Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2007.11.079

New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure-activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC₅₀ = 2.4-0.3 nM and 80- to 780-fold more selective than rofecoxib).

Full text of DOI:10.1016/j.bmc.2007.11.079

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 2183–2199
Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives
as highly potent and specific COX-2 inhibitors
*
´
´
Aurelio Orjales, Ramon Mosquera, Beatriz Lopez, Roberto Olivera,
´
Luis Labeaga and M. Teresa Nunez
˜
Department of Research, Faes Farma S.A., Ma´ximo Aguirre 14, 48940 Leioa, Spain
Received 23 July 2007; revised 22 November 2007; accepted 30 November 2007
Available online 5 December 2007
Abstract—New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their
ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using puri-
fied enzyme (PE) and human whole blood (HWB) assays. Extensive structure–activity relationship (SAR) work was carried out
within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC50 = 2.4–0.3 nM
and 80- to 780-fold more selective than rofecoxib).
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ies on COX-2 that have been focused on cancer11 and
neurodegenerative disorders.12
The discovery and characterization of the cyclooxygen-
ase-2 (COX-2) enzyme early in the 1990s1 led to the
hypothesis that selective inhibitors of this isoform would
exhibit similar clinical efficacy but reduced ulcerogenici-
ty than traditional nonsteroidal antiinflammatory drugs
(NSAIDs), which were dual nonselective cyclooxygen-
ase-1 (COX-1) and COX-2 inhibitors. Rofecoxib2 and
celecoxib3 were the first COX-2 selective inhibitors to
reach the market followed by valdecoxib4 and etoricox-
ib.5 The worldwide withdrawal of rofecoxib (Vioxx) be-
cause of evidence of increased cardiovascular risk6 has
raised concern about the safety of COX-2 selective
inhibitors.7 Research efforts8 to clarify if the observed
cardiovascular events are due to the mechanism of ac-
tion of the entire class of compounds or to the particular
structure of rofecoxib point out to the first reason as the
most probable cause of aforementioned undesired ad-
verse effects.9 Additionally, it has recently been sug-
gested that traditional NSAIDs are not devoid of
toxicity on the cardiovascular system either.10 Neverthe-
less, the potential therapeutic applications of selective
COX-2 inhibitors have been expanded beyond the areas
of analgesia and inflammation, as shown by recent stud-
Tricyclic molecules possessing as a common feature
1,2-diaryl substitution on a central heterocyclic or car-
bocyclic ring system represent a major class of selective
COX-2 inhibitors and extensive work has been carried
out in this area.13 On the other hand, pyrimidine ring
has scarcely been used as template for the synthesis of
new selective COX-2 inhibitors.13,14 Nevertheless, a
group of pyrimidine derivatives have been described re-
cently as a new class of potent and selective COX-2
inhibitors.15 As part of our research programm aimed
at the discovery of new selective COX-2 inhibitors, we
describe herein the synthesis and biological evaluation
of novel 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoyl-
phenyl)pyrimidines I (Fig. 1) as potential antiinflamma-
tory agents. The substitution pattern of these
compounds is substantially different from that of previ-
ously reported pyrimidine based COX-2 inhibitors15 and
R4
R5
N
X
N
3
R2
R
SO2 R1
Keywords: 2-(4-Methylsulfonylphenyl)pyrimidines; 2-(4-Sulfamoylphe-
nyl)pyrimidines; COX-2 inhibitors.
n
I
*
Corresponding author. Tel.: +34 944818300; fax: +34 944818309;
e-mail: aorjales@faes.es
Figure 1. Pyrimidine based COX-2 inhibitors.
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.11.079

2184
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
it has already been demonstrated that this is a crucial
feature for significant activity.16 In this paper, we report
the synthesis and characterization of 2-(4-methylsulfo-
POCl3 to give chloropyrimidines 3a–h. Oxidation of
derivatives 3a–g, using an aqueous solution of OXONE
(potassium peroxymonosulfate), afforded key intermedi-
ates 4a–g, while precursors 4h–l were obtained from 4d
by reaction with the adequate alkoxide or with sodium
ethanethiolate.
nylphenyl)pyrimidines as
a new series of potent
COX-2 inhibitors with unprecedentedly high degree of
selectivity for this enzyme.
Standard methods for aromatic nucleophilic substitu-
tion of 4-chloropyrimidines were employed to obtain
target pyrimidines 5–40, 43–55, 58–71 and 82–93 from
intermediates 3h and 4a–l (Scheme 2). Further synthetic
transformations, such as oxidation, hydrolysis or a sec-
ond nucleophilic displacement, of suitable final pyrimi-
dines provided structures 41-42, 56–57, 72–77 and 80–
81 (Scheme 2).
2. Results and discussion
2.1. Chemistry
Synthetic methods employed to prepare pyrimidines of
general formula I are outlined in Schemes 1–3. Target
compounds were obtained from adequately substituted
intermediates 3h and 4a–l which were synthesized as
illustrated in Scheme 1. Starting amidines 1a and 1b
were readily obtained from the corresponding commer-
cially available nitriles by known methods.17 Condensa-
tion of 1a and 1b with the appropriate acetoacetate or
malonate derivative in the presence of a base afforded
hydroxypyrimidines 2a–h, which were treated with
A more convenient alternative synthetic path was fol-
lowed to prepare 6-unsubstituted derivatives 78 and 79
(Scheme 3). Treatment of commercially available 2,4-
dichloropyrimidine with one equivalent of the adequate
amine and subsequent Suzuki-Miyaura cross-coupling
with 4-(methylthio)phenylboronic acid yielded 4-amino-
O O
NH
NH2
R4
N
N
R5
R4
OR
R5
(i)
HO
R6
R6
1a, R6 = SMe
2a, R6 = SMe, R4 = CF3, R5 = H
2b, R6 = SMe, R4 = iPr, R5 = H
2c, R6 = SMe, R4 = tBu, R5 = H
2d, R6 = SMe, R4 = OH, R5 = H
2e, R6 = SMe, R4 = CF3, R5 = Me
2f, R6 = SMe, R4 = CF3, R5 = Et
2g, R6 = SMe, R4 = OH, R5 = Me
2h, R6 = SO2NH2, R4 = CF3, R5 = H
1b, R6 = SO2NH2
(ii)
R4
N
N
R4
R5
R5
N
(iii)
Cl
Cl
N
R6
SO2Me
3a, R6 = SMe, R4 = CF3, R5 = H
3b, R6 = SMe, R4 = iPr, R5 = H
3c, R6 = SMe, R4 = tBu, R5 = H
3d, R6 = SMe, R4 = Cl, R5 = H
3e, R6 = SMe, R4 = CF3, R5 = Me
3f, R6 = SMe, R4 = CF3, R5 = Et
3g, R6 = SMe, R4 = Cl, R5 = Me
4a, R4 = CF3, R5 = H
4b, R4 = iPr, R5 = H
4c, R4 = tBu, R5 = H
4d, R4 = Cl, R5 = H
4e, R4 = CF3, R5 = Me
4f, R4 = CF3, R5 = Et
4g, R4 = Cl, R5 = Me
4h, R4 = OMe, R5 = H
4i, R4 = OEt, R5 = H
(i)
(iv)
(v)
(vi)
(vii)
3h, R6 = SO2NH2, R4 = CF3, R5 = H
4j, R4 = OCH2CH2OMe, R5 = H
4k, R4 = O-Cyclopentyl, R5 = H
4l, R4 = SEt, R5 = H
Scheme 1. General synthetic path for intermediates 4. Reagents: (i) NaOMe, MeOH; (ii) POCl3; (iii) OXONE, THF, H2O; (iv) EtOH, NaH, THF;
(v) MeOCH2CH2OH, NaH, THF; (vi) NaH, cyclopentanol, THF; (vii) NaSEt, THF.

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2185
R4
N
N
R4
N
N
R5
R3
(i)
3h or 4a-l
R2
R2
X
n
X
SO2R1
SO2Me
5-40
39, X = S, R4 = CF3
43-55
58-71
82-93
(ii)
(iii)
41, X = SO, R4 = CF3
42, X = SO2, R4 = CF3
55, X = NH, R4 = CF3, R2 = (4-OCH2OMe)Ph
56, X = NH, R4 = CF3, R2 = (4-OH)Ph
57, X = NH, R4 = CF3, R2 = (4-OSO2Me)Ph
70 and 71, X = NH, R4 = SEt
72 and 73, X = NH, R4 = SO2Et
(iv)
(v)
(iii)
(ii)
81, X = NH, R4 = SOEt
(vi)
(vii)
74 and 75, X = NH, R4 = OH
76, X = NH, R4 = NHiPr
69, X = NH, R4 = Cl
(vii)
(vii)
77, X = NH, R4 = NHiPr
80, X = NH, R4 = NEt2
Scheme 2. Synthesis of final products 5–77 and 80–93. Reagents: (i) R2(CHR3)nXH, base; (ii) PhI(OH)OTs, CH2Cl2; (iii) OXONE, THF, H2O; (iv)
i
HCl, EtOH; (v) MsCl, DMAP, py; (vi) NaOH aq; (vii) PrNH2 or Et2NH.
(i), (ii)
(iii)
N
N
N
Cl
N
Cl
R2
N
H
N
R2
N
H
N
SMe
SO2Me
94, R2 = Ph
78, R2 = Ph
95, R2 = 2 -thiophenyl
79, R2 = 2-thiophenyl
Scheme 3. Synthetic scheme for 78 and 79. Reagents: (i) R2CH2NH2, Et3N, CH2Cl2; (ii) 4-(Methylthio)phenylboronic acid, Pd(PPh3)4, Na2CO3,
DME, H2O; (iii) OXONE, THF, H2O.
pyrimidine intermediates 94 and 95. After oxidation of
said compounds, pyrimidines 78 and 79 were isolated
with high overall yield. Two-dimensional NMR experi-
ments (HSQC, HMBC and NOESY) were performed
to assess the chemical structure of 78 and 79.
both assays. It has been reported in the literature that
potency of drugs is often significantly reduced in the
HWB assay5b,21 when compared with other in vitro
tests, which is probably due to binding to plasma pro-
teins, to the presence of endogenous arachidonic acid
at the time of COX-2 induction and to possible low cel-
lular permeability profile of the drugs. In consequence
we expected IHWB/PE to be >1 as a general rule. In con-
trast, many of the studied compounds had better values
of HWB COX-2 IC50 than PE COX-2 IC50 and conse-
quently IHWB/PE were usually <1, which might be indic-
ative of good cellular permeability or to low affinity for
plasma proteins, interference of the compounds with the
expression of COX-213e as possible hypothesis. Tables
1–5 show biological data for compounds 5-93. Tables
2–5 do not show PE data, but PE COX-2 IC50 in rela-
tion to HWB COX-2 IC50 are given as IHWB/PE indexes.
2.2. Biology
All compounds herein described were tested for their
ability to inhibit COX-1 and COX-2 by using the
in vitro purified enzyme (PE)18 and human whole blood
(HWB)19 assays. In both assays, the compounds were
tested at 10 lM in triplicate determinations. COX-1
and COX-2 IC50 values were calculated for compounds
that showed a percentage of inhibition higher than 50%
and were obtained by non-linear regression from three
independent experiments with 8–10 different concentra-
tions in triplicate. In all cases, the standard error mean
(SEM) was less than 15%. For each assay Selectivity In-
dex (SI) was calculated as the ratio IC50s COX-1/COX-2.
2.3. Structure–activity relationships
The study was initially focused on 6-trifluoromethyl
substituted pyrimidines as this group is ubiquitously
present in structures of previously reported pyrimidine
based COX-2 inhibitors.15 Extensive structure–activity
relationship (SAR) studies for the diarylheterocycle
class have shown that para-SO2NH2 or SO2Me substitu-
tion at one of the aryl rings is required for optimum
IC50 and SI values obtained from the PE enzyme assay
were useful for SAR studies. HWB assay is widely con-
sidered as the benchmark model20 and values from this
test were also employed as a selection criterion. In all
cases, the ratio HWB COX-2 IC50/PE COX-2 IC50
(IHWB/PE) was used as an index to compare the data of

