U.S. patent application number 16/182266 was filed with the patent office on 2019-03-07 for pyrazole derivative manufacturing method.
This patent application is currently assigned to MOCHIDA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is MOCHIDA PHARMACEUTICAL CO., LTD.. Invention is credited to Tetsuo IWAMA, Takashi KUDOH, Tsutomu SATOH.
Application Number | 20190071441 16/182266 |
Document ID | / |
Family ID | 55217608 |
Filed Date | 2019-03-07 |
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United States Patent
Application |
20190071441 |
Kind Code |
A1 |
SATOH; Tsutomu ; et
al. |
March 7, 2019 |
PYRAZOLE DERIVATIVE MANUFACTURING METHOD
Abstract
The present invention provides a method for manufacturing a
compound represented by formula (I). With this method, provided are
a method for manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative; and an intermediate for this
manufacturing method. ##STR00001##
Inventors: |
SATOH; Tsutomu; (Tokyo,
JP) ; KUDOH; Takashi; (Tokyo, JP) ; IWAMA;
Tetsuo; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MOCHIDA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
MOCHIDA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
55217608 |
Appl. No.: |
16/182266 |
Filed: |
November 6, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15840858 |
Dec 13, 2017 |
10174025 |
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16182266 |
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15329447 |
Jan 26, 2017 |
9879009 |
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PCT/JP2015/071536 |
Jul 29, 2015 |
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15840858 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 213/73 20130101;
C07D 403/04 20130101; C07D 401/14 20130101; A61P 43/00 20180101;
A61P 25/18 20180101; C07D 471/04 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 401/14 20060101 C07D401/14; C07D 213/73 20060101
C07D213/73; C07D 403/04 20060101 C07D403/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 30, 2014 |
JP |
2014-155538 |
Sep 17, 2014 |
JP |
2014-189458 |
Claims
1. A method for manufacturing a compound represented by formula
(AD-2) below: ##STR00178## in formula (AD-2), p denotes an integer
between 0 and 3; R.sup.1 groups each independently denote a group
arbitrarily selected from among a halogen atom, a cyano group, a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a halogenated
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-6
alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II): ##STR00179##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group, the manufacturing method comprising stages in
which a compound represented by formula (AD-1): ##STR00180## in
formula (AD-1), p, R.sup.1, R.sup.2 and ring A group represented by
formula (II) are defined in the same way as for formula (AD-2); and
a 2-amino-4-iodopyridine derivative represented by formula (PY-1):
##STR00181## in formula (PY-1), R.sup.3 denotes a group arbitrarily
selected from among a hydrogen atom and a fluorine atom are reacted
with each other using a solvent which does not take part in the
reaction and which is selected from the group consisting of
1,4-dioxane, tetrahydrofuran and 1,2-dimethoxyethane at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes in the presence of N,N-dimethyl-1,2-ethanediamine,
copper iodide and an inorganic base selected from the group
consisting of potassium carbonate and potassium phosphate, thereby
obtaining the compound represented by formula (AD-2).
2. A method for manufacturing a compound represented by formula
(AD-2) below: ##STR00182## in formula (AD-2), p denotes an integer
between 0 and 3; R.sup.1 groups each independently denote a group
arbitrarily selected from among a halogen atom, a cyano group, a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a halogenated
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.1-6
alkoxy group, a C.sub.1-6 alkoxy-C.sub.2-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II): ##STR00183##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group, the manufacturing method comprising stages in
which a compound represented by formula (ET-1): ##STR00184## in
formula (ET-1), p, R.sup.1, R.sup.2 and ring A group represented by
formula (II) are defined in the same way as for formula (AD-2);
R.sup.D denotes a group arbitrarily selected from among a C.sub.1-6
alkyl group, a C.sub.6-14 aryl group and a C.sub.7-20 aralkyl
group; and an aqueous ammonia solution are reacted with each other
at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes, thereby obtaining a compound
represented by formula (AD-1): ##STR00185## in formula (AD-1), p,
R.sup.1, R.sup.2 and ring A group represented by formula (II) are
defined in the same way as for formula (AD-2), and the compound
represented by formula (AD-1) and a 2-amino-4-iodopyridine
derivative represented by formula (PY-1): ##STR00186## in formula
(PY-1), R.sup.3 denotes a group arbitrarily selected from among a
hydrogen atom and a fluorine atom are reacted with each other using
a solvent which does not take part in the reaction and which is
selected from the group consisting of 1,4-dioxane, tetrahydrofuran
and 1,2-dimethoxyethane at a temperature between 0.degree. C. and a
temperature at which the solvent refluxes in the presence of
N,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic base
selected from the group consisting of potassium carbonate and
potassium phosphate, thereby obtaining the compound represented by
formula (AD-2).
3. A compound represented by formula (AD-1) below: ##STR00187## in
formula (AD-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
and ring A group represented by formula (II): ##STR00188## denotes
a monocyclic 5- to 6-membered heteroaryl group arbitrarily selected
from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group, or a salt of the compound, or a solvate of the
compound or salt.
4. The compound of claim 3, wherein the compound is any one of
intermediate compounds below, or a salt of the intermediate
compound, or a solvate of the intermediate compound or salt:
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide;
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide;
and
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamid-
e.
5. A compound represented by formula (AD-2) below: ##STR00189## in
formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; and ring A group represented by formula
(II): ##STR00190## denotes a monocyclic 5- to 6-membered heteroaryl
group arbitrarily selected from among a thiazol-2-yl group, a
thiazol-4-yl group, a 1-methyl-1H-imidazol-4-yl group, a
1,3,4-thiadiazol-2-yl group, a 1,2,4-thiadiazol-5-yl group, a
pyridin-2-yl group, a pyridazin-3-yl group, a pyrimidin-2-yl group,
a pyrimidin-4-yl group and a pyrazin-2-yl group, or a salt of the
compound, or a solvate of the compound or salt.
6. The compound of claim 5, wherein the compound is any one of
intermediate compounds below, or a salt of the intermediate
compound, or a solvate of the intermediate compound or salt:
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide;
N-(2-amino-5-fluoropyridin-4-yl)-4-(2-methylpyrimidin-4-yl)-1-methyl-1H-p-
yrazole-5-carboxamide; and
N-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-m-
ethyl-1H-pyrazole-5-carboxamide;
N-(2-amino-5-fluoropyridin-4-yl)-4-(4-(trifluoromethyl)thiazol-2-yl)-1-me-
thyl-1H-pyrazole-5-carboxamide.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of copending application
Ser. No. 15/840,858, filed on Dec. 13, 2017, which is a Divisional
of application Ser. No. 15/329,447, filed on Jan. 26, 2017, which
is the National Phase under 35 U.S.C. .sctn. 371 of International
Application No. PCT/JP2015/071536, filed on Jul. 29, 2015, which
claims the benefit under 35 U.S.C. .sctn. 119(a) to Patent
Application No. 2014-155538, filed in Japan on Jul. 30, 2014 and
Patent Application No. 2014-189458, filed in Japan on Sep. 17,
2014, all of which are hereby expressly incorporated by reference
into the present application.
TECHNICAL FIELD
[0002] The present invention relates to a method for manufacturing
a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I),
which exhibits phosphodiesterase 10 (hereinafter shown as "PDE10")
inhibitory activity; and an intermediate for this manufacturing
method.
BACKGROUND ART
[0003] A
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-p-
yrazole-5-carboxylic acid amide derivative represented by formula
(I) exhibits excellent PDE10 inhibitory activity, is useful for
treating and/or preventing a variety of symptoms of mental
disorders linked to PDE10 (for example, paranoid type, disorganized
type, catatonic type, undifferentiated and residual type
schizophrenia, and the like), and has potential as a therapeutic
agent having diminished adverse reactions.
[0004] As a method for manufacturing an
N-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxylic
acid amide derivative (formula (i)), scheme 1 on page 26 of WO
2012/076430 (PTL 1) discloses a manufacturing method in which a
carboxylic acid derivative (formula (ii)) and a
7-amino-[1,2,4]triazolo[1,5-a]pyridine derivative (formula (iii))
are subjected to a condensation reaction.
##STR00002##
[0005] As a method for manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative (formula (I-a)), page 184 of WO
2014/133046 (PTL 2) discloses a manufacturing method in which a
carboxylic acid derivative (formula (CA)) and a
7-amino-[1,2,4]triazolo[1,5-a]pyridine derivative (formula (AM))
are subjected to a condensation reaction.
##STR00003##
[0006] According to PTL 1, a compound represented by formula (iii)
is manufactured using O-(mesitylsulfonyl)hydroxylamine (formula
(v)).
##STR00004##
[0007] A compound represented by formula (I) in the present
invention can be manufactured using a compound represented by
formula (iii) disclosed in PTL 1, but in cases where a compound
represented by formula (iii) is manufactured according to the
manufacturing method disclosed in PTL 1, it is essential to use the
compound represented by formula (v). However, it has been pointed
out that the compound represented by formula (v) is not suitable
for use in large scale synthesis or industrial manufacturing due to
problems relating to the stability and safety of the compound (see
NPL 1). Therefore, in cases where large scale synthesis or
industrial manufacturing of a compound represented by formula (I)
is being considered, it is essential to find a novel manufacturing
method that is different from the manufacturing method disclosed in
PTL 1.
[0008] Meanwhile, a method for manufacturing an analogous compound
to formula (iii) (formula (iii-1)) is disclosed in WO 2013/117610
(PTL 3). However, the yield of a compound having a
R.sup.V.dbd.NH.sub.2 group is low, at 28%, and there are no
synthesis examples of 6,7-2 substituted
[1,2,4]triazolo[1,5-a]pyridine derivatives.
##STR00005##
[0009] In addition, no manufacturing method is known whereby a
6-fluoro-7-amino-4-phenyl-[1,2,4]triazolo[1,5-a]pyridine
derivative, which is a partial structure of a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I), can
be synthesized in large quantities with good efficiency.
[0010] Therefore, there is a need to overcome these problems and
establish an efficient manufacturing method that is suitable for
large scale synthesis or industrial manufacturing of a compound
represented by formula (I).
CITATION LIST
Patent Literature
[0011] [PTL 1] WO 2012/076430 [0012] [PTL 2] WO 2014/133046 [0013]
[PTL 3] WO 2013/117610
Non Patent Literature
[0013] [0014] [NPL 1] Organic Process Research & Development,
13, pages 263-267, 2009.
SUMMARY OF INVENTION
Technical Problem
[0015] The purpose of the present invention is to provide an
efficient manufacturing method that is suitable for large scale
synthesis or industrial manufacturing of a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I), and
especially a novel manufacturing method by which a compound
represented by formula (I) is manufactured without using a
7-amino-[1,2,4]triazolo[1,5-a]pyridine derivative represented by
formula (iii) when obtaining this derivative in large scale or
industrial manufacturing; and an intermediate that is useful for
this manufacturing method.
Solution to Problem
[0016] The inventors of the present invention have carried out
diligent research in order to solve this problem. As a result, the
inventors of the present invention found a method for easily
manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I) below
in a short process and with a good yield, and thereby completed the
present invention on the basis of these findings.
##STR00006##
(The definitions of p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group in formula (I) are explained in mode [1] below.)
Advantageous Effects of Invention
[0017] The present invention is a method for manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I)
below, which exhibits PDE10 inhibitory activity; and an
intermediate that is useful for this manufacturing method. The
present invention can provide a manufacturing method which has a
good yield and a short process and is simple and industrially
advantageous, and is industrially useful.
DESCRIPTION OF EMBODIMENTS
Modes of the Present Invention
[0018] The present invention is a method for manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I),
which is illustrated in the modes below; and an intermediate that
is useful for this manufacturing method, and is described
below.
[0019] [1] A first mode of the present invention is a method for
manufacturing a compound represented by formula (I) below:
##STR00007##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 s independently denote a group
arbitrarily selected from among a halogen atom, a cyano group, a
C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; R.sup.4 groups each independently denote
a group arbitrarily selected from among a halogen atom, a C.sub.1-6
alkyl group and a C.sub.1-6 alkoxy group; and ring A group
represented by formula (II):
##STR00008##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including stages in which a
compound represented by formula (ET-1):
##STR00009##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group (a routine method for
manufacturing a compound represented by formula (ET-1) is described
later)] and an aqueous ammonia solution are reacted with each other
at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes, thereby obtaining a compound
represented by formula (AD-1):
##STR00010##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1]] (stage [1]-1), the compound represented by
formula (AD-1) and a 2-amino-4-iodopyridine derivative represented
by formula (PY-1):
##STR00011##
[in formula (PY-1), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom (a routine method
for manufacturing a compound represented by formula (PY-1) is
described later)] are reacted with each other in the presence of
N,N-dimethyl-1,2-ethanediamine, copper iodide and an inorganic base
such as potassium carbonate or potassium phosphate using a solvent
which does not take part in the reaction, such as 1,4-dioxane,
tetrahydrofuran or 1,2-dimethoxyethane, at a temperature between
0.degree. C. and a temperature at which the solvent refluxes,
thereby obtaining a compound represented by formula (AD-2):
##STR00012##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1]] (stage [1]-2), the compound represented by
formula (AD-2) and a compound represented by formula (IM-1):
##STR00013##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) above; and R.sup.B denotes a C.sub.1-6 alkyl group]
or a salt thereof (the compound represented by formula (IM-1) and
salt thereof are commercially available compounds or compounds that
can be easily obtained from commercially available compounds using
manufacturing methods known from literature) are reacted with each
other using a solvent which does not take part in the reaction,
such as dimethyl sulfoxide or pyridine, at a temperature between
0.degree. C. and a temperature at which the solvent refluxes,
thereby obtaining a compound represented by formula (AD-3):
##STR00014##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [1]] (stage [1]-3), and the compound
represented by formula (AD-3) is subjected to a cyclization
reaction in the presence of air using a solvent which does not take
part in the reaction, such as dimethyl sulfoxide (DMSO) or
N-methylpyrrolidone (NMP), at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes in the presence of
a copper reagent such as copper iodide (CuI) or copper chloride
(CuCl) (stage [1]-4), thereby obtaining the compound represented by
formula (I).
[0020] [1-1] A preferred aspect of mode [1] is a method in which a
compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as for mode [1] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [1]-1) to (stage
[1]-4) in mode [1] above; the definitions of the substituent groups
in the intermediates in (stage [1]-1) to (stage [1]-4) are the same
as the definitions in mode [1-1], and R.sup.B in formula (IM-1) is
a C.sub.1-6 alkyl group].
[0021] [1-2] A more preferred aspect of mode [1] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[1-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [1]-1) to (stage [1]-4) in mode [1] above; the
definitions of the substituent groups in the intermediates in
(stage [1]-1) to (stage [1]-4) are the same as the definitions in
mode [1-2], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0022] [1-3] A yet more preferred aspect of mode [1] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
defined in the same way as for mode [1-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [1]-1) to (stage
[1]-4) in mode [1] above; the definitions of the substituent groups
in the intermediates in (stage [1]-1) to (stage [1]-4) are the same
as the definitions in mode [1-3], and R.sup.B in formula (IM-1) is
a C.sub.1-6 alkyl group].
[0023] [1a] Another aspect of the first mode of the present
invention is a method for manufacturing a compound represented by
formula (I) below:
##STR00015##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00016##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (ET-1):
##STR00017##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1a]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group (a routine method for
manufacturing a compound represented by formula (ET-1) is described
later)] and an aqueous ammonia solution are reacted with each other
at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes, thereby obtaining a compound
represented by formula (AD-1):
##STR00018##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1a]] (stage [1a]-1), the compound represented
by formula (AD-1) and a 2-amino-4-iodopyridine derivative
represented by formula (PY-1):
##STR00019##
[in formula (PY-1), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom (a routine method
for manufacturing a compound represented by formula (PY-1) is
described later)] are reacted with each other in the presence of
N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI) and an
inorganic base such as potassium carbonate or potassium phosphate
using a solvent which does not take part in the reaction, such as
1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-2):
##STR00020##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [1a]] (stage [1a]-2), the compound represented
by formula (AD-2) and a compound represented by formula (IM-1):
##STR00021##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [1a]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-3):
##STR00022##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [1a]] (stage [1a]-3), and the
compound represented by formula (AD-3) is subjected to a
cyclization reaction in the presence of air using a solvent which
does not take part in the reaction, such as dimethyl sulfoxide
(DMSO) or N-methylpyrrolidone (NMP), at a temperature between
0.degree. C. and a temperature at which the solvent refluxes in the
presence of a copper reagent such as copper iodide (CuI) or copper
chloride (CuCl) (stage [1a]-4), thereby obtaining the compound
represented by formula (I).
[0024] [1a-1] A preferred aspect of mode [1a] is a method in which
a compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [1a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [1a]-1) to (stage
[1a]-4) in mode [1a] above; the definitions of the substituent
groups in the intermediates in (stage [1a]-1) to (stage [1a]-4) are
the same as the definitions in mode [1a-1], and R.sup.B in formula
(IM-1) is a C.sub.1-6 alkyl group].
[0025] [1a-2] A more preferred aspect of mode [1a] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[1a-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [1a]-1) to (stage [1a]-4) in mode [1a] above;
the definitions of the substituent groups in the intermediates in
(stage [1a]-1) to (stage [1a]-4) are the same as the definitions in
mode [1a-2], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0026] [1a-3] A yet more preferred aspect of mode [1a] is a method
in which a compound represented by formula (I) above is
manufactured [in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined in the same way as for mode [1a-2] above; ring
A group represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (I) is obtained [these stages are
the same as (stage [1a]-1) to (stage [1a]-4) in mode [1a] above;
the definitions of the substituent groups in the intermediates in
(stage [1a]-1) to (stage [1a]-4) are the same as the definitions in
mode [1a-3], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0027] [2] A second mode of the present invention is formula (AD-2)
below:
##STR00023##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II):
##STR00024##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including stages in which a
compound represented by formula (ET-1):
##STR00025##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [2]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group (a routine method for
manufacturing a compound represented by formula (ET-1) is described
later)] and an aqueous ammonia solution are reacted with each other
at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes, thereby obtaining a compound
represented by formula (AD-1):
##STR00026##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [2]] (stage [2]-1), and the compound
represented by formula (AD-1) and a 2-amino-4-iodopyridine
derivative represented by formula (PY-1):
##STR00027##
[in formula (PY-1), R.sup.3 denotes a hydrogen atom or a fluorine
atom (a routine method for manufacturing a compound represented by
formula (PY-1) is described later)] are reacted with each other in
the presence of N,N-dimethyl-1,2-ethanediamine, copper iodide and
an inorganic base such as potassium carbonate or potassium
phosphate using a solvent which does not take part in the reaction,
such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-2) (stage [2]-2).
[0028] [2-1] A preferred aspect of mode [2] is a method in which a
compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [2] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; and R.sup.2 denotes a methyl group], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [2]-1) and (stage [2]-2) in mode [2] above; and the
definitions of the substituent groups in the intermediates in
(stage [2]-1) and (stage [2]-2) are the same as the definitions in
mode [2-1]].
[0029] [2-2] A more preferred aspect of mode [2] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [2-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [2]-1) and (stage [2]-2) in mode [2] above; and the
definitions of the substituent groups in the intermediates in
(stage [2]-1) and (stage [2]-2) are the same as the definitions in
mode [2-2]].
[0030] [2-3] A yet more preferred aspect of mode [2] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [2-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including stages in which a compound represented by formula (AD-2)
is obtained [these stages are the same as (stage [2]-1) and (stage
[2]-2) in mode [2] above; and the definitions of the substituent
groups in the intermediates in (stage [2]-1) and (stage [2]-2) are
the same as the definitions in mode [2-3]].
[0031] [2a] Another aspect of the second mode of the present
invention is a method for manufacturing a compound represented by
formula (AD-2) below:
##STR00028##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; and ring A group represented by formula
(II):
##STR00029##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-2-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (ET-1):
##STR00030##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [2a]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group (a routine method for
manufacturing a compound represented by formula (ET-1) is described
later)] and an aqueous ammonia solution are reacted with each other
at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes, thereby obtaining a compound
represented by formula (AD-1):
##STR00031##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [2a]] (stage [2a]-1), and the compound
represented by formula (AD-1) and a 2-amino-4-iodopyridine
derivative represented by formula (PY-1):
##STR00032##
[in formula (PY-1), R.sup.3 denotes a hydrogen atom or a fluorine
atom (a routine method for manufacturing a compound represented by
formula (PY-1) is described later)] are reacted with each other in
the presence of N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI)
and an inorganic base such as potassium carbonate or potassium
phosphate using a solvent which does not take part in the reaction,
such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining the compound represented by
formula (AD-2) (stage [2a]-2).
[0032] [2a-1] A preferred aspect of mode [2a] is a method in which
a compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [2a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; and R.sup.2 denotes a methyl
group], the manufacturing method including stages in which a
compound represented by formula (AD-2) is obtained [these stages
are the same as (stage [2a]-1) and (stage [2a]-2) in mode [2a]
above; and the definitions of the substituent groups in the
intermediates in (stage [2a]-1) and (stage [2a]-2) are the same as
the definitions in mode [2a-1]].
[0033] [2a-2] A more preferred aspect of mode [2a] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [2a-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [2a]-1) and (stage [2a]-2) in mode [2a] above; and
the definitions of the substituent groups in the intermediates in
(stage [2a]-1) and (stage [2a]-2) are the same as the definitions
in mode [2a-2]].
[0034] [2a-3] A yet more preferred aspect of mode [2a] is a method
in which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [2a-2] above; ring A group
represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (AD-2) is obtained [these stages
are the same as (stage [2a]-1) and (stage [2a]-2) in mode [2a]
above; and the definitions of the substituent groups in the
intermediates in (stage [2a]-1) and (stage [2a]-2) are the same as
the definitions in mode [2a-3]].
[0035] [3] A third mode of the present invention is a method for
manufacturing a compound represented by formula (AD-2) below:
##STR00033##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II):
##STR00034##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including a stage in which a
compound represented by formula (AD-1):
##STR00035##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [3]] and a 2-amino-4-iodopyridine derivative
represented by formula (PY-1):
##STR00036##
[in formula (PY-1), R.sup.3 denotes a hydrogen atom or a fluorine
atom (a routine method for manufacturing a compound represented by
formula (PY-1) is described later)] are reacted with each other in
the presence of N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI)
and an inorganic base such as potassium carbonate or potassium
phosphate using a solvent which does not take part in the reaction,
such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining the compound represented by
formula (AD-2) (stage [3]-1).
[0036] [3-1] A preferred aspect of mode [3] is a method in which a
compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [3] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; and R.sup.2 denotes a methyl group], the
manufacturing method including a stage in which a compound
represented by formula (AD-2) is obtained [this stage is the same
as (stage [3]-1) in mode [3] above; and the definitions of the
substituent groups in the intermediate in (stage [3]-1) are the
same as the definitions in mode [3-1]].
[0037] [3-2] A more preferred aspect of mode [3] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [3-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including a stage in which a compound
represented by formula (AD-2) is obtained [this stage is the same
as (stage [3]-1) in mode [3] above; and the definitions of the
substituent groups in the intermediate in (stage [3]-1) are the
same as the definitions in mode [3-2]1].
[0038] [3-3] A yet more preferred aspect of mode [3] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [3-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including a stage in which a compound represented by formula (AD-2)
is obtained [this stage is the same as (stage [3]-1) in mode [3]
above; and the definitions of the substituent groups in the
intermediate in (stage [3]-1) are the same as the definitions in
mode [3-3]].
