Synthesis and biological evaluation of C-5 methyl substituted 4-arylthio and 4-aryloxy-3-iodopyridin-2(1H)-one type anti-HIV agents

Article abstract of DOI:10.1021/jm900802y

A series of C-5 methyl substituted 4-arylthio- and 4-aryloxy-3-iodopyridin- 2(1H)-ones has been synthesized as new pyridinone analogues for their evaluation as anti-HIV inhibitors. The optimization at the 5-position was developed through an efficient use of the key intermediates 5-ethoxycarbonyl- and 5-cyano-pyridin-2(1H)-ones (14 and 15). Biological studies revealed that several compounds show potent HIV-1 reverse transcriptase inhibitory properties, for example, compounds 93 and 99 are active at 0.6-50 nM against wild type HIV-1 and a panel of major simple/double HIV mutant strains.

Full text of DOI:10.1021/jm900802y

J. Med. Chem. 2009, 52, 7473–7487 7473
DOI: 10.1021/jm900802y
Synthesis and Biological Evaluation of C-5 Methyl Substituted 4-Arylthio and
4-Aryloxy-3-Iodopyridin-2(1H)-one Type Anti-HIV Agents†
Jerome Guillemont,* Abdellah Benjahad,§ Said Oumouch,§ Laurence Decrane,‡ Patrice Palandjian,‡ Daniel Vernier,‡
,‡
ꢀ ^
Laurence Queguiner, Koen Andries, Marie-Pierre de Bethune, Kurt Hertogs, David S. Grierson, and Chi Hung Nguyen*
‡
^
^
§
,§
ꢀ
‡TIBOTEC, Medicinal Chemistry Department, Campus de Maigremont BP315, 27430 Val de Reuil, France, §UMR 176 CNRS-Institut Curie,
Laboratoire de Pharmacochimie, Section de Recherche, Ba^timent 110, Centre Universitaire, 91405 Orsay, France, Johnson&Johnson
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 June 4, 2009
A series of C-5 methyl substituted 4-arylthio- and 4-aryloxy-3-iodopyridin-2(1H)-ones has been
synthesized as new pyridinone analogues for their evaluation as anti-HIV inhibitors. The optimization
at the 5-position was developed through an efficient use of the key intermediates 5-ethoxycarbonyl- and
5-cyano-pyridin-2(1H)-ones (14 and 15). Biological studies revealed that several compounds show
potent HIV-1 reverse transcriptase inhibitory properties, for example, compounds 93 and 99 are active
at 0.6-50 nM against wild type HIV-1 and a panel of major simple/double HIV mutant strains.
Introduction
mutant strains. This criterion is of particular importance to the
development of the NNRTI class of compounds for which it
has been shown that cross resistance is a major concern.
In our laboratories, it was found that 3-amino-4-phe-
nylthiopyridinones of general structure 1 are potent inhibitors
of wild type HIV-1 reverse transcriptase.6 SAR studies on this
series led to the identification of the 3-dimethylamino-4-
benzyl and 4-benzoylpyridinones 2 and 3 as promising lead
compounds.7 Further systematic optimization of these mole-
cules through modification of the substituents on the phenyl
ring gave analogues 4 and 5, displaying nanomolar range
activities in vitro against a wide panel of HIV-1 mutant strains
commonly encountered in HIV infected patients.8 Prelimin-
ary indications are that analogues of 2, such as 6, in which the
C-5 ethyl group is replaced by a longer heteroalkyl chain, will
also possess promising activity profiles.9
Recently, we described the preparation and anti-HIV prop-
erties of a new 3-iodopyridinone based anti-HIV agent 7 in
which the 3,5-dimethylphenyl motif is linked to the central
heterocycle via an oxygen bridge.10 In the optimization of this
new series, we chose to first look at the influence on activity of
the introduction of different heteroatoms/heterocycles into
the C-5 side chain. This work is inspired from our own studies
on compounds 2/38,9 and from the large amount of back-
ground work on different HEPT systems (cf. MKC-442 and
GCA-186).11-13 In particular, Pedersen et al. recently showed
that HEPT analogues bearing an allyoxy side chain at N-1 are
very potent RT inhibitors.14a
Combination therapy or HAARTa is the only effective
strategy for the treatment of AIDS. However, in some patients,
the long-term use of nucleoside and non-nucleoside RT inhi-
bitors, in combination with protease inhibitors, leads ultimately
to serious problems of drug resistance, toxicity, and associated
side effects (lipodystrophy, hyperlipidaemia, etc.).1-5 To treat
AIDS as a chronic infection, it is thus important to continually
find more potent and less toxic drugs that display a high level of
activity against the clinically relevant HIV single and multiple
†For the 100th anniversary of the Division of Medicinal Chemistry:
The research described in this paper is a prime example of the strengths
of medicinal chemistry. The interplay between chemical synthesis and
pharmacological testing enabled the delineation of structure-activity
relationships and the rational design of improved NNRTIs. The design
of better drugs is not only of pure scientific importance but may have a
positive impact on the lives of large numbers of patients worldwide,
which is another vital aspect of the field of medicinal chemistry. The
here-described optimization of the IOPY and ISPY series of NNRTIs
was based on the concerted efforts and enthusiasm of many people from
many disciplines, researchers originating both from academia and the
industry. The ACS Division of Chemistry plays a crucial role to facilitate
this kind of collaborative research and to disseminate the findings.
Moreover, the efforts of the ACS Division of Chemistry to promote
the practice of medicinal chemistry are fundamental to ensure the inflow
of young medicinal chemists. Therefore, we are happy for the opportu-
nity to dedicate the research described here to the 100-year-old ACS
Division of Medicinal Chemistry.
*To whom correspondence should be addressed. For J.G.: phone,
33-2-32 61 74 58; fax, 33 2 32 61 72 98; e-mail,jguillem@its.jnj.com.
For C.H.N.: phone, 33-1 69 86 30 89; fax, 33-1 69 07 53 81; e-mail, chi.
hung@curie.up-sud.fr.
a Abbreviations: HIV-1, human immunodeficiency virus-1; AIDS,
acquired immunodeficiency syndrome; HAART, highly active antire-
troviral therapy; RT, reverse transcriptase; NNRTI, non-nucleoside
reverse transcriptase inhibitor; LAI, wild type HIV-1; Lys103Asn,
K103N mutant strain; Tyr181Cys, Y188C mutant strain; Tyr188Leu,
Y188L mutant strain; SAR, structure-activity relationship; IC50, 50%
inhibitory concentration for inhibition of viral cytopathicity; IOPY, iodo-
aryloxypyridinone; ISPY, iodoarylthiopyridinone; HEPT, 1-[(2-hydroxy-
ethoxy)methyl]-6-(phenylthio)thymine; DMF, dimethylformamide; DI-
BAL-H, diisobutylaluminum hydride; NIS, N-iodosuccinimide.
The encouraging biological results obtained in our pyridi-
none series inspire new developments of this privileged scaf-
fold. Elsewhere, very recently, a closely related family, the 4-
cycloalkyloxypyridin-2(1H)-one derivatives, has been synthe-
sized and good antiviral activities against mutant viral strains
were reported.14b
In the present report, we describe an efficient strategy
for the rapid synthesis of a diverse library of C-5 modified
r
2009 American Chemical Society
Published on Web 07/31/2009
pubs.acs.org/jmc

7474 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Guillemont et al.
Scheme 1. Structures of Lead Compounds in Various Stages of Development and Design of New 5-Methyl Substituted Analogues 10
3-iodo-4-aryloxypyridinones (IOPY’s) and 3-iodo-4-arylthio-
pyridinones (ISPY’s) (Scheme 1).
Scheme 2. Synthesis of 5-Methyl Substituted-4-phenoxy Deri-
vativesa
Naturally, new 5-methyl substituted 10 could be prepared by
a simple SN2 pathway from 8 and 9. However, the approach,
which was based on the idea that treatment of the 5-chloro-
methyl substituted pyridinones 8 and 9 with mild base would
lead to formation of a conjugated imine intermediate, in turn
would react with a nucleophile present in the medium to give 10.
In this paper, applying this concept, a 48-member library of
new IOPY analogues was prepared from compound 8
(Scheme 2), and each component was evaluated for its anti-
HIV activity in vitro. Similarly, a 43-member library of related
3-iodo-4-arylthiopyridinones (ISPY’s) was prepared from the
corresponding 5-chloromethyl substituted pyridinone
9
(Scheme 3) and tested. It is worth mentioning that, of the more
than 300 molecules synthesized in this work, appoximately 200
displayed activity at submicromolar concentrations (IC50 <
100 nM) against wild type RT. Of these, 106 analogues were
active in the 1-10 nM range and a selection is shown in
Tables 1-6. On the basis of the further evaluation of these
molecules against the three principle HIV mutant strains
Y181C, Y188L, and K103N, a number were chosen for screen-
ing against a wider panel of HIV single and double mutants
(Table 7). Comparison of the in vitro results for these com-
pounds to the data for lead compounds 2/3 and 7, as well as to
nevirapine and efavirenz, it is clear that the optimized com-
pounds 46, 93, and 99 have an activity profile that is superior to
the two clinically used NNRTI drugs. Analysis of the structure
for the compound 24 wild-type RT complex provided a molec-
ular basis for understanding the contribution of the C-5 side
chain substituent in these molecules to their anti-HIV activity.15
Taken together, the biological and the structural data serve as a
valuable guide to the further optimization of the anti-HIV
activity of the 3-iodopyridinone (IOPY/ISPY) family.
Chemistry
a Conditions: (a) diglyme, 120 ꢀC, 2 h; (b) Na2CO3, H2O, rt; (c) DMF, rfx;
(d) DIBAL-H; (e) SOCl2; (f) Nu-H, K2CO3; (g) coumarilic acid, EDCI,
HOBT, NEt3.
The key intermediate 8 required for production of the C-5
modified IOPY library was prepared in five steps (Scheme 2).

