U.S. patent application number 15/052581 was filed with the patent office on 2017-02-02 for pyrimidine compound and medical use thereof.
This patent application is currently assigned to Japan Tobacco Inc.. The applicant listed for this patent is Japan Tobacco Inc.. Invention is credited to Hiroyuki ABE, Kazuhide HAYAKAWA, Yoshikazu HORI, Tetsuya IIDA, Hisashi KAWASAKI, Shinichi KIKUCHI, Hironori KURACHI, Toyomichi NANAYAMA, Toshiyuki SAKAI, Mitsuru TAKAHASHI, Masahiro TAMARU, Takayuki YAMAGUCHI, Takayuki YOSHIDA.
Application Number | 20170029418 15/052581 |
Document ID | / |
Family ID | 35600249 |
Filed Date | 2017-02-02 |
United States Patent
Application |
20170029418 |
Kind Code |
A1 |
KAWASAKI; Hisashi ; et
al. |
February 2, 2017 |
PYRIMIDINE COMPOUND AND MEDICAL USE THEREOF
Abstract
The present invention relates to a pyrimidine compound or a
pharmaceutically acceptable salt thereof represented by the
following formula [I] ##STR00001## wherein each symbol is as
defined in the specification and a method of therapeutically or
prophylactically treating an undesirable cell proliferation,
comprising administering such a compound. The compound of the
present invention has superior activity in suppressing undesirable
cell proliferation, particularly, an antitumor activity, and is
useful as an antitumor agent for the prophylaxis or treatment of
cancer, rheumatism, and the like. In addition, the compound of the
present invention can be a more effective antitumor agent when used
in combination with other antitumor agents such as an alkylating
agent or metabolism antagonist.
Inventors: |
KAWASAKI; Hisashi; (Osaka,
JP) ; ABE; Hiroyuki; (Osaka, JP) ; HAYAKAWA;
Kazuhide; (Osaka, JP) ; IIDA; Tetsuya; (Osaka,
JP) ; KIKUCHI; Shinichi; (Osaka, JP) ;
YAMAGUCHI; Takayuki; (Osaka, JP) ; NANAYAMA;
Toyomichi; (Osaka, JP) ; KURACHI; Hironori;
(Osaka, JP) ; TAMARU; Masahiro; (Osaka, JP)
; HORI; Yoshikazu; (Osaka, JP) ; TAKAHASHI;
Mitsuru; (Osaka, JP) ; YOSHIDA; Takayuki;
(Yokohama-shi, JP) ; SAKAI; Toshiyuki; (Kyoto-shi,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Japan Tobacco Inc. |
Tokyo |
|
JP |
|
|
Assignee: |
Japan Tobacco Inc.
Tokyo
JP
|
Family ID: |
35600249 |
Appl. No.: |
15/052581 |
Filed: |
February 24, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14454404 |
Aug 7, 2014 |
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15052581 |
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12626443 |
Nov 25, 2009 |
8835443 |
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14454404 |
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12053133 |
Mar 21, 2008 |
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12626443 |
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11150792 |
Jun 10, 2005 |
7378423 |
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12053133 |
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60630596 |
Nov 23, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
C07D 239/545 20130101; A61P 29/00 20180101; C07C 2601/16 20170501;
C07D 239/62 20130101; C07D 471/04 20130101; C07C 275/50 20130101;
C07D 239/553 20130101; C07D 471/16 20130101; C07F 9/53 20130101;
A61P 35/00 20180101; C07C 275/30 20130101; C07D 487/04
20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 239/545 20060101 C07D239/545; C07D 239/553
20060101 C07D239/553; C07C 275/30 20060101 C07C275/30; C07D 239/62
20060101 C07D239/62 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 11, 2004 |
JP |
2004-174770 |
Nov 10, 2004 |
JP |
2004-327111 |
Claims
1.-24. (canceled)
25. A method of preparing a compound of the formula: ##STR00677##
comprising (a) reacting ##STR00678## with cyclopropylamine to form
##STR00679## (b) reacting the product of step (a) with ##STR00680##
to form ##STR00681## (c) converting the product of step (b) to
##STR00682## (d) converting the product of step (c) to ##STR00683##
(e) reacting the product of step (d) with ##STR00684## to form
##STR00685## (f) reacting the product of step (e) with ##STR00686##
to form ##STR00687## and (g) reacting the product of step (f) with
##STR00688## to form ##STR00689##
26. A compound of the formula: ##STR00690## or a salt or solvate
thereof.
27. A compound of the formula: ##STR00691## or a salt or solvate
thereof.
28. A compound of the formula: ##STR00692## or a salt or solvate
thereof.
29. A compound of the formula: ##STR00693## or a salt or solvate
thereof.
30. A compound of the formula: ##STR00694## or a salt or solvate
thereof.
31. A compound of the formula: ##STR00695## or a salt or solvate
thereof.
Description
TECHNICAL FIELD
[0001] The present invention relates to a novel pyrimidine compound
or a pharmaceutically acceptable salt thereof useful as an agent
for the prophylaxis or treatment of diseases caused by undesirable
cell proliferation, particularly, an antitumor agent. Moreover, the
present invention relates to novel use of a certain kind of
pyrimidine compound or a pharmaceutically acceptable salt thereof
as an agent for the prophylaxis or treatment of a disease caused by
undesirable cell proliferation, particularly, as an antitumor
agent. More particularly, the present invention relates to a
pharmaceutical agent comprising a pyrimidine compound showing a p15
protein inducing action and/or a p27 protein inducing action and/or
an MEK inhibitory action, or a pharmaceutically acceptable salt
thereof.
BACKGROUND ART
[0002] A "cell cycle" means a cycle wherein the period for a cell
to divide and once again divide is one cycle, and this cycle is
also referred to as a "cell division cycle".
[0003] A cell cycle includes four phases in a determined order.
They are DNA duplication preparation phase (G1 phase), DNA
duplication phase (S phase), division preparation phase (G2 phase)
and division phase (M phase), and regulated by many factors. Among
them, the kinase activity of a cyclin/cyclin dependent kinase (CDK)
complex is essential for the regulation of the cell cycle.
[0004] As a protein to inhibit the kinase activity, a CDK
inhibitory protein is known. The CDK inhibitory proteins of
mammalian cells are p21 family and p16 family, both of which are
considered to negatively regulate the progress of cell cycle and
responsible for cell differentiation, apoptosis and repair of DNA
damage due to irradiation of X ray and the like. At present, p21,
p27 and p57 have been reported as a p21 family, and p16, p15, p18
and p19 have been reported as a p16 family.
[0005] When these CDK inhibitory proteins are highly expressed in
the cell, the cell proliferation is arrested at G1 phase.
[0006] The p21 family shows an inhibitory activity on a relatively
wide range and plural cyclin/CDK complexes. For example, cyclin
E/CDK 2 which is an important cyclin/CDK complex from G1 phase to
G1/S transition phase, cyclin B/Cdc2 which is important for M phase
and the like can be mentioned. The p16 family is a specific
inhibitory factor against cyclin D/CDK 4 and cyclin D/CDK 6, which
are one of the cyclin/CDKs in the G1 phase, and is considered to
dissociate the cyclin/CDK complex by binding with CDK 4 and CDK 6,
respectively.
[0007] From the examination of clinical materials of cancer of
esophagus, pancreatic cancer, non-small cell lung cancer, skin
cancer and the like, highly frequent incidence of genetic
abnormality of P16 has been reported, and high cancer incidence in
p16 knock out mice has been demonstrated, and therefore, clinical
application of p16 inducer has been tried.
[0008] Under such situation, p15 protein (aka: INK4B, also simply
referred to as p15) has been found as a p16 family. In 1994,
induction of p15 expression by TGF-.beta. stimulation was confirmed
in human keratinocyte cell (HaCaT), and p15 was considered to be
one of the factors negatively regulating the cell cycle. It known
that induction of G1 phase cell cycle arrest in HaCaT by TGF-.beta.
leads to the suppression of cell proliferation (Letters to Nature,
Sep. 15, 1994, vol. 371, pp. 257-261).
[0009] While the histondeacetylase (HDAC) inhibitor is known to
arrest cell cycles at G1 phase or G2 phase in human cancer cell, it
has been found recently that trichostatin A, which is an HDAC
inhibitor, induces p15 gene in human colon cancer cell
(HCT116p21(-/-)), and the induction of p15 by trichostatin A is
involved in the inhibition of the cell proliferation of the cancer
cells (FEBS Letters, 2003, vol. 554, pp. 347-350).
[0010] In this way, a compound that induces p15 and/or p27 is
expected to inhibit the cell proliferation of cancer cells and the
like.
[0011] In the meantime, Mitogen-activated protein (MAP)
Kinase/extracellular signal-regulated kinase (ERK) kinase
(hereinafter to be referred to as MEK) is known to be involved in
the regulation of cell proliferation as a kinase that mediates
Raf-MEK-ERK signal transduction pathway, and the Raf family (B-Raf,
C-Raf etc.) activates the MEK family (MEK-1, MEK-2 etc.) and the
MEK family activates the ERK family (ERK-1 and ERK-2).
[0012] Activation of Raf-MEK-ERK signal transduction pathway in
cancer, particularly colorectal cancer, pancreatic cancer, lung
cancer, breast cancer and the like, has been frequently
observed.
[0013] In addition, since the signals produced by signal molecules
such as growth factor, cytokine and the like converge to the
activation of MEK-ERK, inhibition of these functions is considered
to more effectively suppress Raf-MEK-ERK signal transduction than
the suppression of the function of RTK, Ras, Raf and the like in
the upstream.
[0014] Moreover, it is also known in recent years that a compound
having an MEK inhibitory activity extremely effectively induces
inhibition of ERK1/2 activity and suppression of cell proliferation
(The Journal of Biological Chemistry, vol. 276, No. 4, pp.
2686-2692, 2001), and the compound is expected to show effects on
the disease caused by undesirable cell proliferation, such as tumor
and the like. In addition, an MEK inhibitor is expected to inhibit
infiltration or metastaticity of cells via promotion of expression
of Matrix metalloproteinase (MMP) and CD44, and angiogenesis via
promotion of expression of vascular endothelial growth factor
(VEGF).
[0015] Furthermore, application to chronic pain (JP 2003-504401: WO
01/005393), application to diseases or symptoms mediated by
neutrophile (JP2002-332247: CA-2385412), application to graft
rejection (JP 2002-532414: WO 00/35435), application to arthritis
(JP 2002-532415: WO 00/35436), application to asthma (JP
2002-534380: WO 00/40235), application to viral diseases (JP
2002-534381: WO 00/40237), application to diseases caused by
deformation or injury of cartilage (WO2002/087620: US 2004/138285),
application to Peutz-Jeghers syndrome (WO02/006520) are
expected.
[0016] However, such pharmaceutical agent has not been marked
heretofore.
[0017] As an already commercially available antitumor agent, the
following compound (Gefitinib) and the like are known (Iressa
tablet 250 package insert).
##STR00002##
[0018] JP-A-2004-504294 (patent family: WO2002/006213) describe the
following compound and the like as compounds having an antitumor
activity. In addition, the MEK inhibitory activity of such
compounds is described (JP-A-2004-504294, pp. 123-124, Example 39,
Example 241).
##STR00003##
[0019] Known compounds relatively similar to the pharmaceutical
agent of the present invention are described below.
[0020] In the literatures issued in 1991, the antitumor activity of
pyrido[2,3-d]pyrimidine derivative has been studied and it
described, for example, that some of the following compounds and
the like have an inhibitory activity in sarcoma, leukemia cells
(Khimiia geterotsiklicheskikh soedinenii, 1991, No. 5, pp. 674-680
(English translation p. 542, lines 4-7; p. 538, compound
IIIa)).
##STR00004##
[0021] In the literatures issued in 1973, novel synthetic methods
of the following compound and the like are disclosed and the
antitumor activity of pyrido[2,3-d]pyrimidine derivative is
described (Chem. Pharm. Bull., 1973, No. 21, vol. 9, pp. 2014-2018
(p. 2015, chart 2, qompound VIII)).
##STR00005##
[0022] In these literatures, however, the compound of the present
invention is not disclosed, nor is there found a description
suggestive thereof.
[0023] Furthermore, WO2002/094824 discloses the following compound
and the like (WO2002/094824, p. 55, Example 9) as a therapeutic
agent having a cytokine regulating action for immune, inflammatory
or allergic disease.
##STR00006##
In the literatures issued in 1996, synthetic methods of the
following compound and the like are disclosed (Journal fur
Praktische Chemie, 1996, vol. 338, pp. 151-156 (p. 154, Table 1,
compound 8f)).
##STR00007##
[0024] In the literatures issued in 1986, synthetic methods of the
following compound and the like as a synthetic intermediate for
aminopterin analog having an antitumor activity are disclosed
(Journal of Medicinal Chemistry, 1986, vol. 29, No. 5, pp. 709-715
(p. 709 abstract; p. 712, Table 1, compound 9b)).
##STR00008##
[0025] However, this literature does not contain a description
relating to the use of these compounds as antitumor agents, the
compound of the present invention is not disclosed and a
description suggestive thereof is not found.
DISCLOSURE OF THE INVENTION
[0026] An object of the present invention is to provide a
pharmaceutical agent containing a pyrimidine compound showing
undesirable cell proliferation inhibitory action, particularly an
antitumor action or a pharmaceutically acceptable salt thereof.
[0027] The present inventors have conducted intensive studies in an
attempt to find a compound having such action and completed the
present invention.
[0028] More particularly, the present invention provides the
following (1) to (37).
(1) Use of a compound represented by the following formula [I] or a
pharmaceutically acceptable salt thereof as an active ingredient
for the production of a pharmaceutical agent for treating a
tumor:
##STR00009##
wherein X.sup.1 and X.sup.2 are the same or different and each is a
carbon atom or a nitrogen atom, a
##STR00010##
moiety is
##STR00011##
R.sup.1, R.sup.2, and R.sup.6 are the same or different and each is
a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, [0029] wherein
the C.sub.1-6 alkyl group and the C.sub.2-6 alkenyl group are
optionally substituted by 1 to 3 substituents selected from the
following group A, or
[0029] ##STR00012## [0030] wherein m is 0 or an integer of 1 to 4,
[0031] ring Cy is a C.sub.3-12 carbon ring group or a heterocyclic
group, [0032] wherein the heterocyclic group is a saturated or
unsaturated ring group having, besides carbon atom, 1 to 4 hetero
atoms selected from an oxygen atom, a nitrogen atom and a sulfur
atom, the C.sub.3-12 carbon ring group and the heterocyclic group
are optionally substituted by 1 to 5 substituents selected from the
following group B, R.sup.3, R.sup.4, and R.sup.5 are the same or
different and each is a hydrogen atom, a hydroxyl group, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, [0033] wherein
the C.sub.1-6 alkyl group and the C.sub.2-6 alkenyl group are
optionally substituted by 1 to 3 substituents selected from the
following group A, a C.sub.3-12 carbon ring group or a heterocyclic
group, [0034] wherein the heterocyclic group is a saturated or
unsaturated ring group having, besides carbon atom, 1 to 4 hetero
atoms selected from an oxygen atom, a nitrogen atom and a sulfur
atom, and the C.sub.3-12 carbon ring group and the heterocyclic
group are optionally substituted by 1 to 5 substituents selected
from the following group B, or R.sup.2 and R.sup.3 are optionally
linked to form a C.sub.1-4 alkylene group, or R.sup.4 and R.sup.5
are optionally linked to form a C.sub.1-4 alkylene group, wherein
group A is a group consisting of 1) a halogen atom, 2) a nitro
group, 3) a cyano group, 4) a C.sub.1-4 alkyl group, 5) --OR.sup.A1
wherein R.sup.A1 is a hydrogen atom or a C.sub.1-4 alkyl group, 6)
--SR.sup.A2 wherein R.sup.A2 is a hydrogen atom or a C.sub.1-4
alkyl group, 7) --NR.sup.A3R.sup.A4 wherein R.sup.A3 and R.sup.A4
are the same or different and each is a hydrogen atom or a
C.sub.1-4 alkyl group, 8) --COOR.sup.A5 wherein R.sup.A5 is a
hydrogen atom or a C.sub.1-4 alkyl group, 9) --NR.sup.A6COR.sup.A7
wherein R.sup.A6 is a hydrogen atom or a C.sub.1-4 alkyl group,
R.sup.A7 is a C.sub.1-4 alkyl group, a C.sub.3-12 carbon ring group
or a heterocyclic group, 10) --NR.sup.A8COOR.sup.A9 wherein
R.sup.A8 and R.sup.A9 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, 11) a C.sub.3-12 carbon
ring group and 12) a heterocyclic group, [0035] wherein the
heterocyclic group is a saturated or unsaturated ring group having,
besides carbon atom, 1 to 4 hetero atoms selected from an oxygen
atom, a nitrogen atom and a sulfur atom, [0036] each of the
C.sub.1-4 alkyl groups of the above-mentioned 4), R.sup.A1,
R.sup.A2, R.sup.A3, R.sup.A4, R.sup.A5, R.sup.A6, R.sup.A7,
R.sup.A8 and R.sup.A9 is optionally substituted by the same or
different 1 to 3 substituents selected from the following group C,
and [0037] each of the C.sub.3-12 carbon ring groups of the
above-mentioned 11) and R.sup.A7, and the heterocyclic groups of
12) and R.sup.A7 is optionally substituted by the same or different
1 to 5 substituents selected from the following group C group B is
a group consisting of 1) a halogen atom, 2) a nitro group, 3) a
cyano group, 4) a C.sub.1-8a alkyl group, 5) a C.sub.2-4 alkenyl
group, 6) a C.sub.2-4 alkynyl group, 7) --OR.sup.B1 wherein
R.sup.B1 is a hydrogen atom or a C.sub.1-4 alkyl group, 8)
--SR.sup.B2 wherein R.sup.B2 is a hydrogen atom or a C.sub.1-4
alkyl group, 9) --NR.sup.B3R.sup.B4 wherein R.sup.B3 is a hydrogen
atom, a C.sub.1-4 alkyl group, a C.sub.3-12 carbon ring group or a
heterocyclic group, and R.sup.B4 is a hydrogen atom or a C.sub.1-4
alkyl group, 10) --NR.sup.B5COR.sup.B6 wherein R.sup.B5 is a
hydrogen atom or a C.sub.1-4 alkyl group, and R.sup.B6 is a
hydrogen atom, a C.sub.1-4 alkyl group, a C.sub.3-12 carbon ring
group or a heterocyclic group, 11) --NR.sup.B7COOR.sup.B8 wherein
R.sup.B7 and R.sup.B8 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, 12)
--NR.sup.B9CONR.sup.B10R.sup.B11 wherein R.sup.B9, R.sup.B10 and
R.sup.B11 are the same or different and each is a hydrogen atom or
a C.sub.1-4 alkyl group, 13) --NR.sup.B12CONR.sup.B13 OR.sup.B14
wherein R.sup.B12, R.sup.B13 and R.sup.B14 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
14) --NR.sup.B15SO.sub.2R.sup.B16 wherein R.sup.B15 is a hydrogen
atom or a C.sub.1-4 alkyl group, and R.sup.B16 is a C.sub.1-4 alkyl
group, a C.sub.3-12 carbon ring group or a heterocyclic group, 15)
--SO.sub.2--R.sup.B17 wherein R.sup.B17 is a C.sub.1-4 alkyl group
or a heterocyclic group, 16) --SO.sub.2NR.sup.B18R.sup.B19 wherein
R.sup.B18 and R.sup.B19 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, 17)
--P(.dbd.O)(R.sup.B20) (R.sup.B21) wherein R.sup.B20 and R.sup.B21
are the same or different and each is a C.sub.1-4 alkyl group, 18)
--COOR.sup.B22 wherein R.sup.B22 is a hydrogen atom or a C.sub.1-4
alkyl group, 19) --CONR.sup.B23R.sup.B24 wherein R.sup.B23 and
R.sup.B24 are the same or different and each is a hydrogen atom or
a C.sub.1-4 alkyl group, 20)
--NR.sup.B25SO.sub.2NR.sup.B26R.sup.B27 wherein R.sup.B25,
R.sup.B26 and R.sup.B27 are the same or different and each is a
hydrogen atom or a C.sub.1-4 alkyl group, 21)
--NR.sup.B28SO.sub.2NR.sup.B29CONR.sup.B30R.sup.B31 wherein
R.sup.B28, R.sup.B29, R.sup.B30 and R.sup.B31 are the same or
different and each is a hydrogen atom or a C.sub.1-4 alkyl group,
22) a C.sub.3-12 carbon ring group and 23) a heterocyclic group
[0038] wherein each of the "C.sub.1-8 alkyl group" of the
above-mentioned 4), and the C.sub.1-4 alkyl groups for R.sup.B1 to
R.sup.B31 is optionally substituted by the same or different 1 to 3
substituents selected from the above-mentioned group A, [0039] each
of the C.sub.2-4 alkenyl group of 5) and the C.sub.2-4 alkynyl
group of 6) is optionally substituted by the same or different 1 to
3 substituents selected from the above-mentioned group A, [0040]
the heterocyclic group is a saturated or unsaturated ring group
having, besides carbon atom, 1 to 4 hetero atoms selected from an
oxygen atom, a nitrogen atom and a sulfur atom, and [0041] each of
the C.sub.3-12 carbon ring group of the above-mentioned 22),
R.sup.B3, R.sup.B6 and R.sup.B16, and the heterocyclic group of the
above-mentioned 23), R.sup.B3, R.sup.B6, R.sup.B16 and R.sup.B17 is
optionally substituted by the same or different 1 to 5 substituents
selected from the following group C, and group C is a group
consisting of 1) a halogen atom, 2) a cyano group, 3) a C.sub.1-4
alkyl group, 4) --OR.sup.C1 wherein R.sup.C1 is a hydrogen atom or
a C.sub.1-4 alkyl group, 5) --NR.sup.C2R.sup.C3 wherein R.sup.C2
and R.sup.C3 are the same or different and each is a hydrogen atom
or a C.sub.1-4 alkyl group, 6) --COOR.sup.C4 wherein R.sup.C4 is a
hydrogen atom or a C.sub.1-4 alkyl group and 7) an oxo group. (2) A
compound represented by the following formula [I'] or a
pharmaceutically acceptable salt thereof:
##STR00013##
[0041] wherein R.sup.1', R.sup.2' and R.sup.6 are the same or
different and each is a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, [0042] wherein the C.sub.1-6 alkyl group and the C.sub.2-6
alkenyl group are optionally substituted by 1 to 3 substituents
selected from group A of the above-mentioned (1), or
[0042] ##STR00014## [0043] m is an integer of 0 or 1 to 4, [0044]
ring Cy is a C.sub.3-12 carbon ring group or a heterocyclic group
[0045] wherein the heterocyclic group is a saturated or unsaturated
ring having, besides carbon atom, 1 to 4 hetero atoms selected from
an oxygen atom, a nitrogen atom and a sulfur atom, and the
C.sub.3-12 carbon ring group and the heterocyclic group are
optionally substituted by 1 to 5 substituents selected from group B
of the above-mentioned (I), provided that, when the
##STR00015##
[0045] moiety is
##STR00016##
then R.sup.2' is not a methyl group, and when R.sup.2' is a phenyl
group, then R.sup.1' is not a phenyl group, and other symbols are
as defined in the above-mentioned (1). (3) Use of the
above-mentioned (1), wherein the compound is represented by the
following formula [I-1]:
##STR00017##
wherein each symbol in the formula is as defined in the
above-mentioned (1). (4) Use of the above-mentioned (1), wherein
the compound is represented by the following formula [I-2]:
##STR00018##
wherein each symbol in the formula is as defined in the
above-mentioned (1). (5) Use of the above-mentioned (1), wherein
the compound is represented by the following formula [I-3]:
##STR00019##
wherein each symbol in the formula is as defined in the
above-mentioned (1). (6) Use of the above-mentioned (1), wherein
R.sup.1 is a C.sub.1-6 alkyl group. (7) Use of the above-mentioned
(1), wherein R.sup.1 is
##STR00020##
wherein m is 0, and ring Cy is a C.sub.3-12 carbon ring group
[0046] wherein the C.sub.3-12 carbon ring group is optionally
substituted by 1 to 5 substituents selected from group B of the
above-mentioned (1). (8) Use of the above-mentioned (I), wherein
R.sup.1 is a C.sub.3-8 cycloalkyl group. (9) Use of the
above-mentioned (8), wherein R.sup.1 is a cyclopropyl group. (10)
Use of the above-mentioned (1), wherein R.sup.2 is
##STR00021##
[0046] wherein m is 0, and ring Cy is a C.sub.3-12 carbon ring
group or a heterocyclic group wherein the C.sub.3-12 carbon ring
group and the heterocyclic group are optionally substituted by 1 to
5 substituents selected from group B of the above-mentioned (1).
(11) Use of the above-mentioned (1), wherein R.sup.3 is a C.sub.1-6
alkyl group. (12) Use of the above-mentioned (1), wherein R.sup.4
is a hydrogen atom. (13) Use of the above-mentioned (1), wherein
R.sup.5 is a hydrogen atom. (14) Use of the above-mentioned (1),
wherein R.sup.6 is
##STR00022##
wherein m is 0, and ring Cy is a C.sub.3-12 carbon ring group or a
heterocyclic group [0047] wherein the C.sub.3-12 carbon ring group
and the heterocyclic group are optionally substituted by 1 to 5
substituents selected from group B of the above-mentioned (1). (15)
Use of a compound of the formula [I] of the above-mentioned (1) or
a pharmaceutically acceptable salt thereof as an active ingredient
for the production of an antitumor agent. (16) Use of a compound of
the formula [I] of the above-mentioned (1) or a pharmaceutically
acceptable salt thereof as an active ingredient for the production
of a pharmaceutical agent capable of inhibiting MEK. (17) Use of a
compound of the formula [I] of the above-mentioned (1) or a
pharmaceutically acceptable salt thereof as an active ingredient
for the production of a pharmaceutical agent capable of inducing
p15 protein. (18) Use of a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof
as an active ingredient for the production of a pharmaceutical
agents for treating a disease caused by an undesirable cell
proliferation. (19) Use of the above-mentioned (18), wherein the
disease causing by an undesirable cell proliferation is rheumatism.
(20) Use of a compound of the formula [I] of the above-mentioned
(1) or a pharmaceutically acceptable salt thereof as an active
ingredient for the production of a pharmaceutical agent capable of
inhibiting undesirable cell proliferation. (21) Use of a compound
of the formula [1] of the above-mentioned (1) or a pharmaceutically
acceptable salt thereof as an active ingredient for the production
of a pharmaceutical agent capable of regulating cell cycle. (22) A
pharmaceutical composition which comprises a compound of the
formula [I'] of the above-mentioned (2) or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
(23) A pharmaceutical composition for the treatment of a tumor,
which comprises a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier. (24) A pharmaceutical
composition for treating a disease causing by an undesirable cell
proliferation, which comprises a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier. (25) A commercial
package comprising a pharmaceutical composition of the
above-mentioned (23) and a written matter associated therewith, the
written matter stating that the pharmaceutical composition can or
should be used for treating tumor. (26) A commercial package
comprising a pharmaceutical composition of the above-mentioned (24)
and a written matter associated therewith, the written matter
stating that the pharmaceutical composition can or should be used
for treating disease causing by an undesirable cell proliferation.
(27) Use of (a) a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof
as an active ingredient, which is used in combination with (b) at
least one other antitumor compound, for the production of an
antitumor agent. (28) Use of (a) compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof
as an active ingredient and (b) at least one other antitumor
compound, in combination, for the production of an antitumor agent.
(29) A pharmaceutical composition comprising, as an active
ingredient, (a) a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof
and (b) at least one other antitumor compound, and a pharmaceutical
acceptable carrier, in combination. (30) A kit for treating a tumor
comprising (a) a pharmaceutical composition comprising, as an
active ingredient, a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof
and (b) a pharmaceutical composition comprising, as an active
ingredient, at least one other antitumor agent, in combination.
(31) An antitumor agent comprising a compound of the formula [I] of
the above-mentioned (1) or a pharmaceutically acceptable salt
thereof as an active ingredient. (32) A MEK inhibitor comprising a
compound of the formula [I] of the above-mentioned (1) or a
pharmaceutically acceptable salt thereof as an active ingredient.
(33) A p15 protein inducer comprising a compound of the formula [I]
of the above-mentioned (1) or a pharmaceutically acceptable salt
thereof as an active ingredient. (34) An antitumor agent
comprising, as an active ingredient, (a) a compound of the formula
[I] of the above-mentioned (1) or a pharmaceutically acceptable
salt thereof, which is used in combination with (b) at least one
other antitumor compound. (35) An antitumor agent comprising, as an
active ingredient, (a) a compound of the formula [I] of the
above-mentioned (1) or a pharmaceutically acceptable salt thereof,
and (b) at least one other antitumor compound, in combination. (36)
The agent of the above-mentioned (34), wherein (a) a compound of
the formula [I] of the above-mentioned (1) or a pharmaceutically
acceptable salt thereof and (b) at least one other antitumor
compound are administered to a mammal simultaneously or
sequentially. (37) The agent of the above-mentioned (35), wherein
(a) a compound of the formula [I] of the above-mentioned (1) or a
pharmaceutically acceptable salt thereof and (b) at least one other
antitumor compound are administered to a mammal simultaneously or
sequentially.
BEST MODE FOR EMBODYING THE INVENTION
[0048] The definitions of each substituent and each moiety used in
the present specification are as follows.
[0049] X.sup.1 and X.sup.2 are the same or different, and each is a
carbon atom or a nitrogen atom, a
##STR00023##
moiety is
##STR00024##
preferably,
##STR00025##
and particularly preferably
##STR00026##
[0050] The "halogen atom" is a fluorine atom, a chlorine atom, a
bromine atom or an iodine atom, which is preferably a fluorine
atom, a chlorine atom or a bromine atom for 1) of group A and 1) of
group C, more preferably a fluorine atom for 1) of group A, more
preferably a fluorine atom or a bromine atom for 1) of group C, and
preferably a fluorine atom or an iodine atom for 1) of group B.
[0051] The "C.sub.1-6 alkyl group" is a straight chain or branched
chain alkyl group having 1 to 6 carbon atoms, and specifically,
methyl group, ethyl group, propyl group, isopropyl group,
2,2-dimethylpropyl group, butyl group, isobutyl group, sec-butyl
group, tert-butyl group, pentyl group, hexyl group and the like can
be mentioned.
[0052] As R.sup.1, R.sup.1', R.sup.2, R.sup.2 and R.sup.6, methyl
group, ethyl group, propyl group, isopropyl group,
2,2-dimethylpropyl group, butyl group and isobutyl group are
preferable, methyl group and ethyl group are more preferable, and
methyl group is particularly preferable. As R.sup.3, R.sup.4 and
R.sup.5, methyl group, ethyl group, propyl group and isobutyl group
are preferable, and methyl group is more preferable.
[0053] The "C.sub.1-4alkyl group" is a straight chain or branched
chain alkyl group having 1 to 4 carbon atoms, and specifically,
methyl group, ethyl group, propyl group, isopropyl group, butyl
group, isobutyl group, sec-butyl group, tert-butyl group and the
like can be mentioned.
[0054] As 4) of group A and 3) of group C, methyl group and ethyl
group are preferable and methyl group is more preferable. As
R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, R.sup.A5, R.sup.A6,
R.sup.A7, R.sup.A8 and R.sup.A9, methyl group, ethyl group and
butyl group are preferable and methyl group is more preferable. As
R.sup.B1 to R.sup.B31, methyl group, ethyl group, propyl group,
isopropyl group and butyl group are preferable and methyl group,
ethyl group and propyl group are more preferable. As R.sup.C1,
R.sup.C2, R.sup.C3, R.sup.C4 and R.sup.C5, methyl group and ethyl
group are preferable and methyl group is more preferable.
[0055] The "C.sub.1-9 alkyl group" is a straight chain or branched
chain alkyl group having 1 to 8 carbon atoms, and specifically,
methyl group, ethyl group, propyl group, isopropyl group,
1-ethyl-1-propyl group, butyl group, isobutyl group, sec-butyl
group, tert-butyl group, 3-methylbutyl group, 1-propyl-1-butyl
group, pentyl group, isopentyl group, hexyl group, heptyl group,
octyl group and the like can be mentioned.
[0056] As 2) of group B, methyl group, ethyl group, propyl group,
isopentyl group, 1-ethyl-1-propyl group, 3-methylbutyl group and
1-propyl-1-butyl group are preferable and methyl group and ethyl
group are more preferable.
[0057] The "C.sub.2-6 alkenyl group" is a straight chain or
branched chain alkenyl group having 2 to 6 carbon atoms, and
specifically, vinyl group, 1-propenyl group, 2-propenyl group,
isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl
group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group,
2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group,
2-pentenyl group, 3-pentenyl group, 4-pentenyl group,
1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group,
1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group,
1-methyl-1-butenyl group, 1-methyl-2-butenyl group,
2-methyl-1-butenyl group, 1-isopropylvinyl group, 2,4-pentadienyl
group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl
group, 5-hexenyl group, 2,4-hexadienyl group, 1-methyl-1-pentenyl
group and the like can be mentioned.
[0058] As R.sup.1, R.sup.1', R.sup.2, R.sup.2', R.sup.3, R.sup.4,
R.sup.5 and R.sup.6, vinyl group, 1-propenyl group and 2-propenyl
group are preferable and 2-propenyl group is more preferable.
[0059] The "C.sub.2-4 alkenyl group" is a straight chain or
branched chain alkenyl group having 2 to 4 carbon atoms, and
specifically, vinyl group, 1-propenyl group, 2-propenyl group,
isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl
group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group,
2-methyl-2-propenyl group, 1-ethylvinyl group and the like can be
mentioned.
[0060] As 5) of group B, vinyl group and 1-propenyl group are
preferable, and vinyl group is more preferable.
[0061] The "C.sub.2-4 alkynyl group" is a straight chain or
branched chain alkynyl group having 2 to 4 carbon atoms, and
specifically, ethynyl group, 1-propynyl group, 2-propynyl group,
isopropynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl
group, 1-methyl-1-propynyl group, 1-methyl-2-propynyl group,
2-methyl-2-propynyl group, 1-ethylethynyl group and the like can be
mentioned.
[0062] As 6) of group B, ethynyl group, 1-propynyl group and
1-butynyl group are preferable, and ethynyl group is more
preferable.
[0063] The "C.sub.1-4 alkylene group" optionally formed by R.sup.2
in junction with R.sup.3 and the "C.sub.1-4 alkylene group"
optionally formed by R.sup.4 in junction with R.sup.5 is a straight
chain or branched chain alkylene group having 1 to 4 carbon atoms,
and specifically, methylene group, ethylene group, trimethylene
group, 2-methyltrimethylene group, tetramethylene group and the
like can be mentioned.
[0064] The "C.sub.1-4 alkylene group" optionally formed by R.sup.2
in junction with R.sup.3 is preferably methylene group, ethylene
group or trimethylene group, more preferably trimethylene
group.
[0065] The "C.sub.1-4alkylene group" optionally formed by R.sup.4
in junction with R.sup.5 is preferably methylene group, ethylene
group or trimethylene group, more preferably ethylene group.
[0066] As m, preferred is 0 or an integer of 1 or 2, more
preferably 0.
[0067] The "C.sub.3-12 carbon ring group" is a saturated or
unsaturated cyclic hydrocarbon group having 3 to 12 carbon atoms,
which means a phenyl group, naphthyl group, C.sub.3-8cycloalkyl
group, or a fused ring group of C.sub.3-8 cycloalkyl and
benzene.
[0068] The "C.sub.3-8 cycloalkyl group" is a saturated cyclic
hydrocarbon group having 3 to 8 carbon atoms, and specifically,
cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl
group, cycloheptyl group, cyclooctyl group, norbornanyl group and
the like can be mentioned, and preferably cyclopropyl group,
cyclobutyl group, cyclopentyl group or cyclohexyl group.
[0069] As the "fused ring group of C.sub.3-8cycloalkyl group and
benzene", indanyl group, 1,2,3,4-tetrahydronaphthyl group
(1,2,3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naphthyl
group etc.) and the like can be specifically mentioned, which is
preferably indanyl group, 1,2,3,4-tetrahydronaphthyl group and the
like, and more preferably indanyl group.
[0070] As R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6,
phenyl group, cyclopropyl group, cyclobutyl group, cyclopentyl
group and cyclohexyl group are preferable, and phenyl group and
cyclopropyl group are more preferable. As R.sup.1, cyclopropyl
group is particularly preferable, and as R.sup.2 and R.sup.6,
phenyl group is particularly preferable. As 11) of group A,
R.sup.A7, 22) of group B, R.sup.B3, R.sup.B6 and R.sup.B16, phenyl
group, cyclopropyl group, cyclobutyl group, cyclopentyl group and
cyclohexyl group are preferable, and phenyl group and cyclopropyl
group are more preferable.
[0071] The "heterocyclic group" is a saturated monocyclic ring or
an unsaturated monocyclic ring having 5 or 6 ring-constituting
atoms, which contains, besides carbon atom, 1 to 4 hetero atoms
selected from an oxygen atom, a nitrogen atom and a sulfur atom, as
a ring-constituting atom, a fused ring of the monocycle and a
benzene ring or a spiro ring of these monocycles or fused rings and
the above-mentioned C.sub.3-12 carbon ring, each of which may have
1 to 4, preferably 1 or 2, oxo groups.
[0072] As the "heterocyclic group", which is a monocycle of a
saturated ring, pyrrolidinyl group, tetrahydrofuryl group,
tetrahydrothienyl group, imidazolidinyl group, 2-oxoimidazolidinyl
group, 2,4-dioxoimidazolidinyl group, pyrazolidinyl group,
1,3-dioxolanyl group, 1,3-oxathiolanyl group, oxazolidinyl group,
2-oxooxazolidinyl group, thiazolidinyl group, piperidinyl group,
piperazinyl group, 2-oxopiperazinyl group, tetrahydropyranyl group,
tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group,
thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl
group, 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group,
thiadiazolidinyl group (e.g., 1,1-dioxo-1,2,5-thiadiazolidin-2-yl
group etc.) and the like can be mentioned. Preferably, pyrrolidinyl
group, piperidinyl group, piperazinyl group and morpholinyl group
can be mentioned.
[0073] As the "heterocyclic group", which is a monocycle of
unsaturated ring, pyrrolyl group (e.g., 2-pyrrolyl group etc.),
furyl group, thienyl group, imidazolyl group (e.g., 4-imidazolyl
group etc.), 1,2-dihydro-2-oxoimidazolyl group, pyrazolyl group
(e.g., 5-pyrazolyl group etc.), diazolyl group, oxazolyl group,
isoxazolyl group, thiazolyl group, isothiazolyl group,
1,2,4-triazolyl group, 1,2,3-triazolyl group, tetrazolyl group,
1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group,
1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl
group, pyridyl group (e.g., 3-pyridyl group etc.), pyrimidinyl
group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group,
pyrazinyl group, 1,3,5-triazinyl group, imidazolinyl group (e.g.,
2-imidazolinyl group etc.), pyrazolinyl group, oxazolinyl group
(2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolinyl group),
isoxazolinyl group, thiophenyl group, thiazolinyl group,
isothiazolinyl group, pyranyl group, 2-oxopyranyl group,
2-oxo-2,5-dihydrofuranyl group, 1,1-dioxo-1H-isothiazolyl group and
the like can be mentioned. Preferably, pyrrolyl group, thienyl
group, imidazolyl group, pyrazolyl group, oxazolyl group,
isooxazolyl group, thiophenyl group, thiazolyl group, isothiazolyl
group and pyridyl group can be mentioned.
[0074] As the "heterocyclic group" which is a fused ring of
monocycle and benzene ring, indolyl groups (e.g., 4-indolyl group,
5-indolyl group, 6-indolyl group, 7-indolyl group etc.), isoindolyl
group, 1,3-dihydro-1,3-dioxoisoindolyl group and benzofuranyl
groups (e.g., 4-benzofuranyl group, 7-benzofuranyl group etc.),
indazolyl group, isobenzofuranyl group and benzothiophenyl groups
(e.g., 4-benzothiophenyl group, 5-benzothiophenyl group,
7-benzothiophenyl group etc.), benzoxazolyl groups (e.g.,
4-benzoxazolyl group, 7-benzoxazolyl group etc.), benzimidazolyl
groups (e.g., 4-benzimidazolyl group, 5-benzimidazolyl group,
7-benzimidazolyl group etc.), benzothiazolyl groups (e.g.,
4-benzothiazolyl group, 7-benzothiazolyl group etc.), quinolyl
group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group,
quinazolinyl group, quinoxalinyl group, cinnolinyl group,
phthalazinyl group, 2,3-dihydroindolyl group, isoindolinyl group,
1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl
group, benzo[1,3]dioxolyl group, chromanyl group, isochromanyl
group,
##STR00027##
and the like can be mentioned.
[0075] As the spiro ring of the above-mentioned monocycle or fused
ring and the above-mentioned C.sub.3-12 carbon ring, for example,
groups represented by the following formulas can be mentioned.
##STR00028##
[0076] Preferably, it is a fused ring group of monocyclic 5- or
6-membered heterocycle and a benzene ring, which is specifically,
indolyl group, indazolyl group, benzothiophenyl group,
benzimidazolyl group, 2,3-dihydroindolyl group,
1,2,3,4-tetrahydroquinolyl group, benzo[1,3]dioxolyl group and the
like.
[0077] As R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6,
pyrrolidinyl group, piperidinyl group, piperazinyl group,
morpholinyl group, pyridinyl group, thiophenyl group, thiazolyl
group, indolyl group, indazolyl group, benzothiophenyl group,
benzimidazolyl group, 2,3-dihydroindolyl group,
1,2,3,4-tetrahydroquinolyl group and benzo[1,3]dioxolyl group are
preferable, and piperidinyl group, pyridinyl group, thiophenyl
group, thiazolyl group, indolyl group, indazolyl group,
benzothiophenyl group, benzimidazolyl group, 2,3-dihydroindolyl
group, 1,2,3,4-tetrahydroquinolyl group, benzo[1,3]dioxolyl group
are more preferable. As 12) of group A, R.sup.A7 and 23) of group
B, R.sup.B3, R.sup.B6, R.sup.B16 and R.sup.B17, pyrrolidinyl group,
piperidinyl group, piperazinyl group, morpholinyl group, pyridyl
group and oxazolinyl group are preferable, and pyrrolidinyl group,
piperidinyl group, piperazinyl group and morpholinyl group are more
preferable.
[0078] The "C.sub.1-6 alkyl group" and "C.sub.2-6 alkenyl group"
for R.sup.1, R.sup.2 and R.sup.6, and R.sup.3, R.sup.4 and R.sup.5
are optionally substituted by 1 to 3 substituents selected from
group A. That is, the above-defined "C.sub.1-6 alkyl group" and
"C.sub.2-6 alkenyl group" may be substituted by 1 to 3 substituents
selected from group A, and include unsubstituted "C.sub.1-6 alkyl
group" and unsubstituted "C.sub.2-6 alkenyl group".
[0079] Each of the above-defined "C.sub.1-8 alkyl group" for the
below-defined 4) of group B, and the above-defined "C.sub.1-4 alkyl
group" for R.sup.B1 to R.sup.B31 is optionally substituted by the
same or different 1 to 3 substituents selected from group A.
[0080] Each of the above-defined "C.sub.2-4 alkenyl group" for the
below-defined 5) of group B and the above-defined "C.sub.2-4
alkynyl group" for 6) is optionally substituted by the same or
different 1 to 3 substituents selected from group A.
[0081] The "group A" is a group consisting of 1) the above-defined
"halogen atom", 2) nitro group, 3) cyano group, 4) the
above-defined "C.sub.1-4 alkyl group", 5) "--OR.sup.A1", 6)
"--SR.sup.A2", 7) "--NR.sup.A3R.sup.A4", 8) "--COOR.sup.A5", 9)
"--NR.sup.A6COR.sup.A7", 10) "--NR.sup.A8COOR.sup.A9", 11) the
above-defined "C.sub.3-12 carbon ring group" and 12) the
above-defined "heterocyclic group", wherein R.sup.A1, R.sup.A2,
R.sup.A3, R.sup.A4, R.sup.A5, R.sup.A6, R.sup.A8 and R.sup.A9 are
the same or different and each is a hydrogen atom, or, the
above-defined "C.sub.1-4 alkyl group", R.sup.A7 is the
above-defined "C.sub.1-4 alkyl group", the above-defined
"C.sub.3-12 carbon ring group" or the above-defined "heterocyclic
group".
[0082] As the "--OR.sup.A1", hydroxyl group, methoxy group, ethoxy
group, propoxy group, isopropyloxy group, tert-butoxy group and the
like can be specifically mentioned.
[0083] As the "--SR.sup.A2", mercapto group, methylsulfanyl group,
ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group,
tert-butylsulfanyl group and the like can be specifically
mentioned.
[0084] As the "--NR.sup.A3R.sup.A4", amino group, methylamino
group, ethylamino group, propylamino group, isopropylamino group,
tert-butylamino group, dimethylamino group, diethylamino group,
N-ethyl-N-methylamino group, N-methyl-N-propylamino group,
N-isopropyl-N-methylamino group and the like can be specifically
mentioned.
[0085] As the "--COOR.sup.A5", carboxyl group, methoxycarbonyl
group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, tert-butoxycarbonyl group and the like
can be specifically mentioned.
[0086] As the "--NR.sup.A6COR.sup.A7", acetylamino group,
propionylamino group, butyrylamino group, isobutyrylamino group,
pivaloylamino group, N-acetyl-N-methylamino group,
butylcarbonylamino group and the like can be specifically
mentioned.
[0087] As the "--NR.sup.A8COOR.sup.A9", carboxyamino group,
carboxymethylamino group, carboxyethylamino group,
methoxycarbonylamino group, methoxycarbonylmethylamino group and
the like can be specifically mentioned.
[0088] As the "group A", preferably, fluorine atom, chlorine atom,
bromine atom, methyl group, ethyl group, propyl group, hydroxyl
group, methoxy group, ethoxy group, propoxy group, amino group,
methylamino group, ethylamino group, dimethylamino group,
diethylamino group, carboxyamino group, butylcarbonylamino group,
carboxy group, phenyl group, 4-morpholinyl group, 1-pyrrolidinyl
group, 1-piperidinyl group and 1-piperazinyl group can be
mentioned.
[0089] As the "group A", particularly preferably, fluorine atom,
chlorine atom, methyl group, hydroxyl group, methoxy group, amino
group, dimethylamino group, diethylamino group, carboxyamino group,
butylcarbonylamino group, carboxy group, phenyl group,
4-morpholinyl group, 1-pyrrolidinyl group, 1-piperidinyl group and
1-piperazinyl group can be mentioned.
[0090] The preferable number of the substituent is 1, and the
substituent may be used at any substitutable position.
[0091] The "C.sub.3-12 carbon ring group" and "heterocyclic group"
for ring Cy, and "C.sub.3-12 carbon ring group" and "heterocyclic
group" for R.sup.3, R.sup.4 or R.sup.5 are optionally substituted
by 1 to 5 substituents selected from group B. That is, the
above-defined "C.sub.3-12 carbon ring group" and "heterocyclic
group" may be substituted by 1 to 5 substituents selected from
group B, and includes unsubstituted "C.sub.3-12 carbon ring group"
and unsubstituted "heterocyclic group".
[0092] The "group B" is a group consisting of 1) the above-defined
"halogen atom", 2) a nitro group, 3) a cyano group, 4) the
above-defined "C.sub.1-8 alkyl group", 5) the above-defined
"C.sub.2-4 alkenyl group", 6) the above-defined "C.sub.2-4 alkynyl
group", 7) "--OR.sup.B1", 8) "--SR.sup.B2", 9)
"--NR.sup.B3R.sup.B4", 10) "--NR.sup.B5COR.sup.B6", 11)
"--NR.sup.B7COOR.sup.B8", 12) "--NR.sup.B9CONR.sup.B10R.sup.B11",
13) "--NR.sup.B12CONR.sup.B13OR.sup.B14", 14)
"--NR.sup.B15SO.sub.2R.sup.B16", 15) "--SO.sub.2--R.sup.B17", 16)
"--SO.sub.2NR.sup.B18R.sup.B19", 17) "--P(.dbd.O) (R.sup.B20)
(R.sup.B21)", 18) "--COOR.sup.B22", 19) "--CONR.sup.B23R.sup.B24",
20) "--NR.sup.B25SO.sub.2NR.sup.B26R.sup.B27", 21)
"--NR.sup.B28SO.sub.2NR.sup.B29CONR.sup.B30R.sup.B31", 22) the
above-defined "C.sub.3-12 carbon ring group" and 23) the
above-defined "heterocyclic group", wherein R.sup.B1, R.sup.B2,
R.sup.B4, R.sup.B5, R.sup.B7, R.sup.B8, R.sup.B9, R.sup.B10,
R.sup.B11, R.sup.B12, R.sup.B13, R.sup.B14, R.sup.B15, R.sup.B18,
R.sup.B19, R.sup.B22, R.sup.B23, R.sup.B24, R.sup.B25, R.sup.B26,
R.sup.B27, R.sup.B28, R.sup.B29, R.sup.B30 and R.sup.B31 are the
same or different and each is a hydrogen atom or the above-defined
"C.sub.1-4 alkyl group", R.sup.B3 and R.sup.B6 are each a hydrogen
atom, the above-defined "C.sub.1-4 alkyl group", the above-defined
"C.sub.3-12 carbon ring group" or the above-defined "heterocyclic
group", R.sup.B16 is the above-defined "C.sub.1-4 alkyl group", the
above-defined "C.sub.3-12 carbon ring group" or the above-defined
"heterocyclic group", R.sup.B17 is the above-defined "C.sub.1-4
alkyl group" or the above-defined "heterocyclic group", and
R.sup.B20 and R.sup.B21 are the same or different and each is the
above-defined "C.sub.1-4 alkyl group".
[0093] As the "--OR.sup.B1", hydroxyl group, methoxy group, ethoxy
group, propoxy group, isopropyloxy group, tert-butoxy group and the
like can be specifically mentioned.
[0094] As the "--SR.sup.B2", mercapto group, methylsulfanyl group,
ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group,
tert-butylsulfanyl group and the like can be specifically
mentioned.
[0095] As the "--NR.sup.B3R.sup.B4", amino group, methylamino
group, ethylamino group, 2-aminoethylamino group, propylamino
group, isopropylamino group, tert-butylamino group, dimethylamino
group, diethylamino group, N-ethyl-N-methylamino group,
N-methyl-N-propylamino group, N-isopropyl-N-methylamino group,
N-(imidazolin-2-yl)amino group and the like can be specifically
mentioned.
[0096] As the "--NR.sup.B5COR.sup.B6", amino group, formylamino
group, acetylamino group, hydroxyacetylamino group, propionylamino
group, butyrylamino group, isobutyrylamino group, pivaloylamino
group, N-acetyl-N-methylamino group, 3-aminopropionylamino group,
3-(pentanoylamino)propionylamino group, 4-imidazolylcarbonylamino
group, (l-methylpyrrol-2-yl)carbonylamino group,
4-pyrazolylcarbonylamino group and the like can be specifically
mentioned.
[0097] As the "--NR.sup.B7COOR.sup.B8", carboxyamino group,
carboxymethylamino group, carboxyethylamino group,
methoxycarbonylamino group, methoxycarbonylmethylamino group and
the like can be specifically mentioned.
[0098] As the "--NR.sup.B9CONR.sup.B10R.sup.B11",
aminocarbonylamino group, methylaminocarbonylamino group,
dimethylaminocarbonylamino group,
(methylaminocarbonyl)(methyl)amino group,
(dimethylaminocarbonyl)(methyl)amino group,
[(2-hydroxyethyl)carbamoyl]amino and the like can be specifically
mentioned.
[0099] As the "--NR.sup.B12CONR.sup.B13OR.sup.B14",
methoxyaminocarbonylamino group,
(methylmethoxyaminocarbonyl)(methyl)amino group,
(methylmethoxyaminocarbonyl)amino group and the like can be
specifically mentioned.
[0100] As the "--NR.sup.B15SO.sub.2R.sup.B16", sulfonylamino group,
methylsulfonylamino group, ethylsulfonylamino group,
propylsulfonylamino group, N-methyl-N-sulfonylamino group,
N-methyl-N-methylsulfonylamino group, N-ethyl-N-sulfonylamino
group, N-ethyl-N-methylsulfonylamino group, 3-pyridylsulfonylamino
group, morpholinosulfonylamino group,
piperidinomorpholinosulfonylamino group,
2-morpholinoethylsulfonylamino group and the like can be
specifically mentioned.
[0101] As the "--SO.sub.2--R.sup.B17", sulfonyl group,
methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group,
butylsulfonyl group and the like can be specifically mentioned.
[0102] As the "--SO.sub.2NR.sup.B18R.sup.B19, aminosulfonyl group,
methylaminosulfonyl group, dimethylaminosulfonyl group,
ethylmethylaminosulfonyl group and the like can specifically be
mentioned.
[0103] As the "--P(.dbd.O) (R.sup.B20) (R.sup.B21)", phosphinoyl
group, methylphosphinoyl group, dimethylphosphinoyl group,
ethylphosphinoyl group, diethylphosphinoyl group and the like can
be specifically mentioned.
[0104] As the "--COOR.sup.B22, carboxyl group, methoxycarbonyl
group, ethoxycarbonyl group, propoxycarbonyl group,
isopropoxycarbonyl group, tert-butoxycarbonyl group and the like
can be specifically mentioned.
[0105] As the "--CONR.sup.B23R.sup.B24, carbamoyl, methylcarbamoyl,
dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl,
propylcarbamoyl, butylcarbamoyl and the like can be specifically
mentioned.
[0106] As the "--NR.sup.B25SO.sub.2NR.sup.B26R.sup.B27,
sulfamoylamino group, dimethylsulfamoylamino group and the like can
be specifically mentioned.
[0107] As the "--NR.sup.B28SO.sub.2NR.sup.B29CONR.sup.B30R.sup.31",
{[(2-hydroxyethyl)carbamoyl](2-hydroxyethyl)sulfamoyl}amino group
and the like can be specifically mentioned.
[0108] As the "group B", preferably, fluorine atom, chlorine atom,
bromine atom, iodine atom, nitro group, cyano group, methyl group,
ethyl group, propyl group, isopropyl group, butyl group, isobutyl
group, pentyl group, isopentyl group, hexyl group, 1-ethylpropyl
group, 1-propylbutyl group, vinyl group, 1-propenyl group, ethynyl
group, 1-propynyl group, 1-butynyl group, hydroxyl group, methoxy
group, ethoxy group, propoxy group, isopropoxy group, methylthio
group, ethylthio group, amino group, methylamino group, ethylamino
group, dimethylamino group, diethylamino group, ethylmethylamino
group, methylcarbonylamino group, ethylcarbonylamino group,
propylcarbonylamino group, isopropylcarbonylamino group,
(methylcarbonyl)(methyl)amino group, ethoxycarbonylamino group,
methylaminocarbonylamino group, dimethylaminocarbonylamino group,
methoxyaminocarbonylamino group, methylsulfonylamino group,
ethylsulfonylamino group, propylsulfonylamino group,
isopropylsulfonylamino group, phenylsulfonylamino group,
(methylsulfonyl)(methyl)amino group, methylsulfonyl group,
piperazin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group,
piperidin-4-ylsulfonyl group, pyrrolidin-4-ylsulfonyl group,
aminosulfonyl group, methylaminosulfonyl group, ethylaminosulfonyl
group, dimethylaminosulfonyl group, dimethylphosphinoyl group,
carboxy group, methoxycarbonyl group, carbamoyl group,
methylaminocarbonyl group, ethylaminocarbonylamino group,
dimethylaminosulfonylamino group, cyclopropyl group, cyclohexyl
group, phenyl group, piperidinyl group, pyrrolidinyl group,
piperidinyl group, piperazinyl group and morpholinyl group can be
mentioned.
[0109] As the "group B", particularly preferably, fluorine atom,
chlorine atom, bromine atom, iodine atom, nitro group, cyano group,
methyl group, ethyl group, propyl group, isopropyl group, butyl
group, 1-ethylpropyl group, 1-propylbutyl group, butyl group,
isobutyl group, isopentyl group, vinyl group, ethynyl group,
1-propynyl group, 1-butynyl group, hydroxyl group, methoxy group,
propoxy group, isopropoxy group, methylthio group, amino group,
methylamino group, ethylamino group, dimethylamino group,
diethylamino group, ethylmethylamino group, methylcarbonylamino
group, ethylcarbonylamino group, propylcarbonylamino group,
isopropylcarbonylamino group, (methylcarbonyl)(methyl)amino group,
ethoxycarbonylamino group, methylaminocarbonylamino group,
dimethylaminocarbonylamino group, methoxyaminocarbonylamino group,
methylsulfonylamino group, ethylsulfonylamino group,
propylsulfonylamino group, isopropylsulfonylamino group,
phenylsulfonylamino group, (methylsulfonyl)(methyl)amino group,
methylsulfonyl group, piperazin-1-ylsulfonyl group,
morpholin-4-ylsulfonyl group, piperidin-4-ylsulfonyl group,
pyrrolidin-4-ylsulfonyl group, aminosulfonyl group,
methylaminosulfonyl group, ethylaminosulfonyl group,
dimethylaminosulfonyl group, dimethylphosphinoyl group, carboxy
group, methoxycarbonyl group, carbamoyl group, methylaminocarbonyl
group, ethylaminocarbonylamino group, dimethylaminosulfonylamino
group, cyclopropyl group, phenyl group, piperidinyl group,
pyrrolidinyl group, piperidinyl group, piperazinyl group and
morpholinyl group can be mentioned.
[0110] The preferable number of substituent is 1 or 2, and when the
"C.sub.3-12 carbon ring group" is a phenyl group, ring Cy is
preferably mono-substituted at the 2-position, mono-substituted at
the 3-position, mono-substituted at the 4-position, di-substituted
at the 2,3-position, di-substituted at the 2,4-position,
di-substituted at the 2,5-position or di-substituted at the
2,6-position, and particularly preferably mono-substituted at the
4-position or di-substituted at the 2,4-position, R.sup.2 is more
preferably mono-substituted at the 3-position, and R.sup.6 is more
preferably di-substituted at the 2,4-position.
[0111] Each of the above-defined "C.sub.1-4 alkyl group" for 4) of
the above-defined group A, and the above-defined "C.sub.1-4 alkyl
group" for R.sup.A1, R.sup.A2, R.sup.A3, R.sup.A4, R.sup.A5,
R.sup.A6, R.sup.A7, R.sup.A8 or R.sup.A9 is optionally substituted
by the same or different 1 to 3 substituents selected from the
below-defined "group C".
[0112] Each of the above-defined "C.sub.3-12 carbon ring group" for
11) of group A and R.sup.A7, and the above-defined "heterocyclic
group" for 12) and R.sup.A7 is optionally substituted by the same
or different 1 to 5 substituents selected from the below-defined
"group C".
[0113] Each of the above-defined "C.sub.3-12 carbon ring group" for
the above-mentioned 22) of group B, R.sup.B3, R.sup.B6 and
R.sup.B16, and the above-defined "heterocyclic group" for the
above-mentioned 23), R.sup.B3, R.sup.B6, R.sup.B16 and R.sup.B17 is
optionally substituted by the same or different 1 to 5 substituents
selected from the below-defined "group C".
[0114] The "group C" is a group consisting of 1) the above-defined
"halogen atom", 2) a cyano group, 3) the above-defined "C.sub.1-4
alkyl group", 4) "--OR.sup.C1", 5) "--NR.sup.C2R.sup.C3", 6)
"--COOR.sup.C4" and 7) an oxo group, wherein R.sup.C, R.sup.C2,
R.sup.C3 and R.sup.C4 are the same or different and each is a
hydrogen atom or the above-defined "C.sub.1-4 alkyl group".
[0115] As the --OR.sup.C1", hydroxyl group, methoxy group, ethoxy
group, propoxy group, isopropoxy group, tert-butoxy group and the
like can be specifically mentioned.
[0116] As the "--NR.sup.C2R.sup.C3", amino group, methylamino
group, ethylamino group, propylamino group, isopropylamino group,
tert-butylamino group, dimethylamino group, diethylamino group,
N-ethyl-N-methylamino group, N-methyl-N-propylamino group,
N-isopropyl-N-methylamino group and the like can be specifically
mentioned.
[0117] As the "--COOR.sup.C4", carboxyl group, methoxycarbonyl
group, ethoxycarbonyl group, propoxycarbonyl group,
isopropyloxycarbonyl group, tert-butoxycarbonyl group and the like
can be specifically mentioned.
