Title of Invention

NOVEL ANTHRANILIC ACID DERIVATIVE OR SALT THEREOF

Abstract An anthranilic acid derivative represented by the general formula (X) [wherein R1 represents hydrogen or a carboxy-protecting group; R2 represents optionally substituted phenyl, a heterocyclic group, etc.; R3 represents optionally substituted phenyl, a monocyclic heterocyclic group, etc.; X1 represents carbonyl, etc.; X2 represents optionally substituted alkylene group, a bond, etc.; X3 represents oxygen, a bond, etc.; and X4 represents a group represented by the general formula -X5-X6- or -X6-X5- (wherein X5 means oxygen, a bond, etc.; and X6 means optionally substituted alkylene, a bond, etc.)] or a salt of the derivative. The derivative or salt has the inhibitory activity of MMP- 13 production and is hence useful as a therapeutic agent for articular rheumatism, osteoarthritis, cancer, etc.
Full Text W3763458/8 1
DESCRIPTION
NOVEL ANTHRANILIC ACID DERIVATIVE OR SALT THEREOF
TECHNICAL FIELD
[0001]
The present invention relates to a novel
anthranilic acid derivative or a salt thereof having
the inhibitory activity of matrix metalloprotease 13
(MMP-13) production.
BACKGROUND ART
[0002]
Matrix metalloproteases are a family
consisting of zinc-dependent proteases whose substrates
are components of extracellular matrix, and they are
activated by removal of a propeptide after secretion.
More than 20 members of matrix metalloproteases have
been identified in human, and they are classified into
collagenase (MMP-1, 8, 13), gelatinase (MMP-2, 9),
stromelysin (MMP-3, 10), matrilysin (MMP-7, 26),
membrane-type MMP (MMP-14, 15, 16, 17, 24, 25)
according to the domain structure and substrate
specificity. Overexpression of these matrix
metalloproteases are observed in various cancer cells,
and it is considered to be involved in the
proliferation and metastasis thereof. Anticancer agents
that inhibit matrix metalloprotease have been developed
up to now (Non-Patent Document 1).

2
[0003]
Matrix metalloprotease inhibitors have been
developed as a therapeutic agent for rheumatoid
arthritis and osteoarthritis. The articular cartilage
is composed of a cartilage type II collagen network in
which cartilage proteoglycans such as aggrecan and
hyaluronic acid are retained. Matrix metalloprotease
participates in the maintenance of the extracellular
matrix. When matrix metalloprotease and TIMP (tissue
inhibitor of metalloproteinases), an endogenous
inhibitor thereof, are not in balance and matrix
metalloprotease becomes excessively present,
destruction of the cartilages and bones may progress.
Particularly when collagen fibers are damaged, the
joints suffer from progressive destruction as observed
in rheumatoid arthritis and osteoarthritis. Accordingly,
long-term suppression of the progress of joint
destruction in rheumatoid arthritis and osteoarthritis
can be expected by inhibiting excessive matrix
metalloprotease (Non-Patent Document 2).
[0004]
In osteoarthritis, the production of
interleukin-1 (IL-1) and tumor necrosis factor (TNF) a
also increases and extracellular matrix is degraded.
The production of matrix metalloprotease is further
increased by degradation products of type II collagen
and fibronectin, leading to progress in degradation of
matrix in the joints. When this damage of matrix
exceeds a certain threshold, character of cartilage

3
cells pathological change, and joint destruction keeps
progressing. It is MMP-13 that plays a dominant role in
this cleavage of type II collagen (Non-Patent Document
3).
[0005]
Non-Patent Document 1: Current Oncology Reports, Vol. 6,
page 96-102, 2004
Non-Patent Document 2: Annals of the Rheumatic Diseases,
Vol. 60, page 62-67, 2001
Non-Patent Document 3: Biochemical Society Symposia,
Vol. 70, page 115-123, 2003
DISCLOSURE OF THE INVENTION
[0006]
Drugs inhibiting the production of matrix
metalloproteases, particularly MMP-13, are strongly
demanded.
[0007]
Under the circumstances, the present
inventors have conducted extensive studies, and
consequently have found that an anthranilic acid
derivative represented by general formula [1]
[Formula 1]
wherein, R1 represents a hydrogen atom or a carboxyl
protecting group; R2 represents a phenyl, cycloalkyl or


4
heterocyclic group which may be optionally substituted;
R3 represents a phenyl, cycloalkyl, cycloalkenyl,
monocyclic heterocyclic or bicyclic heterocyclic group
which may be optionally substituted; X1 represents a
carbonyl group or sulfonyl group; X2 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted or a bond; provided that when X1
is a sulfonyl group and X4 is a bond, X2 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted; X3 represents an oxygen atom, a
sulfur atom or a bond; X4 represents a group represented
by the general formula, -X5-X6- or -X6-X5-, wherein the
bond on the left side of each general formula is linked
to R3; and X5 represents an oxygen atom, a sulfur atom,
an imino group which may be optionally protected, a
sulfinyl group or a sulfonyl group or a bond; X6
represents an alkylene, alkenylene or alkynylene group
which may be optionally substituted or a bond, or a
salt thereof has the inhibitory activity of MMP-13
production and thus completed the present invention.
[0008]
The novel anthranilic acid derivative or a
salt thereof of the present invention has the
inhibitory activity of MMP-13 production and is
therefore useful as, for example, a therapeutic agent
for rheumatoid arthritis, osteoarthritis, cancer and
the other diseases in which MMP-13 is involved.

5
BEST MODE FOR CARRYING OUT THE INVENTION
[0009]
Hereinbelow, compounds of the present
invention are described in detail.
In the present specification, unless
otherwise stated in particular, a halogen atom refers
to a fluorine atom, a chlorine atom, a bromine atom and
an iodine atom; an alkyl group refers to, for example,
a linear or branched C1-12 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,
tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl;
a lower alkyl group refers to, for example, a linear or
branched C1-6 alkyl group such as methyl, ethyl, propyl,
isopropyl, butyl, sec-butyl, isobutyl, tert-butyl,
pentyl and isopentyl; an alkenyl group refers to, for
example, a linear or branched C2-12 alkenyl group such as
vinyl, allyl, propenyl, isopropenyl, butenyl,
isobutenyl, pentenyl, hexenyl, heptenyl and octenyl; an
alkynyl group refers to, for example, a linear or
branched C2-12 alkynyl group such as ethynyl, 2-propynyl
and 2-butynyl; a cycloalkyl group refers to, for
example, a C3-8 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl; a cycloalkenyl
group refers to, for example, a C3-8 cycloalkenyl group
such as cyclopropenyl, cyclobutenyl, cyclopentenyl and
cyclohexenyl; an alkylene group refers to, for example,
a linear or branched C1-6 alkylene group such as
methylene, ethylene, propylene, butylene and hexylene;
an alkenylene group refers to, for example, a linear or

6
branched C2-6 alkenylene group such as vinylene,
propenylene, 1-butenylene and 2-butenylene; an
alkynylene group refers to, for example, a linear or
branched C2-6 alkynylene group such as ethynylene,
propynylene, 1-butynylene and 2-butynylene; an aryl
group refers to, for example, a group such as phenyl
and naphthyl; an aralkyl group refers to, for example,
an ar-C1-6 alkyl group such as benzyl, diphenylmethyl,
trityl, phenethyl and naphthylmethyl; an alkoxy group
refers to, for example, a linear or branched C1-6
alkyloxy group such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
pentyloxy and isopentyloxy; an aryloxy group refers to,
for example, a group such as phenoxy and naphthoxy; an
alkoxyalkyl group refers to, for example, a C1-6
alkyloxy C1-6 alkyl group such as methoxymethyl and 1-
ethoxyethyl; and an aralkyloxyalkyl group refers to,
for example, an ar-C1-6 alkyloxy C1-6 alkyl group such as
benzyloxymethyl and phenethyloxymethyl;
[0010]
an acyl group refers to, for example, a formyl group, a
linear or branched C2-12 alkanoyl group such as acetyl,
propionyl and isovaleryl, an ar-C1-6 alkylcarbonyl group
such as benzylcarbonyl, a cyclic hydrocarbon carbonyl
group such as benzoyl and naphthoyl, a heterocyclic
carbonyl group such as nicotinoyl, thenoyl,
pyrrolidinocarbonyl and furoyl, a succinyl group, a
glutaryl group, a maleoyl group, a phthaloyl group and
a linear or branched a-aminoalkanoyl group derived from

7
an amino acid (Examples of the amino acid include
glycine, alanine, valine, leucine, isoleucine, serine,
threonine, cysteine, methionine, aspartic acid,
glutamic acid, asparagine, glutamine, arginine, lysine,
histidine, hydroxylysine, phenylalanine, tyrosine,
tryptophan, proline and hydroxyproline.) in which the
N-terminal may be optionally protected; an
alkyloxycarbonyl group refers to, for example, a linear
or branched C1-12 alkyloxycarbonyl group such as
methoxycarbonyl, ethoxycarbonyl, 1,1-
dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-
ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-
pentyloxycarbonyl; an aralkyloxycarbonyl group refers
to, for example, an ar-C1-6 alkyloxycarbonyl group such
as benzyloxycarbonyl and phenethyloxycarbonyl group; an
aryloxycarbonyl group refers to, for example, a group
such as phenyloxycarbonyl;
[0011]
an acyloxy group refers to, for example, a linear or
branched C2-6 alkanoyloxy group such as acetyloxy and
propionyloxy and an aroyloxy group such as benzoyloxy;
an acylalkyl group refers to, for example, a group such
as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl,
p-bromobenzoylmethyl, p-methoxybenzoylmethyl and 1-
benzoylethyl; an acyloxyalkyl group refers to, for
example, a group such as acetoxymethyl,
propionyloxymethyl and pivaloyloxymethyl; an
alkylthioalkyl group refers to, for example, a C1-6
alkylthio C1-6 alkyl group such as methylthiomethyl,

8
ethylthiomethyl and propylthio- methyl; an arylthio
group refers to, for example, a group such as
phenylthio; an alkanesulfonyl group refers to, for
example, a C1-6 alkanesulfonyl group such as
methanesulfonyl, ethanesulfonyl and propanesulfonyl; an
arylsulfonyl group refers to, for example, a group such
as benzenesulfonyl, toluenesulfonyl and
naphthalenesulfonyl; an alkanesulfonyloxy group refers
to, for example, a C1-6 alkanesulfonyloxy group such as
methanesulfonyloxy and ethanesulfonyloxy; an
arylsulfonyloxy group refers to, for example, a group
such as benzenesulfonyloxy and toluenesulfonyloxy; an
arylthioalkyl group refers to, for example, a group
such as phenylsulfenylmethyl and 2-(p-
nitrophenylsulfenyl)ethyl; an arylsulfonylalkyl group
refers to, for example, a group such as p-
toluenesulfonylethyl; and an alkanesulfonamide group
refers to, for example, a C1-6 alkanesulfonamide group
such as methanesulfonamide and ethanesulfonamide.
[0012]
An oxygen-containing heterocyclic group
refers to, for example, a group such as 2-
tetrahydropyranyl and 2-tetrahydrofuranyl; a sulfur-
containing heterocyclic group refers to, for example, a
group such as tetrahydrothiopyranyl; a heterocyclic
oxycarbonyl group refers to, for example, a group such
as 2-furfuryloxycarbonyl and 8-quinolyloxycarbonyl; a
nitrogen-containing heterocyclic alkyl group refers to,
for example, a group such as phthalimidomethyl and

9
succinimidomethyl; a substituted silyl group refers to,
for example, a group such as trimethylsilyl,
triethylsilyl and tributylsilyl; and an alkylsilylalkyl
group refers to, for example, a group such as 2-
(trimethylsilyl)ethyl.
[0013]
A monocyclic heterocyclic group refers to,
for example, a nitrogen-containing monocyclic
heterocyclic group containing a nitrogen atom(s) as
sole ring-member heteroatom such as pyrrolyl,
pyrrolinyl, pyrrolidinyl, piperidyl, piperazinyl,
imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl,
pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl,
imidazolinyl, imidazolidinyl, pyrazolinyl and
pyrazolidinyl group; an oxygen-containing monocyclic
heterocyclic group containing an oxygen atom(s) as sole
ring-member heteroatom such as furyl and pyranyl group;
a sulfur-containing monocyclic heterocyclic group
containing a sulfur atom(s) as sole ring-member
heteroatom such as a thienyl group; a nitrogen-and-
oxygen-containing monocyclic heterocyclic group
containing nitrogen and oxygen atoms as sole ring-
member heteroatoms such as oxazolyl, oxadiazolyl,
isoxazolyl and morpholinyl group; a nitrogen-and-
sulfur-containing monocyclic heterocyclic group
containing nitrogen and sulfur atoms as sole ring-
member heteroatoms such as thiazolyl, isothiazolyl,
thiadiazolyl and thiomorpholinyl group; and an oxygen-
and-sulfur-containing monocyclic heterocyclic group

10
containing oxygen and sulfur atoms as sole ring-member
heteroatoms such as a thioxanyl group.
[0014]
A bicyclic heterocyclic group refers to, for
example, a nitrogen-containing bicyclic heterocyclic
group represented by a condensed or bridged ring
containing only 1 to 3 nitrogen atom(s) as the
heteroatom of the said ring such as indolyl, indolinyl,
2-oxoindolinyl, isoindolyl, indolizinyl, benzimidazolyl,
benzotriazolyl, indazolyl, quinolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl,
quinolizinyl, isoquinolyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, dihydroquinoxalinyl, quinazolinyl,
cinnolinyl, quinuclidinyl and 2,3-dihydrobenzopyrrolyl
group; an oxygen-containing bicyclic heterocyclic group
represented by a condensed or bridged ring containing
only oxygen atom(s) as the heteroatom of the said ring
such as benzofuranyl, isobenzofuranyl, chromenyl,
chromanyl, isochromanyl, benzo-1,3-dioxolyl, benzo-1,4-
dioxanyl and 2,3-dihydrobenzofuranyl group; a sulfur-
containing bicyclic heterocyclic group represented by a
condensed or bridged ring containing only sulfur
atom(s) as the heteroatom of the said ring such as
benzothienyl and 2,3-dihydrobenzothienyl group; a
nitrogen-and-oxygen-containing bicyclic heterocyclic
group represented by a condensed or bridged ring
containing only nitrogen and oxygen atom(s) as the
heteroatom of the said ring such as benzomorpholinyl
and benzomorpholonyl group; and a nitrogen-and-sulfur-

11
containing bicyclic heterocyclic group represented by a
condensed or bridged ring containing only nitrogen and
sulfur atom(s) as the heteroatom of the said ring such
as benzothiazolyl and benzothiadiazolyl group.
[0015]
A heterocyclic group refers to, for example,
a monocyclic heterocyclic group; a bicyclic
heterocyclic group; a tricyclic heterocyclic group such
as thianthrenyl, xanthenyl, phenoxathiinyl, carbazolyl,
P-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenathrolinyl, phenazinyl, phenothiazinyl and
phenoxazinyl.
[0016]
A cyclic amino group may be, for example, a
saturated cyclic amino group and an unsaturated amino
group, may optionally contain one or more heteroatoms
such as nitrogen atom, oxygen atom and sulfur atom and
carbonyl carbon in the ring, and may be monocyclic,
bicyclic or tricylic; and more specifically refers to a
saturated or unsaturated monocyclic 3- to 7-membered
cyclic amino group having one nitrogen atom such as
aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl,
pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl,
tetrahydropyridin-1-yl, piperidin-1-yl, dihydroazepin-
1-yl and perhydroazepin-1-yl; a saturated or
unsaturated monocyclic 3- to 7-membered cyclic amino
group having 2 nitrogen atoms such as imidazol-1-yl,
imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl,
piperazin-1-yl, 1,4-dihydropyrazin-l-yl, 1,2-

12
dihydropyrimidin-1-yl, perhydropyrazin-1-yl and
homopiperazin-1-yl; a saturated or unsaturated
monocyclic 3- to 7-membered cyclic amino group having 3
or more nitrogen atoms such as 1,2,4-triazol-l-yl,
1,2,3-triazol-l-yl, 1,2-dihydro-l,2,4-triazin-l-yl and
perhydro-S-triazin-1-yl; a saturated or unsaturated
monocyclic 3- to 7-membered cyclic amino group having 1
to 4 heteroatoms selected from an oxygen atom and a
sulfur atom in addition to a nitrogen atom(s) such as
oxazolidin-3-yl, isoxazolidin-2-yl, morpholin-4-yl,
thiazolidin-3-yl, thiazolidin-2-yl, thiomorpholin-4-yl,
homothiomorpholin-4-yl and 1,2,4-thiaziazolin-2-yl; a
saturated or unsaturated bicyclic or tricyclic cyclic
amino group such as isoindolin-2-yl, indolin-1-yl, 1H-
indazol-1-yl, lH-indol-1-yl, lH-benzimidazol-1-yl,
purin-7-yl, tetrahydroquinolin-1-yl and
tetrahydroisoquinolin-2-yl; and a saturated or
unsaturated 5- to 12-membered spiro or bridged cyclic
amino group such as 5-azaspiro[2.4]heptan-5-yl, 2,8-
diazabicyclo[4.3.0]nonan-8-yl, 3-
azabicyclo[3.1.0]hexan-3-yl, 2-oxa-5,8-
diazabicyclo[4.3.0]nonan-8-yl, 2,8-
diazaspiro[4.4]nonan-2-yl and 7-
azabicyclo[2.2.1]heptan-7-yl.
[0017]
The amino protecting group includes any group
which can be normally used as a protecting group of an
amino group, and examples thereof include groups
described in W. Greene et al., Protective Groups in

13
Organic Synthesis, third edition, pp. 494-615, 1999,
John Wiley & Sons, INC. Specific examples thereof
include an acyl group, an alkyloxycarbonyl group, an
aralkyloxycarbonyl group, an aryloxycarbonyl group, an
aralkyl group, an alkoxyalkyl group, an aralkyloxyalkyl
group, an arylthio group, an alkanesulfonyl group, an
arylsulfonyl group and a substituted silyl group.
[0018]
The imino protecting group includes any group
which can be normally used as a protecting group of an
imino group, and examples thereof include groups
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 494-615, 1999,
John Wiley & Sons, INC. Specific examples thereof
include an acyl group, an alkyloxycarbonyl group, an
aralkyloxycarbonyl group, an aryloxycarbonyl group, an
aralkyl group, an alkoxyalkyl group, an arylthio group,
an alkanesulfonyl group, an arylsulfonyl group and a
substituted silyl group.
[0019]
The hydroxyl protecting group includes any
group which can be normally used as a protecting group
of a hydroxyl group, and examples thereof include
groups described in W. Greene et al., Protective Groups
in Organic Synthesis, third edition, pp. 17-245, 1999,
John Wiley & Sons, INC. Specific examples thereof
include an acyl group, an alkyloxycarbonyl group, an
aralkyloxycarbonyl group, a heterocyclic oxycarbonyl
group, an alkyl group, an alkenyl group, an aralkyl

14
group, an oxygen-containing heterocyclic group, a
sulfur-containing heterocyclic group, an alkoxyalkyl
group, an aralkyloxyalkyl group, an alkanesulfonyl
group, an arylsulfonyl group and a substituted silyl
group.
[0020]
The carboxyl protecting group includes any
group which can be normally used as a protecting group
of a carboxyl group, and examples thereof include
groups described in W. Greene et al., Protective Groups
in Organic Synthesis, third edition, pp. 369-453, 1999,
John Wiley & Sons, INC. Specific examples thereof
include an alkyl group, an aryl group, an aralkyl group,
an acylalkyl group, an arylthioalkyl group, an
arylsulfonylalkyl group, an oxygen-containing
heterocyclic group, an alkyl silyl alkyl group, an
acyloxyalkyl group, a nitrogen-containing heterocyclic
alkyl group, a cycloalkyl group, an alkoxyalkyl group,
an aralkyloxyalkyl group, an alkylthioalkyl group, an
alkenyl group and a substituted silyl group.
[0021]
The phenolic hydroxyl protecting group
includes any group which can be normally used as a
protecting group of a phenolic hydroxyl group, and
examples thereof include groups described in W. Greene
et al., Protective Groups in Organic Synthesis, third
edition, pp. 246-287, 1999, John Wiley & Sons, INC.
Specific examples thereof include an acyl group, an
alkyl group, an alkenyl group, an aralkyl group, an

15
oxygen-containing heterocyclic group, a sulfur-
containing heterocyclic group, an alkoxyalkyl group, an
alkanesulfonyl group, an arylsulfonyl group and a
substituted silyl group.
[0022]
The thiol protecting group includes any group
which can be normally used as a protecting group of a
thiol group, and examples thereof include groups
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 454-493, 1999,
John Wiley & Sons, INC. Specific examples thereof
include an acyl group, an alkyl group, an alkenyl group,
an aralkyl group, an alkoxyalkyl group and a
substituted silyl group.
[0023]
The acetylene protecting group includes any
group which can be normally used as a protecting group
of acetylene, and examples thereof include groups
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 654-659, 1999,
John Wiley & Sons, INC. Specific examples thereof
include substituted silyl group.
[0024]
Examples of a leaving group include a halogen
atom, an alkanesulfonyloxy group, an arylsulfonyloxy
group and an acyloxy group.
[0025]
The salt of a compound of general formula [1]
includes commonly known salts formed from a basic group

16
such as an amino group or from an acidic group such as
a phenolic hydroxyl group or a carboxyl group.
Examples of salts formed from a basic group
include salts with a mineral acid such as hydrochloric
acid, hydrogen bromide and sulfuric acid; salts with an
organic carboxylic acid such as tartaric acid, formic
acid, acetic acid, citric acid, trichloroacetic acid
and trifluoroacetic acid and salts with a sulfonic acid
such as methanesulfonic acid, benzenesulfonic acid, p-
toluenesulfonic acid, mesitylenesulfonic acid and
naphthalenesulfonic acid.
Examples of salts formed from an acidic group
include salts with an alkali metal such as sodium and
potassium; salts with an alkali earth metal such as
calcium and magnesium; ammonium salt and salts with a
nitrogen-containing organic base group such as
trimethylamine, triethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-
methylmorpholine, diethylamine, dicyclohexylamine,
procaine, dibenzylamine, N-benzyl-p-phenethylamine and
N,N'-dibenzylethylenediamine.
Furthermore, as preferable salts of a
compound of general formula [1], pharmacologically
acceptable salts are included.
[0026]
The phenyl, cycloalkyl and heterocyclic
groups of R2 in the present invention may be optionally
substituted with at least one group selected from a
halogen atom, a cyano group, a nitro group, an acyl

17
group, an acyloxy group, a sulfo group, a phosphoryl
group, an alkanesulfonyl group, an alkanesulfonamide
group, an acetamide group, a carbamoyl group, carboxyl,
amino and hydroxyl groups which may be optionally
protected and alkyl, alkenyl, alkynyl, alkoxy, aryl,
cyclic amino, aralkyl and heterocyclic groups which may
be optionally substituted.
The phenyl, cycloalkyl, cycloalkenyl,
monocyclic heterocyclic and bicyclic heterocyclic
groups in R3 may be optionally substituted with at least
one group selected from a halogen atom, a cyano group,
a nitro group, an acyl group, an acyloxy group, a sulfo
group, a phosphoryl group, an amino group, an
alkanesulfonyl group, an alkanesulfonamide group, an
acetamide group, a dimethylamino group, a carbamoyl
group, carboxyl and hydroxyl groups which may be
optionally protected and an alkyl, alkenyl, alkynyl,
alkoxy, aryl, aryloxy, cyclic amino, aralkyl and
heterocyclic groups which may be optionally substituted.
The alkylene, alkenylene and alkynylene
groups in X2 and X6 may be optionally substituted with
at least one group selected from a halogen atom, a
cyano group, a nitro group, an acyl group, a sulfo
group, a phosphoryl group, an alkanesulfonyl, an
alkanesulfonamide group, an acetamide group, a
carbamoyl group, carboxyl, amino and hydroxyl groups
which may be optionally protected and alkyl, alkenyl,
alkynyl, alkoxy, aryl, cyclic amino, aralkyl and
heterocyclic groups which may be optionally substituted.

18
[0027]
Examples of the substituent of the alkyl,
alkenyl, alkynyl, alkoxy, aryl, cyclic amino, aralkyl
and heterocyclic groups which may be optionally
substituted shown above include a halogen atom, a cyano
group, a nitro group, an acyl group, a sulfo group, a
phosphoryl group, a cyclic amino group, an
alkanesulfonyl group, an alkanesulfonamide group, an
acetamide group, an aralkyl group, a carbamoyl group,
an alkyl group, an alkenyl group, an alkynyl group, an
alkoxy group, an aryl group, a heterocyclic group and
carboxyl, amino and hydroxyl groups which may be
optionally protected.
[0028]
Among the compounds of the present invention,
preferable compounds include the following compounds.
The compounds in which R1 is a hydrogen atom
are preferable.
The compounds in which R2 is a phenyl, C5-7
cycloalkyl or heterocyclic group which may be
optionally substituted are preferable, the compounds in
which R2 is a phenyl or heterocyclic group which may be
optionally substituted with a group selected from a
halogen atom, a cyano group, a nitro group, a hydroxyl
group which may be optionally protected, an alkyl group
which may be optionally substituted, an alkenyl group
which may be optionally substituted, an alkynyl group
which may be optionally substituted, an alkoxy group
which may be optionally substituted, an aryl group

19
Which may be optionally substituted, a cyclic amino
group which may be optionally substituted, an aralkyl
group which may be optionally substituted and a
heterocyclic group which may be optionally substituted
are more preferable, the compounds in which R2 is a
phenyl or heterocyclic group which may be optionally
substituted with a group selected from a halogen atom,
a nitro group, a hydroxyl group, an alkyl group which
may be optionally substituted, an alkenyl group which
may be optionally substituted, an alkoxy group which
may be optionally substituted, an aryl group which may
be optionally substituted, a cyclic amino group which
may be optionally substituted and a monocyclic
heterocyclic group which may be optionally substituted
are still more preferable, and the compounds in which R2
is a phenyl group, an oxygen-containing bicyclic
heterocyclic group represented by a condensed or
bridged ring containing only oxygen atom(s) as the
heteroatom of the said ring, a sulfur-containing
bicyclic heterocyclic group represented by a condensed
or bridged ring containing only sulfur atom(s) as the
heteroatom of the said ring and a nitrogen-and-sulfur-
containing bicyclic heterocyclic group represented by a
condensed or bridged ring containing only nitrogen and
sulfur atom(s) as the heteroatom of the said ring; and
these groups may be optionally substituted with a group
selected from a halogen atom, a hydroxyl group, an
alkyl group which may be optionally substituted with a
halogen atom, an aryl group which may be optionally

20
substituted with a halogen atom, a cyclic amino group
and a nitrogen-containing monocyclic heterocyclic group
containing a nitrogen atom(s) as sole ring-member
heteroatom are still further more preferable.
The compounds in which R3 is a phenyl, C5-7
cycloalkyl, C5-7 cycloalkenyl or monocyclic heterocyclic
or bicyclic heterocyclic group which may be optionally
substituted are preferable, the compounds in which R3 is
a phenyl, monocyclic heterocyclic or bicyclic
heterocyclic group which may be optionally substituted
with a group selected from a halogen atom, a cyano
group, a nitro group, an acyl group, a hydroxyl group,
an alkanesulfonyl group, an alkyl group which may be
optionally substituted, an alkoxy group which may be
optionally substituted, an aryl group which may be
optionally substituted, an aryloxy group which may be
optionally substituted and a heterocyclic group which
may be optionally substituted are more preferable, the
compounds in which R3 is a phenyl, monocyclic
heterocyclic or bicyclic heterocyclic group which may
be optionally substituted with a group selected from a
halogen atom, a hydroxyl group, an alkyl group which
may be optionally substituted and an alkoxy group which
may be optionally substituted are still more preferable,
and the compounds in which R3 is phenyl groups,
nitrogen-containing bicyclic heterocyclic group
represented by a condensed or bridged ring containing
only 1 to 3 nitrogen atom(s) as the heteroatom of the
said ring, oxygen-containing bicyclic heterocyclic

21
group represented by a condensed or bridged ring
containing only oxygen atom(s) as the heteroatom of the
said ring or sulfur-containing bicyclic heterocyclic
group represented by a condensed or bridged ring
containing only sulfur atom(s) as the heteroatom of the
said ring; and these groups may be optionally
substituted with a group selected from a halogen atom,
a hydroxyl group, an alkyl group which may be
optionally substituted with a halogen atom and an
alkoxy group which may be optionally substituted with a
halogen atom are still further more preferable.
[0029]
The compounds in which X1 is a carbonyl group
are preferable.
The compounds in which X2 is an alkylene,
alkenylene or alkynylene group which may be optionally
substituted with a group selected from an alkyl and
phenyl group which may be optionally substituted or a
bond are preferable, the compound in which X2 is an
alkylene group, an alkenylene group, an alkynylene
group or a bond are more preferable, and the compounds
in which X2 is an alkylene group, an alkenylene group or
a bond are still more preferable.
The compounds in which X3 is an oxygen atom or
a bond are preferable, and the compounds in which X3 is
a bond are more preferable.
When X2 is an alkylene, alkenylene or
alkynylene group which may be optionally substituted,

22
the compounds in which X3 is an oxygen atom are
preferable.
[0030]
The compounds in which X4 is the general
formula -X6-X5-, wherein the bond on the left side of
the general formula is linked to R3, and X5 represents
an oxygen atom, a sulfur atom, an imino group which may
be optionally protected, a sulfinyl group, a sulfonyl
group or a bond; X6 represents an alkylene, alkenylene
or alkynylene group which may be optionally substituted
or a bond are preferable.
The compounds in which X4 is the general
formula -X6p-X5p-, wherein the bond on the left side of
the general formula is linked to R3; and X5p represents
an oxygen atom, a sulfur atom, an imino group or a
bond; and X6p represents an alkylene, alkenylene or
alkynylene group which may be optionally substituted
are preferable, the compounds in which X4 is the general
formula -X6p-X5q-, wherein the bond on the left side of
the general formula is linked to R3; and X5q represents
an oxygen atom, a sulfur atom or a bond; and X6p means
the same as above are more preferable, and the
compounds in which X4 is a general formula -X6q-X5r-,
wherein the bond on the left side of the general
formula is linked to R3; and X5r represents a bond; and
X6q represents an alkylene group, an alkenylene group or
an alkynylene group are further preferable.
The compounds in which X4 is the general formula -X6r-
X5p-, wherein the bond on the left side of the general

23

formula is linked to R3; and X6r represents a bond; and
X5p means the same as above are preferable, and the
compounds in which X4 is a general formula -X6r-X5s-,
wherein the bond on the left side of the general
formula is linked to R3; and X5s represents an oxygen
atom or a bond; and X6r means the same as above are more
preferable.
[0031]
Examples of typical compounds, among the
compounds of the present invention, include compounds
of the following Tables 1 to 6.
[0032]
[Table 1]


R3 R3
Phenyl 2-Chlorophenyl
4-(tert-Butyl)phenyl 3-Chlorophenyl
Thiazol-2-yl 4-Chlorophenyl
Thiophen-2-yl 3,5-Dichlorophenyl
Benzofuran-2-yl 3,4-Dichlorophenyl
Benzofuran-5-yl 2,3-Dichlorophenyl
lH-benzimidazol-1-yl 2,4-Dichlorophenyl
lH-indol-1-yl 2,5-Dichlorophenyl
lH-indol -5-yl 3-Chloro-2-fluorophenyl
lH-indol -4-yl 5-Chloro-2-fluorophenyl
4-(Methanesulfonyl)phenyl 2-Chloro-6-fluorophenyl
Benzothiophen-2-yl 3-Chloro-4-fluorophenyl
Benzothiophen-5-yl 4-Hydroxyphenyl
3-Nitrophenyl 3-Chloro-4-hydroxyphenyl
4-Nitrophenyl 3-Cyanophenyl
4-Acetylphenyl 4-Cyanophenyl
2-Fluorophenyl 2-Methylphenyl
3-Fluorophenyl 3-Methylphenyl
4-Fluorophenyl 4-Methylphenyl
2,3-Difluorophenyl 2,3-Dimethylphenyl
2,6-Difluorophenyl 2,6-Dimethylphenyl
3,4-Difluorophenyl 3,4-Dimethylphenyl
2,5-Difluorophenyl 3,5-Dimethyl-4-hydroxyphenyl
3,5-Difluorophenyl 3-Fluoro-4-methylphenyl

2,4-Difluorophenyl 244-Fluoro-2-methylphenyl
2-Methoxyphenyl 3-Chloro-2-methylphenyl
3-Methoxyphenyl 3-Chloro-4-methylphenyl
4-Methoxyphenyl 5-Chloro-2-methylphenyl
5-Chloro-2-methoxyphenyl 2-Phenoxyphenyl
3-Chloro-4-methoxyphenyl 4-Phenoxypheny1
2-1s opropoxyphenyl 4-Benzoylphenyl
4-Isopropoxyphenyl Indolin-1-yl
2-(Trifluoromethoxy)phenyl 2,3-Dihydrobenzo[1,4]dioxin-6-yl
3-(Trifluoromethoxy)phenyl Benzo[1,3]dioxol-5-yl
4-(Trifluoromethoxy)phenyl 4-(lH-pyrrol-1-yl)phenyl
4-Phenylpiperidin-l-yl 1,2,3,4-tetrahydroisoquinolin-2-yl
4-Benzylpiperidin-l-yl


X4 R3 X4
Phenyl CH2 3-(Trifluoromethoxy)phenyl 0
Phenyl CH=CH 4-(Trifluoromethoxy)phenyl 0
Phenyl C=C 3-Fluoro-4-methylphenyl 0
Phenyl 0 4-Fluoro-2-methylphenyl 0
Phenyl S 3-Chloro-4-fluorophenyl 0
Phenyl NH 5-Chloro-2-methylphenyl 0
Phenyl (CH2)2 3-(Trifluoromethyl)phenyl 0
Phenyl (CH2)3 4- (Trifluoromethyl)phenyl 0
2,3-
Phenyl (CH2)4 Dihydrobenzo[1,4]dioxin-6- 0
Phenyl CH2O Benzofuran-5-yl 0
Phenyl (CH2)2O Benzothiophen-5-yl 0
Phenyl (CH2)3O Cyclohexyl (CH2)2
Phenyl CH2S Cyclohexyl (CH2)3
Phenyl SCH2 2-Methylphenyl CH=CH
Cyclohexyl CH=CH 4-Fluorophenyl CH=CH
Cyclohexyl CH2CH=CH 3-Fluoro-4-methylphenyl CH=CH
Cyclohexyl 0 3-Nitrophenyl CH=CH
2-Fluorophenyl 0 4-Acetylphenyl CH=CH
3-Fluorophenyl 0 3-Methoxyphenyl CH=CH
4-Fluorophenyl 0 4-Methoxyphenyl CH=CH
2,3-Difluorophenyl 0 3-Chlorophenyl CH=CH
2,4-Di fluorophenyl 0 2,3-Dihydrobenzo[l,4]dioxin-6-yi CH=CH
2,5-Di fluorophenyl 0 Benzofuran-5-yl CH=CH
2,6-Difluorophenyl 0 Benzothiophen-5-yl CH=CH

25
3,4-Di fluorophenyl 0 Benzo[1,3]dioxol-5-yl CH=CH
3,5-Difluorophenyl2-Chlorophenyl3-Chlorophenyl4-Chlorophenyl 0000 2,1,3-Benzothiadiazol-4-yl4-(Trifluoromethyl)phenyl2,4-Difluorophenyl3,5-Difluorophenyl CH=CHCH=CHCH=CHCH=CH
2,3-Dichlorophenyl 0 3,5-Dichlorophenyl CH=CH
2,4-Dichlorophenyl 0 4-Hydroxyphenyl CH=CH
2,5-Dichlorophenyl 0 4-(Trifluoromethoxy)phenyl CH=CH
2,6-Dichlorophenyl 0 4-Nitrophenyl CH=CH
3,4-Dichlorophenyl 0 2-Methylphenyl (CH2)2
3,5-Dichlorophenyl3-Nitrophenyl4-Nitrophenyl2-Methylphenyl3-Methylphenyl4-Methylphenyl 000000 4-Fluorophenyl3-Fluoro-4-methylphenyl4-Ethylphenyl3-Methoxyphenyl4-(Trifluoromethyl)phenyl3-Chlorophenyl (CH2)2(CH2)2(CH2)2(CH2)2(CH2)2(CH2)2
2,3-Dimethylphenyl 0 Benzofuran-5-yl (CH2)2
2,6-Dimethylphenyl 0 3,5-Difluorophenyl (CH2)2
3,4-Dimethylphenyl 0 4-(Trifluoromethoxy)phenyl (CH2)2

X1 X2-X: J R2 X1 X2-X3 R2
c=o Bond Cyclohexyl c=o Bond Benzofuran-5-yl
c=o Bond 2-Fluorophenyl c=o Bond Benzothiophen-2-yl
c=o Bond 3-Fluorophenyl c=o Bond Benzothiophen-3-yl
c=o Bond 4-Fluorophenyl c=o Bond Benzothiophen-5-yl
c=o Bond 2,4-Difluorophenyl c=o Bond Benzothiazol-2-yl
c=o Bond 2,6-Difluorophenyl c=o Bond Benzo[1,3]dioxol-5-yi
c=o Bond 3,4-Difluorophenyl c=o Bond 2,3-Dihydrobenzo[1,4]dioxin-6-yl
c=o Bond 3,5- c=o Bond 6-Morpholinopyridin-
Difluorophenyl 3-yl
c=o Bond 2-Chlorophenyl c=o Bond 1-Phenyl-lH-pyrazol-5-yl
c=o Bond 3-Chlorophenyl c=o Bond 6-(Piperidin-1-

26
yl)pyridin-3-yl
c=o Bond 4-Chlorophenyl c=o Bond 6-(lH-pyrrol-l-yl)pyridin-3-yl
c=o Bond 2,4-Dichlorophenyl c=o Bond 5-(lH-pyrrol-l-yl)pyridin-3-yl
c=o Bond 2,6-Dichlorophenyl c=o Bond 2-(lH-pyrrol-l-yl)pyridin-4-yl
c=o Bond 3,4- c=o Bond 3-Phenylisoxazol-5-
Dichlorophenyl yi
c=o Bond 3,5- c=o Bond 3-Phenyl-lH-pyrazol-
Dichlorophenyl 5-yl
c=o Bond 2-Methylphenyl c=o Bond 6-Phenylpyrimidin-4-yl
J2-
c=o Bond 3-Methylphenyl c=o Bond (Trifluoromethyl)phe
nyl
3-
c=o Bond 4-Methylphenyl c=o Bond {Tri fluoromethyl)phe
nyl
c=o Bond 2,3-Dimethylphenyl c=o Bond 4-(Tri fluoromethyl)phenyl
c=o Bond 3,4-Dimethylphenyl c=o Bond 2,4-Bis(trifluoromethyl)phenyl
c=o Bond 3,5-Dimethylphenyl c=o Bond Bis(trifluoromethyl)phenyl
c=o Bond 3-Nitrophenyl c=o CH=CH(E) Phenyl
c=o Bond 4-Nitrophenyl c=o CH=CH(E) 3,4-Dimethoxyphenyl
c=o Bond 2-Hydroxyphenyl c=o CH2 Phenyl
c=o Bond 4-Hydroxyphenyl c=o CH2O Phenyl
c=o Bond 3-Biphenyl c=o CH2CH=CH(E) Phenyl
c=o Bond 4-Biphenyl c=o C(CH3)=CH(E) Phenyl
c=o Bond Thiophen-2-yl c=o (CH2)2 Phenyl
c=o Bond Benzofuran-2-yi c=o (CH2)3 Phenyl
c=o 6 Phenyl so2 Bond Phenyl
so2 CH=CH Phenyl


X1 X2-X3 R2 X1 X2-X3 R2
c=oc=o BondBond Cyclohexyl2-Fluorophenyl c=oc=o BondBond 2-Phenylthiazol-4-ylBenzo[l,3]dioxol-5-yi
c=o Bond 3-Fluorophenyl c=o Bond 2,3-Dihydrobenzo[1,4]dio

27
xin-6-yl
c=o Bond 4-Fluorophenyl c=o Bond 1-Methyl-1H-benzotriazol-5-yl
c=o Bond 2,4- c=o Bond 6-Morpholinopyridin-
Di fluorophenyl 3-yl
c=o Bond 2,6-Di fluorophenyl c=o Bond 6-(Piperidin-1-yl)pyridin-3-yl
c=o Bond 3,4-Difluorophenyl c=o Bond 6-(lH-pyrrol-l-yl)pyridin-3-yl
c=o Bond 3,5- c=o Bond 5-(lH-pyrrol-l-
Di fluorophenyl yl)pyridin-3-yl
c=o Bond 2-Chlorophenyl c=o Bond 2-(lH-pyrrol-l-yl)pyridin-4-yl
c=o Bond 3-Chlorophenyl c=o Bond 5-(Thiophen-2-yl)pyridin-3-yl
c=o Bond 4-Chlorophenyl c=o Bond 3-Phenylisoxazol-5-yi
c=o Bond 2,4- c=o Bond 3-Phenyl-lH-pyrazol-
Dichlorophenyl 5-yl
c=o Bond 2,6-Dichlorophenyl c=o Bond 3-(lH-pyrrol-l-yDphenyl
c=o Bond 3,4-Dichlorophenyl c=o Bond 4-(lH-pyrrol-l-yl)phenyl
c=o Bond 3,5- c=o Bond 3-(lH-pyrazol-l-
Dichlorophenyl yl)phenyl
c=o Bond 3- c=o Bond 2-(Trifluoromethyl)
Methoxyphenyl phenyl
c=o Bond 4- c=o Bond 3-(Trifluoromethyl)
Methoxyphenyl phenyl
c=o Bond 2-Methylphenyl c=o Bond 4- (Trifluoromethyl)phenyl
2,4-
c=o Bond 3-Methylphenyl c=o Bond Bis(trifluoromethyl)
phenyl
3,5-
c=o Bond 4-Methylphenyl c=o Bond Bis(trifluoromethyl)
phenyl
c=o Bond 2,3-Dimethylphenyl c=o CH=CH(E) Phenyl
c=o Bond 3,4-Dimethylphenyl c=o CH=CH(E) 3-Chlorophenyl
c=o Bond 3,5-Dimethylphenyl c=o CH=CH(E) 4-Chlorophenyl
c=o Bond 2-Biphenyl c=o CH=CH(E) 3,4-Dichlorophenyl
c=o Bond 3-Biphenyl c=o CH=CH(E) 3-Methoxyphenyl
c=o Bond 4-Biphenyl c=o CH=CH(E) Thiophen-2-yl
c=o Bond 4-Morpholinophen c=o CH=CH(E) Benzo[1,3]dioxol-5-yi
c=o Bond y13-Nitrophenyl c=o CH=CH(E) 3,4-Dimethoxyphenyl
c=o Bond 4-Nitrophenyl c=o CH=CH(E) 3-Nitrophenyl
c=o Bond 2-Hydroxyphenyl c=o CH=CH(E) 4-Hydroxyphenyl
c=o Bond Thiophen-2-yl c=o CH2CH=CH(E) Phenyl
c=o Bond Benzofuran-2-yl c=o C(CH3)=CH(E) Phenyl
c=o Bond Benzofuran-5-yl c=o (CH2)2 Phenyl
c=o Bond Benzothiophen-2-yl c=o (CH2)3 Phenyl

c=o Bond Benzothiophen-3-yl 28c=o CH2O Phenyl
c=o Bond Benzothiophen-5-yl so2 CH2 Phenyl
c=o Bond Benzothiazol-2-yl so2 CH=CH Phenyl
c=o Bond 6-Phenylpyrimidin-4-yl


X1 X2-X R2 X1 X2-X3 R2
C=0 Bond 2-Fluorophenyl C=0 Bond Benzothiophen-5-yl
c=o Bond 3-Fluorophenyl c=o Bond Benzothiazol-2-yl
c=o Bond 4-Fluorophenyl c=o Bond Benzo[l,3]dioxol-5-yi
c=o Bond 2,4-Di fluorophenyl c=o Bond 2,3-Dihydrobenzo[1,4]dioxin-6-yl
c=o Bond 2,6-Difluorophenyl c=o Bond 4-Morpholinophenyl
c=o Bond 3,4-Di fluorophenyl c=o Bond 6-(Piperidin-l-yl)pyridin-3-yl
c=o Bond 3,5-Di fluorophenyl c=o Bond 6-(lH-pyrrol-l-yl)pyridin-3-yl
c=o Bond 2-Chlorophenyl c=o Bond 5-(lH-pyrrol-l-yl)pyridin-3-yl
c=o Bond 3-Chlorophenyl c=o Bond 2-(lH-pyrrol-l-yl)pyridin-4-yl
c=o Bond 4-Chlorophenyl c=o Bond 3-Phenylisoxazol-5-yi
c=o Bond 2,4- c=o Bond 3-Phenyl-lH-pyrazol-
Dichlorophenyl 5-yl
c=o Bond 2,6- c=o Bond 3-(lH-pyrrol-l-
Di chlorophenyl yl)phenyl
c=o Bond 3,4-Dichlorophenyl c=o Bond 4-(lH-pyrrol-l-yl)phenyl
c=o Bond 3,5- c=o Bond 6-Phenylpyrimidin-4-
Dichlorophenyl yi
2-
c=o Bond 3-Methoxyphenyl c=o Bond (Trifluoromethyl)phe
nyl
3-
c=o Bond 4-Methoxyphenyl c=o Bond (Trifluoromethyl)phe
nyl4-
c=o Bond 2-Methylphenyl c=o Bond {Trifluoromethyl)phe
nyl
c=o Bond 3-Methylphenyl c=o Bond 2,4-Bis(trifluoromethyl)

c=o Bond 4-Methylphenyl 29c=o Bond phenyl3,5-Bis(trifluoromethyl)phenyl
c=o Bond 2,3-Dimethylphenyl c=o CH=CH(E) Phenyl
c=o Bond 3,4-Dimethylphenyl c=o CH=CH(E) 3-Chlorophenyl
II II 1! II IIo o o o o BondBondBondBondBond 3,5-Dimethylphenyl3-Nitrophenyl2-Hydroxyphenyl4-Hydroxyphenyl2-Biphenyl c=oc=oc=oc=oc=o CH=CH(E)CH=CH(E)CH=CH(E)CH=CH(E)CH=CH(E) 4-Chlorophenyl3,4-Dichlorophenyl3-MethoxyphenylThiophen-2-ylBenzotl,3]dioxol-5-yl
II 1! IIo o o BondBondBond 3-Biphenyl4-BiphenylBenzofuran-2-yl c=oc=oc=o CH=CH(E)CH=CH(E)CH=CH(E) 3,4-Dimethoxyphenyl3-Nitrophenyl4-Hydroxyphenyl
c=o Bond Benzofuran-5-yl c=o CH2CH=CH(E) Phenyl
c=o Bond Benzothiophen-2-yi c=o C(CH3)=CH(E) Phenyl
c=o Bond Benzothiophen-3-yi c=o (CH2)2 Phenyl
c=o 6 Phenyl so2 CH=CH Phenyl


R3-X4- -X2-X3-R2
3-Chlorophenyl 4-Fluorophenyl
3-Chlorophenyl 4-Nitrophenyl
3-Chlorophenyl 4-(Trifluoromethyl)phenyl
3-Chlorophenyl 4-Hydroxyphenyl
3-Chlorophenyl 2,3-Dimethylphenyl
3-Chlorophenyl Benzothiazol-2-yl
3-Chlorophenyl 5-(lH-pyrrol-1-yl)pyridin-3-yl
3-Chlorophenyl Benzo[1,3]dioxol-5-yl
3-Chlorophenyl 2-Phenylvinyl
2,4-Difluorophenyl 4-Fluorophenyl
2,4-Difluorophenyl 4- (Trifluoromethyl)phenyl
2,4-Difluorophenyl 2,3-Dimethylphenyl
2,4-Difluorophenyl Benzothiazol-2-yl
2,4-Difluorophenyl 5- (lH-pyrrol-1-yl)pyridin-3-yl
2,4-Difluorophenyl 2-Phenylvinyl
4-Hydroxyphenyl 4-Fluorophenyl
4-Hydroxyphenyl 4-(Trifluoromethyl)phenyl
4-Hydroxyphenyl Benzothiazol-2-yl

4-Hydroxyphenyl 305-(lH-pyrrol-l-yl)pyridin-3-yl
4-Hydroxyphenyl 2-Phenylvinyl
Benzofuran-2-yl 4-Fluorophenyl
Benzofuran-2-yl 4-(Tri fluoromethyl)phenyl
Benzofuran-2-yl 2,3-Dimethylphenyl
Benzofuran-2-yl Benzo[1,3]dioxol-5-yl
Benzofuran-2-yl 2-Phenylvinyl
Benzo[1,3]dioxol-5-yl 4-(Trifluoromethyl)phenyl
Benzo[1,3]dioxol-5-yl 2,3-Dimethylphenyl
Benzo[1,3]dioxol-5-yl Benzothiazol-2-yl
Benzo[1,3]dioxol-5-yl Benzo[1,3]dioxol-5-yl
Benzo[1,3]dioxol-5-yl 2-Phenylvinyl
2-(3-Methoxyphenyl)vinyl 4-Fluorophenyl
2-(3-Methoxyphenyl)vinyl 4-Nitrophenyl
2-(3-Methoxyphenyl)vinyl Benzothiazol-2-yl
2-(3-Methoxyphenyl)vinyl 2,3-Dimethylphenyl
2-(3-Methoxyphenyl)vinyl Benzo[1,3]dioxol-5-yl
2-(3-Methoxyphenyl)vinyl 5-(lH-pyrrol-l-yl)pyridin-3-yl
2-(3-Methoxyphenyl)vinyl 2-Phenylvinyl
[0038]
In addition, when any isomer (for example,
optical isomer, geometrical isomer, tautomer and the
like) is present for the compounds of general formula
[1] or a salt thereof, the present invention includes
those isomers and, in addition, includes solvates,
hydrates and crystals of various kinds.
[0039]
Next, production processes of the compounds
of the present invention are described.
The compound of the present invention can be
produced by combining methods well known per se
together, but, for example, can be produced following
the production processes shown below.
[0040]
[Production Process 1]


"In the formula, Rla represents a carboxyl protecting
group; R3a represents a phenyl, cycloalkyl, cycloalkenyl,
or monocyclic heterocyclic or bicyclic heterocyclic
group linking through a ring-member carbon atom, any of
which groups may be optionally substituted; R4
represents a hydrogen atom or a lower alkyl group; X7
represents an alkylene group which may be optionally
substituted; L1 represents a leaving group; and R2, X1,
X2 and X3 mean the same as above."
[0041]
As a compound of general formula [3a], for
example, pyridine-3-boronic acid, 3-
(methanesulfonamide)phenylboronic acid, thiophene-2-
boronic acid, benzofuran-2-boronic acid and 3-
methoxyphenyl boronic acid are known. As a compound of
general formula [3b], for example, 3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)furan is known. In
addition, the compounds of general formulae [3a] and
[3b] can be produced from corresponding halogeno
compounds following a method, for example, described in
JP-A-2003-206290.
The compounds of general formula [la] can be
produced by reacting a compound of general formula [2]

32
with a compound of general formula [3a] or [3b] in the
presence of or in the absence of a base, in the
presence of a palladium catalyst, and in the presence
of or in the absence of a ligand.
[0042]
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; aromatic hydrocarbons such as
benzene, toluene and xylene; amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and 1-methyl-
2-pyrrolidone; halogenated hydrocarbons such as
methylene chloride, chloroform and dichloroethane;
ethers such as dioxane, tetrahydrofuran, anisole,
ethylene glycol dimethyl ether, diethylene glycol
dimethyl ether and diethylene glycol diethyl ether;
ketones such as acetone and 2-butanone; nitriles such
as acetonitrile; esters such as ethyl acetate and butyl
acetate and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
[0043]
Examples of a base optionally used in this
reaction include inorganic bases such as sodium
hydrogen carbonate, sodium carbonate, potassium
carbonate, cesium carbonate and tripotassium phosphate
and organic bases such as triethylamine and
diisopropylethylamine. The used amount of the base can

33
be 1 to 50 times mol, preferably 2 to 5 times mol for
the compound of general formula [2].
The palladium catalyst used in this reaction
includes metal palladium such as palladium-carbon and
palladium black; inorganic palladium salts such as
palladium chloride; organic palladium salts such as
palladium acetate; organopalladium complex such as
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) chloride, 1,1'-
bis(diphenylphosphino)ferrocene palladium (II) chloride
and tris(dibenzylideneacetone)dipalladium (0) and
polymer immobilized organopalladium complex such as
polymer supported bis(acetato)triphenylphosphine
palladium (II) and polymer supported
di(acetato)dicyclohexylphenylphosphine palladium (II)
and these may be optionally used in combination. The
used amount of the palladium catalyst can be 0.00001 to
1 time mol, preferably 0.001 to 0.1 times mol for the
compound of general formula [2].
[0044]
The ligand optionally used in this reaction
includes trialkylphosphines such as trimethylphosphine
and tri-tert-butylphosphine; tricycloalkylphosphines
such as tricyclohexylphosphine; triarylphosphines such
as triphenylphosphine and tritolylphosphine;
trialkylphosphites such as trimethylphosphite,
triethylphosphite and tributylphosphite;
tricycloalkylphosphites such as tricyclohexylphosphite;
triarylphosphite such as triphenylphosphite;

34
imidazolium salts such as 1, 3-bis(2,4, 6-
trimethylphenyl)imidazolium chloride; diketones such as
acetylacetone and octafluoroacetylacetone; amines such
as trimethylamine, triethylamine, tripropylamine and
triisopropylamine; 1,1'-bis(diphenylphosphino)ferrocene,
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-
dicyclohexylphosphino-2',6'-dimethoxybiphenyl, 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, 2-
(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl
and 2-(di-tert-butylphosphino)biphenyl and these may be
optionally used in combination. The used amount of the
ligand can be 0.00001 to 1 time mol and preferably
0.001 to 0.1 time mol for the compound of general
formula [2].
[0045]
The used amount of the compound of general
formula [3a] or [3b] can be 1 to 50 times mol and
preferably 1 to 2 times mol for the compound of general
formula [2].
This reaction can be preferably carried out
in an inert gas (for example, nitrogen, argon)
atmosphere at 40 to 170°C for 1 minute to 96 hours.
[0046]
[Production Process 2]


35
"In the formula, R3b represents a phenyl or monocyclic
heterocyclic or bicyclic heterocyclic group linking
through a ring-member carbon atom, any of which groups
may be optionally substituted; and R5 represents a lower
alkyl group; Rla, R2, X1, X2, X3 and L1 mean the same as
above."
[0047]
As a compound of general formula [4], for
example, 2-(tributyltin)thiazole and 2-
(tributyltin)furan are known.
The compounds of general formula [lb] can be
produced by reacting a compound of general formula [2]
with a compound of general formula [4] in the presence
of or in the absence of silver oxide, in the presence
of a palladium catalyst.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include
aromatic hydrocarbons such as benzene, toluene and
xylene; amides such as N,N-dimethylformamide, N,N-
dimethylacetamide and l-methyl-2-pyrrolidone; ethers
such as dioxane, tetrahydrofuran, anisole, ethylene
glycol dimethyl ether, diethylene glycol dimethyl ether
and diethylene glycol diethyl ether; nitriles such as
acetonitrile and sulfoxides such as dimethylsulfoxide
and these may be optionally mixed for use.
[0048]
The palladium catalyst used in this reaction
includes organopalladium complexes such as

36
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) chloride, 1,1'-
bis(diphenylphosphino)ferrocene palladium (II) chloride
and tris(dibenzylideneacetone)dipalladium (0) and a
polymer immobilized organopalladium complex such as a
polymer supported bis(acetato)triphenylphosphine
palladium (II) and a polymer supported
di(acetato)dicyclohexylphenylphosphine palladium (II)
and these may be optionally used in combination. The
used amount of the palladium catalyst can be 0.00001 to
1 time mol, preferably 0.001 to 0.1 time mol for the
compound of general formula [2].
The amount of silver oxide optionally used in
this reaction can be 1 to 50 times mol, preferably 1 to
10 times mol for the compound of general formula [2].
The used amount of the compound of general
formula [4] can be 1 to 50 times mol, preferably 1 to 2
times mol for the compound of general formula [2].
This reaction can be preferably carried out
in an inert gas (for example, nitrogen, argon)
atmosphere at 40 to 170°C for 1 minute to 96 hours.
[0049]
[Production Process 3]


"In the formula, R3c represents a phenyl, cycloalkyl, or
monocyclic heterocyclic or bicyclic heterocyclic group
linking through a ring-member carbon atom, any of which
groups may be optionally substituted; X2a represents an
alkynyl group which may be optionally substituted or a
bond; X6a represents an alkenylene or alkynylene group
which may be optionally substituted; X6b represents an
alkylene group which may be optionally substituted; Rla,
R2, R3a, X1, X2, X3, X5 and L1 mean the same as above."
[0050]
As a compound of general formula [5], for
example, styrene, allylbenzene, 4-phenyl-l-butene,
vinylcyclohexane and allylcyclohexane are known. In
addition, the compounds of general formula [5] can be
produced by a method, for example, described in "Jikken
Kagaku Kouza", 4th edition, Vol. 19, pp. 298-361, 1992,
Maruzen or the like method.
[0051]
(3-1)
When X6a is an alkenylene group which may be
optionally substituted, the compound of general formula

38
[lc] can be produced by reacting a compound of general
formula [2] with a compound of general formula [5] in
the presence of or in the absence of a base, in the
presence of or in the absence of a phase transfer
catalyst, in the presence of or in the absence of a
ligand, and in the presence of a palladium catalyst.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; aromatic hydrocarbons such as
benzene, toluene and xylene; amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and 1-methyl-
2-pyrrolidone; halogenated hydrocarbons such as
methylene chloride, chloroform and dichloroethane;
ethers such as dioxane, tetrahydrofuran, anisole,
ethylene glycol dimethyl ether, diethylene glycol
dimethyl ether and diethylene glycol diethyl ether;
ketones such as acetone and 2-butanone; nitriles such
as acetonitrile; esters such as ethyl acetate and butyl
acetate and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
Examples of a base optionally used in this
reaction include inorganic bases such as sodium hydride,
sodium hydrogen carbonate, sodium carbonate, potassium
carbonate, cesium carbonate and tripotassium phosphate
and organic bases such as sodium acetate, potassium
acetate, sodium tert-butoxide, triethylamine,
diisopropylethylamine, tributylamine and N,N-

39
dicyclohexylmethylamine. The used amount of the base
can be 1 to 50 times mol, preferably 2 to 5 times mol
for the compound of general formula [2] .
[0052]
Examples of the phase transfer catalyst
optionally used in this reaction include quaternary
ammonium salts such as tetramethylammonium chloride,
benzyltrimethylammonium chloride,
benzyltriethylammonium chloride, benzyltributylammonium
chloride, tetrabutylammonium chloride,
tetrabutylammonium bromide, tetrabutylammonium hydrogen
sulfate and trioctylmethylammonium chloride; N-
laurylpyridinium chloride, N-lauryl-4-picolinium
chloride, N-laurylpicolinium chloride and N-
benzylpicolinium chloride. The used amount of the phase
transfer catalyst can be 0.01 to 50 times mol,
preferably 0.1 to 5 times mol for the compound of
general formula [2].
[0053]
The ligand optionally used in this reaction
includes trialkylphosphines such as trimethylphosphine
and tri-tert-butylphosphine; tricycloalkylphosphines
such as tricyclohexylphosphine; triarylphosphines such
as triphenylphosphine and tritolylphosphine;
trialkylphosphites such as trimethylphosphite,
triethylphosphite and tributylphosphite;
tricycloalkylphosphites such as tricyclohexylphosphite,
triarylphosphites such as triphenylphosphite;
imidazolium salts such as 1,3-bis(2,4,6-

40
trimethylphenyl)imidazolium chloride; diketone such as
acetylacetone and octafluoroacetylacetone; amines such
as trimethylamine, triethylamine, tripropylamine and
triisopropylamine; 1,1'-bis(diphenylphosphino)ferrocene,
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 2-
dicyclohexylphosphino-2',6'-dimethoxy biphenyl, 2-
dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl,
2-(di-tert-butylphosphino)-2',4',6'-triisopropyl
biphenyl and 2-(di-tert-butylphosphino) biphenyl and
these may be optionally used in combination. The used
amount of the ligand can be 0.00001 to 1 time mol and
preferably 0.001 to 0.1 time mol for the compound of
general formula [2].
[0054]
Examples of the palladium catalyst used in
this reaction include metal palladium such as
palladium-carbon and palladium black; inorganic
palladium salts such as palladium chloride; organic
palladium salts such as palladium acetate;
organopalladium complex such as
tetrakis(triphenylphosphine)palladium (0),
bis(triphenylphosphine)palladium (II) chloride, 1,1'-
bis(diphenylphosphino)ferrocene palladium (II) chloride,
(E)-di(^-acetato) bis(o-(di-o-
tolylphosphino)benzyl)dipalladium (II) and
tris(dibenzylideneacetone)dipalladium (0) and polymer
immobilized organopalladium complex such as polymer
supported bis(acetato) triphenylphosphine palladium
(II) and polymer supported di(acetato)

41
dicyclohexylphenylphosphine palladium (II) and these
may be optionally used in combination. The used amount
of the palladium catalyst can be 0.00001 to 1 time mol,
preferably 0.001 to 0.1 time mol for the compound of
general formula [2].
[0055]
The used amount of the compound of general
formula [5] can be 1 to 50 times mol and preferably 1
to 2 times mol for the compound of general formula [2].
This reaction can be preferably carried out
in an inert gas (for example, nitrogen, argon)
atmosphere at 40 to 170°C for 1 minute to 24 hours.
[0056]
(3-2)
When X6a is an alkynylene group which may be
optionally substituted, the compound of general formula
[lc] can be produced by reacting a compound of general
formula [2] with a compound of general formula [5] in
the presence of or in the absence of a base, in the
presence of or in the absence of a copper catalyst, and
in the presence of a palladium catalyst.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; aromatic hydrocarbons such as
benzene, toluene and xylene; amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and 1-methyl-
2-pyrrolidone; halogenated hydrocarbons such as

42
methylene chloride, chloroform and dichloroethane;
ethers such as dioxane, tetrahydrofuran, anisole,
ethylene glycol dimethyl ether, diethylene glycol
dimethyl ether and diethylene glycol diethyl ether;
ketones such as acetone and 2-butanone; nitriles such
as acetonitrile; esters such as ethyl acetate and butyl
acetate and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
[0057]
Examples of a base optionally used in this
reaction include inorganic bases such as sodium
hydrogen carbonate, sodium carbonate, potassium
carbonate, cesium carbonate and tripotassium phosphate
and organic bases such as triethylamine and
diisopropylethylamine. The used amount of the base can
be 1 to 50 times mol, preferably 2 to 5 times mol for
the compound of general formula [2].
Examples of the copper catalyst optionally
used in this reaction include copper bromide and copper
iodide. The used amount of the copper catalyst can be
0.01 to 50 times mol, preferably 0.1 to 5 times mol for
the compound of general formula [2].
Examples of the palladium catalyst used in
this reaction include metal palladium such as
palladium-carbon and palladium black; inorganic
palladium salts such as palladium chloride; organic
palladium salts such as palladium acetate;
organopalladium complex such as
tetrakis(triphenylphosphine)palladium (0),

43
bis(triphenylphosphine)palladium (II) chloride, 1,1'-
bis(diphenylphosphino)ferrocene palladium (II) chloride
and tris(dibenzylideneacetone)dipalladium (0) and
polymer immobilized organopalladium complex such as
polymer supported bis(acetato) triphenylphosphine
palladium (II) and polymer supported di(acetato)
dicyclohexylphenylphosphine palladium (II) and these
may be optionally used in combination. The used amount
of the palladium catalyst can be 0.00001 to 1 time mol,
preferably 0.001 to 0.1 time mol for the compound of
general formula [2].
The used amount of the compound of general
formula [5] can be 1 to 50 times mol and preferably 1
to 2 times mol for the compound of general formula [2].
This reaction can be preferably carried out
in an inert gas (for example, nitrogen, argon)
atmosphere at 10 to 170°C for 1 minute to 24 hours.
[0058]
(3-3)
The compounds of general formula [Id] can be
produced by reducing a compound of general formula [lc].
Examples of the reducing reaction include
catalytic hydrogenation reaction using a metal catalyst.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and l-methyl-2-pyrrolidone;

44
halogenated hydrocarbons such as methylene chloride,
chloroform and dichloroethane; aromatic hydrocarbons
such as benzene, toluene and xylene; ethers such as
dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether and
diethylene glycol diethyl ether; nitriles such as
acetonitrile; ketones such as acetone and 2-butanone;
esters such as ethyl acetate and butyl acetate; and
carboxylic acids such as acetic acid and
heteroaromatics such as pyridine and these may be
optionally mixed for use.
Examples of the metal catalyst used in this
reaction include metal palladium such as palladium-
carbon and palladium black; palladium salts such as
palladium oxide and palladium hydroxide, nickel metal
such as Raney nickel and platinum salts such as
platinum oxide. The used amount of the metal catalyst
can be 0.001 to 5 times amount (W/W), preferably 0.1 to
1 time amount (W/W) for the compound of general formula
[lc].
Examples of the reducing agent used in this
reaction include hydrogen; formic acid; formates such
as sodium formate, ammonium formate and
triethylammonium formate; cyclohexene and
cyclohexadiene. The used amount of the reducing agent
can be 2 to 100 times mol, preferably 2 to 10 times mol
for the compound of general formula [lc].
This reaction can be carried out at 0 to 200°C,
preferably at 0 to 100°C for 1 minute to 24 hours.

45
[0059]
[Production Process 4]

"In the formula, X5a represents an oxygen atom, a sulfur
atom or an imino group which may be optionally
protected; Rla, R2, R3a, X1, X2, X3, X6 and L1 mean the
same as above."
[0060]
As a compound of general formula [6], for
example, aniline, benzylamine, phenol, thiophenol and
benzylmercaptan are known. In addition, for example,
the compounds of general formula [6] can be produced by
an ordinary method from a corresponding halogeno
compound.
[0061]
(4-1)
The compound of general formula [le] can be
produced by reacting a compound of general formula [2]
with a compound of general formula [6] following
production process (3-1).
[0062]
(4-2)
When X5a is an oxygen atom, the compound of
general formula [le] can be produced by reacting a
compound of general formula [2] with a compound of

46
general formula [6] in the presence of or in the
absence of a base, and in the presence of a copper
catalyst.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include
aromatic hydrocarbons such as benzene, toluene and
xylene; amides such as N,N-dimethylformamide, N,N-
dimethylacetamide and l-methyl-2-pyrrolidone;
halogenated hydrocarbons such as methylene chloride,
chloroform and dichloroethane; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl
ether, diethylene glycol dimethyl ether and diethylene
glycol diethyl ether; ketones such as acetone and 2-
butanone; nitriles such as acetonitrile; esters such as
ethyl acetate and butyl acetate and sulfoxides such as
dimethylsulfoxide and these may be optionally mixed for
use.
Examples of a base optionally used in this
reaction include sodium hydride and sodium. The used
amount of the base can be 1 to 50 times mol, preferably
1 to 5 times mol for the compound of general formula
[2].
Examples of the copper catalyst used in this
reaction include copper powder and copper iodide. The
used amount of the copper catalyst can be 0.00001 to 1
time mol, preferably 0.01 to 1 time mol for the
compound of general formula [2].

-47
The used amount of the compound of general
formula [6] can be 1 to 50 times mol and preferably 1
to 5 times mol for the compound of general formula [2].
This reaction can be preferably carried out
at 40 to 200°C for 30 minutes to 72 hours.
[0063]
[Production Process 5]

"In the formula, L2 represents a leaving group; Rla, R2,
R3b, X1, X2, X3 and X6a mean the same as above."
[0064]
As a compound of general formula [8a], for
example, 2-iodotoluene, 3-iodoanisole, 3-
iodonitrobenzene and 6-iodo-2,3-dihydrobenzo[l,4]dioxin
are known.
[0065]
The compound of general formula [If] can be
produced by reacting a compound of general formula [7]
with a compound of general formula [8a] following
production process (3-1) or (3-2).
[0066]
[Production Process 6]


"In the formula, Rla, R2, R3, X1, X2, X3 and X4 mean the
same as above."
[0067]
(6-1)
When X1 is a carbonyl group, the compound of
general formula [lg] can be produced by amidating a
compound of general formula [9]. Specifically, a method
using an acid halide in the presence of or in the
absence of the base, a method using an acid anhydride
in the presence of or in the absence of the base and
the like are included.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include amides
such as N,N-dimethylformamide, N,N-dimethylacetamide
and l-methyl-2-pyrrolidone; halogenated hydrocarbons
such as methylene chloride, chloroform and
dichloroethane; aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl
ether, diethylene glycol dimethyl ether and diethylene
glycol diethyl ether; nitriles such as acetonitrile;
ketones such as acetone and 2-butanone; esters such as
ethyl acetate and butyl acetate and sulfoxides such as

49
dimethylsulfoxide and these may be optionally mixed for
use.
[0068]
Examples of the acid halide used in this
reaction include benzoyl chloride, benzoyl bromide,
2,4-difluorobenzoyl chloride, 2-naphthoyl chloride,
diphenylacetyl chloride, 2,3-dihydrobenzo[l,4]dioxin-6-
carbonyl chloride, cyclohexane carbonyl chloride,
cyclopentylcarbonyl chloride (E)-3-phenylacryloyl
chloride, phenoxyacetyl chloride, 2-furoyl chloride, 1-
benzofuran-2-carbonyl chloride, 2-thenoyl chloride,
nicotinoyl chloride and picolinoyl chloride. In
addition, the acid halide can be produced by reacting a
compound represented by general formula [38]
[Formula 2]
R2—X3—X2-CO2H
[38]
"In the formula, R2, X2 and X3 mean the same as above."
with thionyl chloride, oxalyl chloride or the like. The
used amount of the acid halide can be 1 to 50 times mol
and preferably 1 to 5 times mol for the compound of
general formula [9].
Examples of the acid anhydride used in this
reaction include benzoic anhydride. In addition, acid
halides can be produced from a corresponding carboxylic
acid by a method, for example, described in "Shin
Jikken Kagaku Kouza", Vol. 14, pp. 1120-1133, 1977,
Maruzen or the like method. The used amount of the acid

50
anhydride can be 1 to 50 times mol and preferably 1 to
5 times mol for the compound of general formula [9].
Examples of the base optionally used in this
reaction include inorganic bases such as sodium
hydrogen carbonate, sodium carbonate, potassium
carbonate and cesium carbonate and organic bases such
as triethylamine and diisopropylethylamine. The used
amount of the base can be 1 to 50 times mol and
preferably 1 to 5 times mol for the compound of general
formula [9].
This reaction can be carried out ordinarily
at -78 to 100°C, preferably at 0 to 80°C for 10 minutes
to 24 hours.
[0069]
(6-2)
When X1 is a sulfonyl group, the compound of
general formula [lg] can be produced by sulfonamidating
a compound of general formula [9]. Specifically, a
method using a sulfonyl halide in the presence of or in
the absence of the base is included.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include amides
such as N,N-dimethylformamide, N,N-dimethylacetamide
and l-methyl-2-pyrrolidone; halogenated hydrocarbons
such as methylene chloride, chloroform and
dichloroethane; aromatic hydrocarbons such as benzene,
toluene and xylene; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl

51
ether, diethylene glycol dimethyl ether and diethylene
glycol diethyl ether; nitriles such as acetonitrile;
ketones such as acetone and 2-butanone; esters such as
ethyl acetate and butyl acetate, sulfones such as
sulfolane and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
Examples of the sulfonyl halide used in this
reaction include benzenesulfonyl chloride and cc-
toluenesulfonyl chloride. In addition, a sulfonyl
halide can be produced from a corresponding sulfonic
acid by a method, for example, described in "Shin
Jikken Kagaku Kouza", Vol. 14, pp. 1784-1792, 1978,
Maruzen or the like method. The used amount of the
sulfonyl halide can be 1 to 50 times mol and preferably
1 to 5 times mol for the compound of general formula
[9].
Examples of the base optionally used in this
reaction include inorganic bases such as sodium
hydrogen carbonate, sodium carbonate, potassium
carbonate and cesium carbonate and organic bases such
as triethylamine and diisopropylethylamine. The used
amount of the base can be 1 to 50 times mol and
preferably 1 to 5 times mol for the compound of general
formula [9].
This reaction can be carried out ordinarily
at -78 to 100°C, preferably at 0 to 80°C for 10 minutes
to 24 hours.
[0070]
[Production Process 7]


"In the formula, X6c represents an alkylene group which
may be optionally substituted or a bond; L3 represents a
leaving group; Rla, R2, R3a, X1, X2, X3, X5a and X6b mean
the same as above provided that if X6c represents a bond,
R3a represents a cycloalkyl group which may be
optionally substituted."
[0071]
As a compound of general formula [lla], for
example, benzyl bromide and (2-bromoethyl)benzene are
known. As a compound of general formula [lib], for
example, 3-phenyl-l-propanol and cyclohexanol are known.
[0072]
(7-1)
The compounds of general formula [lh] can be
produced by reacting a compound of general formula [10]
with a compound of general formula [lla] in the
presence of the base.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include amides
such as N,N-dimethylformamide, N,N-dimethylacetamide
and l-methyl-2-pyrrolidone; halogenated hydrocarbons
such as methylene chloride, chloroform and
dichloroethane; aromatic hydrocarbons such as benzene,

53
toluene and xylene; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl
ether, diethylene glycol dimethyl ether and diethylene
glycol diethyl ether; nitriles such as acetonitrile;
ketones such as acetone and 2-butanone; esters such as
ethyl acetate and butyl acetate, sulfones such as
sulfolane and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
The used amount of the compound of general
formula [lla] can be 1 to 20 times mol and preferably 1
to 5 times mol for the compound of general formula [10].
Examples of the base used in this reaction
include organic amines such as dimethylaminopyridine,
triethylamine, and pyridine; alkali metal hydrides such
as sodium hydride and alkali metal carbonates such as
potassium carbonate and sodium carbonate.
The used amount of the base can be 1 to 20
times mol and preferably 1 to 5 times mol for the
compound of general formula [10].
This reaction can be carried out ordinarily
at 0 to 200°C, preferably at 25 to 150°C for 10 minutes
to 24 hours.
[0073]
(7-2)
When X5a is an oxygen atom or a sulfur atom,
the compound of general formula [lh] can be produced by
subjecting a compound of general formula [10] and a
compound of general formula [lib] to Mitsunobu reaction

54
in the presence of an azodicarbonyl compound and a
phosphine.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include
aromatic hydrocarbons such as benzene, toluene and
xylene; ethers such as dioxane, tetrahydrofuran,
anisole, diethylene glycol dimethyl ether, ethylene
glycol monomethyl ether and ethylene glycol dimethyl
ether; esters such as methyl acetate, ethyl acetate and
butyl acetate; nitriles such as acetonitrile; amides
such as N,N-dimethylformamide and N,N-
dimethylacetamide; halogenated hydrocarbons such as
chloroform, methylene chloride and these may be
optionally mixed for use.
Examples of the azodicarbonyl compound used
in this reaction include diethyl azodicarboxylate,
diisopropyl azodicarboxylate and
azodicarbonyldipiperidine. The used amount of the
azodicarbonyl compound can be 1 to 5 times mol and
preferably 1 to 3 times mol for the compound of general
formula [10].
Examples of the phosphines used in this
reaction include triarylphosphines such as
triphenylphosphine and trialkylphosphines such as
tributylphosphine. The used amount of the phosphines
can be 1 to 5 times mol and preferably 1 to 3 times mol
for the compound of general formula [10].

