Synthesis and biological evaluations of 3-substituted indolin-2-ones: A novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases

Article abstract of DOI:10.1021/jm980123i

3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand- dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3- [(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C- 3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK- specific drugs with broad application for the treatment of human diseases.

Full text of DOI:10.1021/jm980123i

2588
J . Med. Chem. 1998, 41, 2588-2603
Syn th esis a n d Biologica l Eva lu a tion s of 3-Su bstitu ted In d olin -2-on es: A Novel
Cla ss of Tyr osin e Kin a se In h ibitor s Th a t Exh ibit Selectivity tow a r d P a r ticu la r
Recep tor Tyr osin e Kin a ses
Li Sun,* Ngoc Tran, Flora Tang, Harald App, Peter Hirth, Gerald McMahon, and Cho Tang*
SUGEN, Inc., 351 Galveston Drive, Redwood City, California 94063
Received February 24, 1998
3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine
kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs).
These compounds have been evaluated for their relative inhibitory properties against a panel
of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified
compounds which showed selective inhibition of the ligand-dependent autophosphorylation of
various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds
and their relative potency and selectivity to inhibit particular RTKs has determined that (1)
3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the
VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky
group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward
the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C-3
position of the indolin-2-one (16) exhibited high potency and selectivity when tested against
the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these
3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind
in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets
of these compounds as specific chemical leads for the development of RTK-specific drugs with
broad application for the treatment of human diseases.
In tr od u ction
potency and specificity toward the EGF RTK. These
chemical classes have provided the basis for the selec-
tion of drug candidates for the treatment of EGF-de-
pendent human cancers. Biochemical and kinetic stud-
ies using the 4-(phenylamino)quinazolines have sug-
gested that these compounds inhibit the EGF RTK in
an ATP-competitive manner.13 Models based upon the
cAMP-dependent kinase have been used to help define
how these molecules may localize in the ATP binding
pocket of the EGF RTK.11,13 The planar quinazoline
core structure has been proposed to bind to the ATP
binding cleft and the substituents around the core struc-
ture have been suggested to confer specificity through
unique interactions between these inhibitors and a few
kinase-specific amino acid residues present in the ATP
binding sites of the EGF RTK.13
Receptor tyrosine kinases (RTKs) have been shown
to be important mediators of cellular signal transduction
in cells.1,2 Many RTKs have been shown to be oncogene
products implicating their role in the transformation
process associated with human cancers.3 In this regard,
deregulated RTK activity has been shown to play a role
in abnormal cell functions associated with the growth,
survival, and spread of human tumors.4 In a broader
sense, increased RTK activity has been implicated in
atherosclerosis, vascular restenosis, fibrosis of the lung,
liver, and kidney, inflammatory disease, and other
immune-mediated disorders.2,3 As a consequence of
these associations, RTKs have been viewed as attractive
therapeutic targets for the development of novel agents
with novel mechanisms to treat human disease.5 Over
the past decade, many investigators have sought to
identify small molecules that block RTK function.
However, only recently has it been possible to identify
several chemical classes that would inhibit kinase
activity associated with particular RTK types.6-8 In this
regard, in vitro testing of compounds for inhibitory
properties against a wide variety of kinases has pro-
vided the rationale to pursue particular chemical sub-
types as RTK-specific drug leads.
Recently, we have elucidated the crystallographic
structure of 3-substituted indolin-2-ones in the catalytic
core of the fibroblast growth factor (FGF) RTK.14 In this
study, the indolin-2-one core was shown to occupy a site
in which the adenine of adenosine triphosphate binds
and the substituents around the indolin-2-one core were
shown to extend into the hinge region between the two
kinase lobes. In this case, compound 42 (3-[(3-(2-car-
boxyethyl)-4-methylpyrrol-2-yl)methylidenyl]indolin-2-
one) (Table 2) was shown to inhibit the FGF RTK in a
specific manner and induced conformational changes in
the nucleotide-binding loop that may, in part, explain
the potency and specificity of this compound. In the
present study, we provide data to suggest that various
substituents around the indolin-2-one core can contrib-
ute to the potency and specificity of this chemical class
Recent studies to identify inhibitors of the epidermal
growth factor (EGF) RTK have been quite successful.
(Phenylamino)quinazolines,9 pyridopyrimidines,10 pyr-
rolopyrimidines,11 and pyrazolopyrimidines12 have been
identified and exhibit promising in vitro and in vivo
* To whom correspondence should be addressed.
S0022-2623(98)00123-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/09/1998

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2589
Sch em e 1. Preparations of 3-Substituted Indolin-2-ones
Ch a r t 1. Structures and Biological Evaluations of the
Three Lead 3-Substituted Indolin-2-ones (1-3)
of compounds containing different five-membered het-
eroaryl rings, including thiophene (Table 3), furan
(Table 4), and pyrazole (Table 5), at the C-3 position of
indolin-2-one. The impact of the substituents on the
indolin-2-one ring on the potency and selectivity of the
inhibitors was also examined.
on various RTKs. This study provides the basis to
associate subsets of 3-substituted indolin-2-ones as
specific chemical leads for the development of particular
RTK-specific drugs with broad application to the treat-
ment of human diseases.
Ch em istr y
3-Substituted indolin-2-ones were prepared by con-
densing substituted indolin-2-ones and aldehydes or
ketones in the presence of bases (Scheme 1). Indolin-
2-one (oxindole), 5-chlorooxindole, and most of the
aldehydes were commercially available, whereas 5-ni-
tro-, 4-methyl-, 5-bromo-, 5-methyl-, and 6-fluorooxin-
doles and a few aldehydes have been prepared by means
of reported or newly developed methods. 5-Nitrooxin-
dole was prepared by nitration of the oxindole at -5 to
0 °C followed by recrystallization in aqueous acetic
acid.15 4-Methyloxindole has been prepared by reported
procedures.16 6-Fluorooxindole (6) was prepared start-
ing from 2,5-difluoronitrobenzene according to literature
procedures17 with some modifications (Scheme 2). Dis-
placement of o-fluoro substitution of 2,5-difluoroni-
trobenzene with dimethyl malonate followed by hydro-
lytic decarboxylation with 6 N aqueous hydrochloric acid
gave 4-fluoro-2-nitrophenylacetic acid (5). Reductive
cyclization of 5 under hydrogenation conditions resulted
in the generation of 6. 5-Bromooxindole (7) was pre-
pared by bromination of oxindole with NBS in acetoni-
trile at 0 °C (Scheme 2). Synthesis of 5-methyloxindole
(8) was achieved by a Wolff-Kishner-like reduction of
5-methylisatin with hydrazine hydrate (Scheme 2).18
Most of the aldehydes (9-12) which are not com-
mercially available were prepared by a Vilsmeier formy-
lation reaction starting from commercially available
chemicals (Scheme 3).
Discover y a n d Design of 3-Su bstitu ted
In d olin -2-on es a s RTK In h ibitor s
Using a random-screening approach, we have identi-
fied three related compounds of the 3-substituted indo-
lin-2-ones (1-3 in Chart 1) that exhibited inhibitory
properties against various RTKs using whole-cell ligand-
dependent autophosphorylation assays. As shown in
Chart 1, both 1 and 3 were found to be potent and
selective inhibitors of the vascular endothelial growth
factor (VEGF) [fetal liver kinase-1 (Flk-1)] RTKs, whereas
2 was found to be nonselective for RTK inhibition. A
comparison of the chemical structures of these com-
pounds provided the foundation to suggest that various
structural features may impart changes in RTK speci-
ficity. Compound 1 contains a nitrogen atom attached
to the C-4′ position of the phenyl at the C-3 position of
the indolin-2-one, whereas 2 contains an isosteric me-
thine moiety. In addition, NMR analysis of these
compounds indicated differences in E and Z isomer
populations. Both 1 and 3 exist as Z isomers, but 2
adopts the E isomeric form. This preliminary analysis
suggested that the relative potency and selectivity of
these compounds for inhibition of these kinases may be
sensitive to the substituent at the C-4′ position of 1 or
the predominant Z-E configurations.
To extend these observations, we sought to expand
the chemical diversity of this structural type and
determine the structure-activity relationship (SAR) for
3-substituted indolin-2-one analogues using a panel of
cell-based RTK assays. Five classes of 3-substituted
indolin-2-ones were designed and synthesized: (A)
compound 1 analogues with different substituent(s) on
the phenyl ring at the C-3 position of the indolin-2-one
core (Table 1); (B) compound 3 analogues having dif-
ferent substituent(s) in the pyrrole ring at the C-3
position of indolin-2-one (Table 2); (C-E) three classes
The 3-substituted indolin-2-ones may exist as either
the Z or E isomer depending on the characteristics of
the substituents at the C-3 position of the 3-substituted
indolin-2-one (Tables 1-5). The two isomer forms could
be distinguished by either 1D or 2D NOE analysis
(Chart 2). The Z-configured compounds should show a
NOE effect between the proton at the C-4 position and
the vinyl proton, whereas the E-configured compounds
should have a NOE effect between the proton at the C-4

2590 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
Ch a r t 2. Determination of the Configurations for
Sch em e 2. Preparations of 6-Fluoro- (6), 5-Bromo- (7),
and 5-Methyloxindoles (8)
3-Substituted Indolin-2-ones Using NOE Experiments
shifts of its particular proton(s) is summarized in Tables
1-5. For example, NOE experiments demonstrated
that the chemical shifts for the protons at the C-2′ and
C-6′ positions in the phenyl ring at the C-3 position of
the 3-(substituted benzylidenyl)indolin-2-ones (Table 1)
were around 7.85-8.53 ppm for the Z isomer but 7.45-
7.84 ppm for the E isomer. We interpret this to be due
to 2′- or 6′-protons being deshielded by the carbonyl at
the C-2 position of the indolin-2-one ring in the Z isomer
form. In the E isomer form, these protons may be
shielded by the phenyl ring of the indolin-2-one core
structure. Thus, configurations of the compounds within
this series could be assigned based on the chemical
shifts of particular protons, H-2′ and/or H-6′, in the
molecules (Table 1).
Most of 3-(substituted benzylidenyl)indolin-2-ones
which do not have any substitution at the C-4 position
in general existed as the mixtures of both Z and E
isomer forms. Compound 3 analogues (Table 2) con-
taining a pyrrole substituent at the C-3 position of the
3-substituted indolin-2-ones existed exclusively as the
Z isomer forms (Table 2). Indolin-2-ones having 3-sub-
stituted thienyl group (Table 3) existed as Z isomers.
3-[(Substituted pyrazolyl)methylidenyl]indolin-2-ones
(Table 5) having a proton at the N-1′ position in the
pyrazole ring (62) existed as the Z isomer, but the
similar compound with substitution at the N-1′ position
of the pyrazole ring existed as the E isomer (63).
However, compounds with a 3-substituted furanyl moi-
ety existed as E isomers (Table 4).
Sch em e 3. Synthesis of the Corresponding Aldehydes
We have observed the equilibrium between the Z and
E isomer forms in polar solvents, such as methanol and
dimethyl sulfoxide (DMSO), or in the presence of light.
The E isomerism of the 3-(substituted benzylidenyl)-
indolin-2-ones in Table 1 may be the result of the steric
interaction between the carbonyl group at the C-2
position of the indolin-2-one ring and the proton at the
C-2′(6′) position of the phenyl ring in their Z isomeric
forms (Scheme 4). 3-[(Substituted furanyl)methylide-
nyl]indolin-2-ones appear to favor the E isomer form.
This may be due to the electrostatic repulsion between
the C-2 carbonyl oxygen atom of the indolin-2-one and
the O-1′ of furan in their Z isomer form (Scheme 4). On
the other hand, the predominance of the Z isomerism
of the 3-[(substituted pyrrolyl)methylidenyl]indolin-2-
ones and 3-[(substituted pyrazolyl)methylidenyl]indolin-
2-ones may be the result of the intramolecular hydrogen
bonding between the C-2 carbonyl oxygen atom of the
indolin-2-one ring and the proton on the N-1′ of pyrrole
or N-2′ of pyrazole rings (Scheme 4). Replacement of
the proton on the N-1′ position of the pyrrole (50) or
pyrazole (63) ring afforded E-configured compounds due
to the unfavorable interaction between the substitution
at the N-1′ position of the pyrrole or the lone pair at
the N-2′ position of the pyrazole ring and the carbonyl
oxygen atom at the C-2 position of the indolin-2-one ring
position and the proton(s) in the C-3 substitution of the
3-substituted indolin-2-ones. The configurations of
some of the compounds (reference compounds) were
determined using NOE analysis, while the configura-
tions of the remaining compounds were assigned by
comparison of their H NMR spectrum with those of the
reference compounds. The relationship between the
Z-E configuration of a compound and the chemical
1