[0118] As the "group C", the group consisting of 1) the
above-defined "halogen atom", 2) a cyano group, 3) the
above-defined "C.sub.1-4 alkyl group", 4) "--OR.sup.C1", 5)
"--NR.sup.C2R.sup.C3" and 6) "--COOR.sup.C4" are preferable, and
specifically, fluorine atom, chlorine atom, bromine atom, cyano
group, methyl group, ethyl group, propyl group, hydroxyl group,
methoxy group, ethoxy group, amino group, dimethylamino group,
diethylamino group, carboxyl group and methoxycarbonyl group can be
mentioned.
[0119] As the "group C", methyl group is particularly
preferable.
[0120] The preferable number of the substituent is 1, and the
substituent may be used at any substitutable position.
[0121] As the "R.sup.1", preferably, a C.sub.1-6 alkyl group
(wherein the C.sub.1-6 alkyl group is optionally substituted by 1
to 3 substituents selected from group A) or
##STR00029##
wherein each symbol is as defined above, can be mentioned.
[0122] Here, m is preferably 0, the "ring Cy" is preferably
C.sub.3-12 carbon ring group, and the "carbon ring group" is
preferably cycloalkyl group (wherein the "C.sub.3-12 carbon ring
group" and "cycloalkyl group" are optionally substituted by 1 to 5
substituents selected from group B).
[0123] Specifically, as the "R.sup.1", methyl group, ethyl group,
2,2,2-trifluoroethyl group, propyl group, isopropyl group, butyl
group, 2-propenyl group, cyclopropyl group, 2-methylcyclopropyl
group, cyclobutyl group, cyclopentyl group, cyclohexyl group,
phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, o-tolyl
group, m-tolyl group, p-tolyl group, 4-methoxyphenyl group,
thiophen-3-yl group, cyclopropylmethyl group, 2-methoxyethyl,
carboxymethyl, 2-hydroxyethyl, 2-(dimethylamino)ethyl and benzyl
group are preferable.
[0124] More preferably, methyl group, ethyl group,
2,2,2-trifluoroethyl group, propyl group, isopropyl group, butyl
group, cyclopropyl group, 2-methylcyclopropyl group, cyclobutyl
group, cyclopentyl group, cyclohexyl group, phenyl group,
4-chlorophenyl group, 4-fluorophenyl group, o-tolyl group, m-tolyl
group, p-tolyl group, 4-methoxyphenyl group, thiophen-3-yl group,
2-methoxyethyl, carboxymethyl, 2-hydroxyethyl and
2-(dimethylamino)ethyl, particularly preferably, methyl group or
cyclopropyl group can be mentioned.
[0125] As the "R.sup.2",
##STR00030##
wherein each symbol is as defined above, is preferable. Here, m is
preferably 0, the "ring Cy" is preferably C.sub.3-12 carbon ring
group, and the "carbon ring group" is preferably phenyl group
(wherein the "C.sub.3-12 carbon ring group" and "phenyl group" are
optionally substituted by 1 to 5 substituents selected from group
B, and as the "group B", "--NR.sup.B3R.sup.B4",
"--NR.sup.B5COR.sup.B6", "--NR.sup.B7COOR.sup.B8",
"--NR.sup.B9CONR.sup.B10R.sup.B11",
"--NR.sup.B12CONR.sup.B13OR.sup.B14",
"--NR.sup.B15SO.sub.2R.sup.B16"
"--NR.sup.B25SO.sub.2NR.sup.B26R.sup.B27", and
"--NR.sup.B28SO.sub.2NR.sup.B29CONR.sup.B30R.sup.B31" are
preferable).
[0126] Specifically, as the "R.sup.2", a hydrogen atom, methyl
group, ethyl group, 2,2,2-trifluoroethyl group, isopropyl group,
butyl group, isobutyl group, 2-propenyl group, cyclopropyl group,
cyclobutyl group, cyclopentyl group, phenyl group, 4-chlorophenyl
group, 2-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl
group, 2,6-difluorophenyl group, o-tolyl group, m-tolyl group,
p-tolyl group, 2,6-dimethylphenyl group, 2-ethylphenyl group,
3-(3-hydroxypropyl)phenyl group, 3-(2-carboxyethyl)phenyl group,
3-(3-morpholin-4-ylpropyl)phenyl group, 3-dimethylaminopropylphenyl
group, 3-hydroxyphenyl group, 4-hydroxyphenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl
group, 3-dimethylaminoethoxyphenyl group, 3-carboxymethoxyphenyl
group, 3-(3-dimethylaminopropoxy)phenyl group,
3-(2-morpholin-4-ylethoxy)phenyl group,
3-(2-pyrrolidin-1-ylethoxy)phenyl group,
3-(2-piperidin-1-ylethoxy)phenyl group,
3-(2-diethylaminoethoxy)phenyl group,
3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl group, 3-aminophenyl
group, 3-methylaminophenyl group, 3-dimethylaminophenyl group,
3-(methanesulfonyl)methylaminophenyl group,
3-methylcarbonylaminophenyl group, 3-methanesulfonylaminophenyl
group, 4-chloro-3-methanesulfonylaminophenyl group,
3-ethanesulfonylaminophenyl group,
3-(propane-1-sulfonylamino)phenyl group,
3-(propane-2-sulfonylamino)phenyl group,
3-chloromethanesulfonylaminophenyl group,
3-trifluoromethanesulfonylaminophenyl group,
3-(2,2,2-trifluoroethanesulfonylamino)phenyl group,
3-(2-methoxyethyl)methylaminophenyl group,
3-methylcarbonylaminophenyl group, 3-ethylcarbonylaminophenyl
group, 3-propylcarbonylaminophenyl group,
3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenyl
group, 3-(hydroxymethylcarbonyl)aminophenyl group,
3-(2-hydroxyethylcarbonylamino)phenyl group,
3-ethylaminocarbonylaminophenyl group,
3-(2-dimethylaminoethylcarbonylamino)phenyl group,
3-(3-dimethylaminopropylcarbonylamino)phenyl group,
3-(methoxymethylcarbonylamino)phenyl group,
3-(butylcarbonylaminomethylcarbonylamino)phenyl group,
3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group,
3-methylaminocarbonylaminophenyl group,
3-methoxyaminocarbonylaminophenyl group,
3-dimethylaminocarbonylaminophenyl group,
3-(dimethylaminomethylcarbonylamino)phenyl group,
3-(2-morpholin-4-ylethylamino)phenyl group,
3-(2-benzyloxycarbonylaminoethyl)sulfonylaminophenyl group,
3-(2-aminoethyl)sulfonylaminophenyl group,
3-(2-butylcarbonylaminoethyl)sulfonylaminophenyl group,
3-dimethylaminosulfonylaminophenyl group, 3-carboxyphenyl group,
3-carbamoylphenyl group, 3-methanesulfonylphenyl group,
4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group,
3-methylaminosulfonyiphenyl group, 3-ethylaminosulfonylphenyl
group, 3-benzenesulfonylaminophenyl group, 3-aminosulfonylphenyl
group, 3-dimethylaminosulfonylphenyl group,
4-dimethylaminosulfonylphenyl group,
3-(4-methylpiperazine-1-sulfonyl)phenyl group,
3-(morpholine-4-sulfonyl)phenyl group,
3-(piperidine-1-sulfonyl)phenyl group,
3-(pyrrolidine-1-sulfonyl)phenyl group, 3-methylaminocarbonylphenyl
group, 3-morpholin-4-ylphenyl group, 3-pyrrolidin-1-ylphenyl group,
3-piperidin-1-ylphenyl group, 3-(4-methylpiperazin-1-yl)phenyl
group, 3-(2-oxopyrrolidin-1-yl)phenyl group,
3-(3-oxomorpholin-4-yl)phenyl group, thiophen-3-yl group,
pyridin-3-yl group, benzyl group and the following groups:
##STR00031##
are preferable.
[0127] More preferably, phenyl group, 4-chlorophenyl group,
2-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group,
2,6-difluorophenyl group, o-tolyl group, m-tolyl group, p-tolyl
group, 2,6-dimethylphenyl group, 2-ethylphenyl group,
3-(3-hydroxypropyl)phenyl group, 3-(2-carboxyethyl)phenyl group,
3-(3-morpholin-4-ylpropyl)phenyl group, 3-dimethylaminopropylphenyl
group, 3-hydroxyphenyl group, 4-hydroxyphenyl group,
2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl
group, 3-dimethylaminoethoxyphenyl group, 3-carboxymethoxyphenyl
group, 3-(3-dimethylaminopropoxy)phenyl group,
3-(2-morpholin-4-ylethoxy)phenyl group,
3-(2-pyrrolidin-1-ylethoxy)phenyl group,
3-(2-piperidin-1-ylethoxy)phenyl group,
3-(2-diethylaminoethoxy)phenyl group,
3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl group, 3-aminophenyl
group, 3-methylaminophenyl group, 3-dimethylaminophenyl group,
3-(methanesulfonyl)methylaminophenyl group,
3-methylcarbonylaminophenyl group, 3-methanesulfonylaminophenyl
group, 4-chloro-3-methanesulfonylaminophenyl group,
3-ethanesulfonylaminophenyl group,
3-(propane-1-sulfonylamino)phenyl group,
3-(propane-2-sulfonylamino)phenyl group,
3-chloromethanesulfonylaminophenyl group,
3-trifluoromethanesulfonylaminophenyl group,
3-(2,2,2-trifluoroethanesulfonylamino)phenyl group,
3-(2-methoxyethyl)methylaminophenyl group,
3-methylcarbonylaminophenyl group, 3-ethylcarbonylaminophenyl
group, 3-propylcarbonylaminophenyl group,
3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenyl
group, 3-(hydroxymethylcarbonyl)aminophenyl group,
3-(2-hydroxyethylcarbonylamino)phenyl group,
3-ethylaminocarbonylaminophenyl group,
3-(2-dimethylaminoethylcarbonylamino)phenyl group,
3-(3-dimethylaminopropylcarbonylamino)phenyl group,
3-(methoxymethylcarbonylamino)phenyl group,
3-(butylcarbonylaminomethylcarbonylamino)phenyl group,
3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group,
3-methylaminocarbonylaminophenyl group,
3-methoxyaminocarbonylaminophenyl group,
3-dimethylaminocarbonylaminophenyl group,
3-(dimethylaminomethylcarbonylamino)phenyl group,
3-(2-morpholin-4-ylethylamino)phenyl group,
3-(2-benzyloxycarbonylaminoethyl)sulfonylaminophenyl group,
3-(2-aminoethyl)sulfonylaminophenyl group,
3-(2-butylcarbonylaminoethyl)sulfonylaminophenyl group,
3-dimethylaminosulfonylaminophenyl group, 3-carboxyphenyl group,
3-carbamoylphenyl group, 3-methanesulfonylphenyl group,
4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group,
3-methylaminosulfonylphenyl group, 3-ethylaminosulfonylphenyl
group, 3-benzenesulfonylaminophenyl group, 3-aminosulfonylphenyl
group, 3-dimethylaminosulfonylphenyl group,
4-dimethylaminosulfonylphenyl group,
3-(4-methylpiperazine-1-sulfonyl)phenyl group,
3-(morpholine-4-sulfonyl)phenyl group,
3-(piperidine-1-sulfonyl)phenyl group,
3-(pyrrolidine-1-sulfonyl)phenyl group, 3-methylaminocarbonylphenyl
group, 3-morpholin-4-ylphenyl group, 3-pyrrolidin-1-ylphenyl group,
3-piperidin-1-ylphenyl group, 3-(4-methylpiperazin-1-yl)phenyl
group, 3-(2-oxopyrrolidin-1-yl)phenyl group and
3-(3-oxomorpholin-4-yl)phenyl group can be mentioned.
[0128] As the "R.sup.6",
##STR00032##
wherein each symbol is as defined above, is preferable. Here, m is
preferably 0, the "ring Cy" is preferably C.sub.3-12 carbon ring
group and the "carbon ring group" is preferably phenyl group
(wherein the "C.sub.3-12 carbon ring group" and "phenyl group" are
optionally substituted by 1 to 5 substituents selected from group
B, where the "group B" preferably includes the above-defined
"halogen atom", the above-defined "C.sub.1-8 alkyl group" and the
above-defined "C.sub.2-4 alkynyl group").
[0129] Specifically, as the "R.sup.6", 2-methoxyethyl group,
2,2-dimethylpropyl group, 3-dimethylaminopropyl group, cyclopropyl
group, cyclohexyl group, phenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl
group, 3,4-dichlorophenyl group, 4-bromophenyl group,
2-fluorophenyl group, 4-fluorophenyl group, 4-iodophenyl group,
o-tolyl group, p-tolyl group, 2-ethylphenyl group, 4-ethylphenyl
group, 2-propylphenyl group, 2-isopropylphenyl group,
4-isopropylphenyl group, 2-butylphenyl group, 4-butylphenyl group,
2-isobutylphenyl group, 4-tert-butylphenyl group,
2-(3-methylbutyl)phenyl group, 4-trifluoromethylphenyl group,
4-(2-fluoroethyl)phenyl group, 4-(2,2-difluoroethyl)phenyl group,
4-(2,2,2-trifluoroethyl)phenyl group, 4-(1-ethylpropyl)phenyl
group, 4-(1-propylbutyl)phenyl group, 4-ethynylphenyl group,
2,4-difluorophenyl group, 2,6-difluorophenyl group,
2,4-dichlorophenyl group, 4-bromo-2-fluorophenyl group,
4-bromo-3-fluorophenyl group, 4-bromo-2-chlorophenyl group,
4-chloro-2-fluorophenyl group, 2-fluoro-4-iodophenyl group,
2-chloro-4-methylphenyl group, 4-chloro-2-methylphenyl group,
4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl group,
2-fluoro-4-methylphenyl group, 2-fluoro-4-trifluoromethylphenyl
group, 4-bromo-2-ethylphenyl group, 4-ethyl-2-fluorophenyl group,
4-(2-carboxyethyl)-2-fluorophenyl group, 2-fluoro-4-propylphenyl
group, 2-fluoro-4-vinylphenyl group,
4-(2-carboxyvinyl)-2-fluorophenyl group, 4-ethynyl-2-fluorophenyl
group, 2-fluoro-4-(prop-1-ynyl)phenyl group,
2-fluoro-4-(3-hydroxyprop-1-ynyl)phenyl group,
2-fluoro-4-(3-methoxyprop-1-ynyl)phenyl group,
4-cyclopropyl-2-fluorophenyl group,
2-fluoro-4-(3-hydroxy-3-methylbut-1-ynyl)phenyl group,
4-(3-dimethylaminoprop-1-ynyl)-2-fluorophenyl group,
4-chloro-2-dimethylaminomethylphenyl group,
4-dimethylamino-2-methylphenyl group, 4-hydroxyphenyl group,
2-methoxyphenyl group, 4-methoxyphenyl group,
4-trifluoromethoxyphenyl group, 4-isopropoxyphenyl group,
2,4-dimethoxyphenyl group, 4-methoxy-2-methylphenyl group,
2-fluoro-4-methoxyphenyl group, 4-bromo-2-hydroxyphenyl group,
4-bromo-2-methoxyphenyl group, 2-bromo-4-methoxyphenyl group,
4-methylthiophenyl group, 4-trifluoromethylthiophenyl group,
2-fluoro-4-methylthiophenyl group, 4-aminophenyl group,
4-methylaminophenyl group, 2-dimethylaminophenyl group,
3-dimethylaminophenyl group, 4-dimethylaminophenyl group,
4-ethylaminophenyl group, 4-diethylaminophenyl group,
4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group,
4-cyanophenyl group, 6-aminopyridin-3-yl group,
6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group,
4-chloropyridin-3-yl group, 4-carboxyphenyl group,
4-methoxycarbonylphenyl group, 4-ethylaminophenyl group,
4-(methylcarbonyl)methylaminophenyl group, 4-methanesulfonylphenyl
group, 4-trifluoromethanesulfonylphenyl group,
4-dimethylamino-2-methylphenyl group,
4-dimethylamino-3-methylphenyl group,
4-dimethylamino-3-trifluoromethylphenyl group,
4-dimethylamino-2-propylphenyl group,
4-dimethylamino-2-fluorophenyl group,
4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoyl phenyl
group, benzo[1,3]dioxol-5-yl group, 1,1'-biphenyl-4-yl group,
4-(piperidin-1-yl)phenyl group, 4-benzylphenyl group,
4-(morpholin-4-yl)phenyl group, 1-methylpiperidin-4-yl group,
1-isopropylpiperidin-4-yl group, thiazol-2-yl group,
2-dimethylaminothiazol-4-yl group,
1-methyl-1,2,3,4-tetrahydroquinolin-6-yl group, 1H-indol-5-yl
group, 1-methyl-1H-indol-5-yl group, 1-ethyl-1H-indol-5-yl group,
1-methyl-1H-indol-6-yl group, 1-methyl-1H-indol-7-yl group,
1,2-dimethyl-1H-indol-5-yl group, 1,2,3-trimethyl-1H-indol-5-yl
group, 6-20 fluoro-1H-indol-5-yl group,
1-methyl-1H-benzimidazol-5-yl group, 1-methyl-1H-indazol-5-yl
group, 1-methyl-2,3-dihydro-1H-indol-5-yl group,
benzo[b]thiophen-5-yl group, 4-chlorobenzyl group, 2-bromobenzyl
group, 3-bromobenzyl group, 4-bromobenzyl group,
5-bromo-2-fluorobenzyl group, 2-morpholin-4-ylethyl group and
pyridin-3-ylmethyl group are preferable.
[0130] More preferably, phenyl group, 2-chlorophenyl group,
3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl
group, 3,4-dichlorophenyl group, 4-bromophenyl group,
2-fluorophenyl group, 4-fluorophenyl group, 4-iodophenyl group,
o-tolyl group, p-tolyl group, 2-ethylphenyl group, 4-ethylphenyl
group, 2-propylphenyl group, 2-isopropylphenyl group,
4-isopropylphenyl group, 2-butylphenyl group, 4-butylphenyl group,
2-isobutylphenyl group, 4-tert-butylphenyl group,
2-(3-methylbutyl)phenyl group, 4-trifluoromethylphenyl group,
4-(2-fluoroethyl)phenyl group, 4-(2,2-difluoroethyl)phenyl group,
4-(2,2,2-trifluoroethyl)phenyl group, 4-(l-ethylpropyl)phenyl
group, 4-(1-propylbutyl)phenyl group, 4-ethynylphenyl group,
2,4-difluorophenyl group, 2,6-difluorophenyl group,
2,4-dichlorophenyl group, 4-bromo-2-fluorophenyl group,
4-bromo-3-fluorophenyl group, 4-bromo-2-chlorophenyl group,
4-chloro-2-fluorophenyl group, 2-fluoro-4-iodophenyl group,
2-chloro-4-methylphenyl group, 4-chloro-2-methylphenyl group,
4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl group,
2-fluoro-4-methylphenyl group, 2-fluoro-4-trifluoromethylphenyl
group, 4-bromo-2-ethylphenyl group, 4-ethyl-2-fluorophenyl group,
4-(2-carboxyethyl)-2-fluorophenyl group, 2-fluoro-4-propylphenyl
group, 2-fluoro-4-vinylphenyl group,
4-(2-carboxyvinyl)-2-fluorophenyl group, 4-ethynyl-2-fluorophenyl
group, 2-fluoro-4-(prop-1-ynyl)phenyl group,
2-fluoro-4-(3-hydroxyprop-1-ynyl)phenyl group,
2-fluoro-4-(3-methoxyprop-1-ynyl)phenyl group,
4-cyclopropyl-2-fluorophenyl group,
2-fluoro-4-(3-hydroxy-3-methylbut-1-ynyl)phenyl group,
4-(3-dimethylaminoprop-1-ynyl)-2-fluorophenyl group,
4-chloro-2-dimethylaminomethylphenyl group,
4-dimethylamino-2-methylphenyl group, 4-hydroxyphenyl group,
2-methoxyphenyl group, 4-methoxyphenyl group,
4-trifluoromethoxyphenyl group, 4-isopropoxyphenyl group,
2,4-dimethoxyphenyl group, 4-methoxy-2-methylphenyl group,
2-fluoro-4-methoxyphenyl group, 4-bromo-2-hydroxyphenyl group,
4-bromo-2-methoxyphenyl group, 2-bromo-4-methoxyphenyl group,
4-methylthiophenyl group, 4-trifluoromethylthiophenyl group,
2-fluoro-4-methylthiophenyl group, 4-aminophenyl group,
4-methylaminophenyl group, 2-dimethylaminophenyl group,
3-dimethylaminophenyl group, 4-dimethylaminophenyl group,
4-ethylaminophenyl group, 4-diethylaminophenyl group,
4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group,
4-cyanophenyl group, 6-aminopyridin-3-yl group,
6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group,
4-chloropyridin-3-yl group, 4-carboxyphenyl group,
4-methoxycarbonylphenyl group, 4-ethylaminophenyl group,
4-(methylcarbonyl)methylaminophenyl group, 4-methanesulfonylphenyl
group, 4-trifluoromethanesulfonylphenyl group,
4-dimethylamino-2-methylphenyl group,
4-dimethylamino-3-methylphenyl group,
4-dimethylamino-3-trifluoromethylphenyl group,
4-dimethylamino-2-propylphenyl group,
4-dimethylamino-2-fluorophenyl group,
4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoylphenyl
group, 1,1'-biphenyl-4-yl group, 4-(piperidin-1-yl)phenyl group,
4-benzylphenyl group and 4-(morpholin-4-yl)phenyl group can be
mentioned.
[0131] As the "R.sup.3", preferably, C.sub.1-6 alkyl group (wherein
the C.sub.1-6 alkyl group is optionally substituted by 1 to 3
substituents selected from group A) can be mentioned.
[0132] Specifically, a hydrogen atom, methyl group, ethyl group,
propyl group, isobutyl group, 2-methoxyethyl group, cyclopropyl
group, 2-dimethylaminoethyl group and 2-propenyl group are
preferable, and methyl group is particularly preferable.
[0133] As the "R.sup.4", preferably, a C.sub.1-6 alkyl group
(wherein the C.sub.1-6 alkyl group is optionally substituted by 1
to 3 substituents selected from group A) can be mentioned.
[0134] Specifically, a hydrogen atom, methyl group, propyl group
and hydroxy group are preferable, and methyl group is particularly
preferable.
[0135] As the "R.sup.5", a hydrogen atom and methyl group are
preferable, and a hydrogen atom is particularly preferable.
[0136] The "pharmaceutically acceptable salt thereof" may be any 20
salt as long as it forms a non-toxic salt with the compounds of the
above-mentioned formula [I], [I'] and [I-1]-[I-3] and can be
obtained by a reaction with an inorganic acid such as hydrochloric
acid, sulfuric acid, phosphoric acid, hydrobromic acid and the
like; an organic acid such as oxalic acid, malonic acid, citric
acid, fumaric acid, lactic acid, malic acid, succinic acid,
tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid,
ascorbic acid, methanesulfonic acid, benzenesulfonic acid and the
like; an inorganic base such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, magnesium hydroxide, ammonium
hydroxide and the like; an organic base such as methylamine,
diethylamine, triethylamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and
the like; or an amino acid such as lysine, arginine, alanine and
the like. The present invention also encompasses hydrate and
solvate of each compound.
[0137] The present invention also encompasses prodrugs and
metabolites of each compound.
[0138] By the "prodrug" is meant a derivative of the compound of
the present invention, which has a chemically or metabolically
decomposable group and which, after administration to a body,
restores to the original compound to show its inherent efficacy,
including a complex and a salt, not involving a covalent bond.
[0139] The prodrug is utilized for, for example, improving
absorption by oral administration or targeting of a target
site.
[0140] As the site to be modified, highly reactive functional
groups in the compound of the present invention, such as hydroxyl
group, carboxyl group, amino group, thiol group and the like, are
mentioned.
[0141] For example, a compound wherein a hydroxyl group is
substituted by --CO-alkyl, --CO.sub.2-alkyl, --CONH-alkyl,
--CO-alkenyl, --CO.sub.2-alkenyl, --CONH-alkenyl, --CO-aryl,
--CO.sub.2-aryl, --CONH-aryl, --CO-heterocycle,
--CO.sub.2-heterocycle, --CONH-heterocycle (wherein alkyl, alkenyl,
aryl and heterocycle are optionally substituted by halogen atom,
alkyl group, hydroxyl group, alkoxy group, carboxy group, amino
group, amino acid residue, --PO.sub.3H.sub.2, --SO.sub.3H,
--OPO.sub.3H.sub.2, --OSO.sub.3H and the like) or --PO.sub.3H.sub.2
and the like, a compound wherein an amino group is substituted by
--CO-- alkyl, --CO.sub.2-alkyl, --CO-alkenyl, --CO.sub.2-alkenyl,
--CO.sub.2-aryl, --CO-aryl, --CO-heterocycle,
--CO.sub.2-heterocycle (wherein alkyl, alkenyl, aryl and
heterocycle are optionally substituted by halogen atom, alkyl
group, hydroxyl group, alkoxy group, carboxy group, amino group,
amino acid residue, --PO.sub.3H.sub.2, --SO.sub.3H,
--OPO.sub.3H.sub.2, --OSO.sub.3H and the like) or --PO.sub.3H.sub.2
and the like and the like can be mentioned.
[0142] Specifically, as the modifying group of hydroxyl group,
acetyl group, propionyl group, isobutyryl group, pivaloyl group,
palmitoyl group, benzoyl group, 4-methylbenzoyl group,
dimethylcarbamoyl group, dimethylaminomethylcarbonyl group, sulfo
group, alanyl group, fumaryl group and the like can be mentioned.
The sodium salt of 3-carboxybenzoyl group or 2-carboxyethylcarbonyl
group and the like can be also mentioned.
[0143] Specifically, as the modifying group of carboxyl group,
methyl group, ethyl group, propyl group, isopropyl group, butyl
group, isobutyl group, tert-butyl group, pivaloyloxymethyl group,
carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy)ethyl
group, 1-(ethoxycarbonyloxy)ethyl group,
1-(isopropyloxycarbonyloxy)ethyl group,
1-(cyclohexyloxycarbonyloxy)ethyl group, carboxylmethyl group,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenyl
group, o-tolyl group, morpholinoethyl group,
N,N-diethylcarbamoylmethyl group, phthalidyl group and the like can
be mentioned.
[0144] Specifically, as the modifying group of amino group,
tert-butyl group, docosanoyl group, pivaloylmethyloxy group, alanyl
group, hexylcarbamoyl group, pentylcarbamoyl group,
3-methylthio-1-(acetylamino)propylcarbonyl group,
1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group,
tetrahydrofuranyl group, pyrrolidylmethyl group and the like can be
mentioned.
[0145] The "tumor" used in the present specification includes
malignant tumor, and the "antitumor agent" contains an anticancer
agent and is a compound having an antitumor activity.
[0146] The compound of the present invention can be administered to
a mammal (human, mouse, rat, hamster, rabbit, cat, dog, bovine,
sheep, monkey etc.) and the like as an antitumor agent and the
like.
[0147] When the compound of the present invention is used as a
pharmaceutical preparation, it is generally admixed with
pharmaceutically acceptable carriers, excipients, diluents,
extending agents, disintegrants, stabilizers, preservatives,
buffers, emulsifiers, flavoring agents, coloring agents, sweetening
agents, thickeners, corrigents, dissolution aids, and other
additives, that are known per se, such as water, vegetable oil,
alcohol (e.g., ethanol, benzyl alcohol etc.), polyethylene glycol,
glycerol triacetate, gelatin, carbohydrate (e.g., lactose, starch
etc.), magnesium stearate, talc, lanolin, petrolatum and the like,
formed into tablet, pill, powder, granule, suppository, injection,
eye drop, liquid, capsule, troche, aerosol, elixir, suspension,
emulsion, syrup and the like by a conventional method, and
administered systemically or topically, and orally or
parenterally.
[0148] While the dose varies depending on age, body weight,
symptom, treatment effect, administration method and the like, it
is generally 0.01 mg to 1 g once for an adult, which is given once
to several times a day orally or in a dosage form of an injection
such as intravenous injection and the like.
[0149] An antitumor agent is generally required to sustain its
effect for a long time, so that can be effective not only for
temporal suppression of the proliferation of cancer cells but also
for the prohibition of the re-prohibition of cancer cells. This
means that a prolonged administration is necessary and that a high
single dose may be frequently inevitable to sustain effect for a
longer period through the night. Such prolonged and high dose
administration increases the risk of causing side effects.
[0150] In view of this, one of the preferable embodiments of the
pyrimidine compound of the present invention is such compound as
permitting high absorption by oral administration, and such
compound capable of maintaining blood concentration of the
administered compound for an extended period of time.
[0151] A compound capable of showing p15 protein induction and/or
p27 protein induction and/or MEK inhibition in combination is
preferable.
[0152] This compound is useful for the treatment of diseases caused
by undesirable cell proliferation.
[0153] As the "diseases caused by undesirable cell proliferation",
for example, tumor, specifically cerebral tumor (neuroglioma having
a component of malignant astroglioma and oligodendroglioma and the
like), cancer of esophangus, stomach cancer, liver cancer,
pancreatic cancer, colorectal cancer (colon cancer, rectal cancer
etc.), lung cancer (non-small cell lung cancer, small cell lung
cancer, primary and metastatic squamous cancer etc.), renal cancer,
breast cancer, ovarian cancer, prostate cancer, skin cancer,
neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma,
seminoma, extragonadal tumor, testicle tumor, uterine cancer
(cervical cancer, endometrial cancer and the like), head and neck
tumor (maxillary cancer, larynx cancer, pharyngeal cancer, lingual
cancer, intraoral cancer and the like), multiple myeloma, malignant
lymphoma (reticulosarcoma, lymphosarcoma, Hodgkin's disease etc.),
polycythemia vera, leukemia (acute myeloid leukemia, chronic
myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic
leukemia etc.), goiter, renal pelvic cancer, ureteral tumor,
bladder tumor, gallbladder cancer, bile duct cancer, chorioma,
malignant melanoma, pediatric tumor (sarcoma of the ewing's family,
Wilms' tumor, rhabdomyosarcoma, vascular sarcoma, embryonal
testicle cancer, neuroblastoma, retinoblastoma, hepatoblastoma,
nephroblastoma etc.) and the like can be mentioned.
[0154] Application to cerebral tumor (neuroglioma having a
component of malignant astroglioma and oligodendroglioma etc.),
cancer of esophangus, stomach cancer, liver cancer, pancreatic
cancer, colorectal cancer (colon cancer, rectal cancer etc.), lung
cancer (non-small cell lung cancer, small cell lung cancer etc.),
renal cancer, breast cancer, ovarian cancer, prostate cancer, skin
cancer, neuroblastoma, sarcoma and the like can be mentioned. more
preferably, colon cancer, pancreas cancer, renal cancer, lung
cancer, and breast cancer is preferable, and application to colon
cancer and pancreas cancer is particularly preferable.
[0155] In addition, treatment of chronic pain, specifically,
neuropathic pain, catapletic pain, pain associated with chronic
alcoholism, vitamin deficiency, uremia and hypothyroidism can be
mentioned. Furthermore, neutrophile-mediated disease or symptoms,
specifically, ischemia reperfusion injury, chronic obstructive
pulmonary disease, acute respiratory disease syndrome, cystic
fibrosis, catapletic pulmonary fibrosis, sepsis, endotoxemia, lung
emphysema and pulmonary asbestosis can be mentioned. Furthermore,
graft rejection can be mentioned. Moreover, arthritis,
specifically, rheumatoid arthritis and osteoarthritis can be
mentioned. In addition, asthma can be mentioned. Moreover, viral
diseases, specifically, herpes virus (HSV-1) infection, human
cytomegalovirus (HCMV) infection, human immunodeficiency virus
(HIV) infection can be mentioned. Furthermore, disease caused by
denaturation or injury of cartilage, specifically, osteoarthrosis,
rheumatoid arthritis, osteochondrosis dissecans and disease
requiring chondrogenesis can be mentioned.
[0156] Besides the above, application to restenosis, psoriasis,
atherosclerosis, cardiac failure, apoplexia and the like can be
mentioned.
[0157] As the "diseases caused by undesirable cell proliferation",
tumor and rheumatism are preferable.
[0158] As other "antitumor agent" used for multiple drug therapy,
alkylating agent, platinum complex, metabolism antagonist,
antibiotics, plant alkaloid, interferon, cyclooxygenase-2 (COX-2)
inhibitor, hormonal anticancer agent, cancer cell vaccine,
bacterial preparation, mushroom extract polysaccharides, cytokine
agonist, interleukin preparation, antibody drug, immunomodulator,
angiogenesis inhibitor, intracellular tube formation inhibitor,
cell proliferation inhibitor, cell cycle regulator, apoptosis
inducer, cancer gene therapy agent and the like can be
mentioned.
[0159] As the alkylating agent, cyclophosphamide, ifosfamide,
melpharan, buslfan, nimustine, ranimustine (MCNU), nitrogen
mustard-N-oxide hydrochloride, thiotepa, procarbazine
hydrochloride, carboquone, mitobronitol, improsulfan tosylate, 20
estramustine phosphate sodium, dacarbazine, temozolomide,
dacarbazine (DTIC), mustine hydrochride, treosulfan, temozolomide,
MS-247, (-)-(S)-bromofosfamide and the like can be mentioned.
[0160] As the platinum complex, cisplatin, carboplatin, 25
nedaplatin, paraplatin, etoposide, Oxaliplatin, eptaplatin,
miriplation, lobaplatin, picoplatin, oxaliplatin, satraplatin,
SLIT-cisplatin and the like can be mentioned.
[0161] As the metabolism antagonist, methotrexate,
6-mercaptopurine, cytosine-arabinoside, enocitabine (BHAC),
5-fluorouracil, tegafur, tegafur-uracil (UFT), carmofur (HCFU),
doxifluridine, gemcitabine hydrochloride, hydroxyl carbamide,
procarbazine hydrochloride, pemetrexed disodium, L-MDAM,
mercaptopurine riboside, fludarabine phosphate,
tegafur-gimestat-otastat, levofolinate-fluorouracil, folinate
calcium levofolinate, bemcitabine, calcium levolecucovorin,
capecitabine, cytarabine, cytarabine ocfosfate, CS-682,
3'-ethynylcytidine, TAS-102, capecitabine, fulvestrant,
idoxuridine, hydroxyurea, pemetrexeddisodium, 3-AP, benspm,
lometrexol, troxacitabine, ABT-510, AP-2/09, AR-726, AVI-4126,
belimumab, CA4P, colorectal cancer vaccine, COU-1, degarelix,
DJ-927, DPC-974, EKB-569, enzastaurin hydrochloride, fentanyl
citrate, fulvestrant, gallium maltolate, HuMax-EGFR, IDD-1, LE-AON,
MDX-070, MT-201, NK-911, NV-07, Oncomyc-NG, pertuzumab, PX-103.1,
renal cancer vaccine, SN-4071, TL-139, topixantrone
dihydrochloride, ZYC-101a and the like can be mentioned.
[0162] As the antibiotics, actinomycin D, daunomycin, doxorubicin
(adriamycin), epirubicin, aclacinomycin A, mitomycin C, bleomycin,
pirarubicin hydrochloride, idarubicin hydrochloride, aclarubicin
hydrochloride, amrubicin hydrochloride, peplomycin sulfate,
neocarzinostatine, zinostatin stimalamer, valrubicin, liposormal
doxorubicin, NK911, BMS-247550(epothilone derivative), KRN5500,
KW-2170, annamycin, becatecarin, PK1, sabarubicin hydrochloride,
CVS-10290 and the like can be mentioned.
[0163] As the plant alkaloid, vincristine, vinblastine, vindesine,
etoposide, docetaxel, paclitaxel, irinotecan hydrochloride,
vinorelbine tartrate, mitoxantrone hydrochloride, noscapine,
vinflunine, docetaxel, E-7010, polyglutamated paclitaxel,
soblidotin, Bay59-8862, E-7389, DJ-927, HTI-286, AC-7700, T-3782,
ABI-007, batabulin sodium, DHA-paclitaxel, deoxyepothilone B,
ixabepilone, MBT-0206, ortataxel, SB-715992, AI-850, synthadotin,
ixabepilone, rubitecan, nogitecan hydrochloride, topotecan
hydrochloride, sobuzoxane, etoposide phosphate disodium salt,
dexrazoxane hydrochloride, rubitecan IST-622, exatecan mesylate,
TOP-53, edotecarin, karenitecan, AG-7352, TAS-103, T-0128, NK-314,
CKD-602, BNP-1350, lurtotecan, pegamotecan, rubitecan, LE-SN38,
CPT-11 and the like can be mentioned.
[0164] As interferon, interferon .alpha., interferon .alpha.-2a,
interferon .alpha.-2b, interferon .beta. and interferon .gamma.,
interferon .gamma.-1a, interferon .gamma.-1b, interferon .gamma.-n1
and the like can be mentioned.
[0165] As the cyclooxygenase-2 inhibitor, rofecoxib, celecoxib,
lumiracoxib, tiracoxib (tilmacozib), CS-502, CS-706, valdecoxib,
parecoxib, R-109339, deguelin, ajulemic acid, p-54, E-6087,
LM-4108, R-109339, CBX-AC, CBX--PR, CBX-BU, L-748706, DMNQ-S64,
ON-09250, ON-09300 and the like can be mentioned.
[0166] As the hormonal anticancer agent, leuprorelin acetate,
goserelin acetate, aminoglutethimide, triptorelin, goserelin,
formestane, fabrozole monohydrochloride, letrozole, exemestane,
deslorelin, buserelin acetate, cetrorelix acetate, histrelin
acetate, abarelix, atrigel-leuprolide, estramustine phosphate
sodium, chlormadinone acetate, fosfetrol, flutamide, bicartamide,
cyproterone acetate, medroxyprogesterone acetate, tamoxifen
citrate, toremifene citrate, mepithiostane, epithiostanol,
medroxyprogesterone acetate, fluvestrant, ormeloxifene, raloxifene
hydrochloride, miproxifene phosphate, TAS-108, FMPA, fadrozole,
anastrozole, exemestan, letrozole, formestane, bosentan,
atrasentan, dutasteride, ESI, KT5555, KAT-682 and the like can be
mentioned.
[0167] As the cancer cell vaccine, cancer vaccine, activated
lymphocyte, UL56 deficient HSV, vaccine for colorectal cancer
treatment, cancer peptide vaccine and the like can be
mentioned.
[0168] As the bacterial preparation, BCG, anti-malignant tumor
streptococcal preparation, LC9018, tubercle bacillus hot water an
extract and the like can be mentioned.
[0169] As the mushroom extract polysaccharides, lentinan, Coriolus
versicolor polysaccharides (krestin), sizofiran, CM6271 and the
like can be mentioned.
[0170] As the cytokine agonist, ubenimex and the like can be
mentioned.
[0171] As the interleukin preparation, interleukin-2, teceleukin,
interleukin-12 and the like can be mentioned. As the antibody
pharmaceutical agent, immunomodulator, trastuzumab, rituximab,
gemtuzumab ozogamicin, iburitumomab tiuxetan, cetuximab,
bevacizumab, caprpmab pendetide, capromab pendetide indium,
pemetrexed disodium, yttrium 90 ibritumab tiuxetan, votumumab,
humanized IL-6 receptor antibody, anti-TA226 human monoclonal
antibody, F(ab') human antibody GAH, EMD72000, partuzumab,
alemtuzumab, VEGF receptor FLt-1 antibody, KW-2871, humanized
anti-GM2 antibody, humanized anti-GD2 antibody, KM2760, TRAIL
receptor-2 monoclonal antibody, anti-TRAIL receptor DR5 antibody,
TRAIL-RImAb, humanized anti-HM1.24 antibody, humanized FasL
antibody, humanized anti-CD26 monoclonal antibody,
.alpha.-galactosylceramide, diphtheria toxin modified transferrin
bond, CD47 monoclonal antibody, anti-human melanoma monoclonal
antibody, HoAKs-1 (anti-lung cancer monoclonal antibody) and the
like can be mentioned.
[0172] As the angiogenesis inhibitor, gefitinib (Iressa),
thalidomide, cetuximab, semaxanib, TSU-68, KRN633, KRN951,
marimastat, S-3304, erlotinib hydrochloride, ZD6474, GW572016,
S-3304, E7820, SU6668, E7080, NK4, TAS-101, lapatinib, priomastat,
RPI-4610, thalidomide, WX-UK1, 2-methoxyestradiol, SG-292, FYK-1388
and the like can be mentioned.
[0173] As the intracellular tube formation inhibitor, TAC-01,
E-7820 and the like can be mentioned.
[0174] As the cell proliferation inhibitor, imatinib mesylate,
trastuzumab, rituximab, gemtuzumab, AHM, mubritinib/TAK-165,
KW-2871, KM8969, CP-724714 and the like can be mentioned.
[0175] As the cell cycle regulator, Boltezomib (NF-.kappa..beta.
Activation inhibitor), histone deacetylase HDAC inhibitor (FK-228,
SAHA, CI-994, LAQ-824, pyroxamide, AN-9, PBA, MS-275 and the like),
E-7070, flavopiritol, UCN-01, CGP41251, CCI-779, KT5555, HMN-214,
Y-27632, vatalanib/PTK-787A, MGCD0130, temsirolirnus,
(R)-roscovitine, indisulam and the like can be mentioned.
[0176] As the apoptosis inducer, bortezomib, arglabin, R-115777,
KW-2401, BMS-214662, tipifarnib, lonafarnib, arglabin, bexarotene,
exisulind, glufosfamide, irofulven, MX-126374, MX-2167, GRN163,
GM95, MST-312, (-)-EGCG(Teavigo) and the like can be mentioned.
[0177] As the cancer gene therapy agent, A-007, Ad/Q5-H-sDd,
apaziquone, AVE-8062, MS-214662, combretastatin A-4, didox,
dolastatin-10, ganglioside vaccine, GivaRex, ILX-23-7553,
interleukins, itriglumide, KW-2401, MCC-465, miriplatin, MUC-1
vaccine, OSI-7904L, platelet factor 4, SR-271425, ZK-230211 and the
like can be mentioned.
[0178] As other antitumor agents, anticancer agents,
L-asparaginase, tretinoin, levoleucovorin calcium, celmoleukin,
111ln-pentetreotide, ibandronate sodium hydrate, aminolevulinic
acid hydrochloride, ukrain, Stem cell factor, denileukin difftitox,
menatetrenone, methoxsalen, trimetrexate glucuronate, IOR-R3,
everolimus, cytokeratin 19, doxercalciferol, alitretionoin,
bexarotene, verteporfin, morphine sulfate sustained-release,
Bacillus Calmette Guerin, megestrol acetate, menadione,
floxuridine, thyrotropin alfa, inositol hexaphosphate, augmerosen,
Thio TEPA, chorionic gonadotropin, histamine dihydrochloride,
lycopene, talaporfin sidium, tasonermin, arsenic trioxide,
levamisole hydrochroride, folic acid, teniposide, mebendazole,
morphine hydrochloride, ALA Me ester, anethole dithiolethion,
testosterone propionate, cinacalcet hydrochloride, anethole
dithiolethione, testosterone, mitotane, sodium thiosulfate,
zevalin, bexxar, salmon calcitonin, novobiocin, aminoglutethimide,
eflornithine hydrochloride, lonidamine, amoxnox, pirarubicin,
vesnarinone, pamidronate sodium, clodronate disodium, zoledronic
acid monohydrate, ambamustine hydrochloride, ubestatin, amifostine
hydrate, deoxyspergualin hydrochloride, pentostatin, bisantrene,
peplomycin, iobenguane, amsacrine, trilostane, tramadol
hydrochloride, elliptinium acetate, ladakamycin, bromebrate sodium,
nitracrin dihydrochloride hydrate, altretamine, OROS-oxyodone,
fentanyl citrate, aspirin, AERx Morphine sulfate, carmustine,
metoclopramide hydrochloride, loperamide hydrochloride, nilutamide,
polysaccharide K, ranimustine, atvogen, pipobroman, imiquimod
(interferon inducers), cladribine, tibolone, suramin sodium,
leflunomide, fentanyl, octreotide acetate, inositol, ursodiol,
feverfew, lentinan, tetranabinex, (cannabinoid receptor agonists),
pegaspargase, triclosan, crbohydrate antigen 19-9, angiopeptin
acetate, fotemustine, gallium nitrate, trabectebin, raltitrexed,
zinostatin stimalamer, hexadecylphosphocholine, tazarotene,
finasteride, clofarabine, temoporfin, SY-801, human angiotensin II,
efaproxiral sodium, amonafide (DNA-Intercalating Drug), SP-1053C
(DNA-Intercalating Drug), antineoplaston AS2-1, fenretinide
(retinoids), trabectebin, mammastatin, DOS-47, ECO-04601,
thymectacin, rhIGFBP-3, carboxyamidotriazole, CoFactor, davanat-1,
tariquidar, ONT-093, minobronic acid, minodronic acid, dofequidar
fumarate (MDR-1 inhibitors), tariquidar (MDR-1 Inhibitors),
Davanat-1, ranpirnase, atrasentan, meclinertant, tacedinline,
troxacitabine, DN-101, EB-1627, ACO-04601, MX-116407, STA-4783,
Davanat-1, moverastin, mitoxantrone hydrochloride, procarbazine
hydrochloride, octreotide acetate, porfimer sodium, pentostatin,
cladribine, sobuzoxane, tretinoin, aceglatone, mitotane, porfimer
sodium, elliptinium Acetate, AZD6126, tirapazamine, Bay4.3-9006,
tipifarnib/R115777, midostaurin, BMS-214662, EKB-569, E7107,
CBP501, HMN-214, FK-866, WF-536, SU-11248, MKT-077, phenoxodiol,
NSC-330507, G-CSF, Edrecolomab (Monoclonal Antibodies), satumomab,
sargramostin (GM-CSF), tamibarotene (retinoid derivative), arsenic
trioxide, dutasteride, menatetrenone, ZD4054, NIK-333, NS-9,
ABT-510, S-2678, methioninase, TAS-105, metastin, TOP-008,
NCO0-700, BCA and the like can be mentioned.
[0179] As "other antitumor agents" used for the multiple drug
therapy with the compound of the present invention, platinum
complex, alkylating agent and metabolism antagonist are preferable.
It is possible to use 2 or 3 or more pharmaceutical agents can be
used in combination, wherein a combination of pharmaceutical agents
having different action mechanism is one of the preferable
embodiments. Moreover, selection of pharmaceutical agents having
non-overlapping side effects is preferable.
[0180] For a combined use of the compound of the present invention
with "other antitumor agents", these two or more kinds of compounds
may be contained in the same composition. In addition, a
composition containing the compound of the present invention and a
composition containing "other antitumor agents" may be
simultaneously or sequentially administered.
[0181] When two agents are simultaneously administered,
"simultaneous" includes administration of 2 agents, with
administration of one agent and then the other agent in several
minutes after the first administration. By "sequentially" is meant
a lapse of a given time. For example, administration of the other
agent several minutes to several dozen minutes after the
administration of the first agent, and administration of the other
agent several hours to several days after the administration of the
first agent are included, wherein the lapse of time is not limited.
For example, one agent may be administered once a day, and the
other agent may be administered 2 or 3 times a day, or one agent
may be administered once a week, and the other agent may be
administered once a day and the like.
[0182] When the compound of the present invention is used as an
antitumor agent, and when the compound of the present invention is
used in combination with "other antitumor agents", radiotherapy,
activation lymphocyte therapy and the like may be further
added.
[0183] Some examples of the Production Methods of the compound used
for embodiment of the present invention are shown in the following.
However, the Production Methods of the compound of the present
invention are not limited to these examples.
[0184] Even in the absence of description in the Production
Methods, efficient production can be afforded by designs such as
introducing, where necessary, a protecting group into a functional
group followed by deprotection in a subsequent step; subjecting a
functional group to each step as a precursor and converting the
group to a desired functional group in a suitable step; exchanging
the order of respective Production Methods and steps; and the
like.
[0185] The work-up treatment in each step can be applied by a
typical method, wherein isolation and purification is performed as
necessary by selecting or combining conventional methods, such as
crystallization, recrystallization, distillation, partitioning,
silica gel chromatography, preparative HPLC and the like.
Production Method 1
##STR00033##
[0186] wherein Hal is a halogen atom such as chlorine atom, bromine
atom and the like, R.sup.c1, R.sup.c2, R.sup.c3 and R.sup.c4 are
the same or different and each is a hydrogen atom or the
above-defined "C.sub.1-6 alkyl group", R.sup.3' is R.sup.3 other
than a hydrogen atom, R.sup.c5 is a leaving group such as a halogen
atom, p-toluenesulfonyloxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy and the like, and other symbols are as
defined above.
Step 1
[0187] The compound [3] can be obtained by reacting compound [1]
with compound [2] in a solvent preferably under a nitrogen
atmosphere from cooling to room temperature.
[0188] As the solvent, ether solvents such as 1,4-dioxane, diethyl
ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like;
hydrocarbon solvents such as benzene, toluene, xylene, hexane and
the like; and the like can be mentioned.
Step 2
[0189] The compound [5] can be obtained by reacting compound [3]
with compound [4] in a solvent preferably under a nitrogen
atmosphere under heating.
[0190] As the solvent, acetic anhydride, acetyl chloride,
phosphorus oxychloride and the like can be mentioned.
Step 3
[0191] Here, Hal is preferably bromine atom or chlorine atom. The
compound [6] can be obtained by reacting compound [5] with a
halogenating agent such as phosphorus oxychloride,
N-bromosuccinimide, N-iodosuccinimide and the like, in a solvent
such as trifluoromethanesulfonic acid, acetic acid, concentrated
sulfuric acid, N,N-dimethylformamide (DMF), water and the like, at
room temperature to under heating.
Step 4
[0192] The compound [8] can be obtained by reacting compound [6]
with compound [7] in a solvent under heating.
[0193] As the solvent, alcohol solvents such as water-containing or
nonaqueous methanol, ethanol and the like; ether solvents such as
1,4-dioxane, tetrahydrofuran (THF) and the like, and the like can
be mentioned.
Step 5
[0194] The compound [10] can be obtained by reacting compound [8]
with compound [9] in a solvent under heating.
[0195] As the solvent, ether solvents such as diphenylether and the
like; acetic anhydride, acetyl chloride and the like can be
mentioned.
Step 6
[0196] The compound [11] can be obtained by introducing a leaving
group into compound [10] by a conventional method.
[0197] For example, compound [11] can be obtained by reacting
compound [10] with methanesulfonyl chloride, p-toluenesulfonyl
chloride, trifluoromethanesulfonic anhydride and the like, in the
presence of base such as trimethylamine hydrochloride,
triethylamine, pyridine and the like as necessary in a solvent.
[0198] As the solvent, acetonitrile; ether solvents such as
tetrahydrofuran and the like; halogen solvents such as
dichloromethane and the like, and the like can be mentioned.
Step 7
[0199] The compound [I-1-1] can be obtained by reacting compound
[11] with compound [12] under heating as necessary in a
solvent.
[0200] As the solvent, N,N-dimethylacetamide, chloroform and the
like can be mentioned.
[0201] To improve reaction efficiency, 2,6-lutidine may be
added.
Production Method 1-1
##STR00034##
[0202] wherein each symbol is as defined above.
Step 1
[0203] The compound [14] can be obtained by reacting compound [1]
with compound [13] in the same manner as in Production Method 1,
Step 1.
Step 2
[0204] The compound [15] can be obtained by reacting compound [14]
with compound [4] in the same manner as in Production Method 1,
Step 2.
Step 3
[0205] The compound [16] can be obtained by reacting compound [15]
in the same manner as in Production Method 1, Step 3.
Step 4
[0206] The compound [17] can be obtained by reacting compound [16]
with compound [7] in the same manner as in Production Method 1,
Step 4.
Step 5
[0207] The compound [18] can be obtained by reacting compound [17]
with compound [9] in the same manner as in Production Method 1,
Step 5.
Step 6
[0208] The compound [19] can be obtained by reacting compound [18]
in the same manner as in Production Method 1, Step 6.
Step 7
[0209] The compound [20] can be obtained by reducing compound [19]
by a conventional method such as reduction with zinc or iron in a
neutral or alkaline condition; iron and acid; tin or tin (II)
chloride and concentrated hydrochloric acid; alkali sulfide;
alkaline hydrosulfite and the like, or hydrogenation under hydrogen
atmosphere and the like.
[0210] For example, compound [20] can be obtained by adding acetic
acid and zinc powder to compound [19] under cooling to allow to
react at room temperature. Alternatively, compound [20] can be
obtained by adding palladium-carbon to a solution of compound [19]
in a mixed solvent of THF and methanol under hydrogen atmosphere to
allow to react at room temperature.
Step 8
[0211] The compound [I-1-2] can be obtained by reacting compound
[20] with compound [12] in the same manner as in Production Method
1, Step 7.
Step 9
[0212] The compound [21] can be obtained by reacting compound [20]
with methanesulfonyl chloride in a solvent in the presence of base
such as triethylamine, pyridine and the like under cooling.
[0213] As the solvent, acetonitrile; ether solvents such as
tetrahydrofuran and the like; halogen solvents such as
dichloromethane and the like, and the like can be mentioned.
Step 10
[0214] The compound [I-1-3] can be obtained by reacting compound
[21] with compound [12] in the same manner as in Production Method
1, Step 7.
Production Method 2
##STR00035##
[0215] wherein R.sup.c6 is a hydrogen atom or an C.sub.1-4 alkyl
group, SR.sup.c7 (R.sup.c7 is lower alkyl such as methyl, ethyl and
the like or benzyl) is a leaving group, and other symbols are as
defined above.
Step 1
[0216] The compound [24] can be obtained by reacting compound [22]
obtained in the same manner as in Production Method 1, Step 1 to
Step 4 with compound [23].
Step 2
[0217] The compound [25] can be obtained by cyclizing compound [24]
by a conventional method. For example, compound [25] can be
obtained by stirring compound [24] in a solvent such as
N,N-dimethylformamide and the like in the presence of triethylamine
at room temperature.
Step 3
[0218] The compound [26] can be obtained by reacting compound [25]
with lower alkyl halide or benzyl halide in the presence of
base.
[0219] As the base, potassium carbonate, sodium carbonate, lithium
hydride, sodium hydride, potassium hydride and the like can be
mentioned, potassium carbonate is preferable.
[0220] As the lower alkyl halide, methyl iodide, ethyl iodide,
benzyl iodide and the like can be mentioned, methyl iodide is
preferable.
Step 4
[0221] The compound [I-2] can be obtained by reacting compound [26]
with compound [12] in the same manner as in Production Method 1,
Step 7.
Production Method 3
##STR00036## ##STR00037##
[0222] wherein R.sup.4' is R.sup.4 other than a hydrogen atom, and
other symbols are as defined above.
Step 1
[0223] The compound [28] can be obtained by reacting compound [1]
with compound [27] in the same manner as in Production Method 1,
Step 1.
Step 2
[0224] The compound [29] can be obtained by reacting compound [28]
with compound [4] in the same manner as in Production Method 1,
Step 2.
Step 3
[0225] The compound [30] can be obtained by reacting compound [29]
in the same manner as in Production Method 1, Step 3.
Step 4
[0226] The compound [32] can be obtained by reacting compound [30]
with compound [31] in the same manner as in Production Method 1,
Step 4.
Step 5
[0227] The compound [34] can be obtained by reacting compound [32]
with compound [33] in the same manner as in Production Method 1,
Step 5.
Step 6
[0228] The compound [35] can be obtained by reacting compound [34]
in the same manner as in Production Method 1, Step 6.
Step 7
[0229] The compound [37] can be obtained by reacting compound [35]
with compound [36] in the same manner as in Production Method 1,
Step 7.
Step 8
[0230] The compound [I-3-1] can be obtained by stirring compound
[37] in a solvent, in the presence of base at room temperature to
under reflux.
[0231] As the base, potassium carbonate, sodium carbonate, lithium
hydride, sodium hydride, potassium hydride, sodium methoxide and
the like can be mentioned, potassium carbonate and sodium methoxide
are preferable.
[0232] As the solvent, alcohol solvents such as methanol, ethanol,
n-propanol, isopropanol and the like; mixed solvents of these
solvent and amide solvents such as N,N-dimethylformamide,
N,N-dimethylacetamide and the like, halogen solvents such as
dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane and the like or ether solvents such as
tetrahydrofuran (THF) and the like, and the like can be
mentioned.
Production Method 4-1
##STR00038## ##STR00039##
[0233] wherein each symbol is as defined above.
Step 1
[0234] The compound [3] can be obtained by reacting compound [36]
with carbonyldiimidazole in a solvent in the presence of tertiary
amine such as triethylamine and the like under nitrogen or argon
atmosphere from cooling to room temperature, and then reacting with
compound [1].
[0235] As the solvent, N,N-dimethylformamide, chloroform,
dichloromethane, tetrahydrofuran and the like can be mentioned.
Step 2
[0236] The compound [39] can be obtained by acylating compound [3]
with compound [38] preferably under a nitrogen atmosphere by a
conventional method.
[0237] for example, when R.sup..degree. c is hydrogen, compound
[38] can be condensed with compound [3] using acetic anhydride,
acetyl chloride, pivaloyl chloride, methanesulfonyl chloride and
the like, particularly methanesulfonyl chloride in a solvent such
as N,N-dimethylformamide, N,N-dimethylacetamide and the like.
Step 3
[0238] The compound [40] can be obtained by reacting compound [39]
in a solvent in the presence of base at room temperature to under
heating.
[0239] As the solvent, water, ethanol-water, tetrahydrofuran-water
and the like can be mentioned, water is preferable.
[0240] As the base, potassium carbonate, sodium carbonate,
potassium hydroxide, sodium hydroxide, lithium hydride, sodium
hydride, potassium hydride and the like can be mentioned, sodium
hydroxide is preferable.
Step 4
[0241] The compound [41] can be obtained by reacting compound [40]
with N,N-dimethylformamide dimethylacetal in a
N,N-dimethylformamide solvent preferably under a nitrogen
atmosphere.
Step 5
[0242] The compound [42] can be obtained by reducing compound [41]
by a conventional method.
[0243] For example, compound [42] can be obtained by treating with
a reducing agent such as sodium borohydride, sodium
cyanoborohydride and the like in an alcohol solvent such as
methanol, ethanol, isopropanol, tert-butanol and the like or a
mixed solvent thereof under a nitrogen atmosphere.
Step 6
[0244] The compound [43] can be obtained by reacting compound [42]
with compound [9] in the same manner as in Production Method 1,
Step 5.
Step 7
[0245] The compound [44] can be obtained by reacting compound 5
[43] in the same manner as in Production Method 1, Step 6.
Step 8
[0246] The compound [I-1-4] can be obtained by reacting compound
[44] with compound [12] in the same manner as in Production Method
1, Step 7.
Production Method 4-2
##STR00040## ##STR00041##
[0247] wherein each symbol is as defined above.
Step 1
[0248] The compound [28] can be obtained by reacting compound [45]
with compound [1] in the same manner as in Production Method 4-1,
Step 1.
Step 2
[0249] The compound [46] can be obtained by reacting compound [28]
with compound [38] in the same manner as in Production Method 4-1,
Step 2.
Step 3
[0250] The compound [47] can be obtained by reacting compound [46]
in the same manner as in Production Method 4-1, Step 3.
Step 4
[0251] The compound [48] can be obtained by reacting compound [47]
in the same manner as in Production Method 4-1, Step 4.
Step 5
[0252] The compound [49] can be obtained by reacting compound [48]
in the same manner as in Production Method 4-1, Step 5.
Step 6
[0253] The compound [50] can be obtained by reacting compound [49]
with compound [33] in the same manner as in Production Method 1,
Step 5.
Step 7
[0254] The compound [51] can be obtained by reacting compound [50]
in the same manner as in Production Method 1, Step 6.
Step 8
[0255] The compound [52] can be obtained by reacting compound [51]
with compound [36] in the same manner as in Production Method 1,
Step 7.
Step 9
[0256] The compound [I-3-2] can be obtained by reacting compound
[52] in the same manner as in Production Method 3, Step 8.
Production Method 4-3
##STR00042## ##STR00043##
[0257] wherein R.sup.c7 is a halogen atom such as bromine atom,
chlorine atom and the like or a hydroxyl group and the other
symbols are as defined above.
Step 1
[0258] The compound [53] can be obtained by reacting compound [45]
with carbonyldiimidazole in a solvent in the presence of tertiary
amine such as triethylamine and the like under a nitrogen or argon
atmosphere from cooling to room temperature, and then reacting with
ammonia.
