JP2002322169A - Chromene derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide chromene derivatives showing excellent preventive or curing activities against diabetic retinitis or retinitis. SOLUTION: The chromene derivatives are represented by general formula (I), [wherein R<1> is hydrogen atom, a 1-6C alkyl group which may be substituted, a 6-10C aryl group or 1-12C acyl group, R<2> , R<3> , R<4> and R<5> are each the same or different, and are hydrogen atoms, 1-6C alkyl groups, 3-6C cycloalkyl groups, R<6> is hydrogen atom, a halogen atom, a 1-6C alkyl group which may be substituted, a 2-6C alkenyl, a 2-6C alkynyl group, R<7> and R<8> are each the same or different, and are hydrogen atoms, halogen atoms, 1-6C alkyl groups, 3-6C cycloalkyl groups, 6-10C aryl groups which may be the same or different, or a 5 to 10 membered heterocyclic group which may be the same or different, dotted line is a double bond or single bond, Ar is a 6-10C aryl group which may be substituted or a 5 to 10 membered heterocyclic group which may be substituted], and pharmacologically acceptable salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a chromene derivative having excellent preventive or therapeutic activity against diabetic retinopathy, a pharmacologically acceptable salt thereof, and a medicament containing the same as an active ingredient.

[0002]

2. Description of the Related Art There has been no effective therapeutic agent for diabetic retinopathy. Tranilast is used as a prophylactic or therapeutic agent for diseases associated with hyperproliferation of retinal pigment epithelial cells.
O98 / 47504. However, the activity of tranilast is not sufficient, and a clinically more potent and safe drug for preventing or treating retinopathy is desired.

A compound having a structure similar to the compound of the present invention is disclosed in Japanese Patent No. 3076066 (Japanese Patent Application No.
No. 502698, WO98 / 08836) and WO00
No. 06085, but nothing at all suggests a relationship with diabetic retinopathy or an angiogenesis inhibitory effect.

[0004]

In order to solve the above problems, the present inventors have conducted various studies on a chromene derivative and a chroman derivative. The present inventors have found that they show excellent preventive or therapeutic activity against diabetic retinopathy or retinopathy, and completed the present invention.

[0005]

SUMMARY OF THE INVENTION The present invention provides

[0006]

Embedded image

[Wherein, R¹Is a hydrogen atom,
C₁~ C₆An alkyl group (the substituent is C₆~ C_TenAnts
A group. ), C₆~ C_TenAryl group or C₁~ C₁₂
Represents an acyl group;^Two, R^Three, R^FourAnd R^FiveAre the same or different
Becomes a hydrogen atom, a halogen atom, C₁~ C₆Alkyl
Group, C_Three~ C₆Cycloalkyl group, optionally substituted C₆~
C_TenAryl group (the substituent is selected from the following substituent group β)
Devour. ), A 5- to 10-membered heterocyclic group which may be substituted (the
The substituent is selected from the following substituent group β. ), Hydroxyl,
C which may be substituted₁~ C₆Alkoxy group ｛the substituent is
Halogen atom and optionally substituted C₆~ C_TenAryl group
(The substituent is selected from the following substituent group β.)
Selected from the group ｝, C_Three~ C₆Cycloalkoxy
Group, C which may be substituted₆~ C_TenAryloxy group (the
The substituent is selected from the following substituent group β. ), C ₁~ C
₁₂Acyloxy group, amino group which may be substituted (substitution
The group is selected from the following substituent group α. ), Nitro group or
R represents a cyano group;⁶Is a hydrogen atom, a halogen atom,
C that may be replaced₁~ C₆Alkyl group ｛the substituent is hydroxyl
Group, C₁~ C₆Alkoxy group, C_Three~ C₆Cycloalkyl group
And optionally substituted C₆~ C_TenAryl group (substituent
Is selected from the following substituent group β. )
Devour. ｝, C_Two~ C₆Alkenyl group, C_Two~ C₆Alkini
Group, C_Three~ C₆Cycloalkyl group, optionally substituted C₆
~ C_TenAryl group (the substituent is a group represented by the following substituent group β)
To be elected. ), A 5- to 10-membered heterocyclic group which may be substituted
The substituent is selected from the following substituent group β. ), Replaced
Good C₁~ C₆Alkoxy group ｛the substituent is hydroxyl
Group, cyano group, formyl group, C₁~ C₆An alkoxy group and
5- to 10-membered heterocyclic group which may be substituted (the substituent is
Selected from the substituent group β. Selected from the group consisting of
You. ｝, C_Two~ C₆Alkenyloxy group, C _Two~ C₆Archi
Nyloxy group, C_Three~ C₆Cycloalkoxy group, substituted
Good C₆~ C_TenAryloxy group (the substituent is
Selected from the substituent group β. ), 5-1 which may be substituted
A 0-membered heterocyclic oxy group (the substituent is the following substituent group β
Selected from ), C_Two~ C₇Alkylcarbonyloxy
Group, C₁~ C₆Alkylthio group or optionally substituted amino
Group (the substituent is selected from the following substituent group α):
And R⁷And R⁸Are the same or different and represent a hydrogen atom,
Logen atom, C₁~ C₆Alkyl group, C_Three~ C₆Cycloal
Kill group, optionally substituted C₆~ C_TenAryl group
The substituent is selected from the following substituent group β. ) Or replaced
5 to 10-membered heterocyclic group (the substituent may be the following substituent
Selected from group β. ),......Is a double bond or a single bond
Represents a bond, wherein Ar is an optionally substituted C₆~ C_TenAryl
Group (the substituent is selected from the following substituent group δ) or
Is an optionally substituted 5- to 10-membered heterocyclic group (the ring is
The substituent is selected from the following substituent group δ. )
The substituent group α is an optionally substituted C₁~ C₆Alkyl group
The substituent is C₆~ C_{1 0}Aryl group, hydroxyl group, substituted
A good amino group (the substituent being a C₁~ C₆An alkyl group
You. ) And a 5- to 10-membered heterocyclic group
You. ｝, C which may be substituted₆~ C_TenAryl group
The substituent is a halogen atom. ), Hydroxyl group, C₁~ C₆A
Lucoxy group, C₆~ C_TenAryloxy group, 5 to 10 members
Heterocyclic oxy group, C_Two~ C₇Alkylcarbonyl group, C₇
~ C₁₁Arylcarbonyl group, 5- to 10-membered heterocyclic carbo
Nyl group, C_Two~ C₇Alkoxycarbonyl group, C_Two~ C₇A
Alkylaminocarbonyl group, C₇~ C₁₁Arylamino
Carbonyl group, C_Two~ C₇Alkylamino (thiocarboni
Ru) group and C₇~ C₁₁Arylamino (thiocarboni
And the substituent group β is a halogen atom
Child, C which may be substituted₁~ C₆Alkyl group (substituent
Is a halogen atom. ), Hydroxyl group, may be substituted
C₁~ C₆An alkoxy group (the substituent is a halogen atom
is there. ), Carboxyl group and C_Two~ C₇Alkoxycal
Is a group consisting of a carbonyl group, and the substituent group γ is a halogen atom.
, Hydroxyl group, C which may be substituted₁~ C₆Alkoxy group (this
The substituent is C₆~ C_TenAn aryl group. ), C₆~ C
_TenAn aryloxy group, an amino group which may be substituted (the
The substituent is selected from the above-mentioned substituent group α. ), Replaced
Good C₆~ C_TenAryl group (the substituent is the above substituent
Selected from group β. ), 5 to 10-membered complex which may be substituted
A ring group (the substituent is selected from the above substituent group β)
You. ), Carboxyl group, C_Two~ C₇Alkylcarbonyl
A group consisting of oxy, nitro and cyano groups.
The substituent group δ is a halogen atom, an optionally substituted C₁~ C₆A
Alkyl group (the substituent is selected from the above-mentioned substituent group γ)
You. ), Optionally substituted C_Two~ C₆Alkenyl group (the
The substituent is selected from the above substituent group γ. ), Replaced
Good C_Two~ C₆An alkynyl group (the substituent is the above substituent
Selected from the group γ. ), C_Three~ C₆Cycloalkyl group, C
_Two~ C₇Alkylcarbonyl group, optionally substituted C₇~ C
₁₁An arylcarbonyl group (the substituent is a group of the substituents described above)
Selected from β. ), 5 to 10-membered heterocyclic ring which may be substituted
A carbonyl group (the substituent is selected from the above substituent group β)
It is. ), Carboxyl group, optionally substituted C_Two~ C₇A
Alkoxycarbonyl group (the substituent is C₆~ C_TenAnts
A group. ), Optionally substituted C₇~ C₁₁Aryl
An oxycarbonyl group (the substituent is the aforementioned substituent group β
Selected from ), A carbamoyl group which may be substituted (the
The substituent is selected from the above-mentioned substituent group α. ), Replaced
Good C₆~ C_TenAryl group (the substituent is
It is selected from the group β. ), 5 to 10 members which may be substituted
A ring group (the substituent is selected from the above substituent group β)
You. ), Hydroxyl group, optionally substituted C₁~ C₆Alkoxy group
(The substituent is selected from the substituent group γ.)
C that may be replaced_Two~ C₆Alkenyloxy group (substituent
Is selected from the above substituent group γ. ), May be replaced
C_Two~ C₆An alkynyloxy group (the substituent is
It is selected from the group γ. ), C_Three~ C₆Cycloalkoxy
Group, C which may be substituted₆~ C_TenAryloxy group (the
The substituent is selected from the above substituent group β. ), Mercap
Group, sulfo group, optionally substituted C₁~ C₆Alkylthio
Groups (the substituents are selected from the above substituent group γ),
C which may be substituted_Two~ C₆Alkenylthio group (substituent
Is selected from the above substituent group γ. ), May be replaced
C_Two~ C₆An alkynylthio group (the substituent is
Selected from the group γ. ), C_Three~ C₆Cycloalkylthio
Group, C which may be substituted₆~ C_TenArylthio group (the
The substituent is selected from the substituent group β. ), Replaced
Good C₁~ C₆An alkylsulfinyl group (the substituent is
It is selected from the above substituent group γ. ), Optionally substituted C_Two
~ C₆An alkenylsulfinyl group (the substituent is
It is selected from the substituent group γ. ), Optionally substituted C_Two~ C₆
An alkynylsulfinyl group (the substituent is the above substituent
Selected from the group γ. ), C_Three~ C₆Cycloalkyl sulf
Ynyl group, optionally substituted C₆~ C_TenAryl sulfy
Nyl group (the substituent is selected from the above substituent group β)
You. ), Optionally substituted C ₁~ C₆Alkylsulfonyl group
(The substituent is selected from the substituent group γ.)
C that may be replaced_Two~ C₆Alkenylsulfonyl group (the
The substituent is selected from the above substituent group γ. ), Replaced
Good C_Two~ C₆An alkynylsulfonyl group (the substituent is
It is selected from the above substituent group γ. ), C_Three~ C₆Cycloal
Kilsulfonyl group, optionally substituted C₆~ C_TenAryl
Sulfonyl group (the substituent is selected from the above-mentioned substituent group β)
It is. ), A sulfamoyl group which may be substituted (substituted
The group is selected from the above-mentioned substituent group α. ), Be replaced
Amino group (the substituent is selected from the above-mentioned substituent group α)
You. ), A nitro group and a cyano group, provided that
And 3-{(2H-chromen-3-carbonyl) amido
NO｝ pyridine, 4-｛(2H-chromen-3-carboni
L) amino} pyridine, N- [3- {2- (diisopro
Pyramino) ethoxy {-4-methoxyphenyl] -6
-Chloro-2H-chromen-3-carboxamide, N-
[3- {3- (diisopropylamino) propoxy}-
4-methoxyphenyl] -6-chloro-2H-chromene
-3-carboxamide and N- [3- {3- (diisopropane)
Ropylamino) propyl {-4-methoxyphenyl]-
Except for 6-chloro-2H-chromen-3-carboxamide
Good. A pharmacologically acceptable salt thereof,
Pharmaceuticals containing them as active ingredients and using them
A method for preventing or treating diabetic retinopathy or retinopathy.
You.

In the present invention, "C ₁ -C ₆ alkyl group"
Is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2 -Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl, preferably having 1 to 4 carbon atoms Is a straight-chain or branched-chain alkyl group (C ₁ -C ₄ alkyl group), more preferably a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms (C ₁ -C ₄ ).
_A C ₁ -C ₃ alkyl group), and even more preferably an alkyl group having 1 or 2 carbon atoms (C ₁ -C ₂ alkyl group).

In the present invention, the "C ₆ -C ₁₀ aryl group" is an aromatic hydrocarbon group having 6 to 10 carbon atoms, and may be, for example, a phenyl group or a naphthyl group. It is.

In the present invention, the term "C which may be substituted"₁~
C₆An alkyl group (the substituent is C₆~ C_TenWith an aryl group
is there. )) Is the same or different one to three of the above-mentioned “C₆
~ C_{1 0}The above-mentioned “C” which may be substituted by the “aryl group”;₁~ C₆Al
A benzyl group, for example, benzyl, α-naphthylmethyl
, Β-naphthylmethyl, indenylmethyl, diphenyl
Methyl, triphenylmethyl, 1-phenethyl, 2-
Phenethyl, 1-naphthylethyl, 2-naphthylethyl
1-phenylpropyl, 2-phenylpropyl, 3
-Phenylpropyl, 1-naphthylpropyl, 2-naph
Tylpropyl, 2-naphthylpropyl, 3-naphthylp
Ropyl, 1-phenylbutyl, 2-phenylbutyl, 3
-Phenylbutyl, 4-phenylbutyl, 1-naphthyl
Butyl, 2-naphthylbutyl, 3-naphthylbutyl, 4
-Naphthylbutyl, 1-phenylpentyl, 2-phenyl
Rupentyl, 3-phenylpentyl, 4-phenylpen
Tyl, 5-phenylpentyl, 1-naphthylpentyl,
2-naphthyl pentyl, 3-naphthyl pentyl, 4-na
Futylpentyl, 5-naphthylpentyl, 1-phenyl
Hexyl, 2-phenylhexyl, 3-phenylhexyl
4-phenylhexyl, 5-phenylhexyl, 6
-Phenylhexyl, 1-naphthylhexyl, 2-naph
Tylhexyl, 3-naphthylhexyl, 4-naphthyl
Xyl, 5-naphthylhexyl or 6-naphthylhexyl
And preferably one phenyl group is substituted
Good C₁~ C_FourAlkyl group, more preferably methyl
Benzyl, or 4-phenylbutyl group.

In the present invention, "C ₁ -C ₁₂ acyl group"
Is an acyl group having 1 to 12 carbon atoms, for example, an optionally substituted alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkoxycarbonyl group, a carbamoyl group, an alkylsulfonyl group, alkenylsulfonyl group, alkynyl-sulfonyl group, a cycloalkyl sulfonyl group, an arylsulfonyl group which may be heterocyclic sulfonyl group or a sulfamoyl group, preferably a, C ₂ -C ₇ alkylcarbonyl group, or a C ₁ -C ₆ alkylsulfonyl group, more preferably a C ₂ -C ₇ alkylcarbonyl group.

In the present invention, "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,
Preferably, it is a fluorine atom, a chlorine atom or a bromine atom,
In the substituent group δ, more preferably, a bromine atom;
In the alkyl substituent, more preferably, it is a fluorine atom or a chlorine atom, even more preferably, it is a fluorine atom, and in the other substituents, it is more preferably a fluorine atom or a chlorine atom. Is more preferably a chlorine atom.

In the present invention, the "C ₃ -C ₆ cycloalkyl group" is a 3- to 6-membered saturated cyclic hydrocarbon and is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl or cyclohexyl group. is there.

In the present invention, "C _1- which may be substituted"
The “C ₆ alkyl group (the substituent is a halogen atom)” is the above “C ₁ -C ₆ alkyl group” which may be substituted by 1 to 9 identical or different “halogen atoms”. For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, -Fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl,
It may be a 6-iodohexyl or 2,2-dibromoethyl group, and preferably 1 to 6 same or different substituents selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom may be substituted. C ₁ -C a _alkyl group, and more preferably, identical or different may C ₁ which 1-4 substituents substituted selected from the group consisting of fluorine and chlorine atoms
-C is ₃ alkyl group, still more preferably a 1 to 3 C ₁ fluorine atom may be substituted -C ₂ alkyl group, particularly preferably a methyl or trifluoromethyl group.

In the present invention, the "C ₁ -C ₆ alkoxy group" is an oxygen atom to which the above "C ₁ -C ₆ alkyl group" is bonded, and is preferably a straight-chain or straight-chain having 1 to 4 carbon atoms. A branched-chain alkoxy group (C ₁ -C ₄ alkoxy group), more preferably a straight-chain or branched-chain alkoxy group having 1 to 3 carbon atoms (C ₁ -C ₃ alkoxy group); Is more preferably an alkoxy group having 1 or 2 carbon atoms (C ₁ -C ₂ alkoxy group), and most preferably a methoxy group.

In the present invention, the term “optionally substituted C _1-
C ₆ alkoxy group (said substituent is a halogen atom.) ", The" substituted C ₁ may -C ₆ alkyl group (the substituent is a halogen atom.) "Is bonded an oxygen atom Preferably, the same or different 1 to 1 selected from the group consisting of fluorine atom, chlorine atom and bromine atom
Six substituents are optionally substituted C ₁ -C ₄ alkoxy groups, more preferably one to four identical or different substituents selected from the group consisting of fluorine atoms and chlorine atoms. A C ₁ -C ₃ alkoxy group which may be substituted, even more preferably a C ₁ -C ₂ alkoxy group which may be substituted by 1 to 3 fluorine atoms, particularly preferably methoxy or trifluoromethoxy Group.

In the present invention, the "C ₂ -C ₇ alkoxycarbonyl group" is a carbonyl group to which the above-mentioned "C ₁ -C ₆ alkoxy group" is bonded, preferably a C ₁ -C ₄ alkoxy group is bonded. Carbonyl group (C ₂ -C ₅ alkoxycarbonyl group), more preferably a carbonyl group having a C ₁ -C ₃ alkoxy group bonded (C ₂ -C ₄ alkoxycarbonyl group), and even more preferably Is a carbonyl group to which a C ₁ -C ₂ alkoxy group is bonded (C ₂ -C ₃ alkoxycarbonyl group), and is most preferably a methoxycarbonyl group.

In the present invention, "C _6- which may be substituted"
The C ₁₀ aryl group (the substituent is selected from the substituent group β) ”is the same as or different from the same or different 1 to 5 substituents selected from the above“ substituent group β ”. A C ₆ -C ₁₀ aryl group ”, preferably a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group which may be substituted (the substituent is a group selected from a fluorine atom, a chlorine atom and a bromine atom). selected from the group consisting.), a hydroxyl group, may be substituted C ₁ -C ₄ alkoxy group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.), a carboxyl group and a C ₂ ~ C ₅ alkoxy same or different 1 to 3 selected from the group consisting of a carbonyl group
Is a phenyl group which may be substituted by two substituents.

In the present invention, a "5- to 10-membered heterocyclic group"
Is a 5- to 10-membered saturated or unsaturated heterocyclic group in which the heteroatoms in the ring are 1 to 4 heteroatoms consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and the heterocycle is a benzene ring or It may be condensed with a pyridine ring, or may be substituted with a C ₃ -C ₄ alkylene group. Aromatic heterocyclic groups such as, 3,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl groups; morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
Saturated or partially unsaturated heterocyclic groups such as imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl or piperazinyl groups; or 4,5,6,7-tetrahydro-benz
[b] furan, 4,5,6,7-tetrahydro-benz [b]
It may be a bicyclic heterocyclic group such as thiophene, 4,5,6,7-tetrahydro-1H-indole, and R ² , R ³ , R
^{In 4} and R ⁵ , preferably a 5- to 6-membered unsaturated heterocyclic group (1 to 3 identical or different hetero atoms in the ring are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) And more preferably a 6-membered unsaturated heterocyclic group (the heteroatom in the ring is 1 to 3 nitrogen atoms), and still more preferably. , A pyridyl group, most preferably a 3-pyridyl group, and in Ar, preferably a 5- to 6-membered unsaturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom, an oxygen atom and a sulfur atom. The same or different 1 to 3 hetero atoms selected from the group consisting of atoms, which may be condensed with a benzene ring or a pyridine ring and substituted by a C ₃ -C ₄ alkylene group.) And more preferably a 5- to 6-membered unsaturated heterocyclic group (wherein the heteroatom in the ring is The same or different 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The ring may be condensed with a pyridine ring and may be substituted by a tetramethylene group.) And even more preferably, a 5-membered unsaturated heterocyclic group (wherein the heteroatoms in the ring are the same or different 1-2 heteroatoms selected from the group consisting of nitrogen and sulfur atoms. The ring may be substituted by a tetramethylene group.), Most preferably a tetrahydrobenzothienyl or imidazolyl group; in other substituents, preferably the heteroatom in the ring is a nitrogen atom , A 5- or 6-membered saturated or unsaturated heterocyclic group which is 1 to 3 heteroatoms consisting of an oxygen atom and a sulfur atom, more preferably thienyl, pyrrolyl, pyrazolyl, pyridyl, piperidi Or 4, 5, 6,
7-tetrahydro-benz [b] thiophene group.

In the present invention, "5-1 to 5 which may be substituted"
The 0-membered heterocyclic group (the substituent is selected from the substituent group β) ”may be substituted with the same or different 1 to 4 substituents selected from the“ substituent group β ”. A "5- to 10-membered heterocyclic group", preferably a 5- or 6-membered unsaturated heterocyclic group which may be substituted, wherein the heteroatom in the ring is
It is the same or different 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The ring may be fused with a benzene or pyridine ring. The substituent is a C ₁ -C ₆ alkyl group which may be substituted (the substituent is a halogen atom). Or a 5- or 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different from each other and are selected from the group consisting of nitrogen atom and oxygen atom,
Complex atoms. ), More preferably, an optionally substituted 5- to 6-membered unsaturated heterocyclic group wherein the heteroatom in the ring is 1
~ 4 nitrogen atoms. The ring may be fused with a benzene ring. The substituent may be substituted C ₁ -C ₄ alkyl group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) It is. And a 6-membered saturated heterocyclic group (wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), and still more preferably. Is a 5- or 6-membered unsaturated heterocyclic group which may be substituted. The heteroatom in the ring is 1 to 2 nitrogen atoms. The substituent is a C ₁ -C ₃ alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom). } Or a morpholyl group, particularly preferably, may be substituted pyridyl group or a pyrazolyl group {said substituents may be substituted C ₁ -C ₃ alkyl group (the substituent is a fluorine atom.) It is. ｝.

In the present invention, "C _1- which may be substituted"
C ₆ alkoxy group ｛The substituent is selected from the group consisting of a halogen atom and a C ₆ -C ₁₀ aryl group which may be substituted (the substituent is selected from the substituent group β). ｝ ”May be substituted by the above-mentioned“ halogen atom ”or the above-mentioned“ optionally substituted C ₆ -C ₁₀ aryl group (the substituent is selected from the substituent group β). ” The above-mentioned “C ₁ -C ₆ alkoxy group” which may be substituted by 1 to 4 “halogen atoms”, preferably 1 to 5 identical or different halogen atoms or 1 C ₆ to A C ₁ -C ₆ alkoxy group which may be substituted by a C ₁₀ aryl group, more preferably 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, or A C ₁ -C ₆ alkoxy group which may be substituted by one phenyl group,
Even more preferably, it is a C ₁ -C ₃ alkoxy group, particularly preferably a methoxy group.

In the present invention, the "C ₃ -C ₆ cycloalkoxy group" is an oxygen atom to which the above "C ₃ -C ₆ cycloalkyl group" is bonded, and is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyl. An oxy group, preferably a cyclopentyloxy or cyclohexyloxy group.

In the present invention, the "C ₆ -C ₁₀ aryloxy group" is an oxygen atom to which the above "C ₆ -C ₁₀ aryl group" is bonded, and is preferably a phenoxy group.

In the present invention, "C _6- which may be substituted"
The “C ₁₀ aryloxy group (the substituent is selected from the substituent group β)” is the “C ₆ -C ₁₀ aryl group which may be substituted (the substituent is selected from the substituent group β). ) "Is a bonded oxygen atom, and in the substituent group δ, preferably substituted by one or two same or different substituents selected from the group consisting of a carboxyl group and a C ₂ -C ₇ alkoxycarbonyl group. And more preferably a phenoxy group which may be substituted by one or two identical or different substituents selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group. And other substituents, preferably, a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted C ₁ -C ₄
An alkyl group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group, a C ₁ -C ₄ alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom and The same or different 1 to 3 selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group.
Is a phenoxy group which may be substituted by two substituents.

In the present invention, the "C ₁ -C ₁₂ acyloxy group" is an oxygen atom to which the above "C ₁ -C ₁₂ acyl group" is bonded, preferably a C ₂ -C ₇ alkylcarbonyloxy group or It is a C ₁ -C ₆ alkylsulfonyloxy group, more preferably a C ₂ -C ₇ alkylcarbonyloxy group.

In the present invention, "an amino group which may be substituted (the substituent is a C ₁ -C ₆ alkyl group)"
Is an amino group which may be substituted by _one or two same or different C ₁ -C ₆ alkyl groups, for example, amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butyl Amino group, pentylamino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dipentylamino group, dihexylamino group or methylethylamino group, preferably An amino group substituted by two identical or different C ₁ -C ₆ alkyl groups, more preferably an amino group substituted by two identical or different C ₁ -C ₄ alkyl groups,
Even more preferably, it is an amino group substituted by the same two C ₁ -C ₃ alkyl groups, particularly preferably a dimethylamino or diisopropylamino group.

In the present invention, the term “optionally substituted C _1-
A C ₆ alkyl group (the substituent is a C ₆ -C ₁₀ aryl group,
A hydroxyl group, an amino group which may be substituted (the substituent is a C ₁
~C is a _6-alkyl group. ) And a 5- to 10-membered heterocyclic group. ", The" C ₆ -C ₁₀ aryl group ", a hydroxyl group, the" amino group which may be substituted (the substituent is a C ₁ -C ₆ alkyl group.) "And" 5
The above-mentioned “C ₁ ” which may be substituted by the same or different one or two substituent (s) selected from the group consisting of “10-membered heterocyclic group”;
To a C ₆ alkyl group ”, preferably a phenyl group, a hydroxyl group, a di (C ₁ -C ₆ alkyl) amino group and a 5- to 6-membered saturated heterocyclic group (the heteroatom in the ring is a nitrogen atom and The same or different one or two hetero atoms selected from the group consisting of oxygen atoms.) The C _1- which may be substituted by the same or different one or two substituents selected from the group consisting of
A C ₆ alkyl group, more preferably a phenyl group, a hydroxyl group, a di (C ₁ -C ₄ alkyl) amino group or a 6-membered saturated heterocyclic group (wherein the heteroatom in the ring is selected from nitrogen and oxygen And C ₁ -C ₆ alkyl groups which may be substituted with the same or different 1 or 2 heteroatoms selected from the group consisting of phenyl group, hydroxyl group,
A C ₁ -C ₄ alkyl group which may be substituted by a di (C ₁ -C ₃ alkyl) amino group or a piperidyl group, particularly preferably a phenyl group, a dimethylamino group, a diisopropylamino group or a piperidino group Good C ₁ ~
Is a C ₄ alkyl group, and most preferably, carbamoyl group, methylcarbamoyl group, 4-phenyl-butylcarbamoyl group, 2-dimethylamino-ethylcarbamoyl group,
2-diisopropylaminoethylcarbamoyl group or 2
-Piperidinoethylcarbamoyl group.

In the present invention, "C _6- which may be substituted"
The “C ₁₀ aryl group (the substituent is a halogen atom)” is the “C ₆ -C ₁₀ aryl group” which may be substituted by 1 to 5 identical or different “halogen atoms”.
Is preferably a phenyl group which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom, more preferably
The same or different one or two substituents selected from the group consisting of a fluorine atom and a chlorine atom are phenyl groups which may be substituted.

In the present invention, the "5- to 10-membered heterocyclic oxy group" is an oxygen atom to which the "5- to 10-membered heterocyclic group" is bonded, preferably a 5- to 6-membered saturated heterocyclic oxy group. (Wherein the heteroatoms in the ring are the same or different one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), and more preferably a 6-membered saturated heterocyclic oxy group. (The heteroatom in the ring is 1 to 2 nitrogen atoms), and still more preferably a tetrahydropyranyl group.

In the present invention, "C_Two~ C₇Alkyl cal
The "bonyl group" is the above-mentioned "C_Two~ C₇Alkyl group "
A carbonyl group;₁~ C_FourAlkyl group
A bonded carbonyl group (C_Two~ C_FiveAlkylcarbonyl
Group) and more preferably C ₁~ C_ThreeAlkyl group is bonded
Carbonyl group (C_Two~ C_FourAlkylcarbonyl group)
Yes, and even more preferably, C₁~ C_TwoAn alkyl group
Carbonyl group (C_Two~ C_ThreeAlkylcarbonyl group)
And most preferably an acetyl group.

In the present invention, the "C ₇ -C ₁₁ arylcarbonyl group" is a carbonyl group to which the above "C ₆ -C ₁₀ aryl group" is bonded, and is preferably a benzoyl group.

In the present invention, the "5- to 10-membered heterocyclic carbonyl group" is a carbonyl group to which the above-mentioned "5- to 10-membered heterocyclic group" is bonded.
A 5- or 6-membered saturated heterocyclic carbonyl group which may be substituted (wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom. Is a hydroxyl group.), And more preferably, a 6-membered saturated heterocyclic carbonyl group which may be substituted, wherein the hetero atom in the ring is the same or different and is selected from the group consisting of a nitrogen atom and an oxygen atom. 1 to 2 heteroatoms, the substituent is a hydroxyl group), and even more preferably, a piperidylcarbonyl group which may be substituted (the substituent is a hydroxyl group); In the substituent group α, preferably, a 5- to 6-membered unsaturated heterocyclic carbonyl group (the same or different 1 to 3 heterocyclic atoms in the ring are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) Complex atoms.) There, more preferably, 6-membered unsaturated heterocyclic-carbonyl group (hetero atom in the ring, 1 to 3
Nitrogen atoms. ).

In the present invention, the “C ₂ -C ₇ alkylaminocarbonyl group” is a carbamoyl group in which one of the above “C ₁ -C ₆ alkyl groups” is bonded to a nitrogen atom. Is a carbamoyl group in which a C ₁ -C ₄ alkyl group is bonded to a nitrogen atom, more preferably one C ₁ -C ₃
The alkyl group is a carbamoyl group bonded to a nitrogen atom, even more preferably one C ₁ -C ₂ alkyl group is a carbamoyl group bonded to a nitrogen atom, most preferably a methylaminocarbonyl group. is there.

In the present invention, the "C ₇ -C ₁₁ arylaminocarbonyl group" is a carbamoyl group in which one of the "C ₆ -C ₁₀ aryl groups" is bonded to a nitrogen atom, and is preferably phenylcarbamoyl. Group.

In the present invention, the “C ₂ -C ₇ alkylamino (thiocarbonyl) group” is a thiocarbamoyl group in which _one “C ₁ -C ₆ alkyl group” is bonded to a nitrogen atom. Is a thiocarbamoyl group in which one C ₁ -C ₄ alkyl group is bonded to a nitrogen atom, more preferably
A single C ₁ -C ₃ thiocarbamoyl group in which an alkyl group is bonded to the nitrogen atom, further preferably more, one C ₁ ~
The C ₂ alkyl group is a thiocarbamoyl group bonded to a nitrogen atom, most preferably a methylamino (thiocarbonyl) group.

In the present invention, the “C ₇ -C ₁₁ arylamino (thiocarbonyl) group” is one of the above “C ₆ -C 11
_The " ₁₀ aryl group" is a thiocarbamoyl group bonded to a nitrogen atom, and is preferably a phenyl (thiocarbamoyl) group.

In the present invention, “an optionally substituted amino group (the substituent is selected from the substituent group α)” is
The same or different 1 selected from the above “substituent group α”
A two and amino group which may be substituted by a substituent machine, preferably, amino group which may be substituted {the substituents, C ₂
-C ₇ alkylcarbonyl group, benzoyl group, 5-6 membered unsaturated heterocyclic carbonyl group (the same or different 1 to 3 hetero atoms in the ring are selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Complex atoms) and C
Selected from the group consisting of ₂ -C ₇ alkoxycarbonyl group. ｝, An optionally substituted ureido group (the substituent is a C
Selected from the group consisting of ₁ -C ₆ alkyl group and a phenyl group. ) Or a thioureido group which may be substituted (the substituent is a phenyl group), more preferably an amino group which may be substituted. The substituent may be a C ₂ -C ₅ alkylcarbonyl group, benzoyl Group, a 6-membered unsaturated heterocyclic carbonyl group (the heteroatom in the ring is 1 to 3 nitrogen atoms) and a C ₂ -C ₅ alkoxycarbonyl group. ｝, A ureido group which may be substituted (the substituent is selected from the group consisting of a C ₁ -C ₄ alkyl group and a phenyl group) or a thioureido group which may be substituted (the substituent is a phenyl group). ), And still more preferably, an amino group which may be substituted (the substituent is
A C ₂ -C ₅ alkoxycarbonyl group. ), And particularly preferably, an amino group which may be substituted (the substituent is
a t-butoxycarbonyl group. ).

In the present invention, "C _1- which may be substituted"
C ₆ alkyl group ｛The substituent is a hydroxyl group, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group and a C ₆ -C ₁₀ aryl group which may be substituted (the substituent is a substituent group β Selected from the group consisting of: } "Represents a hydroxyl group, the" C ₁ -C ₆ alkoxy group ", the" C ₃ -C ₆ cycloalkyl group "and the" substituted C ₆ may -C ₁₀
Aryl group (the substituent is selected from substituent group β) ”or the same or different 1 selected from the group consisting of
The above-mentioned “C ₁ -C ₆ alkyl group” which may be substituted by two substituents, preferably a phenyl group, a hydroxyl group, a di (C ₁ -C ₆ alkyl) amino group or a 5- to 6-membered saturated heterocyclic group. A C ₁ -C ₆ alkyl group which may be substituted by a ring group (wherein the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom) And more preferably, phenyl, hydroxyl, di (C ₁
-C ₄ alkyl) amino group or a 6-membered saturated Hajime Tamaki (hetero atom in the ring, the same or different 1 to 2 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom.) The A C ₁ -C ₆ alkyl group which may be substituted, and even more preferably, a phenyl group, a hydroxyl group, a di (C ₁
-C ₃ alkyl) C ₁ -C ₄ alkyl group which may be substituted by an amino group or a piperidyl group, particularly preferably
Phenyl group, a dimethylamino group, or C ₁ -C ₄ alkyl group substituted by a diisopropylamino group or a piperidino group.

In the present invention, the "C ₂ -C ₆ alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1- Methyl-2-propenyl, 1-methyl-
1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl,
1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 3-methyl-2-butenyl, 2-
Methyl-3-butenyl, 1-ethyl-2-butenyl, 1
-Ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-
Pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,
It can be a 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl group, preferably having 2 to 4 carbon atoms. of a straight-chain or branched alkenyl group (C ₂ -C ₄ alkenyl group), more preferably, a straight-chain or branched alkenyl group having 2 or 3 carbon atoms (C ₂ ~
C ₃ alkenyl group), and even more preferably a 2-propenyl group.

In the present invention, the "C ₂ -C ₆ alkynyl group" is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-alkynyl. Methyl-2-propynyl, 1-methyl-
1-propynyl, 2-methyl-1-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 3-methyl-2-butynyl, 2-
Methyl-3-butethynyl, 1-ethyl-2-butynyl,
1-ethyl-3-butynyl, 1-pentynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2
-Pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 1-hexynyl, 2-hexynyl , 3-hexynyl, 4-hexynyl or 5-hexynyl group, preferably an alkynyl group having 3 or 4 carbon atoms (C ₃
ＣC ₄ alkynyl group), and more preferably a 2-propynyl group.

In the present invention, “C _1- which may be substituted”
C ₆ alkoxy group ｛The substituent is a hydroxyl group, a cyano group,
It is selected from the group consisting of a formyl group, a C ₁ -C ₆ alkoxy group and a 5- to 10-membered heterocyclic group which may be substituted (the substituent is selected from the substituent group β). "｝" Represents a hydroxyl group,
Cyano group, formyl group, the above-mentioned “C ₁ -C ₆ alkoxy group”
And the above-mentioned 5 to 10-membered heterocyclic group which may be substituted (the substituent is selected from the substituent group β) and is substituted by the same or different 1 to 2 substituents selected from the group consisting of And the above-mentioned "C ₁ -C ₆ alkoxy group", preferably a hydroxyl group, a cyano group, a formyl group, a C ₁ -C ₄ alkoxy group or a 5- to 6-membered heterocyclic group (the hetero atom in the ring is ,
1 to 3 identical or different hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. ) Is a C ₁ -C ₄ alkoxy group which may be substituted by).

[0042] In the present invention, "C ₂ -C ₆ alkenyloxy group", said an oxygen atom "C ₂ -C ₆ alkenyl group" is bonded, preferably, binding C ₂ -C ₄ alkenyl group Oxygen atom (C ₂ -C ₄ alkenyloxy group), more preferably an allyloxy group.

In the present invention, the "C ₂ -C ₆ alkynyloxy group" is an oxygen atom to which the above-mentioned "C ₂ -C ₆ alkynyl group" is bonded, and preferably a C ₃ -C ₄ alkynyl group is bonded. Oxygen atom (C ₃ -C ₄ alkynyloxy group), more preferably a 2-propynyloxy group.

In the present invention, "5 to 1 which may be substituted"
The 0-membered heterocyclic oxy group (the substituent is selected from the substituent group β) ”may be substituted by the same or different 1 to 4 substituents selected from the above“ substituent group β ”. wherein a "5 to 10-membered heterocyclic group", preferably a fluorine atom, a chlorine atom, a bromine atom, or C ₁ ~ to be substituted
A C ₄ alkyl group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group, a C ₁ -C ₄ alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom, The same or different 1 to 3 selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group.
5- or 6-membered saturated heterocyclic oxy group which may be substituted by two or more substituents, wherein the heteroatoms in the ring are the same or different one or two heteroatoms selected from the group consisting of nitrogen atom and oxygen atom And more preferably a tetrahydropyranyl group.

In the present invention, the "C ₂ -C ₇ alkylcarbonyloxy group" is an oxygen atom to which the above-mentioned "C ₂ -C ₇ alkylcarbonyl group" is bonded, preferably C ₂ -C ₅ alkylcarbonyl group.
An oxygen atom to which an alkylcarbonyl group is bonded (C ₂ -C ₅ alkylcarbonyloxy group);
₂ -C ₄ oxygen atoms alkylcarbonyl group is bonded (C ₂
A -C ₄ alkylcarbonyloxy group), and even more preferably a C ₂ -C ₄ oxygen atoms alkylcarbonyl group is bonded (C ₂ -C ₃ alkylcarbonyloxy group), most preferably, acetoxy Group.

In the present invention, the “C ₁ -C ₆ alkylthio group” is a sulfur atom to which the above “C ₁ -C ₆ alkyl group” is bonded, and is preferably a linear or linear C ₁ -C ₆ alkyl group. a branched-chain alkylthio group (C ₁ -C ₄ alkylthio group),
More preferably, it is a linear or branched alkylthio group having 1 to 3 carbon atoms (C ₁ -C ₃ alkylthio group), and even more preferably, an alkylthio group having 1 or 2 carbon atoms (C ₁
ＣC ₂ alkylthio group), and most preferably a methylthio group.

In the present invention, “optionally substituted C₁~
C₆An alkoxy group (the substituent is C ₆~ C_TenAryl group
It is. )) Is the above-mentioned “optionally substituted C₁~ C₆Archi
Group (the substituent is a C₆~ C_TenAn aryl group
You. ) "Is an attached oxygen atom, preferably one
C which may be substituted by a phenyl group₁~ C_FourAn alkoxy group
More preferably, methoxy, benzyl
An oxy or 4-phenylbutyloxy group.

In the present invention, "C _1- which may be substituted"
The C ₆ alkyl group (the substituent is selected from the group of substituents γ) ”may be substituted by 1 to 3 identical or different substituents selected from the group of“ substituent γ ”. A C ₁ -C ₆ alkyl group ”, preferably substituted by 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, a carboxyl group and a C ₂ -C ₇ alkoxycarbonyl group. A good C ₁ -C ₆ alkyl group, more preferably a fluorine atom, a chlorine atom, a bromine atom,
A C ₁ -C ₄ alkyl group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group, and even more preferably fluorine. A C ₁ -C ₃ alkyl group which may be substituted by 1 to 3 identical or different substituents or one C ₂ -C ₄ alkoxycarbonyl group selected from the group consisting of atoms and chlorine atoms, and is particularly preferred. Is a C ₁ -C ₂ alkyl group which may be substituted by 1 to 3 fluorine atoms or one C ₂ -C ₃ alkoxycarbonyl group, most preferably a methyl group or an ethoxycarbonylmethyl group. is there.

In the present invention, “optionally substituted C_Two~
C₆Alkenyl group (the substituent is selected from substituent group γ
It is. )) Is the same or selected from the above “substituent group γ”.
May be substituted with 1 to 3 different substituents
"C_Two~ C₆Alkenyl group '', preferably substituted
5- or 6-membered unsaturated heterocyclic group {hetero atom in the ring
Is selected from the group consisting of nitrogen, oxygen and sulfur
1 to 3 hetero atoms which are the same or different. This
The substituent is a halogen atom, C₁~ C₆Alkyl group and position
Phenyl group which may be substituted (the substituent is a halogen atom
It is. ). ｝, Carboxyl
Group and C_Two~ C₇From the group consisting of alkoxycarbonyl groups
Substituted by 1 to 3 identical or different substituents selected
C that may be _Two~ C₆Alkenyl group, more preferably
Is a 5-membered unsaturated heterocyclic group which may be substituted
Elementary atoms are one to three nitrogen atoms. The substituent is
Fluorine atom, chlorine atom, bromine atom, C₁~ C_FourAlkyl group
And an optionally substituted phenyl group (the substituent is fluorine
Selected from the group consisting of atoms, chlorine atoms and bromine atoms
You. ). ｝ And C_Two~ C_FiveArco
Same or different selected from the group consisting of xycarbonyl groups
C which may be substituted by only one or two substituents_Two~ C_FourA
A alkenyl group, and even more preferably, may be substituted
Pyrrolyl group ｛the substituent is phenyl which may be substituted
Group (the substituent is a group consisting of a fluorine atom and a chlorine atom
Selected from. ). ｝ Or C_Two
~ C_FourC which may be substituted by an alkoxycarbonyl group_Two
~ C_FourAn alkenyl group.

In the present invention, "C _2- which may be substituted"
The “C ₆ alkynyl group (the substituent is selected from the substituent group γ)” may be substituted with the same or different 1 to 3 substituents selected from the above “substituent group γ”. A C ₂ -C ₆ alkynyl group ”, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C ₁
-C ₄ alkoxy group (said substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, 5-6
Membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), carboxyl, C
₂ -C ₅ alkylcarbonyloxy group, the same or different 1 to 2 C ₃ may be substituted by a substituent of -C ₄ alkynyl group selected from the group consisting of a nitro group and a cyano group.

In the present invention, “C _7- which may be substituted”
C ₁₁ arylcarbonyl group (the substituent is a substituent group β
Selected from. )) Is the above-mentioned “C ₆ -C optionally substituted”.
₁₀ aryl group (the substituent is selected from substituent group β) ”is a bonded carbonyl group, preferably a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted C ₁ to
A C ₄ alkyl group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group, a C ₁ -C ₄ alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom, The same or different 1 to 3 selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group.
Is a benzoyl group which may be substituted by two substituents.

In the present invention, "5 to 1 which may be substituted"
The 0-membered heterocyclic carbonyl group (the substituent is selected from the substituent group β) ”may be substituted by the same or different 1 to 4 substituents selected from the above“ substituent group β ”. A 5- to 10-membered heterocyclic carbonyl group, which is preferably a 5- to 6-membered saturated heterocyclic carbonyl group which may be substituted by a hydroxyl group (a group in which the heteroatom in the ring comprises a nitrogen atom and an oxygen atom) Same or different 1 or 2 selected from
Complex atoms. ), And more preferably, a 6-membered saturated heterocyclic carbonyl group which may be substituted by a hydroxyl group (the same or different one or two hetero atoms in the ring are selected from the group consisting of a nitrogen atom and an oxygen atom) And even more preferably a piperidylcarbonyl group which may be substituted by a hydroxyl group.

In the present invention, “C _2- which may be substituted”
C ₇ alkoxycarbonyl group (the substituent is a C ₆ -C ₁₀
An aryl group. )) Is the above-mentioned “optionally substituted C ₁
To a C ₆ -alkoxy group (the substituent is a C ₆ -C ₁₀ aryl group) ”, preferably a C ₁ -C ₄ group which may be substituted by one phenyl group. An alkoxycarbonyl group, more preferably, more preferably,
Methoxycarbonyl, benzyloxycarbonyl or 4
-A phenylbutyloxycarbonyl group.

[0054] In the present invention, "may C ₇ ~ to be substituted
The C ₁₁ aryloxycarbonyl group (the substituent is selected from the substituent group β) ”is the same as the above-mentioned“ optionally substituted C
_6- C ₁₀ aryloxy group (the substituent is a substituent group β
Selected from. ) "Is a carbonyl group attached, preferably, fluorine atom, chlorine atom, bromine atom, may be substituted C ₁ -C ₄ alkyl group (said substituent is a fluorine atom,
It is selected from the group consisting of a chlorine atom and a bromine atom. ), Hydroxyl group, may be substituted C ₁ -C ₄ alkoxy group (said substituent is a fluorine atom. Selected from the group consisting of chlorine and bromine), a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group A phenoxycarbonyl group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of:

In the present invention, the “carbamoyl group which may be substituted (the substituent is selected from the substituent group α)” is the same or different from the above “substituent group α”. Is a carbamoyl group which may be substituted by a substituent, preferably a C ₁ -C ₆ alkyl group which may be substituted. The substituent may be a phenyl group, a hydroxyl group, a di (C
₁ -C ₆ alkyl) amino group and a 5- to 6-membered saturated Hajime Tamaki (hetero atom in the ring is the same or different 1 to 2 heteroatoms selected from the group consisting of nitrogen atom and oxygen atom .). ｝, A phenyl group which may be substituted (the substituent is a halogen atom), a hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (the heteroatom in the ring is selected from the group consisting of a nitrogen atom and an oxygen atom) Selected from the group consisting of the same or different 1 or 2 heteroatoms selected from the group consisting of
Carbamoyl groups which may be substituted by a plurality of substituents, more preferably a C ₁ -C ₆ alkyl group which may be substituted. The substituent may be a phenyl group, a hydroxyl group, a di (C ₁ -C ₄ alkyl) Selected from the group consisting of an amino group and a 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom). . ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group or a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is nitrogen A carbamoyl group which may be substituted by the same or different 1 or 2 heteroatoms selected from the group consisting of an atom and an oxygen atom, and even more preferably a C ₁ -C ₄ which may be substituted.
Alkyl group—The substituent is selected from the group consisting of a phenyl group, a hydroxyl group, a di (C ₁ -C ₃ alkyl) amino group and a piperidyl group. ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a carbamoyl group which may be substituted by a hydroxyl group or a tetrahydropyranyloxy group, particularly preferably it may be substituted C ₁ -C ₄ alkyl group (the substituent is a phenyl group, dimethylamino group, selected from the group consisting of a diisopropylamino group and a piperidino group.) or may carbamoyl group substituted by a hydroxyl group.

In the present invention, “C _1- which may be substituted”
The “C ₆ alkoxy group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₁ -C ₆ alkyl group (the substituent is selected from the substituent group γ). Is a bonded oxygen atom, preferably a halogen atom, 5-
A 6-membered saturated heterocyclic group wherein the same or different 1 or 2 hetero atoms in the ring are selected from the group consisting of nitrogen and oxygen
~ 2 complex atoms. ) And a di (C ₁ -C ₆ alkyl) amino group, which is a C ₁ -C ₆ alkoxy group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of Fluorine atom, chlorine atom,
A bromine atom, a 6-membered saturated heterocyclic group (the heteroatom in the ring is
One or two identical or different hetero atoms selected from the group consisting of a nitrogen atom and an oxygen atom. ) And di (C _1-
C ₄ alkyl) or C ₁ which is substituted by the same or different 1 to 3 substituents selected from the group consisting of amino group
-C ₆ alkoxy group, even more preferably more, identical are selected from the group consisting of fluorine atom and a chlorine atom or different 1 to 3 substituents or one piperidyl group or di (C ₁ -C ₃ Alkyl) a C ₁ -C ₃ alkoxy group which may be substituted by an amino group;
Three fluorine atoms or one piperidino group, a which may be substituted C ₁ -C ₃ alkoxy group with a dimethylamino group or a diisopropylamino group, and most preferably, a methoxy group, 2-piperidinoethoxy group, or 2-diisopropylaminoethoxy group.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkenyloxy group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₂ -C ₆ alkenyl group (the substituent is selected from the substituent group γ). ) "Is a bonded oxygen atom, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C
₁ -C ₄ alkoxy group (said substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, 5-6
Membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), carboxyl, C
_A C ₃ -C ₄ alkenyloxy group which may be substituted by one or two identical or different substituents selected from the group consisting of a _2- C ₅ alkylcarbonyloxy group, a nitro group and a cyano group.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkynyloxy group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₂ -C ₆ alkynyl group (the substituent is selected from the substituent group γ). ) "Is a bonded oxygen atom, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C
₁ -C ₄ alkoxy group (said substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, 5-6
Membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), carboxyl, C
₂ -C ₅ alkylcarbonyloxy group, the same or different 1 to 2 C ₃ may be substituted by a substituent of -C ₄ alkynyloxy group selected from the group consisting of a nitro group and a cyano group.