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2591
Sch em e 4. Rationales for the Preferred Z or E
Configuration of 3-Substituted Indolin-2-ones
required to achieve 50% inhibition of tyrosine phospho-
rylation on various RTKs compared to ligand-stimulated
control reactions in the presence of vehicle alone (di-
methyl sulfoxide). Compounds with IC50 values greater
than 100 µΜ were considered inactive. The relative
selectivity of a given inhibitor was assessed using
calculated ratios of the IC50 values corresponding to
specific RTKs. The results are summarized in Tables
1-5.
The primary goal of this study was to establish an
initial SAR on these novel RTK inhibitors and to
identify compounds with high potency and selectivity
against particular RTKs as chemical leads. Five classes
of compounds were designed and synthesized in order
to provide answers to the following questions: (A) What
are the electronic and steric effects of the substitutions
in the phenyl ring of 1 or in the pyrrole ring of 3 at the
C-3 position of 3-substituted indolin-2-ones on the
inhibitory potency and specificity against various RTKs?
(B) Do different heteroaryl substitutions at the C-3
position of 3-substituted indolin-2-ones influence the
inhibitory activity of this series? (C) Is the Z isomer
the active form? (D) Is the vinyl proton essential for
the inhibitory activity? (E) What is the impact of the
substituent(s) in the indolin-2-one core structure on
potency and selectivity of the inhibitors against various
RTKs.
A. SAR of 3-(Su bstitu ted ben zylid en yl)in d olin -
2-on es. Compounds from Table 1 were synthesized and
represented analogues of the two initial leads, 1 and 2.
These compounds possess substituents on the phenyl
ring at the C-3 position of 3-substituted indolin-2-ones.
As mentioned above, there were two differences when
chemical structures of 1 and 2 were compared. The
former has a nitrogen atom and the latter an isosteric
methine attached to the C-4′ position of the phenyl
group at the C-3 position of 3-substituted indolin-2-one.
In addition, 1 exists as the Z isomer, but 2 exists
predominantly as the E isomer. Compound 1 was
shown to be a selective VEGF (Flk-1) RTK inhibitor,
whereas 2 is a nonselective RTK inhibitor. These
results suggested that electron-rich substitution (4′-
dimethylamino in 1) in the phenyl ring at the C-3
position of 3-substituted indolin-2-ones would have a
large impact on the configuration and subsequently the
inhibitory activity of inhibitors against various RTKs.
On the basis of these preliminary results, we designed,
synthesized, and evaluated a series of analogues of 1
with different electron-rich substituents at the C-4′
position of the phenyl ring at the C-3 position of
3-substituted indolin-2-ones. First we maintained the
nitrogen atom at the C-4′ position of 1 and incorporated
this nitrogen atom into the piperazine, morpholine,
pyrrolidine, or piperidine substitution. Second, we
replaced the 4′-dimethylamino substitution of 1 with
other electron-rich substituents such as a hydroxyl or
alkoxy moiety. Third, we introduced electron-with-
drawing substituents into the phenyl ring at the C-3
position of the indolin-2-ones. Fourth, based on our
knowledge of particular tyrphostins that have bulky
substituents and had been shown to be EGF RTK
inhibitors, bulky substituents, such as tert-butyl or
isopropyl, were added on the phenyl at the C-3 position
of the indolin-2-ones in order to achieve specific EGF
in the Z-configured form. The loss of the intramolecular
hydrogen bonding of such compounds is also responsible
for the E isomeric form. Electrostatic interaction be-
tween the C-2 carbonyl oxygen and partial positively
charged S-1′ of the 3-[(substituted thienyl)methylidenyl]-
indolin-2-ones favors the Z isomer form for the com-
pounds in Table 3.
Resu lts a n d Discu ssion
Structure-activity relationships (SAR) for inhibition
of ligand-dependent tyrosine phosphorylation by the
indolin-2-ones were determined in a panel of NIH3T3
mouse fibroblast lines engineered to overexpress various
RTKs including the human PDGF receptor â, the
murine VEGF receptor (Flk-1), the human EGF recep-
tor, and the human insulin-like growth factor-1 (IGF-
1) receptor.19 To assess homology to the EGF receptor
family-2 (Her-2) (p185erbB2) kinase activity, the cyto-
plasmic domain of the human Her-2 was engineered to
contain the extracellular and transmembrane domain
of the human EGF receptor. The chimeric receptor was
overexpressed in NIH3T3 cells, and ligand-dependent
Her-2 kinase activity was assessed following stimulation
of the receptor with EGF as described.19 IC50 values
were defined as the concentration of a compound

2592 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
Ta ble 1. 3-(Substituted benzylidenyl)indolin-2-ones: Preferred Configurations Determined by NMR Experiments and Their
Inhibitory Activities toward Particular RTKs at the Cellular Level

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2593
Ta ble 1 (Continued)
RTK inhibitors. Last, to assess the importance of the
vinyl proton, we replaced the vinyl proton in compound
24 by a methyl group in compound 37. The SAR
analysis of these analogues of 1 is presented below.
We incorporated the 4′-nitrogen atom of 1 into dif-
ferent saturated heterocyclic rings to give 16 (4′-
piperazine), 19 (4′-morpholine), 23 (4′-pyrrolidine), and
24 (4′-piperidine). Evaluation of these compounds
indicated that they were inactive against the EGF, Her-
2, and IGF-1 RTKs as is the case of 1. Using the PDGF
RTK assay, 16 was 4-fold more potent and 19 2-fold less
potent than 1. In contrast, 23 and 24 were found to be
inactive against the PDGF RTK activity. However,
their inhibitory activity against the VEGF (Flk-1) RTK
was 2-6-fold less than that of 1. Interestingly, these
compounds showed similar potency against the VEGF
(Flk-1) RTK regardless of their predominant configura-
tions. However, our cocrystal study indicated that the
binding configuration for 16 was the Z form despite its
predominantly E isomer in solution (Table 1).14 There-
fore, the E form of 16 has to be isomerized to the Z form
before or during the interaction with the VEGF (Flk-1)
RTK. Binding of the Z isomer to the catalytic site may
shift the Z-E equilibrium from the E isomer to the Z
form. This hypothesis may help to explain the loss of
potencies of 16, 19, 23, and 24 against the VEGF (Flk-
1) RTK activity relative to 1 which exists only in the
active Z form.
Since the Z configuration may be the preferred form
for the inhibitory activity of these inhibitors against
both the PDGF and VEGF (Flk-1) RTKs, we have
designed and synthesized conformationally constrained
3-substituted indolin-2-ones. In this regard, a methyl
group was introduced at the C-4 position of the 3-sub-
stituted indolin-2-ones in order to provide more steric
interactions with the substituent at the C-3 position.
In this case, the Z isomer form was more favored than
the E form (Scheme 4). Compound 17 and 20 (Table 1)
were prepared by introducing the methyl group at the
C-4 position of 16 and 19 (Table 1), respectively. Both
17 and 20 existed exclusively as Z isomers compared to
the predominant E isomer forms of their respective
parent compounds, 16 and 19. Compound 14, while
existing as a Z isomer like 1, was found to be inactive
against the PDGF RTK activity and about 4-fold less
active (IC50 ) 3.0 µΜ) than 1 (IC50 ) 0.8 µΜ) against
the VEGF (Flk-1) RTK activity. Therefore, substitution
at the C-4 position of the indolin-2-one core is unfavor-
able for the inhibitory activities against both the PDGF
and VEGF (Flk-1) RTKs. Compound 17 was found to
be 5-fold less potent than 16 against the PDGF RTK
activity. Compound 20 showed similar potency to 19
when tested against the PDGF and VEGF (Flk-1) RTK
activities despite the unfavorable interaction introduced
by the methyl substituent at the C-4 position. In
conclusion, the actual inhibitory activities of these
3-substituted indolin-2-ones may depend on the balance
between the positive inhibitory effect of the Z-configured
piperazine ring of 17 or the piperidine ring of 20 and
the negative inhibitory impact of the methyl group at
the C-4 position.
Other electron-rich substituents, such as a hydroxyl
or methoxy moiety (25 and 26, respectively) were also
introduced at the C-4′ position of the phenyl substitution
at the C-3 position of the 3-substituted indolin-2-ones.
Compound 25 containing the hydroxyl group at the C-4′
position selectively inhibited the VEGF (Flk-1) RTK
activity with an IC50 of 2.7 µΜ. Methylation of this
hydroxyl substitution at the C-4′ position in 25 gave 26
which specifically inhibits VEGF (Flk-1) RTK activity
with an IC50 value of 7.6 µΜ. In contrary, inhibitors
having electron-withdrawing substituents at the C-4′
position of the phenyl ring at the C-3 position of
3-substituted indolin-2-ones totally eliminated the in-
hibitory activity against any RTK, as evidenced by 27
and 28. This result suggests that an electron-rich
substituent may be essential for the inhibitory activity
against the VEGF (Flk-1) RTK, probably through an
impact on the equilibrium between Z and E forms.
Electron-rich substituents could establish a highly

2594 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
Ta ble 2. 3-[(Substituted pyrrol-2-yl)methylidenyl]indolin-2-ones: Preferred Configurations Determined by NMR Experiments and
Their Inhibitory Activity toward Particular RTKs at the Cellular Level
conjugated system, decrease the energy barrier between
the Z and E forms, and enable the Z-E equilibrium to
be established faster than the one without such electron-
rich substituents.
To examine the effects of the substituents around the
indolin-2-one ring on RTK inhibitory potency and
selectivity, 13, 15, 18, 21, and 22 have been synthesized.
Methyl substitution at the N-1 position of 13 abolishes
the inhibitory activity against the PDGF RTK activity
and results in 28-fold loss in potency against the VEGF
(Flk-1) RTK activity (IC50 ) 22.6 µΜ) compared to 1.
This result indicated the importance of the proton at
the N-1 position for inhibitory activity of 1 and is in
agreement with our studies derived from the cocrystal
structure of 16 and FGF RTK catalytic domain.14 In
this latter case, the proton at the N-1 position of 16 was

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2595
Ta ble 3. 3-[(Substituted thien-2-yl)methylidenyl]indolin-2-ones: Preferred Configurations Determined by NMR Experiments and
Their Inhibitory Activity toward Particular RTKs at the Cellular Level
Ta ble 4. 3-[(Substituted furan-2-yl)methylidenyl]indolin-2-ones: Preferred Configurations Determined by NMR Experiments and
Their Inhibitory Activity toward Particular RTKs at the Cellular Level
found to be involved in a critical hydrogen-bonding
interaction with the carbonyl oxygen of Glu562 within
the catalytic domain.14 Compound 15, 6-fluoro-substi-
tuted 1, was found to be 3.4- and 5.8-fold less potent
than 1 against the PDGF and VEGF (Flk-1) RTK
activities, respectively. Thus, the electron-withdrawing
substituents on the indolin-2-one ring are unfavorable
for inhibitory activity against both the PDGF and VEGF
(Flk-1) RTKs.
To examine the effect of multiple substituents in the
phenyl ring on the RTK inhibitory potency and selectiv-
ity, a series of analogues of 25 and 26 were prepared
with substituents at the C-3′ and/or C-5′ position. In-
terestingly, the compound 25 analogue, 29 (which has
tert-butyl at the C-3′ and C-5′ positions), was found to
be active against not only the VEGF (Flk-1) RTK but
also the EGF and Her-2 RTK activities compared to 25.
In addition, the compound 26 analogue, 34 (which has
tert-butyl substitution at the C-3′ position), selectively
inhibited the Her-2 RTK activity. Compound 33, con-
taining 3′,5′-diisopropyl moieties (compound 25 ana-
logue), was found to be a nonselective RTK inhibitor.
Of particular interest, 36, the 5′-bromo analogue of the
parent 32, was a Her-2-specific inhibitor. Deleting the
5-chloro substitution of 32 resulted in 34 which was
shown to specifically inhibit the Her-2 RTK activity. In
contrary, deleting the 5-chloro substitution in compound
36 switched the selectivity from Her-2-specific to EGF/
Her-2/VEGF (Flk-1) RTK-selective (31). The same
5-chloro substitution in different compounds has an

