DESCRIPTION
NEW CCMPOUNDS
TECHNICAL FIELD
The present invention relates to a pyridone derivative
compound and a salt thereof, which are useful for medicaments.
BACKGROUND OP THE INVENTION
Rheumatoid arthritis (RA) is a systemic inflammatory
disease which causes mainly in the arthrosynovia. Today
Methotrexate (MTX) is used generally as disease-modified anti-
rheumatic drugs (DMARD), but the efficacy for inflammatory
responses or arthritis mutilans is not enough. On the other
hand, the biologies, which targeted cytokines (TNF, IL-1, IL-
6), has been revealed recently its efficacy for RA, and it has
been proved the importance of these cytokines in the
manifestation of RA. In particular, the monoclonal TNF
antibody Remicade and soluble TNF receptor fusion protein
Enbrel, which inhibit the TNF function, are worthy of note
because of the unprecedented efficacy not only for
inflammatory response but for arthritis mutilans.
Though the fact above suggests importance of the
treatment for RA in future, these biologies have fundamental
drawbacks related to patient cost, efficacy of production,
limitation of administration to hypodermal or intravenous
injection, and so on. So, the anti-RA drugs in the next
generation are expected to overcome these problems, that is to
be an orally small-molecule drug, which blocks or modulates
selectively the function of these cytokines. In particular
p38a mitogen activated protein kinase (p38a MAPK) belongs to
intracellular phosphorylation kinase participating in
production and/or functional expression of the cytokine (TNF,
IL-1, IL-6), and it is reported that p38a MAPK is activated in
the arthrosynovia of RA patients thereby cytokines are
produced excessively, so that p38cx MAPK has been attracted as
a target of anti-RA drug.
These anti-inflammatory agents or compounds having
cytokine inhibitory activity have been described (W098/22457,
WO00/41698, WO00/43384, WO01/22965, WO02/07772, WO02/58695,
WO03/041644, etc.) but pyridone derivatives having these
activities are only described in WO2006/051826, WO2006/122154,
WO2007/040208, WO2007/053610, WO2007053685, which does not
include the compounds of the present invention, as far as we
know.
DISCLOSURE OF THE INVENTION
The present invention relates to a pyridone derivative
compound and a salt thereof, which are useful as medicaments;
a pharmaceutical composition comprising, as an active
ingredient, said pyridone derivative compound or a
pharmaceutically acceptable salt thereof; a use of said
pyridone derivative compound or a salt thereof as a
medicament; and a method for using said pyridone derivative
compound or a salt thereof for therapeutic purposes, which
comprises administering said pyridone derivative compound or a
salt thereof to a mammal.
The pyridone derivative compound and a salt thereof are
inhibitors of cytokines' production or their transduction, and
through inhibiting the p38a MAPK they possess pharmacological
actions such as analgesic action, anti-inflammatory, anti
arthritis mutilans action, or the like.
They are useful as an analgesic, in particular anti-RA
agent, drug for pain and other conditions associated with
inflammation, drug for Crohn's disease, drug for inflammatory
bowel disease, drug for psoriasis, or the like.
The pyridone derivative compound or a salt thereof of
the present invention is a compound shown by the following
formula (I) (hereinafter also simply referred to as compound
(I)):
wherein
R1 is lower alkyl, cycloalkyl or aromatic hydrocarbon ring,
each of which is optionally substituted with one or
more substituents;
R2 is halogen atom, lower alkyl, halo(lower)alkyl or lower
alkoxy; and
R3 is
(1) a group represented by the formula:

wherein
R4 is lower alkyl, lower alkoxy, cycloalkyl,
aromatic hetero ring, non-aromatic hetero ring or
aromatic hydrocarbon ring, each of which is
optionally substituted with one or more
substituents;
(2) a group represented by the formula:

wherein
R5 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring, aromatic hetero ring or non-aromatic hetero
ring, each of which is optionally substituted
with one or more substituents;
(3) a group represented by the formula:

wherein
R6 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring or non-aromatic hetero ring, each of which
is optionally substituted with one or more
substituents; or
(4) a group selected from halogen atom, carboxy, hydroxy
and lower alkoxy,
or a salt thereof.
BEST MODE FOR CARRYING GOT THE INVENTION
The compound of the present invention can be prepared
by the following processes.

The symbols in the formulas in the above-mentioned
Processes are as defined above.
In the above-mentioned schemes in Processes 1 and 2,
"DMF" means N,N-dimethylformamide, "HATU" means N-
t (dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-
yloxy)methylene]-N-methylmethanaminium hexafluorophosphate,
"iPr2NEt" means N-ethyl-N-isopropyl-2-propanamine, "WSC-HCl"
means N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide
hydrochloride, "HOBt" means 1-hydroxybenzotriazole, "Et3N"
means triethylamine, and "rt" means room temperature.
In the present specification, Process 1 is exemplified
by Example 1, and Process 2 is exemplified by Examples 18, 20
and 25. However, the present invention is not restricted by
these Examples.
In addition to the processes as mentioned above, the
compound (I) and a salt thereof can be prepared, for example,
according to the procedures as illustrated in Examples in the
present specification or in a manner similar thereto.
The starting compounds can be prepared, for example,
according to the procedures as illustrated in Preparations in
the present specification or in a manner similar thereto.
The starting compound (iv) can also be prepared
according to the manner disclosed in WO2004/071440.
It is to be noted that all solvated forms of the
compound (I) (e.g., hydrates, ethanolates, etc.), all
stereoisomers of the compound (I) (e.g., enantiomers,
diastereomers, racemic compounds, etc.) and crystal forms of
the compound (I) are also included within the scope of the
present invention.
It is to be noted that radiolabelled derivatives of
compound (I), which are suitable for biological studies, are
also included within the scope of the present invention.
Suitable salts of the object compound (I) are
conventional pharmaceutically acceptable ones and include
metal salts such as alkali metal salts (e.g. sodium salt,
potassium salt, etc.) and alkaline earth metal salts (e.g.
calcium salt, magnesium salt, etc.), ammonium salts, organic
base salts (e.g. trimethylamine salt, triethylamine salt,
pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-
dibenzylethylenediamine salt, etc.), organic acid salts (e.g.
acetate, trifluoroacetate, maleate, tartrate, fumarate,
methanesulfonate, benzenesulfonate, formate, toluenesulfonate,
etc.), inorganic acid salts (e.g. hydrochloride, hydrobromide,
hydroiodide, sulfate, phosphate, etc.), a salt with an amino
acid (e.g. arginine, aspartic acid, glutamic acid, etc.), etc.
All starting materials and product compounds may be
salts. The compounds of above processes can be converted to
salts according to a conventional method.
Hereinafter the definitions in the formula (I) are
explained in detail.
(General Definitions)
Throughout the specification and claims, the term
"lower" is intended to mean 1 to 6 carbon atom(s) unless
otherwise indicated.
Examples of the "halogen atom" include fluorine atom,
chlorine atom, bromine atom, iodine atom, etc.
Examples of the "lower alkyl" include straight or
branched (C1-6) alkyl such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., of which
preferred are (C1-4) alkyl such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, tert-butyl, etc.
Examples of the "halo(lower)alkyl" include groups in
which the above-mentioned (C1-6) alkyl is substituted with one
or more of the above-mentioned halogen atoms, of which
preferred are halo (C1-4) alkyl such as fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl,
trifluoroethyl, tetrafluoroethyl, fluoropropyl, difluoropropyl,
trifluoropropyl, tetrafluoropropyl, fluorobutyl, difluorobutyl,
trifluorobutyl, tetrafluorobutyl, chloromethyl, dichloromethyl,
trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl,
tetrachloroethyl, chloropropyl, dichloropropyl,
trichloropropyl, tetrachloropropyl, chlorobutyl, dichlorobutyl,
trichlorobutyl, tetrachlorobutyl, bromomethyl, dibromomethyl,
tribromomethyl, bromoethyl, dibromoethyl, tribromoethyl,
tetrabromoethyl, bromopropyl, dibromopropyl, tribromopropyl,
tetrabromopropyl, bromobutyl, dibromobutyl, tribromobutyl,
tetrabromobutyl, chlorofluoromethyl, bromochloroethyl, etc.
Examples of the "lower alkoxy" include straight or
branched (C1-6)alkoxy such as methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy,
hexyloxy, etc., in which the preferred one are (C1-4)alkoxy
such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, tert-butoxy, etc.
Examples of the "cycloalkyl" include (C3-7) cycloalkyl
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl etc., of which preferred are (C3-6)cycloalkyl such
as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
Examples of the "aromatic hydrocarbon ring" include
(C6-16)aryl such as phenyl, naphthyl, anthryl, pyreriyl,
pentalenyl, indenyl, phenanthryl, azulenyl, heptalenyl,
octalenyl, etc., in which preferred are (C6-14)aryl such as
phenyl, naphthyl, etc.
Examples of the "aromatic hetero ring" include aromatic
hetero ring having 5 to 14 ring atoms and p electrons shared
in a cyclic array and containing 1 to 4 heteroatoms selected
from a nitrogen atom, an oxygen atom and a sulfur atom besides
carbon atoms. Suitable examples of the "aromatic hetero ring"
include 5- to 14-membered hetero ring such as thienyl,
benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl,
imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl,
oxazolyl, thiazolyl, isoxazolyl, 1,2,4-oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,5-oxadiazolyl, etc., of which preferred are
5- or 6-membered hetero ring such as thienyl, furyl, pyrrolyl,
imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,3,4-oxadiazolyl,
etc.
Examples of the "non-aromatic hetero ring" include non-
aromatic hetero ring having 5 to 14 ring atoms and containing
1 to 3 heteroatoms selected from nitrogen atom, oxygen atom
and sulfur atom besides carbon atoms. Suitable examples of
"non-aromatic hetero ring" include 5- to 14-membered hetero
ring such as pyrrolidinyl, pyrazolidinyl, imidazolidinyl,
isoxazolidinyl, isothiazolidinyl, piperidyl (e.g., piperidino
etc.), piperazinyl, morpholinyl (e.g., morpholino etc.),
thiomorpholinyl (e.g., thiomorpholino etc.), tetrahydrofuranyl,
tetrahydropyranyl, tetrahydrothienyl, 1,2,3,4-
tetrahydroquinolyl, etc., of which preferred are 5- or 6-
membered hetero ring such as pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, isoxazolidinyl, isothiazolidinyl, piperidyl
(e.g., piperidino etc.), piperazinyl, morpholinyl (e.g.,
morpholino etc.), thiomorpholinyl (e.g., thiomorpholino etc.),
tetrahydrofuranyl, tetrahydrothienyl, etc.
(Definition of R1)
In the compound (I), R1 is lower alkyl, cycloalkyl or
aromatic hydrocarbon ring, each of which is optionally
substituted with one or more suitable substituents.
Suitable examples of the "lower alkyl" for R1 include
(C1-6) alkyl as exemplified in the "General Definitions", of
which preferred are (C1-4)alkyl such as ethyl, tert-butyl, etc.
Suitable examples of the "cycloalkyl" for R1 include
(C3-7) cycloalkyl as exemplified in the "General Definitions",
of which preferred are (C3-6)cycloalkyl such as cyclohexyl, etc.
Suitable examples of the "aromatic hydrocarbon ring"
for R1 includes (C6-16)aryl as exemplified in the "General
Definitions", of which preferred are (C6-14)aryl such as phenyl,
etc.
Each of the "lower alkyl", "cycloalkyl" and "aromatic
hydrocarbon ring" for R1 is optionally substituted by one or
more substituents. Suitable examples of the "substituent"
include:
(i) halogen atom [e.g., fluorine atom, chlorine atom, etc.];
(ii) (C1-6)alkyl [e.g., (C1-4)alkyl such as methyl, etc.];
(iii) (C6-16)aryl [e.g., (C6-14)aryl such as phenyl, etc.];
(iv) (C1-6) alkoxy [e.g., (C1-4)alkoxy such as methoxy, etc.];
(v) hydroxy;
(vi) cyano;
(vii) (C1-6)alkylarnino [e.g., (C1-4)alkylamino such as
methylamino etc.];
(viii) (C3-7)cycloalkyl [e.g., (C3-6)cycloalkyl such as
cyclopropyl, etc.], etc.
The number of the substituents is generally 1 to 4,
preferably 1 to 3.
In a preferred embodiment, R1 is (1)(C1-6)alkyl
optionally substituted with one (C6-16) aryl,
(2) (C3-7)cycloalkyl, or (3) (C6-16)aryl optionally substituted
with 1 to 3 substituents selected from halogen atom,
(C1-6)alkyl and (C6-16)aryl.
(Definition of R2)
In the compound (I), R2 is halogen atom, lower alkyl,
halo(lower)alkyl or lower alkoxy.
Suitable examples of the "halogen atom" for R2 include
those exemplified in the "General Definitions", of which
preferred are chlorine atom, bromine atom, etc.
Suitable examples of the "lower alkyl" for R2 include
(C1-6)alkyl as exemplified in the "General Definitions", of
which preferred are (C1-4)alkyl such as methyl, etc.
Suitable examples of the "halo(lower)alkyl" for R2
include those exemplified in the "General Definitions", of
which preferred are fluoromethyl, difluoromethyl,
trifluoromethyl, etc.
Suitable examples of the "lower alkoxy" for R2 include
(C1-6) alkoxy as exemplified in the "General Definitions", of
which preferred are (C1-4) alkoxy such as methoxy, ethoxy,
isopropoxy, etc.
In a preferred embodiment, R2 is halogen atom or
(C1-6)alkyl.
(Definitions of R3, R4, R5 and R6)
In the compound (I), R3 is
(1) a group represented by the formula:

