), B (R 8) 2} (R 8 is a hydroxyl group, an alkyl group or a C alkoxy group C. Or R ⁸ may combine with each other to form a ring.), MgBr or ZnCl, ring A is independently selected from one to three substituents (two adjacent substituents) Or a heterocyclic ring which may have a ring, wherein the groups may be bonded to each other.) 4. The pyrid according to claim 1 or 3 by reacting a compound represented by the formula: A method for producing a benzoxazine derivative or a salt, hydrate and solvate thereof is provided.

 The inventors of the present invention have provided a pyridobenzoxazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition, which is characterized in that it has a receptor for quinkinin. Provide a body antagonist.

 The present inventors have proposed a substance P receptor comprising a pyridobenzoxazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide a body antagonist.

The present inventors have proposed a pyridobenzoxazine derivative represented by the general formula (1): A prophylactic or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence, which comprises a body or a salt, hydrate and solvate thereof as a pharmaceutical composition. .

 The present inventors have proposed a ulcerative colon having a pyridobenzoxazine derivative represented by the general formula (1) or a salt, hydrate or solvate thereof as a pharmaceutical composition. Provided is a preventive or therapeutic agent for gastrointestinal diseases including inflammation and Crohn's disease.

 The present inventors have provided a pyridobenzoxazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition, which is characterized by comprising an X-ray irradiation. And a prophylactic or therapeutic agent for vomiting induced by chemotherapeutic agents, pregnancy, migraine, post-operative illness, gastrointestinal hypomotility, side effects of drug administration, and the like.

 The present inventors have obtained a tachykinin comprising a pyridobenzoxazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide therapeutic agents for associated asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc.

Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. The alkyl group of c ₁ to c ₆ means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group and the like. The alkoxy group of c ₁ to c ₆ means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a t-butoxy group, a hexoxy group, or the like. The cycloalkoxy group of C ₃ ~ C i 0, cyclo propyl O alkoxy group, cyclobutyl O alkoxy group, means a Shikuropenchiruo alkoxy group, Kishiruokishi group cyclohexylene. c ₃ The consequent b alk Noi Ruo alkoxy group ~ c _{1 0,} meaning cyclopropadiyl Noi Ruo alkoxy group, consequent b pigs Noi Ruo alkoxy group, Shikuropen evening Noiruokishi group, a key Sanoiruokishi group cyclohexylene. C i -C ₆ alkylcarbonyl group Means acetyl group, propionyl group, butyryl group and the like. The C i -C ₆ alkoxycarbonyl group includes a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxyl propyl group, a t-butoxycarbonyl group, a hexyloxycarbonyl group and the like. Means The mono- or di-substituted Ci to c ₆ alkylcarbamoyl groups include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, t-butylcarbamoyl, and hexylcarbamoyl. Dimethylcarbamoyl group, getylcarbamoyl group, dipropyl carbamoyl group, diisopropyl propyl carbamoyl group, dibutyl carbamoyl group, dihexyl carbamoyl group and the like. A 4- to 9-membered cyclic rubamoyl group which may contain 1 to 3 heteroatoms is defined as azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, 4-methylbiperidyl group A carbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, and a 4-methylpiperazinylcarbonyl group. The C i -C ₆ alkylthio group means a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a t-butylthio group, a hexylthio group, and the like. The C i Ce alkylamino group includes a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a t-butylamino group, a hexylamino group, a dimethylamino group, a getylamino group, and a diamino pyramino group. , Diisopropylamino group, dibutylamino group, dihexylamino group and the like. The 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group, morpholino group and thiomorpholino group. , Piperazino group, 4-methylbiperazino group and the like. The alkylcarbonylamino group of C t Ce is an acetylamino group, It means a propionylamino group, a petyrylamino group and the like. The alkoxycarbonylamino group of (^ ~. (^ Is a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexyloxycarbonylamino group, or the like. (The alkylsulfonylamino group of ^ C e means a methylsulfonylamino group, an ethylsulfonylamino group, etc. The arylsulfonylamino group is a phenylsulfonylamino group Group, 4-methylphenylsulfonylamino group, naphthylsulfonylamino group, etc. The homocyclic ring of A ring means a benzene ring, a naphthalene ring, etc. The complex ring of A ring is A 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 3 heteroatoms arbitrarily selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a 9- or 10-membered aromatic ring Means fused heterocycle . The alkyl group optionally (^ ~ ₆ be substituted, a halogen atom, human Doroki sill group, C i C e alkoxy group, C i C e alkylthio group, amino group, mono- or di-substituted alkylamino amino group of C i C e, 1~ 3 pieces of the may contain a hetero atom 4-9 membered cyclic § Mi amino group, Hol Miruami amino group, an alkylcarbonyl § Mi C i to C ₆ Bruno A C ₁ -C ₆ alkyl which may have 1 to 5 substituents selected from a group, a C i C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. means a group. the alkoxy group optionally substituted C i be the C e, halogen atom, arsenic Dorokishiru group, an alkoxy group of 〇 ~ C _6, an alkylthio group having C i to C _6, amino group, mono Or a di-substituted CiC alkylamino group containing 1 to 3 heteroatoms. Idei and may 4-9 membered cyclic Amino groups, Horumiruami amino group, an alkylcarbonyl amino group, Arukirusu Ruhoniruami amino group of C ₁ ~ C _6, optionally substituted § Li one also be Rusuruhoniruami amino group of ◦ C 1 -C optionally having 1 to 5 substituents selected from Means 6 alkoxy groups. The optionally substituted C 1 to C ₆ alkanoyloxy group includes a halogen atom, a hydroxy group, a C ₆ to alkoxy group, a C 1 to C 6 alkylthio group, an amino group, a mono or di alkylamino amino group of C 1 through C 6 substituted from 1 to 3 of the terrorist atom contain an be 4-9 membered cyclic § Mi amino group, Horumiruami amino group, alkylcarbonyl of C i to C ₆ C-C may have 1 to 5 substituents selected from an alkylsulfonylamino group of C! Ce, an optionally substituted arylsulfonylamino group, and the like. It means an alkanoyloxy group of i Ce (acetyloxy group, propionyloxy group, isopropionyloxy group, hexanoyloxy group, etc.). The optionally substituted aryloxy group includes a halogen atom, a C i Cs alkyl group, a hydroxy group, an alkoxy group, a C i -C ₆ alkylthio group, an amino group, a mono- or di-substitution A C i Ce alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, a formylamino group,

Alkylcarbonyl amino group of C _6, having a C ₁ alkyl sulfonyl Ruami amino group of ~ C _6, substituted 1 also selected from Good § Li one Le sulfonylamino group optionally 5 substituents Aryloxy group (benzoyloxy group, naphthyloxy group, pyridyloxy group, pyrimidyloxy group, quinolyloxy group, indriloxy group, etc.). The arylmethyloxy group which may be substituted includes a halogen atom, a C i Ce alkyl group, a hydroxy group, a C! -C ₆ alkoxy group, a C i -C ₆ alkylthio group, and an amino group. group, mono or di-substituted C! C e of alkylamino amino group from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic amino group, Horumiruami amino group, C i to C ₆ Alkylcarbonylamino group of C! To C ₆ alkylsulfonylamino group, optionally substituted arylsulfonylamino Arylmethyloxy groups (phenylmethyloxy, naphthylmethyloxy, pyridylmethyloxy, quinolylmethyloxy, and quinolylmethyloxy) which may have 1 to 5 substituents selected from (Drillmethyloxy group, etc.). The optionally substituted § Li one also be Rusuru Honiruami amino group, a halogen atom, an alkyl group of C ₁ -C _6, human de port hexyl group, an alkoxy group of _{C 1 ~ C 6, C i} C e alkylthio group , Amino groups, mono- or di-substituted C! Alkylamino group ~ C _6, 1 ~ 3 or may contain heteroatoms of 4-9 membered cyclic Amino groups, Horumiruami amino group, an alkylcarbonyl § Mi amino group of C i to C _6, -C It means an arylsulfonylamino group optionally having 1 to 5 substituents selected from ₆ alkylsulfonylamino groups, optionally substituted arylsulfonylamino groups, and the like. A ring in which two adjacent substituents may be bonded to each other to form

And so on.

The aryl group which may be substituted includes a halogen atom, an alkyl group of c _{1 to} c _6, a hydroxyl group, an alkoxy group of CiCe, and 〇! Alkylthio group ~ C _6, amino group, mono- or di-substituted C, § Rukiruami amino group of ~ C _6,. 1 to 3 or even be 4-9 membered contain heteroatoms of the cyclic amino group , Horumiruami amino group, alkylcarbonyl Niruami amino group of C ~ C _6, alkyl C ₁ -C _6. Suruhoniruami amino group 1, selected from such as optionally substituted § Li one also be Rusuruhoniruami cyano group 5 Means an aryl group (phenyl group, naphthyl group, etc.) which may have one or more substituents. The optionally substituted alkylthio group is a halo Gen atom, arsenic Dorokishiru group, an alkoxy group of C! C e, C i~ alkylthio group C _6, amino, mono- or di-substituted C, alkyl Ruami amino group of ~ C _6,. 1 to terrorism three of the atoms may contain from 4 to 9-membered cyclic amino group, Horumiruami amino group, an alkylcarbonyl amino group of C. 1 to C _6, alkylsulfonyl § Mi amino group of C ₁ ~ C _6, optionally substituted Further, it means an alkylthio group optionally having 1 to 5 substituents selected from a arylsulfonylamino group and the like. The optionally substituted alkylsulfenyl group includes a halogen atom, a hydroxy group, a C ₁ to C ₆ alkoxy group, and 〇! To 〇6 alkylthio group, amino group, mono- or di-substituted Ci-C6 alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms , formyl Ruami amino group, C ~ alkylcarbonyl § Mi amino group of C _6, C i C e alkylsulfonyl amino group, 1 selected from such optionally substituted § Li one also be Luz Ruhoniruami cyano group 5 Means an alkylsulfiel group (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, etc.) which may have one or more substituents. The optionally substituted alkylsulfonyl group includes a halogen atom, a hydroxy group, a C i -C ₆ alkoxy group, a C i -C ₆ alkylthio group, an amino group, a mono- or di-substituted C -C ₆ alkylamino amino group of from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic § Mi amino group, formyl Ruami amino group, an alkylcarbonyl § Mi amino group of C ~ C _6, C ₁ To C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, and an optionally substituted alkylsulfonyl group (methylsulfonyl group, Ethylsulfonyl group, propylsulfonyl group, etc.). The reactive residue means a halogen atom, an imidazolyl group, a 4-nitrophenoxy group, a kono, an imidoyloxy group, or the like. Even if halogen is substituted A good C i -C ₆ alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, which may be substituted with 1 to 13 fluorine atoms or chlorine atoms. It means a hexyl group or the like. The ring which may be formed by bonding R ⁸ to each other includes — 0 (CH ₂ ) ₂₀ —, — 0 CH (M e) CH (M e) 0—, ) ₂ C (M e) ₂ means one or one (CH ₂ ) ₃₀ — and the like.

Preferred compounds of the present invention include N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-1-N-methyl-15-oxo-17-phenyl-5H —Pyrido [1,2,3-de] —1,4—Benoxaxazine-1 6-carboxamide, N— [3,5-Bis (trifluoromethyl) benzyl] —2,3-Dihidro 7— (3 —Methoxyfenyl) 1-5-oxo-5H-pyrido [1,2,3-de] — 1,4 benzoxazine-6-carboxamide, N— [3,5—bis (trifluoromethyl) Benzyl] — 2,3-Dihydro-5-oxo-7- (3-Trifluoromethylphenyl) -5-H-pyrido [1,2,3-de] 1-1,4-Benzoxazine 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 7- (2,4-dichlorophenyl) 1-2, 3-dihydro-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzoxazine-6-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] _2,3-Dihydro-1,3, N-dimethyl-7- (3-methoxyphenyl) -1,5-oxo-5, H-pyrido [1,2,3-de] -1,4-Benzoxazine-6 —Carboxamide, N— [35-Bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7- (3-fluorophenyl) -1-N-methyl-15-oxo-5H—pyrido [1 , 2,3—de]-1,4-Benzoxazine-1 6-force lipoxamide, N— [3,5-bis (trifluoromethyl) benzyl 1-7— (3-chlorophenyl) 1-2,3—dihydro N-methyl 5—oxo-5 H-pyrido [1,2,3-de] —1,4,1-benzoxazine 6—Carboxamide, N— [3,5—Bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N-methyl-1- (3-nitrotropenyl) -15—Oxo-5H-pyrido [1, 2, 3— de] — 1,4-benzoxazine-16-carboxamide, ド-(3-aminophenyl) -1-N— [3, 5 —bis (trifluoromethyl) benzyl] — 2, 3—Jihi draw N—Methyl-1 5—Oxo-1

5 H-pyrido [1,2,3-de] — 1,4-benzoxazine

6—Carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,5—dichlorophenyl) 1-2,3-dihydro N—methyl-15—oxo-5H —Pyrido [1,2,3—de] —1,4-Benzoxazine-1-6-carboxamide, N— [3,5—Bis (trifluoromethyl) benzyl] — — [3,5—Bis (T Trifluoromethyl) phenyl] — 2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzooxazine-1-6-carboxamide, N — [3,5 —Bis (trifluoromethyl) benzyl] — 2,3-Dihydro-1-N-methyl-1 7 — (4-Methylphenyl) -1 5 —Oxo-1 5 H—Pyrido [1,2,3 -de] — 1,4,1 Benzoxazine-1 6 —Carboxamide, N— [3,5—Bis (trifluorome Le) benzyl] - 2, 3 - dihydric Draw