2596 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
Ta ble 5. 3-[(Substituted pyrazol-3-yl)methylidenyl]indolin-2-ones: Preferred Configurations Determined by NMR Experiments and
Their Inhibitory Activity toward Particular RTKs at the Cellular Level
opposite impact on the inhibitory activity of these
inhibitors. This may be the result of different RTK
conformational changes induced by inhibitors containing
different structural features. A similar phenomenon
was observed for the 4-(phenylamino)quinazolines.9 In
this series, specific inhibition of the EGF and Her-2 RTK
family was accomplished with compounds that contain
bulky lipophilic substitutions in the phenyl ring at the
C-3 position of the 3-substituted indolin-2-ones, whereas
selective inhibitors of the PDGF or/and VEGF (Flk-1)
RTK family contained electron-rich substitutions in the
phenyl ring.
This finding is in agreement with a cocrystal study of
the indolin-2-ones and the FGF RTK catalytic domain.14
The roles of the substituents in the indolin-2-one core
of these 3-[(substituted pyrrolyl)methylidenyl]indolin-
2-ones in the inhibitory activity against the PDGF and
VEGF (Flk-1) RTKs were evaluated. Compound 38, the
4-methyl analogue of 3, was found to be inactive when
tested against the PDGF RTK activity (IC50 > 100 µΜ)
and 79-fold less active (IC50 ) 31.0 µΜ) than 3 when
tested against the VEGF (Flk-1) RTK activity. There-
fore, substitution at the C-4 position of the indolin-2-
one ring was found to have a negative impact on the
inhibitory activity of compounds when tested against
both PDGF and VEGF (Flk-1) RTK activities. This is
in accordance with conclusions following our SAR
analysis of 3-(substituted benzylidenyl)indolin-2-ones as
shown in Table 1. An electron-withdrawing chloro or
fluoro substitution in the indolin-2-one core of 39 or 40
decreased the potency and selectivity when tested
against the VEGF (Flk-1) RTK activity compared to 3.
The 5-nitro analogue (51) of 3 was found to be a weak
PDGF RTK inhibitor and was found to be inactive when
tested against the VEGF (Flk-1) RTK activity, suggest-
ing that the electron-withdrawing substituents at the
C-5 position of the indolin-2-ones may be detrimental
to inhibitory activities associated with this series of RTK
inhibitors.
To test the importance of the vinyl proton, compound
37, an analogue of 24 (Table 1), was synthesized and
evaluated. Both 37 and 24 exist as E isomers. How-
ever, compound 24, a specific VEGF (Flk-1) RTK inhibi-
tor, can be contrasted to 37 which was found to be
inactive when tested against any RTK activity in the
study. This demonstrates that the vinyl proton is
critical for the inhibitory activity of these novel RTK
inhibitors against VEGF (Flk-1) RTK.
B. 3-[(Su bstitu ted p yr r ol-2-yl)m eth ylid en yl]in -
d olin -2-on es (Com p ou n d 3 An a logu es). Since we
have found that 3 inhibits both VEGF (Flk-1) (IC50
)
0.39 µΜ) and PDGF (IC50 ) 12.0 µΜ) RTK activities,
we designed a series of inhibitors with different five-
membered rings at the C-3 position of 3-substituted
indolin-2-ones, including pyrrole (Table 2), thiophene
(Table 3), furan (Table 4), and pyrazole (Table 5). In
the pyrrole series (Table 2), most of the compounds were
found to exist as Z isomer forms and found to be inactive
against the EGF, Her-2, and IGF-1 RTK activities.
These compounds were found to be more potent and
selective than 3-(substituted benzylidenyl)indolin-2-ones
against the VEGF (Flk-1) RTK, and a few compounds
showed high inhibitory activity against the PDGF RTK
activity. Methylation at the N-1′ position of the pyrrole
in 3 resulted in a compound (50) that existed as an E
isomer and was shown to be a weak inhibitor of the
VEGF (Flk-1) RTK. This suggested that the Z isomer
is required for inhibiting the VEGF (Flk-1) RTK activity
by these 3-substituted indolin-2-ones.
To assess the impact of the substitutions on the
pyrrole ring of 3 on the inhibitory activity against the
VEGF (Flk-1) RTK, small alkyl or electron-withdrawing
groups were introduced into the pyrrole ring. Inhibitory
activities associated with compounds having small alkyl
and electron-withdrawing polar moieties at both the C-3′
and C-4′ positions in the pyrrole ring of 3 were found to
be either highly selective or specific toward the VEGF
(Flk-1) RTK as in the case of 42 and 44. On the other
hand, most of the compounds with substitutions at the
C-3′ and C-5′ positions in the pyrrole ring of 3 have
shown decreased potency when tested against the PDGF
RTK activity and maintained the good inhibitory activ-
ity when tested against the VEGF (Flk-1) RTK activity.
Compound 45, the 3′,5′-dimethyl analogue20 of 3, was

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2597
found to be slightly less potent than 3 when tested
against the PDGF (IC50 ) 20.26 µΜ) and VEGF (Flk-1)
RTK (IC50 ) 1.04 µΜ), respectively. Interestingly, the
4′-ethyl analogue (47) of 45 was found to be inactive
when tested against all of the RTK activities in the
panel, whereas the 4′-ethoxycarbonyl analogue (48) of
45 was found to be the most potent and selective VEGF
(Flk-1) RTK inhibitor shown in Table 2. In contrast,
compound 49 which has a 3′-ethyl-4′,5′-dimethylpyrrole
at the C-3 position of the indolin-2-ones was found to
be highly potent when tested against the VEGF (Flk-1)
RTK activity (IC50 ) 0.14 µΜ) and weakly active when
tested against the PDGF RTK activity. These results
suggest that an electron-withdrawing polar substitution
at the C-4′ position of the pyrrole ring of 3 is favorable
for the VEGF (Flk-1) RTK inhibitory activity of these
inhibitors. Therefore, adjustment of substituents at the
C-4′ position could lead to highly potent and selective
inhibitors of the VEGF (Flk-1) RTK. Compound 52, the
4-methyl analogue of 45, was found to be inactive when
tested against the PDGF RTK activity and was found
to be 3-fold more potent than 45 when tested against
the VEGF (Flk-1) RTK activity. This result is in
contrary to the one derived from the 3-(substituted
benzylidenyl)indolin-2-ones. The methyl group at the
C-4 position of 14 (Table 1) has negative impact on the
potency toward both the PDGF and VEGF (Flk-1) RTKs.
In addition, the methyl substitution at the C-4 position
of 38 decreased the potency against both the PDGF and
VEGF (Flk-1) RTKs when compared to 3. Interestingly,
a methyl substitution at the C-5 position of 53 was found
to be 10-fold more potent than 45 when tested against
the VEGF (Flk-1) RTK activities. In summary, these
studies have shown that small electron-donating sub-
stituents at the C-4 or C-5 position were favorable for
inhibitory activity of the compounds containing 3′,5′-
dimethyl-substituted pyrrole at the C-3 position of the
indolin-2-ones when tested against the VEGF (Flk-1)
RTK.
was shown to specifically inhibit the VEGF (Flk-1) RTK
activity (IC50 ) 7.41 µΜ). Alkylation at the N-1′ position
in the pyrazole ring of 62 resulted in 63 which was found
to be inactive against any RTK activity measured. NOE
NMR experiments indicated that 62 exists as the Z
isomer whereas 63 exists as the E isomer. We suggest
that the proton at the N-1′ position of the pyrazole ring
in 62 may migrate to the N-2′ position and allow
intramolecular hydrogen bonding with the carbonyl
oxygen atom at the C-2 position of the indolin-2-one
(Scheme 4). Such hydrogen bonding may be responsible
for the Z configuration of 62. Methylation at the N-1′
position of the pyrazole ring in 62 may disrupt the
hydrogen bonding and result in a repulsive interaction
between the lone pair electrons at the N-2′ position of
the pyrazole ring and the carbonyl oxygen at the C-2
position of the indolin-2-one. This model may help to
explain why 63 exists as the E isomer and why these
two compounds may have differences in inhibitory
activity against the VEGF (Flk-1) RTK.
Con clu sion s
This report describes the identification, characteriza-
tion, and SAR analysis of a novel chemical series of
tyrosine kinase inhibitors, 3-substituted indolin-2-ones,
which exhibit selectivity toward particular RTKs. In
this report, the potency and selectivity of an inhibitor
using cell-based assays can be further influenced by
many factors including vehicle solubility, membrane
permeability, chemical stability and metabolism, and
alternative targets that may affect RTK activation.
Nonetheless, SAR analysis can be very useful using
these assays to identify chemical leads when performed
with compounds that have similar physical and chemi-
cal properties. In this regard, we have shown that the
potency and selectivity of this chemical series depend
to a large extent on the configuration of the compound
as it relates to substitutions at the C-3 position of the
indolin-2-one core. The 3-[(substituted pyrrolyl-, thi-
enyl-, and pyrazolyl)methylidenyl]indolin-2-ones were
shown to exist exclusively or predominantly as Z
isomers and were also found to be highly selective
toward the VEGF (Flk-1) and/or PDGF RTK activity
while inactive or weakly active against the EGF, Her-
2, and IGF-1 RTK activities. The association of these
inhibitory activities with the Z isomeric forms was found
to be in agreement with our cocrystal studies using 16
and 42 bound in the catalytic core of the FGF RTK.14
In this latter study, the binding configurations for both
16 and 42 were found to be the Z isomer forms. Since
the primary amino acid sequences of the VEGF (Flk-1)
and PDGF receptor kinase domains are highly homolo-
gous to that of the FGF receptor kinase, we suggest that
the ability of many of the indolin-2-ones to show specific
inhibitory properties on the VEGF (Flk-1) and PDGF
RTKs may be due to the existence of Z isomers that can
bind into the ATP binding pocket of these RTKs. In
addition, the same study showed that the pyrrole ring
and the indolin-2-one ring in 42 are near coplanar due
to the intramolecular hydrogen bonding between the
proton at the N-1′ position and oxygen atom at the C-2
position of 42. The cocrystal X-ray structures of the
catalytic domain of the FGF receptor with 16 and 42
suggest that the 3-substituted indolin-2-one compounds
may bind at the ATP binding site with the indolin-2-
C. 3-[(Su bstitu ted th ien -2-yl)m eth ylid en yl]in -
d olin -2-on es. In the 3-[(substituted thien-2-yl)meth-
ylidenyl]indolin-2-one series (Table 3), we have deter-
mined that most of the compounds exist predominantly
as Z isomers. However, these compounds, in general,
are less potent than the 3-[(substituted pyrrol-2-yl)-
methylidenyl]indolin-2-ones against the VEGF (Flk-1)
RTK. Methyl substitution at the C-4 position of the
indolin-2-one ring eliminated the VEGF (Flk-1) RTK
inhibitory activity as in the case of 57 (IC50 > 100 µΜ)
when compared to the parent compound 56 (IC50 ) 2.30
µΜ).
D. 3-[(Su bstitu ted fu r a n -2-yl)m eth ylid en yl]in -
d olin -2-on es. 3-[(Substituted furan-2-yl)methylidenyl]-
indolin-2-ones (Table 4) were found to exist as E
isomers. Given our model, it is not surprising that these
compounds were found to be weak inhibitors of the
VEGF (Flk-1) RTK and inactive against other RTK
activities measured. In addition, the furan ring is less
electron-rich than a pyrrole or thiophene ring. There-
fore, these electronic effects may also influence the
inhibitory activity of these compounds.
E. 3-[(Su bstitu ted p yr a zol-3-yl)m eth ylid en yl]-
in d olin -2-on es. In the series of 3-[(substituted pyrazol-
3-yl)methylidenyl]indolin-2-ones (Table 5), compound 62