2186
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
Table 1. In vitro COX-2 inhibitory activities of compounds 5–34
CF
3
N
2
n
R
N
H
N
1
SO R
2
3
5
4
I (R = R = H, R = CF )
3
Compound
R1
R2(CH2)n
PE
HWB
IHWB/PE
a
a
IC50
SI
IC50
SI
5
6
NH2
Me
3980
140
>25
>71
>10,000
71.0
>5
1408
5.2
0.51
S
S
7
8
NH2
Me
22.3
22.4
3529
>4464
157.6
2.1
>634
10,702
5.50
0.09
9
10
NH2
Me
72.0
17.6
1388
>5692
51.9
46.5
>193
215
0.70
2.60
N
N
11
12
NH2
Me
3000
>10,000
>33
>1
>10,000
>10,000
>10
>1
>3
—
13
14
NH2
Me
>10,000
>10,000
>1
>1
>10,000
>10,000
>1
>1
—
—
15
16
NH2
Me
1890
2950
>52
>34
3330
298.5
>3
>335
1.80
0.10
N
O
17
18
NH2
Me
14.4
200.7
>6920
>498
2790
140
>3
>497
193
0.7
19
20
NH2
Me
15.2
5.92
6570
>10,000
140.4
293.4
>71
341
8.20
49.60
S
S
21
22
NH2
Me
10,000
10,000
>10
>1
>10,000
>10,000
>1
>1
—
—
23
24
NH2
Me
712
>10,000
>140
>3610
803.5
1480
>124
>68
1.10
0.053
S
N
25
26
Me
Me
459.7
177.8
>217
>562
83.6
28.8
>1195
>3467
0.18
0.16
N
27
28
Me
Me
>10,000
>10,000
>1
>1
>10,000
>10,000
>1
>1
—
—
H
N
N
29
30
Me
Me
>10,000
7760
>10
>13
728.6
789.8
137
0.07
0.10
>127

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2187
Table 1 (continued)
Compound
R1
R2(CH2)n
PE
HWB
IHWB/PE
a
a
IC50
SI
IC50
SI
31
32
Me
Me
>10,000
191.6
>1
>10,000
475.9
>1
—
>522
>396
80
2.48
33
Me
252.6
238.5
419
0.94
34
Me
—
43.1
>2317
>342
32.9
>304
104
0.76
0.72
Rofecoxib
—
292.0
211.0
a Data are indicated as IC50 (nM). SEM less than 15%.
COX-2 inhibitory potency and selectivity.22 These polar
groups are known to induce COX-2 selectivity by inser-
tion into the secondary pocket of COX-2 binding site
that is absent in COX-1.22 To compare the ability of
SO2NH2 and SO2Me to induce COX-2 selective inhibi-
tion in pyrimidines I (Fig. 1), a representative group of
2-(4-sulfamoylphenyl) and the corresponding 2-(4-meth-
ylsulfonylphenyl)pyrimidines was prepared (compounds
5–24, Table 1). Noticeable differences between PE and
HWB assays were observed for sulfonamides 7, 17 and
19, which behaved as potent and selective COX-2 inhib-
itors in the PE assay (PE COX-2 IC50 14.4–22.3 nM and
SI >4000), but showed a sharp drop in potency in the
HWB assay (HWB COX-2 IC50 140.4–2790 nM). In
fact, IHWB/PE indexes for sulfonamide derivatives were
>1 (Table 1). Compound 9 was an exception to this
observation. In contrast, it was found that the corre-
sponding sulfonylmethyl analogues 8, 18 and 20 were
even more potent in the HWB assay than in the PE as-
say (IHWB/PE indexes were <1 as for rofecoxib). As the
best potency and selectivity profile in the HWB assay
was observed for methylsulfonyl derivatives (compare
HWB COX-2 IC50 for 6, 8, 18 and 20 vs the correspond-
ing analogues 5, 7, 17 and 19), SO2Me substituent was
chosen as polar group to incorporate in new
pyrimidines.
synthesis of new COX-2 inhibitors. Moreover, given
that 2-thiophenyl 7 and 8 derivatives were more selective
than the corresponding 3-thiophenyl regioisomers 9 and
10, 8 was selected as lead structure for chemical optimi-
zation. Sulfonylmethyl derivatives 25–34 were synthe-
sized to further study the impact of R2 substituent on
activity of pyrimidines I. It was confirmed that the pres-
ence of alkyl or cycloalkyl radicals in this position leads
to low activity products (compounds 29–33). In con-
trast, compound 34, bearing a partially unsaturated car-
bocycle at that position, showed a HWB COX-2 IC50
45-fold lower than the corresponding saturated ana-
logue 24. Several other aromatic and heteroaromatic
rings were introduced at R2 (Table 1, compounds
25–28) and it was finally concluded that best HWB
COX-2 IC50 (2.1–71.0 nM) and SI (1400–10,202) values
were obtained when R2 was phenyl, thiophen-2-yl or
1H-pyrrol-2-yl (pyrimidines 6, 8 and 26, respectively).
Thiazolyl containing derivative 25 was also a promising
structure but synthetically it was less easily accessible.
To explore the effect of X, R3 and n in COX-2 inhibitory
potency and selectivity of pyrimidines I, sulfonylmethyl
derivatives 35–45 were prepared and tested (Table 2).
A substantial decrease in inhibitory activity was found
when X was a fully substituted nitrogen atom (com-
pounds 35 and 36), especially for N-ethyl substituted
derivative 36. On the other hand, sulfur containing
derivatives 40 and 43 have promising COX-2 IC50 values
while a complete loss of COX-2 inhibitory activity was
recorded for compounds 41 and 42, which are oxidized
analogues of 40. The discouraging preliminary studies
aimed at testing 40 and 43 as leaders for the develop-
ment of new coxibs23 along with the aforementioned del-
eterious effect of S-oxidation in activity led us to
discontinue studies on 4-thiopyrimidines.
On the other hand, the nature of the ring present at R2
was found to be crucial for activity. Compounds with
best HWB COX-2 IC50 values (<100 nM) bear a phenyl
(6) or thiophenyl (8–10) ring in this position. On the
contrary, when that cycle was pyridine (11–16) or cyclo-
hexyl (23–24) the resulting pyrimidines both sulfon-
amide and sulfonylmethyl derivatives were inactive. It
is noteworthy that, in one case, even the presence at po-
sition R2 of a different regioisomer caused a complete
loss of activity (compare 2-benzo[b]thiophene contain-
ing pyrimidines 19 and 20 with the corresponding 3-
benzo[b]thiophene isomers 21 and 22). Nevertheless,
the same effect was not observed for 2-thiophenyl deriv-
atives 7 and 8 which show similar potency as the corre-
sponding 3-thiophenyl regioisomers 9 and 10. The slight
differences in HWB COX-2 IC50 values observed for thi-
ophene containing compounds 7–10 evidenced the fact
that they might be promising lead structures for the
In the case of product 37 (R3 = Me) a noticeable de-
crease in potency and selectivity was observed when
compared to the unsubstituted aminopyrimidine 6. Ana-
logues of compound 6 devoid of a methylene bridge in
the 4-aminosubstituent (n = 0) such as pyrimidines 38
and 39 were completely inactive as COX-2 inhibitors.
In the same way, the presence of an ethylene tether in

2188
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
Table 2. In vitro COX-2 inhibitory activities of compounds 35–45 in HWB assay
CF3
R3
N
R2
X
N
n
SO2Me
I (R1 = Me, R4 = CF3, R5 = H)
R3
R2
SI
IHWB/PE
a
IC50 (nM)
Compound
X
n
6b
35
36
37
38
39
40
41
42
NH
NMe
NEt
NH
NH
NH
S
1
1
1
1
0
0
1
1
1
H
Ph
Ph
71.0
454.5
1408
22
0.51
0.50
—
H
H
Ph
Ph
>10,000
521.8
>1
74
Me
—
—
H
18.95
—
—
Ph
4-iPr-Ph
Ph
>10,000
>10,000
527.8
>1
>1
>189
>1
>1
27.7
—
SO
SO2
H
Ph
Ph
>10,000
>10,000
H
—
8b
43
44
NH
S
1
1
2
H
H
H
Thiophen-2-yl
Thiophen-2-yl
Thiophen-2-yl
2.1
4.1
10,702
>24,450
>83
0.09
0.58
NH
1210
<0.12
26b
45
NH
NH
1
2
H
H
1-Methyl-1H-pyrrol-2-yl
1-Methyl-1H-pyrrol-2-yl
28.8
3980
>3467
>25
0.16
<0.40
a SEM less than 15%.
b Included for comparison purposes.
Table 3. In vitro COX-2 inhibitory activities of compounds 46–61 in HWB assay
CF3
N
CF3
N
N
H
N
N
H
N
R
R
S
SO2Me
SO2Me
Ia (R4 = CF3, R5 = H)
Ib (R4= CF3, R5= H)
a
IC50 (nM)
Compound
I
R
SI
IHWB/PE
6b
46
47
48
49
50
51
52
53
54
55
56
57
58
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
Ia
H
71
48.4
1408
>2065
1296
>17
>52
>1
0.50
0.20
0.80
0.90
4.90
—
4-Me
4-F
77.2
5720
2-Me
3-Me
4-iPr
1930
>10,000
300.3
1920
3,5-DiF
4-CF3
4-OCF3
4-OMe
>333
>52
>1
3.50
2.90
—
>10,000
272.3
>10,000
635
>367
>1
<0.03
—
4-OCH2OMe
4-OH
>158
>1
473
2.10
—
4-OSO2Me
4-NH2
>10,000
211.3
1.40
8b
59
60
61
Ib
Ib
Ib
Ib
H
2.1
10,702
189
>852
0.10
9.90
0.50
0.34
3-Me
5-Me
5-Cl
527.8
11.7
5.4
>18,622
a SEM less than 15%.
b Included for comparison purposes.
this substituent (n = 2) led to low activity compounds 44
and 45. Thus, best potency and selectivity was accom-
plished when the group X(CH(R3))nR2 in pyrimidines
I was NHCH2Ar, where Ar was phenyl or 2-thiophenyl
(compounds 6 and 8, respectively).
Accordingly, pyrimidines Ia and Ib (Fig. 2) arose as
feasible templates for further optimization and in an
effort to understand the effect of substituent R for both
templates compounds 46–61 were synthesized (Table 3).
In the case of pyrimidines Ia, when R was 4-fluoro

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
Table 4. In vitro COX-2 inhibitory activities of compounds 62–84 in HWB assay
2189
4
4
R
N
R
N
N
N
N
H
N
H
S
SO Me
SO Me
2
2
5
5
Ia
Ib
(R = R = H)
(R = R = H)
R4
SI
IHWB/PE
a
IC50 (nM)
Compound
I
6b
8b
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
Ia
Ib
CF3
CF3
iPr
71.0
2.1
1408
10,702
>396
0.51
0.09
0.55
0.38
1.63
1.39
0.15
0.06
0.07
0.09
1.56
0.20
0.40
0.15
0.07
0.03
0.02
0.05
—
25.3
9.8
iPr
>1018
1065
>322
tBu
tBu
93.9
31.1
5.1
OMe
OMe
Cl
>19,646
>22,004
>9124
>81,300
414
0.4
10.9
1.2
Cl
SEt
24.1
1.2
SEt
>8403
>110
15
SO2Et
SO2Et
OH
OH
NHiPr
NHiPr
H
90.7
144.5
49.3
79.4
273.8
10.3
>10,000
9.2
>2030
>1259
>365
>9718
>1
>10,905
H
0.06
80
81
82
83
84
Ib
Ib
Ib
Ib
Ib
NEt2
SOEt
OEt
6.1
37.6
0.3
>1642
>266
0.05
0.03
0.02
0.02
0.21
>33,333
>41,841
>13,351
OCH2CH2OCH3
O-Cyclopentyl
2.4
7.5
a SEM less than 15%.
b Included for comparison purposes.
Table 5. In vitro COX-2 inhibitory activities of compounds 85–93 in HWB assay
R4
R4
R5
R5
N
N
N
H
N
N
H
N
R
R
S
SO2Me
SO2Me
Ia
Ib
R4
R5
SI
IHWB/PE
a
IC50 (nM)
Compound
I
R
6b
85
Ia
Ia
H
H
CF3
CF3
H
Me
71.0
18.0
1408
>556
0.51
0.27
8b
86
87
Ib
Ib
Ib
H
H
H
CF3
CF3
CF3
H
2.1
38.2
10,702
>78
>83
0.09
0.73
0.86
Me
Et
120.9
88
89
Ia
Ia
4-Me
4-Me
Cl
Cl
H
Me
44.4
36.7
>2252
>2726
0.19
0.43
47b
90
91
92
93
Ia
Ia
Ia
Ia
Ia
4-F
4-F
4-F
4-F
4-F
CF3
CF3
CF3
Cl
H
77.2
22.4
1296
>447
>972
2969
>145
0.82
0.43
0.67
0.35
0.41
Me
Et
102.8
33.7
68.8
H
Me
Cl
a SEM less than 15%.
b Included for comparison purposes.

