N-(4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl) heterobiarylcarboxamides with functionalized linking chains as high affinity and enantioselective D3 receptor antagonists

Article abstract of DOI:10.1021/jm900095y

In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH₃-phenyl-piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships

Full text of DOI:10.1021/jm900095y

J. Med. Chem. 2009, 52, 2559–2570
2559
N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with
Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists|,
Amy Hauck Newman,*,† Peter Grundt,† George Cyriac,† Jeffrey R. Deschamps,§ Michelle Taylor,‡ Rakesh Kumar,‡ David Ho,‡
and Robert R. Luedtke‡
Medicinal Chemistry Section, National Institute on Drug AbusesIntramural Research Program, National Institutes of Health,
333 Cassell DriVe, Baltimore, Maryland 21224, Department of Pharmacology and Neuroscience, UniVersity of North Texas Health Science
Center, Fort Worth, Texas 76107, and NaVal Research Laboratory, Code 6030, 4555 OVerlook AVenue, Washington, D.C. 20375
ReceiVed January 23, 2009
In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenyl-
piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension
of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3
antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2,
and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity
and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported
to date that show high affinity (Ki ) 1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype.
Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further
underscoring their value as in vivo research tools. These lead compounds also have appropriate physical
characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at
D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric
disorders.
The dopamine D3 receptor, a member of the dopamine D2-
like receptor family, has become a target of intensive research
over the past decade because of several features that have
revealed its potential for development of medications toward
neuropsychiatric disorders, dyskinesias associated with L-DOPA
treatment of Parkinson’s disease, and drug addiction.1-3 Numer-
ous studies have been published that implicate the dopamine
D3 receptors in animal models of these disorders. However,
many of the pharmacological tools that have been available for
in vivo investigation cannot rule out other possible underlying
mechanisms of action, due to lack of D3 receptor selectivity,
poor bioavailability, or predicted toxicity that precludes human
testing. Indeed, another complicating factor is that although
functional coupling of D3 receptors to GRi/o-proteins has been
established,4,5 the question of which G-protein signaling path-
ways are recruited by D3 receptor activation in vivo remains
unanswered.
Nevertheless, the fact that several D3 antagonists have
demonstrated efficacy in animal models of drug abuse without
the concomitant motor side effects associated with nonselective
D2 antagonists supports further pursuit of the D3 receptor as a
potential target for medication development. One of the single
most important drivers of this research is the medicinal
chemistry that has ultimately broken the barriers of nonselective
D2/D3 ligands and enabled the discovery of high affinity and
selective D3 antagonists and partial agonists. Highly selective
and fully efficacious D3 agonists have thus far remained elusive,
likely due to their competition for the orthosteric binding site
and the protein homology that is present within the dopamine
D2-like family of receptors to bind the endogenous substrate
dopamine. Nevertheless, the evolution of structure-activity
relationships (SAR) that have been derived and utilized to result
in D3-preferring and sometimes highly D3-selective ligands has
recently been described in detail6 and the patented compounds
from the decade of 1997-2007 have been summarized.7
Interestingly, despite significant “molecular tinkering”, the
compounds with highest D3 affinity and selectivity typically
are extended molecules with aryl termini and functionalized
linking chains resulting in relatively high molecular weights
(450-600 g/mol) and concomitant lipophilicities as measured
by cLogP values.2,6,7 Significant effort has thus been focused
on attaining the appropriate balance of physical properties that
would allow blood-brain barrier (BBBa) penetration while
limiting nonspecific binding. Cell-based binding and functional
assays have been developed for quick screening of novel
templates, and lead optimization has ensued. An excellent
example of this effort has recently been published in which
significant departure from the D3-selective SB 277011-A (N-
((1s,4s)-4-(2-(6-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cy-
clohexyl)quinoline-4-carboxamide8 and second generation SB-
414796 (3-(2-((1r,4r)-4-(3-(5-methyl-1,2,4-oxadiazol-3-yl)be-
nzamido)cyclohexyl)ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-
7-yl methanesulfonate9 was taken to achieve an improved
pharmacological profile for in vivo testing.10 The resulting 1,2,4-
triazol-3-ylthipropyltetrahydrobenzazepines were reported to
retain the desired D3-selective pharmacological profile (∼100-
fold) but also showed excellent BBB penetrability and accept-
able pharmacokinetics.10 Intensive and biologically based drug
design is undoubtedly key to further characterizing D3-related
|
This manuscript is dedicated to the memory of a dear friend and
colleague, Dr. Andrew Thurkauf, who first introduced A.H.N. to the
dopamine D3 receptor antagonists more than a decade ago.
Atomic coordinates for S-22 have been deposited with the Cambridge
Crystallographic Data Centre.
* To whom correspondence should be addressed. Phone: (443) 740-2887.
Fax: (443) 740-2111. E-mail: anewman@intra.nida.nih.gov.
a Abbreviations: E2, second extracellular loop; BBB, blood-brain barrier;
PSA, polar surface area; TMS, transmembrane spanning; D2/D3E2, a human
D2 receptor with the E2 loop of the D3 receptor; D3/D2E2, a human D3
receptor with the E2 loop of the D2 receptor.
†
National Institute on Drug AbusesIntramural Research Program.
Naval Research Laboratory.
University of North Texas Health Science Center.
§
‡
10.1021/jm900095y CCC: $40.75
2009 American Chemical Society
Published on Web 03/30/2009

2560 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Newman et al.
Table 1. Human D2-Family Receptor Subtype Binding Data on N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamidesa
Ki ( SEM (nM)
R2
X
R1
D2
D3
D4
D2/D3
D4/D3
9b
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
NH
NH
O
O
O
O
S
S
F
H
H
H
I
I
H
H
24.8 ( 8.61
37.4 ( 6.22
44.8 ( 10.6
36.5 ( 3.91
154 ( 13.3
77.0 ( 17.2
64.7 ( 8.91
21.5 ( 1.60
0.52 ( 0.21
0.32 ( 0.12
0.81 ( 0.30
0.92 ( 0.12
1.59 ( 0.31
0.72 ( 0.21
0.81 ( 0.20
0.19 ( 0.04
NTe
476 ( 153
1220 ( 353
NTe
1720 ( 416
335 ( 63.2
1370 ( 430
305 ( 108
50
117
56
40
97
107
80
113
10c
11b
12c
13d
14d
15b
16c
1488
1506
1082
465
1691
1605
a All compounds in this table have been previously reported as noted. They were prepared as described and evaluated under the same assay conditions
for more accurate and direct comparison. The methods for the determination of the binding data (cloned human dopamine D2-like receptors transfected into
HEK293 cells, radioligand 125I-IABN) were described earlier.26 Inhibition of binding constants (Ki) is the mean ( SEM of at least three independent
determinations. b Reference 26. c Reference 58. d Reference 33. e NT ) not tested.
behaviors in vivo and potentially developing these agents as
medications.
13 and 14 were prepared as described in the Experimental
Methods. This series of saturated analogues was evaluated for
hD2, hD3, and hD4 receptor binding, under the same assay
conditions, to make direct SAR comparisons. As noted previ-
ously,2 the wide range of cell lines, radioligands, and binding
assays performed across laboratories has made it impossible to
directly compare Ki values for each other’s novel compounds,
and hence, direct comparison under the same assay conditions
is required to get a true sense of SAR at human D2-like receptor
subtypes.
Numerous reports using some of the prototypic D3 antagonists
and partial agonists have described attenuation of drug seeking
behaviors and effectiveness in animal models of drug reinstate-
ment (relapse) that support D3 receptor blockade as a plausible
target for drug discovery.11-18 Further, these studies suggest
that D3 selective antagonists and/or partial agonists will likely
have therapeutic utility in the treatment of drug addiction in
humans.3,7 In addition, in vivo models in rodents and nonhuman
primates have been designed to more accurately assess D3
receptor-mediated behaviors.19-21 Nevertheless, a correlation
between intrinsic efficacy determined in vitro has yet to be
linked to in vivo behaviors, and hence, additional biological
assays are needed to clarify this apparent disconnect. Moreover,
numerous ligands that show “D3-mediated” behaviors as
determined by their high affinity binding to D3 receptors may
have off-target receptor interactions, including (albeit low
affinity) D2 receptor subtype related effects,22 reduced bio-
availability, poor pharmacokinetics, or functional selectivities23,24
that are typically not defined. Thus, additional discovery and
assessment of novel and D3 receptor selective ligands must
continue to be pursued to validate this target and ultimately
discover efficacious and safe compounds for human clinical
trials.
Structure-activity relationships (SAR) for at least the 4-phe-
nylpiperazine class of D3 antagonists/partial agonists have been
well established. However, continued and, sometimes, incre-
mental modification is required to effectively retain the desired
D3 receptor-selective binding and functional profile while
improving physical properties. This task has presented a
considerable challenge, and thus far only a few D3-preferring
antagonists or partial agonists have been evaluated behaviorally.
Although we have also attempted to diverge from this template25
in the present report, we continue to modify the D3 pharma-
cophore in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of
compounds. Our goal is thus to improve both D3 receptor
affinity and selectivity over the other D2-like receptor subtypes,
as well as additional, related 5-HT receptors, and reduce
lipophilicity so that BBB penetration and D3 receptor-rich brain
localization may be achieved at concentrations that are relevant
to binding affinities.
