WO2001085732A1 - Pyridobenzodiazine derivatives and processes for the preparation thereof - Google Patents

Abstract

The invention provides pyridobenzodiazine derivatives exhibiting tachykinin receptor antagonism, particularly NK1 receptor antagonism, and processes for preparing the same. Pyridobenzodiazine derivatives of the general formula (1) and salts thereof; processes for the preparation of both; and pharmaceutical compositions containing the derivatives or pharmaceutically useful salts thereof. Pyridobenzodiazine derivatives of the general formula (1) or salts of the same, and hydrates and solvates thereof.

Description

 Satsuki Ito »Pyridopenzodiazine derivatives and their production

 Technical field

 TECHNICAL FIELD The present invention relates to a novel pyridobenzodiazine derivative or a pharmacologically acceptable salt thereof having an inhibitory action on evening kininin receptor, a method for producing the same, and a pharmaceutical composition containing the pyridobenzodiazine derivative.

 Tachykinin (substance P, neurokinin A, neurokinin B) is a general term for neuropeptides and their respective receptors in the body (neurokinin 1 (NK1), neurokinin 2 (NK2), neurokinin 3 (NK 3)) is known to express various physiological activities. Among them, substance P acts as a transmitter of central and peripheral primary sensory neurons, as well as physiology such as hyperdiuresis, neuronal excitability, vascular hyperpermeability, vasodilation, smooth muscle contraction, and immunity. Has various activities

(Urinary frequency, urinary incontinence, vomiting, inflammation, allergy, respiratory tract disease, pain, central nervous system disease, etc.). Therefore, the development of compounds having excellent tachykinin receptor antagonistic activity, especially NK1 receptor antagonistic activity, and excellent safety and long-lasting properties, as preventive and therapeutic agents for the various disease states described above, has been required. Is desired.

 At present, the following compounds and the like have been disclosed as compounds having NK1 receptor antagonistic activity.

(1) EP—A—42 9 3 6 6 Formula:

(2) The compound represented by the formula:

 MeO,

 H

A compound represented by H "ΆI No is disclosed. (3) EP—A—5 3 2 4 5 6

(4) EP—A—522—0808 has the formula:

Are disclosed.

 (5) WO 9 3Z0 1 1 6 9 Formula:

Are disclosed.

 (6) In Japanese Patent Application Laid-Open No. 8-676778, the formula is:

(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 —NH ¹ - (R ¹ is H or a hydrocarbon residue) or - 0-, other guard CO- or - CS-, or one - N =, the other = CR ² one (R iH, halogen, hydrocarbon residue , An amino group or a hydroxy group); n represents 1 or 2.) or a salt thereof is opened. It is shown.

 (7) Formula in Japanese Patent Application Laid-Open No. 9-104746

(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. Including alkyl group, carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, (4-phenylbiperazine-11-yl) methyl group, and R ² a hydrogen atom, lower alkyl group, and hydroxyl group. A lower alkyl group, a lower alkanoyl group, a lower alkoxy group, and a ring A and a ring B each represent a benzene ring which may have a substituent.

 (8) Japanese Patent Application Laid-Open No. Hei 9-2666387 shows the formula:

(Wherein the M ring is a heterocyclic ring having a partial structure of 1 N = 2C, 1 CO—N or 1 CS—N <where X = Y <; Ra and R b are bonded together. Forms A ring, or 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 is an optionally substituted heterocyclic ring; ring C is substituted A homo- 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.

 (9) Japanese Patent Application Laid-Open No. H11-24659-99 shows the formula:

(Wherein X is a nitrogen atom or CH group R ¹ is a hydrogen atom, lower alkyl group, aryl group or aralkyl group R ² is a hydrogen atom or lower alkyl group; Rings A and B are the same or different, and And n represents 1 or 2.) The compound represented by the formula is disclosed.

 (1 0) WO 0 0 0 6 57 1 Formula:

The compound represented by is disclosed by the present inventors

(1 1) WO 0 0 0 6 5 7 2 formula:

The compound represented by is disclosed by the present inventors

 (1 2) WO 0 0 0 6 5 7 8 into the formula:

The compound represented by is disclosed by the present inventors

 (13) WO 0 0 0 6 5 8 0 into the formula:

Are disclosed by the present inventors.

 Background art

Currently, it has an excellent antagonistic activity against tachykinin receptor (particularly NK1 receptor antagonistic activity) as a preventive or therapeutic agent for the above-mentioned various disease states, and has safety, sustainability, pharmacokinetics, and pharmacological activity. Etc. from the point of No compound that can be a satisfactory pharmaceutical has been found. An object of the present invention is to provide a pharmaceutical composition having an excellent antagonism against kinkinin receptor, especially a NK1 receptor antagonism, which has a different chemical structure from known compounds including the above compounds, and a tachykinin receptor antagonist. Another 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 and R ² are the same or different and each represent a hydrogen atom or an alkyl group of C i to C ₆ , R ³ is a hydrogen atom, or an optionally substituted C i to C 6

6, an optionally substituted C i C s alkylsulfonyl group, an optionally substituted C i -C ₆ alkyl group, an optionally substituted arylmethyl group and alkoxy A carbonyl group; ring A may have 1 to 3 independently selected substituents (two adjacent substituents may be bonded to each other to form a ring) A good homo or heterocyclic ring, wherein ring B is a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) The ring C has 1 to 3 substituents (two adjacent substituents may be bonded to each other to form 璟) The benzene ring which may be possessed is shown. The present invention provides a pyridobenzodiazine derivative represented by the formula or a salt, hydrate and solvate thereof.

 The present inventors have the following general formula (1)

(R ¹ and R ² are the same or different and each represent a hydrogen atom or C i Ce alkyl,

R ³ is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C ~ C ₆ optionally substituted, substituted alkylsulfonyl group of C 1 ~ C ₆ which may have an alkyl group ~ C ₆ which may be substituted A substituted or unsubstituted arylmethyl group or an alkoxycarbonyl group;

Ring A is a halogen atom, an optionally substituted C i -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted C i C alkoxy group, C ₃ ~ C _1. Cyclo cycloalkoxy group, alkanoyloxy Noi Ruo alkoxy groups optionally substituted C i ~ C _6, optionally substituted Ariroiruokishi group, an optionally substituted Ari Rumechiruokishi group, a C ₃ ~ C i ₀ Arca Noi Ruo alkoxy group, substitution which may have been alkylthio group optionally C _6, an alkylsulfinyl group having a C丄substituted ~ C _6, an alkylsulfonyl group having a C丄substituted ~ C ₆ An amino group, a mono- or di-substituted C ₆ -alkylamino group, a 4- to 9-membered cyclic amino group optionally containing 1 to 3 heteroatoms, a C 丄 to C ₆ -alkylcarbonylamino group Group, C i -C ₆ alkoxycarbonylamino group, C i -C ₆ Le Kill sulfonyl § amino group, an optionally substituted Arirusuruho Niruamino groups, C alkylcarbonyl group ~ C _6, a formyl group, a force Rupokishiru group, an alkoxycarbonyl group having C i C _6, C i ~ mono- or di substitution A C ₆ alkyl group, a 4- to 9-membered cyclic group optionally containing 1 to 3 heteroatoms, a cyano group or a 2-nitro group, each independently selected from 1 Represents a homo- or heterocyclic ring which may have up to 3 substituents (two adjacent substituents may be bonded to each other to form a ring);

Ring B is a halogen atom, an optionally substituted C i -C ₆ alkyl group -C ₃ -C 丄. Sik port alkyl group, it may also be substituted I § Li Ichiru group. Arsenide de port hexyl group, an optionally substituted C ~ C _e alkoxy group, optionally substituted C ₁ ~ C ₆ Arca Noi Ruo alkoxy group, optionally substituted § Li Roiruokishi group, an optionally substituted Ariru Mechiruokishi group, C ₃ cycloalkoxy group _{~ C i 0, C 3 ~} C 1 0 cycloalkadienyl Noi Ruo An xyl 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, alkylamino amino group of C i C e of mono- or di-substituted 1 to 3 heteroatoms the which may contain 4-9 membered cyclic amino groups, alkylcarbonyl C丄~ C ₆ Amino group, Arukokishikaru Boniruamino group of the C丄~ C ₆ , C丄alkylsulfonyl § amino group ~ C _6, optionally substituted § reel sulfonyl § amino groups, C alkylcarbonyl group i ~ C _6, a carboxyl group, an alkoxycarbonyl group having C i ~ C _6, alkyl force Rubamoiru group C丄~ C ₆ mono or di-substituted 1 to 3 heteroatoms the which may contain 4-9 membered cyclic force Rubamoiru group, then in the Shiano group or a nitro group it 1-3 independently selected substituents (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have

C ring is a halogen atom, an optionally substituted alkyl group of C i to C ₆ also inhibit de port hexyl group, an optionally substituted C i to C ₆ alkoxy group, optionally substituted c ₁ Arca Noi Ruo alkoxy group to c _6, optionally substituted § Li Roiruokishi group, it may also be substituted i Ariru Mechiruokishi group, cycloalkoxy group of C ₃ ~ C i _0, cycloalkyl of c ₃ to c ₁₀ Alkanoyloxy group, amino group, mono- or di-substituted

Alkylamino amino group of C _6,. 1 to 3 or 4-9 membered but it may also contain a hetero atom of the cyclic Amino group, an alkylcarbonyl § amino group of C i to C _6, alkoxy C丄~ C ₆ Each independently selected from a carbonylamino group, an alkylsulfonylamino group of CiCe, an optionally substituted arylsulfonylamino group, a cyano group or a nitro group 1 Represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). The present invention provides a pyridobenzodiazine derivative represented by the formula: or a salt, hydrate and solvate thereof.

The present inventors have found that R ³ in the general formula (1)

(R ⁴ is a hydrogen atom, an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, a 4- to 9-membered group which may be substituted and may contain 1 to 3 hetero atoms. cyclic Amino group, C i to alkyl carbonylation Ruamino group C _6, alkoxycarbonyl § Mi amino group of C. 1 to C _6, (丄-alkylsulfonyl § Mi amino group of _6, optionally substituted Ariru sulfonyl 3. The pyridobenzodiazine derivative or a salt, hydrate and solution thereof according to claim 2, wherein n represents an integer of 1 to 6. Provide a solvate.

The present inventors have found that R ³ in the general formula (1)

(R ⁵ is a hydrogen atom, an amino group, an alkylamino group of mono- or di-substituted C ^ Ce, a 4- to 9-membered cyclic group which may be substituted and may contain 1 to 3 hetero atoms. Mi Roh groups, C alkyl carbonylation Ruamino group ~ C _6, C i Cs alkoxycarbonyl § amino groups, C i alkylsulfonyl amino group of C _6, optionally substituted Ariru Suruhoniruamino group, m The pyridobenzodiazine derivative according to claim 2, which is represented by an integer of 1 to 6, or a salt, hydrate or solvate thereof is provided.

The present inventors have found that R ³ in the general formula (1)

(R ⁶ is an optionally substituted C 丄 to C ₆ alkyl S or an optionally substituted aryl group). Provide Japanese food.

The present invention provides the pyridobenzodiazine derivative or the salt, hydrate and solvate thereof according to claim 2, wherein R ³ in the general formula (1) is represented by a C 丄 to C ₆ alkyl group.

The present inventors have found that in the general formula (1), R ³ is 7

(R ⁷ is C port Gen atom, human de port hexyl group, an optionally substituted alkoxy group C丄C ₆ also, 〇 _{^{S 0 2 R 12 (R 1}} 2 is halogen-substituted There may be oc ^ alkyl group ~ c _6, which may be substituted Ariru group), i is an integer of 1-6. A pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 2 represented by the formula:

The present inventors have found that R ³ in the general formula (1)

-C- Nono

(R ⁸ is a nitrogen atom, a hydroxyl group, an optionally substituted C 丄 to C ₆ alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6. A pyridobenzodiazine derivative according to claim 2 or a salt, hydrate or solvate thereof.

^{3. The} pyridobenzodiazine derivative according to claim 2, wherein R ³ in the general formula (1) is a hydrogen atom, an optionally substituted arylmethyl group or an alkoxycarbonyl group, or a salt or hydrate thereof. And a solvate.

 The present inventors have the following general formula (2)

(In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i Ce alkyl group, and ring B has 1 to 3 substituents (when two adjacent substituents are bonded to each other, R ³ represents a hydrogen atom, an optionally substituted C ₆ -C ₆ alkylcarbonyl group, an optionally substituted C i ~ C ₆ al X represents a alkyl group of C i Ce, a substituted or unsubstituted C i C e alkyl group, a substituted or unsubstituted arylmethyl group or an alkoxycarbonyl group; 〇 ₂ R ¹³ (R ¹³ represents a C i -C ₆ alkyl group which may be substituted with nitrogen, an aryl group which may be substituted), and the C ring has 1 to 3 It represents a benzene ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring). And a salt, hydrate and solvate thereof represented by the following general formula (3):

(Wherein, Y is a halogen atom, 〇S 0 ₂ R ¹⁴ (R ¹⁴ is a halogen-substituted C i -C ₆ alkyl group, an optionally substituted aryl group)) B (R ¹⁵ ) ₂ (R ¹⁵ may be a hydroxyl group, a C ^ Cs alkyl group or a C i Ce alkoxy group, or R ¹⁵ may be bonded to each other to form a ring.) , Li, MgBr or ZnCl, wherein the ring A is independently selected from one to three substituents (two adjacent substituents are bonded to each other to form a ring 2. The pyridobenzodiazine derivative or a salt or hydrate thereof according to claim 1, wherein the compound is a compound represented by the formula: And a method for producing a solvate.

 The present inventors have the following general formula (4)

(Four)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C ₆ -C ₆ alkyl group, and the ring A is independently selected from one to three substituents (adjacent 2 Substituents may be bonded to each other to form a ring), and may represent a homo- or heterocyclic ring, and the ring B has 1 to 3 substituents (two adjacent substituents). A benzene ring which may have a benzene ring which may be bonded to each other to form a ring, and the C ring has 1 to 3 substituents (two adjacent substituents are bonded to each other) R ³ represents a benzene ring which may have a ring

(R ⁷ is a halogen atom, human de port hexyl group, an optionally substituted C丄-C ₆ alkoxy ^{_{group, OS 0 2 R 12 (R}} 1 2 is an optionally halogen-substituted C i ~ C ₆ An alkyl group, a substituted or unsubstituted aryl group), and i represents an integer of 1 to 6.) or

(R ⁸ is a halogen atom, a hydroxyl group, a substituted or unsubstituted C 丄 to c ₆ alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6. ) Or a salt, hydrate or solvate thereof, and a derivative thereof represented by the following general formula (5):

HR ⁹ (5)

(In the formula, R ⁹ is an amino group, a mono- or di-substituted C i -C ₆ alkylamino group, a 4- to 9-membered group which may be substituted and may contain 1 to 3 hetero atoms. 5. The pyridobenzoxa according to claim 3, wherein a compound represented by the formula: is reacted. The present invention provides a method for producing a gin derivative or a salt, hydrate and solvate thereof, wherein the following general formula (6)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i C s alkyl group, and ring A is independently selected from one to three substituents (adjacent two A substituent may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have 1 or 3 ring (s), and 1 to 3 substituents (when two adjacent substituents A benzene ring, which may have a ring, which may combine with each other to form a ring), and ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring). And a salt, hydrate and solvate thereof, and a pyridobenzodiazine derivative represented by the following general formula (7):

(In the formula, Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C i Ce, R ⁷ is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C-C ₆ alkoxy ^{_{group, OS 0 2 R 1 2 (}} R 1 2 is an alkyl group which may be substituted Ariru group optionally C i to C ₆ be halogenated), i is an integer from 1 to 6 ) Or The following general formula (8)

(Wherein V is a halogen atom, an optionally substituted C i Ce alkoxy group or 〇 S 0 ₂ R ¹⁶ (R ¹⁶ is an optionally halogenated C i Cs alkyl group, R ⁸ is a hydroxyl group, an optionally substituted C ₆ -C ₆ alkoxy group, an arylmethyloxy group or a reactive residue, j is an integer of 1-6. Or the following general formula (9)

(Wherein, W is a halogen atom, human de port hexyl group, an alkoxy group of C i C s, OS_〇 _2: ^{1 7} (R ^{1 7} is an alkyl group optionally C i to C ₆ be halogen-substituted , An aryl group which may be substituted) or a reactive residue, and R ⁶ is a compound represented by a hydrogen atom or a C i -C ₆ alkyl group). Or a process for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to item 8.

 The present inventors have the following general formula (10)

(Wherein, R ³ is a hydrogen atom, an optionally substituted alkyl carbonyl group of C i Cs, and an optionally substituted C i -C ₆ alkyl sulfo group. Group, optionally substituted C. 1 to alkyl groups of C _6, optionally substituted also shows a good Arirumechiru group and alkoxycarbonyl two Le group, R ^{1 0} is a halogen atom, arsenic Dorokishiru group, C ₁ ~ C _{6 represents} an alkoxy group, arylmethyloxy group or a reactive residue, and ring A represents one to three independently selected substituents (two adjacent substituents are bonded to each other Represents a homo or complex ring which may have a ring, and the ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other Which may form a ring). And a salt, hydrate and solvate thereof represented by the following general formula (11):

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C i C s alkyl group, and ring B has 1 to 3 substituents. Benzene ring which may have a compound represented by the formula: wherein the compound is a compound represented by the formula (I), wherein the pyridobenzodiazine derivative or a salt, hydrate or solvate thereof is used. A manufacturing method is provided.

 The present inventors provide a tachykinin receptor antagonist comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. '

 The present inventors provide a Κ1 receptor antagonist comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition.

The present inventors need to include a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. It is intended to provide a preventive or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence characterized by the following.

 The present inventors have proposed a gastrointestinal tract comprising ulcerative colitis and Crohn's disease, which comprises a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provide an agent for preventing or treating a disease.

 The present inventors have proposed a X-ray irradiation, a chemotherapeutic agent, a pregnancy, a prescription, comprising a pyridobenzodiazine derivative represented by the general formula (1) or a salt, hydrate and solvate thereof as a pharmaceutical composition. Provided is a prophylactic or therapeutic agent for vomiting induced by headache, postoperative disease, gastrointestinal hypomotility or side effects of drug administration.

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

 The present inventors have the following general formula (12)

(Wherein R ¹¹ is a halogen atom, a hydroxyl group, a C ^ Ce alkoxy group, an arylmethyloxy group or a reactive residue and

(R ¹ and R ² are the same or different and are each a hydrogen atom or an alkyl of C i to C ₆ And the ring B and the ring B represent a benzene ring which may have 1 to 3 substituents (adjacent two substituents may combine with each other to form a ring). ),

R ³ is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C ~ C ₆ optionally substituted, an alkylsulfonyl group optionally C. 1 to C ₆ optionally substituted, an optionally substituted in C. 1 to C ₆ also An alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group,

X is a halogen atom, a hydroxyl-containing xyl group or 〇S〇 ₂ R ¹³ (R ¹³ is a C i -C ₆ alkyl group which may be substituted with a nitrogen atom, optionally substituted Group)

C ring is a halogen atom, a substituted optionally alkyl group which may C i to C _6, human de port hexyl group, an optionally substituted C. 1 to C ₆ alkoxy group, optionally substituted C i C ₆ to C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ to C 10 cycloalkoxy group, C _{3 to} C ₁₀ Cycloalkanoyloxy, amino, mono- or di-substituted

Alkylamino of C ₆ amino group from 1 to 3 heteroatom to comprise also have good 4-9 membered cyclic § Mi amino group, an alkylcarbonyl § Mi amino group of C ~ C _6, C i to C ₆ Independently selected from the group consisting of an alkoxycarbonylamino group of the formula: It represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). The present invention provides a pyridobenzodiazine derivative represented by the formula: or a production intermediate in the form of a salt, hydrate or solvate thereof.

The present inventors have the following general formula (13)

(Wherein, R ³ is a hydrogen atom, an optionally substituted C-C ₆ alkylcarbonyl group, an optionally substituted C-C ₆ alkylsulfonyl group, an optionally substituted C i alkyl group -C _6, indicates an optionally substituted Arirumechiru group and alkoxycarbonyl two Le group, R ^{1 0} is a halogen atom, arsenic Dorokishiru group, an alkoxy group of C ₁ -C _6, § reel methyl O alkoxy group Or represents a reactive residue,

Ring A is a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group-an optionally substituted aryl group, a hydroxyl group, an optionally substituted C i Ce alkoxy group, a C _3- C _{1 0} cycloalkoxy group, alkanoyloxy Noi Ruo alkoxy group optionally C丄substituted ~ C _6, optionally substituted Ariroiruokishi group, an optionally substituted Ari Rumechiruokishi group, C ₃ ~ C i . Cycloalkadienyl Noi Ruo alkoxy group, substitution is optionally C ₁ -C ₆ alkylthio group, alkylsulfinyl group optionally substituted C ~ C _6, optionally substituted C i to C ₆ an alkylsulfonyl group, an amino group, mono- or di-substituted alkyl amino group -C _6,. 1 to 3 or may contain heteroatoms of 4-9 membered cyclic amino groups, the C. 1 to C ₆ alkylcarbonyl amino group, an alkoxycarbonyl § Mi amino group of C i C s, C i~ § Le kills sulfonyl § amino group of C _6, optionally substituted Arirusuruho Niruamino group, an alkylcarbonyl group of C i C _6, formyl, force Rupokishiru group, an alkoxycarbonyl group having C ₁ -C _6, mono- or di location A C 1 to C ₆ alkyl group, a 4- to 9-membered cyclic group, which may contain 1 to 3 heteroatoms, a cyano group or a two-port group. Represents 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),

The ring C is a halogen atom, an optionally substituted C i -C ₆ alkyl group-hydroxyl group, an optionally substituted C i Cs alkoxy group, an optionally substituted C -C ₆ An alkanoyloxy group, an optionally substituted aryloyloxy group, an optionally substituted arylmethyloxy group, C ₃ -C 丄. Cycloalkoxy group, cycloalkadienyl Noi Ruo alkoxy group C ₃ -C i _0, amino, mono- or di-substituted (alkyl amino group丄~ C _6, also contain heteroatoms 1-3 pieces of the good not 4-9-membered cyclic § Mi amino group, C i to an alkylcarbonyl § amino group of C _6, C ₁ -C alkoxycarbonyl § Mi amino group of _6, Al kill sulfonylamino group C ₁ ~ C _6, 1 to 3 substituents each independently selected from an optionally substituted 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 be formed) or a pyridobenzodiazine derivative represented by the formula: or a salt or hydrate thereof. Intermediates in products and solvates To provide.

 The present inventors have the following general formula (14)

(14)

(Wherein, R ¹ represents a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group, an arylmethyloxy group or a reactive residue, and R ³ is a hydrogen atom, which may be substituted. alkylcarbonyl group C i~C ₆ - alkylsulfonyl group optionally substituted C i to C _6, optionally substituted (^ _1-6 alkyl group, optionally substituted § Li one also be Rumechiru And X represents a halogen atom, a hydroxyl group or 〇S 02 R ¹³ (R ¹³ is a C 丄 -C ₆ alkyl group which may be halogen-substituted, And the ring C represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). The pyridobenzodiazine derivative represented by) or its salt, hydrate and And solvates with the following general formula (3)

(Wherein, Y is a halogen atom, 0 S 0 ₂ R ¹⁴ (R ¹⁴ is the same as described above), B (R ¹⁵ ) ₂ (R ¹⁵ is a hydroxyl group, an alkyl group of C i to C ₆ or C The alkoxy groups j to C ₆ or R ¹⁵ may be bonded to each other to form a ring.), L i, MgBr or ZnC 1, wherein the ring A is independently 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). 21. A process for producing a pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 21, wherein the compound is reacted with a compound represented by the formula:

The present inventors have the following general formula (15)

(Wherein R ¹¹ is a halogen atom, a hydroxyl group, a C i Ce alkoxy group, an arylmethyloxy group or a reactive residue;

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C i -C ₆ alkyl group; ring B has 1 to 3 substituents (adjacent 2 substituents are bonded to each other to form a ring formed shows a benzene ring which may have a well may) have.) indicates, X is a halogen atom, human Dorokishiru group or 0 S 〇 ₂ R ^{1 3} (R ^{1 3} is being Nono androgenic substituted A C i -C ₆ alkyl group or an optionally substituted aryl group), and the C ring has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) R ³ represents a benzene ring which may have

(R ⁷ is a halogen atom, a hydroxyl group, an optionally substituted C 丄 -C ₆ alkoxy group, 〇 S 0 ₂ R ¹² (R ¹² is an optionally substituted C i- An alkyl group of C ₆ , an aryl group which may be substituted), and i represents an integer of 1 to 6.) or

(R ⁸ is a halogen atom, a hydroxy group, an optionally substituted C ₆ alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.) And the salts, hydrates and solvates thereof, and the following general formula (5)

HR ⁹ (5)

(Wherein, R ⁹ is an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, and may be substituted and may have 1-3 hetero atoms. 21. A method for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to claim 20, wherein the compound is represented by the following formula: .

 The present inventors have the following general formula (16)

(In the formula, R ¹¹ is a halogen atom, a hydroxyl group, an alkoxy group of CiCs, an arylmethyloxy group or a reactive residue.

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C i Cs alkyl group; ring B has 1 to 3 substituents (adjacent two substituents are bonded to each other to form A benzene ring which may have Show. ) Indicates, X is a halogen atom, human de port hexyl _{^{group, 0 S 0 2 R 1 3}} (R 1 3 is halogen optionally substituted C丄-alkyl C _6, optionally substituted Ariru And the ring C represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) And a salt, hydrate and solvate thereof represented by the following general formula (7):

(7)

(In the formula, Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of (丄 to ^); R ⁷ is a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted Cア ル コ キ シ to C ₆ alkoxy group or 0 S 0 ₂ R ¹² (R ¹² is a substituted or unsubstituted C i -C ₆ alkyl group or an optionally substituted aryl group ), I represents an integer of 1 to 6.) or the following general formula (8)

(Wherein, V is a halogen atom, an optionally substituted C i to C ₆ of the alkoxy ^{_{group, OS 0 2 R 1 6 (}} R 1 6 is an alkyl group having optionally C i C s be halogen-substituted An optionally substituted aryl group), R ⁸ is a hydroxy group, an optionally substituted C i Cs alkoxy group, an arylmethyloxy group or a reactive residue, and j is 1 to Or an integer of 6) or the following general formula (9)

W-S 0 ₂ — R ⁶ (9)

(Where W is a halogen atom, a hydroxyl group, a C i C s alkoxide Shi group or a reactive residue, R ⁶ is pyrido benzo O Kisa derivative of claim 2 0, wherein the reacting a compound represented by the alkyl group) hydrogen atom or a C i C s or Provided are methods for producing salts, hydrates and solvates.

