U.S. patent application number 12/111918 was filed with the patent office on 2009-02-26 for pyrazole compounds and pharmaceutical compositions comprising the compound.
Invention is credited to Takashi Doko, Takafumi Motoki, Yoshimitsu Naoe, Norihito Ohi, Nobuaki Sato, Motohiro Soejima, Taro Terauchi.
Application Number | 20090054397 12/111918 |
Document ID | / |
Family ID | 29714298 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090054397 |
Kind Code |
A1 |
Ohi; Norihito ; et
al. |
February 26, 2009 |
PYRAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE
COMPOUND
Abstract
The present invention provides a novel compound having an
excellent JNK inhibitory effect. That is, it provides a compound
represented by the following formula, a salt thereof or a hydrate
of them. ##STR00001## Wherein R.sup.1 designates
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently designate
a hydrogen atom, a halogen atom, hydroxyl group, an optionally
substituted C.sub.1-6 alkyl group or the like; Cy designates a 5-
or 6-membered heteroaryl; and V each independently designate the
formula -L-X--Y (wherein L designates a single bond, an optionally
substituted C.sub.1-6 alkylene group or the like; X designates a
single bond or the formula -A- (wherein A designates NR.sup.2, O,
CO, S, SO or SO.sub.2) and so on; and Y designates a hydrogen atom,
a halogen atom, nitro group or the like).
Inventors: |
Ohi; Norihito; (Ibaraki,
JP) ; Sato; Nobuaki; (Ibaraki, JP) ; Soejima;
Motohiro; (Ibaraki, JP) ; Doko; Takashi;
(Ibaraki, JP) ; Terauchi; Taro; (Ibaraki, JP)
; Naoe; Yoshimitsu; (Ibaraki, JP) ; Motoki;
Takafumi; (Ibaraki, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
29714298 |
Appl. No.: |
12/111918 |
Filed: |
April 29, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10447948 |
May 30, 2003 |
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12111918 |
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Current U.S.
Class: |
514/210.21 ;
514/234.5; 514/249; 514/255.05; 514/256; 514/303; 514/338; 514/364;
514/383; 514/394; 514/403; 514/406; 544/140; 544/333; 544/350;
544/405; 546/119; 546/272.4; 546/275.7; 548/143; 548/267.2;
548/305.1; 548/360.5; 548/362.5 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/4245 20130101; C07D 409/04 20130101; A61K 31/42 20130101;
A61P 25/14 20180101; C07D 471/04 20130101; A61K 31/422 20130101;
C07D 403/06 20130101; A61K 31/437 20130101; A61K 31/5377 20130101;
A61K 31/4178 20130101; C07D 403/04 20130101; C07D 405/06 20130101;
C07D 409/06 20130101; A61P 37/06 20180101; C07D 487/04 20130101;
A61K 31/4439 20130101; C07D 413/04 20130101; A61K 31/506 20130101;
C07D 413/14 20130101; A61P 37/02 20180101; A61K 31/427 20130101;
A61K 31/4162 20130101; A61P 3/00 20180101; A61K 31/4196 20130101;
A61K 31/416 20130101; A61K 31/4184 20130101; A61K 31/454 20130101;
A61K 31/444 20130101; A61P 21/00 20180101; A61K 31/43 20130101;
A61P 29/00 20180101; A61P 25/16 20180101; A61P 43/00 20180101; A61K
31/496 20130101; A61K 31/55 20130101; A61K 31/4985 20130101; A61K
31/497 20130101; A61P 25/28 20180101; C07D 231/56 20130101; A61P
25/02 20180101; C07D 495/04 20130101; C07D 401/06 20130101; A61K
31/407 20130101 |
Class at
Publication: |
514/210.21 ;
546/119; 514/303; 548/362.5; 514/403; 546/275.7; 514/338;
548/267.2; 514/383; 546/272.4; 544/350; 514/249; 548/360.5;
514/406; 548/143; 514/364; 544/333; 514/256; 548/305.1; 514/394;
544/405; 514/255.05; 544/140; 514/234.5 |
International
Class: |
A61K 31/397 20060101
A61K031/397; C07D 471/02 20060101 C07D471/02; A61K 31/437 20060101
A61K031/437; C07D 231/56 20060101 C07D231/56; A61K 31/416 20060101
A61K031/416; C07D 401/02 20060101 C07D401/02; A61K 31/4439 20060101
A61K031/4439; C07D 249/08 20060101 C07D249/08; A61K 31/4245
20060101 A61K031/4245; A61P 25/00 20060101 A61P025/00; A61K 31/5377
20060101 A61K031/5377; C07D 413/02 20060101 C07D413/02; A61K 31/497
20060101 A61K031/497; A61K 31/4184 20060101 A61K031/4184; A61K
31/506 20060101 A61K031/506; C07D 271/10 20060101 C07D271/10; A61K
31/4196 20060101 A61K031/4196; C07D 401/14 20060101 C07D401/14;
C07D 241/36 20060101 C07D241/36; A61K 31/4985 20060101
A61K031/4985; C07D 231/54 20060101 C07D231/54; A61K 31/4162
20060101 A61K031/4162 |
Foreign Application Data
Date |
Code |
Application Number |
May 31, 2002 |
JP |
2002-158467 |
Jan 6, 2003 |
JP |
2003-153 |
Claims
1. A compound represented by the formula (III), a salt thereof or a
hydrate thereof: ##STR00240## wherein R.sup.1 represents a group
represented by the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently represents
a hydrogen atom, halogen atom, hydroxyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.2-6 alkenyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.2-6 alkenyloxy group, an
optionally substituted C.sub.1-6 alkylthio group, an optionally
substituted C.sub.2-6 alkenylthio group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; Ar represents an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; h and j each independently is 0 or
1, and k is 1); R.sup.d and R.sup.f each independently represents a
hydrogen atom, R.sup.e represents a halogen atom, L represents a
single bond, an optionally substituted C.sub.1-6 alkylene group, an
optionally substituted C.sub.2-6 alkenylene group or an optionally
substituted C.sub.2-6 alkynylene group; X represents a single bond,
or a group represented by --CO--NR.sup.8-Z-, --NR.sup.8--CO-Z-,
--NR.sup.8--C(O)O--, --NR.sup.9--CO--NR.sup.10--,
--OC(O)--NR.sup.14-- or --CH.sub.2--NR.sup.8--COR.sup.7-- (wherein
R.sup.8, R.sup.9, R.sup.10 and R.sup.14 each independently
represents a hydrogen atom, halogen atom, hydroxyl group, an
optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.2-6 alkenyl group, an optionally substituted
C.sub.2-6 alkynyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.2-6 alkenyloxy group, an
optionally substituted C.sub.1-6 alkylthio group, an optionally
substituted C.sub.2-6 alkenylthio group, an optionally substituted
C.sub.3-8 cycloalkyl group, an optionally substituted C.sub.3-8
cycloalkenyl group, an optionally substituted 4- to 14-membered
non-aromatic heterocyclic group, an optionally substituted
C.sub.6-14 aryl group or an optionally substituted 5- to
14-membered heteroaryl group, Z represents a single bond or an
optionally substituted C.sub.1-6 alkylene group, and m designates
0, 1 or 2); and Y represents any one group selected from the group
consisting of a hydrogen atom, halogen atom, nitro group, hydroxyl
group, cyano group, carboxyl group or an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl
group, an optionally substituted C.sub.2-6 alkynyl group, an
optionally substituted C.sub.1-6 alkoxy group, an optionally
substituted C.sub.3-8 cycloalkyl group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group, an optionally substituted 5- to
14-membered heteroaryl group, an optionally substituted amino group
and a group represented by the formula --W--R.sup.15 (wherein W
designates CO or SO.sub.2; and R.sup.15 represents an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted amino
group, an optionally substituted C.sub.6-14 aryl group or an
optionally substituted 5- to 14-membered heteroaryl group).
2. The compound according claim 1, a salt thereof or a hydrate
thereof, wherein at least one of R.sup.b and R.sup.c is not a
hydrogen atom, and L is a single bond, an optionally substituted
C.sub.2-6 alkenylene group or an optionally substituted C.sub.2-6
alkynylene group, provided that, when L is a single bond, the case
where X is a single bond, and Y is an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.3-8
cycloalkyl group, an optionally substituted C.sub.3-8 cycloalkenyl
group, an optionally substituted 4- to 14-membered non-aromatic
heterocyclic group, an optionally substituted C.sub.6-14 aryl group
or an optionally substituted 5- to 14-membered heteroaryl group is
excluded.
3. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein at least either h or j is 1.
4. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein h and j are 0.
5. The compound according to any one of claims 3 and 4, a salt
thereof or a hydrate thereof, wherein R.sup.b and/or R.sup.c
are(is) a hydrogen atom.
6. The compound according to claim 5, a salt thereof or a hydrate
thereof, wherein R.sup.b and R.sup.c are a hydrogen atom.
7. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein Ar is a C.sub.6-14 aryl group or a 5- to
14-membered heteroaryl group, and Ar is a group which may be
substituted with 1 to 3 group(s) selected from the following
substituent group (a): the group consisting of (1) each optionally
substituted (a) C.sub.1-6 alkyl groups, (b) C.sub.1-6 alkoxy
groups, (c) C.sub.1-7 acyl groups, (d) amide group, (e) amino
group, (f) C.sub.3-8 cycloalkyl groups, (2) halogen atom, (3)
hydroxyl group, (4) nitro group, (5) cyano group, and (6) carboxyl
group.
8. The compound according to claim 7, a salt thereof or a hydrate
thereof, wherein Ar is a phenyl group, naphthyl group or a 5- to
10-membered heteroaryl group, and Ar is a group optionally
substituted with 1 to 3 group(s) selected from substituent group
(a).
9. The compound according to claim 7, a salt thereof or a hydrate
thereof, wherein Ar is a phenyl group, 2-naphthyl group, pyridyl
group, 2-thienyl group, 2-furyl group, 2-benzofuryl group,
2-quinolyl group or 2-benzothienyl group, and Ar is a group
optionally substituted with 1 to 3 group(s) selected from
substituent group (a).
10. The compound according to claim 7, a salt thereof or a hydrate
thereof, wherein Ar is a phenyl group, pyridyl group, 2-thienyl
group or 2-furyl group, and Ar is a group optionally substituted
with 1 to 3 group(s) selected from substituent group (a).
11. The compound according to claim 7, a salt thereof or a hydrate
thereof, wherein Ar is a 2-naphthyl group, 2-benzofuryl group,
2-quinolyl group or 2-benzothienyl group, and Ar is a group
optionally substituted with 1 to 3 group(s) selected from
substituent group (a).
12. The compound according to any one of claims 7 to 11, a salt
thereof or a hydrate thereof, wherein substituent group (a) is the
group consisting of (1) C.sub.1-6 alkyl groups each optionally
substituted with 1 to 3 group(s) selected from the group consisting
of a halogen atom, hydroxyl group and cyano group, (2) C.sub.1-6
alkoxy groups optionally substituted with 1 to 3 group(s) selected
from the group consisting of a halogen atom, hydroxyl group and
cyano group, (3) halogen atom, (4) hydroxyl group, (5) cyano group,
and (6) C.sub.1-7 acyl groups.
13. The compound according to any one of claims 7 to 11, a salt
thereof or a hydrate thereof, wherein the substituent in
substituent group (a) is a halogen atom.
14. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein L is a single bond or methylene group.
15. The compound according to claim 14, a salt thereof or a hydrate
thereof, wherein L is a single bond.
16. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein X is --CO--NR.sup.8-Z- or --NR.sup.8--CO-Z-.
17. The compound according to claim 16, a salt thereof or a hydrate
thereof, wherein R.sup.8 is a hydrogen atom.
18. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein X is --CO--NR.sup.8-Z-.
19. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein X is --NR.sup.8--CO-Z-.
20. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein X is a single bond.
21. The compound according to claim 1, a salt thereof or a hydrate
thereof, wherein Y is a C.sub.1-6 alkyl group, a C.sub.6-14 aryl
group, a C.sub.1-6 alkoxy group, a C.sub.3-8 cycloalkyl group, a 4-
to 14-membered non-aromatic heterocyclic group or a 5- to
14-membered heteroaryl group, and Y is a group optionally
substituted with 1 to 3 group(s) selected from the following
substituent group a2: the group consisting of (1) each optionally
substituted with at least one selected from the group consisting of
(a) C.sub.1-6 alkyl groups, (b) C.sub.2-6 alkenyl groups, (c)
C.sub.2-6-alkynyl groups, (d) C.sub.1-6 alkoxy groups, (e)
C.sub.2-7 acyl groups, (f) amide group, (g) amino group, (h)
C.sub.3-8 cycloalkyl groups, (i) C.sub.3-8 cycloalkenyl groups, (j)
C.sub.6-14 aryl groups, (k) 5- to 14-membered heteroaryl groups,
(l) C.sub.6-14 aryloxy groups, and (m) 4- to 14-membered
non-aromatic heterocyclic groups, (2) halogen atom, (3) hydroxyl
group, (4) nitro group, (5) cyano group, and (6) carboxyl
group.
22. The compound according to claim 21, a salt thereof or a hydrate
thereof, wherein Y is a C.sub.3-8 cycloalkyl group, phenyl group, a
5- or 6-membered non-aromatic heterocyclic group, or a 5- or
6-membered heteroaryl group, and Y is a group optionally
substituted with 1 to 3 group(s) selected from substituent group
a2.
23. The compound according to claim 21, a salt thereof or a hydrate
thereof, wherein Y is a furyl group, thienyl group, pyrrolyl group,
phenyl group, pyridyl group, C.sub.3-8 cycloalkyl group,
tetrahydrofuran-yl group, tetrahydrothiophene-yl group,
pyrrolidinyl group, tetrahydrofuran-2-on-yl group,
pyrrolidine-2-on-yl group or a group represented by the formula:
##STR00241## (wherein Y.sup.2a designates a group represented by
--CONH.sub.2 or --CH.sub.2OH, Y.sup.2b and Y.sup.2c each
independently designate a hydrogen atom, an optionally substituted
phenyl group or an optionally substituted C.sub.1-6 alkyl group),
and Y is a group optionally substituted with 1 to 3 group(s)
selected from substituent group a2.
24. The compound according to claim 21, a salt thereof or a hydrate
thereof, wherein Y is a furyl group or thienyl group, and Y is a
group optionally substituted with 1 to 3 group(s) selected from
substituent group a2.
25. The compound according to any one of claims 21 to 24, a salt
thereof or a hydrate thereof, wherein Substituent group a2 is the
group consisting of (1) (a) C.sub.1-6 alkyl groups, (b) C.sub.1-6
alkoxy groups, (c) C.sub.1-7 acyl groups, (d) amide group, (e)
amino group, (f) C.sub.3-8 cycloalkyl groups, each of which may be
substituted with 1 to 3 group(s) selected from the following
Substituent group b2, (2) halogen atom, (3) hydroxyl group, (4)
nitro group, (5) cyano group, and (6) carboxyl group, and
substituent group b2 is: the group consisting of C.sub.1-6 alkyl
groups, halogen atom, hydroxyl group, nitro group, cyano group and
carboxyl group.
26. The compound according to any one of claims 21 to 24, a salt
thereof or a hydrate thereof, wherein substituent group a2 is the
group consisting of (1) C.sub.1-6 alkoxy groups, (2) halogen atoms
and (3) cyano groups.
27. The compound according to claim 21, a salt thereof or a hydrate
thereof, wherein L and X are a single bond, Y is a 5- to 6-membered
heteroaryl group, and Y is a group optionally substituted with 1 to
3 group(s) selected from substituent group a2.
28. A pharmaceutical composition comprising: the compound according
to claim 1, 7, 16 or 21, a salt thereof or a hydrate thereof, and a
pharmaceutically acceptable carrier.
29. A method for treating or preventing a disease based on JNK 3
action against which inhibition of a c-Jun amino-terminal kinase 3
(JNK 3) is effective for prevention or treatment, immunological
diseases, inflammatory diseases, metabolic disorders and/or
neurodegenerative diseases, which comprises: administering_a
pharmacologically effective amount of the compound according to
claim 1, 7, 16 or 21, a salt thereof or a hydrate thereof to a
patient in need thereof.
30. A method for treating or preventing a disease based on JNK
action against which inhibition of a c-Jun amino-terminal kinase
(JNK) is effective for prevention or treatment, immunological
diseases, inflammatory diseases, metabolic disorders or
neurodegenerative diseases, which comprises: administering a
pharmacologically effective amount of the compound according to
claim 1, 7, 16 or 21, a salt thereof or a hydrate thereof to a
patient in need thereof.
31. The method according to claim 30, wherein the disease is
Alzheimer's disease, Parkinson's disease, Huntington's chorea,
amyotrophic lateral sclerosis, multiple sclerosis or
spinocerebellar degeneration.
Description
[0001] This application is a Continuation of co-pending application
Ser. No. 10/447,948 filed on May 30, 2003, and for which priority
is claimed under 35 U.S.C. .sctn. 120; and this application claims
priority of Application No. 2002-158467 filed in Japan on May 31,
2002 and Application No. 2003-000153 filed in Japan on Jan. 6, 2003
under 35 U.S.C. .sctn. 119; the entire contents of all are hereby
incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a novel pyrazole compound
having an excellent inhibitory effect on protein kinases, in
particular, JNK c-Jun amino-terminal kinase.
PRIOR ART
[0003] Mitogen-activated protein kinase (hereinafter, referred to
as "MAPK") signaling cascades are generally found in from yeast to
human, and play a very important role in intracellular signal
transduction pathways. As MAPK-related kinases in mammalian cells,
in particular, three kinds of kinases are well known: extracellular
signal-regulation kinase (ERK), p38 and c-Jun amino-terminal kinase
(JNK; or also called as SAPK (=stress-activated protein kinase)).
SAPK is a homologue of JNK found in rat, and its isoform group is
known to have amino acid sequences of 90% or more homologous to the
corresponding isoform group of JNK (Nature, 369, 156, 1994). In
recent years, a number of activators involved with NAPK have been
identified, which have demonstrated that pathways respectively
activating ERK, p38 and JNK have different roles in terms of
function. In particular, the JNK pathway is considered to be one of
valuable intracellular signaling pathways from medical and
pharmaceutical viewpoints because of the following reasons. JNK is
activated, for example, by cytokines such as tumor necrosis factor
.alpha. (TNF-.alpha.) or interleukin-1 (IL-1), or cell stresses
such as heat shock, ultraviolet ray (UV), X-ray and the like, and
is considered to be an important signal transduction pathway
inducing not only cellular proliferation and differentiation but
also apoptosis (cell death) [Science, 270, 1326, 1995.] JNK was
initially discovered as a protein which phosphorylates Ser63 and
Ser73 located at N-terminal of c-Jun (Nature, 353, 670, 1991),
however, at present, JNK is known to phosphorylate a number of
transcription factors such as ATF-2 and Elk-1 and regulate their
activities (EMBO J., 15, 2760, 1996.) There are three kinds of
JNKs: JNK1, JNK2 and JNK3. While JNK1 and JNK2 are expressed in
most of tissues, JNK3 is expressed at high level especially in
brain (Neuron, 14, 67, 1995; Neuron, 22, 667, 1999.) Analysis of
JNK1 or JNK2 knockout mouse demonstrated that these JNKs have an
important role in differentiation and activation of T cell (J. Exp.
Med., 193, 317, 2001). Also, analysis of JNK1 knockout mouse
suggested the importance of JNK1 in onset of metabolic disorders
such as insulin resistance caused by obesity and type II diabetes
(Nature, 420, 333, 2002). On the other hand, other report described
that JNK3 knockout mouse showed resistance against seizure induced
by kainic acid which is an excitatory amino acid receptor agonist,
and that the apoptosis which would be observed subsequently in
hippocampal neurons in normal mouse was not observed while in JNK3
knockout mouse (Nature 389, 865, 1997.) Since previous research
using cultured neurons has proved the necessity of phosphorylation
of c-Jun for induction of apoptosis by removal of neurotrophic
factor (Neuron 14, 927, 1995; J. Neurosci. 18, 751, 1998), JNK
seems to play an important role in inducing apoptosis of neurons.
As for neurodegenerative diseases such as Alzheimer disease and
Parkinson disease, importance of apoptosis in the process of
neurodegeneration has been noticed (Nature 407, 802, 2000), and
investigation using model animals of these diseases (Proc Natl Acad
Sci USA, 98, 10433, 2001; J. Neurosci. 22, 3376, 2002) and analysis
using postmortem brain of patient (Neuron, 14, 67, 1995; J.
Neurochem., 76, 435, 2001) have accumulated the results suggesting
the possibility of involvement of JNK in neurodegeneration in
Alzheimer's disease and Parkinson's disease.
[0004] The following are known reports with regard to substances of
low molecular weight having JNK inhibitory effect.
(1) Compounds having anti-inflammatory effect represented by the
formula (I.sup.1) and the compound represented by the formula
(I.sup.1a) as a concrete embodiment (WO00/00491).
##STR00002##
(2) 4-Allyloxyindole compounds represented by the formula (I.sup.2)
and the compound represented by the formula (I.sup.2a) as a
concrete embodiment (WO00/35909).
##STR00003##
(3) 4,5-Pyrazinoxyindole compounds represented by the formula
(I.sup.3) and the compound represented by the formula (I.sup.3a) as
a concrete embodiment (WO00/35921).
##STR00004##
(4) Compounds represented by the formula (I.sup.4) and the compound
represented by the formula (I.sup.4a) as a concrete embodiment
(WO00/64872).
##STR00005##
(5) Oxyindole derivatives represented by the formula (I.sup.5) and
the compound represented by the formula (I.sup.5a) as a concrete
embodiment (WO00/35906).
##STR00006##
(6) Compounds represented by the formula (I.sup.6) having JNK
inhibitory effect and the compound represented by the formula
(I.sup.6a) as a concrete embodiment (WO00/75118).
##STR00007##
(7) Compounds represented by the formula (I.sup.7) having a JNK
inhibitory effect and the compound represented by the formula
(I.sup.7a) as a concrete embodiment (WO01/12609).
##STR00008##
(8) Compounds represented by the formula (I.sup.8) having JNK
inhibitory effect and the compound represented by the formula
(I.sup.8a) as a concrete embodiment (WO01/12621).
##STR00009##
(9) Sulfonamide derivatives represented by the formula (I.sup.9)
and the compound represented by the formulae (I.sup.9a) (I.sup.9b)
(I.sup.9c) as concrete embodiments (WO01/23378, WO01/23379,
WO01/23382).
##STR00010##
(10) Compounds represented by the formula (I.sup.10) having JNK
inhibitory effect and the compound represented by the formula
(I.sup.10a) as a concrete embodiment (EP01/110957).
##STR00011##
(11) Compounds represented by the formula (I.sup.11) having JNK
inhibitory effect and the compound represented by the formula
(I.sup.11a) as a concrete embodiment (WO01/91749).
##STR00012##
[0005] On the other hand, compounds having pyrazole skeleton are
found only in the report below.
(12) Compounds represented by the formula (I.sup.12) having JNK
inhibitory effect and the compound represented by the formula
(I.sup.12a) as a concrete embodiment (WO02/10137).
##STR00013##
[0006] As described above, JNK pathway is noticed as one of
important mechanisms involved in activation of various cells and
regulation of immuno cells by cytokines, or in apoptosis of neurons
induced by various kinds of stress signals. Therefore, compounds
having inhibitory effect on JNK pathway, especially on JNK protein
kinase can be expected to be useful as therapeutic drugs for a
variety of immunological diseases, inflammatory diseases, metabolic
diseases, neurodegenerative diseases. On the other hand, ERK which
belongs to MAPK to which JNK also belongs is known to play an
important role in signal transduction of growth factors and
neurotrophic factors, and especially in neurons, ERK is deeply
concerned with survival and maintenance of neurons accomplished by
neurotrophic factors such as Brain-derived neurotrophic factor
(BDNF) and the like (Science, 286, 1358, 1999; J. Neurosci., 20,
5775, 2000.) This suggests the possibility of the ERK inhibitory
effect to cancel out the useful effect which the compounds having
inhibitory effect on JNK protein kinase are liable to exhibit,
e.g., protective effect on neurons, so that a need for discovery of
JNK-selective compounds not having ERK inhibitory effect exists.
However, such excellent compounds having selective inhibitory
effect on JNK protein kinase, while satisfying the points of
pharmacological effect, dosage, safety and the like required for
pharmaceutics have not been found yet.
DISCLOSURE OF THE INVENTION
[0007] As a result of strenuous effort and vigorous research in
consideration of the above circumstances, inventors of the present
invention finally found a novel pyrazole compound having a JNK
inhibitory effect.
[0008] That is, the present invention relates to:
1) a compound represented by the formula (I), a salt thereof or a
hydrate of them:
##STR00014##
(wherein, R.sup.1 designates a group represented by the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently designate
a hydrogen atom, halogen atom, hydroxyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.2-6 alkenyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.2-6 alkenyloxy group, an
optionally substituted C.sub.1-6 alkylthio group, an optionally
substituted C.sub.2-6 alkenylthio group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; Ar designates an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; and h, j and k each independently
designate 0 or 1);
[0009] Cy designates a 5- to 6-membered heteroaryl group;
[0010] V designates a group represented by the formula -L-X--Y
(wherein, L designates a single bond, an optionally substituted
C.sub.1-6 alkylene group, an optionally substituted C.sub.2-6
alkenylene group or an optionally substituted C.sub.2-6 alkynylene
group;
X designates a single bond, or a group represented by --NR.sup.7--,
--O--, --CO--, --S--, --SO--, --SO.sub.2--, --CO--NR.sup.8-Z-,
--C(O)O--, --NR.sup.8--CO-Z-, --NR.sup.8--C(O)O--, --NR.sup.8--S--,
--NR.sup.8--SO--, --NR.sup.8--SO.sub.2-Z-,
--NR.sup.9--CO--NR.sup.10--, --NR.sup.9--CS--NR.sup.10--,
--S(O).sub.m--NR.sup.11-Z-, --C(.dbd.NR.sup.12)--NR.sup.13--,
--OC(O)--, --OC(O)--NR.sup.14-- or
--CH.sub.2--NR.sup.8--COR.sup.7-- (wherein R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 each
independently designate a hydrogen atom, halogen atom, hydroxyl
group, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted C.sub.2-6 alkenyl group, an optionally
substituted C.sub.2-6 alkynyl group, an optionally substituted
C.sub.1-6 alkoxy group, an optionally substituted C.sub.2-6
alkenyloxy group, an optionally substituted C.sub.1-6 alkylthio
group, an optionally substituted C.sub.2-6 alkenylthio group, an
optionally substituted C.sub.3-8 cycloalkyl group, an optionally
substituted C.sub.3-8 cycloalkenyl group, an optionally substituted
4- to 14-membered non-heteroaryl group, an optionally substituted
C.sub.6-14 aryl group or an optionally substituted 5- to
14-membered heteroaryl group, Z designates a single bond or an
optionally substituted C.sub.1-6 alkylene group, and m designates
0, 1 or 2); Y designates any one group selected from the group
consisting of a hydrogen atom, halogen atom, nitro group, hydroxyl
group, cyano group, carboxyl group or an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl
group, an optionally substituted C.sub.2-6 alkynyl group, an
optionally substituted C.sub.1-6 alkoxy group, an optionally
substituted C.sub.3-8 cycloalkyl group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted-4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group, an optionally substituted 5- to
14-membered heteroaryl group, an optionally substituted amino group
and a group represented by the formula --W--R.sup.15 (wherein W
designates CO or SO.sub.2; R.sup.15 designates an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted amino
group, an optionally substituted C.sub.6-14 aryl group or an
optionally substituted 5- to 14-membered heteroaryl group));
and
[0011] n designates 0, 1, 2, 3 or 4, and when n is 2 or more,
plural Vs each independently designate -L-X--Y as defined
above);
2) the compound according to 1), a salt thereof or a hydrate of
them, wherein Cy forms a 5-membered heteroaryl group; 3) the
compound according to 1), a salt thereof or a hydrate of them,
wherein Cy forms a thiophene ring; 4) the compound according to 1),
a salt thereof or a hydrate of them, wherein in the formula (I),
the structure of moiety consisting of Cy and the pyrazole ring
adjoining to the Cy is 1H-thieno[2,3-c]pyrazole; 5) a compound
represented by the formula (II), a salt thereof or a hydrate of
them:
##STR00015##
wherein,
[0012] Q.sup.1 to Q.sup.4 each independently designate
--NV.sup.1--, --CV.sup.2.dbd., --N.dbd., --N(.fwdarw.O).dbd. or
--CO--, and at least one of Q.sup.1 to Q.sup.4 designates
--NV.sup.1-- or --N.dbd., --N(.fwdarw.O).dbd.; and
[0013] R.sup.1 designates a group represented by the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently designate
a hydrogen atom, halogen atom, hydroxyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.2-6 alkenyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.2-6 alkenyloxy group, an
optionally substituted C.sub.1-6 alkylthio group, an optionally
substituted C.sub.2-6 alkenylthio group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; Ar designates an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; and h, j and k each independently
designate 0 or 1),
[0014] V.sup.1 and V.sup.2 each independently designate a group
represented by the formula -L-X--Y (wherein, L designates a single
bond, an optionally substituted C.sub.1-6 alkylene group, an
optionally substituted C.sub.2-6 alkenylene group or an optionally
substituted C.sub.2-6 alkynylene group;
X designates a single bond, or a group represented by --NR.sup.7--,
--O--, --CO--, --S--, --SO--, --SO.sub.2--, --CO--NR.sup.8-Z-,
--C(O)O--, --NR.sup.8--CO-Z-, --NR.sup.8--C(O)O--, --NR.sup.8--S--,
--NR.sup.8--SO--, --NR.sup.8--SO.sub.2-Z-,
--NR.sup.9--CO--NR.sup.10--, --NR.sup.9--CS--NR.sup.10--,
--S(O).sub.m--NR.sup.11-Z-, --C(.dbd.NR.sup.12)--NR.sup.13--,
--OC(O)--NR.sup.14-- or --CH.sub.2--NR.sup.8--COR.sup.7-- (wherein
R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13
and R.sup.14 each independently designate a hydrogen atom, halogen
atom, hydroxyl group, an optionally substituted C.sub.1-6 alkyl
group, an optionally substituted C.sub.2-6 alkenyl group, an
optionally substituted C.sub.2-6 alkynyl group, an optionally
substituted C.sub.1-6 alkoxy group, an optionally substituted
C.sub.2-6 alkenyloxy group, an optionally substituted C.sub.1-6
alkylthio group, an optionally substituted C.sub.2-6 alkenylthio
group, an optionally substituted C.sub.3-8 cycloalkyl group, an
optionally substituted C.sub.3-8 cycloalkenyl group, an optionally
substituted 4- to 14-membered non-aromatic heterocyclic group, an
optionally substituted C.sub.6-14 aryl group or an optionally
substituted 5- to 14-membered heteroaryl group, Z designates a
single bond or an optionally substituted C.sub.1-6 alkylene group,
and m designates 0, 1 or 2); and Y designates any one group
selected from the group consisting of a hydrogen atom, halogen
atom, nitro group, hydroxyl group, cyano group, carboxyl group or
an optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.2-6 alkenyl group, an optionally substituted
C.sub.2-6 alkynyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.3-8 cycloalkyl group, an
optionally substituted C.sub.3-8 cycloalkenyl group, an optionally
substituted 4- to 14-membered non-aromatic heterocyclic group, an
optionally substituted C.sub.6-14 aryl group, an optionally
substituted 5- to 14-membered heteroaryl group, an optionally
substituted amino group and a group represented by the formula
--W--R.sup.15 (wherein W designates CO or SO.sub.2; and R.sup.15
designates an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted amino group, an optionally substituted
C.sub.6-14 aryl group or an optionally substituted 5- to
14-membered heteroaryl group); 6) the compound according to 5), a
salt thereof or a hydrate of them, wherein among Q.sup.1 to
Q.sup.4, either one is --N.dbd., and the others are
--CV.sup.2.dbd.; 7) the compound according to 5), a salt thereof or
a hydrate of them, wherein among Q.sup.1 to Q.sup.4, either one of
Q.sup.1, Q.sup.3 and Q.sup.4 is --N.dbd., and the others are
--CV.sup.2.dbd.; 8) the compound according to 6), a salt thereof or
a hydrate of them, wherein Q.sup.1 is --N.dbd.; 9) the compound
according to 6), a salt thereof or a hydrate of them, wherein
Q.sup.2 is --N.dbd.; 10) the compound according to 6), a salt
thereof or a hydrate of them, wherein Q.sup.3 is --N.dbd.; 11) the
compound according to 6), a salt thereof or a hydrate of them,
wherein Q.sup.4 is --N.dbd.; 12) the compound according to 5), a
salt thereof or a hydrate of them, wherein among Q.sup.1 to
Q.sup.4, either two are --N.dbd., and the others are
--CV.sup.2.dbd.; 13) the compound according to 12), a salt thereof
or a hydrate of them, wherein among Q.sup.1 to Q.sup.4, either two
of Q.sup.1, Q.sup.3 and Q.sup.4 are --N.dbd., and the others are
--CV.sup.2.dbd.; 14) the compound according to any one of 5) to
13), a salt thereof or a hydrate of them, wherein when either of
Q.sup.1, Q.sup.3 and Q.sup.4 is CV.sup.2.dbd., the --CV.sup.2.dbd.
in Q.sup.1, Q.sup.3 or Q.sup.4 is --CH.dbd.; 15) the compound
according to 5), a salt thereof or a hydrate of them, wherein among
Q.sup.1 to Q.sup.4, either three are --N.dbd., and the other is
--CV.sup.2.dbd.; 16) the compound according to 15), a salt thereof
or a hydrate of them, wherein Q.sup.1, Q.sup.3 and Q.sup.4 are
--N.dbd.; 17) the compound according to 5), a salt thereof or a
hydrate of them, wherein among Q.sup.1 to Q.sup.4, at least one is
--CO--; 18) the compound according to 5), a slat thereof or a
hydrate of them, wherein Q.sup.1 is --CO--, Q.sup.2 is
--NV.sup.1--, and Q.sup.3 and Q.sup.4 are --CV.sup.2.dbd.; 19) the
compound according to 5), a slat thereof or a hydrate of them,
wherein Q.sup.3 is --CO--, Q.sup.2 is --NV.sup.1--, and Q.sup.1 and
Q.sup.4 are --CV.sup.2.dbd.; 20) a compound represented by the
formula (III), a salt thereof or a hydrate of them:
##STR00016##
wherein
[0015] R.sup.1 designates a group represented by the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently designate
a hydrogen atom, halogen atom, hydroxyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.2-6 alkenyl group, an optionally substituted C.sub.1-6 alkoxy
group, an optionally substituted C.sub.2-6 alkenyloxy group, an
optionally substituted C.sub.1-6 alkylthio group, an optionally
substituted C.sub.2-6 alkenylthio group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; Ar designates an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group; and h, j and k each independently
designate 0 or 1, provided that when h and j are 0, k is 1);
[0016] R.sup.d, R.sup.e and R.sup.f each independently designate a
hydrogen atom, halogen atom, hydroxyl group, cyano group, nitro
group, carboxyl group, an optionally substituted C.sub.1-6 alkyl
group, an optionally substituted C.sub.1-6 alkoxy group, an
optionally substituted C.sub.2-7 acyl group, --CONR.sup.2aR.sup.2b,
--NR.sup.2bCO--R.sup.2a or --NR.sup.2aR.sup.2b (wherein R.sup.2a
and R.sup.2b each independently designate a hydrogen atom or an
optionally substituted C.sub.1-6 alkyl group);
[0017] L designates a single bond, an optionally substituted
C.sub.1-6 alkylene group, an optionally substituted C.sub.2-6
alkenylene group or an optionally substituted C.sub.2-6 alkynylene
group;
[0018] X designates a single bond, or a group represented by
--NR.sup.7--, --O--, --CO--, --S--, --SO--, --SO.sub.2--,
--CO--NR.sup.8-Z-, --C(O)O--, --NR.sup.8--CO-Z-,
--NR.sup.8--C(O)O--, --NR.sup.8--S--, --NR.sup.8--SO--,
--NR.sup.8--SO.sub.2-Z-, --NR.sup.9--CO--NR.sup.10--,
--NR.sup.9--CS--NR.sup.10--, --S(O).sub.m--NR.sup.11-Z-,
--C(.dbd.NR.sup.12)--NR.sup.13--, --OC(O)--, --OC(O)--NR.sup.14--
or --CH.sub.2--NR.sup.8--COR.sup.7-- (wherein R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 each
independently designate a hydrogen atom, halogen atom, hydroxyl
group, an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted C.sub.2-6 alkenyl group, an optionally
substituted C.sub.2-6 alkynyl group, an optionally substituted
C.sub.1-6 alkoxy group, an optionally substituted C.sub.2-6
alkenyloxy group, an optionally substituted C.sub.1-6 alkylthio
group, an optionally substituted C.sub.2-6 alkenylthio group, an
optionally substituted C.sub.3-8 cycloalkyl group, an optionally
substituted C.sub.3-8 cycloalkenyl group, an optionally substituted
4- to 14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group,
Z designates a single bond or an optionally substituted C.sub.1-6
alkylene group, and m designates 0, 1 or 2); and
[0019] Y designates any one group selected from the group
consisting of a hydrogen atom, halogen atom, nitro group, hydroxyl
group, cyano group, carboxyl group or an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.2-6 alkenyl
group, an optionally substituted C.sub.2-6 alkynyl group, an
optionally substituted C.sub.1-6 alkoxy group, an optionally
substituted C.sub.3-8 cycloalkyl group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group, an optionally substituted 5- to
14-membered heteroaryl group, an optionally substituted amino group
and a group represented by the formula --W--R.sup.15 (wherein W
designates CO or SO.sub.2; and R.sup.15 designates an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted amino
group, an optionally substituted C.sub.6-14 aryl group or an
optionally substituted 5- to 14-membered heteroaryl group);
21) the compound according to 20), a salt thereof or a hydrate of
them, wherein at least one of R.sup.d, R.sup.e and R.sup.f is not a
hydrogen atom; 22) the compound according to 20), a salt thereof or
a hydrate of them, wherein either one of R.sup.d, R.sup.e and
R.sup.f is a halogen atom or an optionally substituted C.sub.1-6
alkoxy group; 23) the compound according to anyone of 20) to 22), a
salt thereof or a hydrate of them, wherein at least one of R.sup.b
and R.sup.c is not a hydrogen atom, and L is a single bond, an
optionally substituted C.sub.2-6 alkenylene group or an optionally
substituted C.sub.2-6 alkynylene group, provided that, when L is a
single bond, the case where X is a single bond, and Y is an
optionally substituted C.sub.1-6 alkyl group, an optionally
substituted C.sub.3-8 cycloalkyl group, an optionally substituted
C.sub.3-8 cycloalkenyl group, an optionally substituted 4- to
14-membered non-aromatic heterocyclic group, an optionally
substituted C.sub.6-14 aryl group or an optionally substituted 5-
to 14-membered heteroaryl group is excluded; 24) the compound
according to any one of 1) to 22), a salt thereof or a hydrate of
them, wherein at least either h or j is 1; 25) the compound
according to any one of 1) to 22), a salt thereof or a hydrate of
them, wherein h and j are 0, and k is 1; 26) the compound according
to any one of 1) to 19), a salt thereof or a hydrate of them,
wherein h, j and k are 0; 27) the compound according to any one of
24) and 25), a salt thereof or a hydrate of them, wherein R.sup.b
and/or R.sup.c are(is) a hydrogen atom; 28) the compound according
to 27), a salt thereof or a hydrate of them, wherein R.sup.b and
R.sup.c are a hydrogen atom; 29) the compound according to any one
of 1) to 28), a salt thereof or a hydrate of them, wherein Ar is a
C.sub.6-14 aryl group or a 5- to 14-membered heteroaryl group, and
Ar is a group which may be substituted with 1 to 3 group(s)
selected from the following substituent group (a): <Substituent
group a> the group consisting of (1) each optionally substituted
(a) C.sub.1-6 alkyl groups, (b) C.sub.1-6 alkoxy groups, (c)
C.sub.1-7 acyl groups, (d) amide group, (e) amino group, (f)
C.sub.3-8 cycloalkyl groups, (2) halogen atom, (3) hydroxyl group,
(4) nitro group, (5) cyano group, and (6) carboxyl group; 30) the
compound according to 29), a salt thereof or a hydrate of them,
wherein Ar is a phenyl group, naphthyl group or a 5- to 10-membered
heteroaryl group, and Ar is a group optionally substituted with 1
to 3 group(s) selected from Substituent group a described in 29);
31) the compound according to 29), a salt thereof or a hydrate of
them, wherein Ar is a phenyl group, 2-naphthyl group, pyridyl
group, 2-thienyl group, 2-furyl group, 2-benzofuryl group,
2-quinolyl group or 2-benzothienyl group, and Ar is a group
optionally substituted with 1 to 3 group(s) selected from
Substituent group a described in 29); 32) the compound according to
29), a salt thereof or a hydrate of them, wherein Ar is a phenyl
group, pyridyl group, 2-thienyl group or 2-furyl group, and Ar is a
group optionally substituted with 1 to 3 group(s) selected from
Substituent group a described in 29); 33) the compound according to
29), a salt thereof or a hydrate of them, wherein Ar is a
2-naphthyl group, 2-benzofuryl group, 2-quinolyl group or
2-benzothienyl group, and Ar is a group optionally substituted with
1 to 3 group(s) selected from Substituent group a described in 29);
34) the compound according to anyone of 29) to 33), a salt thereof
or a hydrate of them, wherein Substituent group a is the group
consisting of (1) C.sub.1-6 alkyl groups each optionally
substituted with 1 to 3 group(s) selected from the group consisting
of a halogen atom, hydroxyl group and cyano group, (2) C.sub.1-6
alkoxy groups optionally substituted with 1 to 3 group(s) selected
from the group consisting of a halogen atom, hydroxyl group and
cyano group, (3) halogen atom, (4) hydroxyl group, (5) cyano group,
and (6) C.sub.1-7 acyl groups; 35) the compound according to any
one of 29) to 33), a salt thereof or a hydrate of them, wherein
Substituent group a is a halogen atom; 36) the compound according
to any one of 1) to 35), a salt thereof or a hydrate of them,
wherein L is a single bond or methylene group; 37) the compound
according to 36), a salt thereof or a hydrate of them, wherein L is
a single bond; 38) the compound according to any one of 1) to 37),
a salt thereof or a hydrate of them, wherein X is a group
represented by --CO--NR.sup.8-Z-, --NR.sup.8--CO-Z- or
--NR.sup.8--SO.sub.2-Z- (wherein R.sup.8 and Z have the same
meanings as defined for R.sup.8 and Z in 1)); 39) the compound
according to 38), a salt thereof or a hydrate of them, wherein
R.sup.a is a hydrogen atom; 40) the compound according to 38), a
salt thereof or a hydrate of them, wherein X is a group represented
by --CO--NH--(CH.sub.2).sub.t-- (wherein t designates 0 or 1); 41)
the compound according to 38), a salt thereof or a hydrate of them,
wherein X is a group represented by --NH--CO--(CH.sub.2).sub.t--
(wherein t designates 0 or 1); 42) the compound according to any
one of 1) to 37), a salt thereof or a hydrate of them, wherein X is
a single bond; 43) the compound according to any one of 1) to 42),
a salt thereof or a hydrate of them, wherein Y is a C.sub.1-6 alkyl
group, a C.sub.6-14 aryl group, a C.sub.1-6 alkoxy group, a
C.sub.3-8 cycloalkyl group, a 4- to 14-membered non-aromatic
heterocyclic group or a 5- to 14-membered heteroaryl group, and Y
is a group optionally substituted with 1 to 3 group(s) selected
from the following Substituent group a2: <Substituent group
a2> the group consisting of (1) each optionally substituted (a)
C.sub.1-6 alkyl groups, (b) C.sub.2-6 alkenyl groups, (c) C.sub.2-6
alkynyl groups, (d) C.sub.1-6 alkoxy groups, (e) C.sub.2-7 acyl
groups, (f) amide group, (g) amino group, (h) C.sub.3-8 cycloalkyl
groups, (i) C.sub.3-8 cycloalkenyl groups, (i) C.sub.6-14 aryl
groups, (k) 5- to 14-membered heteroaryl groups, (1) C.sub.6-14
aryloxy groups, and (m) 4- to 14-membered non-aromatic heterocyclic
groups, (2) halogen atom, (3) hydroxyl group, (4) nitro group, (5)
cyano group, and (6) carboxyl group; 44) the compound according to
43), a salt thereof or a hydrate of them, wherein Y is a C.sub.3-8
cycloalkyl group, phenyl group, a 5- or 6-membered non-aromatic
heterocyclic group, or a 5- or 6-membered heteroaryl group, and Y
is a group optionally substituted with 1 to 3 group(s) selected
from Substituent group a2 described in 43); 45) the compound
according to any one of 1) to 42), a salt thereof or a hydrate of
them, wherein Y is a furyl group, thienyl group, pyrrolyl group,
phenyl group, pyridyl group, C.sub.3-8 cycloalkyl group,
tetrahydrofuran-yl group, tetrahydrothiophene-yl group,
pyrrolidinyl group, tetrahydrofuran-2-on-yl group,
pyrrolidine-2-on-yl group or a group represented by the
formula:
##STR00017##
(wherein Y.sup.2a designates a group represented by --CONH.sub.2 or
--CH.sub.2OH, Y.sup.2b and Y.sup.2c each independently designate a
hydrogen atom, an optionally substituted phenyl group or an
optionally substituted C.sub.1-6 alkyl group), and Y is a group
optionally substituted with 1 to 3 group(s) selected from
Substituent group a2 described in 43); 46) the compound according
to 43), a salt thereof or a hydrate of them, wherein Y is a furyl
group or thienyl group, and Y is a group optionally substituted
with 1 to 3 group(s) selected from Substituent group a2 described
in 43); 47) the compound according to any one of 43) to 46), a salt
thereof or a hydrate of them, wherein Substituent group a2 is the
group consisting of (1) (a) C.sub.1-6 alkyl groups, (b) C.sub.1-6
alkoxy groups, (c) C.sub.1-7 acyl groups, (d) amide group, (e)
amino group, (f) C.sub.3-8 cycloalkyl groups, each of which may be
substituted with 1 to 3 group(s) selected from the following
Substituent group b2, (2) halogen atom, (3) hydroxyl group, (4)
nitro group, (5) cyano group, and (6) carboxyl group, and
<Substituent group b2> is the group consisting of C.sub.1-6
alkyl groups, halogen atom, hydroxyl group, nitro group, cyano
group and carboxyl group; 48) the compound according to any one of
43) to 46), a salt thereof or a hydrate of them, wherein
Substituent group a2 is the group consisting of (1) C.sub.1-6
alkoxy groups, (2) halogen atoms and (3) cyano groups; 49) the
compound according to any one of 20) to 35), a salt thereof or a
hydrate of them, wherein L and x are a single bond, Y is a 5- to
6-membered heteroaryl group, and Y is a group optionally
substituted with 1 to 3 group(s) selected from Substituent group a2
described in 43); 50) a pharmaceutical composition comprising the
compound according to any one of 1) to 49), a salt thereof or a
hydrate of them, and a pharmaceutically acceptable carrier; 51) a
c-Jun amino-terminal kinase (JNKs) inhibitor comprising the
compound according to any one of 1) to 49), a salt thereof or a
hydrate of them; 52) a c-Jun amino-terminal kinase 1 (JNK1), c-Jun
amino-terminal kinase 2 (JNK 2) and/or c-Jun amino-terminal kinase
3 (JNK 3) inhibitor, comprising the compound according to any one
of 1) to 49), a salt thereof or a hydrate of them; 53) an agent for
treating or preventing immunological diseases, inflammatory
diseases or metabolic disorders, which comprises the compound
according to any one of 1) to 49), a salt thereof or a hydrate of
them; 54) an agent for treating or preventing neurodegenerative
diseases, which comprises the compound according to any one of 1)
to 49), a salt thereof or a hydrate of them; 55) an agent for
treating or preventing Alzheimer's disease, Parkinson's disease,
Huntington's chorea, amyotrophic lateral sclerosis, multiple
sclerosis or spinocerebellar degeneration, which comprises the
compound according to any one of 1) to 49), a salt thereof or a
hydrate of them; 56) use of the compound according to any one of 1)
to 49), a salt thereof or a hydrate of them for prevention or
treatment of immunological diseases, inflammatory diseases,
metabolic disorders and/or neurodegenerative diseases; 57) use of
the compound according to any one of 1) to 49), a salt thereof or a
hydrate of them, for producing an agent for treating or preventing
a disease based on JNK action against which inhibition of a c-Jun
amino-terminal kinase (JNK) is effective for prevention or
treatment, immunological diseases, inflammatory diseases, metabolic
disorders or neurodegenerative diseases; 58) the use according to
57), wherein the disease is Alzheimer's disease, Parkinson's
disease, Huntington's chorea, amyotrophic lateral sclerosis,
multiple sclerosis or spinocerebellar degeneration; 59) a method
for treating or preventing a disease based on JNK 3 action against
which inhibition of a c-Jun amino-terminal kinase 3 (JNK 3) is
effective for prevention or treatment, immunological diseases,
inflammatory diseases, metabolic disorders and/or neurodegenerative
diseases, which comprises administering a pharmacologically
effective amount of the compound according to any one of 1) to 49),
a salt thereof or a hydrate of them to a patient; 60) a method for
treating or preventing a disease based on JNK action against which
inhibition of a c-Jun amino-terminal kinase (JNK) is effective for
prevention or treatment, immunological diseases, inflammatory
diseases, metabolic disorders or neurodegenerative diseases, which
comprises administering a pharmacologically effective amount of the
compound according to any one of 1) to 49), a salt thereof or a
hydrate of them to a patient; and 61) the method according to 60),
wherein the disease is Alzheimer's disease, Parkinson's disease,
Huntington's chorea, amyotrophic lateral sclerosis, multiple
sclerosis or spinocerebellar degeneration.
[0020] In the following, definition for symbols, terms and the like
used in the present specification will be provided for detailed
explanation of the present invention.
[0021] The term "and/or" used herein intends to embrace both cases
of "and" and "or".
[0022] The term "JNK" used herein refers to enzymes that
phosphorylates N-terminal region of c-Jun protein, and examples of
which include JNK1, JNK2, JNK3 and the like. There are three kinds
of JNKs: JNK1, JNK2 and JNK3. While JNK1 and JNK2 are expressed in
most of tissues, JNK3 is expressed at high level especially in
brain (Neuron, 14, 67, 1995; Neuron, 22, 667, 1999.)
[0023] The term "neurodegenerative diseases" used herein
comprehends all diseases that are generally categorized in
neurodegenerative diseases in the medical field, and concrete
examples of which include, but not limited to, chronic
neurodegenerative diseases such as subarachnoid hemorrhage,
cerebrovascular disorder acute stage, head injury, spinal cord
injury, neuropathy due to low oxygen and low blood sugar,
Alzheimer's disease, Parkinson's disease, Huntington's chorea,
amyotrophic lateral sclerosis, epilepsy, hepatic encephalopathy,
peripheral neuropathy, Parkinson syndrome, exanthematous paralysis,
pain, neuralgia, schizophrenia, depression, anxiety, drug
dependence, nausea, emesis, urination disorder, visual disorder due
to glaucoma, hearing disorder due to antibiotics, alimentary
intoxication, multiple sclerosis or spinocerebellar degeneration,
and acute neurodegenerative diseases.
[0024] The term "immunological diseases" or "inflammatory diseases"
used herein comprehends all diseases that are generally categorized
in immunological diseases in the medical field, and concrete
examples of which include, but not limited to, sepsis, chronic
articular rheumatism, osteoarthritis, gout, psoriasis, psoriatic
arthropathy, bronchitis, chronic obstructive pulmonary disease,
cyst nature fibroid lung, insulin dependent type I diabetes
mellitus, autoimmune thyroiditis, Crohn's disease, colitis
ulcerosa, atopic dermatitis, asthma, allergic rhinitis, hepatitis,
systemic lupus erythematodes, acute and chronic allograft rejection
after organ transplantation, graft-versus-host disease, eczema,
hives, myasthenia gravis, acquired immunodeficiency syndromes
idiopathic thrombocytopenic purpura, glomerulonephritis and the
like.
[0025] The term "metabolic disorders" used herein refers to
diseases caused by metabolic disorder of sugar and lipid, and
examples of which include diabetes mellitus, diabetic complication,
hypercholesterolemia, hyperlipemia, obesity, syndrome X and the
like.
[0026] In the present description, a particular structural formula
may represent certain isomers, and the present invention
comprehends all isomers and mixture of isomers such as geometrical
isomers, optical isomers based on an asymmetric carbon,
stereoisomers and tautomers occurring due to the particular
structure of the compound, but they are not conveniently limited by
the description of the above formula, and may be either one isomer
or mixture thereof. Therefore, optical isomers and racemic bodies
may exist because of an asymmetric carbon in a molecule, however
the present invention includes both cases without particularly
limited. There is also the case that crystal polymorphs occur, and
such crystal polymorphs may exist singly or in mixture without any
limitation. The compound (I) or compound (III) or its salt
according to the present invention may be anhydride or hydrate,
both of which are involved in the scope of claims of the present
specification. Metabolites occurring by biodegradation of the
compound (I) according to the present invention, and prodrugs of
the compound (I) according to the present invention and its salt
are also involved in the scope of claims of the present
specification.
[0027] The "halogen atom" used herein include, for example, a
fluorine atom, chlorine atom, bromine atom iodine atom and the like
atoms, fluorine atom and chlorine atom are preferred, and fluorine
atom is more preferred.
[0028] The term "C.sub.1-6 alkyl group" used herein refers to
linear or branched alkyl groups having 1 to 6 carbon atom(s), and
concrete examples of which include a methyl group, ethyl group,
n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,
sec-butyl group, tert-butyl group, n-pentyl group,
1,1-dimethylpropyl group, 1,2-dimethylpropyl group,
2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group,
n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl
group, 1,1,2-trimethylpropyl group, 1-propylpropyl group,
1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group,
1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl
group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl
group, 3-methylpentyl group and the like, methyl group, ethyl
group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl
group, sec-butyl group, tert-butyl group, n-pentyl group and the
like are more preferred.
[0029] The term "C.sub.2-6 alkenyl group" used herein refers to
linear or branched alkenyl groups having 2 to 6 carbons, and
concrete examples of which include a vinyl group, allyl group,
1-propenyl group, 2-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 3-methyl-1-propenyl group,
2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl
group, 2-butenyl group, 3-butenyl group, 1-pentenyl group,
1-hexenyl group, 1,3-hexadienyl group, 1,6-hexadienyl group and the
like.
[0030] The term "C.sub.2-6 alkynyl group" used herein refers to
linear or branched alkynyl groups having 2 to 6 carbons, and
concrete examples of which include an ethynyl group, 1-propynyl
group, 2-propynyl group, 1-butynyl group, 2-butynyl group,
3-butynyl group, 3-methyl-1-propynyl group, 1-ethynyl-2 propynyl
group, 2-methyl-3-propynyl group, 1-pentynyl group, 1-hexynyl
group, 1,3-hexane-diynyl group, 1,6-hexane-diynyl group, and the
like.
[0031] The term "C.sub.1-6 alkylene group" used herein refers to
bivalent groups derived by removing one hydrogen atom at any
position from the above defined "C.sub.1-6 alkyl group", and
concrete examples of which include a methylene group, ethylene
group, methylethylene group, propylene group, ethylethylene group,
1,1-dimethylethylene group, 1,2-dimethylethylene group,
trimethylene group, 1-methyltrimethylene group, 1-ethyltrimethylene
group, 2-methyltrimethylene group, 1,1-dimethyltrimethylene group,
tetramethylene group, pentamethylene group, hexamethylene group and
the like, with methylene group and 1,2-ethylene group being
preferred.
[0032] The term "C.sub.2-6 alkenylene group" used herein refers to
bivalent groups derived by removing one hydrogen atom from the
above defined "C.sub.2-6 alkenyl group", and concrete examples of
which include a vinylene group, propenylene group, butenylene
group, pentenylene group, hexenylene group and the like, with
vinylene group, propenylene group, butenylene group and pentenylene
group being preferred and vinylene group, propenylene group and
butenylene group more preferred, and 1,2-vinylene group and
1,3-propenylene group further preferred.
[0033] The term "C.sub.2-6 alkynylene group" used herein refers to
bivalent groups derived by removing one hydrogen atom from the
above defined "C.sub.2-6 alkynyl group", and concrete examples of
which include an ethynylene group, propynylene group, butynylene
group, pentynylene group, hexynylene group and the like, ethynylene
group, propynylene group, butynylene group and pentynylene group
are preferred, ethynylene group, propynylene group and butynylene
group are more preferred, ethynylene group and propynylene group
are still preferred, and ethynylene group is most preferred.
[0034] The term "C.sub.3-8 cycloalkyl group" used herein refers to
cyclic aliphatic hydrocarbon groups of from 3 to 8 carbons, and
concrete examples of which include a cyclopropyl group, cyclobutyl
group, cyclopentyl group, cyclohexyl group, cycloheptyl group,
cyclooctyl group and the like, and cyclopropyl group and cyclobutyl
group are preferred.
[0035] The term "C.sub.3-8 cycloalkenyl group" used herein refers
to C.sub.3-8 cycloalkenyl groups having 3 to 8 carbon atoms, and
examples of which include cyclopentene-3-yl, cyclohexene-1-yl,
cyclohexene-3-yl and the like.
[0036] The term "C.sub.1-6 alkoxy group" used herein refers to oxy
groups to which the above-defined "C.sub.1-6 alkyl group" is bound,
and examples of which include methoxy group, ethoxy group,
N-propoxy group, iso-propoxy group, sec-propoxy group, N-butoxy
group, iso-butoxy group, sec-butoxy group, tert-butoxy group,
N-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group,
N-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group,
1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group,
2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group,
1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group,
1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,
1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group,
2,3-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2-ethylbutoxy
group, 1,3-dimethylbutoxy group, 2-methylpentoxy group,
3-methylpentoxy group, hexyloxy group and the like, methoxy group,
ethoxy group, n-propoxy group and iso-propoxy group, sec-propoxy
group are preferred, and methoxy group and ethoxy group are more
preferred.
[0037] The term "C.sub.2-6 alkenyloxy group" used herein refers to
oxy groups to which the above-defined "C.sub.2-6 alkenyl group" is
bound.
[0038] The term "C.sub.2-6 alkenylthio group" used herein refers to
thio groups to which the above-defined "C.sub.2-6 alkenyl group" is
bound.
[0039] The term "C.sub.1-6 alkoxycarbonyl group" used herein refers
to carbonyl groups to which the above-defined "C.sub.1-6 alkoxy
group" is bound, and concrete examples of which include a
methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl
group, iso-propoxycarbonyl group, n-butoxycarbonyl group,
iso-butoxycarbonyl group, sec-butoxycarbonyl group,
tert-butoxycarbonyl group and the like.
[0040] The term "C.sub.2-7 acyl group" used herein refers to
carbonyl groups to which the above-defined "C.sub.1-6 alkyl group"
is bound, and examples of which include an acetyl group, propionyl
group, butylyl group, isobutylyl group, valeryl group, isovaleryl
group, pivaloyl group and the like.
[0041] Concrete examples of "C.sub.1-6 alkylcarbamoyl group" used
herein include a methylcarbamoyl group, ethylcarbamoyl group,
N-propylcarbamoyl group, iso-propylcarbamoyl group,
N-butylcarbamoyl group, iso-butylcarbamoyl group,
sec-butylcarbamoyl group, tert-butylcarbamoyl group,
N-pentylcarbamoyl group, 1,1-dimethylpropylcarbamoyl group,
1,2-dimethylpropylcarbamoyl group, 2,2-dimethylpropylcarbamoyl
group, 1-ethylpropylcarbamoyl group, 2-ethylpropylcarbamoyl group,
N-hexylcarbamoyl group, 1-methyl-2-ethylpropylcarbamoyl group,
1-ethyl-2-methylpropylcarbamoyl group,
1,1,2-trimethylpropylcarbamoyl group, 1-propylpropylcarbamoyl
group, 1-methylbutylcarbamoyl group, 2-methylbutylcarbamoyl group,
1,1-dimethylbutylcarbamoyl group, 1,2-dimethylbutylcarbamoyl group,
2,2-dimethylbutylcarbamoyl group, 1,3-dimethylbutylcarbamoyl group,
2,3-dimethylbutylcarbamoyl group, 2-ethylbutylcarbamoyl group,
2-methylpentylcarbamoyl group, 3-methylpentylcarbamoyl group and
the like.
[0042] The term "C.sub.1-6 alkylcarbonyloxy group" used herein
refers to oxy groups to which the above-defined "C.sub.2-7 acyl
group" is bound, and concrete examples of which include a
methylcarbonyloxy group, ethylcarbonyloxy group,
N-propylcarbonyloxy group, iso-propylcarbonyloxy group,
N-butylcarbonyloxy group, iso-butylcarbonyloxy group,
sec-butylcarbonyloxy group, tert-butylcarbonyloxy group,
N-pentylcarbonyloxy group, 1,1-dimethylpropylcarbonyloxy group,
1,2-dimethylpropylcarbonyloxy group, 2,2-dimethylpropylcarbonyloxy
group, 1-ethylpropylcarbonyloxy group, 2-ethylpropylcarbonyloxy
group, N-hexylcarbonyloxy group, 1-methyl-2-ethylpropylcarbonyloxy
group, 1-ethyl-2-methylpropylcarbonyloxy group,
1,1,2-trimethylpropylcarbonyloxy group, 1-propylpropylcarbonyloxy
group, 1-methylbutylcarbonyloxy group, 2-methylbutylcarbonyloxy
group, 1,1-dimethylbutylcarbonyloxy group,
1,2-dimethylbutylcarbonyloxy group, 2,2-dimethylbutylcarbonyloxy
group, 1,3-dimethylbutylcarbonyloxy group,
2,3-dimethylbutylcarbonyloxy group, 2-ethylbutylcarbonyloxy group,
2-methylpentylcarbonyloxy group, 3-methylpentylcarbonyloxy group
and the like.
[0043] The term "C.sub.1-6 alkylsulfonyl group" used herein refers
to sulfonyl groups to which the above-defined "C.sub.1-6 alkyl
group" is bound, and concrete examples of which include a
methylsulfonyl group, ethylsulfonyl group, N-propylsulfonyl group,
iso-propylsulfonyl group, N-butylsulfonyl group, iso-butylsulfonyl
group, sec-butylsulfonyl group, tert-butylsulfonyl group,
N-pentylsulfonyl group, 1,1-dimethylpropylsulfonyl group,
1,2-dimethylpropylsulfonyl group, 2,2-dimethylpropylsulfonyl group,
1-ethylpropylsulfonyl group, 2-ethylpropylsulfonyl group,
N-hexylsulfonyl group, 1-methyl-2-ethylpropylsulfonyl group,
1-ethyl-2-methylpropylsulfonyl group, 1,1,2-trimethylpropylsulfonyl
group, 1-propylpropylsulfonyl group, 1-methylbutylsulfonyl group,
2-methylbutylsulfonyl group, 1,1-dimethylbutylsulfonyl group,
1,2-dimethylbutylsulfonyl group, 2,2-dimethylbutylsulfonyl group,
1,3-dimethylbutylsulfonyl group, 2,3-dimethylbutylsulfonyl group,
2-ethylbutylsulfonyl group, 2-methylpentylsulfonyl group,
3-methylpentylsulfonyl group and the like.
[0044] The term "C.sub.1-6 alkylsulfinyl group" used herein refers
to sulfinyl groups to which the above-defined "C.sub.1-6 alkyl
group" is bound, and concrete examples of which include a
methylsulfinyl group, ethylsulfinyl group, N-propylsulfinyl group,
iso-propylsulfinyl group, N-butylsulfinyl group, iso-butylsulfinyl
group, sec-butylsulfinyl group, tert-butylsulfinyl group,
N-pentylsulfinyl group, 1,1-dimethylpropylsulfinyl group,
1,2-dimethylpropylsulfinyl group, 2,2-dimethylpropylsulfinyl group,
1-ethylpropylsulfinyl group, 2-ethylpropylsulfinyl group,
N-hexylsulfinyl group, 1-methyl-2-ethylpropylsulfinyl group,
1-ethyl-2-methylpropylsulfinyl group, 1,1,2-trimethylpropylsulfinyl
group, 1-propylpropylsulfinyl group, 1-methylbutylsulfinyl group,
2-methylbutylsulfinyl group, 1,1-dimethylbutylsulfinyl group,
1,2-dimethylbutylsulfinyl group, 2,2-dimethylbutylsulfinyl group,
1,3-dimethylbutylsulfinyl group, 2,3-dimethylbutylsulfinyl group,
2-ethylbutylsulfinyl group, 2-methylpentylsulfinyl group,
3-methylpentylsulfinyl group and the like.
[0045] The term "C.sub.1-6 alkylthio group" used herein refers to
thio groups to which the above-defined "C.sub.1-6 alkyl group" is
bound, and examples of which include a methylthio group, ethylthio
group, N-propylthio group, iso-propylthio group, N-butylthio group,
iso-butylthio group, sec-butylthio group, tert-butylthio group,
N-pentylthio group, 1,1-dimethylpropylthio group,
1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,
1-ethylpropylthio group, 2-ethylpropylthio group, N-hexylthio
group, 1-methyl-2-ethylpropylthio group, 1-ethyl-2-methylpropylthio
group, 1,1,2-trimethylpropylthio group, 1-propylpropylthio group,
1-methylbutylthio group, 2-methylbutylthio group,
1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group,
2,2-dimethylbutylthio group, 1,3-dimethylbutylthio group,
2,3-dimethylbutylthio group, 2-ethylbutylthio group,
2-methylpentylthio group, 3-methylpentylthio group and the
like.
[0046] The term "C.sub.6-14 aryl group" used herein refers to aryl
groups of from 6 to 14 carbon atoms, which include a monocyclic
group and condensed rings such as bicyclic group and tricyclic
group. Concrete examples of such group include a phenyl group,
indanyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group,
heptalenyl group, biphenyl group, indacenyl group, acenaphthyl
group, fluorenyl group, phenalenyl group, phenanthrenyl group,
anthracenyl group, cyclopentacyclooctenyl group, benzocyclooctenyl
group and the like. In the "C.sub.6-14 aryl group", phenyl group,
1-naphthyl group or 2-naphthyl group is preferred, and phenyl
group, indanyl group or 2-naphthyl group is more preferred.
[0047] The term "C.sub.6-14 aryloxy group" used herein refers to
oxy groups to which the above-defined "C.sub.6-14 aryl group" is
bound.
[0048] The term "5- to 14-membered heteroaryl group" used herein
refers to monocyclic, bicyclic or tricyclic, 5- to 14-membered
heteroaryl groups containing one or more hetero atom selected from
the group consisting of a nitrogen atom, sulfur atom and oxygen
atom. Concrete examples of such group include 1)
nitrogen-containing heteroaryl groups such as pyrrolyl group,
pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl
group, triazolyl group, tetrazolyl group, benzotriazolyl group,
pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl
group, isoindolyl group, indolizinyl group, purinyl group,
indazolyl group, quinolyl group, isoquinolyl group, quinolizinyl
group, phthalazyl group, naphthyridinyl group, quinoxalyl group,
quinazolinyl group, cinnolinyl group, pteridinyl group,
imidazotriazinyl group, pyrazino pyridazinyl group, acridinyl
group, phenanthridinyl group, carbazolyl group, carbazolinyl group,
pyrimidinyl group, phenanthrolinyl group, phenacynyl group,
imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl
group, pyrazolopyridinyl group and the like; 2) sulfur-containing
heteroaryl groups such as thienyl group, benzothienyl group and the
like; 3) oxygen-containing heteroaryl groups such as furyl group,
pyranyl group, benzofuryl group, isobenzofuryl group and the like;
4) heteroaryl groups containing two or more different hetero atoms
such as thiazolyl group, isothiazolyl group, benzothiazolyl group,
benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group,
furazanyl group, phenoxazinyl group, oxazolyl group, isoxazoyl
group, benzoxazolyl group, oxadiazolyl group, pyrazolooxazolyl
group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl
group, pyridoxadinyl group and the like.
[0049] The term "4- to 14-membered non-aromatic heterocyclic group"
used herein refers to non-aromatic heterocyclic groups having the
following features:
1) the number of atoms constituting the ring of the cyclic group is
from 4 to 14; 2) at least one hetero atom is contained in the atoms
constituting the ring of the cyclic group; 3) the ring may contain
1 to 3 carbonyl group(s); 4) monocyclic, bicyclic or tricyclic.
Concrete examples of such group include pyrrolidyl group, pyrrolyl
group, piperidyl group, pyperazyl group, imidazolyl group,
pyrazolidyl group, imidazolidyl group, morphoryl group,
tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl group,
oxylanyl group, oxathiolanyl group and the like. Such non-aromatic
heterocyclic groups also include groups derived from pyridine ring
and nonaromatic condensed rings (for example, groups derived from
phthalimide ring, succinimide ring or the like), and pyrrolidyl
group, pyrrolyl group, piperidyl group, pyperazyl group, imidazolyl
group, pyrazolidyl group, imidazolidyl group, morphoryl group,
tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl group,
oxylanyl group, oxathiolanyl group and the like are preferred.
[0050] The term "5- to 10-membered heteroaryl group" used herein
refers to monocyclic or bicyclic heteroaryl groups in which the
ring of the cyclic group is made up of 5 to 10 atoms and at least
one hetero atom(s) is (are) contained in the atoms constituting the
ring of the cyclic group. Examples of such group include 1)
nitrogen-containing heteroaryl groups such as pyrrolyl group,
pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl
group, triazolyl group, tetrazolyl group, benzotriazolyl group,
pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl
group, isoindolyl group, indolizinyl group, purinyl group,
indazolyl group, quinolyl group, isoquinolyl group, quinolizyl
group, phthalazyl group, naphthyridinyl group, quinoxalyl group,
quinazolinyl group, cinnolinyl group, pteridinyl group,
imidazotriazinyl group, pyrazino pyridazinyl group,
imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl
group, pyrazolopyridinyl group and the like; 2) sulfur-containing
heteroaryl groups such as thienyl group, benzothienyl group and the
like; 3) oxygen-containing heteroaryl groups such as furyl group,
pyranyl group, benzofuryl group, isobenzofuryl group and the like;
4) heteroaryl groups containing two or more different hetero atoms
such as thiazolyl group, isothiazolyl group, benzothiazolyl group,
benzthiadiazolyl group, isoxazolyl group, furazanyl group, oxazolyl
group, isoxazoyl group, benzoxazolyl group, oxadiazolyl group,
pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl
group, furopyrrolyl group, pyridoxadinyl group and the like.
[0051] Among these, pyrrolyl group, furyl group, thienyl group,
pyridyl group, benzothienyl group, benzofuryl group, indolyl group,
benzlyl group and indazolyl group are preferred, and furyl group,
thienyl group, benzothienyl group and benzofuryl group are more
preferred.
[0052] The term "5- to 6-membered heteroaryl" used herein refers to
monocyclic heteroaryl group in which the ring of the cyclic group
is made up of 5 to 6 atoms and at least one hetero atom(s) is (are)
contained in the atoms constituting the ring of the cyclic group.
Examples of such group include pyrrolyl group, imidazolyl group,
pyrazolyl group, 1,2,3-triazolyl group, pyridyl group, pyridazyl
group and pyrimidinyl group, pyrazinyl group, triazinyl group,
furyl group, thienyl group, thiazolyl group, oxazolyl group,
isooxazolyl group and the like, and "heteroaryl" used herein
contains an optionally substituted pyridonyl group on a nitrogen
atom. Among these, pyrrolyl group, pyridyl group, piridonyl group,
pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl
group, furyl group or thienyl group is preferred.
[0053] The term "5-membered heteroaryl" used herein refers to
5-membered heteroaryl groups containing at least one heteroatom
selected from the group consisting of a nitrogen atom, sulfur atom
and oxygen atom. Examples of such group include pyrrolyl group,
imidazolyl group, pyrazolyl group, 1,2,3-triazolyl group, furyl
group, thienyl group, oxazolyl group, isooxazolyl group and the
like, furyl group or thienyl group being preferred, and thienyl
group more preferred.
[0054] The term "5- to 6-membered non-aromatic heterocycle" used
herein refers to 5- or 6-membered heterocyclic groups containing at
least one heteroatom selected from the group consisting of a
nitrogen atom, sulphur atom and oxygen atom. Concrete examples of
such group include piperidyl group, piperazyl group, morpholyl
group, thiomorpholyl group, tetrahydro-2-pyron-yl group,
tetrahydropyran-yl group, tetrahydrothiopyran-yl group,
pyperidine-2-on-yl group, tetrahydrofuran-yl group,
tetrahydrothiophene-yl group, pyrrolidinyl group,
tetrahydrofuran-2-on-yl group or pyrrolidine-2-on-yl group. In the
above "5- or 6-membered non-aromatic heterocycle", piperidyl group,
piperazyl group, morpholyl group, thiomorpholyl group,
tetrahydro-2-pyron-yl group, tetrahydropyran-yl group,
tetrahydrothiopyran-yl group and pyperidine-2-on-yl group are
preferred.
[0055] The term "amino group" used herein comprehends primary
amines represented by the formula --NH.sub.2, as well as secondary
amines in which a hydrogen atom is substituted with other
substituent (for example, C.sub.1-6 alkyl group and the like) and
tertiary amines in which two hydrogen atoms are substituted. In the
cases of tertiary amines, two substituents may be bound with each
other, to form a 4- to 8-membered ring (for example, piperidine
ring, piperazine ring, morpholine ring or the like).
[0056] The term "amide group" used herein comprehends groups
represented by --CO--NH.sub.2, as well as secondary or tertiary
amides in which hydrogen atom is substituted with C.sub.1-6 alkyl
group or the like as described in the definition for "amino group".
The term "amide group" also involves amide groups forming a ring
such as lactam.
[0057] The term "furyl group" used herein refers to 2-furyl group
or 3-furyl group, with 2-furyl group being preferred.
[0058] The term "thienyl group" used herein refers to 2-thienyl
group or 3-thienyl group, with 2-thienyl group being preferred.
[0059] The term "pyrrolyl group" used herein refers to 1-pyrrolyl
group, 2-pyrrolyl group or 3-pyrrolyl group, with 2-pyrrolyl group
being preferred.
[0060] The term "tetrahydrofuran-yl group" used herein refers to
tetrahydrofuran-2-yl group or tetrahydrofuran-3-yl group, with
tetrahydrofuran-2-yl group being preferred.
[0061] The term "tetrahydrothiophene-yl group" used herein refers
to tetrahydrothiophene-2-yl group or tetrahydrothiophene-3-yl
group, with tetrahydrothiophene-2-yl group being preferred.
[0062] The term "pyrrolidinyl group" used herein refers to
1-pyrrolidinyl group, 2-pyrrolidinyl group or 3-pyrrolidinyl group,
with 2-pyrrolidinyl group being preferred.
[0063] The term "tetrahydrofuran-2-on-yl group" used herein refers
to tetrahydrofuran-2-on-3-yl group, tetrahydrofuran-2-on-4-yl group
or tetrahydrofuran-2-on-5-yl group, with tetrahydrofuran-2-on-5-yl
group being preferred.
[0064] The term "pyrrolidine-2-on-yl group" used herein refers to
pyrrolidine-2-on-1-yl group, pyrrolidine-2-on-3-yl group,
pyrrolidine-2-on-4-yl group or pyrrolidine-2-on-5-yl group, and
pyrrolidine-2-on-5-yl group is preferred.
[0065] The term "quinolyl group" used herein refers to monovalent
groups derived by removing any one of hydrogen atoms from a
quinoline ring, and concrete examples of which include 2-quinolyl
group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group,
6-quinolyl group, 7-quinolyl group and 8-quinolyl group, and
2-quinolyl group is preferred.
[0066] In the groups represented by the formula:
##STR00018##
(wherein Y.sup.2a, Y.sup.2b and Y.sup.2c have the same meaning as
defined above), preferred examples include the groups represented
by the formula:
##STR00019##
[0067] The term "optionally substituted" used herein is synonymous
with the expression "a site at which substitution is possible may
have one or plural substituent(s) in arbitrary combination".
[0068] Typical examples of substituent involved in "optionally
substituted" include:
(1) halogen atoms; (for example, fluorine atom, chlorine atom,
bromine atom, iodine atom and the like); (2) hydroxyl groups; (3)
cyano groups; (4) nitro groups; (5) carboxyl groups; (6) amino
groups; (7) C.sub.1-6 alkyl groups (for example, methyl group,
ethyl group, N-propyl group, iso-propyl group, N-butyl group,
tert-butyl group, N-pentyl group, 1,1-dimethylpropyl group,
1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl
group, 2-ethylpropyl group, N-hexyl group and the like); (8)
C.sub.2-6 alkenyl groups (for example, vinyl group, allyl group,
1-propenyl group, 2-propenyl group, isopropenyl group,
2-methyl-1-propenyl group, 3-methyl-1-propenyl group and the like);
(9) C.sub.2-6 alkynyl groups (for example, ethynyl group,
1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl
group, 3-butynyl group, 3-methyl-1-propynyl group,
1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group and the
like); (10) C.sub.3-8 cycloalkyl groups (for example, cyclopropyl
group, cyclobutyl group, cyclopentyl group, cyclohexyl group,
cycloheptyl group, cyclooctyl group and the like); (11) C.sub.3-8
cycloalkenyl groups (for example, cyclopropene-1-yl,
cyclopropene-3-yl, cyclobutene-1-yl, cyclobutene-3-yl,
1,3-cyclobutadiene-1-yl, cyclopentene-1-yl, cyclopentene-3-yl,
cyclopentene-4-yl, 1,3-cyclopentadiene-1-yl,
1,3-cyclopentadiene-2-yl, 1,3-cyclopentadiene-5-yl,
cyclohexene-1-yl, cyclohexene-3-yl, cyclohexene-4-yl,
1,3-cyclohexadiene-1-yl, 1,3-cyclohexadiene-2-yl,
1,3-cyclohexadiene-5-yl, 1,4-cyclohexadiene-3-yl,
1,4-cyclohexadiene-1-yl and the like); (12) C.sub.1-6 alkoxy groups
(for example, methoxy group, ethoxy group, N-propoxy group,
iso-propoxy group, sec-propoxy group, N-butoxy group, iso-butoxy
group, sec-butoxy group, tert-butoxy group, N-pentyloxy group,
iso-pentyloxy group, sec-pentyloxy group, N-hexoxy group,
iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy
group, 2,2-dimethylpropyloxy group and the like); (13) C.sub.1-6
alkenyloxy groups (for example, vinyloxy group, allyloxy group,
1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group,
2-methyl-1-propenyloxy group, 3-methyl-1-propenyloxy group,
2-methyl-2-propenyloxy group, 3-methyl-2-propenyloxy group,
1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group,
1-pentenyloxy group, 1-hexenyloxy group, 1,3-hexadienyloxy group,
1,6-hexadienyloxy group and the like); (14) C.sub.1-6 alkylthio
groups (for example, methylthio group, ethylthio group,
N-propylthio group, iso-propylthio group, N-butylthio group,
iso-butylthio group, sec-butylthio group, tert-butylthio group,
N-pentylthio group, 1,1-dimethylpropylthio group,
1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,
1-ethylpropylthio group, 2-ethylpropylthio group, N-hexylthio
group, 1-methyl-2-ethylpropylthio group, and the like); (15)
C.sub.1-6 alkenylthio groups (for example, vinylthio group,
allylthio group, 1-propenylthio group, 2-propenylthio group,
isopropenylthio group, 2-methyl-1-propenylthiogroup,
3-methyl-1-propenylthiogroup, 2-methyl-2-propenylthiogroup,
3-methyl-2-propenylthiogroup, 1-butenylthiogroup,
2-butenylthiogroup, 3-butenylthiogroup, 1-pentenylthio group,
1-hexenylthio group, 1,3-hexane dienylthio group, 1,6-hexane
dienylthio group, and the like); (16) C.sub.1-14 aryloxy groups
(for example, phenyloxy group and the like); (17) C.sub.2-7 acyl
groups (for example, acetyl group, propionyl group, butyroyl group
and the like); (18) C.sub.6-14 aryl groups (for example, phenyl
group, 1-naphthyl group, 2-naphthyl group, and the like); (19) 4-
to 14-membered heterocyclic groups (for example, 1) pyrrolidyl
group, pyrrolilyl group, piperidyl group, pyperazyl group,
imidazolyl group, pyrazolidyl group, imidazolidyl group, morphoryl
group, tetrahydrofuryl group, tetrahydropyranyl group, aziridinyl
group, oxylanyl group and oxathiolanyl group; 2) groups derived
from pyrrolidone ring; 3) groups derived from condensed rings such
as phthalimide ring and succinimide group, and the like); (20) 5-
to 14-membered heteroaryl groups (for example, pyrrolyl group,
pyridyl group, pyridazinyl group, pyrimidyl group, pyrazinyl group,
imidazolyl group, benzimidazolyl group, indolyl group, indazolyl
group, quinolyl group, isoquinolyl group, thienyl group,
benzothienyl group, furyl group, pyranyl group, benzofuryl group,
thiazolyl group, benzothiazolyl group and the like); (21) amide
group, (22) sulfonyl groups having C.sub.1-6 aliphatic hydrocarbon
groups as substituent; (23) sulfonamide groups, (24) C.sub.1-6
alkylcarbamoyl groups, (25) C.sub.1-6 alkoxycarbonyl groups, (26)
C.sub.1-6 alkylcarbonyloxy groups, (27) C.sub.1-6 alkylsulfonyl
groups, (28) C.sub.1-6 alkylsulfinyl groups, (29) formyl group,
(30) the formula:
##STR00020##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group) (31) the formula:
##STR00021##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group) (32) the formula:
##STR00022##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group) and the like groups, and
the term "optionally substituted" used herein means that the
compound may have 1 to 4 substituent(s) selected from the above
substituent groups.
[0069] In the above (6) to (23) listing available substituents for
"optionally substituted", amino group, C.sub.1-6 alkyl groups,
C.sub.2-6 alkenyl groups, C.sub.2-6 alkynyl groups, C.sub.3-8
cycloalkyl groups, C.sub.3-8 cycloalkenyl groups, C.sub.1-6 alkoxy
groups, C.sub.1-6 alkenyloxy groups, C.sub.1-6 alkylthio groups,
C.sub.1-6 alkenylthio groups, C.sub.1-14 allyloxy groups, C.sub.2-7
acyl groups, C.sub.6-14 aryl groups, 4- to 14-membered non-aromatic
hydrocarbon cyclic groups or 5- to 14-membered heteroaryl groups,
amide groups, sulfonyl groups having C.sub.1-6 aliphatic
hydrocarbon groups as substituent or sulfonamide groups may be
further optionally substituted with 1 to 4 group(s) selected from
the group consisting of:
(a) halogen atoms, (b) hydroxyl group, (c) cyano group, (d) nitro
group, (e) carboxyl group, (f) amino group, (g) C.sub.1-6 alkyl
groups, (h) C.sub.2-6 alkenyl groups, (i) C.sub.2-6 alkynyl groups,
(j) C.sub.3-8 cycloalkyl groups, (k) C.sub.3-8 cycloalkenyl groups,
(l) C.sub.1-6 alkoxy groups, (m) C.sub.1-6 alkenyloxy groups, (n)
C.sub.1-6 alkylthio groups, (o) C.sub.1-6 alkenylthio groups, (p)
C.sub.1-14 allyloxy groups, (q) C.sub.2-7 acyl groups, (r)
C.sub.6-14 aryl groups, (s) 4- to 14-membered non-aromatic
hydrocarbon cyclic groups, (t) 5- to 14-membered heteroaryl groups,
(u) amide group, (v) sulfonyl groups having C.sub.1-6aliphatic
hydrocarbon groups as substituent, and (w) sulfonamide groups as
described in (1) to (23).
[0070] Preferred examples of substituents for "optionally
substituted" include:
(a-1) halogen atoms, (a-2) hydroxyl group, (a-3) nitrile group,
(a-4) C.sub.1-6 alkyl groups, C.sub.2-6 alkenyl groups, C.sub.2-6
alkynyl groups, C.sub.3-8 cycloalkyl groups and C.sub.1-6 alkoxy
groups each optionally substituted with 1 to 3 halogen atom(s) or
hydroxyl group, (a-5) C.sub.6-10 aryl groups. (a-6) 5- to
14-membered heteroaryl groups, (a-7) 5- to 14-membered heterocyclic
groups, (a-8) carboxyl group, (a-9) trifluoromethyl group, (a-10)
C.sub.1-6 alkylcarbamoyl groups, (a-11) C.sub.1-6 alkoxycarbonyl
groups, (a-12) C.sub.2-7 acyl groups, (a-13) C.sub.1-6
alkylcarbonyloxy groups, (a-14) C.sub.1-6 alkylsulfonyl groups,
(a-15) C.sub.1-6 alkylsulfinyl groups, (a-16) C.sub.1-6 alkylthio
groups, (a-17) nitro group, (a-18) formyl group, (a-19) the
formula:
##STR00023##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group), (a-20) the formula:
##STR00024##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group), (a-21) the formula:
##STR00025##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group) and the like
substituents.
[0071] More preferred examples of substituents for "optionally
substituted" include:
(a-1) halogen atom, (a-2) hydroxyl group, (a-3) nitrile group,
(a-4) C.sub.1-6 alkyl groups, C.sub.3-8 cycloalkyl groups and
C.sub.1-6 alkoxy groups each optionally substituted with 1 to 3
halogen atom(s) or hydroxyl group, (a-17) nitro group, and the
groups represented by (a-19) the formula:
##STR00026##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group), and (a-20) the
formula:
##STR00027##
(wherein R.sup.10a and R.sup.11a each independently designate a
hydrogen atom or C.sub.1-6 alkyl group).
[0072] More preferred examples of substituents for "optionally
substituted" include halogen atoms, nitrile group, C.sub.1-6 alkyl
groups, C.sub.3-8 cycloalkyl groups, C.sub.1-6 alkoxy groups and
trifluoromethyl groups.
[0073] More preferred examples of substituents for "optionally
substituted" include a fluorine atom, cyclopropyl group,
trifluoromethyl group, methoxy group or the like.
[0074] When the number of substituent is 2 or more in "optionally
substituted" used herein, the substituents may be bound with each
other to form a ring. For example, when referring to "optionally
substituted phenyl group", piperonyl group and the like are
included.
[0075] In the compounds represented by the formula (I) in
accordance with the present invention, Cy is 5- to 6-membered
heteroaryl, preferably 5-membered heteroaryl, more preferably a
thiophene ring, and most preferably such that structure of a moiety
consisting of the Cy and the pyrazole ring adjoining the Cy forms
1H-thieno[2,3-C]pyrazole.
[0076] In the compounds represented by the formula (I) according to
the present invention, n is 0, 1, 2, 3 or 4, and preferably 1 or
2.
[0077] In the compounds represented by the formula (II), Q.sup.1 to
Q.sup.4 each independently designate --NV.sup.1--, --CV.sup.2.dbd.,
--N.dbd., --N(O).dbd. or --CO--, and at least one of Q.sup.1 to
Q.sup.4 is --NV.sup.1-- or --N.dbd., --N(O).dbd., namely containing
a nitrogen atom on the ring, and it is preferred that only one of
Q.sup.1 to Q.sup.4 is --NV.sup.1-- or --N.dbd.,
--N(.fwdarw.O).dbd., and --N.dbd. is more preferable in the
substituents of --NV.sup.1-- or --N.dbd., --N(.fwdarw.O).dbd..
Furthermore, it is preferred that either one of Q.sup.1, Q.sup.3 or
Q.sup.4 is --NV.sup.1-- or --N.dbd., --N(.fwdarw.O).dbd.,
especially --N.dbd..
[0078] In the compounds represented by the formula (III) according
to the present invention, R.sup.d, R.sup.e or R.sup.f each
independently designate a hydrogen atom, halogen atom, hydroxyl
group, cyano group, nitro group, carboxyl group, optionally
substituted C.sub.1-6 alkyl group, optionally substituted C.sub.1-6
alkoxy group, optionally substituted --C.sub.2-7 acyl group,
--CO--NR.sup.2aR.sup.2b, --NR.sup.2bCO--R.sup.2a or
--NR.sup.2aR.sup.2b (wherein R.sup.2a C.sub.2-7 acyl group,
--CO--NR.sup.2aR.sup.2b, --NR.sup.2bCO--R.sup.2a or
--NR.sup.2aR.sup.2b (wherein R.sup.2a and R.sup.2b each
independently designate a hydrogen atom or an optionally
substituted C.sub.1-6 alkyl group), and it is preferable that at
least one of R.sup.d, R.sup.e and R.sup.f is not a hydrogen atom,
and only one of R.sup.d, R.sup.e and R.sup.f is not a hydrogen
atom. That is at least one or more of R.sup.d, R.sup.e and R.sup.f
is (are) preferably a substituent other than hydrogen atom, and it
is more preferred that either two of R.sup.d, R.sup.e and R.sup.f
are hydrogen atoms while the other one is a substituent other than
hydrogen atom. When expresses as "other than hydrogen atom", a
halogen atom, hydroxyl group or optionally substituted alkoxy group
is a preferred substituent, and a fluorine atom or methoxy group is
a more preferred substituent.
