Benzhydrylquinazolinediones: Novel cytosolic phospholipase A2α inhibitors with improved physicochemical properties

Article abstract of DOI:10.1016/j.bmc.2009.05.027

The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA₂α inhibitors are described. Utilizing pharmacophores that were found to be important in our indole series, we discovered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid release arises from selective cPLA₂α inhibition.

Full text of DOI:10.1016/j.bmc.2009.05.027

Bioorganic & Medicinal Chemistry 17 (2009) 4383–4405
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Benzhydrylquinazolinediones: Novel cytosolic phospholipase A2
with improved physicochemical properties
a
inhibitors
a
a
a
a
a
Steven J. Kirincich a, , Jason Xiang , Neal Green , Steve Tam , Hui Y. Yang , Jaechul Shim ,
*
Marina W. H. Shen b, James D. Clark b, John C. McKew a
a Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, MA 02140, USA
b Department of Inflammation, Wyeth Research, 200 Cambridge Park Drive, MA 02140, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 January 2009
Revised 4 May 2009
Accepted 9 May 2009
Available online 18 May 2009
The synthesis and optimization of a class of trisubstituted quinazoline-2,4(1H,3H)-dione cPLA2a inhibi-
tors are described. Utilizing pharmacophores that were found to be important in our indole series, we dis-
covered inhibitors with reduced lipophilicity and improved aqueous solubility. These compounds are
active in whole blood assays, and cell-based assay results indicate that prevention of arachidonic acid
release arises from selective cPLA2a inhibition.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Phospholipase
Inflammation
Inhibitor
Arachidonic acid
1. Introduction
Validation for the role of cPLA2 inhibition to combat inflamma-
a
tory diseases comes from studies on gene-deficient mice bred into
appropriate strains.5–8 These animals are generally healthy, but a
defect in labor induction and reduced fecundity is observed that
The cytosolic phospholipase A2 (cPLA2) family of enzymes is
responsible for cleaving the sn-2 acyl bond of glycerophospholip-
ids. One particular member, cPLA2 , is an 85 kDa, calcium-depen-
is analogous to COX-1 and COX-2 deficiency.9 These cPLA2 defi-
a
a
dent, cytosolic lipase with selectivity for arachidonic acid (AA)
and eicosapentenoic acid-containing glycerophospholipids.1 AA re-
lease initiates the biosynthetic cascade that produces such inflam-
matory mediators as leukotrienes (LTs) via the lipoxygenase (5-LO)
pathway, prostaglandins (PGs), thromboxanes (TXs) via the cyclo-
oxygenase pathway, and platelet activating factor (PAF) which re-
sults from acylation of lyso-glycerophosphatidylcholine.2 NSAIDS
and COX-2 selective inhibitors reduce the pain and edema of osteo-
(OA) and rheumatoid arthritis (RA) via suppression of PGs.3 5-LO
and LT receptor antagonists have demonstrated the role of LTs in
asthma. Inhibition of leukotriene production may also be beneficial
in treating pain and the signs and symptoms of RA, and PGD2 has
been implicated in asthma through the agonism of both DP1 and
cient mice are resistant to disease in models for collagen-induced
rheumatoid arthritis,10 LPS-induced adult respiratory distress
syndrome,11 ova-induced anaphylaxis,12 multiple sclerosis,13 ath-
erosclerosis,14 stroke,15 and colon cancer.16,17 In addition to the
listed diseases, there is a general need for the improved treatment
of inflammatory disease as illustrated by its recent association
with an increased risk for cancer,18 heart attack,19 chronic heart
failure,20 and morbidity.21 A recent report describing a single hu-
man deficient in cPLA2 activity (due to inheritance of two distinct
a
inactivating alleles) has demonstrated the central role of cPLA2 in
a
AA release.22
The increased rate of cardiovascular complications in patients
taking some COX-2 inhibitors may result from the selective inhibi-
tion of anti-thrombotic prostacyclin (PGI2) without affecting pro-
thrombotic TX.23,24 In the case of classical, non-selective COX
inhibitors, simultaneous inhibition of TX and PGI2 provides cardio-
vascular benefits, especially for naproxen which is an effective
inhibitor of COX-1 derived TX. However, the inhibition of gastric
PGE2 leads to an increased risk of gastrointestinal disorders. Inhibi-
CRTH2.4 Therefore, cPLA2 inhibitors, which will block both PG
a
and LT production, are expected to be efficacious in these diseases
and may be more effective than COX-2 inhibitors.
tion of cPLA2 would decrease the supply of AA which would in
a
turn inhibit the formation of both TX and PGI2. The further inhibi-
* Corresponding author. Tel.: +1 617 665 5663; fax: +1 617 665 5682.
E-mail address: skirincich@wyeth.com (S.J. Kirincich).
tion of pro-ulcerogenic LTB4 should make it possible for cPLA2
a
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.027

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S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
inhibitors to possess the desirable properties of selective and non-
OH
O
selective COX inhibitors. Notably, the cPLA2 deficient human has a
a
O
GI phenotype distinct from that associated with NSAID usage
which is characterized by gastroduodenal ulcers and more subtle
small intestinal ulcers. In contrast, all ulcers in this individual were
localized to the small intestine, and there were no signs of gastro-
duodenal ulcers despite numerous endoscopies.22
Cl
N
Ph
Ph
5
A variety of cPLA2 inhibitors have been reported in the
a
GLU IC50= 3.0 μM
literature (Fig. 1).25 The structural motifs include activated
ketones,26–30 pyrrolidines,31,32 indoles,29,33–36 oxamides,37,38 and
triazinetriones.39 Seno (Shionogi) has shown that thiazolidinedi-
one-containing pyrrolidines, as exemplified by 1, are potent cPLA2
a
Although WAY-196025 is potent in whole blood assays and
demonstrates in vivo efficacy, these indoles are large and lipo-
philic, and benefit from a lipid-based formulation to achieve mod-
est bioavailability. Therefore, we initiated the pursuit of a second,
unique, non-indole series that possessed improved physicochemi-
inhibitors.31,32 Likely inspired by Merck-Frosst’s success with
arachidonyl trifluoromethyl ketone, Connolly et al. presented prop-
anone 2, an activated ketone with tunable electrophilicity, but
without a metabolically-unstable unsaturated chain.28 Kokotos
has described 2-oxoamides (3) which are active in the rat-paw car-
rageenan edema model.37,38 Lehr has recently reported on C-3
indole carboxylate compounds (4) which exhibit low nanomolar
in vitro inhibition.40 We have recently published the structures
cal properties. Early efforts in our group to identify cPLA2 inhibi-
a
tors led to the discovery of 1,2,3-trisubstituted indole derivatives
such as 5.42 Considerable improvements in potency were achieved
with the inclusion of the N-1 benzhydryl, C-2 methyl, and C-3 teth-
ered acid moieties. In spite of all efforts to find smaller lipophilic N-
1 substituents and non-ionizable functionality, each of these
groups contributed to the activity.
Our experiences with the indole SAR suggested that a reduction
in molecular weight and lipophilicity could only come about by
finding a new, more polar core. A HTS library using the GLU micelle
assay noted here resulted in only two confirmed hits (data not
of WAY-196025 and Efipladib, indole-based cPLA2
a inhibitors
which have nanomolar activity in the rat whole blood assay, and
oral efficacy in several chronic and acute animal models.35 With
the exception of our indoles, the Shionogi compound is the only
inhibitor from this group to display whole blood activity. Recent
publications by Kokotos41 and Lehr40 provide an excellent sum-
mary of the field of cPLA2 inhibitor research.
a
O
O
S
NH
N
O
O
H
O
O
N
N
O
O
F
C10H21
O
CO2H
2
F
1
CO2H
O
CO2CH3
O
O
H
N
O
N
OH
n
C10H21
O
O
R
3
4
HO2C
R
Cl
O
S
N
H
O
N
GLU IC50
(μM)
0.014
Rat WB
IC50 (μM)
0.03
Compound
WAY-196025 2,6-di-Me
Efipladib 3,4-di-Cl
R
plogD7.4
8.7
9.2
0.04
0.07
Figure 1. cPLA2 inhibitors reported in the literature.

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4385
These routes proceeded without difficulty, but the inability to
efficiently deliver N-3 diversity via imide alkylation after heterocy-
cle formation, the occasionally observed instability of the N-1
benzhydryl group to basic ester hydrolysis conditions, and the ab-
sence of a common quinazolinedione intermediate greatly slowed
progress. A careful examination of the alternative N-3 ben-
zhydrylquinazolinediones revealed that N-1 substitution could be
introduced late in the sequence and this would allow for the rapid,
convergent synthesis of derivatives.
O
N
Cl
Cl
N
N
O
Ph
Ph
Ph Ph
Δ plog P = - 2.9
Δ TPSA = + 39 Å2
Δ Mol. Wt. = + 45
Figure 2. Comparison of calculated physical properties—indoles and quinazo-
linediones.
The N-3 benzhydrylquinazolinediones were made from the
substituted 2-nitrobenzoic acids through a five-step sequence
involving amide coupling, nitro reduction, ring closure in the pres-
ence of triphosgene, N-1 alkylation, and ester hydrolysis (Scheme
6). Additional aromatic ring substitution was accessible through
the use of commercially available anthranilic acids using a similar
route (Scheme 7). A third method for synthesizing N-3 ben-
zhydrylquinazolinediones involved isatoic anhydride aminolysis,
ring closure, N-1 alkylation and ester hydrolysis (Scheme 8). Com-
pounds 44a–d were made from the N-3 benhydrylquinazolinedione
via N-1 alkylation with the 1,4-dihaloolefin, phenol O-alkylation
with methyl 4-hydroxybenzoate and ester hydrolysis (Scheme 9).
The earlier problems associated with introducing diversity via
N-3 substitution had been addressed with the switch to N-3 benz-
hydryl derivatives, but the search for a convergent route to allow
for efficient functionalization of the carbocyclic portion of the bicy-
cle was more challenging. A variety of substituted isatoic anhy-
drides, 2-nitrobenzoic, and anthranilic acids were commercially
available, but this required a new synthesis for each uniquely
substituted heterocyclic core. Ideally, a common intermediate
would be available which would enable the introduction of C-6
and C-7 diversity late in the synthetic sequence. Such an opportu-
nity was realized when it was observed that the 7-fluoro substitu-
ent could be displaced with a variety of nucleophiles (Scheme 10).
Nucleophilic aromatic substitution with oxygen, nitrogen, and sul-
fur nucleophiles in the presence of base followed by TFA-induced
ester cleavage provided C-7 substituted analogs. Further diversifi-
cation could be accomplished by sulfide oxidation or nitro reduc-
tion (Scheme 7). By using the more stable tert-butyl ester rather
than the methyl ester, the final chromatographic purification could
be performed readily on the ester.
shown). Following initial optimization, the IC50s in a human whole
blood assay remained well in excess of 300 lM. Structure-driven
drug design using our cPLA2 X-ray crystal structure43 was not pos-
a
sible because the active site conformation precluded the binding of
an indole-based inhibitor. Furthermore, docking experiments with
either the natural substrate or smaller molecules were not infor-
mative since an amphipathic helix covers the active site, and
movement of the helix to allow binding alters the structure such
that modeling was not predictive. After testing a number of hetero-
cyclic cores that would allow for substituents to be spatially ar-
ranged in a manner similar to the 1,2,3-trisubstituted indoles, we
found the quinazolinediones to be an excellent starting point. In
principle, the quinazolinedione core provides novelty, greater
inherent polarity, and the flexibility to utilize either N-1 or N-3
atoms in place of the N-1 indole position. Calculated properties
for both substituted indole and quinazolinedione cores (Fig. 2) sug-
gest that the desired polarity increase will be accompanied by in-
creased polar surface area and molecular weight.
2. Chemistry
The synthesis of the N-1 benzhydryl quinazolinediones resulted
from a four-step sequence starting from substituted anthranilic
acids (Scheme 1). The acid was converted to the amide using stan-
dard EDCI coupling conditions followed by aniline alkylation with
benzhydryl bromide. Exposure of the aminoamide to triphosgene
and subsequent ester hydrolysis provided the quinazolinedione
acids (see Fig. 3 for substitution key).
Similar chemistry starting from anthranilate esters was utilized
to provide additional compounds (Schemes 2–4). An alternative
approach involved sequential O-alkylation of commercially avail-
able 3-(2-chloroethyl)quinazoline-2,4(1H,3H)-dione followed by
ester hydrolysis to provide the three atom-linked benzoic acid 27
(Scheme 5).
3. Results and discussion
Prior work on the indole series clearly demonstrated that the
linker between the acidic and the hydrophobic moieties need not
include an electrophilic ketone to achieve cPLA2 inhibition, but
a
O
O
O
R1
R2
R1
R1
R2
N
H
OH
N
a
b
H
NH
NH2
NH2
Ph Ph
6a R1 = F
6b R1 = Cl
7a R1 = F, R2 = A1
7b R1 = Cl, R2 = B1
8a R1 = F, R2 = A1
8b R1 = Cl, R2 = B1
O
N
9a R1 = F, R2 = A3
10a R1 = F, R2 = A2
9b R1 = Cl, R2 = C1
10b R1 = Cl, R2 = C2
R1
R2
O
d
N
c
d
Ph Ph
Scheme 1. Reagents and conditions: (a) EDCI, amine, DMAP, DMF, rt; (b) DIEA, BrCH(Ph)2, DCE, 55 °C; (c) triphosgene, THF, reflux; (d) NaOH, THF, H2O, MeOH, 50 °C or TFA,
DCM, rt.

4386
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
CO2X
O
CO2X
O
CO2X
CH2-
CH2CO2X
CH2-
O(CH2)nCO2X
CH2-
CH2-
CH2-
A1 X=CH3
A2 X = H
A3 X = t-Bu
B1 X=CH3
B2 X = H
C1 X=CH3
C2 X = H
D1 X=CH3
D2 X = H
D3 X = t-Bu
E1 n = 1. X=CH3
E2 n = 1, X = H
F1 n = 3, X=CH3
F2 n = 3, X = H
CO2X
CH2CO2X
N
O
CO2X
CH2CO2X
O
CO2X
CH2-
CH2-
O(CH2)n
O(CH2)2
CH2-
H1 X=CH3
H2 X = H
H3 X = Et
J1 n = 2, X=CH3
M1 n = 5, X=CH3
Q1 X = CH3
Q2 X = H
R1 X=CH3
R2 X = H
G1 X=CH3
G2 X = H
J2 n = 2, X = H
K1 n = 3, X=CH3
K2 n = 3, X = H
L1 n = 4, X=CH3
L2 n = 4, X = H
M2 n = 5, X = H
N1 n = 6, X=CH3
N2 n = 6, X = H
P1 n = 7, X=CH3
P2 n = 7, X = H
Figure 3. Quinazolinedione substitution key.
the results did indicate that the distance between these two moi-
eties is important to activity.33 The initial efforts to find quinazo-
linedione-based inhibitors began with the investigation of N-3
tethered carboxylic acids containing an N-1 benzhydryl group.
(Table 1). As demonstrated by the comparison of 10b and 16e,
the potency differences between 6- and 7-halogenated quinazolin-
ediones were generally found to be negligible, but these com-
pounds were more potent than 6,7-unsubstituted analogs (16d
O
O
R1
R2
R1
O
R1
R2
OMe
NH
Ph Ph
OH
c
a
b
OMe
NH2
R2
NH
Ph Ph
11a R1 = R2 = H
11b R1 = Br, R2 = H
11c R1 = H, R2 = Cl
12a R1 = R2 = H
13a R1 = R2 = H
13b R1 = Br, R2 = H
13c R1 = H, R2 = Cl
12b R1 = Br, R2 = H
12c R1 = H, R2 = Cl
15a R1 = R2 = H, R3 = B1
16a R1 = R2 = H, R3 = B2
15b R1 = R2 = H, R3 = A1
16b R1 = R2 = H, R3 = A2
15c R1 = Br, R2 = H, R3 = G1
16c R1 = Br, R2 = H, R3 = G2
15d R1 = H, R2 = Cl, R3 = J1
16d R1 = H, R2 = Cl, R3 = J2
15e R1 = H, R2 = Cl, R3 = C1
16e R1 = H, R2 = Cl, R3 = C2
15f R1 = H, R2 = Cl, R3 = B1
16f R1 = H, R2 = Cl, R3 = B2
15g R1 = H, R2 = Cl, R3 = A1
16g R1 = H, R2 = Cl, R3 = A2
b
b
O
O
R1
R2
R3
N
R1
R2
R3
d
N
H
NH
N O
b
b
b
b
b
Ph Ph
Ph Ph
14a R1 = R2 = H, R3 = B1
14b R1 = R2 = H, R3 = A1
14c R1 = Br, R2 = H, R3 = G1
14d R1 = H, R2 = Cl, R3 = J1
14e R1 = H, R2 = Cl, R3 = C1
14f R1 = H, R2 = Cl, R3 = B1
14g R1 = H, R2 = Cl, R3 = A1
Scheme 2. Reagents and conditions: (a) DIEA, BrCH(Ph)2; (b) NaOH, THF, H2O, MeOH, 50 °C or TFA, DCM, rt; (c) EDCI, DMAP, DMF, rt; (d) triphosgene, THF, reflux.