 The present inventors have the following general formula (17)

(In the formula, R ¹ represents a hydroxyl group, a C ₆ -C ₆ alkoxy group, an arylmethyloxy group or a reactive residue, and each ring A is independently selected from 1 to 3 A homocyclic or heterocyclic ring which may have a substituent (two adjacent substituents may be bonded to each other to form a ring, and ring C is the same as defined above). Pyridobenzodiazine derivative or its salt, hydrate and solvate and the following general formula (7)

(In the formula, Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C i to C ₆ , R ⁷ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C 1 ~ alkoxy or 0 S_〇 ₂ 1 ² C ₆ (R ^{1 2} is an alkyl group of Nono androgenic optionally substituted C i C e, which may be substituted Ariru group), i is the 1-6 Represents an integer.) Or the following general formula (8) -c- I

 (8)

(Wherein, V is a halogen atom, an optionally substituted C i -C ₆ alkoxy group, 〇S〇 ₂ R ¹⁶ (R ¹⁶ is an optionally substituted C ₁ -C ₆ An alkyl group, an optionally substituted aryl group), R ⁸ is a hydroxyl group, an optionally substituted C i -C ₆ alkoxy group, an arylmethyloxy group or a reactive residue, and j is 1 Or an integer of 6 to 6) or the following general formula (9)

W— S 0 ₂ — R ⁶ (9)

(Wherein W is a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkoxy group or a reactive residue, and R ⁶ is a hydrogen atom or a C i -C ₆ alkyl group) And a method for producing the pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to claim 21.

 The present inventors have the following general formula (18)

(Wherein R ³ is a hydrogen atom, an optionally substituted alkyl carbonyl group of C i Ce, an optionally substituted C i -C ₆ alkylsulfonyl group, an optionally substituted C i represents an alkyl group of Ce, an arylmethyl group which may be substituted, and an alkoxycarbonyl group; Rio represents a halogen atom, a hydroxyl group, an alkoxy group of CiC, an arylmethyloxy group or a reactive residue; X represents a halogen atom, A hydroxyl group or 0 S 0 ₂ R ¹³ (R ¹³ is a C 基 -C ₆ alkyl group which may be substituted by halogen, an aryl group which may be substituted); A benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring); And a salt, hydrate and solvate thereof represented by the following general formula (11):

(11)

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of Ci'Cs; ring B has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring; 20. The pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 20, which is reacted with a compound represented by the following formula: It provides a manufacturing method.

 The present inventors have the following general formula (19)

( ¹⁹ )

(Wherein R ³ is a hydrogen atom, an optionally substituted C ₁ -C ₆ alkylcarbonyl group, an optionally substituted C i Cs alkylsulfonyl group, an optionally substituted C Represents a C ₆ alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group, wherein the ring C has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have a benzodiazine derivative represented by the following general formula (20): HC (COR ¹⁰ ) 3 (20)

(In the formula, R ¹ is the same or different and is a halogen atom, a hydroxyxyl group-

Reacting a compound represented by a C ₆ -C ₆ alkoxy group, an arylmethyloxy group or a reactive residue, characterized by the following general formula (21):

(Wherein R ³ and R ¹ ° are the same as described above), and a method for producing a pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 20.

 [0 0 3 2]

Here, the alkylcarbonyl group optionally c ₁ to c ₆ be substituted, a halogen atom, arsenic Dorokishiru group, an alkoxy group of C i to C _6, an alkylthio group having C i~C _6, amino group, mono Or a di-substituted CiCe alkylamino group, a 4- to 9-membered linear amino group which may be substituted and which may contain 1 to 3 hetero atoms, a formylamino group,

C t -C 6 alkylcarbonylamino group, CtCealkylsulfonylamino group, optionally substituted arylsulfonylamino group, carbonyl group (formyl group, acetyl group, propionyl group, benzoyl group) An alkoxycarbonyl group (a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a phenylmethoxycarbonyl group, etc.), Sulfonyl group (methylsulfonyl group, trifluoromethylsulfonyl group, 4-methylphenylsulfonyl group, etc.), mono- or di-substituted C ₁ -C ₆ alkylcarno ' Moyl group, which may contain 1 to 3 hetero atoms, may be substituted, may have 1 to 5 substituents selected from 4- to 9-membered cyclic rubamoyl groups, etc. It means a good C ₁ -C ₆ alkylcarbonyl group. The an optionally substituted alkylsulfonyl group, a halogen atom, arsenic Dorokishiru groups, C丄alkoxy group ~ C _6, C i C s of § alkylthio group, amino groups, C i ~ mono- or di-substituted C ₆ Alkylamino group of 4 to 9-membered cyclic amino group, formylamino group, CiCS alkylalkylamino group which may be substituted and may contain 1 to 3 heteroatoms group, 〇 i alkylsulfonyl § Mi amino group of - C _6, optionally substituted § reel sulfo also be sulfonyl § Mino 1 selected from such groups 5 substituents substituted alkylsulfonyl group ( Methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, etc.). The alkyl group may be substituted C ~ C _6, C androgenic atom, arsenic Dorokishiru group, C丄alkoxy group ~ C _6, C i alkylthio group C _6, amino, mono- or di-substituted C Al Kiruami amino group of i-C _6, substituted 4 may Idei contain heteroatoms is good 1-3 of the optionally to 9-membered cyclic amino group, Horumiruami amino group, (alkyl丄~ C ₆ Carbonylamino group, C i -C ₆ alkylsulfonylamino group, optionally substituted arylsulfonylamino group, carbonyl group (formyl group, acetyl group, propionyl group, benzoyl group, etc. ), Alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, t-butoxycarbonyl group, 2,2,2-trichloromouth ethoxycarbonyl group, Rume butoxycarbonyl group), a sulfonyl group (a methylsulfonyl group, Application Benefits Full O b methylsulfonyl group, 4-methyl-phenylalanine sulfonyl group, etc.), alkyl force Rubamoiru group C i ~ C ₆ mono or di-substituted - It may contain 1-3 heteroatoms and may be substituted 4 A C ₁ to C ₆ alkyl group which may have 1 to 5 substituents selected from a 9-membered cyclic rubamoyl group and the like. An optionally substituted arylmethyl group includes a halogen atom, a CiCe alkyl group, a hydroxy group, a CiCe alkoxy group, a CiCe alkylthio group, an amino group and a mono group. or di-substituted alkylamino amino group of C-C _6, 1 - 3 or heteroatom of which may contain 4-9 membered cyclic § amino group, formylamino group, an alkylcarbonyl § of C丄~ Ji ₆ amino group, C ₁ alkylsulfonyl § amino group-C _6, substituted 1 also selected from goodness I § reel sulfonylamino group optionally to 5 substituents which may have a Arirumechiru group (phenylmethyl Group, naphthylmethyl group, pyridylmethyl group, quinolylmethyl group, indolylmethyl group, etc.). The alkoxycarbonyl group means a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a t-butoxycarbonyl group, a 2,2,2-trichloromouth ethoxycarbonyl group, a phenylmethoxycarbonyl group, or the like. . The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The aryl group which may be substituted includes a halogen atom, a C i -C ₆ alkyl group, a hydroxy group, a C -C ₆ alkoxy group, a C i Cs alkylthio group, an amino group, a mono- or di-substitution A C i -C ₆ alkylamino group, a 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 heteroatoms, a formylamino group, a C C to C ₆ alkylcarbonyl amino group, C ~ Arukirusu Ruhoniruami amino group of C _6, substituted 1 also selected from good § reel sulfonyl amino group or the like have to 5 substituents which may have a Ariru group ( Phenyl, naphthyl, etc.). The optionally substituted C 1 -C ₆ alkoxy group includes a nodogen atom, a hydroxyl group, a C i -C ₆ alkoxy group, a C i -C ₆ alkylthio group, an amino group, Mono- or di-substituted alkylamino group having C ~ C _6, substituted 4 may contain a hetero atom may 1-3 pieces of the optionally 9 membered璟状§ Mi amino group, formylamino group, alkylcarbonyl § amino group C i C e alkylsulfonyl § amino group of the C. 1 to C _6, have chosen 1-5 substituents from optionally substituted § reel sulfonylamino group optionally etc. Means a C i C s alkoxy group. C ₃ ~C i. The cycloalkoxy group means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, or the like. The optionally substituted C ₁ -C ₆ alkanoyloxy group is a nodogen atom, a hydroxy group, a C 丄 -C ₆ alkoxy group, a C 1 -C ₆ alkylthio group, an amino group. group, mono- or di-substituted C丄-alkylamino group C _6, substituted 4 may contain a hetero atom may 1-3 pieces of the optionally 9-membered cyclic amino group, formylamino group, It has 1 to 5 substituents selected from C i Ce alkylcarbonylamino group, C i Cs alkylsulfonylamino group, and optionally substituted arylsulfonylamino group. And a C i Cs alkanoyloxy group (such as an acetyloxy group, a propionyloxy group, an isopropionyloxy group, and a hexanoyloxy group). The substituted optionally may be Ariroiruokishi group, a halogen atom, an alkyl group of C i~C _6, human Dorokishiru group, C i C s alkoxy group, an alkylthio group of C i to C _6, amino group, mono Or a disubstituted C ^ Ce alkylamino group, a 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 hetero atoms, a formylamino group, C 丄 to C ₆ alkylcarbonyl § Mi amino group of, C i to § Le kills sulfonyl § amino group of C _6, which may have a substituted 1 selected from which may Arirusuruho Niruamino group have 5 substituents Aryloxy group (benzoyloxy group, naphthyloxy group, Lyloxy group, pyrimidyloxy group, quinolyloxy group, indyloxy group, etc.). Substituted and which may Arirumechi Ruokishi group, a halogen atom, an alkyl group of C ₁ -C _6, human Doroki sill group, an alkoxy group of C i to C _6, an alkylthio group having C丄~ C _6, an amino group , alkylamino amino group of C i~C ₆ mono- or di-substituted from 1 to 3 heteroatom and which may contain 4-9 membered cyclic amino groups, Hol Miruamino group, alkyl C i to C ₆ Arylmethyl which may have 1 to 5 substituents selected from a carbonylamino group, a C i C ₆ alkylsulfonylamino group, an optionally substituted arylsulfonylamino group, etc. Oxy group (phenylmethyloxy group, naphthylmethyloxy group, pyridylmethyloxy group, quinolylmethyloxy group, indolylmethyloxy group, etc.). Cg C i. The cycloalkanoyloxy group means a cyclopropanoyloxy group, a cyclobutanoinoleoxy group, a cyclopentanoinoleoxy group, a cyclohexanoyloxy group or the like. The optionally substituted C i -C ₆ alkylthio group means a halogen atom, a hydroxyl group, a C -C ₆ alkoxy group, a C i -C ₆ alkylthio group, an amino group, a mono- or di-substituted C 1 -C ₆ alkylthio group. i Cs alkylamino group from 1 to 3 of the hetero atom may be free Ndei 4-9 membered cyclic amino group, formylamino group, an alkylcarbonyl § amino group -C _6, alkyl sulfo C i Ce It means an alkylthio group optionally having 1 to 5 substituents selected from a nilamino group, an optionally substituted arylsulfonylamino group and the like. The alkyl sulfide alkylsulfonyl group optionally C i Ce substituted, a halogen atom, human de port hexyl group, an alkoxy group of C i~C _6, an alkylthio group of C i to C _6, amino group, mono or alkylamino group C i Cs disubstituted from 1 to 3 of the cyclic amino group may 4-9 membered also contain heteroatoms, formylamino group, al of C i~C ₆ Kill carbonyl § amino group, C i to alkylsulfonyl § amino group of C _6, which may have a substituted 1 selected from which may § Li one Le sulfonylamino group optionally 5 substituents It means an alkylsulfinyl group (methylsulfenyl group, ethylsulfinyl group, propylsulfinyl group, etc.). The mono- or di-substituted C ^ 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 acetylamino group, and a dipropylamino group. Group, diisopropylamino group, dibutylamino group, dihexylamino group and the like. A 4- to 9-membered cyclic amino group which may be substituted and may contain 1 to 3 hetero atoms includes azetidino group, pyrrolidino group, piperidino group, 4-methylbiperidino group and 4-dimethylamino Piperidino, 4-pyrrolidinylbiperidino, 4-piperidinylpiperidino, 4-hydroxypiperidino, morpholino, thiomorpholino, piperazino, 4-methylbiperazino, homopiを means radino group, 4-methylhomopiperazino group and the like. The alkylcarbonylamino group of C ^ Ce means an acetylamino group, a propionylamino group, a butyrylamino group, or the like. Alkoxy force of C i C s A ruponylamino group means a methoxycarbonylamino group, an ethoxycarbonylamino group, a t-butoxycarbonylamino group, a hexoxycarbonylamino group or the like. The alkylsulfonyl Niruamino group C i to C _6, means methylsulfonyl § amino group, a Echirusuruhoniru Amino group. The optionally substituted § Li one also be Rusuruhoniru Amino group, a halogen atom, an alkyl group of _6, human Dorokishi group, an alkoxy group of C丄~ C _6, an alkylthio group having C i to C _6, § Mi Bruno Group, mono- or di-substituted CiCs alkylamino group, 4- to 9-membered cyclic amino group optionally containing 1 to 3 hetero atoms, holmi Ruami Roh groups, C丄alkylcarbonyl § Mi amino group of ~ C _6, C ₁ alkylsulfonyl § Mi amino group of ~ C _6, 1 ~ 5 selected from such optionally substituted § Li one also be Luz Ruhoniruamino group Means an arylsulfonylamino group which may have one or more substituents. A ring in which two adjacent substituents may be bonded to each other to form

And so on.

The alkyl force Rubamoiru group C丄~ C ₆ mono or di-substituted, methyl force Rubamoiru group, E Ji carbamoyl group, a propyl force Rubamoiru group, an isopropyl force Rubamoiru group, t - Petit carbamoyl group, the alkoxy carbamoyl group, dimethyl A carbamoyl group, a getyl carbamoyl group, a dipropyl rubamoyl group, a diisopropyl rubamoyl group, a dibutyl rubamoyl group, a dihexyl carbamoyl group, and the like.

A 4- to 9-membered cyclic carbamoyl group which may contain 1 to 3 hetero atoms includes azetidinylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group and 4-methylbiphenyl. It means a peridinylcarbonyl group, a morpholinylcarbonyl group, a thiomorpholinylcarbonyl group, a piperazinylcarbonyl group, a 4-methylbiperazinylcarbonyl group and the like. The homocyclic ring of the ring A means a benzene ring, a naphthalene ring or the like. The heterocyclic ring of the ring A 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 9 members or i. Means a membered aromatic fused heterocycle. The C ₃ ~ cycloalkyl group C i Q, cyclopropyl group, you cyclobutyl group, cyclopentyl group, cyclohexyl group, etc. cyclohexylene. Halogen optionally substituted € ^ 0 ₆ alkyl group, 1 Means a methyl group, an ethyl group, a propyl group, an isopropyl group, a t-butyl group, a hexyl group, etc. which may be substituted with up to 13 fluorine atoms or chlorine atoms. The ring which may be formed by bonding to each other of R ¹⁵ is as follows: 10 (CH ₂ ) ₂ , 1 CH (M e) CH (M e) 0—,-0 C (Me) ₂ C (Me) ₂ 0 or - 0 (CH ₂₎ means ₃ 0- like. The reactive residue means a 1-imidazolyl group, 412 trophenoxy group, imidoyloxy succinate group or the like.

Preferred compounds of the present invention include N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-11, N-dimethyl-7- (3-fluorophenyl) -15-oxo-1-5 H-pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] 17- (3-chlorophenyl) 1,2,3-Dihydro 1, 1-dimethyl-5-oxo-5-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide, Ν— [3,5 —Bis (trifluoromethyl) benzyl] — 2,3-Dihydro 1, Ν-dimethyl 7- (3 12 trophenyl) 1 5-oxo-1 5 Η-pyrido [1,2,3-dθ] 1 1,4-benzodiazine-1 6-carboxamide, 7- (3-aminophenyl) -1-N- [3,5-bis (triff O-methyl) benzyl] — 2,3-Dihydro 1, N-dimethyl-1-5-oxo-5 H-pyrido [1,2,3-dθ]-1,4, benzodiazine-16-carboxamide, N — [3,5-bis (trifluoromethyl) benzyl] -17— (3,5-dichlorophenyl) 1-2,3-dihydro-1,1, N-dimethyl-5-oxo-5H-pyrido [ [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1,1-N-dimethyl7— ( 4-methylphenyl) 1 5-oxo-1 5 H— Pyrido [1,2,3-de] — 1,4-benzodiazine—6-carboxamide, Ν— [3,5—bis (trifluoromethyl) benzyl] —2,3-dihidroh 7— (4 —Methoxy phenyl) 1, 1Ν-Dimethyl-5 -oxo1 5 Η-pyrido [1,2,3-de]-1, 4 —Benzodiazine-1 6 —Carboxamide, Ν— [3,5— Bis (trifluoromethyl) benzyl] —2,3-dihydro-1,1-dimethyl-7- (4-fluorophenyl) -1-5-oxo-5-pyridine [1,2,3-de]- 1,4-benzodiazine-16-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -17- (4-chlorophenyl) 1-2,3-dihydro-1, N-dimethyl-5 —Oxo-1 5 H—Pyrido [1,2,3-de] — 1,4-Benzodiazine 6—Carboxamide, N— [3,5 Bis (trifluoromethyl) benzyl] -7- (3-chloro-1,4-fluorophenyl) 1-2,3-dihydro-1,1-N-dimethyl-15-oxo-5H-pyrido [1, 2,3-de] 1, 1, 1-benzodiazine-6-carboxamide, N-[3,5-bis (trifluoromethyl) benzyl]-2,3-dihydro 1, N-dimethyl 7-(4 —Methyl-3—Nitrophenyl) 1 5 —Oxo 1 5 H—Pyrido [1,2,3-de] 1-1,4,1-Benzodiazine-16—Carboxamide, N— [3,5—Bis (trifluoromethyl) ) Benzyl] 1, 2,3-dihydroxy 1, N-dimethyl-1 7- (2-methoxyphenyl) 1 5 -oxo-5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine 6—force lipoxamide, Ν— [3,5—bis (trifluoromethyl) benzyl] 1—7— (2,4- 1,2-dihydro-1,1-dimethyl-5-oxo-5-pyrido [1,2,3-dθ] 1-1,4-benzodiazine-16-carboxamide Ν— [3,5—Bis (trifluomethyl) benzyl] —2,3—Dihidro 1, Ν —Dimethyl 1 7 — (1 -naphthyl) -1 5 —oxo 1 5 H-pyrido [1 2, 3-d θ] — 1,4 benzodiazine 16 —carboxamide, N— [3, 5 —bis ( Trifluoromethyl) benzyl] — 2,3-Dihydro-1-1, N-dimethyl-17- (3-methoxyphenyl) -5-oxo-5H-pyrido [1,2,3-de] —1, 4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1, N-dimethyl-15-oxo-1 7- [3- (trifluoromethyl ) Phenyl] — 5 H—Pyrido [1,2,3—de] —1,4-Benzodiazin-6-carboxamide, N— [3,5—Bis (trifluoromethyl) benzyl] -2,3 —Dihidro 1, N—dimethyl-7 — (3—methylphenyl) -1-5-oxo-5 H—pyrido [1 , 2,3-de] -1, 4-Benzodazine-1-6-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihidro 1, di-methylo 5-oxo 1- 7-phenyl-5-pyrido [1,2,3-de]-1,4-benzodiazine-16-carboxamide, N— [3,5—bis (trifluoromethyl) benzyl] —2,3 —Dihydro 1 1 — (Methanesulfonyl) — — 1 (3-Methoxyphenyl) — N—Methyl 5-Hoxo 5 H—Pyrido [1,2,3-de] 1-1,4—Benzodiazine 6—carboxamide, 1—acetyl-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-71- (3-methoxyphenyl) -1-N-methyl-5—oxo—5H—pi Lid [1,2,3—de] — 1,4—benzodiazine-1 6—carboxamid, Ν— [3,5—Bis (trifluoromethyl) benzyl] 1-2,3-dihydro 1-[(ethoxycarbonyl) methyl] 1 7-1- (3-methoxyphenyl) 1-methyl-1 5-oxo-5 —Pyrido [1,2,3-de] —1,4-Benzodiazine-1-6-carbo Kisamide, N— [3,5-bis (trifluoromethyl) benzyl] -1- (carboxylmethyl) -1,2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5 H-pyrido [1,2,3-dΘ] — 1,4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7 (3-Methoxyphenyl) 1-N-methyl-1-[(4-Methylbiperazinyl) carbonylmethyl] -1-5-oxo_5H-pyrido [1,2,3-de] —1, 4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1-5-oxo-1 7-phenyl-1 1 (1-pyr Lysinyl acetyl) 1 5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxami , N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-11- (4-morpholinylacetyl) _5-oxo-1 7-phenyl-1-5H-pyri De [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1,2,3-dihydroN— Methyl-5-oxo-1 7-phenyl 1-1 [(4-1 (1-pyrrolidinyl) piperidinyl) acetyl] —5H-pyrido [1,2,3-de] —1,4 —Benzodiazine-1 6-carboxamide, N — '[3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1 — [(4-methylbiperazinyl) acetyl] — 5-oxo-1 7-phenyl-5 H-pyrido [1,2,3-de] 1-1,4-benzodiazine-1-6-carboxamide, Ν— [ 3,5-bis (trifluoromethyl) benzyl] 1, 2,3-dihydroxy 1-methyl-1 7-phenyl-2- (1-piperidinyl acetyl) -5-oxo-1 5-pyrido [ 1 2,3-de] 1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-5-oxo-7-phenyl-1 -— [(4- (1-piperidinyl) piberidinyl) acetyl] —5 H—pyrido [1 2, 3-d Θ] — 1,4 benzodiazine _ 6 —carboxamide, N— [3, 5 —bis (trifluoromethyl) benzyl] — 2,3 -dihidrone 1 [( 4-Hydroxypiperidinyl) acetyl] 1 N —methyl-5-oxo-1 7-phenyl-1 5 H—pyrido [1,2,3-de]-1,4, benzodiazine-1 6-carboxamide, N— [35_Bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1-[(dimethylamino) acetyl] — N-methyl-5-oxo-1 7-phenyl-5H-pyrido [1,2] , 3-de] — 1, 4—Benzodiazine-1 6—Carboxamide, 1— (Aminoacetyl ) 1 N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-5-oxo-1 7-phenyl-1-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (3-methoxyphenyl) -1-N-methyl_5—o Kiso 1- (1-Pyrrolidinyl acetyl) -15H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] —2,3-Dihydro 7— (3-Methoxyphenyl) —N-Methyl-1— (4-Morphorinylacetyl) —5-Oxo-1 5H—Pyrido [1,2,3— de] — 1,4,1-benzodiazine-1 6-carboxamide, Ν— [3,5-bis (trifluoromethyl) Ndyl] 1, 2,3-dihydro-1 7- (2-fluorophenyl) -1-methyl-1-5-oxo-1- (1-pyrrolidinylacetyl) 1-5-pyrido [1,2,3-de] -1,4-benzodiazine-6-carboxamide, N— [3,5-bi (Trifluoromethyl) benzyl j 1 23-dihydro 7- (2-fluorophenyl) 1-N-methyl-1- 1- (4-morpholinylacetyl) 1-5-oxo-1 5H-pyrido [1,2, 3-d θ]-1, 4 -Benzodiazine 6-carboxamide, N- [3, 5-bis (trifluoromethyl) benzyl] — 2,3-dihydro 7-(2-fluorophenyl) 1 N— Methyl 1-[(4- (1-Pyrrolidinipiperidinyl) acetyl] -15-oxo-5H-pyrido [1,2,3-de] —1,4, -benzodiazine-16-carboxamide, N— [3 , 5-bis (trifluoromethyl) pentyl] 1, 2,3-dihydro 7- (3-fluorophenyl) 1 N-methyl-1 5-oxo-1 1- (1-pyrrolidinyl acetyl) 1 5H-pyrido [1 , 2, 3— de] — 1,4-benzodiazine-1 6-carboxa De, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7- (3-fluorophenyl) -1-N-methyl-1- (4-morpholinyl-lacetyl) -15-oxo 1-5H-pyrido [1,2,3-dθ] 1-1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1 7- (3-Fluorophenyl) 1 N-methyl-1 — [(4- (1-1-pyrrolidinyl) piperidinyl) acetyl] 1-5-oxo-5H-pyrido [1,2,3-de] —1, 4 1-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (4-fluorophenyl) 1-N-methyl-1 5-oxo-1 — (1-Pyrrolidinyl acetyl) 1 5 H-pyrido [1, 2, 3-de] — 1, 4-benzo Azine 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (4-fluorophenyl) 1-N-methyl-1- (4 morpholinyl acetyl ) 1-5-oxo-5H-pyrid [1,2, 3-de] — 1,4,1-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 2,3-dihydro-1 7— (4-fluorophenyl) 1-N-methyl 1 — [(4— (1-Pyrrolidinyl) piperidinyl) acetyl] —5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-6-carboxamide, Ν — [3,5-bis (trifluoromethyl) benzyl] -1- 7- (3,4-difluorophenyl) 1,2,3-dihydro-1- 一 -methyl-5-oxo-1 1- (1-pyrrolidinylacetyl) ― 5 Η-pyrido [1,2,3-dθ] 1-1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] ー 7— (3,4— Difluorophenyl) 1, 2,3-dithiol N-methyl-1 _ (4-morpholinylacetyl) ) — 5-oxo-1 5 H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] — 7— (3,4-Difluorophenyl) 1-2,3-dihydro-1-methyl-1-[(4- (1—pyrrolidinyl) piperidinyl) acetyl] 5-5-oxo-5-pyrido [1 , 2,3-dθ] 1-1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-difluoromethylphenyl) 1-2,3 —Dihydro-1-N-methyl-5-oxo-1 -— (1-pyrrolidinylacetyl) -5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide, N— [3 , 5—Bis (trifluoromethyl) benzyl] 1 7 _ (2,4-difluoro mouth phenyl) 1, 2,3-Dihidro N Methyl-1- (4-morpholinylacetyl) —5-oxo-5H-pyrido [1,2,3-dθ] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis ( Trifluoromethyl) benzyl] — 7— (2,4-difluoro Methyl phenyl) 1,2,3-dihydro-1-N-methyl-1-[(4-1 (1-pyrrolidinyl) piberidinyl) acetyl] -15-oxo-5H-pyrido [1,2,3-de] — 1,4-I-benzodiazine-1 6-carboxamide, 、 — [3,5-bis (trifluoromethyl) benzyl] -1 2,3—dihydro-1 7— (3-methoxyphenyl) 1-methyl-1 5 —oxo 1 1 [(4 — (1 -pyrrolidinyl) piberidinyl) acetyl] — 5 ピ リ -pyrido [1, 2, 3 -d Θ] 1, 1, 4-benzodiazine 1 6 —carboxamide, N— [3,5—Bis (trifluoromethyl) benzyl] —2,3-dihidro 7— (3-Methoxyphene