[0259] As the solvent, N,N-dimethylformamide, chloroform,
dichloromethane, tetrahydrofuran and the like can be mentioned.
Step 2
[0260] The compound [54] can be obtained by reacting compound [53]
with compound [38] in the same manner as in Production Method 4-1,
Step 2.
Step 3
[0261] The compound [55] can be obtained by reacting compound [54]
in the same manner as in Production Method 4-1, Step 3. Step 4
[0262] The compound [56] can be obtained by reacting compound [55]
in the same manner as in Production Method 4-1, Step 4.
Step 5
[0263] The compound [57] can be obtained by introducing a
protecting group into compound [56] by a conventional method.
Step 6
[0264] The compound [58] can be obtained by reacting compound [57]
in the same manner as in Production Method 4-1, Step 5.
Step 7
[0265] The compound [59] can be obtained by reacting compound [58]
with compound [33] in the same manner as in Production Method 1,
Step 5.
Step 8
[0266] The compound [60] can be obtained by reacting compound [59]
in the same manner as in Production Method 1, Step 6.
Step 9
[0267] The compound [61] can be obtained by reacting compound [60]
with compound [36] in the same manner as in Production Method 1,
Step 7.
Step 10
[0268] The compound [62] can be obtained by reacting compound [61]
in the same manner as in Production Method 3, Step 8.
Step 11
[0269] The compound [63] can be obtained by deprotecting compound
[62] by a conventional method.
Step 12
[0270] The compound [I-3-3] can be obtained by reacting compound
[63] with compound [64] by a conventional method.
[0271] For example, when R.sup.c7 is a hydroxyl group, compound
[63] is reacted with a condensing agent such as diethyl
azodicarboxylate, diisopropyl azodicarboxylate and the like and
triphenylphosphine in a solvent such as N,N-dimethylformamide,
acetonitrile, tetrahydrofuran and the like under a nitrogen or
argon atmosphere according to Mitsunobu reaction.
EXAMPLES
Example 1
Synthesis of
N-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-triox-
o-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfona-
mide
Step 1 Synthesis of 1-cyclopropyl-3-(nitrophenyl)urea
##STR00044##
[0273] To a solution of cyclopropylamine 1 (9 g) in tetrahydrofuran
(250 ml) was added 3-nitrophenylisocyanate 2 (25 g) by small
portions, and the mixture was stirred at room temperature for 1 hr.
The solid precipitated from the reaction mixture was filtered by
suction, washed with ethyl acetate, and dried to give
1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g, 99%) as a yellow
solid.
Step 2 Synthesis of
1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione
##STR00045##
[0275] To 1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g) obtained in
Step 1 were added acetic anhydride (99 ml) and malonic acid 4 (17
g), and the mixture was stirred under heating at 110.degree. C. for
4 hrs. The reaction mixture was concentrated under reduced
pressure. Chloroform was added to the residue, and the mixture was
stirred at room temperature for 10 min. Chloroform insoluble
material was filtered by suction and dried to give
1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5 (28 g,
65%) as a brown solid.
Step 3 Synthesis of
6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione
##STR00046##
[0277] To 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-trione 5
(28 g) obtained in Step 2 was added water (3 ml), phosphorus
oxychloride (72 ml) was added dropwise by small portions with
stirring, and the mixture was stirred with heating at 110.degree.
C. for 1 hr. The reaction mixture was poured into ice water by
small portions, and the precipitated solid was filtered by suction.
The filtrate was dissolved in chloroform (300 ml), washed with
water (30 ml) and brine (30 ml), and the organic layer was dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by column chromatography
(chloroform:acetone=9:1) to give a 2:1 mixture (10 g, 34%) of
6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6
and
4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7
as a white solid.
Step 4 Synthesis of
3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione
##STR00047##
[0279] To the mixture (30 g) of
6-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6
and
4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7
obtained in Step 3 were added ethanol (300 ml) and a 40% solution
(150 ml) of methylamine in methanol, and the mixture was stirred
with heating at 80.degree. C. for 4.5 hrs, ice-cooled and the
precipitated solid was filtered by suction. The residue was washed
with water (1 liter) and dried to give
3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione
8 (16 g, 55%) as a white solid.
Step 5 Synthesis of
3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyr-
imidine-2,4,7-trione
##STR00048##
[0281] To
3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4--
dione 8 (16 g) obtained in Step 4 were added diphenyl ether (160
ml) and diethyl malonate 9 (40 ml), and the mixture was stirred
under heating at 230.degree. C. for 11 hrs while evaporating the
resulting ethanol. The reaction mixture was purified by column
chromatography (chloroform.fwdarw.chloroform:acetone=9:1) to give
3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyr-
imidine-2,4,7-trione 10 (10 g, 51%) as a brown foamy oil.
Step 6 Synthesis of toluene-4-sulfonic acid
3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ropyrido[2,3-d]pyrimidin-5-yl ester
##STR00049##
[0283] To
3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[-
2,3-d]pyrimidine-2,4,7-trione 10 (18 g) obtained in Step 5 were
added acetonitrile (180 ml), tosyl chloride 11 (11 g) and
triethylamine (8 ml), and the mixture was stirred with heating
under reflux at 110.degree. C. for 1 hr. The reaction mixture was
concentrated under reduced pressure. Water (100 ml) was added to
the residue and the mixture was extracted with chloroform (800 ml).
The organic layer was washed with brine (50 ml), dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was recrystallized from chloroform:diethyl
ether=1:5 to give toluene-4-sulfonic acid
3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ro-pyrido[2,3-d]pyrimidin-5-yl ester 12 (21 g, 82%) as a white
solid.
Step 7 Synthesis of toluene-4-sulfonic acid
1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00050##
[0285] To a suspension of toluene-4-sulfonic acid
3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ro-pyrido[2,3-d]pyrimidin-5-yl ester 12 (21 g) obtained in Step 6
in tetrahydrofuran was added stannous chloride dihydrate (45 g),
and the mixture was stirred at room temperature for 4 hrs. The
reaction mixture was alkalified with saturated aqueous sodium
hydrogen carbonate, an insoluble inorganic product was filtered off
by suction using celite as a filtration aides, and the filtrate was
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (chloroform:acetone=9:1) to give toluene-4-sulfonic
acid
1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ro-pyrido[2,3-d]pyrimidin-5-yl ester 13 (15 g, 74%) as a white
solid.
Step 8 Synthesis of toluene-4-sulfonic acid
3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,-
3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00051##
[0287] To toluene-4-sulfonic acid
1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahyd-
ro-pyrido [2,3-d]pyrimidin-5-yl ester 13 (5 g) obtained in Step 7
was added pyridine (40 ml), a solution of methanesulfonyl chloride
14 (0.9 ml) in chloroform (10 ml) was added dropwise with stirring
under ice-cooling, and the mixture was stirred for 3 hrs in an ice
bath. The reaction mixture was concentrated under reduced pressure,
2N hydrochloric acid was added and the mixture was extracted with
chloroform. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The resultant solid was suspended in diethyl
ether:hexane=1:1, and filtered by suction to give
toluene-4-sulfonic acid
3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,-
3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 15 (5.5 g, 95%)
as a white solid.
Step 9 Synthesis of
N-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-triox-
o-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfona-
mide
##STR00052##
[0289] To toluene-4-sulfonic acid
3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,-
3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 15 (3.5 g)
obtained in Step 8 was added 2-fluoro-4-bromoaniline 16 (23 g), and
the mixture was stirred under heating at 135.degree. C. for 3 hrs.
The reaction mixture was purified by column chromatography
(chloroform:acetone=9:1) to give
N-{3-[5-(4-bromo-2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-triox-
o-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidin-1-yl]phenyl}-methanesulfona-
mide 17 (3.0 g, 83%) as a white solid.
[0290] MS ESI m/e: 590, 592 (M+H), 588, 590 (M-H).
[0291] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.66 (s, 1H), 3.02 (s, 1H), 5.36 (s, 1H),
7.13 (d, J=9.0 Hz, 1H), 7.24-7.30 (m, 2H), 7.43-7.54 (m, 3H), 7.74
(d, J=9.0 Hz, 1H), 10.00 (brs, 1H), 10.53 (brs, 1H).
Examples 1-2 to 1-343
[0292] In the same manner as in Example 1-1, the compounds of
Examples 1-2 to 1-343 were obtained. The structural formulas
thereof are shown in Tables 1-1 to 1-58 with Example 1-1.
TABLE-US-00001 TABLE 1-1 Ex. No. structural formula 1-1
##STR00053## 1-2 ##STR00054## 1-3 ##STR00055## 1-4 ##STR00056## 1-5
##STR00057## 1-6 ##STR00058##
TABLE-US-00002 TABLE 1-2 Ex. No. structural formula 1-7
##STR00059## 1-8 ##STR00060## 1-9 ##STR00061## 1-10 ##STR00062##
1-11 ##STR00063## 1-12 ##STR00064##
TABLE-US-00003 TABLE 1-3 Ex. No. structural formula 1-13
##STR00065## 1-14 ##STR00066## 1-15 ##STR00067## 1-16 ##STR00068##
1-17 ##STR00069## 1-18 ##STR00070##
TABLE-US-00004 TABLE 1-4 Ex. No. structural formula 1-19
##STR00071## 1-20 ##STR00072## 1-21 ##STR00073## 1-22 ##STR00074##
1-23 ##STR00075## 1-24 ##STR00076##
TABLE-US-00005 TABLE 1-5 Ex. No. structural formula 1-25
##STR00077## 1-26 ##STR00078## 1-27 ##STR00079## 1-28 ##STR00080##
1-29 ##STR00081## 1-30 ##STR00082##
TABLE-US-00006 TABLE 1-6 Ex. No. structural formula 1-31
##STR00083## 1-32 ##STR00084## 1-33 ##STR00085## 1-34 ##STR00086##
1-35 ##STR00087## 1-36 ##STR00088##
TABLE-US-00007 TABLE 1-7 Ex. No. structural formula 1-37
##STR00089## 1-38 ##STR00090## 1-39 ##STR00091## 1-40 ##STR00092##
1-41 ##STR00093## 1-42 ##STR00094##
TABLE-US-00008 TABLE 1-8 Ex. No. structural formula 1-43
##STR00095## 1-44 ##STR00096## 1-45 ##STR00097## 1-46 ##STR00098##
1-47 ##STR00099## 1-48 ##STR00100##
TABLE-US-00009 TABLE 1-9 Ex. No. structural formula 1-49
##STR00101## 1-50 ##STR00102## 1-51 ##STR00103## 1-52 ##STR00104##
1-53 ##STR00105## 1-54 ##STR00106##
TABLE-US-00010 TABLE 1-10 Ex. No. structural formula 1-55
##STR00107## 1-56 ##STR00108## 1-57 ##STR00109## 1-58 ##STR00110##
1-59 ##STR00111## 1-60 ##STR00112##
TABLE-US-00011 TABLE 1-11 Ex. No. structural formula 1-61
##STR00113## 1-62 ##STR00114## 1-63 ##STR00115## 1-64 ##STR00116##
1-65 ##STR00117## 1-66 ##STR00118##
TABLE-US-00012 TABLE 1-12 Ex. No. structural formula 1-67
##STR00119## 1-68 ##STR00120## 1-69 ##STR00121## 1-70 ##STR00122##
1-71 ##STR00123## 1-72 ##STR00124##
TABLE-US-00013 TABLE 1-13 Ex. No. structural formula 1-73
##STR00125## 1-74 ##STR00126## 1-75 ##STR00127## 1-76 ##STR00128##
1-77 ##STR00129## 1-78 ##STR00130##
TABLE-US-00014 TABLE 1-14 Ex. No. structural formula 1-79
##STR00131## 1-80 ##STR00132## 1-81 ##STR00133## 1-82 ##STR00134##
1-83 ##STR00135## 1-84 ##STR00136##
TABLE-US-00015 TABLE 1-15 Ex. No. structural formula 1-85
##STR00137## 1-86 ##STR00138## 1-87 ##STR00139## 1-88 ##STR00140##
1-89 ##STR00141## 1-90 ##STR00142##
TABLE-US-00016 TABLE 1-16 Ex. No. structural formula 1-91
##STR00143## 1-92 ##STR00144## 1-93 ##STR00145## 1-94 ##STR00146##
1-95 ##STR00147## 1-96 ##STR00148##
TABLE-US-00017 TABLE 1-17 Ex. No. structural formula 1-97
##STR00149## 1-98 ##STR00150## 1-99 ##STR00151## 1-100 ##STR00152##
1-101 ##STR00153## 1-102 ##STR00154##
TABLE-US-00018 TABLE 1-18 Ex. No. structural formula 1-103
##STR00155## 1-104 ##STR00156## 1-105 ##STR00157## 1-106
##STR00158## 1-107 ##STR00159## 1-108 ##STR00160##
TABLE-US-00019 TABLE 1-19 Ex. No. structural formula 1-109
##STR00161## 1-110 ##STR00162## 1-111 ##STR00163## 1-112
##STR00164## 1-113 ##STR00165## 1-114 ##STR00166##
TABLE-US-00020 TABLE 1-20 Ex. No. structural formula 1-115
##STR00167## 1-116 ##STR00168## 1-117 ##STR00169## 1-118
##STR00170## 1-119 ##STR00171## 1-120 ##STR00172##
TABLE-US-00021 TABLE 1-21 Ex. No. structural formula 1-121
##STR00173## 1-122 ##STR00174## 1-123 ##STR00175## 1-124
##STR00176## 1-125 ##STR00177## 1-126 ##STR00178##
TABLE-US-00022 TABLE 1-22 Ex. No. structural formula 1-127
##STR00179## 1-128 ##STR00180## 1-129 ##STR00181## 1-130
##STR00182## 1-131 ##STR00183## 1-132 ##STR00184##
TABLE-US-00023 TABLE 1-23 Ex. No. structural formula 1-133
##STR00185## 1-134 ##STR00186## 1-135 ##STR00187## 1-136
##STR00188## 1-137 ##STR00189## 1-138 ##STR00190##
TABLE-US-00024 TABLE 1-24 Ex. No. structural formula 1-139
##STR00191## 1-140 ##STR00192## 1-141 ##STR00193## 1-142
##STR00194## 1-143 ##STR00195## 1-144 ##STR00196##
TABLE-US-00025 TABLE 1-25 Ex. No. structural formula 1-145
##STR00197## 1-146 ##STR00198## 1-147 ##STR00199## 1-148
##STR00200## 1-149 ##STR00201## 1-150 ##STR00202##
TABLE-US-00026 TABLE 1-26 Ex. No. structural formula 1-151
##STR00203## 1-152 ##STR00204## 1-153 ##STR00205## 1-154
##STR00206## 1-155 ##STR00207## 1-156 ##STR00208##
TABLE-US-00027 TABLE 1-27 Ex. No. structural formula 1-157
##STR00209## 1-158 ##STR00210## 1-159 ##STR00211## 1-160
##STR00212## 1-161 ##STR00213## 1-162 ##STR00214##
TABLE-US-00028 TABLE 1-28 Ex. No. structural formula 1-163
##STR00215## 1-164 ##STR00216## 1-165 ##STR00217## 1-166
##STR00218## 1-167 ##STR00219## 1-168 ##STR00220##
TABLE-US-00029 TABLE 1-29 Ex. No. structural formula 1-169
##STR00221## 1-170 ##STR00222## 1-171 ##STR00223## 1-172
##STR00224## 1-173 ##STR00225## 1-174 ##STR00226##
TABLE-US-00030 TABLE 1-30 Ex. No. structural formula 1-175
##STR00227## 1-176 ##STR00228## 1-177 ##STR00229## 1-178
##STR00230## 1-179 ##STR00231## 1-180 ##STR00232##
TABLE-US-00031 TABLE 1-31 Ex. No. structural formula 1-181
##STR00233## 1-182 ##STR00234## 1-183 ##STR00235## 1-184
##STR00236## 1-185 ##STR00237## 1-186 ##STR00238##
TABLE-US-00032 TABLE 1-32 Ex. No. structural formula 1-187
##STR00239## 1-188 ##STR00240## 1-189 ##STR00241## 1-190
##STR00242## 1-191 ##STR00243## 1-192 ##STR00244##
TABLE-US-00033 TABLE 1-33 Ex. No. structural formula 1-193
##STR00245## 1-194 ##STR00246## 1-195 ##STR00247## 1-196
##STR00248## 1-197 ##STR00249## 1-198 ##STR00250##
TABLE-US-00034 TABLE 1-34 Ex. No. structural formula 1-199
##STR00251## 1-200 ##STR00252## 1-201 ##STR00253## 1-202
##STR00254## 1-203 ##STR00255## 1-204 ##STR00256##
TABLE-US-00035 TABLE 1-35 Ex. No. structural formula 1-205
##STR00257## 1-206 ##STR00258## 1-207 ##STR00259## 1-208
##STR00260## 1-209 ##STR00261## 1-210 ##STR00262##
TABLE-US-00036 TABLE 1-36 Ex. No. structural formula 1-211
##STR00263## 1-212 ##STR00264## 1-213 ##STR00265## 1-214
##STR00266## 1-215 ##STR00267## 1-216 ##STR00268##
TABLE-US-00037 TABLE 1-37 Ex. No. structural formula 1-217
##STR00269## 1-218 ##STR00270## 1-219 ##STR00271## 1-220
##STR00272## 1-221 ##STR00273## 1-222 ##STR00274##
TABLE-US-00038 TABLE 1-38 Ex. No. structural formula 1-223
##STR00275## 1-224 ##STR00276## 1-225 ##STR00277## 1-226
##STR00278## 1-227 ##STR00279## 1-228 ##STR00280##
TABLE-US-00039 TABLE 1-39 Ex. No. structural formula 1-229
##STR00281## 1-230 ##STR00282## 1-231 ##STR00283## 1-232
##STR00284## 1-233 ##STR00285## 1-234 ##STR00286##
TABLE-US-00040 TABLE 1-40 Ex. No. structural formula 1-235
##STR00287## 1-236 ##STR00288## 1-237 ##STR00289## 1-238
##STR00290## 1-239 ##STR00291## 1-240 ##STR00292##
TABLE-US-00041 TABLE 1-41 Ex. No. structural formula 1-241
##STR00293## 1-242 ##STR00294## 1-243 ##STR00295## 1-244
##STR00296## 1-245 ##STR00297## 1-246 ##STR00298##
TABLE-US-00042 TABLE 1-42 Ex. No. structural formula 1-247
##STR00299## 1-248 ##STR00300## 1-249 ##STR00301## 1-250
##STR00302## 1-251 ##STR00303## 1-252 ##STR00304##
TABLE-US-00043 TABLE 1-43 Ex. No. structural formula 1-253
##STR00305## 1-254 ##STR00306## 1-255 ##STR00307## 1-256
##STR00308## 1-257 ##STR00309## 1-258 ##STR00310##
TABLE-US-00044 TABLE 1-44 Ex. No. structural formula 1-259
##STR00311## 1-260 ##STR00312## 1-261 ##STR00313## 1-262
##STR00314## 1-263 ##STR00315## 1-264 ##STR00316##
TABLE-US-00045 TABLE 1-45 Ex. No. structural formula 1-265
##STR00317## 1-266 ##STR00318## 1-267 ##STR00319## 1-268
##STR00320## 1-269 ##STR00321## 1-270 ##STR00322##
TABLE-US-00046 TABLE 1-46 Ex. No. structural formula 1-271
##STR00323## 1-272 ##STR00324## 1-273 ##STR00325## 1-274
##STR00326## 1-275 ##STR00327## 1-276 ##STR00328##
TABLE-US-00047 TABLE 1-47 Ex. No. structural formula 1-277
##STR00329## 1-278 ##STR00330## 1-279 ##STR00331## 1-280
##STR00332## 1-281 ##STR00333## 1-282 ##STR00334##
TABLE-US-00048 TABLE 1-48 Ex. No. structural formula 1-283
##STR00335## 1-284 ##STR00336## 1-285 ##STR00337## 1-286
##STR00338## 1-287 ##STR00339## 1-288 ##STR00340##
TABLE-US-00049 TABLE 1-49 Ex. No. structural formula 1-289
##STR00341## 1-290 ##STR00342## 1-291 ##STR00343## 1-292
##STR00344## 1-293 ##STR00345## 1-294 ##STR00346##
TABLE-US-00050 TABLE 1-50 Ex. No. structural formula 1-295
##STR00347## 1-296 ##STR00348## 1-297 ##STR00349## 1-298
##STR00350## 1-299 ##STR00351## 1-300 ##STR00352##
TABLE-US-00051 TABLE 1-51 Ex. No. structural formula 1-301
##STR00353## 1-302 ##STR00354## 1-303 ##STR00355## 1-304
##STR00356## 1-305 ##STR00357## 1-306 ##STR00358##
TABLE-US-00052 TABLE 1-52 Ex. No. structural formula 1-307
##STR00359## 1-308 ##STR00360## 1-309 ##STR00361## 1-310
##STR00362## 1-311 ##STR00363## 1-312 ##STR00364##
TABLE-US-00053 TABLE 1-53 Ex. No. structural formula 1-313
##STR00365## 1-314 ##STR00366## 1-315 ##STR00367## 1-316
##STR00368## 1-317 ##STR00369## 1-318 ##STR00370##
TABLE-US-00054 TABLE 1-54 Ex. No. structural formula 1-319
##STR00371## 1-320 ##STR00372## 1-321 ##STR00373## 1-322
##STR00374##
TABLE-US-00055 TABLE 1-55 Ex. No. structural formula 1-323
##STR00375## 1-324 ##STR00376## 1-325 ##STR00377## 1-326
##STR00378## 1-327 ##STR00379## 1-328 ##STR00380##
TABLE-US-00056 TABLE 1-56 Ex. No. structural formula 1-329
##STR00381## 1-330 ##STR00382## 1-331 ##STR00383## 1-332
##STR00384##
TABLE-US-00057 TABLE 1-57 Ex. No. structural formula 1-333
##STR00385## 1-334 ##STR00386## 1-335 ##STR00387## 1-336
##STR00388## 1-337 ##STR00389## 1-338 ##STR00390##
TABLE-US-00058 TABLE 1-58 Ex. No. structural formula 1-339
##STR00391## 1-340 ##STR00392## 1-341 ##STR00393## 1-342
##STR00394## 1-343 ##STR00395##
Example 2-1
Synthesis of
5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrim-
idine-2,4,7-trione
Step 1 Synthesis of 1,3-diphenyl-pyrimidine-2,4,6-trione
##STR00396##
[0294] Acetic anhydride (290 ml) was added to 1,3-diphenylurea 18
(148 g), malonic acid 4 (81.6 g) was added under a nitrogen
atmosphere, and the mixture was stirred at 90.degree. C. for 3 hrs.
The mixture was stirred at 100.degree. C. for 1.5 hrs and allowed
to cool to room temperature. The reaction mixture was concentrated
under reduced pressure. Ethanol (500 ml) was added to the residue,
and the mixture was stirred at 90.degree. C. When the mixture was
cooled to 40.degree. C., the crystals were collected by filtration,
washed with ethanol and dried to give
1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g, yield 40%).
Step 2 Synthesis of
6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione
##STR00397##
[0296] To 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g) obtained
in Step 1 was added water (16 ml). Phosphorus oxychloride (422 ml)
was added dropwise under stirring at room temperature over 50 min.
After the completion of the dropwise addition, the mixture was
stirred under heating at 110.degree. C. for 3 hrs. After allowing
to cool to room temperature, the reaction mixture was added to ice
water by small portions and the mixture was stirred at room
temperature and extracted with ethyl acetate. The organic layer was
washed with brine and saturated aqueous sodium hydrogen carbonate,
and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate
was filtered off and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography
(hexane:ethyl acetate=2:13:2) to give
6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (61.5 g, yield
74%) as pale-yellow crystals.
Step 3 Synthesis of
6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione
##STR00398##
[0298] In the same manner as in Step 4 of Example 1-1 and using
6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (5.0 g) obtained
in Step 2, ethanol (25 ml), a 40% solution (21.7 ml) of methylamine
in methanol, 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione 21
(4.42 g, yield 90%) was obtained as colorless crystals.
Step 4 Synthesis of ethyl
(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thi-
ocarbonyl)-carbamate
##STR00399##
[0300] To 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione 21
(1.18 g) obtained in Step 3 was added N,N-dimethylformamide (5.9
ml), ethyl isothiocyanate formate 22 (0.52 ml) was added under a
nitrogen atmosphere, and the mixture was stirred at room
temperature for 1 hr. Water (30 ml) was added to the reaction
mixture, and the crystals were collected by filtration and washed
with water to give crude ethyl
(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thi-
ocarbonyl)-carbamate 23 (1.68 g) as pale-yellow crystals, which
were used for the next step without purification.
Step 5 Synthesis of
5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-tr-
ione
##STR00400##
[0302] To crude ethyl
(6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thi-
ocarbonyl)-carbamate 23 (1.58 g) obtained in Step 4 was added
N,N-dimethylformamide (8.4 ml), triethylamine (0.63 ml) was added
under a nitrogen atmosphere, and the mixture was stirred at room
temperature for 30 min. Water (25 ml) was added, the mixture was
stirred, 1N hydrochloric acid (5.0 ml) was added, and the mixture
was stirred at room temperature for 1 hr. The crystals were
collected by filtration, washed with water and dried to give crude
5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-tr-
ione 24 (1.53 g, over weight) as yellow crystals, which were used
for the next step without purification.
[0303] Step 6 Synthesis of
8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,-
4,7-trione
##STR00401##
[0304] To crude
5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-tr-
ione 24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide
(0.5 ml). Under a nitrogen atmosphere, potassium carbonate (44 mg)
and methyl iodide 25 (20 .mu.l) were successively added, and the
mixture was stirred at room temperature for 3 hrs. Water was added,
and the mixture was extracted with chloroform. The organic layer
was washed with water and brine, and dried over anhydrous sodium
sulfate. Anhydrous sodium sulfate was filtered off, and the
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography (hexane:ethyl
acetate=4:1.fwdarw.3:1) to give
8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,-
4,7-trione 26 (91 mg, yield 89%) as brown crystals.
Step 7 Synthesis of
5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrim-
idine-2,4,7-trione
##STR00402##
[0306] To
8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyri-
midine-2,4,7-trione 26 (149 mg) obtained in Step 6 was added
toluene (2 ml), 4-chloroaniline 27 (97 mg) was added, and the
mixture was stirred under reflux for 3.5 hrs. After allowing to
cool to room temperature, diethyl ether was added. The crystals
were collected by filtration, washed with diethyl ether and dried
to give
5-(4-chloro-phenylamino)-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrim-
idine-2,4,7-trione 28 (94 mg, yield 53%) as colorless crystals.
[0307] MS ESI m/e: 472 (M+H), 470 (M-H).
[0308] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.68 (s, 3H),
7.34-7.39 (m, 2H), 7.41-7.61 (m, 10H), 7.80-7.87 (m, 2H), 11.34 (s,
1H).
Example 2-2
[0309] In the same manner as in Example 2-1, the compounds of
Example 2-2 were obtained. The structural formulas thereof are
shown in Table 2-1 with Example 2-1.
[0310] Table 2-1
TABLE-US-00059 TABLE 2-1 Ex. No. structural formula 2-1
##STR00403## 2-2 ##STR00404##
Example 3-1
Synthesis of
5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,
6H-pyrido[4,3-d]pyrimidine-2,4,7-trione
Step 1 Synthesis of 1-(4-bromo-phenyl)-3-cyclopropyl-urea
##STR00405##
[0312] Under a nitrogen atmosphere, tetrahydrofuran (80 ml) was
added to 4-bromophenyl isocyanate 30 (10.0 g), and a solution of
cyclopropylamine 1 (3.17 g) in tetrahydrofuran (20 ml) was added
dropwise with stirring under ice-cooling. After the completion of
the dropwise addition, the mixture was stirred at room temperature
for 3 hrs, and the reaction mixture was concentrated under reduced
pressure. Diethyl ether-hexane [1:1 (volume ratio), 100 ml] was
added to the residue and, after stirring, the crystals were
collected by filtration and dried to give
1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g, over weight) as
colorless crystals, which were used for the next step without
purification.
Step 2 Synthesis of
1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione
##STR00406##
[0314] To 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g)
obtained in Step 1 was added acetic anhydride (25.8 ml), malonic
acid 4 (5.79 g) was added under a nitrogen atmosphere, and the
mixture was stirred at 100.degree. C. for 3 hrs. After allowing to
cool to room temperature, the reaction mixture was concentrated
under reduced pressure. Diethyl ether-ethanol [4:1 (volume ratio),
100 ml] was added to the residue and, after stirring, the crystals
were collected by filtration and dried to give
1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.9
g, yield 73%) as pale-yellow crystals.
Step 3 Synthesis of
1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione
##STR00407##
[0316] To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione
32 (11.8 g) obtained in Step 2 was added water (1.31 ml) and
phosphorus oxychloride (17.0 ml) was added dropwise with stirring
at room temperature. After the completion of the dropwise addition,
the mixture was stirred at 110.degree. C. for 3 hrs. After allowing
to cool to room temperature, the reaction mixture was added to ice
water by small portions and the mixture was stirred. The mixture
was stirred at room temperature and extracted with chloroform. The
organic layer was washed with brine, and dried over anhydrous
magnesium sulfate. Anhydrous magnesium sulfate was filtered off,
and the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (hexane:ethyl
acetate=2:1.fwdarw.Tchloroform:acetone=30:1) to give a 1:1.4
mixture (11.6 g, yield 93%) of
1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione
33 and
3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4,-dione
34 as a pale-yellow foamy oil.
Step 4 Synthesis of
1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione
##STR00408##
[0318] A 1:1.3 mixture (5.34 g, yield 78%) of
1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione
35 and
3-(4-bromo-phenyl)-1-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dion-
e 36 was obtained as colorless crystals in the same manner as the
synthesis of compound 8 and using a 1:1.4 mixture (7.00 g) of
1-(4-bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4-dione
33 and
3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4,-dione
34 obtained in Step 3, ethanol (20.9 ml) and a 40% solution (10.5
ml) of methylamine in methanol.
Step 5 Synthesis of
1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3--
d]pyrimidine-2,4,7-trione
##STR00409##
[0320]
1-(4-Bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrid-
o[2,3-d]pyrimidine-2,4,7-trione 38 (0.40 g, yield 32%) was obtained
as pale-yellow crystals in the same manner as in Step 5 of Example
1-1 and using a 1:1.3 mixture (1.00 g) of
1-(4-bromo-phenyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dione
35 and
3-(4-bromo-phenyl)-1-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-dion-
e 36 obtained in Step 4, 2-methyl-diethyl malonate 37 (2.56 ml) and
diphenyl ether (1.49 g).
Step 6 Synthesis of toluene-4-sulfonic acid
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-he-
xahydro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00410##
[0322] To
1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-py-
rido[2,3-d]pyrimidine-2,4,7-trione 38 (400 mg) obtained in Step 5
was added acetonitrile (8.0 ml), tosyl chloride 11 (458 mg) and
triethylamine (0.34 ml) were added under a nitrogen atmosphere, and
the mixture was stirred under reflux for 30 hrs. After allowing to
cool to room temperature, the mixture was concentrated under
reduced pressure. The residue was purified by column chromatography
(chloroform:acetone=25:1.fwdarw.20:1) to give toluene-4-sulfonic
acid
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-he-
xahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (407 mg, yield 74%) as
ocher crystals.
Step 7 Synthesis of
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[-
2,3-d]pyrimidine-2,4,7-trione
##STR00411##
[0324] To toluene-4-sulfonic acid
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-he-
xahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (100 mg) obtained in
Step 6 was added aniline 40 (0.64 ml), and the mixture was stirred
at 150.degree. C. for 2.5 hrs. After allowing to cool to room
temperature, diethyl ether-hexane [1:1 (volume ratio), 30 ml] was
added to the reaction mixture, and the crystals were collected by
filtration. The obtained crystals were purified by column
chromatography (chloroform:acetone=15:1) to give
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[-
2,3-d]pyrimidine-2,4,7-trione 41 (81 mg, yield 93%) as pale-yellow
crystals.
Step 8 Synthesis of
5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-py-
rido[4,3-d]pyrimidine-2,4,7-trione
##STR00412##
[0326] To
1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8-
H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (78 mg) obtained in Step
7 was added chloroform-methanol [1:1 (volume ratio), 2.0 ml],
potassium carbonate (22 mg) was added, and the mixture was stirred
at room temperature for 10 hrs. The mixture was further stirred
under reflux for 3 hrs, and allowed to cool to room temperature.
The mixture was concentrated under reduced pressure and purified by
column chromatography (chloroform:acetone=50:1) to give
5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,
6H-pyrido[4,3-d]pyrimidine-2,4,7-trione 42 (23 mg, yield 26%) as
colorless crystals.
[0327] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0328] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.77-0.82 (m, 2H),
1.09-1.15 (m, 2H), 1.36 (s, 3H), 2.72-2.74 (m, 1H), 3.20 (s, 3H),
6.86 (d, 2H), 7.28-7.32 (m, 2H), 7.34-7.51 (m, 5H), 11.36 (s,
1H).
Example 3-7
Synthesis of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfon-
amide
Step 1 Synthesis of
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfon-
amide
##STR00413##
[0330] To trifluoromethanesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4-
,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (30.0 g)
obtained in the same manner in Example 4-2, Step 6 to be mentioned
later and N-(3-aminophenyl)methanesulfonamide 44 (10.9 g) were
added N,N-dimethylacetamide (60.0 ml) and 2,6-lutidine (6.82 ml),
and the mixture was stirred at 130.degree. C. for 3.5 hrs. After
allowing to cool to room temperature, methanol (60 ml) was added
with stirring and the mixture was stirred for 2 hrs. The crystals
were collected by filtration and dried to give
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfon-
amide 45 (30.5 g, yield 96%) as colorless crystals.
Step 2 Synthesis of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfon-
amide
##STR00414##
[0332] Under a nitrogen atmosphere, to a solution (18.5 g) of 28%
sodium methoxide in methanol was added tetrahydrofuran (284 ml),
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfon-
amide 45 (28.4 g) obtained in Step 1 was added, and the mixture was
stirred at room temperature for 1 hr. Acetic acid (12.5 ml) was
added, and the mixture was stirred at room temperature for 1 hr and
concentrated under reduced pressure. A 9:1 mixed solvent (426 mL)
of 1-butanol and water was added to the obtained solid, and the
mixture was stirred with heating under reflux for 3 hrs. The
mixture was allowed to return to room temperature and stirred
overnight, and the crystals were collected by filtration and dried.
A 9:1 mixed solvent (426 mL) of 1-butanol and water was added again
to the obtained crystals, and the mixture was stirred with heating
under reflux for 3 hrs. The mixture was allowed to return to room
temperature and stirred overnight. The crystals were collected by
filtration and washed with a 9:1 mixed solvent of methanol and
water and dried to give
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfon-
amide 46 (26.35 g, yield 93%) as white crystals.
[0333] MS ESI m/e: 652 (M+H), 650 (M-H).
[0334] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.25 (s, 3H), 2.57-2.67 (m, 1H), 3.01 (s,
3H), 3.08 (s, 3H), 6.92 (t, J=9.0 Hz, 1H), 7.09-7.14 (m, 1H),
7.20-7.26 (m, 2H), 7.37-7.45 (m, 1H), 7.52-7.58 (m, 1H), 7.79 (dd,
J=1.8, 9.0 Hz, 1H), 9.89 (s, 1H), 11.08 (s, 1H).
Example 3-2 to 3-6, 3-8 and 3-9
[0335] In the same manner as in Examples 3-1 and 3-7, the compounds
of Examples 3-2 to 3-6, 3-8 and 3-9 were obtained. The structural
formulas thereof are shown in Table 3-1 to 3-2 with Examples 3-1
and 3-7.
TABLE-US-00060 TABLE 3-1 Ex. No. structural formula 3-1
##STR00415## 3-2 ##STR00416## 3-3 ##STR00417## 3-4 ##STR00418## 3-5
##STR00419## 3-6 ##STR00420##
TABLE-US-00061 TABLE 3-2 Ex. No. structural formula 3-7
##STR00421## 3-8 ##STR00422## 3-9 ##STR00423##
Example 3-10
[0336] By treating
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfon-
amide 46 according to conventional methods, sodium salt and
potassium salt thereof were obtained.
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trio-
xo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfona-
mide sodium salt
[0337] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.47 (brs, 2H),
0.70-0.90 (m, 2H), 1.23 (s, 3H), 2.35 (brs, 1H), 2.82 (s, 3H), 3.22
(s, 3H), 6.69 (t, J=8.8 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.98 (s,
1H), 7.02 (d, J=8.8 Hz, 1H), 7.10-7.30 (m, 2H), 7.38 (d, J=9.2 Hz,
1H), 10.22 (brs, 1H).
[0338] MS (ESI) m/z 652 [MH].sup.+.
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trio-
xo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfona-
mide potassium salt
Example 4-1
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trio-
xo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
Step 1 Synthesis of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)
urea
##STR00424##
[0340] Under a nitrogen atmosphere, to N,N-carbonyldiimidazole
(39.9 g) were added N,N-dimethylformamide (200 ml) and
triethylamine (34.3 ml) and a solution of 2-fluoro-4-iodoaniline 47
(48.5 g) in N,N-dimethylformamide (50 ml) was added dropwise with
stirring under ice-cooling. After the completion of the dropwise
addition, the mixture was stirred at room temperature for 18 hrs.
The reaction mixture was ice-cooled, and cyclopropylamine (21.3 ml)
was added dropwise. The reaction mixture was stirred at room
temperature for 1 hr and added dropwise to water-toluene [2:1
(volume ratio), 750 ml] with stirring. The precipitated crystals
were collected by filtration and dried to give
1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.3 g, yield
93.4%) as colorless crystals.
Step 2 Synthesis of
1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione
##STR00425##
[0342] To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.0 g)
obtained in Step 1 and malonic acid 4 (19.9 g) were added acetic
anhydride (300 ml) and acetyl chloride (27.2 ml), and the mixture
was stirred under a nitrogen atmosphere at 60.degree. C. for 3 hrs.
After allowing to cool to room temperature, the reaction mixture
was added dropwise to water-toluene [2:1 (volume ratio), 900 ml]
with stirring. The precipitated crystals were collected by
filtration and dried to give
1-cyclopropyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione 49
(60.9 g, yield 82%) as pale-yellow crystals.
Step 3 Synthesis of
6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione
##STR00426##
[0344] To
1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine-2,4,6-trione 49
(59.0 g) obtained in Step 2 were added phosphorus oxychloride (85.0
ml) and dimethylaniline (29.0 ml), and water (8.3 ml) was added
dropwise to the mixture at room temperature with stirring. After
the completion of the dropwise addition, the mixture was stirred
with heating at 110.degree. C. for 1 hr. After allowing to cool to
room temperature, the reaction mixture was added dropwise to ice
water-toluene [2:1 (volume ratio), 900 ml] with stirring. The
mixture was stirred at room temperature for 1 hr. The organic layer
was separated, and washed successively with water (300 ml) and
brine (300 ml). Anhydrous magnesium sulfate and activated carbon
were added and the mixture was stirred. Anhydrous magnesium sulfate
and activated carbon were filtered off, and the filtrate was
concentrated under reduced pressure to give a 1:2 mixture (62.9 g)
of
6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione
50 and
6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-
-dione 51 as a yellow foamy oil, which was used for the next step
without purification.
Step 4 Synthesis of
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-d-
ione
##STR00427##
[0346] To a 1:2 mixture (62.9 g) of
6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione
50 and
6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-
-dione 51 obtained in Step 3 were added methanol (189 ml) and a
solution (126 ml) of 40% methylamine in methanol, and the mixture
was stirred at room temperature for 2 hrs. The precipitated
crystals were filtered off and the filtrate was concentrated under
reduced pressure. The residue was extracted with chloroform (200
ml) and water (200 ml), and the organic layer was washed with brine
(200 ml) and dried over anhydrous magnesium sulfate. Anhydrous
magnesium sulfate was filtered off and the filtrate was
concentrated under reduced pressure to give a 2:1 mixture (34.55 g)
of
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,-
4-dione 52 and
1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4,--
dione 53 as yellow crystals, which were used for the next step
without purification.
Step 5 Synthesis of
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyri-
do[2,3-d]pyrimidine-2,4,7-trione
##STR00428##
[0348] To a 2:1 mixture (34.6 g) of
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-d-
ione 52 and
1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methylamino-1H-pyrimidine-2,4,--
dione 53 obtained in Step 4, and 2-methylmalonic acid 54 (10.2 g)
was added acetic anhydride (173 ml), and the mixture was stirred at
100.degree. C. for 2 hrs. After allowing to cool to room
temperature, the reaction mixture was concentrated under reduced
pressure. Acetone (104 ml) was added to the residue, and the
mixture was stirred with heating under reflux for 30 min. After
allowing to cool to room temperature, the precipitated crystals
were collected by filtration and dried to give
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyri-
do[2,3-d]pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48, 21%) as
colorless crystals.
Step 6 Synthesis of trifluoromethanesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4-
,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00429##
[0350] Under a nitrogen atmosphere, to
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,
H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (33.0 g) obtained in Step
5 were added chloroform (165 ml) and 2,6-lutidine (10.4 ml), and
trifluoromethanesulfonic anhydride 56 (14.4 ml) was added dropwise
under ice-cooling with stirring. After the completion of the
dropwise addition, the mixture was stirred at same temperature for
30 min and at room temperature for 2 hrs. The reaction mixture was
washed successively with aqueous sodium hydrogen carbonate (165
ml), 1N hydrochloric acid (165 ml) and brine (165 ml) and dried
over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was
filtered off and the filtrate was concentrated under reduced
pressure. 2-Propanol (198 ml) was added to the residue, and the
mixture was stirred with heating under reflux, and allowed to
return to room temperature. The crystals were collected by
filtration and dried to give trifluoromethanesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4-
,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (31.9 g, yield
93%) as colorless crystals.
Step 7 Synthesis of
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide
##STR00430##
[0352] To trifluoromethanesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4-
,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (25.0 g)
obtained in Step 6 and 3'-aminoacetanilide 57 (7.33 g) were added
N,N-dimethylacetamide (50.0 ml) and 2,6-lutidine (5.68 ml), and the
mixture was stirred at 130.degree. C. for 5 hrs. After allowing to
cool to room temperature, methanol-water [1:2 (volume ratio), 150
ml] was added with stirring. The crystals were collected by
filtration and dried to give
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7--
trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}aceta-
mide 58 (24.8 g, yield 99%) as colorless crystals.
Step 8 Synthesis of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
##STR00431##
[0354] Under a nitrogen atmosphere, to a solution (1.57 g) of 28%
sodium methoxide in methanol was added tetrahydrofuran (40 ml),
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide
58 (5.00 g) obtained in Step 7 was added, and the mixture was
stirred at room temperature for 4 hrs. Acetic acid (0.56 ml) was
added, and the mixture was stirred at room temperature for 30 min.
Water (40 ml) was added and the mixture was further stirred for 1
hr. The crystals were collected by filtration and dried to give
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
59 (4.75 g, yield 95%) as colorless crystals.
[0355] MS ESI m/e: 616 (M+H), 614 (M-H).
[0356] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36
(t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz,
1H), 10.10 (s, 1H), 11.08 (s, 1H).
Example 4-1
Alternative Method
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trio-
xo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
Step 1 Synthesis of
1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea
##STR00432##
[0358] Under a nitrogen atmosphere, to N,N-carbonyldiimidazole
(82.1 g) were added N,N-dimethylformamide (400 ml) and
triethylamine (70.5 ml), and a solution of 2-fluoro-4-iodoaniline
47 (100 g) in N,N-dimethylformamide (100 ml) was added dropwise
under ice-cooling. After the completion of the dropwise addition,
the mixture was stirred at room temperature for 5 hrs. The reaction
mixture was ice-cooled, and cyclopropylamine (44.0 ml) was added
dropwise. The mixture was stirred at room temperature for 1 hr, and
the reaction mixture was added dropwise to water-toluene [2:1
(volume ratio), 1500 ml] with stirring. The precipitated crystals
were collected by filtration and dried to give
1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (129 g, yield
95.5%) as colorless crystals.
Step 2 Synthesis of
1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea
##STR00433##
[0360] Under a nitrogen atmosphere, to
1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 48 (167 g) and
cyanoacetic acid 73 (80.0 g), was added N,N-dimethylformamide (836
ml), and methanesulfonyl chloride (72.8 ml) was added dropwise with
stirring at room temperature. The mixture was stirred at room
temperature for 4 hrs. The reaction mixture was cooled with water,
and water-isopropanol [2:1 (volume ratio), 1670 ml] was added
dropwise. The mixture was stirred under water-cooling for 1 hr, and
the precipitated crystals were collected by filtration and dried to
give
1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74
(192 g).
Step 3 Synthesis of
6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione
##STR00434##
[0362] To
1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74
(192 g) were added water (962 ml) and 2N aqueous sodium hydroxide
solution (24.9 ml), and the mixture was stirred with heating at
80.degree. C. for 1 hr. After allowing to cool to room temperature,
the crystals were collected by filtration and dried to give
6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione
75 (178 g, yield from 48, 88%) as pale-yellow crystals.
Step 4 Synthesis of
N'-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-
-pyrimidin-4-yl]-N,N-dimethyl-formamidine
##STR00435##
[0364] Under a nitrogen atmosphere, to
6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione
75 (178 g) were added N,N-dimethylformamide (356 ml) and
N,N-dimethylformamide dimethylacetal (178 ml), and the mixture was
stirred at room temperature for 2 hrs. Isopropanol (178 ml) was
added with stirring at room temperature, and water (1068 ml) was
added dropwise. The mixture was stirred at room temperature for 2
hrs, and the precipitated crystals were collected by filtration and
dried to give
N'-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-
-pyrimidin-4-yl]-N,N-dimethyl-formamidine 76 (188 g, yield 92%) as
yellow crystals.
Step 5 Synthesis of
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4--
dione
##STR00436##
[0366] Under a nitrogen atmosphere, to t-butanol-ethanol [2:1
(volume ratio), 250 ml] was added sodium borohydride (6.41 g), and
the mixture was stirred at room temperature for 1 hr. Under
water-cooling,
N'-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-
-pyrimidin-4-yl]-N,N-dimethyl-formamidine 76 (50.0 g) was added,
and the mixture was stirred for 2.5 hrs. Under water-cooling, water
(225 ml) and 10% aqueous citric acid solution (175 ml) were
successively added dropwise, and the mixture was stirred for 3 hrs.
The precipitated crystals were collected by filtration and dried to
give crude crystals (34.5 g, LC purity 91%) of
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4--
dione 52, which were used for the next reaction without
purification.
Step 6 Synthesis of
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyr-
ido[2,3-d]pyrimidine-2,4,7-trione
##STR00437##
[0368] Under a nitrogen atmosphere, to
3-cyclopropy-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-d-
ione 52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was added
acetic anhydride (34.4 ml), and the mixture was stirred with
heating at 100.degree. C. for 3 hrs. After allowing to cool to
50.degree. C., acetone (68.8 ml) was added dropwise, and the
mixture was stirred as it was for 30 min. Water (172 ml) was
further added dropwise, and the mixture was stirred for 1 hr. After
allowing to cool to room temperature with stirring, the
precipitated crystals were collected by filtration and dried to
give crude crystals (37.7 g, LC purity 91%) of
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyr-
ido[2,3-d]pyrimidine-2,4,7-trione 55. Isopropanol (92.0 ml) was
added to the obtained crude crystals (30.7 g), and the mixture was
stirred at room temperature for 4 hrs. The crystals were collected
by filtration and dried to give
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyr-
ido[2,3-d]pyrimidine-2,4,7-trione 55 (25.9 g, yield from 76, 58%)
as pale-yellow crystals.
Step 7 Synthesis of p-toluenesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,-
4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00438##
[0370] Under a nitrogen atmosphere, to
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyr-
ido[2,3-d]pyrimidine-2,4,7-trione 55 (23.9 g) was added
acetonitrile (167 ml), and the mixture was stirred under
ice-cooling. Triethylamine (11.0 ml) and trimethylamine
hydrochloride (2.37 g) were added, and a solution of
p-toluenesulfonyl chloride 11 (12.3 g) in acetonitrile (72.0 ml)
was added dropwise. The mixture was stirred under ice-cooling for 1
hr, and stirred at room temperature for 3 hrs. Methanol (239 ml)
was added, and the mixture was stirred at room temperature for 1
hr. The crystals were collected by filtration and dried to give
p-toluenesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,-
4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.7 g, yield
91%) as colorless crystals.
Step 8 Synthesis of
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo--
1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide
##STR00439##
[0372] To p-toluenesulfonic acid
3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,-
4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.0 g) and
3'-aminoacetanilide 57 (13.2 g) were added N,N-dimethylacetamide
(84.0 ml) and 2,6-lutidine (15.3 ml), and the mixture was stirred
at 130.degree. C. for 4 hrs. After allowing to cool with stirring,
methanol (196 ml) was added dropwise, and the mixture was stirred
at room temperature. The crystals were collected by filtration and
dried to give
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo--
1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide
58 (25.2 g, yield 93%) as colorless crystals.
Step 9 Synthesis of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tr-
ioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
##STR00440##
[0374] Under a nitrogen atmosphere, to
N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo--
1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetamide
58 (45.7 g) was added tetrahydrofuran (366 ml), and a solution
(15.7 g) of 28% sodium methoxide in methanol was added dropwise
with stirring at room temperature and the mixture was stirred at
room temperature for 4 hrs. Acetic acid (5.61 ml) was added, and
the mixture was stirred at room temperature for 30 min. With
stirring at 70.degree. C. in an oil bath, water (366 ml) was added
dropwise, and the mixture was stirred for 1 hr. After allowing to
cool with stirring, the crystals were collected by filtration and
dried to give crystal 1 (46.0 g) of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tr-
ioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
59.
[0375] N,N-Dimethylacetamide (184 ml) was added to crystal 1 (46.0
g), and the mixture was stirred with heating at 130.degree. C.
After complete dissolution, the solution was filtered by suction
using with paper (5B), and washed with N,N-dimethylacetamide (92.0
ml). The filtrate was stirred under heating at 130.degree. C.,
1-butanol (138 ml) and water (96.0 ml) were successively added
dropwise, and the mixture was stirred for 30 min. Water (46.0 ml)
was further added dropwise, and the mixture was stirred for 30 min
allowed to cool with stirring. The crystals were collected by
filtration and dried to give crystal 2 (41.7 g) of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tr-
ioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
59 as colorless crystals.
[0376] To crystal 2 (41.5 g) was added 1-butanol-water [19:1
(volume ratio), 415 ml], and the mixture was stirred at 130.degree.
C. for 18 hrs. After allowing to cool with stirring, the crystals
25 were collected by filtration and dried to give
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tr-
ioxo-3,4,6,7-tetrahydro-2H-pyrido[4,
3-d]pyrimidin-1-yl]-phenyl}-acetamide 59 (40.7 g, yield 89%) as
colorless crystals.
Example 4-3
N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-t-
rioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
Step 1 Synthesis of
N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-
-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]p-
henyl}acetamide
##STR00441##
[0378] Under a nitrogen atmosphere, to
N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
59 (14.5 g) obtained in Example 4-1 were added chloroform (145 ml),
trimethylsilylacetylene 60 (4.99 ml) and triethylamine (13.1 ml).
Copper(I) iodide (22 mg) and
bis(triphenylphosphine)palladium(II)chloride (83 mg) were added,
and the mixture was stirred at room temperature for 20 hrs. The
mixture was concentrated under reduced pressure, activated carbon
(435 mg) and methanol (435 ml) were added to the residue, and the
mixture was stirred with heating at reflux for 2 hrs. Activated
carbon was filtered off while it was hot, and the filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography (chloroform:acetone=10:1.fwdarw.4:1) and
toluene-acetone [5:1 (volume ratio), 87 ml] was added to the
obtained crystals. The mixture was stirred at 80.degree. C. for 1
hr. After allowing to cool to room temperature, the crystals were
collected by filtration and dried to give
N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-
-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]p-
henyl}acetamide 61 (12.9 g, yield 93%) as pale-yellow crystals.
Step 2 Synthesis of
N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
##STR00442##
[0380] To
N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenyla-
mino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimid-
in-1-yl]phenyl}acetamide 61 (1.00 g) obtained in Step 2 and
potassium carbonate (236 mg) was added
methanol/N,N-dimethylformamide [1:1 (volume ratio), 10.0 ml], and
the mixture was stirred at room temperature for 20 hrs. The mixture
was neutralized with 2N hydrochloric acid, water (10.0 ml) was
added, and the mixture was stirred at room temperature for 1 hr.
The crystals were collected by filtration and dried to give
N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
62 (815 mg, yield 93%) as pale-yellow crystals.
[0381] MS ESI m/e: 514 (M+H), 512 (M-H).
[0382] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-0.99 (m, 2H), 1.26 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.10 (s, 3H), 4.30 (s, 3H), 7.01-7.06 (m, 1H), 7.09 (t, J=8.4
Hz, 1H), 7.31 (dd, J=1.6, 8.4 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.52
(dd, J=1.6, 11.6 Hz, 1H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.10
(s, 1H).
Example 4-16
N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7--
tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide
Step 1 Synthesis of 1-(2-fluoro-4-iodophenyl)-3-methylurea
##STR00443##
[0384] Under a nitrogen atmosphere, to N,N-carbonyldiimidazole
(61.4 g) were added N,N-dimethylformamide (300 ml) and
triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoaniline 47
(74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with
stirring under ice-cooling. After the completion of the dropwise
addition, the mixture was stirred at room temperature for 5 hrs.
The reaction mixture was ice-cooled, and a solution (60 ml) of 40%
methylamine in methanol was added dropwise. The mixture was stirred
at room temperature for 1 hr, and the reaction mixture was added
dropwise to water-toluene [2:1 (volume ratio), 1125 ml] under
stirring. The precipitated crystals were collected by filtration
and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9
g, yield 94.8%) as colorless crystals.
Step 2 Synthesis of
1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione
##STR00444##
[0386] Under a nitrogen atmosphere, to
1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g) obtained in Step
1 and malonic acid 4 (31.1 g) were added acetic anhydride (264 ml)
and acetyl chloride (42.5 ml), and the mixture was stirred at
65.degree. C. for 3 hrs. After allowing to cool to room
temperature, the reaction mixture was added dropwise to
water-toluene [2:1 (volume ratio), 800 ml] with stirring, and
hexane (132 ml) was successively added. The precipitated crystals
were collected by filtration and dried to give
1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3
g, yield 69.5%) as pale-yellow crystals.
Step 3 Synthesis of
6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione
##STR00445##
[0388] Under a nitrogen atmosphere, to
1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3
g) were added phosphorus oxychloride (116.3 ml) and dimethylaniline
(39.5 ml) and water (11.6 ml) was added dropwise with stirring
under room temperature. After the completion of the dropwise
addition, the mixture was stirred at 125.degree. C. for 1 hr. After
allowing to cool to room temperature, the reaction mixture was
added dropwise with stirring to ice water (500 ml)/chloroform (150
ml). The mixture was stirred at room temperature for 1 hr, and
chloroform (150 ml) was added. The organic layer was separated,
washed successively with water (300 ml) and brine (300 ml), and
dried over anhydrous sodium sulfate.
[0389] Anhydrous sodium sulfate was filtered off, and the filtrate
was concentrated under reduced pressure. To a solution of the
residue in chloroform (250 ml), silica gel (200 ml) was added and
the mixture was stirred. Silica gel was to filtered off and washed
with chloroform/ethyl acetate [10:1 (volume ratio), 11]. The
filtrate was concentrated under reduced pressure to give a 6:5
mixture (75.7 g, yield 95.6%) of
6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione
65 and
6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione
66 as pale-yellow crystals.
Step 4 Synthesis of
1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione
##STR00446##
[0391] To a 6:5 mixture (75.7 g) of
6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione
65 and
6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione
66 obtained in Step 3 were added methanol (227 ml) and 40% solution
(152 ml) of methylamine in methanol, and the mixture was stirred at
room temperature for 2.5 hrs. The reaction mixture was concentrated
under reduced pressure, and toluene (150 ml) and water (150 ml)
were added to the residue, and the mixture was stirred under
heating at reflux for 30 min. After allowing to return to room
temperature, the crystals were collected by filtration and dried to
give a 6:5 mixture (59.6 g, yield 79.9%) of
1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine--
2,4-dione 67 and
3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione
68 as pale-yellow crystals.
Step 5 Synthesis of
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]py-
rimidine-2,4,7-trione
##STR00447##
[0393] To a 6:5 mixture (59.6 g) of
1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione
67 and
3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-
-dione 68 obtained in Step 4 and 2-methyl-malonic acid 54 (20.7 g)
was added acetic anhydride (180 ml), and the mixture was stirred
with heating at 95.degree. C. for 1 hr. After allowing to cool to
room temperature, the mixture was concentrated under reduced
pressure. Tetrahydrofuran (350 ml) was added to the residue, and
the mixture was stirred with heating under reflux for 1 hr. After
allowing to cool to room temperature, the crystals were filtered
off. The filtrate was concentrated under reduced pressure and the
residue was purified by column chromatography
(chloroform:tetrahydrofuran=18:1). Toluene (150 ml) was added to
the obtained solid, and the mixture was stirred with heating under
reflux for 30 min. After allowing to return to room temperature,
the crystals were collected by filtration and dried to give
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]py-
rimidine-2,4,7-trione 69 (27.0 g, yield 37%) as colorless
crystals.
Step 6 Synthesis of trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahy-
dro-pyrido[2,3-d]pyrimidin-5-yl ester
##STR00448##
[0395] Under a nitrogen atmosphere, to
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3,6,8-trimethyl-1H,8H-pyrido[2,3-d]py-
rimidine-2,4,7-trione 69 (27.0 g) obtained in Step 5 were added
chloroform (200 ml) and 2,6-lutidine (11.1 ml) and
trifluoromethanesulfonic anhydride 56 (14.9 ml) was added dropwise
under ice-cooling with stirring. After the completion of the
dropwise addition, the mixture was stirred at the same temperature
for 30 min, and at room temperature for 3 hrs. With stirring under
ice-cooling, water (200 ml) was added to the reaction mixture. The
organic layer was separated, washed successively with water (300
ml) and brine (300 ml), and dried over anhydrous magnesium sulfate.
Anhydrous magnesium sulfate was filtered off, and the filtrate was
concentrated under reduced pressure. 2-Propanol (150 ml) was added
to the residue, and seed crystals were added at room temperature to
allow precipitation of the crystals. The mixture was stirred with
heating under reflux for 30 min, and allowed to cool to room
temperature. The crystals were collected by filtration and dried to
give trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahy-
dro-pyrido[2,3-d]pyrimidin-5-yl ester 70 (22.9 g, yield 66%) as
colorless crystals.
Step 7 Synthesis of
N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8--
hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide
##STR00449##
[0397] To trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahy-
dro-pyrido[2,3-d]pyrimidin-5-yl ester 70 (3.00 g) obtained in Step
6 and N-(3-aminophenyl)methanesulfonamide 44 (1.14 g) were added
N,N-dimethylacetamide (6.00 ml) and 2,6-lutidine (0.712 ml), and
the mixture was stirred at 130.degree. C. for 4 hrs. After allowing
to cool to room temperature, methanol/water [1:2 (volume ratio),
18.0 ml] was added under stirring. The crystals were collected by
filtration and dried to give
N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,-
3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonami-
de 71 (3.13 g, yield 98%) as a pale-gray solid.
Step 8 Synthesis of
N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-
-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide
##STR00450##
[0399] Under ice-cooling, to a suspension of
N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8--
hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide
71 (3.10 g) obtained in Step 7 in tetrahydrofuran (31.0 ml) was
added dropwise a mixture of potassium t-butoxide (1.33 g), methanol
(0.482 ml) and tetrahydrofuran (15.5 ml), and the mixture was
stirred under ice-cooling for 2 hrs. Acetic acid (1.36 ml) was
added, the mixture was allowed to warm to room temperature and
stirred for 1 hr. The reaction mixture was concentrated,
methanol/water [1:2 (volume ratio), 45.0 ml] was added, and the
mixture was further stirred at room temperature for 1 hr. The
crystals were collected by filtration and dried to give
N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-
-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide
72 (3.01 g, yield 97%) as a pale-gray solid.
[0400] MS ESI m/e: 626 (M+H), 624 (M-H).