In the present invention, “C _1- which may be substituted”
The “C ₆ alkylthio group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₁ -C ₆ alkyl group (the substituent is selected from the substituent group γ).” Is a bonded sulfur atom, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C ₁ -C ₄ alkoxy group (the substituent is a phenyl group), and a phenoxy group. An amino group, a phenyl group, a 5- to 6-membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms) .), a carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, the same or different one to two C ₁ may be substituted by a substituent -C ₄ alkylthio group selected from the group consisting of a nitro group and a cyano group It is.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkenylthio group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₂ -C ₆ alkenyl group (the substituent is selected from the substituent group γ). ) "Is a bonded sulfur atom, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C
₁ -C ₄ alkoxy group (said substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, 5-6
Membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), carboxyl, C
_A C ₃ -C ₄ alkenylthio group which may be substituted by one or two identical or different substituents selected from the group consisting of a _2- C ₅ alkylcarbonyloxy group, a nitro group and a cyano group.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkynylthio group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C ₂ -C ₆ alkynyl group (the substituent is selected from the substituent group γ). ) "Is a bonded sulfur atom, preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C
₁ -C ₄ alkoxy group (said substituent is a phenyl group.), A phenoxy group, an amino group, a phenyl group, 5-6
Membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur), carboxyl, C
_A C ₃ -C ₄ alkynylthio group which may be substituted by one or two identical or different substituents selected from the group consisting of a _2- C ₅ alkylcarbonyloxy group, a nitro group and a cyano group.

In the present invention, “C ₃ -C ₆ cycloalkylthio group” is a sulfur atom to which the above “C ₃ -C ₆ cycloalkyl group” is bonded, and is cyclopropylthio, cyclobutylthio, cyclopentylthio or cyclohexyl. A thio group, preferably a cyclopentylthio or cyclohexylthio group.

In the present invention, “optionally substituted C₆~
C_TenArylsulfinyl group (the substituent is a group of substituents
Selected from β. )) Is the above-mentioned “optionally substituted C₆~
C_TenAryl group (the substituent is selected from substituent group β)
You. ) "Is a bonded sulfinyl group, preferably
Fluorine atom, chlorine atom, bromine atom, C which may be substituted ₁
~ C_FourAlkyl group (the substituent is a fluorine atom, chlorine atom
Selected from the group consisting of hydrogen atom and bromine atom. ), Hydroxyl,
C which may be substituted₁~ C_FourAn alkoxy group (the substituent is
Selected from the group consisting of fluorine, chlorine and bromine
It is. ), Carboxyl group and C_Two~ C_FiveAlkoxycal
The same or different 1 selected from the group consisting of a bonyl group
A phenylthio group which may be substituted by three substituents
You.

In the present invention, “C _1- which may be substituted”
The C ₆ alkylsulfinyl group (the substituent is selected from the substituent group γ) ”is the above-mentioned“ optionally substituted C _1-
A C ₆ alkyl group (the substituent is selected from the group of substituents γ) ”.
Fluorine atom, chlorine atom, bromine atom, hydroxyl group, optionally substituted C ₁ -C ₄ alkoxy group (the substituent is a phenyl group), phenoxy group, amino group, phenyl group, 5
A 6-membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), a carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, the same or different 1 selected from the group consisting of a nitro group and a cyano group
A C ₁ -C ₄ alkylsulfinyl group which may be substituted with up to 2 substituents.

In the present invention, “C _2- which may be substituted”
The C ₆ alkenylsulfinyl group (the substituent is selected from the substituent group γ) ”is the above-mentioned“ C ₂ optionally substituted ”.
To a C ₆ alkenyl group (the substituent is selected from the substituent group γ) ”, and is preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C ₁ -C ₄ alkoxy group (said substituent is a phenyl group.), a phenoxy group, an amino group, a heterocyclic atoms of the phenyl group, 5- or 6-membered Hajime Tamaki (in which ring is a nitrogen atom, oxygen atom and sulfur are the same or different one to three hetero atoms selected from the group consisting of atoms.), the same or different selected from the group consisting of carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, a nitro group and a cyano group And a C ₃ -C ₄ alkenylsulfinyl group which may be substituted by one or two substituents.

In the present invention, “C _2- which may be substituted”
The C ₆ alkynylsulfinyl group (the substituent is selected from the group of substituents γ) ”is the above-mentioned“ C ₂ optionally substituted ”.
To a C ₆ alkynyl group (the substituent is selected from the substituent group γ) ”, and is preferably a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, an optionally substituted C ₁ -C ₄ alkoxy group (said substituent is a phenyl group.), a phenoxy group, an amino group, a heterocyclic atoms of the phenyl group, 5- or 6-membered Hajime Tamaki (in which ring is a nitrogen atom, oxygen atom and sulfur are the same or different one to three hetero atoms selected from the group consisting of atoms.), the same or different selected from the group consisting of carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, a nitro group and a cyano group And a C ₃ -C ₄ alkynylsulfinyl group which may be substituted by one or two substituents.

In the present invention, the “C ₃ -C ₆ cycloalkylsulfinyl group” is a sulfinyl group to which the above “C ₃ -C ₆ cycloalkyl group” is bonded, and is cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl or It is a cyclohexylsulfinyl group, preferably a cyclopentylsulfinyl or cyclohexylsulfinyl group.

In the present invention, “C may be substituted₆~
C_TenArylsulfinyl group (the substituent is a group of substituents
Selected from β. )) Is the above-mentioned “optionally substituted C₆~
C_TenAryl group (the substituent is selected from substituent group β)
You. ) "Is a bonded sulfinyl group, preferably
Fluorine atom, chlorine atom, bromine atom, C which may be substituted ₁
~ C_FourAlkyl group (the substituent is a fluorine atom, chlorine atom
Selected from the group consisting of hydrogen atom and bromine atom. ), Hydroxyl,
C which may be substituted₁~ C_FourAn alkoxy group (the substituent is
Selected from the group consisting of fluorine, chlorine and bromine
It is. ), Carboxyl group and C_Two~ C_FiveAlkoxycal
The same or different 1 selected from the group consisting of a bonyl group
Phenylsulfini optionally substituted by three substituents
Group.

In the present invention, “optionally substituted C₁~
C₆An alkylsulfonyl group (the substituent is a substituent group γ
Selected from. )) Is the above-mentioned “optionally substituted C₁~ C₆
Alkyl group (the substituent is selected from substituent group γ;
You. ) "Is a bonded sulfonyl group, and preferably
Nitrogen atom, chlorine atom, bromine atom, hydroxyl group,
C ₁~ C_FourAn alkoxy group (the substituent is a phenyl group
is there. ), Phenoxy, amino, phenyl, 5-
6-membered heterocyclic group (the heteroatom in the ring is a nitrogen atom, an oxygen
Same or different selected from the group consisting of atoms and sulfur atoms
Only one to three complex atoms. ), Carboxyl group,
C_Two~ C_FiveAlkylcarbonyloxy, nitro and
The same or different 1-2 selected from the group consisting of ano groups
Optionally substituted by two substituents₁~ C_FourAlkylsul
It is a honyl group.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkenylsulfonyl group (the substituent is selected from the substituent group γ)” is the above-mentioned “optionally substituted C _2-
A C ₆ alkenyl group (the substituent is selected from the substituent group γ) ”.
Fluorine atom, chlorine atom, bromine atom, hydroxyl group, optionally substituted C ₁ -C ₄ alkoxy group (the substituent is a phenyl group), phenoxy group, amino group, phenyl group, 5
A 6-membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), a carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, the same or different 1 selected from the group consisting of a nitro group and a cyano group
A C ₃ -C ₄ alkenylsulfonyl group which may be substituted with up to 2 substituents.

In the present invention, “C _2- which may be substituted”
The “C ₆ alkynylsulfonyl group (the substituent is selected from the substituent group γ)” is the above-mentioned “C _2- which may be substituted”.
A C ₆ alkynyl group (the substituent is selected from the group of substituents γ) ”.
Fluorine atom, chlorine atom, bromine atom, hydroxyl group, optionally substituted C ₁ -C ₄ alkoxy group (the substituent is a phenyl group), phenoxy group, amino group, phenyl group, 5
A 6-membered heterocyclic group (the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), a carboxyl group, C ₂ -C ₅ alkylcarbonyloxy group, the same or different 1 selected from the group consisting of a nitro group and a cyano group
A C ₃ -C ₄ alkynylsulfonyl group which may be substituted with up to 2 substituents.

In the present invention, the “C ₃ -C ₆ cycloalkylsulfonyl group” is a sulfonyl group to which the above “C ₃ -C ₆ cycloalkyl group” is bonded, and is cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl or It is a cyclohexylsulfonyl group, preferably a cyclopentylsulfonyl or cyclohexylsulfonyl group.

In the present invention, “C _6- which may be substituted”
C ₁₀ arylsulfonyl group (the substituent is a substituent group β
Selected from. )) Is the above-mentioned “C ₆ -C optionally substituted”.
₁₀ aryl group (the substituent is selected from the substituent group β) ”is a bonded sulfonyl group, preferably a fluorine atom, a chlorine atom, a bromine atom, a C ₁ to C
A C ₄ alkyl group (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group, a C ₁ -C ₄ alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom, The same or different 1 to 3 selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group.
Is a phenylsulfonyl group which may be substituted by two substituents.

In the present invention, the term “optionally substituted sulf
Amoyl group (the substituent is selected from substituent group α)
You. )) Is the same or selected from the above “substituent group α”.
Sulf which may be substituted by 1 to 2 different substituents
And is preferably an optionally substituted C₁~ C₆
Alkyl group ｛the substituent is a phenyl group, a hydroxyl group,
(C ₁~ C₆Alkyl) amino group and 5-6 membered saturated heterocycle
Group (where the heteroatom in the ring is a nitrogen atom and an oxygen atom
The same or different one or two complex elements selected from the group consisting of
I am a child. ). ｝, Being replaced
A good phenyl group (the substituent is a halogen atom)
You. ), A hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (the
The heteroatoms in the ring are of the group nitrogen and oxygen
One or two heteroatoms selected from the same or different
You. The same or different 1 or 2 selected from the group consisting of
A sulfamoyl group which may be substituted by
And more preferably an optionally substituted C₁~ C₆Alkyl group
｛The substituent is a phenyl group, a hydroxyl group, a di (C₁~ C_FourA
Alkyl) amino group and 6-membered saturated heterocyclic group
The elementary atom is selected from the group consisting of a nitrogen atom and an oxygen atom
One or two different heteroatoms. From)
Selected from the group ｝, A phenyl group which may be substituted
(The substituent may be a fluorine atom, a chlorine atom and a bromine atom.
Selected from the group consisting of: ), Hydroxyl group or 6-membered saturated heterocycle
An oxy group (where the heteroatom in the ring is a nitrogen atom or an oxygen atom)
Same or different one or two selected from the group consisting of children
It is a complex atom. ))
And even more preferably an optionally substituted C₁~
C_FourAlkyl group ｛the substituent is a phenyl group, a hydroxyl group,
J (C₁~ C_ThreeFrom alkyl) amino and piperidyl groups
Selected from the group ｝, A phenyl group which may be substituted
(The substituent is a group consisting of a fluorine atom and a chlorine atom.
Selected from ), Hydroxyl or tetrahydropyranyloxy
A sulfamoyl group which may be substituted by
Preferably, the optionally substituted C₁~ C_FourAlkyl group
Substituents include phenyl, dimethylamino, diisopro
Selected from the group consisting of a pillamino group and a piperidino group
You. ) Or sulfamoyl optionally substituted by a hydroxyl group
And most preferably a sulfamoyl group.

In the present invention, “C _6- which may be substituted”
The C ₁₀ aryl group (the substituent is selected from the substituent group δ) ”may be substituted with the same or different 1 to 5 substituents selected from the above“ substituent group δ ”. A C ₆ -C ₁₀ aryl group ”, preferably a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group which may be substituted (the substituent is a fluorine atom, a chlorine atom, a bromine atom, selected from the group consisting of carboxyl and C ₂ -C ₅ alkoxycarbonyl group.), or C ₂ ~ which is substituted
C ₄ alkenyl group [The substituent is a 5-membered unsaturated heterocyclic group which may be substituted.] The hetero atom in the ring is 1 to 3 nitrogen atoms. The substituent is a fluorine atom, a chlorine atom,
Bromine, C ₁ -C ₄ alkyl groups and which may be substituted phenyl group (said substituents are fluorine atoms,. Which selected from the group consisting of a chlorine atom and a bromine atom) selected from the group consisting of. ｝ And a C ₂ -C ₅ alkoxycarbonyl group. A C ₂ -C ₅ alkylcarbonyl group, a benzoyl group, a 6-membered saturated heterocyclic carbonyl group which may be substituted (the same or different 1 or 2 hetero atoms in the ring may be selected from the group consisting of a nitrogen atom and an oxygen atom). a to 2 heteroatoms. the substituent is a hydroxyl group.), a carboxyl group, C ₂ -C ₅ alkoxycarbonyl group, which may be substituted carbamoyl group [the substituent may be substituted C
_1- C ₆ alkyl group ｛The substituent is a phenyl group, a hydroxyl group, a di (C ₁ -C ₄ alkyl) amino group or a 6-membered saturated heterocyclic group (where the heteroatom in the ring is a nitrogen atom or an oxygen atom The same or different one or two heteroatoms selected from the group consisting of: ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is nitrogen The same or different one or two heteroatoms selected from the group consisting of atoms and oxygen atoms). A phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted. The hetero atom in the ring is 1 to 4 nitrogen atoms. The ring may be fused with a benzene ring. The substituent may be substituted C ₁ -C ₄ alkyl group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) It is. ｝, A 6-membered saturated heterocyclic group (the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and may be substituted C ₁ -C ₆ alkoxy group {the substituent is a fluorine atom, a chlorine atom, a bromine atom,
Membered saturated heterocyclic group (wherein the heteroatoms in the ring are the same or different from one another selected from the group consisting of nitrogen and oxygen atoms)
Two complex atoms. ) And di (C ₁ -C ₄ alkyl)
It is selected from the group consisting of amino groups. ｝, A C ₃ -C ₆ cycloalkoxy group, a phenoxy group which may be substituted (the substituent is selected from the group consisting of a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group), a mercapto group, a sulfo group, a sulfamoyl Group, an amino group which may be substituted. The substituent is a C ₂ -C ₅ alkylcarbonyl group, a benzoyl group, a 6-membered unsaturated heterocyclic carbonyl group (wherein the heteroatom in the ring is 1 to 3 nitrogen atoms And C ₂ -C ₅ alkoxycarbonyl groups. ｝, A ureido group which may be substituted (the substituent is selected from the group consisting of a C ₁ -C ₄ alkyl group and a phenyl group) and a thioureido group which may be substituted (the substituent is a phenyl group). A) a phenyl group which may be substituted by 1 to 5 identical or different substituents selected from the group consisting of: a fluorine atom, a chlorine atom, a bromine atom, an optionally substituted C ₁ -C ₃ alkyl groups (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a C ₂ -C ₄ alkoxycarbonyl group), an optionally substituted C ₂ -C ₄ alkenyl group [the substituent is a substituted A pyrrolyl group which may be substituted The substituent is selected from the group consisting of a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom). ｝ And C ₂
Selected from the group consisting of -C ₄ alkoxycarbonyl group. ], A benzoyl group, which may be substituted piperidyl group (said substituent is a hydroxyl group.), A carboxyl group, C ₂ -C ₄ alkoxycarbonyl group, which may be substituted carbamoyl group [the substituent is substituted Good C
₁ -C ₄ alkyl group {said substituent is a phenyl group, a hydroxyl group, selected from di (C ₁ -C ₃ alkyl) amino groups and the group consisting of piperidyl group. ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a hydroxyl group and a tetrahydropyranyloxy group. A phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted. The heteroatom in the ring is one or two nitrogen atoms. The substituent is a C ₁ -C ₃ alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom). ｝, Morpholyl group, hydroxyl group, optionally substituted C _1-
C ₃ alkoxy group—The substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a piperidyl group and a di (C ₁ -C ₃ alkyl) amino group. ｝, A mercapto group, a sulfamoyl group and an amino group which may be substituted (the substituent is
A C ₂ -C ₅ alkoxycarbonyl group. A) a phenyl group which may be substituted with the same or different 1 to 4 substituents selected from the group consisting of
A bromine atom, a C ₁ -C ₂ alkyl group which may be substituted (the substituent is a fluorine atom or a C ₂ -C ₃ alkoxycarbonyl group), a carboxyl group, a C ₂ -C ₃ alkoxycarbonyl group, A carbamoyl group {the substituent is a C ₁ -C ₄ alkyl group which may be substituted (the substituent is selected from the group consisting of a phenyl group, a dimethylamino group, a diisopropylamino group and a piperidino group); and a hydroxyl group Selected from the group consisting of }, A phenyl group, which may be substituted pyridyl group or a pyrazolyl group {said substituents may be substituted C ₁ -C ₃ alkyl group (the substituent is a fluorine atom.) Is. ｝, A hydroxyl group, a C ₁ -C ₃ alkoxy group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a piperidino group, a dimethylamino group and a diisopropylamino group), a sulfamoyl group and a substituted group An amino group (the substituent is
a t-butoxycarbonyl group. A) a phenyl group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of
Ethoxycarbonylmethyl group, carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, methylcarbamoyl group, 4-phenylbutylcarbamoyl group, 2-dimethylaminoethylcarbamoyl group,
2-diisopropylaminoethylcarbamoyl group, 2-
Group consisting of piperidinoethylcarbamoyl, 3,5-bistrifluoromethyl-1-pyrazolyl, hydroxyl, methoxy, 2-piperidinoethoxy, 2-diisopropylaminoethoxy and bis-t-butoxycarbonylamino And a phenyl group which may be substituted by one or two identical or different substituents selected from

In the present invention, “5-1 to 1 which may be substituted”
The 0-membered heterocyclic group (the substituent is selected from the substituent group δ) ”may be substituted by the same or different 1 to 4 substituents selected from the above“ substituent group δ ”. a "5 to 10-membered heterocyclic group", preferably, C ₁ -C ₆ alkyl group, a carboxyl group, C ₂ -C ₇ alkoxycarbonyl group and which may be substituted carbamoyl group [the substituent is substituted C ₁ -C ₆ alkyl group which may be substituted with 1 to 4 identical or different substituents selected from the group consisting of a hydroxyl group and a di (C ₁ -C ₆ alkyl) amino group A 5- to 6-membered unsaturated heterocyclic group wherein the heteroatoms in the ring are the same or different 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. a benzene ring or a pyridine ring fused well, C ₃ -C ₄ Alkylene may be substituted by a group.), More preferably, C ₁ -C ₄ alkyl group, carboxyl group, C ₂ -C ₅ alkoxycarbonyl group, and which may be substituted carbamoyl group [the substituent is a substituted C ₁ -C ₄ alkyl group which may be used The substituent is selected from the group consisting of a hydroxyl group and a di (C ₁ -C ₄ alkyl) amino group. ｝. A 5- or 6-membered unsaturated heterocyclic group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom 1 to 3 heteroatoms selected from the group consisting of the same or different groups, and the ring may be condensed with a pyridine ring and may be substituted with a tetramethylene group.) Carboxyl group, C
₂ -C ₄ alkoxycarbonyl group, and which may be substituted carbamoyl group [the substituent may be substituted C ₁ -C ₃ alkyl group {said substituent is a hydroxyl group and di (C ₁ -C ₃ alkyl) amino group Selected from the group consisting of ｝. ]
A 5-membered unsaturated heterocyclic group which may be substituted by the same or different 1 to 3 substituents selected from the group consisting of the same wherein the heteroatom in the ring is selected from the group consisting of a nitrogen atom and a sulfur atom Or 1 to 2 different heteroatoms.
The ring may be substituted by a tetramethylene group. )
And particularly preferably, a carboxyl group, a C ₂ -C ₃ alkoxycarbonyl group and a carbamoyl group which may be substituted. The substituent is a C ₁ -C ₂ alkyl group which may be substituted (the substituent is a hydroxyl group , A dimethylamino group and a diisopropylamino group.). The same or different 1 or 2 selected from the group consisting of｝
Or a tetrahydrobenzothienyl group or an imidazolyl group which may be substituted by a single substituent.

Since the compound represented by the formula (I) of the present invention can have an acidic carboxyl group, it can be converted to a salt by reacting with a base, and further, has a basic amino group. Can be converted into a salt by reacting with an acid. Examples of such a salt with a base include a salt with an alkali metal such as a lithium salt, a sodium salt, and a potassium salt; a calcium salt,
Salts with alkaline earth metals, such as magnesium salts; or salts with organic bases, such as ammonium salts, triethylamine salts, diisopropylamine salts, cyclohexylamine salts.

Examples of the salt with an acid include salts of inorganic acids such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate; acetate, fumarate, maleate and oxalate. Salts of carboxylic acids such as acid salts, malonates, succinates, citrates, malates; salts of sulfonic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate A salt of an amino acid such as glutamate or aspartate, and the like, preferably a salt of an inorganic acid or a salt of a carboxylic acid, more preferably a hydrochloride, a nitrate, a fumarate, a maleate or a oxalate; Acid salts can be mentioned.

Since the compound represented by the formula (I) of the present invention may have an asymmetric carbon in the molecule, there are stereoisomers each having S-coordinate and R-coordination. The invention is
Both the respective isomers and mixtures of the isomers in any proportions are included.

When the compound represented by the formula (I) of the present invention is left in the air or recrystallized, it may absorb water and become adsorbed water or form a hydrate. is there. The compound (I) of the present invention and a salt thereof are intended to include such a hydrate.

The compound (I) of the present invention may absorb some other solvent to form a solvate. Compound (I) of the present invention and salts thereof are intended to include such solvates.

(A) In the present invention, R ¹ is preferably a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₇ alkylcarbonyl group or a C ₁ -C ₆ alkylsulfonyl group. preferably a hydrogen atom or a C ₁ -C ₄ alkyl group, even more preferably more, a hydrogen atom.

(B) In the present invention, R^Two, R^Three, R^Four
And R^FiveAre preferably the same or different, a hydrogen atom,
Halogen atom, C₁~ C₆Alkyl group, C₆~ C_TenAlly
A 5- or 6-membered unsaturated heterocyclic group (a heteroatom in the ring
Is selected from the group consisting of nitrogen, oxygen and sulfur
1 to 3 hetero atoms which are the same or different
You. ), Hydroxyl group, optionally substituted C₁~ C₆Alkoxy group
(The substituent is a halogen atom and C₆~ C_TenAryl
Selected from the group consisting of ) Or C_Two~ C₇Alkylka
Carbonyl group, more preferably the same or different
Means hydrogen, fluorine, chlorine, bromine, C
₁~ C_FourAlkyl group, phenyl group, 6-membered unsaturated heterocyclic group
(The heteroatoms in the ring are 1 to 3 nitrogen atoms.
You. ), Hydroxyl group, optionally substituted C₁~ C₆Alkoxy group
(The substituent is a fluorine atom, a chlorine atom, a bromine atom and
Selected from the group consisting of phenyl groups. ) Or C_Two~ C_FiveA
A alkylcarbonyloxy group, and even more preferably,
Same or different, hydrogen atom, fluorine atom, chlorine atom,
C ₁~ C_FourAlkyl group, pyridyl group, hydroxyl group, C₁~ C_ThreeA
Lucoxy group or C_Two~ C_FourWith an alkylcarbonyloxy group
Yes, particularly preferably the same or different, a hydrogen atom, a salt
A hydrogen atom, a methyl group, a 3-pyridyl group, a methoxy group or
A ethoxy group, most preferably R^Two, R^ThreeAnd R^FiveBut
Methyl group and R^FourIs an acetoxy group; R^TwoAnd R^FiveIs a hydrogen source
Child and R^ThreeAnd R^FourIs a methoxy group; or R^Two, R^ThreeAnd R
^FiveIs a hydrogen atom and R^FourIs a chlorine atom.

(C) In the present invention, R ⁶ is preferably a hydrogen atom.

(D) In the present invention, R ⁷ and R ⁸ are
Preferably, both are hydrogen atoms.

(E) In the present invention, ... Is preferably a double bond.

(F) In the present invention, Ar is preferably a phenyl group which may be substituted [the substituent is a halogen atom, a C ₁ -C ₆ alkyl group which may be substituted; Selected from the group consisting of an atom, a carboxyl group and a C ₂ -C ₇ alkoxycarbonyl group.), A C ₂ -C ₆ alkenyl group which may be substituted, wherein the substituent is a 5- to 6-membered unsaturated heterocyclic group which may be substituted. Ring group: The hetero atoms in the ring are 1 to 3 identical or different hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
The substituents are halogen atom, C ₁ -C ₆ alkyl groups and which may be substituted phenyl group (the substituent is a halogen atom.) Selected from the group consisting of. ｝, A carboxyl group and a C ₂ -C ₇ alkoxycarbonyl group. ], C ₂ -C ₇ alkylcarbonyl group, a benzoyl group, the heteroatom in which may be substituted 5-6 membered saturated heterocyclic carbonyl group (said ring, the same or different selected from the group consisting of nitrogen atom and oxygen atom The substituent is a hydroxyl group), a carboxyl group, a C ₂ -C ₇ alkoxycarbonyl group which may be substituted (the substituent is a phenyl group), Phenoxycarbonyl group, carbamoyl group which may be substituted [The substituent is a C ₁ -C ₆ alkyl group which may be substituted.] The substituent is a phenyl group, a hydroxyl group, di (C ₁ -C ₆ alkyl)
From the group consisting of an amino group and a 5- to 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen atoms). To be elected. ｝, A phenyl group which may be substituted (the substituent is a halogen atom), a hydroxyl group and 5 to 6
Selected from the group consisting of membered saturated heterocyclic oxy groups (wherein the heteroatoms in the ring are the same or different one or two heteroatoms selected from the group consisting of nitrogen and oxygen atoms). A phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted, wherein the heteroatoms in the ring are the same or different 1
~ 4 complex atoms. The ring may be fused with a benzene or pyridine ring. The substituent is a C ₁ -C ₆ alkyl group which may be substituted (the substituent is a halogen atom). ｝, A 5- to 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and a substituted A C ₁ -C ₆ alkoxy group ｛the substituent may be a halogen atom, a 5- or 6-membered saturated heterocyclic group (wherein the hetero atom in the ring is the same or different and is selected from the group consisting of nitrogen and oxygen 1 to 2 heteroatoms) and a di (C ₁ -C ₆ alkyl) amino group. ｝, A C ₃ -C ₇ cycloalkoxy group,
Which may be substituted phenoxy group (the substituent is. Selected from the group consisting of carboxyl and C ₂ -C ₇ alkoxycarbonyl group), a mercapto group, a sulfo group, a sulfamoyl group, amino group which may be substituted {wherein the substituents The group is C
₂ -C ₇ alkylcarbonyl group, a benzoyl group, 1 5-6 membered unsaturated heterocyclic carbonyl group (hetero atoms in the ring, the nitrogen atom, different identical or selected from the group consisting of an oxygen atom and a sulfur atom Three heteroatoms) and C
Selected from the group consisting of ₂ -C ₇ alkoxycarbonyl group. ｝, An optionally substituted ureido group (the substituent is a C
Selected from the group consisting of ₁ -C ₆ alkyl group and a phenyl group. ) And a thioureido group which may be substituted (the substituent is a phenyl group). ]
Or a 5- or 6-membered unsaturated heterocyclic group which may be substituted, wherein the hetero atom in the ring is the same or different 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom . The ring may be condensed with a benzene ring or a pyridine ring may be substituted by a C ₃ -C ₄ alkylene group.
The substituent is a C ₁ -C ₆ alkyl group, a carboxyl group,
A C ₂ -C ₇ alkoxycarbonyl group and an optionally substituted carbamoyl group [the substituent is an optionally substituted C ₁ -C ₆
Alkyl group—The substituent is selected from the group consisting of a hydroxyl group and a di (C ₁ -C ₆ alkyl) amino group. ｝. ] Is selected from the group consisting of: And more preferably a phenyl group which may be substituted [the substituent is a fluorine atom, a chlorine atom, a bromine atom, a C ₁ -C ₄ alkyl group which may be substituted (the substituent is a fluorine atom, Selected from the group consisting of a chlorine atom, a bromine atom, a carboxyl group and a C ₂ -C ₅ alkoxycarbonyl group), and optionally substituted C ₂
-C ₄ alkenyl group [the substituent is optionally substituted 5
Membered heterocyclic group {the heteroatoms in the ring are 1 to 3 nitrogen atoms. The substituents are fluorine atom, chlorine atom, bromine atom, C ₁ -C ₄ alkyl groups and which may be substituted phenyl group (the substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) Selected from the group consisting of ｝ And a C ₂ -C ₅ alkoxycarbonyl group. A C ₂ -C ₅ alkylcarbonyl group, a benzoyl group, a 6-membered saturated heterocyclic carbonyl group which may be substituted (the same or different 1 or 2 hetero atoms in the ring may be selected from the group consisting of a nitrogen atom and an oxygen atom). The substituent is a hydroxyl group.), A carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group, a carbamoyl group which may be substituted [the substituent may be a C ₁ group which may be substituted. -C ₆ alkyl group ｛The substituent is a phenyl group,
A hydroxyl group, a di (C ₁ -C ₄ alkyl) amino group and a 6-membered saturated heterocyclic group (where the heteroatoms in the ring are the same or different and one or two heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom) Is selected from the group consisting of: ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a chlorine atom and a bromine atom), a hydroxyl group and a 6-membered saturated heterocyclic oxy group (where the heteroatom in the ring is nitrogen The same or different one or two heteroatoms selected from the group consisting of atoms and oxygen atoms). ], A phenyl group, 5 to 6 which may be substituted
Membered unsaturated heterocyclic group—the heteroatom in the ring is 1 to 4 nitrogen atoms. The ring may be fused with a benzene ring. The substituent may be substituted C ₁ -C ₄ alkyl group (said substituent is a fluorine atom, selected from the group consisting of chlorine atom and bromine atom.) It is. ｝, A 6-membered saturated heterocyclic group (the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and an oxygen atom), a hydroxyl group, and may be substituted A C ₁ -C ₆ alkoxy group {the substituent is a fluorine atom, a chlorine atom, a bromine atom, a 6-membered saturated heterocyclic group (the same or a hetero atom in the ring is selected from the group consisting of a nitrogen atom and an oxygen atom) And 1 to 2 different heteroatoms) and a di (C ₁ -C ₄ alkyl) amino group. ｝, C ₃ -C ₆
Cycloalkoxy group, which may be substituted phenoxy group (the substituent is selected from the group consisting of carboxyl and C ₂ -C ₅ alkoxycarbonyl group.), A mercapto group, a sulfo group, a sulfamoyl group may be substituted amino The group 置換 the substituent is a C ₂ -C ₅ alkylcarbonyl group,
A benzoyl group, a 6-membered unsaturated heterocyclic carbonyl group (the heteroatom in the ring is 1 to 3 nitrogen atoms) and C
Selected from the group consisting of ₂ -C ₅ alkoxycarbonyl group. ｝, An optionally substituted ureido group (the substituent is a C
Selected from the group consisting of ₁ -C ₄ alkyl group and phenyl group. ) And a thioureido group which may be substituted (the substituent is a phenyl group). ]
Or a 5- or 6-membered unsaturated heterocyclic group which may be substituted, wherein the hetero atom in the ring is the same or different 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom . The ring may be fused with a pyridine ring and may be substituted by a tetramethylene group. The substituent is C ₁
A C ₄ -alkyl group, a carboxyl group, a C ₂ -C ₅ alkoxycarbonyl group and an optionally substituted carbamoyl group [the substituent is an optionally substituted C ₁ -C ₄ alkyl group. It is selected from the group consisting of (C ₁ -C ₄ alkyl) amino groups. ｝. ] Is selected from the group consisting of: And even more preferably a phenyl group which may be substituted [the substituent is a fluorine atom, a chlorine atom,
A bromine atom may be substituted C ₁ -C ₃ alkyl group (said substituent is a fluorine atom. Selected from a chlorine atom, and C ₂ -C ₄ alkoxyalkyl group consisting carbonyl group), or C ₂ ~ which is substituted C ₄ alkenyl group [The substituent is a pyrrolyl group which may be substituted.] The substituent is a group consisting of a phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom). Selected from. ｝ And a C ₂ -C ₄ alkoxycarbonyl group. ], A benzoyl group, which may be substituted piperidyl group (said substituent is a hydroxyl group.), A carboxyl group, C ₂ -C ₄ alkoxycarbonyl group, which may be substituted carbamoyl group [the substituent is substituted Good C
₁ -C ₄ alkyl group {said substituent is a phenyl group, a hydroxyl group, selected from di (C ₁ -C ₃ alkyl) amino groups and the group consisting of piperidyl group. ｝, A phenyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom), a hydroxyl group and a tetrahydropyranyloxy group. A phenyl group, a 5- or 6-membered unsaturated heterocyclic group which may be substituted. The heteroatom in the ring is one or two nitrogen atoms. The substituent is a C ₁ -C ₃ alkyl group which may be substituted (the substituent is selected from the group consisting of a fluorine atom and a chlorine atom). ｝, Morpholyl group, hydroxyl group, optionally substituted C _1-
C ₃ alkoxy group—The substituent is selected from the group consisting of a fluorine atom, a chlorine atom, a piperidyl group and a di (C ₁ -C ₃ alkyl) amino group. ｝, A mercapto group, a sulfamoyl group and an amino group which may be substituted (the substituent is
A C ₂ -C ₅ alkoxycarbonyl group. ). Or a 5-membered unsaturated heterocyclic group which may be substituted [the heteroatoms in the ring are the same or different 1 or 2 heteroatoms selected from the group consisting of a nitrogen atom and a sulfur atom. The ring may be substituted by a tetramethylene group. The substituent may be a carboxyl group, a C ₂ -C ₄ alkoxycarbonyl group and a carbamoyl group which may be substituted [the substituent may be a C ₁ -C ₃ alkyl group which may be substituted. selected from the group consisting of C ₁ -C ₃ alkyl) amino groups. ｝. ] Is selected from the group consisting of: A], particularly preferably which may be substituted phenyl group [the substituent is a bromine atom, may be substituted C ₁ -C ₂ alkyl group (the substituent is a fluorine atom or a C ₂ -C ₃ alkoxy selected from the group consisting of carbonyl group.), a carboxyl group, C ₂ -C ₃ alkoxycarbonyl group, which may be substituted carbamoyl group {said substituent group is substituted C ₁ may -C ₄ alkyl group (the substituent Is selected from the group consisting of a phenyl group, a dimethylamino group, a diisopropylamino group and a piperidino group.) And a group consisting of a hydroxyl group. }, A phenyl group, which may be substituted pyridyl group or a pyrazolyl group {said substituents may be substituted C ₁ -C ₃ alkyl group (the substituent is a fluorine atom.) Is. ｝, A hydroxyl group, a C ₁ -C ₃ alkoxy group which may be substituted (the substituent is selected from the group consisting of a fluorine atom, a piperidino group, a dimethylamino group and a diisopropylamino group), a sulfamoyl group and a substituted group An amino group (the substituent is
a t-butoxycarbonyl group. ). ] Or which may be substituted tetrahydrobenzo thienyl group or an imidazolyl group [the substituent is a carboxyl group, C ₂ -C ₃ alkoxycarbonyl group, and which may be substituted carbamoyl group {said substituents may C ₁ ~ to be substituted A C ₂ alkyl group (the substituent is selected from the group consisting of a hydroxyl group, a dimethylamino group and a diisopropylamino group).か ら is selected from the group consisting of And most preferably a phenyl group which may be substituted (the substituent is a methyl group, an ethoxycarbonylmethyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group,
Phenylbutylcarbamoyl group, 2-dimethylaminoethylcarbamoyl group, 2-diisopropylaminoethylcarbamoyl group, 2-piperidinoethylcarbamoyl group, 3,5-bistrifluoromethyl-1-pyrazolyl group, hydroxyl group, methoxy group, Piperidinoethoxy group,
One or two identical or different substituents selected from the group consisting of a 2-diisopropylaminoethoxy group and a bis-t-butoxycarbonylamino group. ).

In the compound (I) of the present invention, preferably,
(1a) R¹Is a hydrogen atom, C₁~ C₆Alkyl group, C_Two
~ C₇Alkylcarbonyl group or C₁~ C₆Alkylsul
A honyl group, and (1b) R^Two, R^Three, R^FourAnd R^FiveBut,
Same or different, hydrogen atom, halogen atom, C₁~ C₆
Alkyl group, C₆~ C_TenAryl group, 5- or 6-membered unsaturated complex
A ring group (where the heteroatoms in the ring are nitrogen, oxygen,
The same or different 1 selected from the group consisting of
~ 3 complex atoms. ), Hydroxyl group, may be substituted
C₁~ C₆An alkoxy group (the substituent is a halogen atom or
And C₆~ C_TenIt is selected from the group consisting of aryl groups. )or
Is C_Two~ C₇An alkylcarbonyloxy group, (1
c) R⁶Is a hydrogen atom, and (1d) R⁷And R⁸
Are both hydrogen atoms, and (1e)......But a double bond
Or a single bond, wherein (1f) Ar is
Phenyl group [the substituent is a halogen atom;
C₁~ C₆Alkyl group (the substituent is a halogen atom,
Carboxyl group and C_Two~ C₇An alkoxycarbonyl group
Selected from the group consisting of: ), Optionally substituted C_Two~ C₆A
Alkenyl group (the substituent is a 5- or 6-membered
A saturated heterocyclic group, wherein the heteroatom in the ring is a nitrogen atom, an oxygen
Same or different selected from the group consisting of atoms and sulfur atoms
Only one to three complex atoms. The substituent is a halogen
Atom, C₁~ C₆Alkyl group and phenyl which may be substituted
(The substituent is a halogen atom.)
Selected from the group. ｝, Carboxyl group and C_Two~ C₇Al
It is selected from the group consisting of oxycarbonyl groups. ], C_Two
~ C₇Alkylcarbonyl group, benzoyl group, substituted
5- or 6-membered saturated heterocyclic carbonyl group (multiple
The elementary atom is selected from the group consisting of a nitrogen atom and an oxygen atom
One or two different heteroatoms. The place
The substituent is a hydroxyl group. ), Carboxyl group, substituted
Good C_Two~ C₇Alkoxycarbonyl group (substituent
Is a phenyl group. ), Phenoxycarbonyl group,
A carbamoyl group which may be substituted (the substituent is
Good C₁~ C₆Alkyl group ｛the substituent is phenyl
Group, hydroxyl group, di (C₁~ C₆Alkyl) amino group and 5-
A 6-membered saturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom or
The same or different 1 selected from the group consisting of
~ 2 complex atoms. Selected from the group consisting of
You. ｝, An optionally substituted phenyl group (the substituent is
Is a logen atom. ), A hydroxyl group and a 5- to 6-membered saturated heterocyclic ring
An oxy group (where the heteroatom in the ring is a nitrogen atom or an oxygen atom)
Same or different one or two selected from the group consisting of children
It is a complex atom. ). ], Fe
A 5- or 6-membered unsaturated heterocyclic group which may be substituted
Whether the heteroatoms in the ring are nitrogen, oxygen and sulfur
Same or different 1 to 4 complex selected from the group consisting of
Is an atom. The ring is condensed with a benzene ring or a pyridine ring.
May be combined. The substituent is an optionally substituted C₁~ C₆A
Alkyl group (the substituent is a halogen atom).
You. ｝, A 5- to 6-membered saturated heterocyclic group (hetero atom in the ring
Is the same selected from the group consisting of a nitrogen atom and an oxygen atom
Or 1 to 2 different heteroatoms. ), Hydroxyl,
C which may be substituted₁~ C₆Alkoxy group ｛the substituent is
Halogen atom, 5- to 6-membered saturated heterocyclic group (heterocyclic
The atom is selected from the group consisting of a nitrogen atom and an oxygen atom
1 or 2 identical or different heteroatoms. ) And di
(C₁~ C₆Alkyl) amino group
You. ｝, C _Three~ C₇Cycloalkoxy group, which may be substituted
Phenoxy group (the substituent is a carboxyl group and C_Two
~ C₇Selected from the group consisting of alkoxycarbonyl groups
You. ), Mercapto, sulfo, sulfamoyl,
An amino group which may be substituted._Two~ C₇Al
Kilcarbonyl group, benzoyl group, 5- or 6-membered unsaturated complex
A ring carbonyl group (a heteroatom in the ring is a nitrogen atom, an acid
Same or different selected from the group consisting of elemental atoms and sulfur atoms
1 to 3 complex atoms. ) And C_Two~ C₇Al
It is selected from the group consisting of oxycarbonyl groups.置換, replace
Ureido group (the substituent may be C₁~ C₆Archi
And a phenyl group. ) And place
A thioureido group which may be substituted (the substituent is phenyl
Group. ). ] Or is replaced
5- or 6-membered unsaturated heterocyclic group [hetero atom in the ring
Is selected from the group consisting of nitrogen, oxygen and sulfur
1 to 3 hetero atoms which are the same or different. This
The ring may be fused to a benzene or pyridine ring,
_Three~ C_FourIt may be substituted by an alkylene group. The substituent
Is C₁~ C₆Alkyl group, carboxyl group, C_Two~ C₇A
Lucoxycarbonyl group and optionally substituted carbamoyl
Group [the substituent is optionally substituted C₁~ C₆Alkyl group
｛The substituent is a hydroxyl group or a di (C₁~ C₆Alkyl)
It is selected from the group consisting of mino groups. ｝. Consisting of
Selected from the group. And more preferably (2a)
R¹Is a hydrogen atom or C₁~ C_FourAn alkyl group, (2
b) R^Two, R^Three, R^FourAnd R^FiveBut the same or different, water
Element atom, fluorine atom, chlorine atom, bromine atom, C₁~ C_FourA
Alkyl group, phenyl group, 6-membered unsaturated heterocyclic group (in the ring,
Are 1 to 3 nitrogen atoms. ), Hydroxyl
Group, C which may be substituted₁~ C₆Alkoxy group (substituent
Is a fluorine, chlorine, bromine or phenyl group
Selected from the group consisting of: ) Or C_Two~ C_FiveAlkyl carb
A (2c) R⁶Is a hydrogen atom
R (2d) R⁷And R⁸Are both hydrogen atoms,
(2e)......Is a double bond or a single bond, and (2
f) Ar is an optionally substituted phenyl group [substituent
Is a fluorine atom, chlorine atom, bromine atom, may be substituted
C₁~ C_FourAlkyl group (the substituent is a fluorine atom, chlorine
Atom, bromine atom, carboxyl group and C_Two~ C_FiveAlkoki
It is selected from the group consisting of a cicarbonyl group. ), Replaced
Good C_Two~ C_FourAlkenyl group (the substituent is substituted
5-membered unsaturated heterocyclic group wherein the heteroatom in the ring is 1
~ 3 nitrogen atoms. The substituent is a fluorine atom,
Chlorine atom, bromine atom, C₁~ C_FourAlkyl group and substituted
Phenyl group (the substituent may be a fluorine atom, a chlorine atom
Selected from the group consisting of hydrogen atom and bromine atom. Group consisting of)
Selected from. ｝ And C_Two~ C_FiveAlkoxycarbonyl group
Selected from the group consisting of ], C_Two~ C_FiveAlkyl carb
Nyl group, benzoyl group, optionally substituted 6-membered saturated heterocycle
A carbonyl group (where the heteroatom in the ring is a nitrogen atom or an acid
Same or different 1 to 2 selected from the group consisting of elementary atoms
Complex atoms. The substituent is a hydroxyl group.
You. ), Carboxyl group, C_Two~ C_FiveAlkoxycarboni
A carbamoyl group which may be substituted (the substituent is
C which may be substituted₁~ C₆Alkyl group--the substituent is
Enyl group, hydroxyl group, di (C₁~ C_FourAlkyl) amino group
And a 6-membered saturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom
The same or different selected from the group consisting of
1 to 2 heteroatoms. Selected from the group consisting of
You. ｝, A phenyl group which may be substituted (the substituent is
Selected from the group consisting of nitrogen, chlorine and bromine
You. ), Hydroxyl group and 6-membered saturated heterocyclic oxy group (in the said ring,
Are selected from the group consisting of nitrogen and oxygen atoms.
1 to 2 hetero atoms which are the same or different. )
Selected from the group consisting of ], A phenyl group, substituted
A good 5- to 6-membered unsaturated heterocyclic group, wherein the heteroatom in the ring is
1 to 4 nitrogen atoms. The ring is condensed with a benzene ring
May be combined. The substituent is an optionally substituted C₁~ C_FourA
Alkyl group (the substituent is a fluorine atom, a chlorine atom,
It is selected from the group consisting of elementary atoms. ). ｝, Six members
Sum heterocyclic group (where the heteroatom in the ring is nitrogen atom and oxygen
1 or 2 identical or different atoms selected from the group consisting of atoms
Is a complex atom of ), Hydroxyl group, optionally substituted C₁~
C₆An alkoxy group ｛the substituent is a fluorine atom, a chlorine atom
Atom, bromine atom, 6-membered saturated heterocyclic group (hetero atom in the ring
Is the same selected from the group consisting of a nitrogen atom and an oxygen atom
Or 1 to 2 different heteroatoms. ) And di (C
₁~ C_FourAlkyl) amino group
You. ｝, C_Three~ C₆Cycloalkoxy group, which may be substituted
Phenoxy group (the substituent is a carboxyl group and C_Two
~ C_FiveSelected from the group consisting of alkoxycarbonyl groups
You. ), Mercapto, sulfo, sulfamoyl,
An amino group which may be substituted._Two~ C_FiveAl
Killcarbonyl group, benzoyl group, 6-membered unsaturated heterocyclic group
A rubonyl group (where the heteroatom in the ring is one to three nitrogen atoms)
I am a child. ) And C_Two~ C_FiveFrom an alkoxycarbonyl group
Selected from the group ｝, An optionally substituted ureido group
(The substituent is C₁~ C_FourAlkyl and phenyl groups
Selected from the group consisting of: ) And optionally substituted thioure
Consisting of an id group (the substituent is a phenyl group).
Selected from the group. ] Or optionally substituted 5- to 6-membered unsaturated
Heterocyclic group [where the heteroatom in the ring is a nitrogen atom, an oxygen atom
The same or different selected from the group consisting of
1 to 3 complex atoms. The ring is condensed with a pyridine ring
And may be substituted by a tetramethylene group.
The substituent is C₁~ C_FourAlkyl group, carboxyl group,
C_Two~ C_FiveAlkoxycarbonyl group and optionally substituted
Rubamoyl group [the substituent is an optionally substituted C₁~ C_Four
An alkyl group {the substituent is a hydroxyl group or a di (C₁~ C_FourA
Selected from the group consisting of (alkyl) amino groups. ｝
You. ] Is selected from the group consisting of: ] And even better
Suitably, (3a) R¹Is a hydrogen atom, and (3b)
 R^Two, R^Three, R^FourAnd R^FiveAre the same or different,
Child, fluorine atom, chlorine atom, C₁~ C_FourAlkyl group, pyri
Jill group, hydroxyl group, C₁~ C_ThreeAlkoxy group or C_Two~ C_FourA
Alkylcarbonyloxy group, and (3c) R⁶But,
A hydrogen atom, and (3d) R⁷And R⁸But both are hydrogen sources
Child (3e)......Is a double bond, and (3
f) Ar is an optionally substituted phenyl group [substituent
Is a fluorine atom, chlorine atom, bromine atom, may be substituted
C₁~ C_ThreeAlkyl group (the substituent is a fluorine atom, chlorine
Atom and C_Two~ C_FourGroup consisting of alkoxycarbonyl groups
Selected from ), Optionally substituted C_Two~ C_FourAlkenyl group
[The substituent is a pyrrolyl group which may be substituted.
The substituent is a phenyl group which may be substituted (the substituent is a phenyl group).
It is selected from the group consisting of a nitrogen atom and a chlorine atom. From)
Selected from the group ｝ And C_Two~ C_FourAlkoxycarbo
Selected from the group consisting of a nyl group. ], A benzoyl group,
Piperidylcarbonyl group which may be substituted (the substituent is
It is a hydroxyl group. ), Carboxyl group, C_Two~ C_FourAlkoki
A carbamoyl group which may be substituted
The substituent is optionally substituted C₁~ C_FourAlkyl group
Substituents are phenyl, hydroxyl, di (C₁~ C_ThreeAlkyl)
Selected from the group consisting of amino groups and piperidyl groups
You. ｝, A phenyl group which may be substituted (the substituent is
It is selected from the group consisting of a nitrogen atom and a chlorine atom. ),water
From the group consisting of acid groups and tetrahydropyranyloxy groups
To be elected. A phenyl group, a 5- or 6-membered
A saturated heterocyclic group wherein the heteroatom in the ring is 1 to 2 nitrogen atoms
Is an atom. The substituent is an optionally substituted C₁~ C_ThreeA
Alkyl group (the substituent is a group consisting of a fluorine atom and a chlorine atom
Selected from the group ). ｝, Morpholyl group, water
Acid group, optionally substituted C₁~ C_ThreeAlkoxy group ｛substitution
The group is a fluorine atom, a chlorine atom, a piperidyl group and a di (C
₁~ C_ThreeAlkyl) amino group
You. ｝, Mercapto group, sulfamoyl group and substituted
Amino group (the substituent may be C_Two~ C_FiveAlkoxyka
It is a rubonyl group. ). ] Or
A 5-membered unsaturated heterocyclic group which may be substituted [heterogene in the ring;
Is selected from the group consisting of a nitrogen atom and a sulfur atom
One or two different heteroatoms. The ring is
It may be substituted by a tetramethylene group. The substituent
Is a carboxyl group, C_Two~ C_FourAlkoxycarbonyl group
And a carbamoyl group which may be substituted (the substituent is
C that may be replaced₁~ C_ThreeAlkyl group ｛the substituent is hydroxyl
Group and di (C₁~ C_ThreeAlkyl) amino group
To be elected. ｝. ] Is selected from the group consisting of: ]so
And even more preferably (4a) R¹But hydrogen
An atom, and (4b) R^Two, R^Three, R^FourAnd R^FiveBut the same
Or differently, a hydrogen atom, a chlorine atom, a methyl group,
A lysyl group, a methoxy group or an acetoxy group;
c) R⁶Is a hydrogen atom, and (4d) R⁷And R⁸
Are both hydrogen atoms, and (4e)......But a double bond
Wherein (4f) Ar is a phenyl group which may be substituted
[The substituent is a bromine atom, an optionally substituted C₁~ C_TwoA
Alkyl group (the substituent is a fluorine atom or C_Two~ C_ThreeAl
It is a carbonyl group. ), Carboxyl group, C_Two
~ C_ThreeAlkoxycarbonyl group, carba which may be substituted
Moyl group—the substituent is an optionally substituted C₁~ C_FourAl
A kill group (the substituent is a phenyl group, dimethylamino
Group, diisopropylamino group and piperidino group
Selected from the group. ) And hydroxyl group
You. ｝, Phenyl group, pyridyl group which may be substituted or
Is a pyrazolyl group. The substituent is optionally substituted C₁~
C_ThreeAlkyl group (the substituent is a fluorine atom)
It is. ｝, Hydroxyl group, optionally substituted C₁~ C_ThreeAlkoki
Si group (the substituent is a fluorine atom, a piperidino group,
Group consisting of tylamino and diisopropylamino groups
Selected from ), A sulfamoyl group and may be substituted
An amino group (the substituent is a t-butoxycarbonyl group;
is there. ). ] Or be replaced
Tetrahydrobenzothienyl group or imidazolyl
Group [the substituent is a carboxyl group, C_Two~ C_ThreeAlkoki
Sicarbonyl group and carbamoyl group which may be substituted
The substituent is an optionally substituted C₁~ C_TwoAlkyl group
Substituents include hydroxyl, dimethylamino and diisopropyl
Selected from the group consisting of ruamino groups. ). From｝
Selected from the group And particularly preferably (5
a) R¹Is a hydrogen atom, and (5b) R^Two, R^ThreePassing
And R^FiveIs a methyl group and R^FourIs an acetoxy group; R^TwoAnd R^FiveBut
Hydrogen atom and R^ThreeAnd R^FourIs a methoxy group; or R^Two, R^Three
And R^FiveIs a hydrogen atom and R^FourIs a chlorine atom, and (5c)
 R⁶Is a hydrogen atom, and (5d) R⁷And R⁸But,
Both are hydrogen atoms and (5e)......Is a double bond
Wherein (5f) Ar is an optionally substituted phenyl group (the
The substituent is a methyl group, an ethoxycarbonylmethyl group,
Ruboxyl group, methoxycarbonyl group, ethoxycarbo
Nil, carbamoyl, methylcarbamoyl, 4-
Phenylbutylcarbamoyl group, 2-dimethylamino
Tylcarbamoyl group, 2-diisopropylaminoethyl
Carbamoyl group, 2-piperidinoethylcarbamoyl
Group, 3,5-bistrifluoromethyl-1-pyrazolyl
Group, hydroxyl group, methoxy group, 2-piperidinoethoxy group,
2-diisopropylaminoethoxy group and bis-t-buto
Identical or selected from the group consisting of xycarbonylamino groups
Is one or two different substituents. ) And most favorable
Suitably, (6) 6-acetoxy-5,7,8-trime
Tyl-2H-chromen-3-carboxylic acid (3-methylca
Rubamoylphenyl) amide or 6-acetoxy-5
7,8-trimethyl-2H-chromen-3-carboxylic acid
[3- (2-diisopropylaminoethoxy) -4-me
[Toxiphenyl] amide.