1 N-methyl-5-oxo-1 1 (1—piperidinyl aceti — 5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine-1 6—carboxamide, N— [3,5 —Bis (trifluoromethyl) benzyl] -2,3-dihydro-7- (3-methoxyphenyl) —N-methyl-5-oxo-1 — [(4- (1—piperidinyl) piperidinyl) acetyl ] 1-5H-pyrido [1,2,3—de] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1 1 1 [(4-Hydroxypiperidinyl) acetyl] 100 — (3-Methoxyphenyl) 1 N-Methyl-1 5-oxo-1 5H-Pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5—bis (trifluoromethyl) benzyl] 1, 2,3-dihydro 1 1 [(dimethylamino) acetyl] 1 7- (3-methoxyphenyl) 1 N-methyl-1 5 -oxo-5 H-pyrido [1,2,3-de] ― 1,, 4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-7- (3-methoxyphenyl) 1-N-methyl-1 1 [(methylamino) acetyl] — 5 —oxo 1 5 H—pyrid [1, 2, 3-de] — 1, 4 —Penzodiazine-1 6-carboxamide, 1- (aminoacetyl) —N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3—dihydro 7— (3-methoxyphenyl) -1-N-methyl-1 5—oxo 1 5 H—pyrido [1,2,3-de] — 1,4,1-benzodiazine 1—6-carboxamide, Ν— [3,5-bis (trifluoromethyl) benzyl] 1 2,3—Dihydro 1 — [(Ν— (2— (dimethylamino) ethyl) 1—methylamino) acetyl] —7— (3—methoxyphenyl) 1—methyl 1 5—oxo-1 5Η-pyrido [1,2,3-dΘ] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 1 — [(diethylamino) acetyl ] 1, 2, 3-dihydro 1-7-(3-methoxyphenyl) 1-N-methyl- 5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 1— [(2 S- (1—Pyrrolidinylmethyl) pyrrolidinyl) acetyl] 1, 2,3 dihidro 7— (3-Methoxyphenyl) 1 N—methyl-1 5—year old — 1,4—Benzodiazine-6-carboxamide, Ν— [3,5_Bis (trifluoromethyl) benzyl] -12,3-dihydro-7— (3-Methoxyphenyl) — Ν— Methyl-1 — [(Ν— (4 -— (1-methylbiperidinyl)) — Ν—methylamino) acetyl] —5-oxo-1-5-pyrid [1,2,3-dΘ] —1,4 —Benzodiazine-1-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1- 7- (4-methylphenyl) 1-1- (4-1-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzodiazine-6 —Carboxamide, N— [35-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-7- (3-methylphenyl) — 1— (4-morpholinyl acetyl) _5-oxo-1 5H-pyrido [1,2,3-de]

1,4-I-benzodiazine-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro N-methyl-7- (2-methylphenyl) 1-1— (4-1) Morpholinylacetyl) 1-5-oxo-5H-pyrido [1,2,3-de] -1, 4—benzodiazine_6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1 2, 3—Jihidoro 1—

(2,6-cis-dimethylmorpholinyl)) acetyl] — 7— (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [12,3-de] — 1,4-1 Benzodiazine-6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo1-1-1 [ (4-propylpiperazinyl) acetyl]-5 H-pyrido [1, 2, 3-de]-1, 4-benzodiazine-6-carboxamide, Ν-[3, 5-bis (trifluoromethyl) Benzyl] ―2,3-Dihydro 7- (3-Methoxyphenyl) 1-methyl-5-chloro-1 1 _ [(4-Methylhomopiperazinyl) acetyl] ―5Η-pyrido [1 , 2, 3-de]-1, 4 -Benzodiazine-16 -carboxamide, Ν— [3,5-bis (triflu 1-, 2- (3-Methoxy) ethyl 1-[((2-Methoxyhexyl) amino) acetyl] — 7— (3-Methoxyphenyl) 1-methyl-5-oxo-5- Pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihidro 1— [((2-Hydroxyshetyl) amino] acetyl] — 7— (3-Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-1 6—carboxamide, N— [3,5—bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1 — [(4- (dimethylamino) piperidinyl) acetyl] —Ί-1 (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (Trifluoromethyl) benzyl] — 2,3-Dihydro 7— (4-Methoxyphenyl) 1 N—Methyl-1 1 — (4-Morphorolinylacetyl) 15—Oxo-5H—Pyri De [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5—bis (trifluoromethyl) benzyl] —2,3—dihydro-7— (2-meth Toxifenyl) 1 N-methyl-1 — (4-morpholinyl lacetyl) 1 5 — Oki 1 5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihidrone N — Methyl-1- (4-morpholinylacetyl) -1-5-oxo-7— [3- (Trifluoromethyl) phenyl] -1-5-H-pyrido [1,2,3-de] -1,4,1- Benzodiazine-6-carboxamide, N— [35—bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) 1-2,3-dihydro-1-N-methyl-1 -— (4-morpholinyl) Acetyl) 1-5-oxo-5H-pyrido [1,2,3—de] — l, 4,1-benzodiazine-16—carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 7— (3 -chlorophenyl) 1 2, 3 -dihydro 1 -N-methyl-1-(4 -morpholinylacetyl) 1 5 —oxo 1 5 H—pyrido [1,2,3-de] — 1,4,1benzodiazine _6 —carboxamide, N— [3,5—bis (trifluoromethyl) benzyl] — Ί One (3,4-dichlorophenyl) one 2,3-Dihydro-1-N-methyl-1-one (4-morpholinylacetyl) one 5-oxo-5H-pyrido [1,2,3-dΘ] —1,4-benzodiazine-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 7— (2,4-dichlorophenyl) one 2,

3-dihydro-1-N-methyl-1- (4-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-6 —Carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -17- (3-chloro-4-fluorophenyl) —2,3-dihydro N-methyl-11- (4-morpholinylacetyl) 1) 5-oxo-1 5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] -1 7 — (4-Chloro-3-fluorophenyl) — 2,3-dihydro-1-N-methyl-1- (4-morpholinyl acetyl) -1-5-oxo-5H-pyrido [1,2,3-de] — 1 , 4-Benzodiazine-1 6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 7— ( 3,5-difluorophenyl

— 2,3-Dihydro-1-N-methyl-1- (4-morpholinyla — 5-oxo-5H-pyrido [1,2,3-dθ]-1,,

4-benzodiazine-1 6-carboxamide, 1-[(4-acetyl piperazinyl) acetyl] — Ν— [3,5-bis (trifluorometyl) benzyl] —2,3-dihydro 7- (3-methoxyphene 1) -Methyl-1-5-oxo-5-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] — 2, 3-dihid 7

(3-methoxyphenyl) 1 1-[(4-(Methanesulfonyl) piperazinyl) acetyl] 1-N-methyl-5-oxo-1 5 H-pyrid

[1, 2, 3— de] — 1,4-benzodiazine-16-carboxamide, 1— [(41- (acetylamino) piperidinyl) acetyl] — N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3 — De] — 1,4-benzodiazine 6-carboxamide N- [3,5-bis (trifluoromethyl) benzyl] ] 1 7— (3—Methoxyfue

 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dθ] — 1,4-benzodiazine-16-carboxamide, 1 — [(4-acetylhomopiperazinyl) acetyl] N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3 — De] — 1, 4-benzodiazine-6-carboxamide, N- [3,5-bis (trifluromethylmethyl) benzyl] -2,3-dihydro 1-[(4-1-methanesulfonyl) homopiperazinyl ) Acetyl] — 7— (3-Methoxyphenyl) 1 N-methyl-5-oxo 5 H-pyrido [1,2,3-de] 1-1,4-benzodiazine-1 6-carboxamide, Ν— [ 3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- (3-methoxy) 1-Methyl-5-oxo-11- (4-thiomorpholinylacetyl) -15-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide , Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxyphenyl) —Ν—methyl-5-oxo-one [4-one (1-oxo) Thiomorpholyl) acetyl] —5-dipyrido [1,2,3-de] —1,4-benzodiazine-1-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] One, two, three—dihydro 7— (3—methoxyphene

N-methyl-5-oxo1-1-1 [(4- (1,1,1-dioxo) Sothiomorpholinyl)) acetyl] 1-5H-pyrido [1,2,3-d d] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) Benzyl] — 2,3-Dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-1 1- (1—piperazylacetyl) 1-5 H-pyrido [1,2,3 -de]-1,4-benzodiazine-1 6-carboxamide, N- [3,5-bis (trifluoromethyl) benzyl] -1-1 (1-homopiperazinylacetyl) 1-2,3-dihydro-1 7— (3-Methoxyphenyl) 1 N—methyl mono 5—oxo mono 5 H—pyrido [1,2,3-de] -1,4—benzodiazine-1 6-carboxamide, Ν— [3,5— Bis (trifluoromethyl) benzyl] 1,2,3-dihydro-1- (3-methoxyphenyl) -1-methyl-1- [4- (Methylamino) pyridinylacetyl] 1-5-oxo-5-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide, 1 — [(4— (N— Acetyl-N-methylamino) piperidinyl) acetyl] -N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5 Oxoxo 5H-pyrido [1,2,3-de] — 1,4-benzodiazine-6-carboxamide, Ν— [3,5-bis (trifluorometyl) benzyl] —2,3-dihi Draw 11-[(4- (Ν- (methanesulfonyl) -1-methyl-amino) piperidinyl) acetyl] 1 7- (3-Methoxyphenyl) 1-methyl-5-oxo-5-pyridine [ 1,2,3-de] — 1,4-benzodiazine-6-carboxamide, [— [3,5-bi (Trifluoromethyl) benzyl] 1-1 — [(4-Methylbiperazinyl) acetyl] —2,3-Dihydro 7— (3-Methoxyphenyl) mono-methyl-5-oxo-5-pyri De [1, 2, 3— de — 1, 4—benzodiazine 1— Carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1 1 — [(4-1 (acetylamino) 14 4-phenylbiperidiacetyl] —2,3-dihydro-1- 7— (3-methoxyphenyi) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dΘ] — 1,4,1-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] — 1— [(4-aminopyridinyl) acetyl] — .2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2 , 3-d θ]-1,4-benzodiazine-6-carboxamide, 1-benzyl-N-[3,5-bis (trifluoromethyl) benzyl]-2,3-dihydro-7-(3 —Methoxyphenyl) —N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1, 4-benzodiazine-1 6-carboxamide, 1-benzoyl N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-N-methyl-1

5-oxo-1 7-phenyl 5 H-pyrido [1,2,3-dΘ]-1,4-benzodiazine-1 6-carboxamide, 1-benzyl-1 N-[3,5-bis ( Trifluoromethyl) benzyl] — 2,3-dihydro-1 7- (4-fluorophenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine one

6-carboxamide, 1-benzyl-l- [3,5-bis (trifluoromethyl) benzyl] -l, 3-dihydro 7- (3-fluorophenyl) l-methyl-5-oxo-5 Η—pyrido [1,2,3-dθ] — 1,4-benzodiazine-16-carboxamide, 1-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihi Draw 7— (2-Fluorophenyl) -N-methyl—5-Oxo-5H-pyrido [1,2,3-de] —1,4-Benzodiazine-1 6-Carboxamide, 1-Benzyl N — [3, 5— Bis (trifluoromethyl) benzyl] — 7 _ (3,4-difluoromethyl) -1,2,3-dihydro-1-N-methyl-5-oxo-5H—pyrid [1,2,3-dΘ] 1,4-benzodiazine-16-potency lipoxamide, 1-benzyl-1-N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-difluorophenyl) 1,2,3-dihi Dro-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] 1,2,3-dihydro 7- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-1 6-carboxamide, N — [3,5-bis (trifluoromethyl) benzyl] — 2,3-dihydro-N-methyl-5- 1-oxo 7-phenyl 5 H-pyrido [1,2,3-dθ] -11,4-benzodiazine-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl) ] — 2,3-Dihydro 7- (4-fluorophenyl) — N-Methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4, benzodiazine-6-carboxamide, N — [3,5-bis (trifluoromethyl) benzyl] — 2,3-dihydro-1- (3-fluorophenyl) -1-N-methyl-5-oxo-5H-pyrido [12,3- de] — 1,4-benzodiazine-1-6-carboxamide, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (2-fluorophenyl) -N-methyl—5— Oxoiso 5 H-pyrido [1, 2, 3-de] — 1, 4-benzodiazine — 6-carboxamide, Ν— [3, 5 Bis (trifluoromethyl) benzyl] 1-7- (3,4-difluorophenyl) 1-2,3-dihydro-1-methyl-5-oxo-1-5-pyrido [1,2,3-de] 1-1 , 4-benzodiazine-6-carboxamide, N-[3, 5- Bis (trifluoromethyl) benzyl] mono- (2,4-difluoromethyl) 1-2,3-dihydro-1N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] — 1,4,1-benzodiazine-1 6-potassium lipoxamide, Ν— [3,5-bis (trifluoromethyl) benzyl) -1,2,3-dihydro-7- (3-methoxyphenyl) 1-methylyl 1— (4-morpholinyl acetyl) —5-oxo—5Η-pyrido [1,2,3-de] —1,4-benzodiazine-1-6-carboxamide hydrochloride, N— [3 , 5—Bis (trifluoromethyl) benzyl] 1, 2,3-dihydro N-methyl-1 7— (3-methylphenyl) — 1 — (4-morpholinyl acetyl) — 5 —oxo — 5 H —Pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide hydrochloride, Ν— [3,5-bis (tri) Fluoromethyl) benzyl] — 1 — [(4-Methylbiperazinyl) acetyl] — 2, 3-dihidro 7— (3-Methoxyphenyl) 1-methyl-5-oxo-5-pyri De [1,2,3-de] 1-1,4-benzodiazine—6-carboxamide hydrochloride, Ν— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihidro 7— (3 —Methoxyphene — Ν—Methyl-5-oxo-1 -— (1-pyrrolidinylaceti 5 チ —pyrido [1,2,3-de] —1,4,1-benzodiazine-6-carboxamide hydrochloride, Ν— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-[((2-hydroxyxethyl) amino] acetyl] 1-7— (3-methoxyphenyl) -1-methyl-1- 5-oxo-5-pyrido [1,2,3-de] 1,4-benzodiazine-6-cal Oxamide hydrochloride, 1 — [(4-Acetylbiperazinyl) acetyl] -1-N_ [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (3-meth Xyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1, 2, 3—de] —1,4-benzodiazine—6—carboxamide hydrochloride, N— [3,5—bis (trifluoromethyl) benzyl] -1,2,3—dihidro N—methyl1-1,1 (41 moles) (Holinyl acetyl) 1 5 — oxo 1 7 — [3-(trifluoromethyl) phenyl] — 5 H-lide [1, 2, 3-de]-1, 4-benzodiazine 1 6 — carboxamide hydrochloride Salt, Ν— [3,5—Bis (trifluoromethyl) benzyl) —7— (3-chlorophenyl) 1-2,3-dihydro Ν—methyl 1— (4-morpholinylacetyl) — 5 —oxo-5-pyridone [1,2,3-de] —1,4-benzodiazine-16 —carboxamide hydrochloride, Ν- [3,5—bis (trifluoromethyl) benzyl] One, two, three—dihydro-1-one ([(4- (Ν- (methanesulfonyl) -one-methylamino) pipe) Dinyl) acetyl] 1- (3-Methoxyphenyl) 1-：-methyl-5-oxo-5-Η-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide salt Acid salt, N— [3,5—Bis (trifluoromethyl) benzyl] 1—1 (1 1 homopiperazinyl acetyl) 1,2,3—dihydro 1 7— (3—Methoxyphenyl) —N—methyl-5 —Oxo-5H-pyrido [12,3-de] —1,4-benzodiazine — 6 —carboxamide hydrochloride and the like.

 When the compound of the present invention forms a salt, an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, lingoic acid, tartaric acid, citrate, Examples thereof include pharmacologically acceptable salts with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, and palmitic acid.

 The compound of the present invention or a salt thereof includes optically active isomers, stereoisomers, and rotamers in addition to the racemate.

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.

 (First step)

In this step, compound (I) (where R ³ and C ring are the same as above) and compound (II) (where R ¹ is the same as above) are reacted to obtain compound (III) (where R ³ , R ¹⁰ and Ring C is the same as described above). In this reaction, the compound (II) is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, and preferably 100 to 300 ° C, preferably 150 to 25 ° C, based on the compound (I). Performed at 0 ° C. When a solvent is used, an inert solvent which does not participate in the reaction, for example, xylene, mesitylene, nitrobenzene, diphenyl ether, dautherm (a mixture of diphenyl ether and biphenyl) and the like are used. (Second step)

In this step, the compound (III) (R ³ , R ^{1 Q} and the ring C are the same as described above) and the compound (IV) (RR ² and the ring B are the same as described above) This is a step of producing compound (V) (RR ² , R ³ , ring B and ring C are the same as described above). In the condensation reaction in this step, when R ^{1 Q} is a hydroxy group, the condensing agent used is dicyclohexyl carboximide (DCC;), 3-ethyl-1- (3-dimethylaminopropyl) Examples include carbodimid hydrochloride (EDCI) and dimethylimidazolidinyl chloride (DMC), which are added in solid form or as a solution dissolved in an appropriate solvent. When a base is used in the present condensation reaction, an alkali carbonate such as sodium bicarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholin, diazabicyclo [5] . 4.0] —7-Pendecene, pyridine, 4-dimethylaminopyridine 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, acetonitrile, tetrahydrofuran , Dioxane, ethyl ether, dimethoxetane, ethyl acetate, and dichloromethane. This condensation reaction proceeds smoothly from-20 ° C to 80 ° C. In the condensation reaction of this step, R ^{1 Q} is a carboxylic acid halide represented by a reactive residue (for example, a halogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxy succinate group, etc.) In the case of imidazolides of carboxylic acids, active esters of carboxylic acids, mixed anhydrides of carboxylic acids (for example, anhydrides with ethyl carbonic acid, anhydrides with isobutyl carbonic acid, etc.) or triethylamine in the case of symmetrical acid anhydrides N, in the presence or absence of an inorganic base such as sodium bicarbonate or potassium carbonate, or an organic base such as diisopropylethylamine, pyridine, or 4-dimethylaminopyridine. N-Dimethylformamide, N, N-Dimethylacetamide, Dimethylsulfoxide, Acetonitrile Water, a solvent such as tetrahydrofuran, dioxane, ethyl ether, dimethoxetane, ethyl acetate, toluene, dichloromethane, etc. by treating at 120-80 ° C for 30 minutes to 48 hours. Can be. In the condensation reaction of this step, when R ¹ ° is an ester residue such as an alkoxy group or a benzyloxy group of C to C ₆ , in the presence or absence of trimethyl alcohol or tetraisopropoxythiamine, or p — N, N-dimethyl in the presence or absence of an acid or base catalyst such as toluenesulfonic acid, or sodium methoxide, or potassium—t-butoxide, sodium hydride, etc. Formamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitril, tetrahydrofuran, dioxane, toluene, xylene, mesitylene, pyridine, quinoline, dichloromethane, etc. at room temperature ~

It can be carried out by treating at 150 ° C for 30 minutes to 48 hours.

 (Third step)

In this step, the hydroxyl group of compound (V) (RR ² , R ³ , ring B and ring C are the same as described above) is converted to X (X is the same as above), and compound (VI)

(X, R ¹ R ² , R ³ , ring B and ring C are the same as described above). In this step, for example, when X is a chlorine atom, the chlorinating agent may be phosphines such as triphenylphosphine, tributylphosphine or triphenoxyphosphine and carbon tetrachloride, N-chlorosuccinimide or chlorine, thionyl chloride. The reaction is carried out using phosphorus oxychloride, phosphorus 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, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, pyridine, etc. Used. The reaction is carried out from room temperature to the boiling point of the chlorinating agent or the solvent if a solvent is used. Proceed smoothly up to the boiling point of When X is a bromine atom, the reaction can be carried out in the same manner as in chlorination using a corresponding brominating agent.

When X is 0 S 0 ₂ R ¹³ (R ¹³ is the same as described above), the sulfonating reagent used in this reaction is methanesulfonyl chloride, p-toluenesulfonyl chloride, Methanesulfonic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonyl imide, etc. are used, and the reaction is carried out in a solvent in the form of triethylamine, triethylamine The reaction is performed in the presence of a base such as butylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, butyllithium, and lithium diisopropylamide. As the solvent, an inert solvent which does not participate in the reaction, preferably, dichloromethane, tetrahydrofuran or the like is used. The reaction is carried out at a temperature of 170 ° C. to 100 ° C., preferably at a temperature of 130 ° C. to 80 ° C. o

 (Fourth step)

In this step, the compound (VI) (X, RR ² , R ³ , the rings B and C are the same as described above) and the compound (VI I) (the rings Y and A are the same as described above) are mixed with a palladium or nickel complex. the Kurosukatsupuri ring reaction under transition metal catalyst etc., the compound ^{(VI II) (RR 2,} 3, a ring, the B ring及beauty ring C as defined above) is a step for preparing a. 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, acetonitrile, Trahydrofuran, dioxane, dichloromethane, toluene, ethanol or water can be exemplified. These solvents are used alone or in a mixture at an arbitrary ratio. Examples of the palladium complex used in this reaction include palladium chloride, palladium acetate, acetyl acetonato palladium, and tetrax Phenylphosphine) palladium and the like. Examples of the nickel complex used in this reaction include bis (acetylacetonato) nickel, bis (1,5-cyclooxengen) nickel, and tetrakis (triphenylphosphine) nickel. These palladium or nickel complexes are used in the range of 0.001 to 1 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (VI). When a ligand for a palladium or nickel complex is used in this reaction, triphenylphosphine, tri0-tolylphosphine, tri1-2-furylphosphine, 1,2-bis (diphenyl) Examples thereof include phosphino) ethane, 1,1,1-bis (diphenylphosphino) phenyl, and 2,2,1-bis (diphenylphosphino) -11,1, -binaphthyl. These ligands are used in the range of 0.2 to 5 equivalents, preferably 0.3 to 3 equivalents, based on the palladium or nickel complex. When X of the compound (VI) is 0 S 0 ₂ R ^{1 3,} with a palladium or nickel complex, it can be used copper iodide or lithium chlorambucil I de like if necessary. This reaction is preferably carried out in the presence of a suitable base. For example, organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, etc .; Examples thereof include inorganic bases such as sodium, sodium carbonate, calcium 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 (VI). The cross-force pulling reaction in this step can be carried out at room temperature to 150 ° C, preferably at 50 to 120 ° C. Further, when using a Y is B (R ^{1 5)} is not a ₂ compound of the cross power Uz pre ring compounds in the reaction of this step (VII) as a starting material, the compound (VI) or the compound (VII) (wherein Y is B (Not R1 ⁵ ) ₂ ) and HB (R ^{1 5} ) ₂ Or (B (R ^{1 5)} _{2) 2} is reacted with a compound obtained (VI) (X is B (R ^{1 5)} 2) or the compound (VII) (丫8 ^{(1 5)} ₂₎ of engagement things (VII) (wherein Y is not a B (R ^{1 5)} ₂₎ or the compound

Compound (VIII) can also be produced by reacting (VI). The compound (VI) (X is B (R ¹⁵ ) ₂ ) or compound (VII) (Y is B (R ¹⁵ ) ₂ ) and the ring A 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.

 (Fifth process)

In this step, the protecting group of the amino group of the compound (VIII) (R \ R ² , R ³ , A ring, B ring and C ring are the same as described above) is converted into a hydrogen atom, and the compound (IX) ( R \ RA ring, B ring and C ring are the same as described above). This step is carried out, for example, by hydrogenating reductively when R ³ is a phenylmethyl group. When a palladium catalyst is used, palladium carbon, palladium hydroxide or the like is used. The hydrogen donor is hydrogen gas, ammonium formate, hydrazine or the like. As the solvent to be used, a polar solvent such as ethanol or methanol is used.

 (Sixth process)

In this step, compound (IX) (RR ² , ring A, ring B and ring C are the same as described above) is acylated to produce compound (XI). This step is for example R ⁷ is a bromine atom, when n is 1, blanking opening Moasechiruburo mi de a promo acetylating agent, Ru performed using promo acetylchloride Li de like. This reaction is preferably carried out in the presence of a suitable base. For example, organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, etc., and carbonic acid Sodium hydrogen, sodium carbonate, carbon dioxide realm, carbon dioxide Examples thereof include inorganic bases such as lime, cesium carbonate and triphosphate lysate. 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, acetonitrile, Examples thereof include tetrahydrofuran, dioxane, dichloromethane, and toluene. These solvents may be used alone or as a mixture in any ratio.

 (Seventh process)

In this step, the compound (XI) with R ⁷ R ⁹ in the ^{(R \ R 2, R 7} , A ring, B ring and C ring are the same) (R ⁹ is as defined above) is converted into, the compounds (ΧΙΠ) (R \ R ² , R ⁹ , ring A, ring B and ring C are the same as described above). This reaction can be carried out in the presence or absence of salt groups using HR ⁹ 1 to 2 0 equivalents. When a base is used, suitable bases include, for example, organic bases such as triethylamine, triptylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, sodium hydrogen carbonate, and sodium carbonate. Examples thereof include inorganic bases such as tritium, potassium carbonate, calcium carbonate, cesium carbonate, and tricalcium phosphate. When a solvent is used, an inert solvent that does not participate in the reaction, for example, N, N-dimethylformamide, sulfolane, acetonitrile, tetrahydrofuran, dioxane, dichloromethane, toluene, ethanol or water, etc. Is used.

 (XVII) (XVIII)

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

As shown in the ninth step, compound (XVIII) can also be produced from compound (XVII) and compound (XV). In this step, the compound (XV) is used in an amount of 1 to 10 equivalents of the compound (XVII), and an acid catalyst such as p-toluenesulfonic acid or sodium methoxide, potassium tert-butoxide, hydrogen hydride is used. N, N-dimethylforma in the presence of a base such as a stream 30 minutes to 48 hours at 50 to 10 ° C in solvents such as mid, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, toluene, and xylene It can be implemented by processing. Compound (XIII) can be produced from the obtained compound (xyni) 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 together with one or more pharmaceutically acceptable auxiliaries as a pharmaceutical composition, and a pharmacologically acceptable carrier, excipient ( For example, starch, lactose, calcium phosphate, calcium carbonate, etc., lubricants (eg, magnesium stearate, calcium talc, stearic acid, etc.), binders (eg, starch, crystalline cellulose, carboxymethyl cellulose, Gum arabic, polyvinylpyrrolidone, alginic acid, etc., disintegrants (eg, talc, carboxymethylcellulose, calcium, etc.), diluents (eg, aqueous solutions of saline, glucose, mannitol, lactose, etc.) ), Tablets, capsules, granules, powders It can be administered orally or parenterally in the form of preparations, fine granules, ampules or injections. 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, symptoms, etc. 0.001 to 300 mg / kg / day. The administration is performed, for example, once or several times a day. BEST MODE FOR CARRYING OUT THE INVENTION

 Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.

<Example 1>

N- [3,5-bis (trifluoromethyl) benzyl] — 7-chloro-1,2,3-dihydro1, N-dimethyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-Monobenzodiazine _ 6—Carboxamide (51.8 mg, 0.1 l Ommol) to 3-fluorophenylboric acid (42.0 mg, 0.3 ◦ mmo1), polymer-supported Radium (prepared by the method described in TetraHeadron Letters, Vol. 39, pp. 4287, 1999) (20. Omg, about 0.3% Pd), toluene (1 ml) , 1,4-dioxane (0.4 ml) and 2 mo 1/1 aqueous sodium carbonate solution (0.6 ml) were added, and the mixture was heated with stirring under an argon stream for 3 hours. After the reaction solution was filtered, methylene chloride was added, and the mixture was washed with a 2 mol / 1 sodium carbonate aqueous solution, 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 a yellow amorphous N- [3,5-bis (trifluoro). Methyl) benzyl] 1, 2,3-Dihydro-1, N-dimethyl-1 7- (3-fluorophenyl) -15-oxo-5H-pyrido [1,2,3-dΘ] 1-1,4 —Benzodiazine-16-carboxamide (435 mg, 75%) was obtained.