[0401] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
3.01 (s, 3H), 3.09 (s, 3H), 3.21 (s, 3H), 6.93 (t, J=8.3 Hz, 1H),
7.11-7.15 (m, 1H), 7.20-7.28 (m, 2H), 7.42 (t, J=8.3 Hz, 1H),
7.52-7.57 (m, 1H), 7.76-7.81 (m, 1H), 9.94 (brs, 1H), 11.21 (brs,
1H).
Example 4-144
N-{3-[5-(2-Fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,7-
-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetami-
de
Step 1 Synthesis of (2-fluoro-4-iodophenyl)-urea
##STR00451##
[0403] Under argon atmosphere, to a solution of
2-fluoro-4-iodoaniline 47 (20.0 g) and triethylamine (23.6 ml) in
chloroform (200 ml) was added N,N-carbonyldiimidazole (27.4 g) with
stirring under ice-cooling. After the completion of the addition,
the mixture was stirred under ice-cooling for 15 min and at room
temperature for 4 hrs. The reaction mixture was ice-cooled, and 28%
aqueous ammonia (100 ml) was added dropwise. The mixture was
stirred at room temperature for 1.5 hrs. The precipitated crystals
were collected by filtration, washed with water and dried to give
(2-fluoro-4-iodophenyl)-urea 78 (23.5 g, yield 98.8%) as pale-pink
crystals.
Step 2 Synthesis of
1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea
##STR00452##
[0405] To a mixture of (2-fluoro-4-iodophenyl)-urea 78 (21.7 g) and
cyanoacetic acid 73 (7.88 g) in N,N-dimethylformamide (108 ml) was
added, and methanesulfonyl chloride (7.17 ml) was added dropwise
with stirring at room temperature. The mixture was stirred at room
temperature for 2 hrs, and water-isopropyl alcohol [1:2 (volume
ratio), 210 ml] was added dropwise. The mixture was stirred at room
temperature for 1 hr. The precipitated crystals were collected by
filtration and washed with water to give
1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79 (wet crystals),
which was used for the next reaction in the form of wet
crystals.
Step 3 Synthesis of
6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione
##STR00453##
[0407] To a suspension of
1-(2-cyanoacetyl)-3-(2-fluoro-4-iodophenyl)-urea 79 (wet crystals)
in water (110 ml) was added 2N aqueous sodium hydroxide solution
(3.96 ml), and the mixture was stirred with heating at 85.degree.
C. for 1 hr. After allowing to cool to room temperature, 2N
hydrochloric acid (3.96 ml) and isopropyl alcohol (44.0 ml) were
successively added dropwise. The mixture was stirred at room
temperature for 1.5 hrs, the precipitated crystals were collected
by filtration, washed with isopropyl alcohol, and dried to give a
mixture of
6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78
(21.8 g) as colorless crystals, which were used for the next
reaction without purification.
Step 4 Synthesis of
N'-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-
-N,N-dimethylformamidine
##STR00454##
[0409] To a mixture (21.8 g) of
6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78
was added N,N-dimethylformamide (42.0 ml) and
N,N-dimethylformamidedimethylacetal (21.0 ml) and the mixture was
stirred at room temperature for 4.5 hrs. With stirring at room
temperature, isopropyl alcohol (20.0 ml) was added, and water (100
ml) was added dropwise. The mixture was stirred at room temperature
for 45 min, and the precipitated crystals were collected by
filtration, washed with water and dried to give
N'-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-
-N,N-dimethylformamidine 81 (21.7 g, yield 67.7% from 78) as
colorless crystals.
Step 5 Synthesis of
N'-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]-N,N-dimethylformamidine
##STR00455##
[0411] To a solution of
N'-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-
-N,N-dimethylformamidine 81 (20.0 g) in N,N-dimethylformamide (150
ml) was added 1,8-diazabicyclo[5.4.0]undec-7-en (14.9 ml) and
4-methoxybenzyl chloride 82 (10.1 ml) at room temperature. The
mixture was stirred with heating at 75.degree. C. for 2.5 hrs,
1,8-diazabicyclo[5.4.0]undec-7-en (7.50 ml) and 4-methoxybenzyl
chloride (4.00 ml) were added, and the mixture was stirred with
heating at the same temperature for 2.5 hrs. After allowing to cool
to room temperature, isopropyl alcohol (150 ml) and water (300 ml)
were successively added dropwise. The mixture was stirred overnight
at room temperature, and the precipitated crystals were collected
by filtration and dried to give
N'-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]-N,N-dimethylformamidine 83 (20.2 g, yield
77.8%) as yellow crystals.
Step 6 Synthesis of
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-1H-pyrimidine-
-2,4-dione
##STR00456##
[0413] To a suspension of sodium borohydride (326 mg) in
t-butanol/ethanol [2:1 (volume ratio), 18.0 ml] was added
N'-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetra-
hydropyrimidin-4-yl]-N,N-dimethylformamidine 83 (3.00 g) with
stirring at room temperature. The mixture was stirred at room
temperature for 1 hr, and at 65.degree. C. for 2 hrs. With stirring
at the same temperature, water (30.0 ml) and ammonium chloride (461
mg) were successively added, and the mixture was stirred to allow
to cool to room temperature. The reaction solution was extracted
twice with ethyl acetate. The organic layers were combined, washed
successively with saturated aqueous hydrogen carbonate solution and
brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The obtained crude product was purified by column
chromatography to give
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-H-pyrimidine--
2,4-dione 84 (2.57 g, yield 93.1%) as a pale-yellow solid.
Step 7 Synthesis of
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8-
H-pyrido[2,3-d]pyrimidine-2,4,7-trione
##STR00457##
[0415] To a suspension of
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6-methylamino-1H-pyrimidine-
-2,4-dione 84 (13.3 g) in acetic anhydride (13.0 ml) was added
2-methyl-malonic acid 54 (4.90 g), and the mixture was stirred with
heating at 90.degree. C. for 3 hrs and at 100.degree. C. for 1 hr.
After allowing to cool to about 50.degree. C., acetone (13.3 ml)
was added dropwise, and water (75.0 ml) was further added. After
seeding with compound 85, acetone (30.0 ml) was added, and the
mixture was stirred for 1.5 hrs. Water (30.0 ml) as added and the
mixture was stirred for 45 min, and allowed to cool to room
temperature. The precipitated crystals were collected by
filtration, washed with water and dried to give
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8-
H-pyrido[2,3-d]pyrimidine-2,4,7-trione 85 (14.1 g, yield 90.7%) as
pale-ocher crystals.
Step 8 Synthesis of trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester
##STR00458##
[0417] Under argon atmosphere, to a solution of
1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethyl-1H,8-
H-pyrido[2,3-d]pyrimidine-2,4,7-trione 85 (14.1 g) in chloroform
(70.0 ml) was added 2,6-lutidine (3.79 ml) and
trifluoromethanesulfonic anhydride 56 (5.47 ml) under ice-cooling,
and the mixture was stirred under ice-cooling for 1 hr, and at room
temperature for 1.5 hrs. To the reaction mixture was added
saturated aqueous sodium hydrogen carbonate solution and chloroform
to allow partitioning. The organic layer was washed once with
saturated aqueous sodium hydrogen carbonate solution, twice with 1N
hydrochloric acid, once with saturated aqueous sodium chloride
solution, and dried over anhydrous sodium sulfate. After
filtration, the filtrate was concentrated under reduced pressure.
To the obtained crude product was added isopropyl alcohol (35.0
ml), and the mixture was stirred with heating at an outer
temperature of 95.degree. C. for 30 min. After allowing to cool
with stirring to room temperature, isopropyl alcohol (35.0 ml) was
added, and the mixture was stirred for 1 hr. The precipitated
crystals were collected by filtration, washed with isopropyl
alcohol and dried to give trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 86 (14.4 g,
yield 82.8%) as brown crystals.
Step 9 Synthesis of
N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-tr-
ioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetam-
ide
##STR00459##
[0419] To trifluoromethanesulfonic acid
1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1-
,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl ester 86 (1.10 g)
and 3'-aminoacetanilide 57 (285 mg) were added,
N,N-dimethylacetamide (2.20 ml) and 2,6-lutidine (221 .mu.l), and
the mixture was stirred at 130.degree. C. for 2 hrs. After allowing
to return to room temperature, methanol (12.0 ml) was added
dropwise with stirring. The precipitated crystals were collected by
filtration, washed with methanol and dried to give
N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4-
,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-a-
cetamide 87 (1.04 g, yield 94.6%) as colorless crystals.
Step 10 Synthesis of
N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4-
,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-aceta-
mide
##STR00460##
[0421] To a solution (305 mg) of 28% sodium methoxide in methanol
were added tetrahydrofuran (4.00 ml) and
N-{3-[1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-tr-
ioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-ylamino]-phenyl}-acetam-
ide 87 (1.00 g). The wall was washed with tetrahydrofuran (4.00
ml). The mixture was stirred at room temperature for 1.5 hrs., 2N
hydrochloric acid (900 .mu.l) was added, and the mixture was
concentrated under reduced pressure. To the residue was added
isopropyl alcohol, methanol and water, and after refluxing, the
mixture was allowed to cool to room temperature with stirring. The
precipitated crystals were collected by filtration, washed with
methanol, and dried to give
N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4-
,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-aceta-
mide 88 (974 mg, yield 97.2%) as colorless crystals.
Step 11 Synthesis of
N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-te-
trahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
##STR00461##
[0423] To a suspension of
N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4-
,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-aceta-
mide 88 (960 mg) in anisole (10.0 ml) was added aluminum chloride
(1.94 g) with stirring in a water bath. The mixture was stirred at
room temperature for 37 hrs, methanol (12.0 ml) was added dropwise,
and the mixture was concentrated under reduced pressure. The
obtained residue was dissolved in methanol (12.0 ml), and 2N
hydrochloric acid (20.0 ml) was added dropwise with stirring in a
water bath. The mixture was stirred at room temperature for 1 hr,
hexane (10.0 ml) was added, and the mixture was stirred for 1 hr.
The precipitated crystals were collected by filtration, washed with
hexane, water and methanol, and dried to give
N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-te-
trahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (620
mg, yield 78.1%) as colorless crystals.
Step 12 Synthesis of
N-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,-
4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acet-
amide
##STR00462##
[0425] Under argon atmosphere, to a suspension of
N-{3-[5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-te-
trahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide 89 (75.0
mg), 4-benzyloxybutyl alcohol 90 (25.0 .mu.l) and
triphenylphosphine (37.0 mg) in tetrahydrofuran (1.00 ml) was added
diisopropyl azodicarboxylate (28.0 .mu.l) with stirring under ice
cooling. The mixture was stirred at the same temperature for 2 hrs,
and 4-benzyloxybutyl alcohol (13.0 .mu.l), triphenylphosphine (19.0
mg) and diisopropyl azodicarboxylate (14.0 .mu.l) were added. The
mixture was stirred at the same temperature for 1 hr, and water and
ethyl acetate were added to allow partitioning. The organic layer
was washed with saturated aqueous sodium chloride solution, dried
over anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography
(chloroform:ethyl acetate=2:1.fwdarw.1:1) and thin layer
chromatography (hexane:acetone=1:1) for further purification to
give
N-{3-[3-(4-benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,-
4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acet-
amide 91 (74 mg, yield 77%) as a pale-yellow amorphous form.
Step 13 Synthesis of
N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,-
7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetam-
ide
##STR00463##
[0427]
N-{3-[3-(4-Benzyloxybutyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimet-
hyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl-
}-acetamide 91 (74 mg) was stirred under reflux for 5.5 hrs in
trifluoroacetic acid (1.00 ml). The reaction mixture was
concentrated under reduced pressure, and ethyl acetate and
saturated aqueous sodium hydrogen carbonate solution were added to
the residue to allow partitioning. The organic layer was washed
successively with saturated aqueous sodium hydrogen carbonate
solution, water and brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. To the residue was added
diisopropyl ether (1.00 ml), and the mixture was stirred at
60.degree. C. to allow cooling to room temperature with stirring.
The crystals were collected by filtration, washed with diisopropyl
ether, and dried to give compound 93 (26 mg) as colorless crystals.
Compound 93 was stirred in a mixed solution of saturated aqueous
sodium hydrogen carbonate solution (300 .mu.l), methanol (300
.mu.l) and ethyl acetate (300 .mu.l) at room temperature for 1 hr,
and extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. To the residue were added ethyl acetate, hexane
and diethyl ether, and the mixture was stirred at room temperature
for 1 hr. The precipitated crystals were collected by filtration,
washed with hexane and dried to give
N-{3-[5-(2-fluoro-4-iodophenylamino)-3-(4-hydroxybutyl)-6,8-dimethyl-2,4,-
7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetam-
ide 92 (5 mg, yield 8%) as colorless crystals.
Examples 4-2, 4-4-15, 4-17-143 and 4-145-148
[0428] In the same manner as in Examples 4-1, 4-3 and 4-16, the
compounds of Examples 4-2, 4-4-15, 4-17-133 and 4-138-4-140 were
obtained. In addition, in the same manner as in Example 4-144, the
compounds of Examples 4-83-86, Examples 4-134-137, 4-141-143 and
4-145-148 were obtained. The structural formulas thereof are shown
in Table 4-1 to 4-25 with Examples 4-1, 4-3, 4-16 and 4-144.
TABLE-US-00062 TABLE 4-1 Ex. No. structural formula 4-1
##STR00464## 4-2 ##STR00465## 4-3 ##STR00466## 4-4 ##STR00467## 4-5
##STR00468## 4-6 ##STR00469##
TABLE-US-00063 TABLE 4-2 Ex. No. structural formula 4-7
##STR00470## 4-8 ##STR00471## 4-9 ##STR00472## 4-10 ##STR00473##
4-11 ##STR00474## 4-12 ##STR00475##
TABLE-US-00064 TABLE 4-3 Ex. No. structural formula 4-13
##STR00476## 4-14 ##STR00477## 4-15 ##STR00478## 4-16 ##STR00479##
4-17 ##STR00480## 4-18 ##STR00481##
TABLE-US-00065 TABLE 4-4 Ex. No. structural formula 4-19
##STR00482## 4-20 ##STR00483## 4-21 ##STR00484## 4-22 ##STR00485##
4-23 ##STR00486## 4-24 ##STR00487##
TABLE-US-00066 TABLE 4-5 Ex. No. structural formula 4-25
##STR00488## 4-26 ##STR00489## 4-27 ##STR00490## 4-28 ##STR00491##
4-29 ##STR00492## 4-30 ##STR00493##
TABLE-US-00067 TABLE 4-6 Ex. No. structural formula 4-31
##STR00494## 4-32 ##STR00495## 4-33 ##STR00496## 4-34 ##STR00497##
4-35 ##STR00498## 4-36 ##STR00499##
TABLE-US-00068 TABLE 4-7 Ex. No. structural formula 4-37
##STR00500## 4-38 ##STR00501## 4-39 ##STR00502## 4-40 ##STR00503##
4-41 ##STR00504## 4-42 ##STR00505##
TABLE-US-00069 TABLE 4-8 Ex. No. structural formula 4-43
##STR00506## 4-44 ##STR00507## 4-45 ##STR00508## 4-46 ##STR00509##
4-47 ##STR00510## 4-48 ##STR00511##
TABLE-US-00070 TABLE 4-9 Ex. No. structural formula 4-49
##STR00512## 4-50 ##STR00513## 4-51 ##STR00514## 4-52 ##STR00515##
4-53 ##STR00516## 4-54 ##STR00517##
TABLE-US-00071 TABLE 4-10 Ex. No. structural formula 4-55
##STR00518## 4-56 ##STR00519## 4-57 ##STR00520## 4-58 ##STR00521##
4-59 ##STR00522## 4-60 ##STR00523##
TABLE-US-00072 TABLE 4-11 Ex. No. structural formula 4-61
##STR00524## 4-62 ##STR00525## 4-63 ##STR00526## 4-64 ##STR00527##
4-65 ##STR00528## 4-66 ##STR00529##
TABLE-US-00073 TABLE 4-12 Ex. No. structural formula 4-67
##STR00530## 4-68 ##STR00531## 4-69 ##STR00532## 4-70 ##STR00533##
4-71 ##STR00534## 4-72 ##STR00535##
TABLE-US-00074 TABLE 4-13 Ex. No. structural formula 4-73
##STR00536## 4-74 ##STR00537## 4-75 ##STR00538## 4-76 ##STR00539##
4-77 ##STR00540## 4-78 ##STR00541##
TABLE-US-00075 TABLE 4-14 Ex. No. structural formula 4-79
##STR00542## 4-80 ##STR00543## 4-81 ##STR00544## 4-82 ##STR00545##
4-83 ##STR00546## 4-84 ##STR00547##
TABLE-US-00076 TABLE 4-15 Ex. No. structural formula 4-85
##STR00548## 4-86 ##STR00549## 4-87 ##STR00550## 4-88 ##STR00551##
4-89 ##STR00552## 4-90 ##STR00553##
TABLE-US-00077 TABLE 4-16 Ex. No. structural formula 4-91
##STR00554## 4-92 ##STR00555## 4-93 ##STR00556## 4-94 ##STR00557##
4-95 ##STR00558## 4-96 ##STR00559##
TABLE-US-00078 TABLE 4-17 Ex. No. structural formula 4-97
##STR00560## 4-98 ##STR00561## 4-99 ##STR00562## 4-100 ##STR00563##
4-101 ##STR00564## 4-102 ##STR00565##
TABLE-US-00079 TABLE 4-18 Ex. No. structural formula 4-103
##STR00566## 4-104 ##STR00567## 4-105 ##STR00568## 4-106
##STR00569## 4-107 ##STR00570## 4-108 ##STR00571##
TABLE-US-00080 TABLE 4-19 Ex. No. structural formula 4-109
##STR00572## 4-110 ##STR00573## 4-111 ##STR00574## 4-112
##STR00575## 4-113 ##STR00576## 4-114 ##STR00577##
TABLE-US-00081 TABLE 4-20 Ex. No. structural formula 4-115
##STR00578## 4-116 ##STR00579## 4-117 ##STR00580## 4-118
##STR00581## 4-119 ##STR00582## 4-120 ##STR00583##
TABLE-US-00082 TABLE 4-21 Ex. No. structural formula 4-121
##STR00584## 4-122 ##STR00585## 4-123 ##STR00586## 4-124
##STR00587## 4-125 ##STR00588## 4-126 ##STR00589##
TABLE-US-00083 TABLE 4-22 Ex. No. structural formula 4-127
##STR00590## 4-128 ##STR00591## 4-129 ##STR00592## 4-130
##STR00593## 4-131 ##STR00594##
TABLE-US-00084 TABLE 4-23 Ex. No. structural formula 4-132
##STR00595## 4-133 ##STR00596## 4-134 ##STR00597## 4-135
##STR00598## 4-136 ##STR00599## 4-137 ##STR00600##
TABLE-US-00085 TABLE 4-24 Ex. No. structural formula 4-138
##STR00601## 4-139 ##STR00602## 4-140 ##STR00603## 4-141
##STR00604## 4-142 ##STR00605## 4-143 ##STR00606##
TABLE-US-00086 TABLE 4-25 Ex. No. structural formula 4-144
##STR00607## 4-145 ##STR00608## 4-146 ##STR00609## 4-147
##STR00610## 4-148 ##STR00611##
Example 4-149
[0429] By treating
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tr-
ioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
59 by a conventional method, sodium salt, hydrate, acetic acid
solvate, dimethylsulfoxide solvate, ethanol solvate, nitromethane
solvate, chlorobenzene solvate, 1-pentanol solvate, isopropyl
alcohol solvate, ethylene glycol solvate and 3-methylbutanol
solvate thereof were obtained.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
sodium salt
[0430] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.35-0.41 (m,
2H), 0.71-0.77 (m, 2H), 1.16 (s, 3H), 2.02 (s, 3H), 2.18-2.24 (m,
1H), 3.32 (s, 3H), 6.59 (t, J=8.8 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H),
7.04 (d, J=10.2 Hz, 1H), 7.19 (d, J=11.1 Hz, 1H), 7.27 (t, J=8.0
Hz, 1H), 7.34 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 10.00 (s, 1H).
[0431] MS (ESI) m/z 616 [MH].sup.+.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
hydrate
[0432] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.08 (s, 3H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36
(t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz,
1H), 10.09 (s, 1H), 11.08 (s, 1H).
[0433] MS (ESI) m/z 616 [MH].sup.+.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
acetic acid solvate
[0434] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.92-0.98 (m, 2H), 1.25 (s, 3H), 1.91 (s, 3H), 2.04 (s, 3H),
2.59-2.65 (m, 1H), 3.08 (s, 3H), 6.92 (t, J=8.6 Hz, 1H), 7.00-7.05
(m, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.53-7.62 (m, 3H), 7.79 (dd,
J=10.4 Hz, 1H), 10.08 (s, 1H), 11.07 (s, 1H), 11.94 (s, 1H).
[0435] MS (ESI) m/z 616 [MH].sup.+.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
dimethyl sulfoxide solvate
[0436] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.76-0.82 (m, 2H),
1.09-1.15 (m, 2H), 1.41 (s, 3H), 2.14 (s, 3H), 2.62 (s, 6H),
2.71-2.77 (m, 1H), 3.20 (s, 3H), 6.70 (t, J=8.4 Hz, 1H), 7.00 (brs,
1H), 7.32 (brs, 2H), 7.43-7.47 (m, 1H), 7.52 (dd, J=2.0, 9.6 Hz,
1H), 7.71 (brs, 2H), 11.30 (s, 1H).
[0437] MS (ESI) m/z 616 [MH].sup.4.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
ethanol solvate
[0438] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.06 (t, J=7.1 Hz, 3H), 1.25 (s, 3H), 2.04
(s, 3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 3.40-3.49 (m, 2H), 4.33
(t, J 5.1 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36
(t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz,
1H), 10.08 (s, 1H), 11.07 (s, 1H).
[0439] MS (ESI) m/z 616 [MH].sup.+.
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
nitromethane solvate
[0440] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 4.42 (s, 2H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05
(m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd,
J=2.0, 10.4 Hz, 1H), 10.08 (s, 1H), 11.07 (s, 1H).
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
chlorobenzene solvate
[0441] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H),
7.29-7.45 (m, 5H), 7.50-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz,
1H), 10.08 (s, 1H), 11.07 (s, 1H).
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,
6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
1-pentanol solvate
[0442] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.70 (m,
2H), 0.86 (t, J=7.0 Hz, 1.5H), 0.90-0.99 (m, 2H), 1.22-1.30 (m,
5H), 1.35-1.44 (m, 1H), 2.04 (s, 3H), 2.56-2.67 (m, 1H), 3.08 (s,
3H), 3.33-3.41 (m, 1H), 4.30 (t, J=5.1 Hz, 0.5H), 6.91 (t, J=8.5
Hz, 1H), 7.00-7.06 (m, 1H), 7.36 (t, J=8.3 Hz, 1H), 7.52-7.62 (m,
3H), 7.74-7.81 (m, 1H), 10.08 (s, 1H), 11.07 (s, 1H).
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,
3-d]pyrimidin-1-yl]-phenyl}-acetamide isopropyl alcohol solvate
[0443] .sup.1H-NMR (DMSO-d, 400 MHz) .delta. 0.63-0.69 (m, 2H),
0.91-0.98 (m, 2H), 1.04 (d, J=6.0 Hz, 6H), 1.25 (s, 3H), 2.04 (s,
3H), 2.58-2.66 (m, 1H), 3.07 (s, 3H), 3.73-3.81 (m, 1H), 4.34 (d,
J=4.2 Hz, 1H), 6.92 (t, J=8.7 Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t,
J=8.3 Hz, 1H), 7.52-7.62 (m, 3H), 7.79 (dd, J=1.8, 10.2 Hz, 1H),
10.10 (s, 1H), 11.08 (s, 1H).
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
ethylene glycol solvate
[0444] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.24 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 3.36-3.41 (m, 4H), 4.37-4.44 (m, 2H), 6.92 (t,
J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63
(m, 3H), 7.79 (dd, J=2.0, 10.4 Hz, 1H), 10.10 (s, 1H), 11.08 (s,
1H).
N-{3-[3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-tri-
oxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]-phenyl}-acetamide
3-methyl-1-butanol solvate
[0445] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.69 (m,
2H), 0.85 (d, J=6.7 Hz, 6H), 0.92-0.98 (m, 2H), 1.25 (s, 3H), 1.31
(q, J=6.7 Hz, 2H), 1.60-1.70 (m, 1H), 2.04 (s, 3H), 2.59-2.66 (m,
1H), 3.08 (s, 3H), 3.38-3.44 (m, 2H), 4.26 (t, J=5.1 Hz, 1H), 6.92
(t, J=8.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.35 (t, J=8.0 Hz, 1H),
7.52-7.62 (m, 3H), 7.78 (dd, J=1.9, 10.2 Hz, 1H), 10.08 (s, 1H),
11.07 (s, 1H).
Example 4-150
[0446] By treating
N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7--
trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
62 according to a conventional method, acetic acid solvate was
obtained.
N-{3-[3-cyclopropyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-t-
rioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide
acetic acid solvate
[0447] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.60-0.70 (m,
2H), 0.90-1.00 (m, 2H), 1.26 (s, 3H), 1.91 (s, 3H), 2.04 (s, 3H),
2.59-2.66 (m, 1H), 3.10 (s, 3H), 4.29 (s, 1H), 7.01-7.05 (m, 1H),
7.08 (t, J=8.6 Hz, 1H), 7.31 (dd, J=1.6, 8.3 Hz, 1H), 7.36 (t,
J=8.1 Hz, 1H), 7.52 (dd, J=1.6, 11.3 Hz, 1H), 7.57-7.62 (m, 2H),
10.09 (s, 1H), 11.09 (s, 1H), 11.94 (s, 1H).
[0448] MS (ESI) m/z 514 [MH].sup.+.
Example 4-151
[0449] By treating
N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-
-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide
72 according to a conventional method, a sodium salt was
obtained.
N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7--
tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide
sodium salt
[0450] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.25 (s, 3H),
2.78 (s, 3H), 2.97 (s, 3H), 3.24 (s, 3H), 6.68 (t, J=8.7 Hz, 1H),
6.77 (d, J=7.5 Hz, 1H), 6.90-7.00 (m, 2H), 7.10-7.30 (m, 2H), 7.37
(d, J=10.0 Hz, 1H), 10.30 (brs, 1H).
[0451] MS (ESI) m/z 626 [MH]+.
Example 1001-6010
[0452] The compounds shown in Tables 11-1 to 11-6 can be obtained
in the same manner as in Examples 1-1 to 1-148 or by other
conventional method employed as necessary.
TABLE-US-00087 TABLE 11-1 ##STR00612## ##STR00613## Example No.
R.sup.1 Example No. R.sup.1 1001 2-F--Ph-- 1002 2-F--Ph-- 1003
3-F--Ph-- 1004 3-F--Ph-- 1005 4-F--Ph-- 1006 4-F--Ph-- 1007
2-Me--Ph-- 1008 2-Me--Ph-- 1009 3-Me--Ph-- 1010 3-Me--Ph-- 1011
4-Me--Ph-- 1012 4-Me--Ph-- 1013 2-MeO--Ph-- 1014 2-MeO--Ph-- 1015
3-MeO--Ph-- 1016 3-MeO--Ph-- 1017 4-MeO--Ph-- 1018 4-MeO--Ph-- 1019
2-Py-- 1020 2-Py-- 1021 3-Py-- 1022 3-Py-- 1023 4-Py-- 1024 4-Py--
1025 2-MeS(CH2)2-- 1026 2-MeS(CH2)2-- 1027 2-HS(CH2)2-- 1028
2-HS(CH2)2-- 1029 4-(Me)2N--Bzl-- 1030 4-(Me)2N--Bzl-- 1031
3-(Me)2N--Bzl-- 1032 3-(Me)2N--Bzl-- 1033 2-(Me)2N--Bzl-- 1034
2-(Me)2N--Bzl-- 1035 4-(Me)2N-Phenethyl- 1036 4-(Me)2N-Phenethyl-
1037 4-HO--Phenethyl- 1038 4-HO--Phenethyl- 1039 4-HO--Bzl-- 1040
4-HO--Bzl-- 1041 3-HO--Bzl-- 1042 3-HO--Bzl-- 1043 2-HO--Bzl-- 1044
2-HO--Bzl-- 1045 4-MeO--Bzl-- 1046 4-MeO--Bzl-- 1047 4-Py--(CH2)2--
1048 4-Py--(CH2)2-- 1049 3-Py--(CH2)2-- 1050 3-Py--(CH2)2-- 1051
2-Py--(CH2)2-- 1052 2-Py--(CH2)2-- 1053 ##STR00614## 1054
##STR00615## 1055 ##STR00616## 1056 ##STR00617## 1057 Allyl- 1058
Allyl- 1059 CF3CH2-- 1060 CF3CH2-- 1061 n-Propyl- 1062 n-Propyl-
1063 Cyclopropylmethyl- 1064 Cyclopropylmethyl- 1065 HO-- 1066 HO--
1067 HO--(CH2)2--O-- 1068 HO--(CH2)2--O-- 1069 HO--(CH2)3--O-- 1070
HO--(CH2)3--O-- 1071 ##STR00618## 1072 ##STR00619## 1073
##STR00620## 1074 ##STR00621## 1075 ##STR00622## 1076 ##STR00623##
1077 ##STR00624## 1078 ##STR00625## 1079 ##STR00626## 1080
##STR00627## 1081 ##STR00628## 1082 ##STR00629## 1083 ##STR00630##
1084 ##STR00631## Py: Pyridyl, Ph: Phenyl Bzl: Benzyl
TABLE-US-00088 TABLE 11-2 ##STR00632## Example No. R1 2001
##STR00633## 2002 ##STR00634## 2003 ##STR00635## 2004 ##STR00636##
2005 ##STR00637## 2006 ##STR00638## 2007 ##STR00639## 2008
##STR00640## 2009 ##STR00641## 2010 ##STR00642## 2011 ##STR00643##
2012 ##STR00644## 2013 ##STR00645## 2014 ##STR00646## 2015
##STR00647## 2016 ##STR00648## 2017 ##STR00649## 2018 ##STR00650##
2019 ##STR00651## 2020 ##STR00652##
TABLE-US-00089 TABLE 11-3 ##STR00653## Example No. R.sup.3 R.sup.4
R.sup.5 3001 Allyl- Me-- H 3002 n-Propyl- Me-- H 3003 CF3CH2-- Me--
H 3004 MeO(CH2)2-- Me-- H 3005 (Me)2N--(CH2)2-- Me-- H 3006 Ph--
Me-- H 3007 3-Py Me-- H 3008 Me-- Allyl- H 3009 Me-- MeO-- H 3010
Me-- Cyclopropyl H 3011 Me-- Me-- HO-- 3012 Me-- Me-- MeO--
TABLE-US-00090 TABLE 11-4 ##STR00654## Example No. R.sup.3 R.sup.4
R.sup.5 4001 Allyl- Me-- H 4002 n-Propyl- Me-- H 4003 CF3CH2-- Me--
H 4004 MeO(CH2)2-- Me-- H 4005 (Me)2N--(CH2)2-- Me-- H 4006 Ph--
Me-- H 4007 3-Py Me-- H 4008 Me-- Allyl- H 4009 Me-- MeO-- H 4010
Me-- Cyclopropyl H 4011 Me-- Me-- HO-- 4012 Me-- Me-- MeO--
TABLE-US-00091 TABLE 11-5 ##STR00655## Example No. R.sup.6 5001
##STR00656## 5002 ##STR00657## 5003 ##STR00658## 5004 ##STR00659##
5005 ##STR00660## 5006 ##STR00661## 5007 ##STR00662## 5008
##STR00663## 5009 ##STR00664## 5010 ##STR00665##
TABLE-US-00092 TABLE 11-6 ##STR00666## Example No. R.sup.6 6001
##STR00667## 6002 ##STR00668## 6003 ##STR00669## 6004 ##STR00670##
6005 ##STR00671## 6006 ##STR00672## 6007 ##STR00673## 6008
##STR00674## 6009 ##STR00675## 6010 ##STR00676##
Example 5
Evaluation of Growth Inhibitory Effect Against Cancer Cell
Lines
[0453] Renal cancer cell line ACHN cell or colorectal cancer cell
line HT-29 cells were cultured in a 96 well plate at
1.0.times.10.sup.4 cells/90 .mu.L/well for 24 hrs, then a test
substance dissolved in DMSO (dimethyl sulfoxide) was added. After
18 hrs, 3H-thymidine (0.25 .mu.Ci/well) was added and the cells
were cultured for 6 hrs. Using a cell harvester, the cells were
recovered on a UniFilter-96 GF/B glass filter and the .sup.3H
radioactivity uptaken by the cells was measured by TopCount
(Packard). As a control, DMSO was used and the activity of the test
substance was expressed in the concentration (IC.sub.50) necessary
for inhibiting .sup.3H radioactivity uptaken by the cell to 50% of
that of the control group. The measurements were made in
triplicate.
[0454] The results are shown in Tables 5-1 to 5-8 according to the
following.
A: not less than 0.1 .mu.M and less than 1 .mu.M B: not less than
0.01 .mu.M and less than 0.1 .mu.M C: less than 0.01 .mu.M
TABLE-US-00093 TABLE 5-1 IC.sub.50 Example ACHN HT-29 No. cell cell
1-1 B C 1-2 A 1-7 A 1-11 A 1-55 A 1-88 A A 1-89 A B 1-95 A 1-96 A
1-97 A 1-99 A 1-100 A 1-106 A A 1-111 A 1-112 A B 1-113 A A 1-114 A
A 1-116 A 1-117 A 1-126 A 1-127 A 1-129 A 1-132 A 1-133 A 1-136 A
1-138 A 1-140 A 1-142 A 1-143 A 1-151 A 1-152 A B 1-153 A 1-156 A
1-159 A 1-163 A 1-164 B
TABLE-US-00094 TABLE 5-2 IC.sub.50 Example ACHN HT-29 No. cell cell
1-165 A 1-166 B 1-168 B 1-171 B 1-175 A 1-176 A B 1-183 A 1-185 A B
1-186 B 1-188 A B 1-189 A 1-190 A 1-191 A B 1-192 A B 1-193 A C
1-199 A B 1-200 A B 1-201 A 1-205 A C 1-206 A 1-207 B C 1-208 B C
1-211 A 1-212 A C 1-213 A B 1-214 B 1-215 A 1-216 A 1-217 A 1-218 B
1-219 A B 1-221 B C 1-222 A B 1-223 A B 1-224 A C 1-225 A
TABLE-US-00095 TABLE 5-3 IC.sub.50 Example ACHN HT-29 No. cell cell
1-226 A B 1-227 B 1-228 A B 1-229 A 1-230 A 1-232 A B 1-233 A 1-234
A 1-235 A 1-236 A 1-240 B B 1-242 A B 1-243 A B 1-244 A 1-245 B C
1-246 A B 1-249 A B 1-252 B 1-253 A B 1-255 A 1-257 C C 1-258 A
1-259 A C 1-260 C C 1-262 B C 1-263 A C 1-264 A B 1-265 A B 1-266 A
C 1-267 A B 1-268 B B 1-270 A B 1-271 B C 1-272 B B 1-273 A 3-1 A
A
TABLE-US-00096 TABLE 5-4 IC.sub.50 Example ACHN HT-29 No. cell cell
1-274 C C 1-275 B C 1-276 A B 1-277 B 1-278 A B 1-279 A B 1-282 A B
1-283 A B 1-284 A B 1-285 B B 1-286 B C 1-287 A B 1-288 B 1-289 C C
1-290 B C 1-292 B 1-293 A A 1-294 B 1-295 A B 1-296 A C 1-297 B C
1-298 B C 1-299 A B 1-301 A B 1-302 B C 1-303 A B 1-304 A B 1-305 B
1-307 A B 1-308 A B 1-309 B C 1-310 B C 1-311 C C 1-313 B 1-313 B
1-315 A B
TABLE-US-00097 TABLE 5-5 IC.sub.50 Example ACHN HT-29 No. cell cell
1-316 A B 1-317 A B 1-318 A C 1-319 C C 1-320 B C 1-321 B C 1-322 B
C 1-324 B 1-325 A B 1-326 A 1-327 A B 1-328 A B 1-333 B C 1-334 A
1-335 A B 1-336 B C 1-337 B C 1-338 B C 1-339 A 1-340 B C 1-341 B C
1-342 A C 1-343 A B 3-4 B C 3-5 B C 3-6 A C 3-7 C C 3-8 B C 4-1 C C
4-2 C C 4-3 B C 4-4 A 4-5 A B 4-6 B C 4-7 A 4-9 B C
TABLE-US-00098 TABLE 5-6 IC.sub.50 Example ACHN HT-29 No. cell cell
4-10 A B 4-11 B C 4-12 B C 4-13 A 4-15 B C 4-16 C C 4-19 B C 4-20 B
C 4-21 B C 4-25 B C 4-26 B C 4-27 A 4-33 C C 4-34 C C 4-37 A B 4-39
A 4-40 B C 4-41 B B 4-42 B C 4-43 A B 4-44 A B 4-45 A B 4-46 A B
4-47 A 4-48 B C 4-49 B C 4-50 A B 4-51 B C 4-52 A A 4-53 A B 4-54 C
C 4-55 B C 4-56 A B 4-57 A 4-58 B C 4-59 B C
TABLE-US-00099 TABLE 5-7 IC.sub.50 Example ACHN HT-29 No. cell cell
4-60 B C 4-61 B B 4-63 B 4-64 A B 4-66 A B 4-67 B C 4-70 B C 4-71 A
B 4-72 B C 4-73 B C 4-74 B C 4-75 B 4-76 B C 4-77 B C 4-78 A B 4-80
B C 4-81 B C 4-82 B C 4-85 A 4-87 A B 4-88 C C 4-89 A B 4-90 A B
4-91 B C 4-92 B C 4-93 B C 4-94 A B 4-95 A B 4-96 A B 4-97 B C 4-98
B C 4-99 A C 4-101 B C 4-102 A B 4-103 A C 4-104 C C
TABLE-US-00100 TABLE 5-8 IC.sub.50 Example ACHN HT-29 No. cell cell
4-105 B C 4-106 B C 4-107 B C 4-108 B C 4-109 B C 4-110 B C 4-111 A
B 4-112 A C 4-113 C C 4-114 B C 4-115 B C 4-116 A C 4-117 A C 4-118
B C 4-119 B C 4-120 B C 4-121 B C 4-122 B C 4-123 A C 4-124 B C
4-125 C C 4-126 C C 4-127 B C 4-128 B C 4-133 A 4-135 A 4-138 A
4-140 A 4-145 A 4-146 A 4-147 A 4-148 A
Example 6
Evaluation of p15 Induction Activity
[0455] ACHN cells or HT-29 cells were cultured in a 6 well plate at
2.5.times.10.sup.5 cells/1.8 mL/well for 24 hrs, then a test
substance (0.1 kM) dissolved in DMSO was added. After 24 hrs, cells
were detached using trypsin-EDTA (ethylene diamine tetraacetic
acid) and solubilized with NuPAGE LDS sample buffer (Invitrogen).
Using an RC DC protein assay kit (BIO-RAD), the protein
concentration of the sample was quantitated, and a sample in an
amount corresponding to 10 .mu.g of BSA (bovine serum albumin) was
analyzed by Western blotting using an anti-p15 antibody. The
density of the band stained with the anti-p15 antibody was measured
by a densitometer to quantify the amount of p15 protein. As a
control, DMSO was used and the test was performed with n=2 and the
average protein amount was determined.
[0456] The results are shown in Tables 6-1 to 6-6 according to the
following.
+: As compared to DMSO, not less than 1.5-fold induction of p15
protein
TABLE-US-00101 TABLE 6-1 Example Induction of No. p15 protein 1-1 +
1-4 + 1-6 + 1-7 + 1-8 + 1-9 + 1-11 + 1-12 + 1-16 + 1-17 + 1-26 +
1-33 + 1-34 + 1-35 + 1-36 + 1-37 + 1-38 + 1-40 + 1-43 + 1-46 + 1-49
+ 1-51 + 1-53 + 1-55 + 1-65 + 1-77 + 1-78 + 1-79 + 1-80 + 1-81 +
1-84 + 1-85 + 1-86 + 1-88 + 1-89 + 1-92 +
TABLE-US-00102 TABLE 6-2 Example Induction of No. p15 protein 1-93
+ 1-94 + 1-95 + 1-96 + 1-97 + 1-99 + 1-100 + 1-102 + 1-103 + 1-104
+ 1-106 + 1-107 + 1-108 + 1-109 + 1-110 + 1-111 + 1-112 + 1-113 +
1-114 + 1-116 + 1-117 + 1-126 + 1-127 + 1-131 + 1-132 + 1-133 +
1-136 + 1-137 + 1-138 + 1-142 + 1-143 + 1-146 + 1-151 + 1-152 +
1-153 + 1-154 +
TABLE-US-00103 TABLE 6-3 Example Induction of No. p15 protein 1-156
+ 1-157 + 1-162 + 1-163 + 1-165 + 1-166 + 1-167 + 1-168 + 1-172 +
1-173 + 1-175 + 1-176 + 1-183 + 1-185 + 1-186 + 1-188 + 1-191 +
1-192 + 1-193 + 1-199 + 1-200 + 1-205 + 1-207 + 1-208 + 1-212 +
1-213 + 1-218 + 1-219 + 1-221 + 1-222 + 1-223 + 1-224 + 1-226 +
1-240 + 1-242 + 1-243 + 1-245 + 1-246 +
TABLE-US-00104 TABLE 6-4 Example Induction of No. p15 protein 1-264
+ 1-265 + 1-266 + 1-268 + 1-271 + 1-272 + 1-282 + 1-283 + 1-284 +
1-285 + 1-286 + 1-287 + 1-289 + 1-290 + 1-293 + 1-295 + 1-296 +
1-297 + 1-298 + 1-301 + 1-317 + 1-318 + 1-319 + 1-320 + 1-321 +
1-322 + 1-325 + 1-327 + 1-328 + 1-333 + 1-336 + 1-337 + 1-338 +
1-340 + 1-341 + 1-342 + 3-4 + 3-6 +
TABLE-US-00105 TABLE 6-5 Example Induction of No. p15 protein 3-7 +
3-8 + 4-1 + 4-2 + 4-3 + 4-6 + 4-9 + 4-10 + 4-11 + 4-12 + 4-15 +
4-16 + 4-21 + 4-43 + 4-45 + 4-48 + 4-49 + 4-50 + 4-51 + 4-53 + 4-54
+ 4-55 + 4-56 + 4-58 + 4-59 + 4-60 + 4-61 + 4-64 + 4-66 + 4-67 +
4-70 + 4-71 + 4-72 + 4-73 + 4-74 + 4-76 + 4-77 + 4-78 +
TABLE-US-00106 TABLE 6-6 Example Induction of No. p15 protein 4-80
+ 4-81 + 4-82 + 4-88 + 4-89 + 4-90 + 4-91 + 4-92 + 4-93 + 4-97 +
4-98 + 4-101 + 4-102 + 4-103 + 4-104 + 4-105 + 4-106 + 4-107 +
4-108 + 4-109 + 4-110 + 4-111 + 4-112 + 4-113 + 4-114 + 4-115 +
4-116 + 4-117 + 4-118 + 4-119 + 4-120 + 4-121 + 4-122 + 4-123 +
4-124 + 4-125 + 4-126 + 4-127 + 4-128 +
Example 7
Cell Cycle Analysis
[0457] ACHN cells or HT-29 cells were cultured in a 6 well plate at
2.5.times.10.sup.5 cells/1.8 mL/well for 24 hrs, then a test
substance (less than 10 DM) dissolved in DMSO was added. After 24
hrs, cells were detached using trypsin-EDTA and the DNA content of
single cell was analyzed by flow cytometry method using a CycleTEST
PLUS (BECKTON DICKINSON) kit, and the proportion of the cells in
the G0/G1 phaseS phaseG2/M phase was calculated. As a control, DMSO
was used and the test was performed with n=2.
[0458] The results are shown in Tables 7-1 and 7-2 according to the
following.
G1: the ratio of the cells in the G0/G1 phase was not less than
1.2-fold as compared to that of DMSO.
TABLE-US-00107 TABLE 7-1 Example CELL RATIO OF No. G0/G1 PHASE 1-2
G1 1-4 G1 1-6 G1 1-7 G1 1-9 G1 1-11 G1 1-21 G1 1-25 G1 1-26 G1 1-33
G1 1-34 G1 1-38 G1 1-43 G1 1-49 G1 1-50 G1 1-51 G1 1-55 G1 1-69 G1
1-77 G1 1-78 G1 1-84 G1 1-85 G1 1-86 G1 1-88 G1 1-89 G1 1-90 G1
1-91 G1 1-92 G1 1-93 G1 1-94 G1 1-95 G1 1-97 G1 1-99 G1 1-100 G1
1-101 G1 1-102 G1 1-103 G1 1-104 G1
TABLE-US-00108 TABLE 7-2 Example CELL RATIO OF No. G0/G1 PHASE 3-7
G1 4-1 G1 4-3 G1 4-16 G1 4-70 G1 4-82 G1 4-104 G1 4-126 G1
Example 8
Evaluation on the Nude-Mouse Xenograft Model
[0459] HT-29 cells (5.0.times.10.sup.6 cells/100 .mu.L/head,
suspended in HBSS (Hanks' solution)) in the logarithmic growth
phase were implanted in a mouse (Balb/c-nu/nu) at the right lateral
abdomen under ether anesthesia. After 5 days of implantation, the
long diameter and short diameter of the tumor were measured, and
the mice were divided into groups such that each group has an
equivalent average tumor volume. For grouping, a grouping soft
(general grouping system (Visions) was used. From the next day of
the grouping, a test substance suspended in 0.5% MC (methyl
cellulose) was repeatedly orally administered twice a day for 10
days (30 mg/kg). The tumor volume was measured twice a week and
used as an index of antitumor activity. As a control, 0.5% MC was
used and the test was performed with n=6-8.
[0460] The index (T/C (%)) of the antitumor activity was calculated
according to the following formula.
T/C (%)=(The average tumor volume of the group treated with a test
substance)/(The average tumor volume of the Vehicle
group).times.100
The tumor volume was calculated according to the following
formula.
Tumor volume (mm.sup.3)=L.times.W.times.W/2 (L: long diameter (mm)
of tumor, W: short diameter (mm) of tumor)
TABLE-US-00109 TABLE 8 Example T/C No. (%) 1-257 26 3-8 27 4-1 3
4-15 31 4-16 10 4-49 35 4-54 11 4-70 31
Example 9
p27 Protein Induction Test
[0461] ACHN cells or HT-29 cells were cultured in a 6 well plate at
2.5.times.10.sup.5 cells/1.8 mL/well for 24 hrs, a test substance
(0.1 .mu.M) dissolved in DMSO was added. After 24 hrs, cells were
detached using trypsin-EDTA (ethylene diamine tetraacetic acid) and
solubilized with NuPAGE LDS sample buffer (Invitrogen). Using an RC
DC protein assay kit (BIO-RAD), the protein concentration of the
sample was quantitated, and a sample in an amount corresponding to
10 g of BSA (bovine serum albumin) was analyzed by Western blotting
using an anti-p27 antibody. The density of the band stained with
the anti-p27 antibody was measured by a densitometer to quantify
the amount of p27 protein. As a control, DMSO was used and the test
was performed with n=2 and the average protein amount was
determined.
[0462] The results are shown in Tables 9-1 to 9-4 according to the
following.
+: As compared to DMSO, not less than 1.5-fold induction of p27
protein
TABLE-US-00110 TABLE 9-1 Example Induction of No. p27 protein 1-1 +
1-89 + 1-112 + 1-114 + 1-142 + 1-152 + 1-175 + 1-182 + 1-185 +
1-186 + 1-218 + 1-219 + 1-221 + 1-222 + 1-224 + 1-226 + 1-228 +
1-240 + 1-242 + 1-243 + 1-245 + 1-249 + 1-253 + 1-257 + 1-259 +
1-260 + 1-262 + 1-263 + 1-264 + 1-265 + 1-266 + 1-268 + 1-271 +
1-272 + 1-274 + 1-275 + 1-279 + 1-282 +
TABLE-US-00111 TABLE 9-2 Example Induction of No. p27 protein 1-283
+ 1-284 + 1-285 + 1-286 + 1-287 + 1-289 + 1-290 + 1-293 + 1-295 +
1-296 + 1-297 + 1-298 + 1-299 + 1-301 + 1-302 + 1-303 + 1-307 +
1-309 + 1-310 + 1-311 + 1-315 + 1-316 + 1-317 + 1-318 + 1-319 +
1-320 + 1-322 + 1-325 + 1-327 + 1-328 + 1-336 + 1-337 + 1-338 +
1-340 + 1-341 + 1-342 + 3-4 + 3-5 +
TABLE-US-00112 TABLE 9-3 Example Induction of No. p27 protein 3-6 +
3-7 + 3-8 + 4-1 + 4-2 + 4-3 + 4-6 + 4-9 + 4-10 + 4-11 + 4-12 + 4-15
+ 4-16 + 4-21 + 4-43 + 4-45 + 4-48 + 4-49 + 4-50 + 4-51 + 4-53 +
4-54 + 4-55 + 4-56 + 4-58 + 4-59 + 4-60 + 4-61 + 4-64 + 4-66 + 4-67
+ 4-70 + 4-71 + 4-72 + 4-73 + 4-74 + 4-76 + 4-77 +
TABLE-US-00113 TABLE 9-4 Example Induction of No. p27 protein 4-78
+ 4-80 + 4-81 + 4-82 + 4-88 + 4-89 + 4-90 + 4-91 + 4-92 + 4-93 +
4-97 + 4-98 + 4-99 + 4-101 + 4-102 + 4-103 + 4-104 + 4-105 + 4-106
+ 4-107 + 4-108 + 4-109 + 4-110 + 4-113 + 4-114 + 4-115 + 4-116 +
4-117 + 4-118 + 4-119 + 4-120 + 4-121 + 4-122 + 4-123 + 4-124 +
4-125 + 4-126 + 4-127 + 4-128 +
Example 10
Evaluation of MEK Enzyme Inhibitory Activity
[0463] To an evaluation system where Raf (B-Raf or c-Raf) and MEK
(MEK1 or MEK2) were mixed, or MEK (MEK1 or MEK2) and ERK2 were
mixed was added a test substance dissolved in DMSO, and an ATP
solution containing [.gamma.-32P]-ATP was added to start the enzyme
reaction. After reacting at 30.degree. C. for 20 min, the reaction
mixture was subjected to SDS-PAGE (sodium
dodecylsulfate-polyacrylamide gel electrophoresis) and
radioactivity of phosphorylated MEK or ERK2 was measured by Bio
Imaging Analyzer (BAS2000, Fuji photo film).
[0464] With the radioactivity of the solvent added control as 100%,
inhibitory rate (%) by the test substance was determined, and
IC.sub.50 value was calculated.
[0465] The test was performed with n=1 and the average values of
two or three times of testing are shown. The results are summarized
in Table 10.
TABLE-US-00114 TABLE 10 IC.sub.50 of various enzyme reaction system
(.mu.M) enzyme Example 1-257 Example 4-1 B-Raf 0.0060 0.0067 MEK1
B-Raf 0.0188 0.0128 MEK2 c-Raf -- -- MEK1 c-Raf 0.0078 0.0130 MEK2
MEK1 1.3 0.290 ERK2 MEK2 1.6 0.190 ERK2
Example 11
Evaluation on the Mouse Collagen Arthritis Model
[0466] Bovine type II collagen (100 .mu.g) was resuspended with
Freund's complete adjuvant and intracutaneously administered
(initial immunization) to the tail head of mouse (DBA/1). Three
weeks later, the same collagen was given to the tail head as boost,
whereby multiple arthritis was induced. The test substance was oral
administered forcibly once a day for 38 days from immediately
before the initial immunization, and arthritis score after boost
was calculated twice a week to examine the arthritis onset
suppressing effect. For arthritis scores, the level of swelling of
each of the four limbs of the mice was scored in 4 levels, and the
average of the scores of four limbs was taken as the arthritis
score of each individual. The test was performed with n=16.
[0467] The arthritis score at 17 days after boost (after
consecutive administration for 38 days) was 2.2 for the medium
administration group, and 0.57 (p<0.001, wilcoxson test) for the
1 mg/kg acetic acid solvate of compound of Example 4-1
administration group, thus showing a significant suppressive effect
on the arthritis onset.
Example 12
Evaluation on Inflammatory Cytokine Production
[0468] The compounds of Example 4-1 and Example 4-16 suppressed
production of TNF-.alpha. or IL-6 upon stimulation of human 20
peripheral blood-derived nomonuclear cell (PBMC) with LPS. The MS
and NMR data of the Example compounds shown in the above-mentioned
Table 1-1 to Table 4-25 are shown below.
Example 1-1
[0469] MS ESI m/e: 590, 592 (M+H), 588, 590 (M-H).
[0470] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.64-2.70 (m, 4H), 3.02 (s, 3H), 5.36 (s,
1H), 7.13 (d, J=9.0 Hz, 1H), 7.24-7.30 (m, 2H), 7.43-7.54 (m, 3H),
7.74 (d, J=9.0 Hz, 1H), 10.00 (brs, 1H), 10.53 (brs, 1H).
Example 1-2
Example 1-3
Example 1-4
[0471] MS ESI m/e: 470, 471 (M+H), 473, 474, 469 (M-H), 470,
471.
[0472] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.68 (s, 3H),
5.47 (s, 1H), 7.24-7.63 (m, 14H), 10.63 (brs, 1H).
Example 1-5
[0473] MS ESI m/e: 470, 471 (M+H), 473, 474, 469 (M-H), 470,
471.
[0474] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.68 (s, 3H),
5.60 (s, 1H), 7.25-7.57 (m, 14H), 10.52 (brs, 1H).
Example 1-6
[0475] MS ESI m/e: 451 (M+H), 449 (M-H).
[0476] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.34 (s, 3H), 2.88
(s, 3H), 5.79 (s, 1H), 7.08-7.18 (m, 4H), 7.27-7.32 (m, 2H),
7.37-7.54 (m, 8H), 10.24 (s, 1H).
Example 1-7
[0477] MS ESI m/e: 480 (M+H).
[0478] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.87 (s, 3H), 2.95
(s, 6H), 5.66 (s, 1H), 6.67-6.73 (m, 2H), 7.05-7.11 (m, 2H),
7.27-7.32 (m, 2H), 7.37-7.55 (m, 8H), 10.24 (s, 1H).
Example 1-8
[0479] MS ESI m/e: 455 (M+H), 453 (M-H).
[0480] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.88 (s, 3H), 5.69
(s, 1H), 7.03-7.10 (m, 2H), 7.17-7.23 (m, 2H), 7.27-7.32 (m, 2H),
7.37-7.55 (m, 8H), 10.24 (s, 1H).
Example 1-9
[0481] MS ESI m/e: 467 (M+H), 465 (M-H).
[0482] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.88 (s, 3H), 3.81
(s, 3H), 5.67 (s, 1H), 6.86-6.95 (m, 2H), 7.12-7.20 (m, 2H),
7.28-7.34 (m, 2H), 7.37-7.58 (m, 8H), 10.14 (s, 1H).
Example 1-10
[0483] MS ESI m/e: 485 (M+H), 483 (M-H).
[0484] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.86 (s, 3H), 4.32
(d, J=4.0 Hz, 2H), 5.39 (s, 1H), 7.23-7.31 (m, 6H), 7.34-7.38 (m,
2H), 7.39-7.52 (m, 6H), 9.03 (t, J=6.0 Hz, 1H).
Example 1-11
[0485] MS ESI m/e: 515, 517 (M+H), 513, 515 (M-H).
[0486] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.67 (s, 3H),
5.56 (s, 1H), 7.25-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.41-7.55 (m,
8H), 7.57-7.61 (m, 2H), 10.48 (s, 1H).
Example 1-12
Example 1-13
Example 1-14
[0487] MS ESI m/e: 485 (M+H).
[0488] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.74 (s, 3H),
3.22 (s, 3H), 6.03 (s, 1H), 6.99-7.05 (m, 4H), 7.21-7.25 (m, 2H),
7.32-7.40 (m, 3H), 7.44-7.54 (m, 5H).
Example 1-15
[0489] MS ESI m/e: 443 (M+H).
[0490] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.17-1.95 (m,
11H), 2.63 (s, 3H), 5.28 (s, 1H), 7.31-7.55 (m, 10H), 8.76 (d,
J=6.0 Hz, 1H).
Example 1-16
[0491] MS ESI m/e: 481 (M+H), 479 (M-H).
[0492] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.88 (s, 3H), 5.69
(s, 1H), 5.99 (s, 2H), 6.85-6.82 (m, 3H), 7.28-7.34 (m, 2H),
7.37-7.58 (m, 8H), 10.12 (s, 1H).
Example 1-17
[0493] MS ESI m/e: 505, 507 (M+H), 503, 505 (M-H).
[0494] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.90 (s, 3H), 5.87
(s, 1H), 7.07-7.11 (m, 1H), 7.26-7.31 (m, 2H), 7.35-7.56 (m, 10H),
10.45 (s, 1H).
Example 1-18
[0495] MS ESI m/e: 499 (M+H), 497 (M-H).
[0496] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (t, J=7.5
Hz, 3H), 1.05-1.12 (m, 2H), 3.30-3.40 (m, 2H), 5.54 (s, 1H),
7.31-7.56 (m, 14H), 10.52 (s, 1H).
Example 1-19
[0497] MS ESI m/e: 513 (M+H), 511 (M-H).
[0498] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62 (s, 3H),
0.64 (s, 3H), 1.04 (d, J=6.0 Hz, 1H), 1.94-2.06 (m, 1H), 3.13 (brs,
1H), 5.56 (s, 1H), 7.32-7.60 (m, 14H), 10.58 (s, 1H).
Example 1-20
[0499] MS ESI m/e: 515 (M+H), 513 (M-H).
[0500] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.04 (t, J=6.0
Hz, 2H), 3.09 (s, 3H), 3.61 (t, J=4.5 Hz, 2H), 5.53 (s, 1H),
7.32-7.60 (m, 14H), 10.52 (s, 1H).
Example 1-21
[0501] MS ESI m/e: 465 (M+H), 463 (M-H).
[0502] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.19 (t, J=8.0
Hz, 3H), 2.61 (q, J=8.0 Hz, 2H), 2.66 (s, 3H), 5.46 (s, 1H),
7.17-7.21 (m, 2H), 7.25-7.29 (m, 2H), 7.34-7.38 (m, 2H), 7.41-7.55
(m, 8H), 10.37 (s, 1H).
Example 1-22
[0503] MS ESI m/e: 451 (M+H), 449 (M-H).
[0504] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.21 (s, 3H),
2.66 (s, 3H), 5.12 (s, 1H), 7.18-7.55 (m, 14H), 10.22 (s, 1H).
Example 1-23
[0505] MS ESI m/e: 513 (M+H), 511 (M-H).
[0506] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.68 (s, 3H),
5.65 (s, 1H), 7.33-7.56 (m, 15H), 7.66-7.74 (m, 4H), 10.56 (s,
1H).
Example 1-24
[0507] MS ESI m/e: 467 (M+H), 465 (M-H).
[0508] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.89 (s, 3H), 3.82
(s, 3H), 5.83 (s, 1H), 6.91-6.98 (m, 2H), 7.13-7.19 (m, 1H),
7.27-7.33 (m, 2H), 7.37-7.54 (m, 9H), 10.21 (s, 1H).
Example 1-25
[0509] MS ESI m/e: 479 (M+H), 477 (M-H).
[0510] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.25 (d, J=6.7 Hz,
6H), 2.85-2.95 (m, 1H), 2.88 (s, 3H), 5.80 (s, 1H), 7.12-7.17 (m,
2H), 7.19-7.24 (m, 2H), 7.27-7.32 (m, 2H), 7.37-7.55 (m, 8H), 10.24
(s, 1H).
Example 1-26
[0511] MS ESI m/e: 505, 507 (M+H), 503, 505 (M-H).
[0512] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.89 (s, 3H), 5.70
(s, 1H), 7.22-7.32 (m, 3H), 7.37-7.55 (m, 10H), 10.39 (s, 1H).
Example 1-27
[0513] MS ESI m/e: 520 (M+H).
[0514] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.54-1.62 (m, 4H),
1.67-1.75 (m, 4H), 2.87 (s, 3H), 3.14 (t, J=5.6 Hz, 2H), 5.70 (s,
1H), 6.87-6.93 (m, 2H), 7.06-7.11 (m, 2H), 7.27-7.32 (m, 2H),
7.37-7.54 (m, 8H), 10.09 (s, 1H).