wherein
R4 is lower alkyl, lower alkoxy, cycloalkyl,
aromatic hetero ring, non-aromatic hetero ring or
aromatic hydrocarbon ring, each of which is
optionally substituted with one or more
substituents;
(2) a group represented by the formula:

wherein
R5 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring, aromatic hetero ring or non-aromatic hetero
ring, each of which is optionally substituted
with one or more substituents;
(3) a group represented by the formula:

wherein
R6 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring or non-aromatic hetero ring, each of which
is optionally substituted with one or more
substituents; or
(4) a group selected from halogen atom, carboxy, hydroxy and
lower alkoxy.
(1) Suitable examples of the "lower alkyl" for R4 include
(C1-6) alkyl as exemplified in the "General Definitions", of
which preferred are (C1-4) alkyl such as methyl, ethyl,
isopropyl, etc.
Suitable examples of the "lower alkoxy" for R4 include
(C1-6) alkoxy as exemplified in the "General Definitions", of
which preferred are (C1-4)alkoxy such as methoxy, etc.
Suitable examples of the "cycloalkyl" for R4 include
(C3-7)cycloalkyl as exemplified in the "General Definitions",
of which preferred are (C3-6) cycloalkyl such as cyclopropyl,
etc.
Suitable examples of the "aromatic hetero ring" for R4
include "5- to 14-membered aromatic hetero ring" as
exemplified in the "General Definitions", of which preferred
are 5- or 6-membered aromatic hetero ring such as isoxazolyl,
pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, etc.
Suitable examples of the "non-aromatic hetero ring" for
R4 include "5- to 14-membered non-aromatic hetero ring" as
exemplified in the "General Definitions", of which preferred
are 5- or 6-membered hetero ring such as pyrrolidinyl,
piperidyl, tetrahydropyranyl, etc.
Suitable examples of the "aromatic hydrocarbon ring"
for R4 include (C6-16)aryl as exemplified in the "General
Definitions", of which preferred are (C6-14)aryl such as phenyl,
etc.
Each of the "lower alkyl", "lower alkoxy", "cycloalkyl",
"aromatic hetero ring", "non-aromatic hetero ring" and
"aromatic hydrocarbon ring" for R4 is optionally substituted
with one or more substituents. Examples of the "substituent"
include:
(i) (C1-6)alkyl [e.g., (C1-4)alkyl such as methyl, etc.];
(ii) (C3-7)cycloalkyl [e.g., (C3-6) cycloalkyl such as
cyclopropyl, etc.];
(iii) (C6-16)aryl [e.g., (C6-14)aryl such as phenyl, etc.];
(iv) (C1-6) alkylamino [e.g., (C1-3)alkylamino such as
methylamino, etc.];
(v) halo(C1-6)alkyl [e.g., halo(C1-3) alkyl such as
trifluoromethyl, etc.];
(vi) halogen atom [e.g., fluorine atom, etc.], etc.
(vii) non-aromatic hetero ring [e.g., morpholino, etc.];
The number of the substituents is generally 1 to 4,
preferably 1 to 3.
(2) Suitable examples of the "lower alkyl" for R5 include
(C1-6)alkyl as exemplified in the "General Definitions", of
which preferred are (C1-4) alkyl such as methyl, ethyl, etc.
Suitable examples of the "cycloalkyl" for R5 include
(C3-7)cycloalkyl as exemplified in the "General Definitions",
of which preferred are (C3-6) cycloalkyl such as cyclopropyl,
cyclopentyl, etc.
Suitable examples of the "aromatic hydrocarbon ring"
for R5 include (C6-16)aryl as exemplified in the "General
Definitions", of which preferred are (C6-14)aryl such as phenyl,
naphthyl, etc.
Suitable examples of the "aromatic hetero ring" for R5
include "5- to 14-membered aromatic hetero ring" as
exemplified in the "General Definitions", of which preferred
are 5- or 6-membered hetero ring such as isoxazolyl, pyridyl,
pyrazolyl, 1,3,4-oxadiazolyl, etc.
Suitable examples of the "non-aromatic hetero ring" for
R5 include "5- to 14-membered non-aromatic hetero ring" as
exemplified in the "General Definitions", of which preferred
are 5- or 6-membered hetero ring such as pyrrolidinyl,
piperidyl, tetrahydropyranyl, etc.
Each of the "lower alkyl", "cycloalkyl", ""aromatic
hydrocarbon ring", "aromatic hetero ring" and "non-aromatic
hetero ring" for R5 is optionally substituted with one or more
substituents. Suitable examples of the "substituent" include:
(i) (C1-6)alkyl [e.g., (C1-4)alkyl such as methyl, tert-butyl,
etc.];
(ii) (C3-7)cycloalkyl [e.g., (C3-6) cycloalkyl such as
cyclopropyl, etc.];
(iii) (C6-16)aryl [e.g., (C6-14)aryl such as phenyl, etc.] which
is optionally substituted with (C1-6)alkyl [e.g., (C1-6)alkyl
such as methyl, etc.];
(iv) (C1-6)alkylamino [e.g., (C1-3)alkylamino such as
methylamino, etc.];
(v) halo (C1-6)alkyl [e.g., halo (C1-3)alkyl such as
trifluoromethyl, etc.];
(vi) halogen atom [e.g., fluorine atom, etc.];
(vii) non-aromatic hetero ring [e.g., morpholino, etc.], etc.
The number of the substituents is generally 1 to 4,
preferably 1 to 3.
(3) Suitable examples of the "lower alkyl" for R6 include
(C1-6)alkyl as exemplified in the "General Definitions", of
which preferred are (C1-4)alkyl such as methyl, ethyl,
isopropyl, tert-butyl, etc.
Suitable examples of the "cycloalkyl" for R6 include
(C3-7)cycloalkyl as exemplified in the "General Definitions",
of which preferred are (C3-6) cycloalkyl such as cyclopropyl,
etc.
Suitable examples of the "aromatic hydrocarbon ring"
for R6 include (C6-16)aryl as exemplified in the "General
Definitions", of which preferred are (C6-14)aryl such as phenyl,
naphthyl, etc.
Suitable examples of the "non-aromatic hetero ring" for
R6 include "5- to 14-membered non-aromatic hetero ring" as
exemplified in the "General Definitions", of which preferred
are 5- or 6-membered hetero ring such as pyrrolidinyl,
piperidyl, tetrahydropyranyl, etc.
Each of the "lower alkyl", "cycloalkyl", "aromatic
hydrocarbon ring" and "non-aromatic hetero ring" for R6 is
optionally substituted with one or more substituents.
Suitable examples of the "substituent" include:
(i) (C1-6)alkyl [e.g., (C1-4) alkyl such as methyl, etc.];
(ii) (C3-7)cycloalkyl [e.g., (C3-6) cycloalkyl such as
cyclopropyl, etc.];
(iii) (C6-16) aryl [e.g., (C6-14)aryl such as phenyl, etc.];
(iv) (C1-6)alkylamino [e.g., (C1-3) alkylamino such as
methylamino, etc.];
(v) halo (C1-6) alkyl [e.g., halo (C1-3) alkyl such as
trifluoromethyl, etc.];
(vi) halogen atom [e.g., fluorine atom, etc.];
(vii) non-aromatic hetero ring [e.g., morpholino, etc.], etc.
The number of the substituents is generally 1 to 4,
preferably 1 to 3.
(4) Suitable examples of the "halogen atom" for R3 include
halogen atom as exemplified in the "General Definitions", of
which preferred are fluorine atom, chlorine atom, bromine atom,
etc.
Suitable examples of the "lower alkoxy" for R3 include
(C1-6) alkoxy as exemplified in the "General Definitions", of
which preferred are (C1-4) alkoxy such as methoxy, ethoxy, etc.
In a preferred embodiment, R3 is
(1) a group represented by the formula:

wherein
R4 is (C1-6)alkoxy, (C3-7) cycloalkyl, 5- to 14-
membered aromatic hetero ring or (C6-16) aryl, each
of which is optionally substituted with 1 to 3
substituents selected from (C1-6)alkyl,
(C3-7)cycloalkyl and (C6-16)aryl,
(2) a group represented by the formula:

wherein
R5 is (C3-7) cycloalkyl, (C6-16) aryl or 5- to 14-
membered aromatic hetero ring, each of which is
optionally substituted with 1 to 3 substituents
selected from (C1-6)alkyl and (C6-16)aryl which is
optionally substituted with (C1-6)alkyl, or
(3) a group represented by the formula:

wherein
R6 is (C3-7)cycloalkyl.
A preferred embodiment of compound (I) is
R1 is lower alkyl, cycloalkyl or aromatic hydrocarbon ring,
each of which is optionally substituted with one or
more substituents;
R2 is halogen atom or lower alkyl; and
R3 is
(1) a group represented by the formula:

wherein
R4 is lower alkoxy, cycloalkyl, aromatic hetero ring
or aromatic hydrocarbon ring, each of which is
optionally substituted with one or more
substituents,
(2) a group represented by the formula:

wherein
R5 is cycloalkyl, aromatic hydrocarbon ring or
aromatic hetero ring, each of which is optionally
substituted with one or more substituents; or
(3) a group represented by the formula:

wherein
R6 is cycloalkyl, which is optionally substituted
with one or more substituents,
or a salt thereof.
And more preferred embodiment of compound (I) is
R1 is
(1) (C1-6)alkyl optionally substituted with one
(C6-16)aryl,
(2) (C3-7) cycloalkyl, or
(3) (C6-16)aryl optionally substituted with 1 to 3
substituents selected from halogen atom, (C1-6) alkyl and
(C6-16) aryl;
R2 is halogen atom or (C1-6) alkyl, and
R3 is
(1) a group represented by the formula:

wherein
R4 is (C1-6)alkoxy, (C3-7) cycloalkyl, 5- to 14-
membered aromatic hetero ring or (C6-16) aryl, each
of which is optionally substituted with 1 to 3
substituents selected from (C1-6)alkyl,
(C3-7) cycloalkyl and (C6-16)aryl,
(2) a group represented by the formula:

wherein
R5 is (C3-7) cycloalkyl, (C6-16)aryl or 5- to 14-
membered aromatic hetero ring, each of which is
optionally substituted with 1 to 3 substituents
selected from (C1-6)alkyl and (C6-16)aryl which is
optionally substituted with (C1-6)alkyl, or
(3) a group represented by the formula:

wherein
R6 is (C3-7)cycloalkyl,
or a salt thereof.
Specific examples of the preferred compound of the
present invention may be exemplified by Examples below.
In order to show the usefulness of the compound (I) of
the present invention, the pharmacological test results of the
representative compounds of the present invention are shown in
the following.
Test 1: Inhibition of TNF-a production in THP-1 cells
[I] Test method
THP-1 cells, a human monocytic cell line, were
maintained in RPMI 1640 (Sigma R8758) supplemented with
penicillin (50 U/mL), streptomycin (50 µg/mL) and 10% fetal
bovine serum (Moregate BioTech.) at 37°C, 5% C02 in a
humidified incubator. Initial stock solutions of test
compounds were made in DMSO. All cells, reagents and test
compounds were diluted into culture media. THP-1 cells (1.x
105 cells/well final) and lipopolysaccharide (LPS; 10 µg/mL
final; Sigma L-4005, from E. coli serotype 0.55:B5) were added
to 96 well polypropylene culture plates (Sumilon, MS-8196F5;
sterile) containing test compound or 0.1% DMSO vehicle. The
cell mixture was incubated for 20 hr in a humidified incubator
at 37°C, 5% CO2. The culture supernatants were harvested and
TNF-a levels from LPS stimulated cells in the presence of 100
nM test compound was calculated compared with control cells
stimulated in the presence of 0.1% DMSO.
[II] Test compounds
N-{2-Chloro-5-[(cyclopropylamino) carbonyl]phenyl}-1-(2,6-
dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide
(Example 1)
N-{2-Chloro-5-[(methoxyamino) carbonyl]phenyl}-1-(2,6-
dichlorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
(Example 2)
N-{2-Chloro-5- [ (isoxazol-3-ylamino) carbonyl]phenyl}-1- (2,6-
dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide
(Example 3)
N-{2-Chloro-5-[(1-methyl-LH-pyrazol-3-
ylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide (Example 5)
N-{2-Chloro-5-[(1-methyl-1H-pyrazol-5-
ylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide (Example 6)
N-{2-Brcmo-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2, 6-
difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 15)
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2-chloro-
6-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 16)
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2,3-
difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 17)
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-(2,6-
dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 18)
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-tert-
butyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (Example 20)
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-(2,6-
difluorolphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 22)
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-(1-
phenylethyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (Example
24)
N-{5-[(Cyclopropylcarbonyl)amino]-2-methylphenyl}-1-(2,6-
dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 25)
N-{5-[({[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}carbonyl)amino]-2-methylphenyl}-1-(2,6-
dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
(Example 26)
[III] Test results
Table 1: Inhibition of TNF-a production in THP-1 cells
at 100 nM