[0039] [3a] Another aspect of the third mode of the present
invention is a method for manufacturing a compound represented by
formula (AD-2) below:
##STR00037##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; and ring A group represented by formula
(II):
##STR00038##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including a stage in
which a compound represented by formula (AD-1):
##STR00039##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [3a]] and a 2-amino-4-iodopyridine
derivative represented by formula (PY-1):
##STR00040##
[in formula (PY-1), R.sup.3 denotes a hydrogen atom or a fluorine
atom (a routine method for manufacturing a compound represented by
formula (PY-1) is described later)] are reacted with each other in
the presence of N,N-dimethyl-1,2-ethanediamine, copper iodide and
an inorganic base such as potassium carbonate or potassium
phosphate using a solvent which does not take part in the reaction,
such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining the compound represented by
formula (AD-2) (stage [3a]-1).
[0040] [3a-1] A preferred aspect of mode [3a] is a method in which
a compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [3a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; and R.sup.2 denotes a methyl
group], the manufacturing method including a stage in which a
compound represented by formula (AD-2) is obtained [this stage is
the same as (stage [3a]-1) in mode [3a] above; and the definitions
of the substituent groups in the intermediate in (stage [3a]-1) are
the same as the definitions in mode [3a-1]].
[0041] [3a-2] A more preferred aspect of mode [3a] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [3a-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including a stage in which a compound
represented by formula (AD-2) is obtained [this stage is the same
as (stage [3a]-1) in mode [3a] above; and the definitions of the
substituent groups in the intermediate in (stage [3a]-1) are the
same as the definitions in mode [3a-2]].
[0042] [3a-3] A yet more preferred aspect of mode [3a] is a method
in which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [3a-2] above; ring A group
represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including a stage in which a
compound represented by formula (AD-2) is obtained [this stage is
the same as (stage [3a]-1) in mode [3a] above; and the definitions
of the substituent groups in the intermediate in (stage [3a]-1) are
the same as the definitions in mode [3a-3]].
[0043] [4] A fourth mode of the present invention is a method for
manufacturing a compound represented by formula (I) below:
##STR00041##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group
and a C.sub.1-6 alkoxy group; R.sup.2 denotes a C.sub.1-6 alkyl
group; R.sup.3 denotes a group arbitrarily selected from among a
hydrogen atom and a fluorine atom; R.sup.4 groups each
independently denote a group arbitrarily selected from among a
halogen atom, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
and ring A group represented by formula (II):
##STR00042##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including stages in which a
compound represented by formula (AD-2):
##STR00043##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [4]] and a compound represented by formula
(IM-1):
##STR00044##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [4]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes thereby obtaining a compound represented by
formula (AD-3):
##STR00045##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [4]] (stage [4]-1), and the compound
represented by formula (AD-3) is subjected to a cyclization
reaction in the presence of air using a solvent which does not take
part in the reaction, such as dimethyl sulfoxide (DMSO) or
N-methylpyrrolidone (NMP), at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes in the presence of
a copper reagent such as copper iodide (CuI) or copper chloride
(CuCl) (stage [4]-2), thereby obtaining the compound represented by
formula (I).
[0044] [4-1] A preferred aspect of mode [4] is a method in which a
compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as for mode [4] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [4]-1) and (stage
[4]-2) in mode [4] above; the definitions of the substituent groups
in the intermediates in (stage [4]-1) and (stage [4]-2) are the
same as the definitions in mode [4-1], and R.sup.B in formula
(IM-1) is a C.sub.1-6 alkyl group].
[0045] [4-2] A more preferred aspect of mode [4] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[4-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [4]-1) and (stage [4]-2) in mode [4] above; the
definitions of the substituent groups in the intermediates in
(stage [4]-1) and (stage [4]-2) are the same as the definitions in
mode [4-2], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0046] [4-3] A yet more preferred aspect of mode [4] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
defined in the same way as for mode [4-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [4]-1) and (stage
[4]-2) in mode [4] above; the definitions of the substituent groups
in the intermediates in (stage [4]-1) and (stage [4]-2) are the
same as the definitions in mode [4-3], and R.sup.B in formula
(IM-1) is a C.sub.1-6 alkyl group].
[0047] [4a] Another aspect of the fourth mode of the present
invention is a method for manufacturing a compound represented by
formula (I) below:
##STR00046##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00047##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (AD-2):
##STR00048##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [4a]] and a compound represented by formula
(IM-1):
##STR00049##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [4a]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-3):
##STR00050##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [4a]] (stage [4a]-1), and the
compound represented by formula (AD-3) is subjected to a
cyclization reaction in the presence of air using a solvent which
does not take part in the reaction, such as dimethyl sulfoxide
(DMSO) or N-methylpyrrolidone (NMP), at a temperature between
0.degree. C. and a temperature at which the solvent refluxes in the
presence of a copper reagent such as copper iodide (CuI) or copper
chloride (CuCl) (stage [4a]-2), thereby obtaining the compound
represented by formula (I).
[0048] [4a-1] A preferred aspect of mode [4a] is a method in which
a compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [4a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [4a]-1) and (stage
[4a]-2) in mode [4a] above; the definitions of the substituent
groups in the intermediates in (stage [4a]-1) and (stage [4a]-2)
are the same as the definitions in mode [4a-1], and R.sup.B in
formula (IM-1) is a C.sub.1-6 alkyl group].
[0049] [4a-2] A more preferred aspect of mode [4a] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[4a-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [4a]-1) and (stage [4a]-2) in mode [4a] above;
the definitions of the substituent groups in the intermediates in
(stage [4a]-1) and (stage [4a]-2) are the same as the definitions
in mode [4a-2], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0050] [4a-3] A yet more preferred aspect of mode [4a] is a method
in which a compound represented by formula (I) above is
manufactured [in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined in the same way as for mode [4a-2] above; ring
A group represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (I) is obtained [these stages are
the same as (stage [4a]-1) and (stage [4a]-2) in mode [4a] above;
the definitions of the substituent groups in the intermediates in
(stage [4a]-1) and (stage [4a]-2) are the same as the definitions
in mode [4a-3], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0051] [5] A fifth mode of the present invention is a method for
manufacturing a compound represented by formula (I) below:
##STR00051##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group
and a C.sub.1-6 alkoxy group; R.sup.2 denotes a C.sub.1-6 alkyl
group; R.sup.3 denotes a group arbitrarily selected from among a
hydrogen atom and a fluorine atom; R.sup.4 groups each
independently denote a group arbitrarily selected from among a
halogen atom, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
and ring A group represented by formula (II):
##STR00052##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including a stage in which a
compound represented by formula (AD-3):
##STR00053##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [5]] is subjected to a cyclization
reaction in the presence of air using a solvent which does not take
part in the reaction, such as dimethyl sulfoxide (DMSO) or
N-methylpyrrolidone (NMP), at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes in the presence of
a copper reagent such as copper iodide (CuI) or copper chloride
(CuCl) (stage [5]-1), thereby obtaining the compound represented by
formula (I).
[0052] [5-1] A preferred aspect of mode [5] is a method in which a
compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as for mode [5] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including a stage in which a compound represented by formula (I) is
obtained [this stage is the same as (stage [5]-1) in mode [5]
above; and the definitions of the substituent groups in the
intermediate in (stage [5]-1) are the same as the definitions in
mode [5-1]].
[0053] [5-2] A more preferred aspect of mode [5] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[5-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including a stage in which
a compound represented by formula (I) is obtained [this stage is
the same as (stage [5]-1) in mode [5] above; and the definitions of
the substituent groups in the intermediate in (stage [5]-1) are the
same as the definitions in mode [5-2]].
[0054] [5-3] A yet more preferred aspect of mode [5] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
defined in the same way as for mode [5-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including a stage in which a compound represented by formula (I) is
obtained [this stage is the same as (stage [5]-1) in mode [5]
above; and the definitions of the substituent groups in the
intermediate in (stage [5]-1) are the same as the definitions in
mode [5-3]].
[0055] [5a] Another aspect of the fifth mode of the present
invention is a method for manufacturing a compound represented by
formula (I) below:
##STR00054##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00055##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including a stage in
which a compound represented by formula (AD-3):
##STR00056##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [5a]] is subjected to a cyclization
reaction in the presence of air using a solvent which does not take
part in the reaction, such as dimethyl sulfoxide (DMSO) or
N-methylpyrrolidone (NMP), at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes in the presence of
a copper reagent such as copper iodide (CuI) or copper chloride
(CuCl) (stage [5a]-1), thereby obtaining the compound represented
by formula (I).
[0056] [5a-1] A preferred aspect of mode [5a] is a method in which
a compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [5a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including a stage in which a compound represented by formula (I) is
obtained [this stage is the same as (stage [5a]-1) in mode [5a]
above; and the definitions of the substituent groups in the
intermediate in (stage [5a]-1) are the same as the definitions in
mode [5a-1]].
[0057] [5a-2] A more preferred aspect of mode [5a] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[5a-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including a stage in which
a compound represented by formula (I) is obtained [this stage is
the same as (stage [5a]-1) in mode [5a] above; and the definitions
of the substituent groups in the intermediate in (stage [5a]-1) are
the same as the definitions in mode [5a-2]].
[0058] [5a-3] A yet more preferred aspect of mode [5a] is a method
in which a compound represented by formula (I) above is
manufactured [in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined in the same way as for mode [5a-2] above; ring
A group represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including a stage in which a
compound represented by formula (I) is obtained [this stage is the
same as (stage [5a]-1) in mode [5a] above; and the definitions of
the substituent groups in the intermediate in (stage [5a]-1) are
the same as the definitions in mode [5a-3]].
[0059] [6] A sixth mode of the present invention is a method for
manufacturing a compound represented by formula (I) below:
##STR00057##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl group
and a C.sub.1-6 alkoxy group; R.sup.2 denotes a C.sub.1-6 alkyl
group; R.sup.3 denotes a group arbitrarily selected from among a
hydrogen atom and a fluorine atom; R.sup.4 groups each
independently denote a group arbitrarily selected from among a
halogen atom, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
and ring A group represented by formula (II):
##STR00058##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including stages in which a
compound represented by formula (ET-1):
##STR00059##
[in formula (ET-1), p, R.sup.1 and R.sup.2 are defined in the same
way as for formula (I) in mode [6]; R.sup.D denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (ET-1)
is described later)] is subjected to hydrolysis [in cases where
R.sup.D is a C.sub.1-6 alkyl group (for example, a methyl group, an
ethyl group, or the like), a C.sub.6-14 aryl group (for example, a
phenyl group or the like) or a C.sub.7-20 aralkyl group (for
example, a benzyl group), a reaction is carried out in the presence
of a base such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, lithium carbonate, sodium carbonate or potassium
carbonate using a solvent that is inert in the reaction, such as
water, methanol, ethanol, 2-propanol, N,N-dimethylformamide,
1,4-dioxane, tetrahydrofuran or a mixture thereof at a temperature
between 0.degree. C. and a temperature at which the solvent
refluxes; in cases where R.sup.D is a tert-butyl group (a C.sub.1-6
alkyl group), a reaction with an acid such as hydrochloric acid or
trifluoroacetic acid is carried out] or hydrogenation [in cases
where R.sup.D is a C.sub.7-20 aralkyl group (for example, a benzyl
group or the like), a reaction is carried out in the presence of a
catalyst such as palladium-carbon (Pd--C), Raney-nickel (Raney-Ni)
or platinum oxide (PtO.sub.2) in a hydrogen gas atmosphere using a
solvent which does not take part in the reaction, such as an
alcoholic solvent such as methanol, ethanol or 2-propanol, an
ether-based solvent such as diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane or 1,4-dioxane, or a polar solvent such as
ethyl acetate or methyl acetate, or a mixture thereof, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes], thereby obtaining a compound represented by
formula (CA-1):
##STR00060##
[in formula (CA-1), p, R.sup.1 and R.sup.2 are defined in the same
way as for formula (I) in mode [6]] (stage [6]-1), the compound
represented by formula (CA-1) and a compound represented by formula
(PY-2):
##STR00061##
[in formula (PY-2), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom; R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (PY-2)
is described later)] are reacted with each other in the presence of
a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl), 1-hydroxybenzotriazole (Hobt),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (a BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),
2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM), polyphosphoric acid (PPA) or
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate methanaminium (HATU), in the presence or
absence of a base such as N,N-diisopropylethylamine, triethylamine,
pyridine or lutidine, in a solvent which does not take part in the
reaction, such as dichloromethane, chloroform, diethyl ether,
tetrahydrofuran, toluene, benzene, N,N-dimethylformamide,
N-methylpyrrolidone, methanol, ethanol or 2-propanol at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-4):
##STR00062##
[in formula (AD-4), p, R.sup.1, R.sup.2 and R.sup.3 are defined in
the same way as for formula (I) in mode [6]; and R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group] (stage
[6]-2), a --C(.dbd.O)OR.sup.C group (R.sup.C denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group), which is a
protecting group for an amino group in formula (AD-4) is
deprotected using a method known from literature, for example, a
method disclosed in Greene et al., "Protective Groups in Organic
Synthesis", fourth edition, 2007 (John Wiley & Sons), or using
articles that have been publicly expressed, thereby obtaining a
compound represented by formula (AD-2):
##STR00063##
[in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3 are defined in
the same way as for formula (I) in mode [6]] (stage [6]-3), the
compound represented by formula (AD-2) and a compound represented
by formula (IM-1):
##STR00064##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [6]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-3):
##STR00065##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [6]] (stage [6]-4), and the compound
represented by formula (AD-3) is subjected to a cyclization
reaction in the presence of air using a solvent which does not take
part in the reaction, such as dimethyl sulfoxide (DMSO) or
N-methylpyrrolidone (NMP), at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes in the presence of
a copper reagent such as copper iodide (CuI) or copper chloride
(CuCl) (stage [6]-5), thereby obtaining the compound represented by
formula (I).
[0060] [6-1] A preferred aspect of mode [6] is a method in which a
compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as for mode [6] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [6]-1) to (stage
[6]-5) in mode [6] above; and the definitions of the substituent
groups in the intermediates in (stage [6]-1) to (stage [6]-5) are
the same as the definitions in mode [6-1]].
[0061] [6-2] A more preferred aspect of mode [6] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[6-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [6]-1) to (stage [6]-5) in mode [6]above; and
the definitions of the substituent groups in the intermediates in
(stage [6]-1) to (stage [6]-5) are the same as the definitions in
mode [6-2]].
[0062] [6-3] A yet more preferred aspect of mode [6] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
defined in the same way as for mode [6-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [6]-1) to (stage
[6]-5) in mode [6] above; and the definitions of the substituent
groups in the intermediates in (stage [6]-1) to (stage [6]-5) are
the same as the definitions in mode [6-3]].
[0063] [6a] Another aspect of the sixth mode of the present
invention is a method for manufacturing a compound represented by
formula (I) below:
##STR00066##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00067##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (ET-1):
##STR00068##
[in formula (ET-1), p, R.sup.1 and R.sup.2 are defined in the same
way as for formula (I) in mode [6a]; R.sup.D denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (ET-1)
is described later)] is subjected to hydrolysis [in cases where
R.sup.D is a C.sub.1-6 alkyl group (for example, a methyl group, an
ethyl group, or the like), a C.sub.6-14 aryl group (for example, a
phenyl group or the like) or a C.sub.7-20 aralkyl group (for
example, a benzyl group), a reaction is carried out in the presence
of a base such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, lithium carbonate, sodium carbonate or potassium
carbonate using a solvent that is inert in the reaction, such as
water, methanol, ethanol, 2-propanol, N,N-dimethylformamide,
1,4-dioxane, tetrahydrofuran or a mixture thereof at a temperature
between 0.degree. C. and a temperature at which the solvent
refluxes; in cases where R.sup.D is a tert-butyl group (a C.sub.1-6
alkyl group), a reaction with an acid such as hydrochloric acid or
trifluoroacetic acid is carried out] or hydrogenation [in cases
where R.sup.D is a C.sub.7-20 aralkyl group (for example, a benzyl
group or the like), a reaction is carried out in the presence of a
catalyst such as palladium-carbon (Pd--C), Raney-nickel (Raney-Ni)
or platinum oxide (PtO.sub.2) in a hydrogen gas atmosphere using a
solvent which does not take part in the reaction, such as an
alcoholic solvent such as methanol, ethanol or 2-propanol, an
ether-based solvent such as diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane or 1,4-dioxane, or a polar solvent such as
ethyl acetate or methyl acetate, or a mixture thereof, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes], thereby obtaining a compound represented by
formula (CA-1):
##STR00069##
[in formula (CA-1), p, R.sup.1 and R.sup.2 are defined in the same
way as for formula (I) in mode [6a]] (stage [6a]-1), the compound
represented by formula (CA-1) and a compound represented by formula
(PY-2):
##STR00070##
[in formula (PY-2), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom; R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (PY-2)
is described later)] are reacted with each other in the presence of
a condensing agent such as 1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl), 1-hydroxybenzotriazole (Hobt),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (a BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),
2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM), polyphosphoric acid (PPA) or
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate methanaminium (HATU), in the presence or
absence of a base such as N,N-diisopropylethylamine, triethylamine,
pyridine or lutidine, in a solvent which does not take part in the
reaction, such as dichloromethane, chloroform, diethyl ether,
tetrahydrofuran, toluene, benzene, N,N-dimethylformamide,
N-methylpyrrolidone, methanol, ethanol or 2-propanol at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-4):
##STR00071##
[in formula (AD-4), p, R.sup.1, R.sup.2 and R.sup.3 are defined in
the same way as for formula (I) in mode [6a]; and R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group] (stage
[6a]-2), a --C(.dbd.O)OR.sup.C group (R.sup.C denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group), which is a
protecting group for an amino group in formula (AD-4) is
deprotected using a method known from literature, for example, a
method disclosed in Greene et al., "Protective Groups in Organic
Synthesis", fourth edition, 2007 (John Wiley & Sons), or using
articles that have been publicly expressed, thereby obtaining a
compound represented by formula (AD-2):
##STR00072##
[in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3 are defined in
the same way as for formula (I) in mode [6a]] (stage [6a]-3), the
compound represented by formula (AD-2) and a compound represented
by formula (IM-1):
##STR00073##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [6a]; and R.sup.B denotes a C.sub.1-6alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-3):
##STR00074##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [6a]] (stage [6a]-4), and the
compound represented by formula (AD-3) is subjected to a
cyclization reaction in the presence of air using a solvent which
does not take part in the reaction, such as dimethyl sulfoxide
(DMSO) or N-methylpyrrolidone (NMP), at a temperature between
0.degree. C. and a temperature at which the solvent refluxes in the
presence of a copper reagent such as copper iodide (CuI) or copper
chloride (CuCl) (stage [6a]-5), thereby obtaining the compound
represented by formula (I).
[0064] [6a-1] A preferred aspect of mode [6a] is a method in which
a compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [6a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [6a]-1) to (stage
[6a]-5) in mode [6a] above; and the definitions of the substituent
groups in the intermediates in (stage [6a]-1) to (stage [6a]-5) are
the same as the definitions in mode [6a-1]].
[0065] [6a-2] A more preferred aspect of mode [6a] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[6a-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [6a]-1) to (stage [6a]-5) in mode [6a] above;
and the definitions of the substituent groups in the intermediates
in (stage [6a]-1) to (stage [6a]-5) are the same as the definitions
in mode [6a-2]].
[0066] [6a-3] A yet more preferred aspect of mode [6a] is a method
in which a compound represented by formula (I) above is
manufactured [in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined in the same way as for mode [6a-2] above; ring
A group represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (I) is obtained [these stages are
the same as (stage [6a]-1) to (stage [6a]-5) in mode [6a] above;
and the definitions of the substituent groups in the intermediates
in (stage [6a]-1) to (stage [6a]-5) are the same as the definitions
in mode [6a-3]].
[0067] [7] A seventh mode of the present invention is a method for
manufacturing a compound represented by formula (AD-2) below:
##STR00075##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II):
##STR00076##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], the manufacturing method including stages in which a
compound represented by formula (ET-1):
##STR00077##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [7]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.614 aryl group
and a C.sub.7-20 aralkyl group (a routine method for manufacturing
a compound represented by formula (ET-1) is described later)] is
subjected to hydrolysis or hydrogenation (these are the same as the
reactions described in mode [6] above) according to the type of
R.sup.Dgroup, thereby obtaining a compound represented by formula
(CA-1):
##STR00078##
[in formula (CA-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [7]] (stage [7]-1), the compound represented by
formula (CA-1) and a compound represented by formula (PY-2):
##STR00079##
[in formula (PY-2), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom; R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (PY-2)
is described later)] are reacted with each other in the presence of
a condensing agent (condensing agents are the same as the
condensing agents described in mode [6] above), in the presence or
absence of a base such as N,N-diisopropylethylamine, triethylamine,
pyridine or lutidine, in a solvent which does not take part in the
reaction, such as dichloromethane, chloroform, diethyl ether,
tetrahydrofuran, toluene, benzene, N,N-dimethylformamide,
N-methylpyrrolidone, methanol, ethanol or 2-propanol at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-4):
##STR00080##
[in formula (AD-4), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [7]; and R.sup.C denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group] (stage [7]-2), and a
--C(.dbd.O)OR.sup.C group (R.sup.C denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group), which is a protecting group
for an amino group in formula (AD-4) is deprotected (according to
the deprotection method described in mode [6] above) (stage [7]-3),
thereby obtaining the compound represented by formula (AD-2).
[0068] [7-1] A preferred aspect of mode [7] is a method in which a
compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [7] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a cyano group, a methyl group, a trifluoromethyl
group and a methoxy group; and R.sup.2 denotes a methyl group], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [7]-1) to (stage [7]-3) in mode [7] above; and the
definitions of the substituent groups in the intermediates in
(stage [7]-1) to (stage [7]-3) are the same as the definitions in
mode [7-1]].
[0069] [7-2] A more preferred aspect of mode [7] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [7-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [7]-1) to (stage [7]-3) in mode [7] above; and the
definitions of the substituent groups in the intermediates in
(stage [7]-1) to (stage [7]-3) are the same as the definitions in
mode [7-2]].
[0070] [7-3] A yet more preferred aspect of mode [7] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [7-2] above; ring A group
represented by formula (II) is a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], the manufacturing method
including stages in which a compound represented by formula (AD-2)
is obtained [these stages are the same as (stage [7]-1) to (stage
[7]-3) in mode [7] above; and the definitions of the substituent
groups in the intermediates in (stage [7]-1) to (stage [7]-3) are
the same as the definitions in mode [7-3]].
[0071] [7a] Another aspect of the seventh mode of the present
invention is a method for manufacturing a compound represented by
formula (AD-2) below:
##STR00081##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; and ring A group represented by formula
(II):
##STR00082##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (ET-1):
##STR00083##
[in formula (ET-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [7a]; R.sup.D denotes a group arbitrarily
selected from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group and a C.sub.7-20 aralkyl group (a routine method for
manufacturing a compound represented by formula (ET-1) is described
later)] is subjected to hydrolysis or hydrogenation (these are the
same as the reactions described in mode [6a] above) according to
the type of R.sup.D group, thereby obtaining a compound represented
by formula (CA-1):
##STR00084##
[in formula (CA-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [7a]] (stage [7a]-1), the compound represented
by formula (CA-1) and a compound represented by formula (PY-2):
##STR00085##
[in formula (PY-2), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom; R.sup.C denotes a
group arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group (a routine
method for manufacturing a compound represented by formula (PY-2)
is described later)] are reacted with each other in the presence of
a condensing agent (such as a condensing agent described in mode
[6a] above), in the presence or absence of a base such as
N,N-diisopropylethylamine, triethylamine, pyridine or lutidine, in
a solvent which does not take part in the reaction, such as
dichloromethane, chloroform, diethyl ether, tetrahydrofuran,
toluene, benzene, N,N-dimethylformamide, N-methylpyrrolidone,
methanol, ethanol or 2-propanol at a temperature between 0.degree.