Example 1-28
[0515] MS ESI m/e: 508 (M+H), 506 (M-H).
[0516] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.16 (t, J=7.1 Hz,
6H), 2.87 (s, 3H), 3.34 (q, J=7.1 Hz, 4H), 5.65 (s, 1H), 6.60-6.65
(m, 2H), 7.00-7.06 (m, 2H), 7.27-7.31 (m, 2H), 7.36-7.54 (m, 8H),
9.98 (s, 1H).
Example 1-29
[0517] MS ESI m/e: 527 (M+H), 525 (M-H).
[0518] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.88 (s, 3H), 3.97
(s, 2H), 5.83 (s, 1H), 7.12-7.58 (m, 19H), 10.29 (s, 1H).
Example 1-30
[0519] MS ESI m/e: 522 (M+H), 520 (M-H).
[0520] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.66 (s, 3H),
3.10-3.13 (m, 4H), 3.73-3.76 (m, 4H), 5.32 (s, 1H), 7.01 (d, J=9.0
Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 7.35-7.57 (m, 10H), 10.20 (brs,
1H).
Example 1-31
[0521] MS ESI m/e: 493 (M+H), 491 (M-H).
[0522] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.90 (t, J=8.0
Hz, 3H), 1.26-1.36 (m, 2H), 1.52-1.60 (m, 2H), 2.58 (t, J=8.0 Hz,
2H), 2.66 (s, 3H), 5.46 (s, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.25 (d,
J=8.0 Hz, 2H), 7.35-7.37 (m, 2H), 7.41-7.54 (m, 8H), 10.36 (brs,
1H).
Example 1-32
[0523] MS ESI m/e: 409 (M+H), 407 (M-H).
[0524] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 3.46 (s, 3H),
3.48 (s, 3H), 5.49 (s, 1H), 7.28-7.34 (m, 4H), 7.41-7.53 (m, 5H),
10.44 (brs, 1H).
Example 1-33
[0525] MS ESI m/e: 505 (M+H), 503 (M-H).
[0526] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.67 (s, 3H),
5.78 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.40-7.53 (m, 10H), 7.73 (d,
J=8.0 Hz, 2H), 10.75 (brs, 1H).
Example 1-34
[0527] MS ESI m/e: 485 (M+H), 483 (M-H).
[0528] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.32 (s, 3H),
2.67 (s, 3H), 5.35 (s, 1H), 7.23-7.56 (m, 13H), 10.48 (brs,
1H).
Example 1-35
[0529] MS ESI m/e: 409 (M+H), 407 (M-H).
[0530] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.61 (s, 3H),
3.26 (s, 3H), 5.50 (s, 1H), 7.35 (d, J=6.0 Hz, 2H), 7.44-7.54 (m,
5H), 7.49 (d, J=6.0 Hz, 2H), 10.62 (brs, 1H).
Example 1-36
[0531] MS ESI m/e: 431 (M+H).
[0532] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.00 (s, 9H), 2.86
(s, 3H), 2.92 (d, J=8.0 Hz, 2H), 5.43 (s, 1H), 7.24-7.29 (m, 2H),
7.34-7.53 (m, 8H), 8.78 (t, J=6.0 Hz, 1H).
Example 1-37
[0533] MS ESI m/e: 481 (M+H), 479 (M-H).
[0534] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.70 (s, 3H),
5.85 (s, 1H), 7.36-7.54 (m, 10H), 7.43 (d, J=9.0 Hz, 2H), 7.97 (d,
J=9.0 Hz, 2H), 10.81 (brs, 1H).
Example 1-38
[0535] MS ESI m/e: 465 (M+H), 463 (M-H).
[0536] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.18 (t, J=7.5 Hz,
3H), 2.63 (q, J=7.5 Hz, 2H), 2.88 (s, 3H), 5.43 (s, 1H), 7.20-7.36
(m, 6H), 7.39-7.57 (m, 8H), 10.07 (s, 1H).
Example 1-39
[0537] MS ESI m/e: 507 (M+H), 505 (M-H).
[0538] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.78 (t, J=7.3 Hz,
6H), 1.44-1.77 (m, 4H), 2.25-2.38 (m, 1H), 2.89 (s, 3H), 5.85 (s,
1H), 7.10-7.19 (m, 4H), 7.28-7.34 (m, 2H), 7.38-7.57 (m, 8H), 10.28
(s, 1H).
Example 1-40
[0539] MS ESI m/e: 535 (M+H), 533 (M-H).
[0540] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.85 (t, J=7.4 Hz,
6H), 1.08-1.24 (m, 4H), 1.45-1.64 (m, 4H), 2.45-2.58 (m, 1H), 2.89
(s, 3H), 5.84 (s, 1H), 7.10-7.18 (m, 4H), 7.28-7.34 (m, 2H),
7.38-7.57 (m, 8H), 10.27 (s, 1H).
Example 1-41
[0541] MS ESI m/e: 497 (M+H), 495 (M-H).
[0542] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.79-1.00 (m, 4H),
1.70-1.78 (m, 1H), 5.73 (s, 1H), 7.12-7.18 (m, 2H), 7.26-7.34 (m,
4H), 7.35-7.55 (m, 8H), 10.35 (s, 1H).
Example 1-42
[0543] MS ESI m/e: 539, 541 (M+H), 537, 539 (M-H).
[0544] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.92 (s, 3H), 5.80
(s, 1H), 7.14-7.19 (m, 2H), 7.19-7.24 (m, 2H), 7.30-7.36 (m, 4H),
7.45-7.51 (m, 4H), 10.24 (s, 1H).
Example 1-43
[0545] MS ESI m/e: 485 (M+H), 483 (M-H).
[0546] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.57 (s, 3H),
2.76 (s, 3H), 6.93 (d, J=9.0 Hz, 2H), 7.31-7.54 (m, 12H), 10.07
(brs, 1H).
Example 1-44
[0547] MS ESI m/e: 477 (M+H), 475 (M-H).
[0548] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.07-1.85 (m,
11H), 2.60 (s, 3H), 4.65-4.65 (m, 1H), 5.49 (s, 1H), 7.35-7.54 (m,
5H), 10.63 (brs, 1H).
Example 1-45
[0549] MS ESI m/e: 485 (M+H), 483 (M-H).
[0550] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.63 (s, 3H),
5.10 (brs, 2H), 5.51 (s, 1H), 7.24-7.56 (m, 14H), 10.57 (s,
1H).
Example 1-46
[0551] MS ESI m/e: 452 (M+H).
[0552] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H),
5.47 (s, 1H), 7.19 (d, J=9.0 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H),
7.35-7.40 (m, 2H), 7.41-7.57 (m, 8H), 10.40 (s, 1H).
Example 1-47
[0553] MS ESI m/e: 421 (M+H), 419 (M-H).
[0554] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.19-2.30 (m, 2H),
4.09-4.20 (m, 4H), 5.73 (s, 1H), 7.11-7.19 (m, 2H), 7.23-7.36 (m,
4H), 7.45-7.60 (m, 3H), 10.49 (s, 1H).
Example 1-48
[0555] MS ESI m/e: 453 (M+H), 451 (M-H).
[0556] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.65 (s, 3H),
5.08 (s, 1H), 6.07 (brs, 2H), 6.52 (d, J=9.0 Hz, 1H), 7.29-7.57 (m,
11H), 7.80 (d, J=3.0 Hz, 1H), 9.94 (brs, 1H).
Example 1-49
[0557] MS ESI m/e: 466 (M+H).
[0558] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.67 (s, 3H),
2.86 (s, 3H), 5.50 (s, 1H), 7.33-7.57 (m, 14H), 10.44 (brs,
1H).
Example 1-50
[0559] MS ESI m/e: 479 (M+H), 477 (M-H).
[0560] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.90 (t, J=7.3 Hz,
3H), 1.51-1.66 (m, 2H), 2.57 (t, J=7.5 Hz, 2H), 2.88 (s, 3H), 5.43
(s, 11H), 7.17-7.30 (m, 4H), 7.30-7.37 (m, 2H), 7.39-7.58 (m, 8H),
10.07 (s, 1H).
Example 1-51
[0561] MS ESI m/e: 493 (M+H), 491 (M-H).
[0562] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.88 (t, J=6.0 Hz,
3H), 1.26-1.38 (m, 2H), 1.49-1.61 (m, 2H), 2.55-2.61 (m, 2H), 2.88
(s, 3H), 5.43 (s, 1H), 7.14-7.34 (m, 6H), 7.39-7.56 (m, 8H), 10.07
(brs, 1H).
Example 1-52
[0563] MS ESI m/e: 528 (M+H), 526 (M-H).
[0564] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.15 (s, 6H),
2.12-2.22 (m, 2H), 3.72 (t, J=6.5 Hz, 2H), 5.81 (s, 1H), 7.15-7.21
(m, 2H), 7.26-7.35 (m, 4H), 7.40-7.56 (m, 8H), 10.35 (s, 1H).
Example 1-53
[0565] MS ESI m/e: 485 (M+H), 483 (M-H).
[0566] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.24 (s, 3H), 2.88
(s, 3H), 5.39 (s, 1H), 7.17-7.20 (m, 2H), 7.28-7.33 (m, 2H),
7.37-7.55 (m, 9H), 10.04 (s, 1H).
Example 1-54
[0567] MS ESI m/e: 472 (M+H), 470 (M-H).
[0568] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.68 (s, 3H),
5.50 (s, 1H), 7.34-7.38 (m, 2H), 7.41-7.57 (m, 9H), 7.87 (dd,
J=4.0, 8.0 Hz, 1H), 8.37 (d, J=4.0 Hz, 1H), 10.49 (s, 1H).
Example 1-55
[0569] MS ESI m/e: 494 (M+H), 492 (M-H).
[0570] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.15 (s, 3H),
2.64 (s, 3H), 2.90 (s, 6H), 4.92 (s, 1H), 6.63 (dd, J=3.0, 9.0 Hz,
1H), 6.69 (d, J=3.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 7.36-7.57 (m,
10H), 9.89 (s, 1H).
Example 1-56
[0571] MS ESI m/e: 497 (M+H), 495 (M-H).
[0572] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 4.24 (d, J=4.2 Hz,
2H), 4.87 (d, J=16.9 Hz, 1H), 5.02 (d, J=10.4 Hz, 1H), 5.40-5.51
(m, 1H), 5.83 (s, 1H), 7.16-7.21 (m, 2H), 7.26-7.30 (m, 2H),
7.31-7.36 (m, 2H), 7.36-7.41 (m, 2H), 7.43-7.55 (m, 6H), 10.40 (s,
1H).
Example 1-57
[0573] MS ESI m/e: 482 (M+H), 480 (M-H).
[0574] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.93 (s, 3H), 6.20
(s, 1H), 7.28-7.33 (m, 2H), 7.35-7.44 (m, 4H), 7.46-7.59 (m, 6H),
8.20-8.27 (m, 2H), 10.95 (s, 1H).
Example 1-58
[0575] MS ESI m/e: 451 (M+H), 449 (M-H).
[0576] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.83 (d, J=9.0
Hz, 6H), 1.90-2.04 (m, 1H), 3.45 (s, 3H), 3.98 (d, J=9.0 Hz, 2H),
5.50 (s, 1H), 7.28-7.34 (m, 4H), 7.43-7.55 (m, 5H), 10.30 (brs,
1H).
Example 1-59
[0577] MS ESI m/e: 444 (M+H), 442 (M-H).
[0578] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 3.14 (s, 3H), 5.22
(s, 1H), 6.96-7.03 (m, 2H), 7.17-7.41 (m, 5H), 7.41-7.55 (m, 3H),
7.60 (d, J=3.7 Hz, 1H), 7.89 (d, J=3.7 Hz, 1H), 11.57 (s, 1H).
Example 1-60
[0579] MS ESI m/e: 457 (M+H), 455 (M-H).
[0580] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 5.70 (s, 1H),
7.14-7.12 (m, 2H), 7.30-7.43 (m, 6H), 7.43-7.65 (m, 6H), 10.48 (s,
1H).
Example 1-61
[0581] MS ESI m/e: 466 (M+H), 464 (M-H).
[0582] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.95 (s, 3H), 5.56
(s, 1H), 6.65-6.75 (m, 2H), 7.02-7.14 (m, 2H), 7.29-7.67 (m, 10H),
10.18 (s, 1H).
Example 1-62
[0583] MS ESI m/e: 506 (M+H), 504 (M-H).
[0584] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.96 (6H, s), 4.23
(d, J=4.7 Hz, 2H), 4.88 (d, J=17.3 Hz, 1H), 5.02 (d, J=10.6 Hz,
1H), 5.40-5.55 (m, 1H), 5.69 (s, 1H), 6.68-6.75 (m, 2H), 7.07-7.14
(m, 2H), 7.27-7.33 (m, 2H), 7.37-7.56 (m, 8H), 10.10 (s, 1H).
Example 1-63
[0585] MS ESI m/e: 472 (M+H).
[0586] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 2.72 (s, 3H), 7.16
(d, J=9.0 Hz, 1H), 7.34-7.42 (m, 2H), 7.43-7.60 (m, 10H), 7.82 (dd,
J=3.0, 6.0 Hz, 1H), 8.42 (d, J=3.0 Hz, 1H), 11.68 (s, 1H).
Example 1-64
[0587] MS ESI m/e: 487 (M+H).
[0588] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.94 (s, 3H), 3.12
(s, 6H), 7.26-7.32 (m, 2H), 7.34-7.54 (m, 8H), 7.68 (s, 1H), 9.00
(d, J=4.8 Hz, 1H), 10.26 (d, J=5.8 Hz, 1H).
Example 1-65
[0589] MS ESI m/e: 480 (M+H), 478 (M-H).
[0590] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.24 (t, J=7.3
Hz, 3H), 2.68 (s, 3H), 3.27 (q, J=7.3 Hz, 2H), 5.53 (s, 1H),
7.29-7.60 (m, 16H), 10.46 (s, 1H).
Example 1-66
[0591] MS ESI m/e: 478 (M+H), 477 (M-H).
[0592] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.16 (d, J=6.8
Hz, 6H), 2.65 (s, 3H), 3.05-3.15 (m, 1H), 5.00 (s, 1H), 7.27-7.54
(m, 14H), 10.19 (brs, 1H).
Example 1-67
[0593] MS ESI m/e: 485 (M+H), 483 (M-H).
[0594] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56 (t, J=7.0
Hz, 3H), 3.55 (q, 2H, J=7.0 Hz), 5.53 (s, 1H), 7.10-7.13 (m, 2H),
7.32-7.56 (m, 12H), 10.49 (brs, 1H).
Example 1-68
[0595] MS ESI m/e: 528 (M+H), 526 (M-H).
[0596] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.15 (s, 6H), 2.88
(s, 3H), 3.31 (s, 2H), 5.65 (s, 1H), 7.21-7.54 (m, 13H), 10.50 (s,
1H).
Example 1-69
[0597] MS ESI m/e: 493 (M+H), 491 (M-H).
[0598] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.84 (d, J=6.6 Hz,
6H), 1.78-1.88 (m, 1H), 2.45 (d, J=7.2 Hz, 2H), 2.67 (s, 3H), 5.15
(s, 1H), 7.20-7.53 (m, 14H), 10.24 (brs, 1H).
Example 1-70
[0599] MS ESI m/e: 499, 501 (M+H), 497, 499 (M-H).
[0600] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.37 (s, 3H),
2.38 (s, 3H), 2.70 (s, 3H), 5.54 (s, 1H), 7.21-7.50 (m, 12H), 10.51
(brs, 1H).
Example 1-71
[0601] MS ESI m/e: 507, 508 (M+H), 505, 506 (M-H).
[0602] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.85 (d, J=6.5
Hz, 6H,), 1.37-1.42 (m, 2H), 1.49-1.53 (m, 1H), 2.50-2.58 (m, 2H),
2.67 (s, 3H), 5.12 (s, 1H), 7.24-7.55 (m, 14H), 10.23 (brs,
1H).
Example 1-72
[0603] MS ESI m/e: 499 (M+H), 497 (M-H).
[0604] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.12-2.44 (m, 6H),
2.84 (s, 3H), 5.83 (brs, 1H), 7.05-7.48 (m, 12H), 10.47-10.57 (m,
1H).
Example 1-73
[0605] MS ESI m/e: 522 (M+H), 520 (M-H).
[0606] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.91 (t, J=7.3 Hz,
3H), 1.49-1.66 (m, 2H), 2.50 (t, J=7.7 Hz, 2H), 2.87 (s, 3H), 2.95
(s, 6H), 5.33 (s, 1H), 6.54-6.63 (m, 2H), 7.01-7.08 (m, 1H),
7.30-7.37 (m, 2H), 7.38-7.58 (m, 8H), 9.80 (s, 1H).
Example 1-74
[0607] MS ESI m/e: 506 (M+H), 504 (M-H).
[0608] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.91-2.03 (m, 2H),
2.73 (t, J=6.4 Hz, 2H), 2.87 (s, 3H), 2.88 (s, 3H), 3.22 (t, J=5.7
Hz, 2H), 5.68 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.79-6.85 (m, 1H),
6.87-6.93 (m, 1H), 7.28-7.34 (m, 2H), 7.36-7.58 (m, 8H), 10.00 (s,
1H).
Example 1-75
[0609] MS ESI m/e: 531, 533 (M+H), 529, 531 (M-H).
[0610] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 2.63 (s, 3H), 3.72
(s, 3H), 3.73 (s, 3H), 5.45 (s, 1H), 6.97 (t, J=9.1 Hz, 4H),
7.16-7.42 (m, 8H), 10.46 (brs, 1H).
Example 1-76
[0611] MS ESI m/e: 499, 501 (M+H), 497, 499 (M-H).
[0612] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.26 (s. 3H),
2.27 (s, 3H), 2.63 (s, 3H), 5.46 (s, 1H), 7.09-7.42 (m, 12H), 10.42
(brs, 1H).
Example 1-77
[0613] MS ESI m/e: 483, 485 (M+H), 481, 483 (M-H).
[0614] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.68 (s, 3H),
5.45 (s, 1H), 7.00-7.64 (m, 10H), 10.35 (brs, 1H).
Example 1-78
[0615] MS ESI m/e: 423 (M+H), 421 (M-H).
[0616] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.30 (t, J=6.9 Hz,
3H), 2.82 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.77 (s, 1H), 7.19-7.25
(m, 2H), 7.31-7.39 (m, 4H), 7.41-7.54 (m, 3H), 10.53 (s, 1H).
Example 1-79
[0617] MS ESI m/e: 507, 508 (M+H), 505, 503 (M-H).
[0618] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.64 (s, 3H),
5.46 (s, 1H), 7.23-7.51 (m, 12H), 10.37 (brs, 1H).
Example 1-80
[0619] MS ESI m/e: 463 (M+H), 461 (M-H).
[0620] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.52-1.67 (m, 2H),
1.82-2.02 (m, 4H), 2.04-2.20 (m, 2H), 2.80 (s, 3H), 5.21-5.37 (m,
1H), 5.75 (s, 1H), 7.18-7.28 (m, 2H), 7.30-7.56 (m, 7H), 10.54 (s,
1H).
Example 1-81
[0621] MS EST m/e: 437 (M+H), 435 (M-H).
[0622] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.51 (d, J=7.0 Hz,
6H), 2.81 (s, 3H), 5.09-5.23 (m, 1H), 5.75 (s, 1H), 7.18-7.28 (m,
2H), 7.29-7.55 (m, 7H), 10.53 (s, 1H).
Example 1-82
[0623] MS ESI m/e: 437 (M+H), 435 (M-H).
[0624] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.98 (t, J=7.4 Hz,
3H), 1.66-1.79 (m, 2H), 2.82 (s, 3H), 3.96 (t, J=7.6 Hz, 2H), 5.77
(s, 1H), 7.20-7.25 (m, 2H), 7.32-7.40 (m, 4H), 7.41-7.54 (m, 3H),
10.54 (s, 1H).
Example 1-83
[0625] MS ESI m/e: 451 (M+H), 449 (M-H).
[0626] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.96 (t, J=7.4 Hz,
3H), 1.34-1.47 (m, 2H), 1.62-1.73 (m, 2H), 2.81 (s, 3H), 3.99 (t,
J=7.6 Hz, 2H), 5.76 (s, 1H), 7.18-7.24 (m, 2H), 7.31-7.39 (m, 4H),
7.41-7.52 (m, 3H), 10.53 (s, 1H).
Example 1-84
[0627] MS ESI m/e: 435 (M+H), 433 (M-H).
[0628] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.81-0.90 (m, 2H),
1.14-1.24 (m, 2H), 2.71-2.81 (m, 1H), 2.81 (s, 3H), 5.77 (s, 1H),
7.17-7.24 (m, 2H), 7.27-7.39 (m, 4H), 7.39-7.52 (m, 3H), 10.38 (s,
1H).
Example 1-85
[0629] MS ESI m/e: 423 (M+H), 421 (M-H).
[0630] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.25-2.30 (m,
3H), 2.51-2.57 (m, 3H), 3.26-3.31 (m, 3H), 5.48-5.52 (m, 1H),
7.24-7.55 (m, 8H), 10.74 (s, 1H).
Example 1-86
[0631] MS ESI m/e: 423 (M+H), 421 (M-H).
[0632] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.35 (s, 3H),
2.65 (s, 3H), 3.26 (s, 3H), 5.51 (s, 1H), 7.23-7.32 (m, 3H),
7.32-7.45 (m, 3H), 7.46-7.54 (m, 2H), 10.64 (s, 1H).
Example 1-87
[0633] MS ESI m/e: 423 (M+H), 421 (M-H).
[0634] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.37 (s, 3H),
2.63 (s, 3H), 3.26 (s, 3H), 5.50 (s, 1H), 7.29-7.39 (m, 6H),
7.46-7.53 (m, 2H), 10.64 (s, 1H).
Example 1-88
[0635] MS ESI m/e: 444 (M+H), 442 (M-H).
[0636] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.13-1.23 (m, 2H), 2.71-2.80 (m, 1H), 2.80 (s, 3H), 2.97 (s, 6H),
5.62 (s, 1H), 6.69-6.77 (m, 2H), 7.08-7.16 (m, 2H), 7.29-7.35 (m,
2H), 7.38-7.52 (m, 3H), 10.07 (s, 1H).
Example 1-89
[0637] MS ESI m/e: 479, 481 (M+H), 477, 479 (M-H).
[0638] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.15-1.26 (m, 2H), 2.71-2.82 (m, 1H), 2.82 (s, 3H), 5.80 (s, 1H),
7.13-7.21 (m, 2H), 7.28-7.36 (m, 2H), 7.39-7.56 (m, 5H), 10.41 (s,
1H).
Example 1-90
[0639] MS ESI m/e: 477 (M+H), 475 (M-H).
[0640] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.84 (s, 3H), 4.75
(q, J=8.4 Hz, 2H), 5.76 (s, 1H), 7.19-7.28 (m, 2H), 7.31-7.42 (m,
4H), 7.43-7.57 (m, 3H), 10.20 (s, 1H).
Example 1-91
[0641] MS ESI m/e: 513 (M+H), 511 (M-H).
[0642] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64 (t, J=6.0
Hz, 3H), 1.21-1.41 (m, 2H), 2.15 (t, J=7.5 Hz, 2H), 2.76 (s, 3H),
6.93-7.07 (m, 2H), 7.27-7.37 (m, 4H), 7.39-7.64 (m, 8H), 9.92 (s,
1H).
Example 1-92
[0643] MS ESI m/e: 521, 523 (M+H), 519, 521 (M-H).
[0644] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.85 (s, 3H), 4.75
(q, J=8.4 Hz, 2H), 5.78 (s, 1H), 7.14-7.22 (m, 2H), 7.32-7.40 (m,
2H), 7.44-7.58 (m, 5H), 10.20 (s, 1H).
Example 1-93
[0645] MS ESI m/e: 486 (M+H), 484 (M-H).
[0646] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 2.83 (s, 3H), 2.97
(s, 6H), 4.75 (q, J=8.4 Hz, 2H), 5.61 (s, 1H), 6.67-6.81 (m, 2H),
7.08-7.18 (m, 2H), 7.32-7.40 (m, 2H), 7.41-7.56 (m, 3H), 9.92 (s,
1H).
Example 1-94
[0647] MS ESI m/e: 457 (M+H), 455 (M-H).
[0648] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.18 (t, J=6.7
Hz, 3H), 2.66 (s, 3H), 3.93 (q, J=6.7 Hz, 2H), 5.50 (s, 1H), 7.36
(d, J=9.0 Hz, 2H), 7.46-7.56 (m, 4H), 7.57-7.66 (m, 2H), 10.62 (s,
1H).
Example 1-95
[0649] MS ESI m/e: 467, 469 (M+H), 465, 467 (M-H).
[0650] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.28 (s, 3H),
2.53 (s, 3H), 3.28 (s, 3H), 5.51 (s, 1H), 7.23-7.35 (m, 4H),
7.38-7.44 (m, 2H), 7.58-7.65 (m, 2H), 10.72 (s, 1H).
Example 1-96
[0651] MS ESI m/e: 467, 469 (M+H), 465, 467 (M-H).
[0652] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.29 (t, J=7.1 Hz,
3H), 2.81 (s, 3H), 4.07 (q, J=7.1 Hz, 2H), 5.78 (s, 1H), 7.14-7.19
(m, 2H), 7.31-7.36 (m, 2H), 7.40-7.53 (m, 5H), 10.53 (s, 1H).
Example 1-97
[0653] MS ESI m/e: 432 (M+H).
[0654] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.29 (t, J=7.1 Hz,
3H), 2.80 (s, 3H), 2.96 (s, 6H), 4.07 (q, J=7.0 Hz, 2H), 5.59 (s,
1H), 6.69-6.75 (m, 2H), 7.08-7.14 (m, 2H), 7.31-7.36 (m, 2H),
7.38-7.50 (m, 3H), 10.19 (s, 1H).
Example 1-98
[0655] MS ESI m/e: 435 (M+H), 433 (M-H).
[0656] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.80-0.91 (m, 2H),
1.25-1.35 (m, 2H), 3.38-3.49 (m, 1H), 3.74 (s, 3H), 5.76 (s, 1H),
7.09-7.18 (m, 2H), 7.20-7.37 (m, 4H), 7.44-7.60 (m, 3H), 10.23 (s,
1H).
Example 1-99
[0657] MS ESI m/e: 432 (M+H).
[0658] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.27 (s, 3H),
2.51 (s, 3H), 2.92 (s, 6H), 3.27 (s, 3H), 5.21 (s, 1H), 6.76-6.84
(m, 2H), 7.06-7.14 (m, 2H), 7.23-7.38 (m, 2H), 7.38-7.44 (m, 2H),
10.35 (s, 1H).
Example 1-100
[0659] MS ESI m/e: 453 (M+H), 451 (M-H).
[0660] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.14-1.24 (m, 2H), 2.74-2.83 (m, 1H), 2.86 (s, 3H), 5.76 (s, 1H),
7.18-7.33 (m, 5H), 7.33-7.40 (m, 2H), 7.45-7.55 (m, 1H), 10.41 (s,
1H).
Example 1-101
[0661] MS ESI m/e: 503 (M+H), 501 (M-H).
[0662] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.78-0.91 (m, 2H),
1.14-1.26 (m, 2H), 2.73-2.86 (m, 1H), 2.82 (s, 3H), 5.76 (s, 1H),
7.19-7.29 (m, 2H), 7.32-7.41 (m, 2H), 7.42-7.50 (m, 1H), 7.61-7.79
(m, 2H), 7.80-7.89 (m, 1H), 10.50 (s, 1H).
Example 1-102
[0663] MS ESI m/e: 449 (M+H), 447 (M-H).
[0664] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.74-0.96 (m, 2H),
1.11-1.31 (m, 2H), 2.30 (s, 3H), 2.74 (s, 3H), 2.76-2.85 (m, 1H),
5.76 (s, 1H), 7.04-7.12 (m, 1H), 7.18-7.43 (m, 7H), 10.53 (s,
1H).
Example 1-103
[0665] MS ESI m/e: 463 (M+H), 461 (M-H).
[0666] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.76-0.90 (m, 2H),
1.11-1.27 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 2.40-2.67 (m, 2H),
2.71-2.84 (m, 1H), 2.75 (s, 3H), 5.76 (s, 1H), 7.08-7.14 (m, 1H),
7.18-7.47 (m, 7H), 10.54 (s, 1H).
Example 1-104
[0667] MS ESI m/e: 465 (M+H), 463 (M-H).
[0668] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.94 (m, 2H),
1.11-1.28 (m, 2H), 2.71-2.83 (m, 1H), 2.84 (s, 3H), 3.84 (s, 3H),
5.76 (s, 1H), 7.00-7.13 (m, 2H), 7.19-7.30 (m, 3H), 7.32-7.40 (m,
2H), 7.41-7.52 (m, 1H), 10.52 (s, 1H).
Example 1-105
[0669] MS ESI m/e: 445 (M+H), 443 (M-H).
[0670] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.92 (t, J=7.5 Hz,
3H), 1.36 (sext, J=7.5 Hz, 2H), 1.59 (quint, J=7.5 Hz, 2H), 2.33
(s, 3H), 2.62 (t, J=7.5 Hz, 2H), 2.75 (s, 3H), 3.45 (s, 3H), 5.43
(s, 1H), 7.08-7.45 (m, 8H), 10.37 (s, 1H).
Example 1-106
[0671] MS ESI m/e: 458 (M+H).
[0672] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.77-0.92 (m, 2H),
1.14-1.27 (m, 2H), 2.30 (s, 3H), 2.72 (s, 3H), 2.74-2.85 (m, 1H),
2.96 (s, 6H), 5.60 (s, 1H), 6.69-6.79 (m, 2H), 7.03-7.18 (m, 3H),
7.22-7.42 (m, 3H), 10.20 (s, 1H).
Example 1-107
[0673] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0674] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.68-1.79 (m,
2H), 2.19-2.32 (m, 2H), 2.59 (s, 3H), 2.60-2.75 (m, 2H), 4.88-4.98
(m, 1H), 5.49 (s, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.41-7.53 (m, 5H),
7.60 (d, J=8.6 Hz, 2H), 10.52 (brs, 1H).
Example 1-108
[0675] MS ESI m/e: 535, 537 (M+H), 533, 535 (M-H).
[0676] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.27 (s, 3H),
2.54 (s, 3H), 4.62-4.88 (m, 2H), 5.49 (s, 1H), 7.28-7.30 (m, 4H),
7.41-7.42 (m, 2H), 7.62 (d, J=9.0 Hz, 2H), 10.40 (brs, 1H).
Example 1-109
[0677] MS ESI m/e: 437 (M+H), 435 (M-H).
[0678] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.30 (t, J=6.0 Hz,
3H), 2.30 (s, 3H), 2.75 (s, 3H), 4.09 (q, J=6.0 Hz, 2H), 5.75 (s,
1H), 7.12 (d, J=6.0 Hz, 1H), 7.19-7.43 (m, 7H), 10.65 (s, 1H).
Example 1-110
[0679] MS ESI m/e: 446 (M+H), 444 (M-H).
[0680] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.30 (t, J=7.1 Hz,
3H), 2.30 (s, 3H), 2.73 (s, 3H), 2.96 (s, 6H), 4.09 (q, J=2.3 Hz,
2H), 4.84 (q, J=149.0 Hz, 2H), 6.68-6.77 (m, 2H), 7.08-7.17 (m,
3H), 7.25-7.32 (m, 1H), 7.33-7.38 (m, 2H), 10.31 (brs, 1H).
Example 1-111
[0681] MS ESI m/e: 481, 483 (M+H), 479, 481 (M-H).
[0682] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.30 (t, J=6.0 Hz,
3H), 2.30 (s, 1H), 2.75 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 5.77 (s,
1H), 7.08-7.22 (m, 3H), 7.26-7.42 (m, 3H), 7.49-7.56 (m, 2H), 10.66
(brs, 1H).
Example 1-112
[0683] MS ESI m/e: 458 (M+H), 456 (M-H).
[0684] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.93 (m, 2H),
1.14-1.24 (m, 2H), 2.23 (s, 3H), 2.71-2.82 (m, 1H), 2.79 (s, 3H),
2.95 (s, 6H), 5.29 (s, 1H), 6.55-6.64 (m, 2H), 7.02-7.10 (m, 1H),
7.29-7.36 (m, 2H), 7.38-7.53 (m, 3H), 9.86 (s, 1H).
Example 1-113
[0685] MS ESI m/e: 497, 499 (M+H), 495, 497 (M-H).
[0686] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.14-1.24 (m, 2H), 2.73-2.83 (m, 1H), 2.86 (s, 3H), 5.78 (s, 1H),
7.12-7.21 (m, 2H), 7.21-7.34 (m, 3H), 7.45-7.55 (m, 3H), 10.41 (s,
1H).
Example 1-114
[0687] MS ESI m/e: 462 (M+H), 460 (M-H).
[0688] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.93 (m, 2H),
1.13-1.25 (m, 2H), 2.72-2.84 (m, 1H), 2.84 (s, 3H), 2.96 (s, 6H),
5.60 (s, 1H), 6.69-6.77 (m, 2H), 7.08-7.15 (m, 2H), 7.17-7.31 (m,
3H), 7.43-7.53 (m, 1H), 10.09 (s, 1H).
Example 1-115
[0689] MS ESI m/e: 441 (M+H), 439 (M-H).
[0690] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.31 (t, J=7.0 Hz,
3H), 2.86 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.75 (s, 1H), 7.18-7.40
(m, 7H), 7.46-7.56 (m, 1H), 10.54 (s, 1H).
Example 1-116
[0691] MS ESI m/e: 485, 487 (M+H), 483, 485 (M-H).
[0692] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.31 (t, J=7.0 Hz,
3H), 2.86 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.77 (s, 1H), 7.13-7.21
(m, 2H), 7.24-7.34 (m, 3H), 7.46-7.56 (m, 3H), 10.55 (s, 1H).
Example 1-117
[0693] MS ESI m/e: 450 (M+H), 448 (M-H).
[0694] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.31 (t, J=7.0 Hz,
3H), 2.85 (s, 3H), 2.96 (s, 6H), 4.08 (q, J=7.1 Hz, 2H), 5.59 (s,
1H), 6.69-6.77 (m, 2H), 7.08-7.17 (m, 2H), 7.22-7.34 (m, 3H),
7.43-7.54 (m, 1H), 10.21 (s, 1H).
Example 1-118
[0695] MS ESI m/e: 472 (M+H).
[0696] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.89 (m, 2H),
1.14-1.25 (m, 2H), 2.16 (s, 6H), 2.71 (s, 3H), 2.77-2.87 (m, 1H),
2.96 (s, 6H), 5.59 (s, 1H), 6.68-6.77 (m, 2H), 7.08-7.19 (m, 4H),
7.23-7.31 (m, 1H), 10.31 (s, 1H).
Example 1-119
[0697] MS ESI m/e: 480 (M+H).
[0698] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.10 (m, 2H), 2.68-2.79 (m, 1H), 2.71 (s, 1H), 5.21 (s,
1H), 6.79 (d, J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.39 (t, J=9.0
Hz, 2H), 7.65-7.75 (m, 1H), 10.11 (brs, 1H).
Example 1-120
[0699] MS ESI m/e: 515, 517 (M+H), 513, 515 (M-H).
[0700] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.10 (m, 2H), 2.71-2.80 (m, 1H), 2.74 (s, 3H), 5.51 (s,
1H), 7.32 (d, J=9.0 Hz, 2H), 7.41 (t, J=7.5 Hz, 2H), 7.62 (d, J=6.0
Hz, 2H), 7.64-7.76 (m, 1H), 10.47 (brs, 1H).
Example 1-121
[0701] MS ESI m/e: 471 (M+H), 469 (M-H).
[0702] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.03-1.07 (m, 2H), 2.70-2.80 (m, 1H), 2.74 (s, 3H), 5.49 (s,
1H), 7.36-7.43 (m, 4H), 7.50 (d, J=9.0 Hz, 2H), 7.65-7.76 (m, 1H),
10.47 (brs, 1H).
Example 1-122
[0703] MS ESI m/e: 460 (M+H), 458 (M-H).
[0704] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.16 (t, J=7.5
Hz, 3H), 1.18 (t, J=6.0 Hz, 3H), 2.52 (q, J=4.0 Hz, 2H), 2.50 (s,
3H), 2.92 (s, 6H), 3.94 (q, J=5.0 Hz, 2H), 5.20 (s, 1H), 6.79 (d,
J=9.0 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.33 (d, J=3.0 Hz, 2H), 7.47
(s, 2H), 10.35 (brs, 1H).
Example 1-123
[0705] MS ESI m/e: 495, 497 (M+H), 493, 495 (M-H).
[0706] .sup.1H-NMR (DMSO-d, 300 MHz) .delta. 1.16 (t, J=7.5 Hz,
3H), 1.18 (t, J=6.0 Hz, 3H), 2.50-2.56 (m, 2H), 2.53 (s, 3H), 3.96
(q, J=7.0 Hz, 2H), 5.51 (s, 1H), 7.29-7.34 (m, 4H), 7.46-7.48 (m,
2H), 7.62 (d, J=6.0 Hz, 2H), 10.74 (brs, 1H).
Example 1-124
[0707] MS ESI m/e: 451 (M+H), 499 (M-H).
[0708] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.16 (t, J=6.0
Hz, 3H), 1.18 (t, J=6.0 Hz, 3H), 2.50-2.55 (m, 2H), 2.56 (s, 3H),
3.95 (q, J=8.0 Hz, 2H), 5.49 (s, 1H), 7.33-7.38 (m, 4H), 7.48-7.51
(m, 4H), 10.73 (brs, 1H).
Example 1-125
[0709] MS ESI m/e: 463 (M+H), 461 (M-H).
[0710] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.78-0.88 (m, 2H),
1.16-1.29 (m, 2H), 2.15 (s, 6H), 2.72 (s, 3H), 2.77-2.88 (m, 1H),
5.74 (s, 1H), 7.11-7.40 (m, 7H), 10.64 (s, 1H).
Example 1-126
[0711] MS ESI m/e: 458 (M+H).
[0712] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.90 (m, 2H),
1.13-1.23 (m, 2H), 2.39 (s, 3H), 2.71-2.78 (m, 1H), 2.81 (s, 3H),
2.96 (s, 6H), 5.60 (s, 1H), 6.68-6.78 (m, 2H), 7.07-7.32 (m, 6H),
10.08 (brs, 1H).
Example 1-127
[0713] MS ESI m/e: 458 (M+H).
[0714] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.93 (m, 2H),
1.13-1.23 (m, 2H), 2.39 (s, 3H), 2.71-2.81 (m, 1H), 2.83 (s, 3H),
2.96 (s, 6H), 5.62 (s, 1H), 6.70-6.76 (m, 2H), 7.08-7.16 (m, 4H),
7.20-7.25 (m, 1H), 7.31-7.39 (m, 1H), 10.08 (brs, 1H).
Example 1-128
[0715] MS ESI m/e: 472 (M+H).
[0716] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.14-1.25 (m, 2H), 1.18 (t, J=7.0 Hz, 6H), 2.71-2.82 (m, 1H), 2.80
(s, 3H), 3.36 (q, J=7.0 Hz, 4H), 5.62 (s, 1H), 6.63-6.71 (m, 2H),
7.03-7.13 (m, 2H), 7.28-7.36 (m, 2H), 7.37-7.53 (m, 3H), 10.03 (s,
1H).
Example 1-129
[0717] MS ESI m/e: 431 (M+H), 429 (M-H).
[0718] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.90 (m, 2H),
1.15-1.23 (m, 2H), 2.72-2.80 (m, 1H), 2.80 (s, 3H), 3.82 (s, 3H),
5.61 (s, 1H), 6.88-6.94 (m, 2H), 7.14-7.21 (m, 2H), 7.28-7.33 (m,
2H), 7.38-7.50 (m, 3H), 10.15 (s, 1H).
Example 1-130
[0719] MS ESI m/e: 408 (M+H).
[0720] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.73 (m,
4H), 0.96-1.02 (m, 2H), 1.05-1.12 (m, 2H), 2.54-2.63 (m, 1H), 2.91
(s, 6H), 3.30-3.40 (m, 1H), 3.48 (s, 3H), 5.14 (s, 1H), 6.77 (d,
J=9.0 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H), 10.04 (brs, 1H).
Example 1-131
[0721] MS ESI m/e: 468, 470 (M+H), 466, 468 (M-H).
[0722] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.20 (t, J=7.5
Hz, 3H), 2.62 (s, 3H), 3.95 (q, J=7.0 Hz, 2H), 5.53 (s, 1H), 7.32
(d, J=9.0 Hz, 2H), 7.52-7.64 (m, 3H), 7.97 (d, J=9.0 Hz, 1H), 8.67
(d, J=15 Hz, 1H), 8.68 (d, J=15 Hz, 1H), 10.62 (brs, 1H).
Example 1-132
[0723] MS ESI m/e: 462 (M+H), 460 (M-H).
[0724] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.82-0.89 (m, 2H),
1.15-1.22 (m, 2H), 2.72-2.79 (m, 1H), 2.82 (s, 3H), 2.96 (s, 6H),
5.60 (s, 1H), 6.69-6.75 (m, 2H), 7.07-7.21 (m, 4H), 7.27-7.33 (m,
2H), 10.03 (s, 1H).
Example 1-133
[0725] MS ESI m/e: 462 (M+H), 460 (M-H).
[0726] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.89 (m, 2H),
1.15-1.23 (m, 2H), 2.72-2.80 (m, 1H), 2.85 (s, 3H), 2.96 (s, 6H),
5.61 (s, 1H), 6.69-6.75 (m, 2H), 7.03-7.19 (m, 5H), 7.39-7.46 (m,
1H), 10.01 (s, 1H).
Example 1-134
[0727] MS ESI m/e: 444 (M+H), 442 (M-H).
[0728] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.93 (m, 2H),
1.13-1.24 (m, 2H), 2.72-2.82 (m, 1H), 2.82 (s, 3H), 2.96 (s, 6H),
5.90 (s, 1H), 6.55-6.62 (m, 2H), 6.63-6.69 (m, 1H), 7.19-7.24 (m,
1H), 7.30-7.35 (m, 2H), 7.38-7.53 (m, 3H), 10.31 (s, 1H).
Example 1-135
[0729] MS ESI m/e: 416 (M+H).
[0730] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.82 (m,
2H), 0.99-1.09 (m, 2H), 2.60 (s, 3H), 2.63-2.74 (m, 1H), 5.52 (s,
1H), 7.36-7.57 (m, 9H), 10.61 (s, 1H).
Example 1-136
[0731] MS ESI m/e: 430 (M+H).
[0732] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.98-1.08 (m, 2H), 2.60 (s, 3H), 2.63-2.72 (m, 1H), 2.89 (s,
3H), 5.51 (d, J=2.9 Hz, 1H), 7.38-7.56 (m, 9H), 10.59 (brs,
1H).
Example 1-137
[0733] MS ESI m/e: 444 (M+H), 442 (M-H).
[0734] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.98-1.08 (m, 2H), 1.27 (t, J=7.5 Hz, 3H), 2.61 (s, 3H),
2.64-2.72 (m, 1H), 3.31 (q, J=7.0 Hz, 2H), 5.54 (s, 1H), 7.07-7.19
(m, 2H), 7.38-7.57 (m, 9H), 10.62 (brs, 1H).
Example 1-138
[0735] MS ESI m/e: 454 (M+H).
[0736] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.71-0.80 (m, 2H),
0.99-1.08 (m, 2H), 2.57 (s, 3H), 2.62-2.75 (m, 1H), 3.81 (s, 3H),
5.26 (s, 1H), 6.44 (d, J=3.0 Hz, 1H), 7.06 (dd, J=3.0, 3.0 Hz, 1H),
7.37-7.52 (m, 8H), 10.37 (brs, 1H).
Example 1-139
[0737] MS ESI m/e: 444 (M+H).
[0738] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.59 (s, 3H),
2.92 (s, 6H), 4.49 (d, J=3.0 Hz, 2H), 5.15 (d, J=9.0 Hz, 1H), 5.22
(dd, J=3.0, 9.0 Hz, 2H), 6.78 (d, J=6.0 Hz, 2H), 7.10 (d, J=6.0 Hz,
2H), 7.48-7.50 (m, 5H), 10.19 (brs, 1H).
Example 1-140
[0739] MS ESI m/e: 444 (M+H), 442 (M-H).
[0740] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.60 (s, 3H),
3.03 (s, 6H), 4.50 (d, J=3.0 Hz, 2H), 5.17 (dd, J=21.0, 24.0 Hz,
2H), 5.38 (s, 1H), 5.79-5.92 (m, 1H), 7.19-7.38 (m, 4H), 7.41-7.55
(m, 5H), 10.42 (brs, 1H).
Example 1-141
[0741] MS ESI m/e: 456 (M+H), 454 (M-H).
[0742] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.55 (s, 3H), 2.61-2.68 (m, 1H), 2.71 (s,
3H), 2.89 (t, J=9.0 Hz, 2H), 3.28 (t, J=7.5 Hz, 2H), 5.18 (s, 1H),
6.54 (d, J=9.0 Hz, 1H), 6.90 (d, J=6.0 Hz, 1H), 6.96 (s, 1H),
7.39-7.50 (m, 5H), 10.13 (brs, 1H).
Example 1-142
[0743] MS ESI m/e: 476 (M+H).
[0744] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.85-0.93 (m, 2H),
1.14-1.24 (m, 2H), 2.23 (s, 3H), 2.74-2.83 (m, 1H), 2.83 (s, 3H),
2.95 (s, 6H), 5.27 (s, 1H), 6.55-6.65 (m, 2H), 7.02-7.09 (m, 1H),
7.18-7.32 (m, 3H), 7.43-7.54 (m, 1H), 9.89 (s, 1H).
Example 1-143
[0745] MS ESI m/e: 462 (M+H), 460 (M-H).
[0746] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.92 (m, 2H),
1.14-1.25 (m, 2H), 2.71-2.81 (m, 1H), 2.81 (s, 1H), 2.87 (s, 6H),
5.71 (s, 1H), 6.86-7.02 (m, 3H), 7.27-7.35 (m, 2H), 7.41-7.54 (m,
3H), 10.22 (brs, 1H).
Example 1-144
[0747] MS ESI m/e: 454 (M+H), 452 (M-H).
[0748] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.80 (m,
2H), 1.00-1.09 (m, 2H), 2.58 (s, 3H), 2.64-2.71 (m, 11-H), 3.78 (s,
3H), 5.40 (s, 1H), 6.45 (d, J=3.0 Hz, 1H), 6.97 (d, J=6.0 Hz, 1H),
7.34-7.51 (m, 7H), 7.60 (d, J=9.0 Hz, 1H), 8.30 (brs, 1H).
Example 1-145
[0749] MS ESI m/e: 479 (M+H), 477 (M-H).
[0750] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.15-1.26 (m, 2H), 2.73-2.83 (m, 1H), 2.85 (s, 3H), 3.08 (s, 3H),
6.08 (s, 1H), 7.29-7.37 (m, 2H), 7.41-7.56 (m, 5H), 7.92-8.00 (m,
2H), 10.87 (s, 1H).
Example 1-146
[0751] MS ESI m/e: 461 (M+H), 459 (M-H).
[0752] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.13-1.24 (m, 2H), 2.72-2.83 (m, 1H), 2.80 (s, 3H), 3.83 (s, 3H),
3.84 (s, 3H), 5.60 (s, 1H), 6.45-6.58 (m, 2H), 7.19-7.26 (m, 1H),
7.28-7.35 (m, 2H), 7.38-7.52 (m, 3H), 10.01 (s, 1H).
Example 1-147
[0753] MS ESI m/e: 458 (M+H), 456 (M-H).
[0754] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.13-1.23 (m, 2H), 2.32 (s, 3H), 2.67-2.84 (m, 1H), 2.71 (s, 6H),
2.81 (s, 3H), 5.72 (s, 1H), 6.99-7.10 (m, 3H), 7.28-7.36 (m, 2H),
7.38-7.53 (m, 3H), 10.19 (s, 1H).
Example 1-148
[0755] MS ESI m/e: 512 (M+H), 510 (M-H).
[0756] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.90 (m, 2H),
1.16-1.24 (m, 2H), 2.73-2.79 (m, 1H), 2.75 (s, 6H), 2.81 (s, 3H),
5.66 (s, 1H), 7.29-7.37 (m, 3H), 7.39-7.52 (m, 5H), 10.33 (brs,
1H).
Example 1-149
[0757] MS ESI m/e: 472 (M+H), 470 (M-H).
[0758] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.91 (m, 2H),
1.17-1.25 (m, 2H), 1.91 (s, 3H), 2.74-2.81 (m, 1H), 2.83 (s, 3H),
3.28 (s, 3H), 5.84 (s, 1H), 7.18-7.24 (m, 2H), 7.29-7.35 (m, 4H),
7.40-7.52 (m, 3H), 10.47 (s, 1H).
Example 1-150
[0759] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0760] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.39-0.57 (m, 4H),
1.24-1.36 (m, 1H), 2.83 (s, 3H), 3.91 (d, J=7.0 Hz, 2H), 5.80 (s,
1H), 7.15-7.21 (m, 2H), 7.33-7.39 (m, 2H), 7.42-7.55 (m, 5H), 10.57
(s, 1H).
Example 1-151
[0761] MS ESI m/e: 497, 499 (M+H), 495, 497 (M-H).
[0762] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.73-0.79 (m, 2H),
1.01-1.09 (m, 2H), 2.61 (s, 3H), 2.68-2.71 (m, 1H), 5.65 (s, 1H),
7.19 (d, J=9.0 Hz, 1H), 7.40-7.52 (m, 6H), 7.73 (t, J=9.0 Hz, 1H),
10.67 (brs, 1H).
Example 1-152
[0763] MS ESI m/e: 497, 499 (M+H), 495, 497 (M-H).
[0764] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.79 (m,
2H), 1.01-1.09 (m, 2H), 2.60 (s, 3H), 2.62-2.72 (m, 1H), 5.37 (s,
1H), 7.42-7.52 (m, 7H), 7.73 (d, J=12.0 Hz, 1H), 10.55 (brs,
1H).
Example 1-153
[0765] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0766] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.81-1.17 (m,
6H), 2.29-2.35 (m, 1H), 2.58 (s, 3H), 5.50 (s, 1H), 7.29 (d, J=6.0
Hz, 2H), 7.39-7.52 (m, 5H), 7.61 (d, J=9.0 Hz, 2H), 10.56 (brs,
1H).
Example 1-154
[0767] MS ESI m/e: 445 (M+H), 443 (M-H).
[0768] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.84-0.93 (m, 2H),
1.16-1.24 (m, 2H), 2.26 (s, 3H), 2.74-2.80 (m, 1H), 2.80 (s, 3H),
3.81 (s, 3H), 5.27 (s, 1H), 6.73-6.84 (m, 2H), 7.14 (d, J=9.0 Hz,
1H), 7.30-7.35 (m, 2H), 7.39-7.52 (m, 3H), 9.94 (brs, 1H).
Example 1-155
[0769] MS ESI m/e: 444 (M+H), 442 (M-H).
[0770] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.10 (m, 2H), 2.60 (s, 3H), 2.64-2.76 (m, 1H), 2.76 (brs,
6H), 5.51 (brs, 1H), 7.09-7.58 (m, 8H), 10.46 (brs, 1H).
Example 1-156
[0771] MS ESI m/e: 493, 495 (M+H), 491, 495 (M-H).
[0772] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.15-1.25 (m, 2H), 2.29 (s, 3H), 2.73-2.85 (m, 1H), 2.81 (s, 3H),
5.41 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.30-7.39 (m, 3H), 7.40-7.53
(m, 4H), 10.13 (s, 1H).
Example 1-157
[0773] MS ESI m/e: 493, 495 (M+H), 491, 495 (M-H).
[0774] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.14-1.24 (m, 2H), 2.40 (s, 3H), 2.71-2.82 (m, 1H), 2.82 (s, 3H),
5.81 (s, 1H), 6.99 (dd, J=2.6, 8.4 Hz, 1H), 7.17 (d, J=2.6 Hz, 1H),
7.28-7.36 (m, 2H), 7.39-7.57 (m, 4H), 10.37 (s, 1H).
Example 1-158
[0775] MS ESI m/e: 454 (M+H), 452 (M-H).
[0776] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.80 (m,
2H), 1.01-1.09 (m, 2H), 2.55 (s, 3H), 2.63-2.72 (m, 1H), 3.85 (s,
3H), 4.71 (s, 1H), 6.48 (d, J=3.0 Hz, 1H), 6.97 (d, J=15.0 Hz, 1H),
7.06 (t, J=9.0 Hz, 1H), 7.29 (d, J=3.0 Hz, 1H), 7.41-7.56 (m, 6H),
10.37 (brs, 1H).
Example 1-159
[0777] MS ESI m/e: 509, 511 (M+H), 507, 509 (M-H).
[0778] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.79 (m,
2H), 0.96-1.08 (m, 2H), 2.61 (s, 3H), 2.61-2.74 (m, 1H), 3.77 (s,
3H), 5.49 (s, 1H), 7.07 (t, J=6.0 Hz, 1H), 7.20 (d, J=12.0 Hz, 1H),
7.29 (d, J=9.0 Hz, 2H), 7.38 (d, J=6.0 Hz, 1H), 7.48 (t, J=9.0 Hz,
1H), 7.60 (d, J=9.0 Hz, 2H), 10.60 (brs, 1H).
Example 1-160
[0779] MS ESI m/e: 455 (M+H), 453 (M-H).
[0780] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.85-0.93 (m, 2H),
1.15-1.26 (m, 2H), 2.74-2.84 (m, 1H), 2.81 (s, 3H), 3.88 (s, 3H),
5.65 (s, 1H), 7.22-7.29 (m, 1H), 7.30-7.37 (m, 2H), 7.37-7.54 (m,
4H), 7.70 (d, J=1.8 Hz, 1H), 7.90 (s, 1H), 10.36 (s, 1H).
Example 1-161
[0781] MS ESI m/e: 455 (M+H), 453 (M-H).
[0782] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.85-0.94 (m, 2H),
1.15-1.26 (m, 2H), 2.74-2.84 (m, 1H), 2.82 (s, 3H), 4.10 (s, 3H),
5.65 (s, 1H), 7.28-7.37 (m, 3H), 7.39-7.54 (m, 4H), 7.60-7.64 (m,
1H), 7.95-7.98 (m, 1H), 10.36 (s, 1H).
Example 1-162
[0783] MS ESI m/e: 437 (M+H), 435 (M-H).
[0784] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.91 (m, 2H),
1.15-1.24 (m, 2H), 2.73-2.81 (m, 1H), 2.81 (s, 3H), 5.49 (s, 1H),
6.88-6.98 (m, 2H), 7.28-7.38 (m, 3H), 7.39-7.52 (m, 3H), 10.15 (s,
1H).
Example 1-163
[0785] MS ESI m/e: 469, 471 (M+H), 467, 469 (M-H).
[0786] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.90 (m, 2H),
1.16-1.24 (m, 2H), 2.74-2.81 (m, 1H), 2.82 (s, 3H), 5.70 (s, 1H),
7.24-7.34 (m, 3H), 7.39-7.52 (m, 5H), 10.50 (s, 1H).
Example 1-164
[0787] MS ESI m/e: 485, 487 (M+H), 483, 485 (M-H).
[0788] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 1.30 (t, J=7.1 Hz,
3H), 2.82 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.66 (s, 1H), 7.28-7.39
(m, 5H), 7.41-7.53 (m, 3H), 10.48 (s, 1H).
Example 1-165
[0789] MS ESI m/e: 440 (M+H), 438 (M-H).
[0790] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.81 (m,
2H), 1.00-1.10 (m, 2H), 2.58 (s, 3H), 2.62-2.78 (m, 1H), 5.28 (s,
1H), 6.46 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 7.40-7.68 (m, 8H), 10.37
(brs, 1H), 11.22 (brs, 1H).
Example 1-166
[0791] MS ESI m/e: 527, 529 (M+H), 525, 527 (M-H).
[0792] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.81 (m,
2H), 0.99-1.09 (m, 2H), 2.63 (s, 3H), 2.66-2.75 (m, 1H), 3.79 (s,
3H), 5.34 (s, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H),
7.40 (d, J=6.0 Hz, 1H), 7.43-7.54 (m, 3H), 7.73 (d, J=9.0 Hz, 1H),
10.58 (brs, 1H).
Example 1-167
[0793] MS ESI m/e: 468 (M+H), 466 (M-H).
[0794] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.94 (m, 2H),
1.14-1.26 (m, 2H), 1.49 (t, J=7.4 Hz, 3H), 2.72-2.84 (m, 1H), 2.81
(s, 3H), 4.19 (q, J=7.3 Hz, 2H), 5.68 (s, 1H), 6.47 (d, J=3.0 Hz,
1H), 7.10 (dd, J=1.9, 8.6 Hz, 1H), 7.16 (d, J=3.0 Hz, 1H),
7.29-7.38 (m, 3H), 7.38-7.55 (m, 4H), 10.27 (brs, 1H).
Example 1-168
[0795] MS ESI m/e: 433 (M+H), 431 (M-H).
[0796] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.75-0.90 (m, 2H),
1.10-1.25 (m, 2H), 2.37 (s, 3H), 2.77 (m, 1H), 2.81 (s, 3H), 5.59
(s, 1H), 6.90-7.05 (m, 2H), 7.25 (t, J=8.3 Hz, 1H), 7.30-7.35 (m,
2H), 7.40-7.50 (m, 3H), 10.16 (s, 1H).
Example 1-169
[0797] MS ESI m/e: 438 (M+H), 436 (M-H).
[0798] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.75-0.85 (m, 2H),
1.10-1.25 (m, 2H), 2.50-2.55 (m, 4H), 2.65-2.80 (m, 3H), 2.80 (s,
3H), 3.26 (q, J=5.8 Hz, 2H), 3.70-3.80 (m, 4H), 5.37 (s, 1H),
7.25-7.35 (m, 2H), 7.35-7.50 (m, 3H), 8.90 (brs, 1H).
Example 1-170
[0799] MS ESI m/e: 477 (M+H), 475 (M-H).
[0800] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.15-1.26 (m, 2H), 1.76 (d, J=12.8 Hz, 6H), 2.72-2.82 (m, 1H), 2.84
(s, 3H), 5.99 (s, 1H), 7.29-7.36 (m, 2H), 7.39-7.56 (m, 5H),
7.70-7.82 (m, 2H), 10.67 (s, 1H).
Example 1-171
[0801] MS ESI m/e: 453 (M+H), 451 (M-H).
[0802] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.79 (m,
2H), 0.98-1.09 (m, 2H), 2.58 (s, 3H), 2.61-2.71 (m, 1H), 5.32 (s,
1H), 7.34-7.63 (m, 8H), 10.52 (brs, 1H).
Example 1-172
[0803] MS ESI m/e: 417 (M+H), 415 (M-H).
[0804] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.78 (m,
2H), 0.97-1.06 (m, 2H), 2.55 (s, 3H), 2.61-2.69 (m, 1H), 5.19 (s,
1H), 6.82 (d, J=9.0 Hz, 2H), 7.08 (d, J=6.0 Hz, 2H), 7.39-7.50 (m,
5H), 9.53 (brs, 1H), 10.18 (brs, 1H).
Example 1-173
[0805] MS ESI m/e: 419 (M+H), 417 (M-H).
[0806] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.71-2.80 (m,
2H), 1.01-1.09 (m, 2H), 2.60 (s, 3H), 2.64-2.72 (m, 1H), 5.34 (s,
1H), 7.28-7.54 (m, 9H), 10.53 (brs, 1H).
Example 1-174
[0807] MS ESI m/e: 437 (M+H), 435 (M-H).
[0808] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.78 (m,
2H), 0.96-1.08 (m, 2H), 2.57 (s, 3H), 2.61-2.72 (m, 1H), 4.84 (s,
1H), 7.24-7.52 (m, 8H), 10.15 (brs, 1H).
Example 1-175
[0809] MS ESI m/e: 449 (M+H), 447 (M-H).
[0810] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.92 (m, 2H),
1.15-1.24 (m, 2H), 2.72-2.81 (m, 1H), 2.81 (s, 3H), 3.82 (s, 3H),
5.46 (d, J=1.6 Hz, 1H), 6.69-6.79 (m, 2H), 7.19-7.29 (m, 1H),
7.29-7.36 (m, 2H), 7.39-7.54 (m, 3H), 10.01 (brs, 1H).