Test 2: Inhibition of hind paw swelling in adjuvant-induced
arthritis rats
[I] Test method
Arthritis was induced by injection of 0.5 mg of
Mycobacterium tuberculosis (Difco Laboratories, Detroit,
Mich.) in 50 µL of liquid paraffin into the right hind footpad
of female Lewis rats aged 7 weeks (day 0). Normal untreated
rats were used as negative controls. Animals were randomized
and grouped (n>5) for drug treatment based on an increase of
left hind paw volume and body weight on day 15. Test
compounds were suspended in vehicle (0.5% methylcellulose) and
orally administered once a day from days 15 to 24. The volume
of the left hind paw was measured on day 25 by a water
displacement method using a plethymometer for rats (MK-550;
Muromachi Kikai Co., Ltd., Tokyo, Japan).
The compound (I) and a salt thereof of the present
invention are useful as inhibitors of cytokines' production or
their transduction, and through inhibiting the p38a MAPK they
possess pharmacological actions such as analgesic action,
anti-inflammatory, anti arthritis mutilans action, or the like,
and for the prevention and/or the treatment of pain,
rheumatoid arthritis, other conditions associated with
inflammation, Crohn's disease, inflammatory bowel disease,
psoriasis, or the like.
The pharmaceutical composition of the present invention
can be used in the form of a pharmaceutical preparation, for
example, in a solid, semisolid or liquid form, which contains
the compound (I) or a pharmaceutically acceptable salt thereof
as an active ingredient in admixture with an organic or
inorganic carrier or excipient suitable for rectal, pulmonary
(nasal or buccal inhalation), nasal, ocular, external
(topical), oral or parenteral (including subcutaneous,
intravenous and intramuscular) administrations or
insufflations. The active ingredient may be compounded, for
example, with the usual non-toxic, pharmaceutically acceptable
carriers for tablets, pellets, troches, capsules,
suppositories, creams, ointments, aerosols, powders for
insufflation, solutions, emulsions, suspensions, and any other
form suitable for use. In addition, auxiliary, stabilizing
agents, thickening agents, coloring agents and perfumes may be
used where necessary. The compound (I) or a pharmaceutically
acceptable salt thereof is included in a pharmaceutical
composition in an amount sufficient to produce the desired
aforesaid pharmaceutical effect upon the process or condition
of diseases.
For applying the composition to a mammal (e.g., human
being, mouse, rat, swine, dog, cat, horse, bovine, etc.,
especially human being), it is preferable to apply the
composition by intravenous, intramuscular, pulmonary or oral
administration, or insufflation. While the dosage of
therapeutically effective amount of the compound (I) varies
depending on the age and condition of each individual patient
to be treated, in the case of intravenous administration, a
daily dose of 0.01-100 mg of the compound (I) per kg weight of
a mammal, in the case of intramuscular administration, a daily
dose of 0.1-100 mg of the compound (I) per kg weight of a
mammal, and in case of oral administration, a daily dose of
0.5-100 mg of the compound (I) per kg weight of a mammal is
generally given for the prevention and/or treatment of the
aforesaid diseases.
Hereinafter the reactions for preparing the compound
[I] of the invention are explained in more detail with
referring to the Preparations and Examples. However, the
Preparations and Examples are given only for the purpose of
illustration of the present invention, and the present
invention should not be restricted by the Preparations and
Examples in any way.
The abbreviations, symbols and terms used in the
Preparations and Examples have the following meanings.
CH2Cl2: dichloromethane
EtOAc: ethyl acetate
MeOH: methanol
DMF: N,N-dimethylformamide
Et3N: triethylamine
iPr2NEt: N-ethyl-N-isopropyl-2-propanamine
IPE: diisopropyl ether
THF: tetrahydrofuran
HOBt: 1-hydroxybenzotriazole
HATO: N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-
b]pyridin-3-yloxy)methylene]-N-methylmethanaminium
hexafluorophosphate
Pd/C: palladium on carbon
min: minute(s)
hr: hour(s)
HCl: hydrochloric acid
NaOH: sodium hydroxide
WSC-HCl: N-[3-(dimethylamino)propyl]-N'-
ethylcarbodiimide hydrochloride
MgSO4: magnesium sulfate
NaHCO3 : sodium hydrogen carbonate
DMSO: dimethyl sulfoxide
Preparation 1
To a solution of (2,6-dichlorophenyl)amine (12.8 g) in
THF (73 mL) was added an 1M THF solution of lithium
1,1,1,3,3,3-hexamethyldisilazan-2-ide (79.8 mL) at 0°C under a
nitrogen atmosphere, and the mixture was stirred at the same
temperature for 30 min. To this solution was added a solution
of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate
(14.52 g) in THF (35 mL) at once, and the resulting mixture
was stirred at 0°C for 3 hr. The reaction mixture was diluted
with EtQAc (150 mL) and washed with a mixture of 1 M HCl (200
mL) and brine (150 raL), saturated aqueous NaHCO3 (150 mL) and
brine successively, dried over MgSO4 and filtered. The
filtrate was evaporated in vacuo, and the residue was
triturated with a mixture of EtQAc and hexane (1:2) and
collected by filtration to give dimethyl (2E,4Z)-4-{[(2,6-
dichlorophenyl)amino]methylene}-2-pentenedioate (9.28 g). The
filtrate was evaporated in vacuo and the residue was purified
by silica gel (200 g) column chromatography eluting with EtOAc
- hexane (1:2) followed by triturating the isolated material
with EtOAc - hexane (1:2) to afford
dimethyl (2E, 4Z)-4-{[(2,6-dichlorophenyl)amino]methylene}-2-
pentenedioate (1.30 g).
Mass ESI (+) 330 (M+H)
1H-NMR (DMSO-d6) d 3.62 (3H, s), 3.80 (3H, s), 6.20 (1H, d, J =
15.7 Hz), 7.29-7.37 (1H, m), 7.60 (2H, d, J = 8.14 Hz), 8.00
(1H, d, J = 13.3 Hz), 10.27 (1H, d, J = 13.3Hz)
Preparation 2
Dimethyl (2E,4Z)-4-{[(2,6-dimethyl-4-
fluorophenyl)amino]methylene}-2-pentenedioate was obtained
according to a similar manner to Preparation 1.
Mass ESI (+) 330 (M+Na)
1H-NMR (CDCl3) d 2.27 (6H, s), 3.73 (3H, s), 3.86 (3H, s), 6.12
(1H, d, J = 15.72 Hz), 6.81 (1H, d, J = 8.84 Hz), 7.19 ( 1H, d,
J = 13.23 Hz), 7.39 (1H, d, J = 15.68 Hz), 10.08 (1H, d, J =
13.20 Hz)
Preparation 3
Dimethyl (2E,4Z)-4-{[(2-chloro-6-
fluorophenyl) amino] methylene}-2-pentenedioate was obtained
according to a similar manner to Preparation 1.
Mass ESI (+) 336 (M+Na)
1H-NMR (CDCl3) d 3.76 (3H, s), 3.91 (3H, s), 6.21 (1H, d, J =
15.88 Hz), 6.98-7.23 (3H, m), 7.44 (1H, d, J = 15.82 Hz), 7.97
(1H, d, J = 12.86 Hz), 10.96 (1H, d, J = 12.78 Hz)
Preparation 4
Dimethyl (2E,4Z)-4-[(tert-butylamino)methylene]-2-
pentenedioate was obtained according to a similar manner to
Preparation 1.
Mass ESI (+) 264 (M+Na)
1H-NMR (CDCl3) d 1.36 (9H, s) , 3.73 (3H, s), 3.78 (3H, s), 6.02
(1H, d, J = 15.6 Hz), 7.35 (1H, d, J= 14.1 Hz), 7.40 (1H, d,
J = 15.6 Hz), 9.23 (1H, br d)
Preparation 5
Dimethyl (2E,4Z)-4-{[(2,6-
dimethylphenyl) amino]methylene}-2-pentenedioate was obtained
according to a similar manner to Preparation 1.
Mass ESI (+) 312 (M+Na)
1H-NMR (CDCl3) d 2.23 (6H, s), 3.73 (3H, s), 3.86 (3H, s), 6.12
(1H, d, J = 15.7 Hz), 7.02-7.16 (3H, m), 7.29 (1H, d, J = 13.9
Hz), 7.41 (1H, d, J - 15.7 Hz), 10.24 (1H, d, J = 13.0 Hz)
Preparation 6
Dimethyl (2E,4Z)-4-{[(2,6-
difluorophenyl) amino]methylene}-2-pentenedioate was obtained
according to a similar manner to Preparation 1.
Mass ESI (+) 320 (M+Na)
1H-NMR (CDCl3) d 3.76 (3H, s) , 3.94 (3H, s), 6.20 (1H, d, J =
15.72 Hz), 6.76-7.04 (3H, m), 7.44 (1H, d, J = 15.80 Hz), 7.96
(1H, d, J = 12.86 Hz), 10.79 (1H, d, J = 11.68 Hz)
Preparation 7
To a solution of dimethyl (2E,4Z)-4-{[(2,6-
dichlorophenyl)amino]methylene}-2-pentenedioate (7.3 g) in
MeOH (73 mL) was added 28% sodium methoxide in MeOH (4.3 mL) .
The mixture was refluxed for 8 hr under a nitrogen atmosphere.
The reaction mixture was cooled to room temperature and poured
into 1 M HCl (140 mL) at 0°C. The resulting mixture was
extracted with EtOAc (70 mL x 2) . The combined extracts were
washed with saturated aqueous NaHCO3 (100 mL) and brine, dried
over MgSO4 and filtered. The filtrate was evaporated in vacuo,
and the residue was triturated with a mixture of EtOAc and
hexane (1:3) to provide methyl 1-(2,6-dichlorophenyl)-6-oxo-
1, 6-dihydro-3-pyridinecarboxylate (4.3 g).
Mass ESI (+) 300 (M+H)
1H-NMR (CDCl3) d 3.87 (3H, s) , 6.68 (1H, d, J = 10.28 Hz), 7.39
(1H, dd, J= 9.42 and 5.84 Hz), 7.49-7.53 (2H, m), 7.94-8.01
(2H, m)
Preparation 8
Methyl 1-(2,6-dimethyl-4-fluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylate was obtained according to a
similar manner to Preparation 7.
Mass ESI (+) 298 (M+Na)
1H-NMR (CDCl3) d 2.08 (6H, s), 3.86 (3H, s), 6.68 (1H, dd, J =
8.32 and 2.44 Hz), 6.90 (2H, d, J = 8.80 Hz), 7.98 (2H, dd, J
=8.40 and 2.48 Hz)
Preparation 9
Methyl 1-(2-chloro-6-fluorophenyl)-6-oxo-l, 6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 7.
Mass ESI (+) 282 (M+H)
1H-NMR (CDCl3) d 3.87 (3H, s), 6.68 (1H, d, J = 9.38 Hz), 7.02-
7.25 (1H, m), 7.40-7.46 (2H, m), 7.93-8.04 (2H, m)
Preparation 10
Methyl 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 7.
Mass ESI (+) 288 (M+Na)
1H-NMR (CDCl3) d 3.87 (3H, s), 6.67 (1H, d, J = 9.84 Hz), 7.08-
7.13 (2H, m), 7.44-7.48 (1H, m), 7.95 (1H, dd, J= 9.80 and
2.52 Hz), 8.09 (1H, s)
Preparation 11
To a solution of dimethyl (2E,4Z)-4-[(tert-
butylamino) methylene] -2-pentenedioate (1.2 g)
in MeOH (10 mL) was added 28% sodium methoxide in MeOH (1.9
mL), and the mixture was heated to reflux for 8 hr under a
nitrogen atmosphere. The solvent was evaporated in vacuo,, and
the residue was diluted with EtOAc (20 mL) . The resulting
mixture was washed successively with 1 M HCl (20 mL),
saturated aqueous NaHC03 (20 mL) and brine, dried over MgS04
and evaporated in vacuo to give ethyl l-(tert-butyl)-6-oxo-
1,6-dihydro-3-pyridinecarboxylate (657 mg) .
Mass ESI (+) 224 (M+H)
1H-NMR (CDCl3) d 1.35 (3H, t, J = 7.15 Hz) , 1.70 (9H, s) , 4.31
(2H, q, J = 7.14 Hz), 6.44 (1H, d, J = 9.37 Hz), 7.77 (1H, dd,
J = 9.45 and 2.44 Hz), 8.44 (1H, d, J = 2.38 Hz)
Preparation 12
Ethyl 1- (2,6-dimethylphenyl) -6-oxo-l, 6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 11.
Mass ESI (+) 294 (M+Na)
1H-NMR (CDCl3) d 1.35 (3H, t, J = 7.24 Hz), 2.10 (6H, s) , 4.32
(2H, q, J = 7.10 Hz), 6.70 (1H, d, J = 10.04 Hz), 7.17-7.32