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4387
O
O
O
N
Br
Br
Br
N
N
N
H
H
b
a
CO2Me
CO2H
CO2H
NH
NH
O
Ph Ph
Ph Ph
Ph Ph
17
18
19
Scheme 3. Reagents and conditions: (a) NaOH, THF, H2O, MeOH, 50 °C; (b) triphosgene, THF, reflux.
O
O
O
OMe
NH
Ph
OH
NH
Ph
c
a
b
OMe
NH2
11a
20
21
O
O
N
O
O
N
N
d
H
NH
Ph
22
CO2Me
O
CO2R
b
Ph
23 R = CH3
24 R = H
Scheme 4. Reagents and conditions: (a) DIEA, BnBr, DCE, 55 °C; (b) NaOH, THF, H2O, MeOH, 50 °C; (c) EDCI, DMAP, amine, rt; (d) triphosgene, THF, reflux.
O
N
O
N
O
Cl
O
Cl
N
N
N
a
b
O
O
CO2R
N
H
O
Ph Ph
Ph Ph
25
26 R = Me
27 R = H
c
Scheme 5. Reagents and conditions: (a) DIEA, BrCH(Ph)2, DCE, 55 °C (b) NaH, methyl 4-hydroxybenzoate, DMF; (c) NaOH, THF, H2O, MeOH, 50 °C.
O
O
Ph
Ph
O
Ph
Ph
OH
NO2
a
N
N
b
H
H
Cl
Cl
NO2
Cl
NH2
28
29
O
N
Ph
Ph
O
Ph
Ph
31a R1 = H3
32a R1 = H2
31b R1 = J1
32b R1 = J2
e
e
c
d
N
N
Cl
N
O
Cl
O
R1
H
30
Scheme 6. Reagents and conditions: (a) EDCI, DMAP, NH2CH(Ph)2, DMF, rt; (b) SnCl2ꢀ2H2O, EtOH, 80 °C; (c) triphosgene, THF, reflux; (d) NaH, RX, DMF; (e) NaOH, THF, H2O,
MeOH, 50 °C.
vs 27). With the addition of a one-carbon spacer between the aro-
matic ring and the acid of 10b, a sevenfold potency gain was real-
ized with phenylacetic acid 19. When the ether linker spanning the
heterocycle and the benzoic acid was extended from one (10b) to
three atoms (16d), potency was improved by a factor of 20. Replac-
ing the phenyl group of 10b with the trans-substituted cyclopropyl
ring decreased potency. In the case of an unsaturated 5-atom lin-
ker, the potency was sensitive to olefin geometry as shown by
the comparison of 16f and 16g. These data are consistent with
the results from the indole series,33 and suggest that linker length,

4388
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
O
Ph
Ph
O
O
Ph
Ph
R2
R1
R2
R1
R2
R1
N
OH
NH2
N
a
b
H
N
H
O
NH2
R1 = F, R2 = H
R1 = NO2, R2 = H
R1 = CH3, R2 = H
R1 = H, R2 = F
33a R1 = F, R2 = H
33b R1 = NO2, R2 = H
33c R1 = CH3, R2 = H
33d R1 = H, R2 = F
33e R1 = H, R2 = Cl
34a R1= F, R2 = H
34b R1= NO2, R2 = H
34c R1= CH3, R2 = H
34d R1 = H, R2 = F
34e R1 = H, R2 = Cl
35a R1= F, R2 = H, R3 = A3
36a R1= F, R2 = H, R3 = A2
35b R1= NO2, R2 = H R3 = A3
36b R1= NO2, R2 = H, R3 = A2
35c R1= NH2, R2 = H, R3 = A3
36c R1= NH2, R2 = H, R3 = A2
35d R1= CH3, R2 = H, R3 = A3
36d R1= CH3, R2 = H, R3 = A2
35e R1 = H, R2 = F, R3 = B1
36e R1 = H, R2 = F, R3 = B2
35f R1= H, R2 = F, R3 = A1
36f R1= H, R2 = F, R3 = A2
35g R1= H, R2 = Cl, R3 = B1
36g R1= H, R2 = Cl, R3 = B2
35h R1= H, R2 = Cl, R3 = A1
36h R1= H, R2 = Cl, R3 = A2
d
d
d
d
e
O
N
Ph
Ph
R2
R1
N
c
O
R3
d
d
d
d
Scheme 7. Reagents and conditions: (a) EDCI, NH2CH(Ph)2, DMAP, DMF, rt; (b) triphosgene, THF, reflux; (c) NaH, R3X, DMF; (d) NaOH, THF, H2O, MeOH, 50 °C or TFA, DCM; (e)
SnCl2ꢀ2H2O, EtOH, 80 °C.
O
O
Ph
Ph
O
Ph
Ph
R1
R2
R1
R2
R1
R2
O
N
a
c
b
N
H
N
H
O
N
H
O
NH2
R1= R2 = H
37a R1= R2 = H
38a R1= R2 = H
R1= H, R2 = Cl
R1= Br, R2 = H
29 R1= H, R2 = Cl
37c R1= Br, R2 = H
30 R1= H, R2 = Cl
38c R1= Br, R2 = H
39a R1= R2 = H, R3 = D3
40a R1= R2 = H, R3 = D2
39b R1= R2 = H, R3 = E1
40b R1= R2 = H, R3 = E2
39c R1= R2 = H, R3 = F1
40c R1= R2 = H, R3 = F2
39d R1= R2 = H, R3 = H3
40d R1= R2 = H, R3 = H2
39e R1= R2 = H, R3 = M1
40e R1= R2 = H, R3 = M2
39h R1= R2 = H, R3 = K1
40h R1= R2 = H, R3 = K2
39i R1= R2 = H, R3 = A1
40i R1= R2 = H, R3 = A2
39j R1= R2 = H, R3 = Q1
40j R1= R2 = H, R3 = Q2
39k R1= Br, R2 = H, R3 = B1
40k R1= Br, R2 = H, R3 = B2
39l R1= Br, R2 = H, R3 = A1
40l R1= Br, R2 = H, R3 = A2
39m R1= H, R2 = Cl, R3 = R1
40m R1= H, R2 = Cl, R3 = R2
d
d
d
d
O
N
Ph
Ph
R1
R2
N
d
d
d
d
d
O
R3
d
d
Scheme 8. Reagents and conditions: (a) NH2CH(Ph)2, CH3CN, reflux, 48 h; (b) triphosgene, THF, reflux; (c) NaH, R3X, DMF; (d) NaOH, THF, H2O, MeOH, 50 °C or TFA, DCM.
linker flexibility and the placement of the phenyl ring dramatically
affect potency. The fact that 16d and 16g are equipotent indicates
that there may be more than one site on the enzyme capable of
accommodating an interaction with the carboxylate, and the dra-

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4389
O
N
Ph
Ph
O
N
Ph
Ph
N
O
Ph
Ph
R1
O
N
a
b
R1
O
N
R1
N
H
O
O
R2
CO2R3
30 R1= Cl
38a R1= H
42a trans, R1= Cl, R2 = Br
42b cis, R1= Cl, R2 = Cl
42c cis, R1= H, R2 = Cl
42d sat'd, R1= Cl, R2= Br
43a trans, R1= Cl, R3 = CH3
44a trans, R1= Cl, R3 = H
43b cis, R1= Cl, R3 = CH3
44b cis, R1= Cl, R3 = H
43c cis, R1= H, R3 = CH3
44c cis, R1= H, R3 = H
43d sat'd, R1= Cl, R3 = CH3
44d sat'd, R1= Cl, R3 = H
c
c
c
c
a
42e R2 = (CH2)6Br
b
O
N
Ph
Ph
43e R2 = N1
c
44e R2 = N2
N
42f R2 = (CH2)7Br
43f R2 = P1
O
R2
b
c
44f R2 = P2
Scheme 9. Reagants and conditions: (a) NaH, RX, DMF; (b) NaH, methyl 4-hydroxy-benzoate, DMF; (c) NaOH, THF, H2O, MeOH, 50 °C.
O
N
Ph
Ph
O
N
Ph
Ph
N
N
a
F
O
R1
O
O
O
CO2t-Bu
CO2R2
35a
45f R1 =
46f R1 =
R2 = t-Bu
R2 = H
45a R1= MeS, R2 = t-Bu
46a R1= MeS, R2 = H
45b R1= MeSO2, R2 = t-Bu
46b R1= MeSO2, R2 = H
45c R1= PhS, R2 = t-Bu
46c R1= PhS, R2 = H
b
b
b
b
b
N
N
O
S
b
b
c
45g R1=
46g R1=
R2 = t-Bu
R2 = H
45h R1=
46h R1=
R2 = t-Bu
R2 = H
45d R1= MeO, R2 = t-Bu
46d R1= MeO, R2 = H
45e R1 = PhO, R2 = t-Bu
46e R1= PhO, R2 = H
N
N
CO2Me
b
45i R1 =
46i R1 =
R2 = t-Bu
R2 = H
N
b
N
Scheme 10. Reagents and conditions: (a) nucleophile, DMF, 60 °C, 16 h; (b) TFA, DCM; (c) mCPBA, DCM.
matic difference between 16f and 16g suggests that linker length
and configuration can affect this interaction.
From this initial SAR exploration of the N-1 benzhydrylquinazol-
inediones, a comparison with the analogous indole-based cPLA2
a
The departure from indoles to quinazolinediones provided an
opportunity to start with a more polar core, and the elimination
of one of the phenyl rings of the benzhydryl group would address
our general goal of reducing lipophilicity. As shown in Table 2, con-
sistent with the parent indoles, considerable activity is lost in the
quinazolinedione series upon converting the benzhydryl to a ben-
zyl group.
inhibitor 5 is possible (Table 3). Quinazolinedione 16d does have a
slightly higher molecular weight, but the desired reduction in lipo-
philicity has been achieved while maintaining activity in the GLU
micelle assay.33 Indole 5 is slightly more active in the cell-based
MC-9 selectivity assay33,44 which measures the inhibition of both
LTB4 and PGF2 production. A cPLA2 inhibitor would affect the bio-
a
a
synthesis of these inflammatory mediators, but similar results could

4390
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
Table 1
N-3 linked carboxylic acids
five atom-linked benzoic acids was consistent (Table 4). These
additional examples further demonstrate the effect of the trans lin-
ker and the relatively minor influence of C-6 and C-7 core substitu-
tion. Compounds 16d (Table 1) and 16g are equipotent, but the
extended linker of the latter apparently contributes to a notable
O
N
R2
R3
R1
O
N
improvement in aqueous solubility (1 vs 28 lg/mL, pH 7.4).
The early SAR in the project largely consisted of indoles contain-
ing an N-1 benzhydryl group and a para-substituted phenyl ring
containing a carboxylic acid linked to C-3 through a one-carbon
linker.42 Similarly functionalized N-3 benzhydryl-quinazolinedi-
ones were also examined (Table 5). The acids linked to the phenyl
ring with one, two, or four atoms were relatively inactive as was
the compound (40d) containing an oxazole spacer between the
phenyl ring and the acid.
Some of the more active compounds in the N-1 ben-
zhydrylquinazolinedione series have an oxygen containing linker
between the core heterocycle and the benzoic acid, and this
seemed to be an appropriate region for N-3 benzhydrylquinazolin-
edione SAR exploration (Table 6). Lengthening the three-atom lin-
ker of 32b by one carbon atom resulted in a fivefold loss in activity.
The addition of two carbon atoms to 32b resulted in a fourfold
improvement. As shown by the data resulting from further chain
lengthening, the five-atom linker, as also observed in the case of
the N-1 benzhydryl-quinazolinediones, provided the optimal dis-
tance between the core and the acid (44d).
Compound R1
R2 R3 GLU IC50
(lM)
10b
Cl
H
H
90
CO2H
H2C
16e
Cl 80
19
Br
H
H
Cl
H
H
12
4
CH2CO2H
CO2H
H2C
16d
(CH2)2O
27
H
10
120
H2C
CO2H
16c
16f
16g
Br
H
Cl 60
Cl 4.5
cis - CH2CH=CHCH2O
trans - CH2CH=CHCH2O
CO2H
H
CO2H
Table 2
N-1 benzyl–benzhydryl comparison
In the N-1 benzhydrylquinazolinedione series, the most active
compound (16g) contains a trans olefin-containing five atom linker
(four carbons plus oxygen), and it was approximately 10-fold more
potent than 16f which has the corresponding cis linker (Table 1).
This trend is also consistent across a variety of N-3 benzhydryl ana-
logs (Table 7). Compound 44d, which has a saturated linker, is
equipotent to trans analog 44a. These trans-linked benzoic acids
O
O
N
N
O
CO2H
R
Compound
R
GLU IC50 (lM)
were the first non-indole cPLA2 inhibitors to exhibit low micro-
a
24
27
H
>100
10
Ph
Table 4
N-3 linker olefin geometry
Table 3
O
Quinazolinedione–indole comparison
R1
R2
O
N
O
N
O
CO2H
O
N
O
Cl
CO2H
Cl
N
O
CO2H
N
Ph Ph
Compound
R1
R2
Olefin
GLU IC50
(
lM)
Solubility7.4 (lg/mL)
Ph
Ph
16a
16b
10a
16f
H
H
F
H
H
H
H
H
Cl
Cl
Cis
25
2
5.6
60
4.5
37
51
42
51
28
Trans
Trans
Cis
16d
5
16g
Trans
Compound
Mol. wt
plog D7.4
GLU IC50
M)
MC-9 (% Inhib, 5
lM)
(
l
LTB4
PGF2
a
PGF2a
AA feeda
16d
5
527
496
3.3
6.1
4
3
93
96
61
81
0
ꢁ8
Table 5
N-1 benzyl-linked carboxylic acids
a
Exogenous arachidonic acid added to cells.
O
N
N
arise from a dual inhibitor acting on both the 5-LO and COX path-
ways. Upon addition of exogenous AA to the cells, the role of cPLA2
O
a
is bypassed and the lack of PGF2 inhibition is indicative of a selec-
a
R
tive cPLA2 inhibitor that does not affect the activity of downstream
a
enzymes in the PG biosynthetic pathway. These promising early re-
sults indicate that reduced lipophilicity is possible while maintain-
ing activity and target selectivity in enzymatic and cell-based
assays.
The trans-5-atom (butenyloxy) linker provided one of the most
potent N-1 benzhydryl-quinazolinediones, and this result was fol-
lowed-up to determine whether the preference for trans- over cis-
Compound
R
GLU IC50 (lM)
40a
40b
40c
CH2CO2H
OCH2CO2H
O(CH2)3CO2H
260
360
40
N
40d
140
CO2H
O

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4391
Table 6
Table 8
N-1 linked benzoic acid SAR
The effect of carboxylic acid placement
O
N
Ph
Ph
R1
R2
O
N
N
N
O
Cl
O
O
On
CO2H
R
Compound
n
R1
R2
GLU IC50 (lM)
32b
40h
44d
40e
44e
44f
1
2
3
4
5
6
H
H
Cl
H
H
H
Cl
H
H
H
H
H
10
50
2.5
30
47
71
Compound
R
GLU IC50 (lM)
40m
44a
m-CO2H
p-CO2H
100
1
Table 9
Regioisomeric quinazolinedione comparison
CO2H
Table 7
N-1 linker olefin geometry SAR
O
O
O
R
N
N
O
X
N O
X
N
R
O
R1
R2
N
O
B
CO2H
N
O
O
A
Series
Compound
X
R
GLU IC50 (lM)
CO2H
A
B
A
B
A
B
27
H
Cl
H
H
H
H
CH2CH2
10
10
25
44
2
32b
16a
44c
16b
40i
Compound
R1
H
R2
H
Olefin
GLU IC50 (lM)
cis-CH2CH@CHCH2
44c
40i
Cis
Trans
Cis
Trans
Trans
Cis
Trans
Cis
Trans
Cis
Trans
Satd
44
3
40
6
1.4
40
10
30
9
trans-CH2CH@CHCH2
3
36e
36f
36a
36g
36h
40k
40l
44b
44a
44d
F
H
H
Cl
F
H
The early stages of quinazolinedione SAR exploration were
heavily influenced by the experience gained from the indole cPLA2
a
Br
H
H
inhibitors. Isolated enzyme and whole blood activities have been
reduced to low micromolar levels, but the increased polarity of
the quinazolinedione core has just modestly improved upon the
physicochemical properties of the lead indole series. The limited
variety of C-6 and C-7 quinazolinedione substitution has generally
made little or no contribution to the potency, and as such, this pre-
sented an opportunity to introduce polar functionality. As shown
in Table 10, a series of C-7 substituted compounds were examined
with the purpose of exploring the possibility of improving upon the
physicochemical properties of the lead N-3 benzhydrylquinazolin-
edione series. There is no discernable correlation between activity
and either C-7 substituent size, polarity or electronegativity. The
relationship between plog D and solubility is more apparent; the
compounds of greatest polarity have the best aqueous solubility
(46b, 46i, and 36c), and the least polar compounds (46c and 46e)
have the poorest solubility. The quinazolinediones with the best
membrane permeability, as measured in a PAMPA45 assay, have
plog D values in the 2.5–3.5 range. The poor permeability of high
plog D compounds 46c and 46e is most likely the result of low sol-
ubility. Of the three most soluble, polar compounds (46b, 46i, and
36c), 46i is distinguished by its enzymatic activity and good per-
meability. In the case of 46b and 36c, there is a measurable differ-
ence in both activity and permeability, and a comparison of 46b
and 46i shows that good activity can be achieved with lower
plog D. The low correlation between activity and polarity further
corroborates our previous findings from the indole series: the
GLU micelle assay provides enzyme inhibition data that is not
skewed by the possible existence of non-specific, hydrophobic
interactions.33
Cl
30
1
2.5
molar activity in the rat whole blood assay (40i: IC50 = 14
(6 M); 44a (11 M). Like the N-1-benzhydryl analogs, the potency
of these compounds varies minimally with respect to C-6 and C-7
substitution. One of the goals of this non-indole effort was to dis-
cover inhibitors that had improved physical properties. When
compared to both the indoles and the cis-linked acids, the trans-
lM; 36a
l
l
linked quinazolinediones 40i (55
44a (25
(pH 7.4).
l
g/mL), 36f (53
lg/mL) have considerably improved aqueous solubility
lg/mL), and
Like the indole cPLA2 inhibitors, the level of quinazolinedione
a
activity depends on the benzhydryl group and an appropriately
spaced benzoic acid. Previous results in the indole series have
shown that the para-substituted aromatic ring is significantly more
active than the corresponding meta-acid.33,34 In the case of the N-3
benzhydryl-quinazolinediones, para-acid 44a is two orders of mag-
nitude more potent than the meta analog 40m (Table 8).
The switch from N-1 to N-3 benzhydrylquinazolinediones was
made based on synthetic considerations, but a comparison between
the two series is nonetheless worthwhile. In the case of the three
and five atom-linked benzoic acids (Table 9), the activity differences
between N-1 and N-3 substitution are nominal, and the trans-bute-
nyloxy-linked benzoic acid is consistently more potent than the cis
isomer in both the N-1 and N-3 benzhydrylquinazolinediones.