2598 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
one ring occupying the adenine binding pocket. Biden-
tate hydrogen bonding between the indolin-2-one flat
core structure in the adenine binding site may play a
crucial role to block entry of ATP in the binding site.
Both the proton at the N-1 position and the oxygen atom
at the C-2 position of the indolin-2-one were found to
be coordinated to the peptide backbone within the
adenine binding cleft. In this regard, alkylation at the
N-1 position of the indolin-2-ones greatly decreases the
inhibitory potency of these 3-substituted indolin-2-ones
(13 vs 1) against both the PDGF and VEGF (Flk-1)
RTKs.
of human diseases including cancers, metastasis, arte-
rial restenosis, various inflammatory diseases including
psoriasis and rheumatoid arthritis, pulmonary fibrosis,
liver cirrhosis, kidney sclerosis, and other diseases. The
potential to design and synthesize 3-substituted indolin-
2-ones with inhibitory properties for various PTK
subtypes supports the use of compounds of this class to
treat a wide variety of human diseases.
Exp er im en ta l Section
NMR spectra were recorded by Acorn NMR using a Nicolet
NT300 or a Nicolet NT360 spectrometer. Tetramethylsilane
(TMS) was used as an internal standard and chemical shifts
are reported in parts per million (δ) downfield from TMS.
Coupling constants are reported in hertz. Mass spectra
(electron spray) were recorded by SYNPEP CORP, using an
API I PLUS spectrometer. Elemental analyses were per-
formed by Galbraith Laboratories, Inc. Elemental analyses
results are within (0.4% of the theoretical values.
In addition, we have suggested that the substitution
around the indolin-2-ones may be the key determinants
for the potency and especially specificity of the inhibi-
tors. A fluoro substitution at the C-6 position of the
3-[(substituted pyrrolyl)methylidenyl]indolin-2-ones
greatly increased the inhibitory activity against the
PDGF RTK (40 vs 3). A chloro substitution at the C-5
position of the 3-[(substituted pyrrolyl)methylidenyl]-
indolin-2-one decreased inhibitory activity against both
the PDGF and VEGF (Flk-1) RTKs (39 vs 3). A strong
electron-withdrawing nitro group was detrimental to the
inhibitory activity of 51 against the VEGF (Flk-1) RTK.
It was also observed that same substitution could have
different impacts on the inhibitory activity of different
inhibitors depending on other substitutions in the
molecules. In this regard, fluoro substitution at the C-6
position of 15 decreased the inhibitory activity against
both the PDGF and VEGF (Flk-1) RTK activities when
compared to 1. This may imply different conformational
changes of the enzyme induced by different inhibitors.
Therefore, different SAR conclusions have been drawn
for different types of 3-substituted indolin-2-ones. On
the other hand, some of the 3-(substituted benzylidenyl)-
indolin-2-ones that were found to be selective for both
the EGF and Her-2 receptors possessed bulky lipophilic
substitutions in the phenyl ring at the C-3 position of
3-(substituted benzylidenyl)indolin-2-ones. This result
may indicate structural differences in the ATP binding
sites when catalytic domains of the EGF and Her-2
RTKs are compared to those of the PDGF and VEGF
(Flk-1) RTKs.
Gen er a l P r oced u r e for 3-(Su bstitu ted ben zylid en yl)-
in d olin -2-on e An a logu es (Com p ou n d 1 An a logu es).
A
reaction mixture of the proper oxindole (1 equiv), aldehyde (1.2
equiv), and piperidine (0.1 equiv) in ethanol 1-2 mL/1 µmol
oxindole) was stirred at 90 °C for 3-5 h. After the mixture
cooled, the precipitate was filtered, washed with cold ethanol,
and dried to give the target compound in over 80% yield. The
analytical data reported here is for the major isomer. The data
for the minor isomer is not reported. The ratios of Z to E
isomers for each compound are shown in Table 1.
(Z)-3-[4-(Dim eth ylam in o)ben zyliden yl]in dolin -2-on e (1):
1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H, NH-1), 8.44 (d,
J ) 9.24 Hz, 2H, H-2′,6′), 7.60 (s, 1H, H-vinyl), 7.59 (d, J )
7.82 Hz, 1H, H-4), 7.11 (dt, J ) 1.02, 7.82 Hz, 1H, H-6), 6.93
(dt, J ) 0.89, 7.82 Hz, 1H, H-5), 6.80 (d, J ) 7.82 Hz, 1H,
H-7), 6.73 (d, J ) 9.24 Hz, 2H, H-3′,5′), 3.00 (s, 6H, N(CH3)3-
4′); MS m/z (relative intensity, %) 256 (100, [M + 1]+•). Anal.
(C17H16N2O‚0.1H2O) C, H, N.
(Z)-1-Meth yl-3-[4-(dim eth ylam in o)ben zyliden yl]in dolin -
2-on e (13): 1H NMR (360 MHz, DMSO-d6) δ 8.47 (d, J ) 9.15
Hz, 2H, H-2′,6′), 7.67 (s, 1H, H-vinyl), 7.66 (d, J ) 7.79 Hz,
1H, H-4), 7.21 (dt, J ) 1.09, 7.79 Hz, 1H, H-6), 7.02 (dt, J )
0.99, 7.79 Hz, 1H, H-5), 6.95 (d, J ) 7.79 Hz, 1H, H-7), 6.78
(d, J ) 9.15 Hz, 2H, H-3′,5′), 3.22 (s, 3H, NCH3-1), 3.05 (s,
6H, N(CH3)2-4′); MS m/z (relative intensity, %) 279 (100, [M
+ 1]+•), 349 (100, [M + 1]+•). Anal. (C18H18N2O) C, H, N.
(Z)-4-Meth yl-3-[4-(dim eth ylam in o)ben zyliden yl]in dolin -
2-on e (14): 1H NMR (360 MHz, DMSO-d6) δ 10.40 (s, br, 1H,
NH-1), 8.32 (d, J ) 8.24 Hz, 2H, H-2′,6′), 7.61 (s, 1H, H-vinyl),
7.02 (t, J ) 7.81 Hz, 1H, H-6), 6.67-6.75 (m, 4H, H-5,7,3′,5′),
3.02 (s, 6H, N(CH3)2-4′); MS m/z (relative intensity, %) 278
(100, M+•). Anal. (C18H18N2O‚0.1H2O) C, H, N.
(E)-6-Flu or o-3-[4-(dim eth ylam in o)ben zyliden yl]in dolin -
2-on e (15). 2-(4-F lu or o-2-n itr op h en yl)m a lon ic Acid Di-
m eth yl Ester (4). The reaction mixture of sodium hydride
(2.6 g, 108 µmol) and 14.5 g of dimethyl malonate (108 µmol)
in 160 mL of dimethyl sulfoxide was heated to 100 °C for 1 h.
The mixture was cooled to room temperature, and 7.95 g of
2,5-difluoronitrobenzene (70 µmol) was added and stirred for
30 min. The mixture was then heated to 100 °C for 1 h, cooled
to room temperature, and poured into 400 mL of saturated
ammonium chloride solution. The mixture was extracted with
200 mL of ethyl acetate and the organic layer washed with
brine, dried over anhydrous sodium sulfate, and concentrated
under vacuum. The residue was crystallized from methanol
to give 24.4 g (80% yield) of dimethyl 4-fluoro-2-nitrophenyl-
malonate as a white solid. The filtrate was concentrated and
chromatographed on a column of silica gel (ethyl acetate/
hexane, 1:8) to give 5.03 g of dimethyl 4-fluoro-2-nitrophenyl-
malonate (96% total yield): 1H NMR (360 MHz, DMSO-d6) δ
8.02 (dd, J ) 8.54, 2.48 Hz, 1H, H-3), 7.68 (dt, J ) 8.54, 2.48
Hz, 1H, H-5), 7.63 (dd, J ) 8.54, 5.63 Hz, 1H, H-6), 5.47 (s,
1H, CH(COOCH3)2-1), 3.70 (s, 6H, CH(COOCH3)2-1).
In summary of the SAR studies: (1) Proton at the N-1
position of the indolin-2-ones is essential for the inhibi-
tory activity against the PDGF and VEGF (Flk-1) RTKs.
(2) Vinyl proton is critical for 3-substituted indolin-2-
ones to inhibit the PDGF and VEGF (Flk-1) RTKs. (3)
Z Isomeric form is required for the inhibitory activity
against the PDGF and VEGF (Flk-1) RTKs. (4) 3-[(Sub-
stituted pyrrolyl)methylidenyl]indolin-2-ones are the
most potent and selective inhibitors of the PDGF and
VEGF (Flk-1) RTKs. (5) Electron-donating substitution
is preferred for the inhibitory potency of these 3-sub-
stituted indolin-2-ones against the PDGF and VEGF
(Flk-1) RTKs. (6) Bulky lipophilic groups in the phenyl
ring at the C-3 position of 3-(substituted benzylide-
nyl)indolin-2-ones are the key determinants for the
selective inhibitory activity of these inhibitors against
the EGF and Her-2 RTKs.
In conclusion, we described a chemical series that
shows promise in the development of RTK inhibitors
with the capacity to be specific to particular enzymes.
PTK function has been associated with a wide variety