MS (EI) ^ A: 577 (M ⁺ )

_{HRMS (EI): C 29 H} 22 F 7 N 3 0 2 Calculated: 577.1600

 Found: 577.1628

<Example 2>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1,1, N-dimethyl-5-oxo-5H-pyri [1,2,3-dΘ] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 3-clophenylphenylboric acid (46.9 mg, 0 From 30 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) -1,2,3-dihydro-1,1-N-dimethyl-5-oxo-1 There was obtained 5H-pyrido [1,2,3-de] -11,4-benzodiazine-16-carboxamide (59.4 mg, 100%).

MS (EI) i »A: 593 (M ⁺ ) _{HRMS (EI): C 29 H} 22 C1F 6 N 3 0 2 Calculated: 593.1305

 Found: 593.1313

<Example 3>

By the same method as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3-dihydro-11, N-dimethyl-15-oxo-5H-pyri [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 3-ditrophenylborate (50.l mg, 0.1%). From 30 mm 01), N— [3,5-bis (trifluoromethyl) benzyl] —2,3—dihydro-1, N—dimethyl-1-7— (3-ditrophenyl) -1-5-oxo-1 5 H-pyrido [1,2,3-de] -1,4-benzodiazine-16-carboxamide (54.6 mg, 90%) was obtained. '

_{HRMS (EI): C 29 H} 22 F 6 N 4 0 4 Calculated: 604.1545

 Obtained value: 604.1549

<Example 4> Me

 ヽ, 0

 CF

N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-11, N-dimethyl-5-oxo-5H-pyridide was prepared in the same manner as in Example 1. [1,2,3-dΘ] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 3-aminophenylboronic acid (46.5 mg, 0.3 0 mm 0 1), 7- (3-aminophenyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1-1, N-dimethyl-5-oxo-5H-pyri [1,2,3-De] -1, 4-benzodiazine-16-carboxamide (30.7 mg, 53%) was obtained.

_{HRMS (EI): C 29 H} 24 F 6 N 4 0 2 Calculated: 574.1803

 Found: 574.1790

<Example 5>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-11, N-dimethyl-5-oxo-5H-pyrido [ 1, 2 ₃ 3 - de] one 1, 4-Benzojiajin one 6- Karubokisami de (5 1. 8 mg, 0. 1 O mmo l) and 3, 5-dichlorophenyl boric acid (5 7. 2 mg, 0. 3 0 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] _7— (3,5-dichlorophenyl) —2,3-dihydro 1, N-dimethyl-1 5 —Oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (43.2 mg, 69%) was obtained.

MS (EI) ^ A: 627 ( ⁺ )

_{HRMS (EI): C 29 H} 21 C1 2 F 6 N 3 0 2 Calculated: 627.0915

 Found: 627.0928

<Example 6>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-11, N—dimethyl-5-oxo-5H-pyrido [1 , 2,3-de] — 1,4-benzodiazine-1 6-carboxamide (51.8 mg, 0.1 O mmol) and 4-methylphenylborate (40.8 mg, 0.30 mm 0 From 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1,1-N-dimethyl 7— (4-methylphenyl) 1-5-oxo-5H-pyrido [ [1,2,3-dθ] —1,4-benzodiazine-16-carboxamide (37.4 mg, 65%) was obtained.

_{HRMS (EI): C 30 H} 25 F 6 N 3 0 2 Calculated: 573.1851

 Found: 573.1865

<Example Ί>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-1,1-N-dimethyl-15-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 4-methoxyphenylboronic acid (45.6 mg, 0 From 30 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl) benzyl-1,2,3-dihydro-7— (4-methoxypheny)

 1, N-Dimethyl-5-hydroxy-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (59.O mg,

100%).

MS (EI) 589 (M ⁺ )

_{HRMS (EI): C 30 H} 25 F 6 N 3 0 3 and to Calculated: 589.1800

 Found: 589.1799

<Example 8>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-1, N-dimethyl-15-oxo-5H-pyri [1, 2,3 -de] 1,1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 4-fluorophenylboronic acid (42.Omg ヽ 0.30) mm o 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-11, N—dimethyl-17- (4-fluorophenyl) -15-oxo-5H —Pyrido [1,2,3-de] -11,4-benzodiazine-16-carboxamide (32.8 mg, 57%) was obtained.

_{HRMS (EI): C 29 H} 22 F 7 N 3 0 2 Calculated: 577.1600

 Obtained value: 577.1605

<Example 9>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1, N-dimethyl-15-oxo-5H— Pyrido [1,2,3-de] —1,4—benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 4—clofenufenoboric acid (46.9) m: 0.30 mmo 1), N— [3,5_bis (trifluoromethyl) benzyl] -17— (4—chlorophenyl) 1-2,3—dihydro1-1, N—dimethyl 1-5-oxo-5H-pyrido [1,2,3-de] 1,4_benzodiazine-16-carboxamide (39.8 mg, 67%) was obtained.

_{HRMS (EI): C 29 H} 22 C1F 6 N 3 0 2 Calculated: 593.1305

 Found: 593.1284

<Example 10>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1,1, N-dimethyl-5-oxo-5H-pyri [1, 2, 3-d Θ] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.10 mm 01) and 3-chloro-1-fluorophenylboronic acid (52.3 mg, 0.30 mm 01) from N— [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-1-4-fluorophenyl) 1-2 , 3-Dihydro 1, N-dimethyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide (61.0 mg, 100 %).

_{HRMS (EI): C 29 H} 21 C1F 7 N 3 0 2 Calculated: 611 & 1211

 Found: 611.1190

<Example 11>

N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-1,1-N-dimethyl-15-oxo-5H —Pyrido [1,2,3-de] — 1,4-I-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 4-methyl-3-nitrophenylborate (54.3 mg, 0.30 mm 0 1) from N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1, N-dimethyl-7- (4-methyl-13-ni (Trophenyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (54.2 mg, 88%) was obtained.

_{HRMS (EI): C 30 H} 24 F 6 N 4 0 4 and to Calculated: 618.1702

 Found: 618.1709

<Example 1 2>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-1, N-dimethyl-1-methyl-5-oxo-5H— Pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 l Ommol) and 2-methoxyphenyl boric acid (45.6 mg , 0.30 mm 0 1) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydroxy Ι, Ν-dimethyl-17 (2-methoxyphenyl) -1-5-oxo One 5-perido [1,2,3-de] -1,4-benzodiazine-16-carboxamide (40.5 mg, 69%) was obtained.

_{HRMS (EI): C 3 oH} 25 F 6 N 3 0 3 Calculated: 589.1800

Found: 589.1827 Example 1 3>

By the same method as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-1,1-N-dimethyl-15-oxo-5H-pyrido [1,2,3-dΘ]-1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 2,4-dichlorophenylborate (57.3 mg, 0 30 mm o 1) from N- [3,5-bis (trifluoromethyl) benzyl] -17- (2,4-dichlorophenyl) 1-2,3-dihydro ,,-dimethyl-5- Oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (40.8 mg, 65%) was obtained.

_{HRMS (EI): C 29 H} 21 C1 2 F 6 N 3 0 2 Calculated: 627.0915

 Found: 627.0923

<Example 14>

In the same manner as in Example 1, N— [3,5-bis (triflurylmethyl) benzyl] —7-chloro-2,3-dihydro-1,1-N-dimethyl-15-oxo-5H— Pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 1-naphthyl boric acid (51.6 mg, 0.1 3 0 m mol), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-one, Ν—dimethyl-one 7— (1-naphthyl) —5-—oxo-one 5 1-Pyrido [1,2,3-dθ] —1,4,1-benzodiazine-16-carboxamide (58.2 mg, 95%) was obtained.

_{HRMS (EI): C 33 H} 25 F 6 N 3 0 2 Calculated: 609 & 1851

 Found: 609.1862

<Example 15>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-1, N-dimethyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-hexylboxamide (51.8 mg, 0.1 Ommol) and 3-methoxyphenylboronic acid (45.6 mg, From 0.30 mm o 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1, N—dimethyl-1-7— (3-methoxyphenyl) —5 —Oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (21.5 mg, 36%) was obtained.

_{HRMS (EI): C 30 H} 25 F 6 N 3 0 3 Calculated: 589.1800

 Found: 589.1801 Example 16>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro 1, N—dimethyl-5-oxo-5H-pyrido [1 , 2,3—de] — 1,4,1-benzodiazine-6-carboxamide (51.8 mg, 0.1 0 mmo 1) and 3— (trifluoromethyl) phenylborate (57.0 mg, 0.30 mmol) from N— [3,5—bis (trifluoromethyl) benzyl] —2,3 —Dihydro-1,1-N-dimethyl-5-oxo7— [3— (Trifluoromethyl) phenyl] -5H—pyrido [1,2,3—de] —1,4-benzodiazine-6— Carboxamide (62.7 mg, 100%) was obtained.

_{HRMS (EI): C 30 H} 22 F 9 N 3 0 2 Calculated: 627.1568

 Found: 627.1567

<Example 1 Ί>

According to the same method as in Example 1, N— [3,5-bis (triflurylmethyl) benzyl] -17—chloro-1,2,3-dihydro-1,1-N-dimethyl-5-oxo-5 H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (51.8 mg, 0.1 Ommol) and 3-methylphenylboronic acid (40.8 mg, From 0.30 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1--1, N-dimethyl-1-7— (3-methylphenyl) -5— Oxo-1H-pyrido [1,2,3-dΘ] —1,4-benzodiazine-16-carboxamide (57.3 mg, 100%).

_{HRMS (EI): C 3b H} 25 F 6 N 3 0 2 Calculated: 573.1851

 Found: 573.1862

<Example 18>

By the same method as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-1,5-N-dimethyl-15—oxo-5H— Pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (51.8 mg, 0.10111111101) and phenylphosphoric acid (36.6 mg, 0.1%). From 30 mm o 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1, N-dimethyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-De] —1,4-benzodiazine-16-carboxamide (27.2 mg, 9%) was obtained.

_{HRMS (EI): C 29 H} 23 F 6 N 3 0 2 Calculated: 559.1694

 Found: 559.1682

<Example 19>

1-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] _7_chloro-2,3-dihydro-N-methyl_5-oxo—5H-pyrido [1,2,3- de]-1, 4-benzodiazine

6-Carboxamide (3.0 g, 5.1 mmol) and 3-methoxyphenylboronic acid (1.54 g, 10 mmol) were added to toluene (100 ml), 1,4-dioxane. (40 ml) and 2 mol / l sodium carbonate aqueous solution (30.5 ml), and dissolved in the mixture. Tetrax (triphenylphosphine) palladium (584 mg, 0.1%) was added. Then, the mixture was heated and refluxed at 100 ° C. for 3 hours. Methylene chloride was added to the reaction solution, and the mixture was washed with a 2 mol / l sodium carbonate aqueous solution 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 = 5: 1), and the yellow amorphous 1-benzyl-1-N- [35-bis (tol) Trifluoromethyl) benzyl] — 2, 3-dihydro

7- (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (3.33 g, 9 9%).

_{HRMS (EI): C 36 H} 29 F 6 N 3 0 3 and to Calculated: 665.2113

Found: 665.2140 <Example 20>

According to a method similar to that in Example 19, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro-1-N-methyl-15-oxo-5H —Pyrido [1,2,3-dθ] ― 1,4-benzodiazine-16-carboxamide (800 mg, 1.4 mmol) and phenylboric acid (494 mg, 4.1 mmol) From 1), 1-benzyl-1-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N-methyl-1-5-oxo-1 7-phenyl-1-5H-pyrido [ [1,2,3-de] —1,4-benzodiazine-16-carboxamide (804 mg, 94%) was obtained. MS (FAB ⁺ ) i »A: 636 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 28 F 6 N 3 0 2 Calculated: 636 & 2086

 Found: 636.2050

<Example 21>

According to a method similar to that in Example 19, 1-benzyl-1-N- [3,5bis (trifluoromethyl) benzyl] -17-cyclo-1,2,3-dihydro-1-N-methyl-1-5 Oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (1.0 g, 1.7 mmo1) and 4-fluorophenylboronic acid (41 lmg, 3.4 mm 01) from 1-benzyl-1-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (4-fluorophenyl) -1-N-methyl 1-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (1.03 g, 94%) was obtained.

MS (FAB ⁺ ) Λ / Α: 654 (Μ + Η ⁺ )

_{^{HRMS (FAB +): C 35}} H 2T F 7 N 3 0 2 Calculated: 654.1992

 Found: 654.1966

<Example 22>

Me

 , LT ヽ, 0

 CF

According to a method similar to that in Example 19, 1-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] —7—chloro-2,3—dihydro-N-methyl-5—oxo-5 H—Pyrido [1,2,3-de] -1,4-benzodiazine-6-carboxamide (60 Omg: 1.0 Ommol) and 3-fluorophenylboric acid (246 mg, 2 Ommol) from 1-benzyl-1-N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (3-fluorophenyl) -1-N-methyl-5—oxo-1 There was obtained 5H-pyrido [1,2,3-de] 1-1,4-monobenzodiazine-16-carboxamide (635 mg, 96%).

MS (FAB ⁺ ) Λ / Α: 654 (Μ + Η ⁺ )

_{^{HRMS (FAB +): C 35}} H 27 F 7 N 3 0 2 Calculated: 654.1992

Obtained value: 654.1973 Example 2 3>

According to a method similar to that in Example 19, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro N-methyl-15-oxo-5H —Pyrido [1,2,3-dΘ]-1,4-benzodiazine-16-carboxamide (1.00 g, 1.7 mmo 1) and 2-fluorophenylboric acid (41 mg, 3.4 mmo 1) from 1-benzyl-1-N_ [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-7— (2-fluorophenyl) -1-N-methyl-5-oxo One 5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (1.04 g, 95%) was obtained.

_{HRMS (EI): C 35 H} 26 F 7 N 3 0 2 Calculated: 653.1913

 Found: 653.1943

<Example 24>

Me

 IT ヽ ヽ 0 F

By the same method as in Example 19, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-1N-methyl-5-oxo-1 5 H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (5.0 g: 8.4 mmol) and 3,4-difluorophenylborate (5. 32 g, 17 mmol, 50% aqueous solution of tetrahydrofuran in water), 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] — 7— (3,4-difluorophenyl) 1,2,3-Dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (4.96 g, 88% ).

_{HRMS (EI): C 35 H} 25 F 8 N 3 0 2 Calculated: 671 & 1819

Obtained value: 671.1790 Example 2 5>

According to a method similar to that in Example 19, 1 1-benzyl-N— [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro N-methyl-15-oxo-5H —Pyrido [1,2,3-de] —1,4-I-benzodiazine-16-carboxamide (5.0 g, 8.4 mmol) and 2,4-difluorophenylboric acid (2.65 g) , 17 mmol) from 1 1 benzyl N— [3,5-bis (trifluoromethyl) benzyl] —Ί— (2,4-difluorophenyl) 1-2,3—dihydro-1-N-methyl 5-Oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (4.14 g, 73%) was obtained.

_{HRMS (EI): C 35 H} 25 F 8 N 3 0 2 and to Calculated: 671.1819

Obtained value: 671.1790 Example 2 6>

1 Benzyl mono N— [3,5—Bis (trifluoromethyl) benzyl] 1,2,3-dihydro 7— (3—Methoxyphenyl) —N—Methyl mono 5—Oxo-5H pyrid [1,2,3-de]-1,4-1-benzodiazine-16-carboxamide (3.20 g, 4.8 mmo1) was suspended in methanol (60 ml) and 10%. An aqueous solution (3 ml) of palladium on activated carbon (320 mg) and ammonium formate (1.22 g ヽ 19 mmo 1) was added, and the mixture was heated under reflux for 5 hours. After the reaction solution was filtered and concentrated under reduced pressure, water was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent is distilled off and N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-17- (3-methoxyphenyl) -1-N-methyl-5 of pale yellow amorphous Oxo-5H-pyrido [1,2,3—de] —1,1benzo-diazine-16-carboxamide (2.75 g, 9.9%) was obtained.

_{HRMS (EI): C 29 H} 23 F 6 N 3 0 3 Calculated: 575.1644

 Found: 575.1664

<Example 2 Ί>

F

By the same method as in Example 26, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro N-methyl-5-oxo-1 7-phenyl From 5H-pyrido [1,2,3-de] -1,4,4-dibenzodiazine-16-carboxamide (4.40 g, 6.9 mm 01), N— [3,5—bis ( Trifluoromethyl) benzyl] 1,2,3-dihydro-1-N-methyl-5-oxo-7-phenyl-5H-pyrido [1,2,3-dθ] — 1,4-benzodiazine-1 6 —Carboxamide (3.75 g, 99%) was obtained. MS (FAB ⁺ ) 2 »: 546 (M + H +)

_{^{HRMS (FAB +): C 28}} H 22 F 6 N 3 0 2 Calculated: 546.1616

 Obtained value: 546.1621

<Example 28>

Me

, According to a method similar to that in Example 26, 1-benzyl-1-N- [3,5bis (trifluoromethyl) benzyl] -12,3-dihydro-17- (4-fluorophenyl) -1-N-methyl From 1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (1.00 g, 1.53 mmol), N— [ 3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (4-fluorophenyl) -N-methyl-5-oxo-5H-pyrido [12,3-de] —1, 4-benzodiazine-16-carboxamide (753 mg, 87%) was obtained.

MS (FAB ⁺ ) / »: 564 (M + H ⁺ )

_{^{HRMS (FAB +): C 28}} H 21 F Y N 3 0 2 Calculated: 564.1522

 Found: 564.1528

<Example 2 9>

According to a method similar to that of Example 26, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1-7-

(3-fluorophenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (4.35 g, 6. 7 mm 0 1), N— [3, 5—

(Trifluoromethyl) benzyl] 1, 2, 3-dihydro 1 7-(3 —Fluorophenyl) -1-N-methyl-1-5-oxo-5 H-pyrido [12,3-de] -1, 4-benzodiazine-16-carboxamide (379 g, 100%) was obtained. Was.

MS (FAB ⁺ ) 7 »: 564 (M + H ⁺ )

_{^{HRMS (FAB +): C 28}} H 21 F 7 N 3 0 2 and to Calculated: 564.1522

 Found: 564.1517

<Example 30>

According to a method similar to that of Example 26, 1 1-benzyl-2-N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1 7-

(2-Fluorophenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3—de] —1,4-benzodiazine-16—carboxamide (1.00 g, 1.5 mm ol), N— [3,5-bis

(Trifluoromethyl) benzyl] —2,3-Dihydro-7— (2-Fluorophenyl) -1-N-methyl-5—oxo-5H—pyrido [12,3-de] —1,4— Benzodiazine-16-carboxamide (863 mg, 100%) was obtained.

_{HRMS (EI): C 28 H} 20 F 7 N 3 0 2 Calculated: 563.1444

Found: 563.1440 Example 3 1>

According to a method similar to that in Example 26, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] —7— (3,4-difluoromethylphenyl) 1-2,3-dihydro-1-N— Methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-force From ruboxamide (4.827.2 mm 0 1), N— [3 , 5 Bis (trifluoromethyl) benzyl] 1-7— (3,4-Difluorophenyl) 1-2,3-Dihydro-1-N-methyl-1-5-oxo-5H-pyrido [1,2,3- de]-1,4-benzodiazine-16-carboxamide (3.98 g, 95%) was obtained.

_{HRMS (EI): C 28 H} lg F 8 N 3 0 2 Calculated: 581.1350

Obtained value: 581.1354 Example 3 2>

According to a method similar to that in Example 26, 1-benzyl-1-N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-difluoromethylphenyl) 1-2,3-dihydro-1-N-methyl 1-5—oxo-5H—pyrid [1,2,3-de] -1,4,4-benzodiazine-16—potassium (4.04 g, 6.0 mmo1), N— [ 3,5—Bis (trifluoromethyl) benzyl] — 7— (2,4-difluorophenyl) 1-2,3—dihydro-1-N-methyl-5-oxo-5H-pyrido [1,2,3 -de] — 1,4 benzodiazine 16 — carboxamide (3.444 g, 98%) was obtained.

_{HRMS (EI): C 28 H} 19 F 8 N 3 0 2 and to Calculated: 581.1350

 Found: 581.1334

<Example 33>

N- [3,5-bis (trifluoromethyl) benzyl] — 2,3—dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,, [2,3-de] — 1,4-benzodiazine-6-carboxamide (200 mg, 0.35 mmol), sodium carbonate (73.8 mg, 0.70 mmol), bromo Ethyl acetate (70. Omg :, 0.42 mm01) and ethanol (3 ml) were added, and the mixture was stirred at 80 ° C for 12 hours. After the reaction solution was filtered, water was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography.

(Ethyl acetate) to give a yellow amorphous N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-11

[(Ethoxycarbonyl) methyl] 1 7- (3-methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de]

1,4-benzodiazine-16-carboxamide (60.9 mg, 26%) was obtained.

MS (EI) 2 »: 661 (M +)

<Example 3 4>

N— [3,5-bis (trifluoromethyl) benzyl] —2,3 —Dihydro 1 — [(Ethoxycarbonyl) methyl] 1 7— (3—Methoxyphenyl) 1 N—Methyl 1 5—Oxo 1 5 H—Pyrido [1,

2,3 -de]-1,4-I-benzodiazine-16-carboxamide (40.0 mg, 61 / mol) was dissolved in ethanol (0.5 ml), and 1 mo1 / 1 Aqueous aqueous solution (0.1 ml) was added, and the mixture was stirred at room temperature for 3 hours. 1 molZ 1 hydrochloric acid (0.1 ml) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography.

Purified with (methylene chloride: methanol = 5: 1), colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -1- (carboxylmethyl) 1-2,3-dihydro 7- (3-Methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrid [1,2,

[3-de] 1-1,4-I-benzodiazine-16-carboxamide (34.3 mg, 89%) was obtained.

MS (EI) / »A: 589 (M-C0 2 +) Ku Example 3 5>

N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro 11- (carboxymethyl) -17- (3-methoxyphene) — N-Methyl-5-oxo-5H-pyrido [1,2,3-dθ] — 1,4-benzodiazine-16-carboxamide (19.6 mg, 31 / mo 1) and N —Chlorination of methylbiperazine (3.7 mg, 37 / m 0 1) and 1- (3-dimethylaminopropyl) -1-3-ethylethyl porposimide hydrochloride (7.1 mg, 37, πι 0 1) The mixture was stirred in methylene (0.5 ml) at room temperature for 3 hours. Methylene chloride was added to the reaction solution, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: methanol 2 5: 1), and yellow amorphous N- [3,5-bis (trifluoromethyl) benzyl] was obtained. — 2,3—Dihydro 7— (3-Methoxyphenyl) -N-methyl-1 — [(4—Methylbiperazinyl) carbonylmethyl] —5-Oxo-1 5H—Pyrido [1,2,3 -de] —1,4-Monobenzodiazine—6-carboxamide (19.7 mg, 89%) was obtained.

_{HRMS (EI): C 36 H} 35 F 6 N 5 0 4 Calculated: 715.2593

 Found: 715.2595

<Example 3 6>

N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3 Jihi Draw 7— (3-Methoxyphenyl) -N-methyl-1-5-oxo-5H-pyrido [1,2,3-dθ] —1,4, -Benzodiazine-6-carboxamide (25) 0.1 mg, 43 m 0 1) was dissolved in methylene chloride (1 ml), and pyridine (17.2 mg, 0.22 mmo 1) and methanesulfonyl chloride (6.0 mg, 52 mo 1 ) Was added and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with methylene chloride, washed sequentially with water, a saturated aqueous solution of sodium hydrogen carbonate, a 10% aqueous solution of citric acid and a saturated saline solution, and then dried over anhydrous sodium sulfate. The solvent is distilled off to give a colorless amorphous N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 1- (methanesulfonyl) -17- (3-methoxyphenyl) There was obtained 1 N-methyl-15-oxo-5H-pyrido [1,2,3-de] -11,41-benzodiazine-6-carboxamide (27 mg, 96%).

_{HRMS (EI): C 30 H} 25 F 6 N 3 O 5 S Calculated: 653.1419

 Found: 653.1412

<Example 3 7>

In the same manner as in Example 36, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxy) Phenyl) Single N- methyl one 5- Okiso one 5 H- pyrido [1, 2, 3 - de ] - 1 5 4- Benzojiajin one 6- Karubokisami de (2 5. 0 mg, 4 3 m 0 1) and From acetic anhydride (5.5 mg, 54 zmol), 1-acetyl-1N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-7- (3-methoxyphenyl) -1 N-Methyl-1-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (26.8 mg, 100%) was obtained.

_{HMS (EI): C 31 H} 25 F 6 N 3 0 4 Calculated: 617.1749

 Obtained: 617.1760

<Example 3 8>

N- [3,5-bis (trifluoromethyl) benzyl] 111- (mo-acetyl) 1,2,3-dihydro-N-methyl-5-oxo-1 7-phenyl-1 5H-pyrido [1, 2,3—de] — 1,4-Benzodiazine-16-carboxamide (30.0 mg, 45 zm 01) is dissolved in methylene chloride and pyrrolidine (3.9 mg, 55〃) mo 1) and polymer-supported morpholine (100 mg, 3.5 to 4.0 mm o 1 N / g) and stirred at room temperature for 24 hours. After the reaction solution was filtered and the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (methylene chloride: ethanol = 1: 0: 1) to obtain yellow amorphous N— [3,5- Bis (trifluoromethyl) benzyl] — 2,3-dihydro-1-N-methyl-5-oxo-7-phenyl-11- (1-pyrrolidinylacetyl) -15H-pyrido [1,2,3 -de] — 1,4-Benzodiazine-16-carboxamide (22.2 mg, 75%) was obtained.

MS (FAB ⁺ ) / »A: 657 (M + H ⁺ )

_{^{HMS (FAB +): C 34}} H3iF 6 N 4 0 3 and to Calculated: 657.2300

 Obtained value: 657.2303 Example 3 9>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro N-methyl-15-oxo-17-phenyl one 5 H- pyrido [1, 2, 3- de] - 1, 4- Benzojiajin one 6- Karubokisami de (3 0. O mgヽ4 5 mo l) and Moruhori emissions (4. 7 mg ₅ 54 z From mo 1), N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N-methyl-11- (4-morpholinyla-cetyl) -1,5-oxo-1 7-Fenr ル ー 5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (30. 3 mg, 100%) was obtained.

MS (FAB ⁺ ) i »A: 673 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 31 F 6 N 4 0 4 Calculated: 673.2250

 Found: 673.2242

<Example 40>

According to a method similar to that in Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro-1-N-methyl-15-oxo-17- Phenyl 5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (30.O mg, 45 / m01) and 4- (1-pyrrolidinyl) ) from Piperi Jin (8. 4 mg ₃ 5 5〃Mo l), N- [3, 5-bis (g Li Furuoromechiru) benzyl] - 2, 3 dihydric mud one N- methyl one 5-oxo-1 7-phenyl-1-[((4- (1-pyrrolidinyl) piperidinyl) acetyl] -15H-pyrido [1,2,3-dΘ] -1,4-benzodiazine-1 6-carboxami (33.2 mg, 100%).

