Design, synthesis, and structure-activity relationships of novel insulin receptor tyrosine kinase activators

Article abstract of DOI:10.1021/jm800600v

A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl] phenylamines were designed, synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship was established that indicated glucose transport activity was dependent on the presence of two acidic functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-treated rats. These data provide pharmacological validation that small molecule IRTK activators represent a potential new class of antidiabetic agents.

Full text of DOI:10.1021/jm800600v

J. Med. Chem. 2008, 51, 6173–6187
6173
Design, Synthesis, and Structure-Activity Relationships of Novel Insulin Receptor Tyrosine
Kinase Activators
Robert T. Lum,† Mingshan Cheng,† Cristina P. Cristobal,† Ira D. Goldfine,§ Joseph L. Evans,*,# James G. Keck,†
Robert W. Macsata,† Vara Prasad Manchem,† Yukiharu Matsumoto,‡ Sophia J. Park,† Sandhya S. Rao,† Louise Robinson,†
Songyuan Shi,† Wayne R. Spevak,† and Steven R. Schow†
Telik, Inc., 3165 Porter DriVe, Palo Alto, California 94304, UniVersity of California at San Francisco, Mount Zion Medical Center,
San Francisco, California 94115, ReceptorBio, Inc., 1155 Chess DriVe, Suite 116, Foster City, California 95051, and Sanwa Kaguku
Kenkyusho Co. Ltd., Nagoya 461-8631, Japan
ReceiVed May 20, 2008
A novel series of symmetrical ureas of [(7-amino(2-naphthyl))sulfonyl]phenylamines were designed,
synthesized, and tested for their ability to increase glucose transport in mouse 3T3-L1 adipocytes, a surrogate
readout for activation of the insulin receptor (IR) tyrosine kinase (IRTK). A structure-activity relationship
was established that indicated glucose transport activity was dependent on the presence of two acidic
functionalities, two sulfonamide linkages, and a central urea or 2-imidazolidinone core. Compound 30 was
identified as a potent and selective IRTK activator. At low concentrations, 30 was able to increase the
tyrosine phosphorylation of the IR stimulated by submaximal insulin. At higher concentrations, 30 was able
to increase tyrosine the phosphorylation levels of the IR in the absence of insulin. When administered
intraperitoneally (ip) and orally (po), 30 improved glucose tolerance in hypoinsulinemic, streptozotocin-
treated rats. These data provide pharmacological validation that small molecule IRTK activators represent
a potential new class of antidiabetic agents.
Introduction
of the peroxisome proliferator-activated receptor-γ (PPARγa)
in adipose tissue by this class of drugs directs changes in adipose
gene expression including the increased production of adiponec-
tin, which in turn elicits insulin sensitizing effects in the target
tissues.14,15 Mostly recently, inhibitors of dipeptidyl peptidase
IV (DPP-IV), a promiscuous enzyme responsible for the
abbreviated plasma half-life of glucagon-like peptide-1 (GLP-
1), have been developed.16 These compounds serve to elevate
circulating GLP-1 levels, enhance insulin secretion, and improve
glycemic control. Unfortunately, these agents do not work in
all patients, and some have potentially serious side effects.7,17-19
For example, the sulfonylureas, meglitinides, and thiazolidinedi-
ones all have a tendency to cause weight gain. This is
undesirable in a population already at risk for cardiovascular
disease.20,21 In addition, the U.S. Food and Drug Administration
removed the thiazolidinedione, troglitazone, from the market
because of its liver toxicity. Such problems illustrate the need
to develop new treatments for diabetes with novel mechanisms
of action.
The insulin receptor (IR) is a large transmembrane glyco-
protein found in insulin sensitive target cells (liver, muscle, and
fat).22 It comprises two extracellular R-subunits that contain the
insulin-binding domain and two membrane spanning ꢀ-subunits
that contain a ligand activated tyrosine kinase, which will be
referred to as the insulin receptor tyrosine kinase (IRTK). Insulin
acts by binding to the extracellular domain of the IR, thus
inducing autophosphorylation and activation of the IRTK. A
cascade of signaling events is initiated leading to increased
Diabetes mellitus is a serious and growing worldwide medical
problem. In 2000, 171 million people were estimated to be
affected by the disease, and that number is expected to more
than double to 366 million by 2030.1,2 Two major clinically
distinct types of diabetes have been described. Type 1 diabetes
is caused by an autoimmune-mediated destruction of the insulin
producing ꢀ cells of the pancreas leading to an absolute insulin
deficiency. It is managed by administering exogenous insulin.
Type 2 diabetes is, by far, the most common form of diabetes
and accounts for greater than 90% of all cases. This form of
the disease is characterized by insulin resistance, which is a
reduced sensitivity of the target tissues (liver, skeletal muscle,
adipose) to insulin, along with abnormal secretion of insulin.3
Initially, the body is able to compensate for insulin resistance
by secreting more insulin, and this state of hyperinsulinemia is
often an early indicator of the disease.4,5 Eventually, the pancreas
will be unable to secrete enough insulin to maintain glucose
homeostasis, and consequently oral antidiabetic agents will be
needed.6
Current oral antidiabetic agents exert their glucose lowering
effects by five main modes of action.7 The sulfonylureas and
meglitinides stimulate insulin secretion by the pancreatic ꢀ
cells.8,9 Metformin, a biguanide, decreases hepatic glucose
production,10 although it is likely that its ability to stimulate
AMP-activated protein kinase also contributes to its antihyper-
glycemic activity.11 The R-glucosidase inhibitors reduce gas-
trointestinal absorption of carbohydrates.12 The thiazolidinedi-
ones increase glucose utilization in muscle and liver.13 Activation
a Abbreviations: CKD, cytoplasmic kinase domain; DPP-IV, dipeptidyl
peptidase IV; EGFR, epidermal growth factor receptor; GLP-1, glucagon-
like peptide-1; GLUT4, insulin-sensitive glucose transporter; HIV, human
immunodeficiency virus; IGF-1R, insulin-like growth factor-1 receptor; IR,
insulin receptor; IRS-1/2, insulin receptor substrates 1 and 2; IRTK, insulin
receptor tyrosine kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PPARγ,
peroxisome proliferator-activated receptor-γ; SAR, structure-activity re-
lationship; SEM, standard error of the mean; STZ, streptozotocin; TK,
tyrosine kinase; TRAP, target-related affinity profiling.
* To whom correspondence should be addressed. Phone: 650-255-5806.
Fax: 309-406-8212. E-mail: jevansphd@earthlink.net.
†
Telik, Inc.
§
University of California at San Francisco.
ReceptorBio, Inc.
Sanwa Kaguku Kenkyusho Co. Ltd.
#
‡
10.1021/jm800600v CCC: $40.75
2008 American Chemical Society
Published on Web 09/13/2008

6174 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
Figure 1. Summary of changes made to compound 1.
Scheme 1a
tyrosine phosphorylation of multiple intracellular substrates,
including the insulin receptor substrates 1 and 2 (IRS-1/2), and
the activation of second messenger systems such as phosphati-
dylinositol 3-kinase (PI 3-kinase).23 These pathways act to
trigger the translocation of GLUT4 to the cell surface.24 GLUT4
is one of a family of membrane proteins responsible for glucose
uptake in mammalian cells and is the major isoform responsive
to insulin stimulation.25
Given the essential and early role the IR plays in insulin
action, it represents an important and unexploited target for drug
development. A family of quinones has been reported as the
first selective activators of the IRTK.26-29 These compounds
exhibit antihyperglycemic activity in several animal models of
type 2 diabetes26,27,29,30 and thus provide pharmacological
validation that small molecule IRTK activators represent a
potential new class of antidiabetic agents. By use of our
proprietary drug discovery target-related affinity profiling
(TRAP) technology,31 the azonaphthylurea 1 (TLK16998) was
discovered. This compound functions as an IR sensitizer both
in vitro and in vivo.32 Compound 1 increases tyrosine phos-
phorylation of the IRTK, with subsequent enhancement of
downstream signaling events including IRS-1 phosphorylation
and GLUT4 translocation, resulting increased in cellular glucose
transport. Compound 1 is also efficacious at lowering glucose
in two mouse models of type 2 diabetes.32 Compound 1 is also
effective at increasing IRTK in several cellular models of
impaired insulin receptor function.33 A novel series of IRTK
activators that are exemplified by general structure 2 (Figure
1) were designed using the azonaphthyl urea 1 as a starting
point. The design, synthesis, and SAR of this series of novel
antidiabetic agents are reported here.
a (a) triphosgene, THF/aqueous NaOH; (b) POCl3; (c) pyridine, THF.
compounds that were prepared. Reaction of the 7-amino-2-
naphthalenesulfonic acids with triphosgene afforded the corre-
sponding ureas, which were converted to the bis-sulfonyl
chlorides 44 and 45 on treatment with phosphorus oxychloride.
Coupling of these intermediates with the appropriate aniline
furnished, after any necessary deprotection steps, the sulfona-
mides 4-22 and 24-28 (Table 1). Incomplete reaction at the
final stage provided the monoaddition products 31 and 32 (Table
2), which were readily separable from their symmetrical
analogues.
Method B, although requiring an additional synthetic step,
was more convenient on a large scale (Scheme 2). In this
procedure, the 7-amino-2-naphthalenesulfonic acids were acety-
lated prior to formation of the sulfonyl chlorides 46 and 47.
Chemistry
The naphthylureas, as exemplified by 2, were prepared by
one of two general methods. Method A (Scheme 1) represents
the most direct approach and was used for the majority of

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6175
Table 1. Glucose Uptake Data and Experimental Methods for Ureas 3-30a
compd
R1
R2
R3
R4
method
EC50 (µM)
no. of assays
P
1
3
4
5
6
7
8
9
90
26 ( 5.6
22
>200
>200
>200
>200
43
24
73
54
>200
>200
>200
>200
94
103
93
183
41
18 ( 8.7
16
43
9
40
150
121
6 ( 1.0
5 ( 1.2
1
6
2
1
1
1
1
1
1
2
2
1
1
1
1
1
2
2
1
1
3
2
2
2
1
1
1
4
7
OH
H
H
H
H
OH
OH
H
OH
H
OH
H
H
OH
H
OH
OH
H
H
OH
H
OH
H
H
H
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CO2H
H
CO2H
H
H
H
H
H
OH
Cl
H
SO3Na
SO3Na
H
NO2
CN
H
H
H
H
H
H
H
H
H
H
H
H
H
H
SO3Na
CO2H
H
CO2H
H
Cl
Cl
OH
OH
NO2
H
B
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
A
A
B
B
<0.001 vs 1
ns vs 3
inactive compound
inactive compound
inactive compound
inactive compound
<0.05 vs 3
ns vs 4
<0.012 vs 3
<0.05 vs 4
inactive compound
inactive compound
inactive compound
inactive compound
<0.01 vs 4
<0.001 vs 9
<0.001 vs 9
<0.001 vs 10
<0.001 vs 10
<0.001 vs 9
<0.001 vs 10
ns vs 9
<0.001 vs 10
ns vs 10
CF3
CO2H
CO2H
tetrazole
tetrazole
CH2OH
OH
SO2NH2
CH2CO2H
H
H
H
H
H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
SO3Na
SO3Na
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
<0.001 vs 9
<0.05 vs 22
<0.015 vs 4; <0.05 vs 23
<0.002 vs 3; <0.03 vs 22
H
Cl
Cl
OH
H
a Test compounds were evaluated in each screening assay at four concentrations using triplicate incubations in the presence of 5.6 nM insulin, a submaximally
effective concentration, as described in Experimental Section. The EC50 value was calculated using nonlinear regression analysis of the best-fit curve of the
untransformed data. Values shown are the mean ( SEM [when n (number of independent assays) g 3]. Under the conditions employed, the % coefficient
of variation for this screening assay was typically e15%. For statistical comparison of test compounds when n g 2, an unpaired t test was used to compare
the EC50 of two compounds. For statistical comparisons of a panel of compounds when n ) 1, an ANOVA (repeated measures) was used to compare the
counts per minute data (four concentrations, triplicate incubations) followed by the Newman-Keuls multiple comparison test. Significance was accepted at
P < 0.05. Typically, 2-fold differences in EC50 values were statistically significant, while differences less than 2-fold were not. All analyses were performed
using GraphPad Prism (MS Windows, version 4.03), GraphPad Software, San Diego, CA (www.graphpad.com). ns, not significant.
Table 2. Glucose Uptake Data For Truncated Analogues 31 and 32
prepared from the corresponding nitrobenzenesulfonyl chlorides
by esterification with p-cresol followed by reduction of the nitro
group (Scheme 3). 3-(1H-1,2,3,4-Tetrazol-5-yl)phenylamine 57
was prepared in one step from 3-aminobenzonitrile and sodium
azide.34
The amides 33 and 34 were prepared according to the
procedure described in Scheme 4, starting from the known
aminonaphthalenecarboxylic acid 58.35 Protection of the amine
followed by acid chloride formation and amidation with the
appropriate aniline yielded carboxamides 59 and 60. After Fmoc
removal and reaction with triphosgene, protected ureas 61and
62 were obtained. Basic hydrolysis provided the desired diacids
33 and 34.
compd
R
EC50 (µM)
31
32
3-SO3Na, 4-Cl
3-CO2H, 4-OH
>200
>200
Coupling with the appropriate anilines yielded the sulfonamides
48 and 49, which after deprotection were treated with triphos-
gene to afford symmetrical ureas 52 and 53. In this manner,
symmetrical ureas 3, 23, 29, and 30 were prepared.
The N-methylsulfonamide 35 was simply prepared by me-
thylation of sulfonamide 4 (method A, R1 ) H, R2 ) 3-SO3Na)
using potassium carbonate and iodomethane.
For sulfonic acid containing anilines, it proved convenient
to couple them as their sulfonate esters. This allowed for the
facile chromatographic separation (method A) or extractive
separation (methods A and B) of any unreacted naphthalene-
sulfonic acid. The p-cresolaniline sulfonates 54, 55, and 56 were
Compounds 36 and 37, which contain a flexible ethyl linker,
and the constrained 2-imidazolidinone 43 were prepared as
described in Scheme 5. 1,2-Dibromoethane was alkylated with
excess 7-amino-2-naphthalenesulfonic acid, and the nitrogen
atoms were then acetylated prior to sulfonyl chloride formation.