55
The used amount of the compound of general
formula [lib] can be 1 to 5 times mol and preferably 1
to 3 times mol for the compound of general formula [10].
This reaction can be carried out ordinarily
at -20 to 120°C, preferably at 0 to 50°C for 30 minutes
to 24 hours.
[0074]
[Production Process 8]

"In the formula, X2b represents a bond; X3a represents an
oxygen atom or a bond; X5b represents an oxygen atom, a
sulfonyl group or a bond; R2, R3a and X1 mean the same as
above."
[0075]
The compound of the general formula [li] can
be produced by reacting a compound of general formula
[12] with an oxidizing agent in the presence of or in
the absence of an acid or a base, in the presence of or
in the absence of a salt.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
halogenated hydrocarbons such as methylene chloride,
chloroform and dichloroethane; aliphatic hydrocarbons

56
such as hexane and cyclohexane, and pyridine and these
may be optionally mixed for use.
Examples of the acid optionally used in this
reaction include mineral acids such as hydrochloric
acid and sulfuric acid and organic acids such as acetic
acid. The used amount of the acid can be 1 to 1000
times mol for the compound of general formula [12].
Examples of the base optionally used in this
reaction include, inorganic bases such as sodium
hydroxide and potassium hydroxides, and organic base
such as pyridine. The used amount of the base can be 1
to 1000 times mol for the compound of general formula
[12].
Examples of the salt optionally used in this
reaction include magnesium sulfate, ammonium sulfate
and magnesium chloride. The used amount of the salt can
be 1 to 50 times mol, preferably 1 to 10 times mol for
the compound of general formula [12].
Examples of the oxidizing agent used in this
reaction include chromate such as chromium oxide (VI)
and sodium dichromate, and permanganate such as
potassium permanganate, barium permanganate, calcium
permanganate and magnesium permanganate. The used
amount of the oxidizing agent can be 1 to 50 times mol,
preferably 1 to 10 times mol for the compound of
general formula [12].
This reaction can be carried out ordinarily
at 0 to 150°C, preferably at 40 to 130°C for 30 minutes
to 48 hours.


57
[0076]
[Production Process 9]
"R3d represents a monocyclic heterocyclic or bicyclic
heterocyclic group linking through a nitrogen atom
which forms the ring and which group may be optionally
substituted; Rla, R2, X1, X2, X3 and L1 mean the same as
above."
[0077]
As a compound of general formula [13], for
example, pyrrolidine, piperidine, morpholine, pyrrole,
indoline, isoindoline, benzimidazole and indole are
known.
[0078]
The compound of general formula [lj] can be
produced by reacting a compound of general formula [2]
with a compound of general formula [13] following
production process 1.
[0079]
[Production Process 10]


"In the formula, R3e represents a cycloalkenyl group
which may be optionally substituted; R3f represents a
cycloalkyl group which may be optionally substituted;
Rla, R2, X1, X2, X2a, X3 and L1 mean the same as above."
[0080]
As a compound of general formula [14] , for
example, cyclopentene and cyclohexene are known. In
addition, the compound of general formula [14] can be
produced by a method, for example, described in "Jikken
Kagaku Kouza", 4th edition, Vol. 19, pp. 53-298, 1992,
Maruzen or the like method.
[0081]
(10-1)
The compound of general formula [Ik] can be
produced by reacting a compound of general formula [2]
with a compound of general formula [14] following
production process (3-1).
[0082]
(10-2)

59
The compound of general formula [11] can be
produced by reducing a compound of general formula [Ik]
following production process (3-3).
[0083]
[Production Process 11]


"In the formula, L2a represents a chlorine atom, a
bromine atom or an iodine atom; Rla, R2, R3b, X1, X2, X3
and X7 mean the same as above."
[0084]
As a compound of general formula [8b], for
example, 2-iodotoluene, 3-iodoanisole, 3-
iodonitrobenzene and 6-iodo-2,3-dihydrobenzo[1,4]dioxin
are known.
[0085]
The compound of general formula [lb] can be
produced by reacting a compound of general formula [15]
with a compound of general formula [8b] following
production process 1.
[0086]

[Production Process 12]

60
"In the formula, R2, R3, X1, X2, X3, X6 and X6c mean the
same as above."
[0087]
The compound of general formula [In] can be
produced by reducing a compound of general formula [lm]
following production process (3-3).
[0088]
[Production Process 13]



"In the formula, R2, R3, X1, X2, X3, X6a and X6b mean the
same as above."
[0089]
The compound of general formula [lp] can be
produced by reducing a compound of general formula [lo]
following production process (3-3).
[0090]
[Production Process 14]

"In the formula, Rla, R2, R3, X1, X2, X3 and X4 mean the
same as above."

61
[0091]
The compound of general formula [lq] can be
produced by deprotecting a compound of general formula
tig].
Examples of deprotection reaction include
hydrolysis reaction using an acid or a base,
dealkylation reaction using a salt and reductive
dealkylation reaction including metal catalyst
hydrogenation reaction.
[0092]
Examples of the acid in hydrolysis reaction
using an acid include formic acid, hydrochloric acid,
sulfuric acid, hydrobromic acid, trifluoroacetic acid,
aluminum chloride and iodinated trimethylsilane. The
used amount of the acid can be 1 to 100000 times mol
and preferably 1 to 1000 times mol for the compound of
general formula [lg].
Examples of the base in hydrolysis reaction
using a base include inorganic bases such as sodium
hydroxide, potassium hydroxide and lithium hydroxide;
organic bases such as sodium methoxide, sodium ethoxide
and potassium tert-butoxide; carbonates such as
potassium carbonate and sodium carbonate and
tetrabutylammonium fluoride. The used amount of the
base can be 1 to 1000 times mol and preferably 1 to 50
times mol for the compound of general formula [lg].
Examples of the salt in dealkylation reaction
using a salt include lithium iodide and sodium chloride.
The used amount of the salt can be 1 to 100 times mol

62
and preferably 1 to 10 times mol for the compound of
general formula [lg].
The reductive dealkylation reaction including
metal catalyst hydrogenation reaction can be conducted
following production process (3-3).
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl
ether, diethylene glycol dimethyl ether and diethylene
glycol diethyl ether; halogenated hydrocarbons such as
methylene chloride, chloroform and dichloroethane;
nitriles such as acetonitrile; aliphatic hydrocarbons
such as hexane and cyclohexane; aromatic hydrocarbons
such as benzene, toluene and xylene; sulfoxides such as
dimethylsulfoxide; amides such as N,N-
dimethylformamide; nitromethane and pyridine and these
may be optionally mixed for use.
This reaction can be carried out ordinarily
at -78 to 100°C, preferably at 0 to 80°C for 10 minutes
to 24 hours.
[0093]
[Production Process 15]


63
"In the formula, X5c represents a sulfinyl group or a
sulfonyl group; R1, R2, R3, X1, X2, X3 and X6 mean the
same as above."
[0094]
The compound of general formula [Is] can be
produced by reacting a compound of general formula [lr]
with an oxidizing agent.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
halogenated hydrocarbons such as methylene chloride,
chloroform and dichloroethane; aliphatic hydrocarbons
such as hexane and cyclohexane and pyridine and these
may be optionally mixed for use.
Examples of the oxidizing agent used in this
reaction include hydrogen peroxide; hyperacids such as
a peroxyacetic acid, perbenzoic acid and m-
chloroperbenzoic acid; peroxides such as tert-butyl
peroxide and sodium metaperiodate. The used amount of
the oxidizing agent can be 1 to 50 times mol,
preferably 1 to 10 times mol for the compound of
general formula [lr].
This reaction can be carried out ordinarily
at 0 to 150°C, preferably at 10 to 100°C for 30 minutes
to 4 8 hours.
[0095]
[Production Process 16]


"In the formula, R1, R2, R3a, X1, X2, X3, X5c and X6 mean
the same as above."
[0096]
The compound of general formula [lu] can be
produced by reacting a compound of general formula [It]
with an oxidizing agent following production process 15.
[0097]
The thus obtained compounds of general
formulae [la], [lb], [lc], [Id], [le], [If], [lg], [lh],
[li], [lj], [Ik], [11], [In], [lo], [lp], [lq], [lr],
[Is], [It] and [lu] or the salts thereof can be
converted to the other compounds of general formula [1]
or the salts thereof by subjecting them to reactions
known per se such as condensation, addition, oxidation,
reduction, rearrangement, substitution, halogenation,
dehydration and hydrolysis or by combining these
reactions appropriately.
In addition, when there is any isomer (for
example, optical isomer, geometrical isomer, tautomer
and the like) for the compounds in the production
processes mentioned above, these isomers can also be
used, and solvates, hydrates and crystals of various
kinds can be also used.

65
[0098]
Next, production processes of the compounds
of general formulae [2], [7], [9], [10], [12], [15] and
[38], which are raw materials in the production of the
compounds of the present invention, are described.
[0099]
[Production Process A]

"In the formula, Rla, R2, X1, X2, X3 and L1 mean the same
as above".
[0100]
As a compound of general formula [16], for
example, 4-chloro-2-nitrobenzoic acid and 4-bromo-2-
nitrobenzoic acid are known.
[0101]
(A-l)
The compound of general formula [17] can be
produced by esterifying a compound of general formula
[16] . This reaction can be performed by a method
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 369-453, 1999,

66
John Wiley & Sons, INC. or the like method.
Specifically, methods using an alkylating agent in the
presence of or in the absence of a phase transfer
catalyst, in the presence of the base, a method via an
acid halide of the compound of general formula [16] are
included.
[0102]
The solvent used in the reaction using an
alkylating agent is not particularly limited as long as
it does not adversely affect the reaction and examples
thereof include aromatic hydrocarbons such as benzene,
toluene and xylene; amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and 1-methyl-
2-pyrrolidone; halogenated hydrocarbons such as
methylene chloride, chloroform and dichloroethane;
ethers such as dioxane, tetrahydrofuran, anisole,
ethylene glycol dimethyl ether, diethylene glycol
dimethyl ether and diethylene glycol diethyl ether;
ketones such as acetone and 2-butanone; nitriles such
as acetonitrile; esters such as ethyl acetate and butyl
acetate and sulfoxides such as dimethylsulfoxide and
these may be optionally mixed for use.
Examples of the phase transfer catalyst
optionally used in this reaction include quaternary
ammonium salts such as tetramethyl ammonium chloride,
benzyltrimethylammonium chloride,
benzyltriethylammonium chloride, benzyltributylammonium
chloride and tetrabutylammonium bromide. The used
amount of the phase transfer catalyst can be 0.01 mol

67
or more, preferably 0.1 to 5 times mol for the compound
of general formula [16].
Examples of the base used in this reaction
include inorganic bases such as sodium carbonate,
potassium carbonate and cesium carbonate and organic
bases such as triethylamine, pyridine,
dimethylaminopyridine and N-methylmorpholine. The used
amount of the base can be 1 to 50 times mol, preferably
1 to 5 times mol for the compound of general formula
[16].
Examples of the alkylating agent used in this
reaction include methyl iodide, ethyl iodide, dimethyl
sulfate, 2-bromo-2-methylpropane, benzyl chloride and
benzyl bromide. The used amount of the alkylating agent
can be 1 to 50 times mol, preferably 1 to 5 times mol
for the compound of general formula [16].
This reaction can be carried out ordinarily
at 0 to 170°C for 1 minute to 24 hours.
[0103]
For example, in a method via an acid halide,
a compound of general formula [16] can be reacted with
thionyl chloride, oxalyl chloride or the like to
converted it to an acid halide and then reacted with
alcohols such as methanol, ethanol, benzyl alcohol in
the presence of or in the absence of a base.
The solvent used in this reaction is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include
aromatic hydrocarbons such as benzene, toluene and

68
xylene; halogenated hydrocarbons such as methylene
chloride, chloroform and dichloroethane; ethers such as
dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether and
diethylene glycol diethyl ether; ketones such as
acetone and 2-butanone; nitriles such as acetonitrile;
esters such as ethyl acetate and butyl acetate and
sulfoxides such as dimethylsulfoxide and these may be
optionally mixed for use.
Examples of the base optionally used in this
reaction include inorganic bases such as sodium
carbonate, potassium carbonate and cesium carbonate and
organic bases such as triethylamine, pyridine,
dimethylaminopyridine and N-methylmorpholine. The used
amount of the base can be 1 to 50 times mol, preferably
1 to 5 times mol for the compound of general formula
[16].
This reaction can be carried out ordinarily
at 0 to 170°C for 1 minute to 24 hours.
[0104]
(A-2)
The compound of general formula [18] can be
produced by reducing a compound of general formula [17] .
This reaction can be performed by a method described in
Richard C. Larock et al., Comprehensive Organic
Transformations, second edition, pp. 823-827, 1999,
John Wiley & Sons, INC. or the like method.
Specifically, catalytic hydrogenation reaction using a

69
metal catalyst and reductive reaction using a metal
such as iron or zinc are included.
[0105]
When the compound of general formula [17] is
subjected to catalytic hydrogenation reaction, it can
be performed following production process (3-3).
The solvent used for subjecting a compound of
general formula [17] to reduction using a metal is not
particularly limited as long as it does not adversely
affect the reaction and examples thereof include water;
alcohols such as methanol, ethanol, 2-propanol and 2-
methyl-2-propanol; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and l-methyl-2-pyrrolidone;
halogenated hydrocarbons such as methylene chloride,
chloroform and dichloroethane; aromatic hydrocarbons
such as benzene, toluene and xylene; ethers such as
dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether and
diethylene glycol diethyl ether; nitriles such as
acetonitrile; ketones such as acetone and 2-butanone;
esters such as ethyl acetate and butyl acetate and
these may be optionally mixed for use.
Examples of the metal used in this reaction
include iron, zinc, tin and tin (II) chloride. The used
amount of the metal can be 1 to 50 times mol,
preferably 1 to 10 times mol for the compound of
general formula [17].
Examples of the acid optionally used in this
reaction include hydrogen chloride, hydrogen bromide

70
and acetic acid. The used amount of the acid can be
0.001 to 100 times amount (W/V), preferably 0.01 to 20
times amount (W/V) for the compound of general formula
[17].
This reaction can be carried out at 0 to 200°C,
preferably 0 to 100°C for 1 minute to 24 hours.
[0106]
(A-3)
The compound of general formula [2] can be
produced by amidating or sulfonamidating a compound of
general formula [18] following production process 6.
[0107]
[Production Process B]

"In the formula, Rla, R2, X1, X2b, X3a and L1 mean the
same as above."
[0108]
As a compound of general formula [19], for
example, 5-iodo-2-methylaniline is known.

71
[0109]
(B-l)
The compound of general formula [20] can be
produced by amidating or sulfonamidating a compound of
general formula [19] following production process 6.
[0110]
(B-2)
The compound of general formula [21] can be
produced by reacting a compound of general formula [20]
with an oxidizing agent following production process 8.
[0111]
(B-3)
The compound of general formula [2a] can be
produced by esterifying a compound of general formula
[21] following production process (A-l).
[0112]
[Production Process C]

"In the formula, Rla, R2, R4, R5, X1, X2, X3, X6a, X7 and
L1 mean the same as above."
[0113]
The compound of general formula [7] can be
produced by subjecting a compound of general formula

72
[2] to coupling reaction with a compound of general
formula [22a] following production process 2. In
addition, it can also be produced by reacting a
compound of general formula [2] with a compound of
general formula [22b1] or general formula [22b2]
following production process 1.
[0114]
[Production Process D]

"In the formula, R6 represents an acetylene protecting
group; Rla, R2, X1, X2, X3 and L1 mean the same as above."
[0115]
The compound of general formula [7a] can be
produced by reacted a compound of general formula [2]
with a compound of general formula [22c] and then by
performing deprotection following production process
(3-2) .
Deprotection can be performed by a method
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 654-659, 1999,
John Wiley & Sons, INC. or the like method.
[0116]
[Production Process E]


"In the formula, Rla, R3 and X5 mean the same as above."
[0117]
As a compound of general formula [23], for
example, 2-nitro-4-phenoxybenzoic acid [WO03/033480] is
known.
[0118]
(E-l)
The compound of general formula [24] can be
produced by esterifying a compound of general formula
[23] following production process (A-l).
[0119]
(E-2)
The compound of general formula [9a] can be
produced by reducing a compound of general formula [24]
following production process (3-3) or (A-2).
[0120]
[Production Process F]


74
"In the formula, Rla, R3a, R4, X7 and L1 mean the same as
above."
[0121]
(F-l)
The compound of general formula [25] can be
produced by reacting a compound of general formula [17]
with a compound of general formula [3a] or general
formula [3b] following production process 1.
[0122]
(F-2)
The compound of general formula [9b] can be
produced by reducing a compound of general formula [25]
following production process (3-3) or (A-2).
[0123]
[Production Process G]

"In the formula, Rla, R3b, R5 and L1 mean the same as
above."
[0124]
(G-l)
The compound of general formula [26] can be
produced by reacting a compound of general formula [17]
with a compound of general formula [4] following
production process 2.

75
[0125]
(G-2)
The compound of general formula [9c] can be
produced by reducing a compound of general formula [26]
following production process (3-3) or (A-2).
[0126]
[Production Process H]

"In the formula, R6d represents an alkenylene group
which may be optionally substituted; Rla, R3a, R3c, X6b
and L1 mean the same as above."
[0127]
(H-l)
The compound of general formula [28] can be
produced by reacting a compound of general formula [17]
with a compound of general formula [27] following
production process (3-1).
[0128]
(H-2)
The compound of general formula [9d] can be
produced by reducing a compound of general formula [28]
following production process (3-3).
[0129]
[Production Process I]


"In the formula, L4 represents a leaving group; Rla, R3a,
R3c, X5a and X6b mean the same as above."
[0130]
As a compound of general formula [29], for
example, methyl 4-(bromomethyl)-2-nitrobenzoate is
known. In addition, methyl 4-(bromomethyl)-2-
nitrobenzoate can be produced by esterifying 4-
(bromomethyl)-2-nitrobenzoic acid according to an
ordinary method described in Journal of Medicinal
Chemistry, Vol. 29, pp. 589-591, 1986.
[0131]
(I-D
The compound of general formula [31] can be
produced by reacting a compound of general formula [29]
with a compound of general formula [30] following
production process (7-1).
[0132]
(1-2)
The compound of general formula [9e] can be
produced by reducing a compound of general formula [31]
following production process (3-3) or (A-2).
[0133]
[Production Process J]


"In the formula, R7 represents a phenolic hydroxyl
protecting group or a thiol protecting group; Rla, R2, X1,
X2, X3 and X5a mean the same as above."
[0134]
As a compound of general formula [32], for
example, methyl 2-amino-4-methoxybenzoate [Journal of
the Chemical Society, Perkin Transactions 1, Vol. 21,
pp. 3261-3274, 1997] is known.
[0135]
(J-D
The compound of general formula [33] can be
produced by amidating or sulfonamidating a compound of
general formula [32] following production process 6.
[0136]
(J-2)
The compound of general formula [10] can be
produced by deprotecting a compound of general formula
[33] . Deprotection of phenolic hydroxyl protecting
group can be performed, for example, by a method

78
described in W. Greene et al., Protective Groups in
Organic Synthesis, third edition, pp. 249-287, 1999,
John Wiley & Sons, INC. or the like method;
deprotection of thiol protecting group can be performed,
for example, by a method described in W. Greene et al.,
Protective Groups in Organic Synthesis, third edition,
pp. 454-493, 1999, John Wiley & Sons, INC. or the like
method.
[0137]
[Production Process K]

"In the formula, R2, R3, X1, X2b, X3a and X5b mean the
same as above."
[0138]
As a compound of general formula [34], for
example, l-methyl-2-nitro-4-phenoxybenzene
[International Patent Publication WO02/078693] is known.
[0139]
(K-l)
The compound of general formula [35] can be
produced by reducing a compound of general formula [34]
following production process (3-3) or (A-2).
[0140]
(K-2)

79
The compound of general formula [12] can be
produced by amidating or sulfonamidating a compound of
general formula [35] following production process 6.
[0141]
[Production Process L]



"In the formula, Rla, R2, X1, X2, X3, X7 and L1 mean the
same as above."
[0142]
As a compound of general formula [36], for
example, bis(pinacolato)diboron,
bis(neopentylglylato)diboron and
bis(hexyleneglycolato)diboron are known.
[0143]
The compound of general formula [15] can be
produced by reacting a compound of general formula [2]
with a compound of general formula [36] following
production process 1.
[0144]
[Production Process M]


80
"In the formula, Rlb represents a carboxyl protecting
group; R2, X2 and X3 mean the same as above."
[0145]
As a compound of general formula [37], for
example, methyl 2-(lH-pyrrol-l-yl)pyridine-4-
carboxylate [International Patent Publication
WO9426709] is known.
[0146]
The compound of general formula [38] can be
produced by deprotecting a compound of general formula
[37] following production process 14.
[0147]
In the compounds used in the production
processes mentioned above, compounds which can be in
the form of a salt can be used as a salt. Examples of
those salts include salts which are similar to the
salts of the compound of general formula [1].
[0148]
When there is any isomer (for example,
optical isomer, geometrical isomer, tautomer and the
like) for the compounds in the production processes
mentioned above, these isomers can be also used. In
addition, when there are solvates, hydrates and various
kinds of crystals, these solvates, hydrates and various
kinds of crystals can be used. Further, when the
compounds used in the production process mentioned
above have a protectable group, for example, an amino
group, a hydroxyl group or a carboxyl group, these
groups can be protected with ordinary protecting groups

81
beforehand, and these protecting groups can be detached
by methods well known per se after the reaction.
[0149]
When the compounds of the present invention
are used as a drug, drug adjuvants usually used for
preparation such as excipient, carrier and diluent may
be mixed appropriately. They can be administered orally
or parenterally in the forms such as tablet, capsule,
powder, syrup, granule, pill, suspension, emulsion,
solution, powder preparations, suppository, eyedrop,
nose drop, eardrop, patch, ointment or injection. The
administration method, dosage and times of
administration can be selected appropriately according
to the age, weight and conditions of the patient.
Ordinarily, 0.01 to 1000 mg/kg per day can be
administered to an adult orally or parenterally (for
example, injection, intravenous feeding and
administration to a rectal part) at a time or divided
to several times.
[0150]
Usefulness of some representative compounds
of the present invention is described in the following
Test Examples.
[0151]
Test Example 1: MMP-13 production inhibition test
6.8xlO3 human cartilage derived cell line
SW1353 cells were suspended in 100 \iL of Dulbecco
modified Eagle's medium supplemented with 10% fetal
calf serum, plated on 96-well plates and cultured for 3

82
days. After the culture medium was changed to Dulbecco
modified Eagle's medium containing 0.2% lactalbumin
hydrolysate and the cells were cultured for 6 hours,
test compounds were added and then IL-ip was added to
obtain the final concentration of 10 ng/mL 1 hour later.
16 hours after the stimulation, supernatant was
collected and the amount of MMP-13 in the culture
supernatant was determined with an ELISA kit (Amersham).
The inhibition rate was calculated from the amount of
MMP-13 in the presence of a test compound assuming that
the amount of MMP-13 was 100% in the absence of the
test compound.
The results are shown in Table 7.
[0152]
[Table 7]

83
Example No. inhibition rate (%) at 30 pmol/l,
4 80
7 91
8 95
11 92
15 88
19 94
22 81
24 92
25 86
33 97
80 92
83 93
85 60
88 80
89 94
91 95
96 96
97 97
99 71
105 64
130 96
134 99
138 95
141 95
146 97
150 96
157 98
163 98
176 98
189 96
196 97
212 95
217 68
222 98
230 95
234 99
240 94
243 96
251 83
255 91

84
Example No. Inhibition rate (%) at 30 jimol/L
261 94
262 93
264 94
276 86
282 75
301 80
316 96
318 95
325 91
330 68
349 95
358 99
382 98
399 79
411 81
415 97
423 98
425 99
426 98
431 98
433 98
442 99
450 98
467 90
495 99
499 99
503 99
505 82
509 77
512 99
514 91
525 87
539 97
541 97
543 85
551 96
560 85
564 97
570 98

85
[0153]
Test Example 2: type II collagen-induced arthritis in
Mice
Eight-week old male DBA/1J mice were used
(Charles River Laboratories Japan Inc.). 4 mg/mL bovine
type II collagen (Collagen Gijutsu Kenshukai) dissolved
in 0.01 mol/L of acetic acid aqueous solution and an
equal amount of Freund's complete adjuvant (Chondorex)
containing 1 mg/mL of killed tuberculosis bacillus were
added to prepare an emulsion, and 0.1 mL thereof was
intradermally injected at the base of tail. Similar
treatment was conducted on the 21st day to cause
arthritis. The test compound was suspended in 0.5%
methylcellulose aqueous solution, and 30 mg/kg was
orally administered once a day from the 21st day to the
35th day. In the control group, 0.5% methylcellulose
aqueous solution was administered in the same manner.
The severity of arthritis was estimated by scoring at
zero point for an animal without change; one point for
an animal with swelling at the one or two finger joint
or light swelling only at the carpal or tarsal joint;
two points for an animal with severe swelling at the
carpal or tarsal joint or with swelling at three or
more finger joints; three points for an animal with
severe swelling along the whole foreleg or hindleg and
thus counting 12 points at the maximum for the four
limbs as arthritis score. Degree of bone destruction
was estimated by X-ray photographs of the four limbs on
the 36th day observing the interphalangeal joints of

86
the second to fifth fingers, the metacarpophalangeal
and metatarsophalangeal joints of the first to fifth
fingers, carpal or tarsal parts, calcaneal bone and
scoring at 0 or 0.5 point according to the absence or
presence of osteoporotic image in the joint and their
vicinity, 0 point for the bone image without change,
one point for the partially destroyed bone image and, 2
points for the completely destroyed bone image and thus
counting 105 points at the maximum for the four limbs
as bone destruction score. The inhibitory rate was
determined by the following expression.
Inhibitory ratio (%) = 100 - (score of a test compound
treated group/score of the control group)xlOO
The compound shown in Example 25 exhibited
inhibitory action on arthritis and bone destruction.
[Examples]
[0154]
Hereinbelow, the present invention is
described by way of Referential Examples and Examples,
but the present invention is not limited thereto.
The mixing ratio in the eluent is a volume
ratio. Unless indicated otherwise, the carrier in the
silica gel column chromatography is B.W.Silica gel, BW-
127ZH, manufactured by Fuji Silysia Chemical Ltd., and
the carrier in the reversed-phase silica gel column
chromatography is ODS-AM12S05-2520WT of YMC Co., Ltd.
Each of the symbols used in each Example has
the following meaning.

87
Ac: acetyl, Boc: tert-butoxycarbonyl, tBu: tert-butyl,
Bz: benzoyl, Et: ethyl, Me: methyl
DMSO-cU: deuterated dimethylsulfoxide
[0155]
Referential Example 1

To 40 mL of acetone solution containing 4.0 g
of 4-bromo-2-nitrobenzoic acid, 3.4 g of potassium
carbonate and 2.3 mL of dimethyl sulfate were added at
room temperature and stirred at 50°C for 1 hour. After
the reaction mixture was cooled to room temperature,
the solvent was evaporated under reduced pressure.
Water and ethyl acetate were added to the obtained
residue. The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium hydrogen carbonate aqueous solution,
1.0 mol/L hydrochloric acid and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure to obtain 4.1 g
of methyl 4-bromo-2-nitrobenzoate as white solid.
XH-NMR (CDC13) S: 3.97 (3H, s) , 7.85 (1H, d, J = 8.3 Hz),
8.07 (1H, dd, J = 8.3, 2.0 Hz), 8.47 (1H, d, J = 2.0
Hz) .
[0156]
Referential Example 2


To 50 mL of N,N-dimethylacetamide solution
containing 5.0 g of 4-bromo-2-nitrobenzoic acid, 41 g
of potassium carbonate, 4.6 g of benzyltriethylammonium
chloride and 69 mL of 2-bromo-2-methylpropane were
added at room temperature and stirred at 55°C for 10
hours. After the reaction mixture was cooled to room
temperature, 12 mL of 2-bromo-2-methylpropane was added
and stirred at 55°C for 4 hours. After the reaction
mixture was cooled to room temperature, water and ethyl
acetate were added. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. Methanol
was added to the obtained residue and solid substances
were separated by filtration to obtain 3.0 g of tert-
butyl 4-bromo-2-nitrobenzoate as white solid.
1H-NMR (CDC13) 8: 1.55 (9H, s) , 7.63 (1H, d, J = 8.3 Hz),
7.77 (1H, dd, J = 8.3, 1.9 Hz), 7.95 (1H, d, J = 1.9
Hz) .
[0157]
Referential Example 3


89
2.6 g of iron powder was added to a mixed
solution of 20 mL of methanol and 20 mL of acetic acid
containing 4.0 g of methyl 4-bromo-2-nitrobenzoate, and
the resulting mixture was heated to reflux for 3 hours.
After the reaction mixture was cooled to room
temperature, a saturated sodium hydrogen carbonate
aqueous solution and ethyl acetate were added and
insoluble were removed by filtration. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Hexane was added
to the obtained residue and a solid substance was
separated by filtration to obtain 2.0 g of methyl 2-
amino-4-bromobenzoate as white solid.
1H-NMR (CDC13) 8: 3.89 (3H, s) , 4.20 (2H, s) , 7.26 (1H,
dd, J = 8.3, 2.1 Hz), 7.43 (1H, d, J = 2.1 Hz), 7.47
(1H, d, J = 8.3 Hz).
[0158]
Referential Example 4

3.0 g of iron powder was added to a mixed
solution of 28 mL of methanol and 28 mL of acetic acid
containing 5.5 g of tert-butyl 4-bromo-2-nitrobenzoate,
and the resulting mixture was heated to reflux for 1

90
hour. After the reaction mixture was cooled to room
temperature, a saturated sodium hydrogen carbonate
aqueous solution and ethyl acetate were added and
insoluble were removed by filtration. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure to obtain 4.3 g
of tert-butyl 2-amino-4-bromobenzoate as pale yellow
oil.
1H-NMR (DMSO-d6) 5: 1.52 (9H, s) , 6.65 (1H, dd, J = 8.5,
2.0 Hz), 6.78 (2H, s), 6.98 (1H, d, J = 2.0 Hz), 7.55
(1H, d, J = 8.5 Hz).
[0159]
Referential Example 5

0.55 mL of benzoyl chloride was added to 10
mL of a methylene chloride solution containing 1.0 g of
methyl 2-amino-4-bromobenzoate and 0.73 mL of
triethylamine while ice-cooled and stirred at room
temperature for 1 hour. The solvent was evaporated
under reduced pressure and a saturated sodium hydrogen
carbonate aqueous solution and ethyl acetate were added
to the residue. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed

91
with 1.0 mol/L hydrochloric acid and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Diisopropyl
ether was added to the obtained residue and a solid
substance was separated by filtration to obtain 0.9 g
of methyl 2-(benzamido)-4-bromobenzoate as white solid.
XH-NMR (DMSO-d6) 8: 3.88 (3H, s), 7.54-7.58 (2H, m),
7.61-7.66 (1H, m), 7.77 (1H, dd, J = 8.4, 2.2 Hz), 7.90
(1H, d, J = 8.4 Hz), 8.00-8.02 (2H, m), 8.14 (1H, d, J
i = 2.2 Hz), 10.18 (1H, s).
[0160]
Referential Example 6

1.9 mL of benzoyl chloride was added to 42 mL
of a methylene chloride solution containing 4.2 g of
tert-butyl 2-amino-4-bromobenzoate and 2.6 mL of
triethylamine while ice-cooled and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and water and ethyl acetate were
added to the residue. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. Hexane
and diisopropyl ether were added to the obtained
residue and a solid substance was separated by

92
filtration to obtain 4.4 g tert-butyl 2-(benzamido)-4-
bromobenzoate as white solid.
Hi-NMR (DMSO-de) 8: 1.55 (9H, s) , 7.45 (1H, dd, J = 8.5,
2.1 Hz), 7.60-7.69 (3H, m), 7.89 (1H, d, J = 8.5 Hz),
5 7.95-7.97 (2H, m), 8.78 (1H, d, J = 2.1 Hz), 11.68 (1H,
s) .
[0161]
Referential Example 7

To a mixed solution of 42 mL of toluene, 16
mL of ethanol and 7.8 mL of water containing 5.2 g of
methyl 4-bromo-2-nitrobenzoate, 2.9 g of
dihydroxyphenyl borane, 4.2 g of sodium hydrogen
carbonate and 1.1 g of tetrakis(triphenylphosphine)-
palladium (0) were added sequentially and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 2 hours. After the reaction mixture was cooled to
room temperature, 1.1 g of tetrakis(triphenyl-
phosphine) palladium (0) was added to the reaction
mixture and the resulting mixture was heated to reflux
under nitrogen atmosphere for 2 hours. After the
reaction mixture was cooled to room temperature, 1.1 g
of tetrakis(triphenylphosphine)palladium (0) was added
to the reaction mixture and the resulting mixture was
heated to reflux under nitrogen atmosphere for 2 hours.
After the reaction mixture was cooled to room

93
temperature, water was added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid and a
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [eluent; hexane:ethyl acetate =
20:1] to obtain 4.8 g of methyl 2-nitro-4-
phenylbenzoate as pale yellow oil.
1H-NMR (CDC13) 8: 3.94 (3H, s) , 7.44-7.53 (3H, m) , 7.60-
7.63 (2H, m), 7.85-7.86 (2H, m), 8.07 (1H, d, J = 1.4
Hz) .
[0162]
Referential Example 8

3.1 g of iron powder was added to a mixed
solution of 24 mL of methanol and 24 mL of acetic acid
containing 4.8 g of methyl 2-nitro-4-phenylbenzoate,
and the resulting mixture was heated to reflux for 2
hours. After the reaction mixture was cooled to room
temperature, insoluble were removed by filtration and a
saturated sodium hydrogen carbonate aqueous solution
and ethyl acetate added to the filtrate. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium

94
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Hexane was added
to the obtained residue and a solid substance was
separated by filtration to obtain 1.8 g of methyl 2-
amino-4-phenylbenzoate as white solid.
1H-NMR (CDC13) 5: 3.89 (3H, s), 5.79 (2H, s) , 6.87-6.91
(2H, m) , 7.35-7.45 (3H, m) , 7.57-7.61 (2H, m), 7.92 (1H,
d, J = 8.0 Hz).
[0163]
Referential Example 9

2.1 mL of benzoyl chloride was added to 70 mL
of a methylene chloride solution containing 3.5 g of 5-
iodo-2-methylaniline and 2.5 mL of triethylamine at
room temperature and stirred at the same temperature
for 30 minutes. 1.0 mol/L hydrochloric acid was added
to the reaction mixture. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium hydrogen carbonate
aqueous solution, and the solvent was evaporated under
reduced pressure. Diisopropyl ether and hexane were
added to the obtained residue and a solid substance was
separated by filtration to obtain 4.2 g of N-(5-iodo-2-
methylphenyl)benzamide as pale yellow solid.

95
XH-NMR (CDCI3) 8: 2.29 (3H, s) , 6.96 (1H, d, J = 8.0 Hz),
7.44 (1H, dd, J = 1.6, 8.0 Hz), 7.49-7.63 (4H, m) ,
7.86-7.88 (2H, m), 8.39 (1H, d, J = 1.6 Hz).
[0164]
Referential Example 10

2.4 g of potassium permanganate and 1.8 g of
anhydrous magnesium sulfate were added to a suspension
of 40 mL of tert-butyl alcohol and 80 mL of water
containing 4.2 g of N-(5-iodo-2-methylphenyl)benzamide
at room temperature, and the resulting mixture was
heated to reflux for 4 hours. After the reaction
mixture was cooled to room temperature, 2.0 g of
potassium permanganate and 1.5 g of anhydrous magnesium
sulfate were added and the resulting mixture was heated
to reflux for 2 hours. After the reaction mixture was
cooled to room temperature, 2.0 g of potassium
permanganate and 1.5 g of anhydrous magnesium sulfate
were added and the resulting mixture was heated to
reflux for 2 hours. After the reaction mixture was
cooled to room temperature, 20 mL of ethanol was added
and insoluble were removed by filtration. The solvent
was evaporated under reduced pressure and 1.0 mol/L
hydrochloric acid and ethyl acetate were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under

96
reduced pressure. Diisopropyl ether and hexane were
added to the obtained residue and a solid substance was
separated by filtration to obtain 3.3 g of 2-
(benzamido)-4-iodobenzoic acid as pale yellow solid.
XH-NMR (DMSO-de) 5: 7.58-7.69 (4H, m), 7.79 (1H, d, J =
8.3 Hz), 7.94-7.96 (2H, m), 9.17 (1H, d, J = 1.7 Hz),
12.17 (1H, s).
[0165]
Referential Example 11

0.62 g of potassium carbonate and 0.43 mL of
dimethyl sulfate were added to 15 mL of N,N-
dimethylformamide solution containing 1.5 g of 2-
(benzamido)-4-iodobenzoic acid at room temperature and
stirred at the same temperature for 1 hour. Ethyl
acetate and 1.0 mol/L hydrochloric acid were added to
the reaction mixture. The organic layer was separated
and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The
obtained residual was purified with silica gel column
chromatography [eluent; hexane:ethyl acetate =5:1] to
obtain 1.3 g of methyl 2-(benzamido)-4-iodobenzoate as
white solid.
XH-NMR (DMSO-d6) 8: 3.89 (3H, s), 7.59-7.69 (4H, m),
7.75 (1H, d, J = 8.3 Hz), 7.95-7.98 (2H, m) , 9.04 (1H,
d, J = 1.5 Hz), 11.61 (1H, s).


97
[0166]
Referential Example 12
To 48 mL of N,N-dimethylacetamide solution
containing 6.0 g of tert-butyl 4-bromo-2-nitrobenzoate,
2.7 mL of styrene, 2.5 g of sodium acetate, 3.2 g of
tetrabutylammonium bromide and 0.22 g of palladium
acetate (II) were added sequentially, and heated and
stirred under nitrogen atmosphere at 90°C for 3 hours.
After the reaction mixture was cooled to room
temperature, 0.45 mL of styrene and 0.22 g of palladium
acetate (II) were added and heated and stirred at 110°C
for 3 hours. After the reaction mixture was cooled to
room temperature, water and ethyl acetate were added.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with 10%
citric acid aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column
chromatography [eluent; hexane:ethyl acetate =20:1] to
obtain 3.8 g of tert-butyl 2-nitro-4-((E)-2-
phenylvinyl)benzoate as white solid.
1H-NMR (DMSO-d6) 8: 1.51 (9H, s), 7.32-7.45 (4H, m) ,
7.59 (1H, d, J = 16.6 Hz), 7.66 (2H, d, J = 7.4 Hz),

98
7.84 (1H, d, J = 8.1 Hz), 7.98 (1H, dd, J = 8.1, 1.5
Hz), 8.23 (1H, d, J = 1.5 Hz).
[0167]
Referential Example 13

0.74 g of 5% palladium-carbon was added to a
mixed solution of 56 mL of methanol and 56 mL of ethyl
acetate containing 3.7 g of tert-butyl 2-nitro-4- ( (E)-
2-phenylvinyl)benzoate and stirred under hydrogen
atmosphere at room temperature for 2 hours. Insoluble
were removed by filtration, and the solvent was
evaporated under reduced pressure to obtain 3.4 g of
tert-butyl 2-amino-4-phenethylbenzoate as white solid.
1H-NMR (CDC13) 6: 1.58 (9H, s) , 2.79-2.91 (4H, m) , 5.63
(2H, s), 6.44-6.49 (2H, m), 7.17-7.21 (3H, m), 7.26-
7.30 (2H, m), 7.72 (1H, d, J = 8.4 Hz) .
[0168]
Referential Example 14

19 mg of palladium acetate (II) was added to
5 mL of toluene solution containing 0.50 g of tert-
butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-
tolyl)phosphine, 0.44 mL of allylbenzene and 0.46 mL of

99
triethylamine, and the resulting mixture was heated to
reflux under nitrogen atmosphere for 2 hours. After the
reaction mixture was cooled to room temperature, 20 mg
of palladium acetate (II) was added and the resulting
mixture was heated to reflux for 7 hours. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration, and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column
chromatography [eluent; hexane:ethyl acetate = 30:1] to
obtain 0.31 g of tert-butyl 2-nitro-4-(3-phenyl-l-
propenyl)benzoate.
62 mg of 5% palladium-carbon was added to 3
mL of ethyl acetate solution containing 0.31 g of tert-
butyl 2-nitro-4-(3-phenyl-l-propenyl)benzoate at room
temperature and stirred under hydrogen atmosphere at
the same temperature for 5 hours and 30 minutes.
Insoluble were removed by filtration, and the solvent
was evaporated under reduced pressure to obtain 0.31 g
of tert-butyl 2-amino-4-(3-phenylpropyl)benzoate as
yellow oil.
1H-NMR (CDC13) 8: 1.57 (9H, s) , 1.88-1.97 (2H, m) , 2.55
(2H, t, J = 7.6 Hz), 2.63 (2H, t, J = 7.6 Hz), 5.64 (2H,
s), 6.44-6.48 (2H, m) , 7.16-7.21 (3H, m) , 7.26-7.30 (2H,
m) , 7.72 (1H, d, J = 8.0 Hz).
[0169]
Referential Example 15


19 mg of palladium acetate (II) was added to
5 mL of toluene solution containing 0.50 g of tert-
butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-
tolyl)phosphine, 0.50 mL of 4-phenyl-l-butene and 0.46
mL of triethylamine, and the resulting mixture was
heated to reflux under nitrogen atmosphere for 4 hours
and 30 minutes. After the reaction mixture was cooled
to room temperature, 20 mg of palladium acetate (II)
was added and the resulting mixture was heated to
reflux for 5 hours and 30 minutes. After cooled to room
temperature, the reaction mixture was purified with
silica gel column chromatography [eluent; hexane:ethyl
acetate = 30:1] to obtain 0.35 g of tert-butyl 2-nitro-
4-(4-phenyl-l-butenyl)benzoate.
70 mg of 5% palladium-carbon was added to 4
mL of ethyl acetate solution containing 0.35 g of 2-
nitro-4-(4-phenyl-l-butenyl)benzoate and stirred under
hydrogen atmosphere at room temperature for 8 hours.
Insoluble were removed by filtration, and the solvent
was evaporated under reduced pressure to obtain 0.40 g
of tert-butyl 2-amino-4-(4-phenylbutyl)benzoate as
yellow oil.
1H-NMR (CDC13) 8: 1.57 (9H, s), 1.61-1.67 (4H, m), 2.50-
2.54 (2H, m), 2.60-2.63 (2H, m), 5.63 (2H, s), 6.42-

101
6.47 (2H, m), 7.15-7.19 (3H, m), 7.25-7.29 (2H, m) ,
7.70 (1H, d, J = 8.0 Hz).
[0170]
Referential Example 16

0.54 g of tetrakis(triphenylphosphine)-
palladium (0) was added to 35 mL of toluene solution
containing 3.5 g of tert-butyl 2-(benzamido)-4-
bromobenzoate and 5.0 g of tributylvinyl tin, and the
resulting mixture was heated to reflux under nitrogen
atmosphere for 2 hours. After the reaction mixture was
cooled to room temperature, insoluble were removed by
filtration, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [eluent; hexane:
ethyl acetate = 20:1] to obtain 1.4 g of tert-butyl 2-
(benzamido)-4-vinylbenzoate as white solid.
1H-NMR (CDC13) 8: 1.63 (9H, s) , 5.42 (1H, d, J = 11.0
Hz), 5.95 (1H, d, J - 17.7 Hz), 6.77 (1H, dd, J = 17.7,
11.0 Hz), 7.15 (1H, dd, J = 8.2, 1.7 Hz), 7.50-7.60 (3H,
m), 7.97 (1H, d, J = 8.2 Hz), 8.05-8.10 (2H, m), 9.01
(1H, d, J = 1.7 Hz), 12.23 (1H, s) .
[0171]
Referential Example 17


0.67 mL of triethylamine and 0.34 mL of
benzoyl chloride was added to 5 mL of methylene
chloride solution containing 0.51 g of 3-amino-4-
methylbenzophenone while ice-cooled and stirred at room
temperature for 2 hours. The solvent of the reaction
mixture was evaporated under reduced pressure and ethyl
acetate and 1.0 mol/L hydrochloric acid were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
hydrogen carbonate aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. Hexane
and diisopropyl ether were added to the obtained
residue and a solid substance was separated by
filtration to obtain 0.71 g of N-(5-benzoyl-2-
methylphenyl)benzamide as white solid.
1H-NMR (CDC13) 8: 2.43 (3H, s) , 7.37 (1H, d, J = 7.8 Hz),
7.47-7.52 (4H, m) , 7.56-7.63 (3H, m), 7.74 (1H, s),
7.82-7.86 (2H, m), 7.87-7.91 (2H, m), 8.29 (1H, s).
[0172]
Referential Example 18


103
2.7 mL of (trimethylsilyl)acetylene was added
to 30 mL of toluene suspension containing 3.2 g of
methyl 2-(benzamido)-4-bromobenzoate, 92 mg of copper
(I) iodide, 0.34 g of bis(triphenylphosphine)palladium
(II) chloride and 2.7 mL of triethylamine at room
temperature and stirred under nitrogen atmosphere at 70
to 80°C for 2 hours. After the reaction mixture was
cooled to room temperature, ethyl acetate and 1.0 mol/L
hydrochloric acid were added and insoluble were removed
by filtration. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with 1.0 mol/L hydrochloric acid and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 3.5 g of methyl 2-(benzamido)-4-(2-
(trimethylsilyl)ethynyl)benzoate as pale yellow solid.
0.68 g of potassium carbonate was added to a
solution of 17 mL of methanol and 17 mL of
tetrahydrofuran containing 3.5 g of methyl 2-
(benzamido)-4-(2-(trimethylsilyl)ethynyl)benzoate and
stirred at room temperature for 1 hour. The solvent was
evaporated under reduced pressure and ethyl acetate and
1.0 mol/L hydrochloric acid were added and insoluble
were removed by filtration. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid, and the
solvent was evaporated under reduced pressure. The

104
obtained residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate =8:1] to
obtain 1.6 g of methyl 2-(benzamido)-4-ethynylbenzoate
as white solid.
1H-NMR (CDC13) 8: 3.25 (1H, s) , 3.97 (3H, s), 7.22 (1H,
dd, J= 8.3, 1.5 Hz), 7.51-7.58 (3H, m) , 8.02-8.06 (3H,
m) , 9.12 (1H, d, J = 1.5 Hz), 12.02 (1H, s) .
[0173]
Referential Example 19

4.2 g of iron powder was added to a solution
of 57 mL of methanol and 17 mL of acetic acid
containing 5.7 g of l-methyl-2-nitro-4-phenoxybenzene,
and the resulting mixture was heated to reflux for 5
hours. After the reaction mixture was cooled to room
temperature, ethyl acetate and a saturated sodium
hydrogen carbonate aqueous solution were added and
insoluble were removed by filtration. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. The obtained
residue was dissolved in 60 mL of diethyl ether and 2.1
mL of hydrochloric acid was added while ice-cooled.
Solid substance was separated by filtration to obtain

105
4.7 g of 2-methyl-5-phenoxyaniline hydrochloride as
white solid.
XH-NMR (DMSO-de) 5: 2.27 (3H, s), 6.82 (1H, dd, J = 8.3,
2.4 Hz), 6.96 (1H, d, J = 2.4 Hz), 7.03 (2H, d, J = 7.5
Hz), 7.17 (1H, t, J = 7.5 Hz), 7.26 (1H, d, J = 8.3 Hz),
7.39-7.43 (2H, m).
[0174]
Referential Example 20

To a solution of 5 mL of N,N-
dimethylformamide containing 0.50 g of 2-methyl-5-
phenoxyaniline hydrochloride, 0.91 mL of triethylamine
and 0.27 mL of benzoyl chloride were added sequentially
while ice-cooled sequentially and stirred at room
temperature for 3 hours. Ethyl acetate and 1.0 mol/L
hydrochloric acid were added to the reaction mixture.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with 1.0 mol/L
hydrochloric acid, a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 0.42 g of N-(2-methyl-5-phenoxyphenyl)benzamide
as white solid.

106
1H-NMR (CDCI3) 8: 2.31 (3H, s) , 6.78 (1H, dd, J = 8.3,
2.4 Hz), 7.03 (2H, d, J = 7.8 Hz), 7.08 (1H, t, J = 7.5
Hz), 7.17 (1H, d, J = 8.3 Hz), 7.30-7.34 (2H, m), 7.47-
7.51 (2H, m) , 7.54-7.58 (1H, m) , 7.67 (1H, s) , 7.78 (1H,
s), 7.86 (2H, d, J = 7.1 Hz).
[0175]
Referential Example 21

9.9 g of potassium carbonate, 0.82 g of
benzyltriethyl-ammonium chloride and 21 mL of 2-bromo-
2-methylpropane were added to 14 mL of N,N-
dimethylacetamide solution containing 0.93 g of 2-
nitro-4-phenoxybenzoic acid at room temperature and
stirred at 55°C for 18 hours. After the reaction
mixture was cooled to room temperature, water and ethyl
acetate were added. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with a saturated sodium hydrogen carbonate aqueous
solution, 10% citric acid aqueous solution and a
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure
to obtain 0.86 g of tert-butyl 2-nitro-4-
phenoxybenzoate as white solid.
1H-NMR (DMSO-de) 8: 1.48 (9H, s), 7.18-7.23 (2H, m),
7.26-7.32 (2H, m), 7.47-7.53 (2H, m), 7.54 (1H, d, J =
2.4 Hz), 7.85 (1H, d, J = 8.5 Hz).

107
[0176]
Referential Example 22

0.17 g of 5% palladium-carbon was added to a
mixed solution of 8 mL of methanol and 8 mL of ethyl
acetate containing 0.82 g of tert-butyl 2-nitro-4-
phenoxybenzoate and stirred under hydrogen atmosphere
at room temperature for 4 hours and 30 minutes.
Insoluble were removed by filtration and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate = 10:1]
to obtain 0.63 g of tert-butyl 2-amino-4-
phenoxybenzoate as colorless oil.
1H-NMR (CDC13) 8: 1.57 (9H, s) , 6.16 (1H, d, J = 2.3 Hz),
6.27 (1H, dd, J = 9.0, 2.3 Hz), 7.04-7.06 (2H, m),
7.14-7.18 (1H, m) , 7.34-7.38 (2H, m), 7.78 (1H, d, J =
9.0 Hz).
[0177]
Referential Example 23

3.1 mL of triethylamine and 1.3 mL of benzoyl
chloride were added to 19 mL of methylene chloride
solution containing 1.9 g of methyl 2-amino-4-

108
methoxybenzoate while ice-cooled sequentially and
stirred at room temperature for 3 hours. The solvent
was evaporated under reduced pressure and chloroform
and 1.0 mol/L hydrochloric acid were added to the
obtained residue. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with a saturated sodium hydrogen carbonate aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. Hexane and diisopropyl ether
were added to the obtained residue and a solid
substance was separated by filtration to obtain 2.6 g
of methyl 2-(benzamido)-4-methoxybenzoate as white
solid.
1H-NMR (CDC13) 5: 3.92 (3H, s) , 3.93 (3H, s) , 6.65 (1H,
dd, J = 9.0, 2.7 Hz), 7.51-7.59 (3H, m), 8.00 (1H, d, H
= 9.0 Hz), 8.05-8.07 (2H, m), 8.63 (1H, d, J = 2.7 Hz).
[0178]
Referential Example 24

0.94 g of aluminum chloride was added to 7 mL
of toluene solution containing 0.67 g of methyl 2-
(benzamido)-4-methoxybenzoate at room temperature and
stirred at 80°C for 2 hours and 30 minutes. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 1.0 mol/L hydrochloric acid were added and

109
a solid substance was separated by filtration to obtain
0.23 g of methyl 2-(benzamido)-4-hydroxybenzoate as
white solid.
1H-NMR (CDC13) 8: 3.93 (3H, s) , 6.68 (1H, dd, J = 8.9,
2.5 Hz), 7.54-7.62 (3H, m) , 8.02-8.05 (3H, m), 8.84 (1H,
d, J = 2.5 Hz), 9.30-9.40 (1H, broad), 12.46 (1H, s).
[0179]
Referential Example 25

0.50 g of potassium carbonate and 0.50 g of
methyl 4-(bromomethyl)-2-nitrobenzoate were added to 5
mL of N,N-dimethylformamide solution containing 0.18 g
of phenol at room temperature and stirred at the same
temperature for 10 hours. Ethyl acetate and 1.0 mol/L
hydrochloric acid were added to the reaction mixture.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate = 6:1] to
obtain 0.53 g of methyl 2-nitro-4-
(phenoxymethyl)benzoate as colorless oil.
1H-NMR (CDCI3) 8: 3.93 (3H, s), 5.17 (2H, s), 6.95-7.03
(3H, m) , 7.30-7.34 (2H, m), 7.72-7.79 (2H, m), 7.95-
8.00 (1H, m).


110
[0180]
Referential Example 26
1.01 g of potassium carbonate and 0.39 mL of
thiophenol were added to 10 mL of N,N-dimethylformamide
solution containing 1.00 g of methyl 4-(bromomethyl)-2-
nitrobenzoate at room temperature and stirred at the
same temperature for 7 hours. Ethyl acetate was added
to the reaction mixture and insoluble were removed by
filtration and water was added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium hydrogen carbonate
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[eluent; hexane: ethyl acetate = 4:1] to obtain 0.70 g
of methyl 2-nitro-4-((phenylthio)methyl)benzoate as
pale yellow oil.
1H-NMR (CDC13) 8: 3.86 (3H, s) , 4.27 (2H, s) , 6.60-6.74
(5H, m), 7.15-7.19 (2H, m) , 7.82 (1H, d, J = 8.3 Hz).
[0181]
Referential Example 27

1ll

0.39 g of iron powder was added to a mixed
solution of 7 mL of methanol and 2.1 mL of acetic acid
containing 0.70 g of methyl 2-nitro-4-
((phenylthio)methyl)benzoate, and the resulting mixture
was heated to reflux for 3 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and a saturated sodium hydrogen carbonate aqueous
solution were added and insoluble were removed by
filtration. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with a
saturated sodium hydrogen carbonate aqueous solution
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. The obtained residue was dissolved in
10 mL of diethyl ether and 1.2 mL of 1.9 mol/L hydrogen
chloride / ethyl acetate were added while ice-cooled
and a solid substance was separated by filtration to
obtain 0.39 g of methyl 2-amino-4-
((phenylthio)methyl)benzoate hydrochloride as white
solid.
1H-NMR (DMSO-de) 8: 3.76 (3H, s) , 4.13 (2H, s) , 4.30-
4.70 (2H, broad), 6.55 (1H, dd, J = 8.2, 1.7 Hz), 6.79
(1H, d, 1.7 Hz), 7.15-7.19 (1H, m), 7.26-7.33 (4H, m) ,
7.62 (1H, d, J = 8.2 Hz).


112
[0182]
Referential Example 28
The following compound was obtained in the
same manner as in Referential Example 2.
tert-Butyl 4-chloro-2-nitrobenzoate
1H-NMR (CDC13) 8: 1.55 (9H, s) , 7.59-7.62 (1H, m) , 7.70-
7.73 (1H, m), 7.79 (1H, d, J = 2.0 Hz).
[0183]
Referential Example 29

The following compound was obtained in the
same manner as in Referential Example 2.
tert-Butyl 2-(benzamido)-4-iodobenzoate
1H-NMR (CDCI3) 8: 1.62 (9H, a), 7.45 (1H, dd, J= 8.5,
1.7 Hz), 7.51-7.60 (3H, m), 7.68 (1H, d, J = 8.5 Hz),
8.02-8.07 (2H, m), 9.38 (1H, d, J = 1.7 Hz), 12.13-
12.20 (1H, broad).
[0184]
Referential Example 30

113

To 20 mL of toluene solution containing 2.0 g
of tert-butyl 4-bromo-2-nitrobenzoate, 6.0 mL of
ethanol, 3.0 mL of water, 1.2 g of 3-
chlorophenylboronic acid, 1.7 g of sodium carbonate and
0.23 g of tetrakis(triphenylphosphine)palladium (0)
were added sequentially, and the resulting mixture was
heated to reflux under nitrogen atmosphere for 3 hours.
Water was added after the reaction mixture was cooled
to room temperature. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with a saturated sodium chloride aqueous solution, and
the solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [PSQ100B (spherical) manufactured by
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate = 10:1] to obtain 0.70 g of tert-butyl 4-(3-
chlorophenyl)-2-nitrobenzoate as white solid.
1H-NMR (DMSO-de) 8: 1.52 (9H, s) , 7.53-7.59 (2H, m) ,
7.77-7.82 (1H, m), 7.89-7.95 (2H, m), 8.15 (1H, dd, J=
8.1, 1.6 Hz), 8.34 (1H, d, J = 1.6 Hz).
[0185]
Referential Example 31

114

The following compound was obtained in the
same manner as in Referential Example 30.
tert-Butyl 4- (4-(tert-butoxycarbonyl)oxyphenyl)-2-
nitrobenzoate
1H-NMR (DMSO-d6) 5: 1.51 (9H, s) , 1.52 (9H, s) , 7.36 (2H,
d, J = 8.8 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.91 (1H, d,
J = 8.1 Hz), 8.11 (1H, dd, J = 8.1, 1.8 Hz), 8.29 (1H,
d, J = 1.8 Hz).
[0186]
Referential Example 32

To 15 mL of toluene solution containing 1.5 g
of tert-butyl 4-chloro-2-nitrobenzoate, 1.1 g of 2,4-
difluorophenylboronic acid, 2.8 g of cesium carbonate,
27 mg of palladium acetate and 25 mg of 2-
dicyclohexylphosphino-2',6'-dimethoxybiphenyl were
added sequentially, and the resulting mixture was
heated to reflux under nitrogen atmosphere for 8 hours.
After the reaction mixture was cooled to room
temperature, insoluble were removed by filtration and

115
added a saturated sodium hydrogen carbonate aqueous
solution. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with 10%
citric acid aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 0.95 g of tert-butyl 4-(2,4-difluorophenyl)-2-
nitrobenzoate as white solid.
1H-NMR (DMSO-d6) 8: 1.52 (9H, s), 7.26-7.31 (1H, m) ,
7.44-7.51 (1H, m) , 7.72-7.79 (1H, m) , 7.93 (1H, d, J =
7.9 Hz), 7.98 (1H, d, J = 7.9 Hz), 8.17 (1H, s).
[0187]
Referential Example 33

The following compound was obtained in the
same manner as in Referential Example 32.
tert-Butyl 4-(benzo[1,3]dioxol-5-yl)-2-nitrobenzoate
1H-NMR (DMSO-d6) 5: 1.51 (9H, s) , 6.11 (2H, s) , 7.06 (1H,
d, J = 8.1 Hz), 7.34 (1H, dd, J = 8.1, 1.9 Hz), 7.45
(1H, d, J = 1.9 Hz), 7.85 (1H, d, J = 8.1 Hz), 8.04 (1H,
dd, J = 8.1, 1.9 Hz), 8.20 (1H, d, J = 1.9 Hz).
[0188]
Referential Example 34


116
The following compound was obtained in the
same manner as in Referential Example 30.
tert-Butyl 4-(benzofuran-2-yl)-2-nitrobenzoate
1H-NMR (DMSO-d6) 5: 1.53 (9H, s) , 7.30-7.36 (1H, m) ,
7.40-7.45 (1H, m), 7.68-7.76 (1H, m), 7.75 (1H, d, J =
7.3 Hz), 7.82 (1H, d, J = 0.7 Hz), 7.96 (1H, d, J = 8.1
Hz), 8.29 (1H, dd, J = 8.1, 1.6 Hz), 8.49 (1H, d, J =
1.6 Hz).
[0189]
Referential Example 35

0.33 g of 10% palladium-carbon was added to a
mixed solution of 11 mL of methanol and 11 mL of ethyl
acetate containing 1.1 g of tert-butyl 4-(3-
chlorophenyl)-2-nitrobenzoate and stirred under
hydrogen atmosphere at room temperature for 3 hours.
After insoluble were removed by filtration, the solvent
was evaporated under reduced pressure. 11 mL of acetic
acid, 11 mL of methanol and 0.33 g of 10% palladium-
carbon were added to the obtained residue sequentially
and stirred under hydrogen atmosphere at room
temperature for 2 hours. After insoluble were removed

117
by filtration, the solvent was evaporated under reduced
pressure to obtain 0.70 g of tert-butyl 2-amino-4-(3-
chlorophenyl)benzoate as white solid.
1H-NMR (DMSO-de) 5: 1.55 (9H, s), 6.63-6.69 (2H, broad),
6.83 (1H, dd, J = 8.5, 1.9 Hz), 7.06 (1H, d, J = 1.9
Hz), 7.46 (1H, dt, J = 7.8, 1.6 Hz), 7.50 (1H, t, J =
7.8 Hz), 7.57 (1H, dt, J = 7.8, 1.6 Hz), 7.63 (1H, t, J
= 1.6 Hz), 7.73 (1H, d, J = 8.5 Hz).
[0190]
Referential Example 36

The following compound was obtained in the
same manner as in Referential Example 35.
tert-Butyl 2-amino-4-(4-((tert-
butoxycarbonyl)oxy)phenyl)benzoate
1H-NMR (DMSO-de) 8: 1.51 (9H, s), 1.55 (9H, s) , 6.66-
6.70 (2H, broad), 6.80 (1H, dd, J = 8.5, 1.8 Hz), 7.02
(1H, d, J = 1.8 Hz), 7.27-7.32 (2H, m) , 7.61-7.65 (2H,
m), 7.73 (1H, d, J = 8.5 Hz).
[0191]
Referential Example 37


118
0.27 g of 10% palladium-carbon was added to a
mixed solution of 9.0 mL of methanol and 9.0 mL of
ethyl acetate containing 0.90 g of tert-butyl 4-(2,4-
difluorophenyl)-2-nitrobenzoate and stirred under
hydrogen atmosphere at room temperature for 30 minutes.
After insoluble were removed by filtration, the solvent
was evaporated under reduced pressure to obtain 0.80 g
of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate as
white solid.
1H-NMR (DMSO-de) 8: 1.55 (9H, s) , 6.65 (1H, d, J = 8.3
Hz), 6.66-6.73 (2H, broad), 6.91 (1H, s), 7.17-7.22 (1H,
m), 7.33-7.39 (1H, m), 7.50-7.56 (1H, m), 7.72 (1H, d,
J = 8.3 Hz).
[0192]
Referential Example 38

0.42 g of 10% palladium-carbon was added to a
mixed solution of 14 mL of methanol and 14 mL of ethyl
acetate containing 1.4 g of tert-butyl 4-
(benzo[l,3]dioxol-5-yl)-2-nitrobenzoate and stirred
under hydrogen atmosphere at room temperature for 2
hours. After insoluble were removed by filtration, the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [PSQ100B (spherical) manufactured by

119
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate = 20:1] to obtain 0.52 g of tert-butyl 2-amino-
4-(benzo[l,3]dioxol-5-yl)benzoate as pale red solid.
1H-NMR (DMSO-d6) 8: 1.54 (9H, s) , 6.07 (2H, s), 6.57-
6.65 (2H, broad), 6.75 (1H, d, J = 8.5 Hz), 6.96 (1H,
s), 7.00 (1H, d, J = 8.6 Hz), 7.10 (1H, d, J = 8.6 Hz),
7.15 (1H, s), 7.68 (1H, d, J = 8.5 Hz).
[0193]
Referential Example 39

0.69 g of iron powder was added to a
suspension of 7.0 mL of methanol and 7.0 mL of acetic
acid containing 1.4 g of tert-butyl 4-(benzofuran-2-
yl)-2-nitrobenzoate and the resulting mixture was
heated to reflux for 2 hours. After the reaction
mixture was cooled to room temperature, the solvent was
evaporated under reduced pressure. A saturated sodium
hydrogen carbonate aqueous solution and ethyl acetate
were added to the obtained residue and insoluble were
removed by filtration. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with a saturated sodium hydrogen carbonate aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. Hexane was added to the

120
obtained residue and a solid substance was separated by
filtration to obtain 0.88 g of tert-butyl 2-amino-4-
(benzofuran-2-yl)benzoate as white solid.
1H-NMR (DMSO-d6) 5: 1.56 (9H, s), 6.76-6.84 (2H, broad),
7.07 (1H, dd, J = 8.5, 1.6 Hz), 7.26-7.39 (3H, m) , 7.43
(1H, s), 7.64 (1H, d, J = 8.1 Hz), 7.69 (1H, d, J = 8.1
Hz), 7.75 (1H, d, J = 8.5 Hz).
[0194]
Referential Example 40

To 5 mL of N,N-dimethylacetamide solution
containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate,
0.37 mL of 3-vinylanisole, 0.47 mL of triethylamine and
0.11 g of palladium acetate were added at room
temperature and stirred under nitrogen atmosphere at
110°C for 4 hours. Ethyl acetate and water were added
after the reaction mixture was cooled to room
temperature. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with 10%
citric acid aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column
chromatography [PSQ100B (spherical) manufactured by
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate = 10:1] to obtain 0.20 g of tert-butyl 4-((E)-

121
2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate a pale yellow
solid.
1H-NMR (DMSO-de) 5: 1.51 (9H, s), 3.81 (3H, s) , 6.90-
6.94 (1H, m) , 7.20-7.27 (2H, m), 7.34 (1H, t, J = 7.9
Hz), 7.43 (1H, d, J = 16.6 Hz), 7.55 (1H, d, J = 16.6
Hz), 7.84 (1H, d, J = 8.0 Hz), 7.97 (1H, d, J = 7.8 Hz),
8.21 (1H, s).
[0195]
Referential Example 41

0.70 g of iron powder was added to a
suspension of 7.5 inL of methanol and 7.5 mL of acetic
acid containing 1.5 g of tert-butyl 4-((E)-2-(3-
methoxyphenyl)vinyl)-2-nitrobenzoate, and the resulting
mixture was heated to reflux for 2 hours. After the
reaction mixture was cooled to room temperature, the
solvent was evaporated under reduced pressure. A
saturated sodium hydrogen carbonate aqueous solution
and ethyl acetate were added to the obtained residue
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium hydrogen
carbonate aqueous solution and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column

122
chromatography [PSQ100B (spherical) manufactured by-
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate =4:1] to obtain 0.44 g of tert-butyl 2-amino-
4-((E)-2-(3-methoxyphenyl)vinyl)benzoate as white solid.
1H-NMR (DMSO-d6) 8: 1.54 (9H, s) , 3.80 (3H, s) , 6.57-
6.65 (2H, broad), 6.80-6.92 (3H, m), 7.15-7.23 (4H, m) ,
7.29 (1H, t, J = 8.1 Hz), 7.64 (1H, d, J = 8.3 Hz).
[0196]
Referential Example 42

To 40 mL of dioxane solution containing 4.0 g
of tert-butyl 2-(benzamido)-4-bromobenzoate, 3.1 g of
potassium acetate, 5.9 g of bis(pinacolato)diboron and
0.43 g of (1,1'-bis(diphenylphosphino)ferrocene)-
palladium (II) dichloride - methylene chloride complex
were added at room temperature sequentially, and the
resulting mixture was heated to reflux for 3 hours.
After the reaction mixture was cooled to room
temperature, insoluble were removed by filtration, and
the solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [PSQ100B (spherical) manufactured by
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate =4:1] to obtain 3.6 g of tert-butyl 2-

123
(benzamido)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
2-yl)benzoate as white solid.
1H-NMR (DMSO-de) 8: 1.33 (12H, s) , 1.54 (9H, s) , 7.50
(1H, dd, J = 7.8, 1.0 Hz), 7.58-7.68 (3H, m) , 7.92 (1H,
d, J = 7.8 Hz), 7.96-8.00 (2H, m), 8.72 (1H, d, J = 1.0
Hz), 11.43 (1H, s).
[0197]
Referential Example 43

2.0 mL of 2.0 mol/L aqueous sodium hydroxide
was added to a mixed solution of 4.0 mL of methanol and
4.0 mL of tetrahydrofuran containing 0.47 g of methyl
2-(lH-pyrrol-1-yl)pyridine-4-carboxylate and stirred at
room temperature for 1 hour. 5.0 mL of 1.0 mol/L
hydrochloric acid and ethyl acetate were added to the
reaction mixture sequentially. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium chloride aqueous
solution, and the solvent was evaporated under reduced
pressure. Diisopropyl ether was added to the obtained
residue and a solid substance was removed by filtration
to obtain 0.39 g of 2-(lH-pyrrol-l-yl)pyridine-4-
carboxylic acid as white solid.
1H-NMR (DMSO-de) 8: 6.32 (2H, t, J = 2.3 Hz), 7.64 (1H,
dd, J = 5.1, 1.3 Hz), 7.76 (2H, t, J = 2.3 Hz), 8.02

124
(1H, t, J = 0.9 Hz), 8.60 (1H, dd, J = 5.1, 0.9 Hz),
13.70-13.95 (1H, broad).
[0198]
Example 1

0.56 g of 2-(tributyltin)thiazole and 0.090 g
of tetrakis(triphenylphosphine)palladium(0) were added
to 5 mL of toluene solution containing 0.50 g of methyl
2-(benzamido)-4-bromobenzoate, and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 6 hours. After the reaction mixture was cooled to
room temperature, the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [eluent; hexane:
ethyl acetate =3:1] to obtain 0.25 g of methyl 2-
(benzamido)-4-(thiazol-2-yl)benzoate as white solid.
1H-NMR (DMSO-d6) 8: 3.93 (3H, s), 7.61-7.70 (3H, m) ,
7.82 (1H, dd, J = 8.5, 1.8 Hz), 7.95 (1H, d, J = 3.2
Hz), 7.99-8.01 (2H, m), 8.05 (1H, d, J = 3.2 Hz), 8.13
(1H, d, J = 8.5 Hz), 9.29 (1H, d, J = 1.8 Hz), 11.73
(1H, s).
[0199]


125
0.35 mL of 10% aqueous sodium hydroxide was
added to 5 mL of ethanol suspension containing 0.25 g
of methyl 2-(benzamido)-4-(thiazol-2-yl)benzoate at
room temperature, and the resulting mixture was heated
to reflux for 2 hours. After the reaction mixture was
cooled to room temperature, 1.0 mol/L hydrochloric acid
and ethyl acetate were added. The organic layer was
separated and dried over anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure.
Hexane and diisopropyl ether were added to the obtained
residue and a solid substance was separated by
filtration to obtain 0.23 g of 2-(benzamido)-4-
(thiazol-2-yl)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 7.61-7.70 (3H, m) , 7.80 (1H, dd, J =
8.3, 1.7 Hz), 7.94 (1H, d, J = 3.2 Hz), 7.98-8.00 (2H,
m), 8.05 (1H, d, J = 3.2 Hz), 8.17 (1H, d, J = 8.3 Hz),
9.43 (1H, d, J = 1.7 Hz), 12.28 (1H, s) .
[0200]
Example 3

0.28 mL of benzoyl chloride was added to 10
mL of methylene chloride solution containing 0.50 g of
methyl 2-amino-4-phenylbenzoate and 0.36 mL of
triethylamine and stirred at room temperature overnight.
The solvent was evaporated under reduced pressure and
water and ethyl acetate were added. The organic layer

126
was separated and dried over anhydrous magnesium
sulfate after washed with 1.0 mol/L hydrochloric acid
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. Hexane and diisopropyl ether were
added to the obtained residue and a solid substance was
separated by filtration to obtain 0.52 g of methyl 2-
(benzamido)-4-phenylbenzoate as white solid.
1H-NMR (CDC13) 5: 3.99 (3H, s) , 7.37-7.60 (7H, m) , 7.73-
7.75 (2H, m), 8.07-8.10 (2H, m), 8.15 (1H, d, J = 8.3
Hz), 9.29 (1H, d, J = 1.7 Hz), 12.13 (1H, s) .
[0201]
Example 4

1.2 mL of 2.0 mol/L aqueous sodium hydroxide
was added to a suspension of 5 mL of methanol and 2.5
mL of dioxane containing 0.50 g of methyl 2-
(benzamido)-4-phenylbenzoate at room temperature and
stirred at 50°C for 30 minutes. After the reaction
mixture was cooled to room temperature, 1.0 mol/L
hydrochloric acid was added to adjust to pH 3 and water
and ethyl acetate were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium chloride aqueous
solution, and the solvent was evaporated under reduced
pressure. Hexane was added to the obtained residue and

127
a solid substance was separated by filtration to obtain
0.36 g of 2-(benzamido)-4-phenylbenzoic acid as white
solid.
1H-NMR (DMSO-d6) 5: 7.45-7.69 (7H, m) , 7.73-7.75 (2H, m) ,
7.98-8.00 (2H, m), 8.15 (1H, d, J = 8.1 Hz), 9.09 (1H,
d, J = 2.0 Hz), 12.29 (1H, s), 13.70-14.00 (1H, broad).
[0202]
Example 5

55 mg of pyridine-3-boronic acid, 88 mg of
sodium hydrogen carbonate and 17 mg of
tetrakis(triphenylphosphine)palladium(O) were added to
a mixed solution of 2.0 mL of toluene, 0.5 mL of
ethanol and 0.2 mL of water containing 100 mg of methyl
2-(benzamido)-4-bromobenzoate, and heated to reflux
with stirring for 2 hours. After the reaction mixture
was cooled to room temperature, 17 mg of
tetrakis(triphenylphosphine)palladium(O) was added and
heated to reflux with stirring for 2 hours. After the
reaction mixture was cooled to room temperature,
toluene and water were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium hydrogen carbonate
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 3.0 mL of ethanol

128
and 0.5 mL of 2.0 mol/L aqueous sodium hydroxide
solution were added to the obtained residue and stirred
at room temperature for 2 hours. The reaction mixture
was purified with reversed-phase silica gel column
chromatography [eluent; 30-100% acetonitrile/0.1%
trifluoroacetic acid aqueous solution] to obtain 25 mg
of 2-(benzamido)-4-(pyridin-3-yl)benzoic acid
trifluoroacetate as white solid.
1H-NMR (DMSO-de) 6: 7.45-7.49 (2H, m) , 7.56 (1H, t, J =
7.0 Hz), 7.63-7.69 (2H, m), 7.77 (2H, d, J = 7.1 Hz),
7.97 (1H, dd, J = 8.1 Hz, J = 1.2 Hz), 8.09 (1H, s),
8.17 (1H, d, J = 7.6 Hz), 8.65 (1H, d, J = 5.1 Hz),
8.83 (1H, s), 10.25 (1H, s).
[0203]
Example 6

56 mg of 4-(acetamido)phenylboronic acid, 55
mg of sodium carbonate and 30 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 11 hours. After the reaction
mixture was cooled to room temperature, 19 mg of 4-
(acetamido)phenylboronic acid was added and the mixture
was stirred at 90°C for 12 hours. After the reaction

129
mixture was cooled to room temperature, 11 mg of sodium
carbonate and 30 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
and stirred at 90°C for 14 hours. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration and ethyl acetate and 1.2 mol/L
hydrochloric acid were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid, a
saturated sodium hydrogen carbonate aqueous solution
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. 1 mL of 1.0 mol/L aqueous sodium
hydroxide and 2 mL of ethanol were added to the
obtained residue and stirred at room temperature for 1
hour. 0.6 mol/L hydrochloric acid was added, and solid
substances were separated by filtration and purified
with reversed-phase silica gel column chromatography
[eluent; 40-100% acetonitrile /0.1% trifluoroacetic
acid aqueous solution] to obtain 5.9 mg of 4-(4-
(acetamido)phenyl)-2-(benzamido)benzoic acid as white
solid.
1H-NMR (DMSO-de) 5: 2.08 (3H, s) , 7.49-7.52 (1H, m) ,
7.60-7.76 (7H, m), 7.99 (2H, d, J = 7.6 Hz), 8.11 (1H,
d, J = 8.1 Hz), 9.06 (1H, d, J = 1.7 Hz), 10.14 (1H, s) .
[0204]
Example 7


The following compound was obtained in the
same manner as in Example 6.
2-(Benzamido)-4-(thiophen-2-yl)benzoic acid
1H-NMR (DMSO-de) 8: 7.22 (1H, t, J = 4.5 Hz), 7.54-7.67
(5H, m), 7.71 (1H, d, J = 4.5 Hz), 7.99 (2H, d, J = 6.8
Hz), 8.08 (1H, d, J = 8.6 Hz), 9.11 (1H, s).
[0205]
Example 8

51 mg of benzofuran-2-boronic acid, 55 mg of
sodium carbonate and 30 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 22 hours. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration and ethyl acetate and 1.2 mol/L
hydrochloric acid were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid and a
saturated sodium chloride aqueous solution sequentially,

131
and the solvent was evaporated under reduced pressure.
1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 2.0 mL
of ethanol were added to the obtained residue and
stirred at room temperature for 1 hour. 0.6 mol/L
hydrochloric acid was added to the reaction mixture and
a solid substance was separated by filtration to obtain
11 mg of 2-(benzamido)-4-(benzofuran-2-yl)benzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 7.32 (1H, td, J = 7.3, 0.7 Hz), 7.40
(1H, td, J - 7.7, 1.1 Hz), 7.62-7.79 (7H, m), 8.01-8.03
(2H, m), 8.16 (1H, d, J = 8.6 Hz), 9.33 (1H, s).
[0206]
Example 9

36 mg of 3-methoxyphenylboronic acid, 55 mg
of sodium carbonate and 30 mg polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 11 hours. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration and ethyl acetate and 1.2 mol/L
hydrochloric acid were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid, a
saturated sodium hydrogen carbonate aqueous solution

132
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium
hydroxide and 2.0 mL of ethanol were added to the
obtained residue and stirred at room temperature for 1
hour. 0.6 mol/L hydrochloric acid was added to the
reaction mixture and a solid substance was separated by
filtration to obtain 18 mg of 2-(benzamido)-4-(3-
methoxyphenyl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 3.85 (3H, s) , 7.05 (1H, dd, J = 8.2,
2.6 Hz), 7.24 (1H, s), 7.30 (1H, d, J = 8.1 Hz), 7.47
(1H, t, J = 7.9 Hz), 7.53 (1H, dd, J = 8.3, 1.5 Hz),
7.60-7.69 (3H, m), 7.99 (2H, d, J = 7.1 Hz), 8.13 (1H,
d, J = 8.3 Hz), 9.06 (1H, s), 12.30 (1H, s).
[0207]
Example 10

The following compound was obtained in the
same manner as in Example 9.
2-(Benzamido)-4-(4-carboxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.57-7.69 (4H, m), 7.87 (2H, d, J =
8.0 Hz), 7.99-8.01 (2H, m), 8.10 (2H, d, J = 8.3 Hz),
8.17 (1H, d, J = 8.6 Hz), 9.13 (1H, s).
[0208]
Example 11


52 mg of 3,4-methylenedioxyphenylboronic acid,
55 mg of sodium carbonate and 30 mg of polymer
supported bis(acetato)triphenylphosphine palladium(II)
were added to 2.5 mL of N,N-dimethylacetamide solution
containing 70 mg of methyl 2-(benzamido)-4-
bromobenzoate, and stirred at 90°C for 22 hours. After
the reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 1.2 mol/L hydrochloric acid were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with 1.0 mol/L hydrochloric acid
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. 1.0 mL of 1.0 mol/L aqueous sodium
hydroxide and 2.0 mL of ethanol were added to the
obtained residue and stirred at room temperature for 1
hour. 0.6 mol/L hydrochloric acid was added to the
reaction mixture and a solid substance was separated by
filtration to obtain 43 mg of 2-(benzamido)-4-
(benzo[l,3]dioxol-5-yl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 6.11 (2H, s), 7.08 (1H, d, J = 8.1
Hz), 7.24 (1H, dd, J = 8.2, 1.8 Hz), 7.30 (1H, d, J =
1.7 Hz), 7.45-7.47 (1H, m) , 7.59-7.69 (3H, m), 7.98-
8.00 (2H, m), 8.09 (1H, d, J = 8.1 Hz), 9.01 (1H, s).

