JP2009051830A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition comprising as an effective ingredient a nitrogen-containing heterobicyclic compound affinitive for a mineralocorticoid receptor (MR). <P>SOLUTION: The pharmaceutical composition comprises as an effective ingredient a compound represented by general formula [I] [wherein the ring A is a benzene ring or the like optionally bearing a substituent group other than R<SP>1</SP>; R<SP>1</SP>is a group represented by the formula: R<SP>a</SP>SO<SB>2</SB>NH-, or the like; R<SP>a</SP>is an alkyl group or the like; R<SP>2</SP>and R<SP>3</SP>are the same or different and are each a hydrogen atom, a phenyl group, an optionally substituted alkyl group, or the like; X is an oxygen atom or the like; Y is a group represented by the formula: -C(=O)-, or the like; Ar is an optionally substituted aryl group or an optionally substituted heteroaryl group; Q is a single bond, an alkylene group or the like] or a pharmaceutically acceptable salt thereof. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a pharmaceutical composition or an MR modulator useful for the prevention / treatment of various diseases or pathologies involving mineralocorticoid receptor (MR) receptor / and / or aldosterone.

  Low molecular weight hydrophobic physiologically active substances such as steroid hormones exert physiological actions through specific nuclear receptors as ligands. The nuclear steroid hormone receptor group forms one gene superfamily, and these receptors function as ligand-dependent transcription factors to control (activate or activate) the expression of target genes at the transcriptional level. Suppress). Such steroid hormone receptors include mineralocorticoid receptor (MR), glucocorticoid receptor (GR), androgen receptor (AR), estrogen receptor (ER) and progesterone receptor (PR). . Steroid hormones that are ligands of the above receptors, such as mineralocorticoids (aldosterone) and glucocorticoids (cortisol, etc.) exert various physiological functions via their respective receptors (Non-patent Document 1).

  Aldosterone, an MR-specific ligand, is one of the mediators in the renin-angiotensin-aldosterone system (RAAS). Traditionally, aldosterone has been thought to be produced only in the adrenal gland and is only a hormone that acts on distal tubules to regulate the metabolism of sodium and water. However, recent studies have revealed that aldosterone is produced in various tissues such as the heart, blood vessels, and brain, and that its receptors are also widely distributed in cardiovascular tissues and the like. In addition, aldosterone is not only an exacerbation factor of hypertension, but also a risk hormone that exhibits various damaging effects on cardiac and vascular tissues (myocardial fibrosis and necrosis, enhanced catecholamine action, decreased baroreceptor response, etc.) Has come to be recognized as. In recent large-scale clinical trials (RALES and EPHESUS), the combined use of aldosterone receptor antagonists (eprerenone or spironolactone) with conventional therapies such as ACE inhibitors has resulted in hospitalization rates and deaths due to heart disease in patients with severe heart failure It has been confirmed that the rate was significantly reduced and that the prognosis of patients with acute myocardial infarction was significantly improved (Non-patent Documents 2 and 3). Thus, in cardiovascular diseases and the like in which aldosterone and its receptor are involved, it is considered that effective blocking of the hormone is important for establishing an effective therapeutic method.

  As described above, a ligand having affinity for MR and having an activity to modulate the function of the receptor, that is, an inhibitor, antagonist, agonist, partial antagonist or partial agonist for the receptor is aldosterone. It may be useful as a prophylactic / therapeutic agent for various diseases / pathologies involved. On the other hand, steroidal MR ligands such as spironolactone and eplerenone often have their own serious side effects (gynecomastia, abnormal menstrual flow, erectile dysfunction, etc.). Development of highly safe compounds is desired.

  To date, examples of non-steroidal ligands having an affinity for MR include 6H-dibenzo [b, e] oxepin derivatives (Patent Document 1), dihydropyridine derivatives (Patent Document 2), and dibenzo [b, d] pyran derivatives. (Non-patent Document 4), 1,4-dihydro-2H-3,1-benzoxazin-6-ylsulfonamide derivative (Patent Document 7) and the like are known. However, a 1,4-benzoxazine derivative or the like having an MR regulating action (MR antagonism etc.) has not been reported.

On the other hand, 1,4-benzoxazine derivatives are disclosed in Patent Documents 3-6.
International Publication No. 2005/066161 Pamphlet International Publication No. 2005/097118 Pamphlet International Publication No. 97/017333 Pamphlet European Patent Application No. 432893A International Publication No. 2001/057003 Pamphlet International Publication No. 99/00371 Pamphlet International Publication No. 2006/077821 Pamphlet Journal of Endocrinology, 2001; 169: pp 437-445. New England Journal of Medicine, 2003; 341: p. 709-717 New England Journal of Medicine, 2003; 348: p. 1309-1321 Bioorganic & Medicinal Chemistry Letters, 2004; 14: p. 2079-2082

  An object of the present invention is to provide a pharmaceutical composition comprising a nitrogen-containing heterobicyclic compound having a mineralocorticoid receptor (MR) modulating action (in particular, an MR receptor antagonistic action) as an active ingredient.

  The present invention relates to general formula [I]:

[Where,
Ring A, R ¹ Other than the benzene ring may have a substituent, or R ¹ other than the optionally may nitrogen-containing 6-membered aromatic heterocyclic ring having a substituent group,
R ¹ is a group represented by the formula: R ^a SO ₂ NH—, R ^a SO ₂ NH—CH ₂ — or (R ^b ) (R ^c ) NSO ₂ —,
R ^a is an alkyl group, a cycloalkyl group, an amino group which may be substituted with an alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group,
R ^b and R ^c are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group,
R ² and R ³ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkenyl group, a carboxyl group, an alkoxycarbonyl group, an optionally substituted carbamoyl group or an optionally substituted group. They are aryl groups, or they are bonded to each other to form a saturated or unsaturated cyclic group together with adjacent carbon atoms (the cyclic group is the same or different one or two selected from sulfur atom, oxygen atom and nitrogen atom) Or may have a hetero atom of
X is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: —NR ⁴ —;
R ⁴ represents a hydrogen atom, an alkyl group, an optionally substituted aralkyl group or an acyl group,
Y is a group represented by the formula: —C (═O) —, —C (═S) — or —CH (R ⁵ ) —,
R ⁵ is a hydrogen atom, an alkyl group or an optionally substituted aryl group,
Ar represents an optionally substituted aryl group or an optionally substituted heteroaryl group;
Q represents a single bond, an alkylene group or an alkenylene group. ]
And a pharmacologically acceptable salt thereof as an active ingredient.

  The present invention also relates to a mineralocorticoid receptor modulator comprising the compound [I] or a pharmaceutically acceptable salt thereof as an active ingredient.

  Furthermore, the present invention provides a compound of the general formula [Ia]:

[Where,
Ring A, R ¹¹ Other than be a benzene ring optionally having a substituent, or R ¹¹ 6-membered aromatic or nitrogen-containing substituted besides heterocycle,
R ¹¹ is a group represented by the formula: R ^aa SO ₂ NH—, R ^aa SO ₂ NH—CH ₂ — or (R ^b ) (R ^c ) NSO ₂ —,
R ^aa is an alkyl group, a cycloalkyl group, an amino group optionally substituted with 1 to 2 alkyl groups, a phenyl group, or a 5-6 membered monocyclic heteroaryl group,
R ^b and R ^c are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group,
R ²¹ and R ³¹ are either a hydrogen atom, a halogen atom or an alkyl group, the other is a hydrogen atom, an alkyl group, an alkoxycarbonyl group, a phenyl group or a halogenophenyl group, or both are bonded to each other to form an adjacent carbon atom. And forms a saturated or unsaturated cyclic group (the cyclic group may have the same or different 1-2 hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom),
^Xa is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: -NH-
Y ^a is ^{a group} represented by the formula: —C (═O) —, —C (═S) — or —CH (R ⁵¹ ) —,
R ⁵¹ represents a hydrogen atom or a phenyl group,
Ar ¹ is (a) a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxyalkyl group, an acyloxyalkyl group, or 1 to 3 halogen atoms. Optionally substituted alkoxy group, alkoxycarbonylalkoxy group, alkylthio group, alkylenedioxy group optionally substituted with 1 to 2 halogen atoms, optionally substituted with 1 to 2 alkyl groups A phenyl (or naphthyl) group optionally substituted with 1 to 3 groups selected from an amino group, an amino group substituted with an acyl group, a cycloalkyl group and an alkylsulfonyl group;
(B) a thienyl group which may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group (the thienyl group may be condensed with a benzene ring);
(C) a pyridyl group optionally substituted by 1 to 2 groups selected from a halogen atom, a nitro group, an alkyl group and a trihalogenoalkyl group;
(D) a pyrimidinyl group optionally substituted by a halogen atom;
(E) a quinolyl group;
(F) a pyridazinyl group optionally substituted by a halogen atom;
(G) a pyrrolyl group; or (h) a furyl group (the furyl group may be condensed with a benzene ring),
(I) a thiazolyl group (the thiazolyl group may be condensed with a benzene ring), or (j) an imidazolyl group (the imidazolyl group may be condensed with a benzene ring and substituted with an alkyl group). And Q represents a single bond, an alkylene group or an alkenylene group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient.

Compound [I], which is an active ingredient of the present invention, exhibits high affinity for mineralocorticoid receptor (MR) in mammals. For example, in a binding test using rat MR and ³ H-aldosterone (the Journal of Pharmaceutical and Experimental Therapeutics, 1987; conducted in accordance with the method described in 240: p.650-656; details are described in the experimental examples below), N- (3-oxo-2,4-diphenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide, which is an active ingredient of the present invention, and N- (2,2 -Dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide has a Ki value of 10 μM for aldosterone binding to rat kidney-derived MR. Was less than. Therefore, a pharmaceutical composition comprising compound [I] or a pharmacologically acceptable salt thereof as an active ingredient prevents or treats various diseases involving MR (for example, cardiovascular diseases including hypertension and heart failure). It is useful as a medicine for

  In the compound [I] / [Ia], when the ring A is a nitrogen-containing 6-membered aromatic heterocyclic ring, examples of the heterocyclic ring include a pyridine ring, a pyrazine ring, a pyrimidine ring, and a pyridazine ring. 6-membered aromatic heterocycles containing 1 to 2 nitrogen atoms, and among them, a pyridine ring is preferred.

Ring A may have 1 to 3 substituents that are the same or different from R ¹ (or R ¹¹ ). Examples of such a substituent include (a) a halogen atom, (b) an alkyl group (the alkyl group is substituted with a group selected from a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group, and a dialkylamino group). (C) a hydroxyl group, (d) an alkoxy group, (e) an amino group (the amino group may be substituted with one or two groups selected from an alkyl group and an acyl group), (F) a cyano group, (g) a carboxyl group, (h) an alkoxycarbonyl group, (i) an alkenyl group (which may be substituted with an alkoxy group), (j) an alkanoyl group, (k) a cycloalkyl group and ( l) A group selected from a carbamoyl group (which may be substituted with 1 to 2 alkyl groups).

When the substituent on the ring A is a group containing an acyl group (for example, an acylamino group), examples of the acyl group include the following general formula:
R ^x COOH
[Wherein, R ^x represents an alkyl group, an alkyloxy group, an aryl group, or an aralkyloxy group. ]
And a group formed by removing the hydroxyl group from the carboxylic acid represented by (group represented by the formula: R ^x CO—). Examples of such acyl groups include alkanoyl groups such as formyl group, acetyl group, propionyl group and pivaloyl group, methoxycarbonyl group, ethoxycarbonyl group, alkoxycarbonyl group such as tert-butoxycarbonyl group, and aryl such as benzoyl group. An acyl group such as an aralkyloxycarbonyl group such as a carbonyl group and a benzyloxycarbonyl group is exemplified.

In the compound [I], when R ^a or Ar is an aryl or heteroaryl group, examples of the aryl or heteroaryl group include a phenyl group, a naphthyl group, a thienyl group, a pyrrolyl group, a furyl group, a thiazolyl group, and an oxazolyl group. Groups, imidazolyl groups, pyrazolyl groups, pyridyl groups, pyridazinyl groups, pyrimidinyl groups, pyrazinyl groups, benzofuranyl groups, benzoxazolyl groups, benzothienyl groups, quinolyl groups, isoquinolyl groups, monocyclic or bicyclic groups An aryl or heteroaryl group is mentioned. Of these, 6 to 10-membered monocyclic or bicyclic aryl groups such as a phenyl group or a naphthyl group, or 5 to 5 containing the same or different 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom A 10-membered monocyclic or bicyclic heteroaryl group is preferable, and a phenyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a benzothienyl group, a benzofuranyl group, and the like are particularly preferable.

The aryl or heteroaryl group in R ^a or Ar is substituted with (a) a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom), (b) a hydroxyl group, and (c) 1 to 3 halogen atoms. Alkyl groups (methyl group, ethyl group, propyl group, tert-butyl group, trifluoromethyl group, difluoromethyl group etc.), (d) hydroxyalkyl group (hydroxymethyl group, hydroxyethyl group etc.), (E) Acyloxyalkyl group (benzoyloxymethyl group etc.), (f) Alkoxy group (methoxy group, ethoxy group, propoxy group, tert-butoxy group, trifluoro) optionally substituted with 1 to 3 halogen atoms Methoxy group, etc.), (g) alkoxycarbonylalkoxy group (tert-butoxycarbonylmethoxy group, etc.) (H) an alkylthio group (methylthio group, ethylthio group, etc.), (i) an alkylenedioxy group (methylenedioxy group, ethylenedioxy group, difluoromethylenedioxy) optionally substituted by 1 to 2 halogen atoms Group), (j) an amino group (amino group, dimethylamino group, etc.) optionally substituted with one or two alkyl groups, (k) an amino group substituted with an acyl group (such as an acetylamino group). Substituted with 1 to 3 groups selected from (l) cycloalkyl group (cyclopropyl group, cyclopentyl group etc.) and (m) alkylsulfonyl group (methylsulfonyl group, ethylsulfonyl group etc.) It may be. Examples of the acyl group include a group represented by the above formula: R ^x CO—, and among these, an alkanoyl group such as an acetyl group or an arylcarbonyl group such as a benzoyl group is preferable.

In the compound [I], when R ² or R ³ is an aryl group, examples of the aryl group include 6 to 10-membered monocyclic or bicyclic aryl groups such as a phenyl group or a naphthyl group. Of these, a phenyl group is preferred. The aryl group may be substituted with 1 to 2 halogen atoms (fluorine atom, chlorine atom, bromine atom, iodine atom).

In the compound [I], when R ² and R ³ are bonded to each other to form a saturated or unsaturated cyclic group together with adjacent carbon atoms, the cyclic group includes (a) a cycloalkyl group (cyclopropyl group) , Cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.), (b) cycloalkenyl group (cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, etc.) or (c) saturated or unsaturated 5- to 8-membered nitrogen-containing, oxygen-containing Or a 3-8 membered saturated or unsaturated monocyclic group, such as a sulfur-containing monocyclic heterocyclic group, etc. are mention | raise _{| lifted} , Among these, a _C3-8 cycloalkyl group is preferable.

In the compound [I], when R ⁴ is an aralkyl group, examples of the aralkyl group include a C _6-10 monocyclic or bicyclic aryl-C _1-6 alkyl group (benzyl group, phenethyl group, 3- Phenylpropyl group, (1-naphthyl) methyl, 2- (1-naphthyl) ethyl group and the like), among which benzyl group is preferred. The aryl moiety in the aralkyl group may be substituted with a halogen atom or the like. Examples of the acyl group for R ⁴ include a group represented by the aforementioned formula: R ^x CO—. Specific examples of such acyl groups include, for example, alkanoyl groups (acetyl group, propionyl group, pivaloyl group, etc.), alkoxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, etc.), aralkyloxycarbonyl, etc. Group (benzyloxycarbonyl group and the like) and the like.

Examples of the aryl group in R ⁵ include 6 to 10-membered monocyclic or bicyclic aryl groups such as a phenyl group or a naphthyl group, and among these, a phenyl group is preferable. The aryl group may be substituted with 1 to 2 halogen atoms.

  Among the compounds [I], a preferable compound includes, for example, a compound in which X is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: —NH—.

  Among the above, as a more preferable compound, for example, the following general formula [Ia]:

[Wherein the symbols have the same meaning as described above. ]
Or a pharmacologically acceptable salt thereof.

More preferable compounds include, for example, in the general formula [Ia]:
Ring A is a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a trihalogeno-C _1-4 alkyl group, a hydroxy-C _1-4 alkyl group, a C _1-4 alkoxy-C _1-4 alkyl group other than R ¹¹ A benzene ring optionally substituted with a group selected from a C _1-4 alkoxy group, an amino group, a C _2-4 alkenyl group, a C _2-5 alkanoyl group and a C _3-8 cycloalkyl group,
R ¹¹ represents a C _1-4 alkylsulfonylamino group, a C _3-6 cycloalkylsulfonylamino group, a C _1-4 alkylaminosulfonyl group, a C _1-4 alkylsulfonylaminomethyl group, an aminosulfonylamino group, di (C _{1 -4} alkyl) aminosulfonylamino group or a mono _{(C 1-4} alkyl) aminosulfonyl group,
One of R ²¹ and R ³¹ is a hydrogen atom or a C _1-4 alkyl group, and the other represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a phenyl group, or both are bonded to each other to form C Forming a _3-8 cycloalkyl group,
^Xa is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: -NH-,
Ar ¹ is (a) a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C _1-4 alkyl group, a C _1-4 alkyl group substituted with 1 to 3 halogen atoms, a hydroxy-C _1-4 alkyl group , acyloxy _{-C 1-4} alkyl _{group, C 1-4} alkoxy groups, 1-3 _{C 1-4} alkoxy group substituted with a halogen _{atom, C 3-8} cycloalkyl _{group, C 1-4} alkylthio group, 1-2 _{C 1-4} alkyl amino group which may be substituted with a _{group, C 2-5} alkanoylamino _{group, C 1-4} C substituted with an alkylenedioxy group, and one to two halogen atoms _A phenyl group optionally substituted by 1 to 3 groups selected from _1-4 alkylenedioxy groups; (b) a naphthyl group; (c) a halogen atom and 1 selected from a trihalogeno-C _1-4 alkyl group; ~ 2 The thienyl which may be substituted with a group (or benzothienyl) group; (d) a halogen atom, a nitro _group, 1-2 groups selected from _{C 1-4} alkyl group and a trihalogeno _{-C 1-4} alkyl group A pyridyl group optionally substituted by: or (e) a benzofuranyl group,
Examples include compounds in which Q is a single bond or a C _1-4 alkylene group, and Y ^a is ^a group represented by the formula: —C (═O) —, —C (═S) — or —CH ₂ —.

Among the above, particularly preferable compound [Ia] is, for example,
(1) A compound in which R ²¹ and R ³¹ are both hydrogen atoms;
(2) A compound wherein R ²¹ is a hydrogen atom and R ³¹ is a C _1-4 alkyl group;
(3) A compound wherein R ²¹ is a hydrogen atom or a C _1-4 alkyl group, and R ³¹ is a phenyl group;
(4) A compound in which R ²¹ and R ³¹ are both C _1-4 alkyl groups;
(5) a compound in which R ²¹ is a hydrogen atom and R ³¹ is a halogen atom; or (6) a compound in which R ²¹ and R ³¹ are bonded to each other to form a C _3-8 cycloalkyl group with an adjacent carbon atom, etc. Can be given.

Among the particularly preferred compounds mentioned above are, for example:
N- (3-oxo-2,4-diphenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- (2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,4-difluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-chloro-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] ethanesulfonamide;
N- [4- (5-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- (4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- (4-benzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-fluorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (5-chloro-2-thienyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N ′-[4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] -N, N-dimethylsulfami De;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4- (3-thienyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-3,4-dihydrospiro [1,4-benzoxazine-2,1′-cyclobutane] -7-yl] methanesulfonamide;
N- [1- (4-fluorophenyl) -3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] methanesulfonamide;
N- [4- [4-Fluoro-3-trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [2,2-dimethyl-4- (4-methylphenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-3,4-dihydrospiro [1,4-benzoxazine-2,1′-cyclopropane] -7-yl] methanesulfonamide;
N- [2,2-diethyl-4- (4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2-ethyl-4- (4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4-[(4-trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] sulfamide;
N- [4- (2,4-difluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-3-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-3-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-Fluoro-3-methylphenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- [3- (Dimethylamino) -4-fluorophenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [4- (3-chloro-4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2-chloro-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2,6-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [6-amino-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [3- (Difluoromethyl) -4-fluorophenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
4- (4-chlorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (4-Chloro-2-cyanophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-bromophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (5-chloropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-chloro-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromo-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [4-Chloro-3- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [3-Fluoro-4- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (4-Chloro-3-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-Fluoro-4-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-Chloro-2-methylphenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (2,4-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-Chloro-4-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,4-Difluoro-5-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (3,4-dichlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (2-naphthyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-chloro-4- (4-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2,5-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromo-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2,2-Difluoro-1,3-benzodioxol-5-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine -7-yl] methanesulfonamide;
N- (4-mesityl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (5-Bromo-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-fluoro-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,5-dichloropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (4-Fluoro-2,3-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (3-chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4- (1-phenylethyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (3-methylbenzyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- {2,2-dimethyl-4- [2-methyl-5- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
N- [2,2-dimethyl-3-oxo-4- (2,4,6-trifluorophenyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
2-chloro-5- [2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl] benzyl benzoate;
N- [4- (4-Chloro-2-methoxy-5-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-2,2-difluoro-1,3-benzodioxol-5-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1, 4-Benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (3-methyl-5-nitropyridin-2-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [4-Fluoro-2- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [2,2-dimethyl-4- [2-methyl-4- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-chloropyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (3-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [5-Bromo-6-methylpyridin-2-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-Fluoro-4- (5-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [2,2-dimethyl-3-oxo-4-[(5- (trifluoromethyl) -2-thienyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-4-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-bromopyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [4-Chloro-3- (hydroxymethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [4- (6-Bromo-5-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-2-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- {2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) pyridin-2-yl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
N- {2,2-dimethyl-4- [3-methyl-6- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl} methanesulfonamide N- [4- (5-chloro-3-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine -7-yl] methanesulfonamide;
N- [4- (3-chlorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-Bromopyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-methylpyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- {5-Fluoro-2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) pyridin-2-yl] -3,4-dihydro-2H-1,4-benzoxazine-7 -Yl} methanesulfonamide;
N- [4- (5-Fluoro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-fluoropyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- [4-Chloro-3- (hydroxymethyl) phenyl] -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7- Yl] methanesulfonamide;
Benzoic acid 2-chloro-5- [5-fluoro-2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4- Yl] benzyl;
N- [4- (2,6-Dimethylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-cyclopropyl-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-Fluoro-4- [3-fluoro-4- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-3-oxo-4- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-Fluoro-4- [4-fluoro-3- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (3-Chloro-4-fluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (3,4-Difluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-Fluoro-4- (5-fluoro-6-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (6-Chloro-2-methylpyridin-3-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (4-Chloro-2-fluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Fluoro-6-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (benzothien-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (benzofuran-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [2-Chloro-6- (trifluoromethyl) pyridin-3-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (4-Fluorophenyl) -5- (methoxymethyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [2,2-dimethyl-4- [3-methyl-5- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [2,2-dimethyl-4- [2-methyl-6- (trifluoromethyl) pyridin-3-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [2,2-dimethyl-4- [2-methyl-5- (trifluoromethyl) pyridin-3-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-ethyl-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) -2-thienyl] -3,4-dihydro-2H-1,4-benzoxazine-7- Yl] methanesulfonamide;
N- [5-Fluoro-4- (5-fluoro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (6-Chloro-2,2-difluoro-1,3-benzodioxol-5-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2,2-difluoro-1,3-benzodioxol-5-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1, 4-Benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-Bromo-3-methylpyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-4- [3-methyl-5- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4- Benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-methylphenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (3-amino-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (3-chloro-4-fluorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- {2,2-dimethyl-3-oxo-4- [3- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl} methanesulfonamide; and N- {2,2-dimethyl-4- [2-methyl-3- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
Or a pharmacologically acceptable salt thereof selected from the group consisting of:

  When the compound [I] has an asymmetric carbon atom in the molecule, it can exist as a plurality of stereoisomers (diastereoisomers, optical isomers) based on the asymmetric carbon atom. The active ingredient includes any one of these stereoisomers or a mixture thereof.