6176 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
Scheme 2a
a (a) Ac2O, pyridine; (b) POCl3; (c) pyridine, THF; (d) 5 N NaOH, 60°C; (e) triphosgene, THF, 1 M NaOAc buffer, pH 4.7.
Scheme 3a
the six sulfonic acids and four azo linkages and reduction of
the high molecular weight were targeted as early goals for the
improvement of our lead structure. The initial SAR work with
the azo analogues of 1 focused on the role of the benzenesulfonic
acids. It was found that the distal benzenesulfonic acid groups
were not required for activity (Figure 1). However, the sulfonic
acids on the benzene rings directly attached to the central
naphthalene urea core were found to be essential for activity.
Replacement of the inner azo linkages of 1 with another type
of linker to the requisite benzenesulfonic acid groups was next
examined. A subsequent set of compounds using the sulfonic
acids on the naphthalenes as a handle for the formation of
sulfonamide linkages was explored. Changing the linker elimi-
nated the undesirable azo linkages and incorporated neutral
sulfonamides. This strategy provided compounds of the general
structure 2 (Figure 1), many of which retained the IRTK
activation activity of 1. In order to establish the SAR of these
IRTK activators, an expanded series of analogues was designed
and synthesized.
a (a) p-cresol, pyridine, THF; (b) SnCl2, HCl; (c) POCl3, DMA; (d) NaN3,
Et3NHCl, toluene, 100°C.
The resulting sulfonyl chloride 63 was coupled to 5-amino-2-
chlorobenzoic acid followed by liberation of the amines by basic
hydrolysis to give the ethyl linked analogue 37. Triphosgene
induced cyclization afforded the 2-imidazolidinone 43.
Scheme 6 shows the synthesis of the N,N′-dimethylurea 42.
Triphosgene mediated ureidation of 7-amino-2-naphthalene-
sulfonic acid (method A, Scheme 1) was followed by methy-
lation of the urea nitrogens. Conversion to the bis-sulfonyl
chloride, coupling to methyl 5-amino-2-chlorobenzoate, and
subsequent ester hydrolysis gave the desired N,N′-dimethylurea
42.
Compounds 1 and 3 were initially compared by their effect
on autophosphorylation of the cytoplasmic kinase domain of
the human insulin receptor. Both compounds demonstrated a
dose dependent activation of the autophosphorylation activity
(Figure 2). The biphasic dose-response curve is likely a
consequence of incubation conditions associated with the in vitro
(enzymatic) assay. Importantly, neither compound (1 or 3; data
not shown) nor 30 exhibited a biphasic dose-response in a
cellular assay measuring insulin receptor tyrosine phosphory-
lation (Figure 3) or other cellular assays (data not shown).
The importance of the central urea linker was further explored
by the synthesis of thiourea 38 and guanidine analogues 39-41
as depicted in Scheme 7. The 7-aminonaphthalene 64 was
obtained by esterification of intermediate 51 (method B, Scheme
2, R2 ) 3-CO2H, 4-Cl). It was then converted to the thioiso-
cyanate 65 using 1,1′-thiocarbonyldiimidazole. This thioisocy-
anate was treated with 7-aminonaphthalene 64 to afford the
thiourea 66, which was subsequently hydrolyzed to furnish the
dicarboxylic acid 38. The thiourea 66 also gave access to a series
of guanidine isosteres by initial S-methylation followed by
reaction with the appropriate amine in a sealed tube. Basic
hydrolysis of the resulting esters 67-69 gave the desired
guanidines 39-41.
A downstream consequence of IRTK activation in the cell is
the stimulation of glucose transport. This whole-cell functional
assay provides a measure of the ability of test compounds to
activate the insulin receptor and for that activation to lead to a
quantifiable signal reflecting the cellular uptake of glucose.36
This assay uses differentiated mouse 3T3-L1 adipocytes and
measures the ability of test compounds to increase (i.e.,
stimulate) glucose transport in the absence and presence of
insulin using 2-deoxy-D-[14C]glucose. Compound 3 stimulated
glucose transport (EC50 ) 26 µM) in the presence of 5.6 nM
insulin relative to compound 1 (EC50 ) 90 µM). The increased
potency of 3 in the glucose transport assay agrees with the
observed relative potencies of compounds 1 and 3 in the
phosphorylation assay. At high concentrations, 3 increased
glucose transport in the absence of insulin; this was not observed
for compound 1. Therefore, at higher concentrations, 3 acts as
an insulin receptor agonist in 3T3-L1 adipocytes, while at lower
Results and Discussion
The azonaphthylurea 1 contains a number of undesirable
features for a drug candidate. In particular, the elimination of

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6177
Scheme 4a
a (a) Fmoc-Cl, NaOH; (b) SOCl2, pyridine; (c) methyl 3-aminobenzoate or 54; (d) piperidine, CH2Cl2; (e) triphosgene, THF/aqueous NaOH; (f) NaOMe,
THF/H2O.
Scheme 5a
Scheme 6a
a (a) NaH, MeI, DMF, 70 °C; (b) POCl3; (c) methyl 2-amino-5-
chlorobenzoate, pyridine; (d) NaOH.
analogues containing carboxylic acids, 9 and 10, tetrazoles, 11
and 12, alcohols, 13 and 14, and sulfonamide 15 at the 3-position
of the terminal benzene rings were prepared. The alcohols and
sulfonamide were inactive in the glucose transport assay. The
carboxylic acids 9 (EC50 ) 43 µM) and 10 (EC50 ) 24 µM)
were slightly less potent than the corresponding sulfonic acids,
and the tetrazoles 11 (EC50 ) 73 µM) and 12 (EC50 ) 54 µM)
were weaker still. In addition, a derivative in which the terminal
rings were phenylacetic acids (16) was prepared; this analogue
proved to be inactive. As had been observed previously, the
naphthalene hydroxyl groups had little effect on activity.
The effect of the position of the acidic groups on the terminal
benzene rings was next explored. When the sulfonic acid was
moved to the 4-position, 17, the activity was reduced by 4-fold.
Attempts to prepare analogues with the sulfonic acid in the
2-position were unsuccessful, and this was postulated to be due
to steric crowding. However, in the case of the carboxylic acid
series, both the 2- and 4-substituted analogues 18-21 could be
prepared. These analogues were again less active (2- to 8-fold)
than the corresponding 3-substituted carboxylic acid analogues
9 and 10.
a (a) 1,2-Dibromoethane, K2CO3, DMF; (b) Ac2O, pyridine; (c) POCl3;
(d) 5-amino-2-chlorobenzoic acid, pyridine; (e) 5 N NaOH; (f) triphosgene
THF/aqueous Na2CO3.
concentrations, the presence of insulin is required to observe
an increase in glucose transport. The cellular activity of 3
demonstrated that this simplified scaffold was a good starting
point to begin SAR studies.
The importance of the naphthalene hydroxyls of 3 on its
glucose transport activity was first addressed. The des-hydroxyl
analogue 4 (EC50 ) 22 µM) was prepared and was shown to
be equipotent to 3 (Table 1), thus showing that these hydroxyl
groups are not essential for glucose transport activity.
The need for acidic functionalities on the terminal benzene
rings was established as exemplified by compounds 5-8 in
Table 1, suggesting that the sulfonic acid groups are playing a
critical role in activating the IRTK. In order to determine if
other acidic groups could take the place of the sulfonic acids,
After establishment of a preference for acidic functionality
at the 3-position of the terminal ring, exploration of the effects
of additional substituents on that ring was initiated. For synthetic
reasons the 3-substituted carboxylic acids 9 and 10 were chosen
as models for this series. Incorporation of a chlorine at the

6178 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
Scheme 7a
the incorporation of a hydroxyl group at the same 4-position
giving salicylic acid 25. The analogous salicylic acid derivative
containing the naphthalene hydroxyl groups (24) was an outlier
in this series, being only equipotent to its analogue 9. Introduc-
tion of a chlorine or hydroxyl substituent between the acidic
functionality and the sulfonamide linker gave compounds 27
and 28; however, both exhibited a reduction in potency. The
increased potency observed with chlorine substitution in the
4-position in the 3-benzoic acid series was also observed with
the 3-sulfonic acid analogues 29 and 30. These two compounds
had EC50 values of 6 and 5 µM, respectively, and are the most
potent analogues in this series.
To confirm the requirement for acidic functionalities on the
terminal benzene rings, carboxylate and sulfonate ester inter-
mediates of the active compounds were tested in the glucose
uptake assay; all were inactive. In addition, two truncated
analogues, 31 and 32, which lack one of the acid functionalized
terminal benzene rings were also tested; both showed a dramatic
reduction in glucose uptake activity (Table 2).
The 2,7-substitution pattern of the naphthalene rings was
found to be critical to activity. A number of analogues containing
2,6-substituted naphthalenes were synthesized, and all proved
to have little or no activity.
The importance of the sulfonamide linkages was examined
next. Amide analogues 33 and 34 both exhibited a loss in
activity (Table 3), showing that the sulfonamide linkage could
not be replaced by this spatially dissimilar linker. The N-
methylsulfonamide 35 showed a reduction in activity, perhaps
indicating that the sulfonamide proton is also important.
a (a) 1,1′-Thiocarbonyldiimidazole; (b) 64, CH2Cl2; (c) 1 N NaOH; (d)
MeI; (e) R1NH2, sealed tube, 70-80 °C.
To assess the importance of the central linkage, the urea linker
was modified using compound 23 as the comparator (Table 4).
Compounds 36 and 37, which contain a flexible ethyl linker,
were both inactive. Replacement of the urea with a thiourea
38, guanidine 39, or substituted guanidines 40 and 41 resulted
in compounds with vastly diminished or no activity. Methylation
of the urea nitrogens gave 42, which was also inactive. The
only modification to the urea linker that retained moderate
activity was the cyclic 2-imidazolidinone 43, which had an EC50
of 56 µM. These data suggest that it is not the urea protons
that are critical for activity, but perhaps it is the trans, trans
conformation37 adopted by the urea linker that is important. It
is known that N,N′-dimethyldiphenylureas adopt a cis,cis
conformation,38,39 while for thioureas40 and guanidines41 the
mixed cis,trans conformation may predominate. Since the urea
linkage acts as a hinge in the center of the molecule, even subtle
changes in orientation can cause large movements in the relative
positions of the outer rings.
Figure 2. Effects of compounds 1 and 3 on the autophosphorylation
of the insulin receptor cytoplasmic kinase domain (CKD). Results are
mean ( SEM values of three independent experiments.
Compound 30 was chosen for further characterization as a
representative example from this series. At this stage, it is
unknown with certainty if the pharmacological properties of 30
differed compared to 29. This is currently under investigation.
In mouse 3T3-HIR cells that overexpress the human IR, 30 (10
µM) significantly potentiated the effects of 2.5 nM insulin to
increase the tyrosine phosphorylation of the IR (Figure 3). At
3 µM 30 + 2.5 nM insulin, there was a trend toward increasing
in IR phosphotyrosine (∼75%) vs ∼50% with 2.5 nM insulin
alone. At 10 µM, 30 plus insulin increased IR tyrosine
phosphorylation to a degree similar to 100 nM insulin alone.
Compound 30, at concentrations 18 µM or greater, was able to
increase tyrosine phosphorylation of the IR in the absence of
insulin.
Figure 3. Effect of compound 30 on insulin receptor tyrosine
phosphorylation.
The effects of 30 on glucose transport has been evaluated in
3T3-L1 adipocytes.36 In the absence of insulin, 30 and 50 µM
30 produced a significant increase in glucose transport by
4-position of the terminal ring resulted in compounds 22 and
23 with increased potency, and this trend was also observed by

