Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs

Article abstract of DOI:10.1021/jm950639r

Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of nonnucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moleties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double- mutant viruses, HIV-1 (Ile100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC₅₀'s against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED₅₀'s between I and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC₅₀'s between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC₅₀'s between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED₅₀'s between 9 and 100 nM and mutant HIV-1 (Cys181) with ED₅₀'s between 3 and 20 nM.

Full text of DOI:10.1021/jm950639r

J . Med. Chem. 1996, 39, 4261-4274
4261
P h en eth ylth ia zolylth iou r ea (P ETT) Com p ou n d s a s a New Cla ss of HIV-1
Rever se Tr a n scr ip ta se In h ibitor s. 2. Syn th esis a n d F u r th er Str u ctu r e-Activity
Rela tion sh ip Stu d ies of P ETT An a logs
Amanda S. Cantrell,† Per Engelhardt,‡ Marita Ho¨gberg,*,‡ S. Richard J askunas,† Nils Gunnar J ohansson,‡
Christopher L. J ordan,† J ussi Kangasmetsa¨,‡ Michael D. Kinnick,† Peter Lind,‡ J ohn M. Morin, J r.,†
M. A. Muesing,† Rolf Noree´n,‡ Bo O¨ berg,‡,§ Paul Pranc,† Christer Sahlberg,‡ Robert J . Ternansky,†
Robert T. Vasileff,† Lotta Vrang,‡ Sarah J . West,† and Hong Zhang‡
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, Medivir AB, Huddinge, Sweden, and MTC,
Center for Microbiology and Tumorbiology, The Karolinska Institute, Stockholm, Sweden
Received August 29, 1995X
Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-
nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of
compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N′-[2-(5-bromopyridyl)]-
thiourea hydrochloride (trovirdine; LY300046‚HCl) as a highly potent anti-HIV-1 agent.
Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS.
Extension of these structure-activity relationship studies to identify additional compounds in
this series with improved properties is ongoing. A part of this work is described here.
Replacement of the two aromatic moieties of the PETT compounds by various substituted or
unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple
substitution in the phenyl ring were also studied. The antiviral activities were determined on
wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses
derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were
determined on double-mutant viruses, HIV-1 (Ile100/Asn103) and HIV-1 (Ile100/Cys181). A
number of highly potent analogs were synthesized. These compounds displayed IC50’s against
wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1
with ED50’s between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant
HIV-1 RT (Ile 100) with IC50’s between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with
IC50’s between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with
ED50’s between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50’s between 3 and 20 nM.
Sch em e 1
Thus far, only four antiviral drugs have been ap-
proved for use against human immunodeficiency virus
(HIV) in the treatment of AIDS, namely AZT (azido-
thymidine), ddI (2′,3′-dideoxyinosine), ddC (2′,3′-dideoxy-
cytidine),1 and d4T (2′,3′-didehydro-2′,3′-dideoxythymi-
dine).2,3 All of these agents target the retroviral en-
zyme, HIV reverse transcriptase (RT). These nucleoside
analogs are prodrugs and rely on cellular kinases to
convert them into their active triphosphate form. Un-
fortunately, the utility of these agents has been limited
by serious toxic side effects, emergence of resistant
virus, and limited efficacy. Nonucleoside inhibitors of
this vital retroviral enzyme have also been described.
A number of such agents have been, or are being,
investigated in clinical trials including the dipyrido-
diazepinones,4 pyridinones,5 tetrahydroimidazobenzo-
diazepinethiones (TIBO),6 bis(heteroaryl)piperazines
(BHAP),7 and anilidophenylacetamides (R-APA).8 These
agents display high anti-HIV-1 activity and relatively
low toxicity, but rapid development of resistance to such
agents has been a major clinical problem.9,10
known TIBO HIV-1 RT inhibitors. The lead compound
in this series, LY73497 (Scheme 1), was shown to inhibit
HIV-1 RT and HIV-1 in cell culture. Through an
integrated effort involving molecular modeling, chemical
synthesis, and biological evaluation, modification of
LY73497 led to the development of trovirdine N-[2-(2-
pyridyl)ethyl]-N′-[2-(5-bromopyridyl)]thiourea hydro-
chloride (LY300046‚HCl). This compound is currently
in phase one clinical trials for potential use in the
treatment of AIDS.
In order to further explore the potential of the PETT
compounds as anti-HIV agents, we report here the
synthesis and anti-HIV activities of 43 new PETT
compounds. The effects of introducing alternative het-
eroaromatic rings and various substituents on the two
aromatic and heteroaromatic moieties of LY73497 and
LY300046‚HCl were investigated. Inhibition assays
using mutant HIV-1 RT (Ile100) and (Cys181) and virus
with the Ile100 and Cys181 mutations were useful in
the antiviral evaluation of these compounds.15
We recently described a new class of nonnucleoside
HIV-1 RT inhibitors.11-14 These (phenethylthiazolyl-
thioureas) (PETTs) were derived from a systematic
disassemblage of the molecular architecture of the
† Lilly Research Laboratories.
‡ Medivir AB.
§ The Karolinska Institute.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(95)00639-X CCC: $12.00 © 1996 American Chemical Society

4262 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
Sch em e 2a
a
Reagents and conditions: (a) acetonitrile, DMF or 1-methylpyrrolidone, 80-100 °C; (b) (1) acetonitrile, room temperature, (2) DMF,
95 °C or (1) acetonitrile, room temperature, (2) NaH, THF, 0 °C to room temperature; (c) acetonitrile, room temperature; (d) acetonitrile,
0 °C to room temperature; (e) DMF, 100 °C.
Ch em istr y
diimidazole 51 was condensed with the appropriate
aminopyridines, 5217 and 53 (commercially available).
The compounds described in the present study, i.e.
compounds 1-43 (Tables 1 and 2), were synthesized
according to the general routes A-D depicted in Scheme
2. In route A thiocarbonyl reagents 44-46 derived from
appropriate aminopyridines or aminothiazole and 1,1′-
thiocarbonyldiimidazole 51 were condensed with ap-
propriate phenethylamines, either commercially avail-
able or prepared according to Schemes 3 and 4.
Phenethyl isothiocyanates (route B) were condensed
with aminopyridine 47 (prepared by the reaction of
2-amino-5-chloropyridine with sodium cyanide) or the
commercially available aminopyridazines 48 and 49, or
with the anions thereof. Isothiocyanates 5016 derived
from 2-amino-5-chloropyridine and 1,1′-thiocarbonyl-
diimidazole 51 were reacted with phenethylamines
(route C). A thiocarbonyl reagent (route D) which was
prepared from a phenethylamine and 1,1′-thiocarbonyl-
Phenethylamines 64a -q were prepared from alde-
hydes 62a -q by condensation of the appropriate alde-
hyde with nitromethane18 to give compounds 63a -q
followed by reduction with LiAlH4 (Scheme 3). Reaction
of compounds 61a -l with n-BuLi and then DMF af-
forded aldehydes 62a -l. Reaction of 60m ,n with POCl3
or n-BuLi and DMF gave aldehydes 62m ,n . Aldehyde
62o was prepared in three steps from 2,6-difluoro-
benzaldehyde via compounds 57 and 58. Aldehyde 62p
was prepared from 2,5-dihydroxybenzaldehyde 59 by
alkylating with EtI. Aldehyde 62q was commercially
available. Compounds 61a -j were prepared from com-
mercially available phenols by alkylation with MeI or
EtI. Fluorination of 1,4-dimethoxybenzene 56 gave
compound 61k . Compound 61l was commercially avail-
able. Compound 61f was prepared from 2′-fluoro-4′-

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4263
Sch em e 3a
a
Reagents and conditions: (a) mCPBA, NaHCO3, CHCl3, room temperature; (b) NH3, MeOH, room temperature (c) (1) n-BuLi, THF,
room temperature, (2) NFSI, -70 °C; (d) DMF, POCl3; (e) (1) n-BuLi, THF -70 °C, (2) ClCH2OCH3, -70 °C to room temperature; (f)
HCl(aq) dioxane, room temperature; (g) EtI or MeI, K2CO3, acetone 50-60 °C; (h) (1) n-BuLi, THF, -65 °C, (2) DMF, -65 °C to room
temperature; (i) (1) CH3NO2, NaOH, MeOH, -3 °C, (2) HCl or CH3NO2, NH4OAc, EtOH or CH3NO2, NH4OAc, CH3COOH; (j) LiAlH4,
THF, reflux.
methoxyacetophenone 54. Routes from phenethyl-
amines 64a -q to compounds 5, 7-15, 20-30, and 32
are listed in Table 1.
compound 66, which was converted to carboxamide 67
via the acid chloride. Compound 67 was deprotected
to give aldehyde 81b. Reaction of compound 80 with
LDA and DMF gave aldehyde 81a . Aldehyde 81c was
commercially available. Compound 82a was hydrogen-
ated and hydrolyzed to compound 68 followed by acy-
lation with acetic anhydride to afford acid 69. Routes
from phenethylamines 84a -f to compounds 2-4, 16-
19, and 31 are listed in Table 1.
The two furan analogs 35 and 36 were prepared by
the procedure outlined in Scheme 5.19 Heterocyclic
analogs 39, 40, and 41 were prepared as described in
Scheme 6. Compounds 33, 34, 37, and 38 were pre-
pared from commercially available amines. Phthal-
imidyl analogs 42 and 43 were readily prepared starting
from compounds 133 and 45 as outlined in Scheme 7.
Routes from phenethylamines to compounds 33-42 are
listed in Table 2.
Starting amines 84a -f in Scheme 4 were prepared
from acids 69, 78, 79, and 83a -c via the corresponding
azides followed by Curtius rearrangement. The result-
ing isocyanates were then hydrolyzed to the correspond-
ing amines. Acids 69 and 83a -c were obtained from
aldehydes 81a -c (by Wittig reactions) via benzoyl esters
82a -c. Condensation of 81a -c with ((benzyloxycar-
bonyl)methyl)triphenylphosphorane in toluene and hy-
drogenation-hydrolysis of intermediates 82a -c gave
acids 69 and 83a -c. 1-Alkoxy-2-bromo-4-fluoroben-
zenes 70 and 71 were converted with NaCN and Ni-
triphenylphosphine complex to 1-alkoxy-2-cyano-4-
fluorobenzenes 72 and 73. Reaction of compounds 72
and 73 with LDA and DMF gave aldehydes which were
condensed
with
(carbethoxymethylene)triphenyl-
phosphorane to afford compounds 74 and 75. Hydro-
genation and hydrolysis then gave acids 78 and 79.
Compound 65 was prepared from 2,6-difluorobenzalde-
hyde by conversion to the corresponding acetal with
ethylene glycol, triethyl orthoformate, and p-TSA. Re-
action of compound 65 with n-BuLi and CO2 gave
Biologica l Resu lts a n d Discu ssion
All compounds 1-43 in this study were tested in
HIV-1 RT enzyme assays, with wild-type and two
constructed mutants, Ile100 and Cys181.15 These de-