  The pharmaceutical composition of the present invention is useful for the prevention and treatment of various diseases or disease states involving MR and / or aldosterone. Such diseases include the diseases described in (1) to (6) below.

  (1) Cardiovascular diseases or blood-related diseases: essential hypertension; secondary hypertension (renovascular hypertension, fluid retention type hypertension, etc.); pulmonary hypertension; hypotension; circadian blood pressure abnormalities; heart failure (acute heart failure, chronic Heart failure or congestive heart failure); angina; myocardial infarction; cardiomyopathy; cardiac hypertrophy; myocarditis; myocardial / vascular fibrosis; myocardial ischemia; baroreceptor disorder; Sequelae; transient cerebral ischemic attack (TIA); stroke; cerebrovascular dementia; hypertensive encephalopathy; cerebral infarction; cerebral edema; cerebral circulation disorder; peripheral circulatory disorder including Raynaud's disease and Buerger's disease; Venous dysfunction; arteriosclerosis (coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.); vascular thickening; vascular thickening / occlusion after intervention including percutaneous coronary angioplasty (PTCA); bypass construction (CABG) Etc.) Lateral revascularization / Restenosis; rejection after organ transplantation; thrombosis; deep vein thrombosis; obstructive peripheral circulatory disorder; obstructive arteriosclerosis; obstructive thrombotic vasculitis; thrombocytopenia; Vascular endothelial disorder; or renal disease (renal failure, nephritis, glomerulonephritis, IgA nephropathy, progressive nephropathy, glomerulosclerosis, diabetic nephropathy, thrombotic microangiopathy, dialysis complications, irradiation Nephropathy, etc.); vascular purpura; autoimmune hemolytic anemia; disseminated intravascular coagulation syndrome (DIC); or multiple myelopathy.

  (2) Metabolic disease: hyperglycemia / diabetes and its complications (diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, etc.); metabolic syndrome or metabolic disorder (hyperlipidemia, hypercholesterolemia, obesity) Hyperuricemia, hypokalemia, hypernatremia, impaired glucose tolerance, etc.).

  (3) Central nervous system or neurodegenerative diseases: neuropathy based on cerebral hemorrhage, cerebral infarction, head injury, spinal cord injury or brain edema; sensory dysfunction / abnormality; autonomic dysfunction / abnormality; multiple sclerosis; memory impairment Mood disorder including depression and bipolar disorder; anxiety symptoms; personality disorder; amnesia; dementia; epilepsy; alcoholism; Alzheimer's disease; Parkinson's disease; or amyotrophic lateral sclerosis.

  (4) Inflammatory or allergic diseases: rheumatoid arthritis; gout; osteoarthritis of the knee; osteoarthritis; periosteitis; bursitis; ankylosing myelitis; atopic dermatitis; contact dermatitis; Asthma; Urticaria; Bronchitis; Inflammatory lung disease (pneumonia, chronic obstructive pulmonary disease, interstitial pneumonia, Karini pneumonia, pulmonary tuberculosis, pulmonary sarcoidosis, etc.); Inflammatory bowel disease (Crohn's disease, ulcer) Colitis (systemic lupus erythematosus, scleroderma, polyarteritis, etc.); meningitis; Wegener's granulomas; rheumatic fever; postoperative / posttraumatic inflammation; pharyngitis; cystitis; anaphylaxis; Tendinitis; conjunctivitis; or inflammatory eye disease.

  (5) Endocrine diseases: primary or secondary aldosteronism; pseudoaldosteronism; Barter's syndrome and the like.

  (6) Other diseases including local diseases: Liver diseases (hepatitis, cirrhosis, etc.); portal hypertension; gastrointestinal diseases (gastritis, gastric ulcer, gastric cancer, postoperative gastric surgery, esophageal ulcer, esophageal gastric varices rupture, large intestine Polyps, pancreatitis, cholelithiasis, gonorrhea, etc.); prostate disease (prostatic hypertrophy, prostate cancer, etc.); bone disease (tissue damage due to fracture, osteoporosis, osteomalacia, bone Behcet's disease, etc.); cancer / tumor (malignant melanoma, Leukemia, malignant lymphoma, gastric cancer, colon cancer, etc.); cachexia; tumor metastasis; gynecological diseases (menopause, pregnancy intoxication, endometriosis, uterine fibroids, ovarian diseases, breast diseases, etc.); infection; sepsis Glaucoma; elevated intraocular pressure; Meniel syndrome; dysphagia; sleep apnea syndrome; myasthenia gravis; dialysis hypotension;

  Compound [I], which is an active ingredient of the present invention, includes compounds having excellent MR antagonism (aldosterone antagonism), and the present compound or a pharmacologically acceptable salt thereof is used as an active ingredient. The pharmaceutical composition of the invention provides various diseases or disease states resulting from enhanced MR activity and / or elevated aldosterone levels, such as hypertension, heart failure, myocardial infarction, angina, cardiac hypertrophy, myocarditis, myocardial / vascular fibrosis Prevention and treatment of cardiovascular diseases, including baroreceptor disorders, fluid overload and arrhythmia, or endocrine diseases including primary / secondary aldosteronism, Addison's disease, Cushing's syndrome and Barter's syndrome (as diuretics) Particularly useful).

  The above-mentioned compound [I] can be used for pharmaceutical use either in a free form or in the form of a pharmacologically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate and hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone, and the like. Examples thereof include organic acid salts such as acid salts, benzenesulfonic acid salts, tosylate salts and maleate salts, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts.

  The compound [I] or a pharmacologically acceptable salt thereof includes any of its internal salts and adducts, solvates or hydrates thereof.

  The pharmaceutical composition of the present invention can be administered orally or parenterally. The dosage form is not particularly limited, and together with pharmacologically acceptable carriers (excipients, binders, disintegrants, stabilizers, etc.), for example, tablets, granules, capsules, powders , Injections, inhalants, and suppositories.

  The dose of compound [I], which is the active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition, but in the case of parenteral administration, it is 0 per day. 0.001 to 10 mg / kg, particularly 0.01 to 1 mg / kg, and in the case of oral administration, it is usually preferably 0.01 to 100 mg / kg, particularly 0.1 to 10 mg / kg per day.

  Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, can be used alone or in combination with one or more other drugs depending on the disease to be treated. Examples of such drugs include the following.

(A) Antihypertensive agent: angiotensin converting enzyme inhibitor (enalapril maleate, imidapril hydrochloride, captopril, cilazapril, lizinopril, delapril hydrochloride, temocapril hydrochloride, benazepril hydrochloride, perindopril erbumine, sodium fosinopril, quinapril hydrochloride, ramipril hydrochloride, ramipril Trandolapril, alacepril, etc.), angiotensin II receptor antagonists (losartan potassium, candesartan cilexetil, valsartan, irbesartan, telmisartan, olmesartan medoxomil, eprosartan mesylate, folasartan, etc.), beta-blockers (atenolol, betaxolol hydrochloride) , Bisoprolol fumarate, metoprolol tartrate, metoprolol citrate, propranolol hydrochloride, nadolol, ma Timolol innate, acebutolol hydrochloride, penbutolol sulfate, pindolol, carteolol hydrochloride, nipradilol, etc.), α / β blockers (carvedilol, labetalol hydrochloride, etc.), calcium antagonists (amlodipine besylate, felodipine, isradipine, nifedipine, nicardipine hydrochloride, Nisoldipine, nitrendipine, benidipine, manidipine hydrochloride, efonidipine hydrochloride, diltiazem hydrochloride, etc.), α ₁ blockers (such as doxazosin mesylate, prazosin hydrochloride, terazosin hydrochloride), central α ₂ agonists or other central agonists (clonidine hydrochloride, reserpine) , Methyldopa, etc.), vasodilators (hydralazine hydrochloride, minoxidil, etc.), etc .;
(B) Diuretics: thiazide diuretics (chlorothiazide, hydrochlorothiazide, benchylhydrochlorothiazide, hydroflumethiazide, trichlormethiazide, polythiazide, chlorthalidone, indapamide, metrazone, etc.), loop diuretics (bumethanide, furosemide, torsemide, mefluside, Ethacrynic acid, etc.), potassium-sparing diuretics (amiloride hydrochloride, triamterene, etc.);
(C) Heart failure treatment drugs: nitrate drugs (nitroglycerin, etc.), digitalis preparations (digoxin, digitoxin, etc.), catecholamines (dobutamine hydrochloride, denopamine, etc.), endothelin antagonists (bosentan, etc.), phosphodiesterase inhibitors (milrinone lactate, amrinone) , Olprinone, etc.), neutral endopeptidase inhibitors (eg, fasiditol), atrial diuretic peptide, etc.
(D) Antiarrhythmic drugs: Na channel blockers (procainamide hydrochloride, flecainide acetate, quinidine sulfate, etc.), K channel blockers (amiodarone hydrochloride, etc.), Ca channel blockers (verapamil hydrochloride, etc.) and the like;
(E) Hyperlipidemic drugs: HMG-CoA reductase inhibitors (pravastatin sodium, atorvastatin calcium, simvastatin, cerivastatin, lovastatin sodium, fluvastatin sodium, rosuvastatin calcium, pitavastatin calcium, etc.), fibrate derivatives (bezafibrate, fenofibrate, clino) Fibrate, clofibrate, gemfibrozil, etc.), squalene synthase inhibitor, etc .;
(F) Antithrombotic drugs: blood coagulation inhibitors (warfarin sodium, heparin sodium, antithrombin III, etc.), thrombolytic drugs (urokinase, t-PA, etc.), antiplatelet drugs (aspirin, ticlopidine hydrochloride, sulfinpyrazone, dipyridamole) , Cilostazol, etc.);
(G) Drugs for treating diabetes / diabetic complications: insulin, α-glucosidase inhibitors (voglibose, acarbose, miglitol, emiglitate, etc.), biguanides (metformin hydrochloride, buformin, phenformin, etc.), insulin resistance improvers (pioglitazone, troglitazone) , Rosiglitazone, etc.), insulin secretagogues (tolbutamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, glimepiride, glybzide, glybsol, tolazamide, acetohexamide, etc.), amylin antagonists (pramlintide, etc.) Aldose reductase inhibitors (epalrestat, tolrestat, zenarestat, fidarestat, minalrestat, zopolrestat, etc.), neurotrophic factor ( GF, etc.), AGE inhibitors (pimagedine, pyratoxathine, etc.), neurotrophic factor production promoter agent, and the like;
(H) Anti-obesity drugs: Central anti-obesity drugs (mazindol, fenfluramine, dexfenfluramine, sibutramine, etc.), pancreatic lipase inhibitors (orlistat etc.), β ₃ agonists (SB-226552, BMS-196085, SR-5611-A etc.), peptidic appetite suppressants (leptin etc.), cholecystokinin receptor agonists (lynchtrypto etc.) etc .;
(I) Non-steroidal anti-inflammatory drugs: acetaminophen, ibuprofen, ketoprofen, etenzamide, naproxen, diclofenac, loxoprofen, etc. (j) Chemotherapeutic agents: antimetabolites (5-fluorouracil, methotrexate, etc.), anticancer drugs (vincristine, taxol) , Cisplatin, etc.);
(K) Immunomodulators: immunosuppressants (cyclosporine, tacrolimus, azathioprine, etc.), immunopotentiators (krestin, lentinan, schizophyllan, etc.), cytokines (interleukin 1, interferon, etc.), cyclooxygenase inhibitors (indomethacin, celecoxib, Valdecoxib, meloxicam, etc.), anti-TNFα antibodies (infliximab, etc.), etc.

  When the compound [I], which is the active ingredient of the present invention, is used in combination with another drug, the administration form includes (1) a single preparation (compound) containing the compound [I] and another drug And (2) combination administration of a preparation containing compound [I] and a preparation containing other drugs. In the case of (2), the administration route and administration time of each preparation may be different.

Compound [I], which is an active ingredient of the present invention, can be produced by the following method, but is not limited thereto.
(Method A)
Of the compounds [I], R ¹ is a group represented by the formula: R ^a SO ₂ NH—, that is, the following general formula [IA]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the general formula [II-A]:

[Wherein the symbols have the same meaning as described above. ]
And a compound of the general formula:
R ^a SO ₂ -Hal [a]
[In the formula, Hal represents a halogen atom, and other symbols have the same meaning as described above. ]
It can manufacture by making the compound shown by react.

  Examples of the halogen atom in the compound [a] include a chlorine atom and a bromine atom.

  The reaction of compound [II-A] and compound [a] can be carried out, for example, in a suitable solvent or without a solvent, in the presence or absence of a base. The solvent may be any inert solvent that does not interfere with the reaction. For example, halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether , Diisopropyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, esters such as ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolide Amides such as non, nitriles such as acetonitrile, dimethyl sulfoxide, pyridine, 2,6-lutidine, a mixed solvent thereof, or a combination of these solvents and water. Of these solvents, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone or pyridine are preferred, and dichloromethane, chloroform Tetrahydrofuran or pyridine is more preferred. As the base, for example, an organic base or an inorganic base can be used. Examples of the organic base include trialkylamines such as triethylamine, tributylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] non- Tertiary cyclic amines such as 5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, N, N-dimethylaniline, N, N-diethylaniline, 4-dimethylaminopyridine and the like. Examples include amines, pyridine, 2,6-lutidine, 2,3,5-collidine and the like. Examples of the inorganic base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate, alkaline earth metals such as calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium hydroxide, hydroxide Examples thereof include alkali metal hydroxides such as potassium and lithium hydroxide. Of these, pyridine, triethylamine or alkali metal carbonate is preferred. The amount of compound [a] to be used in this reaction can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [II-A]. The amount of the base to be used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [II-A]. This reaction can be carried out under cooling to heating, preferably under ice cooling to room temperature.

In addition, among compounds [I], R ¹ is a group represented by the formula: H ₂ N—SO ₂ NH—, that is, the following general formula [I-A2]:

[Wherein the symbols have the same meaning as described above. ]
The compound represented by the formula [II-A] and the following general formula [a-2]:
_{Hal-SO 2 -NCO [a-} 2]
[Wherein the symbols have the same meaning as described above. ]
It can also be produced by reacting with an isocyanate compound represented by This reaction can be carried out in a solvent in the presence of a base. The solvent may be an inert solvent that does not interfere with the reaction, and examples thereof include a mixed solvent of ethers such as tetrahydrofuran and water. Examples of the base include amines such as triethylamine described above. The amount of compound [a-2] used in this reaction can be 1 to 5 equivalents, preferably 2 to 3 equivalents, relative to compound [II-A]. The usage-amount of a base and water can be 1-5 equivalent with respect to compound [II-A], Preferably it can be 2-3 equivalent. This reaction can be carried out at −78 to 30 ° C., preferably −78 ° C. to room temperature.

Further, among the compounds [I], a compound (compound [I-A3]) in which R ¹ is a group represented by the formula: R ^a SO ₂ NH—CH ₂ — is represented by the general formula [II-A3]:

[Wherein, G ¹ represents an amino-protecting group, and other symbols have the same meaning as described above. ]
The amino-protecting group G ¹ can be removed from the compound represented by the following general method.
(Method B)
Among the compounds [I], compounds in which R ¹ is a group represented by the formula: (R ^b ) (R ^c ) NSO ₂ — (compound [IB]) are represented by the general formula [II-B]:

[Wherein Z represents a halogen atom, and other symbols have the same meaning as described above. ]
A sulfonyl halide compound represented by the general formula:
(R ^b ) (R ^c ) NH [b]
[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making the amine compound shown by react.

In the compound [II-B], examples of the halogen atom represented by Z include a chlorine atom and a bromine atom. The reaction of compound [II-B] and compound [b] can be carried out in the same manner as in the reaction of compound [II-A] and compound [a].
(Method C)
Among the compounds [I], Y is a compound represented by the formula: —C (═S) —, that is, the general formula [IC]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by formula (I) is a corresponding compound [I] in which Y is represented by the formula: —C (═O) —, that is, the following general formula [ID]:

[Wherein the symbols have the same meaning as described above. ]
And a sulfurization agent (for example, niline pentasulfide, bis (trimethylsilyl) sulfide, Lawesson's reagent, etc.) in a solvent. The solvent may be an inert solvent that does not hinder the reaction, and examples thereof include the ethers described above, among which dioxane, tetrahydrofuran and the like are preferable. The amount of the sulfurizing agent to be used can be 0.5 to 5 equivalents, preferably 0.5 to 2 equivalents, relative to compound [ID]. This reaction can be carried out at room temperature to 120 ° C, preferably at room temperature to 60 ° C.
(Method D)
Among compounds [I], a compound in which X is the formula: —CH ₂ — and Y is the formula: —C (═O) —, that is, the following general formula [IE]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the general formula [II-E]:

It can manufacture by reducing the ketone compound shown by these.

  This reaction can be carried out in a solvent in the presence of a reducing agent. The solvent may be any inert solvent that does not interfere with the reaction. Examples thereof include halogenated hydrocarbons such as chloroform, organic acids such as trifluoroacetic acid, boron trifluoride ether complexes, and mixed solvents thereof. can give. Examples of the reducing agent include triethylsilane. The amount of the reducing agent used in this reaction can be 3 to 30 equivalents, preferably 5 to 20 equivalents, relative to compound [II-E]. This reaction can be carried out at −100 ° C., preferably 50–70 ° C. under ice cooling.

Compound [I], which is an active ingredient of the present invention, can also be produced by converting a substituent on R ¹ or Ar in the compound obtained by the above-described methods A to D into another desired substituent. can do. Such a substituent conversion method may be appropriately selected according to the type of the target substituent, and can be carried out, for example, as follows.

(Method a)
Compound [I] having a mono- or dialkylamino group (or a group containing a mono- or dialkylamino group) as a substituent includes, for example, (i) a primary or secondary amino group (or primary or secondary amino group) as a substituent. A corresponding compound [I] having a group) and a desired alkyl halide in a suitable solvent in the presence of a base, or (ii) a halogen atom (or a group containing a halogen atom) as a substituent. Corresponding compound [I] and mono- or dialkylamine in solvent, catalyst (palladium catalyst such as palladium acetate), additive (phosphine compound such as triphenylphosphine) and base (alkali metal carbonate such as potassium carbonate, etc.) ) In the presence or absence of, or (iii) primary or secondary amino groups ( Is it can be prepared by reacting in the presence of a corresponding compound having a group) containing one primary or secondary amino group [I] with an aldehyde compound (formaldehyde, etc.) a reducing agent (sodium borohydride etc.).

(Method b)
Compound [I] having an acylamino group (or a group containing an acylamino group) as a substituent includes, for example, (i) a corresponding compound [I] having a halogen atom as a substituent and the following formula [c]:
R ^x —CO—NH ₂ [c]
[Wherein the symbols have the same meaning as described above. ]
Or (ii) a corresponding compound [I] having an amino group as a substituent and a general formula:
^Rx- CO-Hal [c-1]
[Wherein the symbols have the same meaning as described above. ]
It can manufacture by making it react in presence of a base (pyridine etc.) and an acylating agent shown by these.

(Method c)
Compound [I] having a hydroxyl group (or a group containing a hydroxyl group) as a substituent is, for example, (i) a corresponding compound [I] having an alkoxy group (or a group containing an alkoxy acid group) as a substituent, for example, a solvent. Or (ii) the corresponding compound [I] having an acyloxy group (benzoyloxy group, etc.) as a substituent, for example, a base (sodium hydroxide, etc.) It can be produced by hydrolysis in the presence.

(Method d)
Compound [I] having an alkoxy group (or a group containing an alkoxy group) as a substituent is, for example,
(I) reacting a corresponding compound [I] having a hydroxyl group (or a group containing a hydroxyl group) as a substituent with an alkyl halide in an appropriate solvent; or (ii) changing a hydroxyl group (or a group containing a hydroxyl group) as a substituent. The corresponding compound [I] having an alkanol in a solvent in the presence or absence of a base (such as an alkali metal carbonate such as potassium carbonate) or in the presence of an activator (such as diethyl azodicarboxylate) and a trisubstituted phosphine Or (iii) presence of a catalyst (such as a palladium catalyst such as palladium acetate) in a suitable solvent between the corresponding compound [I] having a halogen atom (or a group containing a halogen atom) as a substituent and an alkanol. As well as additives (triphenylphosphine, racemic-2- (di-tert-butylphosphino) -1,1′-binaphthy Such phosphine compounds, etc.) and a base (potassium carbonate, it can be prepared by reacting in the presence or absence of such cesium carbonate an alkali metal carbonate, etc.).

(Method e)
The compound [I] having a methyl group as a substituent can be obtained, for example, by using a corresponding compound [I] having a halogen atom as a substituent and trimethylboroxine in a solvent in a palladium catalyst ([1,1-bis (triphenylphosphino) Ferrocene] dichloropalladium (II), tetrakis (triphenylphosphine) palladium (0), etc.) and in the presence or absence of a base (potassium carbonate, etc.).

(Method f)
For example, the compound [I] having a hydroxyalkyl group as a substituent is prepared by adding the corresponding compound [I] having an acyloxyalkyl group as a substituent in a solvent (methanol, tetrahydrofuran) in the presence of a base (sodium hydroxide, etc.). It can be manufactured by decomposing. In addition, the compound [I] having a hydroxymethyl group as a substituent is obtained by reacting, for example, the corresponding compound [I] having a vinyl group as a substituent with ozone, and converting the resulting product into a reducing agent (such as sodium borohydride). It can also be manufactured by processing with. Furthermore, the compound [I] having a hydroxyethyl group as a substituent is obtained by, for example, treating the corresponding compound [I] having a vinyl group as a substituent with a borane reagent (borane-dimethylsulfide complex or the like). Can also be produced by treatment with hydrogen peroxide.