(3H, m), 7.95-8.02 (2H, m)
Preparation 13
To a solution of (2,6-difluorophenyl)amine (15.5 g) in
THF (140 mL) was added dropwise an 1 M THF solution of lithium
1,1,1,3,3,3-hexamethyldisilazan-2-ide (120 mL) at 0°C under a
nitrogen atmosphere, and the mixture was stirred at the same
temperature for 30 min. To the solution was added a solution
of dimethyl (2E,4Z)-4-(methoxymethylene)-2-pentenedioate (20
g) in THF (60 mL) at 0°C, and the resulting mixture was
stirred at the same temperature for 2 hr. The reaction was
quenched with a mixture of EtOAc (200 mL) and 0.5 M HCl (200
mL) . The aqueous layer was extracted with EtOAc (200 mL) .
The organic layers were combined, washed with brine, dried
over MgSO4, filtered and evaporated in vacuo. The residue was
diluted with MeOH (100 mL), and to the resulting solution was
added 28% sodium methoxide in MeOH (38.6 mL) . The resulted
mixture was heated to reflux for 6 hr under a nitrogen
atmosphere. The reaction mixture was concentrated under
reduced pressure and the residue was partitioned between EtOAc
(200 mL) and 1 M HCl (300 mL). The aqueous layer was
separated and extracted with EtQAc (200 mL) . The organic
layers were combined, washed with saturated aqueous NaHCO3
(300 mL) and brine successively, dried over MgSO4 and
evaporated in vacuo. The residue was triturated with IPE, and
the precipitates produced were collected by filtration to give
methyl 1-(2,6-difluorophenyl)-6-oxo-l, 6-dihydro-3-
pyridinecarboxylate (5.34 g).
Mass ESI (+) 288 (M+Na)
1H-NMR (CDCl3) d 3.87 (3H, s), 6.67 (1H, d, J = 9.76 Hz), 7.08-
7.13 (2H, m), 7.42-7.50 (1H, m), 7.94 (1H, dd, J= 9.72 and
2.64 Hz), 8.09 (1H, t, J = 1.4 Hz)
Preparation 14
Methyl 1-(4-chloro-2,6-dimethylphenyl)-6-oxo-1, 6-
dihydro-3-pyridinecarboxylate was obtained according to a
similar manner to Preparation 13.
Mass ESI (+) 314 (M+Na)
1H-NMR (CDCl3) d 2.07 (6H, s), 3.86 (3H, a), 6.69 (1H, dd, J =
8.74 and 1.58 Hz), 7.19 (2H, s), 7.95-8.01 (2H, m)
Preparation 15
Methyl 1- (2,3-difluorophenyl) -6-oxo-l, 6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 13.
Mass ESI (+) 288 (M+Na)
1H-NMR (CDCl3) d 3.85 (3H, s), 6.66 (1H, dd, J = 9.68 and 0.56
Hz), 7.13-7.17 (1H, m), 7.22-7.27 (1H, m), 7.28-7.36 (1H, m),
7.94 (1H, d, J = 9.80 Hz), 8.14 (1H, d, J = 1.92 Hz)
Preparation 16
Methyl 6-oxo-1-(1-phenylethyl)-1, 6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 13.
Mass ESI (+) 280 (M+Na)
1H-NMR (CDCl3) d 1.76 (3H, d, J = 7.18 Hz), 3.77 (3H, s), 6.40
(1H, q, J = 7.12 Hz), 6.56 (1H, d, J = 9.50 Hz), 7.28-7.43 (5H,
m), 7.80 (1H, dd, J = 9.52 and 2.50 Hz), 8.04 (1H, d, J = 2.46
Hz)
Preparation 17
To a solution of dimethyl (2E,4Z)-4-(methoxymethylene)-
2-pentenedioate (1.23 g) in DMF (30 mL) was added
cyclohexanamine (670 mg) at 0°C, and the mixture was stirred
at the same temperature for 30 min under a nitrogen atmosphere.
The reaction mixture was heated to reflux for 5 hr. The
mixture was cooled with an ice-water bath and poured into
water (100 mL) . The resulted mixture was extracted with EtOAc
(100 mL x 2), and the organic phases were combined, washed
with brine two times, dried over MgS04, filtered and
evaporated in vacuo. The residue was purified by silica gel
column chromatography eluting with EtQAc - hexane (1:2 - 1:1)
to give methyl 1-cyclohexyl-6-oxo-1,6-dihydro-3-
pyridinecarboxylate (520 mg).
Mass ESI (+) 258 (M+Na)
1H-NMR (CDCl3) d 1.22-1.27 (1H, m) , 1.48-1.53 (4H, m) , 1.75-
1.79 (1H, m), 1.91-1.95 (4H), m), 3.86 (3H, s), 4.84-4.86 (1H,
m), 6.53 (1H, d, J = 9.36 Hz), 7.80 (1H, dd, J = 9.4 and 2.44
Hz), 8.21 (1H, d, J = 2.44 Hz)
Preparation 18
Methyl 1-(2-methylphenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylate was obtained according to a similar manner
to Preparation 17.
Mass ESI (+) 266 (M+Na)
1H-NMR (CDCl3) d 2.16 (3H, s) , 3.85 (3H, s), 6.65 (1H, d, J =
9.94 Hz), 7.16-7.22 (1H, m), 7.29-7.40 (3H, m), 7.95 (1H, dd,
J = 9.62 and 2.54 Hz), 8.11 (1H, d, J = 2.60 Hz)
Preparation 19
To a solution of 3-amino-4-chlorobenzoic acid (3.99 g)
in THF (35 mL) was added dropwise an 1 M THF solution of
lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (46.5 mL) while
keeping the internal temperature below -5°C under a nitrogen
atmosphere, and the mixture was stirred for 15 min around -
10°C. Powder of methyl 1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylate (3.46 g) was added to the
mixture at once, and the resulted mixture was stirred at the
same temperature for 3 hr under a nitrogen atmosphere. The
reaction mixture was poured into a mixture of ice-water (700
mL) and 1 M HCl (100 mL), and the resulting mixture was
extracted with EtOAc (150 mL x 3) . During the extraction,
undissolved materials were produced, which were removed by
filtration. The combined organic layers were washed with
brine, dried over MgSO4 and filtered. The filtrate was
evaporated in vacuo, and the residue was triturated with MeOH,
and the precipitates produced were collected by filtration to
give 4-chloro-3-({[1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-
pyridinyl]carbonyl}amino)benzoic acid (1.74 g).
Mass ESI (-) 437 (M-H)
1H-NMR (DMSO-d6) d 6.72 (1H, d, J = 9.74 Hz), 7.57-7.89 (6H, m) ,
8.08-8.17 (2H, m), 8.48 (1H, d, J = 2.42 Hz), 10.04 (1H, s),
13.3 (1H, br s)
Preparation 20
3-({[1-(2,6-Dichlorophenyl)-6-oxo-1,6-dihydro-3-
pyridinyl]carbonyl} amino)-4-methylbenzoic acid was obtained
according to a similar manner to Preparation 19.
Mass ESI (-) 415 (M-H)
1H-NMR (CD3OD) d 2.33 (3H, s), 6.77 (1H, d, J = 9.56 Hz), 7.39
(1H, d, J = 8.02 Hz), 7.54-7.69 (3H, m) , 7.85 (1H, dd, J =
7.96 and 1.44 Hz), 7.95 (1H, s), 8.19-8.28 (2H, m)
Preparation 21
4-Chloro-3-({[1-(4-chloro-2,6-dimethylphenyl)-6-oxo-
1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid was
obtained according to a similar manner to Preparation 19.
Mass ESI (-) 429 (M-H)
1H-NMR (DMSO-d6) d 2.05 (6H, s), 6.67 (1H, d, J = 9.76 Hz) ,
7.40 (2H, s), 7.67 (1H, d, J = 8.40 Hz) , 7.80 (1H, dd, J =
8.36 and 2.08 Hz), 8.05-8.31 (2H, m), 8.32 (1H, s), 9.98 (1H,
s), 13.55 (1H, br s)
Preparation 22
4-Chloro-3-({[1-(2,6-dimethyl-4-fluorophenyl)-6-oxo-
1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid was
obtained according to a similar manner to Preparation 19.
Mass ESI (-) 413 (M-H)
1H-NMR (DMSO-d6) d 2.49 (6H, s), 6.67 (1H, d, J = 9.72 Hz),
7.17 (2H, d, J = 9.32 Hz), 7.67 (1H, d, J = 8.32 Hz), 7.80 (1H,
dd, J = 8.32 and 2.00 Hz), 8.05-8.10 (2H, m), 8.32 (1H, d, J =
2.40 Hz), 9.99 (1H, s), 13.23 (1H, br s)
Preparation 23
4-Chloro-3-({[(1-cyclohexyl)-6-oxo-1,6-dihydro-3-
pyridinyl]carbonyl}amino)benzoic acid was obtained according
to a similar manner to Preparation 19.
Mass ESI (-) 373 (M-H)
1H-NMR (DMSO-d6) d 1.21-1.26 (1H, m) , 1.39-1.45 (2H, m), 1.65-
1.73 (3H, m), 1.74-1.88 (4H, m), 4.66-4.73 (1H, m), 6.49 (1H,
d, J = 9.52 Hz), 7.69 (1H, d, J = 8.36 Hz), 7.82 (1H, dd, J -
8.36 and 2.00 Hz), 7.91 (1H, dd, J = 9.52 and 2.52 Hz), 8.07
(1H, d, J = 2.00 Hz), 8.46 (1H, d, J = 2.48 Hz), 10.04 (1H, s),
13.28 (1H, s, br s)
Preparation 24
To a solution of methyl 1-(2,6-difluorophenyl)-6-oxo-
1,6-dihydro-3-pyridinecarboxylate (5.41 g) in a mixture of
EtOH (108 mL) and THF (54 mL) was added 1 M aqueous NaOH (82
mL) at 0°C, and the mixture was stirred at the same
temperature for 2 hr. The mixture was concentrated under
reduced pressure and the residue was treated with 1 M HCl (160
mL) . The precipitates produced were collected by filtration
and dried under reduced pressure at 60°C to give 1-(2,6-
difluorophenyl) -6-oxo-l, 6-dihydro-3-pyridinecarboxylic acid
(4.73 g).
Mass ESI (-) 250 (M-H)
1H-NMR (DMSO-d6) d 6.62 (1H, d, J = 9.64 Hz), 7.30-7.39 (2H, m) ,
7.55-7.67 (1H, m), 7.92-7.95 (1H, dd, J= 9.64 and 2.56 Hz),
13.12 (1H, br s)
Preparation 25
1- (2-Chloro-6-fluorophenyl) -6-oxo-l, 6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 266 (M-H)
1H-NMR (DMSO-d6) d 6.62 (1H, d, J = 9.68 Hz), 7.43-7.51 (1H, m) ,
7.56-7.64 (2H, m), 7.94 (1H, dd, J = 9.80 and 2.56 Hz), 8.38
(1H, d, J = 2.44 Hz), 13.06 (1H, s)
Preparation 26
1-(2,3-Difluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 250 (M-H)
1H-NMR (DMSO-d6) d 6.58 (1H, d, J = 9.68 Hz), 7.27-7.47 (2H, m) ,
7.59-7.66 (1H, m), 7.78-7.93 (1H, m) , 8.34 (1H, d, J = 2.4 Hz),
13.05 (1H, br s)
Preparation 27
1-(2,6-Dichlorophenyl)-6-oxo-1, 6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 282 (M-H)
1H-NMR (CDCl3+CD3OD) d 6.70 (1H, dd, J = 8.80 and 1.4 Hz),
7.35-7.56 (3H, m), 8.02-8.07 (2H, m)
Preparation 28
1-(2-Methylphenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 228 (M-H)
1H-NMR (CD3OD) d 2.12 (3H, s) , 6.65 (1H, d, J = 9.64 Hz), 7.24-
7.49 (4H, m), 8.09 (1H, dd, J = 9.52 and 2.50 Hz), 8.21 (1H, d,
J = 2.36 Hz)
Preparation 29
1-tert-Butyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic
acid was obtained according to a similar manner to Preparation
24.
Mass ESI (-) 194 (M-H)
1H-NMR (CDCl3-CD3OD) d 1.71 (9H, s), 6.46 (1H, d, J = 9.32 Hz),
7.82 (1H, dd, J = 9.44 and 2.42 Hz), 8.48 (1H, d, J = 2.34 Hz)
Preparation 30
1-(2,6-Dimethylphenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 242 (M-H)
1H-NMR (CD3OD) d 2.06 (6H, s), 6.70 (1H, d, J = 10.20 Hz),
7.21-7.35 (3H, m), 8.08-8.15 (2H, m)
Preparation 31
1-(2-Chloro-6-fluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 266 (M-H)
1H-NMR (DMSO-d6) d 6.62 (1H, d, J = 9.68 Hz), 7.43-7.51 (1H, m) ,
7.56-7.64 (2H, m), 7.94 (1H, dd, J= 9.80 and 2.56 Hz), 8.38
(1H, d, J = 2.44 Hz), 13.06 (1H, s)
Preparation 32
6-Oxo-1-(1-phenylethyl)-1,6-dihydro-3-
pyridinecarboxylic acid was obtained according to a similar
manner to Preparation 24.
Mass ESI (-) 242 (M-H)
1H-NMR (CD3OD) d 1.78 (3H, d, J = 7.14 Hz), 6.29 (1H, q, J =
7.10 Hz), 6.57 (1H, d, J = 9.46 Hz), 7.28-7.45 (5H, m) , 7.92
(1H, dd, J = 9.36 and 2.40 Hz), 8.19 (1H, d, J = 2.40 Hz)
Preparation 33
To a suspension of 1-(2,6-difluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylic acid (795 mg) in CH2Cl2 (8 mL)
were added DMF (0.025 mL) and ethanedioyl dichloride (603 mg)
at 0°C under a nitrogen atmosphere, and the mixture was
stirred at room temperature for 2 hr. The volatile materials
were removed by evaporation in vacuo to give 1-(2,6-
dif luorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarbonyl chloride
(810 mg).
1H-NMR (CDCl3) d 6.68-6.72 (1H, m), 7.09-7.17 (2H, m) , 7.44-