4392
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
Table 10
C-7 aromatic substitution
benzoic acid and a benzhydryl group. The appropriate length and
geometry of this tether is of critical importance as is the para-
substituted benzoic acid. The incorporation of polar C-7 functional-
O
N
ity provides cPLA2 selective compounds with low micromolar
a
N
activity in both enzymatic and whole blood assays. Furthermore,
this substitution provides water-soluble compounds with plog D
and clog P values below 2 and 5, respectively. As exemplified by
R
O
O
the dearth of polar, low molecular weight cPLA2 inhibitors re-
a
ported in the literature, the quinazolinediones represent a positive
step toward the discovery of drug-like inhibitors.
CO2H
Compound
R
GLU IC50 Solubility7.4 plog D7.4 PAMPA7.4
(
lM)
(lg/mL)
(ꢃ10ꢁ6 cm/s)
5. Experimental
46a
46b
46c
46d
46e
CH3S
CH3SO2
PhS
CH3O
PhO
2
26
>100
0
40
15
3.2
1.4
4.8
2.8
4.8
4.5
0.3
0
1.8
0
15
2.1
3
All solvents and reagents were used as obtained. 1H and 13C NMR
spectra were recorded at 300 MHz on a Varian Gemini 2000 or a
400 MHz Bruker AV-400 spectrometer using TMS (d 0.0) as a refer-
ence. Low resolution mass spectra were obtained using a Micromass
Platform Electrospray Ionization Quadrapole mass spectrometer.
Highresolutionmassspectrawereobtainedusinga Bruker(Billerica,
MA) APEXIII Fourier transform ion cyclotron resonance (FT-ICR)
mass spectrometer equipped with an actively shielded 7 Tesla
superconductingmagnet(MagnexScientificLtd, UK)and anexternal
Bruker APOLLO electrospray ionization (ESI) source. Flash chroma-
tography was performed using EM Science 230–400 mesh silica gel
or Biotage flash columns packed with KP-SIL 60 Angstrom silica
gel. Thin-layer chromatography (TLC) was performed using EMD
1.6
46f
2.2
48
2.5
1.0
O
S
N
46g
2.4
—
3.6
—
N
O
46h
46i
1.8
1.1
30
3.3
1.4
1.0
1.6
N
H3CO
N
>100
N
N
36a
36b
36c
36d
F
1.4
1
9
—
34
>100
40
2.9
2.4
1.7
3.2
—
NO2
NH2
CH3
2.6
0.4
2.0
250
5.1. General procedure for amide coupling
mixture of acid (1.0 mmol), amine (1.5 equiv), EDCI
lm prescored Silica Gel 60 F254 plates.
2.8
Table 11
Secondary assays
A
(1.2 equiv), and DMAP (5 mol %) in DMF (5 mL) was stirred at rt
for 5 h. The mixture was diluted with EtOAc, washed with water
(3 ꢃ 100 mL), dried over MgSO4, evaporated, and flash chromato-
graphed (EtOAc–hexanes) to afford the amide.
Compound
Rat WB IC50
(l
M)
MC-9 (% Inhib, 5 lM)
LTB4
PGF2
PGF2 AA feeda
a
a
16b
40i
36a
44a
46d
46i
12
14
6
11
9
98
97
99
98
99
61
52
83
99
74
ꢁ15
ꢁ476
ꢁ27
ꢁ45
ꢁ98
ꢁ28
ꢁ12
5.2. General procedure for aniline alkylation
A mixture of aniline (1.0 mmol), (bromomethylene)dibenzene
(1.4 equiv), and DIEA (1.1 equiv) in DCE (5 mL) was heated at 55 °C
for 16 h. The solvent was removed by evaporation and the residue
was flash chromatographed (EtOAc–hexanes) to afford the aniline.
11
13
100
97
102
30
36b
a
Exogenous arachidonic acid added to cells.
A subset of N-1 and N-3 quinazolinediones were tested in the rat
whole blood and MC-9 assays (Table 11). These compounds main-
tain activity in this assay, with ꢂ5–10-fold loss in potency when
compared to the enzymatic assay data. All of the compounds inhib-
5.3. General procedure for quinazolinedione cyclization
A
mixture of amino-amide (1.0 mmol) and triphosgene
(5 equiv) in THF was heated at reflux for 20 h. The cooled solution
was partitioned between EtOAc and satd aq NaHCO3. The organic
layer was washed with brine, dried over MgSO4, and flash chro-
matographed (EtOAc–hexanes) to afford the quinazolinedione.
ited COX-1 dependent PGF2
inhibition was lost when exogenous AA was added to bypass cPLA2
These data indicate that the inhibitors are acting on cPLA2 to block
AA release. Interestingly, the quinazolinediones inhibited LTB4 to a
greater extent than PGF2 , suggesting some additional inhibition
a production in the MC-9 assay, and the
a
.
a
a
5.4. General procedure for basic ester hydrolysis
of the 5-LO pathway. A similar bias toward inhibition of LTB4 was
observed when 46i was assayed in human blood. Dual inhibition of
cPLA2aand5-LOpathwayswouldnotbe seenasaliability. Inhibitors
blocking multiple AA processing enzymes are known in the litera-
ture, and subtle changes can shift the relative potency dramati-
cally.46 We continue to explore this series with the expectation,
but not the requirement, that 5-LO inhibition will be minimized.
A solution of ester (1.0 mmol) and either NaOH or LiOH
(3.0 mmol) was dissolved in a mixture of THF, MeOH, and water
(2:1:1 5 mL), and was heated at 50 °C until the starting material
was consumed as determined by TLC. The cooled solution was
acidified with 1 N HCl, diluted with ethyl acetate, washed with
water and brine, dried, filtered, evaporated, and flash chromato-
graphed (EtOAc–hexanes) to afford the carboxylic acid.
4. Conclusions
5.5. General procedure for phenol alkylation
A novel, second series of cPLA2 inhibitors were developed uti-
a
lizing SAR data gathered from an earlier indole series. Good activity
in the quinazolinedione series requires the presence of a tethered
To a solution of phenol (1.0 mmol) in DMF (5 mL) was added
60% NaH (1.1 equiv). After 10 min at rt, the halide (1.0 equiv)

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4393
was added dropwise as a DMF (2 mL) solution, and the reaction
was stirred overnight. The reaction was quenched with water, ex-
tracted with EtOAc, washed with water, 1 N NaOH, and brine,
dried, filtered, evaporated, and flash chromatographed (EtOAc–
hexanes) to afford the ether.
6.58–6.70 (m, 2H), 6.80–6.97 (m, 3H), 7.17–7.32 (m, 10H), 7.93
(d, J = 8.5 Hz, 2H).
5.10.3. tert-Butyl 4-({(2E)-4-[1-(diphenylmethyl)-6-fluoro-2,4-
dioxo-1,4-dihydroquinazolin-3(2H)-yl]but-2-en-1-
yl}oxy)benzoate (9a)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing 8a (342 mg, 53%). 1H NMR (300 MHz, CDCl3) d
1.57 (s, 9H), 4.56 (s, 2H), 4.79 (s, 2H), 6.03 (s, 2H), 6.87 (d,
J = 8.8 Hz, 2H), 7.00–7.10 (m, 2H), 7.22–7.42 (m, 10H), 7.90 (d,
J = 8.8 Hz, 2H).
5.6. General procedure for isatoic anhydride aminolysis
A solution of isatoic anhydride (1 mmol) and diphenylmethan-
amine (1.5 equiv) in ACN (10 mL) was heated at reflux for 48 h.
The solution was diluted with EtOAc (50 mL), washed with H2O,
10% aq HCl, and brine, dried, filtered, and evaporated to provide
the crude aminoamide.
5.10.4. 4-({(2E)-4-[1-(Diphenylmethyl)-6-fluoro-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(10a)
5.7. General procedure for N-1 quinazolinedione alkylation
The general acidic ester hydrolysis conditions were followed
utilizing 9a (141 mg, 91%). 1H NMR (300 MHz, CDCl3) d 4.60 (br
s, 2H), 4.81 (br s, 2H), 6.03 (br s, 2H), 6.93 (d, J = 9.0 Hz, 2H),
7.00–7.15 (m, 2H), 7.25–7.42 (m, 10H), 7.74 (s, 1H), 7.87 (dd,
J = 7.9, 2.2 Hz, 1H), 8.02 (d, J = 8.9 Hz, 2H); 13C NMR (DMSO-d6)
169.26, 159.99, 159.32, 158.57, 156.16, 150.22, 137.18, 136.21,
130.65, 128.74, 128.50, 128.01, 127.56, 127.50, 127.33, 126.77,
122.02, 121.78, 119.24, 119.16, 117.25, 117.18, 113.30, 113.11,
67.19, 61.56, 42.56; HRMS: C32H25FN2O5 requires (M+1)+ at m/z
537.1820; found, 537.1824.
To a solution of quinazolinsdione (1.0 mmol) in DMF (5 mL) was
added 60% NaH (1.1 equiv). After 10 min at rt, the halide
(1.0 equiv) was added dropwise as a DMF (2 mL) solution, and
the reaction was stirred at room temperature for 3 h and then for
2 h at 100 °C. The reaction was quenched with water, extracted
with EtOAc, washed with water and brine, dried, filtered, evapo-
rated, and flash chromatographed (EtOAc–hexanes) to afford the
N-1 alkylated quinazolinedione.
5.8. General procedure for nitro reduction
5.10.5. Methyl 4-({[(2-amino-5-chlorophenyl)carbonyl]amino}-
methyl)benzoate (7b)
A suspension of the nitro compound (1 mmol) and tin chloride
dihydrate (4.8 equiv) in ethanol (10 mL) was stirred at 80 °C for
1.5 h. To the cooled solution was added Celite and solid NaHCO3
(10 equiv) followed by the dropwise addition of water until all acid
is neutralized. The suspension is filtered, diluted with EtOAc,
washed with brine, dried, filtered, evaporated, and flash chromato-
graphed (EtOAc–hexanes) to provide the aniline.
The general amide coupling procedure was followed utilizing
acid 6b and methyl 4-(aminomethyl)benzoate (2.2 g, 73%). 1H
NMR (400 MHz, CDCl3) d ppm 3.91 (s, 3H), 4.64 (d, J = 6.1 Hz,
2H), 5.54 (s, 2H), 6.40–6.53 (m, 1H), 6.63 (d, J = 8.8 Hz, 1H), 7.16
(dd, J = 8.7, 2.4 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 8.6 Hz,
2H), 8.01 (d, J = 8.3 Hz, 2H).
5.10.6. Methyl 4-[({5-chloro-2-[(diphenylmethyl)amino]benzoyl}
amino)methyl]benzoate (8b)
5.9. General procedure for acidic ester hydrolysis
The general aniline alkylation procedure was followed utilizing
7b (3.91 g, 62%, white solid). 1H NMR (300 MHz, CDCl3) d 3.95 (s,
3H), 4.65 (d, J = 5.77 Hz, 2H), 5.59 (d, J = 5.22 Hz, 1H), 6.40–6.46
(m, 1H), 6.52 (d, J = 9.07 Hz, 1H), 7.13 (dd, J = 8.93, 2.33 Hz, 1H),
7.21–7.44 (m, 13H), 8.05 (d, J = 8.52 Hz, 2H), 8.35 (d, J = 4.12 Hz, 1H).
A solution of tert-butyl ester (1 mmol), and triethylsilane
(5 equiv) in DCM (5 mL) and trifluoroacetic acid (5 mL) was stirred
at room temperature for 2 h. The solution was evaporated and flash
chromatographed (EtOAc–hexanes) to provide the carboxylic acid.
5.10. General procedure for nucleophilic aromatic substitution
5.10.7. Methyl 4-{[6-chloro-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}benzoate (9b)
A solution of 35a (200 mg, 0.34 mmol) and nucleophile (3–
5 equiv) in DMF was heated at 60 °C for 16 h. The solution was di-
luted with ethyl acetate, washed with water and brine, dried, fil-
tered, and flash chromatographed (EtOAc–hexanes) to provide
the N-7 functionalized quinazolinedione.
The general quinazolinedione cyclization procedure was fol-
lowed utilizing 8b (549 mg, 50%, white solid). 1H NMR (300 MHz,
CDCl3) d 3.93 (s, 3H), 5.37 (s, 2H), 7.06 (d, J = 9.07 Hz, 1H), 7.23–
7.45 (m, 11H), 7.54 (d, J = 8.52 Hz, 2H), 7.73 (s, 1H), 8.01 (d,
J = 8.24 Hz, 2H), 8.21 (d, J = 2.47 Hz, 1H).
5.10.1. tert-Butyl 4-({(2E)-4-[(2-amino-5-fluorobenzoyl)amino]
but-2-en-1-yl}oxy)benzoate (7a)
5.10.8. 4-{[6-Chloro-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}benzoic acid (10b)
The general amide coupling procedure was followed utilizing
acid 6a and methyl 4-{[(2E)-4-aminobut-2-en-1-yl]oxy}benzoate
(0.74 g, 13%). 1H NMR (300 MHz, CDCl3) d 1.57 (s, 9H), 4.02–4.15
(m, 2H), 4.48–4.57 (m, 2H), 5.93 (d, J = 4.0 Hz, 2H), 6.47–6.53 (m,
1H), 6.70–6.80 (m, 1H), 6.88 (d, J = 9.0 Hz, 2H), 6.90–7.02 (m,
1H), 7.12 (dd, J = 9.0, 3.3 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H).
The general basic ester hydrolysis conditions were followed uti-
lizing ester 9b (0.17 g, 49%, white solid). 1H NMR (300 MHz, CDCl3)
d 5.39 (s, 2H), 7.07 (d, J = 9.34 Hz, 1H), 7.22–7.41 (m, 11H), 7.57 (d,
J = 8.24 Hz, 2H), 7.73 (s, 1H), 8.08 (d, J = 8.24 Hz, 2H), 8.22 (d,
J = 2.47 Hz, 1H); 13C NMR (DMSO-d6) 167.18, 160.18, 150.42,
141.48, 138.61, 137.09, 134.16, 130.23, 129.37, 128.47, 128.04,
127.52, 127.32, 127.13, 127.02, 118.90, 117.34, 61.90, 44.54; HRMS:
C29H21ClN2O4 requires (M+1)+ at m/z 497.1262; found, 497.1268.
5.10.2. tert-Butyl 4-{[(2E)-4-({2-[(diphenylmethyl)amino]-5-
fluorobenzoyl}amino)but-2-en-1-yl]oxy}benzoate (8a)
The general aniline alkylation procedure was followed utilizing
7a (110 mg, 58%). 1H NMR (300 MHz, CDCl3) d 1.58 (s, 9H), 4.06 (br
s, 2H), 4.54 (d, J = 3.5 Hz, 2H), 5.55 (s, 1H), 5.93 (d, J = 4.0 Hz, 2H),
5.10.9. Methyl 2-[(diphenylmethyl)amino]benzoate (12a)
The general aniline alkylation procedure was followed utilizing
11a (75%). 1H NMR (300 MHz, DMSO-d6) d 3.81 (s, 3H), 5.86 (d,