4264 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
Sch em e 4a
a
Reagents and conditions: (a) n-BuLi, THF, -70 °C, CO2; (b) SOCl2, N,N-diisopropylamine, CH3NH2, CH2Cl2, 0-20 °C; (c) p-TSA,
H2O, dioxane, 60 °C; (d) LDA, THF, -75 °C, DMF; (e) ((benzyloxycarbonyl)methyl)triphenylphosphorane toluene, 50 °C; (f) H2, Pd/C,
MeOH, HOAc; (g) (1) TEA, ethyl chloroformate, acetone 0 °C, NaN3/H2O, (2) toluene 90 °C, (3) HCl(aq), dioxane, room temperature; (h)
(AcO)2O, 50-60 °C; (i) NaCN, Ni[P(Ph)3]4, acetonitrile, 50-60 °C; (j) LDA, DMF, HOAc, (carbethoxymethylene)triphenylphosphorane,
-70 °C; (k) H2, Pd/C, MeOH; (l) NaOH, EtOH/H2O; (m) (1) DPPA, TEA, THF, 50 °C, (2) 110 °C, toluene, (3) HCl/dioxane.
rivatives were also tested in cell culture using MT-4
cells20 on both wild-type virus and virus containing the
mutations Ile100 and Cys181. These mutations, Ile100
and Cys181, were observed at an early stage when
studying PETT compounds in cell culture. It is well-
known that non-nucleoside HIV-1 RT inhibitors give rise
to the Cys181 mutation in both cell culture and clinic.21
Since a clinical situation most probably will involve
problems with double mutations, a selection of com-
pounds were also tested on viruses containing the
double mutations Ile100/Asn103 and Ile100/Cys181. The
IC50 and ED50 values from these experiments are shown
in Tables 1-3. In the original SAR studies on the PETT
compounds the lead compound LY73497, N-(2-phenyl-
ethyl)-N′-(2-thiazolyl)thiourea, was segmented into four
quadrants: (1) the phenyl ring, (2) the ethyl linker, (3)
the thiourea moiety, and (4) the thiazole heterocycle.14
In this study only the first and fourth quadrants were
varied. Compounds 1-9 (Table 1) show the influence
of varied substituents in position 3 of the 2,6-difluoro-
phenyl ring on antiviral activity. The greatest effect
was exhibited by carboxamido and acetamido substit-
uents which decreased the activity in all tests. The
N,N-dimethylamino substituent decreased the activity
on RT mutants and in cell culture, while the HIV-1 RT
(wt) activity was less affected.

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4265
Sch em e 5a
a
Reagents and conditions: (a) LDA, THF, -78 °C, DMF; (b) propylene glycol p-TSA, ambient temp; (c) n-BuLi, N-fluorobenzenesulfon-
imide, THF, -78 °C; (d) p-TSA, H2O, dioxane, room temperature; (e) (carbethoxymethylene)triphenylphosphorane, room temperature; (f)
(1) H2, Pd/C, MeOH/H2O, room temperature, (2) dioxane/H2O, NaOH, 50 °C; (g) (1) TEA, toluene, DPPA, reflux, (2) MeOH, reflux or
HCl/dioxane; (h) dioxane/MeOH/H2O, reflux; (i) 1,3-dicyanobenzene, 300 °C; (j) ((benzyloxycarbonyl)methyl)triphenylphosphonium bromide;
(k) (1) H2, Pd/C, MeOH, (2) K2CO3.
Sch em e 6a
a
Reagents and conditions: (a) ethyl bromoacetate, K2CO3, DMF, 40 °C; (b) LiBH4, Et2O; (c) triflic anhydride, pyridine, NH3, -50 °C;
(d) NiCl2, NaBH4, MeOH.
Variation of different heterocycles on the thiazole
portion of the molecule, compounds 10-15, is also
shown in Table 1. 5-Bromopyrid-2-yl, 5-chloropyrid-2-
yl, and 5-cyanopyrid-2-yl gave the highest activity when
considering the effect on both RT mutants (Ile100) and
(Cys181) and mutant HIV-1 (Ile100) and (Cys181). The
same activity spectrum was also seen with the 2-cyano-
3-methoxy-6-fluorophenethyl compounds 17 and 18. A
change from pyridyl to pyridazyl resulted in a decrease
in activity against RT mutants and in the cell culture
assays as evidenced from compounds 11 and 14.
2,6-Difluoro- and 2-fluoro-6-ethoxyphenyl substitution
in quadrant 1, compounds 1 and 22, respectively,
exhibited approximately equal activities, but still com-
pound 22 was better on mutant HIV-1 strains than
compound 1. 2,5-Diethoxy substitution of the phenyl
ring, compound 21, resulted in a decrease in activity
against HIV-1-RT mutants, when compared with 2,5-
dimethoxy substitution on the phenyl ring of compound
20. 2-Fluoro-3,6-dialkoxy substitution of compounds 25
and 26 compared with 2,5-dialkoxy substitution of
compounds 20 and 21 gave much higher activities

4266 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
Sch em e 7a
a
Reagents and conditions: (a) NaN3, NaI, acetone/H2O; (b) PPh3, TFA, H2O, dioxane/H2O; (c) H2NCH2CH2NH2; (d) 3,6-dichlorophthalic
anhydride, acetonitrile.
Ta ble 1. Inhibition of HIV-1 (IIIB) RT and HIV-1 (IIIB) Replication
HIV-1 RT (rCdG), IC50, µMa HIV-1 MT-4 cells, ED50, µMb
compd
R2
R3
R4
R6
Ar
route
wt
Ile100
Cys181
wt
Ile100
Cys181
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
F
F
F
F
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-chloropyrid-2-yl
5-chloropyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-chloropyrid-2-yl
5-iodopyridin-2-yl
5-cyanopyrid-2-yl
5-chloropyridazin-2-yl
5-(trifluoromethyl)-
thiazol-2-yl
D
A
A
A
C
A
A
A
A
A
A
D
B
B
A
0.001
0.023
0.045
0.009
0.008
0.007
0.006
0.004
0.004
0.012
0.006
0.008
0.005
0.005
0.047
0.05
>2.0
>2.0
0.40
1.90
1.90
0.87
0.17
0.72
0.19
0.13
0.42
0.11
0.77
7.0
0.030
>2.0
0.013
0.080
0.900
0.006
0.040
0.040
0.015
0.006
0.006
0.007
0.008
0.015
0.003
0.020
0.070
0.60
>2.0
>2.0
0.80
>2.0
>2.0
0.60
0.10
2.5
0.40
0.60
3.0
0.50
>2.0
>2.0
0.150
0.300
>2.0
0.050
0.700
1.0
0.050
0.006
0.300
0.030
0.007
0.200
0.030
1.0
(CdO)NMe
CH2NAc
CN
N(Me)2
N(Me)2
MeO
EtO
CH2OMe
EtO
EtO
EtO
EtO
EtO
>2.0
0.090
0.190
0.170
0.060
0.020
0.100
0.050
0.030
0.130
0.030
0.260
7.0
EtO
>2.0
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
CN
CN
CN
CN
H
H
F
F
F
EtO
MeO
MeO
MeO
MeO
EtO
H
F
F
MeO
EtO
H
H
H
H
H
H
H
H
H
H
H
H
H
F
F
F
F
F
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-cyanopyrid-2-yl
5-chloropyrid-2-yl
A
A
B
B
A
A
A
A
A
C
C
A
A
C
C
A
A
0.002
0.001
0.003
0.005
0.005
0.018
0.006
0.005
0.003
0.001
0.005
0.007
0.002
0.002
0.020
0.008
0.021
0.200
0.100
0.200
0.14
0.05
0.06
1.10
0.18
1.65
0.05
0.02
0.05
0.08
0.16
0.43
0.09
0.81
0.27
0.21
0.24
32.2
0.85
11.8
0.210
0.050
0.050
1.10
0.004
0.003
0.001
0.011
0.040
0.018
0.013
0.007
0.007
0.002
0.005
0.012
0.018
0.010
0.018
0.013
0.013
0.04
0.25
0.20
0.40
>2.0
>2.0
0.09
1.50
0.60
0.009
0.09
3.0
0.90
2.0
1.50
0.15
1.0
0.005
0.040
0.030
0.100
0.900
0.800
0.007
0.200
0.040
0.003
0.009
0.200
0.050
1.50
MeO 5-chloropyrid-2-yl
EtO 5-bromopyrid-2-yl
EtO 5-bromopyrid-2-yl
EtO 5-bromopyrid-2-yl
MeO 5-bromopyrid-2-yl
MeO 5-chloropyrid-2-yl
MeO 5-chloropyrid-2-yl
F
Cl
F
0.063
0.707
0.025
0.010
0.004
0.054
0.034
0.085
0.009
0.290
0.130
0.110
0.660
13.0
F
F
MeO MeO
F
F
F
F
Cl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
5-chloropyrid-2-yl
5-chloro)pyrid-2-yl
5-bromopyrid-2-yl
5-bromopyrid-2-yl
EtO
H
H
CN
EtO
N(Me)2
N(Me)2
Cl
F
H
F
0.900
0.020
0.160
124
>11
22
32
9-Cl-TIBO
L-697,661
nevirapine
0.250 >22
0.065
0.150
7.70
201
0.85
0.62
a
b
The HIV-1 RT assay which used (poly)rC‚(oligo)dG as the template/primer is described in ref 15. Anti HIV activity assay: MT-4
cells (human T cell line) grown in RPMI 1640 medium supplemented with 10% fetal calf serum, penicillin and streptomycin were seeded
into 96-well microplates (2 × 104 cells/well) and infected with 10-20 TCID50 of wt and mutant HIV-1, IIIB, per well. Test compounds in
different concentrations were added. The cultures were incubated at 37 °C in CO2 atmosphere, and the viability of cells was determined
at day 5 or 6 with XTT vital dye.20 The anti HIV-1 activity was measured as the reduction in cytopathic effect caused by the virus.
Mutant HIV-1 was achieved by passaging the virus in MT-4 cells in stepwise increasing concentrations of different non-nucleoside HIV-1
RT inhibitors. When virus was growing in highest possible, nontoxic concentration of the compound it was passaged once without compound.
Cellular DNA was analyzed with respect to nucleotide sequence in the HIV-1 RT gene, and the supernatant was frozen in aliquots at -70
°C for cross-resistance studies.
against mutant HIV-1 strains. In addition, compounds
29-32 with a substituent in the 4-position of the phenyl
ring displayed diminished activity against both RT
mutants and mutant HIV-1 strains. The activities of