C. and a temperature at which the solvent refluxes, thereby
obtaining a compound represented by formula (AD-4):
##STR00086##
[in formula (AD-4), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-2) in mode [7a]; and R.sup.C denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group] (stage
[7a]-2), and a --C(.dbd.O)OR.sup.C group (R.sup.C denotes a group
arbitrarily selected from among a C.sub.1-6 alkyl group, a
C.sub.6-14 aryl group and a C.sub.7-20 aralkyl group), which is a
protecting group for an amino group in formula (AD-4) is
deprotected (according to the deprotection method described in mode
[6] above) (stage [7a]-3), thereby obtaining the compound
represented by formula (AD-2).
[0072] [7a-1] A preferred aspect of mode [7a] is a method in which
a compound represented by formula (AD-2) above is manufactured [in
formula (AD-2), p, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [7a] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; and R.sup.2 denotes a methyl
group], the manufacturing method including stages in which a
compound represented by formula (AD-2) is obtained [these stages
are the same as (stage [7a]-1) to (stage [7a]-3) in mode [7a]
above; and the definitions of the substituent groups in the
intermediates in (stage [7a]-1) to (stage [7a]-3) are the same as
the definitions in mode [7a-1]].
[0073] [7a-2] A more preferred aspect of mode [7a] is a method in
which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and ring A
group represented by formula (II) are defined in the same way as in
mode [7a-1] above; and R.sup.3 denotes a fluorine atom], the
manufacturing method including stages in which a compound
represented by formula (AD-2) is obtained [these stages are the
same as (stage [7a]-1) to (stage [7a]-3) in mode [7a] above; and
the definitions of the substituent groups in the intermediates in
(stage [7a]-1) to (stage [7a]-3) are the same as the definitions in
mode [7a-2]].
[0074] [7a-3] A yet more preferred aspect of mode [7a] is a method
in which a compound represented by formula (AD-2) above is
manufactured [in formula (AD-2), p, R.sup.1, R.sup.2 and R.sup.3
are defined in the same way as for mode [7a-2] above; ring A group
represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (AD-2) is obtained [these stages
are the same as (stage [7a]-1) to (stage [7a]-3) in mode [7a]
above; and the definitions of the substituent groups in the
intermediates in (stage [7a]-1) to (stage [7a]-3) are the same as
the definitions in mode [7a-3]].
[0075] [8] An eighth mode of the present invention is a compound
represented by formula (AD-1):
##STR00087##
[in formula (AD-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; and ring A group
represented by formula (II):
##STR00088##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0076] [8-1] A preferred aspect of mode [8] is a compound
represented by formula (AD-1) above [in formula (AD-1), p and ring
A group represented by formula (II) are defined in the same way as
for mode [8] above; R.sup.1 denotes a group arbitrarily selected
from among a fluorine atom, a chlorine atom, a cyano group, a
methyl group, a trifluoromethyl group and a methoxy group; and
R.sup.2 denotes a methyl group], or a salt of the compound, or a
solvate of the compound or salt.
[0077] [8-2] A more preferred aspect of mode [8] is a compound
represented by formula (AD-1) above [in formula (AD-1), p, R.sup.1
and R.sup.2 are defined in the same way as for mode [8-1] above;
ring A group represented by formula (II) is a pyrimidin-4-yl group;
and a more specific group obtained by combining the definitions of
p, R.sup.1 and ring A group represented by formula (II) is a
2,5-dimethylpyrimidin-4-yl group], or a salt of the compound, or a
solvate of the compound or salt.
[0078] [8a] Another aspect of the eighth mode of the present
invention is a compound represented by formula (AD-1):
##STR00089##
[in formula (AD-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
and ring A group represented by formula (II):
##STR00090##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], or a salt of the compound, or a solvate of the
compound or salt.
[0079] [8a-1] A preferred aspect of mode [8a] is a compound
represented by formula (AD-1) above [in formula (AD-1), p and ring
A group represented by formula (II) are defined in the same way as
for mode [8a] above; R.sup.1 denotes a group arbitrarily selected
from among a fluorine atom, a chlorine atom, a bromine atom, a
cyano group, a methyl group, an ethyl group, an isopropyl group, a
tert-butyl group, a cyclopropyl group, a difluoromethyl group, a
trifluoromethyl group, a 1-hydroxyethyl group, a vinyl group, an
acetyl group, a methoxy group and an ethoxyethyl group; and R.sup.2
denotes a methyl group], or a salt of the compound, or a solvate of
the compound or salt.
[0080] [8a-2] A more preferred aspect of mode [8a] is a compound
represented by formula (AD-1) above [in formula (AD-1), p denotes
an integer between 1 and 3; R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as in mode
[8a-1] above], or a salt of the compound, or a solvate of the
compound or salt.
[0081] [8a-3] A yet more preferred aspect of mode [8a] is a
compound represented by formula (AD-1) above [in formula (AD-1), p,
R.sup.1 and R.sup.2 are defined in the same way as for mode [8a-2]
above; ring A group represented by formula (II) is a thiazol-2-yl
group or a pyrimidin-4-yl group; and a more specific group obtained
by combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0082] [8']
[0083] Mode no. 8' of the present invention lists the intermediate
compounds shown below as preferred intermediate compounds for
compounds represented by formula (AD-1) in modes [8] to [8-3] above
or modes [8a] to [8a-3] above, or salts of these intermediate
compounds, or solvates of the intermediate compounds or salts. The
listed intermediate compounds are obtained in steps having working
example numbers corresponding to the compound names. For example,
Working Example Number 1-2 means that an intermediate compound
corresponding to <Step 2> in Working Example 1 is obtained.
Moreover, the names of the compounds shown below are based on
English names obtained using the Cambridge Soft Chem BioDraw Ultra
12.0.2.1076 compound nomenclature program.
TABLE-US-00001 TABLE 1 Working Example Compound No.
4-(2,5-dimethylpyrimidin-4-yl)-1- 2 and 6-1
methyl-1H-pyrazole-5-carboxamde
1-methyl-4-(2-methylpyrimidin-4-yl)-1H- 9 pyrazole-5-carboxamide
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1- 13
methyl-1H-pyrazole-5-carboxamide
1-methyl-4-(4-(trifluoromethyl)thiazol- 17
2-yl)-1H-pyrazole-5-carboxamide
[0084] [9] A ninth mode of the present invention is a compound
represented by formula (AD-2):
##STR00091##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; and ring A group represented by formula (II):
##STR00092##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0085] [9-1] A preferred aspect of mode [9] is a compound
represented by formula (AD-2) above [in formula (AD-2), p, R.sup.3
and ring A group represented by formula (II) are defined in the
same way as for mode [9] above; R.sup.1 denotes a group arbitrarily
selected from among a fluorine atom, a chlorine atom, a cyano
group, a methyl group, a trifluoromethyl group and a methoxy group;
and R.sup.2 denotes a methyl group], or a salt of the compound, or
a solvate of the compound or salt.
[0086] [9-2] A more preferred aspect of mode [9] is a compound
represented by formula (AD-2) above [in formula (AD-2), p, R.sup.1,
R.sup.2 and ring A group represented by formula (II) are defined in
the same way as for mode [9-1] above; and R.sup.3 denotes a
fluorine atom], or a salt of the compound, or a solvate of the
compound or salt.
[0087] [9-3] A yet more preferred aspect of mode [9] is a compound
represented by formula (AD-2) above [in formula (AD-2), p, R.sup.1,
R.sup.2 and R.sup.3 are defined in the same way as for mode [9-2]
above; ring A group represented by formula (II) is a pyrimidin-4-yl
group; and a more specific group obtained by combining the
definitions of p, R.sup.1 and ring A group represented by formula
(II) is a 2,5-dimethylpyrimidin-4-yl group], or a salt of the
compound, or a solvate of the compound or salt.
[0088] [9a] Another aspect of the ninth mode of the present
invention is a compound represented by formula (AD-2):
##STR00093##
[in formula (AD-2), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.3 denotes a group arbitrarily selected from among a hydrogen
atom and a fluorine atom; and ring A group represented by formula
(II):
##STR00094##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], or a salt of the compound, or a solvate of the
compound or salt.
[0089] [9a-1] A preferred aspect of mode [9a] is a compound
represented by formula (AD-2) above [in formula (AD-2), p, R.sup.3
and ring A group represented by formula (II) are defined in the
same way as for mode [9a] above; R.sup.1 denotes a group
arbitrarily selected from among a fluorine atom, a chlorine atom, a
bromine atom, a cyano group, a methyl group, an ethyl group, an
isopropyl group, a tert-butyl group, a cyclopropyl group, a
difluoromethyl group, a trifluoromethyl group, a 1-hydroxyethyl
group, a vinyl group, an acetyl group, a methoxy group and an
ethoxyethyl group; and R.sup.2 denotes a methyl group], or a salt
of the compound, or a solvate of the compound or salt.
[0090] [9a-2] A more preferred aspect of mode [9a] is a compound
represented by formula (AD-2) above [in formula (AD-2), p, R.sup.1,
R.sup.2 and ring A group represented by formula (II) are defined in
the same way as for mode [9a-1] above; and R.sup.3 denotes a
fluorine atom], or a salt of the compound, or a solvate of the
compound or salt.
[0091] [9a-3] A yet more preferred aspect of mode [9a] is a
compound represented by formula (AD-2) above [in formula (AD-2), p,
R.sup.1, R.sup.2 and R.sup.3 are defined in the same way as for
mode [9a-2] above; ring A group represented by formula (II) is a
thiazol-2-yl group or a pyrimidin-4-yl group; and a more specific
group obtained by combining the definitions of p, R.sup.1 and ring
A group represented by formula (II) is a
4-(trifluoromethyl)thiazol-2-yl group, a
5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0092] [9']
[0093] Mode no. 9' of the present invention lists the intermediate
compounds shown below as preferred intermediate compounds for
compounds represented by formula (AD-2) in modes [9] to [9-3] above
or modes [9a] to [9a-3] above, or salts of these intermediate
compounds, or solvates of the intermediate compounds or salts. The
listed intermediate compounds are obtained in steps having working
example numbers corresponding to the compound names. Explanations
relating to the names of the compounds and the working example
numbers are the same as the explanations given in mode [8']
above.
TABLE-US-00002 TABLE 2 Working Example Compound No.
N-(2-amino-5-fluoropyridin-4-yl)-4- 5-3 and 6-2
(2,5-dimethylpyrimidin-4-yl)-1-methyl- 1H-pyrazole-5-carboxamide
N-(2-amino-5-fluoropyridin-4-yl)-4-(2- 10-1
methylpyrimidin-4-yl)-1-methyl-1H- pyrazole-5-carboxamide
N-(2-amino-5-fluoropyridin-4-yl)-4-(5- 14-1
fluoro-2-methoxypyrimidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamide
N-(2-amino-5-fluoropyridin-4-yl)-4-(4- 18-1
(trifluoromethyl)thiazol-2-yl)-1-
methyl-1H-pyrazole-5-carboxamide
[0094] [10] A tenth mode of the present invention is a compound
represented by formula (AD-3):
##STR00095##
[in formula (AD-3), p denotes an integer between 0 and 3; q denotes
an integer between 0 and 2; R.sup.1 groups each independently
denote a group arbitrarily selected from among a halogen atom, a
cyano group, a C.sub.1-6 alkyl group, a halogenated C.sub.1-6 alkyl
group and a C.sub.1-6 alkoxy group; R.sup.2 denotes a C.sub.1-6
alkyl group; R.sup.3 denotes a group arbitrarily selected from
among a hydrogen atom and a fluorine atom; R.sup.4 groups each
independently denote a group arbitrarily selected from among a
halogen atom, a C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
and ring A group represented by formula (II):
##STR00096##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0095] [10-1] A preferred aspect of mode [10] is a compound
represented by formula (AD-3) above [in formula (AD-3), p, q,
R.sup.3 and ring A group represented by formula (II) are defined in
the same way as for mode [10] above; R.sup.1 denotes a group
arbitrarily selected from among a fluorine atom, a chlorine atom, a
cyano group, a methyl group, a trifluoromethyl group and a methoxy
group; R.sup.2 denotes a methyl group; and R.sup.4 denotes a group
arbitrarily selected from among a fluorine atom, a methyl group and
a methoxy group], or a salt of the compound, or a solvate of the
compound or salt.
[0096] [10-2] A more preferred aspect of mode [10] is a compound
represented by formula (AD-3) above [in formula (AD-3), p, R.sup.1,
R.sup.2, R.sup.4 and ring A group represented by formula (II) are
defined in the same way as for mode [10-1] above; q denotes the
integer 0; and R.sup.3 denotes a fluorine atom], or a salt of the
compound, or a solvate of the compound or salt.
[0097] [10-3] A yet more preferred aspect of mode [10] is a
compound represented by formula (AD-3) above [in formula (AD-3), p,
q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined in the same
way as for mode [10-2] above; ring A group represented by formula
(II) is a pyrimidin-4-yl group; and a more specific group obtained
by combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 2,5-dimethylpyrimidin-4-yl group],
or a salt of the compound, or a solvate of the compound or
salt.
[0098] [10a] Another aspect of the tenth mode of the present
invention is a compound represented by formula (AD-3):
##STR00097##
[in formula (AD-3), p denotes an integer between 0 and 3; q denotes
an integer between 0 and 2; R.sup.1 groups each independently
denote a group arbitrarily selected from among a halogen atom, a
cyano group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group,
a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00098##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], or a salt of the compound, or a solvate of the
compound or salt.
[0099] [10a-1] A preferred aspect of mode [10a] is a compound
represented by formula (AD-3) above [in formula (AD-3), p, q,
R.sup.3 and ring A group represented by formula (II) are defined in
the same way as for mode [10a] above; R.sup.1 denotes a group
arbitrarily selected from among a fluorine atom, a chlorine atom, a
bromine atom, a cyano group, a methyl group, an ethyl group, an
isopropyl group, a tert-butyl group, a cyclopropyl group, a
difluoromethyl group, a trifluoromethyl group, a 1-hydroxyethyl
group, a vinyl group, an acetyl group, a methoxy group and an
ethoxyethyl group; R.sup.2 denotes a methyl group; and R.sup.4
denotes a group arbitrarily selected from among a fluorine atom, a
methyl group and a methoxy group], or a salt of the compound, or a
solvate of the compound or salt.
[0100] [10a-2] A more preferred aspect of mode [10a] is a compound
represented by formula (AD-3) above [in formula (AD-3), p, R.sup.1,
R.sup.2, R.sup.4 and ring A group represented by formula (II) are
defined in the same way as for mode [10a-1] above; q denotes the
integer 0; and R.sup.3 denotes a fluorine atom], or a salt of the
compound, or a solvate of the compound or salt.
[0101] [10a-3] A yet more preferred aspect of mode [10a] is a
compound represented by formula (AD-3) above [in formula (AD-3), p,
q, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined in the same
way as for mode [10a-2] above; ring A group represented by formula
(II) is a thiazol-2-yl group or a pyrimidin-4-yl group; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group represented by formula (II) is a
4-(trifluoromethyl)thiazol-2-yl group, a
5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0102] [10']
[0103] Mode no. 10' of the present invention lists the intermediate
compounds shown below as preferred intermediate compounds for
compounds represented by formula (AD-3) in modes [10] to [10-3]
above or modes [10a] to [10a-3] above, or salts of these
intermediate compounds, or solvates of the intermediate compounds
or salts. The listed intermediate compounds are obtained in steps
having working example numbers corresponding to the compound names.
Explanations relating to the names of the compounds and the working
example numbers are the same as the explanations given in mode [8']
above.
TABLE-US-00003 TABLE 3 Working Example Compound No.
N-(benzimidamido-5-fluoropyridin-4-yl)- 6-3
4-(2,5-dimethylpyrimidin-4-yl)-1- methyl-1H-pyrazole-5-carboxamide
N-(benzimidamido-5-fluoropyridin-4-yl)- 10-2
4-(2-methylpyrimidin-4-yl)-1-methyl-1H- pyrazole-5-carboxamide
N-(benzimidamido-5-fluoropyridin-4-yl)- 14-2
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-
methyl-1H-pyrazole-5-carboxamide
N-(benzimidamido-5-fluoropyridin-4-yl)- 18-2
4-(4-(trifluoromethyl)thiazol-2-yl)-1-
methyl-1H-pyrazole-5-carboxamide
[0104] [11] An eleventh mode of the present invention is a compound
represented by formula (PY-1-1):
##STR00099##
or a salt of the compound, or a solvate of the compound or
salt.
[0105] [12] A twelfth mode of the present invention is a compound
represented by formula (PY-2-1):
##STR00100##
[in formula (PY-2), R.sup.C denotes a group arbitrarily selected
from among a C.sub.1-6 alkyl group, a C.sub.6-14 aryl group and a
C.sub.7-20 aralkyl group], or a salt of the compound, or a solvate
of the compound or salt.
[0106] [12-1] A preferred aspect of mode [12] is a compound
represented by formula (PY-2-1) above [in formula (PY-2), R.sup.C
denotes a benzyl group], or a salt of the compound, or a solvate of
the compound or salt.
[0107] [13] A thirteenth mode of the present invention is a
compound represented by formula (ET-1):
##STR00101##
[in formula (ET-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.D groups each
independently denote a group arbitrarily selected from among a
C.sub.1-6 alkyl group, a C.sub.6-14 aryl group and a C.sub.7-20
aralkyl group; and ring A group represented by formula (II):
##STR00102##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0108] [13-1] A preferred aspect of mode [13] is a compound
represented by formula (ET-1) above [in formula (ET-1), p denotes
an integer between 0 and 3; R.sup.1 groups each independently
denote a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group;
R.sup.D groups each independently denote a group arbitrarily
selected from among a methyl group, an ethyl group, a tert-butyl
group, a phenyl group and a benzyl group; and ring A group
represented by formula (II) is defined in the same way as in mode
[13] above], or a salt of the compound, or a solvate of the
compound or salt.
[0109] [13-2] A more preferred aspect of mode [13] is a compound
represented by formula (ET-1) above [in formula (ET-1), p denotes
an integer between 1 and 3; R.sup.1, R.sup.2, R.sup.D and ring A
group represented by formula (II) are defined in the same way as in
mode [13-1] above], or a salt of the compound, or a solvate of the
compound or salt.
[0110] [13-3] A preferred aspect of mode [13] is a compound
represented by formula (ET-1) above [in formula (ET-1), p, R.sup.1,
R.sup.2, R.sup.D and ring A group represented by formula (II) are
defined in the same way as in mode [13-2] above; and a more
specific group obtained by combining the definitions of p, R.sup.1
and ring A group is a 2,5-dimethylpyrimidin-4-yl group], or a salt
of the compound, or a solvate of the compound or salt.
[0111] [13a] Another aspect of the thirteenth mode of the present
invention is a compound represented by formula (ET-1) below:
##STR00103##
[in formula (ET-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
R.sup.D denotes a group arbitrarily selected from among a C.sub.1-6
alkyl group, a C.sub.6-14 aryl group and a C.sub.7-20 aralkyl
group; and ring A group represented by formula (II):
##STR00104##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], or a salt of the compound, or a solvate of the
compound or salt.
[0112] [13a-1] A preferred aspect of mode [13a] is a compound
represented by formula (ET-1) above [in formula (ET-1), p denotes
an integer between 0 and 3; R.sup.1 denotes a group arbitrarily
selected from among a fluorine atom, a chlorine atom, a bromine
atom, a cyano group, a methyl group, an ethyl group, an isopropyl
group, a tert-butyl group, a cyclopropyl group, a difluoromethyl
group, a trifluoromethyl group, a 1-hydroxyethyl group, a vinyl
group, an acetyl group, a methoxy group and an ethoxyethyl group;
R.sup.2 denotes a methyl group; R.sup.D groups each independently
denote a group arbitrarily selected from among a methyl group, an
ethyl group, a tert-butyl group, a phenyl group and a benzyl group;
and ring A group represented by formula (II) is defined in the same
way as in mode [13a] above], or a salt of the compound, or a
solvate of the compound or salt.
[0113] [13a-2] A more preferred aspect of mode [13a] is a compound
represented by formula (ET-1) above [in formula (ET-1), p denotes
an integer between 1 and 3; R.sup.1, R.sup.2, R.sup.D and ring A
group represented by formula (II) are defined in the same way as in
mode [13a-1] above], or a salt of the compound, or a solvate of the
compound or salt.
[0114] [13a-3] A yet more preferred aspect of mode [13a] is a
compound represented by formula (ET-1) above [in formula (ET-1), p,
R.sup.1, R.sup.2 and R.sup.D are defined in the same way as in mode
[13a-2] above; ring A group represented by formula (II) is a
thiazol-2-yl group or a pyrimidin-4-yl group; and a more specific
group obtained by combining the definitions of p, R.sup.1 and ring
A group represented by formula (II) is a
4-(trifluoromethyl)thiazol-2-yl group, a
5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0115] [13']
[0116] Mode no. 13' of the present invention lists the intermediate
compounds shown below as preferred intermediate compounds for
compounds represented by formula (ET-1) in modes [13] to [13-3]
above or modes [13a] to [13a-3] above, or salts of these
intermediate compounds, or solvates of the intermediate compounds
or salts. The listed intermediate compounds are obtained in steps
having working example numbers corresponding to the compound names.
Explanations relating to the names of the compounds and the working
example numbers are the same as the explanations given in mode [8']
above.
TABLE-US-00004 TABLE 4 Working Example Compound No. Ethyl
4-(2,5-dimethylpyrimidin-4-yl)-1- 1
methyl-1H-pyrazole-5-carboxylate Methyl
1-methyl-4-(2-methylpyrimidin-4- 7 yl)-1H-pyrazole-5-carboxylate
Methyl 4-(5-fluoro-2-methoxypyrimidin- 11
4-yl)-1-methyl-1H-pyrazole-5- carboxylate Methyl 1-methyl-4-(4-
15-2 (trifluoromethyl)thiazol-2-yl)-1H- pyrazole-5-carboxylate
[0117] [14] A fourteenth mode of the present invention is a
compound represented by formula (CA-1):
##STR00105##
[in formula (CA-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
halogenated C.sub.1-6 alkyl group and a C.sub.1-6 alkoxy group;
R.sup.2 denotes a C.sub.1-6 alkyl group; and ring A group
represented by formula (II):
##STR00106##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a pyridin-2-yl group, a pyridazin-3-yl group, a
pyrimidin-2-yl group, a pyrimidin-4-yl group and a pyrazin-2-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0118] [14-1] A preferred aspect of mode [14] is a compound
represented by formula (CA-1) above [in formula (CA-1), p denotes
an integer between 0 and 3; R.sup.1 groups each independently
denote a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
ring A group represented by formula (II) is defined in the same way
as in mode [14] above], or a salt of the compound, or a solvate of
the compound or salt.
[0119] [14-2] A more preferred aspect of mode [14] is a compound
represented by formula (CA-1) above [in formula (CA-1), p denotes
an integer between 1 and 3; R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as in mode
[14-1] above], or a salt of the compound, or a solvate of the
compound or salt.
[0120] [14-3] A preferred aspect of mode [14] is a compound
represented by formula (CA-1) above [in formula (CA-1), p, R.sup.1,
R.sup.2 and ring A group represented by formula (II) are defined in
the same way as in mode [14-2] above; and a more specific group
obtained by combining the definitions of p, R.sup.1 and ring A
group is a 2,5-dimethylpyrimidin-4-yl group], or a salt of the
compound, or a solvate of the compound or salt.
[0121] [14a] Another aspect of the fourteenth mode of the present
invention is a compound represented by formula (CA-1) below:
##STR00107##
[in formula (CA-1), p denotes an integer between 0 and 3; R.sup.1
groups each independently denote a group arbitrarily selected from
among a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a halogenated C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkoxy-C.sub.1-6 alkyl group, a hydroxy-C.sub.1-6 alkyl group and a
C.sub.2-7 alkanoyl group; R.sup.2 denotes a C.sub.1-6 alkyl group;
and ring A group represented by formula (II):
##STR00108##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], or a salt of the compound, or a solvate of the
compound or salt.