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6179
Table 3. Glucose Uptake Data for Analogues with Changes to the Sulfonamide Linkera
compd
linker (A f B)
R
EC50 (µM)
no. of assays
P
10
4
33
34
35
-SO2NH-
-SO2NH-
-CONH-
CO2H
SO3Na
CO2H
SO3Na
SO3Na
24
22
>200
>200
91
1
2
1
1
1
ns vs 4
ns vs 3
inactive compound
inactive compound
<0.001 vs 10; <0.001 vs 4
-CONH-
-SO2N(CH3)-
a Test compounds were evaluated in each screening assay at four concentrations using triplicate incubations in the presence of 5.6 nM insulin, a submaximally
effective concentration, as described in Experimental Section. The EC50 value was calculated using nonlinear regression analysis of the best-fit curve of the
untransformed data. Values shown are the mean ( SEM [when n (number of independent assays) g 3]. Under the conditions employed, the % coefficient
of variation for this screening assay was typically e15%. For statistical comparison of test compounds when n g 2, an unpaired t test was used to compare
the EC50 of two compounds. For statistical comparisons of a panel of compounds when n ) 1, an ANOVA (repeated measures) was used to compare the
counts per minute data (four concentrations, triplicate incubations) followed by the Newman-Keuls multiple comparison test. Significance was accepted at
P < 0.05. Typically, 2-fold differences in EC50 values were statistically significant, while differences less than 2-fold were not. All analyses were performed
using GraphPad Prism (MS Windows, version 4.03), GraphPad Software, San Diego, CA (www.graphpad.com). ns, not significant.
Figure 5. Effect of a single intraperitoneal (ip) dose of compound 30
in an oral glucose tolerance test in STZ-diabetic rats. Glucose load
was administered 15 min postdose (50 mg/kg): (/) p ) 0.014 (t test,
unpaired).
Figure 4. GLUT4 content at the plasma membrane is increased by
treatment with compound 30: (/) p < 0.05; (//) p < 0.01.
approximately 340% and 875%, respectively. Additional experi-
ments evaluating the effects of 30 on insulin-stimulated glucose
transport in 3T3-L1 adipocytes were also performed using
additional concentrations of insulin. In the presence of 10 and
30 µM 30, the insulin concentration-response curve was
significantly left-shifted, indicative of an IR sensitizing effect.36
Taken together, these results indicate that at concentrations of
g30 µM, compound 30 increases glucose transport in the
absence of insulin but functions more potently to enhance insulin
stimulated glucose transport (i.e., functions as a cellular insulin
sensitizer).
Compound 30 also increased plasma membrane GLUT4
content by ∼85% in adipocytes stimulated with 50 nM insulin
(Figure 4). This is consistent with the increase in glucose
transport activity observed with compound 30 and the expected
translocation of GLUT4 from intracellular stores to the cell
membrane following IRTK activation.
To illustrate the selectivity for the IR, compound 30 was
tested for its ability to enhance tyrosine phosphorylation of the
related insulin-like growth factor-1 (IGF-1R) and epidermal
growth factor (EGFR) receptors. At concentrations up to 30 µM,
30 had no effect on either IGF-1-stimulated tyrosine phospho-
rylation of the IGF-1R or EGF-stimulated phosphorylation of
the EGFR.36
Compound 30 was also tested in vivo for its ability to improve
glucose tolerance in an oral glucose tolerance test in hypoin-
sulinemic rats. A single ip dose of 30 (50 mg/kg) was able to
lower blood glucose (p ) 0.014) by approximately 25% by 30
min after glucose loading (Figure 5).
Compound 30 (1000 mg/kg) was also orally active in this
model and produced an approximate 32% reduction in blood
glucose (p < 0.05) by 30 min after glucose loading (Figure 6).
Protease inhibitor therapy is known to reduce the morbidity
and mortality associated with HIV infection. However,
protease inhibitors are also associated with metabolic ab-
normalities including insulin resistance, hyperglycemia, and
hypertriglyceridemia.42,43 In normal rats made insulin resis-
tant by the HIV protease inhibitor indinavir, oral administra-
tion of 30 (10 mg/kg) resulted in improved glucose tolerance
and reduced plasma insulin levels 30 min after the glucose
challenge.36 Streptozotocin (STZ)-treated rats are hypergly-
cemic and hypoinsulinemic and are significantly more insulin
resistant than indinavir-treated rats. In addition, the hyper-
glycemia that is a consequence of STZ treatment further
exacerbates the insulin resistance, a condition commonly
referred to as glucotoxicity. In contrast, indinavir-treated rats
are normoglycemic with normal insulin levels. Hence, it is

6180 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
Table 4. Glucose Uptake Data for Analogues with Changes to the Urea
Linker
Figure 6. Effect of a single oral (po) dose of compound 30 in an oral
glucose tolerance test in STZ-diabetic rats. Glucose load was admin-
istered 15 min postdose (1000 mg/kg): (/) p < 0.05 (t test, unpaired).
validation that small molecule IRTK activators represent a
potential new class of antidiabetic agent.
Experimental Section
General. Unless otherwise noted, materials were obtained from
commercial suppliers and were used without further purification.
7-Amino-2-naphthalenesulfonic acid (TCI America) and 7-amino-
4-hydroxy-2-naphthalenesulfonic acid (Fluka) were purified prior
to use by filtration (0.2 µm nylon filter) of a 1 N NaOH solution
followed by precipitation of the zwitterion after acidification with
HCl. The silica gel used in column chromatography was 230-400
mesh from EM Science. Reverse-phase HPLC (RP-HPLC) was
performed with a C18 stationary phase and a solvent system of
CH3CN/H2O and 0.5%TFA or CH3CN/H2O and NH4OAc. Melting
points (Pyrex capillary) were determined on a Mel-Temp apparatus
and are uncorrected. 1H (300 Mhz) and 13C (75 Mhz) NMR spectra
were recorded on a Varian XL-300 spectrometer. Chemical shifts
1
for H spectra are reported as δ values in parts per million (ppm)
relative to DMSO at 2.51 ppm, CD3OD at 3.31 ppm, or TMS at
0.00 ppm in CDCl3. Chemical shifts for 13C spectra are reported
as δ values in ppm relative to DMSO at 39.5 ppm or CDCl3 at
77.0 ppm. Coupling constants (J) are reported in hertz (Hz). The
splitting pattern abbreviations are designated as follows: s ) singlet,
d ) doublet; dd ) doublet of doublets, t ) triplet, q ) quartet, br
) broad, m ) multiplet, app ) apparent. Matrix assisted laser
desorption ionization (MALDI) mass spectra were obtained using
a Finnigan Lasermat. Electospray ionization (ES) mass spectra were
obtained using a Hewlett-Packard series 1100 MSD. Elemental
analyses were performed by Quantitative Technologies Inc. (White-
house, NJ).
not unexpected that the efficacious dose of 30 was higher in
STZ-treated rats compared to indinavir-treated rats.
Conclusion
3-{[(4-Hydroxy-7-{[(5-hydroxy-7-{[(3-sulfophenyl)amino]su-
lfonyl}(2-naphthyl))amino]carbonylamino}-2-naphthyl)sulfonyl]-
amino}benzenesulfonic Acid, Disodium Salt (3). The title compound
was prepared as described for compound 23 from compound 47
and 4-methylphenyl 3-aminobenzenesulfonate (54) in 55% overall
A series of compounds based upon the symmetrical ureas of
[(7-amino(2-naphthyl))sulfonyl]phenylamines were designed and
synthesized. The presence of an acidic functionality on the
terminal benzene rings was shown to be critical for activity.
The relative positioning of these two acidic groups was also
important because changes to the central urea linker cause
conformation changes in the central hinge of the molecule, and
therefore, changes in the relative positions of the two acidic
groups invariably gave analogues with little or no activity.
1
yield as a tan solid. H NMR (DMSO-d6) δ 10.83 (2H, s), 10.42
(2H, s), 9.53 (2H, s), 8.13 (2H, d, J ) 1.6 Hz), 8.07 (2H, d, J )
9.0 Hz), 7.74 (2H, s), 7.66 (2H, dd, J ) 1.9 Hz, J ) 9.2 Hz), 7.46
(2H, s), 7.13-7.24 (6H, m), 7.01 (2H, d, J ) 1.6 Hz); 13C NMR
(DMSO-d6) δ 154.2, 152.7, 148.9, 139.1, 138.0, 137.4, 133.9, 128.3,
123.1, 122.1, 121.1, 120.8, 119.6, 117.6, 117.4, 114.3, 102.5; MS
(MALDI(-)) m/z 835 (M - Na). Anal. (C33H24N4Na2O13S4) C, H,
N.
General Method A (Scheme 1). To compound 44 or 45 dissolved
in THF was added a solution of 2.2 equiv of the aniline as a solution
in THF with 5 equiv of pyridine. The mixture was allowed to stir
at ambient temperature for 16 h. The products were purified by
RP-HPLC, silica gel flash chromatography, or extraction followed
by chromatography.
Many compounds in the series stimulated the activity of the
IRTK, leading to an increase in glucose uptake in cells. In
addition several analogues showed activity in animal models
of type 2 diabetes. These data demonstrate that interaction of
these small molecules with the IR is able to elicit a similar
response both in vitro and in vivo as the interaction of insulin
with the IR. Therefore, our data provide pharmacological