(G method)
Compound [I] having an amino group as a substituent can be produced, for example, by subjecting corresponding compound [I] having a nitro group as a substituent to a catalytic reduction reaction using a palladium catalyst or the like.

(Method h)
The compound [I] having an ethyl group as a substituent can be produced, for example, by subjecting the corresponding compound [I] having a vinyl group as a substituent to a catalytic reduction reaction in the presence of a palladium catalyst (palladium carbon or the like).

(I method)
For example, the compound [I] having a cyano group as a substituent is obtained by reacting the corresponding compound [I] having a halogen atom as a substituent with zinc cyanide in the presence of a palladium catalyst (tetrakis (triphenylphosphine) palladium (0), etc.). It can be manufactured by reacting.

(J method)
The compound [I] having a cycloalkyl group as a substituent is obtained by, for example, converting a corresponding compound [I] having a halogen atom as a substituent into a palladium catalyst (tetrakis (triphenylphosphine) palladium (0) or the like) and a base (potassium phosphate). Etc.) It can be produced by reacting with a cycloalkyl boronic acid in the presence.

(K method)
For example, the compound [I] having a trifluoromethyl group as a substituent is obtained by converting the corresponding compound [I] having an iodine atom as a substituent into 2,2-difluoro- in the presence of a copper salt (such as copper (I) bromide). It can be produced by reacting with ethyl 2- (fluorosulfonyl) acetate. The compound [I] having an iodine atom as a substituent is, for example, 2,2-difluoro-2- (2) in the presence of the corresponding compound [I] and an iodinating agent (such as bis (pyridine) iodonium tetrafluoroboric acid). It can be prepared by reacting with (fluorosulfonyl) ethyl acetate.

  The compound [I] obtained as described above can be converted into a pharmacologically acceptable salt, if desired. Conversion to a pharmacologically acceptable salt may be performed according to a conventional method.

  Compound [II-A] and compound [II-B], which are synthetic intermediates of compound [I], can be produced, for example, as follows.

  Among the intermediate compounds [II-A], compounds in which X is an oxygen atom or a sulfur atom and Y is a formula: —C (═O) —, that is, a general formula [II-a]:

[Wherein, X ¹ represents an oxygen atom or a sulfur atom, and other symbols have the same meaning as described above. ]
Can be produced, for example, according to the following reaction scheme A1.
(Reaction Scheme A1):

[In the above scheme, R ^d is an alkyl group or a hydrogen atom, R ′ and R ″ are a hydrogen atom or an alkyl group, or both are bonded to each other to form an alkylene group, and W ¹ and W ³ are Represents a halogen atom, and other symbols have the same meanings as described above.]
Step A1-1:
The reaction of compound [1] and compound [2] can be carried out in a solvent in the presence of a base. Examples of W ¹ in the compound [2] include a bromine atom and a chlorine atom, and examples of R ^d include a hydrogen atom or an alkyl group such as a methyl group or an ethyl group. The solvent may be any inert solvent that does not interfere with the reaction. For example, halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether , Ethers such as diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, amides such as 1,3-dimethyl-2-imidazolidinone, acetonitrile Nitriles such as, methanol, ethanol, isopropanol, n-butanol, alcohols such as tert-butanol, acetone, ketones such as 2-butanone, dimethyl sulfoxide, pyridine, 2,6-lutidine, a mixed solvent thereof, or Combination of these solvents and water. Of these, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, ethanol and acetone are preferred. Examples of the base include alkali metal fluorides such as potassium fluoride and sodium fluoride, alkali metal hydrides such as sodium hydride, alkali metal alkoxides such as potassium t-butoxy, sodium carbonate, potassium carbonate and cesium carbonate. Alkali metal carbonates, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, trialkylamines such as triethylamine, tributylamine and diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1 And tertiary cyclic amines such as 1,5-diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene. The amount of compound [2] used in this reaction can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [1]. The amount of the base to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [1]. This reaction can be carried out under cooling to heating, preferably from room temperature to the boiling point of the reaction mixture.

Step A1-2:
(A) The reaction of compound [3] and compound [4a] (Q = single bond or alkenylene group) can be carried out in a solvent in the presence of a copper salt, a base and an additive. The solvent may be any inert solvent that does not interfere with the reaction. For example, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diisopropyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane. , Alcohols such as methanol, ethanol, 1-propanol, 2-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone Amides such as nitriles, nitriles such as acetonitrile, dimethyl sulfoxide, pyridine, 2,6-lutidine, or a mixed solvent thereof. Of these, toluene, xylene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, 1-methyl-2-pyrrolidinone, and dimethyl sulfoxide are preferable. Examples of the copper salt include copper iodide, copper (I) oxide, copper sulfate, copper chloride, copper acetate, and copper thiophene-2-carboxylate. Bases include alkali metal phosphates such as potassium phosphate, alkali carbonates such as potassium carbonate and cesium carbonate, alkali metal acetates such as cesium acetate, alkali metal fluorides such as potassium fluoride, and sodium-tert-butoxide. Examples thereof include alkali metal alkoxides and alkali metal hydroxides such as sodium hydroxide. Examples of the additive include N, N′-dimethylethylenediamine, ethylenediamine, N, N′-dimethylcyclohexane-1,2-transdiamine, N, N′-cyclohexane-1,2-transdiamine, and o-phenylenediamine. Examples include diamines, glycine, N-methylglycine, N, N-dimethylglycine, amino acids such as proline, amino alcohols such as prolinol, 1,10-phenanthroline, and the like. The usage-amount of copper salt can be 0.01-3.0 equivalent with respect to compound [3], Preferably it can be 0.01-0.3 equivalent. The amount of the base to be used can be 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to compound [3]. The usage-amount of an additive can be 0.01-5.0 equivalent with respect to compound [3], Preferably it can be 0.02-0.6 equivalent. This reaction can be carried out at 50 to 250 ° C, preferably 80 to 150 ° C.

    (B) The reaction of compound [3] and compound [4a] (Q = alkylene group) can be carried out in a solvent in the presence of a base. The solvent may be any inert solvent that does not interfere with the reaction. Examples thereof include ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, 1 Amides such as 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxide, pyridine, 2,6-lutidine, a mixed solvent thereof, or a combination of these solvents and water. Among these, N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone and dimethyl sulfoxide are preferable. Examples of the base include alkali metal hydrides such as sodium hydride, potassium tert-butoxide, alkali metal alkoxides such as sodium methoxide, lithium amides, alkyllithiums, alkylmagnesium halides, sodium carbonate, potassium carbonate, Alkali metal carbonates such as cesium carbonate, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, trialkylamines such as triethylamine, tributylamine and diisopropylethylamine, 1,4-diazabicyclo [2.2.2 And tertiary cyclic amines such as octane, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, and the like. The amount of compound [4a] to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [3]. The amount of the base to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [3]. This reaction can be carried out under cooling to heating, preferably under ice cooling to the boiling point of the reaction mixture.

(C) The reaction of the compound [3] and the aryl boronic acid compound [4b] can be carried out in a solvent in the presence of a catalyst and a base and in the presence or absence of an additive. As the aryl boronic acid compound [4b], R ′ and R ″ are hydrogen atoms or alkyl groups (methyl group, ethyl group, propyl, butyl, etc.), or R ′ and R ″ are bonded to each other to form an alkylene group. (Ethylene group, propylene group, 1,1,2,2-tetramethylethylene group, etc.), and the like. Among these, compounds in which R ′ and R ″ are both hydrogen atoms (or the formula: [ The corresponding boroxine compound represented by ArBO] ₃ is preferable. , Aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetra Hydrofuran, dioxane, 1,2-dimethoxyethane, etc.), esters (ethyl acetate, etc.), amides (N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc. ), Alcohols (such as methanol), dimethyl sulfoxide, etc., and may be a mixed solvent of two or more of these solvents, with dichloromethane being particularly preferred, for example, copper (II) acetate, copper chloride Examples of the base include, for example, triethylamine, pyridine, etc. Examples of the additive include molecular sieves 4A, an oxidizing agent (pyridine), and the like. N-oxide, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4 -Methylmorpholine N-oxide etc. The usage-amount of compound [4b] in this reaction can be 1-5 equivalent with respect to compound [3], Preferably it can be 1-2 equivalent. The amount can be 0.1 to 2 equivalents, preferably 1 to 1.5 equivalents relative to compound [3] The amount of base used is 0.1 to 5 equivalents relative to compound [3]. The additive may be used in an amount of 0 to 1.5 equivalents relative to compound [3] The reaction is performed at room temperature to under heating, preferably at room temperature. Can be implemented.

Step A1-3:
Reduction of the nitro group in compound [5] can be carried out in a solvent in the presence of a reducing agent. The solvent may be any inert solvent that does not interfere with the reaction. For example, water, alcohols such as methanol, ethanol and propanol, esters such as ethyl acetate, N, N-dimethylformamide, N, N- Amides such as dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, a mixed solvent thereof, or a solvent thereof and water And the combination. Of these, ethyl acetate, ethanol, and a mixed solvent of water and alcohol are preferable. As the reducing agent, for example, a metal such as tin, iron, zinc, or a metal salt such as tin chloride can be used. Depending on the type of reducing agent, a mineral acid such as hydrochloric acid or ammonium chloride may be added to the reaction system. The amount of the reducing agent to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [5]. This reaction can be carried out under cooling to heating, preferably from room temperature to the boiling point of the reaction mixture.

  The reduction of compound [5] can also be carried out by hydrogenation in a solvent in the presence of a metal catalyst. The solvent may be any inert solvent that does not interfere with the reaction. For example, in addition to the alcohols, ethers, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, amides or esters described above, Examples thereof include organic acids such as formic acid, acetic acid, propionic acid and trifluoroacetic acid, and mixed solvents thereof. Examples of the metal catalyst include palladium carbon, Raney nickel, Raney cobalt, platinum oxide and the like. A mineral acid such as hydrochloric acid may be added to the reaction system depending on the type of catalyst. This reaction can be carried out under cooling to heating, preferably from −10 ° C. to the boiling point of the reaction mixture.

Step A1-4:
Reduction of the nitro group in compound [3] can be carried out in the same manner as in step A1-3.

Step A1-5:
The reaction of compound [6] with compound [4a] or compound [4b] can be carried out in the same manner as in Step A1-2.

  The compound [3] is represented by the general formula [1a]:

[Wherein the symbols have the same meaning as described above. ]
And the compound [2] is treated in the same manner as in the reaction step A1-1 to give the general formula [3a]:

[Wherein the symbols have the same meaning as described above. ]
Can be produced by treating the compound with nitric acid in a solvent (such as acetic acid) (nitrating).

  Of the above compound [3], the following general formula [31]:

[In the formula, Hal represents a halogen atom, and other symbols have the same meaning as described above. ]
Can also be produced according to the following reaction scheme A2.

  (Reaction Scheme A2)

[In the above reaction scheme, OZ ^a represents a protected hydroxyl group, W ^a and W ^b represent a halogen atom, and other symbols have the same meaning as described above. ]
Step A2-1:
The halogenation of compound [41] can be carried out in a solvent in the presence of a halogenating agent. The solvent may be any inert solvent that does not interfere with the reaction. Examples thereof include halogenated hydrocarbons such as chloroform and amides such as dimethylformamide. Examples of the halogenating agent include N-bromosuccinimide, N-chlorosuccinimide, bromine and the like. In this reaction, the amount of the halogenating agent to be used is 1.0 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents, relative to compound [41]. This reaction can be carried out at 0 ° C to 30 ° C, preferably 0 to 5 ° C.

Step A2-2:
The reaction of compound [51] and compound [71] can be carried out in a solvent in the presence of a base. The solvent may be any inert solvent that does not interfere with the reaction, and examples thereof include halogenated hydrocarbons such as chloroform and ethers such as tetrahydrofuran. Examples of the base include amines such as pyridine and tertiary amines such as triethylamine. In this reaction, the amount of compound [71] to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [51]. Moreover, the usage-amount of a base can be 2.0-3.0 equivalent with respect to compound [51], Preferably it can be made the same equivalent as compound [71]. This reaction can be carried out at 0 ° C to 30 ° C, preferably 15 ° C to 25 ° C.

Step A2-3:
Removal of the protecting group Z ^a of the compound [61] can be carried out according to conventional methods. For example, when the protecting group Za is an alkoxyalkyl group such as ^a methoxymethyl group, the protecting group is removed by removing the compound [61] in a solvent (dichloromethane, water, tetrahydrofuran, dioxane, etc.) in acid (hydrochloric acid, trifluoromethane). For example, acetic acid).

Step A2-4:
The intramolecular ring closure reaction of compound [81] can be carried out in a solvent in the presence of a base. The solvent may be an inert solvent that does not hinder the reaction, and examples thereof include amides such as N, N-dimethylformamide, ketones such as acetone, and the like. Examples of the base include alkali metal carbonates such as potassium carbonate, sodium hydride and the like. The amount of the base used in this reaction can be 1.0 to 3.0 equivalents, preferably 2.0 to 3.0 equivalents, relative to compound [81]. This reaction can be carried out at 30 ° C to 60 ° C, preferably 50 ° C to 60 ° C.

  Furthermore, the intermediate compound [5] can also be produced according to the following reaction scheme A3.

  (Reaction Scheme A3)

[In the above reaction scheme, R ^g represents an alkyl group, and other symbols have the same meaning as described above. ]
Step A3-1:
The reaction of compound [42] and compound [62] can be carried out in a solvent in the presence of a base. The solvent may be any inert solvent that does not interfere with the reaction. Examples thereof include amides such as N, N-dimethylformamide, ketones such as acetone, and nitriles such as acetonitrile. Examples of the base include alkali metal carbonates such as potassium carbonate and cesium carbonate, sodium hydride and the like. The amount of compound [62] used in this reaction can be 1 to 4 equivalents, preferably 1 to 1.2 equivalents, relative to compound [42]. Moreover, the usage-amount of a base can be 1-2 equivalent with respect to compound [42], Preferably it can be 1-1.3 equivalent. This reaction can be carried out at room temperature to 60 ° C., preferably at room temperature.

Step A3-2:
The reaction of compound [52] and compound [72] can be carried out in a solvent in the presence of an amidation activator. The solvent may be any inert solvent that does not hinder the reaction, and examples thereof include dichloromethane and chloroform. Examples of the amidation activator include trialkylaluminum such as trimethylaluminum. The amount of compound [72] used in this reaction can be 1 to 6 equivalents, preferably 1 to 4 equivalents, relative to compound [52]. The amount of the amidation activator used can be 1 to 6 equivalents, preferably 1 to 4 equivalents, relative to compound [52]. This reaction can be carried out at room temperature to 70 ° C, preferably at room temperature to 40 ° C.

  The compound [82] is converted into the corresponding carboxylic acid compound by subjecting the compound [52] to a conventional hydrolysis reaction, and then the carboxylic acid compound or a corresponding reactive derivative thereof (for example, a corresponding acid halide). And compound [72] in a solvent (tetrahydrofuran, chloroform, dichloromethane, etc.) in the presence of a base (n-butyllithium, lithium bis (trimethylsilyl) amide, pyridine, etc.).

Step A3-3:
The intramolecular ring closure reaction of compound [82] can be carried out in a solvent in the presence or absence of a copper salt and in the presence of a base. The solvent may be any inert solvent that does not interfere with the reaction. Examples thereof include amines such as pyridine, amides such as N, N-dimethylformamide, and dimethyl sulfoxide. Examples of the copper salt include copper (I) iodide, copper (I) bromide, copper (I) chloride and the like. Examples of the base include alkali metal phosphates such as potassium phosphate, alkali metal carbonates such as potassium carbonate, sodium carbonate and cesium carbonate, sodium hydride, potassium tert-butoxide and the like. In this reaction, the amount of copper salt to be used can be 0 to 10 equivalents, preferably 0 to 4 equivalents, relative to compound [82]. The amount of the base to be used can be 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound [82]. This reaction can be carried out at room temperature to the boiling point of the reaction mixture.

  Among the intermediate compounds [II-a], the general formula [II-a2]:

[Wherein, R ^w represents an alkenyl group or alkanoyl which may be substituted with an alkoxy group, and other symbols have the same meaning as described above. ]
The compound represented by the following general formula [5a]:

[Wherein, R ⁰⁰ represents an amino group or a nitro group, and other symbols have the same meaning as described above. ]
And a compound of the general formula [x]:
R ^WA -Sn (R) ₃ [x]
[Wherein, R ^WA represents an alkenyl group optionally substituted with an alkoxy group, and R represents an alkyl group. ]
In the presence of a catalyst (a palladium catalyst such as dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0)) in a solvent (dioxane, toluene, etc.) After the reaction, when R ⁰⁰ is a nitro group, the reaction product is treated with a reducing agent, and if necessary, the reactive organism is hydrolyzed in the presence of an acid (such as hydrochloric acid). Can be manufactured.

Furthermore, intermediate compound [II-a] can also be produced according to the following reaction scheme B1.
(Reaction Scheme B1)

[In the above reaction scheme, Z ² represents a leaving group, G ¹ represents an amino-protecting group, and other symbols have the same meaning as described above. ]
Step B1-1:
Examples of the leaving group (Z ² ) in the compound [7] include halogen atoms such as chlorine atom, iodine atom and bromine atom, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group and the like. This step can be performed in the same manner as in step A1-1.

  Of the compound [8], the following general formula [83]:

[Wherein, Z ²¹ represents a halogen atom, and other symbols have the same meaning as described above. ]
For example, the compound represented by the general formula [43]:

[Wherein W ^c represents a halogen atom, and other symbols have the same meaning as described above. ]
And a compound of the general formula [53]:

[Wherein the symbols have the same meaning as described above. ]
Is reacted with a compound represented by general formula [63] in a solvent (such as tetrahydrofuran) in the presence of a base (such as sodium hydride):

[Wherein the symbols have the same meaning as described above. ]
And then subjecting the compound [63] to an intramolecular ring closure reaction in the presence of a reducing agent (such as tin (II) chloride) in a solvent (such as ethyl acetate). .

Step B1-2:
This step can be performed in the same manner as in step A1-2.

Step B1-3:
Examples of the amino-protecting group (G ¹ ) in the compound [10] include an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, an alkoxycarbonyl group such as a tert-butoxycarbonyl group, and the like. The reaction of compound [9] and compound [10] can be carried out in a solvent in the presence of a base and a transition metal catalyst. The solvent may be any inert solvent that does not hinder the reaction, and examples thereof include the alcohols, aromatic hydrocarbons, dioxane and the like described above. Of these, tert-butanol, toluene, xylene, dioxane and the like are preferable. Examples of the base include the aforementioned alkali metal carbonates, alkali metal phosphates, alkali metal phenoxides, and the like. Of these, potassium carbonate, cesium carbonate, potassium phosphate, sodium phenoxide and the like are preferable. Examples of the transition metal catalyst include the palladium catalyst described above, and among them, palladium acetate, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium and the like are preferable. In this reaction, triphenylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, tri-tert-butylphosphine is used as a ligand as necessary. A phosphinic compound such as, and an aryl boronic acid such as phenyl boronic acid may be used as an activator. The amount of compound [10] used in this reaction can be 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound [9]. The amount of the base to be used can be 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound [9]. The usage-amount of a transition metal catalyst (and a ligand) can be 0.01-0.5 equivalent with respect to compound [9], Preferably it can be 0.01-0.2 equivalent. The usage-amount of an activator can be 0.005-0.3 equivalent with respect to compound [9], Preferably it can be 0.005-0.05 equivalent. This reaction can be carried out at 60 ° C to 150 ° C, preferably 80 ° C to 120 ° C.

Step B1-4:
In this step, depending on the type of the protecting group G ^1, it may be carried out by acid treatment, base treatment or the like. For example, when G ¹ is a tert-butoxycarbonyl group, the protecting group can be removed by treating compound [11] with an acid (hydrochloric acid, trifluoroacetic acid, etc.) in a solvent. The solvent may be an inert solvent that does not hinder the reaction, and examples thereof include the alcohols, halogenated aliphatic hydrocarbons, esters, ethers, organic acids, and mixed solvents thereof. This reaction can be carried out under cooling to heating, preferably under ice cooling to room temperature.

Of the intermediate compound [II-A] in the present invention, a compound in which X is an oxygen atom or a sulfur atom and Y is a group represented by the formula: —CH ₂ —, that is, the following general formula [II-b]:

[Wherein the symbols have the same meaning as described above. ]
For example, (i) the compound [II-a] is subjected to a 3-position carbonyl group reduction reaction, or (ii) the compound [5] is subjected to a 3-position carbonyl group reduction reaction. Thereafter, the product can be prepared by treating the product in the same manner as in Step A1-3 to reduce the nitro group on ring A.

  Reduction of the 3-position carbonyl group in compound [II-a] or compound [5] can be carried out in a solvent in the presence of a reducing agent. The solvent may be any inert solvent that does not hinder the reaction, and examples thereof include the ethers described above. Examples of the reducing agent include borane-dimethyl sulfide complex, diborane, borane-tetrahydrofuran complex, borane-1,4-oxathiane complex, borane-dimethylaniline complex, borane-diethylaniline complex, borane-4-phenylmorpholine complex, or hydrogen. And lithium aluminum fluoride. The amount of the reducing agent to be used can be 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound [II-a] or compound [5]. This reaction can be carried out under cooling to heating, preferably from −10 ° C. to the boiling point of the reaction mixture.

In the intermediate compound [II-A], X is an oxygen atom or sulfur atom, Y is a group represented by the formula: —CH (R ⁵ ) —, and R ⁵ is an alkyl group or substituted. A good aryl group, a compound in which Q is a single bond or an alkenylene group, that is, the general formula [II-c]:

[Wherein, R ⁵¹ represents an alkyl group or a substituted or unsubstituted aryl group, Q ¹ represents a single bond or an alkenylene group, and other symbols have the same meaning as described above. ]
The compound represented by, for example, (i) the compound [1] and the general formula [12]:

[Wherein the symbols have the same meaning as described above. ]
Is reacted under the same conditions as in step A1-1 to give a compound of the general formula [13]:

[Wherein the symbols have the same meaning as described above. ]
And (ii) reducing the compound to give a compound of the general formula [14]:

[Wherein the symbols have the same meaning as described above. ]
(Iii) the compound and the following general formula [4aa]:
^{Ar-Q 1 -Z a [4aa} ]
[Wherein, Z ^a represents ^a halogen atom, and other symbols have the same meaning as described above. ]
Is reacted with a compound represented by the general formula [15]:

[Wherein the symbols have the same meaning as described above. ]
(Iv) The compound can be produced by treating in the same manner as in Step A1-3.

  Reduction of the cyclic imine compound [13] can be carried out in a solvent in the presence of a reducing agent. The solvent may be an inert solvent that does not hinder the reaction, and examples thereof include the halogenated aliphatic hydrocarbons, ethers, amides, alcohols, water, and mixed solvents thereof. . Of these, dichloromethane, dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, methanol, ethanol or propanol are preferred. Examples of the reducing agent include metal hydride compounds such as sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride. The amount of the reducing agent to be used can be 0.5 to 5 equivalents, preferably 0.5 to 1 equivalent, relative to compound [13]. This reaction can be carried out under cooling to heating, preferably under ice cooling to room temperature. Compound [14] can also be produced by subjecting compound [13] to a catalytic hydrogen reduction reaction in the presence of a transition metal catalyst. Examples of the transition metal catalyst include palladium-carbon, platinum-carbon, platinum oxide, Raney nickel and the like.