The following Tables 1 to 4 show exemplary compounds of the present invention, but the present invention is not limited thereto.

[0090]

[Table 1]

[0091]

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─────────────────────────────────── Compound number R ¹ R ² R ³ R ⁴ R ⁵ Ar ─────────────────────────────────── 1-1 HHHHH Ph 1-2 HHHHHC ₆ H ₄ -2 -CO ₂ H 1-3 HHHHHC ₆ H ₄ -2-CO ₂ Me 1-4 HHHHHC ₆ H ₄ -2-CO ₂ Et 1-5 HHHHHC ₆ H ₄ -2-CO ₂ Bu 1-6 HHHHHC ₆ H ₄ -2-CO ₂ Ph 1-7 HHHHHC ₆ H ₄ -2-CO ₂ Bn 1-8 HHHHHC ₆ H ₄ -3-CO ₂ H 1-9 HHHHHC ₆ H ₄ -3-CO ₂ Me 1-10 HHHHHC ₆ H ₄ -4-CO ₂ H 1-11 HHHHHC ₆ H ₄ -4-CO ₂ Me 1-12 H Me Me AcO Me Ph 1-13 H Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 1- 14 Me Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 1-15 Et Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 1-16 Ac Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 1-17 MeSO ₂ Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 1-18 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-F 1-19 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Cl 1-20 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Br 1-21 H Me Me AcO Me C ₆ H _3- 2-CO ₂ H-3-OH 1-22 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Ph 1-23 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 1-24 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H- 3- (3-pyr) 1-25 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 1-26 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-F 1-27 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Cl 1-28 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Br 1 -29 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-OH 1-30 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (b-1) 1-31 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (b-2) 1-32 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-O-cycpen 1-33 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Ph 1-34 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 1-35 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (3-pyr) 1-36 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 1-37 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-F 1-38 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-Cl 1-39 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-Br 1-40 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-OH 1-41 H Me Me AcO Me C ₆ H ₃ -2- CO ₂ H-5-Ph 1-42 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (2-pyr) 1-43 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (3-pyr) 1-44 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (4-pyr) 1-45 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-F 1-46 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Cl 1 -47 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Br 1-48 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-OH 1-49 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Ph 1-50 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (2-pyr) 1-51 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 1-52 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (4-pyr) 1-53 H Me Me AcO Me C ₆ H-2-CO ₂ H-4,5,6-tri-OMe 1-54 H Me Me AcO Me C ₆ H ₄ -2-CO ₂ Me 1-55 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-F 1-56 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-Cl 1-57 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me -3-Br 1-58 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-OH 1-59 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-Ph 1- 60 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (2-pyr) 1-61 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (3-pyr) 1-62 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (4-pyr) 1-63 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-F 1- 64 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Cl 1-65 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Br 1-66 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-OH 1-67 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Ph 1-68 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (2-pyr) 1-69 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (3-pyr) 1-70 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (4-pyr) 1-71 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-F 1-72 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Cl 1-73 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Br 1-74 H Me Me AcO Me C ₆ H-2-CO ₂ Me-4,5,6-tri-OMe 1-75 H Me Me AcO Me C ₆ H ₃ -2,5-di-CO ₂ Me 1-76 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-OH 1-77 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Ph 1-78 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5- (2-pyr) 1-79 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me -5- (3-pyr) 1-80 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5- (4-pyr) 1-81 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-F 1-82 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Cl 1-83 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Br 1-84 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-OH 1-85 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Ph 1-86 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6- (2-pyr) 1-87 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6- (3-pyr) 1-88 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ M e-6- (4-pyr) 1-89 H Me Me AcO Me C ₆ H ₂ -2-CO ₂ Me-4,5-di-OMe 1-90 H Me Me AcO Me C ₆ H ₄ -2- CO ₂ Et 1-91 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4-OH 1-92 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-1 ) 1-93 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-2) 1-94 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4-O- cycpen 1-95 H Me Me AcO Me C 6 H 4 -2-CO 2 Bu 1-96 H Me Me AcO Me C 6 H 4 -2-CO 2 Ph 1-97 H Me Me AcO Me C 6 H 4 - 2-CO ₂ Bn 1-98 H Me Me AcO Me C ₆ H ₄ -2-CONH ₂ 1-99 H Me Me AcO Me C ₆ H ₄ -2-CONHMe 1-100 H Me Me AcO Me C ₆ H ₄ -2- (b-3) 1-101 H Me Me AcO Me C ₆ H ₄ -2- (b-4) 1-102 H Me Me AcO Me C ₆ H ₄ -2- (b-5) 1- 103 H Me Me AcO Me C ₆ H ₄ -2- (b-6) 1-104 H Me Me AcO Me C ₆ H ₄ -2- (b-7) 1-105 H Me Me AcO Me C ₆ H ₄ -2-SO ₃ H 1-106 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ H 1-107 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ Me 1-108 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ Et 1-109 H Me Me AcO Me C ₆ H ₄ -3-CONHMe 1-110 H Me Me AcO Me C ₆ H ₄ -3-CH ₂ CO ₂ H 1-111 H Me Me AcO Me C ₆ H ₄ -3-CH ₂ CO ₂ Et 1-112 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ H 1-1 13 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ Me 1-114 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ Et 1-115 H Me Me AcO Me C ₆ H ₄ -4-CONH ₂ 1-116 H Me Me AcO Me C ₆ H ₄ -4-CH ₂ CO ₂ H 1-117 H Me Me AcO Me C ₆ H ₄ -4-CH ₂ CO ₂ Et 1-118 H Me Me AcO Me C ₆ H ₃ -3-OH-4-OMe 1-119 H Me Me AcO Me C ₆ H ₃ -3- (b-1) -4-OMe 1-120 H Me Me AcO Me C ₆ H ₃ -3- (b-2) -4-OMe 1-121 H Me Me AcO Me C ₆ H ₃ -3-O-cycpen-4-OMe 1-122 H Me Me AcO Me C ₆ H ₃ -3,4-di- OMe 1-123 H Me Me AcO Me C ₆ H ₂ -3,4,5-tri-OMe 1-124 H Me Me AcO Me C ₆ H ₃ -3,5-di-CF ₃ 1-125 H Me Me AcO Me C ₆ H ₄ -4- (b-8) 1-126 H Me Me HO Me Ph 1-127 H Me Me HO Me C ₆ H ₄ -2-CO ₂ H 1-128 Me Me Me HO Me C ₆ H ₄ -2-CO ₂ H 1-129 Et Me Me HO Me C ₆ H ₄ -2-CO ₂ H 1-130 Ac Me Me HO Me C ₆ H ₄ -2-CO ₂ H 1-131 MeSO ₂ Me Me HO Me C ₆ H ₄ -2-CO ₂ H 1-132 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-F 1-133 H Me Me HO Me C ₆ H ₃ -2 -CO ₂ H-3-Cl 1-134 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-Br 1-135 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3 -OH 1-136 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-Ph 1-137 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 1-138 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (3-pyr) 1-139 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 1-140 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-F 1-141 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Cl 1-142 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Br 1-143 H Me Me HO Me C ₆ H ₃ -2 -CO ₂ H-4-OH 1-144 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-1) 1-145 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-2) 1-146 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-O-cycpen 1-147 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Ph 1-148 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 1-149 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H -4- (3-pyr) 1-150 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 1-151 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-F 1-152 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Cl 1-153 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Br 1-154 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-OH 1-155 H Me Me HO Me C ₆ H ₃ -2,5-di-CO ₂ H 1-156 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Ph 1-157 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (2-pyr) 1-158 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (3-pyr) 1-159 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (4-pyr) 1-160 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-F 1-161 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Cl 1-162 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Br 1-163 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H -6-OH 1-164 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Ph 1-165 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- (2- pyr) 1-166 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 1-167 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- ( 4-pyr) 1-168 H Me Me HO Me C ₆ H ₂ -2-CO ₂ H-4,5-di-OMe 1-169 H Me Me HO Me C ₆ H-2-CO ₂ H-4, 5,6-tri-OMe 1-170 H Me Me HO Me C ₆ H ₄ -2-CO ₂ Me 1-171 H Me Me HO Me C ₆ H ₄ -2-CO ₂ Et 1-172 H Me Me HO Me C ₆ H ₄ -3-CO ₂ H 1-173 H Me Me HO Me C ₆ H ₄ -3-CO ₂ Me 1-174 H Me Me HO Me C ₆ H ₄ -3-CO ₂ Et 1-175 H Me Me HO Me C ₆ H ₄ -3- (b-3) 1-176 H Me Me HO Me C ₆ H ₄ -4-CO ₂ H 1-177 H Me Me HO Me C ₆ H ₄ -4- CO ₂ Me 1-178 H Me Me HO Me C ₆ H ₄ -4-CO ₂ Et 1-179 H Me Me HO Me C ₆ H ₄ -4- (b-3) 1-180 HH MeO MeO H Ph 1 -181 HH MeO MeO HC ₆ H ₄ -2-CO ₂ H 1-182 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-F 1-183 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3 -Cl 1-184 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-Br 1-185 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-OH 1-186 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-Ph 1-187 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 1-188 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (3-pyr) 1-189 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 1-190 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H -4-F 1-191 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-Cl 1-192 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-Br 1-193 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-OH 1-194 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (b-1) 1-195 HH MeO MeO HC ₆ H ₃ -2 -CO ₂ H-4- (b-2) 1-196 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-O-cycpen 1-197 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H -4-Ph 1-198 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 1-199 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (3- pyr) 1-200 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 1-201 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-F 1-202 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-Cl 1-203 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-Br 1-204 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-OH 1-205 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-Ph 1-206 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5- (2-pyr) 1-207 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5- (3-pyr) 1-208 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5- (4-pyr) 1-209 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-F 1-210 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-Cl 1-211 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H -6-Br 1-212 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-OH 1-213 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-Ph 1-214 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6- (2-pyr) 1-215 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 1-216 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6- (4-pyr) 1-217 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Me 1-218 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Et 1- 219 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Bu 1-220 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Ph 1-221 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Bn 1-222 HH MeO MeO HC ₆ H ₄ -3-CO ₂ H 1-223 HH MeO MeO HC ₆ H ₄ -3-CO ₂ Me 1-224 HH MeO MeO HC ₆ H ₄ -3-CO ₂ Et 1-225 HH MeO MeO HC ₆ H ₄ -3-CONH ₂ 1-226 HH MeO MeO HC ₆ H ₄ -3-CONHMe 1-227 HH MeO MeO HC ₆ H ₄ -3- (b-3) 1-228 HH MeO MeO HC ₆ H ₄ -3- (b-4) 1-229 HH MeO MeO HC ₆ H ₄ -3- (b-9) 1-230 HH MeO MeO HC ₆ H ₄ -3- (b-10) 1-231 HH MeO MeO HC ₆ H ₄ -3- (b-5) 1-232 HH MeO MeO HC ₆ H ₄ -3-CH ₂ CO ₂ H 1-233 HH MeO MeO HC ₆ H ₄ -3-CH ₂ CO ₂ Et 1-234 HH MeO MeO HC ₆ H ₄ -4-CO ₂ H 1-235 HH MeO MeO HC ₆ H ₄ -4 -CO ₂ Me 1-236 HH MeO MeO HC ₆ H ₄ -4-CO ₂ Et 1-237 HH MeO MeO HC ₆ H ₄ -4-CH ₂ CO ₂ H 1-238 HH MeO MeO HC ₆ H ₄ -4 -CH ₂ CO ₂ Et 1-239 HH MeO MeO HC ₆ H ₃ -3- (b-2) -4-OMe 1-240 HH MeO MeO HC ₆ H ₄ -4- (b-8) 1-241 H MeO HHH Ph 1-242 H MeO HHHC ₆ H ₄ -2-CO ₂ H 1-243 H MeO HHHC ₆ H ₄ -2-CO ₂ Me 1-244 H MeO HHHC ₆ H ₄ -3-CH ₂ CO ₂ H 1-245 H MeO HHHC ₆ H ₄ -3-CH ₂ CO ₂ Et 1-246 H MeO HHHC ₆ H ₄ -4-CH ₂ CO ₂ H 1-247 H MeO HHHC ₆ H ₄ -4-CH ₂ CO ₂ Et 1-248 HHHFH Ph 1-249 HHHFHC ₆ H ₄ -2-CO ₂ H 1-250 HHHFHC ₆ H ₄ -2-CO ₂ Me 1-251 HHHFHC ₆ H ₄ -3-CH ₂ CO ₂ H 1-252 _{HHHFHC 6 H 4 -3-CH 2} CO 2 Et 1-253 HHHFHC 6 H 4 -4-CH 2 CO 2 H 1-254 HHHFHC 6 H 4 -4-CH 2 CO 2 Et 1-255 HHHFHC 6 H 4 - 4- (b-8) 1-256 HHH Cl H Ph 1-257 HHH Cl HC ₆ H ₄ -2-CO ₂ H 1-258 HHH Cl HC ₆ H ₄ -2-CO ₂ Me 1-259 HHH Cl HC ₆ H ₄ -3-CH ₂ CO ₂ H 1-260 HHH Cl HC ₆ H ₄ -3-CH ₂ CO ₂ Et 1-261 HHH Cl HC ₆ H ₄ -4-CH ₂ CO ₂ H 1-26 2 HHH Cl HC ₆ H ₄ -4-CH ₂ CO ₂ Et 1-263 HHH Cl HC ₆ H ₄ -4- (b-8) 1-264 HHH MeO H Ph 1-265 HHH MeO HC ₆ H ₄ -2 -CO ₂ H 1-266 HHH MeO HC ₆ H ₄ -2-CO ₂ Me 1-267 HHH MeO HC ₆ H ₄ -3-CH ₂ CO ₂ H 1-268 HHH MeO HC ₆ H ₄ -3-CH ₂ CO ₂ Et 1-269 HHH MeO HC ₆ H ₄ -4-CH ₂ CO ₂ H 1-270 HHH MeO HC ₆ H ₄ -4-CH ₂ CO ₂ Et 1-271 HH t-Bu HO H Ph 1-272 HH t-Bu HO HC ₆ H ₄ -2-CO ₂ H 1-273 HH t-Bu HO HC ₆ H ₄ -2-CO ₂ Me 1-274 HH t-Bu AcO HC ₆ H ₄ -2-CO ₂ H 1-275 HH t-Bu AcO HC ₆ H ₄ -2-CO ₂ Me 1-276 HH t-Bu HO t-Bu C ₆ H ₄ -2-CO ₂ H 1-277 HH t-Bu HO t- Bu C ₆ H ₄ -2-CO ₂ Me 1-278 HH t-Bu AcO t-Bu C ₆ H ₄ -2-CO ₂ H 1-279 HH t-Bu AcO t-Bu C ₆ H ₄ -2- CO ₂ Me 1-280 HH t-Bu AcO t-Bu C ₆ H ₄ -2-CH ₂ CO ₂ H 1-281 HH t-Bu AcO t-Bu C ₆ H ₄ -2-CH ₂ CO ₂ Et 1 -282 HH t-Bu AcO t-Bu C ₆ H ₄ -3-CH ₂ CO ₂ H 1-283 HH t-Bu AcO t-Bu C ₆ H ₄ -3-CH ₂ CO ₂ Et 1-284 HH t -Bu AcO t-Bu C ₆ H ₄ -4-CH ₂ CO ₂ H 1-285 HH t-Bu AcO t-Bu C ₆ H ₄ -4-CH ₂ CO ₂ Et 1-286 HHHHHC ₆ H ₃ -3 -(b-2) -4-OMe 1-287 Me Me Me AcO Me C ₆ H ₄ -2-CO ₂ Me 1-288 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-16) 1-289 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-6-OH 1-290 H Me Me AcO Me C ₆ H ₄ -3-CONHEt 1-291 H Me Me AcO Me C ₆ H ₄ -3-CONHBu 1-292 H Me Me AcO Me C ₆ H ₄ -3-CONHHx 1-293 H Me Me AcO Me C ₆ H ₄ -3-CONHBn 1-294 H Me Me AcO Me C ₆ H ₄ -3- (b-7) 1-295 H Me Me AcO Me C ₆ H ₄ -3- (b-4) 1- 296 H Me Me AcO Me C ₆ H ₄ -3-CONHPh 1-297 H Me Me AcO Me C ₆ H ₄ -3-CONH (C ₆ H ₄ -4-Cl) 1-298 H Me Me AcO Me C ₆ H ₄ -2-CONHOH 1-299 H Me Me AcO Me C ₆ H ₄ -2-CONHO (2-thp) 1-300 H Me Me AcO Me C ₆ H ₄ -2-Ac 1-301 H Me Me AcO Me C ₆ H ₄ -2-COPh 1-302 H Me Me AcO Me C ₆ H ₄ -2-Me 1-303 H Me Me AcO Me C ₆ H ₄ -2-CF ₃ 1-304 H Me Me AcO Me C ₆ H ₄ -2-CH ₂ CO ₂ Et 1-305 H Me Me AcO Me C ₆ H ₄ -2-OH 1-306 H Me Me AcO Me C ₆ H ₄ -3-OH 1-307 H Me Me AcO Me C ₆ H ₄ -3-OMe 1-308 H Me Me AcO Me C ₆ H ₄ -3-OEt 1-309 H Me Me AcO Me C ₆ H ₄ -2-OCF ₃ 1-310 H Me Me AcO Me C ₆ H ₄ -3-OiPen 1-311 H Me Me AcO Me C ₆ H ₄ -4-OPh 1-312 H Me Me AcO Me C ₆ H ₄ -4-O (C ₆ H ₄ -4-CO ₂ Et) 1-313 H M e Me AcO Me C ₆ H ₄ -3-OPh 1-314 H Me Me AcO Me C ₆ H ₄ -2-SH 1-315 H Me Me AcO Me C ₆ H ₄ -2-SO ₂ NH ₂ 1-316 H Me Me AcO Me C ₆ H ₄ -2-Br 1-317 H Me Me AcO Me C ₆ H ₄ -2-Ph 1-318 H Me Me AcO Me C ₆ H ₄ -2- (5-tez) 1 -319 H Me Me AcO Me C ₆ H ₄ -2- (2-pyr) 1-320 H Me Me AcO Me C ₆ H ₄ -2- (3-pyr) 1-321 H Me Me AcO Me C ₆ H ₄ -2- (4-pyr) 1-322 H Me Me AcO Me C ₆ H ₄ -2- (2-Bimid) 1-323 H Me Me AcO Me C ₆ H ₄ -2- (1-pip) 1 -324 H Me Me AcO Me C ₆ H ₄ -2- (4-mor) 1-325 H Me Me AcO Me C ₆ H ₄ -4- (4-mor) 1-326 H Me Me AcO Me C ₆ H ₄ -2-NH ₂ 1-327 H Me Me AcO Me C ₆ H ₄ -2-NHAc 1-328 H Me Me AcO Me C ₆ H ₄ -2-NHCOPh 1-329 H Me Me AcO Me C ₆ H ₄ -2-NHCO (2-pyr) 1-330 H Me Me AcO Me C ₆ H ₄ -2-NHCO (4-pyr) 1-331 H Me Me AcO Me C ₆ H ₄ -2-NHCO ₂ t-Bu 1-332 H Me Me AcO Me C ₆ H ₄ -2-N (CO ₂ t-Bu) ₂ 1-333 H Me Me AcO Me C ₆ H ₄ -2-NHCONHEt 1-334 H Me Me AcO Me C ₆ H ₄ -2-NHCONHPh 1-335 H Me Me AcO Me C ₆ H ₄ -2-NHCSNHPh 1-336 H Me Me AcO Me C ₆ H ₃ -2- (b-16) -4-OMe 1-337 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-1 6) 1-338 H Me Me HO Me C ₆ H ₃ -2-CO ₂ Na-4- (3-pyr) 1-339 H Me Me HO Me C ₆ H ₄ -2-CH ₂ CO ₂ H 1- 340 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-2) 1-341 H Me Me HO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-2) 1-342 H Me Me HO Me C ₆ H ₄ -4-O (C ₆ H ₄ -4-CO ₂ H) 1-343 HH MeO HHC ₆ H ₄ -2-CO ₂ H 1-344 HH MeO HHC ₆ H ₄ -2-CO ₂ Me 1-345 HH BnO HHC ₆ H ₄ -2-CO ₂ H 1-346 HH BnO HHC ₆ H ₄ -2-CO ₂ Me 1-347 HHH Me HC ₆ H ₄ -2- CO ₂ H 1-348 HHH Me HC ₆ H ₄ -2-CO ₂ Me 1-349 HHH t-Bu HC ₆ H ₄ -2-CO ₂ H 1-350 HHH t-Bu HC ₆ H ₄ -2-CO ₂ Me 1-351 HHH Ph HC ₆ H ₄ -2-CO ₂ H 1-352 HHH Ph HC ₆ H ₄ -2-CO ₂ Me 1-353 HHHF ₃ CO HC ₆ H ₄ -2-CO ₂ H 1- 354 HHHF ₃ CO HC ₆ H ₄ -2-CO ₂ Me 1-355 HHH 3-pyr HC ₆ H ₄ -2-CO ₂ H 1-356 HHH 3-pyr HC ₆ H ₄ -2-CO ₂ Me 1- 357 HHHH MeO C ₆ H ₄ -2-CO ₂ H 1-358 HHHH MeO C ₆ H ₄ -2-CO ₂ Me 1-359 H Me Me AcO Me C ₆ H ₃ -3- (b-16) -4 -OMe ───────────────────────────────────

[0093]

[Table 2]

[0094]

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─────────────────────────────────── Compound number R ¹ R ² R ³ R ⁴ R ⁵ Ar ─────────────────────────────────── 2-1 H Me Me AcO Me 2-pyr 2-2 H Me Me AcO Me 3-pyr 2-3 H Me Me AcO Me 4-pyr 2-4 H Me Me AcO Me 6-CO ₂ H-2-pyr 2-5 H Me Me AcO Me 2-CO ₂ H- 3-pyr 2-6 H Me Me AcO Me 6-CO ₂ H-3-pyr 2-7 H Me Me AcO Me 2-CO ₂ H-4-pyr 2-8 H Me Me AcO Me 4-CO ₂ H -3-pyridazinyl 2-9 H Me Me AcO Me 3-CO ₂ H-2-pyrazinyl 2-10 H Me Me AcO Me 3-CO ₂ Me-2-pyrazinyl 2-11 H Me Me AcO Me 4-CO ₂ Et-3-pyra 2-12 H Me Me AcO Me 5-CO ₂ H-4-imidazolyl 2-13 H Me Me AcO Me 5-CO ₂ t-Bu-4-imidazolyl 2-14 H Me Me AcO Me 5 -(b-3) -4-imidazolyl 2-15 H Me Me AcO Me 5- (b-4) -4-imidazolyl 2-16 H Me Me AcO Me (b-11) 2-17 H Me Me AcO Me (b-12) 2-18 H Me Me AcO Me 2-thiazolyl 2-19 H Me Me AcO Me 2-Me-4-quinolyl 2-20 HH MeO MeO H 2-Me-4-quinolyl ───── ── ───────────────────────────

[0096]

[Table 3]

[0097]

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─────────────────────────────────── Compound No. R ¹ R ² R ³ R ⁴ R ⁵ Ar ─────────────────────────────────── 3-1 H Me Me AcO Me C ₆ H ₄ -4 -{C (CO ₂ H) = CH- (b-13)} 3-2 H Me Me AcO Me C ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-14)} 3- 3 H Me Me AcO Me C ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-15)} 3-4 H Me Me AcO Me C ₆ H ₄ -4- {C (CO ₂ Et ) = CH- (b-13)} 3-5 H Me Me AcO Me C ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-14)} 3-6 H Me Me AcO Me C ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-15)} 3-7 H Me Me HO Me C ₆ H ₄ -4- {C (CO ₂ H) = CH- (b- 13)} 3-8 H Me Me HO Me C ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-14)} 3-9 H Me Me HO Me C ₆ H ₄ -4- { C (CO ₂ H) = CH- (b-15)} 3-10 H Me Me HO Me C ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-13)} 3-11 H Me Me HO Me C ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-14)} 3-12 H Me Me HO Me C ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-15)} 3-13 HH MeO MeO HC ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-13)} 3-14 HH MeO MeO HC ₆ H ₄ -4- (C (CO ₂ H) = CH- ( b-14)} 3-15 HH MeO MeO HC ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-15)} 3-16 HH MeO MeO HC ₆ H ₄ -4- {C ( CO ₂ Et) = CH- (b-13)} 3-17 HH MeO MeO HC ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-14)} 3-18 HH MeO MeO HC ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-15)} 3-19 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-13)} 3 -20 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ H) = CH- (b-14)} 3-21 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ H) = CH- ( b-15)} 3-22 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-13)} 3-23 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-14)} 3-24 HHH Cl HC ₆ H ₄ -4- {C (CO ₂ Et) = CH- (b-15)} ─────────── ────────────────────────

[0099]

[Table 4]

[0100]

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─────────────────────────────────── Compound number R ¹ R ² R ³ R ⁴ R ⁵ Ar ─────────────────────────────────── 4-1 HHHHH Ph 4-2 HHHHHC ₆ H ₄ -2 -CO ₂ H 4-3 HHHHHC ₆ H ₄ -2-CO ₂ Me 4-4 HHHHHC ₆ H ₄ -2-CO ₂ Et 4-5 HHHHHC ₆ H ₄ -2-CO ₂ Bu 4-6 HHHHHC ₆ H ₄ -2-CO ₂ Ph 4-7 HHHHHC ₆ H ₄ -2-CO ₂ Bn 4-8 HHHHHC ₆ H ₄ -3-CO ₂ H 4-9 HHHHHC ₆ H ₄ -3-CO ₂ Me 4-10 HHHHHC ₆ H ₄ -4-CO ₂ H 4-11 HHHHHC ₆ H ₄ -4-CO ₂ Me 4-12 H Me Me AcO Me Ph 4-13 H Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 4- 14 Me Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 4-15 Et Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 4-16 Ac Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 4-17 MeSO ₂ Me Me AcO Me C ₆ H ₄ -2-CO ₂ H 4-18 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-F 4-19 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Cl 4-20 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Br 4-21 H Me Me AcO Me C ₆ H _3- 2-CO ₂ H-3-OH 4-22 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3-Ph 4-23 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 4-24 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H- 3- (3-pyr) 4-25 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 4-26 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-F 4-27 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Cl 4-28 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Br 4 -29 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-OH 4-30 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (b-1) 4-31 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (b-2) 4-32 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-O-cycpen 4-33 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4-Ph 4-34 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 4-35 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (3-pyr) 4-36 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 4-37 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-F 4-38 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-Cl 4-39 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-Br 4-40 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5-OH 4-41 H Me Me AcO Me C ₆ H ₃ -2- CO ₂ H-5-Ph 4-42 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (2-pyr) 4-43 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (3-pyr) 4-44 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-5- (4-pyr) 4-45 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-F 4-46 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Cl 4 -47 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Br 4-48 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-OH 4-49 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6-Ph 4-50 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (2-pyr) 4-51 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 4-52 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ H-6- (4-pyr) 4-53 H Me Me AcO Me C ₆ H-2-CO ₂ H-4,5,6-tri-OMe 4-54 H Me Me AcO Me C ₆ H ₄ -2-CO ₂ Me 4-55 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-F 4-56 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-Cl 4-57 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me -3-Br 4-58 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-OH 4-59 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3-Ph 4- 60 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (2-pyr) 4-61 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (3-pyr) 4-62 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-3- (4-pyr) 4-63 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-F 4- 64 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Cl 4-65 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Br 4-66 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-OH 4-67 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4-Ph 4-68 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (2-pyr) 4-69 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (3-pyr) 4-70 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-4- (4-pyr) 4-71 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-F 4-72 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Cl 4-73 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Br 4-74 H Me Me AcO Me C ₆ H-2-CO ₂ Me-4,5,6-tri-OMe 4-75 H Me Me AcO Me C ₆ H ₃ -2,5-di-CO ₂ Me 4-76 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-OH 4-77 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5-Ph 4-78 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5- (2-pyr) 4-79 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me -5- (3-pyr) 4-80 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-5- (4-pyr) 4-81 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-F 4-82 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Cl 4-83 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Br 4-84 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-OH 4-85 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6-Ph 4-86 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6- (2-pyr) 4-87 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Me-6- (3-pyr) 4-88 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ M e-6- (4-pyr) 4-89 H Me Me AcO Me C ₆ H ₂ -2-CO ₂ Me-4,5-di-OMe 4-90 H Me Me AcO Me C ₆ H ₄ -2- CO ₂ Et 4-91 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4-OH 4-92 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-1 ) 4-93 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4- (b-2) 4-94 H Me Me AcO Me C ₆ H ₃ -2-CO ₂ Et-4-O- cycpen 4-95 H Me Me AcO Me C 6 H 4 -2-CO 2 Bu 4-96 H Me Me AcO Me C 6 H 4 -2-CO 2 Ph 4-97 H Me Me AcO Me C 6 H 4 - 2-CO ₂ Bn 4-98 H Me Me AcO Me C ₆ H ₄ -2-CONH ₂ 4-99 H Me Me AcO Me C ₆ H ₄ -2-CONHMe 4-100 H Me Me AcO Me C ₆ H ₄ -2- (b-3) 4-101 H Me Me AcO Me C ₆ H ₄ -2- (b-4) 4-102 H Me Me AcO Me C ₆ H ₄ -2- (b-5) 4- 103 H Me Me AcO Me C ₆ H ₄ -2- (b-6) 4-104 H Me Me AcO Me C ₆ H ₄ -2- (b-7) 4-105 H Me Me AcO Me C ₆ H ₄ -2-SO ₃ H 4-106 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ H 4-107 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ Me 4-108 H Me Me AcO Me C ₆ H ₄ -3-CO ₂ Et 4-109 H Me Me AcO Me C ₆ H ₄ -3-CONHMe 4-110 H Me Me AcO Me C ₆ H ₄ -3-CH ₂ CO ₂ H 4-111 H Me Me AcO Me C ₆ H ₄ -3-CH ₂ CO ₂ Et 4-112 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ H 4-1 13 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ Me 4-114 H Me Me AcO Me C ₆ H ₄ -4-CO ₂ Et 4-115 H Me Me AcO Me C ₆ H ₄ -4-CONH ₂ 4-116 H Me Me AcO Me C ₆ H ₄ -4-CH ₂ CO ₂ H 4-117 H Me Me AcO Me C ₆ H ₄ -4-CH ₂ CO ₂ Et 4-118 H Me Me AcO Me C ₆ H ₃ -3-OH-4-OMe 4-119 H Me Me AcO Me C ₆ H ₃ -3- (b-1) -4-OMe 4-120 H Me Me AcO Me C ₆ H ₃ -3- (b-2) -4-OMe 4-121 H Me Me AcO Me C ₆ H ₃ -3-O-cycpen-4-OMe 4-122 H Me Me AcO Me C ₆ H ₃ -3,4-di- OMe 4-123 H Me Me AcO Me C 6 H 2 -3,4,5-tri-OMe 4-124 H Me Me AcO Me C 6 H 3 -3,5-di-CF 3 4-125 H Me Me AcO Me C ₆ H ₄ -4- (b-8) 4-126 H Me Me HO Me Ph 4-127 H Me Me HO Me C ₆ H ₄ -2-CO ₂ H 4-128 Me Me Me HO Me C ₆ H ₄ -2-CO ₂ H 4-129 Et Me Me HO Me C ₆ H ₄ -2-CO ₂ H 4-130 Ac Me Me HO Me C ₆ H ₄ -2-CO ₂ H 4-131 MeSO ₂ Me Me HO Me C ₆ H ₄ -2-CO ₂ H 4-132 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-F 4-133 H Me Me HO Me C ₆ H ₃ -2 -CO ₂ H-3-Cl 4-134 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-Br 4-135 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3 -OH 4-136 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3-Ph 4-137 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 4-138 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (3-pyr) 4-139 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 4-140 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-F 4-141 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Cl 4-142 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Br 4-143 H Me Me HO Me C ₆ H ₃ -2 -CO ₂ H-4-OH 4-144 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-1) 4-145 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (b-2) 4-146 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-O-cycpen 4-147 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4-Ph 4-148 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 4-149 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H -4- (3-pyr) 4-150 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 4-151 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-F 4-152 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Cl 4-153 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Br 4-154 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-OH 4-155 H Me Me HO Me C ₆ H ₃ -2,5-di-CO ₂ H 4-156 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5-Ph 4-157 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (2-pyr) 4-158 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (3-pyr) 4-159 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-5- (4-pyr) 4-160 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-F 4-161 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Cl 4-162 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Br 4-163 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H -6-OH 4-164 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6-Ph 4-165 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- (2- pyr) 4-166 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 4-167 H Me Me HO Me C ₆ H ₃ -2-CO ₂ H-6- ( 4-pyr) 4-168 H Me Me HO Me C ₆ H ₂ -2-CO ₂ H-4,5-di-OMe 4-169 H Me Me HO Me C ₆ H-2-CO ₂ H-4, 5,6-tri-OMe 4-170 H Me Me HO Me C ₆ H ₄ -2-CO ₂ Me 4-171 H Me Me HO Me C ₆ H ₄ -2-CO ₂ Et 4-172 H Me Me HO Me C ₆ H ₄ -3-CO ₂ H 4-173 H Me Me HO Me C ₆ H ₄ -3-CO ₂ Me 4-174 H Me Me HO Me C ₆ H ₄ -3-CO ₂ Et 4-175 H Me Me HO Me C ₆ H ₄ -3- (b-3) 4-176 H Me Me HO Me C ₆ H ₄ -4-CO ₂ H 4-177 H Me Me HO Me C ₆ H ₄ -4- CO ₂ Me 4-178 H Me Me HO Me C ₆ H ₄ -4-CO ₂ Et 4-179 H Me Me HO Me C ₆ H ₄ -4- (b-3) 4-180 HH MeO MeO H Ph 4 -181 HH MeO MeO HC ₆ H ₄ -2-CO ₂ H 4-182 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-F 4-183 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3 -Cl 4-184 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-Br 4-185 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-OH 4-186 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3-Ph 4-187 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (2-pyr) 4-188 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (3-pyr) 4-189 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-3- (4-pyr) 4-190 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H -4-F 4-191 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-Cl 4-192 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-Br 4-193 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-OH 4-194 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (b-1) 4-195 HH MeO MeO HC ₆ H ₃ -2 -CO ₂ H-4- (b-2) 4-196 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4-O-cycpen 4-197 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H -4-Ph 4-198 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (2-pyr) 4-199 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (3- pyr) 4-200 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-4- (4-pyr) 4-201 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-5-F 4-202 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-Cl 4-203 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-Br 4-204 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-OH 4-205 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-Ph 4-206 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H- (2-pyr) 4-207 HH MeO MeO H C ₆ H ₃ -2-CO ₂ H- (3-pyr) 4-208 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H- (4-pyr) 4-209 HH MeO MeO HC ₆ H ₃ -2 -CO ₂ H-6-F 4-210 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-Cl 4-211 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-Br 4- 212 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-OH 4-213 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6-Ph 4-214 HH MeO MeO HC ₆ H ₃ -2 -CO ₂ H-6- (2-pyr) 4-215 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6- (3-pyr) 4-216 HH MeO MeO HC ₆ H ₃ -2-CO ₂ H-6- (4-pyr) 4-217 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Me 4-218 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Et 4-219 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Bu 4-220 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Ph 4-221 HH MeO MeO HC ₆ H ₄ -2-CO ₂ Bn 4-222 HH MeO MeO HC ₆ H ₄ -3-CO ₂ H 4-223 HH MeO MeO HC ₆ H ₄ -3-CO ₂ Me 4-224 HH MeO MeO HC ₆ H ₄ -3-CO ₂ Et 4-225 HH MeO MeO HC ₆ H ₄ -3 _{-CONH 2 4-226 HH MeO MeO HC 6} H 4 -3-CONHMe 4-227 HH MeO MeO HC 6 H 4 -3- (b-3) 4-228 HH MeO MeO HC 6 H 4 -3- (b _{-4) 4-229 HH MeO MeO HC 6} H 4 -3- (b-9) 4-230 HH MeO MeO HC 6 H 4 -3- (b-10) 4-231 HH MeO MeO HC 6 H 4 - 3- (b-5) 4-232 HH MeO MeO HC ₆ H ₄ -3-CH ₂ CO ₂ H 4-23 3 HH MeO MeO HC ₆ H ₄ -3-CH ₂ CO ₂ Et 4-234 HH MeO MeO HC ₆ H ₄ -4-CO ₂ H 4-235 HH MeO MeO HC ₆ H ₄ -4-CO ₂ Me 4- 236 HH MeO MeO HC ₆ H ₄ -4-CO ₂ Et 4-237 HH MeO MeO HC ₆ H ₄ -4-CH ₂ CO ₂ H 4-238 HH MeO MeO HC ₆ H ₄ -4-CH ₂ CO ₂ Et 4-239 HH MeO MeO HC ₆ H ₃ -3- (b-2) -4-OMe 4-240 HH MeO MeO HC ₆ H ₄ -4- (b-8) 4-241 H MeO HHH Ph 4-242 H MeO HHHC ₆ H ₄ -2-CO ₂ H 4-243 H MeO HHHC ₆ H ₄ -2-CO ₂ Me 4-244 H MeO HHHC ₆ H ₄ -3-CH ₂ CO ₂ H 4-245 H MeO HHHC ₆ H ₄ -3-CH ₂ CO ₂ Et 4-246 H MeO HHHC ₆ H ₄ -4-CH ₂ CO ₂ H 4-247 H MeO HHHC ₆ H ₄ -4-CH ₂ CO ₂ Et 4-248 HHHFH Ph 4-249 HHHFHC ₆ H ₄ -2-CO ₂ H 4-250 HHHFHC ₆ H ₄ -2-CO ₂ Me 4-251 HHHFHC ₆ H ₄ -3-CH ₂ CO ₂ H 4-252 HHHFHC ₆ H ₄ -3 -CH ₂ CO ₂ Et 4-253 HHHFHC ₆ H ₄ -4-CH ₂ CO ₂ H 4-254 HHHFHC ₆ H ₄ -4-CH ₂ CO ₂ Et 4-255 HHHFHC ₆ H ₄ -4- (b-8 ) 4-256 HHH Cl H Ph 4-257 HHH Cl HC ₆ H ₄ -2-CO ₂ H 4-258 HHH Cl HC ₆ H ₄ -2-CO ₂ Me 4-259 HHH Cl HC ₆ H ₄ -3- CH ₂ CO ₂ H 4-260 HHH Cl HC ₆ H ₄ -3-CH ₂ CO ₂ Et 4-261 HHH Cl HC ₆ H ₄ -4-CH ₂ CO ₂ H 4-262 HHH Cl HC ₆ H ₄ -4-CH ₂ CO ₂ Et 4-263 HHH Cl HC ₆ H ₄ -4- (b-8) 4-264 HHH MeO H Ph 4-265 HHH MeO HC ₆ H ₄ -2-CO ₂ H 4 -266 HHH MeO HC ₆ H ₄ -2-CO ₂ Me 4-267 HHH MeO HC ₆ H ₄ -3-CH ₂ CO ₂ H 4-268 HHH MeO HC ₆ H ₄ -3-CH ₂ CO ₂ Et 4- 269 HHH MeO HC ₆ H ₄ -4-CH ₂ CO ₂ H 4-270 HHH MeO HC ₆ H ₄ -4-CH ₂ CO ₂ Et 4-271 HH t-Bu HO H Ph 4-272 HH t-Bu HO HC ₆ H ₄ -2-CO ₂ H 4-273 HH t-Bu HO HC ₆ H ₄ -2-CO ₂ Me 4-274 HH t-Bu AcO HC ₆ H ₄ -2-CO ₂ H 4-275 HH t-Bu AcO HC ₆ H ₄ -2-CO ₂ Me 4-276 HH t-Bu HO t-Bu C ₆ H ₄ -2-CO ₂ H 4-277 HH t-Bu HO t-Bu C ₆ H ₄ -2-CO ₂ Me 4-278 HH t-Bu AcO t-Bu C ₆ H ₄ -2-CO ₂ H 4-279 HH t-Bu AcO t-Bu C ₆ H ₄ -2-CO ₂ Me ── ─────────────────────────────────
In the above table, (b-1) to (b-16) represent the following substituents. (b-1): OCH ₂ CH ₂ NMe ₂ (b-2): OCH ₂ CH ₂ N (iPr) ₂ (b-3): CONHCH ₂ CH ₂ OH (b-4): CONHCH ₂ CH ₂ NMe ₂ (b-5): CO (4-OH-1-pip) (b-6): CONH (C ₆ H ₄ -4-Cl) (b-7): CONHCH ₂ CH ₂ CH ₂ CH ₂ Ph (b -8): 3,5-di-CF ₃ -1-pyra (b-9): CONHCH ₂ CH ₂ N (iPr) ₂ (b-10): CONHCH ₂ CH ₂ (1-pip) (b-11 ): 3-CO ₂ Et-2- (4,5,6,7-tetrahydrobenzo [b] thienyl) (b-12): 3-CO ₂ H-2- (4,5,6,7-tetrahydrobenzo [ b] thienyl) (b-13): 4-Cl-1-Me-3-pyra (b-14): 1-Me-2-pyrro (b-15): 1- (C ₆ H ₅ -4- Cl) -2-pyrro (b-16): OCH ₂ CH ₂ (1-pip) Also, Me is a methyl group, Et is an ethyl group, iPr is an isopropyl group, Bu is a butyl group, and t-Bu is tert-butyl. Group, iPen is isopentyl group, Hx is hexyl group, Ac is acetyl group, cycp
en is cyclopentyl group, Ph is phenyl group, Bn is benzyl group, pyr is pyridyl group, pip is piperidyl group, pyr is pyrazolyl group, pyrro is pyrrolyl group, mor is morpholino group, th
p is a tetrahydropyranyl group, Bimid is a 1H-benzimidazolyl group, tez is a 1H-tetrazolyl group, C ₆ H ₄ -2-CO ₂ H is 2
- carboxyphenyl _{group, C 6 H-2-CO} 2 H-4,5,6-tri-OMe
Represents a 2-carboxyl-4,5,6-trimethoxyphenyl group.

Of the above Tables 1-4, preferred compounds are Compound Nos. 1-12, 1-37, 1-38, 1-54, 1-67, 1-69, 1-70,
1-74, 1-91, 1-98, 1-99, 1-100, 1-101, 1-102, 1-10
3, 1-104, 1-108, 1-109, 1-114, 1-115, 1-120, 1-12
2, 1-123, 1-125, 1-143, 1-168, 1-175, 1-179, 1-21
7, 1-224, 1-225, 1-226, 1-228, 1-229, 1-230, 1-23
1, 1-239, 1-240, 1-243, 1-257, 1-258, 1-262, 1-26
3, 1-272, 1-273, 1-286, 1-288, 1-289, 1-298, 1-29
9,1-301,1-302,1-303,1-304,1-305,1-309,1-31
4,1-315,1-316,1-317,1-319,1-320,1-321,1-32
5,1-326,1-331,1-332,1-336,1-348,1-356,2-1
4, 2-15, 2-16, 2-17 or the compound of No. 3-24, more preferably, the compound number 1-12, 1-67, 1-91, 1-98, 1-99,
1-101, 1-104, 1-108, 1-109, 1-120, 1-224, 1-225, 1
-228, 1-229, 1-230, 1-239, 1-240, 1-257, 1-262, 1-
263, 1-286, 1-289, 1-298, 1-302, 1-303, 1-305, 1-3
09, 1-315, 1-316, 1-317, 1-319, 1-320, 1-326, 1-33
1, 1-332, 1-336, 1-348, 1-356, 2-14, 2-15, 2-16 or 2-17, and even more preferably, compound No. 1-12 , 1-99, 1-101, 1-104, 1-109, 1-120, 1-240, 1
-257, 1-263, 1-286, 1-302, 1-305, 1-332, 1-336, 1-
No. 348, 2-15, 2-16 or 2-17, most preferably 6-acetoxy-5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid (3-methylcarbamoylphenyl) amide (compound No. 1-109) or 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid [3- ( 2-diisopropylaminoethoxy) -4-methoxyphenyl] amide (compound No. 1-120).

[0103]

BEST MODE FOR CARRYING OUT THE INVENTION The compound (I) of the present invention has the following A
It can be manufactured using a method shown as a method to a method F. [Method A] In the method A, the compound (I) of the present invention
^This is a method for producing a compound represented by the formula (I-1) wherein ⁶ , R ⁷ and R ⁸ are hydrogen atoms, and is represented by the following reaction formula.

[0104]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar
Has the same meaning as described above, X represents a halogen atom, and Z represents a cyano group or an ester group.

(First Step) In this step, a phenol derivative represented by the formula (1) is reacted with dichloromethyl C ₁ -C ₆ alkyl ether in a solvent in the presence of an acid to formylate the compound, and )).

The dichloromethyl C ₁ -C ₆ alkyl ether used is preferably dichloromethyl methyl ether or dichloromethyl n-butyl ether.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane; or a mixture thereof, preferably dichloromethane.

The acid used is, for example, titanium tetrachloride,
It can be a Lewis acid such as tin tetrachloride.