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6181
1
3-{[(7-{[(7-{[(3-Sulfophenyl)amino]sulfonyl}-2-naphthyl)am-
ino]carbonylamino}-2-naphthyl)sulfonyl]amino}benzenesulfonic Acid,
Disodium Salt (4). The reaction of 44 with 4-methylphenyl 3-ami-
nobenzenesulfonate (54) according to general method A gave
4-methylphenyl 3-[({7-[({7-[({3-[(4-methylphenyl)oxysulfonyl]
phenyl}amino)sulfonyl]-2-naphthyl}amino)carbonylamino]-2-
naphthyl}sulfonyl)amino]benzenesulfonate in 84% yield as an off-
solid: mp ) 160-165 °C; H NMR (DMSO-d6) δ 10.63 (1H, s),
8.00 (1H, s), 7.80 (1H, d, J ) 8.4 Hz), 7.68 (1H, d, J ) 8.8 Hz),
7.53 (1H, d, J ) 2.6 Hz), 7.39 (1H, d, J ) 8.7 Hz), 7.34 (1H, dd,
J ) 1.5 Hz, J ) 8.7 Hz), 7.27 (1H, dd, J ) 2.7 Hz, J ) 8.7 Hz),
7.11 (1H, dd, J ) 2.0 Hz, J ) 8.7 Hz), 6.96 (1H, s); 13C NMR
(DMSO-d6) δ 165.8, 147.4, 136.8, 136.1, 133.5, 131.6, 131.2, 128.9,
128.5, 127.5, 126.2, 124.8, 123.1, 121.4, 121.2, 116.6, 107.0; MS
(ES(-)) m/z 375 (M - H).
1
white solid. H NMR (DMSO-d6) δ 10.94 (2H, s), 9.23 (2H, s),
8.31 (2H, s), 8.26 (2H, s), 8.05 (2H, d, J ) 8.8 Hz), 7.98 (2H, d,
J ) 9.1 Hz), 7.76 (2H, dd, J ) 2.0 Hz, J ) 8.9 Hz), 7.63 (2H, dd,
J ) 1.7 Hz, J ) 8.7 Hz), 7.57-7.59 (4H, m), 7.50 (2H, app t, J )
8.2 Hz), 7.35 (2H, d, J ) 7.8 Hz), 6.84 (4H, d, J ) 8.4 Hz), 6.51
(4H, d, J ) 8.6 Hz), 2.12 (6H, s); 13C NMR (DMSO-d6) δ 152.2,
146.5, 138.8, 138.7, 136.5, 136.3, 135.2, 132.2, 130.4, 130.3, 129.8,
129.0, 128.4, 126.7, 125.2, 123.0, 122.5, 120.9, 119.5, 118.1, 114.4,
19.9; MS (MALDI(-)) m/z 962 (M - H).
This material was hydrolyzed in a 1:1 mixture of aqueous 2 N
NaOH and methanol at 50 °C for 6 h. Purification by RP-HPLC
gave the title compound in 98% yield as a tan solid. 1H NMR
(DMSO-d6) δ 10.38 (2H, br s), 9.31 (2H, s), 8.28 (2H, s), 8.19
(2H, s), 7.97 (2H, d, J ) 8.7 Hz), 7.93 (2H, d, J ) 9.2 Hz), 7.77
(2H, dd, J ) 1.9 Hz, J ) 9.0 Hz), 7.60 (2H, dd, J ) 1.7 Hz, J )
8.7 Hz), 7.43 (2H, s), 7.12-7.21 (6H, m); 13C NMR (DMSO-d6)
δ 152.5, 149.1, 138.8, 137.2, 137.1, 132.4, 130.2, 128.9, 128.5,
128.3, 126.6, 122.2, 121.1, 119.9, 119.5, 117.4 114.2; MS
(MALDI(-)) m/z 802 (M - Na). Anal. (C33H24N4Na2O11S4) C, H,
N.
5-{[(7-{[(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}-5-hy-
droxy(2-naphthyl))amino]carbonylamino}-4-hydroxy(2-naphthyl))-
sulfonyl]amino}-2-chlorobenzoic Acid (22). The title compound was
prepared by method A from compound 45 and 5-amino-2-
chlorobenzoic acid in 63% yield as a brown solid. 1H NMR
(DMSO-d6) δ 13.41 (2H, br s), 10.84 (2H, s), 10.71 (2H, s), 9.17
(2H, s), 8.15 (2H, s), 8.09 (2H, d, J ) 9.2 Hz), 7.75 (2H, s), 7.67
(2H, dd, J ) 1.8 Hz, J ) 9.1 Hz), 7.55 (2H, d, J ) 2.7 Hz), 7.42
(2H, d, J ) 8.8 Hz), 7.29 (2H, dd, J ) 2.6 Hz, J ) 8.7 Hz), 6.97
(2H, d, J ) 1.5 Hz); 13C NMR (DMSO-d6) δ 165.9, 154.2, 152.4,
139.0, 137.1, 136.9, 133.7, 131.7, 131.4, 126.3, 123.04, 123.01,
122.0, 121.4, 120.9, 117.5, 114.4, 101.9; MS (ES(-) m/z 811 (M
- H). Anal. (C35H24Cl2N4O11S2) C, H, N.
To 3.90 g (10.4 mmol) of 5-{[(7-amino(2-naphthyl))sulfony-
l]amino}-2-chlorobenzoic acid was added 55 mL of 1 M acetate
buffer (pH 4.6), 2.1 mL of 5 N NaOH (10.5 mol), and 34 mL of
THF. To this reaction solution, a solution of 0.508 g (1.71 mmol)
of triphosgene in 2 mL of THF was added slowly over a 1 h period.
The reaction was judged incomplete, so another 4.2 mL of 5 N
NaOH and 25 mL of water were added followed by the dropwise
addition of a THF solution of 0.508 g of triphosgene in 2 mL of
THF. The reaction was still incomplete, so another 4.2 mL of 5 N
NaOH, 25 mL of water, and 0.508 g of triphosgene in 2 mL of
THF (dropwise) were added. The reaction was essentially complete.
The volatiles (THF) were removed from the reaction by rotary
evaporation, and then the mixture was acidified with concentrated
HCl. The resulting solid was collected by vacuum filtration and
was washed with water. After drying in vacuo, this provided 3.79 g
(93%) of the title compound as an off-white solid: mp ) 182-185
1
°C; H NMR (DMSO-d6) δ 13.42 (2H, br s), 10.73 (2H, s), 9.23
(2H, s), 8.32 (2H, s), 8.25 (2H, d, J ) 1.3 Hz), 8.02 (2H, d, J )
8.8 Hz), 7.97 (2H, d, J ) 8.8 Hz), 7.76 (2H, dd, J ) 1.9 Hz, J )
9.0 Hz), 7.62 (2H, dd, J ) 1.6 Hz, J ) 8.7 Hz), 7.54 (2H, d, J )
2.7 Hz), 7.41 (2H, d, J ) 8.7 Hz), 7.31 (2H, dd, J ) 2.6 Hz, J )
8.7 Hz); 13C NMR (DMSO-d6) δ 165.8, 152.4, 138.8, 136.7, 136.6,
132.3, 131.7, 131.4, 130.3, 129.2, 128.6, 126.8, 126.5, 123.2, 122.6,
121.5, 119.8, 114.5; MS (MALDI(-)) m/z 780 (M - H). Anal.
(C35H24Cl2N4O9S2) C, H, N.
5-{[(7-{[(7-{[(3-Carboxy-4-hydroxyphenyl)amino]sulfonyl}-5-hy-
droxy(2-naphthyl))amino]carbonylamino}-4-hydroxy(2-naphthyl))-
sulfonyl]amino}-2-hydroxybenzoic Acid (24). The title compound
was prepared by method A from compound 45 and 5-aminosalicylic
1
acid in 5% yield as a white solid. H NMR (DMSO-d6) δ 10.75
(2H, s), 10.07 (2H, s), 9.14 (2H, s), 8.08 (2H, d, J ) 8.9 Hz), 8.08
(2H, d, J ) 2.1 Hz), 7.66 (2H, dd, J ) 2.0 Hz, J ) 9.2 Hz), 7.61
(2H, s), 7.52 (2H, d, J ) 2.7 Hz), 7.24 (2H, dd, J ) 2.8 Hz, J )
8.8 Hz), 6.92 (2H, d, J ) 1.5 Hz), 6.84 (2H, d, J ) 8.8 Hz); MS
(ES(-)) m/z 773 (M - H). Anal. (C35H26N4O13S2) C, H, N.
2-Hydroxy-5-{[(7-{[(7-sulfo(2-naphthyl))amino]carbonylamino}(2-
naphthyl))sulfonyl]amino}benzoic Acid (25). This compound was
prepared by a variation of the general method A. To 120 mg (0.78
mmol) of 5-aminosalicylic acid suspended in 4 mL of pyridine was
added 100 mg (0.20 mmol) of compound 44 as a solid. The mixture
was allowed to stir at ambient temperature for 16 h. Then 100 mL
of diethyl ether was added and the resulting solid collected by
centrifugation. The title compound was obtained by RP-HPLC
purification using a gradient system of CH3CN/H2O and 0.5% TFA.
This provided 24 mg (20%) of the desired product 25 as a brown
solid. 1H NMR (DMSO-d6) δ 9.73 (1H, s), 9.24 (1H, s), 9.18 (1H,
s), 8.15 (1H, s), 8.14 (1H, s), 8.03 (1H, s), 8.01 (1H, s), 7.96 (1H,
d, J ) 8.0 Hz), 7.94 (1H, d, J ) 8.3 Hz), 7.85 (1H, d, J ) 8.8 Hz),
7.78 (2H, d, J ) 8.3 Hz), 7.67 (1H, dd, J ) 1.8 Hz, J ) 8.7 Hz),
7.57 (1H, dd, J ) 1.4 Hz, J ) 8.4 Hz), 7.53 (1H, dd, J ) 1.8 Hz,
J ) 8.7 Hz), 7.46 (1H, d, J ) 2.8 Hz), 6.94 (1H, d, J ) 8.8 Hz),
6.53 (1H, d, J ) 8.8 Hz); 13C NMR (DMSO-d6) δ 171.4, 159.6,
152.6, 145.8, 138.9, 137.7, 137.3, 132.7, 132.3, 131.3, 129.9, 128.8,
128.5, 128.3, 127.9, 127.6, 126.8, 126.43, 126.36, 124.7, 123.1,
122.1, 121.9, 120.1, 120.0, 116.2, 114.2, 114.1; MS (MALDI(-))
m/z 606 (M - H).
Representative Example of Method B (Scheme 2). 5-{[(7-{[(7-
{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-naphthyl))ami-
no]carbonylamino}(2-naphthyl))sulfonyl]amino}-2-chlorobenzoic
Acid (23). To 4.98 g (22.4 mmol) of methyl 5-amino-2-chloroben-
zoate hydrochloride was added 50 mL of THF followed by 11 mL
(0.136 mol) of pyridine. The stirred suspension was cooled in an
ice bath, and then 5.30 g (18.7 mmol) of N-[7-(chlorosulfonyl)-2-
naphthyl]acetamide (46) was added as a suspension in 50 mL of
THF. The mixture was allowed to warm to ambient temperature
and to stir for 16 h. All volatiles were removed by rotary
evaporation, and the resulting residue was extracted with ethyl
acetate and 1 N HCl. The organic layer was dried (MgSO4) and
filtered and volatiles were removed to provide 6.63 g (82%) of
methyl 5-({[7-(acetylamino)(2-naphthyl)]sulfonyl}amino)-2-chlo-
1
robenzoate as a faint yellow solid: mp ) 165-172 °C; H NMR
(DMSO-d6) δ 10.77 (1H, s), 10.31 (1H, s), 8.42 (1H, s), 8.31 (1H,
s), 8.01 (1H, d, J ) 8.5 Hz), 7.95 (1H, d, J ) 8.9 Hz), 7.74 (1H,
dd, J ) 1.8 Hz, J ) 8.9 Hz), 7.63 (1H, dd, J ) 1.7 Hz, J ) 8.6
Hz), 7.56 (1H, d, J ) 2.6 Hz), 7.43 (1H, d, J ) 8.7 Hz), 7.32 (1H,
dd, J ) 2.7 Hz, J ) 8.8 Hz), 3.81 (3H, s), 2.12 (3H, s); 13C NMR
(DMSO-d6) δ 168.7, 164.6, 138.4, 136.8, 136.4, 132.0, 131.5, 130.7,
130.2, 129.1, 128.3, 127.1, 126.5, 123.7, 122.7, 121.5, 120.1, 115.7,
52.4, 23.9; MS (MALDI(+)) m/z 457 (M + Na).
To 4.81 g (11.1 mmol) of the above material was added 160
mL of 5 N NaOH and 7 mL of dioxane. The mixture was allowed
to stir at 55 °C for 18 h. Then the mixture was diluted with 30 mL
of water and filtered through a 0.2 µm nylon filter. The resulting
clear filtrate was carefully acidified with 26 mL of concentrated
H2SO4. The finely divided solid precipitate was collected by vacuum
filtration and dried in vacuo. This produced 4.01 g (95%) of 5-{[(7-
amino(2-naphthyl))sulfonyl]amino}-2-chlorobenzoic acid as a tan
2-Chloro-5-{[(7-{[(7-{[(4-chloro-3-sulfophenyl)amino]sulfonyl}(2-
naphthyl))amino]carbonylamino}(2-naphthyl))sulfonyl]amino}ben-
zenesulfonic Acid, Disodium Salt (29). The title compound was
prepared as described for compound 23 (method B) from compound
46 and 4-methylphenyl 5-amino-2-chlorobenzenesulfonate (56) in
61% overall yield for three steps as a white solid. 1H NMR (DMSO-
d6) δ 10.51 (2H, s), 9.27 (2H, s), 8.29 (2H, s), 8.21 (2H, s), 8.00