134
[0209]
Examples 12, 13
The compounds shown in Table 8 were obtained
in the same manner as in Example 11.
[0210]

[Table 8]

[0211]
2-(Benzamido)-4-(lH-indol-5-yl)benzoic acid
1H-NMR (DMSO-de) 8: 6.56 (1H, s), 7.43 (1H, t, J= 2.7
Hz), 7.47-7.69 (6H, m), 7.94 (1H, s) , 8.01 (2H, d, J =
7.1 Hz), 8.12 (1H, d, J = 8.3 Hz), 9.14 (1H, d, J = 1.5
Hz), 11.26 (1H, s).
[0212]
2-(Benzamido)-4-(4-(methanesulfonyl)phenyl)benzoic acid
Hl-NMR (DMSO-de) 8: 3.33 (3H, s) , 7.57-7.70 (4H, m) ,
7.99-8.01 (4H, m), 8.09 (2H, d, J = 8.6 Hz), 8.19 (1H,
d, J = 8.3 Hz), 9.13 (1H, d, J = 1.7 Hz), 12.28 (1H, s) .
[0213]
Example 14


61 mg of 3-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)furan, 55 mg of sodium carbonate and
30 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 12 hours. After the reaction
mixture was cooled to room temperature, 41 mg of 3-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)furan and
22 mg of sodium carbonate were added and stirred at 90°C
for 12 hours. After the reaction mixture was cooled to
room temperature, insoluble were removed by filtration
and ethyl acetate and 1.0 mol/L hydrochloric acid were
added. The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with 1.0 mol/L
hydrochloric acid and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 1.0 mL of 2.0 mol/L
aqueous sodium hydroxide and 2.0 mL of ethanol were
added to the obtained residue and stirred at room
temperature for 1 hour. 0.6 mol/L hydrochloric acid was
added to the reaction mixture, and solid substances
were separated by filtration and purified with
reversed-phase silica gel column chromatography
[eluent; 50-100% acetonitrile /0.1% trifluoroacetic

136
acid aqueous solution] to obtain 6.2 mg of 2-
(benzamido)-4-(furan-3-yl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 6.97 (1H, d, J = 1.7 Hz), 7.47 (1H,
dd, J= 8.3, 1.7 Hz), 7.59-7.69 (3H, m), 7.83 (1H, t, J
= 1.6 Hz), 7.98-8.00 (2H, m), 8.06 (1H, d, J = 8.3 Hz),
8.32 (1H, s), 8.94 (1H, d, J = 1.7 Hz), 12.29 (1H, s).
[0214]
Example 15

The following compound was obtained in the
same manner as in Example 14.
2-(Benzamido)-4-(2,3-dihydrobenzo[1,4]dioxin-6-
yl)benzoic acid
1H-NMR (DMSO-d6) 5: 4.31 (4H, s), 7.02 (1H, d, J = 8.8
Hz), 7.21-7.24 (2H, m), 7.46 (1H, dd, J = 8.3, 2.0 Hz),
7.60-7.69 (3H, m), 7.97-7.99 (2H, m), 8.09 (1H, d, J =
8.5 Hz), 9.02 (1H, d, J = 1.7 Hz).
[0215]
Example 16

56 mg of (4-(tert-butyl)phenyl)boronic acid,
55 mg of sodium carbonate and 30 mg of polymer

137
supported bis(acetato)triphenylphosphine palladium(II)
were added to 2.5 mL of N,N-dimethylacetamide solution
containing 70 mg of methyl 2-(benzamido)-4-
bromobenzoate, and stirred at 90°C for 21 hours. After
the reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 1.0 mol/L hydrochloric acid were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with 1.0 mol/L hydrochloric acid
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. 1.0 mL of 2.0 mol/L aqueous sodium
hydroxide and 5.0 mL of ethanol were added to the
obtained residue and stirred at room temperature for 1
hour and 30 minutes. 0.5 mol/L hydrochloric acid and
ethyl acetate were added to the reaction mixture. The
organic layer was separated and the solvent was
evaporated under reduced pressure to obtain 9.3 mg of
2-(benzamido)-4-(4-(tert-butyl)phenyl)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 1.28 (9H, s) , 7.41-7.57 (8H, m) ,
7.78-7.80 (2H, m), 7.90 (1H, dd, J = 8.1, 1.7 Hz), 8.06
(1H, d, J = 1.7 Hz), 9.93 (1H, s), 13.09 (1H, s).
[0216]
Example 17


138
56 mg of benzothiophene-2-boronic acid, 55 mg
of sodium carbonate and 30 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 12 hours. After cooled to room
temperature 37 mg of benzothiophene-2-boronic acid and
22 mg of sodium carbonate were added and stirred at 90°C
for 12 hours. After the reaction mixture was cooled to
room temperature, insoluble were removed by filtration
and ethyl acetate and 1.0 mol/L hydrochloric acid were
added. The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with 1.0 mol/L
hydrochloric acid and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 1.0 mL of 2.0 mol/L
aqueous sodium hydroxide and 2.0 mL of ethanol were
added to the obtained residue and stirred at room
temperature for 1 hour. 0.6 mol/L hydrochloric acid was
added to the reaction mixture and a solid substance was
separated by filtration to obtain 2.5 mg of 2-
(benzamido)-4-(benzothiophen-2-yl)benzoic acid as white
solid.
1HV-NMR (DMSO-de) 5: 7.41-7.46 (2H, m) , 7.61-7.70 (4H, m) ,
7.94-8.06 (5H, m), 8.15 (1H, d, J = 8.3 Hz), 9.24 (1H,
s), 12.30-12.50 (1H, broad).
[0217]
Example 18


51 mg of 4-acetylphenylboronic acid, 61 mg of
sodium hydrogen carbonate and 12 mg of
tetrakis(triphenylphosphine)palladium(O) were added to
a mixed solution of 2.0 mL of toluene, 0.6 mL jof
ethanol and 0.4 mL of water containing 70 mg o|f methyl
2-(benzamido)-4-bromobenzoate, and stirred un4er
pressure at 160°C for 5 minutes. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration, ethyl acetate and 0.5 riiol/L
hydrochloric acid were added and a solid substance was
separated by filtration. The obtained solid sjubstance
was added to a mixed solution of 1.0 mL of 2.0 mol/L
aqueous sodium hydroxide and 5.0 mL of ethanoj. and
stirred at room temperature for 1 hour and 30jminutes.
0.6 mol/L hydrochloric acid and ethyl acetate were
added to the reaction mixture. The organic l^yer was
separated, and the solvent was evaporated undfer reduced
pressure to obtain 50 mg of 4-(4-acetylphenyl^-2-
(benzamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 2.64 (3H, s) , 7.59-7.70 (4JH, m) ,
7.89 (2H, d, J = 8.3 Hz), 7.99-8.01 (2H, m) , J8.12 (2H,
d, J = 8.3 Hz), 8.17 (1H, d, J = 8.3 Hz), 9.14 (1H, d,
J = 1.7 Hz), 12.28 (1H, s), 13.80-14.10 (1H, broad).
[0218] j
Example 19


56 mg of 2,4-difluorophenylboronic acid, 63
mg of sodium carbonate and 34 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
80 mg of methyl 2-(benzamido)-4-bromobenzoate, and
stirred at 90°C for 20 hours. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration and ethyl acetate and 1.2 mol/L
hydrochloric acid were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 1.0 mol/L hydrochloric acid and a
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure.
1.0 mL of 1.0 mol/L aqueous sodium hydroxide and 4.0 mL
of ethanol were added to the obtained residue and
stirred at room temperature for 1 hour. 0.6 mol/L
hydrochloric acid was added to the reaction mixture and
a solid substance was separated by filtration to obtain
24 mg of 2-(benzamido)-4-(2,4-difluorophenyl)benzoic
acid.
1H-NMR (DMSO-de) 5: 7.28 (1H, td, J = 8.2 Hz, J = 2.2
Hz), 7.39 (1H, dt, J = 8.4, 1.6 Hz), 7.42-7.48 (1H, m) ,
7.59-7.70 (4H, m), 7.96-7.99 (2H, m), 8.15 (1H, d, J =
8.1 Hz), 8.95 (1H, d, J = 1.4 Hz), 12.24 (1H, s).

141
[0219]
Examples 20 to 22
The compounds shown in Table 9 were obtained
in the same manner as in Example 19.
[0220]
[Table 9]

[0221]
2-(Benzamido)-4-(4-fluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.36-7.40 (2H, m), 7.51 (1H, dd, J =
8.1, 2.0 Hz), 7.60-7.69 (3H, m), 7.77-7.81 (2H, m),
7.98-8.00 (2H, m), 8.13 (1H, d, J = 8.3 Hz), 9.06 (1H,
s) .
[0222]
2-(Benzamido)-4-(2-methoxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 6: 3.80 (3H, s), 7.09 (1H, td, J = 7.4,
1.0 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.32-7.37 (2H, m),
7.41-7.45 (1H, m), 7.59-7.68 (3H, m) , 7.96-7.98 (2H, m) ,
8.08 (1H, d, J = 8.3 Hz), 8.88 (1H, t, J = 1.6 Hz).
[0223]
2-(Benzamido)-4-(4-methoxyphenyl)benzoic acid

142
1H-NMR (DMSO-de) 8: 3.83 (3H, s) , 7.09-7.12 (2H, m) ,
7.49 (1H, dd, J= 8.3, 1.7 Hz), 7.59-7.72 (5H, m),
7.98-8.00 (2H, m), 8.10 (1H, d, J = 8.3 Hz), 9.06 (1H,
s), 12.20-12.40 (1H, broad).
[0224]
Example 23

0.83 mL of triethylamine, 34 mg of palladium
acetate and 0.69 mL of styrene were added to 10 mL of
N,N-dimethylacetamide solution containing 1.0 g of
methyl 2-(benzamido)-4-bromobenzoate and 91 mg of
tri(o-tolyl)phosphine, and stirred under nitrogen
atmosphere at 120°C for 1 hour and 30 minutes. After
the reaction mixture was cooled to room temperature,
0.35 mL of styrene and 5 mg of palladium acetate were
added and stirred at 120°C for 2 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 1.0 mol/L hydrochloric acid were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[eluent; hexane: ethyl acetate =8:1] to obtain 0.18 g
of methyl 2-(benzamido)-4-((E)-2-phenylvinyl)benzoate
as white solid.

143
1H-NMR (CDCI3) 8: 3.97 (3H, s) , 7.16 (1H, d, J= 16.4
Hz), 7.26-7.41 (5H, m) , 7.52-7.59 (5H, m) , 8.06-8.10
(3H, m), 9.17 (1H, d, J = 1.4 Hz), 12.12 (1H, s) .
[0225]
Example 24

0.37 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 2 mL of
methanol and 2 mL of tetrahydrofuran containing 0.18 g
of methyl 2-(benzamido)-4-((E)-2-phenylvinyl)benzoate
at room temperature, and stirred at the same
temperature for 7 hours. The solvent was evaporated
under reduced pressure and water was added and pH was
adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid.
Solid substances were separated by filtration and
purified with silica gel column chromatography [eluent;
hexane: ethyl acetate =2:1] to obtain 65 mg of 2-
(benzamido)-4-((E)-2-phenylvinyl)benzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 7.31-7.44 (5H, m) , 7.49 (1H, dd, J =
8.4, 1.3 Hz), 7.60-7.67 (3H, m), 7.71 (2H, d, J = 7.6
Hz), 7.99 (2H, d, J = 7.1 Hz), 8.06 (1H, d, J = 8.4 Hz),
8.94 (1H, d, J = 1.3 Hz), 12.27 (1H, s), 13.65-13.85
(1H, broad).
[0226]
Example 25


20 mg of 5% palladium-carbon was added to a
mixed solution of 1 mL of methanol and 2 mL of ethyl
acetate containing 0.10 g of 2-(benzamido)-4-((E)-2-
phenylvinyl)benzoic acid and stirred under hydrogen
atmosphere at room temperature for 5 hours. Insoluble
were removed by filtration and the solvent was
evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 69 mg of 2-(benzamido)-4-phenethylbenzoic acid
as white solid.
1H-NMR (DMSO-de) 8: 2.91-2.99 (4H, m) , 7.07 (1H, dd, J =
8.1, 1.4 Hz), 7.17-7.20 (1H, m) , 7.26-7.31 (4H, m) ,
7.58-7.67 (3H, m), 7.95-7.98 (3H, m), 8.67 (1H, d, J =
1.4 Hz), 12.40-12.50 (1H, broad).
[0227]
Example 2 6

0.037 mL of vinylcyclohexane, 87 mg of cesium
carbonate, 13 mg of tetrabutylammonium bromide and 21
mg of polymer supported
di(acetato)dicyclohexylphosphino palladium(II) were

145
added to 1.0 mL of toluene solution containing 50 mg of
tert-butyl 2-(benzamido)-4-bromobenzoate at room
temperature and stirred at 110°C for 48 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated, and the solvent
was evaporated under reduced pressure after washed with
10% citric acid aqueous solution. 5 mL of
trifluoroacetic acid was added to the obtained residue
i and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure, and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 55-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
i 2.9 mg of 2-(benzamido)-4-((E)-2-
cyclohexylvinyl)benzoic acid as white solid.
The following compound was obtained in the
same manner as in Example 26.
1H-NMR (DMSO-de) 5: 1.16-1.36 (5H, m) , 1.64-1.81 (5H, m) ,
2.16-2.24 (1H, m) , 6.42-6.44 (2H, m), 7.24 (1H, dd, J =
8.3, 1.7 Hz), 7.58-7.67 (3H, m) , 7.95-7.99 (3H, m) ,
i 8.76 (1H, s), 12.20-12.40 (1H, broad).
[0228]
Example 27


146
2-(Benzamido)-4-((E)-3-cyclohexyl-l-propenyl)benzoic
acid
1H-NMR (DMSO-d6) 8: 0.92-1.28 (5H, m) , 1.39-1.49 (1H, m) ,
1.61-1.74 (5H, m), 2.12-2.18 (2H, m), 6.45-6.47 (2H, m),
7.25 (1H, dd, J = 8.3, 1.5 Hz), 7.58-7.67 (3H, m),
7.95-7.99 (3H, m), 8.75 (1H, d, J = 1.5 Hz), 12.20-
12.35 (1H, broad).
[0229]
Example 28

0.074 mL of vinylcyclohexane, 0.17 g cesium
carbonate, 26 mg of tetrabutylammonium bromide and 42
mg of polymer supported
di(acetato)dicyclohexylphosphino palladium(II) were
added to 2.0 mL of toluene solution containing 0.10 g
of tert-butyl 2-(benzamido)-4-bromobenzoate at room
temperature and stirred at 110°C for 48 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated, and the solvent
was evaporated under reduced pressure after washed with
10% citric acid aqueous solution. 2.4 mL of
tetrahydrofuran, 0.6 mL of water, 0.42 g sodium formate,
0.44 mL of acetic acid and 50 mg of 3.9% palladium-
carbon (ethylenediamine complex) were added to the
obtained residue and stirred at 50°C for 12 hours.

147
After the reaction mixture was cooled to room
temperature, ethyl acetate and 10% citric acid aqueous
solution were added. The organic layer was separated
and the solvent was evaporated under reduced pressure.
10 mL of trifluoroacetic acid was added to the obtained
residue and stirred at room temperature for 1 hour, and
the solvent was evaporated under reduced pressure. The
obtained residue was purified with reversed-phase
silica gel column chromatography [eluent; 60-100%
acetonitrile /0.1% trifluoroacetic acid aqueous
solution] to obtain 4.8 mg of 2-(benzamido)-4-(2-
cyclohexylethyl)benzoic acid as white solid.
Hl-NMR (DMSO-de) 8: 0.89-0.98 (2H, m) , 1.12-1.27 (4H, m) ,
1.48-1.78 (7H, m) , 2.65-2.69 (2H, m), 7.05 (1H, dd, J =
8.2, 1.6 Hz), 7.58-7.67 (3H, m), 7.94-7.97 (3H, m),
8.62 (1H, d, J = 1.6 Hz), 12.20-12.35 (1H, broad).
[0230]
Example 29

The following compound was obtained in the
same manner as in Example 28.
2-(Benzamido)-4-(3-cyclohexylpropyl)benzoic acid
1H-NMR (DMSO-de) 5: 0.80-0.91 (2H, m) , 1.09-1.24 (6H, m) ,
1.59-1.70 (7H, m), 2.62-2.65 (2H, m), 7.05 (1H, dd, J=
8.2, 1.6 Hz), 7.55-7.65 (3H, m), 7.94-7.98 (3H, m) ,
8.62 (1H, d, J = 1.6 Hz), 12.25 (1H, s), 13.64 (1H, s) .


148
[0231]
Example 30
0.28 mL of triethylamine and 0.12 mL of
benzoyl chloride were added to 3 mL of methylene
chloride solution containing 0.31 g of tert-butyl 2-
amino-4-(3-phenylpropyl)benzoate sequentially while
ice-cooled and stirred at room temperature for 17 hours.
The solvent was evaporated under reduced pressure, and
the obtained residue was purified with silica gel
column chromatography [eluent; hexane: ethyl acetate =
20:1] to obtain 0.48 g of tert-butyl 2-(benzamido)-4-
(3-phenylpropyl)benzoate as white solid.
1H-NMR (CDC13) 5: 1.62 (9H, s) , 1.96-2.05 (2H, m) , 2.68
(2H, t, J = 7.7 Hz), 2.72 (2H, t, J = 7.8 Hz), 6.92 (1H,
dd, J = 8.3, 1.6 Hz), 7.18-7.22 (3H, m), 7.26-7.30 (2H,
m), 7.52-7.56 (3H, m), 7.93 (1H, d, J = 8.3 Hz), 8.05-
8.07 (2H, m), 8.81 (1H, d, J =1.6 Hz), 12.22 (1H, s).
[0232]
Example 31

4.8 mL of trifluoroacetic acid solution
containing 0.48 g of tert-butyl 2-(benzamido)-4-(3-

149
phenylpropyl)benzoate was stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure, and the obtained residue was purified with
silica gel column chromatography [eluent; hexane: ethyl
acetate = 1:1] to obtain 0.20 g of 2-(benzamido)-4-(3-
phenylpropyl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 1.89-1.97 (2H, m), 2.65 (2H, t, J =
7.9 Hz), 2.69 (2H, t, J = 8.3 Hz), 7.07 (1H, dd, J =
8.2, 1.6 Hz), 7.17-7.25 (3H, m), 7.28-7.32 (2H, m) ,
7.58-7.65 (3H, m) , 7.95-7.99 (3H, m), 8.64 (1H, d, J =
1.6 Hz), 12.23 (1H, s), 13.55-13.75 (1H, broad).
[0233]
Example 32

0.34 mL of triethylamine and 0.15 mL of
benzoyl chloride were added to 4 mL of methylene
chloride solution containing 0.40 g tert-butyl 2-amino-
4-(4-phenylbutyl)benzoate while ice-cooled sequentially
and stirred at room temperature for 19 hours. The
solvent was evaporated under reduced pressure, and the
obtained residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate = 20:1]
to obtain 0.50 g of tert-butyl 2-(benzamido)-4-(4-
phenylbutyl)benzoate as white solid.
1H-NMR (CDC13) 8: 1.55-1.73 (4H, m) , 1.62 (9H, s) , 2.64
(2H, t, J = 7.2 Hz), 2.71 (2H, t, J = 7.2 Hz), 6.90 (1H,

150
dd, J = 8.3, 1.4 Hz), 7.15-7.20 (3H, m), 7.25-7.28 (2H,
m) , 7.51-7.56 (3H, m) , 7.92 (1H, d, J = 8.3 Hz), 8.05-
8.07 (2H, m) , 8.80 (1H, d, J = 1.4 Hz), 12.22 (1H, s) .
[0234]
Example 33

4.9 mL solution of trifluoroacetic acid
containing 0.50 g of tert-butyl 2-(benzamido)-4-(4-
phenylbutyl)benzoate was stirred at room temperature
for 2 hours and 30 minutes. A solid substance was
separated by filtration to obtain 0.16 g of 2-
(benzamido)-4-(4-phenylbutyl)benzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 1.55-1.70 (4H, m) , 2.60-2.74 (4H, m) ,
7.04 (1H, dd, J = 8.2, 1.3 Hz), 7.14-7.21 (3H, m) ,
7.25-7.28 (2H, m) , 7.58-7.65 (3H, m), 7.94-7.98 (3H, m) ,
8.62 (1H, d, J = 1.3 Hz), 12.22 (1H, s).
[0235]
Example 34

0.082 mL of triethylamine, 44 mg of 2-furoyl
chloride and 2.0 mL of methylene chloride were added to

151
1.0 mL of methylene chloride solution containing 50 mg
of tert-butyl 2-amino-4-phenethylbenzoate at room
temperature and stirred at the same temperature for 2
hours. 380 mg of aminomethylated polystyrene was added
to the reaction mixture and stirred at room temperature
overnight. A saturated sodium hydrogen carbonate
aqueous solution was added to the reaction mixture, the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(furan-2-carboxamido)-4-phenethylbenzoate.
2.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(furan-2-carboxamide)-4-
phenethylbenzoate and stirred at room temperature for 1
hour. The solvent was evaporated under reduced pressure
and diisopropyl ether was added to the obtained residue
and a solid substance was separated by filtration to
obtain 32 mg of 2-(furan-2-carboxamido)-4-
phenethylbenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 2.91-2.98 (4H, m) , 6.75 (1H, dd, J =
3.4, 1.7 Hz), 7.07 (1H, dd, J = 8.2, 1.3 Hz), 7.16-7.30
(6H, m), 7.95 (1H, d, J = 8.3 Hz), 8.00 (1H, s) , 8.61
(1H, s), 12.19 (1H, s), 13.50-13.70 (1H, broad).
[0236]
Examples 35 to 54
The compounds shown in Table 10 were obtained
in the same manner as in Example 34.

152
[0237]
[Table 10]

[0238]
2-(2, 4-Difluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.00 (4H, m) , 7.10 (1H, dd, J =
8.0, 1.5 Hz), 7.16-7.20 (1H, m) , 7.26-7.33 (5H, m),
7.50 (1H, ddd, J = 11.4, 9.2, 2.4 Hz), 7.94 (1H, d, J =
8.0 Hz), 8.01 (1H, td, J = 8.8, 6.7 Hz), 8.63 (1H, s),
11.96 (1H, s), 13.54-13.64 (1H, broad).
[0239]
2-(Cinnamamido)-4-phenethylbenzoic acid

153
1H-NMR (DMSO-de) 6: 2.89-2.98 (4H, m) , 6.88 (1H, d, J =
15.6 Hz), 7.05 (1H, dd, J = 8.3, 1.5 Hz), 7.16-7.30 (5H,
m) , 7.42-47 (3H, m), 7.62 (1H, d, J = 15.6 Hz), 7.73-
7.75 (2H, m), 7.91 (1H, d, J = 8.0 Hz), 8.55 (1H, s),
1 11.37 (1H, s), 13.40-13.60 (1H, broad).
[0240]
2-(Cyclohexanecarboxamido)-4-phenethylbenzoic acid
XH-NMR (DMSO-de) 8: 1.17-1.47 (5H, m) , 1.63-1.76 (3H, m) ,
1.87-1.95 (2H, m), 2.25-2.35 (1H, m) , 2.86-2.92 (4H, m),
I 7.00 (1H, dd, J = 8.0, 1.7 Hz), 7.16-7.29 (5H, m), 7.88
(1H, d, J = 8.3 Hz), 8.49 (1H, s), 11.22 (1H, s),
13.35-13.55 (1H, broad).
[0241]
2-(4-Fluorobenzamido)-4-phenethylbenzoic acid
• 1H-NMR (DMSO-dg) 5: 2.90-3.00 (4H, m) , 7.09 (1H, dd, J =
8.1, 1.7 Hz), 7.16-7.20 (1H, m), 7.26-7.30 (4H, m) ,
7.45 (2H, t, J = 8.9 Hz), 7.96 (1H, d, J = 8.1 Hz),
8.00-8.04 (2H, m), 8.62 (1H, d, J = 1.7 Hz), 12.16 (1H,
s).
I [0242]
4-Phenethyl-2-(thiophene-2-carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.90-2.98 (4H, m) , 7.07 (1H, dd, J =
8.2, 1.6 Hz), 7.16-7.30 (6H, m), 7.74 (1H, dd, J = 3.7,
1.0 Hz), 7.93-7.96 (2H, m), 8.52 (1H, s), 12.20 (1H, s) .
[0243]
2-(Cyclopropanecarboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 0.85-0.87 (4H, m) , 1.67-1.73 (1H, m) ,
2.86-2.91 (4H, m), 7.00 (1H, dd, J = 8.2, 1.6 Hz),

154
7.15-7.29 (5H, m), 7.88 (1H, d, J = 8.2 Hz), 8.41 (1H,
d, J = 1.6 Hz), 11.38 (1H, s), 13.35-13.60 (1H, broad).
[0244]
4-Phenethyl-2-(2-phenoxyacetamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.88-2.98 (4H, m) , 4.73 (2H, s) ,
7.00-7.10 (4H, m) , 7.16-7.37 (7H, m), 7.92 (1H, d, J =
8.0 Hz), 8.63 (1H, d, J = 1.7 Hz), 12.19 (1H, s),
13.50-13.75 (1H, broad).
[0245]
4-Phenethyl-2-(pyridine-2-carboxamido)benzole acid
1H-NMR (DMSO-d6) 5: 2.92-2.99 (4H, m) , 7.08-7.10 (1H, m) ,
7.16-7.20 (1H, m), 7.26-7.31 (4H, m), 7.67-7.70 (1H, m) ,
7.96 (1H, d, J = 8.3 Hz), 8.09 (1H, td, J = 7.7, 1.5
Hz), 8.20 (1H, d, J = 7.8 Hz), 8.70-8.75 (1H, m), 8.80
(1H, d, J = 1.5 Hz), 13.07 (1H, s) , 13.44 (1H, s) .
[0246]
4-Phenethyl-2-(pyridine-3-carboxamido)benzoic acid
trifluoroacetate
1H-NMR (DMSO-de) 8: 2.91-3.01 (4H, m) , 7.11 (1H, dd, J =
8.3, 1.5 Hz), 7.16-7.20 (1H, m), 7.27-7.29 (4H, m),
7.65 (1H, dd, J = 7.8, 4.9 Hz), 7.97 (1H, d, J = 8.3
Hz), 8.30 (1H, dt, J - 8.1, 1.9 Hz), 8.60 (1H, s), 8.82
(1H, dd, J = 4.9, 1.2 Hz), 9.13 (1H, d, J = 2.2 Hz),
12.20 (1H, s), 13.60-13.80 (1H, broad).
[0247]
4-Phenethyl-2-(2,2-diphenylacetamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.86-2.93 (4H, m) , 5.28 (1H, s) ,
7.02 (1H, dd, J = 8.0, 1.7 Hz), 7.15-7.40 (15H, m),

155
7.84 (1H, d, J = 8.1 Hz), 8.48 (1H, s) , 11.34 (1H, s) ,
13.30-13.40 (1H, broad).
[0248]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-phenethylbenzoic
acid
1H-NMR (DMSO-de) 5: 2.91-2.98 (4H, m), 6.16 (2H, s) ,
7.06 (1H, dd, J = 8.1, 1.7 Hz), 7.12 (1H, d, J = 8.3
Hz), 7.15-7.20 (1H, m), 7.25-7.30 (4H, m), 7.42 (1H, d,
J = 2.0 Hz), 7.53 (1H, dd, J = 8.2, 1.8 Hz), 7.95 (1H,
d, J = 8.1 Hz), 8.63 (1H, s), 12.06 (1H, s) .
[0249]
2-(Isoxazole-5-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 5: 2.90-3.01 (4H, m) , 7.14-7.30 (7H, m) ,
7.97 (1H, d, 8.1 Hz), 8.53 (1H, s), 8.86 (1H, d, J =
1.5 Hz), 12.41 (1H, s).
[0250]
2-(Benzothiophene-3-carboxamido)-4-phenethylbenzoic
acid
1H-NMR (DMSO-d6) 8: 2.94-3.01 (4H, m), 7.09 (1H, dd, J =
8.2, 1.6 Hz), 7.17-7.21 (1H, m), 7.28-7.30 (4H, m),
7.47-7.54 (2H, m), 7.96 (1H, d, J = 8.1 Hz), 8.11-8.13
(1H, m) , 8.49-8.52 (2H, m), 8.62 (1H, d, J = 1.2 Hz),
12.03 (1H, s), 13.50-13.70 (1H, broad).
[0251]
2-(Benzofuran-2-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.91-3.01 (4H, m) , 7.12 (1H, dd, J =
8.4, 1.6 Hz), 7.17-7.21 (1H, m), 7.26-7.29 (4H, m) ,
7.40 (1H, t, J = 7.6 Hz), 7.54 (1H, t, J = 7.2 Hz),
7.70 (1H, d, J = 8.5 Hz), 7.73 (1H, s), 7.85 (1H, d, J

156
= 7.8 Hz), 7.98 (1H, d, J = 8.0 Hz), 8.66 (1H, s),
12.54 (1H, s).
[0252]
2-(2,3-Dihydrobenzo[1,4]dioxin-6-carboxamido)-4-
phenethylbenzoic acid
1H-NMR (DMSO-d6) 6: 2.90-2.98 (4H, m) , 4.31-4.34 (4H, m) ,
7.05 (2H, d, J = 8.3 Hz), 7.16-7.20 (1H, m) , 7.25-7.30
(4H, m), 7.44-7.47 (2H, m), 7.94 (1H, d, J = 8.3 Hz),
8.65 (1H, d, J = 1.5 Hz), 12.12 (1H, s).
[0253]
2-(Benzofuran-5-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.93-3.00 (4H, m), 7.08 (1H, dd, J=
8.1, 1.7 Hz), 7.15-7.21 (2H, m), 7.28-7.31 (4H, m),
7.81 (1H, d, J = 8.8 Hz), 7.93 (1H, dd, 8.8, 1.9 Hz),
7.97 (1H, d, 8.3 Hz), 8.16 (1H, d, J = 2.2 Hz), 8.30
(1H, d, J = 1.7 Hz), 8.69 (1H, s), 12.27 (1H, s) .
[0254]
2-(2-Morpholinopyridine-5-carboxamido)-4-
phenethylbenzoic acid
1H-NMR (DMSO-de) 5: 2.91-2.97 (4H, m) , 3.61-3.64 (4H, m) ,
3.70-3.72 (4H, m), 6.98 (1H, d, J = 9.0 Hz), 7.04 (1H,
dd, J = 8.3, 1.5 Hz), 7.16-7.20 (1H, m), 7.25-7.30 (4H,
m), 7.94 (1H, d, J = 8.3 Hz), 8.02 (1H, dd, J = 9.0,
2.5 Hz), 8.64 (1H, d, J = 1.5 Hz), 8.72 (1H, d, J = 2.5
Hz), 12.00-12.10 (1H, broad).
[0255]
2-(Benzothiophene-5-carboxamido)-4-phenethylbenzoic
acid

157
1H-NMR (DMSO-de) 5: 2.93-3.01 (4H, m) , 7.07-7.10 (1H, m) ,
7.17-7.22 (1H, m), 7.28-7.31 (4H, m), 7.64 (1H, d, J =
5.6 Hz), 7.91-7.98 (3H, m), 8.24 (1H, d, J = 8.3 Hz),
8.50 (1H, s), 8.70 (1H, s), 12.35 (1H, s).
[0256]
2-(Benzothiazole-2-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.91-3.05 (4H, m) , 7.15-7.31 (6H, m) ,
7.62-7.71 (2H, m), 8.00 (1H, d, J = 7.8 Hz), 8.19 (1H,
d, J = 7.8 Hz), 8.29 (1H, d, J = 7.8 Hz), 8.69 (1H, s),
12.98 (1H, s).
[0257]
4-Phenethyl-2-(l-phenyl-lH-pyrazole-5-
carboxamido)benzoic acid
1H-NMR (DMSO-de) 8: 2.84-2.94 (4H, m), 7.05 (1H, d, J =
2.0 Hz), 7.08 (1H, dd, J = 8.1, 1.7 Hz), 7.14-7.27 (5H,
m), 7.43-7.50 (5H, m), 7.86 (1H, d, J = 2.2 Hz), 7.94
(1H, d, J - 8.1 Hz), 8.37 (1H, s) , 12.04 (1H, s) .
[0258]
Example 55

0.082 mL of triethylamine, 39 mg of
benzylsulfonyl chloride and 2.0 mL of methylene
chloride were added to 1.0 mL of methylene chloride
solution containing 50 mg of tert-butyl 2-amino-4-
phenethylbenzoate at room temperature and stirred at

158
the same temperature for 2 hours. 380 mg of
aminomethylated polystyrene was added to the reaction
mixture and stirred at room temperature overnight. A
saturated sodium hydrogen carbonate aqueous solution
was added to the reaction mixture, and the organic
layer was separated, and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [Flash
Tube 2008 manufactured by Trikonex Company, eluent;
hexane: ethyl acetate =4:1] to obtain tert-butyl 2-
(benzylsulfonamido)-4-phenethylbenzoate.
2.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzylsulfonamido)-4-
phenethylbenzoate and stirred at room temperature for 1
hour. The solvent was evaporated under reduced pressure
and the obtained residue was purified with reversed-
phase silica gel column chromatography [eluent; 65-100%
acetonitrile /0.1% trifluoroacetic acid aqueous
solution] to obtain 5.1 mg of 2-(benzylsulfonamido)-4-
phenethylbenzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 2.86-2.95 (4H, m), 4.53 (2H, s) ,
7.03 (1H, dd, J = 7.9, 1.6 Hz), 7.11-7.15 (3H, m),
7.21-7.33 (8H, m), 7.88 (1H, d, J = 8.0 Hz).
[0259]
Examples 56, 57
The compounds shown in Table 11 were obtained
in the same manner as in Example 55.
[0260]
[Table 11]


[0261]
4-Phenethyl-2-(((E)-2-phenylvinyl)sulfonamido)benzoic
acid
1H-NMR (DMSO-de) 8: 2.76-2.80 (2H, m) , 2.90-2.94 (2H, m) ,
6.94 (1H, dd, J = 8.1, 1.5 Hz), 7.09-7.19 (5H, m),
7.38-7.44 (5H, m) , 7.72-7.77 (3H, m), 7.84 (1H, d, J =
8.1 Hz), 11.02 (1H, s).
[0262]
2-(Benzenesulfonamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.78-2.82 (2H, m) , 2.87-2.91 (2H, m) ,
6.92 (1H, d, J = 8.0 Hz), 7.12-7.18 (3H, m) , 7.22-7.26
(2H, m), 7.39 (1H, s), 7.52-7.56 (2H, m), 7.64 (1H, t,
7.4 Hz), 7.74-7.78 (3H, m).
[0263]
Example 58


160
0.031 mL of 2-iodotoluene, 81 g of cesium
carbonate, 12 mg of tetrabutylammonium bromide and 19
mg of polymer supported di(acetato)
dicyclohexylphosphino palladium(II) were added to 1.0
mL of toluene solution containing 40 mg of tert-butyl
2-(benzamido)-4-vinylbenzoate at room temperature and
stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated, and the solvent was
evaporated under reduced pressure after washed with 10%
citric acid aqueous solution. 5 mL of trifluoroacetic
acid was added to the obtained residue and stirred at
room temperature for 1 hour. The solvent was evaporated
under reduced pressure and the obtained residue was
purified with reversed-phase silica gel column
chromatography [eluent; 65-100% acetonitrile /0.1%
trifluoroacetic acid aqueous solution] to obtain 2.8 mg
of 2-(benzamido)-4-((E)-2-(2-methylphenyl)vinyl)benzoic
acid as white solid.
1H-NMR (DMSO-d6) 8: 2.45 (3H, s), 7.21-7.25 (4H, m),
7.52-7.69 (5H, m) , 7.76-7.78 (1H, m), 7.98-8.00 (2H, m) ,
8.06 (1H, d, J = 8.3 Hz), 8.94 (1H, s) , 12.27 (1H, s).
[0264]
Examples 59 to 66
The compounds shown in Table 12 were obtained
in the same manner as in Example 58.

161
[0265]
[Table 12]

[0266]
2-(Benzamido)-4-((E)-2-(4-fluorophenyl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 7.23-7.42 (4H, m) , 7.48 (1H, dd, J =
8.2, 1.6 Hz), 7.60-7.69 (3H, m) , 7.75-7.79 (2H, m),
7.99 (2H, d, J = 6.8 Hz), 8.06 (1H, d, J = 8.3 Hz),
8.93 (1H, s), 12.28 (1H, s).
[0267]
2-(Benzamido)-4-((E)-2-(3-fluoro-4-
methylphenyl)vinyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.26 (3H, s), 7.29-7.69 (9H, m),
7.99 (2H, d, J = 7.1 Hz), 8.06 (1H, d, J = 8.3 Hz),
8.93 (1H, s), 12.27 (1H, s).
[0268]
2-(Benzamido)-4-((E)-2-(3-nitrophenyl)vinyl)benzoic
acid

162
1H-NMR (DMSO-de) 5: 7.54-7.73 (7H, m) , 7.98-8.00 (2H, m) ,
8.09 (1H, d, J = 8.3 Hz), 8.15-8.20 (2H, m), 8.56 (1H,
s), 8.98 (1H, d, J = 1.5 Hz), 12.24 (1H, s) .
[0269]
4-((E)-2-(4-acetylphenyl)vinyl)-2-(benzamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 2.60 (3H, s) , 7.45-7.69 (6H, m) ,
7.85 (2H, d, J = 8.3 Hz), 7.98-8.00 (4H, m), 8.08 (1H,
d, J = 8.3 Hz), 8.97 (1H, d, J = 1.4 Hz), 12.27 (1H, s) .
[0270]
2-(Benzamido)-4-((E)-2-(4-methoxyphenyl)vinyl)benzoic
acid
1H-NMR (DMSO-d6) 8: 3.80 (3H, s) , 6.98 (1H, d, J = 8.8
Hz), 7.18-7.22 (2H, m), 7.34 (1H, d, J = 16.3 Hz), 7.44
(1H, dd, J = 8.3, 1.7 Hz), 7.57-7.69 (5H, m), 7.98-8.05
(3H, m), 8.91 (1H, s), 12.29 (1H, s).
[0271]
2-(Benzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 3.82 (3H, s), 6.89-6.91 (1H, m) ,
7.26-7.38 (5H, m), 7.48 (1H, dd, J = 8.4, 1.6 Hz),
7.59-7.69 (3H, m), 7.98-8.00 (2H, m), 8.06 (1H, d, J =
8.3 Hz), 8.94 (1H, d, J = 1.7 Hz), 12.20-12.50 (1H,
broad).
[0272]
2-(Benzamido)-4-((E)-2-(2,3-dihydrobenzo[1,4]dioxin-6-
yl)vinyl)benzoic acid

163
1H-NMR (DMSO-d6) 8: 4.27 (4H, s) , 6.88 (1H, d, J = 8.3
Hz), 7.16-7.28 (4H, m), 7.42 (1H, dd, J = 8.2, 1.3 Hz),
7.59-7,68 (3H, m), 7.98-8.04 (3H, m), 8.89 (1H, s).
[0273]
2-(Benzamido)-4-((E)-2-(4-
(trifluoromethyl)phenyl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.48 (1H, d, J = 16.6 Hz), 7.53-7.69
(5H, m) , 7.76 (2H, d, J = 8.0 Hz), 7.93 (2H, d, J = 8.0
Hz), 7.98-8.00 (2H, m), 8.08 (1H, d, J = 8.3 Hz), 8.97
(1H, d, J = 1.5 Hz) .
[0274]
Example 67

0.060 mL of 3-iodoanisole, 0.16 g of cesium
carbonate, 24 mg of tetrabutylammonium bromide and 39
mg of polymer supported
di(acetato)dicyclohexylphosphino palladium(II) were
added to 2.0 mL of toluene solution containing 80 mg of
tert-butyl 2-(benzamido)-4-vinylbenzoate at room
temperature and stirred at 110°C for 24 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated, and the solvent
was evaporated under reduced pressure after washed with
10% citric acid aqueous solution. 10 mL of

164
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
2-(benzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic
acid.
1.0 mL of methanol, 2.0 mL of ethyl acetate
and 2.0 mg of 5% palladium-carbon were added to the
obtained 2-(benzamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoic acid and stirred under
hydrogen atmosphere at room temperature for 2 hours.
Insoluble were removed by filtration, and the solvent
was evaporated under reduced pressure to obtain 6.3 mg
of 2-(benzamido)-4-(2-3-methoxyphenyl)ethyl)benzoic
acid as white solid.
1H-NMR (DMSO-de) 8: 2.87 (4H, s) , 3.73 (3H, s) , 6.74 (1H,
ddd, J = 8.2, 2.5, 1.0 Hz), 6.83-6.88 (3H, m), 7.17-
7.21 (1H, m), 7.52-7.60 (3H, m), 7.92 (1H, d, J = 7.8
Hz), 8.02-8.05 (2H, m), 8.61 (1H, d, J = 1.7 Hz).
[0275]
Examples 68 to 70
The compounds shown in Table 13 were obtained
in the same manner as in Example 67.
[0276]
[Table 13]


[0277]
2-(Benzamido)-4-(2-(3-fluoro-4-
methylphenyl)ethyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.18 (3H, s) , 2.91 (4H, s) , 6.96-
7.00 (2H, m), 7.05 (1H, d, J = 11.0 Hz), 7.17 (1H, t, J
= 7.9 Hz), 7.55-7.63 (3H, m), 7.94 (1H, d, J = 8.0 Hz),
8.00 (2H, d, J = 6.8 Hz), 8.62 (1H, s).
[0278]
2-(Benzamido)-4-(2-(4-ethylphenyl)ethyl)benzoic acid
1H-NMR (DMSO-de) 8: 1.15 (3H, t, J = 7.6 Hz), 2.56 (2H,
q, J = 7.6 Hz), 2.86-2.96 (4H, m), 7.05 (1H, d, J = 8.3
Hz), 7.12 (2H, d, J = 7.9 Hz), 7.18 (2H, d, J = 8.0 Hz),
7.57-7.66 (3H, m), 7.95-7.99 (3H, m), 8.67 (1H, s),
12.65-12.95 (1H, broad).
[0279]
2-(Benzamido)-4-(2-(2-methylphenyl)ethyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.31 (3H, s) , 2.89 (4H, s) , 7.05-
7.21 (5H, m), 7.57-7.66 (3H, m), 7.97-7.99 (3H, m),
8.69 (1H, d, J = 1.5 Hz), 12.55-12.85 (1H, broad).


0.087 mL of 4-bromobenzotrifluoride, 0.20 g
of cesium carbonate, 30 mg of tetrabutylammonium
bromide and 4 9 mg of polymer supported
di(acetato)dicyclohexylphosphino palladium(II) were
added to 2.0 mL of toluene solution containing 100 mg
of tert-butyl 2-(benzamido)-4-vinylbenzoate at room
temperature and stirred at 110°C for 48 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated, and the solvent
was evaporated under reduced pressure after washed with
10% citric acid aqueous solution. 2.4 mL of
tetrahydrofuran, 0.6 mL of water, 0.42 g of sodium
formate, 0.44 mL of acetic acid and 50 mg of 3.9%
palladium-carbon (ethylenediamine complex) were added
to the obtained residue and stirred at 50°C for 12 hours.
The reaction mixture was cooled to room temperature and
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated and the solvent
was evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent

167
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
21 mg of 2-(benzamido)-4-(2-(4-
(trifluoromethyl)phenyl)ethyl)benzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 3.00-3.06 (4H, m), 7.09 (1H, dd, J=
8.1, 1.5 Hz), 7.50 (2H, d, J = 8.1 Hz), 7.58-7.67 (5H,
m), 7.95-7.98 (3H, m), 8.66 (1H, s), 12.24 (1H, s).
[0281]
Example 72

The following compound was obtained in the
same manner as in Example 71.
2-(Benzamido)-4-(2-(4-fluorophenyl)ethyl)benzoic acid
1H-NMR (DMSO-d6) 8: 2.91-2.98 (4H, m) , 7.06-7.12 (3H, m) ,
7.28-7.31 (2H, m) , 7.58-7.67 (3H, m), 7.96 (3H, d, J =
7.8 Hz), 8.66 (1H, d, J = 1.2 Hz), 12.21 (1H, s).
[0282]
Example 73


168
0.35 g of potassium permanganate was added to
a suspension of 7 mL of pyridine and 7 mL of water
containing 0.70 g of N-((5-benzoyl-2-
methyl)phenyl)benzamide at room temperature, and the
resulting mixture was heated to reflux for 30 minutes.
After the reaction mixture was cooled to room
temperature, 0.35 g of potassium permanganate was added
and the resulting mixture was heated to reflux for 30
minutes. After the reaction mixture was cooled to room
temperature, 0.35 g of potassium permanganate was added
and the resulting mixture was heated to reflux for 30
minutes. Ethyl acetate was added after the reaction
mixture was cooled and pH was adjusted to pH 1.3 with
6.0 mol/L hydrochloric acid. Insoluble were removed by
filtration. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with 1.0
mol/L hydrochloric acid and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 0.42 g of 2-(benzamido)-4-benzoylbenzoic acid as
white solid.
1H-NMR (DMSO-de) 8: 7.52-7.83 {9H, m) , 7.95-7.97 (2H, m) ,
8.21 (1H, d, J = 8.3 Hz), 9.05 (1H, d, J = 1.7 Hz),
12.20 (1H, s).
30 mg of 5% palladium-carbon was added to a
mixed solution of 1.5 mL of methanol and 2 mL of ethyl
acetate containing the obtained 0.15 g of 2-

169
(benzamido)-4-benzoylbenzoic acid and stirred under
hydrogen atmosphere at room temperature for ten hours.
Insoluble were removed by filtration and the solvent
was evaporated under reduced pressure. Hexane was added
to the obtained residue and a solid substance was
separated by filtration to obtain 0.11 g of 2-
(benzamido)-4-benzylbenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 4.03 (2H, s), 7.07 (1H, dd, J= 8.1,
1.4 Hz), 7.20-7.34 (5H, m), 7.57-7.66 (3H, m), 7.93-
7.95 (2H, m), 7.98 (1H, d, J = 8.1 Hz), 8.66 (1H, d, J
=1.4 Hz), 12.36 (1H, s).
[0283]
Example 74

0.056 mL of triethylamine and 0.029 mL of 3-
bromobenzoyl chloride were added to 3.0 mL of methylene
chloride solution containing 57 mg of tert-butyl 2-
amino-4-phenoxybenzoate at room temperature
sequentially and stirred at the same temperature for 1
hour. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture. The organic
layer was separated and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [Flash
Tube 2008 manufactured by Trikonex Company, eluent;

170
hexane: ethyl acetate =4:1] to obtain tert-butyl 2-(3-
bromobenzamido)-4-phenoxybenzoate.
5 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(3-bromobenzamido)-4-
phenoxybenzoate and stirred at room temperature for 5
minutes. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 31 mg of 2-(3-bromobenzamido)-4-
phenoxybenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 6.79 (1H, dd, J = 8.9, 2.5 Hz),
7.15-7.22 (2H, m) , 7.26-7.32 (1H, m) , 7.46-7.53 (2H, m) ,
7.56 (1H, t, J = 7.9 Hz), 7.83-7.88 (1H, m) , 7.88-7.92
(1H, m) , 8.05-8.10 (2H, m), 8.33 (1H, d, J = 2.5 Hz),
12.44 (1H, s), 13.70-13.90 (1H, broad).
[0284]
Example 75

1.5 mL of toluene suspension containing 0.15
g of methyl 2-(benzamido)-4-ethynylbenzoate, 0.090 mL
of iodinated benzene, 5 mg of copper(I) iodide, 20 mg
of bis(triphenylphosphine)palladium(II) chloride and
0.15 mL of triethylamine was stirred under nitrogen
atmosphere at room temperature for 2 hours. Ethyl
acetate and 1.0 mol/L hydrochloric acid were added to
the reaction mixture. The organic layer was separated

171
and dried over anhydrous magnesium sulfate after washed
with a saturated sodium chloride aqueous solution, and
the solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate =8:1] to
obtain 0.13 g of methyl 2-(benzamido)-4-
(phenylethynyl)benzoate as white solid.
1H-NMR (CDC13) 8: 3.98 (3H, s), 7.27 (1H, dd, J = 8.2,
1.6 Hz), 7.37-7.39 (3H, m) , 7.52-7.58 (5H, m), 8.05-
8.08 (3H, m), 9.16 (1H, d, J = 1.6 Hz), 12.07 (1H, s).
[0285]
Example 76

0.24 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 1 mL of
methanol and 2 mL of tetrahydrofuran containing 0.13 g
of methyl 2-(benzamido)-4-(phenylethynyl)benzoate at
room temperature and stirred at the same temperature
for 1 hour and 30 minutes. The solvent was evaporated
under reduced pressure and water was added and pH was
adjusted to pH 4.0 while ice-cooled with 1.0 mol/L
hydrochloric acid. A solid substance was separated by
filtration to obtain 0.11 g of 2-(benzamido)-4-
(phenylethynyl)benzoic acid as white solid.

172
1H-NMR (DMSO-d6) S: 7.27 (1H, dd, J = 8.0, 1.6 Hz),
7.45-7.46 (3H, m), 7.56-7.63 (5H, m), 8.03 (2H, d, J =
6.8 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.89 (1H, d, J = 1.6
Hz), 14.30-14.50 (1H, broad).
[0286]
Example 77

2.6 g potassium permanganate was added to a
suspension of 8 mL of tert-butyl alcohol and 8 mL of
water containing 1.7 g of N-((2-methyl-5-
I phenoxy)phenyl)benzamide and 2.0 g of anhydrous
magnesium sulfate at room temperature, and the
resulting mixture was heated to reflux for 5 hours.
After the reaction mixture was cooled to room
temperature, 0.86 g of potassium permanganate and 0.66
g of anhydrous magnesium sulfate were added and the
resulting mixture was heated to reflux for 2 hours.
After the reaction mixture was cooled to room
temperature, ethyl acetate and 1.0 mol/L hydrochloric
acid were added and insoluble were removed by
filtration. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with 1.0
mol/L hydrochloric acid and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography

173
[eluent; hexane: ethyl acetate =2:1] to obtain 0.30 g
of 2-(benzamido)-4-phenoxybenzoic acid as white solid.
1H-NMR (CDC13) 5: 6.71 (1H, dd, J = 9.0, 2.5 Hz), 7.13-
7.15 (2H, m), 7.21-7.25 (1H, m), 7.41-7.58 (5H, m),
7.98-8.00 (2H, m), 8.12 (1H, d, J = 9.0 Hz), 8.63 (1H,
d, J = 2.5 Hz), 11.94 (1H, s) .
[0287]
Example 78

0.029 mL of 2-phenoxyacetyl chloride was
added to 2.5 mL of methylene chloride solution
containing 40 mg of tert-butyl 2-amino-4-
phenoxybenzoate and 0.039 mL of triethylamine at room
temperature and stirred at the same temperature for 2
hours. 0.25 g of aminomethylated polystyrene was added
to the reaction mixture and after stirred at the same
temperature overnight, 5 mL of 10% citric acid aqueous
solution was added. The organic layer was separated and
the solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate: acetic
acid = 20:5:1] to obtain tert-butyl 4-phenoxy-2-(2-
phenoxyacetamido)benzoate.

174
3 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenoxy-2-(2-
phenoxyacetamido)benzoate and stirred at room
temperature for 1 hour. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 38 mg of 4-phenoxy-2-
2-phenoxyacetamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 4.70 (2H, s), 6.74 (1H, dd, J= 9.0,
2.5 Hz), 7.01 (1H, t, J = 7.4 Hz), 7.08 (2H, d, J = 8.1
Hz), 7.16 (2H, d, J = 7.8 Hz), 7.27 (1H, t, J = 7.9 Hz),
7.35 (2H, t, J = 7.9 Hz), 7.47 (2H, t, J = 7.9 Hz),
8.03 (1H, d, J = 9.0 Hz), 8.37 (1H, d, J = 2.5 Hz),
12.32 (1H, s), 13.63 (1H, s).
[0288]
Examples 79 to 97
The compounds shown in Table 14 were obtained
in the same manner as in Example 78.
[Table 14]


[0289]
4-Phenoxy-2-(pyridine-3-carboxamido)benzoic acid
1H-NMR (DMSO-de) 5: 6.81 (1H, dd, J = 8.8, 2.4 Hz), 7.18
(2H, d, J = 7.8 Hz), 7.29 (1H, t, J = 7.5 Hz), 7.48-
7.51 (2H, m), 7.63 (1H, dd, J = 8.0, 4.9 Hz), 8.08 (1H,
d, J = 8.8 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.34 (1H, d,
J = 2.4 Hz), 8.81 (1H, d, J = 4.9 Hz), 9.08 (1H, d, J =
1.5 Hz), 12.52 (1H, s).
[0290]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-phenoxybenzoic
acid

176
1H-NMR (DMSO-d6) 8: 6.15 (2H, s) , 6.76 (1H, dd, J = 8.8,
2.4 Hz), 7.10 (1H, d, J = 8.1 Hz), 7.17 (2H, d, J = 7.8
Hz), 7.28 (1H, t, J = 7.4 Hz), 7.38 (1H, d, J = 1.7 Hz),
7.47-7.50 (3H, m), 8.06 (1H, d, J = 8.8 Hz), 8.36 (1H,
d, J = 2.4 Hz), 12.33 (1H, s), 13.55-13.80 (1H, broad).
[0291]
2-(Isoxazole-5-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 5: 6.83 (1H, dd, J = 8.9, 2.5 Hz), 7.19
(2H, d, J = 7.8 Hz), 7.22 (1H, t, J = 1.0), 7.28-7.31
(1H, m) , 7.47-7.51 (2H, m), 8.08 (1H, d, J = 8.9 Hz),
8.27 (1H, d, J = 2.5 Hz), 8.86 (1H, t, J = 1.0), 12.63
(1H, s) .
[0292]
4-Phenoxy-2-(2-phenylthiazole-4-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.78 (1H, dd, J = 8.9, 2.6 Hz), 7.20
(2H, d, J = 7.8 Hz), 7.29 (1H, t, J = 7.4 Hz), 7.50 (2H,
t, J = 7.9 Hz), 7.56-7.57 (3H, m), 8.09 (1H, d, J = 8.8
Hz), 8.11-8.13 (2H, m), 8.52-8.53 (2H, m) , 13.08 (1H,
s), 13.69 (1H, s).
[0293]
2-(2,3-Dihydrobenzo[1,4]dioxin-6-carboxamido)-4-
phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 4.30-4.34 (4H, m), 6.75 (1H, dd, J=
8.8, 2.6 Hz), 7.04 (1H, d, J = 8.3 Hz), 7.17 (2H, d, J
= 7.8 Hz), 7.28 (1H, t, J = 7.4 Hz), 7.39-7.43 (2H, m) ,
7.48 (2H, d, J = 7.9 Hz), 8.06 (1H, d, J = 8.8 Hz),
8.38 (1H, d, J = 2.6 Hz), 12.31 (1H, s), 13.65 (1H, s).

177
[0294]
2-(Benzothiophene-3-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.77 (1H, dd, J = 8.8, 2.7 Hz), 7.20
(2H, d, J = 8.0 Hz), 7.29 (1H, t, J = 7.4 Hz), 7.45-
7.52 (4H, m), 8.08 (1H, d, J = 8.8 Hz), 8.10-8.12 (1H,
m) , 8.38 (1H, d, J = 2.7 Hz), 8.41-8.43 (1H, m), 8.51
(1H, s), 12.25 (1H, s), 13.64 (1H, s).
[0295]
2-(Cyclohexanecarboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 1.14-1.42 (5H, m) , 1.61-1.74 (3H, m) ,
1.86-1.88 (2H, m), 2.23-2.30 (1H, m), 6.69 (1H, dd, J=
8.8, 2.6 Hz), 7.12-7.14 (2H, m), 7.26 (1H, t, J = 7.5
Hz), 7.46 (2H, t, J = 7.5 Hz), 8.00 (1H, d, J = 8.8 Hz),
8.24 (1H, d, J = 2.6 Hz), 11.43 (1H, s) , 13.47 (1H, s) .
[0296]
4-Phenoxy-2-(thiophene-2-carboxamido)benzoic acid
1H-NMR (DMSO-de) 8: 6.76 (1H, dd, J = 8.8, 2.6 Hz), 7.17
(2H, d, J = 8.1 Hz), 7.26-7.30 (2H, m) , 7.47-7.51 (2H,
m), 7.72 (1H, d, J = 3.6 Hz), 7.94 (1H, d, J = 4.9 Hz),
8.06 (1H, d, J = 8.8 Hz), 8.26 (1H, d, J = 2.6 Hz).
[0297]
2-(Benzylsulfonamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 4.65 (2H, s) , 6.66 (1H, dd, J = 8.9,
2.3 Hz), 7.09 (1H, d, J = 2.3 Hz), 7.18 (4H, d, J = 7.6
Hz), 7.28-7.33 (4H, m), 7.50 (2H, m), 7.97 (1H, d, J =
8.8 Hz), 10.87 (1H, s).
[0298]
2-(Benzenesulfonamido)-4-phenoxybenzoic acid

178
1H-NMR (DMSO-de) 5: 6.70 (1H, dd, J = 8.8, 2.4 Hz), 6.86
(1H, d, J = 2.4 Hz), 7.05-7.07 (2H, m), 7.34 (1H, t, J
= 7.5 Hz), 7.50-7.60 (4H, m), 7.63-7.70 (3H, m), 7.90
(1H, d, J = 8.9 Hz).
[0299]
2-(4-Fluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.78 (1H, dd, J = 8.8, 2.5 Hz), 7.18
(2H, d, J = 7.6 Hz), 7.28 (1H, t, J = 7.2 Hz), 7.41-
7.51 (4H, m), 7.96-8.00 (2H, m), 8.07 (1H, d, J = 8.8
Hz), 8.37 (1H, d, J = 2.5 Hz), 12.39 (1H, s).
[0300]
2-(2,4-Difluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.79 (1H, dd, J = 8.8, 2.6 Hz),
7.17-7.19 (2H, m) , 7.26-7.31 (2H, m), 7.47-7.53 (3H, m) ,
7.97 (1H, td, J = 8.8, 6.6 Hz), 8.06 (1H, d, J = 8.8
Hz), 8.39 (1H, d, J » 2.6 Hz), 12.16 (1H, s).
[0301]
2-(Cinnamamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.74 (1H, dd, J = 8.8, 2.4 Hz), 6.85
(1H, d, J = 15.5 Hz), 7.17 (2H, d, J = 7.6 Hz), 7.28
(1H, t, J = 7.6 Hz), 7.42-7.51 (5H, m), 7.60 (1H, d, J
= 15.5 Hz), 7.72-7.74 (2H, m) , 8.03 (1H, d, J = 8.8 Hz),
8.35 (1H, d, J = 2.4 Hz), 11.57 (1H, s).
[0302]
2-(Cyclopropanecarboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 0.82-0.87 (4H, m) , 1.64-1.70 (1H, m) ,
6.70 (1H, dd, J = 8.8, 2.6 Hz), 7.12 (2H, d, J = 8.3
Hz), 7.25 (1H, t, J = 7.5 Hz), 7.46 (2H, t, J = 7.9 Hz),

179
8.00 (1H, d, J = 8.8 Hz), 8.17 (1H, d, J = 2.6 Hz),
11.63 (1H, s).
[0303]
2-(l-Methyl-lH-pyrrole-2-carboxamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 5: 3.86 (3H, s), 6.15 (1H, dd, J= 4.0,
2.7 Hz), 6.68 (1H, dd, J = 8.9, 2.5 Hz), 6.83 (1H, dd,
J = 4.0, 1.6 Hz), 7.08 (1H, s), 7.16 (2H, d, J = 7.6
Hz), 7.26 (1H, t, J = 7.3 Hz), 7.48 (2H, t, J = 7.9 Hz),
8.03 (1H, d, J = 8.9 Hz), 8.33 (1H, d, J = 2.5 Hz),
12.10 (1H, s).
[0304]
2-(Benzofuran-2-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 5: 6.80 (1H, dd, J = 8.8, 2.4 Hz), 7.19
(2H, d, J = 7.6 Hz), 7.29 (1H, t, J = 7.4 Hz), 7.39 (1H,
t, J = 7.5 Hz), 7.48-7.56 (3H, m), 7.67-7.71 (2H, m),
7.83 (1H, d, J = 7.8 Hz), 8.09 (1H, d, J = 8.8 Hz),
8.39 (1H, d, J = 2.4 Hz), 12.74 (1H, s).
[0305]
2-(l-Methyl-lH-benzotriazole-5-carboxamido)-4-
phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 4.37 (3H, s), 6.81 (1H, dd, J = 8.8,
2.4 Hz), 7.19 (2H, d, J = 7.6 Hz), 7.29 (1H, t, J = 7.7
Hz), 7.50 (2H, t, J = 7.9 Hz), 8.03-8.10 (3H, m), 8.40
(1H, d, J = 2.4 Hz), 8.59 (1H, s) .
[0306]
2-(Benzofuran-5-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.73-6.77 (1H, m) , 7.08-7.29 (4H, m) ,
7.49 (2H, t, J = 7.9 Hz), 7.78 (1H, d, J = 8.6 Hz),

180
7.90 (1H, d, J = 7.9 Hz), 8.08 (1H, d, J = 8.8 Hz),
8.14 (1H, d, J = 2.2 Hz), 8.27 (1H, s), 8.43 (1H, d, J
= 2.2 Hz).
[0307]
2-(Benzothiazole-2-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.85 (1H, dd, J = 8.9, 2.5 Hz), 7.21
(2H, d, J = 7.6 Hz), 7.30 (1H, t, J = 7.4 Hz), 7.51 (2H,
t, J - 7.9 Hz), 7.61-7.70 (2H, m), 8.10 (1H, d, J = 8.9
Hz), 8.18 (1H, d, J = 7.6 Hz), 8.28 (1H, d, J = 7.6 Hz),
8.38 (1H, d, J = 2.5 Hz), 13.15 (1H, s), 13.71 (1H, s) .
[0308]
Example 98

82 mg of potassium carbonate and 0.047 mL of
benzyl bromide were added to 1 mL of N,N-
dimethylformamide solution containing 80 mg of methyl
2-(benzamido)-4-hydroxybenzoate at room temperature and
stirred at the same temperature for 3 hours. Ethyl
acetate and 1.0 mol/L hydrochloric acid were added to
the reaction mixture. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with a saturated sodium hydrogen carbonate aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. Hexane was added to the
obtained residue and a solid substance was separated by

181
filtration to obtain 75 mg of methyl 2-(benzamido)-4-
(benzyloxy)benzoate as white solid.
1H-NMR (CDC13) 8: 3.93 (3H, s) , 5.20 (2H, s) , 6.72 (1H,
dd, J = 9.0, 2.5 Hz), 7.32-7.36 (1H, m), 7.39-7.42 (2H,
m), 7.47-7.49 (2H, m) , 7.51-7.57 (3H, m), 8.02 (1H, d,
J = 9.0 Hz), 8.05-8.08 (2H, m), 8.76 (1H, d, J = 2.5
Hz), 12.26 (1H, s).
[0309]
Example 99

0.11 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 1 mL of
methanol and 2 mL of tetrahydrofuran containing 70 mg
of methyl 2-(benzamido)-4-(benzyloxy)benzoate at room
temperature, and stirred at the same temperature for 6
hours and 30 minutes, at 40°C for 1 hour and 30 minutes
and at 50°C for 2 hours. After the reaction mixture was
cooled to room temperature, the solvent was evaporated
under reduced pressure and water and diethyl ether were
added. The aqueous layer was separated and pH was
adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A
solid substance was separated by filtration to obtain
35 mg of 2-(benzamido)-4-(benzyloxy)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 5: 5.22 (2H, s), 6.86 (1H, dd, J = 8.9,
2.7 Hz), 7.34-7.38 (1H, m), 7.40-7.44 (2H, m) , 7.49-

182
7.51 (2H, m), 7.58-7.68 (3H, m), 7.95-7.97 (2H, m),
8.02 (1H, d, J = 8.9 Hz), 8.52 (1H, d, J = 2.7 Hz),
12.45 (1H, s), 13.30-13.70 (1H, broad).
[0310]
Example 100

0.13 g of potassium carbonate and 0.10 mL of
(2-bromoethyl)benzene were added to 2 mL of N-
dimethylformamide solution containing 0.13 g of methyl
2-(benzamido)-4-hydroxybenzoate, and stirred at room
temperature for 3 hours. 0.10 mL of (2-
bromoethyl)benzene was added to the reaction mixture
and stirred at 50°C for 4 hours and at 80°C for 3 hours.
After the reaction mixture was cooled to room
temperature, 0.10 g of potassium carbonate and 0.10 mL
of (2-bromoethyl)benzene were added and stirred at 80°C
for 2 hours and 30 minutes. After the reaction mixture
was cooled to room temperature, ethyl acetate and 1.0
mol/L hydrochloric acid were added. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [eluent; hexane:
ethyl acetate =8:1] to obtain 0.19 g of methyl 2-
(benzamido)-4-(phenethyloxy)benzoate as colorless oil.