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7475
Scheme 3. Synthesis of 5-Methyl Substituted-4-phenylthio Derivativesa
a Conditions: (a) (i) POCl3, BnNEt3Cl, CH3CN reflux; (ii) NaOAc, AcOH rfx. (b) 3,5-Dimethylthiophenol. (c) LAH. (d) SOCl2. (e) NaOEt, EtOH rfx.
(f) NIS. (g) DIBAL-H. (h) Nu-H, K2CO3. (i) BH3 (CH3)2S, THF. (j) HCO2H, NH2CHO.
3
The first step involved formation of the 5-carbethoxy sub-
stituted pyridinone 14, which has been described in the
literature.16a
derivative 70 and reacting this compound with 3,5-di-
methylthiophenol in ethanol (31% yield for the two steps)
(Scheme 3).
Compound 14 was previously synthesized in 8% yield over
two steps starting from ethyl 3-aminocrotonate, which was
converted to ethyl 3-amino-2-(2-cyano)acetylbut-2-enoate and
cyclized to form the pyridinone ring. We found that this
compound 14 was conveniently prepared in 75% yield in single
step through condensation of ethyl 3-aminocrotonate 11 with
the activated malonate derivative 13 in the absence of added
base. The reaction of 14 at room temperature with dichlor-
oiodo-3,5-dimethylbenzene in water containing Na2CO3 led to
rapid formation of dipole 16.16b This intermediate was isolated
by simple filtration, dried under vacuum, and then heated in
dry DMF at reflux in order to effect rearrangement to the
3-iodo-4-phenoxysubstituted 17 (75% yield from 14). Conver-
sion of 17 to 8 involved ester reduction using DIBAL-H,
leading to hydroxymethyl derivative 21, which was followed
by reaction with thionyl chloride. This chloromethyl inter-
mediate 8 in either ethanol, acetonitrile or dioxane (see Experi-
mental Section) was treated with Et3N or K2CO3 and reacted
with a battery of oxygen, nitrogen, and sulfur containing open
chain nucleophiles (compounds 22-45; Table 1), five-mem-
bered ring heterocycles (compounds 46-61; Table 2), and six-
membered nitrogen heterocycles (compounds 62-69;Table3).
Similarly, the pyridine-3-carbonitrile derivative 15 was
prepared by condensation of aminobutenenitrile 12 with
trichlorophenylmalonate 13. Conversion of this intermediate
to 18, followed by nitrile reduction using DIBAL-H and
peptide coupling of the resulting 5-aminomethyl derivative
19 with coumarilic acid, gave amide 20.
The 5-ethoxymethyl compound 75 (Table 4) was obtained
from this ester via reduction to 72, chlorination, reaction of
the chloromethyl derivative 73 with NaOEt, and introduction
of the 3-iodo substituent by reaction of 74 with NIS. Prepara-
tion of the chloromethyl intermediate 9 from ester 71 involved
introduction of the iodo group prior to modification of the
C-5 position. This intermediate was treated with K2CO3 in
CH3CN or Et3N in EtOH and reacted with different oxygen,
nitrogen, and sulfur containing open-chain nucleophiles
(compounds 83-92; Table 4), five-membered ring hetero-
cycles (compounds 93-111; Table 5), and six-membered
nitrogen heterocycles (compounds 112-125; Table 6).
Results and Discussion
The entire collection of C-5 modified 3-iodo phenoxy and
thiophenylpyridinone analogues were evaluated in vitro
against wild type HIV-1 (HTLV IIIB, LAI cell line) and were
further tested against the three principle mutant strains,
K103N, Y181C, and Y188L, which confer resistance to the
NNRTI’s currently used in clinic.17,18 The biological results
for this new collection of 96 compounds are presented in
Tables 1-6.
Looking at the data for IOPY 7 against the three mutant
strains, one sees that it is 3- and 10-fold more active than
efavirenz (see Table 7) against the Y188L and K103N mu-
tants, respectively, but 10-fold less sensitive than this drug
against the Y181C mutant strain. We thus began the analysis
of the data in Tables 1-6 by identifying the analogues that
inhibit the Y181C mutant with the IC50 value set at less than
35 nM. Of the 96 compounds, 51 in the initial list fell into this
In the ISPY series, the pivotal intermediate 71 was prepared
by converting pyridinone 14 to the corresponding 4-chloro

7476 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Table 1. Biological Activity of C-5 Modified 3-Iodo Phenoxy Pyridinone (IOPY) Analoguesa
Guillemont et al.
a 1Selectivity index or ratio of CC50 to IC50 relative to LAI (fold). 2Method A: ethanol, triethylamine, sealed
tube; method B: acetonitrile, K2CO3, reflux; method C: dioxane, K2CO3, reflux. 3a: Crystallization from
EtOH; b: crystallization from i-Pr2O; c: column chromatography on silica, eluent CH2Cl2/MeOH: 99/1; d:
column chromatography on silica, eluent CH2Cl2/MeOH: 98/2; e: column chromatography on silica, eluent
CH2Cl2/2-propanol: 98/2 then crystallization from Et2O; f: column chromatography on silica, eluent CH2Cl2/
2-propanol: 98/2 then crystallization from Et2O.
category, indicating that a wide variation in the nature of the
substitutents at C-5 was compatible with activity against this
key mutant. Being more restrictive, only 16 compounds in this
set (22, 23, 24, 25, 27, 28, 31, 46, 47, 48, 93, 95, 98, 99, 102, 108)
were active, like efavirenz, in the 1-10 nM concentration
range. Similarly, more than half (54) of the C-5 substituted
pyridinone analogues in Tables 1-6 were active against the
K103N mutant in the IC50 range <10 nM, indicating that
modification in the nature of the substitutent at C-5 also has
little effect on sensitivity toward this mutation. Looking
finally at the activities against the Y188L mutant strain, the
upper limit for the IC50 value was set at 50 nM. Twenty
compounds were identified. Of these, 12 cross reference with
the molecules selected as highly active against Y181C and

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Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7477
Table 2. Substitution of the C-5 Methyl by Azole Derivatives on the IOPY Scaffolda
a 1General procedure B was applied by reluxing in acetonitrile. 2Selectivity Index or ratio of CC50 to
IC50 relative to LAI (fold). 3a: Crystallization from i-Pr2O, b: crystallization from CH3CN, c: column
chromatography on silica, eluent CH2Cl2/MeOH/NH4OH: gradient of elution 100/0/0 to 90/10/0.1, d:
column chromatography on silica, eluent CH2Cl2/MeOH: 98/2 then crystallization from Et2O.
K103N (23, 24, 25, 28, 46, 47, 93, 98, 99, 102, 106, and 108).
Note, in particular, that three of these compounds, 23, 46,
and 99, approach the 10 nM level for the Y188L mutant, which
corresponds to a significant improvement in activity relative to
efavirenz. These 12 compounds were selected for further
evaluation against the larger panel of mutants (Table 7).
However, before analyzing this data, it is of interesting to
look at the trends in substitution versus activity in the two
series of analogues. Introduction of a sulfur atom into the C-5
side chain of the IOPY’s, as in 25 and 28 (Table 1), results in a
molecule that is comparable in activity to the 5-methoxypro-
pyl-3-dimethylaminopyridinone analogue 6. Indeed, the latter
was active with IC50 (nM) values of 2, 10, 50, and 200 at LAI
and 103N, 181C, and 188L mutant strains, respectively.9
Both these analogues are significantly more active against
the Y188L mutant than the corresponding oxygen containing
compounds 22 and 27 and the sulfur analogue 26 with an
additional terminal N-methyl amide motif. Note that thereisa
significant and even total loss of activity against this mutant
Y188L when a terminal OH group is present in the C-5 side
chain (cf. 21 and 29). In contrast to 21, the related analogue of
2 with an hydroxymethyl substituent at C-6 remains moder-
ately active against the Y188L mutant (IC50 = 630 nM).9
Compounds 35, 39, and 43 with an S/O-benzyl group
incorporated into the C-5 side chain were found to be potent
inhibitors of the three mutant strains, even if the activities for
the oxygen analogue 43 is just outside the cut off limit. The
corresponding compounds 23, 24, 30, and 36, wherein the
phenyl ring was replaced by a thiazole, thiophene, or furan
ring, were also highly active against the three mutant strains.
Indeed, thiazole 23 displays excellent acitivity against all three
of the major mutants. Note, however, that the thiazole
analogue 42 (and 87) is inactive against the Y188L mutant
and that there is a small loss in activity against this mutant for
the isomeric thiophene analogue 33 relative to 36.
As illustrated (Table 2), compounds 46-61, where the
pyridinone nucleus is separated from a second heterocyclic
ring by a simple methylene linker, are all highly active against

7478 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Table 3. Substitution of the C-5 Methyl by Substituted Cyclic Amines on the IOPY Scaffolda
Guillemont et al.
a 1General procedure B was applied by reluxing in acetonitrile. 2Selectivity index or ratio of CC50 to
IC50 relative to LAI (fold). 3a: Crystallization from i-Pr2O; b: crystallization from CH3CO2C2H5;
c: column chromato on silica, eluent CH2Cl2/MeOH/NH4OH: gradient of elution 100/0/0 to 90/10/0.1.
Table 4. Biological Activity of C-5 Modified 3-Iodo Thiophenoxy Pyridinone (ISPY) Analoguesa
a 1Selectivity index or ratio of CC50 to IC50 relative to LAI (fold). 2a: Crystallization in EtOH; b: column
chromatography on silica, eluent CH2Cl2/MeOH: 99/1 then crystallization in i-Pr2O; c: column chromatog-
raphy on silica, eluent CH2Cl2/MeOH/NH4OH: 95/5/0.1 then crystallization in i-Pr2O; d: column chroma-
tography on silica, eluent CH2Cl2/MeOH/NH4OH: 98/2 then crystallization in i-Pr2O; e: column
chromatography on silica, eluent CH2Cl2/MeOH: 99/2; f: column chromatography on silica, eluent CH2Cl2/
MeOH: 98/2 then crystallization in i-PrOH; g: column chromatography on silica, eluent CH2Cl2/MeOH: 98/2.

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7479
Table 5. Substitution of the C-5 Methyl by Azole Derivatives on the ISPY Scaffolda
a 1Selectivity index or ratio of CC50 to IC50 relative to LAI (fold). 2a: column chromatography on silica,
eluent CH2Cl2/MeOH/NH4OH: 95/5/0.1 then crystallization in i-Pr2O; b: column chromatography on silica,
eluent CH2Cl2/MeOH/NH4OH: gradient of elution 100/0/0 to 90/10/0.1; c: column chromatography on
silica, eluent CH2Cl2 then crystallization in i-Pr2O/acetone; d: column chromatography on silica, eluent
CH2Cl2/MeOH/NH4OH: 95/5/0.1 then crystallization in Et2O.
the Y181C and K03N mutants and retain significant sensitiv-
ity to the Y188L mutant strain. Indeed, the imidazole analo-
gues 47 and 56 are included in the short list of 12 compounds
forfurthertesting. The corresponding analogues62-69witha
saturated heterocyclic ring at this position also display potent
activities against the three mutant strains.
We looked next at the activities for the ISPY analogues
(Tables 4-6). Although many similarities exist between these
pyridinone analogues and the IOPY compounds, several
amazing differences were observed. Indeed, comparison of
the activities of compounds 26 and 83 and 25 with 86 revealed
that the phenoxy to thiophenyl modification at C-4 results in a
loss of sensitivity toward the Y188L mutant. This trend was
particularily noted for the furan analogue 89 relative to24 and
the thiophene analogue 92 relative to 30.
In Table 5, one sees again that pyridinone analogues with a
methylene linker at C-5 between two heteroaromatic rings
display potent activities, the two isomeric tetrazoles 93 and 99
stand out as having the best profiles in this series.
Interesting also is compound 106, where the connection is
made via the C-2 carbon. This compound is highly active
against the three major mutants and is possibly also more
metabolically stable than the isomeric N-alkylation product,
pyrrole 104.