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4267
Ta ble 2. Inhibition of HIV-1 (IIIB) RT and HIV-1 (IIIB) Replication
a,b
See footnote a and b, Table 1.
9-Cl-TIBO,6 L-697,661,5 and nevirapine4 are included
for reference in Table 1.
hand side of the molecule. The 2-(3-fluorofuranyl)
compound 35 and phthalimidyl compound 42 had the
highest activities in this series. Table 3 shows the
inhibitory activity of 14 selected compounds against
mutant HIV-1 (Ile100/Asn103) and (Ile100/Cys181).
In conclusion, most of these PETT compounds had a
high inhibitory activity both on HIV-1 RT and against
HIV-1 in cell culture, higher than the reference com-
The first candidate of the PETT series chosen for
clinical evaluation, trovirdine (N-[2-(2-pyridyl)ethyl]-N′-
[2-(5-bromopyridyl)]thiourea hydrochloride (LY300046·
HCl)), inhibited HIV-1 RT (wt) with an IC50 of 15 nM
and had an ED50 of 20 nM in cell culture.14,22 Table 2
shows the effects of different heterocycles on the left

4268 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
Ta ble 3. Inhibition of HIV-1 (IIIB) Variants in Cell Culture
HIV-1 MT-4 cells, ED50, µMa
1-[[2-(5-Ch lor op yr id yl)]th ioca r ba m oyl]im id a zole (45).
The title compound was prepared analogously to compound
44: 1H NMR (300 MHz, DMSO-d6) δ 8.58 (m, 1H), 8.25 (m,
1H), 8.05 (br s, 1H), 8.03 (m, 1H), 7.65 (m, 1H), 7.15 (d, 1H),
6.80 (s, 1H).
1-[[2-(5-(Tr iflu or om et h yl)t h ia zolyl)]t h ioca r b a m oyl]-
im id a zole (46). The title compound was prepared analo-
gously to compound 44: 1H NMR (300 MHz, DMSO-d6) δ 9.44
(s, 1H), 8.20 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H); MS (FAB) m/e
279 (M+).
compd
Ile100/Asn103
Ile100/Cys181
4
8
>10
10
>10
1.2
16
17
22
>10
>10
1.6
3.0
>10
1.0
23
24
25
>10
>10
1.0
>10
>10
1.0
Rou te B. Gen er a l P r oced u r e. Alt 1. A solution of 1,1′-
thiocarbonyldiimidazole (1 equiv) and phenyl- or pyridylethyl-
amine (1 equiv) in acetonitrile (4 mL/mmol) was stirred at
room temperature for 1 h. The solution was evaporated and
the residue dissolved in DMF (4 mL/mmol). Aminopyridine
or aminopyridazine (1 equiv) was added as a solid and the
solution was stirred at 95 °C for 24 h. The reaction mixture
was cooled to room temperature; poured into ethyl acetate; and
washed with water, saturated aqueous sodium bicarbonate,
and brine. The organic layer was dried over anhydrous sodium
sulfate and concentrated and the residue purified either by
triturating in dichloromethane or by column chromatography.
Alt 2. A solution of phenethylamine (1 equiv) in acetonitrile
(2 mL/mmol) was added to a stirred solution of 1,1′-thiocar-
bonyldiimidazole (1.03 equiv) in acetonitrile (3 mL/mmol) at
room temperature. The solution was stirred at room temper-
ature for 1 h, and the solvent was evaporated. The residue
was purified by chromatography on silica gel (ethyl acetate/
hexanes, 1:1) to provide pure phenethyl isothiocyanate. So-
dium hydride (1 equiv) was added to a solution of amino-
pyrazine or aminopyridine (1 equiv) in THF at 0 °C under N2.
The reaction mixture was stirred at 0 °C for 30 min. Phenethyl
isothiocyanate (1 equiv) in THF was added, and the reaction
mixture was allowed to reach room temperature and then
stirred overnight. Saturated ammonium chloride and diethyl
ether was added, and the organic layer was washed with brine,
dried over anhydrous sodium sulfate, and concentrated. The
product was purified by recrystallization.
2-Am in o-5-cya n op yr id in e (47). A mixture of NiBr2 (2.18
g, 10 mmol), triphenylphosphine (10 g, 38 mmol), and zinc
powder (1 g, 15.2 mmol) in 100 mL of acetonitrile was stirred
under nitrogen at 60 °C for 1 h. NaCN (6.3 g, 102 mmol) and
2-amino-5-bromopyridine (17.8 g, 100 mmol) were added to the
mixture which was stirred overnight at 60 °C. Then 500 mL
of ethyl acetate was added to the mixture, it was filtered, and
the solvent was evaporated. The product was purified on a
silica gel column eluted with ethyl acetate. 1H NMR (250
MHz, DMSO-d6) δ 8.41 (d, 1H), 7.29 (dd, 1H), 7.12 (s, 2H),
6.58 (d, 1H).
Rou te C. Gen er a l P r oced u r e. Phenethylamine (1 equiv)
and compound 50 (1 equiv) in acetonitrile (2 mL/mmol) were
stirred at room temperature for 0.5 h. The mixture was
filtered. The precipitate was dried and recrystallized from
acetonitrile.
26
28
31
>10
>10
5.5
>10
>10
7.5
35
42
>10
>10
8.0
>10
15
nevirapine
>10
a
See footnote b, Table 1.
pounds, 9-Cl-TIBO, L-697,661, and nevirapine. The
most potent inhibitors of mutant RT (Ile100) were 1,
17, 22, 23, and 24 (Table 1). These compounds contain
hydrogen, fluorine, or methoxy group in the meta
position of the phenyl ring in combination with a 2-(5-
bromopyridyl) on the right hand side (quadrant 4) of
the molecule. Compound 18 (Table 1) with a 2-(5-
cyanopyridyl) moiety in quadrant 4 had comparable
activity against RT (Ile100). The most potent inhibitor
of mutant RT (Cys181) was compound 24, closely
followed by compounds 28 and 23. The most potent
inhibitors of mutant HIV-1 (Ile100) were compounds 16,
25, and 26, and of mutant HIV-1 (Cys181), compounds
8, 11, 16, 22, 25, and 26. Compounds 22 and 25 gave
the highest activities against double-mutant HIV-1
(Ile100/Asn103) and (Ile100/Cys181) (Table 3). 5-Bro-
mo-, 5-chloro-, and 5-cyanopyrid-2-yl were the preferred
substituents for quadrant 4. 2,3,6-Trisubstituted phen-
yl rings with chlorine, fluorine, ethoxy, methoxy, or
cyano substituents were the preferred groups for the left
hand side (quadrant 1) of the molecule.
Exp er im en ta l Section
Ch em istr y. All melting points were determined on an
Electrothermal 9100 capillary melting point apparatus and are
uncorrected. Analytical results are indicated by atom symbols
and are within 0.4% of theoretical values except where
indicated. 1H NMR spectra were recorded on Bruker AC-250
(250 MHz) and General Electric QE-300 (300 MHz) spectrom-
eters using TMS as the internal standard. Yields were not
optimized. Merck silica gel, 230-400 mesh, was used for
chromatography. 9-Cl-TIBO was purchased from Pharmatech
Int. Inc. L-697,661 (3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)-
methyl]amino}-5-ethyl-6-methylpyridin-2(1H)-one) was kindly
supplied by Dr. M. E. Goldman at Merck, Sharp and Dohme
Research Laboratories (Rahway, NY). Nevirapine was syn-
thesized according to published methods.4b
R ou t e A. Gen er a l P r oced u r e. To a suspension of
compound 44, 45, or 46 (1.1 equiv) in acetonitrile, DMF, or
1-methylpyrrolidinone (2 mL/mmol) was added an appropriate
phenyl- or pyridylethylamine (1 equiv). The reaction mixture
was heated to 80-110 °C for 1-68 h and cooled to room
temperature. The reaction mixture was worked up, and the
crude material was purified by either recrystallization or
column chromatography.
2-(5-Ch lor op yr id yl) Isoth iocya n a te (50).16 2-Amino-5-
chloropyridine (10.28 g) was added in portions, with stirring,
over a period of 25 min to a solution of thiocarbonyldiimidazole
(14.26 g) in acetonitrile (100 mL) at room temperature. The
stirring was continued, and the solution/suspension was left
at room temperature for a few hours. The precipitate was
filtered and washed with acetonitrile (3 × 25 mL). The solid
residue was dissolved in hot acetone and filtered. The acetone
solution was evaporated in vacuo, and the residue was
dissolved in hot ethyl acetate and filtered through a pad of
silica (diameter 7 cm × 3 cm). The silica was washed with
another portion of hot ethyl acetate. The combined solutions
were evaporated in vacuo to yield a crude product (5 g) of the
title product: 1H NMR (250 MHz, DMSO-d6) δ 7.54 (d, 1H),
8.17 (dd, 1H), 8.63 (d, 1H).
Rou te D. Gen er a l P r oced u r e. Phenethylamine (1 equiv)
in acetonitrile was added dropwise to a solution of 1,1′-
thiocarbonyldiimidazole in acetonitrile at 0 °C during 20 min.
The reaction mixture was allowed to reach room temperature.
The solvent was evaporated. Aminopyridine (1.2 equiv) in
DMF was added, and the mixture was stirred at 100 °C for 15
h. The reaction mixture was cooled to room temperature and
1-[[2-(5-Br om op yr id yl)]th ioca r ba m oyl]im id a zole (44).
A solution of 1,1′-thiocarbonyldiimidazole (4.95 g, 25 mmol)
and 2-amino-5-bromopyridine (4.46 g, 25 mmol) in acetonitrile
(75 mL) was stirred at room temperature for 23 h. The
resulting precipitate was collected by filtration to provide 5.42
g (76%) of the title product: 1H NMR (300 MHz, DMSO-d6) δ
8.57 (m, 1H), 8.30 (m, 1H), 8.15 (m, 1H), 8.03 (br s, 1H), 7.75
(m, 1H), 7.15 (d, 1H), 6.80 (s, 1H).