  The reaction of compound [14] and compound [4aa] can be carried out in a solvent in the presence of a base and a transition metal catalyst. The solvent may be an inert solvent that does not hinder the reaction, and examples thereof include the aromatic hydrocarbons, alcohols, ethers, amides, dimethyl sulfoxide, and mixed solvents thereof. Of these, toluene and tert-butanol are preferred. Examples of the base include the alkali metal carbonates, alkali metal phosphates, alkali metal alkoxides, and the like. Among these, cesium carbonate is preferable. Examples of the transition metal catalyst include palladium acetate, tris (dibenzylideneacetone) dipalladium, dichlorobis (triphenylphosphine) palladium and the like. In this reaction system, a phosphine compound such as triphenylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl as a ligand, etc., as necessary. May be added. The amount of compound [4aa] used in this reaction can be 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound [14]. The amount of the base used can be 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound [14]. The usage-amount of a transition metal catalyst (and a ligand) can be 0.001-0.1 equivalent with respect to compound [14], Preferably it can be 0.005-0.01 equivalent. This reaction can be carried out at room temperature to under heating, preferably under heating.

Of the intermediate compound [II-A] in the present invention, a compound in which X is a group represented by the formula: —N (R ⁴ ) — and Y is a group represented by the formula: —C (═O) —, General formula [II-e]:

[Wherein the symbols have the same meaning as described above. ]
Can be produced, for example, according to the following reaction scheme C-1.
(Reaction Scheme C-1):

[In the above scheme, the symbols have the same meaning as described above. ]
Step C1-1:
The reaction of compound [17] and compound [2] can be carried out in the same manner as in Step A1-1. In addition, the compound [18] is represented, for example, by the following general formula [17a]:

[Wherein the symbols have the same meaning as described above. ]
And the compound [2] is treated in the same manner as in Step A1-1 to give the following general formula [18a]:

[Wherein the symbols have the same meaning as described above. ]
And then treating the compound with nitric acid (nitration) in a solvent (such as concentrated sulfuric acid).

Step C1-2:
The reaction of compound [18] with compound [4a] or compound [4b] can be carried out in the same manner as in Step A1-2.

Step C1-3:
The reduction reaction of compound [19] can be carried out in the same manner as in the above step A1-3.

Step C1-4:
The reduction reaction of compound [18] can be carried out in the same manner as in the above step A1-3.

Step C1-5:
The reaction of compound [20] with compound [4a] or compound [4b] can be carried out in the same manner as in Step A1-2.

  Among the intermediate compounds [II-A], compounds in which Y is the formula: —C (═S) —, that is, the general formula [II-f]:

[Wherein the symbols have the same meaning as described above. ]
For example, the compound represented by the following general formula [II-g]:

[Wherein the symbols have the same meaning as described above. ]
In the same manner as in the method C, the compound represented by can be reacted with a sulfurizing agent.

  Intermediate compound [II-A3] in the present invention:

[Wherein the symbols have the same meaning as described above. ]
Can be prepared, for example, according to the following reaction scheme D1.

  (Reaction Scheme D1)

[In the above scheme, the symbols have the same meaning as described above. ]
Step D1-1:
Reduction of compound [44] can be carried out, for example, in a solvent in the presence of a reducing agent. Any inert solvent that does not interfere with the reaction may be used, and examples thereof include ethers such as tetrahydrofuran. Examples of the reducing agent include diisobutylaluminum hydride and the like. In this reaction, the amount of the reducing agent to be used can be 2 to 7 equivalents, preferably 4 to 5 equivalents, relative to compound [44]. This reaction can be carried out at -78 ° C to 0 ° C, preferably -78 ° C to -50 ° C.

Step D1-2:
The reaction of compound [54] and compound [74] can be carried out, for example, in a solvent in the presence of an activating agent. Any inert solvent that does not interfere with the reaction may be used, and examples thereof include aromatic hydrocarbons such as toluene and ethers such as tetrahydrofuran. Examples of the activator include cyanomethylenetri n-butylphosphorane, cyanomethylenetrimethylphosphorane and the like. The amount of compound [74] used in this reaction can be 1 to 5 equivalents, preferably 1.5 to 2 equivalents, relative to compound [54]. Moreover, the usage-amount of an activator can be 1-5 equivalent with respect to compound [54], Preferably it can be 1.5-2 equivalent. This reaction can be carried out at room temperature to 100 ° C, preferably 50-80 ° C.

Step D1-3:
The reaction of compound [64] with compound [4a] or compound [4b] can be carried out in the same manner as in Step A1-2.

  The intermediate compound [II-E] of the present invention can be produced, for example, according to the following reaction scheme E1.

  (Reaction Scheme E1)

[In the above scheme, the symbols have the same meaning as described above. ]
Step E1-1:
The reaction of compound [45] with compound [4a] or compound [4b] can be carried out in the same manner as in Step A1-2, respectively.

Step E1-2:
The reaction of compound [55] and compound [10] can be carried out in the same manner as in Step B1-3.

Step E1-3:
Removal of the protecting group from compound [65] can be carried out in the same manner as in Step B1-4.

Step E1-4:
The reaction of compound [85] and compound [a] can be carried out in the same manner as in the above Method A.

  The intermediate compound [II-B] in the present invention includes, for example, (i) a diazotization agent (a nitrite such as sodium nitrite and potassium nitrite) in a hydrohalic acid such as hydrochloric acid. ) To convert to the corresponding diazonium salt, then (ii) the diazonium salt in a solvent in the presence of copper or a salt thereof (copper (II) chloride, copper sulfate, etc.) or sulfur dioxide or bisulfite ( It can be produced by reacting with sodium bisulfite, potassium sulfite, etc. (sulfonylation).

  The solvent used in the diazotization reaction (i) may be any inert solvent that does not hinder the reaction, and examples thereof include acetic acid, hydrochloric acid, sulfuric acid, and a mixed solvent thereof with water. The amount of the diazotizing agent to be used can be 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound [II-A]. This reaction can be carried out under cooling to heating, preferably from -10 ° C to room temperature.

  The solvent in the sulfonylation reaction (ii) may be any inert solvent that does not hinder the reaction, and examples thereof include acetic acid, hydrochloric acid, sulfuric acid, and a mixed solvent thereof with water. The usage-amount of copper or copper salt can be 0.1-5 equivalent with respect to a diazotization reaction product, Preferably it can be 0.1-2 equivalent. The amount of sulfur dioxide or bisulfite used can be 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to the diazotization reaction product. This reaction can be carried out under cooling to heating, preferably at −10 ° C. to room temperature.

  The starting compound such as compound [a] used in each of the above reactions (Methods A to D, methods a to e, or each reaction described in Reaction Schemes A1 to E1) is a known compound per se, or a conventional synthetic chemistry. Can be prepared from known compounds using conventional techniques.

  The following general formula [III] which is the above-mentioned compound [II-A] or a precursor thereof:

[Wherein the symbols have the same meaning as described above. ]
Among the compounds represented by general formula [ii]:

Wherein ring A ² is R ⁰⁰ halogen atoms and one to two benzene ring optionally substituted by a group selected from alkyl group in addition, R ⁰⁰ is a nitro group or amino group, R ²² and R ³² is one of a hydrogen atom or an alkyl group and the other represents an alkyl group, a phenyl group or a halogenophenyl group, X ^b represents an oxygen atom or a sulfur atom, Y ^b is the formula: -C (= O) - or -CH A group represented by (R ⁵² ) —, R ⁵² is a hydrogen atom or a phenyl group, Ar ² is (1) a halogen atom, (2) a cyano group, (3) an alkyl group, (4) a trihalogenoalkyl group and (5 ) Represents a phenyl group which may be substituted with 1 to 3 groups selected from alkylenedioxy groups (which may be substituted with 1 to 2 halogen atoms), and the other symbols have the same meanings as described above Have ]
In addition to being useful as an intermediate for the synthesis of the object compound [I] of the present invention, the compound represented by the formula: mineralocorticoid receptor (MR), glucocorticoid receptor (GR) or androgen receptor (AR) It also has a high affinity for nuclear steroid receptors.

For example, in a binding test using rat kidney-derived mineralocorticoid receptor (MR) and ³ H-aldosterone, 6-chloro-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H— 1,4-benzoxazin-3 (4H) -one or 4- (4-fluoro-2,6-dimethylphenyl) -6-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzo Oxazin-3 (4H) -one had a Ki value of less than 10 μM for ³ H-aldosterone binding to MR.

In a binding test using a rat liver-derived glucocorticoid receptor (GR) and ³ H-dexamethasone,
4- (4-fluorophenyl) -7-nitro-2-phenyl-2H-1,4-benzoxazin-3 (4H) -one,
4-benzyl-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one,
4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-3-phenyl-2H-1,4-benzoxazine,
4- (4-fluoro-3-methylphenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one,
2,2-dimethyl-7-nitro-4-[(E) -2-phenylvinyl] -2H-1,4-benzoxazin-3 (4H) -one,
4-benzyl-2- (4-chlorophenyl) -7-nitro-2H-1,4-benzoxazin-3 (4H) -one,
7-amino-4-benzyl-2- (4-chlorophenyl) -2H-1,4-benzoxazin-3 (4H) -one and 4- (3-trifluoromethyl-4-methylphenyl) -2,2 -Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one had a Ki value for ³ H-dexamethasone binding to GR of less than 10 μM.

Furthermore, in a binding test using rat prostate-derived androgen receptor (AR) and ³ H-methyltrienolone, 7-amino-4- (3,4-difluorophenyl) -2,2-dimethyl-2H-1, 4-Benzoxazin-3 (4H) -one had a Ki value for ³ H-methyltrienolone binding to AR of less than 10 μM (all binding studies were performed in The Journal of Pharmaceutical Therapies, 1987; 240 : It implemented according to the method of p.650-656 description).

  From the above test results, the pharmaceutical composition comprising the compound [ii] or a pharmacologically acceptable salt thereof as an active ingredient is also useful as a nuclear steroid receptor ligand (receptor activity modulator). Furthermore, the pharmaceutical composition comprising the compound [ii] or a pharmacologically acceptable salt thereof as an active ingredient is useful as a prophylactic / therapeutic agent for diseases involving nuclear steroid receptors.

  In the present invention, the “halogen atom” means a fluorine atom, a chlorine atom, an iodine atom or a bromine atom, and the “alkyl” is a straight chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms or “Alkoxy” means linear or branched alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and “alkanoyl” means 1 to 6 carbon atoms. 7 means, preferably a linear or branched alkanoyl having 2 to 5 carbon atoms, and “alkenyl” is a straight or branched chain having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms. “Alkylene” means linear or branched alkylene having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and “alkenylene” means 2 to 6 carbon atoms. Linear, preferably having 2 to 4 carbon atoms Alternatively, it means branched alkenylene, and “alkylenedioxy” means linear or branched alkylenedioxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and “cycloalkyl” Means cycloalkyl having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and “cycloalkenyl” means cycloalkenyl having 3 to 8 carbon atoms, preferably 3 to 7 carbon atoms. "Is an aralkyl having 7 to 16 carbon atoms (aralkyl composed of 6 to 10 membered aryl and alkyl having 1 to 6 carbon atoms), preferably an aralkyl having 7 to 10 carbon atoms (6 member aryl and 1 to 6 carbon atoms). Aralkyl composed of four alkyls).

  Specific examples (production examples) of the compound [I] synthesized by each of the above exemplified methods are shown below, but the present invention is not limited thereby.

Production Example 1
To a solution of 7-amino-2,2-dimethyl-4-phenyl-2H-1,4-benzoxazin-3 (4H) -one (compound obtained in Reference Example 1 (3), 50 mg) in chloroform (2 mL). Under ice-cooling, methanesulfonyl chloride (22 μL) and pyridine (30 μL) are successively added dropwise, and the mixture is stirred at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, and the mixture is extracted with chloroform. The organic layer is washed successively with water, 10% hydrochloric acid and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex NH silica gel; manufactured by Fuji Silysia Chemical, elution solvent: n-hexane / ethyl acetate = 1/1 → ethyl acetate) to give N- (2,2 -Dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide (55 mg) is obtained as a colorless powder.
APCI-MS m / z: 347 [M + H] ^< +>.

Production Examples 2-38
By treating the corresponding raw material compounds in the same manner as in Production Example 1, the compounds shown in Tables 1 to 8 below are obtained.

Production Example 39
7-amino-4- (4-fluorophenyl) -2,2-dimethyl-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (in Reference Example 7 (4) The obtained compound (113 mg) was treated in the same manner as in Production Example 1 to give N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [ 3,2-b] [1,4] oxazin-7-yl] methanesulfonamide (98 mg) is obtained as colorless crystals.
APCI-MS m / z: 366 [M + H] ^< +>.

Production Example 40
N- [4- (4-Methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Object of Production Example 14) A boron tribromide dichloromethane solution (1.0 M, 0.32 mL) is added dropwise to a dichloromethane (5 mL) solution of the compound, 40 mg) while cooling in a dry ice-acetone bath. The reaction mixture is stirred at room temperature for 5.5 hours, saturated aqueous sodium hydrogen carbonate solution is added, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 4/1 → 3/7) to give N- [4- (4-hydroxyphenyl) -2,2-dimethyl. -3-Oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (35 mg) is obtained as a colorless powder.
APCI-MS m / z: 363 [M + H] ^< +>.

Production Example 41
(1) Acetic acid of 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (the compound obtained in Reference Example 15, 50 mg) To a (465 μL) -concentrated hydrochloric acid (570 μL) solution, a solution of sodium nitrite (13.3 mg) in water (115 μL) is added under ice cooling, and the mixture is stirred at the same temperature for 1.5 hours. To the reaction mixture is added a mixed solution of sodium bisulfite (182 mg), copper (II) chloride (23.5 mg), acetic acid (225 μL) and concentrated hydrochloric acid (115 μL) at the same temperature, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is ice-cooled, slowly poured into ice water (15 mL), and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoate. Oxazine-7-sulfonyl chloride is obtained.

(2) A 40% aqueous methylamine solution (1 mL) is added to a chloroform (2 mL) suspension of the compound obtained in (1) above under ice cooling, and the mixture is stirred at room temperature for 1 hour. Chloroform is added to the reaction solution, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 9/1 → 1/1) to give 4- (4-fluorophenyl) -N, 2,2-trimethyl- 3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide (31 mg) is obtained as a colorless powder.
APCI-MS m / z: 365 [M + H] ^< +>.

Production Example 42
7-Amino-4- (4-fluorophenyl) -2,2-dimethyl-2H-1,4-benzothiazin-3 (4H) -one (compound obtained in Reference Example 28 (3), 124 mg) 1 to give N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazin-7-yl] methane. Sulfonamide (149 mg) is obtained as a pink powder.
APCI-MS m / z: 381 [M + H] ^< +>.

Production Example 43
Under an argon atmosphere, palladium acetate (1.3 mg), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (7.2 mg), phenylboronic acid (0.9 mg) , Tert-butanol (2 mL) is stirred at room temperature for 20 minutes. N- [4- (3-Chloro-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone was added to the mixture. Amide (Compound of Preparation 13, 60 mg), potassium carbonate (62 mg), tert-butyl carbamate (35 mg) and tert-butanol (5 mL) are added and the mixture is heated to reflux for 3 hours. To the reaction solution was added palladium acetate (1.3 mg), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (7.2 mg), potassium carbonate (62 mg) and carbamic acid. After adding t-butyl (35 mg), the mixture is further heated to reflux for 20 hours. After allowing to cool, the reaction mixture is diluted with ethyl acetate, washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 → 3/7) to give (5- {2,2-dimethyl-7-[(methylsulfonyl). ) Amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl} -2-fluorophenyl) carbamate tert-butyl (83 mg) is obtained as a colorless powder.
APCI-MS m / z: 497 [M + NH 4] +.

Production Example 44
4N Hydrogen chloride-ethyl acetate solution (10 mL) is added to a chloroform (5 mL) solution of the compound obtained in Production Example 43 (72 mg), and the mixture is stirred at room temperature for 9 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 100/1 → 9/1) to give N- [4- ( 3-amino-4-fluorophenyl) -2,2-dimethyl-3-oxo-2,3-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (40 mg) is obtained as a colorless powder. .
APCI-MS m / z: 380 [M + H] ^< +>.

Production Example 45
6-Amino-1- (4-fluorophenyl) -3,3-dimethyl-3,4-dihydroquinoxalin-2 (1H) -one (compound obtained in Reference Example 29 (4), 62 mg) was produced in Production Example 1. To give N- [1- (4-fluorophenyl) -3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] methanesulfonamide (55 mg). ) As a colorless powder.
APCI-MS m / z: 364 [M + H] ^< +>.

Production Example 46
N- [4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (obtained in Preparation Example 9) To a suspension of the resulting compound, 182 mg) in dioxane (10 mL), Lawesson's Reagent (202 mg) is added and stirred at room temperature for 2 hours and then at 40 ° C. for 24 hours. The reaction mixture is diluted with chloroform and then filtered through a NH-silica gel (Chromatorex NH silica gel) pad. An NH-silica gel (Chromatorex NH silica gel) pad is washed with ethyl acetate, and the filtrate and washings are combined and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 19/1 → 3/2) to give N- [4- (4-fluorophenyl) -2,2- Dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (25 mg) is obtained as a yellow powder.
APCI-MS m / z: 381 [M + H] ^< +>.

Production Example 47
(1) tert-Butyl [(2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methyl] (methylsulfonyl) carbamate (Reference Example 48 ( By treating the compound obtained in 2), 200 mg) and 4-fluorophenylboronic acid (146 mg) in the same manner as in Reference Example 1 (2), {[4- (4-fluorophenyl) -2,2- Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methyl} (methylsulfonyl) carbamate tert-butyl (50 mg) is obtained as a colorless powder.
APCI-MS m / z: 479 [M + H] ^< +>.

(2) The compound (50 mg) obtained in the above (1) is treated in the same manner as in Production Example 44 to give N-{[4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3. , 4-Dihydro-2H-1,4-benzoxazin-7-yl] methyl} methanesulfonamide (19 mg) is obtained as a colorless powder.
APCI-MS m / z: 379 [M + H] ^< +>.

Production Example 48
To a solution of 3M sulfuric acid (4 μL) and 36% formaldehyde solution (9.5 mg) in tetrahydrofuran (2 mL) was added N- [4- (3-amino-4-fluorophenyl) -2,2-dimethyl- under salt-ice cooling. 3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Compound of Preparation 44, 20 mg) and sodium borohydride (1 mg) in tetrahydrofuran (3 mL) Liquid is added and the mixture is stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 7/3 → 3/7) to give N- {4- [3- (dimethylamino) -4-fluoro. Phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methanesulfonamide (10 mg) is obtained as a colorless powder.
APCI-MS m / z: 408 [M + H] ^< +>.

Production Examples 49 to 106
The corresponding raw material compounds are treated in the same manner as in Production Example 1 to obtain the compounds described in Tables 9-16 below.

Production Examples 107 to 113
The corresponding starting material compounds are treated in the same manner as in Production Example 41 to give the compounds shown in Table 17 below.

Production Example 114
To a solution of chlorosulfonyl isocyanate (99 mg) in tetrahydrofuran (2 mL) is added dropwise tetrahydrofuran (0.5 mL) containing water (13 mg) under cooling with a dry ice-acetone bath, and the mixture is stirred at the same temperature for 10 minutes. 4- (4-Fluorophenyl) -7-amino-2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-3 (4H) -one (obtained in Reference Example 14) was added to the reaction mixture. Compound, 100 mg) and triethylamine (97 μL) are added and the mixture is stirred at the same temperature for 0.5 hour, then at room temperature for 2 hours. Water is poured into the reaction mixture and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1 → 2/1) and then triturated with diethyl ether to give N- [4- (4-fluorophenyl). ) -2,2-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] sulfamide (11 mg) is obtained as a colorless powder.
APCI-MS m / z: 366 [M + H] ^< +>.

Production Example 115
N- [4- (4-Fluoro-3-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Preparation The compound obtained in Example 55 (30 mg) was treated in the same manner as in Production Example 40 to give N- [4- (4-fluoro-3-hydroxyphenyl) -2,2-dimethyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (17 mg) is obtained as colorless crystals.
APCI-MS m / z: 381 [M + H] ^< +>.

Production Example 116
N- [4- (3-Amino-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Preparation To a solution of the compound obtained in Example 44 (13 mg) and pyridine (5.5 μL) in dichloromethane (5 mL) is added acetyl chloride (3.6 μL) under ice cooling, and the mixture is stirred at the same temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (eluent: chloroform → chloroform / methanol = 9/1) and then triturated with diisopropyl ether to give N- (5- {2,2-dimethyl-7- [ (Methanesulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl} -2-fluorophenyl) acetamide (10 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 422 [M + H] ^< +>.

Production Example 117
N- [4- (4-Fluorophenyl) -6-methoxy-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Preparation The compound obtained in Example 101 (56 mg) was treated in the same manner as in Production Example 40 to give N- [4- (4-fluorophenyl) -6-hydroxy-2,2-dimethyl-3-oxo-3,4 -Dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (30 mg) is obtained as a colorless powder.
APCI-MS m / z: 381 [M + H] ^< +>.

Production Example 118
(1) [7-Amino-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] carbamic acid tert- By treating butyl (compound obtained in Reference Example 50 (4), 500 mg) in the same manner as in Production Example 1, {4- (4-fluorophenyl) -2,2-dimethyl-7-[(methylsulfonyl) Amino] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl} carbamate tert-butyl (555 mg) is obtained as a colorless powder.
APCI-MS m / z: 497 [M + NH 4] +.

(2) By treating the compound (525 mg) obtained in (1) in the same manner as in Production Example 44, N- [6-amino-4- (4-fluorophenyl) -2,2-dimethyl-3- Oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (165 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 380 [M + H] ^< +>.

Production Example 119
Triethylsilane (93 mg) is added to a solution of the compound obtained in Reference Example 49 (4) (60 mg) in trifluoroacetic acid (1 mL) -chloroform (1 mL), and the mixture is stirred at room temperature for 3 hours and then at 50 ° C. for 24 hours. Triethylsilane (93 mg) is added to the reaction mixture, and the mixture is stirred at 70 ° C. for 24 hours. Then, triethylsilane (185 mg) is further added and stirred at 70 ° C. for 40 hours. After cooling the reaction mixture, water is poured and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, solvent: n-hexane / ethyl acetate = 4/1 → 1/1) to give N- [1- (4-fluorophenyl). ) -3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl] methanesulfonamide (36 mg) as a colorless powder.
APCI-MS m / z: 363 [M + H] ^< +>.

