Structure-activity relationships of a series of pyrrolo[3,2-d]pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists

Article abstract of DOI:10.1021/jm000269t

Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists, a series of pyrrolo[3,2-d]pyrimidine derivatives was prepared and evaluated for their ability to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity relationship investigations for this class of compounds. The target compounds were prepared by a variety of synthetic routes designed to modify both the substitution and the heterocyclic core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5 antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the human Y5 receptor is presented.

Full text of DOI:10.1021/jm000269t

4288
J . Med. Chem. 2000, 43, 4288-4312
Str u ctu r e-Activity Rela tion sh ip s of a Ser ies of P yr r olo[3,2-d ]p yr im id in e
Der iva tives a n d Rela ted Com p ou n d s a s Neu r op ep tid e Y5 Recep tor An ta gon ists
Mark H. Norman,* Ning Chen, Zhidong Chen, Christopher Fotsch, Clarence Hale, Nianhe Han, Ray Hurt,
Tracy J enkins, J ohn Kincaid, Longbin Liu, Yuelie Lu, Ofir Moreno, Vincent J . Santora,
J ennifer D. Sonnenberg, and William Karbon
Departments of Small Molecule Drug Discovery and Neuroscience, Amgen, Inc., One Amgen Center Drive,
Thousand Oaks, California 91320-1789
Received J une 22, 2000
Neuropeptide Y (NPY) has been shown to play an important role in the regulation of food
intake and energy balance. Pharmacological data suggests that the Y5 receptor subtype
contributes to the effects of NPY on appetite, and therefore a Y5 antagonist might be a useful
therapeutic agent for the treatment of obesity. In attempts to identify potential Y5 antagonists,
a series of pyrrolo[3,2-d]pyrimidine derivatives was prepared and evaluated for their ability
to bind to Y5 receptors in vitro. We report here the synthesis and initial structure-activity
relationship investigations for this class of compounds. The target compounds were prepared
by a variety of synthetic routes designed to modify both the substitution and the heterocyclic
core of the pyrrolo[3,2-d]pyrimidine lead 1. In addition to identifying several potent Y5
antagonists for evaluation as potential antiobesity agents, a pharmacophore model for the
human Y5 receptor is presented.
In tr od u ction
High-throughput screening against the Y5 receptor
led to the identification of several potential leads
possessing high affinity to this receptor. Pyrrolo[3,2-d]-
pyrimidine 1 was one of these hits and will be the focus
of the following discussion.
Obesity is the most common metabolic disorder in the
western world and affects more than 30% of the adult
population in the United States.1 Furthermore, obesity
has now been directly implicated as one of the major
risk factors in the development of several potentially
life-threatening disorders including heart disease, high
blood pressure, stroke, late-onset diabetes, and certain
forms of cancer.2 A series of pharmacologic approaches
are currently being investigated within the pharma-
ceutical industry to help manage this disease which is
a major cause of morbidity and mortality.3-7 The ap-
proach that we have investigated is to develop a
neuropeptide Y (NPY) antagonist which may reduce
food intake in humans. In the early 1980s NPY was
shown to potently stimulate appetite and increase food
intake. It was not until recently, however, that inves-
tigators have cloned and characterized an NPY receptor
that is thought to mediate NPY’s orexigenic effects.8-15
Antagonism of this NPY feeding receptor, which has
been designated as the Y5 subtype, might attenuate
NPY signaling in the hypothalamus and provide a
mechanism for treating obesity.16-19 The identification
of the Y5 receptor as a potential feeding receptor
subtype has stimulated a number of investigations in
this area. For example, Novartis20-23 and Synaptic24
were the first to report a series of 2,4-diaminoquinazo-
lines and arylsulfonamides as potent Y5 receptor an-
tagonists. Subsequently, a number of patents have also
claimed a variety of compound classes that act at the
Y5 receptor.25-31 Recently, Youngman and co-workers
have described the results of their structure-activity
investigations of a series of â-aminotetralins targeted
to the Y5 receptor.32
In this structure-activity relationship (SAR) inves-
tigation, we prepared analogues of 1 with specific
changes to the parent structure to better understand
the structural features required for binding to the Y5
receptor (general structure 2). Through the iterative
process of synthesis and biological evaluation, we have
gained insight into the pharmacophores important for
binding within this class of compounds. In addition, we
have prepared several derivatives with very high af-
finities for the Y5 receptor. The preliminary results of
these investigations are reported, and a pharmacophore
model is proposed.
Ch em istr y
A variety of synthetic routes were required to prepare
derivatives of pyrrolopyrimidine 1. Although some of the
methods could be generalized, the synthetic routes
employed were mainly dictated by which heterocyclic
core was being prepared (variables X, Y, Z, and A in
compound 2) and which R group was being modified (R1,
R2, and R3 substituents in compound 2). In this article
we will restrict our discussion to compounds with single
changes to pyrrolopyrimidine 1. For clarity, the discus-
* To whom correspondence should be addressed. Tel: 805-447-1552.
Fax: 805-480-1337. E-mail: markn@amgen.com.
10.1021/jm000269t CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/14/2000

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4289
Sch em e 1
sion of the synthetic methods is organized based on the
heterocyclic core prepared (i.e., pyrrolo[3,2-d]pyrimidine
3, pyrrolo[3,2-d]pyridine 4, pyrrolo[3,4-d]pyridine 5,
furano[3,2-d] pyrimidine 6, thiopheno[3,2-d]pyrimidine
7, and purine 8).
fiying the R1 and the R2 substituents on the pyrrolopy-
rimidine core was difficult. Therefore, we found it
preferable to develop alternative routes to this class of
compounds. The key steps of the four general synthetic
routes employed to prepare pyrrolo[3,2-d]pyrimidines
are outlined in Scheme 1. Route A employs the Made-
lung cyclization of an amide to the o-methyl group of
the pyrimidine. Route B forms the substituted pyrrole
initially followed by the subsequent formation of the
pyrimidine ring. Route C employs an enamine addition
to a dichloronitropyrimidine compound followed by an
intramolecular cyclization to form the pyrrole ring.
Route D involves the addition of an acetylene followed
by a copper(I)-mediated cyclization of the acyetylene
amine intermediate. Each of these methods proved to
be useful in providing access to the appropriately
substituted pyrrolo[3,2-d]pyrimidines.
The majority of the derivatives prepared in this study
are representatives of the pyrrolo[3,2-d]pyrimidine class
of compounds (3). Surprisingly, there are very few
literature examples of the synthesis of pyrrolo[3,2-d]-
pyrimidines. Among these reports Sokolova and co-
workers published a series of papers describing the
synthesis of pyrrolo[3,2-d]pyrimidines by employing the
Madelung cyclization as a key step in the synthesis.33,34
Although this method was useful for the preparation of
several analogues, poor yields were obtained and modi-
The first method that was employed (route A) was
analogous to that reported by Sokolva et al.33 and is
outlined in Scheme 2. Treatment of ethyl acetoacetate
(9) with sodium nitrite and acetic acid provided ethyl
2-hydroxyimino-3-butyrate (10).35,36 This material was
reduced with zinc and sulfuric acid to give the corre-
sponding 2-aminoacetoacetic acid ethyl ester.37 This
amine was isolated and acylated with an appropriate
acid chloride to give 11;38 however, higher yields were
Sch em e 2a
a
(a) NaNO2, AcOH, H2O; (b) Zn, H2SO4, H2O; (c) R2(CdO)Cl, NaOAc; (d) R1(CdNH)NH2‚HCl, NaOEt, EtOH; (e) NaOEt, 360 °C; (f)
POCl3, 1,2-dichloroethane, reflux; (g) 1° or 2° amines (R3 ) NR2), K2CO3, H2O; (h) R3B(OR)2, Pd2(dba)3, 1 M Na2CO3, toluene, EtOH,
reflux.

4290 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
Sch em e 3a
dichloromethane provided the corresponding p-toluene-
sulfonyl enol esters 22.41 The crude enol esters were
immediately condensed with diethyl aminomalonate to
provide pyrrole intermediates 25 in 21-61% yields.
Alternatively, the substituted pyrroles 25 were prepared
by the reaction of diethyl aminomalonate (24) with
sodium ethoxide and substituted cyanoacetylenes 23.42
With a variety of 5-substituted 3-amino-1H-pyrrole-2-
carboxylates (25) in hand, several analogues with
modifications at the R1 position (see general structure
2) were prepared. Derivatives wherein R1 is an alkyl
group were prepared by treating pyrroles 25 with an
alkyl cyanide in anhydrous hydrochloric acid at room
temperature followed by heating with sodium hydroxide
to give alcohol intermediates 26. Attempts to prepare
analogous compounds by the condensation of 25 (where
R2 ) Ph) with acetamidine hydrochloride were unsuc-
cessful; however, the 2-trifluoromethyl derivative could
be obtained by the reaction of pyrrole 25 with trifluo-
romethylacetamidine in refluxing xylene. Treatment of
26 with refluxing phosphorus oxychloride followed by
displacement of the resulting chlorides 27 with primary
or secondary amines provided 2-alkyl-substituted pyr-
rolopyrimidine analogues 28. To synthesize derivatives
with a nitrogen at the R1 position, the intermediate
pyrrole 25 (where R2 ) Ph) was reacted with cyanamide
and concentrated hydrochloric acid in refluxing dioxane
followed by heating the resulting intermediate with
aqueous sodium hydroxide to give 29. Alcohol 29 was
converted to chloride 30 by reaction with phosphorus
oxychloride, and the resulting chloride was displaced
with piperidine to give 31. The 2-amino group of
compound 31 was then modified by either reductive
amination or acylation reactions to give compounds of
types 32 and 33, respectively. Incorporation of a thi-
omethyl group in the R1 position of the pyrrolopyrimi-
dine was accomplished as shown in Scheme 4. The
reaction of pyrrole 25 (where R2 ) Ph) with ethyl
isothiocyanatoformate in refluxing benzene followed by
treatment of the resulting intermediate with potassium
hydroxide provided thiol 34.43 Thiomethyl 35 was
obtained by methylation of 34 with methyl iodide in
acetone. Attempts to chlorinate 35 resulted in decom-
position; however, when compound 35 was treated with
methanesulfonyl chloride the mesylate 36 was obtained.
This material was reacted with piperidine without
isolation to give the thiomethyl-substituted pyrrolopy-
rimidine 37. The two final classes of analogues whose
syntheses are illustrated in Scheme 4 contain a methoxy
or substituted amine group in the R1 position of the
pyrrolopyrimidine ring. These derivatives were prepared
by initially treating pyrrole 25 (where R2 ) Ph) with
potassium cyanate followed by heating the intermediate
in refluxing sodium hydroxide to give diol 38. The
reaction of diol 38 with phosphorus oxychloride gave the
corresponding dichloro compound 39.44 The 4-chloro
group of dichloro intermediate 39 was displaced upon
heating with piperidine in aqueous potassium carbonate
for 4 h to give compound 40; however, displacement of
the 2-chloro group required more vigorous reaction
conditions. Reaction of chloro derivative 40 with either
sodium methoxide or primary and secondary amines at
elevated temperatures (110-189 °C) and for extended
reaction times (44-72 h) resulted in the preparation of
a
(a) Tf2(O), 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2; (b)
bis(pinacolato)diboron, PdCl2(dppf), KOAc, DMSO, 70 °C; (c) 14
(where R1 ) Me and R2 ) Ph), Ph3P, Pd2(dba)3, 1 M Na2CO3,
toluene, EtOH, reflux; (d) H2(70 psi), PtO2, EtOH.
obtained by the in situ acylation of the amine by the
method described by Tarzia and co-workers.39 Conden-
sation of the ethyl N-acylated-2-aminoacetoacetates 11
with acetamidine hydrochloride in sodium ethoxide
provided acylpyrimidine intermediates 12. Madelung
cyclization of pyrimidines 12 at 360 °C gave the desired
3-hydroxypyrrolo[3,2-d]pyrimidines 13, albeit in poor
yields. Pyrrolopyrimidines 13 were converted to their
corresponding chlorides 14 by treatment with phospho-
rus oxychloride in dichloroethane, and these key chloro
intermediates were condensed with a variety of amines
to give 4-amino-substituted pyrrolopyrimidines. Route
A provided easy access to pyrrolopyrimidine derivatives
where R3 was modified; however, modifications at R1
and R2 were limited due to the high temperatures
required for the Madelung cyclization. Therefore, only
a few derivatives with modifications in these positions
were prepared (e.g., R1 was limited to Me, i-Pr, and Ph,
and R2 was limited to Ph and Ph(4-Me)). In addition to
the preparation of 4-amino-subsituted analogues, the
carbon-substituted derivatives were prepared by the
Suzuki coupling of chloro intermediates 14 with the
appropriate boronic acid derivatives.
Of particular interest to our SAR investigation was
the cyclohexyl derivative 20 wherein the piperidine
nitrogen of compound 1 was replaced with a carbon
atom. The synthesis of this derivative involved the
preparation of boronic ester 18 (Scheme 3). The enol
triflate 17, prepared by the reaction of cyclohexanone
with triflic anhydride,40 was treated with bis(pinocola-
to)diboron to give boronic ester 18. The boronic ester
18 was condensed with chloro intermediate 14 (where
R1 ) Me and R2 ) Ph) to give cyclohexene derivative
19 which was hydrogenated to provide the desired
pyrrolo[3,2-d]pyrimidine 20.
The general method involving the use of 3-amino-2-
carboxyl-5-substituted pyrroles (route B) proved to be
very fruitful and allowed synthetic entries into several
pyrrolopyrimidine analogues with varying substitution
patterns. The syntheses of derivatives using this general
route are outlined in Scheme 4. The key 5-substituted
3-amino-1H-pyrrole-2-carboxylate intermediates 25 were
prepared by two different methods. Treatment of R-cy-
ano ketones 21 with p-toluenesulfonic anhydride in

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4291
Sch em e 4a
a
(a) Ts2O, Et3N, CH2Cl2; (b) diethyl aminomalonate hydrochloride, NaOEt, EtOH; (c) NaOEt, EtOH; (d) alkyl-CN, HCl(g); (e) NaOH,
EtOH, reflux; (f) F3C(CdNH)NH2, o-xylene, reflux; (g) H2NCN, HCl(concd), dioxane, reflux; (h) NaOH(aq), reflux; (i) SdCdNCO2Et, benzene,
reflux; (j) KOH(aq), reflux; (k) KNCO, HOAc, H2O; (l) POCl3, reflux; (m) piperidine, K2CO3, H2O, reflux; (n) RCHO, NaCNBH3, MeOH,
reflux; (o) (PhCdO)2O, pyridine, reflux; (p) MeI, K2CO3, acetone; (q) MsCl, CH2Cl2, Et3N; (r) piperidine; (s) NaOMe, DMSO, reflux, 72 h;
(t) HNMe2, or H2NMe, n-BuOH, HCl(concd), reflux (44-72 h); (u) HNR2, dioxane, reflux; (v) HNR2, K2CO3, H2O, 72 h.
methoxy and substituted amino derivatives 41 and 42,
respectively.
yl ketones with pyrrolidine (see Boger et al.48), were
immediately reacted with dichloropyrimidines 45 to give
enamine intermediates 47. These intermediates were
treated directly with piperidine, to give 48, and the nitro
group was subsequently reduced with tin(II) chloride
in dimethylformamide. Upon reduction of the nitro
group the compounds rapidly cyclized to give the desired
substituted pyrrolopyrimidines 49.
The final synthetic route employed to prepare the
pyrrolo[3,2-d]pyrimidine ring system is outlined in
Scheme 6 (route D). Treatment of dichloropyrimidines
45 with a secondary amine at room temperature pro-
vided polysubstituted pyrimidines 50. The nitro group
was reduced with tin(II) chloride, and the resulting
amine 51 was converted to compound 52 by the pal-
ladium-catalyzed addition of a monosubstituted acety-
The third method developed for the preparation of
pyrrolopyrimidine derivatives is based on the work of
Montgomery et al. (route C), wherein the key step
involved the addition of an enamine 46 to a chloropy-
rimidine intermediate 4545 (Scheme 5). This synthetic
route proved to be particularly useful for the preparation
of pyrrolopyrimidine derivatives with modifications in
the R2 position. Nitration of 2-methyl-4,6-dihydroxypy-
rimidine (43) with nitric acid gave 2-methyl-4,6-dihy-
droxy-5-nitropyrimidine (44, where R1 ) Me).46,47 The
requisite dichloro intermediate 45 required for the
enamine reaction was obtained by the treatment of 44
with phosphorus oxychloride. Enamines 46, prepared
by the tin tetrachloride-mediated condensation of meth-

4292 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
Sch em e 5a
a
(a) TFA, HNO3 (90%), 12-21 °C; (b) POCl3, i-Pr2NEt, toluene, reflux; (c) i-Pr2NEt, toluene, rt; (d) piperidine, Et3N, toluene:dioxane
(1:2), 100 °C; (e) SnCl2, DMF, rt-reflux.
Sch em e 6a
Sch em e 8a
a
(a) HN(R)2, Et3N, THF, rt; (b) SnCl2‚2H2O, Et2O, HCl(concd),
0 °C; (c) HCtCR2, Pd(PPh3)2Cl2, CuI, Et3N, 70 °C; (d) CuI, DMF,
110 °C.
Sch em e 7a
a
(a) HNO3 (fuming), H2SO4(concd), 0 °C; (b) POCl3, reflux; (c)
SnCl2‚2H2O, Et2O, HCl(concd); (d) N-bromosuccinimide, DMF, 0
°C; (e) MeB(OH)2, Pd(PPh3)2Cl2, DMF, K2CO3, 100 °C; (f) phenyl-
acetylene, Pd(PPh3)2Cl2, CuI, Et3N, 80 °C; (g) CuI, DMF, 110 °C;
(h) piperidine, o-xylene, 140 °C.
mediated cyclization of an appropriately substituted
acetylenic pyridine as the key step to form the pyrrole
ring (Schemes 8 and 9). The synthesis of the N3 deaza
derivative began with nitration of 2,4-dihydroxypyridine
(58) with fuming nitric acid to provide nitropyridine 59
in good yield. The aminodichloro intermediate 61 was
obtained by treating 59 with phosphorus oxychloride
followed by reduction of the nitro group with tin(II)
chloride. The methyl substituent was introduced by
bromination of the 6-position of the pyridine ring with
N-bromosuccinimide followed by a Suzuki coupling with
methylboronic acid to give compound 63. The synthesis
of pyrrolo[3,2-d]pyridine 65 was completed by an analo-
gous sequence as described for the route D pyrrolopy-
rimidine synthesis. Palladium-catalyzed addition of
phenylacetylene proceeded smoothly at the 2-position
to provided compound 64 in good yield, and displace-
ment of the 4-chloro substituent was not observed.
Treatment of 64 with copper(I) iodide in dimethylfor-
mamide at 110 °C, followed by the addition of piperidine,
provided the desired pyrrolo[3,2-d]pyridine 65.
a
(a) Ac2O, K2CO3, DMAP, DMF, 110 °C; (b) n-BuLi, Me2SO4,
-78 °C; (c) AcOH, Br2, H2O, 45 °C; (d) NaOMe, MeOH, reflux.
lene. Cyclization was accomplished by heating acety-
lenes 52 with copper(I) iodide in dimethylformamide to
provide the targeted pyrrolo[3,2-d]pyrimidines 15.49
Additional derivatives containing single-point changes
were also made directly from the lead pyrrolopyrimidine
1 as shown in Scheme 7. Condensation of 1 with acetic
anhydride in dimethylformamide at 110 °C provided the
7-acetyl derivative 54, and the N-methyl analogue 55
was obtained by alkylating the N5 nitrogen of pyrrol-
opyrimidine 1 with dimethyl sulfate. Treatment of 1
with bromine in acetic acid provided 7-bromo-substi-
tuted derivative 56. Finally, the corresponding 7-meth-
oxy derivative 55 was obtained when bromide 56 was
heated with sodium methoxide in refluxing methanol.
The compounds containing the deazapyrrolopyrimi-
dine ring systems (pyrrolo[3,2-d]pyridine 4 and pyrrolo-
[3,4-d]pyridine 5) were prepared by employing a copper-

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4293
Sch em e 9a
a
(a) POCl3, i-Pr2NEt, reflux; (b) piperidine, ZnCl2, THF, rt; (c) H2, Pd/C; (d) NaHMDS, Boc2O, THF; (e) t-BuLi, THF, -78 to -20 °C,
then 1-chloro-2-iodoethane, -20 °C to rt; (f) 4 M HCl, EtOAc; (g) phenylacetylene, CuI, Et3N, PdCl2(PPh3)2, reflux; (h) CuI, DMF, reflux.
Sch em e 10a
a
(a) PBr3, 170 °C; (b) NCCH2OH, NaH, MgSO4, THF, rt; (c) Me(CdO)NMe2, POCl3, 160 °C; (d) Me(CdNH)NH2‚HCl, NaOMe,
poly(ethylene glycol), 120 °C; (e) POCl3, 100 °C; (f) piperidine (neat or in toluene), 100-160 °C.
The second deaza derivative (pyrrolo[3,4-d]pyridine
73) was prepared starting from 6-methyl-3-nitrohydro-
pyridin-2-one (66) (Scheme 9). Compound 66 was chlo-
rinated with phosphorus oxychloride to give compound
67. The chloride group of 67 was displaced with piperi-
dine, and the nitro group was hydrogenated to give the
corresponding aminopyridine 69. Treatment of amino-
pyridine 69 with di-tert-butyl dicarbonate provided
carbamate 70 in good yield. Ortho-directed metalation
of 70 with tert-butyllithium followed by treatment with
1-chloro-2-iodoethane and hydrolysis of the tert-butyl
carbamate gave the polysubstituted pyridine 71. The
target compound, pyrrolo[3,4-d]pyridine 73, was ob-
tained by the palladium-catalyzed addition of phenyl-
acetylene and the subsequent cyclization of the resulting
acetylene 72 with copper(I) iodide.
4-chlorofurano[3,2-d]pyrimidine intermediate 77. This
chloride was not isolated but was reacted directly with
piperidine to provide the desired furano[3,2-d]pyrimi-
dine 81. The corresponding thiopheno[3,2-d]pyrimidine
82 was prepared in three steps starting from 3-amino-
5-phenylthiophene-2-carboxylate (79). Condensation of
79 with acetamidine hydrochloride provided alcohol 80,
which was converted immediately to the chloride 78
using phosphorus oxychloride. Displacement of the
chloride on compound 78 with piperidine gave the
desired thiopheno[3,2-d]pyrimidine derivative 82.
The final synthetic sequence employed in this study
is shown in Scheme 11 for the preparation of the purine
derivative 87. One of the two chloro groups of dicholo-
pyrimidine 83 was displaced with piperidine at room
temperature to give compound 84. Treatment of 84 with
ammonia in a sealed tube at 90 °C provided the
tetrasubstituted pyrimidine 85 in good yield, and the
reduction of the nitro group of 85 was accomplished by
hydrogenation with 10% palladium on carbon. The final
target compound, purine 87, was obtained by the
condensation of diamine 86 with benzoic acid in phos-
phorus oxychloride.50 In general, the compounds de-
scribed herein were prepared and purified as their
hydrochloride salts.
The syntheses of both the furan and thiophene
derivatives are shown in Scheme 10. Treatment of
benzoyl acetonitrile (74) with phosphorus tribromide at
170 °C provided vinyl bromide 75 in good yield. The
polysubstituted furan intermediate 76 was easily ob-
tained by the condensation of bromonitrile 75 with
glycolonitrile in tetrahydrofuran. The chloroimidate of
N,N-dimethylacetamide was freshly prepared in situ
and reacted with aminonitrile furan 76 to give the

