4-Benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: Optimization and in vitro evaluation against clinically important HIV mutant strains

Article abstract of DOI:10.1021/jm0407658

The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To conduct SAR studies on these two lead compounds, 102 new analogues were p

Full text of DOI:10.1021/jm0407658

J . Med. Chem. 2004, 47, 5501-5514
5501
4-Ben zyl- a n d 4-Ben zoyl-3-d im eth yla m in op yr id in -2(1H)-on es, a New F a m ily of
P oten t An ti-HIV Agen ts: Op tim iza tion a n d in Vitr o Eva lu a tion a ga in st
Clin ica lly Im p or ta n t HIV Mu ta n t Str a in s
Abdellah Benjahad,† Karine Courte´,† J e´roˆme Guillemont,‡ Dominique Mabire,‡ Sophie Coupa,‡ Alain Poncelet,‡
Imre Csoka,‡ Koen Andries,§ Rudi Pauwels,| Marie-Pierre de Be´thune,| Claude Monneret,† Emile Bisagni,†
Chi Hung Nguyen,*,† and David S. Grierson†
UMR 176 CNRS-Institut Curie, Laboratoire de Pharmacochimie, Section de Recherche, Batiment 110, Centre Universitaire,
91405 Orsay, France, J ohnson&J ohnson Pharmaceutical Research and Development, Medicinal Chemistry Department,
Campus de Maigremont BP315, Val de Reuil, France, J ohnson&J ohnson Pharmaceutical Research and Development,
Virology Drug Discovery, Tumhoutseweg 30 B-2340 Beerse, Belgium, and TIBOTEC, Generaal De Wittelaan L 11 B3,
B-2800 Mechelen, Belgium
Received J anuary 5, 2004
The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a
new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To
conduct SAR studies on these two lead compounds, 102 new analogues were prepared. Thirty-
three compounds displayed nanomolar range activity in vitro against wild-type HIV-1, and
among these, 18 were active against the 103N, Y181C, and Y188L mutant strains with IC50
values inferior to 1 µM. Evaluation of this group of analogues against an additional eight single
[100I, 101E, 106A, 138K, 179E, 190A, 190S, 227C] and four double HIV mutant strains [100I
+ 103N, 101E + 103N, 103N + 181C, and 227L + 106A], which are often present in HIV
infected patients, permitted the selection of eight compounds, 17x, 18b, 18c, 18f, 18g, 27, 30,
and 42, which are globally more active than the lead molecules 13/14, emivirine and the
currently used NNRTI, nevirapine. Further comparison of the 3′-CN-substituted benzoylpy-
ridinone compound 18c, and the corresponding 3′-acrylonitrile-substituted analogue 30, to
efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone
analogues displayed a superior inhibition profile in the in vitro cellular assay system. These
results form a solid basis for continued optimization of the pyridinone series.
In tr od u ction
tive inhibitors of RT, binding into a hydrophobic pocket
in the polymerase which is proximal to the catalytic
site.11-14 NNRTI’s, in general, display lower toxicity
than nucleoside-based anti-HIV agents.15,16 However, as
the residues in the hydrophobic binding region are not
implicated in DNA synthesis, resistance develops rapi-
dily to this family of molecules.17-21 Indeed, a single
point mutation can result in cross resistance between
compounds 1-3, precluding, in situations where treat-
ment failure occurs, new regimens where these drugs
are interchanged.22 There is thus a pressing need to
develop new NNRTI type drugs which display a high
level of activity against the clinically relevant HIV
single and multiple mutant strains, and whose phar-
macokinetic/distribution profile are such that lower
doses (single dose per day) are required.
Combination therapy, or HAART (highly active anti-
retroviral therapy) has become the standard in HIV
treatment. Indeed, employing this strategy spectacular
advances have been made for the control of viral levels
in HIV-infected patients.1-3 Thus, in developed coun-
tries, and hopefully soon for the more than 30 million
people in third-world countries contaminanted by HIV,
one can begin to consider HIV infection to be “chronic”
rather than forcibly fatal.
Combination therapy has for the most part involved
the coadministration of nucleoside reverse transcriptase
inhibitors (NRTI’s) and protease inhibitors (PI’s). How-
ever, over the past several years increasing use is being
made of non nucleoside reverse transcriptase inhibitors
(NNRTI’s) in multiple drugs regimens4 in order to
circumvent the serious problems of toxicity, resistance,
and associated side effects (lipodystrophy, hyperlipi-
daemia, etc.) resulting from prolonged use of NRTI +
PI combinations.5-9 Currently, three NNRTI-type in-
hibitors, nevirapine 1, delavirdine 2, and efavirenz 3
are used in clinic.10 These compounds are noncompeti-
Over 30 different families of NNRTI’s have been
developed over the past 14 years.10,23 The marked
structural diversity that is displayed by these molecules,
which in turn reflects a remarkable capacity of the
hydrophobic pocket to accommodate different structural
types, would suggest that there is still a good deal of
opportunity to discover new highly potent non nucleo-
side RT inhibitors. Promising new molecules in the
NNRTI group, which are currently undergoing clinica-
levaluation, include DPC 083 4,24 TMC125 5,25 AG1549
6,26 and GW8248 7.27
* Corresponding author. Phone: 33-1 69 86 30 89. Fax: 33-1 69 07
53 81. E-mail: chi.hung@curie.u-psud.fr.
† UMR 176 CNRS-Institut Curie.
‡ Medicinal Chemistry Department, J ohnson&J ohnson Pharmaceu-
tical Research and Development.
§ Virology Drug Discovery, J ohnson&J ohnson Pharmaceutical Re-
search and Development.
A contribution from our laboratories was the finding
that arylthiopyridinones/benzylpyridinones of general
| TIBOTEC.
10.1021/jm0407658 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/29/2004

5502 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Benjahad et al.
In light of the fact that development of HEPT 8, the
more recent HEPT analogue 9 (emivirine),34 and pyri-
dinone 11 was abandoned22 due to the rapid appearance
of drug resistant strains bearing the Y181C,18 Y188L
and K103N20,41 mutations, a major challenge to the
further optimization of compounds 13/14 is to find
analogues which maintain potent activity against these
principle mutants. As it is phenyl ring in HEPT which
has been shown to interact with these residues in the
hydrophobic pocket,42 our efforts in the pyridinone series
has been directed toward evaluation of the influence of
aryl ring modifications in the C-4 benzyl/benzoyl sub-
stituent in 13 and 14 on anti-HIV activity in in vitro
cell-based assays. Support for this strategy comes from
the observation that the 3′,5′-dimethyl-substituted HEPT
analogue GCA-186 10 is more than 100 times more
active in vitro against the Y181C mutant (IC50 ) 0.18
µM) than HEPT itself.43 At the molecular level, struc-
tural studies on the complex of GCA-186 with wild-type
RT suggest that the two methyl substituents make
additional hydrophobic contact with the residues in the
binding pocket and in particular with the side chain of
Trp229.43 This results in the compound deriving a
smaller fraction of its binding energy from the interac-
tion with the Tyr181 side chain.
In this report we thus present the anti-HIV activity
in cell-based assays of 102 new aryl ring-modified
pyridinone analogues against wild-type HIV (HVTL
IIIB) and the Y181C, Y188L, and K103N mutant strains
(Tables 1-4). Eight compounds 17x, 18b, 18c, 18f, 18g,
27, 30, and 42 were selected from this series and further
evaluated (Table 5) against a larger panel of HIV
mutants including 100I, 101E, 106A, 138K, 179E, 190A,
190S, and 227C, and the four double mutants, 100I +
103N, 101E + 103N, 103N + 181C, and 227L + 106A.
Compounds 18c, 27, 30, and 42 in particular, bearing
a cyano substituent connected either directly to the
phenyl ring or via an acrylonitrile type motif proved to
be highly active against essentially the entire panel of
HIV mutants, displaying an activity profile which is
globally better than that for efavirenz and very consid-
erably improved over that for emivirine and the cur-
rently employed NNRTI nevirapine.
formula 12 are potent inhibitors of wild-type HIV.28,29
Compounds 12 are in many respects hybrids of HEPT
830-34 and the Merck pyridinone 11,35-39 since they
possess the SAr/CH2Ar group of the HEPT’s and pyri-
dinone motif of the latter.29 The more active analogues
in this series inhibit wild-type HIV-1 at nanomolar
concentrations (IC50’s), and recently it has been shown
they may be useful as retrovirocides.40 Preliminary SAR
studies led to the identification of analogues 13 and 14
as lead compounds. Common to both of these molecules
is the presence of the 5-ethyl and 6-methyl substitutu-
ents on the pyridinone ring, and the 3,5-dimethyl
substitution on the aromatic ring.
Ch em istr y
The preparation of the 4-arylmethylpyridinones 17a-y
and the 4-arylketopyridinones 18a -k (Scheme 1; Table
1) involved conversion of 3-cyano-5-ethyl-6-methylpy-
ridin-2(1H)-one 1544 to the 3-pivaloylaminopyridine 16
(six steps on a 20 g scale), and reaction of the ortho-
metalated species generated from this intermediate with
the requisite benzaldehyde derivative.45 Reaction of the
derived carbinol with SnCl2‚2H2O46 proved to be a very
effective means to achieve reductive cleavage of the
benzylic hydroxyl group and both amide and imidate
hydrolysis in a single operation. The derived amines
were subsequently converted in high yields to the
corresponding 3-dimethylamino-substituted compounds
17 under reductive alkylation conditions (HCHO, NaBH3-
CN). Compounds 18 were obtained by MnO2 oxidation
of the carbinol intermediate followed by treatment of
the intermediate ketone with 3 N HCl and reductive
alkylation.
In an identical fashion, analogues 17z-a d , and 18l-n
(Table 2) wherein the aryl ring in the lead compounds