6182 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
(2H, d, J ) 8.8 Hz), 7.95 (2H, d, J ) 8.8 Hz), 7.80 (2H, dd, J )
1.8 Hz, J ) 8.8 Hz), 7.71 (2H, d, J ) 2.7 Hz), 7.60 (2H, dd, J )
1.6 Hz, J ) 8.7 Hz), 7.22 (2H, d, J ) 8.5 Hz), 7.12 (2H, dd, J )
2.7 Hz, J ) 8.6 Hz); 13C NMR (DMSO-d6) δ 152.2, 145.9, 138.4,
137.4, 135.8, 132.1, 130.2, 130.0, 128.4, 128.0, 126.1, 125.2, 122.1,
121.1, 120.6, 119.7, 114.5; MS (ES(-)) m/z 851 (M - H). Anal.
(C33H22Cl2N4Na2O11S4) C, H, N.
5-({[7-({[(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-
naphthyl))amino]thioxomethyl}amino)(2-naphthyl)]sulfonyl}amino)-
2-chlorobenzoic Acid (38). To 53 mg (64.3 µmol) of compound 66
was added 5 mL of 1 N NaOH. The resulting solution was allowed
to stir for 1 h at ambient temperature, and then it was acidified
with 6 N HCl to pH 1. The resulting solid was collected by vacuum
filtration. Drying provided 44 mg (86%) of the title compound as
a white solid. 1H NMR (DMSO-d6) δ 13.42 (2H, br s), 10.73 (2H,
s), 10.31 (2H, s), 8.38 (2H, s), 8.19 (2H, d, J ) 1.4 Hz), 8.07 (2H,
d, J ) 8.8 Hz), 7.98 (2H, d, J ) 9.2 Hz), 7.85 (2H, dd, J ) 1.8
Hz, J ) 8.9 Hz), 7.69 (2H, dd, J ) 1.7 Hz, J ) 8.7 Hz), 7.54 (2H,
d, J ) 2.7 Hz), 7.39 (2H, d, J ) 8.8 Hz), 7.29 (2H, dd, J ) 2.7
Hz, J ) 8.8 Hz); 13C NMR (DMSO-d6) δ 180.0, 165.6, 138.6,
136.5, 131.8, 131.7, 131.6, 131.2, 131.1, 128.9, 127.7, 127.0, 126.7,
126.4, 123.2, 121.6, 120.9, 120.8; MS (ES(-)) m/z 795 (M). Anal.
(C35H24Cl2N4O8S3) C, H, N.
5-{[(7-{2-Amino-1-aza-2-[(7-{[(3-carboxy-4-chlorophenyl)amino]-
sulfonyl}(2-naphthyl))amino]vinyl}(2-naphthyl))sulfonyl]amino}-
2-chlorobenzoic Acid (39). To 50 mg (62.0 µmol) of compound 67
was added 10 mL of 1 N NaOH. The resulting solution was allowed
to stir at ambient temperature for 1 h. The mixture was acidified to
pH 1 using 11 mL of 1 N HCl. A white precipitate formed, which
was collected by vacuum filtration and was washed with water.
The solid was dried in vacuo to provide 45 mg (93%) of the title
compound as a white solid. 1H NMR (DMSO-d6) δ 10.65 (2H, br
s), 8.40 (2H, s), 8.08 (2H, d, J ) 9.3 Hz), 8.06 (2H, s), 8.02 (2H,
d, J ) 8.9 Hz), 7.71 (2H, dd, J ) 1.5 Hz, J ) 8.7 Hz), 7.62 (2H,
dd, J ) 1.7 Hz, J ) 8.7 Hz), 7.43 (2H, d, J ) 2.6 Hz), 7.34 (2H,
d, J ) 8.7 Hz), 7.24 (2H, dd, J ) 2.6 Hz, J ) 8.7 Hz); 13C NMR
(DMSO-d6) δ 166.7, 152.3, 138.3, 136.7, 136.4, 133.8, 132.2, 131.4,
130.8, 129.0, 128.8, 126.9, 126.0, 125.7, 122.5, 121.3, 120.7, 120.5;
MS (MALDI(+)) m/z 779 (M).
5-{[(7-{[N-(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-
naphthyl))-N-methylcarbamoyl]methylamino}(2-naphthyl))sulfo-
nyl]amino}-2-chlorobenzoic Acid (42). To 300 mg (0.58 mmol) of
7-{[(7-sulfo-2-naphthyl)amino]carbonylamino}naphthalene-2-sul-
fonic acid, disodium salt (first intermediate in synthesis of 44)
suspended in 40 mL of DMF was added 60 mg (60% dispersion in
mineral oil, 1.50 mmol) of NaH. The mixture was allowed to stir
for 1 h, and then 90 µL (1.45 mmol) of iodomethane was added.
The mixture was allowed to stir for 19 h, and then another 25 mg
(0.625 mmol) of NaH dispersion was added followed by 30 µL
(0.483 mmol) of iodomethane after 1 h. The mixture was allowed
to stir an additional 24 h before precipitation with diethyl ether.
The resulting solid was collected by vacuum filtration, and the solid
was dissolved in water. The product was precipitated by the addition
of brine and was collected by vacuum filtration. Drying provided
7-{N-methyl[methyl(7-sulfo(2-naphthyl))amino]carbonylamino}-
naphthalene-2-sulfonic acid, disodium salt, as a white solid. 1H
NMR (DMSO-d6) δ 8.01 (2H, s), 7.65 (2H, d, J ) 8.8 Hz), 7.63
(2H, s), 7.55 (4H, d, J ) 6.8 Hz), 7.17 (2H, dd, J ) 1.9 Hz, J )
8.8 Hz), 3.22 (6H, s); MS (MALDI(-)) m/z 521 (M - Na).
To all of the product from step 1 was added 25 mL of phosphorus
oxychloride. This stirred suspension was cooled in an ice bath for
1 h and then allowed to warm to room temperature. The suspension
was allowed to stir at ambient temperature for 26 h. Then the cloudy
suspension was poured onto 1 L of ice and this suspension placed
in a second ice bath. After the ice had melted, the precipitate was
collected by vacuum filtration and was washed with water. The
white solid was dried to provide 247 mg of N-[7-(chlorosulfonyl)(2-
naphthyl)]{[7-(chlorosulfonyl)(2-naphthyl)]methylamino}-N-meth-
ylcarboxamide.
2-Chloro-5-{[(7-{[(7-{[(4-chloro-3-sulfophenyl)amino]sulfonyl}-
5-hydroxy(2-naphthyl))amino]carbonylamino}-4-hydroxy(2-
naphthyl))sulfonyl]amino}benzenesulfonic Acid, Disodium Salt
(30). The title compound was prepared as described for compound
23 (method B) from compound 47 and 4-methylphenyl 5-amino-
2-chlorobenzenesulfonate (56) in 29% overall as a white solid. 1H
NMR (DMSO-d6) δ 10.83 (2H, s), 10.48 (2H, s), 9.23 (2H, s),
8.11 (2H, d, J ) 2.5 Hz), 8.09 (2H, d, J ) 8.7 Hz), 7.75 (2H, d,
J ) 1.4 Hz), 7.73 (2H, d, J ) 2.7 Hz), 7.71 (2H, dd, J ) 2.5 Hz,
J ) 8.7 Hz), 7.22 (2H, d, J ) 8.5 Hz), 7.05 (2H, dd, J ) 2.7 Hz,
J ) 8.5 Hz), 6.96 (2H, d, J ) 1.4 Hz); 13C NMR (DMSO-d6) δ
154.1, 152.4, 145.6, 139.0, 137.5, 135.9, 133.7, 130.8, 125.5, 123.0,
122.0, 120.79, 120.76, 120.5, 117.4, 114.3, 102.1; MS (ES(-)) m/z
882 (M - H). Anal. (C33H22Cl2N4Na2O13S4 ·0.5NaCl) C, H, N, Cl.
3-({7-[(N-{7-[N-(3-Carboxyphenyl)carbamoyl]-2-naphthyl}car-
bamoyl)amino]-2-naphthyl}carbonylamino)benzoic Acid (33). To
20 mg (0.022 mmol) of compound 61 was added 1.5 mL of 1.37
M sodium methoxide in methanol, 1 mL of water, and 0.5 mL of
THF. The resulting solution was allowed to stir at ambient
temperature for 2 days. The reaction was acidified with 1 N HCl
(aqueous), and the organic volatiles were removed in vacuo. The
solid precipitate was collected by vacuum filtration to afford 13
mg (90%) of the title compound as a tan solid. 1H NMR (DMSO-
d6) δ 13.00 (2H, br s), 10.57 (2H, s), 9.19 (2H, s), 8.54 (2H, s),
8.48 (2H, s), 8.34 (2H, s), 8.12 (2H, d, J ) 7.9 Hz), 7.96-8.00
(4H, m), 7.90 (2H, dd, J ) 1.5 Hz, J ) 8.4 Hz), 7.68-7.71 (4H,
m), 7.51 (2H, app t, J ) 7.9 Hz); 13C NMR (DMSO-d6) δ 127.3,
126.0, 113.0, 99.7, 98.3, 93.1, 92.6, 91.6, 90.7, 89.0, 88.5, 87.9,
87.3, 84.7, 82.8, 81.8, 81.5, 74.9; MS (MALDI(-)) m/z 638 (M).
5-({[7-(N-{2-[N-(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-
naphthyl))acetylamino]ethyl}acetylamino)(2-naphthyl)]sulfonyl}-
amino)-2-chlorobenzoic Acid (36). To 750 mg (4.37 mmol) of
5-amino-2-chlorobenzoic acid was added 30 mL of THF and 605
µL of pyridine. This solution was cooled in an ice bath, and then
452 mg (0.76 mmol) of the disulfonyl chloride (63) was added.
The mixture was left to stir and warm to room temperature for
16 h. Then the volatiles were removed by rotary evaporation. The
resulting residue was extracted with ethyl acetate and 0.5 N HCl.
The ethyl acetate layer was dried (MgSO4) and filtered, and the
volatiles were removed by rotary evaporation. The title compound
was purified by silica gel column chromatography, eluting with
20:2:1 ethyl acetate/isopropanol/water and then 10:2:1 ethyl actate/
isopropanol/water. This provided 156 mg (24%) of the desired
product as a white solid. 1H NMR (DMSO-d6) δ 8.26 (2H, s), 8.01
(2H, d, J ) 7.4 Hz), 7.88 (2H, d, J ) 8.4 Hz), 7.78 (2H, s), 7.76
(2H, d, J ) 7.4 Hz), 7.38 (2H, d, J ) 8.4 Hz), 7.26 (2H, s), 7.11
(2H, d, J ) 8.5 Hz), 7.02 (2H, d, J ) 8.1 Hz), 3.87 (4H, s), 1.70
(6H, s); MS (MALDI(+)) m/z 886 (M + Na).
5-({[7-({2-[(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-
naphthyl))amino]ethyl}amino)(2-naphthyl)]sulfonyl}amino)-2-chlo-
robenzoic Acid (37). To 156 mg (0.18 mmol) of compound 36 was
added 10 mL of 5 N NaOH, and the resulting solution was heated
at 70 °C for 16 h. The mixture was cooled and then acidified with
6 N HCl to pH 1. The resulting solid was collected by vacuum
filtration to give, after drying, 137 mg (98%) of the title compound
as a tan solid. 1H NMR (DMSO-d6) δ 13.43 (2H, br s), 10.62 (2H,
s), 8.08 (2H, s), 7.80 (2H, d, J ) 8.4 Hz), 7.68 (2H, d, J ) 8.8
Hz), 7.53 (2H, d, J ) 2.6 Hz), 7.39 (2H, d, J ) 8.7 Hz), 7.35 (2H,
dd, J ) 1.8 Hz, J ) 8.5 Hz), 7.27 (2H, dd, J ) 2.6 Hz, J ) 8.8
Hz), 7.16 (2H, dd, J ) 2.1 Hz, J ) 8.8 Hz), 6.95 (2H, s), 6.35
(2H, br s), methylene protons are under HOD peak; MS (ES(-))
m/z 778 (M - H).
To 300 mg (1.62 mmol) of methyl 5-amino-2-chlorobenzoate
dissolved in 15 mL of freshly distilled THF was added 100 µL
(1.24 mmol) of pyridine. To this solution was added 243 mg (0.452
mmol) of the disulfonylchloride prepared above. The mixture was
heated to reflux for 40 h. Then the mixture was partitioned between
ethyl acetate and 1 N HCl (aq). The organic layer was further
washed with 6 N HCl (2×), 1 N NaHCO3 (2×), water, and brine.
The ethyl acetate layer was dried with MgSO4 and filtered, and the
volatiles were removed by rotary evaporation. This provided 275