[0079] In the compounds represented by the formulae (I) to (III)
according to the present invention, R.sup.1 is a group represented
by the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
(wherein R.sup.a, R.sup.b and R.sup.c each independently designate
a hydrogen atom, halogen atom, hydroxyl group, optionally
substituted C.sub.1-6 alkyl group, optionally substituted C.sub.2-6
alkenyl group, optionally substituted C.sub.1-6 alkoxy group,
optionally substituted C.sub.2-6 alkenyloxy group, optionally
substituted C.sub.1-6 alkylthio group, optionally substituted
C.sub.2-6 alkenylthio group, optionally substituted C.sub.3-8
cycloalkenyl group, optionally substituted 4- to 14-membered
non-aromatic heterocyclic group, optionally substituted C.sub.6-14
aryl group or optionally substituted 5- to 14-membered heteroaryl
group, Ar designates an optionally substituted C.sub.6-14 aryl
group or optionally substituted 5- to 14-membered heteroaryl group,
h, j and k each independently designate 0 or 1), and it is
preferred that h and j are 0, and it is more preferred that h and j
are 0 and k is 1.
[0080] In the compounds represented by the formulae (I) to (III)
according to the present invention, R.sup.a, R.sup.b and R.sup.c
each independently designate a hydrogen atom, halogen atom,
hydroxyl group, optionally substituted C.sub.1-6 alkyl group,
optionally substituted C.sub.2-6 alkenyl group, optionally
substituted C.sub.1-6 alkoxy group, optionally substituted
C.sub.2-6 alkenyloxy group, optionally substituted C.sub.1-6
alkylthio group, optionally substituted C.sub.2-6 alkenylthio
group, optionally substituted C.sub.3-8 cycloalkenyl group,
optionally substituted 4- to 14-membered non-aromatic heterocyclic
group, optionally substituted C.sub.6-14 aryl group or optionally
substituted 5- to 14-membered heteroaryl group, preferably a
hydrogen atom, halogen atom, hydroxyl group, optionally substituted
C.sub.1-6 alkyl group, optionally substituted C.sub.2-6 alkenyl
group or optionally substituted C.sub.1-6 alkoxy group, and more
preferably a hydrogen atom or halogen atom.
[0081] In the compound represented by the formulae (I) to (III)
according to the present invention, Ar is an optionally substituted
C.sub.6-14 aryl group or optionally substituted 5- to 14-membered
heteroaryl group, preferably an optionally substituted benzene
ring, optionally substituted naphthalene ring, optionally
substituted thiophene ring or optionally substituted pyridine
group.
[0082] In the compounds represented by formulae (I) to (III)
according to the present invention, L is a single bond, optionally
substituted C.sub.1-6 alkylene group, optionally substituted
C.sub.2-6 alkenylene group or optionally substituted C.sub.2-6
alkynylene group, preferably a single bond or optionally
substituted C.sub.1-6 alkylene group, and more preferably a single
bond, methylene group or ethylene group.
[0083] In the compounds represented by the formulae (I) to (III)
according to the present invention, X designates a single bond or a
group represented by --NR.sup.7--, --O--, --CO--, --S--, --SO--,
--SO.sub.2--, --CO--NR.sup.8-Z-, --C(O)O--, --NR.sup.8--CO-Z-,
--NR.sup.8--C(O)O--, --NR.sup.8--S, --NR.sup.8--SO--,
--NR.sup.8--SO.sub.2-Z-, --NR.sup.9--CO--NR.sup.10--,
--NR.sup.9--CS--NR.sup.10--, --S(O).sub.mNR.sup.11-Z-,
--C(.dbd.NR.sup.12)--NR.sup.13--, --OC(O)--, --OC(O)--NR.sup.14--
or --CH.sub.2--NR.sup.8--COR.sup.7-- (wherein R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 each
independently designate a hydrogen atom, halogen atom, hydroxyl
group, optionally substituted C.sub.1-6 alkyl group, optionally
substituted C.sub.2-6 alkenyl group, optionally substituted
C.sub.2-6 alkynyl group, optionally substituted C.sub.1-6 alkoxy
group, optionally substituted C.sub.2-6 alkenyloxy group,
optionally substituted C.sub.1-6 alkylthio group, optionally
substituted C.sub.2-6 alkenylthio group, optionally substituted
C.sub.3-8 cycloalkyl group, optionally substituted C.sub.3-8
cycloalkenyl group, optionally substituted 4- to 14-membered
non-aromatic heterocyclic group, optionally substituted C.sub.6-14
aryl group or optionally substituted 5- to 14-membered heteroaryl
group, Z designates a single bond or optionally substituted
C.sub.1-6 alkylene group, m designates 0, 1 or 2), and preferably a
single bond, --CO--NR.sup.8-Z-, or --NR.sup.8--CO-Z-.
[0084] In the compounds represented by the formulae (I) to (III)
according to the present invention, Y is selected from the group
consisting of a hydrogen atom, halogen atom, nitro group, hydroxyl
group, cyano group, carboxyl group or optionally substituted
C.sub.1-6 alkyl group, optionally substituted C.sub.2-6 alkenyl
group, optionally substituted C.sub.2-6 alkynyl group, optionally
substituted C.sub.1-6 alkoxy group, optionally substituted
C.sub.3-8 cycloalkyl group, optionally substituted C.sub.3-8
cycloalkenyl group, optionally substituted 4- to 14-membered
non-aromatic heterocyclic group, optionally substituted C.sub.6-14
aryl group, optionally substituted 5- to 14-membered heteroaryl
group, optionally substituted amino group and group represented by
the formula --W--R.sup.15 wherein W designates CO or SO.sub.2;
R.sup.15 designates an optionally substituted C.sub.1-6 alkyl
group, optionally substituted amino group, optionally substituted
C.sub.6-14 aryl group or optionally substituted 5- to 14-membered
heteroaryl group), preferably an optionally substituted 5- to
14-membered heteroaryl group, and more preferably 5- to 6-membered
heteroaryl group. Furthermore, when Y is --W--R.sup.15, W is CO,
while when R.sup.15 is optionally substituted C.sub.1-6 alkyl
group, preferred is an optionally substituted amino group.
[0085] In the compounds represented by the formulae (I) to (III)
according to the present invention, R.sup.7, R.sup.8, R.sup.9,
R.sup.10, R.sup.11, R.sup.12, R.sup.13 and R.sup.14 each
independently designate a hydrogen atom, halogen atom, hydroxyl
group, optionally substituted C.sub.1-6 alkyl group, optionally
substituted C.sub.2-6 alkenyl group, optionally substituted
C.sub.2-6 alkynyl group, optionally substituted C.sub.1-6 alkoxy
group, optionally substituted C.sub.2-6 alkenyloxy group,
optionally substituted C.sub.1-6 alkylthio group, optionally
substituted C.sub.2-6 alkenylthio group, optionally substituted
C.sub.3-8 cycloalkyl group, optionally substituted C.sub.3-8
cycloalkenyl group, optionally substituted 4- to 14-membered
non-aromatic heterocyclic group, optionally substituted C.sub.6-14
aryl group or optionally substituted 5- to 14-membered heteroaryl
group, and preferably hydrogen atom or optionally substituted
C.sub.1-6 alkyl group.
[0086] Now, general methods for synthesizing the compounds
represented by the formulae (I) to (III) according to the present
invention will be described. It goes without saying that in the
following general synthesis methods, exemplification based on the
above formula (I) also applies to the formulae (II) and (III)
unless otherwise noticed. In particular, as for the method of
introducing the substituent R.sup.1 as described later, it
obviously applies to the formulae (II) and (III).
##STR00028##
[0087] A typical production method of condensed pyrazole compound
represented by the formula (I) according to the present invention
will be described below. It is to be noted that "Cy" used in the
reaction schemes of Production methods 1 to 80 has the same meaning
as defined above. R.sup.1, Q.sup.1, Q.sup.2, Q.sup.3, Q.sup.4 and V
each have the same meaning as defined above. "V" indicated as a
reagent in schemes of the Production methods provided below may
exists alone or associated with an appropriate leaving group. The
symbol "n" designates 0, 1, 2, 3 or 4. T.sup.1 means a hydrogen
atom, bromine atom or iodine atom. T.sup.2 means a halogen atom,
preferably fluorine atom. T.sup.3 means a chlorine atom, bromine
atom or iodine atom, preferably bromine atom or iodine atom. Pro
and Pro.sup.1 each designate a protective group. J, J.sup.1 and
J.sup.2 each independently designate, but not limited to, an alkyl
group or may together form a ring. V.sup.1 and V.sup.2 each have
the same meaning as defined for V.
Production Method 1
##STR00029##
[0089] Compound (I) can be produced by converting aromatic ring
compound 1 into a metal aryl with the use of alkyl lithium, lithium
amide or the like, reacting the metal aryl with aryl aldehyde to
render it alcohol 2, oxidizing alcohol 2 into ketone 3, and then
subjecting ketone 3 to cyclization of indazole ring with the use of
hydrazine. As the alkyl lithium to be used for converting aromatic
ring compound 1 into a metal aryl, for example, N-butyllithium,
sec-butyllithium, tert-butyllithium, phenyl lithium and the like
are used. Additives such as diazabicyclo[2.2.0]octane,
N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoramide and
the like may also be added as is necessary. Further, as the lithium
amide, for example, lithium diisopropylamide, lithium
2,2,6,6-tetramethylpiperidide and the like are used. As the
solvent, any solvents can be used in so far as they are not
concerned with the reaction, and preferred examples of such solvent
include, but are not limited to, ether-based solvents such as
diethyl ether, tetrahydrofuran or dioxane, dimethoxyethane, and the
like, as well as benzene, toluene and the like. The reaction
temperature is from -78.degree. C. to room temperature. As the
oxidizing reagent for oxidizing the alcohol of compound 2, for
example, manganese dioxide, sulfur trioxide-pyridine complex,
N-methylmorpholine-N-oxide, various kinds of chromic acid oxidizing
reagents and the like can be used, and also Swern oxidation, M of
fat oxidation and the like may be applied. As the solvent, any
solvent can be used insofar as they are not concerned with the
reaction, and examples of such solvent include hydrocarbon halides
such as dichloromethane, chloroform and the like, as well as other
ethyl acetate, acetonitrile, dimethyl sulfoxide,
N,N-dimethylformamide and the like. The reaction temperature is
usually from -78.degree. C. to reflux temperature of the solvent.
The reaction of cyclizing compound 3 with the use of hydrazine
monohydrate may be carried out either in the absence of solvent or
in the presence of solvent. Any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include, but are not limited to, ether solvents such as
diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane, alcohol
solvents such as methanol, ethanol or propanol, as well as
pyridine, dimethyl sulfoxide, benzene, toluene and so on. The use
amount of hydrazine monohydrate is from 2 to 20 equivalents with
respect to the material. The reaction temperature is usually from
0.degree. C. to reflux temperature of the solvent.
Production Method 2
##STR00030##
[0091] Compound 2 can also be produced in accordance with
Production method 2. Aromatic ring compound 1 is made into a metal
aryl in accordance with Production method 1, which is then reacted
with formylation agent, to thereby produce compound 4. Examples of
formylation agent include N,N-dimethylformamide,
N-formylpiperidine, methylphenylformamide and so on. As the
reaction solvent, any solvents can be used insofar as they are not
concerned with the reaction, and examples of which include, but are
not limited to, ether solvents such as diethyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and the like, as well as
benzene, toluene and the like. The reaction temperature is from
-78.degree. C. to room temperature. Compound 2 can be produced by
making a metal aryl or metal halogenoaryl to react on compound 4.
The metal aryl or metal halogenoaryl can be readily prepared, for
example, by converting halogenoaryl into aryl lithium or metal
halogenoaryl by using alkyl lithium, magnesium, zinc and the like.
As the alkyl lithium, for example, N-butyllithium,
sec-butyllithium, tert-butyllithium, phenyl lithium and the like
can be used, and N,N,N',N'-tetramethylethylenediamine,
hexamethylphosphoramide and the like additives may be used as
necessary. As the reaction solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, ether solvents
such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane
and the like, as well as benzene, toluene and the like. The
reaction temperature is from -78.degree. C. to room
temperature.
Production Method 3
##STR00031##
[0093] Compound (I) can be produced by cyclizing compound 4 in
accordance with Production method 1 using hydrazine to render
indazole compound 5, halogenating 3-position of compound 5 to
render it compound 6, protecting 1-position of pyrazole of compound
6 to render it composition 7, and then introducing a substituent
into 3-position by coupling reaction, followed by deprotection at
1-position. The R.sup.1 which may be introduced by coupling
reaction has the same meaning as defined above, and the case where
h=j=0 is preferred. Compound 8 wherein an aromatic ring is directly
bonded to 3-position of pyrazole can be produced by Suzuki coupling
with aryl boronic acid or by Stille reaction with aryl trialkyl tin
or the like. Furthermore, in particular, compound 8 having styrene
(h=j=0,k=1) at 3-position can also be produced by coupling based on
Heck reaction in which styrene is reacted on compound 7, besides
the Suzuki coupling. The method for producing 3-styrene compound 8
is described in Production methods 35 to 40 below. As a
halogenation reagent for 3-position, for example,
N-bromosuccinimide, N-iodosuccinimide, N-chlorosuccinimide,
bromine, iodine and the like are used, and radical initiators such
as 2,2'-azodiisobutyronitrile or benzoyl peroxide or bases such as
sodium hydroxide may be added as necessary. The use amount of the
halogenation reagent is from 1.05 to 1.2 equivalents with respect
to the material. As the solvent, any solvents can be used insofar
as they are not concerned with the reaction, and examples of such
solvent include, but are not limited to, hydrocarbon halides such
as dichloromethane, chloroform, carbon tetrachloride and the like,
as well as ethyl acetate, acetonitrile, dimethyl sulfoxide,
N,N-dimethylformamide and so on. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
[0094] Examples of the protective group at 1-position include
tert-butoxycarbonyl group, p-toluenesulfonyl group, trityl group,
methoxymethyl group and the like. Introduction of
tert-butoxycarbonyl group and p-toluenesulfonyl group can be
achieved by letting compound 6 and di-tert-butyldicarbonate or
p-toluenesulfonyl chloride react with each other in the presence of
a base. Preferred examples of the base include, but are not limited
to, triethylamine, 4-N,N-dimethylaminopyridine and the like. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, ether solvents such as diethyl ether,
tetrahydrofuran, dioxane or dimethoxyethane, hydrocarbon halides
such as dichloromethane or chloroform, as well as ethyl acetate,
acetonitrile, dimethyl sulfoxide, dimethylformamide and so on. The
reaction temperature is usually from 0.degree. C. to reflux
temperature of the solvent.
[0095] Introduction of trityl group and methoxymethyl group can be
achieved by letting compound 6 and chlorotriphenylmethane or
chloromethylmethyl ether react with each other in the presence of a
base. Preferred examples of the base include, but are not limited
to, sodium hydride, potassium tert-butoxide, lithium
diisopropylamide, potassium carbonate, sodium hydroxide and the
like. As the solvent, any solvents can be used insofar as they are
not concerned with the reaction, and examples of such solvent
include, but are not limited to, ether solvents such as diethyl
ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as
ethyl acetate, acetonitrile, dimethyl sulfoxide, dimethylformamide
and so on. The reaction temperature is from -20.degree. C. to
reflux temperature of the solvent.
[0096] Aromatic olefins used for Heck reaction and aryl boronic
acids used for Suzuki coupling are commercially available, or may
readily be prepared in a conventional manner if not commercially
available. Aryl boronic acid can be prepared by converting a
halogenoaryl into an aryl lithium or metal halogenoaryl with the
use of a alkyl lithium, magnesium, zinc and the like, and letting
the aryl lithium or metal halogenoaryl react with a trialkyl borate
to render it a boric acid ester, followed by hydrolysis. Examples
of the alkyl lithium include N-butyllithium, sec-butyllithium,
tert-butyllithium, phenyl lithium and the like, and additives such
as N,N,N',N'-tetramethylethylenediamine or hexamethylphosphoramide
may be added as is necessary. The hydrolysis following the reaction
between aryl lithium and trialkyl borate to obtain ester borate may
be carried out by adding water, or by using an acid such as
hydrochloric acid, sulfuric acid. As the solvent, any solvents can
be used insofar as they are not concerned with the reaction, and
preferred examples of such solvent include, but are not limited to,
ether solvents such as diethyl ether, tetrahydrofuran, dioxane or
dimethoxyethane. The reaction temperature is from -78.degree. C. to
room temperature. Aromatic olefins can be prepared by letting an
arylaldehyde and methylphosphonium ylide react with each other. For
example, methyltriphenylphosphonium salt is treated with a base to
make it methylphosphonium ylide, which is then reacted with an aryl
aldehyde in the same system, to thereby produce aromatic olefins.
Examples of the base include potassium tert-butoxide, sodium
methoxide, sodium hydride, potassium carbonate, sodium hydroxide
and the like. Examples of the solvent include, but are not limited
to, ether solvents such as diethyl ether, tetrahydrofuran or
dioxane, hydrocarbon halides such as dichloromethane, chloroform,
as well as toluene and the like. The reaction temperature is from
-20.degree. C. to reflux temperature of the solvent.
[0097] The use amount of aryl boronic acid used for Suzuki coupling
or aromatic olefins used for Heck reaction is from 1 to 3
equivalent(s) with respect to the material. Examples of catalyst to
be used include, palladium acetate(II),
dichlorobistriphenylphosphine palladium(II),
tetrakis(triphenylphosphine) palladium (0) and the like. The use
amount of catalyst is about 5% by mole with respect to the
material. As is necessary, phosphine ligand, twice in mole of
catalyst of a phosphine ligand, for example,
tri-tert-butylphosphine, 2-(di-tert-butylphosphino) biphenyl,
2-(dicyclohexylphosphino) biphenyl, triphenyl phosphine and the
like may be added. Examples of the base to be used include sodium
hydrogen carbonate, sodium carbonate, potassium carbonate, cesium
carbonate, potassium fluoride and the like. As the solvent to be
used, any solvents can be used insofar as they do not inhibit the
reaction, and examples of such solvent include, but are not limited
to, dimethylformamide, N-methylpyrrolidone, tetrahydrofuran,
dioxane, diethylene glycol dimethyl ether, toluene and the like.
The reaction temperature is usually from room temperature to reflux
temperature of the solvent.
[0098] Deprotection of a tert-butoxycarbonyl group and a trityl
group can be readily achieved by acid. Examples of the acid include
hydrochloric acid, sulfuric acid, trifluoroacetic acid and the
like. As is necessary, radical scavengers such as thiophenol or
tri-iso-propylsilane may be added. As the solvent, any solvents can
be used insofar as they are not concerned with the reaction, and
examples of such solvent include, but are not limited to,
hydrocarbon halides such as dichloromethane or chloroform, alcohol
solvents such as methanol or ethanol, as well as anisole and the
like. The reaction temperature is -20.degree. C. or reflux
temperature of the solvent. Deprotection of the tert-butoxycarbonyl
group and p-toluenesulfonyl group can be readily achieved by a
base. Examples of the base include, but are not limited to, aqueous
sodium hydroxide, aqueous potassium hydroxide and the like. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, alcohol solvents such as methanol or ethanol, ether
solvents such as diethyl ether, tetrahydrofuran, dioxane or
dimethoxyethane. The reaction temperature is room temperature or
reflux temperature of the solvent. Deprotection of the
methoxymethyl group is generally achieved by acid treatment,
however, when an animal which is incompletely-deprotected by acid
treatment remains, treatment with ammonia water is carried out to
achieve the deprotection.
Production Method 4
##STR00032##
[0100] Compound (I) can be produced in the following manner:
oxidation of an alcohol which is obtained by metallizing
.alpha.-position adjoining to the amino group suitably protected by
treating compound 9 with a base and nucleophilically adding to an
aldehyde, and deprotection of the amino group are successively
conducted to thereby obtain aminoketone 10; and then aminoketone 10
is diazotizated and reduced so as to be closed into a pyrazole.
[0101] As the protective group for amino group, any groups may be
used insofar as they are base-resistant, and preferred examples of
such protective group include, but are not limited to, a
tert-butoxycarbonyl group, benzyloxycarbonyl group, methoxymethyl
group and the like. Conversion of compound 9 into a metal aryl is
basically conducted in the manner as described in Production method
1, however, in this case 2 or more equivalents of base is required.
Oxidation of alcohol can be achieved in the manner as described in
Production method 1. Deprotection of amino group from
tert-butoxycarbonyl group, benzyloxycarbonyl group, methoxymethyl
group and the like can be readily achieved by acid treatment. The
acid to be used is as same as those recited in Production method 3,
and as for the benzyloxycarbonyl group and the like, for example,
may be deprotected under the condition of catalytic reduction or
the like.
[0102] In the case where compound 10 cannot be derived directly
from compound 9 for such a reason that aromatic aldehyde is
relatively difficult to avail, the ortho position of the protected
amino group is formylated to obtain 11, to which a metal aryl, a
metal halogenoaryl or the like is nucleophilically added, followed
by deprotection of amino group, to thereby obtain compound 10. The
condition for formylation is as described in Production method
2.
[0103] Conversion of compound 10 into diazonium salt is achieved by
letting nitrite esters such as sodium nitrite ester or isoamyl
nitrite ester act in the presence of acid. As the reaction solvent,
for example, alcohol solvents such as methanol, ethanol, water and
the like are used, as the acid, hydrochloric acid, sulfuric acid,
acetic acid and the like can be used. The reaction temperature is
usually around 0.degree. C.
[0104] Reduction of diazonium salt and subsequent ring closing of
indazole ring are achieved by letting tin chloride (II), copper
chloride (II) or the like reducing agent act in the presence of
acid, to thereby obtain hydrazine which is an intermediate, and the
use amounts of these are usually from 1 to 10 equivalent(s) with
respect the starting material. Generally, compound (I) is obtained
as a result of spontaneous ring closing associated with dehydration
within the system. As the reaction solvent, for example, alcohol
solvents such as methanol or ethanol, as well as hydrochloric acid,
sulfuric acid, acetic acid and the like can be used. The reaction
temperature is usually from 0.degree. C. to reflux temperature of
the solvent.
[0105] As an alternative method, an amino group is substituted with
a suitable halogen atom to make compound 3, which is then made
cyclic in the manner as described in Production method 1 using
hydrazine, thereby obtaining compound (I). Preferred example of the
halogen atom is, but are not limited to, a fluorine atom. As a
concrete method, Baltz-Schiemann reaction can be recited, and by
conducting this reaction, it is possible to derive fluoro ketone 3.
Baltz-Schiemann reaction is achieved in the following manner: a
nitrite ester such as sodium nitrite ester or isoamyl nitrite ester
is caused to act on compound 10 in the presence of tetrafluoroboric
acid so as to convert compound 10 into a diazonium
tetrafluoroborate salt, followed by thermal decomposition or
photodegradation. The nitrite ester or nitrite salt used for
diazotization is usually in the amount of from 1 to 2 equivalent(s)
with respect to the material, and the reaction temperature is
preferably and usually 0.degree. C. or less. Besides
tetrafluoroboric acid, hexafluorophosphoric acid, hexafluorosilicic
acid, hexafluoroantimonic acid and the like may be used. After
separating the azonium salt, the thermal decomposition may be
achieved by dilution in barium sulfate, barium fluoride and the
like, or may be achieved by heating in an organic solvent such as
acetone or hexane. In the case where separation of diazonium salt
is difficult, the thermal decomposition may be conducted while
adding a copper salt such as copper chloride or copper powder in
the solution.
Production Method 5
##STR00033##
[0107] Alternatively, Compound 13 may be produced in the manner as
described in Production method 5. Herein, R.sup.1 are as defined,
however, this also achieved in the case where R.sup.1 is a methyl
group as is a hydrogen atom. The protective group recited herein
preferably designates an amino group or carbamoyl group although
such protective group may be absent. That is, starting from a
precursor, compound 13 wherein an amino group or its equivalent
functional group and an active methyl group or an active methylene
group are adjacent with each other on the aromatic ring, the amino
group or its equivalent functional group is made into nitroso
compound using a nitrite salt or nitrite ester, going through the
reaction intermediate as described above, and then the
intramolecular dehydration condensation with the adjoining active
methyl group or methylene group in the presence of a suitable acid
or base in the reaction system is carried out, to thereby lead
pyrazole ring compound 8. As the reagent used for conversion into
nitroso, nitrite salts or nitrite esters can be exemplified.
Examples of nitrite esters include, but are not limited to, isoamyl
nitrite ester and t-butyl nitrite ester, and examples of nitrite
salts include sodium nitrite ester, potassium nitrite ester and the
like. In particular, when a nitrite salt is used, a phase transfer
catalyst such as crown ether may be used together. The use of the
nitrite salt or nitrite ester is from 1 to 10 equivalent(s) with
respect to the material. As the amino group or its equivalent
functional group, amino groups such as acetamide are preferred
without limitation, and in such a case, acetic anhydride is used as
a solvent or present together in most general cases. General
examples of the condensing reagent and base include, but are not
limited to, sodium acetate and potassium acetate, and the use
amount is usually from 1 to 10 equivalent(s). As the reaction
solvent, any solvents besides acetic anhydrous can be used insofar
as they are not concerned with the reaction, however, by conducting
the reaction in, for example, but are not limited to, hydrocarbon
solvents such as benzene, toluene or xylene, halogen solvents such
as chloroform or 1,2-dichloroethane, dioxane, glacial acetic acid,
as well as acidic solvents such as hydrochloric acid or sulfuric
acid, it is possible to complete the condensation. The reaction
temperature is from 0.degree. C. to reflux temperature of the
solvent.
[0108] In the following, concrete Production method of the compound
represented by the general formula (II) including the Production
method for side chain moiety, however it is to be noted that the
Production method is not limited thereto.
[0109] From Production method 6 to Production method 12, Q
designates a nitrogen atom, and at least one atom other than Q
among atoms existing on the aromatic ring in which Q is involved
designates --CH.dbd.. In this case, Q is a generic designation for
Q.sup.1 to Q.sup.4 in the above general formula (II) and means
either 1, 2 or 3 from Q.sup.1 to Q.sup.4.
Production Method 6
##STR00034##
[0111] After treating Halogenoketone compound 14 obtained by using
Production method 1 and so on with a peroxide to lead it into
N-oxide 15, a various kinds of reagents are caused to act on
N-oxide 15, to thereby obtain compound 16 wherein a substituent is
introduced onto a carbon atom around which no substitution occurs
and hence generally having predominant orientation. As the
functional group which can be introduced by using N-oxide as a
starting material, a cyano group, halogen group, acyloxy group,
alkoxy group and the like can be exemplified. The obtained compound
16 is made cyclic in accordance with Production method 1 using
hydrazine, to thereby produce compound (II)-a.
[0112] In the method for leading compound 14 into N-oxide, for
example, peroxides such as m-chloroperbenzoic acid, benzoyl
peroxide or hydrogen peroxide are used, and the use amount of
peroxide is from 1 to 10 equivalent(s) with respect to the
material. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and examples of such solvent
include, but are not limited to, halogen solvents such as
dichloromethane, chloroform or 1,2-dichloroethane, hydrocarbon
solvents such as benzene and toluene, as well as water, acetic acid
and the like. The reaction temperature is usually from 0.degree. C.
to reflux temperature of the solvent.
[0113] As shown in J. Org. Chem. 1983, 48, 1375, for example, the
method of cyanizing the adjoining carbon atom by using N-oxide is
achieved by causing the cyanizing reagent directly to act or
causing the cyanizing reagent to act in the presence of acid
chloride. Examples of reagent for direct cyanation include sodium
prussiate, potassium prussiate, trimethylsilyl cyanide,
diethylcyano phosphate and the like, and bases such as
triethylamine or 1,8-diazabicyclo[5.4.0]unde-7-cene may be present
together in the reaction system. It is also possible to practice
the above reaction with the cyanizing reagent in the presence of
acid chloride, and examples of such acid chloride include benzoyl
chloride, N,N-dimethyl, carbamoyl chloride and the like. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of which include, but are not
limited to, halogen solvents such as dichloromethane, chloroform,
1,2-dichloroethane and the like, and polar solvents such as
acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide,
dimethylsulfuric acid and the like. The use amounts of cyanizing
reagent, base and acid chloride are from 1 to 10 equivalent(s) with
respect to the material. The reaction temperature is usually from
room temperature to reflux temperature of the solvent.
[0114] Examples of the reagent for halogenating the adjoining
carbon atom by using N-oxide include, phosphorus oxychloride,
phosphorus oxybromide, benzoyl chloride, p-toluene sulfonyl
chloride, ethyl chloroformate, trifluoromethanesulfonyl chloride,
thionyl chloride and the like. The reaction may be carried out in
the presence or absence of solvent, and as such a solvent any
solvents can be used in so far as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, halogen solvents such as dichloromethane, chloroform or
1,2-dichloroethane, hydrocarbon solvents such as benzene or
toluene, ether solvents such as tetrahydrofuran,
N,N-dimethylformamide and the like. The use amount of the solvent
is from an equivalent with respect to the material to solvent
amount. When the substrate is unstable to acid, a base such as
triethylamine may coexist in the reaction system. The reaction
temperature is usually from room temperature to reflux temperature
of the solvent.
[0115] As the reagent for acyloxylation of the adjoining carbon
atom of N-oxide, carboxylic anhydrides are usually used. The use
amount is from an equivalent with respect to the material to
solvent amount. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0116] Alkoxylation of the adjoining carbon atom of N-oxide can be
achieved by causing ethyl chloroformate, p-toluenesulfonyl chloride
or the like to act in the presence of a base in alcohol. The use
amount is from 1 to 10 equivalent(s) with respect to the material.
As the base, metal alkoxides, triethylamine and the like are used,
and the use amount is from 1 to 2 equivalent(s) with respect to the
material. As the solvent, any solvents can be used without
particular limitation insofar as they are not concerned with the
reaction, however, it is general to conduct the reaction in a
solvent of alcohol which corresponds to the alkoxy group intended
to be introduced. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
Production Method 7
##STR00035##
[0118] Introduction of functional group using the similar manner as
described in Production method 6 is also applicable to the
nitrogen-containing condensed pyrazole compound 17. That is, after
oxidizing a desired nitrogen atom Q and leading into N-oxide by
protecting the pyrazole ring of compound 17 and letting a peroxide
act on compound 18, various kinds of reagents are made to act on
the N-oxide so as to introduce a substituent into an adjoining
carbon atom having predominant orientation. Then deprotection is
conducted to produce Compound (II)-a.
[0119] Protection and Deprotection of a nitrogen-containing
condensed pyrazole ring are achieved in the manner as described in
Production method 3. The process of protection and deprotection of
pyrazole ring may be eliminated from Production method, however, it
is preferred to employ the process in consideration of yield and
versatility.
Production Method 8
##STR00036##
[0121] In the reaction between N-oxide and various kinds of
reagents as described in Production method 6, when it is difficult
to directly introduce a functional group other than halogens into a
carbon atom at a desired position because of orientation of the
reaction regent, the functional group may be indirectly introduced
to the desired position as is described in Production method 8.
That is, as an alternative method of Production method 6, first
compound 19 wherein a carbon atom at a position of predominant
orientation is substituted with a halogen is obtained by
halogenating N-oxide, then compound 20 wherein a functional group
is introduced to a desired position in the similar manner as
described in Production method 6 is obtained, and then compound 20
is dehalogenated by reduction, to afford objective intermediate 16.
Compound 16 is then made cyclic with hydrazine in accordance with
Production method 1, to there by obtain Compound (II). As the
halogen T.sup.3, chlorine, bromine, iodine which are easy to leave
can be exemplified, with chlorine and bromine being preferred for
which commercially available phosphorous oxychloride, phosphorous
oxybromide and the like can be used.
[0122] As the method for reducing the halogen group introduced into
compound 20 to lead compound 16, for example, hydrogenation using
palladium-carbon, palladium hydride-carbon, platinum oxide, Raney
nickel and the like catalyst, or the condition of zinc-acetic acid,
copper-acetic acid and the like are used. As other conditions, the
condition of hydrazine, palladium-carbon and the like are also
known. As the solvent for hydrogenation, any solvents can be used
in so far as they do not inhibit the reaction, and examples of such
solvent include, but are not limited to, alcohol solvents such as
methanol, ethanol, halogen solvents such as dichloromethane and
chloroform, ether solvents such as tetrahydrofuran or diethyl
ether, as well as ethyl acetate, dimethylformamide, toluene and the
like. The use amount of catalyst for hydrogenation is from 5% to
20% by weight with respect to the material. The pressure of
hydrogen is usually atmospheric pressure to 5 atm. The reaction
temperature is usually from room temperature to reflux temperature
of the solvent. In the catalytic reduction, more gentle reaction
can be achieved in the presence of a base, such as for example,
sodium hydroxide, potassium hydroxide, triethylamine and the like.
The reaction temperature is usually from room temperature to reflux
temperature of the solvent. As the solvent for Zinc-acetic acid,
copper-acetic acid and the like, glacial acetic acid or hydrous
acetic acid and the like are used, and the use amount of metal is
from 3 to 10 equivalents with respect to the material. The reaction
temperature is usually reflux temperature of the solvent.
Production Method 9
##STR00037##
[0124] In the similar manner as described in Production method 8,
when it is difficult to directly introduce a functional group other
than halogens into a carbon atom at a desired position because of
orientation of the reaction regent acting on N-oxide, the similar
way as described in Production method 8 can be generally applied to
nitrogen-containing condensed pyrazole compounds. That is, after
oxidizing compound 17 with a peroxide while protecting 1-position
of pyrazole of compound 17 to lead N-oxide, the N-oxide is
halogenated, thereby producing compound 21 of predominant
orientation. Next, compound 21 is treated again with a peroxide and
allowed to react with a suitable reagent so as to introduce a
substituent to a carbon atom at a more desirable position, followed
by dehalogenation and deprotection, to thereby produce Compound
(II)-a. Protection and deprotection of compound 17 can be achieved
in the manner as described in Production method 3.
Production Method 10
##STR00038##
[0126] As described in Production method 8 and the like, in the
case where the substitution position of the halogen atom which is
introduced by causing a halogenation reagent such as phosphorus
oxychloride to react on N-oxide is ortho- or para-position of the
nitrogen atom constituting the ring, by letting amines to act, it
is possible to readily substitute the halogen atom to obtain
aniline 22. Aniline 22 can be converted into either primary,
secondary or tertiary amine without limitation, and preferably to a
primary amine. For introducing a primary amine, a variety of
methods are applicable, for example, a method of causing imino
chloride to act on the hydrazine and conducting catalytic reduction
to lead an amine; a method of introducing an amine by using liquid
ammonia or concentrated aqueous ammonia; or a method of causing
potassium phthalimide to act and then introducing amine by
hydrolysis using hydrazine or the like. Using the above reaction,
it is possible to convert halide 21 into aniline 22.
[0127] The reaction with hydrazine is conducted, for example in
alcohol solvents such as methanol or ethanol, and various kinds of
solvents such as toluene, benzene, tetrahydrofuran or dioxane. The
use amount of hydrazine is usually from 1 to solvent amount. The
reaction temperature is usually from room temperature to reflux
temperature of the solvent. In the method for catalytic reaction,
Raney nickel is generally and often used. As the reaction solvent,
hydrous alcohol solvents and the like are exemplifies. Amination
using ammonia can be readily achieved by causing a large excess of
ammonia to act. The reaction may be carried out after diluting with
alcohol solvents such as methanol or with water, or liquid ammonia
may be directly caused to act. The reaction may be carried out in a
sealed tube for some cases. The reaction temperature is usually
from -78.degree. C. to reflux temperature of the solvent. The use
amount of potassium phthalimide is usually from 1 to 2 equivalents,
and as the reaction solvent, any solvents insofar as they are not
concerned with the reaction can be used, and preferred examples of
such solvent include, but are not limited to,
N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, pyridine,
tetrahydrofuran, dioxane or the like, as well as alcohols such as
methanol or ethanol. The reaction system may contain a base, and
examples of such base include triethylamine, diisopropylethylamine,
pyridine and the like. The reaction temperature is usually from
room temperature to reflux temperature of the solvent. Deprotection
of phthaloyl group thus introduced can be practiced generally in
strong base or reduction condition, and examples of which include
hydrazine, sodium sulfide, sodium boron hydride and the like.
Preferably, the deprotection is achieved by causing hydrazine to
act in ethanol at room temperature. The use amount is from 1
equivalent to solvent amount with respect to the material.
Production Method 11
##STR00039##
[0129] N-oxide 23 produced in Production method 7 or the like can
be led to compound 24 by letting an acid anhydride act on N-oxide
as is exemplified in Production method 6, followed by
acyloxylation. In the case where the substitution position of the
introduced acyloxy group is ortho- or para-position of the nitrogen
atom constituting the ring, it is readily hydrolyzed to be led to
pyridone compound (II)-b. As the hydrolyzing reagent, hydrochloric
acid, sulfuric acid, p-toluenesulfonic acid, as well as alkalis
such as sodium hydroxide, potassium hydroxide or potassium
carbonate are exemplified, and the hydrolysis can be readily
achieved in aqueous solutions, hydrous alcohol solvents and the
like. The reaction temperature is usually from room temperature to
reflux temperature of the solvent.
Production Method 12
##STR00040##
[0131] In the case where the substitution position of the hydroxyl
group introduced by Production method 11 or the like is ortho- or
para-position of the nitrogen atom constituting the ring, by
letting a variety of halides on compound 25 in the presence of a
base, it is possible to obtain compound 26 wherein a substituent is
introduced to the nitrogen atom. As the base to be used, sodium
hydride, potassium carbonate, cesium carbonate and the like are
exemplified, and the use amount is usually from 1 to 2
equivalent(s). Examples of the halide to be used include, but are
not limited to, bromides and iodides, and the use amount thereof is
usually from 1 to 3 equivalents with respect to the material. The
halides which may be aliphatic or aromatic halides optionally have
a suitable functional group. In the case of aromatic halides,
iodides are especially preferred, and by adding a metal catalyst
such as copper iodide in the presence of a base, it is possible to
achieve excellent result. The use amount of metal catalyst is
usually from a catalyst amount to 1 equivalent. In the cases of
aralkyl halides, allyl halides and the like which are highly
reactive, a salt such as sodium iodide is used together instead of
base. As the solvent, any solvents can be used insofar as they are
not concerned with the reaction, and examples of such solvent
include, but are not limited to, halogen solvents such as
dichloromethane, chloroform or 1,2-dichloroethane, hydrocarbon
solvents such as benzene or toluene, ether solvents such as
tetrahydrofuran, and polar solvents such as N,N-dimethylformamide
or acetonitrile. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0132] By reacting a silylation reagent such as trimethylsilyl
chloride with compound 25 in the presence of a base, it is possible
to obtain compound 27 in which a hydroxyl group is silylated.
Examples of the base to be used include, but are not limited to,
N-butyllithium, sec-butyllithium, tert-butyllithium, phenyl
lithium, triethylamine, potassium carbonate and the like, and the
use amount is from 1 to 2 equivalent(s). Examples of silylation
reagent include, trimethylsilyl chloride and trimethylsilyl
trifluoroacetate, trimethylsilyl trifluoromethanesulfonate and the
like, and the use amount is from 1 to 2 equivalents. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, halogen solvents such as dichloromethane,
chloroform or 1,2-dichloroethane, hydrocarbon solvents such as
benzene or toluene, and ether solvents such as tetrahydrofuran. The
reaction temperature is from -78.degree. C. to reflux temperature
of the solvent.
[0133] It is possible to enable compound 27 to act as a nucleophile
by introduction of trimethylsilyl group or the like. As a result of
this, compound 27 nucleophilically reacts with a variety of
reagents Vin the presence of a Lewis acid, to form a corresponding
adduct 26. Examples of there agent that is reactive with compound
27 having such a property include, but are not limited to, Michael
receptors such as epoxide, aldehyde, ketone or conjugate enone, and
the use amount is from 1 to 2 equivalent(s) with respect to the
material. Examples of the Lewis acid include, but are not limited
to, aluminum chloride, boron trifluoride-diethyl ether complex and
the like, and the use amount is from 1 to 2 equivalent(s). As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, halogen solvents such as dichloromethane,
chloroform or 1,2-dichloroethane, hydrocarbon solvents such as
benzene or toluene, and ether solvents such as tetrahydrofuran. The
reaction temperature is from -78.degree. C. to reflux temperature
of the solvent.
[0134] Deprotection of the protective group in compound 26 is
carried out in the similar manner as described in Production method
3, whereby corresponding (II)-C is obtained.
[0135] The compounds embraced in the general formula (I) or (II)
include a group of compounds which are readily produced by a
production method other than the production method using the
above-exemplified production process, which is specific to the
forming condensed pyrazole ring. Now, production methods which are
useful for production of specific heterocycle are exemplified in
Production method 13 to production method 19. As for synthesis of
this group of compounds, it goes without saying that these
compounds may be produced by using the above-described production
method and the production method is not limited to the following
production methods.
Production Method 13
##STR00041##
[0137] In Q.sup.1 to Q.sup.4 in general formula (II),
1H-pyrazolo[3,4-b]pyridines wherein only Q.sup.4 is --N.dbd. can be
synthesized in the manner as described, for example, in Production
method 13. In general, by letting malonaldehyde or its equivalent
act on 5-amino-1H-pyrazoles 28 in accordance with the known method
(Synthesis. 1987, 1124), it is possible to form
1H-pyrazolo[3,4-b]pyridine ring 29. In this condensing reaction,
when malonaldehyde or its equivalent has a suitable functional
group, direct introduction of the substituent into the 5-position
of the nitrogen-containing pyrazole ring by condensation is
possible. As the equivalent of malonaldehyde having a suitable
functional group, but are not limited to, sodium
2-cyano-3,3-dimethoxy-1-propenolate is preferably exemplified, and
using this, it is possible to synthesize 1H-pyrazolo[3,4-b]pyridine
ring 29 wherein a nitrile group is introduced into 5-position.
Similarly by using sodium 2-nitromalonaldehyde, it is possible to
produce 1H-pyrazolo[3,4-b]pyridine ring 29 wherein a nitrile group
is introduced into 5-position. As the solvent for condensation
reaction, any solvents are used insofar as they do not inhibit the
reaction, and examples of such solvent include, but are not limited
to, alcohol solvents such as methanol or ethanol, water and the
like. The reaction may be carried out in the presence of an acid
for neutralizing alkaline or in an acidic solvent, and as the
reaction solvent, acetic acid, hydrochloric acid, sulfuric acid and
the like can be exemplified. The use amount of malonaldehyde or its
equivalent is usually from 1 to 3 equivalent(s) with respect to the
material, and the reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0138] By deprotecting compound 29, it is possible to produce
compound 30. As the protective group, any groups can be used
insofar as they do not influence on the reaction, and examples of
such group include, but are not limited to, a benzyl group,
benzyloxycarbonyl group, methoxymethyl group, tert-butoxycarbonyl
group, trityl group and the like.
[0139] Deprotection of benzyloxycarbonyl group, methoxymethyl
group, tert-butoxycarbonyl group and trityl group can be achieved
in accordance with Production method 3.
[0140] Deprotection of benzyl group can be achieved, for example,
by the method of letting a Lewis acid act, the method of acidically
hydrolyzing, as well as the method of using active hydrogen such as
the case of catalytic reduction. As a special example, it is known
that heating in pyridine hydrochloride achieves deprotection. As
the catalyst for catalytic reduction, palladium-carbon, platinum
oxide and the like are used as is described in Production method 8,
but other cases use sodium hydride or the like as active hydrogen
species. As a Lewis acid, aluminum chloride is preferably used in
the amount of from 1 to 10 equivalent(s). As the reaction solvent,
any solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, halogen solvents such as dichloromethane or chloroform, benzene
and the like. The reaction temperature is from room temperature to
reflux temperature of the solvent. As the reagent used for the
purpose of acidic deprotection, various chromic acids, permanganic
acid, cerium ammonium sulfate, selenium dioxide and the like are
exemplified, and various chromic acids and permanganic acid are
generally caused to act in an acidic solvent. As the reaction
solvent, for example, sulfuric acid, acetic acid, hydrochloric
acid, water, acetonitrile, acetone or the like is used singly.
Alternatively, by using a phase transfer catalyst, the reaction is
conducted in a double phase reaction system made up of an organic
solvent such as dichloromethane or an acidic solution containing an
oxidizing reagent. The oxidizing reagent is used in an amount of 1
to 5 equivalent(s) with respect to the material, and the reaction
temperature is usually from room temperature to reflux temperature
of the solvent.
Production Method 14
##STR00042##
[0142] In Q.sup.1 to Q.sup.4 in the general formula (II),
1H-pyrazolo[3,4-b]pyrazines wherein Q.sup.1 and Q.sup.4 are
--N.dbd. can be synthesized in the manner as described in
Production method 14. After leading 5-amino-1H-pyrazoles 28
represented by Production method 13 into nitroso compound 31, a
carbonyl compound whose a position is substituted is condensed in
accordance with the known method (J. Chem. Thechnol. Biotechnol.
1990, 49(4) 311-3120 or the like) to thereby form
1H-pyrazolo[3,4-b]pyrazine ring 32. Preferred examples of the
reagent having a suitable substituent include, but are not limited
to, cyanoacetic acid or its ester, cyanoacetoaldehyde, malonic
halide half ester and the like.
[0143] By intermolecular dehydration condensation between compound
31 and the above reaction reagent, amides or imines having an
active methylene can be obtained. By treating these amides or
imines having an active methylene with a suitable base, the formed
anion is dehydration-condensed with the nitroso group in the
molecule, with the result that compound 32 is obtained. Depending
on the reagent to be condensed and reaction condition, a hydroxyl
compound as is compound 33 is sometimes separated, however, by
halogenation and reduction of the hydroxyl group so as to remove
the hydroxyl group, it can be led into compound 32.
[0144] Generally, nitroso reaction is achieved by letting a nitrite
ester or a nitrite salt act on a substrate in an acidic solvent. As
the reaction solvent, a strong acid such as diluted hydrochloric
acid, as well as a mixture thereof with an alcohol such as ethanol
can be used. Examples of the nitrite salt or nitrite ester to be
used include sodium nitrite ester, sodium nitrite ester, isoamyl
nitrite ester and the like, and the use amount is from 1 to 3
equivalent(s) with respect to the material. The reaction
temperature is usually around 0.degree. C.
[0145] As the solvent for intermolecular condensation reaction, any
solvents can be used in so far as they do not inhibit the reaction,
and examples of such solvent include, but are not limited to,
alcohol solvents such as methanol or ethanol, ether solvents such
as 1,2-dimethoxyethane or tetrahydrofuran, N,N-dimethylformamide
and the like. The solvent may contain a base for neutralizing the
acid occurring in the system as is necessary, or by containing an
excess base, intramolecular condensation can be achieved
concurrently in one pot.
[0146] As the solvent for intramolecular condensation reaction, any
solvents can be used in so far as they do not inhibit the reaction,
and examples of such solvent include, but are not limited to,
alcohol solvents such as methanol or ethanol, ether solvents such
as 1,2-dimethoxyethane or tetrahydrofuran, N,N-dimethylformamide,
water and the like, containing a base. As the base to be used,
metal alkoxide, sodium acetate, sodium hydride, tert-butoxy
potassium and the like are exemplified, and the use amount is from
1 to 3 equivalent(s) with respect to the material. As other
reaction solvents, the reaction may be conducted in a basic solvent
of either one of pyridine, triethylamine, picoline and the
like.
[0147] The use amount of reagent used for condensation of
cyanoacetic acid ester, cyanoacetoaldehyde and the like is usually
from 1 to 3 equivalent(s), and the reaction temperature is usually
from room temperature to reflux temperature of the solvent.
[0148] As the halogenation reagent for compound 33, phosphorus
oxychloride, phosphorus oxybromide, phosphorous pentachloride,
dichlorophenylphosphine and the like can be exemplified. The use
amount is usually from 1 to 5 equivalents) with respect to the
material, and as the reaction solvent, hydrocarbon solvents such as
benzene or toluene, N,N-dimethylformamide and the like are used,
however, phosphorus oxychloride, for example may be used in absence
of solvent. The reaction temperature is usually from room
temperature to reflux temperature of the solvent. Next, in
accordance with Production method 9 or the like, the halogen group
is reduced and deprotected, to obtain compound 32.
Production Method 15
##STR00043##
[0150] 1H-pyrazolo[3,4-b]pyrazine ring compound 32 can also be
produced in accordance with Production method 15 as well as
Production method 14. That is, considering that after reducing
nitroso compound 31 described in Production method 14 into diamine
34, a substituent is selectively introduced to 5-position of a
pyrazolopyrazine ring, in accordance with the known method
(Farmaco. Ed. Sci. 1982, 37, 116 or the like), preferably a glyoxal
equivalent is made to act, to thereby obtain compound 35.
Introduction of substituent into compound 35 can be achieved in the
manner as described in Production method 7. As the method of
reducing a nitroso group, for example, hydrogenation using
palladium-carbon, palladium hydroxide-carbon, platinum oxide, Raney
nickel and the like as a catalyst, or the condition of zinc-acetic
acid, copper-acetic acid or the like is used. Also other conditions
such as hydrazine or palladium carbon are known. As the solvent for
hydrogenation, any solvents are used insofar as they do not inhibit
the reaction, and the examples of such solvent include, but are not
limited to, alcohol solvents such as methanol or ethanol, halogen
solvents such as dichloromethane or chloroform, ether solvents such
as tetrahydrofuran or diethyl ether, as well as ethyl acetate,
dimethylformamide, toluene and the like. The use amount of the
catalyst for hydrogenation is 5% to 20% by weight with respect to
the material. The pressure of hydrogen is usually from atmospheric
pressure to 5 atm. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
Production Method 16
##STR00044##
[0152] 1H-pyrazolo[3,4-b]pyrazine ring compound 32 may be produced
in accordance with Production method 16 as is the known method (J.
Org. Chem. 1993, 58(22), 6155-6157). After treating compound 31
with chloroformic acid ester or the like to render it a cyclic
compound 36, various kinds of enamine is caused to act, to thereby
obtain pyrazolopyrazine ring 37 wherein a substituent is
selectively introduced to 5-position. Then compound 37 is
deprotected in accordance with Production method 3 or the like,
thereby obtaining compound 32.
Production Method 17
##STR00045##
[0154] 1H-pyrazolo[4,3-d]pyrimidine ring 41 can be synthesized by a
variety of ring-closing reactions, and preferably it can be
synthesized according to Production method 17. That is, starting
from 4-amino-1H-pyrazole-2-yl carboxylic acid ester 38 obtained by
the known method (Farmaco, Ed. Sci 1984, 39(7), 618), formamide is
caused to act in the known manner (Chem. Pharm, Bull. 1983, 31,
1228) to obtain 1H-pyrazolo[4,3-d]pyrimidine-7-ol 39, and then the
alcohol is removed and a substituent is introduced to 5-position in
the manner as described in the above Production method 14. That is,
following halogenation of compound 39 in accordance with Production
method 14, pyrazole is protected in accordance with Production
method 3 to produce compound 40. Then a substituent is introduced
to 5-position in the method as described in Production method 7 or
the like, followed by dehalogenation by reduction and deprotection,
to thereby produce the objective compound 41. As the solvent for
the condensation reaction with formamide, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, alcohol solvents
such as ethanol, ether solvents such as tetrahydrofuran or diethyl
ether, and hydrocarbon solvents such as benzene or toluene. The use
amount of formamide is from 1 equivalent with respect to the
material to solvent amount, and the reaction temperature is from
room temperature to reflux temperature of the solvent.
Production Method 18
##STR00046##
[0156] As other construction methods for
1H-pyrazolo[4,3-d]pyrimidine ring compound 41, various kinds of
pyrazole analogs can be selected for a starting material as
described in Production method 18. As a compound which is analogous
to 4-amino-1H-pyrazole-2-yl carboxylic acid ester 38 shown in
Production method 17, compound 42 synthesized by the known method
(Bioorg. Med. Chem., Lett. 2000, 17(10), 1983-1986) and the like
can be preferably exemplified.
[0157] Compound 42 is a useful intermediate for constructing a ring
by various kinds of cyclization reactions as is shown in Production
method 18. For example, by condensing compound 42 by action of
formic acid or alkyl orthoformate by way or a known method
(Phrmazie, 1996, 51(12), 983-984), it is possible to obtain
1H-pyrazolo[4,3-d]pyrimidine-7-ol derivative 43 or compound 39.
Furthermore, from compound 39, by successively conducting
halogenation, protection, peroxidation, actions of various reagents
to N-oxide, reduction and deprotection in accordance with the
above-mentioned Production method 17, it is possible to produce
compound 41 wherein a functional group is introduced to
5-position.
[0158] In accordance with the known method (J. Med. Chem. 1988, 31,
454), compound 44 which is easily obtained from compound 42 by
dehydration may be condensed with a suitable carboxylic acid
anhydride so as to introduce a functional group to 5-position.
[0159] Similarly, compound 42 may be condensed with various kinds
of carboxylic acid derivatives, to produce cyclic compound 43. As a
condensing reagent to be acted on 42, acid chlorides and acid
anhydrides are preferably used. Depending on the reagent to be
used, cyclization proceeds stepwise through intermediate 45. With
regard to condensation ring-forming reaction as described above,
reference is made to the known method (Heterocycles. 2000, 53(12),
2643-2652) for detail. It can be obtained by halogenating and
reducing 1H-pyrazolo[4,3-d]pyrimidine-7-ol 43 in which 5-position
is substituted by condensation in accordance with Production method
14.
Production Method 19
##STR00047##
[0161] 1H-pyrazolo[4,3-e][1,2,4]triazine ring compound 50 can be
readily constructed (synthesized) by using, for example, serine
derivative 46 as a starting material. In accordance with a regular
method, an amino group of compound 46 is turned to
dimethylaminomethylidene, a formyl equivalent such as compound 47
is introduced, and then compound 47 is treated with hydrazine in
accordance with the known method (J. Het. Chem. 1985, 22(2), 409),
whereby 6-hydroxytriazine ring is constructed. Subsequently, the
resultant compound is oxidized by using the method of Production
method 1 or the like, to produce compound 48, which is again
treated with hydrazine in accordance with the known method
(Pharmazie, 1984, 39(7), 504), thereby constructing
1H-pyrazolo[4,3-e][1,2,4]triazine ring compound 49. Subsequently, a
side chain moiety is introduced in the manner as described in
Production method 7 or the like, to produce compound 50.
[0162] The followings are concrete production examples for the
compounds represented by the general formula (I)-A including
production methods for the side chain moiety, however, it is to be
understood that production methods are not limited thereto. The
general formula (I)-A represents a compound in which Cy is a
5-membered heteroaryl among the compounds represented by general
formula (I). In this formula, U.sup.1 to U.sup.3 each independently
designate --O--, --NV.sup.1--, --SV--, --CV.dbd., --N.dbd. or
--CO--, and at least one of U.sup.1 to U.sup.3 designates --O--,
--NV.sup.1--, --SV-- or --N.dbd. and U designates --OH, --NH.sub.2
or --SH.
[0163] Production methods 20 to 22 describe for the case where
U.sup.1 at 4-position is a hetero atom.
Production Method 20
##STR00048##
[0165] In the case where U.sup.1 is a hetero atom and at least one
of U.sup.3 and U.sup.3 is --CH.dbd. in the general formula (I)-A,
by introducing a variety of functional groups into a position
corresponding to U.sup.2 or U.sup.3 of compound 52 obtainable by
protecting 1-position of compound 51 by way of electrophilic
substitution reaction using the orientation, followed by
deprotection, it is possible to produce Compound (I)-A-1. As the
functional group which may be introduced by way of electrophilic
substitution reaction, halogen groups, sulfon groups, nitro group,
acyl groups and the like can be exemplified.
[0166] Halogenation can be achieved in accordance with Production
method 3.
[0167] As a sulfonation method, a reaction in the presence of
proton such as sulfuric acid, a condition using pyridine sulfur
trioxide where there are no protons and the like are used. The use
amount of sulfonation reagent is from 1.05 to 1.2 equivalent(s)
with respect to the material. The reaction may be conducted in the
absence of solvent or in the presence of solvent. As the solvent,
any solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, hydrocarbon halides such as dichloromethane, chloroform or
carbon tetrachloride. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0168] As a nitration method, concentrated nitric acid, fuming
nitric acid, mixed acid of nitric acid and sulfuric acid, mixture
of sodium nitrate or potassium nitrate and sulfuric acid, acetyl
nitrate, trifluoroacetyl nitrate, as well as nitronium salts such
as nitronium trifluoromethanesulfonate or nitronium
tetrafluoroborate and the like are used. The use amount of
nitration reagent is from 1.05 equivalents with respect to the
material to solvent amount. The reaction may be conducted in the
absence of solvent or in the presence of solvent. As the solvent,
any solvents can be used in so far as they are not concerned with
the reaction, and examples of such solvent include, but are not
limited to, hydrocarbon halides such as dichloromethane, chloroform
or carbon tetrachloride, hydrocarbons such as hexane or pentane,
and when a nitronium salt is used, sulfolane or acetonitrile can be
used. The reaction temperature is usually from -20.degree. C. to
reflux temperature of the solvent.
[0169] As an acylation method, Friedel-Crafts reaction is
preferably used.
[0170] In the case where U.sup.1 is a NH group, the group may be
protected with a suitable protective group in the similar manner as
described for protection of 1-position, and then deprotected in the
final step. Protection and deprotection of 1-position is achieved
in the manner as described in Production method 3.
Production Method 21
##STR00049##
[0172] Compound (I)-A-2 in which a substituent is introduced to the
position corresponding to U.sup.2 can be produced by protecting
1-position of pyrazole of compound 53 wherein U.sup.2 is --CH.dbd.
to obtain compound 54, and converting compound 54 into a metal aryl
with the use of alkyl lithium, lithium amide or the like,
introducing a substituent V in accordance with the Production
method 6, and then conducting deprotection. As the functional group
which may be introduced, halogen groups, formyl group, acyl groups,
azido group, amino group and the like are exemplified.
[0173] Compound (I)-A-2 is produced in the following manner. After
converting compound 54 into a metal aryl in accordance with
Production method 1, the resultant metal aryl is reacted with a
variety of reagents, followed by deprotection. As the variety of
reagents, the following reagents can be exemplified. Examples of
halogenation reagent include iodine, N-iodosuccinimide, bromine,
N-bromosuccinimide and the like. Examples of formylation reagent
include N,N-dimethylformamide, N-formylpiperidine,
methylphenylformamide and the like. Examples of azidation reagent
include azidomethyltrimethylsilane, toluenesulfonyl azide and the
like.
[0174] Protection and deprotection of 1-position of pyrazole ring
are achieved in the manner as described in Production method 3.
Production Method 22
##STR00050##
[0176] In the Production method 20, when U.sup.2 and U.sup.3 are
--CH.dbd., and hence it is difficult to selectively introduce a
substituent by way of electrophilic substitution reaction using
orientation to U.sup.3, first 1-position of pyrazole of compound 55
is protected in the similar manner as described in Production
method 21, which is then converted into a metal aryl with the use
of alkyl lithium, lithium amide or the like, and then halogenated
by action of a halogenation reagent to obtain compound 56 wherein
U.sup.2 is halogenated; and then a substituent is introduced to
U.sup.3 by electrophilic substitution reaction, followed by a
sequence of reduction and deprotection, whereby Compound (I)-A-3 is
obtained.
[0177] Protection and deprotection of 1-position are achieved in
the manner as described in Production method 3.
[0178] Production methods 23 to 24 describe the case where U.sup.2
at 5-position is a hetero atom.
Production Method 23
##STR00051##
[0180] In the case where U.sup.2 is a hetero atom, and at least one
of U.sup.1 and U.sup.3 is --CH.dbd., in accordance with the method
described in Production method 20, it is possible to produce
Compound (I)-A-4 having a substituent at U.sup.1 or U.sup.3 from
compound 58 which is obtained by protecting 1-position of compound
57.
Production Method 24
##STR00052##
[0182] Compound (I)-A-4 having a substituent at U.sup.1 or U.sup.3
can also be produced in the manner as described in Production
method 21.
[0183] Production methods 25 to 27 describe the case where U.sup.3
at 6-position is a hetero atom.
Production Method 25
##STR00053##
[0185] In the case where U.sup.3 is a hetero atom and at least one
of U.sup.1 and U.sup.2 is --CH.dbd., it is possible to produce
Compound (I)-A-5 into which a substituent is introduced at U.sup.1
or U.sup.2 in the manner as described in Production method 20.
Production Method 26
##STR00054##
[0187] Compound (I)-A-6 in which a substituent is introduced to the
position corresponding to U.sup.2 can be produced in the manner as
described in Production method 21.
Production Method 27
##STR00055##
[0189] In the case where U.sup.1 and U.sup.2 are --CH.dbd. and
hence it is difficult to selectively introduce a substituent by way
of electrophilic substitution reaction using orientation to U.sup.1
in Production method 24, Compound (I)-A-7 can be produced in the
similar manner as described in Production method 22 while
protecting 1-position of pyrazole of compound 63 in the similar
manner as Production method 25.
Production Method 28
##STR00056##
[0191] Methods which are similar to Production methods 20 to 27 may
also be generally applied before ring-closing of pyrazole ring.
That is, after introducing a substituent V to into compound 65, the
pyrazole ring is closed with hydrazine monohydrate, to thereby
produce Compound (I)-A. Cyclization reaction of hydrazine
monohydrate can be achieved in accordance with Production method
1.
Production Method 29
##STR00057##
[0193] In the case where it is difficult to practice Production
method 28 in accordance with Production method 1, first compound 67
is separated, which is then cyclized by Ullmann reaction using a
copper reagent or coupling reaction using a palladium catalyst, to
thereby produce Compound (I)-A.
[0194] Hydrazine may be reacted with compound 66 without being
protected, however, hydrazide which is protected with an acetyl
group or the like is preferably used. This reaction may be
conducted in the absence of solvent or in the presence of solvent.
As the solvent, any solvents can be used insofar as they are not
concerned with the reaction, and examples of such solvent include,
but are not limited to, ether solvents such as diethyl ether,
tetrahydrofuran, dioxane or dimethoxyethane, alcohol solvents such
as methanol, ethanol or propanol, as well as pyridine, dimethyl
sulfoxide, benzene, toluene and the like. The use amount of
hydrazine or hydrazide is from 2 to 20 equivalents with respect to
the material. The reaction temperature is usually from 0.degree. C.
to reflux temperature of the solvent.
[0195] As the copper reagent to be used in Ullmann reaction,
copper, copper chloride, copper bromide, copper iodide, copper
oxide and the like can be exemplified. The use amount is from a
catalyst amount to 2 equivalents with respect to the material.
Examples of the base to be used include, but are not limited to,
potassium carbonate, sodium carbonate, potassium acetate, sodium
acetate and the like. The reaction may be conducted in the absence
of solvent or in the presence of solvent. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, toluene, nitrobenzene, diphenyl ether, dimethylformamide,
dioxane and the like. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0196] Examples of the palladium catalyst to be used when the
reaction is achieved by coupling reaction include, but are not
limited to, tris(dibenzylideneacetone) dipalladium, palladium
acetate and the like. As a ligand,
2,2'-bis(diphenylphosphino)-1,1'-naphtyl,
1,1'-bis(diphenylphosphino) ferrocene, tri(tert-butyl) phosphine or
the like is used in the amount of 1 to 3 equivalent(s) to the
catalyst. As the base, sodium tert-butoxide, potassium
tert-butoxide, cesium carbonate and the like are preferred. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and preferred examples of such solvent include,
but are not limited to, dimethylformamide, tetrahydrofuran,
dioxane, diethyleneglycol dimethyl ether, toluene, xylene and the
like. The reaction temperature is usually from room temperature to
reflux temperature of the solvent.
[0197] Protection and deprotection of 1-position of pyrazole are
achieved in the manner as described in Production method 3.
Production Method 30
##STR00058##
[0199] Synthesis of Compound (I)-A is also achieved by the method
in accordance with Production method 5. That is, using compound 69
wherein an amino group or its equivalent functional group and an
active methyl group or active methylene group are adjacent with
each other on the aromatic ring, as a precursor, the amino group or
its equivalent functional group is converted to a nitroso group
using nitrite salt or nitrite ester. This reaction intermediate is
then subjected to intramolecular dehydrating condensation with the
adjacent active methyl group or methylene group in the presence of
a suitable acid or base, to thereby construct a pyrazole ring.
Finally, deprotection is conducted, to produce Compound (I)-A.
[0200] Protection and deprotection of 1-position of pyrazole are
achieved in the manner as described in Production method 3.
[0201] The compounds embraced in the general formula (I)-A include
other compounds which are readily produced by a production method
other than the production method using the above-exemplified
production process, which is specific to the forming condensed
pyrazole ring. Now, production methods which are useful for
production of specific heterocycle are exemplified in Production
method 31 to Production method 34. As for synthesis of these group
of compounds, it goes without saying that these compounds may be
produced by using the above-described production method and the
production method is not limited to the following production
methods.
Production Method 31
##STR00059##
[0203] Compound 72 can be produced in the following manner:
compound 69 which is easily in accordance with the known methods
(U=hydroxyl group: for example, J. Org. Chem. 1992, 57, 5680-5686.,
U=thiol group: for example, J. Heterocycle. Chem. 1990, 27, 567.,
U=amino group: for example, Synthesis 1987, 1124.) is iodized or
brominated at 4-position of pyrazole to obtain compound 70;
trimethylsilyl acetylene is coupled to this compound 70 by
Sonogashira coupling and detrimethylsilylation is conducted to
obtain compound 71; and then compound 71 is aromatized and
deprotected.
[0204] By halogenating 4-position of compound 69 in accordance with
Production method 1, it is possible to produce compound 70. As the
halogen atom to be substituted, iodine or bromine is preferred.
[0205] Trimethylsilyl acetylene used for Sonogashira coupling is
commercially available one. The use amount of trimethylsilyl
acetylene is from 1 to 3 equivalent(s) with respect to the
material. Examples of catalyst to be used include, but are not
limited to, palladium acetate (II), dichlorobistriphenyl phosphine
palladium (II), tetrakis(triphenylphosphine)palladium (0) and the
like. The use amount of catalyst is about 0.1% by mole with respect
to the material. As is necessary, it is possible to add an
equivalent or twice the catalyst amount of an additive, for
example, copper iodide (I), triphenylphosphine and the like.
Examples of the base to be used include, but are not limited to,
triethylamine, diisopropylamine, piperidine and the like. As the
solvent, any solvents can be used insofar as they do not inhibit
the reaction, and preferred examples of such solvent include, but
are not limited to, dimethylformamide, tetrahydrofuran, dioxane,
diethyleneglycol dimethyl ether, toluene, xylene and the like. The
reaction temperature is usually from room temperature to reflux
temperature of the solvent.
[0206] Detrimethylsilylation can be readily achieved using fluorine
anion or acid. As the fluorine anion, tetrabutylammonium fluoride,
hydrogen fluoride, potassium fluoride, cesium fluoride and the like
can be used. As the solvent, any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include, but are not limited to, hydrocarbon halides such
as dichloromethane or chloroform, alcohol solvents such as methanol
or ethanol, as well as water, diethyl ether, tetrahydrofuran,
dioxane, toluene and the like. The reaction temperature is from
-20.degree. C. to reflux temperature of the solvent. As the acid,
hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like
are used. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and examples of such solvent
include, but are not limited to, hydrocarbon halides such as
dichloromethane or chloroform, alcohol solvents such as methanol or
ethanol, diethyl ether, tetrahydrofuran and the like. The reaction
temperature is -20.degree. C. or reflux temperature of the
solvent.
[0207] Aromatization is achieved in the similar condition as that
of Sonogashira coupling.
[0208] In the case where U is a nitrogen atom, the nitrogen atom
may be protected with a suitable protective group in the similar
manner as is protection of 1-position, and finally protected.
Protection and deprotection of 1-position of pyrazole and U are
achieved in the manner as described in Production method 3.
Production Method 32
##STR00060##
[0210] Compound 74, which already has a substituent introduced to
U.sup.2 of compound 72 before subjected to cyclization can be
readily produced by introducing a hetero group having an active
methylene at .alpha.-position into 5 (3)-position of compound 73
which is readily synthesized in accordance with the known method
(for example, Synlett. 2000, 8, 1115-1118.), followed by
cyclization.
[0211] As a reagent for introducing a hetero atom having a active
methylene into compound 73, t-butoxycarbonyl glycine, thioglycolic
acid or its ester, thioglyconitrile, glycolic acid or its ester,
glyconitrile and the like can be exemplified. Examples of the base
to be used include, but are not limited to, sodium hydroxide,
potassium hydroxide, sodium alkoxide, potassium alkoxide and the
like. As the solvent, any solvents can be used insofar as they are
not concerned with the reaction, and preferred examples of such
solvent include, but are not limited to, alcohols such as methanol,
ethanol, isopropanol or tert-butanol. The reaction temperature is
from room temperature to reflux temperature of the solvent.
[0212] In the case where U is an amino group, the amino group may
be protected with a suitable protective group in the similar manner
as is protection of 1-position, and protected in the final step.
Protection and deprotection of 1-position of pyrazole and U are
achieved in the manner as described in Production method 3.
Production Method 33
##STR00061##
[0214] Compound 77 can be produced in the following manner:
4-position of pyrazole of compound 75 which is easily synthesized
in the documentarily known method (for example, J. Heterocycle.
Chem. 1982, 19, 117.) is formylated by Vilsmeier reaction to render
compound 76; and then compound 76 is aromatized and
deprotected.
[0215] Vilsmeier reaction is achieved by a methylene iminium
compound formed of phosphorus oxychloride and formamide, and as the
formamide, N,N-dimethylformamide is preferred. The use amount of
phosphorus oxychloride is from 1 to 2 equivalent(s) with respect to
a starting material, and the use amount of N,N-dimethylformamide is
from 1 equivalent with respect to the material to solvent amount.
As the solvent, any solvents can be used without particular
limitation insofar as the are not concerned with the reaction, and
no solvent or N,N-dimethylformamide used as the formamide is
preferred. The reaction temperature is usually from 0.degree. C. to
reflux temperature of the solvent.
[0216] As the method for aromatization, a documentarily known
method can be used. For example, Lewis acids such as boron
trifluoride-diethyl ether complex is used for the case of furan
ring (for example, Synth. Commun. 1999, 29, 729-747.), protonic
acids such as trifluoroacetic acid or p-toluenesulfonic acid (for
example, J. Org. Chem. 1998, 63, 2909-2917.) and the like can be
used depending on the type of the hetero atom. In the case of a
thiophene ring, the method of converting a hydroxyl group to a
thiol group by means of Lawesson reagent (for example, J. Org.
Chem. 1998, 63, 2909-2917.), the method of conducting ring-closing
after bromination of hydroxyl group (for example, J. Heterocycle.
Chem. 1998, 35, 71-75.) and the like can be used. Bromination of
hydroxyl group can be achieved with phosphorous tribromide, 48%
hydrobromic acid and the like. In the case of a pyrrole ring, a
method of oxidizing hydroxyl group to aldehyde to obtain
dialdehyde, and then closing the ring (for example, Tetrahedron,
1979, 35, 1433.), and the method of making the diol obtained by
reduction of formyl group into a dibromide compound, and then
closing the ring (for example, Synthesis, 1975, 252.) and the like
can be used. Oxidation of hydroxyl group into aldehyde can be
achieved using manganese dioxide or the like. Reduction of formyl
group into alcohol can be achieved by sodium borohydride or the
like, and dibromination of diol can be achieved by phosphorous
tribromide, 48% hydrobromic acid and the like.
[0217] Protection and deprotection of 1-position of pyrazole can be
achieved in the manner as described in Production method 3.
Production Method 34
##STR00062##
[0219] Compound 81 can be produced by using compound 78 readily
synthesized in the known manner (U=hydroxyl group: for example, J.
Chem. SOC., Perkin Trans., 1985, 81., U=amino group: for example,
J. Am. Chem. Soc. 1950, 72, 2978.) as a starting material. More
specifically, 5(3) position of pyrazole of compound 78 is turned to
a metal aryl by means of alkyl lithium, lithium amide or the like,
followed by iodization or bromination to obtain compound 79, to
which trimethylsilyl acetylene is coupled by Sonogashira coupling.
Then detrimethylsilylation is conducted and the resultant compound
80 is aromatized and deprotected, whereby compound 81 is produced.
In the case where U is a thiol group, after converting the amino
group into diazonium using sodium nitrite ester or the like by way
of the known method (Org. Synth. 1955, III, 809.) or the like, the
resultant compound is treated with potassium O-ethyl
dithiocarbonate or the like, whereby compound 81 is produced.
Alternatively, compound 81 may be produced using a known method (J.
Heterocycle. Chem. 1991, 28, 41.) or the like, by introducing a
thiol group after halogenating 4-position of pyrazole with
N-iodosuccinimide, N-bromosuccinimide or the like.
[0220] Conversion of compound 78 into a metal aryl and subsequent
iodization or bromination are conducted in accordance with
Production method 1, and conversion from compound 79 to compound
80, that is, Sonogashira coupling and subsequent
detrimethylsilylation are conducted in accordance with Production
method 31. Also, protection and deprotection of 1-position of
pyrazole are achieved in the manner described in Production method
3.
[0221] In the general synthesis methods exemplified in Production
method 35 to Production method 44 below, R.sup.1 has the same
meaning as the formula
--(CO).sub.h--(NR.sup.a).sub.j--(CR.sup.b.dbd.CR.sup.c).sub.k--Ar
in the general formula (I). These general synthesis methods are
given as detailed description for conversion of R.sup.1 moiety, and
the present invention is not limited to the exemplified Production
methods. Therefore, a process of introduction and conversion of V
may be included in any reaction route, and protecting a pyrazole
ring in a desired production, step will not influence on the
process.
Production Method 35
##STR00063##
[0223] The compound (I)-a represented by (h=j=0,k=1) in the general
formula (I) can be produced after converting compound 82 into
compound 84 by halogenating 3-position of compound 82 while
protecting 1-position, compound 85 is obtained by Heck reaction or
Suzuki reaction, followed by deprotection.
[0224] 3-position of compound 82 is halogenated in the manner as
described in Production method 3, whereby compound 83 is obtained.
As a protective group for 1-position of pyrazole in compound 83,
tert-butoxycarbonyl group, trityl group and the like are preferred
without limitation, and compound 83 can be led to compound 84 in
accordance with Production method 3.
[0225] By conducting Heck reaction or Suzuki coupling on compound
84 in the manner as described in Production method 3, it is
possible to produce compound 85.
[0226] Deprotection of compound 85 readily proceeds by acid
treatment in accordance with Production method 3, whereby compound
(I)-a is produced.
Production Method 36
##STR00064##
[0228] Compound (I)-b wherein positional relationship between Ar
and pyrazole is "cis" which is different from (I)-a can be produced
by using a boronic acid which corresponds to a position isomer
different from the boronic acid used in Production method 35.
Starting from compound 84 and through compound 86, (I)-b can be
produced in the similar manner as described in Production method
35.
Production Method 37
##STR00065##
[0230] With regard to (I)-c represented by
(h=j=0,k=1,R.sup.b.dbd.R.sup.c.dbd.H) in the general formula (I),
it is possible to construct the R.sup.1 moiety stepwise in the
methods described in Production methods 35 and 36. That is, after
introducing a vinyl unit and a vinylboronic acid unit into compound
84, aromatic ring coupling and deprotection are conducted in
accordance with the Production method 3, whereby II)-c is
produced.
[0231] Introduction of a vinyl group into compound 84 can be
achieved, for example, by Stille reaction, Negishi reaction or Heck
reaction. As a vinylation reagent, commercially available reagent
is purchased and commercially unavailable reagents are prepared in
a commonly used method. As the reaction reagent, vinyl trialkyl tin
for Stille reaction, vinyl zinc halide for Negishi reaction, and
ethylene gas for Heck reaction can be used. As a reagent other than
the above, vinyltrialkoxysilane, vinyltrialkylsilane and the like
can be exemplified.
[0232] Production of compound 88 into which vinyl boronic acid or
vinylboronic acid ester unit is introduced can be achieved, for
example, by Heck reaction with respect to compound 84. As the
reaction reagent, vinylboronic acid pinacol ester or the like is
exemplified without limitation.
[0233] With respect to compound 87, an aromatic ring can be
introduced by Suzuki coupling with aryl boronic acid, Heck reaction
with aryl halide, and Stille reaction with aryltrialkyl tin. With
respect to compound 88, an aromatic ring can be introduced by
Suzuki coupling with aryl halide.
[0234] As a Pd catalyst used in these coupling reactions, for
example, tris(dibenzylideneacetone) dipalladium (0), reagents
described in Production method 3 and the like are used without
limitation, and a suitable phosphine ligand as described in
Production method 3 may coexist. The condition for coupling
reaction is achieved in accordance with Production method 3.
[0235] Furthermore, production of compound 88 into which
vinylboronic acid unit is introduced can be achieved also by
addition reaction of borane with respect to compound 87 in the
presence of a rhodium or iridium catalyst. Examples of such reagent
include, but are not limited to, chloro(1,5-cyclooctadiene) rhodium
(I) dimer and pinacol borane.
Production Method 38
##STR00066##
[0237] (I)-c and (I)-d represented by
(h=j=0,k=1,R.sup.b.dbd.R.sup.c.dbd.H) in the general formula (I)
can be produced by converting compound 84 into alkynyl compound 89
by Sonogashira reaction, and reducing compound 89 to olefin.
[0238] The acetylene derivative used for Sonogashira reaction is
readily prepared by conducting Sonogashira reaction using
commercially available aryl halide and trimethylsilyl acetylene,
and removing the trimethylsilyl group by an acid. It is possible to
produce compound 89 from compound 84 in the manner as described in
Production method 31.
[0239] In reduction from alkyne compound 89 to olefin, it is
possible to control the generation ratio of position isomers by
selecting a variety of reducing agents. As is exemplified in
Production method 38, by reducing compound 89 using lithium
aluminum hydride, Lindlar catalyst and the like under different
conditions, it is possible to obtain trans (I)-c and cis (I)-d
olefins as main products in the respective conditions. By
deprotection in accordance with Production method 3, (I)-c and
(I)-d can be obtained.
Production Method 39
##STR00067##
[0241] (I)-e represented by (h=j=0,k=1,R.sup.b.dbd.H) in the
general formula (I) can be produced by converting aldehyde 90 into
pyrazole 91, then converting a methyl group at 3-position into a
methyl alcohol and then into a formyl group, and then conducting
Wittig reaction. Conversion of aldehyde 90 to pyrazole 91 can be
achieved, for example, by causing methyl metal such as methyl
lithium or methyl magnesium to act on aldehyde 90, oxidizing the
resultant alcohol in accordance with Production method 1, and then
causing hydrazine to act. Conversion from compound 91 to compound
92 can be achieved, for example, by introduction of a halogen,
followed by hydrolysis by treatment with a base. Introduction of
halogen can be conducted in the similar manner as described in
Production method 3, and as is necessary, pyrazole may be
protected. Conversion of halogen compound to alcohol 92 may be
direct conversion using, for example, sodium hydroxide, potassium
hydroxide and the like, however, it is also possible to obtain
compound 92 by first converting into an acetate by action of sodium
acetate, potassium acetate or the like, and then hydrolyzing the
acetate sodium hydroxide, potassium hydroxide or the like. Also, it
is possible to produce compound 93 by oxidizing the methyl group at
3-position of pyrazole of compound 91 with a suitable oxidizing
reagent to an aldehyde.
[0242] Oxidation from alcohol compound 92 to aldehyde 93 can be
conducted in accordance with Production method 1. Wittig reaction
of compound 93 can be achieved by reaction between compound 93 and
phosphonium ylide. The phosphonium ylide can be readily synthesized
by letting a commercially available alkyl halide or the like react
with triphenylphosphine in an ether solvent to render a phosphonium
salt, which is then treated with a base such as sodium hydride,
sodium hydroxide, potassium carbonate or metal alkoxide. As the
reaction solvent for Wittig reaction of compound 93, for example,
ether solvents such as diethyl ether or tetrahydrofuran,
hydrocarbon halides such as dichloromethane or chloroform,
hydrocarbon solvents such as benzene or toluene, alcohol solvents
such as methanol, as well as N,N-dimethylformamide and the like are
used. The use amount of the base is usually from 1 to 3
equivalent(s) with respect to the material. The reaction
temperature is from 0.degree. C. to reflux temperature of the
solvent.
Production Method 40
##STR00068##
[0244] Compound (I)-f represented by (h=j 0,k=1) in the general
formula (I) is obtained by letting a metal reagent such as alkyl
lithium or aryl lithium act on aldehyde 93 to convert it an
alcohol, oxidizing the resultant alcohol to ketone 94 in accordance
with Production method 1, and then subjecting the ketone 94 to
Wittig reaction in the similar manner as described in Production
method 39.
Production Method 41
##STR00069##
[0246] Compound 93 which is a starting material for synthesis in
Production method 39, Production method 40 or the like can be
produced, for example, by lithionating 1-position of halogen
compound 83 with N-butyllithium or phenyllithium, lithionating a
halogen at 3-position with sec-butyllithium or tert-butyllithium,
and then letting the resultant compound react with
N,N-dimethylformamide, N-formylpiperidine, methylphenylformamide or
the like. The amount of N-butyllithium or phenyl lithium is from 1
to 2 equivalent(s) with respect to the material. The amount of
sec-butyllithium or tert-butyllithium is from 1 to 2 equivalent(s)
with respect to the material. The amount of formylation reagent
such as N,N-dimethylformamide is from 1 to 5 equivalent(s) with
respect to the material. The reaction solvent is preferably ether
solvents such as diethyl ether or tetrahydrofuran. The reaction
temperature is from -78.degree. C. to room temperature. The
reaction may be conducted after protecting pyrazole in the similar
manner as described in Production method 1 as is necessary. In this
case, the use amount of lithionating reagent is from theoretical
amount to 2 equivalent(s).
[0247] Formyl compound 93 may be produced by subjecting compound 82
to Vilsmeier reaction in the similar manner as described in
Production method 33.
Production Method 42
##STR00070##
[0249] Compound (I)-g represented by (h=1,j=k=0) in the above
general formula (I) can be produced by letting compound 93 and
metal aryl or metal halogenoaryl react in accordance with
Production method 1 to make alcohol 95, and oxidizing the alcohol
to ketone in accordance with Production method 1.
[0250] Compound (I)-g may also be produced by introducing a
suitable protective group to 1-position of compound 93, executing
the above Production method, and the conducting deprotection.
Production Method 43
##STR00071##
[0252] Compound (I)-h represented by (h=j=1,k=0) in the above
general formula (I) can be produced by protecting 1-position of
compound 93, oxidizing formyl group to convert into carboxylic acid
97, and then successively conducting amidation and
deprotection.
[0253] Introduction of protective group into 1-position of compound
93 can be conducted in accordance with Production method 3. As the
oxidizing reagent for oxidizing compound 96 into carboxylic acid
97, Jones reagent, pyridinium dichromate, sodium chlorite can be
exemplified. As the solvent, any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include hydrocarbon halides such as dichloromethane or
chloroform, as well as ethyl acetate, N,N-dimethylformamide,
dimethyl sulfoxide and the like. The reaction temperature is from
0.degree. C. to reflux temperature of the solvent.
[0254] Amidation of carboxylic acid 97 can be achieved in
accordance with Production method 47. Also amidation of carboxylic
acid 97 can be achieved by converting carboxylic acid 97 into an
acid chloride using thionyl chloride, oxalyl chloride and the like,
and then subjecting the acid chloride to Schotten-Baumann reaction
with an amine in the presence of a base such as triethylamine,
diisopropylethylamine, pyridine and the like.
[0255] The protective group at 1-position is deprotected in
accordance with Production method 3, whereby (I)-h is produced.
Production Method 44
##STR00072##
[0257] Carboxylic acid 97 produced in Production method 43 can also
be produced by hydrolyzing compound 98, and introducing a
protective group at 1-position after diazotization and
reduction.
[0258] For hydrolysis of compound 98, for example, an aqueous
solution of sodium hydroxide, an aqueous solution of potassium
hydroxide and the like is used. The reaction for converting into
diazonium salt is achieved by reaction with a nitrite ester such as
sodium nitrite ester or isoamyl nitrite ester in the presence of an
acid. As the reaction solvent, for example, alcohol solvents such
as methanol or ethanol, water and the like are used, and as the
acid, hydrochloric acid, sulfuric acid, acetic acid and the like
are can be used. The reaction temperature is usually around
0.degree. C.
[0259] Reduction of diazonium salt and subsequent ring-closing of
the indazole ring can be achieved by action of a reducing reagent,
such as tin chloride (II) or copper chloride (II), for example in
the presence of an acid, and the use amount of these reagent is
usually from 1 to 10 equivalent(s) with respect to the material. In
general, the ring-closing occurs spontaneously in the reaction
system accompanied with dehydration, and thereby compound 99 is
obtained. As the reaction solvent, for example, alcohol solvents
such as methanol or ethanol, as well as hydrochloric acid, sulfuric
acid, acetic acid and the like can be used. The reaction
temperature is usually from 0.degree. C. to reflux temperature of
the solvent.
[0260] Introduction of protective group into 1-position of compound
99 can be achieved in accordance with Production method 3. Also
compound 97 can be produced by hydrolysis of ester under a usual
condition after converting a carboxylic acid into an ester in a
usually-used condition, and introducing a protective group into
1-position as is necessary.
[0261] The following production methods are concrete description
for typical functional group conversion after formation of
condensed pyrazole rings represented by the general formulae (I)
(II) and (III). It is to be noted that following production methods
may also be employed in production steps before formation of
pyrazole ring rather than after formation of condensed pyrazole
ring, and commercially available starting materials and
intermediates originally having suitable functional groups may be
used. Diversity of functional groups to be introduced is not
limited to the methods exemplified in Production methods.
Production Method 45
##STR00073##
[0263] In general, aryl halide can be converted into a cyano group
by means of a cyanizing reagent. As the halogen atom T.sup.3, a
chlorine atom, bromine atom and iodine atom are recited, with a
bromine atom or iodine atom being desired. In the case where the
substitution position of halogen atom corresponds to ortho-position
or para-position of a nitrogen atom forming the aromatic ring, the
halogen may be a chlorine atom. Although a protective group for
pyrazole ring is sometimes unnecessary, it is usually preferable to
have a protective group. As the cyanization reagent to act on
compound 100, zinc cyanide, lithium cyanide, sodium cyanide,
potassium cyanide and the like are exemplified, and the cyanization
is achieved by using a transition metal catalyst such as
tetrakis(triphenylphosphine) palladium, tris(dibenzylideneacetone)
dipalladium, dichlorobis(triphenylphosphine) palladium, palladium
diacetate and the like, and adding a catalyst amount of a copper
iodide or a phosphine ligand such triphenylphosphine and
1,1'-bis(diphenylphosphino) ferrocene as is necessary for promoting
the reaction. As the solvent to be used, dimethylformamide,
N-methylpyrrolidone, propionnitrile, acetonitrile and the like are
preferred. The reaction temperature is preferably in the range from
80.degree. C. to 150.degree. C. Furthermore, nitrile 101 may also
be produced by letting copper cyanide and compound 100 react in a
solvent such as dimethylformamide or N-methylpyrrolidone at a
temperature ranging from 140.degree. C. to 200.degree. C.
Production Method 46
##STR00074##
[0265] Hydrolysis of nitrile of compound 102 which is readily
produced by deprotection of compound 101 or the like can be
achieved by using an acid or alkaline. As the acid, hydrochloric
acid, hydrous sulfuric acid and the like can be recited. Although
the reaction may be conducted in the absence of solvent, when a
solvent is used, for example, methanol, ethanol, propanol and the
like alcohol solvents, as well as acetic acid and the like can be
used. The reaction temperature is usually from room temperature to
reflux temperature of the solvent. As the alkaline, for example,
sodium hydroxide, potassium hydroxide and the like can be used. As
the solvent, the reaction may be conducted just in alkaline water,
however, when a solvent is used, for example, methanol, ethanol,
propanol and the like alcohol solvents, dioxane and the like can be
used. The reaction temperature is usually from room temperature to
reflux temperature of the solvent. In this production method, when
compound 101 having tert-butoxycarbonyl group, trityl group or the
like, for example, as a protective group at 1-position is subjected
to the similar hydrolysis condition, deprotection generally occurs
to generate 103.
Production Method 47
##STR00075##
[0267] Amidation of carboxylic acid 103 can be achieved by mixing
amine and a condensing reagent. As the condensing reagent, for
example, dicyclohexylcarbodiimide, diisopropylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the
like can be used. As is necessary, 1-hydroxybenzotriazole,
N-hydroxysuccinimide and the like may be added. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include halogen solvents
such as dichloromethane or chloroform, ether solvents such as ether
or tetrahydrofuran, as well as ethyl acetate,
N,N-dimethylformamide, N-methylpyrrolidone, toluene and the like.
The reaction temperature is usually from 0.degree. C. to reflux
temperature of the solvent.
[0268] Compound 104 may be produced by introducing a suitable
protective group into 1-position of compound 103, executing the
above Production method, and then conducting deprotection.
Production Method 48
##STR00076##
[0270] For converting a carboxyl group of compound 103 into other
functional groups such as amino group, for example, by Curtius
rearrangement, it is preferred to introduce a protective group into
the pyrazole ring as shown in Production method 48 as is necessary,
thereby converting into compound 105. A variety of protective
groups described in the Production method 3 can be used, and a
trityl group or the like is preferred. Any bases can be used as the
base, and sodium hydride or the like is preferred. The use amount
is from 2 to 3 equivalents. As the reagent, tritylchloride is
preferably used in the amount of from 1 to 2 equivalent(s). As the
solvent, any solvents can be used in so far as they are not
concerned with the reaction, and preferred examples of such solvent
include, but are not limited to, ether solvents such as
tetrahydrofuran or dioxane, N,N-dimethylformamide and the like. The
reaction temperature is usually ice-cooled temperature to reflux
temperature of the solvent.