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5503
Sch em e 1a
28 and treated with 3 N HCl, and the liberated aldehyde
function in 29 was engaged in the Wittig-Horner
reaction with diethyl cyanomethylphosphonate to give
a product which was further treated with 6 N HCl and
N,N-dimethylated. In an analogous fashion the acrylate
analogue 31, the diene ester 32, and compounds 35a
and 35d -f were prepared by reaction of aldehyde 29
with the appropriate phosphonate reagent. Note that
for the acrylate analogues 31 and 32 a resesterification
step was required since selective N-pivaloyl/O-methyl
imidate hydrolysis was not achieved. The unsubstituted
styrene 34 was also obtained via a Wittig type reaction
of aldehyde 33, whereas acrylonitrile analogues 35b,c
were more simply accessed by a Knoevenagel condensa-
tion of 33 with malononitrile and ethyl cyanoacetate,
respectively. The acrylonitrile analogues 42 and 43
bearing a methyl substitutent on the â-carbon were also
prepared starting from the ketone analogue 41 via a
Wittig-Horner reaction (Scheme 5).
To further complete the study of the influence of dif-
ferent styrene motifs on the anti-HIV activity of our
pyridinones, aldehyde 29 was converted in three steps
to the phosphonium salt intermediate 38 and condensed
under Wittig conditions with several aliphatic alde-
hydes, benzaldehyde, and a range of heterocyclic alde-
hydes giving analogues 39a -u (Table 3). Note that
when Z/E-isomeric mixtures were formed, the E and Z
isomers were obtained pure after column chromatogra-
phy.
Compounds 44 and 45, wherein the cyano substituent
was separated from the aromatic ring by a two-carbon
linker, were readily obtained by catalytic hydrogenation
of the double bond in acrylonitriles 30 and 35a (Scheme
6). The corresponding compounds 48 and 49 with a one-
carbon linker were prepared by OH f Cl f CN
exchange starting from 36, and either direct treatment
of 46 with hydrochloric acid and subsequent reductive
amination, or alkylation of the anion of 46 with MeI
prior to the hydrolysis and N,N-dimethylation steps
(Scheme 7). Finally, analogues 50 and 51 were prepared
by Mitsunobu reaction of 36 with phenol, and reaction
of 29 with MeMgI (Scheme 8).
a
Conditions: (a) n-BuLi, TMEDA, THF, Aryl-CHO; (b) SnCl2‚
2H2O; (c) (HCHO)n, Na,BH3CN, AcOH; (d) MnO2, toluene; (e) 3 N
HCl.
13/14 was exchanged for a thiazolyl, imidazolyl, indolyl,
pyridyl, quinolyl, thienyl, and furyl motif were prepared
by condensation of the anion of 16 with the appropriate
heterocyclic carboxaldehyde.
To expand the study of the influence of a 3′-nitrogen
substituent on the aromatic ring beyond the dimethyl-
amino and nitro analogues 18k and 18e, the nitro group
in 18e was reduced under Raney Ni-catalyzed hydro-
genation conditions and amine 19 was converted to
compounds 20a -f (Scheme 2, Table 1) by reaction,
respectively, with MeCHO/NaBH3CN, MeCOCl, MsCl,
EtNCO, 4-chlorobutyryl chloride/t-BuOK, and 2,5-
dimethoxytetrahydrofuran. In addition, the cyano group
in 18c was reduced using Raney Ni/H2 giving the
methylamine analogue 21, and the corresponding ac-
etamide 22 (after treatment with AcCl) (Scheme 3).
Using the 3′-bromo analogue 18b as starting material
for a series of Stille coupling reactions compounds
23a -e containing a phenyl, 2-furyl, 2-thiazolyl, 3-py-
ridyl, and phenylethynyl substituent at the 3′-position
of the aryl ring were readily prepared (Scheme 3; Table
1). A Pd(0)-catalyzed coupling reaction was also used
to prepare the Z-configuration acrylonitrile-substituted
analogue 24 (6% isolated yield) from 18b and acryloni-
trile. In view of the interesting activities displayed by
this compound, the corresponding E-acrylonitriles 27
and 30, as well as the more substituted analogues 35a -
f, 42, 48 and acrylates 31, 32, were subsequently
prepared (Scheme 4, 5; Tables 1, 3, and 4).
Resu lts a n d Discu ssion
The pyridinone analogues described in Schemes 1-8
were evaluated in vitro against wild type HIV (HVTL
IIIB, LAI cell line) and against the three principle
mutant strains, 103N, 181C, and 188L, which confer
resistance to the NNRTI’s currently used in clinic.48 The
results are presented in Tables 1-5.
As the data shows, out of the 102 compounds that
were tested, 67 displayed activity with an IC50 value
inferior to 0.1 µM against wild-type HIV, and of these,
33 are active at nanomolar range concentrations. To
select the most interesting molecules in this group their
activities against the three mutant strains were com-
pared.
To prepare 27, the dioxalane 25, obtained by ortho-
metalation of 16 and condensation with the mono-
dioxalane of 1,3-phenyldicarboxaldehyde,47 was treated
with SnCl2‚2H2O, and the derived free amine was N,N-
dimethylated to give compound 26. This intermediate
was then reacted with diethyl cyanomethylphosphonate.
To access analogue 30, compound 25 was oxidized to
Looking first at the data for the compounds in Table
1, one sees that the parent 4-benzylpyridinone 17a (IC50
) 0.004 µM) is equipotent to both lead molecules 13 and
14 against wild type HIV and in fact has a better
selectivity index (SI). However, it was poorly active
against the 188L mutant. Sub-micromolar activities
against wild-type HIV were observed for the mono-

5504 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Ta ble 1. Activity (IC50, µM) versus HIV-1
Benjahad et al.
IC50 (µM)
IC50 (µM)
SIa
103N 181C 188L
compd
R
LAI
SIa
103N
181C
188L compd
R2
LAI
13
3,5-CH3
H
0.008
0.004
0.025
0.002
0.316
0.010
1.585
3.980
0.006
0.006
0.002
0.005
0.004
0.199
1.585
0.004
0.013
1.259
0.100
0.159
0.040
12589
25119
3981
39881
316
10000
6
0.032
0.200
1.259
0.02
12.59
0.398
10
0.1
0.501
1
0.06
10
0.03
10
10
0.251 18a
7.943 18b
7.943 18c
3-CH3
3-Br
3-CN
0.002 39811 nd
0.002 12589 0.02
nd
1.995
17a
17b
17c
17d
17e
17f
17g
17h
17i
0.158 0.794
6310 0.006 0.04 0.398
2-CH3
3-CH3
4- CH3
3-CF3
4- CF3
4-C6H5
2-Cl
2-Br
3-F
3-Cl
3-Br
4-Cl
4-Br
3-OCH3
3-OC2H5
4-N(CH3)2
2,3-CH3
2,5-CH3
3,4-CH3
0.002
3.162
1
nd
18d
18e
4-CN
32 nd
nd
0.2
nd
3.162
3-NO2
3,5-CH3
3,5-Cl
2,6-F
3-F-5-CF3
3-CH3-4-OCH3
3-N(CH3)2
3-NH2
3-N(C2H5)2
3-NHCOCH3
3-NHSO2CH3
3-NHCONHC2H5
3-(1-pyrrolidinyl-2-one) 0.040
3-(1-pyrrolyl)
3-CH2NH2
3-CH2NHCOCH3
3-C6H5
3-(2-furyl)
3-(2-thiazolyl)
3-(3-pyridyl)
3-phenylethinyl
3-CHO
3-CH2OH
3-COCH3
3-CH2CN
3-CH(CH3)CN
3-CH2OPh
0.002 39611 0.02
5.012 18f
0.004
0.002
0.050
2512 0.01
5012 0.013 0.032 0.316
1995 nd
0.063 0.158
nd
nd
18g
18h
3
10
nd
nd
nd
nd
100
nd
10
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
10
nd
15894
15894
39811
19953
25119
50 nd
63 nd
12589 0.1
794 nd
8
200
631
2512
10 100
0.398
0.251
0.063
0.04
0.2
0.794 18i
1.995 18j
1.585 18k
1.585 19
2.512 20a
0.003 31623 nd
0.130
0.16
0.08
0.006
6.31
nd
0.320
nd
10
0.079
0.398
0.012
1.995
0.126
1
200 1.585 100
251 nd nd
2512 0.501 10
50 nd
794 nd
100 nd
50 nd
17j
17k
17l
0.100
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
10
nd
17m
17n
17o
17p
17q
17r
17s
17t
17u
17v
17w
17x
17y
27
nd
nd
20b
20c
0.316 20d
1.995
nd
nd
20e
20f
21
2512 nd
631 nd
251 nd
251 nd
251 nd
158 nd
40 nd
126 0.05
631 nd
2512 0.126 1.259 10
10
2.512
1.995 nd
0.4
0.079
0.398
0.398
0.398
0.063
0.251
0.006
0.158
0.008
0.050
0.010
2.512 nd
nd
nd
nd
nd
22
1
23a
23b
23c
2,4-CH3
2,4,6-CH3
3,5-F
3,5-Cl
3-CH3-4-OCH3
3-CHdCHCN (E)
10
10
0.013
0.008
0.398
100
10
0.1
0.160
nd
0.016
1
7943
3981
10
0.032
0.025
0.501 23d
0.631 23e
251 nd
nd
33
0.0004 25119
0.002
0.158 37
2936 0.364 3.873 18.64
3162 0.126 1.0
41
48
49
50
51
10
0.001 31623 0.006 0.126 1.0
0.003 31623 0.008 0.126 0.251
0.039
0.050
2512 nd
1995 nd
nd
nd
nd
nd
3-CH(OH)CH3
a
Selectivity index or ratio of CC50 to IC50 relative to LAI (fold).
methyl-substituted analogues 17b-d and 18a (IC50’s )
0.316 to 0.002 µM), but only the 3′-Me compound 17c
retained acceptable activity (IC50 ) 1 µM) toward the
188L mutant. Interestingly, with respect to wild-type
HIV, the 2′-Cl- and 2′-Br-substituted analogues 17h and
17i were found to be equipotent to the 3′-halo-substi-
tuted analogues 17j, 17k and 17l/18b. On further
evaluation, however, the 2′-Cl compound 17h (SI )
15894) and the 3′-Br-substituted benzoylpyridinone 18b
were the only compounds that retained activity against
all three mutant strains. Of the remaining 3′-substi-
tuted analogues 17o, 18c, 18e, 23d , 27, 48 and 49
bearing monosubstitution on the phenyl ring, the cyano
compound 18c and the 3′-CH2(Me)CN-substituted ana-
logue 49, and in particular the 3′-acrylonitrile-substi-
tuted compound 27, possessed the best profiles. All three
compounds were active at nanomolar concentrations
against 103N and maintaining good activity against the
181C and 188L mutants.
It is noteworthy that the 2′,3′-, 2′,5′-, and 3′,4′-
dimethyl analogues 17r , 17s, and 17t display submi-
cromolar activities against wild type HIV. However,
from the data for these compounds against the three
mutant strains, and their comparatively low SI’s, it is
clear that these substitution patterns are not optimal
compared to the 3′,5′-positioning of the methyl groups
as found in lead compound 13 and the benzoylpyridi-
none 18f. In fact, analogue 18f was found to be slightly,
but noticably more active than 13. The 3′,5′-F compound
17w and the two 3′,5′-Cl analogues 17x and 18g also
displayed potent activities, comparable to the lead
molecule 13. Earlier SAR studies on the HEPT series
similarily demonstrated that the most active analogues
possessed the 3′,5′ orientation of methyl and halogen
substituents.43,49
In previous work on related arylthiopyridinone-based
anti-HIV agents a number of analogues were synthe-
sized in which the aryl ring was exchanged for different
mono and bis-heterocyclic motifs.28 Unperturbed by the
fact that none of these compounds were active, the
compounds 17z, 17a a -a d , and 18l-n were prepared
and evaluated (Table 2). With the exception of com-
pounds 17a a and 17a d , these analogues were all potent
inhibitors of wild-type HIV replication. In particular the
bromothiophene analogue 18m was highly potent against
wild-type HIV. Overall, however, the N-methylindole
analogue 17a b was the only molecule which combined
activity against wild-type RT and activity against the
188L mutant.
The observation that the 3′-E-acrylonitrile-substituted
analogue 27 is 10 times more potent than lead com-
pound 13 in blocking the replication of wild-type HIV
and the 103N and 181C mutant strains was an impor-
tant finding. The corresponding benzoylpyridinone 30
was consequently tested, and found to display an almost
identical RT inhibition profile (Table 3). Further, the
isomeric 3′-Z-acrylonitrile analogue 24 was found to be
less toxic and 4 times more active against the 188L
mutant.
To optimize the activity of 24 and 27/30, a series of E
and Z-3′-vinyl-substituted benzyloxypyridinone ana-
logues were prepared wherein the CN group was