183
1H-NMR (CDCI3) S: 3.14 (2H, t, J= 7.1 Hz), 3.93 (3H, s) ,
4.31 (2H, t, J = 7.1 Hz), 6.64 (1H, dd, J = 9.0, 2.5
Hz), 7.23-7.35 (5H, m), 7.50-7.56 (3H, m), 7.99 (1H, d,
J = 9.0 Hz), 8.04-8.07 (2H, m), 8.63 (1H, d, J = 2.5
Hz), 12.24 (1H, s).
[0311]
Example 101

0.30 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 2 mL of
methanol and 2 mL of tetrahydrofuran containing 0.19 g
of methyl 2-(benzamido)-4-(phenethyloxy)benzoate while
ice-cooled, and stirred at room temperature for 14
hours and 30 minutes. The solvent was evaporated under
reduced pressure and ethyl acetate and 1.0 mol/L
hydrochloric acid were added. The organic layer was
separated, the solvent was evaporated under reduced
pressure and the residue was purified with silica gel
column chromatography [eluent; hexane: ethyl acetate =
2:1] to obtain 85 mg of 2-(benzamido)-4-
(phenethyloxy)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 3.09 (2H, t, J = 6.8 Hz), 4.29 (2H,
t, J = 6.8 Hz), 6.78 (1H, dd, J = 8.9, 2.5 Hz), 7.22-
7.26 (1H, m), 7.31-7.38 (4H, m), 7.58-7.68 (3H, m) ,
7.94-7.96 (2H, m), 8.00 (1H, d, J = 8.9 Hz), 8.42 (1H,
d, J = 2.5 Hz), 12.44 (1H, s).


184
[0312]
Example 102
0.28 mL of 40% diisopropyl azodicarboxylate /
toluene was added dropwise to 1 mL of tetrahydrofuran
solution containing 0.10 g of methyl 2-(benzamido)-4-
hydroxybenzoate, 0.060 mL of 3-phenyl-l-propanol and
0.15 g of triphenylphosphine at room temperature, and
stirred at the same temperature for 2 hours and 30
minutes. The solvent was evaporated under reduced
pressure, and the obtained residue was purified with
silica gel column chromatography [eluent; hexane: ethyl
acetate = 10:1] to obtain 45 mg of methyl 2-
(benzamido)-4-(3-phenylpropoxy)benzoate as white solid.
1H-NMR (CDC13) 8: 2.11-2.18 (2H, m), 2.83 (2H, t, J =
7.7 Hz), 3.94 (3H, s), 4.12 (2H, t, J = 6.2 Hz), 6.65
(1H, dd, J= 9.0, 2.7 Hz), 7.18-7.31 (5H, m), 7.51-7.57
(3H, m), 8.01 (1H, d, J = 9.0 Hz), 8.05-8.07 (2H, m) ,
8.62 (1H, d, J = 2.7 Hz), 12.24 (1H, s).
[0313]
Example 103


185
0.090 mL of 2.0 mol/L aqueous sodium
hydroxide was added dropwise to a mixed solution of 1
mL of methanol and 1 mL of tetrahydrofuran containing
45 mg of methyl 2-(benzamido)-4-(3-
phenylpropoxy)benzoate while ice-cooled and stirred at
room temperature for 14 hours and 30 minutes. 0.15 mL
of 2.0 mol/L aqueous sodium hydroxide was added
dropwise and stirred at the same temperature for 5
hours and 30 minutes. The solvent was evaporated under
reduced pressure and water was added and pH was
adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A
solid substance was separated by filtration to obtain
32 mg of 2-(benzamido)-4-(3-phenylpropoxy)benzoic acid
as white solid.
1H-NMR (DMSO-de) 5: 2.01-2.08 (2H, m), 2.77 (2H, t, J =
7.7 Hz), 3.99 (2H, t, J = 6.2 Hz), 6.56 (1H, dd, J =
8.6, 2.5 Hz), 7.17-7.21 (1H, m), 7.24-7.31 (4H, m) ,
7.51-7.60 (3H, m), 7.94 (1H, d, J = 8.6 Hz), 8.03-8.05
(2H, m), 8.34 (1H, d, J = 2.5 Hz).
I [0314]
Example 104

0.20 mL of 40% diisopropyl azodicarboxylate /
toluene was added dropwise to 1 mL of tetrahydrofuran
solution containing 90 mg of methyl 2-(benzamido)-4-
hydroxybenzoate, 0.035 mL of cyclohexanol and 0.10 g of

186
triphenylphosphine at room temperature, and stirred at
the same temperature for 5 hours. Ethyl acetate and 1.0
mol/L hydrochloric acid were added to the reaction
mixture. The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with saturated
sodium hydrogen carbonate aqueous solution and
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [eluent; hexane: ethyl acetate =
10:1] to obtain 36 mg of methyl 2-(benzamido)-4-
(cyclohexyloxy)benzoate as white solid.
1H-NMR (CDC13) 5: 1.30-1.49 (4H, m) , 1.54-1.64 (2H, m) ,
1.77-1.87 (2H, m), 1.98-2.07 (2H, m), 3.93 (3H, s),
4.45-4.49 (1H, m), 6.63 (1H, dd, J = 9.0, 2.4 Hz),
7.51-7.58 (3H, m), 7.99 (1H, d, J = 9.0 Hz), 8.05-8.07
(2H, m), 8.61 (1H, d, J = 2.4 Hz), 12.21 (1H, s).
[0315]
Example 105

0.077 mL of 2.0 mol/L aqueous sodium
hydroxide was added dropwise to a mixed solution of 1
mL of methanol and 1 mL of tetrahydrofuran containing
35 mg of methyl 2-(benzamido)-4-(cyclohexyloxy)benzoate
at room temperature and stirred at the same temperature
overnight and at 40°C for 6 hours and 30 minutes. 0.050

187
mL of 2.0 mol/L aqueous sodium hydroxide was added at
room temperature and stirred at the same temperature
for 4 hours and 30 minutes. The solvent was evaporated
under reduced pressure and water was added and pH was
5 adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A
solid substance was separated by filtration to obtain
25 mg of 2-(benzamido)-4-(cyclohexyloxy)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 1.20-1.60 (6H, m) , 1.68-1.78 (2H, m) ,
1.92-2.00 (2H, m), 4.32-4.39 (1H, m), 6.59 (1H, dd, J=
8.7, 2.4 Hz), 7.52-7.59 (3H, m), 7.93 (1H, d, J = 8.7
Hz), 8.01-8.03 (2H, m), 8.33 (1H, d, J = 2.4 Hz).
[0316]
Example 106

0.31 g of iron powder was added to a mixed
solution of 5.3 mL of methanol and 1.6 mL of acetic
acid containing 0.53 g of methyl 2-nitro-4-
(phenoxymethyl)benzoate, and the resulting mixture was
heated to reflux for 3 hours. The reaction mixture was
cooled to room temperature and ethyl acetate and a
saturated sodium hydrogen carbonate aqueous solution
were added and insoluble were removed by filtration.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with saturated
sodium hydrogen carbonate aqueous solution and

188
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure.
The obtained residue was dissolved in 5.3 mL of
methylene chloride and 0.51 mL of triethylamine and
0.26 mL of benzoyl chloride were added while ice-cooled
sequentially and stirred at room temperature for 15
hours. The solvent was evaporated under reduced
pressure and ethyl acetate and 1.0 mol/L hydrochloric
acid were added to the obtained residue. The organic
layer was separated and washed with saturated sodium
chloride aqueous solution and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under
reduced pressure. Hexane and diisopropyl ether were
added to the obtained residue and a solid substance was
separated by filtration to obtain 0.31 g of methyl 2-
(benzamido)-4-(phenoxymethyl)benzoate as white solid.
1H-NMR (CDC13) 8: 3.97 (3H, s) , 5.17 (2H, s) , 6.95-7.00
(3H, m) , 7.25-7.31 (3H, m), 7.54-7.58 (3H, m), 8.05-
8.07 (2H, m), 8.10 (1H, d, J = 8.3 Hz), 9.04 (1H, d, J
= 1.2 Hz), 12.10 (1H, s).
[0317]
Example 107

0.51 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 3 mL of
methanol and 3 mL of tetrahydrofuran containing 0.31 g

189
of methyl 2-(benzamido)-4-(phenoxymethyl)benzoate while
ice-cooled and stirred at room temperature for 5 hours
and 30 minutes. The solvent was evaporated under
reduced pressure and water was added and pH was
adjusted to pH 4.0 with 1.0 mol/L hydrochloric acid. A
solid substance was separated by filtration to obtain
0.27 g of 2-(benzamido)-4-(phenoxymethyl)benzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 5.16 (2H, s), 6.95 (1H, t, J = 7.3
Hz), 7.02-7.04 (2H, m) , 7.17 (1H, dd, J = 8.0, 1.2 Hz),
7.28-7.32 (2H, m) , 7.54-7.61 (3H, m) , 8.00-8.02 (2H, m) ,
8.05 (1H, d, J = 8.0 Hz), 8.82 (1H, d, J = 1.2 Hz).
[0318]
Example 108

0.52 mL of triethylamine and 0.16 mL of
benzoyl chloride were added to 3.8 mL of methylene
chloride suspension containing 0.39 g of methyl 2-
amino-4-((phenylthio)methyl)benzoate hydrochloride
while ice-cooled and stirred at room temperature for 3
hours and 30 minutes. The solvent was evaporated under
reduced pressure and ethyl acetate and 1.0 mol/L
hydrochloric acid were added to the obtained residue.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium hydrogen carbonate aqueous solution

190
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. Hexane and diisopropyl ether were
added to the obtained residue and a solid substance was
separated by filtration to obtain 0.29 g of methyl 2-
(benzamido)-4-((phenylthio)methyl)benzoate as white
solid.
1H-NMR (CDC13) 5: 3.95 (3H, s) , 4.17 (2H, s) , 7.08 (1H,
dd, J = 8.3, 1.6 Hz), 7.16-7.20 (1H, m) , 7.24-7.27 (2H,
m), 7.32-7.34 (2H, m) , 7.51-7.57 (3H, m), 7.99 (1H, d,
J = 8.3 Hz), 8.04-8.06 (2H, m), 8.95 (1H, d, J = 1.6
Hz), 12.04 (1H, s).
[0319]
Example 109

0.50 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 3 mL of
methanol and 3 mL of tetrahydrofuran containing 0.29 g
of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate
while ice-cooled and stirred at room temperature for 5
hours. 0.25 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise and stirred at the same temperature
for 14 hours. The solvent was evaporated under reduced
pressure and water was added and pH was adjusted to pH
4.0 with 1.0 mol/L hydrochloric acid. A solid substance
was separated by filtration to obtain 0.28 g of 2-

191
(benzamido)-4-((phenylthio)methyl)benzoic acid as white
solid.
1H-NMR (DMSO-de) 8: 4.24 (2H, s) , 6.99 (1H, dd, J = 7.9,
1.8 Hz), 7.15-7.19 (1H, m) , 7.27-7.31 (2H, m), 7.34-
7.37 (2H, m), 7.52-7.59 (3H, m), 7.93 (1H, d, J = 7.9
Hz), 8.01-8.04 (2H, m), 8.76 (1H, d, J = 1.8 Hz).
[0320]
Example 110

0.16 mL of aniline, 0.12 g of 1,1'-
bis(diphenylphosphino)ferrocene, 0.057 g of (1,1'-
bis(diphenylphosphino)ferrocene)palladium(II)
dichloride methylene chloride complex and 0.17 g of
sodium tert-butoxide were added to 6 mL of dioxane
solution containing 0.58 g of methyl 2-(benzamido)-4-
bromobenzoate, and the resulting mixture was heated to
reflux under nitrogen atmosphere for 4 hours. After the
reaction mixture was cooled to room temperature, 1 mL
of acetic acid was added and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [eluent;
hexane: ethyl acetate = 5:1] to obtain 0.43 g of methyl
4-(anilino)-2-(benzamido)benzoate as colorless oil.
1H-NMR (DMSO-de) 8: 3.86 (3H, s), 6.79 (1H, dd, J = 9.0,
2.4 Hz), 7.04 (1H, t, J = 7.3 Hz), 7.25 (2H, d, J = 7.6
Hz), 7.35-7.39 (2H, m), 7.59-7.68 (3H, m), 7.89 (1H, d,

192
J = 9.0 Hz), 7.95-7.97 (2H, m) , 8.55 (1H, d, J = 2.4
Hz), 9.03 (1H, s), 12.09 (1H, s).
[0321]
Example 111

1 mL of 10% aqueous sodium hydroxide was
added to 4 mL of ethanol suspension containing 0.43 g
of methyl 4-(anilino)-2-(benzamido)benzoate at room
temperature, and the resulting mixture was heated to
reflux for 2 hours. After the reaction mixture was
cooled to room temperature, 1.0 mol/L hydrochloric acid
and ethyl acetate were added. The organic layer was
separated and dried over anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure.
Diisopropyl ether and hexane were added to the obtained
residue and a solid substance was separated by
filtration to obtain 0.36 g of 4-(anilino)-2-
(benzamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 6.78 (1H, dd, J = 8.9, 2.3 Hz), 7.03
(1H, t, J = 7.3 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.36 (2H,
t, J = 7.7 Hz), 7.57-7.67 (3H, m), 7.90 (1H, d, J = 8.9
Hz), 7.96 (2H, d, J = 7.1 Hz), 8.57 (1H, d, J = 2.3 Hz),
8.97 (1H, s), 12.50 (1H, s), 12.80-13.20 (1H, broad).
[0322]
Example 112


0.16 mL of thiophenol, 0.43 g of potassium
carbonate and 0.030 g of copper(I) iodide were added to
6 mL of ethylene glycol dimethyl ether solution
containing 0.60 g of methyl 2-(benzamido)-4-
iodobenzoate, and the resulting mixture was heated to
reflux under argon atmosphere for 13 hours. After the
reaction mixture was cooled to room temperature, 1.0
mol/L hydrochloric acid and ethyl acetate were added.
The organic layer was separated and dried over
anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[eluent; hexane: ethyl acetate =5:1] to obtain 0.30 g
of methyl 2-(benzamido)-4-(phenylthio)benzoate as white
solid.
1H-NMR (DMSO-de) 8: 3.88 (3H, s), 6.95 (1H, dd, J = 8.4,
1.8 Hz), 7.50-7.67 (8H, m), 7.91-7.96 (3H, m), 8.51 (1H,
d, J = 1.8 Hz), 11.73 (1H, s).
[0323]
Example 113


194
0.4 iriL of 10% aqueous sodium hydroxide was
added to 6 mL of ethanol suspension containing 0.30 g
of methyl 2-(benzamido)-4-(phenylthio)benzoate at room
temperature, and the resulting mixture was heated to
reflux for 1 hour. After the reaction mixture was
cooled to room temperature, 1.0 mol/L hydrochloric acid
and ethyl acetate were added. The organic layer was
separated and dried over anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure.
Diisopropyl ether and hexane were added to the obtained
residue and a solid substance was separated by
filtration to obtain 0.28 g of 2-(benzamido)-4-
(phenylthio)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 6.92 (1H, dd, J = 8.4, 1.8 Hz),
7.47-7.67 (8H, m) , 7.90-7.92 (2H, m), 7.97 (1H, d, J =
8.4 Hz), 8.63 (1H, d, J = 1.8 Hz), 12.25 (1H, s).
[0324]
Example 114

0.15 mL of triethylamine and 0.068 mL of
benzyl mercaptan were added to 2 mL of toluene
suspension containing 0.20 g of methyl 2-(benzamido)-4-
iodobenzoate, 36 mg of 1,1'-bis(diphenylphosphino)-
ferrocene and 24 mg of tris(dibenzylideneacetone)-
dipalladium(O) and stirred under nitrogen atmosphere at
80°C for 2 hours. Insoluble were removed by filtration

195
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [eluent; hexane: ethyl acetate =
10:1] to obtain 0.16 g of methyl 2-(benzamido)-4-
(benzylthio)benzoate as white solid.
1H-NMR (CDC13) 5: 3.94 (3H, s), 4.31 (2H, s), 6.95 (1H,
dd, J = 8.5, 2.0 Hz), 7.24-7.27 (1H, m), 7.30-7.34 (2H,
m), 7.44-7.46 (2H, m), 7.51-7.57 (3H, m), 7.92 (1H, d,
J = 8.5 Hz), 8.04-8.07 (2H, m), 9.03 (1H, d, J = 2.0
Hz), 12.12 (1H, s).
[0325]
Example 115

0.43 mL of 2.0 mol/L aqueous sodium hydroxide
was added dropwise to a mixed solution of 1.5 mL of
methanol and 1.5 mL of tetrahydrofuran containing 0.16
g of methyl 2-(benzamido)-4-(benzylthio)benzoate while
ice-cooled and stirred at room temperature for 18 hours.
The solvent was evaporated under reduced pressure and
water was added and pH was adjusted to pH 4.0 with 1.0
mol/L hydrochloric acid. A solid substance was
separated by filtration to obtain 0.14 g of 2-
(benzamido)-4-(benzylthio)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 4.37 (2H, s) , 7.15 (1H, dd, J = 8.5,
2.0 Hz), 7.24-7.28 (1H, m) , 7.31-7.35 (2H, m), 7.48 (2H,

196
d, J = 7.3 Hz), 7.58-7.68 (3H, m) , 7.94-7.97 (3H, m) ,
8.77 (1H, d, J= 2.0 Hz), 12.30 (1H, s).
[0326]
Example 116

53 mg of tris(dibenzylideneacetone)-
dipalladium(O) and 0.17 g sodium tert-butoxide were
added to 5 mL of toluene solution containing 0.50 g of
tert-butyl 2-(benzamido)-4-iodobenzoate, 0.25 mL of 3-
phenylpropylamine and 36 mg of rac-2,2'-
bis(diphenylphosphino)-1,1-binaphthyl at room
temperature and stirred at 80°C for 7 hours. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration, and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with silica gel column
chromatography [eluent; hexane: ethyl acetate = 6:1] to
obtain 0.11 g of tert-butyl 2-(benzamido)-4-(3-
phenylpropylamino)benzoate as brown oil.
1H-NMR (CDC13) 5: 1.59 (9H, s) , 1.95-2.02 (2H, m) , 2.72-
2.77 (1H, m) , 3.25-3.29 (1H, m), 6.21 (1H, dd, J = 8.8,
2.5 Hz), 7.19-7.22 (3H, m) , 7.26-7.32 (2H, m), 7.49-
7.55 (3H, m), 7.82 (1H, d, J = 8.8 Hz), 8.05-8.07 (2H,
m) , 8.24 (1H, d, J = 2.5 Hz), 12.44-12.46 (1H, broad).
[0327]
Example 117


The following compound was obtained in the
same manner as in Example 116.
tert-Butyl 2-(benzamido)-4-((2-
phenylethyl)amino)benzoate
1H-NMR (CDC13) 8: 1.60 (9H, s) , 2.93-2.98 (2H, m) , 3.50-
3.55 (2H, m), 4.23-4.28 (1H, broad), 6.25 (1H, dd, J=
8.8, 2.4 Hz), 7.23-7.27 (3H, m), 7.31-7.35 (2H, m),
7.50-7.55 (3H, m), 7.83 (1H, d, J = 8.8 Hz), 8.05-8.07
(2H, m), 8.27 (1H, d, J = 2.4 Hz), 12.44-12.48 (1H,
broad).
[0328]
Example 118

1.0 mL of trifluoroacetic acid solution
containing 0.11 g of tert-butyl 2-(benzamido)-4-((3-
phenylpropyl)amino)benzoate was stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and ethyl acetate and water were
added and pH was adjusted to pH 6.3 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride

198
aqueous solution, and the solvent was evaporated under
reduced pressure. Hexane and diisopropyl ether were
added to the obtained residue and a solid substance was
separated by filtration to obtain 71 mg of 2-
3 (benzamido)-4-((3-phenylpropyl)amino)benzoic acid as
white solid.
1H-NMR (DMSO-de) 8: 1.85-1.92 (2H, m) , 2.68-2.72 (2H, m) ,
3.09-3.14 (2H, m), 6.33 (1H, dd, J = 9.0, 2.2 Hz),
6.83-6.86 (1H, m) , 7.16-7.32 (5H, m) , 7.57-7.66 (3H, m) ,
7.77 (1H, d, J = 9.0 Hz), 7.94-7.96 (2H, m), 8.08 (1H,
d, J = 2.2 Hz), 12.54-12.58 (1H, broad), 12.65-12.74
(1H, broad).
[0329]
Example 119

The following compound was obtained in the
same manner as in Example 118.
2-(Benzamido)-4-((2-phenylethyl)amino)benzoic acid
1H-NMR (DMSO-d6-D2O) 5: 2.87-2.91 (2H, m) , 3.32-3.36 (2H,
m), 6.39 (1H, dd, J = 9.0, 2.1 Hz), 7.21-7.26 (1H, m),
7.32-7.33 (4H, m), 7.57-7.66 (3H, m), 7.79 (1H, d, J =
9.0 Hz), 7.94-7.96 (2H, m), 8.11 (1H, d, J = 2.1 Hz).
[0330]
Example 120


0.12 g of 4-iodophenol, 0.18 mL of
tributylamine and 4.2 mg of palladium acetate were
added to 2.4 mL of N,N-dimethylacetamide solution
containing 0.12 g of tert-butyl 2-(benzamido)-4-
vinylbenzoate sequentially at room temperature and
stirred under nitrogen atmosphere at 110°C for 6 hours.
After the reaction mixture was cooled to room
temperature, 10% citric acid aqueous solution and ethyl
acetate were added. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution, a saturated
sodium thiosulfate aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [PSQ100B (spherical) manufactured by
Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate = 1:1] to obtain 0.10 g of tert-butyl 2-
(benzamido)-4-((E)-2-(4-hydroxyphenyl)vinyl)benzoate as
yellow solid.
1H-NMR (DMSO-de) 5: 1.56 (9H, s) , 6.77-6.83 (2H, m) ,
7.11 (1H, d, J = 15.9 Hz), 7.27 (1H, d, J = 15.9 Hz),
7.42 (1H, d, J = 8.4 Hz), 7.50-7.55 (2H, m), 7.59-7.69
(3H, m), 7.94 (1H, d, J = 8.4 Hz), 7.96-8.01 (2H, m) ,
8.68-8.72 (1H, m), 9.71 (1H, s), 11.70 (1H, s).

200
[0331]
Examples 121, 122
The compounds shown in Table 15 were obtained
in the same manner as in Example 120.
[0332]
[Table 15]

[0333]
tert-Butyl 2-(benzamido)-4-((E)-2-(2-
hydroxyphenyl)vinyl)benzoate
1H-NMR (DMSO-de) 5: 1.57 (9H, s) , 6.78-6.93 (2H, m) ,
7.10-7.18 (1H, m), 7.30 (1H, d, J = 16.3 Hz), 7.41 (1H,
dd, J = 8.4, 1.6 Hz), 7.58-7.70 (5H, m), 7.96 (1H, d, J
= 8.4 Hz), 7.98-8.02 (2H, m), 8.76 (1H, d, J = 1.6 Hz),
9.94 (1H, s), 11.71 (1H, s).
[0334]
tert-Butyl 2-(benzamido)-4-((E)-2-(3,5-
dichlorophenyl)vinyl)benzoate
1H-NMR (DMSO-de) 8: 1.56 (9H, s) , 7.36 (1H, d, J = 16.4
Hz), 7.49 (1H, dd, J = 8.3, 1.2 Hz), 7.53 (1H, t, J =
1.8 Hz), 7.56-7.68 (4H, m), 7.82 (2H, d, J = 1.7 Hz),

201
7.97-8.02 (3H, m), 8.74 (1H, d, J = 1.4 Hz), 11.65 (1H,
s) .
[0335]
Example 123

0.14 g of l-bromo-4-nitrobenzene, 0.22 mL of
tributylamine and 5.2 mg of palladium acetate were
added to 2.0 mL of N,N-dimethylacetamide solution
containing 0.15 g of tert-butyl 2-(benzamido)-4-
vinylbenzoate at room temperature and stirred under
nitrogen atmosphere at 110°C for 1 hour and 20 minutes.
After the reaction mixture was cooled to room
temperature, 10% citric acid aqueous solution and ethyl
acetate were added. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution, a saturated
sodium thiosulfate aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-
(4-nitrophenyl)vinyl)benzoate as yellow solid.

202
1H-NMR (DMSO-d6) 5: 1.57 (9H, s) , 7.50-7.68 (6H, m) ,
7.96-8.02 (5H, m) , 8.24-8.28 (2H, m), 8.77 (1H, d, J =
1.5 Hz), 11.64 (1H, s).
[0336]
j Example 124

0.10 mL of l-bromo-4-(trifluoromethoxy)-
benzene, 0.22 mL of tributylamine and 5.2 mg of
palladium acetate were added to 2.0 mL of N,N-
dimethylacetamide solution containing 0.15 g of tert-
butyl 2-(benzamido)-4-vinylbenzoate at room temperature
and stirred under nitrogen atmosphere at 110°C for 3
hours. After the reaction mixture was cooled to room
temperature, 0.07 mL of l-bromo-4-
(trifluoromethoxy)benzene, 0.11 mL of tributylamine and
5.2 mg of palladium acetate were added at room
temperature and stirred under nitrogen atmosphere at
110°C for 2 hours. After the reaction mixture was
cooled to room temperature, 10% citric acid aqueous
solution and ethyl acetate were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with 10% citric acid aqueous
solution, a saturated sodium thiosulfate aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated

203
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; toluene: ethyl acetate = 20:1] to obtain 0.10 g
of tert-butyl 2-(benzamido)-4-((E)-2-(4-
(trifluoromethoxy)phenyl)vinyl)benzoate as white solid.
1H-NMR (DMSO-de) 8: 1.56 (9H, s) , 7.38-7.43 (4H, m) ,
7.51 (1H, dd, J = 8.4, 1.5 Hz), 7.59-7.70 (3H, m),
7.81-7.86 (2H, m), 7.95-8.02 (3H, m), 8.74 (1H, d, J =
1.5 Hz), 11.66 (1H, s).
[0337]
Example 125

The following compound was obtained in the
same manner as in Example 124.
tert-Butyl 2-(benzamido)-4-((E)-2-(3,5-
difluorophenyl)vinyl)benzoate
1H-NMR (DMSO-de) 8: 1.56 (9H, s), 7.18 (1H, tt, J= 9.3,
2.3 Hz), 7.37 (1H, d, J = 16.4 Hz), 7.44-7.54 (4H, m) ,
7.60-7.70 (3H, m), 7.97-8.01 (3H, m), 8.74 (1H, d, J =
1.3 Hz), 11.65 (1H, s).
[0338]
Example 126


204
0.20 g of 6-bromo-2-oxoindoline, 0.40 mL of
N,N-dicyclohexylmethylamine and 18 mg of trans-di(n~
acetato)bis-o-(di-o-tolylphosphino)benzyl
dipalladium(II) were added to 2.0 mL of N,N-
dimethylacetamide solution containing 0.4 6 g of tert-
butyl 2-(benzamido)-4-vinylbenzoate at room temperature
and stirred under nitrogen atmosphere at 110°C for 7
hours. After the reaction mixture was cooled to room
temperature, a saturated sodium hydrogen carbonate
aqueous solution and ethyl acetate were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate =1:1] to
obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(2-
oxoindolin-6-yl)vinyl)benzoate as green solid.
1H-NMR (DMSO-d6) 8: 1.56 (9H, s), 3.50 (2H, s) , 7.11 (1H,
s), 7.21-7.39 (4H, m), 7.50 (1H, dd, J = 8.3, 1.5 Hz),
7.59-7.70 (3H, m), 7.95 (1H, d, J = 8.3 Hz), 7.97-8.02
(2H, m) , 8.69-8.74 (1H, m), 10.50 (1H, s), 11.65 (1H,
s) .
[0339]
Example 127


0.076 mL of 3-chlorostyrene, 0.19 mL of
tributylamine, 2.9 mg of tri-tert-butylphosphine
tetrafluoroborate and 4.5 mg of palladium acetate were
added to 2.0 mL of N,N-dimethylacetamide solution
containing 0.15 g of tert-butyl 2-(benzamido)-4-
bromobenzoate at room temperature and stirred under
nitrogen atmosphere at 110°C for 4 hours and 30 minutes.
After the reaction mixture was cooled to room
temperature, 0.025 mL of 3-chlorostyrene, 2.9 mg of
tri-tert-butylphosphine tetrafluoroborate and 4.5 mg of
palladium acetate were added at room temperature and
stirred under nitrogen atmosphere at 110°C for 1 hour
and 20 minutes. After the reaction mixture was cooled
to room temperature, 10% citric acid aqueous solution
and ethyl acetate were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 10% citric acid aqueous solution, a
saturated sodium thiosulfate aqueous solution and a
saturated sodium chloride aqueous solution sequentially,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [PSQ100B (spherical) manufactured
by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl
acetate = 10:1] to obtain 86 mg of tert-butyl 2-

206
(benzamido)-4-((E)-2-(3-chlorophenyl)vinyl)benzoate as
white solid.
1H-NMR (CDC13) 6: 1.56 (9H, s), 7.13-7.34 (5H, m), 7.40-
7.45 (1H, m), 7.52-7.59 (4H, m), 8.01 (1H, d, J = 8.3
Hz), 8.06-8.11 (2H, m), 9.16 (1H, d, J = 1.7 Hz), 12.27
(1H, s).
[0340]
Example 128

3.0 mL of trifluoroacetic acid suspension
containing 0.17 g of tert-butyl 2-(benzamido)-4-((E)-2-
(2-hydroxyphenyl)vinyl)benzoate was stirred at room
temperature for 30 minutes. The solvent was evaporated
under reduced pressure, toluene was added, and the
solvent was evaporated under reduced pressure. Hexane
was added to the obtained residue and a solid substance
was separated by filtration to obtain 0.12 g of 2-
(benzamido)-4-((E)-2-(2-hydroxyphenyl)vinyl)benzoic
acid as yellow solid.
1H-NMR (DMSO-de) 5: 6.79-6.94 (2H, m) , 7.10-7.19 (1H, m) ,
7.31 (1H, d, J = 16.6 Hz), 7.40 (1H, dd, J = 8.4, 1.6
Hz), 7.55-7.70 (5H, m), 7.97-8.02 (2H, m), 8.05 (1H, d,
J = 8.4 Hz), 8.95 (1H, d, J = 1.6 Hz), 9.94 (1H, s),
12.26 (1H, s).

207
[0341]
Examples 129 to 135
The compounds shown in Table 16 were obtained
in the same manner as in Example 128.
[0342]
[Table 16]

[0343]
2-(Benzamido)-4-((E)-2-(4-nitrophenyl)vinyl)benzoic
acid
1H-NMR (DMSO-d6) 8: 7.50-7.70 (6H, m) , 7.96-8.03 (4H, m) ,
8.09 (1H, d, J = 8.3 Hz), 8.26 (2H, d, J = 8.8 Hz),
8.99 (1H, d, J = 1.4 Hz), 12.23 (1H, s).
[0344]
2-(Benzamido)-4-((E)-2-(3, 5-
difluorophenyl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 6: 7.13-7.22 (1H, m) , 7.38 (1H, d, J =
16.1 Hz), 7.45-7.70 (7H, m), 7.96-8.02 (2H, m) , 8.08
(1H, d, J = 8.3 Hz), 8.95 (1H, s).

208
[0345]
2-(Benzamido)-4-((E)-2-(4-
(trifluoromethoxy)phenyl)vinyl)benzoic acid
1H-NMR (DMSO-de) 5: 7.37-7.44 (4H, m) , 7.47-7.53 (1H, m) ,
7.58-7.70 (3H, m), 7.84 (2H, d, J = 8.6 Hz), 7.96-8.02
(2H, m), 8.07 (1H, d, J = 8.1 Hz), 8.95 (1H, d, J = 1.4
Hz) .
[0346]
2-(Benzamido)-4-((E)-2-(4-hydroxyphenyl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 6.80 (2H, d, J = 8.5 Hz), 7.12 (1H,
d, J = 16.3 Hz), 7.29 (1H, d, J = 16.3 Hz), 7.42 (1H,
dd, J = 8.5, 1.6 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.58-
7.70 (3H, m), 7.96-8.01 (2H, m), 8.03 (1H, d, J = 8.5
Hz), 8.89 (1H, d, J = 1.6 Hz), 9.72 (1H, s) , 12.25 (1H,
s), 13.54-13.80 (1H, broad).
[0347]
2-(Benzamido)-4-((E)-2-(2-oxoindolin-6-yl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 3.50 (2H, s) , 7.12 (1H, s) , 7.21-
7.40 (4H, m), 7.49 (1H, dd, J = 8.3, 1.4 Hz), 7.58-7.69
(3H, m), 7.96-8.02 (2H, m), 8.05 (1H, d, J = 8.3 Hz),
8.91 (1H, d, J = 1.4 Hz), 10.50 (1H, s).
[0348]
2-(Benzamido)-4-((E)-2-(3-chlorophenyl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 7.32-7.51 (5H, m) , 7.56-7.69 (4H, m) ,
7.81 (1H, s), 7.94-8.00 (2H, m), 8.05 (1H, d, J = 8.0
Hz), 8.93 (1H, d, J = 1.2 Hz), 12.23 (1H, s).

209
[0349]
2-(Benzamido)-4-((E)-2- (3,5-
dichlorophenyl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.37 (1H, d, J = 16.6 Hz), 7.49 (1H,
dd, J = 8.4, 1.3 Hz), 7.53 (1H, t, J = 1.9 Hz), 7.58-
7.68 (4H, m), 7.83 (2H, d, J = 1.9 Hz), 7.97-8.01 (2H,
m), 8.08 (1H, d, J = 8.4 Hz), 8.95 (1H, d, J = 1.3 Hz),
12.23 (1H, s).
[0350]
Example 136

12 mg of 5% palladium-carbon was added to a
mixed solution of 1.5 mL of methanol and 1.5 mL of
ethyl acetate containing 60 mg of 2-(benzamido)-4-((E)-
2-(2-hydroxyphenyl)vinyl)benzoic acid and stirred under
hydrogen atmosphere at room temperature for 3 hours and
30 minutes. 6.0 mg of 5% palladium-carbon was added to
the reaction mixture and stirred under hydrogen
atmosphere at room temperature for 3 hours and 20
minutes. 6.0 mg of 5% palladium-carbon was added to the
reaction mixture and stirred under hydrogen atmosphere
at room temperature for 2 hours and 40 minutes.
Insoluble were removed by filtration and the solvent
was evaporated under reduced pressure. Diisopropyl
ether was added to the obtained residue and a solid
substance was separated by filtration to obtain 47 mg

210
of 2-(benzamido)-4-(2-(2-hydroxyphenyl)ethyl)benzoic
acid as white solid.
1H-NMR (DMSO-d6) 5: 2.81-2.94 (4H, m) , 6.68-6.72 (1H, m) ,
6.79-6.82 (1H, m) , 6.98-7.12 (3H, m), 7.57-7.68 (3H, m) ,
7.95-8.01 (3H, m), 8.68 (1H, s), 9.37 (1H, s).
[0351]
Examples 137 to 139
The compounds shown in Table 17 were obtained
in the same manner as in Example 136.
[0352]
[Table 17]

[0353]
2-(Benzamido)-4-(2-(3,5-difluorophenyl)ethyl)benzoic
acid
1H-NMR (DMSO-de) 8: 2.95-3.00 (4H, m) , 6.99-7.10 (4H, m) ,
7.56-7.68 (3H, m), 7.94-8.00 (3H, m), 8.65 (1H, d, J =
1.2 Hz).

211
[0354]
2-(Benzamido)-4-(2-(4-(trifluoromethoxy)phenyl)-
ethyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.96 (4H, s) , 6.98-7.05 (1H, m) ,
7.24-7.30 (2H, m) , 7.37-7.42 (2H, m), 7.55-7.66 (3H, m) ,
7.93-8.00 (3H, m), 8.64 (1H, d, J = 1.5 Hz).
[0355]
2-(Benzamido)-4-(2-(4-hydroxyphenyl)ethyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.78-2.85 (2H, m) , 2.87-2.95 (2H, m) ,
6.64-6.69 (2H, m) , 7.02-7.08 (3H, m) , 7.57-7.68 (3H, m) ,
7.93-7.99 (3H, m), 8.66 (1H, d, J = 1.5 Hz), 9.15 (1H,
s), 12.23 (1H, s).
[0356]
Example 140

9 mg of 5% palladium-carbon was added to a
mixed solution of 2.7 mL of methanol and 2.7 mL of
ethyl acetate containing 30 mg of 2-benzamido -4-((E)-
2-(3-chlorophenyl)vinyl)benzoic acid and stirred under
hydrogen atmosphere at room temperature for 3 hours.
Insoluble were removed by filtration and the solvent
was evaporated under reduced pressure. The obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain

212
2.0 mg of 2-(benzamido)-4-(2-(3-
chlorophenyl)ethyl)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 2.91-3.03 (4H, m) , 7.09 (1H, dd, J =
8.2, 1.5 Hz), 7.22-7.35 (3H, m), 7.37-7.40 (1H, m),
7.57-7.69 (3H, m), 7.94-8.02 (3H, m), 8.67 (1H, d, J =
1.5 Hz), 12.22 (1H, s).
[0357]
Example 141

0.030 mL of 2,4-difluoroiodobenzene, 81 mg of
cesium carbonate, 12 mg of tetrabutylammonium bromide
and 19 mg of polymer supported bis(acetato)-
triphenylphosphine palladium(II) were added to 1.0 mL
of toluene solution containing 40 mg of tert-butyl 2-
(benzamido)-4-vinylbenzoate at room temperature and
stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, 19 mg of
polymer supported bis(acetato)triphenylphosphine
palladium(II) was added and stirred at 110°C for 24
hours. After the reaction mixture was cooled to room
temperature, ethyl acetate and 10% citric acid aqueous
solution were added. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. 10 mL of

213
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and methanol was
added to the obtained residue and a solid substance was
separated by filtration to obtain 15 mg of 2-
(benzamido)-4-((E)-2-(2,4-difluorophenyl)vinyl)benzoic
acid as brown solid.
1H-NMR (DMSO-de) 8: 7.15-7.21 (1H, m) , 7.31-7.46 (3H, m) ,
7.50 (1H, dd, J = 8.3, 1.7 Hz), 7.58-7.71 (3H, m) ,
7.94-8.02 (3H, m), 8.07 (1H, d, J = 8.3 Hz), 8.96 (1H,
s), 12.24 (1H, s), 13.70-13.90 (1H, broad).
[0358]
Example 142

The following compound was obtained in the
same manner as in Example 141.
2-(Benzamido)-4-((E)-2-(benzo[1,3]dioxol-5-
yl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.07 (2H, s), 6.95 (1H, d, J = 8.1
Hz), 7.14 (1H, dd, J = 8.3, 1.5 Hz), 7.23 (1H, d, J =
16.4 Hz), 7.32 (1H, d, J = 16.4 Hz), 7.41 (1H, d, J =
1.7 Hz), 7.44 (1H, dd, J = 8.3, 1.7 Hz), 7.58-7.70 (3H,
m), 7.95-8.01 (2H, m), 8.04 (1H, d, J = 8.3 Hz), 8.90
(1H, d, J = 1.5 Hz), 12.25 (1H, s) , 13.71 (1H, s) .

214
[0359]
Example 14 3

66 mg of 5-bromobenzothiophene, 0.10 g of
cesium carbonate, 15 mg of tetrabutylammonium bromide
and 24 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 1.0 mL of toluene solution containing 50 mg of tert-
butyl 2-(benzamido)-4-vinylbenzoate at room temperature
and stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, 24 mg of
polymer supported bis(acetato)triphenylphosphine
palladium(II) was added and stirred at 110°C for 24
hours. After the reaction mixture was cooled to room
temperature, ethyl acetate and 10% citric acid aqueous
solution were added. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and methanol was
added to the obtained residue and a solid substance was
separated by filtration to obtain 26 mg of 2-

215
(benzamido)-4-((E)-2-(benzothiophene-5-yl)vinyl)benzoic
acid as white solid.
1H-NMR (DMSO-de) 8: 7.41-7.70 (7H, m), 7.77 (1H, dd, J =
8.5, 1.2 Hz), 7.81 (1H, d, J = 5.6 Hz), 7.97-8.10 (4H,
m), 8.18 (1H, d, J = 1.0 Hz), 8.97 (1H, d, J = 1.7 Hz),
12.26 (1H, s), 13.60-13.91 (1H, broad).
[0360]
Example 144

The following compound was obtained in the
same manner as in Example 143.
2-(Benzamido)-4-((E)-2-(quinoxalin-6-yl)vinyl)benzoic
acid
1H-NMR (DMSO-de) 8: 7.58-7.72 (6H, m) , 7.98-8.03 (2H, m) ,
8.08-8.13 (2H, m) , 8.31-8.38 (2H, m), 8.91-9.02 (3H, m) ,
12.24 (1H, s), 13.70-13.90 (1H, broad).
[0361]
Example 14 5

54 mg of 3-iodophenol, 81 mg of cesium
carbonate, 12 mg of tetrabutylammonium bromide and 19
mg of polymer supported bis(acetato)triphenylphosphine
palladium(II) were added to 1.0 mL of toluene solution

216
containing 40 mg of tert-butyl 2-(benzamido)-4-
vinylbenzoate at room temperature and stirred at 110°C
for 24 hours. After the reaction mixture was cooled to
room temperature, 19 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) was added
and stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 40-90% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
25 mg of 2-(benzamido)-4-((E)-2-(3-
hydroxyphenyl)vinyl)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 6.70-6.80 (1H, m) , 7.03-7.07 (1H, m) ,
7.11-7.15 (1H, m) , 7.18-7.33 (3H, m), 7.48 (1H, dd, J =
8.4, 1.5 Hz), 7.58-7.70 (3H, m), 7.96-8.02 (2H, m) ,
8.05 (1H, d, J = 8.4 Hz), 8.91 (1H, s), 9.50 (1H, s),
12.20-12.35 (1H, broad), 13.65-13.85 (1H, broad).
[0362]
Example 146


The following compound was obtained in the
same manner as in Example 145.
2-(Benzamido)-4-((E)-2-(2,1,3-benzothiadiazol-4-
yl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.56-7.72 (4H, m), 7.80 (1H, dd, J=
8.8, 7.1 Hz), 7.87 (1H, d, J = 16.4 Hz), 7.98-8.14 (5H,
m), 8.21 (1H, d, J = 16.4 Hz), 9.06 (1H, s), 12.25-
12.45 (1H, broad).
[0363]
Example 147

0.030 mL of 3-bromopyridine, 0.10 g of cesium
carbonate, 15 mg of tetrabutylammonium bromide and 24
mg of polymer supported bis(acetato)triphenylphosphine
palladium(II) were added to 1.0 mL of toluene solution
containing 50 mg of tert-butyl 2-(benzamido)-4-
vinylbenzoate at room temperature and stirred at 110°C
for 24 hours. After the reaction mixture was cooled to
room temperature, 24 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) was added
and stirred at 110°C for 24 hours. After the reaction

218
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 40-90% acetonitrile
/0.1% trifluoroacetic acid aqueous solution]. Ethyl
acetate and water were added to the obtained purified
substance and pH was adjusted to pH 6.0 with a
saturated sodium hydrogen carbonate aqueous solution.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with water,
and the solvent was evaporated under reduced pressure
to obtain 2.3 mg of 2-(benzamido)-4-((E)-2-(pyridin-3-
yl)vinyl)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 7.39-7.70 (7H, m) , 7.97-8.03 (2H, m) ,
8.08 (1H, d, J = 8.3 Hz), 8.17 (1H, dt, J = 7.9, 1.9
Hz), 8.51 (1H, dd, J = 4.6, 1.5 Hz), 8.86 (1H, d, J =
1.9 Hz), 8.96 (1H, d, J = 1.5 Hz), 12.25-12.50 (1H,
broad).
[0364]
Example 148


61 mg of 5-benzofuran, 0.10 g of cesium
carbonate, 15 mg of tetrabutylammonium bromide and 24
mg of polymer supported bis(acetato)triphenylphosphine
palladium(II) were added to 1.0 mL of toluene solution
containing 50 mg of tert-butyl 2-(benzamido)-4-
vinylbenzoate at room temperature and stirred at 110°C
for 24 hours. After the reaction mixture was cooled to
room temperature, 24 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) was added
and stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain

220
2.4 mg of 2-(benzamido)-4-((E)-2-(benzofuran-5-
yl)vinyl)benzoic acid.
Hi-NMR (DMSO-de) 5: 6.97-7.02 (1H, m) , 7.35 (1H, d, J =
16.3 Hz), 7.46-7.53 (2H, m) , 7.59-7.74 (5H, m), 7.97-
8.08 (5H, m), 8.95 (1H, s), 12.29-12.47 (1H, broad).
[0365]
Example 149

0.12 g of 5-bromobenzofuran, 0.20 g of cesium
carbonate, 30 mg of tetrabutylammonium bromide and 48
mg of polymer supported
di(acetato)dicyclohexylphenylphosphine palladium(II)
were added to 2.0 mL of toluene solution containing
0.10 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at
room temperature and stirred at 110°C for 24 hours.
After the reaction mixture was cooled to room
temperature, 48 mg of polymer supported di(acetato)
dicyclohexylphenyl-phosphine palladium(II) was added
and stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. 2.4 mL of

221
tetrahydrofuran, 0.6 mL of water, 0.44 mL of acetic
acid, 0.42 g sodium formate and 50 mg of 3.9%
palladium-carbon (ethylenediamine complex) were added
to the obtained residue and stirred at 50°C for 12 hours.
After the reaction mixture was cooled to room
temperature, ethyl acetate and 10% citric acid aqueous
solution were added. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. 10 mL of
trifluoroacetic acid was added to the obtained residue
and stirred at room temperature for 1 hour. The solvent
was evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
8.6 mg of 2-(benzamido)-4-(2-(benzofuran-5-
yl)ethyl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 3.02 (4H, s), 6.89 (1H, dd, J = 2.2,
1.0 Hz), 7.09 (1H, dd, J = 8.3, 1.7 Hz), 7.22 (1H, dd,
J = 8.3, 1.6 Hz), 7.49 (1H, d, J = 8.3 Hz), 7.53 (1H, d,
J = 1.7 Hz), 7.57-7.69 (3H, m), 7.92-8.00 (4H, m), 8.69
(1H, d, J = 1.6 Hz), 12.25 (1H, s), 13.54-13.79 (1H,
broad).
[0366]
Example 150


0.055 mL of triethylamine and 0.036 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-(2,4-difluorophenyl)benzoate at room
temperature sequentially and stirred at the same
temperature for 1 hour. 0.014 mL of triethylamine and
0.012 mL of 4-fluorobenzoyl chloride were added to the
reaction mixture at room temperature sequentially and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(4-
fluorobenzamido)benzoate.
10 mL of trifluoroacetic acid was added to
the obtained tert-butyl 4-(2,4-difluorophenyl)-2-(4-
fluorobenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 46 mg of 4-(2,4-

223
difluorophenyl)-2-(4-fluorobenzamido)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 6: 7.27 (1H, td, J = 8.5, 2.5 Hz),
7.36-7.50 (4H, m) , 7.63-7.70 (1H, m), 8.00-8.08 (2H, m) ,
8.14 (1H, d, J = 8.3 Hz), 8.89 (1H, s) , 12.24 (1H, s).
[0367]
Examples 151 to 155
The compounds shown in Table 18 were obtained
in the same manner as in Example 150.
[0368]
[Table 18]

[0369]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-(2,4-
difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 6: 6.17 (2H, s) , 7.13 (1H, d, J = 8.0
Hz), 7.26 (1H, td, J = 8.5, 2.5 Hz), 7.36 (1H, d, J -
8.3 Hz), 7.40-7.48 (2H, m), 7.52-7.57 (1H, m), 7.62-

224
7.69 (1H, m), 8.13 (1H, d, J = 8.3 Hz), 8.91 (1H, s) ,
12.10 (1H, s).
[0370]
2-(Benzothiazole-2-carboxamido)-4-(2,4-
difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.24-7.32 (1H, m) , 7.42-7.50 (2H, m) ,
7.61-7.73 (3H, m) , 8.16-8.23 (2H, m), 8.27-8.32 (1H, m) ,
8.96-8.98 (1H, m), 13.03 (1H, s).
[0371]
4-(2,4-Difluorophenyl)-2-(4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 5: 7.23-7.31 (1H, m) , 7.38-7.49 (2H, m) ,
7.64-7.71 (1H, m), 8.00 (2H, d, J = 8.3 Hz), 8.13-8.18
(3H, m) , 8.88-8.89 (1H, m) , 12.32 (1H, s) .
[0372]
4-(2,4-Difluorophenyl)-2-(4-nitrobenzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.22-7.32 (1H, m) , 7.40-7.49 (2H, m) ,
7.64-7.73 (1H, m) , 8.13-8.23 (3H, m) , 8.42-8.47 (2H, m) ,
8.84-8.85 (1H, m), 12.33 (1H, s).
[0373]
2-Cinnamamido-4-(2,4-difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.92 (1H, d, J = 15.9 Hz), 7.26 (1H,
td, J = 8.4, 2.3 Hz), 7.36 (1H, dt, J = 8.2, 1.7 Hz),
7.39-7.49 (4H, m) , 7.60-7.70 (2H, m) , 7.71-7.79 (2H, m) ,
8.10 (1H, d, J = 8.3 Hz), 8.84 (1H, s), 11.40 (1H, s).
[0374]
Example 156


0.056 mL of triethylamine and 0.036 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-((E)-2-(3-methoxyphenyl)vinyl)benzoate
at room temperature sequentially and stirred at the
same temperature for 1 hour. 0.014 mL of triethylamine
and 0.012 mL of 4-fluorobenzoyl chloride were added to
the reaction mixture at room temperature sequentially
and stirred at the same temperature for 1 hour. A
saturated sodium hydrogen carbonate aqueous solution
was added to the reaction mixture, and the organic
layer was separated, and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [Flash
Tube 2008 manufactured by Trikonex Company, eluent;
hexane: ethyl acetate =4:1] to obtain tert-butyl 2-(4-
fluorobenzamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoate.
10 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(4-fluorobenzamido)-4-((E)-2-
(3-methoxyphenyl)vinyl)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was

226
separated by filtration to obtain 45 mg of 2-(4-
fluorobenzamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoic acid as white solid.
1H-NMR (DMSO-d6) S: 3.82 (3H, s) , 6.90 (1H, dd, J = 7.9,
2.3 Hz), 7.24-7.43 (4H, m), 7.43-7.52 (3H, m), 8.02-
8.08 (3H, m), 8.89 (1H, s), 12.22 (1H, s).
[0375]
Examples 157 to 161
The compounds shown in Table 19 were obtained
in the same manner as in Example 156.
[0376]
[Table 19]

[0377]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoic acid
1H-NMR (DMSO-de) 8: 3.82 (3H, s), 6.17 (2H, s) , 6.88-
6.91 (1H, m), 7.13 (1H, d, J = 8.1 Hz), 7.23-7.43 (5H,

227
m) , 7.44-7.49 (2H, m), 7.56 (1H, dd, J = 8.3, 1.8 Hz),
8.04 (1H, d, J = 8.3 Hz), 8.90 (1H, s), 12.10 (1H, s),
13.60-13.85 (1H, broad).
[0378]
2-(Benzothiazole-2-carboxamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoic acid
1H-NMR (DMSO-d6) 8: 3.83 (3H, s) , 6.88-6.94 (1H, m) ,
7.25-7.46 (5H, m), 7.54 (1H, d, J = 7.9 Hz), 7.61-7.73
(2H, m), 8.09 (1H, d, J = 7.9 Hz), 8.20 (1H, d, J = 7.8
Hz), 8.30 (1H, d, J = 7.8 Hz), 8.96 (1H, s).
[0379]
4-((E)-2-(3-methoxyphenyl)vinyl)-2-(4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-d6) 8: 3.82 (3H, s) , 6.88-6.92 (1H, m) ,
7.24-7.44 (5H, m), 7.39 (2H, d, J = 4.9 Hz), 7.52 (1H,
dd, J = 8.3, 1.4 Hz), 8.01 (2H, d, J = 8.2 Hz), 8.07
(1H, d, J = 8.3 Hz), 8.18 (2H, d, J = 8.2 Hz), 8.88 (1H,
d, J = 1.4 Hz), 12.30 (1H, s).
[0380]
4-((E)-2-(3-methoxyphenyl)vinyl)-2-(4-
nitrobenzamido)benzoic acid
1H-NMR (DMSO-d6) 8: 3.82 (3H, s) , 6.90 (1H, dd, J = 7.7,
1.8 Hz), 7.20-7.46 (5H, m), 7.54 (1H, dd, J = 8.3, 1.6
Hz), 8.07 (1H, d, J = 8.3 Hz), 8.17-8.24 (2H, m), 8.46
(2H, d, J = 8.8 Hz), 8.85 (1H, d, J = 1.6 Hz), 12.32
(1H, s).
[0381]
2-cinnamamido-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic
acid

228
1H-NMR (DMSO-de) 5: 3.82 (3H, s) , 6.86-6.96 (2H, m) ,
7.22-7.40 (5H, m), 7.42-7.50 (4H, m) , 7.65 (1H, d, J =
15.6 Hz), 7.72-7.79 (2H, m), 8.01 (1H, d, J = 8.3 Hz),
8.82 (1H, s), 11.38 (1H, s) .
[0382]
Example 162

0.055 mL of triethylamine and 0.036 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-(3-chlorophenyl)benzoate at room
temperature sequentially and stirred at the same
temperature for 1 hour. 0.014 mL of triethylamine and
0.012 mL of 4-fluorobenzoyl chloride were added to the
reaction mixture at room temperature sequentially and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 4-(3-chlorophenyl)-2-(4-
fluorobenzamido)benzoate.

229
10 mL of trifluoroacetic acid was added to
the obtained tert-butyl 4-(3-chlorophenyl)-2-(4-
fluorobenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 59 mg of 4-(3-
chlorophenyl)-2-(4-fluorobenzamido)benzoic acid as
white solid.
1H-NMR (DMSO-de) 8: 7.46 (2H, t, J = 8.8 Hz), 7.51-7.62
(3H, m) , 7.68-7.74 (1H, m), 7.76 (1H, s), 8.05 (2H, dd,
J = 8.8, 5.4 Hz), 8.14 (1H, d, J = 8.3 Hz), 9.01 (1H, d,
J = 1.7 Hz), 12.20 (1H, s).
[0383]
Examples 163 to 167
The compounds shown in Table 20 were obtained
in the same manner as in Example 162.
[0384]
[Table 20]


230
[0385]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-(3-
chlorophenyl)benzoic acid
1H-NMR (DMSO-de) 8: 6.17 (2H, s) , 7.14 (1H, d, J = 8.3
Hz), 7.45 (1H, d, J = 1.7 Hz), 7.51-7.60 (4H, m), 7.70
(1H, d, J = 7.6 Hz), 7.76 (1H, s), 8.13 (1H, d, J = 8.3
Hz), 9.02 (1H, d, J = 1.7 Hz), 12.13 (1H, s).
[0386]
2-(Benzothiazole-2-carboxamido)-4-(3-
chlorophenyl)benzoic acid
1H-NMR (DMSO-de) 8: 7.52-7.80 (7H, m) , 8.15-8.23 (2H, m) ,
8.30 (1H, d, J = 8.0 Hz), 9.07 (1H, d, J = 1.7 Hz),
13.03 (1H, s).
[0387]
4-(3-Chlorophenyl)-2-(4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.52-7.62 (3H, m) , 7.71 (1H, dt, J =
7.5, 1.6 Hz), 7.77 (1H, t, J = 1.6 Hz), 8.01 (2H, d, J
= 8.2 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.18 (2H, d, J =
8.2 Hz), 8.99 (1H, d, J = 2.0 Hz), 12.30 (1H, s) .
[0388]
4-(3-Chlorophenyl)-2-(4-nitrobenzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.51-7.66 (3H, m) , 7.71 (1H, d, J =
7.6 Hz), 7.78 (1H, s), 8.15 (1H, d, J = 8.3 Hz), 8.21
(2H, d, J = 8.8 Hz), 8.45 (2H, d, J = 8.8 Hz), 8.96 (1H,
d, J = 1.5 Hz), 12.32-12.42 (1H, broad).
[0389]
4-(3-Chlorophenyl)-2-cinnamamidobenzoic acid

231
1H-NMR (DMSO-de) 8: 6.94 (1H, d, J = 15.6 Hz), 7.40-7.49
(3H, m), 7.50-7.60 (3H, m), 7.62-7.79 (5H, m), 8.10 (1H,
d, J = 8.3 Hz), 8.96 (1H, d, J = 1.7 Hz), 11.40 (1H, s)
[0390]
Example 168

0.054 mL of triethylamine and 0.035 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-(benzofuran-2-yl)benzoate at room
temperature sequentially and stirred at the same
temperature for 5 hours. A saturated sodium hydrogen
carbonate aqueous solution was added to the reaction
mixture, and the organic layer was separated, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(benzofuran-2-yl)-2-(4-
fluorobenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(benzofuran-2-yl)-2-(4-
fluorobenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added

232
to the obtained residue and a solid substance was
separated by filtration to obtain 52 mg of 4-
(benzofuran-2-yl)-2-(4-fluorobenzamido)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 6: 7.28-7.35 (1H, m) , 7.38-7.42 (1H, m) ,
7.44-7.52 (2H, m), 7.63 (1H, s) , 7.70-7.81 (3H, m) ,
8.04-8.11 (2H, m), 8.16 (1H, d, J = 8.3 Hz), 9.26-9.27
(1H, m), 12.26 (1H, s).
[0391]
Examples 169 to 172
The compounds shown in Table 21 were obtained
in the same manner as in Example 168.
[0392]
[Table 21]

[0393]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-(benzofuran-2-
yl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.18 (2H, s), 7.15 (1H, d, J = 8.0
Hz), 7.28-7.35 (1H, m), 7.37-7.44 (1H, m), 7.47 (1H, d,
J = 1.7 Hz), 7.58 (1H, dd, J = 8.2, 1.7 Hz), 7.62 (1H,

233
s), 7.70-7.79 (3H, m), 8.15 (1H, d, J = 8.2 Hz), 9.28
(1H, d, J = 1.7 Hz), 12.18 (1H, s).
[0394]
4-(Benzofuran-2-yl)-2-(4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-d6) 5: 7.29-7.35 (1H, m) , 7.39-7.43 (1H, m) ,
7.63 (1H, d, J = 0.9 Hz), 7.70-7.76 (2H, m), 7.80 (1H,
dd, J = 8.4, 1.7 Hz), 8.01 (2H, d, J = 8.2 Hz), 8.15
(1H, d, J = 8.4 Hz), 8.19 (2H, d, J = 8.2 Hz), 9.24-
9.26 (1H, m), 12.37 (1H, s).
[0395]
4-(Benzofuran-2-yl)-2-(4-nitrobenzamido)benzoic acid
1H-NMR (DMSO-d6) 8: 7.29-7.34 (1H, m) , 7.37-7.43 (1H, m) ,
7.63 (1H, s), 7.70-7.74 (2H, m), 7.81 (1H, dd, J= 8.4,
1.7 Hz), 8.16 (1H, d, J = 8.4 Hz), 8.22 (2H, d, J = 8.8
Hz), 8.45 (2H, d, J = 8.8 Hz), 9.21 (1H, d, J = 1.7 Hz),
12.40 (1H, s).
[0396]
4-(Benzofuran-2-yl)-2-(cinnamamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.95 (1H, d, J = 15.4 Hz), 7.29-7.34
(1H, m) , 7.37-7.50 (4H, m), 7.60 (1H, s), 7.66-7.81 (6H,
m), 8.12 (1H, d, J = 8.3 Hz), 9.21 (1H, d, J = 1.7 Hz),
11.47 (1H, s).
[0397]
Example 173


234
0.044 mL of triethylamine and 0.028 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg tert-butyl
2-amino-4-(4-(tert-butoxycarbonyl)oxyphenyl)benzoate at
room temperature sequentially and stirred at the same
temperature for 5 hours. A saturated sodium hydrogen
carbonate aqueous solution was added to the reaction
mixture, and the organic layer was separated, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(4-(tert-
butoxycarbonyl) oxyphenyl)-2-(4-fluorobenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(4-(tert-
butoxycarbonyl) oxyphenyl)-2-(4-fluorobenzamido)benzoate
and stirred at room temperature for 2 hours. The
solvent was evaporated under reduced pressure and
diisopropyl ether was added to the obtained residue and
a solid substance was separated by filtration to obtain
49 mg of 4-(4-hydroxyphenyl)-2-(4-
fluorobenzamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 6: 6.92 (2H, d, J = 8.8 Hz), 7.42-7.50
(3H, m), 7.58 (2H, d, J = 8.8 Hz), 8.00-8.10 (3H, m) ,
8.98 (1H, d, J = 1.7 Hz), 9.79 (1H, s), 12.24 (1H, s).
[0398]
Examples 174 to 178

235
The compounds shown in Table 22 were obtained
in the same manner as in Example 173.
[0399]
[Table 22]

[0400]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-(4-
hydroxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.17 (2H, s) , 6.91 (2H, d, J = 8.8
Hz), 7.13 (1H, d, J = 8.4 Hz), 7.42 (1H, dd, J = 8.4,
1.8 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.52-7.61 (3H, m) ,
8.07 (1H, d, J = 8.3 Hz), 8.99 (1H, d, J = 1.6 Hz),
9.78 (1H, s), 12.14 (1H, s), 13.55-13.85 (1H, broad).
[0401]
2-(Benzothiazole-2-carboxamido)-4-(4-
hydroxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 6.93 (2H, d, J = 8.7 Hz) , 7.52 (1H,
dd, J = 8.4, 1.8 Hz), 7.58-7.72 (4H, m), 8.11 (1H, d, J
= 8.4 Hz), 8.17-8.23 (1H, m), 8.28-8.33 (1H, m), 9.03

236
(1H, d, J = 1.9 Hz), 9.81 (1H, s), 13.05 (1H, s) ,
13.60-14.00 (1H, broad).
[0402]
4-(4-Hydroxyphenyl)-2- (4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-d6) 5: 6.90-6.96 (2H, m) , 7.48 (1H, dd, J =
8.5, 1.8 Hz), 7.56-7.63 (2H, m), 8.01 (2H, d, J = 8.2
Hz), 8.09 (1H, d, J = 8.5 Hz), 8.17 (2H, d, J = 8.2 Hz),
8.97 (1H, d, J = 1.8 Hz), 9.70-9.90 (1H, broad), 12.34
(1H, s).
[0403]
4-(4-Hydroxyphenyl)-2-(4-nitrobenzamido)benzoic acid
1H-NMR (DMSO-de) 8: 6.90-6.95 (2H, m) , 7.49 (1H, dd, J =
8.3, 1.9 Hz), 7.56-7.62 (2H, m) , 8.09 (1H, d, J = 8.3
Hz), 8.17-8.23 (2H, m) , 8.41-8.48 (2H, m), 8.94 (1H, d,
J = 1.9 Hz), 9.80 (1H, s), 12.35 (1H, s).
[0404]
2-(Cinnamamido)-4-(4-hydroxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.88-6.95 (3H, m) , 7.38-7.48 (4H, m) ,
7.53-7.59 (2H, m), 7.65 (1H, d, J = 15.6 Hz), 1.12-1.IS
(2H, m), 8.04 (1H, d, J = 8.6 Hz), 8.92 (1H, d, J = 2.0
Hz), 9.77 (1H, s), 11.43 (1H, s), 13.45-13.70 (1H,
broad).
[0405]
Example 179


237
0.054 mL of triethylamine and 0.034 mL of 4-
fluorobenzoyl chloride were added to 3.5 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-(benzo[l,3]dioxol-5-yl)benzoate at room
temperature sequentially and stirred at the same
temperature for 5 hours. A saturated sodium hydrogen
carbonate aqueous solution was added to the reaction
mixture, and the organic layer was separated, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-
fluorobenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-
fluorobenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 39 mg of 4-
(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoic
acid as white solid.
1H-NMR (DMSO-de) 5: 6.11 (2H, s) , 7.08 (1H, d, J = 8.0
Hz), 7.23 (1H, dd, J = 8.0, 1.9 Hz), 7.29 (1H, d, J =
1.9 Hz), 7.43-7.50 (3H, m) , 8.00-8.16 (3H, m), 8.96 (1H,
d, J = 1.9 Hz), 12.20 (1H, s).
[0406]
Examples 180 to 183

238
The compounds shown in Table 23 were obtained
in the same manner as in Example 17 9.
[0407]
[Table 23]

[0408]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-
(benzo[1,3]dioxol-5-yl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.11 (2H, s) , 6.17 (2H, s) , 7.07 (1H,
d, J = 8.2 Hz), 7.13 (1H, d, J = 8.2 Hz), 7.23 (1H, dd,
J = 8.2, 1.9 Hz), 7.28 (1H, d, J = 1.9 Hz), 7.42-7.47
(2H, m), 7.55 (1H, dd, J = 8.3, 1.9 Hz), 8.07 (1H, d, J
= 8.3 Hz), 8.97 (1H, d, J = 2.0 Hz), 12.12 (1H, s),
13.65-13.85 (1H, broad).
[0409]
4-(Benzo[1,3]dioxol-5-yl)-2-(benzothiazole-2-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.12 (2H, s), 7.09 (1H, d, J = 8.0
Hz), 7.22-7.28 (1H, m), 7.31 (1H, d, J = 1.5 Hz), 7.51-
7.57 (1H, m), 7.60-7.75 (2H, m), 8.12 (1H, d, J = 7.8

239
Hz), 8.16-8.24 (1H, m), 8.30 (1H, d, J = 7.8 Hz), 9.02
(1H, s) , 13.02 (1H, s) .
[0410]
4-(Benzo[l,3]dioxol-5-yl)-2-(4-
(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 5: 6.11 (2H, s) , 7.08 (1H, d, J = 8.1
Hz), 7.24 (1H, dd, J = 8.1, 1.8 Hz), 7.30 (1H, d, J =
1.8 Hz), 7.50 (1H, dd, J = 8.4, 1.9 Hz), 8.01 (2H, d, J
= 8.3 Hz), 8.09 (1H, d, J = 8.4 Hz), 8.17 (2H, d, J =
8.3 Hz), 8.95 (1H, d, J = 1.9 Hz), 12.35 (1H, s) .
[0411]
4-(Benzo[l,3]dioxol-5-yl)-2-(cinnamamido)benzoic acid
1H-NMR (DMSO-d6) 5: 6.11 (2H, s), 6.92 (1H, d, J = 15.6
Hz), 7.07 (1H, d, J = 8.1 Hz), 7.21 (1H, dd, J = 8.1,
1.9 Hz), 7.27 (1H, d, J = 1.9 Hz), 7.41-7.49 (4H, m),
7.65 (1H, d, J = 15.6 Hz), 7.72-7.78 (2H, m), 8.04 (1H,
d, J = 8.3 Hz), 8.90 (1H, d, J = 2.0 Hz), 11.43 (1H, s) .
[0412]
Example 184

1.7 mL of methylene chloride, 1.0 jiL of N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added

240
to a mixed solution of 2.8 mL of methylene chloride and
0.36 mL of triethylamine containing 50 mg of tert-butyl
2-amino-4-(benzofuran-2-yl)benzoate and stirred at room
temperature for 1 hour. A saturated sodium hydrogen
carbonate aqueous solution was added to the reaction
mixture, and the organic layer was separated, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(benzofuran-2-yl)-2-(2,3-
dimethylbenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(benzofuran-2-yl)-2-(2, 3-
dimethylbenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and ethyl acetate was added to
the obtained residue and a solid substance was
separated by filtration to obtain 15 mg of 4-
(benzofuran-2-yl)-2-(2,3-dimethylbenzamido)benzoic acid
as white solid.
1H-NMR (DMSO-de) 8: 2.33 (3H, s) , 2.35 (3H, s) , 7.25 (1H,
t, J = 7.6 Hz), 7.29-7.46 (4H, m), 7.64 (1H, s), 7.71-
7.76 (2H, m), 7.78 (1H, dd, J = 8.3, 1.7 Hz), 8.13 (1H,
d, J = 8.3 Hz), 9.26-9.28 (1H, m) , 11.65 (1H, s).
[0413]
Example 185


The following compound was obtained in the
same manner as in Example 184.
4-(Benzofuran-2-yl)-2-(5-(lH-pyrrol-l-yl)pyridine-3-
carboxamide)benzoic acid
1H-NMR (DMSO-d6) 8: 6.39-6.41 (2H, m) , 7.30-7.43 (2H, m) ,
7.59-7.63 (2H, m), 7.65 (1H, s), 1.11-1.16 (1H, m),
7.83 (1H, dd, J = 8.4, 1.6 Hz), 8.17 (1H, d, J = 8.4
Hz), 8.48-8.51 (1H, m), 9.01 (1H, d, J = 1.5 Hz), 9.18
(1H, d, J = 2.4 Hz), 9.22 (1H, d, J = 1.4 Hz), 12.33
(1H, s).
[0414]
Example 186

1.7 mL of methylene chloride, 1.0 \xL of N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 62 mg of tert-butyl 2-amino-4-
(4-(tert-butoxycarbonyl)oxyphenyl)benzoate, 2.8 mL of
methylene chloride and 0.36 mL triethylamine and

242
stirred at room temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 2-(2,3-dimethylbenzamido)-4-
(4-(tert-butoxycarbonyl)oxyphenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2,3-dimethylbenzamido)-4-(4-
(tert-butoxycarbonyl)oxyphenyl)benzoate and stirred at
room temperature for 2 hours. The solvent was
evaporated under reduced pressure and ethyl acetate was
added to the obtained residue and a solid substance was
separated by filtration to obtain 20 mg of 2-(2,3-
dimethylbenzamido)-4-(4-hydroxyphenyl)benzoic acid as
white solid.
1H-NMR (DMSO-de) 5: 2.31 (3H, s) , 2.33 (3H, s) , 6.90-
6.95 (2H, m), 7.23 (1H, t, J = 7.5 Hz), 7.34 (1H, d, J
= 7.5 Hz), 7.40 (1H, d, J = 7.5 Hz), 7.44 (1H, dd, J =
8.3, 1.7 Hz), 7.56-7.60 (2H, m), 8.05 (1H, d, J = 8.3
Hz), 8.97-8.99 (1H, m), 9.75-9.85 (1H, broad), 11.59
(1H, s), 13.40-13.70 (1H, broad).
[0415]
Example 187


The following compound was obtained in the
same manner as in Example 186.
4-(4-Hydroxyphenyl)-2-(5-(lH-pyrrol-l-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.39 (2H, s), 6.93 (2H, d, J = 8.5
Hz), 7.50 (1H, dd, J = 8.4, 1.3 Hz), 7.56-7.65 (4H, m),
8.09 (1H, d, J = 8.0 Hz), 8.47 (1H, s), 8.93-8.99 (2H,
m) , 9.17 (1H, d, J = 2.2 Hz), 9.80 (1H, s), 12.31 (1H,
s).
[0416]
Example 188

1.7 mL of methylene chloride, 1.0 |J.L N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 50 mg of tert-butyl 2-amino-4-
(benzo[l,3]dioxol-5-yl)benzoate, 2.8 mL of methylene
chloride and 0.36 mL of triethylamine and stirred at

244
room temperature for 1 hour. A saturated sodium
hydrogen carbonate aqueous solution was added to the
reaction mixture, and the organic layer was separated,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-
dimethylbenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-
dimethylbenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and methanol was added to the
obtained residue and a solid substance was separated by
filtration to obtain 31 mg of 4-(benzo[1,3]dioxol-5-
yl)-2-(2,3-dimethylbenzamido)benzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 2.31 (3H, s) , 2.33 (3H, s) , 6.11 (2H,
s), 7.08 (1H, d, J = 8.1 Hz), 7.20-7.27 (2H, m), 7.29
(1H, d, J = 1.7 Hz), 7.34 (1H, d, J = 7.3 Hz), 7.40 (1H,
d, J = 7.3 Hz), 7.46 (1H, dd, J = 8.4, 1.8 Hz), 8.05
(1H, d, J = 8.4 Hz), 8.93-9.00 (1H, broad), 11.58 (1H,
s), 13.55-13.75 (1H, broad).
[0417]
Example 189


1.7 mL of methylene chloride, 1.0 |4.L of N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 49 mg of tert-butyl 2-amino-4-
(2,4-difluorophenyl)benzoate, 2.8 mL of methylene
chloride and 0.36 mL of triethylamine and stirred at
room temperature for 1 hour. A saturated sodium
hydrogen carbonate aqueous solution was added to the
reaction mixture, and the organic layer was separated,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(2,3-
dimethylbenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(2,4-difluorophenyl)-2-(2,3-
dimethylbenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and methanol was added to the
obtained residue and a solid substance was separated by

246
filtration to obtain 17 mg of 4-(2,4-difluorophenyl)-2-
(2,3-dimethylbenzamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 6: 2.31 (3H, s), 2.31 (3H, s), 7.21-
7.30 (2H, m), 7.31-7.49 (4H, m), 7.63-7.70 (1H, m),
8.11 (1H, d, J = 8.0 Hz), 8.89 (1H, s) , 11.58 (1H, s).
[0418]
Example 190

The following compound was obtained in the
same manner as in Example 189.
4-(2,4-Difluorophenyl)-2-(5-(lH-pyrrol-l-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.39 (2H, t, J = 2.2 Hz), 7.28 (1H,
td, J = 8.7, 2.2 Hz), 7.42-7.48 (2H, m), 7.59 (2H, t, J
= 2.2 Hz), 7.68 (1H, td, J = 8.7, 6.6 Hz), 8.16 (1H, d,
J = 8.0 Hz), 8.46 (1H, t, J = 2.2 Hz), 8.85 (1H, d, J =
1.4 Hz), 8.97 (1H, d, J = 1.7 Hz), 9.17 (1H, d, J = 2.3
Hz), 12.22 (1H, s).
[0419]
Example 191


247
1.7 mL of methylene chloride, 1.0 (iL of N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 52 mg of tert-butyl 2-amino-4-
((E)-2-(3-methoxyphenyl)vinyl)benzoate, 2.8 mL of
methylene chloride and 0.36 mL of triethylamine and
stirred at room temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 2-(2,3-dimethylbenzamido)-4-
((E)-2-(3-methoxyphenyl)vinyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2,3-dimethylbenzamido)-4-((E)-2-
(3-methoxyphenyl)vinyl)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and methanol was added to the
obtained residue and a solid substance was separated by
filtration to obtain 15 mg of 2-(2,3-
dimethylbenzamido)-4-((E)-2-(3-
methoxyphenyl)vinyl)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 2.31 (3H, s) , 2.33 (3H, s) , 3.82 (3H,
s), 6.88-6.91 (1H, m) , 7.21-7.52 (9H, m), 8.02 (1H, d,
J = 8.3 Hz), 8.89 (1H, s), 11.59 (1H, s), 13.60 (1H, s).