2190
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
R4
R4
R5
R5
N
N
R
N
H
N
N
H
N
R
S
SO2 Me
SO 2 Me
Ia
Ib
Figure 2. New pyrimidine based templates for the design of COX-2 inhibitors.
(product 47) or 4-methyl (compound 46) HWB COX-2
IC50 values were not affected but, shifting of methyl
group from para- (as in derivative 46) to ortho- (com-
pound 48) or meta-position (compound 49) or presence
caused a progressive loss of activity. In general, when
different substituents were introduced at position R4,
activity of compounds Ib was not as severely affected
as activity of products Ia (Table 4). To confirm this
finding 6-unsubstituted (R4 = H) pyrimidines 78 and
79 were tested and, to our surprise, dramatically dif-
fering biological data were obtained for them. Thus,
compound 78 was inactive, whereas the corresponding
analogue 79 was extremely potent and selective. In
contrast to the large differences in activity found for
derivatives Ia modified at R (see Table 3), variations
at R4 for the same series only moderately affected po-
tency (Table 4, compounds Ia IC50 between 273.8 and
5.1 nM), except for said 6-unsubstituted pyrimidine 78.
Consequently, we concluded that nature and substitu-
tion of R strongly affect activity of pyrimidines I,
while variations at position R4 are useful to modulate
potency and selectivity of these compounds.
i
of a para-high volume substituent such as Pr, CF3,
OCF3, OCH2OMe, or OSO2Me (products 50, 52, 53,
55 and 57) resulted in a complete loss of activity. On
the other hand, for template Ib substitution at the thio-
phene ring (products 60 and 61) did not substantially af-
fect potency. In this case, in contrast with previously
described behaviour of Ia series, even when R was an
ortho-methyl group (compound 59) moderate COX-2
inhibitory activity was detected. In conclusion, substitu-
ent R gives rise to pronounced differences in activity for
compounds Ia but not for derivatives Ib, suggesting that
template Ib is probably more robust than Ia. It is also
remarkable that even though derivatives Ia were potent
COX-2 inhibitors with IC50 < 100 nM, outstanding re-
sults were obtained for compounds Ib such as 8 and
61 that were extremely potent (IC50 = 2.1 and 5.4 nM,
respectively) and specific (SI = 10,702 and >18,622,
respectively) COX-2 inhibitors.
Finally, to evaluate the effect of an additional substitu-
ent (R5) in position 5 of pyrimidines I, 5-methyl and
5-ethyl substituted analogues of a selection of the more
promising compounds obtained to this point were syn-
thesized (products 85–93, Table 5). 5-Methyl substituted
pyrimidines 85 and 86 kept HWB COX-2 IC50 values
similar to the corresponding unsubstituted analogues 6
and 8, but they were generally less selective. The pres-
ence of a more sterically demanding substituent at posi-
tion 5 of the central pyrimidine ring, as in 5-ethyl
substituted compounds 87 and 91, was detrimental to
potency and selectivity.
Afterwards, the effect of nature and volume of radical
R4 in inhibitory activity of proposed series Ia and Ib
was studied (Table 4). Up to this point our investiga-
tion had been focused on 6-trifluoromethylpyrimi-
dines, but we encountered that potency was not
substantially affected by the presence of a large variety
of radicals at position R4. Thus, 6-alkylpyrimidines
62–65 exhibited HWB COX-2 IC50 values similar to
the corresponding 6-trifluoromethyl analogues 6 and
8, although sterically demanding 6-tert-butylsubstitu-
ent (see compounds 64 and 65) caused a mild decrease
in potency. Regarding selectivity, SI for 6-alkylpyrim-
idines were lower than those for the corresponding 6-
trifluoromethylpyrimidines (compare compounds 62 vs
6 and 65 vs 8). Interestingly, 6-chloro and 6-methoxy-
pyrimidines 66–69 showed a remarkable improvement
in potency and selectivity, indeed products 66, 67 and
69 had unprecedentedly high selectivity indexes,
although high ratios of selectivity do not guarantee
the efficacy or safety of these compounds in vivo.
Other 6-alkoxy derivatives 82–84 were also extremely
potent and selective COX-2 inhibitors. Nevertheless,
when oxygen in position 6 of the pyrimidine was
unsubstituted (R4 = OH) the resulting products 74
and 75 showed a noticeable decrease in activity. Other
3. Conclusions
New series of pyrimidines (I) are reported as COX-2
inhibitors. In vitro COX-2 inhibition results showed
that inhibitory potency and selectivity of these com-
pounds is dependent upon the nature of substituents
at positions 2, 4 and 6 of the pyrimidine ring. In this
regard, pyrimidines I exhibited optimum HWB COX-
2 IC50 and SI values when R1 was Me, the group
X[CH(R3)]nR2 was NHCH2R2 where R2 was 4-fluoro-
phenyl, 4-methylphenyl, phenyl, 2-thiophenyl or 3-thio-
phenyl, R4 was CF3, Cl, alkoxy or iPr and R5
preferably was H. The adequate combination of sub-
stituents in these positions allowed access to COX-2
inhibitors with diverse grades of potency and selectiv-
heteroatoms were tested in this position and thus po-
tency of 6-thiopyrimidines 70 and 71 and 6-aminosub-
stituted pyrimidines 76, 77 and 80 was similar to that
of initially reported trifluoromethyl analogues 6 and 8,
although they were usually less selective. Oxidation of
6-ethylthio radical as in pyrimidines 72, 73 and 81
ity. Thus, compound 86 was
a
potent (IC50
(HWB) = 38.2 nM) but not very selective (SI > 78)
COX-2 inhibitor, whereas product 25 which is only
(IC50
2.5-fold
more
potent
than
rofecoxib
(HWB) = 83.6 nM) shows an outstanding selectivity in-
dex of >1195 (11-fold more selective than rofecoxib).

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2191
105
80
55
30
5
80
60
40
20
0
Rofecoxib
Compound 69
Rofecoxib
Compound 69
-20
-11 -10
-9
-8
-7
-6
-5
-4
-11.5
-9.0
-6.5
-4.0
log (mol/L)
log (mol/L)
Figure 3. (a) Concentration–response curve for rofecoxib (IC50 = 292.0 nM) and compound 69 (IC50 = 12.7 nM) in the COX-2 PE assay. (b)
Concentration-response curve for rofecoxib (IC50 = 211.0 nM) and compound 69 (IC50 = 1.2 nM) in the COX-2 HWB assay.
Compounds 8, 43, 61, 63, 66–69, 71, 77, 79, 80 and 82–
84 are extremely potent (IC50 (HWB) between 10.9 and
0.3 nM) and specific (10- to 780-fold more selective
than rofecoxib) COX-2 inhibitors. As a remarkable
example of COX-2 inhibitory potency, activity of se-
lected compound 69 compared to rofecoxib in both
PE (Fig. 3a) and HWB (Fig. 3b) assays (HWB COX-
2 IC50 = 1.2 nM) is illustrated. Compound 69 was also
the most selective pyrimidine derivative of the series
with a calculated HWB selectivity index of 81,300
(780-fold higher than rofecoxib).
and the corresponding amine (2–4 mmol) in CH2Cl2 or
CH3CN (7 mL) was stirred at a temperature of rt to
90 ꢁC for 3–72 h. The solvent was distilled off under vac-
uum and the resulting residue purified by
chromatography.
4.2.1. 4-(4-Benzylamino-6-trifluoromethylpyrimidin-2-yl)ben-
zenesulfonamide (5). Compound 5 was prepared from 3h
and benzylamine following GP1. After flash chromatog-
raphy the title compound was obtained (60% yield) as a
dark syrup. 1H NMR (CD3OD) d 4.60 (s, 2H,
NHCH2Ph), 6.73 (s, 1H, H-5), 7.08–7.29 (m, 5H, Ar-
H), 7.90 (d, J = 8.0 Hz, 2H, Ar-H), 8.41 (d, J = 8.0 Hz,
2H, Ar-H). 13C NMR (CDCl3 and CD3OD) d 45.5
(NHCH2Ph), 102.1 (C-5), 125.2 (q, J = 219 Hz, CF3),
127.8 (CH), 128.1 (CH), 128.7 (CH), 129.1 129.5 (CH),
140.2 (C), 141.5 (C), 146.4 (C), 154.8 (q,
J = 45 Hz, C-6), 164.4 (C). Anal (C18H15F3N4O2S) C,
H, N, S.
4. Experimental
4.1. Chemistry protocols
Except otherwise specified, solvents and reagents were
commercially obtained from Aldrich Co., USA and
Maybridge Co., UK, and were used without further
purification. All reported yields are of isolated products
and are not optimized. Melting points were measured in
4.2.2. Benzyl-[2-(4-methanesulfonylphenyl)-6-trifluorom-
ethylpyrimidin-4-yl]amine (6). Compound 6 was pre-
pared from 4a and benzylamine following GP1. After
flash chromatography the title compound was obtained
(75% yield) as a white solid; mp 196.0–198.2 ꢁC. Anal
(C19H16F3N3O2S) C, H, N, S.
open capillary tubes on a Buchi B-540 apparatus and are
¨
uncorrected. Elemental analyses are within 0.4% of the
theoretical values. 1H NMR and 13C NMR spectra were
obtained on a Brucker AC-200 spectrometer (operating
1
at 200 MHz for H and at 50 MHz for 13C). Chemical
shifts are reported as d values (ppm) downfield relative
to TMS (0.00 ppm) as an internal standard or to resid-
ual solvent peaks (DMSO-d6). Spectral data are consis-
tent with assigned structures. Column chromatography
was carried out in flash mode on silica gel (Merck Kie-
selgel 60, 230–400 mesh) or in Dry Column Vacuum
Chromatography (DCVC) mode on silica gel (Merck
Silica gel 60, 0.015–0.040 mm).
4.2.3. 4-[4-[(Thiophen-2-ylmethyl)amino]-6-trifluorometh-
ylpyrimidin-2-yl]benzenesulfonamide (7). Compound 7
was prepared from 3h and 2-thiophenemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was obtained (94% yield) as a white solid; mp
184.0–186.0 ꢁC. Anal (C16H13F3N4O2S2) C, H, N, S.
4.2.4. [2-(4-Methanesulfonylphenyl)-6-trifluoromethylpyr-
imidin-4-yl]thiophen-2-ylmethylamine (8). Compound 8
was prepared from 4a and 2-thiophenemethylamine
following GP1. After flash chromatography the title
compound was obtained (98% yield) as a white solid;
mp 190.3–192.5 ꢁC. Anal (C17H14F3N3O2S2) C, H,
N, S.
4.2. General procedure for the synthesis of 4-aminopyr-
imidines 5–37, 44–55, 58–71 and 82–93 (GP1)
A mixture of the adequate precursor 4a–l or 3h (1 mmol)
with Et3N (2–4 mmol) as base unless otherwise stated