MS (FAB ⁺ ) ^ A: 740 (M + H ⁺ )

_{HMS (FAB +): C 39} H 4 () F 6 N 5 0 3 Calculated: 740.3035

 Found: 740.3062

<Example 4 1>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -12,3-dihydro N-methyl-15-oxo-17— Phenyl-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (30.0 mg, 45 mol) and 1-methylbiperazine (5.5 mg, 55 From mo 1), N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1-N-methyl-1 — [(4-methylpiperazinyl) acetyl] —5-oxo-1 7— Hueneru 5 H — pyrido [1, 2, 3-d Θ Ί — 1, 4 — benzodiazine-1 6 — power Obtained ruboxamide (30.8 mg, 100%)

MS (FAB ⁺ ) y »A: 686 (M + H ⁺ )

_{^{HMS (FAB +): C 35}} H 34 F 6 N 5 0 3 Calculated: 686.2566

 Found: 686.2542

<Example 4 2>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (bromoacetyl) -12,3-dihydro-1-N-methyl-15—oxo-17— Phenyl-5H-pyrido [1,2,3-dθ]-1,4,1-benzodiazine-16-carboxamide (30.0 mg, 45〃mo1) and pyridin (4.6 mg, 5 4 // m 0 1), N— [3,5—bis (trifluoromethyl) benzyl] —2,3—dihydro-1N—methyl-1 7—Feuniru 1 1 (1 1 Piperidinyl acetyl) 1-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (30.2 mg, 100%) was obtained.

MS (FAB ⁺ ) / BA: 671 (M + H ⁺ )

HRMS (FAB ⁺ ): Calculated as C ₃₅ H ₃₃ F ₆ N ₄ 0 ₃ : 671 · 2457 Obtained value: 671.2466 Example 4 3>

In the same manner as in Example 38, N- [3,5-bis (trifluoromethyl) benzyl] -11- (promoacetyl) -12,3-dihydro-1N-methyl-5-oxo-17-phenyl 1-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (30.0 mg, 45〃mo1) and 41- (1-piperidinyl) piperidine (9.1 l mg, 54 mol) from N— [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro N-methyl-5-oxo-7-phenyl-1— [ (4-1 (1-piperidinyl) piperidinyl) acetyl] — 5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (26.2 mg, 77) was obtained. .

MS (FAB ⁺ ) i »A: 754 (M + H ⁺ )

_{^{HMS (FAB +): C4oH 42}} F 6 N 5 0 3 Calculated: 754.3192

Obtained: 754.3173 <Example 4 4>

In the same manner as in Example 38, N- [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -1,2,3-dihydro N-methyl-5-oxo-7-phenyl-1 5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (30.0 mg, 45〃mo1) and 4-hydroxypiperidine (5.5 mg)ヽ 54 zmol) from N— [3,5-bis (trifluoromethyl) benzyl] _2,3-dihydro 1-[[(4-hydroxypiperidinyl) acetyl] — N-methyl-1-5-oxo One 7-phenyl-5H-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide (23.0 mg, 74%) was obtained.

MS (FAB ⁺ ) i »A: 687 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 4 Calculated: 687 & 2406

 Found: 687.2398

<Example 4 5>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -1,2,3-dihydro-1-N-methyl-15-oxo-7— phenylene Lou 5 H- pyrido _{[1 5 2, 3- de]} - 1, 4- Benzojiajin one 6- Karubokisami de (3 0. 0 mg, 4 5 / mo 1) and Jimechiruami emissions hydrochloride (4.4 mg 5 4 mol) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-([dimethylamino] acetyl) 1-N-methyl-1-5-oxo-1 7-Fenil-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (14.8 mg, 52%) was obtained.

MS (FAB ⁺ ) »A: 631 (M + H ⁺ )

_{^{HRMS (FAB +): C g2}} H 29 F 6 N 4 0 3 Calculated: 631.2144

 Found: 631.2129

<Example 4 6> Me

 CF

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro-1-N-methyl-15-oxo17 —Feniru 5 H—Pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide (30.0 mg, 45 mol) and ammonia (6.2 mg, 9 1 mol, 25% aqueous solution) from 1- (aminoacetyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1-N-methyl-5-oxo-1 7- Feuniru 5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (24.1 mg, 89%) was obtained.

MS (FAB ⁺ ) i »A: 603 (M + H ⁺ )

_{^{HRMS (FAB +): C 30}} H 25 F 6 N 4 0 3 Calculated: 603.1831

 Obtained value: 603.1858

<Example 47>

Me

 ヽ o

 CF.

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (bromoacetyl) -12,3-dihydro 7- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dθ] 1,1,4-benzodiazine-16-carboxamide (200 mg, 0.29 mmol) and pyro From lysine (50.0 mg, 0.70 mmol), N— [3,5-bis

(Trifluoromethyl) benzyl] 1, 2,3-dihydro-7- (3-methoxyphenyl) 1 N-methyl-1 5-oxo-1 1- (1-pyrrolidinylacetyl) 1 5H-pyrido [1 , 2,3-de] 1-1,4-benzodiazine-16-carboxamide (174 mg, 88%) was obtained. ,

MS (FAB ⁺ ) T »A: 687 (M + H ⁺ )

Image _{S (FAB +): C 35} H 33 F 6 N 4 0 4 Calculated: 687.2406

 Found: 687.2416

<Example 4 8>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -1,2,3-dihydro-17— (3-methoxyphenyl) one N- methyl-5-Okiso one 5 H- pyrido [1, 2, 3 - de ] - 1 3 4- Benzojiajin one 6 one Karubokisami de (2 0 0 mg, 0. 2 9 mmo l) and Moruhori down ( 6 0.O mg, 0.69 mmol), N— [3,5-bis

(Trifluoromethyl) benzyl] — 2,3-dihydro-1- 7- (3-methoxyphenyl) 1-N-methyl-11- (4-morpholinylacetyl) 1.5-oxo-5H-pyrido [1,, [2,3-de] 1-1,4-benzodiazine-16-carboxamide (18 lmg, 90%) was obtained.

MS (FAB ⁺ ) i »A: 703 (M + H ⁺ )

_{^{HS (FAB +): C 35}} H 33 F 6 N 4 0 5 Calculated: 703.2355

Obtained value: 703.2366 Example 4 9>

According to the same method as in Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro 7- (2-fluorophenyl) 1- N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16—carboxamide (60.O mg, 88 / mol) and pyridine lysine

(7.42 mg, 0.1 l O mmol) from N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro 7— (2-fluorophenyl) —N-methyl-1 —Oxo-1— (1-Pyrrolidinyl lacetyl) 1 5 H—Pyrido [1,2,3-dθ] — 1,4,1-Benzodiazine 1—6-carboxamide (31.3 mg, 5 3 %)

MS (FAB ⁺ ) sA: 675 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H3oF r N 4 03 and to Calculated: 675.2206

Obtained value: 675.2178 Example 50>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1— (bromoacetyl) -2,3—dihydro 7— (2-fluorophenyl) -1-N —Methyl-5—oxo-5H-pyrido [1,2,3-de] 11,4-benzodiazine-16-carboxamide (60.0 mg, 88 mol) and morpholine (9.1 mg, 0.1 l O mmol) from N— [3,5—bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (2—fluorophenyl) 1-N—methyl-1— (4 mol) (Holinyl acetyl) 1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-1 6-carboxamide (42.8 mg, 71%) was obtained. . MS (FAB ⁺ ) IBA: 691 (M + H ⁺ )

_{^{HRMS (FAB +): C G4}} H 30 F 7 N 4 0 4 Calculated: 691.2155

 Found: 691.2143

<Example 5 1>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] 1-1— (promoacetyl) -12,3-dihydro-17— (2-fluorophenyl) 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-1-6-carboxamide (60.0 mg, 88 zmol) and 4- From (1 -pyrrolidinyl) piperidine (16.1 mg, 0.10 mmo 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-7 — (2 —Fluorophenyl) 1 N-methyl-1 — [(4-(1 —pyrrolidinyl) piperidinyl) acetyl] — 5-oxox 5H-pyrido [1, 2, 3-de] — 1, 4 —Benzodiazine-6—carboxamide (48.4 mg, 73%) was obtained.

_{HRMS (EI): C 39 H} 38 F 7 N 5 0 3 Calculated: 757.2863

 Obtained: 757.2853

<Example 52>

According to a method similar to that of Example 38, N— [3,5_bis (trifluoromethyl) benzyl] —1- (promoacetyl) 1-2,3-dihydro 7— (3-fluorophenyl) 1 N-methyl-1-5-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-16—carboxamide (60.0 mg, 88 zmol) and pyrrolidine ( 7.4 mg, 0.1 l O mmol) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- 7— (3-fluorophenyl) -1-N-methyl-5 —Oxo-1 11 (1-1-pyrrolidinylacetyl) 1 5 H—Pyrido [1,2,3-dΘ] —1,4,1-benzodiazine-1 6-carboxamide (59.O mg, 100 %).

MS (FAB ⁺ ) ?: 675 (M + H ⁺ )

_{^{HRMS (FAB +): C 3}} 4H3oF 7 N 4 0 3 Calculated: 675.2206

 Found: 675.2220

<Example 53>

According to a method similar to that of Example 38, N— [3,5_bis (trifluoromethyl) benzyl] —1- (promoacetyl) -1,2,3-dihydro-17- (3-fluorophenyl) -1-N —Methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-161-carboxamide (60.0 mg, 88 、 mol) and morpholine

(9.1 l mg, 0.1 l O mmol) from N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro 7- (3-fluorophenyl) -1-N-methyl-1 1- (4-morpholinylacetyl) — 5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide (60.5 mg, 1 0 0%)

/ Then o

MS (FAB ⁺ ) isA: 691 (M + H ⁺ )

_{^{HRMS (FAB +): C g4}} H 30 F 7 N 4 04 Calculated: 691.2155

Measured value: 691,2131 Example 5 4>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro-17- (3-fluorophenyl) —N —Methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16—carboxamide (60.O mg, 88〃mol) and 4- (11-pyro Lysinyl) piperidine (16.1 mg, 0.10 mmo 1) to [N- [3,5-bis (trifluoromethyl) benzyl] —2,3—dihydro-7— (3 —Fluorophenyl) 1 N—Methyl-1 1 [[4- (1—Pyrrolidinyl) piperidinyl) acetyl] — 5 —Oxo-1 5H—Pyrido [1,2,3—de] —1,4,1 Benzodiazine-carboxamide (65.8 mg, 99%) was obtained.

_{HRMS (EI): C 39 H} 38 F 7 N 5 0 3 Calculated: 757.2863

 Obtained: 757.2866

<Example 5 5>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (promoacetyl) 1-2,3-dihydro-17- (4-fluorophenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (60.0 mg, 88 / mol) and pyrrolidine (7 4 mg, 0. L O mmol) from N— [3,5—bis (trifluoromethyl) benzyl] -1,2,3—dihydro-1 7— (4-fluorophenyl) 1N—methyl-1 5— Oxo 1-11 (1-pyrrolidinyl acetyl) 1 5H-pyrido [1,2,3-de]-1,4,1benzodiazine 16 -carboxamide (53.6 mg, 91%) Obtained.

MS (FAB ⁺ ) iz? A: 675 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 3 oF Y N 4 0 3 Calculated: 675.2206

Obtained value: 675.2227 Example 5 6>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] 111- (bromoacetyl) 1-2,3-dihydro-17 -— (4-fluorophenyl) ) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-161carboxamide (60.Om ;, 88 juo1) and morpholy N

(9. lmg, 0.1 l Ommol) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3—dihydro 7— (4-fluorophenyl) 1-N-methyl-1 4-Morpholinyl acetyl)-5-oxo-1 5 H-pyrido [1, 2, 3-de]-1, 4-benzodiazine-6-carboxamide (62.2 mg, 100%) ) Get pounded o

MS (FAB ⁺ ) / BA: 691 (M + H ⁺ )

_{^{HMS (FAB +): C 34}} H 30 F 7 N 4 0 4 Calculated: 691.2155

Actual value: 691.2188 Example 5 7>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -1,2,3-dihydro-17- (4-fluorophenyl) N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-161carboxamide (60.Omg, 88zmol) and N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1- (4-pyrrolidinyl) piperidine (16.1 mg, 0.10 mmo1) Fluorophenyl) 1-N-methyl-1-1 [(4- (1-pyrrolidinyl) piperidinyl) acetyl] — 5-oxo-1 5H-pyrido [1,2,3-dθ] 1-1,4-benzodiazi 6-Carboxamide (61.7 mg, 93%) was obtained.

_{HMS (EI): C 39 H} 38 F 7 N 5 0 3 and to Calculated: 757.2863

 Obtained value: 757.2910

<Example 5 8>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (bromoacetyl) -17- (3,4-difluorophenyl) 1-2,3- Dihidro N-methyl-1-oxo-5H-pyrido [1,2,3-de] -11,4-benzodiazine-6-carboxamide (60.0 mg, 88 zmol) and pyrrolidine (7.4 mg, 0.10 mm 0 1) from N— [3,5-bis (trifluoromethyl) benzyl] —di- (3,4-difluorophenol) 1-2,3-dihi Dro-N-methyl-5-oxo-1— (1-pyrrolidinylacetyl) -15H-pyrido [1,2,3-de] 1-1,4—benzodiazine-16-carboxamide (58.0 mg, 98%).

MS (FAB ⁺ ) i »A: 693 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 F 8 N 4 0 3 Calculated: 693.2112

Obtained value: 693.2130 Example 5 9>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] 1-1— (bromoacetyl) hydroxy— (3,4 difluorophenyl) 1-2,3 —Dihydro-1-N-methyl-1-5-oxo-5 H-pyrido [1,2,3-dΘ] -11,4-benzodiazine-6-carboxamide (60.Om :, 88〃mol ) And morpholine (9.1 mg, 0.1 l Ommol) from N— [3,5-bis (trifluoromethyl) benzyl] —7— (3,4-difluorophenyl) 1-2,3- Dihydro-1-N-methyl-1- (4-morpholinyl-2-acetyl) 1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide (54. 0 m ;, 89%).

MS (FAB ⁺ ) sA: 709 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 F 8 N 4 04 Calculated: 709.2061

 Found: 709.2067

<Example 60>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] 111- (bromoacetyl) —Ί- (3,4-difluorophenyl) 1-2,3-dihydro 1-N-methyl-1-5-oxo-5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine 6—carboxamide (60.0 mg, 88 / zmol) and 4 — (1-Pyrrolidinyl) piperidine (16.lmg, 0.10 mm 01) from N— [3,5—Bis (trifluoromethyl) benzyl] — 7— (3,4— Difluorophenyl) 1,2,3-dihydro N-methyl-1 — [(4- (1-pyrrolidinyl) biperidinyl) acetyl] 15-oxo-5H-pyrido [1,2,3-de] — 1,4-Benzodiazine-16-carboxamide (62.0 mg, 94%) was obtained.

_{HRMS (EI): C 39 H} 37 F 8 N 5 0 3 Calculated: 775.2769

 Found: 775.2792

<Example 6 1>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -7- (2,4-difluorophenyl) 1-2,3- Dihidro N-methyl-1-oxo-5H-pyrido [1,2,3-de] -11,4-benzodiazine-6-carboxamide (60.O mg, 88 mol) and pyrrolidine (7.4 mg, 0.1 l O mmol) from N- [3,5-bis (trifluoromethyl) benzyl] -7- (2,4-difluorophenyl) -1,2,3-dihydro 1-N-methyl-5-oxo-1- (1-pyrrolidinylacetyl) -5-H-pyrido [1,2,3-de] -1,4,1-benzodiazine-16-carboxamide (55.0 mg, 9 3%).

MS (FAB ⁺ ) iz? A: 693 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 F 8 N 4 0 3 Calculated: 693.2112

 Found: 693.2107

<Example 6 2>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1— (bromoacetyl) — (— (2,4-difluorophenyl) 1-2,3-dihydro 1 N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-6—carboxamide (60.0 mg, 88 mol) and moles N- [3,5-bis (trifluoromethyl) benzyl] -17- (2,4-difluorophenyl) -12,3-dihydro draw from holylene (9.1 mg, 0.1 mmol) N-methyl-1- (4-morpholinyl-2-acetyl) -1-5-oxo-5H-pyrido [1,2,3-dΘ] -1,4-benzodiazine-16-carboxamide (60.2 mg , 99%).

MS (FAB ⁺ ) i »A: 709 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 2g F 8 N 4 0 4 Calculated: 709.2061

 Found: 709.2051

<Example 6 3>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1— (promoacetyl) -17— (2,4 difluorophenyl) 1-2,3-dihydrodraw N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4,1-benzodiazine-6-carboxamide (60.0 mg, 88 zmol) and 4- From (1 -pyrrolidinyl) piperidine (16.1 mg: 0.10 mmo 1), N- [3,5-bis (trifluoromethyl) benzyl] -17- (2, 4-Difluorophenyl) 1,2,3-dihydro-1-N-methyl-1 — [(4- (1-pyrrolidinyl) piperidinyl) acetyl] 15-oxo-5H-pyrido [1,2,3- dΘ] —1,4 benzodiazine-16-carboxamide (54.0 mg, 82%) was obtained.

_{HRMS (EI): C 39 H} 37 F 8 N 5 0 3 Calculated: 775 & 2769

 Obtained value: 775.2772

<Example 6 4>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1— (promoacetyl) -12,3—dihydro 7_ (3-methoxyphenyl) -1-N— Methyl 5-oxo-5 H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (60.0 mg, 86 zmol) and 4_ (1-pyrro Lysinyl) piperidine (15.5 mg, 0.10 mmo 1) from N— [3,5—bis (trifluoromethyl) benzyl] —2,3—dihydro-7— (3— Methoxyphenyl) 1-methyl-5-oxo-1 — [(4- (1-pyrrolidinyl) piperidinyl) acetyl] -15-pyrido [1,2,3-de] -1,4 Nzodiazine 6-carboxamide (66.4 mg, 100%) was obtained.

_{HRMS (EI): C 4 QH} 41 F 6 N 5 0 4 Calculated: 769.3063

 Found: 769.3057

<Example 6 5>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (bromoacetyl) -1,2,3-dihydro 7- (3-methoxyphenyl) N-Methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.O mg, 86 zmol) and pyridine ( 8.5 mg, 0.1 l O mmol) from N— [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (3-methoxyphenyl) -1-N-methyl-1 1-oxo (1-piperidinyl acetyl) 15H-pyrido [1,2,3-de] 11,4-benzodiazine 16-carboxamide (54.6 mg, 90%) Get o

MS (FAB ⁺ ) BA: 701 (M + H ⁺ )

_{^{HRMS (FAB +): C 36}} H 35 F 6 N 4 0 4 Calculated: 701.2563

 Obtained value: 701.2587

<Example 6 6> Me

 CF

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] -11- (bromoacetyl) —2,3-dihydro-1 7— (3-methoxyphene) Nil) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0111, 866-111101) And 4— (1-Piberidinyl) piperidine (16.9 mg, 0.10 mmo 1) to ヽ N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-Methoxyphenyl) 1 N-methyl-1-5-oxo 1 — [(4- (1-Piperidinyl) piperidinyl) acetyl] —5H—pyrido [1,2,3-de] — 1,4-Benzodiazine-1 6-carboxamide (67.5 mg, 100%) was obtained.

顧_{S (EI): C 41 H} 43 F 6 N 5 0 4 Calculated: 783.3219

 Found: 783.3210

<Example 6 7>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) pentyl] —11- (promoacetyl) -12,3-dihydro 7- (3-methoxyphenyl) -1-N —Methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-161-carboxamide (60.0 mg, 86 zmol) and 4-hydroxy From piperidine (10.2 mg, 0.1 l Ommol), N— [35-bis (trifluoromethyl) benzyl] —2,3-dihydro-1--1 — [(4-hydroxypiperidinyl ) Acetyl]-Ί-1 (3-methoxyphenyl) 1-N-methyl-5-oxo-1 5 H-pyrido [1,2, 3-de]-1,4, 1-benzodiazine-6-carboxamide (61) .7 mg, 100%).

_{^{HRMS (FAB +): C 36}} H 35 F 6 N 4 0 5 Calculated: 717.2512

Measured value: 717.2503 Example 6 8>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1— (promoacetyl) -1,2,3-dihydro 7— (3-methoxyphenyl) -1-N— Methyl-5-oxo-5H-pyrido [1,2,3-de] 11,4-benzodiazine-161-carboxamide (60.0 mg, 86 mol) and dimethylamine (0.10 ml, 0.20 mmol, 2 mol / l methanol solution) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro_1-[(dimethylamino) acetyl] 1- (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (56. 9 mg, 100%).

MS (FAB ⁺ ) i »A: 661 (M + H ⁺ )

_{^{HRMS (FAB +): C 33}} H 31 F 6 N 4 0 4 Calculated: 661.2250

Measured value: 661.2281 Example 6 9>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (60. Omg, 86 mol) and methylamine (2 6. From O mg, 0.17 mmol, 30% ethanol solution), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxyphene) Nyl) 1-N-methyl-1 1-[(methylamino) acetyl] 1-5-oxo-5H-pyrido [1,2,3-dθ]-1,4, -benzodiazine-16-carboxamide (55) .7 mg, 100%).

_{HRMS (EI): C 32 H} 28 F 6 N 4 0 4 and to Calculated: 646.2015

Obtained value: 646.2010 Example 7 0>

In the same manner as in Example 38, N- [3,5-bis (trifluoromethyl) benzyl] 111- (bromoacetyl) 1-2,3-dihydro-17- (3-methoxypheny) 1) N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-161-carboxamide (60.0 mg, 86〃mol) and ammonia

(11.7 mg, 0.21 mm 01, 25% aqueous solution) from 1- (aminoacetyl) 1 N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihi 7- (3-Methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-d-]-1,4—benzodiazine-6-carboxamide (53. 3 mg, 98%).

_{HR S (EI): C 31} H 26 F 6 N 4 0 4 Calculated: 632.1858

 Found: 632.1852

<Example 7 1>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) -1-N —Methyl-5-oxo-5H-pyrido [1,2,3—de] —1,4-benzodiazine-161-carboxamide (60.0 mg, 86 / mol) and N, N, N, — From trimethylethylenediamine (10.3 mg, 0.1 mmol), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 1— [(N— (2- (dimethylamino) ethyl) -1-N-methylamino) acetyl] —7— (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de ]-1,4-I-benzodiazine-16-carboxamide (61.8 mg, 100 were obtained.

_{HRMS (EI): C 36 H} 37 F 6 N 5 0 4 Calculated: 717.2750

 Obtained: 717.2725

<Example 7 2>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (promoacetyl) -12,3-dihydro-17- (3-methoxyphene) Nil) 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0 mg, 86 mol) and N- [3,5-bis (trifluoromethyl) benzyl] _ 1 — [(Jetylamino) acetyl] 1,2,3-dihidedraw from getylamine (7.3 mg, 0.1 mmol) 7— (3-Methoxyphenyl) 1 N monomethyl 1 5-oxo-1 5 H-pyrido [1,2,3-de] 1-1,4,1-benzodiazine-1 6-carboxamide (59.3 mg, 100) I got

MS (FAB ⁺ ) i »A: 689 (M + H ⁺ )

_{^{HMS (FAB +): C 35}} H 35 F 6 N 4 0 4 Calculated: 689.2563

 Found: 689.2552

<Example 73>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] -11- (promoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) 1 N-methyl-5-hydroxy-5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-16—carboxamide (60.0 mg, 86 mol) and 2S— (1 -pyrrolidinylmethyl) pyrrolidine (15.5 mg: 0.10 mmo 1) from N— [3,5-bis (trifluoromethyl) benzyl]-1-[(2 S-( 1-pyrrolidinylmethyl) pyrrolidinyl) acetyl] —2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-5H-pyrido [1,2,3- de] — 1,4-benzodiazine-1 6-carboxamide (66.3 mg, 100 were obtained.

_{HRMS (EI): C 4 oH} 41 F 6 N 5 0 4 Calculated: 769.3063

 Observed value: 769.3080

<Example 7 4>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (promoacetyl) -12,3-dihydro 7- (3-methoxyphenyl) -1-N —Methyl-5—oxo-5 H—pyrido [1,2,3-de] 1-1,4-benzodiazine-16—carboxamide (60.0 mg, 86 juo1) and 1—methyl-4 -(Methylamino) piperidine (12.9 mg, 0.10 mmo1) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- (3 —Methoxyphenyl) 1 N—methyl — 1 [(N- (4- (1-methylbiperidinyl))-1-N-methylamino) acetyl] — 5-oxo-1 5H—pyrid [1,, [2,3-de] 1-1,4-benzodiazine-16-carboxamide (59.6 mg, 93%) was obtained.

_{HRMS (EI): C 38 H} 39 F 6 N 5 0 4 Calculated: 743.2906

 Found: 743.2903

<Example 7 5>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (bromoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) ) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dθ] -1, 4-benzodiazine-16-carboxamide (70.0 mg, 0.1 l Ommol) And 2,6-cis-dimethylmorpholine (13.9 mg, 0.12 mmo 1) from N— [3,5—bis (trifluoromethyl) benzyl] —2,3-dihydro-1 1 [(4-1 (2, 6 -cis-dimethylmorpholinyl)) acetyl] — 7— (3 -methoxyphenyl) 1 -methyl-1 5 -oxo-1 5 -pyridide [1, 2, 3 — de] —1,4-benzodiazine-16-carboxamide (66.O mg, 89%) was obtained. MS (FAB ⁺ ) »A: 731 (M + H ⁺ )

_{^{HRMS (FAB +): C 37}} H 3Y F 6 N 4 0 5 and to Calculated: 731.2668

 Found: 731.2670

<Example Ί 6> Me

F

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -12,3-dihydro-17- (3-methoxyphene) 1) N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (70.0 g, 0.1 l O mmol) N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydrodiamine from pyripurazine dihydrobromide (34.9 mg, 0.12 mmo 1) 7— (3-Methoxyphenyl) 1-methyl-1-5-oxo-1 — [(4-propylpiperazinyl) acetyl] -15-pyrid [1,2,3-de] —1,4— Benzodiazine-6-carboxamide (750 mg, 100%) was obtained.

_{HRMS (EI): C 38 H} 39 F 6 N 5 0 4 Calculated: 743.2906

 Found: 743.2906

<Example Ί Ί>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) -1-N —Methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzo, diazine-16 —carboxamide (70.0 mg, 0.1 l O mmol) and 1 —N- [3,5-bis (trifluoromethyl) benzyl] -2-, 3-dihydro 7- (3-methoxyphenyl) from methyl homopyrazine (13.7 mg, 0.12 mmol) 1) N-methyl-1-5-oxo- 1-[(4-methylhomopiperazinyl) acetyl] —5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-1-6-carboxami (62.1 mg, 84%).

_{HRMS (EI): C 37 H} 37 F 6 N 5 0 4 and to Calculated: 729 & 2750

 Observed value: 729.2760

<Example 7 8> Me

 Γ ヽ o

 CF

N- [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) one by the same method as in Example 38. N-Methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (70. O mg, 0.1 l O mmol) and 2— N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihidro 11-(((2-meth) methoxethylamine (9 O mg: 0.12 mm 01) Toxityl) Amino) Acetyl] — 7— (3-Methoxyphenyl) — N-methyl-1-5-oxo-5 H-pyrido [1,2,3-d d] -11,4-Benzodiazine-1-6-carboxami (70. O mg, 100%).

MS (FAB ⁺ ) z / A: 691 (M + H ⁺ )

_{^{HMS (FAB +): C 34}} H 33 F 6 N 4 0 5 Calculated: 691.2355

Actual value: 691.2343 Example 7 9>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (promoacetyl) -12,3-dihydro 7- (3-methoxyphenyl) -1-N— Methyl 5-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (70.0 mg, 0.1 l Ommol) and 2-hydroxy From shetylamine (7.3 mg, 0.12 mmol), N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-1-(((2- (Hydroxityl) aminio) acetyl] ― 7- (3-Methoxyphenyl) 1 N-methyl-5-oxo-5 H-pyrido [1,2,3-de] — 1,4,1-benzodiazine-6-carboxami (62.4 mg, 91%).