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6183
mg (73%) of methyl 2-chloro-5-({[7-({N-[7-({[4-chloro-3-(methoxy-
carbonyl)phenyl]amino}sulfonyl)(2-naphthyl)]-N-
methylcarbamoyl}methylamino)(2-naphthyl)]sulfonyl}amino)-
benzoate as an off-white solid. 1H NMR (DMSO-d6) δ 10.75 (2H,
br s), 8.28 (2H, s), 7.75 (2H, d, J ) 8.5 Hz), 7.74 (2H, s), 7.56
(2H, dd, J ) 1.6 Hz, J ) 8.7 Hz), 7.55 (2H, d, J ) 2.6 Hz), 7.45
(2H, d, J ) 8.7 Hz), 7.40 (2H, d, J ) 9.1 Hz), 7.29 (2H, dd, J )
2.7 Hz, J ) 8.7 Hz), 7.22 (2H, dd, J ) 2.1 Hz, J ) 8.9 Hz), 3.81
(6H, s), 3.24 (6H, s); MS (ES(-)) m/z 835 (M - H).
To 140 mg (0.168 mmol) of the product from step 3 was added
25 mL of 1 N NaOH (aq). After 1 h, the reaction solution was
acidified with 6 N HCl (aq) to produce a white precipitate. The
solid was collected by vacuum filtration, washed with water, and
dried to give 119 mg (88%) of the title compound as a white solid.
1H NMR (DMSO-d6) δ 13.53 (2H, br s), 10.71 (2H, s), 8.27 (2H,
s), 7.74 (2H, d, J ) 8.7 Hz), 7.72 (2H, s), 7.55 (2H, dd, J ) 1.6
Hz, J ) 8.8 Hz), 7.54 (2H, d, J ) 2.8 Hz), 7.41 (2H, d, J ) 8.8
Hz), 7.35 (2H, d, J ) 8.7 Hz), 7.26 (2H, dd, J ) 2.8 Hz, J ) 8.7
Hz), 7.18 (2H, dd, J ) 2.0 Hz, 8.9 Hz), 3.24 (6H, s); 13C NMR
(DMSO-d6) δ 165.7, 159.1, 143.6, 136.5, 136.2, 131.8, 131.7, 131.6,
131.1, 130.9, 128.5, 127.7, 127.0, 126.4, 126.2, 123.1, 121.5, 120.7,
37.7; MS (ES(-)) m/z 807 (M - H).
an ice bath. After all the ice within the flask had melted, the solid
was collected by vacuum filtration and was washed with water.
The solid was dried under high vacuum for 24 h. This produced
2.29 g (99%) of the title compound as a white solid. 1H NMR
(DMSO-d6) δ 9.10 (2H, s), 8.00 (4H, s), 7.84 (2H, d, J ) 9.1 Hz),
7.77 (2H, d, J ) 8.5 Hz), 7.70 (2H, dd, J ) 2.0 Hz, J ) 8.8 Hz),
7.56 (2H, dd, J ) 1.5 Hz, J ) 8.5 Hz). This compound was used
without further characterization.
N-[7-(Chlorosulfonyl)-5-hydroxy(2-naphthyl)]{[7-(chlorosulfo-
nyl)-5-hydroxy(2-naphthyl)]amino}carboxamide (45). To 10.77 g
(0.045 mol) of 7-amino-4-hydroxy-2-naphthalenesulfonic acid
dissolved in 45 mL of 1 N aqueous NaOH and 50 mL of water
was added 3.70 g (0.045 mol) of sodium acetate. The pH of the
solution was above 9. The mixture was cooled to less than 5 °C in
an ice-water bath. Then 2.23 g (7.50 mmol) of triphosgene
dissolved in 15 mL of THF was added in three portions. The pH
of the mixture fell to 4-5 and was readjusted to 7-8 by the addition
of 1 N aqueous NaOH. TLC (6:2:1 ethyl acetate/isopropanol/water)
indicated the reaction was incomplete. Another 2.20 g (7.50 mmol)
of triphosgene in 10 mL of THF was added portionwise with the
pH kept above 7 by the addition of 1 N aqueous NaOH. When the
reaction was judged complete by TLC, the pH was lowered to 1
with aqueous HCl and the volatiles were removed by rotary
evaporation. The solid product was collected by vacuum filtration.
This afforded 10.85 g (88%) of 4-hydroxy-7-{[(5-hydroxy-7-
sulfo(2-naphthyl))amino]carbonylamino}naphthalene-2-sulfonic acid,
5-[({7-[3-(7-{[(3-Carboxy-4-chlorophenyl)amino]sulfonyl}(2-naph-
thyl))-2-oxoimidazolidinyl](2-naphthyl)}sulfonyl)amino]-2-chlo-
robenzoic Acid (43). To 126 mg (0.16 mmol) of compound 37 was
added 10 mL of saturated Na2CO3, 10 mL of water, and 10 mL of
THF. This formed a clear brown solution. To this solution was
added, dropwise over 30 min, a solution of 52 mg (0.18 mmol) of
triphosgene in 800 µL of THF. An aliquot was examined by HPLC,
and the reaction was determined to be incomplete. Then another
solution of triphosgene (53 mg in 800 µL of THF) was added
dropwise and the reaction monitored by HPLC. This was repeated
six times until all starting amine had been consumed. The reaction
solution was acidified with 6 N HCl and then reduced in volume
by rotary evaporation. The resulting brown solid was collected by
vacuum filtration. The title compound, 73 mg (56%), was obtained
by preparative RP-HPLC (CH3CN/water with 0.5% TFA) as a white
solid. 1H NMR (DMSO-d6) δ 13.45 (2H, br s), 10.75 (2H, s), 8.43
(2H, dd, J ) 2.0 Hz, J ) 8.8 Hz), 8.40 (2H, s), 8.06 (2H, d, J )
9.3 Hz), 8.05 (2H, s), 8.03 (2H, d, J ) 9.3 Hz), 7.66 (2H, dd, J )
1.8 Hz, J ) 8.6 Hz), 7.54 (2H, d, J ) 2.6 Hz), 7.41 (2H, d, J )
1
disodium salt, as a tan solid. H NMR (DMSO-d6) δ 10.06 (2H,
s), 9.22 (2H, s), 8.01 (2H, d, J ) 9.25 Hz), 7.96 (2H, d, J ) 2.15
Hz), 7.58 (2H, dd, J ) 2.15 Hz, J ) 9.25 Hz), 7.50 (2H, s), 7.03
(2H, s); 13C NMR (DMSO-d6) δ 152.9, 152.6, 146.2, 138.1, 134.2,
122.5, 120.3, 118.4, 114.3, 113.5, 104.4; MS (ES(-)) m/z 525 (M
- Na).
To 5.00 g (9.11 mmol) of 4-hydroxy-7-{[(5-hydroxy-7-sulfo(2-
naphthyl))amino]carbonylamino}naphthalene-2-sulfonic acid, di-
sodium salt, suspended in 70 mL of phosphorus oxychloride was
added dropwise 4 mL of dimethylacetamide. The mixture was
allowed to stir at ambient temperature for 24 h. Then the mixture
was poured onto 1 L of ice, and this flask was placed in an ice
bath. After the ice within the flask had melted, the solid was
collected by vacuum filtration and was washed with water. The
product was dried under high vacuum for 24 h to provide 4.1 g
(83%) of the title compound as a tan solid. This compound was
not stable to long-term storage and was therefore prepared and used
within a few weeks. The compound was used without characteriza-
tion.
8.7 Hz), 7.30 (2H, dd, J ) 2.5 Hz, J ) 8.6 Hz), 4.17 (4H, s); 13
C
NMR (DMSO-d6) δ 165.6, 154.1, 139.2, 136.6, 136.5, 131.9, 131.7,
131.2, 130.3, 128.9, 128.1, 127.0, 126.5, 123.3, 121.7, 121.3, 121.2,
120.1, 114.4; MS (ES(-)) m/z 805 (M - H). Anal. (C37H26Cl2-
N4O9S2) C, H, N.
N-[7-(Chlorosulfonyl)-2-naphthyl]acetamide (46). To a mixture
of 300 mL each of acetic anhydride and pyridine cooled in an ice
bath was added 59.7 g (0.27 mol) of solid 7-amino-2-naphthale-
nesulfonic acid portionwise, keeping the reaction temperature below
20 °C. After the final addition, the reaction solution was allowed
to warm to ambient temperature and stirred for 16 h. The suspension
was poured into a mixture of 2 L of diethyl ether and 1 L of THF.
The resulting solid was collected by vacuum filtration. The
pyridinum salt was dissolved in 300 mL of methanol. Next, a
sodium methoxide solution in methanol was prepared by the
addition of 7.9 g (0.34 mol) Na(s) to 300 mL of methanol. After
all of the Na(s) had reacted, this clear solution was added to
the above methanol solution of crude product. A solid began to
form and was allowed to sit for 12 h. The product was collected
by vacuum filtration and dried in vacuo to afford 64.2 g. The filtrate
was reduced in volume to about 400 mL and allowed to sit for an
additional 12 h for precipitate formation. Collection of this second
crop of product provided 4.8 g. This provided a total yield of 69.0 g
(88%) of 7-(acetylamino)naphthalene-2-sulfonic acid, sodium salt,
as a white solid. 1H NMR (DMSO-d6) δ 10.16 (1H, s), 8.16 (1H,s),
7.96 (1H, s), 7.83 (1H, d, J ) 8.8 Hz), 7.77 (1H, d, J ) 8.4 Hz),
7.68 (1H, dd, J ) 2.0 Hz, J ) 8.8 Hz), 7.58 (1H, dd, J ) 1.5 Hz,
J ) 8.5 Hz), 2.10 (3H, s); 13C NMR (DMSO-d6) δ 168.6, 146.0,
137.4, 132.6, 129.4, 127.9, 126.9, 123.5, 122.5, 120.5, 115.7, 24.0;
MS (MALDI(-)) m/z 263 (M - H).
N-[7-(Chlorosulfonyl)(2-naphthyl)]{[7-(chlorosulfonyl)(2-
naphthyl)]amino}carboxamide (44). To 5.25 g (0.024 mol) of
7-amino-2-naphthalenesulfonic acid suspended in 80 mL of water
was added a solution of 6.5 mL of 10 N aqueous NaOH (0.065
mol) diluted to 30 mL with water and a solution of 3.20 g (0.011
mol) of triphosgene in 30 mL of THF portionwise, alternating such
that the pH of the reaction was maintained above 8. After the
reaction was complete by TLC (6:2:1 ethyl acetate/isopropanol/
water) the pH was lowered to 1 with aqueous HCl and the volatiles
were removed by rotary evaporation. The solid product was
collected by vacuum filtration and was washed with water. This
afforded 3.41
g (63%) of 7-{[(7-sulfo-2-naphthyl)amino]-
carbonylamino}naphthalene-2-sulfonic acid, disodium salt, as an
off-white solid. 1H NMR (DMSO-d6) δ 9.04 (2H, s), 8.01 (2H, s),
8.00 (2H, d, J ) 2.0 Hz), 7.85 (2H, d, J ) 8.8 Hz), 7.77 (2H, d,
J ) 8.6 Hz), 7.71 (2H, dd, J ) 2.0 Hz, J ) 8.9 Hz), 7.57 (2H, dd,
J ) 1.5 Hz, J ) 8.5 Hz); 13C NMR (DMSO-d6) δ 152.6, 145.7,
137.8, 132.7, 128.8, 127.9, 126.9, 123.2, 121.9, 120.1, 114.0; MS
(MALDI(-)) m/z 492 (M - Na). To 2.35 g (4.55 mmol) of 7-{[(7-
sulfo-2-naphthyl)amino]carbonyl amino}naphthalene-2-sulfonic acid,
disodium salt, prepared above was added 116 mL of sulfolane, 25
mL of acetonitrile, 31 mL of phosphorus oxychloride, and 1 mL
of dimethylacetamide. The mixture was allowed to stir for 72 h at
ambient temperature. This produced a nearly clear solution. The
mixture was poured onto 1.5 L of ice, and the flask was placed in