4294 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
Sch em e 11a
Ta ble 1. In Vitro Y5 Receptor Binding Affinities for
2-Substituted Pyrrolo[3,2-d]pyrimidines
hY5 receptor bindingb
IC50 (nM)c
compd no.a
R1
88a
1
H
Me
Et
2300 ( 1500
1.1 ( 0.4
88b
88c
88d
88e
88f
88g
88h
31
42a
42b
42c
42d
41
20 ( 0.0
n-Pr
c-Pr
i-Pr
i-Bu
Ph
CF3
NH2
NHMe
NHPr
NMe2
1-piperidinyl
OMe
SMe
28 ( 10
32 ( 18
8300 ( 470
460 ( 230
9300 ( 470
590 ( 49
1.2 ( 0.2
29 ( 3.0
120 ( 2.5
280 ( 80
4000 ( 1000
540 ( 77
4700 ( 1200
750 ( 150
a
(a) Piperidine, i-Pr2NEt, THF, rt; (b) NH3, MeOH, 90 °C, sealed
tube; (c) H2, Pd/C, EtOH; (d) benzoic acid, POCl3, 120 °C.
Resu lts a n d Discu ssion
The pyrrolopyrimidine derivatives prepared in this
study were evaluated in an in vitro radioligand-binding
assay to determine their affinity for the human NPY5
receptor.51 Secondary in vitro functional assays were
also conducted to establish that these derivatives were
acting as antagonists at the Y5 receptor,52 and potent
compounds were examined in in vivo models to evaluate
inhibition of feeding in mice and rats. In this report we
will restrict our discussion to the in vitro activity of the
compounds at the human Y5 receptor.53 To establish the
SAR of this series of compounds, each variable of
general structure 2 was systematically modified, includ-
ing substituents R1, R2, and R3, as well as the different
heterocyclic cores obtained by varying X, Y, Z, and A.
The following structure-activity tables examine each
of these variables independently and report the in vitro
binding affinities of the derivatives at the human Y5
receptor. Data for the lead compound 1 has been
included in most tables for ease of comparison. We begin
our discussion by examining the effects of the various
substituents on the pyrrolo[3,2-d]pyrimidine core struc-
ture (R1, R2, and R3). Derivatives of the original lead
compound 1 with modifications at R1 are shown in Table
1. The pyrrolopyrimidine without substitution at the
2-position (88a , R1) H) showed weak binding affinity
at the Y5 receptor indicating that 2-substitution of the
pyrrolopyrimidine core was preferred for good activity.
Small electron-donating groups such as alkyl and amino
demonstrated the best binding affinities (compounds 1,
88b-d , 31, 42a -c) versus the electron-withdrawing
trifluoromethyl substituent (compound 88h ). However,
the methoxy and thiomethyl derivatives showed lower
activity (compounds 41 and 37, respectively) indicating
that the binding affinity did not correlate well with
electronegativity of the R1 substituent. Alkyl substitu-
ents in the 2-position of the pyrrolopyrimidine ring
exhibited good correlation between binding affinity and
steric size (Me > Et ≈ n-Pr ≈ c-Pr > i-Bu > i-Pr > Ph;
1, 88b-g). This sensitivity to steric size was also
observed in the amino series: the 2-NH2-substituted
derivative 31 showed potent affinity at the Y5 receptor
with an IC50 of 2 nM, whereas the affinity diminished
up to 3 orders of magnitude as the bulk of the substitu-
ent was increased (compounds 42a -d ). When the
electron-donating ability of the nitrogen was reduced
37
33
NH(CdO)Ph
a
b
Hydrochloride salts with the exception of 88g and 37.
[
125I]PYY
binding. c IC50 values reported represent an average of at least
two 6-point determinations for each compound.
as in the case of benzamide 33, decreased activity was
also observed. The increased steric size of benzamide
substituent may also contribute to the lower affinity of
this derivative.
Receptor binding data for derivatives with modifica-
tions at R2 have been divided into two categories. The
effects of substitution on the 6-phenyl group are sum-
marized in Table 2, while alkyl and heterocyclic deriva-
tives are reported in Table 3. In general, substitution
on the phenyl ring is well-tolerated and a number of
very potent derivatives were obtained with IC50’s < 1
nM (Table 2). A clear preference for meta and para
substitution was observed with the ortho-substituted
counterparts possessing significantly lower affinity for
the Y5 receptor. This order of activity was consistent
across three series of compounds (i.e., Cl-, F3C-, and
F-substituted derivatives 89a -c,d -f,g-i, respectively).
The series of polyfluorinated derivatives also demon-
strated that meta and para substitution enhanced
activity over ortho substitution (89m ,n vs 89o-q).
These results suggest that the phenyl ring prefers to
be in a planar orientation relative to the pyrrolopyri-
midine core structure. Molecular mechanics calculations
of the chloro series (89a -c) indicate that there is a
significantly larger dihedral angle between the phenyl
and the pyrrolopyrimidine rings of the ortho derivative
(40.3° for 89a ) as compared to either the meta (89b) or
para (89c) derivatives that have corresponding dihedral
angles of 11.3° and 4.6°, respectively.54 With the excep-
tion of the biphenyl derivative (89l), good activity was
maintained with a variety of substituents in the 4-posi-
tion of the phenyl ring regardless of their electronic
properties (89c,f,i,j). The reduced activity of the biphe-
nyl derivative (89l) may be due to the increased steric
volume of this derivative.

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4295
Ta ble 2. In Vitro Y5 Receptor Binding Affinities for
Substituted 6-Phenylpyrrolo[3,2-d]pyrimidines
tives 90a -d show an excellent correlation between Y5
binding affinity and the length of the alkyl group (n-
pentyl > n-Bu > n-Pr > Me). These results suggest that
these alkyl groups are reaching out to fill a hydrophobic
pocket on the human Y5 receptor, and significant
binding energy is gained at a distance of 4-5 atoms out
from the pyrrolopyrimidine ring. This hydrophobic
pocket was able to accommodate medium alkyl and
alkylaryl groups such as cyclohexyl, methylenecyclo-
hexyl, and phenethylene derivatives (90e,f,k , respec-
tively), as well as bulky groups such as adamantyl (90g).
Insertion of a methylene spacer between the pyrrolopy-
rimidine ring and the cyclohexyl group was beneficial
for activity (90f vs 90e); however, insertion of a meth-
ylene spacer in the phenyl series reduced binding
affinity (89e vs 90h , 89k vs 90i, and 89i vs 90j). A series
of derivatives containing two-atom spacers between the
pyrrolopyrimidine and the phenyl group were also
prepared. Compounds containing the ethylene and ether
spacers retained good affinity (90k -m ), while sulfide
and sulfone derivatives were less active (90n ,o). The
poor activity of sulfone 90o supports the hypothesis that
hydrophobic groups are preferred in this area of the
receptor. The final class of derivatives in this position
consisted of compounds wherein the phenyl ring of 1
was replaced with a heterocyclic group (90p -v). Both
the thiophene 90p and furan 90q showed decreased
affinity as compared to compound 1. However the effect
of adding a methyl group to the 4-position of the furan
analogue was striking. As this alkyl group reached out
into the hydrophobic pocket of the receptor, the affinity
increased 4 orders of magnitude (90q vs 90r ). The
subnanomolar binding affinity was maintained as the
hydrophobic region was expanded further by the addi-
tion of a fused phenyl ring (i.e., benzofuran 90s).
Interestingly, a similar increase in potency was not
observed in the corresponding thiophene (90p ) and
benzthiophene (90t) series. The nitrogen heterocyles,
pyridine 90u and pyrimidine 90v, did not improve
binding interactions in the hydrophobic pocket of the
receptor.
The SARs resulting from modifying the R3 position
of the pyrrolopyrimidine ring system are summarized
in Tables 4-6 below. Initially the effects of various ring
modifications were investigated (Table 4), and series of
derivatives with increasing ring size were prepared. The
smallest ring (azetidine 91a ) showed a slight reduction
in activity; however, derivatives with five-, six-, and
seven-membered rings (91b, 1, and 91c) in the 4-posi-
tion of the pyrrolopyrimidine all demonstrated potent
affinities for the human Y5 receptor. Unsaturation in
these rings had no significant effect on the activity of
these potent compounds (91d ,e); however, when a
heteroatom was introduced into the ring, as in the case
of morpholine 91f and piperizine 91g, activity was
reduced. In addition, removal of the basic nitrogen of
91g by acylation or sulfonylation of the piperizine
nitrogen did not improve activity (compounds 91h ,i,
respectively). Therefore, as was observed in the R2
position, these results show that hydrophobic groups in
the R3 position are preferred. More support for this
conclusion was also obtained for the series of substituted
piperidine derivatives shown in Table 5. Piperidine
analogues with hydrophobic substituents (92a -d ) pos-
hY5 receptor bindingb
IC50 (nM)c
compd no.a
R
1
H
2-Cl
3-Cl
4-Cl
2-CF3
3-CF3
4-CF3
2-F
3-F
4-F
4-Me
4-OMe
4-Ph
2,5-diF
2,6-diF
3,5-diF
3,4-diF
3,4,5-triF
1.1 ( 0.4
660 ( 140
<0.1
89a
89b
89c
89d
89e
89f
89g
89h
89i
89j
89k
89l
89m
89n
89o
89p
89q
<0.1
2500 ( 790
<0.1
0.7 ( 0.6
44 ( 11
0.3 ( 0.1
0.3 ( 0.1
0.5 ( 0.3
41 ( 30
1400 ( 270
79 ( 4.0
380 ( 100
0.4 ( 0.3
<0.1
<0.1
a
b
Hydrochloride salts.
[
125I]PYY binding. c IC50 values reported
represent an average of at least two 6-point determinations for
each compound.
Ta ble 3. In Vitro Y5 Receptor Binding Affinities for
6-Substituted Pyrrolo[3,2-d]pyrimidines
hY5 receptor bindingb
compd no.a
R2
IC50 (nM)c
90a
90b
90c
90d
90e
90f
90g
90h
90i
Me
160 ( 71
66 ( 7.0
n-Pr
n-Bu
n-pentyl
c-Hex
10 ( 3.0
0.2 ( 0.1
11 ( 7.0
8.5 ( 1.5
45 ( 19
CH2(c-Hex)
1-adamantyl
CH2[(3-CF3)Ph]
CH2[(4-OMe)Ph]
CH2[(4-F)Ph]
CH2CH2Ph
170 ( 78
2400 ( 600
860 ( 110
5.3 ( 1.8
150 ( 3.0
18 ( 9.5
670 ( 32
8500 ( 1500
100 ( 74
1100 ( 800
0.5 ( 0.4
0.3 ( 0.2
140 ( 61
150 ( 100
1400 ( 150
90j
90k
90l
CH2CH2[(4-OMe)Ph]
CH2OPh
90m
90n
90o
90p
90q
90r
90s
90t
CH2S[(4-Cl)Ph]
CH2SO2[(4-Cl)Ph]
2-thienyl
2-furanyl
2-(5-Me)furanyl
2-benzofuranyl
2-benzothienyl
2-pyridyl
90u
90v
2-pyrazinyl
a
b
Hydrochloride salts.
[
125I]PYY binding. c IC50 values reported
represent an average of at least two 6-point determinations for
each compound.
Derivatives containing alternative replacements for
the 6-phenyl group of the lead pyrrolopyrimidine are
illustrated in Table 3. The straight chain alkyl deriva-

4296 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
Ta ble 4. In Vitro Y5 Receptor Binding Affinities for
4-Substituted Pyrrolo[3,2-d]pyrimidines
Ta ble 6. In Vitro Y5 Receptor Binding Affinities for
4-Substituted Pyrrolo[3,2-d]pyrimidines
hY5 receptor bindingb
IC50 (nM)c
compd no.a
R3
hY5 receptor bindingb
compd no.a
D
IC50 (nM)c
93a
93b
93c
93d
93e
93f
NH2
NHPh
3100 ( 260
540 ( 170d
1500 ( 370
>10000
91a
91b
1
91c
91d
91e
91f
91g
91h
91i
CH2
CH2CH2
57 ( 2.0
0.7 ( 0.2
NHCH2Ph
NHCH2CF3
NHCH2CH2CH2OEt
CH2CH2CH2
CH2CH2CH2CH2
CHdCH
CH2CHdCH
CH2OCH2
CH2NHCH2
CH2N(Ac)CH2
CH2N(SO2Me)CH2
1.1 ( 0.4
730 ( 330
7800 ( 3900
1.8 ( 0.3
2.2 ( 1.7d
0.4 ( 0.1
100 ( 36
93g
93h
2600 ( 1400
4000 ( 2300
7200 ( 3600
6000 ( 1000
7500 ( 500
a
b
Hydrochloride salts with the exception of 91g.
[
125I]PYY
binding. c IC50 values reported represent an average of at least
two 6-point determinations for each compound. 2.2 ( 1.7 (mean
( standard deviation, n ) 77).
d
93i
93j
NEt2
36 ( 6.0
52 ( 9.0
Ta ble 5. In Vitro Y5 Receptor Binding Affinities for
4-Piperidino-Substituted Pyrrolo[3,2-d]pyrimidines
20
93k
93l
c-Hex
3-thienyl
3-pyridyl
8200 ( 2600
560 ( 100
8500 ( 1500
a
Hydrochloride salts with the exception of 93a ,c-h ,k ,l.
b
[
125I]PYY binding. c IC50 values reported represent an average
of at least two 6-point determinations for each compound. 540
d
( 170 (mean ( standard deviation, n ) 85).
binding affinity of the pyrrolopyrimidine derivatives are
shown in Table 6. When the piperidine ring of compound
1 was removed completely, to give the unsubstituted
amine (93a ), lower activity was observed. Secondary
amines 93b-h also had lower activity regardless of how
much hydrophobic bulk was incorporated on the amine
substituent. However, tertiary amines (e.g., 93i,j) had
higher affinity. This result supports the previous ob-
servation that hydrophobic groups are preferred at R3.
However, further exploration revealed that solely hav-
ing a hydrophobic group at this position was not
sufficient for activity. For example, the lower activity
of the cyclohexyl derivative 20 clearly demonstrated that
the nitrogen atom at R3 was preferred. Similarly, other
heterocyclic groups connected directly to the pyrrolopy-
rimidine core through a carbon-carbon bond were also
less active (e.g., thiophene 93k and pyridine 93l).
The final SARs examined in this investigation re-
sulted from modifications of the lead heterocyclic core
obtained by varying X, Y, Z, and A (Table 7). Replace-
ment of the N1 nitrogen of the pyrrolo[3,2-d]pyrimidine
core system with a carbon gave pyrrolo[3,4-d]pyridine
73. This small modification resulted in a dramatic 1000-
fold reduction in activity, indicating that the N1 nitro-
gen plays a critical role in binding to the human Y5
receptor in this series of compounds. In sharp contrast,
elimination of the N3 nitrogen of the pyrrolo[3,2-d]-
pyrimidine had no effect on activity with the resulting
pyrrolo[3,2-d]pyridine 65 having an IC50 of 1.7 nM. The
next position examined was the 7-position of the pyr-
rolopyrimidine (Z; compound 94). Any substitution at
this position proved to reduce activity (94a -d , 54, 56,
and 57) with the methyl substituent being the best-
hY5 receptor bindingb
compd no.a
R
IC50 (nM)c
1
H
2-Me
1.1 ( 0.4
3.0 ( 1.5
17 ( 9.0
92a
92b
92c
92d
92e
92f
92g
92h
92i
2,6-cis-diMe
2-Et
3,5-diMe
2-CH2CH2OH
2-CH2NMe2
4-OH
74 ( 25d
190 ( 120
730 ( 310
5200 ( 2700
250 ( 17
4-NMe2
>10000
220 ( 330
a
b
Hydrochloride salts with the exception of 92d ,h .
[
125I]PYY
binding. c IC50 values reported represent an average of at least
two 6-point determinations for each compound. 74 ( 25 (mean
d
( standard deviation, n ) 87).
sessed higher affinities than those substituted with
hydrophilic groups (92e-h ). The decrease in activity
was particularly dramatic when a basic amine is
incorporated in this portion of the molecule (91g and
92f,h ). Isoquinoline 92i was prepared to further expand
the hydrophobic space around the piperizine ring.
Although this compound showed lower affinity than
compound 1, its activity was comparable to the 3,5-
dimethyl analogue 92d . The results of 92d ,i suggest
that some steric bulk can be tolerated in the 3-, 4-, and
5-positions of the piperidine ring without a drastic
reduction in activity.
The effects of acyclic amines as well as heterocyclic
and carbocyclic substituents at R3 on the Y5 receptor

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4297
Ta ble 7. In Vitro Y5 Receptor Binding Affinities for
Furano[3,2-d]pyrimidine, Pyrrolo[3,4-d]pyridine,
Pyrrolo[3,2-d]pyridine, Thiopheno[3,2-d]pyrimidine, Pyrimidine,
and 5-Substituted Pyrrolo[3,2-d]pyrimidine Derivatives
position. In general, cyclic hydrophobic amines worked
best followed by tertiary amines, while secondary
amines and the carbon analogues were less active. The
results obtained from alkylation of the N5 nitrogen
suggest a possible hydrogen-bonding interaction at this
position. The SAR results indicated that a large hydro-
phobic pocket was likely at the 6-position. Aromatic
substitution in the meta and para positions of the
6-phenyl ring enhanced Y5 activity and provided a
number of subnanomolar antagonists. Finally, substitu-
tion at the 7-position of the pyrrolopyrimidine, or the
ortho position of the phenyl ring, was not preferred.
hY5 receptor bindingb
compd no.a
X
Y
Z
A
IC50 (nM)c
Con clu sion s
1
73
65
94a
94b
94c
94d
54
56
57
87
55
81
82
N
N
N
CH
CH
CH CH
NH
NH
NH
NH
NH
NH
NH
NH
NH
1.1 ( 0.4
1200 ( 520
1.7 ( 0.3
CH
N
N
N
N
N
N
N
N
N
N
N
N
In summary, synthetic entries into a large series of
novel pyrrolopyrimidines were developed to explore the
SARs of these potential Y5 antagonists. This investiga-
tion concentrated on single-point changes to the lead
pyrrolopyrimidine 1 to better understand the structural
features required for binding to the Y5 receptor. These
new deazapurine derivatives were evaluated in an in
vitro binding assay to assess how the particular struc-
tural modification affected potency. Through the itera-
tive process of synthesis and biological evaluation, we
have gained insight into the pharmacophores important
to binding to the Y5 receptor within this class of
compounds. This study resulted in the development of
a working hypothetical model of the human Y5 receptor
binding site that we are currently using to aid the
development of other novel series of Y5 antagonists.
Results of additional studies with other series will be
reported in due course. In addition to gaining a better
understanding of the receptor interactions, we have
prepared several derivatives with very high affinity for
the Y5 receptor.55 These potent Y5 antagonists are
currently being examined in more detail using second-
ary in vitro, in vivo, ADME, and toxicological assays.
N
N
N
N
N
N
N
N
N
N
N
CMe
53 ( 38
CEt
CP h
CF
CAc
CBr
COMe NH
N
CH
CH
CH
330 ( 94
420 ( 80
1600 ( 810
5100 ( 2900
580 ( 300
910 ( 250
470 ( 100
1300 ( 190
30 ( 0.0
NH
NMe
O
S
220 ( 330
a
b
Hydrochloride salts with the exception of 54-57.
[
125I]PYY
binding. c IC50 values reported represent an average of at least
two 6-point determinations for each compound.
tolerated (compound 94a ). These results support the
hypothesis that planarity between the aromatic ring
relative to the pyrrolopyrimidine core is important to
binding since substitution at the 7-position perturbs the
conformation of the phenyl group. Analogues containing
larger alkyl, aryl, or various electron-withdrawing or
-donating groups at this position all showed reduced
activity. The lower activities of the fluoro derivative 94d
and the purine derivative 87 indicate that not only steric
considerations are important at this position but that
the electronics of this system may also play a role.
Finally, modification of the N5 nitrogen of the pyrrol-
opyrimidine was examined (Table 7). Alkylation of the
N5 nitrogen reduced Y5 binding affinity (compound 55);
however, replacing the nitrogen with other heteroatoms
was better tolerated as was seen with furano[3,2-d]
pyrimidine 81 and thiopheno[3,2-d]pyrimidine 82. Per-
haps alkylation of the N5 nitrogen affects an important
hydrogen-bonding interaction at the receptor as well as
altering the conformation of the phenyl ring relative to
the pyrrolopyrimidine ring.
From the SARs discussed, we have generated a
pharmacophore model for the interactions of this pyr-
rolopyrimidine series with the human Y5 receptor. The
results and key features of the model are summarized
in Figure 1. In general, small electron-donating groups
were preferred in the 2-position of the pyrrolopyrimidine
ring, and branching was not preferred. One of the key
interactions seems to be a hydrogen bond involving the
N1 nitrogen. Due to the dramatic effects observed in
altering the electronics of the pyrrolopyrimidine ring
system, we postulate that the N1 nitrogen may be
protonated at the receptor and acting as a hydrogen
bond donor in this system. On the other hand, the N3
nitrogen did not play a critical role in binding to the Y5
receptor. Substitution at the 4-position indicated that
the receptor had a medium hydrophobic pocket at this
Exp er im en ta l Section
P h a r m a cology. Mem br a n e P r ep a r a tion . Human em-
bryonic kidney cells (HEK 293) expressing the human Y5
receptor were harvested from 150-mm culture dishes using
PBS. Cells were pelleted by centrifugation at 1500 rpm for 2
min. The resulting pellet was homogenized in 15 mL of ice-
cold sucrose buffer (25 mM HEPES, 0.3 M sucrose, pH 7.4)
with a motorized, glass-fitted, Teflon homogenizer. The ho-
mogenate was centrifuged at 48000g at 4 °C for 10 min,
resuspended in 15 mL of assay buffer (minimum essential
medium with Earle’s salts containing 25 mM HEPES, 0.1%
BSA, 0.1 mg/mL STI, 0.1 mg/mL Pefabloc, pH 7.4) using a
Tissue-Tearor (Biospec Products), and recentrifuged at 48000g
for 10 min. The pellet was homogenized a third time in 15 mL
of assay buffer and the resulting homogenate was centrifuged
at 48000g for 10 min. The final pellet was resuspended in
assay buffer to a wet weight concentration of 10-20 mg/mL.
Ra d ioliga n d Bin d in g Assa y. Binding assays were per-
formed in 96-well U-bottom plates. Membranes (200 µg of
tissue) were incubated at 30 °C for 2 h in assay buffer with
various drugs in the presence of 0.15 nM [125I]PYY in a total
volume of 100 µL. Nonspecific binding was assessed in the
presence of 1 µM PYY. The binding reaction was terminated
by rapid filtration through Unfilter-96 GF/C glass fiber filter
plates, followed by three washes with 300 µL of ice-cold water.
Bound radioactivity was determined using a TopCount micro-
plate scintillation and luminescence counter. Nonlinear re-
gression analysis of concentration-response curves to deter-
mine IC50 values was performed using GraphPad Prism.
Ch em istr y. Gen er a l. Unless otherwise noted, all materials
were obtained from commercial suppliers and used without

4298 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
F igu r e 1. Summary of the preferred features of the pyrrolopyrimidine Y5 receptor antagonists and how they interact with a
hypothetical model of the Y5 receptor.
further purification. Anhydrous solvents such as dimethylfor-
mamide (DMF), tetrahydrofuran (THF), dichloromethane (CH2-
Cl2), toluene, and dioxane were obtained from Aldrich Chemi-
cal Co. in Sure/Seal bottles. All reactions involving air- or
moisture-sensitive compounds were performed under a N2
atmosphere. Flash chromatography was performed using ICN
Biomedicals silica gel (SiliTech 32-63D 60A). Thin-layer chro-
matography (TLC) was performed with Analtech or Whatman
silica gel TLC plates (250 µm). Preparatory TLC was per-
formed with Whatman silica gel TLC plates (2000 µm). 1H
NMR spectra were determined with superconducting FT NMR
spectrometers operating at 400 and 500 MHz. Chemical shifts
are expressed in ppm (δ) downfield from internal tetrameth-
(162.5 g, 1.19 mol) was added with stirring. Benzoyl chloride
(18.3 mL, 22.1 g, 0.157 mol) was slowly added to the resulting
cloudy solution via a syringe. After the addition was complete,
the cold bath was removed and the solution was allowed to
stir at room temperature for 24 h. The yellow reaction mixture
was extracted with CH2Cl2 (3 × 100 mL). The organic layers
were washed with saturated aqueous NaHCO3, dried over
MgSO4, filtered, and concentrated on a rotary evaporator to
give 30.3 g of a yellow oil. This material was purified by flash
chromatography on silica gel with 1:4 EtOAc:hexanes as eluant
to give 20.0 g (51%) of the title compound as a viscous pale-
1
yellow oil. H NMR (CDCl3, 500 MHz): δ 1.33 (t, 3, J ) 7.1),
2.46 (s, 3), 4.31 (m, 2), 5.43 (d, 1, J ) 6.4), 7.28 (br m, 1), 7.46
(t, 2, J ) 7.6), 7.54 (m, 1), 7.85 (d, 2, J ) 7.2). MS m/z: 250 (M
+ H), 178 (base).
1
ylsilane. Significant H NMR data are reported in the following
order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; quin, quintet), number of protons, and coupling
constants in hertz (Hz). Elemental analyses were performed
by Atlantic Microlab, Inc., Norcross, GA. Melting points were
determined with a Buchi 535 capillary melting point apparatus
and are uncorrected. Low-resolution mass spectra (MS) were
determined on a Perkin-Elmer-SCIEX API 165 mass spec-
trometer using APCI or ES ionization modes (positive or
negative). High-resolution mass spectra (HRMS) were per-
formed on a PerSeptive Biosystems Mariner TOF or by Mass
Consortium, San Diego, CA, using FAB ionization.
(b) 2,6-Dim eth yl-4-h ydr oxy-5-ben zam idopyr im idin e (12;
R1 ) Me, R2 ) P h ). Absolute EtOH (150 mL) was added to
an oven-dried round-bottomed flask, and small pieces of
sodium (4.95 g, 0.215 mol) were added portionwise. A reflux
condenser was attached to the flask and the solution was
allowed to stir at room temperature until all of the sodium
was consumed. Acetamidine hydrochloride (9.95 g, 0.105 mol)
was added in one portion, and the resulting creamy white
suspension was allowed to stir at room temperature for 0.5 h.
In
a separate flask ethyl 3-oxo-2-(phenylcarbonylamino)-
Four general synthetic methods (routes A-D) were em-
ployed to prepare the various pyrrolo[3,2-d]pyrimidine ana-
logues examined in this study (vide supra). A representative
experimental procedure for each type of synthetic route
employed is described below. The general methods used to
prepare specific pyrrolo[3,2-d]pyrimidine derivatives are in-
dicated, and the supporting characterization data are provided.
Rou te A. (a ) Eth yl 3-Oxo-2-(p h en ylca r bon yla m in o)-
bu ta n oa te (11; R2 ) P h ).38 To a 1-L, round-bottomed flask
were added ethyl 2-(hydroxyimino)-3-oxybutyrate (10)35,36 (25.0
g, 0.157 mol), H2SO4 (30% w/v) (230 mL) and crushed ice (250
g). This solution was cooled in an ice-saltwater bath and the
internal temperature was monitored with an alcohol ther-
mometer. Powdered zinc (100 mesh) (30.0 g, 0.459 mol) was
added to this cooled solution portionwise via a powder addition
funnel. The temperature of the reaction was maintained
between 0 and 10 °C. After the addition of the zinc was
complete the reaction mixture was allowed to stir at 0 °C for
0.5 h. The solution was filtered through a fritted funnel into
a 1-L round-bottomed flask. This clear, colorless solution was
cooled in an ice-water bath and sodium acetate trihydrate
butanoate (23.8 g, 0.956 mol) was dissolved in absolute EtOH
(30 mL). The acetamidine solution was filtered through a plug
of Celite into the ketoester solution. As this solution was
added, the reaction mixture turned from an orange to a dark-
brown color. The mixture was placed under a N2
atmosphere
and allowed to stir at room temperature overnight. As the
reaction proceeded solids precipitated out of solution to give a
thick brown-orange mixture. The reaction mixture was filtered
through a fritted funnel and the solids were washed with
EtOH. The solids were dissolved in distilled H2O, and HCl
(concentrated) was added to acidify the solution to a pH of 4-5
(pH paper). Upon acidification solids precipitated out of
solution. The solution was cooled in an ice-water bath, the
solids were filtered, washed with cold water and dried in a
vacuum oven to give 7.59 g (33%) of the title compound as a
white powder. The EtOH filtrate was concentrated with a
rotary evaporator to give 13 g of a sticky orange oil. This
material was purified by flash chromatography on silica gel
with 95:5 CH2Cl2:MeOH as eluant to give an additional 2.61
g (11%) of the title compound as fluffy pale-yellow flakes (total
1
yield 10.2 g (44%)). Mp: 279-281 °C (lit.56 mp ) 282 °C). H

