Potent platelet-derived growth factor-β receptor (PDGF-βR) inhibitors: Synthesis and structure-activity relationships of 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl} quinoxalin-2(1H)-one derivatives

Article abstract of DOI:10.1248/cpb.55.255

We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H- pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC₅₀=0.05 μmol/l in CPA, 0.03 μmol/l in APA). Therefore, we tried to develop a novel and effective PDGF-βR inhibitor by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with manganese(IV) oxide (MnO₂) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC₅₀=0.014 μmol/l in CPA, 0.007 μmol/l in APA) and selective [IC₅₀ values against vascular endothelial growth factor receptor 2 (VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth factor receptor) and insulin growth factor I receptor (IGF-IR)/IC₅₀ against PDGFR were each >1000] inhibitory activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and VEGF-induced signaling (PDGFR: IC₅₀=0.004 μmol/l in CPA, 0.0008 μmol/l in APA, KDR: IC ₅₀=0.008 μmol/l in APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.

Full text of DOI:10.1248/cpb.55.255

February 2007
Chem. Pharm. Bull. 55(2) 255—267 (2007)
255
b
b
Potent Platelet-Derived Growth Factor- Receptor (PDGF- R) Inhibitors:
Synthesis and Structure–Activity Relationships of 7-[3-
(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl}quinoxalin-2(1H)-one Derivatives
Katsuyuki AOKI, ,a,c Tatsuhiro OBATA,a Yosuke YAMAZAKI,a Yoshikazu MORI,a,c Hiroko HIROKAWA,a
*
Jun-ichi KOSEKI,a Tomohisa HATTORI,a Kazuaki NIITSU,a Shuichi TAKEDA,a Masaki ABURADA,b and
c
Ken-ichi MIYAMOTO
a R & D Division, Tsumura & Co.; 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300–1192, Japan: b Research
Institute of Pharmaceutical Sciences, Musashino University; 1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan: and
c Department of Clinical Pharmacy, Graduate School of Natural Science and Technology, Kanazawa University; 13–1
Takaramachi, Kanazawa, Ishikawa 920–8641, Japan.
Received August 10, 2006; accepted November 14, 2006; published online December 8, 2006
We found previously that 7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinox-
alin-2(1H)-one (7d-6) has considerable potency as a PDGF inhibitor. This compound showed potent inhibitory
activity in a PDGF-induced CPA (Cell Proliferation Assay) and APA (Auto-Phosphorylation Assay) (IC50ꢀ
0.05 mmol/l in CPA, 0.03 mmol/l in APA). Therefore, we tried to develop a novel and effective PDGF-bR inhibitor
by optimizing a series of its derivatives. We found that trifluoroacetic acid (TFA)-catalyzed coupling of
pyrrolo[2,3-b]pyridines with quinoxalin-2-ones proceeded efficiently under mild oxidation condition with man-
ganese(IV) oxide (MnO2) in situ, so this method was applied to prepare a series of derivatives. Results of in vitro
screening of newly synthesized derivatives identified compound 7d-9 as having potent (IC50ꢀ0.014 mmol/l in
CPA, 0.007 mmol/l in APA) and selective [IC50 values against vascular endothelial growth factor receptor 2
(VEGFR2, kinase domain region, KDR), epidermal growth factor receptor (EGFR), c-Met (hepatocyte growth
factor receptor) and insulin growth factor I receptor (IGF-IR)/IC50 against PDGFR were each ꢁ1000] inhibitory
activity. Moreover, in this series of derivatives, 7b-2 showed potent inhibitory activity toward both PDGF- and
VEGF-induced signaling (PDGFR: IC50ꢀ0.004 mmol/l in CPA, 0.0008 mmol/l in APA, KDR: IC50ꢀ0.008 mmol/l in
APA). Herein we report a new and convenient synthetic method for this series of derivatives and its SAR study.
Key words platelet-derived growth factor (PDGF); tyrosine kinase inhibitor; pyrrolo[2,3-b]pyridine; quinoxalin-2-one;
Friedel–Crafts reaction
PDGF1—3) is a glycoprotein that is produced by a large show, 7d-6 had a more potent inhibitory activity in CPA and
number of normal as well as transformed cell types, and it APA against PDGF than did the other compounds. Encour-
acts not only on connective tissue cells but also on other aged by these promising results, we carried out a more exten-
types of cells. It is also well known that PDGF participates in sive Structure–Activity Relationships (SAR) study of 3-
the onset of illness, e.g., arteriosclerosis and restenosis,4—8)
fibrosis,9,10) nephritis,11) along with its role in physiological
Table 1. Inhibitory Activities of the Inhibitors against PDGF
phenomena such as generating processes in living organisms
and aiding the wound healing process. An attractive target to
treat proliferative disorders is to block abnormal PDGF-in-
duced cell proliferation. PDGF-induced cell proliferation is
caused by the ligand binding to its cell surface receptor, fol-
lowed by dimerization of the receptor and auto-phosphoryla-
tion of tyrosine kinase domain.12—16)
Various recent approaches to blocking the pathways medi-
ated by PDGFR tyrosine kinase have led to the discovery of a
wide range of small-molecule inhibitors, e.g., the indole-2-
ones,17—20) the quinoxalines,21—23) the tyrophostines,24,25) the
pyridylpyrimidines,26,27) the quinolines and quinazolines,28—34)
CPA PDGF-BB
IC50 (mmol)
APA PDGFR-b
IC50 (mmol)
the indoles,35,36) the imidazoles,37,38) the pyrazoles.39) We also
found previously that the in-house compound 7-[3-(cyclo-
hexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-
3-yl}quinoxalin-2(1H)-one (7d-6) showed potent inhibitory
activity toward PDGF-induced CPA and APA. Table 1 shows
the inhibitory activity of 7d-6 (IC50ꢀ0.05 mmol/l in CPA,
0.03 mmol/l in APA) against PDGF compared to the in-
hibitory activity of STI-571,26,27) CT5292328) and SU6668,17)
which have been evaluated in a clinical trial. As the data
Compd.
7d-6
0.05
0.4
0.1
0.03
0.34
0.08
0.10
STI-571
CT-52923
SU-6668
0.6
7d-6, (lead compound in this series), CPA: PDGF-induced proliferation of human
MC in vitro. APA: PDGF receptor auto-phosphorylation of human AoSMC in vitro.
PDGF-BB: platelet-derived growth factor-BB, PDGFR-b: platelet-derived growth fac-
tor receptor-b.
∗ To whom correspondence should be addressed. e-mail: aoki_katsuyuki@mail.tsumura.co.jp
© 2007 Pharmaceutical Society of Japan

256
Vol. 55, No. 2
{pyrrolo[2,3b]pyridin-3-yl}quinoxalin-2-ones by modifying sults indicated that the reaction of 7-azaindole with oxalyl
the position and substituent of the urea, modifying the 1 and chloride failed to yield the corresponding 3-{pyrrolo[2,3-
7-position on the pyrrolo[2,3-b]pyridine ring, and changing b]pyridine-3-yl}-3-oxoacetate under conventional conditions
the substituent on the quinoxalin-2-one ring. We also devel- for this reaction. Chupakhin et al.,46) previously reported a
oped a convenient synthetic method for the basic framework, synthetic method for 3-(indol-3-yl)quinoxalin-2-one that in-
i.e. the 3-{pyrrolo[2,3b]pyridin-3-yl}quinoxalin-2-ones, as a cluded acetic acid-catalyzed Friedel–Crafts type coupling
synthetic protocol has never been reported for this com- (see Chart 1, B). The condition for this reaction was mild and
pound. This then allowed us to carry out a more extensive convenient compared with the condition40—45) described pre-
SAR study. Herein we report a new and convenient synthetic viously. However, the yield was not sufficient because prod-
method for this series of derivatives and we describe an in ucts with different oxidizing states were generated, i.e., an
vitro SAR study.
unsaturated coupling-product and a saturated one. It occurred
to us that addition of a mild oxidant such as MnO2 in situ
after the acid-catalyzed coupling of indoles with quinoxalin-
Chemistry
Typical approaches to synthesizing 3-(indol-3-yl)quinox- 2-one might accelerate the oxidation from the saturated cou-
alin-2-ones40—45) rely on condensation of 2-(indol-3-yl)-2- pling-product to the unsaturated one. Thus we attempted a
oxoacetate with 1,2-phenylenediamine (see Chart 1, A). Con- novel synthetic route to generate 3-{pyrrolo[2,3-b]pyridin-3-
densation of 2-(indol-3-yl)-2-oxoacetate, which was prepared yl}quonoxalin-2-one derivatives utilizing this strategy (see
by oxalyl chloride treatment of indoles, with 1,2-phenylene- Chart 1, C).
diamines easily afforded the desired product. However, using
A concise description of the preparation of starting materi-
this condition with a substituted quinoxalin-2-one might gen- als, i.e., compounds 1a—i and 4a—d, is outlined in Charts 2
erate an inseparable mixture of isomers. Moreover, our re- and 3. Almost all of the compounds 1a—h were directly pre-
Chart 1. (A) Typical Synthetic Procedure for 3-(Indol-3-yl)quinoxalin-2-ones and Our Result in Preparing 2-{Pyrrolo[2,3-b]pyridin-3-yl}-2-oxoacetate,
(B) Synthetic Method of Ref. 18, (C) Our Strategy for Synthesis of 3-{Pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2-ones
a) NaH, alkyl halide, DMF, b) 1-bromo-3-chloropropane, NaH, DMF, c) morpholine, 110 °C
Chart 2
a) Ethyl 2-aminoacetate, K2CO3, 80 °C, b) 1) 10% Pd–C, EtOH, 2) 2 mol/l NaOH aq., 3% H2O2 aq., 80 °C, c) fuming HNO3, AcOH, d) NaNO3, cH2SO4.
Chart 3

February 2007
257
pared by coupling of 7-azaindole treated with sodium hy- of the product of this reaction was not necessary. In general,
dride (NaH) in dimethylformamide (DMF) with the corre- the reaction condition for oxidation with MnO2 should pro-
sponding alkylhalides. Compound 1i was prepared by substi- vide the nitro compounds in higher yield than the condition
tuting the corresponding 1h with morpholine in DMF. Nitra- with H2O2 aq. (Entry 1, 2). It is desirable to use a solvent
tion of quinoxalin-2-one as described in the literature47,48) such as DMF for the solvent of this reaction, as it can dis-
provided 4c and 4d. 4a and 4b were prepared from 4-chloro- solve the saturated product obtained by coupling, in order to
2-fluoronitrobenzene or 2,4-difluoronitrobenzene by follow- proceed to the following reaction with MnO2. The other
ing the substitution with ethyl 2-aminoacetate with potas- compounds 5a—m (see Table 3, Entry 1—13) were also pre-
sium carbonate (K2CO3) in DMF, reduction by 10% Pd–C in pared by the same procedure as that used for 5d, from corre-
EtOH, and mild oxidation with 3% H2O2 aq.
sponding indoles (1a—i, 7-azaindole, and 1-methylindole)
Next, we examined the optimal reaction conditions for and quinoxalin-2-ones (4a—d).
Friedel-Crafts type coupling (see Table 2). However, our
Almost all of the amino compounds (6b—d, 6f—m) were
studies using the previous condition46) led to an unsatisfac- prepared (Table 4) from the corresponding nitro compounds
tory result (Entry 3, 4) because the insoluble saturated cou- by a reduction with 10% Pd–C, HCOOH, triethylamine
pling-product was deposited and the reaction did not (TEA) in solvent (typically DMF) without over-reduction
progress following oxidation. In our work-up of this reaction, (Method A, Entry 2—4 and 6—13). tert-Boc (tert-butoxy-
after filtration of manganese residue with celite, the organic carbonyl) protection at the 1-position on pyrrolo[2,3-b]pyri-
solvent is removed in vacuo. Then the deposited precipitate dine ring, followed by the same reduction, provided 6e
is filtered to give the desired compound. Further purification (Method B, Entry 5). 6a could not be obtained by Method A
due to accompanying hydrogenolysis of the chlorine atom at
the 6-position on the quinoxalin-2-one ring, so it was pre-
Table 2. Synthesis of 7-Nitro-3-(1H-pylloro[2,3-b]pyridin-3yl)quinoxalin-
pared by reduction with iron powder in conc. hydrochloric
2(1H)-one (5d)
acid and MeOH (Method C, Entry 1).
The preparation methods for 7d-1—d-5 are outlined in
Chart 4. Condensation of triphosgene-treated 6d with N-(2-
chloroethyl)-Nꢂ-cyclohexylmethylamine hydrochloride (see
Experimental section), followed by addition of 1,8-diazabicy-
clo[5.4.0]undec-7ene (DBU) provided 7d-1 in modest yield.
5d
7d-2 was prepared by a reaction of 6d with cyclohexylmethyl
Yield (%)a) thioisocyanate in THF. 7d-3 was prepared by a reaction of
phenyl chloroformate-treated 6d with cyclohexanemethanol.
Entry
Condition
1
2
TFA/DMF (1/10), 80 °C, 1 h,
then MnO2,b) 80 °C, 0.5 h
TFA/DMF (1/11), 80 °C, 1 h, then 2 mol/l NaO Haq,
3% H2O2 aq., 80 °C, 0.5 h
AcOH, 80 °C, 6 h
87
7d-4 and 7d-5 were prepared by a reaction of 6d with the
corresponding acid chloride. Preparation of the other deriva-
tives is outlined in Chart 5. Almost all of the derivatives 7d-
6—d-20 with various functional groups at the terminal posi-
tion of the urea were prepared by condensation of 6d with
51
3
4
Tracec)
46
AcOH, refl, 24 h
various corresponding amines, after treatment with either
a) Isolated yield, b) 3-fold amount compared to starting material. c) The saturated
product was obtained as a major product.
triphosgene or phenyl chlorocarbonate of 6d. 7c-1, which has
Table 3. Synthesis of Nitro Products (5a—5m)
Nitro products
Entry
Indoles
Quinoxalines
No.
X
Rꢂ
Rꢃ, NO2
Yield (%)a)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
4a
4b
4c
5a
5b
5c
5d
5e
5f
5g
5h
5i
N
N
N
N
N
CH
N
N
N
N
Me
Me
Me
Me
H
Me
Et
n-Pr
6-Cl, 7-NO2
6-F, 7-NO2
6-NO2
7-NO2
7-NO2
66
87
66
87
Quant
84
84
72
Quant
75
71
4d
4d
4d
4b
4b
4b
4b
4b
4b
4b
7-Azaindole
1-Methylindole
7-NO2
1b
1c
1d
1e
1f
6-F, 7-NO2
6-F, 7-NO2
6-F, 7-NO2
6-F, 7-NO2
6-F, 7-NO2
6-F, 7-NO2
6-F, 7-NO2
n-Bu
n-Pent
i-Bu
10
5j
5k
5l
11
12
13
N
N
N
1g
1i
(CH2)2OMe
72
77
5m
(CH2)3Morb)
a) Isolated yield, b) morpholin-1-yl.