MS (FAB ⁺ ) i »A: 677 (M + H ⁺ )

_{^{HRMS (FAB +): C 33}} H 31 F 6 N 4 0 5 Calculated: 677.2199

 Obtained: 677.2200

<Example 80>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] -11- (bromoacetyl) -1,2,3-dihydro-17- (3-methoxyphenyl) ) 1-N-methyl-1-5-oxo-5H-pyrido [1,2,3-dθ] -11,4-benzodiazine-16-carboxamide (70. O mg, 0.1 l O mmol) And 4- (dimethylamino) piperidine dihydrochloride (26.5 mg, 0.13 mmo1) from N— [3,5-bis (trifluoromethyl) benzyl] -2,3- Dihydro-1-([4- (dimethylamino) piperidinyl) acetyl] -17- (3-Methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1 , 4 Benzodiazine-16-carboxamide (50.0 mg, 67%) was obtained.

_{HRMS (EI): C 38 H} 39 F 6 N 5 0 4 and to Calculated: 743 & 2906

 Found: 743.2899

<Example 8 1>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (bromoacetyl) -12,3-dihydro 7— (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-yl lipoxamide (250 mg, 0.36 mmol) and thiomorphol (50〃1, 0.50 mm 0 1), N— [3,5-

(Trifluoromethyl) benzyl] — 2,3-dihydro 7 — (3-Methoxyphenyl) 1 N—Methyl-15-oxo-1 1— (4-thiomorpholinylacetyl) 1 5 H— The pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (258 mg, 100%) was obtained.

MS (FAB ⁺ ) y »A: 719 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 4 S Calculated: 719.2127

Actual value: 719.2124 Example 8 2>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] -11- (bromoacetyl) —2,3-dihydro-17- (3-methoxyphenyl) 1) N-methyl-1-5-oxo-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (70.0 mg, 0.1 l Ommol) and 1,1—Dioxothiomorpholine (22.7 mg, 0.13 mmo 1) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-Methoxyphenyl) 1 N-methyl-5-oxo 1 — [(4-1 (1,1 dioxothiomorpholinyl)) a cetyl] —5H—pyrido [1, 2,3-dΘ] -1,4-benzodiazine-16-carboxamide (25.O mg, 33%) was obtained. MS (FAB ⁺ ) isA: 751 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 Calculated ₆ S: 751.2025

 Obtained value: 751.2058

<Example 8 3>

According to a method similar to that of Example 38, N- [3,5-bis (trifluoromethyl) benzyl] -11- (bromoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) 1) -Methyl-1-5-oxo-5-pyrido [1,2,3-de] —1,4-benzodiazine-16—carboxamide (40.0 mg, 57 zmol) and N- [3,5-bis (trifluoromethyl) benzyl] -111 [(4-methylbiperazinyl) acetyl] from methyl piperazine (6.9 mg ヽ 69〃mol) —Dihydro 7- (3-Methoxyphenyl) -N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-Benzodiazine-6-carboxamide (40. 4 mg, 97%).

_{HRMS (EI): C 36 H} 35 F 6 N 5 0 4 Calculated: 715.2593

 Obtained: 715.2630

<Example 84>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] -11- (bromoacetyl) -12,3-dihydro 7— (3-methoxyphenyl) -1-N— Methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16—carboxamide (40.0 mg, 57 zmol) and 4-acetylamino-4 From 1-phenylbiperidine (17.6 mg, 69 zmol), N- [3,5-bis (trifluoromethyl) benzyl] 1 1 1 [(4- (acetylamino) 1-4-phenylbiyl Peridinyl) acetyl] — 2,3-Dihydro 7- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4 There was obtained 1-benzodiazine-16-carboxamide (17.2 mg, 36%).

MS (FAB ⁺ ) z / A: 834 (M + H ⁺ )

_{^{HRMS (FAB +): C 44}} H 42 F 6 N 5 0 5 and to Calculated: 834.3090

 Found: 834.3118

<Example 8 5>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —11- (bromoacetyl) -12,3-dihydro 7_ (3-methoxyphenyl) -1- N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-pentazodiazine-161-carboxamide (300 mg, 0.43 mmol) and 4- ( From t-butoxycarbonyl) amino / piperidine (120 mg, 0.60 mmo 1), N— [3,5-bis (trifluoromethyl) benzyl] 1-1 —— ((( t-butoxycarbonyl) amino / piperidinyl) acetyl] — 2,3-dihydro-1 7 — (3-methoxyphenyl) 1-N-methyl-1 5 —oxo-1 5H-pyrido [1,2, [3-de] — 1,4-benzodiazine-16-carboxamide (351 mg, 100%) was obtained.

MS (FAB ⁺ ) iz? A: 816 (M + H ⁺ )

_{^{HMS (FAB +): C 41}} H 44 F 6 N 5 0 6 and to Calculated: 816.3196

 Obtained: 816.3174

<Example 8 6>

According to a method similar to that in Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (bromoacetyl) -1,2,3-dihydro 7— (3-methoxyphenyl) -1-N— Methyl-1-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (100 mg, 0.14 mmo1) and 1- (t— Butoxycarbonyl) piperazine (32.2 mg, 0.17 mmo 1) from N— [3,5-bis (trifluoromethyl) benzyl] 1-1 _ [(4— (t— Butoxycarbonyl) piperazinyl) acetyl] 1,2,3-dihydro-1 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,, 4-benzodiazine-1 6-carboxamide (108 mg, 93%) was obtained.

_{HMS (EI): C 4Q H} 41 F 6 N 5 0 6 Calculated: 801.2961

 Obtained value: 801.2918

<Example 8 7>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] -1- (bromoacetyl) -2,3-dihydro-1 7— (3-methoxyphenyl) ) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (350 mg, 0.50 mm 01) and 4 _ (N- (t-butoxycarbonyl) -N-methylamino) piperidine (130 mg, 0.61 mmo1) to N- [3,5-bis (trifluoromethyl) Benzyl] 1 1— [(4- (N- (t-butoxycarbonyl) -1-N-methylamino) piberidinyl) acetyl] -1,2,3-dihydro-1 7— (3-Methoxyphenyl) 1-N-methyl-5-oxo-1 5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (300 mg, 72 were obtained.

MS (FAB ⁺ ) i »A: 830 (M + H ⁺ )

_{^{HRMS (FAB +): C 42}} H 46 F 6 N 5 0 6 Calculated: 830.3352

 Observed value: 830.3320

<Example 8 8>

According to a method similar to that of Example 38, N— [3,5-bis (trifluoromethyl) benzyl] —1- (promoacetyl) -12,3-dihydro-17- (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] — 1,4,1-benzodiazine-16-carboxamide (300 mg, 0.43 mmo1) and 1 From (t-butoxycarbonyl) homopyrazine (120 m; 0.60 mmo 1), N— [3,5-bis (trifluoromethyl) benzyl] — 1 1 [(4 1 ( t-butoxycarbonyl) homopiperazinyl) acetyl] 1, 2,3-dihydro 7- (3-methoxyphenyl) 1 N-methyl-5-oxo-1 5 H-pyrido [1,2,3-de]-1,4 One benzodiazine-16-carboxamide (351 mg, 100 mg) was obtained.

_{HRMS (FAB -): C 41} H 43 F 6 N 5 0 6 Calculated: 815.3118

 Obtained: 815.3111

<Example 8 9>

N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro N-methylol 1_ (4-morpholinylacetyl) was prepared in the same manner as in Example 1. ) — 5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0 mg, 95 urn 0 1) and 4-methylphenyl From yellow acid (27.5 mg, 0.20 mmo 1), yellow amorphous N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N—methyl-17— ( 4-Methylphenyl) 1-11 (4-morpholinyl acetyl) — 5-oxo-1 5H-pyrido [1,2,3-de] —1,4-benzodiazine-1 6-carboxamide (45. 8 mg, 70%).

MS (FAB ⁺ ) »A: 687 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 4 Calculated: 687.2406

 Obtained: 687.2390

<Example 90>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1-N-methyl-1- (4-morpholinyl) Cetyl) — 5-oxo — 5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-6-carboxamide (60. Omg ヽ 95 / zmol) and 3-methylphenyl From boric acid (27.5 mg, 0.20 mmo 1), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-N-methyl—7— (3-Methylphenyl) 1-1- (4-morpholinylacetyl) —5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (53.O mg , 81%).

MS (FAB ⁺ ) i »A: 687 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 4 Calculated: 687.2406

Obtained value: 687.2386 Example 9 1>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] 17-chloro-2,3-dihydro-N-methyl-1- (4-morpholinylacetyl) ) 15-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0 mg, 95 zmol) and 2-methylphenyl From the acid (27.5 mg, 0.20 mmol), N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-N—methyl—7— (2— Methylphenyl) 1- (4-morpholinylacetyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4—benzodiazine-16-carboxamide (55.5 mg, 85) %).

MS (FAB ⁺ ) i »A: 687 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 4 Calculated: 687.2406

 Found: 687.2432

<Example 9 2>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-1- (4-morpholinylacetyl) ) 1-5-oxo-5H-pyrido [1,2,3-de]-1,4,1-benzodiazine-16-carboxamide (60.0 mg, 95 mol) and 4-methoxyphenylborate (28.9 mg, 0.19 mmol) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7—

(4-methoxyphenyl) 1 N-methyl-11 (4-morpholinyl acetyl) 1-5-oxo-5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (64.7 mg, 97%).

MS (FAB ⁺ ) yffA: 703 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 33 F 6 N 4 0 5 Calculated: 703.2355

Obtained value: 703.2347 Example 9 3>

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-2,3-dihydro N-methyl-1- (4-morpholinyl) Cetyl) — 5-oxo-5H-pyrido [1,2,3-de]-1,4-benzodiazine-6-carboxamide (60.0 mg, 95 9mol) and 2-medium N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (2-methoxyphenyl) from toxic phenyl borate (28.9 mg, 0.19 mmol) 1 N-methyl-1- (4-morpholinyl acetyl) 1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (62.3 mg, 9 3%).

MS (FAB ⁺ ) ZB: 703 (M + H ⁺ )

_{^{HMS (FAB +): C 35}} H 33 F 6 N 4 0 5 Calculated: 703.2355

 Found: 703.2355

<Example 9 4>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-2,3-dihydro-1-N-methyl-1- (4-morpholinylacetyl) 1) -5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (60.0 mg, 95 mol) and 3- (trifluorome) N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro N-methyl-11- (4,6 lmg :, 0.19 mmol) 1-Morpholinyl acetyl) 1-5-oxo 7- [3- (Trifluoromethyl) phenyl] —5H-Pyrido [1, .2,3-de] —1,4-Benzodiazine-1 6— Carboxamide (70.7 mg, 100%) was obtained.

MS (FAB ⁺ ) i »A: 741 (M + H ⁺ )

_{^{HRMS (FAB +): C 35}} H 30 F 9 N 4 0 4 Calculated: 741 & 2123

 Found: 741.2130

<Example 9 5>

Me

 ヽ o

 CF

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-1- (4-morpholinyl) Cetyl) 1-5-oxo-5H-pyrido [1,2,3-dθ] —1,4-benzodiazine-6-carboxamide (60.O mg, 95 mol) and 4-chloro N- [3,5-bis (trifluoromethyl) benzyl] —7— (4-chlorophenyl) —2, from oral phenylboronic acid (29.8 mg, 0.19 mmo 1) 3-dihydro-Ν-methyl-11- (4-morpholinylacetyl) -1-5-oxo-5 5-pyrido [1,2,3-de] —1,4-benzo-1-6-carboxami (63.5 mg, 94%).

MS (FAB ⁺ ) J »A: 707 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 3 oClF 6 N 4 04 Calculated: 707.1860

Obtained value: 707.1843 Example 9 6>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-N-methyl-1- (4-morpholinyl) Acetyl) — 5-oxo-5H-pyrido [1,2,3-de] -11,4-benzodiazine-16-carboxamide (60.O mg, 95 mol) and 3-chloro N- [3,5-bis (trifluoromethyl) benzyl] —7— (3-chlorophenyl) —2,3— from oral phenylboronic acid (29.8 mg, 0.19 mmol) Dihidro N-methyl-1- (4-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide (6 5.5 mg, 97%).

MS (FAB ⁺ ) i »A: 707 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 30 C1F 6 N 4 04 Calculated: 707.1860

 Found: 707.1838

<Example 9 7>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro-1-N-methyl-1- (4-morpholinyl) Cetyl) 1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (60.0 mg, 95 mol) and 3,4- From dichlorophenylborate (72.9 mg, 0.19 mmol, 50% aqueous solution of furan in tetrahydrofuran), N— [3,5-bis (trifluoromethyl) benzyl] 17— ( 3,4-dichlorophenyl) 1,2,3-dihydro-1-N-methyl-1- (4-morpholinylacetyl) -5-oxo 5-H-pyrido [1,2,3-de] — 1 , 4-Benzodiazine-6-carboxamide (70.4 mg, 100%) was obtained.

S (FAB ⁺ ) i »A: 741 (M + H ⁺ )

Hokusatsu _{S (FAB +): C 34} H 29 C1 2 F 6 N 4 0 4 Calculated: 741 & 1470

 Found: 741.1490

<Example 9 8>

In the same manner as in Example 1, N— [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-dihydro N-methyl-1- (4-morpholinyl) Cetyl) -5-oxo-5 11-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (60.0 mg, 95 mol) and 2,4-dichloro N- [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-dichlorophenyl) from the phenylboronic acid (36.4 mg, 0.19 mmol) 3-Dihydro N-methyl-1- (4-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide (69. 3 mg, 98%).

MS (FAB ⁺ ) 2BA: 741 (M + H ⁺ )

^{HR S (FAB +): C} 34 H 29 C1 2 F 6 N 4 0 4 Calculated: 741.1470

Actual value: 741.1448 Example 9 9>

Me

 CF

In the same manner as in Example 1, N- [3,5-bis (trifluoromethyl) benzyl] -17-chloro-1,2,3-dihydro-1-N-methyl-1- (4-morpholinyl) Cetyl) 1-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-Penzodiazine-16-carboxamide (60.O mg, 95 mol) and 3-cloth — 4-Fluorophenylboronic acid (34.9 mg, 0.20 mmol) from N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloro-1-fluorophenyl ) 1, 2,3-Dihydro N-methyl-1- (4-morpholinyl acetyl) 1-5-oxo-5H-pyrido

[1,2,3-de] —1,4-benzodiazine-16-carboxamide (59.4 mg ヽ 86%) was obtained.

MS (FAB ⁺ ) / »A: 725 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 C1F Y N 4 0 4 Calculated: 725 & 1766

 Found: 725.1761

<Example 100>

In the same manner as in Example 1, N— [3,5_bis (trifluoromethyl) benzyl] —7—chloro-1,2,3-dihydro-1-N-methyl—1— (4-morpholinyl) Acetyl) — 5 —oxo— 5 H-pyrido [1,2,3-dΘ] —1,4,1-benzodiazine-61-carboxamide (60.0 mg, 95 zmol) and 4-1 N- [3,5-Bis (trifluoromethyl) benzyl] -17- (4-chloro-3-fluoro) from Cloguchi _ 3-Fluorophenylborate (33.3 mg, 0.19 mm 01) Phenyl) 1,2,3-Dihydro-1-N-methyl-1- (4-morpholinylacetyl) -5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine One 6-carboxamide (57.1 mg, 83%) was obtained.

MS (FAB ⁺ ) i »A: 725 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 C1F T N 4 04 Calculated: 725.1766

 Found: 725.1761

<Example 10 1>

N- [3,5-bis (trifluoromethyl) benzyl] 17-chloro-2,3-dihydro-N-methyl-1- (4-morpholinylacetyl) was prepared in the same manner as in Example 1. 1-5-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (60.0 mg, 95 zmol) and 3,5-difluorophene N- [3,5-bis (trifluoromethyl) benzyl] -17— (30.3 mg, 0.19 mmol, 50% tetrahydrofuran monofuran aqueous solution) , 5-Difluorophenyl) — 2,3-Dihydro N-methyl-1- (4-morpholinylacetyl) -1-5-oxo-5H-pyrido [1,2,3-de] 1-1 , 4-Benzodiazine-1-carboxamide (63.6 mg, 94%) was obtained.

MS (FAB ⁺ ) i »A: 709 (M + H ⁺ )

_{^{HRMS (FAB +): C 34}} H 29 F 8 N 4 0 4 Calculated: 709 & 2061

Actual value: 706.2029 Example 1 102>

N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-7- (3-methoxyphenyl) -1-N-methyl-15-oxo-1— (4-thiomorpholinyl) Acetyl) 1 5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (1 OO mg ヽ 0.14 mmo1) to methylene chloride (0.5 ml) ) Was added, and 3-chloroperbenzoic acid (26.4 mg, 0.15 mmo 1) was added thereto, followed by stirring at room temperature for 3 hours. The reaction solution was diluted with methylene chloride, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (methylene chloride: ethanol = 10: 1) to give N- [3,5-bis (trifluoromethyl) as colorless crystals. Benzyl] — 2,3-Dihydro 7- (3-Methoxyphenyl) -1-N-methyl-5-oxo-1- 1- [4- (1-Oxothiomorpholyl) acetyl] -5H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (43.9 mg, 43%) was obtained.

MS (FAB ⁺ ) isA: 735 (M + H ⁺ )

_{^{HMS (FAB +): C 35}} H g3 F 6 N 4 0 5 S Calculated: 735.2076

Found: 735.2078 <Example 10 3>

N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxyphenyl) 1 N-methyl-1 5-oxo-1 1— (1-piperazinylacetyl) 1 5 H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (50.0 mg, 71〃mo1) was added to polymer-supported morpholine (100 mg, 3.5 to 4.0 mmo 1 N / g), acetic anhydride (8.8 mg, 86〃mo 1) and methylene chloride (0.5 ml), and stir at room temperature for 3 hours. did. After the reaction mixture was filtered, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give a pale yellow amorphous 1-[(4-acetylbiperazinyl). A-cetyl] 1 N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3-methoxyphenyl) 1 N—methyl—5-oxo-5H-pyrido [1 , 2,3-de] —1,4-Benzodiazine-16-carboxamide (51.4 mg, 97%) was obtained. MS (FAB ⁺ ) i »A: 744 (M + H ⁺ )

_{^{HRMS (FAB +): C 37}} H 36 F 6 N 5 0 5 Calculated: 744.2621 Obtained value: 744.2657

<Example 10 4>

In the same manner as in Example 103, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (3-methoxyphenyl) -1-N-methyl-5— Oxo 1- (1-piperazinyl acetyl) -1 5H-pyrido [1,2,3-dθ]-1,4,1-benzodiazine-1 6-carboxamide (50.0 mg, 71 urn o 1) and methanesulfonyl chloride (10.0 mg, 87 mo 1) from Ν- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— ( 3-Methoxyphenyl) 1 1 1 [(4- (Methanesulfonyl) piperazinyl) acetyl] — Ν—Methyl-1 5-oxo-1 5 Η—Pyrido [1,2,3-de] —1,4-benzodiazine 6-Carboxamide (55.5 mg, 100%) was obtained.

MS (FAB ⁺ ) i »A: 780 (M + H ⁺ )

_{^{HRMS (FAB +): C 36}} H 36 F 6 N 5 0 6 S Calculated: 780.2291

Observed value: 780.2325 <Example 10 5>

In the same manner as in Example 103, 1-[(4-aminobiperidinyl) acetyl] —N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3 —Methoxyphenyl) —N—Methyl-5-oxo-5H—pyrido [1,2,3-de] —1,

From 4-benzodiazine-6-carboxamide (50.0 mg, 70 m 0 1) and acetic anhydride (10.0 mg, 98〃1! 10 1), 1-[(-(acetylamino) piberidinyl ) Acetyl] one N— [3,

5-bis (trifluoromethyl) benzyl] 1, 2,3-dihydro 7- (3-methoxyphenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3-dθ ] — 1,4-benzodiazine-6-carboxamide (52.0 mg, 98%) was obtained.

MS (FAB ⁺ ) i »A: 758 (M + H ⁺ )

_{^{HRMS (FAB +): C 38}} H 38 F 6 N 5 0 5 Calculated: 758 & 2777

 Obtained value: 758.2800

<Example 10 6>

In the same manner as in Example 103, 1-[(4-aminobiperidinyl) acetyl] —N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3 —Metoxif: n-nil) 1 N-methyl-5-oxo-5 H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (50.0 mg, 70 m 0 1) and methanesulfonyl chloride (10.0 mg, 87 / mol) from N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-((4- (Methanesulfonylamino) piperidinyl) acetyl] — 7— (3-Methoxyphenyl) 1 N—methyl-5-oxo-5H—pyrido [1,2,3-de] -1,4,1-benzodiazine One 6-carboxamide (55.0 mg, 99%) was obtained.

MS (FAB ⁺ ) i »A: 794 (M + H ⁺ )

111 ^ 8 8 ⁺ ) :() ₃₇ 11 _{3 6} ^ 0 ₆ 3 Calculated: 794.2447

 Found: 794.2416

<Example 10 7>

In the same manner as in Example 103, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1- 1— (1 homopiperazinyl acetyl) 17— ( 3-Methoxyphenyl-1 N-methyl-5-oxo-5 H-pyrido [1,2,3-dΘ] —1,4,1-benzodiazine-6-carboxamide (50.0 mg, 70 jumo 1) and acetic anhydride (10.0 mg, 98 mol) from 1-[(4-acetylhomopiperazinyl) acetyl] 1-N— [3,5-bis (trifluoromethyl) Benzyl] 1, 2,3-dihydro 7 — (3-Methoxyphenyl) — N-methyl-1 5-oxo-5 H-pyrido [1,2,3-de] —1,4-benzodiazine—6 —carboxami (49.3 mg, 93%).

MS (FAB ⁺ ) TH: 758 (M + H ⁺ )

_{^{HRMS (FAB +): C 38}} H 38 F 6 N 5 0 5 Calculated: 758.2777

 Found: 758.2761

<Example 10 8>

In the same manner as in Example 103, N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1- (1-homopiperazinyl acetyl) 17- (3 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dθ] —1,4-Benzodiazine-6-carboxamide (50.0 mg, 70 / mo 1) and methanesulfonyl chloride (10.0 mg, 87 zmol) from ヽ N— [3,5-bis (trimethyl romethyl) benzyl] —2,3-dihydro-1- [(4- (Methanesulfonyl) homopiperazinyl) acetyl] — 7— (3-Methoxyphenyl) 1 N—methyl 1 5 —oxo 1 5 H—pyrido [1,2,3—de] —1, 4-benzodiazin-6-carboxamide (33.0 mg, 59%) was obtained. MS (FAB ⁺ ) / »A: 794 (M + H ⁺ )

_{^{HRMS (FAB +): C 37}} H 38 F 6 N 5 0 6 S Calculated: 794.2447

 Found: 794.2426

<Example 10 9>

According to a method similar to that of Example 103, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (3-methoxyphenyl) -1-N-methyl-1 1 L (41- (methylamino) piridinyl) acetyl] — 5-oxo-5 H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (84.7 mg, 0.12 mm 01) and acetic anhydride (14.2 mg, 0.14 mmo 1) from 1-[(4- (N-acetyl-N-methylamino) piperidinyl) acetyl] 1 N— [3,5-bis (trifluoromethyl) pentyl] —2,3-dihydro-1 7— (3-methoxyphenyl) 1 N—methyl-15-oxo-5H—pyrido [1 [2,3-dθ] —1,4,1-benzodiazine-16-carboxamide (89.0 mg, 99%).

MS (FAB ⁺ ) ^ A: 772 (M + H ⁺ )

_{^{HS (FAB +): C 39}} H 40 F 6 N 5 0 5 Calculated: 772.2934

Obtained value: 772.2961 Example 1 1 0>

In the same manner as in Example 103, N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro 7- (3-methoxyphenyl) -N-methyl-1-((4 -(Methylamino) piridinyl) acetyl] —5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-carboxamide (84.7 mg, 0.1 2 mmol) and methanesulfonyl chloride (16.0 mg, 0.1 mm01) from N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 — [(4— (N- (methanesulfonyl) -1-N-methylamino) piperidinyl) acetyl] 1—7— (3-Methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [l, 2, 3—de] —1,4-Benzodiazine-161 carboxamide (56.0 mg, 60%) was obtained.

MS (FAB ⁺ ) isA: 808 (M + H ⁺ )

_{^{HRMS (FAB +): C 38}} H 40 F 6 N 5 0 6 S Calculated: 808.2604

 Observed value: 808.2628

<Example 1 1 1>

N— [3,5-Bis (trifluoromethyl) benzyl] 1-111 ((4- (t-butoxycarbonyl) piperazinyl) acetyl] 1,2,3—Dihydro-1-7— (3-Methoxyphenyl) 1-N-methyl-1-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (9.50 mg, 0.12 mm 01) Dissolve in methylene chloride (0.2 ml), add a solution of trifluoroacetic acid (32.4 mg; 0.32 mmol) in methylene chloride (0.2 ml), and stir at room temperature for 1 hour. did. The reaction solution was adjusted to pH = 10 by adding water and a saturated aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The solvent is distilled off to give a colorless amorphous ヽ N— [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo 1- (1-biperazyl acetyl) 1-5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (66.2 mg, 80%) Obtained.

MS (FAB ⁺ ) i »A: 702 (M + H ⁺ )

丽 _{^{S (FAB +): C 35}} H 34 F 6 N 5 0 4 Calculated: 702.2515

Found: 702.2491 <Example 1 1 2>

Example 11 N— [3,5-bis (trifluoromethyl) benzyl] —11-((41- (t-butoxycarbonyl) homopiperazinyl) acetyl] —2,3 —Dihydro— 7— (3-Methoxyphenyl) -1-N—methyl-5-oxo-5H—pyrido [12,3—de] —1,4-benzodiazine-16-carboxamide (280 mg , 0.34 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] —1— (1 homopiperazinyl acetyl) —2,3-dihidro 7— (3 —Methoxyphenyl) 1 N-methyl-15-oxo-5H-pyrido [1,2,3-de] — 1,4-benzodiazine-16-carboxamide (150 mg, 61%) Obtained. MS (FAB ⁺ ) i »A: 716 (M + H ⁺ )

_{^{HRMS (FAB +): C 36}} H 36 F 6 N 5 0 4 Calculated: 716.2671

 Observed value: 716.2701

<Example 1 1 3>

Example 1 11—N- [3,5-bis (trifluoromethyl) benzyl] —1— [4- (N— (t-butoxycarbonyl) -1-N-methylamino) piperidinylacetyl ] — 2,3-Dihydro 7- (3-Methoxyphenyl) 1 N-methyl _ 5 -oxo 1 5 H-pyrido [1,2,3-dΘ] — 1,4 benzodiazine — From 6-carboxamide (290 mg, 0.35 mmol), N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-7- (3-methoxyphene) Nyl) 1 N-Methyl-1 1- [4- (Methylamino) piperidinylacetyl] — 5-oxo-5 H-Pyrido [1,2,3-de] —1,4-Benzoazine-6 —Carboxamide (255 mg, 100%) was obtained.