7- (4-Methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzoxoxazine-16-force lipoxamide (, N— [3, 5—Bis (trifluoromethyl) benzyl] —2,3-Dihydro 7— (4-Fluorophenyl) 1 N—methyl 1 5 —oxo 1 5 H—pyrido [1,2,3—de ] — 1,4,1-benzoxazine-1-6—carboxamide (, N- [3,5-bis ( Trifluoromethyl) benzyl] — 7— (4-chlorophenyl) 1,2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4— Benzoxazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] — 7— (3—Cro-4-4-fluorophenyl) 1-2,3-dihydro-1-N—methyl—5— Oxo-5H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3- Dihydro-1-N-methyl-7- (4-methyl-3-nitrotropenyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzoxazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1-7— (2-methoxyphene 1) N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4, -benzoxazine-6-carboxamide, N— [3,5-bis (tri) Fluoromethyl) benzyl] — 2,3-Dihydro N-methyl-1- 7- (1-naphthyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine-6 —Carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro 7— (3-formylphenyl) —N-methyl-5-oxo-5H—pyrido [1,2 , 3—de] — 1,4-Benzoxazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-formylphenyl) 1 N —Methyl — 5-oxo-1 5 H-pyrido [1,2,3—de]-1,4—Benzoxazine-1 6-carboxami , N-[3,5-bis (trifluoromethyl) benzyl] 1, 2, 3-dihydro 1-7-(3-hydroxyphenyl) 1-N-methyl-1-5-oxo-5H-pyrido [ 1, 2, 3—de] — 1,4 benzoxazine _ 6—carboxamide, N ― [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1-N-methyl-7- [4- (methylthio) phenyl] -5-oxo-5H-pyrido [1,2 , 3-de] — 1, 4-Benzoxazin-1-6-carboxamide, N-[3, 5-bis (trifluoromethyl) benzyl]-2, 3-dihydro-1-N-methyl 1-7-[4 — (Methylsulfinyl) phenyl] -1-5-oxo-5 H-pyrido [12,3-de] -1, 4-benzoxazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl ] — 2,3-Dihydro-1-N-methyl-7— [4- (Methylsulfonyl) phenyl] — 5-oxo-5 H-pyrido [1,2,3-de] —1,4-Benzoxazine 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —N-cyclopropyl 1,2,3-Dihydro 7- (3-Methoxyphenyl) -1-5-oxo-5H-pyrido [12,3-de] -1,4-benzobenzoxazine-16-carboxamide, N— [3,5_Bis (trifluoromethyl) benzyl] — N-cyclopentyl-1,2,3-dihydro7- (3-methoxyphenyl) 15-year-old 5-H-pyrido [1, 2, 3-de] — 1, 4-benzoxazine 1-6-carboxamide, N-[3, 5-bis (trifluoromethyl) benzyl]-2,3-dihydro N-isopropyl 1 7 -(3-Methoxyfuel) 1-5-oxo-5H-pyrido [1,2,3-de]-1,4,4-benzoxazine-6-carboxamide, N- [3,5-bis (tri) Fluoromethyl) benzyl] — 2,3-dihydro N-ethyl 7- (3-methoxyphenyl) 1-5-oxo 5 H-pyrido [1,2, 3-de] — 1,4-benzoxazin-6-carboxamide, Νarylu Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxyphenyl) One 5-oxo one five-pyrid [1,2,3-de] .

26

— 1,4—Benzoxazine-1-6-carboxamide, N— [3,5—Bis (trifluoromethyl) benzyl] -12,3-Dihydro-1-N-1- (2-Methoxyxetil) -17— (3-Methoxyphenyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine-6-carboxamide, N-benzyl-1-N— [3,5-bis (trifluo mouth) Methyl) benzyl] 1, 2,3-Dihydro 7- (3-Methoxyphenyl) 1-5-oxo-5H-pyrido [1,2,3-de]-1,4,1 Benzoxazine-1 6 _carboxami 1,2,3-Dihidro 7- (3-Methoxyphenyl) -1-methyl- (2-methylbenzyl) -1-5-oxo-5-pyrid [1,2,3-de] -1 1,4-benzoxazine- 1 6-carboxamide, N- (3-cyclobenzyl) 1,2,3-dihydro- 7— (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzoxazine-6-carboxamide, 2,3-dihi 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4, -benzoxazine ー _ [3-— Trifluoromethyl) benzyl] — 6-carboxamide, Ν— (2,3-difluorobenzyl) -1,2,3-dihydro-7- (3-methoxyphenyl) 1-methyl-1-5-oxo 1 5 Η —Pyrido [1,2,3-de] — 1,4-Benzoxazine-16-carboxamide, N— (2,4-difluorobenzyl) 1-2,3-Dihydro-7— ( 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4 Benzoxazine-1-6-carboxamide, N— 3,5—diflurobenzene) 1,2,3-dihydro-7— (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1, 4-benzobenzoxazine _ 6-carboxamide, 2, 3-dihydro-N- (3, 5-Dimethoxybenzyl) 1 7- (3-Methoxyphenyl) 1 N-methyl-5-oxo-5 H-pyrido [1,2,3-de] — 1,4 Benzoxazine-1 6-carboxami 1,2,3-Dihydro-1-N- (2-methoxybenzyl) -17- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4,1-Benzoxazine-16-carboxamide, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3 -de]-1,4-Benzoxazine-N- [3- (Trifluoromethoxy) benzyl]-6-carboxamide, 2,3-dihydro-N- [3-Fluoro-5- (trifluoromethyl) benzyl] — 7— (3-Methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4— Benzoxazine 1-6-carboxamide, N- (3,5-dichlorobenzene) 1,2,3-dihydro7- (3-methoxyphenyl) 1-N-methyl-15-oxo-5H-pyri [1, 2, 3-de] — 1,4-benzoxazine- 1 6-carboxamide, N— (3,5-di-tert-butylbenzyl) 1,2,3-dihydro 7— (3-me 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide, N— (3-t-petit-5 —Methylbenzyl) 1, 2,3—Dihydro 7 _ (3—Methoxy phenyl) 1 N—Methyl 1 5—Oxo 1 5 H—Pyrido [1,2,3-de] -1,4 N-zoxazine-1 6-carboxamide, 2,3-dihydro N- (3,5-dimethylpentyl) 1 7- (3-methoxyphenyl) 1-N-methyl-5-year-old One 5H-pyrido [1,2,3-de]-1,4,1-ben Voxazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihi 7- (3-ethoxyphenyl) -1-N-methyl-1-5-oxo Sodium 5H-pyrido [1,2,3-de] — 1,4-benzoxazin-1-6-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] 1-2,3- Dihidro 1-methyl-5-oxo-7- (3-propyloxyphenyl) -5-pyrido [1,2,3-de] — 1,4_benzoxazine-16-carboxamide, N— [35-Bis (trifluoromethyl) benzyl] — 2,3-dihydro-7- (3-isopropyloxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [ 1, 2, 3-de] — 1, 4-benzoxazine 6-carboxamide, Ν-[3,5-bis (trifluoromethyl) benzyl]-7-(3-butoxyphenyl) 1, 2, 3-dihi 1-methyl-5-oxo-5-pyrido [1,2,3-de] 1-1,4-benzoxazine-6-carboxa De, N— [3,5—Bis (trifluoromethyl) benzyl] 1-2,3-dihydroxy 7- [3— (2-Methoxyethoxy) phenyl] —N-Methyl-5-oxo-5H —Pyrido [1,2,3—de] —1,4-Benoxoxazine-1 6 _carboxamide, N— [3,5-Bis (trifluoromethyl) benzyl] —2,3-Dihydro-7— [3- (2-fluoroethoxy) phenyl] — N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine-16-carboxamide, N-Benzyl-1,2,3-dihydro 7- (3-Methoxyphenyl) 1-N-methyl-1-5-oxo5H-Pyrido [1,2,3-de] —1,4-benzoxazine 6—Carboxamide, 2, 3—Dihydro 7— (3-Methoxyphenyl) -1-N—Methyl-1-N— (3-Methylpenzyl) _ 5-oxo-5H-pyrido [1,2,3-de] 11,4-benzoxazine-6-carboxamide and the like.

When the compound of the present invention forms a salt, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid Inorganic acids such as acids, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, linoleic acid, tartaric acid, cunic acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearinic acid, palmitic acid, etc. Examples thereof include pharmacologically acceptable salts with organic acids.

 The compound of the present invention or a salt thereof includes optically active isomers, stereoisomers, and rotamers as well as racemic isomers.

The compound of the present invention can be produced by various synthetic methods. Next, typical production steps of the compound of the present invention and a salt thereof will be described.

 (VI) (VIII)

 (First step)

In this step, the compound (I) (where R ³ and C ring are the same as described above) and the compound (II) (where R ⁹ is the same or different and are C 1 to C ₆ alkyl groups and benzyl groups) (III) (R ³ , R ⁹ and the C ring are the same as described above). In this reaction, compound (II) is reacted with compound (0)

The reaction is carried out at 100 to 300, preferably 150 to 250 ° C for 1 to 20 equivalents, preferably 1 to 5 equivalents. When a solvent is used, an inert solvent that does not participate in the reaction, for example, xylene, mesitylene, nitrobenezen, diphenyl ether, dausam (a mixture of diphenyl ether and biphenyl) and the like are used. Can be (Second step)

In this step, the hydroxyl group of compound (III) (R ³ , R ⁹ and ring C are the same as described above) is converted to X (X is the same as above), and compound (IV) (X, R ³ , R ⁹ and the C ring are the same as described above). In this step, for example, when X is a chlorine atom, the chlorinating agent is a phosphine such as triphenylphosphine, tributylphosphine or triphenoxyphosphine, and carbon tetrachloride, N-chlorosuccinimide. Alternatively, the reaction is carried out using chlorine, thionyl chloride, oxychloride, pentachloride or oxalyl chloride. When a solvent is used, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitril, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine and the like are used. This reaction proceeds smoothly at a temperature from room temperature to the boiling point of the chlorinating agent or, if a solvent is used, the boiling point of the solvent. When X is a bromine atom, the reaction can be carried out in the same manner as in chlorination using a corresponding brominating agent. X is 〇 S〇 ₂ R ⁶ (R

⁶ is the same as described above), methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trisulfonic acid Fluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonylimide, etc. are used, and the reaction is carried out in a solvent in triethylamine, triptylamine, diisopropylethylamine, N— The reaction is performed in the presence of a base such as methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamine. As the solvent, an inert solvent which does not participate in the reaction, preferably dichloromethane, methane, tetrahydrofuran or the like is used. The reaction is carried out at a temperature of from 178 ° C to 100 ° C, preferably from 130 ° C to 80 ° C.

(Third step) In this step, compound (IV) (X, R ³ , R ⁹ and C ring are the same as described above) and compound (V) (Y and A ring are the same as described above) are reacted with a transition metal catalyst such as palladium or nickel complex. This is a step of producing a compound (VI) (R ³ , R ⁴ and the A ring are the same as described above) by the cross-coupling reaction below. This reaction is preferably performed using an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, Examples thereof include tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol and water. These solvents are used alone or in a mixture at any ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetyl acetonato palladium, and tetrax (triphenylphosphine) palladium. The nickel complex used in this reaction is bis

(Acetylacetonato) Nickel, bis (1,5-cyclooctadiene) nickel, tetrakis (triphenylphosphine), etc. can be exemplified. These palladium or nickel complexes are used in the range of 0.01 to 1 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (IV). When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri-10-tolylphosphine, tri-2-furylphosphine, 1,2-bis (diphenylphosphinoino Examples thereof include ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) 1-1,1, -binaphthyl. These ligands are used in a range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex. When X of compound (IV) is 〇S 0 ₂ R ⁶ , copper iodide or lithium chloride can be used together with a palladium or nickel complex, if necessary. This reaction is preferably performed in the presence of a suitable base, for example, triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine and the like. Examples thereof include inorganic bases such as organic bases, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, and tricalcium phosphate. These bases are used in the range of 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to compound (IV). The cross-coupling reaction in this step can be carried out at room temperature to 150 ° C., preferably at 50 to 120 ° C. In addition, in the cross-coupling reaction of this process, the compound

When a compound in which Y in (V) is not B (R ⁸ ) ₂ is used as a raw material for production, compound (IV) or compound (V) (where Y is not B (R ⁸ ) ₂ ) Compound (IV) obtained by reacting HB (R ⁸ ) ₂ or (B (R ⁸ ) ₂ ) ₂ (X is B (R ⁸ ) ₂ ) or compound (V) (Y is B (R ⁸ ) Compound (VI) can also be produced by reacting ₂ ) with compound (V) (where Y is not B (R ⁸ ) ₂ ) or compound (IV). The compound (IV) (X is B (R ⁸ ) ₂ ) or compound (V) (Y is B (R ⁸ ) ₂ ) and the A ring is the same as the production intermediate obtained at this time is It can be subjected to the next step after isolation and purification, or can be continuously subjected to the next step without isolation and purification.