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4299
NMR (DMSO-d6, 500 MHz): δ 2.09 (s, 3), 2.28 (s, 3), 7.51 (t,
2, J ) 7.1), 7.58 (t, 1, J ) 7.2), 7.96 (d, 2, J ) 7.4), 9.51 (s, 1),
12.51 (br s, 1). MS m/z: 244 (M + H). Anal. (C13H13N3O2) C,
H, N.
the title compound as white needles. Mp: 293-294 °C. 1H
NMR (DMSO-d6, 500 MHz): δ 1.71-1.72 (m, 6), 2.58 (s, 3),
4.06-4.07 (m, 4), 6.89 (s, 1), 7.50-7.57 (m, 3), 7.96 (d, 2, J )
7.1), 12.0 (br s, 1), 14.4 (br s, 1). Anal. (C18H21ClN4‚H2O) C, H,
N, Cl.
(c) 2-Meth yl-6-p h en ylp yr r olo[3,2-d ]p yr im id in -4-ol (13;
R1 ) Me, R2 ) P h ). To an oven-dried, 250-mL, round-
bottomed flask was added absolute EtOH (45 mL). Small
pieces of sodium metal (2.87 g, 0.125 mol) were added
portionwise. After all of the sodium was consumed, 2,6-
dimethyl-4-hydroxy-5-benzamidopyrimidine (10.1 g, 41.7 mol)
was added in one portion via a powder addition funnel. An
additional portion of EtOH (20 mL) was added to rinse the
last portion of the amide from the funnel. The reaction mixture
was heated at reflux for 0.25 h until all of the solids dissolved
to give an orange solution. The condenser was replaced with
a short-path distillation head and the EtOH was distilled off
under a N2 atmosphere. The resulting solids were scraped off
the sides of the flask with a spatula and heated with a heating
mantle at 360 °C for 20 min. The residue was allowed to cool
to room temperature, dissolved in distilled H2O (35 mL), and
HCl (concentrated) was added portionwise to adjust the pH of
the solution to 4-5 (pH paper). The resulting precipitate was
filtered and dried in a vacuum oven to give 6.38 g of a tan
solid. This material was dissolved in 3 N NaOH (∼30 mL),
and the resulting dark-brown solution was filtered through a
fritted funnel. Acetic acid was added to the filtrate with
stirring. The resulting solids were filtered, washed with
distilled H2O, recrystallized from EtOH and dried in a vacuum
oven to give 1.45 g (15%) of the title compound as a tan powder.
Rou te B. (a ) 1-(3-Ch lor op h en yl)-2-cya n ovin yl 4-Meth -
ylben zen esu lfon a te (22; R2 ) 3-ClP h ). To a 100-mL, round-
bottomed flask were added 3-chlorobenzoylacetonitrile (5.13
g, 28.5 mmol), p-toluenesulfonyl chloride (6.53 g, 34.3 mmol)
and CH2Cl2 (50 mL). To the above solution was added Et3N (6
mL, 42.8 mmol) dropwise at 0 °C. The mixture was stirred at
0 °C for 1 h, then at room temperature for 22 h. The cloudy
reaction mixture was partitioned between H2O and CH2Cl2.
The organic layer was separated, washed three times with
H2O, dried over Na2SO4, and concentrated in vacuo to give a
dark-red residue. This material was purified by flash chro-
matography on silica gel with 1:10 EtOAc:hexanes as eluant
to give 8.79 g (92%) of the title compound as a yellow solid. 1H
NMR (CDCl3, 400 MHz): δ [minor isomer 2.45 (s, 3)], 2.47 (s,
3), 5.60 (s, 1) [minor isomer 5.62 (s, 1)], 7.32-7.48 (m, 6), [7.74
(d, 1, J ) 8.37)], 7.88 (d, 1, J ) 8.40). MS m/z: 351 (base peak),
332 (M - H).
(b ) E t h yl 3-Am in o-5-(3-ch lor op h en yl)-1H -p yr r ole-2-
ca r boxyla te (25; R2 ) 3-ClP h ). Sodium ethoxide was freshly
prepared from Na (1.77 g, 77.1 mmol) and EtOH (30 mL). A
solution of 1-(3-chlorophenyl)-2-cyanovinyl 4-methylbenzene-
sulfonate (8.56 g, 25.7 mmol) and aminodiethyl malonate
hydrochloride (5.43 g, 25.7 mmol) in EtOH (70 mL) was added
to the sodium ethoxide solution through a dropping funnel.
After the addition was complete, the reaction mixture was
stirred at room temperature for 2 h. The solvent was evapo-
rated in vacuo and the residue was partitioned between EtOAc
and H2O. The organic layer was separated, dried over Na2-
SO4, and concentrated in vacuo to give 5.93 g of a brown solid.
(This material was used directly in the following step without
further purification.)
(c) 6-(3-Ch lor op h en yl)-2-m eth ylp yr r olo[3,2-d ]p yr im i-
d in -4-ol (26; a lk yl ) Me, R2 ) 3-ClP h ). Dry HCl gas was
bubbled through a solution of ethyl 3-amino-5-(3-chlorophenyl)-
pyrrole-2-carboxylate (3.5 g) in 120 mL of acetonitrile at room
temperature for 1.5 h. The reaction mixture was capped, and
stirred at room temperature overnight. The solvent was
evaporated in vacuo to give a solid, which was dissolved in
EtOH (70 mL) and 6% aqueous NaOH (23 mL). The reaction
mixture was heated at reflux for 6 h. The precipitate that
formed was filtered, and dried in a vacuum oven to give 1.17
g of a tan solid as pure product. The filtrate was concentrated
and the resulting suspension was filtered to give a viscous
solid. This material was purified by flash chromatography on
silica gel with 100:5 CHCl3-MeOH as eluant to give 0.46 g
(41% overall from the tosylate (22; R2 ) 3-ClPh)) of the title
compound as a tan solid. 1H NMR (DMSO-d6, 500 MHz): δ
2.31 (s, 3), 6.86 (s, 1), 7.38 (d, 1, J ) 7.38), 7.45 (t, 1, J ) 7.89),
7.90 (d, 1, J ) 7.82), 8.06 (s, 1), 11.81 (br s, 1), 12.41 (br s, 1).
MS m/z: 260, 262 (M + H), 258, 260 (M - H).
1
Mp: >280 °C (lit.57 mp ) 322 dec). H NMR (DMSO-d6, 400
MHz): δ 2.31 (s, 3), 6.77 (d, 1, J ) 2.2), 7.36 (tm, 1, J ) 6.5),
7.43 (t, 2, J ) 7.6), 7.93 (dd, 2, J ) 1.4, 7.2), 11.80 (s, 1), 12.28
(s, 1). MS m/z: 226 (M + H). Anal. (C13H11N3O) C, H, N.
(d ) 4-Ch lor o-2-m eth yl-6-p h en ylp yr r olo[3,2-d ]p yr im i-
d in e (14; R1 ) Me, R2 ) P h ). Phosphorus oxychloride (2.46
mL, 4.05 g, 26.4 mmol), N,N-diethylaniline (1.2 mL, 1.12 g,
7.5 mmol), 1,2-dichloroethane (4 mL) and 2-methyl-6-phe-
nylpyrrolo[3,2-d]pyrimidin-4-ol (0.50 g, 2.22 mmol) were added
to a 50-mL, oven-dried, round-bottomed flask. The resulting
dark-red solution was placed under N2 and heated at reflux
for 3 h. The solution was concentrated with a rotary evaporator
to give a dark-red oil. This material was cooled in an ice-
water bath and distilled H2O was added. The solution was
filtered through a fritted funnel, and the filtrate was concen-
trated with a rotary evaporator to give a wet solid. This crude
material was basified by the addition of NH4OH and extracted
into EtOAc. The organic layer was dried over MgSO4, filtered
and concentrated with a rotary evaporator to give 0.98 g of an
orange oil. This material was purified by flash chromatography
on silica gel using EtOAc(20-50%):hexanes(80-50%) as eluant
to give 0.24 g (44%) of the title compound as a tan solid. 1H
NMR (CDCl3, 400 MHz): δ 2.76 (s, 3), 6.90 (s, 1), 7.43 (m, 3),
7.80 (dm, 2, J ) 6.5), 10.17 (br s, 1). MS m/z: 243 (M+), 208
(base).
(e) 2-Met h yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Mon oh yd r a te (1).34 To a 5-mL
Wheaton vial were added 4-chloro-2-methyl-6-phenylpyrrolo-
[3,2-d]pyrimidine (1.0 g, 4.1 mmol) and piperidine (2.0 mL,
20.52 mmol). A solution of K2CO3 (2.84 g, 20.52 mmol) in H2O
(30 mL) was added, the vial was securely capped, and the
reaction mixture was heated at 120 °C for 4 h. After cooling
to room temperature, EtOAc was added. The precipitate that
formed was collected by filtration, washed with water and
hexanes to give a brown solid as crude product. This material
was purified by flash chromatography on silica gel with 2:1
EtOAc:hexanes as eluant to give 0.84 g (70%) of the free base
as an off-white solid. 1H NMR (CDCl3, 500 MHz): δ 1.74-
1.76 (m, 6), 2.60 (s, 3), 3.79-3.81 (m, 4), 6.76 (s, 1), 7.38-7.49
(m, 3), 7.66 (d, 2, J ) 7.54). MS m/z: 293 (M + H), 291 (M -
H). A portion of this free base (0.45 g, 1.54 mmol) was dissolved
in minimum amount of CHCl3, and HCl (1.54 mL of a 1 N
solution in ether, 1.54 mmol) was added dropwise. The mixture
was stirred at room temperature for 20 min and the solvent
was evaporated in vacuo to give a light-yellow foam. This
material was recrystallized from MeOH:H2O to give 0.26 g of
(d ) 4-Ch lor o-6-(3-ch lor op h en yl)-2-m eth ylp yr r olo[3,2-
d ]p yr im id in e (27; a lk yl ) Me, R2 ) 3-ClP h ). A mixture of
6-(3-chlorophenyl)-2-methylpyrrolo[3,2-d]pyrimidin-4-ol (1.55
g, 5.97 mmol) and phosphorus oxychloride (14 mL, 149 mmol)
was heated at 120 °C for 24 h. The excess POCl3 was removed
under reduced pressure to give a dark-red residue. The residue
was diluted with ice-water and adjusted to pH 5 with NH4-
OH with stirring and cooling. The resulting mixture was
extracted three times with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, filtered,
and concentrated in vacuo to give 1.42 g (85%) of the title
compound as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ
2.79 (s, 3), 6.92 (s, 1), 7.43-7.46 (m, 2), 7.66 (d, 1, J ) 6.5),
7.74 (s, 1), 9.10 (br s, 1). MS m/z: 278 (M + H), 276 (M - 1).
(e) 6-(3-Ch lor op h en yl)-2-m et h yl-4-p ip er id ylp yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e Mon oh yd r a te (89b). To
a 25-mL, round-bottomed flask were added 4-chloro-6-(3-
chlorophenyl)-2-methylpyrrolo[3,2-d] pyrimidine (0.5 g, 1.8
mmol) and piperidine (0.89 mL, 9 mmol), followed by addition
of a solution of potassium carbonate (2.49 g, 18 mmol) in 10

4300 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
mL of H2O. The reaction mixture was stirred at 120 °C for 4
h. The mixture was allowed to cool to room temperature and
was extracted with CH2Cl2. The organic layer was separated,
dried over Na2SO4, filtered, and concentrated in vacuo to give
a brown solid. This material was purified by flash chroma-
tography on silica gel with 1:1 EtOAc:hexanes as eluant to
give 0.42 g (71%) of a beige solid. A portion of this material
(0.34 g, 1.1 mmol) was dissolved in minimum amount of CHCl3,
and HCl (1.1 mL of a 1 N solution in ether, 1.1 mmol) was
added dropwise. The mixture was stirred at room temperature
for 20 min. Solvent was then evaporated in vacuo to give a
light-yellow foam, which was recrystallized from MeOH to give
0.17 g of the title compound as white crystals. Mp: 244.5-
246 °C dec. 1H NMR (DMSO-d6, 500 MHz): δ 1.72 (m, 6), 2.57
(s, 3), 4.06-4.07 (m, 4), 7.00 (s, 1), 7.56-7.58 (m, 2), 7.93-
7.94 (m, 1), 8.10 (s, 1), 11.99 (br s, 1), 14.31 (br s, 1). MS m/z:
327, 329 (M + H), 325, 327 (M - H). Anal. (C18H20Cl2N4‚H2O)
C, H, N, Cl.
and was stirred at room temperature for 2.5 h. The solution
was filtered through a fritted-funnel and the residue was
washed with hot toluene (3×). The filtrate was concentrated
in vacuo and the residue was dissolved in 1:2 toluene:dioxane
(24 mL). Piperidine (2.0 mL, 20 mmol) and Et3N (2.0 mL) were
slowly added (exothermic reaction). The mixture was stirred
at 100 °C (sand bath temperature) for 1 h and cooled under a
N2 stream. To this solution was added SnCl2 (32 mL of a 1.5
M solution in DMF) and the mixture was stirred at room
temperature overnight. The reaction mixture was poured into
a mixture of NaOH (3.80 g, 95.0 mmol) and ice (∼100 mL)
and stirred vigorously for 30 min. The resulting slurry (pH ∼
9) was filtered through a pad of Celite, and the solid residue
was washed exhaustively with 10:1 EtOAc-MeOH. The clear
filtrate was separated and the organic phase was washed with
H2O (4×) and with saturated aqueous NaCl, dried over Na2-
SO4, filtered, and concentrated with a rotary evaporator. The
residue was purified by flash chromatography on silica gel with
a gradient eluant of i-PrOH(0.4-5%):CH2Cl2(99.6-95%) to
afford 0.73 g (30%) of the title compound as a brown solid. A
portion of this material was converted to its corresponding HCl
salt by treating a solution of the free base in CH2Cl2 with 1 N
ethereal HCl. The resulting solid was filtered and washed with
hot EtOAc. MS m/z: 279 (M + H), 277 (M - H). 1H NMR (CD3-
OD, 500 MHz): δ 2.12 (br s, 6), 4.53 (br s, 4), 7.52 (s, 1), 7.85
(m, 3), 8.01 (m, 2), 8.56 (s, 1). HRMS: calcd for C17H19N4 (M +
H) 279.1606, found 279.1606.
Rou te C. (a ) 2-Meth yl-4,6-d ih yd r oxy-5-n itr op yr im id in e
(44; R1 ) Me). To a three-necked, round-bottomed flask
equipped with an addition funnel, condenser, internal tem-
perature probe and mechanical stirrer were added trifluoro-
acetic acid (120 mL, 710 mmol) and powdered 2-methyl-4,6-
dihydroxypyrimidine (43) (20 g, 160 mmol). The suspension
was stirred under a N2 atmosphere for 15 min to allow
complete dissolution of the solids. Nitric acid (9.7 mL, 210
mmol, 90% aqueous solution) was added over 25 min while
maintaining the internal temperature between 13 and 21 °C
by cooling the reaction flask in an ice bath. Stirring was
continued for 12 h at room temperature. Water (100 mL) was
added, and the resulting precipitate was collected by filtration
and washed with H2O. Recrystallization from H2O followed
by drying in the vacuum oven provided 20 g (68%) of the title
compound as a white crystalline solid. 1H NMR (DMSO-d6,
400 MHz): δ 3.9 (s, 3). 13C NMR (DMSO-d6, 100.6 MHz): δ
17.94, 118.0, 155.7, 161.7. MS m/z: 170 (M - H).
Rou te D. (a) 4-((6S,2R)-2,6-Dim eth ylpiper idyl)-6-ch lor o-
2-m eth yl-5-n itr op yr im id in e (50; R1 ) Me, R3 ) cis-2,6-
d im eth ylp ip er id in e). To a solution of 4,6-dichloro-2-methyl-
5-nitropyrimidine (45; R1 ) Me) (2.4 g, 11.8 mmol) and
triethylamine (2.4 g, 23.6 mmol) in THF (12 mL) was added a
solution of cis-2,6-dimethylpiperidine (1.6 g, 11.8 mmol) in
THF (12 mL) slowly. The final reaction mixture was stirred
at room temperature for 3 days. After the removal of solvent
in vacuo, the crude material was purified by flash chromatog-
raphy on silica gel with EtOAc(0-10%):hexanes(100-90%) as
eluant to afford the title compound (2.8 g, 84%) as a brown
(b) 2-Meth yl-4,6-d ich lor o-5-n itr op yr im id in e (45; R1
)
Me). To a round-bottomed flask equipped with a Dean-Stark
trap, reflux condenser, pressure-equalized addition funnel,
magnetic stirrer, heating mantle, and internal temperature
probe were added 2-methyl-4,6-dihydroxy-5-nitropyrimidine
(2.0 g, 11 mmol) and toluene (16 mL). The Dean-Stark trap
was filled with toluene (12 mL). For 3 h, the reaction mixture
was heated at reflux during which time water collected in the
Dean-Stark trap. The reaction vessel was removed from the
heat, and after 20 min, diisopropylethylamine (2.8 mL, 16
mmol) was poured into the reaction mixture through the reflux
condenser. The reaction mixture was heated at reflux again,
and POCl3 (7 mL, 74 mmol) was added through the addition
funnel at such a rate as to maintain the internal temperature
below 113 °C (8 min). Vigorous bubbling was observed during
the addition of POCl3. Following this addition, the reaction
mixture was heated for an additional 3 h at reflux. Heat was
then removed from the flask, and the reaction was stirred at
room temperature for 18 h. The reaction mixture was then
poured onto ice-water (100 mL), shaken in a separatory
funnel, and filtered through a pad of Celite. The organic layer
was collected from the filtrate, and the aqueous layer was
extracted twice with ether. All organic fractions were com-
bined, dried over Na2SO4, filtered, and concentrated in vacuo.
Heptane was added to the residue, the contents were filtered
through a pad of Celite, and concentrated in vacuo to give the
title compound (1.1 g, 49%) as brown rodlike crystals in
sufficient purity for the next step. 1H NMR (DMSO-d6, 400
MHz): δ 2.5 (s, 3). 13C NMR (DMSO-d6, 100.6 MHz): δ 27.04,
127.0, 153.6, 170.8.
1
solid. H NMR (CDCl3, 500 MHz): δ 1.29 (d, 6, J ) 7.0), 1.56
(m, 1), 1.60-1.63 (m, 2), 1.73 (m, 2), 1.84-1.90 (m, 1), 2.50 (s,
3), 4.42 (m, 2). MS m/z: 285 (M + H), 283 (M - H).
(b) 4-((6S,2R)-2,6-Dim eth ylp ip er id yl)-6-ch lor o-2-m eth -
ylp yr im id in -5-yla m in e (51; R 1 ) Me, R3 ) cis-2,6-d im eth -
ylp ip er id in e). To a solution of 4-((6S,2R)-2,6-dimethylpip-
eridyl)-6-chloro-2-methyl-5-nitropyrimidine (2.3 g, 7.9 mmol)
in anhydrous diethyl ether (15 mL) was added a freshly
prepared solution of SnCl2‚2H2O (32 mL, 2.0 M in concentrated
aqueous HCl) slowly under N2 at 0 °C. The reaction mixture
was stirred at room temperature for 3 h, and then was poured
onto an ice bath containing NaOH (12 g). The aqueous phase
was extracted with EtOAc (4 × 100 mL). The aqueous phase
was passed through a pad of Celite and was extracted again
with EtOAc (3 × 100 mL). The combined organic layers were
dried over Na2SO4, filtered and concentrated in vacuo. The
crude material was purified by flash chromatography on silica
gel using EtOAc(0-50%):hexanes(100-50%) as eluant to af-
1
ford the title compound (0.80 g, 40%) as a yellow oil. H NMR
(CDCl3, 400 MHz): δ 0.75 (d, 6, J ) 6.2), 1.31-1.34 (m, 2),
1.50-1.60 (m, 1), 1.72-1.76 (m, 3), 2.55 (s, 3), 3.03-3.07 (m,
2), 4.34 (br s, 2). MS m/z: 255 (M + H).
(c) 4-((6S,2R)-2,6-Dim et h ylp ip er id yl)-2-m et h yl-6-(2-
p h en yleth yn yl)p yr im id in -5-yla m in e (52; R1 ) Me, R2
)
P h , R3 ) cis-2,6-d im eth ylp ip er id in e). A mixture of 4-((6S,
2R)-2,6-dimethylpiperidyl)-6-chloro-2-methylpyrimidin-5-
ylamine (0.35 g, 1.4 mmol), phenylacetylene (0.28 g, 2.7 mmol),
Pd(PPh3)2Cl2 (0.050 g, 0.068 mmol) and CuI (0.013 g, 0.068
mmol) in triethylamine (3 mL) was stirred under N2 at 70 °C
overnight. Upon cooling to room temperature, the reaction
mixture was diluted with CHCl3 (50 mL), passed through a
pad of Celite and concentrated in vacuo. The crude material
was purified by flash chromatography on silica gel with EtOAc-
(0-8%):hexanes (100-92%) as eluant to afford 0.41 g, (95%)
(c) 6-P h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im id in e Hy-
d r och lor id e (88a ). To a mixture of 1-(N-pyrrolyl)-1-phenyl-
ethylene (1.54 g, 8.90 mmol) [freshly prepared through TiCl4-
mediated condensation between acetophenone and pyrrolidine
(1.70 g, 8.76 mmol) in ether by the method described by Boger
et al.48] and N,N-diisopropylethylamine (1.60 mL, 9.10 mmol)
in toluene (15 mL) at room temperature was added 4,6-
dichloro-5-nitropyrimidine (1.70 g, 8.76 mmol) slowly under a
stream of N2. The reaction mixture became hot upon mixing
1
of the title compound as a cherry-colored semisolid. H NMR
(CDCl3, 400 MHz): δ 0.78 (d, 6, J ) 6.2), 1.25-1.40 (m, 2),