7.55 (1H, m), 7.92-7.97 (1H, m), 8.31 (1H, dd, J= 2.72 and
0.56 Hz)
Preparation 34
1-(2-Chloro-6-fluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinecarbonyl chloride was obtained according to a similar
manner to Preparation 33.
1H-NMR (CDCl3) d 6.71 (1H, d, J = 9.84 Hz), 7.23-7.27 (1H, m),
7.41-7.52 (2H, m), 7.95 (1H, dd, J= 9.88 and 2.72 Hz), 8.12
(1H, s)
Preparation 35
To a solution of 3-amino-4-chlorobenzoic acid (509 mg)
in THF (8 mL) was added dropwise an 1 M THF solution of
lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (6 mL) while
keeping the internal temperature below -5°C under a nitrogen
atmosphere, and the mixture was stirred around -5°C for 30 min.
To the solution was added dropwise a solution of 1-(2,6-
dif luorophenyl) - 6-oxo-1,6-dihydro-3-pyridinecarbonyl chloride
(800 mg) in THF (8 mL), and the resulting mixture was stirred
around -5°C for 1 hr. The reaction mixture was partitioned
between EtOAc (16 mL) and 1 M HCl (16 mL) . The aqueous layer
was extracted with EtOAc (8 mL) . The organic layers were
combined, washed with brine two times, dried over MgSO4,
filtered and evaporated in vacuo. The residue was triturated
with CH2Cl2, and the precipitates produced were collected by
filtration. The isolated product was triturated with MeOH and
collected by filtration to give 4-chloro-3-({[1-(2,6-
difluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinyl]carbonyl}amino)benzoic acid (288 mg).
Mass ESI (-) 403 (M-H)
1H-NMR (DMSO-d6) d 6.70 (1H, d, J = 9.76 Hz), 7.34-7.44 (2H, m),
7.64-7.71 (2H, m), 7.82 (1H, dd, J= 6.88 and 4.80 Hz), 8.08
(1H, s), 8.10 (1H, dd, J = 7.32 and 2.64 Hz), 10.04 (1H, s),
13.27 (1H, br s)
Preparation 36
4-Bromo-3-({[1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-
3-pyridinyl]carbonyl}amino)benzoic acid was obtained according
to a similar manner to Preparation 35.
Mass ESI (-) 403 (M-H)
1H-NMR (DMSO-d6) d 6.70 (1H, d, J = 9.76 Hz), 7.34-7.44 (2H, m),
7.64-7.71 (2H, m), 7.82 (1H, dd, J= 6.88 and 4.80 Hz), 8.08
(1H, s), 8.10 (1H, dd, J = 7.32 and 2.64 Hz), 10.04 (1H, s),
13.27 (1H, br s)
Preparation 37
4-Chloro-3-({[1-(2-chloro-6-fluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinyl]carbonyl}amino)benzoic acid was obtained
according to a similar manner to Preparation 35.
Mass ESI (-) 419 (M-H)
1H-NMR (DMSO-d6) d 6.71 (1H, d, J = 9.84 Hz), 7.53-7.69 (4H, m),
7.81 (1H, dd, J = 8.32 and 2.04 Hz), 8.09-8.13 (2H, m), 8.53
(1H, d, J = 2.44 Hz), 10.04 (1H, s), 13.25 (1H, s)
Preparation 38
To a suspension of 1-(2,3-difluorophenyl)-6-oxo-1, 6-
dihydro-3-pyridinecarboxylic acid (1.24 g) and DMF (0.124 mL)
in CH2Cl2 (124 mL) was added ethanedioyl dichloride (940 mg)
at 0°C under a nitrogen atmosphere, and the mixture was
stirred at anibient temperature for 1 hr. Additional DMF
(0.124 mL) was added, and the mixture was stirred for
additional 30 min. The volatile materials were removed by
evaporation and the residue was suspended in THF (12.4 mL) and
cooled to -78°C. To a solution of 3-amino-4-chlorobenzoic
acid (847 mg) in THF (18 mL) was added an 1 M THF solution of
lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (9.9 mL) at 0°C
under a nitrogen atmosphere, and the mixture was stirred at
room temperature for 30 min. The solution was cooled to -78°C,
and to the solution was added the suspension of l-(2,3-
difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarbonyl chloride
in THF (12.4 mL) prepared as described above. The resulted
mixture was stirred at -78°C for 2 hr under a nitrogen
atmosphere, and then poured into a mixture of EtOAc (30 mL)
and 1 M HCl (20 mL) . The aqueous layer was extracted with
EtOAc (30 mL) and the organic layers were combined, washed
with brine, dried over MgSO4, filtered and evaporated in vacuo.
The residue was triturated with MeOH, and the precipitates
produced were collected by filtration to give 4-chloro-3-({[1-
(2,3-difluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinyl]carbonyl}amino)benzoic acid (780 mg).
Mass ESI (-) 403 (M-H)
1H-NMR (DMSO-d6) d 6.66 (1H, d, J = 9.64 Hz), 7.41-7.47 (1H, m) ,
7.50-7.54 (1H, m), 7.63-7.70 (2H, m), 7.81 (1H, dd, J= 8.36
and 2.04 Hz), 7.91 (1H, d, J = 2.56 Hz), 7.93 (1H, d, J = 2.52
Hz), 8.53 (1H, s), 10.05 (1H, s), 13.27 (1H, br s)
Preparation 39
To a solution of (4-methyl-3-nitrophenyl)amine (304 mg)
in DMF (3 mL) were added cyclopropanecarboxylic acid (258 mg),
HATU (1.14 g) and iPr2NEt (1.55 g) successively, and the
mixture was stirred at room temperature for 16 hr under a
nitrogen atmosphere. The reaction mixture was diluted with
EtOAc (15 mL) and the resulted mixture was washed with 1 M HCl
(15 mL x 2), saturated aqueous NaHC03 (15 mL x 2) and brine,
dried over MgSO4, filtered and evaporated in vacuo. The
residue was purified by silica gel column chromatography
eluting with EtOAc - hexane (1:2) to give N- (4-methyl-3-
nitrophenyl)cyclopropanecarboxamide (413 mg).
Mass ESI (+) 243 (M+Na)
1H-NMR (CD3OD) d 0.82-0.88 (2H, m), 0.90-1.00 (2H# m) , 2.49 (3H,
s), 7.34 (1H, d, J = 8.37 Hz), 7.66 (1H, dd^ J = 8.38 and 2.29
Hz), 8.32 (1H, d, J = 2.18 Hz)
Preparation 40
N-(4-Methyl-3-nitrophenyl) cyclopropanecarboxamide (409
mg) was hydrogenated over 10% Pd/C (50% wet, 80 mg) at
atmospheric pressure of hydrogen in MeOH (20 mL) for 5 hr. The
catalyst was removed by filtration through Celite® pad and the
filtrate was evaporated in vacuo to give N-(3-amino-4-
methylphenyl) cyclopropanecarboxamide (335 mg) .
Mass ESI (+) 213 (M+Na)
1H-NMR (CD3OD) d 0.75-0.84 (2H, m), 0.87-0.95 (2H, m) , 1.65-
1.78 (1H, m), 2.09 (3H, s), 6.73 (1H, dd, J= 8.04 and 2.04
Hz), 6.89 (1H, d, J = 8.06 Hz), 7.00 (1H, d, J = 1.98 Hz)
Preparation 41
To a suspension of 3-tert-butyl-1-(4-methylphenyl)-1H-
pyrazol-5-amine hydrochloride (2.5 g) in EtOAc (18 mL) was
added 2.94 M aqueous NaOH (8 mL) at 0°C under a nitrogen
atmosphere, and the mixture was stirred at the same
temperature for 15 min. To the reaction mixture was added
2,2,2-trichloroethyl chlorocarbonate (2.79 g), and the
resulting mixture was stirred at room temperature for 6 hr.
The organic layer was separated and successively washed with
brine (10 mL x 2), dried over MgSO4, filtered and evaporated
in vacuo. The residue was triturated with IPE, and the
precipitates produced were collected by filtration to give
2,2,2-trichloroethyl [3-tert-butyl-1-(4-methylphenyl)-1H-
pyrazol-5-yl]carbamate (1.96 g) .
Mass ESI (+) 406 (M+H)
1H-NMR (CDCl3) d 1.34 (9H, s), 2.40 (3H, s), 4.81 (2H, s), 6.41
(1H, s), 6.80 (1H, br s), 7.31-7.37 (4H, m).
Preparation 42
To a mixture of 2,2,2-trichloroethyl [3-tert-butyl-1-
(4-methylphenyl) -1H-pyrazol-5-yl] carbamate (101 mg) and (4-
methy 1-3-nitrophenyl) amine (38 mg) in DMSO (1 mL) was added
iPr2NEt (44 µL) under a nitrogen atmosphere and the mixture
was stirred at 60°C for 4 hr. The reaction mixture was
diluted with EtOAc (2 mL) and successively washed with 1M HCl
(2 mL x 2), saturated aqueous NaHCO3 (2 mL) and brine (2 mL),
dried over MgSO4 and filtered. The filtrate was evaporated in
vacuo, and the residue was purified by silica gel column
chromatography eluting with 2% MeOH in CH2Cl2 to give 1-[3-
tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-(4-methyl-3-
nitrophenyl)urea (96 mg).
Mass ESI (+) 408 (M+Na)
1H-NMR(CDCl3) d 1.30 (9H, s), 2.31 (3H, s) , 2.52 (3H,s), 6.40
(1H, s), 6.75 (1H, s), 7.12-7.27 (4H, m), 7.52 (1H, dd, J=
8.32 and 2.26 He), 7.70 (1H, s), 7.90 (1H, d, J = 2.20 Hz).
Preparation 43
1- [3-tert-Butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-
(4-methyl-3-nitrophenyl)urea (93 mg) was hydrogenated over 10%
Pd/C (50% wet, 10 mg) at atmospheric pressure of hydrogen in
MeOH (2 mL) for 4 hr. The catalyst was removed by filtration
through Celite® pad and the filtrate was evaporated in vacuo.
The residue was triturated with IPE and the precipitates
produced were collected by filtration to give 1-(3-amino-4-
methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]urea (74 mg).
Mass ESI (+) 378 (M+H)
1H-NMR (CDCl3) d 1.37 (9H, s), 2.32 (3H, s), 2.43 (3H, s), 7.11
(1H, dd, J = 8.34 and 2.18 Hz), 7.24-7.32 (2H, m), 7.38 (4H,
a), 7.81 (1H, d, J = 2.32 Hz)
Preparation 44
To a solution (4-methyl-3-nitrophenyl)amine (152 mg) in
CH2Cl2 (15 mL) were added iPr2NEt (1.29 g) and trichloroacetic
anhydride (370 mg) successively at 0°C under a nitrogen
atmosphere, and the mixture was stirred at 0°C for 3 hr. To
the solution was added phenylamine (930 mg), and the resulted
mixture was stirred at room temperature for 16 h. The
volatile materials were evaporated in vacuo. The residue was
diluted with EtOAc (10 mL) and the resulted mixture was
successively washed with 1M HCl (5 mL x 2), saturated aqueous
NaHCO3 (5 mL x 2) and brine, dried over MgSO4 and filtered.
The filtrate was evaporated in vacuo, and the residue was
triturated with IPE. The precipitates produced were collected
by filtration to give 1-(4-methyl-3-nitrophenyl)-3-phenylurea
(270 mg).
Mass ESI (+) 294 (M+Na)
1H-NMR (DMSO-d6) d 2.45 (3H, s) , 6.95-7.02 (1H, m) , 7.25-7.57
(6H, m), 8.29 (1H, d, J = 2.24 Hz), 8.81 (1H, s), 9.08 (1H, s)
Preparation 45
1-Cyclopropyl-3- (4-methyl-3-nitrophenyl) urea was
obtained according to a similar manner to Preparation 44.
Mass ESI (+) 258 (M+Na)
1H-NMR (CDCl3) d 0.46-0.54 (2H, m), 0.70-0.79 (2H, m) , 2.47 (3H,
s), 2.52-2.63 (1H, m), 7.28 (1H, d, J = 8.40 Hz), 7.50 (1H, dd,
J = 8.34 and 2.30 Hz), 8.16 (1H, d, J 2.32 Hz)
Preparation 46
1-(3-Amino-4-methylphenyl)-3-phenylurea was obtained
according to a similar manner to Preparation 43.
Mass ESI (+) 264 (M+Na)
1H-NMR (DMSO-d6) d 1.97 (3H, s) , 4.79 (2H, s), 6.53 (1H, d, J =
7.85 Hz), 6.76-6.79 (2H, m), 6.94 (1H, d, J = 7.33 Hz), 7.25
(2H, t, J = 7.74 Hz), 7.42 (2H, d, J = 7.75 Hz), 8.32 (1H, s),
8.55 (1H, s)
Preparation 47
1-(3-Amino-4-methylphenyl)-3-cyclopropylurea was
obtained according to a similar manner to Preparation 43.
Mass ESI (+) 228 (M+Na)
1H-NMR (DMSO-d6) d 0.31-0.39 (2H, m), 1.95 (3H, s), 4.69 (2H,
s), 6.21 (1H, d, J = 2.54 Hz), 6.49 (1H, dd, J = 7.96 and 2.10
Hz), 6.67-6.74 (2H, m), 7.87 (1H, s)
Example 1
To a solution of 4-chloro-3-({[1-(2,6-dichlorophenyl)-
6-oxo-1,6-dihydro-3-pyridinyl]carbonyl}amino)benzoic acid
(1.74 g) in DMF (17 mL) were added HATU (3.03 g) ,
cyclopropanamine (680 mg) and iPr2NEt (3.08 g) successively at