 (Fourth step)

In this step, compound (VII) (R ³ , R ⁴ and ring A are the same as described above) and compound (VII) (RR ² and ring B are the same as described above) are condensed to form compound (VIII ) (RR ² , R ³ , ring A, ring B and ring C are the same as described above). As a condensing agent used when R ⁴ is a hydroxyl group in the condensation reaction of this step, dicyclohexyl carpoimide (DCC), 3-ethyl-1- (3-dimethylaminopropyl) carposimid hydrochloride (EDCI) or Dimethylimidazonium Chloride (DMC) and the like, which are added in solid form or as a solution dissolved in a suitable solvent. When a base is used in this condensation reaction, alkali carbonates such as sodium hydrogencarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5 . 4.0] —7-Pendecene, pyridine, 4-dimethylamino pyridine or tertiary amines such as 1,8-bis (dimethylamino) naphthylene. As the solvent used in the present condensation reaction, an inert solvent which does not participate in the reaction, for example, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran , Dioxan, ethyl ether, dimethoxetane, ethyl acetate, dichloromethane and the like are used. This condensation reaction proceeds smoothly at a temperature of 120 ° C to 80 ° C. In the condensation reaction of this step, halide of a carboxylic acid in which R 4 is represented by a reactive residue (for example, a halogen atom, an imidazolyl group, a 4-nitrophenoxy group, a imidicyloxy conoxy acid group, etc.) In the case of imidazolide of carboxylic acid, active ester of carboxylic acid, mixed anhydride of carboxylic acid (for example, anhydride with ethyl carbonate, anhydride with isobutyl carbonate, etc.) or symmetric acid anhydride, In the presence or absence of organic bases such as lyethylamine, diisopropylethylamine, pyridine, 4-dimethylaminoviridine, and inorganic bases such as sodium hydrogencarbonate and potassium carbonate N, N-dimethylformamide, NN-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethylethyl Le, dimethyl Tokishe Tan, acetic Echiru, toluene, in a solvent such as dichloromethane, can be carried Ri by the treating 3 0 minutes to 48 hours in one 2 0 ~ 8 0 ° C. In the condensation reaction in this step, when R ⁴ is an ester residue such as a C 1 to C 6 alkoxy group or benzyloxy group, trimethyl aluminum In the presence of titanium or tetraisopropoxytitanium or the like, or an acid catalyst such as P-toluenesulfonic acid or a base such as sodium methoxide, sodium hydroxide-t-butoxide or sodium hydride In a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitril, tetrahydrofuran, dioxane, toluene, xylene, dichloromethane, etc. Can be performed by treating at 50 ° C for 30 minutes to 48 hours o

As shown in the fifth step, compound (XI) can also be produced from compound (IX) and compound (X). In this step, the compound (X) is used in an amount of 1 to 10 equivalents with respect to the compound (IX), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium hydroxide, t-butoxide, water N, N — dimethylformamide, N, N — dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene in the presence of a base such as hydrogenated sodium It can be carried out by treating in a solvent such as these at 50 to 150 ° C for 30 minutes to 48 hours. Compound (VIII) can be produced from compound (XI) obtained according to the method described above.

 As shown in the sixth step, compound (XIII) can also be produced from compound (XII) and compound (X). In this step, the compound (X) is used in an amount of 1 to 10 equivalents to the compound (XII), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium 1-butoxide, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, in the presence of a base such as hydrogenated sodium It can be carried out by treating in a solvent such as xylene at 50 to 150 ° C. for 30 minutes to 48 hours. Compound (VIII) can be produced from the obtained compound (XIII) according to the method described above.

 The compound (1) of the present invention can be isolated and purified by usual separation means (eg, extraction, recrystallization, distillation, chromatography, etc.). When the obtained compound forms a salt, various salts can be produced by a usual method or a method analogous thereto (eg, neutralization).

The compound (1) or a salt thereof of the present invention can be used alone or in combination with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition. Agents (eg, starch, lactose, calcium phosphate, calcium carbonate, etc.), lubricants (eg, magnesium stearate, calcium talc, stearic acid, etc.), binders (eg, starch, crystalline cellulose, carboxy) Methylcellulose, gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose, calcium, etc.), diluents (eg, aqueous solutions of physiological saline, glucose, mannitol, lactose, etc.) ) Can be administered orally or parenterally in the form of tablets, capsules, granules, powders, fine granules, ampoules, injections, or the like by ordinary methods. The dose varies depending on the type of the compound (1) of the present invention or a salt thereof, the administration route, the age of the patient, the symptoms, and the like. It is 0. OOO l SOO mg / kg g day as salt. For example, administration is performed once or several times a day.

 The usefulness of the present invention is shown by the following experimental examples and examples, but the present invention is not limited to the experimental examples and examples. BEST MODE FOR CARRYING OUT THE INVENTION

 experimental method

 NK1 receptor antagonism

The method of S. Dion et al. (“Life Sciences”, Vol. 41, pp. 2269 (1989)) was partially modified.

After bruising the guinea pig, blood was removed from the carotid artery and the ileum was removed. The isolated ileum was suspended under a load of 1 g in a Magnus tube. Sample responses were recorded isotonic. Nutrient solution, using a T Yrode solution, 0 ₂ 9 5% was bubbled C 0 ₂ 5% of the mixed gas, liquid temperature and 3 2 ° C. The experiment started after the guinea pig ileum was suspended in a Magnus tube and allowed to equilibrate for 20 minutes. The concentration-response curve of substance P in the absence of the test compound was used as a control.

The NK1 receptor antagonism of the test compound is determined by pretreatment of at least 3 concentrations of the test compound for 10 minutes, followed by cumulative application of the substance. It was determined from the concentration-response curve of P. The pA2 value was determined by the method of Schi Id ("Brit. Journal Pharmaceuticals (Brit. J. Pharmacol.) J14, 48, pp. Year))) and the results are shown in Table 1.

The composition of the Tyrode solution was as follows. Na C l; 1 3 6. 9 , KC 1 2. 7, C a C l 2 - 2 H 2 0; 2. 5, Mg C l 2 * 6 H 20; 1. 0, N a H 2 PO 4 * 2 H ₂ 〇; 0. 4, N aH C 0 3; 1 1. 9, glucose; 1 1. 1 (mM) table 1

 (Example number _p A 2 value ίρΜ)

 7 3 9 7

 8 3 7 3 Example 1

7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzoxazine-16-carboxylic acid ethyl ester (117.5 mg, 0.40 mmol) and tetraxtriphenylphosphine palladium (18.5 mg, 16.0 mol, 0.04 eq.) were dissolved in 5 ml of benzene and 1 ml of 2M sodium carbonate aqueous solution, and phenylboric acid (146.3 mg, 1.2 mmol) in dimethylformamide (2 ml) was added, and the mixture was heated to reflux. On the way, tetrakistriphenylphosphine palladium (18.5 mg, 16.0 mol, 0.04 eq.) Was added, and the mixture was heated under reflux for 8 hours. Water and methylene chloride were added to the reaction solution, and the mixture was extracted three times with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel gel chromatography (methylene chloride: ethyl acetate 20: 1) to give colorless crystals. 2,3-dihydro-5-oxo-17-phenyl-5H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxylic acid ethyl ester (114.8 mg, 86%) Was. Example 2

In the same manner as in Example 1, 7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-6-carvone Colorless crystalline 2,3-dihydro 7- (3-methoxyphenyl) -15-oxo-1H-pyri, formed from acid ethyl ester (117.5 mg, 0.40 mmol) and 3-methoxyphenyl boric acid (182.5 mg, 1.2 mmol). De [1,2,3-de] — 1,4-benzoxazine-16-potassium ethyl ester (120.0 mg, 82%) was obtained.

EIMS m / z: 365CM +) Example 3

According to the same method as in Example 1, 7-chloro-1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzobenzoxazine-1 —Ethyl carboxylate (146.9 mg, 0.50 mmol) and 3 — Trifluoromethylphenylboronic acid (189.9 mg, l.Ommol), 2,3-dihydro-5-oxo-7— 3-Trifluoromethylphenyl-1H-pyrido [1,2,3-de] -1,4-benzoxazine-16-potassium ethyl ester (194.7 mg, 97%) was obtained.

EIMS m / z: 403 (M +) Example 4

CO _z Et

According to the same method as in Example 1, 7-clo mouth-2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzobenzoxazine-6 —Colorless amorphous 7- (2,4-dichlorophenyl) -1,2,3-dihydrofuran from carboxylic acid ethyl ester (117.5 mg, 0.40 mmol) and 2,4-dichlorophenylboronic acid (229.0 mg, 1.2 mmol) 1-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzoxazin-16-carboxylic acid ethyl ester (42.9 mg, 27%) was obtained. EIMS m / z: 404 (M +) Example 5

In the same manner as in Example 1, 7-chloro-2,3-dihydro-3-methyl-1-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine 6-Carboxylic acid ethyl ester (307.7 mg, l.Ommol) and 3-methoxyphenylborate (455.9 mg, 3.0 mmol) are colorless and amorphous 2,3-dihydro 7- (3-methoxyphenyl) — 3-methyl There was obtained 1-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-16-carboxylic acid ethyl ester (249.8 mg, 66%).

EIMS m / z: 379 (M +) Example 6

2,3-dihydro-5-oxo-17-phenyl-5H-pyrido [1,2,3-de] 1-1,4-benzoxazine-16-carboxylate The ester (114.8 mg, 0.342 mmol) and potassium hydroxide (96.0 mg, 1.71 mmol, 5 eq.) Were dissolved in ethanol (4.5 ml) -water (0.5 ml) and heated under reflux for 3 hours. The reaction solution was ice-cooled, neutralized with 2N hydrochloric acid, extracted three times with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. 0.5 ml of thionyl chloride was added to the obtained residue, and the mixture was stirred at room temperature for 0.5 hour. The residue obtained by distilling off thionyl chloride was dissolved in 3 ml of methylene chloride, 0.2 ml of triethylamine and 0.086 ml of N-methyl-3,5-bis (trifluoromethyl) benzylamine were added, and the mixture was stirred for 1 hour. Water and methylene chloride were added to the reaction solution, and extracted three times with methylene chloride. After the extract was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1). The obtained crystals are washed with hexane to give colorless crystals of N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1-5-oxo-1 7—feneru 5 H—Pyrido [1,2,3-de] —1,4—Benoxaxazine-1 6—Carboxamide (138.6 mg, 75%) was obtained o mp. 206-208 ° C

EIMS m / z: 546 (M +) Example Ί

According to the same method as in Example 6, 2, 3—Jihi draw 7— (3—Met Xyphenyl) 1-5-oxo-1 5H-pyrido [1,2,3-de] — 1,4 Benzoxazine-16-carboxylic acid ethyl ester (113.0mg, 0.309mmol) and N-methyl-3,5- Colorless crystals of N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (3-methoxyphenyl) -1-5-oxo from 0.08 ml of bis (trifluoromethyl) benzylamine One 5H-pyrido [1,2,3-de] _1,4-benzoxazine-16-carboxamide (152.1 mg, 85%) was obtained. mp.148-151 ° C

 Anal: C29H22F6N2O4 Calculated C 60.42%, H 3.85%, N 4.86%; Actual C 60.31%, H 3.81%, N 4.88%

EIMS m / z: 576 (M +)

In the same manner as in Example 6, 2,3-dihydro-5-oxo-7- (3-trifluoromethylphenyl) -5-H-pyrido [1,2,3-de ] — Colorless crystals of N- [3] from 1,4-benzoxazine-16-carboxylate ethylester (76.9 mg, 0.191 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.04 ml , 5_Bis (trifluoromethyl) benzyl] — 2,3-Dihidro 5- 7- (3-Trifluoromethylphenyl) -5H-pyrido [1,2,3-de] —1,4-benzoxazine-16-carboxamide (152. lmg, 85%) I got mp. 182-185 ° C

 Anal: C29H19F9N2O3 Calculated C 56.69%, H 3.12%, N 4.56%; Observed C 56.82%, H 3.17%, N 4.57%

EIMS m / z: 614 (M +) Example 9

In the same manner as in Example 6, 7- (2,4-dichlorophenyl) -1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1 Colorless crystals of N- [3,5-bis from 4-, 4-benzoxazine-16-carboxylic acid ethyl ester (42.9 mg, 0.106 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.027 ml (Trifluoromethyl) benzyl] 7 _ (2,4-dichlorophenyl) -1,2,3-dihydro-5-oxo-5H-pyrido [1,2,3-de] -1,4,4-benzoxazine 6-Carboxamide (51.7 mg, 79%) was obtained. mp. 138-142 ° C

EIMS m / z: 614 (M +)

By a method similar to that in Example 6, 2,3-dihydro-17- (3-methoxyphenyl) -13-methyl-15-oxo-5H-pyrido [1,2,3- de] 1, 1-Benzoxazine: 6-Ethylester (130.3 mg, 0.343 mmol) and N-methyl-3,5-bis (trifluoromethyl) benzylamine 0.052 ml from colorless amorphous N- [ 3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1,3, N-dimethyl-1-7— (3-methoxyphenyl)

5 H-pyrido [1,2,3-de] — 1,4-benzoxazine

6-Carboxamide (137.4 mg, 68%) was obtained.