258
Vol. 55, No. 2
Table 4. Synthesis of Amino Products (6a—6m)
Amino products
Entry
Nitro compounds
Method
No.
X
Rꢂ
Rꢃ, NH2
Yield (%)a)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
C
A
A
A
B
A
A
A
A
A
A
A
A
6a
6b
6c
6d
6e
6f
6g
6h
6i
N
N
N
N
N
CH
N
N
N
N
Me
Me
Me
Me
t-Boc
Me
Et
n-Pr
n-Bu
n-Pent
i-Bu
6-Cl, 7-NH2
6-F, 7-NH2
6-NH2
7-NH2
7-NH2
81
Quant
98
71
89b)
89
7-NH2
6-F, 7-NH2
6-F, 7-NH2
6-F, 7-NH2
6-F, 7-NH2
6-F, 7-NH2
6-F, 7-NH2
6-F, 7-NH2
62
69
79
93
69
72
77
10
5j
5k
5l
6j
6k
6l
11
12
13
N
N
N
(CH2)2OMe
5m
6m
(CH2)3Morc)
Method A: 10% Pd–C, HCOOH, TEA, DMF, 80 °C, 1—2 h, Method B: 1) t-Boc2O, TEA, DMAP, DMF, 2) 10% Pd–C, HCOOH, TEA, DMF, 80 °C, 1—2 h, Method C: Fe,
conc. HCl, MeOH–DMF, 100 °C, 2 h. a) Isolated yield, b) 2 steps yield, c) morpholin-1-yl.
a) 1) Triphosgene, DIEA, then amine, THF or NMP (N-methyl pyrrolidone), 2) DBU, b) cyclohexylmethylisothiocyanate, TEA, THF, c) phenyl chloroformate, DIEA, then cy-
clohexanemethanol, NMP, d) carboxylic acid chloride, TEA, THF.
Chart 4
a urea group at the 6-position, and 7f-1, which bears an in- Terminal Urea (Table 5) Although 7d-6, which has a urea
dole ring, were prepared from 6c and 6f following the same unit, has already demonstrated a potent inhibitory effect, 7d-
procedure as that used in the preparation of 7d-6. The halo- 1, which was modified to a cyclic urea, and the amides 7d-4
genated compounds (7a-1, 7b-1) at the 6-position on the and 7d-5 were less active than 7d-6. On the other hand, the
quinoxalin-2-one ring and 1-substituted derivatives (7b-2— carbamate 7d-3 retained PDGF inhibitory potency. 7c-1,
7m-1) were also prepared from the corresponding amines with a cyclohexylmethylurea that was substituted at the 6-po-
(6a, 6b, 6g—m) in the same manner. The same procedure sition on quinoxalin-2-ones showed a significant loss of ac-
was used for the corresponding 6e as in the preparation of tivity. Modification to thiourea in 7d-2 decreased not only the
7d-6, and this was followed by de-protection of each tert-boc inhibitory activity (IC50ꢀ0.81 mmol/l in CPA, 2.64 mmol/l in
derivative with TFA, provided the corresponding 7e-1 and APA), but also the selectivity (VEGF 37.0% inhibition,
7e-2.
b-FGF 44.5% inhibition 2 mmol/l). Moreover, although no
We have demonstrated that the synthetic method described remarkable difference was seen in comparing the inhibitory
here can be used to prepare various analogues and derivatives effect of the quinolin-2-one ring of 7n-1 (see Experimental
through a short process involving direct coupling of various section) with the quinoxalin-2-one ring of 7d-6, the
indols with quinoxalin-2-ones, without carrying out special pyrrolo[2,3-b]pyridine ring of 7d-6 increased the inhibitory
activation reactions. Moreover, since it is not necessary to activity more than did the indole ring of 7f-1. These data
carry out this reaction under strict anhydrous conditions or to showed that nitrogen at the 7-position on indole was neces-
perform special purification in the work-up process, the con- sary for the inhibitory activity; on the other hand, nitrogen at
ditions of this reaction make it a very useful method to syn- the 4-position on quinoxalin-2-one was not sufficient for ef-
thesize the basic framework of interest.
fective inhibition. Although conversion of quinoxalin-2-one
to quinolin-2-one did not make any difference in the in-
hibitory activity described above, it is still necessary to retain
Result and Discussion
Structure Activity Relation Study. Effect of Hetero the synthetic availability of nitrogen at the 4-position on
Atom on the Basic Framework and the Position of the quinoxalin-2-one in order to utilize the basic framework in

February 2007
259
a) 1) Triphosgen or phenyl chloroformate, 2) amines, b) TFA, 1,2-dichloroethane.
Chart 5
Table 5. Effect of Hetero Atom on the Basic Framework and the Position of the Terminal Urea
CPA
CPA
APA
Inhibition (%)a)
IC50 (mmol/l)
Compd. Position
R1
H
R2
H
A
B
C
D
PDGF-BB
VEGF
b-FGF
PDGF-BB
PDGFR-b
7d-6
7d-1
7d-2
7c-1
7n-1
7f-1
7
7
7
6
7
7
7
7
7
N
N
N
N
N
N
O
O
S
O
O
O
O
O
O
N
N
N
N
CH
N
N
N
N
N
N
N
N
N
CH
N
N
129.7b)
26.4
130.6
7.8
119.5
61.1
105.7
46.3
18.3b)
ꢄ1.2
37.0
ꢄ10.1
ꢄ14.1
26.1
ꢄ8.8
23.9
ꢄ7.8
7.8b)
ꢄ4.0
44.5
ꢄ3.0
ꢄ2.5
26.8
10.7
39.5
1.5
0.050
—
0.813
—
0.070
0.116
0.167
2.575
0.621
0.030
1.895
2.640
—
0.020
0.744
0.027
—
CH2CH2
H
H
H
H
H
H
H
H
H
H
H
7d-3
7d-4
7d-5
O
CH2
CH2CH2
N
75.2
—
a) Inhibition % 1 mmol/l, b) 2 mmol/l, —: not tested, CPA: PDGF-induced proliferation of human MC in vitro. APA: PDGF receptor auto-phosphorylation of human AoSMC
in vitro. PDGF-BB: platelet-derived growth factor-BB, PDGFR-b: platelet-derived growth factor receptor-b, VEGF: vascular endothelial growth factor, b-FGF: basic-fibroblast
growth factor.
this series.
a six-carbon. Moreover, when we plotted the length of alkyl
Substituent Effect at the Terminal Urea (Table 6) In chain against the common logarithms of 1/IC50, clear para-
order to examine substituent effects at the terminal urea in bolic curves were obtained for both CPA and APA (Fig. 1).
detail, we decided to obtain the SAR for insertion effects of In the case of the cyclopropylmethyl derivative 7d-13, which
methylenes with lengths from C3 to C8 in a straight alkyl has a smaller-sized aliphatic ring compared with 7d-6, the in-
chain on urea, as seen in 7d-7—d-12. Results showed that hibitory activity has disappeared. Also, the cyclopentyl com-
the maximal inhibitory activity (IC50ꢀ0.007 mmol/l) in the pound 7d-14, with a shorter alkyl chain than that of 7d-6,
APA assay was observed for 7d-9, with a five-carbon on the gave a similar result as 7d-13. Although 7d-15, with an aro-
alkyl chain, and the maximal inhibitory activity (IC50ꢀ0.009 matic ring on the urea, showed loss of potency toward PDGF,
mmol/l) in the CPA assay was observed for 7d-10, which had the 6,7-dimethoxy1-1,2,3,4-tetrahydroisoquinoline derivative