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5505
Ta ble 2. Activity (IC50, µM) versus HIV-1
compounds 44 and 45 are very poor inhibitors of the
188L HIV mutant, suggesting that the acrylonitrile
motif interacts with this crucial residue HIV in a
structure dependent manner. It has previously been
reported that introduction of sterically bulky substi-
tutents onto the C-2 position of nevirapine gives com-
pounds which retain their capacity to inhibit RT.51
However, the molecular basis for binding of these large
molecules in the hydrophobic pocket of RT was not
detailed.
Summarizing these data, 18 analogues (17c, 17h ,
17o, 17x, 27, 18b, 18c, 18f, 18g, 48, 49, 24, 30, 31, 32,
34, 39i and 42) of the lead molecules 13/14 were found
to display better than 1 µM activity against the Y181C,
K103N, and Y188L mutants.
Further evaluation of this series of compounds against
a larger panel of single [100I, 101E, 106A, 138K, 179E,
190A, 190S, 227C] and double mutant [100I + 103N,
101E + 103N, 103N + 181C and 227L + 106A] strains
revealed that compound 17c was inactive against the
103N + 181C double mutant strain, analogues 17c and
17o were inactive against the 227L + 106A double
mutant, compound 24 failed against 101E + 103N, and
analogues 17h , 48, 31, 32, 34, and 39i were essentially
inactive (IC50 ) 2-10 µM) against the 227C simple
mutant (data not shown). On the basis of these observa-
tions, the eight remaining compounds, 17x, 18b, 18c,
18f, 18g, 27, 30, and 42, were selected. The results for
the evaluation of these analogues against the entire
panel of HIV mutant strains is presented in Table 5.
Included also in this table are the data for the reference
compound 13, the closely related HEPT analogue emivir-
ine (MKC-442), and the two NNRTI’s, nevirapine and
efavirenz, which are currently used in tritherapy regi-
mens.
a
See Table 1.
replaced by hydrogen, CO2Et or its vinylogue CHd
CHCO2Et, alkyl, phenyl, benzyl, and a variety of
heterocycles (pyridyl, pyridazyl, pyrrolyl, thienyl, furyl,
and thiazolyl). Immediately apparent from the results
presented in Table 3 for these molecules is that within
a given Z/E couple of analogues, the Z analogue is
always less active and more toxic (lower SI). Five
molecules (compounds 31, 32, 34, 39a and 39i) in this
series were active at nanomolar concentrations against
wild-type HIV. However, although the 3-pyridyl-sub-
stituted compound 39i possessed the best profile, all five
analogues were at least 10 times less active than the
acrylonitrile leads 27/30 against the 103N and 181C
mutants. Comparison of the activities of compounds 31/
39i with 34/39a with respect to the 188L mutant strain
highlights the importance of the presence of a polar
heteroatom at the extremity of the olefin motif.
Comparing compound 13 to the corresponding ben-
zoylpyridinone 18f, one sees that 18f has improved
activity against all the mutant strains studied and most
noticeably against 181C and the double mutant 103N
+ 181C. On the negative side its selectivity index is
lower. The 3′,5′-Cl analogues 17x and 18g and the 3′-
monobromo compound 18b have profiles which are very
similar to that for 13, an approximate 10 fold gain in
activity being observed for 18g against the 181C and
100I mutants. A marked amelioration in the inhibition
profile was achieved for the 3′-CN analogue 18c. This
molecule is more active than 13 against five of the
mutant strains studied and is vastly superior to both
emerivine and nevirapine. More importantly, it was
equipotent to efavirenz against the 227L + 106A double
mutant. The three new acrylonitrile-substituted ana-
logues 27, 30, and 42 also largely surpass emevirine,
nevirapine, and lead molecule 13 in terms of their
activities. Comparing these molecules to each other one
further sees that benzoylpyridinone 30 has the best
overall profile against the 15 mutant strains. Indeed,
this analogue is active against eight of the fifteen
mutants at nanomolar concentrations. Relative to
efavirenz, compound 30 was 10 times more sensitive
toward the 103N, 100I, 106A, 190A, and 101E + 103N
mutant strains. A substantially larger gain in activity
was observed against the 190S and 100I + 103N
mutants. In contrast, efavirenz is much more efficient
at inhibiting the 227 + 106A double mutant strain, and
In Table 4 the data for the more highly functionalized
acrylonitrile analogues 35a -f, 42, and 43 and the two
double bond reduced analogues 44 and 45 is presented.
Compound 42 with an additional methyl group on the
â-carbon was found to be a potent inhibitor of all four
HIV strains. Furthermore, the selectivity index for this
analogue was remarkably high (SI ) 63 090) when
compared to the values for the unsubstituted acryloni-
trile analogue 30 (10 000) and the unsaturated esters
31 (3162) and 32 (398). As the expected order of
reactivity of these compounds in Michael type addition
reactions reactions50 is 42 < 30 < 31 < 32 the observed
trend in SI values may reflect the metabolic lability of
the acrylonitrile/acrylate motif in these structures. Both

5506 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Benjahad et al.
Sch em e 2a
are uncorrected. Proton NMR spectra were recorded on a
Bruker AC-300 (300 MHz) spectrometer at ambient temper-
ature using internal deuterium lock. Chemical shifts (δ) were
reported in ppm units (s, d, t, q, m, and br for singlet, doublet,
triplet, quadruplet, multiplet, and broad, respectively). El-
emental analyses, performed by the “Service Central de
Microanalyze du CNRS” Gif-sur-Yvette (France), were within
0.4% of the theoretical values calculated for C, H, and N.
P r ep a r a tion of 4-Ar ylm eth yl-3-d im eth yla m in op yr id i-
n on es 17a -a d : 4-[(3-Met h ylp h en yl)m et h yl]-5-et h yl-6-
m eth yl-3-dim eth ylam in opyr idin -2(1H)-on e 17c: Exam ple
of th e Gen er a l Meth od . Step 1: Lith ia tion /Con d en sa tion
w ith Ar CHO. n-Butyllithium (1.6 M in hexane, 62.5 mL, 100
mmol) was added dropwise at -78 °C to a solution of 16 (10.0
g, 40 mmol)45 and TMEDA (15 mL, 100 mmol) in THF (150
mL) under nitrogen. The mixture was stirred at 0 °C for 1 h
and then cooled to -78 °C. A solution of the m-tolualdehyde
(10.6 g, 88 mmol) in THF (150 mL) was added dropwise, and
the mixture was stirred at 0 °C for 3 h. This was followed by
addition of H2O and extraction with Et2O. The combined
organic layers were dried (MgSO4), filtered, and concentrated
under vacuum. The residue was crystallized from cyclohexane.
N-[4-[(3-Methylphenyl)hydroxymethyl]-5-ethyl-2-methoxy-6-
methylpyridin-3-yl]-2,2-dimethylpropanamide (9.5 g, 62%) was
a
Conditions: (a) H2, Raney Ni; (b) CH3CHO, NaBH3CN for 20a ;
CH3COCl for 20b; ClSO2CH3 for 20c; EtNCO for 20d ; 4-chlorobu-
tyryl chloride and then t-BuOK for 20e; 2,5-dimethoxytetrahy-
drofuran for 20f.
Sch em e 3
1
obtained as a white solid mp 174 °C; H NMR (DMSO-d6) δ
0.73 (3 H, t, J ) 7.5 Hz), 1.06 (9 H, s), 2.23 (3 H, s), 2.37 (3 H,
s), 2.44-2.67 (2 H, m), 3.79 (3 H, s), 6.03 (1 H, d, J ) 2.6 Hz),
6.17 (1 H, d, J ) 2.6 Hz), 6.99 (1 H, d, J ) 7.9 Hz), 7.02-7.18
(3 H, m), 8.60 (1 H, br s).
Step 2: Rea ction w ith Tin (II) Ch lor id e. A mixture of
the above carbinol intermediate (9.2 g, 25 mmol), tin(II)
chloride dihydrate (22.5 g, 100 mmol), and 12 N HCl (0.35 mL)
in HOAc (80 mL) was stirred at 100 °C overnight and then
poured into ice-water and basified using concentrated NH4-
OH. The mixture was then filtered through Celite and
extracted with CH2Cl2. The combined organic layers were dried
(MgSO4), filtered, and concentrated under vacuum. The resi-
due was silica gel column chromatographed (CH2Cl2/MeOH/
NH4OH 97/3/0.1 and 90/10/0.1), and the concentrated product
fractions were triturated with Et2O providing 3-amino-5-ethyl-
6-methyl-4-[(3-methylphenyl)methyl]pyridin-2(1H)-one (3.5 g,
55%) as a pale yellow solid mp 207 °C; 1H NMR (DMSO-d6) δ
0.85 (3 H, t, J ) 7.5 Hz), 2.08 (2 H, q, J ) 7.5 Hz), 2.15 (3 H,
s), 2.40 (3 H, s), 2.56 (6 H, s), 3.94 (2 H, s), 6.60 (1 H, d, J )
7.9 Hz), 7.00-7.10 (2 H, m), 7.20 (1 H, d, J ) 7.9 Hz), 11.35 (1
H, br s).
Step 3: N-Meth yla tion . Sodium cyanoborohydride (1.8 g,
29 mmol) was added at room temperature (RT) under nitrogen
to a solution of the derived 3-aminopyridinone (2.5 g, 9.7 mmol)
and formaldehyde (37% in H2O, 97 mmol) in acetonitrile (65
mL). Acetic acid (1 mL) was added, and the reaction was
stirred at RT for 2 h. Additional HOAc (1 mL) was then added,
and stirring was continued at RT for 30 min, before pouring
the mixture into H2O and basifying with 10% aqueous K2CO3.
The precipitate was collected, washed several times with H2O,
and dried. Compound 17c (2.33 g, 85% step 3; 29% from 16)
was obtained as a white solid mp 165 °C; 1H NMR (DMSO-d6)
δ 0.78 (3 H, t, J ) 7.4 Hz), 2.12-2.24 (8 H, m), 2.62 (6 H, s),
4.00 (2 H, s), 6.81 (1 H, d, J ) 7.9 Hz), 6.90 (1 H, s), 6.97 (1 H,
d, J ) 7.9 Hz), 7.13 (1 H, t, J ) 7.9 Hz), 11.35 (1 H, br s).
Anal. (C18H24N2O) C, H, N.
a
Conditions (left): (a) H2, Raney Ni; (b) CH3COCl. aConditions
(right): (a) Pd(PPh3)4, R-SnR′3; (b) Pd(PPh3)4, Acrylonitrile.
although 30 is a potent inhibitor of the 181C mutant
(IC50 ) 0.016 µM), it is 10 times weaker than efavirenz
against this crucial HIV mutant. Overall, the data
indicates that benzoylpyridinones 18c and 30 have a
better anti-HIV profile in the cellular assays than
efavirenz.
This study has permitted the identification of two new
lead compounds in the 4-benzoylpyridinone series 18c
and 30. These molecules are potent inhibitors of wild
type HIV-1, as well as a large range of HIV-1 mutant
strains which are responsible for the onset of resistance
to the NNRTI’s that are currently used in HAART
therapy. Interestingly, their activity against wild-type
HIV virus was not predictive of their broad spectrum,
illustrating the necessity for inclusion of both wild type
and mutant viruses in screening panels. It is remark-
able that these compounds were found by simple
modulation of the substituents on the phenyl ring in
the pyridinone lead compounds 13 and 14. These results
form a solid basis for continued exploration of the
pyridinone family of RT inhibitors and in particular
modifications of the C-3, C-5, and C-6 centers on the
pyridinone ring.
Exp er im en ta l Section
P r ep a r a tion of 4-Ar oyl-3-d im eth yla m in op yr id in on es
18a -n : 5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-4-(3-m eth -
ylben zoyl)p yr id in -2(1H)-on e 18a : Exa m p le of th e Gen -
er a l Met h od . St ep 1: Lit h ia t ion /Con d en sa t ion w it h
Ar CHO. As described for 17c (0.3 mol scale, 70% yield).
Step 2: Oxid a tion . MnO2 (20 g, 230 mmol) was added
portionwise at RT to a solution of N-[4-[(3-methylphenyl)-
hydroxymethyl]-5-ethyl-2-methoxy-6-methylpyridin-3-yl]-2,2-
dimethylpropanamide (16.6 g, 45 mmol) in toluene (200 mL).
The mixture refluxed overnight, filtered through Celite, and
concentrated under vacuum. The residue was crystallized from
Et2O to give N-[4-(3-methylbenzoyl)-5-ethyl-2-methoxy-6-me-
thylpyridin-3-yl]-2,2-dimethyl-propanamide (15.2 g, 92%) as
Ch em istr y. Gen er a l Rem a r k s. All solvents were reagent
grade. Diethyl ether and tetrahydrofuran (THF) were distilled
from sodium/benzophenone under argon. Acetonitrile and
dichloromethane (CH2Cl2) were distilled from calcium hydride.
Triethylamine was distilled from calcium hydride and stored
over potassium hydroxide. N,N-Dimethylformamide (DMF)
was purchased from Aldrich and used without purification
unless otherwise noted. All reactions were monitored by thin-
layer chromatography (TLC) using E. Merk 60F254 procoated
silica gel plates. Flash column chromatography was performed
with the indicated solvents and using E. Merk silica gel 60
(particle size 0.035-0.070 mm unless otherwise stated). Melt-
ing points were taken on a Kofler melting point apparatus and