6184 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Lum et al.
To 10.3 g (35.8 mmol) of the above material was added 125
mL of phosphorus oxychloride. The resulting suspension was
allowed to cool in an ice bath until an internal temperature of 5 °C
was reached. Then 5 mL of dimethylacetamide was added dropwise.
The mixture was allowed to stir and warm to ambient temperature
for 23 h. Then the suspension was poured onto 4 L of ice. The
container of ice was placed in a second container of ice and allowed
to melt. When most of the ice had melted, the white solid precipitate
was collected by vacuum filtration and washed with additional
water. The solid was dried in vacuo to afford 6.67 g (66%) of N-[7-
(chlorosulfonyl)-2-naphthyl]acetamide (46) as an off-white solid.
1H NMR (DMSO-d6) δ 10.19 (1H, s), 8.18(1H, s), 7.96 (1H, s),
7.84 (1H, d, J ) 8.8 Hz), 7.78 (1H, d, J ) 8.7 Hz), 7.67 (1H, dd,
J ) 1.8 Hz, J ) 8.8 Hz), 7.58 (1H, dd, J ) 1.4 Hz, J ) 8.5 Hz),
2.10 (3H, s).
J ) 7.3 Hz), 4.58 (2H, d, J ) 6.4 Hz), 4.37 (1H, t, J ) 6.3 Hz),
3.89 (3H, s); MS (MALDI(-)) m/z 542 (M - H).
Methyl 3-[(7-{[(7-{N-[3-(Methoxycarbonyl)phenyl]carbamoyl}-
2-naphthyl)amino]carbonylamino}-2-naphthyl)carbonylamino]ben-
zoate (61). To 380 mg (0.70 mmol) of compound 59 was added 30
mL of dichloromethane, 3 mL of THF, and 1 mL of piperidine.
The resulting clear solution was allowed to stir for 3 h. Then the
reaction was extracted with ethyl acetate and 1 N HCl (aqueous).
The dried organic layer (MgSO4) was filtered, and the volatiles
were removed in vacuo. The resulting residue was dissolved in
dichloromethane, and 3 mL of 1 N HCl in diethyl ether and 50 mL
of diethyl ether were added to form a precipitate that was collected
by vacuum filtration. Drying provided 212 mg (85%) of methyl
3-[(7-amino-2-naphthyl)carbonylamino]benzoate hydrochloride. 1H
NMR (DMSO-d6) δ 10.50 (1H, s), 8.51 (1H, s), 8.42 (2H, br s),
8.20 (1H, s), 8.12 (1H, d, J ) 7.8 Hz), 7.76 (1H, d, J ) 8.4 Hz),
7.70 (1H, d, J ) 8.6 Hz), 7.68 (1H, d, J ) 8.3 Hz), 7.62 (1H, dd,
J ) 1.5 Hz, J ) 8.6 Hz), 7.52 (1H, app t, J ) 7.9 Hz), 7.05 (1H,
dd, J ) 2.0 Hz, J ) 8.7 Hz), 6.96 (1H, s), 3.88 (3H, s); MS
(MALDI(+)) m/z 342 (M + Na).
To 305 mg (0.75 mmol) of methyl 3-[(7-amino-2-naphthyl)car-
bonylamino]benzoate hydrochloride was added 10 mL of chloro-
form, 3.5 mL of thionyl chloride, and 180 µL of pyridine. The
mixture was allowed to stir at ambient temperature for 3 h, followed
by removal of volatiles by rotary evaporation. The resulting residue
was stripped 2 times from chloroform. Then 50 mL of chloroform,
124 mg (0.89 mmol) of methyl-3-aminobenzoate, and 100 µL of
pyridine were added. The mixture was allowed to stir at ambient
temperature for 16 h. The mixture was extracted twice with 1 N
HCl (aqueous) and once with water. The dried organic layer
(MgSO4) was filtered, and the volatiles were removed by rotary
evaporation. The resulting residue was treated with methanol to
form a solid precipitate that was collected by vacuum filtration.
This afforded 380 mg (93%) of the title compound as a white solid.
1H NMR (DMSO-d6) δ 10.59 (1H, s), 10.06 (1H, br s), 8.51 (1H,
d, J ) 1.7 Hz), 8.50 (1H, d, J ) 9.0 Hz), 8.24 (1H, br s), 8.14 (1H,
d, J ) 9.1 Hz), 7.88-7.98 (5H, m), 7.80 (2H, d, J ) 7.3 Hz), 7.72
(1H, d, J ) 7.8 Hz), 7.63 (1H, br s), 7.54 (1H, app t, J ) 7.9 Hz),
7.44 (2H, app t, J ) 7.3 Hz), 7.37 (2H, app t, J ) 7.3 Hz), 4.58
(2H, d, J ) 6.4 Hz), 4.37 (1H, t, J ) 6.3 Hz), 3.89 (3H, s); MS
(MALDI(-)) m/z 542 (M - H).
7-Acetamido-4-hydroxynaphthalene-2-sulfonyl Chloride (47). To
93.0 g (0.389 mol) of 7-amino-4-hydroxynaphthalene-2-sulfonic
acid was added a solution of 200 mL of acetic anhydride and 200
mL of pyridine. The reaction temperature increased, and so the
mixture was was placed in an ice bath for 10 min. The mixture
was removed from the ice bath and allowed to stir at ambient
temperature for 16 h. The solid was collected by vacuum filtration
and was washed with THF. Drying in vacuo provided 155 g (99%)
of 7-(acetylamino)-4-acetyloxynaphthalene-2-sulfonic acid, pyri-
1
dinium salt, as a tan solid. H NMR (DMSO-d6) δ 10.25 (1H, s),
8.84 (2H, d, J ) 4.9 Hz), 8.38 (1H, dt, J ) 1.5 Hz, J ) 7.8 Hz),
8.27 (1H, s), 7.89 (2H, dd, J ) 4.9 Hz, J ) 7.8 Hz), 7.85 (1 H, d,
J ) 9.1 Hz), 7.81 (1H, s), 7.71 (1H, dd, J ) 1.9 Hz, J ) 9.1 Hz),
7.34 (1H, d, J ) 1.4 Hz), 2.44 (3H, s), 2.11 (3H, s); MS (ES(-))
m/z 280 (M - CH3CO).
This was converted to the title compound as described for the
synthesis of N-[7-(chlorosulfonyl)-2-naphthyl]acetamide (46). The
compound was used without characterization.
Methyl
3-({7-[(Fluoren-9-ylmethoxy)carbonylamino]-2-
naphthyl}carbonylamino)benzoate (59). To 0.504 g (2.70 mmol)
of 7-aminonaphthalene-2-carboxylic acid (58) was added 10 mL
of dioxane, 5 mL of 10% sodium carbonate, and 35 mL of water.
To this clear solution was added 0.786 g (3.04 mmol) of 9-fluo-
renylmethyl chloroformate, portionwise, over 15 min. After 3 h,
the mixture was acidified with 1 N HCl and the resulting white
precipitate was collected by vacuum filtration. This solid was
suspended in diethyl ether and stirred to give a fine precipitate that
was collected by vacuum filtration. This provided 0.948 g (86%)
of 7-[(fluoren-9-ylmethoxy)carbonylamino]naphthalene-2-carboxy-
lic acid as an off-white solid. 1H NMR (DMSO-d6) δ 9.93 (1H, br
s), 8.25 (1H, s), 8.02 (1H, br s), 7.94 (2H, d, J ) 7.3 Hz), 7.86
(1H, d, J ) 8.5 Hz), 7.73-7.83 (4H, m), 7.59 (1H, br s), 7.44 (2H,
app t, J ) 7.1 Hz), 7.36 (2H, app t, J ) 6.8 Hz), 4.55 (2H, d, J )
6.0 Hz), 4.35 (1H, t, J ) 6.2 Hz); 13C NMR (DMSO-d6) δ 169.0,
146.3, 142.4, 139.2, 137.2, 137.2, 134.1, 134.0, 128.6, 127.8, 127.2,
126.9, 126.3, 121.5, 120.9, 119.6, 119.0, 109.1, 106.8; MS
(MALDI(+)) m/z 431 (M + Na).
N-[7-(Chlorosulfonyl)(2-naphthyl)]-N-(2-{N-[7-(chlorosulfonyl)(2-
naphthyl)]acetylamino}ethyl)acetamide (63). To 2.04 g (9.33 mmol)
of 7-amino-2-naphthalenesulfonic acid was added 50 mL of dry
DMF. The stirred suspension was heated at 110 °C, and then 1.4 g
of potassium carbonate was added followed by 400 µL (4.6 mmol)
of 1,2-dibromoethane. The mixture was kept at 110 °C for 18 h
and at 80 °C for an additional 18 h. Then the mixture was allowed
to cool to ambient temperature. The resulting insoluble precipitate
was collected by vacuum filtration and washed with methanol. The
crude product was purified by silica gel flash chromatography (6:
2:1 ethyl acetate/isopropanol/water). This provided 596 mg (14%)
of 7-({2-[(7-sulfo-2-naphthyl)amino]ethyl}amino)naphthalene-2-
To 305 mg (0.75 mmol) of 7-[(fluoren-9-ylmethoxy)carbony-
lamino]naphthalene-2-carboxylic acid was added 10 mL of chlo-
roform, 3.5 mL of thionyl chloride, and 180 µL of pyridine. The
mixture was allowed to stir at ambient temperature for three hours,
followed by removal of volatiles by rotary evaporation. The
resulting residue was stripped 2 times from chloroform. Then 50
mL of chloroform, 124 mg (0.89 mmol) of methyl-3-aminobenzoate,
and 100 µL of pyridine were added. The mixture was allowed to
stir at ambient temperature for 16 h. The mixture was extracted
twice with 1 N HCl (aqueous) and once with water. The dried
organic layer (MgSO4) was filtered, and the volatiles were removed
by rotary evaporation. The resulting residue was treated with
methanol to form a solid precipitate that was collected by vacuum
filtration. This afforded 380 mg (93%) of the title compound as a
1
sulfonic acid as a tan solid. H NMR (D2O) δ 7.99 (2H, s), 7.78
(2H, d, J ) 8.7 Hz), 7.63 (2H, d, J ) 8.8 Hz), 7.51 (2H, d, J ) 8.4
Hz), 7.01 (2H, dd, J ) 2.1 Hz, J ) 8.4 Hz), 7.00 (2H, s), 3.44
(4H, s); 13C NMR (DMSO-d6) δ 146.7, 145.6, 134.0, 127.7, 126.4,
125.9, 121.9, 119.0, 118.2, 103.3, 42.0; MS (MALDI(-)) m/z 494
(M - H+Na).
To a solution of 25 mL each of acetic anhydride and pyridine
was added 2.13 g (4.51 mmol) of 7-({2-[(7-sulfo-2-naphthyl)-
amino]ethyl}amino)naphthalene-2-sulfonic acid, and the mixture
was allowed to stir at 70 °C for 16 h. The mixture was poured into
400 mL of THF and left to stir for 12 h. The resulting solid was
collected by vacuum filtration. Then this solid was dissolved in 35
mL of methanol, and a solution of 0.273 g (11.9 mmol) of sodium
in 10 mL of methanol was added. The solution was cooled in an
ice bath and diluted with 100 mL of isopropyl alcohol. The resulting
solid was collected by vacuum filtration. The solid was redissolved
in a minimum of methanol, filtered through a 0.2 µm nylon filter,
and then precipitated by the addition of isopropyl alcohol. Drying
1
white solid. H NMR (DMSO-d6) δ 10.59 (1H, s), 10.06 (1H, br
s), 8.51 (1H, d, J ) 1.7 Hz), 8.50 (1H, d, J ) 9.0 Hz), 8.24 (1H,
br s), 8.14 (1H, d, J ) 9.1 Hz), 7.88-7.98 (5H, m), 7.80 (2H, d,
J ) 7.3 Hz), 7.72 (1H, d, J ) 7.8 Hz), 7.63 (1H, br s), 7.54 (1H,
app t, J ) 7.9 Hz), 7.44 (2H, app t, J ) 7.3 Hz), 7.37 (2H, app t,