[0122] [14a-1] A preferred aspect of mode [14a] is a compound
represented by formula (CA-1) above [in formula (CA-1), p denotes
an integer between 0 and 3; R.sup.1 denotes a group arbitrarily
selected from among a fluorine atom, a chlorine atom, a bromine
atom, a cyano group, a methyl group, an ethyl group, an isopropyl
group, a tert-butyl group, a cyclopropyl group, a difluoromethyl
group, a trifluoromethyl group, a 1-hydroxyethyl group, a vinyl
group, an acetyl group, a methoxy group and an ethoxyethyl group;
R.sup.2 denotes a methyl group; and ring A group represented by
formula (II) is defined in the same way as in mode [14a] above], or
a salt of the compound, or a solvate of the compound or salt.
[0123] [14a-2] A more preferred aspect of mode [14a] is a compound
represented by formula (CA-1) above [in formula (CA-1), p denotes
an integer between 1 and 3; R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as in mode
[14a-1] above], or a salt of the compound, or a solvate of the
compound or salt.
[0124] [14a-3] A yet more preferred aspect of mode [14a] is a
compound represented by formula (CA-1) above [in formula (CA-1), p,
R.sup.1 and R.sup.2 are defined in the same way as in mode [14a-2]
above; ring A group represented by formula (II) is a thiazol-2-yl
group or a pyrimidin-4-yl group; and a more specific group obtained
by combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], or a salt of the compound, or a solvate of the compound or
salt.
[0125] [14']
[0126] Mode no. 14' of the present invention lists the intermediate
compounds shown below as preferred intermediate compounds for
compounds represented by formula (CA-1) in modes [14] to [14-3]
above or modes [14a] to [14a-3] above, or salts of these
intermediate compounds, or solvates of the intermediate compounds
or salts. The listed intermediate compounds are obtained in steps
having working example numbers corresponding to the compound names.
Explanations relating to the names of the compounds and the working
example numbers are the same as the explanations given in mode [8']
above.
TABLE-US-00005 TABLE 5 Working Example Compound No.
4-(2,5-dimethylpyrimidin-4-yl)-1- 5-1
methyl-1H-pyrazole-5-carboxylic acid
1-methyl-4-(2-methylpyrimidin-4-yl)-1H- 8 pyrazole-5-carboxylic
acid 4-(5-fluoro-2-methoxypyrimidin-4-yl)-1- 12
methyl-1H-pyrazole-5-carboxylic acid
1-methyl-4-(4-(trifluoromethyl)thiazol- 16
2-yl)-1H-pyrazole-5-carboxylic acid
[0127] [15] A fifteenth mode of the present invention is a method
for manufacturing a compound represented by formula (I) below:
##STR00109##
[in formula (I), p denotes an integer between 0 and 3; q denotes an
integer between 0 and 2; R.sup.1 groups each independently denote a
group arbitrarily selected from among a halogen atom, a cyano
group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00110##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (AD-1):
##STR00111##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [15]] and a 2-amino-4-iodopyridine derivative
represented by formula (PY-1):
##STR00112##
[in formula (PY-1), R.sup.3 denotes a hydrogen atom or a fluorine
atom (a routine method for manufacturing a compound represented by
formula (PY-1) is described later)] are reacted with each other in
the presence of N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI)
and an inorganic base such as potassium carbonate or potassium
phosphate using a solvent which does not take part in the reaction,
such as 1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-2):
##STR00113##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (I) in mode [15]] (stage [15]-1), the compound represented
by formula (AD-2) and a compound represented by formula (IM-1):
##STR00114##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (I) in mode [15]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-3):
##STR00115##
[in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for formula (I) in mode [15]] (stage [15]-2), and the
compound represented by formula (AD-3) is subjected to a
cyclization reaction in the presence of air using a solvent which
does not take part in the reaction, such as dimethyl sulfoxide
(DMSO) or N-methylpyrrolidone (NMP), at a temperature between
0.degree. C. and a temperature at which the solvent refluxes in the
presence of a copper reagent such as copper iodide (CuI) or copper
chloride (CuCl) (stage [15]-3), thereby obtaining the compound
represented by formula (I).
[0128] [15-1] A preferred aspect of mode [15] is a method in which
a compound represented by formula (I) above is manufactured [in
formula (I), p, q, R.sup.3 and ring A group represented by formula
(II) are defined in the same way as in mode [15] above; R.sup.1
denotes a group arbitrarily selected from among a fluorine atom, a
chlorine atom, a bromine atom, a cyano group, a methyl group, an
ethyl group, an isopropyl group, a tert-butyl group, a cyclopropyl
group, a difluoromethyl group, a trifluoromethyl group, a
1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (I) is
obtained [these stages are the same as (stage [15]-1) to (stage
[15]-3) in mode [15] above; the definitions of the substituent
groups in the intermediates in (stage [15]-1) to (stage [15]-3) are
the same as the definitions in mode [15-1], and R.sup.B in formula
(IM-1) is a C.sub.1-6 alkyl group].
[0129] [15-2] A more preferred aspect of mode [15] is a method in
which a compound represented by formula (I) above is manufactured
[in formula (I), p, R.sup.1, R.sup.2, R.sup.4 and ring A group
represented by formula (II) are defined in the same way as for mode
[15-1] above; q denotes the integer 0; and R.sup.3 denotes a
fluorine atom], the manufacturing method including stages in which
a compound represented by formula (I) is obtained [these stages are
the same as (stage [15]-1) to (stage [15]-3) in mode [15] above;
the definitions of the substituent groups in the intermediates in
(stage [15]-1) to (stage [15]-3) are the same as the definitions in
mode [15-2], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0130] [15-3] A yet more preferred aspect of mode [15] is a method
in which a compound represented by formula (I) above is
manufactured [in formula (I), p, q, R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 are defined in the same way as for mode [15-2] above; ring
A group represented by formula (II) is a thiazol-2-yl group or a
pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (I) is obtained [these stages are
the same as (stage [15]-1) to (stage [15]-3) in mode [15] above;
the definitions of the substituent groups in the intermediates in
(stage [15]-1) to (stage [15]-3) are the same as the definitions in
mode [15-3], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0131] [16] A sixteenth mode of the present invention is a method
for manufacturing a compound represented by formula (AD-3)
below:
##STR00116##
[in formula (AD-3), p denotes an integer between 0 and 3; q denotes
an integer between 0 and 2; R.sup.1 groups each independently
denote a group arbitrarily selected from among a halogen atom, a
cyano group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group,
a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a hydrogen
atom or a fluorine atom; R.sup.4 groups each independently denote a
group arbitrarily selected from among a halogen atom, a C.sub.1-6
alkyl group and a C.sub.1-6 alkoxy group; and ring A group
represented by formula (II):
##STR00117##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including stages in
which a compound represented by formula (AD-1):
##STR00118##
[in formula (AD-1), p, R.sup.1, R.sup.2 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-3) in mode [16]] and a 2-amino-4-iodopyridine
derivative represented by formula (PY-1):
##STR00119##
[in formula (PY-1), R.sup.3 denotes a group arbitrarily selected
from among a hydrogen atom and a fluorine atom (a routine method
for manufacturing a compound represented by formula (PY-1) is
described later)] are reacted with each other in the presence of
N,N-dimethyl-1,2-ethanediamine, copper iodide (CuI) and an
inorganic base such as potassium carbonate or potassium phosphate
using a solvent which does not take part in the reaction, such as
1,4-dioxane, tetrahydrofuran or 1,2-dimethoxyethane, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes, thereby obtaining a compound represented by
formula (AD-2):
##STR00120##
[in formula (AD-2), p, R.sup.1, R.sup.2, R.sup.3 and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-3) in mode [16]] (stage [16]-1), and the compound
represented by formula (AD-2) and a compound represented by formula
(IM-1):
##STR00121##
[in formula (IM-1), q and R.sup.4 are defined in the same way as
for formula (AD-3) in mode [16]; and R.sup.B denotes a C.sub.1-6
alkyl group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes (stage [16]-2), thereby obtaining the compound
represented by formula (AD-3).
[0132] [16-1] A preferred aspect of mode [16] is a method in which
a compound represented by formula (AD-3) above is manufactured [in
formula (AD-3), p, q, R.sup.3 and ring A group represented by
formula (II) are defined in the same way as in mode [16] above;
R.sup.1 denotes a group arbitrarily selected from among a fluorine
atom, a chlorine atom, a bromine atom, a cyano group, a methyl
group, an ethyl group, an isopropyl group, a tert-butyl group, a
cyclopropyl group, a difluoromethyl group, a trifluoromethyl group,
a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including stages in which a compound represented by formula (AD-3)
is obtained [these stages are the same as (stage [16]-1) and (stage
[16]-2) in mode [16] above; the definitions of the substituent
groups in the intermediates in (stage [16]-1) and (stage [16]-2)
are the same as the definitions in mode [16-1], and R.sup.B in
formula (IM-1) is a C.sub.1-6 alkyl group].
[0133] [16-2] A more preferred aspect of mode [16] is a method in
which a compound represented by formula (AD-3) above is
manufactured [in formula (AD-3), p, R.sup.1, R.sup.2, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for mode [16-1] above; q denotes the integer 0; and R.sup.3
denotes a fluorine atom], the manufacturing method including stages
in which a compound represented by formula (AD-3) is obtained
[these stages are the same as (stage [16]-1) and (stage [16]-2) in
mode [16] above; the definitions of the substituent groups in the
intermediates in (stage [16]-1) and (stage [16]-2) are the same as
the definitions in mode [16-2], and R.sup.B in formula (IM-1) is a
C.sub.1-6 alkyl group].
[0134] [16-3] A yet more preferred aspect of mode [16] is a method
in which a compound represented by formula (AD-3) above is
manufactured [in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are defined in the same way as for mode [16-2] above;
ring A group represented by formula (II) is a thiazol-2-yl group or
a pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including stages in which a
compound represented by formula (AD-3) is obtained [these stages
are the same as (stage [16]-1) and (stage [16]-2) in mode [16]
above; the definitions of the substituent groups in the
intermediates in (stage [16]-1) and (stage [16]-2) are the same as
the definitions in mode [16-3], and R.sup.B in formula (IM-1) is a
C.sub.1-6 alkyl group].
[0135] [17] A seventeenth mode of the present invention is a method
for manufacturing a compound represented by formula (AD-3)
below:
##STR00122##
[in formula (AD-3), p denotes an integer between 0 and 3; q denotes
an integer between 0 and 2; R.sup.1 groups each independently
denote a group arbitrarily selected from among a halogen atom, a
cyano group, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group,
a halogenated C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.1-6 alkoxy group, a C.sub.1-6 alkoxy-C.sub.1-6 alkyl group, a
hydroxy-C.sub.1-6 alkyl group and a C.sub.2-7 alkanoyl group;
R.sup.2 denotes a C.sub.1-6 alkyl group; R.sup.3 denotes a group
arbitrarily selected from among a hydrogen atom and a fluorine
atom; R.sup.4 groups each independently denote a group arbitrarily
selected from among a halogen atom, a C.sub.1-6 alkyl group and a
C.sub.1-6 alkoxy group; and ring A group represented by formula
(II):
##STR00123##
denotes a monocyclic 5- to 6-membered heteroaryl group arbitrarily
selected from among a thiazol-2-yl group, a thiazol-4-yl group, a
1-methyl-1H-imidazol-4-yl group, a 1,3,4-thiadiazol-2-yl group, a
1,2,4-thiadiazol-5-yl group, a pyridin-2-yl group, a pyridazin-3-yl
group, a pyrimidin-2-yl group, a pyrimidin-4-yl group and a
pyrazin-2-yl group], the manufacturing method including a stage in
which a compound represented by formula (AD-2):
##STR00124##
[in formula (AD-2), p, R.sup.1, R.sup.2, R and ring A group
represented by formula (II) are defined in the same way as for
formula (AD-3) in mode [17]] and a compound represented by formula
(IM-1):
##STR00125##
[in formula (IM-1), q and R are defined in the same way as for
formula (AD-3) in mode [17]; and R.sup.B denotes a C.sub.1-6 alkyl
group] or a salt thereof (the compound represented by formula
(IM-1) and salt thereof are commercially available compounds or
compounds that can be easily obtained from commercially available
compounds using manufacturing methods known from literature) are
reacted with each other using a solvent which does not take part in
the reaction, such as dimethyl sulfoxide or pyridine, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes (stage [17]-1), thereby obtaining the compound
represented by formula (AD-3).
[0136] [17-1] A preferred aspect of mode [17] is a method in which
a compound represented by formula (AD-3) above is manufactured [in
formula (AD-3), p, q, R.sup.3 and ring A group represented by
formula (II) are defined in the same way as in mode [17] above;
R.sup.1 denotes a group arbitrarily selected from among a fluorine
atom, a chlorine atom, a bromine atom, a cyano group, a methyl
group, an ethyl group, an isopropyl group, a tert-butyl group, a
cyclopropyl group, a difluoromethyl group, a trifluoromethyl group,
a 1-hydroxyethyl group, a vinyl group, an acetyl group, a methoxy
group and an ethoxyethyl group; R.sup.2 denotes a methyl group; and
R.sup.4 denotes a group arbitrarily selected from among a fluorine
atom, a methyl group and a methoxy group], the manufacturing method
including a stage in which a compound represented by formula (AD-3)
is obtained [this stage is the same as (stage [17]-1) in mode [17]
above; the definitions of the substituent groups in the
intermediate in (stage [17]-1) are the same as the definitions in
mode [17-1], and R.sup.B in formula (IM-1) is a C.sub.1-6 alkyl
group].
[0137] [17-2] A more preferred aspect of mode [17] is a method in
which a compound represented by formula (AD-3) above is
manufactured [in formula (AD-3), p, R.sup.1, R.sup.2, R.sup.4 and
ring A group represented by formula (II) are defined in the same
way as for mode [17-1] above; q denotes the integer 0; and R.sup.3
denotes a fluorine atom], the manufacturing method including a
stage in which a compound represented by formula (AD-3) is obtained
[this stage is the same as (stage [17]-1) in mode [17] above; the
definitions of the substituent groups in the intermediate in (stage
[17]-1) are the same as the definitions in mode [17-2], and R.sup.B
in formula (IM-1) is a C.sub.1-6 alkyl group].
[0138] [17-3] A yet more preferred aspect of mode [17] is a method
in which a compound represented by formula (AD-3) above is
manufactured [in formula (AD-3), p, q, R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are defined in the same way as for mode [17-2] above;
ring A group represented by formula (II) is a thiazol-2-yl group or
a pyrimidin-4-yl group; and a more specific group obtained by
combining the definitions of p, R.sup.1 and ring A group
represented by formula (II) is a 4-(trifluoromethyl)thiazol-2-yl
group, a 5-fluoro-2-methoxypyrimidin-4-yl group, a
2,5-dimethylpyrimidin-4-yl group or a 2-methylpyrimidin-4-yl
group], the manufacturing method including a stage in which a
compound represented by formula (AD-3) is obtained [this stage is
the same as (stage [17]-1) in mode [17] above; the definitions of
the substituent groups in the intermediate in (stage [17]-1) are
the same as the definitions in mode [17-3], and R.sup.B in formula
(IM-1) is a C.sub.1-6 alkyl group].
[0139] [18] An eighteenth mode of the present invention is a method
for manufacturing a
4-heteroaryl-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole--
5-carboxylic acid amide derivative represented by formula (I) in
(Scheme 1) below [in (Scheme 1), p, q, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.B, R.sup.C, R.sup.D and ring A group represented by
formula (II) are defined in the same way as modes [1] to [17]
above]; and an intermediate for this manufacturing method.
##STR00126##
[0140] Specific explanations will now be given for the groups in
the formulae in modes [1] to [18].
[0141] For example, in explanations relating to the compound of the
present invention, "C.sub.1-6" means that the number of constituent
carbon atoms is between 1 and 6 and, unless explicitly stated
otherwise, denotes the number of carbon atoms in a straight chain,
branched chain or cyclic group. The number of constituent carbon
atoms includes the total number of carbon atoms in a group that
includes a straight chain or branched chain group substituted with
a cyclic group or in a group that includes a cyclic group
substituted with a straight chain or branched chain group.
Therefore, a chain-like group means "a straight chain or branched
chain having 1 to 6 constituent carbon atoms". In addition, a
cyclic group means "a cyclic group in which the number of
constituent carbon atoms in the ring is 1 to 6". A group that
includes a chain-like group and a cyclic group means "a group
having a total of 1 to 6 carbon atoms".
[0142] Unless explicitly stated otherwise, the term "halogen atom"
in the present specification includes, for example, fluorine atoms,
chlorine atoms, bromine atoms, iodine atoms, and the like.
[0143] Unless explicitly stated otherwise, the term "C.sub.1-6
alkyl group" in the present specification includes, for example,
methylethyl groups, propyl groups, isopropyl groups, butyl groups,
isobutyl groups, sec-butyl groups, tert-butyl groups, pentyl
groups, isopentyl groups, neopentyl groups,
tert-pentyl3-methylbutyl groups, 1,2-dimethylpropyl groups,
1-ethylpropyl groups, hexyl groups, isohexyl groups, 1-methylpentyl
groups, 2-methylpentyl groups, 3-methylpentyl groups,
1,1-dimethylbutyl groups, 1,2-dimethylbutyl groups,
2,2-dimethylbutyl groups, 1,3-dimethylbutyl groups,
2,3-dimethylbutyl groups, 3,3-dimethylbutyl groups, 1-ethylbutyl
groups, 2-ethylbutyl groups, 1,1,2-trimethylpropyl groups,
1,2,2-trimethylpropyl groups, 1-ethyl-1-methylpropyl groups,
1-ethyl-2-methylpropyl groups, cyclopropyl groups, cyclobutyl
groups, cyclopentyl groups, cyclohexyl groups, cyclopropylmethyl
groups, cyclobutylmethyl groups, cyclopentylmethyl groups,
1-cyclopropylethyl groups, 2-cyclopropylethyl groups,
2-cyclobutylethyl groups, 2-methylcyclopropyl groups, and the
like.
[0144] Unless explicitly stated otherwise, the term "halogenated"
in the present specification means that 1 to 5 of the "halogen
atoms" mentioned above may be present as substituent groups. In
addition, the term "halogenated" may also be written as "optionally
halogenated" or "halogeno".
[0145] Unless explicitly stated otherwise, the term "halogenated
C.sub.1-6 alkyl group" in the present specification means a group
in which the "C.sub.1-6 alkyl groups" mentioned above are
arbitrarily substituted with 1 to 5 halogen atoms, and examples
thereof include fluoromethyl groups, difluoromethyl groups,
trifluoromethyl groups, 2,2,2-trifluoroethyl groups,
1,1,2,2-tetrafluoroethyl groups and pentafluoroethyl groups.
[0146] Unless explicitly stated otherwise, the term "C.sub.3-8
cycloalkyl group" in the present specification includes, for
example, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups,
cyclohexyl groups, cycloheptyl groups and cyclooctyl groups.
[0147] Unless explicitly stated otherwise, the term "C.sub.2-6
alkenyl group" in the present specification includes, for example,
vinyl groups, allyl groups, isopropenyl groups, 1-propen-1-yl
groups, 2-methylallyl groups, butenyl groups, pentenyl groups,
isopentenyl groups, hexenyl groups, 1-cyclopropen-1-yl groups,
2-cyclopropen-1-yl groups, 1-cyclobuten-1-yl groups,
1-cyclopenten-1-yl groups, 2-cyclopenten-1-yl groups,
3-cyclopenten-1-yl groups, 1-cyclohexen-1-yl groups,
2-cyclohexen-1-yl groups, 3-cyclohexen-1-yl groups,
2,4-cyclopentadien-1-yl groups, 2,5-cyclohexadien-1-yl groups, and
the like.
[0148] Unless explicitly stated otherwise, the term "C.sub.1-6
alkoxy group" in the present specification includes, for example,
methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups,
butoxy groups, isobutoxy groups, sec-butoxy groups, tert-butoxy
groups, pentyloxy groups, isopentyloxy groups, neopentyloxy groups,
tert-pentyloxy groups, 1-methylbutoxy groups, 2-methylbutoxy
groups, 1,2-dimethylpropoxy groups, 1-ethylpropoxy groups, hexyloxy
groups, isohexyloxy groups, 1-methylpentyloxy groups,
2-methylpentyloxy groups, 3-methylpentyloxy groups,
1,1-dimethylbutyloxy groups, 1,2-dimethylbutyloxy groups,
2,2-dimethylbutyloxy groups, 1,3-dimethylbutyloxy groups,
2,3-dimethylbutyloxy groups, 3,3-dimethylbutoxy groups,
1-ethylbutyloxy groups, 2-ethylbutyloxy groups,
1,1,2-trimethylpropyloxy groups, 1,2,2-trimethylpropyloxy groups,
1-ethyl-1-methylpropyloxy groups, 1-ethyl-2-methylpropyloxy groups,
cyclopropyloxy groups, cyclobutyloxy groups, cyclopentyloxy groups,
cyclohexyloxy groups, cyclopropylmethoxy groups, cyclobutylmethoxy
groups, cyclopentylmethoxy groups, 1-cyclopropylethoxy groups,
2-cyclopropylethoxy groups, 2-cyclobutylethoxy groups,
2-methylcyclopropyloxy groups, and the like.
[0149] Unless explicitly stated otherwise, the term "C.sub.1-6
alkoxy-C.sub.1-6 alkyl group" in the present specification means
groups in which the "C.sub.1-6 alkyl groups" mentioned above are
substituted with the "C.sub.1-6 alkoxy groups" mentioned above.
Unless explicitly stated otherwise, the term "C.sub.1-6
alkoxy-C.sub.1-6 alkyl group" in the present specification
includes, for example, methoxymethyl groups, methoxyethyl groups,
ethoxymethyl groups, ethoxyethyl groups, 1,1-dimethoxymethyl
groups, 1,1-diethoxyethyl groups, and the like.
[0150] Unless explicitly stated otherwise, the term
"hydroxy-C.sub.1-6 alkyl group" in the present specification means
groups in which the "C.sub.1-6 alkyl groups" mentioned above are
arbitrarily substituted with 1 to 5 hydroxyl groups, and examples
thereof include hydroxymethyl groups, hydroxyethyl groups
(specifically, 1-hydroxyethyl groups and 2-hydroxyethyl groups),
hydroxypropyl groups (specifically, 1-hydroxypropyl groups,
2-hydroxypropyl groups, 3-hydroxypropyl groups, and the like) and
2-hydroxy-2-methyl-ethyl groups.
[0151] Unless explicitly stated otherwise, the term "C.sub.2-7
alkanoyl group" in the present specification includes, for example,
acetyl groups, propionyl groups, butyryl groups, isobutyryl groups,
valeryl groups, isovaleryl groups, pivaloyl groups, hexanoyl
groups, heptanoyl groups, cyclopropylcarbonyl groups,
cyclobutylcarbonyl groups, cyclopentylcarbonyl groups,
cyclohexylcarbonyl groups, cyclopropylmethylcarbonyl groups,
2-methylcyclopropylcarbonyl groups, and the like.
[0152] Unless explicitly stated otherwise, the term "monocyclic 5-
to 6-membered heteroaryl group" in the present specification means
a monocyclic 5- to 6-membered heteroaryl ring group having 1 to 5
heteroatoms selected from among nitrogen atoms, sulfur atoms and
oxygen atoms.