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5507
Sch em e 4a
a
Conditions: (a) n-BuLi, TMEDA, THF; (b) SnCl2‚2H2O; (c) (HCHO)n, NaBH3CN,AcOH; (d) (EtO)2POCH2CN, t-BuOK; (e) KMnO4,
TDA-1 (f) aq HCl, 20 °C; (g) aq HCl, 100 °C; (h) (EtO)2POCH2R, t-BuOK; (i) SOCl2, EtOH (j) CH3PPh3Br, n-BuLi; (k) (EtO)2POCHRCN,
t-BuOK; (l) RCH2CN, LDA; (m) NaBH4; (n) SOCl2 and then PPh3; (o) t-BuOK, RCHO.
Sch em e 5a
and washed with CH2Cl2, and the filtrate was evaporated
under reduced pressure. The residue was taken up in CH2-
Cl2, and the solution was washed with water, dried over
MgSO4, filtered, and concentrated. The crude product (1 g) was
crystallized from water and triturated with Et2O providing
compound 19 (0.11 g, 12%) as a white solid mp 252 °C; 1H
NMR (DMSO-d6) δ 0.82 (3 H, t, J ) 7.4 Hz), 1.80-2.15(2 H,
m), 2.18 (3 H, s), 2.47 (6 H, s), 5.37 (2 H, s), 6.80 (1 H, d, J )
8.0 Hz), 6.90 (1 H, d, J ) 8.0 Hz), 7.00 (1 H, s), 7.15 (1 H, t, J
) 8.3 Hz), 11.60 (1 H, br s). Anal. (C17H21N3O2‚0.25H2O) C, H,
N.
a
Conditions: (a) 6 N HCl; (b) (HCHO)n, NaBH3CN HOAc; (c)
5-E t h yl-4-(3-d iet h yla m in ob en zoyl)-6-m et h yl-3-d im e-
th yla m in op yr id in -2(1H)-on e 20a . Sodium cyanoborohydride
(130 mg, 2 mmol) was added at RT under nitrogen to a solution
of 19 (200 mg, 0.67 mmol) and acetaldehyde (300 mg, 6.8
mmol) in acetonitrile (10 mL). Acetic acid (0.22 mL) was added,
and the mixture was stirred at RT for 2 h. Additional HOAc
(0.22 mL) was then added, and after continued stirring for 1
h, the mixture was poured into 10% aqueous K2CO3 and
extracted with ethyl acetate. The combined organic layers were
dried (MgSO4) and concentrated. The residue was silica gel
column chromatographed (CH2Cl2/CH3OH 97/3). Subsequent
crystallization from CH3CN afforded 20a (106 mg, 44%) as a
white solid mp 228 °C; 1H NMR (CDCl3) δ 0.96 (3 H, t, J ) 7.5
Hz), 1.20 (6 H, t, J ) 7.1 Hz), 2.08-2.32(2 H, m), 2.36 (3 H, s),
2.67 (6 H, s), 3.42 (4 H, q, J ) 7.1 Hz), 6.90 (1 H, dd), 6.99 (1
H, d, J ) 8.0 Hz), 7.21-7.32 (2 H, m), 12.56 (1 H, br s). Anal.
(C21H29N3O2‚0.25H2O) C, H.
4-(3-Acetylam in oben zoyl)-5-eth yl-6-m eth yl-3-dim eth yl-
a m in op yr id in -2(1H)-on e 20b. Acetyl chloride (170 mg, 2.2
mmol) in CH2Cl2 (5 mL) was added dropwise at 5 °C to a
solution of 19 (600 mg, 2 mmol) and triethylamine (220 mg,
2.2 mmol) in CH2Cl2 (5 mL). The mixture was stirred at RT
for 4 h, followed by addition of H2O and extraction with CH2-
Cl2. The combined organic layers were dried (MgSO4) and
concentrated. The residue was silica gel column chromato-
graphed (CH2Cl2/CH3OH/NH4OH 95/5/0.1). Trituration with
Et2O afforded 20b (96 mg, 14%) as a pale yellow solid mp 268
°C; 1H NMR (DMSO-d6) δ 0.81 (3 H, t, J ) 7.4 Hz), 1.80-2.20
(2 H, m), 2.04 (3 H, s), 2.46 (6 H, s), 7.40-7.50 (2 H, m), 7.85-
7.95 (1 H, m), 7.99 (1 H, s), 10.11 (1 H, br s), 11.67 (1 H, br s).
Anal. (C19H23N3O3‚0.75H2O) C, H, N.
(EtO)2POCHRCN/t-BuOK.
1
a white powder mp 120 °C; H NMR (DMSO-d6) δ 0.78 (9 H,
s), 0.95 (3 H, t, J ) 8.8 Hz), 2.35 (8 H, m), 3.84 (3 H, s), 7.48
(4 H, m), 8.64 (1 H,br s).
Step 3: N-P iva loyl/O-Meth yl Im id a te Clea va ge. A solu-
tion of the propanamide intermediate (14 g, 38 mmol) in 6 N
HCl (140 mL) was refluxed for 2 h and then poured into ice-
water, basified with concentrated NH4OH, and extracted with
CH2Cl2. The combined organic layers were dried (MgSO4), and
concentrated under vacuum. The residue was crystallized from
Et2O to give 3-amino-5-ethyl-6-methyl-4-(3-methylbenzoyl)-
pyridin-2(1H)-one (6.36 g, 62%) as a white solid mp 202 °C;
1H NMR (DMSO-d6) δ 0.93 (3 H, t, J ) 8.8 Hz), 2.23 (2 H, q,
J ) 8.8 Hz), 2.32 (3 H, s), 2.43 (3 H, s), 4.17 (2 H, s), 7.4 (2 H,
m), 7.73 (2 H, m), 12.70 (1 H, br s).
Step 4: N-Meth yla tion . The intermediate 3-aminopyridi-
none (3.51 g, 13 mmol) was methylated as described for 17c.
The crude product was silica gel column chromatographed
(CH2Cl2/MeOH/NH4OH 98/2/0.1) and the product fractions
were triturated with Et2O to give 18a as a pale yellow solid
(1.16 g, 30%; 12% overall from 16), mp 225 °C; 1H NMR
(CDCl3) δ 0,95 (3 H, t, J ) 7.4 Hz), 2.00-2.30 (2 H, m), 2.37 (3
H, s), 2.44 (3 H, s), 2.63 (3 H, s), 7.30-7.40 (2 H, m), 7.62 (1
H, d, J ) 7.9 Hz), 7.74 (1 H, s), 13.10 (1 H, br s). Anal.
(C18H22N2O2‚0.25H2O) C, H, N.
4-(3-Am in ob en zoyl)-5-et h yl-6-m et h yl-3-d im et h yla m i-
n op yr id in -2(1H)-on e 19. A solution of 18e (1.00 g, 3 mmol)
in MeOH/NH3 (7 N, 10 mL) was hydrogenated at RT under 3
atm of H2 for 1 h, using Raney nickel (1 g) as the catalyst.
The catalyst was then removed by filtration through Celite

5508 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Ta ble 3. Activity (IC50, µM) versus HIV-1
Benjahad et al.
Sch em e 6
Sch em e 7a
a
Conditions: (a) SOCl2; (b) NaCN; (c) t-BuOK, MeI; (d) 6 N
HCl; (e) (HCHO)n, NaBH3CN, AcOH.
Sch em e 8a
a
Conditions: (a) CH3MgI; (b) 6 N HCl; (c) (HCHO)n, NaBH3CN,
HOAc; (d) DEAD, PPh3, C6H5OH.
Hz), 1.82-2.18 (2 H, m), 2.19 (3 H, s), 2.47 (6 H, s), 3.10 (2 H,
m), 6.1 (1 H, br s), 7.24-7.41 (2 H, m), 6.80 (1 H, d, J ) 8.0
Hz), 7.85 (1 H, s), 8.71 (1 H, br s), 11.69 (1 H, br s). Anal.
(C20H26N4O3) C, H, N.
5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-4-[3-(2-oxo-p yr r o-
lid in -1-yl)ben zoyl]p yr id in -2(1H)-on e 20e. A mixture of
4-chlorobutyryl chloride (410 mg, 2.9 mmol) in CH2Cl2 (4 mL)
was added at 5 °C to a solution of 19 (600 mg, 2 mmol) in
CH2Cl2 (26 mL) and triethylamine (0.41 mL; 2.9 mmol). The
mixture was stirred at room temperature for 6 h and then
poured into water. After extraction with CH2Cl2, the organic
layer was dried (MgSO4) and concentrated. The residue was
silica gel column chromatographed (CH2Cl2/CH3OH/NH4OH
90/10/0.1) to afford the chloroamide intermediate. Potassium
tert-butoxide (0.47 g; 4.2 mmol) was added portionwise at 0°C
under nitrogen to a solution of this chloroamide intermediate
in THF (20 mL). The mixture was stirred at room temperature
for 3 h, poured out on ice and extracted with EtOAc. The
organic layer was separated, dried (MgSO4), concentrated,
washed with diethyl ether, and dried to afford 20e (600 mg,
82%) as a pale yellow solid mp 240 °C (Et2O); 1H NMR (CDCl3)
δ 0.95 (3 H, t, J ) 7.4 Hz), 2.05-2.35 (4 H, m), 2.36 (3 H, s),
2.63-2.70 (8 H, m), 3.90-4.00 (2 H, m), 7.48 (1 H, t, J ) 8
a
See Table 1.
Following this protocol, compound 19 was reacted separately
with methanesulfonyl chloride and ethyl isocyanate (triethyl-
amine is not needed for 20d ) to give products 20c and 20d .
Compound 20c: 28% yield; mp 259 °C (Et2O); 1H NMR
(DMSO-d6) δ 0.82 (3 H, t, J ) 6.5 Hz), 1.76-2.25 (2 H, m),
2.20 (3 H, s), 2.46 (6 H, s), 3.00 (3 H, s), 7.40-7.55 (3 H, m),
7.63 (1 H, s), 9.98 (1 H, br s), 11.71 (1 H, br s). Anal.
(C18H23N3O4S‚0.25H2O) C, H, N.
Compound 20d : 70% yield; mp > 260 °C (CH3CN); 1H NMR
(DMSO-d6) δ 0.82 (3 H, t, J ) 7.3 Hz), 1.05 (3 H, t, J ) 7.1