7480 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Table 6. Substitution of the C-5 Methyl by Substituted Cyclic Amines on the ISPY Scaffolda
Guillemont et al.
a 1General procedure B was applied by reluxing in acetonitrile. 2Selectivity index or ratio of CC50 to IC50
relative to LAI (fold). 3a: Crystallization in EtOH; b: crystallization in i-Pr2O; c: column chromatography on
silica, eluent CH2Cl2/MeOH: gradient of elution 100/0 to 90/10 then crystallization in i-Pr2O; d: column
chromatography on silica, eluent toluene/i-PrOH/NH4OH: 85/14/1 then crystallization in acetone/i-PrOH; e:
column chromatography on silica, eluent CH2Cl2/MeOH: 98/2; f: column chromatography on silica, eluent
CH2Cl2/MeOH: gradient of elution 100/0 to 90/10; g: column chromatography on silica, eluent CH2Cl2/
MeOH: gradient of elution 100/0 to 90/10 then crystallization in acetone.
ThepiperidineandmorpholineanaloguespresentedinTable6
all display strong activity against the LAI HIV strain, but many
of these compounds are inactive against the Y188L mutant.
This loss in activity with respect to the Y188L mutant may
reflect the expected differences in the overall geometry/con-
formationof the ISPYand IOPY compounds. In otherwords,
due to the longer C-S bond length and wider C(4)-S-C(Ar)
bond angle in the ISPY analogues, the change in contacts with
the S-Ar substituent in the hydrophobic pocket of RT may
translate into a reduction in room available to, and the
contacts with, the heteroatom functionality present on the
C-5 side chains.
To gain a better understanding as to why often minor
structural modifications can lead to significant or complete
loss of activity, the X-ray crystal structure of the 24 wild-type
RT complex was obtained. In this structure, important inter-
actions of the furan ring in 24 with P236 were revealed. It was
further determined that the iodine atom engages in both
donor and acceptor type interactions with the backbone NH
and CdO of Gly190 and X188, respectively.15
are presented along with the values for the IOPY lead
compound 7, the 3-N-dimethylpyridinones 2 and 3, nevira-
pine, and efavirenz. Immediately evident is that the activity
profile for 7 is significantly better than that for 2/3 and
nevirapine. The discussion will therefore be restricted to a
comparison of the activities of the new pyridinone analogues
relative to 7 and the clinically used NNRTI efavirenz. As
discussed earlier, all the new compounds and 7 are signifi-
cantly more active than efavirenz against the 188L mutant.
Improvement is further noted against 106A and 190S, and the
majority of the new compounds are more active against 227C.
All the IOPY/ISPY compounds are also more active than
efavirenz against the 100I þ 103N, the 101E þ 103N, and the
103N þ 181 C double mutants. Indeed, tetrazole 99 is 1000-
fold more sensitive to the 100I þ 103N mutant than efavirenz.
Equally as important, this compound and 93 are essentially
equipotent to efavirenz against the 227 þ 106A double
mutant. This double mutant has proven to be the “achilles
heal” in the development of the pyridinone based anti-HIV
agents, since up until now very few compounds have been
identified that inhibit this mutant at IC50 < 50 nM concen-
trations.
In Table 7, the activities of the selected C-5 analogues
against an expanded panel of HIV single and double mutants

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7481
Table 7. Activity (IC50, nM) vs HIV-1 of the Selected Compounds
a Selectivity index or ratio of CC50 to IC50 relative to LAI (fold). b NVP: nevirapine; EFV: efavirenz.
Conclusion
uncorrected. Proton NMR spectra were recorded on Bruker
Avance 300 (300 MHz) and Bruker Avance 400 (400 MHz)
spectrometers. Chemical shifts (δ) were reported in ppm units
(s, d, t, q, m, and br for singlet, doublet, triplet, quadruplet,
multiplet, and broad, respectively) using internal deuterium lock
DMSO (2.54 ppm) or CDCl3 (7.28 ppm) and coupling constants
(J) in Hz. Elemental analyses, realized with a Thermo Electron
Corporation instruments EA 1110 or EA 1108, were within
0.4% of the theoretical values calculated for C, H, and N. LC/
MS analyses were performed on a Applied Biosystems API100/
Perkin-Elmer series 200 HPLC system or a Micromass LCT/
Waters’ Alliance 2795 HPLC system with a Kromasil 5 μm C18
column, 150 mm ꢀ 4.633 mm i.d. column from Interchim at
room temperature using the following solvent system: solvent A,
ammonium acetate 500 mg/L in ultrapure water; solvent B,
acetonitrile; solvent C, 0.2% formic acid in ultrapure water at a
flow rate of 1 mL/min. Gradient starting with 30% A/40%
B/30% C from 0 to 1 min and then to 100% B from 1 to 5 min
and continuing at 100% B up to 10 min. From 10 to 12 min, the
gradient was reverted back to 30% A/40% B/30% C and was
held until 13 min. UV detection was at 254 nm, and ionization
was positive or negative ion electrospray. The molecular scan
range was 100-900 amu. Samples were supplied as 0.5-1 mg/
mL in methanol and/or acetonitrile with 5 μL injected on a
partial loop fill.
This work led us to elaborate different ways to obtain
3-iodo-4-phenoxy- (and 4-phenylthio-)-5-methyl substituted
pyridin-2(1H)-one derivatives.9 These compounds constitute
new potent non-nucleoside HIV-1 RT inhibitors related both
to HEPT and Merck-pyridinone series. Biological studies
revealed that new 5-methyl substituted pyridinones show
potent HIV-1 specific reverse transcriptase inhibitory proper-
ties. Indeed, the introduction of functionalized groups at this
C5-position allowed enhancing potency against a panel of
single and double mutant strains. Best results were obtained
with the substitution of the C-5 methyl by azole derivatives
(Tables 2 and 5). Some azoles show very good profile against
the wild-type HIV, 1001E, 103N, 181C, and 188L mutant
strains and proved to be as potent as efavirenz on the whole
profile. Finally, the isomeric tetrazoles46, 93, and99represent
most interesting new leads for the further optimization of the
IOPY/ISPY series and will be selected for in vivo pharmaco-
kinetic studies.
Experimental Section
Chemistry. General Remarks. 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. Merck 60F254 procoated
silica gel plates. Flash column chromatography was performed
with the indicated solvents and using E. Merck silica gel 60
(particle size 0.035-0.070 mm unless otherwise stated). Melting
points were taken on a Kofler melting point apparatus and are
The purity of the final compounds was determined by HPLC
as described above and is 95% or higher unless specified
otherwise.
5-Ethoxycarbonyl-4-hydroxy-6-methylpyridin-2(1H)-one (14).
A solution of ethyl 3-aminocrotonate 11 (12.6 g, 97.5 mmol)
and di-(2,4,6-trichlorophenyl)malonate 13 (49.6 g, 107 mmol)19
in diglyme (400 mL) was heated at 100 ꢀC for 3 h, during which a
precipitate was separated. After cooling, diethyl ether (1.5 L) was
added and the expected 5-carbethoxypyridinone 14 was filtered
(14.2 g, 75%): mp 243-245 ꢀC (Lit. = 231-233 ꢀC).16a 1H NMR
(CDCl3) δ 1.30 (3 H, t, J = 7.0 Hz), 2.35 (3 H, s), 4.28 (2 H, q),
5.51 (1 H, s), 11.17 (1 H, br s), 11.53 (1 H, br s).