The trans-olefin, 3-hydroxybutyl- or 2-hydroxybutyl-linked
analogues (17-37) were designed based on SAR previously
described26,27 wherein the D3 pharmacophore 2-OCH3- or 2,3-
diCl-phenylpiperazine was retained. However, incorporation of
variously substituted heterobiarylamides were explored to
identify combinations of these D3 pharmacophores that provided
the best balance between high D3 receptor affinity and selectiv-
ity, as well as to reduce the cLogP value to the druglike range
of 2-5.28 In addition, since one goal of this program has been
to identify a potential D3-receptor selective radioligand, incor-
poration of F, I, and OCH3 moieties was explored, as these could
readily be replaced with 18F, 125I, O11CH3, or OCT3, using a
modification of the synthetic strategies devised. Finally, as we
had previously discovered that the racemic 3- and 2-hydroxy-
lated linking chain afforded several high affinity and D3 receptor
selective ligands,27 we chose to investigate enantioselectivity
within this class of compounds. We previously showed that the
2-OH analogues were very similar in binding profile to the
unsubstituted butyl-linked analogues,27 suggesting that this
position may not be pivotal for binding; hence, the 3-OH
analogue 22 was chosen for enantiomeric separation.
Of the indole, benzofuran, and benzothiophene carboxylates
required, only the 5-iodoindole and 5-iodobenzothiophene were
not commercially available. In Scheme 1, following a modifica-
tion of a published procedure, 5-iodoindole-2-carboxylate (4)
was readily obtained by converting indole-2-carboxylic acid (1)
to its ethyl ester and iodinating to give the 3,5-diodo intermediate
2. After workup, the crude 3,5-diodoindole ethyl ester was
suspended in concentrated HCl to which Zn dust was added
portionwise at room temperature. Extractive workup and ester
hydrolysis in ethanol and aqueous KOH gave the desired
5-iodoindole-2-carboxylic acid (4). 5-Iodobenzofuran-2-car-
boxylic acid (8) was also obtained via basic hydrolysis of the
ethyl ester 7, which was prepared from 5-iodosalicylaldehyde
(5) and diethyl bromomalonate (6, Scheme 1).
Drug Design and Synthesis
All of the saturated butyl-linked analogs (9-16) have been
described in the literature, as indicated in Table 1. Compounds

Heterobiarylcarboxamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2561
Scheme 1. Synthesis of 5-Iodoheterobiaryl Synthonsa
a Reagents and conditions: (a) I2, EtOH, NaIO3 H2SO4; (b) HCl, Zn; (c) EtOH, KOH; (d) 10 M HCl; (e) N(t-Bu)4I, K2CO3.
Scheme 2. Synthesis of Compounds 17-37a
a Reagents and conditions: (a) CDI, THF (method A); (b) SOCl2 (method B).
The syntheses of the amino synthons with linkers A (e.g.,
4-(4-(2,3-chlorophenyl)piperazin-1-yl)-trans-but-2-enylamine or
4-(4-(2-methoxyphenyl)piperazin-1-yl)-trans-but-2-eny-
lamine), B (e.g., 4-amino-1-(4-(2,3-dichlorophenyl)piperazin-
1-yl)butan-2-ol or 4-amino-1-(4-(2-methoxyphenyl)piperazin-
1-yl)butan-2-ol), and C (e.g., 1-amino-4-(4-(2,3-dichlorophenyl)-
piperazin-1-yl)butan-2-ol or 1-amino-4-(4-(2-methoxyphenyl)pip-
erazin-1-yl)butan-2-ol) have all been previously described.26,27
The convergent reaction sequence used to prepare the com-
pounds 17-37, incorporating a butenyl (A), 3-hydroxybutyl (B),
or 2-hydroxybutyl (C) linking chain, is depicted in Scheme 2,
using classic amidation reactions. The R-22 and S-22, incor-
porating an enantiomerically pure 3-hydroxybutyl linker (B),
were prepared from the corresponding enantiomerically pure
amines. An enantiomeric resolution of 22 using tartaric acid
derivatives failed.
two groups with molecules A and C and molecules B and D,
having similar configurations at C12; the chlorine atoms all fall
in the same hemisphere despite free rotation about the N19-C22
bond (see Supporting Information Figures 1 and 2).
Pharmacological Results and Discussion
All ligands were evaluated in competition binding assays in
HEK 293 cells transfected with human D2L, D3, or D4
dopamine receptors, as described previously.26 The displaced
radioligand was the high-affinity, selective D2-like receptor
antagonist 2,3-dimethoxy-5-(125I)-iodo-N-(9-benzyl-9-azabicy-
clo(3.3.1)nonan-3-yl)benzamide ([125I]IABN).30 Data for the
saturated butyl analogues are compared in Table 1. In addition,
cLogP values and polar surface areas (PSA) were calculated to
provide a measure of lipophilicity and predicted brain penetra-
tion, respectively,31,32 for the novel compounds described in
Table 2. Most of these compounds were also evaluated in a
quinpirole-stimulated mitogenesis assay for functional activity
at dopamine D2 and D3 receptors and for binding affinities at
the dopamine D1 and serotonin 5HT1A receptors (Table 5).
Our initial objective was to evaluate the biarylamides
including indole, benzofuran, and benzothiophene and the 5-F-
and 5-I substitution on these ring system, as available, on the
prototypic 2,3-diCl-or 2-OCH3-phenylpiperazinyl butyl-linked
compounds. All of these compounds had been previously
reported, as indicated in Table 1, but they had not all been tested
in our binding assays. Thus, to more accurately compare, we
X-ray Results
S-22 was crystallized in the triclinic space group P1 with
four independent molecules in the asymmetric unit. Three of
these four molecules contained a disorder dichlorophenyl ring.
The absolute configuration was determined from the anomalous
dispersion data collected as part of the X-ray diffraction data
set, and on the basis of this, the hydroxylated C14 was found
to have an S-configuration (Figure 1). All bond lengths and bond
angles were within the expected range. Although all four
molecules have unique conformations, the four can be split into

2562 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Newman et al.
Figure 1. X-ray crystal structure of S-22. Displacement ellipsoids are at the 50% level. For clarity only one of the four independent molecules in
the asymmetric unit is shown.
Table 2. Human D2-Family Receptor Subtype Binding Data on Functionalized Linking Chain Analoguesa
Ki ( SEM (nM)
R2
[linker]
X
R1
PSAb (Å)
cLogPc
D2
D3
D4
D2/D3
D4/D3
17
2,3-diCl
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2,3-diCl
2,3-diCl
2-MeO
2-n-PropO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2,3-diCl
2-MeO
2-MeO
2,3-diCl
2-MeO
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
C
C
NH
O
O
S
S
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
H
51
49
58
37
45
72
72
72
81
81
72
81
72
81
81
90
69
78
69
78
65
72
81
4.6
4.6
3.1
5.3
4.0
4.2
4.2
4.2
2.5
3.7
4.5
2.8
5.5
3.8
4.3
2.8
4.2
2.6
5.5
3.8
4.9
4.2
2.5
76.4 ( 6.61
76.5 ( 14.0
78.8 ( 2.20
149 ( 5.60
60.0 ( 7.01
502 ( 51.5
433 ( 29.5
715 ( 6.23
249 ( 44.4
47.1 ( 6.01
293 ( 34.0
244 ( 35.4
1060 ( 155
520 ( 7.30
489 ( 8.40
390 ( 20.3
622 ( 30.1
507 ( 99.5
581 ( 87.5
430 ( 59.0
337 ( 15.4
28.4 ( 4.60
52.5 ( 3.10
0.44 ( 0.05
2.11 ( 0.53
11.3 ( 1.40
1.11 ( 0.03
2.61 ( 0.29
1.39 ( 0.19
1.12 ( 0.21
16.6 ( 2.31
1.40 ( 0.11
62.1 ( 2.21
1.61 ( 0.11
2.41 ( 0.40
5.21 ( 0.64
3.60 ( 0.55
1.20 ( 0.10
2.32 ( 0.31
6.11 ( 1.01
7.51 ( 1.10
7.71 ( 0.81
7.50 ( 0.70
4.60 ( 0.20
0.26 ( 0.03
0.51 ( 0.03
640 ( 43.3
1070 ( 238
NTe
174
36
7
135
23
358
394
43
178
0.8
183
102
204
144
408
170
102
68
1455
507
18d
19
H
H
H
H
H
H
H
H
H
F
F
I
I
OMe
OMe
H
H
I
20d
21
22
R-22
S-22
23
24
25
26
27
28
29
30
31
32
33
34
35
1770 ( 508
1610
NTe
4900 ( 1034
3430 ( 1300
>5000
5300
3116
>300
1370
1920 ( 263
NTe
>5000
967 ( 178
>10000
455 ( 144
>10000
1530 ( 238
>10000
3125
>1900
126
>8000
1173
>1600
286
O
O
O
S
NH
NH
2140 ( 623
>10000
75
57
73
108
105
>1300
172
I
1290 ( 412
H
H
H
NTe
36
37
1040 ( 733
176 ( 18.7
4015
352
a The methods for the determination of the binding data (cloned human dopamine D2-like receptors transfected into HEK293 cell, radioligand 125I-IABN)
were described earlier.26 Inhibition of binding constants (Ki) are the mean ( SEM of at least three independent determinations. b Polar surface area (PSA)
was calculated using an algorithm developed by Ertl et al.31 c Partition coefficients (cLogP) were calculated using ChemDraw Ultra, version 11.0, CambridgeSoft
2007.31 d Reference 26. e NT ) not tested.