260
Vol. 55, No. 2
Table 6. Substituent Effect at the Terminal Urea
CPA
CPA
APA
Inhibition (%)a)
IC50 (mmol/l)
Compd.
R3
PDGF-BB
VEGF
b-FGF
PDGF-BB
PDGFR-b
7d-6
7d-7
7d-8
7d-9
NHCH2c-Hex
NH n-Pr
NH n-Bu
NH n-Pent
NH n-Hex
NH n-Hep
NH n-Oct
129.7b)
24.6b)
83.7
118.2
121.9
112.6
97.1
18.3b)
19.9b)
ꢄ1.4
ꢄ1.4
2.4
ꢄ25.9
3.2
ꢄ9.3
30.0b)
20.7b)
5.1
7.8b)
4.7b)
0
ꢄ5.3
1.8
ꢄ0.6
ꢄ29.2
ꢄ10.4
14.3b)
2.4b)
0.050
—
0.030
0.905
0.017
0.007
0.010
0.052
0.230
—
0.140
0.014
0.009
0.025
0.075
—
—
—
0.013
0.020
0.200
—
7d-10
7d-11
7d-12
7d-13
7d-14
7d-15
7d-16
7d-17
7d-18
7d-19
7d-20
NHc-Pr
NHc-Pent
16.6
24.4b)
32.9b)
115.3
110.7
121.4b)
30.9
—
—
NHPh
Dmiqc)
ꢄ3.3
17.4
0.050
0.010
0.070
1.450
—
NHCH2COOt-Bu
ꢄ36.3
NHMord)
14b)
ꢄ1.1b)
NHCH2(4-Pyr)e)
NH(CH2)3COOH
16.4b)
5.7
5.6b)
43.7
15.6
2.904
a) Inhibition % 1 mmol/l, b) 2 mmol/l, —: not tested, CPA: PDGF-induced proliferation of human MC in vitro. APA: PDGF receptor auto-phosphorylation of human AoSMC
in vitro. PDGF-BB: platelet-derived growth factor-BB, PDGFR-b: platelet-derived growth factor receptor-b, VEGF: vascular endothelial growth factor, b-FGF: basic-fibroblast
growth factor, c) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, d) morpholin-1-yl, e) 4-pyridyl.
Table 7. Effect of Introducing a Fluorine Atom on the Quinoxalin-2-one
Ring
CPA
CPA
IC50 (mmol/l)
APA
Inhibition (%)a)
Compd.
R5
PDGF-BB VEGF
b-FGF
PDGF-BB PDGFR-b
7d-6
7b-1
7a-1
H
F
Cl
129.7b)
89.6
13.9
18.3b)
ꢄ11.5
ꢄ3.1
7.8b)
ꢄ8.6
ꢄ0.6
0.050
0.020
—
0.030
0.009
—
a) Inhibition % 1 mmol/l, b) 2 mmol/l, —: not tested, CPA: PDGF-induced prolifera-
tion of human MC in vitro. APA: PDGF receptor auto-phosphorylation of human
AoSMC in vitro. PDGF-BB: platelet-derived growth factor-BB, PDGFR-b: platelet-de-
rived growth factor receptor-b, VEGF: vascular endothelial growth factor, b-FGF:
basic-fibroblast growth factor.
Fig. 1. Correlation of log 1/IC50 and Length of Alkyl Chain (C3—C8) at
the Terminal Urea (7d-7—d-12)
CPA: PDGF-induced proliferation of human MC in vitro. APA: PDGF receptor auto-
phosphorylation of human AoSMC in vitro. Although the exact value of IC50 for a C3-
alkyl compound 7d-7 in CPA was not calculated, we expect from the data regarding in-
hibition % (42.3% 10 mmol/l) that the IC50 is over 10 mmol/l.
position on the quoinoxalin-2-one ring showed more PDGF
potency (3-fold) in the cellular assay (7b-1: IC50ꢀ0.02
7d-16 (IC50ꢀ0.013 mmol/l in CPA, 0.05 mmol/l in APA), mmol/l in CPA, 0.009 mmol/l in APA), but conversion to a
which has a similar aromatic ring to that of 7d-15, showed chlorine atom at the same position completely blocked the
potent inhibitory activity. Introduction of tert-butyl hydan- inhibitory activity (7a-1). Remarkable difference were ob-
toate on urea led to increased inhibitory activity (7d-17: served in these halogenated derivatives because the chlorine
IC50ꢀ0.02 mmol/l in CPA, 0.01 mmol/l in APA). In the case atom was electrically neutral but sterically bulkier, compared
of polar groups such as carboxyl and pyridyl (7d-18—d-20), with the fluorine atom. Thus, it appeared that the fluorine
the inhibitory activity tend to be somewhat decreased. These atom was a more favorable substituent at this position.
data show that it is desirable for the functional group on urea
to be a substituent that can make a lipophilic interaction at a the Pyrrolo[2,3-b]-pyridine Ring (Table 8) Removal of
certain distance from the urea position. the methyl group at the 1-position on the pyrrolo[2,3-b]pyri-
Effect of Introducing Substituents at the 1-Position on
Introduction Effect of a Fluorine Atom on Quinoxalin- dine led to loss of inhibitory activity for the cyclohexyl com-
2-one Ring (Table 7) Promising improvements in PDGF pound 7e-1 and the n-pentyl compound 7e-2. The n-Pentyl
potency were observed for halogenated derivatives. Com- group of urea (7d-9) and the 6-fluoro atom on the quinox-
pared with 7d-6, the introduction of a fluorine atom at the 6- alin-2-one ring (7b-1) have previously been shown to be ef-

February 2007
261
Table 8. Effect of Introducing Substituents at the 1-Position on the Pyrrolo[2,3-b]pyridine Ring
CPA
CPA
APA
Inhibition (%)a)
IC50 (mmol/l)
Compd.
R3
R4
R5
PDGF-BB
VEGF
b-FGF
PDGF-BB
PDGFR-b
7d-6
7e-1
7d-9
7e-2
7b-2
7g-1
7h-1
7i-1
CH2c-Hex
CH2c-Hex
n-Pent
n-Pent
n-Pent
n-Pent
n-Pent
n-Pent
n-Pent
Me
H
Me
H
Me
Et
n-Pr
n-Bu
n-Pent
i-Bu
H
H
H
H
F
F
F
F
F
F
F
F
129.7b)
50
118.2
99.4
122.3
139.3
117.2
117.9
69
117.3
127.2
145.2
18.3b)
11.6
ꢄ1.4
ꢄ7.7
55.1
ꢄ6.1
14.1
7.2
3.8
6.0
11.9
ꢄ14.0
7.8b)
3.4
ꢄ5.25
0.5
0.5
ꢄ19.9
11.8
ꢄ27.3
ꢄ6.2
ꢄ16.5
ꢄ24.4
ꢄ4.8
0.050
—
0.030
—
0.007
0.120
0.0008
0.0060
0.0080
0.0220
0.2740
0.0210
0.0050
0.0180
0.014
0.171
0.004
0.016
0.023
0.040
—
0.054
0.045
0.111
7j-1
7k-1
7l-1
n-Pent
n-Pent
n-Pent
(CH2)2OMe
7m-1
(CH2)3Morc,d)
a) Inhibition % 1 mmol/l, CPA: PDGF-induced proliferation of human MC in vitro. APA: PDGF receptor auto-phosphorylation of human AoSMC in vitro, PDGF-BB:
platelet-derived growth factor-BB, PDGFR-b: platelet-derived growth factor receptor-b, VEGF: vascular endothelial growth factor, b-FGF: basic-fibroblast growth factor, c) mor-
pholin-1-yl, d) HCl salt.
fective substituents increasing the potency against PDGF, and Table 9. Summary of IC50 Values (mmol/l) for a Series of Compounds
Acting against PDGF and the Selectivity with Respect to Other Growth Fac-
tors
still more potent inhibitory activity against PDGF is obtained
by combining these substituents (IC50ꢀ0.004 mmol/l in CPA,
0.0008 mmol/l in APA) (7b-2). Although simple alkyl chains
APA
at the 1-position on the pyrrolo[2,3-b]pyridine ring have not
affected the inhibitory activity in the CPA (7b-2—j-1), the
SAR study indicated that the inhibitory activity of these
compounds in APA might be decreased along with the length
of the alkyl chain. Introduction of an alkyl chain with a 3-
morpholinopropyl group (7m-1: IC50ꢀ0.111 mmol/l in CPA,
0.018 mmol/l in APA) at the 1-position on the pyrrolo[2,3-
b]pyridine ring led to less inhibitory activity in CPA and
APA than was seen for the simple alkyl group. Introduction
of a methoxyethyl group, compared with a simple alkyl
group, retained the potency in both the CPA and APA (7l-1:
IC50ꢀ0.045 mmol/l in CPA, 0.005 mmol/l in APA).
CPA
PDGF-BB
PDGFR-b KDR
EGFR
c-Met
HGF
IGF-IR
IGF-I
Compd.
PDGF
VEGF
EGF
7d-6
7d-9
7b-1
7b-2
7l-1
0.050
0.014
0.020
0.004
0.045
0.111
0.0300
0.0070
0.0090
0.0008
0.0050
0.0180
ꢁ10
ꢁ10
0.100
0.008
0.070
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
ꢁ10
7m-1
CPA: PDGF-induced proliferation of human MC in vitro. APA: PDGF receptor auto-
phosphorylation of human AoSMC in vitro. PDGF-BB: platelet-derived growth factor-
BB, PDGF: platelet-derived growth factor, VEGF: vascular endothelial growth factor,
EGF: epidermal growth factor, HGF: hepatocyte growth factor, IGF-I: Type 1 insulin-
like growth factor, PDGFR-b: platelet-derived growth factor receptor-b, KDR: VEGF
receptor 2, EGFR: epidermal growth factor receptor, c-Met: hepatocyte growth factor
receptor, IGF-IR: Type 1 insulin-like growth factor receptor.
Summary of IC50 Values for a Series of Compounds
Tested against PDGF and Their Selectivity to the Other
Growth Factors (Table 9) Finally, a summary of the IC50
values for a series of compounds tested against PDGF and
other growth factors is given in Table 7. 7d-6, 7d-9 and 7m-1 7b-2 in particular might be a lead compound for a dual
not only potently inhibited PDGF-induced cell proliferation PDGF/VEGF inhibitor20) that could be further improved by
and auto-phosphorylation, but also showed selectivity for optimizing the features affecting potency against both PDGF
PDGF when tested against other growth factors. In particu- and VEGF. In addition to the studies described herein, ho-
lar, 7d-9 showed very good PDGF potency (IC50ꢀ0.014 mology modeling of PDGF-b plus docking studies of the ki-
mmol/l in CPA, 0.007 mmol/l in APA) with strong selectivity nase domain have been completed and the results of these
for PDGF over the other growth factors (the IC50 values studies will be reported soon.
against KDR, EGFR, c-Met and IGF-IR/IC50 against PDGFR
were each ꢁ1000). Taking into consideration the improved Conclusions
water solubility in the successful optimization of derivatives
During our efforts to improve the synthesis of derivatives,
in this series, 7l-1 and 7m-1, which have the water-soluble we discovered that TFA-catalyzed coupling of 7-azaindoles
groups 3-morpholinopropyl and methoxyethyl, might be es- with quinoxalin-2-ones proceeded efficiently under mild oxi-
pecially promising candidates as PDGF inhibitors. Although dation conditions with MnO2 in situ (Tables 2, 3), and we
it appeared that fluorinated derivatives (7b-1, 7b-2) were therefore applied these conditions and prepared a series of
promising candidates as PDGF inhibitors deserving further derivatives (Charts 4, 5). Moreover, as a result of evaluating
optimization, it was revealed that they had not only strong the substituent effect on the pyrrolo[2,3-b]pyridine ring in an
PDGF potency, but they also inhibited VEGF. Nonetheless, SAR study, we found that the nitrogen at the 7-position on