The amount of the dichloromethyl C ₁ -C ₆ alkyl ether to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (1).

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

(Second Step) In this step, the compound represented by the formula (2) is reacted with acrylonitrile or an acrylate ester in the presence or absence of a solvent in the presence of a base to close the ring. This is a step of producing the chromene compound represented by (3).

The acrylate used can be, for example, tert-butyl acrylate, ethyl acrylate and methyl acrylate, preferably tert-butyl acrylate.

When a solvent is used, the solvent used is
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting material to some extent. Examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane. Alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, 1,
Halogenated hydrocarbons such as 2-dichloroethane; or a mixture thereof, preferably in the absence of a solvent when using acrylonitrile, and when using an acrylate ester. , Dimethylformamide is used.

The base used is, for example, an organic base such as 1,4-diazabicyclo [2.2.2] octane or potassium t-butoxide; or an inorganic base such as sodium carbonate, potassium carbonate or cesium carbonate. It can be a base, preferably 1,4-diazabicyclo [2.2.2].
Octane or potassium carbonate.

The amount of the acrylonitrile or acrylate used is usually 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (2).

The reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in the range of from room temperature to heating, preferably from room temperature to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually from 0.5 hour to several days, preferably from 1 hour to 50 hours.

(Third Step) In this step, the compound represented by the formula (3) is hydrolyzed in a solvent in the presence of an acid or a base,
This is a step of producing a compound represented by the formula (4).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or a mixture thereof, preferably dioxane.

If an acid is used, the acid used can be, for example, hydrochloric acid or sulfuric acid.

When a base is used, the base used is
For example, it may be an inorganic base such as sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hour to several days, preferably 1 hour to 10 hours.

(Fourth Step) In this step, a catalyst is added, if necessary, in the presence or absence of a solvent, and the compound represented by the formula (4) is reacted with a halogenating agent to obtain a compound represented by the formula (4) This is a step of producing the compound represented by 5).

When a solvent is used, the solvent used is
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting material to some extent. Examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane. Dichloromethane, chloroform, 1,2
Halogenated hydrocarbons such as dichloroethane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; or a mixture thereof, preferably tetrahydrofuran or dimethylformamide, The reaction in the absence of is also preferred.

The halogenating agent used can be, for example, a chlorinating agent such as oxal chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride; or a brominating agent such as phosphorus tribromide, Preferably, it is thionyl chloride or oxal chloride.

When a catalyst is used, the catalyst used is
For example, it can be dimethylformamide.

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent. .

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hour to several days, preferably 1 hour to 10 hours.

(Fifth Step) In this step, an amine compound represented by the formula R ¹ ArNH is reacted with a compound represented by the formula (5) in the presence or absence of a solvent in the presence of a base. This is the step of producing the target compound represented by the formula (I-1).

When a solvent is used, the solvent used is
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting material to some extent. Examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane. Alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, 1,
Halogenated hydrocarbons such as 2-dichloroethane; or a mixture thereof, preferably tetrahydrofuran or dimethylacetamide, but the reaction in the absence of a solvent is also preferable.

The base used may be, for example, organic bases such as triethylamine and pyridine; or inorganic bases such as sodium hydroxide, potassium hydroxide and sodium carbonate, preferably pyridine or triethylamine. It is.

The amount of the amine compound to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to compound (5).

The reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

As the amine compound used in this step, a commercially available one may be used, or a conventional method (for example, (1)
A method of substituting an aryl halide with a corresponding amine,
(2) When R ¹ is not a hydrogen atom, a method of converting the corresponding arylamine into R ¹ and a method of (3) reductive amination are exemplified. )).

(Sixth Step) This step is a step for obtaining the compound (I-1) of the present invention directly from the compound (4). ) Is reacted with an amine compound represented by the formula R ¹ ArNH.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; esters such as formate and ethyl acetate Or a mixture thereof, preferably tetrahydrofuran or dichloromethane.

The base used can be, for example, organic bases such as triethylamine, pyridine.

The condensing agent used can be, for example, diethyl cyanophosphonate, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide or dicyclohexylcarbodiimide.

The amount of the amine compound to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to compound (4).

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hour to several days, preferably 1 hour to 10 hours.

As the amine compound used in this step, a commercially available one may be used, or a conventional method (for example, (1)
A method of substituting an aryl halide with a corresponding amine,
(2) When R ¹ is not a hydrogen atom, a method of converting the corresponding arylamine into R ¹ and a method of (3) reductive amination are exemplified. )). [Method B]
Method B is a method for producing the chromene compound (I-2) of the present invention.

[0147]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R
⁷ , R ⁸ , Ar and X have the same meanings as described above.

(Seventh Step) In this step, a compound represented by the formula R ⁷ R ⁸ C ＝ O is reacted with a compound represented by the formula (6) in a solvent in the presence of a base to cause condensation. This is a step for producing a compound represented by the formula (7).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or mixtures thereof.

The base used is, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydride; or pyrrolidine, piperazine, potassium tert.
Butoxide, organic bases such as piperidine,
Preferably, it is pyrrolidine or piperazine.

The amount of the compound represented by the formula R ⁷ R ⁸ C ＝ O is usually 0.5 to 5 molar equivalents relative to the compound (6), and preferably 0.5 to 2 molar equivalents. It is a molar equivalent. However, when pyrrolidine or piperazine is used as the base, the compound represented by the formula R ⁷ R ⁸ C ＝ O is
It can be used in an amount of 0.2 to 10 molar equivalents, and preferably 0.5 to 3 molar equivalents, relative to compound (6).

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

(Eighth Step) This step is generally carried out in Vilsmeier-
This is a reaction known as a Haak reaction, and the compound represented by the formula (7) is formylated in a solvent,
This is a step of producing a compound represented by the formula (8).

This step is performed, for example, in Organic Synthesis, C
ollective Volume 4, 539 (1963).

(Ninth Step) This step is carried out by reacting a compound of the formula (8)
In this step, the compound represented by the formula (9) is oxidized to produce a compound represented by the formula (9).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol, isopropanol and t-butyl alcohol; dimethylformamide;
Amides such as dimethylacetamide, hexamethylphosphoric triamide; dichloromethane, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane; or a mixture thereof, preferably dioxane.

The oxidizing agent used can be, for example, silver nitrate, sodium chlorite or potassium chlorite.

The reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C to 50 ° C.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

(Tenth Step) In this step, a compound represented by the formula (10) is produced by reacting a compound represented by the formula (9) with a halogenating agent in a solvent in the presence of a catalyst. This is achieved by a method similar to the above-described fourth step.

(Eleventh Step) In this step, the compound represented by the formula (10) is reacted with the compound represented by the formula R ¹ ArNH in the presence or absence of a solvent in the presence of a base. hand,
This is a step of producing the target compound represented by the formula (I-2), and is achieved by a method similar to the above-mentioned fifth step.

(Twelfth Step) This step is a step of directly obtaining the compound (I-2) of the present invention from the compound (9), and is carried out in a solvent in the presence of a base and a condensing agent to obtain the compound of the formula (9 This is achieved by reacting a compound represented by the formula ( ¹ ) with a compound represented by the formula R ¹ ArNH. This step is achieved by a method similar to the above-described sixth step. [Method C] The method C
^This is a method for producing a compound (I-3) in which ¹ is a hydrogen atom and Ar has an amide group as a substituent.

[0165]

Embedded image

Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
⁸ and X are as defined above, and Ar ^a -COO
H represents an Ar group having a carboxyl group as a substituent, and R ^a and R ^b represent a hydrogen atom or a group selected from the substituent group α.

(Thirteenth Step) In this step, the compound represented by the formula (9) is reacted with a compound represented by the formula H ₂ N—Ar ^a —COOH to form a ring of the formula (12) This is the step of producing the compound represented by This step is achieved by a method similar to the above-described sixth step.

The formula H ₂ N-Ar ^a -COOH used in this step is used.
The compound represented by is a commercially available one, or a conventional method (for example, a method of producing an amino compound by reducing the corresponding nitro compound and hydrolyzing the corresponding nitrile compound to form a carboxylic oxide compound And the like.).

(Step 14) In this step, the compound represented by the formula (10) is reacted with a compound represented by the formula H ₂ N—Ar ^a —COOH to form a ring, whereby the compound represented by the formula (12) This is the step of producing the compound represented by This step is achieved by a method similar to the above-described fifth step. (Fifteenth step) In this step, in a solvent in the presence of a condensing agent and, if necessary, in the presence of a base, a compound represented by the formula (11) in which Ar has a carboxyl group as a substituent, In this step, the compound represented by the formula (12) is produced by performing an intramolecular condensation reaction to close the ring.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or mixtures thereof.

When a base is used, the base used is
For example, it can be pyridine.

The condensing agent used can be, for example, acetic anhydride.

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

(Sixteenth Step) In this step, a compound represented by the formula (12) is converted into an amine compound represented by the formula R ^a R ^b NH in the presence or absence of a solvent in the presence of a base. This is a step of producing a compound represented by the formula (I-3) by amidation by reacting

When a solvent is used, the solvent used is
There is no particular limitation as long as it does not hinder the reaction and dissolves the starting material to some extent. Examples thereof include hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane. Alcohols such as methanol, ethanol and isopropanol; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; dichloromethane, chloroform, 1,
Halogenated hydrocarbons such as 2-dichloroethane; or a mixture thereof.

The base used can be, for example, organic bases such as triethylamine, pyridine.

The amount of the amine compound to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (12).

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range of from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hour to several days, preferably 1 hour to 10 hours. [Method D] In the method D, the ester residue of the compound of the present invention represented by the formula (I-4) having an ester residue as a substituent in the group Ar is converted into a carboxylic acid to obtain a compound represented by the formula (I- This is a method for producing a compound represented by the formula (I-7) by obtaining a compound represented by 5) and, if necessary, converting it to an amide.

[0181]

Embedded image

In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R
⁷ , R ⁸ , X, ^Ra and R ^b have the same meanings as described above, and Ar ^b —COOR ^c represents an Ar group having an alkoxycarbonyl group as a substituent (Step 17). Is
This is a step of producing a compound represented by the formula (I-5) by hydrolyzing a compound represented by the formula (I-4) in a solvent in the presence of an acid or a base.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; water; or a mixture thereof, preferably methanol, ethanol,
4-dioxane, acetone, water or a mixture thereof.

If an acid is used, the acid used can be, for example, hydrochloric acid or sulfuric acid.

When a base is used, the base used is
For example, it may be sodium hydroxide or potassium hydroxide.

The reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours.

(Eighteenth Step and Nineteenth Step) This step comprises:
A compound represented by the formula (I-5) is reacted with a halogenating agent to obtain an acid halide represented by the formula (I-6), and then an amine represented by the formula R ^a R ^b NH This is a step of producing a compound represented by the formula (I-7) by reacting the compound. This step is achieved by a method similar to the above-described fourth step and fifth step.

(Step 20) In this step, a compound represented by the formula (I-5) is reacted with a compound represented by the formula R ^a R ^b NH to give a compound represented by the formula (I-7). This is the step of producing the compound to be prepared. This step is achieved by a method similar to the above-described sixth step. [E Method] E method, a compound wherein R ¹ is represented by the formula (I-8) is a hydrogen atom, a compound wherein R ¹ is represented by the formula (I-9) is a substituent other than a hydrogen atom It is a method of manufacturing.

[0190]

Embedded image

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R
⁸ has the same meaning as described above, and R ^1a represents R ¹ other than a hydrogen atom.

(Step 21) In this step, an inorganic salt
In the presence of the group, the compound of formula (I-8) ^1aY
(Y represents a leaving group, for example, halo
Gen atom, methanesulfonic acid group or phenylsulfonic acid
Group. ) To give a compound of the formula (I-
This is a step of producing the compound represented by 9).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, heptane; ethers such as diethyl ether, tetrahydrofuran, dioxane; alcohols such as methanol, ethanol, isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; water; or a mixture thereof.

The inorganic base used can be, for example, sodium hydride, sodium hydroxide or potassium hydroxide.

The amount of the compound represented by the formula R ^1a to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 2 molar equivalents, relative to compound (I-8). is there.

The reaction temperature varies depending on the types of the starting compound, the reaction reagent and the solvent, but is usually in a range from cooling to heating, preferably from 0 ° C. to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 10 hours. [Method F] Method E is a method for producing a chroman compound by reducing a chromene compound.

[0198]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R
⁷ , R ⁸ and Ar are as defined above.

(Step 22) In this step, a compound represented by the formula (I-11) is produced by reducing the compound represented by the formula (I-10) in a solvent in the presence of a catalyst. This is the step of performing

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
For example, hydrocarbons such as benzene, toluene, xylene, hexane, and heptane; ethers such as diethyl ether, tetrahydrofuran, and dioxane; alcohols such as methanol, ethanol, and isopropanol; dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric triamide; halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; or mixtures thereof.

The catalyst used can be, for example, palladium carbon, palladium hydroxide carbon, palladium black, platinum oxide or platinum black, preferably palladium carbon.

The reaction temperature varies depending on the type of the starting compound, the reaction reagent and the solvent, but is usually in the range of from cooling to heating, preferably from room temperature to the reflux temperature of the solvent.

The reaction time varies depending on the starting compound, the reaction reagent, the type of the solvent and the reaction temperature, but is usually 0.5 hours to several days, preferably 1 hour to 1 day.

After completion of the reaction in each of the above steps, the target compound of the reaction can be collected from the reaction mixture according to a conventional method. For example, an organic solvent that does not mix with water is added to the reaction mixture or the residue obtained by distilling off the solvent of the reaction mixture,
It is obtained by washing with water and distilling off the solvent.

The compounds of the present invention have an excellent angiogenesis inhibitory activity and have no toxicity, and thus are useful as preventive and therapeutic agents for diabetic retinopathy or retinopathy.

The administration form of the compound (I) of the present invention includes, for example, oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injections or suppositories. These preparations include excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin; cellulose derivatives such as crystalline cellulose). Gum arabic; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium metasilicate aluminate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium carbonate; sulfates such as calcium sulfate Mechanical excipients), lubricants (eg, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax). Boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salts; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; And binders (for example, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients). ), Disintegrants (eg, low substituted hydroxypropyl) Cellulose derivatives such as cellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; and chemically modified starch and celluloses such as carboxymethylstarch, sodium carboxymethylstarch, and crosslinked polyvinylpyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The amount of the compound of the present invention varies depending on the condition, age, administration method and the like.
0.1 mg / kg body weight (preferably 1 mg
/ kg body weight), the upper limit is 2000 mg / kg body weight (preferably 500 mg / kg body weight), and in the case of intravenous administration, the lower limit is 0.01 mg / kg body weight (preferably 0.1 mg / kg body weight) per dose.
kg body weight), with an upper limit of 500mg / kg body weight (preferably
It is desirable to administer 50 mg / kg body weight) once or several times a day depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0210]

【Example】

[0211]

Example 1 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
Benzoic acid (Compound No. 1-13) 6-acetoxy-5,7,8-trimethyl-2H-chromene obtained in Reference Example 5
8 ml of a thionyl chloride solution of 0.50 g of 3-carboxylic acid was stirred at room temperature for 1 hour. After the solvent was distilled off from the reaction solution, it was dried under reduced pressure. The residue was dissolved in 8 ml of pyridine, 0.27 g of anthranilic acid was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off from the reaction solution, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with a 2N aqueous hydrochloric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the extract was purified by silica gel column chromatography (ethyl acetate → ethyl acetate: methanol = 85: 15) to give a melting point of 250-150
0.22 g of a yellow powder of the target compound having a temperature of 254 ° C. was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3
H, s), 2.10 (3H, s), 2.12 (3H, s), 2.35 (3H, s), 4.
97 (2H, s), 7.02 (1H, t, J = 7.7 Hz), 7.3-7.4 (1H,
m), 7.57 (1H, s), 8.05 (1H, dd, J = 1.2 and 7.4 H
z), 8.56 (1H, d, J = 8.1 Hz).

[0212]

Example 2 2-[(6,7-Dimethoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No.
1-181) 6,7-Dimethoxy-2H obtained in Reference Example 8
-Chromene-3-carboxylic acid 1.50 g, thionyl chloride 20 ml, anthranilic acid 0.96 g and pyridine 10
When the reaction was carried out in the same manner as in Example 1, the melting point was 210
0.82 g of a tan powder of the target compound having a temperature of -215 ° C
was gotten. ¹ H-NMR spectrum _{(δppm, DMSO-d 6)} 3.7
2 (3H, s), 3.77 (3H, s), 4.96 (2H, s), 6.59 (1H,
s), 6.90 (1H, s), 7.01 (1H, t, J = 7.8 Hz), 7.35
(1H, s), 7.3-7.4 (1H, m), 8.04 (1H, dd, J = 1.4 and
7.8 Hz), 8.54 (1H, d, J = 8.1 Hz).

[0213]

Example 3 3-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
Benzoic acid (Compound No. 1-106) 6- obtained in Reference Example 5
Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 700 mg, oxalyl chloride 0.
One drop of dimethylformamide was dropped into 15 ml of a 24 ml tetrahydrofuran solution. The reaction mixture was added at room temperature for 1.
After stirring for 5 hours, the solvent was distilled off from the reaction solution and dried under reduced pressure. The residue was dissolved in 12 ml of dimethylformamide, and added to 5 ml of a dimethylformamide solution of 384 mg of 3-aminobenzoic acid and 0.39 ml of triethylamine under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours, the reaction solution was added to water, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 2 → ethyl acetate) and recrystallized from n-hexane: ethyl acetate = 2: 1 to obtain a melting point of> 224. 268 mg of a yellow powder of the target compound having a temperature of ° C (dec.) Were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.09 (3H,
s), 2.16 (3H, s), 2.35 (3H, s), 4.91 (2H, s), 7.47
(1H, t, J = 7.9 Hz), 7.66 (1H, d, J = 7.9 Hz), 7.7
0 (1H, s), 8.01 (1H, d, J = 7.9 Hz), 8.29 (1H, s),
10.22 (1H, s, disappeared by addition of heavy water).

[0214]

Example 4 Ethyl 3-[(6,7-dimethoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-224) 6,7-Dimethoxy-2H obtained in Reference Example 8 -Chromene-3-carboxylic acid 100m
g, 0.04 ml of oxalyl chloride, 1 drop of dimethylformamide, 5 ml of tetrahydrofuran, 0.06 ml of 3-aminobenzoic acid ethyl ester and 0.06 ml of triethylamine, and reacted according to Example 3.
Yellow crystals of the target compound having a melting point of 132-136 ° C 1
05 mg was obtained. ¹ H-NMR spectrum (δppm, DMSO-
d ₆ ) 1.33 (3H, t, J = 7.0 Hz), 3.74 (3H, s), 3.78
(3H, s), 4.33 (2H, q, J = 7.0 Hz), 4.92 (2H, s),
6.61 (1H, s), 6.90 (1H, s), 7.4-7.5 (2H, m), 7.66
(1H, d, J = 7.8 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.34
(1H, t, J = 1.7 Hz) 10.16 (1H, s, disappeared by adding heavy water).

[0215]

Example 5 3-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
Benzoic acid ethyl ester (Compound No. 1-108) Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
2.00 g of 2H-chromen-3-carboxylic acid, 0.69 ml of oxalyl chloride, 1 drop of dimethylformamide,
55 ml of tetrahydrofuran, 1.18 ml of 3-aminobenzoic acid ethyl ester and triethylamine 1.10
When the reaction was carried out in the same manner as in Example 3, the melting point was 190.
2.48 g of a pale yellow powder of the target compound having a temperature of -191 ° C
was gotten.

[0216]

Example 6 4-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
Benzoic acid ethyl ester (Compound No. 1-114) Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
500 mg of 2H-chromen-3-carboxylic acid, 0.17 ml of oxalyl chloride, 1 drop of dimethylformamide,
30 ml of tetrahydrofuran, 330 mg of 4-aminobenzoic acid ethyl ester and 0.28 m of triethylamine
When the reaction was carried out according to Example 3 using 1
491 mg of pale yellow crystals of the target compound having a temperature of 243 ° C. were obtained.

[0219]

Example 7 4-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
Benzoic acid (Compound No. 1-112) 6- obtained in Reference Example 5
Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 700 mg, oxalyl chloride 0.
When 24 ml, 15 ml of tetrahydrofuran, 15 ml of dimethylformamide, 384 mg of 4-aminobenzoic acid and 0.39 ml of triethylamine were reacted according to Example 3, the target compound having a melting point> 250 ° C. (dec.) (4-[(6 -Acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid) as light yellow crystals 53 mg and melting point> 190 ° C (d
ec. The target compound (6-acetoxy-5,
175 mg of yellow crystals of 7,8-trimethyl-2H-chromene-3-carboxylic acid-4-aminobenzoic anhydride) were obtained.

[0218]

Example 8 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]
-5-chlorobenzoic acid methyl ester (Compound No. 1-6
4) 6-acetoxy-5,7,8- obtained in Reference Example 5
Trimethyl-2H-chromene-3-carboxylic acid 500m
g, oxalyl chloride 0.17 ml, dimethylformamide 1 drop, tetrahydrofuran 25 ml, 2-amino-5-chlorobenzoic acid methyl ester 371 mg and triethylamine 0.28 ml. 391 mg of a yellow powder of the target compound having the formula was obtained.

[0219]

Example 9 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-methylcarbamoylphenyl) amide (Compound No. 1-109) Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
2H-chromen-3-carboxylic acid 150 mg, oxalyl chloride 0.05 ml, dimethylformamide 4 m
1, tetrahydrofuran 2 ml, 3-aminobenzoylmethylamide 81 mg and triethylamine 0.08 m
When the reaction was carried out according to Example 3 using 1
137 mg of a pale yellow powder of the target compound having a temperature of 223 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01
(3H, s), 2.09 (3H, s), 2.16 (3H, s), 2.35 (3H, s),
2.79 (3H, d, J = 4.5 Hz), 4.91 (2H, s), 7.42 (1H,
t, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.71 (1H,
s), 7.92 (1H, d, J = 7.8 Hz), 8.12 (1H, t, J = 1.
7 Hz), 8.42 (1H, q, J = 4.5 Hz), 10.19 (1H, s, disappeared by addition of heavy water).

[0220]

Example 10 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4,5-dimethoxybenzoic acid methyl ester (Compound No. 1-89) 6-acetoxy- obtained in Reference Example 5
5,7,8-Trimethyl-2H-chromene-3-carboxylic acid 500 mg, oxalyl chloride 0.17 ml, dimethylformamide 1 drop, tetrahydrofuran 25 m
Using 384 mg of 1,2-amino-4,5-dimethoxybenzoic acid methyl ester and 0.28 ml of triethylamine according to Example 3, melting point was 205-20.
362 mg of a yellow powder of the target compound having a temperature of 7 ° C. were obtained.

[0221]

Example 11 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-carbamoylphenyl) amide (Compound No. 1-115) 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 150 mg, oxalyl chloride 0.05 ml, dimethylformamide 4 ml, tetrahydrofuran 2 ml, 4-aminobenzamide 80
Example 3 using mg and 0.08 ml of triethylamine
When the reaction was carried out according to the above, 39 mg of a yellow powder of the target compound having a melting point of 239-244 ° C. was obtained.

[0222]

Example 12 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4-chlorobenzoic acid methyl ester (Compound No.
1-72) 6-Acetoxy-5,7,8 obtained in Reference Example 5
-Trimethyl-2H-chromene-3-carboxylic acid 500
mg, oxalyl chloride 0.17 ml, dimethylformamide 1 drop, tetrahydrofuran 25 ml, 2-amino-4-chlorobenzoic acid methyl ester 371 mg and triethylamine 0.28 ml, and reacted according to Example 3, melting point 186-189 ° C. 297 mg of a light yellow powder of the target compound having the formula was obtained.

[0223]

Example 13 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] terephthalic acid dimethyl ester (Compound No. 1-75)
500 mg of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5,
Oxalyl chloride (0.17 ml), dimethylformamide (1 drop), tetrahydrofuran (25 ml), aminoterephthalic acid dimethyl ester (377 mg) and triethylamine (0.28 ml) were reacted according to Example 3 to give a yellow powder 51 of the target compound having a melting point of 246-248 ° C.
3 mg were obtained.

[0224]

Example 14 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4-fluorobenzoic acid (Compound No. 1-37) 6-acetoxy-5,7,8-trimethyl-2H-chromen-3- obtained in Reference Example 5 Carboxylic acid 500mg, oxalyl chloride 0.17ml, dimethylformamide 1
The reaction was carried out according to Example 3 by using drops, 20 ml of tetrahydrofuran, 330 mg of 2-amino-4-fluorobenzoic acid hydrochloride and 0.55 ml of triethylamine, and 82 mg of a yellow powder of the objective compound having a melting point> 245 ° C. (dec.) was gotten. ¹ H-NMR spectrum (δppm, DMS
Od ₆ ) 2.01 (3H, s), 2.10 (3H, s), 2.12 (3H, s), 2.
35 (3H, s), 4.96 (2H, s), 7.03 (1H, dt, J = 2.6 an
d 8.4 Hz), 7.56 (1H, s), 8.12 (1H, dd, J = 6.8 and
8.9 Hz), 8.44 (1H, dd, J = 2.6 and 12.1 Hz), 12.27
(Disappears with the addition of 1H, s, heavy water).

[0225]

Example 15 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -3,4,5-trimethoxybenzoic acid methyl ester (Compound No. 1-74) 6-acetoxy-5,7,8-trimethyl- obtained in Reference Example 5 500 mg of 2H-chromene-3-carboxylic acid, 0.17 m of oxalyl chloride
1, 1 drop of dimethylformamide, tetrahydrofuran 2
0 ml, 439 mg of methyl 2-amino-3,4,5-trimethoxybenzoate and 0.1 ml of triethylamine.
When the reaction was carried out according to Example 3 using 28 ml, the melting point was 1
Light yellow powder 555 of the target compound having a temperature of 82-183 ° C.
mg was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
2.01 (3H, s), 2.09 (3H, s), 2.13 (3H, s), 2.35 (3
H, s), 3.71 (3H, s), 3.76 (3H, s), 3.84 (3H, s),
3.86 (3H, s), 4.87 (2H, s), 7.19 (1H, s), 7.70 (1
H, s), 9.66 (1H, s, disappeared with the addition of heavy water).

[0226]

Example 16 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid phenylamide (Compound No. 1-12) 6-acetoxy-5,7,8 obtained in Reference Example 5 -Trimethyl-2H-chromene-3-carboxylic acid 500 mg, oxalyl chloride 0.17 ml,
1 drop of dimethylformamide, 18m of tetrahydrofuran
l, aniline 0.16 ml and triethylamine 0.2
When the reaction was carried out according to Example 3 using 8 ml, the melting point was 19
376m of pale yellow powder of the target compound having a temperature of 7-200 ° C
g was obtained.

[0227]

Example 17 {4-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} acetic acid ethyl ester (Compound No. 1-262) 6-chloro-2H-chromene-3-carboxylic acid 0 g, oxalyl chloride4.
14 ml, 2 drops of dimethylformamide, 300 ml of tetrahydrofuran, 10.2 g of 4-aminophenylacetic acid ethyl ester hydrochloride and 13.2 ml of triethylamine
When the reaction was carried out in accordance with Example 3, the melting point was 163-1.
17.6 g of colorless crystals of the target compound having a temperature of 65 ° C. were obtained.

[0228]

Example 18 {3-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} acetic acid ethyl ester (Compound No. 1-260) 6-chloro-2H-chromene-3-carboxylic acid 0 g, oxalyl chloride4.
14 ml, 3 drops of dimethylformamide, 300 ml of tetrahydrofuran, 10.2 g of 3-aminophenylacetic acid ethyl ester hydrochloride and 13.2 ml of triethylamine
When the reaction was carried out according to Example 3, the melting point was 95-97.
12.7 g of pale brown crystals of the target compound having a temperature of ° C. were obtained.

[0229]

Example 19 6-Chloro-2H-chromen-3-carboxylic acid [4- (3,5-bistrifluoromethylpyrazol-1-yl) phenyl] amide (Compound No. 1-26)
3) 6-chloro-2H-chromen-3-carboxylic acid
50 g, oxalyl chloride 0.21 ml, dimethylformamide 2 drops, tetrahydrofuran 25 ml, 4-
When 0.70 g of (3,5-bistrifluoromethylpyrazol-1-yl) phenylamine and 0.33 ml of triethylamine were reacted according to Example 3, white crystals of the target compound having a melting point of 179-180 ° C were obtained.
16 g were obtained.

[0230]

Example 20 6,7-Dimethoxy-2H-chromene
3-Carboxylic acid [4- (3,5-bistrifluoromethylpyrazol-1-yl) phenyl] amide (Compound No. 1-240) 6,7-dimethoxy-2 obtained in Reference Example 8
0.50 g of H-chromen-3-carboxylic acid, 0.18 ml of oxalyl chloride, 2 drops of dimethylformamide, 25 ml of tetrahydrofuran, 0.62 g of 4- (3,5-bistrifluoromethylpyrazol-1-yl) phenylamine and 0 of triethylamine When the reaction was carried out according to Example 3 using 0.30 ml, 1.00 g of a yellow crystal of the target compound having a melting point of 180 to 181 ° C. was obtained.

[0231]

Example 21 2- {4-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} -3- (4
-Chloro-1-methyl-1H-pyrazol-3-yl)
Acrylic acid ethyl ester (Compound No. 3-22) 6-chloro-2H-chromene-3-carboxylic acid 0.25 g, oxalyl chloride 0.10 ml, dimethylformamide 1
Drops, 11 ml of tetrahydrofuran, 2- (4-aminophenyl) -3- (4-chloro-1) obtained in Reference Example 13.
-Methyl-1H-pyrazol-3-yl) acrylic acid ethyl ester 0.37 g and triethylamine 0.17
When the reaction was carried out in the same manner as in Example 3, the melting point was 220
0.39 g of pale yellow crystals of the target compound having -222 ° C
was gotten.

[0232]

Example 22 2- {4-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} -3- (1
-Methyl-1H-pyrrol-2-yl) acrylic acid ethyl ester (Compound No. 3-23) 6-chloro-2H-chromene-3-carboxylic acid 0.20 g, oxalyl chloride 0.083 ml, 1 drop of dimethylformamide, tetrahydrofuran 9 ml, 2- (4-aminophenyl) -3- (1-methyl-1H-pyrrole- obtained in Reference Example 15.
The reaction was carried out according to Example 3 using 0.26 g of ethyl 2-yl) acrylate and 0.13 ml of triethylamine to obtain 0.39 g of pale yellow crystals of the target compound having a melting point of 191-193 ° C.

[0233]

Example 23 2- {4-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} -3- [1
-(4-Chlorophenyl) -1H-pyrrol-2-yl] acrylic acid ethyl ester (Compound No. 3-24) 6-
0.20 g of chloro-2H-chromen-3-carboxylic acid,
Oxalyl chloride 0.083 ml, 1 drop of dimethylformamide, 9 ml of tetrahydrofuran, 2- (4-aminophenyl) -3- [1- (4-
Chlorophenyl) -1H-pyrrol-2-yl] acrylic acid ethyl ester 0.35 g and triethylamine 0.13 ml were reacted according to Example 3 to give pale yellow crystals of the target compound having a melting point of 228-229 ° C. 49 g were obtained.

[0234]

Example 24 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [4- (3,5-
Bistrifluoromethylpyrazol-1-yl) phenyl] amide (Compound No. 1-125) 6 obtained in Reference Example 5
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, 2 drops of dimethylformamide, 20 ml of tetrahydrofuran, 4- (3,5-bistrifluoromethylpyrazole-1 -Yl) phenylamine 0.53 g
The reaction was carried out according to Example 3 using 0.25 ml of triethylamine and triethylamine to obtain 0.88 g of a pale yellow crystal of the target compound having a melting point of 171-173 ° C.

[0235]

Example 25 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3,4,5-trimethoxyphenyl) amide (Compound No. 1-123) 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, dimethylformamide 2
Drops, tetrahydrofuran 20 ml, 3,4,5-trimethoxyaniline 0.33 g and triethylamine 0.2
When the reaction was carried out according to Example 3 using 5 ml, the melting point was 17
0.80 pale yellow crystals of the target compound having a temperature of 5-176 ° C.
g was obtained.

[0236]

Example 26 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3,4-dimethoxyphenyl) amide (Compound No. 1-122) Acetoxy-5,7,8-trimethyl-2
The reaction was carried out according to Example 3 using 0.50 g of H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 2 drops of dimethylformamide, 5 ml of tetrahydrofuran, 0.28 g of 3,4-dimethoxyaniline and 0.25 ml of triethylamine. And 0.67 g of off-white crystals of the target compound having a melting point of 169-170 ° C. were obtained.

[0237]

Example 27 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4-chloro-benzoic acid (Compound No. 1-38) 6-acetoxy-5,7,8-trimethyl-2H-chromene-3 obtained in Reference Example 5. A solution of 500 mg of carboxylic acid and 0.17 ml of oxalyl chloride in tetrahydrofuran 5
One drop of dimethylformamide was added dropwise to the ml. After the reaction mixture was stirred at room temperature for 1.5 hours, the solvent was distilled off from the reaction solution and dried under reduced pressure. Residue is tetrahydrofuran 6m
309m of 2-amino-4-chlorobenzoic acid
g was added to 5 ml of a pyridine solution under ice-cooling. The reaction mixture was stirred at room temperature for 2.5 hours, and the precipitate was collected by filtration. When this precipitate is recrystallized using acetone, the melting point is> 240.
57 mg of yellow crystals of the target compound having a temperature of ° C (dec.)
was gotten. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.0
1 (3H, s), 2.10 (3H, s), 2.12 (3H, s), 2.35 (3H,
s), 4.96 (2H, s), 7.25 (1H, dd, J = 2.1 and 8.6 H
z), 7.56 (1H, s), 8.04 (1H, d, J = 8.6 Hz), 8.69 (1
H, d, J = 2.1 Hz), 12.14 (1H, s, disappeared by adding heavy water).

[0238]

Example 28 3-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] pyrazine-2-carboxylic acid methyl ester (Compound No. 2-10) 6-acetoxy-5 obtained in Reference Example 5
Using 1.0 g of 7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.55 g of oxalyl chloride, 1 drop of dimethylformamide, 20 ml of tetrahydrofuran, 0.55 g of 3-amino-pyrazine-2-carboxylic acid and 10 ml of pyridine The reaction was carried out according to Example 27 to obtain 0.39 g of a pale yellow powder of the target compound having a melting point of 195 to 198 ° C.

[0239]

Example 29 2-[(6-Chloro-2H-chromene-
3-Carbonyl) amino] benzoic acid methyl ester (Compound No. 1-258) One drop of dimethylformamide was added dropwise to 10 ml of a tetrahydrofuran solution of 1.0 g of 6-chloro-2H-chromene-3-carboxylic acid and 0.50 ml of oxalyl chloride. . After the reaction mixture was stirred at room temperature for 2 hours, the solvent was distilled off from the reaction solution and dried under reduced pressure. The residue was dissolved in 5 ml of tetrahydrofuran and added to 4 ml of a dimethylacetamide solution of 0.72 g of methyl 2-aminobenzoate under ice-cooling. The reaction mixture was stirred at room temperature for 3.6
After stirring for an hour, the mixture was left overnight. The solvent was distilled off from the reaction solution, water and diisopropyl ether were added to the obtained residue, and the mixture was made alkaline with a saturated sodium hydrogen carbonate solution and stirred at room temperature. The precipitated crystals were collected by filtration, washed with diisopropyl ether and dried to obtain 1.38 g of a pale yellow powder of the target compound having a melting point of 137 to 139 ° C. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 3.90 (3H, s), 5.06 (2
H, s), 6.93 (1H, d, J = 8.7 Hz), 7.25 (1H, m), 7.32
(1H, dd, J = 2.6 Hz, 8.7 Hz,), 7.40 (1H, s), 7.47
(1H, d, J = 2.7 Hz), 7.66 (1H, m), 7.98 (1H, dd, J
= 1.4 Hz, 8.0 Hz,), 8.34 (1H, d, J = 8.8 Hz), 11.
17 (1H, s, disappeared by adding heavy water).

[0240]

Example 30 Methyl 2-[(6,7-dimethoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-217)
Dimethoxy-2H-chromene-3-carboxylic acid 10.0
g, 3.7 ml of oxalyl chloride, 150 ml of tetrahydrofuran, 3 drops of dimethylformamide, 5.5 ml of 2-amino-benzoic acid methyl ester and 50 ml of dimethylacetamide, having a melting point of 168-169 ° C. 14.1 g of yellow crystals of the target compound were obtained.

[0241]

Example 31 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-54) 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid obtained in Reference Example 5 13.0 g, oxalyl chloride 4.1 ml, tetrahydrofuran 150 m
l, 3 drops of dimethylformamide, 6.1 ml of 2-amino-benzoic acid methyl ester and dimethylacetamide 5
When the reaction was carried out according to Example 29 using 0 ml, the melting point was 1
Yellow crystals of the target compound having a temperature of 89-190 ° C 17.5.
g was obtained.

[0242]

Example 32 3-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -1H-pyrazole-4-carboxylic acid ethyl ester (Compound No. 2-11) 6-acetoxy-5,7,8-trimethyl-2H obtained in Reference Example 5 -Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 m
l, 10 ml of tetrahydrofuran, 2 drops of dimethylformamide, 0.28 g of 3-amino-1H-pyrazole-4-carboxylic acid ethyl ester and 5 ml of dimethylacetamide were reacted according to Example 29 to give a melting point of 1.
0.73 yellow crystals of the target compound having 84-185 ° C
g was obtained.

[0243]

Example 33 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4,5,6,7-tetrahydrobenzo- [b]-
Thiophene-3-carboxylic acid ethyl ester (Compound No. 2-16) 6-acetoxy-5,7, obtained in Reference Example 5
8-Trimethyl-2H-chromene-3-carboxylic acid
50 g, oxalyl chloride 0.19 ml, tetrahydrofuran 15 ml, dimethylacetamide 5 ml, tetrahydrofuran 5 ml and 2-amino-4,5,6,7
The reaction was carried out according to Example 29 using 0.41 g of ethyl tetrahydrobenzo- [b] thiophene-3-carboxylate to obtain 0.69 g of a yellow powder of the target compound having a melting point of 226 to 228 ° C.

[0244]

Working Example 34 5-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -3H-imidazole-4-carboxylic acid-t-butyl ester (Compound No. 2-13) 6 obtained in Reference Example 5
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 5.0 g, oxalyl chloride
89 ml, tetrahydrofuran 75 ml, dimethylacetamide 75 ml, tetrahydrofuran 50 ml and 5
-Amino-3H-imidazole-4-carboxylic acid -t
When 3.32 g of -butyl ester was reacted according to Example 29, 6.04 g of a yellow powder of the target compound having a melting point of 230 to 232 ° C was obtained.

[0245]

Example 35 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4,5,6,7-tetrahydrobenzo- [b]-
Thiophene-3-carboxylic acid (Compound No. 2-17) 1.0 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5, 0.38 ml of oxalyl chloride, 15m of tetrahydrofuran
l, dimethylacetamide 15 ml, tetrahydrofuran 10 ml and 2-amino-4, obtained in Reference Example 18
5,6,7-tetrahydrobenzo- [b] thiophene-
The reaction was carried out according to Example 29 using 0.71 g of 3-carboxylic acid to obtain 1.32 g of a yellow powder of the target compound having a melting point of 250 to 254 ° C.

[0246]

Working Example 36 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- (3-pyridyl) benzoic acid methyl ester (Compound No. 1-69) 6-acetoxy-5,7,8-trimethyl- obtained in Reference Example 5 2H-chromene-3-carboxylic acid 0.10 g, oxalyl chloride 0.04 ml,
Tetrahydrofuran 1ml, dimethylacetamide 1m
l, 1 ml of tetrahydrofuran and 0.09 g of methyl 2-amino-5- (3-pyridyl) benzoate obtained in Reference Example 20 were reacted according to Example 29 to obtain a compound having a melting point of 204-208 ° C. 0.13 g of a yellow powder of the compound was obtained.

[0247]

Example 37 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5-hydroxybenzoic acid ethyl ester (Compound No. 1-91) 6-acetoxy-5 obtained in Reference Example 5
0.50 g of 7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of tetrahydrofuran, 2 drops of dimethylformamide, ethyl 2-amino-5-hydroxybenzoate obtained in Reference Example 11 When the reaction was carried out according to Example 29 using 0.33 g and 5 ml of dimethylacetamide, the melting point was 1
0.75 yellow crystals of the target compound having 92-195 ° C
g was obtained.

[0248]

Working Example 38 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] benzenesulfonic acid (Compound No. 1-105) Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
0.50 g of 2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 m of tetrahydrofuran
1, 2 drops of dimethylformamide, 0.28 g of 2-amino-benzenesulfonic acid and 5 ml of dimethylacetamide
When reacted according to Example 29, the melting point was 277-
0.52 g of pale yellow crystals of the target compound having a temperature of 280 ° C. were obtained.

[0249]

Working Example 39 2-[(6-Hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -4,5-dimethoxybenzoic acid (Compound No. 1-16
8) 2-[(6-acetoxy-) obtained in Example 10
5,7,8-Trimethyl-2H-chromen-3-carbonyl) amino] -4,5-dimethoxybenzoic acid methyl ester 200 mg, 1N aqueous sodium hydroxide solution
The reaction was carried out according to Example 43 using 7 ml and 4 ml of acetone to obtain 109 mg of a yellow powder of the target compound having a melting point of> 222 ° C. (dec.).

[0250]

Example 40 6,7-Dimethoxy-2H-chromene
3-carboxylic acid (3-methylcarbamoylphenyl) amide (Compound No. 1-226) 6,7-
Dimethoxy-2H-chromene-3-carboxylic acid 0.30
g, oxalyl chloride 0.13 ml, tetrahydrofuran 3 ml, dimethylacetamide 3 ml, tetrahydrofuran 5 ml and 3-aminobenzoylmethylamide 0.21 g. Powder 0.
21 g were obtained.

[0251]

Example 41 6,7-Dimethoxy-2H-chromene-
3-carboxylic acid [3- (2-diisopropylaminoethoxy) -4-methoxyphenyl] amide (Compound No. 1-
239) 6,7-Dimethoxy-2H- obtained in Reference Example 8
A solution of 1.00 g of chromene-3-carboxylic acid and 0.71 ml of diethyl cyanophosphonate in 20 ml of anhydrous tetrahydrofuran was stirred at room temperature for 1 hour. Then, 3- (2
-Diisopropylaminoethoxy) -4-methoxyaniline (1.13 g) and triethylamine (0.65 ml) were added, and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 9: 1) to obtain 0.25 g of the target compound as a yellow amorphous having a melting point of 50-56 ° C. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 0.99 (12H, d, J = 6.5
Hz), 2.79 (2H, t, J = 7.3 Hz), 3.02 (2H, m), 3.72
(3H, s), 3.73 (3H, s), 3.77 (3H, s), 3.80 (2H, d, J
= 7.5 Hz), 4.89 (2H, s), 6.59 (1H, s), 6.88 (1H,
s), 6.91 (1H, s), 7.27 (1H, dd, J = 2.2 Hz, 8.7Hz),
7.38 (2H, m), 9.75 (1H, s, disappeared by addition of heavy water).

[0252]

Example 42 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (2-diisopropylaminoethoxy) -4-methoxyphenyl]
Amide (Compound No. 1-120) 6-acetoxy-5,7,8-trimethyl-2H-chromene- obtained in Reference Example 5
0.50 g of 3-carboxylic acid, 0.30 ml of diethyl cyanophosphonate, 0.48 g of 3- (2-diisopropylaminoethoxy) -4-methoxyphenylamine, 0.28 ml of triethylamine, and anhydrous tetrahydrofuran 20
When the reaction was carried out in the same manner as in Example 41, the melting point was 12
Light brown powder of the target compound having a temperature of 3-125 ° C 0.15
g was obtained.

[0253]

Example 43 2-[(6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-127) 2-[(6-acetoxy-5,7,8-trimethyl-) obtained in Example 31
2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (17.0 g), a mixture of 2N aqueous potassium hydroxide solution (150 ml) and methanol (100 ml) was treated at 60 ° C.
For 1 hour. The solvent was distilled off from the reaction solution, and the obtained residue was poured into ice and neutralized with an aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration to obtain 14.6 g of the target compound as yellow crystals having a melting point of> 237 ° C (dec.). ¹ H
-NMR spectrum (δppm, DMSO-d ₆ ) 2.06 (3H, s), 2.1
3 (3H, s), 2.24 (3H, s), 4.85 (2H, s), 7.1-7.2 (1H,
m), 7.58 (1H, s), 7.6-7.7 (1H, m), 7.92 (1H, s, disappeared by adding heavy water), 8.04 (1H, dd, J = 1.4 and 7.9 H
z), 8.62 (1H, d, J = 7.9 Hz), 12.05 (1H, s, disappeared by adding heavy water), 13.88 (1H, br s, disappeared by adding heavy water).

[0254]

Example 44 2-[(6-Chloro-2H-chromene-)
3-carbonyl) amino] benzoic acid (Compound No. 1-25
7) 2-[(6-chloro-2H-) obtained in Example 29
Chromene-3-carbonyl) amino] benzoic acid methyl ester 0.95 g, 2N aqueous sodium hydroxide solution 9 m
The reaction was carried out according to Example 43 using 1 and 9 ml of methanol to obtain 0.74 g of a pale yellow powder of the target compound having a melting point of 238 to 240 ° C.

[0255]

Example 45 3-[(6,7-Dimethoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-222) 3-[(6,7-Dimethoxy) obtained in Example 4 2H-chromen-3-carbonyl) amino] benzoic acid ethyl ester (97 mg), 1N aqueous sodium hydroxide solution (0.50 ml), methanol (2 ml) and acetonitrile (2 ml) were reacted according to Example 43 to obtain a melting point.
Yellow powder 1 of the target compound having a temperature of 242 ° C. (dec.)
00 mg was obtained. ¹ H-NMR spectrum (δppm, DMSO-
d ₆ ) 3.74 (3H, s), 3.78 (3H, s), 4.92 (2H, s), 6.61
(1H, s), 6.89 (1H, s), 7.45 (1H, t, J = 8.0 Hz),
7.49 (1H, s), 7.64 (1H, d, J = 7.9 Hz), 7.97 (1H, d
d, J = 1.8 and 8.0 Hz), 8.33 (1H, t, J = 1.8 Hz), 1
0.11 (1H, s, disappeared by adding heavy water), 12.98 (1H, br s,
Disappears with the addition of heavy water).

[0256]

Example 46 6,7-Dimethoxy-2H-chromene-
3-carboxylic acid [3- (2-diisopropylaminoethylcarbamoyl) phenyl] amide (Compound No. 1-22
9) 0.40 g of 3-[(6,7-dimethoxy-2H-chromen-3-carbonyl) amino] benzoic acid obtained in Example 45, 0.12 ml of oxalyl chloride, 4 ml of tetrahydrofuran, 4 ml of dimethylacetamide, 6 ml of tetrahydrofuran When the reaction was carried out according to Example 29 using 0.22 ml of N and N, N-diisopropylethylenediamine, the target compound having an Rf value of 0.16 (silica gel thin layer chromatography; ethyl acetate: ethanol = 4: 1) was yellow. 0.37 g of amorphous was obtained.

[0257]

Example 47 2-[(6-Hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] terephthalic acid (Compound No. 1-155) 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3- obtained in Example 13 When the reaction was carried out according to Example 43 using 200 mg of carbonyl) amino] terephthalic acid dimethyl ester, 2.6 ml of 1N aqueous sodium hydroxide solution and 4 ml of acetone, the melting point was> 215 ° C. (de
c. ), 112 mg of an orange powder of the target compound having the above formula were obtained.

[0258]

Working Example 48 2-[(6-Hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -3,4,5-trimethoxybenzoic acid (Compound No.
1-169) 200 mg of 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] -3,4,5-trimethoxybenzoic acid methyl ester obtained in Example 15 The reaction was carried out according to Example 43 using 1.8 ml of a 1 N aqueous solution of sodium hydroxide and 2 ml of acetone to obtain 89 mg of orange crystals of the target compound having a melting point of 198-202 ° C.

[0259]

Example 49 2-[(6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- (3-pyridyl) benzoic acid (Compound No. 1-14
9) 2-[(6-acetoxy-) obtained in Example 36
5,7,8-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (3-pyridyl) benzoic acid methyl ester 0.90 g, 2N aqueous sodium hydroxide solution 9
The reaction was carried out in the same manner as in Example 43 using 9 ml of methanol and 9 ml of methanol to obtain 0.79 g of a yellow powder of the target compound having a melting point of 280 to 282 ° C.

[0260]

Example 50 {4-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} acetic acid (Compound No. 1-261) {4-[(6-chloro-acetic acid) obtained in Example 17 2H-Chromen-3-carbonyl) amino] phenyl} acetic acid ethyl ester 1.00 g, the target compound having a melting point of 241-245 ° C. when reacted according to Example 43 using 5 ml of 2N aqueous potassium hydroxide solution and 10 ml of ethanol. 0.93 g of pale yellow crystal was obtained.

[0261]

Example 51 {3-[(6-Chloro-2H-chromen-3-carbonyl) amino] phenyl} acetic acid (Compound No. 1-259) {3-[(6-Chloro-) obtained in Example 18 2H-Chromen-3-carbonyl) amino] phenyl} acetic acid ethyl ester (1.00 g), the target compound having a melting point of 194-198 ° C. by reacting with 5 ml of 2N aqueous potassium hydroxide solution and 10 ml of ethanol according to Example 43. 0.75 g of pale brown crystals of was obtained.