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5509
Ta ble 4. Activity (IC50, µM) versus HIV-1
(triphenylphosphine)palladium (80 mg) in dioxane (5 mL) was
stirred at 80°C for 8 h. Water was then added, and the mixture
was extracted with CH2Cl2. The combined organic layers were
dried (MgSO4) and concentrated. The residue was silica gel
column chromatographed (CH2Cl2/CH3OH/NH4OH 97/3/0.1).
Crystallization from CH3CN afforded 23a (140 mg, 28%) as a
white solid mp 236 °C; 1H NMR (DMSO-d6) δ 0.83 (3 H, t, J )
7.0 Hz), 1.85-2.25 (2 H, m), 2.20 (3 H, s), 2.49 (6 H, s), 7.35-
7.55 (3 H, m), 7.60-7.70 (3 H, m) 7.70-7.80 (1 H, m), 7.92-
8.2 (2 H, d, J ) 8.0 Hz), 11.73 (1 H, br s). Anal. (C23H24N2O2)
C, H, N.
(Z)-3-[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-
1,2-dih ydr opyr idin -4-yl-car bon yl)ph en yl]acr ylon itr ile 24.
Tetrakis(triphenylphosphine)palladium(0) (200 mg), triethyl-
amine (33 mL), and acrylonitrile (1.9 g, 36 mmol) were
sequentially added at RT under nitrogen to a solution of bromo
derivative 18b (6.7 g, 18 mmol) and triphenylphosphine (4.9
g, 18.7 mmol) in DMF (150 mL). The mixture refluxed
overnight. Water was added, and the mixture was extracted
with EtOAc. The combined organic layers were dried (MgSO4),
and concentrated. The residue was silica gel column chro-
matographed (CH2Cl2/CH3OH 97/3). Crystallization from CH3-
1
CN provided 24 (0.35 g, 6%) as a white solid mp 107 °C; H
NMR (DMSO-d6) δ 0.83 (3 H, t, J ) 7.4 Hz), 1.85-2.15 (2 H,
m), 2.19 (3H, s), 2.45 (6 H, s), 5.98 (1 H, t, J ) 12.0 Hz), 7.54
(1 H, d, J ) 12.0 Hz), 7.69 (1 H, d, J ) 8.8 Hz), 7.80 (1 H, d,
J ) 8.8 Hz), 8.05 (1 H, d, J ) 8.8 Hz), 8.29 (1 H, s), 11.7 (1 H,
br s). Anal. (C20H21N3O2) C, H, N.
N-[4-[[3-(1,3)Dioxola n -2-yl-p h en yl]h yd r oxym eth yl]-5-
eth yl-2-m eth oxy-6-m eth ylp yr id in -3-yl]-2,2-d im eth ylp r o-
p ion a m id e 25. n-Butyllithium (1.6 M in hexane, 62.5 mL, 100
mmol) was added dropwise at -78 °C to a solution of 16 (10.0
g, 40 mmol) and TMEDA (15 mL, 100 mmol) in THF (150 mL)
under nitrogen. The mixture was stirred at 0 °C for 1 h and
recooled to -78 °C before dropwise addition of a solution of
the 3-[(1,3)dioxolan-2-yl]benzaldehyde (19 g, 0.107 mol)47 in
THF (150 mL). The mixture was stirred at 0 °C for 3 h,
followed by addition of H2O and extraction with Et2O. The
combined organic layers were dried (MgSO4) and concentrated.
The residue was triturated with Et2O to give 25 (11.7 g, 69%
yield) as a white solid in essentially pure form mp 168 °C.
3-[(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-1,2-d i-
h yd r op yr id in )-4-ylm eth yl]ben za ld eh yd e 26. Reaction of
25 (11.7 g, 27 mmol) with SnCl2‚2H2O as described for 17c
gave the intermediate 3-[(3-amino-5-ethyl-6-methyl-2-oxo-1,2-
dihydropyridin)-4-yl-methyl]benzaldehyde (1.8 g, 24%) which
was followed by N-methylation reaction gave 26 (0.4 g, 20%)
as a solid; 1H NMR (DMSO-d6) δ 0.78(3 H, t, J ) 7.4 Hz), 2.14
(3H, s), 2.21 (2 H, q, J ) 7.4 Hz), 2.61 (6 H, s), 4.16 (2H, s),
7.44 (1 H, d, J ) 8.8 Hz), 7.51 (1 H, t, J ) 8.8 Hz), 7.59 (1 H,
s), 7.73 (1 H, d, J ) 8.8 Hz), 9.97 (1 H, s), 11.4 (1 H, br s).
a
See Table 1.
Hz), 7.58 (1 H, d, J ) 8.0 Hz), 7.96 (1 H, s), 8.20 (1 H, d, J )
8.3 Hz), 13.00 (1 H, br s). Anal. (C21H25N3O3) C, H, N.
5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-4-[3-(1-p yr r olyl)-
ben zoyl]p yr id in -2(1H)-on e 20f. 2,5-Dimethoxytetrahydro-
furan (80 mg, 0.6 mmol) was added at RT to a solution of 19
(150 mg, 0.5 mmol) in acetic acid (5 mL). The mixture was
refluxed for 20 min and then poured into cold 10% aqueous
K2CO3 and extracted with EtOAc. The combined organic layers
were dried (MgSO4) and concentrated. The residue was silica
gel column chromatographed (CH2Cl2/CH3OH/NH4OH 97/3/
0.1). Trituration with Et2O afforded 20f (38 mg, 25%) as a
white powder mp 240 °C; 1H NMR (CDCl3) δ 0.95 (3 H, t, J )
7.4 Hz), 2.05-2.35 (4 H, m), 2.36 (3 H, s), 2.63-2.70 (8 H, m),
3.90-4.00 (2 H, m), 7.48 (1 H, t, J ) 8.0 Hz), 7.58 (1 H, d, J )
8.0 Hz), 7.96 (1 H, s), 8.20 (1 H, d, J ) 8.3 Hz), 13.00 (1 H, br
s). Anal. (C21H25N3O2‚0.33H2O) C, H, N.
(E)-3-[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-
1,2-d ih yd r op yr id in -4-ylm eth yl)p h en yl]a cr ylon itr ile 27.
Potassium tert-butoxide (0.54 g; 4.8 mmol) was added portion-
wise at 5 °C under nitrogen to a mixture of diethyl cyano-
methylphosphonate (0.85 g, 4.8 mmol) in THF (20 mL). The
mixture was stirred at room temperature for 30 min and then
the aldehyde 26 (1.3 g, 4.3 mmol) in THF (5 mL) was added.
After 2 h at room temperature, water was added and the
mixture was extracted with EtOAc. The organic layer was
separated, dried (MgSO4), and concentrated. The acrylonitrile
derivative 27 was crystallized from CH3CN to give a white
4-[3-(Am in om eth yl)ben zoyl]-5-eth yl-6-m eth yl-3-d im e-
th yla m in op yr id in -2(1H)-on e 21. A solution of 18c (300 mg,
1 mmol) in methanol/NH3 (7 N, 30 mL) was hydrogenated
under 3 atm of H2 for 3 h at RT, using Raney nickel (0.3 g) as
the catalyst. The catalyst was removed by filtration through
Celite, washed with methanol, and the filtrate was concen-
trated. The residue was silica gel column chromatographed
(CH2Cl2/CH3OH/NH4OH 93/7/0.5). Crystallization from CH3-
CN afforded 21 (130 mg, 43%) as a pale yellow solid mp 236
°C; 1H NMR (DMSO-d6) δ 0.82 (3 H, t, J ) 7.4 Hz), 1.80-2.25
(2 H, m), 2.19 (3 H, s), 2.46 (6 H, s), 3.79 (2 H, s), 7.46 (1 H, t,
1
powder (0.36 g; 26%), mp 214 °C; H NMR (DMSO-d6) δ 0.77
J
) 8.3 Hz), 7.52-7.62 (2 H, m), 7.83 (1 H, s). Anal.
(3 H, t, J ) 7.4 Hz), 2.13 (3 H, s), 2.19 (2 H, q), 2.61 (6 H, s),
4.09 (2 H, s), 6.41 (1 H, d, J ) 16.7 Hz), 7.10 (1 H, d, J ) 8.8
Hz), 7.31-7.38 (2 H, m), 7.50 (1 H, d, J ) 8.8 Hz), 7.64 (1 H,
d, J ) 16.7 Hz), 11.4 (1 H, br s). Anal. (C20H23N3O) C, H, N.
(C18H23N3O2) C, H, N.
4-[3-(Acetyla m in om eth yl)ben zoyl]-5-eth yl-6-m eth yl-3-
d im eth yla m in op yr id in -2(1H)-on e 22. This compound was
prepared from 21 as described for 20b (white solid, 57% yield),
1
mp 214 °C; H NMR (DMSO-d6) δ 0.81 (3 H, t, J ) 7.1 Hz),
N-[4-[3-(1,3)Dioxola n -2-ylben zoyl]-5-eth yl-2-m eth oxy-
6-m eth ylp yr id in -3-yl]-2,2-d im eth ylp r op ion a m id e 28. To
a solution of 25 (8.1 g, 19 mmol) in CH2Cl2 (100 mL) at RT
were added tri[2-(2-methoxyethoxy)ethyl]amine (1.4 mL, 4.4
mmol) and KMnO4 (11.8 g, 75 mmol). The mixture was stirred
at RT for 12 h, filtered through Celite, and washed with CH2-
Cl2. The filtrate was washed with H2O, dried over MgSO4, and
1.75-2.25 (8 H, m), 2.45 (6 H, s), 4.31 (2 H, d, J ) 5.6 Hz),
7.40-7.68 (3 H, m), 7.72 (1 H, s), 8.45 (1 H, br m), 11.70 (1 H,
br s). Anal. (C20H25N3O3‚0.33H2O) C, H, N.
5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-4-(3-p h en ylb en -
zoyl)p yr id in -2(1H)-on e 23a . A mixture of18b (510 mg, 1.4
mmol), tributylphenyltin (770 mg, 2.1 mmol), and tetrakis-