4394
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
J = 6.3 Hz, 1H), 6.56–6.66 (m, 2H), 7.02–7.10 (m, 1H), 7.16–7.45 (m,
10H), 8.23 (d, J = 7.8 Hz, 1H), 8.50 (d, J = 6.3 Hz, 1H).
12H), 7.47–7.58 (m, 2H), 7.85 (d, J = 8.7 Hz, 2H), 8.09 (dd, J = 7.7,
2.0 Hz, 1H); 13C NMR (DMSO-d6) 169.77, 160.70, 158.74, 150.45,
139.55, 137.39, 134.33, 133.19, 130.52, 128.47, 128.13, 128.00,
127.55, 127.42, 126.93, 122.97, 116.74, 115.67, 112.80, 67.14,
62.51, 61.32, 42.33, 37.12, 28.99; HRMS: C32H26N2O5 requires
(M+1)+ at m/z 519.1914; found, 519.1917.
5.10.10. 2-[(Diphenylmethyl)amino]benzoic acid (13a)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 12a (84%). 1H NMR (300 MHz, CDCl3) d 5.65 (d,
J = 3.0 Hz, 1H), 6.54–6.63 (m, 2H), 7.25–7.38 (m, 11H), 7.97 (d,
J = 7.8 Hz, 1H), 8.31 (br s, 1H).
5.10.17. Methyl 5-bromo-2-[(diphenylmethyl)amino]benzoate
(12b)
The general aniline alkylation procedure was followed utilizing
11b (0.94 g, 60%). 1H NMR (400 MHz, CDCl3) d ppm 3.85 (s, 3H),
5.59 (d, J = 5.6 Hz, 1H), 6.42 (d, J = 9.1 Hz, 1H), 7.19–7.42 (m,
10H), 8.03 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.3 Hz, 1H).
5.10.11. Methyl 4-{[(2Z)-4-({2-[(diphenylmethyl)amino]
benzoyl}amino)but-2-en-1-yl]oxy}benzoate (14a)
The general amide coupling procedure was followed utilizing
acid 13a and cis-4-(4-amino-but-2-enyloxy) benzoate (63 %). 1H
NMR (300 MHz, CDCl3) d 3.89 (s, 3H), 4.13 (t, J = 6.0 Hz, 2H), 4.72
(d, J = 5.7 Hz, 2H), 5.58 (d, J = 6.0 Hz, 1H), 5.74–5.94 (m, 2H),
6.14–6.20 (m, 1H), 6.50–6.55 (m, 2H), 6.92 (d, J = 9.0 Hz, 2H),
7.12–7.40 (m, 12H), 7.98 (d, J = 9.0 Hz, 2H), 8.40 (d, J = 5.7 Hz,
1H).
5.10.18. 5-Bromo-2-[(diphenylmethyl)amino]benzoic acid
(13b)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 12b (95%). 1H NMR (400 MHz, CDCl3) d ppm 5.61 (d,
J = 5.1 Hz, 1H), 6.45 (d, J = 9.1 Hz, 1H), 7.22–7.40 (m, 11H), 8.08
(d, J = 2.5 Hz, 1H), 8.28 (d, J = 4.8 Hz, 1H).
5.10.12. Methyl 4-({(2Z)-4-[1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoate (15a)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 14a (21%). 1H NMR (300 MHz, CDCl3)
d 3.89 (s, 3H), 4.86 (d, J = 6.3 Hz, 2H), 4.92 (d, J = 6.3 Hz, 2H), 5.78–
5.97 (m, 2H), 7.00 (d, J = 9.3 Hz, 2H), 7.05–7.23 (m, 2H), 7.26–7.45
(m, 11H), 7.74 (s, 1H), 7.97 (d, J = 9.3 Hz, 2H), 8.23 (d, J = 8.8 Hz,
1H).
5.10.19. Ethyl 2-[({5-bromo-2-[(diphenylmethyl)amino]
benzoyl}amino)-methyl]cyclopropanecarboxylate (14c)
The general amide coupling procedure was followed utilizing
acid 13b and trans-methyl 2-(aminomethyl)cyclopropane-carbox-
ylate (1.19 g, 52%). 1H NMR (300 MHz, CDCl3) d ppm 0.85–0.96
(m, 1H), 1.21–1.28 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.56–1.66 (m,
1H), 1.66–1.79 (m, 1H), 3.24–3.44 (m, 2H), 4.15 (q, J = 7.0 Hz,
2H), 5.56 (d, J = 4.9 Hz, 1H), 6.36 (t, J = 5.2 Hz, 1H), 6.44 (d,
J = 8.8 Hz, 1H), 7.17–7.43 (m, 12H), 7.49 (d, J = 2.2 Hz, 1H), 8.34
(d, J = 4.9 Hz, 1H).
5.10.13. 4-({(2Z)-4-[1-(Diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(16a)
The general basic ester hydrolysis conditions were followed
utilizing ester 15a (94%, hexane/CHCl3 trituration). 1H NMR
(300 MHz, CDCl3) d 4.70 (d, J = 5.4 Hz, 2H), 4.86 (d, J = 5.4 Hz, 2H),
5.63–5.85 (m, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.15–7.55 (m, 13H),
7.60 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 2H);
13C NMR (DMSO-d6) 169.82, 160.80, 158.69, 150.61, 139.45,
137.30, 134.24, 133.18, 130.54, 128.70, 128.46, 128.09, 128.02,
127.42, 122.94, 116.83, 115.75, 112.86, 63.66, 61.20, 28.98;
HRMS: C32H26N2O5 requires (M+1)+ at m/z 519.1914; found,
519.1915.
5.10.20. Ethyl 2-{[6-bromo-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}cyclopropanecarboxylate
(15c)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 14c (231 mg, 44%). 1H NMR
(300 MHz, CDCl3) d ppm 0.99–1.09 (m, 1H), 1.22–1.29 (m, 1H),
1.30 (t, J = 7.1 Hz, 3H), 1.67–1.75 (m, 1H), 1.77–1.90 (m, 1H), 3.68
(d, J = 5.5 Hz, 2H), 4.17 (q, J = 7.0 Hz, 2H), 6.83 (d, J = 9.1 Hz, 1H),
7.25–7.45 (m, 11H), 8.20 (d, J = 2.2 Hz, 1H).
5.10.21. 2-{[6-Bromo-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}cyclopropanecarboxylic
acid (16c)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15c (188 mg, 86%). 1H NMR (400 MHz, DMSO-d6) d ppm
0.92–1.02 (m, 2H), 1.58–1.73 (m, 2H), 3.87–4.01 (m, 2H), 7.18 (d,
J = 9.1 Hz, 1H), 7.28–7.43 (m, 10H), 7.55 (s, 1H), 7.70 (dd, J = 9.1,
2.5 Hz, 1H), 8.15 (d, J = 2.5 Hz, 1H), 12.13 (s, 1H); HRMS:
C26H21BrN2O4 requires (M+1)+ at m/z 505.0758; found, 505.0762.
5.10.14. Methyl 4-{[(2E)-4-({2-[(diphenylmethyl)amino]
benzoyl}amino)but-2-en-1-yl]oxy}benzoate (14b)
The general amide coupling procedure was followed utilizing
acid 13a and trans-4-(4-amino-but-2-enyloxy) benzoate (76%). 1H
NMR (300 MHz, CDCl3) d 3.88 (s, 3H), 4.05–4.13 (m, 2H), 4.57 (d,
J = 2.6 Hz, 2H), 5.59 (d, J = 5.4 Hz, 1H), 5.86–6.02 (m, 2H), 6.15–
6.24 (m, 1H), 6.52–6.62 (m, 2H), 7.14–7.40 (m, 11H), 7.97 (d,
J = 8.7 Hz, 2H), 8.38 (d, J = 5.4 Hz, 1H).
5.10.15. Methyl 4-({(2E)-4-[1-(Diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoate (15b)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminamide 14b (65%). 1H NMR (300 MHz, CDCl3)
d 3.87 (s, 3H), 4.53–4.59 (m, 2H), 4.78–4.82 (m, 2H), 6.00–6.05
(m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 7.05–7.20 (m, 2H), 7.25–7.40
(m, 11H), 7.71 (br s, 1H), 7.95–8.00 (m, 2H), 8.22 (d, J = 7.5 Hz,
1H).
5.10.22. Methyl 4-[2-({4-chloro-2-[(diphenylmethyl)amino]
benzoyl}amino)ethoxy]benzoate (14d)
The general amide coupling procedure was followed utilizing
acid 13c and methyl 4-(2-aminoethoxy)benzoate (1.04 g, 53%,
white solid). 1H NMR (400 MHz, CDCl3) d 3.81 (dd, J = 5.56 Hz,
2H), 3.89 (s, 3H), 4.16 (t, J = 5.18 Hz, 2H), 5.55 (d, J = 5.81 Hz, 1H),
6.47 (t, J = 5.43 Hz, 1H), 6.52 (s, 1H), 6.55 (d, J = 2.02 Hz, 1H), 6.92
(d, J = 9.09 Hz, 2H), 7.31 (m, 11H), 7.99 (d, J = 9.09 Hz, 2H), 8.57
(d, J = 5.81 Hz, 1H).
5.10.16. 4-({(2E)-4-[1-(Diphenylmethyl)-2,4-dioxo-1,4-dihydro-
quinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoic acid (16b)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15b (80%). 1H NMR (300 MHz, DMSO-d6) d 4.57–4.66
(m, 4H), 5.75–6.00 (m, 2H), 6.99 (d, J = 8.7 Hz, 2H), 7.19–7.40 (m,
5.10.23. Methyl 4-{2-[7-chloro-1-(diphenylmethyl)-2,4-dioxo-
1,4-dihydroquinazolin-3(2H)-yl]ethoxy}benzoate (15d)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 14d (506 mg, 65%, of white solid).

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4395
1H NMR (300 MHz, CDCl3) d 3.90 (s, 3H), 4.36 (t, J = 5.91 Hz, 2H),
5.10.31. Methyl 4-({(2Z)-4-[7-chloro-1-(diphenylmethyl)-2,4-
4.60 (t, J = 5.91 Hz, 2H), 6.90 (d, J = 8.79 Hz, 2H), 7.14 (s, 1H),
7.13–7.17 (m, 1H), 7.24–7.42 (m, 10H), 7.64 (s, 1H), 7.97 (d,
J = 9.07 Hz, 2H), 8.17 (d, J = 7.97 Hz, 1H).
dioxo-1,4-dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)
benzoate (15f)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 14f (72%). 1H NMR (300 MHz, CDCl3)
d 3.89 (s, 3H), 4.81 (d, J = 6.2 Hz, 2H), 4.90 (d, J = 6.0 Hz, 2H),
5.76–5.95 (m, 2H), 6.96 (d, J = 9.0 Hz, 2H), 7.08–7.14 (m, 2H),
7.25–7.44 (m, 10H), 7.67 (s, 1H), 7.96 (d, J = 9.0 Hz, 2H), 8.13 (d,
J = 9.0 Hz, 1H).
5.10.24. 4-{2-[7-Chloro-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]ethoxy}benzoic acid (16d)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15d (0.14 g, 60%, white solid). 1H NMR (300 MHz,
CDCl3) d 4.38 (t, J = 5.8 Hz, 2H), 4.61 (t, J = 5.8 Hz, 2H), 6.93 (d,
J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.15–7.17 (m, 1H), 7.25–7.43 (m,
10H), 7.64 (s, 1H), 8.04 (d, J = 9.1 Hz, 2H), 8.18 (d, J = 8.24 Hz,
1H); 13C NMR (DMSO-d6) 169.52, 160.47, 158.70, 150.47, 140.64,
138.97, 137.08, 133.41, 130.52, 130.04, 128.48, 127.98, 127.52,
123.14, 116.13, 114.62, 112.67, 66.98, 63.83, 61.58, 25.09. HRMS:
C30H23ClN2O5 requires (M+1)+ at m/z 527.1368; found, 527.1370.
5.10.32. 4-({(2Z)-4-[7-Chloro-1-(diphenylmethyl)-2,4-dioxo-1,
4-dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(16f)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15f (33%). 1H NMR (300 MHz, CDCl3) d 4.66 (d,
J = 6.6 Hz, 2H), 4.84 (d, J = 6.6 Hz, 2H), 5.61–5.72 (m, 1H), 5.74–
5.85 (m, 1H), 7.03 (d, J = 8.7 Hz, 2H), 7.22–7.43 (m, 13H), 7.54 (br
s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.4 Hz, 1H); 13C NMR
(DMSO-d6) 169.66, 160.20, 158.78, 150.37, 140.64, 138.87,
137.07, 132.91, 130.56, 130.02, 129.05, 128.73, 128.52, 128.01,
127.57, 127.30, 123.11, 116.25, 114.79, 112.92, 63.67, 62.12,
61.59, 28.86. HRMS: C32H25ClN2O5 requires (M+1)+ at m/z
553.1525; found, 553.1525.
5.10.25. Methyl 4-chloro-2-[(diphenylmethyl)amino]benzoate
(12c)
The general aniline alkylation procedure was followed utilizing
11c (91%). 1H NMR (300 MHz, CDCl3) d 3.84 (s, 3H), 5.59 (d,
J = 5.8 Hz, 1H), 6.52–6.57 (m, 2H), 7.22–7.37 (m, 10H), 7.84 (d,
J = 8.1 Hz, 1H), 8.55–8.60 (m, 1H).
5.10.26. 4-Chloro-2-[(diphenylmethyl)amino]benzoic acid
(13c)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 12c (98%). 1H NMR (400 MHz, DMSO-d6) d ppm 5.93 (d,
J = 6.6 Hz, 1H), 6.58–6.66 (m, 2H), 7.22–7.31 (m, 2H), 7.32–7.45 (m,
8H), 7.82 (d, J = 8.1 Hz, 1H), 8.82 (d, J = 6.6 Hz, 1H), 13.03 (s, 1H).
5.10.33. Methyl 4-{[(2E)-4-({4-chloro-2-[(diphenylmethyl)
amino]benzoyl}amino)but-2-en-1-yl]oxy}benzoate (14g)
The general amide coupling procedure was followed utilizing
acid 13c and trans-4-(4-amino-but-2-enyloxy) benzoate (76%).
1H NMR (300 MHz, CDCl3) d 3.89 (s, 3H), 4.03–4.10 (m, 2H),
4.57–4.60 (m, 2H), 5.55 (d, J = 6.0 Hz, 1H), 5.89–5.95 (m, 2H),
6.10–6.16 (m, 1H), 6.50–6.57 (m, 2H), 6.90 (d, J = 9.0 Hz, 2H),
7.20–7.42 (m, 13H), 7.98 (d, J = 9.0 Hz, 2H), 8.57 (d, J = 6.0 Hz,
1H).
5.10.27. Methyl 4-{[({4-chloro-2-[(diphenylmethyl)amino]
phenyl}carbonyl)amino]methyl}benzoate (14e)
The general amide coupling procedure was followed utilizing
acid 13c and methyl 4-(aminomethyl)benzoate (0.11 g, 52%). 1H
NMR (400 MHz, DMSO-d6) d ppm 3.84 (s, 3H), 4.52 (d, J = 5.8 Hz,
2H), 5.84 (d, J = 6.3 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.64 (dd,
J = 8.3, 2.0 Hz, 1H), 7.19–7.28 (m, 2H), 7.30–7.41 (m, 7H), 7.45 (d,
J = 8.3 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H),
9.02 (d, J = 6.6 Hz, 1H), 9.15 (t, J = 6.2 Hz, 1H).
5.10.34. Methyl 4-({(2E)-4-[7-chloro-1-(diphenylmethyl)-2,4-
dioxo-1,4-dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)
benzoate (15g)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 14g (32%). 1H NMR (300 MHz, CDCl3)
d 3.87 (s, 3H), 4.54–4.58 (m, 2H), 4.74–4.78 (m, 2H), 5.98–6.03 (m,
2H), 6.86–6.94 (m, 2H), 7.09–7.14 (m, 2H), 7.24–7.40 (m, 10H),
7.64 (s, 1H), 7.93–8.00 (m, 2H), 8.13 (d, J = 8.0 Hz, 1H).
5.10.28. Methyl 4-{[7-chloro-1-(diphenylmethyl)-2,4-dioxo-
1,4-dihydroquinazolin-3(2H)-yl]methyl}benzoate (15e)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing 14e (350 mg, 71%). 1H NMR (400 MHz, DMSO-d6)
d ppm 3.84 (s, 3H), 5.18 (s, 2H), 7.29–7.43 (m, 12H), 7.48 (s, 1H),
7.88 (d, J = 8.6 Hz, 2H), 8.10 (d, J = 8.3 Hz, 1H).
5.10.35. 4-({(2E)-4-[7-Chloro-1-(diphenylmethyl)-2,4-dioxo-1,
4-dihydroquinazolin-3(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(16g)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15g (80%). 1H NMR (300 MHz, CDCl3) d 4.57 (br s, 4H),
5.74–5.97 (m, 2H), 6.99 (d, J = 9.0 Hz. 2H), 7.24–7.44 (m, 12H), 7.51
(s, 1H), 7.86 (d, J = 9.0 Hz, 2H), 8.08 (d, J = 8.3 Hz, 1H); 13C NMR
(DMSO-d6) 169.59, 160.10, 158.82, 150.18, 140.73, 138.97,
137.15, 132.88, 130.53, 130.05, 128.51, 127.98, 127.61, 127.56,
127.19, 123.14, 116.16, 114.69, 112.85, 67.13, 61.69, 42.39,
28.84; HRMS: C32H25ClN2O5 requires (M+1)+ at m/z 553.1525;
found, 553.1530.
5.10.29. 4-{[7-Chloro-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}benzoic acid (16e)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 15e (140 mg, 91%). 1H NMR (400 MHz, DMSO-d6) d
ppm 5.17 (s, 2H), 7.28–7.42 (m, 14H), 7.48 (s, 1H), 7.85 (d,
J = 8.1 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H); HRMS: C29H21ClN2O4 re-
quires (M+1)+ at m/z 497.1262; found, 497.1268.
5.10.30. Methyl 4-{[(2Z)-4-({4-chloro-2-[(diphenylmethyl)
amino]benzoyl}amino)but-2-en-1-yl]oxy}benzoate (14f)
The general amide coupling procedure was followed utilizing
acid 13c and cis-4-(4-amino-but-2-enyloxy) benzoate (78 %). 1H
NMR (300 MHz, CDCl3) d 3.88 (s, 3H), 4.12 (t, J = 6.0 Hz, 2H), 4.71
(d, J = 5.7 Hz, 2H), 5.54 (d, J = 6.0 Hz, 1H), 5.75–5.95 (m, 2H), 6.11
(br s, 1H), 6.50–6.54 (m, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7.19–7.40
(m, 11H), 7.97 (d, J = 9.0 Hz, 2H), 8.59 (d, J = 6.0 Hz, 1H).
5.10.36. Methyl {4-[({5-bromo-2-[(diphenylmethyl)amino]
benzoyl}-amino)methyl]phenyl}acetate (17)
The general amide coupling procedure was followed utilizing
acid 13b and methyl [4-(aminomethyl)phenyl]acetate (380 mg,
47%). 1H NMR (300 MHz, CDCl3) d ppm 3.59–3.66 (m, 2H), 3.66–
3.74 (m, 3H), 4.48–4.60 (m, 2H), 5.49–5.61 (m, 1H), 6.33–6.51
(m, 1H), 7.16–7.42 (m, 17H), 7.46–7.57 (m, J = 2.2 Hz, 1H), 8.38–
8.51 (m, 1H).