Production Method 49
##STR00077##
[0272] After converting a carboxyl group of condensed pyrazole ring
compound 105 into a carbamate by Curtius rearrangement, the
carbamate is removed, to thereby obtain compound 106. Curtius
rearrangement of compound 105 can be achieved, for example, by
making an isocyanate using diphenylphosphorylazide and an amine
such as triethylamine or diisopropylethylamine, and letting the
resultant isocyanate react with an alcohol; or making an acid
chloride using thionyl chloride, oxalyl chloride or the like,
converting the resultant acid chloride into an isocyanate using
lithium azide, sodium azide, potassium azide and the like, and
letting the resultant isocyanate react with an alcohol. Preferred
examples of the alcohol include, but are not limited to, benzyl
alcohol or tert-butanol. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of which include, but are not limited to, toluene, benzene,
tetrahydrofuran, dioxane and the like. Alternatively, the reaction
may be conducted using a solvent amount of an alcohol such as
tert-butanol. Usually the reaction temperature is from room
temperature to reflux temperature of the solvent. Deprotection of
carbamate, for example, deprotection of tert-butoxycarbonyl group
is readily achieved by means of acid in accordance with Production
method 3. Deprotection of benzyloxycarbonyl group is readily
achieved by hydrogen addition.
[0273] Amidation of amine 106 can be achieved by mixing a
carboxylic acid and a condensing reagent. The condensation
condition is as described in Production method 47.
[0274] In the case where compound 106 is a nitrogen-containing
aromatic amine, specifically, amidation of compound 22 or the like
can be achieved by the method using the condensing reagent as
described above, and preferably by a method of letting acid
chloride or acid anhydride react in the presence of a base.
Examples of the base include, but are not limited to,
triethylamine, diisopropylethylamine, pyridine and the like. As the
solvent, any solvent can be used insofar as they are not concerned
with the reaction, and examples of such solvent include halogen
solvents such as dichloromethane or chloroform, ether solvents such
as ether or tetrahydrofuran, as well as ethyl acetate, toluene and
the like. The reaction temperature is usually from -78.degree. C.
to reflux temperature of the solvent. For amidation of
nitrogen-containing aromatic amine, dehydration condensation using
triphenylphosphine and bromotrichloromethane is also possible.
Production Method 50
##STR00078##
[0276] In general, aryl halide can be converted into an amino group
by coupling reaction using a palladium catalyst. As the halogen
atom T.sup.3 in compound 100, bromine atom and iodine atom are
represented, with bromine or iodine atom having high reactivity
being preferred. Also in an aromatic ring wherein substitution
position of halogen atom is ortho-position or para-position of the
nitrogen atom constituting the ring, T.sup.3 may be a chlorine
atom. Furthermore, the protective group of pyrazole ring is
sometimes unnecessary, however, it is usually preferred to have a
protective group.
[0277] As a palladium catalyst used for amination of compound 100,
for example, tris(dibenzylideneacetone) dipalladium, palladium
diacetate and the like are used, as the phosphine ligand,
2,2'-bis(diphenylphosphino)-1,1'-naphthyl,
1,1'-bis(diphenylphosphino) ferrocene, tri(tert-butyl)phosphine and
the like are used, and as the base, sodium tert-butoxide, potassium
tert-butoxide, cesium carbonate and the like are used. As an
ammonia equivalent, benzophenoneimine is preferred without
limitation. As the acid used for hydrolysis of the resultant imine
compound, diluted hydrochloric acid, diluted sulfuric acid and the
like can be used without limitation. As the solvent, any solvents
can be used insofar as they are not concerned with the reaction,
and examples of such solvent include, but are not limited to,
toluene, tetrahydrofuran, dioxane, dimethoxyethane and the like.
Usually the reaction temperature is from room temperature to
120.degree. C. As a result of this, it is possible to produce amine
106.
Production Method 51
##STR00079##
[0279] In general, it is possible to readily introduce a variety of
functional groups into aryl halide by coupling using Pd(0). For
example, as exemplified in Production method 51, it is possible to
introduce an acyl group by coupling, to thereby obtain
corresponding acyl compound 108. As the halogen atom T.sup.3,
chlorine atom, bromine atom and iodine atom are recited, with
bromine or iodine atom being desired. Furthermore, in an aromatic
ring wherein substitution position of halogen atom is
ortho-position or para-position of the nitrogen atom constituting
the ring, T.sup.3 may be a chlorine atom. Furthermore, the
protective group of pyrazole ring is sometimes unnecessary,
however, it is usually preferred to have a protective group. As the
method for introducing an acetyl group, Stille coupling using
tributyl(1-ethoxyvinyl)tin can be recited. As the tin reagent,
commercially available one was purchased. The use amount of
tributyl (1-ethoxyvinyl)tin is from 1 to 3 equivalent(s) with
respect to the material. As the catalyst to be used, for example,
tetrakis(triphenylphosphine) palladium(0) and the like is preferred
without limitation. The use amount of catalyst is about 5% by mole
with respect to the material. As the solvent, any solvents can be
used in so far as they do not inhibit the reaction, and examples of
such solvent include, but are not limited to, tetrahydrofuran,
dioxane, N,N-dimethylformamide, diethyleneglycol dimethyl ether,
toluene, xylene and the like. The reaction temperature is usually
from room temperature to reflux temperature of the solvent. The
vinyl ether which is obtainable as an intermediate is readily
hydrolyzed with acid, to be led to a ketone. As such an acid,
diluted hydrochloric acid or the like is preferred without
limitation. Depending on the condition, deprotection may be
conducted as exemplified in Production method. It is also possible
that N-bromosuccinimide is caused to act instead of the acid to be
acted on vinyl ether, thereby introducing a bromomethylketone
unit.
Production Method 52
##STR00080##
[0281] As another way to conversion with respect to substituent V,
for example, as exemplified in Production method 52, a cyano group
of compound 102 may be reduced so as to convert to aralkyl amine
109. Although a protective group is not particularly required, the
reaction may be conducted for compounds having protective groups
introduced therein.
[0282] As the reducing reagent of cyano group, for example, sodium
borohydride, lithium aluminum hydride, aluminum hydride and the
like are recited. As is necessary, additives such as aluminum
trichloride, boron trifluoride, cobalt chloride, Raney nickel and
the like may be added. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, alcohol solvents
such as methanol or ethanol, ether solvents such as diethyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and the like. The
reaction temperature is usually from -78.degree. C. to reflux
temperature of the solvent.
Production Method 53
##STR00081##
[0284] Compound III can be produced by subjecting compound 100 to
Suzuki coupling or Stille coupling, followed by deprotection.
Furthermore, although the protective group of pyrazole ring is
sometimes unnecessary, it is usually preferred to have a protective
group.
[0285] The aryl bronic acid used for Suzuki coupling or aryl
trialkyl tin used for Stille coupling is commercially available, or
readily prepared in accordance with Production method 3 if not
commercially available. The use amount of arylboronic acid used for
coupling reaction, or aryl trialkyl tin is from 1 to 3
equivalent(s) with respect to the material. As the solvent to be
used, for example, palladium acetate (II), dichlorobistriphenyl
phosphine palladium (II), tetrakis(triphenylphosphine) palladium(0)
and the like can be exemplified. The use amount of catalyst is
about 5% by mole with respect to the material. As is necessary,
twice as much as catalyst by mole of phosphine ligand, for example,
tri-tert-butylphosphine, 2-(di-tert-butylphosphino) biphenyl,
2-(dicyclohexylphosphino) biphenyl, triphenyl phosphine and the
like may be added. As the base to be used, sodium hydrogen
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
potassium fluoride and the like can be recited. As the solvent, any
solvents can be used insofar as they do not inhibit the reaction,
and examples of such solvent include, but are not limited to,
N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran,
dioxane, diethyleneglycol dimethyl ether, toluene and the like. The
reaction temperature is usually from room temperature to reflux
temperature of the solvent.
[0286] Deprotection of compound 110 is conducted in accordance with
Production method 3.
Production Method 54
##STR00082##
[0288] Compound 110 obtained by Production method 53 can also be
produced by converting compound 100 into a boronic acid, and
conducting Suzuki coupling.
[0289] Boronic acid 112 can be obtained by converting compound 100
into aryl lithium, letting the aryl lithium react with trialkyl
borate to lead a borate ester, and then hydrolyzing the borate
ester. As the alkyl lithium for converting compound 100 into aryl
lithium, for example, N-butyllithium, sec-butyllithium,
tert-butyllithium, phenyl lithium and the like are used, and
additives such as N,N,N',N'-tetramethylethylenediamine or
hexamethylphosphoramide may be added as necessary. Hydrolysis after
making borate ester by letting aryl lithium and trialkyl borate
react with each other may be achieved by adding water or using an
acid such as hydrochloric acid of sulfuric acid. As the solvent,
any solvents can be used insofar as they are not concerned with the
reaction, and preferred examples of such solvent include, but are
not limited to, diethyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and the like ether solvents. The reaction
temperature is from -78.degree. C. to room temperature.
[0290] Compound 110 can be produced by coupling boronic acid 112
and aryl halide or aryl sulfonates by Suzuki coupling in accordance
with Production method 53.
Production Method 55
##STR00083##
[0292] Compound 110 obtained by Production method 53 may be
produced by converting compound 100 into tin compound 113, and then
conducting Stille coupling.
[0293] Tin compound 113 can be produced by converting compound 100
into aryl lithium in accordance with Production method 54, and then
letting the aryl lithium react with chlorotrialkyl tin or hexaalkyl
ditin.
[0294] Compound 110 can be produced by Stille coupling between tin
compound 113 and aryl halide or aryl sulfonates in accordance with
Production method 53.
Production Method 56
##STR00084##
[0296] Compound 14 can be produced by letting compound 101 produced
in Production method 45 to react with hydrazide after deprotecting
the same.
[0297] Deprotection of compound 101 is conducted in accordance with
Production method 3.
[0298] The hydrazide used for the reaction with compound 102 is
purchased if commercially available, or can be readily prepared if
not commercially available. Compound 102 can also be produced by
amide condensing a carboxylic acid and a mono-protected hydrazine,
and then conducting deprotection. As the reaction solvent, any
solvents can be used in so far as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, ethanol, toluene, xylene, dimethylformamide,
N-methylpyrrolidone, diphenyl ether and the like. The reaction
temperature is usually from room temperature to reflux temperature
of the solvent.
Production Method 57
##STR00085##
[0300] compound 114 produced by Production method 56 can also be
produced by converting compound 102 into an imidate, then reacting
the imidate with hydrazide.
[0301] As the acid used for converting compound 102 into imidate
115, hydrogen chloride, hydrogen bromide, sulfuric acid and the
like can be exemplified. As the alcohol, methanol, ethanol and the
like are preferred without limitation. As the solvent, any solvents
can be used without limitation insofar as they are not concerned
with the reaction, and dichloromethane, 1,4-dioxane, diethyl ether,
toluene or the like is used, or alternatively the alcohol to be
reacted may be used as a solvent. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
[0302] From compound 115 and hydrazide, it is possible to produce
compound 114. A base may be added if necessary. As the base to be
used, triethylamine, diisopropylethylamine, potassium carbonate and
the like can be recited. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and preferred
examples of such solvent include, but are not limited to, methanol,
ethanol, tetrahydrofuran, toluene, 1,4-dioxane, dimethylformamide
and the like. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
Production Method 58
##STR00086##
[0304] Compound 114 produced by Production method 56 can also be
produced by converting compound 102 into a thioimidate and then
letting the thioimidate react with hydrazide.
[0305] Thioimidate 116 can be produced by adding a thiol to
compound 102 in the presence of an acid catalyst. As the acid to be
used, hydrogen chloride, hydrogen bromide, sulfuric acid and the
like can be recited. As the thiol to be used, for example,
ethanethiol, propanethiol, thiophenol and the like can be recited
without limitation. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, ethanol,
dichloromethane, toluene, diethyl ether, dioxane, dimethoxyethane
and the like. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0306] In accordance with Production method 57, by letting compound
116 react with hydrazide, compound 114 can be produced.
Production Method 59
##STR00087##
[0308] Compound 114 produced by Production method 56 can be
produced by converting compound 101 produced by Production method
45 into thioamide 117, letting thioamide 117 to react with alkyl
halide to render it thioimidate 118, then letting the thioimidate
118 react with hydrazide, and conducting deprotection.
[0309] Thioamidation of compound 101 is conducted using the
condition which is usually employed, for example, using hydrogen
sulfide and a base. In this case, as the base, triethylamine,
diisopropylethylamine or the like is used, and as the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, methanol, ethanol, pyridine and the like. The reaction
temperature is from room temperature to reflux temperature of the
solvent.
[0310] As the alkyl halide to be used for thiomidation of thioamide
117, methyl iodide or the like is preferred without limitation. As
the solvent, any solvents can be used insofar as they are not
concerned with the reaction, and examples of such solvent include,
but are not limited to, dichloromethane, acetonitrile, toluene,
tetrahydrofuran, 1,4-dioxane, dimethylformamide and the like. The
reaction temperature is from room temperature to reflux temperature
of the solvent.
[0311] In accordance with Production method 58, thioimidate 118 and
hydrazide are reacted, followed by deprotection in accordance with
Production method 3, to thereby produce compound 114.
Production Method 60
##STR00088##
[0313] Compound 119 produced by Production method 59 can be
produced by esterifying compound 105 produced by Production method
48, letting the resultant ester react with hydrazine to render it
hydrazide, and letting the hydrazide react with imidate or
thioimidate.
[0314] Esterification of compound 105 can be achieved, for example,
by dehydration reaction with alcohol using an acid catalyst,
dehydration reaction with alcohol using a condensing reagent, and
reaction using diazomethane. For example, in the case where a
sulfuric acid is used as the acid catalyst, methanol, ethanol or
the like is preferably used as the alcohol. And the solvent is
preferably the alcohol to be used. The reaction temperature is
usually from 0.degree. C. to reflux temperature of the solvent. As
the reaction solvent in the case of using diazomethane, for
example, diethyl ether, methanol, tetrahydrofuran or the like is
used, and the reaction temperature is usually from 0.degree. C. to
room temperature.
[0315] As the solvent to be used for reaction between ester 120 and
hydrazine, any solvents can be used insofar as they are not
concerned with the reaction, and examples of such solvent include,
but are not limited to, ethanol, 1,4-dioxane, toluene,
N-methylpyrrolidone, N,N-dimethylformamide and the like. The
reaction temperature is from room temperature to reflux temperature
of the solvent.
[0316] As the solvent to be used in the reaction between hydrazide
121 and imidate or thioimidate, any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include, but are not limited to, ethanol, 1,4-dioxane,
dichloromethane, toluene, N-methylpyrrolidone,
N,N-dimethylformamide and the like, and if necessary, a base such
as triethylamine, potassium carbonate or the like may be added. The
reaction temperature is from room temperature to reflux temperature
of the solvent. The imidate to be used is purchased if commercially
available, or can be produced, for example, by causing nitrile to
react with an alcohol such as ethanol in the presence of an acid
such as hydrogen chloride if not commercially available. The
thioimidate to be used is purchased if commercially available, or
can be produced, for example, by causing thioamide to react with an
alkyl halide or causing a nitrile to react with ethanethiol or
thiophenol in the presence of an acid such as hydrogen chloride if
not commercially available.
Production Method 61
##STR00089##
[0318] Carboxylic acid 105 produced by Production method 48 can
also be produced by converting compound 100 into an aryl lithium in
the manner as described in Production method 54, and the letting
the aryl lithium react with carbon dioxide.
Production Method 62
##STR00090##
[0320] Hydrazide 121 produced by Production method 60 can also be
produced by amide-condensing carboxylic acid 105 produced by
Production method 48 and a mono-protected hydrazine, and then
conducting deprotection.
[0321] Amidation of carboxylic acid 105 can be achieved by mixing a
mono-protected hydrazine and a condensing reagent in accordance
with Production method 47. As a protective group of mono-protected
hydrazine, for example, tert-butyloxycarbonyl group,
benzyloxycarbonyl group and the like can be recited.
[0322] As the condition for deprotecting compound 122, in the case
of tert-butyloxycarbonyl group, deprotection can be readily
achieved by using an acid in accordance with Production method 3.
Similarly, in the case of benzyloxycarbonyl group, deprotection can
be easily achieved by catalytic hydrogen reduction.
Production Method 63
##STR00091##
[0324] Compound 119 produced by Production method 59 can also be
produced by converting carboxylic acid produced 105 by Production
method 48 into an acid chloride, letting the acid chloride react
with a thiocyanate salt, letting the resultant compound 124 react
with a nucleophilic reagent to render it compound 125, and then
letting compound 125 react with hydrazine.
[0325] As the method for producing acid chloride 123 from
carboxylic acid 105, usual condition is employed, and for example,
thionyl chloride or oxalyl chloride is used, and as if necessary, a
small amount of N,N-dimethylformamide is added. As the solvent, any
solvents can be used insofar as they do not inhibit the reaction,
and examples of such solvent include, but are not limited to,
dichloromethane, toluene, tetrahydrofuran, 1,4-dioxane and the
like. Also the reaction may be conducted in the absence of solvent.
The reaction temperature is usually from 0.degree. C. to reflux
temperature of the solvent.
[0326] As the solvent used in producing compound 124 from acid
chloride 123 and thiocyanate salt, any solvents can be used insofar
as they do not inhibit the reaction, and examples of such solvent
include, but are not limited to, toluene, acetonitrile, pyridine
and the like. The reaction temperature is usually from 0.degree. C.
to reflux temperature of the solvent.
[0327] As the nucleophilic reagent used in producing compound 125
from compound 124, alcohol and amine, alkyl lithium, Grignard
reagent and the like can be recited. As the solvent to be used when
the nucleophilic reagent is alcohol or amine, any solvents can be
used insofar as they do not inhibit the reaction, and examples of
such solvent include, but are not limited to, toluene,
acetonitrile, pyridine and tetrahydrofuran. The reaction
temperature is usually from 0.degree. C. to reflux temperature of
the solvent. Also the reaction may conducted in the absence of
solvent. As the solvent to be used when the nucleophilic reagent is
alkyl lithium or Grignard reagent, any solvents can be used insofar
as they do not inhibit the reaction, and examples of such solvent
include, but are not limited to, diethyl ether, tetrahydrofuran,
dimethoxyethane and the like. The reaction temperature is usually
from -78.degree. C. to room temperature.
[0328] As the solvent to be used in the reaction between compound
125 and hydrazine, any solvents can be used insofar as they do not
inhibit the reaction, and examples of such solvent include, but are
not limited to, ethanol, methanol, pyridine, toluene,
tetrahydrofuran and the like. The reaction temperature is usually
from room temperature to reflux temperature of the solvent.
Production Method 64
##STR00092##
[0330] Compound 127 can be produced by letting .alpha.-aminoacetal
or .alpha.-aminoketal react on imidate 115 produced by Production
method 57 or thioimidate 116 produced by Production method 58 to
render it 126, and conducting acid treatment on 126.
[0331] As the solvent to be used in producing compound 126 from
compound 115 or 116, any solvents can be used insofar as they do
not inhibit the reaction, and examples of such solvent include, but
are not limited to, methanol, ethanol, acetic acid,
dimethoxyethane, dimethylformamide and the like, and if necessary,
a base such as triethylamine, diisopropylethylamine, potassium
carbonate or the like may be added. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
[0332] As the acid used in acid treatment for compound 126, for
example, hydrochloric acid, sulfuric acid, acetic acid,
para-toluenesulfonic acid and the like can be recited. As the
reaction solvent, for example, methanol, ethanol, acetic acid,
1,2-dimethoxyethane, N,N-dimethylformamide and the like can be
recited. The reaction temperature is usually from room temperature
to reflux temperature of the solvent.
Production Method 65
##STR00093##
[0334] Compound 127 produced by Production method 64 can also be
produced by introducing a protective group to compound 128
(compound in which V.sup.1 is a hydrogen atom in compound 127),
lithionating the imidazole and letting an electrophilic reagent act
on the lithio compound, and then conducting deprotection.
[0335] As the protective group to be introduced into compound 128,
for example, p-toluenesulfonyl group, dimethylsulfamoyl group,
methoxymethyl group and the like can be recited. Introduction of
p-toluenesulfonyl group and dimethylsulfamoyl group and
methoxymethyl group can be achieved by letting compound 128 react
with p-toluenesulfonyl chloride or dimethylsulfamoyl chloride or
chloromethylmethyl ether in the presence of a base. Preferred
examples of the base include, but are not limited to,
triethylamine, 4-N,N-dimethylamionopyridine, sodium hydroxide,
sodium hydride, potassium tert-butoxide, potassium carbonate and
the like. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and examples of such solvent
include, but are not limited to, ether solvents such as diethyl
ether, tetrahydrofuran, dioxane or dimethoxyethane, hydrocarbon
halides such as dichloromethane or chloroform, as well as pyridine,
acetonitrile, dimethyl sulfoxide, dimethylformamide, toluene and
the like. The reaction temperature is usually from 0.degree. C. to
reflux temperature of the solvent.
[0336] As the alkyl lithium for litionation of compound 129, for
example, N-butyllithium, sec-butyllithium, tert-butyllithium, as
well as phenyl lithium is used, and if necessary, an additive such
as N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoramide
and the like may be added. As the lithium amide, for example,
lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide or
the like is used. As the electrophilic reagent to be used, for
example, alkyl halide, aldehyde, isocyanate and the like can be
recited. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and examples of such solvent
include, but are not limited to, ether solvents such as diethyl
ether, tetrahydrofuran, dioxane or dimethoxyethane, as well as
benzene, toluene and the like. The reaction temperature is from
-78.degree. C. to room temperature.
[0337] Deprotection of p-toluenesulfonyl group and
dimethylsulfamoyl group is readily achieved by means of a base. As
the base, sodium hydroxide water, potassium hydroxide water and the
like can be recited without limitation. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, alcohol solvents such as methanol or ethanol, and ether
solvents such as diethyl ether, tetrahydrofuran or dioxane,
dimethoxyethane. The reaction temperature is room temperature or
reflux temperature of the solvent. Deprotection of methoxymethyl
group can be achieved by treating the remaining animal with ammonia
water after acid treatment. Deprotection of dimethylsulfamoyl group
can be readily achieved by an acid. As the acid, hydrochloric acid,
sulfuric acid, hydrobromic acid, perhydrochloric acid and the like
can be recited. As the reaction solvent, any limitation insofar as
they are not concerned with the reaction, and examples of such
solvent include methanol, ethanol, water, dioxane and
dimethoxyethane. The reaction temperature is room temperature or
reflux temperature of the solvent.
Production Method 66
##STR00094##
[0339] Compound 127 produced by Production method 64 can also be
produced by letting imidate 115 produced by Production method 57 or
thioimidate 116 produced by Production method 58 react with ammonia
to render it amidine 131, and then letting amidine 131 react with
.alpha.-haloketone.
[0340] As the solvent to be used in producing 131 from compound 115
or compound 116, any solvents can be used insofar as they are not
concerned with the reaction, and examples of such solvent include,
but are not limited to, methanol, ethanol, propanol, water,
dioxane, dimethoxyethane and tetrahydrofuran. The reaction
temperature is room temperature or reflux temperature of the
solvent.
[0341] By letting amidine 131 and .alpha.-haloketone in the
presence of a base, it is possible to produce 127. As the base to
be used, for example, triethylamine, dimethylaminopyridine, sodium
hydroxide, potassium carbonate, potassium tert-butoxide and the
like can be recited. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, methanol, ethanol,
dioxane, tetrahydrofuran, toluene, pyridine and
N,N-dimethylformamide. The reaction temperature is usually from
room temperature to reflux temperature of the solvent.
Production Method 67
##STR00095##
[0343] Compound 134 can be produced by letting .alpha.-haloketone
132 produced by Production method 51 react with amidine, and then
conducting deprotection.
[0344] By letting compound 132 and amidine react with each other in
the presence of a base, it is possible to produce compound 133. As
the base to be used, for example, triethylamine,
dimethylaminopyridine, sodium hydroxide, potassium carbonate,
potassium tert-butoxide and the like can be recited. As the
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, methanol, ethanol, dioxane, tetrahydrofuran,
toluene, pyridine and N,N-dimethylformamide. The reaction
temperature is usually from room temperature to reflux temperature
of the solvent.
[0345] Deprotection of compound 133 is conducted in accordance with
Production method 3.
Production Method 68
##STR00096##
[0347] Compound 139 can be produced by converting compound 135
produced as an intermediate in Production method 51 into diketone
137 by aldol reaction and subsequent oxidation reaction, then
constructing a pyrazole ring by using hydrazine, and conducting
deprotection.
[0348] As the base to be used in the aldol reaction for compound
135, for example, sodium hydroxide, sodium methoxide, lithium
hexamethyldisilazide, lithium diisopropylamide and the like can be
recited. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and examples of such solvent
include, but are not limited to, diethyl ether, tetrahydrofuran,
dimethoxyethane, toluene and dioxane. The reaction temperature is
usually from 0.degree. C. to reflux temperature of the solvent.
[0349] As the oxidizing reagent to be used in the oxidation
reaction for compound 136, for example, sulfur trioxide-pyridine
complex, N-methylmorpholine-N-oxide, a variety of chromic acid
oxidizing reagents and the like can be used, and also the
oxidization may be achieved by Swern oxidation, Moffat oxidation
and the like. As the solvent, any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include hydrocarbon halides such as dichloromethane or
chloroform, as well as ethyl acetate, acetonitrile, dimethyl
sulfoxide, dimethylformamide and the like. The reaction temperature
is usually from -78.degree. C. to reflux temperature of the
solvent.
[0350] As the reaction solvent used for the reaction between
compound 137 and hydrazine, any solvents can be used insofar as
they do not inhibit the reaction, and examples of such solvent
include, but are not limited to, methanol, ethanol,
tetrahydrofuran, dioxane, pyridine and acetic acid. The reaction
temperature is usually from room temperature to reflux temperature
of the solvent.
[0351] Deprotection of compound 138 is conducted in accordance with
Production method 3.
Production Method 69
##STR00097##
[0353] Compound 138 produced by Production method 68 can also be
produced by converting compound 135 which is produced as an
intermediate in Production method 51 into enamine 140, and then
letting enamine 140 react with hydrazine.
[0354] Enamine 140 can be produced by letting compound 135 and
dimethylamide-dimethylacetal react with each other. As the reaction
solvent, any solvents can be used insofar as they do not inhibit
the reaction, and examples of such solvent include, but are not
limited to, methanol, ethanol, toluene and dimethylformamide. The
reaction temperature is usually from room temperature to reflux
temperature of the solvent.
[0355] As the reaction solvent to be used in the reaction between
enamine 140 and hydrazine, any solvents can be used insofar as they
do not inhibit the reaction, and examples of such solvent include,
but are not limited to, methanol, ethanol, tetrahydrofuran,
dioxane, pyridine and acetic acid. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
Production Method 70
##STR00098##
[0357] Compound 142 can be produced by letting hydrazide 121
produced by production method 60 react with carbonyldiimidazole,
and then conducting deprotection.
[0358] As the reaction solvent used in the reaction between
hydrazide 121 and carbonyldiimidazole, any solvents can be used
insofar as they do not inhibit the reaction, and examples of such
solvent include, but are not limited to, tetrahydrofuran,
dimethoxyethane and dimethylformamide. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
[0359] Deprotection of compound 141 is conducted in accordance with
Production method 3.
Production Method 71
##STR00099##
[0361] Compound 145 can be produced by letting compound 101
produced by Production method 45 react with hydroxyammonium
chloride in the presence of a base, to render it compound 143,
letting compound 143 react with carbonyldiimidazole, and the
conducting deprotection.
[0362] As the base to be used in production of compound 143, for
example, triethylamine, potassium carbonate, sodium hydroxide and
the like can be recited. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, methanol, ethanol,
propanol, dioxane and N,N-dimethylformamide. The reaction
temperature is room temperature or reflux temperature of the
solvent.
[0363] As the solvent to be used in the reaction between compound
143 and carbonyldiimidazole, any solvents can be used insofar as
they do not inhibit the reaction, and examples of such solvent
include, but are not limited to, tetrahydrofuran, dimethoxyethane
and dimethylformamide. The reaction temperature is usually from
room temperature to reflux temperature of the solvent.
[0364] Deprotection of compound 144 is conducted in accordance with
Production method 3.
Production Method 72
##STR00100##
[0366] Compound 149 can be produced by selectively protecting
1-position after deprotecting compound 146 to make compound 148,
introducing a substituent into a phenol group, and the removing the
protective group. J in compound 146 is preferably a methyl
group.
[0367] Deprotection of compound 146 is readily achieved by means of
Lewis acid, alkaline metal salt of thio, acid and the like. As the
Lewis acid, boron tribromide, aluminum trichloride and the like are
used, as the alkaline salt of thiol, sodium salts of ethanethiol or
thiophenol and the like are used, and as the acid, trifluoroacetic
acid, hydrobromic acid and the like are used. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include, but are not limited
to, hydrocarbon halides such as dichloromethane, chloroform or
carbon tetrachloride, as well as ethyl acetate, acetonitrile,
dimethyl sulfoxide, N,N-dimethylformamide and the like. The
reaction temperature is -20.degree. C. or reflux temperature of the
solvent.
[0368] The subsequent selective protection of 1-position is
achieved in the manner as described in Production method 3.
Introduction of alkyl group into compound 148 can be achieved by
reaction with a halide in the presence of a base. As the base to be
used, sodium hydride, potassium carbonate, cesium carbonate and the
like are recited, and the use amount thereof is usually for 1 to 2
equivalent(s). As the halide to be used, bromides and iodides are
preferred without limitation, and the use amount thereof is usually
from 1 to 3 equivalent(s) with respect to the material. As the
halide, both aliphatic halides and aromatic halides can be employed
and they may have suitable functional groups. As for aromatic
halides, iodides are particularly preferred, and by adding a metal
catalyst such as copper iodide in the presence of a base, an
excellent result is achieved. The use amount of metal catalyst is
usually from catalyst amount to 1 equivalent. In the cases of
highly-reactive aralkyl halides or aryl halides, the reaction can
be achieved by using a salt such as sodium iodide instead of the
base. As the reaction solvent, any solvents can be used insofar as
they are not concerned with the reaction, and examples of such
solvent include, but are not limited to, halogen solvents such as
dichloromethane, chloroform or 1,2-dichloroethane, hydrocarbon
solvents such as benzene or toluene, ether solvents such as
tetrahydrofuran, and polar solvents such as N,N-dimethylformamide
or acetonitrile. The reaction temperature is usually from room
temperature to reflux temperature of the solvent.
[0369] Furthermore, compound 148 can be converted into an ester by
reaction with acid chloride or acid anhydride in the presence of a
base. As the base, triethylamine, diisopropylethylamine, pyridine
and the like can be recited without limitation. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include halogen solvents
such as dichloromethane or chloroform, ether solvents such as ether
or tetrahydrofuran, as well as ethyl acetate, toluene and the like.
The reaction temperature is usually from -78.degree. C. to reflux
temperature of the solvent. Furthermore, compound 148 can also be
esterified by mixing a carboxylic acid and a condensing reagent. As
the condensing reagent, for example, dicyclohexylcarbodiimide,
diisopropylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the
like can be recited. 1-Hydroxybenzotriazole, N-hydroxysuccinimide
and the like may be added where appropriate. As the solvent, any
solvents can be used insofar as they are not concerned with the
reaction, and examples of such solvent include halogen solvents
such as dichloromethane or chloroform, ether solvents such as ether
or tetrahydrofuran, as well as ethyl acetate, dimethylformamide,
toluene and the like. The reaction temperature is usually from room
temperature to reflux temperature of the solvent. Furthermore,
compound 148 may be converted into an ester by reaction with a
carboxylic acid under the condition of an acid catalyst. As the
acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid and
the like are exemplified. As the solvent, any solvents can be used
insofar as they are not concerned with the reaction, and examples
of such solvent include, but are not limited to, halogen solvents
such as dichloromethane, chloroform or 1,2-dichloroethane,
hydrocarbon solvents such as benzene or toluene, ether solvents
such as tetrahydrofuran, and polar solvents such as
N,N-dimethylformamide or acetonitrile. The reaction temperature is
usually from room temperature to reflux temperature of the
solvent.
[0370] By deprotecting 1-position in the manner as described in
Production method 3, it is possible to produce compound 149.
Production Method 73
##STR00101##
[0372] Compound 148 obtained by Production method 72 can also be
produced by selectively deprotecting compound 146.
[0373] For selective deprotection of compound 146, for example,
Lewis acids such as boron tribromide or aluminum trichloride,
alkaline metal salts such as sodium salts of ethanethiol or
thiophenol, and acids such as trifluoroacetic acid or hydrobromic
acid are used, and alkaline metal salts of thiol are preferably
used. As the solvent, any solvents can be used insofar as they are
not concerned with the reaction, and examples of such solvent
include, but are not limited to, hydrocarbon halides such as
dichloromethane, chloroform and carbon tetrachloride, as well as
ethyl acetate, acetonitrile, dimethyl sulfoxide,
N,N-dimethylformamide and the like. The reaction temperature is
-20.degree. C. or reflux temperature of the solvent.
Production Method 74
##STR00102##
[0375] Compound 149 can also be produced by letting compound 147
react with halide, carboxylic acid, acid chloride or acid anhydride
in the similar manner as described in Production method 72.
Production Method 75
##STR00103##
[0377] Compound 151 can be produced by letting compound 143
produced by Production method 71 react with an acid chloride,
allowing dehydrating-cyclization to render compound 150, and then
conducting deprotection.
[0378] In producing compound 150 from compound 143, a base may be
added. As the base to be used, for example, triethylamine,
pyridine, sodium hydride and the like are recited. As the reaction
solvent, any solvents can be used insofar as they are not concerned
with the reaction, and examples of such solvent include, but are
not limited to, tetrahydrofuran, dimethoxyethane and
N,N-dimethylformamide. The reaction temperature is room temperature
or reflux temperature of the solvent. A corresponding acid
anhydride or ester may be used instead of the acid chloride used
for acylation.
[0379] Deprotection of compound 150 is conducted in accordance with
Production method 3.
Production Method 76
##STR00104##
[0381] Compound 154 can be produced by letting compound 152 react
with amidoxime, allowing dehydrating-cyclization to render compound
153, and then conducting deprotection.
[0382] In producing compound 153 from compound 152, a base may be
added. As the base to be used, for example, triethylamine,
pyridine, sodium hydride and the like can be recited. As the
reaction solvent, any solvents can be used insofar as they are not
concerned with the reaction, and examples of such solvent include,
but are not limited to, tetrahydrofuran, dimethoxyethane and
N,N-dimethylformamide. The reaction temperature is room temperature
or reflux temperature of the solvent.
[0383] Deprotection of compound 153 is conducted in accordance with
Production method 3.
Production Method 77
##STR00105##
[0385] Compound 156 can be produced by reacting compound 131
produced by Production method 66 and compound 155.
[0386] In the reaction between amidine 131 and compound 155, a base
is used as necessary. As the base, triethylamine,
diisopropylethylamine, potassium carbonate and the like are
recited. As the solvent, any solvents can be used insofar as they
are not concerned with the reaction, and preferred examples of such
solvent include, but are not limited to, methanol, ethanol,
pyridine, acetic acid, tetrahydrofuran, toluene, 1,4-dioxane,
N,N-dimethylformamide and the like. The reaction temperature is
usually from room temperature to reflux temperature of solvent.
Production Method 78
##STR00106##
[0388] Compound 157 can be produced by reacting imidate 115
produced by Production method 57 or thioimidate 116 produced by
Production method 58 with hydrazide in the absence of a base. As
the reaction solvent, any solvents can be used insofar as they are
not concerned with the reaction, and preferred examples of such
solvent include, but are not limited to, methanol, ethanol,
propanol, butanol, tetrahydrofuran, toluene, 1,4-dioxane,
dimethylformamide, pyridine and the like. There action temperature
is usually from room temperature to reflux temperature of
solvent.
Production Method 79
##STR00107##
[0390] Compound 158 can be produced by reacting imidate 115
produced by Production method 57 or thioimidate 116 produced by
Production method 58 with hydrazide in accordance with the method
described in Production method 57 for producing compound 114.
Production Method 80
##STR00108##
[0392] Compound 159 can be produced by reacting imidate 115
produced by Production method 57 or thioimidate 116 produced by
Production method 58 with hydrazide in accordance with the method
described in Production method 57 for producing compound 114.
[0393] The "salt" used herein refers to any pharmaceutically
acceptable salts that form salts with compounds in accordance with
the present invention and are, and preferably, but are not limited
to, hydrohalic acid salts (for example, hydrofluoric acid salts,
hydrochloric acid salts, hydrobromic acid salts, hydroiodic acid
salts and the like), inorganic acid salts (for example, sulfuric
acid salts, nitric acid salts, perchloric acid salts, phosphoric
acid salts, carbonic acid salts, bicarbonic acid salts and the
like), organic carboxylic acid salts (for example, acetic acid
salts, maleic acid salts, tartaric acid salts, fumaric acid salts,
citric acid salts and the like), organic sulfonic acid salts (for
example, methanesulfonic acid salts, ethanesulfonic acid salts,
benzenesulfonic acid salts, toluenesulfonic acid salts,
camphorsulfonic acid salts and the like), amino acid salts (for
example, aspartic acid salts, glutamic acid salts and the like),
quaternary amine salts, alkaline metal salts (for example, sodium
salts, potassium salts and the like), alkaline earth metal salts
(magnesium salts, potassium salts and the like) and the like, and
more preferably hydrochloric acid salts, sulfuric acid salts,
methanesulfonic acid salts, acetic acid salts and the like.
[0394] The compounds represented by the above formulae (I) to (III)
or their salts or hydrates thereof in accordance with the present
invention can be formulated in conventional methods, and examples
of preferred dosage forms include tablet, powder, fine grain agent,
granule, coating tablet, encapsulated formulation, syrup, troche,
inhalant, suppository, injection, ointment, eye ointment agent, eye
drop, nasal drop, ear drops, cataplasm, lotion and the like. In
preparation, commonly used excipient, binder, disintegrator,
lubricant, colorant, flavoring agent, as well as stabilizer,
emulsifying agent, absorption promoter, surfactant, pH modifier,
antiseptics, anti-oxidant and the like can be used as necessary,
and preparation is achieved by means of conventional methods while
blending components that are generally used as raw materials of
pharmaceutical formulation. Examples of the above components
include: (1) animal and vegetable oils such as soybean oil, beef
tallow or synthesis glyceride; (2) hydrocarbons such as liquid
paraffin, squalane or solid paraffin; (3) ester oils such as
octyldodecyl myristate or isopropyl myristate; (4) higher alcohols
such as ceto-stearyl alcohol or behenyl alcohol; (5) silicon resin;
(6) silicon oil; (7) surfactants such as polyoxyethylene fatty acid
esters, sorbitan fatty acid esters, glycerine fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene
hardened castor oil or polyoxyethylene polyoxypropylene block
copolymer; (8) water-soluble polymers such as hydroxyethyl
cellulose, polyacrylic acid, carboxy vinyl polymer, polyethylene
glycol, polyvinylpyrrolidone or methyl cellulose; (9) lower
alcohols such as ethanol or isopropanol; (10) polyols such as
glycerin, propylene glycol, dipropylene glycol or sorbitol; (11)
sugars such as glucose or sucrose; (12) inorganic powders such as
silicic anhydride, aluminum silicate magnesium or aluminum
silicate; and (13) purified water.
[0395] 1) Examples of excipients include lactose, corn starch,
saccharose, glucose, mannitol, sorbit, crystalline cellulose,
silicon dioxide and the like; 2) examples of binders include
polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl
cellulose, gum Arabic, gum tragacanth, gelatine, shellac,
hydroxypropylcellulose, hydroxypropyl methylcellulose,
polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block
polymer, meglumine, calcium citrate, dextrin, pectin and the like;
3) examples of disintegrators include starch, agar, gelatin powder,
crystalline cellulose, calcium carbonate, sodium hydrogen
carbonate, calcium citrate, dextrin, pectin, carboxymethylcellulose
calcium and the like; 4) examples of lubricants include magnesium
stearate, talc, polyethylene glycol, silica, consolidation
vegetable oil and the like; 5) examples of colorants include those
accepted to be added to pharmaceuticals; 6) examples of flavoring
agents include cocoa powder, menthol, aroma powder, mentha oil,
borneol, cassia bark and the like; and 7) examples of anti-oxidants
include ascorbic acid, .alpha.-tocopherol and the like that are
accepted to be added to pharmaceuticals.
[0396] 1) As to oral formulations, after blending the compound or
its pharmaceutically acceptable salt according to the present
invention and an excipient, as well as a binder, disintegrator,
lubricant, colorant, flavoring agent and the like as necessary, the
mixture is formed into powder, fine grain agent, granule, tablet,
coating tablet, encapsulated formulation and the like. 2) In the
cases of tablets and granules, it is allowable to appropriately
coat with sugar, gelatin and other materials if necessary. 3)
Liquid agents such as syrup, injection formulation or eye drop may
produced by blending the compound according to the present
invention or a pharmaceutically acceptable salt thereof with pH
regulating agents, resolvents, tonicity agents, etc., optionally
together with dissolution aids, stabilizers, buffer agents,
suspending agents, antioxidants etc. and processing the resultant
blends into preparations by the conventional methods. Such liquid
agents may be lyophilized and injection may be subcutaneously or
intramuscularly administered. Preferred examples of suspending
agents include methyl cellulose, polysolvate 80, hydroxymethyl
cellulose, gum Arabic, tragacanth powder, carboxymethylcellulose
sodium, polyoxyethylene sorbitan monolaurate and the like;
preferred examples of dissolution aids include polyoxyethylene
hardened castor oil, polysolvate 80, nicotinamide, polyoxyethylene
sorbitan monolaurate and the like; preferred examples of
stabilizers include sodium sulfite, sodium metasulfite, ether and
the like; and preferred examples of preservatives include methyl
paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol,
cresol, chlorocresol and the like. 4) In the cases of External
preparations, may be produced by the conventional methods without
limitation. As the bases, use can be made of various materials
commonly used in drugs, quasi drugs, cosmetics, etc. Particular
examples of the base materials include animal and vegetable oils,
mineral oils, ester oils, waxes, higher alcohols, fatty acids,
silicone oils, surfactants, phospholipids, alcohols, polyhydric
alcohols, water-soluble polymers, clay minerals and purified water.
If needed, it is possible to further add pH regulating agents,
antioxidants, chelating agents, antiseptics, fungicides, coloring
agents, perfumes, etc. If necessary, it is also possible to further
add other ingredients capable of inducing differentiation, blood
flow accelerators, bactericides, antiinflammatory agents, cell
activators, vitamins, amino acids, humectants, keratolytic agents,
etc.
[0397] The dosage amount of the pharmaceutical according to the
present invention differs depending on the severity of symptom,
age, sex, bodyweight, dosage form, type of the salt, sensitivity to
drug, particular type of the disease, and the like, and generally,
these compounds are administered to an adult in a dose of about 30
.mu.g to 1,000 mg, preferably from 100 .mu.g to 500 mg and Stille
preferably from 100 .mu.g to 100 mg, per day once or several times
a day. In the case of injection, generally about 1 .mu.g/kg to
3,000 .mu.g/kg, and preferably about 3 .mu.g/kg to 1,000 .mu.g/kg
is administered.
[0398] In accordance with the present invention, novel indazole
compounds are provided. The compounds (I) to (III) or their salts
according to the present invention have excellent selective
inhibiting effect on c-Jun amino terminal kinase (JNK), especially
on JNK 3. Therefore, the compounds (I) to (III) or their salts and
pharmaceutical compositions containing the same are useful as
therapeutic agents or preventive agents for immunological diseases,
inflammatory disease, metabolic diseases and/or neurodegenerative
diseases, and particularly useful as therapeutic agents or
preventive agents for acute neurodegenerative diseases (for
example, cerebrovascular disorder acute stage, head injury, spinal
cord injury, neuropathy due to low oxygen, neuropathy low blood
sugar and the like), chronic neurodegenerative diseases (for
example, Alzheimer's disease, Parkinson's disease, Huntington's
chorea, amyotrophic lateral sclerosis, multiple sclerosis,
spinocerebellar degeneration and the like), epilepsy, hepatic
encephalopathy, peripheral neuropathy, Parkinson syndrome,
exanthematous paralysis, pain, neuralgia, infectious
encephalomyelitis, cerebrovascular dementia, dementia or neurosis
due to meningitis and the like.
EXAMPLES
[0399] Any Production examples, Examples and Test examples provided
below are merely illustrative, and compounds according to the
present invention are not restricted by the following concrete
examples. Those skilled in the art can conduct the present
invention to the utmost while making various modifications within
the scope of claims associated with the present description as well
as the Examples provided below, and all such modifications are
involved in the boundary of the present description.
Production Example 1
(3-Fluorophenyl)-(3-fluoropyridin-2-yl)-methanol
[0400] Under nitrogen atmosphere, a solution of 9.75 g of
diazabicyclo[2.2.0]octane in 150 mL of dehydrated diethyl ether was
cooled to -40.degree. C., added with 56 mL of 1.56 M n-butyllithium
in hexane, and stirred at -20.degree. C. for 1 hour. The solution
was cooled to -60.degree. C., added dropwise with 6.9 mL of
3-fluoropyridine, stirred at -60.degree. C. for 1 hour, and added
with 9.2 mL of 3-fluorobenzaldehyde. After stirring for 1 hour,
aqueous ammonium chloride and ethyl acetate were successively
added, and the mixture was recovered to room temperature. The
organic layer was extracted, washed with water, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
resulting crude product was purified and separated by silica gel
column chromatography (ethyl acetate:hexane=1:4), to give 12.6 g of
the title compound as colorless needle crystals.
[0401] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.26 (1H, d, J=6.8
Hz), 5.98 (1H, d, J=6.8 Hz), 6.95 (1H, dt, J=2.4, 8.4 Hz), 7.10
(1H, bd, J=9.8 Hz), 7.20 (1H, bd, J=8.4 Hz), 7.29 (1H, dt, J=5.5,
8.4 Hz), 7.30 (1H, dd, J=4.9, 8.8 Hz), 8.39 (1H, dt, J=1.2, 8.8
Hz), 8.42 (1H, d, J=1.2, 4.9 Hz).
Production Example 2
(3-Fluorophenyl)-(3-fluoropyridin-2-yl)-methanone
[0402] A mixed solution of 12.6 g of
(3-fluorophenyl)-(3-fluoropyridin-2-yl)-methanol obtained by
Production example 1 in 30 mL dichloromethane and 30 mL toluene was
added with 10.0 g of activated manganese dioxide, and heated under
reflux for 8 hours. After completion of the reaction, manganese
dioxide was filtered off through Celite, and the solvent was
evaporated, to give 12.1 g of the title compound as a pale yellow
oil.
[0403] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (1H, ddt,
J=1.4, 2.8, 7.9 Hz), 7.47 (1H, dt, J=5.3, 7.9 Hz), 7.54 (1H, dd,
J=4.5, 9.0 Hz), 7.61 (1H, dt, J=1.4, 9.0 Hz), 7.66 (1H, ddd, J=1.4,
2.8, 9.2 Hz), 7.72 (1H, dt, J=1.4, 7.9 Hz), 8.54 (1H, dt, J=1.4,
4.5 Hz).
Example 3
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine
[0404] 1.5 g of (3-fluorophenyl)-(3-fluoropyridin-2-yl)-methanone
was dissolved in 5 mL of methanol, added with 1.0 mL of hydrazine
monohydrate, and heated at 80.degree. C. for 4 hours. The reaction
solution was added with water, and extracted with ethyl acetate.
The organic layer was washed successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
distilled off, and the residue was purified and separated by silica
gel column chromatography (ethyl acetate:n-hexane=1:4), to afford
240 mg of the title compound as a colorless powder.
[0405] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.21 (1H, dt,
J=2.4, 8.0 Hz), 7.44 (1H, dd, J=4.1, 8.6 Hz), 7.55 (1H, dt, J=6.0,
8.0 Hz), 8.07 (1H, dd, J=1.5, 8.6 Hz), 8.30 (1H, dd, J=2.4, 10.9
Hz), 8.35 (1H, d, J=8.0 Hz), 8.64 (1H, dd, J=1.5, 4.1 Hz),
13.47-13.53 (1H, bs).
Production Example 4
(3-Fluoro-1-oxypyridin-2-yl)-(3-fluorophenyl)-methanone
[0406] 3.0 g of (3-fluorophenyl)-(3-fluoropyridin-2-yl)-methanone
obtained by Production example 2 was dissolved in 30 mL of
chloroform, added with 3.6 g of 3-chloro perbenzoic acid under
ice-cooling, and the reaction solution was heated under reflux for
6 hours. After completion of the reaction, aqueous sodium hydrogen
carbonate was added, extracted with ethyl acetate, and the organic
layer was washed with water and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the resulting residue was
purified and separated by silica gel column chromatography (ethyl
acetate:methanol=19:1), to afford 2.1 g of the title compound as
colorless needle crystals.
[0407] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.21 (1H, ddd,
J=0.7, 6.7, 8.9 Hz), 7.35 (1H, ddt, J=1.2, 2.6, 8.0 Hz), 7.40 (1H,
dt, J=6.7, 8.9 Hz), 7.49 (1H, dt, J=5.4, 8.0 Hz), 7.58 (1H, ddd,
J=1.2, 2.6, 8.9 Hz), 7.62 (1H, dt, J=1.2, 8.0 Hz), 8.14 (1H, dt,
J=0.7, 6.7 Hz).
Production Example 5
5-Fluoro-6-(3-fluorobenzoyl)-pyridine-2-carbonitrile
[0408] To 20 mL of a solution of 2.1 g of
(3-fluoro-1-oxypyridin-2-yl)-(3-fluorophenyl)-methanone obtained by
Production example 4 in acetonitrile were added 6.0 mL of
trimethylsilylcyanide and 1.7 mL of dimethylcarbamoyl chloride, and
heated under reflux for 8 hours. After completion of the reaction
was added aqueous sodium hydrogen carbonate and extracted with
ethyl acetate, and the organic layer was washed with water, and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
and the resulting residue was purified and separated by silica gel
column chromatography (ethyl acetate:n-hexane=1:9), to afford 1.0 g
of a crude product of the title compound as a colorless oil.
Example 6
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
[0409] From 1.0 g of crude
5-fluoro-6-(3-fluorobenzoyl)-pyridine-2-carbonitrile, 280 mg of the
title compound was obtained as a pale yellow powder in accordance
with Production example 3.
[0410] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.28 (1H, dt,
J=2.4, 8.0 Hz), 7.61 (1H, dt, J=6.4, 8.0 Hz), 7.98 (1H, dt, J=8.5
Hz), 8.16 (1H, dd, J=2.4, 10.6 Hz), 8.28 (1H, d, J=8.0 Hz), 8.32
(1H, d, J=8.5 Hz), 13.95-14.20 (1H, bs).
Example 7
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
[0411] 140 mg of
3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]-pyridine-5-carbonitrile was
added to a mixed solution of 1 mL water, 1 mL concentrated sulfuric
acid and 1 mL glacial acetic acid, and heated under 100.degree. C.
for 3 hours. The reaction solution was added with 25 mL of
ice-cooled water, neutralized with sodium hydrogen carbonate, and
the precipitated crystals were collected by filtration. The
crystals collected by filtration were washed with cold water, and
dried under reduced pressure, to give 150 mg of a crude product of
the title compound as a colorless powder.
[0412] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.17 (1H, dt,
J=2.8, 8.1 Hz), 7.52 (1H, dt, J=6.8, 8.1 Hz), 7.89 (1H, d, J=9.0
Hz), 7.95 (1H, d, J=9.0 Hz), 8.38 (1H, d, J=8.1 Hz), 8.40 (1H, bd,
J=11.3 Hz).
Production Example 8
(3-Fluoropyridin-2-yl)-(naphthalen-2-yl)-methanol
[0413] In the manner as described in Production example 1 while
using 5.2 mL of 3-fluoropyridine and 10.2 g of 2-naphthaldehyde as
starting materials, 3.8 g of the title compound was obtained as
pale yellow needle crystals.
[0414] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.34 (1H, d, J=6.8
Hz), 6.17 (1H, d, J=6.8 Hz), 7.29 (1H, dd, J=4.9, 8.6 Hz), 7.36
(1H, dt, J=1.0, 8.6 Hz), 7.42-7.50 (3H, m), 7.77-7.84 (1H, m), 7.79
(1H, d, J=8.5 Hz), 7.83 (1H, d, J=8.5 Hz), 7.88 (1H, s), 8.45 (1H,
dt, J=1.0, 4.9 Hz).
Production Example 9
(3-Fluoropyridin-2-yl)-(naphthalen-2-yl)-methanone
[0415] From 3.8 g of
(3-fluoropyridine2-yl)-(naphthalene-2-yl)-methanol, 3.4 g of the
title compound was obtained as colorless needle crystals in
accordance with Production example 2.
[0416] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.54 (1H, dt,
J=1.3, 7.4 Hz), 7.55 (1H, dd, J=4.6, 8.8 Hz), 7.62 (1H, dt, J=1.3,
8.8 Hz), 7.64 (1H, dt, J=1.3, 7.4 Hz), 7.90 (1H, bd, J=7.4 Hz),
7.91 (1H, bd, J=7.4 Hz), 7.94 (1H, d, J=8.6 Hz), 8.07 (1H, dd,
J=1.5, 8.6 Hz), 8.36 (1H, d, J=1.5 Hz), 8.58 (1H, dt, J=1.3, 4.6
Hz).
Example 10
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine
[0417] From 1.2 g of
(3-fluoropyridin-2-yl)-(naphthalen-2-yl)-methanone, 460 mg of the
title compound was obtained as colorless needle crystals in the
same manner as described in Production example 3.
[0418] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.44 (1H, dd,
J=4.1, 8.8 Hz), 7.53 (1H, t, J=8.5 Hz), 7.55 (1H, t, J=8.5 Hz),
7.84 (1H, bd, J=8.8 Hz), 8.03 (2H, d, J=8.5 Hz), 8.09 (1H, dd,
J=0.6, 8.8 Hz), 8.57 (1H, dd, J=1.8, 8.8 Hz), 8.69 (1H, dd, J=0.6,
4.1 Hz), 9.17 (1H, d, J=1.8 Hz).
Production Example 11
(3-Fluoro-1-oxypyridin-2-yl)-naphthalen-2-yl-methanone
[0419] From 1.5 g of
(3-fluoropyridin-2-yl)-(naphthalen-2-yl)-methanone obtained by
Production example 9, 0.8 g of the title compound was obtained as
colorless needle crystals in accordance with Production example
4.
[0420] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.24 (1H, ddd,
J=0.8, 6.5, 8.8 Hz), 7.41 (1H, dt, J=6.5, 8.8 Hz), 7.55 (1H, dt,
J=1.4, 7.4 Hz), 7.63 (1H, dt, J=1.4, 7.4 Hz), 7.89 (1H, bd, J=7.4
Hz), 7.91 (1H, bd, J=7.4 Hz), 7.95 (1H, d, J=8.8 Hz), 8.01 (1H, dd,
J=1.5, 8.8 Hz), 8.18 (1H, dt, J=0.8, 6.5 Hz), 8.27 (1H, d, J=1.5
Hz).
Production Example 12
5-Fluoro-6-(naphthalene-2-carbonyl)-pyridine-2-carbonitrile
[0421] From 780 mg of
(3-fluoro-1-oxypyridin-2-yl)-naphthalen-2-yl-methanone obtained by
Production example 11, 550 mg of a crude product of the title
compound was obtained as a pale yellow oil in the same manner as
described in Production example 5.
[0422] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.49 (1H, dd,
J=8.1, 9.5 Hz), 7.52-7.57 (2H, m), 7.57 (1H, dd, J=2.0, 8.8 Hz),
7.77 (1H, dd, J=3.3, 8.1 Hz), 7.82-7.86 (1H, m), 7.85 (1H, d, J=8.8
Hz), 7.89-7.93 (1H, m), 8.13 (1H, d, J=2.0 Hz).
Production Example 13
3-(Naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine
[0423] From 440 mg of
3-(naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine, 800 mg of the title
compound was obtained as a colorless powder in accordance with
Production example 22.
[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.66 (1H, dd,
J=1.1, 8.8 Hz), 6.95 (1H, dd, J=4.2, 8.8 Hz), 7.25-7.34 (15H, m),
7.43-7.51 (2H, m), 7.83 (1H, dd, J=2.3, 7.9 Hz), 7.88 (1H, d, J=8.5
Hz), 8.00 (1H, dd, J=2.3, 7.9 Hz), 8.42 (1H, dd, J=2.0, 8.5 Hz),
8.62 (1H, dd, J=1.1, 4.2 Hz), 9.18 (1H, d, J=2.0 Hz).
Production Example 14
3-(Naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide
[0425] From 800 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine, 500 mg of
the title compound was obtained as colorless crystals in the same
manner as described in Production example 4.
[0426] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.36 (1H, d,
J=8.6 Hz), 7.10 (1H, dd, J=5.8, 8.6 Hz), 7.24 (6H, bd, J=6.9 Hz),
7.30-7.40 (9H, m), 7.50-7.55 (2H, m), 7.90 (1H, d, J=8.6 Hz),
7.90-7.94 (2H, m), 7.99 (1H, dd, J=1.9, 8.6 Hz), 8.13 (1H, d, J=5.8
Hz), 8.60 (1H, d, J=1.9 Hz).
Production Example 15
3-(Naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
[0427] From 480 mg of
3-naphthalen-2-yl-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide, 380
mg of the title compound was obtained as pale yellow crystals in
the same manner as described in Production example 5.
[0428] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.89 (1H, d,
J=9.1 Hz), 7.23-7.28 (6H, m), 7.33-7.42 (9H, m), 7.54-7.59 (2H, m),
7.77 (1H, d, J=9.1 Hz), 7.92-7.97 (1H, m), 8.02-8.07 (1H, m), 8.04
(1H, d, J=8.7 Hz), 8.25 (1H, dd, J=1.8, 8.7 Hz), 8.97 (1H, d, J=1.8
Hz).
Example 16
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
[0429] To 10 mL of a solution containing 360 mg of
3-naphthalen-2-yl-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
obtained by Production example 15 in dichloromethane, 3 mL of
trifluoroacetic acid was added at room temperature and stirred for
2 hours. The reaction solution was added with aqueous sodium
hydrogen carbonate, extracted with ethyl acetate, washed with
water, and dried over magnesium sulfate. After evaporating, the
residue was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=3:1), to afford 180 mg of
the title compound as a colorless powder.
[0430] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.53-7.60 (2H,
m), 7.94-7.99 (1H, m), 8.00 (1H, d, J=8.6 Hz), 8.05-8.10 (1H, m),
8.08 (1H, d, J=8.6 Hz), 8.33 (1H, d, J=8.6 Hz), 8.51 (1H, dd,
J=1.3, 8.6 Hz), 9.02 (1H, d, J=1.3 Hz), 14.02-14.13 (1H, bs).
[0431] The title compound was also synthesized in an alternative
method as described below.
[0432] Using 550 mg of crude
5-fluoro-6-(naphthalene-2-carbonyl)-pyridine-2-carbonitrile
obtained by Production example 12 as a starting material, 3 mg of
the title compound was obtained in the method similar to Production
example 3.
Example 17
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic
acid
[0433] From 180 mg of
3-(naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
obtained by Example 16, 150 mg of the title compound was obtained
as a colorless powder in the same manner as described in Example
7.
[0434] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.51-7.59 (2H,
m), 7.95 (1H, bd, J=7.9 Hz), 8.03 (1H, bd, J=7.9 Hz), 8.06 (1H, d,
J=8.6 Hz), 8.12 (1H, d, J=8.6 Hz), 8.20 (1H, d, J=8.6 Hz), 8.63
(1H, dd, J=1.6, 8.6 Hz), 9.18 (1H, d, J=1.6 Hz), 13.12-13.27 (1H,
bs), 13.81 (1H, s).
Production Example 18
(3-Fluorophenyl)-(3-fluoropyridin-4-yl)-methanol
[0435] Under nitrogen atmosphere, a solution of 6.1 mL of
diisopropylamine in 100 ml of dehydrated tetrahydrofuran was cooled
to -70.degree. C., added with 28 mL of 1.56 M n-butyllithium in
hexane, and stirred at 0.degree. C. for 15 minutes. After cooling
to -70.degree. C., 3.4 mL of 3-fluoropyridine was added dropwise,
stirred at the same temperature for 4 hours, and then added
dropwise with 4.8 mL of 3-fluorobenzaldehyde. After stirring for 1
hour, aqueous ammonium chloride and ethyl acetate were successively
added, and the reaction solution was recovered to room temperature.
The organic layer was extracted, washed with water, and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
resulting residue was recrystallized from diisopropyl ether, to
afford 7.1 g of the title compound as colorless cubic crystals.
[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.70-3.10 (1H,
bs), 6.13 (1H, s), 7.00 (1H, ddd, J=0.9, 1.7, 8.3 Hz), 7.13 (1H,
dt, J=1.7, 9.2 Hz), 7.18 (1H, dt, J=0.9, 8.3 Hz), 7.32 (1H, dt,
J=5.8, 8.3 Hz), 7.57 (1H, t, J=5.5 Hz), 8.37 (1H, d, J=1.4 Hz),
8.43 (1H, d, J=5.5 Hz).
Production Example 19
(3-Fluorophenyl)-(3-fluoropyridin-4-yl)-methanone
[0437] From 3.5 g of
(3-fluorophenyl)-(3-fluoropyridin-4-yl)-methanol, 3.5 g of the
title compound was obtained as colorless needle crystals in
accordance with Production example 2.
[0438] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (1H, bt,
J=7.8 Hz), 7.43 (1H, t, J=5.4 Hz), 7.50 (1H, dt, J=5.4, 7.8 Hz),
7.54-7.60 (2H, m), 8.62 (1H, dd, J=1.1, 4.8 Hz), 8.66 (1H, d, J=1.1
Hz).
Production Example 20
(3-fluoro-1-oxypyridin-4-yl)-(3-fluorophenyl)-methanone
[0439] From 1.8 g of
(3-fluorophenyl)-(3-fluoropyridine-4-yl)-methanone, 1.65 g of the
title compound was obtained as colorless needle crystals in
accordance with Production example 4.
[0440] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (1H, ddt,
J=1.2, 2.5, 8.1 Hz), 7.48-7.59 (4H, m), 8.13 (1H, ddd, J=1.0, 1.5,
6.8 Hz), 8.20 (1H, dt, J=1.5, 5.3 Hz).
Example 21
3-(3-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridine
[0441] From 2.0 g of
(3-fluorophenyl)-(3-fluoropyridin-4-yl)-methanone obtained by
Production example 19, 490 mg of the title compound was obtained as
colorless powder in accordance with Production example 3.
[0442] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.26 (1H, dt,
J=2.6, 8.2 Hz), 7.58 (1H, dt, J=6.6, 8.2 Hz), 7.78 (1H, dd, J=2.6,
10.4 Hz), 7.89 (1H, d, J=8.2 Hz), 8.10 (1H, dd, J=1.2, 5.9 Hz),
8.31 (1H, d, J=5.9 Hz), 9.10 (1H, d, J=1.2 Hz).
Production Example 22
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine
[0443] To a solution of 2.43 g of
3-(3-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine produced in
Production example 21 in 10 mL of N,N-dimethylformamide was added
80 mg of ice-cooled 60% sodium hydride (oily). After stirring 30
minutes, 500 mg of chlorotriphenylmethane was added and stirred at
room temperature for 1 hour. The reaction solution was added with
water, extracted with ethyl acetate, dried over anhydrous sodium
sulfate, and the solvent was evaporated. The residue was added with
diisopropyl ether and filtered, to afford 560 mg of the title
compound as a colorless powder.
[0444] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.20-7.24 (6H, m),
7.26 (1H, dt, J=2.5, 8.1 Hz), 7.30-7.40 (9H, m), 7.55 (1H, dt,
J=6.4, 8.1 Hz), 7.64 (1H, ddd, J=1.4, 2.5, 10.0 Hz), 7.74 (1H, d,
J=1.4 Hz), 7.78 (1H, dt, J=1.4, 8.1 Hz), 8.13 (1H, dd, J=1.4, 5.7
Hz), 8.24 (1H, d, J=5.7 Hz).
Production Example 23
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[3,4,-c]pyridine-6-oxide
[0445] From 300 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine, 285 mg of
the title compound was obtained as a colorless powder in the same
manner as described in Production example 4.
[0446] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.01 (1H, d, J=1.4
Hz), 7.18-7.24 (6H, m), 7.28 (1H, dt, J=2.5, 8.0 Hz), 7.33-7.42
(9H, m), 7.55 (1H, dt, J=6.0, 8.0 Hz), 7.61 (1H, ddd, J=1.4, 2.5,
10.1 Hz), 7.72 (1H, dt, J=1.4, 8.0 Hz), 7.91 (1H, dd, J=1.4, 7.1
Hz), 8.14 (1H, d, J=7.1 Hz).
Production Example 24
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[3,4-c]pyridine-7-carbonitrile
[0447] From 200 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[3,4,-c]pyridine-6-oxide,
150 mg of the title compound was obtained as a colorless powder in
accordance with Production example 5.
[0448] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.15-7.21 (6H, m),
7.28-7.39 (10H, m), 7.57 (1H, dt, J=6.4, 8.0 Hz), 7.59 (1H, ddd,
J=1.3, 2.5, 10.7 Hz), 7.72 (1H, dt, J=1.3, 8.0 Hz), 8.52 (1H, d,
J=5.7 Hz), 8.60 (1H, d, J=5.7 Hz).
Production Example 25
(3-Fluoropyridin-4-yl)-(naphthalen-2-yl)-methanol
[0449] Using 5.2 mL of 3-fluoropyridine and 10.2 g of
2-naphthaldehyde as starting materials, 17.0 g of the title
compound was obtained as a colorless powder in the same manner as
described in Production example 18.
[0450] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.89 (1H, s), 6.27
(1H, s), 7.44-7.51 (3H, m), 7.64 (1H, t, J=5.7 Hz), 7.80-7.85 (3H,
m), 7.87 (1H, bs), 8.35 (1H, d, J=2.0 Hz), 8.42 (1H, dt, J=1.0, 4.9
Hz).
Production Example 26
(3-Fluoropyridin-4-yl)-(naphthalen-2-yl)-methanone
[0451] From 17.0 g of
(3-fluoropyridin-4-yl)-(naphthalen-2-yl)-methanol, 15.1 g of the
title compound was obtained as colorless needle crystals in
accordance with Production example 2.
[0452] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.49 (1H, dd,
J=4.6, 5.5 Hz), 7.58 (1H, dt, J=1.3, 7.4 Hz), 7.66 (1H, dt, J=1.3,
7.4 Hz), 7.93 (2H, bd, J=7.4 Hz), 7.97 (1H, d, J=8.9 Hz), 8.01 (1H,
dd, J=1.5, 8.9 Hz), 8.22 (1H, bd, J=1.5 Hz), 8.64 (1H, dd, J=1.3,
4.6 Hz), 8.68 (1H, d, J=1.3 Hz).
Production Example 27
(3-Fluoro-1-oxypyridin-4-yl)-(naphthalen-2-yl)-methanone
[0453] From 1.5 g of
(3-fluoropyridin-4-yl)-naphthalen-2-yl-methanone, 1.3 g of the
title compound was obtained as a colorless powder in accordance
with Production example 4.
[0454] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (1H, dd,
J=6.8, 7.8 Hz), 7.61 (1H, dt, J=1.5, 7.5 Hz), 7.68 (1H, dt, J=1.5,
7.5 Hz), 7.93 (1H, bd, J=7.5 Hz), 7.95 (1H, bd, J=7.5 Hz), 7.97
(1H, d, J=8.8 Hz), 7.98 (1H, d, J=8.8 Hz), 8.17 (1H, ddd, J=0.6,
1.8, 6.8 Hz), 8.25 (1H, dd, J=1.8, 5.0 Hz), 8.26 (1H, s).
Production Example 28
(2-Chloro-5-fluoropyridin-4-yl)-(naphthalen-2-yl)-methanone
[0455] A solution containing 1.4 g of
(3-fluoro-1-oxypyridin-4-yl)-(naphthalen-2-yl)-methanone obtained
by Production example 27 in 10 mL of phosphorus oxychloride was
heated under nitrogen atmosphere at 80.degree. C. for 1.5 hours.
The reaction solution was allowed to cool to room temperature, and
the excess phosphorus oxychloride was distilled off under reduced
pressure. The resulting residue was then added with aqueous sodium
hydrogen carbonate, extracted with ethyl acetate, and the organic
layer was washed with water and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the resulting residue was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=19:1), to afford 680 mg of the title compound as
colorless needle crystals and 550 mg of
(2-chloro-3-fluoropyridin-4-yl)-naphthalen-2-yl-methanone described
in Production example 29 described below as colorless needle
crystals.
[0456] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (1H, d, J=4.6
Hz), 7.60 (1H, t, J=7.5 Hz), 7.68 (1H, t, J=7.5 Hz), 7.93 (1H, d,
J=7.5 Hz), 7.95 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=9.1 Hz), 7.99
(1H, d, J=9.1 Hz), 8.21 (1H, bs), 8.45 (1H, s).
Production Example 29
(2-Chloro-3-fluoropyridin-4-yl)-(naphthalen-2-yl)-methanone
[0457] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (1H, t, J=4.6
Hz), 7.60 (1H, t, J=7.5 Hz), 7.68 (1H, t, J=7.5 Hz), 7.93 (1H, d,
J=7.5 Hz), 7.95 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=9.1 Hz), 7.99
(1H, d, J=9.1 Hz), 8.21 (1H, bs), 8.41 (1H, d, J=4.6 Hz).
Production Example 30
2-Benzyl-5-phenyl-2H-pyrazol-3-ylamine
[0458] 2.9 g of .alpha.-cyanoacetophenone and 3.9 g of benzyl
hydrazine dihydrochloride were suspended in 50 mL of ethanol. The
reaction solution was added with 6.0 ml of triethylamine at room
temperature, and heated under reflux for 4 hours. The solvent was
evaporated, and the residue was added with water, extracted with
ethyl acetate, and dried over anhydrous sodium sulfate. After
distilling off the solvent, the residue was purified and separated
by silica gel column chromatography (ethyl acetate:n-hexane=1:4),
to afford 4.1 g of the title compound as a yellow needle
powder.
[0459] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.40 (2H, bs),
5.28 (2H, s), 5.92 (1H, s), 7.22 (2H, d, J=8.0 Hz), 7.28 (2H, t,
J=8.0 Hz), 7.32-7.37 (2H, m), 7.38 (2H, t, J=8.0 Hz), 7.77 (2H, d,
J=8.0 Hz).
Production Example 31
1-Benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[0460] 1.65 g of 2-cyano-3,3-dimethoxy-1-propenolate sodium was
suspended in 30 mL of methanol, and the reaction solution was added
successively with 2.5 g of 2-benzyl-5-phenyl-2H-pyrazole-3-ylamine
obtained by Production example 30 and 1.5 mL of concentrated
hydrochloric acid at room temperature, and heated under reflux for
3 hours. The reaction solution was added with aqueous sodium
hydrogen carbonate, extracted with ethyl acetate, and dried over
anhydrous sodium sulfate. After distilling off the solvent, the
residue was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:9), to afford 0.8 g of the
title compound as a colorless powder.
[0461] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.78 (2H, s),
7.28-7.37 (3H, m), 7.43 (2H, bd, J=7.2 Hz), 7.47 (2H, t, J=7.2 Hz),
7.54 (2H, t, J=7.2 Hz), 7.91 (2H, bd, J=7.2 Hz), 8.66 (1H, d, J=1.9
Hz), 8.78 (1H, d, J=1.9 Hz).
Production Example 32
1-Benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
[0462] Using 600 mg of
1-benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile as a
starting material, 500 mg of the title compound was obtained as a
colorless powder in the same manner as described in Example 7.
[0463] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.78 (2H, s),
7.24-7.30 (5H, m), 7.47 (1H, t, J=8.6 Hz), 7.56 (2H, t, J=8.6 Hz),
8.01 (2H, d, J=8.6 Hz), 8.97 (1H, d, J=2.0 Hz), 9.12 (1H, d, J=2.0
Hz).
Production Example 33
1-Benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
methyl ester
[0464] 100 mg of
1-benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
obtained by Example 32 was dissolved in 5 mL of
N,N-dimethylformamide, added with 60 mg of potassium carbonate and
30 .mu.l of methyl iodide, and stirred all day and night at room
temperature. The residue was added with water, extracted with ethyl
acetate, and dried over anhydrous sodium sulfate. After distilling
off the solvent, the reaction was crystallized from diisopropyl
ether, to afford 100 mg of the title compound as a pale brown
powder.
[0465] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.00 (3H, s),
5.80 (2H, s), 7.25-7.34 (3H, m), 7.41-7.48 (3H, m), 7.53 (2H, t,
J=7.6 Hz), 7.98 (2H, d, J=7.6 Hz), 9.01 (1H, d, J=1.8 Hz), 9.22
(1H, d, J=1.8 Hz).
Example 34
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
[0466] 100 mg of
1-benzyl-3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
obtained by Production example 33 was dissolved in a mixed solvent
of 2 mL sulfuric acid/4 mL acetic acid/2 mL water, and added with
300 mg of chromic acid under ice-cooling. The reaction solution was
heated at 70.degree. C. for 1 hour, allowed to cool to room
temperature, added with sodium hydrogen carbonate, extracted with
ethyl acetate, and dried over anhydrous sodium sulfate. After
distilling off the solvent, the residue was added with diisopropyl
ether, followed by filtration, to afford 60 mg of the title
compound as a colorless powder.
[0467] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.46 (1H, t,
J=7.6 Hz), 7.56 (2H, t, J=7.6 Hz), 8.02 (2H, d, J=7.6 Hz), 8.94
(1H, a, J=2.0 Hz), 9.06 (1H, d, J=2.0 Hz), 13.20-13.35 (1H, bs),
14.18 (1H, s).
Production Example 35
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine
[0468] From 220 mg of 3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 3, 460 mg of the title compound was
obtained as a colorless powder in accordance with Production
example 22.
[0469] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.64 (1H, dd,
J=1.8, 8.7 Hz), 6.93 (1H, dd, J=4.6, 8.7 Hz), 7.02 (1H, dt, J=2.5,
8.0 Hz), 7.21-7.26 (6H, m), 7.27-7.33 (9H, m), 7.40 (1H, dt, J=6.4,
8.0 Hz), 8.19 (1H, dd, J=2.5, 10.3 Hz), 8.31 (1H, d, J=8.0 Hz),
8.57 (1H, dd, J=1.8, 4.6 Hz).
Production Example 36
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide
[0470] From 480 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine, 250 mg of
the title compound was obtained as a colorless powder in the same
manner as described in Production example 4.
[0471] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.36 (1H, d, J=8.8
Hz), 7.09 (1H, dd, J=6.2, 8.8 Hz), 7.17-7.24 (6H, m), 7.29-7.39
(10H, m), 7.42 (1H, dt, J=6.2, 8.2 Hz), 7.79 (1H, d, J=8.2 Hz),
7.91 (1H, bd, J=11.3 Hz), 8.13 (1H, d, J=6.2 Hz).
Production Example 37
3-(3-Fluorophenyl)-5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine
[0472] To 100 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide in
toluene was acted phosphorus oxychloride in toluene in the same
manner as described in Production example 28, to afford 30 mg of
3-(3-fluorophenyl)-5-chloro-1H-pyrazolo[4,3-b]pyridine described in
Example 38 described below as a colorless powder, as well as 60 mg
of a crude product of the title compound as a colorless powder.
[0473] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.54 (1H, d, J=8.9
Hz), 6.92 (1H, d, J=8.9 Hz), 7.03 (1H, dt, J=2.5, 8.1 Hz),
7.17-7.23 (6H, m), 7.24-7.35 (9H, m), 7.40 (1H, dt, J=6.0, 8.1 Hz),
8.10 (1H, ddd, J=1.9, 2.5, 10.7 Hz), 8.25 (1H, bd, J=8.1 Hz).
Example 38
3-(3-Fluorophenyl)-5-chloro-1H-pyrazolo[4,3-b]pyridine
[0474] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.11 (1H, ddt,
J=1.2, 2.8, 8.0 Hz), 7.37 (1H, d, J=8.7 Hz), 7.48 (1H, dt, J=6.0,
8.0 Hz), 7.82 (1H, d, J=8.7 Hz), 8.20 (1H, ddd, J=1.5, 2.8, 10.4
Hz), 8.31 (1H, bd, J=8.0 Hz), 10.20-10.40 (1H, bs).
Example 39
1-[3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]ethanone
[0475] 50 mg of crude
3-(3-fluorophenyl)-5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 37 and 35 .mu.l of
tributyl(1-ethoxyvinyl)tin was dissolved in 2 mL of
N,N-dimethylformamide, added with 10 mg of
tetrakis(triphenylphosphine)palladium(0), and heated at 100.degree.
C. for 15 minutes. After completion of the reaction, the reaction
solution was added with water and extracted with ethyl acetate. The
organic layer was washed with water, dried over magnesium sulfate,
and the solvent was evaporated. The residue was dissolved in a
mixed solvent of 10 mL THF-1 mL water, added with 0.5 mL of 5N
hydrochloric acid and heated at 90.degree. C. for 10 minutes. After
completion of there action, the reaction solution was added with
aqueous sodium hydrogen carbonate and extracted with ethyl acetate.
The organic layer was washed with waters dried over magnesium
sulfate, and the solvent was evaporated. The residue was dissolved
in 3 mL of dichloromethane, added with 0.5 mL of trifluoroacetic
acid and stirred at room temperature for 5 minutes. The reaction
solution was added with aqueous sodium hydrogen carbonate and
extracted with ethyl acetate. The organic layer was washed with
water, dried over magnesium sulfate, and the solvent was
evaporated. The resulting residue was purified and separated by
silica gel column chromatography (ethyl acetate:n-hexane=3:7), to
afford 7 mg of the title compound as a colorless powder.
[0476] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.78 (3H, s),
7.27 (1H, dt, J=2.6, 7.9 Hz), 7.61 (1H, dt, J=6.3, 7.9 Hz), 8.04
(1H, d, J=8.9 Hz), 8.20 (1H, d, J=8.9 Hz), 8.33 (1H, ddd, J=1.3,
2.6, 10.4 Hz), 8.40 (1H, bd, J=7.9 Hz), 13.82-13.96 (1H, bs).
Production Example 40
[3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl]acetate
[0477] 50 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide
obtained by Production example 36 was suspended in 2 mL of acetic
anhydride, and the reaction solution was heated at 80.degree. C.
for 15 minutes. The reaction solution was allowed to cool to room
temperature, and the residue obtained by distilling off excess
acetic anhydride under reduce pressure was added with aqueous
sodium hydrogen carbonate, extracted with ethyl acetate. The
organic layer was washed with water, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the resulting
residue was subjected to silica gel column chromatography (ethyl
acetate:n-hexane=3:17), to obtain a mixture of the title compound
and
[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-yl]acetate
described in Production example 41 which was inseparable from the
title compound as a colorless powder. Generated ratio: about 6:4,
yield: 62 mg.
[0478] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.38 (3H, s), 6.65
(1H, d, J=9.1 Hz), 6.71 (1H, d, J=9.1 Hz), 7.02 (1H, dt, J=2.7, 8.0
Hz), 7.20-7.28 (6H, m), 7.28-7.34 (9H, m), 7.38 (1H, dt, J=5.8, 8.0
Hz), 8.10 (1H, ddd, J=1.8, 2.7, 10.7 Hz), 8.19 (1H, bd, J=8.0
Hz).
Production Example 41
[3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-yl]acetate
[0479] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.23 (3H, s), 6.38
(1H, d, J=2.0 Hz), 7.03 (1H, dt, J=2.7, 8.0 Hz), 7.20-7.28 (6H, m),
7.28-7.34 (9H, m), 7.40 (1H, dt, J=5.8, 8.0 Hz), 8.14 (1H, ddd,
J=1.8, 2.7, 10.7 Hz), 8.26 (1H, bd, J=8.0 Hz), 8.36 (1H, d, J=2.0
Hz).
Example 42
3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-ol
[0480] 62 mg of the mixture of
[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl]acetate
and
[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-6-yl]acetate
obtained by Production example 40 was treated with the method in
accordance with Production example 16, and purified and separated
by silica gel column chromatography (ethyl
acetate:n-hexane=1:1-1:0), to obtain 10 mg of the title compound
which is a high-polar component as a colorless powder and 10 mg of
[3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-6-yl]acetate as
described in Example 43 below which is a low-polar component as a
colorless powder.
[0481] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 6.60 (1H, d, J=9.6
Hz), 7.15 (1H, dt, J=2.6, 8.0 Hz), 7.52 (1H, dt, J=5.9, 8.0 Hz),
7.56 (1H, bd, J=10.4 Hz), 7.62 (1H, bd, J=8.0 Hz), 7.88 (1H, d,
J=9.6 Hz).
Example 43
[3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]acetate
[0482] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.38 (3H, s), 7.12
(1H, dt, J=2.7, 8.4 Hz), 7.49 (1H, dt, J=6.1, 8.4 Hz), 7.80 (1H, d,
J=2.1 Hz), 8.21 (1H, ddd, J=1.6, 2.7, 10.4 Hz), 8.27 (1H, dd,
J=1.6, 8.4 Hz), 8.42 (1H, d, J=2.1 Hz).
Example 44
[0483] 300 mg of 3-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic
acid obtained by Example 34 was dissolved in 5 mL of
N,N-dimethylformamide solution, and each 0.5 mL was poured into 10
test tubes. Each test tube was added successively 130 .mu.l of 1N
amine solution in N,N-dimethylformamide, 130 .mu.l of 1N
1-hydroxybenztriazole solution in N,N-dimethylformamide, 48 mg of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 90
.mu.l diisopropylethylamine, subjected to sonication for 10
minutes, and left still all day and night. Each reaction solution
was separated and purified by LC-MS [developing solvent: 0.1%
trifluoroacetic acid-containing acetonitrile solution:0.1%
trifluoroacetic acid-containing aqueous solution=1:99-100:0/20 min.
cycle, flowrate: 20 mL/mim: YMC Combiprep ODS-AM, 20
mm.PHI..times.50 mm(Long)], blown with nitrogen, and the solvent
was removed, to afford the following test compounds.
Example 45
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
cyclopropylamide
[0484] MS (ESI) m/z 279 MH.sup.+
Example 46
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(pyridin-2-ylmethyl)-amide
[0485] MS (ESI) m/z 330 MH.sup.+
Example 47
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(tetrahydrofuran-2-ylmethyl)-amide
[0486] MS (ESI) m/z 323 MH.sup.+
Example 48
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(furan-2-ylmethyl)-amide
[0487] MS (ESI) m/z 319 MH.sup.+
Example 49
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(1-methoxymethyl-propyl)-amide
[0488] MS (ESI) m/z 325 MH.sup.+
Example 50
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(2-acetylamino-ethyl)-amide
[0489] MS (ESI) m/z 324 MH.sup.+
Example 51
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(2-methylsulfanil-ethyl)-amide
[0490] MS (ESI) m/z 313 MH.sup.+
Example 52
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(1-hydroxymethyl-3-methylsulfanil-propyl)-amide
[0491] MS (ESI) m/z 357 MH.sup.+
Example 53
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(1-aza-bicyclo[2,2,2]octo-3-yl)-amide
[0492] MS (ESI) m/z 348 MH.sup.+
Example 54
3-Phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(trans-4-hydroxycyclohexyl)-amide
[0493] MS (ESI) m/z 337 MH.sup.+
Example 55
[0494] 3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic
acid obtained by Example 7 was condensed with various kinds of
amine in the same manner as described in Example 44, to afford the
following test compounds.
Example 56
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
cyclopropylamide
[0495] MS (ESI) m/z 297 MH.sup.+
Example 57
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(furan-2-ylmethyl)-amide
[0496] MS (ESI) m/z 337 MH.sup.+
Example 58
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(tetrahydrofuran-2-ylmethyl)-amide
[0497] MS (ESI) m/z 340 MH.sup.+
Example 59
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(2-acetylaminoethyl)-amide
[0498] MS (ESI) m/z 342 MH.sup.+
Example 60
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(pyridin-2-ylmethyl)-amide
[0499] MS (ESI) m/z 348 MH.sup.+
Example 61
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-hydroxymethyl-2-methylpropyl)-amide
[0500] MS (ESI) m/z 343 MH.sup.+
Example 62
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-methoxymethylpropyl)-amide
[0501] MS (ESI) m/z 343 MH.sup.+
Example 63
[0502] 3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic
acid obtained by Example 17 was condensed with various kinds of
amine in the same manner as described in Example 44, to afford the
following test compounds.
Example 64
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
cyclopropylamide
[0503] MS (ESI) m/z 329 MH.sup.+
Example 65
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(furan-2-ylmethyl)-amide
[0504] MS (ESI) m/z 369 MH.sup.+
Example 66
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(tetrahydrofuran-2-ylmethyl)-amide
[0505] MS (ESI) m/z 373 MH.sup.+
Example 67
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(2-acetylaminoethyl)-amide
[0506] MS (ESI) m/z 374 MH.sup.+
Example 68
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(pyridin-2-ylmethyl)-amide
[0507] MS (ESI) m/z 380 MH.sup.+
Example 69
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-hydroxymethyl-2-methylpropyl)-amide
[0508] MS (ESI) m/z 375 MH.sup.+
Example 70
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-methoxymethylpropyl)-amide
[0509] MS (ESI) m/z 375 MH.sup.+
Production Example 71
5-Fluoro-4-(naphthalene-2-carbonyl)pyridine-2-carbonitrile
[0510] To a solution of 300 mg of
(3-fluoro-1-oxypyridin-4-yl)naphthalen-2-yl-methanone obtained by
Production example 27 in 3 mL of acetonitrile were added 0.30 mL of
trimethylcyanide and 0.51 mL of dimethylcarbamyl chloride at room
temperature, and heated under reflux for a day. The solution was
added with water, extracted with ethyl acetate, washed with
saturated brine, and then dried over anhydrous magnesium sulfate.
The solvent was evaporated, and the resulting crude product was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:3), to afford 11 mg of the title compound as
colorless crystals.
[0511] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (1H, ddd,
J=0.8, 7.2, 8.0 Hz), 7.68 (1H, ddd, J=0.8, 7.2, 8.0 Hz), 7.88-8.00
(5H, m), 8.15 (1H, s), 8.75 (1H, s).
Production Example 72
3-Fluoro-4-(naphthalene-2-carbonyl)pyridine-2-carbonitrile
[0512] From 300 mg of
(3-fluoro-1-oxypyridin-4-yl)naphthalen-2-yl-methanone, 230 mg of
the title compound was obtained as colorless crystals in accordance
with the method of Production example 71.
[0513] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (1H, ddd,
J=0.8, 7.2, 8.0 Hz), 7.68 (1H, ddd, J=0.8, 7.2, 8.0 Hz), 7.71 (1H,
t, J=4.8 Hz), 7.91 (1H, s), 7.93 (1H, d, J=0.8 Hz), 7.95 (1H, dd,
J=1.6, 8.0 Hz), 7.98 (1H, d, J=8.0 Hz), 7.88-8.00 (5H, m), 8.15
(1H, s), 8.73 (1H, dd, 0.8, 4.8 Hz).
Example 73
5-Chloro-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine
[0514] A solution of 500 mg of
(2-chloro-5-fluoropyridin-4-yl)-(naphthalen-2-yl)-methanone
obtained by Production example 28 in 5 mL pyridine was added at
room temperature with 0.26 mL of hydrazine monohydrate, and heated
under reflux for a day. The reaction solution was evaporated, and
the resulting crystals were washed successively with water and
ethyl acetate, to afford 350 mg of the title compound as pale
yellow crystals.
[0515] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.54 (1H, td,
J=1.6, 7.2 Hz), 7.57 (1H, td, J=1.6, 7.2 Hz), 7.95 (1H, dd, J=1.6,
8.4 Hz), 8.03 (1H, d, J=8.4 Hz), 8.17 (1H, d, J=8.4 Hz), 8.20 (1H,
dd, J=1.6, 8.4 Hz), 8.42 (1H, d, J=1.6 Hz), 8.61 (1H, s), 8.95 (1H,
d, J=1.6 Hz).
Production Example 74
5-Chloro-3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[3,4-c]pyridine
[0516] To a solution of 320 mg of
5-chloro-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine obtained by
Production example 73 in 3 mL of N,N-dimethylformamide was added 55
mg of sodium hydride at room temperature and stirred for 15 minutes
at this temperature. Then the solution was added with 335 mg of
trityl-chloride at this temperature and stirred for 1 hour at this
temperature. Then water was added and diluted with ethyl acetate.
After washing the suspension in ethyl acetate twice with saturated
aqueous ammonium chloride and once with water, crystals were
collected by filtration. The crystals were washed with ethyl
acetate, to afford 335 mg of the title compound as colorless
crystals.
[0517] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.24-7.41 (15H,
m), 7.48 (1H, s), 7.51-7.59 (2H, m), 7.92 (1H, d, J=7.2 Hz), 7.96
(1H, d, J=8.8 Hz), 7.99 (1H, d, J=8.8 Hz), 8.15 (1H, d, J=7.2 Hz),
8.46 (1H, s), 8.57 (1H, s).
Example 75
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile
[0518] From 11 mg of
5-fluoro-4-(naphthalen-2-carbonyl)pyridine-2-carbonitrile obtained
by Production example 71, 9 mg of the title compound was obtained
as colorless crystals in accordance with the method of Production
example 3.
[0519] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.51-7.58 (2H, m),
7.90-7.93 (1H, m), 8.02 (1H, d, J=8.8 Hz), 8.04-8.07 (1H, m), 8.15
(1H, dd, J=1.6, 8.4 Hz), 8.51 (1H, s), 8.79 (1H, d, J=1.6 Hz), 9.12
(1H, d, J=1.6 Hz).