Example 1-176
[0811] MS ESI m/e: 513, 515 (M+H), 511, 513 (M-H).
[0812] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.91 (m, 2H),
1.16-1.24 (m, 2H), 2.75-2.82 (m, 1H), 2.82 (s, 3H), 5.73 (s, 1H),
7.30-7.36 (m, 2H), 7.38-7.53 (m, 4H), 7.41 (d, J=1.8 Hz, 1H), 7.66
(d, J=1.8 Hz, 1H), 10.53 (brs, 1H).
Example 1-177
[0813] MS ESI m/e: 507, 509 (M+H), 505, 507 (M-H).
[0814] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.85-0.89 (m, 2H),
1.17-1.22 (m, 2H), 1.23 (t, J=7.5 Hz, 3H), 2.63 (q, J=7.5 Hz, 2H),
2.74-2.79 (m, 1H), 2.80 (s, 3H), 5.40 (s, 1H), 7.15 (d, J=8.4 Hz,
1H), 7.29-7.36 (m, 3H), 7.40-7.51 (m, 4H), 10.11 (brs, 1H).
Example 1-178
[0815] MS ESI m/e: 459 (M+H), 457 (M-H).
[0816] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.73-0.79 (m,
2H), 1.00-1.09 (m, 2H), 2.63 (s, 3H), 2.65-2.72 (m, 1H), 3.86 (s,
3H), 5.84 (s, 1H), 7.42-7.56 (m, 6H), 7.99-8.03 (m, 2H), 10.96
(brs, 1H).
Example 1-179
[0817] MS ESI m/e: 383 (M+H).
[0818] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.87 (m, 2H),
1.12-1.21 (m, 2H), 2.69-2.76 (m, 1H), 2.80 (s, 3H), 3.36 (q, J=5.4
Hz, 2H), 3.44 (s, 3H), 3.66 (t, J=5.4 Hz, 2H), 5.39 (s, 1H),
7.23-7.31 (m, 2H), 7.37-7.51 (m, 3H), 8.80-8.88 (m, 1H).
Example 1-180
[0819] MS ESI m/e: 422 (M+H).
[0820] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.74 (m,
2H), 0.95-1.05 (m, 2H), 1.42-1.56 (m, 2H), 1.88-1.98 (m, 2H),
2.10-2.21 (m, 2H), 2.18 (s, 3H), 2.55 (s, 3H), 2.58-2.70 (m, 3H),
3.33-3.44 (m, 1H), 5.23 (s, 1H), 7.34-7.41 (m, 2H), 7.42-7.53 (m,
3H), 8.77-8.84 (m, 1H).
Example 1-181
[0821] MS ESI m/e: 365 (M+H).
[0822] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.59-0.67 (m, 2H),
0.77-0.89 (m, 4H), 1.11-1.21 (m, 2H), 2.42-2.50 (m, 1H), 2.66-2.76
(m, 1H), 2.81 (s, 3H), 5.81 (s, 1H), 7.24-7.28 (m, 1H), 7.29-7.31
(m, 1H), 7.37-7.51 (m, 3H), 8.68 (brs, 1H).
Example 1-182
[0823] MS ESI m/e: 450 (M+H).
[0824] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.77-0.86 (m, 2H),
1.01-1.12 (m, 6H), 1.12-1.21 (m, 2H), 1.54-1.74 (m, 2H), 2.03-2.15
(m, 2H), 2.25-2.41 (m, 2H), 2.66-2.76 (m, 1H), 2.79 (s, 3H),
2.82-2.94 (m, 2H), 3.25-3.41 (m, 1H), 5.40 (s, 1H), 7.25-7.28 (m,
1H), 7.29-7.32 (m, 1H), 7.37-7.51 (m, 3H), 8.71-8.79 (m, 1H).
Example 1-183
[0825] MS ESI m/e: 509, 511 (M+H), 507, 509 (M-H).
[0826] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.90 (m, 2H),
1.13-1.24 (m, 2H), 2.71-2.81 (m, 2H), 2.85 (s, 3H), 3.84 (s, 3H),
5.78 (s, 1H), 6.93-7.00 (m, 2H), 7.13-7.19 (m, 2H), 7.19-7.23 (m,
2H), 7.47-7.53 (m, 2H), 10.42 (brs, 1H).
Example 1-184
[0827] MS ESI m/e: 410 (M+H).
[0828] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.75-0.88 (m, 2H),
1.09-1.22 (m, 2H), 1.85 (tt, J=7.0, 14.0 Hz, 2H), 2.26 (s, 6H),
2.40 (t, J=7.1 Hz, 2H), 2.67-2.77 (m, 1H), 2.79 (s, 3H), 3.22 (dt,
J=5.5, 6.2 Hz, 3H), 5.40 (s, 1H), 7.25-7.33 (m, 2H), 7.37-7.52 (m,
3H), 8.74 (t, J=4.8 Hz, 1H).
Example 1-185
[0829] MS ESI m/e: 471, 473 (M+H), 469, 471 (M-H).
[0830] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.62 (s, 3H),
3.27 (s, 3H), 5.37 (s, 1H), 7.40-7.60 (m, 7H), 7.70-7.80 (m, 1H),
10.61 (s, 1H).
Example 1-186
[0831] MS ESI m/e: 527, 529 (M+H), 525, 527 (M-H).
[0832] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.90 (m, 2H),
1.13-1.24 (m, 2H), 2.71-2.82 (m, 1H), 2.85 (s, 3H), 3.84 (s, 3H),
5.64 (d, J=1.1 Hz, 1H), 6.94-7.01 (m, 2H), 7.17-7.24 (m, 2H),
7.29-7.33 (m, 2H), 7.34-7.40 (m, 1H), 10.35 (brs, 1H).
Example 1-187
[0833] MS ESI m/e: 459 (M+H), 457 (M-H).
[0834] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.92 (m, 2H),
1.13-1.24 (m, 2H), 1.35 (d, J=6.0 Hz, 6H), 2.72-2.82 (m, 1H), 2.81
(s, 3H), 4.54 (sept, J=6.0 Hz, 1H), 5.63 (s, 1H), 6.85-6.94 (m,
2H), 7.12-7.20 (m, 2H), 7.29-7.35 (m, 2H), 7.38-7.53 (m, 3H), 10.15
(brs, 1H).
Example 1-188
[0835] MS ESI m/e: 513, 515 (M+H), 511, 513 (M-H).
[0836] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.62-2.72 (m, 1H), 2.66 (s, 3H), 5.35 (d,
J=1.1 Hz, 1H), 6.79-6.89 (m, 2H), 7.15-7.23 (m, 2H), 7.43-7.55 (m,
2H), 7.70-7.76 (m, 1H), 9.90 (brs, 1H), 10.57 (brs, 1H).
Example 1-189
[0837] MS ESI m/e: 509, 511 (M+H), 507, 509 (M-H).
[0838] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.90 (m, 2H),
1.14-1.25 (m, 2H), 2.73-2.80 (m, 1H), 2.82 (s, 3H), 3.89 (s, 3H),
5.80 (s, 1H), 7.07-7.13 (m, 2H), 7.23-7.35 (m, 3H), 7.39-7.53 (m,
3H), 10.29 (brs, 1H).
Example 1-190
[0839] MS ESI m/e: 509, 511 (M+H), 507, 509 (M-H).
[0840] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.67 (s, 3H), 2.66-2.68 (m, 1H), 3.78 (s,
3H), 5.53 (s, 1H), 6.97-7.06 (m, 3H), 7.31 (d, J=9.0 Hz, 2H), 7.41
(dd, J=9.0, 9.0 Hz, 1H), 7.62 (d, J=9.0 Hz, 2H), 10.58 (brs,
1H).
Example 1-191
[0841] MS ESI m/e: 527, 529 (M+H), 525, 527 (M-H).
[0842] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.01-1.09 (m, 2H), 2.67 (s, 3H), 2.66-2.67 (m, 1H), 3.78 (s,
3H), 5.37 (s, 1H), 6.97-7.06 (m, 3H), 7.39-7.51 (m, 3H), 7.73 (d,
J=12.0 Hz, 1H), 10.55 (brs, 1H).
Example 1-192
[0843] MS ESI m/e: 462 (M+H).
[0844] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.08 (m, 2H), 2.55 (s, 3H), 2.60-2.71 (m, 1H), 2.92 (s,
6H), 5.01 (s, 1H), 6.56-6.66 (m, 2H), 7.18 (dd, J=12.0, 9.0 Hz,
1H), 7.39-7.51 (m, 5H), 10.00 (brs, 1H).
Example 1-193
[0845] MS ESI m/e: 582, 584 (M+H), 580, 582 (M-H).
[0846] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (m, 2H),
1.03 (m, 2H), 2.60-2.75 (m, 1H), 2.69 (s, 3H), 3.11 (brs, 4H), 3.73
(brs, 4H), 5.38 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 7.02 (brs, 2H),
7.34 (t, J=8.5 Hz, 1H), 7.40-7.55 (m, 2H), 7.73 (d, J=11.1 Hz, 1H),
10.57 (s, 1H).
Example 1-194
[0847] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0848] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.80-0.89 (m, 2H),
1.12-1.23 (m, 2H), 2.68-2.80 (m, 1H), 2.79 (s, 3H), 4.37 (d, J=6.0
Hz, 2H), 5.33 (s, 1H), 7.18-7.33 (m, 4H), 7.39-7.52 (m, 5H), 9.14
(t, J=5.6 Hz, 1H).
Example 1-195
[0849] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0850] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.89 (m, 2H),
1.12-1.22 (m, 2H), 2.68-2.76 (m, 1H), 2.78 (s, 3H), 4.34 (d, J=5.6
Hz, 2H), 5.34 (s, 1H), 7.20-7.31 (m, 4H), 7.39-7.53 (m, 5H), 9.11
(t, J=5.3 Hz, 1H).
Example 1-196
[0851] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[0852] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.89 (m, 2H),
1.12-1.22 (m, 2H), 2.69-2.77 (m, 1H), 2.79 (s, 3H), 4.46 (d, J=5.6
Hz, 2H), 5.36 (s, 1H), 7.17 (dt, J=1.9, 7.5 Hz, 1H), 7.24-7.33 (m,
3H), 7.35 (dt, J=1.1, 7.7 Hz, 1H), 7.39-7.51 (m, 3H), 7.59 (dd,
J=1.1, 7.9 Hz, 1H), 9.16 (t, J=5.7 Hz, 1H).
Example 1-197
[0853] MS ESI m/e: 445 (M+H), 443 (M-H).
[0854] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.14-1.25 (m, 2H), 2.72-2.83 (m, 1H), 2.80 (s, 3H), 3.11 (s, 6H),
5.44 (s, 1H), 6.53 (d, J=9.0 Hz, 1H), 7.29-7.34 (m, 2H), 7.37 (dd,
J=2.6, 9.0 Hz, 1H), 7.39-7.52 (m, 3H), 8.07 (d, J=2.6 Hz, 1H), 9.96
(brs, 1H).
Example 1-198
[0855] MS EST m/e: 495, 497 (M+H), 493, 495 (M-H).
[0856] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.78 (m,
2H), 0.98-1.08 (m, 2H), 2.59 (s, 3H), 2.61-2.72 (m, 1H), 5.50 (s,
1H), 7.04 (dd, J=2.3, 8.3 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 7.30 (d,
J=8.3 Hz, 1H), 7.38-7.55 (m, 5H), 10.45 (s, 1H), 10.48 (brs,
1H).
Example 1-199
[0857] MS ESI m/e: 540, 542 (M+H), 538, 540 (M-H).
[0858] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.14-1.23 (m, 2H), 2.71-2.82 (m, 1H), 2.93 (s, 3H), 2.96 (s, 6H),
5.66 (s, 1H), 6.52 (t, J=2.1 Hz, 1H), 6.59 (dd, J=1.9, 8.3 Hz, 1H),
6.71 (dd, J=2.6, 8.6 Hz, 1H), 7.26-7.40 (m, 4H), 10.39 (brs,
1H).
Example 1-200
[0859] MS ESI m/e: 487, 489 (M+H), 485, 487 (M-H).
[0860] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.62 (s, 3H),
3.27 (s, 3H), 5.47 (s, 1H), 7.40-7.60 (m, 6H), 7.63 (dd, J=2.1, 8.6
Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 10.83 (s, 1H).
Example 1-201
[0861] MS ESI m/e: 569, 571 (M+H), 567, 569 (M-H).
[0862] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (m, 2H),
1.03 (m, 2H), 2.45-2.60 (m, 2H), 2.60 (s, 3H), 2.67 (m, 1H), 2.85
(t, J=7.4 Hz, 2H), 5.36 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.32 (brs,
2H), 7.41 (t, J=7.9 Hz, 1H), 7.45-7.55 (m, 2H), 7.73 (d, J=9.2 Hz,
1H), 10.54 (s, 1H), 12.15 (brs, 1H).
Example 1-202
[0863] MS ESI m/e: 499, 501 (M+H), 497, 499 (M-H).
[0864] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.74-0.82 (m,
2H), 0.98-1.06 (m, 2H), 2.63-2.70 (m, 1H), 5.74 (s, 1H), 7.25-7.33
(m, 2H), 7.38-7.55 (m, 4H), 7.63 (dd, J=2.2, 8.8 Hz, 1H), 7.92 (d,
J=2.2 Hz, 1H), 10.90 (brs, 1H), 11.14 (brs, 1H).
Example 1-203
[0865] MS ESI m/e: 482 (M+H).
[0866] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.77-0.79 (m, 2H),
1.02-1.17 (m, 2H), 2.18 (s, 3H), 2.34 (s, 3H), 2.57 (s, 3H),
2.65-2.68 (m, 1H), 3.66 (s, 3H), 5.24 (s, 1H), 6.98 (d, J=6.0 Hz,
1H), 7.29 (d, J=3.0 Hz, 1H), 7.40-7.56 (m, 6H), 10.35 (brs,
1H).
Example 1-204
[0867] MS ESI m/e: 468 (M+H).
[0868] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.80 (m,
2H), 1.00-1.09 (m, 2H), 2.41 (s, 3H), 2.57 (s, 3H), 2.62-2.71 (m,
1H), 3.68 (s, 3H), 5.26 (s, 1H), 6.23 (s, 1H), 6.97 (d, J=12.0 Hz,
1H), 7.33 (s, 1H), 7.42-7.52 (m, 6H), 10.35 (brs, 1H).
Example 1-205
[0869] MS ESI m/e: 547 (M+H), 545 (M-H).
[0870] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.86 (m, 2H), 1.18
(m, 2H), 2.75 (m, 1H), 2.89 (s, 3H), 2.97 (s, 6H), 3.16 (t, J=4.8
Hz, 4H), 3.85 (t, J=4.8 Hz, 4H), 5.45 (s, 1H), 6.45 (s, 1H), 6.49
(d, J=3.8 Hz, 1H), 6.75-6.80 (m, 2H), 6.91 (d, J=8.3 Hz, 1H), 7.14
(t, J=9.0 Hz, 1H), 7.33 (t, J=8.4 Hz, 1H), 9.89 (s, 1H).
Example 1-206
[0871] MS ESI m/e: 595, 597 (M+H).
[0872] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.77 (m,
2H), 0.98-1.07 (m, 2H), 2.21 (s, 3H), 2.40-2.46 (m, 4H), 2.61-2.71
(m, 1H), 2.69 (s, 3H), 3.09-3.16 (m, 4H), 5.37 (s, 1H), 6.79-6.84
(m, 1H), 6.96-7.03 (m, 2H), 7.29-7.34 (m, 1H), 7.44-7.54 (m, 2H),
7.69-7.77 (m, 1H), 10.58 (brs, 1H).
Example 1-207
[0873] MS ESI m/e: 545 (M+H), 543 (M-H).
[0874] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.92 (m, 2H),
1.14-1.25 (m, 2H), 2.72-2.82 (m, 1H), 2.82 (s, 3H), 5.69 (d, J=1.1
Hz, 1H), 7.28-7.36 (m, 2H), 7.40-7.59 (m, 6H), 10.36 (s, 1H).
Example 1-208
[0875] MS ESI m/e: 443 (M+H), 441 (M-H).
[0876] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.81-0.91 (m, 2H),
1.16-1.23 (m, 2H), 2.73-2.80 (m, 1H), 2.82 (s, 3H), 3.12 (s, 1H),
5.80 (s, 1H), 7.26-7.33 (m, 3H), 7.35-7.52 (m, 5H), 10.50 (s,
1H).
Example 1-209
[0877] MS ESI m/e: 416 (M+H), 414 (M-H).
[0878] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.79-0.88 (m, 2H),
1.12-1.22 (m, 2H), 2.68-2.77 (m, 1H), 2.79 (s, 3H), 4.42 (d, J=5.6
Hz, 2H), 5.37 (s, 1H), 7.26-7.35 (m, 3H), 7.38-7.52 (m, 3H),
7.65-7.72 (m, 1H), 8.57 (dd, J=1.5, 4.9 Hz, 1H), 8.63 (d, J=1.9 Hz,
1H), 9.15 (t, J=5.3 Hz, 1H).
Example 1-210
[0879] MS ESI m/e: 511, 513 (M+H), 509, 511 (M-H).
[0880] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.80-0.90 (m, 2H),
1.13-1.23 (m, 2H), 2.70-2.78 (m, 1H), 2.79 (s, 3H), 4.43 (d, J=6.0
Hz, 2H), 5.33 (s, 1H), 6.98 (dd, J=9.0, 9.1 Hz, 1H), 7.28-7.33 (m,
2H), 7.35-7.53 (m, 5H), 9.12 (t, J=6.0 Hz, 1H).
Example 1-211
[0881] MS ESI m/e: 509, 511 (M+H), 507, 509 (M-H).
[0882] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.14-1.25 (m, 2H), 2.73-2.84 (m, 1H), 2.81 (s, 3H), 3.83 (s, 3H),
5.46 (s, 1H), 6.89 (dd, J=3.0, 8.7 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H),
7.29-7.36 (m, 3H), 7.38-7.54 (m, 3H), 10.17 (brs, 1H).
Example 1-212
[0883] MS ESI m/e: 580, 581 (M+H), 578, 580 (M-H).
[0884] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.87 (m, 2H), 1.18
(m, 2H), 2.20 (m, 2H), 2.63 (t, J=8.1 Hz, 2H), 2.77 (m, 1H), 2.88
(s, 3H), 3.88 (t, J=7.1 Hz, 2H), 5.66 (s, 1H), 7.07 (d, J=7.9 Hz,
1H), 7.30-7.35 (m, 2H), 7.37 (d, J=9.2 Hz, 1H), 7.46 (t, J=8.1 Hz,
1H), 7.54 (d, J=8.6 Hz, 1H), 7.89 (d, J=2.0 Hz, 1H), 10.34 (s,
1H).
Example 1-213
[0885] MS ESI m/e: 513, 515 (M+H), 511, 513 (M-H).
[0886] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.99-1.09 (m, 2H), 2.68 (s, 3H), 2.61-2.71 (m, 1H), 5.35 (s,
1H), 2.79-2.89 (m, 3H), 7.27 (dd, J=9.0, 9.0 Hz, 1H), 7.48-7.52 (m,
2H), 7.72 (d, J=6.0 Hz, 1H), 9.83 (brs, 1H), 10.53 (brs, 1H).
Example 1-214
[0887] MS ESI m/e: 594, 596 (M+H), 592, 594 (M-H).
[0888] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (m, 2H),
1.03 (m, 2H), 1.85 (brs, 4H), 2.39 (m, 2H), 2.67 (m, 4H), 3.62 (m,
2H), 5.36 (s, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.35-7.40 (m, 2H),
7.45-7.55 (m, 3H), 7.74 (d, J=10.2 Hz, 1H), 10.54 (s, 1H).
Example 1-215
[0889] MS ESI m/e: 566, 568 (M+H), 564, 566 (M-H).
[0890] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.80 (m,
2H), 0.99-1.11 (m, 2H), 1.90-2.01 (m, 4H), 2.64-2.74 (m, 1H),
2.74-2.75 (m, 1H), 3.13-3.27 (m, 4H), 5.39 (s, 1H), 6.54-6.65 (m,
3H), 7.20-7.30 (m, 1H), 7.45-7.55 (m, 2H), 7.71-7.78 (m, 1H), 10.60
(brs, 1H).
Example 1-216
[0891] MS ESI m/e: 580, 582 (M+H), 578, 580 (M-H).
[0892] .sup.1H-NMR (DMSO-d, 300 MHz) .delta. 0.69-0.78 (m, 2H),
0.98-1.08 (m, 2H), 1.48-1.65 (m, 6H), 2.63-2.71 (m, 1H), 2.69 (s,
3H), 3.09-3.17 (m, 4H), 5.37 (s, 1H), 6.72-6.79 (m, 1H), 6.95-7.02
(m, 2H), 7.25-7.32 (m, 1H), 7.46-7.54 (m, 2H), 7.69-7.77 (m, 1H),
10.59 (brs, 1H).
Example 1-217
[0893] MS ESI m/e: 476 (M+H), 474 (M-H).
[0894] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 1.01-1.13 (m, 5H), 2.58 (s, 3H), 2.61-2.72 (m, 1H), 2.90 (s,
3H), 3.42 (q, J=2.0 Hz, 2H), 5.04 (s, 1H), 6.62 (dd, J=9.0, 15.0
Hz, 2H), 7.18 (t, J=9.0 Hz, 1H), 7.40-7.59 (m, 5H), 10.01 (brs,
1H).
Example 1-218
[0895] MS ESI m/e: 584, 585 (M+H), 582, 584 (M-H).
[0896] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.78 (m,
2H), 0.98-1.09 (m, 2H), 2.18 (s, 6H), 2.59 (t, J=3.0 Hz, 2H), 2.66
(s, 3H), 2.65-2.66 (m, 1H), 4.01 (t, J=4.5 Hz, 2H), 5.37 (s, 1H),
6.96-7.08 (m, 3H), 7.38-7.51 (m, 3H), 7.71 (d, J=12.0 Hz, 1H),
10.55 (brs, 1H).
Example 1-219
[0897] MS ESI m/e: 596, 598 (M+H), 594, 596 (M-H).
[0898] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (m, 2H),
1.03 (m, 2H), 2.67 (s, 4H), 3.75 (m, 2H), 3.98 (t, J=4.9 Hz, 2H),
4.21 (s, 2H), 5.36 (s, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.40-7.60 (m,
5H), 7.73 (d, J=9.4 Hz, 1H), 10.53 (s, 1H).
Example 1-220
[0899] MS ESI m/e: 571, 573 (M+H), 569, 571 (M-H).
[0900] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.74-0.76 (m,
2H), 0.99-1.10 (m, 2H), 2.65-2.67 (m, 1H), 2.66 (s, 3H), 4.71 (s,
2H), 5.37 (s, 1H), 6.99-7.08 (m, 3H), 7.41 (t, J=9.0 Hz, 1H),
7.45-7.52 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 10.55 (brs, 1H), 13.04
(brs, 1H).
Example 1-221
[0901] MS ESI m/e: 527 (M+H), 525 (M-H).
[0902] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.14-1.25 (m, 2H), 2.71-2.82 (m, 1H), 2.82 (s, 3H), 5.82 (s, 1H),
7.01-7.09 (m, 2H), 7.28-7.35 (m, 2H), 7.39-7.54 (m, 3H), 7.66-7.74
(m, 2H), 10.42 (s, 1H).
Example 1-222
[0903] MS ESI m/e: 425 (M+H), 423 (M-H).
[0904] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.15-1.24 (m, 2H), 2.71-2.83 (m, 1H), 2.83 (s, 3H), 3.09 (s, 1H),
5.92 (s, 1H), 7.22-7.29 (m, 2H), 7.29-7.35 (m, 2H), 7.40-7.57 (m,
5H), 10.54 (s, 1H).
Example 1-223
[0905] MS ESI m/e: 575, 577 (M+H), 573, 575 (M-H).
[0906] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.91 (m, 2H),
1.17-1.26 (m, 2H), 2.73-2.80 (m, 1H), 2.81 (s, 3H), 3.11 (s, 3H)
5.65 (s, 1H), 7.27-7.35 (m, 2H), 7.35-7.40 (min, 1H), 7.51-7.56 (m,
1H), 7.68-7.75 (m, 1H), 8.00-8.05 (m, 2H), 10.22 (s, 1H).
Example 1-224
[0907] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[0908] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.15-1.27 (m, 2H), 2.72-2.81 (m, 1H), 2.76 (s, 6H), 2.81 (s, 3H),
5.65 (d, J=1.1 Hz, 1H), 7.29-7.34 (m, 2H), 7.35-7.43 (m, 1H),
7.45-7.51 (m, 1H), 7.63-7.72 (m, 1H), 7.83-7.89 (m, 2H), 10.25 (s,
1H).
Example 1-225
[0909] MS ESI m/e: 575, 577 (M+H), 573, 575 (M-H).
[0910] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.16-1.27 (m, 2H), 2.72-2.83 (m, 1H), 2.83 (brs, 3H), 3.10 (s, 3H),
5.63 (brs, 1H), 7.28-7.35 (m, 2H), 7.36-7.42 (m, 1H), 7.58 (d,
J=8.4 Hz, 2H), 8.10 (d, J=8.4 Hz, 2H), 10.22 (s, 1H).
Example 1-226
[0911] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[0912] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.91 (m, 2H),
1.17-1.25 (m, 2H), 2.71-2.81 (m, 1H), 2.75 (s, 6H), 2.84 (brs, 3H),
5.58 (brs, 1H), 7.26-7.35 (m, 2H), 7.35-7.40 (m, 1H), 7.52 (d,
J=8.1 Hz, 2H), 7.89 (d, J=8.1 Hz, 2H), 10.21 (s, 1H).
Example 1-227
[0913] MS ESI m/e: 598, 600 (M+H), 596, 598 (M-H).
[0914] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.78 (m,
2H), 0.99-1.09 (m, 2H), 1.84 (t, J=6.0 Hz, 2H), 2.13 (s, 6H), 2.34
(t, J=6.0 Hz, 2H), 2.66-2.68 (m, 1H), 2.67 (s, 3H), 4.00 (t, J=6.0
Hz, 2H), 5.37 (s, 1H), 6.96-7.09 (m, 3H), 7.40 (dd, J=6.0, 6.0 Hz,
1H), 7.48-7.51 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 10.56 (brs,
1H).
Example 1-228
[0915] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[0916] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.98-1.10 (m, 2H), 2.61-2.71 (m, 1H), 2.68 (s, 3H), 2.96 (s,
3H), 3.25 (s, 3H), 5.37 (s, 1H), 7.39 (d, J=6.0 Hz, 18H), 7.45-7.58
(m, 5H), 7.74 (d, J=9.0 Hz, 1H), 10.53 (brs, 1H).
Example 1-229
[0917] MS ESI m/e: 443 (M+H), 441 (M-H).
[0918] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.90 (m, 2H),
1.14-1.24 (m, 2H), 1.27 (d, J=7.1 Hz, 6H), 2.72-2.81 (m, 1H), 2.81
(s, 3H), 2.92 (sept, J=6.8 Hz, 1H), 5.77 (s, 1H), 7.16-7.22 (m,
28), 7.22-7.28 (m, 2H), 7.29-7.35 (m, 2H), 7.39-7.53 (m, 3H), 10.28
(brs, 1H).
Example 1-230
[0919] MS ESI m/e: 429 (M+H), 427 (M-H).
[0920] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.15-1.24 (m, 2H), 1.25 (t, J=7.5 Hz, 3H), 2.66 (q, J=7.5 Hz, 2H),
2.72-2.81 (m, 1H), 2.81 (s, 3H), 5.76 (s, 1H), 7.15-7.24 (m, 4H),
7.29-7.36 (m, 2H), 7.39-7.53 (m, 3H), 10.29 (brs, 1H).
Example 1-231
[0921] MS ESI m/e: 426 (M+H), 424 (M-H).
[0922] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.90 (m, 2H),
1.15-1.25 (m, 2H), 2.72-2.82 (m, 1H), 2.84 (s, 3H), 6.07 (s, 1H),
7.28-7.34 (m, 2H), 7.36-7.42 (m, 2H), 7.44-7.55 (m, 3H), 7.64-7.70
(m, 2H), 10.84 (brs, 1H).
Example 1-232
[0923] MS ESI m/e: 626, 628 (M+H), 624, 626 (M-H).
[0924] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.01-1.09 (min, 2H), 2.41-2.48 (m, 4H), 2.67 (s, 3H),
2.64-2.70 (m, 3H), 3.45-3.60 (m, 4H), 4.06-4.10 (m, 2H), 5.36 (s,
1H), 7.00 (d, J=3.0 Hz, 1H), 7.03-7.05 (m, 2H), 7.38-0.53 (m, 3H),
7.72 (d, J=6.0 Hz, 1H), 10.54 (brs, 1H).
Example 1-233
[0925] MS ESI m/e: 610, 612 (M+H), 608, 610 (M-H).
[0926] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.09 (m, 2H), 1.62-1.71 (m, 4H), 2.43-2.55 (m, 4H), 2.64
(s, 3H), 2.61-2.70 (m, 1H), 2.77 (t, J=3.0 Hz, 2H), 4.06 (t, J=3.0
Hz, 2H), 5.37 (s, 1H), 6.99 (d, J=3.0 Hz, 1H), 7.02-7.04 (m, 2H),
7.39 (dd, J=3.0, 3.0 Hz, 1H), 7.50-7.52 (m, 2H), 7.74 (d, J=3.0 Hz,
1H), 10.54 (brs, 1)
Example 1-234
[0927] MS ESI m/e: 624, 626 (M+H), 622, 624 (M-H).
[0928] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.01-1.09 (m, 2H), 1.32-1.41 (m, 2H), 1.41-1.52 (m, 4H),
2.37-2.46 (m, 4H), 2.60-2.71 (m, 3H), 2.67 (s, 3H), 4.07 (t, J=6.0
Hz, 2H), 5.38 (s, 1H), 7.01 (dd, J=6.0, 9.0 Hz, 1H), 7.05-7.06 (m,
2H), 7.40 (dd, J=9.0, 9.0 Hz, 1H), 7.49-7.51 (m, 2H), 7.74 (d,
J=12.0 Hz, 1H), 10.55 (brs, 1H).
Example 1-235
[0929] MS ESI m/e: 612, 614 (M+H), 610, 612 (M-H).
[0930] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.96 (t, J=7.5 Hz, 6H), 0.99-1.09 (m, 2H), 2.46-2.59 (m, 5H),
2.68 (s, 3H), 2.75 (t, J=3.0 Hz, 2H), 4.00 (t, J=3.0 Hz, 2H), 5.37
(s, 1H), 7.00 (dd, J=3.0, 3.0 Hz, 1H), 7.01-7.06 (m, 2H), 7.40 (dd,
J=6.0, 3.0 Hz, 1H), 7.49-7.52 (m, 2H), 7.74 (d, J=18.0 Hz, 1H),
10.56 (brs, 1H).
Example 1-236
[0931] MS ESI m/e: 653, 655 (M+H), 651, 653 (M-H).
[0932] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 0.96 (t, J=7.5 Hz, 6H), 0.99-1.09 (m, 2H), 1.80-1.91 (m, 2H),
2.13 (s, 3H), 2.46-2.59 (m, 10H), 2.60-2.73 (m, 4H), 4.00 (t, J=3.0
Hz, 2H), 5.37 (s, 1H), 7.00 (dd, J=3.0, 3.0 Hz, 1H), 7.01-7.06 (m,
2H), 7.40 (dd, J=6.0, 3.0 Hz, 1H), 7.49-7.52 (m, 2H), 7.74 (d,
J=18.0 Hz, 1H), 10.56 (brs, 1H).
Example 1-237
[0933] MS ESI m/e: 444 (M+H), 442 (M-H).
[0934] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.92 (m, 2H),
1.16-1.26 (m, 2H), 2.73-2.83 (m, 1H), 2.85 (s, 3H), 6.01 (s, 1H),
7.29-7.35 (m, 2H), 7.43-7.56 (m, 5H), 7.60-7.70 (m, 1H), 10.93 (s,
1H).
Example 1-238
[0935] MS ESI m/e: 473 (M+H), 471 (M-H).
[0936] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.08 (m, 2H), 2.60 (s, 3H), 2.63-2.71 (m, 1H), 4.31 (d,
J=5.8 Hz, 2H), 5.38 (t, J=5.9 Hz, 1H), 5.50 (s, 1H), 7.29-7.35 (m,
1H), 7.39-7.58 (m, 7H), 10.71 (s, 1H).
Example 1-239
[0937] MS ESI m/e: 501 (M+H), 499 (M-H).
[0938] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.82-0.90 (m, 2H),
1.15-1.24 (m, 2H), 1.63 (s, 6H), 2.07 (s, 1H), 2.73-2.81 (m, 1H),
2.82 (s, 3H), 5.78 (s, 1H), 7.16-7.25 (m, 2H), 7.28-7.33 (m, 2H),
7.34-7.52 (m, 4H), 10.46 (s, 1H).
Example 1-240
[0939] MS ESI m/e: 445 (M+H), 443 (M-H).
[0940] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.90 (m, 2H),
1.16-1.24 (m, 2H), 2.73-2.82 (m, 1H), 2.82 (s, 3H), 5.31 (d, J=10.9
Hz, 1H), 5.74 (d, J=17.6 Hz, 1H), 5.72 (s, 1H), 6.66 (dd, J=10.9,
17.8 Hz, 1H), 7.14-7.25 (m, 2H), 7.28-7.39 (m, 3H), 7.40-7.51 (m,
3H), 10.34 (s, 1H).
Example 1-241
[0941] MS ESI m/e: 487 (M+H), 485 (M-H).
[0942] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.15-1.24 (m, 2H), 2.73-2.83 (m, 1H), 2.83 (s, 3H), 3.47 (s, 3H),
4.33 (s, 2H), 5.79 (s, 1H), 7.22-7.35 (m, 4H), 7.35-7.56 (m, 4H),
10.49 (s, 1H).
Example 1-242
[0943] MS ESI m/e: 447 (M+H), 445 (M-H).
[0944] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.84-0.90 (m, 2H),
1.15-1.22 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H),
2.73-2.81 (m, 1H), 2.81 (s, 3H), 5.59 (d, J=1.2 Hz, 1H), 6.96-7.04
(m, 2H), 7.23-7.34 (m, 3H), 7.39-7.51 (m, 3H), 10.16 (s, 1H).
Example 1-243
[0945] MS ESI m/e: 555, 557 (M+H), 553, 555 (M-H).
[0946] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.92 (m, 2H),
1.14-1.25 (m, 2H), 1.43 (t, J=4.9 Hz, 1H), 1.88 (quint, J=7.3 Hz,
2H), 2.72-2.81 (m, 1H), 2.76 (t, J=7.7 Hz, 2H), 2.82 (s, 3H), 3.65
(q, J=5.7 Hz, 2H), 5.66 (s, 1H), 7.10-7.19 (m, 2H), 7.26-7.33 (m,
3H), 7.35-7.45 (m, 2H), 10.34 (brs, 1H).
Example 1-244
[0947] MS ESI m/e: 486, 488 (M+H), 484, 486 (M-H).
[0948] .sup.1H-NM R (DMSO-d.sub.6, 300 MHz) .delta. 1.19 (t, J=6.0
Hz, 3H), 2.50-2.53 (m, 1H), 2.62 (s, 3H), 3.95 (q, J=7.0 Hz, 2H),
5.37 (s, 1H), 7.48-7.52 (m, 2H), 7.60 (dd, J=3.0, 3.0 Hz, 1H), 7.74
(d, J=12.0 Hz, 1H), 7.97 (d, J=6.0 Hz, 1H), 8.73 (d, J=45.0 Hz,
1H), 10.58 (brs, 1H).
Example 1-245
[0949] MS ESI m/e: 554, 556 (M+H), 552, 554 (M-H).
[0950] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.99-1.09 (m, 2H), 2.04 (s, 3H), 2.63-2.68 (m, 1H), 2.66 (s,
3H), 5.35 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.41 (dd, J=6.0, 6.0 Hz,
1H), 7.49-7.51 (m, 2H), 7.61-7.77 (m, 3H), 10.18 (brs, 1H), 10.54
(brs, 1H).
Example 1-246
[0951] MS ESI m/e: 500 (M+H), 498 (M-H).
[0952] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.14-1.25 (m, 2H), 2.38 (s, 6H), 2.72-2.83 (m, 1H), 2.83 (s, 3H),
3.48 (s, 2H), 5.77 (d, J=0.7 Hz, 1H), 7.20-7.55 (m, 8H), 10.45 (s,
1H).
Example 1-247
[0953] MS ESI m/e: 489 (M+H), 487 (M-H).
[0954] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.81 (m,
2H), 0.99-1.10 (m, 2H), 2.61 (s, 3H), 2.64-2.74 (m, 1H), 5.57 (s,
1H), 6.58 (d, J=16.1 Hz, 1H), 7.40-7.64 (m, 8H), 7.81 (d, J=12.1
Hz, 1H), 10.80 (s, 1H), 12.44 (brs, 1H).
Example 1-248
[0955] MS ESI m/e: 491 (M+H), 489 (M-H).
[0956] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.72-0.78 (m,
2H), 0.99-1.07 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 2.58 (s, 3H),
2.63-2.70 (m, 1H), 2.86 (t, J=7.5 Hz, 2H), 5.25 (d, J=1.2 Hz, 1H),
7.12-7.17 (m, 1H), 7.24-7.30 (m, 1H), 7.35-7.54 (m, 6H), 10.40 (s,
1H), 12.18 (s, 1H).
Example 1-249
[0957] MS ESI m/e: 447 (M+H), 445 (M-H).
[0958] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.72-0.79 (m, 2H),
0.99-1.07 (m, 2H), 2.59 (s, 3H), 2.63-2.70 (m, 1H), 5.45 (s, 1H),
7.25-7.30 (m, 2H), 7.31-7.37 (m, 2H), 7.41-7.55 (m, 5H), 10.49
(brs, 1H).
Example 1-250
[0959] MS ESI m/e: 501 (M+H), 499 (M-H).
[0960] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 1.00-1.08 (m, 2H), 2.62 (s, 1H), 2.66-2.71 (m, 1H), 5.76 (s,
1H), 7.41-7.55 (m, 7H), 7.76 (d, J=8.3 Hz, 2H), 10.86 (brs,
1H).
Example 1-251
[0961] MS ESI m/e: 458 (M+H), 456 (M-H).
[0962] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.72-0.82 (m, 2H),
0.99-1.09 (m, 2H), 2.58 (s, 3H), 2.63-2.74 (m, 1H), 5.13 (d, J=1.1
Hz, 1H), 6.45-6.50 (m, 1H), 7.33-7.61 (m, 8H), 10.28 (brs, 1H),
11.28 (brs, 1H).
Example 1-252
[0963] MS ESI m/e: 582, 584 (M+H), 580, 582 (M-H).
[0964] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.91 (m, 2H),
1.14-1.25 (m, 2H), 1.76-1.90 (m, 2H), 2.26-2.38 (m, 2H), 2.26 (brs,
6H), 2.65-2.73 (m, 2H), 2.74-2.80 (m, 1H), 2.83 (s, 3H), 5.65 (d,
J=0.7 Hz, 1H), 7.10-7.16 (m, 2H), 7.24-7.29 (m, 1H), 7.30-7.34 (m,
2H), 7.34-7.44 (m, 2H), 10.34 (brs, 1H).
Example 1-253
[0965] MS ESI m/e: 584, 586 (M+H), 582, 584 (M-H).
[0966] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.90 (m, 2H),
1.15-1.23 (m, 2H), 2.73-2.80 (m, 1H), 2.93 (s, 3H), 2.97 (s, 3H),
3.34 (s, 3H), 3.44-3.56 (m, 4H), 5.66 (d, J=1.1 Hz, 2H), 6.55-6.60
(m, 2H), 6.70-6.76 (m, 1H), 7.22-7.40 (m, 4H), 10.39 (brs, 1H).
Example 1-254
[0967] MS ESI m/e: 457 (M+H), 455 (M-H).
[0968] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.82-0.89 (m, 2H),
1.15-1.23 (m, 2H), 2.06 (s, 3H), 2.72-2.80 (m, 1H), 2.82 (s, 3H),
5.74 (s, 1H), 7.14-7.21 (m, 2H), 7.28-7.36 (m, 3H), 7.39-7.51 (m,
3H), 10.38 (s, 1H).
Example 1-255
[0969] MS ESI m/e: 624, 626 (M+H), 622, 624 (M-H).
[0970] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.13-1.24 (m, 2H), 1.74-1.90 (m, 2H), 2.28-2.38 (m, 2H), 2.38-2.46
(m, 4H), 2.65-2.72 (m, 2H), 2.73-2.80 (m, 1H), 2.83 (s, 3H),
3.68-3.74 (m, 4H), 5.65 (d, J=1.1 Hz, 1H), 7.10-7.17 (m, 2H),
7.23-7.28 (m, 1H), 7.29-7.33 (m, 2H), 7.34-7.44 (m, 2H), 10.33
(brs, 1H).
Example 1-256
[0971] MS ESI m/e: 549 (M+H), 547 (M-H).
[0972] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.66-0.77 (m,
2H), 0.89-1.05 (m, 2H), 2.54-2.61 (m, 1H), 2.56 (s, 3H), 7.36-7.45
(m, 4H), 7.53-7.63 (m, 3H), 7.65-7.71 (m, 2H), 12.88 (brs, 1H).
Example 1-257
[0973] MS ESI m/e: 638 (M+H), 636 (M-H).
[0974] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.74 (m, 2H),
1.03 (m, 2H), 2.65 (s, 4H), 3.02 (s, 3H), 5.38 (s, 1H), 7.13 (d,
J=8.6 Hz, 1H), 7.20-7.40 (m, 3H), 7.46 (t, J=8.1 Hz, 1H), 7.63 (d,
J=9.3 Hz, 1H), 7.81 (d, J=10.1 Hz, 1H), 10.00 (s, 1H), 10.54 (s,
1H).
Example 1-258
[0975] MS ESI m/e: 461 (M+H), 459 (M-H).
[0976] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.91 (m, 2H),
0.96 (t, J=7.3 Hz, 3H), 1.14-1.25 (m, 2H), 1.58-1.72 (m, 2H), 2.60
(t, J=7.7 Hz, 2H), 2.72-2.82 (m, 1H), 2.82 (s, 3H), 5.61 (d, J=1.1
Hz, 1H), 6.94-7.04 (m, 2H), 7.24-7.36 (m, 3H), 7.41-7.53 (m, 3H),
10.18 (s, 1H).
Example 1-259
[0977] MS ESI m/e: 521 (M+H), 519 (M-H).
[0978] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.17-1.27 (m, 2H), 2.72-2.82 (m, 1H), 2.82 (s, 3H), 3.12 (s, 3H),
3.14 (s, 1H), 5.80 (d, J=0.7 Hz, 18H), 7.28-7.36 (m, 2H), 7.37-7.45
(m, 1H), 7.51-7.57 (m, 1H), 7.68-7.77 (m, 1H), 8.01-8.07 (m, 2H),
10.40 (s, 1H).
Example 1-260
[0979] MS ESI m/e: 536 (M+H), 534 (M-H).
[0980] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.82-0.93 (m, 2H),
1.29-1.28 (m, 2H), 2.71-2.81 (m, 1H), 2.89 (s, 3H), 3.10 (s, 3H),
3.15 (s, 1H), 5.82 (s, 1H), 6.81-6.88 (m, 1H), 7.08 (d, J=9.0 Hz,
1H), 7.21-7.39 (m, 3H), 7.39-7.51 (m, 2H), 10.49 (brs, 1H).
Example 1-261
[0981] MS ESI m/e: 499, 501 (M+H).
[0982] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 1.30 (t, J=7.0 Hz,
3H), 3.63 (s, 3H), 4.13 (q, J=7.0 Hz, 2H), 5.57 (s, 2H), 5.78 (s,
1H), 7.20-7.50 (m, 8H), 10.33 (s, 1H).
Example 1-262
[0983] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[0984] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.99-1.07 (m, 2H), 1.18 (t, J=7.5 Hz, 3H), 2.61-2.70 (m, 4H),
3.13 (q, J=7.0 Hz, 2H), 5.35 (s, 1H), 7.08-7.14 (m, 1H), 7.25-7.34
(m, 2H), 7.41-7.54 (m, 3H), 7.71-7.77 (m, 1H), 10.04 (brs, 1H),
10.53 (s, 1H).
Example 1-263
[0985] MS ESI m/e: 570, 572 (M+H), 568, 570 (M-H).
[0986] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.71-0.79 (m, 2H),
0.99-1.07 (m, 2H), 2.63-2.73 (m, 1H), 2.66 (s, 3H), 3.99 (d, J=6.0
Hz, 2H), 5.36 (s, 1H), 5.65 (t, J=6.0 Hz, 1H), 7.10-7.15 (m, 18H),
7.39-7.52 (m, 3H), 7.71-7.85 (m, 3H), 9.91 (brs, 1H), 10.54 (brs,
1H).
Example 1-264
[0987] MS ESI m/e: 512, 514 (M+H), 510, 512 (M-H).
[0988] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.69-0.77 (m, 2H),
0.97-1.08 (m, 2H), 2.62-2.71 (m, 1H), 2.74 (s, 3H), 5.35 (d, J=1.5
Hz, 1H), 5.38 (brs, 2H), 6.47-6.53 (m, 1H), 6.54-6.57 (m, 1H),
6.58-6.63 (m, 1H), 7.11 (t, J=7.9 Hz, 1H), 7.44-7.53 (m, 2H),
7.70-7.77 (m, 1H), 10.55 (brs, 1H).
Example 1-265
[0989] MS ESI m/e: 459 (M+H), 457 (M-H).
[0990] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.66-0.74 (m, 2H),
0.83-0.91 (m, 2H), 0.97-1.06 (m, 2H), 1.14-1.24 (m, 2H), 1.85-1.96
(m, 1H), 2.72-2.81 (m, 1H), 2.81 (s, 3H), 5.58 (d, J=1.1 Hz, 1H),
6.82-6.92 (m, 2H), 7.21-7.29 (m, 1H), 7.29-7.36 (m, 2H), 7.39-7.53
(m, 3H), 10.16 (s, 1H).
Example 1-266
[0991] MS ESI m/e: 584, 586 (M+H), 582, 584 (M-H).
[0992] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.99-1.08 (m, 2H), 2.63-2.71 (m, 1H), 2.66 (s, 3H), 3.32 (s,
3H), 3.37 (s, 3H), 4.00 (brs, 2H), 5.36 (d, J=0.8 Hz, 1H),
7.10-7.16 (m, 1H), 7.40-7.52 (m, 3H), 7.71-7.80 (m, 3H), 10.00
(brs, 1H), 10.54 (brs, 1H).
Example 1-267
[0993] MS ESI m/e: 658, 660 (M+H), 656, 658 (M-H).
[0994] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.70-0.79 (m, 2H),
0.99-1.10 (m, 2H), 2.62-2.76 (m, 1H), 2.66 (s, 3H), 4.48-4.64 (m,
2H), 5.36 (s, 1H), 7.17 (d, J=9.0 Hz, 1H), 7.28-7.33 (m, 2H),
7.43-7.52 (m, 3H), 7.74 (d, J=12.0 Hz, 1H), 10.52 (brs, 1H), 10.72
(brs, 1H).
Example 1-268
[0995] MS ESI m/e: 554 (M+H), 552 (M-H).
[0996] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.14-1.24 (m, 2H), 1.26 (t, J=7.7 Hz, 3H), 1.37 (t, J=7.3 Hz, 3H),
2.67 (q, J=7.6 Hz, 2H), 2.71-2.81 (m, 1H), 2.85 (s, 3H), 3.17 (q,
J=7.5 Hz, 2H), 5.60 (d, J=1.1 Hz, 1H), 6.94-7.08 (m, 4H), 7.22-7.33
(m, 3H), 7.38-7.47 (m, 1H), 10.15 (s, 1H).
Example 1-269
[0997] MS EST m/e: 541, 543 (M+H), 539, 541 (M-H).
[0998] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.10 (m, 2H), 2.60 (s, 3H), 2.62-2.71 (m, 1H), 5.37 (d,
J=1.1 Hz, 1H), 7.43-7.57 (m, 2H), 7.61-7.78 (m, 3H), 7.95-8.05 (m,
2H), 10.54 (brs, 1H), 13.34 (brs, 1H).
Example 1-270
[0999] MS ESI m/e: 540, 542 (M+H), 538, 540 (M-H).
[1000] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.98-1.09 (m, 2H), 2.61 (s, 3H), 2.63-2.74 (m, 1H), 5.38 (s,
1H), 7.45-7.58 (m, 3H), 7.58-7.65 (m, 2H), 7.70-7.78 (m, 1H), 7.90
(brs, 1H), 7.94-8.00 (m, 1H), 8.11 (brs, 1H), 10.54 (brs, 1H).
Example 1-271
[1001] MS ESI m/e: 618, 620 (M+H), 616, 618 (M-H).
[1002] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.77 (m,
2H), 0.92 (t, J=7.5 Hz, 3H), 1.00-1.07 (m, 2H), 1.66 (q, J=7.0 Hz,
2H), 2.62-2.70 (m, 4H), 3.05-3.13 (m, 2H), 5.36 (s, 1H), 7.09-7.13
(m, 1H), 7.23-7.32 (m, 2H), 7.41-7.53 (m, 3H), 7.71-7.77 (m, 1H),
10.05 (brs, 1H), 10.53 (s, 1H).
Example 1-272
[1003] MS ESI m/e: 618, 620 (M+H), 616, 618 (M-H).
[1004] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.99-1.08 (m, 2H), 1.23 (d, J=6.0 Hz, 6H), 2.62-2.70 (m, 4H),
3.19-3.29 (m, 1H), 5.36 (s, 1H), 7.07-7.13 (m, 1H), 7.26-7.34 (m,
2H), 7.39-7.54 (m, 3H), 7.71-7.76 (m, 1H), 10.00 (brs, 1H), 10.53
(s, 1H).
Example 1-273
[1005] MS ESI m/e: 469 (M+H), 467 (M-1).
[1006] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.80-0.90 (m, 2H),
1.10-1.30 (m, 2H), 2.78 (m, 1H), 2.83 (s, 3H), 5.97 (s, 1H),
7.30-7.35 (m, 2H), 7.35-7.55 (m, 5H), 7.65 (d, J=8.5 Hz, 2H), 10.67
(s, 1H).
Example 1-274
[1007] MS ESI m/e: 652 (M+H), 650 (M-H).
[1008] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.08 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 2.61-2.71 (m, 1H),
2.64 (s, 3H), 3.13 (q, J=7.3 Hz, 2H), 5.38 (brs, 1H), 7.09-7.15 (m,
2H), 7.24-7.38 (m, 3H), 7.40-7.49 (m, 1H), 7.60-7.67 (m, 1H), 7.81
(dd, J=1.8, 9.9 Hz, 1H), 10.04 (s, 1H).
Example 1-275
[1009] MS ESI m/e: 540 (M+H), 538 (M-H).
[1010] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.91 (m, 2H),
1.15-1.23 (m, 2H), 1.26 (t, J=7.6 Hz, 3H), 2.67 (q, J=7.6 Hz, 2H),
2.72-2.80 (m, 1H), 2.85 (s, 3H), 3.05 (s, 3H), 5.60 (d, J=1.2 Hz,
1H), 6.98-7.05 (m, 2H), 7.05-7.10 (m, 1H), 7.23-7.31 (m, 4H),
7.40-7.47 (m, 1H), 10.16 (s, 1H).
Example 1-276
[1011] MS ESI m/e: 653, 655 (M+H).
[1012] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.87 (t, J=7.2 Hz, 3H), 1.00-1.08 (m, 2H), 1.22-1.36 (m, 2H),
1.43-1.54 (m, 2H), 2.15 (t, J=7.3 Hz, 2H), 2.63-2.72 (m, 1H), 2.66
(s, 3H), 3.86 (d, J=5.3 Hz, 2H), 5.36 (s, 1H), 7.05-7.12 (m, 1H),
7.40-7.52 (m, 3H), 7.61-7.77 (m, 3H), 8.08-8.15 (m, 1H), 10.20
(brs, 1H), 10.54 (brs, 1H).
Example 1-277
[1013] MS ESI m/e: 597, 599 (M+H), 595, 597 (M-H).
[1014] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.78 (m,
2H), 0.99-1.07 (m, 2H), 2.28 (s, 6H), 2.64-2.70 (m, 1H), 2.67 (s,
3H), 3.09 (brs, 2H), 5.36 (d, J=1.1 Hz, 1H), 7.10-7.14 (m, 1H),
7.40-7.52 (m, 3H), 7.71-7.79 cm, 3H), 9.97 (brs, 1H), 10.54 (brs,
1H).
Example 1-278
[1015] MS ESI m/e: 568, 570 (M+H), 566, 568 (M-H).
[1016] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.99-1.11 (m, 5H), 2.33 (q, J=7.0 Hz, 2H), 2.63-2.71 (m, 4H),
5.36 (s, 1H), 7.04-7.10 (m, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.46-7.54
(m, 2H), 7.61-7.67 (m, 1H), 7.70-7.77 (m, 2H), 10.08 (s, 1H), 10.54
(s, 1H).
Example 1-279
[1017] MS ESI m/e: 582, 584 (M+H), 580, 582 (M-H).
[1018] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.91 (t, J=7.5 Hz, 3H), 0.99-1.07 (m, 2H), 1.60 (q, J=8.0 Hz,
2H), 2.29 (t, J=7.5 Hz, 2H), 2.63-2.71 (m, 4H), 5.36 (s, 18H), 7.42
(t, J=7.5 Hz, 1H), 7.46-7.54 (m, 2H), 7.62-7.76 (m, 3H), 10.09 (s,
1H), 10.54 (s, 1H).
Example 1-280
[1019] MS ESI m/e: 644, 646 (M+H), 642, 644 (M-H).
[1020] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.80 (m,
2H), 0.97-1.08 (m, 2H), 2.61-2.72 (m, 1H), 2.64 (s, 3H), 5.36 (d,
J=0.7 Hz, 1H), 6.88-7.01 (m, 1H), 7.05-7.17 (m, 2H), 7.23-7.34 (m,
1H), 7.47 (dd, J=2.3, 8.7 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.73
(dd, J=1.5, 10.2 Hz, 18H), 10.56 (brs, 1H).
Example 1-281
[1021] MS ESI m/e: 485 (M+H), 483 (M-H).
[1022] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.71-0.81 (m, 2H),
1.00-1.10 (m, 2H), 2.60 (s, 3H), 2.61-2.72 (m, 1H), 5.52 (s, 1H),
7.41-7.56 (m, 9H), 10.62 (brs, 1H).
Example 1-282
[1023] MS ESI m/e: 624, 626 (M+H), 622, 624 (M-H).
[1024] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.71-0.81 (m, 2H),
0.97-1.10 (m, 2H), 2.61-2.72 (m, 1H), 2.65 (s, 3H), 5.07 (s, 2H),
5.36 (s, 1H), 7.19 (d, J=9.0 Hz, 1H), 7.28-7.38 (m, 2H), 7.42-7.56
(m, 38), 7.74 (d, J=9.0 Hz, 1H), 10.53 (brs, 1H), 10.64 (brs,
1H).
Example 1-283
[1025] MS ESI m/e: 526, 528 (M+H), 524, 526 (M-H).
[1026] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.71-0.79 (m, 2H),
0.99-1.09 (m, 2H), 2.66 (d, J=6.0 Hz, 3H), 2.64-2.67 (m, 1H), 2.74
(s, 3H), 5.36 (s, 1H), 5.92-5.98 (m, 1H), 6.50-6.60 (m, 3H), 7.19
(t, J=7.5 Hz, 1H), 7.49-7.54 (m, 2H), 7.74 (d, J=12.0 Hz, 1H),
10.57 (brs, 1H).
Example 1-284
[1027] MS ESI m/e: 652, 654 (M+H), 650, 652 (M-H).
[1028] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.68-0.80 (m, 2H),
0.99-1.09 (m, 2H), 2.33 (s, 3H), 2.61-2.70 (m, 1H), 5.35 (s, 1H),
7.04 (d, J=12.0 Hz, 1H), 7.13 (d, J=6.0 Hz, 1H), 7.30-7.38 (m, 2H),
7.49-7.62 (m, 5H), 7.73-7.80 (m, 3H), 10.48 (brs, 1H), 10.52 (brs,
1H).
Example 1-285
[1029] MS ESI m/e: 465 (M+H), 463 (M-H).
[1030] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 0.71-0.78 (m, 2H),
1.01-1.07 (m, 2H), 2.53 (s, 3H), 2.59 (s, 3H), 2.64-2.72 (m, 1H),
5.25 (d, J=1.1 Hz, 1H), 7.17 (dd, J=1.9, 8.7 Hz, 1H), 7.32 (dd,
J=1.9, 11.3 Hz, 1H), 7.39-7.55 (m, 6H), 10.41 (brs, 1H).
Example 1-286
[1031] MS ESI m/e: 558 (M+H), 556 (M-H).
[1032] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.78 (m,
2H), 0.99-1.07 (m, 2H), 2.53 (s, 3H), 2.63-2.69 (m, 1H), 2.65 (s,
3H), 3.02 (s, 3H), 5.25 (d, J=1.1 Hz, 1H), 7.11-7.19 (m, 2H),
7.24-7.35 (m, 3H), 7.39-7.50 (m, 2H), 9.99 (brs, 1H), 10.39 (brs,
1H).
Example 1-287
[1033] MS ESI m/e: 582, 584 (M+H), 580, 582 (M-H).
[1034] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.78 (m,
2H), 0.99-1.12 (m, 8H), 2.53-2.70 (m, 5H), 5.36 (s, 1H), 7.05-7.11
(m, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.46-7.55 (m, 2H), 7.62-7.68 (m,
1H), 7.70-7.77 (m, 2H), 10.05 (s, 1H), 10.54 (s, 1H).
Example 1-288
[1035] MS ESI m/e: 576, 578 (M+H), 574, 576 (M-H).
[1036] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.80 (m,
2H), 1.00-1.08 (m, 2H), 2.60-2.70 (m, 4H), 5.37 (s, 1H), 7.47-7.58
(m, 4H), 7.65-7.77 (m, 3H), 7.88-7.93 (m, 2H), 10.52 (s, 1H).
Example 1-289
[1037] MS ESI m/e: 550 (M+H), 548 (M-H).
[1038] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.78 (m,
2H), 0.99-1.09 (m, 2H), 1.18 (t, J=7.3 Hz, 3H), 2.63-2.71 (m, 1H),
2.66 (s, 3H), 3.13 (q, J=7.5 Hz, 2H), 4.32 (s, 1H), 5.51 (s, 1H),
7.09-7.15 (m, 1H), 7.24-7.35 (m, 2H), 7.36-7.41 (m, 1H), 7.41-7.49
(m, 1H), 7.50-7.61 (m, 2H), 10.04 (s, 1H), 10.72 (s, 1H).
Example 1-290
[1039] MS ESI m/e: 518 (M+H), 516 (M-H).
[1040] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.71-0.78 (m,
2H), 1.00-1.08 (m, 2H), 2.61-2.71 (m, 1H), 2.66 (s, 3H), 3.03 (s,
3H), 4.19 (s, 1H), 5.64 (s, 1H), 7.11-7.16 (m, 1H), 7.24-7.29 (m,
1H), 7.30-7.37 (m, 3H), 7.43-7.49 (m, 1H), 7.51-7.56 (m, 2H), 10.01
(s, 1H), 10.70 (s, 1H).
Example 1-291
[1041] MS ESI m/e: 483 (M+H), 481 (M-H).
[1042] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.80 (m,
2H), 0.98-1.10 (m, 2H), 2.60 (s, 3H), 2.62-2.73 (m, 1H), 3.68 (q,
J=11.6 Hz, 2H), 5.54 (s, 1H), 7.30-7.38 (m, 2H), 7.39-7.56 (m, 7H),
10.60 (brs, 1H).
Example 1-292
[1043] MS ESI m/e: 554, 556 (M+H), 552, 554 (M-H).
[1044] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.81 (m,
2H), 0.98-1.09 (m, 2H), 2.60 (s, 3H), 2.63-2.71 (m, 1H), 2.79 (d,
J=4.5 Hz, 3H), 5.38 (d, J=1.1 Hz, 1H), 7.45-7.55 (m, 2H), 7.57-7.65
(m, 2H), 7.71-7.77 (m, 1H), 7.84-7.89 (m, 1H), 7.89-7.95 (m, 1H),
8.57 (q, J=5.3 Hz, 1H), 10.53 (brs, 1H).