5510 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Ta ble 5. Activity (IC50, µM) versus HIV-1
Benjahad et al.
100I
101E
103N
227L
compd
LAI
SIa
103N 181C
188L
0.631 0.05 nd
0.794 0.02 0.014 nd
0.398 0.01 0.007 nd
100I 101E 106A 138K 179E 190A 190S 227C + 103N + 103N + 181C + 106A
17x
18b
18c
18f
18g
27
30
42
13
0.008
0.002 12589 0.02
0.002
0.004
0.002
0.0004 25119 0.002 0.016
0.001 10000 0.002 0.016
0.001 63096 0.003 0.063
0.008 12589 0.032 0.1
3981 0.025 0.160
nd
nd
nd
nd
nd
0.701 0.316
0.005 0.005 0.007 0.003 0.264 0.075
0.004 0.004 0.005 0.002 0.225 0.039
0.200
0.074
0.028
0.013
0.040
0.025
0.016
0.025
nd
0.501
0.974
0.111
0.158
0.158
0.032
0.04
0.2
0.794
100
0.501
0.1
0.158
6310 0.006 0.04
2512 0.01 0.063
5012 0.013 0.032
0.05
0.398
0.06
3.162
1
1.259
nd
100
0.158 0.006 0.008 0.006 0.005 0.002 0.013 0.004 0.631 0.04
0.316 0.008 0.012 nd 0.017 0.014 0.011 0.003 0.631 0.501
0.158 0.01 0.006 0.002 0.003 0.001 0.008 0.04 0.398 0.032
0.158 0.006 0.008 0.002 0.005 0.001 0.006 0.006 0.794 0.025
0.398 0.01 0.008 0.003 0.004 0.002 0.006 0.01 1.259 0.04
0.251 0.05 0.016 0.04 nd
nd
0.063 nd
nd
nd
EMVb 0.008
NVPb 0.032
1259 0.794 1.995 39.81 0.04 0.126 1.995 0.079 0.032 1.585 7.943 79.43 25.12
5012 6.310 10 100 0.316 0.316 5.012 0.050 0.195 7.943 0.044 0.135 1.452
0.002 0.158 0.04 0.006 0.04 0.002 0.005 0.01 0.251 0.158 10
7.943
0.509
0.158
100
0.04
0.163
0.025
EFVb 0.001 10000 0.04
a
b
See Table 1. EMV, emivirine; NVP, nevirapine; EFV, efavirenz.
concentrated to afford 28 (5.9 g, 73%) which was used in the
next step without any further purification.
were dried (MgSO4) and concentrated to afford ethyl ester
derivative (0.95 g, 99%) as a pale yellow solid.
N-[5-Eth yl-4-(3-for m ylben zoyl)-2-m eth oxy-6-m eth ylp y-
r id in -3-yl]-2,2-d im eth ylp r op ion a m id e 29. A solution of
ketone 28 (5.9 g, 14 mmol) in 3 N HCl (60 mL) was stirred at
RT for 1 h. The mixture was then poured into ice-water,
basified using solid K2CO3, and extracted with CH2Cl2. The
combined organic layers were dried (MgSO4), and concentrated
to afford 29 (5.3 g, 100%) as a white solid.
(E)-3-[3-(5-eth yl-6-m eth yl-3-(d im eth yla m in o)-2-oxo-1,2-
d ih yd r op yr id in -4-yl-ca r b on yl)p h en yl]a cr ylon it r ile 30.
Step 1: Wittig-Hor n er Rea ction . Potassium terbutoxide
(0.64 g, 5.7 mmol) was added at 5 °C under nitrogen to a
solution of diethyl cyanomethylphosphonate (1.0 g, 5.7 mmol)
in THF (30 mL), and the mixture was stirred at 5 °C for 30
min. A solution of the benzaldehyde derivative 29 (2.0 g, 5.2
mmol) in THF (10 mL) was added dropwise, and the reaction
was stirred at 5 °C for 1 h and then brought to RT before
addition of H2O and extraction with EtOAc. The combined
organic layers were dried (MgSO4) and concentrated. The
residue was recrystallized from CH3CN to afford the interme-
diate N-{4-[3-(2-cyanovinyl)benzoyl]-5-ethyl-2-methoxy-6-me-
thylpyridin-3-yl}-2,2-dimethylpropionamide (0.85 g, 40%) as
a white solid.
Step 2: N-P iva loyl/O-Meth yl Im id a te Clea va ge. As
described for 18a , the intermediate N-(2-methoxypyridin-3-
yl)-dimethylpropionamide obtained above (0.79 g, 1.9 mmol)
was converted to 3-[3-(3-amino-5-ethyl-6-methyl-2-oxo-1,2-
dihydropyridin-4-yl-carbonyl)phenyl]acrylonitrile (0.53 g, 88%)
as a white solid.
Step 3: N-Meth yla tion . As described for 17c, the 3-ami-
nopyridinone intermediate (0.46 g, 1.5 mmol) obtained above
was converted to 30 as a white solid (0.21 g, 42% step 3; 15%
yield for the three steps), mp 240 °C; 1H NMR (CDCl3) δ 0.96
(3 H, t, J ) 7.4 Hz), 2.50-2.35 (2 H, m), 2.38 (3 H, s), 2.60 (6
H, s), 6.00 (1 H, t, J ) 16.7 Hz), 7.48 (1 H, d, J ) 16.7 Hz),
7.60 (1 H, d, J ) 8.8 Hz), 7.70 (1 H, d, J ) 8.8 Hz), 7.85 (1 H,
d, J ) 8.8 Hz), 8.03 (1 H, s), 13.10 (1 H, br s). Anal.
(C20H21N3O2) C, H, N.
Step 4: N-Meth yla tion . As described for 17c, the com-
pound 31 (0.28 g, 38%) was obtained as a white powder (20%
overall yield from dioxolane 25), mp 221 °C (CH3CN); 1H NMR
(DMSO-d6) δ 0.82 (3 H, t, J ) 4.0 Hz), 1.27 (3 H, t, J ) 7.1
Hz), 1.8-2.2 (2 H, m), 2.2 (3 H, s), 2.44 (6 H, s), 4.2 (2 H, q, J
) 7.1 Hz), 6.7 (1 H, d, J ) 16.2 Hz), 7.6 (1 H, t, J ) 7.9 Hz),
7.78 (1 H, d, J ) 16.8 Hz), 7.81 (1 H, d, J ) 8.8 Hz), 8.0-8.1
(2 H, m), 11.7 (1 H, br s). Anal. (C22H26N2O4) C, H, N.
(E,E)-Eth yl 5-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-
2-oxo-1,2-d ih yd r op yr id in -4-yl-ca r b on yl)p h en yl]p en t a -
2,4-d ien en oa te 32. Following the procedure for 31, compound
29 was reacted with the potassium anion of triethyl 4-phospho-
nocrotonate, folllowed by acid treatment, reesterification, and
N-methylation. Compound 32, a white powder, was prepared
in 22% overall yield from 25 mp 239 °C (CH3CN); 1H NMR
(CDCl3) δ 0.96 (3 H, t, J ) 4.0 Hz), 1.35 (3 H, t, J ) 7.1 Hz),
2.00-2.35 (2 H, m), 2.37 (3 H, s), 2.62 (6 H, s), 4.26 (2 H, q, J
) 7.1 Hz), 6.07 (1 H, d, J ) 15.0 Hz), 6.97 (2 H, m), 7.40-7.50
(2 H, m), 7.71 (2 H, t, J ) 6.5 Hz), 8.04 (1 H, s), 12.30 (1 H, br
s). Anal. (C24H28N2O4) C, H, N.
3-(5-E t h yl-6-m et h yl-3d im et h yla m in o-2-oxo-1,2-d ih y-
d r op yr id in -4-yl ca r bon yl)ben za ld eh yd e 33. Step 1: N-
P iva loyl,O-Meth yl Im id a te, a n d Dioxola n e Clea va ge. A
solution of 28 (1.0 g, 2.3 mmol) in 6 N HCl (30 mL) was
refluxed for 1 h. After dilution of the medium with H2O,
extraction with EtOAc, drying (MgSO4) of the combined
organic layers, and concentration, the intermediate 3-ami-
nopyridinone (0.65 g, 97%) was obtained as a yellow solid.
Step 2: N-Meth yla tion . As described for 17c, the derived
3-aminopyridinone (0.65 g, 2.2 mmol) was converted to 33,
isolated as a white solid (0.30 g, 42% yield) after silica gel
column chromatography (CH2Cl2/CH3OH 98/2) (30% overall
1
yield from 25), mp 220 °C; H NMR (CDCl3) δ 0.97 (3 H, t, J
) 7.45 Hz), 2.10-2.30 (2 H, m), 2.39 (3 H, s), 2.60 (6 H, s),
7.69 (1 H, t, J ) 8.0 Hz), 8.14 (2 H, t, J ) 8.0 Hz), 8.34 (1 H,
s), 10.15 (1 H, s), 12.80 (1 H, br s). Anal. (C18H20N2O3) C, H,
N.
(E)-Eth yl 3-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-2-
oxo-1,2-dih ydr opyr idin -4-yl-car bon yl)ph en yl]acr ylate 31.
Step 1: Wittig-Hor n er Rea ction . Following the protocol
for 30, the potassium anion of triethyl phosphonoacetate (1.34
g, 5.9 mmol) in THF (30 mL) was condensed with 29 (1.5 g,
3.9 mmol). Crystallization of the crude product from diisopro-
pyl ether afforded the acrylate intermediate (1.3 g, 75%), mp
115 °C.
Step 2: N-P iva loyl/O-Meth yl Im id a te, a n d Ester Clea v-
a ge. As described for 18a , this acrylate intermediate (1.15 g,
2.6 mmol) was converted to 3-[3-(3-amino-5-ethyl-6-methyl-2-
oxo-1,2-dihydropyridin-4-yl-carbonyl)phenyl]acrylic acid (0.88
g, 100%) as a white solid.
5-Eth yl-6-m eth yl-3-(dim eth ylam in o)-4-(3-vin ylben zoyl)-
p yr id in -2(1H)-on e 34. n-Butyllithium (1.6 M in hexane, 0.40
mL, 0.64 mmol) was added at -70 °C under nitrogen to a
solution of methyltriphenylphosphonium bromide (230 mg,
0.64 mmol) in THF (2 mL). The mixture was brought to 0 °C,
stirred for 15 min, and cooled to -70 °C. Compound 33 (100
mg, 0.32 mmol) in THF (2 mL) was added dropwise. The
mixture was cooled to 0 °C and stirred for 1 h, treated with
H2O, and extracted with EtOAc. The combined organic layers
were dried (MgSO4) and concentrated. Crystallization from
Et2O gave 34 (40 mg, 40%) as a white solid; mp 215 °C (Et2O);
1H NMR (CDCl3) δ 0.96 (3 H, t, J ) 7.4 Hz), 2.05-2.35 (2 H,
m), 2.37 (3 H, s), 2.63 (6 H, s), 5.36 (1 H, d, J ) 10.9 Hz), 5.85
(1 H, d, J ) 10.9 Hz), 6.70 (1 H, m), 7.45 (1 H, t, J ) 8.8 Hz),
7.60-7.75 (2 H, m), 7.95 (1 H, s), 12.70 (1 H, br s). Anal.
(C19H22N2O2‚0.25H2O) C, H, N.
Step 3: Ester ifica tion . Thionyl chloride (0.75 mL, 10
mmol) was added slowly to the derived acid intermediate (0.88
g, 2.7 mmol) in ethanol (50 mL) at 5 °C. The mixture was
stirred at 80 °C for 2 h, poured into ice cold 10% aqueous K2-
CO3 and extracted with EtOAc. The combined organic layers
(E)-3-[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-
1,2-d ih yd r op yr id in -4-yl-ca r bon yl)p h en yl]-2-m eth yla cr yl-