2192
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
4.2.5. 4-[4-[(Thiophen-3-ylmethyl)amino]-6-trifluorometh-
ylpyrimidin-2-yl]benzenesulfonamide (9). Compound 9
was prepared from 3h and 3-thiophenemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was obtained (33% yield) as a white solid; mp
181.0–183.5 ꢁC. Anal (C16H13F3N4O2S2) C, H, N, S.
4.2.14. Furan-2-ylmethyl-[2-(4-methanesulfonylphenyl)-6-
trifluoromethylpyrimidin-4-yl]amine (18). Compound 18
was prepared from 4a and furfurylamine following
GP1. After flash chromatography the title compound
was isolated (98% yield) as an almost white solid; mp
192.9–195.0 ꢁC. Anal (C17H14F3N3O3S) C, H, N, S.
4.2.6. [2-(4-Methanesulfonylphenyl)-6-trifluoromethylpyr-
imidin-4-yl]thiophen-3-ylmethylamine (10). Compound
10 was prepared from 4a and 3-thiophenemethylamine
following GP1. After flash chromatography the title
compound was isolated (95% yield) as a solid; mp
203.0–205.5 ꢁC. Anal (C17H14F3N3O2S2) C, H, N, S.
4.2.15. 4-[4-[(Benzo[b]thiophen-2-ylmethyl)amino]-6-tri-
fluoromethylpyrimidin-2-yl]benzenesulfonamide (19).
Compound 19 was obtained from 3h and 2-benzo[b]thi-
ophenemethylamine following GP1. After flash chroma-
tography the title compound was isolated (37% yield) as
a white solid; mp 189.0–191.0 ꢁC. Anal (C20H15F3
N4O2S2) C, H, N, S.
4.2.7. 4-[4-[(Pyridin-2-ylmethyl)amino]-6-trifluoromethyl-
pyrimidin-2-yl]benzenesulfonamide (11). Compound 11
was prepared from 3h and 2-(methylamino)pyridine fol-
lowing GP1. After flash chromatography the title com-
pound was obtained (28% yield) as a yellow solid; mp
246.0–248.0 ꢁC. Anal (C17H14F3N5O2S) C, H, N, S.
4.2.16. Benzo[b]thiophen-2-ylmethyl-[2-(4-methanesulfo-
nylphenyl)-6-trifluoromethylpyrimidin-4-yl]amine (20).
Compound 20 was synthesized from 4a and 2-
benzo[b]thiophenemethylamine following GP1. After
flash chromatography the title compound was isolated
(96% yield) as a solid; mp 215.6–218.0 ꢁC. Anal
(C21H16F3N3O2S2) C, H, N, S.
4.2.8. [2-(4-Methanesulfonylphenyl)-6-trifluoromethylpyr-
imidin-4-yl]pyridin-2-ylmethylamine (12). Compound 12
was prepared from 4a and 2-(methylamino)pyridine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (98% yield) as a white solid; mp
208.7–211.5 ꢁC. Anal (C18H15F3N4O2S) C, H, N, S.
4.2.17. 4-[4-[(Benzo[b]thiophen-3-ylmethyl)amino]-6-tri-
fluoromethylpyrimidin-2-yl]benzenesulfonamide (21).
Compound 21 was obtained from 3h and 3-benzo[b]thi-
ophenemethylamine following GP1. After flash chroma-
tography the title compound was isolated (29% yield) as
a yellow solid; mp 224.0–226.0 ꢁC. Anal (C20H15
F3N4O2S2) C, H, N, S.
4.2.9. 4-4-[(Pyridin-3-ylmethyl)amino]-6-trifluoromethyl-
pyrimidin-2-yl]benzenesulfonamide (13). Compound 13
was prepared from 3h and 3-(methylamino)pyridine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (23% yield) as a yellow solid; mp
229.0–231.0 ꢁC. Anal (C17H14F3N5O2S) C, H, N, S.
4.2.18. Benzo[b]thiophen-3-ylmethyl-[2-(4-methanesulfo-
nylphenyl)-6-trifluoromethylpyrimidin-4-yl]amine
(22).
Compound 22 was prepared from 4a and 3-benzo[b]thi-
ophenemethylamine following GP1. The yellow solid
obtained after flash chromatography was washed with
Et2O and the title compound isolated (46% yield) as a
white solid; mp 240.0–242.1 ꢁC. Anal (C21H16F3N3O2S2)
C, H, N, S.
4.2.10. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]pyridin-3-ylmethylamine (14). Compound
14 was obtained from 4a and 3-(methylamino)pyridine
following GP1. After flash chromatography the title
compound was isolated (97% yield) as a grey solid; mp
225.0–227.5 ꢁC. Anal (C18H15F3N4O2S) C, H, N, S.
4.2.19. 4-[4-(Cyclohexylmethylamino)-6-trifluoromethyl-
pyrimidin-2-yl]benzenesulfonamide (23). Compound 23
was prepared from 3h and cyclohexanemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (37% yield) as a white solid; mp
198.0–200.0 ꢁC. Anal (C18H21F3N4O2S) C, H, N, S.
4.2.11. 4-[4-[(Pyridin-4-ylmethyl)amino]-6-trifluorometh-
ylpyrimidin-2-yl]benzenesulfonamide (15). Compound 15
was obtained from 3h and 4-(methylamino)pyridine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (19% yield) as a dark oil. Anal
(C17H14F3N5O2S) C, H, N, S.
4.2.20. Cyclohexylmethyl-[2-(4-methanesulfonylphenyl)-
6-trifluoromethylpyrimidin-4-yl]amine (24). Compound
24 was obtained from 4a and cyclohexanemethylamine
following GP1. After flash chromatography the title
compound was isolated (96% yield) as a white solid;
mp 160.0–161.5 ꢁC. Anal (C19H22F3N3O2S) C, H,
N, S.
4.2.12. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]pyridin-4-ylmethylamine (16). Compound
16 was synthesized from 4a and 4-(methylamino)pyri-
dine following GP1. After flash chromatography the ti-
tle compound was isolated (79% yield) as a pale yellow
solid. Anal (C18H15F3N4O2S) C, H, N, S.
4.2.21. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]thiazol-2-ylmethylamine (25). Compound
25 was prepared from 4a and thiazol-2-ylmethylamine
following GP1. After flash chromatography the title
compound was isolated (89% yield) as a yellow
solid; mp 194.0–196.4 ꢁC. Anal (C16H13F3N4O2S2) C,
H, N, S.
4.2.13. 4-[4-[(Furan-2-ylmethyl)amino]-6-trifluoromethyl-
pyrimidin-2-yl]benzenesulfonamide (17). Compound 17
was obtained from 3h and furfurylamine following
GP1. After flash chromatography, the title compound
was isolated (94% yield) as a white solid; mp 212.0–
214.0 ꢁC. Anal (C16H13F3N4O3S) C, H, N, S.

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2193
4.2.22. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(1-methyl-1H-pyrrol-2-ylmethyl)amine (26).
Compound 26 was obtained from 4a and (1-methyl-1H-
pyrrol-2-yl)methylamine following GP1. After flash
chromatography the title compound was isolated (70%
yield) as a yellow solid; mp 209.5–212.0 ꢁC. Anal
(C18H17F3N4O2S) C, H, N, S.
raphy the title compound was isolated (66% yield) as a
white solid: mp 169.0–171.8 ꢁC. Anal (C19H20F3N3O2S)
C, H, N, S.
4.2.31. Benzyl-[2-(4-methanesulfonylphenyl)-6-trifluorom-
ethylpyrimidin-4-yl]methylamine (35). Compound 35 was
prepared from 4a and N-benzylmethylamine following
GP1. After flash chromatography the title compound
was isolated (97% yield) as a white solid; mp 133.7–
135.8 ꢁC. Anal (C20H18F3N3O2S) C, H, N, S.
4.2.23. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]naphthalen-2-ylmethylamine (27). Com-
pound 27 was obtained from 4a and naphthalen-2-
ylmethylamine following GP1. After flash chromatogra-
phy the title compound was isolated (93% yield) as an
4.2.32. Benzylethyl-[2-(4-methanesulfonylphenyl)-6-triflu-
oromethylpyrimidin-4-yl]amine (36). Compound 36 was
prepared from 4a and N-benzylethylamine following
GP1. After flash chromatography the title compound
was isolated (93% yield) as a white solid; mp 139.9–
141.9 ꢁC. Anal (C21H20F3N3O2S) C, H, N, S.
off-white
(C23H18F3N3O2S) C, H, N, S.
solid;
mp
194.0–195.8 ꢁC.
Anal
4.2.24. (1H-Benzoimidazol-2-ylmethyl)-[2-(4-metha-
nesulfonylphenyl)-6-trifluoromethylpyrimidin-4-yl]amine
(28). Compound 28 was obtained from 4a and 2-(amino-
methyl)benzimidazole following GP1. After flash chro-
matography the title compound was isolated (95%
yield) as a pale rose solid; mp > 253.8 ꢁC. Anal
(C20H16F3N5O2S) C, H; N, S.
4.2.33. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(1-phenylethyl)amine (37). Compound
37 was prepared from 4a and 1-phenylethylamine fol-
lowing GP1 and the title compound was isolated (95%
yield) as a pale yellow solid; mp 186.0–187.8 ꢁC. Anal
(C20H18F3N3O2S) C, H, N, S.
4.2.25. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]pentylamine (29). Compound 29 was pre-
pared from 4a and pentylamine following GP1. After
flash chromatography the title compound was isolated
(97% yield) as an almost white solid; mp 119.6–
122.1 ꢁC. Anal (C17H20F3N3O2S) C, H, N, S.
4.2.34. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]phenylamine (38). Aniline (130 lL,
1.34 mmol) was added to a suspension of NaH (60%
in mineral oil, 0.16 g, 4.00 mmol) in THF (3 mL) at
0 ꢁC and the mixture stirred at rt for 15 min. A solution
of 4a (0.30 g, 0.89 mmol) in THF (4 mL) was added
dropwise to the previously described suspension at
0 ꢁC and the resulting mixture stirred at rt for 22 h.
The reaction was quenched with water (15 mL) and
tha mixture extracted with EtOAc (3· 100 mL). The
combined organic extracts were dried (Na2SO4), the sol-
vents evaporated and the resulting residue purified by
flash chromatography (3· 20 cm, EtOAc/hept 43:57) to
yield the title compound 38 (0.22 g, 63% yield) as an
4.2.26. Isobutyl-[2-(4-methanesulfonylphenyl)-6-trifluo-
romethylpyrimidin-4-yl]amine (30). Compound 30 was
prepared from 4a and isobutylamine following GP1.
After flash chromatography the title compound was iso-
lated (97% yield) as a white solid; mp 192.0–191.2 ꢁC.
Anal (C16H18F3N3O2S) C, H, N, S.
4.2.27. Cyclopentylmethyl-[2-(4-methanesulfonylphenyl)-
6-trifluoromethylpyrimidin-4-yl]amine (31). Compound
31 was obtained from 4a and cyclopentylmethylamine
following GP1. After flash chromatography the title
compound was isolated (95% yield) as a white solid;
mp 171.6–173.2 ꢁC. Anal (C18H20F3N3O2S) C, H, N, S.
1
off-white solid; mp 297.2–298.7 ꢁC. H NMR (CDCl3)
d 3.09 (s, 3H, SO2CH3), 7.35–7.40 (m, 2H, Ar-H and
H-5), 7.64–7.75 (m, 4H, Ar-H), 8.01 (d, J = 8.5 Hz,
2H, Ar-H), 8.46 (d, J = 8.5 Hz, 2H, Ar-H). 13C NMR
(CDCl3) d 44.3 (SO2CH3), 106.9 (C-5), 120.4 (q,
J = 275 Hz, CF3), 127.7 (CH), 128.9 (CH), 129.3 (CH),
129.7 (CH), 131.0 (CH), 139.5 (C), 140.7 (C), 143.0
(C), 156.8 (q, J = 36 Hz, C-6), 162.9 (C). Anal
(C18H14F3N3O2S) C, H, N, S.
4.2.28. Cyclopentyl-[2-(4-methanesulfonylphenyl)-6-triflu-
oromethylpyrimidin-4-yl]amine (32). Compound 32 was
prepared from 4a and cyclopentylamine following
GP1. After flash chromatography the title compound
was isolated (98% yield) as an off-white solid; mp
198.0–200.4 ꢁC. Anal (C17H18F3N3O2S) C, H; N, S.
4.2.35. (4-Isopropylphenyl)-[2-(4-methanesulfonylphenyl)-
6-trifluoromethylpyrimidin-4-yl]amine (39). Compound
39 was prepared from 4a and 4-isopropylaniline accord-
ing to the procedure previously described for the synthe-
sis of compound 38. The title compound was isolated
(64% yield) as a yellowish solid; mp 255.0–257.5 ꢁC.
Anal (C21H20F3N3O2S) C, H, N, S.
4.2.29. Cyclohexyl-[2-(4-methanesulfonylphenyl)-6-triflu-
oromethylpyrimidin-4-yl]amine (33). Compound 33 was
prepared from 4a and cyclohexylamine following GP1.
After flash chromatography the title compound was iso-
lated (92% yield) as a white solid; mp 154.4–156.3 ꢁC.
Anal (C18H20F3N3O2S) C, H, N, S.
4.2.36. 4-Benzylsulfanyl-2-(4-methanesulfonylphenyl)-6-
trifluoromethylpyrimidine
2.96 mmol) was added to a solution of 4a (0.50 g,
1.48 mmol) and phenylmethanethiol (210 lL,
1.77 mmol) in DMF (7.4 mL) and the resulting suspen-
sion stirred at rt for 1 h 45 min. The reaction mixture
(40).
K2CO3
(0.41 g,
4.2.30. Cyclohex-3-enylmethyl-[2-(4-methanesulfonylphe-
nyl)-6-trifluoromethylpyrimidin-4-yl]amine (34). Com-
pound 34 was obtained from 4a and cyclohex-3-
enylmethylamine following GP1. After flash chromatog-