MS (FAB ⁺ ) isA: 730 (M + H ⁺ )

_{^{HRMS (FAB +): C 37}} H 38 F 6 N 5 0 4 and to Calculated: 730 & 2828

 Found: 730.2859

<Example 1 1 4>

In the same manner as in Example 11 1, N— [3,5-bis (trifluoromethyl) benzyl] 1-1 — [(4-((t-butoxycarbonyl) amino) piperidinyl) acetyl] 1, 2, 3-dihydro-1-71- (3-methoxyphenyl) -1-] Si-methyl-1-5-oxo-5-H-pyrido [1,2,3-de] 1-1,4-benzodiazine-1-6-carboxamide (199 mg, 0.24 mmo 1) from N— [3,5-bis (trifluoromethyl) benzyl] —1 — [(4-aminopyridinyl) acetyl] —2,3— Dihydro 7- (3-methoxyphenyl) -1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine—6-carboxamide (12 1 mg, 69%).

MS (FAB ⁺ ) / z / A: 716 (M + H ⁺ )

_{^{HRMS (FAB +): C 36}} H 36 F 6 N 5 0 4 Calculated: 716.2671

 Found: 716.2685

<Example 1 1 5>

N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1- (3-methoxyphenyl) -1-N-methyl-1- (4-morpholinylacetyl) -5 —Oxo-5H—pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (810 mg, 1.2 mm 01) with 3 mo 1 1 hydrogen chloride— Ethyl acetate (5 ml) was added and left at room temperature for 1 hour. The residue obtained by distilling off the solvent was crystallized by adding acetone, and N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-17- (colorless crystals) ( 1-N-methyl-1- (4-morpholinylacetyl) -5-oxo-5-H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6 —Carboxamide hydrochloride (600 mg, 71%) was obtained.

mp. 165.0-169.0. C

Anal: calculated as C ₃₅ H ₃₂ F ₆ N ₄ 0 ₅ / HCl / H ₂ 0 C 55.52%, H 4.66%, N 7.40%;

Example 1 1 6> 55.35%, H 4.60%, N 7.05%

N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-N-methyl-7- (3-methylphenyl) —1— (4 —Morpholinyl acetyl) — 5 —oxo-5H—pyrido [1,2,3-de]-1,4,1-benzodiazine-1—6-carboxamide (3.0 g, 4.4 mmo) l) shows that N- [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-1-N-methyl-1- 7- (3-methylphenyl) -1- (4-morpholinylacetyl) 5 Okiso one 5 H- pyrido [1, 2, 3 - d θ] - 1 3 4- Benzojiajin one 6- Karubokisami de hydrochloride (1, 5 '5 g, 4 9%) was obtained.

mp. 170.0-175.0. C

Anal: C ₃₅ H ₃₂ F ₆ N ₄ 0 ₄ / HCl / 2H ₂ 0 Calculated as C 55.3891, H 4.91% 7.38%;

Example 1 17> C 55.61%, H 4.56%, N 7.15%

Example 11 N- [3,5-bis (trifluoromethyl) benzyl] -1-[(4-methylpiperazinyl) acetyl] 1,2,3-dihydro 7- (3-Methoxyphenyl) 1N-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-6-carboxamide (475 mg, 0.6 6 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] 1-111 [(4-methylbiperadiacetyl) —2,3-dihidro 7— (3-methoxyphene N-methyl- There was obtained 5-oxo-5H-pyrido [1,2,3-dΘ] -1,4-benzodiazine-16-carboxamide hydrochloride (465 mg, 94%).

mp.180.0-185.0 ° C

_{Anal: C 36 H 35 F 6} N 5 0 4 /HCl/2.5H 2 0 and to calculate values C 54.24% H 5.18¾, Ν 8.79 %;

 Found C 54.24%, H 4.93% N

8.69% Example 1 1 8>

N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1 7— (3-methoxyphenyl) 1-N-methyl-1 5— Oxo 1- (1-Pyrrolidinyl acetyl) -15H-pyrido [1,2,3-dΘ] —1,4-benzodiazine-16-carboxamide (174 mg, 0.25 mm o 1), N- [3,5-bis (trifluoromethyl) benzyl] -2,3-dihydro-1- 7- (3-methoxyphenyl) 1-N-methyl-5-oxo-11- (1- pyro Rijiniruasechiru) Single 5 H- pyrido [1, 2, 3 - de ] - 1 3 4 one Benzojiajin one 6- Karubokisami de salt salt (1 6 2 mg, 9 0 %) was obtained.

mp. 185.0-190.0 ° C

_{Anal: C 35 H 32 F 6} N 4 0 4 calculated as the /HCl/2.5H ₂ 0 value C 54.73% H 4.99% N 7.29 %;

 Found C 54.95% H 4.81%, N

7.11%

<Example 1 1 9>

According to a method similar to that of Example 11-15, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydroxy 11-[((2-hydroxylethyl) amino) acetyl] —7— (3-Methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (543 mg, 0.8 0 mm o 1), N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-([((2-hydroxyl) ethylamino) acetyl] —7— (3 —Methoxypropyl) 1 N-methyl — 5-oxo-5 H-pyrido [1,2,3-de] —1,4,1-benzodiazine-1 6-carboxamide hydrochloride (509 mg, 8 9%).

mp. 240.0-245.0. C

_{Anal: C 33 H 30 F 6} N 4 0 5 / HCl / 2H 2 0 and to calculate values _{C 52.91% H 4.71% 3 N} 7.48%;

Actual value C 53.22%, Η 4.43¾, Ν 7.49%

1-[(4-Acetylbiperazinyl) acetyl] —N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7— (3— Methoxyphenyl) 1 N-methyl-5-oxo-5 H-pyrido [1,2,3-de] -1, 4-benzodiazine-16-carboxamide (666 mg, 0.90 mm o 1) From 1-[(4-Acetylbiperazinyl) acetyl] -N- [3,5-bis (trifluoromethyl) benzyl] -2,3 dihydro-1 7- (3-Methoxyphenyl) -N —Methyl-5-oxo-1H-pyrido [1,2,3-dθ] —1,4-Benzodiazine-16-carboxamide hydrochloride (526 mg, 75%) was obtained. . mp. 247.0-252.0 ° C

_{Anal: C 37 H 35 F 6} N 5 0 5 /HCl/0.5H 2 0 and to calculate values C 56.31% H 4.73% N 8.87 %;

 Found C 56.02% H 4.57% N

8.85% Example 1 2 1>

N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1- (4-morpholinylacetyl) 1— 7- [3- (trifluoromethyl) phenyl] -5H-pyrido [1,2,3-dΘ] -1,4-benzodiazine-16-carboxamide (82,6 mg, 1. From 2 mm 0 1), N— [3,5-bis (trifluoromethyl) benzyl] -1,2,3-dihydro-N-methyl—11- (4-morpholinyl lacetyl) -1,5-oxo-1 7— [3- (Trifluoromethyl) phenyl] -5H-pyrido [1,2,3-de] — 1,4-benzodiazine-6-carboxamide hydrochloride (800 mg, 86%) Obtained. mp. 180.0-185.0. C

_{Anal: C 35 H 29 F 9} N 4 0 4 / HC1 / 2H 2 0 Calculated G 51.70%, Ή 4.21% Ν 6.89%;

Actual value C 51.50% Η 4.08ο, Ν 6.89% Example 1 2 2>

N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chlorophenyl) —2,3-dihydro N-methyl-1- (4 —Morpholinyl acetyl) — 5-oxo-5 H-pyrido [1,2,3-de] —1,4-benzodiazine-6-carboxamide (420 mg, 0.59 mmol) From N— [3,5-bis (trifluoromethyl) benzyl] —7—

(3-chloro phenyl)-1, 2, 3-dihydro N-methyl-1-(4-morpholinyl acetyl)-1-oxo-1 5 H-pyrido [1, 2, 3-de]-1, 4-Benzodiazine _ 6-Carboxamide hydrochloride

(405 mg, 92%).

mp. 185.0-190.0 ° C

_{Anal: C 34 H 29 ClF 6} N 4 0 4 / HCl / H 2 0 and to calculate values C 53.62%, H 4.24% N 7.36%;

 Found C 53.44%, H 4.14% N

7.21%

<Example 1 2 3>

According to a method similar to that of Example 1 15, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-1-([4- (N— (methanesulfonyl) -1-N— Methylamino) piperidinyl) acetyl] 1 7— (3-methoxyphenyl) 1 N-methyl-5-oxo—5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-1 6— From carboxamide (430 mg, 0.533 mmol), N— [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro-1 -— ((N— ( Methanesulfonyl) 1-N-methylamino) piperidinyl) acetyl] — 7— (3-methoxyphenyl) 1-N-methyl-5-oxo-5H-pyrido [1,2,3-dΘ] -1,4— Benzodiazine-16-carboxamide hydrochloride (339 mg, 76%) was obtained.

mp. 200.0-205.0 ° C

_{Anal: C 38 H 39 F 6} N 5 0 6 S / HCl / 2H 2 0 and to calculate values C 51.85%, H 5.04% N 7.96¾;

 Found C 52.01% H 4.79% N

7.88% <Example 1 2 4>

N- [3,5-bis (trifluoromethyl) benzyl] 1-1- (11-homopiperazinyl acetyl) —2,3-dihidro 7— (3— Methoxyphenyl) — N-methyl-1-5-oxo-5 H-pyrido [1,2,3-dΘ] —1,4-benzodiazine-16-carboxamide (420 mg, 0.59 mm o 1) shows that N— [3,5-bis (trifluoromethyl) benzyl] —1— (1—homopiperazinyl acetyl) —1,2,3-dihydro—7— (3-methoxyphenyl) N-Methyl-1-oxo-5H-pyrido [1 _: 2,3-de] —1,4-benzodiazine-16-carboxamide hydrochloride (4.13 mg, 89%) was obtained.

mp. 205.0-210.0 ° C

_{Anal: C 36 H 35 F 6} N 5 0 4 /2HCl/2.5H 2 0 and to calculate values C 51.87%, H 5.08% N 8.40%;

 Found C 51.69% H 4.70% N

8.37% <Example 1 2 5>

N— [3,5—Bis (trifluoromethyl) benzyl] _2,3 dihidro 7— (3-Methoxyphenyl) 1-N—methyl-1-5—oxo 5 H—pyrido [1,2,3— de] 1, 1 1-Benzodiazine-6-carboxamide (700 mg, 1.2 mmol) was dissolved in methylene chloride (10 ml) and treated with triethylamine (0.1 ml) under ice-cooling. After adding 3 m 1 and 2.2 mm o 1), bromoacetyl bromide (0.15 ml, 1.7 mm 01) was added dropwise and stirred for 30 minutes. The reaction solution was diluted with methylene chloride, 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 2: 1) to give a yellow amorphous N- [3,5-bis (trifluoromethyl) benzene]. N-Methyl-1-5-oxo-5H-pyrido [12,3-de]-11- (Bromoacetyl) 1-2,3-dihydro-7- (3-Methoxyphenyl)- 1,4-Benzodiazine-16-carboxamide (730 mg, 87%) was obtained.

_{HRMS (EI): C 31 H} 24 BrF 6 N 3 04 Calculated: 695 & 0854

Found: 695.0845 <Example 1 2 6>

N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro N-methyl-1-5-oxo-17-phenyl-5H-pyr From [1,2,3-de] 1-1,4_benzodiazine-16-carboxamide (546 mg, 1.0 mmol) to N— [3,5-bis (trifluoromethyl) benzyl] 1- (bromoacetyl) 1,2,3-dihydro 7-phenyl-1N-methyl-5-oxo-5H-pyrido [1,2,3-de]-1,4, -benzodiazine-1 6-carboxamide (632 mg, 95%).

MS (FAB ⁺ ) »A: 666 (M + H ⁺ )

_{^{HRMS (FAB +): C 3}} oH 23 BrF 6 N 3 0 3 Calculated: 666.0827

Obtained value: 666.0820 Example 1 2 7>

According to a method similar to that of Example 1 25, N— [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro-17- (4-fluorophenyl) -1-N-methyl-5— Oxo-5H-pyrido [1,2,3-de] 11,4-benzodiazine-16-carboxamide (700 mg, 1.2 mmo1) from N- [3,5-bis (Trifluoromethyl) benzyl] — 1— (Promoacetyl) 1,2,3-dihydro 7— (4-Fluorophenyl) 1-N-methyl-15-oxo-5H-pyrido [1,2, 3-de]-1,4-benzodiazine-1 6-carboxamide (791 mg, 93) was obtained.

MS (FAB ⁺ ) iz / A: 684 (M + H ⁺ )

_{^{HRMS (FAB +): C 3}} oH 22 BrF 7 N 3 0 3 Calculated: 684.0733

 Found: 684.0717

<Example 1 2 8>

N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (3-fluorophenyl) -1-N-methyl-5-oxo by a method similar to that of Example 12 25 One 5H-pyrido [1,2,3-de] —1,4,1-benzodiazine-16-carboxamide (2.0 g, 3.6 mmol) gives N— [3,5-bis ( Trifluoromethyl) benzyl] 1 1- (bromoacetyl) 1,2,3-dialdehyde 1 7- (3-fluorophenyl) 1 N-methyl-5-oxo-5H-pyrido [1,2,3 — De] — 1,4-benzodiazine-1 6-carboxamide (2.13 g, 87%) was obtained.

MS (FAB ⁺ ) 7 »Α: 684 (Μ + Η ⁺ )

_{^{HRMS (FAB +): C 30}} H 22 BrF 7 N 3 0 3 Calculated: 684.0733

Obtained value: 684.0709 Example 1 2 9>

N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro 7- (2-fluorophenyl) -1-N-methyl-15-oxo by a method similar to that of Example 125. From 5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (800mg, 1.4mm01), N- [3,5-bis ( Trifluoromethyl) pendyl] ー 1- (bromoacetyl) 1-2,3-dihydro 7- (2-fluorophenyl) 1-N-methyl-15-oxo-5H-pyrido [1,2,3-de ] — 1,4-benzodiazine-1 6-carboxamide (303 mg, 31%) was obtained.

_{HRMS (EI): C 30 H} 21 BrF 7 N 3 0 3 Calculated: 683 & 0655

 Observed value: 683.0851

<Example 13>

According to a method similar to that of Example 1 25, N— [3,5-bis (trifluoromethyl) benzyl] -1 7— (3,4-difluorophenyl) —2,3-dihydro N-methyl-1 5— Oxo-5H-pyrido [1,2,3-de] -1,4,1-benzodiazine-16-carboxamide (200 g, 3,4 mmo1) from N— [3,5-bis (Trifluoromethyl) benzyl] 1- (bromoacetyl) 17- (3,4-difluorophenyl) 1,2,3-dihydro N-methyl-15-oxo-5H-pyrido [1, [2,3-de] 1-1,4-benzodiazine-6-carboxamide (1.97 g, 81%) was obtained.

_{HRMS (EI): C 30 H} 20 BrF 8 N 3 0 3 Calculated: 701.0560

 Observed value: 701.0540

<Example 1 3 1>

According to a method similar to that of Example 1 25, N— [3,5-bis (trifluoromethyl) benzyl] —7— (2,4-difluorophenyl) —2,3-dihydro N-methyl From 5-oxo-5H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (200g, 3,4mmol), N— [3,5— Bis (trifluoromethyl) benzyl] 1-1- (bromoacetyl) -17- (2,4-difluorophenyl) 1-2,3-dihydro-1-N-methyl-5-oxo-5H-pyrido [1, [2,3-de] —1,4-benzodiazine-6-carboxamide (2.05 g, 85) was obtained.

_{HRMS (EI): C 3 oH} 20 BrF 8 N 3 03 Calculated: 701.0560

 Actual value: 701.0519 Example 1 3 2>

1-Methyl-1,2,3,4-Tetrahydro-1,4-benzodiazine (3.15 g, 21 mmol) was added to triethyl methane tricarboxylate (14.8 g, 64 mmol), and the mixture was heated and stirred at 150 ° C for 2 hours, and subsequently at 200 ° C for 6 hours. After cooling the reaction mixture, it was recrystallized from ethanol to give pale yellow crystals of 2,3-dihydro-7-hydroxy-1-methyl-5-oxo-5H-pyrido [1,2,3-] de]-1,4-Monobenzodiazine-6-carboxylic acid ethyl ester (273 g, 44%) was obtained.

MS (EI) τ »Α: 288 (Μ ⁺ )

_{HRMS (EI): C 15 H} 16 N 2 0 4 and to Calculated: 288.1110

 Found: 288.1082

<Example 1 3 3>

Example 13 By the same method as in 32, 1 1-benzyl-1,2,3,4-tetrahydrodraw 1,4-benzodiazine (7.00 g, 31 mmol) and methane tricarboxylate were prepared. From Lietyl (14.5 g, 62 mm 0 1), 1-benzyl-1,2,3-dihydro-7-hydroxy-1-5-oxo-5H-pyrid [1,2,3-d θ] -11,4-benzodiazine-16-carboxylic acid ethyl ester (10.1 g, 88) was obtained.

_{HRMS (EI): C 21 H} 20 N 2 0 4 and to Calculated: 364.1423 Found: 364.1457

<Example 1 34>

2,3-Dihydroxy 7-Hydroxy-1-methyl-5-oxo-5H-pyrido [1,2,3-de] 1-1,4-benzodiazine-16-Carboxylic acid ethyl ester (2.35 g, 8.2 g) and 3,5 monobis (trifluoromethyl) -1-N-methylbenzylamine (2.52 g, 9.8 mm 01) were dissolved in pyridine (20 ml), The mixture was heated and stirred at 20 ° C for 5 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was washed with diisopropyl ether, and N- [3,5-bis (trifluoromethyl) benzyl] light yellow amorphous benzyl] —2,3-dihydroxy was added. 1, N-Dimethyl-7-hydroxy-5-oxo-5H-pyrido [1,2,3-dΘ] —1,4-benzodiazine-16-carboxamide (3.03 g, 74 %).

_{HRMS (EI): C 23 H} 19 F 6 N 3 0 3 Calculated: 499.1331

 Found: 499.1333

<Example 1 3 5>

1-Benzyl-1,2,3-dihydroxy 7-hydroxy-5-oxo-5H-pyrido [1,2,3-de] -1,4-benzodiazine From 6-potassium ethyl ribonate (34.3 g, 94 mmol) and 3,5-bis (trifluoromethyl) -N-methylbenzylamine (29.2 g, 0.1 llmol) , 1—Benzyl mono N— [3,5—Bis (trifluoromethyl) benzyl] , 3-de] — 1, 4-benzodiazine — 6 — carboxamide (54.2 g, 100%).

HMS (EI): Calculated as C ₂₉ H ₂₃ F ₆ N _g 0 ₃ : 575 · 1644

 Obtained value: 575.1664 Example 1 3 6>

N-[3,5 —bis (trifluoromethyl) benzyl] — 2,3 —dihydro 1, N—dimethyl-1 7—hydroxy 5 —oxo 1 5 H—pyrid [1,2,3-dθ ]-1, 4—Benzodiazine 6 — 30% hydrogen chloride-ethanol (60 ml) was added to carboxamide (3.03 g, 6.1 mmol) and stirred at room temperature for 3 hours. Phosphorus oxychloride (30 ml) was added to the residue obtained by evaporating the solvent of the reaction solution, and the mixture was heated with stirring at 50 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, water and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH to 10, then extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was washed with diisopropyl ether, and pale yellow crystals of N- [3,5-bis (trifluoromethyl) benzyl] —7-chloro-1,2,3-diethyl 1,4-N-dimethyl-5-oxo-5H-pyrido [1,2,3-dΘ] -11,41-benzodiazine-6-carboxamide (2.31 g, 73%) Obtained.

_{HRMS (EI): C 23 H} 18 C1F 6 N 3 0 2 Calculated: 517.0992

 Actual value: 517.0944 Example 1 3 7>

According to a method similar to that of Example 13 36, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] -12,3-dihydro-17-hydroxy N-methyl-15-oxo-5 From H-pyrido [1,2,3-dθ]-1,4, -benzodiazine-6-carboxamide (1.00 g, 1.7 mmo1), 1-benzyl-N— [3,5 —Bis (trifluoromethyl) benzyl) — 7-chloro 2,3 Dro-N-methyl-5-oxo-5H-pyrido [1,2,3-dθ] —1,4-benzodiazine-16-carboxamide (1.00 g, 97%) was obtained. .

_{HRMS (EI): C 29 H} 22 C1F 6 N 3 0 2 and to Calculated: 593.1305

 Found: 593.1278

<Example 1 3 8>

N- [3,5-Bis (trifluoromethyl) benzyl] 1-2,3-dihydro 7-hydroxy-1-N-methyl-1- (4-morpholinyl) Acetyl) 1-5-oxo-5H-pyrido [1,2,3-de]-1,4,4-benzodiazine-16-carboxamide (5.00 g, 8.2 mmo1), yellow N- [3,5-Bis (trifluoromethyl) benzyl] 1 7-chloro-2,3—dihydro N-methyl-1— (4-morpholinyl lacetyl) 1 5—oxo 1 5H—pyri [1,2,3-De] -1,4,1-benzodiazine-16-carboxamide (3.38 g, 66) was obtained.

MS (FAB ⁺ ) 2δΑ: 631 (Μ + Η ⁺ )

_{^{HRMS (FAB +): C 28}} H 26 C1F 6 N 4 0 4 Calculated: 631 & 1547 Found: 631.1567

<Example 1 3 9>

In the same manner as in Example 26, 1-benzyl-N- [3,5-bis (trifluoromethyl) benzyl] —2,3-dihydro 7-hydroxy-1-N-methyl-5-oxo-5H— The pyrido [1,2,3-de] —1,4—benzodiazine-16-carboxamide (10.0 g, 17 mmol) was converted to yellow amorphous N— [3,5-bis ( Trifluoromethyl) benzyl] — 2,3-dihydro-1- 7-hydroxy-1-N-methyl-1-oxo-5 H-pyrido [1,2,3-de] —1,4-benzodiazine-16-carboxamide (7.32 g, 87%).

_{HRMS (EI): C 22 H} 17 F 6 N 3 0 3 Calculated: 485.1174

 Found: 485.1190

<Example 14>

N- [3,5-bis (trifluoromethyl) benzyl] 1-2,3-dihydro 7-hydroxy-1-N-methyl-5-oxo-5H-pyrid [1,2,3-de] —1,, After dissolving 4-benzodiazine-6-carboxamide (4.00 g, 8.2 mmol) in methylene chloride (80 ml) and triethylamine (2.83 ml, 20 mm01), Bromoacetyl bromide (1.6 ml, 18 mmo 1) was added dropwise under ice cooling, and the mixture was stirred for 3 hours. Subsequently, morpholine (4.8 ml, 55 mm 01) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with methylene chloride, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (methylene chloride: ethanol = 5: 1) to obtain a red-brown amorphous N— [3., 5-bis (tri-) Fluoromethyl) benzyl] —2,3-Dihydro 7-Hydroxy N-Methyl 1— (4—Morpholinyl Acetyl) -15-Oxo-5 H-Pyrido [1,2,3-d θ ] — 1,4-benzodiazine-16-carboxamide (5.00 g, 99%) was obtained.

MS (FAB ⁺ ) isA: 613 (M + H ⁺ )

_{^{H¾MS (FAB +): C 28}} H 27 F 6 N 4 0 5 Calculated: 613.1886

Found: 613.1868 <Experimental example>

 (experimental method)

 《NK1 receptor antagonism》

 The method of S. Dion et al. (“Life Sciences”, Vol. 41, pp. 229-69 (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%, and the C 0 ₂ 5% of the mixed gas venting, 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 the substance P in the absence of the test compound was used as a control.

 The NK1 receptor antagonism of the test compound was determined from a concentration-response curve of substance P, which was pretreated with at least three concentrations of the test compound for 10 minutes and then cumulatively applied. The K b value is obtained by the method of Schi 1 d (“British Journal of Pharmaceutical Science” (Brit. J. Pharmacol)), Vol. 14, p. 48 (1959). The results are shown in Table 1.

The composition of the Tyrode solution was as follows. Na C l; 1 3 6. 9ヽKC 1; 2. 7, C a C l 2 '2 H 2 0; 2. 5, M g C 1 2 ·

6 H 20; 1. 0, NaH 2 P_〇 ₄ '2 H ₂ 〇; 0. 4, NaH C_〇 _{3; 1 1. 9, lucose;} 1 1. 1 (m mo 1/1) <Experimental results>

 table 1

 Example number Kb value (nmol / 1)

 8 1 0 .5 2 9

 1 0 9 0 .5 2 8

 1 1 5 1.. 6 6

 1 1 6 2. 2 4

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

The scope of the language: The following general formula (1)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i C alkyl group, and R ³ is a hydrogen atom, an optionally substituted C i -C 6 alkylcarbonyl group, good C to C ₆ Al alkylsulfonyl group, a substituted C i C ₆ alkyl group, represents an optionally substituted Arirumechiru group and alkoxycarbonyl group, a ring independently A selected homo- or heterocyclic ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring); 1-3 substituents

A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). Or a salt, hydrate or solvate thereof.

2. The following general formula (1)

(R ¹ and R ² are the same or different and represent a hydrogen atom or a C i Ce alkyl,

R ³ is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C i to C ₆ optionally substituted, an alkylsulfonyl group optionally C i Cs may be substituted, an optionally substituted 〇丄～〇 ₆ alkyl Group, an optionally substituted arylmethyl group and an alkoxycarbonyl group,

Ring A is a halogen atom, an optionally substituted C ₆ -C ₆ alkyl group, an optionally substituted aryl group, a hydroxyl group, an optionally substituted CC e alkoxy group, and CgC i. Cycloalkoxy group, optionally substituted C i -C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyl group, C ₃ -C i ₀ cycloalkadienyl Noi Ruo alkoxy group, an optionally substituted C. 1 to C ₆ alkylthio group, alkylsulfinyl group optionally C i to C ₆ optionally substituted, an optionally substituted C i to C ₆ alkylsulfonyl group, an amino group, mono- or di-substituted alkylamino group C i~C _6, 1~ 3 pieces of the may contain a hetero atom 4-9 membered cyclic § Mi amino group, C丄alkylcarbonyl amino group ~ C _6, C i C g alkoxycarbonyl § Mi amino group, C i C e alkylsulfonyl § amino group, optionally substituted Arirusu Ruhoniruamino group, C T～ C ₆ Alkylcarbonyl group, phor Mill group. Carboxyl group, C i Ce alkoxycarbonyl group, mono- or di-substituted C i -C ₆ alkyl group rubamoyl group, 4- to 9-membered cyclic group rubamoyl optionally containing 1 to 3 heteroatoms 1 to 3 substituents independently selected from a group, a cyano group, or a nitrogeno group (two adjacent substituents may be bonded to each other to form a ring). Represents an allo- or heterocyclic ring which may be

Ring B represents an alkyl group having a halogen atom, an optionally substituted _{C ~ C 6, C 3 ~} C. Sik port alkyl group, optionally substituted § re Ichiru group. Arsenide de port hexyl group, an optionally substituted C i ~ alkoxy group C _6, optionally substituted C i ~ C ₆ Arca Noi Ruo alkoxy group, optionally substituted Ariroiruokishi group, an optionally substituted Ariru Mechiruokishi group, C ₃ cycloalkoxy group ~ C i 0, cycloalkanoyl Noi Ruo alkoxy group of C ₃ ~ C _{1 0} , optionally substituted C ₁ to § alkylthio group C _6, alkyl sulfide alkylsulfonyl group - C ₆ C ₁ may be substituted, an alkylsulfonyl group of - C ₆ optionally C ₁ substituted , amino group, alkylamino amino group mono- or di-substituted C ^ C e, 1 ~ 3 one heteroatom and which may contain 4-9 membered cyclic amino groups, alkylcarbonyl C丄~ C ₆ Amino group, Arukokishikaru Boniruami of C i ~ C ₆ Groups, C丄alkylsulfonyl § Mi amino group of ~ C _6, optionally substituted § Li one even if Le sulfonyl § amino group, an alkylcarbonyl group of C ~ C 6, a carboxyl group, alkoxy C i ~ C ₆ A carbonyl group, a mono- or di-substituted C 1 -C ₆ alkyl group, a 4- to 9-membered cyclic group optionally containing 1 to 3 heteroatoms, a cyano group or a nitro group 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); Show,

Ring C is a halogen atom, an optionally substituted C i Cs alkyl group. Human de port hexyl group, an optionally substituted alkoxy group having C i~C _6, optionally substituted good C ₁ -C ₆ alkanoyloxy Noi Ruo alkoxy group, an optionally substituted § Li Roiruokishi group, An optionally substituted arylmethyloxy group, C ₃ -C 丄. A cycloalkoxy group,

. Of cycloalkanoyloxy group, amino group, mono- or di-substituted (to

Alkylamino amino group of C _6,. 1 to 3 or heteroatom to comprise not but it may also 4-9 membered cyclic Amino group, an alkylcarbonyl § amino group of the C丄~ C _6, alkoxy of C i to C ₆ Karuboniruami amino group, C ₁ -C Al kill sulfonyl § amino groups of _6, optionally substituted Arirusuruhoni Ruami amino group from 1 to 3 are each independently selected from the Shiano group or a preparative port group A benzene ring which may have one or more substituents (two adjacent substituents may be bonded to each other to form a ring). ) A pyridobenzodiazine derivative represented by the formula or a salt, hydrate and solvate thereof.