EIMS m / z: 590 (M +) Reference example 1 C0 ₂ Et

3-Methylbenzoxanazine (1.59 g, 10 mmol) and triethyl methane tricarbonate (4.95 g, 21.3 mmol) were stirred at 220 ° C for 5 hours. Hexane and ether were added to the reaction solution, and the mixture was cooled to room temperature. The precipitated crystals were collected by filtration, washed with hexane and ether, and light yellow crystals of 2,3-dihydroxy-17-hydroxy-3- methyl one 5 - Okiso one 5 H- pyrido [1, 2, 3 - de ] - 1, 4- Benzookisajin one 6 - carboxylic acid Echiruesuteru (1.6 ⁹ g, 54%) was obtained. Reference example 2

2,3-Dihydroxy-7-hydroxy-5-oxo-5H-pyrido [12,3-de] -1,4-benzoxazine-16-carboxylic acid ethyl ester (960.0 mg, 3.49 mmol) And triphenylphosphine (2.10 g, 8.0 mmol) were dissolved in 10 ml of acetonitrile, and carbon tetrachloride (2.4 ml, (24.0 mmol) was heated and refluxed for 4 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride), and the obtained crystals were washed with hexane and ether to give pale yellow crystals of 7-chloro-2,3-dihydro-one. 5-Hydroxy-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-16-potassium ethyl ester (811.7 g, 79%) was obtained. Reference example 3

According to the same method as in Reference Example 2, 2,3-dihydroxy-1 7-hydroxy-5-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4— Benzoxazine-16-carboxylic acid ethyl ester (1.59 _g , 5.50 mmol) was converted to colorless crystalline 7-chloro-1,2,3-dihydro-13-methyl-1-oxo-5H-pyrido [1,2, 3-de]-1, 4-I-benzoxazine-16-carboxylic acid ethyl ester (1.48 g, 88%) was obtained. Example 1 1

N— [3,5—Bis (trifluoromethyl) benzyl] —7—Chloro-1,2,3—dihidro N—Methyl-1 5—Oxo-1 5H—Pyrido [1,2,3—de] I 1,4-benzoxazine-16-carboxamide (50.0 mg, 99 mol) and 3-fluorophenylboric acid (41.6 mg, 0.30ππηο1) in benzene (3 ml), 1,4-dioxane (1.2 ml) and 2M carbonic acid After adding and dissolving in a sodium aqueous solution (0.6 ml), tetrax (triphenylphosphine) palladium (22.9 mg, 20 mol) was added, and the mixture was heated and refluxed at 100 ° C for 2 hours. Methylene chloride was added to the reaction solution, which was washed with water, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1), and N- [3,5-bis (trifluoromethyl) yellow crystals were obtained. Benzyl] —2,3-Dihydro-1- (3-fluorophenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4—Benzoxazine-1 6 —Carboxamide (55.5 mg, 99%) was obtained.

EIMS m / z: 564 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 3 and to Calculated: 564.1284

 Found: 564.1305

Anal: calculated as C ₂₈ H ₁₉ F ₇ N ₂ 0 ₃ C 59.58¾, H 3.39¾, N 4.96%; Measured value C 59.41%, H 3.33¾, N 4.86%

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-15—oxo-5H— From the pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99mol) and 3-chlorophenylboronic acid (46.5mg, 0.30mmol), the colorless amorphous N — [3, 5 —Bis (trifluoromethyl) benzyl] — 7 — (3—Chlorophenyl) 1, 2,3 Dihydro 1 N—Methyl 1 5 —Oxo 5 H—Pyrido [1, 2, 3-de]-1, 4-benzoxazine-6-carboxamide (54.6 mg, 95%) was obtained.

EIMS m / z: 580 ( ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 3 and to Calculated: 580.0988

 Found: 580.0967

_{Anal: C 28 H 19 ClF 6} N 2 0 3 and to calculated values C 57.89% H 3.30%, N 4.82%;

Measured value C 57.74%, H 3.23% N 4.71% Example 11

N— [3,5-Bis (trifluoromethyl) benzyl] —7—chloro-2,3—dihydro N-methyl-5-oxo-5H-pyrido in the same manner as in Example 11 [1, 2,3-de] — 1,4-Benzoxazine-16-carboxamide (50.0 mg, 99 mol) and 3 —nitrophenylborate (50.0ing, 0.30πιπιο1) from the colorless amorphous compound [3 , 5—Bis (trifluoromethyl) benzyl] —2,3-Dihydro-1-methyl-1- 7 — (3-Trophenyl) 1 5 —Oxo-1 5 —Pyrido [1,2,3-de ] — 1, 4-Benzoxazine 6-Carboxamide (58.2 mg, 99%) was obtained.

EIMS m / z: 591 (M ⁺ )

_{HS (EI): C 28 H} 19 F 6 N 3 0 5 and to Calculated: 591 & 1229

 Found: 591.1238

Anal: calculated as C ₂₈ H ₁₉ F ₆ N ₃ 0 ₅ C 56.86% H 3.24%, N 7.10%;

Measured value C 56.60%, H 3.13¾, N 7.01% Example 1-4

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methyl-1-5-oxo-5H— Pyrid [1,2,3-de] -1, 4-benzoxazine-16-carboxamide (50.0mg, 99mol) and 3-aminophosphenylboronic acid (46.0mg, 0.30mmol) 7- (3-Aminopinyl) -1-N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N-methyl-1-5-oxo-5H-pyrido [1, [2,3-de] —1,4-benzoxazin-16-carboxamide (55.0 mg, 99%) was obtained.

FABMS m / z: 562 (M + H ⁺ )

_{^{HRMS (FAB +): C 28}} H 22 F 6 N 3 0 3 and to Calculated: 562.1565

Obtained value: 562.1531 Example 15

According to the same method as in Example 11, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methyl-1-5-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99 / mol) and 3,5-dichlorophenylboric acid (56.7mg, 0.30mmol) Fas N— [3,5-bis (trifluoromethyl) benzyl] —7- (3,5-dichlorophenyl) 1-2,3-dihydro N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-Benzoxazine-16-carboxamide (54.3 mg, 89%) was obtained.

EIMS m / z: 614 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1 2 F 6 N 2 0 3 and to Calculated: 614.0599

 Found: 614.0576

Anal: calculated as C ₂₈ H ₁₈ Cl ₂ F ₆ N ₂ 0 ₃ C 54.65¾, H 2.95%, N 4.55%;

Actual value C 54.70%, H 2.87¾, N 4.36% Example 16

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3—dihydro N-methyl-15—oxo-5H— From pyrido [1,2,3-de] — 1,4-benzoxazine-6—carboxamide (50.0mg, 99mo1) and 3,5—bis (trifluoromethyl) phenylborate (76.6mg, 0.30mfflol) N_ [3,5—Bis (trifluoromethyl) benzyl] amine, a colorless amorphous N— [3,5—Bis (trifluoromethyl) phenyl] 1-2,3—dihydro-1N-methyl-1 —Oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-6-carboxamide (53.8 mg, 80%) was obtained.

EIMS ra / z: 682 (M ⁺ )

_{HRMS (EI): C 30 H} 18 F 12 N 2 0 3 and to Calculated: 682.1126

 Found: 682.1132

Anal: C _3. Calculated as H ₁₈ F ₁₂ N ₂ 0 ₃ C 52.80% H 2.66¾, N 4.10%;

Measured value C 53.13¾, H 2.66¾, N 3.99% Example 1Ί

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7_chloro-1,2,3-dihydro N-methyl-15—oxo-5H— From the pyrido [1,2,3-de] 1-1,4-benzoxazine-16-carboxamide (50.0mg, 99 / mol) and 4-methylphenylboronic acid (40.4mg, 0.30mmol), the colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1- (4-methylphenyl) -1-5-oxo-1-5H-pyrido [1,2,3 -de]-1,4-benzoxazine-6-carboxamide (55.2 mg, 995 was obtained.

EIMS m / z: 560 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 3 and to Calculated: 560.1535

 Obtained value: 560.1531

Anal: Calculated as C ₂₉ H ₂₂ F ₆ N ₂ 0 ₃ C 62.14¾, Η 3.96¾, Ν 5.00 °

Measured value C 62.28%, Η 4.04¾, Ν 4.68% Example 18

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro N-methyl-5-oxo-5H-pyrido [ 1, 2, 3-de] — 1, 4-benzoxazine — 6 — carboxamide (50.0 mg, 99 / mol) and 4 — methoxyphenylboronic acid (45.2 mg, 0.30 mmol) from the colorless amorphous N — [3,5—Bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7- (4-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3- de] — 1,4-benzoxazin-16-carboxamide (55.1 mg, 97%) was obtained.

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 and to Calculated: 576.1484

 Found: 576.1464

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₄ 0.2H ₂ 0 Calculated value C 60.04%, H 3.89%, N 4.83% Measured value C 59.98¾, H 3.88%, N 4.66% Example 19

According to the same method as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3—dihydro N-methyl-15—oxo-5 H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99mol) and 4-monofluorophenylboronic acid (41.6mg, 0.30ramol), colorless amorphous N— [3,5—Bis (trifluoromethyl) benzyl] —2,3—dihydro-7- (4-funolelophenyl) -1-N-methyl-1-5-oxo-1-5H—pyrido [1,, [2,3-de] —1,4-benzoxazine-6-carboxamide (55.5 mg, 995 was obtained.

EIMS m / z: 564 (M ⁺ )

_{HRMS (EI): C 28 H} 19 F 7 N 2 0 3 Calculated: 564.1284

 Found: 564.1277

_{AnaI: C 28 H 19 F 7} N 2 0 3 and to calculated values C 59.58%, H 3.39¾, N 4.96%;

Measured value C 59.31%, H 3.35%, N 4.83% Example 20

In the same manner as in Example 11, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methyl-15-oxo-5 From H-pyrido [1,2,3-de] 1-1,4-benzoxazine-16-carboxamide (50.0mg, 99 / mol) and 4-monochlorophenylboronic acid (46.5mg, 0.30mmol), colorless amorpha N— [3,5-bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [ [1,2,3-de] —1,4,1-benzoxazin-16-carboxamide (57.0 mg, 99%) was obtained.

EIMS m / z: 580 (M ⁺ )

_{HRMS (EI): C 28 H} 19 C1F 6 N 2 0 3 and to Calculated: 580.0988

 Obtained value: 580.0952

Anal: C ₂₈ H ₁₉ ClF ₆ N ₂ 0 ₃ 0.2H ₂ 0 Calculated C 57.54¾, H 3.35%, N 4.79%;

Measured value C 57.35%, H 3.21%, N 4.65% Example 2 1

According to a method similar to that of Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3-dihydro N-methyl-15—oxo-5 H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99zmol) and 3-chloro-1-fluorophenylborate (51.7mg, 0.30nimol)ヽ Colorless amorphous N— [3,5-bis (trifluoromethyl) benzyl] -17— (3—chloro-4-4-fluorophenyl) -1,2,3-dihydro-1-N-methyl-5-oxo-5 H-pyrido [1,2,3-de] -1,4-benzoxazine-16-carboxamide (57.4mg, 97%) was obtained.

EI S m / z: 598 (M ⁺ )

_{HRMS (EI): C 28 H} 18 C1F 7 N 2 0 3 and to Calculated: 598.0894

 Found: 598.0893

Anal: C ₂₈ H ₁₈ ClF ₇ N ₂ 0 ₃ Calculated C 56.15¾, H 3.03%, N 4.68%;

Measured value C 55.98% H 3.00%, N 4.55% Example 22

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3—dihydro N-methyl-15-oxo-5H— From pyrido [1,2,3-de] -1,4-benzoxazine-16-carboxamide (50.0 mg, 99 mol) and 4-methyl-3-nitronitrophenylborate (53.7 mg, 0.30 mmol) Colored amorphous N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-7— (4-methyl-3-nitrotropenyl) 1-5—oxo-5H-pyrido [1,2,3-dθ] —1,4-Benzoxazine-16-carboxamide (50.8 mg, 85%) was obtained.

EIMS m / z: 605 (M ⁺ )

Awakening: _{S (EI): C 29 H} 21 F 6 N 3 0 5 and to Calculated: 605.1385

 Measured value: 605.1400

Anal: calculated as C ₂₉ H ₂₁ F ₆ N ₃ 0 ₅ C 57.53%, H 3.50%, N 6.94%;

Measured value C 57.32%, △ 3.44%, 6.79% Example 2 3

According to the same method as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3—dihydro N-methyl-5—oxo-5 H-pyrido [1,2,3-de] colorless amorph from 1,4-benzoxazine-6-carboxamide (50.0mg, 99mol) and 2-methoxyethoxyboronic acid (45.2mg, 0.30mmol) N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro 7- (7- (2-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2] [, 3-d θ] — 1,4-benzoxazine-6-carboxamide (52.9 mg, 93%).