262
Vol. 55, No. 2
matography on silica-gel (hexane/EtOAc 4/1) to give the title compound as a
yellow solid (5.31 g): 45% Yield; 1H-NMR (DMSO-d6) d: 1.33 (3H, t,
Jꢀ7.1 Hz), 4.06 (2H, d, Jꢀ5.3 Hz), 4.31 (2H, q, Jꢀ7.2 Hz), 6.66—6.72 (2H,
m), 8.16 (1H, d, Jꢀ9.8 Hz), 8.46 (1H, br s).
the pyrrolo[2,3-b]pyridine ring markedly influenced the
PDGF receptor tyrosine kinase inhibition (Table 5, 7d-6 vs.
7f-1). Next, we showed that the 7-position on the quinoxalin-
2-one ring would be the optimal substitution position (Table
Ethyl 2-(4-Fluoro-2-nitrophenylamino)acetate, 2b Replacing 4-
5, 7c-1 vs. 7d-6). Furthermore, as a result of scrutinizing the chloro-2-fluoronitrobenzene with 2,4-difluoronitrobenzene and following the
same procedure as in the preparation of 2a gave 2b as a yellow solid: 44%.
substituent effect on urea, it was found that inhibitory activ-
ity was correlated with the length of a straight alkyl chain
substituent (Table 6, 7d-7—d-12), and we found that the
Yield; 1H-NMR (DMSO-d6) d: 1.33 (3H, t, Jꢀ7.2 Hz), 4.04 (2H, d,
Jꢀ5.3 Hz), 4.30 (2H, q, Jꢀ7.2 Hz), 6.34 (1H, dd, Jꢀ2.5, 11.1 Hz), 6.44 (1H,
ddd, Jꢀ2.5, 7.2, 9.4 Hz), 8.26 (1H, dd, Jꢀ6.0, 9.4 Hz), 8.55 (1H, br s).
PDGF potency was reinforced by nonpolar substituents
(Table 6, 7d-18—d-20). Furthermore, using the insight
gained by evaluating the substituent effect on the quinoxalin-
2-one ring, we showed clearly that potent inhibitory activity
against the PDGF and VEGF receptors resulted from intro-
duction of a fluorine atom at the 6-position (Table 9, 7b-1,
7b-2, 7l-1). Finally, we demonstrated that compound 7d-9,
which has a potent (IC50ꢀ0.014 mmol/l in CPA, 0.007 mmol/l
in APA) and selective (IC50 against KDR, EGFR, c-Met and
IGF-IR/IC50 against PDGFR were each ꢁ1000) inhibitory
activity (Table 9), as well as compound 7b-2, showed potent
inhibitory activity not only toward PDGF-induced signaling
but also toward VEGF (PDGFR: IC50ꢀ0.004 mmol/l in CPA,
0.0008 mmol/l in APA, KDR: IC50ꢀ0.008 mmol/l in APA).
6-Chloroquinoxalin-2(1H)-one, 3a A mixture of 10% Pd–C wet (0.9 g)
and 2a (5.31 g, 21.0 mmol) in EtOH (68 ml) was stirred overnight at room
temperature under H2. After the filtration to remove the catalyst with celite,
the filtrate was concentrated in vacuo. To a solution of this yellow solid in
2 mol/l NaOH aq. (68 ml) in MeOH (34 ml) was added 3% H2O2 aq. (68 ml),
and the reaction mixture was stirred at 100 °C for 1.5 h. The resulting reac-
tion mixture was acidified with acetic acid (AcOH), and water was added to
the mixture. Then the precipitated product was filtered to give the title com-
1
pound as a yellow solid (3.94 g): Quantitative. Yield; H-NMR (DMSO-d6)
d: 7.30 (1H, d, Jꢀ8.7 Hz), 7.51 (1H, dd, Jꢀ2.4, 8.7 Hz), 7.75 (1H, d,
Jꢀ2.4 Hz), 8.09 (1H, s).
6-Fluoroquinoxalin-2(1H)-one, 3b Replacing 2a with 2b and follow-
ing the same procedure as in the preparation of 3a gave the title compound
as a charcoal solid: 76%. Yield; 1H-NMR (DMSO-d6) d: 7.33 (1H, dd,
Jꢀ5.2, 9.0 Hz), 7.48 (1H, ddd, Jꢀ2.9, 9.0, 9.2 Hz), 7.63 (1H, dd, Jꢀ3.8,
9.2 Hz), 12.46 (1H, br s).
6-Chloro-7-nitroquinoxalin-2(1H)-one, 4a Replacing quinoxalin-
2(1H)-one with 3a and following the same procedure as in the preparation
of 4d gave the title compound as a yellow solid: 27% Yield (4 step); 1H-
Experimental
The 1H-NMR spectra were measured with a JEOL EX-200 (200 MHz) NMR (DMSO-d6) d: 7.89 (1H, s), 8.19 (1H, s), 8.36 (1H, s), 12.66 (1H,
spectrometer with TMS as the internal reference, and chemical shifts are ex- br s).
pressed in d (ppm). The IR spectrum was measured with a JASCO FT/IR-
6-Fluoro-7-nitroquinoxalin-2(1H)-one, 4b Replacing quinoxalin-
430 spectrometer. The HR-ESI-MS was taken on a MICROMASS Q-Tof 2(1H)-one with 3b and following the same procedure as in the preparation
micro.
General Procedure for the Synthesis of 1a, 1b, 1c, 1d, 1e, 1f, 1g. 1-
Methyl-1H-pyrrolo[2,3-b]pyridine, 1a To solution of 7-azaindole
(500 mg, 4.23 mmol) in DMF (5.0 ml) was added NaH (2.2 g, 55.0 mmol) at
of 4d gave the title compound as a white solid: 65% Yield; 1H-NMR
(DMSO-d6) d: 6.83 (1H, d, Jꢀ13 Hz), 7.64 (1H, d, Jꢀ7.6 Hz), 8.87 (1H, d,
Jꢀ3.2 Hz), 11.01 (1H, br s).
a
6-Nitroquinoxalin-2(1H)-one, 4c To a solution of quinoxalin-2(1H)-
0 °C under argon, and the reaction mixture was stirred at room temperature one (2.2 g, 15.0 mmol) in conc. H2SO4 (25 ml) was added potassium nitrate
for 0.5 h. Methyl iodide (0.8 ml, 12.7 mmol) was added to the stirring reac-
(1.5 g, 15.0 mmol) quickly at 0 °C, and the reaction mixture was stirred at
tion mixture, and the mixture was allowed to stir at room temperature for room temperature for 0.5 h. The reaction mixture was poured into crushed
15 h. Water was added to the resulting reaction mixture, and the water phase ice (500 ml), and then the precipitated product was filtered and washed with
1
was extracted with Et2O. The combined organic phase was dried over water to give the title compound as a white solid (2.53 g): 88%.Yield; H-
Na2SO4. Then the organic solvent was removed in vacuo. The evaporated NMR (CDCl3) d: 7.45 (1H, d, Jꢀ9.1 Hz), 8.33 (1H, s), 8.39 (1H, dd, Jꢀ2.5,
residue was purified by flash column chromatography on silica-gel 9.1 Hz,), 8.55 (1H, d, Jꢀ2.5 Hz), 12.92 (1H, br s). ESI-MS m/z: ꢅESI 192
(hexane/AcOEt 3/1) to give the title compound as a yellow oil (544 mg): (Mꢅ1), ꢄESI 190 (Mꢄ1).
1
97% Yield; H-NMR (CDCl3) d: 1.48 (3H, s), 6.45 (1H, d, Jꢀ3.5 Hz), 7.05
(1H, dd, Jꢀ4.7, 7.8 Hz), 7.24 (1H, d, Jꢀ3.5 Hz), 7.90 (1H, dd, Jꢀ1.6,
7.8 Hz), 8.32 (1H, dd, Jꢀ1.6, 4.7 Hz).
7-Nitroquinoxalin-2(1H)-one, 4d To a suspension of quinoxalin-
2(1H)-one (25 g, 17.1 mmol) in AcOH (500 ml) was added a solution of
fuming nitric acid (8.6 ml) in AcOH (50 ml) dropwise at room temperature,
1-(3-Chloropropyl)-1H-pyrrolo[2,3-b]pyridine, 1h Replacing methyl and the reaction mixture was stirred at room temperature for 18 h. The reac-
iodide with 1-bromo-2-chloroethane and following the same procedure as in tion mixture was poured into crushed ice (50 ml), and then the precipitated
the preparation of 1a gave the title compound as a colorless oil: 81.4%
Yield; H-NMR (CDCl3) d: 3.92 (2H, t, Jꢀ6.1 Hz), 4.62 (2H, t, Jꢀ6.1 Hz),
6.47 (1H, d, Jꢀ3.5 Hz), 7.08 (1H, dd, Jꢀ4.7, 7.8 Hz), 7.29 (1H, d, NMR (CDCl3) d: 2.52 (3H, s), 7.98—8.11 (3H, m), 8.36 (1H, s), 12.72 (1H,
product was filtered and washed with water and small amount of AcOEt to
1
give the title compound as a pale yellow solid (24.4 g): 74%. Yield; 1H-
Jꢀ3.5 Hz), 7.92 (1H, dd, Jꢀ1.5, 7.8 Hz), 8.30 (1H, dd, Jꢀ1.5, 4.7 Hz).
1-(3-Morpholinopropyl)-1H-pyrrolo[2,3-b]pyridine, 1i To a solution
of 1h (633 mg, 3.52 mmol) in DMF (6.0 ml) was added morpholine
br s).
General Procedure for the Synthesis of 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h,
5i, 5j, 5k, 5l, 5m, 3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-nitro-
(1.23 ml), and the reaction mixture was stirred at 110 °C for 4.5 h. Water was quinoxalin-2(1H)-one, 5d To a mixture of 1a (132 mg, 1.0 mmol) and 4d
added to the resulting reaction mixture, and the water phase was extracted (191 mg, 1.0 mmol) in DMF (10 ml) was added TFA (1.0 ml) at room tem-
with AcOEt. The combined organic phase was dried over Na2SO4. Then the
perature, and the reaction mixture was stirred at 80 °C for 1 h. Then MnO2
organic solvent was removed in vacuo. The evaporated residue was purified (300 mg) was added to the stirring reaction mixture, and the mixture was
by flash column chromatography on silica-gel (AcOEt→AcOEt/MeOH stirred at 80 °C for 1 h. After filtration of the precipitate with celite, the fil-
10/1) to give the title compound as a yellow oil: Quantitative Yield; 1H- trate was concentrated in vacuo. The evaporated residue was triturated in
NMR (CDCl3) d: 2.06 (2H, m), 2.33 (2H, t, Jꢀ7.2 Hz), 2.38—2.42 (4H, m),
3.67—3.72 (4H, m), 4.37 (2H, t, Jꢀ6.8 Hz), 6.43 (1H, d, Jꢀ3.5 Hz), 7.04
(1H, dd, Jꢀ4.7, 7.9 Hz), 7.23 (1H, d, Jꢀ3.5 Hz), 7.89 (1H, dd, Jꢀ1.6,
7.9 Hz), 8.31 (1H, dd, Jꢀ1.6, 4.7 Hz).
Ethyl 2-(4-Chloro-2-nitrophenylamino)acetate, 2a To a mixture of
K2CO3 (4.1 g, 30.0 mmol) and ethyl 2-aminoacetate hydrochloride (7.06 g,
MeOH/Et2O, and the precipitated product was filtrated to give the title com-
pound as a yellow solid (280.3 mg): 87.3% Yield; H-NMR (DMSO-d6) d:
3.95 (3H, s), 7.36 (1H, dd, Jꢀ4.7, 7.8 Hz), 7.99—8.15 (3H, m), 8.42 (1H,
dd, Jꢀ1.7, 4.7 Hz), 9.10 (1H, dd, Jꢀ1.7, 7.8 Hz), 9.14 (1H, s), 12.80 (1H, s).
ESI-MS m/z: ꢅESI 322 (Mꢅ1), ꢄESI 320 (Mꢅ1).
1
Alternative Procedure for the Synthesis of 5d (Table 2, Entry 2) To a
51.0 mmol) in DMF (15 ml) and water (1.0 ml) was added 4-chloro-2-fluo- mixture of 1a (350 mg, 2.64 mmol) and 4d (506 mg, 2.64 mmol) in DMF
ronitrobenzene (8.05 g, 46.0 mmol) at 80 °C, and the reaction mixture was
stirred at 80 °C for 1 h. Water was added to the resulting reaction mixture,
(5.0 ml) was added TFA (0.45 ml), and the reaction mixture was stirred at
80 °C for 15 min. Then 3% H2O2 aq. (10 ml) and 2 mol/l NaOH aq. (10 ml)
and the water phase was extracted with AcOEt. The combined organic phase were added to the stirring reaction mixture, and the mixture was stirred at
was washed with brine and dried over MgSO4. The organic solvent was re- 80 °C for 1 h. The resulting reaction mixture was acidified with AcOH, and
moved in vacuo. The evaporated residue was purified by flash column chro- water was added to the mixture. Then the precipitated product was filtered to