4396
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
5.10.37. {4-[({5-Bromo-2-
[(diphenylmethyl)amino]benzoyl}amino)methyl]phenyl}acetic
acid (18)
CDCl3) d 3.65 (t, J = 6.8 Hz, 2H), 3.81 (t, J = 6.8 Hz, 2H), 4.45–4.58
(m, 2H), 7.05–7.18 (m, 2H), 7.20–7.43 (m, 11H), 7.66 (s, 1H), 8.22
(d, J = 8.0 Hz, 1H).
The general basic ester hydrolysis conditions were followed uti-
lizing ester 17 (321 mg, 93%). 1H NMR (300 MHz, CDCl3) d ppm
3.51–3.60 (m, 2H), 4.45–4.63 (m, 2H), 5.52–5.65 (m, 1H), 6.30–
6.47 (m, 1H), 7.21–7.45 (m, 17H), 7.46–7.57 (m, J = 2.2 Hz, 1H),
8.35–8.48 (m, 1H).
5.10.45. Methyl 4-{2-[1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]ethoxy}benzoate (26)
The general phenol alkylation conditions were followed utiliz-
ing chloride 25 and methyl 4-hydroxybenzoate (27%). 1H NMR
(300 MHz, CDCl3) d 3.87 (s, 3H), 4.34 (t, J = 6.0 Hz, 2H), 4.60 (t,
J = 6.0 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 7.05–7.18 (m, 2H), 7.20–
7.38 (m, 11H), 7.67 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 8.21 (d,
J = 7.9 Hz, 1H).
5.10.38. (4-{[6-Bromo-1-(diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]methyl}phenyl)acetic acid (19)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 18 (115 mg, 50%). 1H NMR
(300 MHz, CDCl3) d ppm 3.64 (s, 2H), 5.31 (s, 2H), 6.97 (d,
J = 9.1 Hz, 1H), 7.22–7.42 (m, 14H), 7.50 (d, J = 8.0 Hz, 2H), 7.76
(s, 1H), 8.34 (d, J = 2.5 Hz, 1H); HRMS: C30H23BrN2O4 requires
(M+1)+ at m/z 555.0914; found, 555.0921.
5.10.46. 4-{2-[1-(Diphenylmethyl)-2,4-dioxo-1,4-
dihydroquinazolin-3(2H)-yl]ethoxy}benzoic acid (27)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 26 (47%, chromatography followed by hexanes tritur-
ation). 1H NMR (400 MHz, DMSO-d6) d 4.21 (t, J = 6.2 Hz, 2H),
4.37 (t, J = 6.2 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 7.16–7.27 (m, 2H),
7.27–7.40 (m, 10H), 7.45–7.54 (m, 1H), 7.57 (s, 1H), 7.74 (d,
J = 8.8 Hz, 2H), 7.74 (d, 3H), 8.11 (dd, J = 7.8, 1.5 Hz, 1H); HRMS:
C30H24N2O5 requires (M+1)+ at m/z 493.1763; found, 493.1757.
5.10.39. Methyl 2-(benzylamino)benzoate (20)
A solution of methyl 2-aminobenzoate (10 g, 66 mmol), benzyl
bromide, and potassium carbonate (22.8 g, 2.5 equiv) in acetone
(200 mL) was heated at reflux for 18 h. The solution was filtered,
evaporated, and flash chromatographed (5% EtOAc/hexanes) to
provide 20 (8.5 g, 53%, amber oil). 1H NMR (400 MHz, chloro-
form-d) d ppm 3.86 (s, 3H), 4.45 (d, J = 5.6 Hz, 2H), 6.57–6.62 (m,
1H), 6.63 (d, J = 8.6 Hz, 1H), 7.23–7.38 (m, 6H), 7.92 (dd, J = 8.1,
1.8 Hz, 1H), 8.16 (br. s., 1H).
5.10.47. 2-Amino-4-chlorobenzoic acid (29)
The general nitro reduction conditions were followed utilizing
nitro compound 28 (3.25 g, 55%). 1H NMR (300 MHz, DMSO-d6) d
6.37 (d, J = 8.79 Hz, 1H), 6.56 (dd, J = 8.52, 2.20 Hz, 1H), 6.64 (s,
2H), 6.77 (d, J = 1.92 Hz, 1H), 7.20–7.40 (m, 10H), 7.70 (d,
J = 8.52 Hz, 1H), 9.11 (d, J = 8.79 Hz, 1H).
5.10.40. 2-(Benzylamino)benzoic acid (21)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 20 (7.9 g, 100%). 1H NMR (400 MHz, DMSO-d6) d ppm
4.46 (s, 2H), 6.53–6.59 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H), 7.23–7.37
(m, 6H), 7.81 (dd, J = 8.0, 1.6 Hz, 1H).
5.10.48. 7-Chloro-3-(diphenylmethyl)quinazoline-2,4(1H,3H)-
dione (30)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 29 (64%). 1H NMR (300 MHz, CDCl3)
d 6.71 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.5, 1.8 Hz, 1H), 7.27–7.47
(m, 10H), 7.51 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 10.80 (s, 1H).
5.10.41. Methyl 4-[2-({[2-(benzylamino)phenyl]carbonyl}
amino)ethoxy]benzoate (22)
The general amide coupling procedure was followed utilizing
acid 21 (0.88 g, 66%). 1H NMR (400 MHz, CDCl3) d ppm 3.85 (q,
J = 5.6 Hz, 2H), 3.89 (s, 3H), 4.19 (t, J = 5.2 Hz, 2H), 4.41 (d,
J = 5.6 Hz, 2H), 6.53 (br t, J = 5.4 Hz, 1H), 6.56–6.65 (m, 2H), 6.91–
6.95 (m, 2H), 7.21–7.25 (m, 2H), 7.29–7.39 (m, 5H), 7.98–8.01
(m, 2H), 8.02–8.06 (m, J = 4.8 Hz, 1H).
5.10.49. Ethyl [2-(4-{[7-chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]methyl}phenyl)-1,3-oxazol-4-
yl]acetate (31a)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 and ethyl [2-(4-bromomethylphenyl) oxa-
zol-4-yl] acetate (82%). 1H NMR (300 MHz, CDCl3) d 1.21 (t,
J = 7.2 Hz, 3H), 3.68 (s, 2H), 4.10 (d, J = 7.2 Hz, 2H), 5.42 (s, 2H),
7.25–7.48 (m, 15H), 7.91 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 8.1 Hz, 2H).
5.10.42. Methyl 4-[2-(1-benzyl-2,4-dioxo-1,4-dihydroquinazolin-
3(2H)-yl)ethoxy]benzoate (23)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 22 (0.23 g, 67%). 1H NMR (400 MHz,
CDCl3) d ppm 3.87 (s, 3H), 4.38 (t, J = 6.2 Hz, 2H), 4.63 (t,
J = 6.2 Hz, 2H), 5.39 (s, 2H), 6.91–6.96 (m, 2H), 7.12 (d, J = 8.3 Hz,
1H), 7.20–7.36 (m, 6H), 7.52–7.58 (m, 1H), 7.94–7.98 (m, 2H),
8.24 (dd, J = 7.8, 1.3 Hz, 1H).
5.10.50. Ethyl [2-(4-{[7-chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]methyl}phenyl)-1,3-oxazol-4-
yl]acetate (32a)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 31a (96%). 1H NMR (400 MHz, DMSO-d6) d 3.11 (s, 2H),
5.41 (s, 2H), 7.26–7.50 (m, 16H), 7.82 (s, 1H), 7.88 (d, J = 8.1 Hz,
2H), 8.07 (d, J = 8.3 Hz, 1H); 13C NMR (DMSO-d6) 172.18, 160.62,
158.83, 150.37, 140.94, 140.28, 140.01, 138.14, 137.88, 135.92,
130.36, 129.56, 128.39, 128.08, 127.18, 126.99, 126.54, 125.98,
123.35, 114.66, 114.20, 59.57, 46.25, 36.69; HRMS: C33H24ClN3O5
requires (M+1)+ at m/z 578.1477; found, 578.1474.
5.10.43. 4-[2-(1-Benzyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-
yl)ethoxy]benzoic acid (24)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 23 (0.2 g, 95%). 1H NMR (400 MHz, DMSO-d6) d ppm
4.33–4.39 (m, 2H), 4.44 (t, J = 5.9 Hz, 2H), 5.40 (s, 2H), 6.99–7.05
(m, 2H), 7.23–7.37 (m, 7H), 7.64–7.71 (m, 1H), 7.85–7.90 (m,
2H), 8.10 (dd, J = 8.2, 1.6 Hz, 1H), 12.61 (s, 1H). HRMS:
C24H20N2O5 requires (M+1)+ at m/z 417.1445; found, 417.1449.
5.10.51. Methyl 4-{2-[7-chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]ethoxy}benzoate (31b)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 and methyl 4-(2-bromoethoxy) benzoate
(96%). 1H NMR (400 MHz, CDCl3) d 3.88 (s, 3H), 4.33 (t, J = 5.1 Hz,
2H), 4.48 (t, J = 5.1 Hz, 2H), 6.77–6.84 (m, 2H), 7.19–7.45 (m,
11H), 7.49 (s, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.92–7.98 (m, 2H), 8.12
(d, J = 8.5 Hz, 1H).
5.10.44. 3-(2-Chloroethyl)-1-(diphenylmethyl)quinazoline-2,
4(1H,3H)-dione (25)
The general N-1 quinazolinedione alkylation conditions were fol-
lowed utilizing 3-(2-chloroethyl)quinazoline-2,4(1H,3H)-dione and
1,10-(bromomethanediyl)dibenzene (61%). 1H NMR (300 MHz,

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4397
5.10.52. 4-{2-[7-Chloro-3-(diphenylmethyl)-2,4-dioxo-3,4-
5.10.60. 4-({(2E)-4-[3-(Diphenylmethyl)-7-nitro-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]ethoxy}benzoic acid (32b)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 31b (82%). 1H NMR (400 MHz, acetone-d6) d 4.40–4.50
(m, 2H), 4.60–4.72 (m, 2H), 6.88–6.94 (m, 2H), 7.24–7.36 (m, 7H),
7.37–7.44 (m, 4H), 7.49 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.90–7.96
(m, 2H), 8.07 (d, J = 8.5 Hz, 1H); HRMS: C30H23ClN2O5 requires
(M+1)+ at m/z 527.1368; found, 527.1368.
dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36b)
The general acidic ester hydrolysis conditions were followed
utilizing ester 35b (0.02 g, 65%). 1H NMR (300 MHz, CDCl3) d 8.27
(d, J = 9.3 Hz, 1H), 7.85–7.93 (m, 4H), 7.38 (s, 1H), 7.14–7.30 (m,
10H), 6.77 (d, J = 8.9 Hz, 2H), 5.84 (br s, 2H), 4.74 (br s, 2H), 4.49
(br s, 2H); 13C NMR (DMSO-d6) 169.46, 160.16, 158.84, 151.48,
149.87, 140.50, 137.97, 130.52, 130.29, 128.42, 128.05, 127.19,
126.19, 119.75, 116.90, 112.97, 110.26, 67.03, 59.88, 44.93; HRMS:
C32H25N3O7 requires (M+1)+ at m/z 564.1765; found, 564.1764.
5.10.53. 2-Amino-N-(diphenylmethyl)-4-fluorobenzamide
(33a)
The general amide coupling procedure was followed utilizing 2-
amino-4-fluorobenzoic acid (2.3 g, >100%). 1H NMR (300 MHz,
CDCl3) d ppm 5.80 (s, 1H), 6.32–6.38 (m, 1H), 6.39 (s, 1H), 6.51–
6.58 (m, 1H), 7.15–7.47 (m, 13H).
5.10.61. tert-Butyl 4-({(2E)-4-[7-amino-3-(diphenylmethyl)-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (35c)
The general nitro reduction conditions were followed utilizing
nitro compound 35b (0.11 g, 58%). 1H NMR (300 MHz, CDCl3) d
1.46 (s, 9H), 4.41 (d, J = 4.4 Hz, 2H), 4.53 (br s, 2H), 5.60–5.84 (m,
2H), 6.07 (s, 1H), 6.33 (dd, J = 8.7, 1.6 Hz, 1H), 6.72 (d, J = 8.9 Hz,
2H), 7.10–7.26 (m, 10H), 7.40 (s, 1H), 7.77–7.85 (m, 3H).
5.10.54. 3-(Diphenylmethyl)-7-fluoroquinazoline-2,4(1H,3H)-
dione (34a)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 33a ((1.1 g, 50%, two steps). 1H NMR
(300 MHz, CDCl3) d 6.38 (dd, J = 8.93, 2.33 Hz, 1H), 6.99–6.99 (m,
1H), 7.28–7.50 (m, 10H), 7.55 (s, 1H), 8.15 (dd, J = 8.93, 5.91 Hz,
1H), 10.98 (s, 1H).
5.10.62. 4-({(2E)-4-[7-Amino-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36c)
The general acidic ester hydrolysis conditions were followed
utilizing ester 36c (0.08 g, 74%). 1H NMR (300 MHz, DMSO-d6) d
7.73 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.10–7.25 (m,
10H), 6.85 (d, J = 8.8 Hz, 2H), 6.32 (d, J = 8.8 Hz, 1H), 6.18–6.23
(m, 2H), 5.60–5.85 (m, 2H), 4.47 (br s, 4H), 3.12 (s, 2H); 13C NMR
(DMSO-d6) 160.56, 158.74, 155.59, 150.40, 141.49, 138.90,
130.54, 129.97, 128.26, 127.96, 127.59, 126.85, 126.75, 112.85,
110.11, 102.93, 95.83, 67.10, 58.39, 44.17, 30.39; HRMS:
C32H27N3O5 requires (M+1)+ at m/z 534.2023; found, 534.2023.
5.10.55. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-fluoro-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (35a)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34a (246 mg, 72%). 1H NMR (300 MHz, CDCl3) d
1.62 (s, 9H), 4.76 (br s, 2H), 4.60 (br s, 1H), 5.82–6.00 (m, 2H),
6.82–7.00 (m, 3H), 7.29–7.55 (m, 11H), 7.56 (s, 1H), 7.95 (d,
J = 8.8 Hz, 2H), 8.26 (dd, J = 8.8, 6.3 Hz, 1H).
5.10.63. 2-Amino-N-(diphenylmethyl)-4-methylbenzamide
(33c)
The general amide coupling procedure was followed utilizing 2-
amino-4-methylbenzoic acid (1.4 g, 67%). 1H NMR (400 MHz,
CDCl3) d 2.25 (s, 3H), 6.36 (d, J = 7.1 Hz, 1H), 6.46 (d, J = 8.1 Hz,
1H), 6.49 (s, 1H), 6.53 (d, J = 7.1 Hz, 1H), 7.24–7.39 (m, 12H).
5.10.56. 4-({(2E)-4-[3-(Diphenylmethyl)-7-fluoro-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36a)
The general acidic ester hydrolysis conditions were followed
utilizing ester 35a (175 mg, 77%). 1H NMR (300 MHz, CDCl3) d
8.26 (dd, J = 8.9, 6.3 Hz, 1H), 8.06 (d, J = 8.9 Hz, 2H), 7.54 (s, 1H),
7.38–7.50 (m, 8H), 6.80–7.05 (m, 6H), 5.85–6.00 (m, 2H), 4.75–
4.80 (m, 2H), 4.60–4.65 (m, 2H); HRMS: calcd for C32H25FN2O5ꢁH+,
535.16747; found, 535.1693.
5.10.64. 3-(Diphenylmethyl)-7-methylquinazoline-2,4(1H,3H)-
dione (34c)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 33c (1.46 g, 97%, crude). 1H NMR
(300 MHz, CDCl3) d 2.50 (s, 3H), 7.08–7.7.20 (m, 2H), 7.30–7.65
(m, 11H), 7.92 (d, J = 8.0 Hz, 1H).
5.10.57. 2-Amino-N-(diphenylmethyl)-4-nitrobenzamide (33b)
The general amide coupling procedure was followed utilizing 2-
amino-4-nitrobenzoic acid (3.3 g, 58%). 1H NMR (400 MHz, CDCl3)
d 5.84 (br s, 2H), 6.37 (d, J = 7.33 Hz, 1H), 6.61 (d, J = 6.57 Hz, 1H),
7.24–7.54 (m, 13H).
5.10.65. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-methyl-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (35d)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34c (0.23 g, 67%). 1H NMR (300 MHz, CDCl3) d
2.29 (s, 3H), 4.43 (d, J = 4.7 Hz, 2H), 4.62 (d, J = 3.5 Hz, 2H), 5.65–
5.88 (m, 2H), 6.70–6.79 (m, 3H), 6.92 (d, J = 8.1 Hz, 1H), 7.10–
7.32 (m, 10H), 7.41 (s, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.97 (d,
J = 8.0 Hz, 1H).
5.10.58. 3-(Diphenylmethyl)-7-nitroquinazoline-2,4(1H,3H)-
dione (34b)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 33b (2.48 g, 70%). 1H NMR
(300 MHz, DMSO-d6) d 7.25–7.38 (m, 11H), 7.92–7.98 (m, 2H),
8.13 (d, J = 8.6 Hz, 1H).
5.10.59. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-nitro-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (35b)
5.10.66. 4-({(2E)-4-[3-(Diphenylmethyl)-7-methyl-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36d)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34b (0.60 g, 75%). 1H NMR (300 MHz, CDCl3) d
1.46 (s, 9H), 1.46 (s, 9H), 4.46 (s, 2H), 4.72 (s, 2H), 5.83 (s, 2H),
6.71 (d, J = 9.0 Hz, 2H), 7.12–7.32 (m, 10H), 7.38 (s, 1H), 7.76 (d,
J = 8.9 Hz, 2H), 7.84–7.92 (m, 2H), 8.26 (d, J = 8.8 Hz, 1H).
The general acidic ester hydrolysis conditions were followed
utilizing ester 35d (0.12 g, 54%). 1H NMR (300 MHz, CDCl3) d 8.10
(d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.9 Hz, 2H), 7.54 (s, 1H), 7.26–7.43
(m, 10H), 7.05 (d, J = 8.1 Hz, 1H), 6.88–6.92 (m, 3H), 5.78–6.02
(m, 2H), 4.75–4.77 (m, 2H), 4.57–4.59 (m, 2H), 2.42 (s, 3H), 13C