2194
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
was diluted with EtOAc (100 mL) and filtered through a
bed of silica gel washed with EtOAc (100 mL). The sol-
vent was evaporated under reduced pressure and the
resulting residue submitted to flash chromatography
(3· 20 cm, AcOEt/Hept 35:65) to yield the title com-
pound 40 (0.66 g, 99% yield) as a white solid; mp
161.0–162.8 ꢁC. 1H NMR (CDCl3) d 3.11 (s, 3H,
SO2CH3), 4.63 (s, 2H, SCH2), 7.28–7.47 (m, 6H, H-5
and Ar-H), 8.07 (d, J = 8.5 Hz, 2H, Ar-H), 8.66 (d,
J = 8.5 Hz, 2H, Ar-H). 13C NMR (CDCl3) d 34.1
(SCH2), 44.4 (SO2CH3), 113.4 (C-5), 120.4 (q,
J = 275 Hz, CF3), 127.6 (CH), 127.8 (CH), 128.7 (CH),
128.8 (CH), 129.4 (CH), 135.9 (C), 141.0 (C), 142.8
(C), 153.8 (q, J = 36 Hz, C-6), 162.7 (C), 173.1 (C). Anal
(C19H15F3N2O2S2) C, H, N, S.
2-ylmethanethiol according to the procedure previously
described for the preparation of 40. The title compound
was isolated (33% yield) as a white solid; mp 148.8–
152.0 ꢁC. Anal (C17H13F3N2O2S3) C, H, N, S.
4.2.40. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(2-thiophen-2-ylethyl)amine (44). Com-
pound 44 was prepared from 4a and 2-thiophen-2-
ylethylamine following GP1. The title compound was
isolated (97% yield) as a solid; mp 143.5–144.8 ꢁC. Anal
(C18H16F3N3O2S2) C, H, N, S.
4.2.41. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-[2-(1-methyl-1H-pyrrol-2-yl)-ethyl]amine
(45). Compound 45 was prepared from 4a and 2-(1-
methyl-1H-pyrrol-2-yl)ethylamine following GP1. After
flash chromatography the title compound was isolated
(80% yield) as an almost white solid; mp 163.0–
165.3 ꢁC. Anal (C19H19F3N4O2S) C, H, N, S.
4.2.37. 2-(4-Methanesulfonylphenyl)-4-phenylmethane-
sulfinyl-6-trifluoromethylpyrimidine (41). A solution of
37 (0.21 g, 0.49 mmol) in CH2Cl2 (3 mL) was added to
a
suspension of [hydroxy(tosyloxy)iodo]benzene
(0.21 g, 0.59 mmol) in CH2Cl2 (4 mL) and the mixture
stirred at rt for 22 h and 2 h at 40 ꢁC. The resulting solu-
tion was diluted with CH2Cl2 (100 mL) and extracted
with H2O (3· 100 mL). The combined organic extracts
were dried (Na2SO4), the solvents evaporated under re-
duced presure and the resulting residue purified by flash
chromatography (2· 20 cm, EtOAc/hept 50:50) to yield
the title compound 41 (0.24 g, 98% yield) as a cream so-
lid; mp 159.0–162.5 ꢁC. 1H NMR (CDCl3) d 3.11 (s, 3H,
SO2CH3), 4.20 (d, J = 13.1 Hz, 1H, SOCH2Ph), 4.48 (d,
J = 13.1 Hz, 1H, SOCH2Ph), 9.90–7.00 (m, 2H, Ar-H),
7.10–7.30 (m, 3H, Ar-H), 7.83 (s, 1H, H-5), 8.10 (d,
J = 8.5 Hz, 2H, Ar-H), 8.68 (d, J = 8.5 Hz, 2H, Ar-H).
13C NMR (CDCl3) d 44.3 (SO2CH3), 60.2 (SOCH2Ph),
112.1 (C-5), 119.8 (q, J = 276 Hz, CF3), 127.9 (CH),
128.5 (CH), 128.8 (CH), 129.7 (CH), 130.0 (CH), 139.5
(C), 143.7 (C), 157.8 (q, J = 37 Hz, C-6), 162.7 (C),
179.2 (C). Anal (C19H15F3N2O3S2) C, H, N, S.
4.2.42. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(4-methylbenzyl)amine (46). Compound
46 was synthesized from 4a and 4-methylbenzylamine
following GP1. After flash chromatography the title
compound was isolated (99% yield) as a white solid;
mp 165.8–167.0 ꢁC. Anal (C20H18F3N3O2S) C, H, N, S.
4.2.43. (4-Fluorobenzyl)-[2-(4-methanesulfonylphenyl)-6-
trifluoromethylpyrimidin-4-yl]amine (47). Compound 47
was prepared from 4a and 4-fluorobenzylamine follow-
ing GP1. After flash chromatography the title com-
pound was isolated (98% yield) as an almost white
solid; mp 171–173 ꢁC. Anal (C19H15F4N3O2S) C, H,
N, S.
4.2.44. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(2-methylbenzyl)amine (48). Compound
48 was prepared from 4a and 2-methylbenzylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (77% yield) as a white solid; mp
221.0–223.5 ꢁC. Anal (C20H18F3N3O2S) C, H, N, S.
4.2.38. 2-(4-Methanesulfonylphenyl)-4-phenylmethane-
sulfonyl-6-trifluoromethylpyrimidine (42). A solution of
OXONE (0.80 g, 1.30 mmol) in H2O (3 mL) was added
to a solution of 37 (0.25 g, 0.59 mmol) in THF (7 mL) at
0 ꢁC and the resulting mixture was stirred at rt for 22 h.
The reaction mixture was diluted with H2O (10 mL) and
extracted with EtOAc (3· 70 mL). The combined organ-
ic layers were dried (Na2SO4) and the solvents
evaporated under reduced pressure. After flash chroma-
tography (3· 16 cm, EtOAc/hept 45:55 and 50:50) the
title compound was isolated (0.15 g, 55% yield) as a
4.2.45. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(3-methylbenzyl)amine (49). Compound
49 was prepared from 4a and 3-methylbenzylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (58% yield) as a white solid; mp
190.0–192.3 ꢁC. Anal (C20H18F3N3O2S) C, H, N, S.
4.2.46. (4-Isopropylbenzyl)-[2-(4-methanesulfonylphenyl)-
6-trifluoromethylpyrimidin-4-yl]amine (50). Compound
50 was prepared from 4a and 4-isopropylbenzylamine
following GP1. After flash chromatography the title
compound was isolated (98% yield) as a solid; mp
157.1–159.9 ꢁC. Anal (C22H22F3N3O2S) C, H, N, S.
1
cream solid; mp 174.0–176.5 ꢁC. H NMR (CDCl3) d
3.14 (s, 3H, SO2CH3), 4.80 (s, 2H, SO2CH2Ph), 7.20–
7.30 (m, 5H, Ar-H), 8.02 (s, 1H, H-5), 8.14 (d,
J = 8.4 Hz, 2H, Ar-H), 8.74 (d, J = 8.4 Hz, 2H, Ar-H).
13C NMR (CDCl3) d 44.2 (SO2CH3), 58.1 (SO2CH2Ph),
116.0 (C-5), 119.6 (q, J = 276 Hz, CF3), 125.7 (C), 128.0
(CH), 129.0 (CH), 129.3 (CH), 129.9 (CH), 131.0 (CH),
138.9 (C), 144.1 (C), 159.2 (q, J = 38 Hz, C-6), 164.3 (C),
167.9 (C). Anal (C19H15F3N2O4S2) C, H, N, S.
4.2.47.
(3,5-Difluorobenzyl)-[2-(4-methanesulfonylphe-
nyl)-6-trifluoromethylpyrimidin-4-yl]amine (51). Com-
pound 51 was prepared from 4a and 3,5-
difluorobenzylamine following GP1. After flash chro-
matography the title compound was isolated (99% yield)
as an almost white solid; mp 200.0–203.1 ꢁC. Anal
(C19H14F5N3O2S) C, H, N, S.
4.2.39.
2-(4-Methanesulfonylphenyl)-4-(thiophen-2-yl-
methylsulfanyl)-6-trifluoromethylpyrimidine (43). Com-
pound 43 was synthesized from 4a and thiophen-