Example 1-293
[1045] MS ESI m/e: 447 (M+H), 445 (M-H).
[1046] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.99-1.08 (m, 2H), 2.59 (s, 3H), 2.62-2.73 (m, 1H), 3.00 (dt,
J=25.2, 6.0 Hz, 2H), 4.67 (dt, J=47.1, 6.4 Hz, 2H), 5.46 (s, 1H),
7.23-7.29 (m, 2H), 7.33-7.39 (m, 2H), 7.40-7.56 (m, 5H), 10.51
(brs, 1H).
Example 1-294
[1047] MS ESI m/e: 590, 592 (M+H), 588, 590 (M-H).
[1048] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.09 (m, 2H), 2.42 (s, 3H), 2.58-2.70 (m, 4H), 5.37 (s,
1H), 7.45-7.54 (m, 2H), 7.70-7.80 (m, 3H), 7.82-7.88 (m, 2H), 10.51
(s, 1H).
Example 1-295
[1049] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[1050] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.79 (m,
2H), 0.96 (t, J=6.0 Hz, 3H), 1.01-1.08 (m, 2H), 2.58-2.71 (m, 4H),
2.74-2.84 (m, 2H), 5.37 (s, 1H), 7.46-7.55 (m, 2H), 7.69-7.79 (m,
4H), 7.84-7.90 (m, 2H), 10.51 (s, 1H).
Example 1-296
[1051] MS ESI m/e: 504 (M+H), 502 (M-H).
[1052] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.91 (m, 2H),
1.12-1.23 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 2.16 (s, 3H), 2.66 (q,
J=7.6 Hz, 2H), 2.72-2.82 (m, 1H), 2.86 (s, 3H), 5.59 (d, J=1.5 Hz,
1H), 6.95-7.08 (m, 3H), 7.22-7.32 (m, 1H), 7.33-7.55 (m, 3H), 7.70
(s, 1H), 10.18 (s, 1H).
Example 1-297
[1053] MS ESI m/e: 602 (M+H), 600 (M-H).
[1054] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.79 (m,
2H), 0.98-1.09 (m, 2H), 2.04 (s, 3H), 2.63-2.71 (m, 1H), 2.66 (s,
3H), 5.38 (d, J=1.5 Hz, 1H), 7.04-7.10 (m, 1H), 7.29-7.38 (m, 1H),
7.38-7.46 (m, 1H), 7.60-7.72 (m, 3H), 7.81 (dd, J=1.8, 10.2 Hz,
1H), 10.15 (s, 1H), 10.55 (s, 1H).
Example 1-298
[1055] MS EST m/e: 532 (M+H), 530 (M-H).
[1056] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.80 (m,
2H), 0.98-1.09 (m, 2H), 1.18 (t, J=7.3 Hz, 3H), 2.61-2.72 (m, 1H),
2.65 (s, 3H), 3.13 (q, J=7.5 Hz, 2H), 4.18 (s, 1H), 5.65 (s, 1H),
7.08-7.15 (m, 1H), 7.24-7.31 (m, 1H), 7.31-7.38 (m, 3H), 7.41-7.49
(m, 1H), 7.51-7.57 (m, 2H), 10.04 (s, 1H), 10.70 (s, 1H).
Example 1-299
[1057] MS ESI m/e: 667, 669 (M+H), 665, 667 (M-H).
[1058] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.77 (m,
2H), 0.83 (t, J=7.4 Hz, 3H), 0.98-1.07 (m, 2H), 1.19-1.29 (m, 2H),
1.39-1.49 (m, 2H), 2.04 (t, J=7.5 Hz, 2H), 2.45-2.53 (m, 2H),
2.63-2.70 (m, 1H), 2.66 (s, 3H), 3.27-3.35 (m, 2H), 5.35 (d, J=1.1
Hz, 1H), 7.05-7.11 (m, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.47-7.52 (m,
2H), 7.60-7.67 (m, 1H), 7.70-7.77 (m, 2H), 7.87-7.94 (m, 1H), 10.17
(brs, 1H), 10.54 (brs, 1H).
Example 1-30.0
[1059] MS ESI m/e: 457 (M+H), 455 (M-1).
[1060] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.80-0.90 (m, 2H),
1.10-1.30 (m, 2H), 1.34 (s, 9H), 2.77 (m, 1H), 2.81 (s, 3H), 5.79
(s, 1H), 7.20 (d, J=8.5 Hz, 2H), 7.30-7.35 (m, 2H), 7.35-7.55 (m,
5H), 10.29 (S, 1H).
Example 1-301
[1061] MS ESI m/e: 580 (M+H), 578 (M-1).
[1062] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (brs, 2H),
1.05 (m, 2H), 2.68 (s, 4H), 3.03 (s, 3H), 3.32 (s, 3H), 5.68 (s,
1H), 7.1.5 (d, J=8.9 Hz, 1H), 7.27 (d, J=8.1 Hz, 1), 7.47 (t, J=8.0
Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.75-7.90 (m, 2H), 10.01 (s, 1H),
10.95 (s, 1H).
Example 1-302
[1063] MS ESI m/e: 620 (M+H), 618 (M-H).
[1064] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.71-0.78 (m,
2H), 0.99-1.07 (m, 2H), 2.62-2.69 (m, 1H), 2.65 (s, 3H), 3.02 (s,
3H), 5.54 (s, 1H), 7.10-7.19 (m, 3H), 7.23-7.28 (m, 1H), 7.29-7.32
(m, 1H), 7.42-7.49 (m, 1H), 7.74-7.80 (m, 2H), 10.00 (s, 1H), 10.57
(s, 1H).
Example 1-303
[1065] MS ESI m/e: 625, 627 (M+H), 623, 625 (M-H).
[1066] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.78 (m,
2H), 0.99-1.09 (m, 2H), 2.34-2.56 (m, 6H), 2.61-2.71 (m, 1H), 2.74
(s, 3H), 3.08-3.19 (m, 2H), 3.50-3.62 (m, 4H), 5.36 (s, 1H), 5.77
(brs, 1H), 6.53-6.70 (m, 3H), 7.18 (dd, J=9.0, 6.0 Hz, 1H),
7.40-7.50 (m, 2H), 7.74 (d, J=9.0 Hz, 1H), 10.56 (brs, 1H).
Example 1-304
[1067] MS ESI m/e: 572, 574 (M+H), 570, 572 (M-H).
[1068] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.74-0.79 (m,
2H), 1.00-1.08 (m, 2H), 2.62-2.68 (m, 4H), 3.02 (s, 3H), 5.53 (s,
1H), 7.12-7.14 (m, 1H), 7.22-7.35 (m, 4H), 7.42-7.44 (m, 1H),
7.60-7.62 (m, 2H), 10.00 (brs, 1H), 10.57 (brs, 1H).
Example 1-305
[1069] MS ESI m/e: 584, 586 (M+H), 582, 584 (M-H).
[1070] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.80 (m,
2H), 0.97-1.08 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.62-2.71 (m, 1H),
2.67 (s, 3H), 3.70 (q, J=5.9 Hz, 2H), 4.69 (t, J=5.1 Hz, 1H), 5.36
(d, J=1.1 Hz, 1H), 7.07 (dd, J=2.6, 7.9 Hz, 1H), 7.42 (t, J=8.1 Hz,
1H), 7.48-7.55 (m, 2H), 7.62-7.69 (m, 1H), 7.71-7.77 (m, 2H), 10.13
(brs, 1H), 10.54 (brs, 1H).
Example 1-306
[1071] MS ESI m/e: 611, 613 (M+H), 609, 611 (M-H).
[1072] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.98-1.08 (m, 2H), 2.16 (s, 6H), 2.39-2.48 (m, 2H), 2.51-2.59
(m, 2H), 2.63-2.72 (m, 1H), 2.67 (s, 3H), 5.35 (d, J=1.1 Hz, 1H),
7.05-7.11 (m, 1H), 7.42 (t, J=8.1 Hz, 1H), 7.47-7.55 (m, 2H),
7.61-7.67 (m, 1H), 7.69-7.77 (m, 2H), 10.22 (brs, 1H), 10.54 (brs,
1H).
Example 1-307
[1073] MS ESI m/e: 583, 585 (M+H), 581, 583 (M-H).
[1074] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.08 (m, 2H), 1.04 (t, J=7.2 Hz, 3H), 2.62-2.74 (m, 1H),
2.68 (s, 3H), 3.09 (quint, J=6.8 Hz, 2H), 5.35 (d, J=1.1 Hz, 1H),
6.16 (t, J=5.8 Hz, 1H), 6.88-6.95 (m, 1H), 7.32 (t, J=7.9 Hz, 1H),
7.36-7.42 (m, 1H), 7.45-7.57 (m, 3H), 7.71-7.77 (m, 1H), 8.73 (brs,
1H), 10.55 (brs, 1H).
Example 1-308
[1075] MS ESI m/e: 584, 586 (M+H), 582, 584 (M-H).
[1076] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.78 (m,
2H), 0.98-1.08 (m, 2H), 1.24 (t, J=7.2 Hz, 3H), 2.61-2.72 (m, 1H),
2.66 (s, 3H), 4.12 (q, J=6.9 Hz, 2H), 5.36 (d, J=1.1 Hz, 1H),
7.00-7.05 (m, 1H), 7.39 (t, J=7.9 Hz, 1H), 7.43-7.55 (m, 3H),
7.60-7.65 (m, 1H), 7.70-7.78 (m, 1H), 9.85 (brs, 1H), 10.54 (brs,
1H).
Example 1-309
[1077] MS ESI m/e: 619, 621 (M+H), 617, 619 (M-H).
[1078] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.80 (m,
2H), 0.98-1.07 (m, 2H), 2.60-2.71 (m, 1H), 2.63 (s, 3H), 2.67 (s,
6H), 5.35 (d, J=1.1 Hz, 1H), 7.09-7.15 (m, 1H), 7.21-7.27 (m, 2H),
7.43 (t, J=8.5 Hz, 1H), 7.47-7.54 (m, 2H), 7.70-7.76 (m, 1H), 10.11
(brs, 1H), 10.54 (brs, 1H).
Example 1-310
[1079] MS ESI m/e: 500 (M+H), 498 (M-H).
[1080] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.08 (m, 2H), 2.05 (s, 3H), 2.63-2.72 (m, 1H), 2.67 (s,
3H), 4.32 (s, 1H), 5.51 (brs, 1H), 7.04-7.12 (m, 1H), 7.35-7.46 (m,
2H), 7.50-7.61 (m, 2H), 7.62-7.67 (m, 1H), 7.67-7.72 (m, 1H), 10.16
(s, 1H), 10.75 (s, 1H).
Example 1-311
[1081] MS ESI m/e: 666 (M+H), 664 (M-H).
[1082] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.71-0.77 (m,
2H), 0.92 (t, J=7.5 Hz, 3H), 1.00-1.07 (m, 2H), 1.59-1.71 (m, 2H),
2.62-2.70 (m, 1H), 2.64 (s, 3H), 3.09 (t, J=7.4 Hz, 2H), 5.38 (d,
J=1.2 Hz, 1H), 7.08-7.14 (m, 1H), 7.23-7.37 (m, 3H), 7.41-7.48 (m,
1H), 7.61-7.66 (m, 1H), 7.79-7.84 (m, 1H), 10.54 (s, 1H).
Example 1-312
[1083] MS ESI m/e: 753, 755 (M+H), 751, 753 (M-H).
[1084] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.81-0.89 (m, 2H),
1.14-1.22 (m, 2H), 2.70-2.79 (m, 1H), 2.81 (s, 3H), 3.21-3.32 (m,
2H), 3.57-3.68 (m, 2H), 5.07 (s, 2H), 5.57-5.67 (m, 1H), 5.65 (d,
J=1.1 Hz, 1H), 7.04-7.09 (m, 1H), 7.21-7.40 (m, 11H), 7.74-7.80 (m,
1H), 10.34 (brs, 1H).
Example 1-313
[1085] MS ESI m/e: 619, 621 (M+H), 617, 619 (M-H).
[1086] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.79 (m,
2H), 0.99-1.09 (m, 2H), 2.63-2.70 (m, 1H), 2.66 (s, 3H), 3.09-3.19
(m, 2H), 3.37-3.49 (m, 2H), 5.36 (d, J=0.9 Hz, 1H), 7.17-7.24 (m,
1H), 7.30-7.39 (m, 2H), 7.47-7.54 (m, 3H), 7.73-7.77 (m, 1H),
7.93-8.14 (m, 3H), 10.39 (brs, 1H), 10.52 (brs, 1H).
Example 1-314
[1087] MS ESI m/e: 703, 705 (M+H), 701, 703 (M-H).
[1088] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.78 (m,
2H), 0.82 (t, J=7.2 Hz, 3H), 0.99-1.08 (m, 2H), 1.15-1.27 (m, 1H),
1.37-1.47 (m, 2H), 2.01 (t, J=7.5 Hz, 2H), 2.62-2.70 (m, 1H), 2.65
(s, 3H), 3.17-3.25 (m, 2H), 3.33-3.43 (m, 2H), 5.36 (d, J=1.1 Hz,
1H), 7.11-7.18 (m, 1H), 7.25-7.30 (m, 1H), 7.33-7.36 (m, 1H),
7.42-7.54 (m, 3H), 7.72-7.77 (m, 1H), 7.87-7.94 (m, 1H), 10.08
(brs, 1H), 10.53 (brs, 1H).
Example 1-315
[1089] MS ESI m/e: 659, 661 (M+H), 657, 659 (M-H).
[1090] .sup.1H-NMR (DMSO-d, 300 MHz) .delta. 0.72-0.79 (m, 2H),
1.01-1.09 (m, 2H), 2.14 (s, 3H), 2.32-2.39 (m, 4H), 2.60-2.72 (m,
4H), 2.83-2.97 (m, 4H), 5.37 (s, 1H), 7.46-7.55 (m, 2H), 7.71-7.87
(m, 5H), 10.51 (s, 1H).
Example 1-316
[1091] MS ESI m/e: 646, 648 (M+H), 644, 646 (M-H).
[1092] .sup.1H-NMR DMSO-d.sub.6, 300 MHz) .delta. 0.72-0.79 (m,
2H), 1.01-1.10 (m, 2H), 2.60-2.71 (m, 4H), 2.81-2.94 (m, 4H),
3.58-3.67 (m, 4H), 5.38 (s, 1H), 7.47-7.55 (m, 2H), 7.71-7.88 (m,
5H), 10.50 (s, 1H).
Example 1-317
[1093] MS ESI m/e: 644, 646 (M+H), 642, 644 (M-H).
[1094] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.00-1.09 (m, 2H), 1.32-1.41 (m, 2H), 1.47-1.58 (m, 4H),
2.58-2.73 (m, 4H), 2.82-2.92 (m, 4H), 5.37 (s, 1H), 7.46-7.54 (m,
2H), 7.71-7.84 (m, 5H), 10.51 (s, 1H).
Example 1-318
[1095] MS ESI m/e: 630, 632 (M+H), 628, 630 (M-H).
[1096] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.79 (m,
2H), 1.01-1.10 (m, 2H), 1.59-1.69 (m, 4H), 2.58 (s, 3H), 2.63-2.71
(m, 1H), 3.03-3.22 (m, 4H), 5.37 (s, 1H), 7.46-7.55 (m, 2H),
7.71-7.82 (m, 3H), 7.87-7.92 (m, 2H), 10.51 (s, 1H).
Example 1-319
[1097] MS ESI m/e: 666 (M+H), 664 (M-H).
[1098] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.99-1.08 (m, 2H), 1.23 (d, J=6.6 Hz, 6H), 2.61-2.71 (m, 1H),
2.64 (s, 3H), 5.38 (s, 1H), 7.08-7.15 (m, 1H), 7.27-7.38 (m, 3H),
7.39-7.47 (m, 1H), 7.60-7.66 (m, 1H), 7.78-7.84 (m, 1H), 9.99 (brs,
1H), 10.54 (s, 1H).
Example 1-320
[1099] MS ESI m/e: 564 (M+H), 562 (M-H).
[1100] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.92 (t, J=7.3 Hz, 3H), 0.99-1.09 (m, 2H), 1.58-1.74 (m, 2H),
2.62-2.72 (m, 1H), 2.66 (s, 3H), 3.05-3.14 (m, 2H), 4.32 (s, 1H),
5.51 (s, 1H), 7.09-7.16 (m, 1H), 7.24-7.34 (m, 2H), 7.35-7.50 (m,
2H), 7.50-7.61 (m, 2H), 10.04 (brs, 1H), 10.73 (s, 1H).
Example 1-321
[1101] MS ESI m/e: 564 (M+H), 562 (M-H).
[1102] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.99-1.08 (m, 2H), 1.23 (d, J=6.6 Hz, 6H), 2.62-2.71 (m, 1H),
2.65 (s, 1H), 3.18-3.30 (m, 1H), 4.31 (s, 1H), 5.51 (s, 1H),
7.08-7.14 (m, 1H), 7.26-7.35 (m, 2H), 7.35-7.48 (m, 2H), 7.50-7.61
(m, 2H), 10.00 (brs, 1H), 10.73 (s, 1H).
Example 1-322
[1103] MS ESI m/e: 655 (M+H), 653 (M-H).
[1104] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.99-1.09 (m, 2H), 2.61-2.71 (m, 4H), 3.02 (s, 3H), 5.49 (s,
1H), 7.15 (d, J=9.0 Hz, 1H), 7.25-7.31 (m, 2H), 7.38-7.49 (m, 2H),
7.74-7.77 (m, 1H), 8.00 (s, 1H), 9.99 (brs, 1H), 10.76 (brs,
1H).
Example 1-323
[1105] MS ESI m/e: 625, 627 (M+H), 623, 625 (M-H).
[1106] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.09 (m, 2H), 1.70 (quint, J=7.2 Hz, 2H), 2.11 (s, 6H),
2.21 (t, J=7.2 Hz, 2H), 2.33 (t, J=7.3 Hz, 2H), 2.62-2.72 (m, 1H),
2.66 (s, 3H), 5.35 (d, J=1.1 Hz, 1H), 7.04-7.11 (m, 1H), 7.41 (t,
J=8.1 Hz, 1H), 7.45-7.54 (m, 2H), 7.60-7.67 (m, 1H), 7.69-7.78 (m,
2H), 10.13 (brs, 1H), 10.54 (brs, 1H).
Example 1-324
[1107] MS ESI m/e: 583, 585 (M+H), 581, 583 (M-H).
[1108] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.97-1.08 (m, 2H), 2.62-2.74 (m, 1H), 2.69 (s, 3H), 2.92 (s,
6H), 5.35 (d, J=1.1 Hz, 1H), 6.94-7.01 (m, 1H), 7.34 (t, J=8.1 Hz,
1H), 7.46-7.54 (m, 2H), 7.54-7.61 (m, 2H), 7.70-7.77 (m, 1H), 8.51
(brs, 1H), 10.54 (brs, 1H).
Example 1-325
[1109] MS ESI m/e: 569, 571 (M+H), 567, 569 (M-H).
[1110] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.80 (m,
2H), 0.98-1.09 (m, 2H), 2.63 (d, J=4.9 Hz, 3H), 2.65-2.73 (m, 1H),
2.68 (s, 3H), 5.35 (d, J=1. Hz, 1H), 6.00-6.08 (m, 1H), 6.89-6.95
(m, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.38-7.45 (m, 1H), 7.46-7.52 (m,
2H), 7.52-7.56 (m, 1H), 7.69-7.77 (m, 1H), 8.77 (brs, 1H), 10.55
(brs, 1H).
Example 1-326
[1111] MS ESI m/e: 465 (M+H), 463 (M-H).
[1112] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.80 (m,
2H), 0.99-1.08 (m, 2H), 2.59 (s, 3H), 2.62-2.72 (m, 1H), 3.21 (dt,
J=4.5, 18.3 Hz, 2H), 5.50 (s, 1H), 6.27 (tt, J=4.3, 56.3 Hz, 1H),
7.26-7.34 (m, 2H), 7.34-7.56 (m, 7H), 10.55 (brs, 1H).
Example 1-327
[1113] MS ESI m/e: 585, 587 (M+H), 583, 585 (M-1).
[1114] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.75 (brs, 2H),
1.03 (m, 2H), 2.68 (s, 4H), 3.61 (s, 3H), 5.36 (s, 1H), 7.00-7.10
(m, 1H), 7.38 (t, J=8.1 Hz, 1H), 7.45-7.55 (m, 2H), 7.65-7.80 (m,
3H), 9.12 (s, 1H), 9.63 (s, 1H), 10.54 (s, 1H).
Example 1-328
[1115] MS ESI m/e: 457 (M+H), 455 (M-H).
[1116] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.74-0.81 (m,
2H), 1.01-1.10 (m, 2H), 2.60 (s, 3H), 2.65-2.74 (m, 1H), 5.50 (s,
18H), 7.32 (dd, J=1.9, 8.7 Hz, 1H), 7.40-7.56 (m, 6H), 7.82-7.87
(m, 2H), 8.07 (d, J=8.3 Hz, 1H), 10.63 (brs, 1H).
Example 1-329
[1117] MS ESI m/e: 437 (M+H), 435 (M-H).
[1118] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 2.89 (s, 3H),
7.15-7.55 (m, 5H), 10.35 (s, 1H).
Example 1-330
[1119] MS ESI m/e: 347 (M+H), 345 (M-H).
[1120] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 3.41 (s, 3H), 3.53
(s, 3H), 3.56 (s, 3H), 7.15-7.23 (m, 2H), 7.32-7.38 (m, 2H), 10.45
(s, 1H).
Example 1-331
[1121] MS ESI m/e: 458 (M+H), 456 (M-H).
[1122] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.40-0.57 (m, 4H),
1.24-1.37 (m, 1H), 2.81 (s, 3H), 2.97 (s, 6H), 3.91 (d, J=7.0 Hz,
2H), 5.61 (s, 1H), 6.70-6.77 (m, 2H), 7.10-7.17 (m, 2H), 7.33-7.54
(m, 5H), 10.22 (s, 1H).
Example 1-332
[1123] MS ESI m/e: 495 (M+I-H), 496, 493 (M-H), 494.
[1124] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 2.70 (s, 3H),
3.84 (s, 3H), 5.88 (s, 1H), 7.36-7.55 (m, 10H), 7.46 (d, J=9.0 Hz,
2H), 7.99 (d, J=9.0 Hz, 2H), 10.85 (brs, 1H).
Example 1-333
[1125] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[1126] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.66-0.74 (m,
2H), 0.98-1.06 (m, 2H), 1.56 (s, 3H), 2.60-2.69 (m, 1H), 2.74 (s,
3H), 3.03 (s, 3H), 6.80 (t, J=8.9 Hz, 1H), 7.10-7.15 (m, 1H),
7.25-7.36 (m, 3H), 7.46 (t, J=8.0 Hz, 1H), 7.59-7.64 (m, 1H), 9.99
(s, 1H), 10.17 (s, 1H).
Example 1-334
[1127] MS ESI m/e: 556 (M+H), 554 (M-H).
[1128] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.78 (m,
2H), 0.99-1.08 (m, 2H), 2.74 (s, 3H), 2.61-2.72 (m, 1H), 2.69-2.79
(m, 2H), 2.98-3.09 (m, 2H), 5.36 (s, 1H), 5.92 (brs, 1H), 6.51-6.68
(m, 3H), 7.15-7.20 (m, 1H), 7.49-7.50 (m, 2H), 7.72-7.75 (m, 1H),
10.60 (brs, 1H).
Example 1-335
[1129] MS ESI m/e: 654 (M+H), 652 (M-H).
[1130] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.67-0.81 (m,
2H), 0.96-1.09 (m, 2H), 2.36 (s, 3H), 2.61-2.69 (m, 1H), 5.35 (s,
1H), 7.08 (d, J=9.0 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 7.31-7.39 (m,
2H), 7.48-7.53 (m, 2H), 7.57-7.62 (m, 1H), 7.74 (d, J=9.0 Hz, 1H),
8.10 (d, J=9.0 Hz, 1H), 8.77-8.80 (m, 1H), 8.88-8.90 (m, 1H), 10.52
(brs, 1H), 10.69 (brs, 1H).
Example 1-336
[1131] MS ESI m/e: 532 (M+H), 530 (M-H).
[1132] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.71-0.80 (m,
2H), 0.99-1.09 (m, 2H), 2.25 (s, 3H), 2.61-2.73 (m, 1H), 2.64 (s,
3H), 3.01 (s, 3H), 4.17 (s, 1H), 5.27 (s, 1H), 7.14-7.48 (m, 7H),
9.98 (brs, 1H), 10.50 (brs, 1H).
Example 1-337
[1133] MS ESI m/e: 552 (M+H), 550 (M-H).
[1134] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.68-0.78 (m,
2H), 0.99-1.10 (m, 2H), 2.66 (s, 3H), 2.61-2.76 (m, 1H), 3.01 (s,
3H), 4.31 (s, 1H), 5.61 (s, 1H), 7.13 (d, J=12.0 Hz, 1H), 7.22-7.32
(m, 2H), 7.41-7.51 (m, 2H), 7.61 (d, J=6.0 Hz, 1H), 7.74 (s, 1H),
9.98 (brs, 1H), 10.90 (brs, 1H).
Example 1-338
[1135] MS ESI m/e: 558 (M+H), 556 (M-H).
[1136] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.81 (m,
2H), 0.99-1.08 (m, 2H), 2.61-2.71 (m, 1H), 2.65 (s, 3H), 3.02 (dt,
J=18.8, 3.4 Hz, 2H), 3.02 (s, 3H), 4.69 (dt, J=47.1, 3.0 Hz, 2H),
5.28 (s, 1H), 7.10-7.16 (m, 1H), 7.17-7.23 (m, 1H), 7.23-7.29 (m,
1H), 7.29-7.39 (m, 2H), 7.41-7.50 (m, 2H), 10.00 (brs, 1H), 10.43
(s, 1H).
Example 1-339
[1137] MS ESI m/e: 690 (M+H), 688 (M-H).
[1138] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.98-1.09 (m, 2H), 2.22-2.32 (m, 4H), 2.64 (s, 3H), 2.60-2.71
(m, 3H), 3.25-3.41 (m, 2H), 3.41-3.51 (m, 4H), 5.34 (s, 1H), 7.09
(d, J=6.0 Hz, 1H), 7.23-7.35 (m, 2H), 7.40-7.51 (m, 3H), 7.73 (d,
J=12.0 Hz, 1H), 10.08 (brs, 1H), 10.52 (brs, 1H).
Example 1-340
[1139] MS ESI m/e: 634 (M+H), 632 (M-H).
[1140] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.79 (m,
2H), 0.98-1.09 (m, 2H), 2.22 (s, 3H), 2.60-2.69 (m, 1H), 2.63 (s,
3H), 3.01 (s, 3H), 5.14 (s, 1H), 7.13 (d, J=9.0 Hz, 2H), 7.22-7.30
(m, 2H), 7.41-7.48 (m, 1H), 7.61-7.64 (m, 1H), 7.74 (s, 1H), 9.98
(brs, 1H), 10.32 (brs, 1H).
Example 1-341
[1141] MS ESI m/e: 522 (M+H), 520 (M-H).
[1142] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.70-0.80 (m, 2H),
0.97-1.09 (m, 2H), 2.06 (s, 3H), 2.54 (s, 3H), 2.63-2.72 (m, 1H),
2.66 (s, 3H), 5.23-5.26 (m, 1H), 7.05-7.20 (m, 2H), 7.28-7.49 (m,
3H), 7.61-7.73 (m, 2H), 10.17 (brs, 1H), 10.41 (brs, 1H).
Example 1-342
[1143] MS ESI m/e: 522 (M+H), 520 (M-H).
[1144] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69-0.79 (m,
2H), 0.97-1.10 (m, 2H), 2.04 (s, 3H), 2.60-2.73 (m, 1H), 2.65 (s,
3H), 3.02 (dt, J=25.2, 2.8 Hz, 2H), 4.69 (dt, J=47.1, 3.2 Hz, 2H),
5.27 (s, 1H), 7.02-7.11 (m, 1H), 7.16-7.23 (m, 1H), 7.29-7.49 (m,
3H), 7.61-7.71 (m, 2H), 10.16 (brs, 1H), 10.44 (brs, 1H).
Example 1-343
[1145] MS ESI m/e: 475 (M+H), 473 (M-H).
[1146] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.85-0.94 (m, 2H),
1.16-1.24 (m, 2H), 2.75-2.83 (m, 1H), 2.82 (s, 3H), 5.54-5.58 (m,
1H), 7.30-7.38 (m, 3H), 7.43-7.54 (m, 5H), 7.63-7.69 (m, 1H), 10.28
(brs, 1H).
Example 2-1
[1147] MS ESI m/e: 472 (M+H), 470 (M-H).
[1148] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 2.68 (s, 3H),
7.34-7.39 (m, 2H), 7.41-7.61 (m, 10H), 7.80-7.87 (m, 2H), 11.34 (s,
1H).
Example 2-2
[1149] MS ES m/e: 592 (M+H), 590 (M-H).
[1150] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.70-0.82 (m,
2H), 1.01-1.13 (m, 2H), 2.64-2.75 (m, 1H), 2.67 (s, 3H), 3.05 (s,
3H), 7.19-7.27 (m, 1H), 7.27-7.34 (m, 1H), 7.35-7.39 (m, 1H),
7.45-7.54 (m, 2H), 7.71 (dd, J=3.0, 12.0 Hz, 1H), 8.51 (t, J=9.0
Hz, 1H), 10.05 (s, 1H), 11.61 (d, J=3.0 Hz, 1H).
Example 3-1
[1151] MS ESI m/e: 493, 495 (M+H), 491, 493 (M-H).
[1152] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.77-0.82 (m, 2H),
1.09-1.15 (m, 2H), 1.36 (s, 3H), 2.72-2.74 (m, 1H), 3.20 (s, 3H),
6.86 (d, 2H), 7.28-7.32 (m, 2H), 7.34-7.51 (m, 5H), 11.36 (s,
1H).
Example 3-2
[1153] MS ESI m/e: 479, 481 (M+H), 477, 479 (M-H).
[1154] .sup.1H-NMR (CDCl.sub.3, 400 MHz) .delta. 0.83-0.90 (m, 2H),
1.10-1.18 (m, 2H), 2.67-2.76 (m, 1H), 3.11 (s, 3H), 5.00 (s, 1H),
7.02 (d, J=8.6 Hz, 2H), 7.10-7.15 (m, 2H), 7.19-7.25 (m, 1H),
7.34-7.41 (m, 2H), 7.63-7.70 (m, 2H), 11.71 (s, 1H).
Example 3-3
[1155] MS ESI m/e: 479, 481 (M+H), 477, 479 (M-H).
[1156] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 0.83-0.92 (m, 2H),
1.09-1.19 (m, 2H), 2.67-2.78 (m, 1H), 3.13 (s, 3H), 5.06 (s, 1H),
6.87-6.94 (m, 2H), 7.21-7.28 (m, 2H), 7.45-7.60 (m, 5H), 11.68 (s,
1H).
Example 3-4
[1157] MS ESI m/e: 604 (M+H), 606, 602 (M-H), 604.
[1158] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.69 (m,
2H), 0.93-0.98 (m, 2H), 1.25 (s, 3H), 2.59-2.64 (m, 1H), 3.01 (s,
3H), 3.08 (s, 3H), 7.08-7.13 (m, 2H), 7.21-7.25 (m, 2H), 7.39-7.43
(m, 2H), 7.70-7.74 (m, 1H), 9.90 (brs, 1H), 11.09 (brs, 1H).
Example 3-5
[1159] MS ESI m/e: 618 (M+H), 620, 616 (M-H), 618.
[1160] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.98 (m, 2H), 1.19 (t, J=9.8 Hz, 3H), 1.24 (s, 3H),
2.58-2.64 (m, 1H), 3.11 (q, J=9.8 Hz, 2H), 3.08 (s, 3H), 7.07-7.13
(m, 2H), 7.21-7.25 (m, 2H), 7.37-7.42 (m, 2H), 7.70-7.74 (m, 2H),
9.95 (brs, 1H), 11.09 (brs, 1H).
Example 3-6
[1161] MS ESI m/e: 604 (M+H), 606, 602 (M-H), 604.
[1162] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.08 (s, 3H), 7.01-7.13 (m, 2H), 7.33-7.43 (m, 2H), 7.58-7.60
(m, 2H), 7.70-7.74 (m, 1H), 10.10 (brs, 1H), 11.09 (brs, 1H).
Example 3-7
[1163] MS ESI m/e: 652 (M+H), 650 (M-H).
[1164] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.25 (s, 3H), 2.57-2.67 (m, 1H), 3.01 (s,
3H), 3.08 (s, 3H), 6.92 (t, J=9.0 Hz, 1H), 7.09-7.14 (m, 1H),
7.20-7.26 (m, 2H), 7.37-7.45 (m, 1H), 7.52-7.58 (m, 1H), 7.79 (dd,
J=1.8, 9.0 Hz, 1H), 9.89 (s, 1H), 11.08 (s, 1H).
Example 3-8
[1165] MS ESI m/e: 550 (M+H), 548 (M-H).
[1166] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.71 (m,
2H), 0.90-1.01 (m, 2H), 1.26 (s, 3H), 2.56-2.66 (m, 1H), 3.01 (s,
3H), 3.10 (s, 3H), 4.30 (s, 1H), 7.05-7.16 (m, 2H), 7.20-7.27 (m,
2H), 7.32 (dd, J=1.7, 9.0 Hz, 1H), 7.37-7.45 (m, 1H), 7.52 (dd,
J=1.7, 12.0 Hz, 1H), 9.90 (s, 1H), 11.10 (s, 1H).
Example 3-9
[1167] MS ESI m/e: 639 (M+H), 638, 637 (M-H).
[1168] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.73 (m,
2H), 0.93-0.98 (m, 2H), 1.26 (s, 3H), 2.58-2.65 (m, 1H), 3.05 (s,
3H), 3.08 (s, 3H), 7.11 (dd, J=10.1 Hz, 13.0 Hz, 1H), 7.32 (d,
J=11.6 Hz, 1H), 7.42 (d, J=10.1 Hz, 1H), 7.48 (s, 1H), 7.63 (d,
J=11.6 Hz, 1H), 7.72 (d, J=13.0 Hz, 1H), 9.65 (brs, 1H), 11.08
(brs, 1H).
Example 4-1
[1169] MS ESI m/e: 616 (M+H), 614 (M-H).
[1170] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), 7.36
(t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, 10.4 Hz,
1H), 10.10 (s, 1H), 11.08 (s, 1H).
Example 4-2
[1171] MS ESI m/e: 666 (M+H), 664 (M-H).
[1172] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.71 (m,
2H), 0.91-1.01 (m, 2H), 1.19 (t, J=7.2 Hz, 3H), 1.24 (s, 3H),
2.56-2.67 (m, 1H), 3.08 (s, 3H), 3.11 (q, J=7.2 Hz, 2H), 6.92 (t,
J=8.7 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 7.21-7.28 (m, 2H), 7.40 (t,
J=8.3 Hz, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.79 (dd, J=1.8, 10.5 Hz,
1H), 9.94 (s, 1H), 11.08 (s, 1H).
Example 4-3
[1173] MS ESI m/e: 514 (M+H), 512 (M-H).
[1174] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.70 (m,
2H), 0.91-0.99 (m, 2H), 1.26 (s, 3H), 2.04 (s, 3H), 2.58-2.66 (m,
1H), 3.10 (s, 3H), 4.30 (s, 1H), 7.01-7.06 (m, 1H), 7.09 (t, J=8.4
Hz, 1H), 7.31 (dd, J=1.6, 8.4 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.52
(dd, J=1.6, 11.6 Hz, 1H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.10
(s, 1H)
Example 4-4
[1175] MS ESI m/e: 568, 570 (M+H), -566, 568 (M-H)
[1176] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) 0.61-0.65 (m, 2H),
0.90-0.95 (m, 2H), 1.20 (s, 3H), 2.04 (s, 3H), 2.56-2.61 (m, 1H),
3.04 (s, 3H), 7.07 (dd, J=8.6, 10.7 Hz, 1H), 7.25 (d, J=8.8 Hz,
2H), 7.38 (d, J=10.7 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.69 (d,
J=8.6 Hz, 1H), 10.07 (s, 1H), 11.05 (s, 1H)
Example 4-5
[1177] MS ESI m/e: 556, 558 (M+1).
[1178] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.67 (m,
2H), 0.91-0.96 (m, 2H), 1.17 (s, 3H), 2.56-2.62 (m, 1H), 3.05 (s,
3H), 7.11 (dd, J=8.6, 10.4 Hz, 1H), 7.40 (d, J-8.6 Hz, 1H), 7.66
(d, J=9.3 Hz, 2H), 7.69 (dd, J=2.1, 10.4 Hz, 1H), 8.30 (d, J=9.3
Hz, 2H), 10.94 (s, 1H)
Example 4-6
[1179] MS ESI m/e: 564 (M+H), 562 (M-H).
[1180] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-0.99 (m, 2H), 1.19 (t, J=7.4 Hz, 3H), 1.25 (s, 3H),
2.57-2.65 (m, 1H), 3.10 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 4.31 (s,
1H), 7.06-7.12 (m, 2H), 7.22-7.27 (m, 2H), 7.32 (dd, J=1.6, 8.0 Hz,
1H), 7.40 (t, J=8.0 Hz, 1H), 7.52 (dd, J=1.6, 11.6 Hz, 1H), 9.95
(s, 1H), 11.10 (s, 1H).
Example 4-7
[1181] MS ESI m/e: 490 (M+H), 488 (M-H).
[1182] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.71 (m,
2H), 0.91-0.99 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.60-2.67 (m,
1H), 3.05 (s, 3H), 7.02-7.06 (m, 1H), 7.13-7.19 (m, 1H), 7.20-7.29
(m, 2H), 7.33-7.41 (m, 2H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.23
(s, 1H).
Example 4-8
[1183] MS ESI m/e: 604, 606 (M+H), 602, 604 (M-H).
[1184] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.23 (s, 3H), 2.57-2.67 (m, 1H), 3.04 (s,
3H), 3.07 (s, 3H), 7.08-7.14 (m, 1H), 7.26 (d, J=9.0 Hz, 2H), 7.34
(d, J=9.0 Hz, 2H), 7.39-7.44 (m, 1H), 7.70-7.75 (m, 1H), 9.96 (s,
1H), 11.08 (s, 1H)
Example 4-9
[1185] MS ESI m/e: 518 (M+H), 516 (M-H).
[1186] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.71 (m,
2H), 0.92-1.00 (m, 2H), 1.19 (t, J=7.6 Hz, 3H), 1.24 (s, 3H), 2.04
(s, 3H), 2.59-2.67 (m, 1H), 2.62 (q, J=7.6 Hz, 2H), 3.03 (s, 3H),
7.01-7.11 (m, 3H), 7.23 (d, J=11.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H),
7.56-7.63 (m, 2H), 10.10 (s, 1H), 11.23 (s, 1H).
Example 4-10
[1187] MS ESI m/e: 603, 605 (M+H), 601, 603 (M-H).
[1188] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.77-0.84 (m, 2H),
1.11-1.18 (m, 2H), 1.32 (t, J=7.3 Hz, 3H), 1.33 (s, 3H), 2.70-2.78
(m, 1H), 3.15 (q, J=7.5 Hz, 2H), 3.20 (s, 3H), 6.89 (t, J=8.3 Hz,
1H), 7.28-7.32 (m, 1H), 7.36 (dd, J=2.3, 9.8 Hz, 1H), 7.60-7.69 (m,
2H), 7.86-7.93 (m, 2H), 11.28 (s, 1H).
Example 4-11
[1189] MS ESI m/e: 516 (M+H), 514 (M-H).
[1190] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.71 (m,
2H), 0.92-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.59-2.67 (m,
1H), 3.07 (s, 3H), 5.32 (d, J=11.1 Hz, 1H), 5.89 (d, J=17.6 Hz,
1H), 6.73 (dd, J=10.9, 17.6 Hz, 1H), 7.01-7.06 (m, 1H), 7.11 (t,
J=8.6 Hz, 1H), 7.28-7.33 (m, 1H), 7.33-7.40 (m, 1H), 7.51-7.57 (m,
1H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.22 (s, 1H).
Example 4-12
[1191] MS ESI m/e: 729 (M+H), 727 (M-H).
[1192] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.68 (m,
2H), 0.83 (t, J=7.3 Hz, 3H), 0.93-0.97 (m, 2H), 1.23-1.26 (m, 5H),
1.40-1.50 (m, 2H), 2.04 (t, J=7.5 Hz, 2H), 2.48-2.50 (m, 2H),
2.59-2.64 (m, 1H), 3.08 (s, 3H), 3.28-3.33 (m, 2H), 6.92 (t, J=8.7
Hz, 1H), 7.03 (d, J=7.9 Hz, 1H), 7.36 (t, J=8.1 Hz, 1H), 7.56-7.59
(m, 2H), 7.64-7.66 (m, 1H), 7.79 (dd, J=10.4, 1.7 Hz, 1H), 7.90 (t,
J=5.7 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H).
Example 4-13
[1193] MS ESI m/e: 603 (M+H), 601 (M-H).
[1194] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.66-0.69 (m,
2H), 0.83 (t, J=7.2 Hz, 3H), 0.93-0.98 (m, 2H), 1.17-1.29 (m, 5H),
1.40-1.50 (m, 2H), 2.04 (t, J=7.3 Hz, 2H), 2.47-2.51 (m, 2H),
2.61-2.65 (m, 1H), 3.05 (s, 3H), 3.29-3.33 (m, 2H), 7.04 (d, J=9.0
Hz, 1H), 7.19-7.34 (m, 5H), 7.59 (d, J=8.7 Hz, 1H), 7.66 (s, 1H),
7.91 (t, J=5.3 Hz, 1H), 10.10 (s, 1H), 11.23 (s, 1H).
Example 4-14
[1195] MS ESI m/e: 685 (M+H), 683 (M-H).
[1196] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.82 (t, J=7.3 Hz, 3H), 0.90-0.98 (m, 2H), 1.14-1.28 (m, 4H),
1.25 (s, 3H), 1.37-1.49 (m, 2H), 1.45 (s, 6H), 2.04 (t, J=7.3 Hz,
2H), 2.58-2.65 (m, 1H), 3.07 (s, 3H), 3.27-3.34 (m, 2H), 5.49 (brs,
1H), 6.99-7.11 (m, 2H), 7.18-7.25 (m, 1H), 7.31-7.42 (m, 2H),
7.55-7.67 (m, 2H), 7.85-7.93 (m, 1H), 10.09 (s, 1H), 11.14 (s,
1H).
Example 4-15
[1197] MS ESI m/e: 590 (M+H), 588 (M-H).
[1198] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 1.42 (s, 3H), 2.16 (s,
3H), 3.21 (s, 3H), 3.37 (s, 3H), 6.69 (t, J=8.3 Hz, 1H), 7.04-7.10
(m, 1H), 7.31-7.55 (m, 5H), 7.70 (s, 1H), 11.41 (s, 1H).
Example 4-16
[1199] MS ESI m/e: 626 (M+H), 624 (M-H).
[1200] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
3.01 (s, 3H), 3.09 (s, 3H), 3.21 (s, 3H), 6.93 (t, J=8.3 Hz, 1H),
7.11-7.15 (m, 1H), 7.20-7.28 (m, 2H), 7.42 (t, J=8.3 Hz, 1H),
7.52-7.57 (m, 1H), 7.76-7.81 (m, 1H), 9.94 (br, 1H), 11.21 (br,
1H).
Example 4-17
[1201] MS ESI m/e: 630 (M+H), 628 (M-H).
[1202] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.81 (m, 2H),
1.05-1.15 (m, 5H), 1.41 (s, 3H), 2.15 (s, 3H), 2.68-2.77 (m, 1H),
3.90-4.00 (m, 2H), 6.72 (t, J=8.3 Hz, 1H), 6.97-7.03 (m, 1H),
7.30-7.54 (m, 5H), 7.65-7.69 (m, 1H), 11.07 (s, 1H).
Example 4-18
[1203] MS ESI m/e: 666 (M+H), 664 (M-H).
[1204] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.81 (m, 2H),
1.06-1.15 (m, 5H), 1.39 (s, 3H), 2.68-2.76 (m, 1H), 3.02 (s, 3H),
3.90-4.00 (m, 2H), 6.74 (t, J=8.3 Hz, 1H), 6.93-6.99 (m, 1H),
7.07-7.13 (m, 1H), 7.20-7.26 (m, 2H), 7.38-7.54 (m, 3H), 11.07 (s,
1H).
Example 4-19
[1205] MS ESI m/e: 654 (M+H), 652 (M-H).
[1206] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (t, J=6.8
Hz, 3H), 1.20 (t, J=7.2 Hz, 3H), 1.25 (s, 3H), 3.08 (s, 3H), 3.12
(q, J=7.4 Hz, 2H), 3.87 (d, J=7.1 Hz, 2H), 6.94 (t, J=8.6 Hz, 1H),
7.12 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 7.41
(t, J=8.0 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.79 (d, J=10.5 Hz, 1H),
9.98 (s, 1H), 11.24 (s, 1H).
Example 4-20
[1207] MS ESI m/e: 640 (M+H), 638 (M-H).
[1208] .sup.1H-NMR (DMSO-ds, 300 MHz) .delta. 1.13 (t, J=6.8 Hz,
3H), 1.26 (s, 3H), 3.02 (s, 3H), 3.09 (s, 3H), 3.88 (q, J=6.8 Hz,
2H), 6.95 (t, J=8.5 Hz, 1H), 7.11-7.18 (m, 1H), 7.21-7.30 (m, 2H),
7.43 (t, J=7.7 Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.76-7.82 (m, 1H),
9.94 (brs, 1H), 11.24 (brs, 1H).
Example 4-21
[1209] MS ESI m/e: 604 (M+H), 602 (M-H).
[1210] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (t, J=6.8
Hz, 3H), 1.26 (s, 3H), 2.04 (s, 3H), 3.08 (s, 3H), 3.87 (q, J=7.5
Hz, 2H), 6.94 (t, J=8.5 Hz, 1H), 7.05-7.11 (m, 1H), 7.37 (t, J=7.9
Hz, 1H), 7.51-7.60 (m, 2H), 7.65-7.71 (m, 1H), 7.78 (d, J=10.2 Hz,
1H), 10.10 (brs, 1H), 11.23 (brs, 1H).
Example 4-22
[1211] MS ESI m/e: 666 (M+H), 664 (M-H).
[1212] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.47 (t, J=7.2
Hz, 3H), 0.63-0.69 (m, 2H), 0.90-0.97 (m, 2H), 1.76-1.94 (m, 2H),
2.57-2.63 (m, 1H), 3.00 (s, 3H), 3.07 (s, 3H), 6.93 (t, J=8.8 Hz,
1H), 7.12-7.16 (m, 1H), 7.23-7.30 (m, 2H), 7.42 (t, J=8.0 Hz, 1H),
7.53-7.58 (m, 1H), 7.79 (dd, J=1.6, 10.0 Hz, 1H), 9.91 (s, 1H),
11.07 (s, 1H).
Example 4-23
[1213] MS ESI m/e: 680 (M+H), 678 (M-H).
[1214] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.47 (t, J=7.4
Hz, 3H), 0.61-0.70 (m, 2H), 0.89-0.98 (m, 2H), 1.20 (t, J=7.4 Hz,
3H), 1.74-1.95 (m, 2H), 2.55-2.65 (m, 1H), 3.07 (s, 3H), 3.11 (q,
J=7.4 Hz, 2H), 6.92 (t, J=8.6 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H),
7.22-7.31 (m, 2H), 7.40 (t, J=7.9 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H),
7.79 (d, J=10.2 Hz, 1H), 9.97 (s, 1H), 11.07 (s, 1H).
Example 4-24
[1215] MS ESI m/e: 630 (M+H), 628 (M-H).
[1216] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.47 (t, J=7.2
Hz, 3H), 0.60-0.69 (m, 2H), 0.87-0.98 (m, 2H), 1.79-1.93 (m, 2H),
2.04 (s, 3H), 2.56-2.66 (m, 1H), 3.07 (s, 3H), 6.92 (t, J=8.6 Hz,
1H), 7.07 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.53-7.69 (m,
3H), 7.79 (d, J=10.2 Hz, 1H), 10.09 (s, 1H), 11.07 (s, 1H).
Example 4-25
[1217] MS ESI m/e: 554 (M+H), 552 (M-H).
[1218] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.73 (m,
2H), 0.91-1.01 (m, 2H), 1.19 (t, J=7.5 Hz, 3H), 1.24 (s, 3H),
2.57-2.68 (m, 1H), 2.62 (q, J=7.4 Hz, 2H), 3.01 (s, 3H), 3.03 (s,
3H), 7.03-7.15 (m, 3H), 7.19-7.27 (m, 3H), 7.41 (t, J=8.1 Hz, 1H),
9.89 (s, 1H), 11.24 (s, 111H).
Example 4-26
[1219] MS ESI m/e: 568 (M+H), 566 (M-H).
[1220] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.73 (m,
2H), 0.91-1.01 (m, 2H), 1.18 (t, J=7.5 Hz, 3H), 1.19 (t, J=7.2 Hz,
3H), 1.23 (s, 3H), 2.57-2.68 (m, 1H), 2.62 (q, J=7.5 Hz, 2H), 3.03
(s, 3H), 3.11 (q, J=7.2 Hz, 2H), 7.03-7.13 (m, 3H), 7.19-7.27 (m,
3H), 7.40 (t, J=8.1 Hz, 1H), 9.94 (s, 1H), 11.24 (s, 1H).
Example 4-27
[1221] MS ESI m/e: 528 (M+H), 526 (M-H).
[1222] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.48 (t, J=7.4
Hz, 3H), 0.60-0.70 (m, 2H), 0.88-0.98 (m, 2H), 1.77-1.92 (m, 2H),
2.04 (s, 3H), 2.55-2.66 (m, 1H), 3.10 (s, 3H), 4.30 (s, 1H),
7.04-7.14 (m, 2H), 7.28-7.41 (m, 2H), 7.52 (d, J=11.7 Hz, 1H),
7.58-7.68 (m, 2H), 10.09 (s, 1H), 11.08 (s, 1H).
Example 4-28
[1223] MS ESI m/e: 564 (M+H), 562 (M-H).
[1224] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.48 (t, J=7.2
Hz, 3H), 0.63-0.69 (m, 2H), 0.90-0.97 (m, 2H), 1.78-1.93 (m, 2H),
2.56-2.64 (m, 1H), 3.01 (s, 3H), 3.10 (s, 3H), 4.31 (s, 1H), 7.09
(t, J=8.4 Hz, 1H), 7.13-7.17 (m, 1H), 7.23-7.34 (m, 3H), 7.42 (t,
J=8.0 Hz, 1H), 7.52 (dd, J=2.0, 11.6 Hz, 1H), 9.92 (s, 1H), 11.08
(s, 1H).
Example 4-29
[1225] MS ESI m/e: 578 (M+M), 576 (M-H).
[1226] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.47 (t, J=7.1
Hz, 3H), 0.61-0.70 (m, 2H), 0.88-0.98 (m, 2H), 1.20 (t, J=7.2 Hz,
3H), 1.75-1.95 (m, 2H), 2.55-2.64 (m, 1H), 3.10 (s, 3H), 3.11 (q,
J=7.2 Hz, 2H), 4.30 (s, 1H), 7.04-7.14 (m, 2H), 7.23-7.35 (m, 3H),
7.40 (t, J=7.8 Hz, 1H), 7.52 (d, J=11.4 Hz, 1H), 9.97 (s, 1H),
11.08 (s, 1H).
Example 4-30
[1227] MS ESI m/e: 532 (M+H), 530 (M-H).
[1228] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) 0.46 (t, J=7.4 Hz, 3H),
0.64-0.70 (m, 2H), 0.90-0.97 (m, 2H), 1.19 (t, J=7.6 Hz, 3H),
1.80-1.90 (m, 2H), 2.04 (s, 3H), 2.57-2.67 (m, 1H), 2.63 (q, J=7.6
Hz, 2H), 3.02 (s, 3H), 7.04-7.13 (m, 3H), 7.23 (d, J=12.0 Hz, 1H),
7.37 (t, J=8.0 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.64 (t, J=2.0 Hz,
1H), 10.09 (s, 1H), 11.24 (s, 1H).
Example 4-31
[1229] MS ESI m/e: 568 (M+H), 566 (M-H).
[1230] .sup.1H-NMR (DMSO-d, 400 MHz) .delta. 0.47 (t, J=7.2 Hz,
3H), 0.63-0.71 (m, 2H), 0.90-0.98 (m, 2H), 1.19 (t, J=7.4 Hz, 3H),
1.74-1.96 (m, 2H), 2.57-2.67 (m, 1H), 2.63 (q, J=7.4 Hz, 2H), 3.01
(s, 3H), 3.02 (s, 3H), 7.06-7.11 (m, 2H), 7.12-7.17 (m, 1H),
7.20-7.30 (m, 3H), 7.42 (t, J=8.0 Hz, 1H), 9.91 (s, 1H), 11.24 (s,
1H).
Example 4-32
[1231] MS ESI m/e: 582 (M+H), 580 (M-H).
[1232] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.46 (t, J=7.2
Hz, 3H), 0.64-0.70 (m, 2H), 0.90-0.98 (m, 2H), 1.19 (t, J=7.6 Hz,
3H), 1.20 (t, J=7.6 Hz, 3H), 1.75-1.93 (m, 2H), 2.58-2.68 (m, 1H),
2.63 (q, J=7.6 Hz, 2H), 3.02 (s, 3H), 3.10 (q, J=7.6 Hz, 2H),
7.05-7.14 (m, 3H), 7.20-7.31 (m, 3H), 7.40 (t, J=8.0 Hz, 1H), 9.97
(s, 1H), 11.23 (s, 1H).
Example 4-33
[1233] MS ESI m/e: 681 (M+H), 679 (M-H).
[1234] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.69 (m,
2H), 0.90-1.00 (m, 2H), 1.22 (s, 3H), 2.52-2.63 (m, 1H), 2.67 (s,
6H), 3.06 (s, 3H), 6.88-6.94 (m, 1H), 7.02-7.09 (m, 1H), 7.18-7.21
(m, 2H), 7.31-7.39 (m, 1H), 7.51-7.56 (m, 1H), 7.75-7.81 (m, 1H),
10.01 (brs, 1H), 11.06 (brs, 1H)
Example 4-34
[1235] MS ESI m/e: 723 (M+H), 721 (M-H).
[1236] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.70 (m,
2H), 0.90-0.99 (m, 2H), 1.24 (s, 3H), 2.55-2.64 (m, 1H), 3.06 (s,
3H), 2.99-3.10 (m, 4H), 3.43-3.53 (m, 4H), 6.88-6.92 (m, 1H),
7.05-7.09 (m, 2H), 7.14-7.22 (m, 1H), 7.31-7.40 (m, 1H), 7.51-7.59
(m, 1H), 7.75-7.81 (m, 1H), 10.21 (brs, 1H), 11.08 (brs, 1H).
Example 4-35
[1237] MS ESI m/e: 519 (M+H), 517 (M-H).
[1238] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.71 (m,
2H), 0.92-1.00 (m, 2H), 1.26 (s, 3H), 2.59-2.67 (m, 1H), 2.73 (t,
J=7.0 Hz, 2H), 3.02-3.12 (m, 2H), 3.05 (s, 3H), 7.04-7.43 (m, 6H),
7.58-7.63 (m, 1H), 7.67 (s, 1H), 7.77-7.88 (m, 3H), 10.39 (s, 1H),
11.23 (s, 1H).
Example 4-36
[1239] MS ESI m/e: 645 (M+H), 643 (M-H).
[1240] .sup.1H-NMR (DMSO-d, 300 MHz) .delta. 0.62-0.70 (m, 2H),
0.92-0.98 (m, 2H), 1.26 (s, 3H), 2.59-2.66 (m, 1H), 2.72 (t, J=7.2
Hz, 2H), 3.03-3.13 (m, 2H), 3.08 (s, 3H), 6.93 (t, J=8.4 Hz, 1H),
7.03-7.08 (m, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.53-7.68 (m, 3H),
7.72-7.85 (m, 4H), 10.37 (s, 1H), 11.08 (s, 1H).
Example 4-37
[1241] MS ESI m/e: 650 (M+H), 648 (M-H).
[1242] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.31 (s, 3H), 2.06 (s, 3H), 2.57-2.64 (m,
1H), 3.08 (s, 3H), 6.93 (dd, J=9.3, 11.1 Hz, 1H), 7.19 (s, 1H),
7.46 (s, 1H), 7.55 (d, J=9.3 Hz, 1H), 7.79 (d, J=11.1 Hz, 1H), 7.83
(s, 1H), 10.27 (s, 1H), 11.03 (s, 1H)
Example 4-38
[1243] MS ESI m/e: 564 (M+H), 562 (M-H).
[1244] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.81 (m, 2H),
1.06-1.16 (m, 5H), 1.40 (s, 3H), 2.69-2.76 (m, 1H), 3.03 (s, 3H),
3.13 (s, 1H), 3.92-4.01 (m, 2H), 6.77-6.84 (m, 1H), 6.92 (t, J=8.1
Hz, 1H), 7.08-7.13 (m, 1H), 7.18-7.33 (m, 4H), 7.42 (t, J=8.1 Hz,
1H), 11.11 (s, 1H).
Example 4-39
[1245] MS ESI m/e: 568 (M+H), 566 (M-H).
[1246] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.83 (m, 2H), 1.02
(t, J=7.0 Hz, 3H), 1.07-1.15 (m, 2H), 1.24 (t, J=7.7 Hz, 3H), 1.38
(s, 3H), 2.60-2.76 (m, 3H), 3.02 (s, 3H), 3.90-4.00 (m, 2H), 6.77
(s, 1H), 6.94-7.03 (m, 3H), 7.08-7.13 (m, 1H), 7.19-7.27 (m, 2H),
7.41 (t, J=7.7 Hz, 1H), 11.19 (s, 1H).
Example 4-40
[1247] MS ESI m/e: 552 (M+H), 550 (M-H).
[1248] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (t, J=6.9
Hz, 3H), 1.20 (t, J=7.3 Hz, 3H), 1.26 (s, 3H), 3.11 (s, 3H), 3.12
(q, J=7.4 Hz, 2H), 3.87 (q, J=7.1 Hz, 2H), 4.30 (s, 1H), 7.05-7.15
(m, 2H), 7.20-7.35 (m, 3H), 7.41 (t, J=8.0 Hz, 1H), 7.52 (d, J=11.6
Hz, 1H), 9.99 (s, 1H), 11.25 (s, 1H).
Example 4-41
[1249] MS ESI m/e: 556 (M+H), 554 (M-H).
[1250] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) 1.10-1.25 (m, 12H), 2.62
(q, J=7.6 Hz, 2H), 3.03 (s, 3H), 3.12 (q, J=7.3 Hz, 2H), 3.88 (q,
J=6.9 Hz, 2H), 7.05-7.15 (m, 3H), 7.20-7.30 (m, 3H), 7.41 (t, J=8.0
Hz, 1H), 9.98 (s, 1H), 11.41 (s, 1H).
Example 4-42
[1251] MS ESI m/e: 538 (M+H), 536 (M-H).
[1252] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (t, J=7.2
Hz, 3H), 1.27 (s, 3H), 3.03 (s, 3H), 3.11 (s, 3H), 3.87 (q, J=6.8
Hz, 2H), 4.30 (s, 1H), 7.05-7.18 (m, 2H), 7.20-7.35 (m, 3H), 7.43
(t, J=7.9 Hz, 1H), 7.52 (d, J=11.3 Hz, 1H), 9.94 (brs, 1H), 11.25
(brs, 1H).
Example 4-43
[1253] MS ESI m/e: 502 (M+H), 500 (M-H).
[1254] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.13 (t, J=7.0
Hz, 3H), 1.27 (s, 3H), 2.05 (s, 3H), 3.11 (s, 3H), 3.87 (q, J=7.1
Hz, 2H), 4.30 (s, 1H), 7.04-7.15 (m, 2H), 7.28-7.34 (m, 1H), 7.37
(t, J=8.1 Hz, 1H), 7.49-7.60 (m, 2H), 7.66-7.70 (m, 1H), 10.10
(brs, 1H), 11.24 (brs, 1H).
Example 4-44
[1255] MS ESI m/e: 542 (M+H), 540 (M-H).