7482 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Guillemont et al.
5-Cyyano-4-hydroxy-6-methylpyridin-2(1H)-one (15). The
carbonitrile derivative 15 was prepared as described in the
literature.20
81%) mp 248-250 ꢀC. 1H NMR (DMSO-d6) δ 2.25 (6 H, s), 2.34
(3 H, s), 4.14 (2 H, br s), 4.72 (1 H, br s), 6.47 (2 H, s), 6.71 (1 H, s),
12.11 (1H, br s); Anal. (C15H16INO3) Calcd C, 46.77; H, 4.19; N,
3.64. Found 46.58; H, 4.21; N, 3.56.
5-Chloromethyl-3-iodo-6-methyl-4-(3,5-dimethylphenoxy)pyridin-
2(1H)-one (8). The heterogeneous solution of hydroxymethylpyr-
idinone 21 (450 mg; 1.2 mmol) in CH2Cl2 (30 mL) became a
homogeneous mixture by addition at room temperature SOCl2
(2.6 mL). After 2 h on stirring at room temperature, all the volatiles
were removed under reduced pressure, giving a yellow solid that
corresponds to the expected chloromethyl derivative 8 in quantita-
tive yield (470 mg) mp 256-258 ꢀC. This compound was used for
the next step without any further purification.
5-Ethoxymethyl-3-iodo-6-methyl-4-(3,5-dimethylphenoxy)pyridin-
2(1H)-one (22).A solution of chloromethylpyridinone 8(60 mg; 0.15
mmol) in absolute ethanol (5 mL) and K2CO3 (60 mg; 0.44 mmol)
was heated under reflux for 16 h. After evaporation under reduced
pressure, water (5 mL) was added and the mixture was extracted
with ethyl acetate (3 ꢀ 10 mL). The organic layer was washed with
brine (5 mL), dried over MgSO4, and the solvent was removed. The
colorless solid residue was then chromatographed on a silica gel
column with CH2Cl2/ethanol (98:2) as the eluent to give the titled
compound 22 (59 mg; 95%) mp 234-236 ꢀC. 1H NMR (CDCl3) δ
1.04 (3 H, t, J=7.0Hz), 2.32(6H, s), 2.50(3H, s), 3.30(2H, q, J=
7.0Hz), 4.21(2H, s),6.47(2H, s),6.69(1H,s), 12.99(1H, brs).MS
(C17H20INO3): m/z 414 (M þ H)þ.
5-Ethoxycarbonyl-3-iodo-6-methyl-4-(3,5-dimethylphenoxy)-
pyridin-2(1H)-one (17). Dichloro-3,5-dimethyliodobenzene
(6.6 g, 21.8 mmol), prepared from 3,5-dimethyliodobenzene
and chlorine as described in the literature,21 was suspended in
water (50 mL) containing sodium carbonate (2.1 g, 20 mmol)
and stirred for 30 min at room temperature. To this mixture, a
solution of pyridinone 14 (3.6 g, 18 mmol) in water (50 mL)
containing also sodium carbonate (2.1 g, 20 mmol) was added.
After stirring for 1 h at 20 ꢀC, the precipitate was filtered off,
washed with water, dried in vacuo, and suspended in DMF
(50 mL). After heating under reflux for 1 h, the solvent was
removed in vacuo. The residue was crystallized in diisopropyl
ether to give the titled compound (5.8 g, 75%) as yellow
1
microcrystals, mp 190 ꢀC. H NMR (DMSO-d6) δ 0.95 (3 H,
t, J = 7.1 Hz), 2.21 (6 H, s), 2.30 (3 H, s), 3.35 (2 H, q, J =
7.1 Hz), 6.47 (2 H, s), 6.70 (1 H, s), 12.30 (1 H, br s). MS 428
(MþH)þ. Anal. (C17H18INO4) Calcd C, 47.79; H, 4.25; N, 3.28.
Found C, 47.71; H, 4.23; N, 3.56.
5-Cyano-3-iodo-6-methyl-4-(3,5-dimethylphenoxy)pyridin-2(1H)-
one (18). Dichloro-3,5-dimethyliodobenzene (18.4 g, 60.8 mmol),
prepared from 1,3-dimethyliodobenzene and chlorine as described
in the literature,21 was suspended in water (100 mL) containing
sodium carbonate (6.5 g, 60.8 mmol) and stirred for 30 min at room
temperature. To this mixture, a solution of pyridinone 1520 (8.3 g,
55.3 mmol) in water (100 mL) containing also Na2CO3 (6.5 g,
60.8 mmol) was added. After stirring for 1 h at 20 ꢀC, the precipitate
wasfilteredoff,washedwithwater, dried in vacuo, and suspended in
DMF (80 mL). After heating under reflux for 1 h, the solvent was
removed in vacuo. The residue was then chromatographed on a
silica gel column with CH2Cl2/CH3OH (98:2) as the eluent to give
the titled compound 18 (8.5 g; 41%), mp 289 ꢀC. 1H NMR (DMSO-
d6) δ2.28 (6 H, s), 2.44 (3 H, s), 6.64 (2 H, s), 6.79 (1 H, s), 12.88 (1 H,
br s). Anal. (C15H13IN2O2) Calcd C, 47.39; H, 3.45; N, 7.37. Found
C, 47.23; H, 3.48; N,7.41.
5-Aminomethyl-4-(3,5-dimethylphenoxy)-3-iodo-6-methylpyr-
idin-2(1H)-one (19). Diisobutylaluminium hydride (20 wt %,
solution in toluene; 149 mL; 0.21 mol) was added at -78 ꢀC to a
solution of cyanopyridinone 18 (8 g; 21 mmol) in toluene
(160 mL). The mixture was stirred at 5 ꢀC for 4 h, hydrolyzed
with the minimum of water, and filtered over celite. The celite
was washed with CH2Cl2/MeOH (50:50). The filtrate was dried
over MgSO4 and concentrated. The residue was then chroma-
tographed on a silica gel column with CH2Cl2/MeOH/NH4OH
(90:10:0.1) as the eluent to give the titled compound 19 (5.7 g;
71%). 1H NMR (DMSO-d6) δ 2.22 (6 H, s), 2.29 (3 H, s), 3.30
(2 H, s), 6.48 (2 H, s), 6.70 (1 H, s). MS (C15H17IN2O2): m/z 385
(M þ H)þ.
Procedure A: Synthesis of 4-(3,5-Dimethylphenoxy)-5-(furan-
2-ylmethylthiomethyl)-3-iodo-6-methyl-pyridin-2(1H)-one (24):
Example of the General Procedure. A solution of chloromethyl-
pyridinone 8 (100 mg; 0.24 mmol), furan-2-ylmethanethiol
(48 mg; 0.48 mmol), and triethylamine (0.1 mL; 0.72 mmol) in
ethanol (2 mL) was heated in a sealed tube at 80 ꢀC for 3 h. The
precipitate was filtered and washed with ethanol. It was then
purified by recrystallization in EtOH to give pure iodopyridi-
none 24 (60 mg; 52%) mp 220 ꢀC (EtOH). 1H NMR (DMSO-d6)
δ 2.15-2.27 (9 H, m), 3.43 (2 H, s), 3.71 (2 H, s), 6.17 (1 H, d, J =
3.0 Hz), 6.35-6.38 (1 H, m), 6.40 (2 H, s), 6.69 (1 H, s), 7.54(1 H,
br s), 12.13 (1 H, br s). MS 482 (M þ H)þ. Anal. (C20H20INO3S)
Calcd C, 49.90; H, 4.19; N, .2.91; S, 6.66. Found C, 49.42; H,
4.28; N, 2.92; S, 6.89.
4-(3,5-Dimethylphenoxy)-3-iodo-5-(2-methoxy-ethoxymethyl)-
6-methylpyridin-2(1H)-one (27). A solution of chloromethylpyr-
idinone 8 (60 mg; 0.15 mmol) in 2-methoxyethanol (5 mL) and
K2CO3 (60 mg; 0.44 mmol) was heated at 110 ꢀC for 16 h. After
evaporation under reduced pressure, water (5 mL) was added
andthe mixture was extractedwith ethylacetate (3 ꢀ 10 mL). The
organic layer was washed with brine (5 mL), dried over MgSO4,
and the solvent was removed. The residue was then chromato-
graphed on a silica gel column with CH2Cl2/ethanol (98:2) as
the eluent to give the titled compound 27 (51 mg; 77%) mp 184-
186 ꢀC. 1H NMR (CDCl3) δ 2.25 (6 H, s), 2.51 (3 H, s), 3.29 (3 H,
s), 3.39 (4 H, m), 4.29 (2 H, s), 6.46 (2 H, s), 6.68 (1 H, s), 13.10
(1 H, br s). MS (C18H22INO4): m/z 444 (M þ H)þ. Anal. Calcd C,
48.77; H, 5,00; N, 3.16. Found C, 48,64; H, 4,94; N, 2,75.
Procedure B: Synthesis of 4-(3,5-Dimethylphenoxy)-5-[N-(furan-
2-ylmethyl)-N-methyl]aminomethyl-3-iodo-6-methylpyridin-2(1H)-
one (32): Example of the General Procedure. A solution of chlor-
omethylpyridinone 8 (100 mg; 0.24 mmol), furfurylmethylamine22
(55 mg; 0.48 mmol), and K2CO3 (100 mg; 0.72 mmol) in acetonitrile
(5 mL) was heated under reflux for 2 h. Water (5 mL) was added, and
the mixture was extracted with ethyl acetate (3 ꢀ 10 mL). The com-
bined organic layers were washed with brine (5 mL), dried over
MgSO4, and the solvent was removed. After crystallization in diiso-
propylether, pure iodopyridinone 32 was isolated (50 mg; 42%) mp
185 ꢀC. 1HNMR(DMSO-d6) δ1.99 (3 H, s), 2.21 (9 H, s), 3.10 (2 H,
s), 3.40 (2 H, s), 6.21 (1 H, d, J = 3.0 Hz), 6.36 (1 H, dd, J = 3.0,
1.1 Hz), 6.40 (2 H, s), 6.67 (1 H, s), 7.54 (1 H, d, J = 1.1 Hz), 12.09
(1 H, br s). MS (C21H23IN2O3): m/z 479 (M þ H)þ.
N-[4-(3,5-Dimethylphenoxy)-5-iodo-2-methyl-6-oxo-1,6-dihy-
dropyridin-3-ylmethyl]-benzofuran-2-carboxylamide (20). A so-
lution of 5-aminomethyl-4-(3,5-dimethylphenoxy)-3-iodo-6-
methylpyridin-2(1H)-one 19 (100 mg; 0.26 mmol), coumarilic
acid (51 mg; 0.31 mmol), EDCI (60 mg; 0.39 mmol), HOBT
(53 mg; 0.39 mmol), and triethylamine (0.054 mL; 0.39 mmol) in
CH2Cl2 was stirred at room temperature for 15 h. The mixture
was washed by a solution of 10% K2CO3, dried over MgSO4,
and the solvent was removed. After crystallization in diethyl-
ether, pure iodopyridinone 20 was isolated (73 mg; 53%). MS
(C24H21IN2O4): m/z 529 (M þ H)þ.
5-Hydroxymethyl-3-iodo-6-methyl-4-(3,5-dimethylphenoxy)-
pyridin-2(1H)-one (21). Diisobutylaluminium hydride (20 wt %,
solution intoluene;42.5mL, 51.5mmol) was added at -78 ꢀCtoa
solution of carbethoxypyridinone 17 (5.5 g, 12.9 mmol) in toluene
(150 mL). The mixture was stirred at 5 ꢀC for 2 h, hydrolyzed with
the minimum of water, and filtered over celite. The celite was
washed with CH2Cl2/methanol (98:2). The filtrate was dried over
MgSO4 and concentrated. Crystallization of the residue from
diisopropyl ether to give the hydroxymethylpyridinone 21 (4.0 g;
Procedure C: Synthesis of 4-(3,5-Dimethylphenoxy)-3-iodo-
5-(thiophen-2-yl-methoxymethyl)-6-methylpyridin-2(1H)-one