3. In general formula (1), R ³ is

(R ⁴ is a hydrogen atom, an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, may be substituted, and may contain 1-3 hetero atoms. membered cyclic amino group, C i to C ₆ alkyl carbonylation Ruamino group, C i Cs alkoxycarbonyl § amino group, C i C alkylsulfonyl § Mi amino group of _6, optionally substituted good i Ariru Suruhoniruami Bruno Group, n represents an integer of 1 to 6. Item 6. The pyridobenzodiazine derivative or the salt, hydrate and solvate thereof according to Item 1 or 2.

4 In the general formula (1), R ³

(R ⁵ is a hydrogen atom, an amino group, a mono- or di-substituted CiCs alkylamino group, may be substituted, and may have 1 to 3 hetero atoms, and may have 4 to 9 members.璟状amino groups, C alkyl carbonylation Ruamino group ~ C _6, C i to alkoxycarbonyl § amino group of C _6, C i alkylsulfonyl § amino group of C _6, optionally substituted Ariru Suruhoniruami amino group, m represents an integer of 1 to 6. 3. The pyridobenzodiazine derivative or a salt, hydrate or solvate thereof according to claim 1 or 2, wherein

5. In the general formula (1), R ³ is S 0 2 R ⁶

(R ⁶ is an optionally substituted C i -C ₆ alkyl group or an optionally substituted aryl group) .The pyridobenzodiazine derivative according to claim 1 or 2, or a salt, hydrate and Solvate.

6. The pyridobenzodiazine derivative or a salt thereof according to claim 1 or 2, wherein in the general formula (1), R ³ is represented by a C ₆ alkyl group. Hydrates and solvates.

7. In general formula (1), R ³ is

 I 0

 G-n

(R ⁷ is a halogen atom, a hydryl xyl group, an optionally substituted c 丄

~ C ₆ alkoxy group, OS 〇 ^₂ R ¹ ₂ (R ¹ ₂ is halogen optionally substituted C i be the ~ alkyl C _6, optionally substituted Ariru group), i is the 1-6 Indicates an integer. 3. The pyridobenzodiazine derivative according to claim 1 or 2, or a salt, hydrate or solvate thereof.

8. In general formula (1), R ³ is

(R ⁸ is a halogen atom, a hydroxyl group, an optionally substituted C 丄 to C ₆ alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.) The pyridobenzodiazine derivative according to claim 1 or 2, or a salt, hydrate or solvate thereof.

9. The pyridobenzodiazine derivative according to claim 1 or 2, wherein R ³ in the general formula (1) is a hydrogen atom, an optionally substituted arylmethyl group or an alkoxycarbonyl group, or a salt or hydrate thereof. And solvates.

1 0. The following general formula (2)

(In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i -C ₆ alkyl group, and the B ring has 1 to 3 substituents (when two adjacent substituents are bonded to each other, R ³ represents a hydrogen atom, an optionally substituted C ₁ -C ₆ alkylcarbonyl group, or an optionally substituted benzene ring A C i -C ₆ alkylsulfonyl group, an optionally substituted ₆ alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group, and X represents a halogen atom, a hydroxyl group or 0 S 0 ₂ R ¹³ (R ¹³ represents a C i -C ₆ alkyl group which may be substituted by halogen, an aryl group which may be substituted), and the ring C has 1 to 3 substituents (neighboring Two adjacent substituents may be bonded to each other to form a ring). Pyridinium Dobenzoji Ajin derivative or a salt thereof shows the Zen ring.), And hydrates and solvates

The following general formula (3)

(In the formula, Y is a halogen ^{_{atom, OS 0 2 R 1 4 (}} R 1 4 is a halogen may be substituted alkyl group of C i~C _6, unsubstituted or may § Li have one Le group), B (R ¹⁵ ) 2 (R ¹⁵ is a hydroxyl group, (^ to ( ₆ alkyl group or C to C ₆ alkoxy group) or R ¹⁵ is bonded to each other to form a ring May be. ), L i, MgBr or ZnC 1, wherein the ring A is each independently selected from one to three substituents (when two adjacent substituents are bonded to each other, Or a heterocyclic ring which may have a ring). 2. The method for producing a pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 1, wherein the compound represented by the formula (1) is reacted.

1 1 The following general formula (4)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring A is independently selected from 1 to 3 substituents (adjacent Two substituents may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have 1 to 3 substituents (two adjacent substituents) A benzene ring, which may have a substituent, wherein the substituents may combine with each other to form a ring), and the ring C has from 1 to 3 substituents (two adjacent substituents are bonded to each other). R ³ represents a benzene ring which may have

(R ⁷ is a halogen atom, a hydroxyl group, an optionally substituted C Alkoxy group ^{_{~C 6, OS 0 2 R 12}} (R 1 2 is an alkyl group, an optionally substituted Ariru group optionally C i~C ₆ be halogenated), i is an integer of 1-6 Is shown. ) Or

(R ⁸ is a halogen atom, a hydroxy group, an optionally substituted C ₆ alkoxy group, an arylmethyloxy group, or a reactive residue, and j represents an integer of 1 to 6.) And the salts, hydrates and solvates thereof, and the following general formula (5)

H R (5)

(Wherein, R ⁹ is an amino group, a mono- or di-substituted C ₆ -C ₆ alkylamino group, a 4- to 9-membered cyclic group which may be substituted and may contain 1 to 3 hetero atoms. 5. The process for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to claim 3, wherein the compound represented by the formula: is reacted.

1 2. The following general formula (6)

(6)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i -C ₆ alkyl group, and ring A is independently selected from one to three substituents (adjacent two A substituent may be bonded to each other to form a ring) or a homocyclic or heterocyclic ring which may have a ring, wherein the ring B has 1 to 3 substituents (two adjacent substituents) May be bonded to each other to form a ring), and the ring C may have 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring And a salt, hydrate and solvate thereof and a pyridobenzodiazine derivative represented by the following general formula (II):

(Wherein, Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C i Cs, R ⁷ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C i- A C ₆ alkoxy group, 〇S 0 ₂ R ¹² (R ¹² is a substituted or unsubstituted C 丄 -C ₆ alkyl group-an optionally substituted aryl group), i is 1 Represents an integer of from 6 to 6.) or

The following general formula (8)

(Wherein, V is a halogen atom, an optionally substituted C i -C ₆ alkoxy group or 〇 S 0 ₂ R ¹⁶ (R ¹⁶ is an optionally substituted C i Cs alkyl Group, aryl group which may be substituted), R ⁸ Represents a hydroxyl group, an optionally substituted C ₆ -C ₆ alkoxy group-arylmethyloxy group or a reactive residue, and j represents an integer of 1-6. Or the following general formula (9)

W- S 0 P-R (9)

(W is a halogen atom, a hydroxy group, a C i-C ₆ alkoxy group, OS〇 ₂ R ¹⁷ (R ¹⁷ is a C i-C ₆ alkyl group which may be halogen-substituted, 9. A compound represented by the following formula ( ₆ ): reacting a compound represented by an aryl group which may be substituted) or a reactive residue: ⁶ is a hydrogen atom or a C ₆ -C ₆ alkyl group. The method for producing the pyridobenzoxazine derivative or the salt, hydrate and solvate thereof according to the above.

1 3 The following general formula (10)

(Wherein, R ³ is a hydrogen atom, an optionally substituted C ^ Ce alkylcarbonyl group, an optionally substituted C ₁ -C ₆ alkylsulfonyl group, an optionally substituted C 1 R ¹ represents a halogen atom, a hydroxyl group, a C i -C ₆ alkoxy group, or an arylmethyloxy group, which represents an alkyl group of -C ₆ , an arylmethyl group which may be substituted, and an alkoxycarbonyl group. Or a reactive residue. A homo- or heterocyclic ring which may have 1 to 3 substituents selected vertically (two adjacent substituents may combine with each other to form a ring) And ring C represents a benzene ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring). ) Or a salt, hydrate or solvate thereof represented by the following general formula (11)

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C ₁ to C ₆ alkyl group; ring B has 1 to 3 substituents (a ring in which two adjacent substituents are The benzene ring which may have a compound represented by the formula: wherein the pyridobenzodiazine derivative or a salt thereof, a hydrate and a solvent thereof. Manufacturing method of Japanese products.

1 4. The following general formula (1)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i -C ₆ alkyl group, R ³ is a hydrogen atom, an optionally substituted C i -C 6 alkylcarbonyl group, C i Ce al which may be substituted A ring sulfonyl group, an optionally substituted CiCe alkyl group, an optionally substituted arylalkyl group and an alkoxycarbonyl group, wherein ring A is independently selected from 1 to 3 substituents (Adjacent two substituents may be bonded to each other to form a ring), which represents a homo- or heterocyclic ring which may have a ring B having 1 to 3 substituents (adjacent A benzene ring, which may have two substituents which may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent substituents Which may be bonded to each other to form a ring). And a salt, hydrate and solvate thereof represented by the formula (1) as a pharmaceutical composition.

1 5. The following general formula (1)

(In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom or an alkyl group of C i to C ₆ , R ³ is a hydrogen atom, C i to C

6, an optionally substituted C t -C ₆ alkylsulfonyl group, an optionally substituted C i -C ₆ alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group Ring A may have 1 to 3 independently selected substituents (two adjacent substituents may be bonded to each other to form a ring) Represents an aromatic or heterocyclic ring, and the B ring has 1 to 3 substituents A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). NK1 receptor antagonist, characterized by containing a pyridobenzodiazine derivative represented by the following or a salt, hydrate and solvate thereof as a pharmaceutical composition.

1 6

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i -C ₆ alkyl group; R ³ represents a hydrogen atom, an optionally substituted C i C ₆ alkylcarbonyl group, Represents an optionally substituted C ₁ to C ₆ alkylsulfonyl group, an optionally substituted ₆ alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group, and each ring A is independently A selected homo- or heterocyclic ring which may have 1 to 3 substituents (adjacent two substituents may be bonded to each other to form a ring); 1-3 substituents

A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). ) Or a salt, hydrate or solvate thereof as a pharmaceutical composition. A prophylactic or therapeutic agent for dysuria including bladder dysfunction such as urinary frequency and urinary incontinence characterized by containing.

1 7. The following general formula (1)

(Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or a C i -C ₆ alkyl group, R ³ is a hydrogen atom, an optionally substituted C i -C ₆ alkylcarbonyl group, substituted optionally may be C i to Al alkylsulfonyl group C _6, indicates an optionally substituted € ^ 0 ₆ alkyl group, a substituted I § Li one good even if Rumechiru group and alkoxycarbonyl group, The ring A may have 1 to 3 independently selected substituents (adjacent two substituents may be bonded to each other to form a ring), Indicates a heterocyclic ring, and ring B has 1 to 3 substituents

A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). ) A prophylactic or therapeutic agent for digestive diseases including ulcerative colitis and Crohn's disease, which comprises a pyridobenzodiazine derivative represented by the formula or a salt, hydrate or solvate thereof as a pharmaceutical composition. 1 8 The following general formula (1)

(Wherein, R ¹ and R ² are the same or different and represent a hydrogen atom or a C i -C ₆ alkyl group, R ³ is a hydrogen atom, an optionally substituted C i -C ₆ alkylcarbonyl group, optionally substituted C i to Al alkylsulfonyl group C _6, optionally substituted C丄-alkyl C _6, shows the optionally substituted Arirumechiru group and alkoxycarbonyl group, a ring Each may be independently selected from 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring); The ring B has 1 to 3 substituents

A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). X-ray irradiation, a chemotherapeutic agent, pregnancy, migraine, postoperative disease, gastrointestinal tract, characterized by containing a pyridobenzodiazine derivative represented by the following formula or a salt, hydrate and solvate thereof as a pharmaceutical composition An agent for preventing or treating vomiting induced by hypokinesia or side effects of drug administration.

1 9. The following general formula (1)

(Wherein, R ¹ and R ² are the same or different and represent a hydrogen atom or a C i -C ₆ alkyl group, R ³ is a hydrogen atom, an optionally substituted C i -C ₆ alkylcarbonyl group, optionally substituted C丄~ al alkylsulfonyl group C _6, indicates an optionally substituted C-alkyl group of C _6, optionally substituted Arirumechiru group and alkoxycarbonyl group, a ring it Represents a homo- or hetero-group which may have 1 to 3 substituents independently selected (two adjacent substituents may be bonded to each other to form a ring); The B ring has 1-3 substituents

A benzene ring which may have a benzene ring (optionally two adjacent substituents may be bonded to each other to form a ring), and the C ring has 1 to 3 substituents (two adjacent And the substituents may be bonded to each other to form a ring). ) A therapeutic agent for asthma, cough, pain, migraine, toothache, rheumatoid arthritis, etc., characterized by containing a pyridobenzodiazine derivative represented by the formula or a salt, hydrate and solvate thereof as a pharmaceutical composition. . 2 0

(Wherein R ¹¹ is a halogen atom, a hydroxyl group, an alkoxy group of C ^ CS, an arylmethyloxy group or a reactive residue,

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or an alkyl group of CiCe, and the B ring has 1 to 3 substituents each other (adjacent 2

Which may form a ring together). ),

R ³ is a hydrogen atom, an alkyl carboxymethyl sulfonyl group optionally C i to C ₆ optionally substituted, an alkylsulfonyl group optionally C. 1 to C 6 optionally substituted, an optionally substituted in the C ~ C ₆ also An alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group,

X is a halogen atom, human de port cyclohexyl group or 0 S_〇 ₂ R ^{1 3} (R ^{1 3} is halo gen optionally substituted C i Ce alkyl group, substituted Moyoi § Li Ichiru group ),

Ring C represents a halogen atom, an optionally substituted C丄-alkyl C _6, human de port hexyl group, an optionally substituted C i to C ₆ alkoxy group, optionally substituted C丄~ C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted aryl Mechiruokishi group, C ₃ ~ C丄. A cycloalkoxy group, a C ₃ -C ₁₀ cycloalkanoyloxy group, an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, and 1 to 3 heteroatoms. good not 4-9 membered cyclic amino group, C i to an alkylcarbonyl § amino group of C _6, C丄alkoxycarbonyl § Mi amino group of ~ C _6, C ^ C s Al kill sulfonyl § Mi amino group, a substituted 1 to 3 substituents each independently selected from an arylsulfonylamino group, a cyano group or a nitro group which may be substituted (two adjacent substituents are bonded to each other to form a ring A benzene ring which may have 4. The intermediate for producing a pyridobenzodiazine derivative or a salt, hydrate or solvate thereof according to claim 2, which is a pyridobenzodiazine derivative represented by the formula:

2 The following general formula (1 3)

(Wherein, R ³ is a hydrogen atom, an optionally substituted C i -C ₆ alkylcarbonyl group, an optionally substituted C -C ₆ alkylsulfonyl group, an optionally substituted C 1 to ₆ are an alkyl group, a substituted or unsubstituted arylmethyl group and an alkoxycarbonyl group, and R ¹⁰ is a halogen atom, a hydroxyl group, a C i Cs alkoxy group, or an arylmethyl group. Represents a xy group or a reactive residue,

Ring A is a halogen atom, an optionally substituted C i -C ₆ alkyl group, Optionally substituted aryl group, hydroxy group, optionally substituted C i -C ₆ alkoxy group, c ₃ -c ₁ . Cycloalkoxy group, optionally substituted C i -C ₆ alkanoyloxy group, optionally substituted aryloyloxy group, optionally substituted arylmethyloxy group, C ₃ -C i. A cycloalkanoyloxy group, an optionally substituted C 丄 -C ₆ alkylthio group, an optionally substituted C i -C ₆ alkylsulfinyl group, an optionally substituted C-C ₆ An alkyl group, an amino group, a mono- or di-substituted C ₆ alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a C i to C ₆ Alkylcarbonylamino group, C i -C ₆ alkoxycarbonylamino group, C i Ce alkylsulfonylamino group, optionally substituted arylsulfonylamino group, C i -C ₆ alkylcarbonyl group , A formyl group, a carboxyl group, a C i -C ₆ alkoxycarbonyl group, a mono- or di-substituted C i -C ₆ alkyl group rubamoyl group, which may contain 1 to 3 heteroatoms 4 ~ 9 member annular force It has 1 to 3 substituents each independently selected from a bamoyl group, a cyano group, and a nitro group (two adjacent substituents may be bonded to each other to form a ring) Represents an allo- or heterocyclic ring which may be

Ring C is a halogen atom, an optionally substituted C i -C ₆ alkyl group-hydroxyl xyl group, an optionally substituted C 丄 -C ₆ alkoxy group, an optionally substituted C i Arca Noi Ruo alkoxy group ~ C _6, optionally substituted § Li Roiruokishi group, an optionally substituted Ariru Mechiruokishi group, cycloalkoxy group of _{C 3 ~ C 1 0, C} ad. Cycloalkadienyl Noi Ruo alkoxy group, an amino group, mono- or di-substituted 〇-alkylamino amino group of C _6, 1 - 3 atoms of but it may also contain heteroatoms 4-9 membered cyclic § Mi amino group , alkylcarbonyl § Mino of C丄~ C ₆ Group, C i -C ₆ alkoxycarbonylamino group, C i C s alkylsulfonylamino group, optionally substituted arylsulfonylamino group, cyano group or nitro group. Represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring). 4. The intermediate for producing a pyridobenzodiazine derivative or a salt, hydrate or solvate thereof according to claim 2, which is a pyridobenzodiazine derivative represented by the formula:

(In the formula, R ¹ represents a halogen atom, a hydroxyl group, a C i Ce alkoxy group, an arylmethyloxy group or a reactive residue, and R ³ represents a hydrogen atom, which may be substituted. C i -C ₆ alkylcarbonyl group; optionally substituted C -C ₆ alkylsulfonyl group, optionally substituted C i -C ₆ alkyl group, optionally substituted arylmethyl group, and indicates alkoxycarbonyl two Le group, X is a halogen atom, human de port cyclohexyl group or a ^{_{0 S 0 2 R 1 3 (}} R 1 3 is an alkyl group optionally C i to C 6 be halogen-substituted, substituted And the ring C is a benzene which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring) A pyridobenzodiazine derivative represented by the following formula: or a salt or hydrate thereof. Fine solvates and the following general formula (3)

(Wherein, Y is a halogen atom, 0 S〇 ₂ R ¹⁴ (R ¹⁴ is the same as described above), B (R ¹⁵ ) 2 (R ¹⁵ is a hydroxyl group, a C i Cs alkyl group or C 丄~.

The 6 alkoxy groups or R ¹⁵ may be bonded to each other to form a ring. ), L i, MgBr or ZnCl; ring A is independently selected from 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring A homo- or heterocyclic ring which may have 22. The method for producing a pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 21, wherein the compound represented by the following formula is reacted.

2 3 The following general formula (15)

(Wherein R ¹¹ is a halogen atom, a hydroxyl group, an alkoxy group of C ^ Cs, an arylmethyloxy group or a reactive residue and

(R ¹ and R ² may be the same or different and each represents a hydrogen atom or a C ₁ -C ₆ alkyl group, and the ring B has 1 to 3 substituents. Which may form a ring together). ) Indicates, X is a halogen atom, human Dorokishiru group or ^{_{0 S 0 2 R 1 3 (}} R 1 3 is halogen optionally substituted C i to alkyl groups of C _6, optionally substituted Ariru group) And ring C represents a benzene ring which may have 1 to 3 substituents (two adjacent substituents may be bonded to each other to form a ring), and R ³ is

(R ⁷ is a halogen atom, human de port hexyl group, an optionally substituted alkoxy group having C丄-C _6, OS_〇 ^₂ R ¹² (R ¹ ₂ is a good C ~ C ₆ be halogen-substituted An alkyl group, an aryl group which may be substituted), and i represents an integer of 1 to 6.) or

(R ⁸ is a halogen atom, a hydroxyl group, an optionally substituted C 丄-( ₆ alkoxy group, arylmethyloxy group, or reactive residue, and j represents an integer of 1-6. ) Or a salt, hydrate or solvate thereof and a general formula (5)

HR ⁹ (5)

(In the formula, R ⁹ is an amino group, a mono- or di-substituted Ci-C ₆ alkylamino group, a 4- to 9-membered group which may be substituted and may contain 1 to 3 hetero atoms. Represents a cyclic amino group.) 21. The method for producing a pyridobenzoxazidi derivative or a salt, hydrate and solvate thereof according to claim 20, wherein

2 4. The following general formula (16)

(In the formula, R ¹¹ is a halogen atom, a hydroxyl group, a C i C s alkoxy group, an arylmethyloxy group or a reactive residue and

(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 has 1 to 3 substituents (adjacent 2 substituents are bonded to each other to form a ring to indicate a benzene璟have also may) have.) indicates, X is a halogen atom, human de port hexyl _{^{group, 0 S 0 2 R 1 3}} (R 1 3 is optionally halogen-substituted A C i -C ₆ alkyl group or an optionally substituted aryl group), and the C ring has 1 to 3 substituents (two adjacent substituents are bonded to each other to form a ring) And a salt, hydrate and solvate thereof represented by the following general formula:

(7)

(Wherein, z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of c _{1 to} c ₆ , R ⁷ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C i Ce alkoxy group or 0 S 0 ₂ R ¹² (R ¹² is an optionally substituted C 丄 to C ₆ alkyl group or an optionally substituted aryl group), i is an integer of 1 to 6 Or the following general formula (8)

(Wherein, V is a halogen atom, alkoxy group having a C丄~ C _{6 ^{substituted, OSO 2: R 1 6 (}} R 1 6 is an optionally halogen-substituted C

Alkyl group of ₁ -C _6, optionally substituted Ariru group), R ⁸ is heat-de port hexyl group, an optionally substituted C i to C ₆ alkoxy group, § Li one Rumechiruokishi group or a reactive The residue, j, represents an integer of 1 to 6. Or the following general formula (9)

W- S 0 R 9)

(Wherein, W is a halogen atom, arsenic Dorokishiru group, C I～C an alkoxy group or a reactive residue of _6, R ⁶ is a hydrogen atom or an alkyl group C i C s) reacting a compound represented by 20. The method for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to claim 20, characterized in that:

2 5. The following general formula (17)

(In the formula, R ¹ ° represents a hydroxyl group, a alkoxy group of CC ₆ , an arylmethyloxy group or a reactive residue, and each of the A rings has 13 independently selected substituents (neighboring Two substituents may be bonded to each other to form a ring), or a homocyclic or heterocyclic ring which may have the same meaning as described above, and the ring C is the same as defined above. Or a salt, hydrate and solvate thereof and the following general formula (7)

(Wherein, Z is a halogen atom, a hydroxyl group, an alkoxy group or a reactive residue of C ^ Cs, R ⁷ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted C i C s is an alkoxy group or 〇S〇 ₂ R ¹² (where R ¹² is a hydrogen atom or an optionally substituted CC ₆ alkyl group or an optionally substituted aryl group), and i is an integer of 16 ) Or the following general formula (8)

(Wherein, V is a halogen atom, an optionally substituted C i C ₆ Al A oxy group, 〇S〇 ₂ R ¹⁶ (R ¹⁶ is a C ₁ C ₆ alkyl group which may be substituted by halogen, an aryl group which may be substituted), and R ⁸ is a hexyl group or substituted group And an alkoxy group, arylmethyloxy group or reactive residue of CC ₆ , and j represents an integer of 16. Or the following general formula (9)

(Wherein, W is a halogen atom, a hydroxy group, a C ₁ C ₆ alkoxy group or a reactive residue, and R ⁶ is a hydrogen atom or a C i C alkyl group). 22. The method for producing a pyridobenzoxazine derivative or a salt, hydrate and solvate thereof according to claim 21.

2 6. The following general formula (18)

(Wherein, R ³ is a hydrogen atom, alkyl ylcarbonyl group optionally CC ₆ substituted, an alkylsulfonyl group optionally CC ₆ substituted, substituted optionally alkyl group which may CC _6, R i Q represents a halogen atom, a hydroxyl group, a C i Cs alkoxy group, an arylmethyloxy group or a reactive residue, and represents an arylmethyl group and an alkoxyl group which may be substituted; X is a halogen atom, a hydroxyl-containing xyl group or 0 S 0 ₂ R ¹³ (R ¹³ is halogen-substituted Alkyl group which may C丄~ C _6, optionally substituted indicates which may Ariru group), C ring 1-3 substituents (bonded two adjacent substituents together to form a ring A benzene ring which may have. And a salt, hydrate and solvate thereof represented by the following general formula (11):

(R ¹ and R ² are the same or different and each is a hydrogen atom or an alkyl group of CiCe; ring B has 1 to 3 substituents (adjacent two substituents are bonded to each other to form a ring 20. The pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 20, which is reacted with a compound represented by the following formula: Production method.

2 7. The following general formula (19)

(Wherein, R ³ is a hydrogen atom, an optionally substituted C i -C ₆ alkylcarbonyl group, an optionally substituted C i -C ₆ alkylsulfonyl group, or an optionally substituted A C 1 to C ₆ alkyl group, an optionally substituted arylmethyl group and an alkoxycarbonyl group; and the C ring has 1 to 3 substituents (a ring in which two adjacent substituents are bonded to each other. Represents a benzene ring which may have A benzodiazine derivative represented by the following general formula (20)

HC (C 0 R ¹ °) (0)

(Wherein R ¹⁰ is the same or different and reacts a compound represented by a halogen atom, a hydroxyl group, a C _{1 to} C ₆ alkoxy group, an arylmethyloxy group or a reactive residue) The following general formula (2 1)

20. The method for producing a pyridobenzodiazine derivative or a salt, hydrate and solvate thereof according to claim 20, wherein R ³ and R ¹ are the same as described above.