[0153] Unless explicitly stated otherwise, the term "monocyclic 5-
to 6-membered heteroaryl group" in the present specification
includes, for example, pyrrolyl groups, furyl groups, thienyl
groups, thiazolyl groups, oxazolyl groups, 1H-imidazolyl groups,
isothiazolyl groups, isoxazolyl groups, 1H-pyrazolyl groups,
1,2,4-thiadiazolyl groups, 1,2,4-oxadiazolyl groups,
1H-1,2,4-triazolyl groups, 1,2,5-thiadiazolyl groups,
1,2,5-oxadiazolyl (furazanyl) groups, 2H-1,2,3-triazolyl groups,
1,3,4-thiadiazolyl groups, 1,3,4-oxadiazolyl groups,
4H-1,2,4-triazolyl groups, 1,2,4-thiadiazolyl groups,
1,2,4-oxadiazolyl groups, 1H-1,2,4-triazolyl groups,
1,2,3-thiadiazolyl groups, 1,2,3-oxadiazolyl groups,
1H-1,2,3-triazolyl groups, 1,2,3,4-thiatriazolyl groups,
1,2,3,4-oxatriazolyl groups, 1,2,3,5-thiatriazolyl groups,
1,2,3,5-oxatriazolyl groups, 1H-tetrazolyl groups, 2H-tetrazolyl
groups, pyridinyl groups, pyridazinyl groups, pyrimidinyl groups,
pyrazinyl groups, 1,2,3-triazinyl groups, 1,2,4-triazinyl groups,
1,3,5-triazinyl groups, 1,2,4,5-tetrazinyl groups,
1,2,3,4-tetrazinyl groups, 1,2,3,5-tetrazinyl groups, and the
like.
[0154] Unless explicitly stated otherwise, the term "C.sub.7-20
aralkyl group" in the present specification includes, for example,
benzyl groups, phenethyl groups, diphenylmethyl groups,
2,2-diphenylethyl groups, 3-phenylpropyl groups, 4-phenylbutyl
groups, 5-phenylpentyl groups, 2-biphenylmethyl groups,
3-biphenylmethyl groups, 4-biphenylmethyl groups, 1-naphthylmethyl
groups, 2-naphthylmethyl groups, 2-(1-naphthyl)ethyl groups,
2-(2-naphthyl)ethyl groups, 1-indanylmethyl groups, 2-indanylmethyl
groups, 1,2,3,4-tetrahydronaphthalen-1-ylmethyl groups,
1,2,3,4-tetrahydronaphthalen-2-ylmethyl groups, and the like.
[0155] Unless explicitly stated otherwise, cases in the present
specification in which a cyclic group is substituted with a
variable substituent group means that the variable substituent
group does not bond to a specific carbon atom in the cyclic group
or to a specific NH group in the cyclic group. For example,
variable substituent group R.sup.x in formula A below can be
substituted at any of carbon atoms i, ii, iii, iv or v in formula
A, variable substituent group R.sup.y in formula B below can be
substituted at either of carbon atoms vi or vii in formula B, and
variable substituent group R.sup.z in formula C below can be
substituted at any of carbon atoms viii, ix, x or xi in formula
C.
##STR00127##
[0156] In all of the modes described above, when the term
"compound" is used, this can also mean "a pharmaceutically
acceptable salt of the compound".
[0157] Depending on the types of substituent group, a compound of
the present invention may form an acid addition salt or form a salt
with a base. Such salts are not particularly limited as long as
these are pharmaceutically acceptable salts, but examples thereof
include metal salts, ammonium salts, salts with organic bases,
salts with inorganic bases, salts with organic acids and salts with
basic or acidic amino acids. Preferred examples of metal salts
include alkali metal salts such as lithium salts, sodium salts,
potassium salts and cesium salts, alkaline earth metal salts such
as calcium salts, magnesium salts and barium salts, and aluminum
salts (these include, for example, mono-salts, disodium salts and
dipotassium salts). Preferred examples of salts with organic bases
include salts with methylamine, ethylamine, t-butylamine,
t-octylamine, diethylamine, trimethylamine, triethylamine,
cyclohexylamine, dicyclohexylamine, dibenzylamine, ethanolamine,
diethanolamine, triethanolamine, piperidine, morpholine, pyridine,
picoline, lysine, arginine, ornithine, ethylenediamine,
N-methylglucamine, glucosamine, phenylglycine alkyl esters,
guanidine, 2,6-lutidine, ethanolamine, diethanolamine,
triethanolamine, N,N'-dibenzylethylenediamine, and the like.
Preferred examples of salts with inorganic acids include salts with
hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid,
sulfuric acid, phosphoric acid, and the like. Preferred examples of
salts with organic acids include salts with aliphatic
monocarboxylic acids such as formic acid, acetic acid,
trifluoroacetic acid, propionic acid, butyric acid, valeric acid,
enanthic acid, capric acid, myristic acid, palmitic acid, stearic
acid, lactic acid, sorbic acid and mandelic acid, salts with
aliphatic dicarboxylic acids such as oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, malic acid and tartaric
acid, salts with aliphatic tricarboxylic acids such as citric acid,
salts with aromatic monocarboxylic acids such as benzoic acid and
salicylic acid, salts with aromatic dicarboxylic acids such as
phthalic acid, salts with organic carboxylic acids such as cinnamic
acid, glycolic acid, pyruvic acid, oxylic acid, salicylic acid and
N-acetylcysteine, salts with organic sulfonic acids such as
methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic
acid, and acid addition salts with acidic amino acids such as
aspartic acid and glutamic acid. Preferred examples of salts with
basic amino acids include salts with arginine, lysine, ornithine,
and the like, and preferred examples of salts with acidic amino
acids include salts with aspartic acid, glutamic acid, and the
like. Of these, pharmaceutically acceptable salts are preferred.
For example, in cases where an acidic functional group is present
in the compound, an inorganic salt such as an alkali metal salt
(for example, a sodium salt, potassium salt, or the like), an
alkaline earth metal salt (for example, a calcium salt, magnesium
salt, barium salt, or the like), an ammonium salt, or the like, can
be used, and in cases where a basic functional group is present in
the compound, a salt with an inorganic acid such as hydrochloric
acid, hydrobromic acid, nitric acid, sulfuric acid or phosphoric
acid or a salt with an organic acid such as acetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, methanesulfonic acid or p-toluenesulfonic acid
can be used.
[0158] These salts can be obtained using conventional methods, for
example by mixing the compound of the present invention with a
solution that contains an appropriate quantity of acid or base,
thereby forming the target salt, and then separating the salt by
filtration or distilling off the mixed solvent. In addition, the
compound of the present invention or salt thereof can form a
solvate with a solvent such as water, ethanol or glycerol.
[0159] "Handbook of Pharmaceutical Salts: Properties, Selection,
and Use" Stahl & Wermuth (Wiley-VCH, 2002) has been published
as a review relating to salts, and detailed explanations are
available in this publication. These salts can be manufactured by
referring to this review.
[0160] The compound of the present invention may be present in a
non-solvated form or a solvated form. In the present specification,
the term "solvate" means a molecular complex that includes the
compound of the present invention and one or more pharmaceutically
acceptable solvent molecules (for example, water or ethanol). When
the solvent molecule is water, the specific term "hydrate" is
used.
[0161] In cases where the compound of the present invention has
isomers such as geometric isomers, configuration isomers,
tautomeric isomers, optical isomers, diastereomers, regioisomers or
rotational isomers, individual isomers and mixtures thereof are
encompassed by the compound of the present invention. Furthermore,
in cases where optical isomers are present in the compound of the
present invention, an optical isomer that has been separated from a
racemate of the compound is encompassed by the compound of the
present invention.
[0162] In cases where the compound of the present invention has one
or more asymmetric carbon atoms, two or more diastereomers may be
present. In addition, in cases where the compound of the present
invention contains a "C.sub.2-6 alkenyl group", geometric isomers
(cis/trans isomers or Z/E isomers) may be present. In addition, in
cases where structural isomers can be interconverted due to low
energy barriers, tautomeric isomerism may occur. Examples of
tautomeric isomerism include proton tautomeric isomerism in
compounds having imino groups, keto groups or oxime groups.
[0163] In cases where the compound of the present invention
includes geometric isomers, configuration isomers, diastereomers,
conformational isomers, or the like, these may be isolated using
publicly known means.
[0164] In addition, in cases where the compound of the present
invention is an optically active compound, a racemate may be
separated into the (+) isomer or (-) isomer [D isomer or L isomer]
using a conventional optical resolution means.
[0165] In cases where the compound of the present invention
includes optical isomers, diastereomers, regioisomers, rotational
isomers or tautomeric isomers, each isomer can be obtained as a
single compound by using a publicly known synthesis means or
separation means. Examples of optical resolution means include
publicly known methods such as (1) partitioning recrystallization
methods, (2) diastereomer methods and (3) chiral column
methods.
[0166] (1) Partitioning recrystallization method: A method in which
an optical resolution agent ionically bonds to a racemate so as to
obtain crystalline diastereomers, these diastereomers are separated
by a partitioning recrystallization method and, if necessary, a
free optically pure compound is obtained by means of a
neutralization step. Examples of optical resolution agents include
(+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid,
(-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine,
cinchonine, (-)-cinchonidine and brucine.
[0167] (2) Diastereomer method: A method in which an optical
resolution agent is covalently bonded (reacted) to a racemate
mixture so as to obtain a mixture of diastereomers, this mixture of
diastereomers is separated into optically pure diastereomers by
means of a conventional separation means (for example, partitioning
recrystallization, silica gel column chromatography or high
performance liquid chromatography (HPLC)), and a chemical treatment
is carried out by means of a hydrolysis reaction or the like so as
to remove the optical resolution agent, thereby obtaining an
optically pure optical isomer. For example, in cases where the
compound of the present invention has a hydroxyl group, a primary
amino group or a secondary amino group in the molecule, a
condensation reaction is carried out between the compound and an
optically active organic acid (for example, MTPA
(.alpha.-methoxy-.alpha.-(trifluoromethyl)phenylacetic acid) or
(-)-methoxyacetic acid), thereby obtaining diastereomers of the
corresponding ester or amide. Meanwhile, in cases where the
compound of the present invention contains a carboxyl group, a
condensation reaction is carried out between the compound and an
optically active amine or alcohol reagent, thereby obtaining
diastereomers of the corresponding amide or ester. The thus
separated diastereomers are converted into optical isomers of the
original compound by carrying out an acid hydrolysis reaction or
base hydrolysis reaction.
[0168] (3) Chiral column method: A method in which direct optical
resolution is carried out by subjecting a racemate or a salt
thereof to chromatography in a chiral column (a column for
separating optical isomers). For example, in the case of high
performance liquid chromatography (HPLC), a mixture of optical
isomers is added to a chiral column such as a CHIRAL series column
manufactured by Daicel Corporation, and development is carried out
using water, a variety of buffer solutions (for example, a
phosphoric acid buffer solution) or organic solvents (for example,
ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid
or diethylamine) either individually or as a mixed solution,
thereby enabling separation of optical isomers. In addition, in the
case of gas chromatography, for example, separation can be carried
out using a chiral column such as CP-Chirasil-DeX CB (manufactured
by GL Sciences Inc.).
[0169] The compound of the present invention may be crystalline,
and the crystal form thereof may be a single form or a mixture of
forms.
[0170] The compound of the present invention may be a
pharmaceutically acceptable cocrystal or cocrystal salt. Here,
cocrystal and cocrystal salt means a crystalline substance
constituted from two or more distinct substances which are solids
at room temperature and which exhibit mutually different physical
properties (for example, structure, melting point, heater fusion,
hygroscopic properties, solubility, stability, and the like). The
cocrystal or cocrystal salt may be manufactured according to a
publicly known cocrystallization method.
[0171] The compound of the present invention encompasses compounds
that are labeled or substituted with isotopes (for example,
hydrogen isotopes such as .sup.2H and .sup.3H, carbon isotopes such
as .sup.11C, .sup.13C and .sup.14C, chlorine isotopes such as
.sup.36Cl, fluorine isotopes such as .sup.18F, iodine isotopes such
as .sup.123I and .sup.125I, nitrogen isotopes such as .sup.13N and
.sup.15N, oxygen isotopes such as .sup.15O, .sup.17O and .sup.18O,
phosphorus isotopes such as .sup.32P, and sulfur isotopes such as
.sup.35S).
[0172] If labeled or substituted with certain types of isotope (for
example, positron-emitting isotopes such as .sup.11C, .sup.18F,
.sup.15O and .sup.13N), the compound of the present invention can
be used as, for example, a tracer (PET tracer) used in positron
emission tomography (PET), and is useful in fields such as medical
diagnostics.
[0173] If labeled or substituted with certain types of isotopic
label, the compound of the present invention is useful in tissue
distribution research for drugs and/or substrates. For example,
.sup.3H and .sup.14C are useful for such research purposes due to
labeling or substitution being easy and detection means being
simple.
[0174] If isotopically labeled, the compound of the present
invention can be obtained using conventional techniques that are
known by persons skilled in the art or by methods similar to the
synthesis methods disclosed in the working examples described
below. In addition, obtained isotopically labeled compounds can be
used instead of unlabeled compounds in pharmacological tests.
[0175] [Methods for Manufacturing Compounds Represented by Formula
(ET-1), Formula (PY-1) and Formula (PY-2) and Separate Method for
Manufacturing Compound Represented by Formula (AD-1) in the Present
Invention]
[0176] Detailed explanations will now be given of methods for
manufacturing compounds represented by formula (ET-1), formula
(PY-1) and formula (PY-2) in (Scheme 2) below and a separate method
for manufacturing a compound represented by formula (AD-1) in the
present invention. In the present invention, compounds represented
by formula (ET-1), formula (PY-1), formula (PY-2) and formula
(AD-1), salts of these compounds and solvates of these compounds
and salts can be easily manufactured by combining ordinary known
chemical manufacturing methods that use, as starting materials or
synthesis intermediates, commercially available compounds or
compounds able to be easily obtained from commercially available
compounds using manufacturing methods known from literature, and
can be manufactured according to the representative manufacturing
methods shown below. In addition, the present invention is in no
way limited to the manufacturing methods explained below.
##STR00128##
[0177] Unless explicitly stated otherwise, the definitions of p,
R.sup.1, R.sup.2, R.sup.3, R.sup.B, R.sup.C, R.sup.D and ring A
represented by formula (II) in the formulae in the manufacturing
methods for compounds represented by formula (ET-1), formula
(PY-1), formula (PY-2) and formula (AD-1) are the same as the
definitions described in modes [1] to [18] above. Unless explicitly
stated otherwise, the definition of R.sup.A in the manufacturing
methods is a C.sub.1-6 alkyl group (for example, a methyl group or
ethyl group), a C.sub.6-14 aryl group (for example, a phenyl group)
or a C.sub.7-20 aralkyl group (for example, a benzyl group). Unless
explicitly stated otherwise, the definition of X in the
manufacturing methods is a halogen atom.
[0178] In the manufacturing methods described below, raw material
compounds used in the manufacture of compounds represented by
formula (ET-1), formula (PY-1), formula (PY-2) and formula (AD-1)
may form salts, and examples of such salts include salts similar to
the salts of formula (I) above. In addition, raw material compounds
used in the manufacture of compounds represented by formula (ET-1),
formula (PY-1), formula (PY-2) and formula (AD-1) may be used in
subsequent reactions either as reaction solutions or as purified
products, but can be isolated from reaction mixtures using
conventional methods, and can be easily purified using publicly
known separation means such as extraction, concentration,
neutralization, filtration, distillation, recrystallization or
chromatography.
[0179] Examples of solvents able to be used in the
recrystallization mentioned above include water; alcohols such as
methanol, ethanol, 2-propanol and butanol; ethers such as diethyl
ether, tetrahydrofuran and 1,4-dioxane; hydrocarbons such as
n-hexane, cyclohexane and heptane; aromatic hydrocarbons such as
benzene, toluene and xylene; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone;
halogenated hydrocarbons such as chloroform, methylene chloride and
1,2-dichloroethane; nitriles such as acetonitrile; ketones such as
acetone and diphenyl ketone; esters such as methyl acetate and
ethyl acetate; sulfoxides such as dimethyl sulfoxide; and organic
acids such as acetic acid, trifluoroacetic acid, methanesulfonic
acid and p-toluenesulfonic acid. It is possible to use one of these
solvents in isolation or a mixture of two or more types thereof at
appropriate proportions, such as 1:1 to 1:10. In addition, in cases
where the compounds in the formulae are commercially available, it
is possible to use commercially available compounds without further
modification or use compounds manufactured using publicly known
methods or methods based on such publicly known methods.
[0180] In cases where substituent groups present in compounds
represented by formula (ET-1), formula (PY-1), formula (PY-2) and
formula (AD-1) contain variable functional groups (for example,
carboxyl groups, amino groups, hydroxyl groups, carbonyl groups,
mercapto groups, C.sub.1-6 alkoxycarbonyl groups, C.sub.6-14
aryloxycarbonyl groups, C.sub.7-20 aralkyloxycarbonyl groups, sulfo
groups (--SO.sub.2OH), halogen atoms, and the like), a variety of
compounds can be manufactured by converting these functional groups
using publicly known methods or methods based on such publicly
known methods.
[0181] A "carboxyl group" can be converted by means of a reaction
such as esterification, chemical reduction, amidation, or
conversion into an optionally protected amino group.
[0182] An "amino group" can be converted by means of a reaction
such as amidation, sulfonylation, nitrosation, alkylation,
arylation or imidation.
[0183] A "hydroxyl group" can be converted by means of a reaction
such as esterification, carbamoylation, sulfonylation, alkylation,
arylation, oxidation or halogenation.
[0184] A "carbonyl group" can be converted by means of a reaction
such as chemical reduction, oxidation, imination (including
oximation and hydrazonation), (thio)ketalation, alkylidenation and
thiocarbonylationation.
[0185] A "mercapto (--SH) group" can be converted by means of a
reaction such as alkylation or oxidation.
[0186] A "C.sub.1-6 alkoxycarbonyl group", "C.sub.6-14
aryloxycarbonyl group" or "C.sub.7-20 aralkyloxycarbonyl group" can
be converted by means of a reaction such as chemical reduction or
hydrolysis.
[0187] A "sulfo (--SO.sub.2OH) group" can be converted by means of
a reaction such as sulfonamidation or chemical reduction.
[0188] A "halogen atom" can be converted by means of, for example,
a variety of nucleophilic substitution reactions, a variety of
coupling reactions, and the like.
[0189] In cases where a compound is obtained in a free form in the
reactions mentioned above, the compound may be converted into a
salt using a conventional method, and in cases where a compound is
obtained in the form of a salt, the salt may be converted into a
free compound or another salt using a conventional method.
[0190] These functional groups may be converted according to
methods disclosed in, for example, Richard C. Larock et al.,
"Comprehensive Organic Transformations", second edition, October
1999 (Wiley-VCH).
[0191] In addition, in the reactions in the methods for
manufacturing compounds represented by formula (ET-1), formula
(PY-1), formula (PY-2) and formula (AD-1) and the reactions used to
synthesize the raw material compounds in the present invention, in
cases where a reactive group such as a hydroxyl group (an alcoholic
hydroxyl group, phenolic hydroxyl group, heterocyclic hydroxyl
group, or the like), an amino group, a carboxyl group or a thiol
group is present as a substituent group, it is possible to protect
these groups as appropriate in the reaction steps and remove the
protecting groups at an appropriate stage.
[0192] Examples of protecting groups able to be used for these
hydroxyl groups (alcoholic hydroxyl groups, phenolic hydroxyl
groups, heterocyclic hydroxyl groups, and the like), include
C.sub.1-6 alkyl groups such as methyl groups, ethyl groups,
n-propyl groups, isopropyl groups, n-butyl groups and tert-butyl
groups; alkoxyalkyl groups such as methoxymethyl (MOM) groups and
methoxyethoxymethyl (MEM) groups; tetrahydropyranyl (THP) groups;
C.sub.7-20 aralkyl groups such as benzyl (Bn) groups and
triphenylmethyl (Tr) groups; silyl groups such as trimethylsilyl
(TMS) groups, triethylsilyl (TES) groups, t-butyldimethylsilyl
(TBDMS) groups and t-butyldiphenylsilyl (TBDPS) groups; alkanoyl
groups such as acetyl (Ac) groups, ethylcarbonyl groups and
pivaloyl (Piv) groups; C.sub.7-20 aralkylcarbonyl groups such as
benzylcarbonyl groups; aroyl groups such as benzoyl (Bz) groups;
alkoxycarbonyl groups such as methoxycarbonyl groups,
ethoxycarbonyl groups and t-butoxycarbonyl (Boc) groups; and
C.sub.7-20 aralkyloxycarbonyl groups such as benzyloxycarbonyl (Z)
groups.
[0193] Examples of protecting groups able to be used for these
amino groups (--NH.sub.2 groups) or imino groups (--NH-- groups)
include alkanoyl groups such as acetyl (Ac) groups, ethylcarbonyl
groups and pivaloyl (Piv) groups; alkoxycarbonyl groups such as
methoxycarbonyl groups, ethoxycarbonyl groups and t-butoxycarbonyl
(Boc) groups; allyloxycarbonyl (Alloc) groups;
fluorenylmethoxycarbonyl (Fmoc) groups; phenyloxycarbonyl groups;
C.sub.7-20 aralkyloxycarbonyl groups such as benzyloxycarbonyl (Z)
groups, para-methoxybenzyloxycarbonyl groups and
para-nitrobenzoyloxycarbonyl groups; C.sub.7-20 aralkyl groups such
as benzyl (Bn) groups and triphenylmethyl (Tr) groups; aroyl groups
such as benzoyl (Bz) groups; C.sub.7-20 aralkylcarbonyl groups such
as benzylcarbonyl groups; sulfonyl groups such as methanesulfonyl
(Ms) groups, p-toluenesulfonyl (Ts) groups,
2,4-dinitrobenzenesulfonyl (Nos) groups and benzenesulfonyl (Bs)
groups; 2-(trimethylsilyl)ethoxymethyl (SEM) groups; phthaloyl
(Pht) groups; and N,N-dimethylaminomethylene groups.
[0194] Examples of protecting groups able to be used for these
carboxyl groups (--COOH groups) include alkyl groups such as methyl
groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl
groups and tert-butyl groups; alkenyl groups such as allyl groups;
aryl groups such as phenyl (Ph) groups; C.sub.7-20 aralkyl groups
such as benzyl (Bn) groups and triphenylmethyl (Tr) groups; and
silyl groups such as trimethylsilyl (TMS) groups, triethylsilyl
(TES) groups, t-butyldimethylsilyl (TBDMS) groups and
t-butyldiphenylsilyl (TBDPS) groups.
[0195] Examples of protecting groups able to be used for these
thiol groups (--SH groups) include alkyl groups such as methyl
groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl
groups and tert-butyl groups; C.sub.7-20 aralkyl groups such as
benzyl (Bn) groups and triphenylmethyl (Tr) groups; alkanoyl groups
such as acetyl (Ac) groups, ethylcarbonyl groups and pivaloyl (Piv)
groups; and aroyl groups such as benzoyl (Bz) groups.
[0196] Methods for introducing and removing such protecting groups
are carried out as appropriate according to the type of group to be
protected and the type of protecting group, but it is possible to
use, for example, a method disclosed in Greene et al., "Protective
Groups in Organic Synthesis", fourth edition, 2007 (John Wiley
& Sons).
[0197] As a method for deprotecting a protecting group, it is
possible to hydrolyze and deprotect acyl type protecting groups,
for example alkanoyl groups such as acetyl (Ac) groups,
ethylcarbonyl groups and pivaloyl (Piv) groups; alkoxycarbonyl
groups such as methoxycarbonyl groups, ethoxycarbonyl groups and
t-butoxycarbonyl (Boc) groups; and aroyl groups such as benzoyl
(Bz) groups, using, for example, an appropriate base such as an
alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide
or potassium hydroxide.