EIMS m / z: 576 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 4 and to Calculated: 576.1484

 Found: 576.1475

_{Anal: C 29 H 22 F 6} N 2 0 4 and to calculated values C 60.42%, H 3.85% N 4.86%;

Measured value C 60.65¾, H 3.91%, Ν 4.66% Example 2 4

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—clo mouth_2,3—dihydro N-methyl-5-oxo-5H —Pyrido [1,2,3-de]-1,4—Benzoxazine-16-carboxamide (50.0 mg, 99, mo 1) and 1 —Naphthyl boric acid (51.1 mg, 0.30 mmol), colorless amorphous N- [3,5—Bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-7— (1-naphthyl) -15—oxo-5H—pyrid [1,2, 3-de] -1,4-benzoxazine-16-potassium lipoxamide (58.3 mg, 99%) was obtained.

EIMS m / z: 596 ( ⁺ )

_{HRMS (EI): C 32 H} 22 F 6 N 2 0 3 and to Calculated: 596.1535

 Obtained value: 596.1550

_{Anal: C 32 H 22 F 6} N 2 0 3 and to calculated values C 64.43%, H 3.72% N 4.70%;

Actual value C 64.27%, H 3.90%, N 4.47%

Example 11 N— [3,5—Bis (trifluoromethyl) benzyl] -17—chloro-1,2,3-dihydro N-methyl-5-oxo-5H—pyri From [1, 2,3 — de] -l, 4-benzoxazine-16-carboxamide (50.0 mg, 99 zmol) and 3 —formylphenylboronic acid (44.5 mg, 0.30fflmol), N- [ 3,5—Bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (3-formylphenyl) -1-N-methyl-5—oxo-5-H—pyrido [1,2,3-de] —1 , 4-Benoxoxazine-6-carboxamide (52.4 mg, 92%) was obtained.

EIMS m / z: 574 (M ⁺ )

_{HRMS (EI): C 29 H} 20 F 6 N 2 0 4 and to Calculated: 574.1327

 Obtained value: 574.1134

_{Anal: C 29 H 20 F 6} N 2 0 4 and to calculated values C 60.63% H 3.51%, N 4.88%;

Measured value C 60.37%, H 3.45%, N 4.76% Example 2 6

According to a method similar to that of Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7_chloro-1,2,3-dihydro N-methyl-1 5—oxo-5 H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99 / mol) and 4-formylphenylboronic acid (44.5fflg, 0.30mmol) N— [3,5—Bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-7— (4-formylphenyl) -1-N—methyl-1-5—oxo-1 5H—pyrido [1,2,3 -de] — 1,4-benzoxazine-6-carboxamide (54.5 mg, 96%) was obtained.

EIMS m / z: 574 (M ⁺ )

_{HRMS (EI): C 29 H} 20 F 6 N 2 0 4 Calculated: 574.1327

 Found: 574.1340

_{Anal: C 29 H 20 F 6} N 2 0 4 and to calculated values C 60.63%, H 3.51%, N 4.88%;

Measured value C 60.43%, H 3.46%, N 4.70% Example 2 7

In the same manner as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro-1-N-methyl-15-oxo-5H-pyri [1,2,3-de] — 1,4-Benzoxazine-16-caprolboxamide (505mg, l.Ommol) and 3-hydroxyphenylboronic acid (207mg, 1.5ππηο1) to give a colorless モ ル -morph [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7- (3-hydroxyphenyl) 1-methyl-5-oxo-5-pyrido [1,2,3-de] —1,4-Benzoxazine-6-carboxamide (560 mg, 100%) was obtained.

EI S m / z: 562 (M ⁺ )

_{HRMS (EI): C 28 H} 20 F 6 N 2 0 4 Calculated: 562.1327

Obtained value: 562.1320 Example 2 8

According to the same method as in Example 11, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-1,2,3—dihydro N-methyl-15-oxo-5 Colorless from H-pyrido [1,2,3-de] — 1,4-benzoxazine-16-carboxamide (50.0mg, 99 / zmol) and 4- (methylthio) phenyl boric acid (49.9mg, 0.30mmol) A Morphas N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N—methyl-1 7 _ [4- (methylthio) phenyl] —5—oxo-5H—pyri [1, 2,3-de] — 1,4 — Benzoxazine-16-carboxamide (58.0 mg, 99%) was obtained. EIMS m / z: 592 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 3 S and to Calculated: 592.1255

 Found: 592.1283

Anal: calculated as C ₂₉ H ₂₂ F ₆ N ₂ 0 ₃ S C 58.78%, H 3.74¾, N 4.73%;

Measured value C 58.80¾, H 3.74% N 4.64% Example 2 9

N— [3,5—Bis (trifluoromethyl) benzyl] -1,2,3-dihydro-7_ [4- (methylthio) phenyl] —N-methyl-5-oxo-5H-pyrido [1,2 , 3-de] — 1,4-Benzoxazine-16-carboxamide (70.0 mg, 0.12 mmol) was dissolved in methylene chloride (1 ml), and the mixture was dissolved in ice-cooled 3-cycloperoxybenzoic acid (29.1 mg, 0.12 mmol) and stirred for 1 hour. Methylene chloride was added to the reaction solution, which was washed sequentially with water, a 2M aqueous sodium carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 2: 1) to give a colorless amorphous N— [3,5-bis (triflur). O-methyl) benzyl] — 2,3-dihydro-1-N-methyl-1 7— [4- (methylsulfiel) phenyl] — 5 —oxo-1 5H-pyrido [1,2,3-de] —1,, 4-benzoxazine-16-carboxamide (67.5 mg, 94%) was obtained.

FABMS ιη / ζ: 609 (Μ + Η ⁺ )

_{^{HRMS (FAB +): C 29}} H 23 F 6 N 2 0 4 S and to Calculated: 609.1283

 Found: 609.1249

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₄ S Calculated as C 57.24%, Η 3.64%, Ν 4.60%

Measured value C 57.06%, 7 3.57%, Ν 4.57% Example 30

N— [3,5—Bis (trifluoromethyl) benzyl] —2,3 dihidro 7— [4— (methylthio) phenyl] —N—methyl-1 5—oxo-5H—pyrido [1,2, 3-de] — 1, 4-benzoxazine — 6 — carboxamide (70.0 mg, 0.12 mmol) is dissolved in methylene chloride (1 ml), and the mixture is dissolved under ice-cooling. , 0.24 mmol) and stirred for 1 hour. Methylene chloride was added to the reaction solution, which was washed sequentially with water, a 2M aqueous sodium carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel chromatography (methylene chloride: ethyl acetate 10: 1), and the colorless amorphous N- [ 3,5—Bis (trifluoromethyl) benzyl] — 2,3 —Dihydro-1-N-methyl-1-7-1 [4- (methylsulfonyl) phenyl] -15-oxo-1-5H—Pyrido [1,2 [3, de] —1,4-benzoxazine-16-carboxamide (73.0 mg, 99%).

EIMS m / z: 624 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 6 N 2 0 5 S and to Calculated: 624.1154

 Found: 624.1179

Anal: C ₂₉ H ₂₂ F ₆ N ₂ 0 ₅ S 0.5H ₂ 0 Calculated as C 54.98%, H 3.66%, N 4.42% Measured value C 54.84¾, H 3.51¾, Ν 4.24 ° Example 3 1

Ν—cyclopropyl — 2, 3-dihydro 7 — (3 — methoxyphenyl) — 5 — oxo 1 5 — pyrido [1, 2, 3-de] — 1,

Dissolve 4-benzoxazine-16-carboxamide (75 · 3mg, 0.20mmol) in anhydrous N, N-dimethylformamide (1ml) and add sodium hydride (9.6mg, 0.24mraol). After stirring at room temperature for 1 hour, 3,5-bis (trifluoromethyl) benzyl bromide (0.05 ml, 0.27 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is washed with diisopropyl ether, and colorless crystals of N— [3,5-bis (trifluoromethyl) benzyl] —N-cyclopropyl-1,2,3-diphenyl Doro 1 7— (3—Methoxyphenyl) 1 5—Oxo 1

5 H-pyrido [1,2,3-de] —1,4,1-benzoxazine-16-carboxamide (92.2 mg, 77%) was obtained.

EIMS m / z: 602 (M ⁺ )

_{HRMS (EI): C 31 H} 24 F 6 N 2 0 4 and to Calculated: 602.1640

Obtained value: 602.1645 _{Anal: C 31 H 24 F 6} N 2 0 4 and to calculated values C 61.80%, H 4.01% N 4.65%

 Measured value C 58.91%, H 3.97%, N 4.56% Example 3 2

In the same manner as in Example 31, N-cyclopentyl-2,3-dihydro-17- (3-methoxyphenyl) -15-oxo-5H-pyrid [1,2,3-de] — 1,4 Benzoxazine-16-carboxamide (80.9 mg, 0.20 mmol) to colorless crystalline N- [3,5-bis (trifluromethyl) benzyl] -N-cyclopentyl 1,2,3 —Dihi Draw 7 — (3-Methoxy phenyl) _ 5 —Oxo 1 5 H —Pyrido [1,2,3-de] — 1,4 _Benzoxazine 16 —Carboxamide (90.2 mg, 72%) I got

EIMS m / z: 630 ( ⁺ )

_{HRMS (EI): C 33 H} 28 F 6 N 2 0 4 and to Calculated: 630.1953

 Found: 630.1962

_{Anal: C 33 H 28 F 6} N 2 0 4 and to calculated values C 62.86%, H 4.48%, N 4.44%

Actual value C 63.12 ⁰ , Η 4.94%, Ν 4.40% Example 3 3

Example 3 By a method similar to that of 1, 2, 3-dihydro-1-N-isop-mouth pill-1 7- (3-methoxyphenyl) -15-oxo-1-5H-pyrido [1,2 , 3 — de] — 1, 4-benzoxazine-6-carboxamide (75.7 mg, 0.20 mmol) from colorless crystals of N— [3, 5 —bis

(Trifluoromethyl) benzyl] — 2,3-dihydro-1-N-isopropyl-17- (3-methoxyphenyl) -1-5-oxo-5H-pyrid [1,2,3-de] — 1 , 4-Benzoxazine-16-carboxamide (71.4 mg, 595) was obtained.

EI S m / z: 604 (M ⁺ )

_{HRMS (EI): C 31 H} 26 F 6 N 2 0 4 and to Calculated: 604.1797

 Obtained value: 604.1785

_{Anal: C 31 H 26 F 6} N 2 0 4 and to calculated values C 61.59¾, H 4.33%, N 4.63%

Measured value C 61.41¾, H 4.42%, N 4.31% Example 3 4

Example 3 By a method similar to 1, 2,3-dihydro-N-ethyl-7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] — 1, 4-Benzoxazine-1-6-carboxamide (72.9 mg, 0.20 mmol) from colorless crystalline N— [3,5 —bis (trifluoromethyl) benzyl] —2,3-dihydro-1-ethyl 1 7 _ (3-methoxyphenyl) 1 -5-oxo-1 5 H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxamide (96.7 mg, 82%) was obtained. .

EIMS m / z: 590 (M ⁺ )

_{HRMS (EI): C 3 oH} 24 F 6 N 2 0 4 and to Calculated: 590.1640

 Obtained value: 590.1642

_{Anal: C 30 H 24 F 6} N 2 0 4 and to calculated values C 61.02%, H 4.10%, N 4.74%

Actual value C 60.76%, H 3.94%, Ν 4.48% Example 3 5

N-aryl-1,2,3-dihydro-7- (3-methoxyphenyl) -5-oxo-5 11 _pyrido [1,2,3—de] —1 Colorless crystalline N-aryl-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3,4,4,4-benzoxazine-6-carboxamide (75.3 mg, 0.20 mmol) —Methoxyfuel) 1-5—oxo-5H-pyrido [1,2,3—de] _1,4-benzobenzoxazine-16-carboxamide (62.1 mg, 52%) was obtained.

EIMS m / z: 602 (M ⁺ )

_{HRMS (EI): C 31 H} 24 F 6 N 2 0 4 and to Calculated: 602.1640

 Obtained value: 602.1635

_{Anal: C 31 H 24 F 6} N 2 0 4 and to calculated values C 61.80¾, Η 4.01¾, Ν 4.65 %

Measured value C 61.79¾, Η 4.025 4.64% Example 3 6

Example 3 By a method similar to 1, 2,3-dihydro-N- (2-methoxyl) -17- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2] , 3-de] — 1,4-benzoxazine-16-carboxamide (78.9 mg, 0.20 mmol) to colorless crystalline N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro N- (2-Methoxyxetil) 1 7- (3-Methoxyphenyl) 1-5-oxo5H-pyrido [1,2,3-de] 1-1,4 Benzoxazine-16-Carboxamide (94.1 mg, 76%).

EIMS m / z: 620 (M ⁺ )

_{HRMS (EI): C 3 iH} 26 F 6 N 2 0 5 and to Calculated: 620.1746

 Found: 620.1754

Anal: calculated as C ₃₁ H ₂₆ F ₆ N ₂ 0 ₅ C 60.00%, H 4.22%, N 4.51%

Measured value C 59.76 ° H 4.16%, N 4.43% Example 37

According to a method similar to that of Example 31, N-benzyl-l, 3-dihydro-l-l7- (3-methoxyphenyl) -15-oxo-l5H-pyrido [12,3-de] — 1,4-Benzoxazine-16-carboxamide (85.3 mg, 0.20 mmol) from colorless crystalline N-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7 -(3-Methoxyphenyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4—benzoxazine-16-carboxamide (71.9 mg, 55%) was obtained.