4398
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
NMR (DMSO-d6) 169.60, 161.00, 158.56, 150.12, 146.47, 139.69,
138.44, 133.44, 130.46, 128.32, 128.19, 128.04, 127.78, 127.04,
126.93, 124.17, 114.92, 112.86, 112.71, 67.04, 59.16, 44.26,
21.71; HRMS: C33H28N2O5 requires (M+1)+ at m/z 533.2071; found,
533.2071.
HRMS: C32H25FN2O5 requires (M+1)+ at m/z 537.1820; found,
537.1819.
5.10.73. 2-Amino-5-chloro-N-(diphenylmethyl)benzamide
(33e)
The general amide coupling procedure was followed utilizing 2-
amino-5-chlorobenzoic acid (2.9 g, 60%). 1H NMR (400 MHz, CDCl3)
d 5.55 (br s, 2H), 6.35 (d, J = 7.33 Hz, 1H), 6.50 (d, J = 6.82 Hz, 1H),
6.62 (d, J = 8.84 Hz, 1H), 7.16 (dd, J = 8.72, 2.40 Hz, 1H), 7.27–7.40
(m, 11H).
5.10.67. 2-Amino-N-(diphenylmethyl)-5-fluorobenzamide
(33d)
The general amide coupling procedure was followed utilizing 2-
amino-5-fluorobenzoic acid (0.78 g, 38%). 1H NMR (300 MHz,
CDCl3) d 5.80 (br s, 1H), 6.45 (m, 2H), 7.25–7.66 (m, 14H).
5.10.74. 6-Chloro-3-(diphenylmethyl)quinazoline-2,4(1H,3H)-
dione (34e)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 33e (1.2 g, 65%). 1H NMR (300 MHz,
CDCl3) d 6.66 (d, J = 8.52 Hz, 1H), 7.24–7.61 (m, 12H), 8.10 (d,
J = 2.47 Hz, 1H), 10.91 (s, 1H).
5.10.68. 3-(Diphenylmethyl)-6-fluoroquinazoline-2,4(1H,3H)-
dione (34d)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 33d (1.1 g, 52%). 1H NMR (300 MHz,
CDCl3) d 6.69 (dd, J = 8.93, 4.26 Hz, 1H), 7.24–7.51 (m, 11H), 7.55
(s, 1H), 7.80 (dd, J = 8.38, 2.88 Hz, 1H), 10.91 (s, 1H).
5.10.75. Methyl 4-({(2Z)-4-[6-chloro-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (35g)
5.10.69. Methyl 4-({(2Z)-4-[3-(diphenylmethyl)-6-fluoro-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (35e)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34e (270 mg, 62%). 1H NMR (300 MHz, CDCl3) d
3.93 (s, 3H), 4.80 (d, J = 5.77 Hz, 2H), 4.90 (d, J = 6.04 Hz, 2H),
5.64–5.75 (m, 1H), 5.91–6.03 (m, 1H), 6.91–6.99 (m, 2H), 7.16 (d,
J = 8.79 Hz, 1H), 7.27–7.47 (m, 11H), 7.53 (s, 1H), 7.59
(dd, J = 9.07, 2.47 Hz, 1H), 7.99–8.05 (m, 2H), 8.21 (d, J = 2.75 Hz,
1H).
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34d (0.28 g, 87%). 1H NMR (300 MHz, CDCl3) d
3.93 (s, 3H), 4.80 (d, J = 5.77 Hz, 2H), 4.92 (d, J = 6.04 Hz, 2H),
5.64–5.77 (m, 1H), 5.91–6.04 (m, 1H), 6.96 (d, J = 8.79 Hz, 2H),
7.19 (dd, J = 9.20, 3.98 Hz, 1H), 7.26–7.48 (m, 11H), 7.54 (s, 1H),
7.92 (dd, J = 8.24, 3.02 Hz, 1H), 8.03 (d, J = 8.79 Hz, 2H).
5.10.70. 4-({(2Z)-4-[3-(Diphenylmethyl)-6-fluoro-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36e)
5.10.76. 4-({(2Z)-4-[6-chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36g)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 35e (90 mg, 31%). 1H NMR (300 MHz, CDCl3) d 4.80 (d,
J = 5.77 Hz, 2H), 4.92 (d, J = 6.04 Hz, 2H), 5.64–5.78 (m, 1H), 5.91–
6.05 (m, 1H), 6.96 (d, J = 8.79 Hz, 2H), 7.19 (dd, J = 9.20, 3.98 Hz,
1H), 7.26–7.50 (m, 11H), 7.54 (s, 1H), 7.92 (dd, J = 8.24, 3.02 Hz,
1H), 8.03 (d, J = 8.79 Hz, 2H); 13C NMR (DMSO-d6) 169.57, 158.79,
158.57, 156.39, 149.89, 138.15, 136.41, 133.49, 130.52, 128.95,
128.40, 128.03, 127.68, 127.61, 127.12, 123.19, 122.95, 117.28,
117.21, 116.59, 116.52, 113.53, 113.29, 112.98, 63.72, 59.63,
41.76; HRMS: C32H25FN2O5 requires (M+1)+ at m/z 537.1820;
found, 537.1819.
The general basic ester hydrolysis conditions were followed uti-
lizing ester 35g ((200 mg, 41%). 1H NMR (300 MHz, CDCl3) d 4.82
(d, J = 5.77 Hz, 2H), 4.91 (d, J = 6.04 Hz, 2H), 5.65–5.77 (m, 1H),
5.91–6.04 (m, 1H), 6.98 (d, J = 8.79 Hz, 2H), 7.17 (d, J = 8.79 Hz,
1H), 7.26–7.48 (m, 10H), 7.54 (s, 1H), 7.60 (dd, J = 8.79, 2.47 Hz,
1H), 8.09 (d, J = 8.79 Hz, 2H), 8.21 (d, J = 2.47 Hz, 1H); 13C NMR
(DMSO-d6) 169.46, 160.04, 158.46, 149.80, 138.51, 138.02,
135.01. 133.47, 130.43, 128.90, 128.34, 127.96, 127.45, 127.12,
127.05, 116.97, 116.69, 112.86, 63.63, 59.58, 41.62; HRMS:
C32H25ClN2O5 requires (M+1)+ at m/z 553.1525; found, 553.1525.
5.10.77. Methyl 4-({(2E)-4-[6-chloro-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (35h)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34e (280 mg, 90%). 1H NMR (300 MHz, CDCl3) d
3.91 (s, 3H), 4.58 (d, J = 4.40 Hz, 2H), 4.78 (d, J = 4.12 Hz, 2H),
5.78–6.03 (m, 2H), 6.85–6.92 (m, 2H), 7.10 (d, J = 8.79 Hz, 1H),
7.27–7.47 (m, 10H), 7.54 (s, 1H), 7.57 (dd, J = 8.93, 2.61 Hz, 1H),
7.95–8.02 (m, 2H), 8.20 (d, J = 2.47 Hz, 1H).
5.10.71. Methyl 4-({(2E)-4-[3-(diphenylmethyl)-6-fluoro-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (35f)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 34d (267 mg, 81%). 1H NMR (300 MHz, CDCl3)
d 3.92 (s, 3H), 4.59 (d, J = 4.40 Hz, 2H), 4.80 (d, J = 3.85 Hz, 2H),
5.80–6.03 (m, 2H), 6.86–6.92 (m, 2H), 7.14 (dd, J = 9.07, 3.85 Hz,
1H), 7.27–7.48 (m, 11H), 7.54 (s, 1H), 7.91 (dd, J = 8.24, 3.02 Hz,
1H), 7.97–8.02 (m, 2H).
5.10.78. 4-({(2E)-4-[6-Chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36h)
5.10.72. 4-({(2E)-4-[3-(Diphenylmethyl)-6-fluoro-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(36f)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 35h (119 mg, 44%). 1H NMR (300 MHz, CDCl3) d 4.60 (d,
J = 4.40 Hz, 2H), 4.79 (d, J = 3.85 Hz, 2H), 5.78–6.05 (m, 2H), 6.93 (d,
J = 8.79 Hz, 2H), 7.11 (d, J = 8.79 Hz, 1H), 7.26–7.50 (m, 10H), 7.52–
7.64 (m, 2H), 8.07 (d, J = 8.79 Hz, 2H), 8.21 (d, J = 2.47 Hz, 1H); 13C
NMR (DMSO-d6) 169.57, 160.09. 158.53, 149.69, 138.54, 138.05,
134.99, 133.21, 130.41, 128.28, 127.96, 127.77, 127.09, 127.05,
126.96, 126.45, 117.33, 116.58, 112.78, 66.96, 59.54, 44.60;
HRMS: C32H25ClN2O5 requires (M+1)+ at m/z 553.1525; found,
553.1527.
The general basic ester hydrolysis conditions were followed uti-
lizing ester 35f (98 mg. 39%). 1H NMR (300 MHz, CDCl3) d 4.61 (d,
J = 4.12 Hz, 2H), 4.80 (d, J = 3.85 Hz, 2H), 5.93 (m, 2H), 6.93 (d,
J = 9.07 Hz, 2H), 7.15 (dd, J = 9.34, 3.85 Hz, 1H), 7.27–7.49 (m,
11H), 7.55 (s, 1H), 7.92 (dd, J = 8.24, 3.02 Hz, 1H), 8.07 (d,
J = 9.07 Hz, 2H); 13C NMR (DMSO-d6) 169.62, 160.35, 158.78,
158.58, 156.38, 149.80, 138.19, 136.45, 133.42, 130.48, 128.36,
128.05, 127.92, 127.12, 126.71, 123.18, 122.95, 117.67, 117.59,
116.48, 116.41, 113.41, 113.17, 112.88, 67.07, 59.61, 44.77;

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4399
5.10.79. 3-(Diphenylmethyl)quinazoline-2,4(1H,3H)-dione
(38a)
The general isatoic anhydride aminolysis conditions were fol-
5.10.86. Ethyl [2-(4-{[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenyl)-1,3-oxazol-4-
yl]acetate (39d)
lowed utilizing 2-amino-N-(diphenylmethyl)benzamide 37a
(1.18 g, 68%). 1H NMR (400 MHz, DMSO-d6) d ppm 7.17–7.24 (m,
2H), 7.25–7.38 (m, 12H), 7.90 (dd, J = 8.1, 1.5 Hz, 1H), 11.51 (s, 1H).
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and ethyl [2-(4-bromomethylphenyl) oxa-
zol-4-yl] acetate (98%). 1H NMR (300 MHz, CDCl3) d 1.23 (t,
J = 7.2 Hz, 3H), 3.68 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 5.42 (s, 2H),
7.25–7.50 (m, 15H), 7.65–7.73 (m, 1H), 7.90 (d, J = 8.1 Hz, 2H),
8.07 (d, J = 8.1 Hz, 1H).
5.10.80. tert-Butyl (4-{[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenyl)acetate (39a)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a (83 mg, 51%). 1H NMR (300 MHz, CDCl3) d
ppm 1.50 (s, 9H), 3.69 (s, 2H), 5.41 (s, 2H), 6.81 (d, J = 7.7 Hz,
1H), 7.08 (d, J = 8.5 Hz, 1H), 7.13–7.42 (m, 10H), 7.45–7.52 (m,
4H), 7.52–7.60 (m, 1H), 7.63 (s, 1H), 8.28 (dd, J = 7.8, 1.2 Hz, 1H).
5.10.87. [2-(4-{[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenyl)-1,3-oxazol-4-
yl]acetic acid (40d)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39d (83%, chromatography and trituration with hex-
ane/CHCl3). 1H NMR (300 MHz, CDCl3) d 3.59 (s, 2H), 5.42 (s, 2H),
7.26–7.45 (m, 15H), 7.71 (m, 1H), 7.90 (d, J = 8.5 Hz, 2H), 8.04 (br
s, 1H), 8.07 (d, J = 8.0 Hz, 1H); 13C NMR (DMSO-d6) 161.13,
158.82, 150.43, 139.65, 138.22, 138.16, 135.88, 135.53, 128.28,
127.99, 127.04, 126.95, 126.37, 125.90, 123.10, 115.11, 114.86,
59.34, 46.12, 36.33; HRMS: C33H25N3O5 requires (M+1)+ at m/z
544.1867; found, 544.1866.
5.10.81. (4-{[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenyl)acetic acid (40a)
The general acidic ester hydrolysis conditions were followed
utilizing ester 39a (34 mg, 50%). 1H NMR (300 MHz, CDCl3) d
ppm 3.81 (s, 2H), 5.40 (s, 2H), 6.84 (d, J = 7.4 Hz, 1H), 7.00 (d,
J = 8.5 Hz, 1H), 7.13–7.41 (m, 10H), 7.47 (d, J = 6.9 Hz, 5H), 7.62
(s, 1H), 8.25 (dd, J = 8.0, 1.4 Hz, 1H); HRMS: C30H24N2O4 requires
(M+1)+ at m/z 477.1814; found, 477.1808.
5.10.88. Methyl 4-({5-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]pentyl}oxy)benzoate (39e)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and methyl 4-(5-bromo-1-pentoxy) benzo-
ate (74%). 1H NMR (300 MHz, CDCl3) d 1.48–1.60 (m, 3H), 1.73–
1.81 (m, 3H), 3.81 (s, 3H), 3.95 (t, J = 6.0 Hz 2H), 4.14 (t, J = 5 Hz,
2H), 6.87 (d, J = 9.0 Hz, 2H), 7.17–7.37 (m, 12H), 7.42 (d,
J = 8.7 Hz, 1H), 7.63–7.70 (m, 1H), 7.98 (d, J = 9.0 Hz, 2H), 8.35
(dd, J = 7.8, 1.2 Hz, 1H).
5.10.82. Methyl (4-{[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenoxy)acetate (39b)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and methyl (4-bromomethylphenoxy) ace-
tate (89%). 1H NMR (300 MHz, DMSO-d6) d 3.68 (s, 3H), 4.76 (s,
2H), 5.28 (s, 2H), 6.87 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H),
7.24–7.36 (m, 11H), 7.38 (s, 1H), 7.44 (s, 1H), 7.67–7.72 (m, 1H),
8.05 (dd, J = 7.8, 1.5 Hz, 1H).
5.10.83. (4-{[3-(Diphenylmethyl)-2,4-dioxo-3,4-
5.10.89. 4-({5-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenoxy)acetic acid (40b)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39b (98%). 1H NMR (300 MHz, DMSO-d6) d 4.63 (s, 2H),
5.27 (s, 2H), 6.84 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.23–
7.47 (m, 12H), 7.67–7.72 (m, 1H), 8.04 (dd, J = 7.8, 1.4 Hz, 1H);
13C NMR (DMSO-d6) 170.42, 161.15, 158.31, 150.55, 139.67,
138.34, 135.49, 128.33, 128.07, 127.43, 127.10, 126.84, 123.01,
115.14, 115.09, 114.66, 67.85, 59.35, 45.78, 42.31; HRMS:
C30H24N2O5 requires (M+1)+ at m/z 493.1758; found, 493.1757.
dihydroquinazolin-1(2H)-yl]pentyl}oxy)benzoic acid (40e)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39e (25%, chromatography and trituration with hex-
ane/EtOAc). 1H NMR (300 MHz, CDCl3) d 1.50–1.63 (m, 2H), 1.72–
1.90 (m, 4H), 3.99 (t, J = 6.3 Hz, 2H), 4.14 (t, J = 6.5 Hz, 2H), 6.90
(d, J = 9.0 Hz, 2H), 7.15–7.38 (m, 7H), 7.39–7.45 (m, 4H), 7.55 (s,
1H), 7.66 (t, J = 6.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H), 8.23 (d,
J = 8.9 Hz, 2H); 13C NMR (DMSO-d6) 169.68, 161.13, 159.29,
149.94, 139.61, 138.36, 135.66, 132.54, 130.54, 128.36, 128.30,
128.01, 127.02, 122.82, 114.99, 114.67, 112.69, 67.19, 59.09,
42.96, 28.38, 26.56, 22.67; HRMS: C33H30N2O5 requires (M+1)+ at
m/z 535.2227; found, 535.2228.
5.10.84. Methyl 4-(4-{[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenoxy)butanoate (39c)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and methyl 4-(4-bromomethylphenoxy)
butyrate (87%). 1H NMR (300 MHz, DMSO-d6) d 1.91–1.98 (m,
2H), 2.44 (t, J = 7.4 Hz, 2H), 3.59 (s, 3H), 3.93 (t, J = 6.3 Hz, 2H),
5.27 (s, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.24–
7.40 (m, 12H), 7.44 (s, 1H), 7.66–7.72 (m, 1H), 8.05 (dd, J = 7.8,
1.6 Hz, 1H).
5.10.90. Methyl 4-{3-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]propoxy}benzoate (39h)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and methyl 4-(3-bromo-1-propoxy) benzo-
ate (85%). 1H NMR (300 MHz, CDCl3) d 2.08–2.13 (m, 2H), 3.81 (s,
3H), 4.12 (d, J = 6.0 Hz, 2H), 4.28 (d, J = 6.7 Hz, 2H), 6.93 (d,
J = 8.7 Hz, 2H), 7.23–7.35 (m, 11H), 7.37 (s, 1H), 7.56 (d,
J = 8.7 Hz, 1H), 7.73–7.79 (m, 1H), 7.87 (d, J = 9.0 Hz, 2H), 8.05
(dd, J = 7.8, 1.2 Hz, 1H).
5.10.85. 4-(4-{[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]methyl}phenoxy)butanoic acid
(40c)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39c (99%). 1H NMR (300 MHz, DMSO-d6) d 1.85–1.95
(m, 2H,), 2.35 (t, J = 7.4 Hz, 2H), 3.93 (t, J = 6.3 Hz, 2H), 5.27 (s,
2H), 6.86 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.24–7.40 (m,
12H), 7.44 (s, 1H), 7.66–7.74 (m, 1H), 8.05 (dd, J = 7.8, 1.4 Hz,
1H); 13C NMR (DMSO-d6) 175.89, 161.07, 157.95, 150.47, 139.59,
138.25, 135.41, 128.25, 127.99, 127.75, 127.47, 127.03, 122.95,
115.03, 114.49, 67.69, 59.29, 45.68, 33.73, 25.88; HRMS:
C32H28N2O5 requires (M+1)+ at m/z 521.2071; found, 502.2071.
5.10.91. 4-{3-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]propoxy}benzoic acid (40h)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39h (97%). 1H NMR (300 MHz, DMSO-d6) d 2.07–2.15
(m, 2H), 4.11 (t, J = 5.5 Hz, 2H), 4.28 (t, J = 5.5 Hz, 2H), 6.91 (d,
J = 9.0 Hz, 2H), 7.25–7.36 (m, 11H), 7.38 (s, 1H), 7.56 (d,
J = 8.3 Hz, 1H), 7.73–7.81 (m, 1H), 7.86 (d, J = 9.0 Hz, 2H), 8.04 (d,
J = 7.8 Hz, 1H); 13C NMR (DMSO-d6) 169.34, 161.10, 158.94,
149.98, 139.67, 138.31, 135.49, 130.44, 128.26, 127.92, 126.93,