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5511
on itr ile 35a . Following the procedure for 30, compound 29
(10 mmol scale) was reacted with the potassium anion of
diethyl 1-cyanoethylphosphonate, followed by acid treatment
and N-methylation. Compound 35a , a white solid, was ob-
tained (11% overall yield from 25); mp 196 °C; 1H NMR
(DMSO-d6) δ 0.82 (3 H, t, J ) 7.2 Hz), 1.80-2.20 (2 H, m),
2.11 (3 H, d, J ) 1.5 Hz), 2.20 (3 H, s), 2.44 (6 H, s), 7.55 (1H,
s), 7.63 (1 H, t, J ) 8.7 Hz), 7.77 (2 H, m), 7.85 (1 H, m), 11.70
(1 H, br s). Anal. (C21H23N3O2) C, H.
were dried (MgSO4) and concentrated. The residue was
crystallized from EtOAc to give the free amine (0.75 g, 84%)
as a pale yellow solid.
Step 2: N-Meth yla tion . As described for 17c, the 3-ami-
nopyridinone intermediate (0.6 g, 2.1 mmol) was converted to
37 (0.51 g, 77%), as a white solid mp 236 °C; 1H NMR (DMSO-
d6) δ 0.82 (3 H, t, J ) 7,4 Hz), 1.80-2.15 (2 H, m), 2.20 (3 H,
s), 2.45 (6 H, s), 4.57 (2 H, d, J ) 4.4 Hz), 7.49 (1 H, t, J ) 4.4
Hz), 7.55-7.65 (2 H, m), 7.80 (1 H, s), 11.7 (1 H, br s). Anal.
(C18H22N2O3) C, H, N.
P r ep a r a tion of Com p ou n d s 39a -u via P h osp h on iu m
Sa lt 38: (Z a n d E) 5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-
4-[3-(2-th ia zol-2-yl-vin yl)ben zoyl]p yr id in -2(1H)-on es 39t
a n d 39u : Exa m p le of th e Gen er a l Meth od . To 37 (1.25 g,
4 mmol) in CH2Cl2 (20 mL) was added dropwise thionyl
chloride (0.9 mL, 12 mmol) at 5 °C. The mixture was stirred
at 5 °C for 1 h and then at RT for 1 h, poured out into ice-
water, and extracted with CH2Cl2. The combined organic layer
was dried (MgSO4) and concentrated to afford 4-(3-chlorometh-
ylbenzoyl)-3-(dimethylamino)-5-ethyl-6-methylpyridin-2(1H)-
one (1.0 g, 75%) as a white solid.
A mixture of this choromethyl intermediate (1.0 g, 3 mmol)
and triphenylphosphine (0.8 g, 3 mmol) in CH3CN (28 mL)
was refluxed for 48 h. The solvent was evaporated, the residue
was taken up in Et2O, filtered, washed with CH3CN and dried
to afford 3-(3-(dimethylamino)-5-ethyl-6-methyl-2-oxo-1,2-di-
hydropyridin)-4-yl-carbonylbenzyltriphenylphosphonium chlo-
ride 38 in quantitative yield (1.8 g).
By reaction of 29 with the requisite diethyl phosphonates,
compounds 35d -f were obtained (the overall yield for the three
operations is given in each case).
Compound 35d : 28% yield; mp 105 °C (CH3CN/i-Pr2O); 1H
NMR (DMSO-d6) δ 0.85 (3 H, t, J ) 7.35 Hz), 1.85-2.15 (2 H,
m), 2.20 (3 H, s), 2.47 (6 H, s), 7.40-7.60 (3 H, m), 7.78 (1 H,
t, J ) 8.8 Hz), 7.80 (2 H, d, J ) 8.5 Hz), 7.90 (1 H, d, J ) 8.8
Hz), 8.19 (1 H, s), 8.22 (1 H, d, J ) 8.8 Hz), 8.38 (1 H, s), 11.70
(1H, br s). Anal. (C26H25N3O2) C, H, N.
1
Compound 35e: 29% yield; mp 221 °C (CH3CN); H NMR
(DMSO-d6) δ 0.86 (3 H, t, J ) 7.3 Hz), 1.85-2.15 (2 H, m),
2.16 (3 H, s), 2.48 (6 H, s), 7.17-7.22 (1 H, m), 7.48-7.53 (1
H, m), 7.70-7.76 (2 H, m), 7.90 (1 H, d, J ) 8.8 Hz), 8.00 (1 H,
s), 8.20 (1 H, d, J ) 8.8 Hz), 8.40 (1 H, s), 11.80 (1 H, br s).
Anal. (C24H23N3O2S) C, H, N.
1
Compound 35f: 23% yield; mp 230 °C (CH3CN/i-Pr2O); H
NMR (DMSO-d6) δ 0.85 (3 H, t, J ) 7.1 Hz), 1.82-2.20 (2 H,
m), 2.20 (3 H, s), 2.47 (6 H, s), 7.50-7.60 (1 H, m), 7.75 (1 H,
t, J ) 8.0 Hz), 7.92 (1 H, d, J ) 8.8 Hz), 8.15 (1 H, d, J ) 8.8
Hz), 8.25 (1 H, d, J ) 8.8 Hz), 8.30 (1 H, s), 8.40 (1 H, s), 8.65
(1 H, d, J ) 8.0 Hz), 8.99 (1 H, s), 11.80 (1 H, br s). Anal.
(C25H24N4O2) C, H, N.
To this intermediate (700 mg, 1.2 mmol) in THF (5 mL)
under nitrogen was added portionwise potassium tert-butoxide
(0.4 g, 3.6 mmol) at 5 °C. The mixture was stirred at 5 °C for
30 min, and then 2-thiazolecarboxaldehyde (140 mg, 1.2 mmol)
in THF (5 mL) was added at 5 °C. The mixture was stirred at
5 °C for 10 min, H2O was added, and the mixture was extracted
with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated. Compounds 39t and 39u were separated
by silica gel column chromatography (CH2Cl2/CH3OH/NH4OH
97/3/0.1) and crystallized from CH3CN.
2-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-2-oxo-1,2-d i-
h yd r op yr id in -4-ylca r b on yl)b en zylid en e]m a lon on it r ile
35b. n-Butyllithium (1.6 M in hexane, 0.40 mL, 0.64 mmol)
was added at -70 °C under nitrogen to a mixture of diisopro-
pylamine (90 µL, 0.64 mmol) in THF (1 mL). The mixture was
brought to 0 °C and cooled to -70 °C. A solution of malono-
nitrile (42 mg, 0.64 mmol) in THF (1 mL) was added. The
mixture was stirred at -70 °C for 1 h. A solution of 33 (100
mg, 0.32 mmol) in THF (1 mL) was added. The mixture was
brought to 0 °C, stirred for 15 min, and then poured into ice-
water and extracted with EtOAc. The combined organic layers
were dried (MgSO4), filtered, and concentrated under vacuum.
The residue was silica gel column chromatographed (CH2Cl2/
CH3OH/NH4OH 97/3/0.1), and the concentrated product frac-
tions were crystallized from diisopropyl ether to give 35b as a
white powder (60 mg, 52%); mp 105 °C; 1H NMR (CDCl3) δ
0.97 (3 H, t, J ) 7.4 Hz), 2.05-2.30 (2 H, m), 2.37 (3 H, s),
2.59 (6 H, s), 7.71 (1 H, t, J ) 8.8 Hz), 7.87 (1 H, s), 8.10 (1 H,
d, J ) 8.8 Hz), 8.22 (1 H, d, J ) 8.8 Hz), 7.28 (1 H, s), 12.70
(1 H, br s). Anal. (C21H20N4O2‚0.25H2O) C, H, N.
Compound 39t (180 mg, 39%) white solid; mp 156 °C; 1H
NMR (CDCl3) δ 0.96 (3 H, t, J ) 7.5 Hz), 2.05-2.32 (2 H, m),
2.35 (3 H, s), 2.61 (6 H, s), 6.95 (2 H, s), 7.18 (1 H, d, J ) 3.3
Hz), 7.52 (1 H, t, J ) 8.4 Hz), 7.70 (1 H, d, J ) 8.4 Hz), 7.75
(1 H, d, J ) 3.3 Hz), 7.88 (1 H, d, J ) 8.4 Hz), 7.99 (1 H, s),
12.6 (1 H, br s). Anal. (C22H23N3O2S) C, H, N.
1
Compound 39u (28 mg, 6%) white solid; mp > 260 °C; H
NMR (CDCl3) δ 0.97 (3 H, t, J ) 7.5 Hz), 2.08-2.37 (2 H, m),
2.40 (3 H, s), 2.64 (6 H, s), 7.32 (1 H, d, J ) 3.5 Hz), 7.38 (1 H,
d, J ) 16.0 Hz), 7.47-7.56 (2 H, m), 7.78 (1 H, d, J ) 8.8 Hz),
7.81-7.88 (2 H, m), 8.03 (1 H, s), 12.8 (1 H, br s). Anal.
(C22H23N3O2S) C, H, N.
N-[4-(3-Acetylben zoyl)-5-eth yl-2-m eth oxy-6-m eth ylp y-
r id in -3-yl]-2,2-d im eth yl-p r op ion a m id e 40. As described for
29, this intermediate was obtained from 16 in three steps.
Following the procedure used to obtain 35b, compound 33
was reacted with ethyl cyanoacetate. Compound 35c was
1
obtained as a white solid (14% yield); mp 200 °C (Et2O); H
Step 1: Lithiation of 16 (6.7 g, 27 mmol)/ condensation with
NMR (DMSO-d6) δ 0.83 (3 H, t, J ) 7.3 Hz), 1.32 (3 H, t, J )
7.1 Hz), 1.80-2.20 (2 H, m), 2.19 (3 H, s), 2.44 (6 H, s), 4.32 (2
H, q, J ) 7.1 Hz), 7.70 (1 H, t, J ) 8.8 Hz), 8.03 (1 H, d, J )
8.8 Hz), 8.27 (1 H, d, J ) 8.8 Hz), 8.52 (1 H, s), 8.54 (1 H, s),
11.75 (1 H, br s). Anal. (C23H25N3O4) C, H, N.
3-(2-methyl-[1,3]dioxolan-2-yl)benzaldehyde54 (63% yield).
Step 2: Oxidation by MnO2 was realized on a 17 mmol scale
in 95% yield.
Step 3: Hydrolysis of dioxolane group afforded 40 in
quantitative yield.
N-[5-Eth yl-4-(3-h yd r oxym eth ylben zoyl)-2-m eth oxy-6-
m eth ylp yr id in -3-yl]-2,2-d im eth ylp r op ion a m id e 36. So-
dium borohydride (0.31 g, 8.1 mmol) was added portionwise
to a solution of 29 (2.6 g, 6.8 mmol) in CH3OH (30 mL) at 5
°C. The mixture was stirred at 5 °C for 2 h, followed by
addition of H2O and extraction with EtOAc. The combined
organic layers were dried (MgSO4) and concentrated. The
residue was silica gel column chromatographed (cyclohexane/
EtOAc 60/40) to afford 36 (1.2 g, 46%) as a pale yellow solid.
5-Eth yl-4-(3-h ydr oxym eth ylben zoyl)-6-m eth yl-3-dim eth -
yla m in op yr id in -2(1H )-on e 37. St ep 1: N-P iva loyl/O-
Meth yl Im id a te Clea va ge. Compound 36 (1.2 g, 3.1 mmol)
in 3 N HCl (15 mL) was refluxed for 2 h. The mixture was
then poured into ice-water, basified with concentrated NH4-
OH, and extracted with CH2Cl2. The combined organic layers
3-Dim eth ylam in o-5-eth yl-4-[3-(1-h ydr oxyeth yl)ben zoyl]-
6-m eth ylp yr id in -2(1H)-on e 41. As described for 33, this
compound was obtained from 40 in two steps.
Step 1: N-Pivaloyl/O-methyl imidate cleavage was realized
on 7 mmol scale in 84% yield.
Step 2: N-Meth yla tion . As described for 17c, the derived
3-aminopyridinone obtained above (1.7 g, 5.7 mmol) was
converted to 41, isolated as a white solid (0.5 g, 27% yield)
after silica gel column chromatography (CH2Cl2/CH3OH 97/
3), mp 205 °C; 1H NMR (DMSO-d6) δ 0.81 (3 H, t, J ) 7.3 Hz),
1.92-2.18 (2 H, m), 2.21 (3 H, s), 2.44 (6 H, s), 2.64 (3 H, s),
7.71 (1 H, t, J ) 7.8 Hz), 8.00 (1 H, d, J ) 7.8 Hz), 8.26 (1 H,
d, J ) 7.8 Hz), 8.29 (1 H, s), 12.80 (1 H, br s). Anal.
(C19H22N2O3) C, H, N.