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4301
1.50-1.60 (m, 1), 1.74-1.77 (m, 3), 2.59 (s, 3), 4.57 (br s, 2),
7.38 (m, 3), 7.60 (m, 2). MS m/z: 321 (M + H).
2-Meth yl-6-p h en yl-4-p yr r olid in ylp yr r olo[3,2-d ]p yr im i-
d in e (91b). Yield: 0.042 g (53%) of an off-white solid. An
analytical sample was obtained by recrystallization from
(d ) 4-((6S,2R)-2,6-Dim eth ylp ip er id yl)-2-m eth yl-6-p h e-
n ylp yr r olo[3,2-d ]p yr im id in e Hyd r och lor id e (92b). A solu-
tion of 4-((6S,2R)-2,6-dimethylpiperidyl)-2-methyl-6-(2-phe-
nylethynyl)pyrimidin-5-ylamine (0.39 g, 1.2 mmol) and CuI
(0.021 g, 0.12 mmol) in anhydrous DMF (3 mL) was stirred
under N2 at 110 °C overnight. Upon cooling to the room
temperature, the reaction mixture was diluted with CH2Cl2
(50 mL), passed through a pad of Celite and concentrated
under reduced pressure. The crude material was purified by
flash chromatography on silica gel with EtOAc(0-80%):
hexanes(100-20%) as eluant to afford the free base of the
1
EtOH. H NMR (CDCl3, 500 MHz): δ 2.07 (t, 4, J ) 6.3), 2.58
(s, 3), 3.88-3.90 (m, 4), 6.71 (s, 1), 7.36-7.46 (m, 3), 7.63 (d,
2, J ) 7.7). MS m/z: 279.5 (M + H), 277.5 (M - H). HRMS:
calcd for C17H19N4 (M + H) 279.1610, found 279.1613.
4-Hom op ip er id yl-2-m eth yl-6-p h en ylp yr r olo[3,2-d ]p y-
r im id in e (91c). Yield: 0.054 g (62%) of a white solid. An
analytical sample was obtained by recrystallization from
EtOAc. Mp: 209-210 °C. 1H NMR (CDCl3, 500 MHz): δ 1.65-
1.68 (m, 4), 1.93-1.97 (m, 4), 2.57 (s, 3), 3.91 (t, 4, J ) 5.9),
6.75 (s, 1), 7.37-7.49 (m, 3), 7.63 (d, 2, J ) 7.43), 8.19 (br s,
1). MS m/z: 307 (M + H), 305 (M - H). HRMS: calcd for
1
product as a brown solid (0.20 g, 50%). Mp: 223-225 °C. H
C
19H23N4 (M + H) 307.1923, found 307.1933.
NMR (CDCl3, 400 MHz): δ 1.28 (d, 6, J ) 6.8), 1.61-1.70 (m,
3), 1.81-1.96 (m, 3), 2.61 (s, 3), 4.63 (br s, 2), 6.78 (s, 1), 7.39
(t, 1, J ) 7.3), 7.48 (t, 2, J ) 7.3), 7.66 (d, 2, J ) 7.3), 8.39 (s,
1). MS m/z: 321 (M + H). The above material (0.19 g, 0.61
mmol) was dissolved in diethyl ether (20 mL) and HCl (0.64
mL of a 1 N solution in ether, 0.64 mmol) was added dropwise.
After stirring at room temperature for 10 min, the solution
was concentrated in vacuo. Recrystallization from MeOH
afforded 0.13 g (65%) of the title compound as an off-white
solid. Mp: >270 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.34
(d, 6, J ) 6.7), 1.59 (m, 1), 1.78 (m, 4), 1.94 (m, 1), 2.61 (s, 3),
5.14 (br s, 2), 6.88 (s, 1), 7.51-7.59 (m, 3), 7.95 (d, 2, J ) 6.8),
11.60 (s, 1), 14.28 (s, 1). MS m/z: 321 (M + H). Anal. (C20H24N4‚
HCl) C, H, N.
2-Met h yl-6-p h en yl-4-p yr r olin ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e Mon oh yd r a te (91d ). Yield: 0.24 g
(85%) of an off-white solid. Mp: 278-278.3 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 2.60 (s, 3), 4.59 (br s, 2), 5.05 (br s,
2), 6.12 (s, 2), 6.91 (s, 1), 7.49-7.58 (m, 3), 7.97 (d, 2, J ) 7.2),
11.62 (s, 1). MS m/z: 277 (M + H), 275 (M - H). Anal.
(C17H16N4‚1.1HCl‚H2O) C, H, N, Cl.
2-Meth yl-6-p h en yl-4-(1,2,3,6-tetr a h yd r op yr id in yl)p yr -
r olo[3,2-d ]p yr im id in e Hyd r och lor id e (91e). Yield: 0.29 g
1
(74%) of product. Mp: 278-279 °C. H NMR (DMSO-d6, 400
MHz): δ 2.57 (s, 2), 2.8 (s, 3), 4.38 (t, 2, J ) 5.53), 4.86 (s, 2),
6.1 (d, 1, J ) 10.2), 6.20 (d, 1, J ) 10), 7.14 (s, 1), 7.72-7.81
(m, 3), 8.2 (d, 2, J ) 7.2), 12.18 (s, 1), 14.81 (br s, 1). MS m/z:
291 (M + H), 289 (M - H). Anal. (C18H18N4‚HCl) C, H, N.
4-(2-Meth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)m or -
p h olin e Hyd r a te (91f). Yield: 0.04 g (33%) of a white solid.
Mp: 276 °C dec. 1H NMR (CDCl3, 500 MHz): δ 2.62 (s, 3),
3.87 (s, 4), 3.90 (s, 4), 6.79 (s, 1), 7.41 (t, 1, J ) 6.8), 7.48 (t, 2,
J ) 7.4), 7.67 (d, 2, J ) 6.8), 8.17 (br s, 1). MS m/z: 295 (M +
H). Anal. (C17H18N4O‚0.25H2O) C, H, N.
P yr r olo[3,2-d ]p yr im id in es 88e,g, 89j, 90e,g, 91a -g,
92a ,c-i, a n d 93a -l. These compounds were prepared by the
methods analogous to those described in route A from ap-
propriate starting materials. The analytical data for these
pyrrolo[3,2-d]pyrimidine analogues are shown below. The
reported yields represent the yields obtained for the final step
of the sequence.
2-Meth yl-6-p h en yl-4-p ip er a zin ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r a te (91g). Yield: 0.035 g (29%) of an off-white solid.
Mp: 236 °C dec. H NMR (DMSO-d6, 500 MHz): δ 2.42 (s, 3),
2.85 (t, 4, J ) 5.2), 3.62 (t, 4, J ) 5.2), 6.77 (s, 1), 7.36 (m, 1),
7.45 (t, 2, J ) 7.8), 7.95 (d, 2, J ) 7.6), 10.96 (s, 1). MS m/z:
294 (M + H). Anal. (C17H19N5‚0.5H2O) C, H, N.
2-Isop r op yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r a te (88e). Yield: 0.048 g (88%) of a cream-colored
solid. Mp: 269.5-272 °C. 1H NMR (DMSO-d6, 500 MHz): δ
1.25 (d, 6, J ) 6.8), 1.66 (br s, 6), 2.95 (septet, 1, J ) 6.8), 3.73
(br s, 4), 6.78 (s, 1), 7.39 (m, 1), 7.48 (m, 2), 7.89 (d, 2, J )
7.7), 11.06 (s, 1). MS m/z: 321 (M + H), 307, 240, 171. Anal.
(C20H24N4‚0.5H2O) C, H, N.
1
2-Meth yl-6-p h en yl-4-(2-m eth ylp ip er id in yl)p yr r olo[3,2-
d ]p yr im id in e Hyd r och lor id e Mon oh yd r a te (92a ). Yield:
2,6-Diph en yl-4-piper idylpyr r olo[3,2-d]pyr im idin e (88g).
1
0.20 g (71%) of product. Mp: 268-269 °C. H NMR (DMSO-
1
Yield: 0.061 g (42%) of a white solid. Mp: 259-261.5 °C. H
d6, 400 MHz): δ 1.17 (d, 3, J ) 6.8), 1.31-1.82 (m, 8), 2.41 (s,
3), 3.3 (br s, 1), 4.46 (br s, 1), 5.11 (br s, 1), 6.72 (s, 1), 7.34-
7.42 (m, 3), 7.77 (d, 2, J ) 7.27), 11.71 (br s, 1). MS m/z: 307
(M + H). Anal. (C19H22N4‚HCl‚H2O) C, H, N, Cl.
NMR (DMSO-d6, 400 MHz): δ 1.71 (br s, 6), 3.85 (br s, 4),
6.94 (d, 1, J ) 1.6), 7.37-7.53 (m, 6), 7.94 (d, 2, J ) 8.3), 8.40
(2, dd, J ) 1.4, 8.3), 11.16 (s, 1). MS m/z: 355 (M + H). Anal.
(C23H22N4‚0.5H2O) C, H, N.
2-Meth yl-6-p h en yl-4-(2-eth ylp ip er id in yl)p yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Hyd r a te (92c). Yield: 0.28 g
2-Meth yl-6-(4-m eth ylp h en yl)-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e (89j). Yield: 0.050 g (60%) of a tan solid. 1H NMR
(CDCl3, 500 MHz): δ 1.74-1.76 (m, 6), 2.40 (s, 3), 2.58 (s, 3),
3.79-3.81 (m, 4), 6.67 (s, 1), 7.25 (d, 2, J ) 7.8), 7.54 (d, 2, J
) 7.7). MS m/z: 307 (M + H), 305 (M - H). HRMS: calcd for
1
(74%) of product. Mp: 228-229 °C. H NMR (DMSO-d6, 400
MHz): δ 0.83 (t, 3, J ) 7.23), 1.63-1.95 (m, 8), 2.57 (s, 3),
3.37 (br s, 3), 4.56-5.13 (br d, 2), 6.89 (s, 1), 7.5-7.58 (m, 3),
7.94 (d, 2, J ) 7.3), 11.96 (br s, 1). MS m/z: 321 (M + H).
Anal. (C20H24N4‚HCl‚0.5H2O) C, H, N, Cl.
C
19H23N4 (M + H) 307.1923, found 307.1910.
6-Cycloh exyl-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
cis/tr a n s-4-(3,5-Dim eth ylp ip er id in yl)-2-m eth yl-6-p h en -
ylp yr r olo[3,2-d ]p yr im id in e (92d ). Yield: 0.054 g (50%) of
a 95:5 mixture of isomers as colorless crystals. Mp: 225.5-
m id in e Hyd r och lor id e Hyd r a te (90e). Yield: 0.12 g (79%)
of a beige sandy solid. Mp: >280 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.43-1.60 (m, 5), 1.79 (br s, 6), 1.92 (m, 3), 2.10 (br
d, 2, J ) 10.9), 2.65 (s, 3), 3.01 (m, 1), 4.16 (br s, 4), 6.38 (s, 1),
11.90 (s, 1), 14.28 (s, 1). MS m/z: 299 (M + H). Anal. (C18H26N4‚
HCl‚0.1H2O) C, H, N, Cl.
6-Ad a m a n ta n yl-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]p y-
r im id in e Hyd r och lor id e Mon oh yd r a te (90g). Yield: 0.034
g (74%) of a beige solid. Mp: >280 °C. 1H NMR (DMSO-d6,
400 MHz): δ 1.49 (br s, 6), 1.60 (s, 6), 1.85 (s, 6), 1.90 (s, 3),
2.32 (s, 3), 3.80 (s, 4), 6.06 (s, 1), 10.83 (s, 1), 13.87 (s, 1). MS
m/z: 351 (M + H). Anal. (C22H30N4‚HCl‚H2O) C, H, N, Cl.
1
227 °C. H NMR (DMSO-d6, 400 MHz) (for major isomer): δ
0.90 (m, 2), 0.91 (d, 6, J ) 6.5), 1.73 (m, 2), 2.40 (s, 3), 2.42 (br
s, 2), 4.42 (br d, 2, J ) 8.2), 6.74 (s, 1), 7.40 (m, 1), 7.49 (br s,
2), 7.89 (d, 2, J ) 7.4), 11.06 (s, 1). MS m/z: 321 (M + H).
Anal. (C20H24N4) C, H, N.
1-(2-Meth yl-6-p h en yl-5H-p yr r olo[3,2-d ]p yr im id in -4-yl)-
2-p ip er id in eeth a n ol Hyd r och lor id e (92e). Yield: 0.039 g
(11%) of product. Mp: 273-273.5 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.34-2.12 (m, 6H), 2.38 (s, 3), 2.47-3.55 (m, 5), 4.67
(br d, 2), 6.76 (s, 1), 7.29-7.36, (m, 3), 7.72 (d, 2, J ) 6.72),
12.35 (br s, 1), 14.02 (br s, 1). MS m/z: 337 (M + H), 335 (M
- H). Anal. (C20H24N4O‚HCl) C, H, N, Cl.
4-Azet id in yl-2-m et h yl-6-p h en ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e Mon oh yd r a te (91a ). Yield: 0.19 g
1
(56%) of white crystals. Mp: >300 °C dec. H NMR (DMSO-
Dim eth yl{[1-(2-m eth yl-6-p h en ylp yr r olo[2,3-e]p yr im i-
d in -4-yl)-2-p ip er id yl]m eth yl}a m in e Hyd r och lor id e (92f).
d6, 500 MHz): δ 2.48-2.52 (m, 2), 2.55 (s, 3), 4.46-4.63 (m,
4), 6.88 (s, 1), 7.49-7.57 (m, 3), 7.95 (d, 2, J ) 7.69), 11.78 (br
s, 1), 14.32 (br s, 1). MS m/z: 265 (M + H), 263 (M - H). Anal.
(C16H16N4‚HCl‚H2O) C, H, N, Cl.
1
Yield: 0.043 g (34%) of a yellow oil. H NMR (DMSO-d6, 400
MHz): δ 1.63 (m, 6), 2.29 (s, 6), 2.40 (s, 3), 2.81 (m, 2), 3.03
(br t, 1, J ) 11.8), 4.53-4.63 (m, 2), 6.75 (s, 1), 7.37 (m, 1),

4302 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
7.50 (t, 2, J ) 7.5), 7.81 (d, 2, J ) 7.8), 12.47 (s, 1). MS m/z:
350 (M + H), 305, 214. HRMS: calcd for C21H28N5 (M + H)
350.2345, found 350.2342.
7.71 (dd, 2, J ) 7.1, 1.4). MS m/z: 319 (M + H), 294, 225, 195,
147. HRMS: calcd for C19H19N4O (M + H) 319.1555, found
319.1566.
1-(2-Meth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)p ip -
er id in -4-ol Hyd r och lor id e Hyd r a te (92g). Yield: 0.30 g
(48%) of a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.51-
1.59 (m, 2), 2.58 (s, 3), 3.78-3.90 (m, 3), 4.34-4.37 (m, 2), 6.89
(s, 1), 7.49-7.57 (m, 3), 7.96 (d, 2, J ) 7.2), 11.8 (br s, 1). MS
m/z: 308 (M + H). Anal. (C18H20N4O‚HCl‚0.25H2O) C, H, N,
Cl.
(2-Meth yl-6-ph en ylpyr r olo[2,3-e]pyr im idin -4-yl)(2-m or -
p h olin -4-yleth yl)a m in e Hyd r a te (93h ). Yield: 0.060 g (43%)
of a white solid. Mp: >280 °C. H NMR (CD3OD, 400 MHz):
1
δ 2.60 (s, 3), 2.67 (m, 4), 2.79 (t, 2, J ) 6.4), 3.81 (m, 4), 3.88
(t, 2, J ) 6.3), 6.78 (s, 1), 7.47 (m, 1), 7.57 (t, 2, J ) 7.4), 7.86
(d, 2, J ) 8.1). 13C NMR (CD3OD, 100.6 MHz): δ 26.3, 39.2,
55.9, 60.1, 68.8, 99.9, 127.3, 128.3, 130.6, 131.2, 134.0, 143.1,
149.8, 151.1, 161.5. MS m/z: 338 (M + H). Anal. (C19H23N5O‚
0.25H2O) C, H, N.
Diet h yl(2-m et h yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-
yl)a m in e (93i). Yield: 0.19 g (68%) of an off-white powder.
Mp: 184-185 °C (lit34 mp ) 183-185 °C). 1H NMR (CDCl3,
500 MHz): δ 1.37 (t, 6, J ) 7.0), 2.57 (s, 3), 3.77 (q, 4, J )
7.0), 6.75 (s, 1), 7.38 (t, 1, J ) 7.3), 7.47 (t, 2, J ) 7.5), 7.63 (d,
2, J ) 7.6), 8.13 (br s, 1). MS m/z: 281 (M + H). Anal.
(C17H20N4) C, H, N.
[(2-F u r ylm et h yl)m et h yl](2-m et h yl-6-p h en ylp yr r olo-
[2,3-e]p yr im id in -4-yl)a m in e (93j). Yield: 0.054 g (59%) of
an off-white solid. An analytical sample was obtained by
recrystallization from EtOAc. Mp: 168-169 °C. 1H NMR
(CDCl3, 500 MHz): δ 2.62 (s, 3), 3.35 (s, 3), 4.83 (s, 2), 6.42-
6.44 (m, 2), 6.79 (s, 1), 7.36-7.48 (m, 4), 7.64 (d, 2, J ) 7.2),
8.91 (br s, 1). MS m/z: 319.5 (M + H), 317.0 (M - H). HRMS:
calcd for C19H19N4O (M + H) 319.1559, found 319.1566.
P yr r olo[3,2-d ]p yr im id in es 93k ,l. These compounds were
prepared by the method analogous to that described for
compound 19 from the appropriate boronic acids. The analyti-
cal data for these pyrrolo[3,2-d]pyrimidine analogues are
shown below. The reported yields represent the yields obtained
for the final step of the sequence.
Dim eth yl[1-(2-m eth yl-6-ph en ylpyr r olo[2,3-e]pyr im idin -
4-yl)-4-p ip er id yl]a m in e Mon oh yd r a te (92h ). Yield: 0.059
g (44%) of product. Mp: 261.5-263 °C. MS m/z: 336 (M + H),
1
291, 237. H NMR (DMSO-d6, 400 MHz): δ 1.50 (br q, 2H, J
) 10.4), 1.86 (d, 2, J ) 11.8), 2.20 (s, 6), 2.36 (m,1), 2.42 (s, 3),
3.00 (br t, 2, J ) 11.2), 4.46 (br d, 2H, J ) 10.4), 6.76 (s, 1),
7.40 (br d, 1, J ) 6.4), 7.47 (t, 2, J ) 6.4), 7.90 (d, 2H, J ) 7.6),
11.02 (s, 1). Anal. (C20H25N5‚H2O) C, H, N.
2-Meth yl-6-p h en yl-4-(1,2,3,4-tetr a h yd r oqu in olin -2-yl)-
p yr r olo[3,2-d ]p yr im id in e (92i). Yield: 0.11 g (75%) of an
off-white solid. Mp: 251-253 °C dec. 1H NMR (CDCl3, 400
MHz): δ 2.63 (s, 3), 3.09 (t, 2, J ) 5.9), 4.13 (t, 2, J ) 5.9),
5.02 (s, 2), 6.78 (s, 1), 7.21-7.25 (m, 4), 7.38-7.50 (m, 3), 7.66
(d, 2, J ) 7.3), 8.37 (br s, 1). MS m/z: 341 (M + H), 339 (M -
H). Anal. (C22H20N4) C, H, N.
2-Meth yl-6-p h en ylp yr r olo[3,2-d ]p yr im id in -4-yla m in e
(93a ). Yield: 0.005 g (5%) of an off-white solid. Mp: >280 °C.
1H NMR (CD3OD, 500 MHz): δ 2.53 (s, 3), 6.74 (s, 1), 7.44 (t,
1, J ) 7.2), 7.52 (t, 2, J ) 7.5), 7.82 (d, 2, J ) 7.5). MS m/z:
225 (M + H). HRMS: calcd for C13H13N4 (M + H) 225.1140,
found 225.1119.
(2-Meth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)p h en -
yla m in e Hyd r och lor id e (93b). Yield: 0.057 g (41%) of an
1
off-white solid. H NMR (DMSO-d6, 400 MHz): δ 2.67 (s, 3),
3-(2-Me t h yl-6-p h e n ylp yr r olo[2,3-e]p yr im id in -4-yl)-
th iop h en e (93k ). Yield: 0.043 g (73%) of an off-white solid.
Mp: 232-233 °C. 1H NMR (CDCl3, 400 MHz): δ 2.86 (s, 3),
6.94 (d, 1, J ) 2.0), 7.46 (t, 1, J ) 7.7), 7.52 (t, 2, J ) 7.7), 7.59
(dd, 1, J ) 2.9, 5.0), 7.66 (m, 3), 8.04 (dd, 1, J ) 1.2, 2.9), 8.57
(s, 1). MS m/z: 292 (M + H), 290 (M - H). HRMS: calcd for
7.04 (s, 1), 7.21-7.23 (m, 1), 7.44-7.59 (m, 5), 8.03 (d, 2, J )
8.0), 8.15 (d, 2, J ) 8.0), 11.61 (br s, 1), 13.84 (br s, 1). MS
m/z: 301 (M + H). HRMS: calcd for C19H16N4 (M + H)
301.1448, found 301.1435.
(2-Meth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)ben zyl-
a m in e (93c). Yield: 0.24 g (93%) of an off-white solid. Mp:
275-276.5 °C. 1H NMR (DMSO-d6, 500 MHz): δ 2.41 (s, 3),
4.73 (s, 2), 6.75 (s, 1), 7.30-7.49 (m, 9), 7.80 (d, 2, J ) 7.3),
11.50 (br s, 1). MS m/z: 315 (M + H). HRMS: calcd for
C20H19N4 (M + H) 315.1610, found 315.1602.
C
17H14N3S (M + H) 292.0908, found 292.0936.
2-Met h yl-6-p h en yl-4-(3-p yr id in yl)p yr r olo[3,2-d ]p yr i-
m id in e (93l). Yield: 0.17 g (64%) of a yellow solid. Mp: 252-
1
254 °C. H NMR (CDCl3, 400 MHz): δ 2.89 (s, 3), 6.99 (s, 1),
7.46 (m, 4), 7.78 (d, 2, J ) 7.1), 8.37 (d, 1, J ) 7.7), 8.66 (d, 1,
J ) 3.9), 9.31 (s, 1), 9.50 (s, 1). MS m/z: 287 (M + H), 285 (M
- H). HRMS: calcd for C18H15N4 (M + H) 287.1297, found
287.1288.
(2-Meth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)(2,2,2-
tr iflu or oeth yl)a m in e (93d ). Yield: 0.021 g (29%) of a white
1
solid. Mp: >310 °C. MS m/z: 307 (M + H), 294, 281, 226. H
NMR (DMSO-d6, 400 MHz): δ 2.31 (s, 3), 2.52 (s, 2), 6.74 (s,
1), 7.33 (t, 1, J ) 7.3), 7.43 (t, 2, J ) 7.8), 7.92 (d, 2, J ) 7.3),
11.74 (s, 1), 12.22 (s, 1). HRMS: calcd for C15H14F3N4 (M + H)
307.1168, found 307.1160.
(3-Eth oxyp r op yl)(2-m eth yl-6-p h en ylp yr r olo[2,3-e]p y-
r im id in -4-yl)a m in e (93e). Yield: 0.056 g (44%) of a light-
yellow oil that solidified upon standing. Mp: 208-209.5 °C.
1H NMR (CDCl3, 500 MHz): δ 1.16 (t, 3, J ) 7.0), 1.99 (quin,
2, J ) 5.8, 6.4), 2.58 (s, 3), 3.52 (q, 2, J ) 7.1), 3.63 (t, 2, J )
5.6), 3.74 (t, 2, J ) 6.6), 5.95 (br s, 1), 6.67 (s, 1), 7.33 (t, 1, J
) 7.4), 7.40 (t, 2, J ) 7.6), 7.66 (d, 2, J ) 7.6). MS m/z: 311 (M
+ H). HRMS: calcd for C18H23N4O (M + H) 311.1872, found
311.1892.
P yr r olo[3,2-d ]p yr im id in es 88b-d ,f,h , a n d 89c,i,k . These
compounds were prepared by the methods analogous to those
described in route B from appropriate starting materials. The
analytical data for these pyrrolo[3,2-d]pyrimidine analogues
are shown below. The reported yields represent the yields
obtained for the final step of the sequence.
2-E t h yl-6-p h e n yl-4-p ip e r id ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e Mon oh yd r a te (88b). Yield: 0.11 g
(28%) of light-tan crystals. Mp: 286-288 °C dec. 1H NMR
(DMSO-d6, 500 MHz): δ 1.32 (t, 3, J ) 7.53), 1.72 (m, 6), 2.87
(q, 2, J ) 7.51), 4.08-4.09 (m, 4), 6.90 (s, 1), 7.51-7.57 (m, 3),
7.96 (d, 2, J ) 7.36), 12.01 (br s, 1), 14.36 (br s, 1). MS m/z:
307 (M + H), 305 (M - H). Anal. (C19H22N4‚HCl‚H2O) C, H,
N, Cl.
6-P h en yl-4-p ip er id yl-2-p r op ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e Mon oh yd r a te (88c). Yield: 0.32 g
(49%) of off-white crystals. Mp: 258.0-262.5 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 0.92 (t, 3, J ) 7.4), 1.67 (m, 6), 1.72-
1.81 (m, 2), 2.77 (t, 2, J ) 7.4), 4.02-4.03 (m, 4), 6.86 (s, 1),
7.45-7.53 (m, 3), 7.91 (d, 2, J ) 7.0), 12.00 (br s, 1). MS m/z:
321 (M + H). Anal. (C20H24N4‚HCl‚H2O) C, H, N, Cl.
(2-Eth ylh exyl)(2-m eth yl-6-p h en ylp yr r olo[2,3-e]p yr im i-
d in -4-yl)a m in e (93f). Yield: 0.061 g (63%) of a white solid.
An analytical sample was obtained by recrystallization from
1
i-PrOH. Mp: 288-289 °C dec. H NMR (CDCl3, 500 MHz): δ
0.72-0.78 (m, 6), 1.15-1.34 (m, 9), 2.62 (s, 3), 3.56 (dd, 2, J )
5.3, 7.6), 6.71 (s, 2), 7.17-7.24 (m, 3), 7.59 (d, 2, J ) 7.6), 12.78
(br s, 1). MS m/z: 337 (M + H), 335 (M - H). HRMS: calcd
for C21H29N4 (M + H) 337.2392, found 337.2397.
[(5-Meth yl-2-fu r yl)m eth yl](2-m eth yl-6-p h en ylp yr r olo-
[2,3-e]p yr im id in -4-yl)a m in e (93g). Yield: 0.037 g (62%) of
a beige solid. Mp: 125-127.5 °C. 1H NMR (CD3OD, 400
MHz): δ 2.28 (s, 3), 2.53 (s, 3), 4.72 (s, 2), 5.97 (d, 1, J ) 3.0),
6.24 (d, 1, J ) 3.0), 6.66 (s, 1), 7.34 (m, 1), 7.43 (t, 2, J ) 7.7),
2-Cyclop r op yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Mon oh yd r a te (88d ). Yield: 0.020
g (14%) of white needles. Mp: 285.4-286.0 °C dec. H NMR
(DMSO-d6, 500 MHz): δ 1.14-1.21 (m, 4), 1.67-1.71 (m, 6),
2.20-2.24 (m, 1), 3.98-3.99 (m, 4), 6.88 (s, 1), 7.49-7.65 (m,
1