4400
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
122.74, 115.05, 114.44, 112.64, 64.91, 59.05, 40.61, 26.67;
HRMS: C31H26N2O5 requires (M+1)+ at m/z 507.1914; found,
507.1914.
5.10.98. Methyl 4-({(2Z)-4-[6-bromo-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (39k)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38c and methyl cis-4-(4-chlorobut-2-enyloxy)
benzoate (75%). 1H NMR (400 MHz, DMSO-d6) d 3.90 (s, 3H), 4.77
(d, J = 6.3 Hz, 2H), 4.87 (d, J = 6.3 Hz, 2H), 5.60–5.71 (m, 1H),
5.89–6.00 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 1H),
7.24–7.43 (m, 10H), 7.50 (s, 1H), 7.70 (d, 8.8 Hz, 1H), 7.99 (d,
J = 9.0 Hz, 2H), 8.33 (s, 1H).
5.10.92. Methyl 4-({(2E)-4-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoate (39i)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a (270 mg, 83%). 1H NMR (300 MHz, CDCl3) d
4.58 (d, J = 4.67 Hz, 2H), 4.81 (d, J = 3.85 Hz, 2H), 5.93 (m, 2H),
6.89 (d, J = 9.07 Hz, 2H), 7.16 (d, J = 8.24 Hz, 1H), 7.23–7.40 (m,
7H), 7.41–7.49 (m, 4H), 7.57 (s, 1H), 7.60–7.69 (m, 1H), 7.99 (d,
J = 8.79 Hz, 2H), 8.25 (dd, J = 7.97, 1.37 Hz, 1H).
5.10.99. 4-({(2Z)-4-[6-Bromo-3-(diphenylmethyl)-2,4-dioxo-3,
4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(40k)
5.10.93. 4-({(2E)-4-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(40i)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39k (35%, chromatography and trituration with hex-
ane/EtOAc). 1H NMR (400 MHz, DMSO-d6) d 4.77 (d, J = 5.6 Hz,
2H), 4.87 (d, J = 5.3 Hz, 2H), 5.57–5.67 (m, 1H), 5.80–5.92 (m,
1H), 6.85 (d, J = 8.8 Hz, 2H), 7.24–7.38 (m, 12H), 7.79 (d,
J = 8.8 Hz, 2H), 7.92 (dd, J = 8.8, 2.3 Hz, 1H), 8.09 (d, J = 2.3 Hz,
1H); 13C NMR (DMSO-d6) 169.35, 160.04, 158.84, 149.88, 138.95,
138.10. 137.83, 130.58, 130.11, 128.91, 128.41, 128.03, 127.55,
127.13, 117.26, 117.13, 114.78, 113.08, 63.73, 61.62, 59.66, 41.66,
28.65; HRMS: C32H25BrN2O5 requires (M+1)+ at m/z 597.1019;
found, 597.1021.
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39i (248 mg, 96%). 1H NMR (300 MHz, CDCl3) d 4.60 (d,
J = 4.40 Hz, 2H), 4.81 (d, J = 3.85 Hz, 2H), 5.82–6.07 (m, 2H), 6.93 (d,
J = 9.07 Hz, 2H), 7.17 (d, J = 8.52 Hz, 1H), 7.23–7.42 (m, 7H), 7.43–
7.51 (m, 4H), 7.59 (s, 1H), 7.61–7.70 (m, 1H), 8.07 (d, J = 8.79 Hz,
2H), 8.26 (d, J = 7.97 Hz, 1H); 13C NMR (DMSO-d6) 169.63, 161.02,
158.52, 149.93, 139.57, 138.27, 135.43, 133.21, 130.40, 128.25,
128.14, 127.96, 127.74, 126.98, 126.80, 122.90, 114.99, 114.92,
112.80, 66.98, 59.23, 44.32; HRMS: C32H26N2O5 requires (M+1)+
at m/z 519.1914; found, 519.1913.
5.10.100. Methyl 4-({(2E)-4-[6-bromo-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (39l)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38c and methyl trans-4-(4-bromobut-2-enyloxy)
benzoate (89%). 1H NMR (300 MHz, CDCl3) d 3.89 (s, 3H), 4.52–4.60
(m, 2H), 4.70–4.80 (m, 2H), 5.78–5.98 (m, 2H), 6.88 (d, J = 8.7 Hz,
2H), 7.03 (d, J = 8.5 Hz, 1H), 7.25–7.45 (m, 10H), 7.50 (s, 1H), 7.68
(d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.7 Hz, 2H), 8.32 (d, J = 2.7 HZ, 1H).
5.10.94. Methyl (4-{2-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]ethoxy}phenyl)acetate (39j)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and methyl [4-(2-bromoethoxy)phenyl] ace-
tate (96%). 1H NMR (300 MHz, DMSO-d6) d 3.57 (s, 2H), 3.58 (s, 3H),
4.25 (t, J = 5.7 Hz, 2H), 4.52 (t, J = 5.5 Hz, 2H), 6.73 (d, J = 8.5 Hz,
2H), 7.11 (d, J = 8.5 Hz, 2H), 7.25–7.36 (m, 11H), 7.39 (s, 1H),
7.66 (d, J = 8.0 Hz, 1H), 7.76–7.82 (m, 1H), 8.03 (dd, J = 7.6, 1.8 Hz,
1H).
5.10.101. 4-{[(E)-4-(3-Benzhydryl-6-bromo-2,4-dioxo-3,4-
dihydro-1(2H)-quinazolinyl)-2-butenyl]oxy}benzoic acid (40l)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39l (84%, trituration with pentane/EtOAc). 1H NMR
(400 MHz, DMSO-d6) d 4.51 (d, J = 4.29 Hz, 2H), 4.76 (s, 2H),
5.83–5.95 (m, 2H), 6.77 (d, J = 8.84 Hz, 2H), 7.25–7.36 (m, 11H),
7.40 (d, J = 8.84 Hz, 1H), 7.74–7.80 (m, 2H), 7.91 (dd, J = 8.97,
2.40 Hz, 1H), 8.09 (d, J = 2.27 Hz, 1H); 13C NMR (DMSO-d6)
169.40, 160.10, 158.88, 149.78, 139.00, 138.14, 137.81, 130.56,
130.04, 128.37, 128.05, 127.80, 127.13, 126.56, 117.63, 117.03,
114.77, 113.01, 67.09, 59.64, 44.65, 28.69; HRMS: C32H25BrN2O5
requires (M+1)+ at m/z 597.1019; found, 597.1021.
5.10.95. (4-{2-[3-(Diphenylmethyl)-2,4-dioxo-3,4-dihydr-
oquinazolin-1(2H)-yl]ethoxy}phenyl)acetic acid (40j)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39j (88%). 1H NMR (300 MHz, DMSO-d6) d 3.46 (s, 2H),
4.19–4.25 (m, 2H), 4.48–4.55 (m, 2H), 6.73 (d, J = 8.5 Hz, 2H), 7.11
(d, J = 8.5 Hz, 2H), 7.25–7.37 (m, 11H), 7.40 (s, 1H), 7.66 (d,
J = 7.8 Hz, 1H), 7.75–7.83 (m, 1H), 8.03 (dd, J = 7.8, 1.5 Hz, 1H);
13C NMR (DMSO-d6) 174.40, 160.99, 155.63, 150.19, 139.94,
138.25, 135.38, 132.55, 129.87, 128.28, 128.11, 127.93, 126.98,
122.87, 115.03, 114.89, 113.35, 64.52, 59.13, 45.10, 42.64;
HRMS: C31H26N2O5 requires (M+1)+ at m/z 507.1913; found,
507.1914.
5.10.102. Methyl 3-({(2E)-4-[7-chloro-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (39m)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 (223 mg, 72%). 1H NMR (400 MHz, CDCl3) d
ppm 3.88 (s, 3H), 4.57 (dd, J = 4.5, 1.0 Hz, 2H), 4.73 (d, J = 3.8 Hz,
2H), 5.80–6.01 (m, 2H), 7.04–7.08 (m, 1H), 7.12 (d, J = 1.8 Hz,
1H), 7.19 (dd, J = 8.5, 1.6 Hz, 1H), 7.27–7.36 (m, 7H), 7.38–7.43
(m, 4H), 7.50 (s, 1H), 7.52 (dd, J = 2.8, 1.5 Hz, 1H), 7.61–7.64 (m,
1H), 8.13 (d, J = 8.3 Hz, 1H).
5.10.96. 2-Amino-5-bromo-N-(diphenylmethyl)benzamide
(37c)
The general isatoic anhydride aminolysis conditions were fol-
lowed
utilizing
6-bromo-2H-3,1-benzoxazine-2,4(1H)-dione
(1.14 g, 32%, yellow solid). 1H NMR (400 MHz, CDCl3) d ppm 5.58
(s, 2H), 6.34 (d, J = 7.3 Hz, 1H), 6.51 (d, J = 7.1 Hz, 1H), 6.57 (d,
J = 8.6 Hz, 1H), 7.26–7.33 (m, 7H), 7.34–7.40 (m, 4H), 7.47 (d,
J = 2.3 Hz, 1H).
5.10.97. 6-Bromo-3-(diphenylmethyl)quinazoline-2,4(1H,3H)-
dione (38c)
The general quinazolinedione cyclization procedure was fol-
lowed utilizing aminoamide 37c (92%). 1H NMR (300 MHz, CDCl3)
d 6.62 (d, J = 8.7 Hz, 1H), 7.25–7.50 (m, 10H), 7.60 (d, J = 8.7 Hz,
1H), 8.23 (J = 2.1 Hz, 1H).
5.10.103. 3-({(2E)-4-[7-Chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(40m)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 39m (90 mg, 91%). 1H NMR (400 MHz, DMSO-d6) d ppm
4.60 (d, J = 4.5 Hz, 2H), 4.78 (d, J = 3.3 Hz, 2H), 5.84–5.98 (m, 2H),

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4401
7.12–7.18 (m, 1H), 7.24–7.43 (m, 14H), 7.49–7.54 (m, 2H), 8.03 (d,
5.10.110. 1-[(2Z)-4-Chlorobut-2-en-1-yl]-3-(diphenylmethyl)
quinazoline-2,4(1H,3H)-dione (42c)
J = 8.3 Hz, 1H); 13C NMR (DMSO-d6) 167.03, 160.50, 158.00, 149.93,
140.77, 140.29, 138.19, 132.17, 130.14, 129.63, 128.36, 128.28,
128.04, 127.61, 127.44, 127.11, 127.07, 126.98, 126.87, 123.15,
121.66, 119.36, 114.93, 114.74, 114.04, 67.27, 59.48, 44.46; HRMS:
C32H25ClN2O5 requires (M+1)+ at m/z 553.1525; found, 553.1524.
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a (80 mg, 30%). 1H NMR (300 MHz, CDCl3) d
4.26 (d, J = 7.97 Hz, 2H), 4.89 (d, J = 6.04 Hz, 2H), 5.61–5.73 (m,
1H), 5.84–5.99 (m, 1H), 7.18–7.41 (m, 7H), 7.41–7.50 (m, 4H),
7.57 (s, 1H), 7.64–7.74 (m, 1H), 8.26 (dd, J = 7.97, 1.37 Hz, 1H).
5.10.104. 1-[(2E)-4-Bromobut-2-en-1-yl]-7-chloro-3-(diphenyl-
methyl)quinazoline-2,4(1H,3H)-dione (42a)
5.10.111. Methyl 4-({(2Z)-4-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoate (43c)
The general phenol alkylation conditions were followed utiliz-
ing 42c and methyl 4-hydroxybenzoate (80 mg, 78%). 1H NMR
(300 MHz, CDCl3) d 3.93 (s, 3H), 4.81 (d, J = 5.77 Hz, 2H), 4.92 (d,
J = 6.04 Hz, 2H), 5.64–5.80 (m, 1H), 5.90–6.03 (m, 1H), 6.96 (d,
J = 9.06 Hz, 2H), 7.18–7.39 (m, 8H), 7.41–7.49 (m, 4H), 7.58 (s,
1H), 7.62–7.71 (m, 1H), 8.02 (d, J = 9.07 Hz, 2H), 8.25 (dd, J = 7.97,
1.37 Hz, 1H).
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 and trans-1,4-dibromo-2-butene (84%). 1H
NMR (300 MHz, CDCl3) d 3.91 (d, J = 6.3 Hz, 2H), 4.68–4.73 (m,
2H), 5.75–5.94 (m, 2H), 7.12 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5,
2.0 Hz, 1H), 7.24–7.43 (m, 10H), 7.50 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H).
5.10.105. Methyl 4-({(2E)-4-[7-chloro-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-
yl}oxy)benzoate (43a)
The general phenol alkylation conditions were followed utiliz-
ing 42a and methyl 4-hydroxybenzoate (1.23 g, 78%). 1H NMR
(400 MHz, CDCl3) d 3.88 (s, 3H), 4.57 (dd, J = 4.55, 1.26 Hz, 2H),
4.73 (d, J = 3.79 Hz, 2H), 5.79–5.99 (m, 2H), 6.87 (d, J = 8.84 Hz,
2H), 7.12 (d, J = 1.77 Hz, 1H), 7.20 (dd, J = 8.34, 1.77 Hz, 1H),
7.27–7.36 (m, 6H), 7.37–7.43 (m, 4H), 7.50 (s, 1H), 7.96 (d,
J = 8.84 Hz, 2H), 8.14 (d, J = 8.34 Hz, 1H).
5.10.112. 4-({(2Z)-4-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(44c)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43c (20 mg, 19%). 1H NMR (300 MHz, CDCl3) d 4.78–
4.87 (d, J = 5.77 Hz, 2H), 4.93 (d, J = 6.04 Hz, 2H), 5.68–5.81 (m,
1H), 5.90–6.03 (m, 1H), 6.95–7.03 (d, J = 9.07 Hz, 2H), 7.42–7.51
(m, 4H), 7.59 (s, 1H), 7.63–7.71 (m, 1H), 8.09 (d, J = 9.07 Hz, 2H),
8.26 (dd, J = 7.97, 1.37 Hz, 1H); HRMS: C32H26N2O5 requires
(M+1)+ at m/z 519.1914; found, 519.1913.
5.10.106. 4-({(2E)-4-[7-Chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(44a)
5.10.113. 7-Chloro-1-(4-bromobutyl)-3-(diphenylmethyl)
quinazoline-2,4(1H,3H)-dione (42d)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43a (1.15 g, 91%, chromatography and trituration with
hexane/EtOAc). 1H NMR (300 MHz, CDCl3) d 4.58–4.60 (m, 2H),
4.70–4.73 (m, 2H), 5.80–6.00 (m, 2H), 6.90 (d, J = 9.1 Hz, 2H),
7.10–7.50 (m, 13H), 8.03 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.4 Hz,
1H); HRMS: calcd for C32H25ClN2O5 + Na, 575.13497; found,
575.1338; Anal. Calcd for C32H25ClN2O5: C, 69.50; H, 4.56; N,
5.07. Found: C, 69.71; H, 4.50; N, 4.96.
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 and 1,4-dibromobutane (82%, 4 equiv, 4 h at
room temperature, then 40 min at 50–70 °C). 1H NMR (300 MHz,
CDCl3) d 1.80–1.98 (m, 4H), 3.43 (t, J = 6.3 Hz, 2H), 4.04–4.14 (m,
2H), 6.90–7.42 (m, 12H), 7.50 (s, 1H), 8.15 (d, J = 9.0 Hz, 1H).
5.10.114. Methyl 4-{4-[7-chloro-3-(diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]butoxy}benzoate (43d)
The general phenol alkylation conditions were followed utiliz-
ing 42d and methyl 4-hydroxybenzoate (56%). 1H NMR
(400 MHz, CDCl3) d 1.80–1.97 (m, 4H), 3.88 (s, 3H), 4.02–4.06 (m,
2H), 4.10–4.17 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 7.18 (s, 2H), 7.24–
7.42 (m, 10H), 7.50 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 8.14 (d,
J = 8.7 Hz, 1H).
5.10.107. 7-Chloro-1-[(2Z)-4-chlorobut-2-en-1-yl]-3-
(diphenylmethyl)quinazoline-2,4(1H,3H)-dione (42b)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 30 and cis-1,4-dichloro-2-butene (70%). 1H
NMR (300 MHz, CDCl3) d 4.21 (d, J = 8.0 Hz, 2H), 4.81 (dd, J = 11.0,
1.2 Hz, 2H), 5.58–5.69 (m, 1H), 5.88–6.00 (m, 1H), 7.17–7.46 (m,
12H), 7.50 (s, 1H), 8.14 (d, J = 8.7 Hz, 1H).
5.10.115. 4-{4-[7-Chloro-3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]butoxy}benzoic acid (44d)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43d (98%). 1H NMR (400 MHz, DMSO-d6) d 1.75 (s, 4H),
3.96 (s, 2H), 4.14 (s, 2H), 6.71–6.78 (m, 2H), 7.24–7.37 (m, 12H),
7.66 (d, J = 1.77 Hz, 1H), 7.72–7.78 (m, 2H), 8.03 (d, J = 8.34 Hz,
1H); 13C NMR (DMSO-d6) 169.67, 160.43, 158.96, 149.85, 140.75,
140.40, 138.13, 133.07, 130.42, 130.18, 128.26, 127.95, 127.02,
122.95, 114.29, 113.92, 112.60, 66.79, 59.23, 43.02, 25.64, 23.37;
HRMS: C32H27ClN2O5 requires (M+1)+ at m/z 555.1681; found,
555.1687.
5.10.108. Methyl 4-({(2Z)-4-[7-chloro-3-(diphenylmethyl)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (43b)
The general phenol alkylation conditions were followed utiliz-
ing 42b and methyl 4-hydroxybenzoate (78%). 1H NMR
(300 MHz, CDCl3) d 3.89 (s, 3H), 4.77 (d, J = 5.4 Hz, 2H), 4.85 (d,
J = 6.0 Hz, 2H), 5.62–5.73 (m, 1H), 5.90–6.05 (m, 1H), 6.94 (d,
J = 9.0 Hz, 2H), 7.18–7.23 (m, 2H), 7.24–7.45 (m, 11H), 7.50 (s,
1H), 7.98 (d, J = 7.5 Hz, 2H), 8.13 (d, J = 9.0 Hz, 1H).
5.10.109. 4-({(2Z)-4-[7-Chloro-3-(Diphenylmethyl)-2,4-dioxo-
3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)benzoic acid
(44b)
5.10.116. 1-(6-Bromohexyl)-3-(diphenylmethyl)quinazoline-2,
4(1H,3H)-dione (42e)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43b (93%). 1H NMR (400 MHz, DMSO-d6) d 4.77 (d,
J = 5.31 Hz, 2H), 4.90 (d, J = 6.06 Hz, 2H), 5.57–5.69 (m, 1H), 5.81–
5.94 (m, 1H), 6.80–6.86 (m, 2H), 7.23–7.39 (m, 12H), 7.50 (d,
J = 1.77 Hz, 1H), 7.77–7.82 (m, 2H), 8.03 (d, J = 8.34 Hz, 1H). HRMS:
C32H25ClN2O5 requires (M+1)+ at m/z 553.1525; found, 553.1530.
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and 1,6-dibromohexane (57%). 1H NMR
(300 MHz, CDCl3) d 1.35–1.50 (m, 4H), 1.66–1.78 (m, 2H), 1.79–
1.90 (m, 2H), 3.38 (t, J = 6.6 Hz, 2H), 4.09 (t, J = 7.5 Hz, 2H), 7.12–
7.37 (m, 8H), 7.38–7.45 (m, 4H), 7.55 (s, 2H), 7.65 (t, J = 6.3 Hz,
1H), 8.22 (d, J = 9.0 Hz, 1H).