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2599
Dimethyl 4-fluoro-2-nitrophenylmalonate (5.0 g, 18.5 µmol)
was refluxed in 20 mL of 6 N hydrochloric acid for 24 h. The
reaction mixture was cooled and the white solid collected by
vacuum filtration, washed with water, and dried to give 3.3 g
(87% yield) of 4-fluoro-2-nitrophenylacetic acid (5): 1H NMR
(360 MHz, DMSO-d6) δ 12.5 (s, br, 1H, CH2COOH-1), 7.96 (d,
J ) 10.21 Hz, 1H, H-3), 7.58-7.61 (m, 2H, H-5,6), and 3.97
(s, 2H, CH2COOH-1).
4-Fluoro-2-nitrophenylacetatic acid (3.3 g, 16.6 µmol) dis-
solved in 15 mL of acetic acid was hydrogenated over 0.45 g
of 10% palladium on carbon under 60 psi for 2 h. The catalyst
was removed by filtration and washed with 15 mL of methanol.
The combined filtrates were concentrated and diluted with
water. The precipitate was collected by vacuum filtration,
washed with water, and dried to give 1.6 g (70% yield) of
6-fluoroindolin-2-one (6): 1H NMR (360 MHz, DMSO-d6) δ
10.43 (s, br, 1H, NH-1), 7.17 (t, J ) 8.13 Hz, 1H, H-4), 6.69
(ddd, J ) 2.22, 8.13, 10.38 Hz, 1H, H-5), 6.60 (dd, J ) 2.22,
9.16, Hz, 1H, H-7), 3.42 (s, 2H, CH2-3); MS m/z (relative
intensity, %) 153 (100, [M + 1]+•).
P r ep a r a tion of 15. The title compound was prepared by
condensation of 6 and (dimethylamino)benzaldehyde using the
same method described for analogues of 1: 1H NMR (360 MHz,
DMSO-d6) δ 10.56 (s, 1H, NH-1), 7.76 (dd, J ) 7.69, 8.41 Hz,
1H, H-4), 7.61 (d, J ) 8.79 Hz, 2H, H-2′,6′), 7.49 (s, 1H,
H-vinyl), 6.80 (d, J ) 8.79 Hz, 2H, H-3′,5′), 6.78-6.64 (m, 2H,
H-5,7), 3.01 (s, 6H, N(CH3)2-4′); MS m/z (relative intensity, %)
283 (100, [M + 1]+•). Anal. (C17H15FN2O) C, H, N.
P r ep a r a tion of (E)-3-[4-(1-F or m ylp ip er a zin -4-yl)ben -
zylid en yl]in d olin -2-on e (16). 4-(1-F or m ylp ip er a zin -4-yl)-
ben za ld eh yd e (11). To a solution of 30 mL (0.3 mol) of
dimethylformamide in 20 mL of anhydrous 1,2-dichloroeth-
ane was added dropwise 30 mL (0.3 mol) of phosphorus
oxychloride at 0 °C. The ice bath was removed. The reac-
tion mixture was stirred for an additional 30 min and cooled
in an ice bath. 1-Phenylpiperazine (16.0 g, 0.1 µmol) was
added to the above solution portionwise over 15 min, and
the reaction mixture was stirred at 50 °C for 1 h. The reac-
tion mixture was poured into ice-cold 1 N sodium hydroxide
solution and stirred at room temperature for 1 h. The or-
ganic layer was separated, and the aqueous layer was ex-
tracted with ethyl acetate. The combined organic layer was
washed with brine until pH ) 7, dried over anhydrous sodium
sulfate, and evaporated. The residue was separated on a silica
gel column eluting with a mixture of ethyl acetate and hexane
to afford 9.0 g (41%) of the title compound as a light-yellow
solid: MS (ES) m/z (relative intensity, %) 217 ([M - 1]+•, 100);
1H NMR (360 MHz, DMSO) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.73
(d, J ) 9.1 Hz, 2H), 7.08 (d, J ) 9.1 Hz, 2H), 3.39-3.53 (m,
8H).
cooled to -10 °C, and 2.0 g of N-bromosuccinimide (10 µmol)
was slowly added with stirring. The reaction mixture was
stirred for 1 h at -10 °C and for 2 h at 0 °C. The precipitate
was collected, washed with water, and dried to give 1.9 g
(90%yield) of 5-bromoindolin-2-one.
Syn th esis of 18. The title compound was synthesized from
7 and 4-(1-formylpiperazin-4-yl)benzaldehyde by the same
condensation method described for analogues of 1: 1H NMR
(360 MHz, DMSO) δ 10.54 (s, 1H, NH-1), 8.04 (s, 1H, H-vinyl),
7.73 (d, J ) 1.87 Hz, 1H, H-4), 7.58 (d, J ) 8.76 Hz, 2H,
H-2′,6′), 7.53 (s, 1H, CHO-4′′), 7.30 (dd, J ) 1.87, 8.27 Hz, 1H,
H-6), 7.05 (d, J ) 8.74 Hz, 2H, H-3′5′), 6.77 (d, J ) 8.27 Hz,
1H, H-7), 3.44-3.48 (m, 2H, H-2′′,6′′), 3.27-3.57 (m, 2H,
H-3′′,5′′). Anal. (C20H18BrN3O2) C, H, N.
P r ep a r a tion of (E)-3-[4-(Mor p h olin -4-yl)ben zylid en yl]-
in d olin -2-on e (19). 4-(Mor p h olin -4-yl)ben za ld eh yd e (9).
To a solution of 15 mL of dimethylformamide in 50 mL of 1,2-
dichloroethane was added dropwise 10 mL of phosphorus
oxychloride at 0 °C. The ice bath was removed, and the
reaction mixture was stirred for an additional 30 min. 4-Phe-
nylmorpholine (16.3 g) was added to the above solution
portionwise, and the reaction mixture was refluxed for 2 days.
Triethylamine (2.5 mL) was added to the above reaction
mixture, and the reaction mixture was refluxed for 2 days.
The reaction mixture was poured into ice-cold 1 N sodium
hydroxide solution (pH ) 9 after mixing), and the resulting
mixture was stirred at room temperature for 1 h. The organic
layer was separated, and the aqueous layer was extracted with
2 × 20 mL of dichloromethane. The combined organic layer
was washed with brine until pH ) 7, dried over anhydrous
sodium sulfate, and evaporated. The residue was separated
on a silica gel column eluting with a solvent mixture of ethyl
acetate and hexane to afford 12.95 g (68%) of the title
compound as a white solid.
(E)-3-[4-(Mor ph olin -4-yl)ben zyliden yl]in dolin -2-on e (19).
A reaction mixture of 6.66 g of oxindole, 11.50 g of 9, and 5
mL of piperidine in 50 mL of ethanol was stirred at 90 °C for
5 h. After cooling, the precipitate was filtered, washed with
cold ethanol, and dried to yield 15.0 g (98%) of the title
compound as a yellow solid: 1H NMR (360 MHz, DMSO-d6) δ
10.45 (s, 1H, NH-1), 7.74 (d, J ) 7.20 Hz, 1H, H-4), 7.66 (d, J
) 8.98 Hz, 2H, H-2′,6′), 7.54 (s, 1H, H-vinyl), 7.20 (t, J ) 7.20
Hz, 1H, H-6), 7.05 (d, J ) 8.98 Hz, 2H, H-3′,5′), 6.86-6.90 (m,
2H, H-5,7), 3.75 (t, J ) 4.77 Hz, 4H, H-2′′,4′′), 3.28 (t, J )
4.77 Hz, 4H, H-3′′,5′′); MS m/z (relative intensity, %) 307 (100,
[M + 1]+•). Anal. (C19H18N2O2) C, H, N.
(Z)-4-Meth yl-3-[4-(m or p h olin -4-yl)ben zylid en yl]in d o-
lin -2-on e (20): 1H NMR (360 MHz, DMSO-d6) δ 10.44 (s, 1H,
NH-1), 8.28 (d, J ) 8.98 Hz, 2H, H-2′,6′), 7.62 (s, 1H, H-vinyl),
7.04 (t, J ) 7.69 Hz, 1H, H-6), 6.96 (d, J ) 8.98 Hz, 2H, H-3′,5′),
6.76 (d, J ) 7.69 Hz, 1H, H-5), 6.68 (d, J ) 7.69 Hz, 1H, H-7),
3.74 (t, J ) 4.98 Hz, 4H, H-2′′,6′′), 3.28 (t, J ) 4.98 Hz, 4H,
H-3′′,5′′), 2.57 (s, 1H, CH3-4); 2D-NOE 1H NMR showed the
correlation between, H-vinyl and CH3-4, which confirmed the
Z conformer; MS m/z (relative intensity, %) 320 (100, M+•).
Anal. (C20H20N2O2) C, H, N.
(E)-5-Ch lor o-3-[4-(m or p h olin -4-yl)b en zylid en yl]in d o-
lin -2-on e (21): 1H NMR (360 MHz, DMSO-d6) δ 110.59 (s, 1H,
NH-1), 7.67 (d, J ) 2.33 Hz, 1H, H-4), 7.66 (s, 1H, H-vinyl),
7.62 (d, J ) 9.91 Hz, 2H, H-2′,6′), 7.25 (dd, J ) 2.33, 8.20 Hz,
1H, H-6), 7.09 (d, J ) 9.91 Hz, 2H, H-3′,5′), 6.88 (d, J ) 8.20
Hz, 1H, H-7), 3.74-3.77 (m, 4H, H-2′′,4′′), 3.30-3.33 (m, 4H,
H-3′′,5′′). Anal. (C19H17ClN2O2‚0.6H2O) C, H, N.
(E)-3-[4-(1-F or m ylp ip er a zin -4-yl)ben zylid en yl]in d olin -
2-on e (16). A reaction mixture of 133.15 mg (1 µmol) of
oxindole, 228.3 mg (1.2 µmol) of 11, and 3 drops of piperidine
in 2 mL of ethanol was stirred at 90 °C for 5 h. After the
mixture cooled, the precipitate was filtered, washed with cold
ethanol, and dried to yield 199.5 mg (65%) of the title
compound as a yellow solid: MS (ES) m/z (relative intensity,
1
%) 333 (M+•, 17); H NMR (360 MHz, DMSO) δ 10.52 (s, 1H,
NH-1), 8.11 (s, 1H, CHO-4′′), 7.75 (d, J ) 7.3 Hz, 1H, H-4),
7.67 (d, J ) 8.7 Hz, 2H, H-2′,6′), 7.55 (s, 1H, H-vinyl), 7.21 (t,
J ) 7.3 Hz, 1H, H-5), 7.10 (d, J ) 8.7 Hz, 2H, H-3′,5′), 6.87-
6.92 (m, 2H, H-6,7), 3.31-3.56 (m, 8H). Anal. (C20H19N3O2)
C, H, N.
(Z)-3-[4-(1-For m ylp ip er a zin -4-yl)ben zylid en yl]-4-m eth -
ylin d olin -2-on e (17): 1H NMR (360 MHz, DMSO) δ 10.42 (s,
1H, NH-1), 8.26 (d, J ) 9.14 Hz, 2H, H-2′,6′), 8.09 (s, 1H,
H-vinyl), 7.60 (s, 1H, CHO-1′), 7.03 (t, J ) 7.75 Hz, 1H, H-6),
7.00 (d, J ) 9.14 Hz, 2H, H-3′,5′), 6.74 (d, J ) 7.75 Hz, 1H,
H-5), 6.66 (d, J ) 7.75 Hz, 1H, H-7), 3.51 (m, 4-H, H-2′,6′),
3.36 (m, 4H, H-3′,5′); MS (ES) m/z (relative intensity, %) 348
(100, [M + 1]+•). Anal. (C21H21N3O2‚0.2H2O) C, H, N.
(E)-5-Br om o-3-[4-(m or ph olin -4-yl)ben zyliden yl]in dolin -
2-on e (22): 1H NMR (360 MHz, DMSO-d6) δ 10.53 (s, br, 1H,
NH-1), 7.73 (d, J ) 1.96 Hz, 1H, H-4), 7.57 (d, J ) 9.25 Hz,
2H, H-2′,6′), 7.53 (s, 1H, H-vinyl), 7.30 (dd, J ) 1.96, 8.33 Hz,
1H, H-6), 7.01 (d, J ) 9.25 Hz, 2H, H-3′,5′), 6.76 (d, J ) 8.33
Hz, 1H, H-7), 3.67 (m, 4H, H-2′′,6′′), 3.25 (m, 4H, H-3′′,5′′);
MS m/z (relative intensity, %) 386 (100, [M + 1]+•). Anal.
(C19H17BrN2O2) C, H, N.
(E)-5-Br om o-3-[4-(1-for m ylpiper azin -4-yl)ben zyliden yl]-
in d olin -2-on e (18). P r ep a r a tion of 5-Br om oin d olin -2-on e
(7). Oxindole (1.3 g, 10 µmol) in 20 mL of acetonitrile was
(Z)-3-[4-(P yr r olidin -1-yl)ben zyliden yl]in dolin -2-on e (23):
1H NMR (300 MHz, DMSO-d6) δ 10.46 (s, 1H, NH-1), 8.46 (d,
J ) 9.14 Hz, 2H, H-2′,6′), 7.62 (s, 1H, H-vinyl), 7.61 (d, J )