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2195
4.2.48. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(4-trifluoromethylbenzyl)amine (52).
Compound 52 was prepared from 4a and 4-trifluorom-
ethylbenzylamine following GP1. After flash chroma-
tography the title compound was isolated (89% yield)
EtOAc (3· 100 mL). The residue obtained after evapo-
ration of the organic solvents was purified by flash chro-
matography (1.5· 16 cm, EtOAc/hept/iPrNH2 70:30:3)
and the title compound was isolated (0.06 g, 31% yield)
1
as a white solid. H NMR (DMSO-d6) d 3.25 (s, 3H,
as
(C20H15F6N3O2S) C, H, N, S.
a
white solid; mp 187.2–189.3 ꢁC. Anal
CH3), 3.35 (s, 3H, CH3), 4.78 (d, J = 5.5 Hz, 2H,
NHCH2Ar), 6.95 (s, 1H, H-5), 7.34 (d, J = 8.5 Hz, 2H,
Ar-H), 7.52 (d, J = 8.5 Hz, 2H, Ar-H), 8.04 (d,
J = 8.3 Hz, 2H, Ar-H), 8.50 (d, J = 8.3 Hz, 2H, Ar-H),
8.76 (t, J = 5.5 Hz, 1H, NH). 13C NMR (DMSO-d6) d
37.4 (CH3SO3Ar), 43.1 (NHCH2Ar), 43.4 (SO2CH3),
101.7 (C-5), 121.0 (q, J = 274 Hz, CF3), 122.3 (CH),
127.3 (CH), 128.6 (CH), 129.3 (CH), 138.1 (C), 141.3
(C), 142.6 (C), 148.1 (C), 152.0 (q, J = 34 Hz, C-6),
162.5 (C), 162.8 (C). Anal (C20H18F3N3O5S2) C, H, N, S.
4.2.49. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(4-trifluoromethoxybenzyl)amine
(53).
Compound 53 was prepared from 4a and 4-trifluoro-
methoxybenzylamine following GP1. After flash chro-
matography the title compound was isolated (99%
yield) as a pale yellow solid; mp 168.0–170.5 ꢁC. Anal
(C20H15F6N3O3S) C, H, N, S.
4.2.50. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(4-methoxybenzyl)amine (54). Com-
pound 54 was prepared from 4a and 4-
methoxybenzylamine following GP1. After flash chro-
matography the title compound was isolated (97% yield)
4.2.54. (4-Aminobenzyl)-[2-(4-methanesulfonylphenyl)-6-
trifluoromethylpyrimidin-4-yl]amine (58). Compound 58
was prepared from 4a and 4-aminobenzylamine follow-
ing GP1. After flash chromatography the title com-
pound was isolated (97% yield) as a yellow solid; mp
200.0–202.5 ꢁC. Anal (C19H17F3N4O2S) C, H, N, S.
as
a
(C20H18F3N3O3S) C, H, N, S.
white solid; mp 182.8–185.0 ꢁC. Anal
4.2.55. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(3-methylthiophen-2-ylmethyl)amine (59).
Compound 59 was prepared from 4a and (3-methylthio-
phen-2-yl)methylamine following GP1. After flash chro-
matography the title compound was isolated (56% yield)
as a yellow solid; mp 225.0–226.8 ꢁC. Anal (C18H16F3
N3O2S2) C, H, N, S.
4.2.51. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(4-methoxymethoxybenzyl)amine
Compound 55 was prepared from 4a and 4-methoxy-
methoxybenzylamine following GP1. After flash chro-
matography the title compound was isolated (98%
(55).
yield) as
(C21H20F3N3O4S) C, H, N, S.
a
solid; mp 144.2–146.5 ꢁC. Anal
4.2.56. [2-(4-Methanesulfonylphenyl)-6-trifluoromethyl-
pyrimidin-4-yl]-(5-methylthiophen-2-ylmethyl)amine (60).
Compound 60 was obtained from 4a and (5-methylthio-
phen-2-yl)methylamine following GP1. After flash chro-
matography the title compound was isolated (81% yield)
as white solid: mp 167.0–168.5 ꢁC. Anal (C18H16F3
N3O2S2) C, H, N, S.
4.2.52. 4-[[2-(4-Methanesulfonylphenyl)-6-trifluorometh-
ylpyrimidin-4-ylamino]methyl]phenol (56). A saturated
solution of HCl in EtOH (2.25 L) was added to a solu-
tion of compound 55 (0.42 g, 0.90 mmol) in THF
(1.35 mL) and the mixture stirred at rt for 4 h. The reac-
tion was quenched with H2O (1 mL) and 10% aqueous
solution of NaOH added until pH = 6. The aqueous
layer was extracted with EtOAc (3· 175 mL). The resi-
due obtained after evaporation of the solvents at re-
duced pressure was submitted to flash chromatography
(2· 16 cm, EtOAc/hept/iPrNH2 70:30:3) to yield a
yellow solid that was washed with Et2O. The title com-
pound was isolated (0.38 g, 98% yield) as an off-white
4.2.57. (5-Chlorothiophen-2-ylmethyl)-[2-(4-methane-
sulfonylphenyl)-6-trifluoromethylpyrimidin-4-yl]amine
(61). Compound 61 was prepared from 4a and (5-chlo-
rothiophen-2-yl)methylamine following GP1. After flash
chromatography the title compound was isolated (84%
yield) as a yellow solid; mp 165.5–167.4 ꢁC. Anal
(C17H13ClF3N3O2S2) C, H, N, S.
1
solid; mp 225.0–227.1 ꢁC. H NMR (DMSO-d6) d 3.26
(s, 3H, SO2CH3), 4.61 (d, J = 5.2 Hz, 2H, NHCH2Ar),
6.74 (d, J = 8.2 Hz, 2H, Ar-H), 6.90 (s, 1H, H-5), 7.21
(d, J = 8.2 Hz, 2H, Ar-H), 8.05 (d, J = 8.3 Hz, 2H, Ar-
H), 8.53 (d, J = 8.3 Hz, 2H, Ar-H), 8.40–8.70 (m, 1H),
9.34 (s, 1H). 13C NMR (DMSO-d6) d 43.5 (SO2CH3),
101.6 (C-5), 115.2 (CH), 121.0 (q, J = 274 Hz, CF3),
127.3 (CH), 128.6 (CH), 129.1 (CH), 141.4 (C), 142.6
(C), 151.9 (q, J = 34 Hz, C-6), 156.6 (C), 162.5 (C),
162.6 (C). Anal (C19H16F3N3O3S) C, H, N, S.
4.2.58. Benzyl-[6-isopropyl-2-(4-methanesulfonylphenyl)-
pyrimidin-4-yl]amine (62). Compound 62 was prepared
from 4b and benzylamine following GP1. After flash
chromatography the title compound was isolated (85%
yield) as a yellow solid; mp 136.5–139.2 ꢁC. Anal
(C21H23N3O2S) C, H, N, S.
4.2.59. [6-Isopropyl-2-(4-methanesulfonylphenyl)pyrimi-
din-4-yl]thiophen-2-ylmethylamine (63). Compound 63
was prepared from 4b and 2-thiophenemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (97% yield) as a yellowish solid;
mp 141.1–143.4 ꢁC. Anal (C19H21N3O2S2) C, H, N, S.
4.2.53. Methanesulfonic acid 4-[[2-(4-methanesulfonyl-
phenyl)-6-trifluoromethylpyrimidin-4-ylamino]methyl]-
phenyl ester (57). MsCl (50 lL, 0.57 mmol) was added to
a solution of compound 56 (0.16 g, 0.38 mmol) and
DMAP (6 mg) in pyridine (760 lL) at 0 ꢁC and the
resulting suspension was stirred at rt for 21 h. The mix-
ture was treated with water (8 mL) and extracted with
4.2.60. Benzyl-[6-tert-butyl-2-(4-methanesulfonylphenyl)-
pyrimidin-4-yl]amine (64). Compound 64 was prepared

2196
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
from 4c and benzylamine following GP1. After flash
chromatography the title compound was isolated (95%
yield) as a white solid; mp 145.0–147.0 ꢁC. Anal
(C22H25N3O2S) C, H, N, S.
72 (1.15 g, 87% yield); mp 170.0–173.0 ꢁC. 1H NMR
(CDCl3) d 1.35 (t, J = 7.4 Hz, 3H, SO2CH2CH3), 3.09
(s, 3H, SO2CH3), 3.46 (q, J = 7.4 Hz, 2H, SO2CH2CH3),
4.4–5.0 (m, 2H, NHCH2Ph), 6.02 (br s, 1H, NH), 7.09
(s, 1H, H-5), 7.30–7.40 (m, 5H, Ar-H), 8.01 (d,
J = 8.6 Hz, 2H, Ar-H), 8.58 (d, J = 8.6 Hz, 2H, Ar-H).
13C NMR (DMSO-d6) d 6.6 (SO2CH2CH3), 43.4
(SO2CH3), 44.0 (CH2), 45.0 (CH2), 102.5 (C-5), 126.9
(CH), 127.2 (CH), 127.7 (CH), 128.5 (CH), 128.7
(CH), 128.9 (CH), 138.6 (C), 141.2 (C), 142.7 (C),
162.0 (C), 162.5 (C), 163.1 (C). Anal (C20H21N3O4S2)
C, H, N, S.
4.2.61. [6-tert-Butyl-2-(4-methanesulfonylphenyl)pyrimi-
din-4-yl]thiophen-2-ylmethylamine (65). Compound 65
was prepared from 4c and 2-thiophenemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (95% yield) as a white solid; mp
143.0–145.0 ꢁC. Anal (C20H23N3O2S2) C, H, N, S.
4.2.62. Benzyl-[2-(4-methanesulfonylphenyl)-6-methoxy-
pyrimidin-4-yl]amine (66). Compound 66 was prepared
from 4h and benzylamine following GP1. After flash
chromatography the title compound was isolated (59%
yield) as an almost white solid; mp 124.0–126.5 ꢁC. Anal
(C19H19N3O3S) C, H, N, S.
4.2.69. [6-Ethanesulfonyl-2-(4-methanesulfonylphenyl)-
pyrimidin-4-yl]thiophen-2-ylmethylamine (73). Com-
pound 73 was prepared from product 71 following the
procedure previously described for the synthesis of com-
pound 72. After flash chromatography the title com-
pound was isolated (78% yield) as a white solid: mp
151.0–152.5 ꢁC. Anal (C18H19N3O4S3) C, H, N, S.
4.2.63. [2-(4-Methanesulfonylphenyl)-6-methoxypyrimi-
din-4-yl]thiophen-2-ylmethylamine (67). Compound 67
was prepared from 4h and 2-thiophenemethylamine fol-
lowing GP1. After flash chromatography the title com-
pound was isolated (23% yield) as an off-white solid;
mp 120.0–124.1 ꢁC. Anal (C17H17N3O3S2) C, H, N, S.
4.2.70. 6-Benzylamino-2-(4-methanesulfonylphenyl)pyr-
imidin-4-ol (74). A solution of compound 72 (0.50 g,
1.16 mmol) in THF (10.4 mL) was treated with 50%
aqueous solution of NaOH (190 mL). The mixture was
stirred at 70 ꢁC for 4 days. The reaction mixture was di-
luted with H2O (20 mL) and extracted with EtOAc (3·
350 mL). The yellow solid obtained after evaporation
of the solvents at reduced pressure was washed with
CH2Cl2 and MeOH, suspended in H2O and 10% aque-
ous solution of NaOH was added until pH 10. The aque-
ous layer was extracted with EtOAc and the solvents
were evaporated to yield the title compound 74
4.2.64. Benzyl-[6-chloro-2-(4-methanesulfonylphenyl)pyr-
imidin-4-yl]amine (68). Compound 68 was prepared
from 4d and benzylamine following GP1. After flash
chromatography the title compound was isolated (97%
yield) as a white solid; mp 144.0–145.7 ꢁC. Anal
(C18H16ClN3O2S) C, H, N, S.
1
4.2.65. [6-Chloro-2-(4-Methanesulfonylphenyl)pyrimidin-
4-yl]thiophen-2-ylmethylamine (69). Compound 69 was
prepared from 4d and 2-thiophenemethylamine follow-
ing GP1. After flash chromatography the title com-
pound was isolated (87% yield) as a white solid; mp
167.0–169.1 ꢁC. Anal (C16H14ClN3O2S2) C, H, N, S.
(0.14 g, 35% yield) as a solid; mp > 265 ꢁC. H NMR
(DMSO-d6)
d 3.25 (s, 3H, SO2CH3), 4.44 (d,
J = 6.0 Hz, 2H, NHCH2Ph), 5.22 (s, 1H, H-5), 7.19–
7.33 (m, 5H, Ar-H), 7.58 (t, J = 6.0 Hz, 1H, NH), 8.00
(d, J = 8.4 Hz, 2H, Ar-H), 8.34 (d, J = 8.4 Hz, 2H,
Ar-H). Anal (C18H17N3O3S) C, H, N, S.
4.2.66. Benzyl-[6-ethylsulfanyl-2-(4-methanesulfonylphe-
nyl)pyrimidin-4-yl]amine (70). Compound 70 was pre-
pared from 4l and benzylamine following GP1. After
flash chromatography the title compound was isolated
(81% yield) as a white solid; mp 160.0–162.2 ꢁC. Anal
(C20H21N3O2S2) C, H, N, S.
4.2.71.
2-(4-Methanesulfonylphenyl)-6-[(thiophen-2-yl-
methyl)amino]pyrimidin-4-ol (75). Compound 75 was
prepared from product 73 following the procedure pre-
viously described for the synthesis of compound 74.
After flash chromatography the title compound was iso-
lated (38% yield) as a yellow solid; mp 261.0–267.4 ꢁC.
Anal (C16H15N3O3S2) C, H, N, S.
4.2.67. [6-Ethylsulfanyl-2-(4-methanesulfonylphenyl)pyr-
imidin-4-yl]thiophen-2-ylmethylamine (71). Compound
71 was prepared from 4l and 2-thiophenemethylamine
following GP1. After flash chromatography the title
compound was isolated (99% yield) as a white solid;
mp 152.0–153.9 ꢁC. Anal (C18H19N3O2S3) C, H, N, S.
4.2.72. N-Benzyl-N0-isopropyl-2-(4-methanesulfonylphe-
nyl)pyrimidine-4,6-diamine (76). A solution of com-
pound 72 (0.18 g, 0.42 mmol) in isopropylamine
(4 mL) was stirred under pressure at 100 ꢁC for 6 days.
The crude residue obtained after evaporation of the sol-
vent was purified by flash chromatography (2· 16 cm,
EtOAc/hept 45:55) to provide the title compound 76
(0.12 g, 71% yield) as an off-white solid; mp 69.7–
4.2.68.
Benzyl-[6-ethanesulfonyl-2-(4-methanesulfonyl-
phenyl)pyrimidin-4-yl]amine (72). A solution of com-
pound 70 (1.14 g, 2.85 mmol) in THF (28 mL) at 0 ꢁC
was treated with a solution of OXONE (4.37 g,
7.12 mmol) in H2O (17 mL) and the resulting suspension
was stirred at rt for 15 h. The reaction mixture was di-
luted with H2O and extracted with EtOAc (2·
110 mL). The cream solid obtained after evaporation
of the solvents was characterized as the title compound
1
73.4 ꢁC. H NMR (CDCl3) d 1.11 (d, J = 6.4 Hz, 6H,
CH(CH3)2), 2.95 (s, 3H, SO2CH3), 3.72 (hept,
J = 6.4 Hz, 1H, CH(CH3)2), 4.41 (d, J = 5.8 Hz, 2H,
NHCH2), 4.69 (d, J = 7.5 Hz, 1H, NH), 5.13 (s, 1H,
H-5), 5.32 (d, J = 4.7 Hz, 1H, NH), 7.18–7.27 (m, 5H,
Ar-H), 7.86 (d, J = 8.4 Hz, 2H, Ar-H), 8.41 (d,
J = 8.4 Hz, 2H, Ar-H). 13C NMR (CDCl3) d 22.6