Table 3. Amino Acid Sequence of the E2 Loops of the Human D2 and
5-position of the biarylamide as a potential place for radioligand
development, as previously suggested.33
D3 Dopamine Receptors45 a
,
E2 loop
amino acid sequence
Previous studies from our laboratory had demonstrated that
replacing the saturated butyl linker with either a trans-olefin or
hydroxylated butyl chain often improved D3 selectivity while
retaining high affinity.26,27 Thus, the compounds described in
Scheme 2 were designed. These analogues are arranged in Table
2 according to linking chain template with the trans olefins
having linker A, the 3-OH-subsituted analogues having linker
B, and the 2-OH-butyl analogues with linker C. We have
previously reported that the combinations of extended aryla-
mides and these linking chains yielded high affinity and selective
D3 antagonists and partial agonists. However, many of the
previous compounds had high cLogP values, which limited H2O
solubility and potentially bioavailability, as discussed.27 Hence,
by limiting the size of the arylamides, we were typically able
hD2
hD3
NNADQNE*CIIAN
-TTG-PTV-S-S-
a Amino acid sequence of the human D2 and D3 dopamine receptor
second extracellular (E2) loop is shown using the single letter code. The
asterisk (*) denotes a shift in the sequence alignment to maximize homology,
and a dashed line (-) denotes sequence homology. The cysteine residue is
conserved and forms a disulfide bond.
prepared and evaluated these compounds for binding at D2, D3,
and D4 receptors. As expected, all of the compounds showed
high affinity binding at D3 and relatively low affinities for D4.
In this set, the 2-OCH3-phenylpiperazines 10, 14, and 16 showed
>100-fold D3-selectivity over D2. Further, the 5-F and 5-I
substituents were generally well tolerated, supporting the

Heterobiarylcarboxamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2563
Table 4. Comparison of the Binding for the Enantiomers of 22 to Wild
which joins the conserved cysteine residue located within the
E2 loop with the top of the third transmembrane spanning (TMS)
region, brings the E2 loop in proximity to the extracellular
portion of the helical receptor TMS regions. In addition, several
studies have suggested that amino acid residues within the E2
loop of the dopamine receptors can interact with ligands
positioned in the neurotransmitter binding site, thereby influenc-
ing binding affinity.43,44
Type and Chimeric D2-like Receptorsa
Ki ( SEM (nM)
compd D2 receptor D2/D3E2 loop D3 receptor D3/D2E2 loop
R-22 433 ( 30 (1.0) 211 ( 40 (2.1) 1.1 ( 0.2 (394) 8.3 ( 1.8 (52)
S-22 715 ( 6.0 (1.0) 389 ( 66 (1.8) 16.6 ( 2.3 (43) 63.7 ( 3.5 (11)
a All of the dissociation constants were obtained from competitive
radioligand binding studies. Ki values using transfected HEK 293 cells, and
125I-IABN are expressed in nanomolar and are the mean ( the SEM for n
g 3. The number shown in parentheses is the ratio of the Ki values for D2
receptor/receptor.
The primary structure of the D2 and D3 receptor E2 loops
exhibits less than 50% homology (Table 3).45 To test the
possibility that the enantioselective binding of the R- and S-22
was influenced by the composition of the D2-like receptor E2
loops, we prepared two chimeric receptor proteins: (1) a human
D2 receptor with the E2 loop of the D3 receptor (D2/D3E2)
and (2) a human D3 receptor with the E2 loop of the D2 receptor
subtype (D3/D2E2). A comparison of the affinities of the R-
and S- 22 for the wild type (D2 or D3) receptors and the two
chimeric D2-like receptors (D2/D3E2 and D3/D2E2) is shown
in Table 4. The binding of both enantiomers of 22 to the D2/
D3E2 receptor modestly increased the affinity approximately
2-fold compared to the binding affinity at the wild type D2
receptor. In addition, the substitution of the D2E2 loop onto
the D3 receptor scaffold decreased the affinity of the R-22 by
8-fold and S-22 by 4-fold compared to the wild type human
D3 receptor. These results suggest that (1) the hydroxylated
linking chain of these compounds may be in direct contact with
the E2 extracellular loop of D3 and (2) this interaction may
play a role in, although it does not fully account for, the
enantioselective binding observed. Recently the E2 extracellular
loop has been identified as contributing to the allosteric binding
of 4-(3-chlorophenyl)carbamoyloxy)-2-butynyltrimethylammo-
nium chloride (McN-A-343), a muscarinic M2 receptor partial
agonist that has been described as binding to both allosteric
and orthosteric binding sites on M2 muscarinic receptors.46
Thus, we speculate that direct interaction of our novel analogues
at E2 might be through an allosteric binding site that may play
a pivotal role in their D3-selectivity.
In Table 5, functional activity data at both D2 and D3
receptors, using the quinpirole-stimulated mitogenesis assay in
HEK 293 cells, are shown. In addition, data at the serotonin
1A (5-HT1A) receptor subtype that often shows cross-reactivity
with the D3 antagonists for a few of these analogues are shown.
None of the compounds showed high affinity for D1 receptors,
and all were selective for D3 over the 5-HT1A receptor subtype.
It is worth noting that other arylpiperazinylalkyl analogues have
been developed as 5-HT1A serotonin ligands recently.47 Al-
though in that report D3 receptor binding affinities were not
assessed, based on data from our studies and others, it appears
that SAR between D3 and 5HT1A receptors is separable.
Moreover, in another class of D3-preferring antagonists, the
serotonergic interactions were determined to have no adverse
effects on the desired in vivo profile.48
to keep the cLogP values less than 5 and PSA values in the
range of 50-81, predicting drug-like properties.28,32
None of the analogues showed high affinity for D4 receptors.
In the trans-olefin group (A), all except compound 19 showed
high binding affinities for D3 (0.44-2.5 nM) and selectivity
over D2 receptors. In the 3-OH-butyl linked group (B) high
affinities for D3 were retained, but in several cases, D2 binding
affinities were further reduced compared to the trans olefins,
and thus, several compounds were 145- to 400-fold selective
for D3 over D2 (e.g., 22, 23, 25, 27-30). Most of the cLogP
values in this group were within the 2-5 range and, hence,
were deemed as good candidates for in vivo exploration.
Moreover, several contained 5-F, -I, or -OCH3 substitutions that
might be candidates for future radioligand development (e.g.,
27-29). In addition to the in vitro data reported in Tables 2
and 5, all three of these analogues were tested in 63 radioligand/
enzyme assays at concentrations of 100 and 10 000 nM, in
duplicate. Neither 27 nor 29 inhibited binding activity >50% at
either concentration, and 28 showed only modest affinity at R1
adrenergic receptors (Ki ) 115 nM). Thus, these compounds
are among the most selective D3 receptor ligands reported to
date.
It is noted that significant effort has been directed toward
the development of both D3-selective radioligands and potential
PET imaging agents.33-38 However, despite a promising in vitro
profile, most of these ligands have proven unsuccessful and there
is yet to be a commercially available radiolabeled D3 receptor
antagonist for development of non-cell-based binding and
functional assays.
Both the 2-hydroxylated analogues showed high D3 affinity
and D3 selectivity over the D2-like receptor subtypes of ∼100-
fold. However, because of their relatively high D2 affinity, this
template will not be pursued toward radioligand development.
All of the hydroxyl-linked compounds are racemic, and thus,
it was of interest to attempt to separate an enantiomeric pair
and evaluate R- and S-enantiomers for enantioselectivity in the
D2-like family of receptors. The R-enantiomer of 22 showed
the highest D3 affinity and a remarkable 394-fold D3 receptor
selectivity over the D2 receptor subtype. In contrast, the
S-enantiomer, although D3-selective, was significantly less
active at D3 (15-fold) than its R-enantiomer and enantioselec-
tivity was less pronounced at D2 (<2-fold). Similar D3 enan-
tioselectivities were recently reported for a series of 4-phe-
nylpiperazine hybrid molecules, although the absolute configura-
tion of these compounds was not described.39
In addition, all of the compounds were D3-selective antago-
nists or partial agonists and in some cases (e.g., 16, 25, 26)
selectivity over D2 receptor mediated mitogenesis was ∼100-
fold. In others, D2 activity was not determined because of very
low D2 binding affinity (Ki > 400 nM, e.g., 29 and 30), and
they are likely >100-fold D3-selective. Finally, several of these
analogues showed potent partial agonist activity in this assay
(e.g., S-22, 27, 29). Although partial agonists, determined in
vitro, have yet to be differentiated from antagonists in vivo,
compounds with both high D3 affinity and selectivity will
provide excellent tools with which to further pursue these
Although the precise determination of the molecular basis
for the enantioselective binding of the R- and S-22 is beyond
the scope of the present study, we investigated whether or not
these enantiomers could be interacting differentially with the
second extracellular loop (E2) of the D2 and D3 receptors. Initial
studies on the three-dimensional structure of the bovine rhodop-
sin protein,40 and more recently on members of the adrenergic
receptors,41,42 have indicated that the conserved disulfide bond,

2564 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Newman et al.
Table 5. Additional In Vitro Functional and Binding Data for Selected Compoundsa
IC50 ( SEM, nM
Ki ( SEM, nM
compd
D2 mitogenesis
D3 mitogenesis
D1 [3H]SCH23390
5-HT1A [3H]8-OH-DPAT
11
12
13
14
15
16
17
18
19
20
21
22
R-22
S-22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
118 ( 13.9
9.01 ( 1.36
2100 ( 359
2000 ( 350
2920 ( 940
900 ( 190
1195 ( 47.4
800 ( 130
931 ( 181
1460 ( 95.6
990 ( 150
1730 ( 184
678 ( 56.0
4630 ( 1300
>10000
>10000
>10000
4960 ( 140
>10000
5060 ( 290
>10000
>10000
>10000
>10000
27.9 ( 1.07
8.20 ( 1.70
1030 ( 270
170 ( 57.0
94.7 ( 18.2
21.4 ( 7.10
175 ( 2.55
111 ( 18.5
23.0 ( 9.7
254 ( 34.8
58.0 ( 17.0
4370 ( 59.4,c 171.2 ( 60.5 (22%)b
NDd
2.39 ( 0.79
520 ( 180
22.9 ( 7.60
4.94 ( 0.26
198 ( 2.71
0.22 ( 0.05
7.00 ( 0.76
193 ( 42.2
58.8 ( 8.91
18.7 ( 2.75
14.9 ( 5.4
9.62 ( 0.63
388 ( 46.4
104 ( 23.5
1.09 ( 0.23
29.9 ( 5.76
18.2 ( 3.50
NDd
6.60 ( 2.02 (42.2%)b
12.1 ( 2.80
427 ( 97.1
162 ( 57.0
2160 ( 760
270 ( 100
NDd
132 ( 30.0
6.51 ( 2.82
23.9 ( 7.91
1.76 ( 0.76
38.0 ( 18.0 (26%)b
173 ( 77.1
NDd
NDd
1.51 ( 0.35 (34.9%)b
1.58 ( 0.53
NDd
NDd
13.7 ( 4.41,c 22.8 ( 9.11 (22.6%)b
11.2 ( 3.31
>10000
>10000
>10000
3690 ( 700
6650 ( 630
>10000
NDd
NDd
217 ( 56.0,c 84.0 ( 28.0 (23.6%)b
14.5 ( 3.71
405 ( 21.0
146.1 ( 6.20
340 ( 100
39.1 ( 12.3
25.7 ( 8.12
58.3 ( 2.81
a Unless otherwise noted, data were obtained through the NIDA Addiction Treatment Discovery Program contract with Southern Research Institute
(N01DA-1-8816) or Oregon Health & Science University (Y1 DA 5007-05). b Percent stimulation compared to standard agonist quinpirole. c The first value
is the antagonist IC50; the second value is the agonist EC50 with % stimulation in parentheses. d ND ) not determined because of Ki value in the D2 binding
assay was >400 nM (by the contractor).