5512 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22
Benjahad et al.
(E)-3-[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-
1,2-d ih yd r op yr id in -4-yl-ca r b on yl)p h en yl]-b u t -2-en en i-
tr ile 42. As described for 27, compound 42 was obtained from
41 (0.10 g, 0.3 mmol) and diethyl cyanomethylphosphonate in
64% yield as a white solid mp 204 °C; 1H NMR (CDCl3) δ 0.97
(3 H, t, J ) 7.4 Hz), 2.09-2.38 (2 H, m), 2.40 (3 H, s), 2.56 (3
H, d, J ) 1.0 Hz), 2.63 (6 H, s), 5.74 (1 H, d, J ) 1.0 Hz), 7.55
(1 H, t, J ) 7.7 Hz), 7.70 (1 H, d, J ) 7.7 Hz), 7.83 (1 H, d, J
) 7.7 Hz), 8.09 (1 H, t, J ) 1.5 Hz), 13.10 (1 H, br s). Anal.
(C21H23N3O2) C, H, N.
[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-1,2-d i-
h yd r op yr id in -4-yl-ca r bon yl)p h en yl]a ceton itr ile 48. Ac-
cording to the procedure described for 18a , the intermediate
46 (2.5 g, 6.4 mmol) was successively submitted to N-pivaloyl/
O-methyl imidate cleavage (85% yield) and N-methylation to
give 48(1.2 g, 75%) as white solid mp 193 °C; 1H NMR (CDCl3)
δ 0.96 (3 H, t, J ) 7.4 Hz), 2.05-2.35 (2 H, m), 2.38 (3 H, s),
2.62 (6 H, s), 3.85 (2 H, s), 7.52 (1 H, t, J ) 8.4 Hz), 7.60 (1 H,
d, J ) 8.4 Hz), 7.78 (1 H, d, J ) 8.4 Hz), 7.89 (1 H, s), 13.0 (1
H, br s). Anal. (C19H21N3O2) C, H, N.
2-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-2-oxo-1,2-d i-
h ydr opyr idin e-4-yl-car bon yl)ph en yl]pr opion itr ile 49. Ac-
cording to the procedure described for 18a , the intermediate
47 (0.30 g, 0.7 mmol) was successively submitted to N-pivaloyl/
O-methyl imidate cleavage (78% yield) and N-methylation to
give 49 (40 mg, 23%) as a white solid mp 168 °C; 1H NMR
(CDCl3) δ 0.95 (3 H, t, J ) 7.5 Hz), 1.71 (3 H, d, J ) 7.3 Hz),
2.05-2.34 (2 H, m), 2.38 (3 H, s), 2.62 (6 H, s), 4.02 (1 H, q, J
) 7.3 Hz), 7.53 (1 H, t, J ) 8.8 Hz), 7.68 (1 H, d, J ) 8.8 Hz),
7.79 (1 H, d, J ) 8.8 Hz), 7.90 (1 H, s), 12.70 (1 H, br s). Anal.
(C20H23N3O2‚0.25H2O) C, H, N.
5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-4-(3-p h en oxym e-
th ylben zoyl)p yr id in -2(1H)-on e 50. To 36 (3.8 g, 10 mmol),
triphenylphosphine (3.9 g, 15 mmol), and phenol (3.7 g, 40
mmol) in THF (40 mL) under nitrogen was added dropwise
diethyl azodicarboxylate (2.4 mL, 15 mmol) at 5 °C. The
mixture was stirred at RT for 12 h. Water was added, and the
mixture was extracted with EtOAc, dried (MgSO4), filtered,
and concentrated under vacuum. The residue was silica gel
column chromatographed (CH2Cl2/CH3OH 99/1) to afford N-[5-
ethyl-2-methoxy-6-methyl-4-(3-phenoxymethylbenzoyl)pyridin-
3-yl]-2,2-dimethylpropionamide (3.4 g, 75%).
(E)-3-[3-(5-E t h yl-6-m et h yl-3-(d im et h yla m in o)-2-oxo-
1,2-d ih yd r op yr id in -4-yl-ca r bon yl)p h en yl]-2-m eth ylbu t-
2-en en itr ile 43. As described for 27, compound 43 was
obtained from 41 (130 mg, 0.4 mmol) and diethyl (1-cyano-
ethyl)phosphonate in 18% yield as a white solid mp 184 °C;
1H NMR (CDCl3) δ 0.96 (3 H, t, J ) 7.5 Hz), 1.84 (3 H, d, J )
1.4 Hz), 2.09-2.35 (2 H, m), 2.37 (3 H, s), 2.40 (3 H, d, J ) 1.4
Hz), 2.61 (6 H, s), 7.39 (1 H, d, J ) 8.8 Hz), 7.53 (1 H, d, J )
8.8 Hz), 7.67 (1 H, s), 7.82 (1 H, d, J ) 8.8 Hz), 12.4 0(1 H, br
s). Anal. (C22H25N3O2) C, H, N.
3-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-2-oxo-1,2-d i-
h yd r op yr id in -4-yl-ca r bon yl)p h en yl]p r op ion itr ile 44. A
mixture of 30 (200 mg, 0.6 mmol) in methanol (40 mL) was
hydrogenated under a 3 bar pressure for 2 h, using 10% Pd-C
(100 mg) as the catalyst. The catalyst was removed by
filtration through Celite and washed with methanol, and the
filtrate was concentrated. The residue was silica gel column
chromatographed (CH2Cl2/CH3OH 97/3). Crystallization from
CH3CN and i-Pr2O afforded 44 (100 mg, 50%) as a white solid
mp 159 °C; 1H NMR (CDCl3) δ 0.96 (3 H, t, J ) 7.4 Hz), 2.05-
2.35 (2 H, m), 2.37 (3 H, s), 2.62 (6 H, s), 2.70 (2 H, t, J ) 7.3
Hz), 3.05 (2 H, t, J ) 7.3 Hz), 7.40-7.55 (2 H, m), 7.71 (1 H,
d, J ) 8.8 Hz), 7.79 (1 H, s), 12.50 (1 H, s). Anal. (C20H23N3O2)
C, H, N.
This intermediate (3.4 g, 7.4 mmol) was then successively
submitted to N-pivaloyl/O-methyl imidate cleavage and N-
methylation as described for 18a to give 50 (0.51 g; 18% yield);
3-[3-(5-Eth yl-6-m eth yl-3-(d im eth yla m in o)-2-oxo-1,2-d i-
h yd r op yr id in -4-yl-ca r b on yl)p h en yl]-2-m et h ylp r op ion i-
tr ile 45. Similar preparation starting from the compound 35a
gave the corresponding analogue 45 as a pale yellow solid (20%
yield), mp 162 °C; 1H NMR (CDCl3) δ 0.95 (3 H, t, J ) 7.4 Hz),
1.38 (3 H, d, J ) 6.3 Hz), 2.05-2.35 (2 H, m), 2.37 (3 H, s),
2.62 (6 H, s), 2.87-3.10 (3 H, m), 7.42-7.53 (2 H, m), 7.70-
7.80 (2 H, m), 12.80 (1 H, br s). Anal. (C21H25N3O2) C, H, N.
1
mp 186 °C; H NMR (DMSO-d6) δ 0.80 (3 H, t, J ) 7.4 Hz),
1.80-2.14 (2 H, m), 2.19 (3 H, s), 2.44 (6 H, s), 5.21 (2 H, s),
6.90-7.03 (3 H, m), 7.28 (2 H, t, J ) 8.2 Hz), 7.57 (1 H, t, J )
9.3 Hz), 7.74 (2 H, d, J ) 9.3 Hz), 7.86 (1 H, s), 11.70 (1 H, br
s). Anal. (C24H26N2O3) C, H, N.
3-Dim eth ylam in o-5-eth yl-4-[3-(1-h ydr oxyeth yl)ben zoyl]-
6-m eth ylp yr id in -2(1H)-on e 51. This compound was obtained
in three steps from benzaldehyde derivative 29.
N-[4-(3-Cya n om eth ylben zoyl)-5-eth yl-2-m eth oxy-6-m e-
th ylp yr id in -3-yl]-2,2-d im eth ylp r op ion a m id e 46. Step 1:
Ch lor a tion by SOCl2. To 36 (4 g, 10.4 mmol) in CH2Cl2 (120
mL) was added dropwise thionyl chloride (2 mL, 27 mmol) at
5 °C. The mixture was stirred at 5 °C for 1 h and then at RT
for 1 h, poured into ice-water, and extracted with CH2Cl2. The
organic layer was dried over MgSO4, filtered, and evaporated
to afford N-[4-(3-chloromethylbenzoyl)-5-ethyl-2-methoxy-6-
methylpyridin-3-yl]-2,2-dimethylpropionamide (4.2 g, 100%).
Step 1: Grignard reaction was realized on 2.0 g, (5.2 mmol)
of 29 (60% yield) with 3.3 equivalents of CH3MgI.
Step 2: N-Pivaloyl/O-methyl imidate cleavage was realized
on 3 mmol (70% yield).
Step 3: N-Meth yla tion . The intermediate 3-aminopyridone
(0.63 g, 2.1 mmol) was converted to 51 as a white solid (0.35
g, 51% yield) after silica gel column chromatography (CH2Cl2/
1
CH3OH/NH4OH 93/7/0.5), mp 192 °C; H NMR (DMSO-d6) δ
0.81 (3 H, t, J ) 7.4 Hz), 1.32 (3 H, d, J ) 6.4 Hz), 1.85-2.18
(2 H, m), 2.20 (3 H, s), 2.46 (6 H, s), 4.80 (1 H, m), 5.31 (1 H,
d, J ) 4.3 Hz), 7.48 (1 H, t, J ) 8.8 Hz), 7.59-7.67 (2 H, m),
7.80 (1 H, s), 11.70 (1 H, br s). Anal. (C19H24N2O3) C, H, N.
Biology. Eva lu a tion of An tivir a l Activity of th e Com -
p ou n d s. Cells a n d Vir u ses. MT4 cells are human T-lym-
phoblastoid cells that are highly sensitive to HIV infection,
producing a rapid and pronounced cytopathic effect. All cells
were cultured in RPMI 1640 medium supplemented with 10%
fetal calf serum and antibiotics in a humidified incubator with
a 5% CO2 atmosphere at 37 °C.
Step 2: Cya n a tion . To this intermediate (3.7 g, 9.2 mmol)
in EtOH (20 mL) were added water (14 mL) and then sodium
cyanide (0.78 g, 15.7 mmol). The mixture was stirred at 80 °C
for 2 h, poured into 10% K2CO3 solution, extracted with CH2-
Cl2, dried (MgSO4), filtered, and concentrated under vacuum.
The residue was silica gel column chromatographed (cyclo-
hexane/EtOAc 60/40) to give a residue which was crystallized
from diisopropyl ether to afford N-[4-(3-cyanomethylbenzoyl)-
5-ethyl-2-methoxy-6-methylpyridin-3-yl]-2,2-dimethylpropi-
onamide 46 (2.6 g, 72%).
N-{4-[3-(1-Cya n oet h yl)b en zoyl]-5-et h yl-2-m et h oxy-6-
m eth ylp yr id in -3-yl}-2,2-d im eth ylp r op ion a m id e 47. Po-
tassium tert-butoxide (0.54 g, 4.8 mmol) was added at 5 °C
under nitrogen to a solution of 46 (1.72 g, 4.4 mmol) in THF
(15 mL), and the mixture was stirred at 5 °C for 30 min.
Iodomethane (0.30 mL, 4.8 mmol) in THF (3 mL) was then
added. The mixture was stirred at 5 °C for 2 h, poured into
ice-water, extracted with EtOAc, dried (MgSO4), filtered, and
concentrated under vacuum. The residue was silica gel column
chromatographed (CH2Cl2/EtOAc 93/7) to give a residue which
was crystallized from CH3CN to afford 47 (0.40 g, 22%) as a
white solid mp 131 °C.
Site-Dir ected Mu ta n ts. Mutant RT coding sequences were
generated from a pGEM vector containing the HIV-1 LAI
(clone HXB2) protease (PR) and RT coding sequence, using
the QuikChange Site-Directed Mutagenesis Kit (Stratagene),
and HPLC-purified primers (Genset Oligos). Plasmids were
checked to confirm that they contained the desired mutations
by sequencing. Mutant viruses were created by recombination
of the mutant PR-RT sequence with a PR-RT deleted HIV-1
HXB2 proviral clone.48
Dr u g Sen sitivity Assa ys. The antiviral activity of com-
pounds against laboratory adapted strains, site-directed mu-
tants, and clinical sample-derived recombinant viruses was

New Family of Potent Anti-HIV Agents
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 22 5513
(15) J ain, R. G.; Furfine, E. S.; Pednrault, L.; White, A. J .; Lenhard,
J . M. Metabolic complications associated with antiretroviral
therapy. Antiviral Res. 2001, 51, 151-177.
tested using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-
zolium bromide (MTT) colorimetric assay as previously de-
scribed.48,55 Briefly, various concentrations of the test com-
pounds were added to wells of a flat-bottom microtiter plate.
Subsequently, virus and MT4 cells were added to a final
concentration of 200 CCID50/well and 30 000 cells/well, re-
spectively. To determine the toxicity of the test compound,
mock-infected cell cultures, containing an identical compound
concentration range, were incubated in parallel with the virus
infected cell cultures. After 5 days of incubation (37 °C, 5%
CO2), the viability of the cells was determined using MTT. The
results of drug susceptibility assays were expressed as an EC50
defined as the concentration of drug at which there was 50%
infection compared with the drug-free control. In some cases
a fold change in susceptibility was calculated by dividing the
EC50 for the tested virus by the EC50 for the wild-type virus
(HIV-1 LAI) tested in parallel. Toxicity results are expressed
as CC50, defined as the concentration of drug at which the cell
viability was reduced by 50% compared to the drug-free
control.
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