0°C, and the mixture was stirred at room temperature for 16 hr
under a nitrogen atmosphere. The mixture was partitioned
between EtOAc (50 mL) and 1 M HCl (50 mL), and the
precipitates produced were removed by filtration. The organic
layer of the filtrate was separated and washed with 1 M HCl
(50 mL), saturated aqueous NaHCO3 (50 mL x 2) and brine
successively, dried over MgSO4 and filtered. The filtrate was
evaporated in vacuo, and the residue was triturated with a
mixture of IPE and MeOH. The precipitates were collected by
filtration, triturated with EtOH and collected by filtration
to give N-{2-chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-dichlorophenyl)-6-oxo-l, 6-dihydro-3-pyridinecarboxamide
(890 mg).
Mass ESI (+) 498 (M+Na)
1H-NMR (DMSO-d6) d 0.52-0.59 (2H, m), 0.61-0.74 (2H, m), 2.78-
2.91 (1H, m), 6.72 (1H, d, J = 9.74 Hz), 7.58-7.79 (4H, m),
7.97 (1H, d, J = 1.96 Hz), 8.14 (1H, dd, J = 9.66 and 2.56 Hz),
8.47 (1H, d, J = 2.46 Hz), 8.52 (1H, d, J = 4.14 Hz), 10.03
(1H, s)
Example 2
N-{2-Chloro-5-[(methoxyamino)carbonyl]phenyl}-1-(2, 6-
dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 1.
Mass ESI (+) 490 (M+Na)
1H-NMR (DMSO-d6) d 3.70 (3H, s), 6.71 (1H, d, J = 9.80 Hz),
7.60-7.68 (3H, m), 7.76-7.78 (2H, m), 7.92 (1H, d, J = 1.52
Hz), 8.13 (1H, dd, J - 9.72 and 2.64 Hz), 8.48 (1H, d, J =
2.40 Hz), 10.04 (1H, s), 11.86 (1H, s)
Example 3
N-{2-Chloro-5-[(isoxazol-3-ylamino)carbonyl]phenyl}-1-
(2,6-dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxaroide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 526 (M+Na)
1H-NMR (DMSO-d6) d 6.72 (1H, d, J = 9.80 Hz), 7.04 (1H, d, J =
1.64 Hz), 7.60-7.64 (2H, m), 7.71-7.78 (3H, m), 7.94 (1H, dd,
J = 8.44 and 2.16 Hz), 8.15 (1H, dd, J = 9.68 and 2.56 Hz),
8.23 (1H, d, J = 2.20 Hz), 8.50 (1H, d, J = 2.40 Hz), 8.86 (1H,
d, J = 1.68 Hz), 10.07 (1H, s)
Example 4
N-{2-Chloro-5-[(pyridin-3-ylamino) carbonyl]phenyl}-1-(2, 6-dichlorophenyl) -6-oxo-l, 6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 537 (M+Na)
1H-NMR (DMSO-d6) d 6.72 (1H, d, J = 9.72 Hz), 7.41 (1H, dd, J =
8.32 and 4.88 Hz), 7.62 (1H, dd, J = 8.68 and 7.44 Hz), 7.73-
7.78 (3H, m), 7.93 (1H, dd, J= 8.44 and 2.08 Hz), 8.16-8.20
(3H, m), 8.33 (1H, dd, J = 4.76 and 1.48 Hz), 8.53 (1H, d, J =
2.44 Hz), 8.93 (1H, d, J = 2.56 Hz),10.18 (1H, s), 10.58 (1H,
s)
Example 5
N-{2-Chloro-5-[(1-methyl-1H-pyrazol-3-
ylamino)carbonyl]phenyl}-1-(2, 6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide was obtained according to a
similar manner to Example 1.
Mass ESI (+) 540 (M+Na)
1H-NMR (DMSO-d6) d 3.78 (3H, s), 6.58 (1H, d, J = 2.0 Hz], 6.72
(1H, df J = 9.6 Hz), 7.60-7.67 (3H, m), 7.77 (2H, d, J = 8.0
Hz), 7.91 (1H, dd, J = 8.0 and 1.6 Hz), 8.17 [1H, dd, J = 10.0
and 2.8 Hz), 8.20 (1H, d, J =2.0 Hz), 8.49 (1H, d, J = 2.8
Hz), 10.04 (1H, s), 10.93 (1H, s)
Example 6
N-{2-Chloro-5-[(1-methyl-1H-pyrazol-5-
ylamino)carbonyl]phenyl}-1-(2, 6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide was obtained according to a
similar manner to Example 1.
Mass ESI (+) 538 (M+Na)
1H-NMR (DMSO-d6) d 3.68 (3H, s), 6.23 (1H, d, J = 2.0 Hz),
6.72 (1H, d, J = 9.6 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.62 (1H,
dd, J= 8.8 and 7.6 Hz), 7.73-7.78 (3H, m), 7.88 (1H, d, J =
2.0 Hz), 8.13-8.16 (2H, m), 8.50 (1H, d, J = 2.4 Hz), 10.09
(1H, s), 10.40 (1H, s)
Example 7
N-{2-Chloro-5-[(1-phenyl-1H-pyrazol-5-
ylamino)carbonyl]phenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide was obtained according to a
similar manner to Example 1.
Mass ESI (+) 602 (M+Na)
1H-NMR (DMSO-d6) d 6.48 (1H, s) , 6.71 (1H, d, J = 9.64 Hz),
7.32-7.79 (11H, m), 8.04 (1H, s), 8.13 (1H, dd, J= 9.76 and
2.64 Hz), 8.48 (1H, d, J = 2.36 Hz), 10.06 (1H, s), 10.49 (1H,
s)
Example 8
N-{2-Chloro-5-[(cyclopropylamino) carbonyl] phenyl}-1-
(2,6-dichloro-4-methylphenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxamide was obtained according to a similar manner
to Example 1.
]Mass ESI (+) 492 (M+Na)
1H-NMR(DMSO-d6) d 0.54-0.58 (2H, m), 0.66-0.71 (2H, m), 2.04
(6H, s), 2.82-2.86 (1H, m), 6.67 (1H, d, J = 9.64 Hz), 7.41
(2H, s), 7.62 (1H, d, J = 8.39 Hz), 7.72 (1H, dd, J = 8.39 and
2.08 Hz), 7.97 (1H, d, J = 2.10 Hz), 8.08 (1H, dd, J = 9.63
and 2.65 Hz), 8.32 (1H, d, J = 2.60 Hz), 8.53 (1H, s), 9.99
(1H, s)
Example 9
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-
cyclohexyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 1.
Mass ESI (+) 436 (M+Na)
1H-NMR (DMSO-d6) d 0.56-0.59 (2H, m), 0.67-0.70 (2H, m), 1.20-
1.28 (1H, m), 1.36-1.47 (2H, m), 1.63-1.74 (3H, m), 1.73-1.88
(4H, m), 2.83-2.89 (1H, m], 4.67-4.74 (1H, m), 6.50 (1H, d, J
= 9.52 Hz), 7.63 (1H, d, J = 8.40 Hz), 7.75 (1H, dd, J = 8.40
and 2.20 Hz), 7.91 (1H, dd, J = 9.40 and 2.48 Hz), 7.96 (1H, d,
J = 1.88 Hz), 8.46 (1H, d, J = 2.48 Hz), 8.54 (1H, d, J = 4.16
Hz), 10.04 (1H, s)
Example 10
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-dimethyl-4-fluorophenyl)-6-oxo-1,6-dihydro-3-
pyridinecarboxamide was obtained according to a similar manner
to Example 1.
Mass ESI (+) 476 (M+Na)
1H-NMR (DMSO-d6) d 0.54-0.58 (2H, m), 0.66-0.71 (2H, m), 2.05
(6H, s), 2.83-2.85 (1H, m), 6.67 (1H, d, J = 9.60 Hz), 7.17
(2H, d, J = 9.31 Hz), 7.62 (1H, d, J = 8.36 Hz), 7.72 (1H, dd,
J = 8.35 and 2.01 Hz), 7.97 (1H, d, J = 2.08 Hz), 8.08 (1H, dd,
J = 9.57 and 2.54 Hz), 8.32 (1H, d, J = 2.56 Hz), 4.14 Hz),
9.99 (1H, s)
Example 11
N-{2-Chloro-5-[(cyclopropylamino) carbonyl] phenyl}-1-
(2,6-difluorophenyl)-6-oxo-l, 6-dihydro-3-pyridinecarboxaraide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 466 (M+Na)
1H-NMR (DMSO-d6) d 0.54-0.58 (2H, m), 0.67-0.71 (2H, m), 2.81-
3.31 (1H, m), 6.70 (1H, d, J = 9.76 Hz), 7.42 (2H, t, J = 8.28
Hz), 7.62-7.74 (3H, m), 7.97 (1H, d, J = 2.12 Hz), 8.10 (1H,
dd, J = 9.72 and 2.76 Hz), 8.53 (1H, d, J = 4.16 Hz), 8.58 (1H,
d, J = 2.48 Hz), 10.03 (1H, s)
Example 12
N-{2-Chloro-5-[(l-methyl-1H-pyrazol-5-
ylamino) carbonyl]phenyl}-1-(2, 6-difluorophenyl) -6-oxo-l, 6-
dihydro-3-pyridinecarboxamide was obtained according to a
similar manner to Example 1.
Mass ESI (+) 506 (M+Na)
1H-NMR (DMSO-d6) 3.69 (3H, s), 6.23 (1H, d, J = 1.92 Hz), 6.71
(1H, d, J = 9.64 Hz), 7.39-7.44 (3H, m), 7.66-7.70 (2H, m) ,
7.74 (1H, d, J = 8.40 Hz), 7.90 (1H, dd, J = 8.40 and 2.04 Hz),
8.10-8.14 (2H, m), 8.60 (1H, d, J = 2.52 Hz), 10.1 (1H, br s),
10.42 (1H, br s)
Example 13
N-{2-Chloro-5-
[(cyclopropylmethoxyamino) carbonyl]phenyl}-1-(2,6-
difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 1.
Mass ESI (+) 496 (M+Na)
1H-NMR (DMSO-d6) 0.24-0.27 (2H, m), 0.51-0.55 (2H, m), 1.08-
1.12 (1H, m), 3.65-3.71 (2H, m), 6.71 (1H, d, J = 9.84 Hz),
7.42 (2H, t, J = 8.20 Hz), 7.64-7.71 (3H, m), 7.92 (1H, d, J =
1.60 Hz), 8.10 (1H, dd, J = 9.72 and 1.60 Hz), 8.58 (1H, d, J
= 2.52 Hz), 10.04 (1H, s), 11.75 (1H, s, J = 11.76 Hz)
Example 14
N-{2-Chloro-5-[(l-methyl-1H-pyrazol-3-
ylamino)carbonyl]phenyl}-1-(2,6-difluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide was obtained according to a
similar manner to Example 1.
Mass ESI (+) 506 (M+Na)
1H-NMR (DMSO-de) 5 3.78 (3H, s), 6.58 (1H, d, J = 2.20 Hz),
6.71 (1H, d, J = 9.72 Hz), 7.40-7.45 (2H, m), 7.61-7.70 (3H,
m), 7.91 (1H, dd, J - 8.44 and 2.16 Hz), 8.12 (1H, dd, J =
9.72 and 2.60 Hz), 8.19 (1H, d, J = 2.16 Hz), 8.60 (1H, d, J =
2.52 Hz), 10.05 (1H, s), 10.94 (1H, s)
Example 15
N-{2-Bromo-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 512 (M+Na)
1H-NMR (DMSO-d6) d 0.55-0.58 (2H, m), 0.67-0.70 (2H, m), 2.83-
2.86 (1H, m), 6.71 (1H, d, J = 9.76 Hz), 7.40-7.44 (2H, m),
7.64-7.68 (2H, m), 7.79 (1H, d, J = 8.40 Hz), 7.92 (1H, d, J =
2.08 Hz), 8.11 (1H, dd, J= 9.72 and 2.60 Hz), 8.54 (1H, d, J
= 4.20 Hz), 8.57 (1H, d, J = 2.92 Hz), 10.02 (1H, s)
Example 16
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2-
chloro-6-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 482 (M+Na)
1H-NMR (DMSO-de) d 0.54-0.58 (2H, m), 0.67-0.71 (2H, m), 2.82-
2.87 (1H, m), 6.71 (1H, d, J = 9.76 Hz), 7.53-7.58 (1H, m), .
7.62-7.67 (3H, m), 7.73 (1H, dd, J = 8.40 and 2.04 Hz), 7.97
(1H, d, J = 2.04 Hz), 8.12 (1H, dd, J = 9.72 and 2.60 Hz),
8.52 (2H, d, J = 2.76 Hz), 10.02 (1H, s)
Example 17
N-{2-Chloro-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,3-difluorophenyl) -6-oxo-l, 6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 1.
Mass ESI (+) 466 (M+Na)
1H-NMR (DMSO-d6) d 0.54-0.58 (2H, m), 0.67-0.71 (2H, m) , 2.82-
2.87 (1H, ra), 6.66 (1H, d, J = 9.52 Hz), 7.43-7.47 (2H, m) ,
7.50-7.74 (3H, m), 7.96 (1H, d, J = 2.08 Hz), 8.08 (1H, dd, J
= 9.68 and 2.60 Hz), 8.52 (1H, s), 8.54 (1H, d, J = 5.20 Hz),
10.03 (1H, s)
Example 18
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylic acid (56 mg) in DMF (0.76 mL)
were added 3-amino-N-cyclopropyl-4-methylbenzamide (45 mg),
WSC-HCl (57 mg), HOBt (35 mg) and Et3N (27 mg) , and the
mixture was stirred under a nitrogen atmosphere at room
temperature for 16 hr. The reaction mixture was diluted with
EtOAc (2 mL), washed with water (4 mL x 2) and brine
successively, dried over MgSO4, filtered and evaporated in
vacuo. The residue was purified by preparative thin layer
chromatography eluting with 10% MeOH in CH2Cl2 to give N-{5-
[(cyclopropylamino) carbonyl] -2-methylphenyl}-1-(2, 6-
dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (60
mg).
Mass ESI (+) 480 (M+Na)
1H-NMR (CDCl3) d 0.54-0.62 (2H, m) , 0.76-0.86 (2H, m), 2.29 (3H,
s), 2.77-2.84 (1H, m), 6.61 (1H, s), 6.70 (1H, d, J = 10.24
Hz), 7.18 (1H, d, J = 7.96Hz), 7.34-7.52 (4H, m), 7.68 (1H,
s), 8.00-8.06 (2H, m), 8.41 (1H, s)
Example 19
N-{5-[(Cyclopropylamino) carbonyl] -2-methylphenyl}-1-(2-
methylphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 18.
1H-NMR (CDCl3) d 0.53-0.61 (2H, m) , 0.76-0.88 (2H, m), 2.17 (3H,
s), 2.35 (3H, s), 2.76-2.84 (1H, m), 6.49 (1H, s), 6.69 (1H, d,
J= 9.56), 7.18-7.46 (6Hr m), 7.74 (1H, s), 7.97 (1H, dd, J =
9.76 and 2.72 Hz), 8.18 (1H, d, J = 2.44 Hz), 8.25 (1H, s)
Example 20
To a solution of l-tert-butyl-6-oxo-1,6-dihydro-3-
pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were added 3-
amino-N-cyclopropyl-4-methylbenzamide (44 mg), HATU (88 mg)
and iPr2NEt (89 mg) , and the mixture was stirred under a
nitrogen atmosphere at room temperature for 3 hr. The
reaction mixture was diluted with EtOAc (3 mL) and the
resulting mixture was washed with 1 M HCl (3 mL x 2), water (3
mL), saturated aqueous NaHCO3 (3 mL) and brine successively,