Production Example 76
(2-Chlorothiophen-3-yl)naphthalen-2-yl methanol
[0520] Under nitrogen atmosphere, to a solution of 3.2 mL of 1.57 M
n-butyllithium in hexane in 7 mL of diethyl ether was added a
solution of 1.00 g of 3-bromo-2-chlorothiophene in 8 mL diethyl
ether at -78.degree. C., and stirred at this temperature for 1
hour. At the same temperature, 0.87 g of 2-naphthaldehyde was
added, stirred for 3 hours while raising the temperature to room
temperature, then added with water, extracted with ethyl acetate,
washed successively with saturated aqueous ammonium chloride and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the resultant crude product was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:20-1:5), to afford 1.18 g of the title compound
as colorless crystals.
[0521] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.19 (1H, d, J=3.6
Hz), 6.95 (1H, d, J=6.0 Hz), 7.05 (1H, dd, J=0.4, 6.0 Hz),
7.43-7.50 (3H, m), 7.78-7.85 (3H, m), 7.91 (1H, d, J=0.4 Hz).
Production Example 77
(2-Chlorothiophen-3-yl)-(naphthalen-2-yl)-methanone
[0522] To a solution of 1.18 g of
(2-chlorothiophen-3-yl)-(naphthalen-2-yl)-methanol in 12 mL of
toluene was added 1.12 g of activated manganese dioxide at room
temperature, and after stirring at 50.degree. C. for a day,
manganese dioxide was filtered off through Celite. The solvent was
distilled off, and the resultant crude product was purified and
separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:50) to afford 0.61 g of the title compound as a
colorless oil.
[0523] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.18 (1H, d, J=6.0
Hz), 7.20 (1H, d, J=6.0 Hz), 7.55 (1H, ddd, J=1.6, 7.2, 8.0 Hz),
7.61 (1H, ddd, J=1.6, 7.2, 8.0 Hz), 7.88-7.95 (3H, m), 7.96 (1H,
dd, J=1.6, 8.0 Hz), 8.28 (1H, d, J=0.8 Hz).
Example 78
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole
[0524] To a solution of 0.61 g of
(2-chlorothiophen-3-yl)-(naphthalen-2-yl)-methanone in 6 mL of
ethanol was added 0.12 mL of hydrazine monohydrate at room
temperature and heated under reflux for 2 days. The reaction
solution was diluted with ethyl acetate, and the organic layer
washed successively with saturated aqueous ammonium chloride and
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was evaporated. The resultant crude product was purified
and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:30-1:5), to afford 32 mg of the title compound
as colorless crystals.
[0525] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.37 (1H, d,
J=5.6 Hz), 7.51 (1H, td, J=1.6, 8.0 Hz), 7.55 (1H, td, J=1.6, 8.0
Hz), 7.57 (1H, d, J=5.6 Hz), 7.92 (1H, dd, J=1.6, 8.0 Hz),
7.98-8.09 (3H, m), 8.42 (1H, s).
Production Example 79
1,5-Dibromo-2,4-difluorobenzene
[0526] Under ice cooling, a solution of 25.35 g of
1-bromo-2,4-difluorobenzene in 100 mL of concentrated sulfuric acid
was added with 25.7 g of N-bromosuccinimide, and stirred for 30
minutes at this temperature and for 2 days at room temperature.
After cooling on ice, the reaction solution was added with ice, and
extracted with 300 mL of diethyl ether. The organic layer was
successively washed with water, saturated aqueous sodium hydrogen
carbonate and saturated brine, and then dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the resulting
crude product was purified and separated by silica gel column
chromatography (n-hexane), to afford 34.6 g of the title compound
as a colorless oil.
[0527] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.99 (1H, t, J=8.4
Hz), 7.77 (1H, t, J=6.8 Hz)
Production Example 80
5-Bromo-2,4-difluoro-benzaldehyde
[0528] Under nitrogen atmosphere and at a temperature of
-78.degree. C., a solution of 34.0 g of
1,5-dibromo-2,4-difluorobenzene obtained by Production example 79
in 250 mL of diethyl ether was added with 83 mL of 1.58 M
n-butyllithium in n-hexane, and stirred at this temperature for 30
minutes. To the reaction solution, 12 mL of N,N-dimethylformamide
was added dropwise, and stirred at this temperature for 30 minutes.
The reaction solution was added successively with 20 mL of glacial
acetic acid and 300 mL of water, and extracted with diethyl ether.
The organic layer was washed successively with 0.2N hydrochloric
acid, water, saturated aqueous sodium hydrogen carbonate and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the resulting crude product was
purified and separated by silica gel column chromatography
(n-hexane:ethyl acetate=49:1), to afford 21.4 g of the title
compound as a pale yellow oil.
[0529] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (1H, dd,
J=8.0, 9.6 Hz), 8.11 (1H t, J=7.2 Hz), 10.24 (1H, s)
Production Example 81
2,4-Difluoro-5-formyl-benzonitrile
[0530] To a solution of 21.4 g of 5-bromo-2,4-difluoro-benzaldehyde
obtained by Production example 80 in 120 mL of
N-methyl-2-pyrrolidone, 10.1 g of copper cyanide (I) was added and
stirred at 175.degree. C. for 4 hours. After allowing the solution
to cool, the reaction solution was added with water and diethyl
ether, and the impurities were filtered off through Celite. The
organic layer was washed successively with water (.times.3) and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the resulting crude product was
purified and separated by silica gel column chromatography
(n-hexane:ethyl acetate=9:1), to afford 9.87 g of the title
compound as pale yellow crystals.
[0531] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.14 (1H, dd,
J=8.4, 9.6 Hz), 8.25 (1H t, J=7.2 Hz), 10.27 (1H, s)
Production Example 82
6-Fluoro-1H-indazole-5-carbonitrile
[0532] 2.50 g of 2,4-difluoro-5-formyl-benzonitrile obtained by
Production example 81 was dissolved in 15 mL of pyridine, added
with 4.0 mL of hydrazine monohydrate and stirred at room
temperature for 2 hours. After evaporating the pyridine, the
residue was dissolved in 200 mL of ethyl acetate and 40 mL of
tetrahydrofuran, washed successively with 1N hydrochloric acid,
water, saturated aqueous sodium hydrogen carbonate and saturated
brine, and dried over anhydrous magnesium sulfate. After making the
organic layer pass through a silica gel pad (4 cm in
diameter.times.3 cm), the solvent was evaporated, to afford 1.63 g
of the title compound as bright yellow crystals.
[0533] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.66 (1H, d,
J=10.0 Hz), 8.28 (1H, s), 8.51 (1H, d, J=6.0 Hz), 13.68 (1H, s)
Production Example 83
3-Bromo-6-fluoro-1-trityl-1H-indazole-5-carbonitrile
[0534] At room temperature, a solution containing 1.25 g of
6-fluoro-1H-indazole-5-carbonitrile obtained by Production example
82 in 12 mL of N,N-dimethylformamide was added with 1.52 g of
N-bromosuccinimide and stirred overnight at this temperature. The
reaction solution was added to 120 mL of ethyl acetate, and washed
successively with semi saturated aqueous sodium hydrogen carbonate,
water (twice) and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the resultant
residue was dissolved in 15 mL of N,N-dimethylformamide. Under ice
cooling, 2.16 g trityl-chloride and 310 mg of 60% sodium hydride
were successively added, and stirred at this temperature for 10
minutes, and further at room temperature for 20 minutes. After
adding ice, to the reaction solution was extracted with 120 mL of
ethyl acetate. The organic layer was washed successively with water
(twice) and saturated brine, and dried over anhydrous magnesium
sulfate. After making the organic layer pass through a silica gel
pad (4 cm in diameter.times.3 cm), the solvent was distilled off
under reduced pressure, and the resultant crude crystals were
recrystallized from ethyl acetate-diisopropyl ether, to afford 1.55
g of the title compound as pale yellow crystals.
[0535] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.17 (1H, d,
J=10.8 Hz), 7.13-7.22 (6H, m), 7.32-7.42 (9H, m), 8.44 (1H, d,
J=6.4 Hz)
Production Example 84
2,4-Difluoro-3-formyl-benzonitrile
[0536] Under nitrogen atmosphere and ice cooling, to a solution of
11.1 g of N,N-diisopropylamine in 100 mL of tetrahydrofuran was
added 66 mL of 1.6 M n-butyllithium in n-hexane and stirred at this
temperature for 20 minutes. After cooling to -78.degree. C., 15 mL
of a solution containing 13.9 g of 2,4-difluorobenzonitrile in
tetrahydrofuran was added dropwise. After stirring at this
temperature for 10 minutes, 8.6 mL of N,N-dimethylformamide was
added dropwise and stirred at this temperature for 15 minutes. The
reaction solution was added with 20 mL of glacial acetic acid,
followed by 200 mL water, and extracted twice with diethyl ether.
The organic layer was washed successively with 0.2N hydrochloric
acid and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the resultant crude
crystals were triturated with diethyl ether n-hexane, to afford
8.61 g of the title compound as bright yellow crystals.
[0537] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.53 (1H, t,
J=8.8 Hz), 8.33 (1H, ddd, J=6.0, 7.2, 8.8 Hz), 10.17 (1H, s)
Production Example 85
4-Fluoro-1H-indazole-5-carbonitrile
[0538] 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained by
Production example 84 was dissolved in 40 mL of tetrahydrofuran and
40 mL of methanol, added with 5.1 mL of hydrazine monohydrate,
stirred at room temperature for 3 days, at 50.degree. C. for 3
hours, and at 70.degree. C. for 3 hours. The reaction solution was
added with 150 mL of ice water, further with 300 mL of ethyl
acetate and 100 mL of tetrahydrofuran, and unnecessary substances
were filtered out. The organic layer was washed successively with
water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the crude product was
purified and separated by silica gel column chromatography (ethyl
acetate:toluene=1:9-1:4), to afford 509 mg of the title compound as
bright yellow crystals. Then the combined fraction with impurities
was purified again by silica gel column chromatography (ethyl
acetate:n-hexane=1:4-1:0), to obtain 1.80 g of the title compound
as bright yellow crystals.
[0539] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.58 (1H, d,
J=8.8 Hz), 7.70 (1H, dd, J=6.0, 8.8 Hz), 8.45 (1H, s), 13.94 (1H,
s)
Production Example 86
4-Fluoro-1H-indazole-5-carboxylic acid methyl ester
[0540] To 1.65 g of 4-fluoro-1H-indazole-5-carbonitrile obtained by
Production example 85, 8 mL of glacial acetic acid, 8 mL of water
and 16 mL of concentrated sulfuric acid were added and stirred at
110.degree. C. for 4 hours. After allowing the reaction solution to
cool, 150 mL of ice water was added, and the precipitated
carboxylic acid was collected by filtration. Under ice cooling, to
a solution of the obtained carboxylic acid in N,N-dimethylformamide
12 mL-tetrahydrofuran 40 mL, a solution containing excess
diazomethane in diethyl ether was added, and stirred at this
temperature for 45 minutes. After distilling off the solvent under
reduced pressure, the residue was dissolved in 100 mL of ethyl
acetate, washed successively with saturated aqueous sodium hydrogen
carbonate, water and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, to afford 1.98 g of
the title compound as bright yellow crystals.
[0541] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.87 (3H, s),
7.45 (1H, d, J=8.8 Hz), 7.82 (1H, dd, J=6.8, 8.8 Hz), 8.36 (1H, s),
13.70 (1H, s)
Production Example 87
3-Bromo-4-fluoro-1H-indazole-5-carboxylic acid methyl ester
[0542] At room temperature, to a solution of 2.2 g of
4-fluoro-1H-indazole-5-carboxylic acid methyl ester obtained by
Production example 86 in 20 mL of N,N-dimethylformamide was added
2.12 g of N-bromosuccinimide and stirred at this temperature for 1
hour. After distilling off the solvent, the residue was added with
120 mL of ethyl acetate, and washed successively with
semi-saturated aqueous sodium hydrogen carbonate, water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, to afford 3.0 g of the title compound as
bright yellow crystals.
[0543] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.88 (3H, s),
7.48 (1H, d, J=8.8 Hz), 7.85 (1H, dd, J=6.4, 8.8 Hz), 14.00 (1H,
s)
Production Example 88
3-Bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl
ester
[0544] Under ice cooling, to a solution of 2.99 g of
3-bromo-4-fluoro-1H-indazole-5-carboxylic acid methyl ester
obtained by Production example 87 in 30 mL of tetrahydrofuran was
added 526 mg of 60% sodium hydride, stirred for 25 minutes, added
with 3.21 g of trityl chloride, and stirred at this temperature for
15 minutes and at room temperature for 45 minutes. The reaction
solution was cooled again on ice, added with semi-saturated aqueous
sodium hydrogen carbonate, and extracted with 100 mL of ethyl
acetate. The organic layer was washed successively with water
(twice) and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, the crude product purified and
separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:9), and the obtained crude crystals were
recrystallized from diisopropyl ether, to afford 1.73 g of the
title compound as white needle crystals.
[0545] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.83 (3H, s),
6.30 (1H, d, J=8.8 Hz), 7.12-7.20 (6H, m), 7.30-7.40 (9H, m), 7.55
(1H, dd, J=6.8, 8.8 Hz)
Production Example 89
1-Bromo-4-fluoro-2-methoxybenzene
[0546] 10 g of 2-bromo-5-fluorophenol was dissolved in 105 mL of
N,N-dimethylformamide, and added with 10.9 g of potassium carbonate
and 4.9 mL of iodomethane under cooling, and stirred at room
temperature for 3 hours. The reaction solution was added with
water, extracted with diethyl ether, and the resultant organic
layer was washed with saturated brine, and dried over magnesium
sulfate. The solvent was evaporated, to afford 9.75 g of the title
compound as a yellow oil.
[0547] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.88 (3H, s), 6.59
(1H, td, J=8.4, 2.8 Hz), 6.65 (1H, dd, J=10.4, 2.8 Hz), 7.47 (1H,
dd, J=8.4, 6.0 Hz)
Production Example 90
5-Bromo-2-fluoro-4-methoxybenzaldehyde
[0548] 8.4 g of 1-bromo-4-fluoro-2-methoxybenzene obtained by
Production example 89 was dissolved in 200 mL of dichloromethane,
added under nitrogen atmosphere at 0.degree. C. with 21 mL of
titanium tetrachloride and 5.6 mL of dichloromethylmethylether, and
stirred at room temperature for 4 hours and 30 minutes. The
reaction solution was slowly poured into ice water, and extracted
twice with diethyl ether. The organic layer was washed successively
with water, saturated aqueous sodium hydrogen carbonate and water,
and then dried over magnesium sulfate. The solvent was evaporated,
to afford 9.44 g of the title compound as white crystals.
[0549] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.97 (3H, s), 6.67
(1H, d, J=12.0 Hz), 8.05 (1H, d, J=7.6 Hz), 10.15 (1H, s)
Production Example 91
4-Fluoro-5-formyl-2-methoxybenzonitrile
[0550] 5.33 g of 5-bromo-2-fluoro-4-methoxybenzaldehyde obtained by
Production example 90 was dissolved in 73 mL of
1-methyl-2-pyrrolidone, added with 2.46 g of copper cyanide, and
stirred at 180.degree. C. for 5 hours and 30 minutes. After
allowing to cool, the reaction solution was added with water and
diethyl ether, and insoluble substances were filtered off through
celite. The organic layer was washed with water and saturated
brine, and dried over magnesium sulfate. The solvent was
evaporated, and purified and separated by silica gel column
chromatography, to afford 0.983 g of the title compound as pale
yellow crystals.
[0551] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.03 (3H, s), 6.76
(1H, d, J=12.0 Hz), 8.14 (1H, d, J=7.2 Hz), 10.17 (1H, s)
Production Example 92
6-Methoxy-1H-indazole-5-carbonitrile
[0552] 0.983 g of 4-fluoro-5-formyl-2-methoxybenzonitrile obtained
by Production example 91 was dissolved in 15 mL of pyridine, and
added with 2.66 mL of hydrazine monohydrate. After stirring at
50.degree. C. for 2 hours, the solution was added with water and
extracted twice with ethyl acetate. The resultant organic layer was
washed with 1N hydrochloric acid, water, saturated aqueous sodium
hydrogen carbonate and saturated brine, and dried over magnesium
sulfate. The solvent was evaporated, to afford 0.915 g of the title
compound as pale yellow crystals.
[0553] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.99 (3H, s), 7.10
(1H, s), 8.06 (1H, s), 8.15 (1H, s)
Production Example 93
3-Bromo-6-methoxy-1H-indazole-5-carbonitrile
[0554] To a solution of 0.915 g of
6-methoxy-1H-indazole-5-carbonitrile obtained by Production example
92 in 7.5 mL of N,N-dimethylformamide, 0.986 g of
N-bromosuccinimide was added at room temperature, and stirred at
this temperature for 1 hour and 30 minutes. The reaction solution
was added with ethyl acetate, washed successively with
semi-saturated aqueous sodium hydrogen carbonate, water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, to afford 1.2 g of the title compound as
yellow crystals.
[0555] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.00 (3H, s), 7.10
(1H, s), 7.97 (1H, s)
Production Example 94
3-Bromo-6-methoxy-1-trityl-1H-indazole-5-carbonitrile
[0556] To a solution of 1.2 g of
3-bromo-6-methoxy-1H-indazole-5-carbonitrile obtained by Production
example 93 in 50 mL of N,N-dimethylformamide were added 171 mg of
sodium hydride and 1.6 g of triphenylmethane chloride under ice
cooling, and stirred at this temperature for 1 hour and 30 minutes.
The reaction solution was added with water and extracted with ethyl
acetate. The organic layer was washed successively with water and
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was evaporated, to afford 2.41 g of the title compound as
brown crystals.
[0557] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.36 (3H, s), 5.60
(1H, s), 7.14-7.17 (5H, m), 7.24-7.32 (10H, m), 7.81 (1H, s)
Production Example 95
4-Fluoro-2-methoxybenzonitrile
[0558] 15 g of 1-bromo-4-fluoro-2-methoxybenzene obtained by
Production example 89 was dissolved in 150 mL of
1-methyl-2-pyrrolidone, added with 9.9 g of copper cyanide (I), and
stirred at 180.degree. C. for 5 hours. After allowing to cool, the
reaction solution was poured into 500 mL of 14% ammonia aqueous
solution, stirred for 45 minutes, then added with 150 mL of diethyl
ether, and stirred for another 10 minutes. After filtering off the
insoluble substances through Celite, the solution was extracted
with diethyl ether. The organic layer was washed with diluted
aqueous ammonia, 5N hydrochloric acid, water and saturated brine,
and dried over magnesium sulfate. The solvent was evaporated, to
afford 10.1 g of the title compound as white crystals.
[0559] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.93 (3H, s),
6.67-6.74 (2H, m), 7.54 (1H, dd, J=6.0, 8.4 Hz)
Production Example 96
4-Fluoro-3-formyl-2-methoxybenzonitrile
[0560] Under nitrogen atmosphere and at -78.degree. C., to a
solution of 10.7 g of N,N-diisopropylamine in 150 mL of
tetrahydrofuran was added 40 mL of 2.66 M n-butyllithium in
n-hexane, stirred at this temperature for 1 hour and 15 minutes,
and added dropwise with a solution of 14.5 g of
4-fluoro-2-methoxybenzonitrile obtained by Production example 95 in
50 mL of tetrahydrofuran. After stirring at this temperature for 2
hours, 11.94 g of N-formylpiperidine was added. After stirring at
this temperature for 40 minutes, the solution was added with 20 mL
of acetic acid at this temperature, added with water at room
temperature, and extracted three times with diethyl ether. The
organic layer was washed successively with 0.2N hydrochloric acid,
water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the crude product was
purified and separated by silica gel column chromatography, to
afford 6.4 g of the title compound 6.4 g as pale yellow
crystals.
[0561] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.22 (3H, s), 6.99
(1H, t, J=8.8 Hz), 7.78 (1H, dd, J=5.6, 8.8 Hz), 10.34 (1H, s).
Production Example 97
4-Methoxy-1H-indazole-5-carbonitrile
[0562] From 6.4 g of 4-fluoro-3-formyl-2-methoxybenzonitrile, 6.03
g of the title compound was obtained as yellow crystals in
accordance with the method of Production example 92.
[0563] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.37 (3H, s),
7.20 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=8.8 Hz), 8.57 (1H, s), 13.61
(1H, bs)
Production Example 98
3-Bromo-4-methoxy-1H-indazole-5-carbonitrile
[0564] From 72 mg of 4-methoxy-1H-indazole-5-carbonitrile, 69 mg of
the title compound was obtained as white crystal in accordance with
the method of Production example 93.
[0565] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.15 (3H, s),
7.42 (1H, d, J=8.8 Hz), 7.59 (1H, d, J=8.8 Hz), 13.94 (1H, bs)
Production Example 99
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile
[0566] From 69 mg of 3-bromo-4-methoxy-1H-indazole-5-carbonitrile,
150 mg of the title compound was obtained as a brown oil in
accordance with the method of Production example 94.
[0567] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.29 (3H, s), 6.11
(1H, d, J=8.8 Hz), 7.00 (1H, d, J=8.8 Hz), 7.11-7.32 (15H, m)
Example 100
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
[0568] To a solution of 1.35 g of
3-bromo-6-fluoro-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 83 in 9 mL of N,N-dimethylformamide were
successively added 685 mg of 3-fluoro-styrene, 167 mg of
2-(di-tert-butylphosphino)biphenyl, 63 mg of palladium acetate (II)
and 1.95 mL of triethylamine, and stirred at 80.degree. C. for 2
hours. The solvent was evaporated, to obtain 2.75 g of a crude
coupling compound. The obtained crude coupling compound was
suspended in 9 mL of dichloromethane, added with 3 mL of
trifluoroacetic acid and 0.5 mL triisopropylsilane, and stirred at
room temperature for 4 hours. The reaction solution was poured into
a stirred and mixed solution of 100 mL saturated aqueous sodium
hydrogen carbonate/90 mL ethyl acetate/10 mL tetrahydrofuran. The
organic layer was washed successively with saturated aqueous sodium
hydrogen carbonate and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, the crude product
purified and separated by silica gel column chromatography (ethyl
acetate:toluene=1:19-1:9), to afford 645 mg of the title compound
as bright yellow crystals.
[0569] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.08 (1H, dt,
J=2.0, 8.4 Hz), 7.44 (1H, dt, J=5.6, 7.6 Hz), 7.48 (1H, d, J=9.6
Hz), 7.48-7.54 (2H, m), 7.56 (1H, d, J=16.4 Hz), 7.62 (1H, d,
J=16.4 Hz), 8.71 (1H, d, J=6.0 Hz)
Example 101
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid
[0570] To a suspension of 544 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
obtained by Example 100 in 2 mL of acetic acid and 3 mL of water
was added 6 mL of concentrated sulfuric acid, and stirred at
110.degree. C. for 12 hours. After allowing to cool, the reaction
solution was added with ice, and extracted with a mixed solvent of
200 mL of ethyl acetate and 50 mL of tetrahydrofuran. The organic
layer was washed successively with water and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
to afford 491 mg of the title compound as pale brown crystals.
[0571] .sup.1H-NMR (400 MHz, DMSO-D) .delta. 7.12 (1H, dt, J=2.0,
8.4 Hz), 7.41 (1H, d, J=11.2 Hz), 7.42 (1H, dt, J=5.6, 7.6 Hz),
7.53 (1H, d, J=16.8 Hz), 7.57 (1H, d, J=8.0 Hz), 7.69 (1H, d,
J=10.8 Hz), 7.76 (1H, d, J=16.8 Hz), 8.75 (1H, d, J=, 6.8 Hz),
13.02 (1H, br s), 13.50 (1H, s). Compounds of Examples 102-h to
107-h were synthesized according to the following synthesizing
method.
[0572]
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid synthesized in Example 101 was dissolved in
N,N-dimethylformamide and dispensed into test tubes. Each test tube
was added successively with preliminarily prepared 1.5 equivalents
of different kind of amine in 1M dimethylformamide solution, 2
equivalents of 1-hydroxybenztriazole monohydrate in 1 M
dimethylformamide solution, and 2 equivalents of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(.dbd.WSC.HCl), and stirred at room temperature overnight. The
resultant reaction solution was purified and separated by LC-MS
[developing solvent: 0.1% trifluoroacetic acid-containing
acetonitrile solution:0.1% trifluoroacetic acid-containing aqueous
solution=20:80-80:20, 10 min. cycle, flow rate: 30 mL/min., column:
Wakopak Combi ODs, 20 mm.PHI..times.50 mm(Long)], to afford the
compounds of the following Examples.
Example 102
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0573] MS (ESI) m/z 340 MH.sup.+
Example 103
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0574] MS (ESI) m/z 380 MH.sup.+
Example 104
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid (tetrahydrofuran-2-ylmethyl)-amide
[0575] MS (ESI) m/z 384 MH.sup.+
Example 105
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0576] MS (ESI) m/z 386 MH.sup.+
Example 106
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid (pyridine-3-ylmethyl)-amide
[0577] MS (ESI) m/z 391 MH.sup.+
Example 107
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0578] MS (ESI) m/z 763 2M+Na.sup.+
Production Example 108
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazole-5-carboxyli-
c acid
[0579] Under ice cooling, to a solution of 350 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Example 101 in 6 mL of N,N-dimethylformamide was
added 103 mg of 60% sodium hydride, stirred for 30 minutes, then
added with 390 mg of tritylchloride, and stirred at this
temperature for 20 minutes and at room temperature for 1 hour. The
reaction solution was added with water and extracted with 80 mL of
ethyl acetate. The organic layer was washed successively with water
and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated, and the crude product was purified and
separated by silica gel column chromatography (ethyl
acetate:toluene=1:9), to afford 370 mg of the title compound as
bright yellow crystals.
[0580] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.95 (1H, d,
J=12.4 Hz), 7.05-7.40 (18H, m), 7.50 (1H, d, J=7.6 Hz), 7.66 (1H,
d, J=10.4 Hz), 7.68 (1H, d, J=16.4 Hz), 8.72 (1H, d, J=7.2 Hz),
13.16 (1H, br s)
Production Example 109
{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yl}carbam-
ic acid tert-butyl ester
[0581] To a suspension of 369 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazole-5-carboxyl-
ic acid obtained by Production example 108 in 6 mL of toluene were
added 69 mg of triethylamine, 0.15 mL of 2-methyl-2-propanol and
187 mg of diphenyl phosphoryl azide, and stirred at 80.degree. C.
for 7.5 hours. After adding 10 mL of ethyl acetate to the reaction
solution, the organic layer was washed successively with water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the crude product purified and
separated by silica gel column chromatography
(n-hexane:toluene=1:1), to afford 102 mg of the title compound as a
white non-crystalline powder.
[0582] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.44 (9H, s),
5.99 (1H, d, J=11.6 Hz), 7.11 (1H, dt, J=2.0, 8.0 Hz), 7.16-7.45
(17H, m), 7.50 (1H, d, J=7.6 Hz), 7.56 (1H, d, J=16.8 Hz), 7.63
(1H, d, J=10.4 Hz), 8.21 (1H, d, J=7.6 Hz), 8.86 (1H, s)
Example 110
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-ylamine
[0583] A solution of 96 mg of
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yl}carba-
mic acid obtained by Production example 109 in a solution of
tert-butyl ester dissolved in 1 mL of 95% trifluoroacetic acid was
stirred at room temperature for 1 hour and 20 minutes. The reaction
solution was added with saturated aqueous sodium hydrogen
carbonate, and extracted with 20 mL of ethyl acetate. The organic
layer was washed successively with saturated aqueous sodium
hydrogencarbonate and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, the crude product
purified and separated by silica gel column chromatography (ethyl
acetate:toluene=1:1), to afford 28 mg of the title compound as a
bright yellow non-crystalline powder.
[0584] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.92 (2H, s),
7.07 (1H, dt, J=2.0, 8.0 Hz), 7.22 (1H, d, J=11.2 Hz), 7.28 (1H, d,
J=16.8 Hz), 7.38 (1H, d, J=8.8 Hz), 7.37 (1H, dt, J=6.0, 8.0 Hz),
7.45 (1H, d, J=7.6 Hz), 7.49 (1H, d, J=16.8 Hz), 7.51 (1H, d,
J=10.4 Hz), 12.86 (1H, s)
[0585] Compounds of Examples 111-114 were synthesized in the
following synthesizing method.
[0586]
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-ylamine
synthesized in Example 110 was dissolved in N,N-dimethylformamide
and dispensed into test tubes. Each test tube was added
successively with preliminarily prepared 1.2 equivalents of
different kind of carboxylic acid in 1M dimethylformamide solution,
1.6 equivalents of 1-hydroxybenztriazole monohydrate in 1 M
dimethylformamide solution, and 1.6 equivalents of
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride
(.dbd.WSC.HCl), and stirred at room temperature for 3 days. The
resultant reaction solution was purified and separated by LC-MS
[developing solvent: 0.1% trifluoroacetic acid-containing
acetonitrile solution:0.1% trifluoroacetic acid-containing aqueous
solution=20:80-80:20, 10 min. cycle, flow rate: 30 mL/min., column:
Wako Wakopak Combi ODS, 20 mm .PHI..times.50 mm(Long)], to afford
the compounds of the following Examples.
Example 111
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[0587] MS (ESI) m/z 340 MH.sup.+
Example 112
(2S)-5-oxo-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[0588] MS (ESI) m/z 383 MH.sup.+
Example 113
N-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(thiophen--
2-yl)-acetamide
[0589] MS (ESI) m/z 396 MH.sup.+
Example 114
Furan-2-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[0590] MS (ESI) m/z 366 MH.sup.+
Example 115
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid amide
[0591] To a suspension of 89 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
obtained by Example 100 in 0.4 mL of acetic acid and 0.4 mL of
water was added 1.2 mL of concentrated sulfuric acid, and stirred
at 110.degree. C. for 50 minutes. After allowing to cool, ice was
added, and extracted with a mixed solvent of 20 mL of ethyl acetate
and 10 mL of tetrahydrofuran. The organic layer was washed
successively with water, saturated aqueous sodium hydrogen
carbonate and saturated brine, and dried over anhydrous magnesium
sulfate. After making the organic layer pass through an alumina pad
(2.5 diameter.times.2 cm), the solvent was evaporated, to afford 76
mg of the title compound as pale yellow crystals.
[0592] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.12 (1H, dt,
J=2.0, 8.4 Hz), 7.39 (1H, d, J=10.8 Hz), 7.41 (1H, dt, J=6.0, 8.4
Hz), 7.53 (1H, d, J=16.8 Hz), 7.56 (1H, d, J=8.0 Hz), 7.61 (1H, s),
7.66 (1H, d, J=10.8 Hz), 7.70 (1H, d, J=16.8 Hz), 7.74 (1H, s),
8.50 (1H, d, J=, 6.8 Hz), 13.40 (1H, s)
Production Example 116
(6-Bromo-2,3-difluorophenyl)trimethylsilane
[0593] Under nitrogen atmosphere, to a solution of 18.2 mL of
N,N-diisopropylamine in 200 mL of tetrahydrofuran was added 66.0 mL
of 1.57 M n-butyllithium in hexane at 0.degree. C., and stirred at
this temperature for 10 minutes. After cooling to -78.degree. C., a
solution containing 20.0 g of 1-bromo-3,4-difluorobenzene in 100 mL
of tetrahydrofuran was added dropwise and stirred at this
temperature for 30 minutes, stirred at this temperature for 30
minutes, added dropwise with 32.9 mL of chlorotrimethylsilane, and
the reaction solution was allowed to warm gradually to room
temperature, and stirred for a day. After diluting with water and
ethyl acetate, the organic layer was washed with saturated brine,
dried over anhydrous magnesium sulfate, and the solvent was
evaporated. The crude product was purified and separated by silica
gel column chromatography (n-hexane), to afford 20.3 g of the title
compound as a colorless oil.
[0594] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.47 (9H, s), 6.99
(1H, dt, J=9.6, 8.8 Hz), 7.27 (1H, ddd, J=2.0, 4.0, 8.8 Hz).
Production Example 117
5-Bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde
[0595] Under nitrogen atmosphere, to a solution containing 6.34 mL
of N,N-diisopropylamine in 100 mL of tetrahydrofuran, 26.4 mL of
1.57 M n-butyllithium in hexane was added at 0.degree. C., and
stirred at this temperature for 10 minutes. After cooling to
-78.degree. C., a solution containing 10.0 g of
(6-bromo-2,3-difluorophenyl)trimethylsilane in 100 mL of
tetrahydrofuran was added dropwise, stirred at this temperature for
1 hour, then added dropwise with 2.92 mL of N,N-dimethylformamide,
allowed to gradually warm to room temperature, and stirred for 3
hours. After diluting with water and ethyl acetate, the organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The crude
product was purified and separated by silica gel column
chromatography (n-hexane), to afford 9.70 g of the title compound
as a colorless oil.
[0596] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.50 (9H, s), 7.77
(1H, dd, J=4.8, 2.0 Hz), 10.27 (1H, s).
Production Example 118
5-Bromo-2,3-difluoro benzaldehyde
[0597] To a solution of 18.0 g of
5-bromo-2,3-difluoro-4-trimethylsilanyl benzaldehyde in 20 mL of
N,N-dimethylformamide and 2 mL of water was added 1.63 g of cesium
fluoride at room temperature, and stirred at this temperature for 1
hour. After diluting with ethyl acetate, the organic layer was
washed successively with saturated aqueous ammonium chloride and
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was evaporated, to afford 10.26 g of the title compound as
a colorless oil.
[0598] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.58 (1H, ddd,
J=9.2, 6.8, 2.4 Hz), 7.76 (1H, ddd, J=4.8, 2.4, 2.0 Hz), 10.27 (1H,
s).
Production Example 119
3,4-Difluoro-5-formylbenzonitrile
[0599] To a solution of 10.0 g of 5-bromo-2,3-difluorobenzaldehyde
in 40.0 mL of 1-methyl-2-pyrrolidone was added 4.26 g of copper
cyanide (I) at room temperature and stirred at 170.degree. C. for 8
hours. Adding ethyl acetate and water, the solution was stirred,
and insoluble substances were filtered out through celite. The
organic layer of filtrate was washed successively with saturated
aqueous ammonium chloride, water and saturated brine, dried over
anhydrous magnesium sulfate, and the solvent was evaporated. The
crude product was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:20), to afford 2.64 g of
the title compound as colorless crystals.
[0600] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.72 (1H, ddd,
J=9.2, 6.8, 2.0 Hz), 7.98 (1H, dt, J=5.6, 2.0 Hz), 10.32 (1H,
s).
Production Example 120
7-Fluoro-1H-indazole-5-carbonitrile
[0601] From 2.60 g of 3,4-difluoro-5-formyl benzonitrile, 2.46 g of
the title compound was obtained as pale yellow crystals according
to the method of Production example 92.
[0602] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.68 (1H, dd,
J=11.2, 0.8 Hz), 8.27 (1H, d, J=0.8 Hz), 8.37 (1H, d, J=3.2
Hz).
Production Example 121
3-Bromo-7-fluoro-1H-indazole-5-carbonitrile
[0603] From 2.40 g of 7-fluoro-1H-indazole-5-carbonitrile, 2.91 g
of the title compound was obtained as pale red crystals according
to the method of Production example 93.
[0604] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.84 (1H, dd,
J=10.8, 0.8 Hz), 8.13 (1H, d, J=0.8 Hz).
Production Example 122
3-Bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile
[0605] From 2.91 g of 3-bromo-7-fluoro-1H-indazole-5-carbonitrile,
2.08 g of the title compound was obtained as colorless crystals
according to the method of Production example 94.
[0606] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.01 (1H, dd,
J=10.8, 0.8 Hz), 7.09-7.32 (15H, m), 7.82 (1H, d, J=0.8 Hz).
Production Example 123
7-Fluoro-1-trityl-3-vinyl-1H-indazole-5-carbonitrile
[0607] Under nitrogen atmosphere, 3.32 g of
3-bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile was dissolved
in 100 mL of toluene, added with 398 mg of
tetrakis(triphenylphosphilne)palladium(0) and 2.50 mL of
vinyltributyltin, and stirred at 100.degree. C. for 95 minutes.
After cooling to room temperature, 10 g of silica gel was added,
the solvent was evaporated, followed by purification by silica gel
column chromatography, to afford 2.59 g of the title compound as
white crystals.
[0608] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.55 (1H, dd,
J=0.8, 11.2 Hz), 6.00 (1H, dd, J=0.8, 18.0 Hz), 6.86-6.97 (2H, m),
7.10-7.30 (15H, m), 8.07 (1H, d, J=1.2 Hz).
Production Example 124
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitril-
e
[0609] Under nitrogen atmosphere, 2.59 g of
7-fluoro-1-trityl-3-vinyl-1H-indazole-5-carbonitrile was dissolved
in 50 mL of acetonitrile, added with 10 mL of triethylamine, 271 mg
of palladium acetate (II), 450 mg of
2-(di-tert-butylphosphino)biphenyl and 726 .mu.l of 3-bromo
pyridine, and refluxed overnight. The solution was cooled to room
temperature, added with 10 g of silica gel, the solvent was
evaporated, followed by purification by silica gel column
chromatography, to afford 2.00 g of the title compound as yellow
crystals.
[0610] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.09 (6H, d,
J=6.4 Hz), 7.27-7.33 (9H, m), 7.40 (1H, dd, J=4.8, 8.0 Hz), 7.52
(1H, d, J=16.8 Hz), 7.56 (1H, dd, J=1.2, 13.2 Hz), 7.62 (1H, d,
J=16.8 Hz), 8.17 (1H, m), 8.48 (1H, dd, J=1.6, 4.8 Hz), 8.84 (1H,
d, J=1.2 Hz), 8.87 (1H, d, J=1.6 Hz).
Production Example 125
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid
[0611] 3.60 g of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitri-
le was dissolved in 500 mL of ethanol, added with 154 g of
potassium hydroxide, and stirred at 80.degree. C. overnight. After
cooling to room temperature, the solution was adjusted to pH 3 by
5N hydrochloric acid, and extracted with ethyl acetate. The organic
layer was washed with water and saturated brine, dried over
magnesium sulfate, and the solvent was evaporated. The obtained
crude product was purified by silica gel column chromatography, and
the resultant dark brown solid was washed with 10 mL of diethyl
ether, to afford 3.58 g of the title compound as dark brown
crystals.
[0612] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.11 (6H, d,
J=7.2 Hz), 7.26-7.35 (9H, m), 7.40 (1H, d, J=16.8 Hz), 7.42 (1H,
dd, J=1.2, 12.4 Hz), 7.63 (1H, m), 7.85 (1H, d, J=16.8 Hz), 8.47
(1H, m), 8.59 (1H, d, J=5.2 Hz), 8.68 (1H, d, J=1.2 Hz), 9.00 (1H,
bs).
Example 126
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid
[0613] By treating 1.00 g of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid in the manner similar to that described in Example 16, 741 mg
of the title compound was obtained as yellow crystals.
[0614] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.56 (1H, m),
7.60 (1H, d, J=16.8 Hz), 7.67 (1H, d, J=12.4 Hz), 7.91 (1H, d,
J=16.4 Hz), 8.39 (1H, m), 8.55 (1H, d, J=4.8 Hz), 8.66 (1H, s),
8.99 (1H, s).
Example 127
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0615] 376 mg of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid was dissolved in 10 mL of N,N-dimethylformamide, and added
with 903 .mu.l of N,N-diisopropylethylamine, 244 mg of
1-hydroxybenzotriazole monohydrate and 147 .mu.l of furfurylamine,
and stirred at room temperature for 10 minutes. The solution was
cooled to 0.degree. C., added with 509 mg of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and
stirred at room temperature overnight. After diluting with water
and ethyl acetate, the organic phase was washed with water and
saturated brine, and dried over magnesium sulfate. The solvent was
evaporated, and the resultant crude product was purified by silica
gel column chromatography, to afford 159 mg of the title compound
as yellow crystals.
[0616] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.53 (2H, d,
J=6.0 Hz), 6.32 (1H, d, J=2.8 Hz), 6.41 (1H, dd, J=2.0, 3.2 Hz),
7.43 (1H, dd, J=4.8, 7.2 Hz), 7.58 (1H, d, J=16.8 Hz), 7.59 (1H,
s), 7.71 (1H, d, J=12.0), 7.72 (1H, d, J=16.8 Hz), 8.18 (1H, d,
J=8.0 Hz), 8.49 (1H, d, J=4.8 Hz), 8.56 (1H, s), 8.88 (1H, d, J=2.4
Hz), 9.07 (1H, bs).
Example 128
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0617] By treating 200 mg of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Example 126 and 94.5 .mu.l L-valinol in accordance
with Example 127, 102 mg of the title compound was obtained as
white crystals.
[0618] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.94 (6H, t,
J=6.4 Hz), 1.96 (1H, m), 3.56 (2H, t, J=5.6 Hz), 4.10 (1H, t, J=4.8
Hz), 4.63 (1H, m), 7.43 (1H, dd, J=4.8, 7.2 Hz), 7.51-7.68 (2H, m),
7.74 (1H, d, J=16.8 Hz), 8.05 (1H, m), 8.16 (1H, m), 8.46 (1H, s),
8.48 (1H, s), 8.86 (1H, s).
[0619] MS (ESI) m/z 369 MH.sup.+
Example 129
7-Fluoro-3-[(EZ)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0620] By treating 200 mg of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Example 126 and 106 mg of
(2S)-2-amino-propioneamide hydrochloride in accordance with Example
127, 132 mg of the title compound was obtained as a mixture of
E/Z=3/1.
[0621] (E) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
1.38 (3H, d, J=7.2 Hz), 4.46 (1H, m), 7.44 (1H, dd, J=4.8, 8.0 Hz),
7.58 (1H, d, J=16.8 Hz), 7.70 (1H, d, J=12.4 Hz), 7.74 (1H, d,
J=16.4 Hz), 8.18 (1H, d, J=7.6 Hz), 8.48 (1H, dd, J=1.6, 4.4 Hz),
8.51 (1H, s), 8.87 (1H, s).
[0622] (Z) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
1.30 (3H, d, J=7.2 Hz), 4.26 (1H, m), 6.84 (1H, m), 7.06 (1H, d,
J=12.8 Hz), 7.32 (1H, dd, J=5.2, 8.0 Hz), 7.92 (1H, d, J=8.4 Hz),
8.06 (1H, s), 8.08 (1H, s), 8.34 (1H, dd, J=1.9, 5.1 Hz), 8.77 (1H,
s).
[0623] MS (ESI) m/z 354 MH.sup.+
Example 130
[0624] From
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Example 126 and various kinds of amine, compounds
of Examples 131-132 were obtained in accordance with the method of
Example 102.
Example 131
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0625] MS (ESI) m/z 403 MH.sup.+
Example 132
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0626] MS (ESI) m/z 323 MH.sup.+
Production Example 133
{7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-carbami-
c acid tert-butyl ester
[0627] Under nitrogen atmosphere, 200 mg of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid obtained by Production example 125 was dissolved in toluene,
added with 79.6 .mu.l of triethylamine and 81.8 .mu.l of
diphenylphosphoryl azide, and stirred at room temperature for 30
minutes. Then after adding 1 mL of tert-butanol, the reaction
solution was heated to 120.degree. C. and stirred for 95 minutes.
After cooling to room temperature, 1 g silica gel was added, the
solvent was evaporated, and purified by silica gel column
chromatography, to afford 121 mg of the title compound as a yellow
solid solution.
[0628] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.47 (9H, s),
7.10 (6H, d, J=6.8 Hz), 7.23 (1H, d, J=8.0 Hz), 7.25-7.33 (10H, m),
7.39 (1H, dd, J=5.2, 8.0 Hz), 7.51 (1H, d, J=16.8 Hz), 8.03 (1H,
s), 8.13 (1H, m), 8.46 (1H, dd, J=1.6, 4.4 Hz), 8.75 (1H, d,
J=2.0), 9.44 (1H, bs).
Example 134
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-ylamine
[0629] By treating 655 mg of
{7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-carbam-
ic acid tert-butyl ester by the method in accordance with Example
16, 153 mg of the title compound was obtained as a dark brown solid
solution.
[0630] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.11 (2H, bs),
6.65 (1H, d, J=13.6 Hz), 6.98 (1H, s), 7.29 (1H, d, J=17.6 Hz),
7.40 (1H, dd, J=5.2, 8.0 Hz), 7.56 (1H, d, J=16.8 Hz), 8.10 (1H,
m), 8.44 (1H, dd, J=1.6, 4.8 Hz), 8.79 (1H, s), 13.3 (1H, bs).
Production Example 135
Furan-2-carboxylic acid
{7-fluoro-1-(furan-2-carbonyl)-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-
-5-yl}-amide
[0631] Following amidation using 217 mg of
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-ylamine and
286 mg of 2-furancarboxylic acid in accordance with the method of
Example 127, purification by LC-MS was carried out, to afford 143
mg of the title compound as yellow crystals.
[0632] MS (ESI) m/z 443 MH.sup.+
Example 136
Furan-2-carboxylic acid
[7-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indazol-5-yl]-amide
[0633] 208 mg of furan-2-carboxylic acid
{7-fluoro-1-(furan-2-carbonyl)-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol--
5-yl}-amide was suspended in 20 mL ethanol, added with 5 mL of
concentrated aqueous ammonia and stirred at room temperature
overnight. The reaction solution was added with saturated brine,
extracted with ethyl acetate, and the organic phase was washed with
saturated brine, and dried over magnesium sulfate. The solvent was
evaporated, purified by LC-MS and the obtained crystals were
suspended in ethyl acetate, neutralized with saturated aqueous
sodium hydrogen carbonate, and the organic phase was washed with
water and saturated brine, and dried over magnesium sulfate. The
solvent was evaporated, to afford 96.2 mg of the title compound as
yellow crystals.
[0634] MS (ESI) m/z 349 MH.sup.+
Production Example 137
2-[(E)-2-(3-Fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
[0635] To a solution of 11 mg of
chloro(1,5-cyclooctadiene)-rhodium(I) dimer and 0.61 mL of
4,4,5,5-tetramethyl-[1,3,2]dioxaborolane in 15 mL toluene was added
dropwise 1.0 mL of 3-fluorostyrene, and stirred at room temperature
for 4 hours. The reaction solution was added with water, and dried
over anhydrous magnesium sulfate. The solvent was evaporated, and
the resultant crude product was purified and separated by silica
gel column chromatography (diethyl ether:n-hexane=1:19) to afford
311 mg of the title compound as a pale yellow oil.
[0636] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.25 (12H, s),
6.22 (1H, d, J=18.8 Hz), 7.16 (1H, dt, J=2.4, 8.8 Hz), 7.30 (1H, d,
J=18.8 Hz), 7.37-7.52 (3H, m).
Production Example 138
{4-[(E)-2-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolane-2-yl)-vinyl]-phenyl}--
carbamic acid tert-butyl ester
[0637] From 0.921 g of (4-vinylphenyl)-carbamic acid tert-butyl
ester, 0.41 g of the title compound was obtained as white crude
crystals in accordance with the method of Production example
137.
[0638] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.30 (12H, s),
1.51 (9H, s), 6.04 (1H, d, J=17.6 Hz), 6.52 (1H, bs), 7.32 (2H, d,
J=8.8 Hz), 7.33 (1H, d, J=17.6 Hz), 7.41 (2H, d, J=8.8 Hz).
Production Example 139
2-[(E)-2-(2-Fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
[0639] From 5 g of 1-fluoro-2-vinylbenzene, 4.22 g of the title
compound was obtained as a yellow oil in accordance with the method
of Production example 137.
[0640] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.31 (12H, s),
6.23 (1H, d, J=18.0 Hz), 6.97-7.07 (1H, m), 7.07-7.14 (1H, m),
7.18-7.29 (1H, m), 7.55 (1H, dt, J=2.0, 8.0 Hz), 7.57 (1H, d,
J=18.0 Hz).
Production Example 140
6-Fluoro-1H-indazole-5-carboxylic acid methyl ester
[0641] From 1.22 g of 6-fluoro-1H-indazole-5-carbonitrile obtained
by Production example 82, 1.11 g of the title compound was obtained
as ocher crystal in accordance with the method of Production
Example 86.
[0642] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.86 (3H, s),
7.43 (1H, d, J=11.6 Hz), 8.26 (1H, s), 8.44 (1H, d, J=7.2 Hz),
13.43 (1H, s).
Production Example 141
3-Bromo-6-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl
ester
[0643] From 1.11 g of 6-fluoro-1H-indazole-5-carboxylic acid methyl
ester, 1.38 g of the title compound was obtained as pale red
crystal in accordance with Production example 87 and Production
example 88.
[0644] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.84 (3H, s),
6.04 (1H, d, J=12.0 Hz), 7.12-7.23 (6H, m), 7.30-7.44 (9H, m), 8.12
(1H, d, J=6.8 Hz).
Example 142
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester
[0645] In accordance with the method of Example 100, from 800 mg of
3-bromo-6-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl
ester and 350 mg of 2-vinylthiophene, were obtained 211 mg of the
title (E)-compound as bright yellow crystals and 85 mg of
(Z)-compound of Example 143 as bright yellow crystals.
[0646] (E) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
3.85 (3H, s), 7.11 (1H, dd, J=3.6, 5.2 Hz), 7.32 (1H, d, J=16.4
Hz), 7.41 (1H, d, J=3.6 Hz), 7.44 (1H, d, J=11.2 Hz), 7.54 (1H, d,
J=5.2 Hz), 7.71 (1H, d, J=16.4 Hz), 8.70 (1H, d, J=6.8 Hz), 13.51
(1H, s).
Example 143
6-Fluoro-3-[(Z)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester
[0647] (Z) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
3.85 (3H, s), 6.82 (1H, d, J=12.0 Hz), 7.03 (1H, d, J=12.0 Hz),
7.06 (1H, dd, J=3.6, 5.2 Hz), 7.44 (1H, d, J=11.6 Hz), 7.50 (1H, d,
J=5.2 Hz), 7.63 (1H, d, J=3.6 Hz), 8.34 (1H, d, J=6.8 Hz), 13.63
(1H, s).
Example 144
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0648] To a mixed solution of 60 mg of
6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester obtained by Example 142 in a mixture of 2 mL
tetrahydrofuran/0.5 mL methanol was added 0.5 mL of 5N sodium
hydroxide aqueous solution, and stirred at 50.degree. C.-55.degree.
C. for 6 hours. The reaction solution was made acidic with 1N
hydrochloric acid, and extracted with 15 mL of ethyl acetate. The
organic layer was washed successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to afford 53 mg of the title compound as bright yellow
crystals.
[0649] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.11 (1H, dd,
J=3.2, 5.2 Hz), 7.31 (1H, d, J=16.0 Hz), 7.39 (1H, d, J=11.2 Hz),
7.41 (1H, d/J=3.2 Hz), 7.54 (1H, d, J=5.2 Hz), 7.69 (1H, d, J=16.0
Hz), 8.67 (1H, d, J=7.2 Hz), 13.07 (1H, bs), 13.46 (1H, s).
Example 145
[0650] In accordance with the method of Example 102, from
6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 146-151 were
obtained.
Example 146
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0651] MS (ESI) m/z 328 MH.sup.+
Example 147
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0652] MS (ESI) m/z 368 MH.sup.+
Example 148
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[0653] MS (ESI) m/z 408 MH.sup.+
Example 149
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(1-hydroxymethyl-2-methyl-propyl)]-amide
[0654] MS (ESI) m/z 374 MH.sup.+
Example 150
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[0655] MS (ESI) m/z 379 MH.sup.+
Example 151
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(1-carbamoyl-ethyl)]-amide
[0656] MS (ESI) m/z 359 MH.sup.+
Production Example 152
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid
[0657] 151 mg of
6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester obtained by Example 142 was tritylated in the
same manner as described in Production example 22, followed by
hydrolysis in the same manner as described in Example 144, to
afford 320 mg of the title compound as bright yellow crystals.
[0658] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.99 (1H, d,
J=12.0 Hz), 7.11 (1H, dd, J=3.2, 5.2 Hz), 7.14-7.48 (17H, m), 7.54
(1H, d, J=5.2 Hz), 7.59 (1H, d, J=16.4 Hz), 8.66 (1H, d, J=6.8 Hz),
13.18 (1H, bs).
Production Example 153
{6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-carbam-
ic acid tert-butyl ester
[0659] From 320 mg of
6-fluoro-3-[(E)-2-thiophen-2-yl-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid, 66 mg of the title compound was obtained as orange crystals
in the similar method as described in Production example 109.
[0660] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.44 (9H, s),
6.00 (1H, d, J=11.6 Hz), 7.09 (1H, dd, J=2.8, 5.6 Hz), 7.14-7.55
(19H, m), 8.15 (1H, d, J=7.6 Hz), 8.85 (1H, s).
Example 154
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-ylamine
[0661] From 90 mg of
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-carba-
mic acid tert-butyl ester, 22 mg of the title compound was obtained
as a dark brown powder in the similar method as described in
Example 110.
[0662] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.94 (2H, s),
7.09 (1H, dd, J=3.6, 5.2 Hz), 7.12 (1H, d, J=16.4 Hz), 7.22 (2H, d,
J=10.8 Hz), 7.25 (1H, d, J=3.6 Hz), 7.33 (1H, d, J=8.4 Hz), 7.44
(1H, d, J=16.4 Hz), 7.47 (1H, d, J=5.2 Hz), 12.83 (1H, s).
Example 155
[0663] From
6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-ylamine and
various kinds of carboxylic acid, compounds of Examples 156-159
were obtained in accordance with the method of Example 111.
Example 156
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[0664] MS (ESI) m/z 328 MH.sup.+
Example 157
(2S)-5-Oxo-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[0665] MS (ESI) m/z 371 MH.sup.+
Example 158
N-{6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-2-(thiophen-2-
-yl)-acetamide
[0666] MS (ESI) m/z 384 MH.sup.+
Example 159
Furan-2-carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[0667] MS (ESI) m/z 354 MH.sup.+
Example 160
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
[0668] From 1.0 g of
3-bromo-6-fluoro-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 83 and 674 mg of 2-vinylnaphthalene, 590 mg of
the title compound was obtained as ocher crystals in accordance
with the method of Example 100.
[0669] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.47-7.58 (2H,
m), 7.67 (1H, d, J=10.0 Hz), 7.72 (1H, d, J=16.8 Hz), 7.83 (1H, d,
J=16.4 Hz), 7.93 (2H, d, J=9.2 Hz), 7.96 (1H, d, J=8.8 Hz), 8.01
(1H, d, J=8.4 Hz), 8.20 (1H, s), 9.06 (1H, d, J=6.4 Hz), 13.76 (1H,
s).
Example 161
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0670] To a suspension of 588 mg of
6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
in 3 mL of acetic acid and 1 mL of water was added 3 mL of
concentrated sulfuric acid, and stirred at 110.degree. C. for 1
hours. After allowing to cool, the reaction solution was added with
ice, and extracted with a mixed solvent of 30 mL ethyl acetate/15
mL tetrahydrofuran. The organic layer was washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the resultant crude product was dissolved in 6 mL
of 1,4-dioxane, added with 6 mL of 4N lithium hydroxide, and
stirred at 120.degree. C. for 15 hours. The reaction solution was
made acidic with 5N hydrochloric acid, and then extracted with a
mixed solvent of 30 mL ethyl acetate/20 mL tetrahydrofuran. The
organic layer was washed successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to afford 477 mg of the title compound as ocher
crystals.
[0671] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.41 (1H, d,
J=11.6 Hz), 7.48-7.57 (2H, in), 7.70 (1H, d, J=16.4 Hz), 7.82 (1H,
d, J=16.4 Hz), 7.92 (1H, d, J=8.8 Hz), 7.94 (2H, d, J=8.8 Hz), 8.05
(1H, d, J=8.4 Hz), 8.17 (1H, s), 8.79 (1H, d, J=7.2 Hz), 13.08 (1H,
bs), 13.49 (1H, s).
Example 162
[0672] From
6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 163-166 were
obtained in accordance with the method of Example 102.
Example 163
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0673] MS (ESI) m/z 372 MH.sup.+
Example 164
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0674] MS (ESI) m/z 412 MH.sup.+
Example 165
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[0675] MS (ESI) m/z 423 MH.sup.+
Example 166
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(1-carbamoyl-ethyl)]-amide
[0676] MS (ESI) m/z 403 MH.sup.+
Production Example 167
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1-trityl-1H-indazole-5-carboxyl-
ic acid
[0677] From 350 mg of
6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Example 161, 188 mg of the title compound was
obtained as bright yellow non-crystalline powder in accordance with
Production example 108.
[0678] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.00 (1H, d,
J=12.4 Hz), 7.10-7.44 (15H, m), 7.48-7.56 (2H, m), 7.58 (1H, d,
J=16.4 Hz), 7.75 (1H, d, J=16.4 Hz), 7.88-7.98 (3H, m), 8.04 (1H,
d, J=8.8 Hz), 8.13 (1H, s), 8.79 (1H, d, J=7.2 Hz), 13.19 (1H,
bs).
Production Example 168
{6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-carb-
amic acid tert-butyl ester
[0679] From 182 mg of
6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1-trityl-1H-indazole-5-carboxy-
lic acid, 42 mg of the title compound was obtained as a yellow
viscous oil in the similar method as described in Production
example 109.
[0680] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.46 (9H, s),
6.02 (1H, d, J=11.2 Hz), 7.10-7.58 (18H, m), 7.62 (1H, d, J=16.4
Hz), 7.85-7.95 (3H, m), 7.99 (1H, d, J=8.4 Hz), 8.13 (1H, s), 8.26
(1H, d, J=7.2 Hz), 8.88 (1H, s).
Example 169
6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazole-5-ylamine
[0681] From 42 mg of
{6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1-trityl-1H-indazol-5-yl}-car-
bamic acid tert-butyl ester, 14 mg of the title compound was
obtained as ocher crystals in the similar method as described in
Example 110.
[0682] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.96 (2H, s),
4.23 (1H, d, J=10.0 Hz), 7.40-7.56 (4H, m), 7.57 (1H, d, J=16.8
Hz), 7.85-7.97 (4H, m), 8.04 (1H, s), 12.86 (1H, s).
Example 170
[0683] From
6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazol-5-ylamine and
various kinds of carboxylic acid, compounds of Examples 171-173
were obtained in accordance with the method of Example 111.
Example 171
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[0684] MS (ESI) m/z 372 MH.sup.+
Example 172
(2S)-5-Oxo-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[0685] MS (ESI) m/z 415 MH.sup.+
Example 173
N-{6-Fluoro-3-[(E)-2-(naphthalen-2-yl)-vinyl]-1H-indazol-5-yl}-2-(thiophen-
-2-yl)-acetamide
[0686] MS (ESI) m/z 428 MH.sup.+
Production Example 174
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[0687] To a solution of 2.95 g of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazole-5-carboxyl-
ic acid obtained by Production example 108 in 55 mL of
N,N-dimethylformamide, 1.58 g of potassium carbonate and 1.50 g of
diphenyl phosphoryl azide were added and stirred at room
temperature for 30 minutes followed by stirring at 40-50.degree. C.
for 2.5 hours. After adding water, the reaction solution was
allowed to cool to room temperature, and extracted with 200 mL of
ethyl acetate. The organic layer was washed successively with water
and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated, and the resulting crude product was
purified and separated by silica gel column chromatography
(n-hexane:toluene=1:1-1:2), to afford 1.57 g of the title compound
as yellow crystals.
[0688] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.00 (2H, s),
5.91 (1H, d, J=12.4 Hz), 7.09 (1H, t, J=8.0 Hz), 7.14-7.48 (19H,
m), 7.54 (1H, d, J=10.4 Hz).
Example 175
N-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-acetamide
[0689] 525 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
and 80 .mu.l of glacial acetic acid were dehydraing-condensed in
accordance with Example 127, followed by deprotection in the
similar method as described in Example 16, to afford 150 mg of the
title compound as bright yellow crystals.
[0690] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.11 (3H, s),
7.15 (1H, dt, J=2.4, 8.0 Hz), 7.38-7.48 (3H, m), 7.52 (1H, d, J=8.0
Hz), 7.58-7.66 (2H, m), 8.40 (1H, d, J=7.6 Hz), 9.72 (1H, s), 13.26
(1H, s).
Production Example 176
N-(5-Fluoro-2-methyl-phenyl)-acetamide
[0691] To a solution of 5 g of 5-fluoro-2-methylaniline in 30 mL of
pyridine was added 4.6 mL of acetic anhydride, and stirred at room
temperature for 4 hours. After distilling off the pyridine under
reduced pressure, the residue was dissolved in 250 mL of ethyl
acetate, and washed successively with water, 1N hydrochloric acid,
water, saturated aqueous sodium hydrogen carbonate and saturated
brine. The solution was dried over anhydrous magnesium sulfate,
allowed to pass though a silica gel pad, and then the solvent was
evaporated. The residue was recrystallized from
ethylacetate-diethyl ether, to afford 5.34 g of the title compound
as white needle crystals. The mother liquor was further
concentrated, and triturated with diethyl ether, to afford 907 mg
of the title compound as purple needle crystals.
[0692] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.22 (3H, s), 6.76
(1H, ddd, J=2.0, 7.2, 8.0 Hz), 7.00 (1H, bs), 7.11 (1H, t, J=7.2
Hz), 7.77 (1H, dd, J=2.0, 6.8 Hz).
Production Example 177
N-(5-Fluoro-2-methyl-4-nitrophenyl)-acetamide
[0693] To a solution of 5.01 g of
N-(5-fluoro-2-methyl-phenyl)-acetamide in 30 mL of concentrated
sulfuric acid was added dropwise 2.74 g of 70% nitric acid (d=1.42)
while keeping the inner temperature at 3.degree. C. After stirring
for 40 minutes at this temperature, the reaction solution was
poured dropwise into ice water under stirring. After collecting the
precipitated powder by filtration, the powder was dissolved in 100
mL of ethyl acetate, washed successively with saturated aqueous
sodium hydrogen carbonate(twice) and saturated brine. After drying
over anhydrous magnesium sulfate, the solvent was evaporated. The
residue was crystallized from ethanol, to afford 3.68 g of the
title compound as yellow needle crystals.
[0694] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.29 (3H, s), 2.32
(3H, s), 7.17 (1H, bs), 7.94 (1H, d, J=8.0 Hz), 8.34 (1H, d, J=13.6
Hz).
Production Example 178
5-Fluoro-2-methyl-4-nitro-phenylamine
[0695] A suspension of 3.5 g of
N-(5-fluoro-2-methyl-4-nitrophenyl)-acetamide in 5N hydrochloric
acid was heated under reflux for 1 hour. After allowing to cool,
the solution was neutralized with potassium carbonate, and
extracted with 80 mL of ethyl acetate. The organic layer was dried
over anhydrous magnesium sulfate, allowed to pass through a silica
gel pad, and then the solvent was distilled off under reduced
pressure, to afford 2.69 g of the title compound as ocher
crystals.
[0696] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.16 (3H, s), 4.39
(2H, bs), 6.39 (1H, d, J=12.8 Hz), 7.88 (1H, d, J=8.4 Hz).
Production Example 179
6-Fluoro-5-nitro-1H-indazole
[0697] To a suspension of 2 g of
5-fluoro-2-methyl-4-nitro-phenylamine in 50 mL of glacial acetic
acid, an aqueous solution of 812 mg of sodium sulfite was added,
and stirred at room temperature overnight. The reaction solution
was added with 100 mL of water, the precipitated powder filtered
out, and the filtrate was concentrated to 50 mL. After extracting
with 100 mL of ethyl acetate, the organic layer was washed
successively with aqueous sodium hydrogen carbonate, 10% sodium
thiosulfate aqueous solution, water and saturated brine, dried over
anhydrous magnesium sulfate, and then the solvent was evaporated.
The obtained crude crystals were triturated with toluene, to afford
589 mg of the title compound as bright yellow crystals.
[0698] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.69 (1H, d,
J=11.6 Hz), 8.39 (1H, s), 8.79 (1H, d, J=7.2 Hz), 13.76 (1H,
s).
Production Example 180
3-Bromo-6-fluoro-5-nitro-1-trityl-1H-indazole
[0699] In accordance with Production example 87 and Production
example 88, from 500 mg of 6-fluoro-5-nitro-1H-indazole, 651 mg of
the title compound was obtained as pale brown crystals.
[0700] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.20 (1H, d,
J=12.4 Hz), 7.15-7.23 (6H, m), 7.33-7.43 (9H, m), 8.47 (1H, d,
J=7.2 Hz).
Production Example 181
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
[0701] To a solution of 600 mg of
3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole in 6 mL of
N,N-dimethylformamide were successively added 292 mg of
4-fluorostyrene, 71 mg of 2-(di-tert-butylphosphino)biphenyl, 27 mg
of palladium acetate (II) and 0.85 mL of triethylamine, and stirred
at 80.degree. C. for 6.5 hours. The solvent was evaporated, and the
resulting residue was dissolved in 25 mL of ethyl acetate. The
organic layer was successively washed with water (twice) and
saturated brine, dried over anhydrous magnesium sulfate, and then
the solvent was evaporated. The obtained crude crystal was
recrystallized from ethyl acetate-diisopropylether, to afford 304
mg of the title compound as bright yellow crystals.
[0702] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.12 (1H, d,
J=12.8 Hz), 7.15-7.30 (8H, m), 7.32-7.46 (9H, m), 7.47 (1H, d,
J=16.4 Hz), 7.63 (1H, d, J=16.4 Hz), 7.81 (1H, dd, J=5.6, 8.4 Hz),
9.16 (1H, d, J=6.8 Hz).
Production Example 182
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[0703] To a solution of 290 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
in a mixture of 5 mL N,N-dimethylformamide/9 mL methanol/1 mL water
were added 30 mg of ammonium chloride and 150 mg of iron powder,
and stirred at 80.degree. C. for 8 hours. After filtering off the
insoluble substances through Celite, the solvent was evaporated,
and the resultant residue was dissolved in 15 mL of ethyl acetate.
The organic layer was washed successively with water, saturated
aqueous sodium hydrogen carbonate and saturated brine. After drying
over anhydrous magnesium sulfate, the solvent was evaporated, to
afford 252 mg of the title compound as pale brown non-crystalline
powder.
[0704] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.98 (2H, s),
5.91 (1H, d, J=12.0 Hz), 7.14-7.24 (8H, m), 7.25-7.37 (11H, m),
7.40 (1H, d, J=8.8 Hz), 7.69 (1H, dd, J=5.6, 8.8 Hz).
Example 183
[0705]
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yla-
mine synthesized in Production example 182 was dissolved in
N,N-dimethylformamide, and dispensed into test tubes. Each test
tube was added successively with preliminarily prepared 1.5
equivalents of different kind of carboxylic acid in 1M
dimethylformamide solution, 1.5 equivalents of
1-hydroxybenztriazole monohydrate in 1 M dimethylformamide
solution, and 1.5 equivalents of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(.dbd.WSC.HCl), and stirred at room temperature for 6 days. After
adding semi-saturated sodium hydrogen carbonate to each test tube,
the solution was extracted with ethyl acetate. After distilling off
the solvent, the residue was dissolved in 10% trifluoroacetic
acid/2% tripropylsilane/dichloromethane and stirred for 6.5 hours.
After adding 5% water/methanol to each test tube, the solvent was
distilled off. The residue was dissolved in N,N-dimethylformamide,
and purified and separated by LC-MS [developing solvent: 0.1%
trifluoroacetic acid-containing acetonitrile solution:0.1%
trifluoroacetic acid-containing aqueous solution=20:80-80:20, 10
min. cycle, flow rate: 30 mL/min., column: Wako Wakopak Combi ODS,
20 mm .PHI..times.50 mm(Long)], to afford the compounds of Examples
184-188.
Example 184
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[0706] MS (ESI) m/z 340 MH.sup.+
Example 185
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(thiophen--
2-yl)-acetamide
[0707] MS (ESI) m/z 396 MH.sup.+
Example 186
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-acetamide
[0708] MS (ESI) m/z 314 MH.sup.+
Example 187
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-2,-
2-dimethyl-propanamide
[0709] MS (ESI) m/z 372 MH.sup.+
Example 188
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-2--
phenyl-propanamide
[0710] MS (ESI) m/z 420 MH.sup.+
Example 189
C-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-methylamine
[0711] To a suspension of 5 mg of lithium aluminum hydride in 1 mL
of tetrahydrofuran was added 13 mg of aluminum chloride (III),
followed by 9 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitril-
e obtained by Example 100, and stirred at room temperature
overnight. After adding saturated aqueous ammonium chloride, the
reaction solution was added with 15 mL of ethyl acetate. The
organic layer was washed successively with saturated aqueous sodium
hydrogen carbonate(twice) and saturated brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
crude product was purified and separated by silica gel column
chromatography (methanol:chloroform=1:9), to afford 3 mg of the
title compound as a yellow oil.
[0712] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.3.86 (2H, s),
7.12 (1H, t, J=8.4 Hz), 7.29 (1H, d, J=10.0 Hz), 7.44 (1H, dt,
J=6.0, 8.0 Hz), 7.52 (1H, d, J=16.8 Hz), 7.54 (1H, d, J=8.8 Hz),
7.59 (1H, d, J=16.8 Hz), 7.61 (1H, d, J=10.8 Hz), 8.22 (1H, d,
J=7.2 Hz), 13.19 (1H, s).
Example 190
N-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-ylmethyl}-2-meth-
oxy-benzamide
[0713] From 2.9 mg of
C-{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-methylamine-
, 1.42 mg of the title compound was obtained in accordance with the
method of Example 111.
[0714] MS (ESI) m/z 420 MH.sup.+
Production Example 191
6-Fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid methyl
ester
[0715] 0.77 g of 3-bromo-6-fluoro-1-trityl-1H-indazole-5-carboxylic
acid methyl ester obtained by Production example 141 was treated in
the method of Production example 123, to obtain 600 mg of the title
compound as colorless needle crystals.
[0716] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.90 (3H, s), 5.52
(1H, d, J=11.5 Hz), 6.05 (1H, d, J=12.4 Hz), 6.08 (1H, d, J=18.2
Hz), 6.94 (1H, dd, J=12.4, 18.2 Hz), 7.14-7.22 (6H, m), 7.24-7.32
(9H, m), 8.51 (1H, d, J=6.9 Hz).
Production Example 192
6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid methyl ester
[0717] 600 mg of 6-fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic
acid methyl ester and 190 .mu.l of 3-bromopyridine were treated in
the same manner as described in Example 124, to afford 75 mg of the
title compound as a colorless powder.
[0718] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.93 (3H, s), 6.11
(1H, d, J=11.9 Hz), 7.15-7.25 (6H, m), 7.25-7.42 (12H, m), 7.89
(1H, dt, J=1.8, 8.3 Hz), 8.51 (1H, dd, J=1.8, 4.7 Hz), 8.59 (1H, d,
J=6.8 Hz), 8.76 (1H, d, J=1.8 Hz).
Example 193
N-[6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl]-2-(thiophen-2--
yl)-acetamide
[0719] 75 mg of
6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid methyl ester was alkaline hydrolyzed in the same manner as
described in Example 144, to give 70 mg of
6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid as a colorless powder. Then in the same manner as described in
Example 174, 30 mg of
6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazol-5-ylamine
was obtained. Further, in the same manner as described in Example
175, this compound was subjected to dehydration condensation with
10 mg of 2-thiophene acetic acid, followed by deprotection, to
obtain 8 mg of the title compound as a colorless powder.
[0720] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.02 (2H, s), 7.00
(1H, dd, J=3.5, 4.7 Hz), 7.06 (1H, dd, J=1.0, 3.5 Hz), 7.32 (1H,
dd, J=1.0, 4.7 Hz), 7.34 (1H, d, J=11.5 Hz), 7.45 (1H, dd, J=4.7,
8.0 Hz), 7.47 (1H, d, J=16.3 Hz), 7.56 (1H, d, J=16.3 Hz), 8.15
(1H, dt, J=1.8, 8.0 Hz), 8.43 (1H, dd, J=1.8, 4.7 Hz), 8.57 (1H, d,
J=6.8 Hz), 8.76 (1H, d, J=1.8 Hz).
Example 194
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester
[0721] To a solution of 150 mg of
3-bromo-4-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl
ester obtained by Production example 88 in 6 mL of
N,N-dimethylformamide were successively added 200 mg of
2-[(E)-2-(3-fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
obtained by Production example 137, 24 mg of
2-(di-tert-butylphosphino)biphenyl, 9 mg of palladium acetate (II),
117 mg of potassium fluoride and 0.6 mL of water, and stirred
80.degree. C. for 1.5 hours. The reaction solution was added with
30 mL of ethyl acetate, and the organic layer was washed
successively with water, semi-saturated brine and saturated brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to give 260 mg of a crude coupling compound. Then the
crude coupling compound was deblocked in the manner as described in
Example 6, to afford 32 mg of the title compound as bright yellow
crystals.
[0722] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.3.89 (3H, s),
7.15 (1H, dt, J=2.4, 8.4 Hz), 7.42-7.62 (6H, m), 7.84 (1H, dd,
J=6.4, 8.8 Hz), 13.81 (1H, s).
Example 195
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid
[0723] From 35 mg of
4-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester, 31 mg of the title compound was obtained as
ocher crystals in accordance with the method of Example 144.
[0724] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.15 (1H, dt,
J=2.4, 8.4 Hz), 7.38-7.60 (6H, m), 7.83 (1H, dd, J=6.4, 8.8 Hz),
13.08 (1H, bs), 13.76 (1H, s).
Example 196
[0725] From
4-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 197-202 were
obtained in accordance with the method of Example 102.
Example 197
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0726] MS (ESI) m/z 340 MH.sup.+
Example 198
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0727] MS (ESI) m/z 380 MH.sup.+
Example 199
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0728] MS (ESI) m/z 396 MH.sup.+
Example 200
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0729] MS (ESI) m/z 386 MH.sup.+
Example 201
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0730] MS (ESI) m/z 763 2M+Na.sup.+
Example 202
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-(2-methoxy-ethylcarbamoyl)-ethyl]amide
[0731] MS (ESI) m/z 429 MH.sup.+
Production Example 203
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazole-5-carboxyli-
c acid
[0732] From 72 mg of
4-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester obtained by Example 194, 45 mg of the title
compound was obtained as yellow crystals in accordance with the
method of Production example 152.
[0733] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.23 (1H, d,
J=8.8 Hz), 7.10-7.60 (22H, m), 13.14 (1H, bs).
Production Example 204
4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[0734] From 45 mg of
4-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazole-5-carboxyl-
ic acid, 4 mg of the title compound was obtained as a dark brown
powder in accordance with the method of Production example 174.
[0735] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.4.90 (2H, s),
5.95 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=8.4 Hz), 7.06-7.48 (21H,
m).
Example 205
N-{4-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic
acid}-2-(thiophen-2-yl)-acetamide
[0736] From 4 mg
4-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
and 2-thiopheneacetic acid, 0.83 mg of the title compound was
obtained in accordance with the method of Example 183.
[0737] MS (ESI) m/z 396 MH.sup.+
Production Example 206
4-Fluoro-3-iodo-1H-indazole-5-carbonitrile
[0738] To a solution of 161 mg of
4-fluoro-1H-indazole-5-carbonitrile obtained by Production example
85 in 4 mL of N,N-dimethylformamide was added 285 mg of
N-iodosuccinimide was added, and stirred at 75.degree. C. for 4
hours. The reaction solution was added with 40 mL of ethyl acetate,
then washed successively with semi-saturated aqueous sodium
hydrogen carbonate, water, semi-saturated brine and saturated
brine, and dried over anhydrous magnesium sulfate. The resultant
crude product was purified and separated by silica gel column
chromatography (ethyl acetate:toluene=1:9), to afford 273 mg of the
title compound as white crystals.
[0739] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.60 (1H, d,
J=8.4 Hz), 7.16 (1H, dd, J=6.0, 8.4 Hz), 14.23 (1H, s).
Production Example 207
4-Fluoro-3-iodo-1-trityl-1H-indazole-5-carbonitrile
[0740] From 250 mg of 4-fluoro-3-iodo-1H-indazole-5-carbonitrile,
247 mg of the title compound was obtained as white crystals in
accordance with the method of Production example 88.
[0741] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.6.34 (1H, d,
J=8.8 Hz), 7.08-7.16 (6H, m), 7.30-7.39 (9H, m), 8.47 (1H, dd,
J=6.4, 8.8 Hz).
Example 208
4-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
[0742] In accordance with the method of Example 100, from 235 mg of
4-fluoro-3-iodo-1-trityl-1H-indazole-5-carbonitrile and 98 mg of
2-vinylthiophene, 11 mg of (Z)-compound described in Example 209
was obtained as bright yellow crystal and further 79 mg of the
title (E)-compound was obtained as bright yellow crystals.
[0743] (E) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6)
.delta.7.12 (1H, dd, J=3.6, 5.2 Hz), 7.14 (1H, d, J=16.4 Hz), 7.38
(1H, d, J=3.6 Hz), 7.54 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=5.2 Hz),
7.70 (1H, d, J=16.4 Hz), 7.71 1H, dd, J=6.0, 8.8 Hz), 13.99 (1H,
s).
Example 209
4-Fluoro-3-[(Z)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitri-
le
[0744] (Z) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6)
.delta.6.71 (1H, d, J=12.0 Hz), 7.07 (1H, dd, J=4.0, 5.2 Hz), 7.10
(1H, d, J=12.0 Hz), 7.51 (1H, d, J=5.2 Hz), 7.57 (1H, d, J=8.8 Hz),
7.59 (1H, d, J=4.0 Hz), 7.71 (1H, dd, J=6.0, 8.8 Hz), 14.09 (1H,
s).
Example 210
4-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0745] A suspension of 25 mg of
4-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
in 2 mL of 4N lithium hydroxide was heated under reflux for 9
hours. After allowing to cool, 2N hydrochloric acid was added to
make acidic, and extracted with 15 mL of ethyl acetate. The organic
layer was washed with water and saturated brine. After drying over
anhydrous magnesium sulfate, and passing through a silica gel pad,
the solvent was evaporated, to afford 10 mg of the title compound
as a dark brown powder.
[0746] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.11 (1H, dd,
J=3.2, 4.8 Hz), 7.20 (1H, d, J=16.4 Hz), 7.35 (1H, d, J=3.2 Hz),
7.40 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=4.8 Hz), 7.69 (1H, d, J=16.4
Hz), 7.82 (1H, dd, J=6.8, 8.8 Hz), 13.07 (1H, bs), 13.71 (1H,
s).
Example 211
[0747] From
4-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 212-213 were
obtained in accordance with the method of Example 102.
Example 212
4-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0748] MS (ESI) m/z 328 MH.sup.+
Example 213
4-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0749] MS (ESI) m/z 368 MH.sup.+
Example 214
4-Methoxy-3-(E)-styryl-1H-indazole-5-carbonitrile
[0750] 161.5 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 82.3 mg of (E)-2-phenylvinylboronic acid
were coupled in the same manner as described in Example 194,
followed by deprotection, to afford 35 mg of the title compound as
brown crystals.
[0751] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.29 (3H, s),
7.28-7.41 (3H, m), 7.31 (1H, d, J=8.8 Hz), 7.47 (1H, d, J=8.8 Hz),
7.56 (1H, d, J=16.8 Hz), 7.56-7.61 (2H, m), 7.61 (1H, d, J=16.8
Hz).
Example 215
4-Methoxy-3-(E)-styryl-1H-indazole-5-carboxylic acid amide
[0752] 35 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carbonitrile
was dissolved in a mixed solvent 2 mL concentrated sulfuric acid/1
mL water, and stirred at 110.degree. C. for 1 hour and 15 minutes.
After cooling the reaction mixture on ice, water was slowly poured
under ice cooling, and the precipitated crystals were collected by
filtration, and washed with water. After drying under reduced
pressure, 22 mg of the title compound was obtained as brown crude
crystals.
[0753] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.01 (3H, s),
7.20-7.78 (7H, m), 7.33 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=8.8
Hz).
Example 216
4-methoxy-3-(E)-styryl-1H-indazole-5-carboxylic acid
[0754] 22 mg of 4-methoxy-3-(E)-styryl-1H-indazole-5-carboxylic
acid amide was added to 3 mL of 4N lithium hydroxide aqueous
solution, and stirred at 110.degree. C. for 4 hours. After cooling
on ice, the reaction solution was neutralized with 2N hydrochloric
acid under ice cooling, and the precipitated crystals were
collected by filtration and washed with water. This was then dried
under reduced pressure, to afford 20 mg of the title compound as
brown crude crystals.
[0755] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.0 (3H, s),
7.22-7.75 (7H, m), 7.28 (1H, d, J=8.8 Hz), 7.88 (1H, d, J=8.8
Hz).
[0756] MS (ESI) m/z 293 (M-H).sup.-
Example 217
[0757] From 4-methoxy-3-(E)-styryl-1H-indazole-5-carboxylic acid
and various kinds of amine, compounds of Examples 218-222 were
obtained in accordance with the method of Example 102.
Example 218
4-Methoxy-3-styryl-1H-indazole-5-carboxylic acid
[(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0758] MS (ESI) m/z 380 MH.sup.+
Example 219
4-Methoxy-3-styryl-1H-indazole-5-carboxylic acid
cyclopropylamide
[0759] MS (ESI) m/z 334 MH.sup.+
Example 220
4-Methoxy-3-styryl-1H-indazole-5-carboxylic acid
(furan-2-ylmethyl)-amide
[0760] MS (ESI) m/z 374 MH.sup.+
Example 221
4-Methoxy-3-styryl-1H-indazole-5-carboxylic acid
[(1S)-2-hydroxy-1-phenylethyl]-amide
[0761] MS (ESI) m/z 414 MH.sup.+
Example 222
4-Methoxy-3-styryl-1H-indazole-5-carboxylic acid
[(1S)-1-carbamoylethyl]-amide
[0762] MS (ESI) m/z 365 MH.sup.+
Example 223
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile
[0763] 180.3 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 154 mg of
2-[(E)-2-(3-fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
obtained by Production example 137 were coupled in accordance with
the method of Example 194, followed by deprotection, to afford 30.8
mg of the title compound as brown crystals.
[0764] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.30 (3H, s),
6.99-7.51 (4H, m), 7.31 (1H, d, J=8.8 Hz), 7.48 (1H, d, J=8.8 Hz),
7.57 (1H, d, J=16.4 Hz), 7.61 (1H, d, J=16.4 Hz).
Example 224
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid amide
[0765] From 30.8 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile,
22 mg of the title compound was obtained as brown crude crystals in
accordance with the method of Example 215.
[0766] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.00 (3H, s),
7.00-7.05 (1H, m), 7.21-7.43 (3H, m), 7.33 (1H, d, J=8.8 Hz), 7.57
(1H, d, J=16.4 Hz), 7.64 (1H, d, J=16.4 Hz), 7.88 (1H, d, J=8.8
Hz).
Example 225
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0767] From 22 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid amide, 19 mg of the title compound was obtained as brown crude
crystal in accordance with the method of Example 216.
[0768] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.05 (3H, s),
6.99-7.04 (1H, m), 7.22-7.41 (3H, m), 7.55 (1H, d, J=16.4 Hz), 7.69
(1H, d, J=16.4 Hz), 7.77 (1H, d, J=8.6 Hz).
[0769] MS (ESI) m/z 311 (M-H).sup.-
Example 226
[0770] From
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 227-231 were
obtained in accordance with the method of Example 102.
Example 227
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0771] MS (ESI) m/z 398 MH.sup.+
Example 228
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0772] MS (ESI) m/z 352 MH.sup.+
Example 229
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0773] MS (ESI) m/z 392 MH.sup.+
Example 230
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0774] MS (ESI) m/z 432 MH.sup.+
Example 231
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0775] MS (ESI) m/z 383 MH.sup.+
Example 232
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile
[0776] From 420 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 241 mg of
(E)-2-(4-fluorophenyl)vinylboronic acid, 66.2 mg of the title
compound was obtained as pale yellow crystals in accordance with
the method of Example 214.
[0777] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.23 (3H, s),
7.24 (2H, t, J=8.8 Hz), 7.37 (1H, d, J=8.6 Hz), 7.47 (1H, d, J=16.4
Hz), 7.55 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=16.4 Hz), 7.72 (2H, dd,
J=5.8, 8.8 Hz), 13.68 (1H, s).
Example 233
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid amide
[0778] From 66.2 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile,
61.1 mg of the title compound was obtained as pale yellow crude
crystals in accordance with the method of Example 215.
[0779] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.00 (3H, s),
7.08-7.15 (2H, m), 7.32 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=16.4 Hz),
7.58 (1H, d, J=16.4 Hz), 7.58-7.68 (2H, m), 7.87 (1H, d, J=8.6
Hz).
Example 234
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0780] From 61.1 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid amide, 85.2 mg of the title compound was obtained as pale
yellow crude crystal in accordance with the method of Example
216.
[0781] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.04 (3H, s),
7.10-7.16 (2H, m), 7.24 (1H, d, J=8.6 Hz), 7.55 (1H, d, J=16.8 Hz),
7.61 (1H, d, J=16.8 Hz), 7.60-7.65 (2H, m), 7.79 (1H, d, J=8.6
Hz).
[0782] MS (ESI) m/z 311 (M-H).sup.-
Example 235
[0783] From
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 236-241 were
obtained in accordance with the method of Example 102.
Example 236
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0784] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.06 (3H, d, J=6.6
Hz), 1.08 (3H, d, J=6.6 Hz), 2.02-2.12 (1H, m), 3.73 (1H, dd,
J=4.4, 11.2 Hz), 3.78 (1H, dd, J=5.2, 11.2 Hz), 3.97-4.03 (1H, m),
4.02 (3H, s), 7.11-7.16 (2H, m), 7.34 (1H, d, J=8.8 Hz), 7.54 (1H,
d, J=16.6 Hz), 7.59 (1H, d, J=16.6 Hz), 7.63-7.66 (2H, m), 7.84
(1H, d, J=8.8 Hz).
[0785] MS (ESI) m/z 398 MH.sup.+
Example 237
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0786] MS (ESI) m/z 352 MH.sup.+
Example 238
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0787] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.89 (3H, s), 4.64
(2H, s), 6.36 (1H, dd, J=0.8, 3.2 Hz), 6.39 (1H, dd, J=1.8, 3.2
Hz), 7.09-7.16 (2H, m), 7.32 (1H, d, J=8.8 Hz), 7.47 (1H, dd,
J=0.8, 1.8 Hz), 7.53 (1H, d, J=16.4 Hz), 7.58 (1H, d, J=16.4 Hz),
7.59-7.66 (2H, m), 7.78 (1H, d, J=8.8 Hz).
[0788] MS (ESI) m/z 392 MH.sup.+
Example 239
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0789] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.88 (1H, dd,
J=6.6, 11.4 Hz), 3.94 (1H, dd, J=4.8, 11.4 Hz), 3.97 (3H, s),
5.22-5.25 (1H, m), 7.14 (2H, t, J=8.8 Hz), 7.26-7.39 (4H, m),
7.44-7.48 (2H, m), 7.55 (1H, d, J=16.4 Hz), 7.60 (1H, d, J=16.4
Hz), 7.63-7.67 (2H, m), 7.81 (1H, d, J=8.8 Hz).
[0790] MS (ESI) m/z 432 MH.sup.+
Example 240
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0791] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.52 (3H, d, J=7.0
Hz), 4.01 (3H, s), 4.69 (1H, q, J=7.0 Hz), 7.12-7.16 (2H, m), 7.35
(1H, d, J=8.6 Hz), 7.55 (1H, d, J=16.2 Hz), 7.60 (1H, d, J=16.2
Hz), 7.64-7.67 (2H, m), 7.89 (1H, d, J=8.6 Hz).
[0792] MS (ESI) m/z 383 MH.sup.+
Example 241
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (tetrahydrofuran-2-ylmethyl)-amide
[0793] MS (ESI) m/z 396 MH.sup.+
Example 242
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carbonitrile
[0794] From 160 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 89 mg of
(E)-2-(4-methylphenyl)vinylboronic acid, 46.7 mg of the title
compound was obtained as colorless crystals in accordance with the
method of Example 214.
[0795] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.23 (3H, s), 4.14
(3H, s), 6.09-7.42 (5H, m), 7.06-7.09 (2H, m), 7.15 (1H, d, J=8.4
Hz).
Example 243
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic
acid
[0796] By treating 46.7 mg of
4-methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carbonitrile in
the method according to Example 216, 30.8 mg of the title compound
was obtained as colorless crude crystals.
[0797] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.37 (3H, s), 4.04
(3H, s), 7.21 (2H, d, J=8.2 Hz), 7.26 (2H, d, J=8.8 Hz), 7.49 (2H,
d, J=8.2 Hz), 7.54 (1H, d, J=16.4 Hz), 7.61 (1H, d, J=16.4 Hz),
7.83 (1H, d, J=8.8 Hz).
[0798] MS (ESI) m/z 309 MH.sup.+
Example 244
[0799] From
4-methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
and various kinds of amine, compounds of Examples 245-249 were
obtained in accordance with the method of Example 102.
Example 245
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
[(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0800] MS (ESI) m/z 394 MH.sup.+
Example 246
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
cyclopropylamide
[0801] MS (ESI) m/z 348 MH.sup.+
Example 247
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
(furan-2-ylmethyl)-amide
[0802] MS (ESI) m/z 388 MH.sup.+
Example 248
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
[(1S)-2-hydroxy-1-phenylethyl]-amide
[0803] MS (ESI) m/z 428 MH.sup.+
Example 249
4-Methoxy-3-[(E)-2-(p-tolyl)-vinyl]-1H-indazole-5-carboxylic acid
[(1S)-1-carbamoylethyl]-amide
[0804] MS (ESI) m/z 379 MH.sup.+
Example 250
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0805] 160 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 100.3 mg of
(E)-2-(4-chlorophenyl)vinylboronic acid were allowed to react in
accordance with the method of Example 214, and then alkaline
hydrolyzed in accordance with the method of Example 216, to afford
64.8 mg of the title compound as orange crude crystals.