[0198] Alkoxyalkyl protecting groups such as methoxymethyl (MOM)
groups, methoxyethoxymethyl (MEM) groups and tetrahydropyranyl
(THP) groups; alkoxycarbonyl protecting groups such as
t-butoxycarbonyl (Boc) groups; C.sub.7-20 aralkyloxycarbonyl
protecting groups such as benzyloxycarbonyl (Z) groups and
para-methoxybenzyloxycarbonyl groups; and silyl protecting groups
such as trimethylsilyl (TMS) groups, triethylsilyl (TES) groups and
t-butyldimethylsilyl (TBDMS) groups can be deprotected using an
appropriate acid such as acetic acid, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic
acid or trifluoromethanesulfonic acid, or a combination of these
acids.
[0199] In addition, these silyl protecting groups can be
deprotected using an appropriate reagent that generates fluoride
ions (F), for example a reagent such as tetrabutyl ammonium
fluoride or hydrogen fluoride.
[0200] C.sub.7-20 aralkyloxycarbonyl groups such as
benzyloxycarbonyl (Z) groups, para-methoxybenzyloxycarbonyl groups
and para-nitrobenzoyloxycarbonyl groups and C.sub.7-20 aralkyl
groups such as benzyl (Bn) groups can be deprotected by means of,
for example, hydrogenolysis using a palladium-carbon (Pd--C)
catalyst.
[0201] In addition, benzyl groups can also be deprotected by, for
example, Birch reduction in liquid ammonia using metallic
sodium.
[0202] Triphenylmethyl (Tr) groups can be deprotected using an
appropriate acid such as acetic acid, hydrochloric acid,
hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic
acid or trifluoromethanesulfonic acid, or a combination of these
acids. In addition, triphenylmethyl (Tr) groups can be deprotected
by Birch reduction in liquid ammonia using metallic sodium or
metallic lithium or by hydrogenolysis using a palladium-carbon
catalyst.
[0203] Sulfonyl (--SO.sub.2--) groups can be deprotected by, for
example, one-electron reduction at a low temperature using
Na/anthracene or Na/naphthalene, or Birch reduction in liquid
ammonia using metallic sodium or metallic lithium.
[0204] In addition, among sulfonyl groups, 2-nitrobenzenesulfonyl
(Ns) groups can be deprotected under mild conditions by, for
example, reacting with a thiol in the presence of a basic reagent
such as potassium carbonate or triethylamine.
[0205] These methods for deprotecting protecting groups are merely
examples, and deprotection can be carried out using, for example, a
method disclosed in Greene et al., "Protective Groups in Organic
Synthesis", fourth edition, 2007 (John Wiley & Sons) or using
articles that have been publicly expressed.
[0206] Unless explicitly stated otherwise, reaction conditions in
the methods for manufacturing compounds represented by formula
(ET-1), formula (PY-1), formula (PY-2) and formula (AD-1) described
below are as follows. The reaction temperature is not limited as
long as this temperature falls within the range between -78.degree.
C. and the temperature at which the solvent refluxes. The reaction
duration is not limited as long as this duration is sufficient for
the reaction to progress adequately.
[0207] With respect to the reaction temperature in the
manufacturing methods disclosed in the present specification,
unless explicitly stated otherwise, the expression "at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes" means a temperature within a range between
0.degree. C. and the temperature at which the solvent (or mixed
solvent) used in the reaction refluxes. For example, in cases where
methanol is used as the solvent, "at a temperature between
0.degree. C. and a temperature at which the solvent refluxes" means
a temperature within a range between 0.degree. C. and the
temperature at which methanol refluxes. Similarly, the expression
"at a temperature between 0.degree. C. and a temperature at which
the reaction solution refluxes" means a temperature within a range
between 0.degree. C. and a temperature at which the reaction
solution refluxes.
[0208] In addition, the steps in the methods for manufacturing
compounds represented by formula (ET-1), formula (PY-1), formula
(PY-2) and formula (AD-1) may be carried out in the absence of a
solvent or by dissolving or suspending raw material compounds prior
to the reaction in an appropriate solvent which does not take part
in the reaction. Specific examples of solvents that do not take
part in the reaction include water; saturated hydrocarbon-based
solvents such as cyclohexane and hexane; aromatic hydrocarbon-based
solvents such as benzene, chlorobenzene, toluene and xylene;
alcoholic solvents such as methanol, ethanol, 1-propanol,
2-propanol, tert-butyl alcohol and 2-methoxyethanol; polar
amide-based solvents such as N,N-dimethylformamide,
N,N-dimethylacetamide, hexamethylphosphoric triamide and
1,3-dimethyl-2-imidazolidinone; sulfoxide-based solvents such as
dimethyl sulfoxide; nitrile-based solvents such as acetonitrile and
propionitrile; ether-based solvents such as diethyl ether,
diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane and
1,2-dimethoxyethane; ester-based solvents such as methyl acetate,
ethyl acetate and butyl acetate; ketone-based solvents such as
acetone and methyl ethyl ketone; halogenated hydrocarbon-based
solvents such as dichloromethane, chloroform, carbon tetrachloride
and 1,2-dichloroethane; basic solvents such as triethylamine,
N,N-diisopropylethylamine, pyridine and lutidine; acid anhydrides
such as acetic anhydride; organic acids such as formic acid, acetic
acid, propionic acid, trifluoroacetic acid and methanesulfonic
acid; and inorganic acids such as hydrochloric acid and sulfuric
acid. It is possible to use one of these solvents in isolation or a
mixture of appropriate proportions of two or more of these
solvents, selected according to reaction conditions. Unless
explicitly stated otherwise, the term "a solvent which does not
take part in the reaction" in the manufacturing method in the
present specification means that it is possible to use a single
type of solvent in isolation or use a mixture of appropriate
proportions of two or more solvents, selected according to reaction
conditions.
[0209] Specific examples of bases (or deoxidizing agents) able to
be used in the methods for manufacturing compounds represented by
formula (ET-1), formula (PY-1), formula (PY-2) and formula (AD-1)
include inorganic bases such as lithium hydroxide, sodium
hydroxide, potassium hydroxide, magnesium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
calcium carbonate and sodium hydrogen carbonate; organic bases such
as triethylamine, N,N-diisopropylethylamine, tributylamine,
cyclohexyldimethylamine, pyridine, lutidine,
4-dimethylaminopyridine (DMAP), N,N-dimethylaniline,
N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]-5-nonene, 1,4-diazabicyclo[2.2.2]octane,
1,8-diazabicyclo[5.4.0]-7-undecene and imidazole; metal alkoxides
such as sodium methoxide, sodium ethoxide, potassium tert-butoxide
and sodium tert-butoxide; alkali metal hydroxides such as sodium
hydroxide and potassium hydroxide; metal amides such as sodium
amide, lithium diisopropylamide and lithium hexamethyldisilazide;
and organic lithium reagents such as methyl lithium, n-butyl
lithium, sec-butyl lithium and tert-butyl lithium. In addition,
specific examples of acids and acid catalysts able to be used in
the method for manufacturing the compound of the present invention
include inorganic acids such as hydrochloric acid, sulfuric acid,
nitric acid, hydrobromic acid and phosphoric acid; organic acids
such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic
acid, fumaric acid, tartaric acid, maleic acid, citric acid,
succinic acid, methanesulfonic acid, p-toluenesulfonic acid and
10-camphorsulfonic acid; and Lewis acids such as boron trifluoride
ether complexes, zinc iodide, anhydrous aluminum chloride,
anhydrous zinc chloride and anhydrous iron chloride. However, acids
and acid catalysts able to be used in the method for manufacturing
the compound of the present invention are not necessarily limited
to those listed above.
[0210] Salts represented by formula (ET-1), formula (PY-1), formula
(PY-2) and formula (AD-1) can be manufactured using publicly known
means, for example, in cases where compounds represented by formula
(ET-1), formula (PY-1) and formula (PY-2) are basic compounds, it
is possible to manufacture the salts mentioned above by adding an
inorganic acid (a mineral acid) such as hydrochloric acid,
hydrobromic acid, nitric acid, sulfuric acid or phosphoric acid or
an organic acid such as formic acid, acetic acid, trifluoroacetic
acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,
maleic acid, citric acid, succinic acid, malic acid,
methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic
acid, and in cases where compounds represented by formula (CA-1),
formula (PY-1) and formula (PY-2) are acidic compounds, it is
possible to manufacture the salts mentioned above by adding an
organic base such as ammonia, trimethylamine, triethylamine,
pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine,
triethanolamine, cyclohexylamine, dicyclohexylamine,
N,N-diisopropylethylamine, N,N'-dibenzylethylenediamine or a
N,N-dialkylaniline or an inorganic base such as lithium carbonate,
sodium carbonate, potassium carbonate, cesium carbonate, lithium
hydroxide, sodium hydroxide, potassium hydroxide or sodium hydrogen
carbonate.
[0211] <Manufacturing Method A>
[0212] Method for manufacturing ester derivative represented by
formula (ET-1):
##STR00129##
[0213] <Step 1>
[0214] <W=Boronic Acid Ester>
[0215] A boronic acid ester represented by formula (A-2) can be
manufactured using a method known from literature, for example,
according to the method disclosed in "The Journal of Organic
Chemistry", 60, 7508-2665, 1995, by subjecting a compound
represented by formula (A-1) to a reaction in the presence of a
diboron ester such as bis(pinacolato) diboron or bis(neopentyl
glycolato) diboron, in the presence of a palladium catalyst such as
palladium (II) acetate, palladium tetrakis(triphenylphosphine),
dipalladium tri(dibenzylideneacetone), [1,1'-bis(diphenylphosphino)
ferrocene]dichloro palladium (II) or a
[1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium
(II)-dichloromethane complex, in the presence or absence of a
phosphine-based reagent such as triphenylphosphine,
tri(tert-butyl)phosphine, tri(o-tolyl)phosphine or
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl and an organic or
inorganic base such as triethylamine, N,N-diisopropylethylamine,
potassium carbonate or potassium acetate or in the presence or
absence of tetramethyl ammonium chloride, tetrabutyl ammonium
chloride or the like instead of a phosphine-based reagent, in a
solvent which does not take part in the reaction, such as toluene,
N,N-dimethylformamide, dimethyl sulfoxide or 1,4-dioxane, or a
mixture of these solvents, at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes.
[0216] <W=Boronic Acid>
[0217] A boronic acid represented by formula (A-2) can be
manufactured using a method known from literature, for example,
according to the method disclosed in "Chemische Berichte" 42, 3090,
1909, by using a solvent which does not take part in the reaction,
such as toluene, tetrahydrofuran or 1,4-dioxane, or a mixture of
these solvents, in the presence of a Grignard reagent such as an
alkyl lithium compound, such as n-butyl lithium or sec-butyl
lithium, or isopropyl magnesium chloride or in the presence of
metallic magnesium, adding a trialkyl borate such as trimethyl
borate or triisopropyl borate, subjecting a compound represented by
formula (A-1) to a reaction at a temperature between -78.degree. C.
and room temperature, then adding an acid such as hydrochloric acid
or sulfuric acid, and carrying out a reaction at a temperature
between 0.degree. C. and a temperature at which the solvent
refluxes.
[0218] <W=Trifluoroborate Salt>
[0219] A trifluoroborate salt represented by formula (A-2) can be
manufactured using a method known from literature, for example,
according to the method disclosed in "Chemical Reviews", 108,
288-325, 2008, by subjecting the boronic acid ester or boronic acid
represented by formula (A-2), which are obtained in the methods
mentioned above, to a reaction in the presence of potassium
hydrogen difluoride (KHF.sub.2) using a solvent which does not take
part in the reaction, such as methanol, ethanol or water, or a
mixture of these solvents, at a temperature between 0.degree. C.
and a temperature at which the solvent refluxes.
[0220] <W=Boronic Acid N-Methyliminodiacetic Acid (MIDA)
Ester>
[0221] A boronic acid N-methyliminodiacetic acid (MIDA) ester
represented by formula (A-2) can be manufactured using a method
known from literature, for example, according to the method
disclosed in "The Journal of Organometallic Chemistry", 307 (1),
pages 1-6, 1986, by subjecting the boronic acid represented by
formula (A-2), which is obtained in the method mentioned above, to
a reaction in the presence of N-methyliminodiacetic acid (MIDA),
using a solvent which does not take part in the reaction, such as
benzene, toluene, xylene or dimethyl sulfoxide, or a mixture of
these solvents, at a temperature between 0.degree. C. and a
temperature at which the solvent refluxes.
[0222] <Step 2>
[0223] A compound represented by formula (ET-1) can be manufactured
using a method known from literature, for example, according to
"The Fifth Series of Experimental Chemistry, 18. Organic Compound
Synthesis VI--Organic Synthesis Using Metals--", pages 327-352,
2004, Maruzen and "Journal of Medicinal Chemistry" 48(20), pages
6326-6339, 2005, by subjecting a compound represented by formula
(A-2), which was obtained in <Step 1> in <Manufacturing
Method A>, and a halogenated heteroaryl derivative represented
by formula (A-3) to a reaction in the presence of a palladium
catalyst such as palladium (II) acetate (Pd(OAc).sub.2), palladium
tetrakis(triphenylphosphine) (Pd(PPh.sub.3).sub.4), dipalladium
tri(dibenzylideneacetone) ((dba).sub.3Pd.sub.2), palladium
bis(dibenzylideneacetone) ((dba).sub.2Pd) or
[1,1'-bis(diphenylphosphino) ferrocene]dichloro palladium (II)
(Pd(dppf)Cl.sub.2), a phosphine-based reagent such as
triphenylphosphine, tri(tert-butyl)phosphine,
tri(o-tolyl)phosphine,
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl or
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and an
organic or inorganic base such as triethylamine,
N,N-diisopropylethylamine, potassium phosphate, potassium carbonate
or cesium carbonate, using a solvent which does not take part in
the reaction, such as toluene, xylene, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,2-dimethoxyethane, acetonitrile
(acetonitrile/water), 1,4-dioxane (1,4-dioxane/water) or
tetrahydrofuran (tetrahydrofuran/water), or a mixture of these
solvents, at a temperature between 0.degree. C. and a temperature
at which the solvent refluxes. In addition, a compound represented
by formula (ET-1) can be manufactured using a similar method, using
tetramethyl ammonium chloride, tetrabutyl ammonium chloride, or the
like, instead of the phosphine-based reagent.
[0224] <Manufacturing Method B>
[0225] Method for manufacturing pyridine acid derivative
represented by formula (PY-1) (formula (PY-1-1) in cases where
R.sup.3 is a fluorine atom):
##STR00130##
[0226] <Step 1>
[0227] A compound represented by formula (B-2) can be manufactured
according to a method known from literature, for example, a method
disclosed in "Bioorganic & Medicinal Chemistry Letters",
22(10), pages 3431-3436, 2012 or "Step (A) in Example 56 on page
116 of WO 2011/073845" (published 23 Jun. 2011), by adding a
compound represented by formula (B-1) (in cases where R.sup.3 is a
fluorine atom, the starting material is 2,5-difluoropyridine [CAS
No.: 84476-99-3]) at a temperature of -78.degree. C. to a mixed
solution of lithium diisopropylamide (LDA) prepared from
N,N-diisopropylamine and n-butyl lithium (an n-hexane solution) in
a solvent that is inert in the reaction, such as tetrahydrofuran,
diethyl ether or 1,2-dimethoxyethane, or a mixture of these
solvents, stirring for 3 hours, further adding iodine, and carrying
out a reaction at a temperature between -78.degree. C. and
0.degree. C.
[0228] <Step 2>
[0229] A compound represented by formula (PY-1) can be manufactured
according to a method known from literature, for example, a method
disclosed in "Synthesis", 12, pages 905-908, 1989, by subjecting
the compound represented by formula (B-2), which was obtained in
<Step 1> in <Manufacturing Method B> to a sealed tube
reaction at a temperature between 0.degree. C. and 150.degree. C.
in the presence of aqueous ammonia using a solvent that is inert in
the reaction, such as 1,4-dioxane.
[0230] <Manufacturing Method C>
[0231] Method for manufacturing pyridine acid derivative
represented by formula (PY-2):
[In cases where R.sup.3 is F, the starting material is
2-bromo-5-fluoropyridine [CAS No.: 41404-58-4], which is
represented by formula (C-1). In cases where R.sup.3 is H, the
starting material is 2-amino-isonicotinic acid ethyl ester [CAS
No.: 13362-30-6], which is represented by formula (C-4).]
##STR00131## ##STR00132##
[0232] <Step 1>
[0233] According to a method known from literature, for example, a
method disclosed in WO 2008/126899 (published on 23 Oct. 2008),
n-butyl lithium (an n-hexane solution) is added at a temperature of
-70.degree. C. to a solvent that is inert in the reaction, such as
tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, or a mixture
of these solvents. A compound represented by formula (C-2) can be
manufactured by adding a compound represented by formula (C-1)
dropwise to a mixed solution of n-butyl lithium at the same
temperature, stirring for 2 hours at this temperature, adding an
excess of dry ice, and carrying out a reaction at a temperature
between -70.degree. C. and 0.degree. C.
[0234] <Step 2>
[0235] A compound represented by formula (C-3) can be manufactured
according to a method known from literature, for example, a method
disclosed in WO 1998/024782 (published on 11 Jun. 1998) by
subjecting the compound represented by formula (C-2), which was
obtained in <Step 1> in <Manufacturing Method C>, to a
sealed tube reaction at a temperature between 0.degree. C. and
150.degree. C. in the presence of a copper catalyst such as copper
iodide using 28% aqueous ammonia and, following the reaction,
adding concentrated hydrochloric acid to the reaction solution at a
temperature below freezing point.
[0236] <Step 3>
[0237] A compound represented by formula (C-4) can be manufactured
according to a method known from literature, for example, a method
disclosed in "The Fourth Series of Experimental Chemistry", 22,
Organic Synthesis IV, Acids, Amino acids and Peptides, pages 1-82,
1992, Maruzen, by subjecting the compound represented by formula
(C-3), which was obtained in <Step 2> in <Manufacturing
Method C>, to a reaction in the presence of an acidic reagent
such as hydrochloric acid, sulfuric acid, thionyl chloride or
acetyl chloride, using ethanol, at a temperature between 0.degree.
C. and a temperature at which the solvent refluxes.
[0238] In addition, a compound represented by formula (C-4) can be
manufactured according to a method known from literature, for
example, a method disclosed in "Synthetic Communications", 31(14),
pages 2177-2183, 2001, by subjecting the compound represented by
formula (C-3), which was obtained in <Step 2> in
<Manufacturing Method C>, to a reaction in the presence of
ethyl iodide and in the presence of a base such as potassium
carbonate, sodium carbonate, potassium hydroxide or sodium
hydroxide, using a polar solvent, such as N,N-dimethylformamide or
dimethyl sulfoxide, at a temperature between 0.degree. C. and a
temperature at which the solvent refluxes.
[0239] In addition, a compound represented by formula (C-4) can be
manufactured according to a method known from literature, for
example, a method disclosed in "The Fourth Series of Experimental
Chemistry", 22, Organic Synthesis IV, Acids, Amino acids and
Peptides, pages 191-309, 1992, Maruzen, by subjecting the compound
represented by formula (C-3), which was obtained in <Step 2>
in <Manufacturing Method C>, and ethanol to a reaction in the
presence of a condensing agent, such as
1,3-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(WSC.HCl), 1-hydroxybenzotriazole (Hobt),
benzotriazol-1-yloxy-tris(dimethylamino)phosphonium
hexafluorophosphate (a BOP reagent),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl),
2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP),
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
(DMTMM), polyphosphoric acid (PPA) or
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate methanaminium (HATU), in a solvent which does
not take part in the reaction, for example a halogen-based solvent
such as dichloromethane or chloroform, an ether-based solvent such
as diethyl ether or tetrahydrofuran, aromatic hydrocarbon-based
solvent such as toluene or benzene, or a polar solvent such as
N,N-dimethylformamide, at a temperature between 0.degree. C. and a
temperature at which the solvent refluxes, in the presence or
absence of a base such as triethylamine or pyridine.
[0240] In addition, a compound represented by formula (C-4) can be
similarly manufactured according to a method known from literature,
for example, a method disclosed in "The Journal of the American
Chemical Society", 109(24), pages 7488-7494, 1987, by subjecting
the compound represented by formula (C-3) to a reaction in the
presence or absence of a base such as triethylamine,
N,N-diisopropylethylamine or N,N-dimethylaminopyridine, using a
halogenating agent, such as thionyl chloride, oxalyl chloride,
phosphoryl chloride, sulfuryl chloride, phosphorus trichloride,
phosphorus pentachloride or phosphorus tribromide, and a solvent
that is inert in the reaction, such as 1,4-dioxane,
tetrahydrofuran, benzene, toluene, dichloromethane,
1,2-dichloroethane or chloroform, or a mixture of these solvents,
at a temperature between 0.degree. C. and a temperature at which
the solvent refluxes, so as to convert into an acid halide, and
then, according to a method known from literature, for example, a
method disclosed in "The Fourth Series of Experimental Chemistry",
22, Organic Synthesis IV, Acids, Amino acids and Peptides, pages
144-146, 1992, Maruzen, carrying out a reaction using ethanol in
the presence of a base such as triethylamine,
N,N-diisopropylethylamine, pyridine or 4-dimethylaminopyridine,
using a solvent which does not take part in the reaction, for
example, a halogen-based solvent such as dichloromethane,
chloroform or 1,2-dichloro ethane, an ether-based solvent such as
diethyl ether, tetrahydrofuran or 1,4-dioxane, an aromatic
hydrocarbon-based solvent such as toluene or benzene or a polar
solvent such as N,N-dimethylformamide, at a temperature between
0.degree. C. and a temperature at which the solvent refluxes.
[0241] <Step 4>
[0242] Using the compound represented by formula (C-4), which was
obtained in <Step 3> in <Manufacturing Method C>, a
compound represented by formula (C-5) can be manufactured according
to a method known from literature, for example, a method disclosed
in "Protective Groups in Organic Synthesis", 4th Edition, 2007
(John Wiley & Sons), Greene et al., by subjecting a variety of
reagents (for example, methyl chloroformate or the like in cases
where R.sup.C is a methyl group; ethyl chloroformate or the like in
cases where R.sup.C is an ethyl group; di-tert-butyl dicarbonate,
2-(2-tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, or the like
in cases where R.sup.C is a tert-butyl group; benzyl chloroformate
or the like in cases where R.sup.C is a benzyl group) to a reaction
using a method that depends on the type of protecting group
(RCOC(.dbd.O)--).
[0243] <Step 5>
[0244] A compound represented by formula (C-6) can be manufactured
by subjecting the compound represented by formula (C-5), which was
obtained in <Step 4> in <Manufacturing Method C>, to a
reaction according to <Step 1> in <Manufacturing Method
D>, which is described below.
[0245] <Step 6>
[0246] Using the compound represented by formula (C-6), which was
obtained in <Step 5> in <Manufacturing Method C>, a
compound represented by formula (C-7) can be manufactured according
to a method known from literature, for example, a method disclosed
in "Strategic Applications of Named Reactions in Organic
Synthesis", Elsevier Academic Press, 2005, pages 116, 117, Curtius
Rearrangement, by subjecting diphenylphosphoryl azide (DPPA) to a
reaction in the presence of a base such as triethylamine, using a
solvent that is inert in the reaction, such as toluene or benzene,
or a mixture of these solvents, at a temperature between 0.degree.
C. and a temperature at which the solvent refluxes, and then
reacting with tert-butyl alcohol.
[0247] <Step 7>
[0248] Using the compound represented by formula (C-7), which was
obtained in <Step 6> in <Manufacturing Method C>, a
compound represented by formula (PY-2) can be manufactured
according to a method known from literature, for example, a method
disclosed in "Protective Groups in Organic Synthesis", 4th Edition,
2007 (John Wiley & Sons), Greene et al., by deprotecting the
protecting group (.sup.tBuOC(.dbd.O)--).