comparisons and to determine whether intrinsic activity at D3
(or lack thereof) is important for therapeutic efficacy.
to date. Compounds such as 22 and 29 show high affinity (Ki
) 1 nM) for D3 and ∼400-fold selectivity over the D2 receptor
subtype. Importantly, in this study we have identified the first
enantioselective D3 antagonists (R- and S-22) to be reported
wherein enantioselectivity is more pronounced at D3 than at
D2 and that a binding region on the extracellular loop E2 may
play a role in both enantioselectivity and D3 vs D2 binding
selectivity. These lead compounds also have appropriate physical
properties for in vivo exploration and therefore will be useful
in determining how intrinsic activity at D3 receptors tested in
vitro is related to behavior in animals. Furthermore, these novel
and selective D3 antagonists and partial agonists will undoubt-
edly aid in further determining the role of D3 receptors in
addiction and other neuropsychiatric disorders.
Selective inhibition of cocaine seeking in rodents was first
described with the D3 partial agonist N-(4-(4-(2-methox-
yphenyl)piperazin-1-yl)butyl)-2-naphthamide (BP 897)11,12
and then followed with several reports using the now
prototypic D3 antagonist 38 (SB 277011-A).8b,13-15 Ad-
ditional studies showed that not only could the D3 antagonists
reduce cocaine-induced and brain stimulation reward but
these agents were also able to attenuate cocaine-, cue-, and
stress-induced reinstatement of cocaine taking in rodent
models of relapse.2,3 Additional reports using N-(4-(4-(2,3-
dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxa-
mide (NGB 2904),15,16,49 as well as studies that have been
extended to other drugs of abuse,3,17 further demonstrate the
efficacy of selective D3 antagonists in these animal models
of drug reward and addiction. The similar in vivo profiles of
the D3 partial agonists to the antagonists have brought into
question the correlation of intrinsic activity, as measured in
cell-based models, to behavior.50,51 Nevertheless, other
reports of D3 partial agonists suggest that they may indeed
have different profiles in vivo than the antagonists21,52 and
that these agents might provide a therapeutic advantage.
Recently, D3-preferring full agonists and highly selective
partial agonists were reported and evaluated in models of
contralateral rotation39 yawning and body temperature,53 the
latter being models predictive of D3 receptor stimulation.19,20
It will be very interesting to see how these D3 agonists affect
cocaine-induced behaviors in future studies.
Experimental Methods
The 1H and 13C NMR spectra were recorded on a Varian Mercury
Plus 400 spectrometer. Proton chemical shifts are reported as parts
per million (δ ppm) relative to tetramethylsilane (0.00 ppm) as an
internal standard. Coupling constants are measured in hertz (Hz).
Chemical shifts for 13C NMR spectra are reported as δ relative to
the deuterium signal of the solvent (CDCl3, 77.5 ppm; CD3OD,
49.3 ppm). Combustion analysis was performed by Atlantic
Microlab, Inc. (Norcross, GA) and agrees within 0.4% of calculated
values. Melting point determination was conducted using a Thomas-
Hoover melting point apparatus, and the melting points are
uncorrected. Anhydrous solvents were purchased from Aldrich
(pyridine, acetonitrile, dichloromethane, chloroform, hydrazine) or
JT Baker (diethyl ether) and were used without further purification,
except for tetrahydrofuran, which was freshly distilled from sodium
benzophenone ketyl. If not stated otherwise, final compounds were
purified by column chromatography (silica gel, Merck, 230-400
mesh, 60 Å) or preparative thin layer chromatography (silica gel,
Analtech, 1000 µm) using EtOAc/CHCl3 (5:5:1), 1% triethylamine
or CHCl3/MeOH (10:1), 1% triethylamine as an eluent. Yields and
Summary
An extension of SAR at D3 receptors has resulted in the
discovery of some of the most D3-selective compounds reported

Heterobiarylcarboxamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2565
reaction conditions are not optimized. Generally, yields and
spectroscopic data refer to the free base. With the exception of
R-22 and S-22 all hydroxy compounds described in this paper are
racemates. Oxalate or HCl salts were prepared and recrystallized
as indicated. On the basis of NMR, GC-MS (where obtainable),
and combustion analysis data, all final compounds are >95% pure.
The procedures to determine the binding affinities at the human
dopamine D2-like receptors have been described.26
concentrated in vacuo. The crude product was purified by crystal-
lization from Et2O or preparative thin layer chromatography, as
indicated.
Procedure B. Thionyl chloride (2 mL/mol) was added to the
carboxylic acid (1 equiv). The solution was stirred at reflux for 3 h
and concentrated in vacuo. Residual thionyl chloride was removed
by azeotropic distillation in dry toluene. The resulting solid was
dissolved in amylene stabilized CHCl3 (5 mL). To a stirring solution
of amine (1 equiv) in stabilized CHCl3 (20 mL) and 0.5 M aqueous
NaOH (8 mL) cooled to 0 °C was added the acid chloride solution
dropwise. The solution was stirred vigorously for 3 h at room
temperature. The organic layer was separated, dried with Na2SO4,
and concentrated in vacuo. The crude product was purified by
crystallization from Et2O or preparative thin layer chromatography,
as indicated.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)-5-iodoben-
zofuran-2-carboxamide (13). 13 was prepared from 5-iodoben-
zofuran-2-carboxylic acid (8) and 4-(4-(2,3-dichlorophenyl)piper-
azin-1-yl)butan-1-amine54,55 according to general procedure B.
Yield: 85%. Mp (HCl salt, recrystallized from CHCl3) 265-266
°C. 1H NMR (CDCl3) δ 1.68-1.73 (m, 4H), 2.48 (t, J ) 7.2, 2 H),
2.66 (s, br, 4H), 3.08 (s, br, 4H), 3.53 (q, J ) 5.6, 2H), 6.91 (dd,
J ) 2.0, 7.6, 1H), 7.00 (m, 1H), 7.11-7.16 (m, 2H), 7.25 (d, J )
8.4, 1H), 7.38 (s, 1H), 7.66 (dd, J ) 1.6, 8.4, 1H), 8.01 (d, J )
1.6, 1H). 13C NMR (CDCl3) δ 24.6, 27.8, 39.5, 51.5, 53.6, 58.2,
87.4, 109.4, 113.8, 118.8, 124.8, 127.7, 130.5, 131.7, 134.3, 135.6,
149.9, 151.4, 154.2, 158.6. Anal. (C23H24Cl2IN3O2 ·HCl·0.5H2O)
C, H, N.
Synthesis. 5-Iodoindole-2-carboxylic Acid Ethyl Ester (3).
Adapted from Beshore and Dinsmore,29 to a stirring solution of
indole-2-carboxylic acid (1, 2.5 g, 13 mmol) in EtOH (25 mL) was
added I2 (3.35 g, 13 mmol), NaIO3 (1.42 g, 6.6 mmol), and
concentrated H2SO4 (1.5 mL). The resulting solution was stirred at
reflux for 1.5 h. After the reaction mixture was cooled to room
temperature, a solution of saturated aqueous Na2CO3 (40 mL) was
added. The product was extracted with EtOAc (3 × 40 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and the solvent was removed by distillation to
yield the intermediate 3,5-diiodoindole-2-carboxylic acid ethyl ester
(2) as a yellow solid, which was used without further purification.
To a vigorously stirred suspension of this 3,5-diiodo intermediate
(2) in EtOH (125 mL) and concentrated HCl (11 mL) was added
Zn dust (13.5 g, 20.5 mmol) at room temperature over 90 min in
4 equal portions. The mixture was diluted in H2O (60 mL), and
the product was extracted with EtOAc (3 × 60 mL). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and the solvent was removed by distillation. The crude product 3
was recrystallized with EtOAc/hexanes to yield pure product as a
5-Iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)benzo-
furan-2-carboxamide (14). 14 was prepared from 5-iodobenzo-
furan-2-carboxylic acid (8) and 4-(4-(2-methoxyphenyl)piperazin-
1-yl)butan-1-amine57 according to general procedure A. Yield: 49%.
1
white solid (1.2 g). Yield: 28%. H NMR (DMSO-d6) δ 1.34 (t, J
) 7.2, 3H), 4.34 (q, J ) 7.2, 2H), 7.10 (d, J ) 1.2, 1H), 7.30 (d,
J ) 8.8, 1H), 7.50 (dd, J ) 1.6, 8.8, 1H), 8.06 (d, J ) 1.6, 1H),
12.07 (s, 1H). 13C NMR (DMSO-d6) δ 14.9, 61.3, 84.6, 107.4,
115.7, 128.8, 130.1, 131.2, 133.2, 136.9, 161.7.