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4303
3), 7.95 (d, 2, J ) 7.78), 11.95 (br s, 1), 14.51 (br s, 1). MS m/z:
319 (M + H), 317 (M - H). Anal. (C20H22N4‚HCl‚H2O) C, H,
N, Cl.
2-(2-Meth ylp r op yl)-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (88f). Yield:
0.31 g (40%) of orange crystals. Mp: 226.0-229.5 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.19 (d, 6, J ) 7.0), 1.93 (m, 6), 2.40-
2.50 (m, 1), 2.92 (d, 2, J ) 7.0), 4.28-4.30 (m, 4), 7.13 (s, 1),
7.72-7.81 (m, 3), 8.18 (d, 2, J ) 8.3), 12.25 (br s, 1). MS m/z:
335 (M + H). Anal. (C21H26N4‚HCl‚H2O) C, H, N.
6-P h en yl-4-p ip er id yl-2-(tr iflu or om eth yl)p yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (88h ). Yield:
0.10 g (21%) of light-pink crystals. Mp: 235.1-237.5 °C dec.
1H NMR (DMSO-d6, 500 MHz): δ 1.68 (m, 6), 3.84-3.85 (m,
4), 7.02 (s, 1), 7.44-7.55 (m, 3), 7.93 (d, 2, J ) 7.68), 11.53 (br
s, 1). MS m/z: 347 (M + H), 345 (M - H). Anal. (C18H17F3N4‚
HCl‚H2O) C, H, N, Cl.
containing a THF solution of the appropriate alk-2-ynenitrile
(0.1 mol). An additional portion of NaOEt (1.0 equiv) was
freshly prepared from Na (2.6 g, 0.11 mol) and absolute ethanol
(100 mL) and added dropwise through an addition funnel into
the THF solution. After the addition was complete, the
resulting cloudy red solution was stirred at ambient temper-
ature overnight and concentrated in vacuo to give an oil. Water
and EtOAc were added, and the aqueous layer was extracted
with EtOAc (3×). The combined EtOAc layers were dried over
Na2SO4 and concentrated in vacuo to give a red oil. The
compounds were isolated by flash chromatography on silica
gel with 1:5 EtOAc:hexanes as eluant to give the requisite
pyrroles 25 (R2 ) n-Pr, n-pentyl, and c-Hex) as a red oils. These
pyrroles were employed to prepare pyrrolo[3,2-d]pyrimidines
90b,d ,f by the methods analogous to those described in route
B. The analytical data for the pyrrolo[3,2-d]pyrimidine ana-
logues are shown below.
2-Met h yl-4-p ip er id yl-6-p r op yl-5H -p yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e (90b). Yield: 81% of a white solid.
6-(4-Ch lor op h en yl)-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (89c). Yield:
0.14 g (36%) of tan crystals. Mp: 253.8-255.2 dec. 1H NMR
(DMSO-d6, 500 MHz): δ 1.70-1.71 (m, 6), 2.57 (s, 3), 4.06-
4.07 (m, 4), 6.94 (s, 1), 7.63 (d, 2, J ) 8.60), 8.01 (d, 2, J )
8.6), 12.0 (br s, 1), 14.3 (br s, 1). MS m/z: 327, 329 (M + H),
325, 327 (M - H). Anal. (C18H19ClN4‚HCl‚H2O) C, H, N, Cl.
6-(4-Flu or op h en yl)-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (89i). Yield:
1
Mp: 179 °C. H NMR (CDCl3, 400 MHz) δ 1.00 (3, t, J ) 7.4),
1.77 (8, m), 2.57 (3, s), 2.73 (2, t, J ) 7.4), 3.71 (4, m), 6.23 (1,
s), 7.93 (1, br s). 13C NMR (CDCl3, 100.6 MHz): δ 13.81, 22.40,
24.80, 25.88, 25.94, 30.65, 47.56, 100.55, 113.20, 143.25,
150.40, 152.14, 159.27. MS (ESI) m/z: 259 (M + H), 257 (M -
H). Anal. (C15H22N4‚HCl) C, H, N.
2-Met h yl-6-p en t yl-4-p ip er id yl-5H -p yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Hyd r a te (90d ). Yield: 88% of a
1
0.067 g (19%) of off-white crystals. Mp: 287-289 °C dec. H
1
white solid. Mp: 170 °C. H NMR (CDCl3, 400 MHz): δ 0.87
NMR (DMSO-d6, 500 MHz): δ 1.87-1.88 (m, 6), 2.74 (s, 3),
4.22-4.23 (m, 4), 7.05 (s, 1), 7.55-7.59 (m, 2), 8.19-8.22 (m,
2), 12.18 (br s, 1), 14.63 (br s, 1). MS m/z: 311 (M + H), 309
(M - H). Anal. (C18H19FN4‚HCl‚H2O) C, H, N, Cl.
(3, t, J ) 6.8), 1.31 (4, m), 1.68 (8, m), 2.57 (3, s), 2.70 (2, t, J
) 7.6), 3.72 (4, m), 6.19 (1, s), 8.66 (1, br s). 13C NMR (CDCl3,
100.6 MHz): δ 16.44, 24.86, 27.26, 28.23, 28.41, 30.98, 31.28,
33.92, 50.02, 102.54, 115.64, 146.39, 152.94, 154.34, 161.42.
MS (ESI) m/z: 287 (M + H), 285 (M - H). Anal. (C17H26N4‚
HCl‚0.25H2O) C, H; N: calcd, 17.11; found, 16.62.
4-Meth oxy-1-(2-m eth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr i-
m id in -6-yl)ben zen e Hyd r och lor id e Mon oh yd r a te (89k ).
Yield: 0.077 g (35%) of light-tan crystals. Mp: 267.5-268 °C
1
6-Cycloh exylm eth yl-2-m eth yl-4-p ip er id yl-5H-p yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e (90f). Yield: 95% of a
dec. H NMR (DMSO-d6, 500 MHz): δ 1.63-1.72 (m, 6), 2.54
(s, 3), 3.84 (s, 3), 4.00 (m, 4), 6.78 (s, 1), 7.10 (d, 2, J ) 8.67),
7.90 (d, 2, J ) 8.67), 8.56 (br s, 1), 11.73 (br s, 1). Anal.
(C19H22N4O‚HCl‚H2O) C, H, N, Cl.
1
white solid. Mp: 250 °C. H NMR (CDCl3, 400 MHz): δ 0.97
(2, m), 1.19 (5, m), 1.73 (10, m), 2.57 (3, s), 2.62 (2, d, J ) 6.9),
3.71 (4, m), 6.21 (1, s), 7.74 (1, br s). 13C NMR (CDCl3, 100.6
MHz): δ 24.94, 25.95, 26.09, 26.28, 26.48, 33.36, 36.77, 38.56,
47.73, 101.29, 113.34, 142.51, 150.57, 152.08, 159.22. MS (ESI)
m/z: 313 (M + H), 311 (M - H). Anal. (C19H28N4‚HCl) C, H,
N.
P yr r olo[3,2-d ]p yr im id in es 90b,d ,f. These compounds
were prepared by the methods analogous to those described
in route B from appropriate starting materials. The requisite
substituted pyrroles 25 needed for these derivatives were
prepared via the acetylene intermediates 23 by the general
method as described below.
P yr r olo[3,2-d ]p yr im id in es 89a ,d-h ,l-q, 90a ,c,h -v, a n d
94a -d . These compounds were prepared by the methods
analogous to those described in route C from appropriate
starting materials. The analytical data for these pyrrolo[3,2-
d]pyrimidine analogues are shown below. The reported yields
represent the yields obtained for the final step of the sequence.
2-Met h yl-4-p ip er id yl-6-(2-ch lor op h en yl)p yr r olo[3,2-
d ] p yr im id in e Hyd r och lor id e Mon oh yd r a te (89a ). Yield:
0.34 g (17%) of the title compound as brown needles. Mp: 240-
241.5 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.71 (br s, 6), 2.59
(s, 3), 4.03 (s, 4), 6.74 (s, 1), 7.55 (d quintet, 2, J ) 1.3, 7.8),
7.70 (dt, 2, J ) 0.9, 8.2), 12.34 (s, 1), 14.64 (s, 1). MS m/z: 327
(M + H for free base). Anal. (C18H19ClN4‚HCl‚H2O) C, H, N,
Cl.
2-Meth yl-4-piper idyl-6-[2-(tr iflu or om eth yl)ph en yl]pyr -
r olo[3,2-d]pyr im idin e Hydr och lor ide Mon oh ydr ate (89d).
Yield: 0.20 g (11%) of beige cube-shaped crystals. Mp: >280
°C. 1H NMR (DMSO-d6, 400 MHz): δ 1.70 (br s, 6), 2.58 (s, 3),
4.01 (s, 4), 6.62 (s, 1), 7.74 (d, 1, J ) 7.5), 7.79 (t, 1, J ) 7.5),
7.86 (t, 1, J ) 7.4), 7.97 (d, 1, J ) 7.8), 12.45 (s, 1), 14.43 (s,
1). MS m/z: 361 (M + H for free base). Anal. (C19H19F3N4‚
HCl‚H2O) C, H, N, Cl.
2-Meth yl-4-piper idyl-6-[3-(tr iflu or om eth yl)ph en yl]pyr -
r olo[3,2-d]pyr im idin e Hydr och lor ide Mon oh ydr ate (89e).
Yield: 0.49 g (15%) of a white solid. Mp: 241-243 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.72 (br s, 6), 2.59 (s, 3), 4.08 (s, 4),
7.14 (s, 1), 7.79 (t, 1, J ) 7.6), 7.85 (d, 1, J ) 7.5), 8.30 (d, 1,
J ) 7.6), 8.34 (s, 1), 12.92 (s, 1), 14.53 (s, 1). MS m/z: 361 (M
+ H for free base). Anal. (C19H19F3N4‚HCl‚H2O) C, H, N, Cl.
2-Meth yl-4-piper idyl-6-[4-(tr iflu or om eth yl)ph en yl]pyr -
r olo[3,2-d ]p yr im id in e H yd r och lor id e H yd r a t e (89f).
Yield: 0.19 g (10%) of a beige solid. Mp: 278-280 °C. 1H NMR
Gen er a l Meth od of P yr r oles 25 fr om Acetylen es 23.
Into a dry three-necked 1-L round-bottomed flask equipped
with a mechanical stirrer, thermometer, and 150-mL addition
funnel under nitrogen pressure were placed anhydrous Et2O
(90 mL) and 0.2 mol of the appropriate terminal alkyne. The
solution was cooled to -70 °C, and n-butyllithium (100 mL,
0.2 mol of a pentane solution) was added at a rate to maintain
the reaction temperature below -40 °C. Phenyl cyanate (0.22
mol) was added slowly via a syringe pump at such a rate as to
prevent the reaction from rising above -60 °C. After stirring
for an additional 30 min, the solution was allowed to warm to
room temperature. To this dark solution were successively
added 6 N NaOH (240 mL) and Et2O (500 mL). The solution
was stirred for 15 min and transferred into a 1-L separatory
funnel. The phases were separated and the aqueous layer
extracted with Et2O (2 × 200 mL). The combined organic
phases were washed with 6 N NaOH (2 × 200 mL) and with
saturated aqueous NaCl (4 × 200 mL), and dried over Na2-
SO4. The solvents were removed in vacuo and the residue was
dissolved in pentane (500 mL). The pentane solution was
passed through a short path of Celite. The solvent was
removed and the dark oils were distilled under a vacuum to
give the desired nitriles 23 (R2 ) n-Pr, n-pentyl, and c-Hex)
as colorless oils.
Diethyl aminomalonate hydrochloride (24 g, 0.1 mol) was
dissolved in absolute ethanol (80 mL). To the above solution
was then added NaOEt which was prepared freshly from Na
(2.6 g, 0.11 mol) and absolute ethanol (100 mL). The resulting
white cloudy solution was stirred for 1 h and then passed
through a short bed of Celite to afford a clear solution which
was transferred directly into a 500-mL, round-bottomed flask

4304 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
(DMSO-d6, 400 MHz): δ 1.72 (br s, 6), 2.58 (s, 3), 4.08 (s, 4),
7.05 (s, 1), 7.93 (d, 2, J ) 8.3), 8.20 (d, 2, J ) 8.2), 12.16 (s, 1),
14.32 (s, 1). MS m/z: 361 (M + H for free base). Anal.
(C19H19F3N4‚HCl‚1.5H2O) C, H, N, Cl.
4-piperidyl-7-propylpyrrolo[3,2-d]pyrimidine as a pale-yellow
solid was also obtained.)
2-Met h yl-4-p ip er id yl-6-([3-(t r iflu or om et h yl)p h en yl]-
m eth yl)p yr r olo[3,2,-d ]p yr im id in e Hyd r och lor id e (90h ).
1
Yield: 0.058 g (2.1%) of a brown solid. Mp: 219-221 °C. H
6-(2-Flu or op h en yl)-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (89g). Yield:
NMR (DMSO-d6, 400 MHz): δ 1.56-1.69 (m, 6), 2.45 (s, 3),
3.90-3.97 (m, 4), 4.28 (s, 2), 6.21(s, 1), 7.48-7.61 (m, 3), 7.69
(s, 1), 12.20 (s, 1), 14.09 (s, 1). MS m/z: 375 (M + H for free
base). Anal. (C20H21F3N4‚HCl) C, H, N, Cl. (0.60 g (21%) of the
isomer, 2,6-dimethyl-4-piperidyl-7-[3-(trifluoromethyl)phenyl]-
pyrrolo[3,2-d]pyrimidine, as a brown solid was also obtained.)
4-Meth oxy-1-[(2-m eth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr i-
m id in -6-yl)m eth yl]ben zen e Hyd r och lor id e (90i). Yield:
0.49 g (9%) of tan crystals. Mp: 263-267 °C. 1H NMR (DMSO-
d6, 400 MHz): δ 1.73 (br s, 6), 3.75 (s, 3), 4.01 (br s, 4), 4.15 (s,
2), 6.19 (s, 1), 6.94 (d, 2, J ) 8.7), 7.27 (d, 2, J ) 8.6), 12.02 (s,
1), 13.93 (s, 1). MS m/z: 337 (M + H for free base). Anal.
(C20H24N4O‚HCl) C, H, N, Cl. (0.47 g (10%) of 1-[2,6-dimethyl-
4-piperidylpyrrolo[3,2-d]pyrimidin-7-yl]-4-methoxybenzene as
a beige solid was also obtained.)
1
0.14 g (8%) of long white needles. Mp: 287-289 °C. H NMR
(DMSO-d6, 400 MHz): δ 1.72 (br s, 6), 2.58 (s, 3), 4.05 (br s,
4), 6.80 (d, 1, J ) 1.6), 7.39-7.46 (m, 2), 7.57 (q, 1, J ) 7.1),
7.89 (t, 1, J ) 7.7), 12.13 (s, 1), 14.37 (s, 1). MS m/z: 311 (M
+ H). Anal. (C18H19FN4‚HCl‚H2O) C, H, N, Cl.
6-(3-Flu or op h en yl)-2-m eth yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (89h ). Yield:
0.082 g (5%) of small beige needles. Mp: >285 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.71 (br s, 6), 2.57 (s, 3), 4.06 (br s,
4), 6.99 (s, 1), 7.35 (t, 1, J ) 8.5), 7.60 (q, 1, J ) 7.7), 7.83 (d,
1, J ) 7.6), 7.91 (d, 1, J ) 10.2), 11.99 (s, 1), 14.34 (s, 1). MS
m/z: 311 (M + H). Anal. (C18H19FN4‚HCl‚H2O) C, H, N, Cl.
2-Meth yl-6-(4-p h en ylp h en yl)-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Mon oh yd r a te (89l). Yield:
0.20 g (9%) of a pale-yellow solid. Mp: >280 °C. 1H NMR
(DMSO-d6, 500 MHz): δ 1.72 (br s, 6), 2.58 (s, 3), 4.07 (br s,
4), 6.96 (s, 1), 7.43 (t, 1, J ) 7.2), 7.52 (t, 2, J ) 7.7), 7.77 (d,
2, J ) 7.9), 7.86 (d, 2, J ) 8.1), 8.06 (d, 2, J ) 8.1), 12.00 (s, 1),
14.29 (s, 1). MS m/z: 369 (M + H). Anal. (C24H24 N4‚HCl‚H2O)
C, H, N, Cl.
6-(2,5-Diflu or op h en yl)-2-m et h yl-4-p ip er id ylp yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e Mon oh yd r a te (89m ).
Yield: 0.34 g (19%) of white needles. Mp: 279-281 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.06 (s, 4),
6.85 (s, 1), 7.42-7.55 (m, 2), 7.86-7.91 (m, 1), 12.13 (s, 1), 14.41
(s, 1). MS m/z: 329 (M + H for free base). Anal. (C18H18F2N4‚
HCl‚H2O) C, H, N.
6-(2,6-Diflu or op h en yl)-2-m et h yl-4-p ip er id ylp yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e Hyd r a te (89n ). Yield:
0.033 g (2%) of a pale-yellow sandy solid. Mp: >280 °C. 1H
NMR (DMSO-d6, 400 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.02
(s, 4), 6.77 (s, 1), 7.35 (t, 2, J ) 8.3), 7.67 (d quintet, 1, J ) 1.4,
6.8), 12.41 (s, 1), 14.51 (s, 1). MS m/z: 329 (M + H for free
base). Anal. (C18H18F2N4‚HCl‚1.2H2O) C, H, N, Cl.
6-[(4-F lu or op h en yl)m eth yl]-2-m eth yl-4-p ip er id ylp yr -
r olo[3,2-d ]p yr im id in e Hyd r och lor id e (90j). Yield: 0.10 g
1
(3%) of a white solid. Mp: 254-255 °C. H NMR (DMSO-d6,
400 MHz): δ 1.70 (br s, 6), 2.51 (s, 3), 3.98 (br s, 4), 6.21 (s, 1),
7.17 (t, 2, J ) 8.9), 7.35 (dd, 2, J ) 8.6, 8.5), 12.04 (s, 1), 13.90
(s, 1). MS m/z: 325 (M + H for free base). Anal. (C19H21FN4‚
HCl) C, H, N, Cl.
2-Meth yl-6-(2-p h en yleth yl)-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Hyd r a te (90k ). Yield: 0.27 g
(7%) of a beige powder. Mp: 236-238 °C. 1H NMR (DMSO-
d6, 400 MHz): δ 1.60 (br s, 6), 2.45 (s, 3), 2.95 (t, 2, J ) 8.4),
3.09 (t, 2, J ) 8.4), 3.92 (br s, 4), 6.24 (s, 1), 7.11-7.14 (m, 1),
7.16-7.25 (m, 4), 11.88 (s, 1), 14.06 (s, 1). MS m/z: 321 (M +
H for free base). Anal. (C20H24N4‚HCl‚0.25H2O) C, H, N, Cl.
4-Meth oxy-1-[(2-m eth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr i-
m id in -6-yl)eth yl]ben zen e Hyd r och lor id e Hyd r a te (90l).
Yield: 0.40 g (6.5%) as beige crystals. Mp: 234-235 °C. 1H
NMR (DMSO-d6, 400 MHz): δ 1.53-1.69 (m, 6), 2.45 (s, 3),
2.87 (t, 2, J ) 7.7), 3.04 (t, 2, J ) 7.7), 3.64 (s, 3), 3.87-3.94
(m, 4), 6.21(s, 1), 6.78 (d, 2, J ) 8.6), 7.09 (d, 2, J ) 8.6), 11.86
(s, 1), 14.0 (s, 1). MS m/z: 351 (M + H for free base). Anal.
(C21H26N4O‚HCl‚0.4H2O) C, H, N, Cl. (0.26 g (17%) of the
isomer, 1-[(2,6-dimethyl-4-piperidylpyrrolo[3,2-d]pyrimidin-7-
yl)methyl]-4-methoxybenzene as a beige solid was also ob-
tained.)
6-(3,5-Diflu or op h en yl)-2-m et h yl-4-p ip er id ylp yr r olo-
[3,2-d ]p yr im id in e H yd r och lor id e Mon oh yd r a t e (89o).
Yield: 0.44 g (19%) of pale-yellow needles. Mp: >280 °C. 1H
NMR (DMSO-d6, 500 MHz): δ 1.61 (br s, 6), 2.47 (s, 3), 3.97
(br s, 4), 6.97 (s, 1), 7.28 (tt, 1, J ) 2.1, 7.1), 7.74 (d, 2, J )
6.6), 11.93 (s, 1), 14.35 (s, 1). MS m/z: 329 (M + H for free
base). Anal. (C18H18F2N4‚HCl‚H2O) C, H, N, Cl.
[(2-Met h yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im id in -6-yl)-
m eth oxy]ben zen e Hyd r och lor id e (90m ). Yield: 0.066 g
1
(2%) of a white solid. Mp: 238-239 °C. H NMR (DMSO-d6,
6-(3,4-Diflu or op h en yl)-2-m et h yl-4-p ip er id ylp yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e Hyd r a te (89p ). Yield:
0.16 g (6%) of a beige solid. Mp: 243-245 °C. 1H NMR (DMSO-
d6, 500 MHz): δ 1.71 (br s, 6), 2.57 (s, 3), 4.06 (t, 4, J ) 5.0),
6.85 (s, 1), 7.63 (q, 1, J ) 10.0), 7.89 (d, 1, J ) 8.1), 8.19 (dt,
1, J ) 1.3, 9.5), 12.01 (s, 1), 14.39 (s, 1). MS m/z: 329 (M + H
for free base). Anal. (C18H18F2N4‚HCl‚1.25H2O) C, H, N, Cl.
2-Meth yl-4-p ip er id yl-6-(3,4,5-tr iflu or op h en yl)p yr r olo-
[3,2-d ]p yr im id in e Hyd r och lor id e Hyd r a te (89q). Yield:
0.43 g (16%) of a white fluffy solid. Mp: >280 °C. 1H NMR
(DMSO-d6, 500 MHz): δ 1.71 (br s, 6), 2.58 (s, 3), 4.07 (s, 4),
7.07 (s, 1), 8.14 (m, 2), 12.04 (s, 1), 14.45 (s, 1). MS m/z: 347
(M + H for free base). Anal. (C18H17F3N4‚HCl‚0.5H2O) C, H,
N, Cl.
400 MHz): δ 1.64 (br s, 6), 2.48 (s, 3), 3.94 (br s, 4), 5.22 (s, 2),
6.66 (s, 1), 6.92 (t, 1, J ) 7.3), 7.01 (d, 2, J ) 7.9), 7.26 (dt, 2,
J ) 1.1, 7.4), 12.64 (s, 1), 14.18 (s, 1). MS m/z: 323 (M + H for
free base). Anal. (C19H22N4O‚HCl) C, H, N, Cl.
4-Ch lor o-1-[(2-m eth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im i-
d in -6-yl)m eth ylth io]ben zen e
Hyd r och lor id e
(90n ).
1
Yield: 0.043 g (1.3%) of a yellow solid. Mp: 205-206 °C. H
NMR (CDCl3, 400 MHz): δ 1.73 (s, 6), 2.62 (s, 3), 4.03 (s, 4),
4.34 (s, 2), 6.42 (s, 1), 6.98 (d, 2, J ) 8.6), 7.02 (d, 2, J ) 8.6),
12.20 (s, 1), 14.31 (s, 1). MS m/z: 373 (M + H for free base).
Anal. (C19H21ClN4S‚HCl): C H, N, Cl.
4-Ch lor o-1-[((2-m et h yl-4-p ip er id ylp yr r olo[4,5-d ]p yr i-
m id in -6-yl)m eth yl)su lfon yl]ben zen e Hyd r och lor id e Hy-
d r a te (90o). Yield: 0.30 g (9%) of a white solid. Mp: 199-
201 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.57 (m, 4), 1.65 (m,
2), 2.47 (s, 3), 3.85 (br s, 4), 5.02 (s, 2), 6.23 (s, 1), 7.65 (AB q,
4, J ) 6.2, 6.2), 12.20 (s, 1), 14.18 (s, 1). MS m/z: 405 (M + H
for free base). Anal. (C19H21ClN4O2S‚HCl‚0.9H2O) C, H, N, Cl.
2-(2-Meth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im id in -6-yl)-
th iop h en e Hyd r och lor id e (90p ). Yield: 0.55 g (13%) of a
tan solid. Mp: >280 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.71
(s, 6), 2.56 (s, 3), 4.04 (br s, 4), 6.70 (s, 1), 7.26 (t, 1, J ) 4.2),
7.80 (d, 1, J ) 5.0), 7.89 (d, 1, J ) 3.0), 12.15 (s, 1), 14.44 (s,
1). MS m/z: 299 (M + H). Anal. (C16H18N4S‚HCl) C, H, N, Cl.
2-(2-Meth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im id in -6-yl)-
fu r a n Hyd r och lor id e (90q). Yield: 0.50 g (70%) of a yellow
2,6-Dim eth yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im id in e Hy-
d r och lor id e Hyd r a te (90a ). Yield: 0.54 g (12%) of brown
1
needles. Mp: 244-245.5 °C. H NMR (DMSO-d6, 500 MHz):
δ 1.67 (m, 4), 1.72 (m, 2), 2.48 (s, 3), 2.52 (s, 3), 3.97 (t, 4), 6.30
(s, 1), 11.92 (s, 1), 14.00 (s, 1). MS m/z: 231 (M + H). Anal.
(C13H18N4‚1.1HCl‚H2O) C, H, N Cl.
6-Bu t yl-2-m e t h yl-4-p ip e r id ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e (90c). Yield: 0.53 g (15%) of white cube-
shaped crystals. Mp: 246-248 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.17 (t, 3, J ) 7.4), 1.59 (quintet, 2, J ) 7.3), 1.87-
1.94 (m, 8), 2.77 (s, 3), 3.06 (t, 2, J ) 7.8), 4.22 (m, 4), 6.55 (s,
1), 12.08 (s, 1), 14.39 (s, 1). MS m/z: 273 (M + H for free base).
Anal. (C16H24N4‚HCl) C, H, N, Cl. (0.33 g (11%) of 2,6-dimethyl-
1
solid. Mp: >280 °C. H NMR (DMSO-d6, 400 MHz): δ 1.56-