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S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
5.10.117. Methyl 4-({6-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]hexyl}oxy)benzoate (43e)
The general phenol alkylation conditions were followed utiliz-
ing 42e and methyl 4-hydroxybenzoate (100% crude yield, used
in the next step without further purification). 1H NMR (300 MHz,
CDCl3) d 1.35–1.63 (m, 4H), 1.73–1.85 (m, 4H), 3.88 (s, 3H), 3.98
(t, J = 6.6 Hz, 2H), 4.14 (t, J = 6.5 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H),
7.15–7.35 (m, 7H), 7.39–7.45 (m, 4H), 7.65 (t, J = 6.0 Hz, 1H), 7.96
(d, J = 9.0 Hz, 2H), 8.22 (d, J = 8.8 Hz, 1H).
2H), 4.58 (br s, 2H), 2.50 (s, 3H); HRMS: C33H28N2O5S requires
(M+1)+ at m/z 565.1792; found, 565.1793.
5.10.124. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-
(methylsulfonyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-
yl]but-2-en-1-yl}oxy)benzoate (45b)
A solution of sulfide 45a (122 mg, 0.2 mmol), TPAP (12 mg,
10 mol %), NMO (119 mg, 3 equiv), and 4 Å molecular sieves
(200 mg) in acetonitrile (4 mL) was stirred at room temperature
for 16 h. The solution was evaporated and flash chromatographed
(30–40% EtOAc–hexanes) to afford sulfone 45b (63 mg, 28%) as a
white foam. 1H NMR (300 MHz, CDCl3) d 1.58 (s, 9H), 3.05 (s,
3H), 4.56 (s, 2H), 4.84 (s, 2H), 5.94 (s, 2H), 6.82 (d, J = 9.0 Hz, 2H),
7.25–7.42 (m, 10H), 7.51 (s, 1H), 7.70–7.75 (m, 2H), 7.89 (d,
J = 8.9 Hz, 2H), 8.41 (d, J = 8.2 Hz, 1H).
5.10.118. 4-({6-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]hexyl}oxy)benzoic acid (44e)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43e (75%, hexane/EtOAc trituration). 1H NMR
(300 MHz, CDCl3) d 1.35–1.60 (m, 4H), 1.70–1.83 (m, 4H), 4.02 (t,
J = 6.6 Hz, 2H), 4.11 (t, J = 6.5 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H),
7.15–7.35 (m, 7H), 7.39–7.45 (m, 4H), 7.68 (t, J = 6.0 Hz, 1H), 8.03
(d, J = 9.0 Hz, 2H), 8.21 (d, J = 8.8 Hz, 1H); mp 142–143 °C; HRMS:
C34H32N2O5 requires (M+1)+ at m/z 549.2384; found, 549.2390.
5.10.125. 4-({(2E)-4-[3-(Diphenylmethyl)-7-(methylsulfonyl)-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoic acid (46b)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45b (50 mg, 84%). 1H NMR (300 MHz, CDCl3) d
8.41 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.8 Hz, 2H), 7.70–7.76 (m, 2H),
7.51 (s, 1H), 7.16–7.42 (m, 10H), 6.87 (d, J = 8.9 Hz, 2H), 5.94 (s,
2H), 4.85 (s, 2H), 4.58 (s, 2H), 3.06 (s, 3H); HRMS: C33H28N2O7S re-
quires (M+1)+ at m/z 597.1690; found, 597.1690.
5.10.119. 1-(7-Bromoheptyl)-3-(diphenylmethyl)quinazoline-
2,4(1H,3H)-dione (42f)
The general N-1 quinazolinedione alkylation conditions were
followed utilizing 38a and 1,7-dibromoheptane (79%). 1H NMR
(300 MHz, CDCl3) d 1.28–1.45 (m, 6H), 1.63–1.77 (m, 4H), 1.83 (t,
J = 9.0 Hz, 2H), 3.39 (t, J = 9.0 Hz, 2H), 4.08 (t, J = 9.0 Hz, 2H),
7.10–7.38 (m, 7H), 7.41 (m, 4H), 7.55 (s, 1H), 7.66 (t, 6.0 Hz, 1H),
8.22 (d, J = 6.0 Hz, 2H).
5.10.126. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-2,4-dioxo-
7-(phenylthio)-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}
oxy)benzoate (45c)
5.10.120. Methyl 4-({7-[3-(diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]heptyl}oxy)benzoate (43f)
To a solution of thiophenol (139 lL, 4 equiv) in DMF (1 mL) was
added neat 60% NaH (54 mg, 4 equiv). After stirring room temper-
ature for 30 min, fluoride 35a (200 mg, 0.34 mmol) was added as a
DMF (2 mL) solution. After 4.5 h, the solution was quenched with
water, diluted with ethyl acetate, washed with water and brine,
dried, filtered, evaporated, and flash chromatographed (20–30%
EtOAc–hexanes) to afford sulfide 45c (200 mg, 86%). 1H NMR
(300 MHz, CDCl3) d 1.58 (s, 9H), 4.45 (d, J = 5.0 Hz, 2H), 4.53 (d,
J = 5.0 Hz, 2H), 5.44–5.55 (m, 2H), 5.68–5.79 (m, 2H), 6.70 (s, 1H),
6.86 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 7.23–7.58 (m,
16H), 7.94 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.5 Hz, 1H).
The general phenol alkylation conditions were followed utiliz-
ing 42f and methyl 4-hydroxybenzoate (100% crude yield, used
in the next step without further purification). 1H NMR (300 MHz,
CDCl3) d 1.32–1.51 (m, 6H), 1.63–1.83 (m, 4H), 3.89 (s, 3H), 3.99
(t, J = 6.6 Hz, 2H), 4.10 (t, J = 6.6 Hz, 2H), 6.88 (d, J = 6.8 Hz, 2H),
7.15–7.38 (m, 8H), 7.39–7.45 (m, 4H), 7.55 (s, 1H), 7.65 (t,
J = 6.0 Hz, 1H), 7.97 (d, J = 9.0 Hz, 2H), 8.21 (d, J = 8.9 Hz, 1H).
5.10.121. 4-({7-[3-(Diphenylmethyl)-2,4-dioxo-3,4-
dihydroquinazolin-1(2H)-yl]heptyl}oxy)benzoic acid (44f)
The general basic ester hydrolysis conditions were followed uti-
lizing ester 43f (89%, hexane/EtOAc trituration); 1H NMR
(300 MHz, CDCl3) d 1.30–1.50 (m, 6H), 1.63–1.83 (m, 4H), 4.00 (t,
J = 6.6 Hz, 2H), 4.09 (t, J = 6.6 Hz, 2H), 6.92 (d, J = 6.8 Hz, 2H),
7.15–7.38 (m, 7H), 7.39–7.45 (m, 4H), 7.55 (s, 1H), 7.65 (t,
J = 6.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H), 8.22 (d, J = 8.9 Hz, 1H); mp
131–132 °C; HRMS: C35H34N2O5 requires (M+1)+ at m/z 563.2541;
found, 563.2537.
5.10.127. 4-({(2E)-4-[3-(Diphenylmethyl)-2,4-dioxo-7-
(phenylthio)-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}
oxy)benzoic acid (46c)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45c (54 mg, 78%). 1H NMR (300 MHz, CDCl3) d 8.05
(m, 3H), 7.16–7.55 (m, 11H), 6.99 (d, J = 8.5 Hz, 1H), 6.91 (d,
J = 8.8 Hz, 2H), 6.71 (s, 1H), 5.50–5.82 (m, 2H), 4.45–4.60 (m,
4H); HRMS: C38H30N2O5S requires (M+1)+ at m/z 627.1948; found,
627.1952.
5.10.122. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-
(methylthio)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-
en-1-yl}oxy)benzoate (45a)
The general nucleophilic substitution procedure was followed
utilizing sodium thiomethoxide (122 mg, 58%). 1H NMR (300 MHz,
CDCl3) d 1.58 (s, 9H), 2.48 (s, 3H), 4.55 (br s, 2H), 4.76 (br s, 2H),
5.80–5.98 (m, 2H), 6.78–6.90 (m, 3H), 7.05 (d, J = 8.5 Hz, 1H), 7.23–
7.56 (m, 10H), 7.83–7.98 (m, 2H), 8.02–8.16 (m, 1H).
5.10.128. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-methoxy-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (45d)
A solution of fluoride 35a (200 mg, 0.34 mmol) and potassium
hydroxide (112 mg, 5 equiv) in methanol (2 mL) and THF (2 mL)
was heated at 50 °C for 16 h. The cooled solution was neutral-
ized with 10% aq HCl, diluted with ethyl acetate, washed with
water and brine, dried, filtered, evaporated, and flash chromato-
graphed (30% EtOAc–hexanes) to afford methyl ether 45d
(106 mg, 53%). 1H NMR (300 MHz, CDCl3) d 1.58 (s, 9H), 3.84
(s, 3H), 4.55 (br s, 2H), 4.73 (br s, 2H), 5.79–5.97 (m, 2H), 6.55
(s, 1H), 6.76 (d, J = 9.1 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.24–
7.48 (m, 10H), 7.53 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 8.14 (d,
J = 8.8 Hz, 1H).
5.10.123. 4-({(2E)-4-[3-(Diphenylmethyl)-7-(methylthio)-2,4-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoic acid (46a)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45a (70 mg, 88%). 1H NMR (300 MHz, CDCl3) d
8.01–8.15 (m, 3H), 7.52 (s, 1H), 7.23–7.44 (m, 10H), 7.05 (d,
J = 8.3 Hz, 1H), 6.80–6.95 (m, 3H), 5.80–6.00 (m, 2H), 4.77 (br s,

S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
4403
5.10.129. 4-({(2E)-4-[3-(Diphenylmethyl)-7-methoxy-2,4-
5.10.134. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-2,4-dioxo-
dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoic acid (46d)
7-thiomorpholin-4-yl-3,4-dihydroquinazolin-1(2H)-yl]but-2-
en-1-yl}oxy)benzoate (45g)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45d (80 mg, 88%). 1H NMR (300 MHz, DMSO-d6) d
7.81 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.00–7.25 (m,
11H), 6.82 (d, J = 8.7 Hz, 2H), 6.75 (dd, J = 8.9, 2.0 Hz, 1H), 6.67 (s,
1H), 5.75–5.80 (m, 2H), 4.64 (br s, 2H), 4.48 (br s, 2H), 3.69 (s,
3H); 13C NMR (DMSO-d6) 169.53, 164.90, 160.62, 158.81, 150.26,
141.51, 138.49, 132.50, 130.53, 130.29, 128.30, 128.02, 127.13,
127.01, 112.94, 110.48, 108.22, 99.16, 67.03, 59.00, 55.87, 44.41;
HRMS: C33H28N2O6 requires (M+1)+ at m/z 549.2020; found,
549.2020.
The general nucleophilic substitution procedure was followed
utilizing thiomorpholine (90 mg, 39%).1H NMR (300 MHz, CDCl3)
d 1.58 (s, 9H), 2.62–2.67 (m, 4H), 3.71–3.78 (m, 4H), 4.52–4.55
(m, 2H), 4.70–4.75 (m, 2H), 5.80–5.95 (m, 2H), 6.31 (s, 1H), 6.65–
6.70 (m, 1H), 6.84 (d, J = 8.9 Hz, 2H), 7.23–7.48 (m, 10H), 7.53 (s,
1H), 7.90 (d, J = 8.7 Hz, 2H), 8.02 (d, J = 9.0 Hz, 1H).
5.10.135. 4-({(2E)-4-[3-(Diphenylmethyl)-2,4-dioxo-7-
thiomorpholin-4-yl-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-
1-yl}oxy)benzoic acid (46g)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45g (24 mg, 29%). 1H NMR (300 MHz, CDCl3) d 8.03
(dd, J = 8.9, 2.7 Hz, 3H), 7.52 (s, 1H), 7.23–7.42 (m, 8H), 6.88 (d,
J = 8.9 Hz, 2H), 6.68 (dd, J = 9.0, 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz,
1H), 5.87–5.93 (m, 2H), 4.75–4.78 (m, 2H), 4.56–4.57 (m, 2H),
3.74–3.78 (m, 4H), 2.64–2.67 (m, 4H); HRMS: C36H33N3O5S re-
quires (M+1)+ at m/z 620.2214; found, 660.2213.
5.10.130. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-2,4-dioxo-
7-phenoxy-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoate (45e)
To a solution of phenol (159 mg, 5 equiv) in DMF (1 mL) was
added neat 60% NaH (68 mg, 5 equiv). After stirring room temper-
ature for 30 min, fluoride 35a (200 mg, 0.34 mmol) was added as a
DMF (2 mL) solution and the reaction was heated at 60 °C for 16 h.
The solution was quenched with water, diluted with ethyl acetate,
washed with water and brine, dried, filtered, evaporated, and flash
chromatographed (10% EtOAc–hexanes) to afford ether 45e
(150 mg, 66%). 1H NMR (300 MHz, CDCl3) d 1.58 (s, 9H), 4.49 (d,
J = 4.6 Hz, 2H), 4.63 (d, J = 5.0 Hz, 2H), 5.63–5.90 (m, 2H), 6.64 (d,
J = 2.0 Hz, 1H), 6.79 (dd, J = 8.9, 2.1 Hz, 1H), 6.85 (d, J = 9.0 Hz,
2H), 7.07 (d, J = 8.9 Hz, 2H), 7.23–7.46 (m, 10H), 7.52 (s, 1H), 7.92
(d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H).
5.10.136. Methyl 1-[1-{(2E)-4-[4-(tert-butoxycarbonyl)
phenoxy]but-2-en-1-yl}-3-(diphenylmethyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-7-yl]piperidine-4-carboxylate (45h)
The general nucleophilic substitution procedure was followed
utilizing methyl piperidine-4-carboxylate (165 mg, 68%). 1H NMR
(300 MHz, CDCl3) d 1.58 (s 9H), 1.70–1.88 (m, 2H), 1.93–2.02 (m,
2H), 2.48–2.60 (m, 1H), 2.89–3.00 (m, 2H), 3.69 (s, 3H), 3.72–3.82
(m, 2H), 4.54–4.56 (m, 2H), 4.75 (s, 2H), 5.82–5.98 (m, 2H), 6.37
(s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 2H), 7.23–7.37
(m, 6H), 7.38 (m, 4H), 7.53 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 8.01
(d, J = 9.0 Hz, 1H).
5.10.131. 4-({(2E)-4-[3-(Diphenylmethyl)-2,4-dioxo-7-
phenoxy-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoic acid (46e)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45e (90 mg, 95%). 1H NMR (300 MHz, CDCl3) d 8.14
(d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.9 Hz, 2H), 7.52 (s, 1H), 7.20–7.50
(m, 13H), 7.07 (dd, J = 8.7, 1.2 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H),
6.79 (dd, J = 8.8, 2.0 Hz, 1H), 6.65 (d, J = 2.1 Hz, 1H), 5.62–5.90 (m,
2H), 4.64 (d, J = 4.8 Hz, 2H), 4.53 (d, J = 4.7 Hz, 2H);
HRMS: C38H30N2O6 requires (M+1)+ at m/z 611.2177; found,
611.2175.
5.10.137. 4-({(2E)-4-[3-(Diphenylmethyl)-7-[4-(methoxycar-
bonyl)piperidin-1-yl]-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-
yl]but-2-en-1-yl}oxy)benzoic acid (46h)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45h (140 mg, 92%). 1H NMR (300 MHz, CDCl3) d
8.08 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.52 (s, 1H), 7.16–
7.41 (m, 10H), 6.87–6.89 (m, 3H), 6.67 (s, 1H), 5.89–5.92 (m, 2H),
4.76 (br s, 2H), 4.56–4.57 (m, 2H), 3.73–3.80 (m, 2H), 3.71 (s,
3H), 3.05–3.13 (m, 2H), 2.55–2.65 (m, 1H), 1.82–2.15 (m, 4H);
13C NMR (DMSO-d6) 174.40, 169.89, 160.47, 158.73, 154.83,
141.31, 138.75, 132.93, 130.51, 129.65, 128.28, 128.11, 127.98,
127.63, 126.90, 112.79, 110.04, 104.34, 97.42, 67.06, 58.63, 51.48,
46.34, 44.07, 30.39, 26.80; HRMS: C3H37N3O7 requires (M+1)+ at
m/z 660.2704; found, 660.2701.
5.10.132. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-7-
morpholin-4-yl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-
2-en-1-yl}oxy)benzoate (45f)
The general nucleophilic substitution procedure was followed
utilizing morpholine (160 mg, 71%). 1H NMR (300 MHz, CDCl3) d
1.58 (s, 9H), 3.22–3.26 (m, 4H), 3.80–3.84 (m, 4H), 4.56 (s, 2H),
4.75 (br s, 2H), 5.80–6.00 (m, 2H), 6.39 (d, J = 1.9 Hz, 1H), 6.74
(dd, J = 9.0, 2.0 Hz, 1H), 6.83 (d, J = 9.1 Hz, 2H), 7.24–7.47
(m, 11H), 7.53 (s, 1H), 7.89 (d, J = 8.9 Hz, 2H), 8.05 (d, J = 8.9 Hz,
1H).
5.10.138. tert-Butyl 4-({(2E)-4-[3-(diphenylmethyl)-2,4-dioxo-
7-(1H-1,2,4-triazol-1-yl)-3,4-dihydroquinazolin-1(2H)-yl]but-2-
en-1-yl}oxy)benzoate (45i)
The general nucleophilic substitution procedure was followed
utilizing 1,2,4-triazole, sodium derivative (160 mg, 73%). 1H NMR
(300 MHz, CDCl3) d 1.58 (s, 9H), 4.57 (s, 2H), 4.84 (s, 2H), 5.96
(br s, 2H), 6.82 (d, J = 9.0 Hz, 2H), 7.25–7.55 (m, 12H), 7.65 (s,
1H), 7.85 (d, J = 9.1 Hz, 2H), 8.14 (s, 1H), 8.33 (d, J = 8.7 Hz, 1H),
8.68 (s, 1H).
5.10.133. 4-({(2E)-4-[3-(Diphenylmethyl)-7-morpholin-4-yl-
2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}oxy)
benzoic acid (46f)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45f (115 mg, 79%). 1H NMR (300 MHz, CDCl3) d
8.05 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 7.26–
7.42 (m, 8H), 6.87 (d, J = 8.8 Hz, 2H), 6.74 (dd, J = 9.0, 1.6 Hz, 1H),
6.36 (s, 1H), 5.80–6.00 (m, 2H), 4.76 (br s, 2H), 4.57–4.58 (m,
2H), 4.08–4.14 (m, 4H), 3.81–3.84 (m, 4H); 13C NMR (DMSO-d6)
160.54, 158.77, 155.70, 150.43, 141.14, 138.70, 130.54, 129.51,
128.28, 128.08, 128.00, 127.53, 126.93, 112.82, 109.81, 105.24,
97.53, 67.07, 65.70, 58.70, 46.82, 44.13; HRMS: C36H33N3O6 re-
quires (M+1)+ at m/z 604.2442; found, 604.2441.
5.10.139. 4-({(2E)-4-[3-(Diphenylmethyl)-2,4-dioxo-7-(1H-1,2,
4-triazol-1-yl)-3,4-dihydroquinazolin-1(2H)-yl]but-2-en-1-yl}
oxy)benzoic acid (46i)
The general acidic ester hydrolysis conditions were followed
utilizing ester 45i (112 mg, 77%). 1H NMR (400 MHz, DMSO-d6) d
4.51 (s, 2H), 4.86 (s, 2H), 5.93–5.99 (m, 2H), 6.75 (d, J = 8.84 Hz,
2H), 7.25–7.41 (m, 11H), 7.75 (d, J = 8.84 Hz, 2H), 7.80–7.87 (m,
2H), 8.20 (d, J = 8.59 Hz, 1H), 8.35 (s, 1H), 9.53 (s, 1H); 13C NMR

4404
S. J. Kirincich et al. / Bioorg. Med. Chem. 17 (2009) 4383–4405
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at 8 mg/mL. Thirteen microliters of this stock solution was added
to 1.0 mL of pH 7.4 pION buffer. The solution is mixed and allowed
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Acknowledgments
The authors thank Nelson Huang, Ying Ge, Walter Massefski, Va-
silios Marathias, Ning Pan, and Li Di for analytical support, and Weili
Duan, Elizabeth Murphy, and Wen Zhang for assay support. We also
thank Howard Sard, Anu Mahadevan, Mario Gonzalez, and Shanghao
LiuofOrganix, Inc. forthepreparationofchemicalintermediates.We
thank Katherine Lee for reviewing this manuscript.
36. Lee, K. L.; Behnke, M. L.; Foley, M. A.; Chen, L.; Wang, W.; Vargas, R.; Nunez, J.;
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