1
Mp (oxalate, recrystallized from EtOAc) 151-154 °C. H NMR
(CDCl3) δ 1.65-1.73 (m, 4H), 2.48 (t, J ) 7.2, 2H), 2.68 (s, br,
4H), 3.12 (s, br, 4H), 3.53 (q, J ) 5.6, 2H), 3.86 (s, 3H), 6.85 (d,
J ) 7.6, 1H), 6.91-6.93 (m, 2H), 6.98-7.01 (m, 1H), 7.07 (m,
1H), 7.22 (d, J ) 8.8, 1H), 7.37 (s, 1H), 7.64 (dd, J ) 2.0, 8.4),
8.00 (d, J ) 1.6, 1H). 13C NMR (CDCl3) δ 24.6, 27.7, 39.5, 50.84,
53.7, 55.6, 58.2, 87.4, 109.4, 111.4, 113.9, 118.4, 121.2, 123.2,
130.5, 131.7, 135.6, 141.5, 149.9, 152.5, 154.2, 158.6. Anal.
(C24H28IN3O3 ·2(COOH)2) C, H, N.
5-Iodoindole-2-carboxylic Acid (4). 4 was prepared from 3 in
a similar manner as described for 8. Yield: 83%. 1H NMR (DMSO-
d6) δ 7.06 (d, J ) 1.2, 1H), 7.29 (d, J ) 8.8, 1H), 7.50 (dd, J )
1.2, 8.8, 1H), 8.06 (s, 1H), 11.97 (s, 1H), 13.14 (br s, 1H). 13C
NMR (DMSO-d6) δ 84.5, 107.0, 115.6, 129.9, 130.2, 131.1, 132.9,
136.8, 163.2.
5-Iodobenzofuran-2-carboxylic Acid Ethyl Ester (7). 5-Io-
dosalicylaldehyde (5, 2.18 g, 8.53 mmol) was added to a suspension
containing toluene (40 mL), tert-butylammonium iodide (320 mg,
0.866 mmol), diethyl bromomalonate (6, 2.44 g, 9.39 mmol), and
K2CO3 (1.75 g, 12.3 mmol). The reaction flask was fitted with a
Dean-Stark adapter, and the mixture was stirred at reflux for 36 h.
The suspension was filtered, washed with deionized H2O (20 mL),
dried over Na2SO4, and concentrated. Flash chromatography
(CHCl3/hexanes 3:1) afforded 7 as a yellow solid (1.73 g). Yield:
1H-Indole-2-carboxylic Acid (4-[4-(2,3-Dichlorophenyl)pip-
erazin-1-yl]-trans-but-2-enyl)amide (17). 17 was prepared from
1H-indole-2-carboxylic acid and 4-(4-(2,3-chlorophenyl)-piperazin-
1-yl)-trans-but-2-enylamine26 according to general procedure A.
Yield: 47%. Mp (HCl salt, recrystallized from methanol/diethyl
ether) 266-268 °C (dec). 1H NMR (CDCl3) δ 2.65 (s, 4H),
3.06-3.10 (m, 6H), 4.16 (m, 2H), 5.80-5.82 (m, 2H), 6.39 (t, J )
5.6, 1H), 6.86 (m, 1H), 6.93 (“dd”, J′′ ) 7.2, 2.5, 1H), 7.11-7.17
(m, 3H), 7.28 (m, 1H), 7.45 (dd, J ) 8.2, 0.8, 1H), 7.64 (dd, J )
8.2, 0.8, 1H), 9.87 (s, 1H). 13C NMR (CDCl3) δ 41.6, 51.7, 53.7,
60.6, 102.6, 112.5, 119.1, 121.1, 122.4, 125.0, 125.1, 127.9, 128.0,
129.7, 130.0, 131.0, 134.5, 136.9, 151.6, 162.0. Anal.
(C23H24Cl2N4O·HCl·1.5H2O) C, H, N.
Benzo[b]furan-2-carboxylic Acid (4-[4-(2-Methoxyphenyl)pip-
erazin-1-yl]-trans-but-2-enyl)amide (19). 19 was prepared from
benzo[b]furan-2-carboxylic acid and 4-(4-(2-methoxyphenyl)pip-
erazin-1-yl)-trans-but-2-enylamine26 according to general procedure
A. Yield: 67%. Mp (HCl salt, recrystallized from methanol/diethyl
ether) 210-212 °C (dec). 1H NMR (CDCl3) δ 2.66 (s, 4H),
3.06-3.15 (m, 6H), 3.85 (s, 3H), 4.12 (t, J ) 5.3, 2H), 5.75-5.86
(m, 2H), 6.78 (t, J ) 5.0, 1H), 6.86 (d, 7.5, 1H), 6.91-7.20 (m,
4H), 7.28 (m, 1H), 7.42 (t, J ) 7.5, 1H), 7.47-7.53 (m, 2H), 7.66
(d, J ) 7.0, 1H). 13C NMR (CDCl3) δ 41.0, 50.8, 53.6, 55.5, 60.5,
110.8, 112.0, 112.3, 118.4, 121.2, 123.0, 123.2, 123.9, 127.1, 127.8,
129.4, 129.5, 141.5, 148.9, 152.5, 154.9, 158.9. Anal. (C24H27N3O3 ·
2HCl·H2O) C, H, N.
1
65%. H NMR (CDCl3) δ 1.43 (t, J ) 7.2, 3H), 4.45 (q, J ) 6.8,
2H), 7.35 (d, J ) 8.4, 1H), 7.43 (s, 1H), 7.69 (dd, J ) 6.8, 2.0,
1H), 8.02 (d, J ) 2.0, 1H). 13C NMR (CDCl3) δ 14.5, 61.9, 87.5,
112.7, 114.6, 129.8, 131.8, 136.4, 146.7, 155.1, 159.4.
5-Iodobenzofuran-2-carboxylic Acid (8). A suspension of 7
(2.2 g, 7.0 mmol) in ethanol (20 mL) and 2 M aqueous KOH (14
mL, 28 mmol) was stirred at reflux for 1 h. The free acid product
was obtained by acidifying a hot aqueous solution of the potassium
salt of 8 with 10 M aqueous HCl (pH 2-3) and collecting and
drying the white precipitated product (1.33 g). Yield: 66%. 1H NMR
(DMSO-d6) δ 7.53 (d, J ) 9.2, 1H), 7.55 (s, 1H), 7.75 (dd, J )
1.6, 8.8, 1H), 8.15 (d, J ) 1.6, 1H). 13C NMR (DMSO-d6) δ 88.6,
112.9, 115.2, 130.4, 132.2, 136.2, 136.3, 148.0, 154.9, 160.5.
General Amidation Procedures. Procedure A. CDI (1 equiv)
was added to a solution of the carboxylic acid (1 equiv) in THF
(10 mL/mmol). The reaction mixture was stirred at room temper-
ature for 2 h. The solution was cooled to 0 °C, and the appropriate
amine (1 equiv) was added dropwise. The reaction mixture was
allowed to warm to room temperature and stirred for 2-3 h. The
solvent was removed in vacuo. The residue was diluted in CHCl3
(30 mL) and washed with saturated aqueous NaHCO3 solution (2
× 10 mL). The organic layer was dried with Na2SO4 and
Benzo[b]thiophene-2-carboxylic Acid (4-[4-(2-Methoxyphe-
nyl)piperazin-1-yl]-trans-butenyl)amide (21). 21 was prepared
from benzo[b]thiophene-2-carboxylic acid and 4-(4-(2-methox-
yphenyl)piperazin-1-yl)-trans-but-2-enylamine according to general

2566 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Newman et al.
procedure A. Yield: 51%. Mp (HCl salt, recrystallized from
methanol/diethyl ether) 225-226 °C. 1H NMR (CDCl3) δ 2.62 (m,
4H), 3.04-3.14 (m, 6H), 3.85 (s, 3H), 4.10 (t, J ) 3.9, 2H),
5.74-5.82 (m, 2H), 6.52 (t, J ) 5.4, 1H), 6.86 (d, J ) 7.8, 1H),
6.89-6.95 (m, 2H), 6.99 (m, 1H), 7.35-7.44 (m, 2H), 7.76-7.86
(m, 3H). 13C NMR (CDCl3) δ 41.9, 50.8, 53.6, 55.6, 60.5, 111.6,
118.4, 121.2, 122.9, 123.2, 125.1, 125.3, 125.5, 126.6, 129.5, 129.6,
138.6, 139.3, 141.0, 141.4, 152.4, 162.4. Anal. (C24H27N3O2S ·
2HCl·0.5H2O) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
1H-indole-2-carboxamide (22). 22 was prepared from 1H-indole-
2-carboxylic acid and 4-amino-1-(4-(2,3-dichlorophenyl)piperazin-
1-yl)butan-2-ol27 according to general procedure A. Yield: 72%.
Mp (oxalate salt, recrystallized from EtOH) 212-214 °C. 1H NMR
(CDCl3) δ 1.64 (m, 1H), 1.83 (m, 1H), 2.46 (m, 2H), 2.62 (s, 2H),
2.88 (dd, J ) 10.0, 4.7, 2H), 3.08 (s, 4H), 3.51 (ddd, J ) 12.7,
8.1, 3.9, 1H), 3.92 (m, 2H), 6.85 (dd, J ) 2.1, 0.8, 1H), 6.95 (dd,
J ) 7.0, 2.6, 1H), 7.11-7.18 (m, 3H), 7.27 (ddd, J ) 8.2, 7.0, 1.2,
1H), 7.41 (m, 1H), 7.45 (dd, J ) 8.3, 0.9, 1H), 7.64 (dd, J ) 8.0,
0.8), 9.51 (s, 1H). 13C NMR (CDCl3) δ 33.4, 38.2, 51.5, 53.3, 63.8,
66.5, 101.9, 112.0, 118.7, 120.6, 121.9, 124.3, 124.8, 127.6, 127.6,
127.8, 131.2, 134.2, 136.3, 151.1, 161.7. Anal. (C23H26Cl2N4O2-
(COOH)2 ·0.25H2O) C, H, N.