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2197
(CH(CH3)2), 42.8 (CH(CH3)2), 44.4 (SO2CH3), 45.8
(NHCH2), 79.6 (C-5), 127.0 (CH), 127.2 (CH), 127.3
(CH), 128.6 (C), 128.7 (C), 138.4 (C), 140.9 (C), 143.9
(C), 161.5 (C), 162.6 (C), 163.4 (C). Anal
(C21H24N4O2S) C, H, N, S.
compound was isolated (59% yield) as a solid; mp
160–162.2 ꢁC. Anal (C18H19N3O3S2) C, H, N, S.
4.2.79. [2-(4-Methanesulfonylphenyl)-6-(2-methoxyethoxy)-
pyrimidin-4-yl]thiophen-2-ylmethylamine (83). Compound
83 was prepared from 4j and 2-thiophenemethylamine
following GP1. After flash chromatography the title
compound was isolated (67% yield) as a brown solid;
mp 147.4–150.3 ꢁC. Anal (C19H21N3O4S2) C, H, N, S.
4.2.73. N-Isopropyl-2-(4-methanesulfonylphenyl)-N0-thio-
phen-2-ylmethylpyrimidine-4,6-diamine (77). Compound
77 was prepared from product 69 and isopropylamine
following the procedure described for the synthesis of
compound 76. The title compound was isolated (57%
yield) as an oil. Anal (C19H22N4O2S2) C, H, N, S.
4.2.80. [6-Cyclopentyloxy-2-(4-methanesulfonylphenyl)-
pyrimidin-4-yl]thiophen-2-ylmethylamine (84). Com-
pound 84 was prepared from 4k and 2-thiophenemethyl-
amine following GP1. After flash chromatography the
title compound was isolated (54% yield) as a cream
solid; mp 184.0–184.6 ꢁC. Anal (C21H23N3O3S2) C, H,
N, S.
4.2.74. Benzyl-[2-(4-methanesulfonylphenyl)pyrimidin-4-
yl]amine (78).
A
solution of OXONE (4.44 g,
7.22 mmol) in H2O (17 mL) was added dropwise to a
solution of 94 (0.98 g, 2.89 mmol) in CH2Cl2 (29 mL)
at 0 ꢁC. The mixture was stirred for 2 h and the aque-
ous layer was extracted with CH2Cl2 (4· 300 mL). The
crude residue obtained after evaporation of the solvent
was purified by flash chromatography (3· 16 cm,
EtOAc/hept 40:60 and 50:50) to provide the title com-
pound (0.40 g, 36% yield) as an almost white solid; mp
186.3–187.3 ꢁC. 1H NMR (DMSO-d6) d 3.24 (s, 3H,
SO2CH3), 4.73 (d, J = 5.9 Hz, 2H, NHCH2), 7.17–
7.43 (m, 6H, Ar-H and H-5), 7.99 (d, J = 8.4 Hz, 2H,
Ar-H), 8.31 (t, J = 5.9 Hz, 1H, NH), 8.41 (d,
J = 4.0 Hz, 1H, H-6), 8.45 (d, J = 8.4 Hz, 2H, Ar-H).
4.2.81.
[5-Methyl-2-(4-methylsulfonylphenyl)-6-trifluo-
romethylpyrimidin-4-yl]benzylamine (85). Compound 85
was prepared from 4e and benzylamine following GP1
and using Cs2CO3 as a base. After flash chromatogra-
phy the title compound was isolated (66% yield) as a
white solid; mp 194.0–196.5 ꢁC. Anal (C20H18F3N3O2S)
C, H, N, S.
4.2.82. [2-(4-Methanesulfonylphenyl)-5-methyl-6-trifluo-
romethylpyrimidin-4-yl]thiophen-2-ylmethylamine (86).
Compound 86 was prepared from 4e and 2-thiophenem-
ethylamine following GP1 and using Cs2CO3 as a base.
After flash chromatography the title compound was iso-
lated (16% yield) as an oil. Anal (C18H16F3N3O2S2) C,
H, N, S.
13C NMR (DMSO-d6)
d
43.4 (SO2CH3), 43.8
(NHCH2), 113.1 (C-5), 126.8 (CH), 127.2 (CH), 127.4
(CH), 128.3 (CH), 139.5 (C), 141.7 (C), 142.1 (C),
152.9 (C-6), 157.3 (C), 159.3 (C). Anal (C18H17N3O2S)
C, H, N, S.
4.2.75. [2-(4-Methanesulfonylphenyl)pyrimidin-4-yl]thio-
phen-2-ylmethylamine (79). Compound 79 was prepared
from 95 following the procedure previously described
for the synthesis of 78. After flash chromatography the ti-
tle compound was isolated (69% yield) as a cream solid;
mp 145.6–148.0 ꢁC. Anal (C16H15N3O2S2) C, H, N, S.
4.2.83.
[2-(4-Methanesulfonylphenyl)-5-ethyl-6-trifluo-
romethylpyrimidin-4-yl]thiophen-2-ylmethylamine (87).
Compound 87 was prepared from 4f and 2-thiophenem-
ethylamine following GP1 and using Cs2CO3 as a base.
After flash chromatography the title compound was iso-
lated (41% yield) as a yellow solid; mp 168.0–171.0 ꢁC.
Anal (C19H18F3N3O2S2) C, H, N, S.
4.2.76. N,N-Diethyl-2-(4-methanesulfonylphenyl)-N0-
thiophen-2-ylmethylpyrimidine-4,6-diamine (80). Com-
pound 83 was prepared from product 69 and diethyl-
amine following the procedure previously described for
the synthesis of compound 76. After flash chromatogra-
phy the title compound was isolated (83% yield) as a yel-
low solid; mp 149.0–151.5 ꢁC. Anal (C20H24N4O2S2) C,
H, N, S.
4.2.84. [6-Chloro-2-(4-methanesulfonylphenyl)pyrimidin-
4-yl]-(4-methylbenzyl)amine (88). Compound 88 was pre-
pared from 4d and 4-methylbenzylamine following GP1.
After flash chromatography the title compound was iso-
lated (86% yield) as a white solid; mp 158.5–159.9 ꢁC.
Anal (C20H18F3N3O2S) C, H, N, S.
4.2.85. [6-Chloro-2-(4-methanesulfonylphenyl)-5-methyl-
pyrimidin-4-yl]-(4-methylbenzyl)amine (89). Compound
89 was prepared from 4g and 4-methylbenzylamine fol-
lowing GP1 and using Cs2CO3 as a base. After flash
chromatography the title compound was isolated (47%
yield) as a yellow solid; mp 182.0–186.0 ꢁC. Anal
(C21H20F3N3O2S) C, H, N, S.
4.2.77. [6-Ethanesulfinyl-2-(4-methanesulfonylphenyl)pyr-
imidin-4-yl]thiophen-2-ylmethylamine (81). Compound
81 was prepared from product 71 following the proce-
dure previously described for the synthesis of compound
41. After flash chromatography the title compound was
isolated (40% yield) as a yellow solid; mp 152.0–
153.9 ꢁC. Anal (C18H19N3O3S3) C, H, N, S.
4.2.86. N-(4-Fluorobenzyl)-[2-(4-methanesulfonylphenyl)-
5-methyl-6-trifluoromethylpyrimidin-4-yl]amine
4.2.78. [6-Ethoxy-2-(4-methanesulfonylphenyl)pyrimidin-
4-yl]thiophen-2-ylmethylamine (82). Compound 82 was
prepared from product 4i and 2-thiophenemethylamine
following GP1. After flash chromatography the title
(90).
Compound 90 was prepared from 4e and 4-fluoroben-
zylamine following GP1 and using Cs2CO3 as a base.
After flash chromatography the title compound was iso-