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7483
(36): Example of the General Procedure. A solution of chloro-
methylpyridinone 8 (150 mg; 0.37 mmol) and thiophen-2-ylmethanol
(0.1 mL; 1.11 mmol) in dioxanne (1 mL) was heated at reflux for
15 h. The mixture is taken in K2CO3 10% (5 mL) and extracted
with AcOEt (3 ꢀ 10 mL). The combined organic layers were
washed with brine (5 mL), dried over MgSO4, and the solvent
was removed. The residue was chromatographed on a silica gel
column with CH2Cl2/propan-2-ol (98:2) as eluent. After crystal-
lization in diethylether, pure iodopyridinone 36 was isolated
(68 mg; 38%) mp 200 ꢀC. 1H NMR (DMSO-d6) δ 2.20 (6 H, s),
2.25 (3 H, s), 4.14 (2 H, s), 4.45 (2 H, s), 6.41 (2 H, s), 6.68 (1 H, s),
6.90-7.00 (2 H, m), 7.48 (1 H, dd, J = 4.8, 1.3 Hz), 12.17 (1 H, br
s). MS (C20H20INO3S): m/z 482 (M þ H)þ.
0.278 mol) in acetonitrile (200 mL) was added in one portion
of phosphorus oxychloride (27.9 mL; 0.298 mol). The obtained
mixture was stirred at room temperature under nitrogen atmo-
sphere for 5 min and heated under reflux for 4 h. After
evaporation of all the volatiles under reduced pressure, the
residue was poured into ice water and basified using NH4OH
and extracted with CH2Cl2. The combined organic layers were
dried over MgSO4 and evaporated to give the 4,6-dichloro-2-
methyl-3-carbethoxypyridine (16.3 g; 100%), which was directly
transformed into the chloropyridinone 70 by refluxing for 15 h
in a mixture of sodium acetate (11.4 g; 0.139 mol) and acetic acid
(200 mL). The acetic acid was evaporated under reduced
pressure. The residue was poured into ice water, basified using
K2CO3, and extracted with CH2Cl2. The combined organic
layers were dried over MgSO4 and evaporated. The product
(12.0 g) was crystallized from diisopropyl ether to give the titled
4-chloropyridinone 70 (5.9 g; 39%) mp 161-163 ꢀC. 1H NMR
(CDCl3) δ 1.40 (3 H, t, J = 7.2 Hz), 2.46 (3 H, s), 4.40 (2 H, q),
Most of the products showed in Tables 1-6 were prepared in
the manner of either procedure A, B, or C. The yields, different
reaction times, and purification methods are mentioned for each
product.
4-(3,5-Dimethylphenoxy)-5-(2-hydroxy-ethoxymethyl)-3-iodo-
6-methylpyridin-2(1H)-one (29). A solution of chloromethylpyr-
idinone 8 (60 mg; 0.15 mmol) in 1,2-ethanediol (5 mL) and
K2CO3 (60 mg; 0.44 mmol) was heated at 110 ꢀC for 16 h. After
evaporation under reduced pressure, water (5 mL) was added
and the mixture was extracted with ethyl acetate (3 ꢀ 10 mL).
The organic layer was washed with brine (5 mL), dried over
MgSO4, and the solvent was removed. The residue was then
chromatographed on a silica gel column with CH2Cl2/ethanol
(98:2) as the eluent to give the titled compound 29 (31 mg; 48%)
mp 224-226 ꢀC. 1H NMR (CDCl3) δ 2.26 (6 H, s), 2.50 (3 H, s),
3.38 (2 H, q, J = 4.5 Hz), 3.50 (2 H, q, J = 4.5 Hz), 4.28 (2 H, s),
6.47 (2 H, s), 6.69 (1 H, s), 13.10 (1 H, br s). MS (C17H20INO4):
m/z 430 (M þ H)þ.
6.54 (1 H, s), 13.06 (1 H, br s). Anal. (C9H10ClNO3 0.10 EtOAc)
3
Calcd C, 50.30; H, 4.85; N,.6.24. Found C, 50.68; H, 4.45; N,
6.41. MS m/z 215-217 (M þ H)þ.
Ethyl 4-(3,5-Dimethylphenylsulfanyl)-2-methyl-6-oxo-1,6-di-
hydropyridin-3-yl-carboxylate (71). A mixture of the 4-chloro-
pyridinone 70 (5.9 g; 27.4 mmol) in ethanol (60 mL),
triethylamine (5.9 mL), and 3,5-dimethylthiophenol (4.1 mL;
30 mmol) was heated under reflux for 16 h. After cooling, the
precipitate was filtered off, washed with diisopropyl ether, and
dried. The product 71 was obtained (7 g; 80%) as a colorless
1
solid mp 233-235 ꢀC. H NMR (CDCl3) δ 1.43 (3 H, t, J =
7.2 Hz), 2.33 (6 H, s), 2.48 (3 H, s), 4.42 (2 H, q), 5.76 (1 H, s),
7.07 (1 H, s), 7.14 (2 H, s), 12.82 (1 H, br s). MS (C17H19NO3S)
m/z 318 (M þ H)þ.
4-(3,5-Dimethylphenoxy)-5-(ethanesulfonylmethyl)-3-iodo-6-meth-
ylpyridin-2(1H)-one (37). To a solution of 4-(3,5-dimethylphenoxy)-
5-(ethylthiomethyl)-3-iodo-6-methylpyridin-2(1H)-one 25 (0.35 g;
0.81 mmol) in CH2Cl2 (20 mL) was added a solution of 3-chloro-
peroxybenzoic acid (0.24 g; 0;97 mmol) in CH2Cl2 (20 mL). The
mixture was stirred at room temperature for 1 h. Water (10 mL) was
added, and the mixture was extracted with CH2Cl2. The combined
organic layers were dried over MgSO4, and the solvent was removed.
The residue was chromatographed on a silica gel column with
CH2Cl2/MeOH (98:2) as eluent. After crystallization in diisopropyl-
ether, pure iodopyridinone 37 was isolated (34 mg; 9%) mp>
250 ꢀC. MS (C17H20cINO4S): m/z 462 (M þ H)þ.
5-Hydroxymethyl-6-methyl-4-(3,5-dimethylphenylsulfanyl)pyridin-
2(1H)-one (72). Under nitrogen atmosphere, the ester 71 (500 mg;
1.6 mmol) was suspended in dry THF (20 mL) and LiAlH4 (120mg;
3.2 mmol) was added at 0 ꢀC. The mixture was stirred at room
temperature for 18 h and poured in ethyl acetate (50 mL) at 0 ꢀC
and a solution 10% H2SO4 (100 mL) was added dropwise. The
mixture was extracted with ethyl acetate (2 ꢀ 100 mL), and the
organic layer was removed under reduced pressure giving the
hydroxymethylpyridinone 72 (310 mg; 71%) mp 268-270 ꢀC. 1H
NMR (DMSO-d6) δ2.31 (9 H, s), 4.46 (2 H, s), 4.67 (1 H, br s), 5.46
(1 H, s), 7.07 (1 H, s), 7.11 (2 H, s), 11.36 (1 H, br s). MS
(C15H17NO3S): m/z 276 (M þ H)þ.
1-[4-(3,5-Dimethylphenoxy)-5-iodo-2-methyl-6-oxo-1,6-dihydro-
pyridin-3-ylmethyl]pipe ridin-4-ylcarbamate (64). A solution of
chloromethylpyridinone 8 (150 mg; 0.37 mmol), piperidin-4-ol
(75 mg; 0.74 mmol), and K2CO3 (150 mg; 1.12 mmol) in acetonitrile
(5 mL) was heated under reflux for 1 h. Water (5 mL) was added,
and the resulting precipitate was filtered, washed with water and
then with diethyl ether, and dried to give 4-(3,5-dimethylphenoxy)-
5-(4-hydroxypiperidin-1-ylmethyl)-3-iodo-6-methylpyridin-2(1H)-
5-Chloromethyl-6-methyl-4-(3,5-dimethylphenylsulfanyl)pyridin-
2(1H)-one (73). The heterogeneous solution of hydroxymethylpyr-
idinone 72 (275 mg; 1 mmol) in CH2Cl2 (10 mL) became a
homogeneous mixture by addition at room temperature SOCl2
(2.3 mL). After 2 h on stirring at room temperature, all the volatiles
were removed under reduced pressure, giving a yellow solid that
corresponds to the expected chloromethyl derivative 73 in quanti-
tative yield (294 mg). This compound was used for the next step
without any further purification.
5-Ethoxymethyl-6-methyl-4-(3,5-dimethylphenylsulfanyl)pyridin-
2(1H)-one (74). A solution of chloromethylpyridinone 73 (250 mg;
0.85 mmol) in absolute ethanol (10 mL) and triethylamine
(0.24 mL) was heated at 50 ꢀC for 18 h. After evaporation under
reduced pressure, the residue was chromatographed on a silica gel
column with CH2Cl2/ethanol (99:1) as the eluant to give the titled
compound 74 (243 mg; 94%) mp 203-205 ꢀC. 1HNMR(CDCl3) δ
1.27 (3 H, t, J = 7.2 Hz), 2.33 (6 H, s), 2.38 (3 H, s), 3.60 (2 H, q),
4.48 (2 H, s), 5.80 (1 H, s), 7.01 (1 H, s), 7.16 (2 H, s), 12.77 (1 H,
br s). Anal. (C17H21NO2S) Calcd C, 67.29; H, 6.98; N, 4.62; S,
10.57. Found 66.98; H, 6.78; N, 4.79; S, 10.38.
1
one (140 mg; 81%) mp >250 ꢀC. H NMR (DMSO-d6) δ 1.20
(2 H, q, J = 10.5 Hz), 1.52-1.62 (2 H, m), 1.90 (2 H, t, J = 6.9 Hz),
2.22 (6 H, s), 2.29 (3 H, s), 2.48-2.55 (2 H, m), 3.02 (2 H, s), 3.28-
3.40 (1 H, m), 4.45 (1 H, d, J = 2.5 Hz), 6.40 (2 H, s), 6.67 (1 H, s),
12.09 (1 H, br s). To a solution of this intermediate (140 mg;
0.3 mmol) in AcOEt (3 mL) was added dropwise chlorosulfonyl
isocyanate (0.06 mL; 0.68 mmol) at -30 ꢀC. The mixture was
stirred at -30 ꢀC for 1 h. Water (0.15 mL) was added at 5 ꢀC and
then 12 N HCl (0.15 mL) and MeOH (0.3 mL) were added. This
mixture was heated at 40 ꢀC for 2 h. The residue was poured into ice
water, basified using K2CO3, and extracted with ethyl acetate (3 ꢀ
10 mL). The combined organic layers were washed with brine
(5 mL), dried over MgSO4, and evaporated. The residue was
chromatographed on a silica gel column with CH2Cl2/methanol
(95:5) as the eluent to give pure iodopyridinone 64 (22 mg; 14%)
mp >250 ꢀC. MS (C21H26IN3O4): m/z 512 (M þ H)þ.
5-Ethoxymethyl-3-iodo-6-methyl-4-(3,5-dimethylphenylsulfanyl)-
pyridin-2(1H)-one (75). The compound 74 (100 mg; 0.33 mmol) was
dissolved in acetic acid (2 mL) and ethyl acetate (2 mL). At room
temperature and in the dark, N-iodosuccinimide (75 mg; 0.33
mmol) was added in one portion. After 2.5 h under stirring at
room temperature, the mixture was poured into water (5 mL) and
Ethyl 4-Chloro-2-methyl-6-oxo-1,6-dihydropyridin-3ylcarbo-
xylate (70). To a solution of 4-hydroxypyridinone 14 (13.7 g;
0.0695 mol) and benzyltriethylammonium chloride (63.3 g;