EIMS m / z: 652 (M ⁺ )

_{HRMS (EI): C 35 H} 26 F 6 N 2 0 4 and to Calculated: 652.1797

 Found: 652.1795

Anal: C ₃₅ H ₂₆ F ₆ N ₂ 0 ₄ Calculated value as 0.5H ₂ 0 C 63.54%, H 4.11%, N 4.23% Actual value C 63.61%, H 3.93%, Ν 4.25% Example 3 8

According to the same method as in Example 31, 1,2,3-dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de- ]-1,4 Benzoxazine-16-carboxamide (60.0 mg, 0.17 mmol) from colorless crystals of 2,3-dihydro-7- (3-methoxyphenyl) -N-methyl-N- (2- Methylbenzyl) -5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-6-carboxamide (72.2 mg, 93%) was obtained.

EIMS m / z: 454 (M ⁺ )

_{HRMS (EI): C 28 H} 26 N 2 0 4 Calculated: 454.1893

 Found: 454.1895

_{Anal: C 28 H 26 N 2} 0 4 and to calculated values C 73.99¾, H 5.77%, N 6.16%

Actual value C 74.18 ° H 5.78¾, N 5.95% Example 3 9

According to the same method as that of Example 31, 1,2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3- de]-1, 4-Benzoxazine-16-carboxamide (60.0 mg, 0.17 mmol) from colorless crystals of N- (3-cyclobenzyl) -2,3-dihydro-1-7- (3-methoxyphene 1) N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1,4, -benzoxazine-6-carboxamide (70.2 mg, 86%) was obtained.

EIMS m / z: 474 (M ⁺ )

_{HRMS (EI): C 27 H} 23 C1N 2 0 4 and to Calculated: 474.1346

 Found: 474.1342

_{Anal: C 27 H 23 ClN 2} 0 4 and to calculated values _{C 68.28%, H 4.88¾ 5 Ν} 5.90%

Measured value C 68.42¾, Η 4.87% Ν 5.88% Example 40

According to a method similar to that of Example 31 1, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3-] de]-1, 4-Benzoxazine-16-carboxamide (60.0 mg, 0.17 mmol) from colorless crystals of 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-1 5 H-pyrido [12,3-de] — 1,4-benzoxazine-N- [3- (trifluoromethyl) benzyl] — 6-carboxamide (76.0 mg, 87%) was obtained.

EIMS m / z: 508 (M ⁺ )

_{HRMS (EI): C 28 H} 23 F 3 N 2 0 4 and to Calculated: 508.1610

Obtained value: 508.1619 Example 4 1

Example 3 By a method similar to 1, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3-de] -Colorless, crystalline N- (2,3-difluorobenzoyl) -1,2,3-dihydro-17- (3-methoxyethoxy) from 1,4-benzoxazin-1-6-carboxamide (60.0 mg, 0.17 mmol) Nil) 1 N monomethyl 1 5 -oxo 1 5 H-pyrido [1,2,3-de]-1,4-benzoxazine-6 -carboxamide (75.8 mg, 93%) was obtained. EIMS m / z: 476 (M ⁺ )

_{HRMS (EI): C 27 H} 22 F 2 N 2 0 4 and to Calculated: 476.1548

 Found: 476.1544

_{Anal: C 27 H 22 F 2} N 2 0 4 and to calculated values C 68.06% H 4.65% N 5.88 %

Actual value C 67.85%, H 4.64¾, N 5.83% Example 4 2

According to a method similar to that of Example 31 1, 2,3-dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — From 1,4-benzoxazine-1 6-carboxamide (60.0 mg, 0.17 mmol), colorless crystalline N- (2,4-difluoromethylbenzene) 1,2,3-dihydro 7- (3-methoxyphenyl) N-methyl-15-oxo-5H-pyrido [1,2,3-de] -1,4-benzoxazine-16-carboxamide (66.6 mg, 82%) was obtained. EIMS m / z: 476 (M ⁺ )

_{HRMS (EI): C 27 H} 22 F 2 N 2 0 4 and to Calculated: 476.1548

Obtained value: 476.1556 Example 4 3—

According to a method similar to that of Example 31 1, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-] de]-1, 4-Benzoxazine-16-carboxamide (60.0 mg, 0.17 mmol) to colorless crystalline N- (3,5-dibenzobenzene) 1-2,3-Dihydro-7- (3— (Methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine-16-carboxamide (73.6 mg, 90%) was obtained. EIMS m / z: 476 (M ⁺ )

删_{S (EI): C 27 H} 22 F 2 N 2 0 4 and to Calculated: 476.1548

 Found: 476.1537

_{Anal: C 27 H 22 F 2} N 2 0 4 and to calculated values _{C 68.06%} H 4.65% N} 5.88%

Actual value C 67.84¾, H 4.70¾, N 5.80% Example 4 4

According to a method similar to that of Example 31, 1, 2, 3-dihydro-7- (3-methoxyphenyl) 1-N-methyl-15-oxo-5H-pyrido [1,2,3- de] — 1,4,1 Benzoxazine-16 —carboxamide (60.0 mg, 0.17 mmol) from colorless crystals of 2,3 —dihidrow N— (3,5 —dimethoxybenzyl) 1 7— (3 —me (Toxiphenyl) 1 N-methyl-1 5 -oxo-5 H-pyrido [1,2,3-de] -1,4 -benzoxazine-16-carboxamide (75.0 mg, 88%) was obtained. EIMS m / z: 500 (M ⁺ )

_{HRMS (EI): C 29 H} 28 N 2 0 6 and to Calculated: 500.1947

 Obtained value: 500.1927

Anal: C ₂₉ H ₂₈ N ₂ 0 ₆ 0.5H ₂ 0 Calculated value C 68.36%, H 5.74¾, Ν 5.50% Actual value C 68.63 °, Η 5.68¾, Ν 5.37% Example 4 5

2,3-Dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] From 1,4-benzoxazine-16-carboxamide (73.1 mg, 0.16 mmol), colorless crystalline 2,3-dihydro-N- (2-methoxybenzyl) 17- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -11,4-benzoxazine-6-carboxamide (24.5 mg, 33%) was obtained.

EIMS ra / z: 470 (M ⁺ )

_{HRMS (EI): C 28 H} 26 N 2 0 5 and to Calculated: 470.1842

 Observed value: 470.1840

_{Anal: C 28 H 26 N 2} 0 5 0.2H 2 0 and to calculate values C 70.93¾, H 5.61¾, N 5.91 % Found C 70.75¾, H 5.65% N 5.92 ° Example 4 6

According to the same method as that of Example 31, 1,2,3-dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3- de] — 1, 4-Benzoxazine-1 6 —Carboxamide (81.7 mg, 0.16 marl), colorless crystalline 2,3-dihidro 7 _ (3 —Methoxyphenyl) -1-N-methyl-1-5-oxo 1-5H-pyrido [12,3-de] 1-1,4-benzoxazine-1N- [3- (trifluoromethoxy) benzyl] -6-carboxamide (54.3 mg, 65 °) was obtained. Was.

EIMS m / z: 524 (M ⁺ )

Noodles _{S (EI): C 28 H} 23 F 3 N 2 0 5 and to Calculated: 524.1559

 Obtained: 524.1559

_{Anal: C 28 H 23 F 3} N 2 0 5 and to calculate values C 64.12¾, H 4.42%, N 5.34%

Actual value C 64.30%, H 4.50%, N 5.37% Example 4 7

According to a method similar to that of Example 31 1, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3- de]-1, 4-Benzoxazine-16-carboxamide (82.0 mg ₅ 0.16imnol) to colorless crystalline 2,3-dihydro N— [3-fluoro-5— (trifluoromethyl) benzyl] —7— ( 3-Methoxyphenyl) 1 N-methyl-15-oxo-5H-pyrido [1,2,3-de] -1,4-benzobenzoxazine-16-carboxamide (45.7 mg, 54%) was obtained.

EIMS m / z: 526 (M ⁺ )

_{HR S (EI): C 28} H 22 F 4 N 2 0 4 Calculated: 526.1516

 Obtained value: 526.1535

_{Anal: C 28 H 22 F 4} N 2 0 4 and to calculated values C 63.88¾, H 4.21%, N 5.32%

Actual value C 63.65%, H 4.43% N 5.64% Example 4 8

N- (3,5-dichlorobenzene-2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5 From H-pyrido [1,2,3-de] —1,4—benzoxazine-16-carboxamide (79.3mg, 0.16mmol), N- (3,5-dichlorobenzyl) 1-2,3 as colorless crystals —Dihydro 1 7— (3—Methoxyphenyl) 1 N—Methyl-5—Oxo 1 5H—Pyrido [1,2,3-de] — 1,4—Benoxoxazine 16—Carboxamide (48.0mg) , 59%).

EI S m / z: 508 (M ⁺ )

_{HRMS (EI): C 27 H} 22 C1 2 N 2 0 4 and to Calculated: 508.0957

 Observed value: 508.0962

_{Anal: C 27 H 22 Cl 2} N 2 0 4 and to calculated values C 63.66%, H 4.35¾, Ν 5.50%

Measured value C 63.44% Η 4.52¾, Ν 5.71% Example 4 9

According to the same method as that of Example 31, 1,2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de- ]-From 1, 4-benzoxazine-6-carboxamide (60.0 mg, 0.17 mmol), colorless crystalline N- (3,5-di-tert-butylbenzyl) -1,2,3-dihydro-7- (3- 1-N-methyl-1-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-16-carboxamide (85.1 mg, 90%) . EIMS m / z: 552 (M ⁺ )

_{HRMS (EI): C 35 H} 4 oN 2 0 4 and to Calculated: 552.2988

Obtained value: 552.2980 Example 50

Example 3 2,3-Dihydro-7- (3-methoxyphenyl) -1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] -1 , 4 Benzoxazine-16-carboxamide (60.0 mg, 0.17mfflol) from colorless crystalline N- (3-t-butyl-5-methylbenzyl) 1-2,3-dihydro-7- (3-methoxyphene) Nil) 1-N-methyl-15-oxo-5H-pyrido [1,2,3-de] -1,4-benzoxazine-16-carboxamide (80.3 mg, 92%) was obtained.

EIMS m / z: 510 (M ⁺ )

Image _{S (EI): C 32 H} 34 N 2 0 4 and to Calculated: 510.2519

Obtained value: 510.2495 Example 5 1

According to a method similar to that of Example 31 1, 2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3— de] — 1,4-Benzoxazine-16-carboxamide (60.0 mg, 0.17 mmol) from colorless crystals of 2,3-dihydro-N— (3,5-dimethylbenzyl) -17- (3-methoxyphenyl) 1) N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4-benzoxazine-16-carboxamide (76.0 mg, 95%) was obtained.

EIMS m / z: 468 (M ⁺ )

_{HRMS (EI): C 29 H} 28 N 2 0 4 and to Calculated: 468.2049

Obtained value: 468.2040 Example 5 2

Example 3 2,3-Dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3-de] — 1,4_Benzoxazine-16-carboxamide (200. Omg, 0.57mmol) from colorless amorphous N-benzyl-1,2,3-dihydro-17- (3-methoxyphenyl) -1-N-methyl-5 Oxo-5H-pyrido [1,2,3-de] -11,4-benzoxazin-6-carboxamide (233 mg, 93%) was obtained.

EIMS m / z: 440 (M ⁺ )

_{HRMS (EI): C 2Y H} 24 N 2 0 4 and to Calculated: 440.1736

Obtained value: 440.1721 Example 5 3—

Example 3 2,3-Dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-year-old quinol 5H-pyrido [1,2,3—de] by the same method as in Example 1. From 1,4-benzoxazine- 1 6-carboxamide (200.Omg, 0.57mmol), colorless amorphous 2,3-dihydro-1 7- (3-methoxyphenyl) 1N-methyl-1N— (3— Methylbenzyl-1-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-16-carboxamide (241 mg, 93%) was obtained. EIMS m / z: 454 (M ⁺ )

_{HRMS (EI): C 28 H} 26 N 2 0 4 and to Calculated: 454.1893

Obtained value: 454.1905 Example 5 4

N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7- (3-hydroxyphenyl) -N-methyl-15-oxo-5H-pyrido [1,2, 3-de] — 1,4-I-benzoxazine-6-carboxamide (50.0 mg, 89 mol) was dissolved in anhydrous N, N-dimethylformamide (0.1 ml), and cesium carbonate (57.9 mg, 178 mol) was dissolved. ) Was added and the mixture was stirred at room temperature for 1 hour. Then, iodide chill (201, 0.25 minol) was added and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethyl acetate 10: 1) to give N- [3,5_bis (trifluoromethyl) as a colorless amorphous substance. ) Benzyl] -2,3-dihydro 7- (3-ethoxyphenyl) 1-N-methyl-15-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine — 6-Carboxamide (32.4 mg, 62%) was obtained.

EIMS m / z: 590 (M ⁺ )

_{HRMS (EI): C 30 H} 24 F 6 N 2 0 4 and to Calculated: 590.1640

Obtained value: 590.1644 Example 5 5

According to a method similar to that in Example 54, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (3-hydroxyxyphenyl) 1-N-methyl-1 5— Oxo-5H-pyrido [1,2,3-de] 1-1,4-benzoxazine-16-carboxamide (50.0mg, 89mol) was converted to colorless amorphous N- [3,5-bis ( Trifluoromethyl) benzyl] — 2,3-Dihydro N-methyl-5-oxo-7 — (3-Proviroxyphenyl) -5H-pyrido [1,2,3-de] —1 , 4-Benzoxazine-16-carboxamide (37.5 mg, 705) was obtained.