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4305
1.70 (m, 6), 2.46 (s, 3), 3.89-3.96 (m, 4), 6.75 (s, 2), 7.30 (d, 1,
J ) 3.2), 7.89 (d, 1, J ) 1.2), 12.10 (s, 1), 14.15 (s, 1). MS m/z:
281 (M - H for free base). Anal. (C16H18N4O‚HCl) C, H, N, Cl.
5-Meth yl-2-(2-m eth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im i-
d in -6-yl)fu r a n Hyd r och lor id e (90r ). Yield: 0.35 g (21%) as
were washed with H2O (3 × 40 mL), saturated NaCl (50 mL),
and dried over Na2SO4 and concentrated in vacuo. Bulb-to-
bulb distillation (oven temperature 90-100 °C) afforded 1.06
g (85%) of the title compound as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ 1.26 (s, 12), 1.59 (m, 4), 2.09 (br s, 4),
6.56 (s, 1).
1
a yellow solid. Mp: >280 °C. H NMR (DMSO-d6, 400 MHz):
δ 1.63 (br s, 6), 2.34 (s, 3), 2.48 (s, 3), 3.95 (m, 4), 6.30 (d, 1, J
) 3.3), 6.59 (s, 1), 7.21 (d, 1, J ) 3.3), 12.02 (s, 1), 14.23 (s, 1).
MS m/z: 297 (M + H for free base). Anal. (C17H20N4O‚HCl) C,
H, N, Cl.
2-(2-Meth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im id in -6-yl)-
ben zo[b]fu r a n Hyd r och lor id e Mon oh yd r a te (90s).
Yield: 0.59 g (95%) of a beige solid. Mp: >280 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.73 (s, 6), 2.58 (s, 3), 4.08 (s, 4), 7.00
(s, 1), 7.35 (t, 1, J ) 7.5), 7.44 (t, 1, J ) 8.0), 7.71 (d, 1, J )
8.2), 7.79 (d, 1, J ) 7.7), 7.88 (s, 1), 12.48 (s, 1), 14.40 (s, 1).
MS m/z: 333 (M + H). Anal. (C20H20N4O‚HCl‚H2O) C, H, N,
Cl.
2-(2-Meth yl-4-p ip er id ylp yr r olo[4,5-d ]p yr im id in -6-yl)-
ben zo[b]th iop h en e Hyd r och lor id e Hyd r a te (90t). Yield:
0.88 g (31%) of a yellow powder. Mp: >280 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.66 (br s, 6), 2.51 (s, 3), 4.00 (br s,
4), 6.74 (s, 1), 7.39 (m, 2), 7.91 (t, 1, J ) 6.9), 8.00 (t, 1, J )
4.0), 8.16 (s, 1), 12.22 (s, 1), 14.21 (s, 1). MS m/z: 349 (M + H
for free base). Anal. (C20H20N4S‚HCl‚0.70H2O) C, H, N, Cl.
2-Met h yl-4-p ip er id yl-6-(2-p yr id yl)p yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Hyd r a te (90u ). Yield: 0.62 g (85%)
of a brown solid. Mp: >280 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.72 (s, 6), 2.58 (s, 3), 4.06 (br s, 4), 7.16 (s, 1), 7.51
(dd, 1, J ) 7.4, 7.4), 8.01 (dt, 1, J ) 1.4, 7.6), 8.24 (d, 1, J )
7.9), 8.76 (d, 1, J ) 4.4), 12.19 (s, 1), 14.36 (s, 1). MS m/z: 294
(M + H). Anal. (C17H19N5‚1.2HCl‚0.4H2O) C, H, N, Cl.
2-Meth yl-4-p ip er id yl-6-p yr a zin -2-ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Hyd r a te (90v). Yield: 0.068 g (53%)
of a brown solid. Mp: 280-283.5 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.72 (s, 6), 2.59 (s, 3), 4.08 (br s, 4), 7.29 (s, 1), 8.74
(d, 1, J ) 2.4), 8.82 (br s, 1), 9.49 (s, 1), 12.41 (s, 1), 14.41 (s,
1). MS m/z: 295 (M + H for free base). Anal. (C16H18N6‚HCl‚
1.4H2O) C, H, N, Cl.
4-Cycloh ex-1-en yl-2-m eth yl-6-p h en ylp yr r olo[3,2-d ]p y-
r im id in e (19). A mixture of 4-chloro-2-methyl-6-phenylpyr-
rolo[3,2-d]pyrimidine (14; R1 ) Me, R2 ) Ph) (0.26 g), 2-cyclohex-
1-enyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18) (0.24 g,
1.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.025 g,
0.027 mmol) and triphenylphosphine (0.056 g, 0.21 mmol) in
a mixture of solvents (1.2 mL of toluene, 0.3 mL of 1.0 M Na2-
CO3 and 0.3 mL of ethanol) was refluxed under N2 for 2 days.
Upon cooling to room temperature, the reaction mixture was
diluted with H2O (40 mL) and the solution was extracted with
CHCl3 (4 × 40 mL). The organic extracts were washed with
water (50 mL), saturated NaCl (50 mL), dried over Na2SO4
and concentrated with a rotary evaporator. Chromatography
on silica gel with a gradient eluant of EtOAc(0-30%):hexanes
(100-70%) afforded 0.15 g (48%) of the title compound as an
off-white solid. Mp: 247-249 °C. 1H NMR (CDCl3, 400 MHz):
δ 1.79 (m, 2), 1.88 (m, 2), 2.36 (m, 2), 2.68 (m, 2), 2.79 (s, 3),
6.63 (m, 1), 6.87 (d, 1, J ) 2.0), 7.45 (t, 1, J ) 7.2), 7.49 (t, 2,
J ) 7.2), 7.72 (d, 2, J ) 7.2), 8.47 (s, 1). MS m/z: 290 (M + H),
288 (M - H). HRMS: calcd for C19H20N3 (M + H) 290.1657,
found 290.1657.
4-Cycloh exyl-2-m eth yl-6-p h en ylp yr r olo[3,2-d ]p yr im i-
d in e (20). A solution of 2-methyl-4-(1-cyclohexenyl)-5H-6-
phenylpyrrolo[3,2-d]pyrimidine (0.096 g, 0.33 mmol) in EtOH
(5 mL) was agitated on a Parr apparatus at room temperature
in the presence of PtO2 (0.020 g, 0.088 mmol) under H2 (70
psi) for 30 h. The reaction mixture was filtered through a pad
of Celite and concentrated on a rotary evaporator. Chroma-
tography on silica gel with a gradient eluant of EtOAc(0-20%):
hexanes (100-80%) afforded 0.055 g (57%) of the title com-
pound as an off-white solid. Mp: >280 °C. 1H NMR (CDCl3,
400 MHz): δ 1.44-1.49 (m, 2), 1.81-1.88 (m, 4), 1.93-2.01
(m, 4), 2.99 (m, 1), 6.86 (d, 1, J ) 1.4), 7.44 (t, 1, J ) 6.1), 7.51
(t, 2, J ) 6.1), 7.74 (d, 2, J ) 6.1), 8.40 (s, 1). MS m/z: 292 (M
+ H), 290 (M - H). HRMS: calcd for C19H22N3 (M + H)
292.1814, found 292.1806.
2,7-Dim et h yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Mon oh yd r a te (94a ). Yield: 0.22 g
(90%) of a white solid. Mp: >280 °C. 1H NMR (DMSO-d6, 400
MHz): δ 1.69 (br s, 6), 2.35 (s, 3), 2.64 (s, 3), 4.03 (br s, 4),
7.52-7.60 (m, 3), 7.65-7.68 (m, 2), 11.94 (s, 1), 14.16 (s, 1).
MS m/z: 307 (M + H). Anal. (C19H22N4‚1.1HCl‚H2O) C, H, N,
Cl.
2-Cya n o-1-p h en ylvin yl-4-m eth ylben zen esu lfon a te (22;
R2 ) P h ). This material was prepared according to the method
described in route B (step a) from benzoylacetonitrile (3.4 g,
23 mmol) and p-toluenesulfonyl chloride (5.1 g, 27 mmol) to
afforded 4.0 g (57%) of the title compound as a yellow solid.
1H NMR (CDCl3, 400 MHz): δ 2.46 (d, 3), 5.57 (d, 1), 7.31-
7.50 (m, 5), 7.58 (d, 1, J ) 7.93), 7.65 (d, 1, J ) 7.92), 7.76 (d,
1, J ) 8.22), 7.90 (d, 1, J ) 8.26). MS m/z: 300 (M + H), 298
(M - H).
7-E t h yl-2-m et h yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e Hyd r a te (94b). Yield: 0.034 g
1
(1%) of a white solid. Mp: 261-263 °C. H NMR (DMSO-d6,
400 MHz): δ 1.05 (t, 3, J ) 7.5), 1.63 (br s, 6), 2.56 (s, 3), 2.69
(q, 2, J ) 7.2), 3.95 (br s, 4), 7.46-8.02 (m, 5), 11.90 (s, 1),
13.86 (s, 1). MS m/z: 321 (M + H for free base). Anal.
(C20H24N4‚HCl‚0.7H2O) C, H, N, Cl.
Eth yl 3-Am in o-5-p h en yl-1H-p yr r ole-2-ca r boxyla te (25;
R2 ) P h ). This material was prepared according to the method
described in route B (step b) from 2-cyano-1-phenylvinyl
4-methylbenzenesulfonate (4.0 g, 13 mmol) and diethyl ami-
nomalonate hydrochloride (2.8 g, 13 mmol) and was used
without further purification. An analytical sample was ob-
tained as off-white crystals by recrystallization from toluene:
2-Met h yl-6,7-d ip h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Mon oh yd r a te (94c). Yield: 0.083
1
g (51%) of a beige solid. Mp: 169-171 °C. H NMR (DMSO-
d6, 400 MHz): δ 1.72 (br s, 6), 2.56 (s, 3), 4.06 (br s, 4), 7.29
(dd, 2, J ) 1.7, 6.0), 7.37-7.45 (m, 8), 12.26 (s, 1), 13.40 (s, 1).
MS m/z: 369 (M + H). Anal. (C24H24N4‚HCl‚H2O) C, H, N, Cl.
7-F lu or o-2-m et h yl-6-p ip er id ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e (94d ). Yield: 0.27 g (6%) of pale-green
needles. Mp: >280 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.72
(br s, 6), 2.59 (s, 3), 4.07 (br s, 4), 7.53-7.57 (m, 1), 7.61 (t, 2,
J ) 7.7), 7.87 (d, 2, J ) 7.5), 12.07 (s, 1), 14.56 (s, 1). MS m/z:
311 (M + H for free base). Anal. (C18H19FN4‚HCl) C, H, N, Cl.
2-Cycloh ex-1-en yl-4,4,5,5-tetr a m eth yl-1,3,2-d ioxa bor o-
la n e (18). A mixture of cyclohexenyl trifluoroacetate (1.36 g,
5.9 mmol), bis(pinacolacto)diboron (1.65 g, 6.5 mmol), dichloro-
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane adduct [PdCl2(dppf)] (0.14 g, 0.18 mmol), and
potassium acetate (1.74 g, 17.7 mmol) in anhydrous dimethyl
sulfoxide (10 mL) was stirred under nitrogen at 70 °C for
overnight. Upon cooling to the room temperature, the reaction
mixture was diluted with H2O (30 mL), and the crude product
was extracted with benzene (3 × 40 mL). The organic extracts
1
cyclohexane. H NMR (DMSO-d6, 400 MHz): δ 1.28 (t, 3, J )
7.12), 4.22 (q, 2, J ) 7.20), 5.06 (br s, 2), 5.98-6.03 (m, 1),
7.16-7.38 (m, 3), 7.72-7.76 (m, 2), 10.68 (br s, 1). MS m/z:
231 (M + H), 229 (M - H).
ter t-Bu tyl 2-Aza -3-[(ter t-bu toxy)ca r bon yla m in o]-3-{[2-
(e t h oxyca r b on yl)-5-p h e n ylp yr r ol-3-yl]a m in o}p r op -2-
en oa te. To a 25-mL round-bottomed flask were added ethyl
3-amino-5-phenyl-1H-pyrrole-2-carboxylate (1.1 g) and MeOH
(5 mL). To the reaction flask was added 1,3-bis(tert-butoxy-
carbonyl)-2-methyl-2-thiopseudourea (1.6 g, 5.5 mmol), fol-
lowed by glacial acetic acid (1.43 mL, 25 mmol). The reaction
mixture was stirred at room temperature under N2 for 28 h.
A heavy precipitate formed and was collected by filtration,
washed with H2O (3 × 10 mL) and dried in a vacuum oven
overnight to give 0.71 g (32% from 22; R2 ) Ph) of the title
compound as an off-white solid. 1H NMR (DMSO-d6, 400
MHz): δ 1.38 (t, 3, J ) 7.00), 1.44 (s, 9), 1.46 (s, 9), 4.38 (q, 2,

4306 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
J ) 6.97), 7.31-7.46 (m, 3), 7.76 (d, 2, J ) 7.86), 11.06 (br s,
1), 11.25 (s, 1), 11.61 (s, 1), 11.95 (br s, 1). MS m/z: 473 (M +
H), 471 (M - H).
was stirred at room temperature for 15 h. The precipitate
formed was collected by filtration, washed with H2O and ether,
and dried to give a white solid. To the above solid in a 1-L
round-bottomed flask was added 6% aqueous sodium hydrox-
ide (435 mL). The suspension was heated at reflux for 2 h.
After cooling to 22 °C, the reaction mixture was acidified using
12 N HCl to pH 6. The resultant precipitate was filtered,
washed with H2O, and dried in a vacuum oven overnight to
give 15.2 g (77%) of the title compound as a white solid. 1H
NMR (DMSO-d6, 500 MHz): δ 6.29 (s, 1), 7.33-7.43 (m,3), 7.85
(d, 2, J ) 7.3), 10.62 (br s, 1), 10.85 (br s, 1), 12.19 (br s,1). MS
m/z: 226 (M - H).
2,4-Dich lor o-6-p h en ylp yr r olo[3,2-d ]p yr im id in e (39). A
mixture of 6-phenyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-diol (38)
(6.0 g, 26.6 mmol) and POCl3 (210 mL, 229 mmol) in a 500-
mL, round-bottomed flask was heated at 120 °C for 60 h. POCl3
was removed in vacuo to give a dark-red residue. Ice-water
was added, and the pH of the reaction mixture was adjusted
to pH 6 by the addition of NH4OH at 0 °C. The resulting
mixture was extracted three times with EtOAc. The combined
organic layers were washed with brine, dried over Na2SO4,
filtered, concentrated in vacuo and dried in a vacuum oven
overnight to give 2.84 g (40%) of the title compound as an
orange solid. 1H NMR (DMSO-d6, 400 MHz): δ 6.95 (s, 1),
7.50-7.66 (m, 3), 7.77 (d, 2, J ) 8.1), 8.88 (br s, 1).
2-Am in o-6-p h en ylp yr r olo[3,2-d ]p yr im id in -4-ol (29). To
a round-bottomed flask was added a solution of tert-butyl
2-aza-3-[(tert-butoxy)carbonylamino]-3-{[2-(ethoxycarbonyl)-5-
phenylpyrrol-3-yl]amino}prop-2-enoate (0.679 g, 1.44 mmol)
in CH2Cl2 (8 mL). Trifluoroacetic acid (2 mL) was added, and
the reaction mixture was stirred at room temperature under
N2 for 4.5 h. After the solvent was evaporated in vacuo, the
residue was heated in EtOH (8 mL) and 1 N NaOH (4 mL) at
reflux for 2 h. The reaction mixture was concentrated in vacuo
to ca. 4 mL, and the pH of the resulting suspension was
adjusted to pH 6 (pH paper) with 10% HCl. The precipitate
that formed was collected by filtration, washed with water and
dried in a vacuum oven overnight to give 0.2 g (61%) of the
1
title compound as an off-white solid. H NMR (DMSO-d6, 500
MHz): δ 5.81 (br s, 2), 6.56 (s, 1), 7.28-7.41 (m, 3), 7.87 (d, 2,
J ) 7.44), 10.40 (br s, 1), 11.78 (br s, 1). MS m/z: 227 (M +
H), 225 (M - H).
6-P h e n yl-4-p ip e r id ylp yr r olo[3,2-d ]p yr im id in -2-yl-
a m in e Hyd r och lor id e Hyd r a te (31). In a round-bottomed
flask were added 2-amino-6-phenylpyrrolo[3,2-d]pyrimidin-4-
ol (29) (0.26 g, 1.2 mmol) and phosphorus oxychloride (2.7 mL,
28.8 mmol). The mixture was heated in a 124 °C oil bath for
24 h, then excess POCl3 was removed in vacuo to afford a
brown residue. Ice-cold water was added and the pH of the
solution was adjusted to pH 8 (pH paper) by adding aqueous
Na2CO3. The resulting precipitate was collected by filtration,
washed with water and then dried in a vacuum oven at 40 °C
to give a brown solid. This material was transferred to a round-
bottomed flask and heated with piperidine (0.57 mL, 5.75
mmol) and dioxane (8 mL) in a 110 °C oil bath for 15 h. Most
of the solvent was then evaporated in vacuo. Chloroform was
added to the residue, and the organic layer was separated,
washed with water, dried over Na2SO4, filtered, and concen-
trated in vacuo to give a brown foam. Purification by flash
chromatography on silica gel with 100:2:1 CHCl3:MeOH:Et3N
as eluant afforded 0.092 g (27%) of the title compound as a
tan solid. The above material (0.078 g, 0.27 mmol) was
dissolved in a minimal amount of CHCl3 and HCl (0.6 mL of
a 1 N solution in ether, 0.6 mmol) was added dropwise. The
mixture was stirred at room temperature for 20 min, and the
solvent was evaporated in vacuo to give a tan foam. Recrys-
tallization from MeOH/H2O gave 0.026 g (6%) of the title
compound as off-white crystals. Mp: >300 °C dec. 1H NMR
(DMSO-d6, 500 MHz): δ 1.66-1.67 (m, 6), 3.97 (m, 4), 6.66 (s,
1), 7.32 (br s, 2), 7.45-7.53 (m, 3), 7.87 (d, 2, J ) 7.26), 11.53
(br s, 1), 12.51 (br s, 1). MS m/z: 294 (M + H), 292 (M - H).
Anal. (C17H19N5‚HCl‚0.2H2O) C, H, N, Cl.
2-Ch lor o-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im i-
d in e (40). This compound was prepared according to the
method described in route A (step e) by employing 2,4-dichloro-
6-phenylpyrrolo[3,2-d]pyrimidine (39) (2.84 g, 10.8 mmol),
piperidine (5.3 mL, 53.8 mmol), and K2CO3 (14.9 g, 108 mmol)
in H2O (100 mL) to give 3.23 g (96%) of the title compound as
an orange solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.77 (m, 6),
3.83 (m, 4), 6.75 (s, 1), 7.37-7.55 (m, 3), 7.64 (d, 2, J ) 7.3),
8.21 (br s, 1). MS m/z: 313, 315 (M + H), 311, 313 (M - H).
Meth yl(6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im id in -
2-yl)a m in e Hyd r och lor id e Mon oh yd r a te (42a ). A mixture
of 2-chloro-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (40)
(0.63 g, 2.0 mmol), aqueous methylamine (40 wt %, 3.1 mL,
35 mmol), 10 mL of n-butanol and 0.4 mL of 12 N HCl in a
25-mL, round-bottomed flask was heated at reflux for 48 h
under a stream of N2. After cooling to room temperature, the
solvent was evaporated in vacuo and the residue was parti-
tioned between 5% NaHCO3 and CH2Cl2. The aqueous layer
was extracted with CH2Cl2 and the combined CH2Cl2 layers
were dried over Na2SO4, filtered, concentrated in vacuo, and
purified by flash chromatography on silica gel with 100:2 to
100:5 CHCl3-MeOH as eluant to give 0.030 g (5%) of the free
base. 1H NMR (DMSO-d6, 500 MHz): δ 1.68 (m, 6), 3.19 (s, 6),
3.95 (m, 4), 6.70 (s, 1), 7.45-7.54 (m, 3), 7.86 (d, 2, J ) 7.4),
11.58 (br s, 1), 12.22 (br s, 1). To a solution of the above
material in CHCl3 (5 mL) was added HCl (0.1 mL of a 1 N
solution in ether, 0.1 mmol). After stirring the reaction at room
temperature for 30 min, the solvent was evaporated in vacuo
and the solid obtained was recrystallized in MeOH/H2O to give
0.015 g of the title compound as orange crystals. Mp: 195-
200 °C. MS m/z: 308.5 (M + H). Anal. (C18H21N5‚HCl‚H2O) C,
H, N.
(6-P h en yl-4-pip er idylpyr r olo[3,2-d]pyr im id in -2-yl)p r o-
p yla m in e Hyd r och lor id e Hyd r a te (42b). To a solution of
6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidin-2-ylamine (31) (0.10
g, 0.34 mmol) in MeOH (3.5 mL) in a 25-mL round-bottomed
flask were added propionaldehyde (0.074 mL, 1.02 mmol) and
sodium cyanoborohydride (0.043 g, 0.68 mmol). The pH of the
reaction was adjusted to 6 by the addition of methanolic HCl
and the reaction was heated at reflux for 40 h. The pH was
lowered to 4 by addition of 10% HCl and the reaction was
stirred for 1 h. The pH was then raised to 10 by addition of
saturated Na2CO3. The solvent was removed in vacuo, and the
residue was dissolved in water and extracted with CH2Cl2
three times. The combined organic layers were dried over Na2-
SO4 and concentrated in vacuo to give an orange oil. The
residue was purified by preparative TLC using 95:5 CHCl3-
MeOH as eluant to give 0.032 g (28%) of a light-yellow solid.
The above material was dissolved in CHCl3 (2 mL) and HCl
(0.25 mL of a 1 N solution in ether, 0.25 mmol) was added.
P h en yl-N-(6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im i-
d in -2-yl)for m a m id e Hyd r och lor id e Hyd r a te (33). To a
mixture of 6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidin-2-
ylamine (31) (0.10 g, 0.34 mmol) in pyridine (7 mL) in a 25-
mL, round-bottomed flask was added benzoic anhydride (0.081
g, 0.36 mmol). The reaction was heated at reflux for 15 h. The
solvent was removed in vacuo and 0.1 M NaOH (10 mL) was
added to the residue. The precipitate that formed was filtered,
washed with water, dried in a vacuum oven overnight to give
0.16 g of an orange solid. The above material was dissolved in
CHCl3 (10 mL). HCl (0.35 mL of a 1 N solution in ether, 0.35
mmol) was added. The mixture was stirred at room temper-
ature for 20 min. The solvent was evaporated to give a foam,
which was recrystallized from MeOH:H2O to give 0.030 g (19%)
1
of the title compound as orange crystals. H NMR (DMSO-d6,
500 MHz): δ 1.74 (m, 6), 4.09 (m, 4), 7.07 (s, 1), 7.50-7.74 (m,
6), 7.89 (d, 2, J ) 7.63), 8.08 (d, 2, J ) 7.67), 11.85 (br s, 1),
11.94 (br s, 1), 13.61 (br s, 1). MS m/z: 398 (M + H), 396 (M
- H). Anal. (C24H23N4O‚HCl‚2.2H2O) C, H, N, Cl.
6-P h en ylp yr r olo[3,2-d ]p yr im id in e-2,4-d iol (38). In a 1-L
round-bottomed flask was added ethyl 3-amino-5-phenylpyr-
role-2-carboxylate (25; R2 ) Ph) (20 g, 87 mmol), followed by
acetic acid (435 mL) and H2O (44 mL). Potassium cyanate (21.2
g, 261 mmol) dissolved in 70 mL of H2O was then added
dropwise through an addition funnel. The reaction mixture