2600 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
8.21 Hz, 1H, H-4), 7.10 (dt, J ) 1.09, 8.21 Hz, 1H, H-6), 6.93
(dt, J ) 1.02, 7.65 Hz, 1H, H-5), 6.79 (d, J ) 7.65 Hz, 1H,
H-7), 6.61 (d, J ) 9.14 Hz, 2H, H-3′,5′), 3.33-3.37 (m, 2H,
H-2′′,5′′), 1.95-2.00 (m, 2H, H-3′′,4′′). Anal. (C19H18N2O) C,
H, N.
CH(CH3)2-3′,5′); MS m/z (relative intensity, %) 356 (100, [M +
1]+•). Anal. (C21H22ClNO2) C, H, N.
(E)-3-(3-Br om o-5-ter t-bu tyl-4-m eth oxyben zylid en yl)in -
1
d olin -2-on e (31): H NMR (360 MHz, DMSO-d6) δ 10.64 (s,
1H, NH-1), 7.84 (d, J ) 2.02 Hz, H-2′), 7.68 (d, J ) 2.02 Hz,
1H, H-6′), 7.54 (s, 1H, H-vinyl), 7.51 (d, J ) 7.69 Hz, 1H, H-4),
7.26 (dt, J ) 1.29, 7.75 Hz, 1H, H-6), 6.85-6.87 (m, 2H, H-5,7),
3.93 (s, 3H, OCH3-4′), 1.37 (s, 9H, C(CH3)3-5′); MS m/z (relative
intensity, %) 388 (100, [M + 2]+•). Anal. (C20H20BrNO2‚
0.5H2O) C, H, N.
Syn th esis of (E)-3-[4-(P ip er id in -1-yl)ben zylid en yl]in -
d olin -2-on e (24). 4-(P ip er id in -1-yl)ben za ld eh yd e (10). To
a solution of 2.3 mL of dimethylformamide in 10 mL of 1,2-
dichloroethane was added dropwise 2.8 mL of phosphorus
oxychloride at 0 °C. The ice bath was removed, and the
reaction mixture was stirred for 15 min. 1-Phenylpiperidine
(3.2 mL) was added to the above solution portionwise, and the
reaction mixture was refluxed overnight. The reaction mixture
was poured into ice-cold 2 N sodium hydroxide solution and
stirred at room temperature for 1 h. The organic layer was
separated, and the aqueous layer was extracted with 2 × 20
mL of ethyl acetate. The combined organic layer was washed
with brine until pH ) 7, dried over anhydrous sodium sulfate,
and evaporated. The residue was separated on a silica gel
column eluting with ethyl acetate and hexane to afford 1.5 g
(40%) of the title compound as a white solid.
(E)-3-[4-(P iper idin -1-yl)ben zyliden yl]in dolin -2-on e (24).
A reaction mixture of 134.0 mg of oxindole, 226.8 g of 10, and
3 drops of piperidine in 2 mL of ethanol was stirred at 90 °C
for 5 h. After the mixture cooled, the precipitate was filtered,
washed with cold ethanol, and dried to yield 268.5 mg (88%)
of the title compound as a yellow solid: 1H NMR (300 MHz,
DMSO-d6) δ 10.48 9 (s, 1H, NH-1), 7.77 (d, J ) 7.69 Hz, 1H,
H-4), 7.64 (d, J ) 8.91 Hz, 2H, H-2′,6′), 7.51 (s, 1H, H-vinyl),
7.19 (dt, J ) 1.12, 7.69 Hz, 1H, H-6), 7.03 (d, J ) 8.91 Hz, 2H,
H-3′,5′), 6.89 (dt, J ) 0.78, 7.69 Hz, 1H, H-5), 6.86 (d, J )
7.69 Hz, 1H, H-7), 3.36 (s, br, 4H, CH2-2′′,6′′), 1.60 (s, br, 6H,
CH2-3′′,4′′,5′′); MS m/z (relative intensity, %) 305 (100, [M +
1]+•). Anal. (C20H20N2O) C, H, N.
(Z)-5-Ch lor o-3-(3-ter t-bu tyl-4-m eth oxyben zylid en yl)in -
1
d olin -2-on e (32): H NMR (360 MHz, DMSO-d6) δ 10.58 (s,
1H, NH-1), 8.53 (d, J ) 2.13 Hz, 1H, H-2′), 8.41 (dd, J ) 2.13,
8.44 Hz, 1H, H-6′), 7.89 (s, 1H, H-vinyl), 7.81 (d, J ) 2.22 Hz,
1H, H-4), 7.18 (dd, J ) 2.22, 8.26 Hz, 1H, H-6), 7.10 (d, J )
8.44 Hz, 1H, H-5′), 6.81 (d, J ) 8.26 Hz, 1H, H-7), 3.90 (s, 3H,
OCH3-4′), 1.35 (s, 9H, C(CH3)3-3′); MS m/z (relative intensity,
%) 342 (100, M+•). Anal. (C20H20ClNO2) C, H, N.
(E)-3-(4-Isop r op ylben zylid en yl)in d olin -2-on e (2): 1H
NMR (300 MHz, DMSO-d6) δ 10.57 (s, 1H, NH-1), 7.59-7.65
(m, 4H, H-4,vinyl,2′,6′), 7.38 (d, J ) 8.49 Hz, 2H, H-3′,5′), 7.21
(dt, J ) 0.91, 7.82 Hz, 1H, H-6), 6.83-6.88 (m, 2H, H-5,7),
2.94 (h, J ) 6.99 Hz, 1H, CH(CH3)2-4′), 1.23 (d, J ) 6.99 Hz,
6H, CH(CH3)2-4′); MS m/z (relative intensity, %) 264 (100, [M
+ 1]+•). Anal. (C18H17NO) C, H, N.
(E)-3-(3,5-Diisop r op yl-4-h yd r oxyben zylid en yl)in d olin -
2-on e (33): 1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H,
NH-1), 8.87 (s, br, 1H, OH-4′), 7.74 (d, J ) 7.47 Hz, 1H, H-4),
7.58 (s, 1H, H-vinyl), 7.45 (s, 2H, H-2′,6′), 7.20 (dt, J ) 1.10,
8.37 Hz, 1H, H-6), 6.88 (d, J ) 7.47 Hz, 1H, H-5), 6.87 (dt, J
) 1.03, 8.37 Hz, 1H, H-7), 3.37 (m, 2H, CH(CH3)2-3′,5′), 1.20
(d, J ) 6.77 Hz, 12H, CH(CH3)2-3′,5′). Anal. (C21H23NO2) C,
H, N.
(E)-3-(4-Hyd r oxyben zylid en yl)in d olin -2-on e (25): 1H
NMR (360 MHz, DMSO-d6) δ 10.46 (s, 1H, NH-1), 10.06 (s,
br, 1H, OH-4′), 7.69 (d, J ) 7.52 Hz, 1H, H-4), 7.62 (d, J )
8.54 Hz, 2H, H-2′,6′), 7.54 (s, 1H, H-vinyl), 7.21 (dt, J ) 1.09,
7.52 Hz, 1H, H-6), 6.86-6.93 (m, 4H, H-3′,5′,5,7); MS m/z
(E)-3-(3-ter t-Bu t yl-4-m et h oxyb en zylid en yl)in d olin -2-
1
on e (34): H NMR (360 MHz, DMSO-d6) δ 10.50 (s, 1H, NH-
1), 7.66 (d, J ) 7.82 Hz, 1H, H-4), 7.58-7.62 (m, 3H, H-vinyl
and H-2′,6′), 7.20 (t, J ) 7.65 Hz, 1H, H-6), 7.13 (d, J ) 8.26
Hz, 1H, H-5′), 6.84-6.88 (m, 2H, H-5,7), 3.89 (s, 3H, OCH3-
4′), 1.35 (s, 9H, C(CH3)3-3′); MS m/z (relative intensity, %) 308
(100, [M + 1]+•). Anal. (C20H21NO2) C, H, N.
(relative intensity, %) 238 (100, [M + 1]+•). Anal. (C15H11
NO2) C, H, N.
-
(E)-3-(4-Meth oxyben zylid en yl)in d olin -2-on e (26): 1H
NMR (360 MHz, DMSO-d6) δ 10.48 (s, 1H, NH-1), 7.69 (d, J
) 8.82 Hz, 2H, H-2′,6′), 7.64 (d, J ) 7.55 Hz, 1H, H-4), 7.57 (s,
1H, H-vinyl), 7.20 (t, J ) 7.55 Hz, 1H, H-6), 7.08 (d, J ) 8.82
Hz, 2H, H-3′,5′), 6.83-6.88 (m, 2H, H-5,7), 3.83 (s, 3H, OCH3-
4′); MS m/z (relative intensity, %) 252 (100, [M + 1]+•). Anal.
(C16H13NO2) C, H, N.
(E)-3-(4-Br om oben zyliden yl)in dolin -2-on e (27): 1H NMR
(300 MHz, DMSO-d6) δ 10.61 (s, 1H, NH-1), 7.70 (d, J ) 8.63
Hz, 2H, H-2′,6′), 7.63 (d, J ) 8.63 Hz, 2H, H-3′,5′), 7.55 (s,
1H, H-vinyl), 7.47 (d, J ) 7.58 Hz, 1H, H-4), 7.22 (t, J ) 7.58
Hz, 1H, H-6), 6.81-6.87 (m, 2H, H-5,7); MS m/z (relative
intensity, %) 300 (100, M+•). Anal. (C15H10BrNO‚0.3H2O) C,
H, N.
(E)-3-(4-Ca r boxyben zylid en yl)in d olin -2-on e (28): 1H
NMR (360 MHz, DMSO-d6) δ 13.08 (s, br, 1H, COOH-4′), 10.61
(s, br, 1H, NH-1), 8.07 (d, J ) 8.06 Hz, 2H), 7.80 (d, J ) 8.06
Hz, 2H), 7.65 (s, 1H, H-vinyl), 7.45 (d, J ) 7.51 Hz, 1H, H-4),
7.25 (dt, J ) 0.94, 7.53 Hz, 1H, H-6), 6.83-6.90 (m, 2H, H-5,7).
Anal. (C16H11NO3‚0.125H2O) C, H, N.
(E)-3-(3,5-Di-ter t-bu tyl-4-h yd r oxyben zyliden yl)in dolin -
2-on e (29): 1H NMR (360 MHz, DMSO-d6) δ 10.43 (s, 1H, NH-
1), 7.58 (s, 1H, H-vinyl), 7.57 (d, J ) 6.80 Hz, 1H, H-4), 7.53
(s, 2H, H-2′,6′), 7.19 (t, J ) 6.80 Hz, 1H, H-6), 6.85-6.89
(m, 2H, H-5,7), 1.41 (s, 18H, C(CH3)3-3′,5′); MS m/z (rela-
tive intensity, %) 350 (100, [M + 1]+•). Anal. (C23H27NO2) C,
H, N.
(Z)-3-(4-Br om oben zyliden yl)-1-m eth ylin dolin -2-on e (35):
1H NMR (300 MHz, DMSO-d6) δ 8.33 (d, J ) 8.56 Hz, 2H,
H-2′,6′), 7.83 (s, 1H, H-vinyl), 7.75 (d, J ) 7.42 Hz, 1H, H-4),
7.67 (d, J ) 8.56 Hz, 2H, H-3′,5′), 7.33 (t, J ) 7.42 Hz, 1H,
H-6), 7.07 (t, J ) 7.70 Hz, 1H, H-5), 7.00 (d, J ) 7.70 Hz, 1H,
H-7), 3.20 (s, 3H, NCH3-1); MS m/z (relative intensity, %) 315
(100, [M + 1]+•). Anal. (C16H12BrNO) C, H, N.
(E)-3-(3-Br om o-5-ter t-bu tyl-4-m eth oxyben zylid en yl)-5-
1
ch lor oin d olin -2-on e (36): H NMR (360 MHz, DMSO-d6) δ
10.70 (s, 1H, NH-1), 8.83 (d, J ) 2.15 Hz, 1H, H-2′), 8.38 (d, J
) 2.15 Hz, 1H, H-6′), 7.90 (s, 1H, H-vinyl), 7.82 (d, J ) 1.97
Hz, 1H, H-4), 7.30 (dd, J ) 1.97, 8.16 Hz, 1H, H-6), 6.83 (d, J
) 8.16 Hz, 1H, H-7), 3.92 (s, 3H, OCH3-4′), 1.39 (s, 9H,
C(CH3)3-3′); MS m/z (relative intensity, %) 420 (100, M+•). Anal.
(C20H19BrClNO2) C, H, N.
(E)-3-[1-[4-(P ip er id in -1-yl)p h en yl]eth ylid en yl]in d olin -
2-on e (37). The reaction mixture of 142.3 mg of pyrrolidine
(2.0 µmol) and 243.9 mg of 4-(piperidin-1-yl)phenylacetone (1.2
µmol) was refluxed for 1 h in toluene. A Dean-Stark trap
filled with anhydrous sodium sulfate was used to remove
water. Oxindole (133.0 mg, 1.0 µmol) was added to the above
mixture, and the reaction mixture was stirred for an additional
5 h. Toluene was removed by a rotary pump, and the residue
was separated on a silica gel column eluting with ethyl acetate
1
and hexane to give 63.0 mg of the title compound (20%); H
NMR (360 MHz, DMSO-d6) δ 10.43 (s, 1H, NH-1), 7.21 (d, J
) 8.70 Hz, 2H, H-2′,6′), 7.04 (dt, J ) 1.27, 7.72 Hz, 1H, H-6),
7.01 (d, J ) 8.70 Hz, 2H, H-3′,5′), 6.76 (d, J ) 7.72 Hz, 1H,
H-7), 6.59 (dt, J ) 1.12, 7.72 Hz, 1H, H-5), 6.44 (d, J ) 7.72
Hz, 1H, H-4), 3.25 (t, J ) 5.39 Hz, 4H, CH2-2′′,6′′), 2.66 (s,
3H, CH3-vinyl), 1.59-1.64 (m, 6H, CH2-3′′,4′′,5′′). MS m/z
(relative intensity, %) 319 (100, [M + 1]+•). Anal. (C21H22N2O‚
0.6H2O) C, H, N.
(E)-3-(3,5-Diisopr opyl-4-h ydr oxyben zyliden yl)-5-ch lor o-
in d olin -2-on e (30): 1H NMR (300 MHz, DMSO-d6) δ 10.64
(s, 1H, NH-1), 8.94 (s, br, 1H, OH-4′), 7.73 (d, J ) 1.96 Hz,
1H, H-4), 7.66 (s, 1H, H-vinyl), 7.45 (s, 2H, H-2′,6′), 7.26 (dd,
J ) 1.96, 8.36 Hz, 1H, H-6), 6.89 (d, J ) 8.36 Hz, 1H, H-7),
3.31-3.42 (m, 2H, CH(CH3)2-3′,5′), 1.21 (d, J ) 6.51 Hz, 12H,