EIMS m / z: 604 (M ⁺ )

_{H MS (EI): C 31} H 26 F 6 N 2 0 4 and to Calculated: 604.1797

Obtained value: 604.1814 Example 5 6

According to a method similar to that in Example 54, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7— (3-hydroxythifenyl) 1-N— Methyl _ 5 -oxo-5H-pyrido [1,2,3-de]-1,4 -benzoxazine-16 -carboxamide (50.0 mg, 89 mol) from colorless amorphous N— [3,5 —Bis (trifluoromethyl) benzyl] —2,3—Dihydro 7— (3-dipropyloxyphenyl) 1 N—Methyl 1 5 —Oxo 1 5 H—Pyrido [1,2, 3-de] — 1,4-benzoxazine-16-carboxamide (37.7 mg, 70%) was obtained.

EIMS m / z: 604 (M ⁺ )

_{HRMS (EI): C 3 iH} 26 F 6 N 2 0 4 and to Calculated: 604.1797

Obtained value: 604.1791 Example 5 7

According to a method similar to that in Example 54, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7_ (3-hydroxyhydroxyphenyl) -1-N-methyl-1 —Oxo-5H—pyrido [1,2,3-de] 1-1,4—benzoxazine-16—carboxamide (50.0 mg, 89 / mol) from colorless amorphous N— [3,5-bis (Trifluoromethyl) benzyl] 1 7- (3-butoxyphenyl) 1,2,3-dihydro N-methyl-15-oxo-5H-pyrido [1,2,3-de] -1,4-benzobenzoxazine _ 6_Carboxamide (38.0 mg, 69%) was obtained.

EIMS m / z: 618 (M ⁺ )

_{HRMS (EI): C 32 H} 28 F 6 N 2 0 4 and to Calculated: 618.1953

Obtained value: 618.1963 Example 5 8_

According to a method similar to that in Example 54, N— [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-17- (3-hydroxythienyl) -1-N— Methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4 Benzoxazine-16—from carboxamide (50.0mg, 89 / zmol) to the colorless amorphous N— [3,5—Bis (trifluoromethyl) benzyl] —2,3-dihydro 7— [3- (2-Methoxyethoxy) phenyl] —N-methyl-5-oxo-5H—pyrido [1 [2,3-De]]-1,4-benzoxazine-16-carboxamide (38.5 mg, 70%) was obtained.

EIMS m / z: 620 (M +)

_{HRMS (EI): C 31 H} 26 F 6 N 2 0 5 and to Calculated: 620.1746

Obtained value: 620.1757 Example 5 9

According to a method similar to that in Example 54, N— [3,5—bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1 7— (3—hydroxy phenyl) -1-N-methyl-5-oxo One 5H-pyrido [1,2,3-de]-1,4_benzoxazine-16-carboxamide (50.0mg, 89zmol) was converted to a colorless amorphous N- [3,5—bis (tri Fluoromethyl) benzyl] 1, 2,3-dihydro 7 — [3 — (2 —Fluoroethoxy) phenyl] — N—methyl-1 5 —oxo-1 5 H —pyrido [1,2,3-de] —1, 4-benzoxazine-16-carboxamide (39.6 mg, 73%) was obtained.

EIMS m / z: 608 (M ⁺ )

_{HRMS (EI): C 30 H} 23 F Y N 2 0 4 and to Calculated: 608.1546

Obtained value: 608.1559 Example 60

7-Hydroxy-1,2,3-dihydroxy-5-oxo-5H-pyrido [1,2,3-de] —1,4-Benzoxazine-16—capillyl ester ethyl ester (2.49 g, 9.1 mmol) N-Methyl-3,5-bis (trifluoromethyl) benzylamine (2.33 g, 9. lmmo 1) and pyridine (20 ml) were added to the mixture, and the mixture was heated under reflux for 4 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is crystallized by adding diisopropyl ether. As a colorless crystal, N— [3,5-bis (trifluoromethyl) benzyl] —2,3— Dihidro 7 —Hydroxy-1-N-methyl-5 —oxo-5 H—pyrido [1,2,3-de] —1,4-Benzoxazine-1 6 —Power Lupoxamide (3.80 g, 89%) Was.

FABMS m / z: 485 (MH ⁺ ) Example 6 1

CI 0

N- [3,5-bis (trifluoromethyl) benzyl] — 2,3-dihydro 7-hydroxy-1-N-methyl-5-oxo-5H-pyrid [1,2,3-de]- 1,4-Benzothiazine-16-carboxamide (3.80 g, 8.0 mmol) was added to phosphorus oxychloride (10 ml) and heated at 50 ° C for 2 hours. The reaction solution was poured into ice, and the resulting crystals were collected by filtration, purified by silica gel column chromatography (methylene chloride: ethyl acetate 20: 1), and further washed with diisopropyl ether. Colorless crystalline N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-5-oxo-5H monopyrido [1,2,3- de] — 1,4-benzothiazine-1 6-potassium lipoxamide (3.40 g, 84%) was obtained.

CIMS m / z: 505 (M + H ⁺ ) Example 6 2

2, 3-dihydro 7 _ (3-methoxyphenyl) 1-5-year-old oxo — 5 H-pyrido [1, 2, 3, 3-de]-1, 4, 4-benzoxazine-6-carboxylic acid (200mg) , 0.59 mmol), and thionyl chloride (0.5 ml) was added, followed by stirring at room temperature for 1 hour. The residue obtained by distilling thionyl chloride was dissolved in methylene chloride (3 ml), and triethylamine (0.4 ml, 2.9 mmol) was added under ice-cooling. And cyclopropylamine (50.8 mg, 0.89 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with methylene chloride (10 ml) -diisopropyl ether (50 ml), and colorless crystals of N-cyclopropyl-12,3-dihydro-17- (3 —Methoxyphenyl) 1-5-oxo-5H-pyrido [1,2,3-de] -1,4—benzoxazine-6-carboxamide (178 mg, 80%) was obtained. EIMS m / z: 376 (M ⁺ ) Example 6 3

Example 6 2,3-Dihydro-7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] —1,4 N-zoxazine 1-6 — carboxylic acid (200 mg,

0.59 mmol) from N-cyclopentyl • 2,3-dihydro 7- (3-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzoxazine 6— Carboxamide (196 mg, 82%) was obtained.

EIMS m / z: 404 (M ⁺ ) Example 6 4

According to a method similar to that of Example 6 2, 2,3-dihydro-1 7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] 1-1 , 4 — Benzoxazine 1 6 — From carboxylic acid (200 mg, 0.59 mmol), 2, 3-dihydro-1-N-isopropyl 17 — (3-methoxyphenyl) 15 — oxo-5 H— The pyrido [1,2,3-de] -1,4-benzoxazine-16-carboxamide (183mg, 82%) was obtained.

EIMS m / z: 378 (M ⁺ ) Example 6 5

According to the same method as that of Example 62, 2,3-dihydro-1- (3-methoxyethoxy) -1-5-oxo-5H-pyrido [1,2,3-de] -1,4 — Benzoxazin 16 — From carboxylic acid (200 mg, 0.59 mmol), 2,3-dihydro N-ethyl 1 7 — (3-methoxyphenyl) 15 —oxo 1 5 H-pyrido [ [1,2,3-de] 1-1,4-benzoxazine-16-carboxamide (138 mg, 64%) was obtained.

EIMS m / z: 363 (M ⁺ ) Example 6 6

Example 6 2,3-Dihydro-7- (3-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4 — Benzoxazine 1 6 — From carboxylic acid (200 mg, 0.59 mmol), N-aryl 1-2, 3 — dihydro 7 — (3-methoxyphenyl) 15 — oxo 5 H-pyrido [ [1,2,3-de]-1,4-Benzoxazine-16-carboxamide (158mg, 71%) Noni o

EIMS m / z: 376 (M ⁺ ) Example 6 7

According to a method similar to that of Example 62, 2,3-dihydro-7— (3—methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1 , 4 — Benzoxazine 1 6 — Power from olevonic acid (200 mg, 0.59πππο1), 2, 3 —Dihydro-1- (2-Methoxyxetil) 17- (3-Methoxyphenyl) 1 5-Oxo One 5-pyrido [1,2,3-de] _l, 4-benzoxazine-16-carboxamide (112rag ₅ 48%) was obtained.

EIMS m / z: 394 (M ⁺ ) Example 6 8

In the same manner as in Example 6, 2, 2, 3-dihydro 7-(3 Methoxyphenyl) 1-5-oxo-5H-pyrido [1,2,3-de] — 1,4 — benzoxazin-1 6—force From oleic acid (200 mg, 0.59 mmol), N-benzylone 2,3-Dihydro 7- (3-Methoxy phenyl) -1 5-oxo-5 H-pyrido [1,2,3-de] —1,4-Benzoxazine-16-carboxamide (237mg, 94 %).

EIMS m / z: 426 ( ⁺ ) Example 6 9

According to a method similar to that of Example 62, 2,3-dihydro-7- (3-methoxyethoxy) -1-5-oxo-5H-pyrido [1,2,3-de] -1 , 4-Benzoxazine-1-6-hydrofuronic acid (2.00 g, 5.9 mmol) from 2,3-Dihydro 7- (3-Methoxyphenyl) -1-N-methyl-1-5-H-oxo-5H-pyrido [1,2,3-de] —1,4-Benzoxazine-16-carboxamide (1.48 g, 71%) was obtained.

CIMS m / z: 351 (M + H ⁺ ) Example Ί 0

According to the same method as in Example 6, 2, 3, 3-dihydro 7- (3- methoxyphenyl) 1 5-oxo 1 5 H-pyrido [1, 2, 3, 3-de]-1 , 4 — Benzoxazine 1 6 — Carbonic acid (120 mg, 0.36 mmol) from 2,3-dihydro-N- (2-Methoxybenzyl) -7- (3-Methoxyphenyl) 1 5 —Oxo-1 5H—pyrido [1,2,3-de] -1, 4,1 Benzoxazine-16—carboxamide (128 mg, 79%) was obtained.

Example Ί 1

According to a method similar to that of Example 6 2, 2,3-dihydro-7- (3-methoxyphenyl) -1-5-oxo-5H-pyrid "1,2,3-d e] — 1, 4 — Benzoxazine 1 6 — From carboxylic acid (120 mg, 0.36 mmol), 2, 3-dihydro 1 7 — (3 — methoxyphenyl) — 5 — oxo 1 5 H — Pyrid [1,2,3-de] —1,4—benzoxazine-1-N— [2— (trifluorometoxyl) benzyl] —6—carboxamide (146 mg, 80%) was obtained.

EIMS m / z: 510 (M ⁺ ) Example Ί 2

Example 6 By a method similar to 2, 2,3-dihydro-7- (3-methoxyphenyl) -1-5-oxo-1-5-pyrido [1,2,3-de] —1,4 — Benzoxazin-1 6 — From carboxylic acid (120 mg, 0.36 mmol), 2,3-dihydro-1-N— [3-fluoro-15— (trifluoromethyl) benzyl] -17— (3—methoxyphenyl) 1) 5-Oxo-5H-pyrido [1,2,3-de] -1, 4-benzoxazine-16-carboxamide (155 mg, 85%) was obtained.

EIMS ra / z: 512 (M ⁺ ) Example Ί 3

According to a method similar to that of Example 62, 2,3-dihydro-7- (3-methoxyphenyl) -15-oxo-5H-pyrido [1,2,3-de] 1-1,4 -Benzoxazine-16-carboxylate (120 mg, 0.36 mmol) to N- (3,5-dichlorobenzyl) 1-2,3-dihydro-17- (3-methoxyphenyl) 15 —Oxo-5H-pyrido [1,2,3-de] —1,4-Benzoxazine-16-carboxamide (162 mg, 92%) was obtained.

EIMS m / z: 494 (M ⁺ ) Example Ί 4

OMe 2,3-dihydro-1- 7- (3-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzobenzoxazine-6-carboxylic acid ethyl ester (4.33 g, 12 mmol) was suspended in ethanol (40 ml), 2N sodium hydroxide (11.9 ml) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was adjusted to pH = 1 by adding 2N hydrochloric acid while cooling with ice, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent is distilled off, and colorless crystalline 2,3-dihydro 7- (3-methoxyphenyl) -1-5-oxo-5H-pyrido [1,2,3-de]-1,4-benzoxazine One 6-carboxylic acid (4.00 g, 100%) was obtained. EIMS m / z: 337 (M ⁺ ) Industrial applicability

 The compounds of the present invention and salts thereof have excellent tachykinin receptor antagonistic activity, have low toxicity, and are safe as pharmaceuticals. Therefore, the compounds of the present invention and salts thereof are useful as pharmaceutical compositions, tachykinin receptor antagonists, therapeutic agents for dysuria, and the like.