The following compound was obtained in the
same manner as in Example 191.
4-((E)-2-(3-Methoxyphenyl)vinyl)-2- (5-(lH-pyrrol-1-
yl)pyridine-3-carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 3.83 (3H, s), 6.40 (2H, t, J = 2.2
Hz), 6.91 (1H, ddd, J = 8.0, 2.5, 0.9 Hz), 7.25-7.44
(5H, m), 7.53 (1H, dd, J = 8.3, 1.6 Hz), 7.59 (2H, t, J
= 2.2 Hz), 8.07 (1H, d, J = 8.3 Hz), 8.45-8.47 (1H, m) ,
8.84 (1H, d, J = 1.7 Hz), 8.99 (1H, d, J = 1.6 Hz),
9.17 (1H, d, J = 2.4 Hz), 12.20-12.35 (1H, broad).
[0421]
Example 193

1.7 mL of methylene chloride, 1.0 ^L of N,N-
dimethylformamide and 0.025 mL of oxalyl chloride were
added to 41 mg of 2,3-dimethylbenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added

249
to a mixed solution of 49 mg of tert-butyl 2-amino-4-
(3-chlorophenyl)benzoate, 2.8 mL of methylene chloride
and 0.36 mL of triethylamine and stirred at room
temperature for 1 hour. A saturated sodium hydrogen
carbonate aqueous solution was added to the reaction
mixture, and the organic layer was separated, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 4-(3-chlorophenyl)-2-(2,3-
dimethylbenzamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-(3-chlorophenyl)-2-(2,3-
dimethylbenzamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and methanol was added to the
obtained residue and a solid substance was separated by
filtration to obtain 32 mg of 4-(3-chlorophenyl)-2-
(2,3-dimethylbenzamido)benzoic acid as white solid.
1H-NiyiR (DMSO-d6) 8: 2.31 (3H, s), 2.33 (3H, s) , 7.24 (1H,
t, J = 7.5 Hz), 7.34 (1H, d, J = 7.5 Hz), 7.41 (1H, d,
J = 7.5 Hz), 7.52-7.61 (3H, m) , 7.69-7.78 (2H, m), 8.11
(1H, d, J = 8.3 Hz), 9.01 (1H, s), 11.58 (1H, s),
13.60-13.90 (1H, broad).
[0422]
Examples 194, 195
The compounds shown in Table 24 were obtained
in the same manner as in Example 193.


[0424]
4-(3-Chlorophenyl)-2-(5-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.39 (2H, t, J = 2.2 Hz), 7.52-7.64
(5H, m), 7.72 (1H, dt, J = 7.6, 1.6 Hz), 7.78 (1H, t, J
= 1.6 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.46-8.48 (1H, m),
8.96 (1H, d, J = 1.7 Hz), 8.99 (1H, d, J = 1.7 Hz),
9.17 (1H, d, J = 2.7 Hz), 12.23 (1H, s) .
[0425]
1H-NMR (DMSO-d6) 8: 2.32 (3H, s) , 7.39 (2H, d, J = 8.5
Hz), 7.52-7.62 (3H, m) , 7.68-7.74 (1H, m), 7.77 (1H, s),
8.03 (2H, d, J = 8.5 Hz), 8.14 (1H, d, J = 8.3 Hz),
9.03 (1H, d, J = 1.7 Hz), 12.23 (1H, s).
[0426]
Example 196


251
7.6 mg of potassium carbonate was added to a
mixed solution of 0.5 mL of methanol and 0.5 mL of
tetrahydrofuran containing 15 mg of 2-(4-
acetoxybenzamido)-4-(3-chlorophenyl)benzoic acid and
stirred at room temperature for 2 hours. After
insoluble were removed by filtration, 10% citric acid
aqueous solution was added and a solid substance was
separated by filtration to obtain 10 mg of 4-(3-
chlorophenyl)-2-(4-hydroxybenzamido)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 5: 6.91-6.97 (2H, m) , 7.47-7.60 (3H, m) ,
7.69 (1H, dt, J = 7.5, 1.6 Hz), 7.75 (1H, t, J = 1.6
Hz), 7.83-7.89 (2H, m), 8.12 (1H, d, J = 8.3 Hz), 9.07
(1H, d, J = 1.9 Hz), 10.28 (1H, s) .
[0427]
Example 197

0.21 mL of cyclopentene, 0.14 g of potassium
acetate, 0.13 g of tetrabutylammonium chloride, 3.1 mg
of triphenylphosphine and 2.7 mg of palladium acetate
were added to 1.0 mL of N-dimethylformamide solution
containing 0.20 g of tert-butyl 2-(benzamido)-4-
iodobenzoate at room temperature and stirred under
nitrogen atmosphere at the same temperature for 17
hours. 0.21 mL of cyclopentene, 23 mg of potassium
acetate, 3.1 mg of triphenylphosphine and 2.7 mg of

252
palladium acetate were added to the reaction mixture
and stirred at 70°C for 3 hours after stirred at room
temperature for 9 hours. After the reaction mixture was
cooled to room temperature, ethyl acetate and 10%
citric acid aqueous solution were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with 10% citric acid aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [eluent;
toluene] to obtain 94 mg of tert-butyl 2-(benzamido)-4-
(2-cyclopenten-l-yl)benzoate as white solid.
1H-NMR (CDC13) 8: 1.62 (9H, s) , 1.72-1.84 (1H, m) , 2.37-
2.61 (3H, m), 3.94-4.03 (1H, m) , 5.78-5.82 (1H, m) ,
5.98-6.03 (1H, m), 6.93 (1H, dd, J = 8.3, 1.6 Hz),
7.49-7.59 (3H, m), 7.94 (1H, d, J = 8.3 Hz), 8.04-8.09
(2H, m), 8.80 (1H, d, J = 1.6 Hz), 12.22 (1H, s).
[0428]
Example 198

10 mL of trifluoroacetic acid solution
containing 87 mg of tert-butyl 2-(benzamido)-4-(2-
cyclopenten-1-yl)benzoate was stirred at room
temperature for 1 hour. The solvent was evaporated
under reduced pressure and methanol was added to the

253
obtained residue and a solid substance was separated by
filtration to obtain 52 mg of 2-(benzamido)-4-(2-
cyclopenten-l-yl)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 1.62-1.74 (1H, m) , 2.35-2.55 (3H, m) ,
3.92-4.00 (1H, m) , 5.78-5.83 (1H, m) , 6.00-6.04 (1H, m) ,
7.03 (1H, dd, J = 8.2, 1.5 Hz), 7.57-7.68 (3H, m) ,
7.93-8.01 (3H, m), 8.63 (1H, d, J = 1.5 Hz), 12.24 (1H,
s) .
[0429]
Example 199

5.0 mg of 5% palladium-carbon was added to a
mixed solution of 1.0 mL of methanol and 0.5 mL of
ethyl acetate containing 25 mg of 2-(benzamido)-4-(2-
cyclopenten-1-yl)benzoic acid and stirred at room
temperature under hydrogen atmosphere for 7 hours and
then at 40°C for 8 hours and stirred at 45°C for 15
hours. Insoluble were removed by filtration and the
solvent was evaporated under reduced pressure. Methanol
was added to the obtained residue and a solid substance
was separated by filtration to obtain 16 mg of 2-
(benzamido)-4-cyclopentyl benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 1.52-1.86 (6H, m) , 1.98-2.12 (2H, m) ,
3.02-3.12 (1H, m), 7.10 (1H, dd, J = 8.0, 1.6 Hz),
7.57-7.68 (3H, m), 7.94-8.00 (3H, m), 8.70 (1H, d, J =
1.6 Hz), 12.22 (1H, s).


0.11 g of 4-nitrophenylboronic acid, 0.11 g of
sodium hydrogen carbonate, 1.2 mL of ethanol, 0.6 mL of
water and 31 mg of
tetrakis(triphenylphosphine)palladium(O) were added to
4.0 mL of toluene solution containing 0.20 g of tert-
butyl 2-(benzamido)-4-bromobenzoate, and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 3 hours. A saturated sodium hydrogen carbonate
aqueous solution was added after the reaction mixture
was cooled to room temperature. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium chloride aqueous
solution, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [PSQ100B (spherical)
manufactured by Fuji Silysia Chemical Ltd., eluent;
hexane: ethyl acetate = 10:1] to obtain 40 mg of tert-
butyl 2-(benzamido)-4-(4-nitrophenyl)benzoate as white
solid.
1H-NMR (DMSO-d6) 8: 1.57 (9H, s), 7.60-7.70 (4H, m) ,
7.98-8.04 (3H, m), 8.09 (1H, d, J = 8.8 Hz), 8.35-8.40
(3H, m), 8.90 (1H, d, J = 1.7 Hz), 11.66 (1H, s).

255
[0431]
Examples 201 to 205
The compounds shown in Table 25 were obtained
in the same manner as in Example 200.
[0432]
[Table 25]

[0433]
tert-Butyl 2-(benzamido)-4-(4-chlorophenyl)benzoate
1H-NMR (DMSO-de) 5: 1.57 (9H, s) , 7.55 (1H, dd, J = 8.4,
1.6 Hz), 7.58-7.70 (5H, m) , 7.73-7.78 (2H, m), 7.97-
8.02 (2H, m), 8.04 (1H, d, J = 8.4 Hz), 8.85 (1H, d, J
=1.6 Hz), 11.69 (1H, s).
[0434]
tert-Butyl 2-(benzamido)-4-(3,5-dichlorophenyl)benzoate
1H-NMR (DMSO-de) 8: 1.56 (9H, s) , 7.60-7.70 (4H, m) ,
7.72-7.73 (1H, m), 7.77 (2H, d, J = 1.7 Hz), 7.98-8.04
(3H, m) , 8.77 (1H, d, J = 2.0 Hz), 11.58 (1H, s) .
[0435]
tert-Butyl 2-(benzamido)-4-(3,5-dimethyl-4-
hydroxyphenyl)benzoate

256
1H-NMR (CDCI3) 8: 1.65 (9H, s) , 2.33 (6H, s) , 4.78 (1H,
s), 7.29 (1H, dd, J = 8.4, 1.8 Hz), 7.36 (2H, s), 7.51-
7.60 (3H, m), 8.03 (1H, d, J = 8.4 Hz), 8.06-8.11 (2H,
m) , 9.18 (1H, d, J = 1.8 Hz), 12.28 (1H, s) .
[0436]
tert-Butyl 2-(benzamido)-4-(2-oxoindolin-5-yl)benzoate
1H-NMR (CDCI3) 5: 1.65 (9H, s) , 3.64 (2H, s) , 6.96 (1H,
d, J = 8.1 Hz), 7.29 (1H, dd, J = 8.5, 1.9 Hz), 7.52-
7.65 (5H, m) , 7.82 (1H, s) , 8.05-8.11 (3H, m) , 9.22 (1H,
d, J = 1.9 Hz), 12.30 (1H, s).
[0437]
tert-Butyl 2-(benzamido)-4-(3-chloro-2-
fluorophenyl)benzoate
1H-NMR (DMSO-d6) 8: 1.57 (9H, s), 7.40 (1H, t, J = 7.9
Hz), 7.43-7.47 (1H, m) , 7.54-7.72 (5H, m) , 7.96-8.01
(2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.72 (1H, s), 11.66
(1H, s).
[0438]
Example 206

0.10 g of 2,6-difluorophenylboronic acid, 0.52
g of cesium carbonate, 2.4 mg of palladium acetate and
2.2 mg of 2-dicyclohexylphosphino-2',6'-
dimethoxybiphenyl were added to 2.5 mL of toluene
solution containing 0.20 g of tert-butyl 2-(benzamido)-
4-bromobenzoate at room temperature sequentially, and

257
stirred under nitrogen atmosphere at 80°C for 1 hour and
10 minutes and then heated to reflux for 1 hour. After
the reaction mixture was cooled to room temperature,
2.4 mg of palladium acetate and 2.2 mg of 2-
dicyclohexylphosphino-2', 6'-dimethoxybiphenyl were
added and the resulting mixture was heated to reflux
under nitrogen atmosphere for 1 hour. After the
reaction mixture was cooled to room temperature, 2.4 mg
of palladium acetate and 2.2 mg of 2-
dicyclohexylphosphino-2',6'-dimethoxybiphenyl were
added and the resulting mixture was heated to reflux
under nitrogen atmosphere for 1 hour. After the
reaction mixture was cooled to room temperature, were
added 2.0 mL of toluene, 0.04 g of 2,6-
difluorophenylboronic acid, 2.4 mg of palladium acetate
and 2.2 mg of 2-dicyclohexylphosphino-2',6'-
dimethoxybiphenyl and the resulting mixture was heated
to reflux under nitrogen atmosphere for 1 hour. A
saturated sodium hydrogen carbonate aqueous solution
and ethyl acetate were added after the reaction mixture
was cooled to room temperature. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium hydrogen carbonate
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate = 20:1] to

258
obtain 31 mg of tert-butyl 2-(benzamido)-4-(2,6-
difluorophenyl)benzoate as white solid.
1H-NMR (DMSO-d6) 5: 1.57 (9H, s) , 7.26-7.36 (3H, m) ,
7.53-7.67 (4H, m), 7.95-8.00 (2H, m), 8.07 (1H, d, J =
8.0 Hz), 8.57-8.61 (1H, m) , 11.63 (1H, s).
[0439]
Example 207

48 mg of 5-bromobenzothiophene, 40 mg of
sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of
water and 11 mg of tetrakis(triphenylphosphine)-
palladium(0) were added to 1.6 mL of toluene solution
containing 80 mg of tert-butyl 2-(benzamido)-4-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate
at room temperature, and the resulting mixture was
heated to reflux under nitrogen atmosphere for 5 hours.
Ethyl acetate and water were added after the reaction
mixture was cooled to room temperature. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate = 20:1] to obtain 47 mg

259
of tert-butyl 2-(benzamido)-4-(benzothiophen-5-
yl)benzoate as white solid.
1H-NMR (CDC13) 8: 1.66 (9H, s) , 7.40-7.44 (2H, m) , 7.50
(1H, d, J= 5.4 Hz), 7.51-7.61 (3H, m), 7.71 (1H, dd, J
= 8.5, 1.7 Hz), 7.96 (1H, d, J = 8.3 Hz), 8.08-8.13 (3H,
m), 8.19 (1H, d, J = 1.5 Hz), 9.34 (1H, d, J = 1.7 Hz),
12.31 (1H, s).
[0440]
Examples 208 to 210
The compounds shown in Table 26 were obtained
in the same manner as in Example 207.
[0441]
[Table 26]

[0442]
tert-Butyl 2-(benzamido)-4-(benzofuran-5-yl)benzoate
1H-NMR (CDCI3) 8: 1.66 (9H, s) , 6.84 (1H, dd, J = 2.2,
1.0 Hz), 7.38 (1H, dd, J = 8.3, 2.0 Hz), 7.51-7.61 (4H,
m), 7.64-7.68 (2H, m), 7.96 (1H, d, J = 1.5 Hz), 8.07-
8.12 (3H, m), 9.30 (1H, d, J = 2.0 Hz), 12.29 (1H, s).
[0443]
tert-Butyl 2-(benzamido)-4-(lH-indol-4-yl)benzoate

260
1H-NMR (CDCI3) 8: 1.66 (9H, s), 6.93-6.97 (1H, m), 7.24-
7.36 (3H, m), 7.40-7.50 (2H, m), 7.50-7.60 (3H, m),
8.07-8.13 (2H, m), 8.13 (1H, d, J = 8.3 Hz), 8.31 (1H,
s), 9.33 (1H, d, J = 1.5 Hz), 12.24 (1H, s) .
[0444]
tert-Butyl 2-(benzamido)-4-(4-(lH-pyrrol-1-
yl)phenyl)benzoate
1H-NMR (CDCI3) 5: 1.66 (9H, s) , 6.38 (2H, t, J = 2.2 Hz),
7.16 (2H, t, J = 2.2 Hz), 7.35 (1H, dd, J = 8.3, 1.7
Hz), 7.47-7.52 (2H, m) , 7.52-7.61 (3H, m), 7.76-7.82
(2H, m) , 8.07-8.12 (3H, m), 9.29 (1H, d, J = 1.7 Hz),
12.29 (1H, s).
[0445]
Example 211

3.0 mL of trifluoroacetic acid solution
containing 40 mg of tert-butyl 2-(benzamido)-4-(4-
nitrophenyl)benzoate was stirred at room temperature
for 1 hour. The solvent was evaporated under reduced
pressure and ethyl acetate and methanol were added to
the obtained residue and a solid substance was
separated by filtration to obtain 15 mg of 2-
(benzamido)-4-(4-nitrophenyl)benzoic acid as white
solid.

261
1H-NMR (DMSO-d6) 8: 7.60-7.70 (4H, m) , 7.98-8.04 (4H, m) ,
8.20 (1H, d, J - 8.6 Hz), 8.39 (2H, d, J = 8.5 Hz),
9.16 (1H, s), 12.26-12.32 (1H, broad).
[0446]
Examples 212 to 221
The compounds shown in Table 27 were obtained
in the same manner as in Example 211.
[0447]
[Table 27]

[0448]
2-(Benzamido)-4-(4-chlorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.53 (1H, dd, J = 8.3, 1.8 Hz),
7.59-7.70 (5H, m) , 7.75-7.79 (2H, m) , 7.97-8.01 (2H, m) ,
8.14 (1H, d, J = 8.3 Hz), 9.08 (1H, d, J = 1.8 Hz),
12.28 (1H, s).
[0449]
2-(Benzamido)-4-(3,5-dichlorophenyl)benzoic acid

262
1H-NMR (DMSO-de) 5: 7.58-7.70 (4H, m), 7.73 (1H, t, J =
1.8 Hz), 7.77 (2H, d, J = 2.0 Hz), 7.97-8.02 (2H, m),
8.14 (1H, d, J = 8.3 Hz), 9.03 (1H, d, J = 1.7 Hz),
12.24-12.31 (1H, broad).
[0450]
2-(Benzamido)-4-(3,5-dimethyl-4-hydroxyphenyl)benzoic
acid
1H-NMR (DMSO-de) 8: 2.26 (6H, s) , 7.32 (2H, s) , 7.44 (1H,
dd, J = 8.3, 1.8 Hz), 7.58-7.70 (3H, m), 7.96-8.02 (2H,
m) , 8.07 (1H, d, J = 8.3 Hz), 8.60 (1H, s), 9.01 (1H, d,
J= 1.8 Hz), 12.27 (1H, s), 13.60-13.80 (1H, broad).
[0451]
2-(Benzamido)-4-(2-oxoindolin-5-yl)benzoic acid
1H-NMR (DMSO-de) 5: 3.60 (2H, s), 6.97 (1H, d, J = 8.1
Hz), 7.47 (1H, dd, J = 8.5, 1.8 Hz), 7.56-7.70 (5H, m),
7.96-8.02 (2H, m), 8.10 (1H, d, J = 8.5 Hz), 9.06 (1H,
d, J = 1.8 Hz), 10.57 (1H, s), 12.28 (1H, s), 13.60-
13.90 (1H, broad).
[0452]
2-(Benzamido)-4-(3-chloro-2-fluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.37-7.44 (2H, m) , 7.56-7.72 (5H, m) ,
7.95-8.00 (2H, m), 8.17 (1H, d, J = 8.3 Hz), 8.97 (1H,
s), 12.22-12.26 (1H, broad).
[0453]
2-(Benzamido)-4-(2,6-difluorophenyl)benzoic acid
1H-NMR (DMSO-de) 8: 7.24-7.35 (3H, m) , 7.52-7.69 (4H, m) ,
7.93-8.00 (2H, m), 8.17 (1H, d, J = 8.3 Hz), 8.86 (1H,
s), 12.24 (1H, s).

263
[0454]
2-(Benzamido)-4-(benzothiophen-5-yl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.58-7.71 (5H, m) , 7.74 (1H, dd, J =
8.5, 1.7 Hz), 7.87 (1H, d, J = 5.4 Hz), 7.98-8.04 (2H,
m) , 8.14-8.20 (2H, m), 8.27 (1H, d, J = 1.4 Hz), 9.18
(1H, d, J = 1.7 Hz), 12.31 (1H, s), 13.75-13.95 (1H,
broad).
[0455]
2-(Benzamido)-4-(benzofuran-5-yl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.09 (1H, dd, J = 2.2, 1.0 Hz), 7.56
(1H, dd, J = 8.3, 2.0 Hz), 7.59-7.71 (4H, m) , 7.76 (1H,
d, J = 8.5 Hz), 7.98-8.04 (2H, m), 8.03 (1H, d, J = 1.5
Hz), 8.09 (1H, d, J = 2.2 Hz), 8.15 (1H, d, J = 8.3 Hz),
9.14 (1H, d, J = 2.0 Hz), 12.30 (1H, s), 13.70-13.95
(1H, broad).
[0456]
2-(Benzamido)-4-(lH-indol-4-yl)benzoic acid
1H-NMR (DMSO-de) 5: 6.75-6.79 (1H, m) , 7.21-7.27 (2H, m) ,
7.47-7.54 (2H, m), 7.53 (1H, dd, J = 8.3, 1.8 Hz),
7.58-7.70 (3H, m), 7.98-8.03 (2H, m), 8.17 (1H, d, J =
8.3 Hz), 9.17 (1H, d, J = 1.8 Hz), 11.37 (1H, s), 12.29
(1H, s).
[0457]
2-(Benzamido)-4-(4-(lH-pyrrol-l-yl)phenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.32 (2H, t, J = 2.2 Hz), 7.48 (2H,
t, J = 2.2 Hz), 7.57 (1H, dd, J = 8.4, 1.9 Hz), 7.59-
7.71 (3H, m), 7.74-7.80 (2H, m), 7.80-7.86 (2H, m),
7.98-8.03 (2H, m), 8.15 (1H, d, J = 8.4 Hz), 9.12 (1H,
d, J = 1.9 Hz), 12.30 (1H, s) .


44 mg of 3-chlorophenylboronic acid, 4 9 mg of
sodium carbonate and 6 mg of polymer supported
di(acetato)dicyclohexylphenylphosphine palladium(II)
were added to 2.5 mL of N,N-dimethylacetamide solution
containing 70 mg of tert-butyl 2-(benzamido)-4-
bromobenzoate, and stirred at 90°C for 15 hours. After
the reaction mixture was cooled to room temperature,
5.7 mg of polymer supported di(acetato)
dicyclohexylphenylphosphine palladium(II) was added and
stirred at 110°C for 9 hours and 30 minutes. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate = 4:1] to obtain tert-
butyl 2-(benzamido)-4-(3-chlorophenyl)benzoate.

265
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(3-
chlorophenyl)benzoate and stirred at room temperature
for 1 hour. The solvent was evaporated under reduced
pressure and methanol was added to the obtained residue
and a solid substance was separated by filtration to
obtain 21 mg of 2-(benzamido)-4-(3-chlorophenyl)benzoic
acid as white solid.
1H-NMR (DMSO-d6) 8: 1.52-1.1 A (7H, m) , 7.77 (1H, s) ,
7.97-8.03 (2H, m), 8.14 (1H, d, J = 8.3 Hz), 9.06 (1H,
d, J = 2.0 Hz), 12.27 (1H, s) .
[0459]
Examples 223 to 231
The compounds shown in Table 28 were obtained
in the same manner as in Example 222.
[0460]
[Table 28]


266
[0461]
2-(Benzamido)-4-(3-fluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.27-7.36 (1H, m) , 7.53-7.70 (7H, m) ,
7.96-8.02 (2H, m), 8.14 (1H, d, J = 8.0 Hz), 9.08 (1H,
d, J = 1.7 Hz) , 12.24 (1H, s) .
[0462]
2-(Benzamido)-4-(2,3-difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.34-7.47 (3H, m) , 7.50-7.70 (4H, m) ,
7.95-8.01 (2H, m), 8.17 (1H, d, J = 8.3 Hz), 8.98 (1H,
s), 12.25 (1H, s).
[0463]
2-(Benzamido)-4-(3,5-difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.36 (1H, tt, J = 9.1, 2.2 Hz),
7.43-7.51 (2H, m) , 7.56-7.71 (4H, m), 7.96-8.03 (2H, m) ,
8.14 (1H, d, J = 8.3 Hz), 9.04 (1H, d, J = 1.7 Hz),
12.27 (1H, s) .
[0464]
2-(Benzamido)-4-(2-hydroxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.90-7.02 (2H, m) , 7.20-7.28 (1H, m) ,
7.32 (1H, dd, J = 7.7, 1.6 Hz), 7.40 (1H, dd, J = 8.3,
1.7 Hz), 7.57-7.69 (3H, m), 7.95-8.01 (2H, m), 8.07 (1H,
d, J = 8.3 Hz), 8.96 (1H, d, J = 1.7 Hz), 9.75 (1H, s) ,
12.20-12.45 (1H, broad).
[0465]
2-(Benzamido)-4-(4-isopropoxyphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 1.31 (6H, d, J = 6.1 Hz), 4.65-4.76
(1H, m) , 7.05-7.10 (2H, m), 7.48 (1H, dd, J = 8.3, 1.7
Hz), 7.59-7.70 (5H, m), 7.96-8.02 (2H, m), 8.10 (1H, d,
J = 8.3 Hz), 9.05 (1H, d, J = 1.7 Hz), 12.32 (1H, s) .

267
[0466]
2-(Benzamido)-4-(2-phenoxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 6.91-6.97 (2H, m) , 7.02-7.09 (2H, m) ,
7.29-7.50 (5H, m) , 7.54-7.69 (4H, m), 7.93-8.00 (2H, m) ,
8.04 (1H, d, J = 8.2 Hz), 8.99 (1H, d, J = 1.6 Hz),
12.22 (1H, s).
[0467]
2-(Benzamido)-4-(4-(trifluororaethoxy)phenyl)benzoic
acid
1H-NMR (DMSO-de) 8: 7.51-7.57 (3H, m) , 7.58-7.70 (3H, m) ,
7.84-7.89 (2H, m), 7.96-8.02 (2H, m), 8.15 (1H, d, J =
8.3 Hz), 9.08 (1H, d, J = 1.7 Hz), 12.27 (1H, s) ,
13.70-14.05 (1H, broad).
[0468]
2-(Benzamido)-4-(2,3-dimethylphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.16 (3H, s) , 2.33 (3H, s) , 7.09 (1H,
d, J = 7.1 Hz), 7.15 (1H, dd, J = 8.1, 1.7 Hz), 7.17-
7.27 (2H, m), 7.57-7.69 (3H, m), 7.94-7.99 (2H, m),
8.11 (1H, d, J = 8.1 Hz), 8.70 (1H, d, J = 1.7 Hz),
12.30 (1H, s).
[0469]
2-(Benzamido)-4-(3-nitrophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.59-7.71 (4H, m) , 7.82-7.88 (1H, m) ,
7.98-8.03 (2H, m), 8.19 (1H, d, J = 8.3 Hz), 8.21 (1H,
ddd, J = 7.8, 1.7, 1.0 Hz), 8.29-8.34 (1H, m), 8.48-
8.50 (1H, m), 9.14 (1H, d, J = 1.9 Hz), 12.27 (1H, s),
13.80-14.15 (1H, broad).
[0470]
Example 232


42 mg of 3-hydroxymethylphenylboronic acid, 49
mg of sodium carbonate and 6 mg of polymer supported
di(acetato) dicyclohexylphenylphosphine palladium(II)
were added to 2.5 mL of N,N-dimethylacetamide solution
containing 70 mg of tert-butyl 2-(benzamido)-4-
bromobenzoate, and stirred at 90°C for 15 hours. After
the reaction mixture was cooled to room temperature, 6
mg of polymer supported di(acetato)
dicyclohexylphenylphosphine palladium(II) was added and
stirred at 110°C for 9 hours and 30 minutes. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(benzamido)-4-(3-(hydroxymethyl)phenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(3-
(hydroxymethyl)phenyl)benzoate and stirred at room

269
temperature for 1 hour. The solvent was evaporated
under reduced pressure and the obtained residue was
purified with reversed-phase silica gel column
chromatography [eluent; 60-100% acetonitrile /0.1%
trifluoroacetic acid aqueous solution] to obtain 12 mg
of 2-(benzamido)-4-(3-(hydroxymethyl)phenyl)benzoic
acid as white solid.
1H-NMR (DMSO-d6) 8: 4.61 (2H, s), 5.26-5.40 (1H, broad),
7.41 (1H, d, J = 7.6 Hz), 7.47-7.55 (2H, m), 7.58-7.73
(5H, m) , 7.97-8.04 (2H, m), 8.15 (1H, d, J = 8.3 Hz),
9.09 (1H, d, J = 1.7 Hz), 12.33 (1H, s).
[0471]
Examples 233 to 235
[0473]
2-(Benzamido)-4-(2-isopropoxyphenyl)benzoic acid
The compounds shown in Table 29 were obtained
in the same manner as in Example 232.
[0472]
[Table 29]


270
1H-NMR (DMSO-d6) 8: 1.26 (6H, d, J = 6.1 Hz), 4.59-4.72
(1H, m), 7.05 (1H, t, J = 7.3 Hz), 7.17 (1H, d, J = 8.1
Hz), 7.32-7.41 (3H, m) , 7.57-7.68 (3H, m), 7.95-8.01
(2H, m), 8.07 (1H, d, J = 8.3 Hz), 8.98 (1H, d, J = 1.7
Hz) .
[0474]
2-(Benzamido)-4-(3-(trifluoromethoxy)phenyl)benzoic
acid
1H-NMR (DMSO-d6) 8: 7.48 (1H, d, J - 8.0 Hz), 7.57 (1H,
dd, J = 8.3, 1.9 Hz), 7.59-7.73 (5H, m), 7.79 (1H, d, J
= 7.8 Hz), 7.97-8.03 (2H, m), 8.16 (1H, d, J = 8.3 Hz),
9.08 (1H, d, J = 1.9 Hz), 12.35 (1H, s).
[0475]
2-(Benzamido)-4-(3-methylphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.42 (3H, s) , 7.28 (1H, d, J = 7.6
Hz), 7.43 (1H, t, J = 7.6 Hz), 7.49-7.57 (3H, m), 7.59-
7.70 (3H, m), 7.97-8.02 (2H, m), 8.13 (1H, d, J = 8.3
Hz), 9.07 (1H, d, J = 1.7 Hz), 12.29 (1H, s).
[0476]
Example 236

60 mg of 4-phenoxyphenylboronic acid, 4 9 mg of
sodium carbonate and 6 mg of polymer supported
di(acetato) dicyclohexylphenylphosphine palladium(II)
were added to 2.5 mL of N,N-dimethylacetamide solution

271
containing 70 mg of tert-butyl 2-(benzamido)-4-
bromobenzoate, and stirred at 110°C for 24 hours. After
the reaction mixture was cooled to room temperature, 6
mg of polymer supported di(acetato)
dicyclohexylphenylphosphine palladium(II) was added and
stirred at 110°C for 24 hours. After the reaction
mixture was cooled to room temperature, insoluble were
removed by filtration and ethyl acetate and 10% citric
acid aqueous solution were added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with 10% citric acid aqueous solution and
a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [Flash Tube 2008
manufactured by Trikonex Company, eluent; hexane: ethyl
acetate =4:1] to obtain tert-butyl 2-(benzamido)-4-(4-
phenoxyphenyl)benzoate.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(4-
phenoxyphenyl)benzoate and stirred at room temperature
for 3 hours. The solvent was evaporated under reduced
pressure, and the obtained residue was purified with
silica gel column chromatography [PSQ100B (spherical)
manufactured by Fuji Silysia Chemical Ltd., eluent;
hexane: ethyl acetate =1:2] to obtain 8.0 mg of 2-
(benzamido)-4-(4-phenoxyphenyl)benzoic acid as white
solid.

272
XH-NMR (DMSO-d6) 8: 7.08-7.23 (5H, m) , 7.41-7.48 (2H, m) ,
7.51 (1H, dd, J = 8.3, 1.9 Hz), 7.58-7.70 (3H, m) ,
7.74-7.79 (2H, m), 7.96-8.02 (2H, m), 8.13 (1H, d, J =
8.3 Hz), 9.07 (1H, d, J = 1.9 Hz), 12.30 (1H, s) .
[0477]
Example 237

The following compound was obtained in the
same manner as in Example 236.
2-(Benzamido)-4-(4-benzoylphenyl)benzoic acid
XH-NMR (DMSO-d6) 8: 7.57-7.75 (7H, m) , 7.78-7.84 (2H, m) ,
7.89-7.96 (4H, m), 7.98-8.03 (2H, m), 8.19 (1H, d, J =
8.3 Hz), 9.17 (1H, d, J = 1.5 Hz), 12.29 (1H, s).
[0478]
Example 238

46 mg of 4-(dimethylamino)phenylboronic acid,
49 mg of sodium carbonate and 5.7 mg of polymer
supported di(acetato)dicyclohexylphenylphosphine
palladium(II) were added to 2.5 mL of N,N-
dimethylacetamide solution containing 70 mg of tert-

273
butyl 2-(benzamido)-4-bromobenzoate, and stirred at
110°C for 24 hours. After the reaction mixture was
cooled to room temperature 5.7 mg polymer supported
di(acetato)dicyclohexylphenylphosphine palladium(II)
was added and stirred at 110°C for 24 hours. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate = 4:1] to obtain tert-
butyl 2-(benzamido)-4-(4-(dimethylamino)phenyl)benzoate.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(4-
(dimethylamino)phenyl)benzoate and stirred at room
temperature for 3 hours. The solvent was evaporated
under reduced pressure, ethyl acetate and water were
added and pH was adjusted to pH 6.5 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. Methanol was added to the obtained
residue and a solid substance was separated by

274
filtration to obtain 3.8 mg of 2-(benzamido)-4-(4-
(dimethylamino)phenyl)benzoic acid as pale yellow solid.
1H-NMR (DMSO-d6) 8: 2.98 (6H, s), 6.83-6.89 (2H, m),
7.45 (1H, dd, J = 8.3, 1.8 Hz), 7.58-7.69 (5H, m) ,
7.97-8.02 (2H, m), 8.06 (1H, d, J = 8.3 Hz), 9.05 (1H,
d, J = 1.8 Hz), 12.32 (1H, s) .
[0479]
Example 239

38 mg of 2-methylphenylboronic acid, 49 mg of
sodium carbonate and 6 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and
stirred at 110°C for 20 hours. After the reaction
mixture was cooled to room temperature, 6 mg of polymer
supported bis(acetato)triphenylphosphine palladium(II)
was added and stirred at 110°C for 22 hours. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue

275
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(benzamido)-4-(2-methylphenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(2-
methylphenyl)benzoate and stirred at room temperature
for 1 hour. The solvent was evaporated under reduced
pressure and methanol was added to the obtained residue
and a solid substance was separated by filtration to
obtain 14 mg of 2-(benzamido)-4-(2-methylphenyl)benzoic
acid as white solid.
1H-NMR (DMSO-d6) 5: 2.29 (3H, s) , 7.18-7.38 (5H, m) ,
7.57-7.69 (3H, m) , 7.94-8.00 (2H, m), 8.12 (1H, d, J =
8.1 Hz), 8.74 (1H, d, J = 1.4 Hz), 12.27 (1H, s) .
[0480]
Examples 240 to 242
The compounds shown in Table 30 were obtained
in the same manner as in Example 239.
[0481]
[Table 30]


276
[0482]
2-(Benzamido)-4-(4-methylphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 2.38 (3H, s), 7.35 (2H, d, J = 8.0
Hz), 7.50 (1H, dd, J = 8.3, 1.9 Hz), 7.58-7.70 (5H, m),
7.96-8.02 (2H, m), 8.12 (1H, d, J = 8.3 Hz), 9.07 (1H,
d, J = 1.9 Hz), 12.33 (1H, s).
[0483]
2-(Benzamido)-4-(3-cyanophenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.58-7.70 (4H, m) , 7.76 (1H, t, J =
7.8 Hz), 7.92-7.97 (1H, m) , 7.97-8.02 (2H, m), 8.05-
8.11 (1H, ), 8.16 (1H, d, J = 8.3 Hz), 8.19-8.23 (1H,
in), 9.08 (1H, d, J = 2.0 Hz), 12.28 (1H, s) .
[0484]
2-(Benzamido)-4-(4-cyanophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.56-7.69 (4H, m) , 7.90-8.02 (6H, m) ,
8.16 (1H, d, J = 8.3 Hz), 9.10 (1H, d, J = 2.0 Hz),
12.29 (1H, s).
[0485]
Example 24 3

39 mg of 4-hydroxyphenylboronic acid, 4 9 mg of
sodium carbonate and 6 mg of polymer supported
bis(acetato)triphenylphosphine palladium(II) were added
to 2.5 mL of N,N-dimethylacetamide solution containing
70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and

277
stirred at 110°C for 20 hours. After the reaction
mixture was cooled to room temperature, 6 mg of polymer
supported bis(acetato)triphenylphosphine palladium(II)
was added and stirred at 110°C for 22 hours. After the
reaction mixture was cooled to room temperature,
insoluble were removed by filtration and ethyl acetate
and 10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =2:1] to obtain tert-
butyl 2-(benzamido)-4-(4-hydroxyphenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(4-
hydroxyphenyl)benzoate and stirred at room temperature
for 1 hour. The solvent was evaporated under reduced
pressure and the obtained residue was purified with
reversed-phase silica gel column chromatography
[eluent; 55-90% acetonitrile /0.1% trifluoroacetic acid
aqueous solution] to obtain 1.9 mg of 2-(benzamido)-4-
(4-hydroxyphenyl)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 6.88-6.96 (2H, m), 7.44 (1H, dd, J=
8.3, 1.9 Hz), 7.56-7.69 (5H, m) , 7.96-8.02 (2H, m),
8.08 (1H, d, J = 8.3 Hz), 9.03 (1H, d, J = 1.9 Hz),
9.79 (1H, s), 12.33 (1H, s).


The following compound was obtained in the
same manner as in Example 243.
2-(Benzamido)-4-(3-hydroxyphenyl)benzoic acid
1H-NMR (DMSO-de) 5: 6.86 (1H, dd, J = 8.1, 1.9 Hz),
7.11-7.19 (2H, m), 7.33 (1H, t, J = 7.9 Hz), 7.47 (1H,
dd, J = 8.1, 1.7 Hz), 7.59-7.70 (3H, m), 7.97-8.02 (2H,
m), 8.13 (1H, d, J = 8.1 Hz), 9.06 (1H, d, J = 1.7 Hz),
9.69 (1H, s), 12.30 (1H, s) .
[0487]
Example 245

56 mg of 2-fluorophenylboronic acid, 0.10 g of
sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of
water and 23 mg of
tetrakis(triphenylphosphine)palladium(0) were added to
2.1 mL of toluene solution containing 0.15 g of tert-
butyl 2-(benzamido)-4-bromobenzoate, and the resulting
mixture was heated to reflux for 2 hours. After the
reaction mixture was cooled to room temperature, 17 mg
of 2-fluorophenylboronic acid and 23 mg of

279
tetrakis(triphenylphosphine)palladium(0) were added and
the resulting mixture was heated to reflux for 2 hours.
After the reaction mixture was cooled to room
temperature, toluene and a saturated sodium hydrogen
carbonate aqueous solution were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [Flash Tube 2008
manufactured by Trikonex Company, eluent; hexane: ethyl
acetate = 10:1] to obtain tert-butyl 2-(benzamido)-4-
(2-fluorophenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(2-
fluorophenyl)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure and toluene was added. The solvent was
evaporated under reduced pressure and diisopropyl ether
was added to the obtained residue and a solid substance
was separated by filtration to obtain 93 mg of 2-
(benzamido)-4-(2-fluorophenyl)benzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 7.34-7.44 (3H, m) , 7.47-7.55 (1H, m) ,
7.56-7.70 (4H, m) , 7.94-8.01 (2H, m), 8.16 (1H, d, J =
8.3 Hz), 8.96-9.00 (1H, m), 12.27 (1H, s).
[0488]
Examples 246 to 250

280
The compounds shown in Table 31 were obtained
in the same manner as in Example 245.
[0489]
[Table 31]

[0490]
2-(Benzamido)-4-(3-fluoro-4-methylphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 2.28-2.34 (3H, m) , 7.42-7.57 (4H, m) ,
7.58-7.70 (3H, m), 7.96-8.02 (2H, m), 8.12 (1H, d, J -
8.3 Hz), 9.06 (1H, d, J = 1.7 Hz), 12.27 (1H, s).
[0491]
2-(Benzamido)-4-(2-chlorophenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.29 (1H, dd, J = 8.3, 1.7 Hz),
7.45-7.51 (3H, m) , 7.57-7.69 (4H, m), 7.94-8.00 (2H, m) ,
8.15 (1H, d, J = 8.3 Hz), 8.84 (1H, d, J = 1.7 Hz),
12.28 (1H, s).
[0492]
2-(Benzamido)-4-(3,4-dichlorophenyl)benzoic acid
1H-NMR (DMSO-de) 5: 7.57 (1H, dd, J = 8.3, 1.9 Hz),
7.58-7.70 (3H, m), 7.73 (1H, dd, J = 8.3, 2.2 Hz), 7.81

281
(1H, d, J = 8.6 Hz), 7.96-8.01 (3H, m), 8.14 (1H, d, J
= 8.3 Hz), 9.05 (1H, d, J = 1.9 Hz), 12.24 (1H, s) .
[0493]
2-(Benzamido)-4-(5-chloro-2-fluorophenyl)benzoic acid
1H-NMR (DMSO-de) 5: 7.40-7.50 (2H, m) , 7.55-7.70 (5H, m) ,
7.95-8.01 (2H, m), 8.16 (1H, d, J = 8.0 Hz), 8.96 (1H,
s), 12.27 (1H, s).
[0494]
2-(Benzamido)-4-(2,6-dimethylphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.03 (6H, s) , 7.02 (1H, dd, J = 8.1,
1.6 Hz), 7.13-7.25 (3H, m), 7.56-7.69 (3H, m), 7.93-
7.99 (2H, m), 8.15 (1H, d, J = 8.1 Hz), 8.53 (1H, d, J
=1.6 Hz), 12.29 (1H, s).
[0495]
Example 251

83 mg of 2-chloro-6-fluorophenylboronic acid,
0.10 g of sodium hydrogen carbonate, 0.6 mL of ethanol,
0.3 mL of water and 23 mg of
tetrakis(triphenylphosphine)palladium(O) were added to
2.1 mL of toluene solution containing 0.15 g of tert-
butyl 2-(benzamido)-4-bromobenzoate, and the resulting
mixture was heated to reflux for 2 hours. After the
reaction mixture was cooled to room temperature, 21 mg
of 2-chloro-6-fluorophenylboronic acid and 23 mg

282
tetrakis(triphenylphosphine)palladium(O) were added and
the resulting mixture was heated to reflux for 2 hours.
After the reaction mixture was cooled to room
temperature, toluene and a saturated sodium hydrogen
carbonate aqueous solution were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [Flash Tube 2008
manufactured by Trikonex Company, eluent; hexane: ethyl
acetate = 10:1] to obtain tert-butyl 2-(benzamido)-4-
(2-chloro-6-fluorophenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(2-chloro-6-
fluorophenyl)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure and toluene was added. The solvent was
evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 70-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
5.8 mg of 2-(benzamido)-4-(2-chloro-6-
fluorophenyl)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 7.23 (1H, dd, J = 8.3, 1.6 Hz),
7.37-7.45 (1H, m) , 7.49-7.70 (5H, m) , 7.93-7.99 (2H, m) ,
8.17 (1H, d, J = 8.3 Hz), 8.73-8.77 (1H, m) , 12.28 (1H,
s).


0.15 g of 4-bromo-2-chlorophenol, 0.18 g of
sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of
water and 42 mg of tetrakis(triphenylphosphine)
palladium(0) were added to 2.1 mL of toluene solution
containing 0.37 g of tert-butyl 2-(benzamido)-4-
(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate
at room temperature, and the resulting mixture was
heated to reflux for 4 hours. Toluene and a saturated
sodium hydrogen carbonate aqueous solution were added
after the reaction mixture was cooled to room
temperature. The organic layer was separated and ethyl
acetate was added after washed with a saturated sodium
chloride aqueous solution and dried over anhydrous
magnesium sulfate, and the solvent was evaporated under
reduced pressure. Hexane was added to the obtained
residue and a solid substance was separated by
filtration to obtain tert-butyl 2-(benzamido)-4-(3-
chloro-4-hydroxyphenyl)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(benzamido)-4-(3-chloro-4-
hydroxyphenyl)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced

284
pressure and toluene was added. The solvent was
evaporated under reduced pressure and diisopropyl ether
was added to the obtained residue and a solid substance
was separated by filtration to obtain 94 mg of 2-
(benzamido)-4-(3-chloro-4-hydroxyphenyl)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 6: 7.13 (1H, d, J = 8.3 Hz), 7.48 (1H,
dd, J = 8.3, 1.7 Hz), 7.56 (1H, dd, J = 8.4, 2.3 Hz),
7.57-7.72 (4H, m) , 7.96-8.01 (2H, m), 8.09 (1H, d, J =
8.3 Hz), 9.01 (1H, d, J = 1.7 Hz), 10.50-10.66 (1H,
broad), 12.26 (1H, s).
[0497]
Example 253

0.031 mL of indoline, 0.12 g of cesium
carbonate, 1.7 mg of
tris(dibenzylideneacetone)dipalladium(O), 0.8 mg of
palladium acetate and 4.4 mg of 2-dicyclohexylphosphino
-2',4',6'-triisopropylbiphenyl were added to 1.4 mL of
toluene solution containing 70 mg of tert-butyl 2-
(benzamido)-4-bromobenzoate at room temperature, and
the resulting mixture was heated to reflux under
nitrogen atmosphere for 3 hours. After the reaction
mixture was cooled to room temperature, ethyl acetate
and 10% citric acid aqueous solution were added and
insoluble were removed by filtration. The organic layer

285
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate = 10:1] to obtain 77 mg
of tert-butyl 2-(benzamido)-4-(indolin-1-yl)benzoate as
yellow oil.
1H-NMR (CDC13) 8: 1.63 (9H, s) , 3.17 (2H, t, J = 8.4 Hz),
4.10 (2H, t, J = 8.4 Hz), 6.86 (1H, td, J = 7.4, 0.8
Hz), 6.96 (1H, dd, J = 8.9, 2.5 Hz), 7.16-7.24 (2H, m),
7.46-7.57 (4H, m), 7.97 (1H, d, J = 8.9 Hz), 8.06-8.10
(2H, m), 8.81 (1H, d, J = 2.5 Hz), 12.40 (1H, s).
[0498]
Example 254

5.0 mL of trifluoroacetic acid solution
containing 75 mg of tert-butyl 2-(benzamido)-4-
(indolin-1-yl)benzoate was stirred at room temperature
for 1 hour and 30 minutes. The solvent was evaporated
under reduced pressure, ethyl acetate and water were
added and pH was adjusted to pH 6.5 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with water and a saturated sodium

286
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Methanol was
added to the obtained residue and a solid substance was
separated by filtration to obtain 51 mg of 2-
(benzamido)-4-(indolin-1-yl)benzoic acid a yellow solid.
1H-NMR (DMSO-d6) 8: 3.17 (2H, t, J = 8.4 Hz), 4.06 (2H,
t, J = 8.4 Hz), 6.88 (1H, t, J = 7.4 Hz), 6.95 (1H, dd,
J = 9.0, 2.4 Hz), 7.19 (1H, t, J = 7.6 Hz), 7.27 (1H, d,
J = 7.3 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.58-7.69 (3H,
m), 7.96-8.02 (2H, m), 8.02 (1H, d, J = 9.0 Hz), 8.82
(1H, d, J = 2.4 Hz), 12.50 (1H, s), 13.26 (1H, s).
[0499]
Examples 255 to 277
The compounds shown in Table 32 were obtained
in the same manner as in Example 34.
[0500]
[Table 32]


[0501]
4-Phenethyl-2-(2-(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 2.90-3.02 (4H, m) , 7.13 (1H, dd, J =
8.1, 1.7 Hz), 7.16-7.22 (1H, m) , 7.26-7.32 (4H, m) ,
7.73-7.81 (1H, m) , 7.81-7.86 (2H, m), 7.86-7.97 (2H, m) ,
8.49 (1H, s), 11.62 (1H, s), 13.50-13.70 (1H, broad).
[0502]
4-Phenethyl-2-(2-phenylacetamido)benzoic acid
1H-NMR (DMSO-d6) 6: 2.82-2.94 (4H, m), 3.75 (2H, s) ,
6.99 (1H, dd, J = 8.2, 1.5 Hz), 7.13-7.20 (1H, m) ,

288
7.20-7.32 (5H, m) , 7.32-7.42 (4H, m), 7.84 (1H, d, J =
8.2 Hz), 8.44 (1H, d, J = 1.5 Hz), 11.16 (1H, s).
[0503]
2-(2-Methylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.45 (3H, s), 2.90-3.02 (4H, m),
7.09 (1H, dd, J = 8.3, 1.6 Hz), 7.16-7.23 (1H, m),
7.26-7.37 (6H, m) , 7.40-7.50 (1H, m), 7.59 (1H, d, J =
7.6 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.62 (1H, s), 11.62
(1H, s), 13.45-13.65 (1H, broad).
[0504]
2-(3-Methylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.42 (3H, s) , 2.90-3.02 (4H, m) ,
7.08 (1H, dd, J = 8.1, 1.6 Hz), 7.16-7.22 (1H, m),
7.25-7.32 (4H, m) , 7.44-7.52 (2H, m), 7.73-7.81 (2H, m) ,
7.96 (1H, d, J = 8.1 Hz), 8.67 (1H, d, J = 1.6 Hz),
12.24 (1H, s).
[0505]
2-(4-Methylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.40 (3H, s), 2.88-3.01 (4H, m),
7.07 (1H, dd, J = 8.1, 1.7 Hz), 7.15-7.22 (1H, m) ,
7.24-7.32 (4H, m), 7.40 (2H, d, J = 8.2 Hz), 7.86 (2H,
d, J = 8.2 Hz), 7.95 (1H, d, J = 8.1 Hz), 8.67 (1H, d,
J == 1.7 Hz) , 12.22 (1H, s) .
[0506]
2-(4-Nitrobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.89-3.04 (4H, m) , 7.09-7.14 (1H, m) ,
7.15-7.22 (1H, m) , 7.25-7.32 (4H, m) , 7.97 (1H, d, J =
8.3 Hz), 8.19 (2H, d, J = 8.8 Hz), 8.44 (2H, d, J = 8.8
Hz), 8.58 (1H, d, J = 1.5 Hz).

289
[0507]
2-(3, 4-Dimethylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.32 (3H, s), 2.32 (3H, s) , 2.90-
3.00 (4H, m), 7.06 (1H, d, J = 8.2 Hz), 7.15-7.20 (1H,
m) , 7.25-7.30 (4H, m), 7.35 (1H, d, J = 7.7 Hz), 7.68
(1H, d, J = 7.7 Hz), 7.74 (1H, s), 7.95 (1H, d, J = 8.2
Hz), 8.68 (1H, s), 12.16-12.20 (1H, broad).
[0508]
2-(2,3-Dimethylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.30 (6H, s), 2.90-3.00 (4H, m) ,
7.06-7.11 (1H, m) , 7.16-7.38 (8H, m) , 7.93 (1H, d, J =
8.0 Hz), 8.61 (1H, s), 11.50-11.56 (1H, broad).
[0509]
2-(3-Nitrobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.05 (4H, m) , 7.10-7.21 (2H, m) ,
7.26-7.30 (4H, m) , 7.89-7.99 (2H, m), 8.36-8.42 (1H, m) ,
8.47-8.52 (1H, m), 8.58 (1H, d, J = 1.7 Hz), 8.76 (1H,
t, J = 2.0 Hz), 12.36-12.48 (1H, broad).
[0510]
4-Phenethyl-2-(4-(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-de) 8: 2.90-3.02 (4H, m), 7.11 (1H, d, J =
8.0 Hz), 7.16-7.21 (1H, m), 7.25-7.31 (4H, m), 7.94-
8.02 (3H, m), 8.15 (2H, d, J = 7.6 Hz), 8.61 (1H, s),
12.28 (1H, s).
[0511]
2-(Benzothiophene-2-carboxamido)-4-phenethylbenzoic
acid

290
1H-NMR (DMSO-de) 8: 2.90-3.02 (4H, m) , 7.10 (1H, dd, J =
8.1, 1.2 Hz), 7.17-7.21 (1H, m), 7.25-7.32 (4H, m) ,
7.48-7.55 (2H, m), 7.98 (1H, d, J = 8.1 Hz), 8.06-8.11
(3H, m) , 8.53-8.57 (1H, m) , 12.34 (1H, s) .
[0512]
2-(2-Fluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 6: 2.91-3.00 (4H, m), 7.10 (1H, d, J =
8.0 Hz), 7.16-7.21 (1H, m) , 7.25-7.31 (4H, m), 7.38-
7.44 (2H, m), 7.64-7.69 (1H, m), 7.90-7.96 (2H, m),
8.66 (1H, s), 11.94-12.00 (1H, broad), 13.54-13.60 (1H,
broad).
[0513]
2-(3-Fluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 5: 2.90-3.00 (4H, m) , 7.10 (1H, dd, J =
8.1, 1.7 Hz), 7.16-7.20 (1H, m) , 7.25-7.31 (4H, m) ,
7.49-7.52 (1H, m) , 7.64-7.73 (2H, m), 7.78-7.81 (1H, m) ,
7.96 (1H, d, J = 8.1 Hz), 8.60-8.62 (1H, m), 12.16-
12.22 (1H, broad), 13.64-13.76 (1H, broad).
[0514]
2-(2,6-Difluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 5: 2.90-3.02 (4H, m) , 7.12-7.21 (2H, m) ,
7.26-7.33 (6H, m), 7.61-7.69 (1H, m), 7.94 (1H, d, J =
8.0 Hz), 8.50 (1H, s), 11.74-11.82 (1H, broad).
[0515]
4-Phenethyl-2-(3-(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-de) 5: 2.90-3.03 (4H, m) , 7.10-7.13 (1H, m) ,
7.16-7.21 (1H, m) , 7.25-7.31 (4H, m), 7.87 (1H, t, J =
7.9 Hz), 7.96 (1H, d, J = 8.1 Hz), 8.04 (1H, d, J = 7.8

291
Hz), 8.24-8.28 (2H, m), 8.60 (1H, s), 12.28-12.34 (1H,
broad).
[0516]
2-(2-Chlorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-dg) 5: 2.90-3.02 (4H, m) , 7.12 (1H, dd, J =
8.3, 1.5 Hz), 7.16-7.22 (1H, m) , 7.26-7.32 (4H, m) ,
7.48-7.63 (3H, m), 7.71 (1H, dd, J = 7.3, 1.7 Hz), 7.94
(1H, d, J = 8.3 Hz), 8.53-8.59 (1H, m) , 11.62-11.70 (1H,
broad), 13.54-13.62 (1H, broad).
[0517]
2-(3-Chlorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.02 (4H, m) , 7.10 (1H, dd, J =
8.3, 1.2 Hz), 7.16-7.22 (1H, m), 7.25-7.31 (4H, m),
7.64 (1H, t, J = 7.8 Hz), 1.12-1.15 (1H, m), 7.91 (1H,
d, J = 7.8 Hz), 7.95-7.97 (2H, m) , 8.58-8.61 (1H, m) ,
12.18-12.24 (1H, broad).
[0518]
2-(4-Chlorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.90-3.01 (4H, m) , 7.09 (1H, dd, J =
8.0, 1.0 Hz), 7.16-7.20 (1H, m) , 7.26-7.32 (4H, m) ,
7.69 (2H, d, J = 8.5 Hz), 7.93-7.98 (3H, m) , 8.61-8.63
(1H, m), 12.17-12.22 (1H, broad).
[0519]
2-(2,4-Bis(trifluoromethyl)benzamido)-4-
phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.02 (4H, m) , 7.14-7.22 (2H, m) ,
7.26-7.30 (4H, m), 7.93 (1H, d, J = 8.0 Hz), 8.09 (1H,
d, J = 8.0 Hz), 8.24 (1H, s), 8.28 (1H, d, J = 8.3 Hz),
8.36-8.39 (1H, m), 11.60-11.64 (1H, broad).

292
[0520]
2-(2,4-Dichlorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.02 (4H, m) , 7.10-7.15 (1H, m) ,
7.16-7.22 (1H, m) , 7.26-7.32 (4H, m), 7.61 (1H, dd, J=
8.4, 2.1 Hz), 7.75 (1H, d, J = 8.3 Hz), 7.81 (1H, d, J
= 2.1 Hz), 7.93 (1H, d, J = 8.3 Hz), 8.50 (1H, s),
11.62-11.68 (1H, broad).
[0521]
4-Phenethyl-2-((E)-3-(pyridin-4-yl)acrylamido)benzoic
acid trifluoroacetate
1H-NMR (DMSO-de) 5: 2.88-3.00 (4H, m), 7.09 (1H, dd, J=
8.1, 1.5 Hz), 7.16-7.21 (1H, m) , 7.23-7.29 (4H, m),
7.32 (1H, d, J = 15.6 Hz), 7.67 (1H, d, J = 15.6 Hz),
7.93 (1H, d, J = 8.1 Hz), 8.00 (2H, d, J = 6.2 Hz),
8.53 (1H, d, J = 1.5 Hz), 8.78 (2H, d, J = 6.2 Hz),
11.48 (1H, s).
[0522]
4-Phenethyl-2-(5-(lH-pyrrol-l-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.91-3.03 (4H, m) , 6.39 (2H, t, J =
2.2 Hz), 7.13 (1H, dd, J = 8.1, 1.6 Hz), 7.16-7.31 (5H,
m), 7.58 (2H, t, J = 2.2 Hz), 7.97 (1H, d, J = 8.1 Hz),
8.44 (1H, t, J = 2.3 Hz), 8.57 (1H, d, J = 1.6 Hz),
8.96 (1H, d, J = 2.3 Hz), 9.16 (1H, d, J = 2.3 Hz),
12.20 (1H, s).
[0523]
4-Phenethyl-2-(2-(pyrrolidin-1-yl)pyridine-3-
carboxamido)benzoic acid

293
1H-NMR (DMSO-d6) 8: 1.80-1.89 (4H, m) , 2.88-3.01 (4H, m) ,
3.32-3.42 (4H, m), 6.72 (1H, dd, J = 7.4, 4.8 Hz), 7.08
(1H, dd, J = 8.2, 1.7 Hz), 7.15-7.22 (1H, m) , 7.24-7.31
(4H, m), 7.78 (1H, dd, J = 7.4, 1.9 Hz), 7.92 (1H, d, J
= 8.2 Hz), 8.22 (1H, dd, J = 4.8, 1.9 Hz), 8.57 (1H, s),
11.58 (1H, s).
[0524]
Example 278

2.0 mg of 5% palladium-carbon was added to a
mixed solution of 1.0 mL of methanol and 2.0 mL of
ethyl acetate containing 7.0 mg of 2-(4-
nitrobenzamido)-4-phenethylbenzoic acid and stirred
under hydrogen atmosphere at room temperature for 2
hours. After insoluble were removed by filtration, the
solvent was evaporated under reduced pressure to obtain
4.0 mg of 2-(4-aminobenzamido)-4-phenethylbenzoic acid
as pale yellow solid.
Hi-NMR (DMSO-d6) 8: 2.80-2.96 (4H, m), 5.55-5.91 (2H,
broad), 6.61 (2H, d, J = 8.6 Hz), 6.81 (1H, dd, J = 8.0,
1.6 Hz), 7.15-7.20 (1H, m), 7.24-7.31 (4H, m), 7.74 (2H,
d, J = 8.6 Hz), 7.89 (1H, d, J = 8.0 Hz), 8.61 (1H, d,
J = 1.6 Hz) .
[0525]
Example 27 9


0.061 mL of pyridine and 0.086 mL of 2,6-
dichlorobenzoyl chloride were added to 3.0 mL of
toluene solution containing 0.15 g of tert-butyl 2-
amino-4-phenethylbenzoate at room temperature
sequentially, and the resulting mixture was heated to
reflux for 8 hours. The reaction mixture was cooled to
room temperature and a saturated sodium hydrogen
carbonate aqueous solution was added. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with 10% citric acid aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. The obtained residue was
purified with silica gel column chromatography [Flash
Tube 2008 manufactured by Trikonex Company, eluent;
hexane: ethyl acetate =4:1] to obtain tert-butyl 2-
(2,6-dichlorobenzamido)-4-phenethylbenzoate.
3.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-
phenethylbenzoate and stirred at room temperature for 1
hour. The solvent was evaporated under reduced pressure
and diisopropyl ether was added to the obtained residue
and a solid substance was separated by filtration to

295
obtain 18 mg of 2-(2,6-dichlorobenzamido)-4-
phenethylbenzoic acid as white solid.
1H-NMR (DMSO-de) 5: 2.91-3.02 (4H, m) , 7.15-7.22 (2H, m) ,
7.26-7.30 (4H, m) , 7.53-7.57 (1H, m), 7.61-7.64 (2H, m) ,
7.64 (1H, d, J = 1.7 Hz), 7.94 (1H, d, J = 8.0 Hz),
8.48-8.50 (1H, broad), 11.56-11.62 (1H, broad).
[0526]
Example 280

0.090 mL of pyridine and 0.12 mL of 2,6-
dichlorobenzoyl chloride were added to 3.0 mL of
toluene solution containing 0.15 g of tert-butyl 2-
amino-4-phenylbenzoate at room temperature sequentially,
and the resulting mixture was heated to reflux for 4
hours. The reaction mixture was cooled to room
temperature and 0.023 mL of pyridine and 0.040 mL of
2,6-dichlorobenzoyl chloride were added sequentially
and the resulting mixture was heated to reflux for 2
hours. The reaction mixture was cooled to room
temperature and water was added. The organic layer was
separated and dried over anhydrous magnesium sulfate
after washed with a saturated sodium chloride aqueous
solution, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured

296
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-
phenylbenzoate.
3.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-
phenylbenzoate and stirred at room temperature for 1
hour. The solvent was evaporated under reduced pressure
and diisopropyl ether was added to the obtained residue
and a solid substance was separated by filtration to
obtain 0.10 g of 2-(2,6-dichlorobenzamido)-4-
phenylbenzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 7.46-7.65 (7H, m) , 7.73 (2H, d, J =
7.8 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.87-8.89 (1H,
broad), 11.62-11.68 (1H, broad), 13.76-13.88 (1H,
broad).
[0527]
Example 281

0.084 mL of pyridine and 0.11 mL of 2,6-
dichlorobenzoyl chloride were added to 3.0 mL of
toluene solution containing 0.15 g of tert-butyl 2-
amino-4-phenoxybenzoate at room temperature
sequentially, and the resulting mixture was heated to
reflux for 4 hours. The reaction mixture was cooled to
room temperature and 0.021 mL of pyridine and 0.037 mL

297
of 2,6-dichlorobenzoyl chloride were added sequentially
and heated to reflux for 4 hours. The reaction mixture
was cooled to room temperature and water was added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
hydrogen carbonate aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-
phenoxybenzoate.
3.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(2,6-dichlorobenzamido)-4-
phenoxybenzoate and stirred at room temperature for 1
hour. The solvent was evaporated under reduced pressure
and diisopropyl ether was added to the obtained residue
and a solid substance was separated by filtration to
obtain 70 mg of 2-(2,6-dichlorobenzamido)-4-
phenoxybenzoic acid as white solid.
1H-NMR (DMSO-de) 5: 6.79 (1H, dd, J = 8.9, 2.1 Hz),
7.19-7.23 (2H, m) , 7.26-7.32 (1H, m) , 7.48-7.57 (3H, m) ,
7.61-7.65 (2H, m), 8.05 (1H, d, J = 8.9 Hz), 8.24-8.28
(1H, m) .
[0528]
Example 282


0.063 mL of triethylamine and 0.040 mL of 2-
fluorobenzoyl chloride were added to 3.0 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-phenylbenzoate at room temperature
sequentially and stirred at the same temperature for 1
hour. 0.51 g of aminomethylated polystyrene was added
to the reaction mixture and stirred at room temperature
overnight. A saturated sodium hydrogen carbonate
aqueous solution was added to the reaction mixture, and
the organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(2-fluorobenzamido)-4-phenylbenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-fluorobenzamido)-4-
phenylbenzoate and stirred at room temperature for 2
hours. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 61 mg of 2-(2-fluorobenzamido)-4-
phenylbenzoic acid as white solid.

299
1H-NMR (DMSO-d6) 8: 7.39-7.50 (3H, m) , 7.52-7.59 (3H, m) ,
7.65-7.76 (3H, m), 7.96 (1H, td, J = 7.8, 1.8 Hz), 8.13
(1H, d, J = 8.3 Hz), 9.07 (1H, d, J = 1.7 Hz), 12.00-
12.10 (1H, broad), 13.65-13.85 (1H, broad).
[0529]
Examples 283 to 319
The compounds shown in Table 33 were obtained
in the same manner as in Example 282.
[0530]
[Table 33]



301
1H-NMR (DMSO-de) 8: 7.44-7.49 (1H, m) , 7.51-7.58 (4H, m) ,
7.65-7.72 (1H, m) , 7.72-7.77 (3H, m) , 7.81-7.85 (1H, m) ,
8.14 (1H, d, J = 8.3 Hz), 9.02 (1H, d, J = 1.7 Hz),
12.25 (1H, s).
[0532]
2-(4-Fluorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.43-7.59 (6H, m) , 7.71-7.77 (2H, m) ,
8.02-8.09 (2H, m), 8.14 (1H, d, J = 8.3 Hz), 9.04 (1H,
d, J = 1.7 Hz), 12.24 (1H, s), 13.75-13.95 (1H, broad).
[0533]
2-(2,4-Difluorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.32 (1H, td, J = 8.4, 2.4 Hz) ,
7.44-7.58 (5H, m), 7.70-7.76 (2H, m), 8.04 (1H, td, J =
8.8, 6.6 Hz), 8.13 (1H, d, J = 8.3 Hz), 9.04 (1H, d, J
= 2.0 Hz), 12.02-12.06 (1H, m), 13.77 (1H, s).
[0534]
2-(2,6-Difluorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.28-7.35 (2H, m) , 7.44-7.50 (1H, m) ,
7.52-7.61 (3H, m) , 7.62-7.78 (3H, m), 8.12 (1H, d, J =
8.3 Hz), 8.90 (1H, s), 11.86 (1H, s), 13.70-13.95 (1H,
broad).
[0535]
2-(2-Methylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 2.48 (3H, s) , 7.33-7.39 (2H, m) ,
7.43-7.50 (2H, m) , 7.50-7.59 (3H, m), 7.62-7.66 (1H, m) ,
7.71-7.76 (2H, m), 8.11 (1H, d, J = 8.3 Hz), 9.03 (1H,
d, J = 1.7 Hz), 11.69 (1H, s), 13.71 (1H, s) .
[0536]
2-(3-Methylbenzamido)-4-phenylbenzoic acid

302
1H-NMR (DMSO-d6) 8: 2.43 (3H, s), 7.44-7.58 (6H, m) ,
7.71-7.83 (4H, m), 8.14 (1H, d, J = 8.0 Hz), 9.09 (1H,
d, J = 1.7 Hz), 12.27 (1H, s) , 13.80-13.95 (1H, broad).
[0537]
2-(4-Methylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 5: 2.41 (3H, s), 7.40-7.58 (6H, m),
7.72-7.75 (2H, m), 7.89 (2H, d, J = 8.3 Hz), 8.14 (1H,
d, J = 8.3 Hz), 9.09 (1H, d, J = 1.7 Hz), 12.24 (1H, s),
13.75-13.90 (1H, broad).
[0538]
4-Phenyl-2-(2-(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.4, 1.5 Hz),
7.52-7.60 (3H, m) , 7.70-7.94 (6H, m) , 8.12 (1H, d, J =
8.3 Hz), 8.88 (1H, s), 11.69 (1H, s), 13.65-13.85 (1H,
broad).
[0539]
4-Phenyl-2-(3-(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.3, 1.5 Hz),
7.52-7.58 (3H, m) , 7.72-7.77 (2H, m), 7.86-7.91 (1H, m),
8.05 (1H, d, J = 8.1 Hz), 8.14 (1H, d, J = 8.3 Hz),
8.27-8.32 (2H, m), 9.01 (1H, d, J = 2.0 Hz), 12.38 (1H,
s), 13.80-14.05 (1H, broad).
[0540]
4-Phenyl-2-(4-(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.6, 1.5 Hz),
7.52-7.59 (3H, m), 7.72-7.77 (2H, m), 8.01 (2H, d, J =
8.3 Hz), 8.12-8.22 (3H, m), 9.02 (1H, d, J = 1.7 Hz),
12.34 (1H, s).