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4307
The mixture was stirred at room temperature for 20 min.
Solvent was evaporated to give 0.033 g (2%) of the title
compound as a light-yellow solid. 1H NMR (DMSO-d6, 500
MHz): δ 0.93 (t, 3, J ) 7.22), 1.58-1.62 (m, 2), 1.68 (m, 6),
3.25 (m, 2), 3.96 (m, 4), 6.66 (s, 1), 7.45-7.54 (m, 3), 7.68 (br
s, 1), 7.86 (d, 2, J ) 7.32), 11.54 (br s, 1), 12.23 (br s, 1). MS
m/z: 336 (M + H), 334 (M - H). Anal. (C18H21N5‚HCl‚0.5H2O)
C, H, N.
Dim eth yl(6-ph en yl-4-piper idylpyr r olo[3,2-d]pyr im idin -
2-yl)a m in e Hyd r och lor id e Hyd r a te (42c). A mixture of
2-chloro-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (40) (0.31
g, 1 mmol), aqueous dimethylamine (40 wt. %, 1.5 mL, 12
mmol), n-butanol (5 mL), and 12 N HCl (0.2 mL) in a 25-mL,
round-bottomed flask was heated at reflux for 32 h under a
stream of N2. After cooling to room temperature, the precipi-
tate was collected by filtration, washed with hexanes and dried
in a vacuum oven overnight to give 0.24 g (74%) of the title
compound as orange crystals. Mp: >300 °C. 1H NMR (DMSO-
d6, 500 MHz): δ 1.68 (m, 6), 3.19 (s, 6), 3.95 (m, 4), 6.70 (s, 1),
7.45-7.54 (m, 3), 7.86 (d, 2, J ) 7.4), 11.58 (br s, 1), 12.22 (br
s, 1). MS m/z: 322.5 (M + H). Anal. (C19H23N5‚1.2HCl‚1.75H2O)
C, H, N, Cl.
6-P h en yl-2,4-d ip ip er id ylp yr r olo[3,2-d ]p yr im id in e Hy-
d r och lor id e (42d ). To a solution of 2-chloro-6-phenyl-4-
piperidylpyrrolo[3,2-d]pyrimidine (40) (0.25 g, 0.80 mmol) in
dioxane (2 mL) in a 5-mL, Wheaton vial was added piperidine
(0.39 mL, 4.0 mmol). The vial was capped and heated at 110
°C for 44 h. After cooling to room temperature, the precipitate
was collected by filtration, washed with hexanes and dried in
air to give 0.20 g (69%) of the free base as a tan solid. To a
solution of the above material in CHCl3 (10 mL) was added
HCl (0.54 mL of a 1 N solution in ether, 0.54 mmol). After
stirring the reaction at room temperature for 30 min, the
solvent was evaporated in vacuo and the solid obtained was
recrystallized in MeOH:H2O to give 0.038 g of the title
compound as light-yellow crystals. Mp: >272 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.61-1.70 (m, 6), 3.74 (m, 4), 3.94
(m, 4), 6.71 (s, 1), 7.45-7.55 (m, 3), 7.87 (d, 2, J ) 7.3), 11.61
(br s, 1), 12.44 (br s, 1). Anal. (C22H27N5‚HCl) C, H, N, Cl.
6-P h en yl-2-su lfa n ylp yr r olo[3,2-d ]p yr im id in -4-ol (34).
To a solution of ethyl 3-amino-5-phenylpyrrole-2-carboxylate
(25; R2 ) Ph) (4.6 g) in dry benzene (100 mL) was added ethyl
isothiocyanatoformate (2.4 mL, 20 mmol). The reaction mix-
ture was heated to 90 °C for 1 h. A precipitate formed and
was filtered and washed with hexanes to give 4.6 g of a brown
solid. The crude solid was treated with 10 g of potassium
hydroxide in water (160 mL), and heated at reflux for 15 h at
100 °C. After cooling to ambient temperature, the pH of the
solution was adjusted to pH 5 with 12 M HCl. A precipitate
formed and was collected by filtration. This material was
washed with water, and dried in a vacuum oven to give 1.2 g
of the title compound as a brown solid. 1H NMR (DMSO-d6,
400 MHz): δ 6.40 (s, 1), 7.35-7.54 (m, 3), 7.88 (d, 2, J ) 7.44),
12.04 (s, 1), 12.58 (s, 1), 12.68 (br s, 1). MS m/z: 244 (M + H),
242 (M - H).
precipitate was then separated from the reaction mixture by
filtration, and the filtrate was concentrated in vacuo to give
an orange residue. Purification by flash chromatography on
silica gel with a gradient of EtOAc(14-20%):hexanes(86-80%)
as eluant gave 0.1 g (6%) of a white solid. 1H NMR (CDCl3,
500 MHz): δ 1.76 (m, 6), 2.60 (s, 3), 3.80 (m, 4), 6.74 (s, 1),
7.38-7.49 (m, 3), 7.64 (d, 2, J ) 7.11), 8.04 (br s, 1). The above
material (0.090 g, 0.28 mmol) was dissolved in minimum
amount of CHCl3, and HCl (0.3 mL of a 1 N solution in ether,
0.3 mmol) was added dropwise. The mixture was stirred at
room temperature for 20 min, and the solvent was then
evaporated in vacuo to give a white foam that was recrystal-
lized from CHCl3-petroleum ether to give 0.055 g (3%) of the
title compound as white crystals. Mp: 281-283 °C dec. 1H
NMR (DMSO-d6, 500 MHz): δ 1.73 (m, 6), 2.67 (s, 3), 4.05 (m,
4), 6.82 (s, 1), 7.49-7.57 (m, 3), 7.95 (d, 2, J ) 7.45), 11.92 (br
s, 1). MS m/z: 325 (M + H), 323 (M - H). Anal. (C18H20N4S‚
HCl‚1.8H2O) C, H, N, Cl.
2-Meth oxy-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr im i-
d in e Hyd r och lor id e Mon oh yd r a te (41). A mixture of
2-chloro-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (40) (0.63
g, 2 mmol), sodium methoxide (25 wt %, 0.78 mL, 4.5 mmol),
and DMSO (2 mL) in a 15-mL, round-bottomed flask was
heated at reflux for 72 h under a stream of N2. After cooling
to room temperature, the residue was partitioned between H2O
and CH2Cl2. The aqueous layer was extracted with CH2Cl2,
and the combined CH2Cl2 layers were dried over Na2SO4,
filtered, concentrated in vacuo. The crude material was puri-
fied by flash chromatography on silica gel with EtOAc(20-
33%):hexanes(80-67%) as eluant to give 0.22 g (35%) of the
free base as a purple solid. To a solution of the above material
in CHCl3 (10 mL) was added HCl (0.75 mL of a 1 N solution
in ether, 0.75 mmol). After stirring the reaction at room
temperature for 30 min, the solvent was evaporated in vacuo
and the solid obtained was recrystallized in MeOH/H2O to give
0.117 g of the title compound as a light-green crystals. Mp:
270-276 °C. 1H NMR (DMSO-d6, 500 MHz): δ 1.73 (m, 6),
4.05 (m, 7), 6.75 (s, 1), 7.48-7.56 (m, 3), 7.92 (d, 2, J ) 8.3),
11.87 (br s, 1), 13.87 (br s, 1). MS m/z: 309 (M + H). Anal.
(C18H20N4O‚HCl‚H2O) C, H, N, Cl.
7-Acetyl-2-m eth yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e (54). A mixture of 2-methyl-6-phenyl-4-pip-
eridylpyrrolo[3,2-d]pyridine (1) (0.050 g, 0.17 mmol), acetic
anhydride (0.17 g, 1.64 mmol), K2CO3 (0.23 g, 1.64 mmol) and
4-(N,N-dimethylamino)pyridine (0.003 g, 0.021 mmol) in an-
hydrous DMF (2.0 mL) was stirred under N2 at 110 °C
overnight. After cooling to the room temperature, the reaction
was quenched by the addition of saturated NaHCO3 (5 mL)
and extracted with CHCl3 (3 × 30 mL). The organic layers were
washed with saturated NaCl, dried over Na2SO4, filtered, and
concentrated with a rotary evaporator. The crude material was
purified by flash chromatography on silica gel with a gradient
eluant of EtOAc(0-25%):hexanes(100-75%) to afford 0.013 g
(22%) of the title compound as an off-white solid. Mp: 188-
1
190 °C. H NMR (CDCl3, 400 MHz): δ 1.73 (br s, 6), 2.11 (s,
3), 2.58 (s, 3), 4.06 (br s, 2), 4.88 (br s, 2), 7.37 (t, 1, J ) 7.4),
7.43 (t, 2, J ) 7.4), 7.61 (d, 2, J ) 7.4), 11.43 (s, 1). MS m/z:
335 (M + H), 333 (M - H). HRMS: calcd for C20H23N4O (M +
H) 335.1888, found 335.1872.
2-Meth ylth io-6-ph en ylpyr r olo[3,2-d]pyr im idin -4-ol (35).
To a solution of 6-phenyl-2-sulfanylpyrrolo[3,2-d]pyrimidin-
4-ol (34) (1.1 g, 4.7 mmol) in acetone (100 mL) was added
anhydrous potassium carbonate (0.52 g, 3.7 mmol), followed
by iodomethane (0.47 mL, 7.5 mmol). The reaction mixture
was stirred at room temperature for 1.5 h. Most of the solvent
was evaporated in vacuo and the resultant precipitate was
collected by filtration and dried in a vacuum oven overnight
to give 1.0 g (84%) of the title compound as a tan solid. 1H
NMR (DMSO-d6, 400 MHz): δ 2.32 (s, 3), 6.41 (s, 1), 7.18-
7.36 (m, 3), 7.84 (d, 2, J ) 7.87), 11.01 (br s, 1). MS m/z: 258
(M + H), 256 (M - H).
2-Meth ylth io-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m id in e Hyd r och lor id e Hyd r a te (37). To a suspension of
2-methylthio-6-phenylpyrrolo[3,2-d]pyrimidin-4-ol (35) (1.3 g,
5.0 mmol) in CH2Cl2 (50 mL) was added Et3N (0.84 mL, 6
mmol), followed by methanesulfonyl chloride (0.4 mL, 5.3
mmol) at 0 °C. The reaction mixture was then warmed to room
temperature over 3 h. Piperidine (1.5 mL, 15 mmol) was then
added, and the reaction mixture was stirred for 15 h. A
2,5-Dim et h yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]p yr i-
m idin e (55). A suspension of 2-methyl-6-phenyl-4-piperidylpyr-
rolo[3,2-d]pyridine (1) (0.057 g, 0.20 mmol) in THF (3 mL) was
placed under a N2 atmosphere and cooled with a dry ice bath
to -78 °C. n-Butyllithium (360 µL of a 2.5 M solution in
hexanes, 0.90 mmol) was added slowly. The reaction mixture
was stirred at -78 °C for 1 h and allowed to warm to 0 °C.
Dimethyl sulfate (0.074 g, 0.60 mmol, 3.0) was added slowly
at 0 °C. The solution was allowed to warm to room temperature
and stir overnight. The reaction was quenched by the addition
of 10% NH4Cl (3 mL) and the THF was evaporated under
reduced pressure. The solution was extracted with CHCl3 (3
× 50 mL), and the combined organic layers were washed with
saturated NaCl, dried over Na2SO4, filtered and concentrated
with a rotary evaporator. The crude material was purified by
flash chromatography on silica gel with a gradient eluant of

4308 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
EtOAc(0-20%):hexanes(100-80%) to provide 0.020 g (34%) of
the title compound as a white solid [0.030 g (53%) of recovered
starting material was also obtained]. Mp: 131-132 °C. 1H
NMR (acetone-d6, 400 MHz): δ 1.70 (m, 2), 1.78 (m, 4), 2.50
(s, 3), 3.40 (t, 4, J ) 4.9), 3.84 (s, 3), 7.47 (t, 1, J ) 7.0), 7.54
(t, 2, J ) 7.0), 7.68 (d, 2, J ) 7.0). MS m/z: 307 (M + H).
resulting solid was suspended in distilled H2O, and the mixture
was adjusted to neutral pH by the addition of concentrated
NH4OH at 0 °C. The resulting solution was extracted with
EtOAc (2×). The combined extracts were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo to afford
1.2 g (90%) of the title compound as a colorless crystalline solid.
1H NMR (DMSO-d6, 500 MHz): δ 5.88 (s, 2) 7.35 (d, 1, J )
5.1), 7.63 (d, 1, J ) 5.1). MS m/z: 163 (M + H).
3-Am in o-6-br om o-2,4-d ich lor op yr id in e (62). 3-Amino-
2,4-dichloropyridine (61) (0.50 g, 3.1 mmol) was dissolved in
DMF (16 mL) and cooled to 0 °C in an ice-water bath. A
solution of N-bromosuccinimide (0.66 g, 3.7 mmol) in DMF (7
mL) was then added slowly. After 15 min, the solution was
poured into H2O and extracted with EtOAc (2×). The combined
extracts were washed with H2O and brine, dried over MgSO4,
filtered and concentrated in vacuo to obtain a red residue. This
residue was dissolved in 1:1 EtOAc:hexanes, filtered through
a plug of silica gel, and concentrated in vacuo to afford 0.68 g
(90%) of the title compound as a colorless crystalline solid. 1H
NMR (DMSO-d6, 500 MHz): δ 6.10 (s, 2), 7.69 (s, 1). MS m/z:
243 (M + H; 81Br), 241 (M + H; 79Br).
3-Am in o-2,4-d ich lor o-6-m eth ylp yr id in e (63). 3-Amino-
6-bromo-2,4-dichloropyridine (62) (0.50 g, 2.1 mmol) was
dissolved in anhydrous DMF (10 mL), and MeB(OH)2 (0.38 g,
6.3 mmol), K2CO3 (1.5 g, 10 mmol), and (PPh3)2PdCl2 (0.15 g,
0.21 mmol) were added. The mixture was heated to 100 °C
for 24 h, then cooled to room temperature, poured into H2O
and extracted with EtOAc (2×). The combined extracts were
washed with H2O and brine, dried over MgSO4, filtered and
concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel with 1:4 EtOAc:hexanes to
afford 0.31 g (85%) of the title compound as a colorless
crystalline solid. 1H NMR (DMSO-d6, 500 MHz): δ 2.28 (s, 3),
5.65 (s, 2), 7.34 (s, 1). MS m/z: 177 (M + H).
3-Am in o-4-ch lor o-6-m et h yl-2-(2-p h en ylet h yn yl)p yr i-
d in e (64). To a solution of 3-amino-2,4-dichloro-6-methylpy-
ridine (63) (0.22 g, 1 mmol) in NEt3 (5 mL) were added
(PPh3)2PdCl2 (0.035 g, 0.05 mmol) and CuI (0.010 g, 0.05
mmol). The mixture was cooled to 0 °C and phenylacetylene
(160 µL, 1.5 mmol) was added. The mixture was allowed to
warm to room temperature then heated at 80 °C for 4 h. The
mixture was cooled to room temperature and filtered through
Celite. The Celite was rinsed with NEt3, and the filtrate was
concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel with 1:4 EtOAc:hexanes to
afford 0.22 g (90%) of the title compound as a dark-brown solid.
1H NMR (DMSO-d6, 500 MHz): δ 2.31 (s, 3), 5.55 (br s, 2),
7.26 (s, 1), 7.44 (m, 3), 7.69 (m, 2). MS m/z: 243 (M + H).
7-Br om o-2-m eth yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-d ]-
p yr im id in e Hyd r och lor id e (56). In an oven-dried, 50-mL,
round-bottomed flask, 2-methyl-6-phenyl-4-(piperidinyl)pyr-
rolo[3,2-d]pyrimidine (1) (0.50 g, 1.7 mmol) was dissolved in
glacial AcOH (15 mL). To this solution was added Br2 (0.090
mL, 1.8 mmol) dropwise over 2 min. The resulting dark
mixture was diluted with H2O (10 mL) and the mixture was
warmed to 45 °C and stirred for 2 h. The reaction was allowed
to cool to room temperature, and the crude material was
extracted with EtOAc (50 mL) and washed with saturated
NaHCO3 (3 × 50 mL). The organic layer was washed with
brine (50 mL), dried over MgSO4, filtered and evaporated in
vacuo to give an oily residue. The residue was purified by silica
gel chromatography with 1:1 EtOAc:hexanes as eluant to give
0.50 g (79% yield) of a yellow solid. Mp: 239-240 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.74 (s, 6), 2.63 (s, 3), 3.83 (s, 4), 7.44
(t, 1, J ) 2.4), 7.5 (t, 2, J ) 7.0), 7.80 (d, 2, J ) 7.1). MS m/z:
373.0 (M + H), 369.0, 371.0 (M - H). HRMS: calcd for
C
18H19N4Br (M + H) 371.0866, found 371.0854.
7-Meth oxy-2-m eth yl-6-p h en yl-4-p ip er id ylp yr r olo[3,2-
d ]p yr im id in e Hyd r och lor id e Hyd r a te (57). Sodium meth-
oxide (2.0 g, 6.2 mmol) was added to a stirring solution of
7-bromo-2-methyl-6-phenyl-4-piperidylpyrrolo[3,2-d]pyrimi-
dine (56) (0.90 g, 2.4 mmol) in MeOH (20 mL). The reaction
was heated at 50 °C for 24 h and heated at reflux for an
additional 24 h. The reaction mixture was cooled and concen-
trated. Purification of the residue by silica gel chromatography
(33:67 EtOAc:hexanes) gave the free base as a green solid, 0.20
g (26%). A portion of the free base (0.16 g, 0.50 mmol) was
dissolved in EtOAc (5 mL) and treated with HCl (0.5 mL of a
1 N solution in ether, 0.5 mmol). The resultant precipitate was
collected by filtration, washed with ether, and dried in vacuo
1
to give 0.17 g (94%) of the title compound as a green solid. H
NMR (DMSO-d6, 400 MHz): δ 1.71 (s, 6), 2.62 (s, 3), 3.78 (s,
3), 4.06 (m, 4), 7.52 (t, 1, J ) 7.2), 7.59 (t, 2, J ) 7.3), 7.80 (d,
2, J ) 7.4), 11.82 (s, 1). MS m/z: 323 (M + H). Anal.
(C19H22N4O‚HCl‚0.45H2O) C, H, N, Cl.
2,4-Dih yd r oxy-3-n itr op yr id in e (59). Fuming HNO3 (40
mL) was added to a stirring solution of 2,4-dihydroxypyridine
(58) (9.0 g, 81 mmol) in H2SO4 (concentrated) (40 mL) at 0 °C.
After 30 min, the solution was poured onto crushed ice (∼80
mL) (a nonviolent exothermic reaction resulted), and the
mixture was chilled in a freezer. The resulting precipitate was
filtered, washed with cold water, and dried to constant weight
in vacuo to afford 11.4 g (90%) of the title compound as a
5-Met h yl-2-p h en yl-7-p ip er id ylp yr r olo[3,2-b]p yr id in e
(65). 3-Amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine
(64) (1.24 g, 5.1 mmol) was dissolved in anhydrous DMF (90
mL), CuI (0.15 g, 0.8 mmol) was added and the mixture was
heated at 110 °C for 18 h. The cooled mixture was poured into
H2O (125 mL) and extracted with EtOAc (2 × 100 mL). The
combined extracts were washed with H2O and brine, dried over
MgSO4 and filtered through a plug of silica using CHCl3. The
crude product was triturated with 1:20 EtOAc:hexanes, fil-
tered, and dried under high vacuum to afford 0.60 g (48%) of
7-chloro-5-methyl-2-phenylpyrrolo[3,2-b]pyridine. 1H NMR (DM-
SO-d6, 500 MHz): δ 2.40 (s, 3), 7.05 (s, 1), 7.16 (s, 1), 7.38 (t,
1, J ) 5.2), 7.49 (m, 2), 8.02 (d, 2, J ) 7.2). MS m/z: 243 (M +
H). This intermediate chloride (0.27 g, 1.1 mmol) was taken
up in 4:1 o-xylene:piperidine (10 mL) and heated to 140 °C in
a Teflon-capped pressure tube for 7 days. The mixture was
cooled to room temperature, diluted with H2O (125 mL) and
extracted with EtOAc (2 × 100 mL). The combined organic
layers were washed with H2O and brine, dried over MgSO4
filtered, and concentrated in vacuo. Chromatography on silica
gel eluting with 10:1 CHCl3-MeOH afforded 0.24 g (75%, 36%
1
colorless solid. H NMR (DMSO-d6, 400 MHz): δ 6.13 (d, 1, J
) 7.2), 7.48 (d, 1, J ) 7.0), 11.93 (s, 1), 12.42 (br s, 1). MS m/z:
157 (M + H).
2,4-Dich lor o-3-n itr op yr id in e (60). 2,4-Dihydroxy-3-nitro-
pyridine (59) (1.56 g, 10 mmol) was taken up in POCl3 (20 mL)
and the resulting black mixture was heated at reflux for 24 h.
The volume of the solution was reduced by 70% in vacuo, and
the cooled mixture was carefully poured onto crushed ice (a
violent exothermic reaction resulted) and extracted with
EtOAc (2×). The combined extracts were washed with brine,
dried over MgSO4, filtered and concentrated in vacuo. The
residue was dissolved in 1:1 EtOAc:hexanes, filtered through
a plug of silica gel, and concentrated in vacuo to afford 1.5 g
(80%) of the title compound as a colorless crystalline solid. 1H
NMR (DMSO-d6, 400 MHz): δ 8.14 (d, 1, J ) 5.1), 8.72 (d, 1,
J ) 5.2).
3-Am in o-2,4-d ich lor op yr id in e (61). 2,4-Dichloro-3-nitro-
pyridine (60) (1.5 g, 8 mmol) was dissolved in Et2O (8 mL). A
solution of SnCl2‚2H2O (18 g, 80 mmol) in HCl (concentrated)
(18 mL) was added cautiously. The reaction was exothermic
upon addition, and the Et2O boiled off of the solution. The
reaction mixture was allowed to stir overnight at room
temperature. The solution was cooled to 0 °C in an ice-water
bath and the precipitate was collected via filtration. The
1
overall) of the title compound as a pale-yellow solid. H NMR
(DMSO-d6, 500 MHz): δ 1.65 (m, 2), 1.75 (m, 4), 2.42 (s, 3),
3.32 (br s, 4), 6.49 (s, 1), 6.80 (s, 1), 7.33 (t, 1, J ) 7.2), 7.43
(m, 2), 7.90 (d, 2, J ) 7.2), 11.1 (br s, 1). MS m/z: 292 (M +
H). HRMS: calcd for C19H22N3 (M + H) 292.1814, found
292.1839.