Production Example 120
(1) To a solution of the compound (100 mg) obtained in Reference Example 57 (2) in chloroform (15 mL) was added 10% palladium-carbon (75 mg, water content: about 50%) and concentrated hydrochloric acid (one drop), and atmospheric hydrogen Stir at room temperature for 3 hours under atmosphere. The reaction mixture is diluted with 1,2-dimethoxyethane and then filtered. The filtrate is concentrated under reduced pressure to give 7-amino-2-fluoro-4- (4-fluorophenyl) -2H-1,4-benzoxazin-3 (4H) -one hydrochloride as a crude product.

  (2) By treating the compound (crude product) obtained in (1) above in the same manner as in Production Example 1, N- [2-fluoro-4- (4-fluorophenyl) -3-oxo-3, 4-Dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (9 mg) is obtained as a colorless powder.

Production Examples 121-162
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds described in Tables 18-23 below.

Production Example 163
Benzoic acid 2-chloro-5- {2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl} benzyl ester To a solution of the compound obtained in Production Example 141 (80 mg) in tetrahydrofuran (3 mL) -methanol (3 mL) was added 2N aqueous sodium hydroxide solution (0.39 mL) under ice cooling, and the reaction mixture was kept at the same temperature for 8 hours. Stir. The reaction mixture is acidified with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 7/3 → 2/3) and then triturated with diisopropyl ether-n-hexane (1: 1). N- {4- [4-Chloro-3- (hydroxymethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide (39 mg) is obtained as a colorless powder.
APCI-MS m / z: 411 [M + H] ⁺ .

Production Example 164
Benzoic acid 4- {2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl} benzyl ester (Production Example 140 N- {4- [4- (hydroxymethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H- is treated in the same manner as in Production Example 163. 1,4-Benzoxazin-7-yl} methanesulfonamide (88 mg) is obtained as a colorless powder.
APCI-MS m / z: 377 [M + H] +.

Production Example 165
N- [2,2-dimethyl-4- (3-nitrophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (obtained in Preparation Example 146) 10% palladium-carbon (100 mg) is added to a methanol (5 mL) -tetrahydrofuran (5 mL) solution of the obtained compound, 240 mg), and the mixture is stirred at room temperature for 2 hours under an atmospheric hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give N- [4- (3-aminophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoate. [Oxazin-7-yl] methanesulfonamide is obtained as a colorless powder.
APCI-MS m / z: 362 [M + H] ^< +>.

Production Examples 166 to 177
By treating the corresponding raw material compounds in the same manner as in Production Example 1, the compounds described in Tables 24 to 25 below are obtained.

Production Example 178
N- [4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Preparation 10% Palladium-carbon (water content: about 50%, 200 mg) is added to a solution of the compound obtained in Example 158 (200 mg) in ethanol (20 mL), and the mixture is stirred at room temperature for 20 hours in an atmospheric hydrogen atmosphere. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform → chloroform / ethyl acetate = 10/1) to give N- [5-ethyl. -4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (209 mg) is obtained as a colorless powder. .
APCI-MS m / z: 393 [M + H] ^< +>.

Production Example 179
N- [4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (Preparation To a solution of the compound obtained in Example 158 (200 mg) in tetrahydrofuran (5 mL) is added 10M borane-dimethyl sulfide complex tetrahydrofuran solution (0.03 mL) under ice cooling. After stirring the mixture at room temperature for 5 hours, 10M borane-dimethyl sulfide complex tetrahydrofuran solution (0.03 mL) is added, and the mixture is further stirred for 15 hours. Tetrahydrofuran (5 mL), 30% aqueous hydrogen peroxide (0.6 mL) and 2N aqueous sodium hydroxide solution (0.77 mL) are successively added to the mixture, and the mixture is stirred at room temperature for 3 hr. The reaction mixture is poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: chloroform / ethyl acetate = 100/0 → 0/100) to give N- [4- (4-fluorophenyl) -5- (2-hydroxy Ethyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (113 mg) is obtained as a colorless powder.
APCI-MS m / z: 409 [M + H] ^< +>.

Production Example 180
7-amino-4- (4-fluorophenyl) -5- (hydroxymethyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (obtained in Reference Example 175 (3) The resulting compound, 117 mg) and pyridine (0.12 mL) in dichloromethane (5 mL) are added dropwise with methanesulfonyl chloride (0.085 mL) under ice-cooling, and the mixture is stirred at room temperature for 4 hours. Water is poured into the reaction mixture and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in methanol (4 mL) and heated to reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: chloroform → chloroform / methanol = 85/15) to give N- [4- (4-fluorophenyl) -5- (Methoxymethyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide (40 mg, pale yellow powder, APCI-MS m / z : 409 [M + H] ⁺ ) and N- [4- (4-fluorophenyl) -5- (hydroxymethyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzo Oxazin-7-yl] methanesulfonamide (52 mg, light brown powder, APCI-MS m / z: 395 [M + H] ⁺ ) is obtained.

Production Examples 181 to 196
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds described in Tables 26 to 27 below.

Production Example 197
Benzoic acid 2-chloro-5- {5-fluoro-2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4- Yl} benzyl ester (the compound obtained in Production Example 183, 128 mg) was treated in the same manner as in Production Example 163 to give N- {4- [4-chloro-3- (hydroxymethyl) phenyl] -5-fluoro- 2,2-Dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methanesulfonamide (28 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 429/431 [M + H] ^< +>.

Production Examples 198-207
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to give the compounds shown in Table 28 below.

Production Example 208
By treating the corresponding starting material compound in the same manner as in Production Example 1, N- [4- (4-fluorophenyl) -2-methyl-3-oxo-2-phenyl-3,4-dihydro-2H-1,4 -Benzoxazin-7-yl] methanesulfonamide is obtained as a colorless powder.
APCI-MS m / z: 427 [M + H] ^< +>.

Production Examples 209 to 214
The corresponding starting material compounds are treated in the same manner as in Production Example 1 to give the compounds shown in Table 29 below.

Reference example 1
(1) Add 2-amino-5-nitrophenol (5.00 g) to a suspension of potassium fluoride (4.71 g) in N, N-dimethylformamide (40 mL) and stir at room temperature for 1 hour. A solution of ethyl α-bromoisobutyrate (6.33 g) in N, N-dimethylformamide (10 mL) is added dropwise to the suspension over about 20 minutes, and then the reaction solution is stirred at 60 ° C. for 20 hours. After cooling, add cold water to the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with 10% hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate, and the precipitate was collected by filtration and washed with ethyl acetate, whereby 2,2-dimethyl-7-nitro-2H-1,4-benzoxazine-3 (4H)- On (2.80 g) is obtained as a light brown powder.
ESI-MS m / z: 221 [M−H] ⁻ .

(2) Phenylboronic acid (659 mg), copper (II) acetate (589 mg) and molecular sieves-4A powder (600 mg) were added to a suspension of the compound (600 mg) obtained in (1) above in dichloromethane (12 mL), Triethylamine (753 μL) is then added and the mixture is stirred vigorously at room temperature for 20 hours. The reaction mixture is filtered and the residue is washed with chloroform. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1) to give 2,2-dimethyl-7-nitro- 4-Phenyl-2H-1,4-benzoxazin-3 (4H) -one (755 mg) is obtained as a pale yellow solid.
APCI-MS m / z: 316 [M + NH 4] +.

(3) Tin (II) chloride dihydrate (567 mg) was added to an ethanol (6 mL) suspension of the compound (150 mg) obtained in (2) above at room temperature, and the mixture was stirred at 80 ° C. for 3 hours. To do. After cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate are added to the reaction mixture, and the mixture is stirred at room temperature for 1 hour. The mixture is filtered through celite and the filtrate is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (Chromatorex NH silica gel, elution solvent: n-hexane / ethyl acetate = 4/1) to give 7-amino-2,2-dimethyl-4-phenyl- 2H-1,4-benzoxazin-3 (4H) -one (113 mg) is obtained as a colorless powder.
APCI-MS m / z: 269 [M + H] ^< +>.

Reference example 2
(1) 60% oily sodium hydride (43 mg) was added to a solution of the compound (200 mg) obtained in Reference Example 1 (1) in N, N-dimethylformamide (3 mL) under ice cooling, and 0.5% at room temperature. Stir for hours. Benzyl bromide (128 μL) is added dropwise to the reaction mixture under ice cooling, followed by stirring at room temperature for 3 hours. Pour cold water into the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (Chromatorex NH silica gel, solvent: n-hexane / ethyl acetate = 9/1 → 4/1) to give 4-benzyl-2,2-dimethyl-7. -Nitro-2H-1,4-benzoxazin-3 (4H) -one (216 mg) is obtained as a yellow powder.

(2) By treating the compound (150 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4-benzyl-2,2-dimethyl-2H-1,4-benzo Oxazin-3 (4H) -one (102 mg) is obtained as a colorless powder.
APCI-MS m / z: 283 [M + H] ^< +>.

Reference example 3
(1) To a solution of the compound (500 mg) obtained in Reference Example 1 (1) in tetrahydrofuran (7 mL) -methanol (5 mL) was added 10% palladium-carbon (100 mg, water content: about 50%), and an atmospheric hydrogen atmosphere Stir at room temperature overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (429 mg) as a pale pink solid. .
APCI-MS m / z: 193 [M + H] ^< +>.

(2) Compound (43 mg) obtained in (1) above, 2-bromo-5-fluoropyridine (79 mg), copper (I) iodide (4.3 mg), potassium phosphate (96 mg) and N, N ′ Stir a mixture of dimethylethylenediamine (5 μL) in dioxane (2 mL) at 110 ° C. for 3 hours under argon atmosphere. Copper (I) iodide (12.9 mg) and N, N′-dimethylethylenediamine (15 μL) are added to the reaction solution, and the mixture is stirred at the same temperature for 0.5 hour. After allowing to cool, water is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1 → 1/1) to give 7-amino-4- (5-fluoropyridin-2-yl). -2,2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (55 mg) is obtained as a pale orange powder.
APCI-MS m / z: 288 [M + H] ^< +>.

Reference example 4
(1) The corresponding starting material compound was treated in the same manner as in Reference Example 1 (1) to give 7-nitro-2H-1,4-benzoxazin-3 (4H) -one (ESI-MS m / z: 193 [M- H] ⁻ ), and then treating the compound in the same manner as in Reference Example 3 (1), thereby converting 7-amino-2H-1,4-benzoxazin-3 (4H) -one as a light brown powder. obtain.
APCI-MS m / z: 165 [M + H] ^< +>.

(2) 60% oily sodium hydride (59 mg) is added to a solution of the compound obtained in (1) (200 mg) in N, N-dimethylformamide (3 mL) under ice cooling, and the mixture is stirred at room temperature for 15 minutes. Benzyl bromide (160 μL) is added dropwise to the reaction mixture under ice cooling, followed by stirring at room temperature for 2 hours. Pour cold water into the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane / ethyl acetate = 5/1 → 1/1), whereby 7-amino-4-benzyl-2H-1,4-benzoxazine- 3 (4H) -one (221 mg) is obtained as a yellow powder.
APCI-MS m / z: 255 [M + H] ^< +>.

Reference Example 5
(1) Potassium fluoride (3.40 g) was added to a suspension of 2-amino-5-nitrophenol (3.00 g) in N, N-dimethylformamide (30 mL) and stirred at room temperature for 15 minutes. -Add bromo-2-methylpropiophenone (4.42 g). The mixture is stirred at room temperature for 0.5 hours, then at 60 ° C. for 20 hours and at 80 ° C. for 3 days. After allowing to cool, pour cold water into the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1) to give 2,2-dimethyl-7-nitro-3-phenyl-2H-1,4- Benzoxazine (3.65 g) is obtained as a pale yellow powder.
APCI-MS m / z: 283 [M + H] ^< +>.

(2) Sodium borohydride (0.20 g) is added to a suspension of the compound (1.50 g) obtained in (1) above in methanol (15 mL) under ice cooling, and the mixture is stirred at room temperature for 1 hour. . Saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was triturated with diethyl ether-n-hexane, and the precipitate was collected by filtration to give 2,2-dimethyl-7-nitro-3-phenyl-3,4-dihydro-2H-1,4- Benzoxazine (1.06 g) is obtained as a pale yellow powder.
APCI-MS m / z: 285 [M + H] ^< +>.

(3) Compound (200 mg) obtained in the above (2), 4-bromofluorobenzene (116 μL), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (16 .8 mg), tris (dibenzylideneacetone) dipalladium (6.4 mg) and cesium carbonate (321 mg) in toluene (4 mL) / tert-butanol (0.8 mL) at 100 ° C. for 17 hours under argon atmosphere. Stir. After allowing to cool, pour cold water into the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1 → 3/1) to give 4- (4-fluorophenyl) -2,2-dimethyl-7. -Nitro-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine (186 mg) is obtained as a yellow powder.
APCI-MS m / z: 379 [M + H] ^< +>.

(4) Tin (II) chloride dihydrate (790 mg) is added to a suspension of the compound (265 mg) obtained in (3) above in ethanol (10 mL) at room temperature, and the mixture is refluxed for 6 hours. Additional tin (II) chloride dihydrate (239 mg) is added to the reaction mixture and refluxed for 2 hours. After cooling, a saturated aqueous sodium bicarbonate solution and ethyl acetate are poured into the reaction mixture, and the mixture is stirred at room temperature for 1 hour. The mixture is filtered and the filtrate is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1 → 1/1) to give 4- (4-fluorophenyl) -2,2-dimethyl-3. -Phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-amine (219 mg) is obtained as a pale yellow viscous body.
APCI-MS m / z: 349 [M + H] ^< +>.

Reference Example 6
(1) By treating the compound (200 mg and 4-fluorophenylboronic acid (252 mg) obtained in Reference Example 1 (1) in the same manner as in Reference Example 1 (2), 4- (4-fluorophenyl)- 2,2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (220 mg) is obtained as a pale yellow solid.
APCI-MS m / z: 334 [M + NH 4] +.

(2) A borane-dimethyl sulfide complex-tetrahydrofuran solution (10M, 0.38 mL) was added to a solution of the compound (300 mg) obtained in (1) (300 mg) in tetrahydrofuran (10 mL) at room temperature, followed by 3 hours at room temperature, followed by 50 ° C. For 8 hours. After allowing to cool, methanol is gradually added to the reaction mixture and heated to reflux for 0.5 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 10/1 → 4/1) to give 4- (4-fluorophenyl)- 2,2-Dimethyl-7-nitro-3,4-dihydro-2H-1,4-benzoxazine (273 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 303 [M + H] ^< +>.

(3) By treating the compound (200 mg) obtained in (2) above in the same manner as in Reference Example 5 (4), 4- (4-fluorophenyl) -2,2-dimethyl-3,4-dihydro- 2H-1,4-benzoxazine-7-amine (153 mg) is obtained as a colorless powder.
APCI-MS m / z: 273 [M + H] ^< +>.

Reference Example 7
(1) A suspension of 60% oily sodium hydride (0.68 g) in N, N-dimethylformamide (15 mL) at room temperature with 2-amino-5-bromopyridin-3-ol (3.22 g) in N, N-dimethylformamide (25 mL) solution is added dropwise over 10 minutes and stirred at room temperature for 20 minutes. Ethyl α-bromoisobutyrate (3.32 g) is added dropwise to the mixture over about 20 minutes, and then the reaction solution is stirred at room temperature for 1 hour and subsequently at 80 ° C. for 2 hours. After cooling, add cold water to the reaction mixture and extract with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated to half volume under reduced pressure. The precipitate was collected by filtration to give 7-bromo-2,2-dimethyl-2H-pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (0.90 g) as a powder. obtain.
APCI-MS m / z: 257/259 [M + H] ^< +>.

(2) By treating the compound (500 mg) obtained in (1) in the same manner as in Reference Example 1 (2), 7-bromo-4- (4-fluorophenyl) -2,2-dimethyl-2H- Pyrido [3,2-b] [1,4] oxazin-3 (4H) -one (477 mg) is obtained as a colorless powder.
APCI-MS m / z: 351/353 [M + H] ⁺ .

(3) Palladium acetate (12 mg), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (63 mg), phenylboronic acid (6 mg), tert-butanol (8 mL) The mixture is stirred at room temperature for 20 minutes under an argon atmosphere. The compound obtained in (2) (460 mg), potassium carbonate (543 mg), t-butyl carbamate (307 mg) and tert-butanol (20 mL) are added to the reaction solution, and the mixture is heated to reflux for 3 hours. After allowing to cool, ethyl acetate is added to the reaction mixture, washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (Chromatorex NH silica gel, solvent: n-hexane / ethyl acetate = 9/1 → 7/3) to give 4- (4-fluorophenyl) -2, Tert-butyl 2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl] carbamate is obtained.
(4) A 4N hydrogen chloride-ethyl acetate solution (15 mL) is added to a chloroform (10 mL) solution of the compound obtained in (3) above, and the mixture is stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-2H-pyrido [3,2-b] [1,4] oxazine. -3 (4H) -one (129 mg) is obtained as a colorless powder.
APCI-MS m / z: 288 [M + H] ^< +>.

Reference Examples 8-19
By treating the corresponding starting material compound in the same manner as in Reference Example 1, the compounds described in Tables 30 to 31 below are obtained.

Reference Examples 20-22
(1) The following compound is obtained by processing the corresponding raw material compound in the same manner as in Reference Examples 1 (1) and (2).

Reference Example 20 (1): 4- (4-Fluorophenyl) -7-nitro-2-phenyl-2H-1,4-benzoxazin-3 (4H) -one APCI-MS m / z: 382 [M + NH ₄ ] ⁺ .

Reference Example 21 (1): 4- (4-Fluoro-3-methylphenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one pale yellow powder APCI- MS m / z: 331 [M + H] ^< +>.

Reference Example 22 (1): 2,2-Dimethyl-7-nitro-4-[(E) -2-phenylvinyl] -2H-1,4-benzoxazin-3 (4H) -one APCI-MS m / z: 325 [M + H] ⁺ .

  (2) By treating the compound obtained in (1) above in the same manner as in Reference Example 1 (3), the following compound is obtained.

Reference Example 20 (2): 7-amino-4- (4-fluorophenyl) -2-phenyl-2H-1,4-benzoxazin-3 (4H) -one APCI-MS m / z: 335 [M + H] ⁺ .

Reference Example 21 (2): 7-amino-4- (4-fluoro-3-methylphenyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one APCI-MS m / z: 301 [M + H] ⁺ .

Reference Example 22 (2): 7-amino-2,2-dimethyl-4-[(E) -2-phenylvinyl] -2H-1,4-benzoxazin-3 (4H) -one APCI-MS m / ^{z: 295 [M + H]} +.

Reference Example 23
(1) The corresponding starting material compound is treated in the same manner as in Reference Examples 1 (1) and (2) to give 6-chloro-2,2-dimethyl-7-nitro-4-fluorophenyl-2H-1,4- Benzoxazin-3 (4H) -one is obtained as a yellow powder.
APCI-MS m / z: 368/370 [M + NH 4] +.

(2) By treating the compound obtained in (1) above in the same manner as in Reference Example 1 (3), 7-amino-6-chloro-2,2-dimethyl-4-fluorophenyl-2H-1,4 -Benzoxazin-3 (4H) -one is obtained as a pale red powder.
APCI-MS m / z: 321/323 [M + H] ⁺ .

Reference Example 24
(1) 4-Benzyl-2- (4-chlorophenyl) -7-nitro-2H-1,4-benzoxazine-3 (4H) is obtained by treating the corresponding starting material compound in the same manner as in Reference Example 2 (1). -On is obtained as a pale yellow powder.

(2) By treating the compound obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4-benzyl-2- (4-chlorophenyl) -2H-1,4-benzoxazine -3 (4H) -one is obtained as a pale yellow powder.
APCI-MS m / z: 365/367 [M + H] ⁺ .

Reference Examples 25-27
The corresponding starting material compounds are treated in the same manner as in Reference Example 2 to give the compounds listed in Table 32 below.

Reference Example 28
(1) A solution of 6-nitrobenzothiazole (5.00 g) and hydrazine hydrate (10 mL) in ethanol (50 mL) is refluxed for 2 hours. One third of the reaction mixture is collected and concentrated under reduced pressure. After the residue is diluted with ethanol (20 mL), a mixed solution of α-bromoisobutyric acid (5.51 g), sodium hydroxide (0.4 g) and water (2 mL) is added, and the mixture is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure, dilute acetic acid (5 mL) is added to the residue, and the mixture is heated at 50 ° C. for 1 hr. The reaction mixture was cooled, the precipitated solid was collected by filtration, washed successively with water and ethanol, and recrystallized from ethyl acetate to give 2,2-dimethyl-7-nitro-2H-1,4-benzothiazine-3 ( 4H) -one (0.63 g) is obtained as pale yellow crystals.
ESI-MS m / z: 237 [M−H] ⁻ .

(2) By treating the compound (310 mg) obtained in (1) above in the same manner as in Reference Example 1 (2), 4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H- 1,4-Benzothiazin-3 (4H) -one (221 mg) is obtained as an orange solid.
APCI-MS m / z: 333 [M + H] ^< +>.

(3) By treating the compound (218 mg) obtained in (2) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-2H- 1,4-Benzothiazin-3 (4H) -one (126 mg) is obtained as a pale pink powder.
APCI-MS m / z: 303 [M + H] ^< +>.

Reference Example 29
(1) A solution of 1,2-phenylenediamine (16.96 g) in N, N-dimethylformamide (80 mL) was added successively with N, N-diisopropylethylamine (36.4 mL) and ethyl α-bromoisobutyrate (39.8 g). In addition, heat at 110 ° C. for 3 days. After cooling, add cold water to the reaction mixture and extract with ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the combined organic layer is washed successively with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is recrystallized from dichloromethane-n-hexane to obtain 3,3-dimethyl-3,4-dihydroquinoxalin-2 (1H) -one (15.90 g) as pale yellow crystals.
APCI-MS m / z: 177 [M + H] ^< +>.

(2) After cooling a concentrated sulfuric acid (12 mL) solution of the compound (300 mg) obtained in (1) above to −15 ° C., a concentrated sulfuric acid (0.6 mL) solution of nitric acid (44 μL) was added dropwise, and the mixture was mixed. Stir at warm for 3 hours. Sodium hydroxide (5.4 g) and ice are added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is suspended in ethyl acetate-diethyl ether, and the precipitate is collected by filtration. The resulting solid was purified by NH-silica gel column chromatography (Chromatorex NH silica gel, elution solvent: n-hexane / ethyl acetate = 4/1 → 1/4) to give 3,3-dimethyl-6-nitro- 3,4-Dihydroquinoxalin-2 (1H) -one (26 mg) is obtained as a yellow powder.
APCI-MS m / z: 222 [M + H] ^< +>.

(3) The compound (717 mg) obtained in (2) above is treated in the same manner as in Reference Example 1 (2) to give 1- (4-fluorophenyl) -3,3-dimethyl-6-nitro-3, 4-Dihydroquinoxalin-2 (1H) -one (346 mg) is obtained as a yellow powder.
APCI-MS m / z: 316 [M + H] ^< +>.