[0806] MS (ESI) m/z 327 (M-H).sup.-
Example 251
[0807] From
3-[(E)-2-(4-chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 252-256 were
obtained in accordance with the method of Example 102-h.
Example 252
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0808] MS (ESI) m/z 415 MH.sup.+
Example 253
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0809] MS (ESI) m/z 369 MH.sup.+
Example 254
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0810] MS (ESI) m/z 409 MH.sup.+
Example 255
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0811] MS (ESI) m/z 449 MH.sup.+
Example 256
3-[(E)-2-(4-Chlorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0812] MS (ESI) m/z 400 MH.sup.+
Example 257
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0813] 180 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 185.5 mg of
{4-[(E)-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-vinyl]-phenyl}-c-
arbamic acid tert-butyl ester obtained by Production example 138
were coupled in accordance with the method of Example 214, followed
by alkaline hydrolysis in accordance with the method of Example
216, to afford 30 mg of the title compound as brown crude
crystals.
[0814] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 4.03 (3H, s), 6.72
(2H, d, J=8.6 Hz), 7.19 (1H, d, J=8.6 Hz), 7.36 (2H, d, J=8.6 Hz),
7.41 (1H, d, J=16.6 Hz), 7.46 (1H, d, J=16.6 Hz), 7.73 (1H, d,
J=8.6 Hz).
[0815] MS (ESI) m/z 308 (M-H).sup.-
Example 258
[0816] From
3-[(E)-2-(4-aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 259-263 were
obtained in accordance with the method of Example 10.
Example 259
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0817] MS (ESI) m/z 395 MH.sup.+
Example 260
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0818] MS (ESI) m/z 349 MH.sup.+
Example 261
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0819] MS (ESI) m/z 389 MH.sup.+
Example 262
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0820] MS (ESI) m/z 429 MH.sup.+
Example 263
3-[(E)-2-(4-Aminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0821] MS (ESI) m/z 380 MH.sup.+
Example 264
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile
[0822] 208 mg of
3-bromo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 99 and 177 mg of
2-[(E)-2-(2-fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
obtained by Production example 139 were coupled in accordance with
the method of Example 214, followed by deprotection, to afford 31
mg of the title compound as colorless crystals.
[0823] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.35 (3H, s), 7.44
(1H, d, J=8.8 Hz), 7.05-7.29 (3H, m), 7.19 (1H, d, J=8.8 Hz),
7.60-7.65 (1H, m), 7.65 (1H, d, J=16.6 Hz), 7.78 (1H, d, J=16.6
Hz).
Example 265
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0824] From 31 mg of
3-[(E)-2-(2-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonitrile,
20 mg of the title compound was obtained as yellow crude crystals
in accordance with the method of Example 216.
[0825] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.03 (3H, s),
7.12-7.17 (1H, m), 7.20-7.24 (1H, m), 7.28-7.34 (1H, m), 7.29 (1H,
d, J=8.8 Hz), 7.70-7.75 (1H, m), 7.73 (1H, d, J=15.6 Hz), 7.77 (1H,
d, J=15.6 Hz), 7.88 (1H, d, J=8.8 Hz).
Example 266
[0826] From
3-[(E)-2-(2-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 267-271 were
obtained in accordance with the method of Example 102.
Example 267
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0827] MS (ESI) m/z 398 MH.sup.+
Example 268
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0828] MS (ESI) m/z 352 MH.sup.+
Example 269
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0829] MS (ESI) m/z 392 MH.sup.+
Example 270
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0830] MS (ESI) m/z 432 MH.sup.+
Example 271
3-[(E)-2-(2-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0831] MS (ESI) m/z 383 MH.sup.+
Production Example 272
4-Methoxy-1H-indazole-5-carboxylic acid amide
[0832] By treating 4.7 g of 4-methoxy-1H-indazole-5-carbonitrile
obtained by Production example 97 in the same method as described
in Example 215, 15 g of a crude product of the title compound was
obtained as brown crystals.
[0833] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.4.28 (3H, s),
7.14 (1H, d, J=8.8 Hz), 7.44 (1H, bs), 7.60 (1H, bs), 7.80 (1H, d,
J=8.8 Hz), 8.43 (1H, s).
Production Example 273
4-Methoxy-1H-indazole-5-carboxylic acid
[0834] By treating 15 g of 4-methoxy-1H-indazole-5-carboxylic acid
amide in the manner as described in Example 216, 4.5 g of the title
compound was obtained as brown crude crystals.
[0835] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.31 (3H, s), 7.18
(1H, d, J=8.8 Hz), 7.84 (1H, d, J=8.8 Hz), 8.39 (1H, s).
Production Example 274
4-Methoxy-1H-indazole-5-carboxylic acid ethyl ester
[0836] 2 g of 4-methoxy-1H-indazole-5-carboxylic acid was added to
a mixed solvent of 40 mL ethanol/2.2 mL concentrated sulfuric acid,
and stirred at 95.degree. C. for 11 hours. After cooling the
reaction solution on ice, water was slowly added under ice cooling,
and the precipitated crystals were collected by filtration and
washed with water. Thereafter, the crystals were dried under
reduced pressure, to afford 1.52 g of the title compound as pale
brown crude crystals.
[0837] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.41 (3H, t, J=7.0
Hz), 4.26 (3H, s), 4.38 (2H, q, J=7.0 Hz), 7.12 (1H, d, J=8.8 Hz),
7.86 (1H, d, J=8.8 Hz), 8.30 (1H, s).
Production Example 275
3-Iodo-4-methoxy-1H-indazole-5-carboxylic acid ethyl ester
[0838] To 15 mL of a solution of 1.33 g of
4-methoxy-1H-indazole-5-carboxylic acid ethyl ester in
N,N-dimethylformamide were added 1.95 g of iodine and 0.85 g of
potassium hydroxide, stirred at room temperature for 1 hour and 40
minutes, added with another 0.8 g of iodine, and stirred for 3
hours and 20 minutes. Thereafter, 10% sodium hydrogensulfite
aqueous solution was added, extracted twice with ethyl acetate, and
the organic layer was washed once with saturated brine, dried over
magnesium sulfate, and the solvent was evaporated. The crude
product was purified and separated by silica gel column
chromatography, to afford 1.68 g of the title compound as colorless
crystals.
[0839] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.43 (3H, t, J=7.2
Hz), 4.07 (3H, s), 4.42 (2H, q, J=7.2 Hz), 7.24 (1H, d, J=9.0 Hz),
7.92 (1H, d, J=9.0 Hz), 10.36 (1H, bs).
Production Example 276
3-Iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl
ester
[0840] From 1.68 g of 3-iodo-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester, 3.21 g of the title compound was obtained as
colorless crude crystals in accordance with the method of
Production Example 94.
[0841] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.37 (3H, t, J=7.2
Hz), 4.05 (3H, s), 4.35 (2H, q, J=7.2 Hz), 6.14 (1H, d, J=9.0 Hz),
7.14-7.17 (5H, m), 7.25-7.30 (10H, m), 7.45 (1H, d, J=9.0 Hz).
Production Example 277
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxyl-
ic acid ethyl ester
[0842] From 560 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
and 3-acetylstyrene, 150 mg of the title compound was obtained as
pale yellow needle crystals in accordance with the method of
Production example 181.
[0843] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.38 (3H, t, J=7.5
Hz), 2.63 (3H, s), 4.05 (3H, s), 4.37 (2H, q, J=7.5 Hz), 6.14 (1H,
d, J=8.8 Hz), 7.17-7.25 (6H, m), 7.25-7.32 (9H, m), 7.45 (1H, d,
J=8.8 Hz), 7.45 (1H, t, J=7.7 Hz), 7.53 (1H, d, J=16.3 Hz), 7.69
(1H, d, J=16.3 Hz), 7.74 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=7.7 Hz),
8.08 (1H, bs).
Example 278
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester
[0844] By treating 150 mg of
3-[(E)-2-(3-acetylphenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxy-
lic acid ethyl ester in the similar method as described in Example
16, 70 mg of the title compound was obtained as a colorless
powder.
[0845] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.44 (3H, t, J=7.5
Hz), 2.65 (3H, s), 4.05 (3H, s), 4.43 (2H, q, J=7.5 Hz), 7.23 (1H,
d, J=8.6 Hz), 7.49 (1H, t, J=7.7 Hz), 7.71 (1H, d, J=16.8 Hz), 7.74
(1H, d, J=16.8 Hz), 7.80 (1H, bd, J=7.7 Hz), 7.89 (1H, bd, J=7.7
Hz), 7.91 (1H, d, J=8.6 Hz), 8.16 (1H, bs).
Example 279
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0846] By treating 70 mg of
3-[(E)-2-(3-acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester in the similar method as described in Example 144,
65 mg of the title compound was obtained as a colorless powder.
[0847] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.63 (3H, s),
3.96 (3H, s), 7.30 (1H, d, J=8.6 Hz), 7.56 (1H, t, J=7.7 Hz), 7.63
(1H, d, J=16.4 Hz), 7.68 (1H, d, J=16.4 Hz), 7.73 (1H, d, J=8.6
Hz), 7.87 (1H, bd, J=7.7 Hz), 7.93 (1H, bd, J=7.7 Hz), 8.15 (1H,
bs), 12.60-12.75 (1H, bs), 13.49 (1H, bs).
Example 280
[0848] From
3-[(E)-2-(3-acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Example 281-287 were
obtained in accordance with the method of Example 102.
Example 281
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0849] MS (ESI) m/z 376 MH.sup.+
Example 282
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0850] MS (ESI) m/z 416 MH.sup.+
Example 283
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0851] MS (ESI) m/z 422 MH.sup.+
Example 284
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0852] MS (ESI) m/z 432 MH.sup.+
Example 285
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenyl-ethyl)-amide
[0853] MS (ESI) m/z 483 MH.sup.+
Example 286
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-hydroxy-ethyl)-amide
[0854] MS (ESI) m/z 423 MH.sup.+
Example 287
3-[(E)-2-(3-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0855] MS (ESI) m/z 407 MH.sup.+
Production Example 288
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxyl-
ic acid ethyl ester
[0856] By treating 560 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276 and 4-acetylstyrene in the
similar method as described in Production example 181, 100 mg of
the title compound was obtained as pale yellow needle crystals.
[0857] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.38 (3H, t, J=7.5
Hz), 2.61 (3H, s), 4.06 (3H, s), 4.38 (2H, q, J=7.5 Hz), 6.14 (1H,
d, J=9.3 Hz), 7.18-7.25 (6H, m), 7.25-7.32 (9H, m), 7.45 (1H, d,
J=9.3 Hz), 7.49 (1H, d, J=16.4 Hz), 7.60 (2H, d, J=8.3 Hz), 7.75
(1H, d, J=16.4 Hz), 7.84 (2H, d, J=8.3 Hz).
Example 289
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl
[0858] By treating 100 mg of
3-[(E)-2-(4-acetylphenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxy-
lic acid ethyl ester in the similar method as described in Example
16, 50 mg of the title compound was obtained as a colorless
powder.
[0859] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.45 (3H, t, J=7.2
Hz), 2.63 (3H, s), 4.07 (3H, s), 4.43 (2H, q, J=7.2 Hz), 7.24 (1H,
d, J=9.1 Hz), 7.67 (2H, d, J=8.5 Hz), 7.70 (1H, d, J=16.2 Hz), 7.79
(1H, d, J=16.2 Hz), 7.92 (1H, bd, J=9.1 Hz), 7.99 (2H, d, J=8.5
Hz).
Example 290
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[0860] By treating 50 mg of
3-[(E)-2-(4-acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester in the similar method as described in Example 144,
45 mg of the title compound was obtained as a colorless powder.
[0861] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.58 (3H, s),
3.96 (3H, s), 7.30 (1H, d, J=8.8 Hz), 7.62 (1H, d, J=16.4 Hz), 7.73
(1H, d, J=16.4 Hz), 7.74 (1H, d, J=8.8 Hz), 7.78 (2H, d, J=8.5 Hz),
7.97 (2H, d, J=8.5 Hz), 12.60-12.75 (1H, bs), 13.54 (1H, bs).
Example 291
[0862] From
3-[(E)-2-(4-acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 292-298 were
obtained in accordance with the method of Example 102.
Example 292
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[0863] MS (ESI) m/z 376 MH.sup.+
Example 293
3-[(E)-2-4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0864] MS (ESI) m/z 416 MH.sup.+
Example 294
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0865] MS (ESI) m/z 422 MH.sup.+
Example 295
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0866] MS (ESI) m/z 432 MH.sup.+
Example 296
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenyl-ethyl)-amide
[0867] MS (ESI) m/z 483 MH.sup.+
Example 297
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-hydroxy-ethyl)-amide
[0868] MS (ESI) m/z 423 MH.sup.+
Example 298
3-[(E)-2-(4-Acetylphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0869] MS (ESI) m/z 407 MH.sup.+
Production Example 299
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester
[0870] By treating 560 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276 and 160 .mu.l of 4-vinylpyridine
in the similar method as described in Production example 181, 300
mg of the title compound was obtained as a pale yellow oil.
[0871] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.38 (3H, t, J=7.5
Hz), 4.04 (3H, s), 4.38 (2H, q, J=7.5 Hz), 6.15 (1H, d, J=8.8 Hz),
7.17-7.23 (6H, m), 7.26-7.32 (9H, m), 7.17 (2H, d, J=6.0 Hz), 7.18
(1H, d, J=16.4 Hz), 7.46 (1H, d, J=8.8 Hz), 7.82 (1H, d, J=16.4
Hz), 8.57 (2H, d, J=6.0 Hz).
Example 300
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester
[0872] By treating 300 mg of
4-methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1-trityl-1H-indazole-5-carboxyli-
c acid ethyl ester in the similar method as described in Example
16, 150 mg of the title compound was obtained as a colorless
powder.
[0873] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 1.36 (3H, t,
J=7.5 Hz), 3.97 (3H, s), 4.33 (2H, q, J=7.5 Hz), 7.37 (1H, d, J=8.7
Hz), 7.55 (1H, d, J=16.4 Hz), 7.63 (2H, d, J=5.7 Hz), 7.74 (1H, d,
J=8.7 Hz), 7.84 (1H, d, J=16.4 Hz), 8.58 (2H, d, J=5.7 Hz).
Example 301
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0874] 150 mg of
4-methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester was dissolved in a mixed solvent of 3 mL
tetrahydrofuran/1 mL methanol, added with 0.5 mL of 5N sodium
hydroxide aqueous solution, and heated at 50.degree. C. for 4
hours. The reaction solution was neutralized with acetic acid, and
the solvent distilled off under reduced pressure, to give 500 mg of
the crudely produced title compound as a mixture with sodium
acetate.
[0875] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 4.01 (3H, s),
7.13 (1H, d, J=8.7 Hz), 7.49 (1H, d, J=16.4 Hz)/7.54 (1H, d, J=8.7
Hz), 7.58 (2H, d, J=6.3 Hz), 7.87 (1H, d, J=16.4 Hz), 8.56 (2H, d,
J=6.3 Hz).
Example 302
[0876] From
4-methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 303-309 were
obtained in accordance with the method of Example 102.
Example 303
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0877] MS (ESI) m/z 335 MH.sup.+
Example 304
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0878] MS (ESI) m/z 375 MH.sup.+
Example 305
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0879] MS (ESI) m/z 381 MH.sup.+
Example 306
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0880] MS (ESI) m/z 391 MH.sup.+
Example 307
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenyl-ethyl)-amide
[0881] MS (ESI) m/z 442 MH.sup.+
Example 308
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-hydroxy-ethyl)-amide
[0882] MS (ESI) m/z 382 MH.sup.+
Example 309
4-Methoxy-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0883] MS (ESI) m/z 366 MH.sup.+
Production Example 310
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-c-
arboxylic acid ethyl ester
[0884] By treating 560 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276 and 500 mg of crudely produced
2-methoxy-5-vinylpyridine in the similar method as described in
Production example 181, 70 mg of the title compound was obtained as
a colorless powder.
[0885] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.38 (3H, t, J=7.5
Hz), 3.96 (3H, s), 4.03 (3H, s), 4.37 (2H, q, J=7.5 Hz), 6.11 (1H,
d, J=8.5 Hz), 6.75 (1H, d, J=8.5 Hz), 7.15-7.24 (6H, m), 7.24-7.36
(10H, m), 7.44 (1H, d, J=8.5 Hz), 7.52 (1H, d, J=16.3 Hz), 7.81
(1H, dd, J=2.2, 8.5 Hz), 8.24 (1H, d, J=2.2 Hz).
Example 311
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester
[0886] By treating 70 mg of
4-methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5--
carboxylic acid ethyl ester in the similar method as described in
Example 16, 35 mg of the title compound was obtained as a colorless
powder.
[0887] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.42 (3H, t, J=7.5
Hz), 3.94 (3H, s), 4.01 (3H, s), 4.38 (2H, q, J=7.5 Hz), 6.89 (1H,
d, J=9.0 Hz), 7.28 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=16.6 Hz), 7.57
(1H, d, J=16.6 Hz), 7.83 (1H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.4,
9.0 Hz), 8.28 (1H, d, J=2.4 Hz).
Example 312
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0888] By treating 35 mg of
4-methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxyli-
c acid ethyl ester in the similar method as described in Example
144, 30 mg of the title compound was obtained as a colorless
powder.
[0889] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.89 (3H, s),
3.97 (3H, s), 6.89 (1H, d, J=8.7 Hz), 7.28 (1H, d, J=8.7 Hz), 7.51
(1H, d, J=16.4 Hz), 7.54 (1H, d, J=16.4 Hz), 7.73 (1H, d, J=8.7
Hz), 8.09 (1H, dd, J=2.2, 8.7 Hz), 8.39 (1H, d, J=2.2 Hz).
Example 313
[0890] From
4-methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxyli-
c acid and various kinds of amine, compounds of Examples 314-320
were obtained in accordance with the method of Example 102-h.
Example 314
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0891] MS (ESI) m/z 365 MH.sup.+
Example 315
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0892] MS (ESI) m/z 405 MH.sup.+
Example 316
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0893] MS (ESI) m/z 411 MH.sup.+
Example 317
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0894] MS (ESI) m/z 421 MH.sup.+
Example 318
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenyl-ethyl)-amide
[0895] MS (ESI) m/z 472 MH.sup.+
Example 319
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-hydroxy-ethyl)-amide
[0896] MS (ESI) m/z 412 MH.sup.+
Example 320
4-Methoxy-3-[(E)-2-(6-methoxypyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoyl-ethyl]-amide
[0897] MS (ESI) m/z 396 MH.sup.+
Production Example 321
3-Iodo-4-methoxy-1H-indazole-5-carbonitrile
[0898] From 28.4 g of 4-methoxy-1H-indazole-5-carbonitrile obtained
by Production example 97, 52.8 g of the title compound was obtained
as yellow crude crystal in accordance with the method of Production
example 275.
[0899] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.4.14 (3H, s),
7.42 (1H, d, J=8.6 Hz), 7.56 (1H, d, J=8.6 Hz), 13.96 (1H, s).
Production Example 322
3-Iodo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile
[0900] From 52.8 g of 3-iodo-4-methoxy-1H-indazole-5-carbonitrile,
104.5 g of the title compound was obtained as brown crude crystal
in accordance with the method of Production example 94.
[0901] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.4.31 (3H, s), 6.13
(1H, d, J=9.0 Hz), 7.00 (1H, d, J=9.0 Hz), 7.10-7.18 (5H, m),
7.22-7.37 (10H, m).
Production Example 323
3-Vinyl-4-methoxy-1-trityl-1H-indazole-5-carbonitrile
[0902] By treating 1.02 g of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile in the method
of Production example 123, 700 mg of the title compound was
obtained as colorless needle crystals.
[0903] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.27 (3H, s), 5.35
(1H, d, J=2.0, 11.0 Hz), 6.05 (1H, d, J=8.7 Hz), 6.08 (1H, dd,
J=2.0, 17.9 Hz), 6.96 (1H, d, J=8.7 Hz), 7.12-7.18 (6H, m), 7.14
(1H, d, J=11.0, 17.9 Hz), 7.25-7.34 (9H, m).
Production Example 324
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitri-
le
[0904] 300 mg of
3-vinyl-4-methoxy-1-trityl-1H-indazole-5-carbonitrile and 180 .mu.l
of 3-bromopyridine were dissolved in a mixed solvent of 1 mL
triethylamine/5 mL acetonitrile, added with 40 mg of
tri-p-tolylphosphine and 27 mg of palladium acetate (II), and
heated at 110.degree. C. for 24 hours. The reaction solution was
added with silica gel, the solvent was evaporated, and the
resultant residue was purified by column chromatography
(hexane:ethyl acetate=7:3), to afford 120 mg of the title compound
as a pale yellow oil.
[0905] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.35 (3H, s), 6.10
(1H, d, J=9.0 Hz), 7.00 (1H, d, J=9.0 Hz), 7.16-7.22 (6H, m),
7.26-7.34 (10H, m), 7.41 (1H, d, J=16.1 Hz), 7.60 (1H, d, J=16.1
Hz), 7.83 (1H, dt, J=2.2, 8.3 Hz), 8.50 (1H, dd, J=2.2, 5.3 Hz) r
8.72 (1H, d, J=2.2 Hz).
Example 325
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carbonitrile
[0906] By treating 120 mg of
4-methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitr-
ile in the similar method as described in Example 16, 76 mg of the
title compound was obtained as a colorless powder.
[0907] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 4.24 (3H, s),
7.40 (1H, d, J=8.5 Hz), 7.45 (1H, dd, J=4.8, 8.2 Hz), 7.57 (1H, d,
J=8.5 Hz), 7.59 (1H, d, J=16.6 Hz), 7.66 (1H, d, J=16.6 Hz), 8.14
(1H, dt, J=1.9, 8.2 Hz), 8.51 (1H, dd, J=1.9, 4.8 Hz), 8.84 (1H, d,
J=1.9 Hz), 13.77 (1H, bs).
Example 326
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0908] 70 mg of
4-methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carbonitrile
was alkaline hydrolyzed in the similar method as described in
Example 243, to afford 42 mg of the title compound as a pale yellow
powder.
[0909] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.97 (3H, s),
7.32 (1H, d, J=8.6 Hz), 7.44 (1H, dd, J=4.5, 7.7 Hz), 7.59 (1H, d,
J=16.4 Hz), 7.70 (1H, d, J=16.4 Hz), 7.75 (1H, d, J=8.6 Hz), 8.12
(1H, dt, J=1.8, 7.7 Hz), 8.50 (1H, dd, J=1.8, 4.5 Hz), 8.72 (1H, d,
J=1.8 Hz), 13.53 (1H, bs).
Example 327
[0910] From
4-methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 328-334 were
obtained in accordance with the method of Example 102.
Example 328
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0911] MS (ESI) m/z 375 MH.sup.+
Example 329
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (tetrahydro-furan-2-ylmethyl)-amide
[0912] MS (ESI) m/z 379 MH.sup.+
Example 330
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (2-acetylamino-ethyl)-amide
[0913] MS (ESI) m/z 380 MH.sup.+
Example 331
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0914] MS (ESI) m/z 381 MH.sup.+
Example 332
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide
[0915] MS (ESI) m/z 415 MH.sup.+
Example 333
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0916] MS (ESI) m/z 391 MH.sup.+
Example 334
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0917] MS (ESI) m/z 335 MH.sup.+
Example 335
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
[0918] 2-Vinylthiophene and 500 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 322 were reacted in accordance with Example 100,
to afford 110 mg of the title compound as a pale yellow powder.
[0919] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 4.21 (3H, s),
7.11 (1H, dd, J=3.7, 5.3 Hz), 7.27 (1H, d, J=16.3 Hz), 7.34 (1H,
bd, J=3.7 Hz), 7.38 (1H, d, J=8.5 Hz), 7.54 (1H, bd, J=5.3 Hz),
7.55 (1H, d, J=8.5 Hz), 7.72 (1H, d, J=16.3 Hz).
Example 336
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0920] 110 mg of
4-methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carbonitrile
was alkaline hydrolyzed in the similar method as described in
Example 243, to afford 40 mg of the title compound as a colorless
powder.
[0921] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.94 (3H, s),
7.11 (1H, dd, J=3.6, 5.1 Hz), 7.31 (1H, d, J=5.1 Hz), 7.32 (1H, d,
J=8.6 Hz), 7.35 (1H, d, J=16.1 Hz), 7.52 (1H, bd, J=3.6 Hz), 7.72
(1H, d, J=16.1 Hz), 7.75 (1H, d, J=8.6 Hz).
Example 337
[0922] From
4-methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 338-342 were
obtained in accordance with the method of Example 102.
Example 338
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[0923] MS (ESI) m/z 340 MH.sup.+
Example 339
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0924] MS (ESI) m/z 380 MH.sup.+
Example 340
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[0925] MS (ESI) m/z 386 MH.sup.+
Example 341
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide
[0926] MS (ESI) m/z 420 MH.sup.+
Example 342
4-Methoxy-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[0927] MS (ESI) m/z 396 MH.sup.+
Example 343
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carbonitrile
[0928] From 2-vinylpyridine and 500 mg of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 322, 110 mg of the title compound was obtained
as a colorless powder in accordance with Example 100.
[0929] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 4.23 (3H, s),
7.30 (1H, ddd, J=1.1, 4.6, 7.6 Hz), 7.41 (1H, d, J=8.8 Hz), 7.57
(1H, d, J=8.8 Hz), 7.61 (1H, d, J=7.6 Hz), 7.62 (1H, d, J=16.0 Hz),
7.82 (1H, dt, J=1.8, 7.6 Hz), 8.05 (1H, d, J=16.0 Hz), 8.64 (1H,
ddd, J=1.1, 1.8, 4.6 Hz), 13.73-13.85 (1H, bs).
Example 344
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[0930] 110 mg of
4-methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carbonitrile
was alkaline hydrolyzed in the similar method as described in
Example 243, to afford 40 mg of the title compound as a pale yellow
powder.
[0931] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.95 (3H, s),
7.27 (1H, dd, J=5.0, 7.7 Hz), 7.30 (1H, d, J=8.5 Hz), 7.56 (1H, d,
J=7.7 Hz), 7.58 (1H, d, J=16.1 Hz), 7.73 (1H, d, J=8.5 Hz), 7.79
(1H, dt, J=1.7, 7.7 Hz), 8.06 (1H, d, J=16.1 Hz), 8.61 (1H, bd,
J=5.0 Hz), 13.53 (1H, bs).
Example 345
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid ethyl ester
[0932] To a solution of 5.05 g of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276 in 70 mL of 1,2-dimethoxyethane
were successively added 1.57 g of
(E)-2-(4-fluorophenyl)-vinylboronic acid, a solution containing
2.16 g of sodium hydrogen carbonate in 34 mL of water and 496.9 mg
of tetrakis(triphenylphosphine)palladium(0), and stirred under
nitrogen atmosphere at 110.degree. C. for 21 hours. The reaction
solution was cooled to room temperature, poured slowly with
saturated aqueous ammonium chloride, extracted with ethyl acetate
twice, and the resultant organic layer was washed each once with
water and saturated brine, and dried over magnesium sulfate. The
solvent was evaporated, to obtain a crude coupling product. The
obtained crude product was dissolved in 85 mL of dichloromethane,
added with 21.5 mL of a boron tribromide 1M solution in
dichloromethane under ice cooling, and stirred under nitrogen
atmosphere at room temperature for 19 hours. Thereafter, saturated
aqueous ammonium chloride was poured slowly, and extracted twice
with a mixed solvent of ethyl acetate:tetrahydrofuran=1:1, and the
resultant organic layer was washed once with saturated brine, and
dried over magnesium sulfate. The solvent was evaporated, and the
obtained crude product was purified and separated by silica gel
column chromatography, to afford 608 mg of the title compound as
orange crystals.
[0933] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.37 (3H, t,
J=6.8 Hz), 4.40 (2H, q, J=6.8 Hz), 7.04 (1H, d, J=8.8 Hz), 7.25
(2H, t, J=8.8 Hz), 7.58 (1H, d, J=16.8 Hz), 7.64 (1H, d, J=16.8
Hz), 7.64-7.72 (3H, m), 12.21 (1H, s), 13.47 (1H, s).
Production Example 346
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxylic
acid 1-tert-butyl ester 5-ethyl ester
[0934] To a solution of 553 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid ethyl ester in 15 mL of tetrahydrofuran were added 257.5 mg of
di-tert-butyl dicarbonate and 41.5 mg of 4-(dimethylamino)pyridine,
and stirred for 1 hour and 15 minutes under ice cooling. Then the
reaction solution was added with water, extracted twice with
diethyl ether, and the resultant organic layer was washed each once
with water and saturated brine, and dried over magnesium sulfate.
The solvent was evaporated, and the crude product was purified and
separated by silica gel column chromatography, to afford 431.2 mg
of the title compound as colorless crystals.
[0935] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.45 (3H, t, J=7.2
Hz), 1.74 (9H, s) .delta. 4.46 (2H, q, J=7.2 Hz), 7.05-7.11 (2H,
m), 7.58-7.64 (2H, m), 7.61 (1H, d, J=9.0 Hz), 7.65 (1H, d, J=16.2
Hz), 7.87 (1H, d, J=16.2 Hz), 7.94 (1H, bs), 12.15 (1H, s).
Production Example 347
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-1H-
-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl
ester
[0936] To a solution of 200 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxylic
acid 1-tert-butyl ester 5-ethyl ester in 13 mL of
N,N-dimethylformamide were added 196.5 mg of
2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate,
stirred for 1 hour and 30 minutes at room temperature, stirred at
50.degree. C. for 17 hours, added with 196.5 mg of
2-(2-bromoethoxy)-tetrahydropyran and 306.3 mg of cesium carbonate,
stirred for 3 hours at room temperature and for 2 hours at
50.degree. C., added with 554 mg of
2-(2-bromoethoxy)-tetrahydropyran, and further stirred at
50.degree. C. for 4 hours. Then, the reaction solution was added
saturated aqueous ammonium chloride, extracted twice with ethyl
acetate, and the resultant organic layer was washed once with
saturated brine and dried over magnesium sulfate. The solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography, to afford 147 mg of the title
compound as a colorless oil.
[0937] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.36-1.79 (6H, m),
1.44 (3H, t, J=7.2 Hz), 1.75 (9H, s), 3.40-3.56 (1H, m), 3.74-3.84
(1H, m), 3.85-3.94 (1H, m), 4.09-4.16 (1H, m), 4.28-4.47 (2H, m),
4.43 (2H, q, J=7.2 Hz), 4.57-4.61 (1H, m), 7.02-7.10 (2H, m),
7.60-7.66 (2H, m), 7.70 (1H, d, J=16.4 Hz), 7.81 (1H, d, J=16.4
Hz), 7.86 (1H, d, J=8.8 Hz), 7.99 (1H, d, J=8.8 Hz).
Production Example 348
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-1,5-dicar-
boxylic acid 1-tert-butyl ester 5-ethyl ester
[0938] To a solution of 147 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-[2-(tetrahydropyran-2-yloxy)-ethoxy]-1-
H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl ester
in 1.5 mL of tetrahydrofuran was added 1.5 mL of 2N hydrochloric
acid, and stirred at room temperature for 19 hours. Thereafter, the
reaction solution was added with water and extracted twice ethyl
acetate, and the resultant organic layer was washed once with
saturated brine, and dried over magnesium sulfate. The solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography, to afford 87.1 mg of the title
compound as a colorless oil.
[0939] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.43 (3H, t, J=6.8
Hz), 1.75 (9H, s), 3.42-3.45 (1H, m), 3.96-4.00 (2H, m), 4.24-4.26
(2H, m), 4.43 (2H, q, J=6.8 Hz), 7.05-7.12 (2H, m), 7.57 (1H, d,
J=16.4 Hz), 7.57-7.63 (2H, m), 7.80 (1H, d, J=16.2 Hz), 7.93 (1H,
d, J=8.8 Hz), 8.08 (1H, d, J=8.8 Hz).
Example 349
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid ethyl ester
[0940] By treating 87.1 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-1,5-dica-
rboxylic acid 1-tert-butyl ester 5-ethyl ester in the similar
method as described in Example 16, 31.3 mg of the title compound
was obtained as a colorless oil.
[0941] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.42 (3H, t, J=6.8
Hz), 3.99 (2H, t, J=4.0 Hz), 4.29 (2H, t, J=4.0 Hz), 4.41 (2H, q,
J=6.8 Hz), 7.01-7.10 (2H, m), 7.22 (1H, d, J=8.8 Hz), 7.48-7.58
(2H, m), 7.53 (1H, d, J=16.4 Hz), 7.60 (1H, d, J=16.4 Hz), 7.91
(1H, d, J=8.8 Hz).
[0942] MS (ESI) m/z 371 MH.sup.+
Example 350
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid
[0943] To a solution of 31.3 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carbox-
ylic acid ethyl ester obtained by Example 349 in 0.7 mL of
tetrahydrofuran were added 0.3 mL of ethanol and 0.2 mL of 5N
sodium hydroxide aqueous solution, and stirred at 70.degree. C. for
1 hour and 20 minutes. After cooling on ice, the solution was
neutralized with 2N hydrochloric acid under ice cooling, and the
precipitated crystals were collected by filtration, and dried under
reduced pressure, to afford 25 mg of the title compound as yellow
crude crystals.
[0944] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.3.98 (2H, t, J=4.4
Hz), 4.25 (2H, t, J=4.4 Hz), 7.06-7.14 (2H, m), 7.28 (1H, d, J=8.8
Hz), 7.54 (1H, d, J=16.6 Hz), 7.68-7.74 (2H, m), 7.86 (1H, d,
J=16.6 Hz), 7.89 (1H, d, J=8.8 Hz).
[0945] ESI-MS: m/z=341 (M-H).sup.-
Example 351
[0946] From
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carbox-
ylic acid and various kinds of amine, compounds of Examples 352-356
were obtained in accordance with the method of Example 102.
Example 352
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0947] MS (ESI) m/z 428 MH.sup.+
Example 353
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid cyclopropylamide
[0948] MS (ESI) m/z 382 MH.sup.+
Example 354
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid (furan-2-ylmethyl)-amide
[0949] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.82 (2H, t, J=4.4
Hz), 4.08 (2H, t, J=4.4 Hz), 4.62 (2H, s), 6.35 (1H, dd, J=0.8, 3.6
Hz), 6.38 (1H, dd, J=2.0, 3.6 Hz), 7.06-7.14 (2H, m), 7.33 (1H, d,
J=8.8 Hz), 7.46 (1H, dd, J=0.8, 2.0 Hz), 7.53 (1H, d, J=16.6 Hz),
7.64-7.72 (2H, m), 7.74 (1H, d, J=16.6 Hz), 7.85 (1H, d, J=8.8
Hz).
[0950] MS (ESI) m/z 422 MH.sup.+
Example 355
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0951] MS (ESI) m/z 462 MH.sup.+
Example 356
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(2-hydroxyethoxy)-1H-indazole-5-carboxy-
lic acid [(1S)-1-carbamoylethyl]-amide
[0952] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.52 (3H, d, J=6.8
Hz), 3.94-4.06 (2H, m), 4.15-4.25 (2H, m), 4.60-4.67 (1H, m),
7.08-7.16 (2H, m), 7.34 (1H, d, J=8.8 Hz), 7.55 (1H, d, J=16.2 Hz),
7.66-7.74 (2H, m), 7.75 (1H, d, J=16.2 Hz), 7.91 (1H, d, J=8.8
Hz).
[0953] MS (ESI) m/z 413 MH.sup.+
Example 357
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid
[0954] By treating 51.6 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid ethyl ester obtained by Example 345 in the method according to
Example 216, 61.8 mg of the title compound was obtained as brown
crude crystals.
[0955] MS (ESI) m/z 297 MH.sup.+
Example 358
[0956] From
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid and various kinds of amine, compounds of Examples 359-363 were
obtained in accordance with the method of Example 102.
Example 359
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[0957] MS (ESI) m/z 385 MH.sup.+
Example 360
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid cyclopropyl amide
[0958] MS (ESI) m/z 338 MH.sup.+
Example 361
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[0959] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.58 (2H, s),
6.30-6.33 (1H, m), 6.35-6.38 (1H, m), 6.93 (1H, d, J=8.8 Hz),
7.08-7.16 (2H, m), 7.42-7.45 (1H, m), 7.56-7.68 (2H, m), 7.62 (1H,
d, J=16.8 Hz), 7.65 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=16.8 Hz).
[0960] MS (ESI) m/z 378 MH.sup.+
Example 362
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]-amide
[0961] MS (ESI) m/z 418 MH.sup.+
Example 363
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-5-carboxylic
acid [(1S)-1-carbamoylethyl]-amide
[0962] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.51 (3H, d, J=7.2
Hz), 4.62 (1H, q), 6.96 (1H, d, J=9.2 Hz), 7.05-7.20 (2H, m),
7.46-7.72 (4H, m), 7.77 (1H, d, J=9.2 Hz).
[0963] MS (ESI) m/z 369 MH.sup.+
Production Example 364
Acetic acid 2-(N'-benzyloxycarbonyl-hydrazino)-2-oxo-ethyl
ester
[0964] To a solution of 2.04 g of hydrazine carboxylic acid benzyl
ester in 40 mL of dichloromethane was added 2.57 mL of
triethylamine. Under ice cooling, a solution of 1.32 mL of
acetoxyacetylchloride in 20 mL of dichloromethane was added
dropwise over 25 minutes, and stirred at room temperature for 1
hour. The reaction solution was added with water, extracted with
ethyl acetate, and the resultant organic layer was washed with 1N
hydrochloric acid, saturated aqueous sodium hydrogen carbonate and
saturated brine, and then dried over magnesium sulfate. The solvent
was evaporated, and the resulting solid product was washed with
diethyl ether and collected by filtration, to give 1.92 g of the
title compound as white crystals.
[0965] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.09 (3H, s),
4.52 (2H, s), 5.07 (2H, s), 7.26-7.40 (5H, m), 9.25 (1H, bs), 9.95
(1H, bs).
Production Example 365
Acetic Acid Hydrazinocarbonyl Ethyl Ester
[0966] 1.92 g of acetic acid
2-(N'-benzyloxycarbonyl-hydrazino)-2-oxo-ethyl ester was dissolved
in 20 mL of ethanol, and added with 900 mg of 10% palladium-carbon.
At room temperature, the solution was stirred for 5 hours under 1
atm hydrogen atmosphere, and filtrated through Celite, and the
filtrate was evaporated, to afford 0.96 g of the title compound as
a pale yellow oil.
[0967] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.07 (3H, s),
4.27 (2H, bs), 4.42 (2H, s), 9.20 (1H, bs).
Production Example 366
N'-[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-hydrazine
carboxylic acid benzyl ester
[0968] 6.95 g of 2-(tert-butoxycarbonyl-methyl-amino)-acetic acid,
6.1 g of hydrazine carboxylic acid benzyl ester, 6.18 g of
1-hydroxybenzotriazole monohydrate and 19.2 mL of
N,N-diisopropylethylamine were dissolved in 120 mL of
N,N-dimethylformamide, and 10.6 g of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was
added under stirring at room temperature. After stirring at room
temperature for 17 hours, the reaction solution was added with
water and extracted with ethyl acetate, and the resultant organic
layer was washed with saturated brine and dried over magnesium
sulfate. The solvent was evaporated, followed by purification by
silica gel column chromatography (hexane:ethyl acetate=1:1), to
obtain 10.9 g of the title compound.
[0969] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.25-1.46 (9H,
m), 2.68-2.86 (3H, m), 3.80 (2H, d, J=16.8 Hz), 5.07 (2H, s),
7.25-7.46 (5H, m), 9.21 (1H, bs), 9.76 (1H, bs).
Production Example 367
Hydrazine carbonylmethyl-methyl-carbamic acid tert-butyl ester
[0970] From 10.9 g of
N'-[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-hydrazine
carboxylic acid benzyl ester, 6.64 g of the title compound was
obtained in accordance with Production example 365.
[0971] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.36 (9H, d,
J=19.6 Hz), 2.77 (3H, d, J=14.8 Hz), 3.69 (2H, d, J=10.0 Hz), 4.18
(2H, bs), 8.98 (1H, d, J=11.6 Hz).
Production Example 368
3-Iodo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile
[0972] By treating 12.8 g of 7-fluoro-1H-indazole-5-carbonitrile
obtained by Production example 120 in the similar method as
described in Production example 206, followed by treatment in the
similar method as describe in Production example 22, 21.2 g of the
title compound was obtained as pale brown crystals.
[0973] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.03 (1H, dd,
J=10.4, 1.2 Hz), 7.07-7.38 (15H, m), 7.72 (1H, d, J=1.2 Hz).
Example 369
7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
[0974] By treating 1.03 g of
3-bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile in the similar
method as described in Example 100, 348 mg of the title compound
was obtained as pale yellow crystals.
[0975] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.14 (1H, t,
J=9.2 Hz), 7.14-7.47 (1H, m), 7.56-7.71 (4H, m), 7.77 (1H, d,
J=10.4 Hz).
Example 370
7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboximidic
acid ethyl ester hydrochloride
[0976] 4.88 g of
7-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
was dissolved in 100 mL of ethanol, and under stirring and ice
cooling, hydrogen chloride was bubbled thereinto for 20 minutes.
After stirring at room temperature for 19 hours, the solvent was
evaporated, and the generated crystals were washed with diethyl
ether, and collected by filtration, to afford 2.86 g of the title
compound as pale yellow crystals.
[0977] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.68 (3H, t, J=6.8
Hz), 4.69 (2H, q, J=6.8 Hz), 7.07 (1H, dt, J=1.2, 8.0 Hz),
7.38-7.52 (3H, m), 7.57 (1H, d, J=16.4 Hz), 7.68 (1H, d, J=16.4
Hz), 7.77 (1 h, dd, J=1.2, 7.2 Hz), 8.81 (1H, s).
Example 371
[0978]
7-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboximidi-
c acid ethyl ester hydrochloride, 3 equivalents of commercially
available hydrazide or 3 equivalents of hydrazide obtained in
Production example 365, and 3 equivalents of triethylamine were
dissolved in ethanol, and stirred at 80.degree. C. for 18 hours.
After distilling off the solvent, purification by LC-MS was
performed to obtain compounds of Examples 372-374.
Example 372
7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-5-(5-methyl-4H-[1,2,4]triazol-3--
yl)-1H-indazole
[0979] MS (ESI) m/z 338 MH.sup.+
Example 373
(5-{7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-yl)-methanol
[0980] MS (ESI) m/z 354 MH.sup.+
Example 374
(5-{7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-yl}-4H-[1,2,4]-
triazol-3-ylmethyl)-dimethyl-amine
[0981] MS (ESI) m/z 381 MH.sup.+
Example 375
(5-{7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-methyl-amine
[0982]
7-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboximidi-
c acid ethyl ester hydrochloride obtained in Example 370, 3
equivalents of hydrazide obtained in Production example 367 and 3
equivalents of triethylamine were dissolved in ethanol, and stirred
at 80.degree. C. for 18 hours. After distilling off the solvent,
treatment with trifluoroacetic acid and purification by LC-MS were
performed to afford the title compound.
[0983] MS (ESI) m/z 367 MH.sup.+
Example 376
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride
[0984] From 100 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
obtained by Example 100, 120 mg of the title compound was obtained
as pale yellow crystals in accordance with the method of Example
370.
[0985] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.51 (3H, t,
J=6.8 Hz), 4.66 (2H, q, J=6.8 Hz), 7.10-7.22 (1H, m), 7.41-7.48
(1H, m), 7.56 (1H, d, J=8.0 Hz), 7.60-7.69 (4H, m), 8.83 (1H, d,
J=6.8 Hz).
Example 377
[0986] From
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboximidic
acid ethyl ester hydrochloride compounds of Examples 378-381 were
obtained in accordance with the method of Example 371 or 375.
Example 378
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-5-(5-methyl-4H-[1,2,4]-triazol-3-
-yl)-1H-indazole
[0987] MS (ESI) m/z 338 MH.sup.+
Example 379
(5-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-yl)-methanol
[0988] MS (ESI) m/z 354 MH.sup.+
Example 380
(5-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-dimethyl-amine
[0989] MS (ESI) m/z 381 MH.sup.+
Example 381
(5-{6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-methyl-amine
[0990] MS (ESI) m/z 367 MH.sup.+
Example 382
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
[0991] From 5.15 g of
3-iodo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 368 and 4-fluoro-styrene, 1.68 g of the title
compound was obtained in the similar method as described in Example
100.
[0992] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.24 (2H, t,
J=8.8 Hz), 7.54 (1H, d, J=16.8 Hz), 7.64 (1H, d, J=16.8 Hz), 7.74
(1H, d, J=10.8 Hz), 7.81 (2H, dd, J=8.8, 5.6 Hz), 8.76 (1H, s).
Example 383
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboximidic
acid ethyl ester hydrochloride
[0993] From 1.68 g of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile,
1.81 g of the title compound was obtained in accordance with
Example 370.
[0994] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.52 (3H, t,
J=7.2 Hz), 4.64 (2H, q, J=7.2 Hz), 7.25 (2H, t, J=8.8 Hz), 7.54
(1H, d, J=16.8 Hz), 7.82-7.93 (4H, m), 9.20 (1H, s).
Example 384
[0995] From
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboximidic
acid ethyl ester hydrochloride, compounds of Examples 385-387 were
obtained in accordance with the method of Example 371 or 375.
Example 385
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(5-methyl-4H-[1,2,4]triazol-3--
yl)-1H-indazole
[0996] MS (ESI) m/z 338 MH.sup.+
Example 386
(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-yl)-methanol
[0997] MS (ESI) m/z 354 MH.sup.+
Example 387
(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-methyl-amine
[0998] MS (ESI) m/z 367 MH.sup.+
Production Example 388
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxyl-
ic acid ethyl ester
[0999] By coupling 3.21 g of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276 and 2.3 g of
2-[(E)-2-(3-fluorophenyl)-vinyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
obtained by Production example 137 in accordance with the method of
Example 194, 1.72 g of the title compound was obtained as colorless
crystals.
[1000] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.38 (3H, t, J=7.4
Hz), 4.04 (3H, s), 4.36 (2H, q, J=7.4 Hz), 6.11 (1H, d, J=9.0 Hz),
6.91-6.96 (1H, m), 7.14-7.46 (19H, m), 7.43 (1H, d, J=9.0 Hz), 7.61
(1H, d, J=16.4 Hz).
Production Example 389
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxyl-
ic acid
[1001] By hydrolyzing 1.61 g of
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxy-
lic acid ethyl ester in accordance with the method of Example 350,
1.64 g of the title compound was obtained as orange crude
crystals.
[1002] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.04 (3H, s), 6.19
(1H, d, J=9.2 Hz), 6.97-7.01 (1H, m), 7.17-7.41 (20H, m), 7.66 (1H,
d, J=16.4 Hz).
Production Example 390
N'-{3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carb-
onyl}-hydrazine carboxylic acid tert-butyl ester
[1003] 94 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-carboxy-
lic acid and 34.4 mg of hydrazine carboxylic acid tert-butyl ester
were condensed in the manner as described in Example 127, to afford
126.9 mg of the title compound as pale yellow crude crystals.
[1004] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.50 (9H, s), 4.09
(3H, s), 6.22 (1H, d, J=9.0 Hz), 6.75 (1H, bs), 6.92-6.98 (1H, m),
7.15-7.33 (18H, m), 7.40 (1H, d, J=16.2 Hz), 7.50 (1H, d, J=16.2
Hz), 7.63 (1H, d, J=9.0 Hz), 9.40 (1H, bs).
Example 391
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid hydrazide
[1005] 113.7 mg of
N'-{3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1-trityl-1H-indazole-5-car-
bonyl}-hydrazinecarboxylic acid tert-butyl ester was deprotected in
the manner as described in Example 16, to afford 38 mg of the title
compound as colorless crude crystals.
[1006] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.96 (3H, s),
7.10-7.14 (1H, m), 7.35 (1H, d, J=8.8 Hz), 7.40-7.52 (3H, m), 7.54
(1H, d, J=16.4 Hz), 7.59 (1H, d, J=16.4 Hz), 7.66 (1H, d, J=8.8
Hz), 10.55 (1H, s), 13.49 (1H, bs).
Example 392
3-[(E)-2-(3-Fluorophenyl)-vinyl]-4-methoxy-5-(5-methyl-2H-[1,2,4]triazol-3-
-yl)-1H-indazole
[1007] To a suspension of 19 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid hydrazide in 4 mL of ethanol were added 50 mg of O-methyl
acetimidate hydrochloride and 0.19 mL of triethylamine, and stirred
in a sealed tube at 150.degree. C. for 17.5 hours. The reaction
solution was allowed to cool to room temperature, the solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography, and further purified and
separated by LC-MS, to afford 1.17 mg of the title compound as a
yellow amorphous.
[1008] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.62 (3H, s), 3.89
(3H, s), 7.02-7.08 (1H, m), 7.37-7.44 (3H, m), 7.47 (1H, d, J=8.8
Hz), 7.62 (1H, d, J=16.4 Hz), 7.67 (1H, d, J=16.4 Hz), 7.89 (1H, d,
J=8.8 Hz).
[1009] MS (ESI) m/z 392 MH.sup.+
Production Example 393
6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid methyl ester
[1010] In accordance with method of Production example 181, 576 mg
of 3-bromo-6-fluoro-1-trityl-1H-indazole-5-carboxylic acid methyl
ester obtained by Production example 141 and 235 mg of
3-vinylpyridine were made to react, to afford 312 mg of the title
compound as bright yellow crystals.
[1011] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.86 (3H, s),
6.01 (1H, d, J=12.4 Hz), 7.16-7.25 (6H, m), 7.32-7.46 (11H, m),
7.76 (1H, d, J=16.8 Hz), 8.21 (1H, d, J=8.4 Hz), 8.49 (1H, dd,
J=1.2, 8.8 Hz), 8.77 (1H, d, J=6.8 Hz), 8.88 (1H, d, J=1.2 Hz).
Production Example 394
6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid
[1012] From 187 mg of
6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid methyl ester, 187 mg of the title compound was obtained as
ocher crystals in accordance with the method of Example 144.
[1013] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.99 (1H, d,
J=12.0 Hz), 7.16-7.25 (6H, m), 7.30-7.46 (1H, m), 7.74 (1H, d,
J=16.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.48 (1H, d, J=4.0 Hz), 8.75
(1H, d, J=7.2 Hz), 8.88 (1H, s), 13.20 (1H, bs).
Production Example 395
6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxylic
acid hydrazide
[1014] In accordance with the method as described in Example 127,
110 mg of
6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carboxy-
lic acid and 210 mg of hydrazine monohydrate were condensed, to
afford 29 mg of the title compound as a yellow powder.
[1015] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.50 (2H, s),
6.01 (1H, d, J=11.6 Hz), 7.16-7.26 (6H, m), 7.28-7.46 (10H, m),
7.48 (1H, d, J=16.8 Hz), 7.74 (1H, d, J=16.8 Hz), 8.20 (1H, d,
J=7.6 Hz), 8.42 (1H, d, J=7.2 Hz), 8.48 (1H, d, J=4.0 Hz), 8.87
(1H, s), 9.57 (1H, s).
Production Example 396
6-Fluoro-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-3-[(E)-2-(pyridin-3-yl)-vinyl-
]-1-trityl-1H-indazole
[1016] To a solution of 28 mg of trityl-1H-indazole-5-carboxylic
acid hydrazide in 2 mL of methanol was added 11 mg of S-methyl
thioacetimidate hydriodate, and stirred at room temperature for 20
minutes. Then the reaction solution was added with 50 .mu.l of
triethylamine, and stirred at 60-75.degree. C. overnight. The
reaction solution was added with 15 mL of ethyl acetate, and the
organic layer was washed successively with water, saturated aqueous
sodium hydrogen carbonate and saturated brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
crude product was purified and separated by silica gel column
chromatography (methanol:chloroform=1:49), to afford 16 mg of the
title compound as white non-crystalline powder.
[1017] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.40 (3H, s),
6.07 (1H, d, J=12.0 Hz), 7.16-7.26 (6H, m), 7.28-7.46 (11H, m),
7.73 (1H, d, J=16.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.48 (1H, d, J=4.8
Hz), 8.67 (1H, d, J=7.2 Hz), 8.87 (1H, s), 13.80 (1H, bs).
Example 397
6-Fluoro-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-3-[(E)-2-(pyridin-3-yl)-vinyl-
]-1H-indazole
[1018] 16 mg of
6-fluoro-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-3[(E)-2-(pyridin-3-yl)-vinyl-
]-1-trityl-1H-indazole was deprotected in accordance with Example
16, and then purified and separated by LC-MS, to afford 4.7 mg of
the title compound.
[1019] MS (ESI) m/z 321 MH.sup.+
Example 398
7-Fluoro-5-(5-methyl-4H-[1,2,4]triazol-3-yl)-3-[(E)-2-(pyridin-3-yl)-vinyl-
]-1H-indazole
[1020]
7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carb-
onitrile obtained by Production example 124 was deprotected in the
similar method as described in Example 16, followed by reactions in
accordance with Examples 370 and 372, and purification and
isolation by LC-MS, to afford the title compound.
[1021] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.40 (3H, s),
7.41 (1H, dd, J=8.0, 4.8 Hz), 7.52 (1H, d, J=16.4 Hz), 7.74 (1H, d,
J=12.4 Hz), 7.81 (1H, d, J=16.4 Hz), 8.23 (1H, d, J=8.0 Hz), 8.47
(1H, d, J=4.8 Hz), 8.53 (1H, s), 8.89 (1H, s).
Example 399
(5-{7-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]tri-
azol-3-ylmethyl)dimethylamine
[1022] After removing the trityl group from
7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitri-
le obtained by Production example 124 in accordance with the method
of Example 16, reactions as described in Examples 370 and 374 as
well as separation and purification by LC-MS were followed, to
obtain the title compound.
[1023] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.25 (6H, s),
3.62 (2H, s), 7.43 (1H, dd, J=8.0, 4.4 Hz), 7.54 (1H, d, J=16.8
Hz), 7.78 (1H, d, J=12.0 Hz), 7.83 (1H, d, J=16.8 Hz), 8.24 (1H,
dt, J=8.0, 1.6 Hz), 8.49 (1H, dd, J=4.4, 1.6 Hz), 8.56 (1H, s),
8.90 (1H, d, J=1.6 Hz).
Example 400
4-Methoxy-5-(5-methyl-2H-[1,2,4]triazol-3-yl)-3-[(E)-2-(pyridin-3-yl)-viny-
l]-1H-indazole
[1024]
4-Methoxy-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Production example 326 was led to hydrazide in
accordance with Production examples 390 and 391. A suspension of 30
mg of hydrazide in 5 mL of ethanol was added 32 mg of s-methyl
thioacetimidate hydriodate, and stirred at room temperature for 1
hour. Then the reaction solution was added with 0.069 mL of
triethylamine, and allowed to react at 150.degree. C. for 30
minutes under microwave irradiation. The reaction mixture was
purified and separated by LC-MS, to obtain 2.04 mg of the title
compound and 1.44 mg of
4-methoxy-5-(5-methyl-2H-[1,3,4]oxadiazol-2-yl)-3-[(E)-2-(pyridin-3-yl)-v-
inyl]-1H-indazole as described in Example 401 below.
[1025] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.2.60 (3H, s),
3.88 (3H, s), 7.43-7.73 (1H, m), 7.70-7.77 (2H, m), 7.86-7.96 (4H,
m), 8.61-8.71 (2H, m), 8.95-8.99 (1H, m).
[1026] MS (ESI) m/z 333 MH.sup.+
Example 401
4-Methoxy-5-(5-methyl-2H-[1,3,4]oxadiazol-2-yl)-3-[(E)-2-(pyridin-3-yl)-vi-
nyl]-1H-indazole
[1027] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.2.67 (3H, s),
4.00 (3H, s), 7.09 (1H, d, J=8.4 Hz), 7.48 (1H, d, J=8.8 Hz),
7.90-7.99 (4H, m), 8.66 (1H, bs), 8.76 (1H, d, J=8.4 Hz), 9.01 (1H,
d, J=7.6 Hz).
[1028] MS (ESI) f/Z 334 MH.sup.+
Example 402
3-(3-Fluorophenyl)-5-methoxy-1H-pyrazolo[4,3-b]pyridine
[1029] 35 mg of
3-(3-fluorophenyl)-5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 37 was dissolved in 2 mL of
methanol, added with 20 .mu.l of triethylamine and 15 .mu.l of
ethyl chloroformate, and heated at reflux for 16 hours. The
reaction solution was allowed to cool to room temperature, the
solvent was evaporated, and the residue was dissolved in 3 mL of
dichloromethane. After adding 0.5 mL of trifluoroacetic acid and
stirring at room temperature for 30 minutes, the reaction solution
was partitioned between saturated aqueous sodium hydrogen carbonate
and ethyl acetate, extracted with ethyl acetate, and the organic
layer was washed with water, and dried over magnesium sulfate. The
solvent was evaporated, and the residue was purified by silica gel
column chromatography (ethyl acetate:hexane=3:7), to afford 7.25 mg
of the title compound as a pale yellow powder.
[1030] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.4.08 (3H, s), 6.88
(1H, d, J=9.1 Hz), 7.08 (1H, dt, J=2.5, 8.1 Hz), 7.46 (1H, dt,
J=6.2, 8.1 Hz), 7.71 (1H, d, J=9.1 Hz), 8.29 (1H, bd, J=8.1 Hz),
8.32 (1H, bd, J=11.0 Hz).
Example 403
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic
acid
[1031] From 40 mg of
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile
obtained by Example 75, 33 mg of the title compound was obtained as
pale brown crystals in accordance with the method of Example 7.
[1032] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.52-7.63 (2H,
m), 7.93-8.23 (4H, m), 8.59 (1H, s), 8.88 (1H, s), 9.20 (1H,
s).
Production Example 404
1-Benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[1033] 900 mg of 2-benzyl-5-(2-naphthyl)-2H-pyrazol-3-ylamine
obtained from 3-(naphthalen-2-yl)-3-oxopropionitrile and benzyl
hydrazine in the similar method as described in Production example
30 was subjected to the similar reaction as described in Production
example 31, to afford 770 mg of the title compound as a pale yellow
powder.
[1034] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.5.81 (2H, s),
7.25-7.36 (5H, m), 7.54-7.62 (2H, m), 7.94-7.99 (1H, m), 8.04 (1H,
d, J=8.7 Hz), 8.13-8.18 (1H, m), 8.19 (1H, dd, J=2.0, 8.7 Hz), 8.70
(1H, d, J=2.0 Hz), 9.03 (1H, d, J=2.0 Hz), 9.53 (1H, d, J=2.0
Hz).
Example 405
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic
acid
[1035] 500 mg of 1-benzyl-3-(naphthalen-2-yl)-1
h-pyrazolo[3,4-b]pyridine-5-carbonitrile obtained by Production
example 404 was treated in the similar method as described in
Example 437, to obtain 230 mg of the title compound as a pale brown
powder in which deprotection and hydrolysis had proceeded, as well
as 20 mg of
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
described in Example 406 as a pale brown powder.
[1036] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.55-7.60 (2H,
m), 8.08 (1H, d, J=8.5 Hz), 8.14-8.19 (1H, m), 8.18 (1H, dd, J=1.5,
8.5 Hz), 8.59 (1H, s), 9.09 (1H, d, J=1.5 Hz), 9.12 (1H, d, J=1.5
Hz), 13.25-13.40 (1H, bs), 14.25 (1H, bs).
Example 406
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
[1037] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.55 (1H, bt,
J=8.4 Hz), 7.58 (1H, bt, J=8.4 Hz), 7.96 (1H, bd, J=8.4 Hz), 8.05
(1H, d, J=8.4 Hz), 8.15 (1H, bd, J=8.4 Hz), 8.23 (1H, dd, J=2.1,
8.4 Hz), 8.69 (1H, d, J=2.1 Hz), 8.93 (1H, d, J=2.1 Hz), 9.47 (1H,
d, J=2.1 Hz), 14.35-14.60 (1H, bs).
Production Example 407
N-(2-Methyl-pyridin-3-yl)-acetamide
[1038] Under nitrogen atmosphere, 47.6 g of
2-chloro-3-nitropyridine was dissolved in 500 mL of
tetrahydrofuran, and 150 mL of 2M methylzinc chloride in
tetrahydrofuran and 6.9 g of tetrakis(triphenylphosphine) palladium
(0) were added, and the reaction solution was stirred at 70.degree.
C. for 2 hours. The reaction solution was poured into cold water,
extracted with ethyl acetate, washed with water, and dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
residue was subjected to column chromatography (n-hexane:ethyl
acetate=3:1) to obtain 35.4 g of 2-methyl-3-nitropyridine as a
colorless oil. Then 35.4 g of 2-methyl-3-nitropyridine was
dissolved in a mixed solution of 300 mL methanol/5 mL
triethylamine, added with 5 g of 10% palladium carbon, and stirred
for 6 hours under hydrogen atmosphere and at normal temperature and
pressure. The reaction solution was filtered thorough Celite, the
solvent was evaporated, and 33.0 g of crudely produced
2-methyl-3-aminopyridine was obtained as a pale brown oil. Next, to
100 mL of a solution of 65 g of crude 3-amino-2-methylpyridine in
dichloromethane were added 60 mL of pyridine and 71 mL of acetic
anhydride at room temperature and stirred for 3 hours. The reaction
solution was added with about 150 mL of silica gel powder, the
solvent was evaporated, and the residue was purified by silica gel
column chromatography (ethyl acetate:methanol=100:3), to afford 74
g of the title compound as colorless crystals.
[1039] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.25 (3H, s), 2.53
(3H, s), 7.00 (1H, bs), 7.18 (1H, dd, J=4.6, 8.0 Hz), 8.23 (1H, d,
J=8.0 Hz), 8.30 (1H, d, J=4.6 Hz).
Production Example 408
1-Pyrazolo[4,3-b]pyridin-1-yl-ethanone
[1040] To a solution of 74 g of N-(2-methyl-pyridin-3-yl)-acetamide
obtained by Production example 407 in toluene were added 106 mL of
isoamyl sulfite, 140 mL of acetic anhydride and 57.6 g of potassium
acetate at room temperature, and the reaction solution was heated
at 80.degree. C. for 2 hours. The reaction solution was partitioned
into water and ethyl acetate, and the organic layer was extracted
and dried over magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:5), to afford 20 g of the title compound as
colorless crystals.
[1041] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.83 (3H, s), 7.48
(1H, dd, J=4.7, 8.3 Hz), 8.37 (1H, s), 8.72 (1H, bd, J=8.3 Hz),
8.73 (1H, d, J=4.7 Hz).
Production Example 409
1H-Pyrazolo[4,3-b]pyridine
[1042] 20 g of 1-pyrazolo[4,3-b]pyridin-1-yl-ethanone obtained by
Production example 408 was dissolved in a mixed solution of 20 mL
methanol/80 mL tetrahydrofuran, added with 10 mL of 2N sodium
hydroxide aqueous solution at room temperature and stirred for 0.5
hours. The reaction solution was neutralized by adding 2 mL of 5N
hydrochloric acid, then added with about 50 mL of silica gel
powder, and the solvent was evaporated. The residue was purified by
silica gel column chromatography (ethyl acetate:methanol=100:2), to
afford 14.6 g of the title compound as pale yellow cubic
crystals.
[1043] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.35 (1H, dd,
J=4.3, 8.6 Hz), 7.89 (1H, d, J=8.6 Hz), 8.36 (1H, bs), 8.64 (1H,
dd, J=1.5, 4.3 Hz).
Production Example 410
3-Bromo-1H-pyrazolo[4,3-b]pyridine
[1044] 750 mg of N-bromosuccinimide was reacted on 0.5 g of
1H-pyrazolo[4,3-b]pyridine in the similar method as described in
Production example 87, to afford 570 mg of the title compound as a
colorless powder.
[1045] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.43 (1H, dd,
J=4.3, 8.6 Hz), 8.07 (1H, dd, J=1.4, 8.6 Hz), 8.59 (1H, dd, J=1.4,
4.3 Hz), 13.68 (1H, bs).
Production Example 411
3-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine
[1046] By treating 570 mg of 3-bromo-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 410 in the similar method as
described in Production example 22, 860 mg of the title compound
was obtained as a colorless powder.
[1047] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.6.73 (1H, d,
J=8.8 Hz), 7.14-7.19 (6H, m), 7.20 (1H, dd, J=4.1, 8.8 Hz),
7.28-7.38 (9H, m), 8.51 (1H, dd, J=4.1 Hz).
Production Example 412
3-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide
[1048] By treating 110 mg of
3-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine in the similar method
as described in Production example 4, 70 mg of the title compound
was obtained as a colorless powder.
[1049] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.6.25 (1H, d, J=8.8
Hz), 7.06 (1H, dd, J=6.4, 8.8 Hz), 7.12-7.17 (6H, m), 7.28-7.38
(9H, m), 8.08 (1H, d, J=6.4 Hz).
Production Example 413
3-Bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
[1050] By treating 300 mg of
3-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine 4-oxide in the same
manner as described in Production example 57240 mg of the title
compound was obtained as a colorless powder.
[1051] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.6.65 (1H, d, J=9.0
Hz), 7.14-7.18 (6H, m), 7.27 (1H, d, J=9.0 Hz), 7.29-7.35 (9H,
m).
Production Example 414
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-car-
bonitrile
[1052] By treating 180 mg of
3-bromo-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile obtained
by Production example 413 in the similar method as described in
Example 194, 180 mg of a crude product of the title compound as a
colorless oil.
[1053] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.6.66 (1H, d, J=8.5
Hz), 6.95-7.01 (1H, m), 7.13-7.22 (7H, m), 7.23-7.40 (12H, m), 7.26
(1H, d, J=8.5 Hz), 7.40 (1H, d, J=16.6 Hz), 8.19 (1H, d, J=16.6
Hz).
Example 415
3-[(E)-2-(3-Fluorophenyl)-vinyl]1H-pyrazolo[4,3-b]-pyridine-5-carbonitrile
[1054] By treating 180 mg of the crude
3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-ca-
rbonitrile obtained by Production example 414 in the similar method
as described in Example 16, 60 mg of the title compound was
obtained as a pale yellow powder.
[1055] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.00-7.06 (1H, m),
7.35-7.40 (2H, m), 7.40-7.45 (1H, m), 7.47 (1H, d, J=16.9 Hz), 7.72
(1H, d, J=8.5 Hz), 7.95 (1H, d, J=8.5 Hz), 8.25 (1H, d, J=16.9
Hz).
Example 416
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid
[1056] By treating 60 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridine-5-carbonitril-
e in the similar method as described in Example 7, 36 mg of the
title compound was obtained as a colorless powder.
[1057] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.14 (1H, bt, 8.5
Hz), 7.44 (1H, dt, 6.2, 7.7 Hz), 7.50 (1H, bd, 7.7 Hz), 7.57 (1H,
bd, 8.5 Hz), 7.61 (1H, d, J=16.6 Hz), 8.09 (1H, d, J=8.8 Hz), 8.14
(1H, d, J=8.8 Hz), 8.19 (1H, d, J=16.6 Hz), 13.07 (1H, bs), 13.68
(1H, bs).
Production Example 417
3-Iodo-1H-pyrazolo[4,3-b]pyridine
[1058] In the similar method as described in Production example
206, 9.5 g of N-iodosuccinimide was reacted on 5 g of
1H-pyrazolo[4,3-b]pyridine, to afford 5.9 g of the title compound
as a colorless powder.
[1059] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.43 (1H, dd,
J=4.2, 8.2 Hz), 8.00 (1H, dd, J=1.3, 8.2 Hz), 8.53 (1H, dd, J=1.3,
4.2 Hz), 13.64-13.83 (1H, bs).
Production Example 418
3-Iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine
[1060] By treating 5.9 g of 3-iodo-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 417 in the similar method as
described in Production example 22, 10.7 g of the title compound
was obtained as a colorless powder.
[1061] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.6.56 (1H, dd,
J=1.2, 8.7 Hz), 6.96 (1H, dd, J=4.3, 8.7 Hz), 7.15-7.22 (6H, m),
7.25-7.35 (9H, m), 8.53 (1H, dd, J=1.2, 4.3 Hz).
Production Example 419
3-(Naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine
[1062] By treating 731 mg of
3-iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine obtained by Example 418
and 340 mg of 2-naphthaleneboronic acid in the manner as described
in Production example 194, 210 mg of the title compound was
obtained as a colorless powder.
[1063] The instrumental data coincided with that of Production
example 13.
Example 420
5-Chloro-3-naphthalen-2-yl-1H-pyrazolo[4,3-b]pyridine
[1064] After treating 210 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine obtained by
Production example 419 in the similar method as described in
Production example 4, 2 mL of residue solution in toluene was added
at room temperature with 190 .mu.l of phosphorus oxychloride, and
treated in the similar method as described in Production example
28, to afford 60 mg of the title compound as a pale yellow
powder.
[1065] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.38 (1H, d, J=8.9
Hz), 7.48-7.55 (2H, m), 7.83 (1H, d, J=8.9 Hz), 7.85-7.90 (1H, m),
7.97 (1H, d, J=8.9 Hz), 8.01-8.06 (1H, m), 8.52 (1H, dd, J=1.8, 8.9
Hz), 9.08 (1H, d, J=1.8 Hz).
Production Example 421
5-Chloro-3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine
[1066] By treating 170 mg
5-chloro-3-(naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridine obtained by
Example 420 in the similar method as described in Production
example 22, 340 mg of the title compound was obtained as a
colorless powder.
[1067] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.6.56 (1H, d, J=8.7
Hz), 6.94 (1H, d, J=8.7 Hz), 7.22-7.28 (6H, m), 7.28-7.36 (9H, m),
7.44-7.52 (2H, m), 7.81-7.85 (1H, m), 7.87 (1H, d, J=8.7 Hz),
7.97-8.03 (1H, m), 8.38 (1H, dd, J=2.0, 8.7 Hz), 9.08 (1H, d, J=2.0
Hz).
Production Example 422
3-(Naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
[1068] 280 mg of
5-chloro-3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridine
was dissolved in 8 mL of toluene, added with 73 mg sodium
t-butoxide, 180 .mu.l of benzophenone imine, 100 mg of
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 56 mg of
tris(dibenzylidene acetone)bispalladium, and stirred at 100.degree.
C. for 1.5 hours. The reaction solution was allowed to cool to room
temperature, the solvent evaporated, and the residue was added with
5 mL of tetrahydrofuran and 0.3 mL of 5N hydrochloric acid and
stirred at room temperature for 1 hour. The resultant reaction
solution was added with aqueous sodium hydrogen carbonate,
extracted with ethyl acetate, and the organic layer was washed with
water and dried over magnesium sulfate. The solvent was evaporated,
and the residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:3), to afford 220 mg of the title compound
as a colorless powder.
[1069] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.4.47-4.63 (2H, bs),
6.25 (1H, d, J=9.1 Hz), 6.43 (1H, d, J=9.1 Hz), 7.24-7.33 (15H, m),
7.39-7.48 (2H, m), 7.78-7.82 (1H, m), 7.83 (1H, d, J=8.8 Hz),
7.92-7.96 (1H, m), 8.36 (1H, dd, J=1.6, 8.8 Hz), 9.06 (1H, d, J=1.6
Hz).
Production Example 423
Cyclopropane carboxylic acid
[3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl]amide
[1070] 20 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
was dissolved in 3 mL of toluene, and added with 20 .mu.l of
triethylamine and 10 .mu.l of cyclopropanecarbonyl chloride at room
temperature and stirred all day and night. The reaction solution
was added with saturated aqueous sodium hydrogencarbonate,
extracted with sodium acetate, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the residue was purified
by silica gel column chromatography (ethyl acetate:hexane=1:4), to
afford 20 mg of the title compound as a colorless powder.
[1071] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.0.88-0.95 (2H, m),
1.03-1.12 (2H, m), 1.57-1.65 (1H, m), 6.64 (1H, d, J=9.4 Hz),
7.23-7.33 (15H, m), 7.42-7.51 (2H, m), 7.80-7.86 (1H, m), 7.86 (1H,
d, J=8.4 Hz), 7.92-7.98 (1H, m), 7.96 (1H, d, J=9.4 Hz), 8.35 (1H,
dd, J=1.8, 8.4 Hz), 8.45 (1H, bs), 9.01 (1H, d, J=1.8 Hz).
Example 424
Cyclopropane carboxylic acid
[3-(naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]amide
[1072] By deprotecting 20 mg of cyclopropane carboxylic acid
(3-naphthalen-2-yl-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl)amide
obtained by Production example 423 in the similar method as
described in Example 16, 9.1 mg of the title compound was obtained
as a colorless powder.
[1073] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.0.89-0.95 (2H, m),
1.00-1.15 (2H, m), 1.96-2.04 (1H, m), 7.45-7.54 (2H, m), 7.84-7.90
(1H, m), 7.93 (1H, d, J=8.9 Hz), 7.97 (1H, d, J=9.2 Hz), 7.97-8.03
(1H, m), 8.25 (1H, d, J=9.2 Hz), 8.49 (1H, dd, J=1.9, 8.9 Hz), 9.11
(1H, s).
Production Example 425
2-Iodo-4-methyl-5-nitropyridine
[1074] To a solution of 1.0 g of 2-amino-4-methyl-5-nitropyridine
in 10 mL of diiodomethane was added 1.8 mL of isopentyl sulfite at
room temperature, stirred at this temperature for 30 minutes, and
after raising the temperature to 80.degree. C., the solution was
stirred for 2 hours. The diiodomethane was evaporated, and the
crude product was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:20), to afford 897 mg of
the title compound as colorless crystals.
[1075] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.58 (3H, s), 7.77
(1H, s), 8.90 (1H, s).
Production Example 426
6-Iodo-4-methylpyridin-3-ylamine
[1076] To a solution of 1.76 g of 2-iodo-4-methyl-5-nitropyridine
in 7.0 mL of concentrated hydrochloric acid and 7.0 mL of diethyl
ether was added 6.32 g of tin chloride (II) at room temperature,
and stirred at 100.degree. C. for 4 hours. After cooling the
solution to room temperature, 5N sodium hydroxide aqueous solution
was added to make the solution alkaline. Then the solution was
diluted with dichloromethane and the insoluble substances were
filtered off through Celite. The organic layer of the filtrate was
dried over anhydrous magnesium sulfate, and the solvent was
evaporated, to afford 897 mg of the title compound as orange-brown
crystals.
[1077] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.10 (3H, s), 3.61
(2H, bs), 7.33 (1H, s), 7.80 (1H, s).
Production Example 427
N-(6-Iodo-4-methylpyridin-3-yl)acetamide
[1078] By treating 1.55 g of 6-iodo-4-methylpyridin-3-ylamine
obtained by Production example 426 in the similar method as
described in Production example 176, 1.68 g of the title compound
was obtained as colorless crystals.
[1079] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.21 (3H, s), 2.22
(3H, s), 6.89 (1H, bs), 7.56 (1H, s), 8.62 (1H, s).
Production Example 428
1-(5-Iodo-pyrazolo[3,4-c]pyridin-1-yl)ethanone
[1080] By treating 1.68 g of
N-(6-iodo-4-methylpyridin-3-yl)acetamide in the similar method as
described in Production example 408, 1.58 g of the title compound
was obtained as colorless crystals.
[1081] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.80 (3H, s), 8.10
(2H, d, J=0.8 Hz), 9.56 (1H, t, J=0.8 Hz).
Production Example 429
1H-Pyrazolo[3,4-c]pyridine-5-carbonitrile
[1082] A suspension of 6.40 g of
1-(5-iodo-pyrazolo[3,4-c]pyridin-1-yl)ethanone obtained by
Production example 428, 5.24 g of zinc cyanide and 2.58 g of
tetrakis(triphenylphosphine)palladium(0) in 70 mL of
N,N-dimethylformamide was stirred at 40.degree. C. for 2 days. The
suspension was diluted with ethyl acetate, and the insoluble
substances were filtered through Celite. The filtrate was washed
successively with saturated ammonium chloride and saturated brine,
and then dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:1),
to afford 2.78 g of the title compound as colorless crystals.
[1083] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.8.34 (1H, d, J=0.8
Hz), 8.38 (1H, d, J=0.8 Hz), 9.09 (1H, t, J=0.8 Hz).
Production Example 430
3-Iodo-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile
[1084] From 2.78 g of 1H-pyrazolo[3,4-c]pyridine-5-carbonitrile,
5.89 g of the title compound (N,N-dimethylformamide still
remaining) was obtained as colorless crystals in accordance with
the method of Production example 206.
[1085] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.8.08 (1H, d, J=0.8
Hz), 9.05 (1H, t, J=0.8 Hz).
Production Example 431
3-Iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile
[1086] To a solution of 5.8 g of
3-iodo-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile in 70 mL of
dichloromethane were added 13.1 mL of diisopropylethylamine, 2.4 g
of tetra-n-butylammonium iodide and 12.0 g of trityl chloride at
room temperature, and stirred at this temperature for a day. The
solution was evaporated, diluted with ethyl acetate, washed
successively with saturated ammonium chloride and saturated brine,
and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography (ethyl acetate:n-hexane=1:10), to
afford 5.2 g of the title compound as colorless crystals.
[1087] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.7.10-7.15 (6H, m),
7.27-7.36 (9H, m), 7.60 (1H, d, J=1.2 Hz), 7.84 (1H, d, J=1.2
Hz).
Production Example 432
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-car-
bonitrile
[1088] From 1.0 g of
3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile, 326 mg
of the title compound was obtained as colorless crystals in
accordance with the method of Example 194.
[1089] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.6.98-7.04 (1H, m),
7.15-7.36 (20H, m), 7.73 (1H, d, J=1.2 Hz), 8.30 (1H, d, J=1.2
Hz).
Example 433
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]pyridine-5-carboxylic
acid
[1090] From 87 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-ca-
rbonitrile obtained by Production example 432, the trityl group was
deprotected in accordance with Example 16, followed by treatment in
accordance with the method of Example 7, to thereby afford 55 mg of
the title compound as pale yellow crystals.
[1091] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.7.11 (1H, td,
J=8.0, 2.0 Hz), 7.42 (1H, dd, J=14.4, 8.0 Hz), 7.57 (1H, d, J=8.0
Hz), 7.58 (1H, d, 16.4 Hz), 7.69 (1H, d, J=10.4 Hz), 7.79 (1H, d,
J=14.4 Hz), 8.89 (1H, d, J=1.2 Hz), 9.07 (1H, s).
Production Example 434
2-Benzyl-5-(naphthalen-2-yl)-4-nitroso-2H-pyrazol-3-ylamine
[1092] 600 mg of 2-benzyl-5-(2-naphthyl)-2H-pyrazol-3-ylamine
obtained as an intermediate of Production example 404 was dissolved
in a mixed solvent of 15 mL ethanol/0.5 mL concentrated
hydrochloric acid, and 340 .mu.l of isoamyl sulfite was added
dropwise under ice cooling. The reaction solution was partitioned
between saturated aqueous sodium hydrogen carbonate and ethyl
acetate, and the organic layer was extracted and washed with water.
The organic layer was dried over magnesium sulfate, the solvent was
evaporated, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=3:7), to afford 440 mg of the
title compound as red-brown needle crystals.
[1093] .sup.1H-NMR (400 MHz, DMSO-d.sub.6), 5.24 (2H, s), 7.26-7.31
(3H, m), 7.33-7.38 (2H, m), 7.51-7.58 (2H, m), 7.92-7.96 (1H, m),
7.97-8.01 (1H, m), 7.99 (1H, d, J=8.8 Hz), 8.26 (1H, dd, J=1.6, 8.8
Hz), 8.57 (2H, bs), 8.88 (1H, s).
Production Example 435
2-Benzyl-5-(naphthalen-2-yl)-2H-pyrazole-3,4-diamine
[1094] 200 mg of
2-benzyl-5-(naphthalen-2-yl)-4-nitroso-2H-pyrazol-3-ylamine
obtained by Production example 434 was dissolved in a mixed solvent
of methanol/tetrahydrofuran, added with 100 mg of palladium-carbon,
and stirred for 2 hours under hydrogen atmosphere at normal
temperature and normal pressure. The reaction solution was filtered
through Celite, and the solvent was evaporated, to afford 190 mg of
the title compound as yellow-brown needle crystals.
[1095] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.3.45 (2H, bs),
4.77 (2H, bs), 5.16 (2H, s), 7.19 (2H, d, J=7.1 Hz), 7.22 (1H, t,
J=7.1 Hz), 7.30 (2H, t, J=7.1 Hz), 7.41 (1H, bt, J=7.9 Hz), 7.45
(1H, bt, J=7.9 Hz), 7.82 (1H, d, J=8.8 Hz), 7.83 (1H, d, J=7.9 Hz),
7.86 (1H, d, J=7.9 Hz), 8.05 (1H, dd, J=1.6, 8.8 Hz), 8.38 (1H, dd,
J=1.6 Hz).
Production Example 436
1-Benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine
[1096] 190 mg of
2-benzyl-5-(naphthalen-2-yl)-2H-pyrazole-3,4-diamine was dissolved
in 10 mL of methanol, added with 100 .mu.l of 40% glyoxal aqueous
solution, and stirred at room temperature for 5 hours. The reaction
solution was partitioned between water and ethyl acetate, and the
organic layer was extracted and washed with water. The organic
layer was dried over magnesium sulfate, the solvent was evaporated,
and the residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:5), to afford 180 mg of the title compound
as a pale yellow powder.
[1097] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.5.80 (2H, s),
7.26-7.36 (3H, m), 7.42-7.47 (2H, m), 7.48-7.55 (2H, m), 7.85-7.90
(1H, m), 8.02 (1H, d, J=8.4 Hz), 7.99-8.04 (1H, m), 8.53 (1H, d,
J=2.1 Hz), 8.55 (1H, dd, J=1.7, 8.4 Hz), 8.70 (1H, d, J=2.1 Hz),
9.08 (1H, s).
Example 437
3-Naphthalen-2-yl-1H-pyrazolo[3,4-b]pyrazine
[1098] A mixture of 50 mg of
1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine obtained by
Production example 436 and 1.0 g of pyridine hydrochloride was
heated at 200.degree. C. for 24 hours. The reaction solution was
allowed to cool to room temperature, partitioned between water and
ethyl acetate, extracted with ethyl acetate, and the organic layer
was washed with water and dried over magnesium sulfate. The solvent
was evaporated, and the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=3:7), to afford 21 mg of the
title compound as a pale yellow powder.
[1099] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.7.52-7.59 (2H,
m), 7.93-7.98 (1H, m), 8.02-8.07 (1H, m), 8.06 (1H, d, J=9.0 Hz),
8.50 (1H, dd, J=1.4, 9.0 Hz), 8.67 (1H, d, J=2.0 Hz), 8.78 (1H, d,
J=2.0 Hz), 9.06 (1H, s), 14.27 (1H, bs).
Production Example 438
N-[2-Benzyl-5-(naphthalen-2-yl)-4-nitroso-2H-pyrazole-3-ylamino]-maronamic
acid ethyl ester
[1100] 200 mg of
2-benzyl-5-(naphthalen-2-yl)-4-nitroso-2H-pyrazol-3-ylamine
obtained by Production example 434 was dissolved in 10 mL of
tetrahydrofuran, added with 300 .mu.l of triethylamine and 270
.mu.l of ethyl chlorocarbonylethyl acetate, and stirred at room
temperature all day and night. The reaction solution was
partitioned between water and ethyl acetate, and the organic layer
was extracted and washed with water. The organic layer was dried
over magnesium sulfate, the solvent was evaporated, and the residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=3:7), to afford 2100 mg of the title compound as
green needle crystals.
[1101] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.1.19 (3H, t,
J=7.3 Hz), 3.61 (2H, s), 4.14 (2H, q, J=7.3 Hz), 5.32 (2H, s),
7.27-7.38 (5H, m), 7.53-7.61 (2H, m), 7.95-8.00 (1H, m), 8.02-8.06
(1H, m), 8.03 (1H, d, J=8.7 Hz), 8.17 (1H, dd, J=1.4, 8.7 Hz), 8.72
(1H, bs), 11.02 (1H, bs).
Production Example 439
1-Benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic
acid
[1102] 50 mg of
N-[2-benzyl-5-(naphthalen-2-yl)-4-nitroso-2H-pyrazol-3-ylamino]-maronamic
acid ethyl ester obtained by Production example 438 was dissolved
in 5 mL of tetrahydrofuran, added with 30 mg of a sodium methoxide
(28%) solution in methanol, and stirred at 50.degree. C. for 10
minutes. The reaction solution was partitioned between diluted
hydrochloric acid and ethyl acetate, and the organic layer was
extracted and washed with water. The organic layer was dried over
magnesium sulfate, the solvent was evaporated, and the residue was
purified by silica gel column chromatography (ethyl
acetate:hexane=1:1), to afford 22 mg of the title compound as a
pale yellow powder.
[1103] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.5.38 (2H, s),
7.24-7.31 (3H, m), 7.31-7.36 (2H, m), 7.50-7.56 (2H, m), 7.90-7.95
(1H, m), 7.99-8.04 (1H, m), 8.02 (1H, d, J=8.8 Hz), 8.21 (1H, bs),
8.39 (1H, dd, J=1.4, 8.8 Hz), 8.91 (1H, d, J=1.4 Hz).
Production Example 440
1-Benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic
acid methyl ester
[1104] 20 mg of
1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic
acid was dissolved in 5 mL of N,N-dimethylformamide, added with 10
mg of potassium carbonate and 20 .mu.l methyl iodide, and stirred
at room temperature for 3 hours. The reaction solution was
partitioned between water and ethyl acetate, and the organic layer
was extracted and washed with water. The organic layer was dried
over magnesium sulfate, the solvent was evaporated, and the residue
was purified by silica gel column chromatography (ethyl
acetate:hexane=1:10), to afford 20 mg the title compound as a
colorless powder. 1H-n (400 MHz, CDCl.sub.3) .delta.4.07 (3H, s),
5.65 (2H, s), 7.25-7.36 (3H, m), 7.40-7.44 (2H, m), 7.45-7.52 (2H,
m), 7.82-7.87 (1H, m), 7.93 (1H, d, J=8.5 Hz), 7.96-8.01 (1H, m),
8.27 (1H, s), 8.48 (1H, dd, J=1.5, 8.5 Hz), 8.97 (1H, s).
Example 441
3-Naphthalen-2-yl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid
[1105] By treating 150 mg of
1-benzyl-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic
acid methyl ester obtained by Production example 440 in the similar
method as described in Example 437, 54 mg of the title compound was
obtained as a pale brown powder.
[1106] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.7.52-7.58 (2H, m),
7.88-7.93 (1H, m), 7.93-7.99 (1H, m), 7.98 (1H, s), 8.00 (1H, d,
J=9.1 Hz), 8.24 (1H, d, J=9.1 Hz), 8.72 (1H, bs).
Example 442
[1107] 3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic
acid obtained by Example 7 and various kinds of amine were
condensed in the similar method as described in Example 44, to
afford the compounds of Examples 443-446.
Example 443
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
carbamoylmethyl-amide
[1108] MS (ESI) m/z 314 MH.sup.+
Example 444
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-carbamoyl-ethyl)-amide
[1109] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.1.44 (3H, d,
J=7.5 Hz), 4.99 (1H, dq, J=7.5 Hz), 7.28 (1H, dt, J=2.4, 7.9 Hz),
7.27 (1H, bs), 7.59 (1H, dt, J=6.0, 7.9 Hz), 7.64 (1H, bs), 8.13
(1H, bd, J=9.0 Hz), 8.25 (1H, bd, J=9.0 Hz), 8.29 (1H, dd, J=2.4,
10.5 Hz), 8.39 (1H, bd, J=7.9 Hz), 8.83 (1H, d, J=7.5 Hz).
[1110] MS (ESI) m/z 328 MH.sup.+
Example 445
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-carbamoyl-2-hydroxy-ethyl)-amide
[1111] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.3.95 (1H, dd,
J=4.7, 11.2 Hz), 4.05 (1H, dd, J=4.4, 11.2 Hz), 4.66 (1H, bt, J=4.7
Hz), 7.14 (1H, dt, J=2.6, 8.6 Hz), 7.56 (1H, dt, J=6.0, 8.0 Hz),
8.16 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz), 8.23 (1H, bd,
J=10.5 Hz), 8.47 (1H, bd, J=8.6 Hz).
[1112] MS (ESI) m/z 344 MH.sup.+
Example 446
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid
(1-carbamoyl-2-phenyl-ethyl)-amide
[1113] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.15 (1H, dd,
J=8.4, 13.9 Hz), 3.22 (1H, dd, J=5.5, 13.9 Hz), 4.66 (1H, dt,
J=5.5, 8.4 Hz), 7.16 (1H, bt, J=7.4 Hz), 7.23 (2H, bt, J=7.4 Hz),
7.23 (1H, bs), 7.30 (1H, dt, J=2.8, 7.9 Hz), 7.38 (2H, d, J=7.4
Hz), 7.60 (1H, dt, J=6.2, 7.9 Hz), 7.66 (1H, bs), 8.04 (1H, bd,
J=9.0 Hz), 8.20 (1H, bd, J=9.0 Hz), 8.29 (1H, bd, J=10.5 Hz), 8.36
(1H, bd, J=7.9 Hz), 8.63 (1H, d, J=8.4 Hz).
[1114] MS (ESI) m/z 404 MH.sup.+
Example 447
[1115] 3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic
acid obtained by Example 403 and various kinds of amine were
condensed in the similar method as described in Example 44, to
afford the compounds of Examples 448-451.