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4269
poured into ice. The organic layer was washed with dilute
HCl, water, and brine, dried over anhydrous sodium sulfate,
and concentrated. The product was purified by chromatogra-
phy on silica gel.
difluoro-3-(formamidomethyl)phenethyl)amine hydrochloride
84b. The title product was prepared according to route A: mp
222.5-223.4 °C; 1H NMR (250 MHz, d-MeOD, CDCl3) δ 8.1-
8.0 (s, 1H),7.8-7.7 (m, 2H), 7.0-6.9 (t, 2H), 6.9-6.8 (d, 1H),
4.1-4.0 (t, 2H), 3.2-3.1 (t, 2H), 3.0-2.9 (s, 3H). Anal. (C16H15
-
2-Am in o-5-iod op yr id in e (52). The compound was pre-
pared from 2-aminopyridine:17 1H NMR (250 MHz, CDCl3) δ
8.21 (s, 1H), 7.61 (q, 1H), 6.34 (d, 1H), 4.52 (br s, 2H).
N-[2-(2,6-Diflu or op h en eth yl)]-N′-[2-(5-br om op yr id yl)]-
th iou r ea (1). 2,6-Difluorobenzonitrile (5 g, 33 mmol) and
cobalt chloride hexahydrate (11.6 g, 49 mmol) were dissolved
in 500 mL of methanol. To the solution was added NaBH4
(9.3 g, 244 mmol) in portions. The reaction mixture was
filtered after 3 h, and the residue was washed twice with
methanol. Evaporation of the combined filtrates gave a
residue which was dissolved in 1 M HCl, and this solution was
washed with dichloromethane. Alkalizing with ammonia and
extraction with dichloromethane gave after washing with
water and evaporation of solvent 2.9 g of 2-(2,6-difluorophen-
ethyl)amine. The title product was prepared according to route
D: mp 174-175 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.20 (s,
1H), 10.68 (s,1H), 8.11 (s, 1H), 7.95-7.91(m, 1H), 7.33-7.28
(m, 1H), 7.09-7.01 (m, 3H), 3.83-3.77 (m, 2H), 2.98-2.94 (m,
2H). Anal. (C14H12BrF2N3S)C, H, N.
N-[2-(2,6-Diflu or o-3-(for m a m id om et h yl)p h en et h yl)]-
N′-[2-(5-br om op yr id yl)]th iou r ea (2). 2,6-Difluorobenzal-
dehyde (10 g, 70.4 mmol), ethylene glycol (20 mL), triethyl-
orthoformate (10 mL), and p-TSA in 1,2-dichloroethane were
heated to 80 °C for 2 h. The solution was neutralized with
sodium hydrogen carbonate, washed with water, dried over
sodium sulfate, filtered, and evaporated.
The residual oil, compound 65, was dissolved in THF (700
mL) under nitrogen. The solution was stirred and cooled to
-70 °C, and n-BuLi (48 mL, 1.6 M) was added slowly. The
solution was stirred for 20 min. Dry ice (20 g, 455 mmol) was
added as quickly as possible. The solution was brought slowly
to room temperature. Water was added, and the solution was
washed with ethyl acetate, acidified with acetic acid, and
extracted with ethyl acetate. The organic phase was dried over
Na2SO4, filtered, and evaporated.
One gram of the residual solid, compound 66 (4.35 mmol),
and N,N-diisopropylamine (2.0 mL) were dissolved in dichlo-
romethane (50 mL), and the solution was cooled to 0 °C.
Thionyl chloride (0.50 mL, 6.9 mmol) was added and the
solution slowly heated to ambient temperature. Methylamine
(3 mL) was added. The solution was stirred for 30 min,
washed with water, dried over Na2SO4, filtered, and evapo-
rated.
The residue, compound 67, was dissolved in a mixture of
water and dioxane (1:2, 20 mL), and p-TSA (0.5 g, 2.63 mmol)
was added. The solution was stirred and heated to 60 °C for
2 h. The solution was neutralized with sodium hydrogen
carbonate and extracted with ethyl acetate. The organic layer
was dried over Na2SO4, filtered, and evaporated.
The residue, compound 81b, was dissolved in toluene, and
[(benzyloxycarbonyl)methyl]triphenylphosphorane (1.5 g, 3.7
mmol) was added. The solution was stirred for 30 min at 50
°C and then put onto a silica gel column which was eluted
with ethyl acetate/hexane (1:2), and the collected fractions
were evaporated.
A part of the residue, compound 82b (0.15 g), was hydro-
genated in methanol (50 mL) and acetic acid (5 mL) over 10%
Pd/C catalyst (100 mg), using a Parr hydrogenation apparatus
at 1.0 psi for 1 h. The solution was filtered through Celite
and evaporated.
BrF2N4OS) H, N; C: calc, 44.77; found, 43.70.
N-[2-(3-(Aceta m id om eth yl)-2,6-d iflu or op h en eth yl)]-N′-
[2-(5-br om op yr id yl)]th iou r ea (3). Under a nitrogen atmo-
sphere, 2,4-difluorobenzonitrile, 80 (4.6 g, 33 mmol), was
dissolved in THF (200 mL) with stirring. The solution was
cooled to -75 °C, and lithium diisopropylamide (25 mL, 1.5
M solution) was added. The solution was stirred for 15 min,
and DMF (10 mL) was added. The cooling was withdrawn,
and the solution was diluted with toluene (200 mL), washed
with water, dried over Na2SO4, filtered, and evaporated. The
residue, compound 81a (4.76 g, 28.5 mmol), was dissolved in
250 mL of toluene, and [(benzyloxycarbonyl)methyl]triphenyl-
phosphorane (14 g, 34 mmol) was added. The solution was
stirred for 40 min at 35 °C (slightly exothermic reaction) and
then put onto a silica gel column which was eluted with ethyl
acetate/hexane, 1:4, and the collected fractions were evapo-
rated.
A small part of the residue, compound 82a (0.5 g), was
dissolved in methanol (50 mL) and acetic acid (6 mL), and 5%
Pd/C (300 mg) was added. The mixture was hydrogenated on
a Parr hydrogenation apparatus at 1.0 psi for 1 h. The solution
was filtered through Celite and evaporated.
The residue, compound 68, was dissolved in acetic anhy-
dride, and the solution was stirred and heated to 50 °C for 20
min. Excess reagent was evaporated, and the residue was
dissolved in water. The solution was heated to 60 °C for 20
min under stirring.
The residue, compound 69 (0.29 g, 1.14 mmol), was dissolved
in acetone at 0 °C. Triethylamine (0.315 mL, 2.3 mmol) was
added, followed by ethyl chloroformate (0.16 mL, 1.7 mmol).
The solution was stirred for 15 min, and sodium azide (220
mg, 3.3 mmol) in water (2 mL) was added. Stirring was
continued for 15 min, and the solution was diluted with ethyl
acetate, washed with water, dried over Na2SO4, and evapo-
rated. The residue was dissolved in toluene (20 mL) and
heated at 90 °C for 1 h. The solution was evaporated, and
the residue was dissolved in a dioxane/water/hydrochloric acid
(concentrated aqueous) mixture (50:10:1, 50 mL) and stirred
at room temperature for 20 min. The solution was evaporated,
to give 3-(acetamidomethyl)-2,6-difluorophenethylamine hy-
drochloride, 84d . The title product was prepared according
to route A: mp 180.3-181.6 °C; 1H NMR (250 MHz, d-MeOD,
CDCl3) δ 8.2-8.1 (s, 1H), 7.8-7.7 (d, 1H), 7.4-7.2 (m, 1H),
6.9-6.8 (m, 2H), 4.4-4.3 (s, 2H), 4.1-3.9 (br s, 2H), 3.1-3.0
(br s, 2H), 2.0-1.9 (s, 3H). Anal. (C17H17BrF2N4OS) H, N; C:
calc, 46.06; found, 45.20.
N -[2-(3-Cya n o-2,6-d iflu or op h e n e t h yl)]-N ′-[2-(5-b r o-
m op yr id yl)]t h iou r ea (4). 3-Cyano-2,6-difluorophenethyl-
amine 84a was prepared from 3-cyano-2,6-difluorobenzalde-
hyde 81a by a procedure described for compound 2. Aldehyde
81a was prepared from 2,4-difluorobenzonitrile 80 by a
procedure described for compound 3. The title product was
1
prepared according to route A: mp 189.2-191.2 °C; H NMR
(250 MHz, CDCl3 + CD3OD) δ 11.4 (br s, 1H), 8.1 (d, 1H), 7.7-
7.5 (m, 2H), 7.0 (t, 1H), 6.9 (d, 1H), 4.1 (q, 2H), 3.2 (t, 2H).
Anal. (C15H11ClF2N4S) H, N; C: calc, 51.07; found, 51.9.
N-[2-(2,6-Diflu or o-3-(d im eth yla m in o)p h en eth yl)]-N′-[2-
(5-ch lor op yr id yl)]th iou r ea (5). A mixture of 2,4-difluoro-
aniline (5.0 g, 38.7 mmol) and trimethyl phosphate (3.6 g, 25.8
mmol) was refluxed at 180 °C for 2 h. After the mixture was
cooled to 50 °C, NaOH (3.2 g, 80.6 mmol) in 12 mL of H2O
was added to it, and it was refluxed again for 1 h. The mixture
was cooled, H2O was added to it, and it was extracted with
diethyl ether, which was dried over Na2SO4 and evaporated.
The crude material was filtrated through an Al2O3 column
using diethyl ether as eluent to give 4.4 g (73%) of 1-(di-
methylamino)-2,4-difluorobenzene, 60n . 2,6-Difluoro-3-(di-
methylamino)phenethylamine (64n ) was prepared from this
compound by using the procedure described for compound 10.
The title product was prepared according to route C: mp 167
°C; 1H NMR (250 MHz, CDCl3) δ 11.32 (br s, 1H), 8.95 (s, 1H),
A part of the residue, compound 83b (50 mg, 0.26 mmol),
was dissolved in acetone at 0 °C. Triethylamine (50 mL, 0.36
mmol) was added followed by ethyl chloroformate (30 mL, 0.32
mmol). The solution was stirred for 15 min, and sodium azide
(30 mg, 0.46 mmol) in water (2 mL) was added. The solution
was stirred for 15 min, diluted with ethyl acetate, and washed
with water. The organic layer was dried over Na2SO4, filtered,
and evaporated. The residue was dissolved in toluene (20 mL)
and stirred at 90 °C for 1 h. The solution was evaporated and
dissolved in a dioxane/water/hydrochloric acid (concentrated
aqueous) mixture (1:3:1). The solution was stirred at room
temperature for 20 min and then evaporated to give 2-(2,6-