Insulin Receptor Tyrosine Kinase ActiVators
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 6185
in vacuo provided 2.01 g (74%) of 7-(N-{2-[N-(7-sulfo-2-naphthyl)-
128.3, 127.2, 126.2, 124.7, 123.5, 121.4, 121.0, 116.3, 106.2, 52.2;
MS (ES(-)) m/z 389 (M - H).
acetylamino]ethyl}acetylamino)naphthalene-2-sulfonic acid, diso-
1
dium salt, the title compound as a white solid. H NMR (DMSO-
Methyl 2-Chloro-5-{[(7-isothiocyanato(2-naphthyl))sulfonyl]-
amino}benzoate (65). To 4.5 g (11.5 mmol) of compound 64 and
9.01 g (50.6 mmol) of 1,1′-thiocarbonyldiimidazole was added 50
mL of THF. The solution was allowed to stir at ambient temperature
for 1.5 h. Then the mixture was poured into 300 mL of ethyl acetate
and extracted with 1 N HCl, water, and brine. The organic layer
was dried (MgSO4) and filtered, and the volatiles were removed
by rotary evaporation to yield 4.77 g (96%) of the title compound
d6) δ 8.12 (2H, s), 7.93 (2H, d, J ) 7.3 Hz), 7.90 (2H, d, J ) 7.9
Hz), 7.89 (2H, s), 7.74 (2H, d, J ) 7.4 Hz), 7.32 (2H, d, J ) 8.3
Hz), 3.88 (4H, s), 1.73 (6H, s); 13C NMR (DMSO-d6) δ 169.2,
146.4, 140.4, 132.3, 131.4, 128.8, 126.9, 126.7, 126.1, 124.5, 123.9,
46.3, 22.3; MS (ES(-)) m/z 555 (M - H).
To 511 mg (0.85 mmol) of compound 44 was added 50 mL of
phosphorus oxychloride in an ice bath. The mixture was allowed
to stir and warm slowly to room temperature. The mixture was
allowed to stir for a total of 4 days. Then the mixture was poured
onto 600 mL of ice and this suspension placed in a second ice
bath. After the ice had melted, the yellow solid was collected by
vacuum filtration. This provided 455 mg (90%) of the title
compound (63) as a white solid. It was used immediately without
characterization.
1
as a tan solid. H NMR (DMSO-d6) δ 10.86 (1H, br s), 8.48 (1H,
s), 8.27 (1H, d, J ) 1.9 Hz), 8.16 (1H, d, J ) 8.8 Hz), 8.10 (1H,
d, J ) 8.8 Hz), 7.80 (1H, dd, J ) 1.8 Hz, J ) 8.7 Hz), 7.72 (1H,
dd, J ) 2.0 Hz, J ) 8.8 Hz), 7.54 (1H, d, J ) 2.6 Hz), 7.44 (1H,
d, J ) 8.7 Hz), 7.30 (1H, dd, J ) 2.7 Hz, J ) 8.8 Hz), 3.81 (3H,
s); MS (MALDI(-)) m/z 431 (M - H).
Methyl 5-({[7-({[(7-{[(3-Methoxycarbonyl-4-chlorophenyl)ami-
no]sulfonyl}(2-naphthyl))amino]thioxomethyl}amino)(2-naphthyl)]-
sulfonyl} amino)-2-chlorobenzoate (66). To 4.0 g (9.26 mmol) of
compound 65 dissolved in 200 mL of dichloromethane was added
3.0 g (7.67 mmol) of compound 64. The mixture was allowed to
stir at ambient temperature for 16 h. A white solid had formed,
which was collected by vacuum filtration. This provided 5.2 g (82%)
Methyl 5-{[(7-Amino(2-naphthyl))sulfonyl]amino}-2-chloroben-
zoate (64). To 4.98 g (22.4 mmol) of methyl 5-amino-2-chloroben-
zoate hydrochloride was added 50 mL of THF followed by 11 mL
(0.136 mol) of pyridine. The stirred suspension was cooled in an
ice bath, and then 5.30 g (18.7 mmol) of N-[7-(chlorosulfonyl)-2-
naphthyl]acetamide (46) prepared above was added as a suspension
in 50 mL of THF. The mixture was allowed to warm to ambient
temperature and to stir for 16 h. All volatiles were removed by
rotary evaporation, and the resulting goo was extracted with ethyl
acetate and 1 N HCl. The organic layer was dried (MgSO4) and
filtered, and volatiles were removed to provide 6.63 g (82%) of
methyl 5-{[(7-amino(2-naphthyl))sulfonyl]amino}-2-chlorobenzoate
1
of the title compound as a white solid: mp ) 157 - 163 °C; H
NMR (DMSO-d6) δ 10.80 (2H, s), 10.32 (2H, s), 8.40 (2H, s),
8.20 (2H, s), 8.07 (2H, d, J ) 8.8 Hz), 7.98 (2H, d, J ) 8.9 Hz),
7.85 (2H, dd, J ) 1.9 Hz, J ) 8.8 Hz), 7.70 (2H, dd, J ) 1.7 Hz,
J ) 8.7 Hz), 7.57 (2H, d, J ) 2.6 Hz), 7.43 (2H, d, J ) 8.7 Hz),
7.32 (2H, dd, J ) 2.7 Hz, J ) 8.7 Hz), 3.80 (6H, s); MS (ES(-))
m/z 823 (M - H).
1
as a faint yellow solid: mp ) 165-172 °C; H NMR (DMSO-d6)
δ 10.77 (1H, s), 10.31 (1H, s), 8.42 (1H, s), 8.31 (1H, s), 8.01
(1H, d, J ) 8.5 Hz), 7.95 (1H, d, J ) 8.9 Hz), 7.74 (1H, dd, J )
1.8 Hz, J ) 8.9 Hz), 7.63 (1H, dd, J ) 1.7 Hz, J ) 8.6 Hz), 7.56
(1H, d, J ) 2.6 Hz), 7.43 (1H, d, J ) 8.7 Hz), 7.32 (1H, dd, J )
2.7 Hz, J ) 8.8 Hz), 3.81 (3H, s), 2.12 (3H, s); 13C NMR (DMSO-
d6) δ 168.7, 164.6, 138.4, 136.8, 136.4, 132.0, 131.5, 130.7, 130.2,
129.1, 128.3, 127.1, 126.5, 123.7, 122.7, 121.5, 120.1, 115.7, 52.4,
23.9; MS (MALDI(+)) m/z 457 (M + Na).
Methyl 5-({[7-(2-Amino-1-aza-2-{[7-({[4-chloro-3-(methoxycarbon-
yl)phenyl]amino}sulfonyl)(2-naphthyl)]amino}vinyl)(2-naphthyl)]sul-
fonyl}amino)-2-chlorobenzoate (67). To 1.0 g (1.21 mmol) of
compound 66 dissolved in 50 mL of acetonitrile was added 1.1
mL of methyl iodide (17.7 mmol). The mixture was allowed to
stir under an argon atmosphere for 72 h. The volatiles were removed
by rotary evaporation, and the resulting yellow solid was extracted
using ethyl acetate and 1 M sodium carbonate. The organic layer
was washed with 50/50 brine/water followed by brine. The organic
layer was separated and dried (MgSO4), and volatiles were removed
by rotary evaporation to yield 0.95 g (94%) of methyl 5-{[(7-{[(1Z)-
2-aza-2-(7-{[(3-methoxycarbonyl-4-chlorophenyl)amino]sulfonyl}(2-
naphthyl))-1-methylthiovinyl]amino}(2-naphthyl))sulfonyl]amino}-
To 4.81 g (11.1 mmol) of methyl 5-{[(7-amino(2-naphthyl))sul-
fonyl]amino}-2-chlorobenzoate was added 160 mL of 5 N NaOH
and 7 mL of dioxane. The mixture was allowed to stir at 55 °C for
18 h. Then the mixture was diluted with 30 mL of water and filtered
through a 0.2 µm nylon filter. The resulting clear filtrate was
carefully acidified with 26 mL of concentrated H2SO4. The finely
divided solid precipitate was collected by vacuum filtration and
dried in vacuo. This produced 4.01 g (95%) of 5-{[(7-amino(2-
naphthyl))sulfonyl]amino}-2-chlorobenzoic acid as a tan solid: mp
1
2-chlorobenzoate as a yellow solid. H NMR (DMSO-d6) δ 9.17
(1H, s), 8.40 (1H, s), 8.28 (1H, s), 8.21 (1H, s), 7.95 (1H, d, J )
9.2 Hz), 7.90 (1H, s), 7.90 (1H, d, J ) 9.0 Hz), 7.88 (2H, s), 7.61
(2H, d, J ) 8.6 Hz), 7.50 (1H, s), 7.45 (2H, dd, J ) 2.1 Hz, J )
10.1 Hz), 7.33 (1H, dd, J ) 1.8 Hz, J ) 8.5 Hz), 7.30 (1H, app t,
J ) 8.5 Hz), 7.25 (1H, d, J ) 8.8 Hz), 7.20 (1H, dd, J ) 2.4 Hz,
J ) 8.9 Hz), 7.15 (1H, dd, J ) 2.4 Hz, J ) 8.9 Hz), 3.80 (3H, s),
3.74 (3H, s), 2.42 (3H, s); MS (ES(-)) m/z 836 (M - H).
1
) 160-165 °C; H NMR (DMSO-d6) δ 10.63 (1H, s), 8.00 (1H,
s), 7.80 (1H, d, J ) 8.4 Hz), 7.68 (1H, d, J ) 8.8 Hz), 7.53 (1H,
d, J ) 2.6 Hz), 7.39 (1H, d, J ) 8.7 Hz), 7.34 (1H, dd, J ) 1.5
Hz, J ) 8.7 Hz), 7.27 (1H, dd, J ) 2.7 Hz, J ) 8.7 Hz), 7.11 (1H,
dd, J ) 2.0 Hz, J ) 8.7 Hz), 6.96 (1H, s); 13C NMR (DMSO-d6)
δ 165.8, 147.4, 136.8, 136.1, 133.5, 131.6, 131.2, 128.9, 128.5,
127.5, 126.2, 124.8, 123.1, 121.4, 121.2, 116.6, 107.0; MS (ES(-))
m/z 375 (M - H).
To 220 mg (0.26 mmol) of the material obtained above was
added 10 mL of a 0.5 M NH3 solution in dioxane. The resulting
solution was placed in a sealed tube and heated at 70 °C for 18 h,
followed by 24 h at 80 °C. Then additional NH3 gas was bubbled
into the mixture for 4 min. The mixture was sealed, and heating at
80 °C continued for an additional 51 h. Then the reaction
temperature was lowered to 65 °C, and the reaction continued for
11 days. At this point, the reaction had reached 70% completion
based upon HPLC analysis. The reaction was stopped by removal
of the volatiles using rotary evaporation. The product was purified
by silica gel column chromatography, eluting with 3% methanol
in dichloromethane followed by 5% methanol in dichloromethane.
Finally, the product was eluted with 90:2:1 ethyl acetate/isopro-
panol/water. This provided 117 mg (56%) of the title compound
as an off-white solid. This compound exists as a mixture of
To 10.1 g (0.027 mol) of 5-{[(7-amino(2-naphthyl))sulfony-
l]amino}-2-chlorobenzoic acid dissolved in 250 mL of methanol
was added 50 mL of 4 N HCl in dioxane. This solution was allowed
to stir at ambient temperature for 18 h. The reaction was incomplete,
so the solution was heated at reflux for an additional 5 h. Then the
volatiles were removed by rotary evaporation and the resulting solid
was extracted with ethyl acetate and 0.4 N sodium bicarbonate,
water, and brine. The organic layer was dried (MgSO4) and filtered,
and the volatiles were removed by rotary evaporation to yield 8.71 g
1
(83%) of the title compound as a tan solid. H NMR (DMSO-d6)
δ 10.66 (1H, s), 7.98 (1H, d, J ) 1.4 Hz), 7.78 (1H, d, J ) 8.7
Hz), 7.66 (1H, d, J ) 8.8 Hz), 7.56 (1H, d, J ) 2.7 Hz), 7.43 (1H,
d, J ) 8.7 Hz), 7.31 (1H, dd, J ) 1.8 Hz, J ) 8.5 Hz), 7.30 (1H,
dd, J ) 2.8 Hz, J ) 8.7 Hz), 7.08 (1H, dd, J ) 2.2 Hz, J ) 8.8
Hz), 6.91 (1H, d, J ) 2.0 Hz), 5.71 (2H, s), 3.82 (3H, s); 13C NMR
(DMSO-d6) δ 164.6, 148.0, 136.9, 135.9, 133.5, 131.3, 130.2, 128.8,
1
tautomers: H NMR (DMSO-d6) δ 10.65 (2H, br s), 8.27 (2H, s),
7.98 (3H, d, J ) 8.8 Hz), 7.90 (3H, d, J ) 8.9 Hz), 7.57 (6H, m),
7.42 (2H, d, J ) 8.7 Hz), 7.31 (2H, dd, J ) 2.6 Hz, J ) 8.8 Hz),
5.30 (3H, br s), 3.80 (6H, s); MS (MALDI(+)) m/z 806 (M).

6186 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
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Supporting Information Available: Table of purity of all target
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