2198
A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
Manning, P. T. Proc. Natl. Acad. Sci. U.S.A. 1994, 91,
3228; (g) Vane, J. R.; Bakhle, Y. S.; Botting, R. M.
Annu. Rev. Pharmacol. Toxicol. 1998, 38, 97; (h)
Garavito, R. M.; De Witt, D. L. Biochim. Biophys.
Acta 1999, 1441, 278.
lated (32% yield) as a solid; mp 169.0–173.0 ꢁC. Anal
(C20H17F4N3O2S) C, H, N, S.
4.2.87. (4-Fluorobenzyl)-[2-(4-methanesulfonylphenyl)-5-
ethyl-6-trifluoromethylpyrimidin-4-yl]amine (91). Com-
pound 91 was prepared from 4f and 4-fluorobenzyl-
amine following GP1 and using Cs2CO3 as a base.
After flash chromatography the title compound was iso-
lated (16% yield) as a yellow solid; mp 189.0–192.0 ꢁC.
Anal (C21H19F4N3O2S) C, H, N, S.
2. Prasit, P.; Wang, Z.; Brideau, C.-C.; Chan, S.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutch-
inson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.;
Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.;
Le¨ger, S.; Mancini, P.; O’Neill, G. P.; Ouellet, M.;
Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.;
´
Tagari, P.; Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J.;
Young, R. N.; Zamboni, R. Bioorg. Med. Chem. Lett.
1999, 9, 1773.
4.2.88. [6-Chloro-2-(4-methanesulfonylphenyl)pyrimidin-
4-yl]-(4-fluorobenzyl)amine (92). Compound 92 was pre-
pared from 4d and 4-fluorobenzylamine following GP1.
After flash chromatography the title compound was iso-
lated (24% yield) as a beige solid; mp 134.0–137.5 ꢁC.
Anal (C18H15ClFN3O2S) C, H, N, S.
3. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J.
S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.;
Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn,
J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.;
Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P.
C. J. Med. Chem. 1997, 40, 1347.
4. (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M.
J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.;
Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.;
Seibert, K. J. Med. Chem. 2000, 43, 775; (b) Ormrod, D.;
Wellington, K.; Wagstaff, A. J. Drugs 2002, 62, 2059.
5. (a) Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson,
4.2.89. [6-Chloro-2-(4-methanesulfonylphenyl)-5-methyl-
pyrimidin-4-yl]-(4-fluorobenzyl)amine (93). Compound
93 was prepared from 4g and 4-fluorobenzylamine fol-
lowing GP1 and using Cs2CO3 as a base. After flash
chromatography the title compound was isolated (51%
yield) as a yellow solid; mp 181.0–184.0 ꢁC. Anal
(C19H17ClFN3O2S) C, H, N, S.
ˆ
´
S.; Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.;
Gauthier, J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.;
Riendeau, D.; Savoie, C.; Wang, Z.; Wong, E. Bioorg.
Med. Chem. Lett. 1998, 8, 2777; (b) Riendeau, D.;
Acknowledgments
´
Percival, M. D.; Brideau, C.; Charleson, S.; Dube, D.;
Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Gordon,
R.; Greig, G.; Guay, J.; Mancini, J.; Ouellet, M.; Wong,
E.; Xu, L.; Boyce, S.; Visco, D.; Girard, Y.; Prasit, P.;
Zamboni, R.; Rodger, I. W.; Gresser, M.; Ford-Hutch-
inson, A. W.; Young, R. N.; Chan, C.-C. J. Pharmacol.
Exp. Ther. 2001, 296, 558; (c) Davies, I. W.; Marcoux,
J.-F.; Corley, E. G.; Journet, M.; Cai, D.-W.; Palucki,
M.; Wu, J.; Larsen, R. D.; Rossen, K.; Pye, P. J.;
DiMichele, L.; Dormer, P.; Reider, P. J. J. Org. Chem.
2000, 65, 8415.
We thank the Ministry of Science and Technology of
Spain (PROFIT 2000–2003) and the Department of
Industry, Commerce and Tourism of the Basque Gov-
ernment (INTEK 2002) for financial support of this re-
´
search. B. Lopez was granted by the Ministry of Science
and Technology of Spain and the European Social Fund
(Programa Torres Quevedo). We also thank Dr. M. C.
Pumar for reading and providing valuable comments
on the manuscript.
6. Merck & Co. Press Release, 30 September 2004. Available
from: http://www.merck.com.
7. (a) Mukherjee, D.; Nissen, S. E.; Topol, E. J. J. Am. Med.
Assoc. 2001, 286, 954; (b) Mamdani, M.; Jurlink, D. N.;
Lee, D. S.; Rochon, P. A.; Kopp, A.; Naglie, G.; Austin,
P. C.; Laupacis, A.; Stukel, T. A. The Lancet 2004, 363,
1751; (c) Scheen, A. J. Rev. Med. Liege 2004, 59, 565; (d)
Bresalier, R. S.; Sandier, R. S.; Quan, H.; Bolognese, J. A.;
Oxenius, B.; Horgan, K.; Lines, C.; Riddell, R.; Morton,
D.; Lanas, A.; Konstam, M. A.; Baron, J. A. N. Engl. J.
Med. 2005, 352, 1092; (e) Solomon, S. D.; McMurray, J. J.
V.; Pfeffer, M. A.; Wittes, J.; Fowler, R.; Finn, P.;
Anderson, W. F.; Zauber, A.; Hawk, E.; Bertagnolli, M.
N. Engl. J. Med. 2005, 352, 1071; (f) FitzGerald, G. A. N.
Engl. J. Med. 2004, 351, 1709; (g) Lagakos, S. W. N. Eng.
J. Med. 2006, 355, 113.
Supplementary data
Description of the in vitro assays for COX-1 and COX-2
inhibitory activity determination; full experimental pro-
cedures for the synthesis of intermediate compounds 2–4
and 95–94; characterization data (1H NMR, 13C NMR)
for compounds 2–4 and 5–95; elemental analyses. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.bmc.
2007.11.079.
References and notes
8. (a) Editorial. Br. Med. J. 2004, 329, 867; (b) Fitzgerald,
G. A. Nat. Rev. Drug Disc. 2003, 2, 879; (c) Davies, N.
M.; Jamali, F. J. Pharm. Pharmaceut. Sci. 2004, 7, 332;
(d) Chung, S.; Lim, M. L.; Shin, S. S. Expert Opin.
1. (a) Fu, J. Y.; Masferrer, J. L.; Seibert, K.; Raz, A.;
Needleman, P. J. Biol. Chem. 1990, 265, 16737; (b) Xie,
W.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.;
Simmons, D. L. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
2692; (c) Hla, T.; Neilson, K. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 7382; (d) Kujubu, D. A.; Fletcher, B.
S.; Varnum, B. C.; Lim, R. W.; Herschman, H. R.
J. Biol. Chem. 1991, 266, 12866; (e) Vane, J. R. Nature
1994, 367, 215; (f) Masferrer, J. L.; Zweifel, B. S.;
´
Ther. Patents 2005, 15, 9; (e) Dogne, J.-M.; Supuran, C.
T.; Pratico, D. J. Med. Chem. 2005, 48, 2251; (f) Dogne,
´
J.-M.; Hanson, J.; Supuran, C.; Pratico, D. Curr.
Pharm. Des. 2005, 12, 971.
9. (a) Grosser, T.; Fries, S.; FitzGerald, G. A. J. Clin. Invest.
2006, 116, 4; (b) Sohn, H.-Y.; Kro¨tz, F. Curr. Drug
Targets 2006, 7, 1275.

A. Orjales et al. / Bioorg. Med. Chem. 16 (2008) 2183–2199
2199
10. (a) Maillard, M.; Burnier, M. Expert Opin. Drug Saf.
2006, 5, 83; (b) Hermann, M.; Ruschitzka, F. Int. Med. J.
2006, 36, 308.
15. (a) Glaxo Group Ltd. Expert Opin. Ther. Patents 2003, 13,
1465; (b) Carter, M. C.; Naylor, A.; Payne, J. J.; Pegg, N.
A. WO 03014091, 2003; (c) Weingarten, G.; Bravi, G. WO
2004018452, 2004.
11. (a) Oshima, M.; Dinchuk, J. E.; Kargman, S. L.; Oshima,
H.; Hancock, B.; Kwong, E.; Trzaskos, J. M.; Evans, J. F.;
Taketo, M. M. Cell 1996, 87, 803; (b) Vainio, H. Int. J.
Cancer 2001, 94, 613; (c) Singh, B.; Lucci, A. J. Surg. Res.
2002, 108, 173; (d) Kim, S. I.; Kwon, S. M.; Kim, Y. S.;
Hong, S. J. Urology 2002, 60, 816; (e) Fujita, H.; Koshida,
K.; Keller, E. T.; Takahashi, Y.; Yoshimito, T.; Namiki,
M.; Mizokami, A. Prostate 2002, 53, 232; (f) Chu, J.;
Lloyd, F. L.; Trifan, O. C.; Knapp, B.; Rizzo, M. T. Mol.
Cancer Ther. 2003, 2, 1; (g) Subbaramaiah, K.; Dannen-
berg, A. J. Trends Pharmacol. Sci. 2003, 24, 96.
12. (a) Pasinetti, G. M. J. Neurosci. Res. 1998, 54, 1; (b)
Xiang, Z.; Ho, L.; Yemul, S.; Zhao, Z.; Quing, W.; Pompl,
P.; Kelley, K.; Dang, A.; Qing, W.; Teplow, D.; Pasinetti,
G. M. Gene Expr. 2002, 10, 271; (c) Teismann, P.; Tieu,
K.; Choi, D. K.; Wu, D. C.; Naini, A.; Hunot, S.; Vola,
M.; Jackson-Lewis, V.; Przedborski, S. Proc. Natl. Acad.
Sci. U.S.A. 2003, 100, 5473.
16. Orjales, A.; Mosquera, R.; Labeaga, L.; Berisa, A.; Nu´n˜ez,
´
´
M. T.; Lopez, B.; Dieguez, M. C. Poster to the XVIIIth
International Symposium on Medicinal Chemistry.
August 15–19, 2004. Copenhagen, Denmark and Malmoe,
Sweden.
17. Cheng, C. C. Org. Prep. Proceed. Int. 1990, 22, 643.
18. (a) Futaki, N.; Takahashi, S.; Yokoyama, M.; Arai, I.;
Higuchi, S.; Otomo, S. Prostaglandins 1994, 55; (b)
Janusz, J. J. Med. Chem. 1998, 41, 1112.
19. (a) Patrignani, P.; Panara, M. R.; Greco, A.; Fusco, O.;
´
Natoli, C.; Iacobelli, S.; Cipollone, F.; Ganci, A.; Cremi-
non, C.; Maclouf, J.; Patrono, C. J. Pharmacol. Exp. Ther.
1994, 271, 1705; (b) Brideau, C.; Kargman, S.; Liu, S.;
Sallob, A. L.; Ehrich, E. W.; Rodger, I. W.; Chan, C. C.
Inflamm. Res. 1996, 45, 68; (c) Warner, T. D.; Giuliano,
F.; Vojnovic, I.; Bukasa, A.; Mitchell, J. A.; Vane, J. R.
Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 7563.
20. Bennett, A.; Tavares, I. Expert Opin. Pharmacother. 2001,
2, 1859.
13. (a) Talley, J. J. Progr. Med. Chem. 1999, 36, 201; (b) de
Leval, X.; Delarge, J.; Somers, F.; de Tullio, P.; Henrotin,
´
Y.; Pirotte, B.; Dogne, J.-M. Curr. Med. Chem. 2000, 7,
21. (a) Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.;
McDonald, J. J.; Stegeman, R. A.; Pak, J. Y.; Gildehaus,
D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson,
P. C.; Stallings, W. C. Nature 1996, 384, 644; (b) Talley, J.
J. Prog. Med. Chem. Res. 1999, 36, 201.
1041; (c) Carter, J. S. Exp. Opin. Ther. Patents 2000, 10,
1011; (d) Dannhardt, G.; Kiefer, W. Eur. J. Med. Chem.
´
2001, 36, 109; (e) de Leval, X.; Julemont, F.; Delarge, J.;
Sanna, V.; Pirotte, B.; Dogne, J.-M. Expert Opin. Ther.
´
Patents 2002, 12, 969.
14. Sondhi, S. M.; Singhal, N.; Johar, M.; Narayan Reddy, B.
S.; Lown, J. W. Curr. Med. Chem. 2002, 9, 1045.
22. Ouellet, M.; Falgueyret, J-P.; Percival, M. D. Biochem. J.
2004, 377, 675.
23. Unpublished results.