[0262]

Example 52 2-[(6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5-hydroxybenzoic acid (Compound No. 1-143) 2-[(6-acetoxy-5,7,
8-Trimethyl-2H-chromen-3-carbonyl) amino] -5-hydroxybenzoic acid ethyl ester 0.4
The reaction was carried out according to Example 43 using 5 g of 2 g of 2N aqueous potassium hydroxide solution and 5 ml of ethanol, to obtain 0.16 g of yellow crystals of the target compound having a melting point of> 195 ° C. (dec.).

[0263]

Example 53 5-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -3H-imidazole-4-carboxylic acid (Compound No. 2-12) 5-[(6-acetoxy-5,7,8-trimethyl) obtained in Example 34 2H-Chromen-3-carbonyl) amino] -3H-imidazole-4-carboxylic acid-t-butyl ester To 90 ml of 1,4-dioxane solution of 4.85 g, 90 ml of 4N hydrochloric acid-1,4-dioxane solution was added. After stirring at 50 ° C. for 5 hours, the mixture was left overnight at room temperature. The solvent was distilled off from the reaction solution, and ethyl acetate was added to the obtained residue, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration, washed with water, and then recrystallized from methanol.
55 g were obtained.

[0264]

Example 54 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid {5- [4- (2
-Dimethylaminoethylcarbamoyl)]-3H-imidazole-amide (Compound No. 2-15) 5- (6-acetoxy-5,7,8-trimethyl- obtained in Reference Example 23
2H-chromen-3-yl) -1H-imidazo [4,5
-D] [1,3] oxazin-7-one 0.50 g,
10 ml of a pyridine solution of 0.73 ml of N, N-dimethylethylenediamine was stirred at room temperature for 2 hours, and then left at room temperature overnight. The solvent was distilled off from the reaction solution, and water and diisopropyl ether were added to the obtained residue, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration, washed with water and diisopropyl ether, and dried to obtain 0.44 g of a yellow powder of the target compound having a melting point of 210-212 ° C. ¹ HN
MR spectrum _{(δppm, DMSO-d 6)} 2.01 (3H, s), 2.10
(3H, s), 2.13 (3H, s), 2.17 (6H, s), 2.35 (2H, m),
3.33 (2H, s), 4.94 (2H, s), 7.41 (1H, s), 7.58 (1
H, s), 7.81 (1H, s, disappeared by adding heavy water), 10.64 (1H,
d, J = 2.9 Hz, disappeared by adding heavy water), 12.70 (1H, s, disappeared by adding heavy water).

[0265]

Example 55 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-methylcarbamoylphenyl) amide (Compound No. 1-99) Reference Example 2
2- (6-acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d] obtained in 4
Example 5 Using 100 mg of [1,3] oxazin-4-one, 18 mg of methylamine hydrochloride and 2 ml of pyridine
By reacting according to 4, 90 mg of yellow crystals of the target compound having a melting point of 251-257 ° C. were obtained.

[0266]

Example 56 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (2-hydroxyethylcarbamoyl) phenyl] amide (Compound No. 1-100) obtained in Reference Example 24. 2- (6-acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d] [1,3] oxazin-4-one 20
0 mg, ethanolamine 0.04 ml and pyridine 4
When the reaction was carried out according to Example 54 using a solution having a melting point of 22
196 mg of a yellow powder of the target compound having a temperature of 7 to 230 ° C.
was gotten.

[0267]

Example 57 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-carbamoylphenyl) amide (Compound No. 1-98) 2- (6) obtained in Reference Example 24 -Acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d] [1,3]
Oxazin-4-one 200 mg, aqueous ammonia 0.0
The reaction was carried out according to Example 54 using 4 ml of pyridine and 4 ml of pyridine to obtain 185 mg of a yellow powder of the target compound having a melting point of 239 to 245 ° C.

[0268]

Example 58 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (2-dimethylaminoethylcarbamoyl) phenyl] amide (Compound No. 1-101) The obtained 2- (6-acetoxy-5,7,8-trimethyl-2H-chromene-3
-Yl) benzo [d] [1,3] oxazin-4-one 200 mg, N, N-dimethylethylenediamine 0.0
The reaction was carried out according to Example 54 using 6 ml and 4 ml of pyridine to obtain 212 mg of a yellow powder of the target compound having a melting point of 199-201 ° C.

[0269]

Example 59 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid {5- [4- (2
-Hydroxyethylcarbamoyl)]-3H-imidazole-amide (Compound No. 2-14) 5- (6-acetoxy-5,7,8-trimethyl-2H obtained in Reference Example 23
-Chromen-3-yl) -1H-imidazo [4,5-
d] [1,3] oxazin-7-one 0.20 g, 2-
Aminoethanol 0.036ml and pyridine solution 4m
When the reaction was carried out according to Example 54 using l, the melting point was 276.
0.18 g of a yellow powder of the target compound having a temperature of -278 ° C. was obtained.

[0270]

Example 60 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (4-hydroxypiperidine-1-carbonyl) phenyl] amide (Compound No. 1-102) Reference Example 2- (6-
Acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d] [1,3] oxazine-4-
0.20 g, 4-hydroxypiperidine hydrochloride 0.1 mg.
36 g, 0.37 ml of triethylamine in anhydrous N, N-
4 ml of the dimethylformamide solution was stirred at 120 ° C. for 2 hours. The solvent was distilled off from the reaction solution, water was added to the resulting residue, the mixture was acidified with a 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Diisopropyl ether was added to the residue obtained by distilling off the solvent from the extract, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration and dried to give a melting point of> 144.
Light yellow-brown powder of the target compound having a temperature of ℃ (softening) 0.13
g was obtained.

[0271]

Example 61 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (4-chlorophenylcarbamoyl) phenyl] amide (Compound No. 1-103) obtained in Reference Example 24. 2- (6-acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d] [1,3] oxazin-4-one.
20 g, 0.34 g of 4-chloroaniline in anhydrous 1,4-
4 ml of the dioxane solution was heated and refluxed at 120 ° C. for 5.75 hours. The solvent was distilled off from the reaction solution, water was added to the resulting residue, the mixture was acidified with a 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain 0.21 g of the target compound as yellow crystals having a melting point of 234-238 ° C.

[0272]

Example 62 6,7-Dimethoxy-2H-chromene-
3-carboxylic acid [3- (2-hydroxyethylcarbamoyl) phenyl] amide (Compound No. 1-227)
0.10 g of 3-[(6,7-dimethoxy-2H-chromen-3-carbonyl) amino] benzoic acid obtained in 5,
One drop of dimethylformamide was added dropwise to 1 ml of a tetrahydrofuran solution of 0.029 ml of oxalyl chloride.
After the reaction mixture was stirred at room temperature for 1 hour, the solvent was distilled off from the reaction solution and dried under reduced pressure. The residue was dissolved in 1 ml of tetrahydrofuran, and 0.019 ml of 2-aminoethanol was added.
Was added to 1 ml of an N, N-dimethylacetamide solution under ice-cooling. The reaction mixture was stirred at room temperature for 4.25 hours and left at room temperature overnight. The solvent was distilled off from the reaction solution, water was added to the resulting residue, the mixture was made alkaline with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (ethyl acetate) to give a melting point of 152-154.
66 mg of a pale yellow powder of the target compound having a temperature of ° C. were obtained.

[0273]

Example 63 6,7-Dimethoxy-2H-chromene
3-Carboxylic acid [3- (2-dimethylaminoethylcarbamoyl) phenyl] amide (Compound No. 1-228) 3-[(6,7-dimethoxy-2H-) obtained in Example 45
Chromen-3-carbonyl) amino] benzoic acid 0.30
g, oxalyl chloride 0.088 ml, tetrahydrofuran 3 ml, N, N-dimethylacetamide 3 ml,
When the reaction was carried out according to Example 62 using 5 ml of tetrahydrofuran and 0.10 ml of N, N-dimethylethylenediamine, 0.15 g of a yellow powder of the target compound having a melting point of> 142 ° C. (softening) was obtained.

[0274]

Example 64 6,7-Dimethoxy-2H-chromene
3-carboxylic acid [3- (2-piperidin-1-ylethylcarbamoyl) phenyl] amide (Compound No. 1-23
0) 0.30 g of 3-[(6,7-dimethoxy-2H-chromen-3-carbonyl) amino] benzoic acid obtained in Example 45, 0.088 ml of oxalyl chloride, 3 ml of tetrahydrofuran, N, N-dimethylacetamide The reaction was carried out according to Example 62 using 3 ml, 5 ml of tetrahydrofuran and 0.13 ml of N- (2-aminoethyl) piperidine, to obtain 0.27 g of a yellow powder of the target compound having a melting point of> 119 ° C. (softening). .

[0275]

Example 65 6,7-Dimethoxy-2H-chromene-
3-carboxylic acid [3- (4-hydroxypiperidine-1)
-Carbonyl) phenyl] amide (Compound No. 1-231)
3-[(6,7-dimethoxy-2) obtained in Example 45
H-chromen-3-carbonyl) amino] benzoic acid
40 g, oxalyl chloride 0.12 ml, tetrahydrofuran 4 ml, N, N-dimethylacetamide 4 m
1, 5 ml of tetrahydrofuran and 0.17 g of 4-hydroxypiperidine hydrochloride, 0.17 m of triethylamine
When the reaction was carried out according to Example 62 using l, the Rf value =
80 mg of a yellow oil of the desired compound having 0.15 (silica gel thin layer chromatography; ethyl acetate) were obtained.

[0276]

Example 66 6-Hydroxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (2-hydroxyethylcarbamoyl) phenyl] amide (Compound No. 1-175) Obtained in Example 5. 3-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid ethyl ester 200 mg
And 1 ml of ethanolamine were stirred at room temperature for 3 hours, at 50 ° C. for 3 hours, at 70 ° C. for 2.5 hours, and left overnight. Water and ethyl acetate were added to the reaction mixture, and the insolubles were collected by filtration to obtain 150 mg of a yellow powder of the target compound having a melting point of 207 to 213 ° C.

[0277]

Example 67 6-Hydroxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [4- (2-hydroxyethylcarbamoyl) phenyl] amide (Compound No. 1-179) Obtained in Example 6. 200 mg of ethyl 4-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoate
Reaction with 1 ml of ethanolamine according to Example 66 gave 135 mg of a yellow powder of the target compound having a melting point of> 150 ° C. (dec.).

[0278]

Example 68 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-hydroxy-4-methoxyphenyl) amide (Compound No. 1-118)
2.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5,
Using 0.80 ml of oxalyl chloride, 2 drops of dimethylformamide, 70 ml of tetrahydrofuran, 1.25 g of 3-hydroxy-4-methoxyaniline and 1.25 ml of triethylamine, the reaction was carried out according to Example 3,
2.00 g of yellow crystals of the target compound having a melting point of 180-184 ° C. were obtained.

[0279]

Example 69 4-[(6,7-Dimethoxy-2H-chromen-3-carbonyl) amino] -2-methylquinoline (Compound No. 2-20) 1.49 g of 2H-chromene-3-carboxylic acid,
Oxalyl chloride 0.55 ml, dimethylformamide 2 drops, tetrahydrofuran 45 ml, 4-amino-2
1.00 g of methylquinoline and 0.1 g of triethylamine.
When the reaction was carried out according to Example 3 using 88 ml, the melting point was 2
0.50 yellow crystals of the target compound having a temperature of 02-205 ° C.
g was obtained.

[0280]

Example 70 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -6-chlorobenzoic acid (Compound No. 1-19) Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
0.50 g of 2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 2 drops of dimethylformamide,
When the reaction was carried out according to Example 29 using 10 ml of tetrahydrofuran, 0.31 g of 2-amino-6-chlorobenzoic acid and 5 ml of dimethylacetamide, the melting point was 237-2.
0.73 g of white crystals of the target compound having a temperature of 38 ° C. were obtained.

[0281]

Example 71 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5-hydroxybenzoic acid (Compound No. 1-29) 6-acetoxy-5,7,8-trimethyl-2H-chromen-3- obtained in Reference Example 5 Carboxylic acid 5.00 g, oxalyl chloride 1.6 ml, dimethylformamide 3
Drops, 100 ml of tetrahydrofuran, 3.30 g of 5-hydroxyanthranilic acid and 50 of dimethylacetamide
When the reaction was carried out according to Example 29 using a solution having a melting point of 27
6.20 g of yellow crystals of the target compound having a temperature of 5-278 ° C.
was gotten.

[0282]

Example 72 3-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] pyridine (Compound No. 2-2) 6 obtained in Reference Example 5
Using 0.50 g of -acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid, 0.16 ml of oxalyl chloride, 2 drops of dimethylformamide, 10 ml of tetrahydrofuran, 0.17 g of 3-aminopyridine and 5 ml of dimethylacetamide The reaction was carried out according to Example 29 to obtain 0.64 g of the target compound as white crystals having a melting point of 217 to 219 ° C.

[0283]

Example 73 4-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] pyridine (Compound No. 2-3) 6 obtained in Reference Example 5
Using 0.50 g of -acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid, 0.16 ml of oxalyl chloride, 2 drops of dimethylformamide, 10 ml of tetrahydrofuran, 0.17 g of 4-aminopyridine and 5 ml of dimethylacetamide The reaction was carried out according to Example 29 to obtain 0.12 g of white crystals of the target compound having a melting point of 141 to 144 ° C.

[0284]

Example 74 2-[(7-t-butyl-6-hydroxy-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-273) 7-t obtained in Reference Example 27 -Butyl-6-hydroxy-2H-chromene-3-carboxylic acid 0.60 g, oxalyl chloride 0.21 ml, dimethylformamide 2 drops, tetrahydrofuran 12 ml, anthranilic acid methyl ester 0.
Example 2 using 36 g and 5 ml of dimethylacetamide
The reaction was carried out according to 9 to obtain 0.47 g of the target compound as yellow crystals having a melting point of 218-222 ° C.

[0285]

Example 75 2-[(2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-
3) 1.00 g of 2H-chromen-3-carboxylic acid, 0.50 ml of oxalyl chloride, dimethylformamide 2
Drops, tetrahydrofuran 20 ml, anthranilic acid methyl ester 0.86 g and dimethylacetamide 10 m
When the reaction was carried out according to Example 29 using 1
1.39 g of yellow crystals of the target compound having a temperature of -102 ° C. were obtained.

[0286]

Example 76: 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3,5-bis-
Trifluoromethyl-phenyl) -amide (compound number
1-124) 6-acetoxy-5,7, obtained in Reference Example 5
8-Trimethyl-2H-chromene-3-carboxylic acid
Using 50 g, 0.19 ml of oxalyl chloride, 10 ml of tetrahydrofuran, 10 ml of dimethylacetamide, 5 ml of tetrahydrofuran and 0.31 ml of 3,5-bis (trifluoromethyl) aniline according to Example 29, and have a melting point of 241-245 ° C. 0.80 g of a pale yellow powder of the target compound was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.10 (3H, s), 2.1
7 (3H, s), 2.36 (3H, s), 4.92 (2H, s), 7.75 (1H,
s), 7.80 (1H, s), 8.43 (2H, s), 10.62 (1H, s, disappeared by adding heavy water).

[0287]

Example 77 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] pyridine (Compound No. 2-1) 6 obtained in Reference Example 5
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (0.50 g), 2-aminopyridine (0.17 g), triethylamine (0.28 ml) in anhydrous tetrahydrofuran (10 ml) were added with 10 ml of diethyl cyanophosphonate under ice-cooling. Then, the mixture was stirred at room temperature for 6 hours. After leaving overnight, the solvent was distilled off from the reaction solution, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 3: 1). Diisopropyl ether was added to the obtained crystals, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration and dried to obtain 0.14 g of light brown crystals of the target compound having a melting point of 142 to 145 ° C.

[0288]

Working Example 78 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] thiazole (Compound No. 2-18) 0.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid obtained in Reference Example 5 0.18 g of 2-aminothiazole, 0.28 ml of triethylamine, 10 ml of anhydrous tetrahydrofuran solution and 0.30 ml of diethyl cyanophosphonate were reacted in the same manner as in Example 77 to give a pale yellow color of the target compound having a melting point of 205-207 ° C. 0.36 g of crystals were obtained.

[0289]

Example 79 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- [2- (diisopropylamino) ethoxy]
Benzoic acid ethyl ester (Compound No. 1-93) Example 37
2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino]-obtained in
0.50 g of 5-hydroxybenzoic acid ethyl ester, 2
-0.20 ml of diisopropylaminoethanol, 1,
0.57 g of 1'-azodicarbonyldipiperidine and 0.57 ml of tributylphosphine in anhydrous toluene 2
Ultrasonic vibration was applied to 0 ml at room temperature for 3 hours, followed by stirring at room temperature for 5 hours. After leaving overnight, the solvent was distilled off from the reaction solution from which the insoluble matter was removed by filtration, and the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → ethyl acetate), Melting point 114-115
0.34 g of yellow crystals of the target compound having a temperature of 0.3 ° C. were obtained.

[0290]

Example 80 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-cyclopentyloxy-4-methoxyphenyl) amide (Compound No. 1-121) Obtained in Example 68 6-acetoxy-5
7,8-Trimethyl-2H-chromen-3-carboxylic acid (3-hydroxy-4-methoxyphenyl) amide
50 g, cyclopentanol 0.11 ml, 1,1′-
Azodicarbonyl dipiperidine 0.63 g, tributylphosphine 0.63 ml and anhydrous toluene solution 20 ml
When the reaction was carried out according to Example 79, the melting point was 167-
0.46 g of yellow crystals of the target compound having a temperature of 170 ° C. were obtained.

[0291]

Example 81 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5-cyclopentyloxybenzoic acid ethyl ester (Compound No. 1-94) 2-[(6
-Acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] -5-hydroxybenzoic acid ethyl ester 0.50 g, cyclopentanol 0.1%.
The reaction was carried out according to Example 79 using 10 ml, 0.57 g of 1,1'-azodicarbonyldipiperidine, 0.57 ml of tributylphosphine and 20 ml of anhydrous toluene solution to give yellow crystals of the target compound having a melting point of 169-170 ° C. 0.58 g was obtained.

[0292]

Example 82 2-[(6-Hydroxy-5,7,8-
[Trimethyl-chroman-3-carbonyl) amino] benzoic acid (Compound No. 4-127) 2-
[(6-hydroxy-5,7,8-trimethyl-2H-
Chromene-3-carbonyl) amino] benzoic acid 0.50
g, a mixture of 0.10 g of a 10% palladium-carbon catalyst and 20 ml of ethanol were stirred at room temperature under a hydrogen atmosphere for 8 hours and left overnight. 10 ml of ethyl acetate was added to the reaction mixture.
Was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. After filtering off the palladium-carbon catalyst from the reaction mixture, the solvent was distilled off. Isopropyl ether was added to the obtained residue, and ultrasonic vibration was applied. The insoluble crystals were collected by filtration to give light brown crystals of the target compound having a melting point of 230-231 ° C.
48 g were obtained.

[0293]

Example 83 6,7-Dimethoxy-2H-chromene-
3-carboxylic acid (3-carbamoyl-phenyl) amide
(Compound No. 1-225) 3- obtained in Example 45
[(6,7-Dimethoxy-2H-chromen-3-carbo
Nyl) -amino] benzoic acid 0.40 g, oxalylchloro
To a solution of 0.12 ml of lid in 5 ml of tetrahydrofuran
One drop of methylformamide was added dropwise. Reaction mixture at room temperature
After stirring for 1 hour, the solvent was distilled off from the reaction solution and the pressure was reduced.
Dried. Dissolve the residue in 4 ml of tetrahydrofuran,
0.62 ml of 2M ammonia ethanol solution in dimethyl
The solution was added to 4 ml of a formamide solution under ice-cooling, and the reaction mixture was added.
Stirred at room temperature for 5.25 hours. Solvent is distilled off from the reaction solution
Water was added to the resulting residue, and saturated sodium bicarbonate was added.
The solution was made basic. After extraction with ethyl acetate,
Washed with brine and dried over anhydrous sodium sulfate. Extraction
Ethyl acetate is distilled off from the liquid, and the residue is
Melting point> 256 when subjected to chromatography (ethyl acetate)
° C (dec.) Yellow powder of the target compound 0.05
0 g was obtained. ¹H-NMR spectrum (δppm, DMSO-d₆)
 2.95 (1H, m), 3.33 (1H, m), 3.74 (3H, s), 3.78 (3
H, s), 6.61 (1H, s), 6.89 (1H, s), 7.34 (1H, s, weight
(Disappears with addition of water), 7.39 (1H, t, J = 7.9 Hz), 7.49 (1
H, s), 7.56 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J =
2.0 Hz), 7.90 (1H, m, disappeared by adding heavy water), 8.15 (1H,
 m), 10.06 (1H, s, disappeared by addition of heavy water).

[0294]

Example 84 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (4-phenyl-butylcarbamoyl) -phenyl] -amide (Compound No. 1-104) Reference Example 2- (6-acetoxy-5,7,8-trimethyl-2H-chromene-3 obtained in Step 24
A solution of 0.50 g of -yl) benzo [d] [1,3] oxazin-4-one and 0.23 ml of 4-phenylbutylamine in 10 ml of pyridine was stirred at room temperature for 8.25 hours, and then left at room temperature overnight. The solvent is distilled off from the reaction solution,
Water and ethyl acetate were added to the obtained residue, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration, washed with water and ethyl acetate, and dried to obtain 0.56 g of a yellow powder of the target compound having a melting point of 175 to 177 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.57 (4H, m), 2.02 (3H, s), 2.1
0 (3H, s), 2.11 (3H, s), 2.35 (3H, s), 2.60 (2H,
m), 3.32 (2H, m), 4.94 (2H, s), 7.18 (6H, m), 7.50
(1H, s), 7.54 (1H, m), 7.79 (1H, m), 8.48 (1H, d,
J = 8.0Hz), 8.87 (1H, t, J = 5.4Hz, disappeared by adding heavy water), 12.33 (1H, s, disappeared by adding heavy water).

[0295]

Example 85 2-[(7-tert-butyl-6-hydroxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-272)
[(7-tert-butyl-6-hydroxy-2H-chromen-3-carbonyl) amino] Methyl benzoate 0.28 g, 2N aqueous sodium hydroxide solution 3 ml and methanol 3 ml were reacted according to Example 43. This gave 0.26 g of yellow crystals of the target compound having a melting point of 170-171 ° C.

[0296]

Example 86 2-[(2H-Chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-2) 2-[(2H-Chromen-3-carbonyl) amino] benzoic acid obtained in Example 75 The reaction was carried out according to Example 43 using 0.40 g of acid methyl ester and 4 ml of 2N aqueous sodium hydroxide solution and 4 ml of methanol.
0.32 g of pale yellow crystals of the target compound having a temperature of ° C. were obtained.

[0297]

Working Example 87 2-[(6-Hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- [2- (diisopropylamino) ethoxy]
Benzoic acid (Compound No. 1-145) 2 obtained in Example 79
-[(6-acetoxy-5,7,8-trimethyl-2H
-Chromen-3-carbonyl) amino] -5- [2-
(Diisopropylamino) ethoxy] benzoic acid ethyl ester 0.20 g, 2N sodium hydroxide aqueous solution 2 m
The reaction was carried out according to Example 43 using 1 l of ethanol and 2 ml of ethanol to obtain 71 mg of the target compound as yellow crystals having a melting point of> 225 ° C (dec.).

[0298]

Working Example 88 2-[(6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5-cyclopentyloxybenzoic acid (Compound No.
1-146) 0.30 g of 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] -5-cyclopentyloxybenzoic acid ethyl ester obtained in Example 81, The reaction was carried out according to Example 43 using 3 ml of a 2N aqueous sodium hydroxide solution and 3 ml of ethanol to obtain 0.24 g of a yellow crystal of the target compound having a melting point of 224-227 ° C.

[0299]

Working Example 89 2-[(6-acetoxy-5,7,8-
[Trimethyl-2H-chromen-3-carbonyl) amino] benzenesulfonamide (Compound No. 1-315) 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl chloride 0 obtained in Reference Example 28 .5
6 g, 0.21 g of 2-amino-benzenesulfonamide
And 20 ml of anhydrous dimethylacetamide was stirred at room temperature for 1 hour and then left for 1 day. The solvent was distilled off from the reaction mixture, and a 5% aqueous sodium hydrogen carbonate solution was added to the obtained residue, followed by extraction with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The precipitate obtained by distilling off the solvent from the extract was collected by filtration with diisopropyl ether and washed to give a melting point of> 235 ° C.
c. ), And 0.73 g of a pale yellow powder of the target compound having the following formula: was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3
H, s), 2.10 (3H, s), 2.11 (3H, s), 2.35 (3H, s), 4.
94 (2H, s), 7.30-7.33 (1H, m), 7.53 (1H, s), 7.61-
7.65 (1H, m), 7.77 (1H, br), 7.88-7.90 (1H, dd, J
= 1.2 and 8.0 Hz), 8.33-8.35 (1H, d, J = 8.0 Hz),
10.01-10.11 (2H.br).

[0300]

Example 90 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-hydroxyphenyl) (Compound No. 1-305) 6 obtained in Reference Example 5.
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 10 ml, dimethylformamide 2 drops, 2-aminophenol 0.20
Example 2 using g and 5 ml of anhydrous dimethylacetamide
The reaction was carried out according to 9 to obtain 0.67 g of yellow crystals of the target compound having a melting point of 212-215 ° C. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.09 (3
H, s), 2.13 (3H, s), 2.35 (3H, s), 4.90 (2H, s), 6.
81 (1H, dt, J = 1.1 and 7.4 Hz), 6.91 (1H, dd, J =
1.3 and 8.0 Hz), 7.03 (1H, dt, J = 1.3 and 7.7 H
z), 7.48 (1H, dd, J = 1.3 and 7.9 Hz), 7.69 (1H,
s), 9.49 (1H, s, disappeared by adding heavy water), 9.59 (1H, s,
Disappears with the addition of heavy water).

[0301]

Working Example 91 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-piperidin-1-ylethoxy) benzoic acid ethyl ester (Compound No. 1-288) 2-[(6-acetoxy-) obtained in Example 37 5,7,8-Trimethyl-2H-chromen-3-carbonyl) amino] -5
-Hydroxybenzoic acid ethyl ester 0.50 g, 1-
When 0.15 ml of piperidine ethanol, 0.57 g of 1,1′-azodicarbonyldipiperidine, 0.57 ml of tributylphosphine and 20 ml of anhydrous toluene are reacted according to Example 79, the target compound having a melting point of 221-223 ° C. 0.28 g of yellow crystal was obtained. ¹ H
-NMR spectrum (δppm, DMSO-d ₆ ) 1.29 (3H, t, J =
7.2 Hz), 1.35-1.45 (1H, br m), 1.6-1.9 (5H, br m),
2.01 (3H, s), 2.10 (3H, s), 2.14 (3H, s), 2.36 (3
H, s), 2.9-3.1 (2H, br m), 3.4-3.6 (4H, br m), 4.3
1 (2H, q, J = 7.2 Hz), 4.4-4.5 (2H, br m), 4.92 (2
H, s), 7.32 (1H, dd, J = 3.0 and 9.2Hz), 7.47 (1H,
d, J = 3.0 Hz), 7.62 (1H, s), 8.04 (1H, d, J = 9.
2 Hz), 9.87 (1H, br s, disappeared by addition of heavy water).

[0302]

Working Example 92 2-[(6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -3-hydroxybenzoic acid ethyl ester (Compound No. 1-289) 6-acetoxy-5 obtained in Reference Example 5
0.50 g of 7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of anhydrous tetrahydrofuran, dimethylformamide 2
Drops, 3-hydroxyanthranilic acid ethyl ester 0.
The reaction was carried out according to Example 29 using 33 g and 5 ml of anhydrous dimethylacetamide to obtain 0.48 g of a yellow crystal of the target compound having a melting point of 164-166 ° C. ¹ H
-NMR spectrum (δppm, DMSO-d ₆ ) 1.19 (3H, t, J =
7.0 Hz), 2.01 (3H, s), 2.09 (3H, s), 2.13 (3H, s),
2.35 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.86 (2H,
s), 7.12 (1H, dd, J = 1.8 and 7.7 Hz), 7.1-7.25
(2H, m), 7.74 (1H, s), 9.67 (1H, s, disappeared by adding heavy water), 9.79 (1H, s, disappeared by adding heavy water).

[0303]

Working Example 93 2-[(6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-piperidin-1-ylethoxy) benzoic acid (Compound No. 1-337) 2-
[(6-acetoxy-5,7,8-trimethyl-2H-
Chromene-3-carbonyl) amino] -5- (2-piperidin-1-ylethoxy) benzoic acid ethyl ester 0.20 g, 2N aqueous potassium hydroxide solution 2 ml and ethanol 2 ml were reacted according to Example 43, 0.13 g of yellow crystals of the target compound having a melting point> 243 ° C. (dec.) Were obtained. ¹ H-NMR spectrum (δ
ppm, DMSO-d ₆ ) 1.5-1.6 (2H, br m), 1.7-1.9 (4H, br
m), 2.05 (3H, s), 2.12 (3H, s), 2.23 (3H, s), 3.1
-3.5 (6H, br m), 4.34 (2H, t, J = 4.8 Hz), 4.84 (2
H, s), 7.00 (1H, dd, J = 3.2 and 9.1 Hz), 7.58 (1H,
s), 7.69 (1H, d, J = 3.2 Hz), 7.87 (1H, s, disappeared by adding heavy water), 8.51 (1H, d, J = 9.1 Hz), 11.7 (1H, br
s, disappeared by addition of heavy water).

[0304]

Working Example 94 2H-Chromene-3-carboxylic acid [3-
(2-Diisopropylaminoethoxy) -4-methoxyphenyl] amide (Compound No. 1-286) 2.00 g of 2H-chromene-3-carboxylic acid, oxalyl chloride
The reaction was carried out according to Example 29 using 0 ml, 40 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 3.00 g of 3- (2-diisopropylaminoethoxy) -4-methoxyaniline obtained in Reference Example 22, and 30 ml of anhydrous dimethylacetamide. And Rf value = 0.19
2.24 g of a yellow foamy powder of the target compound having (silica gel thin layer chromatography; ethyl acetate) were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 0.99 (12H,
d, J = 6.6 Hz), 2.79 (2H, t, J = 7.3 Hz), 3.02 (2H,
qq, J = 6.5 and 6.5 Hz), 3.73 (3H, s), 3.80 (2H,
t, J = 7.3 Hz), 4.97 (2H, d, J = 1.2 Hz), 6.85-6.9
5 (2H, m), 6.99 (1H, t, J = 7.2 Hz), 7.2-7.3 (3H,
m), 7.38 (1H, d, J = 2.2 Hz), 7.43 (1H, s), 9.87
(Disappears with the addition of 1H, s, heavy water).

[0305]

Example 95 2-[(6-Fluoro-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-250) 6-Fluoro-2H-chromene-3 obtained in Reference Example 31 -Reaction according to Example 29 using 0.67 g of carboxylic acid, 0.33 ml of oxalyl chloride, 20 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 0.38 ml of anthranilic acid methyl ester and 20 ml of anhydrous dimethylacetamide,
0.74 g of a light brown powder of the target compound having a melting point of 136-138 ° C. was obtained. ¹ H-NMR spectrum (δ ppm, D
MSO-d ₆ ) 4.08 (3H, s), 5.02 (2H, s), 6.91-6.95 (1H,
dd, J = 4.6 and 8.9 Hz), 7.11-7.16 (1H, m), 7.23-
7.29 (2H, m), 7.40 (1H, s), 7.64-7.68 (1H, m), 7.9
8-8.00 (1H, dd, J = 1.3 and 8.0 Hz), 8.34-8.35 (1
H, d, J = 7.9 Hz), 11.17 (1H, s).

[0306]

Working Example 96 2-[(6-Fluoro-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-24)
9) 2-[(6-Fluoro-2H) obtained in Example 95
-Chromene-3-carbonyl) amino] benzoic acid methyl ester 0.70 g, 1N aqueous sodium hydroxide solution 1
5 ml, methanol 15 ml and tetrahydrofuran 2
When the reaction was carried out according to Example 43 using 0 ml, the melting point was 2
Light yellow powder of the target compound having a temperature of 25-226 ° C.
28 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-
d ₆ ) 5.04 (2H, s), 6.91-6.94 (1H, dd, J = 4.6 and
8.9 Hz), 7.01-7.25 (3H, m), 7.37 (1H, s), 7.62-7.6
6 (1H, m), 8.03-8.05 (2H, dd, J = 1.5 and 8.0 Hz),
8.54-8.56 (2H, m), 11.87 (1H, br), 13.84-13.86 (1
H, br).

[0307]

Working Example 97 2-[(6-Methyl-2H-chromene-)
3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-348) 6-methyl-2 obtained in Reference Example 33
H-chromene-3-carboxylic acid 0.50 g, anthranilic acid methyl ester 0.30 g, carbon tetrachloride 0.77
g, 1.30 g of triphenylphosphine and 10 ml of anhydrous dimethylacetamide were stirred at room temperature for 6 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent is distilled off from the extract,
The obtained residue was subjected to a solid phase extraction cartridge (HF Mega Bond Elut SI, 10 g / 60 ml + HF Mega Bond Elut NH ₂ , 5 g / 20 ml (Varian), n-
Purification using hexane: ethyl acetate = 1: 1) gives
0.50 g of a pale yellow powder of the target compound having a melting point of 116-117 ° C. was obtained. ¹ H-NMR spectrum (δppm, DMS
Od ₆ ) 2.25 (3H, s), 3.90 (3H, s), 4.98 (2H, s), 6.
79-6.81 (1H, d, J = 8.2 Hz), 7.01-7.11 (1H, dd, J
= 1.3 and 8.3 Hz), 7.14-7.15 (1H, d, J = 1.5 Hz),
7.21-7.25 (1H, m), 7.36 (1H, s), 7.64-7.68 (1H,
m), 7.98-8.00 (1H, dd, J = 1.4 and 8.0 Hz), 8.39-
8.41 (1H, d, J = 7.8 Hz), 11.22 (1H, s).

[0308]

Working Example 98 2-[(6-Methyl-2H-chromene-)
3-carbonyl) amino] benzoic acid (Compound No. 1-34
7) 2-[(6-methyl-2H-) obtained in Example 97
Chromene-3-carbonyl) amino] benzoic acid methyl ester 0.40 g, 1N aqueous sodium hydroxide solution 6 m
1, methanol 5ml and dimethylformamide 5ml
And reacted according to Example 43 to obtain a melting point of 224
0.25 g of pale yellow powder of the target compound having 226 ° C.
was gotten. ¹ H-NMR spectrum _{(δppm, DMSO-d 6)} 2.2
5 (3H, s), 5.00 (2H, s), 6.79-6.81 (1H, d, J = 7.8
Hz), 7.09-7.21 (1H, m), 7.33 (1H, s), 7.61-7.66 (1
H, m), 8.03-8.05 (1H, dd, J = 1.3 and 7.6 Hz), 8.5
6-8.57 (1H, d, J = 7.9 Hz), 11.86 (1H, s), 13.83 (1
H, br).

[0309]

Example 99 2-[(7-Benzyloxy-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-346) 7-benzyloxy-2H-chromene obtained in Reference Example 35 -3-carboxylic acid 0.5
0 g, anthranilic acid methyl ester 0.20 g, carbon tetrachloride 0.62 g, triphenylphosphine 1.10 g
And Example 9 using 10 ml of anhydrous dimethylacetamide
The reaction was carried out according to 7 to obtain 0.40 g of a pale yellow powder of the target compound having a melting point of 133-135 ° C. ¹ HN
MR spectrum _{(δppm, DMSO-d 6)} 3.90 (3H, s), 5.00
(2H, s), 5.14 (2H, s), 6.58-6.59 (1H, d, J = 2.4 H
z), 6.66-6.69 (1H, dd, J = 2.6 and 8.5 Hz), 7.20-
7.46 (8H, m), 7.63-7.67 (1H, m), 7.97-8.00 (1H, d
d, J = 1.5 and8.0 Hz), 8.38-8.40 (1H, d, J = 7.9 H
z), 11.16 (1H, s).

[0310]

Example 100 2-[(7-benzyloxy-2H-
Chromene-3-carbonyl) amino] benzoic acid (Compound No. 1-345) 2-[(7-benzyloxy-2H-chromen-3-carbonyl) amino] obtained in Example 99
The reaction was carried out according to Example 43 using 0.30 g of benzoic acid methyl ester, 6 ml of 1N aqueous sodium hydroxide solution, 5 ml of methanol and 5 ml of dimethylformamide. was gotten. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 5.01 (2H, s), 5.14 (2H, s), 6.58-6.59
(1H, d, J = 2.4 Hz), 6.65-6.68 (1H, dd, J = 2.4 and
8.4 Hz), 7.16-7.46 (8H, m), 7.60-7.65 (1H, m), 8.0
2-8.04 (1H, dd, J = 1.4 and 7.9 Hz), 8.56-8.58 (1
H, d, J = 8.4 Hz), 11.85 (1H, s), 13.83 (1H, br).

[0311]

Working Example 101 Methyl 2-[(6-methoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-266) 6-methoxy-2H-chromene-
3-carboxylic acid 0.25 g, anthranilic acid methyl ester 0.15 g, carbon tetrachloride 0.38 g, triphenylphosphine 0.66 g and anhydrous dimethylacetamide 5
When the reaction was carried out in the same manner as in Example 97, the melting point was 15
0.26 pale yellow powder of target compound having 8-160 ° C
g was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
3.75 (3H, s), 3.90 (3H, s), 4.96 (2H, s), 6.84-6.89
(2H, m), 6.96-6.97 (1H, d, J = 2.7 Hz), 7.22-7.26
(1H, m), 7.40 (1H, s), 7.64-7.68 (1H, m), 7.98-8.
00 (1H, dd, J = 1.3 and 8.0 Hz), 8.37-8.39 (1H, d,
J = 8.5 Hz), 11.20 (1H, s).

[0312]

Working Example 102 2-[(6-Methoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-
265) 2-[(6-methoxy-) obtained in Example 101
2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (0.15 g), 1N aqueous sodium hydroxide solution (3 ml), methanol (4 ml) and dimethylformamide (4 ml) were reacted according to Example 43 to give a melting point of 1
Yellow powder 0.10 of the target compound having a temperature of 90-191 ° C.
g was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
3.74 (3H, s), 4.96 (2H, s), 6.84-6.89 (2H, m), 6.93
-6.94 (1H, d, J = 2.5 Hz) 7.18-7.21 (1H, m), 7.37
(1H, s), 7.62-7.66 (1H, m), 8.03-8.05 (1H, dd, J =
1.3 and 8.0 Hz), 8.56-8.58 (1H, d, J = 8.0 Hz), 1
1.88 (1H, s), 13.85 (1H, br).

[0313]

Working Example 103 Methyl 2-[(8-methoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-243) 8-methoxy-2H-chromene-
3-carboxylic acid 0.25 g, anthranilic acid methyl ester 0.15 g, carbon tetrachloride 0.38 g, triphenylphosphine 0.66 g and anhydrous dimethylacetamide 5
When the reaction was carried out in the same manner as in Example 97, the melting point was 13
0.21 light yellow powder of target compound having 1-133 ° C
g was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
3.80 (3H, s), 3.90 (3H, s), 4.99 (2H, d, J = 1.1 H
z), 6.93-6.98 (2H, m), 7.02-7.08 (1H, m), 7.22-7.2
6 (1H, m), 7.40 (1H, s), 7.64-7.79 (1H, m), 7.97-
8.00 (1H, dd, J = 1.7 and 7.9 Hz), 8.35-8.37 (1H,
m), 11.19 (1H, s).

[0314]

Working Example 104 2-[(8-Methoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-
242) 2-[(8-methoxy-) obtained in Example 103
2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (0.11 g), 1N aqueous sodium hydroxide solution (3 ml), methanol (2 ml) and dimethylformamide (2 ml) were reacted according to Example 43 to give a melting point of 2
Pale yellow powder of the target compound having a temperature of 38-240 ° C 0.0
8 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
3.79 (3H, s), 5.01 (2H, d, J = 0.9 Hz), 6.90-6.97
(2H, m), 7.03-7.05 (1H, dd, J = 1.6 and 7.8 Hz),
7.18-7.21 (1H, t, J = 7.5 Hz), 7.36 (1H, s), 7.62-
7.66 (1H, m), 8.03-8.05 (1H, dd, J = 1.3 and 7.7 H
z), 8.55-8.57 (1H, d, J = 8.5 Hz), 11.88 (1H, s),
13.84 (1H, br).

[0315]

Example 105 2-[(6-Phenyl-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-352) 6-phenyl-2H-chromene-3 obtained in Reference Example 38 -Reaction according to Example 29 using 0.60 g of carboxylic acid, 0.25 ml of oxalyl chloride, 17 ml of anhydrous tetrahydrofuran, 1 drop of dimethylformamide, 0.34 ml of anthranilic acid methyl ester and 10 ml of anhydrous dimethylacetamide,
0.48 g of yellow needle crystals of the target compound having a melting point of 171-173 ° C were obtained. ¹ H-NMR spectrum (δ ppm, D
MSO-d ₆ ) 3.91 (3H, s), 5.09 (2H, d, J = 1.0 Hz),
7.00 (1H, d, J = 8.4 Hz), 7.23-7.27 (1H, m), 7.33-
7.37 (1H, m), 7.44-7.50 (3H, m), 7.60 (1H, d, J =
2.3 Hz), 7.62 (1H, d, J = 2.2 Hz), 7.65-7.69 (3H,
m), 8.01 (1H, dd, J = 1.4 and 8.0 Hz), 8.41 (1H, d
d, J = 5.8 and 8.8 Hz), 11.24 (1H, s, disappeared with the addition of heavy water).

[0316]

Working Example 106 2-{[6- (3-pyridyl) -2H
-Chromen-3-carbonyl] amino} benzoic acid methyl ester (Compound No. 1-356) 6 obtained in Reference Example 40
0.16 g of-(3-pyridyl) -2H-chromene-3-carboxylic acid, 0.066 ml of oxalyl chloride, 1 drop of dimethylformamide, 10 m of anhydrous tetrahydrofuran
l, 0.082 ml of anthranilic acid methyl ester and 10 ml of anhydrous dimethylacetamide were reacted according to Example 29 to obtain 40.2 mg of a pale yellow powder of the target compound having a melting point of 177 to 179 ° C. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 3.91 (3H, s), 5.10 (2
H, s), 7.04 (1H, d, J = 8.4 Hz), 7.25 (1H, t, J =
7.7 Hz), 7.47 (1H, d, J = 4.7 Hz), 7.49 (1H, d, J
= 4.7 Hz), 7.66 (1H, d, J = 1.2 Hz), 7.68 (1H, dd,
J = 2.2 and 8.2 Hz), 7.77 (1H, d, J = 2.2 Hz), 8.
01 (1H, dd, J = 1.3 and 8.0 Hz), 8.09 (1H, ddd, J =
3.0, 4.9 and 4.9 Hz), 8.40 (1H, d, J = 7.9 Hz),
8.56 (1H, t, J = 2.5 Hz), 8.91 (1H, d, J = 2.2 Hz),
11.24 (1H, s, disappeared by addition of heavy water).

[0317]

Working Example 107 2-[(6-Phenyl-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-
351) 2-[(6-phenyl-) obtained in Example 105
2H-chromen-3-carbonyl) amino] benzoic acid methyl ester 0.28 g, 2N aqueous sodium hydroxide solution 2.8 ml, methanol 2.8 ml and tetrahydrofuran 4 ml were reacted according to Example 43,
0.26 g of a pale yellow powder of the target compound having a melting point of> 256 ° C. (dec.) Was obtained. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 5.10 (2H, s), 7.00 (1H, d, J = 8.3 H
z), 7.20 (1H, t, J = 7.8 Hz), 7.35 (1H, ddd, J = 1.
5, 7.3 and 7.4 Hz), 7.46 (1H, t, J = 7.7 Hz), 7.58-
7.67 (5H, m), 8.05 (1H, dd, J = 1.4 and 8.0 Hz),
8.59 (1H, t, J = 4.3 Hz), 11.91 (1H, s, disappeared by adding heavy water), 13.86 (1H, br s, disappeared by adding heavy water).

[0318]

Working Example 108 2-[(6-Hydroxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) amino]-[5- (3-pyridyl)] benzoic acid sodium salt (Compound No. 1-338) 2-[(6
-Hydroxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] -5- (3-pyridyl)
0.20 g of benzoic acid, saturated aqueous sodium hydrogen carbonate solution 2
0 ml of the mixture was stirred at room temperature for 4 hours and left at room temperature for 3 days. Diisopropyl ether was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration, washed with water and diisopropyl ether, and dried under reduced pressure to obtain 0.17 g of a yellow powder of the target compound having a melting point of> 271 ° C (dec.). ¹ H-NMR spectrum (δ
ppm, DMSO-d ₆ ) 2.07 (3H, s), 2.13 (3H, s), 2.25 (3
H, s), 4.87 (2H, s), 7.49 (1H, dd, J = 4.7 and 7.9
Hz), 7.63 (1H, s), 7.76-7.91 (1H, m), 7.91 (1H, b
r, s, disappeared by adding heavy water), 8.09 (1H, ddd, J = 3.2,
4.9 and 4.9 Hz), 8.34 (1H, d, J = 2.3 Hz), 8.56 (1
H, d, J = 4.3 Hz), 8.72 (1H, d, J = 8.7 Hz), 8.90
(1H, d, J = 1.1 Hz), 13.65 (1H, br, disappeared by adding heavy water).

[0319]

Working Example 109 2-[(6-acetoxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) amino] -5-phenylbenzoic acid methyl ester (Compound No. 1-67) 6-acetoxy-5,7,
8-Trimethyl-2H-chromene-3-carboxylic acid
According to Example 29, 50 g, oxalyl chloride 0.19 ml, dimethylformamide 1 drop, anhydrous tetrahydrofuran 15 ml, 2-amino-5-phenylbenzoic acid methyl ester 0.41 g obtained in Reference Example 41 and anhydrous dimethylacetamide 10 ml were used. The yellow powder of the target compound having a melting point of 237-240 ° C.
80 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-
d ₆ ) 2.02 (3H, s), 2.11 (3H, s), 2.16 (3H, s), 2.36
(3H, s), 3.92 (3H, s), 4.97 (2H, s), 7.38-7.39 (1
H, m), 7.41-7.49 (2H, m), 7.63 (1H, s), 7.71 (2H,
d, J = 7.3 Hz), 7.99 (1H, dd, J = 2.4 and 8.6 Hz),
8.21 (1H, d, J = 2.3 Hz), 8.44 (1H, d, J = 8.7 H
z), 11.19 (1H, s, disappeared by addition of heavy water).

[0320]

Example 110 2-[(6-hydroxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amido
No] -5-phenylbenzoic acid (Compound No. 1-147)
2-[(6-acetoxy-5,7,
8-trimethyl-2H-chromen-3-carbonyl) a
Mino] -5-phenylbenzoic acid methyl ester 0.40
g, 2N aqueous sodium hydroxide solution 4.0 ml,
Example using 4 ml of toluene and 8 ml of tetrahydrofuran
When the reaction was carried out according to Example 43, the melting point was> 209 ° C. (de
c. 0.33 g of a tan powder of the target compound having
Was done. ¹H-NMR spectrum (δppm, DMSO-d₆) 2.07 (3
H, s), 2.13 (3H, s), 2.25 (3H, s), 4.87 (2H, s), 7.
38 (1H, t, J = 7.3 Hz), 7.48 (2H, t, J = 7.7 Hz),
7.60 (1H, s), 7.70 (2H, t, J = 4.3 Hz), 7.92 (1H,
s, disappeared by adding heavy water), 7.96 (1H, dd, J = 2.5 and 8.
7 Hz), 8.29 (1H, d, J = 2.3 Hz), 8.72 (1H, d, J =
8.7 Hz), 12.18 (1H, br, s, disappeared by adding heavy water), 14.0
6 (1H, br, s, disappeared by adding heavy water).

[0321]

Example 111 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-biphenyl) amide (Compound No. 1-317) 6 obtained in Reference Example 5.
-Acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid 1.00 g, oxalyl chloride 0.38 ml, 1 drop of dimethylformamide, 30 ml of anhydrous tetrahydrofuran, 0.67 of 2-aminobiphenyl
g and 10 ml of anhydrous dimethylacetamide were reacted according to Example 29 to obtain 1.34 g of a brown powder of the target compound having a melting point of 168 to 170 ° C. ¹ HN
MR spectrum _{(δppm, DMSO-d 6)} 1.99 (3H, s), 2.02
(3H, s), 2.06 (3H, s), 2.34 (3H, s), 4.77 (2H, s),
7.31-7.52 (10H, m), 9.65 (1H, s, disappeared by adding heavy water).

[0322]

Example 112 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [4-methoxy-3- (2-piperidin-1-ylethoxy) phenyl] amide (Compound No. 1-359) ) 0.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-hydroxy-4-methoxyphenyl) amide obtained in Example 68, 0.17 ml of 1-piperidineethanol The reaction was carried out according to Example 79 using 0.63 g of 1,1′-azodicarbonyldipiperidine, 0.63 ml of tributylphosphine and 10 ml of anhydrous toluene. 44 g were obtained. ¹ H-NMR spectrum (δ
ppm, DMSO-d ₆ ) 1.3-1.45 (2H, m), 1.45-1.55 (4H,
m), 2.01 (3H, s), 2.09 (3H, s), 2.14 (3H, s), 2.35
(3H, s), 2.4-2.5 (4H, brm), 2.66 (2H, t, J = 6.2 H
z), 3.74 (3H, s), 4.01 (2H, t, J = 6.2 Hz), 4.89
(2H, s), 6.93 (1H, d, J = 8.7 Hz), 7.23 (1H, dd, J
= 2.3 and 8.7 Hz), 7.38 (1H, d, J = 2.3 Hz), 7.60
(1H, s), 9.90 (1H, s, disappeared by adding heavy water).