Example 448
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid
cyclopropylamide
[1116] MS (ESI) m/z 329 MH.sup.+
Example 449
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid
(furan-2-ylmethyl)amide
[1117] MS (ESI) m/z 369 MH.sup.+
Example 450
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid
[(1S)-1-hydroxymethyl-2-methylpropyl]amide
[1118] MS (ESI) m/z 375 MH.sup.+
Example 451
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid
[(1S)-2-hydroxy-1-phenylethyl]amide
[1119] MS (ESI) m/z 409 MH.sup.+
Example 452
[1120]
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridine-5-carbo-
xylic acid obtained by Example 416 and various kinds of amine were
condensed in the similar method as described in Example 44, to
afford the compounds of Examples 453-463.
Example 453
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid cyclopropylamide
[1121] MS (ESI) m/z 323 MH.sup.+
Example 454
3-[(E)-2-(3-Fluorophenyl)-vinyl]]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1122] MS (ESI) m/z 363 MH.sup.+
Example 455
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (tetrahydrofuran-2-ylmethyl)-amide
[1123] MS (ESI) m/z 367 MH.sup.+
Example 456
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (2-acetylamino-ethyl)-amide
[1124] MS (ESI) m/z 368 MH.sup.+
Example 457
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (1-hydroxymethyl-2-methyl-propyl)-amide
[1125] MS (ESI) m/z 369 MH.sup.+
Example 458
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (2-hydroxy-1-phenyl-ethyl)-amide
[1126] MS (ESI) m/z 403 MH.sup.+
Example 459
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1127] MS (ESI) m/z 374 MH.sup.+
Example 460
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1128] MS (ESI) m/z 379 MH.sup.+
Example 461
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (1-carbamoyl-2-phenyl-ethyl)-amide
[1129] MS (ESI) m/z 430 MH.sup.+
Example 462
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (1-carbamoyl-2-hydroxy-ethyl)-amide
[1130] MS (ESI) m/z 370 MH.sup.+
Example 463
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]-pyridine-5-carboxylic
acid (1-carbamoyl-ethyl)-amide
[1131] MS (ESI) m/z 354 MH.sup.+
Example 464
[1132]
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]-pyridine-5-carb-
oxylic acid obtained by Example 433 and various kinds of amine were
condensed in the similar method as described in Example 44, to
afford the compounds of Examples 465-469.
Example 465
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]-pyridine-5-carboxylic
acid cyclopropylamide
[1133] MS (ESI) m/z 323 MH.sup.+
Example 466
3-[(E)-2-(3-Fluorophenyl)-vinyl]]-1H-pyrazolo[3,4-c]-pyridine-5-carboxylic
acid (furan-2-ylmethyl)amide
[1134] MS (ESI) m/z 363 MH.sup.+
Example 467
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]-pyridine-5-carboxylic
acid [(1S)-1-hydroxymethyl-2-methylpropyl]]amide
[1135] MS (ESI) m/z 369 MH.sup.+
Example 468
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]-pyridine-5-carboxylic
acid [(1S)-2-hydroxy-1-phenylethyl]amide
[1136] MS (ESI) m/z 403 MH.sup.+
Example 469
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]-pyridine-5-carboxylic
acid [(1S)-1-carbamoylethyl]amide
[1137] MS (ESI) m/z 354 MH.sup.+
Example 470
[1138] 3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic
acid obtained by Example 405 and various kinds of amine were
condensed in the similar method as described in Example 44, to
afford the compounds of Examples 471-477.
Example 471
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
cyclopropylamide
[1139] MS (ESI) m/z 329 MH.sup.+
Example 472
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(furan-2-ylmethyl)-amide
[1140] MS (ESI) m/z 369 MH.sup.+
Example 473
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(tetrahydrofuran-2-ylmethyl)-amide
[1141] MS (ESI) m/z 373 MH.sup.+
Example 474
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(2-acetylamino-ethyl)-amide
[1142] MS (ESI) m/z 374 MH.sup.+
Example 475
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(pyridin-3-ylmethyl)-amide
[1143] MS (ESI) m/z 380 MH.sup.+
Example 476
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(1-hydroxymethyl-2-methyl-propyl)-amide
[1144] MS (ESI) m/z 375 MH.sup.+
Example 477
3-(Naphthalen-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid
(thiophen-2-ylmethyl)-amide
[1145] MS (ESI) m/z 385 MH.sup.+
Example 478
Furan-2-carboxylic acid
[3-(naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]amide
[1146] 20 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
obtained by Production example 422 and furan-2-carboxylic acid
chloride were allowed to react in the similar method as described
in Production example 423, followed by deprotection in the similar
method as described in Example 16, to afford 10.3 mg of the title
compound as pale brown crystals.
[1147] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 6.69 (1H, dd,
J=1.9, 3.5 Hz), 7.39 (1H, dd, J=0.8, 3.5 Hz), 7.46-7.54 (2H, m),
7.81 (1H, dd, J=0.8, 1.9 Hz), 7.86-7.90 (1H, m), 7.95 (1H, d, J=8.5
Hz), 8.02-8.05 (1H, m), 8.05 (1H, d, J=9.5 Hz), 8.34 (1H, d, J=9.5
Hz), 8.47 (1H, dd, J=1.5, 8.5 Hz), 9.10 (1H, s).
Example 479
N-[3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]acetamide
[1148] From 20 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
and acetyl chloride, 9.4 mg of the title compound was obtained as
colorless crystals in the similar method as described in Example
478.
[1149] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.2.24 (3H, bs),
7.45-7.53 (2H, m), 7.85-7.89 (1H, m), 7.93 (1H, d, J=8.7 Hz),
7.96-8.00 (1H, m), 7.98 (1H, d, J=9.1 Hz), 8.27 (1H, bd, J=9.1 Hz),
8.48 (1H, dd, J=1.6, 8.7 Hz), 9.10 (1H, s).
Example 480
N-[3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-2-(thiophen-2-yl)ac-
etamide
[1150] From 20 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
and 2-thiopheneacetic acid chloride, 11.6 mg of the title compound
was obtained as colorless crystals in the similar method as
described in Example 478.
[1151] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.06 (2H, s), 6.99
(1H, dd, J=3.6, 5.1 Hz), 7.07 (1H, dd, J=1.2, 3.6 Hz), 7.31 (1H,
dd, J=1.2, 5.1 Hz), 7.46-7.54 (2H, m), 7.86-7.90 (1H, m), 7.94 (1H,
d, J=8.5 Hz), 7.97-8.03 (1H, m), 7.99 (1H, d, J=9.1 Hz), 8.28 (1H,
d, J=9.1 Hz), 8.49 (1H, dd, J=1.7, 8.5 Hz), 9.11 (1H, s).
Example 481
3-(Naphthalen-2-yl)-1H-pyrazolo[4,3-b]pyridin-5-ylamine
[1152] 15 mg of
3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
obtained by Production example 422 was deprotected in the similar
method as described in Example 16, to afford 7.1 mg of the title
compound as pale brown crystals.
[1153] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.6.79 (1H, d, J=9.1
Hz), 7.44-7.52 (2H, m), 7.74 (1H, d, J=9.1 Hz), 7.84-7.88 (1H, m),
7.93 (1H, d, J=8.7 Hz), 7.93-7.97 (1H, m), 8.32 (1H, d, J=8.7 Hz),
8.86 (1H, bs).
Production Example 482
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine
[1154] 1.95 g of 3-iodo-1-trityl-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 418 and 1.0 g of
2-[(E)-2-(3-fluorophenyl)-vinyl]-4,4,5,5-tetramethyl[1,3,2]dioxaborolane
obtained by Production example 137 were allowed to react in the
manner as described in Example 194, to afford 730 mg of the title
compound as a colorless powder.
[1155] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.62 (1H, dd,
J=1.0, 9.0 Hz), 6.92 (1H, dd, J=4.5, 9.0 Hz), 7.04 (2H, t, J=8.7
Hz), 7.21-7.32 (15H, m), 7.38 (1H, d, J=16.7 Hz), 7.57 (2H, dd,
J=5.2, 8.7 Hz), 8.15 (1H, d, J=16.7 Hz), 8.53 (1H, dd, J=1.0, 4.5
Hz).
Production Example 483
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxi-
de
[1156] 470 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 482 and 216 mg of m-chloroperbenzoic
acid were allowed to react in the manner as described in Production
example 4, to afford 210 mg of the title compound as a colorless
oil.
[1157] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.21 (1H, d, J=8.7
Hz), 6.76 (1H, dd, J=6.0, 8.7 Hz), 7.02 (2H, t, J=8.8 Hz),
7.16-7.23 (6H, m), 7.28-7.35 (9H, m), 7.46 (1H, d, J=16.5 Hz), 7.53
(2H, dd, J=5.6, 8.8 Hz), 8.03 (1H, d, J=16.5 Hz), 8.06 (1H, dd,
J=6.0 Hz).
Example 484
5-Chloro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridine
[1158] 210 mg of
3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-ox-
ide obtained by Production example 483 was dissolved in 5 mL of
toluene, added with 240 .mu.l of phosphorus oxychloride at room
temperature and stirred for 4 days. The reaction solution was added
with aqueous sodium hydrogen carbonate, extracted with ethyl
acetate and washed with water, and dried over magnesium sulfate.
The solvent was evaporated, and the residue was purified by silica
gel column chromatography (n-hexane:ethyl acetate=3:1), to afford
75 mg of the title compound as a colorless powder.
[1159] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.08 (2H, t, J=8.7
Hz), 7.36 (1H, d, J=8.9 Hz), 7.37 (1H, d, J=16.4 Hz), 7.62 (2H, dd,
J=6.0, 8.7 Hz), 7.80 (1H, d, J=8.9 Hz), 8.10 (1H, d, J=16.4
Hz).
Production Example 485
3-[(E)-2-(3-Fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylam-
ine
[1160] 60 mg of
5-chloro-3-[(2E)-2-(3-fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyri-
dine which is obtained by tritylating
5-chloro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridine
obtained by Example 484 in accordance with Production example 22
was treated with benzophenoneimine in the similar method as
described in Production example 422, to afford 40 mg of the title
compound as a pale yellow oil.
[1161] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.53 (2H, bs),
6.21 (1H, d, J=9.0 Hz), 6.40 (1H, d, J=9.0 Hz), 7.02 (2H, t, J=8.6
Hz), 7.19-7.25 (6H, m), 7.25-7.32 (10H, m), 7.53 (2H, dd, J=5.0,
8.6 Hz), 7.98 (1H, d, J=16.5 Hz).
Production Example 486
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
[1162] 1.1 g of
3-(3-fluorophenyl)-5-chloro-1-trityl-1H-pyrazolo[4,3-b]pyridine
obtained by Production example 37 was treated with
benzophenoneimine in the similar method as described in Production
example 422, to afford 690 mg of the title compound as pale yellow
crystals.
[1163] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.40-4.65 (2H,
bs), 6.22 (1H, d, J=9.0 Hz), 6.40 (1H, d, J=9.0 Hz), 7.18-7.25 (6H,
m), 7.26-7.32 (9H, m), 7.35 (1H, dt, J=6.2, 8.2 Hz), 8.15 (1H, bd,
J=11.2 Hz), 8.18 (1H, d, J=8.2 Hz).
Example 487
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-ylamine
[1164]
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was
treated with trifluoroacetic acid in the similar method as
described in Example 16 and so on, followed by purification by
LC-MS, to give the title compound.
[1165] MS (ESI) m/z 229 MH.sup.+
Example 488
[1166] Each 25 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine
obtained by Production example 486 was put into several test tubes,
added with 0.5 mL of tetrahydrofuran, further added with 0.07 mmol
of various kinds of acid chloride and 0.07 mmol of triethylamine,
and left at room temperature all day and night. The reaction
solution was added with 2 mL of water, extracted with 4 mL of ethyl
acetate, and the solvent was distilled of by blowing nitrogen
thereto. The resultant residue was added with 0.5 mL of 70%
trifluoroacetic acid solution in dichloromethane, sonicated at room
temperature for 15 minutes, and the solvent was distilled off by
blowing nitrogen thereto. The residue was dissolved in 0.25 mL of
N,N-dimethylformamide, and purified by LC-MS, to afford the
compounds of Examples 489-492.
Example 489
Cyclopropane carboxylic acid
[3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-amide
[1167] MS (ESI) m/z 297 MH.sup.+
Example 490
Furan-2-carboxylic acid
[3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-amide
[1168] MS (ESI) m/z 323 MH.sup.+
Example 491
N-[3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-acetamide
[1169] MS (ESI) m/z 271 MH.sup.+
Example 492
N-[3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine-5-yl]-2-(thiophen-2-yl)-a-
cetamide
[1170] MS (ESI) m/z 353 MH.sup.+
Example 493
[1171]
3-[(E)-2-(3-Fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[4,3-b]pyridin--
5-ylamine obtained by Production example 485 was reacted with
various kinds of acid chloride in the similar method as described
in Example 488, followed by deprotection and LC-MS purification, to
afford the compounds of Examples 494-497.
Example 494
Cyclopropane carboxylic acid
{3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridin-5-yl}-amide
[1172] MS (ESI) m/z 323 MH.sup.+
Example 495
Furan-2-carboxylic acid
{3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridin-5-yl}-amide
[1173] MS (ESI) m/z 349 MH.sup.+
Example 496
N-{3-[(E)-2-(4-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridin-5-yl}-acetam-
ide
[1174] MS (ESI) m/z 297 MH.sup.+
Example 497
N-{3-[(E)-2-(4-Fluorophenyl)-vinyl]-1H-pyrazolo[4,3-b]pyridin-5-yl}-2-(thi-
ophen-2-yl)-acetamide
[1175] MS (ESI) m/z 379 MH.sup.+
Production Example 498
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
[1176] 13.3 g of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-4-oxide
obtained by Production example 36 was cyanized in accordance with
Production example 5, to afford 11.9 g of the title compound as a
colorless powder.
[1177] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.6.90 (1H, d,
J=9.0 Hz), 7.20-7.25 (6H, m), 7.31 (1H, dt, J=2.8, 8.6 Hz),
7.34-7.43 (9H, m), 7.61 (1H, dt, J=6.0, 8.0 Hz), 7.77 (1H, d, J=9.0
Hz), 8.03 (1H, ddd, J=1.6, 2.8, 10.4 Hz), 8.16 (1H, d, J=8.0
Hz).
Production Example 499
Ethyl
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carboxyimid-
ate
[1178] Under nitrogen atmosphere, 100 mg of metal sodium was added
to 10 mL of dry methanol, and upon complete consumption of the
metal, 480 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carbonitrile
obtained by Production example 498 and 5 mL of dry tetrahydrofuran
were added and stirred at room temperature for 2 days. The product
was collected by filtration, and washed with diethyl ether, to
afford 440 mg of the title compound as a colorless powder.
[1179] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.89 (3H, s),
6.88 (1H, d, J=8.8 Hz), 7.18-7.23 (6H, m), 7.26 (1H, dt, J=3.0, 8.0
Hz), 7.32-7.40 (9H, m), 7.58 (1H, dt, J=5.5, 8.0 Hz), 7.63 (1H, d,
J=8.8 Hz), 8.08 (1H, bd, J=10.5 Hz), 8.29 (1H, bd, J=8.0 Hz), 9.27
(1H, s).
Production Example 500
3-(3-Fluorophenyl)-5-(5-methyl-1H-[1,2,4]triazol-3-yl)-1-trityl-1H-pyrazol-
o[4,3-b]pyridine
[1180] 100 mg of
ethyl[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carboxylmi-
date obtained by Production example 499 and 44 mg of acetohydrazide
were dissolved in 3 mL of pyridine, and heated at 130.degree. C.
for 2.5 days. The reaction solution was added with silica gel, the
solvent was evaporated, and the resultant residue was purified by
silica gel column chromatography (ethyl acetate:hexane=4:6), to
afford 60 mg of the title compound as a colorless powder.
[1181] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.50 (3H, s),
6.72 (1H, d, J=8.7 Hz), 7.02 (1H, dt, J=2.9, 8.1 Hz), 7.18-7.25
(6H, m), 7.27-7.32 (9H, m), 7.37 (1H, dt, J=5.8, 8.1 Hz), 7.80 (1H,
d, J=8.7 Hz), 8.13 (1H, bd, J=10.4 Hz), 8.23 (1H, bd, J=8.1
Hz).
Example 501
3-(3-Fluorophenyl)-5-(5-methyl-2H-[1,2,4]triazol-3-yl)-1H-pyrazolo[4,3-b]p-
yridine
[1182] 30 mg of
3-(3-fluorophenyl)-5-(5-methyl-1H-[1,2,4]triazol-3-yl)-1-trityl-1H-pyrazo-
lo[4,3-b]pyridine was deprotected in the similar method as
described in Production example 16, and the resultant residue was
purified by LC-MS, to afford 16 mg of the title compound as a
colorless powder.
[1183] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.46 (3H, s),
7.24 (1H, bt, J=8.4 Hz), 7.57 (1H, bdt, J=6.7, 8.4 Hz), 8.13 (1H,
d, J=8.7 Hz), 8.19 (1H, d, J=8.7 Hz), 8.40 (1H, bd, J=10.4 Hz),
8.51 (1H, bd, J=8.4 Hz), 13.70 (1H, bs), 13.80-14.00 (1H, bs).
[1184] MS (ESI) m/z 295 MH.sup.+
Production Example 502
{5-[3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl]-2H-[1,2,4]-
triazol-3-ylmethyl}methyl carbamic acid tert-butyl ester
[1185] 100 mg of
ethyl[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridine-5-carboxylmi-
date obtained by Production example 499 and 80 mg of
hydrazinocarbonylmethyl-methylcarbamic acid tert-butyl ester
produced by Production example 367 were dissolved in a mixed
solvent of 3 mL methanol-3 mL pyridine, and heated at 110.degree.
C. for 3 days. The reaction solution was added with silica gel, the
solvent was evaporated, and the residue was purified by silica gel
column chromatography (n-hexane:ethyl acetate=2:1), to afford 74 mg
of the title compound as a colorless oil.
[1186] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.50 (9H, s), 2.97
(3H, s), 4.60 (2H, bs), 6.73 (1H, bd, J=8.8 Hz), 7.06 (1H, dt,
J=7.6 Hz), 7.20-7.28 (6H, m), 7.28-7.35 (9H, m), 7.42 (1H, dt,
J=5.8, 7.6 Hz), 7.84 (1H, bd, J=8.8 Hz), 8.17 (1H, d, J=10.8 Hz),
8.22-8.32 (1H, m).
Example 503
{5-[3-(3-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-1H-[1,2,4]triazol-3-
-ylmethyl}-methylamine
[1187] 30 mg of
{5-[3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-yl]-2H-[1,2,4-
]triazol-3-ylmethyl}methylcarbamic acid tert-butyl ester was
deprotected in the similar method as described in Production
example 16, and the resultant residue was purified by LC-MS, to
obtain 15 mg of the title compound as a colorless powder.
[1188] MS (ESI) m/z 324 MH.sup.+
Production Example 504
(2-Chlorothiophen-3-yl)methanol
[1189] To a solution of 3.0 g thiophene-2-methanol in 26 mL of
dimethylformamide was added 3.5 g of N-chlorosuccinimide at room
temperature, and stirred at this temperature for a day. Adding 10
mL of 10% sodium thiosulfate, and the resultant solution was
diluted with ethyl acetate. The organic layer was washed
successively with saturated aqueous ammonium chloride and saturated
brine, dried over anhydrous magnesium sulfate, and the solvent was
evaporated, to afford 3.0 g of the title compound as a colorless
oil.
[1190] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.64 (2H, d, J=6.0
Hz), 7.01 (1H, d, J=6.0 Hz), 7.09 (1H, d, J=6.0 Hz).
Production Example 505
(5-Bromo-2-chlorothiophen-3-yl)methanol
[1191] To a solution of 3.0 g of (2-chlorothiophen-3-yl)methanol in
60 mL of dimethylformamide was added 3.59 g of N-bromosuccinimide
at room temperature, and stirred at this temperature for 2 hours.
Adding 10 mL of 10% sodium thiosulfate, and the resultant solution
was diluted with ethyl acetate. The organic layer was washed
successively with saturated aqueous ammonium chloride and saturated
brine, dried over anhydrous magnesium sulfate, and the solvent was
evaporated, to afford 3.7 g of the title compound as a colorless
oil.
[1192] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.58 (2H, d, J=6.0
Hz), 7.01 (1H, s).
Production Example 506
5-Chloro-4-hydroxymethylthiophene-2-carbonitrile
[1193] To a solution of 25.0 g
(5-bromo-2-chlorothiophen-3-yl)methanol in 330 mL of
dimethylformamide, 25.8 g of zinc cyanide (I) and 12.7 g
tetrakis(triphenylphosphine)palladium(0) were added at room
temperature, and stirred at 100.degree. C. for 4 hours. Diluting
with ethyl acetate, the organic layer was washed successively with
saturated aqueous ammonium chloride and saturated brine, dried over
anhydrous magnesium sulfate, and the solvent was evaporated. The
crude product was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:10-1:5), to afford 16.0 g
of the title compound as colorless crystals.
[1194] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 4.65 (2H, s), 7.57
(1H, s).
Production Example 507
5-Chloro-4-formylthiophene-2-carbonitrile
[1195] To a solution of 3.0 g of
5-chloro-4-hydroxymethylthiophene-2-carbonitrile in 34 mL of
dichloromethane was added 8.06 g of Dess-Martin reagent at room
temperature, and stirred at this temperature for a day. After
diluting with dichloromethane, washing successively with aqueous
sodium hydrogencarbonate and saturated brine, and drying over
anhydrous magnesium sulfate, the solvent was evaporated, to afford
4.5 g of a crude product of the title compound as colorless
crystals.
[1196] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (1H, s),
10.00 (1H, s).
Production Example 508
Acetic acid(2-chloro-5-cyanothiophen-3-ylmethylene)hydrazide
[1197] To a suspension of 4.5 g of
5-chloro-4-formylthiophene-2-carbonitrile in ethanol was added 2.56
g of acetylhydrazide at room temperature, and heated at reflux for
2 hours. After cooling to room temperature, the crystals were
collected by filtration, washed with ethanol, to afford 2.53 g of
the title compound (diastereomic mixture of E form:Z form=5:2) as
pale yellow crystals.
[1198] (E) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
2.18 (3H, s), 7.97 (1H, s), 8.22 (1H, s), 11.39 (1H, bs).
[1199] (Z) compound: .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.
1.95 (3H, s), 8.09 (1H, s), 8.20 (1H, s), 11.55 (1H, bs).
Production Example 509
1-Acetyl-1H-thieno[2,3-c]pyrazole-5-carbonitrile
[1200] To a solution of 2.53 g of acetic acid
(2-chloro-5-cyanothiophen-3-ylmethylene)hydrazide in 22 mL of
diphenyl ether were added copper powder and potassium acetate at
room temperature, and stirred at 200.degree. C. for 6 hours.
Following filtration through Celite, the filtrate was washed
successively with saturated aqueous ammonium chloride and saturated
brine, dried over anhydrous magnesium sulfate, and the solvent was
evaporated. The crude product was purified and separated by silica
gel column chromatography (ethyl acetate:n-hexane=1:10-1:5), to
afford 215 mg of the title compound as colorless crystals.
[1201] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.72 (3H, s),
8.17 (1H, s), 8.40 (1H, s).
Production Example 510
1H-Thieno[2,3-c]pyrazole-5-carbonitrile
[1202] To a suspension of 215 mg of
1-acetyl-1H-thieno[2,3-c]pyrazole-5-carbonitrile in 8 mL of
ethanol, 1 mL of 5N sodium hydroxide aqueous solution was added at
room temperature, and stirred at this temperature for 10 minutes.
Then the solution was neutralized with 5N hydrochloric acid,
extracted with ethyl acetate, and the organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was evaporated, to afford 168 mg of the title compound as
colorless crystals.
[1203] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 8.07 (1H, s),
8.34 (1H, s).
Production Example 511
3-Bromo-1H-thieno[2,3-c]pyrazole-5-carbonitrile
[1204] To a solution of 168 mg of 1H-thieno[2,3-c]pyrazole
5-carbonitrile in 5 mL of dimethylformamide was added 200 mg of
N-bromosuccinimide at room temperature and stirred at this
temperature for 2 hours. After adding 1 mL of 10% sodium
thiosulfate aqueous solution, the solution was diluted with ethyl
acetate. The organic layer was washed successively with saturated
aqueous ammonium chloride and saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. This afforded
3.7 g of the title compound as a colorless oil. The crude product
was purified and separated by silica gel column chromatography
(ethyl acetate:n-hexane=1:10), to afford 220 mg of the title
compound as colorless crystals.
[1205] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (1H, s).
Example 512
5-Iodo-3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole
[1206] To a solution of 70 mg of
3-naphthalene-2-yl-1H-thieno[2,3-c]pyrazole obtained by Example 78
in 3.0 mL of N,N-dimethylformamide was added 63 mg of
N-iodosuccinimide at room temperature, and stirred at 40.degree. C.
for a day. Then the solution was added with 1.0 mL of 10% sodium
thiosulfate aqueous solution, and extracted with ethyl acetate. The
organic layer was washed successively with saturated aqueous
ammonium chloride and saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The crude
product was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:3), to afford 75 mg of the
title compound as colorless crystals.
[1207] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.49-7.57 (2H,
m), 7.90-7.94 (1H, m), 7.98-8.07 (3H, m), 8.01 (1H, s), 8.43 (1H,
s).
Production Example 513
5-Iodo-3-(naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]-pyrazole
[1208] To a solution of 75 mg of
5-iodo-3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole in 1 mL of
N,N-dimethylformamide 1 was added 12 mg of sodium hydride at room
temperature, stirred for 15 minutes, then added with 56 mg of
trityl chloride, and stirred at this temperature for a day. The
solution was added with water and diluted with ethyl acetate, and
the organic layer was washed successively with saturated aqueous
ammonium chloride and saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The residue was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:30), to afford 93 mg of the title compound as
colorless crystals.
[1209] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.25-7.38 (15H,
m), 7.43-7.50 (2H, m), 7.57 (1H, s), 7.80-7.89 (3H, m), 8.03 (1H,
dd, J=8.4, 2.0 Hz), 8.25 (1H, d, J=0.8 Hz).
Example 514
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonitrile
[1210] To a solution of a crude product which was obtained by
treating 93 mg of
5-iodo-3-(naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]pyrazole
obtained by Production example 513 in the manner as described in
Production example 506 (purification by silica gel column is not
executed) in 2 mL of dichloromethane, 1 mL of trifluoroacetic acid
was added at room temperature and stirred at this temperature for
30 minutes. The reaction solution was poured into aqueous sodium
hydrogen carbonate, extracted with ethyl acetate, and the organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The crude
product was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:3), to afford 33 mg of the
title compound as colorless crystals.
[1211] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.53-7.61 (2H,
m), 7.94-7.97 (1H, m), 8.01-8.11 (2H, m), 8.05 (1H, s), 8.53 (1H,
d, J=0.8 Hz), 8.70 (1H, s).
Example 515
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid
[1212] To a solution of 33 mg of
3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carbonitrile in 1.0
mL of acetic acid and 0.3 mL of water was added 0.3 mL of
concentrated sulfuric acid at room temperature and stirred at
110.degree. C. for a day. After cooling the solution to room
temperature, 10 mL of ice water was added, and the precipitated
crystals were collected by filtration and washed with water, to
afford 33 mg of the title compound as pale brown crystals.
[1213] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.50-7.60 (2H,
m), 7.91-8.15 (4H, m), 8.34 (1H, s), 8.54 (1H, s).
Production Example 516
3-(Naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]pyrazole-5-carboxylic
acid
[1214] By treating 56 mg of
3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid in
the manner as described in Production example 513, 61 mg of the
title compound was obtained as pale brown crystals.
[1215] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.22-7.27 (6H,
m), 7.39-7.45 (9H, m), 7.50-7.57 (2H, m), 7.90-7.93 (1H, m), 7.96
(1H, d, J=9.2 Hz), 8.03 (1H, dd, J=9.2, 1.6 Hz), 8.14-8.18 (1H, m),
8.28 (1H, s), 8.53 (1H, s).
Production Example 517
3-(Naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]pyrazole-5-carbonitrile
[1216] By treating 310 mg of
5-iodo-3-(naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]-pyrazole
obtained by Production example 513 in the manner as described in
Production example 506, 167 mg of the title compound was obtained
as colorless crystals.
[1217] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.25-7.42 (15H,
m), 7.47-7.54 (2H, m), 7.83-7.92 (3H, m), 7.90 (1H, s), 8.02 (1H,
dd, J=8.4, 2.0 Hz), 8.28 (1H, d, J=0.8 Hz).
Production Example 518
c-[3-(Naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]pyrazol-5-yl]methylamine
[1218] Under nitrogen atmosphere, a suspension of 51.2 mg of
lithium aluminum hydride in 1.0 mL of tetrahydrofuran was added
with 180 mg of aluminum chloride at 0.degree. C., and stirred at
room temperature for 20 minutes. A solution of 167 mg of
3-(naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]pyrazole-5-carbonitrile
in 2.0 mL of tetrahydrofuran was added and stirred at this
temperature for 3 hours. Under ice cooling, 10 mL of Rochelle salt
aqueous solution was slowly added, followed by filtration through
Celite. The filtrate was diluted with ethyl acetate, washed with
saturated brine, dried over anhydrous magnesium sulfate, and then
the solvent was evaporated. The crude product was purified and
separated by NH silica gel column chromatography (ethyl
acetate:n-hexane=1:1), to afford 86 mg of the title compound as
colorless crystals.
[1219] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.91 (2H, s), 7.17
(1H, t, J=1.2 Hz), 7.27-7.35 (15H, m), 7.45 (2H, ttd, 6.8, 6.8, 1.6
Hz), 7.81 (1H, dd, J=8.4, 1.6 Hz), 7.84 (1H, d, J=8.4 Hz), 7.87
(1H, dd, J=8.4, 1.6 Hz), 8.07 (1H, dd, J=8.4, 1.6 Hz), 8.29 (1H, d,
J=1.2 Hz).
Example 519
[1220]
3-(Naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]-pyrazol-5-carboxylic
acid obtained by Production example 516 and various kinds of amine
were dehydration-condensed in accordance with Example 44,
deprotected in accordance with the deprotection condition of
Example 183 and purified by LC-MS, to afford the compounds of
Examples 520-523.
Example 520
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-carboxylic acid
cyclopropylamide
[1221] MS (ESI) m/z 334 MH.sup.+
Example 521
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-carboxylic acid
(furan-2-ylmethyl)amide
[1222] MS (ESI) m/z 374 MH.sup.+
Example 522
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-carboxylic acid
(2-hydroxy-1-phenylethyl)amide
[1223] MS (ESI) m/z 414 MH.sup.+
Example 523
3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-carboxylic acid
(1-carbamoylethyl)amide
[1224] MS (ESI) m/z 365 MH.sup.+
Example 524
[1225]
c-[3-(Naphthalen-2-yl)-1-trityl-1H-thieno[2,3-c]-pyrazol-5-yl]methy-
lamine obtained by Production example 518 and various kinds of
carboxylic acid were amidated in accordance with Example 183,
deprotected and purified by LC-MS, to afford the compounds of
Examples 525-532.
Example 525
N-[3-(Naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]acetamide
[1226] MS (ESI) m/z 322 MH.sup.+
Example 526
Cyclopropane carboxylic acid
[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]amide
[1227] MS (ESI) m/z 348 MH.sup.+
Example 527
Thiophene-2-carboxylic acid
[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]amide
[1228] MS (ESI) m/z 390 MH.sup.+
Example 528
Furan-2-carboxylic acid
[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]amide
[1229] MS (ESI) m/z 374 MH.sup.+
Example 529
(2S)-5-Oxopyrrolidine-2-carboxylic acid
[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]amide
[1230] MS (ESI) m/z 391 MH.sup.+
Example 530
2-Methoxy-N-[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]benzam-
ide
[1231] MS (ESI) m/z 414 MH.sup.+
Example 531
3-Methoxy-N-[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]benzam-
ide
[1232] MS (ESI) m/z 414 MH.sup.+
Example 532
Pyridine-2-carboxylic acid
[3-(naphthalen-2-yl)-1H-thieno[2,3-c]pyrazol-5-ylmethyl]amide
[1233] MS (ESI) m/z 385 MH.sup.+
Production Example 533
2,2-Dimethyl-N-(pyridin-4-yl)-propionamide
[1234] To a solution of 20.0 g of 4-aminopyridine in 100 mL of
dichloromethane, 32.6 mL of triethylamine was added at 0.degree.
C., followed by 27.5 mL of pivaloyl chloride, and stirred at this
temperature for 1 hour. The organic layer was washed successively
with water and saturated brine, dried over anhydrous magnesium
sulfate, and the solvent was evaporated, and the precipitated
crystals were collected by filtration, and washed with a mixed
solvent of diethyl ether and n-hexane. The filtrate was diluted
with ethanol, and treated with 5 N sodium hydroxide at room
temperature, thereby hydrolyzing coexisting dipivaloyl compounds
into monopivaloyl compounds. Following neutralization with 5N
hydrochloric acid, and extraction with ethyl acetate, the organic
layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated, the precipitated
crystals were collected by filtration, and washed with a mixed
solvent of diethyl ether and n-hexane. This was then combined with
the previously obtained crystals, to afford 25.1 g of the title
compound as colorless crystals.
[1235] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.32 (9H, s), 7.47
(1H, bs), 7.49 (2H, dd, J=4.8, 1.6 Hz), 8.48 (2H, dd, J=4.8, 1.6
Hz).
Production Example 534
2,2-Dimethyl-N-(3-methylpyridin-4-yl)propionamide
[1236] From 20.0 g of 2,2-dimethyl-N-(pyridin-4-yl)-propionamide,
19.9 g of the title compound was obtained as pale yellow oil in the
manner as described in the document (J. Org. Chem., 1983, 48,
3401.).
[1237] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.35 (9H, s), 7.40
(1H, bs), 8.17 (1H, d, J=5.6 Hz), 8.34 (1H, s), 8.39 (1H, d, J=5.6
Hz).
Production Example 535
N-(3-Methylpyridin-4-yl)acetamide
[1238] To 17.5 g of
2,2-dimethyl-N-(3-methylpyridin-4-yl)propionamide, 70 mL of 5N
hydrochloric acid aqueous solution was added and stirred at
90.degree. C. for a day. Under ice cooling, the solution was
neutralized with 5N sodium hydroxide aqueous solution, and the
solvent was evaporated. The crystals were washed with a mixed
solution of dichloromethane:methanol=10:1, and the solvent of
filtrate was evaporated. To a solution of the resultant crude
product in 100 mL of pyridine, 17.2 mL of acetic anhydride was
added at room temperature and stirred at this temperature for 6
hours. The solvent was evaporated, and the residue was purified and
separated by NH silica gel column chromatography (ethyl
acetate:n-hexane=1:1), to afford 12.1 g of the title compound as
colorless crystals.
[1239] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.25 (3H, s)/2.25
(3H, s), 7.10 (1H, bs), 8.12 (1H, d, J=5.6 Hz), 8.35 (1H, s), 8.39
(1H, d, J=5.6 Hz).
Production Example 536
1-Pyrazolo[4,3-c]pyridin-1-yl-ethanone
[1240] By treating 12.1 g of N-(3-methylpyridin-4-yl)acetamide in
the manner as described in Production example 408, 6.44 g of the
title compound was obtained as colorless crystals.
[1241] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.81 (3H, s), 8.25
(1H, d, J=0.8 Hz), 8.28 (1H, dt, J=6.0, 0.8 Hz), 8.66 (1H, d, J=6.0
Hz), 9.13 (1H, d, J=0.8 Hz).
Production Example 537
1H-Pyrazolo[4,3-c]pyridine
[1242] To a solution of 6.44 g of
1-pyrazolo[4,3-c]pyridin-1-yl-ethanone in 120 mL of ethanol, 10 mL
of 5N sodium hydroxide aqueous solution was added at room
temperature and stirred at this temperature for 30 minutes. After
neutralization with 5N hydrochloric acid, the solvent was
evaporated, the residue was washed with ethyl acetate, and the
solvent of filtrate was evaporated, to afford 3.88 g of the title
compound as pale yellow crystals.
[1243] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.43 (1H, dt,
J=6.0, 0.8 Hz), 8.24 (1H, d, J=0.8 Hz), 8.46 (1H, d, J=6.0 Hz),
9.17 (1H, d, J=0.8 Hz).
Production Example 538
3-Bromo-1H-pyrazolo[4,3-c]pyridine
[1244] To a solution of 3.85 g of 1H-pyrazolo[4,3-c]pyridine in 50
mL of N,N-dimethylformamide was added 6.04 g of N-bromosuccinimide
at room temperature and stirred at this temperature for 2 hours.
Adding 10 mL of 10% sodium thiosulfate aqueous solution, the
solution was diluted with ethyl acetate. The organic layer was
washed successively with saturated aqueous ammonium chloride and
saturated brine, dried over anhydrous magnesium sulfate, and the
solvent was evaporated, to afford 4.69 g of the title compound as
pale red-brown crystals.
[1245] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.58 (1H, d,
J=2.0 Hz), 8.42 (1H, d, J=2.0 Hz), 8.95 (1H, s), 13.81 (1H,
bs).
Production Example 539
3-Bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine
[1246] To a solution of 4.69 g of
3-bromo-1H-pyrazolo[4,3-c]pyridine in 72 mL of dimethylformamide
was added 1.42 g of sodium hydride at room temperature and stirred
for 15 minutes, and then added with 6.6 g of trityl chloride and
stirred at this temperature for a day. The solution was diluted
with dichloromethane, and the organic layer was washed successively
with saturated aqueous ammonium chloride and saturated brine, dried
over anhydrous magnesium sulfate, and the solvent was evaporated.
The precipitated crystals were washed with ethyl acetate, the
filtrate was evaporated, and the residue was purified and separated
by silica gel column chromatography (ethyl
acetate:n-hexane=1:10-1:3), an the resultant product was combined
with the above crystals, to afford 5.28 g of the title compound as
colorless crystals.
[1247] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.6.22 (1H, dd,
J=6.4, 1.2 Hz), 7.13-7.40 (15H, m), 8.15 (1H, d, J=6.4 Hz), 8.93
(1H, d, J=1.2 Hz).
Production Example 540
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine
[1248] A solution of 500 mg of
3-bromo-1-trityl-1H-pyrazolo[4,3-c]pyridine, 131 mg of
3-fluorophenylboronic acid,
tetrakis(triphenylphosphine)palladium(0) and 537 mg of barium
hydroxide octahydrate in a mixed solution of 18 mL of
dimethoxyethane and 3 mL of water was stirred at 80.degree. C. for
2 hours. The solution was diluted with ethyl acetate and water,
followed by filtration through Celite. The organic layer of
filtrate was washed with saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The crude
product was purified and separated by silica gel column
chromatography (ethyl
acetate:n-hexane=1:10-1:3-dichloromethane:n-hexane=1:2-1:1-dichloromethan-
e:methanol 100:1), to afford 399 mg of the title compound as
colorless crystals.
[1249] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.20 (1H, dt,
J=6.0, 0.8 Hz), 7.08 (1H, td, J=8.0, 0.8 Hz), 7.17-7.32 (15H, m),
7.43 (1H, td, J=8.0, 6.0 Hz), 7.61 (1H, ddd, J=10.0, 2.0, 1.6 Hz),
7.73 (1H, dt, J=8.0, 1.2 Hz), 8.05 (1H, d, 6.4 Hz), 9.35 (1H, d,
J=0.8 Hz).
Example 541
3-(3-Fluorophenyl)-1H-pyrazolo[4,3-c]pyridine
[1250] To a solution of 12 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine in 2 mL of
dichloromethane was added 1 mL of trifluoroacetic acid at room
temperature and stirred at this temperature for 10 minutes. The
reaction solution was poured into aqueous sodium hydrogen
carbonate, extracted with ethyl acetate, and the organic layer was
washed with saturated brine, dried over anhydrous magnesium
sulfate, and the solvent was evaporated. The crude product was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:10-1:3), to afford 4 mg of the title compound as
colorless crystals.
[1251] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.21 (1H, tdd,
J=8.0, 2.4, 0.8 Hz), 7.57 (1H, td, J=8.0, 6.0 Hz), 7.60 (1H, dd,
J=6.0, 1.2 Hz), 7.75 (1H, ddd, J=10.4, 2.8, 1.6 Hz), 7.86 (1H, dt,
J=8.0, 1.2 Hz), 8.37 (1H, d, 6.0 Hz), 9.33 (1H, d, J=0.8 Hz).
Production Example 542
3-(3-Fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-5-ol
[1252] By treating 380 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine obtained by
Production example 540 in the manner as described in Production
example 4, 341 mg of the title compound was obtained as colorless
crystals.
[1253] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.14 (1H, d, J=8.0
Hz), 7.09 (1H, td, J=8.0, 0.8 Hz), 7.16-7.34 (15H, m), 7.42 (1H,
td, J=8.0, 6.0 Hz), 7.48 (1H, dt, J=10.0, 1.6 Hz), 7.55 (1H, dd,
J=8.0, 0.8 Hz), 7.74 (1H, dd, 8.0, 1.6 Hz), 8.96 (1H, d, J=0.8
Hz).
Production Example 543
3-(3-Fluorophenyl)-1-trityl-1,5-dihydropyrazolo[4,3-c]-pyridin-4-one
[1254] A solution of 340 mg of
3-(3-fluorophenyl)-1-trityl-1H-pyrazolo[4,3-c]pyridine-5-ol in
acetic anhydride was stirred at 80.degree. C. for a day and at
100.degree. C. for 12 hours. Excess acetic anhydride was distilled
off under reduced pressure, and a solution of residue in 5 mL of
ethanol was added with 1 mL of 5N sodium hydroxide aqueous solution
at room temperature and stirred for 1 hour. The solution was
diluted with ethyl acetate, washed successively with saturated
aqueous sodium hydrogen carbonate and saturated brine, dried over
anhydrous magnesium sulfate, and the solvent was evaporated. The
resultant crude product was purified and separated by silica gel
column chromatography (ethyl acetate:n-hexane=1:3-1:0), to give 195
mg of the title compound as colorless crystals, as well as 45 mg of
3-(3-fluorophenyl)-1,5-dihydropyrazolo[4,3-c]pyridin-4-one
described in Example 544 described below in which detritylation
partially proceeded as colorless crystals.
[1255] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.23 (1H, d,
J=7.2 Hz), 6.92 (1H, dd, J=7.2, 6.0 Hz), 7.10-7.42 (17H, m), 8.01
(1H, dt, J=7.6, 1.2 Hz), 8.22 (1H, ddd, J=11.2, 2.4, 1.2 Hz), 11.19
(1H, d, J=6.0 Hz).
Example 544
3-(3-Fluorophenyl)-1,5-dihydropyrazolo[4,3-c]pyridin-4-one
[1256] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.45 (1H, d,
J=7.2 Hz)>7.17 (2H, m), 7.45 (1H, td, J=8.0, 2.4 Hz), 8.19 (1H,
d, J=8.0 Hz), 8.37 (1H, ddd, J=7.6, 2.4, 1.2 Hz), 11.04 (1H, d,
J=4.8 Hz).
Example 545
3-(3-Fluorophenyl)-5-(2-methoxyethyl)-1,5-dihydropyrazolo[4,3-c]pyridin-4--
one
[1257] To a solution of 10 mg of
3-(3-fluorophenyl)-1-trityl-1,5-dihydropyrazolo[4,3-c]pyridin-4-one
obtained by Production example 543 in 0.5 mL of dimethylformamide
was added 2 mg of sodium hydride at room temperature, stirred for 5
minutes, then added with 25 .mu.l 2-bromoethylmethylether (in 1.0 M
dimethylformamide), and stirred at this temperature for a day.
After adding aqueous ammonium chloride, the solution was extracted
with ethyl acetate, and the organic layer was concentrated. The
residue was dissolved in dichloromethane, added with 0.5 mL of
trifluoroacetic acid at room temperature and stirred for 10
minutes. Following concentration, separation and purification by
LC-MS were performed, to afford 0.89 mg of the title compound as
colorless crystals.
[1258] MS (ESI) m/z 288 MH.sup.+
Example 546
3-(3-Fluorophenyl)-4-oxo-1,4-dihydropyrazolo[4,3-c]pyridine-5-carboxylic
acid ethylamide
[1259] To a solution of 10 mg of
3-(3-fluorophenyl)-1-trityl-1,5-dihydropyrazolo[4,3-c]pyridin-4-one
obtained by Production example 543 in 0.5 mL of chloroform was
added 25 .mu.l of ethyl isocyanate (in 1.0 M chloroform) at room
temperature, and stirred at the same temperature for a day. At the
same temperature, 0.5 mL of trifluoroacetic acid was added and
stirred for 10 minutes. Following concentration, the residue was
separated and purified by LC-MS, to afford 1.57 mg of the title
compound as colorless crystals.
[1260] MS (ESI) m/z 301 MH.sup.+
Example 547
3-(3-Fluorophenyl)-4-oxo-1,4-dihydropyrazolo[4,3-c]pyridine-5-carboxylic
acid benzylamide
[1261] From 10 mg of
3-(3-fluorophenyl)-1-trityl-1,5-dihydropyrazolo[4,3-c]pyridin-4-one
obtained by Production example 543 and 25 .mu.l of benzyl
isocyanate (in 1.0 M chloroform), 1.16 mg of the title compound was
obtained as colorless crystals in accordance with Example 546.
[1262] MS (ESI) m/z 363 MH.sup.+
Production Example 548
5-Bromo-2-chloro-4-methylpyrimidine
[1263] 5 g of 5-bromo-2,4-dichloropyrimidine was dissolved in 70 mL
of tetrahydrofuran, and under stirring at room temperature, 15.8 g
of trimethyl aluminum in 15% n-hexane and 1.77 g of
tetrakis(triphenyl)phosphine were added, and stirred at 80.degree.
C., under nitrogen atmosphere for 7 hours. Under ice cooling, 70 mL
of water was added little by little, followed by 46 g of potassium
sodium tartrate tetrahydrate, and stirred at room temperature for 1
hour. Then the solution was extracted twice with ethyl acetate, and
the resultant organic layer was washed with saturated brine. After
drying over magnesium sulfate, the solvent was evaporated, and
purification and isolation by silica gel column chromatography
(ethyl acetate:n-hexane=1:8) were followed, to obtain 1.6 g of the
title compound as a pale yellow syrup.
[1264] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.63 (3H, s), 8.57
(1H, s)
Production Example 549
2-Chloro-4-methylpyridin-5-ylamine
[1265] 308 mg of 5-bromo-2-chloro-4-methylpyridine was dissolved in
6 mL of toluene, added with 680 mg cesium carbonate, 0.3 mL of
benzophenoneimine, 42 mg of
2,2'-bis(diphenylphosphino)-1,1'-binaphtyl and 46 mg of
tris(dibenzylideneacetone)bis palladium, and stirred under nitrogen
atmosphere at 110.degree. C. for 15 hours. The reaction solution
was allowed to cool to room temperature, then added with saturated
brine, extracted with ethyl acetate, dried over magnesium sulfate,
and then the solvent was evaporated. The residue was added with 10
mL of tetrahydrofuran and 10 mL of 5N hydrochloric acid, and
stirred at room temperature for 1 hour. The reaction solution was
added with aqueous sodium hydrogen carbonate, extracted with ethyl
acetate, and the organic layer was washed with saturated brine, and
dried over magnesium sulfate. The solvent was evaporated, and the
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:1), to afford 56 mg of the title compound.
[1266] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.40 (3H, s), 3.67
(2H, brs), 7.96 (1H, s)
Production Example 550
N-(2-Chloro-4-methylpyrimidin-5-yl)-acetamide
[1267] 1.36 g of 2-chloro-4-methylpyrimidin-5-ylamine was dissolved
in 20 mL of dichloromethane, and under stirring on ice, 1.53 mL of
pyridine, 2.7 mL of acetic anhydride and 1.16 g of
4-dimethylaminopyridine were added. After stirring at room
temperature for 1 hour, water was added, extracted with ethyl
acetate, and the resultant organic layer was washed with saturated
brine and dried over magnesium sulfate. After evaporating the
solvent, the residue was purified by silica gel column
chromatography (ethyl acetate:hexane=2:1), to afford 178 mg of the
title compound as a brown oil.
[1268] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.26 (3H, s), 2.50
(3H, s), 7.07 (1H, brs), 9.01 (1H, s)
Production Example 551
1-(5-Chloro-pyrazolo[4,3-d]pyrimidin-1-yl)-ethanone
[1269] From 110 mg of
N-(2-chloro-4-methylpyrimidin-5-yl)-acetamide, 27 mg of the title
compound was obtained in the manner as described in Production
example 408.
[1270] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.83 (3H, s), 8.33
(1H, s), 9.71 (1H, s)
Production Example 552
5-Chloro-1H-pyrazolo[4,3-d]pyrimidine
[1271] 27 mg of 1-(5-chloro-pyrazolo[4,3-d]pyrimidin-1-yl)-ethanone
was dissolved in 1.5 mL of acetonitrile, added with 1.5 mL of 5N
sodium hydroxide aqueous solution, and stirred for 2 hours. After
adding 2N hydrochloric acid to the reaction solution to render it
acidic, the solution was extracted with ethyl acetate, and the
resultant organic layer was washed with saturated brine, then dried
over magnesium sulfate, and the solvent was evaporated, to afford
16 mg of the title compound.
[1272] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 8.32 (1H, s), 9.14
(1H, s)
Production Example 553
5-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-d]pyrimidine
[1273] From 58 mg of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine, 160 mg
of the title compound was obtained in the manner as described in
Production example 206, followed by the manner as described in
Production example 22.
[1274] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.11-7.36 (16H,
m)
Production Example 554
5-Chloro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-d]pyrim-
idine
[1275] From 43 mg of
5-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-d]pyrimidine, 29 mg of the
title compound was obtained in accordance with Production example
181.
[1276] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (2H, t, J=8.8
Hz), 7.10-7.37 (17H, m), 7.52-7.58 (2H, m), 8.01 (1H, d, J=16.8
Hz)
Example 555
5-Chloro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-pyrazolo[4,3-d]pyrimidine
[1277] From 15 mg of
5-chloro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-pyrazolo[4,3-d]pyri-
midine obtained by Production example 554, 0.61 mg of the title
compound was obtained in accordance with Production example 16.
[1278] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.14 (2H, t, J=8.8
Hz), 7.39 (1H, d, J=16.8 Hz), 7.66 (2H, dd, J=8.8, 5.2 Hz), 8.04
(1H, d, J=16.8 Hz), 9.13 (1H, s)
Production Example 556
6-Fluoro-3-iodo-1H-indazole-5-carbonitrile
[1279] From 6.01 g of 6-fluoro-1H-indazole-5-carbonitrile obtained
by Production example 82, 11.6 g of the title compound was obtained
as pale brown crystal in accordance with the method of Production
example 206.
[1280] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (1H, d, J=8.8
Hz), 7.88 (1H, d, J=8.8 Hz), 10.8 (1H, brs)
Production Example 557
6-Fluoro-3-iodo-1-trityl-1H-indazole-5-carbonitrile
[1281] From 11.6 g of 6-fluoro-3-iodo-1H-indazole-5-carbonitrile
obtained by Production example 556, 14.9 g of the title compound
was obtained as pale brown crystal in accordance with the method of
Production example 22.
[1282] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.07 (1H, d,
J=10.4 Hz), 7.10-7.17 (6H, m), 7.25-7.33 (9H, m), 7.78 (1H, d,
J=6.0 Hz)
Example 558
6-Fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carbonitrile
[1283] By treating 4 g of
6-fluoro-3-iodo-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 557 in the similar method as described in
Example 100, 1.37 g of the title compound was obtained as pale
brown crystals.
[1284] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.24 (2H, t,
J=8.8 Hz), 7.49 (1H, d, J=16.8 Hz), 7.62 (1H, d, J=16.8 Hz), 7.63
(1H, d, J=9.6 Hz), 7.79 (2H, dd, J=8.8, 5.6 Hz), 8.95 (1H, d, J=6.0
Hz)
Example 559
6-Fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride
[1285] From 1.37 of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile
obtained by Example 558, 1.78 g of the title compound was obtained
as pale yellow crystals in accordance with Example 370.
[1286] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.49 (3H, t,
J=7.2 Hz) 4.66 (2H, q, J=7.2 Hz) 7.25 (2H, t, J=8.8 Hz), 7.54 (1H,
d, J=16.8 Hz), 7.62 (1H, d, J=9.6 Hz), 7.68 (1H, d, J=16.8 Hz),
7.77-7.84 (2H, m), 8.85 (1H, d, J=6.4 Hz)
Production Example 560
N-Formyl-N-methylhydrazine
[1287] 5 g of Methylhydrazine was dissolved in 50 mL of
tetrahydrofuran, and under stirring at room temperature, 8.8 mL of
ethyl formate was added and stirred for 14 hours. By evaporating
the solvent, 8.42 g of a crudely purified product of the title
compound as a pale yellow syrup.
[1288] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.91 (3H, s),
4.80 (2H, brs), 8.01 (1H, s)
Production Example 561
N-Acetyl-N-methylhydrazine
[1289] 5.2 g of methylhydrazine was dissolved in 50 mL of
tetrahydrofuran, and under stirring on ice, 10.6 mL of acetic
anhydride was added and stirred at room temperature for 7 hours. By
distilling off the solvent under reduced pressure, 17.8 g of a
crudely purified product of the title compound as a colorless
syrup.
[1290] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.01 (3H, s),
2.97 (3H, s), 4.71 (2H, brs)
Example 562
[1291] In accordance with the method described in Example 371 or
375, from
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 and
6-fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559, the
compounds of Examples 563-598 were produced. Hydrazines used in
Examples 563-591, 597, 598 were produced in accordance with
Production examples 366-367 unless they were commercially
available. In Examples 592 and 594, N-formyl-N-methylhydrazine
produced by Production example 560 was used, and in Example 593
N-acetyl-N-methylhydrazine produced by Production example 561 was
used.
Example 563
1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-ethanol
[1292] MS (ESI) m/z 368 MH.sup.+
Example 564
3-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-propan-1-ol
[1293] MS (ESI) m/z 382 MH.sup.+
Example 565
1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-ethanol
[1294] MS (ESI) m/z 368 MH.sup.+
Example 566
3-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-propan-1-ol
[1295] MS (ESI) m/z 382 MH.sup.+
Example 567
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(4H-[1,2,4]triazol-3-yl)-1H-in-
dazole
[1296] MS (ESI) m/z 324 MH.sup.+
Example 568
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(4H-[1,2,4]triazol-3-yl)-1H-in-
dazole
[1297] MS (ESI) m/z 324 MH.sup.+
Example 569
6-Fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-5-(5-methyl-4H-[1,2,4]triazol-3--
yl)-1H-indazole
[1298] MS (ESI) m/z 338 MH.sup.+
Example 570
(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-yl)-methanol
[1299] MS (ESI) m/z 354 MH.sup.+
Example 571
(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-methyl-amine
[1300] MS (ESI) m/z 367 MH.sup.+
Example 572
(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-dimethyl-amine
[1301] MS (ESI) m/z 381 MH.sup.+
Example 573
C-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-methylamine
[1302] MS (ESI) m/z 353 MH.sup.+
Example 574
(1S)-1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[-
1,2,4]triazol-3-yl)-2-methyl-propylamine
[1303] MS (ESI) m/z 395 MH.sup.+
Example 575
(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]t-
riazol-3-ylmethyl)-dimethyl-amine
[1304] MS (ESI) m/z 381 MH.sup.+
Example 576
C-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-methylamine
[1305] MS (ESI) m/z 353 MH.sup.+
Example 577
(1S)-1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[-
1,2,4]triazol-3-yl)-2-methyl-propylamine
[1306] MS (ESI) m/z 395 MH.sup.+
Example 578
2-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-propan-2-ol
[1307] MS (ESI) m/z 382 MH.sup.+
Example 579
2-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-propan-2-ol
[1308] MS (ESI) m/z 382 MH.sup.+
Example 580
1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-1-methyl-ethylamine
[1309] MS (ESI) m/z 382 MH.sup.+
Example 581
1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-4H-[1,2,-
4]triazole-3-yl)-1-methyl-ethylamine
[1310] MS (ESI) m/z 382 MH.sup.+
Example 582
[(1S)-1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H--
[1,2,4]triazol-3-yl)-2-methyl-propyl]-methyl-amine
[1311] MS (ESI) m/z 409 MH.sup.+
Example 583
1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-cyclopropylamine
[1312] MS (ESI) m/z 379 MH.sup.+
Example 584
1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-cyclopropylamine
[1313] MS (ESI) m/z 379 MH.sup.+
Example 585
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-[5-(thiophen-2-yl)methyl-4H-[1-
,2,4]triazol-3-yl]-1H-indazole
[1314] MS (ESI) m/z 379 MH.sup.+
Example 586
5-(5-Benzyl-4H-[1,2,4]triazol-3-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)-vin-
yl]-1H-indazole
[1315] MS (ESI) m/z 379 MH.sup.+
Example 587
(1S)-1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[-
1,2,4]triazol-3-yl)-2-phenyl-ethylamine
[1316] MS (ESI) m/z 443 MH.sup.+
Example 588
[2-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,-
4]triazol-3-yl)-ethyl]-dimethyl-ethylamine
[1317] MS (ESI) m/z 395 MH.sup.+
Example 589
[2-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,-
4]triazol-3-yl)-ethyl]-dimethyl-ethylamine
[1318] MS (ESI) m/z 395 MH.sup.+
Example 590
5-[5-(Azetidin-3-yl)-4H-[1,2,4]triazol-3-yl]-6-fluoro-3-[(E)-2-(4-fluoroph-
enyl)-vinyl]-1H-indazole
[1319] MS (ESI) m/z 379 MH.sup.+
Example 591
5-[5-(Azetidine-3-yl)-4H-[1,2,4]triazol-3-yl]-7-fluoro-3-[(E)-2-(4-fluorop-
henyl)-vinyl]-1H-indazole
[1320] MS (ESI) m/z 379 MH.sup.+
Example 592
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1-methyl-1H-[1,2,4]triazol-3--
yl)-1H-indazole
[1321] MS (ESI) m/z 338 MH.sup.+
Example 593
5-(1,5-Dimethyl-1H-[1,2,4]triazol-3-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)-
-vinyl]-1H-indazole
[1322] MS (ESI) m/z 352 MH.sup.+
Example 594
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1-methyl-1H-[1,2,4]triazol-3--
yl)-1H-indazole
[1323] MS (ESI) m/z 338 MH.sup.+
Example 595
2-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-acetamide
[1324] After reacting 15 mg of
6-fluoro-3-{(E)-2-(4-fluorophenyl)vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 and 18 mg of
hydrazinocarbonylacetic acid ethyl ester in accordance with Example
371, the reaction solution was stirred at 70.degree. C. for 10
hours in 5 mL of 2N ammonia-ethanol solution. After distilling off
the solvent, purification by LC-MS was conducted, to give 4.62 mg
of the title compound
[1325] MS (ESI) m/z 381 MH.sup.+
Example 596
2-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-acetamide
[1326] From 15 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383, 1.42 mg of
the title compound was obtained in accordance with Example 595.
[1327] MS (ESI) m/z 381 MH.sup.+
Example 597
[1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,4]o-
xadiazol-2-yl)-1-methyl-ethyl]-methyl-amine
[1328] 15 mg of
6-fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride produced by Example 559 and 19 mg of
(1-hydrazinocarbonyl-1-methyl-ethyl)-methyl-carbamic acid
tert-butyl ester were dissolved in 1 mL of pyridine, and stirred at
110.degree. C. for 12 hours. After allowing to cool to room
temperature, water was added and extracted twice with ethyl
acetate, and then the solvent was distilled off. The resultant
residue was added with 1 mL of 4N hydrochloric acid-ethyl acetate
solution, stirred at room temperature for 4 hours, then the solvent
distilled off, followed by purification by LC-MS, to give 0.36 mg
of the title compound.
[1329] MS (ESI) m/z 396 MH.sup.+
Example 598
(S)-1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,-
4]oxadiazol-2-yl)-2-methyl-propylamine
[1330] 15 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 and 19 mg of
((1S)-1-hydrazinocarbonyl-2-methyl-propyl)-carbamic acid tert-butyl
ester were dissolved in 1 mL of 1,4-dioxane, and stirred at
85.degree. C. for 12 hours. After distilling off the solvent, 1 mL
of 4N hydrochloric acid-ethyl acetate solution was added and
stirred at room temperature for 3 hours. After distilling off the
solvent, purification by LC-MS was conducted, to give 6.05 mg of
the title compound.
[1331] MS (ESI) m/z 396 MH.sup.+
Example 599
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine
hydrochloride
[1332] 400 mg of
6-fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride produced by Example 559 was
dissolved in 20 mL of 2N ammonia-ethanol solution, and stirred at
50.degree. C. for 6 hours. After allowing to cool to room
temperature, was added saturated brine, extracted with a mixed
solvent of ethyl acetate:tetrahydrofuran=1:1, dried over magnesium
sulfate, and evaporated. After adding 4N hydrochloric
acid-ethylacetate solution to the residue, the solvent was
evaporated, and the resultant solid was washed with diethyl ether,
followed by filtration, to afford 351 mg of the title compound as
pale yellow crystals.
[1333] MS (ESI) m/z 299 MH.sup.+
Example 600
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(pyrimidin-2-yl)-1H-indazole
[1334] 36 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine
hydrochloride obtained by Example 599 and 15 .mu.l of
3-dimethylaminopropenal were dissolved in 1 mL of pyridine, and
stirred at 120.degree. C. for 7 hours. After distilling off the
solvent, purification by LC-MS was conducted, to give 0.61 mg of
the title compound.
[1335] MS (ESI) m/z 335 MH.sup.+
Example 601
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(4-methyl-pyrimidin-2-yl)-1H-i-
ndazole
[1336] From 20 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine
hydrochloride obtained by Example 599 and 14 mg of
4-dimethylamino-3-buthene-2-on, 1.94 mg of the title compound was
obtained in accordance with Example 600.
[1337] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.66 (3H, s), 7.12
(2H, t, J=8.8 Hz), 7.36 (1H, d, J=10.8 Hz), 7.39 (1H, d, J=4.8 Hz),
7.42 (1H, d, J=16.4 Hz), 7.57 (1H, d, J=16.4 Hz), 7.67 (1H, dd,
J=8.8, 5.2 Hz), 8.62 (1H, d, J=6.8 Hz), 8.75 (1H, d, J=4.8 Hz)
Example 602
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(5-methyl-pyrimidin-2-yl)-1H-i-
ndazole
[1338] From 20 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxamidine
hydrochloride obtained by Example 599 and 14 mg of
(E)-3-dimethylamino-2-buthenal, 8.43 mg of the title compound was
obtained in accordance with Example 600.
[1339] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.43 (3H, s), 7.12
(2H, t, J=8.8 Hz), 7.35 (1H, d, J=11.2 Hz), 7.40 (1H, d, J=16.8
Hz), 7.56 (1H, d, J=16.8 Hz), 7.67 (1H, dd, J=8.8, 5.2 Hz), 8.64
(1H, d, J=6.8 Hz), 8.78 (2H, s)
Example 603
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1H-imidazol-2-yl)-1H-indazole
[1340] After suspending 108 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 in 2 mL of
ethanol, 206 .mu.l of triethylamine and 50 .mu.l of
aminoacetoaldehyde ethylacetal were added, and stirred at
70.degree. C. for 5 hours. After cooling to room temperature, water
was added, extracted with ethyl acetate, and the resultant layer
was washed with saturated brine and dried over anhydrous sodium
sulfate. After evaporating the solvent, the resultant crude product
was dissolved in 5 mL of tetrahydrofuran, added with 5 mL of 5N
hydrochloric acid and stirred at room temperature overnight. After
neutralization by adding saturated sodium hydrogen carbonate, the
reaction mixture was extracted with ethyl acetate, and washed with
water and saturated brine. The organic layer was dried over
magnesium sulfate, and the solvent was evaporated. The resultant
crude product was purified by preparative TLC, to obtain 36.5 mg of
the title compound as yellow crystals.
[1341] MS (ESI) m/z 323 MH.sup.+
Production Example 604
5-(1-Dimethylsulfamoyl-1H-imidazol-2-yl)-7-fluoro-3-[(E)-2-(4-fluorophenyl-
)-vinyl]-indazole-1-sulfonic acid dimethylamide
[1342] 36.5 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1H-imidazol-2-yl)-1H-indazol-
e obtained by Example 603 was dissolved in N,N-dimethylformamide,
and added with 14 mg of sodium hydride (containing 60%) under ice
cooling and stirred for 10 minutes. Adding dropwise with 30.3 .mu.l
of N,N-dimethylsulfamoyl chloride, the solution was warmed to room
temperature and stirred overnight. After stopping the reaction by
adding water, the solution was extracted with ethyl acetate, and
the organic layer was washed with water and saturated brine. After
drying the organic layer over magnesium sulfate, the solvent was
evaporated. The crude product was purified by preparative TLC, to
afford 14.2 mg of the title compound.
[1343] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.60 (6H, s), 3.17
(6H, s), 7.09 (2H, t, J=8.4 Hz), 7.17 (1H, d, J=1.6 Hz), 7.24 (1H,
d, J=16.8 Hz), 7.51 (1H, d, J=1.6 Hz), 7.53-7.59 (2H, m), 7.60 (1H,
d, J=16.8 Hz), 7.68 (1H, dd, J=11.6, 1.2 Hz), 8.26 (1H, d, J=1.6
Hz)
Example 605
(2-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3H-imidazol-
-4-yl)-methanol
[1344] 14.2 mg of
5-(1-dimethylsulfamoyl-1H-imidazol-2-yl)-7-fluoro-3-[(E)-2-(4-fluoropheny-
l)-vinyl]-indazole-1-sulfonic acid dimethylamide obtained by
Production example 604 was dissolved in 1 mL of tetrahydrofuran,
added at -78.degree. C. with 20.1 .mu.l of 1.58 M n-butyllithium in
hexane, stirred at this temperature for 10 minutes, then added with
5 .mu.l of benzylchloromethylether, warmed to room temperature, and
stirred for 20 minutes. After stopping the reaction by adding
water, the solution extracted with ethyl acetate, and the organic
layer was washed with water and saturated brine and then dried over
anhydrous magnesium sulfate. After evaporating the solvent, the
resultant crude product was dissolved in 2 mL of aqueous hydrogen
bromide, and stirred at 60.degree. C. overnight. After cooling to
room temperature, the reaction solution was neutralized with
saturated aqueous sodium hydrogen carbonate and extracted with
ethyl acetate. The organic layer was washed with water and
saturated brine, and then dried over anhydrous magnesium sulfate.
After evaporating the solvent, purification by LC-MS was conducted,
to obtain 0.58 mg of the title compound.
[1345] MS (ESI) m/z 353 MH.sup.+
Example 606
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1H-imidazol-2-yl)-1H-indazole
[1346] By treating 108 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 in the
similar method as described in Example 603, 34.4 mg of the title
compound was obtained as white crystals.
[1347] MS (ESI) m/z 323 MH.sup.+
Production Example 607
5-(1-Dimethylsulfamoyl-1H-imidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl-
)-vinyl]-indazole-1-sulfonic acid dimethylamide
[1348] 34.4 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(1H-imidazol-2-yl)-1H-indazol-
e obtained by Example 606 was treated in the similar method as
described in Production example 604, to afford 29.5 mg of the title
compound.
[1349] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.71 (6H, s), 3.03
(6H, s), 7.06-7.12 (2H, m), 7.24 (1H, d, J=2.0 Hz), 7.50 (1H, d,
J=1.2 Hz), 7.53-7.63 (3H, m), 7.69 (1H, d, J=16.4 Hz)
Example 608
(2-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3H-imidazol-
-4-yl)-methanol
[1350] 29.5 mg of
5-(1-dimethylsulfamoyl-1H-imidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluoropheny-
l)-vinyl]-indazole-1-sulfonic acid dimethylamide obtained by
Production example 607 was treated in the similar method as
described in Example 605, to afford 0.54 mg of the title
compound.
[1351] MS (ESI) m/z 353 MH.sup.+
Example 609
5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]tr-
iazol-3-ol
[1352] 20 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 was
dissolved in 3 mL of pyridine, added with 6.1 mg of semicarbazide
hydrochloride and refluxed for 8 hours. After cooling to room
temperature, the solvent was distilled off under reduced pressure,
followed by purification by LC-MS, to afford 1.66 mg of the title
compound.
[1353] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.15 (2H, t, J=8.8
Hz), 7.41 (1H, d, J=16.8 Hz), 7.62 (1H, d, J=16.8 Hz), 7.66 (1H, d,
J=12.4 Hz), 7.70 (1H, dd, J=6.0, 8.8 Hz), 8.32 (1H, s)
[1354] MS (ESI) m/z 340 MH.sup.+
Example 610
5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]tr-
iazol-3-ylamine
[1355] 20 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 was
dissolved in 3 mL of pyridine, added with 6.1 mg of aminoguanidine
hydrochloride, and refluxed for 8 hours. After cooling to room
temperature, the solvent was evaporated, followed by purification
by LC-MS, to afford 0.72 mg of the title compound.
[1356] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.15 (2H, t, J=8.8
Hz), 7.43 (1H, d, J=16.8 Hz), 7.61 (1H, d, J=16.4 Hz), 7.67-7.73
(3H, m), 8.44 (1H, d, J=1.2 Hz)
[1357] MS (ESI) m/z 339 MH.sup.+
Example 611
4-Amino-5-{7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2,4--
dihydro-[1,2,4]triazol-3-one
[1358] 20 mg of
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 was
dissolved in 5 mL of ethanol, added with 5.5 mg of carbohydrazide
and refluxed overnight. The solvent was evaporated, followed by
purification by LC-MS, to afford 1.47 mg of the title compound.
[1359] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.49 (2H, s),
7.24 (2H, t, J=8.8 Hz), 7.53 (2H, s), 7.72-7.80 (3H, m), 8.68 (1H,
s), 11.9 (1H, s)
[1360] MS (ESI) m/z 355 MH.sup.+
Example 612
5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]tr-
iazol-3-ylamine
[1361] 20 mg
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 was treated
in accordance with Example 610, to afford 0.64 mg of the title
compound.
[1362] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 7.14 (2H, t, J=8.8
Hz), 7.41 (1H, d, J=17.2 Hz), 7.44 (1H, d, J=10.8 Hz), 7.58 (1H, d,
J=16.8), 7.69 (1H, dd, J=5.4, 8.4 Hz), 8.62 (1H, d, J=6.4 Hz)
[1363] MS (ESI) m/z 339 MH.sup.+
Example 613
5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4]tr-
iazol-3-ol
[1364] 20 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 was treated
in accordance with Example 609, followed by purification by
preparative TLC, to afford 1.55 mg of the title compound as white
crystals.
[1365] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.24 (2H, t,
J=8.8 Hz), 7.47-7.54 (3H, m), 7.76-7.80 (2H, m), 8.48 (1H, d, J=6.4
Hz)
[1366] MS (ESI) m/z 340 MH.sup.+
Example 614
4-Amino-5-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2,4--
dihydro-[1,2,4]triazol-3-one
[1367] 20 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 was treated
in the similar method as described in Example 611, followed by
purification by preparative TLC, to afford 2.19 mg of the title
compound as white crystals.
[1368] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.27 (2H, s),
7.24 (2H, t, J=8.7 Hz), 7.47 (1H, d, J=10.8 Hz), 7.52 (2H, s),
7.77-7.80 (2H, m), 8.43 (1H, d, J=6.0 Hz)
[1369] MS (ESI) m/z 355 MH.sup.+
Example 615
5-(1H-Benzimidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indaz-
ole
[1370] To a solution of 10 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxydimic
acid ethyl ester hydrochloride obtained by Example 559 in 0.5 mL of
acetic acid was added 85 .mu.l of phenylene diamine (in 1 molar
acetic acid) at room temperature and stirred at 120.degree. C. for
a day. Following addition of water and extraction with ethyl
acetate, the organic layer was concentrated. The residue was
separated and purified by LC-MS, to afford 10.08 mg of the title
compound as colorless crystals.
[1371] MS (ESI) m/z 373 MH.sup.+
Example 616
[1372] The compounds of Examples 617-623 were synthesized from
6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazole-5-carboxydimic
acid ethyl ester hydrochloride and commercially available
substituted phenylene diamine in accordance with the method of
Example 615.
Example 617
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(7-methyl-1H-benzimidazol-2-yl-
)-1H-indazole
[1373] MS (ESI) m/z 387 MH.sup.+
Example 618
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(6-methyl-1H-benzimidazol-2-yl-
)-1H-indazole
[1374] MS (ESI) m/z 387 MH.sup.+
Example 619
5-(6-Chloro-1H-benzimidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl-
]-1H-indazole
[1375] MS (ESI) m/z 407 M.sup.+
Example 620
6-Fluoro-5-(6-fluoro-1H-benzimidazol-2-yl)-3-[(E)-2-(4-fluorophenyl)-vinyl-
]-1H-indazole
[1376] MS (ESI) m/z 391 MH.sup.+
Example 621
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-(6-nitro-1H-benzimidazol-2-yl)-
-1H-indazole
[1377] MS (ESI) m/z 418 MH.sup.+
Example 622
5-(5,6-Dichloro-1H-benzimidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)-v-
inyl]-1H-indazole
[1378] MS (ESI) m/z 441 M.sup.+
Example 623
5-(5-Chloro-6-fluoro-1H-benzimidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophen-
yl)-vinyl]-1H-indazole
[1379] MS (ESI) m/z 425 M.sup.+
Production Example 624
5-Bromo-1H-indazole-3-carboxylic acid
[1380] A mixture of 15 g of 5-bromoisatine, 34 mL of water and 2.79
g of sodium hydroxide was stirred at 50.degree. C. for 5 minutes,
and then under stirring on ice, added with a solution containing
4.58 g of sodium sulfite in 16 mL of water. The reaction mixture
was added dropwise under cooling on ice to a mixed solution of 6.72
mL concentrated sulfuric acid/133 mL water in such a speed that did
not cause the temperature of the reaction solution to exceed
4.degree. C. After stirring for 15 minutes under ice cooling, a
solution containing 30.2 g of tin chloride (II) in 56 mL of
concentrated hydrochloric acid was added dropwise in such a speed
that did not cause the temperature of the reaction solution to
exceed 4.degree. C., followed by 1-hour stirring on ice. Then the
reaction mixture was added with water and extracted with a mixed
solvent of ethyl acetate:tetrahydrofuran=1:1, and the resultant
organic layer was washed with saturated brine, and dried over
magnesium sulfate. The solvent was evaporated, and the generated
crystals were washed with diethyl ether and filtered, to obtain
4.64 g of the title compound as pale yellow crystals.
[1381] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.54 (1H, dd,
J=8.8, 2.0 Hz), 7.63 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=2.0 Hz)
Production Example 625
5-Bromo-1H-indazole-3-carboxylic acid ethyl ester
[1382] 3 g of 5-bromo-1H-indazole-3-carboxylic acid was dissolved
in 60 mL of ethanol, added with 0.6 mL of concentrated sulfuric
acid, and heated under reflux for 8 hours. After allowing to cool
to room temperature, addition of water and extraction with ethyl
acetate were conducted, and the resultant organic layer was washed
with saturated aqueous sodium hydrogen carbonate and saturated
brine, dried over magnesium sulfate, and the solvent was
evaporated, to afford 2.7 g of the title compound as yellow
crystals.
[1383] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.50 (3H, t, J=7.2
Hz), 4.54 (2H, q, J=7.2 Hz), 7.54 (2H, d, J=1.2 Hz), 8.37 (1H, t,
J=1.2 Hz)
Production Example 626
5-Bromo-1-trityl-1H-indazole-3-carboxylic acid
[1384] 2.19 g of 5-bromo-1H-indazole-3-carboxylic acid ethyl ester
was dissolved in 40 mL of dimethylformamide, added with 391 mg of
60% sodium hydride (oil-based) and 2.38 g of trityl chloride, and
stirred at room temperature for 1 hour. After adding a saturated
aqueous ammonium chloride, the reaction solution was extracted with
ethyl acetate, and the resultant organic layer was washed with
saturated brine, dried over magnesium sulfate, and the solvent was
evaporated. The resultant residue was dissolved in a solution of 20
mL of ethanol, 20 mL of tetrahydrofuran and 15 mL of 5N sodium
hydroxide aqueous, and stirred at 60.degree. C. for 2 hours. After
allowing to cool to room temperature, the reaction solution was
neutralized by adding 1N hydrochloric acid, extracted with a mixed
solvent of ethyl acetate:tetrahydrofuran=1:1, and the resultant
organic layer was washed with saturated brine and dried over
magnesium sulfate. After evaporated the solvent, the generated
crystals were washed with diethyl ether and filtered to afford 3.3
g of the title compound as pale yellow crystals.
[1385] MS (ESI) m/z 481, 483 (M-H).sup.-
Production Example 627
5-Bromo-1-trityl-1H-indazole-3-carboxylic acid phenylamide
[1386] From 1 g of 5-bromo-1-trityl-1H-indazole-3-carboxylic acid
and 0.23 mL of aniline, 755 mg of the title compound was obtained
as pale yellow crystal in accordance with Example 127.
[1387] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.28 (1H, d, J=8.8
Hz), 6.65-6.70 (1H, m), 6.75 (1H, t, J=6.8 Hz), 7.06-7.39 (17H, m),
7.56 (2H, d, J=8.8 Hz), 8.55 (1H, brs), 8.62 (1 h, d, J=2.0 Hz)
Production Example 628
5-Amino-1-trityl-1H-indazole-3-carboxylic acid phenylamide
[1388] From 318 mg of 5-bromo-1-trityl-1H-indazole-3-carboxylic
acid phenylamide, 258 mg of the title compound was obtained in
accordance with Production example 422.
[1389] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.20 (1H, d, J=8.8
Hz), 6.47 (1H, dd, J=8.8, 2.4 Hz), 7.02-7.82 (21H, m), 8.59 (1H,
brs)
Production Example 629
3-Phenylcarbamoyl-1-trityl-1H-indazole-5-carboxylic acid
[1390] 470 mg of 5-bromo-1-trityl-1H-indazole-3-carboxylic acid
phenylamide obtained by Production example 627 was dissolved in 8.4
mL of tetrahydrofuran, and added with 1.58 mL of 1.6 M
n-butyllithium hexane solution under stirring at -70.degree.. After
stirring at -70.degree. C. for 15 minutes, dry ice-ethanol bath was
removed, and carbon dioxide was blown into the reaction for 25
minutes. After adding a saturated aqueous ammonium chloride, the
reaction solution was extracted with ethyl acetate, and the
resultant organic layer was washed with saturated brine and dried
over magnesium sulfate. The solvent was evaporated, and the
generated crystals were washed with a mixed solvent of
hexane:diethyl ether=2:1 and filtered, to afford 230 mg of the
title compound as pale yellow crystals.
[1391] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.46 (1H, d, J=9.2
Hz), 6.98-7.45 (18H, m), 7.54-7.64 (2H, m), 7.73 (1H, dd, J=8.8,
1.6 Hz), 8.58 (1H, s), 9.25 (1H, s)
Example 630
[1392] 5-Amino-1-trityl-1H-indazole-3-carboxylic acid phenylamide
produced by Production example 628 and various kinds of carboxylic
acid were treated in the similar method as described in Example
183, to afford the compounds of Examples 631-635.
Example 631
5-Acetylamino-1H-indazole-3-carboxylic acid phenylamide
[1393] MS (ESI) m/z 295 MH.sup.+
Example 632
5-Cyclopropane carbonylamino-1H-indazole-3-carboxylic acid
phenylamide
[1394] MS (ESI) m/z 321 MH.sup.+
Example 633
5-[((2S)-5-Oxopyrrolidine-2-carbonyl)-amino]-1H-indazole-3-carboxylic
acid phenylamide
[1395] MS (ESI) m/z 364 MH.sup.+
Example 634
5-[(Furan-2-carbonyl)-amino]-1H-indazole-3-carboxylic acid
phenylamide
[1396] MS (ESI) m/z 347 MH.sup.+
Example 635
5-[2-(Thiophen-2-yl)-acetylamino]-1H-indazole-3-carboxylic acid
phenylamide
[1397] MS (ESI) m/z 377 MH.sup.+
Example 636
5-Methanesulfonylamino-1H-indazole-3-carboxylic acid
phenylamide
[1398] 10 mg of 5-amino-1-trityl-1H-indazole-3-carboxylic acid
phenylamide obtained by Production example 628 was dissolved in
dichloromethane, added with 6 .mu.l triethylamine and 4 mg of
methanesulfonyl chloride, and stirred at room temperature for 3
hours. Following addition of water and extraction with ethyl
acetate, the residue obtained by evaporating the solvent was added
with 0.5 mL of dichloromethane and 0.5 mL of trifluoroacetic acid,
and stirred at room temperature for 1 hour. After evaporating the
solvent, purification by LC-MS was conducted, to afford 0.22 mg of
the title compound.
[1399] MS (ESI) m/z 331 MH.sup.+
Example 637
[1400] 3-Phenylcarbamoyl-1-trityl-1H-indazole-5-carboxylic acid
produced by Production example 629 and various kinds of amine were
amidated in the similar method as described in Example 44, followed
by deprotection in accordance with the deprotection condition of
Example 183, and purification by LC-MS, to afford the compounds of
Examples 638-640.
Example 638
3-Phenylcarbamoyl-1H-indazole-5-carboxylic acid
[(1S)-1-hydroxymethyl-2-methylpropyl]-amide
[1401] MS (ESI) m/z 367 MH.sup.+
Example 639
3-Phenylcarbamoyl-1H-indazole-5-carboxylic acid
[(1S)-2-hydroxy-1-phenylethyl]-amide
[1402] MS (ESI) m/z 401 MH.sup.+
Example 640
3-Phenylcarbamoyl-1H-indazole-5-carboxylic acid
[(1S)-1-carbamoylethyl]-amide
[1403] MS (ESI) m/z 352 MH.sup.+
Example 641
3-Phenylcarbamoyl-1H-indazole-5-carboxylic acid
[1404] 10 mg of 3-phenylcarbamoyl-1-trityl-1H-indazole-5-carboxylic
acid produced by Production example 629 was dissolved in 0.5 mL of
dichloromethane and 0.5 mL of trifluoroacetic acid, and stirred at
room temperature for 3 hours, followed by purification by LC-MS, to
afford 0.72 mg of the title compound.
[1405] MS (ESI) m/z 282 MH.sup.+
Production Example 642
6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
[1406] From 2.0 g 3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole
obtained by Production example 180 and 1.46 g of 2-fluorostyrene,
1.15 g of the title compound was obtained as bright yellow crystals
in accordance with the method of Example 181.
[1407] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.13 (1H, d,
J=12.8 Hz), 7.17-7.45 (18H, m), 7.54 (1H, d, J=16.8 Hz), 7.81 (1H,
d, J=16.8 Hz), 8.01 (1H, t, J=7.6 Hz), 9.15 (1H, d, J=7.2 Hz)
Production Example 643
6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[1408] From 1.14 g of
6-fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
obtained by Production example 642, 1.07 g of the title compound
was obtained as bright yellow crystals in accordance with the
method of Example 182.
[1409] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.09 (2H, br s),
5.92 (1H, d, J=12.4 Hz), 7.16-7.38 (20H, m), 7.41 (1H, d, J=16.8
Hz), 7.87 (1H, t, J=7.6 Hz)
Production Example 644
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
[1410] In accordance with the method of Example 181, from 1.5 g of
3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole obtained by
Production example 180 and 730 mg of 3-fluorostyrene, 872 mg of the
title compound was obtained as bright yellow crystals.
[1411] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.12 (1H, d,
J=12.8 Hz), 7.15 (1H, dt, J=2.0, 8.8 Hz), 7.20-7.45 (16H, m), 7.48
(1H, d, J=16.4 Hz), 7.54 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=10.8
Hz), 7.77 (1H, d, J=16.4 Hz), 9.19 (1H, d, J=7.2 Hz)
Production Example 645
6-Fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[1412] In accordance with the method of Example 182, from 870 mg of
6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
obtained by Production example 644, 707 mg of the title compound
was obtained as bright yellow crystals. The instrumental data
coincided with that of Production example 174.
Production Example 646
6-Fluoro-5-nitro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole
[1413] In accordance with the method of Example 181, from 1.0 g of
3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole obtained by
Production example 180 and 314 mg of 3-vinylpyridine, 588 mg of the
title compound was obtained as bright yellow crystals.
[1414] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.14 (1H, d,
J=12.8 Hz), 7.10-7.45 (16H, m), 7.50 (1H, d, J=16.8 Hz), 7.81 (1H,
d, J=16.8 Hz), 8.01 (1H, d, J=8.0 Hz), 8.50 (1H, dd, J=2.0, 4.8
Hz), 8.90 (1H, d, J=2.0 Hz), 9.19 (1H, d, J=7.2 Hz)
Production Example 647
6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[1415] In accordance with the method of Example 182, from 587 mg of
6-fluoro-5-nitro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole
obtained by Production example 646, 465 mg of the title compound
was obtained as bright yellow crystals.
[1416] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.99 (2H, br s),
5.90 (1H, d, J=12.4 Hz), 7.13-7.45 (18H, m), 7.46 (1H, d, J=16.8
Hz), 8.11 (1H, d, J=7.6 Hz), 8.43 (1H, d, J=2.0, 4.4 Hz), 8.75 (1H,
d, J=2.0 Hz)
Production Example 648
6-Fluoro-5-nitro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1
h-indazole
[1417] In accordance with the method of Example 181, from 2.0 g of
3-bromo-6-fluoro-5-nitro-1-trityl-1H-indazole obtained by
Production example 180 and 1.10 g of 2-vinylthiophene, 684 mg of
the title compound was obtained as yellow crystals.
[1418] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.14 (1H, d,
J=12.4 Hz), 7.11 (1H, dd, J=3.6, 4.8 Hz), 7.17-7.45 (17H, m), 7.57
(1H, d, J=4.8 Hz), 7.67 (1H, d, J=16.4 Hz), 9.15 (1H, d, J=7.2
Hz)
Production Example 649
6-Fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazol-5-ylamine
[1419] In accordance with the method of Example 182, from 647 mg of
6-fluoro-5-nitro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1-trityl-1H-indazole
obtained by Production example 648, 623 mg of the title compound
was obtained as bright yellow crystals.
[1420] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.00 (2H, br s),
5.90 (1H, d, J=12.0 Hz), 7.01 (1H, d, J=16.4 Hz), 7.08 (1H, dd,
J=3.6, 5.2 Hz), 7.16-7.44 (18H, m), 7.49 (1H, d, J=5.2 Hz)
Production Example 650
1-(tert-Butoxycarbonyl-methyl-amino)-cyclopropane carboxylic acid
ethyl ester
[1421] To a solution of 500 mg of
1-tert-butoxycarbonylamino-cyclopropane carboxylic acid ethyl ester
which was obtained from 1,1-cyclopropane dicarboxylic acid diethyl
ester in accordance with the method described in the document
(Journal of Medicinal Chemistry, 31, 2004 (1988)) in 5 mL of
dimethylformamide, 0.2 mL of methyl iodide and 88 mg of 60% sodium
hydride were added and stirred at room temperature for 1 hour.
After adding water, the reaction solution was extracted with
diethyl ether. The organic layer was washed with water and
saturated brine, and dried over anhydrous magnesium sulfate. The
residue obtained by evaporating the solvent was purified by silica
gel column chromatography (ethyl acetate:n-hexane=1:19), to afford
59 mg of the title compound as a pale yellow oil.
[1422] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.17 (3H, t,
J=7.2 Hz), 1.22 (2H, br s), 1.36, 1.40 (11H, each s), 2.76, 2.81
(3H, each s), 4.09 (2H, q, J=7.2 Hz)
Production Example 651
1-(tert-Butoxycarbonyl-methyl-amino)-cyclopropane carboxylic
acid
[1423] To a solution of 48 mg of
1-(tert-butoxycarbonyl-methyl-amino)-cyclopropane carboxylic acid
ethyl ester in 0.4 mL of methanol, 0.1 mL of 5N sodium hydroxide
aqueous solution was added and stirred at room temperature
overnight. After adding water, the reaction solution was washed
with diethyl ether. The aqueous layer was added with 0.7 mL of 1N
hydrochloric acid, and extracted with ethyl acetate. The organic
layer was washed with saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, to afford 36 mg of
the title compound as white crystals.
[1424] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.18-1.46 (4H,
m), 1.36, 1.39 (9H, each s), 2.76, 2.80 (3H, each s), 12.50 (1H, br
s)
Production Example 652
1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropane carboxylic
acid ethyl ester
[1425] To a solution of 700 mg of 1-hydroxymethyl-cyclopropane
carboxylic acid ethyl ester obtained from 1,1-cyclopropane
dicarboxylic acid diethyl ester in accordance with the method
described in the document (Tetrahedron Letters, 40, 5467 (1988)) in
7 mL of N,N-dimethylformamide, 430 mg of imidazole and 916 mg of
tert-butyldimethylchlorosilane were added and stirred at room
temperature overnight. After adding n-hexane to the reaction
solution, the organic layer was washed successively with water, 1N
hydrochloric acid, water, saturated aqueous sodium hydrogen
carbonate and saturated brine. The organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated, to afford
1.13 g of the title compound as a colorless oil.
[1426] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.03 (6H, s),
0.85 (11H, s), 1.13 (2H, dd, J=4.0, 6.8 Hz), 1.17 (3H, t, J=7.2 Hz)
3.74 (2H, s), 4.05 (2H, q, J=7.2 Hz)
Production Example 653
1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopropane carboxylic
acid
[1427] 1.10 g of
1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopropane carboxylic
acid ethyl ester was hydrolyzed in the manner as described in
Production method 651, to afford 781 mg of the title compound as a
colorless oil.