303
[0541]
2-(3,4-Dimethylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.32 (3H, s) , 2.33 (3H, s) , 7.37 (1H,
d, J = 7.8 Hz), 7.44-7.58 (4H, m), 7.69-7.79 (4H, m),
8.13 (1H, d, J = 8.3 Hz), 9.09 (1H, d, J = 2.0 Hz),
12.25 (1H, s), 13.75-13.95 (1H, broad).
[0542]
2-(2, 3-Dimethylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.31 (3H, s) , 2.33 (3H, s) , 7.24 (1H,
t, J = 7.6 Hz), 7.34 (1H, d, J = 7.6 Hz), 7.41 (1H, d,
J = 7.6 Hz), 7.44-7.58 (4H, m) , 7.71-7.75 (2H, m), 8.11
(1H, d, J = 8.3 Hz), 9.03 (1H, s) , 11.60 (1H, s) ,
13.60-13.80 (1H, broad).
[0543]
2-(6-Morpholinopyridine-3-carboxamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 3.60-3.75 (8H, m) , 7.00 (1H, d, J =
9.0 Hz), 7.43-7.58 (4H, m) , 7.70-7.75 (2H, m) , 8.04 (1H,
dd, J = 9.0, 2.5 Hz), 8.12 (1H, d, J = 8.3 Hz), 8.75
(1H, d, J = 2.5 Hz), 9.06 (1H, d, J = 1.7 Hz), 12.08
(1H, s), 13.70-13.90 (1H, broad).
[0544]
2-(Cyclohexanecarboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 1.14-1.52 (5H, m) , 1.60-1.71 (1H, m) ,
1.72-1.81 (2H, m) , 1.88-1.99 (2H, m), 2.30-2.39 (1H, m) ,
7.41-7.56 (4H, m), 7.65-7.71 (2H, m), 8.06 (1H, d, J =
8.3 Hz), 8.90 (1H, d, J = 1.7 Hz), 11.28 (1H, s), 13.61
(1H, s) .

304
[0545]
4-Phenyl-2-(2-phenylacetamido)benzoic acid
1H-NMR (DMSO-d6) 5: 3.80 (2H, s), 7.26-7.54 (9H, m),
7.64-7.69 (2H, m) , 8.03 (1H, d, J = 8.3 Hz), 8.87 (1H,
d, J = 1.7 Hz), 11.23 (1H, s), 13.55-13.75 (1H, broad).
[0546]
2-(Cinnamamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 6.94 (1H, d, J = 15.6 Hz), 7.41-7.57
(7H, m), 7.66 (1H, d, J = 15.6 Hz), 7.69-7.78 (4H, m),
8.10 (1H, d, J = 8.3 Hz), 8.98 (1H, d, J = 1.7 Hz),
11.42 (1H, s), 13.55-13.75 (1H, broad).
[0547]
2-(2-Phenoxyacetamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 4.77 (2H, s) , 7.03 (1H, t, J = 7.3
Hz), 7.09-7.15 (2H, m), 7.33-7.40 (2H, m), 7.43-7.57
(4H, m), 7.67-7.73 (2H, m), 8.10 (1H, d, J = 8.3 Hz),
9.06 (1H, d, J = 1.7 Hz), 12.26 (1H, s) , 13.82 (1H, s) .
[0548]
2-(Furan-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 6.77 (1H, dd, J = 3.5, 1.7 Hz), 7.30
(1H, dd, J = 3.5, 0.6 Hz), 7.44-7.57 (4H, m) , 7.69-7.75
(2H, m), 8.02 (1H, dd, J = 1.7, 0.6 Hz), 8.13 (1H, d, J
= 8.3 Hz), 9.03 (1H, d, J = 2.0 Hz), 12.26 (1H, s),
13.79 (1H, s).
[0549]
4-Phenyl-2-(thiophene-2-carboxamido)benzoic acid
1H-NMR (DMSO-de) 8: 7.30 (1H, dd, J = 5.0, 3.8 Hz),
7.44-7.50 (1H, m) , 7.50-7.58 (3H, m), 7.70-7.76 (2H, m) ,
7.78 (1H, dd, J = 3.8, 1.1 Hz), 7.96 (1H, dd, J = 5.0,

305
1.1 Hz), 8.13 (1H, d, J= 8.3 Hz), 8.94 (1H, d, J = 1.7
Hz), 12.23 (1H, s), 13.80-14.00 (1H, broad).
[0550]
2-(Benzo[1,3]dioxole-5-carboxamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 6.17 (2H, s), 7.13 (1H, d, J = 8.1
Hz), 7.43-7.59 (6H, m), 7.70-7.76 (2H, m), 8.13 (1H, d,
J = 8.3 Hz), 9.05 (1H, d, J = 2.0 Hz), 12.14 (1H, s),
13.70-13.95 (1H, broad).
[0551]
2-(2,3-Dihydrobenzo[1,4]dioxine-6-carboxamido)-4-
phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 4.28-4.39 (4H, m), 7.07 (1H, d, J =
8.3 Hz), 7.43-7.57 (6H, m) , 7.70-7.75 (2H, m) , 8.13 (1H,
d, J = 8.3 Hz), 9.07 (1H, d, J = 1.7 Hz), 12.16 (1H, s),
13.70-13.90 (1H, broad).
[0552]
2-(Benzothiophene-5-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 7.45-7.58 (4H, m), 7.65 (1H, d, J =
5.4 Hz), 1.12-1.18 (2H, m), 7.92-7.97 (2H, m), 8.15 (1H,
d, J = 8.3 Hz), 8.25 (1H, d, J = 8.5 Hz), 8.53 (1H, d,
J = 1.5 Hz), 9.11 (1H, d, J = 1.7 Hz), 12.37 (1H, s).
[0553]
2-(l-Methyl-lH-benzotriazole-5-carboxamido)-4-
phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 4.39 (3H, s), 7.45-7.51 (1H, m) ,
7.53-7.59 (3H, m), 7.73-7.78 (2H, m), 8.07 (1H, d, J =
8.8 Hz), 8.16 (2H, d, J = 8.1 Hz), 8.66 (1H, s), 9.07
(1H, d, J = 1.7 Hz), 12.37 (1H, s).

306
[0554]
2-(3-Nitrobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 7.48 (1H, tt, J = 7.3, 1.5 Hz),
7.52-7.61 (3H, m), 7.72-7.78 (2H, m), 7.93 (1H, t, J =
8.0 Hz), 8.15 (1H, d, J = 8.3 Hz), 8.41 (1H, ddd, J =
8.0, 1.5, 1.0 Hz), 8.51 (1H, ddd, J = 8.1, 2.4, 1.0 Hz),
8.78-8.80 (1H, m) , 8.98-9.00 (1H, m) , 12.42 (1H, s).
[0555]
2-(Benzofuran-5-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 7.16 (1H, dd, J = 2.2, 1.0 Hz), 7.47
(1H, tt, J = 7.4, 1.5 Hz), 7.50-7.59 (3H, m), 1.12-1.1%
(2H, m), 7.83 (1H, d, J = 8.5 Hz), 7.96 (1H, dd, J =
8.7, 1.7 Hz), 8.12-8.19 (2H, m), 8.33 (1H, d, J = 1.7
Hz), 9.10 (1H, d, J = 1.7 Hz), 12.31 (1H, s).
[0556]
2-(Benzothiazole-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.46-7.51 (1H, m) , 7.53-7.79 (7H, m) ,
8.16-8.22 (2H, m) , 8.29-8.32 (1H, m), 9.10 (1H, d, J =
1.7 Hz), 13.04 (1H, s).
[0557]
2-(Benzothiophene-3-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.45-7.61 (6H, m) , 7.73-7.80 (2H, m) ,
8.11-8.18 (2H, m), 8.51-8.55 (1H, m), 8.56 (1H, s),
9.04 (1H, d, J = 2.0 Hz), 12.09 (1H, s) .
[0558]
2-(Benzofuran-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-dg) 8: 7.37-7.48 (1H, m) , 7.48 (1H, tt, J =
7.4, 1.5 Hz), 7.52-7.59 (4H, m), 7.69-7.78 (4H, m),

307
7.86 (1H, d, J = 7.8 Hz), 8.16 (1H, d, J = 8.3 Hz),
9.08 (1H, d, J = 1.7 Hz), 12.61 (1H, s) .
[0559]
2-(Benzothiophene-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 6: 7.45-7.59 (6H, m) , 1.11-1.IB (2H, m) ,
8.06-8.18 (4H, m), 8.95 (1H, d, J = 1.5 Hz), 12.43 (1H,
s).
[0560]
4-Phenyl-2-(l-phenyl-lH-pyrazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-de) 8: 7.09 (1H, d, J = 2.0 Hz), 7.41-7.55
(9H, m), 7.64-7.69 (2H, m), 7.88 (1H, d, J = 2.0 Hz),
8.12 (1H, d, J = 8.3 Hz), 8.77 (1H, d, J = 1.7 Hz),
12.12 (1H, s).
[0561]
2-(2, 2-Diphenylacetamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 5.34 (1H, s), 7.28 (1H, tt, J= 7.2,
1.7 Hz), 7.33-7.54 (13H, m), 7.65-7.71 (2H, m), 8.02
(1H, d, J = 8.3 Hz), 8.92 (1H, d, J = 1.7 Hz), 11.42
(1H, s), 13.50-13.70 (1H, broad).
[0562]
2-(2-Chlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.44-7.65 (7H, m) , 7.71-7.78 (3H, m) ,
8.12 (1H, d, J = 8.3 Hz), 8.97 (1H, s) , 11.72 (1H, s).
[0563]
2-(3-Chlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.44-7.50 (1H, m) , 7.52-7.59 (3H, m) ,
7.66 (1H, t, J = 7.9 Hz), 1.11-1.18 (3H, m), 7.92-7.96

308
(1H, in), 7.99 (1H, t, J = 1.8 Hz), 8.14 (1H, d, J = 8.0
Hz), 9.00 (1H, d, J = 2.0 Hz), 12.27 (1H, s) .
[0564]
2-(4-Chlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 6: 7.47 (1H, tt, J = 7.4, 1.6 Hz),
7.52-7.59 (3H, m) , 7.68-7.77 (4H, m), 7.97-8.02 (2H, m) ,
8.14 (1H, d, J = 8.3 Hz), 9.02-9.04 (1H, m) , 12.25 (1H,
s).
[0565]
2-(2,4-Dichlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.3, 1.5 Hz),
7.52-7.59 (3H, m), 7.63 (1H, dd, J = 8.3, 2.0 Hz),
7.70-7.76 (2H, m), 7.79 (1H, d, J = 8.3 Hz), 7.83 (1H,
d, J = 2.0 Hz), 8.11 (1H, d, J = 8.3 Hz), 8.91 (1H, s),
11.72 (1H, s).
[0566]
4-Phenyl-2-(2,4-bis(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.4, 1.6 Hz),
7.53-7.57 (2H, m), 7.60 (1H, dd, J= 8.3, 1.7 Hz),
7.70-7.76 (2H, m), 8.10-8.15 (2H, m), 8.25 (1H, s),
8.28-8.33 (1H, m), 8.76 (1H, d, J = 1.4 Hz), 11.69 (1H,
s) .
[0567]
4-Phenyl-2-(3-phenylpropanamido)benzoic acid
1H-NMR (DMSO-de) 8: 2.76 (2H, t, J = 7.6 Hz), 2.97 (2H,
t, J = 7.6 Hz), 7.16-7.22 (1H, m), 7.26-7.31 (4H, m) ,
7.42-7.48 (2H, m) , 7.50-7.56 (2H, m) , 7.65-7.71 (2H, m) ,

309
8.05 (1H, d, J = 8.3 Hz), 8.85 (1H, d, J = 2.0 Hz),
11.23 (1H, s), 13.55-13.75 (1H, broad).
[0568]
Example 320

1.3 mL of methylene chloride, 1.3 JJ.L of N,N-
dimethylformainide and 0.031 mL of oxalyl chloride were
added sequentially to 69 mg of 6-(piperidin-1-
yl)pyridine-3-carboxylic acid at room temperature, and
stirred at the same temperature for 1 hour. The
reaction mixture was added to a mixed solution of 57 mg
of tert-butyl 2-amino-4-phenoxybenzoate, 3.7 mL of
methylene chloride and 0.22 mL of triethylamine and
stirred at room temperature for 2 hours. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
8:1] to obtain tert-butyl 4-phenoxy-2-(6-(piperidin-1-
yl)pyridine-3-carboxamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenoxy-2-(6-(piperidin-1-

310
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and water was added and pH was
adjusted to pH 6.5 with a saturated sodium hydrogen
carbonate aqueous solution. A solid substance was
separated by filtration to obtain 23 mg of 4-phenoxy-2-
(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoic acid
as white solid.
1H-NMR (DMSO-de) 5: 1.47-1.70 (6H, m) , 3.62-3.70 (4H, m) ,
6.73 (1H, dd, J = 9.0, 2.6 Hz), 6.93 (1H, d, J = 9.2
Hz), 7.15-7.18 (2H, m) , 7.25-7.30 (1H, m) , 7.45-7.52
(2H, m), 7.91 (1H, dd, J = 9.2, 2.6 Hz), 8.05 (1H, d, J
= 9.0 Hz), 8.38 (1H, d, J = 2.6 Hz), 8.63 (1H, d, J =
2.6 Hz), 12.22 (1H, s).
[0569]
Example 321

0.059 mL of triethylamine and 0.037 mL of 2-
fluorobenzoyl chloride were added to 3.0 mL of
methylene chloride solution containing 60 mg of tert-
butyl 2-amino-4-phenoxybenzoate at room temperature
sequentially and stirred at the same temperature for 2
hours. 0.48 g of aminomethylated polystyrene was added
to the reaction mixture and stirred at room temperature
overnight. A saturated sodium hydrogen carbonate

311
aqueous solution was added to the reaction mixture, the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(2-fluorobenzamido)-4-phenoxybenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-fluorobenzamido)-4-
phenoxybenzoate and stirred at room temperature for 2
hours. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 30 mg of 2-(2-fluorobenzamido)-4-
phenoxybenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 6.79 (1H, dd, J = 8.9, 2.5 Hz),
7.16-7.21 (2H, m), 7.25-7.31 (1H, m), 7.35-7.53 (4H, m) ,
7.63-7.69 (1H, m), 7.88 (1H, td, J = 7.8, 1.8 Hz), 8.06
(1H, d, J = 8.9 Hz), 8.41 (1H, d, J = 2.5 Hz), 12.15-
12.19 (1H, broad), 13.50-13.70 (1H, broad).
[0570]
Examples 322 to 344
The compounds shown in Table 34 were obtained
in the same manner as in Example 321.
[0571]
[Table 34]


[0572]
4-Phenoxy-2-(2-(trifluoromethyl)benzamido)benzole acid
1H-NMR (DMSO-d6) 8: 6.77 (1H, dd, J = 8.8, 2.4 Hz), 7.19
(2H, d, J = 7.8 Hz), 7.28 (1H, t, J = 7.4 Hz), 7.46-
7.53 (2H, m), 7.74-7.87 (3H, m), 7.89 (1H, d, J = 8.1
Hz), 8.04 (1H, d, J = 8.8 Hz), 8.27 (1H, d, J = 2.4 Hz),
11.82 (1H, s), 13.60 (1H, s).
[0573]
4-Phenoxy-2-(4-(trifluoromethyl)benzamido)benzoic acid

313
1H-NMR (DMSO-de) 8: 6.80 (1H, dd, J = 8.9, 2.5 Hz),
7.16-7.22 (2H, m) , 7.26-7.32 (1H, m), 7.47-7.53 (2H, m) ,
7.98 (2H, d, J = 8.3 Hz), 8.06-8.14 (3H, m), 8.37 (1H,
d, J = 2.5 Hz), 12.51 (1H, s), 13.65-13.85 (1H, broad).
[0574]
2-(2-Methylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 6: 2.42 (3H, s), 6.75 (1H, dd, J = 8.9,
2.7 Hz), 7.16-7.21 (2H, m), 7.25-7.36 (3H, m), 7.41-
7.52 (3H, m), 7.56-7.60 (1H, m), 8.05 (1H, d, J = 8.9
Hz), 8.39 (1H, d, J = 2.7 Hz), 11.82 (1H, s), 13.45-
13.65 (1H, broad).
[0575]
2-(3-Methylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.40 (3H, s) , 6.77 (1H, dd, J = 8.8,
2.7 Hz), 7.16-7.21 (2H, m) , 7.26-7.31 (1H, m), 7.44-
7.53 (4H, m) , 7.68-7.74 (1H, m), 7.74 (1H, s) , 8.07 (1H,
d, J = 8.8 Hz), 8.41 (1H, d, J = 2.7 Hz), 12.41 (1H, s) ,
13.71 (1H, s).
[0576]
2-(4-Methylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.39 (3H, s) , 6.76 (1H, dd, J = 8.9,
2.6 Hz), 7.15-7.21 (2H, m), 7.26-7.31 (1H, m), 7.39 (2H,
d, J = 8.2 Hz), 7.46-7.52 (2H, m), 7.82 (2H, d, J = 8.2
Hz), 8.07 (1H, d, J = 8.9 Hz), 8.41 (1H, d, J = 2.6 Hz),
12.38 (1H, s), 13.67 (1H, s).
[0577]
2-(4-Nitrobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.82 (1H, dd, J = 8.9, 2.5 Hz),
7.16-7.21 (2H, m) , 7.26-7.32 (1H, m), 7.46-7.53 (2H, m) ,

314
8.09 (1H, d, J - 8.9 Hz), 8.12-8.17 (2H, m), 8.35 (1H,
d, J = 2.5 Hz), 8.40-8.45 (2H, m), 12.53 (1H, s),
13.65-13.90 (1H, broad).
[0578]
2-(3,4-Dimethylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.30 (6H, s) , 6.75 (1H, dd, J = 8.9,
2.7 Hz), 7.15-7.20 (2H, m) , 7.25-7.31 (1H, m), 7.34 (1H,
d, J = 7.8 Hz), 7.45-7.53 (2H, m), 7.64 (1H, dd, J =
7.8, 1.9 Hz), 7.71 (1H, d, J = 1.9 Hz), 8.06 (1H, d, J
= 8.9 Hz), 8.42 (1H, d, J = 2.7 Hz), 12.38 (1H, s),
13.69 (1H, s).
[0579]
2-(2,3-Dimethylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.27 (3H, s) , 2.29 (3H, s) , 6.75 (1H,
dd, J = 8.8, 2.6 Hz), 7.16-7.38 (6H, m), 7.46-7.52 (2H,
m), 8.04 (1H, d, J = 8.8 Hz), 8.40 (1H, d, J = 2.6 Hz),
11.73 (1H, s), 13.53 (1H, s).
[0580]
2-(6-Morpholinopyridine-3-carboxamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-de) 8: 3.57-3.75 (8H, m) , 6.75 (1H, dd, J =
9.0, 2.6 Hz), 6.96 (1H, d, J = 9.0 Hz), 7.13-7.22 (2H,
m), 7.24-7.31 (1H, m), 7.45-7.53 (2H, m), 7.97 (1H, dd,
J = 9.0, 2.4 Hz), 8.05 (1H, d, J = 9.0 Hz), 8.37 (1H, d,
J = 2.6 Hz), 8.67 (1H, d, J = 2.4 Hz), 12.23 (1H, s),
13.64 (1H, s).
[0581]
4-Phenoxy-2-(2-phenylacetamido)benzoic acid

315
1H-NMR (DMSO-d6) 5: 3.73 (2H, s), 6.69 (1H, dd, J = 8.8,
2.5 Hz), 7.12 (2H, d, J = 7.6 Hz), 7.22-7.38 (6H, m),
7.43-7.49 (2H, m), 7.96 (1H, d, J = 8.8 Hz), 8.21 (1H,
d, J = 2.5 Hz), 11.35 (1H, s), 13.45 (1H, s).
[0582]
2-(3-Fluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.80 (1H, dd, J = 8.8, 2.7 Hz) ,
7.16-7.21 (2H, m) , 7.26-7.31 (1H, m), 7.46-7.55 (3H, m) ,
7.62-7.70 (2H, m) , 7.74-7.78 (1H, m), 8.08 (1H, d, J =
8.8 Hz), 8.35 (1H, d, J = 2.7 Hz), 12.42 (1H, s),
13.60-13.85 (1H, broad).
[0583]
2-(2,6-Difluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 5: 6.81 (1H, dd, J = 8.8, 2.4 Hz), 7.19
(2H, d, J = 7.8 Hz), 7.24-7.34 (3H, m) , 7.46-7.54 (2H,
m), 7.61-7.70 (1H, m), 8.05 (1H, d, J = 8.8 Hz), 8.25-
8.29 (1H, m), 11.99 (1H, s), 13.50-13.80 (1H, broad).
[0584]
4-Phenoxy-2-(3-(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.8, 2.4 Hz),
7.16-7.21 (2H, m), 7.26-7.32 (1H, m), 7.46-7.53 (2H, m),
7.85 (1H, t, J = 8.0 Hz), 8.03 (1H, d, J = 7.8 Hz),
8.08 (1H, d, J = 8.8 Hz), 8.18-8.24 (2H, m), 8.35 (1H,
d, J = 2.4 Hz), 12.54 (1H, s) .
[0585]
2-(3-Nitrobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.8, 2.4 Hz),
7.17-7.21 (2H, m) , 7.26-7.33 (1H, m), 7.46-7.54 (2H, m) ,
7.89 (1H, t, J = 7.9 Hz), 8.08 (1H, d, J = 8.8 Hz),

316
8.30-8.37 (2H, m) , 8.46-8.50 (1H, m), 8.71 (1H, s),
12.62 (1H, s), 13.70-14.00 (1H, broad).
[0586]
2-(2-Chlorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.79 (1H, dd, J = 8.9, 2.4 Hz),
7.16-7.22 (2H, m), 7.26-7.32 (1H, m), 7.46-7.63 (5H, m),
7.69 (1H, dd, J = 7.4, 1.6 Hz), 8.05 (1H, d, J = 8.9
Hz), 8.30-8.34 (1H, m), 11.86 (1H, s), 13.50-13.75 (1H,
broad).
[0587]
2-(3-Chlorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.79 (1H, dd, J = 8.8, 2.4 Hz) ,
7.16-7.21 (2H, m), 7.25-7.31 (1H, m), 7.45-7.53 (2H, m),
7.60-7.65 (1H, m), 7.69-7.76 (1H, m), 7.84-7.95 (2H, m),
8.07 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 2.4 Hz),
12.43 (1H, s).
[0588]
2-(4-Chlorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.78 (1H, dd, J = 8.9, 2.6 Hz),
7.16-7.21 (2H, m) , 7.26-7.32 (1H, m), 7.46-7.52 (2H, m) ,
7.64-7.70 (2H, m), 7.88-7.95 (2H, m) , 8.07 (1H, d, J =
8.9 Hz), 8.36 (1H, d, J = 2.6 Hz), 12.42 (1H, s).
[0589]
2-(2,4-Dichlorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.80 (1H, dd, J = 8.8, 2.7 Hz), 7.18
(2H, d, J = 7.8 Hz), 7.28 (1H, t, J = 7.4 Hz), 7.45-
7.53 (2H, m), 7.60 (1H, dd, J = 8.3, 2.2 Hz), 7.74 (1H,
d, J = 8.3 Hz), 7.81 (1H, d, J = 1.9 Hz), 8.05 (1H, d,

317
J = 8.8 Hz), 8.26-8.28 (1H, m) , 11.88 (1H, s), 13.45-
13.80 (1H, broad).
[0590]
2-(Benzothiophene-5-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 5: 6.78 (1H, dd, J = 8.8, 2.7 Hz),
7.17-7.22 (2H, m) , 7.27-7.32 (1H, m) , 7.47-7.53 (2H, m) ,
7.62 (1H, d, J = 5.4 Hz), 7.87 (1H, dd, J = 8.4, 1.7
Hz), 7.93 (1H, d, J = 5.4 Hz), 8.09 (1H, d, J = 8.8 Hz),
8.22 (1H, d, J = 8.4 Hz), 8.44 (1H, d, J = 2.7 Hz),
8.47 (1H, d, J = 1.7 Hz), 12.52 (1H, s) .
[0591]
2-(Benzothiophene-2-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.80 (1H, dd, J = 8.8, 2.6 Hz),
7.17-7.22 (2H, m) , 7.26-7.32 (1H, m) , 7.46-7.56 (4H, m) ,
8.04-8.12 (4H, m), 8.28 (1H, d, J = 2.6 Hz), 12.57 (1H,
s), 13.65-13.90 (1H, broad).
[0592]
4-Phenoxy-2-(l-phenyl-lH-pyrazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.73 (1H, dd, J = 8.9, 2.7 Hz), 7.04
(1H, d, J = 2.1 Hz), 7.10-7.15 (2H, m), 7.20-7.25 (1H,
m), 7.40-7.48 (7H, m), 7.86 (1H, d, J = 2.1 Hz), 8.04
(1H, d, J = 8.9 Hz), 8.13 (1H, d, J = 2.7 Hz), 12.22
(1H, s).
[0593]
4-Phenoxy-2-(2,4-bis(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-de) 8: 6.80 (1H, dd, J = 8.9, 2.3 Hz), 7.19
(2H, d, J = 7.8 Hz), 7.26-7.31 (1H, m), 7.45-7.53 (2H,

318
m), 8.05 (1H, d, J = 8.9 Hz), 8.09 (1H, d, J = 7.9 Hz),
8.19 (1H, d, J = 2.3 Hz), 8.23 (1H, s), 8.27 (1, d, J =
7.9 Hz), 11.86 (1H, s).
[0594]
4-Phenoxy-2-(3-phenylpropanamido)benzoic acid
1H-NMR (DMSO-de) 5: 2.69 (2H, t, J = 7.7 Hz) , 2.90 (2H,
t, J = 7.7 Hz), 6.69 (1H, dd, J = 8.9, 2.5 Hz), 7.11-
7.21 (3H, m), 7.21-7.31 (5H, m) , 7.43-7.50 (2H, m) ,
7.98 (1H, d, J = 8.9 Hz), 8.21 (1H, d, J = 2.5 Hz),
11.36 (1H, s), 13.40-13.60 (1H, broad).
[0595]
Example 345

1.3 mL of methylene chloride, 1.3 ^L of N,N-
dimethylformamide and 0.031 mL of oxalyl chloride were
added to 69 mg of 3,4-dimethoxycinnamic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 54 mg of tert-butyl 2-amino-4-
phenylbenzoate, 3.7 mL of methylene chloride and 0.22
mL of triethylamine and stirred at room temperature for
2 hours. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was

319
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain (E)-
tert-butyl 2-(3-(3,4-dimethoxyphenyl)acrylamido)-4-
phenylbenzoate.
10 mL of trifluoroacetic acid was added to
obtain (E)-tert-butyl 2- (3-(3,4-
dimethoxyphenyl)acrylamido)-4-phenylbenzoate and
stirred at room temperature for 2 hours. The solvent
was evaporated under reduced pressure, diisopropyl
ether was added to the obtained residue, and a solid
substances was separated by filtration to obtain 20 mg
of (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-4-
phenylbenzoic acid as white solid.
1H-NMR (DMSO-d6) 6: 3.81 (3H, s) , 3.85 (3H, s) , 6.84 (1H,
d, J = 15.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.26 (1H, dd,
J = 8.4, 1.7 Hz), 7.40 (1H, d, J = 1.5 Hz), 7.43-7.57
(4H, m), 7.59 (1H, d, J = 15.5 Hz), 7.71 (2H, d, J =
7.8 Hz), 8.09 (1H, d, J = 8.4 Hz), 9.00 (1H, d, J = 1.7
Hz), 11.37 (1H, s), 13.50-13.75 (1H, broad).
[0596]
Examples 346 to 367
The compounds shown in Table 35 were obtained
in the same manner as in Example 345.
[0597]
[Table 35]


[0598]
4-Phenyl-2-((E)-3-(pyridin-4-yl)acrylamido)benzoic acid
trifluoroacetate
1H-NMR (DMSO-de) 6: 7.40 (1H, d, J = 15.6 Hz), 7.47 (1H,
tt, J = 7.3, 1.5 Hz), 7.51-7.58 (3H, m), 7.68-7.75 (3H,
m), 8.07 (2H, d, J = 6.1 Hz), 8.11 (1H, d, J = 8.3 Hz),
8.82 (2H, d, J = 6.1 Hz), 8.96 (1H, d, J = 1.7 Hz),
11.56 (1H, s).
[0599]
2-(3-Methylpyridine-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 2.71 (3H, s) , 7.44-7.61 (5H, m) ,
7.72-7.77 (2H, m), 7.85-7.88 (1H, m), 8.12 (1H, d, J =

321
8.0 Hz), 8.56-8.59 (1H, m), 9.20 (1H, d, J = 1.7 Hz),
13.09 (1H, s), 13.45-13.70 (1H, broad).
[0600]
4-Phenyl-2-(3-phenylpropiolamido)benzoic acid
1H-NMR (DMSO-d6) 5: 6.56-6.70 (1H, m) , 7.21 (1H, d, J =
7.8 Hz), 7.27-7.32 (2H, m) , 7.34-7.41 (3H, m), 7.61-
7.70 (3H, m), 7.88-7.92 (2H, m), 8.42 (1H, d, J = 7.8
Hz) .
[0601]
4-Phenyl-2-(6-phenylpyrimidine-4-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 7.45-7.50 (1H, m) , 7.54-7.66 (6H, m) ,
7.74-7.79 (2H, m), 8.17 (1H, d, J = 8.3 Hz), 8.30-8.38
(2H, m), 8.67 (1H, d, J = 1.2 Hz), 9.24 (1H, d, J = 1.7
Hz), 9.49 (1H, d, J = 1.2 Hz), 13.24 (1H, s) .
[0602]
4-Phenyl-2-(5-phenyl-lH-pyrazole-4-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 7.38-7.55 (8H, m), 7.67-7.75 (4H, m),
8.08 (1H, d, J = 8.3 Hz), 8.95 (1H, d, J = 1.4 Hz),
11.65-11.80 (1H, broad), 12.82-12.90 (1H, broad).
[0603]
4-Phenyl-2-(3-phenyl-lH-pyrazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-de) 8: 7.25 (1H, s), 7.38-7.59 (7H, m),
7.71-7.77 (2H, m) , 7.83-7.89 (2H, m), 8.13 (1H, d, J =
8.0 Hz), 9.17 (1H, s), 12.45 (1H, s), 14.01 (1H, s) .

322
[0604]
4-Phenyl-2-(3-phenylisoxazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 7.45-7.51 (1H, m), 7.53-7.63 (7H, m),
7.74 (2H, d, J = 7.8 Hz), 7.98-8.05 (2H, m), 8.16 (1H,
d, J = 8.3 Hz), 9.05 (1H, d, J = 1.7 Hz), 12.56 (1H, s),
13.75-14.10 (1H, broad).
[0605]
2-(3-Acetoxybenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 6: 2.33 (3H, s), 7.43-7.50 (2H, m),
7.51-7.59 (3H, m), 7.67 (1H, t, J = 7.9 Hz), 7.70-7.77
(3H, m) , 7.85-7.90 (1H, m), 8.14 (1H, d, J = 8.3 Hz),
9.03 (1H, d, J = 1.7 Hz), 12.27 (1H, s), 13.75-14.05
(1H, broad).
[0606]
2-(4-Acetoxybenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 6: 2.33 (3H, s) , 7.36-7.42 (2H, m) ,
7.47 (1H, tt, J = 7.3, 1.5 Hz), 7.51-7.59 (3H, m) ,
7.71-7.77 (2H, m), 8.00-8.06 (2H, m), 8.14 (1H, d, J =
8.3 Hz), 9.06 (1H, d, J = 2.0 Hz), 12.25 (1H, s),
13.75-13.95 (1H, broad).
[0607]
2-((E)-3-(4-Acetoxyphenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-de) 8: 2.29 (3H, s) , 6.92 (1H, d, J = 15.7
Hz), 7.21 (2H, d, J = 8.7 Hz), 7.43-7.58 (4H, m), 7.66
(1H, d, J = 15.7 Hz), 7.68-7.75 (2H, m), 7.81 (2H, d, J
= 8.7 Hz), 8.10 (1H, d, J = 8.3 Hz), 8.98 (1H, d, J =
1.7 Hz), 11.43 (1H, s), 13.50-13.80 (1H, broad).

323
[0608]
2-((E)-3-(3-Methoxyphenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 3.82 (3H, s) , 6.96 (1H, d, J = 15.6
Hz), 6.97-7.04 (1H, m) , 7.28-7.39 (3H, m) , 7.43-7.58
(4H, m), 7.62 (1H, d, J = 15.6 Hz), 7.71 (2H, d, J =
8.0 Hz), 8.09 (1H, d, J = 8.3 Hz), 8.97 (1H, d, J = 1.7
Hz), 11.45 (1H, s) .
[0609]
2-((E)-3-(4-Chlorophenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 6.98 (1H, d, J = 15.7 Hz), 7.46 (1H,
tt, J = 7.3, 1.5 Hz), 7.48-7.57 (5H, m), 7.64 (1H, d, J
= 15.7 Hz), 7.69-7.74 (2H, m), 7.77-7.83 (2H, m), 8.10
(1H, d, J = 8.3 Hz), 8.98 (1H, d, J = 2.0 Hz), 11.43
(1H, s), 13.55-13.80 (1H, broad).
[0610]
2-((E)-3-(3-Chlorophenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 7.08 (1H, d, J = 15.6 Hz), 7.43-7.57
(6H, m), 7.63 (1H, d, J = 15.6 Hz), 7.69-7.75 (3H, m) ,
7.92 (1H, s), 8.10 (1H, d, J = 8.0 Hz), 8.98 (1H, d, J
= 2.0 Hz), 11.42 (1H, s), 13.55-13.85 (1H, broad).
[0611]
2-((E)-3-(3,4-Dichlorophenyl)acrylamido)-4-
phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 7.12 (1H, d, J = 15.6 Hz), 7.46 (1H,
tt, J = 7.3, 1.5 Hz), 7.48-7.57 (3H, m), 7.63 (1H, d, J
= 15.6 Hz), 7.68-7.7.4 (3H, m) , 7.77 (1H, dd, J = 8.5,

324
2.0 Hz), 8.10 (1H, d, J = 8.3 Hz), 8.14 (1H, d, J = 2.0
Hz), 8.99 (1H, d, J = 1.7 Hz), 11.43 (1H, s), 13.55-
13.80 (1H, broad).
[0612]
2-((E)-3-(Benzo[1,3]dioxol-5-yl)acrylamido)-4-
phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 6.10 (2H, s) , 6.81 (1H, d, J = 15.6
Hz), 6.98 (1H, d, J = 8.1 Hz), 7.21 (1H, dd, J = 8.1,
1.7 Hz), 7.43-7.51 (3H, m) , 7.51-7.61 (3H, m), 7.68-
7.74 (2H, m), 8.09 (1H, d, J = 8.1 Hz), 9.00 (1H, d, J
= 1.9 Hz), 11.37 (1H, s), 13.55-13.75 (1H, broad).
[0613]
4-Phenyl-2-((E)-3-(thiophen-2-yl)acrylamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.60 (1H, d, J = 15.4 Hz), 7.17 (1H,
dd, J = 5.1, 3.6 Hz), 7.43-7.58 (5H, m) , 7.68-7.74 (3H,
m) , 7.80 (1H, d, J = 15.4 Hz), 8.08 (1H, d, J = 8.3 Hz),
8.90 (1H, d, J = 1.7 Hz), 11.30 (1H, s) .
[0614]
2-(4-Morpholinobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 3.27-3.31 (4H, m) , 3.74-3.77 (4H, m) ,
7.10 (2H, d, J = 9.0 Hz), 7.43-7.51 (2H, m) , 7.51-7.58
(2H, m), 7.71-7.76 (2H, m), 7.86 (2H, d, J = 9.0 Hz),
8.12 (1H, d, J = 8.3 Hz), 9.12 (1H, d, J = 1.7 Hz),
12.16 (1H, s).
[0615]
2-(2-(4-Nitrophenyl)acetamido)-4-phenylbenzoic acid

325
1H-NMR (DMSO-d6) 8: 4.03 (2H, s), 7.42-7.54 (4H, m),
7.64-7.71 (4H, m), 8.04 (1H, d, J = 8.3 Hz), 8.22-8.27
(2H, m), 8.82 (1H, d, J = 1.7 Hz), 11.18 (1H, s).
[0616]
2-((E)-3-(3-Nitrophenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-de) 8: 7.23 (1H, d, J = 15.9 Hz), 7.43-7.58
(4H, m), 7.69-7.81 (4H, m), 8.10 (1H, d, J = 8.3 Hz),
8.20-8.28 (2H, m), 8.63 (1H, t, J = 1.8 Hz), 8.98 (1H,
d, J = 1.7 Hz), 11.52 (1H, s) .
[0617]
2-((E)-3-(4-Nitrophenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-dg) 8: 7.20 (1H, d, J = 15.6 Hz), 7.46 (1H,
tt, J = 7.3, 1.6 Hz), 7.50-7.57 (3H, m), 7.69-7.79 (3H,
m), 8.02-8.07 (2H, m), 8.10 (1H, d, J = 8.3 Hz), 8.26-
8.32 (2H, m), 8.97 (1H, d, J = 1.7 Hz), 11.50 (1H, s) .
[0618]
4-Phenyl-2-(4-phenylbutanamido)benzoic acid
1H-NMR (DMSO-d6) 8: 1.91-2.01 (2H, m) , 2.44 (2H, t, J =
7.3 Hz), 2.66 (2H, t, J = 7.7 Hz), 7.15-7.33 (5H, m) ,
7.42-7.48 (2H, m) , 7.49-7.56 (2H, m), 7.66-7.71 (2H, m) ,
8.06 (1H, d, J = 8.3 Hz), 8.86 (1H, d, J = 1.9 Hz),
11.22 (1H, s), 13.55-13.75 (1H, broad).
[0619]
4-Phenyl-2-((E)-4-phenyl-3-butenamido)benzoic acid
1H-NMR (DMSO-d6) 8: 3.40 (2H, dd, J = 7.3, 1.2 Hz), 6.45
(1H, dt, J = 15.9, 7.3 Hz), 6.68 (1H, d, J = 15.9 Hz),
7.25 (1H, tt, J = 7.3, 1.5 Hz), 7.32-7.37 (2H, m),

326
7.41-7.55 (6H, m), 7.65-7.71 (2H, m), 8.05 (1H, d, J =
8.3 Hz), 8.89 (1H, d, J« 2.0 Hz), 11.28 (1H, s).
[0620]
Example 368

1.3 niL of methylene chloride, 1.3 |4.L of N,N-
dimethylformamide and 0.031 mL of oxalyl chloride were
sequentially added to 69 mg of 6-(piperidin-1-
yl)pyridine-3-carboxylic acid at room temperature, and
stirred at the same temperature for 1 hour. The
reaction mixture was added to a mixed solution of 54 mg
of tert-butyl 2-amino-4-phenylbenzoate, 3.7 mL of
methylene chloride and 0.22 mL of triethylamine and
stirred at room temperature for 2 hours. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 4-phenyl-2-(6-(piperidin-1-
yl)pyridine-3-carboxamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenyl-2-(6-(piperidin-1-

327
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and water was added and pH was
adjusted to pH 6.5 with a saturated sodium hydrogen
carbonate aqueous solution. A solid substance was
separated by filtration to obtain 56 mg of 4-phenyl-2-
(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 1.50-1.70 (6H, m) , 3.65-3.72 (4H, m) ,
6.99 (1H, d, J = 9.3 Hz), 7.43-7.58 (4H, m) , 7.70-7.76
(2H, m), 7.99 (1H, dd, J = 9.3, 2.6 Hz), 8.12 (1H, d, J
= 8.3 Hz), 8.70 (1H, d, J - 2.6 Hz), 9.07 (1H, d, J =
1.7 Hz), 12.05 (1H, s).
[0621]
Example 369

1.3 mL of methylene chloride, 1.3 JAL of N,N-
dimethylformamide and 0.031 mL of oxalyl chloride were
added to 69 mg of 3,4-dimethoxycinnamic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 57 mg of tert-butyl 2-amino-4-
phenoxybenzoate, 3.7 mL of methylene chloride and 0.22
mL of triethylamine and stirred at room temperature for

328
2 hours. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-((E)-3-(3,4-dimethoxyphenyl)acrylamido)-4-
phenoxybenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-( (E)-3-(3,4-
dimethoxyphenyl)acrylamido)-4-phenoxybenzoate and
stirred at room temperature for 2 hours. The solvent
was evaporated under reduced pressure, and diisopropyl
ether was add to the obtained residue, and a solid
substance was separated by filtration to obtain 13 mg
of (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-4-
phenoxybenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 3.80 (3H, s), 3.83 (3H, s) , 6.69-
6.81 (2H, m), 6.99 (1H, d, J = 8.5 Hz), 7.14-7.20 (2H,
m), 7.22-7.31 (2H, m), 7.38 (1H, s), 7.45-7.51 (2H, m),
7.54 (1H, d, J = 15.6 Hz), 8.03 (1H, d, J = 8.8 Hz),
8.38 (1H, d, J = 2.4 Hz), 11.50 (1H, s), 13.40-13.60
(1H, broad).
[0622]
Examples 370 to 387
The compounds shown in Table 36 were obtained
in the same manner as in Example 369.


[0624]
4-Phenoxy-2-((E)-3-(pyridin-4-yl)acrylamido)benzoic
acid trifluoroacetate
1H-NMR (DMSO-de) 8: 6.78 (1H, dd, J = 8.8, 2.6 Hz),
7.15-7.20 (2H, m) , 7.23-7.32 (2H, m) , 7.45-7.53 (2H, m) ,
7.65 (1H, d, J = 15.6 Hz), 7.94 (2H, d, J = 6.4 Hz),
8.05 (1H, d, J = 8.8 Hz), 8.34 (1H, d, J = 2.6 Hz),
8.75 (2H, d, J = 5.1 Hz), 11.68 (1H, s) .
[0625]
4-Phenoxy-2-(5-(thiophen-2-yl)pyridine-3-
carboxamido)benzoic acid

330
1H-NMR (DMSO-de) 8: 6.83 (1H, dd, J = 8.8, 2.6 Hz),
7.17-7.23 (2H, m), 7.25 (1H, dd, J= 5.1, 3.7 Hz),
7.27-7.33 (1H, m), 7.47-7.54 (2H, m), 7.75 (1H, dd, J=
5.1, 1.1 Hz), 7.78 (1H, dd, J = 3.7, 1.1 Hz), 8.09 (1H,
d, J = 8.8 Hz), 8.34 (1H, d, J = 2.6 Hz), 8.43 (1H, t,
J = 2.2 Hz), 8.98 (1H, d, J = 2.2 Hz), 9.14 (1H, d, J =
2.2 Hz), 12.51 (1H, s).
[0626]
4-Phenoxy-2-(6-phenylpyrimidine-4-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.85 (1H, dd, J = 8.8, 2.4 Hz),
7.19-7.25 (2H, m), 7.31 (1H, t, J = 7.5 Hz), 7.48-7.55
(2H, m), 7.57-7.64 (3H, m), 8.10 (1H, d, J = 8.8 Hz),
8.33 (2H, dd, J = 8.0, 1.7 Hz), 8.52 (1H, d, J = 2.4
Hz), 8.60 (1H, d, J = 1.2 Hz), 9.45 (1H, d, J = 1.2 Hz),
13.33 (1H, s), 13.35-13.75 (1H, broad).
[0627]
4-Phenoxy-2-(5-phenyl-lH-pyrazole-4-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.68 (1H, dd, J = 8.8, 2.7 Hz),
7.12-7.17 (2H, m), 7.24 (1H, t, J = 7.4 Hz), 7.32-7.52
(6H, m), 7.64-7.70 (2H, m), 8.00 (1H, d, J = 8.8 Hz),
8.29 (1H, d, J = 2.7 Hz), 11.65-12.00 (1H, broad),
13.35-13.75 (2H, broad).
[0628]
4-Phenoxy-2-(3-phenyl-lH-pyrazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.74 (1H, dd, J = 8.9, 2.6 Hz) ,
7.16-7.24 (3H, m) , 7.28 (1H, t, J = 7.4 Hz), 7.40 (1H,

331
t, J = 7.3 Hz), 7.45-7.53 (4H, m), 7.82 (2H, d, J = 7.6
Hz), 8.05 (1H, d, J = 8.9 Hz), 8.48-8.49 (1H, m), 12.52
(1H, s), 13.30-13.55 (1H, broad), 13.98 (1H, s) .
[0629]
4-Phenoxy-2-(3-phenylisoxazole-5-carboxamido)benzoic
acid
1H-NMR (DMSO-de) 5: 6.82 (1H, dd, J = 8.9, 2.6 Hz),
7.18-7.23 (2H, m) , 7.27-7.33 (1H, m) , 7.47-7.62 (6H, m) ,
7.94-8.02 (2H, m), 8.08 (1H, d, J = 8.9 Hz), 8.38 (1H,
d, J = 2.6 Hz), 12.66 (1H, s).
[0630]
2-(3-Acetoxybenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 2.31 (3H, s), 6.78 (1H, dd, J = 8.9,
2.7 Hz), 7.15-7.22 (2H, m), 7.28 (1H, t, J = 7.6 Hz),
7.40-7.45 (1H, m) , 7.46-7.53 (2H, m), 7.61-7.68 (2H, m) ,
7.79-7.81 (1H, m), 8.07 (1H, d, J = 8.9 Hz), 8.37 (1H,
d, J = 2.7 Hz), 12.43 (1H, s), 13.65-13.85 (1H, broad).
[0631]
2-(2-Hydroxybenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 6: 6.75 (1H, ddd, J = 8.8, 2.5, 0.9 Hz),
6.92-7.02 (2H, m), 7.14-7.19 (2H, m), 7.23-7.29 (1H, m) ,
7.39-7.51 (3H, m), 7.80 (1H, d, J = 7.6 Hz), 8.04 (1H,
dd, J = 8.8, 0.9 Hz), 8.41 (1H, dd, J = 2.5, 0.9 Hz),
11.31 (1H, s), 12.42 (1H, s).
[0632]
2-(4-Acetoxybenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.31 (3H, s), 6.78 (1H, dd, J = 8.9,
2.5 Hz), 7.15-7.21 (2H, m), 7.26-7.31 (1H, m), 7.33-
7.39 (2H, m), 7.46-7.53 (2H, m), 7.93-7.99 (2H, m),

332
8.07 (1H, d, J = 8.9 Hz), 8.39 (1H, d, J = 2.5 Hz),
12.39 (1H, s), 13.60-13.80 (1H, broad).
[0633]
2-((E)-3-(3-Methoxyphenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 3.81 (3H, s) , 6.74 (1H, dd, J = 8.8,
2.6 Hz), 6.88 (1H, d, J = 15.6 Hz), 6.99 (1H, dd, J =
8.0, 1.5 Hz), 7.15-7.20 (2H, m), 7.25-7.38 (4H, m),
7.45-7.52 (2H, m), 7.57 (1H, d, J = 15.6 Hz), 8.03 (1H,
d, J = 8.8 Hz), 8.35 (1H, d, J = 2.6 Hz), 11.56 (1H, s),
13.40-13.60 (1H, broad).
[0634]
2-((E) -3-(4-Chlorophenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 6.74 (1H, dd, J = 8.9, 2.6 Hz), 6.89
(1H, d, J = 15.6 Hz), 7.15-7.20 (2H, m), 7.28 (1H, t, J
= 7.4 Hz), 7.45-7.52 (4H, m), 7.60 (1H, d, J = 15.6 Hz),
7.76-7.79 (2H, m), 8.03 (1H, d, J = 8.9 Hz), 8.35 (1H,
d, J = 2.6 Hz), 11.57 (1H, s), 13.40-13.65 (1H, broad).
[0635]
2-((E)-3-(3-Chlorophenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-de) 8: 6.75 (1H, dd, J = 8.9, 2.5 Hz), 6.99
(1H, d, J = 15.6 Hz), 7.14-7.20 (2H, m), 7.28 (1H, t, J
= 7.4 Hz), 7.45-7.52 (4H, m) , 7.59 (1H, d, J = 15.6 Hz),
7.66-7.73 (1H, m), 7.90 (1H, s), 8.04 (1H, d, J = 8.9
Hz), 8.35 (1H, d, J = 2.5 Hz), 11.59 (1H, s).

333
[0636]
2-((E)-3-(3,4-Dichlorophenyl)acrylamido)-4-
phenoxybenzoic acid
1H-NMR (DMSO-de) 6: 6.75 (1H, dd, J = 9.0, 2.7 Hz), 7.04
(1H, d, J = 15.6 Hz), 7.15-7.21 (2H, m) , 7.28 (1H, t, J
= 7.4 Hz), 7.45-7.53 (2H, m), 7.58 (1H, d, J = 15.6 Hz),
7.69 (1H, d, J = 8.6 Hz), 7.75 (1H, dd, J = 8.6, 2.0
Hz), 8.03 (1H, d, J = 9.0 Hz), 8.12 (1H, d, J = 2.0 Hz),
8.35 (1H, d, J = 2.7 Hz), 11.60 (1H, s) .
[0637]
2-((E)-3-(Benzo[1,3]dioxol-5-yl)acrylamido)-4-
phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.08 (2H, s) , 6.68-6.77 (2H, m) ,
6.96 (1H, d, J = 8.0 Hz), 7.14-7.22 (3H, m), 7.25-7.31
(1H, m), 7.43-7.55 (4H, m), 8.02 (1H, d, J = 9.0 Hz),
8.36 (1H, d, J = 2.7 Hz), 11.50 (1H, s).
[0638]
4-Phenoxy-2-((E)-3-(thiophen-2-yl)acrylamido)benzoic
acid
1H-NMR (DMSO-de) 8: 6.49 (1H, d, J = 15.4 Hz), 6.73 (1H,
dd, J = 9.0, 2.5 Hz), 7.13-7.19 (3H, m), 7.25-7.30 (1H,
m), 7.44-7.54 (3H, m), 7.71 (1H, d, J = 5.1 Hz), 7.75
(1H, d, J = 15.4 Hz), 8.02 (1H, d, J = 9.0 Hz), 8.30
(1H, d, J = 2.5 Hz), 11.50 (1H, s).
[0639]
2-(4-Morpholinobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 3.28 (4H, t, J = 4.9 Hz), 3.74 (4H,
t, J = 4.9 Hz), 6.72 (1H, dd, J = 8.8, 2.4 Hz), 7.07
(2H, d, J = 9.0 Hz), 7.14-7.20 (2H, m) , 7.24-7.32 (1H,

334
m) , 7.45-7.52 (2H, m), 7.79 (2H, d, J = 9.0 Hz), 8.05
(1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4 Hz), 12.28
(1H, s), 13.50-13.70 (1H, broad).
[0640]
2-(2-(4-Nitrophenyl)acetamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 5: 3.96 (2H, s) , 6.71 (1H, dd, J= 8.9,
2.5 Hz), 7.09-7.15 (2H, m), 7.24 (1H, t, J = 7.3 Hz),
7.42-7.49 (2H, m), 7.59-7.67 (2H, m), 7.97 (1H, d, J =
8.9 Hz), 8.17 (1H, d, J = 2.5 Hz), 8.18-8.24 (2H, m) ,
11.31 (1H, s), 13.40-13.55 (1H, broad).
[0641]
4-Phenoxy-2-((E)-4-phenyl-3-butenamido)benzoic acid
1H-NMR (DMSO-d6) 6: 3.35 (2H, dd, J = 7.3, 1.0 Hz), 6.41
(1H, dt, J = 15.9, 7.3 Hz), 6.64 (1H, d, J = 15.9 Hz),
6.71 (1H, dd, J = 8.9, 2.6 Hz), 7.11-7.17 (2H, m) ,
7.23-7.29 (2H, m), 7.31-7.37 (2H, m) , 7.43-7.50 (4H, m),
7.99 (1H, d, J = 8.9 Hz), 8.26 (1H, d, J = 2.6 Hz),
11.48 (1H, s), 13.40-13.60 (1H, broad).
[0642]
Example 388

0.059 mL of triethylamine and 65 mg of 5-(lH-
pyrrol-l-yl)pyridine-3-carbonyl chloride were added to
5.0 mL of methylene chloride solution containing 60 mg
of tert-butyl 2-amino-4-phenoxybenzoate at room

335
temperature sequentially and stirred at the same
temperature for 2 hours. 0.029 mL of triethylamine and
22 mg of 5-(lH-pyrrol-1-yl)pyridine-3-carbonyl chloride
were added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 1
hour. 0.58 g aminomethylated polystyrene was added to
the reaction mixture and stirred at room temperature
overnight. A saturated sodium hydrogen carbonate
aqueous solution was added to the reaction mixture, the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 4-phenoxy-2-(5-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenoxy-2-(5-(lH-pyrrol-1-
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure, ethyl acetate and water were
added and pH was adjusted to pH 7.0 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and the solvent was evaporated
under reduced pressure. Diisopropyl ether was added to
the obtained residue and a solid substance was
separated by filtration to obtain 7.0 mg of 4-phenoxy-
2-(5-(lH-pyrrol-1-yl)pyridine-3-carboxamido)benzoic
acid as white solid.

336
1H-NMR (DMSO-de) 8: 6.37 (2H, t, J = 2.2 Hz), 6.84 (1H,
dd, J = 8.9, 2.6 Hz), 7.17-7.22 (2H, m), 7.30 (1H, t, J
= 7.4 Hz), 7.47-7.54 (2H, m), 7.58 (2H, t, J = 2.2 Hz),
8.09 (1H, d, J = 8.9 Hz), 8.32 (1H, d, J = 2.6 Hz),
8.40 (1H, t, J = 2.2 Hz), 8.92 (1H, d, J = 2.2 Hz),
9.15 (1H, d, J = 2.2 Hz), 12.46 (1H, s).
[0643]
Example 389

0.25 mL of acetic acid and 4.3 ^L of 2,5-
dimethoxytetrahydrofuran were added sequentially to 10
mg of 2-(3-aminobenzamido)-4-phenylbenzoic acid at room
temperature and stirred at 90°C for 5 minutes. Ethyl
acetate and a saturated sodium hydrogen carbonate
aqueous solution were added to the reaction mixture.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure to obtain
8.3 mg of 4-phenyl-2-(3-(lH-pyrrol-1-
yl)benzamido)benzoic acid as brown solid.
1H-NMR (DMSO-de) 5: 6.34 (2H, t, J = 2.1 Hz), 7.45-7.51
(3H, m), 7.53-7.59 (3H, m), 7.69 (1H, t, J = 7.9 Hz),
1.13-1.IB (2H, m), 7.82-7.90 (2H, m) , 8.11-8.18 (2H, m) ,
9.08 (1H, d, J = 1.7 Hz), 12.37 (1H, s) .


0.062 mL of triethylamine and 69 mg of 5-(lH-
pyrrol-1-yl)pyridine-3-carbonyl chloride were added to
5.0 mL of methylene chloride solution containing 60 mg
of tert-butyl 2-amino-4-phenylbenzoate at room
temperature sequentially and stirred at the same
temperature for 2 hours. 0.031 mL of triethylamine and
23 mg of 5-(lH-pyrrol-1-yl)pyridine-3-carbonyl chloride
were added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 1
hour. 0.62 g of aminomethylated polystyrene was added
to the reaction mixture and stirred at room temperature
overnight. A saturated sodium hydrogen carbonate
aqueous solution was added to the reaction mixture, the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 4-phenyl-2-(5-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenyl-2-(5-(lH-pyrrol-1-

338
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure, ethyl acetate and water were
added and pH was adjusted to pH 7.0 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and the solvent was evaporated
under reduced pressure. Diisopropyl ether was added to
the obtained residue and a solid substance was
separated by filtration to obtain 23 mg of 4-phenyl-2-
(5-(lH-pyrrol-1-yl)pyridine-3-carboxamido)benzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 6.39 (2H, t, J = 2.2 Hz), 7.45-7.51
(1H, m) , 7.53-7.61 (5H, m), 7.73-7.77 (2H, m), 8.15 (1H,
d, J = 8.3 Hz), 8.47 (1H, t, J = 2.4 Hz), 8.97-9.02 (2H,
m), 9.17 (1H, d, J = 2.4 Hz), 12.26 (1H, s).
[0645]
Example 391

The following compound was obtained in the
same manner as in Example 390.
4-Phenyl-2-(2-(pyrrolidin-1-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-de) 8: 1.80-1.89 (4H, m) , 3.35-3.44 (4H, m) ,
6.74 (1H, dd, J = 7.4, 4.9 Hz), 7.44-7.58 (4H, m) ,

339
7.69-7.74 (2H, m), 7.83 (1H, dd, J = 7.4, 1.8 Hz), 8.10
(1H, d, J = 8.3 Hz), 8.24 (1H, dd, J = 4.9, 1.8 Hz),
9.02 (1H, s), 11.67 (1H, s).
[0646]
Example 392

0.056 rtiL of triethylamine and 45 mg of ((E)-2-
phenylvinyl)sulfonyl chloride were added to 3.0 mL of
methylene chloride solution containing 54 mg of tert-
butyl 2-amino-4-phenylbenzoate at room temperature
sequentially and stirred at the same temperature for 1
hour. 0.028 mL of triethylamine and 8.1 mg of ((E)-2-
phenylvinyl)sulfonyl chloride were added to the
reaction mixture at room temperature sequentially and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 4-phenyl-2-(((E)-2-
phenylvinyl) sulfonamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenyl-2-(((E)-2-phenylvinyl)

340
sulfonamido)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 26 mg of 4-phenyl-2-(((E)-2-
phenylvinyl) sulfonamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 8: 7.39-7.58 (8H, m) , 7.61-7.66 (2H, m) ,
7.73-7.81 (4H, m), 8.05 (1H, d, J = 8.3 Hz), 11.04 (1H,
s) .
[0647]
Examples 393, 394
The compounds shown in Table 37 were obtained
in the same manner as in Example 392.
[0648]
[Table 37]

[0649]
2-(Benzylsulfonamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 6: 4.78 (2H, s), 7.23-7.33 (5H, m),
7.41-7.49 (2H, m) , 7.50-7.56 (2H, m) , 7.60-7.65 (2H, m) ,
7.67 (1H, d, J = 1.7 Hz), 8.05 (1H, d, J = 8.3 Hz),
10.75-10.90 (1H, broad).
[0650]
2-(3-Bromobenzamido)-4-phenylbenzoic acid

341
1H-NMR (DMSO-d6) 8: 7.44-7.50 (1H, m) , 7.51-7.63 (4H, m) ,
7.70-7.77 (2H, m), 7.85-7.90 (1H, m), 7.95-8.00 (1H, m),
8.10-8.16 (2H, m), 8.99 (1H, d, J = 1.7 Hz), 12.26 (1H,
s), 13.75-14.00 (1H, broad).
[0651]
Example 395

0.056 mL of triethylamine and 61 mg of ((E)-2-
phenylvinyl) sulfonyl chloride were added to 5.0 mL of
methylene chloride solution containing 57 mg of tert-
butyl 2-amino-4-phenoxybenzoate at room temperature
sequentially and stirred at the same temperature for 1
hour. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 4-phenoxy-2-{((E)-2-phenylvinyl)
sulfonamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenoxy-2-(((E)-2-phenylvinyl)
sulfonamido)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced

342
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 17 mg of 4-phenoxy-2-(((E)-2-
phenylvinyl) sulfonamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 5: 6.68 (1H, dd, J = 8.8, 2.4 Hz), 6.99
(1H, d, J = 2.4 Hz), 7.04-7.09 (2H, m), 7.23-7.29 (1H,
m), 7.32-7.51 (7H, m), 7.64-7.70 (2H, m), 7.98 (1H, d,
J = 8.8 Hz), 11.16 (1H, s).
[0652]
Example 396

2.0 mL of methylene chloride, 3.9 \iL of N,N-
dimethylformamide and 0.094 mL of oxalyl chloride were
added to 206 mg of 4-acetoxycinnamic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 8 6 mg of tert-butyl 2-amino-4-
phenoxybenzoate, 3.0 mL of methylene chloride and 0.67
mL of triethylamine and stirred at room temperature for
1 hour. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,

343
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-
phenoxybenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-((E)-3-(4-
acetoxyphenyl)acrylamido)-4-phenoxybenzoate and stirred
at room temperature for 2 hours. The solvent was
evaporated under reduced pressure and the obtained
residue was purified with reversed-phase silica gel
column chromatography [eluent; 60-100% acetonitrile
/0.1% trifluoroacetic acid aqueous solution] to obtain
34 mg of 2-((E)-3-(4-acetoxyphenyl)acrylamido)-4-
phenoxybenzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 2.28 (3H, s) , 6.74 (1H, dd, J= 8.9,
2.5 Hz), 6.83 (1H, d, J = 15.6 Hz), 7.14-7.23 (4H, m) ,
7.25-7.31 (1H, m) , 7.45-7.52 (2H, m), 7.61 (1H, d, J =
15.6 Hz), 7.76-7.82 (2H, m), 8.03 (1H, d, J = 8.9 Hz),
8.35 (1H, d, J = 2.5 Hz), 11.58 (1H, s), 13.40-13.65
(1H, broad).
[0653]
Example 397

2.0 mL of methylene chloride, 3.9 jiL of N,N-
dimethylformamide and 0.094 mL of oxalyl chloride were
added to 180 mg of 2-acetoxybenzoic acid at room

344
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 81 mg of tert-butyl 2-amino-4-
phenylbenzoate, 3.0 mL of methylene chloride and 0.67
mL triethylamine, and stirred at room temperature for 1
hour. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(2-acetoxybenzamido)-4-phenylbenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-acetoxybenzamido)-4-
phenylbenzoate, and stirred at room temperature for 2
hours. The solvent was evaporated under reduced
pressure and 0.50 mL of methanol, 0.50 mL of
tetrahydrofuran and 6.1 mg of potassium carbonate were
added to the obtained residue sequentially and stirred
at room temperature for 2 hours. 10% citric acid
aqueous solution was added to the reaction mixture and
a solid substance was separated by filtration to obtain
8.2 mg of 2-(2-hydroxybenzamido)-4-phenylbenzoic acid
as white solid.
1H-NMR (DMSO-d6) 5: 6.96-7.05 (2H, m) , 7.42-7.49 (2H, m) ,
7.49-7.58 (3H, m) , 7.71-7.76 (2H, m) , 7.89-7.93 (1H, m),
8.10 (1H, d, J = 8.3 Hz), 9.02 (1H, d, J = 1.7 Hz),
11.46 (1H, s), 12.32 (1H, s) .


0.50 mL of methanol, 0.50 mL of
tetrahydrofuran and 8.3 mg of potassium carbonate were
added to 15 mg of 2-(3-acetoxybenzamido)-4-
phenylbenzoic acid at room temperature sequentially and
stirred at the same temperature for 2 hours. 10% citric
acid aqueous solution was added to the reaction mixture
and a solid substance was separated by filtration to
obtain 12 mg of 2-(3-hydroxybenzamido)-4-phenylbenzoic
acid as white solid.
1H-NMR (DMSO-d6) 5: 7.00-7.07 (1H, m) , 7.35-7.59 (7H, m) ,
7.73 (2H, d, J = 7.6 Hz), 8.14 (1H, d, J = 8.0 Hz),
9.08 (1H, d, J = 1.4 Hz), 9.92 (1H, s) , 12.22 (1H, s) .
[0655]
Examples 399, 400
The compounds shown in Table 38 were obtained
in the same manner as in Example 398.
[0656]
[Table 38]


[0657]
2-(4-Hydroxybenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 6: 6.94 (2H, d, J = 8.8 Hz), 7.43-7.51
(2H, m), 7.54 (2H, t, J = 7.6 Hz), 1.10-1.16 (2H, m),
7.85 (2H, d, J = 8.8 Hz), 8.13 (1H, d, J = 8.3 Hz),
9.09 (1H, d, J = 1.7 Hz), 10.29 (1H, s), 12.16 (1H, s).
[0658]
2-((E)-3-(4-Hydroxyphenyl)acrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-d6) 8: 6.67 (1H, d, J = 15.6 Hz), 6.82 (2H,
d, J = 8.5 Hz), 7.43-7.50 (2H, m), 7.50-7.62 (5H, m) ,
7.68-7.74 (2H, m), 8.09 (1H, d, J = 8.3 Hz), 9.00 (1H,
d, J = 2.0 Hz), 9.98 (1H, s), 11.37 (1H, s), 13.50-
13.80 (1H, broad).
[0659]
Example 401


347
0.50 mL of methanol, 0.50 mL of
tetrahydrofuran and 4.2 mg of potassium carbonate were
added sequentially to 8.0 mg of 2-(3-acetoxybenzamido)-
4-phenoxybenzoic acid at room temperature and stirred
at the same temperature for 2 hours. 10% citric acid
aqueous solution was added to the reaction mixture and
a solid substance was separated by filtration to obtain
4.4 mg of 2-(3-hydroxybenzamido)-4-phenoxybenzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 6.76 (1H, dd, J = 8.8, 2.7 Hz), 7.02
(1H, ddd, J = 7.6, 2.3, 1.5 Hz), 7.15-7.21 (2H, m),
7.25-7.40 (4H, m), 7.46-7.52 (2H, m), 8.07 (1H, d, J =
8.8 Hz), 8.41 (1H, d, J = 2.7 Hz), 9.90 (1H, s), 12.34
(1H, s), 13.55-13.75 (1H, broad).
[0660]
Examples 402, 403
[0662]
2-(4-Hydroxybenzamido)-4-phenoxybenzoic acid
The compounds shown in Table 39 were obtained
in the same manner as in Example 401.
[0661]
[Table 39]


348
1H-NMR (DMSO-dg) 8: 6.73 (1H, dd, J = 8.8, 2.4 Hz) , 6.91
(2H, d, J = 8.8 Hz), 7.15-7.19 (2H, m), 7.27 (1H, t, J
= 7.4 Hz), 7.45-7.52 (2H, m), 7.78 (2H, d, J = 8.8 Hz),
8.05 (1H, d, J = 8.8 Hz), 8.41 (1H, d, J = 2.4 Hz),
10.28 (1H, s), 12.27 (1H, s) .
[0663]
2-((E)-3-(4-Hydroxyphenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 6.58 (1H, d, J = 15.6 Hz), 6.71 (1H,
dd, J = 8.8, 2.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 7.13-
7.19 (2H, m), 7.24-7.30 (1H, m) , 7.44-7.53 (3H, m) ,
7.56 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 8.8 Hz),
8.35 (1H, d, J = 2.6 Hz), 9.97 (1H, s), 11.60 (1H, s).
[0664]
Example 404

3.0 mL of methanol, 2.0 mL of ethyl acetate
and 4.0 mg of 5% palladium-carbon were added to 20 mg
of 2-(4-nitrobenzamido)-4-phenoxybenzoic acid at room
temperature and stirred under hydrogen atmosphere at
40°C for 8 hours. Insoluble were removed by filtration,
and the solvent was evaporated under reduced pressure
to obtain 20 mg of 2-(4-aminobenzamido)-4-
phenoxybenzoic acid as white solid.

349
1H-NMR (DMSO-d6) 8: 6.57-6.65 (3H, m) , 7.07-7.13 (2H, m) ,
7.20 (1H, t, J = 7.4 Hz), 7.41-7.46 (2H, m), 7.67 (2H,
d, J = 8.8 Hz), 8.02 (1H, d, J = 8.6 Hz), 8.39 (1H, d,
J = 2.4 Hz).
[0665]
Example 405

2.0 mL of methanol, 2.0 mL of ethyl acetate
and 3.0 mg of 5% palladium-carbon were added to 15 mg
of 2-(3-nitrobenzamido)-4-phenylbenzoic acid at room
temperature and stirred under hydrogen atmosphere at
40°C for 2 hours. Insoluble were removed by filtration,
and the solvent was evaporated under reduced pressure
to obtain 5.1 mg of 2-(3-aminobenzamido)-4-
phenylbenzoic acid as white solid.
1H-NMR (DMSO-de) 8: 6.74-6.81 (1H, m) , 7.13-7.22 (3H, m) ,
7.36 (1H, dd, J = 8.1, 1.7 Hz), 7.42 (1H, t, J = 7.3
Hz), 7.49-7.54 (2H, m), 7.66-7.72 (2H, m), 8.10 (1H, d,
J = 8.1 Hz), 9.05 (1H, d, J = 1.7 Hz).
[0666]
Example 406


350
0.019 mL of lH-pyrrole, 0.12 g of cesium
carbonate, 5.1 mg of
tris(dibenzylideneacetone)dipalladium(O), 1.6 mg of
tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added to 1.4 mL of toluene solution containing 70
mg of tert-butyl 2-(benzamido)-4-bromobenzoate at room
temperature, and the resulting mixture was heated to
reflux under nitrogen atmosphere for 3 hours. After the
reaction mixture was cooled to room temperature, 5.1 mg
of tris(dibenzylideneacetone)dipalladium(O), 1.6 mg of
tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added and the resulting mixture was heated to
reflux under nitrogen atmosphere for 3 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 10% citric acid aqueous solution were added
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =10:1] to obtain 60 mg
of tert-butyl 2-(benzamido)-4-(lH-pyrrol-l-yl)benzoate
as white solid.
1H-NMR (CDC13) 5: 1.65 (9H, s) , 6.38 (2H, t, J = 2.2 Hz),
7.12 (1H, dd, J = 8.6, 2.3 Hz), 7.25-7.28 (2H, m) ,

351
7.51-7.61 (3H, m) , 8.05-8.10 (3H, m), 9.16 (1H, d, J =
2.3 Hz), 12.36 (1H, s).
[0667]
Example 407

33 mg of lH-indole, 0.12 g of cesium carbonate,
5.1 mg of tris(dibenzylideneacetone)dipalladium(O), 1.6
mg of tri-tert-butylphosphine tetrafluoroborate and 4.4
mg of 2-dicyclohexylphosphino-2',4',6'-
triisopropylbiphenyl were added to 1.4 mL of toluene
solution containing 70 mg of tert-butyl 2-(benzamido)-
4-bromobenzoate at room temperature, and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 4 hours. After the reaction mixture was cooled to
room temperature, 33 mg of lH-indole, 79 mg of
tripotassium phosphate, 5.1 mg of
tris(dibenzylideneacetone)dipalladium(O), 1.6 mg of
tri-tert-butylphosphine tetrafluoroborate and 4.4 mg of
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added and the resulting mixture was heated to
reflux under nitrogen atmosphere for 4 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 10% citric acid aqueous solution were added
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium

352
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =20:1] to obtain 45 mg
of tert-butyl 2-(benzamido)-4-(lH-indol-l-yl)benzoate
as colorless oil.
1H-NMR (CDC13) 5: 1.67 (9H, s) , 6.73 (1H, d, J = 3.4 Hz),
7.18-7.22 (1H, m) , 7.25-7.33 (2H, m), 7.48 (1H, d, J =
3.4 Hz), 7.51-7.62 (3H, m) , 7.66-7.70 (1H, m) , 7.83 (1H,
d, J = 8.3 Hz), 8.06-8.10 (2H, m), 8.17 (1H, d, J = 8.8
Hz), 9.22 (1H, d, J = 2.2 Hz), 12.35 (1H, s).
[0668]
Example 408

The following compound was obtained in the
same manner as in Example 200.
tert-Butyl 2-(benzamido)-4-(3, 4-
dimethoxyphenyl)benzoate
1H-NMR (CDCI3) 5: 1.65 (9H, s) , 3.94 (3H, s) , 3.99 (3H,
s), 6.96 (1H, d, J = 8.3 Hz), 7.23 (1H, d, J = 2.2 Hz),
7.28-7.34 (2H, m) , 7.51-7.61 (3H, m) , 8.04-8.11 (3H, m) ,
9.22 (1H, d, J = 2.0 Hz), 12.27 (1H, s).