[0323]

Example 113 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-t-butoxycarbonylaminophenyl) amide (Compound No. 1-)
331) 6-acetoxy-5, 7, 8 obtained in Reference Example 5
-Trimethyl-2H-chromene-3-carboxylic acid 2.0
0 g, oxalyl chloride 0.63 ml, anhydrous tetrahydrofuran 60 ml, dimethylformamide 2 drops, 2-aminophenylcarbamic acid-t obtained in Reference Example 44
-Butyl ester 1.51 g and triethylamine 1.
When the reaction was carried out according to Example 3 using 0 ml, the melting point was 15
3.02 g of white crystals of the target compound having a temperature of 9 to 160 ° C
was gotten. ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 1.4
5 (9H, s), 2.01 (3H, s), 2.09 (3H, s), 2.13 (3H,
s), 2.35 (3H, s), 4.90 (2H, s), 7.05-7.15 (1H, m),
7.15-7.25 (1H, m), 7.41 (1H, d, J = 7.1 Hz), 7.59
(1H, d, J = 8.0 Hz), 7.63 (1H, s), 8.54 (1H, s,
9.68 (1H, s, disappeared by addition of heavy water).

[0324]

Example 114 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-aminophenyl) amide (Compound No. 1-326) 5,7,8-trimethyl-2H
After stirring a mixture of 1.10 g of -chromene-3-carboxylic acid (2-t-butoxycarbonylaminophenyl) amide and 10 ml of 4N hydrochloric acid-dioxane for 1 hour at room temperature, the solvent was distilled off from the reaction solution to obtain a mixture. Ice water was added to the resulting residue, an aqueous sodium hydrogen carbonate solution and diisopropyl ether were added, and the mixture was stirred at room temperature. The precipitated crystals are collected by filtration,
Recrystallization from diisopropyl ether gave a melting point of 182.
0.77 g of yellow crystals of the target compound having a temperature of -184 DEG C. are obtained. ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 2.00
(3H, s), 2.09 (3H, s), 2.13 (3H, s), 2.35 (3H, s),
4.89 (2H, s), 4.89 (2H, s, disappeared by adding heavy water), 6.58
(1H, t, J = 7.3 Hz), 6.76 (1H, d, J = 8.0 Hz), 6.
90-7.0 (1H, m), 7.09 (1H, d, J = 6.9 Hz), 7.66 (1H,
s), 9.50 (1H, s, disappeared by adding heavy water).

[0325]

Working Example 115 2-[(6-acetoxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) methylamino] benzoic acid methyl ester (Compound No. 1-28)
7) 6-acetoxy-5,7,8- obtained in Reference Example 5
Trimethyl-2H-chromene-3-carboxylic acid 0.50
g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 10 ml, dimethylformamide 2 drops, N-methylanthranilic acid methyl ester 0.26 g and anhydrous dimethylacetamide 5 ml. There was obtained 0.76 g of yellow crystals of the target compound. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.62 (3H, s), 1.92 (3H, s), 1.9
8 (3H, s), 2.29 (3H, s), 3.24 (3H, s), 3.80 (3H,
s), 4.3-4.5 (2H, m), 6.37 (1H, s), 7.4-7.5 (1H,
m), 7.6-7.7 (1H, m), 7.65-7.75 (1H, m), 7.83 (1H,
d, J = 7.0 Hz).

[0326]

Example 116 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-di-t-
(Butoxycarbonylaminophenyl) amide (Compound No. 1-332) 6-acetoxy-5 obtained in Reference Example 5
0.50 g of 7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of anhydrous tetrahydrofuran, dimethylformamide 2
The reaction was carried out according to Example 29 using 0.56 g of N, N-di-t-butoxycarbonyl-1,2-phenylenediamine obtained in Reference Example 45 and 5 ml of anhydrous dimethylacetamide. 0.71 g of white crystals of the target compound having a temperature of 0.7 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.34 (18H, s), 2.00 (3H,
s), 2.08 (3H, s), 2.10 (3H, s), 2.35 (3H, s), 4.84
(2H, s), 7.2-7.3 (2H, m), 7.3-7.4 (1H, m), 7.4-7.5
(1H, m), 7.58 (1H, s), 9.75 (1H, s, disappeared by adding heavy water).

[0327]

Example 117 2-[(6-hydroxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) methylamino] benzoic acid (Compound No. 1-128) Example 115
0.25 g of 2-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) methylamino] benzoic acid methyl ester obtained in the above was added with 3 ml of 2N aqueous potassium hydroxide solution and 3 ml of methanol. When the reaction was carried out according to Example 43, the melting point was> 140 ° C. (de
c. ) Was obtained in an amount of 0.20 g of pale yellow crystals of the target compound having the following formula: ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 1.71 (3
H, s), 1.94 (3H, s), 2.02 (3H, s), 3.23 (3H, s), 4.
2-4.5 (2H, m), 6.35 (1H, s), 7.4-7.5 (1H, m), 7.55
(1H, d, J = 7.7 Hz), 7.66 (1H, dt, J = 1.4 and 7.7 Hz
Hz), 7.71 (1H, s, disappeared by adding heavy water), 7.82 (1H, d
d, J = 1.3 and 7.9 Hz), 13.23 (1H, br s, disappeared with the addition of heavy water).

[0328]

Example 118 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-benzoylphenyl) amide (Compound No. 1-301) 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 10 m
l, 2 drops of dimethylformamide, 0.36 g of 2-aminobenzophenone and 5 ml of anhydrous dimethylacetamide according to Example 29 to give a melting point of 219-2.
0.65 g of yellow crystals of the target compound having a temperature of 20 ° C. were obtained. ¹ H-NMR spectrum _{(δppm, DMSO-d 6)} 1.98 (3H,
s), 2.04 (3H, s), 2.05 (3H, s), 2.34 (3H, s), 4.66
(2H, s), 7.21 (1H, s), 7.3-7.4 (1H, m), 7.4-7.7 (8
H, m), 10.36 (1H, s, disappeared with the addition of heavy water).

[0329]

Working Example 119 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-acetylphenyl) amide (Compound No. 1-300) 6-acetoxy-5 obtained in Reference Example 5 5,7,8-trimethyl-2H-
0.50 g of chromene-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of anhydrous tetrahydrofuran,
The reaction was carried out according to Example 29 using 2 drops of dimethylformamide, 0.24 g of 2-aminoacetophenone and 5 ml of anhydrous dimethylacetamide, and the melting point was 195 to 196 ° C.
0.71 g of a yellow crystal of the target compound having the following formula: was obtained.
¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s),
2.10 (3H, s), 2.16 (3H, s), 2.36 (3H, s), 2.68 (3H, s)
s), 4.96 (2H, s), 7.26 (1H, t, J = 7.4 Hz), 7.59
(1H, s), 7.66 (1H, t, J = 7.2 Hz), 8.08 (1H, dd, J
= 1.2 and 8.0 Hz), 8.47 (1H, d, J = 7.9 Hz), 12.0
5 (1H, s, disappeared by adding heavy water).

[0330]

Example 120 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-trifluoromethylphenyl) amide (Compound No. 1-303) Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 10 ml, dimethylformamide 2 drops, 2-aminobenzotrifluoride 0.23 ml and anhydrous dimethylacetamide When the reaction was carried out according to Example 29 using 5 ml,
0.59 g of white crystals of the target compound having a melting point of 168-169 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMS
Od ₆ ) 2.01 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.
35 (3H, s), 4.88 (2H, s), 7.50 (1H, d, J = 7.9 H
z), 7.54 (1H, t, J = 8.0 Hz), 7.70 (1H, s), 7.73 (1
H, t, J = 7.8 Hz), 7.80 (1H, d, J = 7.5 Hz), 9.98
(Disappears with the addition of 1H, s, heavy water).

[0331]

Example 121 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-methylphenyl) amide (Compound No. 1-302) 0.50 g of 5,7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 0.19 ml of o-toluidine
Example 29 using 5 ml of anhydrous dimethylacetamide and anhydrous dimethylacetamide
When the reaction was carried out according to the above, 0.64 g of pale brown crystals of the target compound having a melting point of 150-151 ° C. was obtained. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.09 (3
H, s), 2.13 (3H, s), 2.22 (3H, s), 2.35 (3H, s), 4.
90 (2H, s), 7.1-7.3 (4H, m), 7.68 (1H, s), 9.72 (1
H, s, disappeared by addition of heavy water).

[0332]

Example 122 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (4-morpholinophenyl) amide (Compound No. 1-336) 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 10 m
l, 2 drops of dimethylformamide, 0.32 g of 4-morpholinoaniline and 5 ml of anhydrous dimethylacetamide according to Example 29 to give a melting point of 235-23.
0.64 g of off-white crystals of the target compound having a temperature of 7 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.00 (3H,
s), 2.09 (3H, s), 2.14 (3H, s), 2.35 (3H, s), 3.07
(4H, t, J = 4.6 Hz), 3.74 (4H, t, J = 4.6 Hz), 4.
89 (2H, s), 6.93 (2H, d, J = 8.9 Hz), 7.54 (2H, d,
J = 8.9 Hz), 7.60 (1H, s), 9.89 (1H, s, disappeared by adding heavy water).

[0333]

Working Example 123 2-{[6- (3-Pyridyl) -2H
-Chromen-3-carbonyl] amino} benzoic acid (Compound No. 1-355) 2-{[6- (3
-Pyridyl) -2H-chromen-3-carbonyl] amino} benzoic acid methyl ester 28 mg, 2N aqueous sodium hydroxide solution 0.5 ml, methanol 0.5 ml and tetrahydrofuran 0.5 ml were reacted according to Example 43. 22.4 mg of a yellow powder of the target compound having a melting point> 244 ° C. (dec.) Were obtained. ¹ H-NMR
Spectrum (δppm, DMSO-d ₆ ) 5.12 (2H, d, J = 0.9
Hz), 7.04 (1H, d, J = 8.3 Hz), 7.19 (1H, t, J = 4.
1 Hz), 7.23-7.50 (2H, m), 7.63-7.69 (2H, m), 7.74
(1H, d, J = 2.2 Hz), 8.05 (1H, d, J = 1.5 Hz), 8.0
7 (1H, d, J = 1.4 Hz), 8.08 (1H, d, J = 4.3 Hz), 8.
09 (1H, d, J = 2.0 Hz), 8.56 (2H, t, J = 7.1 Hz),
8.89 (1H, s), 11.89 (1H, s, disappeared by adding heavy water), 13.
83 (disappears with the addition of 1H, br, s, heavy water).

[0334]

Example 124 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-bromophenyl) amide (Compound No. 1-316) 5,7,8-Trimethyl-2H-chromen-3-carboxylic acid 5.00 g, oxalyl chloride 1.89 ml, dimethylformamide 3 drops, anhydrous tetrahydrofuran 150 ml, 2-bromoaniline 3.1
The reaction was carried out according to Example 29 using 1 g and 50 ml of anhydrous dimethylacetamide to obtain 7.20 g of a yellow powder of the target compound having a melting point of 173-177 ° C. ¹ H
-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.0
9 (3H, s), 2.13 (3H, s), 2.35 (3H, s), 4.90 (2H,
s), 7.21 (1H, ddd, J = 1.1, 7.7 and 7.7Hz), 7.42 (1
H, ddd, J = 1.1, 7.7 and 7.7 Hz), 7.51 (1H, t, J =
3.9 Hz), 7.70 (1H, d, J = 0.9 Hz), 7.73 (1H, d, J
= 8.6 Hz), 9.90 (1H, s, disappeared by addition of heavy water).

[0335]

Example 125 6-Acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid [2- (O-tetrahydropyran-2-yl-oxycarbamoyl) phenyl] amide (Compound No. 1-299) ) 2- (6-acetoxy-5,7,8-trimethyl- obtained in Reference Example 24)
0.50 g of 2H-chromen-3-yl) benzo [d] [1,3] oxazin-4-one and 0.47 g of O- (tetrahydropyran-2-yl) -hydroxylamine in 10 ml of anhydrous pyridine at 60 ° C. 4.5 hours at 100
Stirred at C for 5 hours. The solvent was distilled off from the reaction solution, water was added to the resulting residue, the mixture was acidified with a 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give 0.4 of a yellow powder of the desired compound having a melting point of 184-186 ° C.
8 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
1.55 (3H, t, J = 3.3 Hz), 1.74 (3H, s), 2.01 (3H,
s), 2.09 (3H, s), 2.12 (3H, s), 2.35 (3H, s), 3.53
(1H, d, J = 11.2 Hz), 4.02-4.09 (1H, m), 4.94 (2H,
s), 5.07 (1H, s), 7.19 (1H, t, J = 7.6 Hz), 7.53
(1H, s), 7.57 (1H, d, J = 7.5 Hz), 7.68 (1H, d, J
= 7.8 Hz), 8.36 (1H, d, J = 8.3 Hz), 11.58 (1H, s,
Disappears when heavy water is added), 11.95 (1H, s, disappears when heavy water is added).

[0336]

Example 126 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (3-pyridyl) phenyl] amide (Compound No. 1-320) Obtained in Example 124 1.00 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-bromophenyl) amide, 0.29 g of pyridine-3-boronic acid, tetrakis (triphenylphosphine) palladium (0 ) 0.11 g, 2 ml of 2 M aqueous potassium carbonate solution 2.3 ml of anhydrous dimethylformamide solution 20 ml was stirred at 80 ° C for 9.75 hours and left at room temperature overnight. The solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (ethyl acetate), and diisopropyl ether was added thereto. The mixture was irradiated with ultrasonic waves, and the precipitated crystals were collected by filtration.
0.16 g of a light brown powder of the target compound having a temperature of 187 ° C. was obtained. ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 1.99
(3H, s), 2.05 (3H, s), 2.06 (3H, s), 2.34 (3H, s),
4.75 (2H, s), 7.39-7.50 (6H, m), 7.83 (1H, ddd, J
= 2.9, 4.9 and 4.9 Hz), 8.52 (1H, dd, J = 1.6 and
4.7 Hz), 8.62 (1H, d, J = 2.2 Hz), 9.83 (1H, s, disappeared by addition of heavy water).

[0337]

Example 127 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (4-pyridyl) phenyl] amide (Compound No. 1-321) Obtained in Reference Example 5. 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.34 g, oxalyl chloride 0.13 ml, dimethylformamide 1
The target compound having a melting point of 217 to 219 ° C by reacting according to Example 29 by using 12 ml of anhydrous tetrahydrofuran, 0.21 g of 2- (4-pyridyl) aniline obtained in Reference Example 47 and 7 ml of anhydrous dimethylacetamide. 0.44 g of brown powder was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.99 (3H, s), 2.06 (3H, s),
2.34 (3H, s), 4.78 (2H, s), 7.39-7.50 (7H, m), 8.60
(2H, dd, J = 1.1 and 4.7 Hz), 9.87 (1H, s, disappeared by addition of heavy water).

[0338]

Working Example 128 2-[(6-acetoxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (4-pyridyl) benzoic acid methyl ester (Compound No. 1-70) 6-acetoxy-5,7,8-trimethyl obtained in Reference Example 5 -2H-chromene-3-carboxylic acid 0.28 g, oxalyl chloride 0.11 ml,
1 drop of dimethylformamide, anhydrous tetrahydrofuran 1
2 ml, 2-amino-5- (4-
When 0.23 g of methyl pyridyl) benzoate and 6 ml of anhydrous dimethylacetamide were reacted according to Example 29, 0.13 g of a yellow powder of the target compound having a melting point of 260-262 ° C was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s), 2.10 (3H, s), 2.1
5 (3H, s), 2.36 (3H, s), 3.93 (3H, s), 4.97 (2H,
s), 7.63 (1H, s), 7.75 (2H, t, J = 3.0 Hz), 8.13
(1H, dd, J = 2.1 and 8.7 Hz), 8.33 (1H, d, J = 1.6
Hz), 8.49 (1H, d, J = 8.7 Hz), 8.65 (2H, d, J =
5.9 Hz), 11.25 (1H, s, disappeared by adding heavy water).

[0339]

Working Example 129 2-[(6-hydroxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (4-pyridyl) benzoic acid (Compound No. 1-15
0) 2-[(6-acetoxy-) obtained in Example 128
5,7,8-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (4-pyridyl) benzoic acid methyl ester 80 mg, 2N aqueous sodium hydroxide solution
The reaction was carried out according to Example 43 using 0 ml and 2 ml of methanol to obtain 38 mg of a tan powder of the target compound having a melting point of> 273 ° C. (dec.). ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.07 (3H, s), 2.13 (3H,
s), 2.26 (3H, s), 4.87 (2H, s), 7.61 (1H, s), 7.77
(2H, t, J = 7.4 Hz), 7.94 (1H, s, disappeared by adding heavy water), 8.12-8.16 (2H, m), 8.43 (1H, d, J = 2.3 Hz),
8.66 (2H, s), 8.77 (1H, d, J = 8.8 Hz, disappeared by adding heavy water), 12.15 (1H, s, disappeared by adding heavy water).

[0340]

Example 130 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (2-pyridyl) phenyl] amide (Compound No. 1-319) Obtained in Reference Example 5. 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.80 g, oxalyl chloride 0.30 ml, dimethylformamide 1
The target compound having a melting point of 209-211 ° C. by reacting according to Example 29 using droplets, 26 ml of anhydrous tetrahydrofuran, 0.49 g of 2- (2-pyridyl) aniline obtained in Reference Example 50 and 16 ml of anhydrous dimethylacetamide. 60.2 mg of a pale yellow powder was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s), 2.10 (3H,
s), 2.16 (3H, s), 2.36 (3H, s), 4.96 (2H, s), 7.25
-7.29 (1H, m), 7.45-7.49 (3H, m), 7.91 (1H, dd, J
= 1.2 and 8.0 Hz), 8.02 (1H, d, J = 1.1 Hz), 8.04
(1H, d, J = 1.5 Hz), 8.46 (1H, t, J = 4.3 Hz), 8.74
(1H, d, J = 4.7 Hz), 12.73 (1H, s, disappeared by adding heavy water).

[0341]

Example 131 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (hydroxycarbamoyl) phenyl] amide (Compound No. 1-29)
8) 6-acetoxy-5, 7, 8 obtained in Reference Example 51
-Trimethyl-2H-chromene-3-carboxylic acid [2-
(Benzyloxycarbamoyl) phenyl] amide 0.
The reaction was carried out according to Example 82 using 25 g, 10% palladium carbon (0.050 g), methanol (40 ml) and tetrahydrofuran (25 ml) to obtain 0.12 g of a pale yellow powder of the target compound having a melting point of 195 to 197 ° C.
¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s),
2.10 (3H, s), 2.14 (3H, s), 2.36 (3H, s), 4.95 (2H,
s), 7.13-7.18 (1H, m), 7.51-7.56 (2H, m), 7.68 (1
H, t, J = 4.0 Hz), 8.45 (1H, d, J = 8.3 Hz), 9.36
(1H, br, s, disappeared by adding heavy water), 12.00 (1H, s, disappeared by adding heavy water).

[0342]

Example 132 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-mercaptophenyl) amide (Compound No. 1-314) 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 15 m
l, 2 drops of dimethylformamide, 0.19 ml of 2-aminothiophenol and 0.25 ml of triethylamine were reacted according to Example 3 to obtain a melting point of 167-17.
0.47 g of yellow crystals of the target compound having a temperature of 2 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H,
s), 2.08 (3H, s), 2.13 (3H, s), 2.35 (3H, s), 4.87
(2H, s), 7.2-7.4 (3H, m), 7.65 (1H, d, J = 7.7 H
z), 7.71 (1H, s), 10.15 (1H, s, disappeared by adding heavy water).

[0343]

Example 133 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-trifluoromethoxyphenyl) amide (Compound No. 1-309) Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 15 ml, dimethylformamide 2 drops, 2-trifluoromethoxyaniline hydrochloride 0.39 g and triethylamine When the reaction was carried out according to Example 3 using 0.50 ml, 0.64 g of a yellow crystal of the target compound having a melting point of 168-170 ° C. was obtained. ¹ H-NMR spectrum (δ ppm, D
MSO-d ₆ ) 2.01 (3H, s), 2.09 (3H, s), 2.13 (3H, s),
2.35 (3H, s), 4.88 (2H, s), 7.3-7.4 (1H, m), 7.4-
7.5 (2H, m), 7.6-7.7 (1H, m), 7.70 (1H, s), 10.04
(Disappears with the addition of 1H, s, heavy water).

[0344]

Working Example 134 2- (6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonylamino)
Phenylacetic acid ethyl ester (Compound No. 1-304) 0.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5, 0.16 ml of oxalyl chloride, anhydrous tetrahydrofuran 15 ml, 2 drops of dimethylformamide, 0.32 of 2-aminophenylacetic acid ethyl ester obtained in Reference Example 53
Example 3 using 0.55 ml of triethylamine and 0.50 ml of triethylamine
Reaction yielded 0.78 g of brown crystals of the target compound having a melting point of 142-143 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.10 (3H, t, J = 7.1 H
z), 2.01 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.35
(3H, s), 3.71 (2H, s), 4.01 (2H, q, J = 7.1 Hz),
4.88 (2H, s), 7.2-7.3 (1H, m), 7.3-7.4 (3H, m), 7.
62 (1H, s), 9.82 (1H, s, disappeared by adding heavy water).

[0345]

Working Example 135 2- (6-hydroxy-5,7,8-
Trimethyl-2H-chromen-3-carbonylamino)
Phenylacetic acid (Compound No. 1-339) 2- (6-acetoxy-5,7,8-trimethyl- obtained in Example 134
2H-chromen-3-carbonylamino) phenylacetic acid ethyl ester 0.40 g, the reaction was carried out according to Example 43 using 4 ml of a 2N aqueous solution of potassium hydroxide and 4 ml of methanol. 0.28 g of crystals were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.05 (3H, s), 2.12 (3H, s),
2.23 (3H, s), 3.65 (2H, s), 4.78 (2H, s), 7.19 (1H,
t, J = 7.3 Hz), 7.25-7.35 (2H, m), 7.43 (1H, d, J
= 7.8 Hz), 7.62 (1H, s), 7.85 (1H, s, disappeared by adding heavy water), 9.77 (1H, s, disappeared by adding heavy water), 12.41 (1
H, s, disappeared by addition of heavy water).

[0346]

Working Example 136 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-morpholinophenyl) amide (Compound No. 1-324) 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 15 m
l, 2 drops of dimethylformamide, 0.32 g of 2-morpholinoaniline and 0.50 ml of triethylamine according to Example 3 to give a melting point of 214-216 ° C.
0.77 g of brown crystals of the target compound having the formula was obtained.
¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s),
2.10 (3H, s), 2.16 (3H, s), 2.35 (3H, s), 2.86 (4H,
t, J = 4.4 Hz), 3.78 (4H, t, J = 4.4 Hz), 4.96 (2
H, s), 7.1-7.2 (2H, m), 7.2-7.3 (1H, m), 7.58 (1H,
s), 7.95-8.05 (1H, m), 9.46 (1H, s, disappeared by addition of heavy water).

[0347]

Working Example 137 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (1H-
[Benzimidazol-2-yl) phenyl] amide (Compound No. 1-322) 6-acetoxy- obtained in Reference Example 5
0.50 g of 5,7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 15 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 0.28 g of 2- (2-aminophenyl) benzimidazole and triethylamine The reaction was carried out according to Example 3 using 0.50 ml to obtain 0.77 g of a light brown crystal of the target compound having a melting point of 275-277 ° C.
¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.04 (3H, s),
2.14 (3H, s), 2.20 (3H, s), 2.38 (3H, s), 5.09 (2H,
s), 7.3-7.35 (3H, m), 7.53 (1H, t, J = 7.7Hz), 7.
6-7.65 (2H, m), 7.74 (1H, s), 8.17 (1H, d, J = 7.9
Hz), 8.82 (1H, t, J = 8.4 Hz), 13.28 (1H, s, disappeared by adding heavy water), 13.57 (1H, s, disappeared by adding heavy water).

[0348]

Working Example 138 Methyl 2-[(7-methoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-344) 7-Methoxy-2H-chromene-3 obtained in Reference Example 55 Carboxylic acid 0.28 g, anthranilic acid methyl ester 0.17 g, carbon tetrachloride 0.1 g.
The reaction was carried out according to Example 97 using 51 g, 0.87 g of triphenylphosphine and 10 ml of anhydrous dimethylacetamide to obtain 0.24 g of a pale yellow powder of the target compound having a melting point of 125 to 128 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 3.78 (3H, s), 3.90 (3H, s),
5.00 (2H, s), 6.50-6.51 (1H, d, J = 2.4 Hz), 6.59-
6.61 (1H, dd, J = 23.7 and 8.7Hz), 7.20-7.24 (1H,
m), 7.27-7.30 (1H, d, J = 8.5 Hz), 7.39 (1H, s),
7.63-7.68 (1H, m), 7.97-8.00 (1H, dd, J = 1.4 and
7.8 Hz), 8.38-8.40 (1H, d, J = 7.8 Hz), 11.17 (1H,
s).

[0349]

Working Example 139 2-[(7-Methoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-
343) 2-[(7-methoxy-) obtained in Example 138
A mixture of 0.15 g of [2H-chromen-3-carbonyl) amino] benzoic acid methyl ester, 3 ml of 1N aqueous sodium hydroxide solution and 15 ml of dimethylformamide was irradiated with ultrasonic waves at room temperature for 5 minutes and then left overnight. Water was added to the reaction mixture, which was adjusted to be acidic with a 2N aqueous hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling off the solvent from the extract, the precipitate was collected by filtration using diisopropyl ether and washed to obtain 0.08 g of the target substance as a pale yellow powder having a melting point of 220-221 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 3.78 (3H, s), 5.01 (2H, s),
6.50-6.51 (1H, d, J = 2.4 Hz), 6.58-6.61 (1H, dd,
J = 2.7 and 8.6 Hz), 7.16-7.20 (1H, m), 7.24-7.26
(1H, d, J = 8.2 Hz), 7.35 (1H, s), 7.61-7.65 (1H,
m), 8.02-8.05 (1H, dd, J = 1.7 and 7.9 Hz), 8.56-8.
58 (1H, d, J = 7.8 Hz), 11.84 (1H, s), 13.83-13.82
(1H, br).

[0350]

Working Example 140 Methyl 2-[(5-methoxy-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-358) 5-Methoxy-2H-chromen-3 obtained in Reference Example 57 Carboxylic acid 0.28 g, anthranilic acid methyl ester 0.17 g, carbon tetrachloride 0.1 g.
The reaction was carried out according to Example 97 using 51 g, 0.87 g of triphenylphosphine and 10 ml of anhydrous dimethylacetamide to obtain 0.29 g of a pale yellow powder of the target compound having a melting point of 147 to 149 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 3.88 (3H, s), 3.90 (3H, s),
4.96 (2H, s), 6.53-6.55 (1H, d, J = 8.4 Hz), 6.67-
6.69 (1H, d, J = 8.3 Hz), 7.21-7.29 (2H, m), 7.62-
7.69 (1H, m), 7.96-7.99 (1H, dd, J = 1.5 and 8.0 H
z), 8.35-8.38 (1H, d, J = 9.0 Hz), 11.21 (1H, s).

[0351]

Working Example 141 2-[(5-Methoxy-2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-
357) 2-[(5-methoxy-) obtained in Example 140.
2H-Chromen-3-carbonyl) amino] benzoic acid methyl ester (0.15 g), 1N aqueous sodium hydroxide solution (3 ml) and dimethylformamide (15 ml) were reacted according to Example 139 to give a melting point of 249-251 ° C.
0.11 g of a pale yellow powder of the target compound having the formula was obtained. ¹ H-NMR spectrum _{(δppm, DMSO-d 6)} 3.86 (3H,
s), 4.96 (2H, d, J = 1.0 Hz), 6.53-6.55 (1H, d, J
= 8.3 Hz), 6.67-6.69 (1H, d, J = 8.4 Hz), 7.16-7.2
0 (1H, m), 7.25-7.29 (1H, t, J = 8.3 Hz), 7.59-7.6
5 (2H, m) 8.03-8.05 (1H, dd, J = 1.6 and 8.0 Hz),
8.59-8.62 (1H, d, J = 8.8 Hz), 12.01 (1H, s), 13.9
0-13.88 (1H, br).

[0352]

Working Example 142 2-[(6-trifluoromethoxy-
2H-Chromen-3-carbonyl) amino] benzoic acid methyl ester (Compound No. 1-354) 6-trifluoromethoxy-2H-chromen-3-carboxylic acid 0.36 g obtained in Reference Example 59, anthranilic acid methyl ester 0.17 g, carbon tetrachloride 0.51 g, triphenylphosphine 0.87 g and anhydrous dimethylacetamide 10 m
When the reaction was carried out according to Example 97 by using
0.19 pale yellowish white powder of target compound having -123 ° C
g was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
3.90 (3H, s), 5.08 (2H, d, J = 1.1 Hz), 6.99-7.01
(1H, d, J = 8.8 Hz), 7.23-7.30 (2H, m), 7.44-7.47
(2H, m), 7.64-7.69 (1H, m), 7.98-8.00 (1H, dd, J =
1.7 and 7.9 Hz), 8.33-8.35 (1H, d, J = 7.9 Hz), 1
1.16 (1H, s).

[0353]

Working Example 143 2-[(6-trifluoromethoxy-
2H-chromen-3-carbonyl) amino] benzoic acid (Compound No. 1-353) 2-
[(6-trifluoromethoxy-2H-chromen-3-
Carbonyl) amino] benzoic acid methyl ester 0.12
g, 1N aqueous sodium hydroxide solution (3 ml) and dimethylformamide (15 ml) were reacted according to Example 139 to obtain 0.085 g of a pale yellowish white powder of the target compound having a melting point of 215-216 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 5.10 (2H, s), 6.99-7.01 (1H,
d, J = 8.8 Hz), 7.17-7.21 (1H, m), 7.42 (2H, s),
7.60-7.64 (1H, m), 8.03-8.06 (1H, dd, J = 1.4 and
7.6 Hz), 8.53-8.55 (1H, d, J = 7.8 Hz), 12.01-12.1
8 (1H, br), 13.86-13.87 (1H, br).

[0354]

Working Example 144 Methyl 2-[(6-t-butyl-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-350)
Butyl-2H-chromene-3-carboxylic acid 0.32 g,
When the reaction was carried out according to Example 97 using 0.17 g of anthranilic acid methyl ester, 0.51 g of carbon tetrachloride, 0.87 g of triphenylphosphine and 10 ml of anhydrous dimethylacetamide, the light yellow color of the target compound having a melting point of 103 to 104 ° C was obtained. 0.22 g of a powder was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.28 (9H, s), 3.91 (3H,
s), 4.99 (2H, s), 6.82-6.84 (1H, d, J = 8.5 Hz), 7.
22-7.26 (1H, m), 7.31-7.35 (2H, m), 7.43 (1H, s),
7.64-7.68 (1H, m), 7.98-8.01 (1H, dd, J = 1.4 and
8.0 Hz), 8.38-8.40 (1H, m), 11.20 (1H, s).

[0355]

Example 145 2-[(6-t-butyl-2H-chromen-3-carbonyl) amino] benzoic acid (compound number
1-349) 0.15 g of 2-[(6-t-butyl-2H-chromen-3-carbonyl) amino] benzoic acid methyl ester obtained in Example 144, 3 ml of 1N aqueous sodium hydroxide solution and 15 ml of dimethylformamide Was reacted according to Example 139 to give a melting point of 211-21.
0.045 g of a pale yellow-white powder of the target compound having a temperature of 2 ° C. was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.27
(9H, s), 5.00 (2H, s), 6.82-6.84 (1H, m), 7.16-7.20
(1H, t, J = 7.7 Hz), 7.31-7.33 (2H, m), 7.40 (1H,
s), 7.60-7.64 (1H, m), 8.03-8.06 (1H, dd, J = 1.4
and 7.9 Hz), 8.56-8.58 (1H, m), 12.06-12.09 (1H,
br), 13.85-13.86 (1H, br).

[0356]

Working Example 146 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (1H-
Tetrazol-5-yl) phenyl] amide (Compound No. 1-318) 6-acetoxy-5 obtained in Reference Example 5
0.50 g of 7,8-trimethyl-2H-chromene-3-carboxylic acid, 0.16 ml of oxalyl chloride, 10 ml of tetrahydrofuran, 2 drops of dimethylformamide,
When the reaction was carried out according to Example 29 using 0.29 g of-(1H-tetrazol-5-yl) phenylamine and 5 ml of anhydrous dimethylacetamide, the melting point was 248-250.
0.10 g of yellow crystals of the target compound having a temperature of ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H,
s), 2.11 (3H, s), 2.20 (3H, s), 2.37 (3H, s), 4.98
(2H, s), 7.34 (1H, t, J = 7.6 Hz), 7.60 (1H, t, J =
7.9 Hz), 7.80 (1H, s), 8.04 (1H, d, J = 7.6 Hz),
8.49 (1H, d, J = 7.9 Hz), 11.51 (1H, s, disappeared by addition of heavy water).

[0357]

Working Example 147 2-[(6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-pyridyl) benzoic acid methyl ester (Compound No. 1-68) 6-acetoxy-5,7,8-trimethyl obtained in Reference Example 5 0.50 g of -2H-chromene-3-carboxylic acid, 0.16 ml of oxalyl chloride,
10 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 2-amino-5- (2-
When the reaction was carried out according to Example 29 using 0.41 g of methyl pyridyl) benzoate and 5 ml of anhydrous dimethylacetamide, 0.60 g of pale yellow crystals of the target compound having a melting point of 260-262 ° C were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.02 (3H, s), 2.11 (3H, s),
2.16 (3H, s), 2.36 (3H, s), 3.95 (3H, s), 4.98 (2H,
s), 7.38 (1H, dd, J = 5.0 and7.4 Hz), 7.63 (1H,
s), 7.91 (1H, dt, J = 1.8 and 7.7 Hz), 8.02 (1H,
d, J = 8.0 Hz), 8.37 (1H, dd, J = 2.2 and 8.8 Hz),
8.51 (1H, d, J = 8.8 Hz), 8.69 (1H, d, J = 3.8 H
z), 8.78 (1H, d, J = 2.2 Hz), 11.32 (1H, s, disappeared by addition of heavy water).

[0358]

Example 148 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (1-piperidino) phenyl] amide (Compound No. 1-323) Obtained in Reference Example 5. 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 15 ml, dimethylformamide 2 drops, 2- (1-piperidino) aniline 0.32 g And triethylamine 0.
When the reaction was carried out according to Example 3 using 50 ml, the melting point was 1
0.77 pale brown crystals of the target compound having a temperature of 39-140 ° C.
4 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
1.5-1.6 (2H, m), 1.65-1.75 (4H, m), 2.01 (3H, s),
2.10 (3H, s), 2.14 (3H, s), 2.35 (3H, s), 2.80 (4
H, t, J = 5.1 Hz), 4.96 (2H, s), 7.05-7.15 (2H, m),
7.2-7.25 (1H, m), 7.55 (1H, s), 8.0-8.05 (1H, m),
9.40 (1H, s, disappeared by addition of heavy water).

[0359]

Working Example 149 2-[(6-hydroxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-pyridyl) benzoic acid (Compound No. 1-13
7) 2-[(6-acetoxy-) obtained in Example 147
5,7,8-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-pyridyl) benzoic acid methyl ester 0.15 g, 2N aqueous potassium hydroxide solution 2 m
l, 2 ml of methanol and 2 ml of tetrahydrofuran, and reacted according to Example 43, melting point> 229 ° C.
0.088 g of a yellow crystal of the target compound having the following formula: was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.07 (3H,
s), 2.13 (3H, s), 2.25 (3H, s), 4.88 (2H, s), 7.34
(1H, dd, J = 5.4 and 7.3 Hz), 7.62 (1H, s), 7.88 (1
H, dt, J = 1.8 and 7.7 Hz), 7.92 (1H, s, disappeared by adding heavy water), 7.97 (1H, d, J = 8.0 Hz), 8.27 (1H, dd,
J = 2.1 and 8.8 Hz), 8.67 (1H, d, J = 4.4Hz), 8.72
(1H, d, J = 8.8 Hz), 8.81 (1H, d, J = 2.1 Hz), 1
3.05 (1H, s, disappeared by addition of heavy water).

[0360]

Example 150 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid {2- [3-phenyl (thioureido) phenyl]} amide (Compound No. 1-335) 6-acetoxy obtained
A solution of 0.30 g of 5,7,8-trimethyl-2H-chromen-3-carboxylic acid (2-aminophenyl) amide and 0.12 ml of phenylisothiocyanate in 8 ml of anhydrous tetrahydrofuran was stirred at room temperature for 2 hours, and 16 ml of anhydrous dimethylformamide was added. And further stirred at 40 ° C. for 2 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Diisopropyl ether was added to the residue obtained by distilling off the solvent from the extract, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration and dried to obtain 0.32 g of white crystals of the target compound having a melting point of 170 to 171 ° C. ¹ HN
MR spectrum _{(δppm, DMSO-d 6)} 2.01 (3H, s), 2.10
(6H, s), 2.35 (3H, s), 4.83 (2H, s), 7.17 (1H, t, J
= 7.4 Hz), 7.25-7.3 (2H, m), 7.3-7.4 (2H, m), 7.4
-7.5 (3H, m), 7.6-7.7 (2H, m), 8.93 (1H, s, disappeared by adding heavy water), 10.00 (1H, s, disappeared by adding heavy water), 10.1
3 (1H, s, disappeared by adding heavy water).

[0361]

Example 151 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (3-phenylureido) phenyl] amide (Compound No. 1-33)
4) 6-acetoxy-5,7, obtained in Example 114
8-trimethyl-2H-chromen-3-carboxylic acid (2
A solution of 0.30 g of -aminophenyl) amide and 0.11 ml of phenylisocyanate in 8 ml of anhydrous dimethylformamide was stirred at 40C for 30 minutes. After standing at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Diisopropyl ether was added to the residue obtained by distilling off the solvent from the extract, and ultrasonic vibration was applied. The precipitated crystals were collected by filtration and dried to obtain 0.33 g of yellow crystals of the target compound having a melting point of 207 to 208 ° C. ¹ H
-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.1
0 (3H, s), 2.11 (3H, s), 2.35 (3H, s), 4.94 (2H,
s), 6.96 (1H, t, J = 7.3 Hz), 7.05 (1H, t, J = 7.3
Hz), 7.2-7.4 (4H, m), 7.45 (2H, d, J = 7.8 Hz), 7.
75 (1H, s), 7.9-8.0 (1H, m), 8.00 (1H, s, disappeared by adding heavy water), 9.23 (1H, s, disappeared by adding heavy water), 9.89 (1
H, s, disappeared by addition of heavy water).

[0362]

Working Example 152 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (3-ethylureido) phenyl] amide (Compound No. 1-333)
6-acetoxy-5,7,8- obtained in Example 114
When 0.30 g of trimethyl-2H-chromen-3-carboxylic acid (2-aminophenyl) amide, 0.08 ml of ethyl isocyanate and 8 ml of anhydrous dimethylformamide were reacted according to Example 151, the melting point was 186-
0.30 g of yellow crystals of the target compound having a temperature of 188 ° C. were obtained. ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 1.05 (3
H, t, J = 7.3 Hz), 2.01 (3H, s), 2.09 (3H, s), 2.1
3 (3H, s), 2.51 (3H, s), 3.10-3.15 (2H, m), 4.92
(2H, s), 6.75 (1H, t, J = 5.4 Hz, disappeared by adding heavy water), 6.95-7.05 (1H, m), 7.1-7.2 (1H, m), 7.3-7.4
(1H, m), 7.68 (1H, s), 7.75-7.85 (1H, m), 7.84 (1
H, s, disappeared by adding heavy water), 9.98 (1H, s, disappeared by adding heavy water).

[0363]

EXAMPLE 153 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-benzoylaminophenyl) amide (Compound No. 1-328) 6-acetoxy obtained in Example 114 -5,7,8-trimethyl-2H-chromen-3-carboxylic acid (2-aminophenyl) amide 0.30 g, triethylamine 0.11
The reaction was carried out according to Example 3 using 0.1 ml of benzoyl chloride and 8 ml of anhydrous dimethylformamide to obtain 0.11 g of yellow crystals of the target compound having a melting point of 211 to 213 ° C. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 1.99 (3H, s), 2.02 (3H, s), 2.08 (3H,
s), 2.34 (3H, s), 4.91 (2H, s), 7.25-7.35 (2H, m),
7.5-7.75 (6H, m), 7.95-8.05 (2H, m), 9.90 (1H, s,
10.01 (1H, s, disappeared by adding heavy water).

[0364]

EXAMPLE 154 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-acetylaminophenyl) amide (Compound No. 1-327)
6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-aminophenyl) amide 0.30 g obtained in 14 and triethylamine 0.11 m
l, 0.10 ml of acetic anhydride and 8 ml of dimethylformamide were reacted according to Example 3 to obtain a melting point of 2
0.20 yellow crystals of the target compound having a temperature of 50-252 ° C.
g was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ )
2.01 (3H, s), 2.09 (6H, s), 2.13 (3H, s), 2.35 (3H,
s), 4.91 (2H, s), 7.15-7.25 (2H, m), 7.5-7.7 (3H,
m), 9.65 (1H, s, disappeared by adding heavy water), 9.71 (1H, s,
Disappears with the addition of heavy water).

[0365]

Example 155 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (4-phenoxyphenyl) amide (Compound No. 1-311) 6-acetoxy-5-amino acid obtained in Reference Example 5 5,7,8-trimethyl-2H
-Chromene-3-carboxylic acid 0.50 g, oxalyl chloride 0.16 ml, anhydrous tetrahydrofuran 15 m
l, 2 drops of dimethylformamide, 0.34 g of 4-phenoxyaniline and 0.50 ml of triethylamine, and reacted according to Example 3, melting point 185-186 ° C.
0.79 g of pale yellow crystals of the target compound having the formula were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H,
s), 2.09 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 4.90
(2H, s), 6.99 (2H, d, J = 7.9 Hz), 7.03 (2H, d, J =
8.9 Hz), 7.12 (1H, t, J = 7.4 Hz), 7.38 (2H, t, J
= 7.9 Hz), 7.64 (1H, s), 7.70 (2H, d, J = 8.9 H
z), 10.09 (1H, s, disappeared by addition of heavy water).

[0366]

Example 156 4- {4-[(6-acetoxy-5,
7,8-Trimethyl-2H-chromen-3-carbonyl) amino] phenoxy {benzoic acid ethyl ester (Compound No. 1-312) 6-acetoxy- obtained in Reference Example 5
0.50 g of 5,7,8-trimethyl-2H-chromen-3-carboxylic acid, 0.16 ml of oxalyl chloride, 15 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 4- (4-aminophenoxy) obtained in Reference Example 64 The reaction was carried out according to Example 3 using 0.47 g of benzoic acid ethyl ester and 0.50 ml of triethylamine to obtain 0.91 g of pale yellow crystals of the target compound having a melting point of 175 to 177 ° C. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 1.31 (3H, t, J = 7.1 Hz), 2.01 (3H,
s), 2.10 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 4.29
(2H, q, J = 7.1 Hz), 4.91 (2H, s), 7.04 (2H, d, J
= 8.8 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.65 (1H,
s), 7.77 (2H, d, J = 8.9 Hz), 7.96 (2H, d, J = 8.8 Hz)
Hz), 10.15 (1H, s, disappeared by addition of heavy water).

[0367]

Example 157 4- {4-[(6-hydroxy-5,
7,8-Trimethyl-2H-chromen-3-carbonyl) amino] phenoxydibenzoic acid (Compound No. 1-34
2) 4- {4-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3- obtained in Example 156
Carbonyl) amino] phenoxy {benzoic acid ethyl ester 0.40 g, 2N aqueous potassium hydroxide solution 4 ml,
When reacted according to Example 43 using 4 ml of methanol and 4 ml of tetrahydrofuran, the melting point was 160-162.
0.35 g of yellow crystals of the target compound having a temperature of 0.3 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.06 (3H,
s), 2.12 (3H, s), 2.26 (3H, s), 4.80 (2H, s), 7.01
(2H, d, J = 8.8 Hz), 7.13 (2H, d, J = 8.9 Hz), 7.6
5 (1H, s), 7.77 (2H, d, J = 8.9 Hz), 7.87 (1H, s,
(Disappears with the addition of heavy water), 7.94 (2H, d, J = 8.8 Hz), 10.10
(1H, s, disappeared by adding heavy water), 12.79 (1H, s, disappeared by adding heavy water).

[0368]

Example 158 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (2-dimethylaminoethylcarbamoyl) phenyl] amide (Compound No. 1-295) The obtained 3-[(6-
Acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.066 ml, tetrahydrofuran 9
ml, 2 drops of dimethylformamide, 0.081 ml of N, N-dimethylethylenediamine and 0.11 ml of triethylamine according to Example 3, yielding 0.32 g of pale yellow crystals of the target compound having a melting point of 105-107 ° C. Obtained. ¹ H-NMR spectrum (δppm, DMS
Od ₆ ) 2.01 (3H, s), 2.09 (3H, s), 2.16 (3H, s), 2.
19 (6H, s), 2.35 (3H, s), 2.42 (2H, t, J = 6.8 H
z), 3.3-3.4 (2H, m), 4.91 (2H, s), 7.42 (1H, t, J =
7.9 Hz), 7.54 (1H, d, J = 7.9 Hz), 7.71 (1H, s),
7.92 (1H, dd, J = 1.6 and 7.9 Hz), 8.09 (1H, t, J
= 1.6 Hz), 8.36 (1H, t, J = 5.5 Hz, disappeared by adding heavy water), 10.20 (1H, s, disappeared by adding heavy water).

[0369]

Example 159 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-phenylcarbamoylphenyl) amide (Compound No. 1-296) 3- [ (6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.06
When 6 ml, 9 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 70 mg of aniline and 0.11 ml of triethylamine were reacted according to Example 3, yellow crystals of the target compound having a melting point of 139-141 ° C. were obtained.
23 g were obtained. ¹ H-NMR spectrum (δppm, DMSO-
d ₆ ) 2.01 (3H, s), 2.10 (3H, s), 2.16 (3H, s), 2.36
(3H, s), 4.93 (2H, s), 7.11 (1H, t, J = 7.3 Hz),
7.36 (2H, t, J = 7.8 Hz), 7.51 (1H, t, J = 8.0 Hz),
7.69 (1H, d, J = 8.0 Hz), 7.73 (1H, s), 7.78 (2H,
d, J = 7.7 Hz), 8.00 (1H, d, J = 8.0 Hz), 8.20 (1
H, t, J = 1.6 Hz), 10.26 (1H, s, disappeared by adding heavy water),
10.28 (1H, s, disappeared by addition of heavy water).

[0370]

Working Example 160 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-ethylcarbamoylphenyl) amide (Compound No. 1-290) 3- [ (6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.06
When 6 ml, anhydrous tetrahydrofuran 9 ml, dimethylformamide 2 drops, ethylamine hydrochloride 62 mg and triethylamine 0.22 ml were reacted according to Example 3, 0.32 g of pale yellow crystals of the target compound having a melting point of 102-106 ° C were obtained. Was done. ¹ H-NMR spectrum (δ
ppm, DMSO-d ₆ ) 1.12 (3H, t, J = 7.3 Hz), 2.01 (3H,
s), 2.09 (3H, s), 2.16 (3H, s), 2.35 (3H, s), 3.2
5-3.4 (2H, m), 4.91 (2H, s), 7.42 (1H, t, J = 7.8 H
z), 7.54 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 7.92
(1H, d, J = 7.8 Hz), 8.10 (1H, s), 8.46 (1H, t, J
= 5.4 Hz), 10.19 (1H, s, disappeared with the addition of heavy water).

[0371]

Working Example 161 6-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-butylcarbamoylphenyl) amide (Compound No. 1-291) 3- [ (6-acetoxy-5,7,8-
Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.06
The reaction was carried out according to Example 3 using 6 ml, 9 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 55 mg of butylamine and 0.11 ml of triethylamine to obtain 0.16 g of pale yellow crystals of the target compound having a melting point of 117 to 119 ° C. . ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 0.91 (3H, t, J = 7.3 Hz), 1.33 (2H, t
q, J = 7.3 and 7.3 Hz), 1.51 (2H, tt, J = 7.3 and
7.3 Hz), 2.01 (3H, s), 2.09 (3H, s), 2.16 (3H, s),
2.35 (3H, s), 3.26 (2H, dt, J = 6.6 and 6.6Hz, t with heavy water addition, J = 7.1Hz), 4.91 (2H, s), 7.42 (1H,
t, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.71 (1H,
s), 7.92 (1H, d, J = 7.8 Hz), 8.08 (1H, s), 8.42
(1H, t, J = 5.6 Hz, disappeared by adding heavy water), 10.19 (1H,
s, disappeared by addition of heavy water).