4270 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
8.06 (d, 1H), 7.57 (dd, 1H), 6.81-6.76 (m, 3H), 4.01 (q, 2H),
NaOH (2.43 g, 60.7 mmol) in 12 mL of ice/water was added
dropwise at -3 °C to a solution of compound 62b (11.7 g, 57.8
mmol) and nitromethane (3.12 mL, 57.8 mmol) in 260 mL of
methanol. The solution was stirred at -3 °C for 15 min and
then added dropwise to 35 mL of 4 N HCl(aq) while stirring.
The mixture was extracted with diethyl ether, and the organic
layer was washed with a small volume of brine, dried over
Na2SO4, and evaporated to give 12.1 g (85%) of 2-nitro-1-(2-
chloro-3-ethoxy-6-fluorophenyl)ethene, 63b.
3.11 (t, 2H), 2.76 (s, 6H). Anal. (C16H17ClF2N4S) C, H, N.
N-[2-(2,6-Diflu or o-3-(d im eth yla m in o)p h en eth yl)]-N′-[2-
(5-br om op yr id yl)]th iou r ea (6). The title product was pre-
pared using the same starting amine 64n as for compound 5
1
and route A: mp 175 °C; H NMR (250 MHz, CDCl3) δ 11.33
(br s, 1H), 8.92 (br s, 1H), 8.16 (d, 1H), 7.70 (dd, 1H), 6.81-
6.75 (m, 3H), 4.01 (q, 2H), 3.11 (t, 2H), 2.77 (s, 6H). Anal.
(C16H17BrF2N4S) C, H, N.
Lithium aluminum hydride (6.81 g, 179.2 mmol) was added
to 200 mL of dry THF. To this mixture was added dropwise
compound 63b (11.0 g, 44.8 mmol) in 200 mL of dry THF. The
mixture was refluxed for 2 h, treated with 6.9 mL of H2O, 6.9
mL of 15% NaOH(aq), and 20.7 mL of H2O, filtered, dried over
Na2SO4, and evaporated to give crude 2-chloro-3-ethoxy-6-
fluorophenethylamine, 64b (8.2 g, 84%). This amine using
route A gave the title product (30% yield): mp 150 °C; 1H NMR
(250 MHz, CDCl3) δ 11.30 (br s, 1H), 9.35 (s, 1H), 8.08 (d, 1H),
7.69 (dd, 1H), 6.93-6.76 (m, 3H), 4.11-4.00 (m, 4H), 3.24 (t,
2H), 1.46 (t, 3H). Anal. (C16H16BrClFN3OS) C, H, N.
N-[2-(2,6-Diflu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-br o-
m op yr id yl)]th iou r ea (7). 2,6-Difluoro-3-methoxyphenethyl-
amine (64h ) was prepared from 2,4-difluorophenol as described
for compound 10. The title product was prepared according
to route A: mp 158.5 °C; 1H NMR (250 MHz, DMSO-d6) δ 11.35
(s, 1H), 9.16 (s, 1H), 8.12 (d, 1H), 7.68-7.72 (m, 1H), 6.82 (m,
3H), 4.00 (m, 2H), 3.86 (s, 3H), 3.12 (t, 2H). Anal. (C15H14
BrF2N3OS) C, H, N.
-
N-[2-(2,6-Diflu or o-3-et h oxyp h en et h yl)]-N′-[2-(5-b r o-
m op yr id yl)]th iou r ea (8). 2,6-Difluoro-3-ethoxyphenethyl-
amine (64i) was prepared from 2,4-difluorophenol as described
for compound 10. The title product was prepared according
to route A: mp 124 °C; 1H NMR (250 MHz, CDCl3) δ 11.35 (s,
1H), 9.2 (s, 1H), 8.15 (d, 1H), 7.7 (m, 1H), 6.9-6.7 (m, 3H),
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
ch lor op yr id yl)]th iou r ea (11). This compound was prepared
1
as compound 10: mp 160 °C; H NMR (250 MHz, DMSO-d6)
δ 11.28 (br s, 1H), 10.85 (s, 1H), 8.16 (d, 1H), 7.97 (dd, 1H),
7.29-7.15 (m, 3H), 4.18 (q, 2H), 3.98 (q, 2H), 3.24 (t, 2H), 1.44
(t, 3H). Anal. (C16H16Cl2FN3OS)C, H, N.
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
iod op yr id yl)]th iou r ea (12). Starting amine 64b was the
same as for compound 10. The title product was prepared
according to route D: mp 170 °C; 1H NMR (250 MHz, CDCl3)
δ 11.27 (br s, 1H), 8.94 (s, 1H), 8.22 (d, 1H), 7.84 (dd, 1H),
6.96-6.77 (m, 2H), 6.65 (d, 1H), 4.11-3.99 (m, 4H), 3.25 (t,
2H), 1.47 (t, 3H). Anal. (C16H16ClFIN3OS) C, H, N.
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
cya n op yr id yl)]th iou r ea (13). Starting amine 64b was the
same as for compound 10. The title product was prepared
according to route B: mp 211 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.35 (br s, 1H), 11.14 (s, 1H), 8.59 (d, 1H), 8.26 (dd,
1H), 7.35-7.13 (m, 3H), 4.17 (q, 2H), 3.98 (q, 2H), 3.23 (t, 2H),
1.43 (t, 3H). Anal. (C17H16ClFN4OS) C, H, N.
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
ch lor op yr id a zyl)]th iou r ea (14). Starting amine 64b was
the same as for compound 10. The title product was prepared
according to route B: mp 188-189 °C; 1H NMR (250 MHz,
DMSO-d6) δ 11.21(br s, 1H), 11.00 (br s, 1H), 7.93 (d, 1H), 7.64
(d, 1H), 7.21-7.13 (m, 2H), 4.15 (q, 2H), 4.00 (q, 2H), 3.21 (t,
2H), 1.41 (t, 3H). Anal. (C15H15Cl2FN4OS) C, H, N.
4.1-3.95 (q + t, 4H), 3.1 (t, 3H), 1.38 (t, 2H). Anal. (C16H16
BrF2N3OS) C, H, N.
-
N-[2,6-Diflu or o-3-(m eth oxym eth yl)p h en eth yl]-N′-[2-(5-
br om op yr id yl)]th iou r ea (9). A solution of 2,6-difluorobenz-
aldehyde (7.05 g, 0.05 mol), propylene glycol (20 mL, 0.25 mol),
and p-TSA (50 mg) in 300 mL of toluene was refluxed utilizing
a Dean-Stark trap for 2 h. The cooled solution was washed
with saturated NaHCO3(aq), dried over Na2SO4, and concen-
trated in vacuo to give 2,6-difluorobenzaldehyde propylene
acetal 57 as an oil (9.08 g, 92%).
To a solution of the compound 57 (7.0 g, 0.035 mol) in 100
mL of THF was added 2.5 M n-BuLi in hexane (16.8 mL, 0.042
mol) at -70 °C under nitrogen over a period of 10 min. The
solution was stirred at -70 °C for 1 h, chloromethyl methyl
ether (7.0 mL, 0.084 mol) was added, the mixture was allowed
to warm to room temperature, and stirring was continued for
18 h. The mixture was diluted with Et2O and washed with
water and 25% NH3(aq); the organic layer was dried over
Na2SO4 and concentrated in vacuo. The residue was purified
by chromatography on silica gel by elution with Et2O/hexane
to give 2,6-difluoro-3-(methoxymethyl)benzaldehyde propylene
acetal, 58 (4.0 g, 47%).
A solution of the compound 58 (3.98 g, 0.016 mol) in 100
mL of dioxane and 50 mL of 2 M HCl was stirred for 70 h at
room temperature. The solution was diluted with water,
extracted with Et2O, dried over Na2SO4, and concentrated in
vacuo to give 2,6-difluoro-3-(methoxymethyl)benzaldehyde
(62o) as an oil (2.77 g, 93%). From this aldehyde (62o), 2,6-
difluoro-3-(methoxymethyl)phenethylamine (64o) was pre-
pared as described for compound 10. The title product was
prepared according to route A: mp 142-143 °C; 1H NMR (250
MHz, CDCl3) δ 11.31 (br s, 1H), 8.78 (br s, 1H), 8.15 (d, 1H),
7.28 (m, 1H), 7.22 (dd, 1H), 6.88 (dd, 1H), 6.69 (m, 1H), 4.44
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
(tr iflu or om eth yl)th ia zolyl)]th iou r ea (15). Starting amine
64b was the same as for compound 10. The title product was
prepared according to route A: mp 181 °C; 1H NMR (250 MHz,
DMSO-d6) δ 11.86 (br s, 1H), 8.48 (br s, 1H), 7.80 (s, 1H), 7.22-
7.15 (m, 2H), 4.19 (q, 2H), 3.91 (q, 2H), 3.19 (t, 2H), 1.44 (t,
3H). Anal. (C15H14ClF4N3OS2) C, H, N.
N-[2-(2-Cyan o-3-eth oxy-6-flu or oph en eth yl)-N′-[2-(5-br o-
m op yr id yl)]th iou r ea (16). 2-Bromo-4-fluorophenol (20 g,
165 mmol) was dissolved in acetone. K2CO3 and ethyl iodide
(31 g, 200 mmol) were added. The mixture was refluxed
overnight. Solid material was filtered off and rinsed with
acetone. Distillation gave pure 1-bromo-2-ethoxy-5-fluoroben-
zene 71. 2-Cyano-3-ethoxy-6-fluorophenethylamine (84f) was
prepared from compound 71 as described for compound 17.
The title product was prepared according to route A: mp 184
(s, 2H), 4.00 (m, 2H), 3.39 (s, 3H), 3.10 (m, 2H). Anal. (C16H16
BrF2N3OS) C, H, N.
-
N-[2-(2-Ch lor o-3-et h oxy-6-flu or op h en et h yl)]-N′-[2-(5-
br om op yr id yl)]th iou r ea (10). 2-Chloro-4-fluorophenol (18.2
g, 124 mmol), ethyl iodide (30 mL, 372 mmol), and K2CO3 (34.3
g, 248 mmol) in 250 mL of acetone were stirred at 60 °C for 5
h. The mixture was cooled, filtered, and evaporated. The
residue was stirred with hexane, cooled, filtered, and evapo-
rated to give 20.85 g (96%) of 1-chloro-2-ethoxy-5-fluoroben-
zene, 61b.
1
°C; H NMR (250 MHz, CDCl3) δ 11.29 (s, 1H), 10.87 (s, 1H),
8.22-8.21 (m, 1H), 8.12-8.07 (m,1H), 7.68-7.60 (m, 1H),
7.29-7.21 (m, 2H), 4.27 (q, 2H), 4.06 (q, 2H), 3.22 (m, 2H),
1.46 (t, 3H). Anal. (C17H16BrFN4OS) C, H, N.
BuLi (2.5 M) in hexane (27.2 mL, 68.1 mmol) was added
slowly (20 min) to a solution of compound 61b (10.8 g, 61.9
mmol) in 220 mL of dry THF at -65 °C under nitrogen. The
solution was stirred at -65 °C for 0.5 h. DMF (5.3 mL, 68.1
mmol) was added dropwise to the solution. The mixture was
allowed to warm to room temperature, poured into ice (500
mL), and extracted with diethyl ether. Diethyl ether was
washed with brine, dried over Na2SO4, and evaporated to give
2-chloro-3-ethoxy-6-fluorobenzaldehyde, 62b (11.72 g, 94%).
N-[2-(2-Cya n o-6-flu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-
br om op yr id yl)]th iou r ea (17). A mixture of NiBr2 (2.0 g,
9.2 mmol), triphenylphosphine (9.5 g, 36.2 mmol), and zinc
powder (1.95 g, 30 mmol) in 100 mL of acetonitrile was stirred
under nitrogen at 50 °C for 0.5 h. NaCN (23.5 g, 480 mmol)
and 2-bromo-4-fluoroanisole (70) (95 g, 463 mmol) were added.
The mixture was stirred overnight at 60 °C, and 700 mL of
CHCl3 was added. The mixture was then heated to the boiling
point, and solids were filtered off while hot. The solvent was