[1256] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (t, J=7.2
Hz, 3H), 1.19 (t, J=7.5 Hz, 3H), 1.25 (s, 3H), 2.63 (q, J=7.5 Hz,
2H), 3.02 (s, 3H), 3.03 (s, 3H), 3.89 (q, J=7.0 Hz, 2H), 7.04-7.18
(m, 3H), 7.20-7.30 (m, 3H), 7.42 (t, J=8.1 Hz, 1H), 9.93 (brs, 1H),
11.41 (brs, 1H).
Example 4-45
[1257] MS ESI m/e: 506 (M+H), 504 (M-H).
[1258] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.14 (t, J=6.2
Hz, 3H), 1.19 (t, J=7.5 Hz, 3H), 1.25 (s, 3H), 2.05 (s, 3H), 2.63
(q, J=7.5 Hz, 2H), 3.03 (s, 3H), 3.89 (q, J=6.8 Hz, 2H), 7.04-7.15
(m, 3H), 7.23 (d, J=12.0 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.53-7.60
(m, 1H), 7.65-7.70 (m, 1H), 10.10 (brs, 1H), 11.41 (brs, 1H).
Example 4-46
[1259] MS ESI m/e: 528 (M+H), 526 (M-H).
[1260] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.82 (m, 2H),
1.06-1.16 (m, 5H), 1.42 (s, 3H), 2.17 (s, 3H), 2.68-2.78 (m, 1H),
3.13 (s, 1H), 3.92-4.01 (m, 2H), 6.90 (t, J=7.9 Hz, 1H), 6.99-7.06
(m, 1H), 7.22-7.46 (m, 5H), 7.63-7.68 (m, 1H), 11.10 (s, 1H).
Example 4-47
[1261] MS ESI m/e: 532 (M+H), 530 (M-H).
[1262] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.83 (m, 2H), 1.02
(t, J=7.0 Hz, 3H), 1.08-1.16 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 1.40
(s, 3H), 2.16 (s, 3H), 2.61-2.77 (m, 3H), 3.91-4.00 (m, 2H),
6.93-7.05 (m, 4H), 7.26-7.48 (m, 3H), 7.59-7.64 (m, 1H), 11.19 (s,
1H).
Example 4-48
[1263] MS ESI m/e: 488 (M+H), 486 (M-H).
[1264] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 1.42 (s, 3H), 2.15 (s,
3H), 3.13 (s, 1H), 3.23 (s, 3H), 3.38 (s, 3H), 6.86 (t, J=8.7 Hz,
1H), 7.03-7.10 (m, 1H), 7.22-7.41 (m, 5H), 7.70 (s, 1H), 11.46 (s,
1H).
Example 4-49
[1265] MS ESI m/e: 524 (M+H), 522 (M-H).
[1266] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 1.41 (s, 3H), 3.04 (s,
3H), 3.14 (s, 1H), 3.23 (s, 3H), 3.38 (s, 3H), 6.75 (s, 1H), 6.89
(t, J=8.5 Hz, 1H), 7.11-7.17 (m, 1H), 7.18-7.33 (m, 4H), 7.43 (t,
J=8.1 Hz, 1H), 11.47 (s, 1H).
Example 4-50
[1267] MS ESI m/e: 492 (M+H), 490 (M-H).
[1268] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 1.24 (t, J=7.5 Hz, 3H),
1.41 (s, 3H), 2.15 (s, 3H), 2.65 (q, J=7.7 Hz, 2H), 3.18 (s, 3H),
3.38 (s, 3H), 6.88-7.11 (m, 4H), 7.32-7.46 (m, 3H), 7.63-7.69 (m,
1H), 11.45 (s, 1H).
Example 4-51
[1269] MS ESI m/e: 528 (M+H), 526 (M-H).
[1270] .sup.1H-NMR (CDCL3, 300 MHz) .delta. 1.24 (t, J=7.5 Hz, 3H),
1.39 (s, 3H), 2.65 (q, J=7.3 Hz, 2H), 3.03 (s, 3H), 3.18 (s, 3H),
3.38 (s, 3H), 6.84 (s, 1H), 6.90-7.03 (m, 3H), 7.11-7.17 (m, 1H),
7.19-7.30 (m, 2H), 7.42 (t, J=8.1 Hz, 1H), 11.46 (s, 1H).
Example 4-52
[1271] MS ESI m/e: 528 (M+H), 526 (M-H).
[1272] .sup.1H-NMR (DMSO-dc, 400 MHz) .delta. 0.64-0.70 (m, 2H),
0.91-0.99 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.05 (s, 3H),
2.58-2.66 (m, 1H), 3.07 (s, 3H), 7.01-7.10 (m, 2H), 7.20-7.25 (m,
1H), 7.32-7.43 (m, 2H), 7.57-7.63 (m, 2H), 10.10 (s, 1H), 11.14 (s,
1H).
Example 4-53
[1273] MS ESI m/e: 532 (M+H), 530 (M-H).
[1274] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.71 (m,
2H), 0.89 (t, J=7.4 Hz, 3H), 0.92-0.99 (m, 2H), 1.24 (s, 3H),
1.54-1.65 (m, 2H), 2.04 (s, 3H), 2.57 (t, J=7.5 Hz, 2H), 2.60-2.67
(m, 1H), 3.02 (s, 3H), 7.01-7.12 (m, 3H), 7.18-7.24 (m, 1H),
7.33-7.39 (m, 1H), 7.58-7.62 (m, 2H), 10.10 (s, 1H), 11.24 (s,
1H).
Example 4-54
[1275] MS ESI m/e: 653 (M+H), 651 (M-H).
[1276] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.60-0.71 (m,
2H), 0.90-1.01 (m, 2H), 1.27 (s, 3H), 2.58-2.67 (m, 1H), 3.08 (s,
3H), 6.89-7.01 (m, 2H), 7.09-7.23 (m, 4H), 7.30-7.39 (m, 1H),
7.51-7.59 (m, 1H), 7.73-7.83 (m, 1H), 9.69 (brs, 1H), 11.09 (brs,
1H).
Example 4-55
[1277] MS ESI m/e: 637 (M+H), 635 (M-H).
[1278] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.69 (m, 2H),
0.96 (m, 2H), 1.17 (s, 3H), 2.62 (m, 1H), 3.09 (s, 3H), 3.26 (s,
3H), 6.95 (t, J=8.6 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.70-7.85 (m,
3H), 7.90-8.00 (m, 2H), 11.04 (s, 1H).
Example 4-56
[1279] MS ESI m/e: 504 (M+H), 502 (M-H).
[1280] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.65-0.71 (m,
2H), 0.92-0.99 (m, 2H), 1.24 (s, 3H), 2.04 (s, 3H), 2.32 (s, 3H),
2.58-2.67 (m, 1H), 3.02 (s, 3H), 7.00-7.10 (m, 3H), 7.20 (d, J=12.0
Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.56-7.63 (m, 2H), 10.10 (s, 1H),
11.24 (s, 1H).
Example 4-57
[1281] MS ESI m/e: 558 (M+H), 556 (M-H).
[1282] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.64-0.71 (m,
2H), 0.90-0.99 (m, 2H), 1.24 (s, 3H), 1.46-1.57 (m, 2H), 1.58-1.69
(m, 2H), 1.71-1.83 (m, 2H), 1.97-2.07 (m, 2H), 2.04 (s, 3H),
2.58-2.68 (m, 1H), 2.93-3.06 (m, 1H), 3.03 (s, 3H), 7.00-7.14 (m,
3H), 7.24 (dd, J=1.2, 12.0 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H),
7.57-7.63 (m, 1H), 10.10 (s, 1H), 11.22 (s, 1H).
Example 4-58
[1283] MS ESI m/e: 651 (M+H), 649 (M-H).
[1284] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.71 (m,
2H), 0.93-1.00 (m, 2H), 1.10 (t, J=7.3 Hz, 3H), 1.17 (s, 3H),
2.56-2.66 (m, 1H), 3.09 (s, 3H), 3.29-3.40 (m, 2H), 6.95 (t, J=8.7
Hz, 1H), 7.52-7.58 (m, 1H), 7.73-7.82 (m, 3H), 7.88-7.95 (m, 2H),
11.04 (s, 1H).
Example 4-59
[1285] MS ESI m/e: 721 (M+H), 719 (M-H).
[1286] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.71 (m,
2H), 0.91-1.01 (m, 2H), 1.26 (s, 3H), 1.35-1.60 (m, 6H), 2.59-2.67
(m, 1H), 2.99-3.12 (m, 4H), 3.07 (s, 3H), 6.89-6.94 (m, 1H),
7.04-7.06 (m, 1H), 7.13-7.17 (m, 2H), 7.34-7.39 (m, 1H), 7.54-7.57
(m, 1H), 7.77-7.80 (m, 1H), 10.06 (brs, 1H), 11.06 (brs, 1H).
Example 4-60
[1287] MS ESI m/e: 630 (M+H), 628 (M-H).
[1288] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.09 (t, J=7.5 Hz, 3H), 1.27 (s, 3H), 2.34
(q, J=7.0 Hz, 2H), 2.59-2.70 (m, 1H), 3.09 (s, 3H), 6.91-7.08 (m,
2H), 7.34-7.40 (m, 1H), 7.56-7.69 (m, 3H), 7.78-7.82 (m, 1H), 10.03
(brs, 1H), 11.09 (brs, 1H).
Example 4-61
[1289] MS ESI m/e: 533 (M+H), 531 (M-H).
[1290] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.73 (m,
2H), 0.91-1.01 (m, 2H), 1.22 (s, 3H), 2.04 (s, 3H), 2.58-2.68 (m,
1H), 2.92 (s, 6H), 2.98 (s, 3H), 6.55 (dd, J=3.0, 9.1 Hz, 1H), 6.62
(dd, J=2.6, 14.3 Hz, 1H), 6.99-7.11 (m, 2H), 7.35 (t, J=7.9 Hz,
1H), 7.55-7.62 (m, 2H), 10.09 (brs, 1H), 11.27 (brs, 1H).
Example 4-62
[1291] MS ESI m/e: 673 (M+H), 671 (M-H)
[1292] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) 0.63-0.69 (m, 2H),
0.91-0.98 (m, 2H), 1.33 (s, 3H), 2.03 (s, 6H), 3.08 (s, 3H), 6.91
(dd, J=10.5, 9.6 Hz, 1H), 7.28 (s, 2H), 7.55 (d, J=9.6 Hz, 1H),
7.78 (d, J=10.5 Hz, 1H), 10.09 (s, 1H), 7.92 (s, 1H), 11.09 (s,
1H)
Example 4-63
[1293] MS ESI m/e: 646.0 (M+H), 644.0 (M-H).
[1294] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.91-0.98 (m, 2H), 1.28 (s, 3H), 2.08 (s, 3H), 2.57-2.65 (m,
1H), 3.07 (s, 3H), 3.89 (s, 3H), 6.91 (dd, J=12.0, 9.0 Hz, 1H),
7.07 (s, 2H), 7.55 (d, J=9.0 Hz, 1H), 7.79 (d, J=12.0 Hz, 1H), 7.95
(s, 1H), 9.27 (s, 1H), 11.12 (s, 1H)
Example 4-64
[1295] MS ESI m/e: 685.9, 687.9, 684.0, 685.9
[1296] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-0.99 (m, 2H), 1.31 (s, 3H), 2.57-2.63 (m, 1H), 3.08 (s,
6H), 6.94 (dd, J=9.0, 12.0 Hz, 1H), 7.22-7.22 (m, 1H), 7.27-7.27
(m, 2H), 7.56 (d, J=9.0 Hz, 1H), 7.79 (d, J=12.0 Hz, 1H), 10.16 (s,
1H), 11.04 (s, 1H)
Example 4-65
[1297] MS ESI m/e: 571.1 (M+H),569.2 (M-H).
[1298] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.93-1.00 (m, 2H), 1.35 (s, 3H), 2.04 (s, 6H), 2.59-2.67 (m,
1H), 3.11 (s, 3H), 4.32 (s, 1H), 7.09 (dd, J=9.0, 12.0 Hz, 1H),
7.30 (s, 2H), 7.33 (d, J=9.0 Hz, 1H), 7.53 (d, J=12.0 Hz, 1H), 7.94
(s, 1H), 10.11 (s, 2H), 11.12 (s, 1H)
Example 4-66
[1299] MS ESI m/e: 616.0 (M+H),614.0 (M-H).
[1300] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.68 (m,
2H), 0.92-0.99 (m, 2H), 1.23 (s, 3H), 2.07 (s, 3H), 2.58-2.66 (m,
1H), 3.07 (s, 3H), 6.92 (dd, J=9.0, 9.0 Hz, 1H), 7.28 (d, J=9.0 Hz,
2H), 7.55 (d, J=9.0 Hz, 1H), 7.64 (d, J=9.0 Hz, 2H), 7.79 (d, J=9.0
Hz, 1H), 10.10 (s, 1H), 11.06 (s, 1H)
Example 4-67
[1301] MS ESI m/e: 530 (M+H), 528 (M-H).
[1302] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.76 (m,
4H), 0.90-1.03 (m, 4H), 1.24 (s, 3H), 1.88-2.02 (m, 1H), 2.04 (s,
3H), 2.58-2.68 (m, 1H), 3.01 (s, 3H), 6.92-7.11 (m, 4H), 7.35 (t,
J=8.6 Hz, 1H), 7.55-7.64 (m, 2H), 10.09 (s, 1H), 11.23 (s, 1H).
Example 4-68
[1303] MS ESI m/e: 660 (M+H), 658 (M-H).
[1304] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56-0.64 (m,
2H), 0.85-0.95 (m, 2H), 1.26 (s, 3H), 2.04 (s, 3H), 2.46-2.60 (m,
1H), 3.20 (brs, 3H), 3.46-3.55 (m, 2H), 4.01-4.11 (m, 2H), 6.91 (t,
J=8.5 Hz, 1H), 6.97-7.07 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.45 (d,
J=8.4 Hz, 1H), 7.54-7.67 (m, 2H), 7.73 (d, J=9.9 Hz, 1H), 10.09 (s,
1H), 10.13 (s, 1H).
Example 4-69
[1305] MS ESI m/e: 696 (M+H), 694 (M-H).
[1306] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.56-0.66 (m,
2H), 0.81-0.97 (m, 2H), 1.26 (s, 3H), 2.50-2.59 (m, 1H), 3.00 (s,
3H), 3.19 (s, 3H), 3.50 (t, J=5.3 Hz, 2H), 4.05 (t, J=5.1 Hz, 2H),
6.90 (t, J=8.9 Hz, 1H), 7.07-7.15 (m, 1H), 7.18-7.27 (m, 2H),
7.35-7.50 (m, 2H), 7.69-7.78 (m, 1H), 9.90 (brs, 1H), 10.16 (brs,
1H).
Example 4-70
[1307] MS ESI m/e: 652.0 (M+H),650.0 (M-H).
[1308] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.60-0.64 (m,
2H), 0.89-0.94 (m, 2H), 1.19 (s, 3H), 2.55-2.62 (m, 1H), 2.99 (s,
3H), 3.03 (s, 3H), 6.88 (dd, J=8.0, 8.0 Hz, 1H), 7.21 (d, J=8.0 Hz,
2H), 7.29 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0
Hz, 1H), 9.91 (s, 1H), 11.02 (s, 1H)
Example 4-71
[1309] MS ESI m/e: 514.1 (M+H), 512.2 (M-H).
[1310] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.91-0.99 (m, 2H), 1.24 (s, 3H), 2.07 (s, 3H), 2.59-2.66 (m,
1H), 3.10 (s, 3H), 4.30 (s, 1H), 7.09 (dd, J=8.7, 8.4 Hz, 1H), 7.28
(d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),
7.64 (d, J=8.4 Hz, 2H), 10.10 (s, 1H), 11.08 (s, 1H)
Example 4-72
[1311] MS ESI m/e: 559 (M+H), 557 (M-H).
[1312] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.90-1.01 (m, 2H), 1.18 (s, 3H), 2.57-2.67 (m, 1H), 3.07 (s,
3H), 6.93 (t, J=8.5 Hz, 1H), 7.34-7.50 (m, 5H), 7.52-7.58 (m, 1H),
7.79 (dd, J=1.5, 10.2 Hz, 1H), 11.06 (brs, 1H).
Example 4-73
[1313] MS ESI m/e: 668 (M+H), 666 (M-H).
[1314] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.92-1.01 (m, 2H), 1.30 (s, 3H), 2.60-2.69 (m, 1H), 3.10 (s,
3H), 6.91-6.99 (m, 1H), 7.06-7.11 (m, 1H), 7.38-7.42 (m, 1H),
7.52-7.60 (m, 1H), 7.75-7.95 (m, 5H), 9.98 (brs, 1H), 11.09 (brs,
1H), 12.68 (brs, 1H).
[1315] MS ESI m/e: 681 (M+H), 679 (M-H).
[1316] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.72 (m,
2H), 0.90-1.02 (m, 2H), 1.31 (s, 3H), 2.60-2.69 (m, 1H), 3.09 (s,
3H), 3.89 (s, 3H), 6.09-6.11 (m, 1H), 6.90-6.97 (m, 1H), 7.01-7.11
(m, 3H), 7.37-7.42 (m, 1H), 7.52-7.60 (m, 1H), 7.73-7.84 (m, 3H),
9.90 (brs, 1H), 11.10 (brs, 1H).
Example 4-74
[1317] MS ESI m/e: 647 (M+H), 645 (M-H).
[1318] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.27 (s, 3H), 2.58-2.66 (m, 1H), 3.08 (s,
3H), 3.62 (s, 3H), 6.92 (t, J=-8.6 Hz, 1H), 6.99-7.02 (m, 1H), 7.33
(t, J=8.1 Hz, 1H), 7.54-7.57 (m, 1H), 7.61-7.66 (m, 2H), 7.79 (dd,
J=1.8, 10.2 Hz, 1H), 9.05 (s, 1H), 9.58 (s, 1H), 11.08 (s, 1H).
Example 4-75
[1319] MS ESI m/e: 518.0 (M+H), 516.0 (M-H).
[1320] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-1.00 (m, 2H), 1.19 (t, J=7.8 Hz, 3H), 1.23 (s, 3H), 2.07
(s, 3H), 2.57-2.65 (m, 1H), 2.63 (q, J=7.8 Hz, 2H), 3.02 (s, 3H),
7.07-7.09 (m, 2H), 7.21-7.25 (m, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.63
(d, J=8.7 Hz, 2H), 10.10 (s, 1H), 11.22 (s, 1H)
Example 4-76
[1321] MS ESI m/e: 550.1 (M+H), 548.1 (M-H)
[1322] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.91-0.99 (m, 2H), 1.24 (s, 3H), 2.07 (s, 3H), 2.59-2.66 (m,
1H), 3.10 (s, 3H), 4.30 (s, 1H), 7.09 (dd, J=8.7, 8.4 Hz, 1H), 7.28
(d, J=8.4 Hz, 2H), 7.31 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H),
7.64 (d, J=8.4 Hz, 2H), 10.10 (s, 1H), 11.08 (s, 1H)
Example 4-77
[1323] MS ESI m/e: 666.0 (M+H), 664.0 (M-H).
[1324] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.21 (t, J=7.4 Hz, 3H), 1.23 (s, 3H),
2.58-2.65 (m, 1H), 3.14 (q, J=7.4 Hz, 2H), 6.92 (dd, J=7.5, 10.5
Hz, 1H), 7.26 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.55 (d,
J=7.5 Hz, 1H), 7.79 (d, J=10.5 Hz, 1H), 9.98 (s, 1H), 11.06 (s,
1H)
Example 4-78
[1325] MS ESI m/e: 554.2 (M+H), 552.1 (M-H)
[1326] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-0.99 (m, 2H), 1.19 (t, J=7.5 Hz, 3H), 1.22 (s, 3H),
2.55-2.63 (m, 1H), 2.63 (q, J=7.5 Hz, 2H), 3.02 (s, 3H), 3.04 (s,
3H), 7.07-7.09 (m, 2H), 7.21-7.25 (m, 1H), 7.25 (d, J=9.3 Hz, 2H),
7.34 (d, J=9.3 Hz, 2H), 9.95 (s, 1H), 11.22 (s, 1H)
Example 4-79
[1327] MS ESI m/e: 664 (M+H), 662 (M-H).
[1328] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.28-0.34 (m,
2H), 0.69-0.77 (m, 2H), 1.06 (brs, 3H), 2.30-2.37 (m, 1H), 2.99 (s,
3H), 4.21 (t, J=9.2 Hz, 2H), 4.72 (t, J=8.6 Hz, 2H), 6.50-6.57 (m,
1H), 7.06-7.11 (m, 1H), 7.14-7.24 (m, 3H), 7.29-7.35 (m, 1H),
7.35-7.41 (m, 1H), 9.91 (brs, 1H).
Example 4-80
[1329] MS ESI m/e: 661 (M+H), 659 (M-H).
[1330] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.69 (m,
2H), 0.93-0.98 (m, 2H), 1.27 (s, 3H), 2.60-2.65 (m, 1H), 3.05 (s,
3H), 3.08 (s, 3H), 3.67 (s, 3H), 6.92 (t, J=8.5 Hz, 1H), 7.00-7.03
(m, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.54-7.57 (m, 1H), 7.61-7.67 (m,
2H), 7.77-7.81 (m, 1H), 9.24 (s, 1H), 11.08 (s, 1H).
Example 4-81
[1331] MS ESI m/e: 617 (M+H), 615 (M-H).
[1332] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.70 (m,
2H), 0.92-0.98 (m, 2H), 1.28 (s, 3H), 2.59-2.66 (m, 1H), 3.08 (s,
3H), 5.89 (s, 2H), 6.87-6.94 (m, 2H), 7.28 (t, J=7.9 Hz, 1H),
7.35-7.45 (m, 2H), 7.53-7.56 (m, 1H), 7.75-7.81 (m, 1H), 8.71 (s,
1H), 11.09 (s, 1H).
Example 4-82
[1333] MS ESI m/e: 632 (M+H), 630 (M-H).
[1334] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.98 (m, 2H), 1.25 (s, 3H), 2.60-2.64 (m, 1H), 3.08 (s,
3H), 3.99 (d, J=6.0 Hz, 2H), 5.64 (t, J=6.0 Hz, 1H), 6.92 (t, J=8.5
Hz, 1H), 7.05-7.08 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.53-7.56 (m,
1H), 7.71-7.81 (m, 3H), 9.83 (s, 1H), 11.07 (s, 1H).
Example 4-83
[1335] MS ESI m/e: 511, 513 (M+H), 509, 511 (M-H).
[1336] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.20 (s, 3H),
3.08 (s, 3H), 3.22 (s, 3H), 3.50 (t, J=6.2 Hz, 2H), 4.04 (t, J=6.2
Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 7.35-7.51 (m, 5H), 7.55 (d, J=8.7
Hz, 2H), 11.06 (s, 1H).
Example 4-84
[1337] MS ESI m/e: 511, 513 (M+H), 509, 511 (M-H).
[1338] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.22 (s, 3H),
3.08 (s, 3H), 4.50 (s, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.38-7.52 (m,
5H), 7.55 (d, J=8.7 Hz, 2H), 10.89 (s, 1H).
Example 4-85
[1339] MS ESI m/e: 497, 499 (M+H), 495, 497 (M-H).
[1340] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.20 (s, 3H),
3.08 (s, 3H), 3.53 (q, J=6.3 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.77
(t, J=5.8 Hz, 1H), 7.06 (d, J=9.0 Hz, 2H), 7.37-7.51 (m, 5H), 7.55
(d, J=9.0 Hz, 2H), 11.10 (s, 1H).
Example 4-86
[1341] MS ESI m/e: 524, 526 (M+H), 522, 524 (M-H).
[1342] .sup.1H-NMR (DMSO-d, 300 MHz) .delta. 1.20 (s, 3H), 2.16 (s,
6H), 2.42 (t, J=6.8 Hz, 2H), 3.08 (s, 3H), 3.94 (t, J=7.2 Hz, 2H),
7.07 (d, J=9.0 Hz, 2H), 7.37-7.51 (m, 5H), 7.56 (d, J=8.7 Hz, 2H),
11.07 (s, 1H).
Example 4-87
[1343] MS ESI m/e: 681 (M+H), 679 (M-H).
[1344] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.72 (m,
2H), 0.90-1.02 (m, 2H), 1.31 (s, 3H), 2.60-2.69 (m, 1H), 3.09 (s,
3H), 3.89 (s, 3H), 6.09-6.11 (m, 1H), 6.90-6.97 (m, 1H), 7.01-7.11
(m, 3H), 7.37-7.42 (m, 1H), 7.52-7.60 (m, 1H), 7.73-7.84 (m, 3H),
9.90 (brs, 1H), 11.10 (brs, 1H).
Example 4-88
[1345] MS ESI m/e: 614 (M+H), 612 (M-H).
[1346] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.31 (s, 3H), 2.55-2.68 (m, 1H), 3.09 (s,
3H), 3.57 (s, 2H), 6.87-6.96 (m, 3H), 7.25-7.28 (m, 1H), 7.55-7.58
(m, 1H), 7.78-7.81 (m, 1H), 10.49 (brs, 1H), 11.08 (brs, 1H).
Example 4-89
[1347] MS ESI m/e: 668 (M+H), 666 (M-H).
[1348] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.71 (m,
2H), 0.91-1.01 (m, 2H), 1.29 (s, 3H), 2.60-2.70 (m, 1H), 3.08 (s,
3H), 6.93 (dd, J=9.0, 9.0 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 7.40
(dd, J=9.0, 9.0 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.70 (s, 1H), 7.80
(d, J=9.0 Hz, 2H), 8.05 (s, 1H), 8.38 (s, 1H), 9.96 (brs, 1H),
11.08 (brs, 1H), 13.27 (brs, 1H).
Example 4-90
[1349] MS EST m/e: 603 (M+H), 601 (M-H).
[1350] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.71 (m,
2H), 0.93-1.00 (m, 2H), 1.19 (s, 3H), 2.58-2.66 (m, 1H), 3.08 (s,
3H), 6.95 (t, J=8.5 Hz, 1H), 7.46-7.58 (m, 3H), 7.79 (dd, J=1.5,
10.2 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H), 11.01 (s, 1H), 13.14 (br,
1H).
Example 4-91
[1351] MS ESI m/e: 602 (M+H), 600 (M-H).
[1352] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.71 (m,
2H), 0.92-1.00 (m, 2H), 1.19 (s, 3H), 2.59-2.65 (m, 1H), 3.08 (s,
3H), 6.94 (t, J=8.7 Hz, 1H), 7.42-7.49 (m, 3H), 7.53-7.58 (m, 1H),
7.76-7.81 (m, 1H), 7.94 (d, J=8.7 Hz, 2H), 8.07 (brs, 1H), 11.02
(s, 1H).
Example 4-92
[1353] MS ESI m/e: 616 (M+H), 614 (M-H).
[1354] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-1.00 (m, 2H), 1.18 (s, 3H), 2.58-2.66 (m, 1H), 2.81 (d,
J=4.5 Hz, 3H), 3.08 (s, 3H), 6.94 (t, J=8.7 Hz, 1H), 7.47 (d, J=8.6
Hz, 2H), 7.52-7.58 (m, 1H), 7.76-7.82 (m, 1H), 7.90 (d, J=8.6 Hz,
2H), 8.51-8.56 (m, 1H), 11.02 (brs, 1H).
Example 4-93
[1355] MS ESI m/e: 630 (M+H), 628 (M-H).
[1356] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.92-1.00 (m, 2H), 1.22 (s, 3H), 2.59-2.66 (m, 1H), 2.93 (brs,
3H), 3.00 (brs, 3H), 3.08 (s, 3H), 6.94 (t, J=8.5 Hz, 1H),
7.42-7.49 (m, 4H), 7.53-7.57 (m, 1H), 7.77-7.81 (m, 1H), 11.04 (s,
1H).
Example 4-94
[1357] MS ESI m/e: 617 (M+H), 615 (M-H).
[1358] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.69 (m,
2H), 0.92-0.99 (m, 2H), 1.19 (s, 3H), 2.58-2.65 (m, 1H), 3.07 (s,
3H), 3.63 (s, 2H), 6.92 (t, J=8.7 Hz, 1H), 7.28-7.36 (m, 4H),
7.53-7.57 (m, 1H), 7.75-7.81 (m, 1H), 11.07 (br, 1H), 12.39 (br,
1H).
Example 4-95
[1359] MS ESI m/e: 661 (M+H), 659 (M-H).
[1360] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.71 (m,
2H), 0.90-1.00 (m, 2H), 1.28 (s, 3H), 2.55-2.68 (m, 1H), 3.08 (s,
3H), 3.14 (q, J=5.6 Hz, 2H), 3.43 (q, J=5.6 Hz, 2H), 4.74 (t, J=5.6
Hz, 1H), 6.20 (t, J=5.6 Hz, 1H), 6.83-6.97 (m, 2H), 7.22-7.38 (m,
2H), 7.48 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.78 (d, J=10.5 Hz, 1H),
8.75 (s, 1H), 11.08 (s, 1H).
Example 4-96
[1361] MS ESI m/e: 784 (M+H), 782 (M-H).
[1362] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.71 (m,
2H), 0.90-1.02 (m, 2H), 1.24 (s, 3H), 2.57-2.69 (m, 1H), 3.00 (q,
J=6.7 Hz, 4H), 3.07 (s, 3H), 3.35 (q, J=6.7 Hz, 2H), 3.89 (t, J=6.7
Hz, 2H), 4.60 (t, J=5.7 Hz, 1H), 6.86-7.05 (m, 3H), 7.10-7.21 (m,
2H), 7.35 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.71 (t, J=5.7
Hz, 1H), 7.79 (dd, J=1.8, 9.6 Hz, 1H), 9.88 (s, 1H), 11.09 (s,
1H).
Example 4-97
[1363] MS ESI m/e: 530 (M+H), 528 (M-H).
[1364] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.71 (m,
2H), 0.91-1.00 (m, 2H), 1.25 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H),
2.58-2.68 (m, 1H), 3.07 (s, 3H), 5.16 (s, 1H), 5.52 (s, 1H), 7.04
(d, J=6.9 Hz, 1H), 7.11 (t, J=8.6 Hz, 1H), 7.32-7.40 (m, 2H), 7.51
(dd, J=1.8, 12.6 Hz, 1H), 7.56-7.63 (m, 2H), 10.10 (s, 1H), 11.22
(s, 1H).
Example 4-98
[1365] MS ESI m/e: 532 (M+H), 530 (M-H).
[1366] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.60-0.73 (m,
2H), 0.89-1.00 (m, 2H), 1.20 (d, J=6.4 Hz, 6H), 1.24 (s, 3H), 2.04
(s, 3H), 2.56-2.68 (m, 1H), 2.84-2.97 (m, 1H), 3.03 (s, 3H),
6.97-7.16 (m, 3H), 7.19-7.29 (m, 1H), 7.35 (t, J=8.0 Hz, 1H),
7.53-7.66 (m, 2H), 10.10 (s, 1H), 11.22 (s, 1H).
Example 4-99
[1367] MS ESI m/e: 634.0 (M+H), 632.1 (M-H).
[1368] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.69 (m,
2H), 0.91-0.98 (m, 2H), 1.28 (s, 3H), 2.09 (s, 3H), 2.57-2.66 (m,
1H), 3.07 (s, 3H), 6.92 (dd, J=9.0, 8.7 Hz, 1H), 7.14-7.19 (m, 1H),
7.33 (dd, J=8.7, 10.5 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.79 (d,
J=12.0 Hz, 1H), 7.88-7.92 (m, 1H), 9.87 (s, 1H), 11.09 (s, 1H)
Example 4-100
[1369] MS ESI m/e: 646 (M+H), 644 (M-H).
[1370] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.52-0.62 (m,
2H), 0.82-0.96 (m, 2H), 1.28 (s, 3H), 2.04 (s, 3H), 2.44-2.59 (m,
1H), 3.58-3.65 (m, 2H), 4.01-4.08 (m, 2H), 5.58 (t, J=4.5 Hz, 1H),
6.91 (t, J=8.6 Hz, 1H), 6.99-7.08 (m, 1H), 7.30-7.45 (m, 2H),
7.57-7.65 (m, 2H), 7.66-7.75 (m, 1H), 10.09 (brs, 1H), 10.12 (brs,
1H).
Example 4-101
[1371] MS ESI m/e: 670.0 (M+H), 668.0 (M-H)
[1372] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.60-0.67 (m,
2H), 0.89-0.96 (m, 2H), 1.35 (s, 3H), 2.56-2.62 (m, 1H), 2.60 (s,
3H), 3.09 (s, 3H), 6.49-6.56 (m, 1H), 6.84-6.99 (m, 3H), 7.22 (dd,
J=2.4, 7.5 Hz, 1H), 7.46-7.52 (m, 1H)
Example 4-102
[1373] MS ESI m/e: 532.1 (M+H), 530.2 (M-H).
[1374] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.69 (m,
2H), 0.92-0.94 (m, 2H), 1.29 (s, 3H), 2.09 (s, 3H), 2.59-2.63 (m,
1H), 3.10 (s, 3H), 4.29 (s, 1H), 7.06-7.54 (m, 5H), 7.90 (d, 1H,
J=6.6 Hz), 9.86 (s, 1H), 11.11 (s, 1H).
Example 4-103
[1375] MS ESI m/e: 615.1 (M+H), 613.1 (M-H)
[1376] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.71 (m,
2H), 0.91-0.98 (m, 2H), 1.23 (s, 3H), 2.57-2.65 (m, 1H), 3.07 (s,
3H), 6.88-6.96 (m, 4H), 7.55 (d, J=8.7 Hz, 1H), 7.78 (d, J=10.5 Hz,
1H), 10.76 (s, 1H), 10.79 (s, 1H), 11.10 (s, 1H)
Example 4-104
[1377] MS ESI m/e: 638 (M+H), 636 (M-H).
[1378] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.70 (m,
2H), 0.93-0.99 (m, 2H), 1.19 (s, 3H), 2.57-2.65 (m, 1H), 3.08 (s,
3H), 6.90-6.98 (m, 1H), 7.48 (s, 2H), 7.52-7.61 (m, 3H), 7.75-7.82
(m, 1H), 7.89 (d, J=8.6 Hz, 2H), 11.00 (s, 1H).
Example 4-105
[1379] MS ESI m/e: 536 (M+H), 534 (M-H).
[1380] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.71 (m,
2H), 0.91-1.00 (m, 2H), 1.24 (s, 3H), 2.04 (s, 3H), 2.51 (s, 3H),
2.59-2.65 (m, 1H), 3.04 (s, 3H), 7.00-7.14 (m, 3H), 7.27-7.40 (m,
2H), 7.56-7.62 (m, 2H), 10.09 (brs, 1H), 11.22 (brs, 1H).
Example 4-106
[1381] MS ESI m/e: 572 (M+H), 570 (M-H).
[1382] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.24 (s, 3H), 2.51 (s, 3H), 2.60-2.67 (m,
1H), 3.01 (s, 3H), 3.04 (s, 3H), 7.05-7.15 (m, 3H), 7.20-7.34 (m,
3H), 7.40 (t, J=4. Hz, 1H), 9.88 (s, 1H), 11.22 (s, 1H).
Example 4-107
[1383] MS ESI m/e: 599 (M+H), 597 (M-H).
[1384] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.66-0.72 (m,
2H), 0.93-0.98 (m, 2H), 1.12 (d, J=3.0 Hz, 3H), 2.60-2.67 (m, 1H),
3.08 (s, 3H), 6.90-6.97 (m, 1H), 7.15-7.25 (m, 1H), 7.54-7.57 (m,
2H), 7.64-7.69 (m, 1H), 7.77-7.81 (m, 1H), 8.31 (d, J=3.8 Hz, 1H),
11.12 (d, J=3.4 Hz, 1H), 12.60 (d, J=14.3 Hz, 1H).
Example 4-108
[1385] MS ESI m/e: 657 (M+H), 655 (M-H).
[1386] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.74 (m,
2H), 0.90-1.01 (m, 2H), 1.26 (s, 3H), 2.58-2.70 (m, 1H), 3.08 (s,
3H), 4.06 (s, 2H), 6.92 (t, J=8.6 Hz, 1H), 7.36-7.47 (m, 3H),
7.51-7.60 (m, 2H), 7.78 (dd, J=1.8, 10.2 Hz, 1H), 8.31 (s, 1H),
11.04 (s, 1H).
Example 4-109
[1387] MS ESI m/e: 657 (M+H), 655 (M-H).
[1388] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.71 (m,
2H), 0.90-0.99 (m, 2H), 1.26 (s, 3H), 2.56-2.67 (m, 1H), 3.08 (s,
3H), 4.44 (s, 2H), 6.93 (t, J=8.7 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H),
7.45 (t, J=8.1 Hz, 1H), 7.50-7.58 (m, 2H), 7.71-7.82 (m, 2H), 11.10
(s, 1H), 11.23 (s, 1H).
Example 4-110
[1389] MS ESI m/e: 643 (M+H), 641 (M-H).
[1390] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.90-1.00 (m, 2H), 1.27 (s, 3H), 2.58-2.67 (m, 1H), 3.08 (s,
3H), 3.60-3.86 (m, 2H), 4.16-4.32 (m, 2H), 6.84-6.97 (m, 2H), 7.28
(t, J=7.8 Hz, 1H), 7.40-7.73 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.78
(dd, J=1.5, 10.2 Hz, 1H), 9.15-9.51 (brs, 1H), 11.09 (s, 1H).
Example 4-111
[1391] MS ESI m/e: 613 (M+H), 611 (M-H).
[1392] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.74 (m,
2H), 0.91-1.01 (m, 2H), 1.11 (s, 3H), 2.58-2.69 (m, 1H), 3.08 (s,
3H), 3.89 (s, 3H), 6.94 (t, J=8.4 Hz, 1H), 7.26-7.34 (m, 1H),
7.51-7.58 (m, 1H), 7.59-7.67 (m, 2H), 7.74-7.84 (m, 1H), 8.27 (s,
1H), 11.10 (brs, 1H).
Example 4-112
[1393] MS ESI m/e: 613 (M+H), 611 (M-H).
[1394] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.74 (m,
2H), 0.91-1.02 (m, 2H), 1.13 (s, 3H), 2.57-2.69 (m, 1H), 3.08 (s,
3H), 4.09 (s, 3H), 6.94 (t, J=8.5 Hz, 1H), 7.39-7.47 (m, 1H),
7.51-7.60 (m, 1H), 7.66-7.74 (m, 2H), 7.75-7.83 (m, 1H), 8.09 (s,
1H), 11.10 (brs, 1H).
Example 4-113
[1395] MS ESI m/e: 602 (M+H), 600 (M-H).
[1396] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz, 120.degree. C.) .delta.
0.72 (m, 2H), 0.95 (m, 2H), 1.30 (s, 3H), 2.67 (m, 1H), 3.12 (s,
3H), 6.88 (t, J=8.4 Hz, 1H), 7.07 (dd, J=1.8, 8.8 Hz, 1H), 7.36 (t,
J=7.9 Hz, 1H), 7.40-7.55 (m, 3H), 7.67 (dd, J=1.8, 10.3 Hz, 1H),
8.39 (brs, 1H), 9.84 (brs, 1H), 10.90 (s, 1H).
Example 4-114
[1397] MS ESI m/e: 679 (M+H), 677 (M-H).
[1398] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.62-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.25 (s, 3H), 2.59-2.66 (m, 1H), 3.08 (s,
3H), 3.48-3.56 (m, 2H), 3.84 (t, J=6.4 Hz, 2H), 6.92 (t, J=8.6 Hz,
1H), 7.09 (d, J=8.0 Hz, 1H), 7.16-7.26 (m, 2H), 7.44 (t, J=8.2 Hz,
1H), 7.55 (d, J=8.0 Hz, 1H), 7.74-7.83 (m, 2H), 11.10 (s, 1H).
Example 4-115
[1399] MS ESI m/e: 599 (M+H), 597 (M-H).
[1400] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.73 (m,
2H), 0.91-1.00 (m, 2H), 1.14 (s, 3H), 2.59-2.67 (m, 1H), 3.09 (s,
3H), 6.92 (t, J=4.1 Hz, 1H), 7.11-7.16 (m, 1H), 7.53-7.59 (m, 2H),
7.76-7.83 (m, 2H), 8.14 (s, 1H), 11.10 (s, 1H), 13.20 (s, 1H).
Example 4-116
[1401] MS ESI m/e: 685.9 (M+H), 684.0 (M-H).
[1402] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.70 (m,
2H), 0.92-0.98 (m, 2H), 1.26 (s, 3H), 2.57-2.65 (m, 1H), 3.08 (s,
3H), 3.09 (s, 3H), 6.94 (dd, J=9.0, 8.7 Hz, 1H), 7.38 (dd, J=2.3,
8.6 Hz, 1H), 7.51-7.57 (m, 3H), 7.63 (d, J=2.3 Hz, 1H), 7.78 (dd,
J=1.5, 10.2 Hz, 1H), 9.59 (s, 1H), 11.01 (s, 1H)
Example 4-117
[1403] MS ESI m/e: 666.0 (M+H), 664.1 (M-H).
[1404] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.68 (m,
2H), 0.90-0.97 (m, 2H), 1.23 (s, 3H), 2.30 (s, 3H), 2.55-2.63 (m,
1H), 3.09 (s, 3H), 6.88-6.95 (m, 1H), 7.15-7.34 (m, 3H), 7.47-7.57
(m, 2H), 7.70-7.80 (m, 2H).
Example 4-118
[1405] MS ESI m/e: 630 (M+H), 628 (M-H).
[1406] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.75-0.81 (m, 2H),
1.09-1.15 (m, 2H), 1.47 (s, 3H), 2.70-2.77 (m, 1H), 3.20 (s, 3H),
4.66 (s, 2H), 6.70 (t, J=8.5 Hz, 1H), 6.81-6.88 (m, 2H), 7.00 (d,
J=8.3 Hz, 1H), 7.43-7.55 (m, 2H), 8.12 (s, 1H), 11.31 (s, 1H).
Example 4-119
[1407] MS ESI m/e: 612 (M+H), 610 (M-H).
[1408] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.21 (s, 3H),
3.09 (s, 3H), 3.21 (s, 3H), 6.96 (t, J=8.5 Hz, 1H), 7.48 (s, 2H),
7.53-7.64 (m, 3H), 7.76-7.81 (m, 1H), 7.90 (d, J=8.3 Hz, 2H), 11.13
(s, 1H).
Example 4-120
[1409] MS ESI m/e: 573 (M+H), 571 (M-H).
[1410] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.66-0.69 (m,
2H), 0.94-0.98 (m, 2H), 1.26 (s, 3H), 2.50 (s, 3H), 2.61-2.66 (m,
1H), 3.04 (s, 3H), 6.98 (d, J=7.3 Hz, 1H), 7.10-7.19 (m, 6H),
7.31-7.33 (m, 2H), 9.66 (s, 1H), 11.23 (s, 1H).
Example 4-121
[1411] MS ESI m/e: 600 (M+H), 598 (M-H).
[1412] .sup.1H-NMR (CDCl3, 300 MHz) .delta. 0.80-0.90 (m, 2H),
1.11-1.20 (m, 2H), 1.27 (s, 3H), 2.74-2.83 (m, 1H), 3.24 (s, 3H),
6.75 (t, J=8.3 Hz, 1H), 7.37 (dd, J=1.9, 8.7 Hz, 1H), 7.45-7.57 (m,
2H), 7.80 (brs, 3H), 11.37 (s, 1H).
Example 4-122
[1413] MS ESI m/e: 671 (M+H), 669 (M-H).
[1414] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.60-0.67 (m,
2H), 0.87-0.95 (m, 2H), 1.21 (s, 13H), 2.24 (brs, 3H), 2.54-2.61
(m, 1H), 2.69 (brs, 2H), 3.04 (s, 3H), 3.07 (brs, 2H), 3.62 (brs,
2H), 6.89 (t, J=8.7 Hz, 1H), 7.24-7.29 (m, 1H), 7.30-7.35 (m, 2H),
7.40-7.46 (m, 1H), 7.48-7.53 (m, 1H), 7.72-7.77 (m, 1H), 11.01 (s,
1H).
Example 4-123
[1415] MS ESI m/e: 628 (M+H), 626 (M-H).
[1416] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.61-0.71 (m,
2H), 0.90-1.00 (m, 2H), 1.30 (s, 3H), 2.50 (t, J=7.5 Hz, 2H),
2.55-2.67 (m, 1H), 2.95 (t, J=7.5 Hz, 2H), 3.09 (s, 3H), 6.87-6.95
(m, 3H), 7.24 (d, J=9.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.80 (d,
J=9.0 Hz, 1H), 10.11 (brs, 1H), 11.07 (brs, 1H).
Example 4-124
[1417] MS ESI m/e: 643 (M+H), 641 (M-H).
[1418] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.63-0.72 (m,
2H), 0.90-1.00 (m, 2H), 1.27 (s, 3H), 2.58-2.67 (m, 1H), 3.08 (s,
3H), 3.41 (t, J=8.3 Hz, 2H), 3.85 (t, J=8.3 Hz, 2H), 6.92 (t, J=8.5
Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 7.05 (s, 1H), 7.37 (t, J=8.1 Hz,
1H), 7.49 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.67-7.71 (m,
1H), 7.79 (dd, J=1.8, 10.5 Hz, 1H), 11.11 (s, 1H).
Example 4-125
[1419] MS EST m/e: 644 (M+H), 642 (M-H).
[1420] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.72 (m,
2H), 0.89-1.01 (m, 2H), 1.25 (s, 3H), 2.56-2.68 (m, 1H), 3.08 (s,
3H), 4.07 (t, J=8.4 Hz, 2H), 4.45 (t, J=8.4 Hz, 2H), 6.92 (t, J=8.3
Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.46 (t, J=8.1 Hz, 1H), 7.51-7.60
(m, 2H), 7.65-7.69 (m, 1H), 7.78 (d, J=9.3 Hz, 1H), 11.10 (s,
1H).
Example 4-126
[1421] MS ESI m/e: 616 (M+H), 614 (M-H).
[1422] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.73 (m,
2H), 0.90-1.00 (m, 2H), 1.24 (s, 3H), 2.57-2.67 (m, 1H), 3.08 (s,
3H), 6.93 (t, J=8.6 Hz, 1H), 7.08 (dd, J=2.4, 8.7 Hz, 1H), 7.18 (d,
J=2.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.79
(dd, J=1.5, 10.5 Hz, 1H), 11.08 (s, 1H), 11.80 (s, 1H).
Example 4-127
[1423] MS ESI m/e: 638 (M+H), 636 (M-H).
[1424] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.64-0.72 (m,
2H), 0.90-1.01 (m, 2H), 1.19 (s, 3H), 2.57-2.66 (m, 1H), 3.09 (s,
3H), 6.94 (t, J=8.7 Hz, 1H), 7.51 (brs, 2H), 7.53-7.58 (m, 1H),
7.61-7.70 (m, 2H), 7.76-7.88 (m, 3H), 11.05 (brs, 1H).
Example 4-128
[1425] MS ESI m/e: 642 (M+H), 640 (M-H).
[1426] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.59-0.72 (m,
2H), 0.88-1.01 (m, 2H), 1.27 (s, 3H), 1.29 (s, 6H), 2.55-2.67 (m,
1H), 3.07 (s, 3H), 6.86-6.97 (m, 2H), 7.34 (d, J=7.9 Hz, 1H), 7.55
(dd, J=1.1, 7.9 Hz, 1H), 7.78 (dd, J=1.1, 10.6 Hz, 1H), 10.44 (brs,
1H), 11.07 (s, 18H).
Example 4-129
[1427] MS ESI m/e: 574 (M+H), 572 (M-H).
[1428] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.59-0.69 (m,
2H), 0.89-0.99 (m, 2H), 1.35 (s, 3H), 2.52-2.66 (m, 1H), 3.07 (s,
3H), 5.25 (brs, 2H), 6.46 (d, J=6.0 Hz, 1H), 6.53 (s, 1H), 6.55 (d,
J=9.0 Hz, 1H), 6.90 (dd, J=9.0, 9.0 Hz, 1H), 7.06 (dd, J=9.0, 9.0
Hz, 1H), 7.55 (d, J=9.0 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 11.06
(brs, 1H).
Example 4-130
[1429] MS ESI m/e: 640 (M+H), 638 (M-H).
[1430] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.60-0.71 (m,
2H), 0.89-1.00 (m, 2H), 1.29 (s, 3H), 1.47-1.55 (m, 2H), 1.58-1.68
(m, 2H), 2.55-2.68 (m, 1H), 3.07 (s, 3H), 6.87-6.96 (m, 3H), 7.02
(d, J=7.9 Hz, 1H), 7.52-7.58 (m, 1H), 7.78 (dd, J=1.9, 10.2 Hz,
1H), 10.66 (brs, 1H), 11.07 (brs, 1H).
Example 4-131
[1431] MS ESI m/e: 472 (M+H), 470 (M-H).
[1432] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.59-0.70 (m,
2H), 0.89-1.01 (m, 2H), 1.36 (s, 3H), 2.56-2.67 (m, 1H), 3.10 (s,
3H), 4.28 (s, 1H), 5.24 (s, 2H), 6.42-6.62 (m, 3H), 6.99-7.14 (m,
2H), 7.26-7.36 (m, 1H), 7.46-7.57 (m, 1H), 11.08 (s, 1H).
Example 4-132
[1433] MS ESI m/e: 716 (M+H), 714 (M-H).
[1434] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.62-0.74 (m,
2H), 0.91-1.04 (m, 2H), 1.28 (s, 3H), 1.36 (s, 9H), 2.48 (s, 3H),
2.59-2.69 (m, 1H), 3.08 (s, 3H), 6.94 (t, J=8.6 Hz, 1H), 7.17-7.24
(m, 2H), 7.38-7.57 (m, 3H), 7.79 (d, J=10.3 Hz, 1H), 11.0 (brs,
1H).
Example 4-133
[1435] MS EST m/e: 694 (M+H), 692 (M-H).
[1436] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.62-0.71 (m,
2H), 0.92-1.01 (m, 2H), 1.17 (s, 3H), 1.95 (s, 3H), 2.59-2.69 (m,
1H), 3.08 (s, 3H), 3.54 (s, 3H), 6.94 (d, J=9.0 Hz, 1H), 7.52-7.60
(m, 5H), 7.79 (d, J=10.4 Hz, 1H), 11.0 (brs, 1H).
Example 4-134
[1437] MS ESI m/e: 620 (M+H), 618 (M-H).
[1438] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.27 (s, 3H),
2.06 (s, 3H), 3.10 (s, 3H), 3.49-3.60 (m, 2H), 3.89-4.01 (m, 2H),
4.78 (brs, 1H), 6.95 (t, J=8.7 Hz, 1H), 7.03-7.10 (m, 1H), 7.41 (t,
J=8.0 Hz, 1H), 7.51-7.60 (m, 2H), 7.68 (s, 1H), 7.78-7.82 (m, 1H),
10.1 (brs, 1H), 11.3 (brs, 1H).
Example 4-135
[1439] MS ESI m/e: 634 (M+H), 632 (M-H).
[1440] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.27 (s, 3H),
2.65-2.79 (m, 2H), 2.06 (s, 3H), 3.09 (s, 3H), 3.39-3.50 (m, 2H),
3.82-3.94 (m, 2H), 4.46 (brs, 1H), 6.95 (t, J=8.7 Hz, 1H),
7.07-7.10 (m, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.55-7.58 (m, 2H), 7.68
(s, 1H), 7.78-7.81 (m, 1H), 10.1 (brs, 1H), 11.3 (brs, 1H).
Example 4-136
[1441] MS ESI m/e: 650 (M+H), 648 (M-1).
[1442] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.27 (s, 3H),
2.05 (s, 3H), 3.09 (s, 3H), 3.70-3.90 (m, 2H), 4.02 (q, J=7.8 Hz
1H), 4.55 (t, J=5.7 Hz, 1H), 4.77 (d, J=5.4 Hz, 1H), 6.94 (t, J=8.7
Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.56 (d,
J=8.7 Hz, 2H), 7.68 (s, 1H), 7.79 (dd, J=1.5, 10.2 Hz, 1H), 10.10
(s, 1H), 11.30 (s, 1H).
Example 4-137
[1443] MS ESI m/e: 650 (M+H), 648 (M-1).
[1444] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.27 (s, 3H),
2.05 (s, 3H), 3.09 (s, 3H), 3.70-3.90 (m, 2H), 4.02 (q, J=7.1 Hz,
1H), 4.55 (brs, 1H), 4.77 (d, J=3.9 Hz, 1H), 6.94 (t, J=8.5 Hz,
1H), 7.04 (d, J=8.7 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.56 (d, J=8.7
Hz, 2H), 7.68 (s, 1H), 7.79 (dd, J=2.4, 10.8 Hz, 1H), 0.1.10 (s,
1H), 11.30 (s, 1H).
Example 4-138
[1445] MS ESI m/e: 723 (M+H), 721 (M-H).
[1446] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 0.65-0.72 (m,
2H), 0.91-1.01 (m, 2H), 1.27 (s, 3H), 1.91 (s, 3H), 2.59-2.69 (m,
1H), 2.93 (s, 6H), 3.10 (s, 3H), 6.98 (t, J=8.6 Hz, 1H), 7.43-7.60
(m, 5H), 7.80 (d, J=10.3 Hz, 1H), 11.0 (brs, 1H).
Example 4-139
[1447] MS ESI m/e: 630 (M+H), 628 (M-H).
[1448] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.63-0.71 (m,
2H), 0.92-1.00 (m, 2H), 1.26 (s, 3H), 1.82 (brs, 3H), 2.58-2.67 (m,
1H), 3.08 (s, 3H), 3.16 (brs, 3H), 6.94 (t, J=8.7 Hz, 1H),
7.30-7.46 (m, 3H), 7.47-7.60 (m, 2H), 7.76-7.82 (m, 1H), 11.02 (s,
1H).
Example 4-140
[1449] MS ESI m/e: 658 (M+H), 656 (M-H).
[1450] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 0.61-0.72 (m,
2H), 0.92-1.01 (m, 2H), 1.28 (s, 3H), 2.20 (s, 6H), 2.58-2.66 (m,
1H), 3.08 (s, 3H), 6.94 (t, J=8.6 Hz, 1H), 7.29-7.35 (m, 1H),
7.36-7.40 (m, 1H), 7.42-7.48 (m, 1H), 7.51-7.58 (m, 2H), 7.75-7.82
(m, 1H), 11.00 (s, 1H).
Example 4-141
[1451] MS ESI m/e: 633 (M+H), 631 (M-H).
[1452] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.27 (s, 3H),
1.81-1.93 (m, 2H), 2.05 (s, 3H), 2.75-2.87 (m, 2H), 3.09 (s, 3H),
3.91 (t, 2H, J=6.2 Hz), 6.93 (t, 1H, J=8.5 Hz), 7.04-7.10 (m, 1H),
7.38 (t, 1H, J=8.1 Hz), 7.48-7.59 (m, 2H), 7.69-7.86 (m, 5H), 10.18
(s, 1H), 11.21 (s, 1H).
Example 4-142
[1453] MS ESI m/e: 664 (M+H), 662 (M-H).
[1454] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
1.46-1.57 (m, 1H), 1.65-1.80 (m, 1H), 2.05 (s, 3H), 3.08 (s, 3H),
3.15-3.36 (m, 2H), 3.40-3.51 (m, 1H), 3.78-3.91 (m, 1H), 3.98-4.11
(m, 1H), 4.46-4.56 (m, 2H), 6.94 (t, 1H, J=8.7 Hz), 7.04-7.10 (m,
1H), 7.37 (t, 1H, J=8.1 Hz), 7.52-7.59 (m, 2H), 7.65-7.69 (m, 1H),
7.79 (dd, 1H, J=1.9, 10.5 Hz), 10.10 (s, 1H), 11.28 (s, 1H).
Example 4-143
[1455] MS ESI m/e: 664 (M+H), 662 (M-H).
[1456] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
1.43-1.59 (m, 1H), 1.67-1.79 (m, 1H), 2.04 (s, 3H), 3.08 (s, 3H),
3.15-3.32 (m, 2H), 3.40-3.50 (m, 1H), 3.78-3.91 (m, 1H), 3.97-4.10
(m, 1H), 4.45-4.54 (m, 2H), 6.94 (t, 1H, J=8.7 Hz), 7.04-7.09 (m,
1H), 7.37 (t, 1H, J=8.1 Hz), 7.53-7.59 (m, 2H), 7.65-7.69 (m, 1H),
7.79 (dd, 1H, J=1.9, 10.2 Hz), 10.10 (s, 1H), 11.27 (s, 1H).
Example 4-144
[1457] MS ESI m/e: 648 (M+H), 646 (M-H).
[1458] .sup.1H-NMR (CDCL3, 300 MHz) .delta. 1.42 (s, 3H), 1.53-1.82
(m, 4H), 2.17 (s, 3H), 3.21 (s, 3H), 3.68 (t, 2H, J=6.2 Hz),
3.96-4.04 (m, 2H), 6.70 (t, 1H, J=8.3 Hz), 7.05-7.12 (m, 1H),
7.22-7.56 (m, 6H), 7.70 (s, 1H), 11.47 (s, 1H).
Example 4-145
[1459] MS ESI m/e: 670 (M+H), 668 (M-H).
[1460] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
1.66-1.75 (m, 2H), 3.02 (s, 3H), 3.08 (s, 3H), 3.42 (q, 2H, J=5.9
Hz), 3.88-3.91 (m, 2H), 4.45 (t, 1H, J=5.1 Hz), 6.94 (t, 1H, J=8.6
Hz), 7.12-7.15 (m, 1H), 7.23-7.29 (m, 2H), 7.42 (t, 1H, J=7.9 Hz),
7.54-7.57 (m, 1H), 7.78 (dd, 1H, J=10.5, 1.7 Hz), 9.92 (s, 1H),
11.26 (s, 1H).
Example 4-146
[1461] MS ESI m/e: 634 (M+H), 632 (M-H).
[1462] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) .delta. 1.25 (s, 3H),
1.66-1.75 (m, 2H), 3.08 (s, 3H), 3.42 (q, 2H, J=4.5 Hz), 3.86-3.93
(m, 2H), 4.46 (t, 1H, J=3.8 Hz), 6.95 (t, 1H, J=6.4 Hz), 7.11 (dd,
1H, J=1.7, 6.4 Hz), 7.22 (d, 1H, J=1.6 Hz), 7.35 (d, 1H, J=6.4 Hz),
7.53-7.58 (m, 1H), 7.79 (dd, 1H, J=1.4, 7.8 Hz), 11.27 (s, 1H),
11.84 (s, 1H).
Example 4-147
[1463] MS ESI m/e: 577 (M+H), 575 (M-H).
[1464] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.19 (s, 3H),
1.65-1.76 (m, 2H), 3.08 (s, 3H), 3.43 (q, 2H, J=5.9 Hz), 3.86-3.94
(m, 2H), 4.46 (t, 1H, J=5.3 Hz), 6.95 (t, 1H, J=8.7 Hz), 7.38-7.51
(m, 5H), 7.52-7.58 (m, 1H), 7.79 (dd, 1H, J=1.9, 10.2 Hz), 11.25
(s, 1H).
Example 4-148
[1465] MS ESI m/e: 650 (M+H), 648 (M-H).
[1466] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta. 1.26 (s, 3H),
1.70-1.72 (m, 2H), 3.08 (s, 3H), 3.42 (q, 2H, J=5.7 Hz), 3.89-3.91
(m, 2H), 3.99 (d, 2H, J=5.9 Hz), 4.44 (t, 1H, J=5.3 Hz), 5.64 (t,
1H, J=6.1 Hz), 6.94 (t, 1H, J=8.6 Hz), 7.11 (d, 1H, J=7.0 Hz), 7.39
(t, 1H, J=8.3 Hz), 7.55 (d, 1H, J=8.1 Hz), 7.70-7.81 (m, 3H), 9.83
(s, 1H), 11.25 (s, 1H).
INDUSTRIAL APPLICABILITY
[1467] The compound of the present invention shows superior p15
protein inducing action and/or p27 protein inducing action and/or
MEK inhibitory action.
[1468] In addition, the compound of the present invention shows
superior antitumor activity, and anti-rheumatism activity.
[1469] Therefore, the compound can be a pharmaceutical agent
effective for the prophylaxis or treatment of a disease caused by
undesirable cell proliferation, particularly, tumor or
rheumatism.
[1470] This application is based on patent application Nos.
174770/2004 and 327111/2004 filed in Japan, the contents of which
are hereby incorporated by reference.
* * * * *