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2601
Gen er a l P r oced u r e for 3-[(Su bstitu ted p yr r olyl)m eth -
ylid en yl]in d olin -2-on e An a logu es (Com p ou n d 3 An a -
logu es). A reaction mixture of the proper oxindole (indolin-
2-one) (1 equiv), the appropriate aldehyde (1.2 equiv), and
piperidine (0.1 µmol) in ethanol (1-2 mL/1 µmol oxindole) was
stirred at 90 °C for 3-5 h. After the mixture cooled, the
precipitate was filtered, washed with cold ethanol, and dried
to give the target compound in over 80% yield. The analytical
data reported here belongs to the major isomer. The data for
the minor isomer is not reported. The ratios of Z to E isomers
for each compound are shown in Tables 2-6.
7.14 (m, 2H, H-6,5′), 6.98 (dt, J ) 0.84, 7.59 Hz, 1H, H-5), 6.87
(d, J ) 7.59 Hz, 1H, H-7), 3.60 (s, 3H, CH2CH2COOCH3-3′),
2.69 (t, J ) 7.29 Hz, 2H, CH2CH2COOCH3-4′), 2.56 (t, J ) 7.29
Hz, 2H, CH2CH2COOCH3-3′), 2.26 (s, 3H, CH3-4′); MS m/z
(relative intensity, %) 311 (56, [M + 1]+•). Anal. (C18H18N2O3)
C, H, N.
(Z)-3-[[3-(Eth oxyca r bon yl)-4-m eth ylp yr r ol-5-yl]m eth -
ylid en yl]in d olin -2-on e (44): 1H NMR (300 MHz, DMSO-d6)
δ 13.81 (s, br, 1H, NH-1′), 11.04 (s, br, 1H, NH-1), 7.84-7.85
(m, 2H, H-4,2′), 7.72 (s, 1H, H-vinyl), 7.18 (dt, J ) 1.34, 7.70
Hz, 1H, H-6), 7.02 (dt, J ) 1.02, 7.70 Hz, 1H, H-5), 6.90 (d, J
) 7.70 Hz, 1H, H-7), 4.22 (q, J ) 7.05 Hz, COOCH2CH3-3′),
2.54 (s, 3H, CH3-4′), 1.29 (t, J ) 7.05 Hz, 3H, COOCH2CH3-
3′); MS m/z (relative intensity, %) 297 (100, [M + 1]+•). Anal.
(C17H16N2O3) C, H, N.
(Z)-3-[(2,4-Dim eth ylp yr r ol-5-yl)m eth ylid en yl]in d olin -
2-on e (45). A reaction mixture of 134.0 mg of oxindole, 147.8
mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops
of piperidine in 2 mL of ethanol was stirred at 90 °C for 3 h.
After the mixture cooled, the precipitate was filtered, washed
with cold ethanol, and dried to yield 136.7 mg (57%) of the
title compound as a yellow solid: 1H NMR (300 MHz, DMSO-
d6) δ 13.36 (s, br, 1H, NH-1′), 10.77 (s, 1H, NH-1), 7.71 (d, J )
7.70 Hz, 1H, H-4), 7.55 (s, 1H, H-vinyl), 7.09 (dt, J ) 1.24,
7.70 Hz, 1H, H-6), 6.97 (dt, J ) 0.97, 7.70 Hz, 1H, H-5), 6.87
(d, J ) 7.66 Hz, 1H, H-7), 6.00 (d, J ) 2.25 Hz, 1H, H-3′), 2.32
(s, 3H, CH3-4′(2′)), 2.30 (s, 3H, CH3-2′(4′)); MS m/z (rela-
tive intensity, %) 239 (100, [M + 1]+•). Anal. (C15H14N2O) C,
H, N.
1
(Z)-3-[(P yr r ol-2-yl)m eth ylid en yl]in d olin -2-on e (3): H
NMR (360 MHz, DMSO-d6) δ 13.34 (s, br, 1H, NH-1′), 10.83
(s, 1H, NH-1), 7.71 (s, 1H, H-vinyl), 7.61 (d, J ) 7.68 Hz, 1H,
H-4), 7.33 (s, br, 1H, H-5′), 7.14 (t, J ) 7.68 Hz, 1H, H-6), 6.98
(t, J ) 7.68 Hz, 1H, H-5), 6.88 (d, J ) 7.68 Hz, 1H, H-7), 6.83
(t, J ) 1.71 Hz, 1H, H-3′), 6.33-6.36 (m, 1H, H-4′); MS m/z
(relative intensity, %) 211 (100, [M + 1]+•). Anal. (C13H10N2O)
C, H, N.
(Z)-4-Met h yl-3-[(p yr r ol-2-yl)m et h ylid en yl]in d olin -2-
1
on e (38): H NMR (360 MHz, DMSO-d6) δ 13.50 (s, br, 1H,
NH-1′), 10.87 (s, 1H, NH-1), 7.65 (s, 1H, H-vinyl), 7.32 (d, J )
1.68 Hz, 1H, H-3′), 7.05 (t, J ) 7.76 Hz, 1H, H-6), 6.91 (t, J )
1.63 Hz, 1H, H-5′), 6.80 (d, J ) 7.66 Hz, 1H, H-7), 6.76 (t, J )
7.76 Hz, 1H, H-5), 6.33-6.36 (m, 1H, H-4′), 2.57 (s, 3H, CH3-
4); MS m/z (relative intensity, %) 247 (100, [M + Na]+•). Anal.
(C14H12N2O3‚0.1H2O) C, H, N.
(Z)-5-Ch lor o-3-[(p yr r ol-2-yl)m et h ylid en yl]in d olin -2-
1
on e (39): H NMR (360 MHz, DMSO-d6) δ 13.30 (s, br, 1H,
NH-1′), 10.93 (s, 1H, NH-1), 7.86 (s, 1H, H-vinyl), 7.74 (d, J )
2.27 Hz, 1H, H-4), 7.38-7.40 (m, 1H, H-5′), 7.16 (dd, J ) 2.27,
8.28 Hz, 1H, H-6), 6.88 (d, J ) 8.28 Hz, 1H, H-7), 6.85 (dd, J
) 1.59, 3.44 Hz, 1H, H-3′), 6.37-6.39 (m, 1H, H-4′); MS m/z
(relative intensity, %) 245 (100, M+•). Anal. (C13H9N2OCl) C,
H, N.
(Z)-6-F lu or o-3-[(p yr r ol-2-yl)m et h ylid en yl]in d olin -2-
on e (40): 1H NMR (360 MHz, DMSO-d6) δ 13.19 (s, 1H, NH-
1′), 10.98 (s, 1H, NH-1), 7.69 (s, 1H, H-vinyl), 7.61 (dd, J )
5.47, 8.34 Hz, 1H, H-4), 7.32-7.33 (m, 1H, H-5′), 6.76-6.82
(m, 2H, H-5,3′), 7.69 (dd, J ) 2.31, 9.19 Hz, 1H, H-7), 6.33-
6.35 (m, 1H, H-4′); MS m/z (relative intensity, %) 229 (100,
[M + 1]+•). Anal. (C13H9FN2O) C, H, N.
(Z)-3-[(3,4-Dim eth ylp yr r ol-2-yl)m eth ylid en yl]in d olin -
2-on e (41). A reaction mixture of 67.0 mg of oxindole, 73.0
mg of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops
of piperidine in 2 mL of ethanol was stirred at 90 °C for 3 h.
After the mixture cooled, the precipitate was filtered, washed
with cold ethanol, and dried to yield 87.7 mg (37%) of the title
compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ
13.28 (s, br, 1H, NH-1′), 10.82 (s, 1H, NH-1), 7.75 (d, J ) 7.62
Hz, 1H, H-4), 7.62 (s, 1H, H-vinyl), 7.09-7.14 (m, 2H, H-6,5′),
6.98 (dt, J ) 1.03, 7.62 Hz, 1H, H-5), 6.87 (d, J ) 7.62 Hz, 1H,
H-7), 2.25 (s, 3H, CH3-4′), 2.02 (s, 3H, CH3-3′); MS m/z (rela-
tive intensity, %) 239 (100, [M + 1]+•). Anal. (C15H14N2O) C,
H, N.
(Z)-3-[(3-(2-Ca r b oxyet h yl)-4-m et h ylp yr r ol-2-yl)m et h -
ylid en yl]in d olin -2-on e (42). A reaction mixture of 134.0 mg
(1.0 µmol) of oxindole, 217.43 mg (1.2 µmol) of the 3-(2-
carboxyethyl)-4-methylpyrrole-2-carboxaldehyde, and 3 drops
of piperidine in 3 mL of ethanol was stirred at 90 °C for 3 h.
After the mixture cooled, the precipitate was filtered, washed
with cold ethanol, and dried to yield 172.4 mg (58%) of the
title compound as a yellow solid: 1H NMR (300 MHz, DMSO-
d6) δ 13.27 (s, 1H, CH2CH2COOH-3′), 10.84 (s, br, 1H, NH-1),
7.67-7.70 (m, 2H, H-4, vinyl), 7.08-7.13 (m, 2H, H-6,5′), 6.97
(dt, J ) 0.99, 7.47 Hz, 1H, H-5), 6.86 (d, J ) 7.47 Hz, 1H,
H-7), 2.92 (t, J ) 7.37 Hz, 2H, CH2CH2COOH-3′), 2.32 (t, J )
7.37 Hz, 2H, CH2CH2COOH-3′), 2.03 (s, 3H, CH3-4′); MS m/z
(relative intensity, %) 297 (100, [M + 1]+•). Anal. (C17H16N2O3)
C, H, N.
(Z)-6-Flu or o-3-[(2,4-dim eth ylpyr r ol-5-yl)m eth yliden yl]-
in d olin -2-on e (46): 1H NMR (300 MHz, DMSO-d6) δ 13.19
(s, br, 1H, NH-1′), 10.85 (s, 1H, NH-1), 7.00 (dd, J ) 5.48, 8.38
Hz, 1H, H-4), 7.52 (s, 1H, H-vinyl), 6.74-6.79 (m, 1H, H-5),
6.67 (dd, J ) 2.43, 9.17 Hz, 1H, H-7), 5.98 (d, J ) 2.41 Hz,
1H, H-3′), 2.30 (s, 3H, CH3-2′), 2.23 (s, 3H, CH3-4′); MS m/z
(relative intensity, %) 257 (100, [M + 1]+•). Anal. (C15H13
-
FN2O) C, H, N.
(Z)-3-[(3-Eth yl-2,4-d im eth ylp yr r ol-5-yl)m eth ylid en yl]-
in d olin -2-on e (47). P r ep a r a tion of 3,5-Dim eth yl-4-eth -
ylp yr r ole-2-ca r boxa ld eh yd e (13). To a solution of 2.3 mL
(30 mol) of dimethylformamide in 50 mL of anhydrous 1,2-
dichloroethane was added dropwise 2.8 mL (30 mol) of
phosphorus oxychloride at 0 °C. The ice bath was removed.
The reaction mixture was further stirred for 30 min, and cooled
with ice bath. 2,5-Dimethyl-4-ethylpyrrole (2.46 g, 20 µmol)
was added to the above solution portionwise, and the reaction
mixture was stirred at 50 °C for 3 h. The reaction mixture
was poured into ice-cold 1 N sodium hydroxide solution and
stirred at room temperature for 2 h. The gray precipitate was
filtered and washed with water to a pH of 7. The solid was
dried in an oven overnight to give 13 (2.42 g, 80%): 1H NMR
(360 MHz, DMSO) δ 11.33 (s, br, 1H, CHO-2), 9.42 (s, 1H, NH-
1), 2.38 (q, J ) 7.55 Hz, 2H, CH2CH3-4), 2.20 (s, 3H, CH3-3),
2.15 (s, 3H, CH3-5), 0.99 (t, J ) 7.55 Hz, 3H, CH2CH3-4).
P r ep a r a tion of 47. Condensation of 13 with oxindole using
the same procedure for analogues of 3 gave 47: 1H NMR (360
MHz, DMSO-d6) δ 13.38 (s, br, 1H, NH-1′), 10.69 (s, 1H, NH-
1), 7.69 (d, J ) 7.34 Hz, 1H, H-4), 7.54 (s, 1H, H-vinyl), 7.07
(dt, J ) 1.12, 7.34 Hz, 1H, H-6), 6.96 (dt, J ) 1.07, 7.34 Hz,
1H, H-5), 6.86 (d, J ) 7.34 Hz, 1H, H-7), 2.40 (q, J ) 7.61 Hz,
2H, CH2CH3-3′), 2.29 (s, 3H, CH3-2′(4′)), 2.25 (s, 3H, CH3-4′-
(2′)), 1.04 (t, J ) 7.61 Hz, 3H, CH2CH3-3′); MS m/z (rela-
tive intensity, %) 267 (100, [M + 1]+•). Anal. (C17H18N2O) C,
H, N.
(Z)-3-[(2,4-Dim et h yl-3-(et h oxyca r b on yl)p yr r ol-5-yl)-
m eth ylid en yl]in d olin -2-on e (48). A reaction mixture of
134.0 mg of oxindole, 234.3 mg of 4-(ethoxycarbonyl)-3,5-
dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine
in 3 mL of ethanol was stirred at 90 °C for 3 h. After the
mixture cooled, the precipitate was filtered, washed with cold
ethanol, and dried to yield 244.6 mg (79%) of the title
compound as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ
13.88 (s, br, 1H, NH-1′), 10.95 (s, br, 1H, NH-1), 7.80 (d, J )
7.53 Hz, 1H, H-4), 7.62 (s, 1H, H-vinyl), 7.15 (dt, J ) 1.10,
(Z)-3-[[3-(2-(Meth oxyca r bon yl)eth yl)-4-m eth ylp yr r ol-
5-yl]m eth ylid en yl]in d olin -2-on e (43): 1H NMR (360 MHz,
DMSO-d6) δ 13.31 (s, br, 1H, NH-1′), 10.78 (s, br, 1H, NH-1),
7.74 (d, J ) 7.59 Hz, 1H, H-4), 7.61 (s, 1H, H-vinyl), 7.09-