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4271
compound 10. The title product was prepared according to
removed at reduced pressure. Crystallization from dichloro-
ethane/hexane gave 2-cyano-4-fluoroanisole, 72.
1
route A: mp 166 °C; H NMR (250 MHz, DMSO-d6) δ 11.23
(t, 1H), 10.80 (s, 1H), 8.18 (d, 1H), 8.06 (dd, 1H), 7.33 (q, 1H),
7.21 (d, 1H), 6.87 (t, 2H), 4.07 (q, 2H), 3.91 (q, 2H), 3.03 (t,
2H), 1.41 (t, 3H). Anal. (C16H17BrFN3OS) H, N; C: calc, 48.2;
found, 47.7.
Lithium diisopropylamide was added dropwise to a solution
of compound 72 (4.65 g, 34 mmol) in 200 mL of THF at -70
°C. The reaction mixture was heated to -55 °C and kept at
this temperature for 1 h. The mixture was cooled again to
-70 °C, and DMF (4 mL) was added. Acetic acid (3.6 g) was
added after 30 min at -55 °C, and then ((ethoxycarbonyl)-
methylene)triphenylphosporane (12.0 g, 34 mmol) was added.
The mixture was allowed to come to room temperature and
was left overnight. Purification on a silica gel column eluted
with ethyl acetate/hexane gave a cis-trans mixture of ethyl
3-(2-cyano-3-methoxy-6-fluorophenyl) propenoate, 74.
Compound 74 was added to 100 mL of methanol, and 100
mg of 10% Pd/C was added. The stirred mixture was hydro-
genated at atmospheric pressure until H2 consumption ceased
(3 h). The solution was filtered, and the solvent was evapo-
rated. The product, ester 76, was then hydrolyzed for 30 min
in a refluxing mixture of NaOH (2 g, 50 mmol) in 50 mL of
ethanol/water, 1:1. Acidification (HCl), extraction to dichloro-
methane, drying (Na2SO4), and crystallization from dichloro-
ethane/hexane gave 2.55 g of 3-(2-cyano-3-methoxy-6-fluoro-
phenyl)propanoic acid, 78.
N-[2-(2,3-Diflu or o-6-et h oxyp h en et h yl)]-N′-[2-(5-b r o-
m op yr id yl)]th iou r ea (23). 2,3-Difluoro-6-ethoxyphenethyl-
amine (64e) was prepared from 2,3-difluorophenol as described
for compound 10. The title product was prepared according
1
to route A: mp 170.7 °C; H NMR (250 MHz, CDCl3) δ 11.22
(s, 1H), 8.20 (s, 1H), 8.13 (d, 1H), 7.73 (dd, 1H), 7.00(dd, 1H),
6.18 (d, 1H), 6.07 (m, 1H), 4.0 (m, 4H), 3.13 (m, 2H), 1.45 (t,
3H). Anal. (C16H16BrF2N3OS) C, H, N.
N-[2-(2,3-Diflu or o-6-m eth oxyp h en eth yl)]-N′-[2-(5-br o-
m op yr id yl)]t h iou r ea (24). 2,3-Difluoro-6-methoxyphen-
ethylamine (64j) was prepared from 2,3-difluorophenol as
described for compound 10. The title product was prepared
according to route A: mp 160 °C;
1H NMR (250 MHz, CDCl3)
δ 11.35 (s, 1H), 9.65 (s, 1H), 8.15 (d, 1H), 7.7 (m, 1H), 7.05-
6.8 (m, 2H), 6.55 (m, 1H), 4.0 (s, 2H), 3.8 (s, 3H), 3.1 (m, 2H).
Anal. (C15
H14BrF2N3OS) C, H, N.
N-[2-(3,6-Dim eth oxy-2-flu or op h en eth yl)]-N′-[2-(5-ch lo-
r op yr id yl)]th iou r ea (25). To a solution of 1,4-dimethoxy-
benzene (56) (15.0 g, 0.109 mol) in 300 mL of dry THF was
added 2.5 M n-BuLi (45.6 mL, 0.114 mol) at room temperature
under nitrogen. After addition was complete, the solution was
stirred for 1 h. The mixture was cooled to -70 °C, and
N-fluorobenzenesulfonimide (36.0 g, 0.114 mol) in 150 mL of
THF was added slowly, keeping the temperature below -60
°C. The solution was allowed to warm to room temperature
overnight. Then 100 mL of saturated NH4Cl(aq) was added
and the mixture extracted with diethyl ether/THF. The
organic phase was washed with 1 M NaOH (2 × 60 mL), dried
over MgSO4, and evaporated. Column chromatography (silica
gel, n-hexane followed by 1, 5, and 10% EtOAc in n-hexane)
provided 11.43 g of a mixture of 1,4-dimethoxy-2-fluorobenzene
(61k ) and 1,4-dimethoxybenzene (4.3:1). 3,6-Dimethoxy-2-
fluorophenethylamine (64k ) was prepared from 1,4-dimethoxy-
2-fluorobenzene (61k ) as described for compound 10. The title
product was prepared according to route C: mp 172-173 °C;
1H NMR (250 MHz, CDCl3) δ 11.28 (s, 1H), 9.20 (s, 1H), 8.04
(d, 1H), 7.55 (dd, 1H), 6.81 (m, 2H), 6.54 (dd, 1H), 3.97 (m,
Compound 78 was dissolved in a mixture of triethylamine
(30 mmol) and 30 mL of THF. Diphenyl phosphorazidate
(4.125 g, 15 mmol) was added and the mixture heated to 50
°C for 1 h. The solvent was removed, and the residue was
partitioned between water and dichloromethane. The organic
phase was dried, and the solvent was removed. The residue
was dissolved in toluene (50 mL) and heated to near reflux
until N2 evolution ceased (about 15 min). The solvent was
removed, the residue was redissolved in 50 mL of dioxane, and
50 mL of concentrated HCl was added. The mixture was then
refluxed for 3 h. The solvent was removed, and the residue
was dissolved in 30 mL of 2 M HCl(aq) and washed with
dichloromethane. The aqueous phase was made strongly basic
with 40% NaOH(aq). 2-Cyano-3-methoxy-6-fluorophenethyl-
amine (84e) was extracted with dichloromethane. The title
1
product was prepared according to route A: mp 177.7 °C; H
NMR (250 MHz, CDCl3) 11.35 (t, 1H), 9.05 (s, 1H), 8.18 (m,
1H), 7.72 (m, 1H), 7.2 (m, 1H), 6.8 (m, 2H), 4.1 (q, 2H), 3.93
(s, 3H), 3.3 (t, 2H). Anal. (C16H14BrFN4OS) C, H, N.
N-[2-(2-Cya n o-6-flu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-
cya n op yr id yl)]th iou r ea (18). Starting amine 84e was the
same as for compound 17. The title product was prepared
according to route B: mp 215 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.40 (t, 1H), 11.15 (s, 1H), 8.58 (m, 1H), 8.24 (m, 1H),
7.65 (m, 1H), 7.35 (m, 1H), 7.26 (m, 1H), 4.05 (m, 2H), 3.95 (s,
3H), 3.22 (t, 2H). Anal. (C17H14FN5OS) C, H; N: calc, 19.61;
found, 20.65.
N-[2-(2-Cya n o-6-flu or o-3-m eth oxyp h en eth yl)]-N′-[2-(5-
ch lor op yr id a zyl)]th iou r ea (19). Starting amine 84e was
the same as for compound 17. The title product was prepared
according to route B: mp 211 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.20 (t, 1H), 11.05 (s, 1H), 7.97 (d, 1H), 7.64 (m, 2H),
7.23 (dd, 1H), 4.10 (m, 2H), 3.98 (s, 3H), 3.25 (t, 2H). Anal.
(C15H13ClFN5OS) C, N; H: calc, 3.5; found, 3.0.
2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.09 (m, 2H). Anal. (C16H17
ClN3O2S) C, H, N.
-
N-[2-(3-Eth oxy-2-flu or o-6-m eth oxyp h en eth yl)]-N′-[2-(5-
ch lor op yr id yl)]th iou r ea (26). A suspension of 2-fluoro-4-
methylacetophenone (54) (10.0 g, 0.059 mol), mCPBA (26.0 g,
0.128 mol), and MgSO4 (30.0 g) in 500 mL of CHCl3 was stirred
for 12 h at room temperature. The mixture was then filtered,
washed with 2 M NaOH, dried over Na2SO4, and concentrated
in vacuo to give 1-acetyl-2-fluoro-4-methoxybenzene (55) as a
solid (10.7 g, 98%).
A solution of the compound 55 (5.3 g, 0.029 mol) in 100 mL
of MeOH and 20 mL of 25% NH3(aq) was stirred for 1 h at
room temperature. The mixture was then concentrated in
vacuo, diluted with water, extracted with EtOAc, dried over
Na2SO4, and concentrated in vacuo to give 2-fluoro-4-methoxy-
phenol as an oil (3.85 g, 94%). Alkylation of this compound
with EtI as described for compound 10 gave 2-ethoxy-1-fluoro-
4-methoxybenzene, 61f. 3-Ethoxy-2-fluoro-6-methoxyphen-
ethylamine (64f) was prepared from compound 61f as de-
scribed for compound 10. The title product was prepared
according to route C: mp 194-196 °C; 1H NMR (250 MHz,
CDCl3) δ 11.24 (br s, 1H), 9.00 (br s, 1H), 8.10 (d, 1H), 7.55
(dd, 1H),6.88-6.69 (m, 2H), 6.50 (d, 1H), 4.10-3.89 (m, 4H),
N-[2-(2,5-Dim eth oxyph en eth yl)]-N′-[2-(5-ch lor opyr idyl)]-
th iou r ea (20). 2,5-Dimethoxyphenethylamine (64q) was
prepared from 2,5-dimethoxybenzaldehyde (62q) as described
for compound 10. The title product was prepared according
1
to route A: mp 130.5 °C; H NMR (250 MHz, CDCl3) δ 11.19
(br s, 1H), 8.82 (br s, 1H), 8.12 (d, 1H), 7.69 (dd, 1H), 6.83-
6.67 (m, 4H), 4.00 (dd, 2H), 3.78 (s, 3H), 3.76 (s, 3H), 3.00 (dd,
2H). Anal. (C16H18BrN3O2S) H, N; C: calc, 48.5; found, 48.0.
N-[2-(2,5-Dieth oxyp h en eth yl)]-N′-[2-(5-br om op yr id yl)]-
th iou r ea (21). 2,5-Diethoxyphenethylamine (64p ) was pre-
pared from 2,5-dihydroxybenzaldehyde (59) as described for
compound 10. The title product was prepared according to
route A: mp 162 °C;1H NMR (250 MHz, DMSO-d6) δ 11.24
(br s, 1H), 10.80 (s, 1H), 8.26 (d, 1H), 8.07 (dd, 1H), 7.21 (d,
1H), 6.99-6.85 (m, 3H), 4.03 (t, 4H), 3.91 (q, 2H), 2.97 (t, 2H),
1.41 (t, 6H). Anal. (C18H22BrN3O2S) C, H, N.
3.75 (s, 3H), 3.10 (m, 2H), 1.45 (t, 3H). Anal. (C17H19
ClFN3O2S) C, H, N.
-
N-[2-(2,3-Dim eth oxy-6-flu or op h en eth yl)]-N′-[2-(5-br o-
m op yr id yl)]t h iou r ea (27). 2,3-Dimethoxy-6-fluorophen-
ethylamine (64g) was prepared from 4-fluoroveratrole (61g)
as described for compound 10. The title product was prepared
according to route A: mp 159-160 °C; 1H NMR (250 MHz,
CDCl3) δ 11.26 (s, 1H), 8.71 (s, 1H), 8.14 (d, 1H), 7.69 (dd, 1H),
6.77 (d, 2H), 6.68 (d, 1H), 3.98 (m, 2H), 3.88 (s, 3H), 3.85 (s,
3H), 3.09 (m, 2H). Anal. (C16H17BrFN3O2S) C, H, N.
N -[2-(2-E t h oxy-6-flu or op h e n e t h yl)]-N ′-[2-(5-b r om o-
p yr id yl)]th iou r ea (22). 2-Ethoxy-6-fluorophenethylamine
(64a ) was prepared from 3-fluorophenol as described for