N-(3-Hydroxy-4-(4-(2-propoxyphenyl)piperazin-1-yl)butyl)-
1H-indole-2-carboxamide (24). (a) To obtain 1-amino-4-(4-(2-
propoxyphenyl)piperazin-1-yl)butan-3-ol, 1.0 g (4.6 mmol) of 1-(2-
propoxyphenyl)piperazine in 25 mL 2-propanol was reacted with
0.75 g (5.0 mmol) of 2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione
in the microwave cavity (pressure vessel, 300 W, cooling, 110 °C,
15 min). The solvent was removed in vacuo, and the foamy residue
was washed twice with 5 mL of 2-propanol to yield 1.2 g (77%)
of 2-(3-hydroxy-4-(4-(2-propoxyphenyl)piperazin-1-yl)butyl)isoin-
doline-1,3-dione, which was used without further characterization.
This intermediate (1.0 g, 2.3 mmol) was fully dissolved in 20 mL
of warm ethanol and treated with 0.3 g (6.0 mmol) of hydrazine
hydrate in the microwave (pressure vessel, 300 W, cooling, 100
°C, 15 min). The cooled reaction mixture was filtered, and the
filtrate was evaporated in vacuo. Both the distillation residue and
the initial precipitate were partitioned between CHCl3 and 20%
aqueous K2CO3 solution. The layers were separated and the aqueous
layer was dried with Na2SO4 to give the amine as an oil. Yield:
1
0.48 g (69%). H NMR (CDCl3) δ 1.05 (t, J ) 7.0, 3H), 1.71 (m,
1H), 1.76-1.91 (m, 3H), 2.46 (m, 2H), 2.61 (s, br, 2H), 2.79-2.95
(m, 3H), 3.11 (m, br, 6H), 5.62 (s, br, 2H), 6.82-6.98 (m, 4H).
13C NMR (CDCl3) δ 11.1, 22.9, 34.1, 38.8, 50.8, 53.8, 64.2, 66.2,
69.7, 112.4, 118.3, 121.1, 123.0, 141.3, 151.8.)
(b) The above amine was reacted with 1H-indole-2-carboxylic
(R)-N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybu-
tyl)-1H-indole-2-carboxamide (R-22). A solution of 27 mg (44
µmol) of (R,R)-N,N′-bis(3,5-di-tert-buytlsalicylidene)-1,2-cyclo-
hexanediaminocobalt(II) (Aldrich) in 5 mL of anhydrous THF was
treated with 2-(2-bromoethyl)oxirane56 (3.32 g, 22.0 mmol) and
HOAc (15 µL, 270 µmol), followed by H2O (220 µL, 12.2 mmol)
at 0 °C. The reaction mixture was allowed to warm to room
temperature overnight. After this time 10 mL of DMF and 3.70 g
(20.0 mmol) of phthalimide potassium salt were added and stirring
at room temperature was continued for another 72 h. The reaction
mixture was diluted with 50 mL of ethyl acetate and washed 3×
with 10 mL of H2O. The organics were dried with Na2SO4 and
concentrated in vacuo. Flash chromatography (CHCl3/EtOAc 3:1)
yielded 2.07 g (21%) of 2-(3-hydroxy-4-(4-(2-propoxyphenyl)pip-
erazin-1-yl)butyl)isoindoline-1,3-dione which was converted into
the title compound in a similar manner as described for racemic
22. The optical purity of R-22 was determined by HPLC analysis
(Daicel Chiralcel OD, hexane/i-PrOH ) 7:3, flow rate ) 1 mL/
min, tR ) 2.1 min) to be >90% ee (Supporting Information). The
product appeared to be somewhat acid sensitive. Attempts to
increase the optical purity by crystallization with tartaric acid or
camphorsulfonic acid failed because of partial racemization. Mp
(free base) 204-206 °C. Anal. (C23H26Cl2N4O2) C, H, N.
acid and according to general procedure A. Yield: 48%. Mp (oxalate
salt, EtOH) 186-188 °C. H NMR (CDCl3) δ 1.08 (t, J ) 7.4,
1
3H), 1.64 (m, 1H), 1.79-1.90 (m, 3H), 2.44 (m, 2H), 2.61 (m,
2H), 2.88 (m, 4H), 3.14 (s, 4H), 3.51 (m, 1H), 3.84-3.94 (m, 2H),
3.95 (t, J ) 7.6, 2H), 6.84 (m, 2H), 6.92 (m, 2H), 6.97 (m, 1H),
7.12 (t, J ) 7.4, 1H), 7.26 (t, J ) 7.4, 1H), 7.46 (d, J ) 8.6, 1H),
7.50 (s, br, 1H), 7.63 (d, J ) 7.8, 1H), 9.72 (s, 1H). Anal.
(C26H34N4O3 ·1.5(COOH)2 ·0.25H2O) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
5-fluoro-1H-indole-2-carboxamide (25). 25 was prepared from
5-fluoro-1H-indole-2-carboxylic acid and 4-amino-1-(4-(2,3-dichlo-
rophenyl)piperazin-1-yl)butan-2-ol according to general procedure
A. Yield: 64%. Mp (HCl salt recrystallized from absolute EtOH)
244-246 °C. 1H NMR (DMSO-d6) δ 1.49-1.54 (m, 1H), 1.74-1.81
(m, 1H), 2.39-2.40 (m, 2H), 2.58 (s, br, 4H), 2.94 (s, br, 4H),
3.30-3.47 (m 2H), 3.72 (s, br, 1H), 4.50 (s, br, 1H), 7.01 (dt, J )
2.4, 9.6, 1H), 7.08-7.10 (m, 2H), 7.25-7.27 (m, 2H), 7.35-7.41
(m, 2H), 8.50 (t, J ) 5.6, 1H), 11.66 (s, 1H). 13C NMR (DMSO-
d6) δ 36.0, 36.8, 51.7, 54.1, 65.1, 66.1, 102.9, 106.3 (d, J ) 23),
112.5 (d, J ) 25), 114.1 (d, J ) 11), 120.2, 125.0, 126.7, 128.9 (d,
J ) 11), 129.1, 133.3, 133.8, 134.3, 151.9, 157.8 (d, J ) 230),
161.44. Anal. (C23H25Cl2FN4O2 ·HCl·0.25H2O) C, H, N.
5-Fluoro-N-(3-hydroxy-4-(4-(2-methoxy-phenyl)piperazin-1-
yl)butyl)-1H-indole-2-carboxamide (26). 26 was prepared from
5-methoxy-1H-indole-2-carboxylic acid and 4-amino-1-(4-(2-meth-
oxyphenyl)piperazin-1-yl)butan-2-ol according to general procedure
A. Yield: 47%. Mp (free base) 158-160 °C. 1H NMR (DMSO-d6)
δ 1.51-1.55 (m, 1H), 1.79-1.81 (m, 1H), 2.32 (m, 2H), 2.54 (s,
br, 4H), 2.91 (s, br, 4H), 3.34-3.47 (m, 3H), 3.73 (s, 3H), 4.48 (s,
1H), 6.82-6.89 (m, 3H), 6.99-7.10 (m, 3 H), 7.36-7.43 (m, 2H),
8,53 (s, br, 1H), 11.69 (s, br, 1H). 13C NMR (DMSO-d6) δ 36.0,
36.9, 50.8, 54.3, 55.9, 65.3, 66.1, 102.9 (d, J ) 5), 106.3 (d, J )
23, 1C), 112.5 (d, J ) 26), 112.5, 114.2 (d, J ) 10), 118.5, 121.5,
123.0, 127.9 (d, J ) 11), 133.8, 134.4, 142.0, 152.6, 157.8 (d, J )
230) 161.5. Anal. (C24H29FN4O3) C, H, N.
(S)-N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybu-
tyl)-1H-indole-2-carboxamide (S-22). S-22 was prepared from
commercially available (S)-2-(2-bromoethyl)oxirane (Aldrich), using
the procedure described for racemic 22. The optical purity of S-22
was determined by HPLC analysis (Daicel Chiralcel OD, hexane/
i-PrOH ) 7:3, flow rate ) 1 mL/min, tR ) 6.8 min) > 99% ee. Mp
(free base) 206-208 °C. Its absolute configuration was confirmed
by X-ray crystallography (see below). Anal. (C23H26Cl2N4O2) C,
H, N.