[0249] <Manufacturing Method D>
[0250] Method for manufacturing amide derivative represented by
formula (AD-1):
##STR00133##
[0251] <Step 1>
[0252] <R.sup.D.dbd.C.sub.1-6 Alkyl Group (for Example, Methyl
Group, Ethyl Group, or the Like)>
[0253] A compound represented by formula (CA-1) can be manufactured
according to a method known from literature, for example, a method
disclosed in "The Fourth Series of Experimental Chemistry", 22,
Organic Synthesis IV, Acids, Amino acids and Peptides, pages 1-43,
1992, Maruzen, by subjecting the compound represented by formula
(ET-1), which was obtained in <Step 2> in <Manufacturing
Method A>, to a reaction in the presence of a base, such as
lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate or potassium carbonate, using water and
a solvent that is inert in the reaction, such as methanol, ethanol,
2-propanol, N,N-dimethylformamide, 1,4-dioxane or tetrahydrofuran,
or a mixture of these solvents, at a temperature between 0.degree.
C. and a temperature at which the solvent refluxes.
[0254] <R.sup.D=Tert-Butyl Group>
[0255] A compound represented by formula (CA-1) can be manufactured
using a method known from literature, for example, according to a
deprotection method disclosed in "Protective Groups in Organic
Synthesis", 4th Edition, 2007 (John Wiley & Sons), Greene et
al., by subjecting the compound represented by formula (ET-1),
which was obtained in <Step 2> in <Manufacturing Method
A>, to a reaction using an acid, such as hydrochloric acid,
sulfuric acid, acetic acid or trifluoroacetic acid, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes.
[0256] <R.sup.D=Benzyl Group>
[0257] A compound represented by formula (CA-1) can be manufactured
according to a method known from literature, for example, a method
disclosed in "The Fourth Series of Experimental Chemistry", 26,
Organic Synthesis VIII, Asymmetric Synthesis, Chemical Reduction,
Sugar and Labeled Compounds, pages 159-266, 1992, Maruzen", by
subjecting the compound represented by formula (ET-1), which was
obtained in <Step 2> in <Manufacturing Method A>, to a
reaction in the presence of a catalyst, such as palladium-carbon
(Pd--C), Raney-nickel (Raney-Ni), platinum oxide (PtO.sub.2) or
dichlorotri(triphenylphosphine) ruthenium, in a hydrogen gas
atmosphere, using a solvent which does not take part in the
reaction, for example, an alcoholic solvent such as methanol,
ethanol or 2-propanol, an ether-based solvent such as diethyl
ether, tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane or a
polar solvent such as ethyl acetate or methyl acetate, or a mixture
of these solvents, at a temperature between 0.degree. C. and a
temperature at which the solvent refluxes.
[0258] <Step 2>
[0259] Using the compound represented by formula (CA-1), which was
obtained in <Step 1> in <Manufacturing Method D>, an
active ester is formed according to a method known from literature,
for example, a method disclosed in "Synthesis", (12), pages 954,
955, 1979, by subjecting a compound represented by ClCOOR.sup.A or
di-tert-butyl dicarbonate (Boc.sub.2O) to a reaction in the
presence of a base, such as N,N-diisopropylethylamine,
triethylamine or pyridine, using a solvent which does not take part
in the reaction, such as tetrahydrofuran, diethyl ether or
1,2-dimethoxyethane, or a mixture of these solvents, at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes. Without isolating the active ester, a compound
represented by formula (AD-1) can then be manufactured according to
a method known from literature, for example, a method disclosed in
"The Journal of the American Chemical Society", 75, pages 637-640,
1953, by adding a base, such as N,N-diisopropylethylamine,
triethylamine or pyridine, and ammonium carbonate to the reaction
solution above and carrying out a reaction at a temperature between
0.degree. C. and a temperature at which the solvent refluxes.
[0260] <Step 3>
[0261] A compound represented by formula (AD-1) can be manufactured
according to a method known from literature, for example, a method
disclosed in Example 43 on page 120 of WO 2006/043145 (published 27
Apr. 2006), by subjecting the compound represented by formula
(ET-1) to a reaction using an aqueous ammonia solution at a
temperature between 0.degree. C. and a temperature at which the
solvent refluxes.
WORKING EXAMPLES
[0262] Working examples and reference examples will now be given in
order to explain the present invention in greater detail, but the
present invention is not limited to these examples.
[0263] Nuclear magnetic resonance (NMR) spectra measurements
involved the use of a JEOL JNM-ECX400 FT-NMR (manufactured by JEOL
Ltd.) and a (JEOL JNM-ECX300) FT-NMR (manufactured by JEOL Ltd.).
LC-Mass measurements were carried out using any of the methods
below. A Waters Fraction Lynx MS system (manufactured by Waters)
was used, the column was a SunFire column (4.6 mm.times.5 cm, 5
.mu.m) manufactured by Waters, and the mobile phase was a methanol:
0.05% acetic acid aqueous solution at a gradient of 10:90 (0
min)-100:0 (2 min)-100:0 (3 min).
[0264] In the physical property data in the working examples, LC-MS
means LC-Mass, and in LC-MS measurements, M denotes molecular
weight, RT denotes retention time, and [M+H].sup.+, [M+3H].sup.3+
and [M+Na].sup.+ denote molecular ion peaks. In .sup.1H-NMR data, s
denotes singlet, d denotes doublet, t denotes triplet, q denotes
quartet and m denotes multiplet in NMR signal patterns.
(Working Example 1) Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
Acid Ethyl Ester (alternative name: ethyl
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate)
##STR00134##
[0266] 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester
(CAS No.: 1328640-39-6, 5 g, 21 mmol), dipalladium (0)
tri(dibenzylideneacetone) (Pd.sub.2(dba).sub.3) (0.39 g, 0.43
mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.35
g, 0.86 mmol) and triethylamine (9.0 mL, 64 mmol) were mixed in
toluene (25 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.1
mL, 21 mmol) was added at room temperature. The obtained mixture
was stirred for 45 minutes at 90.degree. C.,
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 mL, 10.5 mmol) was
added, and a reaction was carried out at the same temperature for
45 minutes. Potassium carbonate (8.9 g, 64 mmol) was dissolved in
water (10 mL) and added slowly to the reaction mixture, after which
4-chloro-2,5-dimethylpyrimidine (3.1 g, 21 mmol) and ethanol (20
mL) were added. The obtained mixture was refluxed for 2 hours,
cooled to room temperature, filtered with celite, and washed with
ethyl acetate and water. The filtrate was extracted with 3N
hydrochloric acid. The aqueous layer was washed with methyl
tert-butyl ether (MTBE), rendered basic by means of potassium
carbonate, and extracted using dichloromethane. The organic layer
was concentrated under reduced pressure, and crude
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid ethyl ester (4.1 g, 52% yield, 71% purity) was obtained as a
brown oily substance.
[0267] (Physical property data) LC-MS: M=260, RT=0.83 (min),
[M+H].sup.+=261. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta. ppm):
8.50 (1H, s), 7.56 (1H, s), 4.22 (3H, s), 4.17 (2H, q, J=7 Hz),
2.72 (3H, s), 2.16 (2H, s), 1.05 (3H, t, J=7 Hz).
(Working Example 2) Separate Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00135##
[0269]
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (alternative name:
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid) (0.5 g, 2.2 mmol), which was synthesized using a method
similar to that in <Step 1> in Working Example 5 below, and
diisopropylethylamine (0.4 mL, 2.4 mmol) was dissolved in
tetrahydrofuran (5 mL), and ethyl chloroformate (0.23 mL, 2.4 mmol)
was added dropwise under ice cooling. After stirring for 20 minutes
under ice cooling, ammonium carbonate (0.41 g, 4.3 mmol) and
diisopropylethylamine (0.75 mL, 4.3 mmol) were added, and the
obtained mixture was stirred for 45 minutes at room temperature. A
saturated aqueous solution of sodium hydrogen carbonate was added
to the reaction mixture, and the reaction mixture was then
extracted using ethyl acetate. The organic layer was washed with
water, washed with a saturated saline solution, dried using sodium
sulfate, and then concentrated under reduced pressure.
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(0.37 g, 73%) was obtained as a white solid. Data for the obtained
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
was identical to data for the
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
synthesized in <Step 1> in Working Example 6 below.
(Working Example 3) Synthesis of
5-fluoro-4-iodopyridine-2-amine
##STR00136##
[0270]<Step 1> Synthesis of 2,5-difluoro-4-iodopyridine
##STR00137##
[0272] Using 2,5-difluoro-4-pyridine, crude
2,5-difluoro-4-iodopyridine (crude yield 96%) was obtained using a
method similar to that disclosed in step (A) in Example 56 on page
116 of WO 2011/073845 (published 23 Jun. 2011) .sup.1H NMR data for
the obtained 2,5-difluoro-4-iodopyridine was identical to data
disclosed in WO 2011/073845.
<Step 2> Synthesis of 5-fluoro-4-iodopyridine-2-amine
##STR00138##
[0274] Crude 2,5-difluoro-4-iodopyridine (2.26 g, 9.4 mmol), which
was obtained in <Step 1> in Working Example 3, 28% aqueous
ammonia (6.8 mL) and 1,4-dioxane (2.3 mL) were added to a sealed
reaction vessel and heated for 53 hours using an oil bath at
135.degree. C. Water was added to the reaction mixture, and the
reaction mixture was then extracted using methyl tert-butyl ether
(MTBE). The obtained organic layer was washed with water and
concentrated under reduced pressure. Crude
5-fluoro-4-iodopyridine-2-amine (1.90 g, 85%) was obtained as a
moss green-colored solid.
[0275] (Physical property data) LC-MS: M=238, RT=0.55 (min),
[M+H].sup.+=239. H NMR (400 MHz, DMSO-d.sub.6, .delta. ppm): 7.82
(1H, s), 6.92 (1H, d, J=4 Hz), 6.00 (2H, s).
(Working Example 4) Synthesis of Benzyl
(4-amino-5-fluoropyridin-2-yl)carbamate Hydrochloride
##STR00139##
[0276]<Step 1> Synthesis of 2-bromo-5-fluoroisonicotinic
Acid
##STR00140##
[0278] n-butyl lithium (2.6 M hexane solution, 100 mL, 0.26 mol)
was added to a tetrahydrofuran solution (630 mL) of
diisopropylamine (27 g, 0.26 mol) at a temperature of -60.degree.
C. or lower, and the obtained mixture was stirred for 15 minutes at
-70.degree. C. A tetrahydrofuran solution (620 mL) of
2-bromo-5-fluoropyridine (42 g, 0.24 mol) was added at a
temperature of -60.degree. C. or lower, and the obtained mixture
was stirred for 90 minutes at -70.degree. C. An appropriate
quantity of dry ice was added at -70.degree. C., after which the
temperature of the reaction mixture was allowed to increase to room
temperature. The reaction mixture was rendered acidic by adding 2N
dilute hydrochloric acid (400 mL), after which tetrahydrofuran was
distilled off under reduced pressure. Precipitated crystals were
filtered off and washed with water, after which toluene was added,
and the obtained mixture was dried by means of azeotropic
distillation. 2-bromo-5-fluoroisonicotinic acid (48 g, 92%) was
obtained as a white solid.
[0279] (Physical property data) LC-MS: M=219, RT=0.74 (min),
[M+H].sup.+=220, [M+3H].sup.3+=222. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6, .delta. ppm): 8.63 (1H, d, J=2 Hz), 7.95 (1H, d, J=5
Hz).
<Step 2> Synthesis of 2-amino-5-fluoroisonicotinic Acid
Hydrochloride
##STR00141##
[0281] 2-bromo-5-fluoroisonicotinic acid (10 g, 45 mmol), which was
synthesized using a method similar to that in <Step 1> in
Working Example 4, 28% aqueous ammonia (30 mL) and copper iodide
(CuI) (0.43 g, 2.3 mmol) were placed in a sealed reaction vessel
and heated for 17.5 hours using an oil bath at 120.degree. C.
Acetone (30 mL) was added, after which concentrated hydrochloric
acid was added under ice cooling so as to obtain a pH of 4. Acetone
(60 mL) was again added, and the obtained solid was filtered off,
washed with acetone, and dried at 45.degree. C. Crude
2-amino-5-fluoroisonicotinic acid hydrochloride (13 g, 148%,
including ammonium salt) was obtained as a beige solid.
[0282] (Physical property data) LC-MS: M (free amine)=156, RT=0.17
(min), [M+H].sup.+=157. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta.
ppm): 8.06 (1H, brs), 6.85 (1H, brs), 6.13 (2H, brs).
<Step 3> Synthesis of 2-amino-5-fluoroisonicotinic Acid Ethyl
Ester
##STR00142##
[0284] Crude 2-amino-5-fluoroisonicotinic acid hydrochloride (20 g,
104 mmol), which was synthesized using a method similar to that in
<Step 2> in Working Example 4, was suspended in ethanol (200
mL), and thionyl chloride (38 mL, 520 mmol and
N,N-dimethylformamide (DMF, 0.8 mL, 10 mmol) were added under ice
cooling. The obtained mixture was heated for 5.75 hours at
80.degree. C. After cooling the mixture, methyl tert-butyl ether
(MTBE) (400 mL) was added, and a precipitated solid was filtered
off and washed with methyl tert-butyl ether (MTBE). The obtained
solid was dissolved in ethyl acetate and washed with a saturated
aqueous solution of sodium hydrogen carbonate. The aqueous layer
was extracted using ethyl acetate, and the obtained organic layer
was combined with the organic layer mentioned above and washed with
dilute aqueous ammonia, water and a saturated saline solution in
that order. The organic layer was dried using sodium sulfate and
concentrated under reduced pressure. The obtained solid was
suspended in heptadecane, filtered off and dried.
2-amino-5-fluoroisonicotinic acid ethyl ester (19 g, 98%) was
obtained as a beige solid.
[0285] (Physical property data) LC-MS: M=184, RT=0.68 (min),
[M+H].sup.+=185. .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta. ppm):
8.01 (1H, d, J=3 Hz), 6.82 (1H, d, J=6 Hz), 6.18 (2H, s), 4.31 (2H,
q, J=7 Hz), 1.29 (3H, t, J=7 Hz).
<Step 4> Synthesis of
2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic Acid Ethyl
Ester
##STR00143##
[0287] Benzyl chlorocarbonate (5.0 mL, 35 mmol) was added under ice
cooling to a pyridine solution (40 mL) of
2-amino-5-fluoroisonicotinic acid ethyl ester (5.0 g, 27 mmol),
which was synthesized in <Step 3> in Working Example 4. The
obtained mixture was stirred for 4 hours at 25.degree. C., after
which benzyl chlorocarbonate (3.1 mL) was added. Water was added to
the reaction mixture, and a precipitated solid was filtered off and
washed with water. The obtained solid was suspended in a mixed
solvent (1:1) of methyl tert-butyl ether (MTBE) and heptane,
filtered off and dried.
2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid ethyl
ester (7.6 g, 88%) was obtained as a white solid.
[0288] (Physical property data) LC-MS: M=318, RT=1.12 (min),
[M+Na].sup.+=341. .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta. ppm):
10.6 (1H, s), 8.46 (1H, d, J=3 Hz), 8.26 (1H, d, J=6 Hz), 7.45-7.31
(5H, m), 5.19 (2H, s), 4.36 (2H, q, J=7 Hz), 1.32 (3H, t, J=7
Hz).
<Step 5> Synthesis of
2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic Acid
##STR00144##
[0290] A 1N aqueous solution of sodium hydroxide (26 mL) was added
under ice cooling to an ethanol suspension of
2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid ethyl
ester (7.5 g, 23 mmol), which was synthesized in <Step 4> in
Working Example 4. The obtained suspension was stirred for 4 hours
at room temperature. Water was added, after which the pH was
adjusted to 4 to 5 by means of concentrated hydrochloric acid. The
obtained solid was filtered off, washed with water and dried.
2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid (6.4 g,
93%) was obtained as a white solid.
[0291] (Physical property data) LC-MS: M=290, RT=0.98 (min),
[M+H].sup.+=291, [M+Na].sup.+=313. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6, .delta. ppm): 10.6 (1H, s), 8.42 (1H, d, J=4 Hz),
8.24 (1H, d, J=8 Hz), 7.44-7.31 (5H, m), 5.19 (2H, s).
<Step 6> Synthesis of benzyl
tert-butyl(5-fluoropyridin-2,4-diyl)dicarbamate
##STR00145##
[0293] 2-(((benzyloxy)carbonyl)amino)-5-fluoroisonicotinic acid
(0.19 g, 0.65 mmol), which was synthesized in <Step 5> in
Working Example 4, was suspended in tert-butanol (2.85 mL), and
triethylamine (0.27 mL, 2.0 mmol) was then added. The obtained
mixture was heated, and diphenylphosphoryl azide (0.16 mL, 0.72
mmol) was added dropwise at 80.degree. C. After heating for 4 hours
at 80.degree. C., diphenylphosphoryl azide (0.03 mL) was added.
Heptane (2 mL) was added, and the obtained solid was filtered off,
washed with heptane and then dried. Benzyl
tert-butyl(5-fluoropyridin-2,4-diyl)dicarbamate (0.21 g, 87%) was
obtained as a white solid.
[0294] (Physical property data) LC-MS: M=361, RT=1.1 (min),
[M+Na].sup.+=384. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
10.2 (1H, s), 9.57 (1H, s), 8.49 (1H, d, J=8 Hz), 8.11 (1H, d, J=3
Hz), 7.43-7.31 (5H, m), 5.16 (2H, s), 1.49 (9H, s).
<Step 7> Synthesis of Benzyl
(4-amino-5-fluoropyridin-2-yl)carbamate Hydrochloride
##STR00146##
[0296] Benzyl tert-butyl (5-fluoropyridin-2,4-diyl)dicarbamate
(0.19 g, 0.53 mmol), which was synthesized in <Step 6> in
Working Example 4, was suspended in 1,4-dioxane (1.9 mL), and a 4N
hydrochloric acid solution (1,4-dioxane solution: 0.39 mL) was
added. The obtained mixture was stirred at room temperature and
then stirred for 3.5 hours at 60.degree. C., and a 4N hydrochloric
acid solution (1,4-dioxane solution: 0.39 mL) was then added.
Methyl tert-butyl ether (MTBE) (5 mL) was added, the obtained solid
was filtered off, washed with methyl tert-butyl ether (MTBE) and
dried, and benzyl (4-amino-5-fluoropyridin-2-yl)carbamate
hydrochloride (0.15 g, 93%) was obtained as a white solid.
[0297] (Physical property data) LC-MS: M=261, RT=0.76 (min),
[M+Na].sup.+=284. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.4 (1H, s), 8.10 (1H, d, J=4 Hz), 8.07 (2H, brs), 7.46-7.35 (5H,
m), 6.79 (1H, d, J=8 Hz), 5.24 (2H, s).
(Working Example 5) Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide
##STR00147##
[0298]<Step 1> Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (Alternative Name:
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
Acid)
##STR00148##
[0300] A 1N aqueous solution of sodium hydroxide (19 mL, 19 mmol)
and toluene (20 mL) were added to crude
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid ethyl ester (4.0 g, 16 mmol), which was synthesized in Working
Example 1, and the obtained mixture was stirred for 5 hours at room
temperature. The aqueous layer was separated and adjusted to a pH
of 1 by adding concentrated hydrochloric acid. A precipitated solid
was filtered off, washed with water and dried, and
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (2.4 g, 65%) was obtained as a pale yellow solid.
[0301] (Physical property data) LC-MS: M=232, RT=0.65 (min),
[M+H].sup.+=233. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
8.49 (1H, s), 7.61 (1H, s), 4.07 (3H, s), 2.55 (3H, s), 2.15 (3H,
s).
<Step 2> Synthesis of Benzyl
(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5--
fluoropyridin-2-yl)carbamate
##STR00149##
[0303] Benzyl (4-amino-5-fluoropyridin-2-yl) carbamate
hydrochloride (50 mg, 0.17 mmol), which was synthesized using a
method similar to that in Working Example 4, was dissolved in
N-methylpyrrolidone (NMP) (0.4 mL) and 2,6-lutidine (0.06 mL), and
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (47 mg, 0.2 mmol), which was synthesized using a method
similar to that in <Step 1> in Working Example 5, and
O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N',N'-tetramethyl uronium
hexafluorophosphate (HATU, CAS No.: 148893-10-1) (89 mg, 0.24 mmol)
were added. The obtained mixture was stirred for 54 hours at
60.degree. C., and lutidine 2,6-lutidine (0.11 mL) and HATU (0.18
g) were then added. Water (1 mL) was added, and the obtained
mixture was stirred for 2 hours at room temperature. The obtained
solid was filtered off, washed with water, suspended again in
ethanol, filtered off, washed with ethanol and dried, and benzyl
(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5--
fluoropyridin-2-yl)carbamate (64 mg, 80%) was obtained as a beige
solid.
[0304] (Physical property data) LC-MS: M=475, RT=1.1 (min),
[M+H].sup.+=476, [M+Na].sup.+=498. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6, .delta. ppm): 10.9 (1H, s), 10.3 (1H, s), 8.67 (1H,
brs), 8.55 (1H, s), 8.25 (1H, d, J=4 Hz), 8.00 (1H, s), 7.43-7.31
(5H, m), 5.17 (2H, s), 4.01 (3H, s), 2.38 (3H, s), 2.37 (3H,
s).
<Step 3> Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide
##STR00150##
[0306] Benzyl
(4-(4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide)-5--
fluoropyridin-2-yl)carbamate (50 mg, 0.11 mmol), Which was
synthesized using a method similar to that in <Step 2> in
Working Example 5, was dissolved in dichloromethane (0.75 mL) and
methanol (0.25 mL), palladium-carbon (5 mg) was added, and the
obtained mixture was stirred for 6.5 hours at room temperature in a
hydrogen gas atmosphere. The palladium-carbon was removed by
filtration, the obtained liquid was concentrated under reduced
pressure, and
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide (33 mg, 92%) was obtained as a pale
yellow solid.
[0307] (Physical property data) LC-MS: M=341, RT=0.67 (min),
[M+H].sup.+=342. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
10.7 (1H, s), 8.56 (1H, s), 7.98 (1H, s), 7.84 (1H, d, J=3 Hz),
7.29 (1H, brs), 5.95 (2H, s), 4.00 (3H, s), 2.43 (3H, s), 2.36 (3H,
s).
(Working Example 6) Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a-
]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00151##
[0308]<Step 1> Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00152##
[0310] A mixture of crude
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid ethyl ester (0.50 g, 1.9 mmol), which was synthesized using a
method similar to that in Working Example 1, and 25% aqueous
ammonia (5 mL) was stirred for 20 hours at room temperature. A
saturated aqueous solution of sodium hydrogen carbonate was added
to the reaction mixture, and the reaction mixture was then
extracted using ethyl acetate. The obtained organic layer was
washed with a saturated saline solution, dried using sodium
sulfate, and then concentrated under reduced pressure.
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(0.13 g, 30%) was obtained as a pale yellow solid.
[0311] (Physical property data) LC-MS: M=231, RT=0.54 (min),
[M+H].sup.+=232. .sup.1H-NMR (300 MHz, DMSO-d.sub.6, .delta. ppm):
8.57 (1H, s), 8.28 (1H, brs), 7.84 (1H, s), 7.79 (1H, brs), 3.98
(3H, s), 2.56 (3H, s), 2.30 (2H, s).