February 2007
263
give the title compound as a charcoal solid (436 mg): 51% Yield.
(1H, m), 8.38 (1H, dd), 8.95 (1H, s), 9.10 (1H, dd), 12.38 (1H, s). IR (KBr)
7-Amino-6-chloro-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinox- cmꢄ1: 2920, 2849, 1694, 1661. ESI-MS m/z: ꢅESI 457 (Mꢅ1), ꢄESI 455
alin-2(1H)-one, 6a (Table 4, Method C) To a mixture of 5a (50 mg,
0.14 mmol) conc. HCl (0.5 ml) and MeOH (0.5 ml) in DMF was added pow-
(Mꢄ1). HR-ESI-MS m/z: 457.2331 (Calcd for C26H29N6O2: 457.2352).
7-[3-(Cyclohexylmethyl)thioureido]-3-{1-methyl-1H-pyrrolo[2,3-
der of iron (124 mg) at room temperature, and the reaction mixture was b]pyridin-3-yl}quinoxalin-2(1H)-one, 7d-2 To
a suspension of 6d
stirred at 100 °C for 2 h. The resulting reaction mixture was filtered with (289 mg, 1.0 mmol) and DIEA (1 drop) in 1-methyl pyrrolidone (5.0 ml) was
celite, and the filtrate was concentrated in vacuo. The precipitate was added cyclohexylmethylisocyanate (168 mg, 1.08 mmol) at room tempera-
washed with MeOH to give title compound as a yellow solid (37 mg): 81% ture. The reaction mixture was stirred at room temperature for 18 h. Cyclo-
Yield; 1H-NMR (DMSO-d6) d: 3.91 (3H, s), 6.64 (1H, s), 7.27 (1H, dd, hexylmethylisocyanate (620 mg, 4.0 mmol) and DIEA (903 mg, 7.0 mmol)
Jꢀ4.7, 7.8 Hz), 7.78 (1H, s), 8.37 (1H, dd, Jꢀ1.5, 4.7 Hz), 8.86 (1H, s), 9.08 were added to the reaction mixture at room temperature. The reaction mix-
(1H, dd, Jꢀ1.5, 7.8 Hz), 12.27 (1H, br s). ESI-MS m/z: ꢅESI 327 (Mꢅ1), ture was stirred at 100 °C for 24 h. To the resulting reaction mixture was
ꢄESI 325 (Mꢄ1).
General Procedure for the Synthesis of 6b, 6c, 6d, 6f, 6g, 6h, 6i, 6i, 6j,
6k, 6l, 6m, 7-Amino-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinox- (5H, m), 1.50—1.85 (6H, m), 3.93 (3H, s), 7.31 (1H, dd, Jꢀ4.7, 7.9 Hz),
added MeOH, and the precipitate was filtered to give the title compound as a
charcoal solid (147 mg): 33% Yield; 1H-NMR (DMSO-d6) d: 0.78—1.40
alin-2(1H)-one, 6d (Method A) To a mixture of 5d (436 mg, 1.35 mmol)
7.38—7.50 (1H, m), 7.61 (1H, d, Jꢀ2.3 Hz), 7.80 (1H, d, Jꢀ8.8 Hz), 7.86—
and 10% Pd–C wet (85 mg) in MeOH (50 ml) were added TEA (19 ml) and 8.06 (1H, m), 8.39 (1H, dd, Jꢀ1.7, 4.7 Hz), 8.99 (1H, s), 9.10 (1H, dd,
HCOOH (2.4 ml) at room temperature, and then the reaction mixture was re- Jꢀ1.7, 7.9 Hz), 9.78 (1H, br s), 12.50 (1H, s). IR (KBr) cmꢄ1: 3242, 2921,
fluxed for 1.5 h. The catalyst was removed by filtration with celite, and the 1662, 1538. ESI-MS m/z: ꢅESI 447 (Mꢅ1), ꢄESI 445 (Mꢄ1). HR-ESI-
filtrate was concentrated in vacuo. Water was added to the residue, and the MS m/z: 447.1943 (Calcd for C24H27N6OS: 447.1967).
precipitated product was filtered and washed with a small amount of AcOEt
Cyclohexylmethyl {3,4-Dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-
to give the title compound as a yellow solid (281 mg): 71% Yield; 1H-NMR 3-yl}-3-oxoquinoxalin-6-yl}carbamate, 7d-3 Replacing aminomethylcy-
(DMSO-d6) d: 3.80 (3H, s), 5.86 (2H, s), 6.39 (1H, d, Jꢀ2.3 Hz), 6.59 (1H,
dd, Jꢀ2.3, 8.7 Hz), 7.25 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.53 (1H, d, Jꢀ8.7 Hz),
8.35 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.82 (1H, s), 9.04 (1H, dd, Jꢀ1.6, 7.9 Hz),
12.14 (1H, br s). ESI-MS m/z: ꢅESI 292 (Mꢅ1), ꢄESI 290 (Mꢄ1).
clohexane with cyclohexanemethanol and following the same procedure as
in the preparation of 7d-6 gave the title compound as a pale yellow solid:
81% Yield; 1H-NMR (DMSO-d6) d: 0.98—1.91 (11H, m), 3.93 (3H, s), 3.97
(2H, d), 7.28—7.35 (2H, m), 7.70 (1H, d, Jꢀ2.1 Hz), 7.78 (1H, d,
tert-Butyl 3-(6-Amino-3,4-dihydro-3-oxoquinoxalin-2-yl)-1H-pyrrolo- Jꢀ8.7 Hz), 8.39 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.96 (1H, s), 9.10 (1H, dd, Jꢀ1.6,
[2,3-b]pyridine-1-carboxylate, 6e (Method B) To
a
mixture of 5e 7.8 Hz), 10.25 (1H, s), 12.47 (1H, s). IR (KBr) cmꢄ1: 3422, 2925, 1720,
(600 mg, 1.95 mmol) and TEA (0.82 ml, 5.85 mmol) and dimethylaminopy-
ridine (DMAP) (120 mg) in DMF (20 ml) was added tert-Boc2O (1.27 g,
5.85 mmol) at room temperature, and then the reaction mixture was stirred at
60 °C for 1 h. Water was added to the resulting reaction mixture, and the
1667, 1546, 1233. ESI-MS m/z: ꢅESI 432 (Mꢅ1), ꢄESI 430 (Mꢄ1). HR-
ESI-MS m/z: 432.2018 (Calcd for C24H26N5O3: 432.2036).
2-Cyclohexyl-N-{3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl}-3-oxoquinoxalin-6-yl}acetamide, 7d-4. To a solution of cyclohexyl-
water phase was extracted with CHCl3. The combined organic phase was acetic acid (31 mg, 0.22 mmol) and DMF (1 drop) in CH2Cl2 (5.0 ml) was
washed with Brine and dried over Na2SO4. The organic solvent was removed added thionyl chloride (125 mg, 1 mmol), and the mixture was refluxed for
in vacuo, and the residue was triturated in Et2O. The precipitate was filtered 0.5 h. After evaporation of the organic solvent, a solution of 6d (58 mg,
to give tert-butyl 3-(1,2-dihydro-7-nitro-2-oxoquinoxalin-3-yl)-1H-pyrrolo- 0.2 mmol) and TEA (20 mg, 0.2 mmol) in DMF (4.0 ml) was added to the
[2,3-b]pyridin-1-carboxylate as a yellow solid (588 mg): 74% Yield; 1H- stirring residue. The reaction mixture was sonicated for 10 min at room tem-
NMR (DMSO-d6) d: 1.67 (9H, s), 7.48 (1H, dd, Jꢀ4.7, 8.0 Hz), 8.14—8.16 perature. Diluted sodium bicarbonate aq was added to the resulting reaction
(3H, m), 8.53 (1H, dd, Jꢀ1.8, 4.7 Hz), 9.20 (1H, dd, Jꢀ1.8, 8.0 Hz), 9.35
mixture, and the precipitated crude product was collected by filtration. The
(1H, s). ESI-MS m/z: ꢅESI 408 (Mꢅ1), ꢄESI 406 (Mꢄ1). Replacing 5d crude product was purified by flash column chromatography on silica-gel
with tert-butyl 3-(1,2-dihydro-7-nitro-2-oxoquinoxalin-3-yl)-1H-pyrrolo- (hexane/AcOEt 1/1→1/3) to give the title compound as a pale yellow solid
[2,3-b]pyridine-1-carboxylate and following the same procedure in DMF as (15 mg): 18% Yield; 1H-NMR (DMSO-d6) d: 0.82—1.40 (5H, m), 1.55—
in the preparation of 6d gave the title compound as a yellow solid: 65% 1.99 (6H, m), 2.24 (2H, d, Jꢀ7.1 Hz), 3.93 (3H, s), 7.31 (1H, dd, Jꢀ4.8,
Yield; 1H-NMR (DMSO-d6) d: 1.65 (9H, s), 6.08 (2H, s), 6.41 (1H, d, 8.1 Hz), 7.43 (1H, dd, Jꢀ2.1, 8.7 Hz), 7.79 (1H, d, Jꢀ8.7 Hz), 7.86 (1H, d,
Jꢀ2.4 Hz), 6.64 (1H, dd, Jꢀ2.2, 8.7 Hz), 7.41 (1H, dd, Jꢀ4.7, 8.0 Hz), 7.59
Jꢀ2.1 Hz), 8.39 (1H, dd, Jꢀ1.5, 4.8 Hz), 8.97 (1H, s), 9.10 (1H, dd, Jꢀ1.5,
(1H, d, Jꢀ8.7 Hz), 8.46 (1H, dd, Jꢀ1.7, 4.7 Hz), 9.07 (1H, s), 9.16 (1H, dd, 8.1 Hz), 10.19 (1H, s), 12.46 (1H, s). IR (KBr) cmꢄ1: 3264, 2918, 2850,
Jꢀ1.7, 8.0 Hz), 12.23 (1H, s). ESI-MS m/z: ꢅESI 378 (Mꢅ1), ꢄESI 376
(Mꢄ1).
1666, 1536. ESI-MS m/z: ꢅESI 416 (Mꢅ1), ꢄESI 414 (Mꢄ1). HR-ESI-
MS m/z: 416.2074 (Calcd for C24H26N5O2: 416.2087).
7-[3-(Cyclohexylmethyl)-2-oxoimidazolidin-1-yl]-3-{1-methyl-1H-
3-Cyclohexyl-N-{3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-
pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-2(1H)-one, 7d-1 To a mixture of yl}-3-oxoquinoxalin-6-yl}propanamide, 7d-5 Replacing cyclohexylacetic
cyclohexane carboxyaldehyde (3.6 ml, 30 mmol) and 2-chloroethylamine acid with 3-cyclohexylpropanoic acid and following the same procedure as
(1.16 g, 10 mmol) in EtOH (12 ml) was added 10% Pd–C (100 mg), and then
in the preparation of 7d-4 gave the title compound as a pale yellow solid:
the mixture was stirred at room temperature for 2 h under H2. After remov- 8% Yield; 1H-NMR (DMSO-d6) d: 0.78—1.03 (2H, m, 2H), 1.05—1.35
ing the catalyst by filtration with celite, the filtrate was crystallized from (4H, m), 1.44—1.83 (7H, m), 2.37 (2H, d, Jꢀ7.6 Hz), 3.93 (3H, s), 7.31
Et2O to give a N-(2-chloroethyl)-Nꢂ-(cyclohexylmethyl)amine hydrochloride (1H, dd, Jꢀ4.7, 7.9 Hz), 7.43 (1H, dd, Jꢀ2.3, 8.8 Hz), 7.80 (1H, d,
1
as a white solid (357 mg): 17% Yield; H-NMR (DMSO-d6) d: 0.85—1.24 Jꢀ8.8 Hz), 7.86 (1H, d, Jꢀ2.3 Hz), 8.39 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.97 (1H,
(5H, m), 1.65—1.80 (6H, m), 2.79 (2H, d), 3.27 (2H, t, Jꢀ6.5 Hz), 3.94
(2H, t, Jꢀ6.5 Hz), 9.02 (2H, br s). To a suspension of 6d (100 mg,
0.346 mmol) and DIEA (0.2 ml, 1.04 mmol) in THF (5.0 ml) was added
triphosgene (102 mg, 0.346 mmol) at room temperature, and the mixture was
s), 9.10 (1H, dd, Jꢀ1.6, 7.9 Hz), 10.21 (1H, s), 12.48 (1H, s). ESI-MS m/z:
ꢅESI 430 (Mꢅ1), ꢄESI 428 (Mꢄ1).
7-[3-(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-yl}quinoxalin-2(1H)-one, 7d-6 To a suspension of 6d (145 mg,
stirred at 60 °C for 3 h. N-(2-chloroethyl)-Nꢂ-(cyclohexylmethyl)amine hy- 0.5 mmol) and TEA (0.1 ml) in THF (5.0 ml) was added triphosgene
drochloride (220 mg, 1.04 mmol) and diisopropylethylamine (DIEA) (0.3 ml, (163 mg, 0.55 mmol) at room temperature, and the mixture was stirred at
1.72 mmol) were added to the mixture, and the reaction mixture was stirred
60 °C for 6 h. Aminomethylcyclohexane (0.3 ml) was added to the mixture,
at room temperature for 1 h. Water was added to the resulting reaction mix- and the reaction mixture was stirred at 60 °C for 18 h. Aminomethylcyclo-
ture, and the water phase was extracted with CHCl3. The combined organic hexane (0.3 ml) was added to the mixture again, and the reaction mixture
phase was dried over Na2SO4. The organic solvent was removed in vacuo.
Then to a mixture of the residue in THF (5.0 ml) was added DBU (0.5 ml) at
was stirred at 80 °C for 1 h. Water was added to the resulting reaction mix-
ture, and the precipitate was filtered to give the title compound as a pale yel-
1
1
room temperature, and the reaction mixture was refluxed for 1.5 h. Water low solid (133 mg); 61% Yield; H-NMR (DMSO-d6) d: H-NMR (DMSO-
was added to the resulting reaction mixture, and the water phase was ex- d6) d: 0.84—1.86 (11H, m), 2.97 (2H, t, Jꢀ6.1 Hz), 3.92 (3H, s), 6.27 (1H,
tracted with AcOEt. The combined organic phase was dried over Na2SO4. t), 7.21—7.33 (2H, m), 7.59 (1H, d, Jꢀ2.2 Hz), 7.72 (1H, d, Jꢀ8.8 Hz), 8.38
The organic solvent was removed in vacuo. The residue was purified by flash (1H, dd, Jꢀ1.6, 4.7 Hz), 8.82 (1H, s), 8.93 (1H, s), 9.08 (1H, dd, Jꢀ1.6,
column chromatography on silica-gel (CH2Cl2/Acetone 4/1→CH2Cl2/MeOH 7.9 Hz), 11.98 (1H, br s). IR (KBr) cmꢄ1: 3306, 2920, 1662, 1538. ESI-MS
14/1) to give title compound as a yellow solid (28 mg): 17% Yield; 1H-NMR m/z: ꢅESI 431 (Mꢅ1), ꢄESI 429 (Mꢄ1). HR-ESI-MS m/z: 431.2178
(DMSO-d6) d: 0.90—1.70 (11H, m), 3.06 (2H, d), 3.42—3.54 (2H, m), (Calcd for C24H27N6O2: 431.2195).
3.84—3.89 (2H, m), 3.93 (3H, s), 7.30 (1H, dd), 7.54—7.59 (2H, m), 7.81
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-propylureido)-