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-
1H-indole-2-carboxamide (23). 23 was prepared from 1H-indole-
2-carboxylic acid and 4-amino-1-(4-(2-methoxyphenyl)piperazin-
1-yl)butan-2-ol according to general procedure A. Yield: 17%. Mp
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
5-iodo-1H-indole-2-carboxamide (27). 27 was prepared from
5-iodo-1H-indole-2-carboxylic acid (4) and 4-amino-1-(4-(2,3-
dichlorophenyl)piperazin-1-yl)butan-2-ol according to general pro-
cedure A. Yield: 70%. Mp (free base) 224-226 °C. 1H NMR
(DMSO-d6) δ 1.51-1.55 (m, 1H), 1.79-1.81 (m, 1H), 2.30-2.35
(m, 2H), 2.58 (s, br, 4H), 2.94 (s, br, 4H), 3.34-3.46 (m, 2H),
3.74 (s, 1H), 4.52 (d, J ) 2.4, 1H), 7.06-7.09 (m, 2H), 7.27 (d, J
) 4.8, 3H), 7.40 (d, J ) 8.0, 1H), 8.00 (s, 1H), 8.58 (s, J ) 4.8,
1H), 11.76 (s, br, 1H). 13C NMR (DMSO-d6) δ 36.0, 36.9, 51.7,
54.1, 65.1, 66.1, 84.1, 102.1, 115.4, 120.2, 125.0, 126.7, 129.1,
1
(oxalate salt recrystallized from absolute EtOH) 140-142 °C. H
NMR (CDCl3) δ 1.64 (m, 1H), 1.86 (m, 1H), 2.43 (d, J ) 6.7,
2H), 2.87 (m, 2H), 3.09 (s, 4H), 3.52 (m, 1H), 3.85 (s, 3H), 3.93
(m, 2H), 4.07 (s, br1H), 6.86 (d, J ) 7.8, 1H), 6.88 (d, J ) 0.8,
1H), 6.92 (m, 2H), 7.00 (m, 1H), 7.13 (m, 1H), 7.26 (m, 1H), 7.45
(dd, J ) 8.2, 0.8, 1H), 7.56 (dd, J ) 6.3, 3.9, 1H), 7.62 (d, 8.2,
1H). 13C NMR (CDCl3) δ 38.1, 50.8, 53.4, 55.4, 63.9, 66.4, 102.2,
111.3, 112.2, 118.3, 120.5, 121.1, 121.9, 123.2, 124.2, 127.8, 131.3,
136.5, 141.1, 152.3, 161.9. Anal. (C24H30N4O3 ·(COOH)2 ·0.5H2O)
C, H, N.

Heterobiarylcarboxamides
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8 2567
130.5, 130.6, 131.8, 133.3, 133.5, 136.0, 151.9, 161.4. Anal.
(C23H25Cl2IN4O2 ·0.5H2O) C, H, N.
dichlorophenyl)piperazin-1-yl)butan-2-ol according to general
procedure B. Yield: 78%. Mp (HCl salt recrystallized from
EtOH) 251-254 °C. 1H NMR (DMSO-d6) δ 1.50-1.54 (m, 1H),
1.76-1.77 (s, br, 1H), 2.30-2.37 (m 2H), 2.58 (s, br, 4H), 2.94
(s, br, 4 H), 3.35-3.42 (m, 2H), 3.72 (s, br, 1H), 4.52 (s, br,
1H), 7.07-7.10 (m, 1H), 7.26-7.27 (m, 2H), 7.46-7.49 (m,
2H), 7.70 (dd, J ) 1.6, 8.8, 1H), 8.15 (d, J ) 1.6, 1H), 8.74 (t,
J ) 5.2, 1H). 13C NMR (DMSO-d6) δ 35.7, 36.9, 51.6, 54.1,
65.0, 66.2, 88.5, 108.9, 114.9, 120.2, 125.0, 126.7, 129.1, 130.7,
131.9, 133.3, 135.5, 150.7, 151.9, 154.2, 158.3. Anal.
(C23H24Cl2IN3O3 · HCl · 0.5H2O) C, H, N.
N-(3-Hydroxy-4-(4-(2-methoxy-phenyl)piperazin-1-yl)butyl)-
5-iodo-1H-indole-2-carboxamide (28). 28 was prepared from
5-iodo-1H-indole-2-carboxylic acid (4) and 4-amino-1-(4-(2-meth-
oxyphenyl)piperazin-1-yl)butan-2-ol according to general procedure
A. Yield: 65%. Mp (free base) 205-209 °C. 1H NMR (DMSO-d6)
δ 1.51-1.55 (m, 1H), 1.79-1.81 (m, 1H), 2.27-2.36 (m, 2H), 2.54
(s, br, 4H), 2.92 (s, br, 4H), 3.36 (s, 2H), 3.43-3.46 (m, 1H), 3.74
(s, 3H), 4.47 (d, J ) 4.0, 1H), 6.81-6.87 (m, 4H), 6.91 (s, 1H),
7.28 (d, J ) 8.8, 1H), 7.40 (dd, J ) 1.6, 8.8, 1H), 8.00 (s, 1H),
8.55 (t, J ) 1.6, 1H), 11.77 (s, 1H). 13C NMR (DMSO-d6) δ 36.0,
36.9, 50.8, 54.4, 56.0, 65.3, 66.1, 84.1, 102.0, 112.5, 115.4, 118.5,
121.5, 123.0, 130.5, 130.6, 131.8, 133.5, 136.0, 142.0, 152.6, 161.3.
Anal. (C24H29IN4O3) C, H, N.
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
5-methoxy-1H-indole-2-carboxamide (29). 29 was prepared from
5-methoxy-1H-indole-2-carboxylic acid and 4-amino-1-(4-(2,3-
dichlorophenyl)piperazin-1-yl)butan-2-ol according to general pro-
cedure A. Yield: 63%. Mp (free base) 211-215 °C. 1H NMR
(DMSO-d6) δ 1.51-1.54 (m, 1H), 1.77-1.79 (m, 1H), 2.34 (m,
2H), 2.58 (s, br, 4H), 2.94 (s, br, 4H), 3.34 (m, 2H), 3.43 (m, 1H),
3.73 (s, 3H), 4.51 (d, J ) 3.6, 1H), 6.80 (dd, J ) 8.6, 1.6, 1H),
7.00-7.09 (m, 3H), 7.25-7.31 (m, 3H), 8.40 (t, J ) 5.2, 1H), 11.39
(s, 1H). 13C NMR (DMSO-d6) δ 36.1, 36.8, 51.7, 54.1, 55.9, 65.1,
66.2, 102.6, 113.8, 115.0, 120.2, 125.0, 126.7, 128.1, 129.1, 132.3,
132.9, 133.3, 151.9, 154.4, 161.8. Anal. (C24H28Cl2N4O3) C, H, N.
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-
5-methoxy-1H-indole-2-carboxamide (30). 30was prepared from
5-methoxyindole-2-carboxylic acid and 4-amino-1-(4-(2-methox-
yphenyl)piperazin-1-yl)butan-2-ol according to general procedure
A. Yield: 70%. Mp (free base) 207-209 °C. 1H NMR (DMSO-d6)
δ 1.48-1.53 (m, 1H), 1.72-1.79 (m, 1H), 2.34 (s, br, 2H), 2.56
(s, br, 4H), 3.35-3.43 (m, 2H), 2.93 (s, br, 4H), 3.72 (s, br, 1H),
3.73 (s, 3H), 3.74 (s, 3H), 4.50 (s, br, 1H), 6.79-6.92 (m, 5H),
7.05 (m, 2H), 7.30 (d, J ) 9.2, 1H), 8.40 (s, br, 1H), 11.38 (s, br,
1H). 13C NMR (DMSO-d6) δ 36.1, 36.8, 50.7, 54.3, 55.9, 56.0,
65.2, 66.0, 102.6, 112.6, 113.8, 115.0, 118.5, 121.5, 123.0, 128.1,
132.3, 132.9, 141.9, 152.64, 154.4, 161.8. Anal. (C25H32N4O4 ·
0.5H2O) C, H, N.
N-(3-Hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-
5-iodobenzofuran-2-carboxamide (34). 34 was prepared from
5-iodobenzofuran-2-carboxylic acid (8) and 4-amino-1-(4-(2-meth-
oxyphenyl)piperazin-1-yl)butan-2-ol according to general procedure
B. Yield: 63%. Mp (HCl salt recrystallized from MeOH) 239-240
1
°C. H NMR (DMSO-d6) δ 1.49-1.53 (m, 1H), 1.76-1.78 (m,
1H), 2.27-2.36 (m, 2H), 2.30 (dq, J ) 7.2, 12.8, 2H), 2.54 (s, br,
4H), 2.91 (s, br, 4H), 3.37-3.42 (m, 2H), 3.72 (s, 1H), 3.74 (s,
3H), 3.48 (d, J ) 4.4, 1H), 6.81-6.86 (m, 2H), 6.88-6.91 (m,
2H), 7.46-7.49 (m, 2H), 7.70 (dd, J ) 1.6, 8.8, 1H), 8.14 (d, J )
1.6,1H), 8.74 (t, 5.2, 1H). 13C NMR (DMSO-d6) δ 35.7, 36.9, 50.8,
54.3, 56.0, 65.2, 6 2,3Cl-2-hydroxy 6.2, 88.5, 108.9, 112.6, 114.9,
118.5, 121.5, 123.0, 130.8, 131.9, 135.5, 142.0, 150.7, 152.6, 154.2,
158.3. Anal. (C24H28IN3O4 ·2HCl) C, H, N.
N-(3-Hydroxy-4-(4-(2-methoxy-phenyl)piperazin-1-yl)butyl)-
benzo[b]thiophene-2-carboxamide (35). 35 was prepared from
benzo[b]thiophene-2-carboxylic acid and 4-amino-1-(4-(2-methox-
yphenyl)piperazin-1-yl)butan-2-ol according to general procedure
1
A. Yield: 62%. Mp (oxalate salt, EtOH) 214-216 °C. H NMR
(CDCl3) δ 1.63 (m, 1H), 1.87 (m, 1H), 3.05 (m, 2H), 3.11 (d, J )
3.9, 2H), 3.38 (s, br, 8H), 3.83 (s, 3H), 4.46 (m, 1H), 6.83-6.89
(m, 3H), 7.05 (td, J ) 7.4, 1.2, 1H), 7.29 (t, J ) 7.8, 1H), 7.34 (t,
J ) 7.0, 1H), 7.77 (t, J ) 7.6, 2H), 8.16 (s, 1H), 8.37 (s, br, 1H).