4272 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Cantrell et al.
N-[2-(6-Ch lor o-3-et h oxy-2-flu or op h en et h yl)]-N′-[2-(5-
br om op yr id yl)]th iou r ea (28). 6-Chloro-3-ethoxy-2-fluoro-
phenethylamine (64d ) was prepared from 4-chloro-2-fluoro-
phenol as described for compound 10. The title product was
prepared according to route A: mp 157-158 °C; 1H NMR (250
MHz, CDCl3) δ 11.31 (s, 1H), 9.28 (s, 1H), 8.15 (d, 1H), 7.69
(dd, 1H), 7.09 (dd, 1H), 6.84-6.77 (m, 2H), 4.11-4.00 (m, 4H),
3.22 (m, 2H), 1.46 (t, 3H). Anal. (C16H16BrClFN3OS) C, H,
N.
N-[2-(2,3,6-Tr iflu or oph en eth yl)]-N′-[2-(5-ch lor opyr idyl)]-
th iou r ea (29). 2,3,6-Trifluorophenethylamine (64l) was pre-
pared from 1,3,5-trifluorobenzene (61l) as described for com-
pound 10. The title product was prepared according to route
C: mp 171-172 °C; 1H NMR (250 MHz, DMSO-d6) δ 11.23 (t,
1H), 10.74 (s, 1H), 8.12 (d, 1H), 7.87 (dd, 1H), 7.20-7.13 (m,
3H), 3.83 (q, 2H), 2.96 (t, 2H). Anal. (C14H11ClF3N3S) C, H,
N.
°C for 15 min and N-fluorobenzenesulfonimide (11 g, 35 mmol)
dissolved in THF (40 mL) was added through a dropping
funnel. The temperature was kept below -68 °C during the
addition. The solution was stirred without cooling, and at -10
°C water (30 mL) and triethylamine (3 mL) were added. The
solution was diluted with Et2O, washed with water, dried over
Na2SO4, filtered, and evaporated with caution.
The residue, compound 111, was dissolved in dioxane/water
(50 mL, 2:1), and p-TSA (3 g) was added. The solution was
stirred for 60 min, the pH was adjusted to 8.0 with K2CO3,
and (carbethoxymethylene)triphenylphosphorane (5.8 g, 16.6
mmol) was added. The solution was stirred for 30 min at
ambient temperature, diluted with water, and extracted with
dichloromethane. The organic phase was dried over Na2SO4,
filtered, and evaporated. The residue was purified with flash
chromatography by elution with ethyl acetate/n-hexane (1:9).
The combined fractions were evaporated.
N-[2-(2,6-Diflu or o-4-(d im eth yla m in o)p h en eth yl)]-N′-[2-
(5-ch lor op yr id yl)]th iou r ea (30). 2,6-Difluoro-4-(dimethyl-
amino)phenethylamine (64m ) was prepared from 3,5-di-
fluoroaniline as described for compound 5. The title product
was prepared according to route C: mp 191.5-193 °C; 1H NMR
(250 MHz, CDCl3) δ 11.33 (t, 1H), 9.28 (s, 1H), 7.99 (d, 1H),
7.54 (dd, 1H), 6.84 (d, 1H), 6.21-6.10 (m, 2H), 3.92 (q, 2H),
2.98-2.90 (m, 8H). Anal. (C16H17ClF2N4S) C, H, N.
N-[2-(3-Cya n o-4-(d im eth yla m in o)-2-flu or op h en eth yl)]-
N′-[2-(5-br om op yr id yl)]th iou r ea (31). 3-Cyano-4-(dimeth-
ylamino)-2-fluorophenethylamine (84c) was prepared from
3-cyano-4-(dimethylamino)-2-fluorobenzaldehyde (81c) as de-
scribed for compound 2. The title product was prepared
according to route A: mp 190 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.28 (t, 1H), 10.84 (s, 1H), 8.27 (d, 1H), 8.07 (dd, 1H),
7.54 (t, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 3.89 (q, 2H), 3.11 (s,
6H), 2.99 (t, 2H). Anal. (C17H17BrFN5S) C, H, N.
N-[2-(2,4-Dich lor o-3-eth oxy-6-flu or op h en eth yl)]-N′-[2-
(5-br om op yr id yl)]th iou r ea (32). 2,4-Dichloro-3-ethoxy-6-
fluorophenethylamine (64c) was prepared from 2,6-dichloro-
4-fluorophenol as described for compound 10. The title product
was prepared according to route A: mp 131 °C; 1H NMR (250
MHz, CDCl3) δ 11.26 (br s, 1H), 8.99 (s, 1H), 8.15 (d, 1H), 7.72
(dd, 1H), 7.06 (d, 1H), 6.76 (d, 1H), 4.05-3.99 (m, 4H), 3.22 (t,
2H), 1.45 (t, 3H). Anal. (C16H15BrCl2FN3OS) C, H, N.
N-[2-[2-(1-Meth ylpyr r olyl)]eth yl]-N′-[2-(5-cyan opyr idyl)]-
th iou r ea (33). The title product was prepared by using 2-(2-
aminomethyl)-1-methylpyrrole as starting amine and route
B: mp 199-201 °C dec.; 1H NMR (250 MHz, DMSO-d6) δ 11.37
(t, 1H), 11.05 (s, 1H), 8.60 (d, 1H), 8.16 (dd, 1H), 7.25 (d, 1H),
6.64 (t, 1H), 5.93-5.90 (m, 2H), 3.81 (q, 2H), 3.56 (s, 3H), 2.90
(t, 2H). Anal. (C14H15N5S) C, H; N: calc, 25.5; found, 24.0.
N-[2-[2-(1-Methylpyrrolyl)]ethyl]-N′-[2-(5-chloropyridyl)]-
th iou r ea (34). The title product was prepared by using 2-(2-
aminoethyl)-1-methylpyrrole as starting amine and route C:
mp 169.5-171.0 °C; 1H NMR (250 MHz, DMSO-d6) δ 11.36 (t,
1H), 10.76 (br s, 1H), 8.27 (d, 1H), 7.97 (dd, 1H), 7.32 (d, 1H),
6.74 (s, 1H), 6.03-6.00 (m, 2H), 3.93 (q, 2H), 3.67 (s, 3H), 3.01
(t, 2H). Anal. (C13H15ClN4S) H, N; C: calc, 53.0; found, 52.1.
N-[2-[2-(3-Flu or ofu r an yl)]eth yl]-N′-[2-(5-ch lor opyr idyl)]-
th iou r ea (35). 3-Bromo-furan (108) (5.0 mL, 56 mmol) was
dissolved in dry THF under nitrogen. The solution was cooled
to -78 °C, and LDA (28 mL, 2 M, 56 mmol) was added. The
solution was stirred for 20 min at -78 °C, and DMF (10 mL)
was added. The solution was stirred for 5 min at -30 °C and
then diluted with water and dichloromethane. The organic
phase was washed with water, dried over Na2SO4, filtered, and
evaporated with caution.
The residue, compound 113, was dissolved in methanol/
water (5:1) containing NaHCO3 (200 mg) and hydrogenated
over Pd/C catalyst at ambient pressure. After theoretical H2
consumption (340 mL), the solution was filtered through Celite
and evaporated. The residue was dissolved in dioxane/water
(1:1), and NaOH (400 mg) was added. The solution was heated
with stirring to 50 °C for 60 min. The solution was diluted
with water and washed with Et2O. The aqueous phase was
acidified with acetic acid and extracted with ethyl acetate. The
organic phase was dried over Na2
SO4, filtered, and evaporated.
The residue, compound 114 (404 mg, 2.6 mmol), was
dissolved in toluene, and triethylamine (0.6 mL, 4.3 mmol) and
diphenyl phosphorazidate (0.6 mL, 2.8 mmol) were added. The
solution was refluxed for 10 min. Hexane was added to
precipitate the phosphate salt, and the solution was filtered.
Methanol (20 mL) was added, and the solution was refluxed
for an additional 40 min. The solution was evaporated, and
the residue was purified with flash chromatography on silica
gel by elution with ethyl acetate/n-hexane (1:4). The combined
fractions were evaporated.
The residue, compound 115, was dissolved in dioxane/
methanol/water (1:1:1), NaOH (400 mg) was added, and the
solution was refluxed over night. The solution was diluted
with water and extracted with Et2O. The organic phase was
extracted with dilute HCl (pH 2), and the acidic water phase
was evaporated to give 2-(3-fluorofuranyl)ethylamine hydro-
chloride, 116. The title product was prepared according to
1
route A: mp 153.5-154.0 °C; H NMR (250 MHz, DMSO-d6)
δ 11.4 (br s, 1H), 10.9 (br s, 1H), 8.3-8.2 (d, 1H), 8.0-7.9 (m,
1H), 7.6-7.5 (m, 1H), 7.3-7.2 (d, 1H), 6.6 (t, 1H), 4.0-3.9 (m,
2H), 3.1-3.0 (m, 2H). Anal. (C12H11ClFN3OS) C, H, N.
N-[2-[2-(3-Cyan ofu r an yl)]eth yl]-N′-[2-(5-ch lor opyr idyl)]-
th iou r ea (36). 3-Furoic acid (117) (5.0 g, 45 mmol) and 1,3-
dicyanobenzene (10.0 g, 78 mmol) were mixed and heated to
300 °C, and 2.0 g of 3-cyanofuran (118) was collected via a
short Vigreux column equipped with a distilling head. The
material was pure enough to use in the next step.
3-Cyanofuran (1.4 g, 15 mmol) was dissolved in dry THF
(50 mL) and cooled to -77 °C under nitrogen. LDA (15 mmol,
2 M) was added as quickly as possible, keeping the tempera-
ture below -65 °C. The solution was stirred for 10 min, and
DMF (5mL) was added rapidly. Stirring was continued for
30 s, and ((benzyloxycarbonyl)methyl)triphenylphosphonium
bromide (7.3 g, 15 mmol) dissolved in MeOH (20 mL) was
added rapidly. The solution was diluted with diethyl ether
and washed with water. The organic phase was dried over
sodium sulfate, and evaporated.
The crude residue, compound 120, which contained some
triphenylphosphine oxide as an impurity, was dissolved in
MeOH, and 5% Pd/C (0.5 g) was added. The solution was
hydrogenated at atmospheric pressure until about 400 mL of
H2 was consumed. The solution was filtered and diluted with
water, and potassium carbonate (4 g) was added. The solution
was washed with dichloromethane, acidified with acetic acid,
and extracted with dichloromethane. The organic phase was
dried over sodium sulfate and evaporated.
The residue, compound 109, was dissolved in propylene
glycol (100 mL), and p-TSA (4 g) and a 4 Å molecular sieve
(20 g) were added. The mixture was stirred for 60 min at
ambient temperature. The solution was neutralized with
K2CO3(aq), diluted with ethyl acetate, washed with water,
dried over Na2SO4, filtered, and evaporated. The residue was
distilled using a small column, and the fraction with bp 95-
99 °C (6 mmHg) was collected.
The product, compound 110 (7.8 g, 33.5 mmol), was dis-
solved in THF under nitrogen and cooled to -78 °C. n-BuLi
(14 mL, 35 mmol) was added. The solution was stirred at -78
The residue, compound 121, was dissolved in toluene and
triethylamine (0.22 mL, 1.6 mmol), and diphenyl phosphor-
azidate (0.34 mL, 1.6 mmol) was added. The solution was