<Step 2> Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide
##STR00153##
[0313] Crude 5-fluoro-4-iodopyridine-2-amine (104 mg, 0.44 mmol),
which was synthesized in Working Example 3,
4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(92 mg, 0.4 mmol), which was synthesized in Working Example 2,
N,N'-dimethyl-1,2-ethanediamine (4.1 mg, 0.05 mmol), copper iodide
(CuI) (9.1 mg, 0.05 mmol) and potassium carbonate (110 mg, 0.8
mmol) were mixed in 1,4-dioxane (1 mL), and heated for 20 hours
using an oil bath at 100.degree. C. Crude
5-fluoro-4-iodopyridine-2-amine (16 mg, 0.07 mmol),
N,N'-dimethyl-1,2-ethanediamine (2 mg, 0.02 mmol) and copper iodide
(CuI) (4 mg, 0.02 mmol) were added, the obtained mixture was heated
for 6 hours using an oil bath at 100.degree. C., after which crude
5-fluoro-4-iodopyridine-2-amine (16 mg, 0.07 mmol) was added, and
the obtained mixture was heated and stirred for 15 hours. Water and
dichloromethane were added to the reaction mixture, insoluble
substances were removed by filtration, and the organic layer was
then separated. The obtained organic layer was washed with water
and concentrated under reduced pressure. The obtained solid was
washed with methyl tert-butyl ether (MTBE) in order to remove
excess 5-fluoro-4-iodopyridine-2-amine, and
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-met-
hyl-1H-pyrazole-5-carboxamide (82 mg, 60%) was obtained as a brown
solid. Data for the obtained
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide was identical to the data for the
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide synthesized in <Step 3> in Working
Example 5.
<Step 3> Synthesis of
N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-
-methyl-1H-pyrazole-5-carboxamide
##STR00154##
[0315] Pyridine (0.5 mL) and dimethyl sulfoxide (0.25 mL) were
added to a mixture of
N-(2-amino-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-methyl--
1H-pyrazole-5-carboxamide (100 mg, 0.29 mmol), which was
synthesized using a method similar to that in <Step 3> in
Working Example 5 or <Step 2> in Working Example 6, and
methylbenzimidothioate hydroiodide (106 mg, 0.38 mmol). The
obtained solution was stirred for 7 hours in an oil bath at
80.degree. C. Acetone (0.5 mL), a saturated aqueous solution of
sodium hydrogen carbonate (0.5 mL) and water (2 mL) were added to
the reaction mixture and stirred for 1 hour at room temperature.
The obtained solid was filtered off, washed with water and dried,
and
N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-yl)-1-
-methyl-1H-pyrazole-5-carboxamide (112 mg, 86%) was obtained as a
white-yellow solid.
[0316] (Physical property data) LC-MS: M=444, RT=0.81 (min),
[M+H].sup.+=445. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
10.9 (1H, s), 9.86 (1H, brs), 8.57 (1H, s), 8.31 (1H, d, J=2 Hz),
8.03-8.01 (3H, m), 7.92 (1H, brs), 7.67-7.47 (3H, m), 4.02 (3H, s),
2.41 (3H, s), 2.37 (3H, s).
<Step 4> Synthesis of
4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a-
]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00155##
[0318]
N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(2,5-dimethylpyrimidin-4-
-yl)-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 0.45 mmol), which
was synthesized using a method similar to that in <Step 3> in
Working Example 6, and a copper chloride (CuCl) catalyst (4.5 mg,
0.04 mmol) were mixed in pyridine (0.8 mL), and the obtained
mixture was stirred in air for 2.5 hours using an oil bath at
100.degree. C. 28% aqueous ammonia (0.2 mL) and water were added,
and the obtained suspension was stirred for 10 minutes under ice
cooling. The generated solid was filtered off, washed with water
and dried, and
4-(2,5-dimethylpyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a-
]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (159 mg, 80%) was
obtained as an off-white solid.
[0319] (Physical property data) LC-MS: M=442, RT=1.13 (min),
[M+H].sup.+=443. .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta. ppm):
11.72 (1H, s), 8.78 (1H, d, J=8 Hz), 8.63 (1H, s), 8.59 (1H, d, J=8
Hz), 8.27-8.24 (2H, m), 7.70 (1H, s), 7.51-7.49 (3H, m), 4.31 (3H,
s), 2.78 (3H, s), 2.42 (3H, s).
(Working Example 7) Synthesis of methyl
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate
##STR00156##
[0321] Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl
ester (CAS No.: 514816-42-3, 2.0 g, 9.1 mmol) and
4-chloro-2-methylpyrimidine (0.94 g), methyl
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (1.26
g) was obtained as a yellow oily substance using a method similar
to that in <Step 1> in Working Example 1 or a method based on
this method.
[0322] (Physical property data) LC-MS: M=232, RT=0.75 (min),
[M+H].sup.+=233. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta. ppm)
8.62 (1H, d, J=5 Hz), 7.85 (1H, s), 7.29 (1H, d, J=5 Hz), 4.15 (3H,
s), 3.87 (3H, s), 2.74 (3H, s).
(Working Example 8) Synthesis of
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic
Acid
##STR00157##
[0324] Using methyl
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylate (1.26
g), which was obtained in Working Example 7, the title compound
(682 mg) was obtained as a colorless solid using a method similar
to that in <Step 1> in Working Example 5 or a method based on
this method.
[0325] (Physical property data) LC-MS: M=218, RT=0.67 (min),
[M+H].sup.+=219. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta. ppm):
8.79 (1H, d, J=6 Hz), 8.09 (1H, s), 7.56 (1H, d, J=6 Hz), 4.36 (3H,
s), 2.81 (3H, s).
(Working Example 9) Synthesis of
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide
##STR00158##
[0327] 1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxylic
acid (2.0 g, 9.2 mmol), which was synthesized using a method
similar to that in Working Example 8, and diisopropylethylamine
(1.8 mL, 10 mmol) were suspended in tetrahydrofuran (20 mL), and
benzyl chloroformate (1.7 mL, 10 mmol) was added dropwise under ice
cooling. After stirring for 30 minutes under ice cooling, ammonium
carbonate (1.8 g, 18 mmol) and diisopropylethylamine (3.2 mL, 18
mmol) were added, and the obtained mixture was stirred for 1.25
hours at room temperature. An aqueous solution of sodium hydrogen
carbonate was added to the reaction mixture, and the reaction
mixture was extracted using ethyl acetate. The solid in the aqueous
layer was filtered off, and the obtained aqueous layer was
extracted using ethyl acetate. The organic layer was added, washed
with water, washed with a saturated saline solution, dried using
sodium sulfate, and then concentrated under reduced pressure. The
obtained solid residue and the solid obtained from the aqueous
layer were combined, the obtained mixture was triturated with
methyl tert-butyl ether (MTBE), filtered off, washed with MTBE and
dried, and
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide (1.2
g, 59%) was obtained as a white solid.
[0328] (Physical property data) LC-MS: M=217, RT=0.57 (min),
[M+H].sup.+=218. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
9.17 (1H, s), 8.66 (1H, d, J=6 Hz), 8.12 (1H, s), 8.03 (1H, s),
7.54 (1H, d, J=6 Hz), 3.96 (3H, s), 2.60 (3H, s).
(Working Example 10) Synthesis of
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(2-me-
thylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide
##STR00159##
[0329]<Step 1> Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-p-
yrazole-5-carboxamide
##STR00160##
[0331] 5-fluoro-4-iodopyridine-2-amine (482 mg, 2.0 mmol), which
was synthesized using a method similar to that in Working Example
3, and
1-methyl-4-(2-methylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide (400
mg, 1.8 mmol), which was synthesized in Working Example 9, were
subjected to a reaction using a method based on <Step 2> in
Working Example 6, after which a 28% aqueous solution of ammonia
(0.8 mL) was added, and the obtained mixture was stirred at room
temperature, and then diluted with water. The precipitated solid
was filtered off, washed with water and dried, the obtained crude
product was triturated in ethyl acetate/ethanol/MTBE (1:2:10), and
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-p-
yrazole-5-carboxamide (299 mg, 50%) was obtained as a white
solid.
[0332] (Physical property data) LC-MS: M=327, RT=0.69 (min),
[M+H].sup.+=328. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.6 (1H, s), 8.68 (1H, d, J=5 Hz), 8.22 (1H, s), 7.87 (1H, d, J=2
Hz), 7.66 (1H, d, J=5 Hz), 7.30 (1H, s), 5.90 (2H, s), 4.00 (3H,
s), 2.49 (3H, s).
<Step 2> Synthesis of
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4--
yl)-1H-pyrazole-5-carboxamide
##STR00161##
[0334] Using
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4-yl)-1H-p-
yrazole-5-carboxamide (290 mg, 0.89 mmol), which was synthesized
using a method similar to that in <Step 1> in Working Example
10, and methylbenzimidothioate hydroiodide (322 mg, 1.2 mmol; 74
mg, 0.27 mmol; or 49 mg, 0.18 mmol),
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4--
yl)-1H-pyrazole-5-carboxamide (368 mg, 97%) was obtained as a gray
solid using a method similar to that in <Step 3> in Working
Example 6.
[0335] (Physical property data) LC-MS: M=430, RT=0.84 (min),
[M+H].sup.+=431. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.8 (1H, s), 9.80 (1H, s), 8.70 (1H, d, J=6 Hz), 8.35 (1H, d, J=1
Hz), 8.27 (1H, s), 8.04 (2H, d, J=7 Hz), 7.91 (1H, d, J=5 Hz), 7.68
(1H, d, J=5 Hz), 7.53-7.46 (3H, m), 4.03 (3H, s), 2.49 (3H, s).
<Step 3> Synthesis of
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(2-m-
ethylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide
##STR00162##
[0337] Using
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(2-methylpyrimidin-4--
yl)-1H-pyrazole-5-carboxamide (320 mg, 0.74 mmol), which was
synthesized in <Step 2> in Working Example 10,
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(2-m-
ethylpyrimidin-4-yl)-1H-pyrazole-5-carboxamide (263 mg, 83%) was
obtained as a beige solid using a method similar to that in
<Step 4> in Working Example 6.
[0338] (Physical property data) LC-MS: M=428, RT=1.16 (min),
[M+H].sup.+=429. .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta. ppm):
13.39 (1H, s), 8.75-8.64 (3H, m), 8.28-8.26 (2H, m), 7.96 (1H, s),
7.52-7.47 (4H, m), 4.36 (3H, s), 2.79 (3H, s).
(Working Example 11) Synthesis of methyl
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate
##STR00163##
[0340] Using 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl
ester (CAS No.: 514816-42-3, 2.52 g, 11.5 mmol) and
4-chloro-5-fluoro-2-methoxypyrimidine (1.5 g), methyl
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate
(1.6 g) was obtained as a pale yellow liquid using a method similar
to that in <Step 1> in Working Example 1 or a method based on
this method.
[0341] (Physical property data) LC-MS: M=266, RT=0.91 (min),
[M+H].sup.+=267. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta. ppm):
8.35 (1H, d, J=2 Hz), 7.86 (1H, d, J=1 Hz), 4.15 (3H, s), 4.00 (3H,
s), 3.86 (3H, s).
(Working Example 12) Synthesis of
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
Acid
##STR00164##
[0343] Using methyl
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate
(1.6 g), which was obtained in Working Example 11,
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (0.65 g) was obtained as a colorless solid using a method
similar to that in <Step 1> in Working Example 5 or a method
based on this method.
[0344] (Physical property data) LC-MS: M=252, RT=0.81 (min),
[M+Na].sup.+=275. .sup.1H-NMR (300 MHz, CDCl.sub.3, .delta. ppm):
8.54 (1H, d, J=3 Hz), 8.28 (1H, d, J=4 Hz), 4.36 (3H, s), 4.09 (3H,
s).
(Working Example 13) Synthesis of
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00165##
[0346] Using
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic
acid (0.50 g, 2.0 mmol), which was synthesized using a method
similar to that in Working Example 12, and ethyl chloroformate
(0.21 mL, 2.2 mmol),
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(0.40 g, 80%) was obtained as a white solid using a method similar
to that in Working Example 9.
[0347] (Physical property data) LC-MS: M=251, RT=0.67 (min),
[M+H].sup.+=252. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
8.64 (1H, d, J=3 Hz), 8.18 (1H, s), 7.97 (1H, s), 7.95 (1H, d, J=3
Hz), 3.90 (3H, s), 3.89 (3H, s).
(Working Example 14) Synthesis of
4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo-
[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00166##
[0348]<Step 1> Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-m-
ethyl-1H-pyrazole-5-carboxamide
##STR00167##
[0350] 5-fluoro-4-iodopyridine-2-amine (104 mg, 0.44 mmol), which
was synthesized using a method similar to that in Working Example
3,
4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(100 mg, 0.4 mmol), which was synthesized in Working Example 13,
trans-N,N'-dimethylcyclohexane-1,2-diamine (34 mg, 0.24 mmol),
copper iodide (CuI) (23 mg, 0.12 mmol) and potassium phosphate (169
mg, 0.8 mmol) were mixed in dimethyl sulfoxide (1 mL), and heated
for 3.7 hours at 60.degree. C. A 28% aqueous solution of ammonia
(0.2 mL) was added, and the obtained mixture was stirred at room
temperature and then diluted with water. The reaction mixture was
extracted using methylene chloride, and the obtained organic layer
was washed with water and a saline solution, dried using sodium
sulfate, and concentrated. The obtained solid residue was
triturated with methyl tert-butyl ether (MTBE), filtered off,
washed with methyl tert-butyl ether, and dried, and
N-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-m-
ethyl-1H-pyrazole-5-carboxamide (99 mg, 69%) was obtained as a gray
solid.
[0351] (Physical property data) LC-MS: M=361, RT=0.71 (min),
[M+H].sup.+=362.
[0352] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm): 10.8 (1H,
s), 8.65 (1H, d, J=3 Hz), 8.02 (1H, d, J=3 Hz), 7.84 (1H, s), 7.37
(1H, d, J=5 Hz), 5.91 (2H, s), 3.92 (3H, s), 3.68 (3H, s).
<Step 2> Synthesis of
N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-
-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00168##
[0354] Pyridine (0.4 mL) and dimethyl sulfoxide (0.2 mL) were added
to a mixture of
N-(2-amino-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-yl)-1-m-
ethyl-1H-pyrazole-5-carboxamide (80 mg, 0.22 mmol), which was
synthesized in <Step 1> in Working Example 14, and
methylbenzimidothioate hydroiodide (80 mg, 0.29 mmol). The obtained
solution was stirred for 35 minutes at 80.degree. C., and
methylbenzimidothioate hydroiodide (12 mg, 0.04 mmol) was added and
stirred for a further 40 minutes. Acetone (0.4 mL) and a saturated
aqueous solution of sodium hydrogen carbonate (0.4 mL) were added
to the reaction mixture, the reaction mixture was stirred for 30
minutes at room temperature, after which water (1.6 mL) was added,
and the reaction mixture was stirred for a further 1 hour. The
obtained solid was filtered off, washed with water and dried, and
N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-(5-fluoro-2-methoxypyrimidin-4-
-yl)-1-methyl-1H-pyrazole-5-carboxamide (86 mg, 84%) was obtained
as a gray solid.
[0355] (Physical property data) LC-MS: M=464, RT=0.82 (min),
[M+H].sup.+=465. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.1 (1H, s), 8.67 (1H, d, J=3 Hz), 8.30 (1H, s), 8.07-8.01 (3H,
m), 7.99-7.90 (1H, m), 7.54-7.45 (3H, m), 3.97 (3H, s), 3.68 (3H,
s).
<Step 3> Synthesis of
4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo-
[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide
##STR00169##
[0357] N-(2-benzimidamido-5-fluoropyridin-4-yl)-4-
(5-fluoro-2-methoxypyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxamide
(70 mg, 0.15 mmol), which was synthesized in <Step 2> in
Working Example 14, and a copper chloride (CuCl) catalyst (1.5 mg,
0.02 mmol) were mixed in pyridine (0.28 mL), and the obtained
mixture was stirred in air for 3.5 hours at 100.degree. C. 28%
aqueous ammonia (0.07 mL) and water were added, and the obtained
suspension was stirred for 45 minutes at room temperature. The
generated solid was filtered off, washed with water and dried, and
4-(5-fluoro-2-methoxypyrimidin-4-yl)-N-(6-fluoro-2-phenyl-[1,2,4]triazolo-
[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (56 mg,
80%) was obtained as a beige solid.
[0358] (Physical property data) LC-MS: M=462, RT=1.10 (min),
[M+H].sup.+=463. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.3 (1H, s), 9.45 (1H, d, J=6 Hz), 8.69 (1H, d, J=3 Hz), 8.57 (1H,
d, J=7 Hz), 8.20-8.17 (2H, m), 8.08 (1H, d, J=3 Hz), 7.57-7.49 (3H,
m), 4.00 (3H, s), 3.67 (3H, s).
(Working Example 15) Synthesis of methyl
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate
<Step 1> Synthesis of
methyl-4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-c-
arboxylate
##STR00170##
[0360] A 1,1'-bis(diphenylphosphino) ferrocene-palladium (II)
dichloride dichloromethane complex (0.37 g, 0.46 mmol) and
potassium acetate (3.6 g, 37 mmol) were added to a dimethyl
sulfoxide solution (10 mL) of
4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (CAS
No.: 514816-42-3, 2.0 g, 9.1 mmol) and
5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (4.1 g, 18
mmol), and stirred for 4 hours at 100.degree. C. in a nitrogen
atmosphere. The reaction solution was cooled, water (50 mL) was
added, and the reaction solution was extracted twice using ethyl
acetate (100 mL). An organic layer was combined, and the obtained
mixture was washed with water and a saturated saline solution in
that order, and then dried with anhydrous sodium sulfate. A residue
obtained by distilling of the solvent under reduced pressure was
purified by means of silica gel column chromatography (silica
gel:eluate; heptane:ethyl acetate 90:10 to 40:60), and the title
compound (1.0 g) was obtained as a brown solid.
[0361] (Physical property data) LC-MS: M=252, RT=0.67 (min),
[M+H].sup.+ of corresponding boronic acid=185. .sup.1H-NMR (300
MHz, CDCl.sub.3, .delta. ppm): 7.58 (1H, s), 4.11 (3H, s), 3.88
(3H, s), 3.74 (4H, s), 1.05 (6H, s).
<Step 2> Synthesis of methyl
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylate
##STR00171##
[0363] Using
methyl-4-(5,5-dimethyl-1,3,2-dioxaborinan)-2-yl)-1-methyl-1H-pyrazole-5-c-
arboxylate (300 mg, 1.19 mmol), which was synthesized in <Step
1> in Working Example 15, and
2-bromo-4-(trifluoromethyl)thiazole (291 mg), methyl
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxy-
late (259 mg) was obtained as a light brown solid using a method
similar to that in <Step 1> in Working Example 1 or a method
based on this method.
[0364] (Physical property data) LC-MS: M=291, RT=1.05 (min),
[M+H].sup.+=292. .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta. ppm):
8.11 (1H, s), 7.77-7.76 (1H, m), 4.21 (3H, s), 3.98 (3H, s).
(Working Example 16) Synthesis of
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic
Acid
##STR00172##
[0366] 2-yl)-1H-pyrazole-5-carboxylate (210 mg), which was obtained
in Working Example 15,
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic
acid (173 mg) was obtained as a brown-white solid using a method
similar to that in <Step 1> in Working Example 5 or a method
based on this method.
[0367] (Physical property data) LC-MS: M=277, RT=4.98 (min),
[M+H].sup.+=278. .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta. ppm):
8.48-8.46 (1H, m), 8.08 (1H, s), 4.12 (3H, s).
(Working Example 17) Synthesis of
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide
##STR00173##
[0369] Using
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic
acid (0.15 g, 0.54 mmol), which was synthesized using a method
similar to that in Working Example 16, and ethyl chloroformate
(0.057 mL, 0.6 mmol),
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide
(66 mg, 44%) was obtained as a white solid using a method similar
to that in Working Example 9.
[0370] (Physical property data) LC-MS: M=276, RT=0.90 (min),
[M+H].sup.+=277. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
8.65 (1H, s), 8.44 (1H, q, J=1 Hz), 8.12 (1H, s), 8.02 (1H, s),
3.96 (3H, s).
(Working Example 18) Synthesis of
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-4-(4-(t-
rifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide
##STR00174##
[0371]<Step 1> Synthesis of
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-
-yl)-1H-pyrazole-5-carboxamide
##STR00175##
[0373] 5-fluoro-4-iodopyridine-2-amine (38 mg, 0.16 mmol), which
was synthesized using a method similar to that in Working Example
3, and
1-methyl-4-(4-(trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide
(40 mg, 0.14 mmol), which was synthesized in Working Example 17,
were subjected to a reaction using a method based on <Step 2>
in Working Example 6, after which a 28% aqueous solution of ammonia
(0.08 mL) was added, stirred at room temperature, diluted with
water, and extracted using methylene chloride. The obtained organic
layer was washed with water and a saline solution, dried with
sodium sulfate, and then concentrated. The obtained solid residue
was triturated in MTBE, and
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-
-yl)-1H-pyrazole-5-carboxamide (33 mg, 59%) was obtained as a beige
solid.
[0374] (Physical property data) LC-MS: M=386, RT=0.86 (min),
[M+H].sup.+=387. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.2 (1H, s), 8.46 (1H, s), 8.13 (1H, s), 7.87 (1H, s), 7.32 (1H,
d, J=4 Hz), 5.94 (2H, s), 4.02 (3H, s).
<Step 2> Synthesis of
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)t-
hiazol-2-yl)-1H-pyrazole-5-carboxamide
##STR00176##
[0376] Using
N-(2-amino-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)thiazol-2-
-yl)-1H-pyrazole-5-carboxamide (25 mg, 0.06 mmol), which was
synthesized in <Step 1> in Working Example 18, and
methylbenzimidothioate hydroiodide (23 mg, 0.08 mmol; or 3.6 mg,
0.01 mmol),
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)t-
hiazol-2-yl)-1H-pyrazole-5-carboxamide (27 mg, 85%) was obtained as
a beige solid using a method similar to that in <Step 3> in
Working Example 6.
[0377] (Physical property data) LC-MS: M=489, RT=0.95 (min),
[M+H].sup.+=490. .sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta. ppm):
11.4 (1H, s), 9.82 (1H, s), 8.46 (1H, s), 8.33 (1H, s), 8.16 (1H,
s), 8.04 (2H, d, J=6 Hz), 7.89 (1H, s), 7.53-7.45 (3H, m), 4.06
(3H, s).
<Step 3> Synthesis of
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(4-(-
trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide
##STR00177##
[0379] Using
N-(2-benzimidamido-5-fluoropyridin-4-yl)-1-methyl-4-(4-(trifluoromethyl)t-
hiazol-2-yl)-1H-pyrazole-5-carboxamide (20 mg, 0.04 mmol), which
was synthesized in <Step 2> in Working Example 18,
N-(6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1l-methyl-4-(4-(-
trifluoromethyl)thiazol-2-yl)-1H-pyrazole-5-carboxamide (15 mg,
75%) was obtained as a beige solid using a method similar to that
in <Step 4> in Working Example 6.
[0380] (Physical property data) LC-MS: M=487, RT=1.25 (min),
[M+H].sup.+=488. .sup.1H-NMR (400 MHz, CDCl.sub.3, .delta. ppm):
12.32 (1H, s), 8.86-8.80 (1H, m), 8.65-8.60 (1H, m), 8.30-8.22 (2H,
m), 7.96-7.90 (1H, m), 7.85-7.80 (1H, m), 7.54-7.43 (3H, m), 4.37
(3H, s).
INDUSTRIAL APPLICABILITY
[0381] Provided by the present invention is a method for
manufacturing a compound represented by formula (I), which has a
short process and is suitable for industrial manufacturing. Also
provided by the present invention is a synthesis intermediate that
is useful for this manufacturing method.
* * * * *