[0372]

Working Example 162 6-Acetoxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid (3-hexylcarbamoylphenyl) amide (Compound No. 1-292) 3- [ (6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.06
When 6 ml, anhydrous tetrahydrofuran 9 ml, dimethylformamide 2 drops, hexylamine 77 mg and triethylamine 0.11 ml were reacted according to Example 3, 0.20 g of pale yellow crystals of the target compound having a melting point of 110-112 ° C. were obtained. Was. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 0.87 (3H, t, J = 6.8 Hz), 1.2-1.4 (6
H, m), 1.52 (2H, tt, J = 7.0 and 7.0 Hz), 2.01 (3
H, s), 2.09 (3H, s), 2.16 (3H, s), 2.35 (3H, s),
3.25 (2H, dt, J = 6.6 and 6.6 Hz), 4.91 (2H, s),
7.42 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 H
z), 7.71 (1H, s), 7.92 (1H, dd, J = 1.7 and 7.8 H
z), 8.09 (1H, t, J = 1.7 Hz), 8.43 (1H, t, J = 5.5
Hz), 10.19 (1H, s, disappeared by adding heavy water).

[0373]

Example 163 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-benzylcarbamoylphenyl) amide (Compound No. 1-293) 3- [ (6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, oxalyl chloride 0.06
When 6 ml, 9 ml of anhydrous tetrahydrofuran, 2 drops of dimethylformamide, 81 mg of benzylamine hydrochloride and 0.11 ml of triethylamine were reacted according to Example 3, 0.26 g of pale yellow crystals of the target compound having a melting point of 105-108 ° C were obtained. Obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H, s), 2.09 (3H, s), 2.1
6 (3H, s), 2.35 (3H, s), 4.48 (2H, d, J = 6.0 Hz),
4.91 (2H, s), 7.2-7.3 (1H, m), 7.3-7.4 (4H, m), 7.4
4 (1H, t, J = 7.8 Hz), 7.62 (1H, d, J = 7.6 Hz), 7.
71 (1H, s), 7.93 (1H, dd, J = 1.9 and 8.0 Hz), 8.1
5 (1H, s), 9.04 (1H, t, J = 6.0 Hz), 10.20 (1H,
s).

[0374]

Example 164 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (pyridin-4-ylcarbonylamino) phenyl] amide (Compound No. 1-330) Example 114 0.30 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-aminophenyl) amide obtained in the above, 0.66 ml of triethylamine, 0.3 g of isonicotinoyl chloride hydrochloride and 8 ml of anhydrous dimethylformamide
Was reacted according to Example 3 to obtain a melting point of 181-1.
0.25 g of white crystals of the target compound having a temperature of 85 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H,
s), 2.02 (3H, s), 2.07 (3H, s), 2.34 (3H, s), 4.90
(2H, s), 6.75 (1H, t, J = 5.4 Hz, disappeared by adding heavy water), 7.2-7.4 (2H, m), 7.60 (1H, s), 7.6-7.7 (2H,
m), 7.85-7.95 (2H, m), 8.75-8.85 (1H, m), 9.85 (1H,
s, disappeared by adding heavy water), 10.22 (1H, s, disappeared by adding heavy water).

[0375]

Example 165 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (pyridin-2-ylcarbonylamino) phenyl] amide (Compound No. 1-329) Example 114 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (2-aminophenyl) amide 0.30 g, triethylamine 0.66 ml, picolinoyl chloride hydrochloride 0.29 g and anhydrous When the reaction was carried out according to Example 3 using 8 ml of dimethylformamide, the melting point was 170-17.
0.07 g of brown crystals of the target compound having a temperature of 2 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H,
s), 2.10 (3H, s), 2.11 (3H, s), 2.35 (3H, s), 4.95
(2H, s), 7.2-7.3 (1H, m), 7.3-7.4 (1H, m), 7.4-7.5
(1H, m), 7.6-7.7 (1H, m), 7.73 (1H, s), 8.0-8.1
(2H, m), 8.17 (1H, d, J = 7.9 Hz), 8.64 (1H, d, J =
4.6 Hz), 10.20 (1H, s, disappeared by adding heavy water), 10.45 (1
H, s, disappeared by addition of heavy water).

[0376]

Working Example 166 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-hydroxyphenyl) amide (Compound No. 1-306) 5,7,8-trimethyl-2
H-chromen-3-carbonyl chloride 5.00 g, 3
1.90 g of aminophenol, 2.
7. Reaction with 4 ml and 85 ml of anhydrous dimethylacetamide according to Example 29 to yield yellow crystals of the desired compound having an Rf value of 0.48 (silica gel thin layer chromatography; n-hexane: ethyl acetate 1: 1). 06
g was obtained.

[0377]

Example 167 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (3-methylbutoxy) phenyl] amide (Compound No. 1-310)
6-acetoxy-5,7,8- obtained in Example 166
0.4 g of trimethyl-2H-chromen-3-carboxylic acid (3-hydroxyphenyl) amide, 3-methyl-1-
Butanol 0.24 ml, 1,1′-azodicarbonyldipiperidine 1.1 g, tributylphosphine 1.08
The reaction was carried out according to Example 79 using 10 ml of anhydrous toluene and 10 ml of anhydrous toluene, to obtain 0.25 g of white crystals of the target compound having a melting point of 150 to 152 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 0.94 (6H, d, J = 6.6 Hz), 1.6
2 (2H, q, J = 6.7 Hz), 1.79 (1H, m), 2.01 (3H, s),
2.09 (3H, s), 2.14 (3H, s), 2.35 (3H, s), 3.9-4.0
5 (2H, m), 4.89 (2H, s), 6.6-6.7 (1H, m), 7.25-7.4
(2H, m), 7.38 (1H, d, J = 2.1 Hz), 7.63 (1H, s),
10.00 (1H, s, disappeared by adding heavy water).

[0378]

Example 168 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (3-methoxy) phenyl] amide (Compound No. 1-307) Obtained in Reference Example 28 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl chloride 0.40
g, 0.19 ml of triethylamine, 0.15 ml of m-anisidine and 10 ml of anhydrous tetrahydrofuran, and reacted according to Example 3, melting point 201-203.
0.37 g of white crystals of the target compound having a temperature of ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3H,
s), 2.09 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 3.74
(3H, d, J = 6.5 Hz), 4.89 (2H, s), 6.65-6.7 (1H,
m), 7.2-7.3 (2H, m), 7.38 (1H, d, J = 1.7 Hz), 7.6
4 (1H, s), 10.03 (1H, s, disappeared by adding heavy water).

[0379]

Example 169 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (3-ethoxy) phenyl] amide (Compound No. 1-308) Obtained in Reference Example 28. 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl chloride 0.40
g, 0.19 ml of triethylamine, 0.18 ml of m-phenetidine and 10 ml of anhydrous tetrahydrofuran, and reacted according to Example 3, melting point 168-171.
0.22 g of white crystals of the target compound having a temperature of ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.33 (3H,
t, J = 6.9 Hz), 2.01 (3H, s), 2.09 (3H, s), 2.15
(3H, s), 2.35 (3H, s), 4.01 (2H, dd, J = 7.0 Hz),
4.89 (2H, s), 6.6-6.7 (1H, m), 7.2-7.3 (2H, m), 7.
38 (1H, d, J = 2.1 Hz), 7.63 (1H, s), 10.03 (1H,
s, disappeared by addition of heavy water).

[0380]

Example 170 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (3-phenoxy) phenyl] amide (Compound No. 1-313) Obtained in Reference Example 28 6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl chloride 0.4
0 g, triethylamine 0.19 ml, 3-phenoxyaniline 0.25 g and anhydrous tetrahydrofuran 10 m
When the reaction was carried out according to Example 3 using l, the melting point was 203-
0.21 g of white crystals of the target compound having a temperature of 206 ° C. were obtained. ¹ H-NMR spectrum (δ ppm, DMSO-d ₆ ) 2.00
(3H, s), 2.08 (3H, s), 2.15 (3H, s), 2.34 (3H, s),
4.87 (2H, s), 6.7-6.8 (1H, m), 7.04 (2H, d, J =
8.4Hz), 7.35 (1H, t, J = 8.1 Hz), 7.35-7.5 (5H,
m), 7.61 (1H, s), 10.11 (1H, s, disappeared by addition of heavy water).

[0381]

Example 171 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (4-phenylbutylcarbamoyl) phenyl] amide (Compound No. 1-294) 0.30 g of 3-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid obtained, 0.12 ml of 4-phenylbutylamine, 0.12 ml of diethyl cyanophosphonate, The reaction was carried out according to Example 77 using 0.11 ml of triethylamine and 5 ml of anhydrous tetrahydrofuran to obtain 0.35 g of yellow crystals of the target compound having a melting point of 160 to 161 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.5-1.7 (4H, m), 2.01 (3H, s),
2.09 (3H, s), 2.15 (3H, s), 2.36 (3H, s), 2.61 (2
H, t, J = 7.4 Hz), 3.25-3.35 (2H, m), 4.91 (2H, s),
7.1-7.25 (3H, m), 7.26 (2H, d, J = 7.4 Hz), 7.41
(1H, t, J = 7.9 Hz), 7.54 (1H, d, J = 7.9 Hz), 7.7
1 (1H, s), 7.92 (1H, dd, J = 1.8 and 7.9 Hz), 8.09
(1H, d, J = 1.9 Hz), 8.46 (1H, t, J = 5.7 Hz, disappeared by adding heavy water), 10.18 (1H, s, disappeared by adding heavy water).

[0382]

Example 172 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (4-chlorophenylcarbamoyl) phenyl] amide (Compound No. 1-297) Obtained in Example 3. 3-[(6-acetoxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoic acid 0.30 g, 4-chloroaniline 97 mg, diethyl cyanophosphonate 0.12 m
l, 0.11 ml of triethylamine and 5 ml of anhydrous tetrahydrofuran were reacted according to Example 77 to obtain 0.38 g of white crystals of the target compound having a melting point of 229-231 ° C. ¹ H-NMR spectrum (δ ppm, D
MSO-d ₆ ) 2.01 (3H, s), 2.10 (3H, s), 2.16 (3H, s),
2.36 (3H, s), 4.92 (2H, s), 7.42 (2H, d, J = 8.8 H
z), 7.51 (1H, t, J = 7.9 Hz), 7.68 (1H, d, J = 7.6
Hz), 7.73 (1H, s), 7.82 (2H, d, J = 8.8 Hz), 8.00
(1H, dd, J = 1.7 and 8.0 z), 8.20 (1H, t, J = 1.7
Hz), 10.27 (1H, s, disappeared by adding heavy water), 10.41 (1H, s,
Disappears with the addition of heavy water).

[0383]

Working Example 173 2-[(6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] -3,4,5-trimethoxybenzoic acid (compound number
1-53) 6-Acetoxy-5,7,8 obtained in Reference Example 5
-Trimethyl-2H-chromene-3-carboxylic acid 0.5
0 g, oxalyl chloride 0.16 ml, 2 drops of dimethylformamide, 10 ml of anhydrous tetrahydrofuran, 0.41 g of 3,4,5-trimethoxyanthranilic acid obtained in Reference Example 65 and 10 ml of anhydrous dimethylacetamide
And reacted according to Example 29 to obtain a melting point of 208-
0.08 g of white crystals of the target compound having a temperature of 210 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.01 (3
H, s), 2.09 (3H, s), 2.11 (3H, s), 2.35 (3H, s), 3.7
8 (3H, s), 3.78 (3H, s), 3.79 (3H, s), 4.90 (2H,
s), 7.28 (1H, s), 7.87 (1H, s), 11.82 (1H, s, disappeared by adding heavy water).

[0384]

Working Example 174 Ethyl 5- (2-diisopropylaminoethoxy) -2-[(6-hydroxy-5,7,8-trimethyl-2H-chromen-3-carbonyl) amino] benzoate (Compound No. 1-) 341) 6-hydroxy-5,7,8-trimethyl-2H obtained in Reference Example 4
-Chromene-3-carboxylic acid 0.30 g, oxalyl chloride 0.11 ml, dimethylformamide 2 drops, anhydrous tetrahydrofuran 10 ml, 5 obtained in Reference Example 68
The reaction was carried out according to Example 29 using 0.40 g of-(2-diisopropylaminoethoxy) anthranilic acid ethyl ester and 10 ml of anhydrous dimethylacetamide,
0.13 g of yellow crystals of the target compound having a melting point of 148-150 ° C. were obtained. ¹ H-NMR spectrum (δppm, DMS
Od ₆ ) 0.99 (12H, d, J = 6.5 Hz), 1.30 (3H, t, J =
7.0 Hz), 2.06 (3H, s), 2.12 (3H, s), 2.24 (3H, s),
2.76 (2H, t, J = 6.8 Hz), 2.95-3.1 (2H, m), 3.92
(2H, t, J = 6.9 Hz), 4.25-4.4 (2H, m), 4.81 (2H,
s), 7.2-7.3 (1H, m), 7.41 (1H, d, J = 3.0 Hz), 7.5
9 (1H, s), 7.89 (1H, s), 8.10 (1H, d, J = 8.9 Hz),
10.77 (1H, s, disappeared by adding heavy water).

[0385]

Example 175 2-[(6-acetoxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) amino] -5- (2-diisopropylaminoethoxy) benzoic acid (Compound No. 1-340) 6-acetoxy-5,7,8-trimethyl obtained in Reference Example 5 -2H-chromen-3
Carboxylic acid 0.11 g, oxalyl chloride 0.03
The reaction was carried out according to Example 29 using dimethylformamide (2 drops), anhydrous tetrahydrofuran (5 ml), 5- (2-diisopropylaminoethoxy) anthranilic acid obtained in Reference Example 70 (0.09 g), and dimethylacetamide (5 ml). 0.02 g of yellow crystals of the target compound having a temperature of -164 ° C were obtained.

[0386]

Working Example 176 [3- (6-acetoxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester (Compound No. 1-111)
0.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5,
0.32 g of ethyl 3-aminophenylacetic acid hydrochloride obtained in Reference Example 10, 0.5 m of triethylamine
The reaction was carried out according to Example 77 using 1, 10 ml of anhydrous tetrahydrofuran and 0.27 ml of diethyl cyanophosphonate to obtain 0.41 g of white crystals of the target compound having a melting point of 119 to 123 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.19 (3H, t, J = 7.2 Hz), 2.01
(3H, s), 2.09 (3H, s), 2.15 (3H, s), 2.35 (3H, s),
3.64 (2H, s), 4.05-4.2 (2H, m), 4.90 (2H, s), 6.99
(1H, d, J = 7.6 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.
55-7.7 (3H, m), 10.06 (1H, s, disappeared by adding heavy water).

[0387]

Working Example 177 [4- (6-acetoxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester (Compound No. 1-117)
0.50 g of 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 5,
0.32 g of 4-aminophenylacetic acid ethyl ester hydrochloride obtained in Reference Example 9, 0.5 ml of triethylamine,
The reaction was carried out according to Example 77 using 10 ml of anhydrous tetrahydrofuran and 0.27 ml of diethyl cyanophosphonate to obtain 0.49 g of the target compound as yellow crystals having a melting point of 133 to 136 ° C. ¹ H-NMR spectrum (δpp
m, DMSO-d ₆ ) 1.18 (3H, t, J = 7.2 Hz), 2.01 (3H,
s), 2.09 (3H, s), 2.15 (3H, s), 2.35 (3H, s), 3.62
(2H, s), 4.08 (2H, q, J = 7.2 Hz), 4.90 (2H, s),
7.23 (2H, d, J = 8.4 Hz), 7.63 (3H, d, J = 8.4 H
z), 7.64 (1H, s), 10.05 (1H, s, disappeared by adding heavy water).

[0388]

Working Example 178 [3- (6-hydroxy-5,7,8)
-Trimethyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-110) [3- (6-acetoxy-5,7,8-trimethyl-2H-chromene-3) obtained in Example 176. Example 4 using 0.17 g of [carbonyl] aminophenyl] acetic acid ethyl ester, 2 ml of a 2N aqueous potassium hydroxide solution and 2 ml of ethanol.
The reaction was carried out according to 3 to give 0.03 g of yellow crystals of the target compound having a melting point of 142-146 ° C.

[0389]

Working Example 179 [4- (6-hydroxy-5,7,8
-Trimethyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-116) [4- (6-acetoxy-5,7,8-trimethyl-2H-chromene-3) obtained in Example 177. Example 43 using 0.17 g of [carbonyl] aminophenyl] acetic acid ethyl ester, 2 ml of 2N aqueous potassium hydroxide solution and 2 ml of ethanol.
When the reaction was carried out in accordance with the above, 0.07 g of a yellow crystal of the target compound having a melting point of 161-165 ° C was obtained. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 2.05 (3H, s), 2.09 (3H,
s), 2.12 (3H, s), 3.53 (2H, s), 4.79 (2H, s), 7.22
(2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.
65 (1H, s), 7.85 (1H, s, disappeared by adding heavy water), 9.99
(1H, s, disappeared by adding heavy water), 12.28 (1H, br s, disappeared by adding heavy water).

[0390]

Working Example 180 Ethyl 3- [6- (6-acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-283)
6-acetoxy-5,7-di-t obtained in Reference Example 72
-Butyl-2H-chromene-3-carboxylic acid 0.80
g, 3-aminophenylacetic acid ethyl ester hydrochloride 0.50 g obtained in Reference Example 10, triethylamine 0.6
The reaction was carried out according to Example 77 using 4 ml, 10 ml of anhydrous tetrahydrofuran and 0.35 ml of diethyl cyanophosphonate to obtain 0.60 g of yellow crystals of the target compound having a melting point of 70 to 71 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.19 (3H, t, J = 7.1 Hz), 1.27
(9H, s) 1.42 (9H, s), 2.35 (3H, s), 3.64 (2H, s),
4.08 (2H, q, J = 7.1 Hz), 4.5-4.6 (1H, m), 5.05 (1
H, d, J = 13.4 Hz), 6.87 (1H, s), 7.00 (1H, d, J =
7.8 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.5-7.65 (2H,
m), 7.75 (1H, d, J = 1.6 Hz), 10.09 (1H, s, disappeared by addition of heavy water).

[0391]

Working Example 181 [4- (6-acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester (Compound No. 1-285)
6-acetoxy-5,7-di-t obtained in Reference Example 72
-Butyl-2H-chromene-3-carboxylic acid 0.80
g, 4-aminophenylacetic acid ethyl ester hydrochloride 0.50 g obtained in Reference Example 9, triethylamine 0.64
The reaction was carried out according to Example 77 using 10 ml of anhydrous tetrahydrofuran and 0.35 ml of diethyl cyanophosphonate to obtain 0.86 g of white crystals of the target compound having a melting point of 199 to 200 ° C. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.18 (3H, t, J = 7.1 Hz), 1.27
(9H, s) 1.42 (9H, s), 2.35 (3H, s), 3.62 (2H, s),
4.08 (2H, d, J = 7.1 Hz), 4.5-4.6 (1H, m), 5.05 (1
H, d, J = 13.3 Hz), 6.87 (1H, s), 7.23 (2H, d, J =
8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.75 (1H, d, J
= 1.5 Hz), 10.07 (1H, s, disappeared by adding heavy water).

[0392]

Example 182 [4- (6-Acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-284) Obtained in Example 181 Example 4 using 0.40 g of 4- (6-acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester, 5 ml of 2N aqueous potassium hydroxide solution and 5 ml of ethanol.
By reacting according to 3, 0.32 g of white crystals of the target compound having a melting point of 226-229 ° C. were obtained. ¹ H-NMR
Spectrum _{(δppm, DMSO-d 6)} 1.27 (9H, s) 1.42 (9
H, s), 2.35 (3H, s), 3.53 (2H, s), 4.5-4.6 (1H, m),
5.06 (1H, d, J = 13.3 Hz), 6.87 (1H, s), 7.22 (2H,
d, J = 8.5 Hz), 7.61 (2H, d, J = 8.5 Hz), 7.75
(1H, d, J = 1.5 Hz), 10.06 (1H, s, disappeared by adding heavy water), 12.30 (1H, s, disappeared by adding heavy water).

[0393]

Example 183 [3- (6-Acetoxy-5,7-di-tert-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-282) Obtained in Example 180 Example 4 using 0.30 g of 3- (6-acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester, 5 ml of 2N aqueous potassium hydroxide solution and 5 ml of ethanol.
By reacting according to 3, white crystals 0.21 g of the target compound having a melting point of 191 ° -193 ° C. were obtained. ¹ H-NMR
Spectrum _{(δppm, DMSO-d 6)} 1.27 (9H, s) 1.42 (9
H, s), 2.35 (3H, s), 3.54 (2H, s), 4.5-4.6 (1H, m),
5.05 (1H, d, J = 13.3 Hz), 6.87 (1H, s), 6.99 (1H,
d, J = 7.5 Hz), 7.27 (1H, t, J = 7.7 Hz), 7.5-
7.7 (2H, m), 7.76 (1H, d, J = 1.4 Hz), 10.08 (1H,
br s, disappeared with the addition of heavy water).

[0394]

Working Example 184 [2- (6-Acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester (Compound No. 1-281)
6-acetoxy-5,7-di-t obtained in Reference Example 72
-Butyl-2H-chromene-3-carboxylic acid 1.10
g, oxalyl chloride 0.57 ml, dimethylformamide 2 drops, 2-aminophenylacetic acid ethyl ester hydrochloride 0.70 g and anhydrous tetrahydrofuran 60 ml.
0.38 g of yellow crystals of the target compound having a temperature of 2 ° C. were obtained. ¹ H-NMR spectrum (δppm, CDCl ₃ ) 1.24 (3H, t,
J = 7.3 Hz), 1.33 (9H, s) 1.50 (9H, s), 2.34 (3H, s)
s), 3.6-3.7 (2H, m), 4.16 (2H, q, J = 7.3 Hz), 4.6
-4.75 (1H, m), 5.22 (1H, d, J = 13.3 Hz), 6.94 (1
H, s), 7.05-7.15 (1H, m), 7.2-7.25 (1H, m), 7.3-7.4
(1H, m), 7.92 (1H, d, J = 1.8 Hz), 8.00 (1H, d, J
= 8.0 Hz), 9.86 (1H, s, disappeared by adding heavy water).

[0395]

Example 185 [2- (6-Acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid (Compound No. 1-280) Obtained in Example 184. Example 43 using 0.30 g of 2- (6-acetoxy-5,7-di-t-butyl-2H-chromen-3-carbonyl) aminophenyl] acetic acid ethyl ester 1 ml of 2N aqueous sodium hydroxide solution and 3 ml of ethanol. 0.10 g of white crystals of the target compound having a melting point of 134 to 136 ° C. were obtained. ¹ HN
MR spectrum (δppm, CDCl ₃ ) 1.32 (9H, s) 1.45 (9
H, s), 2.34 (3H, s), 3.67 (2H, s), 4.6-4.7 (1H,
m), 5.17 (1H, d, J = 13.3 Hz), 6.93 (1H, s), 7.1-7.2
(1H, m), 7.3-7.4 (2H, m), 7.81 (1H, d, J = 1.1 H
z), 7.85 (1H, d, J = 8.1 Hz), 9.11 (1H, s, disappeared by addition of heavy water).

[0396]

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[0397]

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[0398]

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[0399]

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[0400]

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[0401]

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[0402]

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[0403]

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[0404]

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[0405]

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[0406]

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[0407]

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[0408]

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[0409]

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[0410]

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[0411]

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[0412]

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[0413]

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[0414]

Reference Example 1 2,5-dihydroxy-3,4,6-trimethylbenzaldehyde trimethylhydroquinone 5
Titanium tetrachloride 7 (0.0 g) and dichloromethyl methyl ether (59 ml) in methylene chloride (500 ml) under ice cooling
100 ml of a 2 ml methylene chloride solution was added dropwise over 30 minutes, and the mixture was stirred at 3 ° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into ice and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After distilling off the solvent from the extract, the residue obtained is ethyl acetate, n-H
ex was added and ultrasound was applied. The precipitated crystals were collected by filtration to obtain 23.2 g of yellow crystals of the target compound having a melting point of 140 to 142 ° C.

[0415]

Reference Example 2 5-acetoxy-2-hydroxy-3,
4,6-trimethylbenzaldehyde 36.8 g of 2,5-dihydroxy-3,4,6-trimethylbenzaldehyde obtained in Reference Example 1 27 ml of acetic anhydride pyridine 23
The reaction mixture of ml and 400 ml of methylene chloride was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with methylene chloride. The extract was washed with an aqueous solution of sodium hydrogen carbonate, an aqueous solution of hydrochloric acid and water, and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, ethyl acetate and n-Hex were added to the obtained residue, and ultrasonic waves were applied. The precipitated crystals were collected by filtration to give a melting point of 148-152.
43.6 g of yellow crystals of the target compound having a temperature of 4.degree. C. were obtained.

[0416]

Reference Example 3 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carbonitrile and 6-hydroxy-5,7,8-trimethyl-2H-chromen-3-
5-acetoxy-2 obtained in Carbonitrile Reference Example 2
-Hydroxy-3,4,6, -trimethylbenzaldehyde 43.0 g, 1,4-diazabicyclo [2.2.
2] A mixture of 4.99 g of octane and acrylonitrile was stirred for 14 hours while heating under reflux. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed with a 2N aqueous sodium hydroxide solution, a 2N aqueous hydrochloric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, ethanol was added to the obtained residue and ultrasonic waves were applied.
The precipitated crystals were collected by filtration to obtain 14.7 g of yellow crystals of the target compound (6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carbonitrile) having a melting point of 135 to 137 ° C. When the mother liquor was concentrated and subjected to silica gel column chromatography (n-hexane: ethyl acetate = 3: 1), the target compound (6-acetoxy-
5,7,8-trimethyl-2H-chromen-3-carbonitrile: 6-hydroxy-5,7,8-trimethyl-
15.5 g of yellow crystals of 2H-chromen-3-carbonitrile (5: 3) were obtained.

[0417]

Reference Example 4 6-Hydroxy-5,7,8-trimethyl-2H-chromen-3-carboxylic acid 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 3. Carbonitrile 25.0 g, Reference Example 3
6-hydroxy-5,7,8-trimethyl- obtained in
5.20 g of 2H-chromen-3-carbonitrile, 300 ml of 3N aqueous sodium hydroxide solution and dioxane 3
The mixture (00 ml) was stirred for 4 hours while heating under reflux. After completion of the reaction, the reaction mixture was poured into ice and neutralized with a 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration to give a melting point of> 225.
27.8 ° C. (dec.) Yellow crystals of the target compound
g was obtained.

[0418]

Reference Example 5 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 6-hydroxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid obtained in Reference Example 4. Carboxylic acid 27.8 g, acetic anhydride 17.1 m
When the reaction was carried out according to Reference Example 2 using 1 and 300 ml of pyridine, 31.5 g of yellow crystals of the target compound having a melting point of> 235 ° C. (dec.) were obtained.

[0419]

Reference Example 6 2-hydroxy-4,5-dimethoxybenzaldehyde 3,4-dimethoxyphenol 20.0
g, 32.8 g of dichloromethyl methyl ether, 54.1 g of titanium tetrachloride and 260 ml of methylene chloride were reacted according to Reference Example 1 to obtain 19.5 g of a brown powder of the target compound having a melting point of 94-96 ° C. Was.

[0420]

Reference Example 7 6,7-dimethoxy-2H-chromene-3
-2-Hydroxy obtained in Carbonitrile Reference Example 6
19.2 g of 4,5-dimethoxybenzaldehyde, 1,
2.72 g of 4-diazabicyclo [2.2.2] octane
When 28.0 g of acrylonitrile and 28.0 g of acrylonitrile were reacted, 17.3 g of yellow needle crystals of the target compound having a melting point of 95 to 110 ° C. were obtained.

[0421]

Reference Example 8 6,7-dimethoxy-2H-chromene-3
6,7-dimethoxy obtained in Reference Example 7 of carboxylic acid
10.0 g of 2H-chromen-3-carbonitrile, 200 ml of 3N aqueous sodium hydroxide solution and dioxane 1
When the reaction was carried out according to Reference Example 4 using 100 ml, the melting point was 2
8. Yellow needle crystals of the target compound having a temperature of 23-225 ° C.
24 g were obtained.

[0422]

REFERENCE EXAMPLE 9 4-Amino-phenylacetic acid ethyl ester hydrochloride 20.0 g of 4-amino-phenylacetic acid, 100 ml of ethanol and 4N hydrogen chloride-dioxane solution 10
0 ml of the mixture was stirred at room temperature for 6 hours. After standing overnight, the solvent was distilled off from the reaction solution, and ethyl acetate was added to the obtained residue, and ultrasonic waves were applied. The precipitated crystals were collected by filtration to obtain 27.9 g of colorless crystals of the target compound having a melting point of 190 to 192 ° C.

[0423]

Reference Example 10 3-amino-phenylacetic acid ethyl ester hydrochloride 20.0 g of 3-amino-phenylacetic acid, 100 ml of ethanol and 4N hydrogen chloride-dioxane solution 1
When the reaction was carried out according to Reference Example 9 using 100 ml, the melting point was 1
28.6 brown crystals of the target compound having a temperature of 17-119 ° C.
g was obtained.

[0424]

Reference Example 11 2-amino-5-hydroxybenzoic acid ethyl ester 2-amino-5-hydroxybenzoic acid 1
0.0 g, ethanol 100 ml and 4N hydrogen chloride
When the reaction was carried out according to Reference Example 9 using 100 ml of a dioxane solution, 4.18 g of dark brown crystals of the target compound having a melting point of 143-144 ° C were obtained.

[0425]

Reference Example 12 3- (4-Chloro-1-methyl-1H-)
Pyrazol-3-yl) -2- (4-nitrophenyl)
Acrylic acid ethyl ester 4-nitrophenylacetic acid ethyl ester 3.00 g, 4-chloro-1-methyl-1H
-Pyrazole-3-carbaldehyde 2.07 g, piperazine 0.71 ml, acetic acid 0.41 ml and toluene 60
The ml mixture was stirred at 100 ° C. for 7 hours and left at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain 1.35 g of the target compound as white crystals having a melting point of 152 to 153 ° C.

[0426]

Reference Example 13 2- (4-aminophenyl) -3- (4
-Chloro-1-methyl-1H-pyrazol-3-yl)
3-ethyl acrylate obtained in Reference Example 12
(4-Chloro-1-methyl-1H-pyrazol-3-yl) -2- (4-nitrophenyl) acrylic acid ethyl ester 0.40 g, zinc 1.25 g, acetic acid 0.25 ml
And 40 ml of methanol were stirred for 2 hours while heating under reflux. Zinc was removed from the reaction mixture using celite, and the obtained mother liquor was washed with an aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the extract was dried under reduced pressure.
0.37 g of yellow oily substance of the target compound having 39 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 2: 1) was obtained.

[0427]

Reference Example 14 3- (1-Methyl-1H-pyrrole-2)
-Yl) -2- (4-nitrophenyl) acrylic acid ethyl ester 4-nitrophenylacetic acid ethyl ester
00g, 1-methyl-1H-pyrrole-2-carbaldehyde 0.51 ml, piperazine 0.19 ml, acetic acid 0.1 ml.
When the reaction was carried out according to Reference Example 12 using 11 ml and 20 ml of toluene, 0.71 g of orange crystals of the target compound having a melting point of 135 to 137 ° C. were obtained.

[0428]

Reference Example 15 2- (4-aminophenyl) -3- (1
-Methyl-1H-pyrrol-2-yl) acrylic acid ethyl ester 3- (1-methyl-1) obtained in Reference Example 14
H-pyrrol-2-yl) -2- (4-nitrophenyl) acrylic acid ethyl ester 0.65 g, zinc 2.2
The reaction was conducted according to Reference Example 13 using 6 g, 0.40 ml of acetic acid and 16 ml of methanol.
0.59 g of yellow crystals of the target compound having a temperature of 0.5 ° C. were obtained.

[0429]

Reference Example 16 3- [1- (4-chlorophenyl) -1
[H-pyrrol-2-yl] -2- (4-nitrophenyl) acrylic acid ethyl ester 1.27 g of 4-nitrophenylacetic acid ethyl ester, 1- (4-chlorophenyl) -1H-pyrrole-2-carbaldehyde 1. 25
g, 0.30 ml of piperazine, 0.17 ml of acetic acid and 30 ml of toluene were reacted according to Reference Example 12 to obtain 0.49 g of yellow crystals of the target compound having a melting point of 135 to 137 ° C.

[0430]

Reference Example 17 2- (4-aminophenyl) -3- [1
-(4-chlorophenyl) -1H-pyrrol-2-yl] acrylic acid ethyl ester 3 obtained in Reference Example 16
-[1- (4-chlorophenyl) -1H-pyrrole-2
-Yl] -2- (4-nitrophenyl) acrylic acid ethyl ester 0.45 g, zinc 1.19 g, acetic acid 0.25
The reaction was carried out in the same manner as in Reference Example 13 using 10 ml of methanol and 10 ml of methanol to obtain 0.42 g of the target compound as yellow crystals having a melting point of 141 to 143 ° C.

[0431]

Reference Example 18 2-amino-4,5,6,7-tetrahydrobenzo- [b] thiophen-3-carboxylic acid 2-amino-4,5,6,7-tetrahydrobenzo- [b] thiophen-3 -3.0 g of carboxylic acid ethyl ester, 5.33 g of sodium hydroxide, and 75 ml of a methanol solution of 18.6 ml of water were heated under reflux for 5.5 hours. The solvent was distilled off from the reaction solution, and water was added to the residue.
Neutralized with 6 ml. The precipitated crystals are collected by filtration and washed with water,
After drying under reduced pressure, 2.21 g of a light brown powder of the target compound having a melting point of 124 to 130 ° C. was obtained.

[0432]

Reference Example 19 3- (4,4,5,5-tetramethyl-
[1,3,2] dioxaborolan-2-yl) pyridine bispinacolatodiboron 0.88 g, dichloro [1,1
1′-bis (diphenylphosphino) ferrocene] A mixture of 0.07 g of palladium (II) and 0.93 g of potassium acetate was replaced with nitrogen, and then anhydrous dimethyl sulfoxide 5m
l, and 0.50 g of 3-bromopyridine was added thereto.
Stirred at 4.6 ° C for 4.6 hours. The solvent is distilled off from the reaction solution,
Water was added to the obtained residue and extracted with toluene. The extract was washed with a saturated saline solution, the insolubles were removed by filtration, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off from the extract and the residue was dried under reduced pressure to obtain 0.42 g of a dry solid of the target compound having a melting point of 52 to 68 ° C.

[0433]

REFERENCE EXAMPLE 20 Methyl 2-amino-5- (3-pyridyl) benzoate 0.45 g of methyl 2-amino-5-bromobenzoate, 3- (4,4,4) obtained in Reference Example 19
0.40 g of 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine, 0.09 g of tetrakis (triphenylphosphine) palladium (0), 2
10 ml of anhydrous N, N-dimethylformamide solution of 2.0 ml of M aqueous potassium carbonate solution was stirred at 80 ° C. for 16 hours. The solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain 0.12 g of pale yellow crystals of the target compound having a melting point of 119-122 ° C. Was.

[0434]

Reference Example 21 3- (2-Diisopropylaminoethoxy) -4-methoxy-nitrobenzene 2-methoxy-5
-Nitrophenol 10.0 g, 2- (diisopropylamino) ethanol 8.59 g, 1,1 ′-(azodicarbonyl) dipiperidine 29.8 g, tri-n-butylphosphine 23.9 g toluene solution 400 ml in toluene at room temperature. After applying ultrasonic vibration for hours, stir at room temperature for 5 hours,
Left overnight. After filtering off the insoluble matter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1).
20.1 g of a yellow oil of the target compound having a value of 69 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 1: 1) was obtained.

[0435]

REFERENCE EXAMPLE 22 3- (2-Diisopropylaminoethoxy) -4-methoxyaniline
Example 82 was prepared using 17.4 g of (2-diisopropylaminoethoxy) -4-methoxy-nitrobenzene, 2.6 g of 10% palladium carbon and 200 ml of methanol.
The reaction was carried out according to After completion of the reaction, 10% palladium carbon was removed by filtration, and methanol was distilled off from the filtrate. The residue was subjected to reverse phase liquid chromatography (acetonitrile: water =
2: 3), Rf value = 0.18 (silica gel thin layer chromatography; ethyl acetate: methanol = 9:
14.5 g of a brown oil of the target compound having 1) was obtained.

[0436]

REFERENCE EXAMPLE 23 5- (6-acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) -1H-imidazo [4,5-d] [1,3] oxazin-7-one 5-[(6-acetoxy-5,7,8) obtained in Example 53
-Trimethyl-2H-chromen-3-carbonylamino] -3H-imidazole-4-carboxylic acid 3.91
g, 2.87 ml of acetic anhydride and 80 ml of a pyridine solution were stirred at room temperature for 1.5 hours. The solvent is distilled off from the reaction solution,
Water was added to the residue, and the mixture was acidified with a 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give 3.58 g of a yellow powder of the target compound having a melting point of 308-310 ° C.

[0437]

Reference Example 24 2- (6-acetoxy-5,7,8-trimethyl-2H-chromen-3-yl) benzo [d]
[1,3] oxazin-4-one 6 obtained in Reference Example 5
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid 25.0 g, thionyl chloride 100 ml
And 3 drops of dimethylformamide were stirred at room temperature for 6 hours. After the solvent was distilled off from the reaction solution, it was dried under reduced pressure. The obtained solid was added to 250 ml of a pyridine solution of 13.6 g of anthranilic acid, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate was added to the residue obtained by evaporating the solvent from the reaction solution, and ultrasonic waves were applied. The precipitated crystals were collected by filtration, water was added thereto, and ultrasonic waves were applied. The precipitated crystals were collected by filtration.
11.0 g of yellow crystals of the target compound having a temperature of 47 ° C. were obtained.

[0438]

REFERENCE EXAMPLE 25 2,5-dihydroxy-4-t-butylbenzaldehyde t-butylhydroquinone 49.84
g, 58.63 g of dichloromethyl methyl ether, 96.75 g of titanium tetrachloride and 1250 ml of methylene chloride, the reaction was carried out according to Reference Example 1, and the melting point was 178-17.
9.43 g of a brown powder of the target compound having a temperature of 9 ° C. were obtained.

[0439]

Reference Example 26 7-t-butyl-6-hydroxy-2H
-Chromen-3-carboxylic acid t-butyl ester 5.53 g of 2,5-dihydroxy-4-t-butylbenzaldehyde obtained in Reference Example 25, and potassium carbonate 3.94
g, 5.48 g of acrylic acid t-butyl ester and 111 ml of dimethylformamide were reacted according to Reference Example 3 to obtain 1.92 g of yellow needle crystals of the target compound. ¹ H-NMR spectrum (δppm, DMSO-d ₆ ) 1.38 (9
H, s), 1.53 (9H, s), 4.69 (1H, s), 4.87 (2H, s), 6.
47 (1H, s), 6.80 (1H, s), 7.24 (1H, s).

[0440]

Reference Example 27 7-t-butyl-6-hydroxy-2H
-Chromene-3-carboxylic acid 7- obtained in Reference Example 26-
A mixture of 1.92 g of t-butyl-6-hydroxy-2H-chromene-3-carboxylic acid t-butyl ester, 19 ml of trifluoroacetic acid and 38 ml of methylene chloride was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction solution, n-hexane and isopropyl ether were added to the residue, and the crystals were collected by filtration to obtain 1.46 g of yellow needle crystals of the target compound having a melting point of 202 ° C (dec.). .

[0441]

Reference Example 28 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carbonyl chloride Reference Example 5
6-acetoxy-5,7,8-trimethyl- obtained in
0.50 g of 2H-chromene-3-carboxylic acid, 0.25 g of oxalyl chloride and tetrahydrofuran anhydride 20
Two drops of dimethylformamide were added dropwise at room temperature to the ml mixture. After stirring the reaction mixture at room temperature for 1 hour, the solvent was distilled off from the reaction solution and dried under reduced pressure to obtain 0.56 g of a brown solid of the target compound as a crude purified product.

[0442]

Reference Example 29 Reference Example 71 of 6-acetoxy-5,7-di-t-butyl-2H-chromene-3-carboxylic acid amide
6-acetoxy-5,7-di-t-butyl- obtained in
A mixture of 11.7 g of 2H-chromene-3-carbonitrile, 52.2 ml of 3N potassium hydroxide and 99 ml of 1,4-dioxane was heated under reflux for 28 hours. The reaction mixture was allowed to cool, neutralized with 3 N hydrochloric acid, and the precipitated crystals were filtered to obtain 6.98 g of orange crystals of the target compound.

[0443]

Reference Example 30 6-Fluoro-2H-chromen-3-carbonitrile 5-fluorosalicylaldehyde 1.00
g, 1,4-diazabicyclo [2.2.2] octane, 0.17 g, and acrylonitrile, 1.90 g, were reacted according to Reference Example 3 to obtain a pale yellow powder of the target compound having a melting point of 85-88 ° C. 80 g were obtained.

[0444]

Reference Example 31 6-Fluoro-2H-chromene-3-carboxylic acid 0.78 g of 6-fluoro-2H-chromene-3-carbonitrile obtained in Reference Example 30, 2.40 g of sodium hydroxide, 1,4 -A mixture of 20 ml of dioxane and 20 ml of distilled water was heated under reflux for 8 hours. After leaving at room temperature overnight, the mixture was refluxed for 4.5 hours, and then ethanol 25m
The mixture was heated and refluxed for further 36 hours. After cooling to room temperature, a concentrated hydrochloric acid aqueous solution was added to the reaction mixture to make it acidic, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent from the extract, the precipitate was collected by filtration using n-hexane and washed to obtain 0.69 g of a target yellow powder having a melting point of 208 to 209 ° C.

[0445]

Reference Example 32 5.00 g of 6-methyl-2H-chromen-3-carbonitrile 5-methylsalicylaldehyde,
8.30 g of potassium carbonate and 30 ml of acrylonitrile
The mixture was heated to reflux for 3.5 hours and then left overnight.
3.40 g of 1,4-diazabicyclo [2.2.2] octane and N, N-dimethylformamide 30 were added to the reaction mixture.
Then, the mixture was stirred at 85 ° C. for 9 hours and left at room temperature for 4 days. 100 ml of water and 150 ml of ethyl acetate were added to the reaction mixture.
After addition of 50 ml of acetone and 50 ml of acetone, the insoluble matter was removed by filtration, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent from the extract was subjected to column chromatography (silica gel 50 g + “LiChroprepNH ₂ ” (MERCK)).
50 g, n-hexane: ethyl acetate = 3: 1) gave 1.18 g of a white powder of the target compound having a melting point of 88-90 ° C.

[0446]

Reference Example 33 6-Methyl-2H-chromene-3-carboxylic acid 1.10 g of 6-methyl-2H-chromen-3-carbonitrile obtained in Reference Example 32, 2.00 g of potassium hydroxide, 1,4 -A mixture of 15 ml of dioxane, 30 ml of ethanol and 20 ml of distilled water was heated under reflux for 2 days. After cooling to room temperature, a 2N aqueous hydrochloric acid solution was added to the reaction mixture to make it acidic, followed by stirring for 1 hour. The precipitate is collected by filtration,
Washed with distilled water and then with diisopropyl ether, 1.04 g of the target yellow powder having a melting point of 192-193 ° C.
was gotten.

[0447]

Reference Example 34 7-benzyloxy-2H-chromene
3-carbonitrile 4-benzyloxysalicylaldehyde 5.00 g, potassium carbonate 6.10 g, acrylonitrile 30 ml, 1,4-diazabicyclo [2.2.
2] 2.50 g of octane and 30 of dimethylformamide
When the reaction was carried out according to Reference Example 32, the melting point was 71
2.66 g of an off-white powder of the target compound having a temperature of -73 ° C. were obtained.

[0448]

Reference Example 35 7-benzyloxy-2H-chromene
2.60 g of 7-benzyloxy-2H-chromen-3-carbonitrile obtained in 3-carboxylic acid reference example 34,
2.80 g of potassium hydroxide, 15 m of 1,4-dioxane
l, 35 ml of ethanol and 25 ml of distilled water were reacted according to Reference Example 33 to obtain 1.67 g of an off-white powder of the target compound having a melting point of 198-203 ° C.

[0449]

Reference Example 36 6-bromo-2H-chromen-3-carbonitrile 5-bromosalicylaldehyde 25.0 g,
A mixture of 24.4 ml of acrylonitrile, 2.79 g of 1,4-diazabicyclo [2.2.2] octane and 250 ml of anhydrous dimethylformamide was stirred at 80 ° C. for 14 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture,
The extract was washed with a 2N aqueous sodium hydroxide solution, a 2N aqueous hydrochloric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, silica gel column chromatography (n-hexane: ethyl acetate = 9:
When applied to 1), Rf value = 0.39 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 9: 1)
8.69 g of yellow needle crystals of the target compound having the following formula: were obtained.

[0450]

Reference Example 37 6-phenyl-2H-chromen-3-carbonitrile 6-bromo-2H- obtained in Reference Example 36
According to Example 126 using 1.00 g of chromene-3-carbonitrile, 0.52 g of phenylboronic acid, 0.20 g of tetrakis (triphenylphosphine) palladium (0), 4.2 ml of 2M aqueous potassium carbonate solution and 20 ml of anhydrous dimethylformamide. When reacted, the Rf value = 0.
This gave 0.75 g of a pale yellow powder of the target compound having a molecular weight of 38 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 9: 1).

[0451]

Reference Example 38 6-phenyl-2H-chromene-3-carboxylic acid 0.80 g of 6-phenyl-2H-chromene-3-carbonitrile obtained in Reference Example 37, 16 ml of a 3N aqueous sodium hydroxide solution and 8 ml of dioxane When the reaction was carried out according to Reference Example 4, Rf value = 0.041
(Silica gel thin layer chromatography; n-hexane:
0.66 g of a pale yellow powder of the target compound having (ethyl acetate = 9: 1) was obtained.

[0452]

Reference Example 39 6- (3-Pyridyl) -2H-chromen-3-carbonitrile 1.00 g of 6-bromo-2H-chromen-3-carbonitrile obtained in Reference Example 36, pyridine-3-boronic acid 0.52 g, 0.20 g of tetrakis (triphenylphosphine) palladium (0), 2M
When the reaction was carried out according to Example 126 using 4.2 ml of an aqueous potassium carbonate solution and 20 ml of anhydrous dimethylformamide, the object having an Rf value of 0.37 (silica gel thin-layer chromatography; n-hexane: ethyl acetate = 1: 3) was obtained. 0.40 g of a pale yellow powder of the compound was obtained.

[0453]

Reference Example 40 6- (3-Pyridyl) -2H-chromene-3-carboxylic acid 0.36 of 6- (3-pyridyl) -2H-chromen-3-carbonitrile obtained in Reference Example 39.
g, 3 ml of a 3N aqueous solution of sodium hydroxide and 4 ml of dioxane were reacted according to Reference Example 4. After completion of the reaction, the reaction mixture was poured into ice, acidified with a 2N aqueous hydrochloric acid solution, and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. After extraction with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, the extract was dried under reduced pressure.
As a result, 0.17 g of a pale yellow powder of the target compound having a ratio of 06 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 1: 3) was obtained.

[0454]

Reference Example 41 methyl 2-amino-5-phenylbenzoate methyl 2-amino-5-bromobenzoate
00g, 1.59 g of phenylboronic acid, 0.60 g of tetrakis (triphenylphosphine) palladium (0),
When reacted according to Example 126 using 13.0 ml of a 2M aqueous potassium carbonate solution and 60 ml of anhydrous dimethylformamide, it has an Rf value of 0.49 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 3: 1). 1.30 g of a milky white solid of the target compound was obtained.

[0455]

Reference Example 42 Nt-butoxycarbonyl-2-nitrophenylcarbamic acid-t-butyl ester 10.0 g of 2-nitroaniline, 49.9 ml of di-t-butyldicarbonate and 0.88 of 4-dimethylaminopyridine
g of methanol solution (200 ml) was stirred at room temperature for 3 hours. After standing at room temperature overnight, the solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate.
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 10: 1 → 2: 1) to give a melting point of 5
23.1 g of yellow crystals of the target compound having a temperature of 5-57 DEG C. are obtained.

[0456]

Reference Example 43 2-Nitrophenylcarbamic acid-t-
Butyl ester 28% sodium methoxide-methanol solution was added to 200 ml of methanol solution of 18.0 g of N-tert-butoxycarbonyl-2-nitrophenylcarbamic acid-t-butyl ester obtained in Reference Example 42.
Then, the mixture was stirred at room temperature for 3 hours. After standing at room temperature overnight, the solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, the resulting residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1).
0: 1) gave 5.70 g of yellow crystals of the target compound having a melting point of 83-84 ° C.

[0457]

Reference Example 44 2-aminophenylcarbamic acid-t-
Butyl ester 2-nitrophenylcarbamic acid-t-butyl ester obtained in Reference Example 43 3.20 g, 10
% Of palladium on carbon and 60 ml of methanol were reacted according to Example 82 to obtain a melting point of 102-1.
2.81 g of white crystals of the target compound having a temperature of 03 ° C. were obtained.

[0458]

Reference Example 45 N, N-di-t-butoxycarbonyl-
N- obtained in Reference Example 42 of 1,2-phenylenediamine
When the reaction was carried out according to Example 82 using 3.40 g of t-butoxycarbonyl-2-nitrophenylcarbamic acid-t-butyl ester, 0.70 g of 10% palladium carbon and 60 ml of methanol, an object having a melting point of 96-98 ° C. 3.11 g of white crystals of the compound were obtained.