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4309
6-Meth yl-3-n itr oh yd r op yr id in -2-on e (66). A solution of
2-nitroacetamide (11.8 g, 113 mmol), 3-oxobutanal sodium salt
in aqueous piperidinium acetate58 (257 mL, 1.76 M) was stirred
under N2 at room temperature for 2 days. The reaction mixture
was acidified to about pH 4 and extracted with EtOAc (200
mL × 6). The organic extract was concentrated under reduced
pressure. The crude material was purified by column chroma-
tography on silica gel with MeOH(0-5%):CH2Cl2(100-95%)
as eluant to afford 4.3 g, (25%) of the title compound as an
orange solid. Mp: 215-217 °C. 1H NMR (DMSO-d6, 400
MHz): δ 2.32 (s, 3), 6.24 (d, 1, J ) 7.9), 8.39 (d, 1, J ) 7.9),
12.82 (s, 1). MS m/z: 153 (M - H).
2-Ch lor o-6-m eth yl-3-n itr op yr id in e (67). To a solution of
6-methyl-3-nitrohydropyridin-2-one (66) (0.86 g, 5.6 mmol) in
POCl3 (7 mL) at room temperature was added diisopropyl-
ethylamine (0.72 g, 5.6 mmol). The reaction mixture was
stirred under N2 at 90 °C for 3.5 h. The reaction mixture was
allowed to cool to room temperature and poured into an ice
bath. The aqueous phase was extracted with diethyl ether (100
mL × 3). The extracts were washed with half-saturated
NaHCO3 and brine, dried with Na2SO4, filtered, and concen-
trated under reduced pressure. The title compound was
obtained as a brown solid (0.74 g, 76%). Mp: 59-60 °C. 1H
NMR (CDCl3, 400 MHz): δ 2.65 (s, 3), 7.27 (d, 1, J ) 8.1),
8.15 (d, 1, J ) 8.1), 12.82 (s, 1). MS m/z: 173 (M + H).
for 2.5 h. The reaction mixture was treated with 1-chloro-2-
iodoethane (0.28 g, 1.5 mmol) in THF (1.5 mL) and stirred at
room temperature for 25 min. The reaction mixture was
quenched with H2O (5 mL) and extracted with EtOAc (10 mL
× 4). Organic extracts were washed with brine, dried over Na2-
SO4, filtered, and concentrated. Chromatography with EtOAc-
(0-5%):hexanes(100-95%) as eluant afforded recovered start-
ing material (0.060 g, 36%) and (tert-butoxy)-N-(4-iodo-6-
methyl-2-piperidyl-3-pyridyl)carboxamide (0.073 g, 47% based
on recovered starting material) as a white solid. Mp: 99-101
1
°C. H NMR (CDCl3, 400 MHz): δ 1.51 (s, 9), 1.59 (m, 2), 1.66
(m, 4), 2.36 (s, 3), 3.08 (br s, 4), 6.05 (s, 1). MS m/z: 418 (M +
H), 416 (M - H). A solution of (tert-butoxy)-N-(4-iodo-6-methyl-
2-piperidyl-3-pyridyl)carboxamide (0.073 g, 0.175 mmol) in 4.0
M HCl/EtOAc (5 mL) was stirred at room temperature for 1.5
h. The reaction mixture was diluted with H2O (5 mL),
neutralized over Na2CO3 and extracted with EtOAc (10 mL ×
3). Organic extracts were washed with brine, dried with Na2-
SO4, filtered and concentrated. The title compound was
1
obtained as light-yellow oil (0.055 g, 100%). H NMR (CDCl3,
400 MHz): δ 1.60 (m, 2), 1.70 (m, 4), 2.33 (s, 3), 3.00 (m, 4),
4.08 (br s, 2), 7.12 (s, 1). MS m/z: 318 (M + H).
6-Met h yl-4-(2-p h en ylet h yn yl)-2-p ip er id yl-3-p yr id yl-
a m in e (72). To a mixture of 4-iodo-6-methyl-2-piperidyl-3-
pyridylamine (71) (0.062 g, 0.20 mmol), dichlorobis(triphe-
nylphosphine)palladium(II) (0.007 g, 0.0099 mmol), copper(I)
iodide (0.002 g, 0.0099 mmol) in triethylamine (1 mL) at 0 °C
was added phenylacetylene (0.040 g, 0.39 mmol) slowly. The
reaction mixture was warmed to 75 °C and stirred at this
temperature for 3 h. The reaction mixture was passed through
a pad of Celite and concentrated under reduced pressure.
Chromatography with EtOAc (0-3%):hexanes(100-97%) as
eluant afforded the title compound (0.057 g, 99%) as an orange
6-Meth yl-3-n itr o-2-p ip er id ylp yr id in e (68). A mixture of
2-chloro-6-methyl-3-nitropyridine (67) (0.35 g, 2.0 mmol),
piperidine (0.86 g, 10.1 mmol), triethylamine (0.61 g, 6.03
mmol) and zinc chloride (0.055 g, 0.40 mmol) in THF was
stirred at room temperature overnight. After the removal of
THF under reduced pressure, the crude reaction mixture was
diluted with H2O (50 mL), and extracted with CHCl3 (50 mL
× 3). The organic extract was washed with brine, dried over
Na2SO4, filtered and concentrated under reduced pressure.
Chromatography with EtOAc(0-5%):hexanes(100-95%) as an
eluant afforded the title compound (0.38 g, 85%) as a yellow
1
semisolid. H NMR (CDCl3, 400 MHz): δ 1.62 (m, 2), 1.71 (m,
4), 2.37 (s, 3), 3.05 (m, 4), 4.24 (s, 2), 6.80 (s, 1), 7.36 (m, 3),
7.53 (m, 2). MS m/z: 292 (M + H).
5-Met h yl-2-p h en yl-7-p ip er id ylp yr r olo[2,3-c]p yr id in e
Hyd r och lor id e (73). A mixture of 6-methyl-4-(2-phenylethy-
nyl)-2-piperidyl-3-pyridylamine (72) (0.057 g, 0. 20 mmol) and
copper(I) iodide (0.004 g, 0.020 mmol) in DMF (1 mL) was
stirred at 110 °C under nitrogen overnight. DMF was removed
under reduced pressure. Chromatography with EtOAc (0-
50%):hexanes(100-50%) as eluant afforded the free base
1
solid. Mp: 50-52 °C. H NMR (CDCl3, 400 MHz): δ 1.67 (br
s, 6), 2.43 (s, 3), 3.41 (br s, 4), 6.50 (d, 1, J ) 8.2), 8.03 (d, 1,
J ) 8.2). MS m/z: 222 (M + H).
6-Meth yl-2-p ip er id yl-3-p yr id yla m in e (69). A solution of
6-methyl-3-nitro-2-piperidylpyridine (68) (0.90 g, 4.1 mmol) in
methanol (20 mL) was placed on a Parr shaker (60 psi of H2)
at room temperature in the presence of 10% Pd/C (0.090 g)
overnight. The reaction mixture was passed through a pad of
Celite and concentrated under reduced pressure. Chromatog-
raphy with EtOAc(0-8%):hexanes(100-92%) afforded the title
1
(0.034 g, 60%) as a light-green solid. Mp: 92-94 °C. H NMR
(CDCl3, 400 MHz): δ 1.69 (m, 2), 1.81 (m, 4), 2.51 (s, 3), 3.41
(m, 4), 6.66 (d, 1, J ) 2.1), 6.97 (s, 1), 7.37 (t, 1, J ) 7.3), 7.47
(t, 2, J ) 7.3), 7.68 (d, 2, J ) 7.3), 8.21 (s, 1). MS m/z: 292 (M
+ H), 290 (M - H). This material was combined with an
additional 33 mg of product obtained from a previous experi-
ment. The free base was dissolved in CHCl3 (2 mL) and HCl
(2.0 mL of a 1 N solution in ether, 2.0 mmol) was added. After
stirring for 10 min, the solvents were removed and the sample
was dried in a vacuum oven to give 0.075 g of the title
compound as a brown solid. Mp: 263-265 °C. 1H NMR
(DMSO-d6, 400 MHz): δ 1.71 (m, 2), 1.78 (m, 4), 3.30 (s, 3),
3.75 (m, 4), 7.03 (s, 1), 7.13 (s, 1), 7.50 (t, 1, J ) 6.9), 7.56 (t,
2, J ) 6.9), 7.94 (d, 2, J ) 6.9), 11.94 (s, 1), 12.04 (s, 1). MS
m/z: 292 (M + H), 290 (M - H). HRMS: calcd for C19H22N3
(M + H) 292.1814, found 292.1819.
1
compound (0.61 g, 78%) as a brown solid. Mp: 62-63 °C. H
NMR (CDCl3, 400 MHz): δ 1.59 (m, 2), 1.69 (m, 4), 2.37 (s, 3),
3.02 (m, 4), 3.64 (br s, 2), 6.64 (d, 1, J ) 7.7), 6.84 (d, 1, J )
7.7). MS m/z: 192 (M + H).
(ter t-Bu t oxy)-N-(6-m et h yl-2-p ip er id yl-3-p yr id yl)ca r -
boxa m id e (70). To a solution of 6-methyl-2-piperidyl-3-
pyridylamine (69) (0.25 g, 1.3 mmol) in THF (1 mL) at room
temperature was added sodium bis(trimethylsilyl)amide (2.9
mL of a 1 M solution in THF, 2.9 mmol). After the reaction
mixture was stirred at room temperature for 10 min, a solution
of di-tert-butyl dicarbonate (0.35 g, 1.6 mmol) in THF (3 mL)
was added slowly. The reaction mixture was stirred at room
temperature for additional 3 h. The reaction mixture was
quenched with 10% NH4Cl (15 mL), and extracted with EtOAc
(30 mL × 4). Organic extracts were washed with brine, dried
over Na2SO4, filtered and concentrated. Chromatography with
EtOAc(0-5%):hexanes(100-95%) as eluant afforded the title
compound (0.31 g, 80%) as an off-white solid. Mp: 83-85 °C.
1H NMR (CDCl3, 500 MHz): δ 1.53 (m, 9), 1.60 (m, 2), 1.72
(m, 4), 2.41 (s, 3), 2.94 (t, 4, J ) 5.4), 6.82 (d, 1, J ) 8.1), 7.16
(s, 1), 8.15 (s, 1). MS m/z: 292 (M + H).
4-Iod o-6-m eth yl-2-p ip er id yl-3-p yr id yla m in e (71). To a
solution of (tert-butoxy)-N-(6-methyl-2-piperidyl-3-pyridyl)-
carboxamide (70) (0.17 g, 0.58 mmol) in THF (1 mL) at -78
°C under nitrogen were added tetramethylethylenediamine
(0.17 g, 1.5 mmol) and tert-butyllithium (0.85 mL of a 1.7 M
solution in pentane, 1.45 mmol). The reaction mixture was
warmed to -20 °C gradually and stirred at this temperature
(2Z)-3-Br om o-3-ph en ylpr op-2-en en itr ile (75). To an oven-
dried, 250-mL, round-bottomed flask were added benzoyl-
acetonitrile (5.00 g, 34.4 mmol) and PBr3 (100 mL), and the
resulting mixture was heated at 170 °C with stirring under
N2. After 48 h, the mixture was allowed to cool to room
temperature and was carefully poured into ice (500 g). CHCl3
(250 mL) was added and the mixture was stirred for 1 h. The
layers were separated and the aqueous layer was extracted
with CHCl3 (125 mL). The organic layers were combined and
washed with saturated NaHCO3 (3 × 200 mL) and brine (250
mL). The organic layer was dried over MgSO4, filtered, and
1
evaporated in vacuo to give 8.0 g (98% yield) of a black oil. H
NMR (CDCl3, 400 MHz): δ 6.35 (s, 1), 7.60 (d, 2, J ) 6.3),
7.40 (m, 3).
3-Am in o-5-p h en ylfu r a n -2-ca r bon itr ile (76). To an oven-
dried, 150-mL, round-bottomed flask was added glycolonitrile

4310 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22
Norman et al.
(4.6 g, 55 wt % in H2O, 24.0 mmol), followed by THF (100 mL),
and MgSO4 (10 g). The mixture was stirred for 1 h before a
solution of (2Z)-3-bromo-3-phenylprop-2-enenitrile (75) (2.5 g,
12.0 mmol) was added. The mixture was stirred rapidly at
room temperature as NaH (1.0 g, 60% in mineral oil, 25 mmol)
was carefully added in portions over 1 h. The mixture was
poured into ice (100 g) and stirred for 10 min. The reaction
was extracted with a mixture of 3:1 CHCl3:i-PrOH (3 × 75
mL). The combined organic layers were washed with brine (200
mL), dried over MgSO4, filtered and evaporated to give 2.0 g
by column chromatography using EtOAc(0-5%):hexanes(100-
95%) gave 7.8 g (78%) of the title compound as a light-yellow
oil which solidified upon standing. 1H NMR (CDCl3, 400
MHz): δ 1.65 (m, 6), 2.50 (s, 3), 3.52 (m, 4). MS m/z: 257 (M
+ H).
2-Meth yl-5-n itr o-6-p ip er id ylp yr im id in -4-yla m in e (85).
4-Chloro-2-methyl-5-nitro-6-piperidylpyrimidine (84) (3.0 g,
11.7 mmol) was partially dissolved in MeOH (5.0 mL) and
placed in a pressure tube containing a stir bar. Ammonia (12
mL of a 2 M solution in MeOH, 24.0 mmol) was added in one
portion and the reaction tube was sealed. The reaction vessel
was placed in a 90 °C oil bath and stirred. After 5 h, the
reaction mixture was concentrated to a yellow residue which
was partitioned between saturated aqueous NaHCO3 and 3:1
CHCl3:i-PrOH. The layers were separated and the aqueous
layer extracted with CHCl3:i-PrOH. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated to give a bright yellow solid. Recrystallization
from MeOH gave the title compound, 2.2 g (77%), as a bright
1
(90% yield) of an oil. H NMR (CDCl3, 400 MHz): δ 4.01 (br,
2), 6.35 (s, 1), 7.40 (m, 3), 7.63 (d, 2, J ) 7.1).
2-Me t h yl-6-p h e n yl-4-p ip e r id ylfu r a n o[3,2-d ]p yr im i-
d in e Hyd r och lor id e Hyd r a te (81). To an oven-dried, 150-
mL, round-bottomed flask was added N,N-dimethylacetamide
(1.0 mL, 11 mmol) followed by POCl3 (50 mL). The mixture
was stirred at room temperature for 1 h. To this mixture was
added 3-amino-5-phenylfuran-2-carbonitrile (76) (0.68 g, 3.7
mmol). The resulting mixture was heated at 160 °C for 36 h.
The solvent was evaporated in vacuo and toluene (50 mL) was
added. The solvent was again evaporated in vacuo and to the
crude residue was added piperidine (3.0 mL, 30.3 mmol). The
reaction was heated to 160 °C for 1 h and then allowed to cool
to room temperature. The crude material was dissolved in
CHCl3 (100 mL) and washed with saturated NaHCO3 (3 × 100
mL), brine (100 mL), and dried over MgSO4. The organic layer
was filtered and evaporated in vacuo to give a residue that
was purified by silica gel chromatography with 1:1 EtOAc:
hexanes as eluant. The product was isolated to give 0.20 g (19%
yield) as a light-yellow solid. The free base (0.18 g, 0.62 mmol)
was dissolved in hot EtOAc (20 mL) and HCl (0.62 mL of a 1
N solution in ether, 0.62 mmol) was added dropwise. A
precipitate formed immediately and the mixture was allowed
to cool to room temperature. The solid was filtered and dried
under vacuum to give 0.20 g (97% yield) of the title compound.
Mp: >290 °C. 1H NMR (DMSO-d6, 400 MHz): δ 1.75 (br s, 6),
2.58 (s, 3), 4.16 (s, 4), 7.61 (m, 4), 8.08 (d, 2, J ) 6.8). MS m/z:
294.0 (M + H). Anal. (C18H19N3O‚1.1HCl‚1.8H2O) C, H, N, Cl.
2-Meth yl-6-p h en yl-4-p ip er id ylth iop h en o[3,2-d ]p yr im i-
d in e Hyd r och lor id e (82). A mixture of methyl 3-amino-5-
phenylthiophene 2-carboxylate (79) (2.4 g, 10.6 mmol), acet-
amidine hydrogen chloride (1.2 g, 12.3 mmol), and NaOMe (1.0
g, 18.5 mmol) in poly(ethylene glycol) (20 mL) was heated at
120 °C for 2 days. The mixture was poured into aqueous 0.13
M HCl (50 mL, 6.4 mmol) and the resulting slurry was filtered.
The solid was washed with distilled H2O, dissolved in CH2Cl2
and DMF, and concentrated in vacuo. Toluene was added to
the residue and the solution was concentrated to remove the
residual H2O (this process was repeated two additional times).
To this material was added neat POCl3 (15 mL) and the
mixture was heated at 100 °C for 12 h. The solvent was
evaporated in vacuo, and the residue was dissolved in toluene
and concentrated (this process was repeated two additional
times) to remove the residual POCl3. The residue was dissolved
in toluene (15 mL) and treated with piperidine (5 mL). The
mixture was heated at 100 °C for 12 h, cooled to room
temperature, washed with aqueous NaHCO3, dried over Na2-
SO4, and concentrated in vacuo. This material was purified
by flash chromatography on silica gel with 1:1 EtOAc:hexanes
as eluant. Treatment of the free base with 1 N ethereal HCl
afforded 0.080 g (2.2%) of the title compound as a yellow solid.
1H NMR (2:1 DMSO-d6:CD3OD-d6,400 MHz): δ 1.79 (br s, 6),
2.54 (s, 3), 4.16 (br s, 4), 7.56 (m, 3), 7.73 (s, 1), 7.91 (m, 2).
HRMS: calcd for C18H20N3S (M + H) 310.1374, found 310.1377.
1
yellow solid. H NMR (CDCl3, 400 MHz): δ 1.69 (m, 6), 2.33
(s, 3), 3.48 (m, 4). MS m/z: 238 (M + H).
2-Met h yl-6-p ip er id ylp yr im id in e-4,5-d ia m in e (86). 2-
Methyl-5-nitro-6-piperidylpyrimidin-4-ylamine (85) (2.0 g, 8.4
mmol) was partially dissolved in 95% EtOH (50.0 mL). 10%
Palladium on carbon (catalytic) was added and the system was
evacuated and filled with hydrogen. The system was evacuated
and filled two more times and the reaction allowed to stir
under atmospheric H2 using a balloon. After 16 h, the reaction
mixture was filtered through Celite and concentrated to give
the title compound, 1.7 g (95%), as an off-white solid. 1H NMR
(CDCl3, 400 MHz): δ 1.61-1.69 (m, 6), 2.41 (s, 3), 2.99 (br s,
2), 3.10 (m, 4), 4.43 (br s, 2). MS m/z: 208 (M + H).
2-Meth yl-8-p h en yl-6-p ip er id ylp u r in e Hyd r och lor id e
Mon oh yd r a te (87). 2-Methyl-6-piperidylpyrimidine-4,5-di-
amine (86) (0.41 g, 2.0 mmol) was dissolved in POCl3 (8.0 mL).
Benzoic acid (0.24 g, 2.0 mmol) was added in one portion and
the mixture was refluxed in a 120 °C oil bath. After 4 h, the
reaction mixture was concentrated to give a light-brown
residue. The residue was acidified with 1 N HCl and neutral-
ized with 10 N NaOH (the residue did not dissolve). The
aqueous mixture was extracted three times with 3:1 CHCl3:
i-PrOH. The combined organic layers were washed with brine,
dried over MgSO4, and concentrated to give a yellow-orange
solid (0.56 g). The solid was dissolved in a large quantity (200
mL) of hot MeOH and treated with HCl (1.9 mL of a 1 N
solution in ether, 1.9 mmol). The solution was concentrated
and the residue was recrystallized from hot MeOH to give the
title compound, 0.14 g (22%), as a light-yellow solid. The
filtrate was concentrated to a residue and recrystallized to give
a second crop of the title compound, 0.19 g (30%). 1H NMR
(DMSO-d6, 400 MHz): δ 1.71 (m, 6), 2.56 (s, 3), 4.32 (m, 4),
7.56 (m, 3), 8.15 (m, 2). MS m/z: 294 (M + H). Anal. (C17H19N3‚
HCl‚H2O) C, H, N, Cl.
1-Acetyl-4-(2-m eth yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -
4-yl)p ip er a zin e Hyd r och lor id e (91h ). To an oven-dried, 50-
mL, round-bottomed flask were added 4-chloro-2-methyl-6-
phenylpyrrolo[3,2-d]pyrimidine (14; R1 ) Me, R2 ) Ph) (0.50
g, 2.0 mmol) and 1-acetylpiperazine (0.53 g, 4.1 mmol). The
flask was purged with N2 and the mixture was heated to 180
°C for 30 min. The reaction was allowed to cool to room
temperature and the crude material was purified by flash
chromatography on silica gel with 1:9 MeOH:EtOAc as eluant
to give 0.60 g (87% yield) of an off-white solid. The free base
(0.40 g, 1.2 mmol) was dissolved in hot EtOAc (10 mL) and
HCl (1.2 mL of a 1 N solution, 1.2 mmol) was added dropwise.
The mixture was stirred for 2 h and allowed to cool to room
temperature. The resulting solid was filtered and dried under
high vacuum to give 0.20 g (96% yield) of the title compound
4-Ch lor o-2-m eth yl-5-n itr o-6-p ip er id ylp yr im id in e (84).
A mixture of piperidine (3.8 mL, 38.4 mmol) and diisopropy-
lethylamine (6.8 mL, 39.0 mmol) in THF (160 mL) was charged
into a 250-mL addition funnel. The solution was added
dropwise to a stirring solution of 4,6-dichloro-2-methyl-5-
nitropyrimidine (8.0 g, 38.7 mmol) in THF (60 mL) over 10 h.
The reaction mixture was concentrated and the residue
partitioned between CH2Cl2 and saturated aqueous NaHCO3.
The aqueous layer was extracted with fresh CH2Cl2 and the
combined organic layers were dried over MgSO4, filtered, and
concentrated to give 9.2 g of a crude red-yellow oil. Purification
1
as a light-yellow solid. Mp: 282-283 °C. H NMR (DMSO-d6,
400 MHz): δ 2.09 (s, 3), 2.61 (s, 3), 3.7 (s, 4), 4.14 (dt, 4, J )
5.3, 14), 6.95 (s, 1), 7.54 (m, 3), 8.00 (d, 2, J ) 6.88). MS m/z:
336 (M + H), 334 (M - H). Anal. (C19H21N5O‚HCl) C, H, N,
Cl.
1-(2-Met h yl-6-p h en ylp yr r olo[2,3-e]p yr im id in -4-yl)-4-
(m et h ylsu lfon yl)p ip er a zin e H yd r och lor id e Mon oh y-

Pyrrolopyrimidines as NPY5 Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 22 4311
(12) Woldbye, D. P.; Larsen, P. J . The How and Y of Eating. Nat.
Med. 1998, 4, 671-672.
d r a te (91i). To an oven-dried, 50-mL, round-bottomed flask
was added 2-methyl-6-phenyl-4-piperazinylpyrrolo[3,2-d]py-
rimidine (91g) (0.40 g, 1.36 mmol). The solid was suspended
in anhydrous THF (20 mL) and Et3N (0.4 mL, 2.8 mmol) was
added. The mixture was cooled to 0 °C and methanesulfonyl
chloride (0.12 mL, 1.5 mmol) was added dropwise. Upon
complete addition, the reaction mixture was allowed to warm
to room temperature over 30 min. The reaction was diluted
with EtOAc (50 mL) and extracted with saturated NaHCO3
(3 × 50 mL). The organic layer was washed with brine (75
mL), dried over MgSO4, filtered, and evaporated in vacuo to
give 0.45 g (89% yield) as a light-yellow solid. The free base
(0.44 g, 1.2 mmol) was dissolved in hot EtOAc (20 mL) and
HCl (1.2 mL of a 1 N solution in ether, 1.2 mmol) was added
dropwise. The mixture was stirred for 2 h and allowed to cool
to room temperature. The resulting solid was filtered and dried
under high vacuum to give 0.46 g (96%) of the title compound
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1
as a light-yellow solid. Mp: 280-282 °C. H NMR (DMSO-d6,
400 MHz): δ 2.54 (s, 3), 2.88 (s, 3), 3.29 (s, 4), 4.13 (t, 4, J )
4.62), 6.90 (s, 1), 7.51 (m, 3), 7.94 (d, 2, J ) 6.85). MS m/z:
372 (M + H), 370 (M - H). Anal. (C18H21N5O2S‚HCl‚H2O) C,
H, N, Cl.
Ack n ow led gm en t. The authors thank the Neuro-
biology Division at Amgen for their support in this
research program. Special thanks are given to H. Yan,
J . Yang, J . Baumgartner, and J . Marasco for the cloning
and expression of the human Y5 receptor. We also
acknowledge J . Sommers and J . Novotny for their
assistance in sample preparation, R. Delmendo for
conducting the initial primary screen, S. Thomas for his
help with data management, and S. Eisenberg for the
preparation of compound 83.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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J M000269T