264
Vol. 55, No. 2
quinoxalin-2(1H)-one, 7d-7 Replacing aminomethylcyclohexane with n-
propylamine and following the same procedure as in the preparation of 7d-6
gave the title compound as a charcoal solid: 98% Yield; H-NMR (DMSO-
Jꢀ9.0 Hz), 8.38 (1H, dd, Jꢀ1.5, 4.6 Hz), 8.81 (1H, s), 8.93 (1H, s), 9.08
(1H, dd, Jꢀ1.5, 7.9 Hz), 12.37 (1H, s). IR (KBr) cmꢄ1: 3315, 2926, 1663,
1539. ESI-MS m/z: ꢅESI 447 (Mꢅ1), ꢄESI 445 (Mꢄ1). HR-ESI-MS m/z:
447.2489 (Calcd for C25H31N6O2: 447.2508).
1
d6) d: 0.89 (3H, t, Jꢀ6.6 Hz), 1.46 (2H, qui, Jꢀ6.6 Hz), 3.09 (2H, td, Jꢀ6.6,
5.6 Hz), 3.93 (3H, s), 6.77 (1H, d, Jꢀ5.6 Hz), 7.25—7.31 (2H, m), 7.61—
7.72 (2H, m), 8.36 (1H, dd), 8.98 (1H, s), 9.12 (1H, dd), 9.25 (1H, s). IR
(KBr) cmꢄ1: 3309, 2960, 1663, 1538. ESI-MS m/z: ꢅESI 377 (Mꢅ1), ꢄESI
375 (Mꢄ1). HR-ESI-MS m/z: 377.1725 (Calcd for C20H21N6O2: 377.1726).
7-(3-Butylureido)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinox-
alin-2(1H)-one, 7d-8 To a suspension of 6d (5.77 g, 20 mmol) and DIEA
(5.6 ml, 32 mmol) in 1-methyl pyrrolidone (50 ml) was added phenyl chloro-
formate (3.9 g, 25 mmol) at room temperature, and the mixture was stirred at
room temperature for 21 h. To the resulting reaction mixture was added
MeOH (200 ml), and the deposited precipitate was filtered to give phenyl
{3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-
7-[3-(Cyclopropylmetyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-yl}quinoxalin-2(1H)-one, 7d-13 Replacing aminomethylcyclo-
hexane with cyclopropylmethylamine and following the same procedure as
in the preparation of 7d-6 gave the title compound as a charcoal solid: 84%
Yield; 1H-NMR (DMSO-d6) d: 0.13—0.27 (2H, m), 0.36—0.52 (2H, m),
0.85—1.11 (1H, m), 2.92—3.10 (2H, m), 3.92 (3H, s), 6.29 (1H, t,
Jꢀ5.9 Hz), 7.24 (1H, dd, Jꢀ2.1, 8.6 Hz), 7.30 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.61
(1H, d, Jꢀ2.1 Hz), 7.73 (1H, d, Jꢀ8.6 Hz), 8.38 (1H, dd, Jꢀ1.6, 4.7 Hz),
8.86 (1H, s), 8.93 (1H, s), 9.08 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.36 (1H, s). IR
(KBr) cmꢄ1: 3314, 1662, 1539. ESI-MS m/z: ꢅESI 389 (Mꢅ1), ꢄESI 387
(Mꢄ1). HR-ESI-MS m/z: 389.1718 (Calcd for C21H21N6O2: 389.1726).
7-(3-Cyclopenylureido)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-
quinoxalin-2(1H)-one, 7d-14 Replacing aminomethylcyclohexane with
cyclopentylamine and following the same procedure as in the preparation of
7d-6 gave the title compound as a yellow solid: 48% Yield; 1H-NMR
(DMSO-d6) d: 1.35—1.91 (8H, m), 3.31 (3H, s), 3.32 (1H, m), 6.27 (1H, d),
7.22 (1H, dd, Jꢀ2.1, 8.7 Hz), 7.29 (1H, dd, Jꢀ4.6, 7.9 Hz), 7.59 (1H, d,
Jꢀ2.1 Hz), 7.72 (1H, d, Jꢀ8.7 Hz), 8.37 (1H, dd, Jꢀ1.6, 4.6 Hz), 8.71 (1H,
s), 8.93 (1H, s), 9.07 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.35 (1H, br s). IR (KBr)
cmꢄ1: 3302, 2954, 1662, 1539. ESI-MS m/z: ꢅESI 403 (Mꢅ1), ꢄESI 401
(Mꢄ1). HR-ESI-MS m/z: 403.1873 (Calcd for C22H23N6O2: 403.1882).
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-phenylureido)-
quinoxalin-2(1H)-one, 7d-15 Replacing aminomethylcyclohexane with
cyclopentylamine and following the same procedure as in the preparation of
7d-6 gave the title compound as a charcoal solid: 56% Yield; 1H-NMR
(DMSO-d6) d: 3.93 (3H, s), 6.99 (1H, t), 7.31 (4H, m), 7.49 (2H, m), 7.68
(1H, d), 7.78 (1H, d), 8.38 (1H, dd), 8.82 (1H, s), 8.95 (1H, s), 9.10 (1H,
dd), 9.18 (1H, s), 12.42 (1H, br s). IR (KBr) cmꢄ1: 3301, 3137, 3056, 2948,
1659, 1539. ESI-MS m/z: ꢅESI 411 (Mꢅ1), ꢄESI 409 (Mꢄ1). HR-ESI-
MS m/z: 411.1576 (Calcd for C23H19N6O2: 411.1569).
3,4-Dihydro-N-{3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-
yl}-3-oxoquinoxalin-6-yl}-6,7-dimethoxyisoquinoline-2(1H)-carboxam-
ide, 7d-16 Replacing aminomethylcyclohexane with 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same proce-
dure as in the preparation of 7d-6 gave the title compound as a pale yellow
solid: 33% Yield; 1H-NMR (DMSO-d6) d: 2.78 (2H, t, Jꢀ5.5 Hz), 3.72 (2H,
t, Jꢀ5.5 Hz), 3.74 (6H, s), 3.93 (3H, s), 4.59 (2H, s), 6.77 (2H, s), 7.29 (1H,
dd, Jꢀ4.7, 7.9 Hz), 7.43 (1H, dd, Jꢀ2.1, 8.8 Hz), 7.67 (1H, d, Jꢀ2.1 Hz),
7.76 (1H, d, Jꢀ8.8 Hz), 8.38 (1H, dd, Jꢀ1.5, 4.7 Hz), 8.95 (1H, br s), 8.95
(1H, s), 9.09 (1H, dd, Jꢀ1.5, 7.9 Hz), 12.44 (1H, br s). IR (KBr) cmꢄ1: 3415,
2837, 1656, 1536, 1516. ESI-MS m/z: ꢅESI 511 (Mꢅ1), ꢄESI 509 (Mꢄ1).
HR-ESI-MS m/z: 511.2086 (Calcd for C28H27N6O4: 511.2094).
tert-Butyl {3-{2-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3,4-dihy-
dro-3-oxoquinoxalin-6-yl}ureido}acetate, 7d-17 Replacing n-butylamine
with tert-butyl 2-aminoacetate and following the same procedure from
phenyl {3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3-oxo-
quinoxalin-6-yl}carbamate as in the preparation of 7d-8 gave the title com-
pound as a charcoal solid: 67% Yield; 1H-NMR (DMSO-d6) d: 1.44 (9H, s),
3.79 (2H, d, Jꢀ5.8 Hz), 3.93 (3H, s), 6.46 (1H, t, Jꢀ5.8 Hz), 7.26 (1H, dd,
Jꢀ2.2, 8.7 Hz), 7.30 (1H, dd, Jꢀ4.8, 7.8 Hz), 7.62 (1H, d, Jꢀ2.2 Hz), 7.74
(1H, d, Jꢀ8.7 Hz), 8.38 (1H, dd, Jꢀ1.5, 4.8 Hz), 8.94 (1H, s), 9.09 (1H, dd,
Jꢀ1.5, 7.8 Hz), 9.20 (1H, s), 12.39 (1H, s). IR (KBr) cmꢄ1: 3389, 2978,
1741, 1654, 1540. ESI-MS m/z: ꢅESI 449 (Mꢅ1), ꢄESI 447 (Mꢄ1). HR-
ESI-MS m/z: 449.1911 (Calcd for C23H25N6O2: 449.1937).
1
6-yl}carbamate as a brown solid (6.11 g); 74% Yield; H-NMR (DMSO-d6)
d: 3.93 (3H, s), 7.16—7.55 (7H, m), 7.73 (1H, d, Jꢀ2.4 Hz), 7.84 (1H, d,
Jꢀ8.8 Hz), 8.39 (1H, dd, Jꢀ1.7, 4.6 Hz), 8.97 (1H, s), 9.10 (1H, dd, Jꢀ1.7,
7.9 Hz), 10.59 (1H, s), 12.51 (1H, br s).
To a solution of phenyl {3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-yl}-3-oxoquinoxalin-6-yl}carbamate (88 mg, 0.24 mmol) in DMF
(2.0 ml) was added n-butylamine (78 mg, 1.2 mmol) at room temperature,
and the mixture was stirred at 100 °C for 1 h. To the resulting reaction mix-
ture was added MeOH (8.0 ml), and the deposited precipitate was filtered to
give the title compound as a brown solid (67 mg); 71% Yield; 1H-NMR
(DMSO-d6) d: 0.91 (3H, t, Jꢀ7.1 Hz), 1.18—1.58 (4H, m), 3.02—3.22 (2H,
m), 3.92 (3H, s), 6.20 (1H, t, Jꢀ5.6 Hz), 7.32—7.21 (2H, m), 7.60 (1H, d,
Jꢀ2.3 Hz), 7.72 (1H, d, Jꢀ8.7 Hz), 8.38 (1H, dd, Jꢀ1.5, 4.8 Hz), 8.81 (1H,
s), 8.93 (1H, s), 9.08 (1H, dd, Jꢀ1.5, 7.9 Hz), 12.36 (1H, s). IR (KBr) cmꢄ1
:
3316, 2932, 1663, 1539. ESI-MS m/z: ꢅESI 391 (Mꢅ1), ꢄESI 389 (Mꢄ1).
HR-ESI-MS m/z: 391.1882 (Calcd for C21H23N6O2: 391.1882).
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-pentylureido)quinox-
alin-2(1H)-one, 7d-9 Replacing n-butylamine with n-pentylamine and
following the same procedure from phenyl {3,4-dihydro-2-{1-methyl-1H-
pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-6-yl}carbamate as in the pre-
paration of 7d-8 gave the title compound as a charcohol charcoal solid: 84%
Yield; 1H-NMR (DMSO-d6) d: 0.89 (3H, t, Jꢀ6.5 Hz, 3H), 1.16—1.55 (6H,
m), 3.00—3.19 (2H, m), 3.92 (3H, s), 6.22 (1H, t, Jꢀ5.0 Hz), 7.24 (1H, dd,
Jꢀ2.2, 8.6 Hz), 7.30 (1H, dd, Jꢀ4.6, 7.8 Hz), 7.60 (1H, d, Jꢀ2.2 Hz), 7.72
(1H, d, Jꢀ8.6 Hz), 8.38 (1H, dd, Jꢀ1.5, 4.6 Hz), 8.83 (1H, s), 8.93 (1H, s),
9.08 (1H, dd, Jꢀ1.5, 7.8 Hz), 12.36 (1H, br s). IR (KBr) cmꢄ1: 3315, 2931,
1663, 1539. ESI-MS m/z: ꢅESI 405 (Mꢅ1), ꢄESI 403 (Mꢄ1). HR-ESI-
MS m/z: 405.2016 (Calcd for C22H25N6O2: 405.2039).
7-(3-Hexylureido)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}quinox-
alin-2(1H)-one, 7d-10 Replacing n-butylamine with n-hexylamine and
following the same procedure from phenyl {3,4-dihydro-2-{1-methyl-1H-
pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-6-yl}carbamate as in the pre-
paration of 7d-8 gave the title compound as a charcoal solid: 82% Yield; 1H-
NMR (DMSO-d6) d: 0.77—1.00 (3H, m), 1.11—1.59 (8H, m), 3.00—3.20
(2H, m), 3.92 (3H, s), 6.20 (1H, t, Jꢀ5.5 Hz), 7.32—7.21 (2H, m), 7.60 (1H,
d, Jꢀ2.3 Hz), 7.72 (1H, d, Jꢀ8.5 Hz), 8.38 (1H, dd, Jꢀ1.6, 4.6 Hz), 8.81
(1H, s), 8.93 (1H, s), 9.08 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.37 (1H, s). IR (KBr)
cmꢄ1: 3313, 2929, 1663, 1539. ESI-MS m/z: ꢅESI 419 (Mꢅ1), ꢄESI 417
(Mꢄ1). HR-ESI-MS m/z: 419.2173 (Calcd for C23H27N6O2: 419.2195).
7-(3-Heptylureido)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-
quinoxalin-2(1H)-one, 7d-11 Replacing n-butylamine with n-heptyl-
amine and following the same procedure from phenyl {3,4-dihydro-2-{1-
methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-6-yl}carbamate as
in the preparation of 7d-8 gave the title compound as a charcoal solid: 87%
Yield; 1H-NMR (DMSO-d6) d: 0.87 (3H, t, Jꢀ6.5 Hz), 1.10—1.58 (10H,
m), 2.99—3.17 (2H, m), 3.92 (3H, s), 6.21 (1H, t, Jꢀ5.5 Hz), 7.32—7.21
(2H, m), 7.60 (1H, d, Jꢀ2.2 Hz), 7.72 (1H, d, Jꢀ8.8 Hz), 8.38 (1H, dd,
Jꢀ1.5, 4.8 Hz), 8.82 (1H, s), 8.93 (1H, s), 9.08 (1H, dd, Jꢀ1.5, 8.1 Hz),
12.37 (1H, s). IR (KBr) cmꢄ1: 3314, 2926, 1663, 1599. ESI-MS m/z: ꢅESI
433 (Mꢅ1), ꢄESI 431 (Mꢄ1). HR-ESI-MS m/z: 433.2333 (Calcd for
C24H29N6O2: 433.2352).
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-morpholinoureido)-
quinoxalin-2(1H)-one, 7d-18 Replacing aminomethylcyclohexane with
1-aminomorpholine and following the same procedure as in the preparation
of 7d-6 gave the title compound as a pale yellow solid: 47% Yield; 1H-NMR
(DMSO-d6) d: 2.77 (4H, m), 3.73 (3H, s), 3.93 (3H, s), 7.29 (1H, dd, Jꢀ4.6,
7.9 Hz), 7.41 (1H, dd, Jꢀ2.0, 8.8 Hz), 7.77 (1H, d, Jꢀ8.8 Hz), 7.85 (1H, d,
Jꢀ2.0 Hz), 7.94 (1H, s), 8.38 (1H, dd, Jꢀ1.6, 4.6 Hz), 8.87 (1H, s), 8.94
(1H, s), 9.11 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.37 (1H, br s). IR (KBr) cmꢄ1: 3399,
3216, 2958, 1689, 1536. ESI-MS m/z: ꢅESI 420 (Mꢅ1), ꢄESI 418 (Mꢄ1).
HR-ESI-MS m/z: 420.1766 (Calcd for C21H22N7O3: 420.1784).
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-octylureido)quinox-
alin-2(1H)-one, 7d-12 Replacing n-butylamine with n-octylamine and
following the same procedure from phenyl {3,4-dihydro-2-{1-methyl-
1H-pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-6-yl}carbamate as in the
preparation of 7d-8 gave the title compound as a charcoal solid: 84% Yield;
1H-NMR (DMSO-d6) d: 0.73—1.00 (3H, m), 1.10—1.60 (12H, m), 3.00—
3.20 (2H, m), 3.92 (3H, s), 6.20 (1H, t, Jꢀ5.5 Hz), 7.24 (3H, dd, Jꢀ2.2,
9.0 Hz), 7.30 (1H, dd, Jꢀ4.6, 7.9 Hz), 7.59 (1H, d, Jꢀ2.2 Hz), 7.72 (1H, d,
3-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-{3-[(4-pyridyl)methyl]-
ureido}quinoxalin-2(1H)-one, 7d-19 Replacing aminomethylcyclohexane
with 4-pycolylamine and following the same procedure as in the preparation
1
of 7d-6 gave the title compound as a charcoal solid: 17% Yield; H-NMR
(DMSO-d6) d: 3.92 (3H, s), 4.38 (2H, d), 7.25—7.38 (6H, m), 7.64—7.74
(2H, m), 8.37 (1H, dd), 8.50 (2H, m), 8.97 (1H, s), 9.11 (1H, dd), 9.52 (1H,