(4) By treating the compound (170 mg) obtained in (3) in the same manner as in Reference Example 1 (3), 6-amino-1- (4-fluorophenyl) -3,3-dimethyl-3, 4-Dihydroquinoxalin-2 (1H) -one (114 mg) is obtained as a colorless powder.
APCI-MS m / z: 286 [M + H] ^< +>.

Reference Example 30
The corresponding starting compound was treated in the same manner as in Reference Example 3 to give 7-amino-4- (5-chloro-2-thienyl) -2,2-dimethyl-2H-1,4-benzoxazine-3 (4H). -Get on.
APCI-MS m / z: 309/311 [M + H] ^< +>.

Reference Example 31
The corresponding starting material compound is treated in the same manner as in Reference Example 28 to give 7-amino-4- (4-fluorophenyl) -2H-1,4-benzothiazin-3 (4H) -one.
APCI-MS m / z: 275 [M + H] ^< +>.

Reference Examples 32-45
The corresponding starting materials are treated in the same manner as in Reference Example 1 to give the compounds described in Tables 33 to 34 below.

Reference Example 46
(1) 4- (3-Chloro-4-methylphenyl) -2,2-dimethyl-7-nitro-2H- is prepared by treating the corresponding starting compound in the same manner as in Reference Examples 1 (1) to (2). 1,4-Benzoxazin-3 (4H) -one is obtained as a pale yellow powder.
APCI-MS m / z: 347/349 [M + H] ^< +>.

(2) The compound (110 mg) obtained in (1) above is treated in the same manner as in Reference Example 1 (3) to give 7-amino-4- (3-chloro-4-methylphenyl) -2,2- Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (100 mg) is obtained as a colorless viscous body.
APCI-MS m / z: 317/319 [M + H] ^< +>.

Reference Example 47
(1) 2,2-Dimethyl-7-nitro-4- (1-phenylethyl) -2H-1,4-benzoxazine-3 is obtained by treating the corresponding starting material compound in the same manner as in Reference Example 2 (1). (4H) -one is obtained as a pale yellow viscous body.
APCI-MS m / z: 327 [M + H] ^< +>.

(2) By treating the compound (200 mg) obtained in (1) in the same manner as in Reference Example 2 (2), 7-amino-2,2-dimethyl-4- (1-phenylethyl) -2H- 1,4-Benzoxazin-3 (4H) -one (123 mg) is obtained as a light brown powder.
APCI-MS m / z: 297 [M + H] ^< +>.

Reference Example 48
(1) Under an argon atmosphere, a solution of methyl 2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-carboxylate (1.00 g) in tetrahydrofuran (50 mL) was added. A 1M diisobutylaluminum hydride toluene solution (13.1 mL) is added dropwise under cooling with a dry ice-acetone bath. After stirring the mixture at the same temperature for 2.5 hours, further 1M diisobutylaluminum hydride in toluene (8.5 mL) is added, and the mixture is stirred at the same temperature for 1.5 hours. The reaction mixture is poured into 2N hydrochloric acid and the mixture is extracted with diethyl ether. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is triturated with ethyl acetate to give 7- (hydroxymethyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (389 mg) as a colorless powder.
APCI-MS m / z: 222 [M + H + MeOH-H 2 O] +.

(2) Under a argon atmosphere, a solution of the compound obtained in (1) (388 mg) and N- (tert-butoxycarbonyl) methanesulfonamide (548 mg) in a toluene (10 mL) solution in cyanomethylene tri-n-butylphosphorane ( 678 mg) is added and the mixture is stirred at 50 ° C. for 8 hours. Additional cyanomethylene tri-n-butylphosphorane (678 mg) is added to the reaction mixture and the mixture is stirred at 80 ° C. for 18 hours. Saturated aqueous sodium hydrogen carbonate solution is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 → 1/1) and then triturated with diisopropyl ether to give [(2,2-dimethyl-3 -Oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methyl] (methylsulfonyl) carbamate tert-butyl (217 mg) is obtained as a colorless powder.
APCI-MS m / z: 402 [M + NH 4] +.

Reference Example 49
(1) 6-Bromo-3,3-dimethylquinoline-2,4 (1H, 3H) -dione (1.00 g) and 4-fluorophenylboronic acid (1.04 g) as Reference Example 1 (2) By treating similarly, 6-bromo-1- (4-fluorophenyl) -3,3-dimethylquinoline-2,4 (1H, 3H) -dione (1.02 g) is obtained as a colorless solid.
APCI-MS m / z: 362/364 [M + H] ⁺ .

(2) The compound (650 mg) obtained in the above (1) is treated in the same manner as in Reference Example 7 (3) to give [1- (4-fluorophenyl) -3,3-dimethyl-2,4-dioxo. -1,2,3,4-Tetrahydroquinolin-6-yl] carbamate tert-butyl (209 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 399 [M + H] ^< +>.

(3) The compound (570 mg) obtained in (2) above is treated in the same manner as in Reference Example 7 (4) to give 6-amino-1- (4-fluorophenyl) -3,3-dimethylquinoline-2. , 4 (1H, 3H) -dione (342 mg) is obtained as a yellow powder.
APCI-MS m / z: 299 [M + H] ^< +>.

(4) By treating the compound (150 mg) obtained in (3) in the same manner as in Production Example 1, N- [1- (4-fluorophenyl) -3,3-dimethyl-2,4-dioxo- 1,2,3,4-Tetrahydroquinolin-6-yl] methanesulfonamide (173 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 377 [M + H] +.

Reference Example 50
(1) By treating 2-amino-4-chloro-5-nitrophenol (10.00 g) and ethyl α-bromoisobutyrate (7.4 mL) in the same manner as in Reference Example 1 (1), 6-chloro -2,2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (6.82 g) is obtained as a light brown powder.
ESI-MS m / z: 255/257 [M−H] ⁻ .

(2) By treating the compound (6.82 g) obtained in (1) and 4-fluorophenylboronic acid (7.44 g) in the same manner as in Reference Example 1 (2), 6-chloro-4- (4-Fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (6.22 g) is obtained as a pale yellow powder.
APCI-MS m / z: 368/370 [M + NH 4] +.

(3) The compound (300 mg) obtained in (2) above is treated in the same manner as in Production Example 43 to give [4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-3-oxo- 3,4-Dihydro-2H-1,4-benzoxazin-6-yl] carbamate tert-butyl (63 mg) is obtained as a yellow solid.
APCI-MS m / z: 432 [M + H] ^< +>.

(4) The compound (150 mg) obtained in (3) above is treated in the same manner as in Reference Example 1 (3) to give [7-amino-4- (4-fluorophenyl) -2,2-dimethyl-3. -Oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl] carbamate tert-butyl (78 mg) is obtained as a colorless powder.
APCI-MS m / z: 402 [M + H] ^< +>.

Reference Example 51
(1) Under an argon atmosphere, 6-chloro-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 50 ( 2) Trimethylboroxine (80 μL) was added to a mixture of the compound obtained in 2), 200 mg), potassium carbonate (236 mg), tetrakis (triphenylphosphine) palladium (0) (66 mg) and dioxane (2 mL), Heat at reflux for hours. After allowing to cool, the reaction mixture is filtered through celite, and the insoluble material is washed with tetrahydrofuran. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1) to give 4- (4-fluorophenyl) -2. , 2,6-Trimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (10 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 331 [M + H] ^< +>.

(2) By treating the compound (122 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -2,2,6-trimethyl- 2H-1,4-benzoxazin-3 (4H) -one (28 mg) is obtained as a colorless powder.
APCI-MS m / z: 301 [M + H] ^< +>.

Reference Example 52
(1) Under an argon atmosphere, 6-chloro-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 50 ( 2), 400 mg), palladium acetate (5.1 mg), racemic-2- (di-tert-butylphosphino) -1,1′-binaphthyl (11.4 mg), cesium carbonate (557 mg), A mixture of methanol (1 mL) and toluene (4 mL) is stirred at 70 ° C. for 26 hours. After allowing to cool, water is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was suspended in chloroform (4 mL), 1-hydroxybenzotriazole (154 mg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (208 mg) were added, and the mixture was stirred at room temperature for 3 hours. To do. Water is poured into the reaction mixture and extracted with chloroform. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, solvent: n-hexane / ethyl acetate = 9/1) to give 4- (4-fluorophenyl) -6-methoxy-2. , 2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (147 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 347 [M + NH 4] +.

(2) By treating the compound (130 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -6-methoxy-2,2- Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (110 mg) is obtained as a colorless powder.
APCI-MS m / z: 317 [M + H] ^< +>.

Reference Example 53
(1) To a solution of 2-amino-5-nitrophenol (4.62 g) in N, N-dimethylformamide (150 mL), potassium carbonate (12.44 g) is added, and chloromethyl methyl ether (2.73 mL) is added dropwise. The mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, solvent: n-hexane / ethyl acetate = 2/1). 2- (Methoxymethoxy) -4-nitrophenyl] amine (4.76 g) is obtained as a yellow oil.
APCI-MS m / z: 199 [M + H] ^< +>.

(2) N-bromosuccinimide (4.04 g) is added to a chloroform (130 mL) solution of the compound (3.00 g) obtained in (1) above, and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with chloroform, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The organic layer is filtered through NH-silica gel (Chromatorex NH-silica gel) and a pad of celite, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 19/1 → 1/1) and then powdered with n-hexane / diisopropyl ether to give [2-bromo- 6- (Methoxymethoxy) -4-nitrophenyl] amine (2.19 g) is obtained as an orange powder.
ESI-MS m / z: 275/277 [M−H] ⁻ .

(3) 2-Bromo-2-methylpropionyl bromide (1.35 mL) was added dropwise to a solution of the compound obtained in (2) (1.51 g) and pyridine (0.89 mL) in chloroform (40 mL) under ice cooling. The mixture is stirred at room temperature for 24 hours. The reaction mixture is diluted with chloroform, washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 2-bromo-N- [2-bromo-6- (methoxymethoxy) -4- Nitrophenyl] -2-methylpropionic acid amide (1.81 g) is obtained as an orange oil.
ESI-MS m / z: 423/425 [M−H] ⁻ .

(4) To a solution of the compound obtained in (3) (1.43 g) in dichloromethane (100 mL) is added trifluoroacetic acid (4 mL), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with dichloromethane, washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 17/3 → 1/1) to give 2-bromo-N- (2-bromo-6-hydroxy-4 -Nitrophenyl) -2-methylpropionic acid amide (1.09 g) is obtained as a pale yellow powder.
ESI-MS m / z: 379/381/383 [M−H] ⁻ .

(5) To a solution of the compound obtained in (4) (1.09 g) in N, N-dimethylformamide (40 mL) is added potassium carbonate (1.19 g), and the mixture is stirred at 50 ° C. for 17 hours. After allowing to cool, the reaction mixture is diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is triturated with diisopropyl ether to give 5-bromo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazine-3. (4H) -one (0.79 g) is obtained as a colorless powder.
ESI-MS m / z: 299/301 [M−H] ⁻ .

(6) By treating the compound (570 mg) obtained in (5) above and 4-fluorophenylboronic acid (529 mg) in the same manner as in Reference Example 1 (2), 5-bromo-4- (4-fluoro Phenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (306 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 395/397 [M + H] ⁺ .

(7) By treating the compound (305 mg) obtained in (6) in the same manner as in Reference Example 1 (3), 7-amino-5-bromo-4- (4-fluorophenyl) -2,2- Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (218 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 365/367 [M + H] ⁺ .

Reference Example 54
(1) The compound (3.39 g) obtained in Reference Example 53 (1) and N-chlorosuccinimide (3.43 g) were treated in the same manner as in Reference Example 53 (2), and then the product (1.76 g) was obtained. ) In the same manner as in Reference Examples 53 (3) to (5) to give 5-chloro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one ( 0.85 g) is obtained as a colorless powder.
ESI-MS m / z: 255/257 [M−H] ⁻ .

  (2) By treating the compound (134 mg) obtained in (1) and 4-fluorophenylboronic acid (292 mg) in the same manner as in Reference Example 1 (2), 5-chloro-4- (4-fluoro Phenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (206 mg) is obtained as a yellow powder (crude).

(3) By treating the compound (206 mg) obtained in (2) above in the same manner as in Reference Example 1 (3), 7-amino-5-chloro-4- (4-fluorophenyl) -2,2- Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (107 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 321/323 [M + H] ⁺ .

Reference Example 55
Under an argon atmosphere, 7-amino-5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 53 (7) , 140 mg), potassium carbonate (159 mg), dioxane (11 mL), trimethylboroxine (134 μL) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (31 mg) Is heated to reflux for 2 hours. After allowing to cool, water is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3/1 → 3/7) to give 7-amino-4- (4-fluorophenyl) -2,2 , 5-Trimethyl-2H-1,4-benzoxazin-3 (4H) -one (102 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 301 [M + H] ^< +>.

Reference Example 56
(1) Ethyl α-bromoisobutyrate (1.3 mL) was added to a suspension of 6-amino-2,4-xylenol (0.69 g) and potassium carbonate (3.46 g) in N, N-dimethylformamide (20 mL). In addition, the reaction mixture is stirred at room temperature for 16 hours. After allowing to cool, the reaction mixture is diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer is dried over magnesium sulfate, and the solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 19/1 → 3/1) and then powdered with diisopropyl ether to give 2,2,6,8-tetra Methyl-2H-1,4-benzoxazin-3 (4H) -one (0.28 g) is obtained as a gray powder.
APCI-MS m / z: 206 [M + H] ^< +>.

(2) 70% nitric acid (115 μL) is added to a solution of the compound obtained in (1) (337 mg) in acetic anhydride (6 mL) and stirred at room temperature for 1.5 hours. Additional 70% nitric acid (94 μL) is added to the reaction mixture and the mixture is stirred at room temperature for 17 hours. The reaction mixture is slowly poured into a mixture of ice and saturated aqueous sodium bicarbonate and extracted with diethyl ether. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was triturated with n-hexane / diisopropyl ether to give 2,2,6,8-tetramethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (138 mg) Is obtained as a colorless powder.
ESI-MS m / z: 249 [M−H] ⁻ .

(3) By treating the compound (185 mg) obtained in (2) and 4-fluorophenylboronic acid (207 mg) in the same manner as in Reference Example 1 (2), 4- (4-fluorophenyl) -2 , 2,6,8-Tetramethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (128 mg) is obtained as a colorless powder.
APCI-MS m / z: 362 [M + NH 4] +.

(4) To a solution of the compound (125 mg) obtained in (3) above in methanol (17 mL) is added 10% palladium-carbon (100 mg), and the mixture is stirred at room temperature for 2 hours in an atmospheric hydrogen atmosphere. After filtration of the reaction solution, the filtrate is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 19/1 → ethyl acetate) and then triturated with diisopropyl ether to give 7-amino-4- (4-fluoro Phenyl) -2,2,6,8-tetramethyl-2H-1,4-benzoxazin-3 (4H) -one (103 mg) is obtained as a colorless powder.
APCI-MS m / z: 315 [M + H] ^< +>.

Reference Example 57
(1) To a suspension of 2-amino-5-nitrophenol (1.98 g) and potassium fluoride (2.24 g) in N, N-dimethylformamide (40 mL) was added ethyl bromofluoroacetate (2.85 g). The mixture is stirred at 60 ° C. for 44 hours. After allowing to cool, the reaction mixture is diluted with ethyl acetate and washed successively with water and saturated brine. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 19/1 → 1/1) and then powdered with n-hexane / diisopropyl ether to give 2-fluoro-7. -Nitro-2H-1,4-benzoxazin-3 (4H) -one (1.14 g) is obtained as a yellow powder.
ESI-MS m / z: 211 [M−H] ⁻ .

(2) By treating the compound (0.86 g) obtained in (1) and 4-fluorophenylboronic acid (1.13 g) in the same manner as in Reference Example 1 (2), 2-fluoro-4- (4-Fluorophenyl) -7-nitro-2H-1,4-benzoxazin-3 (4H) -one (0.65 g) is obtained as a yellow powder.
APCI-MS m / z: 339 [M + H + MeOH] ^< +>.

Reference Example 58
Concentrated sulfuric acid (0.1 mL) is added to a solution of 1-hydroxycyclopentanecarboxylic acid (2.00 g) in methanol (15 mL) and the mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with diethyl ether and washed with cold saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to give methyl 1-hydroxycyclopentanecarboxylate (2.06 g) as a light brown oil.
APCI-MS m / z: 162 [M + NH 4] +.

Reference Example 59
By treating 1-hydroxycyclohexanecarboxylic acid (2.50 g) in the same manner as in Reference Example 58, methyl 1-hydroxycyclohexanecarboxylate (2.55 g) is obtained as a pale yellow oil.
APCI-MS m / z: 176 [M + NH 4] +.

Reference Example 60
(1) Concentrated sulfuric acid (0.25 mL) is added to a solution of 2-ethyl-2-hydroxybutyric acid (5.00 g) in methanol (35 mL), and the mixture is refluxed at room temperature for 18 hours and then heated to reflux for another 18 hours. After allowing to cool, the reaction mixture is concentrated under reduced pressure, and the resulting residue is diluted with diethyl ether. The solution is washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is distilled to give methyl 2-ethyl-2-hydroxybutyrate (3.70 g) as a colorless oil.
b. p. 60-61 ° C / 20mmHg
(2) To a solution of the compound obtained in (1) (525 mg) and 4-chloro-2-fluoronitrobenzene (600 mg) in tetrahydrofuran (10 mL) was added 60% oily sodium hydride (150 mg) under ice-cooling, The mixture is stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 20/1 → 3/1) to give 2- (5-chloro-2-nitrophenoxy) -2-ethyl. Methyl butyrate (788 mg) is obtained as a colorless oil.
APCI-MS m / z: 319/321 [M + NH 4] +.

(3) Tin (II) chloride dihydrate (2.88 g) was added to a solution of the compound obtained in (2) (0.77 g) in ethyl acetate (10 mL), and the mixture was stirred at 80 ° C. for 4 hours. To do. After cooling, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added to the reaction mixture, and the mixture is stirred at room temperature for 1 hour. The mixture is filtered through celite and the filtrate is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 10/1 → 2/1) to give 7-chloro-2,2-diethyl-2H-1,4- Benzoxazin-3 (4H) -one (490 mg) is obtained as a colorless powder.
ESI-MS m / z: 238/240 [M−H] ⁻ .

(4) By treating the compound (475 mg) obtained in (3) and 4-fluorophenylboronic acid (554 mg) in the same manner as in Reference Example 1 (2), 7-chloro-2,2-diethyl- 4- (4-Fluorophenyl) -2H-1,4-benzoxazin-3 (4H) -one (514 mg) is obtained as a colorless powder.
APCI-MS m / z: 334/336 [M + H] ^< +>.

(5) The compound (150 mg) obtained in the above (4) is treated in the same manner as in Reference Example 7 (3) to give [2,2-diethyl-4- (4-fluorophenyl) -3-oxo-3. , 4-Dihydro-2H-1,4-benzoxazin-7-yl] carbamate tert-butyl (187 mg) is obtained as a colorless powder.
APCI-MS m / z: 415 [M + H] ^< +>.

(6) The compound (175 mg) obtained in (5) above is treated in the same manner as in Reference Example 7 (4) to give 7-amino-2,2-diethyl-4- (4-fluorophenyl) -2H- 1,4-Benzoxazin-3 (4H) -one (126 mg) is obtained as a colorless powder.
APCI-MS m / z: 315 [M + H] ^< +>.

Reference Example 61
7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (compound of Reference Example 3 (1), 150 mg), 5-bromo-2-chlorotoluene (321 mg), A mixture of copper (I) iodide (37 mg), potassium carbonate (216 mg), N, N′-dimethylethylenediamine (40 μL) and toluene (8 mL) is heated at 110 ° C. overnight under an argon atmosphere. After allowing to cool, water is poured into the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1 → 1/1) to give 7-amino-4- (4-chloro-3-methylphenyl). -2,2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (98 mg) is obtained as a pale orange powder.
APCI-MS m / z: 317/319 [M + H] ^< +>.

Reference Example 62
(1) Ethyl α-bromoisobutyrate (2.46 g) was added to a solution of 2-bromo-5-nitrophenol (1.83 g) and cesium carbonate (5.48 g) in N, N-dimethylformamide (31 mL) and reacted. The mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with ethyl acetate, washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 19/1 → 87/13) to give 2- (2-bromo-5-nitrophenoxy) -2-methyl. Ethyl propionate (1.93 g) is obtained as a colorless viscous oil.
APCI-MS m / z: 349/351 [M + NH 4] +.

(2) To a solution of the compound obtained in (1) (150 mg) and 2-chloro-4-fluoroaniline (263 mg) in dichloromethane (10 mL), 2M trimethylaluminum toluene solution (903 μL) was added dropwise under an argon atmosphere. The mixture is stirred at room temperature for 1.5 hours. Under ice-cooling, 1N hydrochloric acid (20 mL) is poured into the reaction mixture, and the mixture is extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 24/1 → 17/3) to give 2- (2-Bromo-5-nitrophenoxy) -N- (2-chloro-4-fluorophenyl) -2-methylpropionic acid amide (194 mg) is obtained as a pale yellow viscous oil.
APCI-MS m / z: 448/450 [M + NH 4] +.

(3) A mixture of the compound obtained in (2) (190 mg), copper (I) iodide (168 mg), potassium carbonate (73 mg) and pyridine (8 mL) is heated at 100 ° C. overnight under an argon atmosphere. After allowing to cool, the reaction mixture is diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (Chromatorex NH silica gel, elution solvent: n-hexane / ethyl acetate = 24/1 → 41/9), and then powdered with n-hexane / diethyl ether. 4- (2-Chloro-4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (73 mg) is obtained as an orange solid.
APCI-MS m / z: 351/353 [M + H] ⁺ .

(4) By treating the compound (63 mg) obtained in (3) in the same manner as in Reference Example 1 (3), 7-amino-4- (2-chloro-4-fluorophenyl) -2,2- Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (54 mg) is obtained as an orange powder.
APCI-MS m / z: 321/323 [M + H] ⁺ .

Reference Example 63
(1) 5N in a solution of ethyl 2- (2-bromo-5-nitrophenoxy) -2-methylpropionate (a compound obtained in Reference Example 62 (1), 332 mg) in tetrahydrofuran (1 mL) -ethanol (2 mL) Aqueous sodium hydroxide (2 mL) is added and the mixture is stirred at room temperature for 2 hours. The reaction mixture is acidified with 6N hydrochloric acid (3 mL) and extracted with diethyl ether. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid (297 mg) as colorless crystals.
ESI-MS m / z: 302/304 [M−H] ⁻ .

(2) Oxalyl chloride (253 μL) and N, N-dimethylformamide (1 drop) were sequentially added to a solution of the compound obtained in (1) (295 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature overnight. To do. The reaction mixture is concentrated under reduced pressure to give 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid chloride as a crude product. Under an argon atmosphere, a solution of 4-fluoro-2,6-dimethylaniline (149 mg) in tetrahydrofuran (15 mL) was added with 1.6 N n-butyllithium hexane solution (680 μL) for 1 minute under cooling with a dry ice-acetone bath. And the mixture is stirred at the same temperature for 5 minutes. A solution of 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic chloride in tetrahydrofuran (10 mL) prepared above is quickly added to the reaction solution, and the mixture is stirred at the same temperature for 30 minutes. Aqueous citric acid solution is added to the reaction mixture, and the mixture is basified with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, solvent: n-hexane / ethyl acetate = 19/1 → 3/1) to give 2- (2-bromo-5-nitro Phenoxy) -N- (4-fluoro-2,6-dimethylphenyl) -2-methylpropionic acid amide (262 mg) is obtained as a colorless solid.
APCI-MS m / z: 425/427 [M + H] ^< +>.