Claims

Scope of word blue

1. The following general formula (1)

(Wherein R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C ₆ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring), may be a homo- or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents A benzene ring, which may have a ring, which may be bonded to each other, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) Or a salt, hydrate or solvate of the pyridobenzoxazine derivative represented by the formula:

2. Ring A is a halogen atom, an optionally substituted C i -C ₆ alkyl group, an optionally substituted aryl group, a hydroxy group, an optionally substituted C! Cs alkoxy A cycloalkoxy group of c _{3 to} c ₁₀ , an alkanoyloxy group of C i Cs which may be substituted. An aryloyloxy group which may be substituted, arylmethylo which may be substituted alkoxy group, cycloalkadienyl Noi Ruo alkoxy groups c ₃ to c _10, which may be substituted alkylthio group C i~C _6, alkylsulfinyl group may be substituted, may be substituted Good c! An alkylsulfonyl group having ~ c _6, an amino group, a mono- or di-alkylamino amino group substitution C i C e, 1~ 3 pieces of the may contain a hetero atom 4-9 membered cyclic § Mi amino group , C, alkylcarbonyl amino group ~ C _6, C ₁ alkoxycarbonyl § Mi amino group of ~ C _6, C i~ alkylsulfonyl § amino group of C _6, optionally substituted § Li one also be Luz Ruhoniruami Bruno Group, C i -C ₆ alkylcarbonyl group, formyl group, carboxyl group, C i -C ₆ alkoxycarbonyl group, mono- or di-substituted C -C ₆ alkyl group rubamoyl group, 1-3 hetero groups 1 to 3 substituents independently selected from a 4- to 9-membered cyclic rubamoyl group, a cyano group or a nitro group which may contain atoms (where two adjacent substituents are (Which may be bonded to each other to form a ring) Shows a good homo- or heterocyclic ring,

B ring is a halogen atom, optionally substituted C ~ alkyl group C _6, C ₃ ~ C. A cycloalkyl group, a substituted or unsubstituted aryl group, a hydroxy group, a substituted or unsubstituted C! Cs alkoxy group, or a substituted or unsubstituted C ₆ to C ₆ alkanol A alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylmethyloxy group, C g C i. A C ₃ -C ₁₀ cycloalkanoloxy group, an optionally substituted C ₁ -C ₆ alkylthio group, an optionally substituted C i -C ₆ alkylsulfur A substituted or unsubstituted C1-C6 alkylsulfonyl group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, and 1-3 heteroatoms. may also be 4-9 membered cyclic amino group, C j~ alkylcarbonyl § amino group of C _6, C! alkoxy force Ruboniruami amino group of C e, alkylsulfonyl § Mi amino group of C i to C _6, optionally substituted Arylsulfonylamino group, C! Ce alkylcarbonyl group, carboxyl group, C i -C ₆ alkoxycarbonyl group Group, a mono- or alkyl force Rubamoiru group C it to C ₆ disubstituted from 1 to 3 may also be 4-9 membered contain heteroatoms of the cyclic forces Rubamoiru group, Shiano group or two preparative port group Represents a benzene ring which may have 1 to 3 substituents independently selected from (optionally two adjacent substituents may be bonded to each other to form a ring) ,

C ring is a halogen atom, an alkyl group optionally C i to C ₆ substituted - human Dorokishiru group, an optionally substituted C i to C ₆ alkoxy group, optionally substituted C ₁ ~ C _6, an alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmyloxy group, CsCi. A cycloalkoxy group, a C ₃ -C ₁₀ cycloalkanoyloxy group, an amino group, a mono- or di-substituted (丄 -C ₆ alkylamino group, and 1 to 3 heteroatoms good not 4-9-membered cyclic § Mi Roh group, C i to an alkylcarbonyl § amino group of C _6, alkoxycarbonyl § Mi amino group of _{C ~ C 6, C i C} e Al kill sulfonyl amino group, 1-3 substituents each independently selected from an optionally substituted arylsulfonylamino group, a cyano group or a nitrite group (two adjacent substituents are bonded to each other 2. The pyridobenzoxazine derivative according to claim 1, which represents a benzene ring which may have a ring.

3. The following general formula (2)

(Wherein, R ³ is a hydrogen atom or an alkyl group of C Ce, R ⁴ is a hydroxyl group, an alkoxy group of C i Ce, a benzyloxy group or a reactive residue, the A ring is a halogen atom, and may be substituted ₆ Optionally substituted aryl group, hydroxy group, optionally substituted C! Ce alkoxy group, C ₃ -C ₁₀ cycloalkoxy group, optionally substituted C i C ₆ to C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C _{3 to} C ₁ cycloalkanoyloxy group, substituted C i -C ₆ alkylthio group, optionally substituted C! C fi alkylsulfinyl group, optionally substituted C i -C ₆ alkylsulfonyl group, amino group, mono or Disubstituted C i -C ₆ alkylamino groups A 4- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, an alkylcarbonylamino group, an CiCe alkoxycarbonylamino group, an C! Ce § Le kill sulfonyl § Mi amino group, it may also be substituted I Arirusuruho Niruamino group, an alkylcarbonyl group of C ~ C _6, a formyl group, a force carboxyl group, an alkoxycarbonyl group having C t~ C _6, mono- or di substitution Independently selected from the group consisting of a C ₆ -C ₆ alkyl group, a 4- to 9-membered cyclic group that may contain 1 to 3 hetero atoms, a cyano group or a nitro group. 1 to 3 substituents (adjacent Or two substituents may be bonded to each other to form a ring)

Ring C is a halogen atom, an optionally substituted C ₆ -C ₆ alkyl group hydroxy group, an optionally substituted C ₆ -C ₆ alkoxy group, an optionally substituted C 1 -C ₆ alkano Aryloxy group, optionally substituted aryloyloxy group, optionally substituted arylylmethyloxy group, C ₃ -C ₁₀ cycloalkoxy group, C ₃ -C i ₀ cycloalkanoyloxy group An amino group, mono- or di-substituted c ₁ to

C ₆ alkylamino group, 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, C i to C ₆ alkylcarbonylamino group, C i to C ₆ independently selected from the group consisting of ₆ alkoxycarbonylamino groups, C i Ce alkylsulfonylamino groups, optionally substituted arylsulfonylamino groups, cyano groups and nitro groups. And a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). Or a salt, hydrate or solvate thereof.

4. The following general formula (3)

(Wherein, R ³ is a hydrogen atom or a C i Cs alkyl group, and R ⁵ is

(R ¹ and R ² are the same or different and each is a hydrogen atom or a C i C s alkyl group; ring B is 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, X is a halogen atom or 0 S 0 ₂ R ⁶ (R ⁶ may be halogen-substituted C 1 to C 4). An alkyl group of _{6 or} an aryl group which may be substituted), the C ring may be a halogen atom, and may be substituted (~. An alkyl group of ^^, a hydroxyl group, an optionally substituted C i C e An optionally substituted C i Ce alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylalkyloxy group, C ₃ -C ₀ Sik port alkoxy group, C ₃ ~ C i. cycloalkadienyl Noi Ruo alkoxy group, amino group, mono- or Substituted alkylamino amino group of C i~C _6, 1~ 3 ring-shaped § Mi Roh group which may 4-9 membered contain a hetero atom, an alkylcarbonyl amino group of C ~ C _6, C, ~ alkoxycarbonyl amino group of C _6, alkylsulfonyl § Mi amino group of C i C e, it may also be substituted i § reel sulfonyl § amino groups, each independently selected from among Shiano group or a Toro group A benzene ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring). Oxazine derivatives or salts, hydrates and solvates thereof.

5. The following general formula (4)

(Wherein, R ³ is a hydrogen atom or a C alkyl group, and R ⁵ is

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, and the ring C is a halogen atom, an optionally substituted C ₆ -C ₆ alkyl group, a hydroxyl group, or a substituted benzene ring. An optionally substituted CiCs alkoxy group, an optionally substituted alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C ₃ ~ C i. The alkoxy group of the mouth, C ₃ -C i. A cycloalkanoyloxy group, an amino group, a mono- or di-substituted CiCe alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, alkylcarbonyl § Mi amino group of C ~ C _6, C alkoxycarbonyl amino group ~ C _6, C i C e alkylsulfonyl § Mi amino group, it may also be substituted i § reel sulfonyl § Mi amino group, It has 1 to 3 substituents each independently selected from a cyano group or a nitrogeno group (two adjacent substituents may be bonded to each other to form a ring); Also Shows a good benzene ring. ) A pyridobenzoxazine derivative represented by the formula or a salt, hydrate and solvate thereof.

6. The following general formula (2)

(Wherein, R ³ is a hydrogen atom or a C i Cs alkyl group, R ⁴ is a hydroxyl group, a C i C alkoxy group, a benzyloxy group or a reactive residue, and the A ring is independently selected. A homo- or heterocyclic ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring); A benzene ring which may have two or more substituents (adjacent two substituents may be bonded to each other to form a ring).

And a salt, hydrate and solvate thereof.

The following general formula (5)

(Wherein R ¹ and R ² are the same or different and are each a hydrogen atom or an alkyl group of C! Ce; ring B has 1 to 5 substituents (two adjacent substituents are A benzene ring which may have any of the following formulas: 2. The method for producing a compound or a salt, hydrate and solvate thereof according to claim 1, wherein the compound or a salt, hydrate and solvate thereof are reacted with each other.

7. The following general formula (6)

(In the formula, R ³ is a hydrogen atom or an alkyl group of C Ce, R ⁷ is a hydroxyl group.C ₁ -C ₆ alkoxy group, benzyloxy group,

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 5 substituents (adjacent two substituents are bonded to each other to form a ring Or a reactive residue, and X is a halogen atom or 0 S 0 ₂ R ⁶ (where R ⁶ is optionally substituted C) alkyl group i to C _6, substituted optionally may be Ariru group), C ring may 1-3 substituents (bonded two adjacent substituents together to be combined to form a ring) Represents a benzene ring which may have ) And pyridobenzoxazine derivatives or their salts, hydrates and solvates The following general formula (7)

(Wherein, Y is a halogen ^{_{atom, OS 0 2 R 6 (R}} 6 is the ^{same), B (R 8) 2} (R 8 is a hydroxyl group, an alkyl group or alkoxy of C i to C ₆ of the C ~ C ₆ Alternatively, R ⁸ may be bonded to each other to form a ring.), MgBr or ZnCl, and the A ring are each independently selected from 1 to 3 substituents (adjacent Wherein the two substituents may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have the formula (1). 3. The process for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to item 3.

8. The following general formula (1)

(Wherein R ¹ R ² and R ³ are the same or different and are a hydrogen atom or a C ₆ -C ₆ alkyl group, and the A ring is each independently selected from 1 to 3 substituents (adjacent 2 May be bonded to each other to form a ring) may be a homo- or heterocyclic ring, and ring B is 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a bond to form a ring, and a C-ring may have 1 to 3 substituents (neighboring Two adjacent substituents may be bonded to each other to form a ring). A tachykinin receptor antagonist comprising a pyridobenzoxazine derivative represented by the formula or a salt, hydrate or solvate thereof as a pharmaceutical composition.

9. General formula (1) below

(Wherein, R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C i -C ₆ alkyl group, and A ring is independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) A benzene ring which may have a pyridobenzoxazine derivative represented by the formula: or a salt, hydrate or solvate thereof as a pharmaceutical composition. A substance P receptor antagonist.

10. The following general formula (1

(Wherein R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C i -C ₆ alkyl group, and A ring is each independently selected from one to three substituents (adjacent 2 May be bonded to each other to form a ring), may be a homo- or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents A benzene ring, which may have a ring, which may be bonded to each other, and a ring C may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) A benzene ring which may have a pyridobenzoxazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. For preventing or treating dysuria including urinary frequency, urinary incontinence and other bladder dysfunctions.

1 1. The following general formula (1)

(Wherein, R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C! To C ₆ alkyl group, and A ring is independently selected from 1 to 3 A homo- or heterocyclic ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring); the ring B has 1 to 5 substituents (adjacent A benzene ring, which may have two substituents which may combine with each other to form a ring), and a C-ring, which has 1 to 3 substituents (two adjacent substituents are A benzene ring which may be bonded to a benzene ring. Or a salt, hydrate or solvate thereof as a pharmaceutical composition for preventing or treating gastrointestinal diseases including ulcerative colitis and Crohn's disease. .

1 2. The following general formula (1

(Wherein, R ¹ R ² and R ³ are the same or different and are each a hydrogen atom or a C ₆ -C ₆ alkyl group; May be bonded to each other to form a ring) or a homocyclic or heterocyclic ring, and ring B may have 1 to 5 substituents (when two adjacent substituents are A benzene ring, which may have a ring, which may be bonded to each other, and C ring, has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) A benzene ring which may have a pyridobenzoxazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. X-ray irradiation, chemotherapeutics, pregnancy, migraine, An agent for preventing or treating vomiting induced by postoperative illness, gastrointestinal motility, or side effects of drug administration.

1 3. The following general formula (1)

(Wherein RR ² and R ³ are the same or different and are each a hydrogen atom or a C! -C ₆ alkyl group, and the A ring is independently selected from one to three substituents (adjacent two May be bonded to each other to form a ring) may have a homo- or heterocyclic ring, and the ring B has 1 to 5 substituents (two adjacent substituents are The benzene ring and the C ring which may have a ring may be bonded to each other and have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). A benzene ring which may have a pyridobenzoxazine derivative or a salt, hydrate or solvate thereof as a pharmaceutical composition. A therapeutic agent for asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc. involving evening kikinin.