February 2007
265
br s). IR (KBr) cmꢄ1: 3306, 1663, 1537, 1443. ESI-MS m/z: ꢅESI 426
(Mꢅ1), ꢄESI 424 (Mꢄ1). HR-ESI-MS m/z: 426.1674 (Calcd for
C23H20N7O2: 426.1678).
MS m/z: 465.1786 (Calcd for C24H26N6O235Cl: 465.1806), 467.1792 (Calcd
for C24H26N6O237Cl: 467.1776).
7-[3-(Cyclohexylmethyl)ureido]-6-fluoro-3-{1-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl}quinoxalin-2(1H)-one, 7b-1 Replacing 6d with 6b and
following the same procedure as in the preparation of 7d-6 gave the title
compound as a yellow solid: 11% Yield; 1H-NMR (DMSO-d6) d: 3.93 (3H,
s), 6.83 (1H, t), 7.29 (1H, dd, Jꢀ4.6, 7.9 Hz), 7.17 (1H, d, Jꢀ12 Hz), 8.27
(1H, d, Jꢀ8.0 Hz), 8.59 (1H, d, Jꢀ2.8 Hz), 8.97 (1H, s), 9.06 (1H, dd,
Jꢀ1.6, 7.9 Hz), 12.44 (1H, br s). IR (KBr) cmꢄ1: 3343, 2923, 1672, 1538.
ESI-MS m/z: ꢅESI 450 (Mꢅ1), ꢄESI 448 (Mꢄ1). HR-ESI-MS m/z:
449.2080 (Calcd for C24H26N6O2F: 449.2101).
6-Fluoro-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-pentyl-
ureido)quinoxalin-2(1H)-one, 7b-2 Replacing 6c with 6b and following
the same procedure as in the preparation of 7c-1 gave the title compound as
a yellow solid: 50% Yield; 1H-NMR (DMSO-d6) d: 0.89 (3H, t), 1.26—1.49
(6H, m), 3.13 (2H, m), 3.93 (3H, s), 7.29 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.72 (1H,
d, Jꢀ12.2 Hz), 8.27 (1H, d, Jꢀ7.9 Hz), 8.38 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.57
(1H, br s), 8.96 (1H, s), 9.09 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.18 (1H, s). IR
(KBr) cmꢄ1: 3338, 2928, 2857, 1671, 1537. ESI-MS m/z: ꢅESI 423 (Mꢅ1),
ꢄESI 421(Mꢄ1). HR-ESI-MS m/z: 423.1928 (Calcd for C22H24N6O2F:
423.1945).
3-{1-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-6-fluoro-7-(3-pentylureido)-
quinoxalin-2(1H)-one, 7g-1 Replacing 6c with 6g and following the same
procedure as in the preparation of 7c-1 gave the title compound as a yellow
solid: 66% Yield; 1H-NMR (DMSO-d6) d: 0.89 (3H, t), 1.28—1.48 (9H, m),
3.13 (2H, dd), 4.41 (1H, q), 6.79 (1H, t), 7.29 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.72
(1H, d, Jꢀ12.2 Hz), 8.27 (1H, d, Jꢀ7.9 Hz), 8.37 (1H, dd, Jꢀ1.6, 4.7 Hz),
8.58 (1H, br s), 9.00 (1H, s), 9.10 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.44 (1H, s). IR
(KBr) cmꢄ1: 3343, 2933, 1664, 1534. ESI-MS m/z: ꢅESI 437 (Mꢅ1), ꢄESI
435 (Mꢄ1). HR-ESI-MS m/z: 437.2117 (Calcd for C23H26N6O2F:
437.2101).
6-Fluoro-7-(3-pentylureido)-3-{1-propyl-1H-pyrrolo[2,3-b]pyridin-3-
yl}quinoxalin-2(1H)-one, 7h-1 Replacing 6c with 6h and following the
same procedure as in the preparation of 7c-1 gave the title compound as a
yellow solid: 46% Yield; 1H-NMR (DMSO-d6) d: 0.88 (3H, t, Jꢀ7.4 Hz),
0.89 (3H, t, Jꢀ6.8 Hz), 1.26—1.87 (8H, m), 3.13 (1H, td), 4.34 (2H, t,
Jꢀ7.0 Hz), 6.79 (1H, t), 7.29 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.72 (1H, d,
Jꢀ12.1 Hz), 8.27 (1H, d, Jꢀ7.9 Hz), 8.37 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.57 (1H,
br s), 8.98 (1H, s), 9.09 (1H, d, Jꢀ1.6, 7.9 Hz), 12.45 (1H, br s). IR (KBr)
cmꢄ1: 3343, 2961, 2931, 1665, 1533. ESI-MS m/z: ꢅESI 451 (Mꢅ1), ꢄESI
449 (Mꢄ1). HR-ESI-MS m/z: 451.2234 (Calcd for C24H28N6O2F:
451.2258).
4-{3-{2-{1-Methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3,4-dihydro-3-oxo-
quinoxalin-6-yl}-ureido}butyric Acid, 7d-20 Replacing n-butylamine
with ethyl 4-aminobutylate and following the same procedure from phenyl
{3,4-dihydro-2-{1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-3-oxoquinoxalin-
6-yl}carbamate as in the preparation of 7d-8 gave the title compound as a
charcoal solid: 81% Yield; 1H-NMR (DMSO-d6) d: 1.58—1.80 (2H, m),
2.27 (2H, t, Jꢀ7.4 Hz), 3.15—2.97 (2H, m), 3.93 (3H, s), 6.16—6.40 (1H,
m), 7.25 (1H, dd, Jꢀ2.1, 8.8 Hz), 7.30 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.61 (1H, d,
Jꢀ2.1 Hz), 7.73 (1H, d, Jꢀ8.8 Hz), 8.38 (1H, dd, Jꢀ1.6, 4.7 Hz), 8.89 (1H,
s), 8.93 (1H, s), 9.09 (1H, dd, Jꢀ1.6, 7.9 Hz), 12.38 (1H, s). IR (KBr) cmꢄ1
:
3300—2500, 2941, 1663, 1539. ESI-MS m/z: ꢅESI 421 (Mꢅ1), ꢄESI 419
(Mꢄ1). HR-ESI-MS m/z: 421.1599 (Calcd for C21H21N6O4: 421.1599).
6-[3-(Cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-b]-
pyridin-3-yl}quinoxalin-2(1H)-one, 7c-1 To a suspension of 6c (70 mg,
0.24 mmol) and DIEA (0.25 ml, 1.44 mmol) and DMAP (10 mg) in CH2Cl2
(3.0 ml) was added phenyl chloroformate (0.18 ml, 1.44 mmol) at room tem-
perature, and the mixture was stirred at room temperature for 1.5 h.
Aminomethylcyclohexane (0.6 ml) and DMF (4.0 ml) were added to the
mixture, and the reaction mixture was stirred at 80 °C for 15 h. Water was
added to the resulting reaction mixture, and the water phase was extracted
with CHCl3. The combined organic phase was dried over Na2SO4. The or-
ganic solvent was removed in vacuo. The residue was triturated in Et2O, and
the precipitate was filtered to give the title compound as pale yellow solid
(41 mg); 40% Yield; 1H-NMR (DMSO-d6) d: 0.89—1.91 (11H, m), 2.97
(2H, t), 3.94 (3H, s), 6.21 (1H, t), 7.19 (1H, d, Jꢀ8.7 Hz), 7.29 (1H, d,
Jꢀ2.2 Hz), 7.35 (1H, dd, Jꢀ4.6, 7.9 Hz), 8.11 (1H, d, Jꢀ2.2 Hz), 8.40 (1H,
dd, Jꢀ1.6, 4.6 Hz), 8.51 (1H, s), 9.04 (1H, s), 9.09 (1H, dd, Jꢀ1.6, 7.9 Hz),
12.39 (1H, s). IR (KBr) cmꢄ1: 3318, 2919, 1665, 1538. ESI-MS m/z: ꢅESI
431 (Mꢅ1), ꢄESI 429 (Mꢄ1). HR-ESI-MS m/z: 431.2185 (Calcd for
C24H27N6O2: 431.2195).
7-[3-(Cyclohexylmethyl)ureido]-3-(1-methyl-indolyl-3-yl)quinoxalin-
2(1H)-one, 7f-1 Replacing 6d with 6f and following the same procedure
in DMF as in the preparation of 7d-6 gave the title compound as a charcoal
1
solid: 73% Yield; H-NMR (DMSO-d6) d: 0.77—1.55 (6H, m), 1.55—1.81
(5H, m), 2.90—3.05 (2H, m), 3.90 (3H, s), 6.17—6.32 (1H, m), 7.16—7.37
(3H, m), 7.49—7.65 (2H, m), 7.70 (1H, d, Jꢀ8.5 Hz), 8.71—8.93 (3H, m),
12.28 (1H, br s). IR (KBr) cmꢄ1: 3302, 2918, 1661, 1537. ESI-MS m/z:
ꢅESI 430 (Mꢅ1), ꢄESI 428 (Mꢄ1). HR-ESI-MS m/z: 430.2225 (Calcd for
C25H28N5O2: 430.2243).
3-{1-Butyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-6-fluoro-7-(3-pentyl-
ureido)quinoxalin-2(1H)-one, 7i-1 Replacing 6c with 6i and following
the same procedure as in the preparation of 7c-1 gave the title compound as
a yellow solid: 54% Yield; 1H-NMR (DMSO-d6) d: 0.87—0.94 (6H, m),
1.25—1.49 (8H, m), 1.76—1.97 (2H, m), 3.13 (2H, td), 4.37 (2H, t), 6.79
(1H, t), 7.29 (1H, dd, Jꢀ4.7, 8.0 Hz), 7.72 (1H, d, Jꢀ12.1 Hz), 8.27 (1H, d,
Jꢀ7.9 Hz), 8.37 (1H, dd, Jꢀ1.4, 4.7 Hz), 8.57 (1H, br s), 8.98 (1H, s), 9.10
(1H, dd, Jꢀ1.4, 7.9 Hz), 12.43 (1H, br s). IR (KBr) cmꢄ1: 3343, 2956, 2931,
1665, 1534. ESI-MS m/z: ꢅESI 465 (Mꢅ1), ꢄESI 463 (Mꢄ1). HR-ESI-
MS m/z: 465.2417 (Calcd for C25H30N6O2F: 465.2414).
7-[3-(Cyclohexylmethyl)ureido]-3-{1H-pyrrolo[2,3-b]pyridin-3-
yl}quinoxalin-2(1H)-one, 7e-1 Replacing 6d with 6e and following the
same procedure as in the preparation of 6d gave a crude product. Then to a
mixture of TFA (1.0 ml) the above crude product in 1,2-dichloroethane
(5.0 ml) was stirred at 60 °C for 1 h. The precipitate was filtered and washed
with a small amount of AcOEt to give the title compound as a yellow solid
(49 mg): 44% Yield (2 steps); 1H-NMR (DMSO-d6) d: 0.87—1.72 (11H, m),
2.96 (2H, t), 6.25 (1H, t), 7.19—7.29 (2H, m), 7.61 (1H, d, Jꢀ2.1 Hz), 7.73
(1H, d, Jꢀ9.0 Hz), 8.33 (1H, d, Jꢀ4.9 Hz), 8.79 (1H, s), 8.85 (1H, d,
Jꢀ2.7 Hz), 9.08 (1H, d, Jꢀ8.0 Hz), 12.13 (1H, s), 12.31 (1H, s). IR (KBr)
cmꢄ1: 3316, 3221, 2923, 2852, 1676, 1558. ESI-MS m/z: ꢅESI 417 (Mꢅ1),
ꢄESI 415 (Mꢄ1). HR-ESI-MS m/z: 417.2026 (Calcd for C22H27N6O2:
417.2039).
6-Fluoro-3-{1-pentyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-pentyl-
ureido)quinoxalin-2(1H)-one, 7j-1 Replacing 6c with 6j and following
the same procedure as in the preparation of 7c-1 gave the title compound as
1
a yellow solid: 51% Yield; H-NMR (DMSO-d6) d: 0.81—1.97 (18H, m),
7-(3-Pentylureido)-3-{1H-pyrrolo[2,3-b]pyridin-3-yl}quinoxalin-
2(1H)-one, 7e-2 Replacing aminomethylcyclohexane with n-pentylamine
and following the same procedure as in the preparation of 7e-1 gave the title
3.13 (2H, td), 4.37 (2H, d, Jꢀ7.2 Hz), 6.79 (1H, t), 7.28 (1H, dd, Jꢀ4.7,
8.0 Hz), 7.74 (1H, d, Jꢀ12.1 Hz), 8.27 (1H, d, Jꢀ7.9 Hz), 8.37 (1H, dd,
Jꢀ1.6, 4.7 Hz), 8.57 (1H, br s), 8.98 (1H, s), 9.09 (1H, d, Jꢀ1.6, 8.0 Hz),
12.44 (1H, br s). IR (KBr) cmꢄ1: 3343, 2930, 1665, 1534. ESI-MS m/z:
ꢅESI 479 (Mꢅ1), ꢄESI 477 (Mꢄ1). HR-ESI-MS m/z: 479.2567 (Calcd for
C26H32N6O2F: 479.2571).
1
compound as a yellow solid: 37% Yield (2 steps); H-NMR (DMSO-d6) d:
0.89 (3H, t, Jꢀ6.7 Hz), 1.27—1.49 (6H, m), 3.11 (2H, td), 6.22 (1H, t), 7.23
(1H, dd, Jꢀ2.4, 8.7 Hz), 7.27 (1H, dd, Jꢀ4.6, 7.8 Hz), 7.62 (1H, d,
Jꢀ2.4 Hz), 7.73 (1H, d, Jꢀ8.7 Hz), 8.33 (1H, dd, Jꢀ1.6, 4.6 Hz), 8.82 (1H,
s), 8.85 (1H, d, Jꢀ2.8 Hz), 9.09 (1H, dd, Jꢀ1.6, 7.8 Hz), 12.15 (1H, s),
12.32 (1H, s). IR (KBr) cmꢄ1: 3309, 3223, 2932, 1676, 1558. ESI-MS m/z:
ꢅESI 391 (Mꢅ1), ꢄESI 389 (Mꢄ1). HR-ESI-MS m/z: 391.1881 (Calcd for
C21H23N6O2: 417.391.1882).
6-Fluoro-3-{1-isobutyl-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-pentyl-
ureido)quinoxalin-2(1H)-one, 7k-1 Replacing 6c with 6k and following
the same procedure as in the preparation of 7c-1 gave the title compound as
a yellow solid: 54% Yield; 1H-NMR (DMSO-d6) d: 0.87—0.91 (9H, m),
1.27—1.34 (6H, m), 2.22 (1H, m), 3.14 (2H, td), 4.19 (2H, d, Jꢀ7.2 Hz),
6.79 (1H, t), 7.29 (1H, dd, Jꢀ4.7, 7.9 Hz), 7.72 (1H, d, Jꢀ12.2 Hz), 8.28
(1H, d, Jꢀ7.9 Hz), 8.36 (1H, dd, Jꢀ1.5, 4.7 Hz), 8.57 (1H, br s), 8.96 (1H,
s), 9.10 (1H, d, Jꢀ1.5, 7.9 Hz), 12.39 (1H, br s). IR (KBr) cmꢄ1: 3346, 2958,
2930, 1665, 1534. ESI-MS m/z: ꢅESI 465 (Mꢅ1), ꢄESI 463 (Mꢄ1). HR-
ESI-MS m/z: 465.2416 (Calcd for C25H30N6O2F: 465.2414).
6-Chloro-7-[3-(cyclohexylmethyl)ureido]-3-{1-methyl-1H-pyrrolo[2,3-
b]pyridin-3-yl}quinoxalin-2(1H)-one, 7a-1 Replacing 6d with 6a and
following the same procedure as in the preparation of 7d-6 gave the title
compound as a yellow solid: 11% Yield; 1H-NMR (DMSO-d6) d: 3.93 (3H,
s), 7.26 (1H, t, Jꢀ4.7 Hz), 7.30 (1H, dd, Jꢀ4.7, 8.0 Hz), 7.97 (1H, s), 7.17
(1H, d, Jꢀ12 Hz), 8.32 (1H, s), 8.39 (1H, dd, Jꢀ1.7, 4.7 Hz), 8.96 (1H, s),
9.11 (1H, dd, Jꢀ1.7, 8.0 Hz), 12.44 (1H, br s). IR (KBr) cmꢄ1: 3317, 2921,
1662, 1536. ESI-MS m/z: ꢅESI 465 (Mꢅ1), ꢄESI 462 (Mꢄ1). HR-ESI-
6-Fluoro-3-{1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl}-7-(3-
pentylureido)quinoxalin-2(1H)-one, 7l-1 Replacing 6c with 6l and fol-