0.24 mL of 2.0 mol/L aqueous sodium hydroxide
was added to a mixed solution of 1.0 mL of dioxane and
1.0 mL of methanol containing 58 mg of tert-butyl 2-
(benzamido)-4-(lH-pyrrol-l-yl)benzoate and stirred at
50°C for 1 hour and 30 minutes. After the reaction
mixture was cooled to room temperature, water was added
and after pH was adjusted to pH 3.0 with 1.0 mol/L
hydrochloric acid, ethyl acetate was added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with water and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Diisopropyl
ether were added to the obtained residue and a solid
substance was separated by filtration to obtain 41 mg
of 2-(benzamido)-4-(lH-pyrrol-1-yl)benzoic acid as
white solid.
1H-NMR (DMSO-de) 5: 6.37 (2H, t, J = 2.2 Hz), 7.41-7.47
(3H, m), 7.59-7.71 (3H, m), 7.96-8.02 (2H, m), 8.12 (1H,
d, J = 8.5 Hz), 8.96 (1H, d, J = 2.2 Hz), 12.40 (1H, s).
[0670]
Example 410


The following compound was obtained in the
same manner as in Example 409.
2-(Benzamido)-4-(lH-indol-1-yl)benzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 3.4, 0.5 Hz),
7.18-7.24 (1H, m) , 7.28-7.33 (1H, m), 7.47 (1H, dd, J =
8.6, 2.4 Hz), 7.59-7.73 (4H, m), 7.79 (1H, d, J = 3.4
Hz), 7.85 (1H, dd, J = 8.4, 0.6 Hz), 7.98-8.03 (2H, m) ,
8.24 (1H, d, J = 8.6 Hz), 9.09 (1H, d, J = 2.4 Hz),
12.46 (1H, s).
[0671]
Example 411

The following compound was obtained in the
same manner as in Example 211.
2-(Benzamido)-4-(3,4-dimethoxyphenyl)benzoic acid
1H-NMR (DMSO-de) 6: 3.83 (3H, s) , 3.87 (3H, s) , 7.12 (1H,
d, J - 9.0 Hz), 7.27-7.32 (2H, m), 7.52 (1H, dd, J =
8.3, 1.8 Hz), 7.58-7.70 (3H, m) , 7.97-8.02 (2H, m) ,
8.10 (1H, d, J = 8.3 Hz), 9.04 (1H, d, J = 1.8 Hz),
12.26 (1H, s).


55 mg of 2-nitroaniline, 0.17 g of cesium
carbonate, 2.4 mg of
tris(dibenzylideneacetone)dipalladium(O), 1.2 mg of
palladium acetate and 6.3 mg of 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added to 2.0 mL of toluene solution containing
0.10 g of tert-butyl 2-(benzamido)-4-bromobenzoate at
room temperature, and the resulting mixture was heated
to reflux under nitrogen atmosphere for 4 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added and insoluble were removed by filtration. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate =1:1] to
obtain 94 mg of tert-butyl 2-(benzamido)-4-(2-
nitroanilino)benzoate as yellow solid.

356
1H-NMR (CDCI3) 6: 1.64 (9H, s), 6.90-6.96 (2H, m), 7.50-
7.60 (4H, m), 7.66 (1H, dd, J = 8.5, 1.2 Hz), 8.02 (1H,
d, J = 8.5 Hz), 8.02-8.08 (2H, m), 8.22 (1H, dd, J =
8.7, 1.6 Hz), 8.94 (1H, d, J = 2.2 Hz), 9.53 (1H, s),
12.33 (1H, s).
[0673]
Example 413

10 mg of 5% palladium-carbon was added to a
mixed solution of 4.0 mL of methanol and 8.0 mL of
ethyl acetate containing 50 mg of tert-butyl 2-
(benzamido)-4-(2-nitroanilino)benzoate and stirred
under hydrogen atmosphere at room temperature for 1
hour and 30 minutes. After insoluble were removed by
filtration, the solvent was evaporated under reduced
pressure to obtain 46 mg of tert-butyl 4-(2-
aminoanilino)-2-(benzamido)benzoate as pale yellow
solid.
1H-NMR (CDCI3) 5: 1.59 (9H, s), 3.79 (2H, s), 5.67 (1H,
s), 6.30 (1H, dd, J = 8.8, 2.3 Hz), 6.76-6.85 (2H, m) ,
7.06-7.12 (1H, m) , 7.15-7.18 (1H, m) , 7.49-7.58 (3H, m) ,
7.85 (1H, d, J = 8.8 Hz), 8.03-8.08 (2H, m), 8.41 (1H,
d, J = 2.3 Hz), 12.41 (1H, s).
[0674]
Example 414


28 mg of formamidine acetate was added to 1.0
mL of ethylene glycol monomethyl ether solution
containing 44 mg of tert-butyl 4-(2-aminoanilino)-2-
(benzamido)benzoate at room temperature and stirred at
80°C for 3 hours. After the reaction mixture was cooled
to room temperature, ethyl acetate and water were added.
The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium hydrogen carbonate aqueous solution
and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =1:1] to obtain 36 mg of
tert-butyl 2-(benzamido)-4-(lH-benzimidazol-1-
yl)benzoate as pale yellow oil.
1H-NMR (CDC13) 6: 1.68 (9H, s) , 7.24-7.30 (1H, m) , 7.34-
7.44 (2H, m), 7.53-7.63 (3H, m) , 7.78-7.82 (1H, m) ,
7.87-7.92 (1H, m) , 8.06-8.10 (2H, m), 8.23 (1H, d, J =
8.6 Hz), 8.26 (1H, s), 9.30 (1H, d, J = 2.2 Hz), 12.38
(1H, s).
[0675]
Example 415


5.0 mL trifluoroacetic acid solution
containing 34 mg of tert-butyl 2-(benzamido)-4-(1H-
benzimidazol-l-yl)benzoate was stirred at room
temperature for 1 hour and 30 minutes. The solvent was
evaporated under reduced pressure and methanol was
added to the obtained residue and a solid substance was
separated by filtration to obtain 24 mg of 2-
(benzamido)-4-(lH-benzimidazol-1-yl)benzoic acid as
white solid.
0.5 mL of trifluoroacetic acid and 0.01 mL of
4.0 mol/L hydrogen chloride/dioxane were added to 1.0
mL suspension containing 15 mg of 2-(benzamido)-4-(1H-
benzimidazol-1-yl)benzoic acid in ethyl acetate
sequentially while ice-cooled and stirred at the same
temperature for 10 minutes. A solid substance was
separated by filtration to obtain 12 mg of 2-
(benzamido)-4-(lH-benzimidazol-1-yl)benzoic acid
hydrochloride as white solid.
1H-NMR (DMSO-d6) 8: 7.46-7.56 (2H, m) , 7.59-7.72 (4H, m) ,
7.87-7.92 (2H, m) , 7.98-8.03 (2H, m), 8.32 (1H, d, J =
8.6 Hz), 9.15 (1H, d, J = 2.2 Hz), 9.16 (1H, s), 12.38
(1H, s).
[0676]
Examples 416 to 425

359
The compounds shown in Table 40 were obtained
in the same manner as in Example 251.
[0677]
[Table 401

[0678]
2-(Benzamido)-4-(3-chloro-4-fluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.52-7.70 (5H, m) , 1.12-1 .IS (1H, m) ,
7.93 (1H, dd, J = 7.1, 2.4 Hz), 7.96-8.02 (2H, m), 8.13
(1H, d, J = 8.3), 9.03 (1H, s), 12.23 (1H, s).
[0679]
2-(Benzamido)-4-(3,4-difluorophenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 7.54 (1H, dd, J= 8.3, 1.7 Hz),
7.56-7.70 (5H, m) , 7.78-7.86 (1H, m) , 7.96-8.05 (2H, m) ,
8.13 (1H, d, J = 8.3 Hz), 9.04 (1H, d, J = 1.7 Hz),
12.22 (1H, s).

360
[0680]
2-(Benzamido)-4-(2,5-difluorophenyl)benzoic acid
1H-NMR (DMSO-de) 5: 7.33-7.52 (4H, m) , 7.58-7.70 (3H, m) ,
7.95-8.00 (2H, m), 8.16 (1H, d, J = 8.3 Hz), 8.96-8.99
(1H, m), 12.25 (1H, s).
[0681]
2-(Benzamido)-4-(2,4-dichlorophenyl)benzoic acid
1H-NMR (DMSO-de) 5: 7.28 (1H, dd, J = 8.3, 1.7 Hz), 7.52
(1H, d, J = 8.3 Hz), 7.56-7.70 (4H, m), 7.80 (1H, d, J
= 2.2 Hz), 7.94-8.00 (2H, m), 8.15 (1H, d, J = 8.3 Hz),
8.82 (1H, d, J = 1.7 Hz), 12.27 (1H, s) .
[0682]
2-(Benzamido)-4-(4-fluoro-2-methylphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.30 (3H, s) , 7.11-7.25 (3H, m) ,
7.32 (1H, dd, J = 8.5, 6.1 Hz), 7.57-7.69 (3H, m) ,
7.94-7.99 (2H, m), 8.12 (1H, d, J = 8.1 Hz), 8.72 (1H,
d, J = 1.7 Hz).12.26 (1H, s).
[0683]
2-(Benzamido)-4-(2-trifluoromethoxyphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 7.32 (1H, dd, J = 8.1, 1.6 Hz),
7.52-7.69 (7H, m), 7.95-8.00 (2H, m), 8.16 (1H, d, J =
8.1 Hz), 8.91 (1H, d, J = 1.6 Hz), 12.27 (1H, s) .
[0684]
2-(Benzamido)-4-(3,4-dimethylphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 2.29 (3H, s) , 2.33 (3H, s) , 7.29 (1H,
d, J = 7.8 Hz), 7.43-7.53 (3H, m), 7.58-7.70 (3H, m),
7.96-8.02 (2H, m), 8.11 (1H, d, J = 8.3 Hz), 9.06 (1H,
d, J = 1.7 Hz), 12.27 (1H, s).

361
[0685]
2-(Benzamido)-4-(3-chloro-4-methoxyphenyl)benzoic acid
1H-NMR (DMSO-de) 8: 3.94 (3H, s) , 7.32 (1H, d, J = 8.7
Hz), 7.52 (1H, dd, J = 8.3, 1.8 Hz), 7.58-7.74 (4H, m),
7.79 (1H, d, J = 2.2 Hz), 7.96-8.02 (2H, m), 8.11 (1H,
d, J = 8.3 Hz), 9.04 (1H, d, J = 1.8 Hz), 12.26 (1H, s),
13.70-13.95 (1H, broad).
[0686]
2-(Benzamido)-4-(2,3-dichlorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.29 (1H, dd, J = 8.1, 1.7 Hz), 7.45
(1H, dd, J = 7.8, 1.7 Hz), 7.51 (1H, t, J = 7.8 Hz),
7.58-7.69 (3H, m), 7.75 (1H, dd, J = 7.8, 1.7 Hz),
7.94-7.99 (2H, m), 8.15 (1H, d, J = 8.1 Hz), 8.80-8.83
(1H, m) , 12.27 (1H, s) .
[0687]
2-(Benzamido)-4-(2,5-dichlorophenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 7.30 (1H, dd, J = 8.2, 1.6 Hz),
7.54-7.70 (6H, m), 7.94-8.00 (2H, m) , 8.15 (1H, d, J =
8.2 Hz), 8.83 (1H, d, J = 1.6 Hz), 12.25 (1H, s).
[0688]
Example 42 6

0.031 mL of 2-chloro-4-iodotoluene, 39 mg of
sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of
water and 11 mg of

362
tetrakis(triphenylphosphine)palladium(0) were added to
1.6 mL of toluene solution containing 79 mg of tert-
butyl 2-(benzamido)-4-(4,4,5,5-tetramethyl-l,3,2-
dioxaborolan-2-yl)benzoate at room temperature, and the
resulting mixture was heated to reflux for 8 hours.
After the reaction mixture was cooled to room
temperature, 11 mg of
tetrakis(triphenylphosphine)palladium(0) was added and
the resulting mixture was heated to reflux for 7 hours.
After the reaction mixture was cooled to room
temperature, ethyl acetate and water were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate =10:1] to
obtain tert-butyl 2-(benzamido)-4-(3-chloro-4-
methylphenyl)benzoate as white solid.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(3-chloro-4-
methylphenyl)benzoate and stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure and methanol was added to the obtained residue
and a solid substance was separated by filtration to
obtain 14 mg of 2-(benzamido)-4-(3-chloro-4-
methylphenyl)benzoic acid as white solid.

363
1H-NMR (DMSO-d6) 8: 2.40 (3H, s) , 7.50-7.70 (6H, m) ,
7.76 (1H, d, J = 1.7 Hz), 7.97-8.02 (2H, m), 8.13 (1H,
d, J = 8.3 Hz), 9.06 (1H, d, J = 1.7 Hz), 12.26 (1H, s).
[0689]
Examples 427 to 429
The compounds shown in Table 41 were obtained
in the same manner as in Example 252.
[0690]
[Table 41]

[0691]
2-(Benzamido)-4-(3-chloro-2-methylphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 2.29 (3H, s) , 7.20 (1H, dd, J = 8.3,
1.8 Hz), 7.26 (1H, dd, J = 7.7, 1.2 Hz), 7.35 (1H, dd,
J = 7.9, 7.7 Hz), 7.53 (1H, dd, J = 7.9, 1.2 Hz), 7.58-
7.69 (3H, m), 7.94-7.99 (2H, m), 8.13 (1H, d, J = 8.3
Hz), 8.70-8.72 (1H, m) , 12.29 (1H, s).
[0692]
2-(Benzamido)-4-(5-chloro-2-methylphenyl)benzoic acid
1H-NMR (DMSO-d6) 8: 2.26 (3H, s), 7.23 (1H, dd, J = 8.2,
1.7 Hz), 7.32 (1H, d, J = 1.7 Hz), 7.37-7.44 (2H, m) ,

364
7.58-7.70 (3H, m) , 7.94-8.00 (2H, m), 8.13 (1H, d, J =
8.2 Hz), 8.73 (1H, d, J = 1.7 Hz), 12.25 (1H, s).
[0693]
2-(Benzamido)-4-(5-chloro-2-methoxyphenyl)benzoic acid
1H-NMR (DMSO-d6) 5: 3.81 (3H, s), 7.21 (1H, d, J = 8.8
Hz), 7.34 (1H, dd, J = 8.2, 1.7 Hz), 7.38 (1H, d, J =
2.7 Hz), 7.48 (1H, dd, J = 8.8, 2.7 Hz), 7.58-7.69 (3H,
m), 7.95-8.00 (2H, m), 8.09 (1H, d, J = 8.2 Hz), 8.86
(1H, d, J = 1.7 Hz), 12.21 (1H, s).
[0694]
Example 430

2.0 mL of methylene chloride, 2.7 ^L of N,N-
dimethylformamide and 0.061 mL of oxalyl chloride were
sequentially added to 0.13 g of 3,5-dichlorobenzoic
acid at room temperature and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 3.0 mL of methylene chloride and
0.45 mL of triethylamine containing 60 mg of tert-butyl
2-amino-4-phenethylbenzoate at room temperature and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica

365
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 2-(3,5-dichlorobenzamido)-4-
phenethylbenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(3,5-dichlorobenzamido)-4-
phenethylbenzoate and stirred at room temperature for 2
hours. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 62 mg of 2-(3,5-
dichlorobenzamido)-4-phenethylbenzoic acid as white
solid.
1H-NMR (DMSO-d6) 8: 2.89-3.02 (4H, m) , 7.12 (1H, dd, J =
8.0, 1.7 Hz), 7.16-7.21 (1H, m) , 7.24-7.31 (4H, m) ,
7.91-7.97 (4H, m) , 8.48-8.52 (1H, m) , 12.14 (1H, s),
13.65-13.85 (1H, broad).
[0695]
Examples 431 to 439
The compounds shown in Table 42 were obtained
in the same manner as in Example 430.
[0696]
[Table 42]


[0697]
2-(3,4-Dichlorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.89-3.02 (4H, m) , 7.11 (1H, dd, J =
8.1, 1.5 Hz), 7.16-7.21 (1H, m), 7.24-7.31 (4H, m) ,
7.88-7.91 (2H, m), 7.95 (1H, d, J = 8.1 Hz), 8.13 (1H,
s), 8.54 (1H, d, J = 1.5 Hz), 12.17 (1H, s), 13.60-
13.85 (1H, broad).
[0698]
2-(3,5-Difluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 5: 2.88-3.02 (4H, m) , 7.12 (1H, dd, J =
8.1, 1.6 Hz), 7.15-7.21 (1H, m), 7.23-7.32 (4H, m) ,
7.56-7.66 (3H, m), 7.96 (1H, d, J = 8.1 Hz), 8.52 (1H,
d, J = 1.6 Hz), 12.12 (1H, s), 13.60-13.80 (1H, broad).
[0699]
2-(3,4-Difluorobenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.88-3.02 (4H, m) , 7.10 (1H, dd, J =
8.1, 1.7 Hz), 7.16-7.21 (1H, m), 7.24-7.31 (4H, m) ,
7.66-7.74 (1H, m), 7.79-7.85 (1H, m), 7.91-7.99 (2H, m),

367
8.55 (1H, d, J = 1.7 Hz), 12.12 (1H, s), 13.60-13.80
(1H, broad).
[0700]
2-(3,5-Dimethylbenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.37 (6H, s) , 2.88-3.02 (4H, m) ,
7.07 (1H, dd, J = 8.1, 1.5 Hz), 7.16-7.21 (1H, m),
7.24-7.31 (5H, m), 7.57 (2H, s), 7.95 (1H, d, J = 8.1
Hz), 8.66-8.68 (1H, m), 12.19 (1H, s), 13.65-13.80 (1H,
broad).
[0701]
2-(4-Acetoxybenzamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 5: 2.32 (3H, s) , 2.89-3.02 (4H, m) ,
7.09 (1H, dd, J = 8.3, 1.6 Hz), 7.16-7.21 (1H, m) ,
7.25-7.32 (4H, m), 7.35-7.40 (2H, m), 7.96 (1H, d, J =
8.3 Hz), 7.96-8.03 (2H, m) , 8.63-8.65 (1H, m), 12.17
(1H, s), 13.60-13.75 (1H, broad).
[0702]
4-Phenethyl-2-(6-phenylpyrimidine-4-carboxamido)benzoic
acid
1H-NMR (DMSO-de) 8: 2.92-3.05 (4H, m) , 7.12-7.22 (2H, m) ,
7.25-7.32 (4H, m), 7.58-7.67 (3H, m), 7.99 (1H, d, J =
8.3 Hz), 8.30-8.37 (2H, m), 8.64 (1H, d, J = 1.2 Hz),
8.82 (1H, d, J = 1.5 Hz), 9.47 (1H, d, J = 1.2 Hz),
13.16 (1H, s).
[0703]
4-Phenethyl-2-(3-phenylisoxazole-5-carboxamido)benzoic
acid

368
1H-NMR (DMSO-de) 8: 2.90-3.04 (4H, m) , 7.12-7.21 (2H, m) ,
7.25-7.32 (4H, m) , 7.52-7.63 (4H, m) , 7.96-8.02 (3H, m),
8.63 (1H, d, J = 1.4 Hz), 12.49 (1H, s) .
[0704]
4-Phenethyl-2-( (E)-4-phenyl-3-butenaxnido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.84-2.97 (4H, m) , 3.35-3.38 (2H, m) ,
6.40-6.50 (1H, m), 6.66 (1H, d, J = 15.8 Hz), 7.01 (1H,
dd, J = 8.0, 1.6 Hz), 7.14-7.20 (1H, m) , 7.21-7.30 (5H,
m), 7.31-7.38 (2H, m), 7.44-7.50 (2H, m), 7.87 (1H, d,
J = 8.0 Hz), 8.49 (1H, d, J = 1.6 Hz), 11.29 (1H, s).
[0705]
2-((E)-2-Methyl-3-phenylacrylamido)-4-phenethylbenzoic
acid
1H-NMR (DMSO-d6) 8: 2.19 (3H, d, J = 1.2 Hz), 2.88-3.01
(4H, m), 7.05 (1H, dd, J= 8.1, 1.5 Hz), 7.16-7.21 (1H,
m) , 7.24-7.32 (4H, m) , 7.35-7.41 (1H, m) , 7.43-7.53 (5H,
m), 7.94 (1H, d, J = 8.1 Hz), 8.65 (1H, s), 11.86 (1H,
s).
[0706]
Examples 440 to 446
The compounds shown in Table 43 were obtained
in the same manner as in Example 369.
[0707]
[Table 43]


[0708]
2-((E)-3-(4-Nitrophenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 6.77 (1H, ddf J = 8.8, 2.5 Hz), 7.12
(1H, d, J = 15.6 Hz), 7.14-7.21 (2H, m), 7.28 (1H, t, J
= 7.5 Hz), 7.45-7.53 (2H, m) , 7.71 (1H, d, J = 15.6 Hz),
8.00-8.08 (3H, m), 8.26 (2H, d, J = 9.0 Hz), 8.35 (1H,
d, J = 2.6 Hz), 11.66 (1H, s), 13.40-13.65 (1H, broad).
[0709]
2-(3,5-Dichlorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 6: 6.81 (1H, dd, J = 8.8, 2.7 Hz),
7.16-7.22 (2H, m), 7.29 (1H, t, J = 7.4 Hz), 7.46-7.53
(2H, m), 7.88 (2H, d, J = 1.8 Hz), 7.94 (1H, t, J = 1.8
Hz), 8.07 (1H, d, J = 8.8 Hz), 8.26 (1H, d, J = 2.7 Hz),
12.43 (1H, s).
[0710]
2-(3,4-Dichlorobenzamido)-4-phenoxybenzoic acid

370
1H-NMR (DMSO-d6) S: 6.80 (1H, dd, J = 8.9, 2.5 Hz),
7.15-7.21 (2H, m), 7.26-7.32 (1H, m) , 7.46-7.53 (2H, m) ,
7.84-7.92 (2H, m), 8.07 (1H, d, J = 8.9 Hz), 8.09 (1H,
d, J = 1.7 Hz), 8.30 (1H, d, J = 2.5 Hz), 12.43 (1H, s) .
[0711]
2-(3,5-Difluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.8, 2.7 Hz),
7.15-7.22 (2H, m), 7.26-7.32 (1H, m), 7.46-7.64 (5H, m) ,
8.07 (1H, d, J = 8.8 Hz), 8.28 (1H, d, J = 2.7 Hz),
12.39 (1H, s).
[0712]
2-(3, 4-Difluorobenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.80 (1H, dd, J = 8.9, 2.5 Hz),
7.15-7.22 (2H, m) , 7.25-7.32 (1H, m), 7.45-7.53 (2H, m),
7.65-7.73 (1H, m) , 7.75-7.82 (1H, m) , 7.88-7.94 (1H, m) ,
8.07 (1H, d, J = 8.9 Hz), 8.30 (1H, d, J = 2.5 Hz),
12.37 (1H, s).
[0713]
2-(3,5-Dimethylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.35 (6H, s) , 6.76 (1H, dd, J = 8.9,
2.4 Hz), 7.16-7.22 (2H, m), 7.26-7.32 (2H, m), 7.45-
7.57 (4H, m), 8.06 (1H, d, J = 8.9 Hz), 8.41 (1H, d, J
= 2.4 Hz), 12.40 (1H, s).
[0714]
2-((E)-2-Methyl-3-phenylacrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 2.16 (3H, d, J = 1.5 Hz), 6.75 (1H,
dd, J = 8.8, 2.6 Hz), 7.15-7.19 (2H, m), 7.25-7.31 (1H,

371
m), 7.34-7.41 (1H, m) , 7.42-7.52 (7H, m), 8.05 (1H, d,
J = 8.8 Hz), 8.38 (1H, d, J = 2.6 Hz), 12.06 (1H, s).
[0715]
Examples 447 to 452
The compounds shown in Table 44 were obtained
in the same manner as in Example 345.
[0716]
[Table 44]

[0717]
2-(3,5-Dichlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.47 (1H, tt, J = 7.3, 1.6 Hz),
7.51-7.59 (3H, m), 7.70-7.75 (2H, m), 7.94 (3H, s) ,
8.12 (1H, d, J = 8.3 Hz), 8.90 (1H, d, J = 1.7 Hz),
12.21 (1H, s).
[0718]
2-(3,4-Dichlorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.44-7.50 (1H, m) , 7.52-7.59 (3H, m) ,
7.70-7.76 (2H, m), 7.89-7.96 (2H, m), 8.13 (1H, d, J =

372
8.3 Hz), 8.15-8.19 (1H, m), 8.95 (1H, d, J = 1.7 Hz),
12.23 (1H, s).
[0719]
2-(3,5-Difluorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 5: 7.47 (1H, tt, J = 7.2, 1.5 Hz),
7.52-7.67 (6H, m), 7.70-7.77 (2H, m), 8.13 (1H, d, J =
8.3 Hz), 8.93 (1H, d, J = 1.7 Hz), 12.18 (1H, s) .
[0720]
2-(3,4-Difluorobenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 7.44-7.50 (1H, m) , 7.52-7.58 (3H, m) ,
7.67-7.77 (3H, m) , 7.82-7.88 (1H, m) , 7.94-8.02 (1H, m) ,
8.13 (1H, d, J = 8.3 Hz), 8.96 (1H, d, J = 1.7 Hz),
12.19 (1H, s).
[0721]
2-(3, 5-Dimethylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 5: 2.38 (6H, s) , 7.30 (1H, s) , 7.44-
7.58 (4H, m), 7.60 (2H, s), 7.70-7.76 (2H, m), 8.13 (1H,
d, J = 8.3 Hz), 9.08 (1H, d, J = 1.7 Hz), 12.26 (1H, s).
[0722]
2-((E) -2-Methyl-3-phenylacrylamido)-4-phenylbenzoic
acid
1H-NMR (DMSO-de) 5: 2.22 (3H, d, J = 1.2 Hz), 7.36-7.41
(1H, m) , 7.44-7.58 (9H, m) , 7.70-7.74 (2H, m) , 8.12 (1H,
d, J = 8.3 Hz), 9.08 (1H, d, J = 1.7 Hz), 11.93 (1H, s).
[0723]
Example 453


1.0 mL of methylene chloride, 2.7 jaL of N,N-
dimethylformamide and 0.061 mL of oxalyl chloride were
added to 0.11 g of 2-methoxybenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 4.0 mL of methylene chloride and
0.45 mL triethylamine containing 57 mg of tert-butyl 2-
amino-4-phenoxybenzoate and stirred at room temperature
for 1 hour. A saturated sodium hydrogen carbonate
aqueous solution was added to the reaction mixture, and
the organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 2-(2-methoxybenzamido)-4-phenoxybenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-methoxybenzamido)-4-
phenoxybenzoate and stirred at room temperature for 3
minutes. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 52 mg of 2-(2-methoxybenzamido)-4-
phenoxybenzoic acid as white solid.

374
1H-NMR (DMSO-d6) 8: 3.99 (3H, s) , 6.74 (1H, dd, J = 8.9,
2.6 Hz), 7.06-7.12 (1H, m), 7.14-7.20 (2H, m), 7.21-
7.29 (2H, m), 7.44-7.52 (2H, m) , 7.55-7.60 (1H, m) ,
7.91 (1H, dd, J = 7.8, 1.7 Hz), 8.04 (1H, d, J = 8.9
Hz), 8.55 (1H, d, J = 2.6 Hz), 12.40 (1H, s), 13.41 (1H,
s).
[0724]
Example 454

The following compound was obtained in the
same manner as in Example 453.
2-(3-Methoxybenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 5: 3.84 (3H, s), 6.78 (1H, dd, J= 8.8,
2.4 Hz), 7.16-7.24 (3H, m), 7.29 (1H, t, J = 7.3 Hz),
7.43-7.55 (5H, m), 8.07 (1H, d, J = 8.8 Hz), 8.40 (1H,
d, J = 2.4 Hz), 12.40 (1H, s), 13.65-13.85 (1H, broad).
[0725]
Example 455


375
5.0 mL of methylene chloride, 0.056 mL of
triethylamine and 51 mg of 4-methoxybenzoyl chloride
were added sequentially to 57 mg of tert-butyl 2-amino-
4-phenoxybenzoate at room temperature, and stirred at
the same temperature for 1 hour. A saturated sodium
hydrogen carbonate aqueous solution was added to the
reaction mixture, and the organic layer was separated,
and the solvent was evaporated under reduced pressure.
The obtained residue was purified with silica gel
column chromatography [Flash Tube 2008 manufacture by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 2-(4-methoxybenzamido)-4-
phenoxybenzoate.
10 mL of trifluoroacetic acid was added to
tert-butyl 2-(4-methoxybenzamido) 4-phenoxybenzoate and
stirred at room temperature for 3 minutes. The solvent
was evaporated under reduced pressure and diisopropyl
ether was added to the obtained residue and a solid
substance was separated by filtration to obtain 55 mg
of 2-(4-methoxybenzamido)-4-phenoxybenzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 3.85 (3H, s) , 6.75 (1H, dd, J = 9.0,
2.5 Hz), 7.09-7.15 (2H, m) , 7.15-7.21 (2H, m), 7.28 (1H,
t, J = 7.4 Hz), 7.46-7.52 (2H, m), 7.86-7.93 (2H, m) ,
8.06 (1H, d, J = 9.0 Hz), 8.41 (1H, d, J = 2.5 Hz),
12.33 (1H, s), 13.55-13.75 (1H, broad).
[0726]
Example 456


1.0 mL of methylene chloride, 2.7 fiL of N,N-
dimethylformamide and 0.061 mL of oxalyl chloride were
added to 0.11 g of 2-methoxybenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 4.0 mL of methylene chloride and
0.4 5 mL of triethylamine containing 54 mg of tert-butyl
2-amino-4-phenylbenzoate at room temperature and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =
4:1] to obtain tert-butyl 2-(2-methoxybenzamido)-4-
phenylbenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-methoxybenzamido)-4-
phenylbenzoate and stirred at room temperature for 3
minutes. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by

377
filtration to obtain 65 mg of 2-(2-methoxybenzamido)-4-
phenylbenzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 4.03 (3H, s), 7.10-7.17 (1H, m) ,
7.26 (1H, d, J = 8.3 Hz), 7.43-7.64 (5H, m), 7.70-7.77
(2H, m), 8.02 (1H, dd, J = 7.8, 1.7 Hz), 8.11 (1H, d, J
= 8.3 Hz), 9.19 (1H, d, J = 1.7 Hz), 12.34 (1H, s),
13.59 (1H, s).
[0727]
Example 457

The following compound was obtained in the
same manner as in Example 456.
2-(3-Methoxybenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-d6) 8: 3.86 (3H, s), 7.22-7.26 (1H, m),
7.44-7.59 (7H, m), 7.72-7.77 (2H, m), 8.14 (1H, d, J =
8.0 Hz), 9.09 (1H, d, J = 1.7 Hz), 12.26 (1H, s),
13.80-14.00 (1H, broad).
[0728]
Examples 458, 459
The compounds shown in Table 45 were obtained
in the same manner as in Example 34.
[0729]
[Table 45]


[0730]
4-Phenethyl-2-(3-phenylpropanamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.71 (2H, t, J = 7.7 Hz), 2.84-2.96
(4H, m), 2.94 (2H, t, J = 7.7 Hz), 7.00 (1H, dd, J =
8.2, 1.6 Hz), 7.15-7.31 (10H, m), 7.87 (1H, d, J = 8.2
Hz), 8.43 (1H, d, J = 1.6 Hz), 11.15 (1H, s), 13.45 (1H,
s) .
[0731]
4-Phenethyl-2-(3,5-
bis(trifluoromethyl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 2.90-3.04 (4H, m) , 7.14 (1H, dd, J =
8.1, 1.7 Hz), 7.15-7.21 (1H, m), 7.24-7.32 (4H, m) ,
7.96 (1H, d, J = 8.1 Hz), 8.45 (1H, s), 8.49-8.52 (1H,
m), 8.54 (2H, s), 12.32 (1H, s), 13.70-13.90 (1H,
broad).
[0732]
Example 4 60


379
The following compound was obtained in the
same manner as in Example 282.
4-Phenyl-2-(3,5-bis(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-de) 8: 7.45-7.51 (1H, m) , 7.52-7.61 (3H, m) ,
7.71-7.77 (2H, m), 8.13 (1H, d, J = 8.1 Hz), 8.46 (1H,
s), 8.56 (2H, s), 8.91 (1H, d, J = 1.7 Hz), 12.38 (1H,
s) .
[0733]
Example 4 61

The following compound was obtained in the
same manner as in Example 321.
4-Phenoxy-2-(3,5-bis(trifluoromethyl)benzamido)benzoic
acid
1H-NMR (DMSO-d6) 8: 6.84 (1H, dd, J = 8.9, 2.6 Hz),
7.17-7.22 (2H, m) , 7.27-7.33 (1H, m) , 7.47-7.54 (2H, m) ,
8.08 (1H, d, J = 8.9 Hz), 8.28 (1H, d, J = 2.6 Hz),
8.44 (1H, s), 8.50 (2H, s), 12.63 (1H, s).
[0734]
Example 462


The following compound was obtained in the
same manner as in Example 396.
2-((E)-3-(3-Nitrophenyl)acrylamido)-4-phenoxybenzoic
acid
1H-NMR (DMSO-d6) 8: 6.76 (1H, dd, J = 8.9, 2.7 Hz),
7.12-7.22 (3H, m), 7.28 (1H, t, J = 7.4 Hz), 7.46-7.51
(2H, m), 7.68-7.78 (2H, m), 8.04 (1H, d, J = 8.9 Hz),
8.18-8.29 (2H, m), 8.35 (1H, d, J = 2.7 Hz), 8.61 (1H,
s), 11.61 (1H, s).
[0735]
Example 463

5.0 mL of methylene chloride, 0.049 mL of
triethylamine and 45 mg of 4-methoxybenzoyl chloride
were added sequentially to 40 mg of methyl 2-amino-4-
phenylbenzoate at room temperature and stirred at the
same temperature for 1 hour. A saturated sodium
hydrogen carbonate aqueous solution was added to the
reaction mixture, and the organic layer was separated,
and the solvent was evaporated under reduced pressure.

381
The obtained residue was purified with silica gel
column chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain methyl 2-(4-methoxybenzamido)-4-
phenylbenzoate.
1.0 mL of 2.0 mol/L aqueous sodium hydroxide
and 3.0 mL of ethanol were added to the obtained methyl
2-(4-methoxybenzamido)-4-phenylbenzoate and stirred at
40°C for 2 hours. After the reaction mixture was cooled
to room temperature, 8.0 mL of 0.38 mol/L hydrochloric
acid and 10 mL of ethyl acetate were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with
reversed-phase silica gel column chromatography
[eluent; 55-100% acetonitrile /0.1% trifluoroacetic
acid aqueous solution] to obtain 6.1 mg of 2-(4-
methoxybenzamido)-4-phenylbenzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 3.86 (3H, s) , 7.15 (2H, d, J = 8.8
Hz), 7.44-7.57 (4H, m), 7.73 (2H, d, J = 7.4 Hz), 7.95
(2H, d, J = 8.8 Hz), 8.13 (1H, d, J = 8.3 Hz), 9.09 (1H,
d, J = 1.4 Hz), 12.21 (1H, s), 13.70-13.90 (1H, broad).
[0736]
Example 4 64


382
2.0 mL of methylene chloride, 2.7 |aL of N,N-
dimethylformamide and 0.061 mL of oxalyl chloride were
sequentially added to 0.13 g of 3-phenyl-lH-pyrazole-5-
carboxylic acid at room temperature and stirred at the
same temperature for 1 hour. The reaction mixture was
added to a mixed solution of 3.0 mL of methylene
chloride and 0.45 mL of triethylamine containing 60 mg
of tert-butyl 2-amino-4-phenethylbenzoate at room
temperature was stirred at the same temperature for 1
hour. A saturated sodium hydrogen carbonate aqueous
solution was added to the reaction mixture, and the
organic layer was separated, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate =4:1] to obtain tert-
butyl 4-phenethyl-2-(3-phenyl-lH-pyrazole-5-
carboxamido)benzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 4-phenethyl-2-(3-phenyl-lH-
pyrazole-5-carboxamido)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure, and the obtained residue was
purified with silica gel column chromatography [Flash
Tube 2008 manufactured by Trikonex Company, eluent;
ethyl acetate] to obtain 2.6 mg of 4-phenethyl-2-(3-
phenyl-lH-pyrazole-5-carboxamido)benzoic acid as white
solid.

383
1H-NMR (DMSO-d6) 6: 2.89-3.04 (4H, m) , 7.05 (1H, d, J =
7.7 Hz), 7.15-7.33 (6H, m) , 7.38-7.44 (1H, m), 7.47-
7.53 (2H, m) , 7.84 (2H, d, J = 7.6 Hz), 7.95 (1H, d, J
= 7.7 Hz), 8.74 (1H, s), 12.39 (1H, s), 13.96 (1H, s).
[0737]
Example 465

2.0 inL of methylene chloride, 2.7 \iL of N,N-
dimethylformamide and 0.061 mL of oxalyl chloride were
added to 0.13 g of 2-acetoxybenzoic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added
to a mixed solution of 3.0 mL of methylene chloride and
0.45 mL of triethylamine containing 60 mg of tert-butyl
2-amino-4-phenethylbenzoate at room temperature and
stirred at the same temperature for 1 hour. A saturated
sodium hydrogen carbonate aqueous solution was added to
the reaction mixture, and the organic layer was
separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified with silica
gel column chromatography [Flash Tube 2008 manufactured
by Trikonex Company, eluent; hexane: ethyl acetate =

384
4:1] to obtain tert-butyl 2-(2-acetoxybenzamido)-4-
phenethylbenzoate.
10 mL of trifluoroacetic acid was added to the
obtained tert-butyl 2-(2-acetoxybenzamido)-4-
phenethylbenzoate and stirred at room temperature for 2
hours. The solvent was evaporated under reduced
pressure and 0.50 mL of methanol, 0.50 mL of
tetrahydrofuran and 10 mg of potassium carbonate were
added to the obtained residue sequentially and stirred
at room temperature for 3 hours. After insoluble were
removed by filtration, 3.0 mL of 10% citric acid
aqueous solution was added and a solid substance was
separated by filtration to obtain 11 mg of 2-(2-
hydroxybenzamido)-4-phenethylbenzoic acid as white
solid.
10 mg of potassium carbonate were added to a
mixed solution of 1.0 mL of methanol and 1.0 mL of
1H-NMR (DMSO-d6) 5: 2.88-3.02 (4H, m) , 6.95-7.03 (2H, m) ,
7.07 (1H, dd, J = 8.1, 1.4 Hz), 7.15-7.21 (1H, m) ,
7.24-7.32 (4H, m) , 7.41-7.47 (1H, m), 7.87 (1H, dd, J =
7.9, 1.6 Hz), 7.92 (1H, d, J = 8.1 Hz), 8.59 (1H, d, J
= 1.4 Hz), 11.46 (1H, s), 12.22 (1H, s).
[0738]
Example 4 66


385
tetrahydrofuran containing 20 mg of 2-(4-
acetoxybenzamido)-4-phenethylbenzoic acid and stirred
at room temperature for 3 hours. After insoluble were
removed by filtration, 3.0 mL of 10% citric acid
aqueous solution was added and a solid substance was
separated by filtration to obtain 15 mg of 2-(4-
hydroxybenzamido)-4-phenethylbenzoic acid as white
solid.
1H-NMR (DMSO-de) 8: 2.88-3.00 (4H, m) , 6.93 (2H, d, J =
8.7 Hz), 7.04 (1H, dd, J = 8.1, 1.6 Hz), 7.15-7.21 (1H,
m) , 7.24-7.32 (4H, m), 7.82 (2H, d, J = 8.7 Hz), 7.94
(1H, d, J = 8.1 Hz), 8.68 (1H, d, J = 1.6 Hz), 10.26
(1H, s), 12.09 (1H, s), 13.50-13.70 (1H, broad).
[0739]
Example 4 67

1.3 mg of 10% palladium-carbon was added to a
mixed solution of 1.0 mL of methanol and 1.0 mL of
ethyl acetate containing 10 mg of 4-phenoxy-2-((E)-4-
phenyl-3-butenamido)benzoic acid and stirred under
hydrogen atmosphere at room temperature for 6 hours.
After insoluble were removed by filtration, the solvent
was evaporated under reduced pressure. Hexane and
diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to

386
obtain 4.6 mg of 4-phenoxy-2-(4-
phenylbutanamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 1.83-1.94 (2H, m) , 2.28 (2H, t, J =
7.6 Hz), 2.60 (2H, t, J = 7.7 Hz), 6.49-6.57 (1H, m) ,
7.02 (2H, d, J = 7.8 Hz), 7.11-7.31 (6H, m) , 7.35-7.43
(2H, m), 7.95 (1H, d, J = 8.6 Hz), 8.17 (1H, d, J = 2.4
Hz) .
[0740]
Example 468

1.0 mg of 10% palladium-carbon was added to a
mixed solution of 0.50 mL of methanol and 0.50 mL ethyl
acetate containing 8.0 mg of 4-phenethyl-2-((E)-4-
phenyl-3-butenamido)benzoic acid and stirred under
hydrogen atmosphere at room temperature for 1 hour and
30 minutes. After insoluble were removed by filtration,
the solvent was evaporated under reduced pressure and
the obtained residue was purified with silica gel
column chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; ethyl acetate] to obtain 4.6
mg of 4-phenethyl-2-(4-phenylbutanamido)benzoic acid as
white solid.
1H-NMR (DMSO-de) 8 (D2O treatment): 1.86-2.02 (2H, m) ,
2.39 (2H, t, J = 7.3 Hz), 2.64 (2H, t, J = 7.6 Hz),
2.85-2.96 (4H, m), 6.56 (1H, s), 7.01 (1H, d, J = 8.2

387
Hz), 7.14-7.34 (9H, m), 7.87 (1H, d, J = 8.2 Hz), 8.43
(1H, s) .
[0741]
Example 4 69

2.5 mL of methylene chloride, 0.015 mL of N,N-
dimethylformamide and 0.095 mL of oxalyl chloride were
added to 0.17 g of 3-cyanobenzoic acid at room
temperature sequentially and stirred at the same
temperature for 30 minutes. The reaction mixture was
added to a mixed solution of 2.0 mL of methylene
chloride and 0.35 mL of triethylamine containing 0.25 g
of tert-butyl 2-amino-4-phenylbenzoate at room
temperature and stirred at the same temperature for 10
minutes. Ethyl acetate, 1.0 mol/L hydrochloric acid and
tetrahydrofuran were added to the reaction mixture. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; chloroform] to obtain 0.29 g of
tert-butyl 2-(3-cyanobenzamido)-4-phenylbenzoate as
white solid.

388
1H-NMR (CDCI3) 8: 1.66 (9H, s) , 7.37-7.44 (2H, m), 7.45-
7.52 (2H, m) , 7.66-7.74 (3H, m), 7.84-7.87 (1H, m) ,
8.10 (1H, d, J = 8.3 Hz), 8.28-8.31 (1H, m), 8.37 (1H,
t, J = 1.5 Hz), 9.19 (1H, d, J = 1.9 Hz), 12.44 (1H, s).
[0742]
Examples 470 to 476
The compounds shown in Table 46 were obtained
in the same manner as in Example 469.
[0743]
[Table 46]

[0744]
tert-Butyl 4-phenyl-2-(6-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate
1H-NMR (CDCI3) 8: 1.66 (9H, s) , 6.41 (2H, t, J = 2.3 Hz),
7.37 (1H, dd, J = 8.5, 2.0 Hz), 7.38-7.50 (4H, m), 7.61
(2H, t, J = 2.3 Hz), 7.70-7.74 (2H, m), 8.10 (1H, d, J
= 8.5 Hz), 8.43 (1H, dd, J = 8.8, 2.4 Hz), 9.15 (1H, d,
J = 2.4 Hz), 9.23 (1H, d, J = 2.0 Hz), 12.44 (1H, s).

389
[0745]
tert-Butyl 4-phenyl-2-(2-(lH-pyrrol-l-yl)pyridine-4-
carboxamido)benzoate
1H-NMR (CDC13) 5: 1.68 (9H, s) , 6.40 (2H, t, J = 2.3 Hz),
7.38-7.52 (4H, m), 7.64 (2H, t, J = 2.3 Hz), 7.68 (1H,
dd, J = 5.2, 1.4 Hz), 7.71-7.75 (2H, m), 8.00 (1H, s),
8.12 (1H, d, J = 8.3 Hz), 8.64 (1H, d, J = 5.2 Hz),
9.22 (1H, d, J = 2.0 Hz), 12.59 (1H, s).
[0746]
tert-Butyl 4-phenyl-2-(3-(lH-pyrazol-1-
yl)benzamido)benzoate
1H-NMR (CDCI3) 8: 1.67 (9H, s) , 6.51-6.53 (1H, m) , 7.35-
7.44 (2H, m), 7.45-7.51 (2H, m), 7.62-7.68 (1H, m) ,
7.70-7.78 (3H, m) , 7.94-8.00 (1H, m) , 8.04-8.12 (3H, m) ,
8.36-8.38 (1H, m), 9.25 (1H, d, J = 1.7 Hz), 12.42 (1H,
s).
[0747]
tert-Butyl 2-(biphenyl-4-carboxamido)-4-phenylbenzoate
1H-NMR (CDCI3) 8: 1.67 (9H, s) , 7.36 (1H, dd, J = 8.4,
1.8 Hz), 7.37-7.44 (2H, m) , 7.45-7.53 (4H, m), 7.65-
7.70 (2H, m), 7.72-7.80 (4H, m), 8.10 (1H, d, J = 8.4
Hz), 8.14-8.18 (2H, m), 9.28 (1H, d, J = 1.8 Hz), 12.33
(1H, s).
[0748]
tert-Butyl 2-(3-acetylbenzamido)-4-phenylbenzoate
1H-NMR (CDCI3) 8: 1.66 (9H, s) , 2.72 (3H, s) , 7.36-7.44
(2H, m), 7.45-7.51 (2H, m), 7.67 (1H, t, J = 7.8 Hz),
7.70-7.76 (2H, m), 8.11 (1H, d, J = 8.3 Hz), 8.16-8.22

390
(1H, m), 8.25-8.30 (1H, m) , 8.68-8.72 (1H, m) , 9.25 (1H,
d, J = 1.9 Hz), 12.49 (1H, s).
[0749]
tert-Butyl 4-phenyl-2-(3-(lH-tetrazol-1-
yl)benzamido)benzoate
1H-NMR (CDC13) 8: 1.67 (9H, s) , 7.38-7.45 (2H, m) , 7.46-
7.53 (2H, m), 7.70-7.75 (2H, m), 7.81 (1H, t, J = 7.9
Hz), 8.03-8.07 (1H, m), 8.12 (1H, d, J = 8.3 Hz), 8.21-
8.24 (1H, m) , 8.42 (1H, t, J = 1.8 Hz), 9.13 (1H, s) ,
9.22 (1H, d, J = 1.7 Hz), 12.57 (1H, s).
[0750]
tert-Butyl 2-(3-(3,5-dimethyl-lH-pyrazol-l-
yl)benzamido)-4-phenylbenzoate
1H-NMR (CDCI3) 8: 1.65 (9H, s) , 2.32 (3H, s) , 2.46 (3H,
s), 6.05 (1H, s), 7.36 (1H, dd, J = 8.3, 1.9 Hz), 7.36-
7.43 (1H, m), 7.44-7.50 (2H, m), 7.64 (1H, t, J = 7.9
Hz), 7.70-7.74 (2H, m) , 7.74-7.79 (1H, m), 8.02-8.07
(1H, m), 8.09 (1H, d, J = 8.3 Hz), 8.12 (1H, t, J = 1.7
Hz), 9.25 (1H, d, J = 1.7 Hz), 12.40 (1H, s).
[0751]
Example 477

To 0.17 g of 3-cyanobenzoic acid were added
2.5 inL of methylene chloride, 0.015 mL of N,N-
dimethylformamide and 0.095 mL of oxalyl chloride at

391
room temperature sequentially and stirred at the same
temperature for 30 minutes. The reaction mixture was
added to a mixed solution of 2.0 mL of methylene
chloride and 0.35 mL of triethylamine containing 0.26 g
of tert-butyl 2-amino-4-phenoxybenzoate at room
temperature and stirred at the same temperature for 10
minutes. Ethyl acetate, 1.0 mol/L hydrochloric acid and
tetrahydrofuran were added to the reaction mixture. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; chloroform] to obtain 0.20 g of
tert-butyl 2-(3-cyanobenzamido)-4-phenoxybenzoate as
white solid.
1H-NMR (CDC13) 5: 1.63 (9H, s) , 6.70 (1H, dd, J = 8.9,
2.7 Hz), 7.08-7.13 (2H, m) , 7.18-7.24 (1H, m), 7.38-
7.45 (2H, m), 7.62-7.68 (1H, m), 7.83 (1H, dt, J = 7.6,
1.5 Hz), 8.00 (1H, d, J = 8.9 Hz), 8.21-8.26 (1H, m),
8.31 (1H, t, J = 1.5 Hz), 8.53 (1H, d, J = 2.7 Hz),
12.48 (1H, s).
[0752]
Examples 478 to 484
The compounds shown in Table 47 were obtained
in the same manner as in Example 477.
[0753]
[Table 47]


[0754]
tert-Butyl 4-phenoxy-2-(6-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate
1H-NMR (CDCI3) 8: 1.63 (9H, s) , 6.40 (2H, t, J = 2.3 Hz),
6.69 (1H, dd, J = 8.9, 2.5 Hz), 7.08-7.14 (2H, m) ,
7.18-7.24 (1H, m) , 7.38-7.45 (3H, m), 7.59 (2H, t, J =
2.3 Hz), 8.00 (1H, d, J = 8.9 Hz), 8.37 (1H, dd, J =
8.8, 2.4 Hz), 8.56 (1H, d, J = 2.5 Hz), 9.09 (1H, d, J
=2.4 Hz), 12.48 (1H, s).
[0755]
tert-Butyl 4-phenoxy-2-(2-(lH-pyrrol-1-yl)pyridine-4-
carboxamido)benzoate
1H-NMR (CDCI3) 8: 1.64 (9H, s) , 6.39 (2H, t, J = 2.2 Hz),
6.72 (1H, dd, J = 8.9, 2.5 Hz), 7.08-7.14 (2H, m) ,
7.18-7.25 (1H, m), 7.38-7.46 (2H, m) , 7.60-7.64 (3H, m) ,
7.93 (1H, s), 8.01 (1H, d, J = 8.8 Hz), 8.54 (1H, d, J
= 2.5 Hz), 8.60 (1H, d, J = 5.1 Hz), 12.62 (1H, s) .

393
[0756]
tert-Butyl 4-phenoxy-2-(2-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate
1H-NMR (CDC13) 5: 1.49 (9H, s) , 6.22 (2H, t, J = 2.3 Hz),
6.63 (1H, dd, J = 8.9, 2.5 Hz), 7.06-7.14 (2H, m),
7.16-7.24 (3H, m), 7.30 (1H, dd, J = 7.7, 4.9 Hz),
7.37-7.44 (2H, m), 7.88 (1H, d, J = 8.9 Hz), 8.05 (1H,
dd, J = 7.7, 1.8 Hz), 8.51 (1H, d, J = 2.5 Hz), 8.59
(1H, dd, J = 4.9, 1.8 Hz), 11.62 (1H, s).
[0757]
tert-Butyl 4-phenoxy-2-(3-(lH-pyrazol-1-
yl)benzamido)benzoate
1H-NMR (CDCI3) 8: 1.63 (9H, s) , 6.51 (1H, t, J = 2.1 Hz),
6.69 (1H, dd, J = 8.9, 2.4 Hz), 7.09-7.14 (2H, m), 7.21
(1H, t, J = 7.3 Hz), 7.38-7.44 (2H, m), 7.61 (1H, t, J
= 7.9 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.88-7.92 (1H, m) ,
8.00 (1H, d, J = 8.9 Hz), 8.02-8.07 (2H, m) , 8.28-8.31
(1H, m), 8.58 (1H, d, J = 2.4 Hz), 12.45 (1H, s).
[0758]
tert-Butyl 2-(biphenyl-4-carboxamido)-4-phenoxybenzoate
1H-NMR (CDCI3) 8: 1.63 (9H, s) , 6.67 (1H, dd, J = 8.9,
2.5 Hz), 7.08-7.14 (2H, m) , 7.16-7.23 (1H, m), 7.36-
7.52 (5H, m), 7.63-7.68 (2H, m), 7.72-7.78 (2H, m) ,
7.99 (1H, d, J = 8.9 Hz), 8.07-8.13 (2H, m), 8.62 (1H,
d, J = 2.5 Hz), 12.37 (1H, s) .
[0759]
tert-Butyl 2-(3-acetylbenzamido)-4-phenoxybenzoate
1H-NMR (CDCI3) 8: 1.63 (9H, s), 2.70 (3H, s) , 6.69 (1H,
dd, J = 9.0, 2.7 Hz), 7.10-7.15 (2H, m) , 7.18-7.23 (1H,

394
m), 7.38-7.45 (2H, m), 7.63 (1H, t, J = 7.8 Hz), 8.00
(1H, d, J = 9.0 Hz), 8.14-8.19 (1H, m) , 8.20-8.24 (1H,
m), 8.57 (1H, d, J = 2.7 Hz), 8.62-8.64 (1H, m), 12.52
(1H, s).
[0760]
tert-Butyl 2-(3-(3,5-dimethyl-lH-pyrazol-l-
yl)benzamido)-4-phenoxybenzoate
1H-NMR (CDC13) 8: 1.61 (9H, s) , 2.31 (3H, s) , 2.44 (3H,
s), 6.03 (1H, s), 6.67 (1H, dd, J = 8.9, 2.5 Hz), 7.08-
7.13 (2H, m), 7.16-7.22 (1H, m), 7.37-7.43 (2H, m) ,
7.60 (1H, t, J = 7.9 Hz), 7.72-7.76 (1H, m), 7.96-8.01
(2H, m), 8.06 (1H, t, J = 1.8 Hz), 8.59 (1H, d, J = 2.5
Hz), 12.43 (1H, s).
[0761]
Example 485

0.015 mL of N,N-dimethylformamide was added to
a mixed solution of 2.0 mL of methylene chloride and
0.024 mL of oxalyl chloride containing 47 mg of 6-(lH-
pyrrol-l-yl)pyridine-3-carboxylic acid and stirred at
room temperature for 30 minutes. 74 mg of tert-butyl 2-
amino-4-phenethylbenzoate and 0.090 mL of triethylamine
were added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 1

395
hour and 40 minutes. 1.0 mol/L hydrochloric acid and
ethyl acetate were added to the reaction mixture. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; chloroform] to obtain 62 mg of
tert-butyl 4-phenethyl-2-(6-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoate as white solid.
1H-NMR (CDC13) 8: 1.63 (9H, s) , 2.90-3.08 (4H, m), 6.41
(2H, t, J = 2.3 Hz), 6.90 (1H, dd, J = 8.1, 1.7 Hz),
7.17-7.32 (5H, m), 7.46 (1H, d, J = 8.7 Hz), 7.60 (2H,
d, J = 2.3 Hz), 7.93 (1H, d, J = 8.1 Hz), 8.41 (1H, dd,
J = 8.7, 2.3 Hz), 8.83 (1H, d, J = 1.7 Hz), 9.13 (1H, d,
J = 2.3 Hz), 12.40 (1H, s).
[0762]
Examples 486 to 488
The compounds shown in Table 48 were obtained
in the same manner as in Example 4 85.
[0763]
[Table 48]


[0764]
tert-Butyl 4-phenethyl-2-(2-(lH-pyrrol-1-yl)pyridine-4-
carboxamido)benzoate
1H-NMR (CDCI3) 8: 1.64 (9H, s) , 2.94-3.05 (4H, m) , 6.40
(2H, t, J = 2.3 Hz), 6.94 (1H, dd, J = 8.2, 1.7 Hz),
7.18-7.33 (5H, m), 7.63 (2H, t, J = 2.3 Hz), 7.66 (1H,
dd, J = 5.1, 1.5 Hz), 7.94 (1H, d, J = 8.2 Hz), 7.97-
7.99 (1H, m), 8.63 (1H, d, J = 5.1 Hz), 8.81 (1H, d, J
= 1.7 Hz), 12.55 (1H, s).
[0765]
tert-Butyl 2-(biphenyl-3-carboxamido)-4-
phenethylbenzoate
1H-NMR (CDCI3) 6: 1.64 (9H, s) , 2.94-3.06 (4H, m) , 6.89
(1H, dd, J = 8.2, 1.6 Hz), 7.16-7.34 (5H, m) , 7.35-7.43
(1H, m) , 7.45-7.52 (2H, m), 7.61 (1H, t, J = 7.7 Hz),
7.70-7.75 (2H, m), 7.78-7.84 (1H, m), 7.93 (1H, d, J =
8.2 Hz), 8.80-8.05 (1H, m), 8.36 (1H, t, J = 1.7 Hz),
8.88 (1H, d, J = 1.6 Hz), 12.38 (1H, s).
[0766]
tert-Butyl 2-(biphenyl-4-carboxamido)-4-
phenethylbenzoate

397
1H-NMR (CDCI3) 5: 1.64 (9H, s), 2.92-3.06 (4H, m) , 6.89
(1H, dd, J = 8.1, 1.6 Hz), 7.16-7.34 (5H, m), 7.37-7.44
(1H, m), 7.45-7.53 (2H, m), 7.64-7.70 (2H, m), 7.74-
7.80 (2H, m), 7.93 (1H, d, J = 8.1 Hz), 8.12-8.17 (2H,
m), 8.89 (1H, d, J = 1.6 Hz), 12.30 (1H, s).
[0767]
Example 48 9

0.015 mL of N,N-dimethylformamide was added to
a mixed solution of 2.0 mL of methylene chloride and
0.024 mL of oxalyl chloride containing 47 mg of 4-(lH-
pyrrol-1-yl)benzoic acid and stirred at room
temperature for 30 minutes. 67 mg of tert-butyl 2-
amino-4-phenylbenzoate and 0.090 mL of triethylamine
were added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 30
minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid
were added to the reaction mixture. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,

398
eluent; chloroform] to obtain 64 mg of tert-butyl 4-
phenyl-2-(4-(lH-pyrrol-1-yl)benzamido)benzoate as white
solid.
1H-NMR (CDC13) 8: 1.66 (9H, s) , 6.40 (2H, t, J = 2.2 Hz),
7.20 (2H, t, J = 2.2 Hz), 7.35 (1H, dd, J = 8.3, 1.8
Hz), 7.37-7.43 (1H, m), 7.44-7.50 (2H, m), 7.54-7.59
(2H, m), 7.71-7.76 (2H, m), 8.10 (1H, d, J = 8.3 Hz),
8.14-8.18 (2H, m), 9.26 (1H, d, J = 1.8 Hz), 12.33 (1H,
s) .
[0768]
Example 4 90

The following compound was obtained in the
same manner as in Example 489.
tert-Butyl 2-(biphenyl-2-carboxamido)-4-phenylbenzoate
1H-NMR (CDCI3) 8: 1.52 (9H, s) , 7.20-7.40 (5H, m) , 7.40-
7.58 (7H, m), 7.64-7.70 (2H, m), 7.74-7.78 (1H, m) ,
7.93 (1H, d, J = 8.3 Hz), 9.10 (1H, s), 11.26 (1H, s).
[0769]
Example 4 91


399
0.015 mL of N,N-dimethylformamide was added to
a mixed solution of 2.0 mL of methylene chloride and
0.024 mL of oxalyl chloride containing 47 mg of 3-(lH-
pyrrol-1-yl)benzoic acid and stirred at room
temperature for 30 minutes. 71 mg of tert-butyl 2-
amino-4-phenoxybenzoate and 0.090 mL of triethylamine
were added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 30
minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid
were added to the reaction mixture. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =40:1] to obtain 31 mg
of tert-butyl 4-phenoxy-2-(3-(lH-pyrrol-1-
yl)benzamido)benzoate as white solid.
1H-NMR (CDC13) 8: 1.63 (9H, s) , 6.38 (2H, t, J = 2.2 Hz),
6.68 (1H, dd, J = 8.9, 2.5 Hz), 7.09-7.14 (2H, m) ,
7.17-7.24 (3H, m), 7.37-7.44 (2H, m), 7.55-7.60 (2H, m) ,
7.84-7.88 (1H, m), 8.00 (1H, d, J = 8.9 Hz), 8.09-8.11
(1H, m), 8.58 (1H, d, J = 2.5 Hz), 12.46 (1H, s).
[0770]
Example 492


The following compound was obtained in the
same manner as in Example 4 91.
tert-Butyl 2-(biphenyl-2-carboxamido)-4-phenoxybenzoate
1H-NMR (CDCI3) 8: 1.48 (9H, s) , 6.54 (1H, dd, J= 9.0,
2.6 Hz), 7.02-7.08 (2H, m), 7.16 (1H, t, J = 7.4 Hz),
7.21-7.40 (5H, m) , 7.41-7.56 (5H, m) , 7.69-7.73 (1H, m) ,
7.81 (1H, d, J = 9.0 Hz), 8.47-8.52 (1H, broad), 11.23-
11.27 (1H, broad).
[0771]
Example 493

4.0 mL of methylene chloride, 0.015 mL of N,N-
dimethylformamide and 0.050 mL of oxalyl chloride were
added to 99 mg of 3-biphenylcarboxylic acid at room
temperature sequentially and stirred at the same
temperature for 20 minutes. 0.16 mL of triethylamine
and 0.12 g of tert-butyl 2-amino-4-phenylbenzoate were
added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 10

401
minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid
were added to the reaction mixture. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; chloroform] to obtain 0.14 g of tert-butyl 2-
(biphenyl-3-carboxamido)-4-phenylbenzoate as white
solid.
1H-NMR (CDC13) 5: 1.67 (9H, s) , 7.34-7.43 (3H, m) , 7.45-
7.51 (4H, m), 7.62 (1H, t, J = 7.7 Hz), 7.70-7.76 (4H,
m) , 7.82 (1H, ddd, J = 7.7, 1.8, 1.0 Hz), 8.04 (1H, ddd,
J = 7.8, 1.8, 1.0 Hz), 8.10 (1H, d, J = 8.3 Hz), 8.37-
8.40 (1H, m), 9.28 (1H, d, J = 1.7 Hz), 12.42 (1H, s).
[0772]
Example 494

4.0 mL of methylene chloride, 0.015 mL of N,N-
dimethylformamide and 0.050 mL of oxalyl chloride were
added to 99 mg of 3-biphenylcarboxylic acid at room
temperature sequentially and stirred at the same
temperature for 20 minutes. 0.16 mL of triethylamine
and 0.13 g of tert-butyl 2-amino-4-phenoxybenzoate were

402
added to the reaction mixture at room temperature
sequentially and stirred at the same temperature for 10
minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid
were added to the reaction mixture. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; chloroform] to obtain 14 mg of tert-butyl 2-
(biphenyl-3-carboxamido)-4-phenoxybenzoate as white
solid.
1H-NMR (CDC13) 8: 1.63 (9H, s) , 6.68 (1H, dd, J= 8.9,
2.5 Hz), 7.08-7.15 (2H, m), 7.16-7.22 (1H, m), 7.35-
7.52 (5H, m), 7.58 (1H, t, J = 7.7 Hz), 7.68-7.74 (2H,
m), 7.77-7.82 (1H, m) , 7.95-8.04 (2H, m) , 8.30-8.32 (1H,
m), 8.61 (1H, d, J = 2.5 Hz), 12.46 (1H, s).
[0773]
Example 495

0.25 mL of acetic acid and 4.1 \iL of 2,5-
dimethoxytetrahydrofuran were added sequentially to 10
mg of 2-(4-aminobenzamido)-4-phenoxybenzoic acid at
room temperature and stirred at 90°C for 5 minutes.

403
After the reaction mixture was cooled to room
temperature, ethyl acetate and a saturated sodium
hydrogen carbonate aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; ethyl acetate] to obtain 3.8 mg
of 4-phenoxy-2-(4-(lH-pyrrol-1-yl)benzamido)benzoic
acid a brown solid.
1H-NMR (DMSO-de) 5: 6.33 (2H, t, J - 2.2 Hz), 6.78 (1H,
dd, J = 8.8, 2.6 Hz), 7.16-7.21 (2H, m), 7.28 (1H, t, J
= 7.4 Hz), 7.46-7.53 (2H, m), 7.53 (2H, t, J = 2.2 Hz),
7.80-7.85 (2H, m) , 7.96-8.01 (2H, m), 8.08 (1H, d, J =
8.8 Hz), 8.41 (1H, d, J = 2.6 Hz), 12.49 (1H, s).
[0774]
Example 496

1.0 mL of methylene chloride, 0.010 mL of N,N-
dimethylformamide and 0.064 mL of oxalyl chloride were
added to 0.13 g of 3,4-dimethoxycinnamic acid at room
temperature sequentially and stirred at the same
temperature for 1 hour. The reaction mixture was added

404
to a mixed solution of 1.5 mL of methylene chloride and
0.14 mL of triethylamine containing 0.15 g of tert-
butyl 2-amino-4-phenethylbenzoate while ice-cooled and
stirred at room temperature overnight. The solvent was
evaporated under reduced pressure and ethyl acetate and
10% citric acid aqueous solution were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 10% citric acid
aqueous solution, a saturated sodium hydrogen carbonate
aqueous solution and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate =4:1] to
obtain 0.12 g of tert-butyl 2-( (E)-3-(3,4-
dimethoxyphenyl)acrylamido)-4-phenethylbenzoate as
white solid.
1H-NMR (CDC13) 8: 1.63 (9H, s), 2.94-3.01 (4H, m), 3.93
(3H, s), 3.97 (3H, s), 6.51 (1H, d, J = 15.5 Hz), 6.86
(1H, dd, J = 8.3, 1.3 Hz), 6.89 (1H, d, J = 8.3 Hz),
7.13 (1H, d, J = 1.7 Hz), 7.16-7.32 (6H, m), 7.71 (1H,
d, J = 15.5 Hz), 7.89 (1H, d, J = 8.3 Hz), 8.82 (1H, d,
J = 1.3 Hz), 11.45 (1H, s).
[0775]
Example 4 97


1.5 mL of methylene chloride, 0.010 mL of N,N-
dimethylformamide and 0.062 mL of oxalyl chloride were
added sequentially to 0.13 g of 6-(piperidin-1-
yl)pyridine-3-carboxylic acid at room temperature and
stirred at the same temperature for 1 hour and 30
minutes. The solvent was evaporated under reduced
pressure, 1.5 mL of methylene chloride was added and,
while ice-cooled, the mixture was added to a mixed
solution of 1.5 mL of methylene chloride and 0.14 mL of
triethylamine containing 0.15 g of tert-butyl 2-amino-
4-phenethylbenzoate and stirred at room temperature
overnight. The solvent was evaporated under reduced
pressure and ethyl acetate and 10% citric acid aqueous
solution were added. The organic layer was separated
and dried over anhydrous magnesium sulfate after washed
with a saturated sodium hydrogen carbonate aqueous
solution and a saturated sodium chloride aqueous
solution sequentially, and the solvent was evaporated
under reduced pressure. Hexane and diisopropyl ether
were added to the obtained residue and a solid
substance was separated by filtration to obtain 0.17 g
of tert-butyl 4-phenethyl-2-(6-(piperidin-1-
yl)pyridine-3-carboxamido)benzoate as white solid.