[1428] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.03 (6H, s),
0.81 (2H, dd, J=3.6, 6.8 Hz) 0.85 (9H, s), 0.99 (2H, dd, J=3.6, 6.8
Hz) 3.74 (2H, s), 12.18 (1H, br s)
Production Example 654
(2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic
acid methyl ester
[1429] To a solution of 2.5 g of
4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic
acid 1-benzylester 2-methyl ester obtained from
trans-4-hydroxy-L-proline in accordance with the method of JP-A
62-155279 in 25 mL of methanol was added 250 mg of 20% palladium
hydroxide, and stirred overnight at normal pressure under nitrogen
atmosphere. After filtering out the catalyst, the solvent was
evaporated, to afford 1.64 g of the title compound as a colorless
oil.
[1430] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.78-1.93 (2H,
m), 2.60 (1H, dd, J=2.4, 11.2 Hz), 3.03 (1H, dd, J=5.2, 11.2 Hz),
3.61 (3H, s), 3.79 (1H, t, J=8.0 Hz), 4.32-4.39 (1H, m)
Production Example 655
(2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-1-methyl-pyrrolidine-2-carboxyl-
ic acid methyl ester
[1431] To a solution of 800 mg of
(2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic
acid methyl ester in 8 mL of methanol, 0.35 mL of 37% formalin and
80 mg of 10% palladium carbon were added, and stirred at 4 atm.
Hydrogen pressure for 10 hours. After filtering out the catalyst,
the solvent was evaporated, and the residue was separated and
purified by silica gel column chromatography (ethyl
acetate:n-hexane-1:6), to afford 489 mg of the title compound as a
colorless oil.
[1432] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.80-1.90 (1H,
ddd, 4.0, 8.0, 12.0 Hz), 2.08 (1H, td, J=4.0, 12.0 Hz), 2.20 (1H,
dd, J=5.6, 9.2 Hz), 2.27 (3H, s), 3.15-3.24 (2H, m), 3.62 (3H, s),
4.32-4.39 (1H, m)
Production Example 656
(2S,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-1-methyl-pyrrolidine-2-carboxyl-
ic acid
[1433] From 488 mg of
(2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-methyl-pyrrolidine-2-carboxyli-
c acid methyl ester, 625 mg of the title compound was obtained as
white non-crystalline powder in the method as described in
Production method 651.
[1434] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.80-1.90 (1H,
ddd, 4.0, 8.0, 12.0 Hz), 2.08 (1H, td, J=4.0, 12.0 Hz), 2.20 (1H,
dd, J=5.6, 9.2 Hz), 2.27 (3H, s), 3.15-3.24 (2H, m), 3.62 (3H, s),
4.32-4.39 (1H, m)
Production Example 657
(2S,4R)-1-Acetyl
4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic
acid
[1435] To a solution of 800 mg of
(2S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxylic
acid methyl ester obtained by Production example 654 in 10 mL of
pyridine, 0.35 mL of acetic anhydride was added and stirred at room
temperature for 1.5 hours. After adding ethyl acetate to the
reaction solution, the organic layer was washed successively with
water, 1N hydrochloric acid, water, saturated aqueous sodium
hydrogen carbonate and saturated brine. After drying the organic
layer over anhydrous magnesium sulfate, the solvent was evaporated,
to obtain crude
(2S,4R)-1-acetyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carboxy-
lic acid methyl ester. Then this ester was hydrolyzed in the manner
as described in Production example 651, to afford 337 mg of the
title compound as pale red crystals.
[1436] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.07 (6H, s),
0.85 (9H, s), 1.92-2.13 (2H, m), 1.95 (3H, s), 3.70 (1H, dd, J=5.2,
10.8 Hz), 4.20 (1H, t, J=8.0 Hz), 4.46-4.53 (1H, m), 12.45 (1H, br
s)
Example 658
[1437] various kinds of amine obtained by Production example 182,
Production example 643, Production example 645, Production example
647 and Production example 649, and various kinds of carboxylic
acid obtained by Production example 651, Production example 653,
Production example 656 and Production example 657 or commercially
available carboxylic acid were amidated in the manner as described
in Example 183, followed by deprotection (deprotection of compounds
having a tert-butyldimethylsilyl group was conducted using 95%
trifluoroacetic acid) and purification by LC-MC, to afford the
compounds of Examples 659-688.
Example 659
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1438] MS (ESI) m/z 340 MH.sup.+
Example 660
N-{6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-acetamide
[1439] MS (ESI) m/z 314 MH.sup.+
Example 661
N-{6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-2,-
2-dimethyl-propionamide
[1440] MS (ESI) m/z 372 MH.sup.+
Example 662
N-{6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-3--
methyl-butylamide
[1441] MS (ESI) m/z 372 MH.sup.+
Example 663
N-{6-Fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-pr-
opionamide
[1442] MS (ESI) m/z 344 MH.sup.+
Example 664
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-3--
methyl-butylamide
[1443] MS (ESI) m/z 372 MH.sup.+
Example 665
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-pr-
opionamide
[1444] MS (ESI) m/z 344 MH.sup.+
Example 666
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-bu-
tylamide
[1445] MS (ESI) m/z 358 MH.sup.+
Example 667
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-(3R)-3-hydro-
xy-3-phenyl-propionamide
[1446] MS (ESI) m/z 420 MH.sup.+
Example 668
Cyclopropane-1,1-dicarboxylic acid amide
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1447] MS (ESI) m/z 383 MH.sup.+
Example 669
N-{6-Fluoro-3-[(E)-2-(pyridine-3-yl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-2,2-
-dimethyl-propionamide
[1448] MS (ESI) m/z 355 MH.sup.+
Example 670
N-{6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-3-hydroxy-3-me-
thyl-butylamide
[1449] MS (ESI) m/z 355 MH.sup.+
Example 671
1-Hydroxy-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1450] MS (ESI) m/z 339 MH.sup.+
Example 672
Cyclopropane-1,1-dicarboxylic acid amide
{6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1451] MS (ESI) m/z 366 MH.sup.+
Example 673
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1452] MS (ESI) m/z 323 MH.sup.+
Example 674
N-{6-Fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-acetamide
[1453] MS (ESI) m/z 297 MH.sup.+
Example 675
cis-2-Hydroxy-cyclopentane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1454] MS (ESI) m/z 384 MH.sup.+
Example 676
1-Hydroxy-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1455] MS (ESI) m/z 356 MH.sup.+
Example 677
(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1456] MS (ESI) m/z 385 MH.sup.+
Example 678
1-Hydroxymethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1457] MS (ESI) m/z 320 MH.sup.+
Example 679
1-Hydroxymethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1458] MS (ESI) m/z 370 MH.sup.+
Example 680
1-Hydroxymethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1459] MS (ESI) m/z 358 MH.sup.+
Example 681
1-Methylamino-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1460] MS (ESI) m/z 369 MH.sup.+
Example 682
1-Methylamino-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1461] MS (ESI) m/z 369 MH.sup.+
Example 683
1-Methylamino-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1462] MS (ESI) m/z 357 MH.sup.+
Example 684
1-Hydroxy-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1463] MS (ESI) m/z 356 MH.sup.+
Example 685
1-Hydroxy-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1464] MS (ESI) m/z 344 MH.sup.+
Example 686
2-Cyclopropyl-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl-
}-acetamide
[1465] MS (ESI) m/z 354 MH.sup.+
Example 687
(2S,4R)-4-Hydroxy-1-methyl-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1466] MS (ESI) m/z 399 MH.sup.+
Example 688
(2S,4R)-1-Acetyl-4-hydroxy-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1467] MS (ESI) m/z 427 MH.sup.+
Production Example 689
1-(6-Fluoro-5-nitro-1H-indazole-1-yl)-ethanone
[1468] A mixed solution of 10 g of
N-(5-fluoro-2-methyl-4-nitrophenyl)-acetamide obtained by
Production example 177, 40 mL of glacial acetic acid and 13.4 mL of
acetic anhydride was added dropwise with 10.1 mL of isoamyl nitrite
while heating to 80.degree. C., and after completion of the
dropping, the mixture was stirred at 90.degree. C. for 3 hours. The
solvent was evaporated, and the precipitated crystals were
collected by filtration, to afford 1.71 g of the title compound as
bright yellow crystals.
[1469] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.76 (3H, s),
8.27 (1H, d, J=11.6 Hz), 8.68 (1H, s), 8.88 (1H, d, J=7.6 Hz)
Production Example 690
6-Fluoro-5-nitro-1H-indazole
[1470] 1.6 g of 1-(6-fluoro-5-nitro-1H-indazole-1-yl)-ethanone was
hydrolyzed in accordance with the method of Production example 409,
to afford 1.26 g of the title compound as pale red crystals. The
instrumental data coincided with that of Production Example
179.
Example 691
[1471]
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yla-
mine synthesized by Production example 182 and various kinds of
carboxylic acid were treated in the similar method as described in
Example 183, to afford the compounds of Examples 692-730.
Example 692
2-Amino-N-[6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl]-3-me-
thyl-butylamide
[1472] MS (ESI) m/z 371 MH.sup.+
Example 693
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-methyl-2-m-
ethylamino-butylamide
[1473] MS (ESI) m/z 385 MH.sup.+
Example 694
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-benzamide
[1474] MS (ESI) m/z 376 MH.sup.+
Example 695
Pyridine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1475] MS (ESI) m/z 377 MH.sup.+
Example 696
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-nicotinamide
[1476] MS (ESI) m/z 377 MH.sup.+
Example 697
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-isonicotinam-
ide
[1477] MS (ESI) m/z 377 MH.sup.+
Example 698
Pyrimidine-5-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1478] MS (ESI) m/z 378 MH.sup.+
Example 699
Pyrazine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1479] MS (ESI) m/z 378 MH.sup.+
Example 700
Thiophene-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1480] MS (ESI) m/z 382 MH.sup.+
Example 701
1-Methyl-1H-pyrrole-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1481] MS (ESI) m/z 379 MH.sup.+
Example 702
1H-Pyrrole-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1482] MS (ESI) m/z 365 MH.sup.+
Example 703
5-Methyl-isoxazole-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-amide
[1483] MS (ESI) m/z 381 MH.sup.+
Example 704
3,5-Dimethyl-isoxazole-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1484] MS (ESI) m/z 395 MH.sup.+
Example 705
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2,6-dimethox-
y-nicotinamide
[1485] MS (ESI) m/z 437 MH.sup.+
Example 706
6-Hydroxy-pyridine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1486] MS (ESI) m/z 393 MH.sup.+
Example 707
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-methoxy-ni-
cotinamide
[1487] MS (ESI) m/z 407 MH.sup.+
Example 708
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-hydroxy-ni-
cotinamide
[1488] MS (ESI) m/z 393 MH.sup.+
Example 709
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-6-hydroxy-ni-
cotinamide
[1489] MS (ESI) m/z 393 MH.sup.+
Example 710
Cyclobutane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-amide
[1490] MS (ESI) m/z 354 MH.sup.+
Example 711
1-Cyano-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1491] MS (ESI) m/z 365 MH.sup.+
Example 712
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2,2-dimethyl-
-propioneamide
[1492] MS (ESI) m/z 356 MH.sup.+
Example 713
1-Methyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1493] MS (ESI) m/z 354 MH.sup.+
Example 714
2-Methyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1494] MS (ESI) m/z 354 MH.sup.+
Example 715
Thiazole-5-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1495] MS (ESI) m/z 383 MH.sup.+
Example 716
2-Ethyl-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-buty-
lamide
[1496] MS (ESI) m/z 370 MH.sup.+
Example 717
2,2-Difluoro-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-
-acetamide
[1497] MS (ESI) m/z 350 MH.sup.+
Example 718
Thiophene-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1498] MS (ESI) m/z 382 MH.sup.+
Example 719
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(pyridin-2-
-yl)-acetamide
[1499] MS (ESI) m/z 391 MH.sup.+
Example 720
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(pyridin-3-
-yl)-acetamide
[1500] MS (ESI) m/z 391 MH.sup.+
Example 721
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(pyridin-4-
-yl)-acetamide
[1501] MS (ESI) m/z 391 MH.sup.+
Example 722
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(thiophen--
3-yl)-acetamide
[1502] MS (ESI) m/z 396 MH.sup.+
Example 723
2-Benzo[1,3]dioxol-5-yl-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-in-
dazol-5-yl}-acetamide
[1503] MS (ESI) m/z 434 MH.sup.+
Example 724
2-Amino-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-acet-
amide
[1504] MS (ESI) m/z 329 MH.sup.+
Example 725
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-methylamin-
o-acetamide
[1505] MS (ESI) m/z 343 MH.sup.+
Example 726
2-Dimethylamino-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5--
yl}-acetamide
[1506] MS (ESI) m/z 357 MH.sup.+
Example 727
2-Acetoylamino-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-y-
l}-acetamide
[1507] MS (ESI) m/z 371 MH.sup.+
Example 728
N-{6-Fluoro-3-[E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-methoxy-ace-
tamide
[1508] MS (ESI) m/z 344 MH.sup.+
Example 729
2-Cyano-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-acet-
amide
[1509] MS (ESI) m/z 339 MH.sup.+
Example 730
Furan-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1510] MS (ESI) m/z 366 MH.sup.+
Production Example 731
5-Formylfuran-2-carboxylic acid benzyl ester
[1511] 500 mg of 5-formylfuran-2-carboxylic acid was dissolved in
10 mL of tetrahydrofuran, added with 990 .mu.l of triethylamine,
cooled to 0.degree. C., and then added with 374 .mu.l of ethyl
chloroformate. After stirring at this temperature for 30 minutes,
406 .mu.l of benzylalcohol was added and stirred at room
temperature overnight. Adding water to stop the reaction, the
solution was extracted with ethyl acetate. The organic phase was
washed with water and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and purified by
silica gel column chromatography, to afford 508 mg of the title
compound as white crystals.
[1512] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.38 (2H, s),
7.31-7.49 (5H, m), 7.54 (1H, dd, J=1.2, 3.6 Hz), 7.63 (1H, dd,
J=1.2, 3.6 Hz)
Production Example 732
Furan-2,5-dicarboxylic acid monobenzyl ester
[1513] 490 mg of 5-formylfuran-2-carboxylic acid benzyl ester was
dissolved in 10 mL of acetonitrile, and added with a solution
containing 413 mg of sulfamic acid in 5 mL of water. After cooling
to 0.degree. C., a solution containing 202 mg of sodium chlorite
and 232 mg of potassium dihydrogen phosphate in 5 mL of water was
added dropwise. After cooling at this temperature for 30 minutes,
sodium thiosulfate aqueous solution was added at 0.degree. C. to
stop the reaction, and extracted with a mixture of tetrahydrofuran
and ethyl acetate. The organic phase was washed with water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was distilled off to afford 520 mg of the title compound as
white crystals.
[1514] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.36 (2H, s),
7.32-7.48 (7H, m)
Production Example 733
5-Carbamoylfuran-2-carboxylic acid benzyl ester
[1515] 170 mg of furan-2,5-dicarboxylic acid monobenzyl ester was
dissolved in 5 mL of tetrahydrofuran, and added with 144 .mu.l of
triethylamine. After cooling to 0.degree. C., 72.3 .mu.l of ethyl
chloroformate was added dropwise and stirred at this temperature
for 30 minutes. 1 mL of concentrated ammonia water was added and
stirred at room temperature for 10 minutes, and then aqueous
ammonium chloride was added to stop the reaction. After extracting
the aqueous phase with ethyl acetate, the organic phase was washed
with water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, to afford 185 mg of the title
compound as white crystals.
[1516] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 5.35 (2H, s),
7.25 (1H, d, J=1.2 Hz), 7.35-7.47 (6H, m), 7.67 (1H, bs), 8.04 (1H,
bs)
Production Example 734
5-Methylcarbamoylfuran-2-carboxylic acid benzyl ester
[1517] 170 mg of furan-2,5-dicarboxylic acid monobenzyl ester
obtained by Production example 732 was dissolved in 15 mL of
N,N-dimethylformamide, and this solution was added with 470 .mu.l
of diisopropylethylamine, 127 mg of hydroxybenzotriazole, and 414
.mu.l of 2.0 M methylamine in tetrahydrofuran, and stirred room
temperature for 10 minutes. After adding 265 mg of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and
stirring overnight, ice was added to stop the reaction. The aqueous
phase was extracted with ethyl acetate, and the organic phase was
washed with water and saturated brine and dried over anhydrous
magnesium sulfate. The solvent was distilled off, to afford 128 mg
of the title compound as pale yellow crystals.
[1518] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.76 (3H, d,
J=4.8 Hz), 5.36 (2H, s), 7.20 (1H, d, J=3.6 Hz), 7.31-7.47 (6H, m),
8.57 (1H, d, J=4.8 Hz)
Production Example 735
5-Dimethylcarbamoylfuran-2-carboxylic acid benzyl ester
[1519] In accordance with Production example 734, from 170 mg of
furan-2,5-dicarboxylic acid monobenzyl ester obtained by Production
example 732 and 414 .mu.l of 2.0 M dimethyl amine in
tetrahydrofuran, 139 mg of the title compound was obtained as a
yellow oil.
[1520] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.98 (3H, bs),
3.18 (3H, bs), 5.35 (2H, s), 7.12 (1H, dd, J=0.8, 4.0 Hz),
7.31-7.47 (6H, m)
Production Example 736
5-Carbamoylfuran-2-carboxylic acid
[1521] 90 mg of 5-carbamoylfuran-2-carboxylic acid benzyl ester
obtained by Production example 733 was suspended in 2 mL of
ethanol, added with 9 mg of palladium carbon, and stirred overnight
at room temperature under hydrogen atmosphere. The insoluble
substances were filtered, and the filtrate was evaporated, and the
resultant white solid was washed with 500 .mu.l of diethyl ether,
to afford 48 mg of the title compound.
[1522] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.12-7.17 (2H,
m), 7.54 (1H, bs), 7.89 (1H, bs)
Production Example 737
5-Methylcarbamoylfuran-2-carboxylic acid
[1523] In accordance with the method of Production example 736,
from 60 mg of 5-methylcarbamoylfuran-2-carboxylic acid benzyl ester
obtained by Production example 734, 48 mg of the title compound was
obtained.
[1524] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.75 (3H, d,
J=4.8 Hz), 7.03 (1H, bs), 7.07 (1H, bs), 8.39 (1H, bs)
Production Example 738
5-Dimethylcarbamoylfuran-2-carboxylic acid
[1525] In accordance with the method of Production example 736,
from 56 mg of 5-dimethylcarbamoylfuran-2-carboxylic acid benzyl
ester obtained by Production example 735, 34 mg of the title
compound was obtained.
[1526] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 2.99 (3H, bs),
3.20 (3H, bs), 7.06 (1H, d, J=3.6 Hz), 7.20 (1H, d, J=3.6 Hz)
Example 739
[1527] In accordance with the method of Example 183, from amines
obtained by Production example 182 and Production example 649 and
carboxylic acids obtained by Production examples 736-738, the
compounds of Examples 740-745 were obtained.
Example 740
Furan-2,5-dicarboxylic acid 2-amide
5-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1528] MS (ESI) m/z 409 MH.sup.+
Example 741
Furan-2,5-dicarboxylic acid
2-({6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide)
5-methylamide
[1529] MS (ESI) m/z 423 MH.sup.+
Example 742
Furan-2,5-dicarboxylic acid 2-dimethylamide
5-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1530] MS (ESI) m/z 437 MH.sup.+
Example 743
Furan-2,5-dicarboxylic acid 2-amide
5-{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1531] MS (ESI) m/z 397 MH.sup.+
Example 744
Furan-2,5-dicarboxylic acid
2-{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
5-methylamide
[1532] MS (ESI) m/z 411 MH.sup.+
Example 745
Furan-2,5-dicarboxylic acid 2-dimethylamide
5-{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1533] MS (ESI) m/z 425 MH.sup.+
Production Example 746
6-Fluoro-3-iodo-5-nitro-1H-indazole
[1534] In accordance with the method of Production example 206,
from 5.57 g of 6-fluoro-5-nitro-1H-indazole obtained by Production
example 179 and 7.97 g of N-iodosuccinimide, 9.24 g of the title
compound was obtained as yellow crystals.
[1535] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.78 (1H, d,
J=11.6 Hz), 8.29 (1H, d, J=6.8 Hz), 14.16 (1H, br s)
Production Example 747
6-Fluoro-3-iodo-5-nitro-1-trityl-1H-indazole
[1536] 4.0 g of 6-fluoro-3-iodo-5-nitro-1H-indazole obtained by
Production example 746 was dissolved in 150 mL of
N,N-dimethylformamide, added with 782 mg of sodium hydride
(containing 60%) at 0.degree. C. and stirred at this temperature
for 10 minutes. After adding 4.35 g of trityl chloride and stirring
at room temperature for 5 hours and 30 minutes, ice was added to
stop the reaction. The solid precipitated by adding water was
collected via glass filter, and washed with water and 50% diethyl
ether in hexane. The solvent was evaporated, to afford 5.9 g of the
title compound as yellow crystals.
[1537] .sup.1H-NMR (400 MHz, DMSO-D) .delta. 6.18 (1H, d, J=12.8
Hz), 7.16-7.19 (6H, m), 7.35-7.40 (9H, m), 8.28 (1H, d, J=7.2
Hz)
Production Example 748
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-5-nitro-1-trityl-1
h-indazole
[1538] Under nitrogen atmosphere, 1 g of
6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole was dissolved in 10 mL
of acetonitrile, added successively with 1.35 g of
5-vinyl-benzo[1,3]dioxole, 81.7 mg of palladium acetate (II), 162
mg of 2-(di-tert-butylphosphino)biphenyl and 2 mL of triethylamine,
and stirred at 100.degree. C. for 5 hours. After cooling to room
temperature, 5 g of silica gel was added, and the solvent was
evaporated, and purified by silica gel column chromatography, to
obtain 468 mg of the crude product as yellow crystal. This crude
product was washed with 50% diethyl ether solution in hexane, and
the solvent was evaporated, to afford 143 mg of the title compound
as yellow crystals.
[1539] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.06 (2H, s),
6.09 (1H, d, J=12.8 Hz), 6.93 (1H, d, J=8.4 Hz), 7.13 (1H, d, J=8.4
Hz), 7.02-7.23 (6H, m), 7.35-7.39 (10H, m), 7.51 (1H, s), 7.56 (1H,
d, J=16.4), 9.14 (1H, d, J=7.2 Hz)
Production Example 749
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1-trityl-1H-indazole-5-yl-
amine
[1540] 123 mg of
3-[(E)-2-(benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-5-nitro-1-trityl-1H-inda-
zole was treated in the similar method as described in Production
example 182, to afford 95 mg of the title compound as a yellow
solid.
[1541] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.97 (2H, s), 6.03
(1H, d, J=12.0 Hz), 6.78 (1H, d, J=8.0 Hz), 6.94 (1H, dd, J=1.2,
8.0 Hz), 7.07 (1H, d, J=0.8 Hz), 7.16-7.33 (16H, m)
Example 750
[1542] In accordance with Example 183, from
3-[(E)-2-benzo[1,3]dioxol-5-yl-vinyl]-6-fluoro-1-trityl-1H-indazol-5-ylam-
ine obtained by Production example 749 and various kinds of
carboxylic acid, the compounds of Examples 751-756 were
obtained.
Example 751
N-{3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-aceta-
mide
[1543] MS (ESI) m/z 340 MH.sup.+
Example 752
Cyclopropane carboxylic acid
{3-[(E)-2-(benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[1544] MS (ESI) m/z 366 MH.sup.+
Example 753
Furan-2-carboxylic acid
{3-[(E)-2-(benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[1545] MS (ESI) m/z 392 MH.sup.+
Example 754
N-{3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-2-(th-
iophen-2-yl)-acetamide
[1546] MS (ESI) m/z 422 MH.sup.+
Example 755
1-Hydroxy-cyclopropane carboxylic acid
{3-[(E)-2-(benzo[1,3]-dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[1547] MS (ESI) m/z 382 MH.sup.+
Example 756
(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid
{3-[(E)-2-(benzo[1,3]dioxol-5-yl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[1548] MS (ESI) m/z 411 MH.sup.+
Production Example 757
1-Aminomethyl-cyclopropane carboxylic acid
[1549] To a solution of 500 mg of 1-cyanocyclopropane carboxylic
acid in 50 mL acetic acid was added 50 mg of platinum dioxide,
stirred at room temperature for 4 hours under 4 atm. hydrogen
atmosphere, and then the platinum dioxide was filtered off. The
solvent was evaporated, to afford 518 mg of the title compound as a
yellow oil.
[1550] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.58-0.64 (2H,
m), 0.93 (2H, dd, J=3.6, 6.4 Hz), 2.78 (2H, s).
Example 758
1-Aminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1551] 518 mg of 1-aminomethyl-cyclopropane carboxylic acid
obtained by Production example 757 was dissolved in a mixed solvent
of 9 mL 1,4-dioxane/4.5 mL water, added with 4.5 mL of 1N sodium
hydroxide aqueous solution, stirred for 10 minutes under ice
cooling, added with 1.08 g of tert-butyl dicarbonate under ice
cooling, and further stirred at room temperature for 21 hours. Then
the solvent was evaporated, added with saturated aqueous ammonium
chloride under ice cooling, extracted twice with ethyl acetate, and
the organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was evaporated, to afford
1-(tert-butoxycarbonylaminomethyl)-cyclopropane carboxylic acid as
a colorless oil.
[1552] To a solution of 200 mg
6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
obtained by Production example 182 in 3 mL of N,N-dimethylformamide
were successively added 126 mg of
1-(tert-butoxycarbonylaminomethyl)-cyclopropane carboxylic acid,
151 mg of diisopropylethylamine, 89.4 mg of 1-hydroxybenztriazole
monohydrate and 112 mg of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(.dbd.WSC.HCl), stirred at room temperature for 46 hours, then
added with aqueous ammonium chloride, extracted twice with ethyl
acetate, an the organic layer was washed successively with water
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the resultant crude product was
purified and separated by silica gel column chromatography, to
afford
(1-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylcar-
bamoyl}-cyclopropylmethyl)-carbamic acid tert-butyl ester. This was
then dissolved in 2 mL of dichloromethane, several drops of
triisopropylsilane was added followed by 2 mL of trifluoroacetic
acid, and stirred at room temperature for 4.5 hours. Thereafter,
saturated aqueous sodium hydrogen carbonate was added, extracted
twice with ethyl acetate, and the organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the resultant crude product was
purified and separated by LC-MS, to afford 46.64 mg of the title
compound.
[1553] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.24 (2H, dd,
J=5.2, 6.8 Hz), 1.60 (2H, dd, J=5.2, 6.8 Hz), 3.19 (2H, s),
7.08-7.18 (2H, m), 7.31 (1H, d, J=10.4 Hz), 7.35 (1H, d, J=16.8
Hz), 7.46 (1H, d, J=16.8 Hz), 7.60-7.68 (2H, m), 8.14 (1H, d, J=6.8
Hz).
[1554] MS (ESI) m/z 369 MH.sup.+
Example 759
1-(Acetylamino-methyl)-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1555] To a solution of 10 mg of 1-aminomethyl-cyclopropane
carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
obtained by Example 758 in 0.3 mL of N,N-dimethylformamide was
added 2.9 mg of acetic anhydride, and stirred at room temperature
for 38 hours under nitrogen atmosphere, and separated and purified
by LC-MS, to afford 3.66 mg of the title compound.
[1556] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.0.98 (2H, dd,
J=4.4, 7.2 Hz), 1.32 (2H, dd, J=4.4, 7.2 Hz), 2.03 (3H, s), 3.60
(2H, s), 7.06-7.16 (2H, m), 7.30 (1H, d, J=10.0 Hz), 7.35 (1H, d,
J=16.8 Hz), 7.46 (1H, d, J=16.8 Hz), 7.60-7.69 (2H, m), 8.30 (1H,
d, J=7.2 Hz).
[1557] MS (ESI) m/z 411 MH.sup.+
Production Example 760
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[3-(tetrahydropyran-2-yloxy)-propoxy]-1-
H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester 5-ethyl
ester
[1558] In accordance with the method of Production example 347,
from 200 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarbox-
ylic acid 1-tert-butyl ester 5-ethyl ester obtained by Production
example 346 and 1.05 g of 2-(3-bromopropoxy)-tetrahydropyran, 267
mg of the title compound was obtained as a colorless oil.
[1559] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.23-2.33 (8H, m),
1.44 (3H, t, J=6.8 Hz), 1.75 (9H, s), 3.36-3.44 (1H, m), 3.52-3.60
(1H, m), 3.68-3.76 (1H, m), 3.85-3.91 (1H, m), 4.18-4.29 (2H, m),
4.43 (2H, q, J=6.8 Hz), 4.49 (1H, t, J=4.0 Hz), 7.05-7.12 (2H, m),
7.52-7.62 (3H, m), 7.80 (1H, d, J=16.4 Hz), 7.87 (1H, d, J=8.8 Hz),
7.99 (1H, d, J=8.8 Hz).
Example 761
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid
[1560] In accordance with the methods of Example 16 and Example
350, from 267 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-[3-(tetrahydropyran-2-yloxy)-
-propoxy]-1H-indazole-1,5-dicarboxylic acid 1-tert-butyl ester
5-ethyl ester obtained by Production example 760, 83.1 mg of the
title compound was obtained as flesh color crude crystals.
[1561] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.2.06-2.18 (2H,
m>), 3.82 (2H, t, J=6.0 Hz), 4.26 (2H, t, J=6.4 Hz), 7.10-7.17
(2H, m), 7.25 (1H, d, J=8.4 Hz), 7.54 (1H, d, J=16.0 Hz), 7.59-7.67
(2H, m), 7.63 (1H, d, J=16.0 Hz), 7.84 (1H, d, J=8.4 Hz).
[1562] MS (ESI) m/z 355 (M-H).sup.-
Production Example 762
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-1,5-dic-
arboxylic acid 1-tert-butyl ester 5-ethyl ester
[1563] In accordance with the method of Production example 347,
from 120 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarbox-
ylic acid 1-tert-butyl ester 5-ethyl ester obtained by Production
example 346 and 427.1 mg of 3-bromopropionamide, 110 mg of the
title compound was obtained as colorless crystals.
[1564] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.45 (3H, t, J=7.2
Hz), 1.75 (9H, s), 2.84 (2H, t, J=5.6 Hz), 4.37 (2H, t, J=5.6 Hz),
4.42 (2H, q, J=7.2 Hz), 7.06-7.15 (2H, m), 7.50 (1H, d, J=16.4 Hz),
7.58-7.66 (2H, m), 7.80 (1H, d, J=16.4 Hz), 7.94 (1H, d, J=8.8 Hz),
8.07 (1H, d, J=8.8 Hz).
Example 763
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid ethyl ester
[1565] In accordance with the method of Example 16, from 110 mg of
4-(2-carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-1,5-di-
carboxylic acid 1-tert-butyl ester 5-ethyl ester obtained by
Production example 762, 78 mg of the title compound was obtained as
colorless crude crystals.
[1566] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.42 (3H, t, J=6.8
Hz), 2.83 (2H, t, J=6.0 Hz), 4.39 (2H, t, J=6.0 Hz), 4.40 (2H, q,
J=6.8 Hz), 7.09-7.18 (2H, m), 7.28 (1H, d, J=8.8 Hz), 7.53 (1H, d,
J=16.4 Hz), 7.62 (1H, d, J=16.4 Hz), 7.66-7.74 (2H, m), 7.85 (1H,
d, J=8.8 Hz).
[1567] MS (ESI) m/z 396 (M-H).sup.-
Example 764
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid
[1568] 85.3 mg of
4-(2-carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carb-
oxylic acid ethyl ester obtained by Example 763 was dissolved in 3
mL of concentrated sulfuric acid, stirred at 35.degree. C. for 16
hours, and then added with ice under ice cooling. The precipitated
crystals were collected by filtration, washed with water, and then
dried under reduced pressure, to afford 43.7 mg of the title
compound as yellow crude crystals.
[1569] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.2.85 (2H, t, J=6.0
Hz), 4.41 (2H, t, J=6.0 Hz), 7.06-7.18 (2H, m), 7.28 (1H, d, J=8.8
Hz), 7.44-7.76 (2H, m), 7.51 (1H, d, J=16.4 Hz), 7.60 (1H, d,
J=16.4 Hz), 7.92 (1H, d, J=8.8 Hz).
[1570] MS (ESI) m/z 370 MH.sup.+
Production Example 765
4-(2-Bromoethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-1,5-dicarbo-
xylic acid 1-tert-butyl ester 5-ethyl ester
[1571] In accordance with the method of Production example 347,
from 3.34 g of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-hydroxy-1H-indazole-1,5-dicarboxy-
lic acid 1-tert-butyl ester 5-ethyl ester obtained by Production
example 346 and 14.7 g of 1,2-dibromoethane, 3.20 g of the title
compound was obtained as a colorless foam.
[1572] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.44 (3H, t, J=7.2
Hz), 1.75 (9H, s), 3.78 (2H, t, J=5.6 Hz), 4.42 (2H, q, J=7.2 Hz),
4.46 (2H, t, J=5.6 Hz), 7.04-7.13 (2H, m), 7.56-7.68 (2H, m), 7.64
(1H, d, J=16.4 Hz), 7.81 (1H, d, J=16.4 Hz), 7.91 (1H, d, J=8.8
Hz), 8.03 (1H, d, J=8.8 Hz).
Example 766
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(morpholin-4-yl)ethoxy]-1H-indazole--
5-carboxylic acid ethyl ester
[1573] 100 mg of
4-(2-bromoethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-1,5-dicarb-
oxylic acid 1-tert-butyl ester 5-ethyl ester obtained by Production
example 765 was dissolved in 1 mL of N,N-dimethylformamide, added
with 40.8 mg of morpholine, and stirred at room temperature for 14
hours and 30 minutes, followed by stirring at 50.degree. C. for 3
hours and further at 80.degree. C. for 1 hour. Then adding water
and extracting twice with ethyl acetate, the organic layer was
washed successively with water and saturated brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated, to afford
81.9 mg of the title compound.
[1574] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.41 (3H, t, J=7.2
Hz), 2.45 (4H, bs), 2.86 (2H, t, J=6.0 Hz), 3.45-3.70 (4H, m), 4.27
(2H, t, J=6.0 Hz), 4.39 (2H, q, J=7.2 Hz), 7.07-7.18 (2H, m), 7.27
(1H, d, J=8.4 Hz), 7.52 (1H, d, J=16.8 Hz), 7.58-7.70 (3H, m), 7.83
(1H, d, J=8.4 Hz).
Example 767
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(morpholin-4-yl)ethoxy]-1H-indazole--
5-carboxylic acid
[1575] In accordance with the method of Example 350, from 81.9 mg
of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-[2-(morpholin-4-yl)ethoxy]-1H-indazole-
-5-carboxylic acid ethyl ester obtained by Example 766, 64.1 mg of
the title compound was obtained.
[1576] MS (ESI) m/z 412 MH.sup.+
Example 768
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1H-pyrrol-2-yl)-methyl]-amide
[1577] To a solution of 1H-pyrrole-2-carboaldehyde in 31.5 mL of
methanol, 8.1 g ammonium acetate and 462 mg of sodium cyano
borohydride were added, and under nitrogen atmosphere stirred at
room temperature for 27 hours. Then, concentrated hydrochloric acid
was added until pH decreased to not more than 2, and the solvent
was evaporated. After dissolving the residue in water, the solution
was extracted twice with diethyl ether. Then, the aqueous phase was
added with potassium hydroxide until pH reached to not less than
10, extracted twice with ethyl acetate, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, followed by
purification and separation by NH silica gel column chromatography,
to afford 475 mg of C-(1H-pyrrol-2-yl)-methylamine as a brown
oil.
[1578] In accordance with the method of Example 102, from 10 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 and 9.2 mg of
C-(1H-pyrrol-2-yl)-methylamine, 0.98 mg of the title compound was
obtained.
[1579] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.3.84 (3H, s), 4.58
(2H, s), 6.03 (1H, dd, J=2.8, 5.6 Hz), 6.09-6.13 (1H, m), 6.67-6.72
(1H, m), 7.06-7.18 (2H, m), 7.32 (1H, d, J=8.4 Hz), 7.52 (1H, d,
J=16.4 Hz), 7.56 (1H, d, J=16.4 Hz), 7.56-7.66 (2H, m), 7.82 (1H,
d, J=8.4 Hz).
[1580] MS (ESI) m/z 391 MH.sup.+
Production Example 769
[Oxazol-2-yl-(toluene-4-sulfonyl)-methyl]-carbamic acid tert-butyl
ester
[1581] 300 mg of oxazole 2-carboaldehyde was dissolved in a mixed
solvent of 3 mL of methanol and 6 mL of water, added successively
with 363 mg of tert-butyl carbamate, 552 mg of sodium
p-toluenesulfonate and 0.76 mL of formic acid and stirred at room
temperature for 16 hours and 30 minutes. The precipitated crystals
were collected by filtration, washed with water, and dried under
reduced pressure, to afford 247 mg of the title compound as
colorless crystals.
[1582] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.23 (9H, s),
2.40 (3H, s), 6.12 (1H, d, J=10.0 Hz), 7.35 (1H, s), 7.46 (2H, d,
J=7.6 Hz), 7.71 (2H, d, J=7.6 Hz), 8.28 (1H, s), 8.86 (1H, d,
J=10.0 Hz).
Production Example 770
Oxazole-2-ylmethyl-carbamic acid tert-butyl ester
[1583] To 4 mL of tetrahydrofuran was added 51.4 mg of sodium
borohydride, and added with 240 mg of
[oxazole-2-yl-(toluene-4-sulfonyl)-methyl]-carbamic acid tert-butyl
ester obtained by Production example 769 over 13 minutes at room
temperature under stirring. Thereafter, the solution was stirred
for another 2 hours and 30 minutes under room temperature, added
with saturated aqueous ammonium chloride under ice cooling, and
stirred for another 30 minutes under ice cooling. Thereafter, water
was added, extracted twice with diethyl ether and dried over
anhydrous magnesium sulfate. The solvent was evaporated, followed
by purification and separation by silica gel column chromatography,
to afford 72.3 mg of the title compound as colorless crystals.
[1584] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.39 (9H, s),
4.44 (1H, d, J=5.6 Hz), 7.51 (1H, s), 7.61 (1H, t, J=5.6 Hz), 8.38
(1H, s).
Example 771
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (oxazol-2-ylmethyl)-amide
[1585] In accordance with the method of Example 16, from 36 mg
oxazol-2-ylmethyl-carbamic acid tert-butyl ester obtained by
Production example 770, C-(oxazol-2-yl)-methylamine was obtained as
transparent oil. From this and 10 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234, 3.82 mg of the title compound was
obtained in accordance with the method of Example 102.
[1586] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.00 (3H, s), 4.78
(2H, s), 7.09-7.19 (2H, m), 7.16 (1H, d, J=0.8 Hz), 7.43 (1H, d,
J=8.8 Hz), 7.55 (1H, d, J=16.4 Hz), 7.60 (1H, d, J=16.4 Hz),
7.59-7.68 (2H, m), 7.85 (1H, d, J=8.8 Hz), 7.90 (1H, d, J=0.8
Hz).
[1587] MS (ESI) m/z 393 MH.sup.+
Production Example 772
Acetic Acid 5-(tert-butoxycarbonylamino-methyl)-furan-2-ylmethyl
ester
[1588] In accordance with the methods of Production example 769 and
Production example 770, from 1 g of acetic acid
5-formyl-furan-2-ylmethyl ester, 443 mg of the title compound was
obtained as a colorless oil.
[1589] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.36 (9H, s),
2.00 (3H, s), 4.07 (2H, d, J=5.2 Hz), 4.95 (2H, s), 6.13 (1H, d,
J=2.8 Hz), 6.40 (1H, d, J=2.8 Hz), 7.32 (1H, bs).
Production Example 773
(5-Hydroxymethyl-furan-2-ylmethyl)-carbamic acid tert-butyl
ester
[1590] 416 mg of acetic acid
5-(tert-butoxycarbonylamino-methyl)-furan-2-yl methyl ester was
dissolved in a mixed solvent of 8 mL of methanol and 8 mL of water,
added with 639 mg of potassium carbonate, and stirred at room
temperature for 30 minutes. Then, the solution was added with
saturated aqueous ammonium chloride, extracted twice with ethyl
acetate, the organic layer washed with saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was evaporated, to
afford 363 mg of the title compound as a colorless oil.
[1591] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.36 (9H, s),
4.05 (2H, d, J=5.6 Hz), 4.30 (2H, d, J=5.6 Hz), 5.13 (1H, t, J=5.6
Hz), 6.06 (1H, d, J=2.8 Hz), 6.15 (1H, d, J=2.8 Hz), 7.28 (1H, t,
J=5.6 Hz).
Production Example 774
(5-Azidomethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester
[1592] 99.4 mg of (5-hydroxymethyl-furan-2-ylmethyl)-carbamic acid
tert-butyl ester was added to 4.5 mL of toluene, added successively
with 83.7 mg of 1,8-diazabicyclo[5,4,0]undec-7-ene and 151.6 mg of
diphenylphosphoryl azide, and stirred at room temperature under
nitrogen atmosphere for 1 hour and 45 minutes. Then the solvent was
evaporated, followed by purification and separation by silica gel
column chromatography, to afford 88.6 mg of the title compound as a
colorless oil.
[1593] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.36 (9H, s),
4.07 (2H, d, J=5.2 Hz), 4.39 (2H, s), 6.14 (1H, t, J=2.8 Hz), 6.38
(1H, d, J=2.8 Hz), 7.32 (1H, t, J=5.2 Hz).
Production Example 775
(5-Aminomethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester
[1594] To a solution of 88.6 mg of
(5-azidomethyl-furan-2-ylmethyl)-carbamic acid tert-butyl ester in
3 mL of ethanol was added 30 mg of Lindlar catalyst, stirred at
room temperature under hydrogen atmosphere for 15 hours, the
catalyst filtered off, and the solvent was evaporated, to afford 81
mg of the title compound as a colorless oil.
[1595] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 1.43 (9H, s), 3.71
(2H, s), 4.15 (2H, s), 6.05-6.20 (2H, m).
[1596] MS (ESI) m/z 225 (M-H).sup.-
Example 776
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-aminomethyl-furan-2-ylmethyl)-amide
[1597] In accordance with the methods of Example 102 and Example
16, from 19 mg (5-aminomethyl-furan-2-ylmethyl)-carbamic acid
tert-butyl ester obtained by Production example 775 and 17.5 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234, 4.26 mg of the title compound was
obtained.
[1598] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.92 (3H, s), 4.15
(2H, s), 4.65 (2H, s), 6.40 (1H, d, J=3.6 Hz), 6.51 (1H, d, J=3.6
Hz), 7.08-7.18 (2H, m), 7.34 (1H, d, J=8.4 Hz), 7.53 (1H, d, J=16.4
Hz), 7.58 (1H, d, J=16.4 Hz), 7.58-7.66 (2H, m), 7.81 (1H, d, J=8.4
Hz).
[1599] MS (ESI) m/z 421 MH.sup.+
Example 777
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-methylaminomethyl-furan-2-ylmethyl)-amide
[1600] To a solution of 15 mg of acetic acid
5-(tert-butoxycarbonylamino-methyl)-furan-2-ylmethylester obtained
by Production example 772 in 0.5 mL of N,N-dimethylformamide were
added 31.8 mg of iodomethane and 2.5 mg of sodium hydride under ice
cooling, and stirred for another 2 hours under ice cooling. Then
saturated aqueous ammonium chloride was added under ice cooling,
extracted twice with diethyl ether, the organic layer washed with
water, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to afford acetic acid
5-[(tert-butoxycarbonyl-methyl-amino)-methyl]-furan-2-ylmethylester.
This was then subjected to the reactions similar to those described
in Production example 773, Production example 774 and Production
example 775, to afford
(5-aminomethyl-furan-2-ylmethyl)-methyl-carbamic acid tert-butyl
ester.
[1601] This was then reacted with
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 in accordance with the methods of
Example 102 and Example 16, followed by separation and purification
by LC-MS, to afford 0.58 mg of the title compound.
[1602] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.70 (3H, s), 3.93
(3H, s), 4.24 (2H, s), 4.66 (2H, s), 6.43 (1H, d, J=3.2 Hz), 6.60
(1H, d, J=3.2 Hz), 7.10-7.18 (2H, m), 7.35 (1H, d, J=8.8 Hz), 7.53
(1H, d, J=16.4 Hz), 7.59 (1H, d, J=16.4 Hz), 7.60-7.68 (2H, m),
7.81 (1H, d, J=8.8 Hz).
[1603] MS (ESI) m/z 435 MH.sup.+
Example 778
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-dimethylaminomethyl-furan-2-ylmethyl)-amide
[1604] 10 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-aminomethyl-furan-2-ylmethyl)-amide obtained by Example 776
was dissolved in a mixed solvent of 0.25 mL methanol/0.25 mL
tetrahydrofuran, added with 7.2 mg of 37% formaldehyde aqueous
solution, 6 .mu.l of acetic acid, and 3.8 mg of
sodiumcyanoborohydride, and stirred at room temperature under
nitrogen atmosphere for 18 hours. Then the solvent was evaporated,
followed by separation and purification by LC-MS, to afford 0.60 mg
of the title compound.
[1605] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.87 (6H, s)/3.94
(3H, s), 4.38 (2H, s), 4.67 (2H, bs), 6.47 (1H, d, J=2.8 Hz), 6.69
(1H, d, J=2.8 Hz), 7.10-7.20 (2H, m), 7.35 (1H, d, J=8.8 Hz), 7.53
(1H, d, J=16.8 Hz), 7.59 (1H, d, J=16.8 Hz), 7.60-7.68 (2H, m),
7.80 (1H, d, J=8.8 Hz).
[1606] MS (ESI) m/z 450 MH.sup.+
Example 779
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-hydroxymethyl-furan-2-ylmethyl)-amide
[1607] In accordance with the method of Example 16, from acetic
acid 5-(tert-butoxycarbonylamino-methyl)-furan-2-ylmethyl ester
obtained by Production example 772, acetic acid
5-aminomethyl-furan-2-ylmethyl ester was obtained.
[1608] This compound and 17.5 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 were amidated in accordance with
Example 102, followed by hydrolysis of acetate in accordance with
the method of Production example 773. Then the resultant product
was separated and purified by LC-MS, to afford 1.95 mg of the title
compound.
[1609] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.91 (3H, s), 4.49
(2H, s), 4.63 (2H, s), 6.27 (1H, d, J=3.2 Hz), 6.31 (1H, d, J=3.2
Hz), 7.08-7.18 (2H, m), 7.33 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=16.4
Hz), 7.58 (1H, d, J=16.4 Hz), 7.59-7.67 (2H, m), 7.79 (1H, d, J=8.8
Hz).
[1610] MS (ESI) m/z 422 MH.sup.+
Example 780
(S)-({3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-a-
mino)-phenyl-acetic acid
[1611] In accordance with the methods of Example 102 and Example
16, from 40 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid obtained by Example 234 and (S)-amino-phenyl-acetic acid
tert-butyl ester, 110 mg of the title compound was obtained as a
yellow oil.
[1612] MS (ESI) m/z 446 MH.sup.+
Example 781
[1613] From carboxylic acids obtained by Example 761, Example 764,
Example 234 and Example 780 and various kinds of amine, the
compounds of Examples 782-794 were obtained in accordance with the
method of Example 102.
Example 782
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[1614] MS (ESI) m/z 443 MH.sup.+
Example 783
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid cyclopropylamide
[1615] MS (ESI) m/z 396 MH.sup.+
Example 784
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid (furan-2-ylmethyl)-amide
[1616] MS (ESI) m/z 436 MH.sup.+
Example 785
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide
[1617] MS (ESI) m/z 477 MH.sup.+
Example 786
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-(3-hydroxypropoxy)-1H-indazole-5-carbox-
ylic acid [(1S)-1-carbamoyl-ethyl]-amide
[1618] MS (ESI) m/z 427 MH.sup.+
Example 787
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid [(1S)-1-hydroxymethyl-2-methyl-propyl]-amide
[1619] MS (ESI) m/z 456 MH.sup.+
Example 788
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid cyclopropylamide
[1620] MS (ESI) m/z 409 MH.sup.+
Example 789
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid (furan-2-ylmethyl)-amide
[1621] MS (ESI) m/z 449 MH.sup.+
Example 790
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide
[1622] MS (ESI) m/z 490 MH.sup.+
Example 791
4-(2-Carbamoylethoxy)-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carbo-
xylic acid [(1S)-1-carbamoyl-ethyl]-amide
[1623] MS (ESI) m/z 440 MH.sup.+
Example 792
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylmethyl-amide
[1624] MS (ESI) m/z 366 MH.sup.+
Example 793
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(3R)-2-oxo-tetrahydrofuran-3-yl]-amide
[1625] MS (ESI) m/z 396 MH.sup.+
Example 794
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(S)-cyclopropylcarbamoyl-phenyl-methyl]-amide
[1626] MS (ESI) m/z 486 MH.sup.+
Example 795
[1627] To a solution of either carboxylic acid obtained by Example
767, Example 234 and Example 780 in 1.5 mL of tetrahydrofuran were
successively added 6 equivalents of triethylamine and 2.5
equivalents of ethyl chloroformate under ice cooling, and stirred
under ice cooling for 1 hour. Then an excess amount of various
kinds of amine was added and stirred at room temperature overnight.
The solvent was distilled off, and the resultant residue was
separated and purified by LC-MS, to afford the compounds of
Examples 796-799.
Example 796
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(morpholin-4-yl)ethoxy]-1H-indazole--
5-carboxylic acid amide
[1628] MS (ESI) m/z 411 MH.sup.+
Example 797
3-[E)-2-(4-Fluorophenyl)-vinyl]-4-[2-(morpholin-4-yl)-ethoxy]-1H-indazole--
5-carboxylic acid methylamide
[1629] MS (ESI) m/z 425 MH.sup.+
Example 798
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid methylamide
[1630] MS (ESI) m/z 326 MH.sup.+
Example 799
3-[2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(S)-dimethylcarbamoyl-phenyl-methyl]-amide
[1631] MS (ESI) m/z 474 MH.sup.+
Production Example 800
1-Benzyloxymethyl-cyclopropylamine
[1632] The title compound was prepared in accordance with the known
method (J. Org. Chem. 2002, 67, 3965.).
Production Example 801
1-(2-Benzyloxy-ethyl)-cyclopropylamine
[1633] The title compound was prepared in accordance with the known
method (J. Org. Chem. 2002, 67, 3965.).
Production Example 802
1-Azido-2-methyl-propan-2-ol
[1634] 3.6 g of isobutylene oxide was dissolved in 100 mL of water,
added with 18.2 g of cetyltrimethyl ammonium bromide and 16.3 g of
sodium azide, and stirred at 30.degree. C. overnight. The solution
was extracted with 50% tetrahydrofuran solution in ethyl acetate,
the organic phase was washed with water and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
followed by purification by silica gel column chromatography, and
the solvent was evaporated at room temperature, to afford 6.44 g of
the title compound as a mixture with ethyl acetate.
[1635] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.1.26 (6H, s), 2.04
(2H, s)
Production Example 803
1-Amino-2-methyl-propan-2-ol
[1636] 3.22 g of 1-azido-2-methyl-propan-2-ol obtained by
Production example 802 was dissolved in 50 mL of ethanol, added
with 30 mg of palladium carbon, and stirred overnight at room
temperature under hydrogen atmosphere. The insoluble substances
were filtered off through Celite, and the solvent was evaporated,
to afford 1.5 g of the title compound as a colorless oil
substance.
[1637] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.16 (6H, s),
2.71 (2H, dd, J=6, 11.6 Hz)
Production Example 804
1-Amino-3-methyl-buthan-3-ol hydrochloride
[1638] To 3 g of 3-hydroxy-3-methylbutyronitrile, 10 mL of ethanol,
5 mL of concentrated hydrochloric acid and 100 mg of platinum
dioxide were added, and under 5-atom hydrogen atmosphere, the
solution was stirred at room temperature for 5 hours. The insoluble
substances were filtered off through Celite, and the solvent
evaporated, to afford 3.5 g of the title compound as a dark brown
solid.
[1639] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta.1.12 (6H, s),
1.65 (2H, t, J=8.0 Hz), 2.82-2.87 (2H, m)
Production Example 805
2-Amino-N,N-dimethyl-acetamide
[1640] 10 g of glycine ethyl ester hydrochloride was suspended in
200 mL of dichloromethane, added with 22 mL of triethylamine,
cooled to 0.degree. C., and added with 11.3 mL of
benzylchloroformate. The suspension was allowed to warm to room
temperature, stirred for 4 days, and added with water to stop the
reaction. Extracting with ethyl acetate, the organic layer was
washed with water and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated, and 12.2 g of the
resultant white crystal was suspended in 200 mL of ethanol, added
with 100 mL of 1N sodium hydroxide aqueous solution, and stirred
overnight at room temperature. The organic solvent was evaporated,
and the residual aqueous phase was washed twice with 100 mL of
ether. The aqueous phase was made to pH 2 by using 5N hydrochloric
acid, and extracted with ethyl acetate. The organic phase was
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and the solvent was evaporated, to afford 4.82 g
of white crystals. 497 mg of this white crystals were dissolved in
20 mL of DMF, added with 1.62 mL of diisopropylethylamine, 1.4 mL
of dimethyl amine in 2.0 M tetrahydrofuran and 437 mg of
hydroxybenzotriazole, and stirred at room temperature for 10
minutes. After cooling to 0.degree. C., 912 mg of WSC hydrochloride
was added and stirred overnight at room temperature. Water was
added to stop the reaction, the solution was extracted with ethyl
acetate, and the organic phase washed with water and saturated
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated, followed by purification by silica gel column
chromatography, to afford 402 mg of a colorless oil substance. This
was then dissolved in 5 mL of ethanol, added with 40 mg of
palladium carbon, and stirred overnight at room temperature under
hydrogen atmosphere. The insoluble substances were filtered off
through Celite.RTM., and the filtrate was evaporated, to afford 113
mg of the title compound.
[1641] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.2.95 (3H, s), 2.97
(3H, s), 3.44 (2H, s)
Production Example 806
[1642] The compounds of Production example 807 to Production
example 811 were prepared in accordance with method of Production
example 805.
Production Example 807
3-Amino-N-methyl-propionamide
[1643] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.2.39 (2H, t, J=6.8
Hz), 2.71 (3H, s), 3.46 (2H, t, J=6.4 Hz)
Production Example 808
3-Amino-N,N-dimethyl-propionamide
[1644] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.60 (2H, t, J=6.8
Hz), 2.93 (3H, s), 3.03 (3H, s), 3.47 (2H, t, J=6.8 Hz)
Production Example 809
4-Amino-butylamide
[1645] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.80 (2H, quint,
J=7.2 Hz), 2.24 (2H, t, J=7.2 Hz), 3.25 (2H, t, J=7.2 Hz)
Production Example 810
4-Amino-N-methyl-butylamide
[1646] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.79 (2H, quint,
J=7.2 Hz), 2.21 (2H, t, J=7.2 Hz), 2.71 (3H, s), 3.23 (2H, t, 17.2
Hz)
Production Example 811
4-Amino-N,N-dimethyl-butylamide
[1647] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.1.79 (2H, quint,
J=7.2 Hz), 2.41 (2H, t, J=7.2 Hz), 2.92 (3H, s), 3.05 (3H, s), 3.25
(2H, t, J=7.2 Hz)
Example 812
[1648] In accordance with the method of Example 102, from
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 or commercially available amine, or
various kinds of amine obtained by Production example 800, 801,
803, 804, 805, 807-811, the compounds of Examples 813-887 were
obtained.
Example 813
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-benzyloxymethyl-cyclopropyl)-amide
[1649] MS (ESI) m/z 472 MH.sup.+
Example 814
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [1-(2-benzyloxyethyl)-cyclopropyl]-amide
[1650] MS (ESI) m/z 486 MH.sup.+
Example 815
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-hydroxymethyl-cyclopentyl)-amide
[1651] MS (ESI) m/z 410 MH.sup.+
Example 816
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxy-1,1-dimethyl-ethyl)-amide
[1652] MS (ESI) m/z 384 MH.sup.+
Example 817
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1R)-1-hydroxymethyl-2-methyl-propyl]-amide
[1653] MS (ESI) m/z 398 MH.sup.+
Example 818
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1R)-2-hydroxy-1-phenyl-ethyl]-amide
[1654] MS (ESI) m/z 432 MH.sup.+
Example 819
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-hydroxy-1-(pyridin-3-yl)-ethyl]-amide
[1655] MS (ESI) m/z 433 MH.sup.+
Example 820
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxyethyl)-amide
[1656] MS (ESI) m/z 356 MH.sup.+
Example 821
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxy-2-methyl-propyl)-amide
[1657] MS (ESI) m/z 384 MH.sup.+
Example 822
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-hydroxy-3-methyl-butyl)-amide
[1658] MS (ESI) m/z 398 MH.sup.+
Example 823
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(2S)-2-hydroxy-2-phenyl-ethyl]-amide
[1659] MS (ESI) m/z 432 MH.sup.+
Example 824
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(2R)-2-hydroxy-2-phenyl-ethyl]-amide
[1660] MS (ESI) m/z 432 MH.sup.+
Example 825
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(2S)-2-hydroxypropyl]-amide
[1661] MS (ESI) m/z 370 MH.sup.+
Example 826
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(2R)-2-hydroxypropyl]-amide
[1662] MS (ESI) m/z 370 MH.sup.+
Example 827
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-amino-propyl)-amide
[1663] MS (ESI) m/z 369 MH.sup.+
Example 828
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-methylamino-propyl)-amide
[1664] MS (ESI) m/z 383 MH.sup.+
Example 829
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-ethylamino-propyl)-amide
[1665] MS (ESI) m/z 397 MH.sup.+
Example 830
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-dimethylamino-propyl)-amide
[1666] MS (ESI) m/z 397 MH.sup.+
Example 831
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide
[1667] MS (ESI) m/z 437 MH.sup.+
Example 832
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [3-(morpholin-4-yl)-propyl]-amide
[1668] MS (ESI) m/z 439 MH.sup.+
Example 833
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [3-(1H-imidazol-1-yl)-propyl]-amide
[1669] MS (ESI) m/z 420 MH.sup.+
Example 834
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(1H-imidazol-4-yl)-ethyl]-amide
[1670] MS (ESI) m/z 406 MH.sup.+
Example 835
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (4-amino-cyclohexyl)-amide
[1671] MS (ESI) m/z 409 MH.sup.+
Example 836
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(3R)-pyrrolidin-3-yl]-amide
[1672] MS (ESI) m/z 381 MH.sup.+
Example 837
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(3S)-pyrrolidin-3-yl]-amide
[1673] MS (ESI) m/z 381 MH.sup.+
Example 838
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (piperidin-4-ylmethyl)-amide
[1674] MS (ESI) m/z 409 MH.sup.+
Example 839
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (piperidin-4-yl)-amide
[1675] MS (ESI) m/z 395 MH.sup.+
Example 840
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid carbamoylmethyl-amide
[1676] MS (ESI) m/z 369 MH.sup.+
Example 841
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid methylcarbamoylmethyl-amide
[1677] MS (ESI) m/z 383 MH.sup.+
Example 842
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid dimethylcarbamoylmethyl-amide
[1678] MS (ESI) m/z 397 MH.sup.+
Example 843
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-carbamoyl-ethyl)-amide
[1679] MS (ESI) m/z 383 MH.sup.+
Example 845
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-methylcarbamoyl-ethyl)-amide
[1680] MS (ESI) m/z 397 MH.sup.+
Example 846
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-dimethylcarbamoyl-ethyl)-amide
[1681] MS (ESI) m/z 411 MH.sup.+
Example 847
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-carbamoyl-propyl)-amide
[1682] MS (ESI) m/z 397 MH.sup.+
Example 848
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-methylcarbamoyl-propyl)-amide
[1683] MS (ESI) m/z 411 MH.sup.+
Example 849
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-dimethylcarbamoyl-propyl)-amide
[1684] MS (ESI) m/z 425 MH.sup.+
Example 850
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-1-methylcarbamoyl-ethyl]-amide
[1685] MS (ESI) m/z 397 MH.sup.+
Example 851
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-oxo-azepan-3-yl)-amide
[1686] MS (ESI) m/z 423 MH.sup.+
Example 852
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-2-ylmethyl)-amide
[1687] MS (ESI) m/z 403 MH.sup.+
Example 853
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1688] MS (ESI) m/z 403 MH.sup.+
Example 854
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-4-ylmethyl)-amide
[1689] MS (ESI) m/z 403 MH.sup.+
Example 855
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid benzylamide
[1690] MS (ESI) m/z 402 MH.sup.+
Example 856
3-[E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(pyridin-2-yl)ethyl]-amide
[1691] MS (ESI) m/z 417 MH.sup.+
Example 857
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(pyridin-3-yl)ethyl]-amide
[1692] MS (ESI) m/z 417 MH.sup.+
Example 858
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(pyridin-4-yl)ethyl]-amide
[1693] MS (ESI) m/z 417 MH.sup.+
Example 859
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)-amide
[1694] MS (ESI) m/z 404 MH.sup.+
Example 860
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(thiophen-2-yl)-ethyl]-amide
[1695] MS (ESI) m/z 422 MH.sup.+
Example 861
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1696] MS (ESI) m/z 408 MH.sup.+
Example 862
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclobutylamide
[1697] MS (ESI) m/z 366 MH.sup.+
Example 863
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopentylamide
[1698] MS (ESI) m/z 380 MH.sup.+
Example 864
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid allylamide
[1699] MS (ESI) m/z 352 MH.sup.+
Example 865
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid propan-2-ynylamide
[1700] MS (ESI) m/z 352 MH.sup.+
Example 866
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyanomethyl-amide
[1701] MS (ESI) m/z 351 MH.sup.+
Example 867
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-3-ylmethyl)-amide
[1702] MS (ESI) m/z 408 MH.sup.+
Example 868
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (5-methyl-furan-2-ylmethyl)-amide
[1703] MS (ESI) m/z 406 MH.sup.+
Example 869
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 2-fluoro-benzylamide
[1704] MS (ESI) m/z 420 MH.sup.+
Example 870
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3-fluoro-benzylamide
[1705] MS (ESI) m/z 420 MH.sup.+
Example 871
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 4-fluoro-benzylamide
[1706] MS (ESI) m/z 420 MH.sup.+
Example 872
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 2-methoxy-benzylamide
[1707] MS (ESI) m/z 432 MH.sup.+
Example 873
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3-methoxy-benzylamide
[1708] MS (ESI) m/z 432 MH.sup.+
Example 874
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 4-methoxy-benzylamide
[1709] MS (ESI) m/z 432 MH.sup.+
Example 875
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3,4-dimethoxy-benzylamide
[1710] MS (ESI) m/z 462 MH.sup.+
Example 876
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 2,4-dimethoxy-benzylamide
[1711] MS (ESI) m/z 462 MH.sup.+
Example 877
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3,5-dimethoxy-benzylamide
[1712] MS (ESI) m/z 462 MH.sup.+
Example 878
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (benzo[1,3]dioxol-5-ylmethyl)-amide
[1713] MS (ESI) m/z 446 MH.sup.+
Example 879
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3,4,5-trimethoxy-benzylamide
[1714] MS (ESI) m/z 492 MH.sup.+
Example 880
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 2,4,6-trimethoxy-benzylamide
[1715] MS (ESI) m/z 492 MH.sup.+
Example 881
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 2-trifluoromethyl-benzylamide
[1716] MS (ESI) m/z 470 MH.sup.+
Example 882
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3-trifluoromethyl-benzylamide
[1717] MS (ESI) m/z 470 MH.sup.+
Example 883
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 4-trifluoromethyl-benzylamide
[1718] MS (ESI) m/z 470 MH.sup.+
Example 884
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 3-chloro-benzylamide
[1719] MS (ESI) m/z 436 MH.sup.+
Example 885
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid 4-methanesulfonyl-benzylamide
[1720] MS (ESI) m/z 480 MH.sup.+
Example 886
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-cyano-ethyl)-amide
[1721] MS (ESI) m/z 365 MH.sup.+
Example 887
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (4-amino-2H-pyrazol-3-ylmethyl)-amide
[1722] MS (ESI) m/z 407 MH.sup.+
Example 888
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [1-(2-hydroxyethyl)-cyclopropyl]-amide
[1723] 20 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-benzyloxyethyl-cyclopropyl)-amide obtained by Example 814
was dissolved in 1 mL of dichloromethane, added with 6.4 .mu.l of
trimethylsilyliodide at 0.degree. C. under nitrogen atmosphere, and
stirred at this temperature for 2 hours. The reaction solution was
added with methanol to stop the reaction, and the solvent was
concentrated, followed by purification by LC-MS, to afford 1.7 mg
of the title compound.
[1724] MS (ESI) m/z 396 MH.sup.+
Production Example 889
3-Iodo-4-methoxy-1H-indazole-5-carboxylic acid
[1725] In accordance with the method of Example 216, from 14.5 g of
3-iodo-4-methoxy-1H-indazole-5-carbonitrile obtained by Production
example 321, 5.4 g of the title compound was obtained as beige
crude crystals.
[1726] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta.4.04 (3H, s), 7.31
(1H, d, J=8.8 Hz), 7.89 (1H, d, J=8.8 Hz).
Production Example 890
3-Iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid methyl
ester
[1727] 3.1 g of crude 3-iodo-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Production example 889 was esterified in methanol
in the manner as described in Production example 274, and further
tritylated in the manner as described in Production example 94, to
afford 2.0 g of the title compound as a colorless powder.
[1728] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.3.80 (3H, s),
3.94 (3H, s), 6.22 (1H, d, J=8.9 Hz), 7.10-7.15 (6H, m), 7.28-7.37
(9H, m), 7.42 (1H, d, J=8.9 Hz).
Example 891
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester
[1729] 550 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid methyl ester obtained by Production example 890 and 160 mg of
2-vinylpyridine were reacted in the similar method as described in
Production example 181, followed by deprotection in the similar
method as described in Example 16, to afford 150 mg of the title
compound as a colorless powder.
[1730] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.87 (3H, s),
3.95 (3H, s), 7.29 (1H, dd, J=4.8, 7.7 Hz), 7.36 (1H, d, J=9.2 Hz),
7.60 (1H, d, J=7.7 Hz), 7.61 (1H, d, J=15.9 Hz), 7.74 (1H, d, J=9.2
Hz), 7.81 (1H, dt, J=1.9, 7.7 Hz), 8.08 (1H, d, J=15.9 Hz), 8.63
(1H, dd, J=1.9, 4.8 Hz), 13.61 (1H, bs).
Example 892
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[1731] 150 mg of
4-methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid methyl ester was treated in the similar method as described in
Example 144, to afford 120 mg of the title compound as a pale
yellow powder.
[1732] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.96 (3H, s),
7.29 (1H, dd, J=4.8, 7.7 Hz), 7.33 (1H, d, J=8.6 Hz), 7.59 (1H, d,
J=7.7 Hz), 7.61 (1H, d, J=16.0 Hz), 7.75 (1H, d, J=8.6 Hz), 7.81
(1H, dt, J=1.7, 7.7 Hz), 8.09 (1H, d, J=16.0 Hz), 8.63 (1H, bd,
J=4.8 Hz), 12.65-12.80 (1H, bs), 13.55 (1H, bs).
Example 893
[1733] In the similar method as described in Example 44,
4-methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid obtained by Production example 892 and various kinds of amine
were condensed, followed by purification by LC-MS, to afford the
compounds of Examples 894-898.
Example 894
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1734] MS (ESI) m/z 335 MH.sup.+
Example 895
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1735] MS (ESI) m/z 375 MH.sup.+
Example 896
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1736] MS (ESI) m/z 391 MH.sup.+
Example 897
4-Methoxy-3-[(E)-2-[(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenylethyl)-amide
[1737] MS (ESI) m/z 442 MH.sup.+
Example 898
4-Methoxy-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (1-hydroxymethyl-2-methyl-propyl)-amide
[1738] MS (ESI) m/z 381 MH.sup.+
Example 899
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid methyl ester
[1739] 550 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid methyl ester obtained by Production example 890 and 270 mg of
2-tert-butoxy-5-vinylpyridine were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 120 mg of
the title compound as a yellow powder.
[1740] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.87 (3H, s),
3.94 (3H, s), 6.50 (1H, bd, J=9.1 Hz), 6.58 (1H, bd, J=7.0 Hz),
7.30 (1H, d, J=16.1 Hz), 7.35 (1H, d, J=9.1 Hz), 7.46 (1H, dd,
J=7.0, 9.1 Hz), 7.74 (1H, d, J=9.1 Hz), 7.83 (1H, d, J=16.1
Hz).
Example 900
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid
[1741] 120 mg of
3-[(E)-2-(6-hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyl-
ic acid methyl ester obtained by Example 899 was treated in the
similar method as described in Example 144, to afford 95 mg of the
title compound as a yellow powder.
[1742] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.95 (3H, s),
6.35 (1H, d, J=9.2 Hz), 6.64 (1H, bd, J=7.1 Hz), 7.33 (1H, d,
J=16.8 Hz), 7.34 (1H, d, J=8.8 Hz), 7.51 (1H, dd, J=7.1, 9.2 Hz),
7.75 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=16.8 Hz).
Example 901
[1743]
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-ca-
rboxylic acid and various kinds of amine were condensed in the
similar method as described in Example 44, followed by purification
by LC-MS, to afford the compounds of Examples 902-906.
Example 902
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1744] MS (ESI) m/z 351 MH.sup.+
Example 903
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid (furan-2-ylmethyl)-amide
[1745] MS (ESI) m/z 391 MH.sup.+
Example 904
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid (thiophene-2-ylmethyl)-amide
[1746] MS (ESI) m/z 407 MH.sup.+
Example 905
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid (1-carbamoyl-2-phenylethyl)-amide
[1747] MS (ESI) m/z 458 MH.sup.+
Example 906
3-[(E)-2-(6-Hydroxy-pyridin-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid (1-hydroxymethyl-2-methyl-propyl)-amide
[1748] MS (ESI) m/z 397 MH.sup.+
Example 907
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid methyl ester
[1749] 400 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid methyl ester obtained by Production example 890 and 160 mg of
1-(5-vinylpyridin-2-yl)ethanone were reacted in the similar method
as described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 50 mg of
the title compound as an orange powder.
[1750] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.66 (3H, s),
3.87 (3H, s), 3.99 (3H, s), 7.37 (1H, d, J=8.8 Hz), 7.69 (1H, d,
J=16.8 Hz), 7.74 (1H, d, J=8.8 Hz), 7.84 (1H, d, J=16.8 Hz), 7.99
(1H, d, J=8.2 Hz), 8.32 (1H, dd, J=2.2, 8.2 Hz), 8.98 (1H, d, J=2.2
Hz), 13.70 (1H, bs).
Example 908
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[1751] 50 mg of
3-[(E)-2-(6-acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid methyl ester was treated in the similar method as described in
Example 144, to afford 50 mg of the title compound as an orange
powder.
[1752] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.66 (3H, s),
3.99 (3H, s), 7.33 (1H, d, J=8.7 Hz), 7.69 (1H, d, J=16.6 Hz), 7.55
(1H, d, J=8.7 Hz), 7.84 (1H, d, J=16.6 Hz), 7.99 (1H, d, J=8.1 Hz),
8.30 (1H, dd, J=2.1, 8.1 Hz), 8.98 (1H, d, J=2.1 Hz), 13.63 (1H,
bs).
Example 909
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid and various kinds of amine were condensed in the similar
method as described in Example 44, followed by purification by
LC-MS, to afford the compounds of Examples 910-916.
Example 910
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1753] MS (ESI) m/z 377 MH.sup.+
Example 911
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1754] MS (ESI) m/z 417 MH.sup.+
Example 912
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1755] MS (ESI) m/z 433 MH.sup.+
Example 913
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenylethyl)-amide
[1756] MS (ESI) m/z 484 MH.sup.+
Example 914
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-hydroxymethyl-2-methyl-propyl)-amide
[1757] MS (ESI) m/z 423 MH.sup.+
Example 915
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxy-propyl)-amide
[1758] MS (ESI) m/z 395 MH.sup.+
Example 916
3-[(E)-2-(6-Acetylpyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-acetylaminoethyl)-amide
[1759] MS (ESI) m/z 422 MH.sup.+
Example 917
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid methyl ester
[1760] 400 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid methyl ester obtained by Production example 890 and 160 mg of
5-vinylbenzo[1,3]dioxole were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 150 mg of
the title compound as a colorless powder.
[1761] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.97 (3H, s), 4.04
(3H, s), 6.01 (2H, s), 6.83 (1H, d, J=7.9 Hz), 7.03 (1H, dd, J=1.6,
7.9 Hz), 7.15 (1H, d, J=1.6 Hz), 7.21 (1H, d, J=8.9 Hz), 7.48 (1H,
d, J=16.6 Hz), 7.58 (1H, d, J=16.6 Hz), 7.90 (1H, d, J=8.9 Hz).
Example 918
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[1762] 150 mg of
3-[(E)-2-(benzo[1,3]dioxole-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyl-
ic acid methyl ester was treated in the similar method as described
in Example 144, to afford 130 mg of the title compound as a pale
yellow powder.
[1763] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.94 (3H, s),
6.06 (2H, s), 6.94 (1H, d, J=8.0 Hz), 7.09 (1H, dd, J=1.6, 8.0 Hz),
7.27 (1H, d, J=8.8 Hz), 7.27 (1H, d, J=1.6 Hz), 7.40 (1H, d, J=16.0
Hz), 7.47 (1H, d, J=16.0 Hz), 7.72 (1H, d, J=8.8 Hz), 12.65 (1H,
bs), 13.25 (1H, bs).
Example 919
[1764]
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-car-
boxylic acid and various kinds of amine were condensed in the
similar method as described in Example 44, followed by purification
by LC-MS, to afford the compounds of Examples 920-930.
Example 920
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1765] MS (ESI) m/z 378 MH.sup.+
Example 921
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1766] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.90 (3H, s), 4.74
(2H, d, J=6.0 Hz), 6.01 (2H, s), 6.34 (1H, d, J=3.9 Hz), 6.38 (1H,
d, J=3.9 Hz), 6.83 (1H, d, J=8.0 Hz), 7.03 (1H, dd, J=1.6, 8.0 Hz),
7.15 (1H, d, J=1.6 Hz), 7.30 (1H, d, J=9.0 Hz), 7.37 (1H, d, J=16.4
Hz), 7.42 (1H, s), 7.57 (1H, d, J=16.4 Hz), 8.16 (1H, d, J=9.0 Hz),
8.18 (1H, bt, J=6.0 Hz).
[1767] MS (ESI) m/z 418 MH.sup.+
Example 922
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1768] MS (ESI) m/z 434 MH.sup.+
Example 923
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-carbamoyl-2-phenylethyl)-amide
[1769] MS (ESI) m/z 485 MH.sup.+
Example 924
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (1-hydroxymethyl-2-methyl-propyl)-amide
[1770] MS (ESI) m/z 424 MH.sup.+
Example 925
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxy-propyl)-amide
[1771] MS (ESI) m/z 396 MH.sup.+
Example 926
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-acetylaminoethyl)-amide
[1772] MS (ESI) m/z 423 MH.sup.+
Example 927
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)-amide
[1773] MS (ESI) m/z 430 MH.sup.+
Example 928
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylmethyl-amide
[1774] MS (ESI) m/z 392 MH.sup.+
Example 929
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid benzylamide
[1775] MS (ESI) m/z 428 MH.sup.+
Example 930
3-[(E)-2-(Benzo[1,3]dioxol-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1776] MS (ESI) m/z 429 MH.sup.+
Example 931
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester
[1777] 1.12 g of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 160 mg of
2-vinylpyrazine were reacted in the similar method as described in
Production example 181, followed by deprotection in the similar
method as described in Example 16, to afford 440 mg of the title
compound as a pale yellow powder.
[1778] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (3H, t, J=7.2
Hz), 4.08 (3H, s), 4.45 (2H, q, J=7.2 Hz), 7.26 (1H, d, J=8.8 Hz),
7.77 (1H, d, J=16.0 Hz), 7.90 (1H, d, J=8.8 Hz), 8.30 (1H, d,
J=16.0 Hz), 8.45 (1H, d, J=2.4 Hz), 8.61 (1H, dd, J=1.6, 2.4 Hz),
8.71 (1H, d, J=1.6 Hz).
Example 932
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid
[1779] 440 mg of
4-methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester was treated in the similar method as described in
Example 144, to afford 340 mg of the title compound as a yellow
powder.
[1780] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.97 (3H, s),
7.35 (1H, d, J=8.8 Hz), 7.68 (1H, d, J=16.0 Hz), 7.76 (1H, d, J=8.8
Hz), 8.20 (1H, d, J=16.0 Hz), 8.53 (1H, d, J=2.4 Hz), 8.69 (1H, dd,
J=1.2, 2.4 Hz), 8.85 (1H, d, J=1.2 Hz), 12.70-12.90 (1H, bs), 13.67
(1H, bs).
Example 933
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid and various kinds of amine were condensed in the similar
method as described in Example 44, followed by purification by
LC-MS, to afford the compounds of Examples 934-940.
Example 934
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)-amide
[1781] MS (ESI) m/z 388 MH.sup.+
Example 935
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-3-ylmethyl)-amide
[1782] MS (ESI) m/z 376 MH.sup.+
Example 936
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylmethyl-amide
[1783] MS (ESI) m/z 350 MH.sup.+
Example 937
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-3-ylmethyl)-amide
[1784] MS (ESI) m/z 392 MH.sup.+
Example 938
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1785] MS (ESI) m/z 336 MH.sup.+
Example 939
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid benzylamide
[1786] MS (ESI) m/z 386 MH.sup.+
Example 940
4-Methoxy-3-[(E)-2-(pyrazin-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1787] MS (ESI) m/z 387 MH.sup.+
Example 941
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid ethyl ester
[1788] 550 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
3-fluoro-4-methoxystyrene were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 170 mg of
the title compound as a colorless powder.
[1789] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (3H, t, J=7.2
Hz), 3.93 (3H, s), 4.04 (3H, s), 4.44 (2H, q, J=7.2 Hz), 6.97 (1H,
t, J=8.6 Hz), 7.21 (1H, d, J=8.8 Hz), 7.25-7.30 (1H, m), 7.36 (1H,
dd, J=2.2, 12.6 Hz), 7.52 (1H, d, J=16.4 Hz), 7.56 (1H, d, J=16.4
Hz), 7.90 (1H, d, J=8.8 Hz).
Example 942
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid
[1790] 170 mg of
3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carbox-
ylic acid ethyl ester was treated in the similar method as
described in Example 144, to afford 150 mg of the title compound as
a pale yellow powder.
[1791] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.88 (3H, s),
3.96 (3H, s), 7.20 (1H, t, J=8.8 Hz), 7.29 (1H, d, J=8.8 Hz), 7.42
(1H, bd, J=8.8 Hz), 7.46 (1H, d, J=16.1 Hz), 7.50 (1H, d, J=16.1
Hz), 7.55 (1H, dd, J=2.2, 12.8 Hz), 7.74 (1H, d, J=8.8 Hz), 12.60
(1H, bs), 13.42 (1H, s).
Example 943
3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid and various kinds of amine were condensed in the similar
method as described in Example 44, followed by purification by
LC-MS, to afford the compounds of Examples 944-953.
Example 944
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyrazin-2-ylmethyl)amide
[1792] MS (ESI) m/z 434 MH.sup.+
Example 945
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (furan-2-ylmethyl)amide
[1793] MS (ESI) m/z 422 MH.sup.+
Example 946
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyclopropylmethyl amide
[1794] MS (ESI) m/z 396 MH.sup.+
Example 947
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (thiophen-2-ylmethyl)amide
[1795] MS (ESI) m/z 438 MH.sup.+
Example 948
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyclopropylamide
[1796] MS (ESI) m/z 382 MH.sup.+
Example 949
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid benzylamide
[1797] MS (ESI) m/z 432 MH.sup.+
Example 950
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyridin-3-ylmethyl)amide
[1798] MS (ESI) m/z 433 MH.sup.+
Example 951
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyridin-2-ylmethyl)amide
[1799] MS (ESI) m/z 433 MH.sup.+
Example 952
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (thiophen-3-ylmethyl)amide
[1800] MS (ESI) m/z 438 MH.sup.+
Example 953
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (oxazol-2-ylmethyl)amide
[1801] MS (ESI) m/z 423 MH.sup.+
Example 954
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid ethyl ester
[1802] 550 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
4-fluoro-3-methoxystyrene were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 160 mg of
the title compound as a colorless powder.
[1803] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.45 (3H, t, J=7.2
Hz), 3.94 (3H, s), 4.06 (3H, s), 4.45 (2H, q, J=7.2 Hz), 7.06-7.17
(2H, m), 7.19 (1H, dd, J=1.6, 8.0 Hz), 7.23 (1H, d, J=8.8 Hz), 7.57
(1H, d, J=16.4 Hz), 7.61 (1H, d, J=16.4 Hz), 7.91 (1H, d, J=8.8
Hz).
Example 955
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid
[1804] 160 mg of
3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carbox-
ylic acid ethyl ester was treated in the similar method as
described in Example 144, to afford 140 mg of the title compound as
a colorless powder.
[1805] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta.3.93 (3H, s),
3.96 (3H, s), 7.22-7.28 (2H, m), 7.30 (1H, d, J=8.4 Hz), 7.42 (1H,
dd, J=1.6, 7.6 Hz), 7.54 (1H, d, J=16.3 Hz), 7.55 (1H, d, J=16.3
Hz), 7.74 (1H, d, J=8.4 Hz), 12.60-12.80 (1H, bs), 13.46 (1H,
bs).
Example 956
[1806]
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5--
carboxylic acid and various kinds of amine were condensed in the
similar method as described in Example 44, followed by purification
by LC-MS, to afford the compounds of Examples 957-966.
Example 957
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyrazin-2-ylmethyl)amide
[1807] MS (ESI) m/z 434 MH.sup.+
Example 958
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (furan-2-ylmethyl)amide
[1808] MS (ESI) m/z 422 MH.sup.+
Example 959
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyclopropylmethyl amide
[1809] MS (ESI) m/z 396 MH.sup.+
Example 960
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (thiophen-2-ylmethyl)amide
[1810] MS (ESI) m/z 438 MH.sup.+
Example 961
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyclopropylamide
[1811] MS (ESI) m/z 382 MH.sup.+
Example 962
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid benzylamide
[1812] MS (ESI) m/z 432 MH.sup.+
Example 963
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyridin-3-ylmethyl)amide
[1813] MS (ESI) m/z 433 MH.sup.+
Example 964
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (pyridin-2-ylmethyl)amide
[1814] MS (ESI) m/z 433 MH.sup.+
Example 965
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (thiophen-3-ylmethyl)amide
[1815] MS (ESI) m/z 438 MH.sup.+
Example 966
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid (oxazol-2-ylmethyl)amide
[1816] MS (ESI) m/z 423 MH.sup.+
Example 967
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester
[1817] 410 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
3,4-difluorostyrene were reacted in the similar method as described
in Production example 181, followed by deprotection in the similar
method as described in Example 16, to afford 110 mg of the title
compound as a colorless powder.
[1818] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.45 (3H, t, J=7.2
Hz), 4.05 (3H, s), 4.46 (2H, q, J=7.2 Hz), 7.17 (1H, dt, J=8.1, 9.8
Hz), 7.23 (1H, d, J=9.0 Hz), 7.26-7.31 (1H, m), 7.40 (1H, ddd,
J=2.1, 8.1, 11.4 Hz), 7.56 (1H, d, J=16.4 Hz), 7.58 (1H, d, J=16.4
Hz), 7.92 (1H, d, J=9.0 Hz).
Example 968
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[1819] 110 mg of
3-[(E)-2-(3,4-difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester was treated in the similar method as described in
Example 144, to afford 100 mg of the title compound as a colorless
powder.
[1820] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.97 (3H, s),
7.31 (1H, d, J=8.8 Hz), 7.46 (1H, dt, J=8.4, 10.4 Hz), 7.49-7.55
(1H, m), 7.54 (1H, d, J=16.4 Hz), 7.57 (1H, d, J=16.4 Hz), 7.75
(1H, d, J=8.8 Hz), 7.77 (1H, ddd, J=1.9, 8.4, 12.1 Hz), 12.75 (1H,
bs), 13.51 (1H, bs).
Example 969
[1821]
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbox-
ylic acid and various kinds of amine were condensed in the similar
method as described in Example 44, followed by purification by
LC-MS, to afford the compounds of Examples 970-979.
Example 970
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)amide
[1822] MS (ESI) m/z 422 MH.sup.+
Example 971
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)amide
[1823] MS (ESI) m/z 410 MH.sup.+
Example 972
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylmethyl amide
[1824] MS (ESI) m/z 384 MH.sup.+
Example 973
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)amide
[1825] MS (ESI) m/z 426 MH.sup.+
Example 974
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1826] MS (ESI) m/z 370 MH.sup.+
Example 975
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid benzylamide
[1827] MS (ESI) m/z 420 MH.sup.+
Example 976
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)amide
[1828] MS (ESI) m/z 421 MH.sup.+
Example 977
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-2-ylmethyl)amide
[1829] MS (ESI) m/z 421 MH.sup.+
Example 978
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-3-ylmethyl)amide
[1830] MS (ESI) m/z 426 MH.sup.+
Example 979
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (oxazol-2-ylmethyl)amide
[1831] MS (ESI) m/z 411 MH.sup.+
Example 980
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester
[1832] 410 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
2,4-difluorostyrene were reacted in the similar method as described
in Production example 181, followed by deprotection in the similar
method as described in Example 16, to afford 50 mg of the title
compound as a colorless powder.
[1833] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.46 (3H, t, J=7.2
Hz), 4.05 (3H, s), 4.43 (2H, q, J=7.2 Hz), 6.87 (1H, ddd, J=2.6,
8.4, 11.2 Hz), 6.93 (1H, dt, J=2.7, 8.4 Hz), 7.24 (1H, d, J=8.8
Hz), 7.62 (1H, dt, J=6.4, 8.4 Hz), 7.70 (1H, d, J=16.4 Hz), 7.75
(1H, d, J=16.4 Hz), 7.92 (1H, d, J=8.8 Hz).
Example 981
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[1834] 50 mg of
3-[(E)-2-(2,4-difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester was treated in the similar method as described in
Example 144, to afford 40 mg of the title compound as a colorless
powder.
[1835] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.95 (3H, s),
7.17 (1H, dt, J=2.4, 8.8 Hz), 7.30-7.38 (1H, m), 7.32 (1H, d, J=8.8
Hz), 7.61 (1H, d, J=16.4 Hz), 7.67 (1H, d, J=16.4 Hz), 7.75 (1H, d,
J=8.8 Hz), 7.88 (1H, dt, J=6.8, 8.8 Hz), 12.68-12.82 (1H, bs),
13.52 (1H, bs).
Example 982
[1836]
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbox-
ylic acid and various kinds of amine were condensed in the similar
method as described in Example 44, followed by purification by
LC-MS, to afford the compounds of Examples 983-992.
Example 983
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)amide
[1837] MS (ESI) m/z 422 MH.sup.+
Example 984
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)amide
[1838] MS (ESI) m/z 410 MH.sup.+
Example 985
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylmethyl amide
[1839] MS (ESI) m/z 384 MH.sup.+
Example 986
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)amide
[1840] MS (ESI) m/z 426 MH.sup.+
Example 987
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1841] MS (ESI) m/z 370 MH.sup.+
Example 988
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid benzylamide
[1842] MS (ESI) m/z 420 MH.sup.+
Example 989
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)amide
[1843] MS (ESI) m/z 421 MH.sup.+
Example 990
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-2-ylmethyl)amide
[1844] MS (ESI) m/z 421 MH.sup.+
Example 991
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-3-ylmethyl)amide
[1845] MS (ESI) m/z 426 MH.sup.+
Example 992
3-[(E)-2-(2,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (oxazol-2-ylmethyl)amide
[1846] MS (ESI) m/z 411 MH.sup.+
Production Example 993
6-Fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-5-nitro-1-trityl-1H-in-
dazole
[1847] 505 mg of 6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole
obtained by Production example 747 and 304 mg of
3-methoxy-4-fluorostyrene were reacted in the similar method as
described in Production example 181, to afford 145 mg of the title
compound as a yellow powder.
[1848] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.93 (3H, s),
6.16 (1H, d, J=12.4 Hz), 7.21-7.30 (6H, m), 7.30-7.45 (11H, m),
7.46 (1H, d, J=16.4 Hz), 7.57 (1H, d, J=2.0, 8.4 Hz), 7.62 (1H, d,
J=16.4 Hz), 9.12 (1H, d, J=7.6 Hz).
Production Example 994
6-Fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1-trityl-1H-indazol-5--
ylamine
[1849] 145 mg of
6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-5-nitro-1-trityl-1H-i-
ndazole obtained by Production example 993 was reduced in the
similar method as described in Production example 182, to afford
130 mg of the title compound as a pale brown oil.
[1850] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.93 (3H, s), 6.16
(1H, d, J=11.9 Hz), 7.00-7.26 (2H, m), 7.14 (1H, dd, J=2.0, 8.1
Hz), 7.20-7.35 (18H, m).
Example 995
[1851] In the similar method as described in Example 183, from
6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1-trityl-1H-indazol-5-
-ylamine and various kinds of carboxylic acid, the compounds of
Examples 996-1004 were obtained.