266
Vol. 55, No. 2
lowing the same procedure as in the preparation of 7c-1 gave the title com-
lated by 10 ng/ml rhVEGF (R&D) for 5 min and the anti-KDR Ab (SIGMA)
1
pound as a yellow solid: 35% Yield; H-NMR (DMSO-d6) d: 0.89 (3H, t, was used for receptor capture. Auto-phosphorylation of EGFR was assayed
Jꢀ6.8 Hz), 1.27—1.49 (6H, m), 3.13 (2H, td), 3.26 (3H, s), 3.76 (2H, t, using human epithelial carcinoma cells (A431) treated with 50 ng/ml rhEGF
Jꢀ5.1 Hz), 4.54 (2H, d, Jꢀ5.1 Hz), 6.79 (1H, t), 7.30 (1H, dd, Jꢀ4.7, (R&D) for 3 min and anti-EGFR Ab (R&D) was used for receptor capture.
7.9 Hz), 7.72 (1H, d, Jꢀ12.2 Hz), 8.28 (1H, d, Jꢀ7.9 Hz), 8.37 (1H, dd, Similarly, auto-phosphorylation of Met using A431 was induced by
Jꢀ1.7, 4.7 Hz), 8.57 (1H, br s), 8.98 (1H, s), 9.10 (1H, d, Jꢀ1.7, 7.9 Hz),
100 ng/ml rhHGF (R&D) for 5 min, and Met was captured with anti-Met Ab
12.43 (1H, br s). IR (KBr) cmꢄ1: 3340, 2930, 1660, 1536. ESI-MS m/z: (SIGMA). For auto-phosphorylation of IGF-IR, human breast cancer cells
ꢅESI 467 (Mꢅ1), ꢄESI 465 (Mꢄ1). HR-ESI-MS m/z: 467.2209 (Calcd for
C24H28N6O3F: 467.2207).
(MCF-7) were treated with 100 ng/ml rhIGF-I (PEPRO TECH) for 3 min
and IGF-IR was bound by anti-IGF-IR Ab (R&D). Inhibition % was calcu-
6-Fluoro-3-{1-(3-morpholinopropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl}- lated using the following equation and inserting the value of each ab-
7-(3-pentylureido)quinoxalin-2(1H)-one Hydrochloride, 7m-1 Replac- sorbance. Inhibition %ꢀ{1ꢄ(AꢄC)/(BꢄC)}ꢆ100 (A: absorbance of sam-
ing 6c with 6m and following the same procedure as in the preparation of
7c-1 gave the title compound as a yellow solid: 33% Yield; 1H-NMR
(DMSO-d6) d: 0.89 (3H, t, Jꢀ6.7 Hz), 1.24—1.49 (6H, m), 1.97—3.81
(10H, m), 4.41 (2H, t, Jꢀ5.6 Hz), 6.83 (1H, t), 7.30 (1H, dd, Jꢀ4.6, 8.0 Hz),
7.72 (1H, d, Jꢀ12.1 Hz), 8.27 (1H, d, Jꢀ7.9 Hz), 8.37 (1H, dd, Jꢀ1.4,
4.6 Hz), 8.60 (1H, br s), 9.03 (1H, s), 9.10 (1H, d, Jꢀ1.4, 8.0 Hz), 12.47 (1H,
s). IR (KBr) cmꢄ1: 3340, 2931, 1663, 1536. ESI-MS m/z: ꢅESI 536 (Mꢅ1-
HCl), ꢄESI 534 (Mꢄ1-HCl). HR-ESI-MS m/z: 536.2780 (Calcd for
C28H35N7O3F: 536.2785).
ple addition well, B: absorbance of control well, C: absorbance of non-stim-
ulated well). The IC50 values were calculated with SOFT max PRO.
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