(3) The compound (260 mg) obtained in the above (2) is treated in the same manner as in Reference Example 62 (3) to give 4- (4-fluoro-2,6-dimethylphenyl) -2,2-dimethyl- 7-Nitro-2H-1,4-benzoxazin-3 (4H) -one (76 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 345 [M + H] ^< +>.

(4) By treating the compound (69 mg) obtained in (3) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluoro-2,6-dimethylphenyl) -2, 2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (62 mg) is obtained as an orange powder.
APCI-MS m / z: 315 [M + H] ^< +>.

Reference Example 64
(1) Oxalyl chloride (253 μL) and N, N-dimethylformamide (1 drop) were sequentially added to a solution of the compound obtained in Reference Example 63 (1) (295 mg) in dichloromethane (10 mL), and the mixture was added at room temperature. Stir overnight. The reaction mixture is concentrated under reduced pressure to give 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid chloride. Under argon atmosphere, a solution of 2-amino-5-bromo-3-methylpyridine (727 mg) in tetrahydrofuran (20 mL) was cooled with a dry ice-acetone bath, and 1M lithium bis (trimethylsilyl) amide-tetrahydrofuran solution (3.88 mL). Is added dropwise over 1 minute and stirred at the same temperature for 5 minutes. A solution of 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic chloride in tetrahydrofuran (10 mL) prepared above is quickly added dropwise to the reaction solution, and the mixture is stirred at the same temperature for 30 minutes. After pouring a citric acid aqueous solution into the reaction solution, the mixture is made basic by adding a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, elution solvent: n-hexane / ethyl acetate = 19/1 → 3/1) to give N- (5-bromo-3- Methylpyridin-2-yl) -2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid amide (599 mg) is obtained as a colorless powder.
APCI-MS m / z: 472/474 [M + H] ^< +>.

(2) By treating the compound (598 mg) obtained in (1) and copper (I) bromide (733 mg) in the same manner as in Reference Example 62 (3), 4- (5-bromo-3-methylpyridine) -2-yl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (154 mg) is obtained as a pale orange powder.
APCI-MS m / z: 392/394 [M + H] ⁺ .

(3) By treating the compound (148 mg) obtained in (2) in the same manner as in Reference Example 1 (3), 7-amino-4- (5-bromo-3-methylpyridin-2-yl)- 2,2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (136 mg) is obtained as a colorless powder.
APCI-MS m / z: 362/364 [M + H] ⁺ .

Reference Example 65
(1) The corresponding starting material compound is treated in the same manner as in Reference Examples 62 (1) to (3) to give 2,2-dimethyl-4- [4-methyl-3- (trifluoromethyl) phenyl] -7- Nitro-2H-1,4-benzoxazin-3 (4H) -one is obtained as a pale yellow powder.
APCI-MS m / z: 381 [M + H] ^< +>.

(2) By treating the compound (75 mg) obtained in the above (1) in the same manner as in Reference Example 1 (3), 7-amino-2,2-dimethyl-4- [4-methyl-3- (tri Fluoromethyl) phenyl] -2H-1,4-benzoxazin-3 (4H) -one (65 mg) is obtained as an orange solid.
APCI-MS m / z: 351 [M + H] ^< +>.

Reference Example 66
(1) By treating the corresponding starting compound in the same manner as in Reference Examples 62 (1) to (3), 4- (2,2-difluoro-1,3-benzodioxol-5-yl) -2, 2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one is obtained as a pale orange powder.
APCI-MS m / z: 363 [M + H] ^< +>.

(2) By treating the compound (40 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4- (2,2-difluoro-1,3-benzodioxole) -5-yl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (13 mg) is obtained as a colorless powder.
APCI-MS m / z: 349 [M + H] ^< +>.

Reference Examples 68-71
The corresponding starting material compounds are treated in the same manner as in Reference Example 3 to give the compounds shown in Table 35 below.

Reference Examples 72-74
The corresponding starting material compounds are treated in the same manner as in Reference Example 2 to give the compounds listed in Table 36 below.

Reference Examples 75-109
The corresponding starting material compounds are treated in the same manner as in Reference Example 61 to give the compounds described in Tables 37 to 41 below.

Reference Examples 110-126
The corresponding starting material compounds are treated in the same manner as in Reference Example 62 to give the compounds described in Tables 42 to 44 below.

Reference examples 127-128
The corresponding starting material compounds are treated in the same manner as in Reference Example 53 to give the compounds listed in Table 45 below.

Reference Examples 129 to 131
The corresponding starting material compounds are treated in the same manner as in Reference Examples 60 (1) to (6) or Reference Examples 60 (2) to (6) to obtain the compounds described in Table 46 below.

Reference Examples 132 to 136
The corresponding starting material compounds are treated in the same manner as in Reference Example 63 to give the compounds described in Table 47 below.

Reference Examples 137 to 141
The corresponding starting material compound is treated in the same manner as in Reference Example 64 to give the compound described in Table 48 below.

Reference Example 142
(1) To a solution of 5-bromo-2-chlorobenzyl alcohol (1.00 g) and pyridine (0.44 mL) in chloroform (40 mL) was added benzoyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at room temperature. Stir overnight. Under ice-cooling, 1N hydrochloric acid is poured into the reaction mixture, and the mixture is extracted with chloroform. The organic layer is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is triturated with diisopropyl ether to give benzoic acid 5-bromo-2-chlorobenzyl ester (753 mg) as a colorless powder.
APCI-MS m / z: 325/327 [M + H] ^< +>.

(2) By treating the compound (150 mg) obtained in Reference Example 3 (1) and the compound (508 mg) obtained in (1) above in the same manner as in Reference Example 61, benzoic acid 5- (7-amino-2) , 2-Dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) -2-benzyl (163 mg) is obtained as a green powder.
APCI-MS m / z: 437/439 [M + H] ^< +>.

Reference Example 143
(1) 4-Bromobenzyl alcohol (2.00 g) is treated in the same manner as in Reference Example 142 (1) to give 4-bromobenzyl benzoate (2.96 g) as a colorless oil.
APCI-MS m / z: 308/310 [M + NH 4] +.

(2) By treating the compound (454 mg) obtained in (1) above and the compound (150 mg) obtained in Reference Example 3 (1) in the same manner as in Reference Example 61, benzoic acid 4- (7-amino-2) , 2-Dimethyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl) benzyl (220 mg) is obtained as an orange powder.
APCI-MS m / z: 403 [M + H] ^< +>.

Reference Example 143B
(1) 7-amino-5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 53 (under argon atmosphere) A mixture of the compound of 7), 100 mg), tributyl (1-ethoxyvinyl) tin (278 μL) and dichlorobis (triphenylphosphine) palladium (II) (19 mg) is heated in toluene at 105 ° C. for 4 hours. After allowing to cool, the reaction mixture was filtered through a NH-silica gel (Chromatorex NH silica gel) pad, and the filtrate was concentrated under reduced pressure to give 7-amino-5- (1-ethoxyvinyl) -4- (4-fluorophenyl). ) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one is obtained as a crude product.

(2) 6N hydrochloric acid (1 mL) is added to a dioxane (8 mL) solution of the compound obtained in (1) above. The reaction mixture is stirred at room temperature for 1.5 hours, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 → 1/1) to give 5-acetyl-7-amino-4- (4-fluorophenyl) -2. , 2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (64 mg) is obtained as a yellow oil.
APCI-MS m / z: 329 [M + H] ^< +>.

Reference Example 144
(1) Under an argon atmosphere, 5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 53 ( A mixture of the compound obtained in 6), 100 mg), tributyl (vinyl) tin (78 μL) and tetrakis (triphenylphosphine) palladium (0) (59 mg) is heated to reflux in dioxane for 6 hours. After cooling, the reaction mixture is concentrated under reduced pressure, and the residue is diluted with acetonitrile and n-hexane. After removing the n-hexane layer of the mixture, the acetonitrile layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 8/1 → 4/1), and then filtered through a NH-silica gel (Chromatorex NH silica gel) pad. The filtrate was concentrated under reduced pressure to give 4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-5-vinyl-2H-1,4-benzoxazin-3 (4H) -one (40 mg). Is obtained as a pale yellow oil.

(2) By treating the compound (40 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-5 Vinyl-2H-1,4-benzoxazin-3 (4H) -one (23 mg) is obtained as a pale yellow oil.
APCI-MS m / z: 313 [M + H] ^< +>.

Reference Example 145
(1) Oxalyl chloride (174 μL) and N in 2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid (compound obtained in Reference Example 63 (1), 304 mg) in dichloromethane (5 mL) , N-dimethylformamide (1 drop) are added sequentially and the mixture is stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the residue (2- (2-bromo-5-nitrophenoxy) -2-methylpropionic acid chloride) is dissolved in chloroform (5 mL). To the solution is added 5-amino-6-chloro-2,2-difluoro-1,3-benzodioxole (228 mg) and pyridine (0.12 mL) and the mixture is stirred at room temperature overnight. The reaction mixture is diluted with chloroform, washed with 2N hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (Chromatorex NH-silica gel, elution solvent: n-hexane / ethyl acetate = 97/3 → 85/15) to give 2- (2-bromo-5-nitrophenoxy) -N- (6-Chloro-2,2-difluoro-1,3-benzodioxol-5-yl) -2-methylpropionic acid amide (401 mg) is obtained as colorless crystals.
APCI-MS m / z: 493/495 [M + H] ^< +>.

(2) The compound (400 mg) obtained in the above (1) is treated in the same manner as in Reference Example 62 (3) to give 4- (6-chloro-2,2-difluoro-1,3-benzodioxole. -5-yl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (245 mg) is obtained as colorless crystals.
APCI-MS m / z: 413/415 [M + H] ^< +>.

(3) A mixture of the compound (140 mg) obtained in the above (2), methanol (2 mL), tetrahydrofuran (4 mL), ethyl acetate (4 mL) and Raney nickel is stirred at room temperature for 4 hours under an atmospheric hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 7-amino-4- (6-chloro-2,2-difluoro-1,3-benzoate. Dioxol-5-yl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (122 mg) is obtained as a colorless powder.
APCI-MS m / z: 383/385 [M + H] ^< +>.

Reference Example 146
(1) Under an argon atmosphere, 5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 53 ( 6), 2.00 g), zinc cyanide (0.60 g), tetrakis (triphenylphosphine) palladium (0) (0.60 g) and N, N-dimethylformamide (30 mL) Heat in a reactor at 175 ° C. for 5 minutes. After allowing to cool, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 → 65/35) to give 4- (4-fluorophenyl) -2,2-dimethyl-7. -Nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-5-carbonitrile (1.42 g) is obtained as a pale yellow powder.
APCI-MS m / z: 342 [M + H] ^< +>.

(2) By treating the compound (70 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-3- Oxo-3,4-dihydro-2H-1,4-benzoxazine-5-carbonitrile (41 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 312 [M + H] ^< +>.

Reference Example 147
The corresponding starting material compound was treated in the same manner as in Reference Example 64 to give 7-amino-4- (6-chloro-2-methylpyridin-3-yl) -2,2-dimethyl-2H-1,4-benzoxazine. -3 (4H) -one is obtained as a pale yellow powder.
APCI-MS m / z: 318/320 [M + H] ^< +>.

Reference Examples 148 to 173
The corresponding starting material compounds are treated in the same manner as in Reference Example 61 to give the compounds described in Tables 49 to 51 below.

Reference Example 174
(1) In an argon atmosphere, 5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (Reference Example 53) A mixture of the compound of (6), 200 mg), cyclopropylboronic acid (65 mg), potassium phosphate (410 mg), tetrakis (triphenylphosphine) palladium (0) (66 mg) and water (0.1 mL) was dissolved in toluene (5 mL). ) At 100 ° C. for 4 hours. After allowing to cool, water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 → 65/35) to give 5-cyclopropyl-4- (4-fluorophenyl) -2, 2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (146 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 357 [M + H] ^< +>.

(2) By treating the compound (140 mg) obtained in (1) in the same manner as in Reference Example 1 (3), 7-amino-5-cyclopropyl-4- (4-fluorophenyl) -2,2 -Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (116 mg) is obtained as a brown powder.
APCI-MS m / z: 327 [M + H] ^< +>.

Reference Example 175
(1) 4- (4-Fluorophenyl) -2,2-dimethyl-7-nitro-5-vinyl-2H-1,4-benzoxazin-3 (4H) -one (obtained in Reference Example 144 (1) Into a dichloromethane (20 mL) solution of the resulting compound, 500 mg), ozone is introduced for 15 minutes under cooling in a dry ice-acetone bath. Argon gas was bubbled through the reaction mixture under the same cooling to remove excess ozone, and dimethyl sulfide (0.22 mL) was added. The mixture was stirred at room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90/10 → 65/35) to give 4- (4 -Fluorophenyl) -2,2-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-5-carbaldehyde (1.42 g) is obtained as a pale yellow powder.

(2) Sodium borohydride (33 mg) is added to an ethanol (7 mL) solution of the compound (200 mg) obtained in (1) above and stirred at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 → 50/50) to give 4- (4-fluorophenyl) -5- (hydroxymethyl)- 2,2-Dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (156 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 364 [M + NH ₄ ] ⁺
(3) By treating the compound (150 mg) obtained in (2) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -5- (hydroxymethyl) -2 , 2-Dimethyl-2H-1,4-benzoxazin-3 (4H) -one (120 mg) is obtained as a light brown powder.
APCI-MS m / z: 317 [M + H] ^< +>.

Reference Example 176
The corresponding starting material compound was treated in the same manner as in Reference Example 63 to give 7-amino-2,2-dimethyl-4- (1H-pyrrol-1-yl) -2H-1,4-benzoxazine-3 (4H) -The ON is obtained as a colorless powder.
APCI-MS m / z: 258 [M + H] ^< +>.

Reference examples 177 to 184
The corresponding starting material compounds are treated in the same manner as in Reference Example 145 to give the compounds listed in Table 52 below.

Reference Example 185
By treating the corresponding starting material compound in the same manner as in Reference Example 60, 7-amino-4- (4-fluorophenyl) -2-methyl-2-phenyl-2H-1,4-benzoxazine-3 (4H)- The ON is obtained as a colorless powder.
APCI-MS m / z: 349 [M + H] ^< +>.

Reference Example 186
(1) A 1.6 M n-butyllithium-n-hexane solution (6.37 mL) in a tetrahydrofuran (15 mL) solution of diisopropylamine (1.42 mL) in an argon atmosphere under cooling in a dry ice-acetone bath. Is dripped. The reaction mixture is stirred for 20 minutes under the same cooling, and then a solution of 2-chloro-6- (trifluoromethyl) pyridine (1.81 g) in tetrahydrofuran (5 mL) is added dropwise, followed by further stirring for 2 hours. Next, methyl iodide (0.69 mL) is added dropwise to the reaction mixture, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is washed successively with 0.5N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane → n-hexane / ethyl acetate = 90/10) to give 2-chloro-3-methyl-6- (trifluoromethyl) pyridine. (0.90 g) is obtained as a yellow powder.
APCI-MS m / z: 196/198 [M + H] ⁺ .

(2) Under an argon atmosphere, chlorotrimethylsilane (0.51 mL) was added to a mixture of the compound obtained in (1) (0.78 g) and sodium iodide (1.80 g) in propionitrile (8 mL), and 105 Heat at ° C for 2 days. The reaction mixture is poured into a mixture of 2.0M aqueous sodium hydroxide and ice and extracted with diethyl ether. The organic layer is washed successively with water, 10% aqueous sodium thiosulfate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is triturated with cold n-hexane to give 2-iodo-3-methyl-6- (trifluoromethyl) pyridine (0.27 g) as a pale yellow powder.
APCI-MS m / z: 288 [M + H] ^< +>.

Reference Example 187
Under an argon atmosphere, 2-amino-3-chloro-5- (trifluoromethyl) pyridine (393 mg), trimethylboroxine (0.42 mL), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl A mixture of -1,1′-biphenyl (38 mg), tris (dibenzylideneacetone) dipalladium (18 mg) and potassium phosphate (850 mg) is heated and stirred in dioxane (4 mL) at 100 ° C. for 1 hour. After allowing to cool, cold water is poured into the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 70/30 → 30/70) and then recrystallized from cold n-hexane to give 2-amino-3-methyl. -5- (Trifluoromethyl) pyridine (264 mg) is obtained as a colorless powder.
APCI-MS m / z: 177 [M + H] ^< +>.

Reference Example 188
3-Amino-2-chloro-6- (trifluoromethyl) pyridine (393 mg) was treated in the same manner as in Reference Example 187 to give 3-amino-2-methyl-6- (trifluoromethyl) pyridine (118 mg). Is obtained as a pale green powder.
APCI-MS m / z: 177 [M + H] ^< +>.

Reference Example 189
(1) Tin (II) chloride dihydrate (8.22 g) was added to a solution of 2-chloro-3-nitro-5- (trifluoromethyl) pyridine (1.87 g) in ethyl acetate (40 mL) at room temperature. After the addition, the mixture is stirred at 80 ° C. for 2 hours. After cooling, a saturated aqueous sodium carbonate solution is poured into the reaction solution and vigorously stirred at room temperature for 2 hours. The mixture is filtered through celite and the residue is washed with ethyl acetate. The filtrate and washing solution are combined, washed successively with saturated aqueous sodium carbonate solution, water and saturated brine, and dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The obtained residue is pulverized with n-hexane to give 3-amino-2-chloro-5- (trifluoromethyl) pyridine (0.99 g) as a pale yellow powder.
APCI-MS m / z: 197/199 [M + H] ^< +>.

(2) Acetyl chloride (0.48 mL) was added dropwise to dichloromethane (30 mL) of the compound obtained in (1) (885 mg), triethylamine (1.25 mL) and 4-dimethylaminopyridine (550 mg) under ice-cooling. To do. The mixture is stirred at room temperature for 15 hours, acetyl chloride (0.48 mL) and triethylamine (1.25 mL) are added, and the mixture is further stirred at room temperature for 5 hours. Water is added to the reaction mixture, and the mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 85/15 → 50/50), and then powdered with n-hexane-ethyl acetate to give N- [2- Chloro-5- (trifluoromethyl) pyridin-3-yl] acetamide (0.38 g) is obtained as a pale yellow powder.
ESI-MS m / z: 237/239 [M−H] ⁻ .

(3) Under an argon atmosphere, the compound obtained in (2) (358 mg), trimethylboroxine (315 μL), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (62 mg), palladium acetate (17 mg) and A mixture of potassium carbonate (622 mg) is stirred with heating in acetonitrile (2.5 mL) -water (1.5 mL) at 100 ° C. for 1 hour. Trimethylboroxine (315 μL), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (62 mg) and palladium acetate (17 mg) are added to the reaction mixture, and the mixture is further heated and stirred at 100 ° C. for 14 hours. After allowing to cool, water and ethyl acetate are poured into the reaction mixture, and the mixture is filtered through Celite. The organic layer is separated from the filtrate and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated brine, dried over sodium sulfate, treated with activated carbon, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50/50 → ethyl acetate) and then pulverized with n-hexane-ethyl acetate to give N- [2-methyl. -5- (Trifluoromethyl) pyridin-3-yl] acetamide (179 mg) is obtained as a colorless powder.
APCI-MS m / z: 219 [M + H] ^< +>.

(4) A suspension of the compound (170 mg) obtained in (3) above in 6N hydrochloric acid (4 mL) is heated to reflux for 1 hour. After cooling, the reaction mixture is basified with saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is recrystallized from n-hexane to give 3-amino-2-methyl-5- (trifluoromethyl) pyridine (98 mg) as a colorless powder.
APCI-MS m / z: 177 [M + H] ^< +>.

Reference Example 190
(1) 2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (compound obtained in Reference Example 1 (1), 1.00 g) in dichloromethane (50 mL) Bis (pyridine) iodonium tetrafluoroborate (1.68 g) is added to the suspension and stirred at room temperature for 1 hour. Add bis (pyridine) iodonium tetrafluoroborate (0.84 g) and trifluoromethanesulfonic acid (1.2 mL) to the reaction mixture and stir at room temperature for an additional 15 hours. The reaction mixture is concentrated under reduced pressure, and the residue is diluted with ethyl acetate, tetrahydrofuran and water, and extracted with ethyl acetate. The organic layer is washed successively with saturated aqueous sodium hydrogen carbonate solution, 15% aqueous sodium thiosulfate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was triturated with n-hexane-ethyl acetate to give 5-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (0. 90 g) is obtained as a light brown powder.
ESI-MS m / z: 347 [M−H] ⁻ .

(2) By treating the compound (0.90 g) obtained in (1) and 4-fluorophenylboronic acid (1.44 g) in the same manner as in Reference Example 1 (2), 4- (4-fluoro Phenyl) -5-iodo-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (0.16 g) is obtained as a brown powder.
APCI-MS m / z: 443 [M + H] ^< +>.

  (3) To a solution of the compound obtained in (2) (160 mg) in N-methylpyrrolidone (3 mL), methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (0.046 mL) and copper (I) bromide After sequentially adding (5.5 mg), the reaction mixture is stirred at 120 ° C. for 17 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 → 70/30) to give 4- (4-fluorophenyl) -2,2-dimethyl-7. -Nitro-5- (trifluoromethyl) -2H-1,4-benzoxazin-3 (4H) -one (94 mg) is obtained as a pale yellow powder.

(4) By treating the compound (90 mg) obtained in (3) in the same manner as in Reference Example 1 (3), 7-amino-4- (4-fluorophenyl) -2,2-dimethyl-5 (Trifluoromethyl) -2H-1,4-benzoxazin-3 (4H) -one (73 mg) is obtained as a light brown powder.
APCI-MS m / z: 355 [M + H] ^< +>.

Reference Example 191
7-amino-2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (a compound obtained in Reference Example 3 (1), 200 mg) and 2-bromobenzothiazole (445 mg). By processing in the same manner as in Reference Example 61,
7-Amino-4- (1,3-benzothiazol-2-yl) -2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (12 mg) is obtained as a pale yellow powder.
APCI-MS m / z: 326 [M + H] ^< +>.

Reference Example 192
(1) Water (7 mL) and 48% hydrobromic acid (3 mL) were added to 2-amino-3-fluoro-5-nitrophenol (1.00 g), and sodium nitrite was cooled in an ice-salt cooling bath. A solution of (0.41 g) in water (2 mL) is slowly added dropwise. After completion of dropping, the mixture is stirred for 15 minutes under the same cooling. The diazonium salt solution prepared above was slowly added dropwise to copper (I) bromide (0.96 g) in water (5 mL) and 48% hydrobromic acid (5 mL) under ice-cooling. Stir for 30 minutes at ° C. The reaction mixture is cooled to room temperature and extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 90/10 → 70/30) to give 2-bromo-3-fluoro-5-nitrophenol (1.15 g). ) As a pale yellow powder.
ESI-MS m / z: 234/236 [M−H] ⁻ .