dried over MgSO4, filtered and evaporated in vacuo. The
residue was purified by preparative thin layer chromatography
eluting with 10% MeOH in CH2Cl2 to give N-{5-
[(cyclopropylamino) carbonyl] -2-methylphenyl}-1-tert-butyl-6-
oxo-1, 6-dihydro-3-pyridinecarboxamide (27 mg).
Mass ESI (+) 390 (M+Na)
1H-NMR (CD3OD) d 0.58-0.66 (2H, m), 0.75-0.85 (2H, m), 1.74 (9H,
s), 2.79-2.87 (1H, m), 4.60 (2H, s), 6.51 (1H, d, J = 9.34 Hz),
7.37 (1H, d, J = 7.98 Hz), 7.63 (1H, dd, J = 7.94 and 1.86 Hz),
7.74 (1H, d, J = 1.72 Hz), 7.98 (1H, dd, J = 9.42 and 2.48 Hz),
8.55 (1H, d, J = 2.42 Hz)
Example 21
N-{5-[(Cyclopropylamino) carbonyl] -2-methylphenyl}-1-
(2, 6-dimethylphenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 20.
Mass ESI (+) 438 (M+Na)
1H-NMR (CD3OD) d 0.57-0.64 (2H, m), 0.74-0.84 (2H, m) , 2.11 (6H,
s), 2.77-2.85 (1H, m), 6.78 (1H, d, J = 10.44 Hz), 7.23-7.37
(4H, m), 7.62 (1H, dd, J = 7.96 and 1.88 Hz), 7.73 (1H, d, J =
1.84 Hz), 8.19-8.25 (2H, m)
Example 22
N-{5-[(Cyclopropylamino) carbonyl] -2-methylphenyl} -1-
(2,6-difluorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 20.
Mass ESI (+) 446 (M+Na)
1H-NMR (CD3OD) d 0.57-0.67 (2H, m), 0.70-0.84 (2H, m), 2.77-
2.88 (1H, m), 6.75 (1H, d, J = 9.72 Hz), 7.22-7.37 (3H, m),
7.55-7.70 (2H, m) , 7.74 (1H, d, J = 1.60 Hz), 8.18 (1H, dd, J
= 9.72 and 2.56 Hz), 8.39 (1H, d, J = 2.22 Hz)
Example 23
N-{5-[(Cyclopropylamino) carbonyl] -2-methylphenyl}-1-(2-
chloro-6-fluorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
was obtained according to a similar manner to Example 20.
Mass ESI (+) 462 (M+Na)
1H-NMR (CD3OD) d 0.57-0.65 (2H, m), 0.70-0.84 (2H, m) , 2.77-
2.98 (1H, m), 6.75 (1H, d, J = 9.62 Hz), 7.34-7.43 (2H, m),
7.54-7.65 (3H, m), 7.74 (1H, d, J = 1.74 Hz), 8.20 (1H, dd, J
= 9.64 and 2.58 Hz), 8.33 (1H, d, J = 2.46 Hz)
Example 24
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-1-(1-
phenylethyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 20.
Mass ESI (+) 438 (M+Na)
1H-NMR (CD3OD) d 0.56-0.66 (2H, m), 0.69-0.83 (2H, m), 1.82
(3H, d, J = 7.16 Hz), 2.25 (3H, s), 2.76-2.87 (1H, m) , 6.33
(1H, q, J = 7.11 Hz), 6.64 (1H, d, =9.50 Hz), 7.32-7.39 (5H,
m), 7.62 (1H, dd, J = 8.02 and 1.40 Hz), 7.68 (1H, s), 8.03
(1H, dd, J = 9.47 and 2.43 Hz), 8.27 (1H, d, J = 2.35 Hz)
Example 25
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylic acid (30 mg) in DMF (0.6 mL) were
added N-(3-amino-4-methylphenyl) cyclopropanecarboxamide (30
mg), HATU (60 mg) and iPr2NEt (62 mg) successively, and the
mixture was stirred under a nitrogen atmosphere at room
temperature for 16 hr. The reaction mixture was diluted with
EtOAc (3 mL), and the resulting mixture was washed with 1 M
HCl (3 mL x 2), saturated aqueous NaHCO3 (3 mL x 2) and brine
successively, dried over MgSO4 and evaporated in vacuo. The
residue was triturated with 10% MeOH in CH2Cl2, and the
precipitates produced were collected by filtration to give N-
{5- [ (cyclopropylcarbonyl) amino]-2-methylphenyl}-1-(2,6-
dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide (25
mg).
Mass ESI (+} 478 (M+Na)
1H-NMR (DMSO-d6) d 0.76 (4H, d, J = 6.08 Hz), 1.70-1.80 (1H, m),
2.13 (3H, s), 6.68 (1H, d, J = 9.70 Hz),. 7.15 (1H, d, J = 8.34
Hz), 7.33 (1H, dd, J= 8.20 and 2.02 Hz), 7.57-7.65 (2H, m),
7.74 (1H, s), 7.78 (1H, d, J = 1.48 Hz), 8.13 (1H, dd, J=
9.66 and 2.54 Hz), 8.40 (1H, d, J = 2.42 Hz), 9.69 (1H, s),
10.16 (1H, s)
Example 26
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxylic acid (35 mg) and 1-(3-amino-4-
methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl) -1H-pyrazol-5-
yl]urea (70 mg) in DMF (1 mL) were added HATU (71 mg) and
iPr2NEt (96 mg) successively under a nitrogen atmosphere, and
the mixture was stirred at room temperature for 16 hr. The
reaction mixture was diluted with EtOAc (5 mL) and the
resulted mixture was successively washed with 1M HCl (5 mL x
2), saturated aqueous NaHCO3 (5 mL x 2) and brine, dried over
MgSO4, filtered and evaporated in vacuo. The residue was
purified by silica gel column chromatography eluting with 5%
MeOH in CH2Cl2. The isolated material was triturated with
CH2Cl2, and the precipitates were collected by filtration to
give N-{5-[({[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-
yl]amino}carbonyl) amino ]-2-methylphenyl}-1-(2, 6-
dichlorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide (34
mg).
Mass ESI (+) 665 (M+Na)
1H-NMR (DMSO-d6) d 1.26 (9H, s), 2.12 (3H, s), 2.36 (3H, s),
6.34 (lHf s), 6.69 (1H, d, J = 9.72 Hz), 7.06-7.15 (2H, m),
7.32 (2H,d, J = 8.52 Hz), 7.39 (2H, d, J = 8.62 Hz), 7.53 (1H,
d, J = 1.52 Hz), 7.61 (1H, dd, J = 9.16 and 6.90 Hz), 7.74 (1H,
s), 7.78 (1H, d, J = 1.56 Hz), 8.13 (1H, dd, J = 9.68 and 2.60
Hz), 8.31 (1H, brs), 8.40 (1H, d, J = 2.34 Hz), 9.00 (1H, br
s), 9.65 (1H, s)
Example 27
N-{5-[(Anilinocarbonyl) amino]-2-methylphenyl}-1-(2,6-
dichlorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide was
obtained according to a similar manner to Example 26.
Mass ESI (+) 531 (M+Na)
1H-NMR (DMSO-d6) d 2.13 (3H, s), 6.70 (1H, d, J = 9.64 Hz),
6.95 (1H, t, J = 7.40 Hz), 7.15-7.30 (4H, m), 7.41-7.65 (4H,
m), 7.74-7.78 (2H, d, J = 7.54 Hz), 8.14 (1H, dd, J= 9.94 and
2.44 Hz), 8.41 (1H, d, J = 2.10 Hz), 8.63 (2H, d, J = 4.32 Hz),
9.70 (1H, s)
Example 28
N-(5-{[(Cyclopropylamino)carbonyl]amino}-2-
methylphenyl)-1-(2, 6-dichlorophenyl) -6-oxo-l, 6-dihydro-3-
pyridinecarboxamide was obtained according to a similar manner
to Example 26.
Mass ESI (+) 493 (M+Na)
1H-NMR (DMSO-d6) d 0.34-0.42 (2H, m), 0.57-0.66 (2H, m), 2.10
(3H, s), 6.34 (1H, d, J = 2.32 Hz), 6.68 (1H, d, J = 9.70 Hz),
7.00-7.17 (2H, m), 7.43 (1H, d, J = 1.72 Hz), 7.61 (1H, dd, J
= 9.14 and 6.94 Hz), 7.74 (1H, s) , 7.78 (1H, d, J = 1.48 Hz),
8.13 (1H, dd, J = 9.72 and 2.54 Hz), 8.24 (1H, s), 8.39 (1H, d,
J = 2.32 Hz), 9.65 (1H, s)
The following compounds could be obtained in a similar
manner to Preparations, Examples and methods obvious to those
skilled in the art or modified methods thereof.
Example 29
N-{2-Bromo-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 30
N-{2-Bromo-5-[(cyclopropylamino)carbonyl]phenyl}-1-(2-
chloro-6-fluorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 31
N-{2-Bromo-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-dimethylphenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 32
N-{2-Bromo-5-[(cyclopropylamino) carbonyl]phenyl}-1-(2-
methylphenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 33
N-{2-Bromo-5-[(cyclopropylamino)carbonyl]phenyl}-1-
(2,6-dimethyl-4-fluorophenyl)-6-oxo-1, 6-dihydro-3-
pyridinecarboxamide
Example 34
N-[5-(Anilinocarbonyl)-2-bromophenyl]-1-(2, 6-
dichlorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 35
N-[5-(Anilinocarbonyl)-2-bromophenyl]-1-(2,6-
difluorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 36
N-[5-(Anilinocarbonyl)-2-bromophenyl]-1-(2, 6-
dimethylphenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 37
N-[5-(Anilinocarbonyl)-2-chlorophenyl]-1-(2, 6-
dichlorophenyl)-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 38
N-[5-(Anilinocarbonyl)-2-chlorophenyl] -1-(2,6-
dif luorophenyl) -6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 39
N-[5-(Anilinocarbonyl)-2-chlorophenyl]-1-(2,6-
dimethylphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 40
N-[5-(Anilinocarbonyl)-2-methylphenyl]-1-(2,6-
dimethylphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 41
N-{2-Bromo-5-[(cyclopropylcarbonyl) amino]phenyl}-1-
(2, 6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 42
N-{2-Bromo-5-[(cyclopropylcarbonyl)amino]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro~3-pyridinecarboxamide
Example 43
N-{2-Bromo-5-[(cyclopropylcarbonyl) amino]phenyl}-1-
(2,6-dimethylphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 44
N-{2-Chloro-5-[(cyclopropylcarbonyl)amino]phenyl}-1-
(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 45
N-{2-Chloro-5-[(cyclopropylcarbonyl)amino]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 46
N-{2-Chloro-5-[(cyclopropylcarbonyl)amino]phenyl}-1-
(2,6-dimethylphenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 47
N-{2-Bromo-5-[(1H-pyrazol-3-ylamino)carbonyl]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 48
N-{2-Bromo-5-[(1-methyl-1H-pyrazol-5-
ylamino)carbonyl]phenyl}-1-(2,6-difluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide
Example 49
N-{2-Bromo-5-[(1-methyl-1H-pyrazol-3-
ylamino)carbonyl]phenyl}-1-(2,6-difluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide
Example 50
N-{2-Bromo-5-[(5-methyl-1,3,4-oxadiazol-2-
ylamino)carbonyl]phenyl}-1-(2,6-difluorophenyl)-6-oxo-1,6-
dihydro-3-pyridinecarboxamide
Example 51
N-{2-Bromo-5-[(methoxyamino)carbonyl]phenyl}-1-(2,6-
difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 52
N-{2-Bromo-5-[(isoxazol-3-ylamino)carbonyl]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 53
N-{2-Bromo-5-[(pyridin-3-ylamino)carbonyl]phenyl}-1-
(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide
Example 54
1-(2,6-Difluorophenyl)-N-{2-methyl-5-[(1H-pyrazol-3-
ylamino)carbonyl]phenyl}-6-oxo-1,6-dihydro-3-
pyridinecarboxamide
Example 55
1-(2,6-Difluorophenyl)-N-{2-methyl-5-[(1-methyl-1H-
pyrazol-5-ylamino)carbonyl]phenyl}-6-oxo-1,6-dihydro-3-
pyridinecarboxamide
Example 56
1-(2,6-Difluorophenyl)-N-{2-methyl-5-[(1-methyl-1H-
pyrazol-3-ylamino)carbonyl]phenyl}-6-oxo-1,6-dihydro-3-
pyridinecarboxamide
Example 57
1-(2,6-Difluorophenyl)-N-{2-methyl-5-[(5-methyl-1,3,4-
oxadiazol-2-ylamino)carbonyl]phenyl}-6-oxo-1,6-dihydro-3-
pyridinecarboxamide
Example 58
1-(2,6-Difluorophenyl)-N-{5-[(methoxyamino)carbonyl]-2-
methylphenyl}-6-oxo-1, 6-dihydro-3-pyridinecarboxamide
Example 59
1-(2,6-Difluorophenyl)-N-{5-[(isoxazol-3-
ylamino) carbonyl] -2-methylphenyl}-6-oxo-1, 6-dihydro-3-
pyridinecarboxamide
Example 60
1-(2,6-Difluorophenyl)-N-{2-methyl-5-[(pyridin-3-
ylamino)carbonyl]phenyl}-6-oxo-1,6-dihydro-3-
pyridinecarboxamide
The compounds of the present invention are listed in
the following tables.
No. : Example No.
CLAIMS
1. A compound represented by the formula (I) :
wherein
R1 is lower alkyl, cycloalkyl or aromatic hydrocarbon ring,
each of which is optionally substituted with one or
more substituents;
R2 is halogen atom, lower alkyl, halo(lower)alkyl or lower
alkoxy; and
]R3 is
(1) a group represented by the formula:

wherein
R4 is lower alkyl, lower alkoxy, cycloalkyl,
aromatic hetero ring, non-aromatic hetero ring or
aromatic hydrocarbon ring, each of which is
optionally substituted with one or more
substituents;
(2) a group represented by the formula:

wherein
R5 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring, aromatic hetero ring or non-aromatic hetero
ring, each of which is optionally substituted
with one or more substituents;
(3) a group represented by the formula:

wherein
R6 is lower alkyl, cycloalkyl, aromatic hydrocarbon
ring or non-aromatic hetero ring, each of which
is optionally substituted with one or more
substituents; or
(4) a group selected from halogen atom, carboxy, hydroxy
and lower alkoxy,
or a salt thereof.
2. The compound of claim 1, wherein
R1 is lower alkyl, cycloalkyl or aromatic hydrocarbon ring,
each of which is optionally substituted with one or
more substituents;
R2 is halogen atom or lower alkyl; and
R3 is
(1) a group represented by the formula:

wherein
R4 is lower alkoxy, cycloalkyl, aromatic hetero ring
or aromatic hydrocarbon ring, each of which is
optionally substituted with one or more
substituents,
(2) a group represented by the formula:

wherein
R5 is cycloalkyl, aromatic hydrocarbon ring or
aromatic hetero ring, each of which is optionally
substituted with one or more substituents; or
(3) a group represented by the formula:

wherein
R6 is cycloalkyl, which is optionally substituted
with one or more substituents,
or a salt thereof.
3. The compound of claim 2, wherein
R1 is
(1) (C1-6) alkyl optionally substituted with one
(C6-16) aryl,
(2) (C3-7) cycloalkyl, or
(3) (C6-16)aryl optionally substituted with 1 to 3
substituents selected from halogen atom, (C1-6)alkyl and
(C6-16)aryl;
R2 is halogen atom or (C1-6) alkyl, and
R3 is
(1) a group represented by the formula:

wherein
R4 is (C1-6)alkoxy, (C3-7) cycloalkyl, 5- to 14-
membered aromatic hetero ring or (C6-16)aryl, each
of which is optionally substituted with 1 to 3
substituents selected from (C1-6)alkyl,
(C3-7) cycloalkyl and (C6-16)aryl,
(2) a group represented by the formula:

wherein
R5 is (C3-7)cycloalkyl, (C6-16)aryl or 5- to 14-
membered aromatic hetero ring, each of which is
optionally substituted with 1 to 3 substituents
selected from (C1-6)alkyl and (C6-16) aryl which is
optionally substituted with (C1-6) alkyl, or
(3) a group represented by the formula:

wherein
R6 is (C3-7) cycloalkyl,
or a salt thereof.
4. A pharmaceutical composition comprising the compound of
claim 1 or a pharmaceutically acceptable salt thereof in
admixture with a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4, which is for the
prevention or the treatment of a disease selected from the
group consisting of pain, rheumatoid arthritis, other
conditions associated with inflammation, Crohn's disease,
inflammatory bowel disease and psoriasis.
6. A method for preventing or treating a disease selected from
the group consisting of pain, rheumatoid arthritis, other
conditions associated with inflammation, Crohn's disease,
inflammatory bowel disease and psoriasis, which comprises
administering an effective amount of the compound of claim 1
or a pharmaceutically acceptable salt thereof to a mammal in
need thereof.
7. Use of the compound of claim 1 or a pharmaceutically
acceptable salt thereof for the production of a pharmaceutical
composition for the prevention or the treatment of a disease
selected from the group consisting of pain, rheumatoid
arthritis, other conditions associated with inflammation,
Crohn's disease, inflammatory bowel disease and psoriasis.

A compound
represented by the formula (I): wherein
R1 is lower alkyl, cycloalkyl or
aromatic hydrocarbon ring, each of
which is optionally substituted with one
or more substituents; R2 is hydrogen
atom, halogen atom, lower alkyl,
halo(lower)alkyl or lower alkoxy; and
R3 is (1) a group represented by the
formula: wherein R4 is lower alkyl,
etc.; (2) a group represented by the
formula: wherein R5 is lower alkyl,
etc.; (3) a group represented by the
formula: wherein R6 is lower alkyl,
etc.; or (4) a group selected from
halogen atom, carboxy, hydroxy and
lower alkoxy, or a salt thereof.