[0459]

Reference Example 46 2- (4-pyridyl) -nitrobenzene 0.66 g of 2-bromonitrobenzene, pyridine-4-
0.40 g of boronic acid, 0.15 g of tetrakis (triphenylphosphine) palladium (0), 3.3 ml of 2M aqueous potassium carbonate solution and 15 m of anhydrous dimethylformamide
When the reaction was carried out according to Example 126 using l, the Rf value =
This gave 0.26 g of a brown oil of the desired compound having 0.45 (silica gel thin layer chromatography; ethyl acetate).

[0460]

Reference Example 47 Reference Example 4 for 2- (4-pyridyl) aniline
Using 0.25 g of 2- (4-pyridyl) -nitrobenzene obtained in 6 and 0.05 g of 10% palladium on carbon and 5 ml of methanol according to Example 82,
0.2 colorless solid of the target compound having an Rf value = 0.31 (silica gel thin layer chromatography; ethyl acetate)
2 g were obtained.

[0461]

Reference Example 48 Methyl 2-amino-5- (4-pyridyl) benzoate 0.90 g of methyl 2-amino-5-bromobenzoate, 0.48 g of pyridine-4-boronic acid
0.18 g of tetrakis (triphenylphosphine) palladium (0), 3.9 ml of 2M aqueous potassium carbonate solution
Example 1 using dimethylformamide and 18 ml of anhydrous dimethylformamide
When reacted according to No. 26, 0.24 g of a white powder of the desired compound having an Rf value of 0.16 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 1: 2)
was gotten.

[0462]

Reference Example 49 2- (2-pyridyl) -nitrobenzene 1.50 g of 2-iodonitrobenzene, 2.44 g of tri-n-butyl- (2-pyridyl) -tin, and dichlorobis (triphenylphosphine) palladium (II) 0 .2
1 g of an anhydrous tetrahydrofuran solution (30 ml) was stirred for 47 hours while heating under reflux. The solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent from the extract, silica gel column chromatography (n-hexane: ethyl acetate = 2:
When applied to 1), Rf value = 0.29 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 2: 1)
0.69 g of a yellow oil of the target compound having the formula was obtained.

[0463]

Reference Example 50 Reference Example 4 for 2- (2-pyridyl) aniline
The reaction was carried out according to Example 82 using 0.68 g of 2- (2-pyridyl) -nitrobenzene obtained in 9 and 0.14 g of 10% palladium on carbon and 10 ml of methanol, whereby Rf value = 0.65 (silica gel thin layer). Chromatography: 0.49 g of a colorless oil of the target compound having n-hexane: ethyl acetate = 1: 1) was obtained.

[0464]

REFERENCE EXAMPLE 51 6-acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [2- (benzyloxycarbamoyl) phenyl] amide 2- (6-acetoxy-amide obtained in Reference Example 24 5,7,8-Trimethyl-2H-chromen-3-yl) benzo [d] [1,3]
Oxazin-4-one 0.50 g, O-benzylhydroxylamine hydrochloride 0.63 g, anhydrous pyridine 10 ml
And the reaction was carried out according to Example 125. After the completion of the reaction, the solvent was distilled off from the reaction solution, and water and ethyl acetate were added to the obtained residue, and the mixture was irradiated with ultrasonic waves. The precipitated crystals were collected by filtration to give an Rf value of 0.43 (silica gel thin layer chromatography 0.36 g of a yellow powder of the target compound having the following characteristics:

[0465]

Reference Example 52 2-Nitrophenylacetic acid ethyl ester 6.80 g of 2-nitrophenylacetic acid, 70 m of ethanol
The reaction was carried out according to Reference Example 9 using 70 ml of a 1N and 4N hydrogen chloride-dioxane solution to obtain 7.70 g of a light brown crystal of the target compound having a melting point of 57 to 58 ° C.

[0466]

Reference Example 53 2-Aminophenylacetic acid ethyl ester The reaction was carried out according to Example 82 using 1.10 g of 2-nitrophenylacetic acid ethyl ester obtained in Reference Example 52, 1.00 g of 10% palladium carbon and 20 ml of methanol. And 0.92 g of light brown crystals of the target compound having an Rf value of 0.55 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 1: 1).

[0467]

Reference Example 54 7-methoxy-2H-chromen-3-carbonitrile 4-methoxysalicylaldehyde 5.00
g, 3.7 g of 1,4-diazabicyclo [2.2.2] octane, 10.6 g of acrylonitrile and 50 ml of anhydrous toluene were heated to reflux for 4 days. After the reaction mixture was cooled to room temperature, it was subjected to column chromatography (silica gel 30 g + "ChromatorexNH" (manufactured by Fuji Silysia) 30 g, n-hexane: ethyl acetate = 3: 1) to give the target compound having a melting point of 90-93.degree. 1.69 g of an orange powder were obtained.

[0468]

Reference Example 55 7-Methoxy-2H-chromene-3-carboxylic acid 1.65 g of 7-methoxy-2H-chromene-3-carbonitrile obtained in Reference Example 54, 2.5 g of potassium hydroxide, 1,4 When the reaction was carried out according to Reference Example 33 using 15 ml of dioxane, 30 ml of ethanol and 20 ml of distilled water, 1.03 g of a yellow powder of the target compound having a melting point of 201 to 203 ° C. was obtained.

[0469]

Reference Example 56 5-Methoxy-2H-chromen-3-carbonitrile 6-methoxysalicylaldehyde 5.00
g, 3.7 g of 1,4-diazabicyclo [2.2.2] octane, 10.6 g of acrylonitrile and 50 ml of anhydrous toluene, the reaction was carried out according to Reference Example 54 to obtain a yellowish compound having a melting point of 66-69 ° C. Powder 3.93
g was obtained.

[0470]

Reference Example 57 5-methoxy-2H-chromen-3-carboxylic acid 3.90 g of 5-methoxy-2H-chromene-3-carbonitrile obtained in Reference Example 56, 5.6 g of potassium hydroxide, and 1,4 When the reaction was carried out according to Reference Example 33 using 30 ml of dioxane, 60 ml of ethanol and 40 ml of distilled water, 2.40 g of a pale yellow powder of the target compound having a melting point of 232 to 233 ° C. was obtained.

[0471]

Reference Example 58 6-trifluoromethoxy-2H-chromen-3-carbonitrile 4.00 g of 5-trifluoromethoxysalicylaldehyde, 2.10 g of 1,4-diazabicyclo [2.2.2] octane, 5.10 g of acrylonitrile Reference Example 54 using 30 g and 50 ml of anhydrous toluene
2.86 g of an orange solid of the target compound having a melting point of 48-50 ° C. was obtained.

[0472]

Reference Example 59 6-trifluoromethoxy-2H-chromene-3-carboxylic acid 2.80 g of 6-trifluoromethoxy-2H-chromene-3-carbonitrile obtained in Reference Example 58 and 3.4 g of potassium hydroxide 25 ml of 1,4-dioxane, 50 ml of ethanol and 30 ml of distilled water
When reacted according to Reference Example 33, the melting point was 186-
0.91 g of a pale yellow powder of the target compound having a temperature of 188 ° C. was obtained.

[0473]

Reference Example 60 6-t-butyl-2H-chromen-3-
4. Carbonitrile 5-t-butylsalicylaldehyde
00g, 3.10 g of 1,4-diazabicyclo [2.2.2] octane, 10.6 g of acrylonitrile and 50 ml of anhydrous toluene, the reaction was carried out according to Reference Example 54 to give the target compound having a melting point of 84-86 ° C. 1.96 g of a solid were obtained.

[0474]

Reference Example 61 6-t-butyl-2H-chromen-3-
6-t-butyl-2H obtained in carboxylic acid reference example 60
Chromene-3-carbonitrile 1.90 g, potassium hydroxide 2.5 g, 1,4-dioxane 15 ml, ethanol 30 ml and distilled water 20 ml. When reacted according to Reference Example 33, it has a melting point of 197-199 ° C. 0.36 g of a yellow powder of the target compound was obtained.

[0475]

Reference Example 62 2-amino-5- (2-pyridyl) benzoic acid methyl ester 1.70 g of methyl 2-amino-5-bromobenzoate, tri-n-butyl- (2-pyridyl)
Using 3.00 g of tin, 0.26 g of dichlorobis (triphenylphosphine) palladium (II) and 30 ml of anhydrous tetrahydrofuran and reacting according to Reference Example 49, the Rf value was 0.47 (silica gel thin-layer chromatography; n-hexane). : Ethyl acetate = 1: 1) to obtain 0.44 g of the target compound as a pale yellow solid.

[0476]

Reference Example 63 4- (4-Nitrophenoxy) benzoic acid ethyl ester 1-fluoro-4-nitrobenzene5.
55 g by weight at room temperature in 100 ml of dimethylformamide anhydrous solution of 00 g and 4.89 g of 4-hydroxybenzoic acid.
1.55 g of sodium hydride are added little by little, and
Stirred for hours. After leaving at room temperature for 2 days, the solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off from the extract, the obtained residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 10: 1),
9.77 g of pale yellow crystals of the target compound having an Rf value of 0.25 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 10: 1) were obtained.

[0477]

Reference Example 64 Ethyl 4- (4-aminophenoxy) benzoate 7.50 g of ethyl 4- (4-nitrophenoxy) benzoate obtained in Reference Example 63, 10
% Palladium on carbon 0.70g and methanol 150ml
When the reaction was carried out in accordance with Example 82, Rf value = 0.
There was obtained 6.72 g of a yellow oily substance of the target compound having the following formula: 06 (silica gel thin layer chromatography; n-hexane: ethyl acetate = 5: 1).

[0478]

Reference Example 65 3,4,5-Trimethoxyanthranilic acid 3,4,5-trimethoxyanthranilic acid methyl ester 2.00 g, 2N aqueous sodium hydroxide solution 25 m
The reaction was carried out according to Reference Example 43 using 1 and 25 ml of methanol to obtain 0.40 g of purple crystals of the target compound having an Rf value of 0.73 (silica gel thin layer chromatography; ethyl acetate).

[0479]

Reference Example 66 5-Hydroxy-2-nitrobenzoic acid ethyl ester 5-hydroxy-2-nitrobenzoic acid 1
0.0 g, ethanol 100 ml and 4N hydrogen chloride
When the reaction was carried out according to Reference Example 9 using 100 ml of dioxane solution, 7.20 g of yellow crystals of the target compound having an Rf value of 0.79 (silica gel thin-layer chromatography; n-hexane: ethyl acetate = 1: 1) was obtained. Obtained.

[0480]

REFERENCE EXAMPLE 67 5- (2-Diisopropyloxyaminoethoxy) -2-nitrobenzoic acid ethyl ester 7.20 g of 5-hydroxy-2-nitrobenzoic acid ethyl ester obtained in Reference Example 66, diisopropylaminoethanol 1
When the reaction was carried out according to Example 79 using 4.6 ml, 34.0 g of 1,1′-azodicarbonyldipiperidine, 34.0 ml of tributylphosphine and 170 ml of anhydrous toluene, the Rf value was 0.24 (silica gel thin layer chromatography). This gave 2.30 g of a yellow oily substance of the target compound having the following characteristics: n-hexane: ethyl acetate = 1: 1).

[0481]

REFERENCE EXAMPLE 68 5- (2-Diisopropylaminoethoxy) anthranilic acid ethyl ester 1.00 g of 5- (2-diisopropylaminoethoxy) -2-nitrobenzoic acid ethyl ester obtained in Reference Example 67, 10% palladium carbon When the reaction was carried out according to Example 82 using 0.10 g and 15 ml of ethanol, a yellow oily substance of the target compound having an Rf value of 0.35 (silica gel thin-layer chromatography; n-hexane: ethyl acetate = 1: 1) 0.
88 g were obtained.

[0482]

REFERENCE EXAMPLE 69 5- (2-diisopropylamino) ethoxy-2-nitrobenzoic acid 5- (2
-Diisopropylamino) ethoxy-2-nitrobenzoic acid ethyl ester (0.6 g), 2N aqueous potassium hydroxide solution (5 ml) and ethanol (5 ml) were reacted according to Example 43 to give an Rf value of 0.05 (silica gel thin layer chromatography). (Ethyl acetate) was obtained as white crystals (0.12 g).

[0483]

Reference Example 70 5- (2-Diisopropylamino) ethoxyanthranilic acid 0.12 g of 5- (2-diisopropylamino) ethoxy-2-nitrobenzoic acid obtained in Reference Example 69, 0.01 g of 10% palladium carbon and When the reaction was carried out according to Example 82 using 2 ml of ethanol, the target compound having a Rf value of 0.63 (silica gel thin-layer chromatography; ethyl acetate) was added in a yellow oil.
09 g were obtained.

[0484]

Reference Example 71 19.8 g of 6-acetoxy-5,7-di-t-butyl-2H-chromene-3-carbonitrile 5-acetoxy-4,6-di-t-butyl-5-salicylaldehyde When 1.75 g of 1,4-diazabicyclo [2.2.2] octane and 18.2 g of acrylonitrile were reacted according to Reference Example 3, the target compound was 15.0.
g was obtained.

[0485]

Reference Example 72 6-acetoxy-5,7-di-t-butyl-2H-chromene-3-carboxylic acid 6-acetoxy-5,7-di-t-butyl-2H- obtained in Reference Example 29
13.1 g of chromene-3-carboxylic acid amide, 268 ml of 4N hydrochloric acid-dioxane and 50 m of 6N hydrochloric acid aqueous solution
The mixture was heated to reflux for 70 hours. The reaction mixture was allowed to cool, and the precipitated inorganic salt was filtered. The filtrate was concentrated, and ethyl acetate was added to the obtained residue. The ethyl acetate solution was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off from the extract, and the obtained residue was washed with methanol to obtain 6.69 g of the target compound.

[0486]

[Test Example 1] Cell growth inhibitory action vascular endothelial growth factor (VEG
F, human recombinant) and the cell growth inhibitory effect of the test substance on it. Human umbilical vein endothelial cells (Kurabo) are 5% fetal calf serum (Hyclo
ne), Me added with penicillin (GIBCO BRL) at a final concentration of 60 U / ml, streptomycin (GIBCO BRL) at a final concentration of 60 mg / ml, and amphotericin B (GIBCO BRL) at a final concentration of 1 mg / ml.
Cultured in dium199 (GIBCO BRL). Culture at 37 ° C, 5% CO ₂
Performed under aeration. VEGF (Wako Pure Chemical Industries) was added to the cells at a final concentration of 50 ng / ml, and a test substance at a concentration of 0.29 μM to 300 μM was added. Three days later, the Cell Counting Kit-8 (DOJIND
The degree of cell growth (cell growth rate) at each concentration was determined using O). From these results, the cell growth inhibitory concentration was 50% (the cell growth inhibitory concentration was 50% in the absence of VEGF, and the cell growth rate was 100% in the presence of 50 ng / ml VEGF. The concentration was adjusted to 50.) to evaluate the degree of the cell growth inhibitory effect of the test substance. For comparison,
Tranilast (Kissei Chemical) was used.

As a result, Example 4 (Compound No. 1-22)
4), Example 5 (Compound No. 1-108), Example 6 (Compound No. 1-114), Example 9 (Compound No. 1-109), Example 1
1 (Compound No. 1-115), Example 14 (Compound No. 1-3)
7), Example 15 (Compound No. 1-74), Example 16 (Compound No. 1-12), Example 17 (Compound No. 1-262), Example 19 (Compound No. 1-263), Example 20 (Compound No. 1-240), Example 23 (Compound No. 3-24), Example 2
4 (Compound No. 1-125), Example 25 (Compound No. 1-12)
3), Example 26 (Compound No. 1-122), Example 27 (Compound No. 1-38), Example 29 (Compound No. 1-258), Example 30 (Compound No. 1-217), Example 31 (Compound No. 1-54), Example 33 (Compound No. 2-16), Example 35
(Compound No. 2-17), Example 36 (Compound No. 1-69),
Example 37 (Compound No. 1-91), Example 39 (Compound No. 1-168), Example 40 (Compound No. 1-226), Example 4
1 (Compound No. 1-239), Example 42 (Compound No. 1-12)
0), Example 44 (Compound No. 1-257), Example 46 (Compound No. 1-229), Example 52 (Compound No. 1-143), Example 54 (Compound No. 2-15), Example 55 (Compound number
1-99), Example 56 (Compound No. 1-100), Example 57
(Compound No. 1-98), Example 58 (Compound No. 1-10)
1), Example 59 (Compound No. 2-14), Example 60 (Compound No. 1-102), Example 61 (Compound No. 1-103), Example 63 (Compound No. 1-228), Example 64 (Compound No. 1-230), Example 65 (Compound No. 1-231), Example 6
6 (Compound No. 1-175), Example 67 (Compound No. 1-17)
9), Example 74 (Compound No. 1-273), Example 83 (Compound No. 1-225), Example 84 (Compound No. 1-104), Example 85 (Compound No. 1-272), Example 89 (Compound No. 1-315), Example 90 (Compound No. 1-305), Example 9
1 (Compound No. 1-288), Example 92 (Compound No. 1-28)
9), Example 94 (Compound No. 1-286), Example 97 (Compound No. 1-348), Example 103 (Compound No. 1-243),
Example 106 (Compound No. 1-356) Example 109 (Compound No. 1-67), Example 111 (Compound No. 1-317), Example 112 (Compound No. 1-336), Example 113 (Compound No. 1) -331), Example 114 (Compound No. 1-326), Example 116 (Compound No. 1-332), Example 118 (Compound No. 1-301), Example 120 (Compound No. 1-303), Example 121 (Compound No. 1-302), Example 122 (Compound No. 1-325), Example 124 (Compound No. 1-316), Example 125 (Compound No. 1-299), Example 126 (Compound No. 1- 320), Example 127 (Compound No. 1-321), Example 128 (Compound No. 1-70), Example 130 (Compound No. 1-319), Example 131 (Compound No. 1-298), Example 132 (Compound No. 1-314), Example 133 (Compound No. 1-309) and Example 134 (Compound No. 1-304) It shows a cell growth inhibitory action three times or more that of tranilast, and is effective in Example 4 (Compound No. 1-224), Example 5 (Compound No. 1-108), Example 9 (Compound No. 1-109), Example 16 ( Compound No. 1-12), Example 17 (Compound No. 1-26)
2), Example 19 (Compound No. 1-263), Example 20 (Compound No. 1-240), Example 33 (Compound No. 2-16), Example 35 (Compound No. 2-17), Example 37 (Compound number
1-91), Example 41 (Compound No. 1-239), Example 42
(Compound No. 1-120), Example 44 (Compound No. 1-25)
7), Example 46 (Compound No. 1-229), Example 54 (Compound No. 2-15), Example 55 (Compound No. 1-99), Example 57 (Compound No. 1-98), Example 58 (Compound No. 1-
101), Example 59 (Compound No. 2-14), Example 63
(Compound No. 1-228), Example 64 (Compound No. 1-23)
0), Example 84 (Compound No. 1-104), Example 83 (Compound No. 1-225), Example 89 (Compound No. 1-315), Example 90 (Compound No. 1-305), Example 92 (Compound No. 1-289), Example 94 (Compound No. 1-286), Example 9
7 (Compound No. 1-348), Example 106 (Compound No. 1-3)
56), Example 109 (Compound No. 1-67), Example 111
(Compound No. 1-317), Example 112 (Compound No. 1-33)
6), Example 113 (Compound No. 1-331), Example 114
(Compound No. 1-326), Example 116 (Compound No. 1-33)
2), Example 120 (Compound No. 1-303), Example 121
(Compound No. 1-302), Example 124 (Compound No. 1-31)
6), Example 126 (Compound No. 1-320), Example 130
(Compound No. 1-319), Example 131 (Compound No. 1-29)
8) or the compound of Example 133 (Compound No. 1-309) exhibits a cell growth inhibitory effect at least 10 times that of tranilast,
Example 16 (Compound No. 1-12), Example 19 (Compound No. 1-263), Example 20 (Compound No. 1-240), Example 3
3 (Compound No. 2-16), Example 35 (Compound No. 2-1)
7), Example 42 (Compound No. 1-120), Example 44 (Compound No. 1-257), Example 54 (Compound No. 2-15), Example 58 (Compound No. 1-101), Example 84 (Compound No. 1-104), Example 90 (Compound No. 1-305), Example 9
4 (Compound No. 1-286), Example 97 (Compound No. 1-34)
8), Example 112 (Compound No. 1-336), Example 116
(Compound No. 1-332) or Example 121 (Compound No. 1-3)
Compound No. 02) exhibited a cell growth inhibitory effect 30 times or more that of tranilast.

[0488]

Formulation Example 1 Injection 1.5% by weight of the compound of Example 1 was
Stir in 0% by volume propylene glycol, then make up to volume with water for injection and sterilize to produce.

[0489]

Formulation Example 2 Soft capsule digestible oil, for example,
A mixture of the compound of Example 1 in soybean oil, cottonseed oil or olive oil was prepared and injected into gelatin with a positive displacement pump to give soft capsules containing 100 mg of active ingredient, washed and dried I do.

[0490]

Formulation Example 3 Tablet A powder having the following formulation is mixed, wet-granulated using corn starch paste, dried, and then tableted with a tableting machine to give a tablet of 490 mg per tablet.

[0490] In addition, if desired, a coating can be applied.

[0492]

The compound (I) of the present invention and a pharmacologically acceptable salt thereof are useful as therapeutic or preventive agents for diabetic retinopathy and retinopathy because they exhibit an excellent cell growth inhibitory action.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/41 A61K 31/41 31/4155 31/4155 31/4178 31/4178 31/4184 31/4184 31 / 427 31/427 31/4433 31/4433 31/453 31/453 31/4709 31/4709 31/497 31/497 31/5377 31/5377 A61P 3/10 A61P 3/10 9/10 9/10 43 / 00 105 43/00 105 C07D 405/04 C07D 405/04 405/12 405/12 407/12 407/12 409/12 409/12 417/12 417/12 (72) Inventor Tomiku Yokoyama Shinagawa-ku, Tokyo 1-258 Hiromachi, Sankyo Co., Ltd. (72) Inventor Tatsuya Inoue 1-25-2, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. F-term (reference) 4C062 FF01 4C063 AA01 BB01 BB09 CC79 CC94 DD04 DD10 DD12 DD14 DD22 DD25 DD26 DD34 DD47 DD62 DD78 DD79 EE01 4C086 AA01 AA02 AA03 BA08 BB03 BC05 BC17 BC21 BC28 BC36 BC38 BC39 BC48 B C62 BC73 BC82 GA02 GA04 GA07 GA08 GA10 GA12 MA01 MA02 MA03 MA04 MA05 NA14 ZA33 ZA36 ZA44 ZB21 ZC35

Claims (21)

[Claims] (1) Formula (1)[Wherein, R¹Is a hydrogen atom, an optionally substituted C₁~ C₆A
Alkyl group (the substituent is C₆~ C_TenAn aryl group
You. ), C₆~ C_TenAryl group or C₁~ C₁₂An acyl group
Indicates, R^Two, R^Three, R^FourAnd R^FiveAre the same or different
Child, halogen atom, C₁~ C₆Alkyl group, C_Three~ C₆Shiku
Loalkyl group, optionally substituted C₆~ C_TenAryl group
(The substituent is selected from the following substituent group β.)
5 to 10-membered heterocyclic group which may be substituted (the substituent is
Selected from the substituent group β. ), Hydroxyl group, may be substituted
C₁~ C₆Alkoxy group--the substituent is a halogen atom or
And optionally substituted C₆~ C_TenAryl group (substituent
Is selected from the following substituent group β. )
Devour. ｝, C_Three~ C₆Cycloalkoxy group, substituted
Good C₆~ C_TenAryloxy group (the substituent is
Selected from the substituent group β. ), C ₁~ C₁₂Acyloxy
Group, an amino group which may be substituted (the substituent is
It is selected from the group α. ), Nitro group or cyano group
Then R⁶Is a hydrogen atom, a halogen atom, an optionally substituted C₁~
C₆Alkyl group ｛the substituent is a hydroxyl group, C₁~ C₆Al
Coxy group, C_Three~ C₆Cycloalkyl group and substituted
C₆~ C_TenAryl group (the substituent is a group of the following substituents)
Selected from β. ). ｝, C_Two
~ C₆Alkenyl group, C_Two~ C₆Alkynyl group, C_Three~ C₆
Cycloalkyl group, optionally substituted C₆~ C_TenAryl
Groups (the substituents are selected from the following substituent group β):
5- to 10-membered heterocyclic group which may be substituted (the substituent is
Selected from the substituent group β. ), Optionally substituted C₁~
C₆An alkoxy group ｛the substituent is a hydroxyl group, a cyano group,
Formyl group, C₁~ C₆Alkoxy group and may be substituted
A 5- to 10-membered heterocyclic group (the substituent is the following substituent group β
Selected from ). ｝, C_Two~ C₆
Alkenyloxy group, C _Two~ C₆Alkynyloxy group, C
_Three~ C₆Cycloalkoxy group, optionally substituted C₆~ C_Ten
An aryloxy group (the substituent is the following substituent group β
To be elected. ), Optionally substituted 5 to 10 membered heterocyclic oxy
Groups (the substituents are selected from the following substituent group β):
C_Two~ C₇Alkylcarbonyloxy group, C₁~ C₆Archi
A ruthio group or an amino group which may be substituted (the substituent is
It is selected from the following substituent group α. ), R⁷And R⁸Are the same or different and represent a hydrogen atom, a halogen
Atom, C₁~ C₆Alkyl group, C_Three~ C₆Cycloalkyl
Group, C which may be substituted₆~ C_TenAryl group (substituent
Is selected from the following substituent group β. ) Or be replaced
Or a 5- to 10-membered heterocyclic group (the substituent is the following substituent group β
Selected from. ),...... Represents a double bond or a single bond, and Ar represents an optionally substituted C₆~ C_TenAryl group (substituted
The group is selected from the following substituent group δ. ) Or replaced
A good 5- to 10-membered heterocyclic group (wherein the ring is
Selected from the substituent group δ. And the substituent group α is an optionally substituted C₁~ C₆Alkyl group
The substituent is C₆~ C_{1 0}Aryl group, hydroxyl group, substituted
Amino group (the substituent may be C₁~ C₆With an alkyl group
is there. ) And a 5- to 10-membered heterocyclic group
You. ｝, C which may be substituted₆~ C_TenAryl group
The substituent is a halogen atom. ), Hydroxyl group, C₁~ C₆A
Lucoxy group, C₆~ C_TenAryloxy group, 5 to 10 members
Heterocyclic oxy group, C_Two~ C₇Alkylcarbonyl group, C₇
~ C₁₁Arylcarbonyl group, 5- to 10-membered heterocyclic carbo
Nyl group, C_Two~ C₇Alkoxycarbonyl group, C_Two~ C₇A
Alkylaminocarbonyl group, C₇~ C₁₁Arylamino
Carbonyl group, C_Two~ C₇Alkylamino (thiocarboni
Ru) group and C₇~ C₁₁Arylamino (thiocarboni
And the substituent group β is a halogen atom, an optionally substituted C₁~ C₆
An alkyl group (the substituent is a halogen atom),
Hydroxyl group, optionally substituted C₁~ C₆An alkoxy group
The substituent is a halogen atom. ), Carboxyl group and
C_Two~ C₇Is a group consisting of an alkoxycarbonyl group, and the substituent group γ is a halogen atom, a hydroxyl group, and may be substituted.
C₁~ C₆An alkoxy group (the substituent is C₆~ C_TenAnts
A group. ), C₆~ C_TenAryloxy group, substituted
An amino group which may be
Selected from ), Optionally substituted C₆~ C_TenAryl group
(The substituent is selected from the substituent group β.)
5 to 10-membered heterocyclic group which may be substituted (the substituent is
Selected from the substituent group β. ), Carboxyl group, C_Two~
C₇Alkylcarbonyloxy group, nitro group and cyano
And the substituent group δ is a halogen atom, an optionally substituted C₁~ C₆
An alkyl group (the substituent is selected from the above substituent group γ;
You. ), Optionally substituted C_Two~ C₆Alkenyl group (the
The substituent is selected from the above substituent group γ. ), Replaced
Good C_Two~ C₆An alkynyl group (the substituent is the above substituent
Selected from the group γ. ), C_Three~ C₆Cycloalkyl group, C
_Two~ C₇Alkylcarbonyl group, optionally substituted C₇~ C
₁₁An arylcarbonyl group (the substituent is a group of the substituents described above)
Selected from β. ), 5 to 10-membered heterocyclic ring which may be substituted
A carbonyl group (the substituent is selected from the above substituent group β)
It is. ), Carboxyl group, optionally substituted C_Two~ C₇A
Alkoxycarbonyl group (the substituent is C₆~ C_TenAnts
A group. ), Optionally substituted C₇~ C₁₁Aryl
An oxycarbonyl group (the substituent is the aforementioned substituent group β
Selected from ), A carbamoyl group which may be substituted (the
The substituent is selected from the above-mentioned substituent group α. ), Replaced
Good C₆~ C_TenAryl group (the substituent is
It is selected from the group β. ), 5 to 10 members which may be substituted
A ring group (the substituent is selected from the above substituent group β)
You. ), Hydroxyl group, optionally substituted C₁~ C₆Alkoxy group
(The substituent is selected from the substituent group γ.)
C that may be replaced_Two~ C₆Alkenyloxy group (substituent
Is selected from the above substituent group γ. ), May be replaced
C_Two~ C₆An alkynyloxy group (the substituent is
It is selected from the group γ. ), C_Three~ C₆Cycloalkoxy
Group, C which may be substituted₆~ C_TenAryloxy group (the
The substituent is selected from the above substituent group β. ), Mercap
Group, sulfo group, optionally substituted C₁~ C₆Alkylthio
Groups (the substituents are selected from the above substituent group γ),
C which may be substituted_Two~ C₆Alkenylthio group (substituent
Is selected from the above substituent group γ. ), May be replaced
C_Two~ C₆An alkynylthio group (the substituent is
Selected from the group γ. ), C_Three~ C₆Cycloalkylthio
Group, C which may be substituted₆~ C_TenArylthio group (the
The substituent is selected from the substituent group β. ), Replaced
Good C₁~ C₆An alkylsulfinyl group (the substituent is
It is selected from the above substituent group γ. ), Optionally substituted C_Two
~ C₆An alkenylsulfinyl group (the substituent is
It is selected from the substituent group γ. ), Optionally substituted C_Two~ C₆
An alkynylsulfinyl group (the substituent is the above substituent
Selected from the group γ. ), C_Three~ C₆Cycloalkyl sulf
Ynyl group, optionally substituted C₆~ C_TenAryl sulfy
Nyl group (the substituent is selected from the above substituent group β)
You. ), Optionally substituted C ₁~ C₆Alkylsulfonyl group
(The substituent is selected from the substituent group γ.)
C that may be replaced_Two~ C₆Alkenylsulfonyl group (the
The substituent is selected from the above substituent group γ. ), Replaced
Good C_Two~ C₆An alkynylsulfonyl group (the substituent is
It is selected from the above substituent group γ. ), C_Three~ C₆Cycloal
Kilsulfonyl group, optionally substituted C₆~ C_TenAryl
Sulfonyl group (the substituent is selected from the above-mentioned substituent group β)
It is. ), A sulfamoyl group which may be substituted (substituted
The group is selected from the above-mentioned substituent group α. ), Be replaced
Amino group (the substituent is selected from the above-mentioned substituent group α)
You. ), A nitro group and a cyano group, provided that 3-{(2H-chromen-3-carbonyl) amido
NO｝ pyridine, 4-｛(2H-chromen-3-carboni
L) amino} pyridine, N- [3- {2- (diisopro
Pyramino) ethoxy {-4-methoxyphenyl] -6
-Chloro-2H-chromen-3-carboxamide, N-
[3- {3- (diisopropylamino) propoxy}-
4-methoxyphenyl] -6-chloro-2H-chromene
-3-carboxamide and N- [3- {3- (diisopropane)
Ropylamino) propyl {-4-methoxyphenyl]-
Except for 6-chloro-2H-chromen-3-carboxamide
Good. And a pharmacologically acceptable salt thereof. 2. A method according to claim 1, wherein R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group,
A C ₂ -C ₇ alkylcarbonyl group or a C ₁ -C ₆ alkylsulfonyl group, compound and a pharmacologically acceptable salt thereof according to claim 1. 3. The compound according to claim ₁ , wherein R ¹ is a hydrogen atom or a C ₁ -C ₄ alkyl group, and a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, wherein R ¹ is a hydrogen atom, and a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group,
₆ -C ₁₀ aryl group, 5- or 6-membered unsaturated Hajime Tamaki (hetero atom in the ring, the nitrogen atom, the same or different one to three hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom ), A hydroxyl group, a C ₁ -C ₆ alkoxy group which may be substituted (the substituent is selected from the group consisting of a halogen atom and a C ₆ -C ₁₀ aryl group), or a C ₂ -C ₇ alkylcarbonyl The compound according to any one of claims 1 to 4, which is an oxy group, and a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and each is hydrogen, fluorine, chlorine, bromine, C ₁
A C ₄ alkyl group, a phenyl group, a 6-membered unsaturated heterocyclic group (the heteroatom in the ring is 1 to 3 nitrogen atoms), a hydroxyl group, a C ₁ -C ₆ alkoxy group which may be substituted (the substituent is a fluorine atom, a chlorine atom, selected from the group consisting of bromine and a phenyl group.) or a C ₂ -C ₅ alkylcarbonyloxy group, according to any one of claims 1 to 4 And a pharmacologically acceptable salt thereof. 7. R ² , R ³ , R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a fluorine atom, a chlorine atom, a C ₁ -C ₄ alkyl group, a pyridyl group, a hydroxyl group, a C ₁ -C ₃ group. an alkoxy group or a C ₂ -C ₄ alkylcarbonyloxy group, claim 1
Or a pharmacologically acceptable salt thereof. 8. A compound according to claim 1, wherein R ² , R ³ , R ⁴ and R ⁵ are the same or different and are each a hydrogen atom, a chlorine atom, a methyl group, a 3-pyridyl group,
The compound according to any one of claims 1 to 4, which is a methoxy group or an acetoxy group, and a pharmacologically acceptable salt thereof. 9. R ² , R ³ and R ⁵ are a methyl group and R ⁴ is an acetoxy group; R ² and R ⁵ are a hydrogen atom and R ³ and R ⁴ are a methoxy group; or R ² , R ³ and R ⁵ is a hydrogen atom and R ⁴ is a chlorine atom, compound and a pharmacologically acceptable salt thereof according to any one of claims 1 to 4. 10. The method according to claim 1, wherein R ⁶ is a hydrogen atom.
And a pharmacologically acceptable salt thereof. 11. The compound according to any one of claims 1 to 10, wherein R ⁷ and R ⁸ are both hydrogen atoms, and a pharmaceutically acceptable salt thereof. 12. The method according to claim 1, wherein ... is a double bond.
2. The compound according to any one of the above 1 and a pharmacologically acceptable salt thereof. (13) Ar is a phenyl group which may be substituted;
The substituent is a halogen atom, an optionally substituted C₁~ C₆Al
Kill group (the substituent is a halogen atom, a carboxyl group
And C _Two~ C₇Selected from the group consisting of alkoxycarbonyl groups
Devour. ), Optionally substituted C _Two~ C₆Alkenyl group (this
The substituent is a 5- or 6-membered unsaturated heterocyclic group which may be substituted.
複 素 The heteroatoms in the ring are nitrogen, oxygen and sulfur
1 to 3 identical or different atoms selected from the group consisting of atoms
Is a complex atom of The substituent is a halogen atom, C₁
~ C₆Alkyl group and optionally substituted phenyl group (the
The substituent is a halogen atom. Selected from the group consisting of
It is. ｝, Carboxyl group and C_Two~ C₇Alkoxycal
It is selected from the group consisting of a bonyl group. ], C_Two~ C₇Archi
Carbonyl group, benzoyl group, 5-6 which may be substituted
Membered heterocyclic carbonyl group (where the heteroatom in the ring is nitrogen
Same or different selected from the group consisting of elemental atoms and oxygen atoms
1 to 2 complex atoms. The substituent is hydroxyl
Group. ), Carboxyl group, optionally substituted C_Two~
C₇An alkoxycarbonyl group (the substituent is phenyl
Group. ), Phenoxycarbonyl group, may be substituted
A carbamoyl group (the substituent is an optionally substituted C₁
~ C₆Alkyl group ｛the substituent is a phenyl group, hydroxyl
Group, di (C₁~ C₆Alkyl) amino group and 5-6 member saturation
A heterocyclic group (where the heteroatom in the ring is a nitrogen atom or an oxygen atom)
Same or different one or two selected from the group consisting of children
It is a complex atom. ).置換, replace
Phenyl group (the substituent is a halogen atom
is there. ), A hydroxyl group and a 5- to 6-membered saturated heterocyclic oxy group (such as
The group in which the heteroatom in the ring consists of a nitrogen atom and an oxygen atom
Same or different one or two heteroatoms selected from
You. ). ], Phenyl group, substitution
5- or 6-membered unsaturated heterocyclic group which may be substituted
Is selected from the group consisting of nitrogen, oxygen and sulfur
The same or different 1 to 4 heteroatoms selected.
The ring may be fused with a benzene or pyridine ring.
The substituent is an optionally substituted C₁~ C₆Alkyl group (this
The substituent is a halogen atom. ). ｝, 5
A 6-membered saturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom or
The same or different 1 selected from the group consisting of
~ 2 complex atoms. ), Hydroxyl group, may be substituted
C₁~ C₆Alkoxy group ｛the substituent is a halogen atom,
A 5- to 6-membered saturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom
The same or different selected from the group consisting of oxygen and oxygen
Or one or two heteroatoms. ) And di (C₁~ C₆Al
Selected from the group consisting of: ｝, C_Three~ C₇
Cycloalkoxy group, phenoxy group which may be substituted
The substituent is a carboxyl group and C_Two~ C₇Alkoxyka
It is selected from the group consisting of a rubonyl group. ), Mercapto
Group, sulfo group, sulfamoyl group,
No group ｛The substituent is C _Two~ C₇Alkylcarbonyl group,
Benzoyl group, 5- or 6-membered unsaturated heterocyclic carbonyl group (this
The heteroatoms in the ring are nitrogen, oxygen and sulfur
1 to 3 identical or different groups selected from the group consisting of
Elementary atom. ) And C_Two~ C₇Alkoxycarbonyl group
Selected from the group consisting ofウ, ureido that may be replaced
Group (the substituent is C₁~ C₆Alkyl group and phenyl group
Selected from the group consisting of ) And optionally substituted thio
From a raid group (the substituent is a phenyl group).
Selected from the group. ] Or optionally substituted 5- to 6-membered unsaturated
Sum heterocyclic group [where the heteroatom in the ring is a nitrogen atom, an oxygen atom
The same or different selected from the group consisting of
Or 1 to 3 complex atoms. The ring may be a benzene ring or
May be fused with a pyridine ring, and C_Three~ C_FourTo the alkylene group
More may be substituted. The substituent is C₁~ C₆Alkyl
Group, carboxyl group, C_Two~ C₇Alkoxycarbonyl group
And a carbamoyl group which may be substituted (the substituent is
C that may be replaced₁~ C₆Alkyl group ｛the substituent is hydroxyl
Group and di (C₁~ C₆Alkyl) amino group
To be elected. ｝. ] Is selected from the group consisting of: ]so
13. A compound as claimed in any one of claims 1 to 12 and
And pharmacologically acceptable salts thereof. (14) Ar is a phenyl group which may be substituted;
The substituent is a fluorine atom, a chlorine atom, a bromine atom,
Good C₁~ C_FourAlkyl group (the substituent is a fluorine atom
Atom, chlorine atom, bromine atom, carboxyl group and C_Two~ C_Five
It is selected from the group consisting of alkoxycarbonyl groups. ),
C which may be substituted_Two~ C_FourAn alkenyl group (the substituent is
Optionally substituted 5-membered unsaturated heterocyclic group {hetero atom in the ring;
The offspring are one to three nitrogen atoms. The substituent is
Element atom, chlorine atom, bromine atom, C₁~ C_FourAlkyl group and
A phenyl group which may be substituted (the substituent is a fluorine atom
Selected from the group consisting of hydrogen, chlorine and bromine. )
Selected from the group consisting of ｝ And C_Two~ C_FiveAlkoxyka
It is selected from the group consisting of a rubonyl group. ], C_Two~ C_FiveAl
Killcarbonyl group, benzoyl group, 6-membered which may be substituted
A saturated heterocyclic carbonyl group (where the heteroatom in the ring is nitrogen
Same or different selected from the group consisting of atoms and oxygen atoms
Only one or two complex atoms. The substituent is a hydroxyl group
It is. ), Carboxyl group, C _Two~ C_FiveAlkoxycal
Bonyl group, carbamoyl group which may be substituted [substituent
Is an optionally substituted C₁~ C₆Alkyl group ｛the substituent
Represents a phenyl group, a hydroxyl group, a di (C₁~ C_FourAlkyl)
And a 6-membered saturated heterocyclic group (where the heteroatom in the ring is nitrogen)
Same or different selected from the group consisting of elemental atoms and oxygen atoms
1 to 2 complex atoms. )
Devour. ｝, An optionally substituted phenyl group (the substituent
Is from the group consisting of fluorine, chlorine and bromine
To be elected. ), A hydroxyl group and a 6-membered saturated heterocyclic oxy group
The group in which the heteroatom in the ring consists of a nitrogen atom and an oxygen atom
Same or different one or two heteroatoms selected from
You. ). ], Phenyl group, substitution
5- or 6-membered unsaturated heterocyclic group which may be substituted
The offspring are 1-4 nitrogen atoms. The ring is benzene
It may be fused with a ring. The substituent is an optionally substituted C₁
~ C_FourAlkyl group (the substituent is a fluorine atom, chlorine atom
Selected from the group consisting of hydrogen atom and bromine atom. )
You. ｝, A 6-membered saturated heterocyclic group (where the heteroatom in the ring is nitrogen
Same or different selected from the group consisting of elemental atoms and oxygen atoms
1 to 2 complex atoms. ), Hydroxyl, substituted
Good C₁~ C₆Alkoxy group ア ル コ キ シ the substituent is fluorine
Atom, chlorine atom, bromine atom, 6-membered saturated heterocyclic group (the ring
Heteroatoms in the group consisting of nitrogen and oxygen
One or two heteroatoms selected from the same or different
You. ) And di (C₁~ C_FourGroup consisting of alkyl) amino groups
Selected from. ｝, C_Three~ C₆Cycloalkoxy group, substitution
Phenoxy group (the substituent may be carboxyl
Group and C_Two~ C_FiveFrom the group consisting of alkoxycarbonyl groups
To be elected. ), Mercapto group, sulfo group, sulfamoy
A substituted or unsubstituted amino group._Two~
C_FiveAlkylcarbonyl group, benzoyl group, 6-membered unsaturated
Heterocyclic carbonyl group (when the number of heteroatoms in the ring is 1 to 3
Is a nitrogen atom. ) And C_Two~ C_FiveAlkoxycarboni
Selected from the group consisting of ｝ 、 Ure which may be substituted
Id group (the substituent is C₁~ C_FourAlkyl group and phenyl
Selected from the group consisting of ) And may be substituted
An oleido group (the substituent is a phenyl group) or
Selected from the group consisting of: ] Or 5 to 6 members which may be substituted
An unsaturated heterocyclic group wherein the heteroatom in the ring is a nitrogen atom, an acid,
Same or different selected from the group consisting of elemental atoms and sulfur atoms
1 to 3 complex atoms. The ring is pyridine
May be condensed with a ring,
Good. The substituent is C₁~ C_FourAlkyl group, carboxy
Group, C_Two~ C_FiveAlkoxycarbonyl group and substituted
A good carbamoyl group [the substituent is an optionally substituted C
₁~ C_FourAn alkyl group {the substituent is a hydroxyl group or a di (C ₁
~ C_FourSelected from the group consisting of alkyl) amino groups. ｝
It is. ] Is selected from the group consisting of: ]
The compound according to any one of 1 to 12 and pharmacologically thereof
Acceptable salt. 15. Ar is a phenyl group which may be substituted.
The substituent is a fluorine atom, a chlorine atom, a bromine atom,
Good C₁~ C_ThreeAlkyl group (the substituent is a fluorine atom
Child, chlorine atom and C_Two~ C_FourFrom an alkoxycarbonyl group
Selected from the group ), Optionally substituted C_Two~ C_FourAl
Kenyl group [the substituent is a pyrrolyl group which may be substituted;
｛The substituent is a phenyl group which may be substituted (the substituted
The group is selected from the group consisting of a fluorine atom and a chlorine atom
You. ). ｝ And C_Two~ C_FourArco
It is selected from the group consisting of xycarbonyl groups. ], Benzo
Yl group, an optionally substituted piperidylcarbonyl group (the
The substituent is a hydroxyl group. ), Carboxyl group, C_Two~
C_FourAlkoxycarbonyl group, carbamo which may be substituted
Yl group [the substituent is optionally substituted C₁~ C_FourArchi
Group—the substituent is a phenyl group, a hydroxyl group, a di (C₁~
C_ThreeA group consisting of alkyl) amino and piperidyl groups
Selected from ｝, A phenyl group which may be substituted (substituted
The group is selected from the group consisting of a fluorine atom and a chlorine atom
You. ), From hydroxyl and tetrahydropyranyloxy groups
Selected from the group ], A phenyl group, which may be substituted
5- to 6-membered unsaturated heterocyclic group wherein the heteroatoms in the ring are 1 to
Two nitrogen atoms. The substituent may be substituted
C ₁~ C_ThreeAlkyl group (the substituent is a fluorine atom or a salt
It is selected from the group consisting of elementary atoms. ). ｝, Morpho
Ryl group, hydroxyl group, optionally substituted C₁~ C_ThreeAlkoxy group
｛The substituent is a fluorine atom, a chlorine atom, a piperidyl group
And di (C₁~ C_ThreeAlkyl) amino group
Devour. ｝, Mercapto group, sulfamoyl group and substitution
Amino group (the substituent may be C_Two~ C_FiveAlkoki
It is a cyclocarbonyl group. ). ]
Or a 5-membered unsaturated heterocyclic group which may be substituted
The elementary atom is selected from the group consisting of a nitrogen atom and a sulfur atom
One or two different heteroatoms. The ring
May be substituted by a tetramethylene group. The replacement
The group is a carboxyl group, C_Two~ C_FourAlkoxycarbonyl
Group and a carbamoyl group which may be substituted (the substituent is
C which may be substituted₁~ C_ThreeAlkyl group ｛the substituent is water
Acid groups and di (C₁~ C_ThreeGroup consisting of (alkyl) amino groups
Selected from ｝. ] Is selected from the group consisting of: ]
The compound according to any one of claims 1 to 12, which is
And pharmacologically acceptable salts thereof. 16. Ar is a phenyl group which may be substituted [the substituent is a bromine atom, a C ₁ -C ₂ alkyl group which may be substituted (the substituent is a fluorine atom or a C ₂ -C ₃ alkoxycarbonyl) is a group.), a carboxyl group, C ₂ -C ₃ alkoxycarbonyl group, which may be substituted carbamoyl group {said substituents may be substituted C ₁ -C ₄ alkyl group (the substituent is a phenyl group, Selected from the group consisting of a dimethylamino group, a diisopropylamino group and a piperidino group) and a hydroxyl group. }, A phenyl group, which may be substituted pyridyl group or a pyrazolyl group {said substituents may be substituted C ₁ -C ₃ alkyl group (the substituent is a fluorine atom.) Is. ｝,
A hydroxyl group, an optionally substituted C ₁ -C ₃ alkoxy group (the substituent is selected from the group consisting of a fluorine atom, a piperidino group, a dimethylamino group and a diisopropylamino group), a sulfamoyl group and an optionally substituted amino group (The substituent is a t-butoxycarbonyl group.)
Selected from the group consisting of ] Or which may be substituted tetrahydrobenzo thienyl group or an imidazolyl group [the substituent is a carboxyl group, C ₂ -C ₃ alkoxycarbonyl group, and which may be substituted carbamoyl group {said substituents may C ₁ ~ to be substituted A C ₂ alkyl group (the substituent is selected from the group consisting of a hydroxyl group, a dimethylamino group and a diisopropylamino group).か ら is selected from the group consisting of 13. The method according to claim 1, wherein
And a pharmacologically acceptable salt thereof. 17. An phenyl group which may be substituted with Ar (the substituent is a methyl group, an ethoxycarbonylmethyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group,
Phenylbutylcarbamoyl group, 2-dimethylaminoethylcarbamoyl group, 2-diisopropylaminoethylcarbamoyl group, 2-piperidinoethylcarbamoyl group, 3,5-bistrifluoromethyl-1-pyrazolyl group, hydroxyl group, methoxy group, Piperidinoethoxy group,
One or two identical or different substituents selected from the group consisting of a 2-diisopropylaminoethoxy group and a bis-t-butoxycarbonylamino group. The compound according to any one of claims 1 to 12 and a pharmaceutically acceptable salt thereof. 18. The 6-acetoxy- according to claim 1.
5,7,8-trimethyl-2H-chromene-3-carboxylic acid (3-methylcarbamoylphenyl) amide or 6
-Acetoxy-5,7,8-trimethyl-2H-chromene-3-carboxylic acid [3- (2-diisopropylaminoethoxy) -4-methoxyphenyl] amide. 19. A medicament comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable salt thereof as an active ingredient. 20. A preventive or therapeutic agent for diabetic retinopathy or retinopathy, comprising the compound according to any one of claims 1 to 18 and a pharmaceutically acceptable salt thereof as an active ingredient. 21. A method for preventing or treating diabetic retinopathy or retinopathy using the compound according to any one of claims 1 to 18 and a pharmacologically acceptable salt thereof.