(2) By treating the compound (1.14 g) obtained in the above (1) and ethyl α-bromoisobutyrate (0.93 mL) in the same manner as in Reference Example 62 (1), 2- (2-bromo- Ethyl 3-fluoro-5-nitrophenoxy) -2-methylpropionate (0.85 g) is obtained as a pale yellow viscous oil.
APCI-MS m / z: 367/369 [M + NH 4] +.

(3) The compound (0.85 g) obtained in (2) above is treated in the same manner as in Reference Example 63 (1) to give 2- (2-bromo-3-fluoro-5-nitrophenoxy) -2- Methylpropionic acid (0.60 g) is obtained as a pale yellow powder.
ESI-MS m / z: 320/322 [M−H] ⁻ .

(4) By treating the compound (150 mg) obtained in (3) above and 2-amino-5-bromo-3-methylpyridine (104 mg) in the same manner as in Reference Example 145 (1), 2- (2 -Bromo-3-fluoro-5-nitrophenoxy) -N- (5-bromo-3-methylpyridin-2-yl) -2-methylpropionic acid amide (117 mg) is obtained as a colorless powder.
APCI-MS m / z: 490/492/494 [M + H] ⁺ .

(5) To a solution of the compound (115 mg) obtained in (4) above in dimethyl sulfoxide (7 mL) is added potassium carbonate (35 mg), and the mixture is stirred at 50 ° C. for 1.5 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate, and washed successively with aqueous ammonium chloride and water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 95/5 → 80/20) to give 4- (5-bromo-3-methylpyridin-2-yl) -5-Fluoro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3 (4H) -one (72 mg) is obtained as a colorless powder.
APCI-MS m / z: 410/412 [M + H] ⁺ .

(6) By treating the compound (66 mg) obtained in (5) in the same manner as in Reference Example 1 (3), 7-amino-4- (5-bromo-3-methylpyridin-2-yl)- 5-Fluoro-2,2-dimethyl-2H-1,4-benzoxazin-3 (4H) -one (55 mg) is obtained as a colorless powder.
APCI-MS m / z: 380/382 [M + H] ^< +>.

Reference Examples 193 to 195
The corresponding starting material compounds are treated in the same manner as in Reference Examples 192 (2) to (6) to give the compounds described in Table 53 below.

Experimental example 1
[Aldosterone receptor binding test]
(1) Preparation of renal cytosol fraction Kidneys were collected from Sprague-Dawley male rats (7 weeks old) from which the adrenal glands had been removed, homogenized using a buffer solution having the following composition, and centrifuged (100,000 g, 1 hour). ) The subsequent supernatant was the kidney cytosol fraction (protein concentration: 15 mg / mL), which was used as a specimen for the binding test.

Buffer composition:
Tris-hydrochloric acid (50 mM, pH 7.5), sucrose (250 mM), potassium chloride (50 mM), magnesium chloride (3 mM), sodium molybdate (20 mM), mercaptoethanol (1 mM)
(2) Binding test 5 μL of sample compound solution dissolved in dimethyl sulfoxide, 200 μL of renal cytosol fraction and 50 μL of physiological saline (or 50 μL of unlabeled aldosterone solution, final concentration = 1 μM) and 50 μL of [ ³ H] aldosterone (about 2 nM) Was added to the tube and incubated overnight at 4 ° C. To the reaction solution, 100 μL of dextran-coated charcoal / 10 mM Tris-HCl buffer was added, followed by incubation at 4 ° C. for 30 minutes. After the reaction solution was centrifuged at the same temperature (3,000 rpm × 10 minutes), 150 μL of the supernatant was mixed with 5 mL of a scintillator (product name: Clearsol I, manufactured by Nacalai Tesque), and a liquid scintillation counter (TRI CARB 2200CA, Packard). Radioactivity was measured. Based on the measured value, the IC ₅₀ value of each analyte compound in the aldosterone-receptor binding reaction (analyte concentration that inhibits aldosterone binding to the receptor by 50%: μM) was calculated. Further, the dissociation constant Ki of each analyte compound was determined from the Cheng and Prusoff equation (Ki = IC ₅₀ / (1+ [L] / Kd)).
[In the formula, [L] represents the concentration of [ ³ H] aldosterone, and Kd represents the affinity constant of [ ³ H] aldosterone. ]
(3) Results The results of this experiment are shown in Table 54 below.

  The symbols (++ and ++) in the table have the following meanings.

++: 0.5 μM <Ki <1 μM
+++: Ki ≦ 0.5 μM

  Since the compound [I], which is an active ingredient of the present invention, has high affinity for MR and regulatory activity (receptor antagonism, etc.), the pharmaceutical composition of the present invention comprising the compound as an active ingredient is MR receptor. It is useful as a medicament for the prevention and treatment of various diseases involving the body and / or aldosterone (for example, cardiovascular diseases including hypertension and heart failure).

Claims (22)

Formula [I]:

[Where,
Ring A, R ¹ Other than the benzene ring may have a substituent, or R ¹ other than the optionally may nitrogen-containing 6-membered aromatic heterocyclic ring having a substituent group,
R ¹ is a group represented by the formula: R ^a SO ₂ NH—, R ^a SO ₂ NH—CH ₂ — or (R ^b ) (R ^c ) NSO ₂ —,
R ^a is an alkyl group, a cycloalkyl group, an amino group which may be substituted with an alkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group,
R ^b and R ^c are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group,
R ² and R ³ are the same or different and are a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkenyl group, a carboxyl group, an alkoxycarbonyl group, an optionally substituted carbamoyl group or an optionally substituted group. They are aryl groups, or they are bonded to each other to form a saturated or unsaturated cyclic group together with adjacent carbon atoms (the cyclic group is the same or different one or two selected from sulfur atom, oxygen atom and nitrogen atom) Or may have a hetero atom of
X is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: —NR ⁴ —;
R ⁴ represents a hydrogen atom, an alkyl group, an optionally substituted aralkyl group or an acyl group,
Y is a group represented by the formula: —C (═O) —, —C (═S) — or —CH (R ⁵ ) —,
R ⁵ is a hydrogen atom, an alkyl group or an optionally substituted aryl group,
Ar represents an optionally substituted aryl group or an optionally substituted heteroaryl group;
Q represents a single bond, an alkylene group or an alkenylene group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. Ring A is a benzene ring or a nitrogen-containing 6-membered aromatic heterocyclic ring (the benzene ring or nitrogen-containing 6-membered aromatic heterocyclic ring is a halogen atom, an optionally substituted alkyl group, a hydroxyl group, an alkoxy group, a substituted group in addition to R ^1. 2. It may have 1 to 3 substituents selected from an optionally substituted amino group, cyano group, carboxyl group, alkoxycarbonyl group and optionally substituted carbamoyl group. Pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein X is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: -NH-. Formula [Ia]:

[Where,
Ring A, R ¹¹ Other than be a benzene ring optionally having a substituent, or R ¹¹ 6-membered aromatic or nitrogen-containing substituted besides heterocycle,
R ¹¹ is a group represented by the formula: R ^aa SO ₂ NH—, R ^aa SO ₂ NH—CH ₂ — or (R ^b ) (R ^c ) NSO ₂ —,
R ^aa is an alkyl group, a cycloalkyl group, an amino group optionally substituted with 1 to 2 alkyl groups, a phenyl group, or a 5-6 membered monocyclic heteroaryl group,
R ^b and R ^c are the same or different and each represents a hydrogen atom, an alkyl group or a cycloalkyl group,
R ²¹ and R ³¹ are either a hydrogen atom, a halogen atom or an alkyl group, the other is a hydrogen atom, an alkyl group, an alkoxycarbonyl group, a phenyl group or a halogenophenyl group, or both are bonded to each other to form an adjacent carbon atom. And forms a saturated or unsaturated cyclic group (the cyclic group may have the same or different 1-2 hetero atoms selected from a sulfur atom, an oxygen atom and a nitrogen atom),
^Xa is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: -NH-
Y ^a is ^{a group} represented by the formula: —C (═O) —, —C (═S) — or —CH (R ⁵¹ ) —,
R ⁵¹ represents a hydrogen atom or a phenyl group,
Ar ¹ is (a) a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group optionally substituted with 1 to 3 halogen atoms, a hydroxyalkyl group, an acyloxyalkyl group, or 1 to 3 halogen atoms. Optionally substituted alkoxy group, alkoxycarbonylalkoxy group, alkylthio group, alkylenedioxy group optionally substituted with 1 to 2 halogen atoms, optionally substituted with 1 to 2 alkyl groups A phenyl (or naphthyl) group optionally substituted with 1 to 3 groups selected from an amino group, an amino group substituted with an acyl group, a cycloalkyl group and an alkylsulfonyl group;
(B) a thienyl group which may be substituted with one or two groups selected from a halogen atom and a trihalogenoalkyl group (the thienyl group may be condensed with a benzene ring);
(C) a pyridyl group optionally substituted by 1 to 2 groups selected from a halogen atom, a nitro group, an alkyl group and a trihalogenoalkyl group;
(D) a pyrimidinyl group optionally substituted by a halogen atom;
(E) a quinolyl group;
(F) a pyridazinyl group optionally substituted by a halogen atom;
(G) a pyrrolyl group; or (h) a furyl group (the furyl group may be condensed with a benzene ring),
(I) a thiazolyl group (the thiazolyl group may be condensed with a benzene ring), or (j) an imidazolyl group (the imidazolyl group may be condensed with a benzene ring and substituted with an alkyl group). And Q represents a single bond, an alkylene group or an alkenylene group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. Ring A is substituted with a group selected from (a) a halogen atom, (b) an alkyl group (wherein the alkyl group is a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group, and a dialkylamino group) in addition to R ¹ (C) a hydroxyl group, (d) an alkoxy group, (e) an amino group (the amino group may be substituted with one or two groups selected from an alkyl group and an acyl group), (F) a cyano group, (g) a carboxyl group, (h) an alkoxycarbonyl group, (i) an alkenyl group (the alkenyl group may be substituted with an alkoxy group), (j) an alkanoyl group, (k) cyclo A benzene ring which may have 1 to 3 substituents selected from an alkyl group and (l) a carbamoyl group (which may be substituted with 1 to 2 alkyl groups) The pharmaceutical composition according to claim 1, wherein is a nitrogen-containing 6-membered aromatic heterocyclic ring. Ring A is substituted with a group selected from (a) a halogen atom, (b) an alkyl group (the alkyl group is a halogen atom, a hydroxyl group, an alkoxy group, an amino group, a monoalkylamino group and a dialkylamino group) in addition to R ¹¹ (C) a hydroxyl group, (d) an alkoxy group, (e) an amino group (the amino group may be substituted with one or two groups selected from an alkyl group and an acyl group), (F) a cyano group, (g) a carboxyl group, (h) an alkoxycarbonyl group, (i) an alkenyl group (the alkenyl group may be substituted with an alkoxy group), (j) an alkanoyl group, (k) cyclo A benzene ring optionally having 1 to 3 substituents selected from an alkyl group and (l) a carbamoyl group (the carbamoyl group may be substituted with 1 to 2 alkyl groups) Or the pharmaceutical composition of Claim 4 which is a nitrogen-containing 6-membered aromatic heterocyclic ring. Ring A is a halogen atom, a hydroxyl group, a C _1-4 alkyl group, a trihalogeno-C _1-4 alkyl group, a hydroxy-C _1-4 alkyl group, a C _1-4 alkoxy-C _1-4 alkyl group other than R ¹¹ A benzene ring optionally substituted with a group selected from a C _1-4 alkoxy group, an amino group, a C _2-4 alkenyl group, a C _2-5 alkanoyl group and a C _3-8 cycloalkyl group,
R ¹¹ represents a C _1-4 alkylsulfonylamino group, a C _3-6 cycloalkylsulfonylamino group, a C _1-4 alkylaminosulfonyl group, a C _1-4 alkylsulfonylaminomethyl group, an aminosulfonylamino group, di (C _{1 -4} alkyl) aminosulfonylamino group or a mono _{(C 1-4} alkyl) aminosulfonyl group,
One of R ²¹ and R ³¹ is a hydrogen atom or a C _1-4 alkyl group, and the other represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group or a phenyl group, or both are bonded to each other to form C Forming a _3-8 cycloalkyl group,
^Xa is an oxygen atom, a sulfur atom, a methylene group or a group represented by the formula: -NH-,
Ar ¹ is (a) a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C _1-4 alkyl group, a C _1-4 alkyl group substituted with 1 to 3 halogen atoms, a hydroxy-C _1-4 alkyl group , acyloxy _{-C 1-4} alkyl _{group, C 1-4} alkoxy groups, 1-3 _{C 1-4} alkoxy group substituted with a halogen _{atom, C 3-8} cycloalkyl _{group, C 1-4} alkylthio group, 1-2 _{C 1-4} alkyl amino group which may be substituted with a _{group, C 2-5} alkanoylamino _{group, C 1-4} C substituted with an alkylenedioxy group, and one to two halogen atoms _A phenyl group optionally substituted by 1 to 3 groups selected from _1-4 alkylenedioxy groups; (b) a naphthyl group; (c) a halogen atom and 1 selected from a trihalogeno-C _1-4 alkyl group; ~ 2 The thienyl which may be substituted with a group (or benzothienyl) group; (d) a halogen atom, a nitro _group, 1-2 groups selected from _{C 1-4} alkyl group and a trihalogeno _{-C 1-4} alkyl group A pyridyl group optionally substituted by: or (e) a benzofuranyl group,
7. Q is a single bond or a C _1-4 alkylene group, and Y ^a is ^a group represented by the formula: —C (═O) —, —C (═S) — or —CH ₂ —. Pharmaceutical composition. 8. The pharmaceutical composition according to claim 7, wherein R ²¹ and R ³¹ are both hydrogen atoms. The pharmaceutical composition according to claim 7, wherein R ²¹ is a hydrogen atom, and R ³¹ is a C _1-4 alkyl group. The pharmaceutical composition according to claim 7, wherein R ²¹ is a hydrogen atom or a C _1-4 alkyl group, and R ³¹ is a phenyl group. _8. The pharmaceutical composition according to claim 7, wherein R ²¹ and R ³¹ are both C _1-4 alkyl groups. The pharmaceutical composition according to claim 7, wherein R ²¹ is a hydrogen atom, and R ³¹ is a halogen atom. The pharmaceutical composition according to claim 7, wherein R ²¹ and R ³¹ are bonded to each other to form a C _3-8 cycloalkyl group together with adjacent carbon atoms. N- (3-oxo-2,4-diphenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -3-oxo-2-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- (2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,4-difluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-chloro-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] ethanesulfonamide;
N- [4- (5-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- (4-benzyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- (4-benzyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (4-fluorophenyl) -2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-fluorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (5-chloro-2-thienyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N ′-[4- (4-Fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] -N, N-dimethylsulfami De;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4- (3-thienyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-3,4-dihydrospiro [1,4-benzoxazine-2,1′-cyclobutane] -7-yl] methanesulfonamide;
N- [1- (4-fluorophenyl) -3,3-dimethyl-2-oxo-1,2,3,4-tetrahydroquinoxalin-6-yl] methanesulfonamide;
N- [4- [4-Fluoro-3-trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [2,2-dimethyl-4- (4-methylphenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -3-oxo-3,4-dihydrospiro [1,4-benzoxazine-2,1′-cyclopropane] -7-yl] methanesulfonamide;
N- [2,2-diethyl-4- (4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2-ethyl-4- (4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4-[(4-trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] sulfamide;
N- [4- (2,4-difluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-3-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-3-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-Fluoro-3-methylphenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- [3- (Dimethylamino) -4-fluorophenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [4- (3-chloro-4-fluorophenyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2-chloro-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2,6-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [6-amino-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [3- (Difluoromethyl) -4-fluorophenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
4- (4-chlorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (4-Chloro-2-cyanophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-bromophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (5-chloropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-chloro-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromo-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [4-Chloro-3- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [3-Fluoro-4- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (4-Chloro-3-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-Fluoro-4-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (4-Chloro-2-methylphenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- [4- (2,4-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3-Chloro-4-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,4-Difluoro-5-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (3,4-dichlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (2-naphthyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-bromo-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-chloro-4- (4-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-fluorophenyl) -2,2,5-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Bromo-3-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2,2-Difluoro-1,3-benzodioxol-5-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine -7-yl] methanesulfonamide;
N- (4-mesityl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl) methanesulfonamide;
N- [4- (2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2,6-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (5-Bromo-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-fluoro-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (3,5-dichloropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (4-Fluoro-2,3-dimethylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [4- (3-chloro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-fluoro-2-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-3-oxo-4- (1-phenylethyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (3-methylbenzyl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- {2,2-dimethyl-4- [2-methyl-5- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
N- [2,2-dimethyl-3-oxo-4- (2,4,6-trifluorophenyl) -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
2-chloro-5- [2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl] benzyl benzoate;
N- [4- (4-Chloro-2-methoxy-5-methylphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-2,2-difluoro-1,3-benzodioxol-5-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1, 4-Benzoxazin-7-yl] methanesulfonamide;
N- [2,2-dimethyl-4- (3-methyl-5-nitropyridin-2-yl) -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [4-Fluoro-2- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [2,2-dimethyl-4- [2-methyl-4- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-5-vinyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-chlorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-chloropyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- [3-Chloro-5- (trifluoromethyl) pyridin-2-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (3-chlorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [5-Bromo-6-methylpyridin-2-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-Fluoro-4- (5-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [2,2-dimethyl-3-oxo-4-[(5- (trifluoromethyl) -2-thienyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-4-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-bromopyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [4-Chloro-3- (hydroxymethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [4- (6-Bromo-5-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (6-Chloro-2-methylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- {2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) pyridin-2-yl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
N- {2,2-dimethyl-4- [3-methyl-6- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl} methanesulfonamide N- [4- (5-chloro-3-fluoropyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine -7-yl] methanesulfonamide;
N- [4- (3-chlorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-Bromopyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-methylpyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- {5-Fluoro-2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) pyridin-2-yl] -3,4-dihydro-2H-1,4-benzoxazine-7 -Yl} methanesulfonamide;
N- [4- (5-Fluoro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Chloro-3-fluoropyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- [4-Chloro-3- (hydroxymethyl) phenyl] -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7- Yl] methanesulfonamide;
Benzoic acid 2-chloro-5- [5-fluoro-2,2-dimethyl-7-[(methylsulfonyl) amino] -3-oxo-2,3-dihydro-4H-1,4-benzoxazine-4- Yl] benzyl;
N- [4- (2,6-Dimethylpyridin-3-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-cyclopropyl-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-Fluoro-4- [3-fluoro-4- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-3-oxo-4- [4- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [5-Fluoro-4- [4-fluoro-3- (trifluoromethyl) phenyl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (3-Chloro-4-fluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (3,4-Difluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide ;
N- [5-Fluoro-4- (5-fluoro-6-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (6-Chloro-2-methylpyridin-3-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (4-Chloro-2-fluorophenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (5-Fluoro-6-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (benzothien-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (benzofuran-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- [2-Chloro-6- (trifluoromethyl) pyridin-3-yl] -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (4-Fluorophenyl) -5- (methoxymethyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfone An amide;
N- [2,2-dimethyl-4- [3-methyl-5- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [2,2-dimethyl-4- [2-methyl-6- (trifluoromethyl) pyridin-3-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [2,2-dimethyl-4- [2-methyl-5- (trifluoromethyl) pyridin-3-yl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-ethyl-4- (4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-3-oxo-4- [5- (trifluoromethyl) -2-thienyl] -3,4-dihydro-2H-1,4-benzoxazine-7- Yl] methanesulfonamide;
N- [5-Fluoro-4- (5-fluoro-3-methylpyridin-2-yl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [4- (6-Chloro-2,2-difluoro-1,3-benzodioxol-5-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (2,2-difluoro-1,3-benzodioxol-5-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1, 4-Benzoxazin-7-yl] methanesulfonamide;
N- [4- (5-Bromo-3-methylpyridin-2-yl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7 -Yl] methanesulfonamide;
N- [5-Fluoro-2,2-dimethyl-4- [3-methyl-5- (trifluoromethyl) pyridin-2-yl] -3-oxo-3,4-dihydro-2H-1,4- Benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Chloro-2-methylphenyl) -5-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methane Sulfonamide;
N- [4- (3-amino-4-fluorophenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
N- [4- (4-Fluoro-2-methoxyphenyl) -2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl] methanesulfonamide;
4- (3-chloro-4-fluorophenyl) -N, 2,2-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-7-sulfonamide;
N- {2,2-dimethyl-3-oxo-4- [3- (trifluoromethyl) phenyl] -3,4-dihydro-2H-1,4-benzoxazin-7-yl} methanesulfonamide; and N- {2,2-dimethyl-4- [2-methyl-3- (trifluoromethyl) phenyl] -3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl} methane Sulfonamide;
A pharmaceutical composition comprising as an active ingredient a compound selected from the group consisting of: or a pharmacologically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 14, which is a mineralocorticoid receptor modulator. The mineralocorticoid receptor modulator according to claim 15, which is a mineralocorticoid receptor antagonist or an aldosterone antagonist. The mineralocorticoid receptor modulator according to claim 16, which is a prophylactic / therapeutic agent for various diseases or disease states resulting from enhanced MR activity and / or elevated aldosterone levels. The mineralocorticoid receptor modulator according to claim 17, which is a diuretic. The mineralocorticoid receptor according to claim 17, which is a prophylactic / therapeutic agent for hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, myocardial / vascular fibrosis, baroreceptor disorder, excessive fluid volume or arrhythmia. Regulator. The mineralocorticoid receptor modulator according to claim 17, which is a prophylactic / therapeutic agent for primary / secondary aldosteronism, Addison's disease, Cushing's syndrome or Barter's syndrome. General formula [ii]:

[Where,
Ring A ² is a benzene ring which may be substituted with one or two groups selected from a halogen atom and an alkyloxy group in addition to R ⁰⁰ ,
R ⁰⁰ represents a nitro group or amino group, R ²² and R ^{32 each} represents a hydrogen atom or an alkyl group, and the other represents an alkyl group, a phenyl group or a halogenophenyl group,
X ^b is an oxygen atom or a sulfur atom,
Y ^b is a group represented by the formula: —C (═O) — or —CH (R ⁵² ) —,
R ⁵² represents a hydrogen atom or a phenyl group,
Ar ² is substituted with 1 to 3 groups selected from a halogen atom, a cyano group, an alkyl group, a trihalogenoalkyl group and an alkylenedioxy group (which may be substituted with 1 to 2 halogen atoms). An optionally substituted phenyl group or a pyridyl group optionally substituted with 1 to 2 groups selected from a halogen atom and an alkyl group; and Q represents a single bond, an alkylene group or an alkenylene group. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 21, which is a nuclear steroid hormone receptor modulator.