7484 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Guillemont et al.
the pH of the solution was adjusted to ca. 7 with 28% ammonia.
The combined organic layers obtained by extraction with CH2Cl2
(3 ꢀ 10 mL) were washed with water (15 mL), dried over MgSO4,
and evaporated to give a solid residue. It was then chromato-
graphed on silica gel column with CH2Cl2/ethanol (99:1) as the
eluant to give a the titled compound 75 as colorless microcrystals
(96 mg; 68%) mp 220-222 ꢀC. 1H NMR (CDCl3) δ 1.13 (3H, t,
J = 7.2 Hz), 2.26 (6 H, s), 2.50 (3 H, s), 3.41 (2 H, q), 4.55 (2 H, s),
6.78 (2 H, s), 6.83 (s, 1H, H-40), 12.82 (1 H, br s). Anal.
(C17H20INO2S) Calcd C, 47.56; H, 4.70; N, 3.26; S, 7.47. Found
C, 47.62; H, 4.51; N,.3.48; S, 7.44.
Ethyl 4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-
1,6-dihydropyridin-3-ylcarboxylate (76). N-Iodosuccinimide (28 g;
110 mmol) was added at room temperature to a solution of 71 (7 g;
22 mmol) in N,N-dimethylformamide (50 mL). The mixture was
stirred for 48 h in darkness, poured into water, and extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO4, and the solvent was removed. After crystal-
lization from a mixture of diisopropyl ether and 2-propanol, pure
iodopyridinone 76 was isolated (7.5 g; 77%) mp 210 ꢀC. 1H NMR
(DMSO-d6) δ 1.00-1.10 (3 H, m), 2.13 (3 H, br s), 2.22 (6 H, s),
3.75-3.90 (2 H, m), 6.85 (2 H, br s), 6.93 (1H, br s), 12.30 (1 H, br s).
Anal. (C17H18INO3S) Calcd C, 46.06; H, 4.09; N, 3.16; S, 7.23.
Found C, 45.88; H, 4.21; N, 3.12; S, 7.27.
5-Hydroxymethyl-3-iodo-6-methyl-4-(3,5-dimethylphenylsulfanyl)-
pyridin-2(1H)-one (77). Diisobutylaluminium hydride (20 wt %,
solution in toluene; 56 mL, 67.7 mmol) was added at -78 ꢀC to a
solution of carbethoxypyridinone 76 (7.5 g, 16.9 mmol) in toluene
(500mL).Themixturewasstirredat5ꢀC for 2 h, hydrolyzed with the
minimum of water, and filtered over celite. The celite was washed
with CH2Cl2/methanol (98:2). The filtrate was dried over MgSO4
and concentrated. Crystallization of the residue from diisopropyl
ether to give the hydroxymethylpyridinone 77 (5.7 g; 84%) mp
240 ꢀC. MS (C15H16INO2S): m/z 402 (M þ H)þ. This compound
was used for the next step without any further purification.
5-Chloromethyl-3-iodo-6-methyl-4-(3,5-dimethylphenylsulfanyl)-
pyridin-2(1H)-one (9). SOCl2 (0.9 mL; 12.3 mmol) was added
dropwise at 0 ꢀC to a solution of hydroxymethylpyridinone 77
(800 mg; 1.9 mmol) in CH2Cl2 (90 mL). The mixture was stirred at
room temperature overnight and all the volatiles were removed
under reduced pressure, giving a yellow solid that corresponds to
the expected chloromethyl derivative 9 (700 mg; 89%) mp 218 ꢀC.
This compound was used for the next step without any further
purification.
4-Chloro-2-methyl-6-oxo-1,6-dihydropyridin-3ylcarbonitrile (78).
To a solution of 4-hydroxypyridinone 15 (3.0 g; 0.02 mol) and
benzyltriethylammonium chloride (9.1 g; 0.04 mol) in acetonitrile
(120 mL) was added in one portion phosphorus oxychloride
(3.7 mL; 0.04 mol). The obtained mixture was stirred at room
temperature under nitrogen atmosphere for 5 min and heated
under reflux for 15 h. After evaporation of all the volatiles under
reduced pressure, the residue was poured into ice-water and
basified using NH4OH and extracted with CH2Cl2. The combined
organic layers were dried over MgSO4 and evaporated to give the
4,6-dichloro-2-methyl-3-cyanopyridine (3.1 g; 83%), which was
directly transformed into the chloropyridinone 78 by refluxing for
15 h in a mixture of sodium acetate (3.0 g; 0.036 mol) and acetic acid
(50 mL). The acetic acid was evaporated under reduced pressure.
The residue was poured into ice water, basified using K2CO3, and
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4 and evaporated. The product (12.0 g) was crystallized
from diisopropyl ether to give the titled 4-chloropyridinone 78
(2.8 g; 100%). MS (C7H5ClN2O): m/z 169-171 (M þ H)þ. This
unstable chloronitrile derivative was used for the next step without
any further purification.
filteredoff, washedwithdiisopropyl ether, and dried. The product
79 was obtained (800 mg; 13%) mp >250 ꢀC. 1H NMR (DMSO-
d6) δ 2.33 (6 H, s), 2.40 (3 H, s), 5.23 (1 H, s), 7.25 (3 H, m), 12.32
(1 H, br s). MS (C15H14N2OS): m/z 271 (M þ H)þ.
4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-di-
hydropyridine-3-ylcarbonitrile (80). N-Iodosuccinimide (3.1 g;
12.6 mmol) was added at room temperature to a solution of 79
(680 mg; 2.5 mmol) in N,N-dimethylformamide (3 mL). The
mixture was stirred for 48 h in darkness, poured into water, and
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO4, and the solvent was
removed. After crystallization from 2-propanol, pure iodopyr-
idinone 80 was isolated (600 mg; 61%) mp >250 ꢀC. 1H NMR
(DMSO-d6) δ 2.23 (6 H, s), 2.35 (3 H, s), 6.83-6.98 (3 H, m),
12.85 (1 H, br s). MS (C15H13IN2OS): m/z 397 (M þ H)þ.
5-Aminomethyl-4-(3,5-dimethylphenylsulfanyl)-3-iodo-6-methyl-
pyridin-2(1H)-one (81). Borane-methyl sulfide complex (2 M
solution in tetrahydrofuran; 6.4 mL, 12.6 mmol) was added at
0ꢀC to a solution of cyanopyridinone 80 (0.5 g, 1.26 mmol) in THF
(10 mL). The mixture was stirred at room temperature for 2 h,
hydrolyzed with 3 N HCl, and then basified with 3 N NaOH and
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, and the solvent was removed. The residue was
chromatographed on a silica gel column with CH2Cl2/methanol/
NH4OH (95:5:0.1) as the eluent to give the aminomethylpyridi-
none 81 (250 mg; 50%) mp >250 ꢀC. 1H NMR (DMSO-d6) δ 2.21
(6 H, s), 2.35 (3 H, s), 3.43 (2 H, s), 6.71 (2 H, s), 6.88 (1 H, s), 7.50-
9.50 (3 H, br s). MS (C15H17IN2OS): m/z 401 (M þ H)þ.
N-[4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-
dihydropyridin-3-ylmethyl]formamide (82). A solution of 5-ami-
nomethylpyridinone 81 (100 mg; 0.25 mmol), formic acid (0,
1 mL), and formamide (0.5 mL) was heated at 100 ꢀC for 1 h. The
mixture was neutralized by addition of a solution of 10%
K2CO3. The resulting precipitate was filtered and chromato-
graphed on a silica gel column with CH2Cl2/methanol (95:5) as
the eluant to give the titled compound 82 (15 mg; 14%). MS
(C16H17IN2O2S): m/z 429 (M þ H)þ.
3-Iodo-4-(3,5-dimethylphenylsulfanyl)-6-methyl-5-(2-pyrazin-
2-yl-ethylthiomethyl)pyridin-2(1H)-one (84). A solution of chloro-
methylpyridinone 9 (150 mg; 0.36 mmol), pyrazineethanethiol
(100 mg; 0.71 mmol), and triethylamine (0.15 mL; 1.07 mmol) in
ethanol (2 mL) was heated in an sealed tube at 70 ꢀC for 2 h. The
precipitate was filtered and washed with ethanol. It was then
purified by chromatography on silica gel column with CH2Cl2/
methanol (90:10) as the eluent to give, after crystallization from
diisopropyl ether, pure iodopyridinone 84 (55 mg; 29%) mp
166 ꢀC. 1H NMR (DMSO-d6) δ 2.19 (6 H, s), 2.29 (3 H, s), 2.89
(2 H, t, J = 7.0 Hz), 3.03 (2 H, t, J = 7.0 Hz), 3.84 (2 H, s), 6.70
(2 H, s), 6.83 (1 H, s), 8.47 (1 H, d, J = 2.3 Hz), 8.51-8.60 (2 H,
m), 12.20 (1 H, br s). MS (C21H22IN3OS2): m/z 524 (M þ H)þ.
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-6-methyl-5-(tetrazol-2-yl-
methyl)pyridin-2(1H)-one (93) and 4-(3,5-Dimethylphenylsulfanyl)-
3-iodo-6-methyl-5-(tetrazol-1-ylmethyl)pyridin-2(1H)-one (99). A
solution of chloromethylpyridinone 9 (360 mg; 0.86 mmol), 1H-
tetrazole (120 mg; 1.72 mmol), and K2CO3 (360 mg; 2.58 mmol) in
acetonitrile (20 mL) was heated at 80 ꢀCfor1h. Water(20mL) was
added, and the mixture was extracted with ethyl acetate (3 ꢀ
25 mL). The organic layer was washed with brine (10 mL), dried over
MgSO4, and the solvent was removed. The compounds 93 and 99
were separated by silica gel chromatography with CH2Cl2/metha-
nol/NH4OH (90:10:0.1) as the eluent and crystallized from Et2O.
Compound 93 (15 mg; 4%); mp >250 ꢀC (Et2O). 1H NMR
(DMSO-d6) δ 2.15 (6 H, s), 2.38 (3 H, s), 5.90 (2 H, s), 6.55 (2 H,
s), 6.79 (1 H, s), 8.83 (1 H, s), 12.46 (1 H, br s). MS
(C16H16IN5OS): m/z 454 (M þ H)þ.
4-(3,5-Dimethylphenylsulfanyl)-2-methyl-6-oxo-1,6-dihydro-
pyridin-3-ylcarbonitrile (79). A mixture of the 4-chloropyridi-
none 78 (4 g; 23 mmol) in ethanol (100 mL), triethylamine
(4 mL), and 3,5-dimethylthiophenol (3.2 mL; 23 mmol) was
heated under reflux for 16 h. After cooling, the precipitate was
Compound 99 (45 mg; 12%); mp >250 ꢀC (Et2O). 1H NMR
(DMSO-d6) δ 2.15 (6 H, s), 2.37 (3 H, s), 5.62 (2 H, s), 6.57 (2 H,
s), 6.78 (1 H, s), 9.25 (1 H, s), 12.44 (1 H, br s).
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-6-methyl-5-(3-
methyl-1H-[1,2,4]triazol-1-ylmethyl)pyridin-2(1H)-one (94) and

Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23 7485
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-6-methyl-5-(5-methyl-
1H-[1,2,4]triazol-1-ylmethyl)pyridin-2(1H)-one (101). A solution
of chloromethylpyridinone 9 (300 mg; 0.71 mmol), 3-methyl-
1H-[1,2,4]triazole23 (90 mg; 1.07 mmol), and K2CO3 (300 mg;
2.14 mmol) in acetonitrile (15 mL) was heated at 80 ꢀC for 1 h.
Water (20 mL) was added, and the mixture was extracted with ethyl
acetate (3 ꢀ 25 mL). The organic layer was washed with brine
(10 mL), dried over MgSO4, and the solvent was removed. After pre-
purification on silica gel chromatography with CH2Cl2/methanol
(96:4) as the eluent, the compounds 94 and 101 were separated on
Hypersil C18 with methanol/H2O (64:36) as the eluent.
{1-[4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-
dihydropyridin-3-ylmethyl]-5-methyl-1H-[1,2,4]triazol-3-yl}aceto-
nitrile (107). A solution of chloromethylpyridinone 9 (300 mg;
0.71 mmol), (5-methyl-2H-[1,2,4]triazol-3-yl)acetonitrile25 (180mg;
1.43 mmol), and K2CO3 (300 mg; 2.14 mmol) in acetonitrile
(20 mL) was heated at 80 ꢀC for 1 h. Water (20 mL) was added,
and the mixture was extracted with ethyl acetate (3 ꢀ 25 mL). The
organic layer was washed with brine (10 mL), dried over MgSO4,
and the solvent was removed. It was then purified by chromatog-
raphy on Hypersil C18 with CH3CN/H2O (35:65) as the eluent to
give after crystallization from Et2O/acetone the product, which
corresponds to the title compound 107 (62 mg; 17%); mp 224 ꢀC
(Et2O/acetone). 1H NMR (DMSO-d6) δ 2.15 (6 H, s), 2.35 (3 H, s),
2.40 (3 H, s), 3.95 (2 H, s), 5.20 (2 H, s), 6.49 (2 H, s), 6.78 (1 H, s),
12.40 (1 H, br s). MS (C20H20IN5OS): m/z 506 (M þ H)þ. The by-
product (not shown) {2-[4-(3,5-dimethylphenylsulfanyl)-5-iodo-2-
methyl-6-oxo-1,6-dihydropyridin-3-ylmethyl]-5-methyl-2H-[1,2,4]-
triazol-3-yl}acetonitrile was also isolated (95 mg; 26%); mp >
250 ꢀC. 1H NMR (DMSO-d6) δ 2.10 (3 H, s), 2.15 (6 H, s), 2.37
(3 H, s), 4.30 (2 H, s), 5.20 (2 H, s), 6.47 (2 H, m), 6.76 (1 H, s), 12.38
(1 H, br s). MS (C20H20IN5OS): m/z 506 (M þ H)þ.
Compound 94 (73 mg; 22%); mp 248 ꢀC. 1H NMR (DMSO-
d6) δ 2.13 (6 H, s), 2.33 (3 H, s), 2.40 (3 H, s), 5.22 (2 H, s), 6.45
(2 H, s), 6.76 (1 H, s), 7.68 (1 H, s), 12.40 (1 H, br s). MS
(C18H19IN4OS): m/z 467 (M þ H)þ.
Compound 101 (57 mg; 17%); mp >250 ꢀC. 1H NMR
(DMSO-d6) δ 2.17 (9 H, s), 2.37 (3 H, s), 5.27 (2 H, s), 6.58
(2 H, s), 6.80 (1 H, s), 8.21 (1 H, s), 12.36 (1 H, br s). MS
(C18H19IN4OS): m/z 467 (M þ H)þ.
3-[4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-di-
hydropyridin-3-ylmethyl]-5-methyl-3H-imidazol-4-ylcarbonitrile (100).
To a solution of 109 obtained as described below (370 mg; 0.73 mmol)
in tetrahydrofuran (30 mL), 1,10-carbonyldiimidazole (370 mg; 2.9
mmol) was added. The mixture was stirred at reflux for 15 h, poured
into water, and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4, and the solvent was removed. The solid
residue was washed with hot acetone to give the titled compound 100
(300 mg, 84%) mp >250 ꢀC. 1H NMR (DMSO-d6) δ 2.07 (3 H, s),
2.15(6H,s),2.29(3H,s),5.19(2H,s),6.56(2H,s),6.76(1H,s),7.63
(1 H, s), 12.36 (1 H, br s). MS (C20H19IN4OS): m/z 491 (M þ H)þ.
4-(3,5-Dimethylphenylsulfanyl)-5-(3-furan-2-yl-5-methyl-[1,2,4]-
triazol-1-ylmethyl)-3-iodo-6-methylpyridin-2(1H)-one (103). A so-
lution of chloromethylpyridinone 9 (300 mg; 0.71 mmol), 5-furan-
2-yl-3-methyl-1H-[1,2,4]triazole (160 mg; 1.07 mmol,)24 and
K2CO3 (300 mg; 2.14 mmol) in acetonitrile (20 mL) was heated
at 80 ꢀC for 1 h. Water (20 mL) was added, and the mixture was
extracted with ethyl acetate (3 ꢀ 25 mL). The organic layer was
washed with brine (10 mL), dried over MgSO4, andthesolventwas
removed. It was then purified by chromatography on silica gel
column with CH2Cl2/methanol (97:3) as the eluent to give after
crystallization from EtOH the main product, which corresponds
to the title compound (100 mg; 26%); mp >250 ꢀC (EtOH). 1H
NMR (DMSO-d6) δ 2.00 (6 H, s), 2.36 (3 H, s), 2.44 (3 H, s), 5.26
(2 H, s), 6.41 (2 H, s), 6.55 (1 H, s), 6.68 (1 H, s), 6.76 (1 H, d, J =
2.5 Hz), 7.70 (1 H, s), 12.44 (1 H, br s). MS (C22H21IN4O2S): m/z
533 (M þ H)þ. The byproduct (not shown) 4-(3,5-dimethylphe-
nylsulfanyl)-5-(5-furan-2-yl-3-methyl-[1,2,4]triazol-1-ylmethyl)-3-
iodo-6-methylpyridin-2(1H)-one was also isolated (60 mg; 16%);
mp >250 ꢀC (EtOH). 1H NMR (DMSO-d6) δ 2.10 (6 H, s), 2.15
(3 H, s), 2.37 (3 H, s), 5.52 (2 H, s), 6.31 (2 H, s), 6.70 (1 H, m), 6.74
(1 H, s), 6.95 (1 H, d, J = 2.5 Hz), 7.86 (1 H, s), 12.40 (1 H, br s).
MS (C22H21IN4O2S): m/z 533 (M þ H)þ.
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-6-methyl-5-(3-phenyl-
[1,2,4]triazol-1-ylmethyl)-pyridin-2(1H)-one (108). A solution
of chloromethylpyridinone 9 (250 mg; 0.6 mmol), 5-phenyl-
1H-[1,2,4]triazole26 (174 mg; 1.2 mmol), and K2CO3 (250 mg;
1.8 mmol) in acetonitrile (20 mL) was heated at 80 ꢀC for 1 h 30.
Water (20 mL) was added, and the mixture was extracted with
ethyl acetate (3 ꢀ 25 mL). The organic layer was washed with
brine (10 mL), dried over MgSO4, and the solvent was removed.
It was then purified by chromatography on silica gel column
with CH2Cl2/methanol/NH4OH (95:5:0.1) as the eluent to give
after crystallization from Et2O the product, which corresponds
to the title compound 108 (60 mg; 19%); mp >250 ꢀC (Et2O).
1H NMR (DMSO-d6) δ 2.18 (6 H, s), 2.47 (3 H, s), 5.44 (2 H, s),
6.57 (2 H, s), 6.73 (1 H, s), 7.35-7.47 (3 H, m), 7.90 (2 H, d, J =
7.5 Hz), 8.40 (1 H, s), 12.40 (1 H, br s). MS (C23H21IN4OS): m/z
529 (M þ H)þ. The byproduct (not shown) 4-(3,5-dimethyl-
phenylsulfanyl)-3-iodo-6-methyl-5-(3-phenyl-[1,2,4]triazol-4-yl-
methyl)-pyridin-2(1H)-one was also isolated (60 mg; 19%);
mp >250 ꢀC (Et2O). 1H NMR (DMSO-d6) δ 2.10(6 H, s), 2.43
(3 H, s), 5.39 (2 H, s), 6.05 (2 H, s), 6.73 (1 H, s), 7.49-7.60 (5 H,
m), 7.90 (1 H, s), 12.40 (1 H, br s). MS (C23H21IN4OS): m/z 529
(M þ H)þ.
3-[4-(3,5-Dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-
dihydropyridin-3-ylmethyl]-5-methyl-3H-imidazol-4ylcarbalde-
hyde oxime (109). Step 1: A solution of chloromethylpyridi-
none 9 (1.5 g; 3.57 mmol), 5-methyl-3H-imidazole-4-carbal-
dehyde (0.72 g; 6.54 mmol), and K2CO3 (300 mg; 9.9 mmol)
in acetonitrile (80 mL) was heated at 80 ꢀC for 15 h. Water
(50 mL) was added, and the mixture was extracted with ethyl
acetate (3 ꢀ 75 mL). The organic layer was washed with brine
(25 mL), dried over MgSO4, and the solvent was removed. It
was then purified by chromatography on silica gel column with
CH2Cl2/methanol/NH4OH (94:6:0.6) as the eluent to give the
main product, which corresponds to the 3-[4-(3,5-dimethyl-
phenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-dihydropyridin-3-
ylmethyl]-5-methyl-3H-imidazol-4-ylcarbaldehyde (0.66 g; 41%);
mp >250 ꢀC. 1H NMR (DMSO-d6) δ 2.12 (6 H, s), 2.22 (3 H, s),
2.28 (2 H, s), 5.40 (2 H, s), 6.58 (2 H, s), 6.75 (1 H, s), 7.47 (1 H, s),
12.30 (1 H, br s). Besides this intermediate 3H-imidazol-4-ylcar-
baldehyde, the byproduct 1H-imidazol-4-ylcarbaldehyde was
also isolated (0.41 g; 26%); mp >250 ꢀC. 1H NMR (DMSO-d6)
δ2.12(6 H, s),2.28(3 H, s),2.40(2 H, s), 5.03(2 H, s), 6.58(2 H, s),
6.70 (1 H, s), 7.37 (1 H, s), 12.30 (1 H, br s). Step 2: A solution of
3-[4-(3,5-dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-di-
hydropyridin-3-ylmethyl]-5-methyl-3H-imidazol-4-ylcarbaldehyde
obtained above (600 mg; 1.2 mmol) and hydroxylamine hydro-
chloride (100 mg; 1.56 mmol) in ethanol (50 mL) was heated at
50 ꢀC. A solution of 5 N NaOH (10 mL) was added dropwise. The
mixture was heated at 50 ꢀC for 2 h, poured into water, and
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-6-methyl-5-pyrrol-1-yl-
methylpyridin-2(1H)-one (104) and 4-(3,5-Dimethylphenylsulfanyl)-
3-iodo-6-methyl-5-(1H-pyrrol-2-ylmethyl)pyridin-2(1H)-one (106).
A solution of chloromethylpyridinone 9 (500 mg; 1.19 mmol),
pyrrole (160 mg; 2.38 mmol), and K2CO3 (490 mg; 3.57 mmol) in
acetonitrile (20 mL) was heated at 80 ꢀCfor2h. Water(20mL) was
added, and the mixture was extracted with ethyl acetate (3 ꢀ
25 mL). The organic layer was washed with brine (10 mL), dried
over MgSO4, and the solvent was removed. It was then purified by
chromatography on silica gel with CH2Cl2/methanol/NH4OH
(97:3) as the eluent. Two pure fractions were collected which
correspond to (i) the pyrrol-1-ylmethylpyridinone derivative 104
(70 mg; 13%), MS (C19H19IN2OS), m/z 451 (M þ H)þ and (ii) the
pyrrol-2-ylmethylpyridinone analogue 106 (80 mg; 15%), mp
240 ꢀC (EtOH). 1H NMR (DMSO-d6) δ 2.18 (9 H, s), 3.91 (2 H,
s), 5.46 (1 H, s), 5.83 (1 H, s), 6.53 (1 H, s), 6.65 (2 H, s), 6.80 (1 H,
s), 10.40 (1 H, br s), 12.18 (1 H, br s). MS (C19H19IN2OS): m/z 451
(M þ H)þ.