Example 996
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1852] MS (ESI) m/z 370 MH.sup.+
Example 997
1-Hydroxycyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1853] MS (ESI) m/z 386 MH.sup.+
Example 998
1-Acetyl piperidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1854] MS (ESI) m/z 455 MH.sup.+
Example 999
Tetrahydrofuran-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1855] MS (ESI) m/z 400 MH.sup.+
Example 1000
1-Methylaminocyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1856] MS (ESI) m/z 399 MH.sup.+
Example 1001
N-{6-Fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}-2--
(thiophen-2-yl)acetamide
[1857] MS (ESI) m/z 426 MH.sup.+
Example 1002 Furan-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1858] MS (ESI) m/z 396 MH.sup.+
Example 1003
2-Cyclopropyl-N-{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-in-
dazol-5-yl}acetamide
[1859] MS (ESI) m/z 384 MH.sup.+
Example 1004
(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluoro-3-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1860] MS (ESI) m/z 415 MH.sup.+
Production Example 1005
6-Fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-5-nitro-1-trityl-1H-in-
dazole
[1861] 505 mg of 6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole
obtained by Production example 747 and 304 mg of
4-methoxy-3-fluorostyrene were reacted in the similar method as
described in Production example 181, to afford 160 mg of the title
compound as a yellow powder.
[1862] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.87 (3H, s),
6.11 (1H, d, J=12.4 Hz), 7.18 (1H, t, J=8.8 Hz), 7.18-7.27 (6H, m),
7.31-7.44 (11H, m), 7.60 (1H, d, J=16.4 Hz), 7.75 (1H, d, J=2.0,
13.2 Hz), 9.15 (1H, d, J=7.6 Hz).
Production Example 1006
6-Fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1-trityl-1H-indazol-5--
ylamine
[1863] 160 mg of
6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-5-nitro-1-trityl-1H-i-
ndazole obtained by Production example 1005 was reduced in the
similar method as described in Production example 182, to afford
140 mg of the title compound as a pale brown oil.
[1864] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.89 (3H, s), 6.15
(1H, d, J=12.6 Hz), 6.92 (1H, t, J=8.8 Hz), 7.15-7.38 (20H, m).
Example 1007
[1865] In the similar method as described in Example 183, from
6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1-trityl-1H-indazol-5-
-ylamine and various kinds of carboxylic acid, the compounds of
Examples 1008-1016 were obtained.
Example 1008
Cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1866] MS (ESI) m/z 370 MH.sup.+
Example 1009
1-Hydroxycyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1867] MS (ESI) m/z 386 MH.sup.+
Example 1010
1-Acetyl piperidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1868] MS (ESI) m/z 455 MH.sup.+
Example 1011
Tetrahydrofuran-3-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1869] MS (ESI) m/z 400 MH.sup.+
Example 1012
1-Methylaminocyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1870] MS (ESI) m/z 399 MH.sup.+
Example 1013
N-{6-Fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}-2--
(thiophen-2-yl)acetamide
[1871] MS (ESI) m/z 426 MH.sup.+
Example 1014
Furan-2-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1872] MS (ESI) m/z 396 MH.sup.+
Example 1015
2-Cyclopropyl-N-{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-in-
dazol-5-yl}acetamide
[1873] MS (ESI) m/z 384 MH.sup.+
Example 1016
(2S,4R)-4-Hydroxypyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluoro-4-methoxyphenyl)-vinyl]-1H-indazol-5-yl}amid-
e
[1874] MS (ESI) m/z 415 MH.sup.+
Example 1017
[1875] 96 pieces of polystyrene labeled with TRANSTEM.TM. (SynPhase
Polystyrene D-Seriese,Trityl.TM.) were prepared and left in 130 mL
of a solution of 20 mL acetyl chloride in dichloromethane for 3
hours. After removing the solution, the resin pieces were washed
three times with dichloromethane, dried under reduced pressure, and
the resin was heated at 80.degree. C. for 4 hours in 100 mL of
solution of 4.7 g of 3-iodo-4-methoxy-1H-indazole-5-carboxylic acid
methyl ester produced as intermediate of Production example 890 and
2.2 mL of diisopropylethylamine in N-methylpyrrolidone. After
removing the solution, the resin was washed successively with
N-methylpyrrolidone, ethanol, water, methanol and tetrahydrofuran,
and dried under reduced pressure.
[1876] The resultant resin pieces were divided into several groups
each consisting of 10 pieces in accordance with the label, and each
resin piece was added to 10 mL of previously-prepared several kinds
of 0.5 M styrene compound in a mixed solution of
N-methylpyrrolidone-triethylamine (7.5:2.5). To each reaction
solution were added 150 mg of 0.5M
2-(di-tert-butylphosphino)biphenyl and 110 mg of palladium acetate
(II), and heated at 100.degree. C. for 8 hours. After removing the
solution, the resin was washed in the manner as described in the
above operation, and dried under reduced pressure.
[1877] The resultant resin was heated at reflux for 12 hours in a
mixed solution of ethanol (2 mL), dioxane (0.7 mL), 5N sodium
hydroxide aqueous solution (2 mL), washed in the similar method as
described in the above operation, and dried under reduced
pressure.
[1878] Then the resin pieces were divided into several groups in
accordance with the label, and each resin piece was added with 15
mL of a previously-prepared different 0.5 M amine in
N-methylpyrrolidone. To each container, 1.15 g of
1-hydroxybenzotriazole monohydrate, 1.2 mL of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (.dbd.WSC) and 2.0 mL
of diisopropylethylamine were successively added, sonicated for 1
hour, and then left overnight at room temperature. After removing
the solution, the resin was washed in the manner as described in
the above operation, and dried under reduced pressure. In
accordance with the label of resin, they were arranged in a 96-well
pin plate.
[1879] The resin was immersed in a mixed solution of 0.5 mL
trifluoroacetic acid/0.1 mL triisopropylsilane/0.5 mL
dichloromethane prepared in advance in 96-well plate, and after
conducting sonication for 10 minutes, they were left for 30
minutes. This operation was repeated twice, and then the resin was
washed with 1 mL of N,N-dimethylformamide. Next, nitrogen was blown
in to the acid-treated wells and the resultant residues were
dissolved in N,N-dimethylformamide solution obtained during washing
operation, followed by purification and separation by LC-MS, to
afford the compounds of Examples 1018-1029.
Example 1018
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)-amide
[1880] MS (ESI) m/z 416 MH.sup.+
Example 1019
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1881] MS (ESI) m/z 404 MH.sup.+
Example 1020
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1882] MS (ESI) m/z 420 MH.sup.+
Example 1021
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid benzylamide
[1883] MS (ESI) m/z 414 MH.sup.+
Example 1022
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1884] MS (ESI) m/z 415 MH.sup.+
Example 1023
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyrazin-2-ylmethyl)-amide
[1885] MS (ESI) m/z 446 MH.sup.+
Example 1024
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-3-ylmethyl)-amide
[1886] MS (ESI) m/z 434 MH.sup.+
Example 1025
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylmethyl-amide
[1887] MS (ESI) m/z 408 MH.sup.+
Example 1026
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (thiophen-2-ylmethyl)-amide
[1888] MS (ESI) m/z 450 MH.sup.+
Example 1027
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1889] MS (ESI) m/z 394 MH.sup.+
Example 1028
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid benzylamide
[1890] MS (ESI) m/z 444 MH.sup.+
Example 1029
3-[(E)-2-(3,4-Dimethoxy-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (pyridin-3-ylmethyl)-amide
[1891] MS (ESI) m/z 445 MH.sup.+
Example 1030
[1892]
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yla-
mine obtained by Production example 182 and various kinds of
carboxylic acid were treated in the similar method as described in
Example 183, to afford the compounds of Examples 1031-1053.
Example 1031
3-Oxo-cyclopentane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1893] MS (ESI) m/z 382 MH.sup.+
Example 1032
1-(4-Methoxy-phenyl)-cyclopentane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1894] MS (ESI) m/z 474 MH.sup.+
Example 1033
2,2-Dimethyl-5-oxo-tetrahydrofuran-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1895] MS (ESI) m/z 412 MH.sup.+
Example 1034
(4S)-2-oxo-thiazolidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1896] MS (ESI) m/z 401 MH.sup.+
Example 1035
5-oxo-tetrahydrofuran-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1897] MS (ESI) m/z 384 MH.sup.+
Example 1036
(2S)-Pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1898] MS (ESI) m/z 369 MH.sup.+
Example 1037
(2R)-Pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1899] MS (ESI) m/z 369 MH.sup.+
Example 1038
(4S)-Thiazolidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1900] MS (ESI) m/z 387 MH.sup.+
Example 1039
1-Amino-cyclopentane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1901] MS (ESI) m/z 383 MH.sup.+
Example 1040
Tetrahydrofuran-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1902] MS (ESI) m/z 370 MH.sup.+
Example 1041
Tetrahydrofuran-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1903] MS (ESI) m/z 370 MH.sup.+
Example 1042
(2R)-2-Amino-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-
-2-(thiophen-2-yl)-acetamide
[1904] MS (ESI) m/z 411 MH.sup.+
Example 1043
5-Oxo-1-(thiophen-2-ylmethyl)-pyrrolidine-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1905] MS (ESI) m/z 479 MH.sup.+
Example 1044
1-(Furan-2-ylmethyl)-5-oxo-pyrrolidine-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-amide
[1906] MS (ESI) m/z 463 MH.sup.+
Example 1045
Piperidine-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1907] MS (ESI) m/z 383 MH.sup.+
Example 1046
Piperidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1908] MS (ESI) m/z 383 MH.sup.+
Example 1047
Piperidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1909] MS (ESI) m/z 383 MH.sup.+
Example 1048
1-Acetyl-piperidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1910] MS (ESI) m/z 425 MH.sup.+
Example 1049
1-Amino-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1911] MS (ESI) m/z 355 MH.sup.+
Example 1050
2-Oxo-imidazolidine-4-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1912] MS (ESI) m/z 384 MH.sup.+
Example 1051
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(morpholin-
-4-yl)-acetamide
[1913] MS (ESI) m/z 399 MH.sup.+
Example 1052
(2S)-1-Methyl-pyrrolidine-2-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1914] MS (ESI) m/z 383 MH.sup.+
Example 1053
2-Amino-N-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(p-
yridin-3-yl)-acetamide
[1915] MS (ESI) m/z 406 MH.sup.+
Example 1054
1-Ethyl-3-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-urea
[1916] 10 mg of
6-fluoro-3-[E-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamine
obtained by Production example 182 and 3 .mu.l of ethyl isocyanate
was dissolved in 5 mL of chloroform, and heated at reflux for 2
hours. The reaction solution was allowed to cool to room
temperature, added with 0.5 mL of trifluoroacetic acid, stirred at
room temperature for 30 minutes, and the reaction mixture was
purified and separated by LC-MS, to afford 0.67 mg of the title
compound as pale yellow powder.
[1917] MS (ESI) m/z 343 MH.sup.+
Example 1055
[1918]
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yla-
mine obtained by Production example 182 and various kinds of
isocyanate were treated in the similar method as described in
Example 1054, to afford the compounds of Examples 1056-1060.
Example 1056
1-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-propyl-ure-
a
[1919] MS (ESI) m/z 357 MH.sup.+
Example 1057
1-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-3-isopropyl-
-urea
[1920] MS (ESI) m/z 357 MH.sup.+
Example 1058
1-tert-Butyl-3-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-
-urea
[1921] MS (ESI) m/z 371 MH.sup.+
Example 1059
1-Cyclohexyl-3-{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-
-urea
[1922] MS (ESI) m/z 397 MH.sup.+
Example 1060
1-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-3-phenyl-ure-
a
[1923] MS (ESI) m/z 391 MH.sup.+
Example 1061
[1924] 3-vinyl-4-methoxy-1-trityl-1H-indazole-5-carbonitrile
obtained by Production example 323 and various kinds of aryl halide
were subjected to Heck reaction in accordance with Production
Example 324, and deprotected in accordance with Example 16,
followed by separation and purification by LC-MS, to afford the
compounds of Examples 1062-1065.
Example 1062
4-Methoxy-3-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-1H-indazole-5-carboni-
trile
[1925] MS (ESI) m/z 344 MH.sup.+
Example 1063
4-Methoxy-3-[(E)-2-(3-trifluoromethyl-phenyl)-vinyl]-1H-indazole-5-carboni-
trile
[1926] MS (ESI) m/z 344 MH.sup.+
Example 1064
3-[(E)-2-(5-Hydroxymethyl-pyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-car-
bonitrile
[1927] MS (ESI) m/z 307 MH.sup.+
Example 1065
4-Methoxy-3-[(E)-2-(2-trifluoromethyl-phenyl)-vinyl]-1H-indazole-5-carboni-
trile
[1928] MS (ESI) m/z 344 MH.sup.+
Production Example 1066
4-Methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid ethyl
ester
[1929] In accordance with Production example 123, from 2.80 g of
3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic acid ethyl ester
obtained by Production example 276, 1.87 g of the title compound
was obtained as ocher crystals.
[1930] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.37 (3H, t, J=6.8
Hz), 4.00 (3H, s), 4.35 (3H, q, J=6.8 Hz), 5.36 (1H, d, J=16.0 Hz),
6.07-6.14 (2H, m), 7.18-7.23 (17H, m)
Production Example 1067
4-Methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
[1931] In accordance with Production example 350, from 1.87 g of
4-methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid ethyl
ester, 1.07 g of the title compound was obtained as white
crystals.
[1932] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.89 (3H, s),
5.37 (1H, d, J=11.2 Hz), 5.91 (1H, d, J=17.6 Hz), 6.07 (1H, d, 8.8
Hz), 7.08-7.15 (7H, m), 7.26-7.35 (10H, m)
Production Example 1068
4-Methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
cyclopropylamide
[1933] In accordance with Production example 127, from 400 mg of
4-methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid and
cyclopropylamine, 464 mg of the title compound was obtained as
white crystals.
[1934] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.48-0.52 (2H,
m), 0.63-0.66 (2H, m), 2.79-2.82 (1H, m), 3.84 (3H, s), 5.37 (1H,
d, J=11.2 Hz), 5.92 (1H, d, J=17.6 Hz), 6.07 (1H, d, J=8.8 Hz),
7.04 (1H, d, J=8.8 Hz), 7.08-7.16 (6H, m), 7.28-7.36 (10H, m), 8.26
(1H, d, J=4.8 Hz)
Production Example 1069
4-Methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
[(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1935] In accordance with Production example 127, from 310 mg of
4-methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid obtained
by Production example 1067 and (2S)-2-amino-2-phenyl-ethanol, 270
mg of the title compound was obtained as white crystals.
[1936] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.60-3.63 (2H,
m), 3.81 (3H, s), 4.92 (1H, t, J=6.8 Hz), 5.10 (1H, br s), 5.37
(1H, d, J=11.2 Hz), 5.92 (1H, d, J=17.6 Hz), 6.08 (1H, d, J=8.8
Hz), 7.08-7.36 (22H, m), 8.65 (1H, d, J=8.4 Hz)
Production Example 1070
4-Methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
(furan-2-ylmethyl)-amide
[1937] In accordance with Production example 127, from 542 mg of
4-methoxy-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid obtained
by Production example 1067 and furan-2-ylmethylamine, 329 mg of the
title compound was obtained as white crystals.
[1938] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 3.84 (3H, s), 4.65
(2H, d, J=5.2 Hz), 5.37 (1H, d, J=11.2 Hz), 6.07 (1H, d, 17.6 Hz),
6.18 (1H, d, J=8.8 Hz), 6.30 (1H, d, J=16.8 Hz), 7.06-7.27 (18H,
m), 7.63 (1H, d, J=9.6 Hz), 8.05 (1H, br s)
Production Example 1071
3-Bromo-7-fluoro-1H-indazole-5-carboxylic acid
[1939] In accordance with Production example 7, from 10.00 g of
3-bromo-7-fluoro-1-trityl-1H-indazole-5-carbonitrile obtained by
Production example 122, 3.80 g of the title compound was obtained
as ocher crystals.
[1940] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 7.25-7.39 (1H,
br s), 7.75 (1H, d, J=11.6 Hz), 8.03 (1H,
Production Example 1072
7-Fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
[1941] From 3.80 g of 3-bromo-7-fluoro-1H-indazole-5-carboxylic
acid, an ester compound was obtained in accordance with Production
Example 274, then the ester was tritylated in accordance with
Production example 22, and a vinyl group was introduced in
accordance with Production example 123. Further, by hydrolyzing the
ester in accordance with Production example 350, 410 mg of the
title compound was obtained as white crystals.
[1942] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 5.53 (1H, d,
J=11.2 Hz), 6.19 (1H, d, J=17.6 Hz), 7.10-7.38 (16H, m), 7.45 (1H,
d, J=11.2 Hz), 8.53 (1H, s)
Production Example 1073
7-Fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid
cyclopropylamide
[1943] In accordance with Production example 127, from 120 mg of
7-fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid and
cyclopropylamine, 73 mg of the title compound was obtained as white
crystals.
[1944] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 0.58-0.62 (2H, m),
0.84-0.91 (2H, m), 2.81-2.94 (1H, m), 5.51 (1H, d, J=11.2 Hz), 6.04
(1H, d, J=18.0 Hz), 6.21 (1H, br s), 6.93 (1H, dd, J=18.0, 18.0
Hz), 7.10-7.16 (6H, m), 7.22-7.32 (10H, m), 8.09 (1H, s)
Example 1074
[1945] Vinyl compounds obtained by Production examples 1068-1070
and 1073 and various kinds of aryl halide were subjected to Heck
reaction in accordance with Production example 324, and deprotected
in accordance with Example 16, followed by separation and
purification by LC-MS, to afford the compounds of Examples
1075-1125.
Example 1075
3-[(E)-2-(2-Hydroxymethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1946] MS (ESI) m/z 364 MH.sup.+
Example 1076
3-[(E)-2-(3-Hydroxymethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1947] MS (ESI) m/z 364 MH.sup.+
Example 1077
7-Fluoro-3-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-1H-indazole-5-carboxyl-
ic acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1948] MS (ESI) m/z 470 MH.sup.+
Example 1078
4-Methoxy-3-[(E)-2-(2-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1949] MS (ESI) m/z 364 MH.sup.+
Example 1079
4-Methoxy-3-[(E)-2-(3-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1950] MS (ESI) m/z 364 MH.sup.+
Example 1080
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1951] MS (ESI) m/z 364 MH.sup.+
Example 1081
3-[(E)-2-(4-Hydroxymethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1952] MS (ESI) m/z 364 MH.sup.+
Example 1082
3-{(E)-2-[4-(2-Hydroxyethyl)-phenyl]-vinyl}-4-methoxy-1H-indazole-5-carbox-
ylic acid cyclopropylamide
[1953] MS (ESI) m/z 378 MH.sup.+
Example 1083
3-[(E)-2-(4-Cyanomethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1954] MS (ESI) m/z 373 MH.sup.+
Example 1084
3-[(E)-2-(4-Acetylaminophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1955] MS (ESI) m/z 471 MH.sup.+
Example 1085
3-[(E)-2-(4-Dimethylamino-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1956] MS (ESI) m/z 457 MH.sup.+
Example 1086
3-[(E)-2-(3-Dimethylamino-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1957] MS (ESI) m/z 457 MH.sup.+
Example 1087
4-Methoxy-3-[(E)-2-(2-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1958] MS (ESI) m/z 444 MH.sup.+
Example 1088
4-Methoxy-3-[(E)-2-(3-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1959] MS (ESI) m/z 444 MH.sup.+
Example 1089
4-Methoxy-3-[(E)-2-(4-methoxy-phenyl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1960] MS (ESI) m/z 444 MH.sup.+
Example 1090
3-[(E)-2-(3-Hydroxymethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1961] MS (ESI) m/z 444 MH.sup.+
Example 1091
4-Methoxy-3-[(E)-2-(3-methoxymethyl-phenyl)-vinyl]-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1962] MS (ESI) m/z 458 MH.sup.+
Example 1092
3-[(E)-2-(3-Aminomethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1963] MS (ESI) m/z 443 MH.sup.+
Example 1093
3-{(E)-2-[3-(Acetylamino-methyl)-phenyl]-vinyl}-4-methoxy-1H-indazole-5-ca-
rboxylic acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1964] MS (ESI) m/z 485 MH.sup.+
Example 1094
3-[(E)-2-(4-Hydroxymethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1965] MS (ESI) m/z 444 MH.sup.+
Example 1095
4-Methoxy-3-[(E)-2-(4-methoxymethyl-phenyl)-vinyl]-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1966] MS (ESI) m/z 458 MH.sup.+
Example 1096
3-[(E)-2-(4-Aminomethyl-phenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1967] MS (ESI) m/z 443 MH.sup.+
Example 1097
3-{(E)-2-[4-(Acetylamino-methyl)-phenyl]-vinyl}-4-methoxy-1H-indazole-5-ca-
rboxylic acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1968] MS (ESI) m/z 485 MH.sup.+
Example 1098
4-Methoxy-3-[(E)-2-(thiophen-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1969] MS (ESI) m/z 340 MH.sup.+
Example 1099
4-Methoxy-3-[(E)-2-(thiophen-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1970] MS (ESI) m/z 420 MH.sup.+
Example 1100
4-Methoxy-3-[(E)-2-(thiophen-3-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1971] MS (ESI) m/z 380 MH.sup.+
Example 1101
4-Methoxy-3-[(E)-2-(3-methyl-thiophen-2-yl)-vinyl]-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1972] MS (ESI) m/z 354 MH.sup.+
Example 1102
4-Methoxy-3-[(E)-2-(3-methyl-thiophen-2-yl)-vinyl]-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1973] MS (ESI) m/z 434 MH.sup.+
Example 1103
4-Methoxy-3-[(E)-2-(3-methyl-thiophen-2-yl)-vinyl]-1H-indazole-5-carboxyli-
c acid (furan-2-ylmethyl)-amide
[1974] MS (ESI) m/z 394 MH.sup.+
Example 1104
3-[(E)-2-(5-Acetyl-thiophen-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid cyclopropylamide
[1975] MS (ESI) m/z 382 MH.sup.+
Example 1105
3-[(E)-2-(5-Acetyl-thiophen-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1976] MS (ESI) m/z 462 MH.sup.+
Example 1106
3-[(E)-2-(5-Acetyl-thiophen-2-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxyli-
c acid (furan-2-ylmethyl)-amide
[1977] MS (ESI) m/z 422 MH.sup.+
Example 1107
3-[(E)-2-(Furan-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1978] MS (ESI) m/z 324 MH.sup.+
Example 1108
3-[(E)-2-(Furan-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1979] MS (ESI) m/z 404 MH.sup.+
Example 1109
3-[(E)-2-(Furan-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1980] MS (ESI) m/z 364 MH.sup.+
Example 1110
4-Methoxy-3-[(E)-2-(thiazol-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylamide
[1981] MS (ESI) m/z 341 MH.sup.+
Example 1111
4-Methoxy-3-[(E)-2-(thiazol-2-yl)-vinyl]-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1982] MS (ESI) m/z 381 MH.sup.+
Example 1112
3-[(E)-2-(6-Fluoro-pyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylamide
[1983] MS (ESI) m/z 353 MH.sup.+
Example 1113
3-[(E)-2-(6-Fluoro-pyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(1S)-(2-hydroxy-1-phenyl-ethyl)]-amide
[1984] MS (ESI) m/z 433 MH.sup.+
Example 1114
3-[(E)-2-(6-Fluoro-pyridin-3-yl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (furan-2-ylmethyl)-amide
[1985] MS (ESI) m/z 393 MH.sup.+
Example 1115
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1986] MS (ESI) m/z 340 MH.sup.+
Example 1116
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[1987] MS (ESI) m/z 340 MH.sup.+
Example 1117
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-yl}-amide
[1988] MS (ESI) m/z 340 MH.sup.+
Example 1118
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-styryl]-1H-indazol-5-yl}-amide
[1989] MS (ESI) m/z 322 MH.sup.+
Example 1119
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1990] MS (ESI) m/z 328 MH.sup.+
Example 1120
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(thiophen-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1991] MS (ESI) m/z 328 MH.sup.+
Example 1121
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(pyridin-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1992] MS (ESI) m/z 323 MH.sup.+
Example 1122
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1993] MS (ESI) m/z 323 MH.sup.+
Example 1123
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(pyridin-4-yl)-vinyl]-1H-indazol-5-yl}-amide
[1994] MS (ESI) m/z 323 MH.sup.+
Example 1124
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(6-methoxy-pyridin-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[1995] MS (ESI) m/z 353 MH.sup.+
Example 1125
Cyclopropane carboxylic acid
{7-fluoro-3-[(E)-2-(6-methoxy-pyridin-3-yl)-vinyl]-1H-indazol-5-yl}-amide
[1996] MS (ESI) m/z 353 MH.sup.+
Production Example 1126
3-Iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid
[1997] To a suspension of 3.0 g of
3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile obtained
by Production example 431 in 20 mL of ethanol was added 20 mL of 4N
lithium hydroxide aqueous solution at room temperature, and heated
at reflux for a day. After cooling to room temperature, the
solution was neutralized with 5N hydrochloric acid aqueous
solution, and the precipitated crystals were collected by
filtration. The crystals were washed successively with water and
diethyl ether, to afford 3.0 g of the title compound as colorless
crystals.
[1998] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.14-7.18 (6H, m),
7.33-7.39 (9H, m), 7.57 (1H, d, J=1.2 Hz), 8.07 (1H, d, J=1.2
Hz).
Production Example 1127
(3-Iodo-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamic acid
tert-butyl ester
[1999] To a suspension of 1.0 g of
3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridine-5-carboxylic acid in
tert-butanol were added 0.57 g of diphenylphosphoryl azide and 0.31
mL of triethylamine at room temperature, and heated at reflux for 6
hours. The solution was diluted with ethyl acetate, the organic
layer was washed successively with water and saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
and the crude product was purified and separated by silica gel
column chromatography (ethyl acetate:n-hexane=1:10), to afford 455
mg of the title compound as colorless crystals.
[2000] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.53 (9H, s), 7.07
(1H, bs), 7.15-7.19 (6H, m), 7.21 (1H, d, J=1.2 Hz), 7.25-7.29 (9H,
m), 7.84 (1H, bs).
Production Example 1128
{3-[(E)-2-(4-Fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl}c-
arbamic acid tert-butyl ester
[2001] To a solution of 400 mg of
(3-iodo-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl)carbamic acid
tert-butyl ester and 162 mg of 4-fluorostyrene in 2.0 mL of
N,N-dimethylformamide were added 15 mg of palladium acetate, 40 mg
of 2-(di-tert-butylphosphino)biphenyl and 0.46 mL of triethylamine
at room temperature, and stirred at 80.degree. C. for 6 hours.
After diluting with ethyl acetate, the organic layer was washed
successively with saturated aqueous ammonium chloride and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and the crude product was purified and separated by
silica gel column chromatography (ethyl
acetate:n-hexane=1:10-dichloromethane:n-hexane-1:1-ethyl
acetate:n-hexane=1:3). The resultant crystals were washed with
diethyl ether, to afford 270 mg of the title compound as colorless
crystals.
[2002] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.55 (9H, s)/7.04
(2H, t, J=8.4 Hz), 7.08 (1H, bs), 7.20-7.30 (m, 16H), 7.31 (1H, d,
J=1.6 Hz), 7.37 (1H, d, J=16.4 Hz), 7.51 (2H, dd, J=8.4, 5.6 Hz),
8.32 (1H, bs)
Example 1129
3-[(E)-2-(4-Fluorophenyl)vinyl]-1H-pyrazolo[3,4-c]pyridin-5-ylamine
[2003] To a solution of 10 mg of
{3-[(E)-2-(4-fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl}-
carbamic acid tert-butyl ester in 0.5 mL of dichloromethane was
added 0.2 mL of trifluoroacetic acid at room temperature, and
stirred at this temperature for 10 minutes. Following concentration
by nitrogen blowing, the residue was separated and purified by
LC-MS, to afford the title compound.
[2004] MS (ESI) m/z 255 MH.sup.+
Example 1130
N-{3-[(E)-2-(4-Fluorophenyl)vinyl]-1H-pyrazolo[3,4-c]-pyridin-5-yl}acetami-
de
[2005] To a solution of 10 mg of
{3-[(E)-2-(4-fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl}-
carbamic acid tert-butyl ester obtained by Production example 1128
in 0.2 mL of dichloromethane were successively added 7 .mu.l of
diisopropylethylamine at room temperature and 3 .mu.l of acetyl
chloride, and stirred at this temperature for a day. To this
reaction solution was added 0.1 mL of trifluoroacetic acid at this
temperature and stirred for 10 minutes. Following concentration by
nitrogen blowing, the residue was separated and purified by LC-MS,
to afford the title compound.
[2006] MS (ESI) m/z 297 MH.sup.+
Example 1131
[2007] The compounds of Examples 1132 and 1133 were synthesized
from
{3-[(E)-2-(4-fluorophenyl)vinyl]-1-trityl-1H-pyrazolo[3,4-c]pyridin-5-yl}-
carbamic acid tert-butyl ester and commercially available acid
chloride in accordance with the procedure of Example 1130.
Example 1132
Cyclopropane carboxylic acid
{3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}amide
[2008] MS (ESI) m/z 323 MH.sup.+
Example 1133
Furan-2-carboxylic acid
{3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-pyrazolo[3,4-c]pyridin-5-yl}amide
[2009] MS (ESI) m/z 349 MH.sup.+
Example 1134
[2010] In accordance with the method of Example 598,
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 or
6-fluoro-3-[(E)-2-(4-fluoro-phenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 559 and various
kinds of hydrazide, the compounds of Examples 1135-1138 were
obtained.
Example 1135
(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,4]oxad-
iazol-2-ylmethyl)-methyl-amine
[2011] MS (ESI) m/z 368 MH.sup.+
Example 1136
1-(5-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,4]ox-
adiazol-2-yl)-cyclopropylamine
[2012] MS (ESI) m/z 380 MH.sup.+
Example 1137
(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,4]oxad-
iazol-2-ylmethyl)-methyl-amine
[2013] MS (ESI) m/z 368 MH.sup.+
Example 1138
1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-[1,3,4]ox-
adiazol-2-yl)-cyclopropylamine
[2014] MS (ESI) m/z 380 MH.sup.+
Production Example 1139
Piperidin-1-yl-acetic acid hydrazide
[2015] 3.86 g of piperidin-1-yl-acetic acid ethyl ester was
dissolved in 40 mL of ethanol, added with 3.39 mL of hydrazine
monohydrate, and stirred at 70.degree. C. for 5 hours. After
allowing the solution to cool to room temperature, the solvent was
evaporated, to afford 3.8 g of the title compound as pale yellow
crystals.
[2016] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.38-1.48 (2H, m),
1.51-1.63 (4H, m), 2.42 (4H, brs), 3.02 (2H, s), 3.84 (2H, brs),
8.22 (1H, brs)
Production Example 1140
Pyridin-3-yl-acetic acid hydrazide
[2017] In accordance with Production example 1139, from 5.37 g of
pyridin-3-yl-acetic acid ethyl ester, 6.0 g of the title compound
was obtained as pale yellow crystals.
[2018] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 4.22 (2H, brs),
7.32 (1H, ddd, J=7.6, 4.8, 0.8 Hz), 7.64-7.68 (1H, m), 8.42-8.46
(2H, m), 9.29 (1H, brs)
Example 1141
[2019] In accordance with the method of Example 371 or 375, from
7-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383, and
hydrazide obtained by Production example 1140 or various kinds of
hydrazide synthesized in accordance with Production examples
366-367, the compounds of Examples 1142-1145 were obtained.
Example 1142
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-[5-(piperidin-4-yl)-4H-[1,2,4]-
triazol-3-yl]-1H-indazole
[2020] MS (ESI) m/z 407 MH.sup.+
Example 1143
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-[5-(pyridine-3-yl)methyl-4H-[1-
,2,4]triazol-3-yl]-1H-indazole
[2021] MS (ESI) m/z 415 MH.sup.+
Example 1144
1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H-[1,2,4-
]triazol-3-yl)-cyclopentylamine
[2022] MS (ESI) m/z 407 MH.sup.+
Example 1145
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-[5-(piperidin-4-yl)methyl-4H-[-
1,2,4]triazol-3-yl]-1H-indazole
[2023] MS (ESI) m/z 421 MH.sup.+
Example 1146
7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-5-[5-(piperidin-1-yl)methyl-4H-[-
1,2,4]triazol-3-yl]-1H-indazole
[2024] 13 mg piperidin-1-yl-acetic acid hydrazide produced by
Production example 1139 and 15 mg of
7-fluoro-3-{E-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 were
dissolved in 1 mL of butanol, and added with 30 .mu.l of
triethylamine. After stirring at 105.degree. C. for 8 hours, the
solution was purification by LC-MS, to afford 2.08 mg of the title
compound.
[2025] MS (ESI) m/z 421 MH.sup.+
Example 1147
[(1S)-1-(5-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-4H--
[1,2,4]triazol-3-yl)-2-methyl-propyl]-methyl-amine
[2026] 20.2 mg of
[(1S)-1-hydrazinocarbonyl-2-methyl-propyl]-methylcarbamic acid
tert-butyl ester and 15 mg of
7-fluoro-3-{(E)-2-(4-fluorophenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383 were reacted
in accordance with Example 1146, the solvent was distilled off,
treated with 1 mL of 4N hydrogen chloride-ethyl acetate for 3
hours, and then purified by LC-MS, to afford 5.31 mg of the title
compound.
[2027] MS (ESI) m/z 409 MH.sup.+
Production Example 1148
N-Methyl-hydrazine carboxylic acid tert-butyl ester
[2028] 10 mL of methyl hydrazine was dissolved in 90 mL of ethanol,
and under stirring at ice-cooling, a solution of 41 g of
di-tert-butyldicarbonate in 90 mL of ethanol was added dropwise
over 45 minutes. After stirring at room temperature for 7 hours,
the solvent was evaporated, to afford 24.7 g of the title compound
as a colorless oil.
[2029] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.47 (9H, s), 3.05
(3H, s), 4.05 (2H, brs)
Production Example 1149
N'-benzyloxycarbonyl-N-methyl-hydrazine carboxylic acid tert-butyl
ester
[2030] 13.5 g of N-methyl-hydrazine carboxylic acid tert-butyl
ester was dissolved in 90 mL of chloroform, added with 90 mL of 1N
sodium hydroxide aqueous solution and 28 mL of benzyl
chloroformate, and stirred at room temperature for 6 days. Adding
water, extracting with chloroform, and the resultant organic layer
was washed with saturated brine and dried over magnesium sulfate.
The solvent was evaporated, followed by purification by silica gel
column chromatography (ethyl acetate:hexane=1:4), to afford 17.7 g
of the title compound as a colorless oil.
[2031] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.42 (9H, s), 3.14
(3H, brs), 5.17 (2H, s), 7.28-7.42 (5H, m)
Production Example 1150
N'-Methyl-hydrazine carboxylic acid benzyl ester hydrochloride
[2032] 17.7 g of N'-benzyloxycarbonyl-N-methyl-hydrazine carboxylic
acid tert-butyl ester was dissolved in 20 mL of ethyl acetate,
added with 70 mL 4N hydrogen chloride-ethyl acetate solution, and
stirred at room temperature for 4 hours. The solvent was
evaporated, and the resulting crystals were washed with diethyl
ether and filtered, to afford 11.4 g of the title compound as white
crystals.
[2033] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.72 (3H, s),
5.19 (2H, s), 7.32-7.44 (5H, m)
Production Example 1151
Methyl-(N-methyl-hydrazinocarbonylmethyl)-carbamic acid tert-butyl
ester
[2034] 2.1 g of (tert-butoxycarbonyl-methyl-amino)-acetic acid was
dissolved in 150 mL of tetrahydrofuran, and 4.64 mL of
triethylamine and 1.51 mL of isobutyl chloroformate were added
under stirring at ice-cooling. After stirring at room temperature
for 10 minutes, N'-methyl-hydrazine carboxylic acid benzyl ester
hydrochloride was added and stirred at room temperature for 50
minutes. The reaction solution was added with water, extracted with
ethyl acetate, and the resultant organic layer was washed with
saturated brine and dried over magnesium sulfate. The solvent was
evaporated, followed by purification by silica gel column
chromatography (ethyl acetate:n-hexane=1:1), to afford 3.2 g of
N'-[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-N'-methyl-hydrazine
carboxylic acid benzyl ester. Subsequently, by conducting catalytic
hydrogen reduction in accordance with Production Example 365, 1.9 g
of the title compound was obtained.
[2035] MS (ESI) m/z 240 MNa.sup.+
Example 1152
(5-{7-Fluoro-3-[(E)-2-(4-fluoro-phenyl)-vinyl]-1H-indazol-5-yl}-2-methyl-2-
H-[1,2,4]triazol-3-ylmethyl)-methylamine
[2036] In accordance with Example 1147, from
methyl-(N-methyl-hydrazinocarbonylmethyl)-carbamic acid tert-butyl
ester and
7-fluoro-3-{(E)-2-(4-fluoro-phenyl)-vinyl}-1H-indazole-5-carboxymidic
acid ethyl ester hydrochloride obtained by Example 383, the title
compound was obtained.
[2037] MS (ESI) m/z 381 MH.sup.+
Example 1153
5-(4,5-Dihydro-1H-imidazol-2-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]--
1H-indazole
[2038] To a suspension of 10 mg of
6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazole-5-carboxydimic
acid ethyl ester hydrochloride obtained by Example 559 in 0.5 mL of
ethanol was added 30 .mu.l (1 mole in ethanol) of ethylenediamine
at room temperature, and heated under reflux for 2 days. After
filtering out the insoluble substances, the residue was separated
and purified by LC-MS, to afford the title compound.
[2039] MS (ESI) m/z 325 MH.sup.+
Example 1154
[2040] In accordance with the procedure of Example 1153, from
6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazole-5-carboxydimic
acid ethyl ester hydrochloride obtained by Example 559 or
7-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazole-5-carboxydimic
acid ethyl ester hydrochloride obtained by Example 383, and
commercially available substituted ethylenediamine or substituted
1,3-diaminopropane, the compounds of Examples 1155-1165 were
synthesized.
Example 1155
6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1-methyl-4,5-dihydro-1H-imidaz-
ol-2-yl)-1H-indazole
[2041] MS (ESI) m/z 339 MH.sup.+
Example 1156
6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(5-methyl-4,5-dihydro-1H-imidaz-
ol-2-yl)-1H-indazole
[2042] MS (ESI) m/z 339 MH.sup.+
Example 1157
6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1,4,5,6-tetrahydropyrimidin-2--
yl)-1H-indazole
[2043] MS (ESI) m/z 439 MH.sup.+
Example 1158
6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1-methyl-1,4,5,6-tetrahydropyr-
imidin-2-yl)-1H-indazole
[2044] MS (ESI) m/z 353 MH.sup.+
Example 1159
2-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazole-5-yl}-1,4,5,6-tetr-
ahydropyrimidin-5-ol
[2045] MS (ESI) m/z 355 MH.sup.+
Example 1160
5-(4,5-Dihydro-1H-imidazol-2-yl)-7-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]--
1H-indazole
[2046] MS (ESI) m/z 325 MH.sup.+
Example 1161
7-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1-methyl-4,5-dihydro-1H-imidaz-
ol-2-yl)-1H-indazole
[2047] MS (ESI) m/z 339 MH.sup.+
Example 1162
7-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(5-methyl-4,5-dihydro-1H-imidaz-
ol-2-yl)-1H-indazole
[2048] MS (ESI) m/z 339 MH.sup.+
Example 1163
7-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1,4,5,6-tetrahydropyrimidin-2--
yl)-1H-indazole
[2049] MS (ESI) m/z 339 MH.sup.+
Example 1164
7-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1-methyl-1,4,5,6-tetrahydropyr-
imidin-2-yl)-1H-indazole
[2050] MS (ESI) m/z 353 MH.sup.+
Example 1165
2-{7-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1H-indazol-5-yl}-1,4,5,6-tetra-
hydropyrimidin-5-ol
[2051] MS (ESI) m/z 355 MH.sup.+
Example 1166
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-oxopropyl)amide
[2052] 100 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (2-hydroxylpropyl)amide obtained by Example 825 and 300 .mu.l
of triethylamine were dissolved in a mixed solvent of 4 mL
dichloromethane/1 mL dimethyl sulfoxide, added with 1 mL of a
solution of 260 mg of pyridine sulfur trioxide complex in dimethyl
sulfoxide under ice cooling, and the reaction solution was heated
at 40.degree. C. for 3 hours. The reaction solution was diluted
with water, extracted with ethyl acetate, washed with water, and
then dried over magnesium sulfate. The solvent was evaporated, and
the residue was purified by silica gel column chromatography (ethyl
acetate:methanol=100:3), and then crystallized from ethyl acetate
and diisopropyl ether, to afford 80 mg of the title compound as a
colorless powder.
[2053] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 2.18 (3H, s),
3.98 (3H, s), 4.22 (2H, d, J=5.5 Hz), 7.25 (2H, t, J=8.8 Hz), 7.35
(1H, d, J=8.4 Hz), 7.51 (1H, d, J=16.4 Hz), 7.51 (1H, d, J=16.4
Hz), 7.57 (1H, d, J=16.4 Hz), 7.72 (2H, dd, J=5.6, 8.8 Hz), 7.73
(1H, d, J=8.4 Hz), 8.64 (1H, bt, J=5.5 Hz), 13.48 (1H, bs).
Example 1167
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-hydroxy-3-(morpholin-4-yl)propyl]amide
[2054] 100 mg of
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 and 130 mg of
1-amino-3-(morpholine-4-yl)propane-2-ol were condensed in the
similar method as described in Example 44, to afford 66 mg of the
title compound as colorless needle crystals.
[2055] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 2.51 (2H, d, J=6.4
Hz), 2.53-2.62 (4H, m), 3.44 (1H, dd, J=6.8, 13.6 Hz), 3.68 (1H,
dd, J=4.4, 13.6 Hz), 3.71 (4H, t, J=4.6 Hz), 4.00 (3H, s),
4.00-4.07 (1H, m), 7.14 (2H, t, J=8.8 Hz), 7.34 (1H, d, J=8.8 Hz),
7.54 (1H, d, J=16.4 Hz), 7.59 (1H, d, J=16.4 Hz), 7.64 (2H, dd,
J=5.6, 8.8 Hz), 7.87 (1H, d, J=8.8 Hz).
Example 1168
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid ethyl ester
[2056] 410 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
5-vinyl-2,3-dihydrobenzofuran were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 50 mg of
the title compound as a colorless powder.
[2057] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.44 (3H, t, J=7.2
Hz), 3.26 (2H, t, J=8.7 Hz), 4.05 (3H, s), 4.42 (2H, q, J=7.2 Hz),
4.62 (2H, t, J=8.7 Hz), 6.81 (1H, d, J=8.4 Hz), 7.21 (1H, d, J=8.6
Hz), 7.36 (1H, bd, J=8.4 Hz), 7.48 (1H, bs), 7.50 (1H, d, J=16.4
Hz), 7.62 (1H, d, J=16.4 Hz), 7.91 (1H, d, J=8.6 Hz).
Example 1169
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid
[2058] 50 mg of
3-[(E)-2-(2,3-dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carb-
oxylic acid ethyl ester was treated in the similar method as
described in Example 144, to afford 35 mg of the title compound as
a colorless powder.
[2059] .sup.1H-NMR (400 MHz, CD.sub.3OD) .delta. 3.25 (2H, t, J=8.8
Hz), 4.02 (3H, s), 4.58 (2H, t, J=8.8 Hz), 6.75 (1H, d, J=8.4 Hz),
7.27 (1H, d, J=8.6 Hz), 7.34 (1H, dd, J=1.6, 8.4 Hz), 7.47 (1H, d,
J=16.4 Hz), 7.51 (1H, bs), 7.52 (1H, d, J=16.4 Hz), 7.88 (1H, d,
J=8.6 Hz).
Example 1170
4-Methoxy-3-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester
[2060] 470 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
4-methoxystyrene were reacted in the similar method as described in
Production example 181, followed by deprotection in the similar
method as described in Example 16, to afford 130 mg of the title
compound as a pale yellow oil.
[2061] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.45 (3H, t, J=7.2
Hz), 3.85 (3H, s), 4.05 (3H, s), 4.43 (2H, q, J=7.2 Hz), 6.93 (2H,
d, J=8.8 Hz), 7.20 (1H, d, J=8.8 Hz), 7.54 (2H, d, J=8.8 Hz), 7.54
(1H, d, J=16.4 Hz), 7.62 (1H, d, J=16.4 Hz), 7.89 (1H, d, J=8.8
Hz).
Example 1171
4-Methoxy-3-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid
[2062] 50 mg of
4-methoxy-3-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid ethyl ester was treated in the similar method as described in
Example 144, to afford 40 mg of the title compound as a colorless
powder.
[2063] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.80 (3H, s),
3.96 (3H, s), 6.99 (2H, d, J=8.6 Hz), 7.29 (1H, d, J=8.6 Hz), 7.44
(1H, d, J=16.4 Hz), 7.51 (1H, d, J=16.4 Hz), 7.59 (2H, d, J=8.6
Hz), 7.74 (1H, d, J=8.6 Hz), 13.38 (1H, bs).
Example 1172
3-[(E)-2-(3,4-Dimethoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester
[2064] 470 mg of 3-iodo-4-methoxy-1-trityl-1H-indazole-5-carboxylic
acid ethyl ester obtained by Production example 276 and 300 mg of
3,4-dimethoxystyrene were reacted in the similar method as
described in Production example 181, followed by deprotection in
the similar method as described in Example 16, to afford 120 mg of
the title compound as a pale yellow powder.
[2065] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 1.45 (3H, t, J=7.2
Hz), 3.93 (3H, s), 3.96 (3H, s), 4.05 (3H, s), 4.44 (2H, q, J=7.2
Hz), 6.90 (1H, d, J=8.8 Hz), 7.15 (1H, dd, J=1.6, 8.8 Hz), 7.16
(1H, bs), 7.22 (1H, d, J=8.8 Hz), 7.53 (1H, d, J=16.4 Hz), 7.62
(1H, d, J=16.4 Hz), 7.91 (1H, d, J=8.8 Hz).
Example 1173
3-[(E)-2-(3,4-Dimethoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid
[2066] 50 mg of
3-[(E)-2-(3,4-dimethoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethyl ester was treated in the similar method as described in
Example 144, to afford 40 mg of the title compound as a colorless
powder.
[2067] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 3.79 (3H, s),
3.85 (3H, s), 3.96 (3H, s), 7.00 (1H, d, J=8.4 Hz), 7.17 (1H, dd,
J=2.0, 8.4 Hz), 7.23 (1H, d, J=2.0 Hz), 7.29 (1H, d, J=8.4 Hz),
7.45 (1H, d, J=16.4 Hz), 7.51 (1H, d, J=16.4 Hz), 7.74 (1H, d,
J=8.6 Hz), 13.39 (1H, bs).
Example 1174
[2068] After condensing various kinds of carboxylic acid obtained
by Example 942, 955, 968, 1169, 1171 and 1173, and various kinds of
amine in the similar method as described in Example 44,
purification by LC-MS was conducted, to afford the compounds of
Examples 1175-1195.
Example 1175
4-Methoxy-3-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid cyclopropylmethyl amide
[2069] MS (ESI) m/z 378 MH.sup.+
Example 1176
4-Methoxy-3-[(E)-2-(4-methoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid (oxazol-2-ylmethyl)amide
[2070] MS (ESI) m/z 405 MH.sup.+
Example 1177
3-[(E)-2-(4-Methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyanomethylamide
[2071] MS (ESI) m/z 363 MH.sup.+
Example 1178
3-[(E)-2-(4-Methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid allylamide
[2072] MS (ESI) m/z 364 MH.sup.+
Example 1179
4-Methoxy-3-[(E)-2-(3,4-dimethoxyphenyl)-vinyl]-1H-indazole-5-carboxylic
acid (oxazol-2-ylmethyl)amide
[2073] MS (ESI) m/z 435 MH.sup.+
Example 1180
3-[(E)-2-(3,4-Dimethoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyanomethylamide
[2074] MS (ESI) m/z 393 MH.sup.+
Example 1181
3-[(E)-2-(3,4-Dimethoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid allylamide
[2075] MS (ESI) m/z 394 MH.sup.+
Example 1182
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid (furan-2-ylmethyl)amide
[2076] MS (ESI) m/z 416 MH.sup.+
Example 1183
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid cyclopropylmethyl amide
[2077] MS (ESI) m/z 390 MH.sup.+
Example 1184
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid (thiophen-2-ylmethyl)amide
[2078] MS (ESI) m/z 432 MH.sup.+
Example 1185
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid cyclopropylamide
[2079] MS (ESI) m/z 376 MH.sup.+
Example 1186
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid (pyridin-3-ylmethyl)amide
[2080] MS (ESI) m/z 427 MH.sup.+
Example 1187
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid (oxazol-2-ylmethyl)amide
[2081] MS (ESI) m/z 417 MH.sup.+
Example 1188
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid cyanomethylamide
[2082] MS (ESI) m/z 375 MH.sup.+
Example 1189
3-[(E)-2-(2,3-Dihydrobenzofuran-5-yl)-vinyl]-4-methoxy-1H-indazole-5-carbo-
xylic acid allylamide
[2083] MS (ESI) m/z 376 MH.sup.+
Example 1190
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyanomethylamide
[2084] MS (ESI) m/z 381 MH.sup.+
Example 1191
3-[(E)-2-(4-Fluoro-3-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid allylamide
[2085] MS (ESI) m/z 382 MH.sup.+
Example 1192
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid cyanomethylamide
[2086] MS (ESI) m/z 381 MH.sup.+
Example 1193
3-[(E)-2-(3-Fluoro-4-methoxyphenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxy-
lic acid allylamide
[2087] MS (ESI) m/z 382 MH.sup.+
Example 1194
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyanomethylamide
[2088] MS (ESI) m/z 369 MH.sup.+
Example 1195
3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid allylamide
[2089] MS (ESI) m/z 370 MH.sup.+
Production Example 1196
Acetic acid 5-(morpholin-4-yl)methyl-furan-2-ylmethyl ester
[2090] Under nitrogen atmosphere, to a solution of 2.0 g of
5-acetoxymethyl-2-furanaldehyde and 1.1 mL of morpholine in 35 mL
of 1,2-dichloroethane was added 4.0 g of sodium triacetoxy
borohydride at room temperature, and stirred at this temperature
for 3 hours. The reaction solution was diluted with
dichloromethane, washed successively with saturated aqueous sodium
hydrogen carbonate and saturated brine, and then dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
residue was purified and separated by silica gel column
chromatography, to afford 2.3 g of the title compound as a
colorless oil.
[2091] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.08 (3H, s), 2.49
(4H, m), 3.53 (2H, s), 3.73 (4H, m), 5.02 (2H, s), 6.19 (1H, d,
J=3.2 Hz), 6.34 (1H, d, J=3.2 Hz).
Production Example 1197
[5-(Morpholin-4-yl)methyl-furan-2-yl]-methanol
[2092] In accordance with the method of Production example 773,
from 2.2 g of acetic acid 5-(morpholin-4-yl)methyl-furan-2-ylmethyl
ester, 1.4 g of the title compound was obtained as colorless
crystals.
[2093] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.48 (4H, m), 3.52
(2H, s), 3.72 (4H, m), 4.59 (2H, s), 6.17 (1H, d, J=3.2 Hz), 6.23
(1H, d, J=3.2 Hz).
Production Example 1198
4-(5-Azidomethyl-furan-2-ylmethyl)-morpholine
[2094] In accordance with the method of Production example 774,
from 1.0 g of [5-(morpholin-4-yl)methyl-furan-2-yl]-methanol, 1.07
g of the title compound was obtained as a colorless oil.
[2095] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.48 (4H, m), 3.54
(2H, s), 3.73 (4H, m), 4.29 (2H, s), 6.20 (1H, d, J=3.2 Hz), 6.30
(1H, d, J=3.2 Hz).
Production Example 1199
C-[5-(Morpholin-4-yl)methyl-furan-2-yl]-methylamine
[2096] In accordance with the method of Production example 775,
from 1.07 g of 4-(5-azidomethyl-furan-2-ylmethyl)-morpholine, 900
mg of the title compound was obtained as colorless oil.
[2097] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.48 (4H, m), 3.50
(2H, s), 3.74 (4H, m), 3.80 (2H, s), 6.06 (1H, d, J=3.2 Hz), 6.13
(1H, d, J=3.2 Hz).
Production Example 1200
Acetic acid 5-(4-methyl-piperazin-1-ylmethyl)-furan-2-ylmethyl
ester
[2098] In accordance with the method of Production example 1196,
from 1.44 mL of 1-methylpiperazine, 2.1 g of the title compound was
obtained as a pale yellow oil.
[2099] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.08 (3H, s), 2.29
(3H, s), 2.49 (8H, m), 3.55 (2H, s), 5.02 (2H, s), 6.18 (1H, d,
J=3.2 Hz), 6.33 (1H, d, J=3.2 Hz).
Production Example 1201
[5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-yl]-methanol
[2100] In accordance with the method of Production example 773,
from 2.1 g of acetic acid
5-(4-methyl-piperazin-1-ylmethyl)-furan-2-ylmethyl ester, 1.26 g of
the title compound was obtained as a colorless oil.
[2101] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.29 (3H, s), 2.51
(8H, bs), 3.54 (2H, s), 4.57 (2H, s), 6.16 (1H, d, J=3.2 Hz), 6.22
(1H, d, J=3.2 Hz).
Production Example 1202
1-(5-Azidomethyl-furan-2-ylmethyl)-4-methyl-piperazine
[2102] In accordance with the method of Production example 774,
from 1.26 g of
[5-(4-methyl-piperazin-1-ylmethyl)-furan-2-yl]-methanol, 1.0 g of
the title compound was obtained as a colorless oil.
[2103] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.29 (3H, s), 2.49
(8H, bs), 3.55 (2H, s), 4.28 (2H, s), 6.19 (1H, d, J=3.2 Hz), 6.29
(1H, d, J=3.2 Hz).
Production Example 1203
C-[5-(4-Methyl-piperazin-1-ylmethyl)-furan-2-yl]-methylamine
[2104] In accordance with the method of Production example 775,
from 1.0 g of
1-(5-azidomethyl-furan-2-ylmethyl)-4-methyl-piperazine, 920 mg of
the title compound was obtained as a colorless oil.
[2105] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.2.28 (3H, s), 2.49
(8H, bs), 3.52 (2H, s), 3.79 (2H, s), 6.05 (1H, d, J=3.2 Hz), 6.12
(1H, d, J=3.2 Hz).
Example 1204
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 and amine obtained by Production
example 1199 and 1203 were condensed in accordance with the method
of Example 44, followed by purification by LC-MS, to afford the
compounds of Examples 1205-1206.
Example 1205
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [5-(4-methylpiperazin-1-ylmethyl)-furan-2-ylmethyl)-amide
[2106] MS (ESI) m/z 505 MH.sup.+
Example 1206
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [5-(morpholin-4-ylmethyl)-furan-2-ylmethyl]-amide
[2107] MS (ESI) m/z 492 MH.sup.+
Example 1207
{3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-aminoa-
cetic acid tert-butyl ester
[2108]
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid obtained by Example 234 and 258 mg of glycine ter-butyl ester
hydrochloride were dissolved in 20 mL of N,N-dimethylformamide, and
0.871 mL of diisopropylethylamine and 235 mg of
1-hydroxybenzotriazole were added, and stirred at room temperature
for 10 minutes. After cooling to 0.degree. C., 491 mg of WSC
hydrochloride was added, and stirred overnight at room temperature.
After adding ice water to stop the reaction, the solution was
extracted with ethyl acetate. The organic phase was washed with
water and saturated brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated, to afford 547 mg of the title
compound as pale green crystals.
[2109] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.45 (9H, s),
3.98 (5H, s), 7.25 (2H, t, J=8.8 Hz), 7.34 (1H, d, J=8.4 Hz), 7.51
(1H, d, J=16.4 Hz), 7.57 (1H, d, J=16.4 Hz), 7.68-7.72 (3H, m),
8.63 (1H, t, J=6.0 Hz)
Example 1208
{3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-aminoa-
cetic acid
[2110] 472 mg of
{3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-amino-
acetic acid tert-butyl ester was dissolved in 5 mL of
dichloromethane, 2.5 mL of trifluoroacetic acid was added, and
stirred overnight at room temperature. The reaction solution was
added with water, and extracted with a mixed solution of ethyl
acetate:tetrahydrofuran=1:1. The organic layer was washed with
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, to give 384 mg of the title compound as a
pale yellow solid.
[2111] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 3.98 (3H, s),
4.02 (2H, d, J=6.0 Hz), 7.25 (2H, t, J=8.4 Hz), 7.34 (1H, d, J=8.4
Hz), 7.51 (1H, d, J=16.0 Hz), 7.57 (1H, d, J=16.0 Hz), 7.70-7.72
(3H, m), 8.62 (1H, t, J=5.6 Hz)
Example 1209
[2112] In accordance with the method of Example 102, from
{3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}-amino-
acetic acid obtained by Example 1208 and various kinds of amine,
the compounds of Examples 1210-1224 were obtained.
Example 1210
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [(cyclohexyl-methyl-carbamoyl)-methyl]-amide
[2113] MS (ESI) m/z 465 MH.sup.+
Example 1211
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (benzylcarbamoyl-methyl)-amide
[2114] MS (ESI) m/z 459 MH.sup.+
Example 1212
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-oxo-2-(pyrrolidin-1-yl)-ethyl]-amide
[2115] MS (ESI) m/z 423 MH.sup.+
Example 1213
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-oxo-2-(piperidin-1-yl)-ethyl]-amide
[2116] MS (ESI) m/z 437 MH.sup.+
Example 1214
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(morpholin-4-yl)-2-oxo-ethyl]-amide
[2117] MS (ESI) m/z 439 MH.sup.+
Example 1215
4-[2-({3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carbonyl}--
amino)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester
[2118] MS (ESI) m/z 538 MH.sup.+
Example 1216
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide
[2119] MS (ESI) m/z 452 MH.sup.+
Example 1217
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid diethylcarbamoylmethyl-amide
[2120] MS (ESI) m/z 425 MH.sup.+
Example 1218
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclohexylcarbamoylmethyl-amide
[2121] MS (ESI) m/z 451 MH.sup.+
Example 1219
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopentylcarbamoylmethyl-amide
[2122] MS (ESI) m/z 437 MH.sup.+
Example 1220
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclobutylcarbamoylmethyl-amide
[2123] MS (ESI) m/z 423 MH.sup.+
Example 1221
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid cyclopropylcarbamoylmethyl-amide
[2124] MS (ESI) m/z 409 MH.sup.+
Example 1222
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid ethylcarbamoylmethyl-amide
[2125] MS (ESI) m/z 397 MH.sup.+
Example 1223
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid propylcarbamoylmethyl-amide
[2126] MS (ESI) m/z 411 MH.sup.+
Example 1224
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid butylcarbamoylmethyl-amide
[2127] MS (ESI) m/z 425 MH.sup.+
Example 1225
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid [2-oxo-2-(piperazin-1-yl)-ethyl]-amide
[2128]
4-[2-({3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-car-
bonyl}-amino)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester
obtained by Example 1215 was dissolved in 1 mL of dichloromethane,
added with 1 mL of trifluoroacetic acid, and stirred at room
temperature for 2 hours. The solvent was evaporated, followed by
purification by LC-MS, to afford the title compound.
[2129] MS (ESI) m/z 438 MH.sup.+
Example 1226
3-[(E)-2-(4-Fluorophenyl)-vinyl]-4-methoxy-1H-indazole-5-carboxylic
acid (3-hydroxyisoxazol-5-ylmethyl)-amide
[2130] In accordance with the method of Example 102,
3-[(E)-2-(4-fluorophenyl)-vinyl]-4-methoxyl
1H-indazole-5-carboxylic acid obtained by Example 234 and
5-aminomethyl-isooxazol-3-ol, the title compound was obtained.
[2131] MS (ESI) m/z 409 MH.sup.+
Production Example 1227
1-Methanesulfonyloxymethyl-cyclopropane carboxylic acid ethyl
ester
[2132] In accordance with the method described in the document
(Tetrahedron Letters, 40, 5467 (1988)), a solution of 720 mg of
1-hydroxymethyl-cyclopropane carboxylic acid ethyl ester obtained
from 1,1-cyclopropane dicarboxylic acid diethyl ester in 10 mL of
dichloromethane was added with 1.05 mL of triethylamine and 0.5 mL
of methanesulfonyl chloride under ice cooling, and stirred at this
temperature for 2 hours. After adding water, the reaction solution
was extracted with ethyl acetate. The organic layer was washed
successively with 1N hydrochloric acid, saturated brine, saturated
aqueous sodium hydrogen carbonate and saturated brine. The organic
layer was dried over anhydrous magnesium sulfate. The solvent was
evaporated, to afford 1.04 g of the title compound as a pale yellow
oil.
[2133] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 1.11 (2H, dd,
J=4.0, 6.8 Hz), 1.18 (3H, t, J=7.2 Hz), 1.24 (2H, dd, J=4.0, 6.8
Hz), 3.18 (3H, s), 4.09 (2H, q, J=7.2 Hz), 4.32 (2H, s)
Production Example 1228
1-Dimethylaminomethyl-cyclopropane carboxylic acid ethyl ester
[2134] To a solution of 222 mg of
1-methanesulfonyloxymethyl-cyclopropane carboxylic acid ethyl ester
in 5 mL of tetrahydrofuran was added 3 mL of 2M dimethyl amine in
tetrahydrofuran, and stirred at room temperature for 3 days. The
solvent was distilled of f, and the residue was added with 2 mL of
1N hydrochloric acid, and washed with diethyl ether. The aqueous
layer was added with 10% potassium carbonate aqueous solution, and
extracted with ethyl acetate. The extracted layer was washed with
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, to afford 56 mg of the title compound as a
pale yellow oil.
[2135] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.79 (2H, dd,
J=3.6, 6.8 Hz), 1.07 (2H, dd, J=3.6, 6.8 Hz), 1.16 (3H, t, J=7.2
Hz), 2.13 (6H, s), 2.46 (2H, s), 4.03 (2H, q, J=7.2 Hz)
Production Example 1229
1-Dimethylaminomethyl-cyclopropane carboxylic acid
[2136] To a solution of 222 mg of
1-dimethylaminomethyl-cyclopropane carboxylic acid ethyl ester in
0.4 mL of ethanol was added 0.1 mL of 5N sodium hydroxide aqueous
solution, and stirred overnight at room temperature. The reaction
solution was added with 0.5 mL of 1N hydrochloric acid, and the
solvent and water were evaporated, to give 78 mg of a mixture of
the title compound and sodium chloride as a white powder.
[2137] .sup.1H-NMR (400 MHz, D.sub.2O) .delta. 0.83 (2H, br s),
1.20 (2H, br s), 2.86 (6H, s), 3.16 (2H, s)
Production Example 1230
1-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-cyclopropane
carboxylic acid ethyl ester
[2138] To a solution of 222 mg of
1-methanesulfonyloxymethyl-cyclopropanecarboxylic acid ethyl ester
obtained by Production example 1227 in 2 mL of tetrahydrofuran was
added 3 mL of 2M methylamine in tetrahydrofuran, and stirred at
room temperature for 2 days. The reaction solution was added with
1.5 mL of 2N hydrochloric acid, and then washed with diethyl ether.
The aqueous layer was added with 10% potassium carbonate aqueous
solution, the water distilled off, and extracted with ethyl
acetate. The extracted layer was added with 114 mg of
di-tert-butyldicarbonate, and stirred for 1 hour. The reaction
solution was washed successively with water and saturated brine,
and dried over anhydrous magnesium sulfate. The solvent was
evaporated, to afford 105 mg of the title compound as a colorless
oil.
[2139] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.91 (2H, br s),
1.11 (2H, br), 1.16 (3H, t, J=7.2 Hz), 1.39 (9H, s), 2.80 (3H, br),
3.50 (2H, s), 4.05 (2H, q, J=7.2 Hz)
Production Example 1231
1-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-cyclopropane
carboxylic acid
[2140] In accordance with the method of Production example 651,
from 105 mg of
1-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclopropane
carboxylic acid ethyl ester, 50 mg of the title compound was
obtained as a colorless oil.
[2141] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 0.85 (2H, br s),
1.09 (2H, br), 1.38 (9H, s), 2.78, 2.82 (3H, each s), 3.48 (2H, s),
12.30 (1H, br s)
Example 1232
[2142] Various kinds of amine obtained by Production examples 182,
643, 645 and 649, and various kinds of carboxylic acid obtained by
Production examples 1229 and 1231 were amidated in the manner
described in Example 183, deblocked, and purified by LC-MS [1%-100%
gradient], to afford the compounds of Examples 1233-1240.
Example 1233
1-Dimethylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2143] MS (ESI) m/z 397 MH.sup.+
Example 1234
1-Dimethylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2144] MS (ESI) m/z 397 MH.sup.+
Example 1235
1-Dimethylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2145] MS (ESI) m/z 397 MH.sup.+
Example 1236
1-Dimethylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[2146] MS (ESI) m/z 385 MH.sup.+
Example 1237
1-Methylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2147] MS (ESI) m/z 383 MH.sup.+
Example 1238
1-Methylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2148] MS (ESI) m/z 383 MH.sup.+
Example 1239
1-Methylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(2-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2149] MS (ESI) m/z 383 MH.sup.+
Example 1240
1-Methylaminomethyl-cyclopropane carboxylic acid
{6-fluoro-3-[(E)-2-(thiophen-2-yl)-vinyl]-1H-indazol-5-yl}-amide
[2150] MS (ESI) m/z 371 MH.sup.+
Production Example 1241
6-Fluoro-3-[(E)-2-(3,4-difluorophenyl)-vinyl]-5-nitro-1-trityl-1H-indazole
[2151] 600 mg of 6-fluoro-3-iodo-5-nitro-1-trityl-1H-indazole
obtained by Production example 747 and 305 mg of
1,2-difluoro-4-vinylbenzene was dissolved in 10 mL of 1,4-dioxane.
The resultant solution was added with 56 mg of
bis(tri-tert-butylphosphine)palladium(0) and 408 .mu.l of
diisopropylethylamine, and refluxed overnight under nitrogen
atmosphere. After cooling to room temperature, the reaction mixture
was added with silica gel, and the solvent was evaporated, followed
by purification by silica gel column chromatography, to afford 513
mg of the title compound as yellow crystals.
[2152] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 6.13 (1H, d,
J=12.4 Hz), 7.22 (6H, d, J=7.6 Hz), 7.34-7.49 (11H, m), 7.53 (1H,
d, J=8.4 Hz), 7.71 (1H, d, J=16.8 Hz), 7.95 (1H, t, J=10.4 Hz),
9.16 (1H, d, J=7.2 Hz)
Production Example 1242
6-Fluoro-3-[(E)-2-(3,4-difluorophenyl)-vinyl]-1-trityl-1H-indazol-5-ylamin-
e
[2153] In accordance with the method of Production example 182,
from 513 mg of
6-fluoro-3-[(E)-2-(3,4-difluorophenyl)-vinyl]-5-nitro-1-trityl-1H-i-
ndazole, 150 mg of the title compound was obtained as yellow
crystals.
[2154] .sup.1H-NMR (400 MHz, DMSO-D.sub.6) .delta. 4.98 (2H, bs),
5.91 (1H, d, J=11.6 Hz), 7.18-7.45 (20H, m), 7.83 (1H, dd, J=8.4,
14.0 Hz)
Example 1243
[2155]
6-Fluoro-3-[(E)-2-(3,4-difluorophenyl)-vinyl]-1-trityl-1H-indazol-5-
-ylamine obtained by Production example 1242 and various kinds of
carboxylic acid were treated in the similar method as described in
Example 183, to afford the compounds of Examples 1244-1256.
Example 1244
Cyclopropane carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2156] MS (ESI) m/z 358 MH.sup.+
Example 1245
1-Hydroxycyclopropane carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2157] MS (ESI) m/z 374 MH.sup.+
Example 1246
1-Acetyl-piperidine-4-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2158] MS (ESI) m/z 443 MH.sup.+
Example 1247
Tetrahydrofuran-3-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2159] MS (ESI) m/z 388 MH.sup.+
Example 1248
1-Methylaminocyclopropane carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazole-5-yl}-amide
[2160] MS (ESI) m/z 387 MH.sup.+
Example 1249
N-{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-2-(thiop-
hen-2-yl)-acetamide
[2161] MS (ESI) m/z 414 MH.sup.+
Example 1250
Furan-2-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2162] MS (ESI) m/z 384 MH.sup.+
Example 1251
2-Cyclopropyl-N-{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol--
5-yl}-acetamide
[2163] MS (ESI) m/z 372 MH.sup.+
Example 1252
(2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2164] MS (ESI) m/z 403 MH.sup.+
Example 1253
N-{3-[(E)-2-(3,4-Difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-2-(morph-
olin-4-yl)-acetamide
[2165] MS (ESI) m/z 417 MH.sup.+
Example 1254
Piperidine-4-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2166] MS (ESI) m/z 401 MH.sup.+
Example 1255
(2S)-1-Methyl-pyrrolidine-2-carboxylic acid
{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-yl}-amide
[2167] MS (ESI) m/z 401 MH.sup.+
Example 1256
(2S)-2-Amino-N-{3-[(E)-2-(3,4-difluorophenyl)-vinyl]-6-fluoro-1H-indazol-5-
-yl}-2-(thiophen-2-yl)-acetamide
[2168] MS (ESI) m/z 429 MH.sup.+
Example 1257
[2169]
6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1-trityl-1H-indazol-5-yla-
mine synthesized by Production example 182 and various kinds of
carboxylic acid were treated in the similar method as described in
Example 183, to afford the compounds of Examples 1258-1260.
Example 1258
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-methoxy-2--
(thiophen-2-yl)-acetamide
[2170] MS (ESI) m/z 426 MH.sup.+
Example 1259
Azetidine-3-carboxylic acid
{6-fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-amide
[2171] MS (ESI) m/z 355 MH.sup.+
Example 1260
N-{6-Fluoro-3-[(E)-2-(4-fluorophenyl)-vinyl]-1H-indazol-5-yl}-2-(piperazin-
-1-yl)-acetamide
[2172] MS (ESI) m/z 398 MH.sup.+
Production Example 1261
4-Bromo-5-fluoro-2-methylphenylamine
[2173] To a solution of 49.0 g of 5-fluoro-o-toluidine in 600 mL of
dichloromethane was added 69.7 g of N-bromosuccinimide at 0.degree.
C., and stirred at this temperature for an hour. Then sodium
thiosulfate aqueous solution was added, and the reaction solution
was evaporated and diluted with ethyl acetate. The organic layer
was washed successively with water and saturated brine and dried
over anhydrous magnesium sulfate. Then the solvent was evaporated,
and the precipitated crystals were washed with diethyl
ether:n-hexane=1:10, to afford 81.6 g of the title compound as
colorless crystals.
[2174] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.09 (3H, s), 3.69
(2H, bs), 6.44 (1H, d, J=10.4 Hz), 7.14 (1H, dd, J=7.6, 0.8
Hz).
Production Example 1262
N-(4-Bromo-5-fluoro-2-methylphenyl)acetamide
[2175] 73.6 mL of acetic anhydride was added with 80.0 g of
4-bromo-5-fluoro-2-methylphenylamine at room temperature, and
stirred at this temperature for 10 minutes. Excess acetic anhydride
was distilled off under reduced pressure, and the precipitated
crystals were washed with water, to afford 77.6 g of the title
compound as colorless crystal.
[2176] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.21 (6H, s), 6.92
(1H, bs), 7.32 (1H, d, J=7.6 Hz), 7.90 (1H, d, J=10.4 Hz).
Production Example 1263
1-(5-Bromo-6-fluoro-indazol-1-yl)ethanone
[2177] To a solution of 77.0 g of
N-(4-bromo-5-fluoro-2-methylphenyl)acetamide in 930 mL of toluene
were added 93.0 mL of acetic anhydride and 37.0 g of potassium
acetate at room temperature, and the resultant solution was heated
at 90.degree. C., slowly added dropwise with 67.0 mL of
isoamylnitrite, and stirred at this temperature for 3 hours. After
diluting with ethyl acetate, washing successively with water and
saturated brine, and drying over anhydrous magnesium sulfate, the
solvent was evaporated. The precipitated crystals were washed with
diethyl ether:n-hexane=1:10, the filtrate concentrated and purified
and separated by silica gel column chromatography (ethyl
acetate:n-hexane=0:100-1:5) and finally combined with the previous
crystals, to afford 22.5 g of the title compound as pale brown
crystals.
[2178] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.78 (3H, s), 7.93
(1H, d, J=6.4 Hz), 8.05 (1H, d, J=0.8 Hz), 8.23 (1H, dd, J=4.8, 0.8
Hz).
Production Example 1264
5-Bromo-6-fluoro-1H-indazole
[2179] To a solution of 22.5 g of
1-(5-bromo-6-fluoro-indazol-1-yl)ethanone in 250 mL of ethanol was
added 20.0 mL of 5N sodium hydroxide aqueous solution at room
temperature, and stirred at this temperature for 5 minutes. After
neutralizing in 5N hydrochloric acid aqueous solution, the solution
was diluted with ethyl acetate. The organic layer was successively
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and then the solvent was evaporated. The residue
was purified and separated by silica gel column chromatography
(ethyl acetate:n-hexane=1:3), to afford 16.7 g of the title
compound as pale brown crystals.
[2180] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 7.24-7.27 (1H, m),
7.94-7.97 (1H, m), 8.01 (1H, d, J=0.8 Hz), 10.26 (1H, bs).
Production Example 1265
5-Bromo-6-fluoro-3-iodo-1H-indazole
[2181] To a solution of 10.0 g of 5-bromo-6-fluoro-1H-indazole in
150 mL of N,N-dimethylformamide was added 10.5 g of
N-iodosuccinimide at room temperature, and stirred at 70.degree. C.
for 2 days. Then the solution was diluted with ethyl acetate,
washed successively with aqueous ammonium chloride and saturated
brine, dried over anhydrous magnesium sulfate, and the solvent was
evaporated. The crystals precipitated by adding diethyl ether to
the residue were collected by filtration. The filtrate was further
concentrated and purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:10-1:5) and combined with
the previous crystals, to afford 14.5 g of the title compound as
colorless crystals.
[2182] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 7.61 (1H, d,
J=9.2 Hz), 7.75 (1H, d, J=6.4 Hz), 13.75 (1H, bs).
Production Example 1266
5-Bromo-6-fluoro-3-iodo-1-trityl-1H-indazole
[2183] To a solution of 3.0 g of
5-bromo-6-fluoro-3-iodo-1H-indazole in N,N-dimethylformamide in 150
mL was added 0.42 g of sodium hydride at room temperature, and the
resultant solution was stirred for 15 minutes, added with 2.45 g of
trityl-chloride, and stirred at this temperature for 1 hour. After
adding water and diluting with ethyl acetate, washing successively
with aqueous ammonium chloride and saturated brine and drying over
anhydrous magnesium sulfate, the solvent was evaporated. The
residue was purified and separated by silica gel column
chromatography (ethyl acetate:n-hexane=1:30-1:5), and the resultant
product was added with n-hexane. Then the precipitated crystals
were washed with diethyl ether:n-hexane=1:10, to afford 3.79 g of
the title compound as colorless crystals.
[2184] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.07 (1H, d, J=9.2
Hz), 7.14-7.20 (6H, m), 7.26-7.31 (9H, m), 7.64 (1H, d, J=6.4
Hz).
Production Example 1267
5-Bromo-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1-trityl-1H-indazole
[2185] A solution of 3.0 g of
5-bromo-6-fluoro-3-iodo-1-trityl-1H-indazole, 628 mg of
4-fluorostyrene, 115 mg of palladium acetate, 307 mg of
2-(di-ter-butylphosphino) biphenyl and 3.60 mL of triethylamine in
N,N-dimethylformamide was stirred at 70.degree. C. for a day. After
diluting with ethyl acetate, washing successively with aqueous
ammonium chloride and saturated brine, and drying over anhydrous
magnesium sulfate, the solvent was evaporated. The residue was
purified and separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:100), to afford 2.2 g of the title compound as
colorless crystals.
[2186] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 6.14 (1H, d,
J=10.0 Hz), 7.06 (2H, t, J=8.8 Hz), 7.18-7.24 (17H, m), 7.51 (2H,
dd, J=8.8, 6.4 Hz), 8.13 (1H, d, J=6.8 Hz).
Production Example 1268
1-{5-(1-Acetyl-1H-pyrazol-4-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1-
H-indazol-1-yl}ethanone
[2187] A solution of 40 mg of
5-bromo-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-1-trityl-1H-indazole,
29.4 mg of 1-tritylpyrazole-4-boronic acid, 4 mg of
tetrakis(triphenylphosphine)palladium(0) and 32.8 mg of barium
hydroxide octahydrate in a mixture of dimethoxyethane:water=0.6
mL:0.1 mL was stirred at 80.degree. C. for a day. The solution was
diluted with ethyl acetate and water, and the organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. Then the solvent was evaporated. A solution of the crude
product in 1 mL of dichloromethane was added with 0.2 mL of
trifluoroacetic acid at room temperature, and stirred at this
temperature for 1 hour. The reaction solution was poured to aqueous
sodium hydrogen carbonate, and extracted with ethyl acetate. The
organic layer was washed with saturated brine, dried over anhydrous
magnesium sulfate, and the then the solvent was evaporated. A
solution of the crude product in 1 mL of tetrahydrofuran and 0.5 mL
of diisopropylethylamine was added with 0.1 mL of acetic anhydride
at room temperature and stirred at this temperature for a day. The
reaction solution was evaporated, and the residue was purified and
separated by silica gel column chromatography (ethyl
acetate:n-hexane=1:3-1:1), to afford 13 mg of the title compound as
colorless crystals.
[2188] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. 2.78 (3H, s), 2.82
(3H, s), 7.14 (2H, t, J=8.8 Hz), 7.26 (1H, d, J=16.4 Hz), 7.61-7.66
(3H, m), 8.05 (1H, d, J=6.8 Hz), 8.14 (1H, s), 8.29 (1H, d, J=11.2
Hz), 8.67 (1H, s).
Example 1269
6-Fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]-5-(1H-pyrazolo-4-yl)-1H-indazole
[2189] To a solution of 13 mg of
1-{5-(1-acetyl-1H-pyrazol-4-yl)-6-fluoro-3-[(E)-2-(4-fluorophenyl)vinyl]--
1H-indazol-1-yl}ethanone in 1 mL of ethanol was added 0.2 mL of 5N
sodium hydroxide aqueous solution at room temperature, and stirred
at this temperature for 10 minutes. The solution was neutralized
with 5N hydrochloric acid aqueous solution and diluted with ethyl
acetate. After washing the organic layer with saturated brine and
drying over anhydrous magnesium sulfate, the solvent was
evaporated. The residue was purified and separated by silica gel
column chromatography (ethyl acetate:n-hexane=1:3-1:1), to afford
7.09 mg of the title compound as colorless crystal.
[2190] MS (ESI) m/z 323 MH.sup.+
[2191] The compounds (I) to (III) according to the present
invention or a salt thereof exhibited an excellent action in tests
for determining JNK inhibitory action. For example, the inhibitory
actions on JNK 3 were as follows.
Test Example 1
Measurement of JNK 3 Inhibition
[2192] Human JNK 3 was expressed as a fusion protein (GST-JNK 3)
with glutathione S-transferase (GST) in Escherichia coli and was
purified using glutathione Sepharose 4B beads. The amino acid
sequence 1-169 of c-Jun was prepared as a fusion protein
(GST-c-Jun) with GST in Escherichia coli, was purified using
glutathione Sepharose 4B beads and was used as a substrate. A test
compound was solved in 100% dimethyl sulfoxide into 10 mm and was
then further diluted with 10% aqueous dimethyl sulfoxide solution
to yield a dilution series. In 96-well OPTI plate (available from
ParkinElmer Life Sciences), 20 .mu.l of diluted compound, 30 .mu.l
of substrate solution (1.2 .mu.g GST-c-Jun, 0.2 .mu.Ci
[.gamma.-.sup.33P]ATP, 25 mM HEPES pH=7.5, 10 mM MgAcetate, 3.33
.mu.M ATP) and 50 .mu.l of enzyme solution (0.04 .mu.g GST-JNK3, 25
mM HEPES pH=7.5, 10 mM Mg Acetate) were mixed per 1-well, made up
to 100 .mu.l, and allowed to react for 30 minutes. After
terminating the reaction by adding 100 .mu.l of a reaction
terminator (80 mM ATP, 50 mg/ml glutathione SPA beads (available
from Amersham Pharmacia Biotech)), the reaction mixture was shaken
for 30 minutes. The mixture was centrifuged at room temperature at
1000.times.g for 5 minutes, and the emission intensity thereof was
determined on a TopCount.TM. illuminator (available from available
from ParkinElmer Life Sciences). The activity is expressed by the
50% inhibitory concentration on the enzymatic activity of JNK,
i.e., IC.sub.50 (nM).
Results
[2193] The compounds (I) to (III) according to the present
invention or a salt thereof exhibited an excellent JNK3 inhibitory
action.
[2194] The following shows examples of IC.sub.50 values.
TABLE-US-00001 JNK3 inhibitory Example No. activity 56 234 nM 106
195 nM 128 117 nM 136 167 nM 213 117 nM 353 148 nM 392 403 nM 466
578 nM 472 505 nM 495 118 nM 522 146 nM 571 63 nM 573 66 nM 603 117
nM 786 175 nM 790 70 nM 992 107 nM 1003 122 nM 1056 132 nM
Test Example 2
Measurement of ERK2 Inhibition
[2195] A plate for ELISA was coated for 1 hour with 1 .mu.g/well
myelin basic protein (available from Upstate Biotech) serving as a
reaction substrate. Following washing operation with PBs-Tween,
blocking with 1% BSA-PBS was conducted for 3 hours. After washing
with PBS-Tween, 25 .mu.l of a reaction solution (20 mM MOPS, 25 mM
.beta.-glycerophosphoric acid, 5 mM EGTA, 1 mM orthovanadic acid, 1
mM dithiothreitol), 5 .mu.l of a dilution sample of compound from
dilution series which was prepared using 1% DMSO-1% BSA solution,
10 .mu.l of 0.5 .mu.g/ml ERK2 (available from Upstate Bioech), 10
.mu.l of 500 .mu.M ATP were added to made up to 50 .mu.l, and
allowed to react at room temperature for 30 minutes. 100 .mu.l of
200 mM EDTA (pH 8.0) was added to stop the reaction, which was then
washed with PBS-Tween. This was then added with mouse
anti-phospho-myelin basic protein antibody (available from Usptate
Biotech), allowed to react for 1 hour, and washed with PBS-Tween,
thereafter added with anti-mouse IgG antibody combined with
horseradish peroxidase (available from ICN), allowed to react for 1
hour, and washed with PBS-Tween. Subsequently 100 .mu.l of a TMB
peroxidase substrate solution (available from KPL) was added,
coloring reaction was allowed for 10 minutes, and then measurement
at OD 450 nm was conducted. The activity is represented by the
concentration at which ERK2 enzyme activity was inhibited to 50%,
namely by IC.sub.50 (nM).
Results
[2196] The compounds of the present invention exhibited an
excellent selectivity.
TABLE-US-00002 JNK3 inhibitory ERK2 inhibitory activity activity
Example 103 55 nM 22100 nM Reference example 1 92 nM 710 nM
[2197] The compound of Reference example 1,
3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carboxylic acid
(furan-2-ylmethyl)-amide was synthesized while referring to
WO02-10137 (A2).
[2198] MS (ESI) m/z 362 MH.sup.+
[2199] The compounds according to the present invention had an
excellent JNK3 inhibitory action as described above, and hence
desired results were obtained also in the following tests.
Test Example 3
Cell Death Induced by Low K.sup.+ Exposure in Primary Culture of
Mouse Cerebellar Granular Neurons
[2200] Cerebellum was removed from an ICR mouse (CHARLES RIVER
JAPAN, INC.) of 7-8 days old, and cerebellar granular neurons were
isolated by means of enzyme treatment and physical treatment. The
cerebellar granular neurons were seeded in a 96-well plate so that
the density was 3.times.10.sup.5-4.times.10.sup.5 cells/cm.sup.2,
and cultured for about 1 week in a culture medium A (Basal medium
Eagle+10% FBS, 20 mM K.sup.+). Then the medium was changed from the
culture medium A to a culture medium B in which K.sup.+
concentration was low, namely Basal medium Eagle. A test compound
was dissolved in 100% DMSO to concentration of 10 mM, diluted with
the culture medium B into an objective concentration, and added at
the time of medium replacement. After 24 hours from medium
replacement, survival of cerebellar granular cells was determined
by MTT assay.
Test Example 4
Cell death Induced by MPP.sup.+ in Primary Culture of Rat
Mesencephalic Dopaminergic Neurons
[2201] Ventral mesencephalon was removed from 14-day fetal Wistar
rat (CHARLES RIVER JAPAN, INC.), and mesencephalic neurons were
isolated by means of enzyme treatment and physical treatment. The
mesencephalic neurons were seeded in a 48-well or 96-well plate so
that the density was 2.times.10.sup.5 cells/cm.sup.2, and cultured
for about 1 week in a culture medium (DMEM+10% FBS). To this
medium, a solution of test compound dissolved in 100% DMSO to 10 mM
and diluted with the culture medium into .times.22 concentration of
objective concentration was added in an amount of 1/22 of the
medium volume, and next 660 .mu.M MPP.sup.+ was added in an amount
of 1/22 of the medium volume. After 48 hours from addition of
MPP.sup.+, the cells were fixed by paraformaldehyde, and
immunostained using anti-tyrosine hydroxylase antibody. Then
surviving cells was counted under microscope, and quantified by
using an image analyzer (ANAX50, Kyusyu Matsushita Electric Co.,
Ltd.)
Test Example 5
Cell Death Induced by Amyloid .beta. (A.beta.) in Primary Culture
of Rat Cerebral Cortex and Hippocampus Neurons
[2202] Cerebral cortex and hippocampus were removed from 17-day
fetal Wistar rat (CHARLES RIVER JAPAN, INC.), and neurons of each
site were isolated by means of enzyme treatment and physical
treatment. Each neurons were seeded in a 96-well plate so that the
density was 2.times.10.sup.5 cells/cm.sup.2, and cultured for 4
days in a culture medium A (Neurobasal.TM. mediuM+B27 supplement).
To this medium, a solution of test compound dissolved in 100% DMSO
to 10 mM and diluted into an objective concentration with the
culture medium B (D/F medium+N2 supplement) was added, and then an
appropriate concentration of A.beta.1-40 was added in an amount of
1/10 of the medium volume. After 48 hours from addition of
A.beta.1-40, cell injury was quantitatively measured by LDH
assay.
Test Example 6
Protective Effect Against Dopaminergic Neuron Degeneration in
MPTP-Treated Mouse
[2203] To a group consisting of 5 male C57BL/6 mice (Japane SLC) in
8-10 weeks old, 40 mg/kg of MPTP hydrochloride (Sigma) dissolved in
saline was subcutaneously administered. After 3 days, contents of
dopamine and its metabolites (DOPAC and HVA) in striatum were
measured by HPLC. For determination of drug effect, a drug was
orally or intrapenetorially administered twice a day including 1
hour before treating of MPTP. The recovery rate of dopamine content
owing to administration of drug was determined in accordance with
the following formula.
Recovery rate ( % ) = 100 .times. [ ( striatal dopamine content in
M P T P - untreated mouse ) - ( striatal dopamine content of drug -
administered group in M P T P - treated mouse ) ( striatal dopamine
content in MPTP - untreated mouse ) - ( striatal dopamine content
of control group in MPTP - treated mouse ) ] ##EQU00001##
Test Example 7
LPS Induced Tumor Necrosis Factor .alpha. (TNF-.alpha.)
Production
[2204] A group consisting of 5 male C57BL/6 mice (Japane SLC) in
7-12 weeks old was sensitized by intravenously administering 2 mg
of BCG vaccine (Japan BCG). After 1 to 2 weeks, 0.3 mg/kg of
lipopolysaccharoid (LPS; Sigma) was intravenously administered, and
after 1 hour plasma was obtained by collecting blood from cerebral
hemorrhage. TNF-.alpha. produced in plasma was measured by using a
commercially available ELISA kit (Biosource). For determination of
drug effect, a drug was orally or intrapenetorially administered 1
hour before treating of LPS. The suppression rate of TNF-.alpha.
production owing to drug was determined in accordance with the
following formula.
Suppression rate ( % ) = 100 .times. [ 1 - ( plasma T N F - .alpha.
concentration of drug - administered group ) ( plasma T N F -
.alpha. concentration of control group ) ] ##EQU00002##
Test Example 8
Analysis Using Insulin-Resistant Model Mouse (db/db Mouse, ob/ob
Mouse)
[2205] A db/db mouse or an ob/ob mouse was administered with a test
compound once a day for 7 days, and blood glucose was measured in
fasting state and non-fasting state. Also after single
administration and final administration, glucose tolerance test
with 2 g glucose/kg was conducted. Furthermore, organs were
extracted during autopsy, and a variety of phosphorylation of c-jun
or IRS-1 in different organs were analyzed.
[2206] Structural formulae for compounds of the above Production
examples and Examples are shown below.
##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##
##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123##
##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128##
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##
##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##
##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143##
##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148##
##STR00149## ##STR00150## ##STR00151## ##STR00152## ##STR00153##
##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158##
##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163##
##STR00164## ##STR00165## ##STR00166## ##STR00167## ##STR00168##
##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173##
##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178##
##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183##
##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188##
##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193##
##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198##
##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203##
##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208##
##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213##
##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218##
##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223##
##STR00224## ##STR00225## ##STR00226## ##STR00227## ##STR00228##
##STR00229## ##STR00230## ##STR00231## ##STR00232## ##STR00233##
##STR00234## ##STR00235## ##STR00236## ##STR00237## ##STR00238##
##STR00239##
* * * * *