406
1H-NMR (CDCI3) 5: 1.52-1.77 (6H, m), 1.61 (9H, s) , 2.97
(4H, s), 3.66-3.73 (4H, m), 6.70 (1H, d, J = 9.2 Hz),
6.84 (1H, dd, J = 8.2, 1.7 Hz), 7.17-7.31 (5H, m), 7.90
(1H, d, J = 8.2 Hz), 8.10 (1H, dd, J = 9.2, 2.7 Hz),
8.86 (1H, d, J = 1.7 Hz), 8.89 (1H, d, J = 2.7 Hz),
12.11 (1H, s) .
[0776]
Example 498

0.5 mL of trifluoroacetic acid was added to
0.5 mL of methylene chloride solution containing 10 mg
of tert-butyl 2-(3-cyanobenzamido)-4-phenoxybenzoate
and stirred at room temperature for 2 hours. The
solvent was evaporated under reduced pressure and
diisopropyl ether was added to the obtained residue and
a solid substance was separated by filtration to obtain
5.0 mg of 2-(3-cyanobenzamido)-4-phenoxybenzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.9, 2.6 Hz),
7.16-7.20 (2H, m), 7.29 (1H, t, J = 7.2 Hz), 7.47-7.52
(2H, m), 7.81 (1H, t, J = 7.8 Hz), 8.08 (1H, d, J = 8.9
Hz), 8.12 (1H, d, J = 7.8 Hz), 8.20 (1H, d, J = 8.0 Hz),
8.29 (1H, s), 8.31 (1H, d, J = 2.6 Hz), 12.48 (1H, s).
[0777]
Examples 499 to 507

407
The compounds shown in Table 49 were obtained
in the same manner as in Example 498.
[0778]
[Table 49]

[0779]
4-Phenoxy-2-(6-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-de) 5: 6.37 (2H, t, J = 2.3 Hz), 6.81 (1H,
dd, J = 8.9, 2.6 Hz), 7.16-7.22 (2H, m), 7.26-7.32 (1H,
m), 7.46-7.54 (2H, m), 7.78 (2H, t, J = 2.3 Hz), 7.92
(1H, d, J = 8.8 Hz), 8.09 (1H, d, J = 9.0 Hz), 8.30-
8.36 (2H, m), 8.92 (1H, d, J = 2.4 Hz), 12.40 (1H, s).
[0780]
4-Phenoxy-2-(2-(lH-pyrrol-1-yl)pyridine-4-
carboxamido)benzoic acid
Hl-NMR (DMSO-de) 6: 6.35 (2H, t, J = 2.3 Hz), 6.85 (1H,
dd, J= 8.9, 2.7 Hz), 7.16-7.24 (2H, m), 7.26-7.34 (1H,
m), 7.46-7.54 (2H, m), 7.61 (1H, dd, J = 5.1, 1.2 Hz),
7.74 (2H, t, J = 2.3 Hz), 8.05 (1H, s), 8.10 (1H, d, J

408
= 8.9 Hz), 8.32 (1H, d, J = 2.7 Hz), 8.66 (1H, d, J =
5.1 Hz), 12.50 (1H, s).
[0781]
4-Phenoxy-2-(2-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 5: 6.21 (2H, t, J = 2.2 Hz), 6.75 (1H,
dd, J = 8.9, 2.7 Hz), 7.16-7.22 (4H, m), 7.25-7.30 (1H,
m) , 7.46-7.54 (3H, m), 7.98 (1H, d, J = 8.9 Hz), 8.15-
8.22 (2H, m), 8.64 (1H, dd, J = 4.9, 1.7 Hz), 11.67 (1H,
s) .
[0782]
4-Phenoxy-2-(3-(lH-pyrazol-1-yl)benzamido)benzoic acid
1H-NMR (DMSO-de) 8: 6.60 (1H, dd, J = 2.6, 1.8 Hz), 6.80
(1H, dd, J = 8.9, 2.6 Hz), 7.16-7.23 (2H, m), 1.21-1.32
(1H, m) , 7.46-7.55 (2H, m), 7.71 (1H, t, J = 7.9 Hz),
7.80-7.86 (2H, m) , 8.07-8.13 (2H, m) , 8.41-8.42 (2H, m) ,
8.61 (1H, d, J = 2.4 Hz), 12.53 (1H, s).
[0783]
2-(Biphenyl-3-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.79 (1H, dd, J = 8.8, 2.1 Hz),
7.17-7.22 (2H, m) , 7.26-7.33 (1H, m), 7.43 (1H, tt, J =
7.4, 1.5 Hz), 7.46-7.55 (4H, m), 7.68 (1H, t, J = 7.8
Hz), 7.72-7.77 (2H, m) , 7.90-7.97 (2H, m), 8.08 (1H, d,
J = 8.8 Hz), 8.19 (1H, t, J = 1.7 Hz), 8.43 (1H, d, J =
2.7 Hz), 12.54 (1H, s).
[0784]
2-(Biphenyl-4-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-de) 8: 6.78 (1H, dd, J = 8.9, 2.5 Hz),
7.16-7.22 (2H, m) , 7.26-7.32 (1H, m) , 7.41-7.55 (5H, m) ,

409
7.75-7.80 (2H, m) , 7.87-7.93 (2H, m) , 7.98-8.04 (2H, m) ,
8.09 (1H, d, J = 8.9 Hz), 8.43 (1H, d, J = 2.5 Hz),
12.48 (1H, s).
[0785]
2-(3-Acetylbenzamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.66 (3H, s), 6.80 (1H, dd, J= 8.9,
2.6 Hz), 7.16-7.22 (2H, m), 7.26-7.32 (1H, m), 7.46-
7.54 (2H, m), 7.75 (1H, t, J = 7.8 Hz), 8.09 (1H, d, J
= 8.9 Hz), 8.15-8.19 (1H, m), 8.20-8.24 (1H, m), 8.40
(1H, d, J = 2.6 Hz), 8.48-8.51 (1H, m) , 12.58 (1H, s) ,
13.60-14.00 (1H, broad).
[0786]
2-(3-(3,5-Dimethyl-lH-pyrazol-l-yl)benzamido)-4-
phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 2.20 (3H, s) , 2.37 (3H, s) , 6.13 (1H,
s), 6.79 (1H, dd, J = 8.9, 2.5 Hz), 7.17-7.21 (2H, m) ,
7.26-7.32 (1H, m) , 7.46-7.53 (2H, m), 7.70 (1H, t, J =
7.8 Hz), 7.76-7.81 (1H, m) , 7.88-7.93 (1H, m), 7.99 (1H,
t, J = 2.0 Hz), 8.08 (1H, d, J = 8.9 Hz), 8.40 (1H, d,
J = 2.5 Hz), 12.46 (1H, s), 13.50-14.00 (1H, broad).
[0787]
2-(Biphenyl-2-carboxamido)-4-phenoxybenzoic acid
1H-NMR (DMSO-d6) 8: 6.66 (1H, dd, J = 8.8, 2.4 Hz) ,
7.11-7.16 (2H, m), 7.22-7.43 (6H, m) , 7.44-7.55 (4H, m) ,
7.62 (1H, td, J = 7.6, 1.5 Hz), 7.67 (1H, dd, J = 7.6,
1.2 Hz), 7.91 (1H, d, J = 8.8 Hz), 8.22 (1H, s), 11.44
(1H, s), 13.30-13.60 (1H, broad).
[0788]
Example 508


0.5 mL of trifluoroacetic acid was added to
0.5 mL of methylene chloride solution containing 10 mg
of tert-butyl 2-(3-cyanobenzamido)-4-phenylbenzoate and
stirred at room temperature for 1 hour and 30 minutes.
The solvent was evaporated under reduced pressure and
diisopropyl ether was added to the obtained residue and
a solid substance was separated by filtration to obtain
7.6 mg of 2-(3-cyanobenzamido)-4-phenylbenzoic acid as
white solid.
1H-NMR (DMSO-de) 5: 7.44-7.50 (1H, m) , 7.52-7.60 (3H, m) ,
7.72-7.77 (2H, m), 7.84 (1H, t, J = 7.9 Hz), 8.12-8.18
(2H, m) , 8.25-8.30 (1H, m) , 8.35-8.38 (1H, m) , 8.95 (1H,
d, J = 1.7 Hz) , 12.24 (1H, s) .
[0789]
Examples 509 to 516
The compounds shown in Table 50 were obtained
in the same manner as in Example 508.
[0790]
[Table 50]


[0791]
4-Phenyl-2-(6-(lH-pyrrol-l-yl)pyridine-3-
carboxamido)benzoic acid
1H-NMR (DMSO-de) 5: 6.38 (2H, t, J = 2.1 Hz), 7.44-7.50
(1H, m), 7.52-7.58 (3H, m), 7.71-7.76 (2H, m) , 7.80 (2H,
t, J = 2.1 Hz), 7.96 (1H, d, J = 8.6 Hz), 8.15 (1H, d,
J = 8.3 Hz), 8.40 (1H, dd, J = 8.6, 2.4 Hz), 8.98-9.02
(2H, m), 12.25 (1H, s).
[0792]
4-Phenyl-2-(2-(lH-pyrrol-1-yl)pyridine-4-
carboxamido)benzoic acid
1H-NMR (DMSO-de) 8: 6.37 (2H, t, J = 2.3 Hz), 7.48 (1H,
tt, J = 7.3, 1.6 Hz), 7.53-7.62 (3H, m), 7.69 (1H, dd,
J = 5.1, 1.4 Hz), 7.74-7.78 (4H, m), 8.13 (1H, s), 8.16
(1H, d, J = 8.3 Hz), 8.69 (1H, dd, J = 5.1, 0.8 Hz),
8.98 (1H, d, J = 1.7 Hz), 12.29 (1H, s).
[0793]
4-Phenyl-2-(3-(lH-pyrazol-l-yl)benzamido)benzoic acid

412
1H-NMR (DMSO-dg) 5: 6.62 (1H, dd, J = 2.4, 2.0 Hz),
7.45-7.51 (1H, m) , 7.53-7.60 (3H, m) , 1.12-1 .I'd (3H, m) ,
7.82-7.84 (1H, m) , 7.88-7.94 (1H, m) , 8.10-8.17 (2H, m) ,
8.49 (1H, t, J = 1.8 Hz), 8.63 (1H, d, J = 2.4 Hz),
9.09 (1H, d, J = 1.7 Hz), 12.38 (1H, s).
[0794]
2-(Biphenyl-3-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 5: 7.42-7.60 (7H, m) , 7.69-7.80 (5H, m) ,
7.94-8.02 (2H, m), 8.15 (1H, d, J = 8.3 Hz), 8.26 (1H,
s), 9.11 (1H, d, J = 1.7 Hz), 12.40 (1H, s).
[0795]
2-(Biphenyl-4-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.42-7.60 (7H, m) , 7.74-7.82 (4H, m) ,
7.90-7.95 (2H, m), 8.06-8.11 (2H, m), 8.16 (1H, d, J =
8.3 Hz), 9.11 (1H, d, J = 1.7 Hz), 12.34 (1H, s) .
[0796]
2-(3-Acetylbenzamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 2.69 (3H, s), 7.45-7.50 (1H, m),
7.52-7.59 (3H, m), 7.72-7.82 (3H, m), 8.15 (1H, d, J =
8.3 Hz), 8.24 (2H, dd, J = 7.8, 1.7 Hz), 8.57 (1H, t, J
= 1.7 Hz), 9.07 (1H, d, J = 2.0 Hz), 12.41 (1H, s) .
[0797]
2-(3-(3,5-Dimethyl-lH-pyrazol-l-yl)benzamido)-4-
phenylbenzoic acid
1H-NMR (DMSO-de) 8: 2.21 (3H, s), 2.39 (3H, d, J = 0.5
Hz), 6.14 (1H, s), 7.47 (1H, tt, J = 7.3, 1.5 Hz),
7.52-7.58 (3H, m) , 7.70-7.77 (3H, m) , 7.79-7.82 (1H, m) ,
7.96-7.99 (1H, m), 8.06-8.07 (1H, m), 8.14 (1H, d, J =
8.3 Hz), 9.05-9.07 (1H, m) , 12.30 (1H, s).

413
[0798]
2-(Biphenyl-2-carboxamido)-4-phenylbenzoic acid
1H-NMR (DMSO-de) 8: 7.29 (1H, tt, J = 7.2, 1.7 Hz),
7.34-7.48 (6H, m) , 7.48-7.59 (4H, m) , 7.61-7.70 (3H, m) ,
7.73 (1H, dd, J = 7.6, 1.2 Hz), 7.99 (1H, d, J = 8.3
Hz), 8.85 (1H, s), 11.35 (1H, s), 13.40-13.80 (1H,
broad).
[0799]
Example 517

1.0 mL of trifluoroacetic acid was added to
1.0 mL of methylene chloride solution containing 20 mg
of tert-butyl 4-phenethyl-2-(6-(lH-pyrrol-1-
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 1 hour and 30 minutes. The solvent was
evaporated under reduced pressure and diisopropyl ether
was added to the obtained residue and a solid substance
was separated by filtration to obtain 17 mg of 4-
phenethyl-2-(6-(lH-pyrrol-1-yl)pyridine-3-
carboxamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 2.90-3.02 (4H, m) , 6.38 (2H, t, J =
2.3 Hz), 7.11 (1H, dd, J = 8.3, 1.6 Hz), 7.15-7.24 (1H,
m) , 7.25-7.32 (4H, m), 7.79 (2H, t, J = 2.3 Hz), 7.94
(1H, d, J = 8.7 Hz), 7.97 (1H, d, J = 8.3 Hz), 8.37 (1H,

414
dd, J = 8.7, 2.3 Hz), 8.58-8.61 (1H, m), 8.97 (1H, d, J
= 2.3 Hz), 12.15 (1H, s), 13.60-13.80 (1H, broad).
[0800]
Examples 518 to 521
The compounds shown in Table 51 were obtained
in the same manner as in Example 517.
[0801]
[Table 51]

[0802]
4-Phenethyl-2-(2-(lH-pyrrol-l-yl)pyridine-4-
carboxamido)benzoic acid
1H-NMR (DMSO-d6) 8: 2.90-3.04 (4H, m) , 6.37 (2H, t, J =
2.3 Hz), 7.12-7.22 (2H, m) , 7.25-7.32 (4H, m), 7.66 (1H,
dd, J = 5.1, 1.5 Hz), 7.74 (2H, t, J = 2.3 Hz), 7.97
(1H, d, J = 8.3 Hz), 8.10 (1H, s), 8.56 (1H, d, J = 1.5
Hz), 8.67 (1H, d, J = 5.1 Hz), 12.21 (1H, s).
[0803]
2-(Biphenyl-3-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-de) 8: 2.88-3.04 (4H, m) , 7.10 (1H, dd, J =
8.3, 1.5 Hz), 7.15-7.24 (1H, m), 7.24-7.33 (4H, m) ,
7.41-7.46 (1H, m), 7.51-7.55 (2H, m), 7.70 (1H, t, J =

415
7.7 Hz), 7.73-7.78 (2H, m), 7.92-8.00 (3H, m), 8.23 (1H,
s), 8.70 (1H, s), 12.31 (1H, s), 13.50-14.00 (1H,
broad).
[0804]
2-(Biphenyl-4-carboxamido)-4-phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.90-3,01 (4H, m), 7.09 (1H, dd, J =
8.1, 1.5 Hz), 7.15-7.25 (1H, m), 7.25-7.30 (4H, m),
7.44 (1H, tt, J = 7.3, 1.4 Hz), 7.49-7.56 (2H, m) ,
7.76-7.80 (2H, m) , 7.88-7.94 (2H, m), 7.97 (1H, d, J =
8.1 Hz), 8.03-8.08 (2H, m), 8.70 (1H, d, J = 1.5 Hz),
12.27 (1H, s).
[0805]
2-((E)-3-(3,4-Dimethoxyphenyl)acrylamido)-4-
phenethylbenzoic acid
1H-NMR (DMSO-d6) 8: 2.89-2.98 (4H, m) , 3.81 (3H, s) ,
3.84 (3H, s), 6.79 (1H, d, J = 15.5 Hz), 7.00 (1H, d, J
= 8.5 Hz), 7.04 (1H, dd, J = 8.3, 1.4 Hz), 7.15-7.20
(1H, m), 7.23-7.30 (5H, m) , 7.38 (1H, d, J = 1.7 Hz),
7.56 (1H, d, J = 15.5 Hz), 7.91 (1H, d, J = 8.3 Hz),
8.58 (1H, d, J = 1.4 Hz), 11.30 (1H, s).
[0806]
1.0 mL of trifluoroacetic acid was added to
1.0 mL of methylene chloride solution containing 20 mg
Example 522


416
of tert-butyl 4-phenyl-2-(3-(lH-tetrazol-1-
yl)benzamido)benzoate and stirred at room temperature
for 1 hour. The solvent was evaporated under reduced
pressure and ethyl acetate and tetrahydrofuran were
added to the obtained residue and heated to 50°C.
Insoluble were removed by filtration at the same
temperature, and the solvent was evaporated under
reduced pressure. Tetrahydrofuran was added to the
obtained residue and a solid substance was separated by
filtration to obtain 5.0 mg of 4-phenyl-2-(3-(1H-
tetrazol-1-yl)benzamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 7.48 (1H, tt, J = 7.3, 1.5 Hz),
7.53-7.60 (3H, m) , 1.12-1.1% (2H, m), 7.92 (1H, t, J =
7.9 Hz), 8.15 (2H, d, J = 8.3 Hz), 8.20-8.24 (1H, m) ,
8.54 (1H, t, J = 1.8 Hz), 9.04 (1H, d, J = 1.7 Hz),
10.23 (1H, s), 12.44 (1H, s).
[0807]
Example 523

1.0 mL of methanol and 0.5 mL of 2.0 mol/L
aqueous sodium hydroxide were added to 1.0 mL of
dioxane solution containing 20 mg of tert-butyl 4-
phenyl-2-(4-(lH-pyrrol-1-yl)benzamido)benzoate at room
temperature and stirred at 50°C for 30 minutes. Ethyl

417
acetate and 1.0 mol/L hydrochloric acid were added
after the reaction mixture was cooled to room
temperature. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure.
Diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 15 mg of 4-phenyl-2-(4-(lH-pyrrol-1-
yl)benzamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 6.34 (2H, t, J = 2.2 Hz), 7.47 (1H,
tt, J = 7.3, 1.5 Hz), 7.50-7.59 (5H, m), 7.72-7.78 (2H,
m) , 7.83-7.88 (2H, m) , 8.03-8.09 (2H, m), 8.15 (1H, d,
J = 8.5 Hz), 9.09 (1H, d, J = 2.0 Hz), 12.33 (1H, s).
[0808]
Example 524

1.0 mL of methanol and 0.5 mL of 2.0 mol/L
aqueous sodium hydroxide were added to 1.0 mL of
dioxane solution containing 20 mg of tert-butyl 4-
phenoxy-2-(3-(lH-pyrrol-l-yl)benzamido)benzoate at room
temperature and stirred at 50°C for 30 minutes. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 1.0 mol/L hydrochloric acid were
added. The organic layer was separated and dried over

418
anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure.
Diisopropyl ether were added to the obtained residue
and a solid substance was separated by filtration to
obtain 7.6 mg of 4-phenoxy-2-(3-(lH-pyrrol-1-
yl)benzamido)benzoic acid as white solid.
1H-NMR (DMSO-de) 5: 6.32 (2H, t, J = 2.2 Hz), 6.80 (1H,
dd, J= 8.9, 2.7 Hz), 7.16-7.22 (2H, m), 7.26-7.32 (1H,
m), 7.46 (2H, t, J = 2.2 Hz), 7.47-7.54 (2H, m), 7.66
(1H, t, J = 7.9 Hz), 7.74-7.80 (1H, m), 7.84-7.88 (1H,
m), 8.05 (1H, t, J = 1.8 Hz), 8.09 (1H, d, J = 8.9 Hz),
8.39 (1H, d, J = 2.7 Hz), 12.52 (1H, s).
[0809]
Example 525

1.7 mL of trifluoroacetic acid was added to
0.17 g of tert-butyl 4-phenethyl-2-(6-(piperidin-1-
yl)pyridine-3-carboxamido)benzoate and stirred at room
temperature for 3 hours. The solvent was evaporated
under reduced pressure, and hexane and diisopropyl
ether were added to the obtained residue and a solid
substance was separated by filtration. Ethyl acetate
and water were added to the obtained solid substance

419
and pH was adjusted to pH 6.8 with a saturated sodium
hydrogen carbonate aqueous solution. A solid substance
was separated by filtration to obtain 65 mg of 4-
phenethyl-2-(6-(piperidin-1-yl)pyridine-3-
carboxamido)benzoic acid as white solid.
1H-NMR (DMSO-d6) 5: 1.51-1.68 (6H, m) , 2.88-2.97 (4H, m) ,
3.62-3.72 (4H, m), 6.94 (1H, d, J = 9.3 Hz), 7.01 (1H,
d, J = 8.1 Hz), 7.16-7.20 (1H, m), 7.25-7.30 (4H, m) ,
7.94 (1H, d, J = 8.0 Hz), 7.94-8.00 (1H, m), 8.65 (1H,
s), 8.69 (1H, d, J = 2.4 Hz), 12.30-12.50 (1H, broad).
[0810]
Example 526

29 mg of 3,5-difluorophenol, 79 mg of
tripotassium phosphate, 4.7 mg of 2-(di-tert-
butylphosphino)-2',4',6'-triisopropylbiphenyl and 6.8
mg of tris(dibenzylideneacetone)dipalladium(O) were
added to 1.4 mL of toluene solution containing 70 mg of
tert-butyl 2-(benzamido)-4-bromobenzoate at room
temperature, and the resulting mixture was heated to
reflux under nitrogen atmosphere for 3 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 10% citric acid aqueous solution were added
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride

420
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =10:1] to obtain 71 mg
of tert-butyl 2-(benzamido)-4-(3,5-
difluorophenoxy)benzoate as colorless oil.
1H-NMR (CDC13) 8: 1.64 (9H, s) , 6.56-6.63 (3H, m) , 6.73
(1H, dd, J = 8.8, 2.4 Hz), 7.50-7.60 (3H, m), 8.01-8.07
(3H, m), 8.70 (1H, d, J = 2.4 Hz), 12.34 (1H, s).
[0811]
Examples 527 to 533
The compounds shown in Table 52 were obtained
in the same manner as in Example 526.
[0812]
[Table 52]

[0813]
tert-Butyl 2-(benzamido)-4-(2,3-
dimethylphenoxy)benzoate

1H-NMR (CDCI3) 8: 1.61 (9H, s), 2.12 (3H, s), 2.33 (3H,
s), 6.50 (1H, dd, J = 8.9, 2.5 Hz), 6.89 (1H, d, J =
7.8 Hz), 7.04 (1H, d, J = 7.6 Hz), 7.10-7.15 (1H, m) ,
7.48-7.58 (3H, m), 7.94 (1H, d, J = 8.9 Hz), 8.00-8.05
(2H, m), 8.53 (1H, d, J = 2.5 Hz), 12.31 (1H, s).
[0814]
tert-Butyl 2-(benzamido)-4-(3-fluoro-4-
methylphenoxy)benzoate
1H-NMR (CDCI3) 8: 1.62 (9H, s) , 2.26 (3H, d, J = 1.7 Hz),
6.67 (1H, dd, J = 8.9, 2.5 Hz), 6.75-6.83 (2H, m), 7.18
(1H, t, J = 8.5 Hz), 7.48-7.59 (3H, m), 7.99 (1H, d, J
= 8.9 Hz), 7.99-8.05 (2H, m), 8.61 (1H, d, J = 2.5 Hz),
12.32 (1H, s) .
[0815]
tert-Butyl 2-(benzamido)-4-(3-
(trifluoromethoxy)phenoxy)benzoate
1H-NMR (CDCI3) 8: 1.63 (9H, s), 6.69 (1H, dd, J = 8.9,
2.7 Hz), 6.94-6.98 (1H, m), 7.00-7.06 (2H, m), 7.39 (1H,
t, J = 8.3 Hz), 7.49-7.60 (3H, m), 8.00-8.06 (3H, m),
8.67 (1H, d, J = 2.7 Hz), 12.32 (1H, s).
[0816]
tert-Butyl 2-(benzamido)-4-(benzo[1,3]dioxol-5-
yloxy)benzoate
1H-NMR (CDCI3) 8: 1.61 (9H, s) , 6.00 (2H, s) , 6.58 (1H,
dd, J = 8.3, 2.4 Hz), 6.61-6.66 (2H, m), 6.80 (1H, d, J
= 8.3 Hz), 7.48-7.58 (3H, m), 7.97 (1H, d, J = 9.0 Hz),
8.00-8.05 (2H, m), 8.56 (1H, d, J = 2.7 Hz), 12.31 (1H,
s).

422
[0817]
tert-Butyl 2-(benzamido)-4-(2,3-
dihydrobenzo[1,4]dioxin-6-yloxy)benzoate
1H-NMR (CDC13) 8: 1.61 (9H, s), 4.27 (4H, s), 6.58-6.67
(3H, m), 6.87 (1H, d, J = 8.8 Hz), 7.48-7.58 (3H, m) ,
7.96 (1H, d, J = 9.0 Hz), 8.00-8.05 (2H, m), 8.57 (1H,
d, J = 2.4 Hz), 12.30 (1H, s).
[0818]
tert-Butyl 2-(benzamido)-4-(benzofuran-5-yloxy)benzoate
1H-NMR (CDCI3) 8: 1.61 (9H, s) , 6.64 (1H, dd, J = 9.0,
2.7 Hz), 6.75 (1H, dd, J = 2.2, 1.0 Hz), 7.07 (1H, dd,
J = 8.8, 2.4 Hz), 7.33 (1H, d, J = 2.4 Hz), 7.47-7.57
(4H, m), 7.66 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 9.0
Hz), 7.98-8.04 (2H, m), 8.58 (1H, d, J = 2.7 Hz), 12.31
(1H, s).
[0819]
tert-Butyl 2-(benzamido)-4-(benzothiophen-5-
yloxy)benzoate
1H-NMR (CDCI3) 8: 1.62 (9H, s) , 6.67 (1H, dd, J = 8.9,
2.5 Hz), 7.15 (1H, dd, J = 8.9, 2.1 Hz), 7.27-7.30 (1H,
m), 7.48-7.58 (5H, m), 7.88 (1H, d, J = 8.5 Hz), 7.98
(1H, d, J = 8.8 Hz), 7.99-8.04 (2H, m), 8.63 (1H, d, J
= 2.5 Hz), 12.32 (1H, s).
[0820]
Example 534


423
6.0 mg of palladium acetate was added to 5 mL
of toluene suspension containing 0.50 g tert-butyl 2-
(benzamido)-4-bromobenzoate, 0.18 mL of 3-methoxyphenol,
17 mg of 2-(di-tert-butylphosphino)-2',4',6'-
triisopropylbiphenyl and 0.57 g of tripotassium
phosphate at room temperature, and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 5 hours. After the reaction mixture was cooled to
room temperature, ethyl acetate and 10% citric acid
aqueous solution were added and insoluble were removed
by filtration. The organic layer was separated and
dried over anhydrous magnesium sulfate after washed
with 10% citric acid aqueous solution and a saturated
sodium chloride aqueous solution sequentially, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 6:1]
to obtain 0.32 g of tert-butyl 2-(benzamido)-4-(3-
methoxyphenoxy)benzoate as white solid.
1H-NMR (CDC13) 5: 1.62 (9H, s) , 3.80 (3H, s), 6.64-6.76
(4H, m), 7.28 (1H, t, J = 8.0 Hz), 7.48-7.59 (3H, m) ,
7.98 (1H, d, J = 8.8 Hz), 8.01-8.06 (2H, m), 8.63 (1H,
d, J = 2.7 Hz) , 12.30 (1H, s) .
[0821]
Example 535


The following compound was obtained in the
same manner as in Example 534.
tert-Butyl 2-(benzamido)-4-(4-methoxyphenoxy)benzoate
1H-NMR (CDC13) 5: 1.61 (9H, s) , 3.82 (3H, s), 6.62 (1H,
dd, J= 9.0, 2.7 Hz), 6.90-6.96 (2H, m) , 7.02-7.08 (2H,
m) , 7.48-7.58 (3H, m), 7.96 (1H, d, J = 9.0 Hz), 7.99-
8.06 (2H, m), 8.54 (1H, d, J = 2.7 Hz), 12.31 (1H, s).
[0822]
Example 536

31 mg of 4-nitrophenol was added to 1.0 mL of
toluene suspension containing of 8.9 mg of 60% sodium
hydride at room temperature, and the resulting mixture
was heated to reflux under nitrogen atmosphere for 15
minutes. After the reaction mixture was cooled to room
temperature, 0.5 mL of toluene solution containing 3.8
mg of 2-(di-tert-butylphosphino)-2',41,61-
triisopropylbiphenyl, 1.3 mg of palladium acetate and
56 mg of tert-butyl 2-(benzamido)-4-bromobenzoate were
added and the resulting mixture was heated to reflux
under nitrogen atmosphere for 3 hours. After the
reaction mixture was cooled to room temperature, 1.3 mg

425
of tri-tert-butylphosphine tetrafluoroborate and 4.1 mg
of tris(dibenzylideneacetone)dipalladium(O) were added
and the resulting mixture was heated to reflux under
nitrogen atmosphere for 4 hours. After the reaction
mixture was cooled to room temperature, 10% citric acid
aqueous solution and ethyl acetate were added and
insoluble were removed by filtration. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =10:1] to obtain 18 mg
of tert-butyl 2-(benzamido)-4-(4-nitrophenoxy)benzoate
as white solid.
1H-NMR (CDC13) 6: 1.65 (9H, s) , 6.79 (1H, dd, J= 8.8,
2.4 Hz), 7.12-7.17 (2H, m) , 7.50-7.61 (3H, m), 8.01-
8.06 (2H, m), 8.09 (1H, d, J = 8.8 Hz), 8.23-8.29 (2H,
m), 8.74 (1H, d, J = 2.4 Hz), 12.36 (1H, s).
[0823]
Example 537

26 mg of 5-hydroxy-l-methyl-lH-indole, 64 mg
of tripotassium phosphate, 3.8 mg of 2-(di-tert-
butylphosphino)-2',4',6'-triisopropylbiphenyl and 5.5

426
mg of tris(dibenzylideneacetone)dipalladium(O) were
added to 1.0 mL of toluene solution containing 50 mg of
methyl 2-(benzamido)-4-bromobenzoate at room
temperature, and the resulting mixture was heated to
reflux under nitrogen atmosphere for 2 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 10% citric acid aqueous solution were added
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate = 5:1] to obtain 53 mg of
methyl 2-(benzamido)-4-(l-methyl-lH-indol-5-
yloxy)benzoate as pale yellow solid.
1H-NMR (CDC13) 8: 3.83 (3H, s), 3.93 (3H, s) , 6.47 (1H,
dd, J = 3.1, 0.9 Hz), 6.63 (1H, dd, J = 9.0, 2.6 Hz),
7.02 (1H, dd, J = 8.8, 2.2 Hz), 7.10 (1H, d, J = 2.9
Hz), 7.32-7.38 (2H, m) , 7.47-7.57 (3H, m) , 7.97-8.03
(3H, m), 8.58 (1H, d, J = 2.6 Hz), 12.14 (1H, s).
[0824]
Example 538


427
The following compound was obtained in the
same manner as in Example 537.
Methyl 2-(benzamido)-4-(3-chlorophenoxy)benzoate
1H-NMR (CDC13) 5: 3.96 (3H, s) , 6.70 (1H, dd, J = 9.0,
2.5 Hz), 7.01 (1H, ddd, J = 8.1, 2.1, 0.9 Hz), 7.10 (1H,
t, J = 2.1 Hz), 7.17 (1H, ddd, J = 8.1, 2.1, 0.9 Hz),
7.33 (1H, t, J = 8.1 Hz), 7.48-7.59 (3H, m) , 8.00-8.05
(2H, m), 8.07 (1H, d, J = 9.0 Hz), 8.65 (1H, d, J = 2.5
Hz), 12.17 (1H, s).
[0825]
Example 539

5.0 mL of trifluoroacetic acid solution
containing 69 mg of tert-butyl 2-(benzamido)-4-(3,5-
difluorophenoxy)benzoate was stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 41 mg of 2-
(benzamido)-4-(3,5-difluorophenoxy)benzoic acid as
white solid.
1H-NMR (DMSO-de) 5: 6.90 (1H, dd, J = 8.8, 2.4 Hz) ,
6.96-7.04 (2H, m), 7.17 (1H, tt, J = 9.4, 2.3 Hz),
7.56-7.69 (3H, m) , 7.91-7.97 (2H, m), 8.12 (1H, d, J =
8.8 Hz), 8.48 (1H, d, J = 2.7 Hz), 12.42 (1H, s).

428
[0826]
Examples 540 to 549
The compounds shown in Table 53 were obtained
in the same manner as in Example 539.
[0827]
[Table 53]

[0828]
2-(Benzamido)-4-(4-nitrophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.98 (1H, dd, J = 8.7, 2.5 Hz),
7.33-7.38 (2H, m), 7.57-7.69 (3H, m), 7.91-7.97 (2H, m),
8.17 (1H, d, J = 8.7 Hz), 8.30-8.36 (2H, m), 8.54 (1H,
d, J = 2.5 Hz), 12.46 (1H, s).
[0829]
2-(Benzamido)-4-(2,3-dimethylphenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 2.07 (3H, s) , 2.31 (3H, s) , 6.63 (1H,
dd, J = 8.9, 2.7 Hz), 6.94 (1H, d, J = 7.7 Hz), 7.13
(1H, d, J = 7.5 Hz), 7.17-7.22 (1H, m) , 7.55-7.68 (3H,
m), 7.90-7.94 (2H, m), 8.04 (1H, d, J = 8.9 Hz), 8.33

429
(1H, d, J = 2.7 Hz), 12.41 (1H, s), 13.50-13.70 (1H,
broad).
[0830]
2-(Benzamido)-4-(3-fluoro-4-methylphenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 2.26 (3H, d, J = 1.7 Hz), 6.79 (1H,
dd, J = 8.9, 2.5 Hz), 6.94 (1H, dd, J = 8.3, 2.2 Hz),
7.07 (1H, dd, J = 10.6, 2.3 Hz), 7.35-7.41 (1H, m) ,
7.56-7.68 (3H, m) , 7.90-7.95 (2H, m), 8.08 (1H, d, J =
8.9 Hz), 8.42 (1H, d, J = 2.5 Hz), 12.42 (1H, s) .
[0831]
2-(Benzamido)-4-(3-methoxyphenoxy)benzoic acid
1H-NMR (DMSO-de) 5: 3.78 (3H, s) , 6.70-6.88 (4H, m) ,
7.38 (1H, t, J = 8.2 Hz), 7.55-7.68 (3H, m) , 7.91-7.95
(2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.4
Hz), 12.41 (1H, s).
[0832]
2-(Benzamido)-4-(4-methoxyphenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 3.79 (3H, s) , 6.71 (1H, dd, J = 8.9,
2.7 Hz), 7.01-7.06 (2H, m), 7.11-7.17 (2H, m), 7.55-
7.68 (3H, m), 7.89-7.95 (2H, m), 8.05 (1H, d, J = 8.9
Hz), 8.36 (1H, d, J = 2.7 Hz), 12.41 (1H, s).
[0833]
2-(Benzamido)-4-(3-(trifluoromethoxy)phenoxy)benzoic
acid
1H-NMR (DMSO-de) 8: 6.85 (1H, dd, J = 8.8, 2.6 Hz),
7.20-7.31 (3H, m) , 7.56-7.69 (4H, m), 7.90-7.96 (2H, m),
8.11 (1H, d, J = 8.8 Hz), 8.46 (1H, d, J = 2.6 Hz),
12.43 (1H, s).

430
[0834]
2-(Benzamido)-4-(benzo[1,3]dioxol-5-yloxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.10 (2H, s) , 6.65 (1H, dd, J = 8.3,
2.3 Hz), 6.73 (1H, dd, J = 8.8, 2.7 Hz), 6.87 (1H, d, J
= 2.3 Hz), 6.99 (1H, d, J = 8.3 Hz), 7.56-7.68 (3H, m),
7.90-7.96 (2H, m), 8.05 (1H, d, J = 8.8 Hz), 8.38 (1H,
d, J = 2.7 Hz), 12.42 (1H, s), 13.55-13.75 (1H, broad).
[0835]
2-(Benzamido)-4-(2,3-dihydrobenzo[1, 4]dioxin-6-
yloxy)benzoic acid
1H-NMR (DMSO-d6) 8: 4.25-4.31 (4H, m) , 6.65 (1H, dd, J =
8.7, 2.8 Hz), 6.69-6.74 (2H, m), 6.95 (1H, d, J = 8.5
Hz), 7.56-7.68 (3H, m), 7.90-7.96 (2H, m), 8.05 (1H, d,
J = 8.8 Hz), 8.38 (1H, d, J = 2.7 Hz), 12.42 (1H, s) .
[0836]
2-(Benzamido)-4-(benzofuran-5-yloxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.76 (1H, dd, J = 8.9, 2.5 Hz), 7.00
(1H, dd, J = 2.2, 1.0 Hz), 7.15 (1H, dd, J = 8.9, 2.5
Hz), 7.49 (1H, d, J = 2.5 Hz), 7.54-7.67 (3H, m), 7.71
(1H, d, J = 8.9 Hz), 7.88-7.93 (2H, m), 8.06 (1H, d, J
= 8.9 Hz), 8.09 (1H, d, J = 2.2 Hz), 8.39 (1H, d, J =
2.5 Hz), 12.42 (1H, s), 13.50-13.75 (1H, broad).
[0837]
2-(Benzamido)-4-(benzothiophen-5-yloxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.9, 2.7 Hz), 7.23
(1H, dd, J = 8.7, 2.3 Hz), 7.47 (1H, dd, J = 5.5, 0.6
Hz), 7.54-7.67 (3H, m), 7.70 (1H, d, J = 2.3 Hz), 7.88
(1H, d, J = 5.5 Hz), 7.88-7.93 (2H, m), 8.08 (1H, d, J

431
= 8.8 Hz), 8.11 (1H, d, J = 8.5 Hz), 8.42 (1H, d, J =
2.7 Hz), 12.42 (1H, s).
[0838]
Example 550

0.094 mL of 2.0 mol/L aqueous sodium hydroxide
was added to a mixed solution of 1.5 mL of dioxane and
1.5 mL of methanol containing 50 mg of methyl 2-
(benzamido)-4-(l-methyl-lH-indol-5-yloxy)benzoate at
room temperature, stirred at 50°C for 1 hour, and 0.031
mL of 2.0 mol/L aqueous sodium hydroxide was added at
the same temperature and then stirred at 50°C for 30
minutes. After the reaction mixture was cooled to room
temperature, water was added and pH was adjusted to pH
3.5 with 1.0 mol/L hydrochloric acid and ethyl acetate
was added. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with
water and a saturated sodium chloride aqueous solution
sequentially, and the solvent was evaporated under
reduced pressure. Hexane was added to the obtained
residue and a solid substance was separated by
filtration to obtain 37 mg of 2-(benzamido)-4-(1-
methyl-lH-indol-5-yloxy)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 3.84 (3H, s), 6.45 (1H, d, J = 2.9
Hz), 6.71 (1H, dd, J = 8.8, 2.3 Hz), 6.98 (1H, dd, J =
8.8, 2.2 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.42 (1H, d, J

432
= 2.9 Hz), 7.51-7.67 (4H, m), 7.87-7.92 (2H, m), 8.03
(1H, d, J = 8.8 Hz), 8.36 (1H, d, J = 2.3 Hz), 12.43
(1H, s), 13.45-13.70 (1H, broad).
[0839]
Example 551

0.16 mL of 2.0 mol/L aqueous sodium hydroxide
was added to a mixed solution of 1.0 mL of methanol and
1.0 mL of tetrahydrofuran containing 0.10 g of methyl
2-(benzamido)-4-(3-chlorophenoxy)benzoate while ice-
cooled and stirred at room temperature for 5 hours. The
reaction mixture was added to water and 1.0 mol/L
hydrochloric acid while ice-cooled, and a solid
substance was separated by filtration to obtain 92 mg
of 2-(benzamido)-4-(3-chlorophenoxy)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 6.83 (1H, dd, J = 8.8, 2.4 Hz),
7.15-7.18 (1H, m), 7.29-7.32 (1H, m) , 7.33-7.37 (1H, m) ,
7.51 (1H, t, J = 8.2 Hz), 7.57-7.68 (3H, m), 7.91-7.96
(2H, m), 8.10 (1H, d, J = 8.8 Hz), 8.44 (1H, d, J = 2.4
Hz), 12.42 (1H, s), 13.59-13.92 (1H, broad).
[0840]
Example 552


433
0.22 g of aluminum chloride was added to 1.0
mL of toluene solution containing 0.10 g of 2-
(benzamido)-4-(3-methoxyphenoxy)benzoic acid at room
temperature and stirred at 80°C for 8 hours. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 1.0 mol/L hydrochloric acid were added. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with 1.0 mol/L
hydrochloric acid and a saturated sodium chloride
aqueous solution sequentially, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[Flash Tube 2008 manufactured by Trikonex Company,
eluent; hexane: ethyl acetate: acetic acid = 15:10:1]
to obtain 54 mg of 2-(benzamido)-4-(3-
hydroxyphenoxy)benzoic acid as white solid.
1H-NMR (DMSO-d6) 5: 6.52 (1H, t, J = 2.2 Hz), 6.55-6.60
(1H, m), 6.64-6.70 (1H, m), 6.78 (1H, dd, J= 8.9, 2.5
Hz), 7.26 (1H, t, J = 8.0 Hz), 7.54-7.71 (3H, m), 7.89-
7.99 (2H, m), 8.07 (1H, d, J = 8.9 Hz), 8.42 (1H, d, J
= 2.5 Hz), 9.77 (1H, s), 12.43 (1H, s).
The following compound was obtained in the
same manner as in Example 552.
[0841]
Example 553


434
2-(Benzamido)-4-(4-hydroxyphenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 6.69 (1H, dd, J = 8.8, 2.7 Hz),
6.82-6.88 (2H, m) , 6.97-7.04 (2H, m) , 7.54-7.68 (3H, m) ,
7.90-7.95 (2H, m), 8.03 (1H, d, J = 8.8 Hz), 8.34 (1H,
d, J = 2.7 Hz), 9.51 (1H, s), 12.44 (1H, s).
[0842]
Example 554

0.023 mL of p-cresol, 79 mg of tripotassium
phosphate, 2.4 mg of 2-(di-tert-butylphosphino)-
2',4',6'-triisopropylbiphenyl and 0.8 mg of palladium
acetate were added to 1.4 mL of toluene solution
containing 70 mg of tert-butyl 2-(benzamido)-4-
bromobenzoate at room temperature, and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 1 hour. After the reaction mixture was cooled to
room temperature, 4.7 mg of 2-(di-tert-butylphosphino)-
2',4',6'-triisopropylbiphenyl and 1.7 mg of palladium
acetate were added and the resulting mixture was heated
to reflux under nitrogen atmosphere for 6 hours. After
the reaction mixture was cooled to room temperature,
ethyl acetate and 10% citric acid aqueous solution were
added. The organic layer was separated and dried over
anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure. The

435
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 2-(benzamido)-4-(4-
methylphenoxy)benzoate.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(4-
methylphenoxy)benzoate and stirred at room temperature
for 3 hours. The solvent was evaporated under reduced
pressure and methanol was added to the obtained residue
and a solid substance was separated by filtration to
obtain 6.2 mg of 2-(benzamido)-4-(4-
methylphenoxy)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 2.35 (3H, s) , 6.74 (1H, dd, J= 8.8,
2.6 Hz), 7.05-7.10 (2H, m) , 7.26-7.32 (2H, m), 7.56-
7.68 (3H, m), 7.90-7.95 (2H, m), 8.05 (1H, d, J = 8.8
Hz), 8.39 (1H, d, J = 2.6 Hz), 12.43 (1H, s).
[0843]
Examples 555, 556
The compounds shown in Table 54 were obtained
in the same manner as in Example 554.
[0844]
[Table 54]


436
[0845]
2-(Benzamido)-4-(2-chlorophenoxy)benzoic acid
1H-NMR (DMSO-de) 5: 6.73 (1H, dd, J = 8.8, 2.5 Hz),
7.33-7.42 (2H, m) , 7.45-7.53 (1H, m) , 7.54-7.72 (4H, m) ,
7.87-7.96 (2H, m) , 8.08 (1H, d, J = 8.8 Hz), 8.36 (1H,
d, J = 2.5 Hz), 12.42 (1H, s), 13.59-13.84 (1H, broad).
[0846]
2-(Benzamido)-4-(4-chlorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 5: 6.81 (1H, dd, J = 8.8, 2.4 Hz),
7.18-7.26 (2H, m) , 7.50-7.69 (5H, m) , 7.88-7.97 (2H, m) ,
8.09 (1H, d, J = 8.8 Hz), 8.42 (1H, d, J = 2.4 Hz),
12.41 (1H, s), 13.60-13.85 (1H, broad).
[0847]
Example 557

0.018 mL of 2,4-difluorophenol was added to 1
mL of toluene suspension containing 10 mg of 60% sodium
hydride at room temperature, and the resulting mixture
was heated to reflux under nitrogen atmosphere for 15
minutes. After the reaction mixture was cooled to room
temperature, 0.5 mL of toluene solution containing 4.7
mg of 2-(di-tert-butylphosphino)-2',4',6'-
triisopropylbiphenyl, 1.7 mg of palladium acetate and
70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate was
added and the resulting mixture was heated to reflux
under nitrogen atmosphere for 4 hours. After the

437
reaction mixture was cooled to room temperature, 4.5 mg
of 60% sodium hydride, 4.7 mg of 2-(di-tert-
butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7
mg of palladium acetate were added and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 2 hours. After the reaction mixture was cooled to
room temperature, 0.018 mL of 2,4-difluorophenol, 7.4
mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-
butylphosphino)-2',4',6'-triisopropylbiphenyl and 1.7
mg of palladium acetate were added and the resulting
mixture was heated to reflux under nitrogen atmosphere
for 2 hours. After the reaction mixture was cooled to
room temperature, 1.6 mg of tri-tert-butylphosphine
tetrafluoroborate and 5.1 mg of
tris(dibenzylideneacetone)dipalladium(O) were added,
and the resulting mixture was heated to reflux under
nitrogen atmosphere for 1 hour and 30 minutes. 10%
citric acid aqueous solution and ethyl acetate were
added after the reaction mixture was cooled to room
temperature. The organic layer was separated and dried
over anhydrous magnesium sulfate after washed with a
saturated sodium chloride aqueous solution, and the
solvent was evaporated under reduced pressure. The
obtained residue was purified with silica gel column
chromatography [Flash Tube 2008 manufactured by
Trikonex Company, eluent; hexane: ethyl acetate = 4:1]
to obtain tert-butyl 2-(benzamido)-4-(2,4-
difluorophenoxy)benzoate.

438
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(2,4-
difluorophenoxy)benzoate and stirred at room
temperature for 3 hours. The solvent was evaporated
under reduced pressure and diisopropyl ether was added
to the obtained residue and a solid substance was
separated by filtration to obtain 3.8 mg of 2-
(benzamido)-4-(2,4-difluorophenoxy)benzoic acid as pale
yellow solid.
1H-NMR (DMSO-d6) 8: 6.79 (1H, dd, J = 8.8, 2.7 Hz) ,
7.20-7.28 (1H, m), 7.46-7.52 (1H, m) , 7.54-7.68 (4H, m),
7.90-7.95 (2H, m), 8.07 (1H, d, J = 8.8 Hz), 8.38 (1H,
d, J = 2.7 Hz), 12.44 (1H, s) .
[0848]
Example 558

52 mg of tert-butyl 5-hydroxy-lH-indole-l-
carboxylate, 79 mg of tripotassium phosphate, 4.7 mg of
2-(di-tert-butylphosphino)-2',4',6'-
triisopropylbiphenyl and 6.8 mg of
tris(dibenzylideneacetone)dipalladium(O) were added to
1.4 mL of toluene solution containing 70 mg of tert-
butyl 2-(benzamido)-4-bromobenzoate at room temperature,
and the resulting mixture was heated to reflux under
nitrogen atmosphere for 2 hours and 30 minutes. After
the reaction mixture was cooled to room temperature,

439
ethyl acetate and 10% citric acid aqueous solution were
added and insoluble were removed by filtration. The
organic layer was separated and dried over anhydrous
magnesium sulfate after washed with a saturated sodium
chloride aqueous solution, and the solvent was
evaporated under reduced pressure. The obtained residue
was purified with silica gel column chromatography
[PSQ100B (spherical) manufactured by Fuji Silysia
Chemical Ltd., eluent; hexane: ethyl acetate = 10:1] to
obtain tert-butyl 5-(3-(benzamido)-4-(tert-
butoxycarbonyl)phenoxy)-lH-indole-1-carboxylate.
1.0 mL of trifluoroacetic acid was added to
4.0 mL of methylene chloride solution containing the
obtained tert-butyl 5-(3-(benzamido)-4-(tert-
butoxycarbonyl)phenoxy)-lH-indole-1-carboxylate while
ice-cooled and stirred at the same temperature for 2
hours and 30 minutes. After the reaction mixture was
warmed to room temperature, ethyl acetate and a
saturated sodium hydrogen carbonate aqueous solution
were added. The aqueous layer was separated and washed
with ethyl acetate after adjusted to pH 6.5 with 6.0
mol/L hydrochloric acid and allowed to stand still for
17 hours. A solid substance was separated by filtration
to obtain 10 mg of 2-(benzamido)-4-(lH-indol-5-
yloxy)benzoic acid as white solid.
1H-NMR (DMSO-d6) 8: 6.41-6.43 (1H, m) , 6.54 (1H, dd, J =
8.6, 2.7 Hz), 6.87 (1H, dd, J = 8.6, 2.3 Hz), 7.25 (1H,
d, J = 2.2 Hz), 7.39-7.41 (1H, m), 7.43 (1H, d, J = 8.5

440
Hz), 7.46-7.59 (3H, m) , 7.96-8.04 (3H, m), 8.30 (1H, d,
J = 2.4 Hz), 11.19 (1H, s).
[0849]
Example 559

31 mg of 3-nitrophenol, 79 mg of tripotassium
phosphate, 4.7 mg of 2-(di-tert-butylphosphino)-
2',4',6'-triisopropylbiphenyl and 6.8 mg of
tris(dibenzylideneacetone)dipalladium(O) were added to
1.4 mL of toluene solution containing 70 mg of tert-
butyl 2-(benzamido)-4-bromobenzoate at room temperature,
and the resulting mixture was heated to reflux under
nitrogen atmosphere for 2 hours. After the reaction
mixture was cooled to room temperature, 4.7 mg of 2-
(di-tert-butylphosphino)-2',4',6'-triisopropylbiphenyl
and 6.8 mg of tris(dibenzylideneacetone)dipalladium(O)
were added and the resulting mixture was heated to
reflux under nitrogen atmosphere for 1 hour. After the
reaction mixture was cooled to room temperature, ethyl
acetate and 10% citric acid aqueous solution were added
and insoluble were removed by filtration. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B

441
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =10:1] to obtain tert-
butyl 2-(benzamido)-4-(3-nitrophenoxy)benzoate.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(3-
nitrophenoxy)benzoate and stirred at room temperature
for 3 hours. The solvent was evaporated under reduced
pressure and diisopropyl ether was added to the
obtained residue and a solid substance was separated by
filtration to obtain 34 mg of 2-(benzamido)-4-(3-
nitrophenoxy)benzoic acid as pale yellow solid.
1H-NMR (DMSO-d6) 5: 6.91 (1H, dd, J = 8.8, 2.6 Hz),
7.56-7.71 (4H, m), 7.78 (1H, t, J = 8.2 Hz), 7.90-7.98
(3H, m) , 8.10-8.16 (2H, m), 8.49 (1H, d, J = 2.6 Hz),
12.41 (1H, s).
[0850]
Examples 560 to 570
The compounds shown in Table 55 were obtained
in the same manner as in Example 559.
[0851]
[Table 55]


[0852]
2-(Benzamido)-4-(4-fluorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.76 (1H, dd, J = 8.9, 2.7 Hz),
7.21-7.28 (2H, m) , 7.29-7.37 (2H, m) , 7.55-7.68 (3H, m) ,
7.90-7.95 (2H, m), 8.07 (1H, d, J = 8.9 Hz), 8.39 (1H,
d, J = 2.7 Hz), 12.41 (1H, s).
[0853]
2-(Benzamido)-4-(4-(trifluoromethoxy)phenoxy)benzoic
acid
1H-NMR (DMSO-de) 8: 6.82 (1H, dd, J = 8.9, 2.7 Hz),
7.28-7.34 (2H, m) , 7.46-7.52 (2H, m), 7.56-7.69 (3H, m) ,
7.90-7.96 (2H, m), 8.10 (1H, d, J = 8.9 Hz), 8.44 (1H,
d, J = 2.7 Hz), 12.41 (1H, s).
[0854]
2-(Benzamido)-4-(2-methylphenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 2.16 (3H, s), 6.67 (1H, dd, J = 8.9,
2.7 Hz), 7.08-7.13 (1H, m), 7.21-7.26 (1H, m), 7.29-
7.34 (1H, m), 7.38-7.41 (1H, m), 7.55-7.68 (3H, m),

443
7.89-7.95 (2H, m), 8.05 (1H, d, J = 8.9 Hz), 8.32 (1H,
d, J = 2.7 Hz), 12.41 (1H, s).
[0855]
2-(Benzamido)-4-(3-methylphenoxy)benzoic acid
hi-NMR (DMSO-d6) 8: 2.34 (3H, s), 6.76 (1H, dd, J = 9.0,
2.6 Hz), 6.94-7.02 (2H, m), 7.07-7.12 (1H, m), 7.36 (1H,
dd, J = 8.0, 7.7 Hz), 7.56-7.68 (3H, m), 7.90-7.96 (2H,
m), 8.07 (1H, d, J = 9.0 Hz), 8.41 (1H, d, J = 2.6 Hz),
12.41 (1H, s).
[0856]
2-(Benzamido)-4-(2,6-dimethylphenoxy)benzoic acid
1H-NMR (DMSO-d6) 5: 2.10 (6H, s), 6.58 (1H, dd, J= 9.0,
2.5 Hz), 7.14-7.25 (3H, m) , 7.55-7.68 (3H, m), 7.89-
7.95 (2H, m), 8.04 (1H, d, J = 9.0 Hz), 8.25 (1H, d, J
=2.5 Hz), 12.43 (1H, s).
[0857]
2-(Benzamido)-4-(3-fluorophenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 6.84 (1H, dd, J = 8.8, 2.4 Hz),
7.00-7.05 (1H, m) , 7.08-7.16 (2H, m), 7.48-7.68 (4H, m) ,
7.90-7.96 (2H, m), 8.10 (1H, d, J = 8.8 Hz), 8.45 (1H,
d, J = 2.4 Hz), 12.41 (1H, s).
[0858]
2-(Benzamido)-4-(2-fluorophenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 6.79 (1H, dd, J = 8.8, 2.6 Hz),
7.29-7.51 (4H, m), 7.55-7.69 (3H, m) , 7.89-7.95 (2H, m) ,
8.08 (1H, d, J = 8.8 Hz), 8.39 (1H, d, J = 2.6 Hz),
12.41 (1H, s).
[0859]
2-(Benzamido)-4-(2,6-difluorophenoxy)benzoic acid

444
1H-NMR (DMSO-de) 8: 6.85 (1H, dd, J = 9.0, 2.7 Hz),
7.34-7.51 (3H, m) , 7.55-7.68 (3H, m) , 7.89-7.95 (2H, m) ,
8.09 (1H, d, J = 9.0 Hz), 8.42 (1H, d, J = 2.7 Hz),
12.43 (1H, s).
[0860]
2-(Benzamido)-4-(3,4-dimethylphenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 2.24 (6H, s), 6.72 (1H, dd, J= 8.9,
2.7 Hz), 6.89 (1H, dd, J = 8.1, 2.5 Hz), 6.98 (1H, d, J
= 2.5 Hz), 7.23 (1H, d, J = 8.1 Hz), 7.56-7.68 (3H, m) ,
7.90-7.95 (2H, m), 8.05 (1H, d, J = 8.9 Hz), 8.39 (1H,
d, J = 2.7 Hz), 12.40 (1H, s).
[0861]
2-(Benzamido)-4-(3-(trifluoromethyl)phenoxy)benzoic
acid
1H-NMR (DMSO-dg) 8: 6.85 (1H, dd, J = 9.0, 2.7 Hz),
7.48-7.52 (1H, m), 7.54-7.68 (5H, m), 7.72 (1H, t, J =
7.9 Hz), 7.90-7.95 (2H, m), 8.11 (1H, d, J = 9.0 Hz),
8.46 (1H, d, J = 2.7 Hz), 12.41 (1H, s) .
[0862]
2-(Benzamido)-4-(4-(trifluoromethyl)phenoxy)benzoic
acid
1H-NMR (DMSO-de) 8: 6.90 (1H, dd, J = 8.8, 2.6 Hz),
7.33-7.39 (2H, m) , 7.56-7.69 (3H, m), 7.81-7.88 (2H, m) ,
7.91-7.96 (2H, m), 8.13 (1H, d, J = 8.8 Hz), 8.50 (1H,
d, J = 2.6 Hz), 12.41 (1H, s), 13.70-13.95 (1H, broad).
[0863]
Example 571


91 mg of 2,4-dichlorophenol was added to 2.1
mL of toluene suspension containing 22 mg of 60% sodium
hydride at room temperature, and the resulting mixture
was heated to reflux under nitrogen atmosphere for 15
minutes. After the reaction mixture was cooled to room
temperature, 70 mg of tert-butyl 2-(benzamido)-4-
bromobenzoate, 4.7 mg of 2-(di-tert-butylphosphino)-
2',4',6'-triisopropylbiphenyl and 6.8 mg of
tris(dibenzylideneacetone)dipalladium(O) were added and
the resulting mixture was heated to reflux under
nitrogen atmosphere for 6 hours. After the reaction
mixture was cooled to room temperature, 61 mg of 2,4-
dichlorophenol, 15 mg of 60% sodium hydride, 4.7 mg of
2-(di-tert-butylphosphino)-2',4',6'-
triisopropylbiphenyl and 6.8 mg of
tris(dibenzylideneacetone)dipalladium(O) were added and
the resulting mixture was heated to reflux under
nitrogen atmosphere for 10 hours. After the reaction
mixture was cooled to room temperature, 10% citric acid
aqueous solution and ethyl acetate were added and
insoluble were removed by filtration. The organic layer
was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under

446
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate =20:1] to obtain tert-
butyl 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoate.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(2, 4-
dichlorophenoxy)benzoate and stirred at room
temperature for 2 hours. The solvent was evaporated
under reduced pressure and the obtained residue was
purified with reversed-phase silica gel column
chromatography [eluent; 80-100% acetonitrile /0.1%
trifluoroacetic acid aqueous solution] to obtain 8.7 mg
of 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoic acid as
white solid.
1H-NMR (DMSO-d6) 8: 6.77 (1H, dd, J = 8.8, 2.7 Hz), 7.41
(1H, d, J = 8.8 Hz), 7.53-7.68 (4H, m), 7.88 (1H, d, J
= 2.4 Hz), 7.90-7.95 (2H, m), 8.08 (1H, d, J = 8.8 Hz),
8.36 (1H, d, J = 2.7 Hz), 12.43 (1H, s).
[0864]
Examples 572 to 583
The compounds shown in Table 56 were obtained
in the same manner as in Example 571.
[0865]
[Table 56]


[0866]
2-(Benzamido)-4-(2,3-difluorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.86 (1H, dd, J = 8.9, 2.7 Hz),
7.20-7.26 (1H, m) , 7.30-7.48 (2H, m), 7.56-7.68 (3H, m) ,
7.90-7.95 (2H, m), 8.10 (1H, d, J = 8.9 Hz), 8.44 (1H,
d, J = 2.7 Hz), 12.41 (1H, s) .
[0867]
2-(Benzamido)-4-(3-chloro-2-fluorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.84 (1H, dd, J = 8.8, 2.7 Hz),
7.32-7.43 (2H, m), 7.53-7.69 (4H, m), 7.90-7.96 (2H, m) ,
8.10 (1H, d, J = 8.8 Hz), 8.43 (1H, d, J = 2.7 Hz),
12.42 (1H, s).
[0868]
2-(Benzamido)-4-(3-chloro-4-fluorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.81 (1H, dd, J = 8.8, 2.7 Hz) ,
7.21-7.28 (1H, m) , 7.52-7.69 (5H, m), 7.90-7.96 (2H, m) ,
8.09 (1H, d, J = 8.8 Hz), 8.42 (1H, d, J = 2.7 Hz),
12.41 (1H, s).

448
[0869]
2-(Benzamido)-4-(3,5-dichlorophenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 6.88 (1H, dd, J = 8.8, 2.6 Hz), 7.32
(2H, d, J = 1.9 Hz), 7.52 (1H, t, J = 1.9 Hz), 7.56-
i 7.69 (3H, m), 7.91-7.97 (2H, m), 8.12 (1H, d, J = 8.8
Hz), 8.46 (1H, d, J = 2.6 Hz), 12.42 (1H, s).
[0870]
2-(Benzamido)-4-(4-fluoro-2-methylphenoxy)benzoic acid
1H-NMR (DMSO-de) 5: 2.15 (3H, s) , 6.67 (1H, dd, J = 8.9,
I 2.5 Hz), 7.11-7.20 (2H, m), 7.27-7.31 (1H, m), 7.55-
7.68 (3H, m), 7.89-7.95 (2H, m), 8.05 (1H, d, J = 8.9
Hz), 8.31 (1H, d, J - 2.5 Hz), 12.43 (1H, s).
[0871]
2-(Benzamido)-4-(3,4-difluorophenoxy)benzoic acid
1H-NMR (DMSO-de) 5: 6.81 (1H, dd, J = 8.8, 2.7 Hz),
7.04-7.11 (1H, m) , 7.42-7.48 (1H, m), 7.52-7.69 (4H, m) ,
7.90-7.96 (2H, m), 8.09 (1H, d, J = 8.8 Hz), 8.42 (1H,
d, J = 2.7 Hz), 12.42 (1H, s) .
[0872]
I 2-(Benzamido)-4-(2,5-difluorophenoxy)benzoic acid
1H-NMR (DMSO-de) 8: 6.84 (1H, dd, J = 8.8, 2.7 Hz),
7.21-7.28 (1H, m) , 7.38-7.44 (1H, m) , 7.51-7.69 (4H, m) ,
7.90-7.96 (2H, m), 8.09 (1H, d, J = 8.8 Hz), 8.43 (1H,
d, J = 2.7 Hz), 12.42 (1H, s).
» [0873]
2-(Benzamido)-4-(5-chloro-2-methylphenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 2.15 (3H, s), 6.72 (1H, dd, J= 8.9,
2.7 Hz), 7.22 (1H, d, J = 2.2 Hz), 7.30 (1H, dd, J =
8.3, 2.2 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.55-7.68 (3H,

449
m), 7.90-7.95 (2H, m), 8.08 (1H, d, J = 8.9 Hz), 8.34
(1H, d, J = 2.7 Hz), 12.42 (1H, s).
[0874]
2-(Benzamido)-4-(3,4-dichlorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.86 (1H, dd, J = 9.0, 2.5 Hz), 7.22
(1H, dd, J= 8.9, 2.7 Hz), 7.54-7.69 (4H, m), 7.74 (1H,
d, J = 8.9 Hz), 7.90-7.96 (2H, m), 8.10 (1H, d, J = 9.0
Hz), 8.45 (1H, d, J = 2.5 Hz), 12.41 (1H, s).
[0875]
2-(Benzamido)-4-(2,3-dichlorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.78 (1H, dd, J = 8.8, 2.6 Hz), 7.36
(1H, dd, J = 8.3, 1.2 Hz), 7.50 (1H, t, J = 8.2 Hz),
7.56-7.69 (4H, m), 7.90-7.96 (2H, m), 8.09 (1H, d, J =
8.8 Hz), 8.38 (1H, d, J = 2.6 Hz), 12.44 (1H, s).
[0876]
2-(Benzamido)-4-(2,5-dichlorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.78 (1H, dd, J = 8.9, 2.7 Hz), 7.46
(1H, dd, J = 8.8, 2.5 Hz), 7.54 (1H, d, J = 2.5 Hz),
7.56-7.69 (3H, m), 7.73 (1H, d, J = 8.8 Hz), 7.90-7.96
(2H, m), 8.09 (1H, d, J = 8.9 Hz), 8.38 (1H, d, J = 2.7
Hz), 12.41 (1H, s).
[0877]
2-(Benzamido)-4-(2,6-dichlorophenoxy)benzoic acid
1H-NMR (DMSO-d6) 8: 6.70 (1H, dd, J = 8.8, 2.7 Hz), 7.46
(1H, t, J = 8.3 Hz), 7.55-7.68 (3H, m), 7.71 (2H, d, J
= 8.3 Hz), 7.89-7.96 (2H, m), 8.08 (1H, d, J = 8.8 Hz),
8.31 (1H, d, J = 2.7 Hz), 12.49 (1H, s).


8 6 mg of 4-phenylpiperidine, 0.22 g of cesium
carbonate, 2.4 mg of
tris(dibenzylideneacetone)dipalladium(O), 1.2 mg of
palladium acetate and 6.3 mg of 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added to 3.0 mL of toluene solution containing
0.10 g of tert-butyl 2-(benzamido)-4-bromobenzoate, and
the resulting mixture was heated to reflux for 2 hours.
After the reaction mixture was cooled to room
temperature, 2.4 mg of
tris(dibenzylideneacetone)dipalladium(O), 1.2 mg of
palladium acetate and 6.3 mg of 2-
dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
were added and the resulting mixture was heated to
reflux for 6 hours. After the reaction mixture was
cooled to room temperature, ethyl acetate and 10%
citric acid aqueous solution were added. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with a saturated sodium chloride
aqueous solution, and the solvent was evaporated under
reduced pressure. The obtained residue was purified
with silica gel column chromatography [PSQ100B

451
(spherical) manufactured by Fuji Silysia Chemical Ltd.,
eluent; hexane: ethyl acetate = 10:1] to obtain tert-
butyl 2-(benzamido)-4-(4-phenylpiperidin-l-yl)benzoate
as pale yellow solid.
5.0 mL of trifluoroacetic acid was added to
the obtained tert-butyl 2-(benzamido)-4-(4-
phenylpiperidin-1-yl)benzoate and stirred at room
temperature for 3 hours. The solvent was evaporated
under reduced pressure, ethyl acetate and water were
added and pH was adjusted to pH 6.5 with a saturated
sodium hydrogen carbonate aqueous solution. The organic
layer was separated and dried over anhydrous magnesium
sulfate after washed with water and a saturated sodium
chloride aqueous solution sequentially, and the solvent
was evaporated under reduced pressure. Diisopropyl
ether was added to the obtained residue and a solid
substance was separated by filtration to obtain 20 mg
of 2-(benzamido)-4-(4-phenylpiperidin-l-yl)benzoic acid
as white solid.
1H-NMR (DMSO-d6) 8: 1.65-1.78 (2H, m) , 1.86-1.95 (2H, m) ,
2.76-2.87 (1H, m), 2.97-3.08 (2H, m), 4.01-4.11 (2H, m),
6.78 (1H, dd, J = 9.1, 2.5 Hz), 7.17-7.23 (1H, m) ,
7.25-7.34 (4H, m) , 7.56-7.68 (3H, m), 7.88 (1H, d, J =
9.1 Hz), 7.94-7.99 (2H, m), 8.47 (1H, d, J = 2.5 Hz),
12.53 (1H, s).
[0879]
Examples 585 to 588
The compounds shown in Table 57 were obtained
in the same manner as in Example 584.


[0881]
2-(Benzamido)-4-(1,2,3,4-tetrahydroisoquinolin-2-
yl)benzoic acid
1H-NMR (DMSO-de) 8: 2.95-3.01 (2H, m) , 3.64-3.70 (2H, m) ,
4.58 (2H, s), 6.77 (1H, dd, J = 9.0, 2.6 Hz), 7.18-7.32
(4H, m), 7.57-7.68 (3H, m), 7.90 (1H, d, J = 9.0 Hz),
7.95-8.00 (2H, m), 8.45 (1H, d, J = 2.6 Hz), 12.53 (1H,
s), 12.97 (1H, s) .
[0882]
2-(Benzamido)-4-(4-benzylpiperidin-l-yl)benzoic acid
1H-NMR (DMSO-d6) 8: 1.17-1.31 (2H, m) , 1.62-1.71 (2H, m) ,
1.74-1.88 (1H, m) , 2.50-2.57 (2H, m), 2.82-2.92 (2H, m) ,
3.86-3.96 (2H, m), 6.69 (1H, dd, J = 9.3, 2.5 Hz),
7.16-7.22 (3H, m) , 7.26-7.32 (2H, m), 7.56-7.67 (3H, m) ,
7.84 (1H, d, J = 9.3 Hz), 7.92-7.98 (2H, m) , 8.39 (1H,
d, J = 2.5 Hz), 12.49 (1H, s), 12.94 (1H, s) .
[0883]
2-(Benzamido)-4-(4-benzoylpiperidin-l-yl)benzoic acid
1H-NMR (DMSO-d6) 8: 1.58-1.72 (2H, m) , 1.86-1.95 (2H, m) ,
3.10-3.21 (2H, m) , 3.73-3.83 (1H, m), 3.93-4.03 (2H, m) ,

453
6.76 (1H, dd, J = 9.1, 2.4 Hz), 7.53-7.70 (6H, m) , 7.87
(1H, d, J = 9.1 Hz), 7.93-7.98 (2H, m) , 8.01-8.06 (2H,
m), 8.43 (1H, d, J = 2.4 Hz), 12.49 (1H, s), 12.90-
13.15 (1H, broad).
[0884]
2-(benzamido)-4-(4-phenyl-l,2,3,6-tetrahydropyridin-l-
yl)benzoic acid
1H-NMR (DMSO-de) 5: 2.64-2.72 (2H, m) , 3.65-3.71 (2H, m) ,
4.02-4.09 (2H, m), 6.32-6.37 (1H, m), 6.78 (1H, dd, J=
9.1, 2.5 Hz), 7.25-7.32 (1H, m) , 7.35-7.41 (2H, m) ,
7.48-7.53 (2H, m), 7.57-7.68 (3H, m), 7.90 (1H, d, J =
9.1 Hz), 7.95-8.00 (2H, m), 8.47 (1H, d, J = 2.5 Hz),
12.53 (1H, s), 12.90-13.15 (1H, broad).
INDUSTRIAL APPLICABILITY
[0885]
The compounds of general formula [1] of the present
invention or the salts thereof have the inhibitory
activity of MMP-13 production and therefore they are
useful as, for example, therapeutic agents for
rheumatoid arthritis, osteoarthritis, cancer and the
other diseases in which MMP-13 is involved.

454
CLAIMS
1. An anthranilic acid derivative represented by
the general formula:
[Formula 1]

wherein, R1 represents a hydrogen atom or a carboxyl
protecting group; R2 represents a phenyl, cycloalkyl or
heterocyclic group which may be optionally substituted;
R3 represents a phenyl, cycloalkyl, cycloalkenyl,
monocyclic heterocyclic or bicyclic heterocyclic group
which may be optionally substituted; X1 represents a
carbonyl group or a sulfonyl group; X2 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted or a bond; provided that when X1
is a sulfonyl group and X4 is a bond, X2 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted; X3 represents an oxygen atom, a
sulfur atom or a bond; and X4 represents a group
represented by the general formula, -X5-X6- or -X6-X5-,
wherein the bond on the left side of each general
formula is linked to R3; and
X5 represents an oxygen atom, a sulfur atom, an imino
group which may be optionally protected, a sulfinyl
group, a sulfonyl group or a bond; and X6 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted or a bond or a salt thereof.

455
2. The anthranilic acid derivative or a salt
thereof according to claim 1 wherein X1 is a carbonyl
group.
3. The anthranilic acid derivative or a salt
thereof according to claim 1 or 2, wherein R1 represents
a hydrogen atom; R2 represents a phenyl or heterocyclic
group which may be optionally substituted with a group
selected from a halogen atom, a cyano group, a nitro
group, a hydroxyl group which may be optionally
protected, an alkyl group which may be optionally
substituted, an alkenyl group which may be optionally
substituted, an alkynyl group which may be optionally
substituted, an alkoxy group which may be optionally
substituted, an aryl group which may be optionally
substituted, a cyclic amino group which may be
optionally substituted, an aralkyl group which may be
optionally substituted and a heterocyclic group which
may be optionally substituted; R3 represents a phenyl,
monocyclic heterocyclic or bicyclic heterocyclic group
which may be optionally substituted with a group
selected from a halogen atom, a hydroxyl group, an
alkyl group which may be optionally substituted and an
alkoxy group which may be optionally substituted; X2
represents an alkylene group, an alkenylene group, an
alkynylene group or a bond; provided that when X1 is a
sulfonyl group and X4 is a bond, X2 represents an
alkylene group, an alkenylene group or an alkynylene
group; X3 represents an oxygen atom or a bond; and X4
represents the general formula -X6-X5-, wherein the bond

456
on the left side of the general formula is linked to R3;
and
X5 represents an oxygen atom, a sulfur atom, an imino
group which may be optionally protected, a sulfinyl
group, a sulfonyl group or a bond; and X6 represents an
alkylene, alkenylene or alkynylene group which may be
optionally substituted or a bond.
4. The anthranilic acid derivative or a salt
thereof according to claims 1 to 3, wherein R3
represents a phenyl group, a nitrogen-containing
bicyclic heterocyclic group represented by a condensed
or bridged ring containing only 1 to 3 nitrogen atom(s)
as the heteroatom of the said ring, an oxygen-
containing bicyclic heterocyclic group represented by a
condensed or bridged ring containing only oxygen
atom(s) as the heteroatom of the said ring or a sulfur-
containing bicyclic heterocyclic group or represented
by a condensed or bridged ring containing only sulfur
atom(s) as the heteroatom of the said ring; and these
groups may be optionally substituted with a group
selected from a halogen atom, a hydroxyl group, an
alkyl group which may be optionally substituted with a
halogen atom and an alkoxy group which may be
optionally substituted with a halogen atom.
5. The anthranilic acid derivative or a salt
thereof according to claims 1 to 4, wherein X4
represents the general formula -X6p-X5q-, wherein the
bond on the left side of the general formula is linked
to R3; and X5q represents an oxygen atom, a sulfur atom

457
or a bond; and X6p represents an alkylene, alkenylene or
alkynylene group which may be optionally substituted.
6. The anthranilic acid derivative or salts
thereof according to claims 1 to 4, wherein X4
represents the general formula -X6r-X5s-, wherein the
bond on the left side of the general formula is linked
to R3; and X5s represents an oxygen atom or a bond; and
X6r represents a bond.
7. A matrix metalloprotease 13 production
inhibitor which comprises the anthranilic acid
derivative or a salt thereof according to claims 1 to 6.
8. A therapeutic agent for rheumatoid arthritis
which comprises the anthranilic acid derivative or a
salt thereof according to claims 1 to 6.

An anthranilic acid derivative represented by
the general formula (X) [wherein R1 represents hydrogen
or a carboxy-protecting group; R2 represents optionally
substituted phenyl, a heterocyclic group, etc.; R3
represents optionally substituted phenyl, a monocyclic
heterocyclic group, etc.; X1 represents carbonyl, etc.;
X2 represents optionally substituted alkylene group, a
bond, etc.; X3 represents oxygen, a bond, etc.; and X4
represents a group represented by the general formula
-X5-X6- or -X6-X5- (wherein X5 means oxygen, a bond,
etc.; and X6 means optionally substituted alkylene, a
bond, etc.)] or a salt of the derivative. The
derivative or salt has the inhibitory activity of MMP-
13 production and is hence useful as a therapeutic
agent for articular rheumatism, osteoarthritis, cancer,
etc.

Documents:


Patent Number 251577
Indian Patent Application Number 1796/KOLNP/2007
PG Journal Number 13/2012
Publication Date 30-Mar-2012
Grant Date 26-Mar-2012
Date of Filing 21-May-2007
Name of Patentee TOYAMA CHEMICAL CO., LTD.
Applicant Address A CORPORATION ORGANIZED UNDER THE LAWS OF JAPAN, OF 2-5, NISHISHINJUKU 3-CHOME, SHINJUKU-KU TOKYO
Inventors:
# Inventor's Name Inventor's Address
1 EIJI HARA C/O TOYAMA CHEMICAL CO., LTD. 4-1, SHIMOOKUI 2-CHOME, TOYAMA-SHI, TOYAMA
2 HITOSHI AKITSU C/O TOYAMA CHEMICAL CO., LTD. 4-1, SHIMOOKUI 2-CHOME, TOYAMA-SHI, TOYAMA
3 YUKIE TADA C/O TOYAMA CHEMICAL CO., LTD. 4-1, SHIMOOKUI 2-CHOME, TOYAMA-SHI, TOYAMA
4 JUNICHI YOKOTANI C/O TOYAMA CHEMICAL CO., LTD. 4-1, SHIMOOKUI 2-CHOME, TOYAMA-SHI, TOYAMA
5 YOICHI TANIGUCHI C/O TOYAMA CHEMICAL CO., LTD. 4-1, SHIMOOKUI 2-CHOME, TOYAMA-SHI, TOYAMA
PCT International Classification Number C07C 233/55
PCT International Application Number PCT/JP2005/022367
PCT International Filing date 2005-12-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2004-353725 2004-12-07 Japan