7486 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 23
Guillemont et al.
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, and the solvent was removed. After crystallization in
diisopropylether, pure pyridinone oxime 109 was isolated (500 mg;
81%); mp >250 ꢀC. 1H NMR (DMSO-d6) δ 2.10 (3 H, s), 2.15
(6 H, s), 2.20 (3 H, s), 5.20 (2 H, s), 6.61 (2 H, s), 6.76 (1 H, s), 7.15
(1 H, s), 8.06 (1 H, s), 10.96 (1 H, s), 12.33 (1 H, br s). MS
(C20H21IN4O2S): m/z 509 (M þ H)þ.
phenylsulfanyl)-3-iodo-6-methylpyridin-2(1H)-one (260 mg; 95%),
which was directly transformed into the aminomethylmorpholine
derivative. Step 3: To a solution of this aminomethylmorpholine
intermediate (260 mg, 0.52 mmol) and formaldehyde (37% in H2O,
0.39 mL, 5.2 mmol) in acetonitrile (10 mL), sodium cyanoborohy-
dride (100 mg, 1.56 mmol) was added portionwise at room tem-
perature under nitrogen. Acetic acid (0.2 mL) was added, and the
reaction was stirred at room temperature for 1 h. The mixture was
poured into ice-water, basified with K2CO3, and extracted with
CH2Cl2 (3 ꢀ 10 mL). The combined organic layers were dried over
MgSO4 and evaporated. It was then chromatographed on silica gel
column with CH2Cl2/methanol/NH4OH (90:10:0.1) as the eluent
to give, after crystallization from diisopropyl ether, the titled
4-(3,5-Dimethylphenylsulfanyl)-3-iodo-5-[2-(2-methoxyethyl)-
morpholin-4-ylmethyl)]-6-methylpyridin-2(1H)-one (117). Step 1:
To the 2-(4-benzylmorpholin-2-yl)ethanol27 (1.5 g; 6.78 mmol)
in 10 mL of dry DMF at 5 ꢀC under N2 was added NaH
portionwise (60% in mineral oil; 300 mg; 7.45 mmol). The
suspension was stirred at 5 ꢀC for 10 min, after which a solution
of CH3I (0.46 mL; 7.45 mmol) in DMF (2 mL) was added. After
the mixture was stirred for 30 min at 5 ꢀC, the mixture was
poured in water and extracted with ethyl acetate. The organic
layer was washed with brine, dried over MgSO4, and the solvent
was removed. The residue was then chromatographed on a silica
gel column with cyclohexane/AcOEt (50:50) as the eluent to give
the 4-benzyl-2-(2-methoxyethyl)morpholine (700 mg; 44%). 1H
NMR (CDCl3) δ 1.60-1.78 (2 H, m), 1.89 (3 H, t, J = 10.2 Hz),
2.15 (1 H, td, J = 10.2, 3.0 Hz), 2.65 (1 H, d, J = 10.2 Hz), 2.75
(1 H, d, J = 10.2 Hz), 3.32 (3 H, s), 3.40-3.53 (4 H, m), 3.60-
3.70 (2 H, m), 3.80-3.86 (1 H, m), 7.24- 7.36 (5 H, m). Step 2:
After displacing the air with N2, palladium on charcoal (10%;
100 mg) was added to a solution of 4-benzyl-2-(2-methoxy-
ethyl)morpholine (400 mg; 1.7 mmol) in MeOH (30 mL). After
hydrogenation under 3 bar at 40 ꢀC for 3 h, the palladium
catalyst was removed by filtration over a bed of celite. The celite
was washed with methanol. The filtrate was evaporated to give
2-methoxyethylmorpholine (220 mg; 90%). Step 3: A solution of
chloromethylpyridinone 9 (150 mg; 0.36 mmol), 2-methoxy-
ethylmorpholine (100 mg; 0.71 mmol), and K2CO3 (150 mg;
1.07 mmol) in acetonitrile (5 mL) was heated at 80 ꢀC for 1 h.
Water (5 mL) was added, and the mixture was extracted with
ethyl acetate (3 ꢀ 10 mL). The organic layer was washed with
brine (5 mL), dried over MgSO4, and the solvent was removed.
The colorless solid residue was then chromatographed on a silica
gel column with CH2Cl2/ethanol (95:5) as the eluent to give after
recrystallization from diisopropyl ether, the titled compound
1
compound 119 (116 mg; 42%) mp 164 ꢀC; (i-Pr2O). H NMR
(CDCl3) δ 1.86 (1 H, t, J = 10.4 Hz), 2.05-2.22 (5 H, m), 2.24 (9 H,
s), 2.36-2.46 (1 H, m), 2.49 (4 H, s), 2.56 (2 H, t, J = 10.4 Hz), 3.45
(2 H, t, J = 10.9 Hz), 3.56 (2 H, s), 3.80 (1 H, d, J = 10.9 Hz), 6.69
(2H, s),6.80(1H,s),12.83(1H, brs).MS(C22H30IN3O2S): m/z528
(M þ Hþ).
Biology. Evaluation of Antiviral Activity of the Compounds.
Cells and Viruses. MT4 cells are human T-lymphoblastoid 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.
Site-Directed Mutants. 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.29
Drug Sensitivity Assays. The antiviral activity of compounds
against laboratory adapted strains, site-directed mutants, and
clinical sample derived recombinant viruses was tested using a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) colorimetric assay as previously described30 Briefly,
various concentrations of the test compounds 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 30000 cells/well, respectively. 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 IC50 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 IC50 for the tested virus by the IC50
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.
1
117 (100 mg; 53%) mp 146 ꢀC (i-Pr2O). H NMR (CDCl3) δ
1.59-1.73 (2 H, m), 1.89 (1 H, t, J = 10.4 Hz), 2.15-2.23 (1 H,
m), 2.24 (6 H, s), 2.48 (3 H, s), 2.50-2.63 (2 H, m), 3.31 (3 H, s),
3.38-3.50 (4 H, m), 3.55 (2 H, s), 3.76 (1 H, d, J = 11.1 Hz), 6.69
(2 H, s), 6.80 (1 H, s), 12.64 (1 H, br s). Anal. (C22H29IN2O3S)
Calcd C, 50.00; H, 5.53; N,.5.30; S, 6.07. Found C, 49.84; H,
5.63; N, 5.27; S, 5.83
5-(2-Dimethylaminomethylmorpholin-4-ylmethyl)-4-(3,5-dimeth-
ylphenylsulfanyl)-3-iodo-6-methylpyridin-2(1H)-one (119). Step 1:
A solution of chloromethylpyridinone 9 (300 mg; 0.715 mmol),
tert-butyl morpholin-2-ylmethylcarbamate28 (310 mg; 1.43 mmol),
and K2CO3 (300 mg; 2.14 mmol) in acetonitrile (10 mL) was heated
at 80 ꢀC for 1 h. Water (15 mL) was added, and the mixture was
extracted with ethyl acetate (3 ꢀ 25 mL). The combined organic
layers were washed with brine (15 mL), dried over MgSO4, and the
solvent was removed. After crystallization from Et2O, tert-butyl
{4-[4-(3,5-dimethylphenylsulfanyl)-5-iodo-2-methyl-6-oxo-1,6-di-
hydropyridin-3-ylmethyl]-morpholin-2ylmethyl}-carbamate was
1
isolated (350 mg; 80%) as an oil. H NMR (DMSO-d6) δ 1.37
Acknowledgment. Financial support from “Ensemble con-
tre le SIDA-Sidaction”.
(9 H, s), 1.70 (1 H, t, J = 10.2 Hz), 2.05 (1 H, td, J = 10.2 Hz, 2.6
Hz), 2.20 (6 H, s), 2.30 (3 H, s), 2.58 (1 H, d, J = 10.2 Hz), 2.85-
2.95 (2 H, m), 3.12-3.25 (2 H, m), 3.35-3.52 (2 H, m), 3.67 (1 H, d,
J = 10.2 Hz), 6.65 (2 H, s), 6.78-6.85 (2 H, m), 11.90 (1 H, br s).
MS (C25H34IN3O4S): m/z 600 (M þ H)þ. Step 2: A solution of this
carbamate intermediate (330 mg; 0.55 mmol) in 3 N HCl (7 mL)
and isopropyl alcohol (3 mL) was heated at 50 ꢀC for 30 min. After
dilution with H2O (10 mL), the mixture was basified with K2CO3
and extracted with CH2Cl2 (2 ꢀ 15 mL). The combined organic
layers were dried over MgSO4 and the solvent was removed to
afford 5-(2-aminomethylmorpholin-4-ylmethyl)-4-(3,5-dimethyl-
Supporting Information Available: Synthetic procedure, inter-
mediate and final product characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
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