2602 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14
Sun et al.
7.53 Hz, 2H, H-6), 7.00 (dt, J ) 1.06, 7.53 Hz, 1H, H-5), 6.89
(d, J ) 7.53 Hz, 1H, H-7), 4.21 (q, J ) 7.32 Hz, 2H,
COOCH2CH3-3′), 2.54 (s, 3H, CH3-4′(2′)), 2.49 (s, 3H, CH3-
2′(4′)), 1.30 (t, J ) 7.32 Hz, 3H, COOCH2CH3-3′); MS m/z
(relative intensity, %) 311 (100, [M + 1]+•). Anal. (C18H18N2O3)
C, H, N.
(Z)-3-[(4-Eth yl-2,3-d im eth ylp yr r ol-5-yl)m eth ylid en yl]-
in d olin -2-on e (49): 1H NMR (360 MHz, DMSO-d6) δ 13.39
(s, br, 1H, NH-1′), 10.69 (s, 1H, NH-1), 7.69 (d, J ) 7.67 Hz,
1H, H-4), 7.52 (s, 1H, H-vinyl), 7.07 (dt, J ) 1.11, 7.67 Hz,
1H, H-6), 6.96 (dt, J ) 1.17, 7.67 Hz, 1H, H-5), 6.86 (d, J )
7.67 Hz, 1H, H-7), 2.70 (q, J ) 7.47 Hz, 2H, CH2CH3-4′), 2.27
(s, 3H, CH3-2′(3′)), 1.97 (s, 3H, CH3-3′(2′)), 1.11 (t, J ) 7.47
Hz, 3H, CH2CH3-4′); MS m/z (relative intensity, %) 267 (100,
[M + 1]+•). Anal. (C17H18N2O) C, H, N.
(Z)-3-[(2-(Meth ylth io)th ien -5-yl)m eth ylid en yl]in d olin -
2-on e (56). A reaction mixture of 134.0 mg of oxindole, 189.9
mg of the 5-(methylthio)thiophene-2-carboxaldehyde, and 3
drops of piperidine in 2 mL of ethanol was stirred at 90 °C for
3 h. After cooling, the precipitate was filtered, washed with
cold ethanol, and dried to yield 246.6 mg (90%) of the title
compound as an orange solid: 1H NMR (360 MHz, DMSO-d6)
δ 10.56 (s, br, 1H, NH-1), 7.98 (s, 1H, H-vinyl), 7.73 (d, J )
4.28 Hz, 1H, H-4′(3′)), 7.64 (d, J ) 7.54 Hz, 1H, H-4), 7.19 (dt,
J ) 1.11, 7.54 Hz, 1H, H-6), 7.13 (d, J ) 4.28 Hz, 1H, H-3′-
(4′)), 6.98 (dt, J ) 0.75, 7.54 Hz, 1H, H-5), 6.85 (d, J ) 7.54
Hz, 1H, H-7), 2.64 (s, 3H, SCH3-2′); MS m/z (relative intensity,
%) 274 (100, [M + 1]+•). Anal. (C14H11NOS2) C, H, N.
(Z)-4-Meth yl-3-[(2-(m eth ylth io)th ien -5-yl)m eth yliden yl]-
in d olin -2-on e (57): 1H NMR (300 MHz, DMSO-d6) δ 10.60
(s, br, NH-1), 7.87 (s, 1H, H-vinyl), 7.76 (d, J ) 4.33 Hz, 1H,
H-4′), 7.12 (d, J ) 4.33 Hz, 1H, H-3′), 7.08 (t, J ) 7.92 Hz, 1H,
H-6), 6.78 (d, J ) 7.92 Hz, 1H, H-5), 6.72 (d, J ) 7.92 Hz, 1H,
H-7), 2.63 (s, 3H, SCH3-2′), 2.57 (s, 3H, CH3-4); 2D-NOE 1H
NMR showed the correlation between H-vinyl and CH3-4,
which confirmed the Z conformer; MS m/z (relative inten-
sity, %) 310 (100, [M + Na]+•). Anal. (C15H13NOS2‚0.1H2O)
C, H, N.
(Z)-3-[(1-Met h ylp yr r ol-5-yl)m et h ylid en yl]in d olin -2-
1
on e (50): H NMR (360 MHz, DMSO-d6) δ 10.45 (s, 1H, NH-
1), 7.98 (d, J ) 7.38 Hz, 1H, H-4), 7.47 (s, 1H, H-vinyl), 7.17-
7.22 (m, 2H, H-6,5′), 7.05 (dd, J ) 0.88, 3.82 Hz, 1H, H-3′),
6.95 (dt, J ) 1.08, 7.38 Hz, 1H, H-5), 6.88 (d, J ) 7.38 Hz, 1H,
H-7), 6.31 (dd, J ) 2.73, 3.82 Hz, 1H, H-4′), 3.78 (s, 3H, NCH3-
1′); MS m/z (relative intensity, %) 225 (100, [M + 1]+•). Anal.
(C14H12N2O) C, H, N.
(Z)-5-Nit r o-3-[(p yr r ol-2-yl)m e t h ylid e n yl]in d olin -2-
on e (51): H NMR (360 MHz, DMSO-d6) δ 13.16 (s, br, 1H,
(E)-3-[(2-(Eth ylth io)th ien -5-yl)m eth ylid en yl]in d olin -2-
on e (58): H NMR (360 MHz, DMSO-d6) δ 10.52 (s, 1H, NH-
1
1
NH-1′), 11.49 (s, 1H, NH-1), 8.58 (d, J ) 2.10 Hz, 1H, H-4),
8.14 (s, 1H, H-vinyl), 8.08 (dd, J ) 2.10, 8.51 Hz, 1H, H-6),
7.47 (dd, J ) 2.67, 3.66 Hz, 1H, H-5′), 7.05 (d, J ) 8.51 Hz,
1H, H-7), 6.97-6.98 (m, 1H, H-3′), 6.42-6.44 (m, 1H, H-4′);
MS m/z (relative intensity, %) 255 (100, M+•). Anal.
(C13H9N3O3‚0.1H2O) C, H, N.
(Z)-4-Meth yl-3-[(2,4-dim eth ylpyr r ol-5-yl)m eth yliden yl]-
in d olin -2-on e (52): 1H NMR (360 MHz, DMSO-d6) δ 10.75
(s, br, NH-1), 7.51 (s, 1H, H-vinyl), 7.00 (t, J ) 7.65 Hz, 1H,
H-6), 6.79 (d, J ) 7.93 Hz, 1H, H-5), 6.75 (d, J ) 7.93 Hz, 1H,
H-7), 6.01 (d, J ) 2.81 Hz, 1H, H-3′), 2.57 (s, 3H, CH3-4),
2.32 (s, 3H, CH3-2′), 2.24 (s, 3H, CH3-4′); MS m/z (relative
intensity, %) 253 (100, [M + 1]+•). Anal. (C16H16N2O‚0.3H2O)
C, H, N.
(Z)-5-Meth yl-3-[(2,4-dim eth ylpyr r ol-5-yl)m eth yliden yl]-
in d olin -2-on e (53). P r ep a r a tion of 5-Meth ylin d olin -2-
on e (8). 5-Methylisatin (15.0 g, 10.2 µmol) and 60 mL of
hydrazine hydrate were heated to 140-160 °C for 4 h. The
reaction mixture was cooled to room temperature, poured into
300 mL of ice water, and acidified to pH 2 with 6 N
hydrochloric acid. After standing at room temperature for 2
days the precipitate was collected by vacuum filtration, washed
with water, and dried under vacuum to give 6.5 g (47% yield)
of 5-methylindolin-2-one: 1H NMR (360 MHz, DMSO-d6) δ
10.19 (s, 1H, NH-1), 6.98 (s, 1H, H-4), 6.94 (d, J ) 8.11 Hz,
1H, H-6), 6.68 (d, J ) 8.11 Hz, 1H, H-7), 3.39 (s, 2H, CH2-3),
and 2.22 (s, 3H, CH3-5).
Syn th esis of 53. The title compound was prepared in the
same way as 3 as described above: 1H NMR (300 MHz, DMSO-
d6) δ 13.35 (s, br, 1H, NH-1′), 10.64 (s, 1H, NH-1), 7.52 (s, 1H,
H-4), 7.49 (s, 1H, H-vinyl), 6.89 (d, J ) 7.72 Hz, 1H, H-6), 6.73
(d, J ) 7.72 Hz, 1H, H-7), 5.98 (d, J ) 1.91 Hz, 1H, H-3′), 2.29
(s, 9H, CH3-5,2′,4); MS m/z (relative intensity, %) 253 (100,
[M + 1]+•). Anal. (C16H16N2O) C, H, N.
1), 7.98 (s, 1H, H-vinyl), 7.76 (d, J ) 3.92 Hz, 1H, H-4′(3′)),
7.64 (d, J ) 7.40 Hz, 1H, H-4), 7.17 (dt, J ) 1.13, 7.40 Hz, 1H,
H-6), 6.95-6.99 (m, 2H, H-5,3′(4′)), 6.84 (d, J ) 7.40 Hz, 1H,
H-7), 2.90 (q, J ) 7.49 Hz, 2H, CH2CH3-2), and 1.29 (t, J )
7.49 Hz, 3H, CH2CH3-2); MS m/z (relative intensity, %) 256
(100, [M + 1]+•). Anal. (C15H13NOS) C, H, N.
(E)-3-[(F u r a n -2-yl)m eth ylid en yl]in d olin -2-on e (59): 1H
NMR (360 MHz, DMSO-d6) δ 10.58 (s, 1H, NH-1), 8.35 (d, J
) 7.55 Hz, 1H, H-4), 8.13 (d, J ) 1.87 Hz, 1H, H-5′), 7.33 (s,
1H, H-vinyl), 7.22-7.26 (m, 2H, H-6,3′), 7.00 (dt, J ) 1.08,
7.55 Hz, 1H, H-5), 6.87 (d, J ) 7.59 Hz, 1H, H-7), 6.78 (dd, J
) 1.87, 3.11 Hz, H-4′); MS m/z (relative intensity, %) 212 (100,
[M + 1]+•). Anal. (C13H9NO2) C, H, N.
(E )-3-[(2-Me t h ylfu r a n -5-yl)m e t h ylid e n yl]in d olin -2-
1
on e (60): H NMR (360 MHz, DMSO-d6) δ 10.48 (s, 1H, NH-
1), 8.29 (d, J ) 7.78 Hz, 1H, H-4), 7.24 (s, 1H, H-vinyl), 7.22
(t, J ) 7.67 Hz, 1H, H-6), 7.15 (d, J ) 3.28 Hz, 1H, H-4′), 7.01
(t, J ) 7.78 Hz, 1H, H-5), 6.86 (d, J ) 7.67 Hz, 1H, H-7), 6.44
(d, J ) 3.28 Hz, 1H, H-3′), 2.51 (s, 3H, CH3-2′); MS m/z (rela-
tive intensity, %) 226 (100, [M + 1]+•). Anal. (C14H11NO2) C,
H, N.
(E)-3-[(2-E t h ylfu r a n -5-yl)m et h ylid en yl]in d olin -2-on e
(61): 1H NMR (360 MHz, DMSO-d6) δ 10.49 (s, 1H, NH-1),
8.31 (d, J ) 7.68 Hz, 1H, H-4), 7.25 (s, 1H, H-vinyl), 7.21 (dt,
J ) 1.08, 7.60 Hz, 1H, H-6), 7.15 (d, J ) 3.16 Hz, 1H, H-4′),
7.00 (dt, J ) 1.08, 7.68 Hz, 1H, H-5), 6.86 (d, J ) 7.60 Hz, 1H,
H-7), 6.45 (d, J ) 3.16 Hz, 1H, H-3′), 2.85 (q, J ) 7.49 Hz, 2H,
CH2CH3-2′), 1.29 (t, J ) 7.49 Hz, 3H, CH2CH3-2′); MS m/z
(relative intensity, %) 240 (100, [M + 1]+•). Anal. (C15H13
NO2) C, H, N.
-
(Z)-3-[(4-Ch lor op yr a zol-3-yl)m et h ylid en yl]in d olin -2-
1
on e (62): H NMR (360 MHz, DMSO-d6) δ 14.59 (s, 1H, NH-
1′), 11.26 (s, 1H, br, NH-1), 7.86-7.88 (m, 2H, H-4,5′), 7.53 (s,
1H, H-vinyl), 7.30 (dt, J ) 1.03, 7.74 Hz, 1H, H-6), 7.07 (dt, J
) 1.02, 7.74 Hz, 1H, H-5), and 6.94 (d, J ) 7.74 Hz, 1H, H-7);
MS m/z (relative intensity, %) 246 (100, M+•). Anal. (C12H8-
ClN3O) C, H, N.
(Z)-3-[(3-Br om ot h ie n -2-yl)m e t h ylid e n yl]in d olin -2-
1
on e (54): H NMR (300 MHz, DMSO-d6) δ 10.72 (s, 1H, NH-
1), 8.00 (d, J ) 5.62 Hz, 1H, H-4′(5′)), 7.82 (s, 1H, H-vinyl),
7.65 (d, J ) 7.61 Hz, 1H, H-4), 7.35 (d, J ) 5.62 Hz, 1H, H-5′-
(4′)), 7.26 (dt, J ) 1.03, 7.61 Hz, 1H, H-6), 7.02 (dt, J ) 0.84,
7.61 Hz, 1H, H-5), 6.88 (d, J ) 7.61 Hz, 1H, H-7); MS m/z
(relative intensity, %) 306 (43, M+•). Anal. (C13H8BrNOS) C,
H, N.
(E)-3-[(4-Ch lor o-1-m et h ylp yr a zol-3-yl)m et h ylid en yl]-
in d olin -2-on e (63): 1H NMR (360 MHz, DMSO-d6) δ 10.57
(s, 1H, NH-1), 8.88 (d, J ) 7.57 Hz, 1H, H-4), 8.19 (s, 1H,
H-vinyl), 7.34 (s, 1H, H-5′), 7.28 (dt, J ) 1.14, 7.57 Hz, 1H,
H-6), 7.02 (dt, J ) 1.07, 7.57 Hz, 1H, H-5), 6.87 (d, J ) 7.57
Hz, 1H, H-7), 4.05 (s, 3H, CH3-1′); MS m/z (relative intensity,
%) 260 (100, M+•). Anal. (C13H10ClN3O) C, H, N.
(Z)-3-[(3-Br om ot h ie n -5-yl)m e t h ylid e n yl]in d olin -2-
1
on e (55): H NMR (300 MHz, DMSO-d6) δ 10.70 (s, 1H, NH-
1), 8.04 (s, 1H, H-vinyl), 7.95-7.97 (m, 2H, H-2′,4′), 7.59 (d, J
) 7.57 Hz, 1H, H-4), 7.23 (dt, J ) 1.10, 7.57 Hz, 1H, H-6),
7.01 (dt, J ) 0.87, 7.57 Hz, 1H, H-5), 6.87 (d, J ) 7.57 Hz, 1H,
H-7); MS m/z (relative intensity, %) 306 (100, M+•). Anal.
(C13H8BrNOS) C, H, N.
Ack n ow led gm en t. The authors would like to thank
Brian Dowd and Sarah Shimer for screening all of the
compounds against various RTKs and Congxin Liang

Synthesis, Evaluation of 3-Substituted Indolinones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 14 2603
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(20) Compound 45 has been named as either 3-[(2,4-dimethylpyrrol-
5-yl)methylidenyl]indolin-2-one or 3-[(3,5-dimethylpyrrol-2-yl)-
methylidenyl]indolin-2-one in this paper and other presenta-
tions. However, the wrong name, 3-[(2,3-dimethylpyrrol-5-
yl)methylidenyl]indolin-2-one, was given in our patent (PCT Int.
Appl. 293pp, WO 9807695).
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