13C NMR (CDCl3) δ 34.6, 36.3, 47.6, 53.8, 55.7, 63.2, 63.4, 111.5,
118.9, 121.4, 122.8, 124.6, 125.0, 125.5, 125.9, 126.3, 139.0, 139.3,
139.6, 141.2, 152.2, 163.4. Anal. (C24H29N3O3S · (COOH)2 ·
0.25H2O) C, H, N.
1H-Indole-2-carboxylic Acid (4-[4-(2,3-Dichlorophenyl)pip-
erazin-1-yl]-2-hydroxybutyl)amide (36). 36 was prepared from
1H-Indole-2-carboxylic acid and 1-amino-4-(4-(2,3-dichlorophe-
nyl)piperazin-1-yl)butan-2-ol according to general procedure A.
Yield: 40%. Mp (HCl salt recrystallized from EtOAc/2-PrOH)
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
benzofuran-2-carboxamide (31). 31 was prepared from benzofu-
ran-2-carboxylic acid and 4-amino-1-(4-(2,3-dichlorophenyl)piperazin-
1-yl)butan-2-ol according to general procedure A. Yield: 45%. Mp
1
226-228 °C. H NMR (CDCl3) δ 1.72 (m, 2H), 2.50-2.86 (m,
1
(HCl salt recrystallized from abs. EtOH) 209-212 °C. H NMR
6H), 3.06 (s, 4H), 3.36 (m, 1H), 3.59 (m, 1H), 3.83 (s, 3H), 3.95
(m, 1H), 5.92 (s, br, 1H), 6.83-6.90 (m, 3H), 6.94 (m, 1H), 6.96
(m, 1H), 7.11 (s, 1H), 7.17 (t, J ) 7.8, 1H), 7.46 (d, J ) 7.8, 1H),
7.59 (d, J ) 7.8, 1H), 8.07 (t, J, 5.4, 1H). 13C NMR (CDCl3) δ
10.8, 22.7, 26.2, 33.4, 37.9, 50.4, 53.5, 63.7, 66.1, 69.5, 102.2,
111.9, 112.2, 118.1, 120.5, 120.9, 121.9, 123.0, 124.2, 127.7, 131.1,
136.2, 140.8, 151.6, 161.7. Anal. (C23H26Cl2N4O2 ·HCl ·0.5H2O) C,
H, N.
(DMSO-d6) δ 1.51-1.55 (m, 1H), 1.76-1.79 (m, 1H), 2.30-2.34
(m, 2H), 2.58 (s, br, 4H), 2.95 (s, br, 4H), 3.33-3,44 (m, 2H),
3.72 (s, br, 1H), 4.53 (s, br, 1H), 7.07-7.10 (m, 1H), 7.26-7.27
(m, 2H), 7.31 (t, J ) 8.0, 1H), 7.43 (t, J ) 7.8, 1H), 7.51 (s, 1H),
7.61 (d, J ) 8.0, 1H), 7.34 (d, J ) 8.0, 1H), 8.69 (t, J ) 2.6, 1H).
13C NMR (DMSO-d6) δ 35.7, 36.8, 51.6, 54.1, 65.0, 66.3, 109.8,
112.4, 120.2, 123.4, 124.3, 125.0, 126.7, 127.4, 127.9, 129.1, 133.3,
150.0, 151.9, 154.8, 158.7. Anal. (C23H25Cl2N3O3 ·HCl ·0.5H2O) C,
H, N.
1H-Indole-2-carboxylic Acid (2-Hydroxy-4-[4-(2-methoxyphe-
nyl)piperazin-1-yl]butyl)amide (37). 37 was prepared from 1H-
Indole-2-carboxylic acid and 1-amino-4-(4-(2-methoxyphenyl)pip-
erazin-1-yl)butan-2-ol according to general procedure A. Yield:
51%. Mp (HCl salt, recrystallized from methanol/diethyl ether)
N-(3-Hydroxy-4-(4-(2-methoxy-phenyl)piperazin-1-yl)butyl)-
benzofuran-2-carboxamide (32). 32 was prepared from benzofu-
ran-2-carboxylic acid and 4-amino-1-(4-(2-methoxyphenyl)piperazin-
1-yl)butan-2-ol according to general procedure A. Yield: 77%. Mp
(HCl salt recrystallized from EtOH/2-PrOH) 218-222 °C. 1H NMR
(CDCl3) δ 1.61-1.67 (m, 1H), 1.82-1.86 (m, 1H), 2.44-2.46 (m,
2H), 2.62 (s, br, 4 H), 2.88-2.91 (m, 2H), 3.11 (s, br, 4H),
3.49-3.55 (m, 1H), 3.89 (s, 3H), 3.84-3.95 (m, 1H), 6.86 (d, J )
7.6, 1H), 6.93-6.95 (m, 2H), 6.99-7.03 (m, 1H), 7.28 (t, J ) 7.8,
1H), 7.40 (t, J ) 7.8, 1H), 7.45 (s, 1H), 7.50 (d, J ) 8.2, 1H), 7.54
(s, br, 1H), 7.65 (d, J ) 7.8, 1H). 13C NMR (CDCl3) δ 33.8, 37.7,
51.0, 53.6, 55.6, 64.0, 66.2, 110.3, 111.4, 112.0, 118.4, 121.2, 122.9,
123.3, 123.8, 126.9, 127.9, 141.3, 149.3, 152.5, 155.0, 159.2. Anal.
(C24H29N3O4 ·2HCl) C, H, N.
1
210-212 °C (dec). H NMR (CDCl3) δ 1.58 (d, J ) 14.0, 1H),
1.79 (m, 1H), 2.60 (s, 2H), 2.71 (m, 2H), 2.83 (s, 2H), 3.07 (s,
4H), 3.41 (m, 1H), 3.73 (m, 1H), 3.84 (s, 3H), 4.08 (s, 1H), 6.85
(d, J ) 8.2, 1H), 7.42 (d, J ) 8.2, 1H), 7.61-7.69 (m, 2H), 8.62
(d, J ) 4.0, 1H), 10.19 (s, 1H). 13C NMR (CDCl3) δ 28.8, 45.4,
50.7, 53.4, 55.4, 57.4, 72.6, 102.7, 111.2, 112.1, 118.3, 120.5, 121.1,
122, 123.3, 123.9, 124.3, 127.7, 131, 135.3, 136.2, 136.6, 140.9,
149.8, 152.3, 162.2. Anal. (C24H30N4O3 ·HCl·H2O) C, H, N.
X-ray Crystal Structure of S-22. Single-crystal X-ray diffrac-
tion data on compound S-22 were collected at 123 K using Mo
KR radiation and a Bruker APEX II CCD area detector. A 0.53 ×
0.18 × 0.07 mm3 crystal was prepared for data collection coating
with high viscosity microscope oil (Paratone-N, Hampton Research).
The oil-coated crystal was mounted on a glass rod and transferred
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-
5-iodobenzofuran-2-carboxamide (33). 33 was prepared from
5-iodobenzofuran-2-carboxylic acid (8) and 4-amino-1-(4-(2,3-

2568 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 8
Newman et al.
immediately to the cold stream on the diffractometer. The crystal
was triclinic in space group P1 with unit cell dimensions a )
5.6352(3) Å, b ) 18.4468(9) Å, c ) 22.5318(11) Å, R )
71.273(1)°, ꢀ ) 86.514(1)°, and γ ) 88.997(1)°. Corrections were
applied for Lorentz, polarization, and absorption effects. Data were
98.4% complete to 25.0° θ (approximately 0.75 Å) with an average
redundancy of 2.0. The structure was solved by direct methods and
refined by full-matrix least-squares on F2 values using the programs
found in the SHELXTL suite59 (Bruker, SHELXTL, version 6.10,
2000, Bruker AXS Inc., Madison, WI). Parameters refined included
atomic coordinates and anisotropic thermal parameters for all non-
hydrogen atoms. Hydrogen atoms on carbons were included using
a riding model [coordinate shifts of C applied to H atoms] with
C-H distance set at 0.96 Å. The absolute configuration was
determined from anomalous scattering (Flack parameter )
0.01(5)).60 Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, U.K.
[fax, +44(0)-1223-336033; e-mail, deposit@ccdc.cam.ac.uk].
Radioligand Dopamine Receptor Binding Assays. A filtration
binding assay was used to characterize the binding properties of
membrane-associated receptors. For human D2L, D3, and D4
dopamine receptors expressed in HEK 293 cells, tissue homogenates
(50 mL) were suspended in 50 mM Tris-HCl/150 mM NaCl/10
mM EDTA buffer, pH 7.5, and incubated with 50 µL of 125I-IABN
at 37 °C for 60 min. Nonspecific binding was determined using 25
µM (+)-butaclamol. For competition experiments, the radioligand
concentration was generally equal to 0.5 times the Kd value, and
the concentration of the competitive inhibitor ranged over 5 orders
of magnitude. Binding was terminated by the addition of cold wash
buffer (10 mM Tris-HCl/150 mM NaCl, pH 7.5) and filtration over
glass-fiber filters (Schleicher and Schuell no. 32). Filters were
washed with 10 mL of cold buffer, and the radioactivity was
measured using a Packard Cobra γ counter. Estimates of the
equilibrium dissociation constant and maximum number of binding
sites were obtained using unweighted nonlinear regression analysis
of data modeled according to the equation describing mass action
binding. Data from competitive inhibition experiments were mod-
eled using nonlinear regression analysis to determine the concentra-
tion of inhibitor that displaced 50% of the specific binding of the
radioligand. Competition curves were modeled for a single site,
and the IC50 values were converted to equilibrium dissociation
constants (Ki values) using the Cheng-Prusoff correction. Mean
Ki values SEM are reported for at least three independent
experiments.
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IRP, NIH Grants DA13584-03S1 and DA13584-01 (R.R.L.) and
NIDA Addiction Treatment Discovery Program contract with
SRI (Grant N01DA-1-8816). Crystallographic studies were
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