PETT Compounds as HIV-1 Reverse Transcriptase Inhibitors
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4273
refluxed for 20 min, then diluted with diethyl ether, and
filtered through Celite. The solution was mixed with 0.1 M
hydrochloric acid and dioxane and stirred for 1 h. The water
phase was separated, it was made basic with NH3(aq) and
extracted with dichloromethane, and the organic phase was
dried over sodium sulfate and evaporated to yield 2-(3-
cyanofuranyl)ethylamine (122) as an oil. The title product was
phine (7.0 g, 27 mmol) and trifluoroacetic acid (25.0 mL) were
added. The solution was refluxed for 60 min and diluted with
water, and the aqueous phase was washed with ethyl acetate
and evaporated to yield N-(2-aminoethyl)phthalimide 135 as
trifluoroacetate salt. The title product was prepared according
to route A: mp 189.5-190.0 °C; H NMR (250 MHz, DMSO-
d6) δ 11.3 (br s, 1H), 10.5 (br s, 1H), 8.1-7.8 (m, 6H), 7.3-7.2
(d, 1H), 4.1-3.9 (m, 4H). Anal. (C16H13ClN4O2S) C, H, N.
1
1
prepared according to route A: mp 160.2-163.4 °C; H NMR
(250 MHz, d-MeOD, CDCl3) δ 8.1 (d, 1H), 7.7-7.6 (m, 1H),
7.5 (d, 1H), 7.0-6.9(d, 1H), 6.6 (d, 1H), 4.1-4.0 (t, 2H), 3.3-
3.2 (t, 2H). Anal. (C13H11ClN4OS) C, H, N.
N-[2-[N′-(3,6-Dich lor oph th alim idyl)]eth yl]-N′′-[2-(5-ch lo-
r op yr id yl)]th iou r ea (43). 1-[[2-(5-Chloropyridyl)]thiocar-
bamoyl]imidazole 45 (0.31 g, 1.3 mmol) and ethylenediamine
(5.0 mL) were mixed, and the mixture was heated to 100 °C
for 5 min. The mixture was evaporated, dissolved in water,
and extracted with dichloromethane. The organic phase was
dried over sodium sulfate and evaporated. The residue was
dissolved in acetonitrile, and 3,6-dichlorophthalic anhydride
(0.15 g, 0.7 mmol) was added. The mixture was refluxed for
12 h. The solution was cooled, and the precipitate was filtered
off, suspended in water/methanol (1:2), and boiled for 5 min.
The suspension was cooled to room temperature, and the solid
was collected by filtration, washed with acetonitrile, and dried
to yield the title product as a crystalline solid: mp 271.3-
272.6 °C; 1H NMR (250 MHz, DMSO-d6) δ 11.3 (br s, 1H), 10.5
(br s, 1H), 8.1 (s, 1H), 7.9 (m, 3H), 7.4-7.2 (d, 1H), 4.1-3.9
(m, 2H), 3.2-3.0 (m, 2H). Anal. (C16H11Cl3N4O2S) H, N; C:
calc, 44.7; found, 43.9.
N -[2-(3-In d olyl)e t h yl]-N ′-[2-(5-b r om op yr id yl)]t h io-
u r ea (37). The title product was prepared by using tryptamine
1
hydrochloride as starting amine and route A: mp 200 °C; H
NMR (250 MHz, DMSO-d6) δ 11.30 (s, 1H), 11.02 (s, 1H), 10.77
(s, 1H), 8.09 (s, 1H), 8.02 (d, 1H), 7.74 (d, 1H), 7.47 (d, 1H),
7.39 (s, 1H), 7.20-7.04 (m, 3H), 3.99 (q, 2H), 3.16 (t, 2H). Anal.
(C16H15BrN4S) C, H, N.
N -[2-[3-(5-Me t h o x y in d o ly l)]e t h y l]-N ′-[2-(5-b r o m o -
p yr id yl)]th iou r ea (38). The title product was prepared by
using 5-methoxytryptamine hydrochloride as starting amine
and route A: mp 180-181 °C; 1H NMR (250 MHz, DMSO-d6)
δ 11.30 (br s, 1H), 10.84 (s, 1H), 10.76 (s, 1H), 8.10 (s, 1H),
8.02 (dd, 1H), 7.37-7.17 (m, 4H), 6.79 (d, 1H), 3.98 (q, 2H),
3.84 (s, 3H), 3.12 (t, 2H). Anal. (C17H17BrN4OS) H, N; C: calc,
50.4; found, 48.8.
N-[2-(Ben zotr ia zol-2-yl)eth yl]-N′-[2-(5-br om op yr id yl)]-
th iou r ea (39). Benzotriazole (123) (100 mmol) was dissolved
in 600 mL of DMF, and K2CO3 (120 mmol) was added. Ethyl
bromoacetate (100 mL) was added to the stirred mixture. The
reaction mixture was stirred at 40 °C overnight and filtered,
and the solvent was removed in vacuo. The two product
isomers were separated by fractional crystallization from
mixtures of ethanol/ethyl acetate to give pure compound 125.
The reduction of compound 125 with lithium borohydride
in Et2O gave a mixture of two alcohols: 2-(2-hydroxyethyl)-
benzotriazole (127) and 1-(2-hydroxyethyl)benzotriazole. 2-(2-
Hydroxyethyl)benzotriazole (127) (4.7 g, 28.8 mmol) and
pyridine (2.28 g, 28.8 mmol) were dissolved in 200 mL of Et2O,
and the mixture was cooled to -50 °C. Triflic anhydride (8.18
g, 29 mmol) was added dropwise. The mixture was heated to
-30 °C. A solution of 150 mL of NH4Cl and 50 mL of Et2O
was added to the cold solution. The mixture was heated to
room temperature, and the solvent was removed. The residue
was acidified with HCl and washed with dichloromethane. The
mixture was alkalized with NaOH. Extraction with dichloro-
methane followed by evaporation gave 2-(2-aminoethyl)-
benzotriazole (129) (2.10 g). The title product was prepared
according to route A: mp 218.3 °C; 1H NMR (250 MHz, DMSO-
d6) δ 11.4 (t, 1H), 10.9 (s, 1H), 8.05 (m, 3H), 7.9 (d, 1H), 7.55
Ack n ow led gm en t. We thank C. Rydegård and C.
Åhgren for assistance with the biological assays and L.
Pettersson for assistance in the preparation of the
manuscript. In addition, we thank the Physical Chem-
istry Department of the Lilly Research Laboratories for
providing analytical and spectral data.
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(m, 2H), 7.2 (d, 1H), 5.15 (t, 2H), 4.4 (m, 2H). Anal. (C14H13
BrN6S) C, H, N.
-
N-[2-(5,6-Dim eth ylben zotr ia zol-2-yl)eth yl]-N′-[2-(5-br o-
m op yr id yl)]th iou r ea (40). Starting amine 130 was pre-
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described for compound 39. The title product was prepared
according to route A: mp 231.9 °C; 1H NMR (250 MHz, DMSO-
d6/MeOD-d4) δ 7.95 (m, 1H), 7.73 (m, 3H), 7.13 (d, 1H), 5.0 (t,
2H), 4.4 (t, 2H), 2.5 (s, 6H). Anal. (C16H17BrN6S) H; C: calc,
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N-[2-(2-Ben zim id a zolyl)eth yl]-N′-[2-(5-br om op yr id yl)]-
th iou r ea (41). 2-(2-Aminoethyl)benzimidazole (132) was
prepared from 2-benzimidazolacetonitrile (137) by reduction
with NaBH4/NiCl2 in MeOH. The title product was prepared
according to route A: mp 203 °C; 1H NMR (250 MHz, DMSO-
d6) δ 12.43 (s, 1H), 11.61 (t, 1H), 10.83 (s, 1H), 8.06-7.98 (m,
2H), 7.8-7.5 (br d, 2H), 7.30-7.18 (m, 3H), 4.23 (q, 2H), 3.28
(t, 2H). Anal. (C15H14BrN5S) C, H, N.
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was refluxed for 24 h, diluted with water, and extracted with
ethyl acetate. The organic phase was dried over sodium
sulfate and evaporated. The residue, compound 134, was
dissolved in dioxane/water (10:1, 200 mL), and triphenylphos-

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